Harvey I Pass, M.D.

Increasing dyspnea due to an anterior mediastinal mass
Alpert, Jeffrey B; Nonaka, Daisuke; Chachoua, Abraham; Pass, Harvey I; Ko, Jane P
2011 Jan;139(1):217-223, Chest
— id: 117359, year: 2011, vol: 139, page: 217, stat: Journal Article,

Telomerase activity in pleural malignant mesotheliomas
Au AY; Hackl T; Yeager TR; Cohen SB; Pass HI; Harris CC; Reddel RR
2011 Sep;73(3):283-288, Lung cancer
New treatments are needed for malignant pleural mesothelioma (MPM), which currently has a poor prognosis. Cellular immortalisation, one of the hallmarks of cancer, depends on the activity of a telomere length maintenance mechanism (TMM) - either telomerase or alternative lengthening of telomeres (ALT). The TMMs are widely regarded as potential targets for cancer therapies and telomerase inhibitors have entered clinical trials. The aim of this study was to determine what proportion of MPMs use ALT and/or telomerase. Forty-three MPMs from 42 patients were examined for telomerase and ALT activity. Telomerase activity was detected by immunoaffinity purification followed by the telomere repeat amplification protocol (TRAP), and ALT activity was determined by the C-circle assay and by assessing telomere lengths using terminal restriction fragment analyses. We found that 43 of 43 MPMs were telomerase-positive[+] and ALT-negative[-]. Therefore, to investigate whether pleural mesothelial cells are unusually susceptible to activation of telomerase, we examined activation of the TMMs in an in vitro model of cellular immortalisation, in which normal pleural mesothelial cells were transduced with simian virus 40 (SV40) oncogenes. We found that normal mesothelial cells were TMM-negative, and that expression of the SV40 oncogenes did not directly activate telomerase or ALT. Immortalisation, which in this experimental system results from additional genetic changes that have not yet been identified, was accompanied by activation of either TMM. Therefore, pleural mesothelial cells are capable of activating either TMM in vitro, and the observation that 100% of MPMs were telomerase[+] suggests that there are factors in vivo that select for telomerase activity during oncogenesis of this tumour type. We conclude that MPM is a tumour that could be considered for anti-telomerase therapy
— id: 135524, year: 2011, vol: 73, page: 283, stat: Journal Article,

BRCA1 is an essential mediator of vinorelbine induced apoptosis in mesothelioma
Busacca S; Sheaff M; Arthur K; Gray SG; O'Byrne KJ; Richard DJ; Soltermann A; Opitz I; Pass H; Harkin DP; Quinn JE; Fennell DA
2011 Dec 21;:?-?, Journal of pathology
Therapeutic options for malignant pleural mesothelioma (MPM) are limited despite the increasing incidence globally. The vinca alkaloid, vinorelbine exhibits clinical activity, however, to date, treatment optimization has not been achieved using biomarkers. BRCA1 regulates sensitivity to microtubule poisons, however its role in regulating vinorelbine induced apoptosis in mesothelioma is unknown. Here we demonstrate that BRCA1 plays an essential role in mediating vinorelbine induced apoptosis, as evidenced by: 1) the strong correlation between vinorelbine sensitivity and BRCA1 expression level, 2) induction of resistance to vinorelbine by BRCA1 using siRNA oligonucleotides, 3) dramatic downregulation of BRCA1 following selection for vinorelbine resistance, and 4) the re-activation of vinorelbine induced apoptosis following re-expression of BRCA1 in resistant cells. To determine whether loss of BRCA1 expression in mesothelioma was potentially relevant in vivo, BRCA1 immunohistochemistry was subsequently performed on 144 primary mesothelioma specimens. Loss of BRCA1 protein expression was identified in 38.9% of samples. Together, this data suggests BRCA1 plays a critical role in mediating apoptosis by vinorelbine in mesothelioma, warranting its clinical evaluation as a predictive biomarker.
— id: 149985, year: 2011, vol: , page: ?, stat: Journal Article,

Malignant mesothelioma: Facts, myths and hypotheses
Carbone M; Ly BH; Dodson RF; Pagano I; Morris PT; Dogan UA; Gazdar AF; Pass HI; Yang H
2011 Jan;227(1):44-58 L, Journal of cellular physiology
Malignant mesothelioma (MM) is a neoplasm arising from mesothelial cells lining the pleural, peritoneal, and pericardial cavities. Over 20 million people in the US are at risk of developing MM due to asbestos exposure. MM mortality rates are estimated to increase by 5-10% per year in most industrialized countries until about 2020. The incidence of MM in men has continued to rise during the past 50 years, while the incidence in women appears largely unchanged. It is estimated that about 50-80% of pleural MM in men and 20-30% in women developed in individuals whose history indicates asbestos exposure(s) above that expected from most background settings. While rare for women, about 30% of peritoneal mesothelioma in men has been associated with exposure to asbestos. Erionite is a potent carcinogenic mineral fiber capable of causing both pleural and peritoneal MM. Since erionite is considerably less widespread than asbestos, the number of MM cases associated with erionite exposure is smaller. Asbestos induces DNA alterations mostly by inducing mesothelial cells and reactive macrophages to secrete mutagenic oxygen and nitrogen species. In addition, asbestos carcinogenesis is linked to the chronic inflammatory process caused by the deposition of a sufficient number of asbestos fibers and the consequent release of pro-inflammatory molecules, especially HMGB-1, the master switch that starts the inflammatory process, and TNF-alpha by macrophages and mesothelial cells. Genetic predisposition, radiation exposure and viral infection are co-factors that can alone or together with asbestos and erionite cause MM. J. Cell. Physiol. (c) 2011 Wiley-Liss, Inc
— id: 135523, year: 2011, vol: 227, page: 44, stat: Journal Article,

Erionite exposure in North Dakota and Turkish villages with mesothelioma
Carbone, Michele; Baris, Y Izzettin; Bertino, Pietro; Brass, Brian; Comertpay, Sabahattin; Dogan, A Umran; Gaudino, Giovanni; Jube, Sandro; Kanodia, Shreya; Partridge, Charles R; Pass, Harvey I; Rivera, Zeyana S; Steele, Ian; Tuncer, Murat; Way, Steven; Yang, Haining; Miller, Aubrey
2011 Aug 16;108(33):13618-13623, Proceedings of the National Academy of Sciences of the United States of America
Exposure to erionite, an asbestos-like mineral, causes unprecedented rates of malignant mesothelioma (MM) mortality in some Turkish villages. Erionite deposits are present in at least 12 US states. We investigated whether increased urban development has led to erionite exposure in the United States and after preliminary exploration, focused our studies on Dunn County, North Dakota (ND). In Dunn County, ND, we discovered that over the past three decades, more than 300 miles of roads were surfaced with erionite-containing gravel. To determine potential health implications, we compared erionite from the Turkish villages to that from ND. Our study evaluated airborne point exposure concentrations, examined the physical and chemical properties of erionite, and examined the hallmarks of mesothelial cell transformation in vitro and in vivo. Airborne erionite concentrations measured in ND along roadsides, indoors, and inside vehicles, including school buses, equaled or exceeded concentrations in Boyali, where 6.25% of all deaths are caused by MM. With the exception of outdoor samples along roadsides, ND concentrations were lower than those measured in Turkish villages with MM mortality ranging from 20 to 50%. The physical and chemical properties of erionite from Turkey and ND are very similar and they showed identical biological activities. Considering the known 30- to 60-y latency for MM development, there is reason for concern for increased risk in ND in the future. Our findings indicate that implementation of novel preventive and early detection programs in ND and other erionite-rich areas of the United States, similar to efforts currently being undertaken in Turkey, is warranted
— id: 138001, year: 2011, vol: 108, page: 13618, stat: Journal Article,

Onconase mediated NFKbeta downregulation in malignant pleural mesothelioma
Goparaju, C M; Blasberg, J D; Volinia, S; Palatini, J; Ivanov, S; Donington, J S; Croce, C; Carbone, M; Yang, H; Pass, H I
2011 Jun 16;30(24):2767-2777, Oncogene
Treatment of malignant pleural mesothelioma (MPM) with Ranpirnase (Onconase) results in disruption of protein translation and cell apoptosis. We hypothesize that Onconase exerts an effect via downregulation of nuclear factor kappa B (NFKbeta) by specific microRNAs (miRNAs) and that interference of this pathway could have implications for MPM resistance to chemotherapy. Three immortalized MPM cell lines (H2959, H2373 and H2591) were exposed to Onconase at 0-20 mug/ml. Cell counts were measured at 48 and 72 h. Gene expression in miRNA-enriched RNA was validated by reverse transcription-PCR (RT-PCR). The functional implications of miRNA expression were evaluated by transfecting miRNA mimics or inhibitors into MPM cell lines, and performing Matrigel invasion, cell proliferation, soft agar colony formation and scratch closure assays. Effects on NFKbeta expression and downstream targets including ABC transporters, BCL-xl and IAP were assessed by RT-PCR and western blotting. Treatment with 20 mug/ml of Onconase significantly decreased cell count and invasion. Hsa-miR-17* was significantly upregulated and hsa-miR-30c was significantly downregulated by Onconase treatment in all cell lines. Forced expression of hsa-miR-17* mimic and hsa-miR-30c inhibitor each significantly decreased functional activity of Onconase in all assays. NFKB1 (p50) expression and downstream targets were also decreased with Onconase treatment, as well as with forced expression of miRNA mimic and inhibitors. Onconase treatment caused a significant decrease in cell proliferation, invasion and in expression of certain miRNAs. Recapitulation of the resultant miRNA expression pattern with hsa-miR-17* mimic and hsa-miR-30c inhibitor resulted in downregulation of NFKB1 and reduced malignant behavior in functional assays. Thus, Onconase likely exerts its antitumor effect through these miRNAs
— id: 134435, year: 2011, vol: 30, page: 2767, stat: Journal Article,

Expression of the receptor MST1R/RON and its ligand MSP in malignant pleural mesothelioma
Gray, S. G.; Easty, D.; Baird, A. M.; Opitz, I.; Nonaka, D.; Fennell, D. A.; Pass, H. I.; Mutti, L.; Solterm, A.; O'Byrne, K. J.
2011 JAN ;71(3):S18-S18, Lung cancer
— id: 129015, year: 2011, vol: 71, page: S18, stat: Journal Article,

Increased efficacy of doxorubicin delivered in multifunctional microparticles for mesothelioma therapy
Hillegass, Jedd M; Blumen, Steven R; Cheng, Kai; Macpherson, Maximilian B; Alexeeva, Vlada; Lathrop, Sherrill A; Beuschel, Stacie L; Steinbacher, Jeremy L; Butnor, Kelly J; Ramos-Nino, Maria E; Shukla, Arti; James, Ted A; Weiss, Daniel J; Taatjes, Douglas J; Pass, Harvey I; Carbone, Michele; Landry, Christopher C; Mossman, Brooke T
2011 Jul 1;129(1):233-244, International journal of cancer
New and effective treatment strategies are desperately needed for malignant mesothelioma (MM), an aggressive cancer with a poor prognosis. We have shown previously that acid-prepared mesoporous microspheres (APMS) are nontoxic after intrapleural or intraperitoneal (IP) administration to rodents. The purpose here was to evaluate the utility of APMS in delivering chemotherapeutic drugs to human MM cells in vitro and in two mouse xenograft models of MM. Uptake and release of doxorubicin (DOX) alone or loaded in APMS (APMS-DOX) were evaluated in MM cells. MM cell death and gene expression linked to DNA damage/repair were also measured in vitro. In two severe combined immunodeficient mouse xenograft models, mice received saline, APMS, DOX or APMS-DOX injected directly into subcutaneous (SC) MM tumors or injected IP after development of human MMs peritoneally. Other mice received DOX intravenously (IV) via tail vein injections. In comparison to DOX alone, APMS-DOX enhanced intracellular uptake of DOX, MM death and expression of GADD34 and TP73. In the SC MM model, 3x weekly SC injections of APMS-DOX or DOX alone significantly inhibited tumor volumes, and systemic DOX administration was lethal. In mice developing IP MMs, significant (p < 0.05) inhibition of mesenteric tumor numbers, weight and volume was achieved using IP administration of APMS-DOX at one-third the DOX concentration required after IP injections of DOX alone. These results suggest APMS are efficacious for the localized delivery of lower effective DOX concentrations in MM and represent a novel means of treating intracavitary tumors
— id: 134262, year: 2011, vol: 129, page: 233, stat: Journal Article,

Epigenetic silencing of microRNA-34b/c plays an important role in the pathogenesis of malignant pleural mesothelioma
Kubo T; Toyooka S; Tsukuda K; Sakaguchi M; Fukazawa T; Soh J; Asano H; Ueno T; Muraoka T; Yamamoto H; Nasu Y; Kishimoto T; Pass HI; Matsui H; Huh NH; Miyoshi S
2011 Aug 1;17(15):4965-4974, Clinical cancer research
PURPOSE: Malignant pleural mesothelioma (MPM) is an aggressive tumor with a dismal prognosis. Unlike other malignancies, TP53 mutations are rare in MPM. Recent studies have showed that altered expression of microRNA (miRNA) is observed in human malignant tumors. In this study, we investigated the alterations of miR-34s, a direct transcriptional target of TP53, and the role of miR-34s on the pathogenesis of MPM. EXPERIMENTAL DESIGN: Aberrant methylation and expression of miR-34s were examined in MPM cell lines and tumors. miR-34b/c was transfected to MPM cells to estimate the protein expression, cell proliferation, invasion, and cell cycle. RESULTS: Aberrant methylation was present in 2 (33.3%) of 6 MPM cell lines and 13 (27.7%) of 47 tumors in miR-34a and in all 6 MPM cell lines (100%) and 40 (85.1%) of 47 tumors in miR-34b/c. Expression of miR-34a and 34b/c in all methylated cell lines was reduced and restored with 5-aza-2'-deoxycytidine treatment. Because epigenetic silencing was the major event in miR-34b/c, we investigated the functional role of miR-34b/c in MPM. miR-34b/c-transfected MPM cells with physiological miR-34b/c expression exhibited anti-proliferation with G1 cell cycle arrest and suppression of migration, invasion, and motility . The forced overexpression of miR-34b/c, but not p53, showed a significant anti-tumor effect with the induction of apoptosis in MPM cells. CONCLUSIONS: We demonstrate that the epigenetic silencing of miR-34b/c by methylation is a crucial alteration and plays an important role in the tumorigenesis of MPM, suggesting potential therapeutic options for MPM
— id: 135520, year: 2011, vol: 17, page: 4965, stat: Journal Article,

Ranpirnase Interferes with NF-kappaB Pathway and MMP9 Activity, Inhibiting Malignant Mesothelioma Cell Invasiveness and Xenograft Growth
Nasu, Masaki; Carbone, Michele; Gaudino, Giovanni; Ly, Bevan H; Bertino, Pietro; Shimizu, David; Morris, Paul; Pass, Harvey I; Yang, Haining
2011 May;2(5):576-584, Genes & cancer
The ribonuclease ranpirnase (Onconase) has been used empirically to treat malignant mesothelioma (MM) patients, and some of them had prolonged survivals. The aim of this study was to investigate the mechanisms of the therapeutic function of ranpirnase in MM cells. The effects of ranpirnase were studied in vivo and in vitro on 2 MM cell lines (epithelioid REN and sarcomatoid PPM-Mill). We found that ranpirnase was able to inhibit NF-kappaB nuclear translocation, evaluated by cell fractionation and immunoblotting as well as by immunofluorescence. Also, MMP9 secretion by MM cells was decreased by ranpirnase treatment, as assessed by the reduction of metalloproteinase activity, evaluated by zymography on culture-conditioned media. Ranpirnase induced apoptosis of MM cells in vitro and in vivo, causing a powerful inhibition of MM tumor growth in SCID xenografts, determined by In Vivo Imaging System (IVIS) of tumor cells engineered by lentiviral transduction of the luciferase gene. Finally, mice treated with ranpirnase showed a significantly prolonged survival. Our data provide a mechanistic rationale to explain the beneficial antitumor activity observed in some patients treated with ranpirnase and demonstrate that ranpirnase interferes with the NF-kappaB pathway, thus influencing MM tumor cell invasiveness and survival. It is hoped that this information will also facilitate the identification of those patients who are more likely to benefit from this drug and will also open a new frontier for the use of this drug in tumor types other than MM
— id: 138816, year: 2011, vol: 2, page: 576, stat: Journal Article,

Surgery and mesothelioma: If not randomization, at least standardization and registration!
Pass, Harvey
2011 Jan;71(1):1-2, Lung cancer
— id: 116208, year: 2011, vol: 71, page: 1, stat: Journal Article,

Recommendations for uniform definitions of surgical techniques for malignant pleural mesothelioma: a consensus report of the international association for the study of lung cancer international staging committee and the international mesothelioma interest group
Rice, David; Rusch, Valerie; Pass, Harvey; Asamura, Hisao; Nakano, Takashi; Edwards, John; Giroux, Dorothy J; Hasegawa, Seiki; Kernstine, Kemp H; Waller, David; Rami-Porta, Ramon
2011 Aug;6(8):1304-1312, Journal of thoracic oncology
INTRODUCTION: Extrapleural pneumonectomy has been well defined; however, surgeons vary regarding the surgical extent and goals of 'pleurectomy/decortication' (P/D). We explored mesothelioma surgeons' concepts of P/D with the aim of unifying surgical nomenclature. METHODS: A web-based survey was administered to surgeons who operated on malignant pleural mesothelioma (MPM) for diagnosis, staging, palliation, or cytoreduction. One hundred thirty surgeons from 59 medical centers were included. Surgeons who did not perform surgery for MPM within the last year were excluded. RESULTS: There were 62 (48%) respondents from 39 medical centers in 14 countries. The mean number of patients with MPM seen annually at each medical center was 46, and the mean annual number of cytoreductive procedures performed per surgeon was 8. Most (88%) agreed that the goal of cytoreductive surgery should be macroscopic complete resection of tumor. P/D was defined as resection of parietal and visceral pleura with the aim of achieving macroscopic complete resection by 72% of respondents. If the diaphragm or pericardium required resection, 64% preferred the term 'radical P/D,' whereas 'P/D' (40%) or 'total pleurectomy' (39%) was preferred if these structures were not removed. Most surgeons believed that extrapleural pneumonectomy (90%) or 'radical P/D' (68%) could provide adequate cytoreduction, whereas only 23% thought that P/D could. CONCLUSIONS: There was significant variation regarding surgical nomenclature for procedures for MPM. The International Staging Committee of the International Association for the Study of Lung Cancer and the International Mesothelioma Interest Group recommend that P/D should aim to remove all macroscopic tumor involving the parietal and visceral pleura and should be termed 'extended' P/D when the diaphragm or pericardium is resected
— id: 149989, year: 2011, vol: 6, page: 1304, stat: Journal Article,

Biomarker Discovery and Verification of a Lung Cancer Signature with SOMAmer Proteomic Technology
Rom, William N; Ostroff, Rachel M; Pass, Harvey I; Bigbee, William L; Franklin, Wilbur; Gold, Larry; Mehan, Mike; Miller, York; Siegfried, Jill M; Stewart, Alex; Walker, Jeffrey J; Weissfeld, Joel L; Williams, Stephen; Zichi, Dom; Brody, Edward
2011 May;8(2):209-210, Proceedings of the American Thoracic Society
— id: 131977, year: 2011, vol: 8, page: 209, stat: Journal Article,

RRM-1 IS PREDICTIVE OF CLINICAL BENEFIT FROM FIRST LINE PLATINUM DOUBLET THERAPY IN NON-SMALL CELL LUNG CANCER
Seetharamu, Nagashree; Pass, Harvey I.; Levinson, Benjamin; Ballas, Marc; Musovic, Sabina; Metz, Michael; Mathew, Lynn; Sorensen, Audrey; Chachoua, Abraham
2011 JUN ;6(6):S995-S996, Journal of thoracic oncology
— id: 134899, year: 2011, vol: 6, page: S995, stat: Journal Article,

An ERK2 Survival Pathway Mediates Resistance of Human Mesothelioma Cells to Asbestos-Induced Injury
Shukla A; Barrett TF; Macpherson MB; Hillegass JM; Fukagawa NK; Swain WA; O'Byrne KJ; Testa JR; Pass HI; Faux SP; Mossman BT
2011 Nov;45(5):906-914, American journal of respiratory cell & molecular biology
We hypothesized that normal human mesothelial cells acquire resistance to asbestos-induced toxicity via induction of one or more EGFR-linked survival pathways (PI3K/AKT/mTOR and ERK1/2) during SV40 transformation and carcinogenesis. Both isolated HKNM-2 mesothelial cells and a telomerase-immortalized mesothelial line (LP9/TERT-1) were more sensitive to crocidolite asbestos toxicity than an SV40 Tag-immortalized mesothelial line (MET5A) and mesothelioma (MM) cell lines (HMESO and PPM Mill). Whereas increases in phosphorylation of AKT (pAKT) were observed in MET5A cells in response to asbestos, LP9/TERT-1 cells exhibited dose-related decreases in pAKT levels. Pretreatment with an EGFR phosphorylation or MEK1/2 inhibitor abrogated asbestos-induced pERK1/2 levels in both LP9/TERT-1 and MET5A cells as well as increases in pAKT levels in MET5A cells. Transient transfection of siRNAs targeting ERK1, ERK2 or AKT revealed that ERK1/2 pathways were involved in cell death by asbestos in both cell lines. Asbestos-resistant HMESO or PPM Mill cells with high endogenous levels of ERKs or AKT did not show dose-responsive increases in pERK1/ERK1, pERK2/ERK2 or pAKT/AKT levels by asbestos. However, shERK2 stable cell lines created from both MM lines were more sensitive to asbestos toxicity than shERK1 and shControl lines, and exhibited unique, tumor-specific changes in endogenous cell-death-related gene expression. Our results suggest that EGFR phosphorylation is causally linked to pERK and pAKT activation by asbestos in normal and SV40 Tag-immortalized human mesothelial cells. They also indicate that ERK2 plays a role in modulating asbestos toxicity by regulating genes critical to cell injury and survival that are differentially expressed in human mesotheliomas
— id: 135522, year: 2011, vol: 45, page: 906, stat: Journal Article,

ERK2 is essential for the growth of human epithelioid malignant mesotheliomas
Shukla, Arti; Hillegass, Jedd M; Macpherson, Maximilian B; Beuschel, Stacie L; Vacek, Pamela M; Butnor, Kelly J; Pass, Harvey I; Carbone, Michele; Testa, Joseph R; Heintz, Nicholas H; Mossman, Brooke T
2011 Sep 1;129(5):1075-1086, International journal of cancer
Members of the extracellular signal-regulated kinase (ERK) family may have distinct roles in the development of cell injury and repair, differentiation and carcinogenesis. Here, we show, using a synthetic small-molecule MEK1/2 inhibitor (U0126) and RNA silencing of ERK1 and 2, comparatively, that ERK2 is critical to transformation and homeostasis of human epithelioid malignant mesotheliomas (MMs), asbestos-induced tumors with a poor prognosis. Although MM cell (HMESO) lines stably transfected with shERK1 or shERK2 both exhibited significant decreases in cell proliferation in vitro, injection of shERK2 cells, and not shERK1 cells, into immunocompromised severe combined immunodeficiency (SCID) mice showed significant attenuated tumor growth in comparison to shControl (shCon) cells. Inhibition of migration, invasion and colony formation occurred in shERK2 MM cells in vitro, suggesting multiple roles of ERK2 in neoplasia. Microarray and quantitative real-time PCR analyses revealed gene expression that was significantly increased (CASP1, TRAF1 and FAS) or decreased (SEMA3E, RPS6KA2, EGF and BCL2L1) in shERK2-transfected MM cells in contrast to shCon-transfected MM cells. Most striking decreases were observed in mRNA levels of Semaphorin 3 (SEMA3E), a candidate tumor suppressor gene linked to inhibition of angiogenesis. These studies demonstrate a key role of ERK2 in novel gene expression critical to the development of epithelioid MMs. After injection of sarcomatoid human MM (PPMMill) cells into SCID mice, both shERK1 and shERK2 lines showed significant decreased tumor growth, suggesting heterogeneous effects of ERKs in individual MMs
— id: 135518, year: 2011, vol: 129, page: 1075, stat: Journal Article,

Simulating video-assisted thoracoscopic lobectomy: A virtual reality cognitive task simulation
Solomon, Brian; Bizekis, Costas; Dellis, Sophia L; Donington, Jessica S; Oliker, Aaron; Balsam, Leora B; Zervos, Michael; Galloway, Aubrey C; Pass, Harvey; Grossi, Eugene A
2011 Jan;141(1):249-255, Journal of thoracic & cardiovascular surgery
OBJECTIVE: Current video-assisted thoracoscopic surgery training models rely on animals or mannequins to teach procedural skills. These approaches lack inherent teaching/testing capability and are limited by cost, anatomic variations, and single use. In response, we hypothesized that video-assisted thoracoscopic surgery right upper lobe resection could be simulated in a virtual reality environment with commercial software. METHODS: An anatomy explorer (Maya [Autodesk Inc, San Rafael, Calif] models of the chest and hilar structures) and simulation engine were adapted. Design goals included freedom of port placement, incorporation of well-known anatomic variants, teaching and testing modes, haptic feedback for the dissection, ability to perform the anatomic divisions, and a portable platform. RESULTS: Preexisting commercial models did not provide sufficient surgical detail, and extensive modeling modifications were required. Video-assisted thoracoscopic surgery right upper lobe resection simulation is initiated with a random vein and artery variation. The trainee proceeds in a teaching or testing mode. A knowledge database currently includes 13 anatomic identifications and 20 high-yield lung cancer learning points. The 'patient' is presented in the left lateral decubitus position. After initial camera port placement, the endoscopic view is displayed and the thoracoscope is manipulated via the haptic device. The thoracoscope port can be relocated; additional ports are placed using an external 'operating room' view. Unrestricted endoscopic exploration of the thorax is allowed. An endo-dissector tool allows for hilar dissection, and a virtual stapling device divides structures. The trainee's performance is reported. CONCLUSIONS: A virtual reality cognitive task simulation can overcome the deficiencies of existing training models. Performance scoring is being validated as we assess this simulator for cognitive and technical surgical education
— id: 116215, year: 2011, vol: 141, page: 249, stat: Journal Article,

Aberrant methylation of p21 gene in lung cancer and malignant pleural mesothelioma
Teramen, Hirotake; Tsukuda, Kazunori; Tanaka, Norimitsu; Ueno, Tsuyoshi; Kubo, Takafumi; Ando, Midori; Soh, Junichi; Asano, Hiroaki; Pass, Harvery I; Toyooka, Shinichi; Miyoshi, Shinichiro
2011 Jun;65(3):179-184, Acta medica Okayama
Suppression of p21 has been implicated in the genesis and progression of many human malignancies. DNA methylation is an important mechanism of gene silencing in human malignancies. In this study, we examined the expression status and aberrant methylaion of p21 in lung cancers and malignant pleural mesotheliomas (MPM). We used 12 small cell lung cancer (SCLC) cell lines, 13 non-small cell lung cancer (NSCLC) cell lines, 50 primary NSCLCs, 6 MPM cell lines and 10 primary MPMs. The expression and methylation of p21 was examined by reverse transcription-PCR (RT-PCR), Western blotting and methylation-specific PCR (MSP) assay. Loss of p21 protein expression was observed in 7 SCLC cell lines (58.3%), 5 NSCLC cell lines (38.5%) and 3 MPM cell lines (50%) while mRNA expression was lost in 2 SCLC cell lines (16.7%), 2 NSCLC cell lines (15.4%) and none of the MPM cell lines. Aberrant methylation of p21 was found in 8.3% of SCLC cell lines, 30.2% of NSCLCs and 6.3% of MPMs. Among primary NSCLCs, methylation in adenocarcinomas was significantly more frequent than in squamous cell carcinomas. Loss of p21 expression was frequently observed in lung cancers and MPMs and aberrant methylation was one of the mechanisms of suppression of p21, especially in NSCLCs
— id: 137994, year: 2011, vol: 65, page: 179, stat: Journal Article,

Germline BAP1 mutations predispose to malignant mesothelioma
Testa, Joseph R; Cheung, Mitchell; Pei, Jianming; Below, Jennifer E; Tan, Yinfei; Sementino, Eleonora; Cox, Nancy J; Dogan, A Umran; Pass, Harvey I; Trusa, Sandra; Hesdorffer, Mary; Nasu, Masaki; Powers, Amy; Rivera, Zeyana; Comertpay, Sabahattin; Tanji, Mika; Gaudino, Giovanni; Yang, Haining; Carbone, Michele
2011 Oct;43(10):1022-1025, Nature genetics
Because only a small fraction of asbestos-exposed individuals develop malignant mesothelioma, and because mesothelioma clustering is observed in some families, we searched for genetic predisposing factors. We discovered germline mutations in the gene encoding BRCA1 associated protein-1 (BAP1) in two families with a high incidence of mesothelioma, and we observed somatic alterations affecting BAP1 in familial mesotheliomas, indicating biallelic inactivation. In addition to mesothelioma, some BAP1 mutation carriers developed uveal melanoma. We also found germline BAP1 mutations in 2 of 26 sporadic mesotheliomas; both individuals with mutant BAP1 were previously diagnosed with uveal melanoma. We also observed somatic truncating BAP1 mutations and aberrant BAP1 expression in sporadic mesotheliomas without germline mutations. These results identify a BAP1-related cancer syndrome that is characterized by mesothelioma and uveal melanoma. We hypothesize that other cancers may also be involved and that mesothelioma predominates upon asbestos exposure. These findings will help to identify individuals at high risk of mesothelioma who could be targeted for early intervention
— id: 149988, year: 2011, vol: 43, page: 1022, stat: Journal Article,

Processing and analysis of serum antibody binding signals from Printed Glycan Arrays for diagnostic and prognostic applications
Vuskovic, Marko I; Xu, Hongyu; Bovin, Nicolai V; Pass, Harvey I; Huflejt, Margaret E
2011 ;7(4):402-426, International journal of bioinformatics research & applications
Procedures for data preprocessing, quality control, data analysis, evaluation and visualization of the new high-throughput biomarker platform based on printed glycan arrays (PGA) are presented in this paper. PGAs are similar in concept to DNA arrays but contain deposits of various carbohydrate structures (glycans) instead of spotted DNAs. PGA biomarker discovery for the early detection, diagnosis and prognosis of human malignancies and viral diseases is based on the response of the immune system as measured by the level of binding of anti-glycan antibodies from human serum to the glycans on the array. Procedures related to PGA data processing are herein demonstrated in a pilot study of cases representing 50 sera from patients with malignant mesothelioma and a control sample of 65 sera from high risk subjects exposed to asbestos without symptoms of disease
— id: 149986, year: 2011, vol: 7, page: 402, stat: Journal Article,

Curcumin suppresses growth of mesothelioma cells in vitro and in vivo, in part, by stimulating apoptosis
Wang Y; Rishi AK; Wu W; Polin L; Sharma S; Levi E; Albelda S; Pass HI; Wali A
2011 Nov;357(1-2):83-94, Molecular & cellular biochemistry
Malignant pleural mesothelioma (MPM) is an aggressive, asbestos-related malignancy of the thoracic pleura. Although, platinum-based agents are the first line of therapy, there is an urgent need for second-line therapies to treat the drug-resistant MPM. Cell cycle as well as apoptosis pathways are frequently altered in MPM and thus remain attractive targets for intervention strategies. Curcumin, the major component in the spice turmeric, alone or in combination with other chemotherapeutics has been under investigation for a number of cancers. In this study, we investigated the biological and molecular responses of MPM cells to curcumin treatments and the mechanisms involved. Flow-cytometric analyses coupled with western immunoblotting and gene-array analyses were conducted to determine mechanisms of curcumin-dependent growth suppression of human (H2373, H2452, H2461, and H226) and murine (AB12) MPM cells. Curcumin inhibited MPM cell growth in a dose- and time-dependent manner while pretreatment of MPM cells with curcumin enhanced cisplatin efficacy. Curcumin activated the stress-activated p38 kinase, caspases 9 and 3, caused elevated levels of proapoptotic proteins Bax, stimulated PARP cleavage, and apoptosis. In addition, curcumin treatments stimulated expression of novel transducers of cell growth suppression such as CARP-1, XAF1, and SULF1 proteins. Oral administration of curcumin inhibited growth of murine MPM cell-derived tumors in vivo in part by stimulating apoptosis. Thus, curcumin targets cell cycle and promotes apoptosis to suppress MPM growth in vitro and in vivo. Our studies provide a proof-of-principle rationale for further in-depth analysis of MPM growth suppression mechanisms and their future exploitation in effective management of resistant MPM
— id: 135521, year: 2011, vol: 357, page: 83, stat: Journal Article,

Detection of integrin-linked kinase in the serum of patients with malignant pleural mesothelioma
Watzka, Stefan B; Posch, Florian; Pass, Harvey I; Huflejt, Margaret; Bernhard, David; Hannigan, Gregory E; Muller, Michael R
2011 Aug;142(2):384-389, Journal of thoracic & cardiovascular surgery
OBJECTIVE: Integrin-linked kinase, which is relevant to neoplastic transformation, is highly expressed in malignant pleural mesothelioma. Recently, detection of integrin-linked kinase in serum of patients with ovarian cancer has been reported. This study asks whether integrin-linked kinase can also be detected in serum of patients with malignant pleural mesothelioma and whether serum level has diagnostic or prognostic relevance for that disease. METHODS: A sandwich enzyme-linked immunosorbent assay was designed to detect integrin-linked kinase and applied to serum samples from 46 patients with malignant pleural mesothelioma, 98 patients with other malignant chest disease, and 23 patients with benign chest disease. Integrin-linked kinase serum concentration and clinical data were correlated statistically. RESULTS: Median serum integrin-linked kinase concentration was significantly higher in malignant pleural mesothelioma (8.89 ng/mL) than in other malignant chest disease (0.66 ng/mL) or benign chest disease (0.78 ng/mL, P < .001). There was no relevant correlation of serum integrin-linked kinase with cell lysis parameters (R(2) < 0.1). Serum integrin-linked kinase concentration greater than 2.48 ng/mL had diagnostic sensitivity of 80%, specificity of 95%, positive predictive value of 85.7%, negative predictive value of 92.7%, and overall accuracy of 91% for distinction between malignant pleural mesothelioma and other diseases. Serum integrin-linked kinase concentration in malignant pleural mesothelioma was independent of histologic subtype or asbestos exposure. There was no statistically significant impact of serum integrin-linked kinase concentration on prognosis. CONCLUSIONS: Integrin-linked kinase can be detected in serum of patients with malignant pleural mesothelioma and may be a diagnostic marker for the disease
— id: 135519, year: 2011, vol: 142, page: 384, stat: Journal Article,

The MARS feasibility trial: conclusions not supported by data
Weder, Walter; Stahel, Rolf A; Baas, Paul; Dafni, Urania; de Perrot, Marc; McCaughan, Brian C; Nakano, Takashi; Pass, Harvey I; Robinson, Bruce W S; Rusch, Valerie W; Sugarbaker, David J; van Zandwijk, Nico
2011 Nov;12(12):1093-1094, Lancet oncology
— id: 149987, year: 2011, vol: 12, page: 1093, stat: Journal Article,

New insight into the molecular mechanisms of the biological effects of DNA minor groove binders
Zhang, Xinbo; Zhang, Siyu Crystal; Sun, Dejun; Hu, Jiang; Wali, Anil; Pass, Harvey; Fernandez-Madrid, Felix; Harbut, Michael R; Tang, Naimei
2011 ;6(10):e25822-e25822, PLoS ONE
BACKGROUND: Bisbenzimides, or Hoechst 33258 (H258), and its derivative Hoechst 33342 (H342) are archetypal molecules for designing minor groove binders, and widely used as tools for staining DNA and analyzing side population cells. They are supravital DNA minor groove binders with AT selectivity. H342 and H258 share similar biological effects based on the similarity of their chemical structures, but also have their unique biological effects. For example, H342, but not H258, is a potent apoptotic inducer and both H342 and H258 can induce transgene overexpression in in vitro studies. However, the molecular mechanisms by which Hoechst dyes induce apoptosis and enhance transgene overexpression are unclear. METHODOLOGY/PRINCIPAL FINDINGS: To determine the molecular mechanisms underlying different biological effects between H342 and H258, microarray technique coupled with bioinformatics analyses and multiple other techniques has been utilized to detect differential global gene expression profiles, Hoechst dye-specific gene expression signatures, and changes in cell morphology and levels of apoptosis-associated proteins in malignant mesothelioma cells. H342-induced apoptosis occurs in a dose-dependent fashion and is associated with morphological changes, caspase-3 activation, cytochrome c mitochondrial translocation, and cleavage of apoptosis-associated proteins. The antagonistic effect of H258 on H342-induced apoptosis indicates a pharmacokinetic basis for the two dyes' different biological effects. Differential global gene expression profiles induced by H258 and H342 are accompanied by unique gene expression signatures determined by DNA microarray and bioinformatics software, indicating a genetic basis for their different biological effects. CONCLUSIONS/SIGNIFICANCE: A unique gene expression signature associated with H342-induced apoptosis provides a new avenue to predict and classify the therapeutic class of minor groove binders in the drug development process. Further analysis of H258-upregulated genes of transcription regulation may identify the genes that enhance transgene overexpression in gene therapy and promote recombinant protein products in biopharmaceutical companies. DATA DEPOSITION: The microarray data reported in this article have been deposited in the Gene Expression Omnibus (GEO) database, www.ncbi.nlm.nih.gov/geo (accession no.GSE28616)
— id: 139773, year: 2011, vol: 6, page: e25822, stat: Journal Article,

Phase II proof-of-concept study of pazopanib monotherapy in treatment-naive patients with stage I/II resectable non-small-cell lung cancer
Altorki, Nasser; Lane, Maureen E; Bauer, Thomas; Lee, Paul C; Guarino, Michael J; Pass, Harvey; Felip, Enriqueta; Peylan-Ramu, Nili; Gurpide, Alfonso; Grannis, Frederic W; Mitchell, John D; Tachdjian, Sabrina; Swann, R Suzanne; Huff, Anne; Roychowdhury, Debasish F; Reeves, Anthony; Ottesen, Lone H; Yankelevitz, David F
2010 Jul 1;28(19):3131-3137, Journal of clinical oncology
PURPOSE: Patients with early-stage, resectable, non-small-cell lung cancer (NSCLC) are at risk for recurrent disease, and 5-year survival rates do not exceed 75%. Angiogenesis inhibitors have shown clinical activity in patients with late-stage NSCLC, raising the possibility that targeting the vascular endothelial growth factor pathway in earlier-stage disease may be beneficial. This proof-of-concept study examined safety and efficacy of short-term, preoperative pazopanib monotherapy in patients with operable stage I/II NSCLC. PATIENTS AND METHODS: Patients scheduled for resection received oral pazopanib 800 mg/d for 2 to 6 weeks preoperatively. Tumor response was measured by high-resolution computed tomography, permitting estimation of change in tumor volume and diameter. Gene-expression profiling was performed on 77 pre- and post-treatment lung samples from 34 patients. RESULTS: Of 35 patients enrolled, 33 (94%) had clinical stage I NSCLC and two (6%) had clinical stage II NSCLC. Median treatment duration was 16 days (range, 3 to 29 days). Thirty patients (86%) achieved tumor-volume reduction after pazopanib treatment. Two patients achieved tumor-volume reduction > or = 50%, and three patients had partial response according to Response Evaluation Criteria in Solid Tumors. Pazopanib was generally well tolerated. The most common adverse events included grade 2 hypertension, diarrhea, and fatigue. One patient developed pulmonary embolism 11 days after surgery. Several pazopanib target genes and other angiogenic factors were dysregulated post-treatment. CONCLUSION: Short-duration pazopanib was generally well tolerated and demonstrated single-agent activity in patients with early-stage NSCLC. Several target genes were dysregulated after pazopanib treatment, validating target-specific response and indicating a persistent pazopanib effect on lung cancer tissue. Further clinical evaluation of pazopanib in NSCLC is planned
— id: 110886, year: 2010, vol: 28, page: 3131, stat: Journal Article,

Initial experience with endobronchial ultrasound in an academic thoracic surgery program
Bizekis, Costas S; Santo, Thomas J; Parker, Kathryn L; Zervos, Michael D; Donington, Jessica S; Crawford, Bernard K; Pass, Harvey I
2010 Jan;11(1):25-29, Clinical lung cancer
BACKGROUND: Mediastinoscopy is considered the gold standard for evaluating mediastinal lymph nodes. However, endobronchial ultrasound-guided transbronchial needle aspiration has lately offered a less invasive alternative, with the ability to obtain nodal samples under direct visualization. Recent literature found an early learning curve for this technique. We present the initial experience of 4 thoracic surgeons with the procedure. MATERIALS AND METHODS: A retrospective chart review was performed on the first 51 patients on whom an endobronchial ultrasound-guided transbronchial needle aspiration was performed from January 5, 2007, to July 24, 2008. This group included 43 patients with a history or known diagnosis of malignancy as well as 8 patients with a presumed sarcoidosis diagnosis. All negative results were confirmed with mediastinoscopy. The technique's sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were assessed. RESULTS: A total of 73 lymph nodes underwent biopsy in 51 patients. These individuals included 34 men and 17 women, with an average age of 62 years (range, 21-89 years). No surgical or postoperative complications were noted. Overall, a correct diagnosis was established in 88% of the patients (45 of 51). After the first 25 cases (a mean of 6 cases per surgeon), a technique modification was adapted to increase diagnostic yield. The first 25 cases had a 72.22% sensitivity and 80% accuracy, whereas the last 26 cases had a 95.45% sensitivity and 96.15% accuracy (P = .07). CONCLUSION: Endobronchial ultrasound-guided transbronchial needle aspiration is a quickly mastered technique that offers a safe, minimally invasive, and accurate means to evaluate mediastinal lymph nodes
— id: 106286, year: 2010, vol: 11, page: 25, stat: Journal Article,

Lung cancer osteopontin isoforms exhibit angiogenic functional heterogeneity
Blasberg, Justin D; Goparaju, Chandra M; Pass, Harvey I; Donington, Jessica S
2010 Jun;139(6):1587-1593, Journal of thoracic & cardiovascular surgery
OBJECTIVE: Osteopontin is a multifunctional phosphoprotein with an important but poorly understood role in non-small cell lung cancer pathogenesis. We hypothesize that osteopontin isoforms (OPNa, OPNb, and OPNc) have divergent roles in non-small-cell lung cancer angiogenesis and divergent impact on vascular endothelial growth factor secretion. METHODS: We examined mRNA expression using reverse transcriptase-polymerase chain reaction primers for 3 osteopontin isoforms in non-small-cell lung cancer and immortalized bronchial epithelial cell lines, and correlated expression with osteopontin secretion into media detected by enzyme-linked immunosorbent assay. Angiogenic properties conferred by osteopontin isoforms were evaluated by transfecting cDNA plasmids specific to each isoform and controls into non-small-cell lung cancer cell lines, H153 and H358 (low endogenous osteopontin) and A549 and H460 (high endogenous osteopontin), analyzing conditioned media on a bovine capillary endothelial platform, and measuring vascular endothelial growth factor levels by enzyme-linked immunosorbent assay. RESULTS: OPNa mRNA expression correlated with osteopontin secretion in cell lines (r = 0.912, P = .0006). OPNa overexpression significantly increased tubule length compared with controls, OPNb had a similar, but less pronounced effect, and OPNc significantly decreased tubule length compared with controls in each cell line. OPNa overexpression was associated with significant increases in vascular endothelial growth factor secretion, whereas OPNb had no effect and OPNc overexpression was associated with significant decreases in vascular endothelial growth factor compared with controls in each cell line. CONCLUSION: We demonstrated divergent effects of osteopontin isoforms on non-small-cell lung cancer angiogenesis and vascular endothelial growth factor secretion. OPNa overexpression was associated with increased bovine capillary endothelial tubule length and vascular endothelial growth factor secretion, whereas OPNc was associated with decreases in both. These findings may lead to therapeutic strategies for selective isoform inhibition in non-small cell lung cancer
— id: 109787, year: 2010, vol: 139, page: 1587, stat: Journal Article,

Sublobar resection: a movement from the Lung Cancer Study Group
Blasberg, Justin D; Pass, Harvey I; Donington, Jessica S
2010 Oct;5(10):1583-1593, Journal of thoracic oncology
The 1995 Lung Cancer Study Group consensus recommending lobectomy for stage I non-small cell lung cancer (NSCLC) has directed lung cancer resections since its publication. However, enhancements in imaging technology over the last decade have produced larger cohorts of patients presenting with localized, early-stage disease. Today, multislice computer tomography is widely available, capable of detecting NSCLC at smaller sizes, with improved spatial resolution, and is used in screening programs for high-risk individuals. Furthermore, the maturation of minimally invasive surgical resection (video-assisted thoracoscopic surgery) has reduced perioperative morbidity and mortality, improved postoperative lung function, and demonstrated equivalent oncologic effectiveness to open surgery. The mandatory use of lobectomy for patients with small stage IA NSCLC is now being challenged. Numerous single-institution trials have demonstrated that well-selected use of sublobar resection can afford comparable survival and recurrence rates to lobectomy, particularly in high-risk patients. Currently, a prospective, randomized multi-institutional phase III trial is being conducted by the Cancer and Lymphoma Group B (CALGB 140503) to determine whether patients with small (< or =2 cm) peripheral NSCLC tumors can safely undergo sublobar resection while maintaining rates of survival and recurrence that are comparable to lobectomy. This review summarizes the literature from the past 15 years to assist in applying those conclusions to future research innovation
— id: 135526, year: 2010, vol: 5, page: 1583, stat: Journal Article,

Reduction of elevated plasma osteopontin levels with resection of non-small-cell lung cancer
Blasberg, Justin D; Pass, Harvey I; Goparaju, Chandra M; Flores, Raja M; Lee, Suzie; Donington, Jessica S
2010 Feb 20;28(6):936-941, Journal of clinical oncology
PURPOSE Plasma osteopontin (OPN) levels in advanced non-small-cell lung cancer (NSCLC) correlate with therapeutic response and survival, but the utility of plasma OPN for diagnosis and monitoring of early-stage NSCLC has not been investigated. We hypothesize that plasma OPN levels are elevated in early-stage NSCLC and decrease with resection. PATIENTS AND METHODS Presurgery plasma OPN levels (in ng/mL) were measured by enzyme-linked immunosorbent assay (ELISA) in a discovery set of 60 patients with early-stage NSCLC and were compared with data from 56 cancer-free smokers. Presurgery OPN was validated in an independent cohort of 96 patients with resectable NSCLC. The presurgery levels in the latter cohort were compared with matched postsurgery levels. Perioperative OPN levels were correlated with demographics, tumor characteristics, and perioperative events. OPN was monitored during follow-up. Results Discovery set presurgery NSCLC OPN (271 +/- 31 ng/mL) was higher than smokers (40 +/- 2 ng/mL; P = .001). Presurgery OPN was similar in the NSCLC validation cohort (324 ng/mL +/- 20 ng/mL; P = .134). Postsurgery OPN (256 ng/mL +/- 21 ng/mL) measured at mean of 9.8 weeks (range, 2 to 46 weeks) was lower than presurgery OPN (P = .005). Time from surgery significantly impacted postsurgery OPN: OPN </= 6 weeks postsurgery (303 n/mL +/- 26 ng/mL) was higher than OPN greater than 6 weeks postsurgery (177 ng/mL +/- 29 ng/mL; P = .003). Multivariate analysis noted correlations between albumin and creatinine to presurgery OPN and use of thoracotomy to postsurgery OPN. Recurrence rate was 5% at 29 weeks mean follow-up. OPN at recurrence was elevated from postsurgery nadir. CONCLUSION Plasma OPN levels are elevated in early-stage NSCLC. They are reduced after resection and appear to increase with recurrence. Plasma OPN may have utility as a biomarker in early-stage NSCLC
— id: 107374, year: 2010, vol: 28, page: 936, stat: Journal Article,

The promyelocytic leukemia zinc-finger gene, PLZF, is frequently downregulated in malignant mesothelioma cells and contributes to cell survival
Cheung, M; Pei, J; Pei, Y; Jhanwar, SC; Pass, HI; Testa, JR
2010 MAR 18 ;29(11):1633-1640, Oncogene
DNA copy number analysis was performed, using single-nucleotide polymorphism mapping arrays, to. ne map genomic imbalances in human malignant mesothelioma (MM) cell lines derived from primary tumors. Chromosomal losses accounted for the majority of genomic imbalances. All 22 cell lines examined showed homozygous deletions of 9p21.3, centering at the CDKN2A/ARF and CDKN2B loci. Other commonly underrepresented segments included 1p36, 1p22, 3p21-22, 4q13, 4q34, 11q23, 13q12-13, 14q32, 15q15, 18q12, and 22q12, each observed in 55-90% of cell lines. Focal deletions of 11q23 encompassed the transcriptional repressor gene promyelocytic leukemia zinc finger (PLZF), which was validated by analysis of genomic DNA using real-time polymerase chain reaction (PCR). Semi-quantitative RT PCR and immunoblot analysis revealed that PLZF is greatly downregulated in MM cell lines compared with non-malignant mesothelial cells. Ectopic expression of PLZF in PLZF-deficient MM cells resulted in decreased cell viability, reduced colony formation, as well as increased apoptosis, the latter based on results of various cell death assays and the observation of increased cleavage of caspase 3, PARP, and Mcl-1. These data indicate that deletions of PLZF are a common occurrence in MM and that downregulation of PLZF may contribute to MM pathogenesis by promoting cell survival. Oncogene (2010) 29, 1633-1640; doi:10.1038/onc.2009.455; published online 14 December 2009
— id: 108816, year: 2010, vol: 29, page: 1633, stat: Journal Article,

Molecular heterogeneity of osteopontin isoforms in non-small cell lung cancer
Donington, J; Goparaju, C; Blasberg, J; Harrington, R; Hirsch, N; Pass, H
2010 JUN ;5(6):S250-S251, Journal of thoracic oncology
— id: 111928, year: 2010, vol: 5, page: S250, stat: Journal Article,

RON receptor tyrosine kinase as a potential translational therapeutic target in malignant pleural mesothelioma
Easty, D; Gray, SG; Nonaka, D; Soltermann, A; Murer, B; Kennedy, MJ; Mutti, L; Pass, HI; O'Donnell, DM; O'Byrne, KJ
2010 JAN ;67(4):S19-S20, Lung cancer
— id: 110141, year: 2010, vol: 67, page: S19, stat: Journal Article,

Frequency of use and predictors of cancer-directed surgery in the management of malignant pleural mesothelioma in a community-based (Surveillance, Epidemiology, and End Results [SEER]) population
Flores, Raja M; Riedel, Elyn; Donington, Jessica Scott; Alago, William; Ihekweazu, Ugonna; Krug, Lee; Rosenzweig, Kenneth; Adusumilli, Prasad S; Carbone, Michele; Pass, Harvey I
2010 Oct;5(10):1649-1654, Journal of thoracic oncology
INTRODUCTION: Surgical intervention rates for mesothelioma patients treated at specialized tertiary hospitals are well more than 42%. Mesothelioma surgical strategies in the community are less well defined. This study evaluates the frequency of use and predictors of cancer-directed surgical intervention in a nontertiary-based population and the predictors for surgical intervention. METHODS: The Surveillance, Epidemiology, and End Results database was searched from 1990 to 2004. Variables analyzed included age, sex, race, year of diagnosis, region, vital status, stage, surgery, and reasons for no surgery. The association of patient variables on receipt of cancer-directed surgery was evaluated using chi(2) tests and logistic regression. The incidence of mesothelioma was also evaluated over this period of time. RESULTS: Pathologically proven malignant pleural mesothelioma was identified in 1166 women and 4771 men. The rate of cancer-directed surgery was 22% (n = 1317). Significant predictors of receiving cancer-directed surgery included race, age, and stage (all p < 0.0001). A landmark analysis on the effect of cancer-directed surgery on survival after adjusting for patient and disease characteristics demonstrated a hazard ratio of 0.68 (p < 0.0001). The incidence rate of malignant pleural mesothelioma has remained constant. CONCLUSIONS: The rate of surgical intervention in the community is lower compared with tertiary referral centers. Age, stage, and race predict the likelihood of receiving cancer-directed surgery. A lower rate of cancer-directed surgery and worse overall outcome were observed in black patients. As part of quality assurance, referral of patients to centers with multidisciplinary programs that include thoracic surgical expertise should be considered
— id: 135527, year: 2010, vol: 5, page: 1649, stat: Journal Article,

Functional heterogeneity of osteopontin isoforms in non-small cell lung cancer
Goparaju, Chandra M V; Pass, Harvey I; Blasberg, Justin D; Hirsch, Nathalie; Donington, Jessica S
2010 Oct;5(10):1516-1523, Journal of thoracic oncology
INTRODUCTION: Osteopontin (OPN) is a multifunctional protein with an important but poorly understood role in non-small cell lung cancer (NSCLC) pathogenesis. Moreover, the role of the three known mRNA isoforms (OPNa, OPNb, and OPNc) has not been reported. We hypothesize that OPN isoforms play different roles in determining the metastatic potential of NSCLC. METHODS: We amplified mRNA for each OPN isoform in NSCLC tumors and matched normal lung. The functional impact of each isoform was evaluated by transfecting cDNA plasmids specific to each isoform into NSCLC cell lines and comparing behavior to empty vector controls in scratch closure, cell proliferation, soft-agar colony formation, and Matrigel invasion assays. Gene array was used to evaluate differences in downstream targets and was compared with a panel of markers for epithelial-mesenchymal transition (EMT). RESULTS: OPNa expression was increased in 91% of NSCLC tumors compared with matched lung. OPNa overexpression significantly increased activity in scratch closure, proliferation, soft-agar colony formation, and Matrigel invasion assays compared with controls in all cell lines. OPNb overexpression produced a less significant modulation of function. OPNc overexpression significantly decreased activity in proliferation, colony formation, and invasion assays compared with controls. Expression arrays revealed an increase in EMT with OPNa overexpression but not OPNc. Differences were validated by quantitative reverse transcriptase-polymerase chain reaction. CONCLUSIONS: Overexpression of the individual OPN isoforms in NSCLC results in divergent functional phenotypes. OPNa produced an aggressive phenotype, whereas OPNc produced a more indolent phenotype. Exon 4, which is transcribed in OPNa but absent in OPNc, may be central to this phenomenon and could serve as a target for isoform-specific inhibition of OPN in NSCLC
— id: 113654, year: 2010, vol: 5, page: 1516, stat: Journal Article,

Inflammation precedes the development of human malignant mesotheliomas in a SCID mouse xenograft model
Hillegass, Jedd M; Shukla, Arti; Lathrop, Sherrill A; MacPherson, Maximilian B; Beuschel, Stacie L; Butnor, Kelly J; Testa, Joseph R; Pass, Harvey I; Carbone, Michele; Steele, Chad; Mossman, Brooke T
2010 Aug;1203:7-14, Annals of the New York Academy of Sciences
Asbestos fibers cause chronic inflammation that may be critical to the development of malignant mesothelioma (MM). Two human MM cell lines (Hmeso, PPM Mill) were used in a SCID mouse xenograft model to assess time-dependent patterns of inflammation and tumor formation. After intraperitoneal (IP) injection of MM cells, mice were euthanized at 7, 14, and 30 days, and peritoneal lavage fluid (PLF) was examined for immune cell profiles and human and mouse cytokines. Increases in human MM-derived IL-6, IL-8, bFGF, and VEGF were observed in mice at 7 days postinjection of either MM line, and a striking neutrophilia was observed at all time points. Free-floating tumor spheroids developed in mice at 14 days, and both spheroids and adherent MM tumor masses occurred in all mice at 30 days. Results suggest that inflammation and cytokine production precede and may be critical to the development of MMs
— id: 133793, year: 2010, vol: 1203, page: 7, stat: Journal Article,

Pro-tumorigenic effects of miR-31 loss in mesothelioma
Ivanov, Sergey V; Goparaju, Chandra M V; Lopez, Peter; Zavadil, Jiri; Toren-Haritan, Ginat; Rosenwald, Shai; Hoshen, Moshe; Chajut, Ayelet; Cohen, Dalia; Pass, Harvey I
2010 Jul 23;285(30):22809-22817, Journal of biological chemistry
The human genome encodes several hundred microRNA (miRNA) genes that produce small (21-23n) single strand regulatory RNA molecules. Although abnormal expression of miRNAs has been linked to cancer progression, the mechanisms of this dysregulation are poorly understood. Malignant mesothelioma (MM) of pleura is an aggressive and highly lethal cancer resistant to conventional therapies. We and others previously linked loss of the 9p21.3 chromosome in MM with short time to tumor recurrence. In this study, we report that MM cell lines derived from patients with more aggressive disease fail to express miR-31, a microRNA recently linked with suppression of breast cancer metastases. We further demonstrate that this loss is due to homozygous deletion of the miR-31-encoding gene that resides in 9p21.3. Functional assessment of miR-31 activity revealed its ability to inhibit proliferation, migration, invasion, and clonogenicity of MM cells. Re-introduction of miR-31 suppressed the cell cycle and inhibited expression of multiple factors involved in cooperative maintenance of DNA replication and cell cycle progression, including pro-survival phosphatase PPP6C, which was previously associated with chemotherapy and radiation therapy resistance, and maintenance of chromosomal stability. PPP6C, whose mRNA is distinguished with three miR-31-binding sites in its 3'-untranslated region, was consistently down-regulated by miR-31 introduction and up-regulated in clinical MM specimens as compared with matched normal tissues. Taken together, our data suggest that tumor-suppressive propensity of miR-31 can be used for development of new therapies against mesothelioma and other cancers that show loss of the 9p21.3 chromosome
— id: 138201, year: 2010, vol: 285, page: 22809, stat: Journal Article,

UNLOCKING BIOMARKER DISCOVERY FOR EARLY DETECTION OF LUNG CANCER
Ostroff, R.; Bigbee, W.; Franklin, W.; Gold, L.; Mehan, M.; Miller, Y.; Pass, H.; Rom, W.; Siegfried, J.; Stewart, A.; Walker, J.; Weissfeld, J.; Williams, S.; Zichi, D.; Brody, E.
2010 AUG ;31:S14-S14, Tumour biology
— id: 132750, year: 2010, vol: 31, page: S14, stat: Journal Article,

Unlocking biomarker discovery: large scale application of aptamer proteomic technology for early detection of lung cancer
Ostroff, Rachel M; Bigbee, William L; Franklin, Wilbur; Gold, Larry; Mehan, Mike; Miller, York E; Pass, Harvey I; Rom, William N; Siegfried, Jill M; Stewart, Alex; Walker, Jeffrey J; Weissfeld, Joel L; Williams, Stephen; Zichi, Dom; Brody, Edward N
2010 ;5(12):e15003-e15003, PLoS ONE
BACKGROUND: Lung cancer is the leading cause of cancer deaths worldwide. New diagnostics are needed to detect early stage lung cancer because it may be cured with surgery. However, most cases are diagnosed too late for curative surgery. Here we present a comprehensive clinical biomarker study of lung cancer and the first large-scale clinical application of a new aptamer-based proteomic technology to discover blood protein biomarkers in disease. METHODOLOGY/PRINCIPAL FINDINGS: We conducted a multi-center case-control study in archived serum samples from 1,326 subjects from four independent studies of non-small cell lung cancer (NSCLC) in long-term tobacco-exposed populations. Sera were collected and processed under uniform protocols. Case sera were collected from 291 patients within 8 weeks of the first biopsy-proven lung cancer and prior to tumor removal by surgery. Control sera were collected from 1,035 asymptomatic study participants with >/= 10 pack-years of cigarette smoking. We measured 813 proteins in each sample with a new aptamer-based proteomic technology, identified 44 candidate biomarkers, and developed a 12-protein panel (cadherin-1, CD30 ligand, endostatin, HSP90alpha, LRIG3, MIP-4, pleiotrophin, PRKCI, RGM-C, SCF-sR, sL-selectin, and YES) that discriminates NSCLC from controls with 91% sensitivity and 84% specificity in cross-validated training and 89% sensitivity and 83% specificity in a separate verification set, with similar performance for early and late stage NSCLC. CONCLUSIONS/SIGNIFICANCE: This study is a significant advance in clinical proteomics in an area of high unmet clinical need. Our analysis exceeds the breadth and dynamic range of proteome interrogated of previously published clinical studies of broad serum proteome profiling platforms including mass spectrometry, antibody arrays, and autoantibody arrays. The sensitivity and specificity of our 12-biomarker panel improves upon published protein and gene expression panels. Separate verification of classifier performance provides evidence against over-fitting and is encouraging for the next development phase, independent validation. This careful study provides a solid foundation to develop tests sorely needed to identify early stage lung cancer
— id: 119198, year: 2010, vol: 5, page: e15003, stat: Journal Article,

100 questions & answers about mesothelioma
Pass HI; Metula A; Vento S
Sudbury, Mass. : Jones and Bartlett Publishers, 2010,
— id: 1872, year: 2010, vol: , page: , stat: ,

Principles and practice of lung cancer : the official reference text of the IASLC
Pass, Harvey I
Philadelphia PA : Wolters Kluwer Health/Lippincott Williams & Wilkins, 2010,
— id: 2172, year: 2010, vol: , page: , stat: ,

Medical registries: continued attempts for robust quality data
Pass, Harvey I
2010 Jun;5(6 Suppl 2):S198-S199, Journal of thoracic oncology
Medical registries are useful to summarize retrospective or prospective data in a fashion that, on interpretation, could result in changes in the standard of care or highlight issues that must be further investigated in the management of certain diseases. Registries involve collection of data and registries are only as good as the fidelity of the data that are collected. There are a number of sources of error in registry formation. This brief review summarizes the errors that could influence the quality of the data in a registry and points out methods that could decrease those errors
— id: 110110, year: 2010, vol: 5, page: S198, stat: Journal Article,

hsa-miR-29c* Is Linked to the Prognosis of Malignant Pleural Mesothelioma
Pass, Harvey I; Goparaju, Chandra; Ivanov, Sergey; Donington, Jessica; Carbone, Michele; Hoshen, Moshe; Cohen, Dalia; Chajut, Ayelet; Rosenwald, Shai; Dan, Harel; Benjamin, Sima; Aharonov, Ranit
2010 Mar 1;70(5):1916-1924, Cancer research
The inability to forecast outcomes for malignant mesothelioma prevents clinicians from providing aggressive multimodality therapy to the most appropriate individuals who may benefit from such an approach. We investigated whether specific microRNAs (miR) could segregate a largely surgically treated group of mesotheliomas into good or bad prognosis categories. A training set of 44 and a test set of 98 mesothelioma tumors were analyzed by a custom miR platform, along with 9 mesothelioma cell lines and 3 normal mesothelial lines. Functional implications as well as downstream targets of potential prognostic miRs were investigated. In both the training and test sets, hsa-miR-29c* was an independent prognostic factor for time to progression as well as survival after surgical cytoreduction. The miR was expressed at higher levels in epithelial mesothelioma, and the level of this miR could segregate patients with this histology into groups with differing prognosis. Increased expression of hsa-miR-29c* predicted a more favorable prognosis, and overexpression of the miR in mesothelioma cell lines resulted in significantly decreased proliferation, migration, invasion, and colony formation. Moreover, major epigenetic regulation of mesothelioma is mediated by hsa-miR-29c* and was shown through downregulation of DNA methyltransferases as well as upregulation of demethylating genes. A single miR has the potential to be a prognostic biomarker in mesothelioma, and validation of these findings as well as investigation of its downstream targets may give insight for potential therapies in the future. Cancer Res; 70(5); 1916-24
— id: 107776, year: 2010, vol: 70, page: 1916, stat: Journal Article,

Optical detection of buccal epithelial nanoarchitectural alterations in patients harboring lung cancer: implications for screening
Roy, Hemant K; Subramanian, Hariharan; Damania, Dhwanil; Hensing, Thomas A; Rom, William N; Pass, Harvey I; Ray, Daniel; Rogers, Jeremy D; Bogojevic, Andrej; Shah, Maitri; Kuzniar, Tomasz; Pradhan, Prabhakar; Backman, Vadim
2010 Oct 15;70(20):7748-7754, Cancer research
We have recently developed a novel optical technology, partial wave spectroscopic (PWS) microscopy, which is exquisitely sensitive to the nanoarchitectural manifestation of the genetic/epigenetic alterations of field carcinogenesis. Our approach was to screen for lung cancer by assessing the cheek cells based on emerging genetic/epigenetic data which suggests that the buccal epithelium is altered in lung field carcinogenesis. We performed PWS analysis from microscopically normal buccal epithelial brushings from smokers with and without lung cancer (n = 135). The PWS parameter, disorder strength of cell nanoarchitecture (L(d)), was markedly (>50%) elevated in patients harboring lung cancer compared with neoplasia-free smokers. The performance characteristic was excellent with an area under the receiver operator characteristic curve of >0.80 and was equivalent for both disease stage (early versus late) and histologies (small cell versus non-small cell lung cancers). An independent data set validated the findings with only a minimal degradation of performance characteristics. Our results offer proof of concept that buccal PWS may potentially herald a minimally intrusive prescreening test that could be integral to the success of lung cancer population screening programs
— id: 135525, year: 2010, vol: 70, page: 7748, stat: Journal Article,

ERK2 is essential for the growth of human epithelioid malignant mesotheliomas
Shukla A; Hillegass JM; Macpherson MB; Beuschel SL; Vacek PM; Butnor KJ; Pass HI; Carbone M; Testa JR; Heintz NH; Mossman BT
2010 Nov 12;:?-? #, International journal of cancer
Members of the extracellular signal-regulated kinase (ERK) family may have distinct roles in the development of cell injury and repair, differentiation and carcinogenesis. Here, we show, using a synthetic small-molecule MEK1/2 inhibitor (U0126) and RNA silencing of ERK1 and 2, comparatively, that ERK2 is critical to transformation and homeostasis of human epithelioid malignant mesotheliomas (MMs), asbestos-induced tumors with a poor prognosis. Although MM cell (HMESO) lines stably transfected with shERK1 or shERK2 both exhibited significant decreases in cell proliferation in vitro, injection of shERK2 cells, and not shERK1 cells, into immunocompromised severe combined immunodeficiency (SCID) mice showed significant attenuated tumor growth in comparison to shControl (shCon) cells. Inhibition of migration, invasion and colony formation occurred in shERK2 MM cells in vitro, suggesting multiple roles of ERK2 in neoplasia. Microarray and quantitative real-time PCR analyses revealed gene expression that was significantly increased (CASP1, TRAF1 and FAS) or decreased (SEMA3E, RPS6KA2, EGF and BCL2L1) in shERK2-transfected MM cells in contrast to shCon-transfected MM cells. Most striking decreases were observed in mRNA levels of Semaphorin 3 (SEMA3E), a candidate tumor suppressor gene linked to inhibition of angiogenesis. These studies demonstrate a key role of ERK2 in novel gene expression critical to the development of epithelioid MMs. After injection of sarcomatoid human MM (PPMMill) cells into SCID mice, both shERK1 and shERK2 lines showed significant decreased tumor growth, suggesting heterogeneous effects of ERKs in individual MMs
— id: 138350, year: 2010, vol: , page: ?, stat: Journal Article,

Blocking of ERK1 and ERK2 sensitizes human mesothelioma cells to doxorubicin
Shukla, Arti; Hillegass, Jedd M; MacPherson, Maximilian B; Beuschel, Stacie L; Vacek, Pamela M; Pass, Harvey I; Carbone, Michele; Testa, Joseph R; Mossman, Brooke T
2010 ;9:314-314, Molecular cancer
BACKGROUND: Malignant mesotheliomas (MM) have a poor prognosis, largely because of their chemoresistance to anti-cancer drugs such as doxorubicin (Dox). Here we show using human MM lines that Dox activates extracellular signal-regulated kinases (ERK1 and 2), causally linked to increased expression of ABC transporter genes, decreased accumulation of Dox, and enhanced MM growth. Using the MEK1/2 inhibitor, U0126 and stably transfected shERK1 and shERK2 MM cell lines, we show that inhibition of both ERK1 and 2 sensitizes MM cells to Dox. RESULTS: U0126 significantly modulated endogenous expression of several important drug resistance (BCL2, ABCB1, ABCC3), prosurvival (BCL2), DNA repair (BRCA1, BRCA2), hormone receptor (AR, ESR2, PPARgamma) and drug metabolism (CYP3A4) genes newly identified in MM cells. In comparison to shControl lines, MM cell lines stably transfected with shERK1 or shERK2 exhibited significant increases in intracellular accumulation of Dox and decreases in cell viability. Affymetrix microarray analysis on stable shERK1 and shERK2 MM lines showed more than 2-fold inhibition (p </= 0.05) of expression of ATP binding cassette genes (ABCG1, ABCA5, ABCA2, MDR/TAP, ABCA1, ABCA8, ABCC2) in comparison to shControl lines. Moreover, injection of human MM lines into SCID mice showed that stable shERK1 or shERK2 lines had significantly slower tumor growth rates in comparison to shControl lines after Dox treatment. CONCLUSIONS: These studies suggest that blocking ERK1 and 2, which play critical roles in multi-drug resistance and survival, may be beneficial in combination with chemotherapeutic drugs in the treatment of MMs and other tumors
— id: 122283, year: 2010, vol: 9, page: 314, stat: Journal Article,

The diagnostic value of endobronchial ultrasound-guided needle biopsy in lung cancer and mediastinal adenopathy
Sun, Wei; Song, Kunchang; Zervos, Michael; Pass, Harvey; Cangiarella, Joan; Bizekis, Costas; Crawford, Bernard; Wang, Beverly Y
2010 May;38(5):337-342, Diagnostic cytopathology
Endobronchial ultrasonography (EBUS) has emerged as a new diagnostic tool that allows the bronchoscopist to see beyond the airway, including pulmonary and mediastinal lesion. The real time EBUS-guided transbronchial needle aspiration (TBNA) has advanced the diagnostic yield in primary lung pathology and mediastinal lymph node staging of lung carcinoma. Sixty-four patients (36 males, 28 females, ages ranging from 16 to 86 years) with peribronchial lung lesions and mediastinal and/or hilar lymph node lesions underwent EBUS-TBNA. All patients had intraoperative cytological assessment by smears on aspiration samples or touch preparation on needle core biopsies.The cytological final diagnoses were categorized as negative, suspicious/positive, and non-diagnostic. Forty-nine samples were obtained from lymph node lesions and 15 samples were obtained from lung lesions. In cytology specimens, 32 patients had suspicious/positive diagnoses and 32 patients had negative diagnosis. In follow-up histology specimens, 35 patients had malignant diagnoses, including 18 adenocarcinomas, 8 small cell carcinomas, 6 squamous cell carcinomas, 1 metastatic hepatocellular carcinoma, 1 metastatic melanoma, and 1 lymphoma. Twenty-nine patients had negative diagnoses. Sensitivity and specificity were 88.9% and 96.4%, respectively. Positive and negative predictive values were 97.0% and 87.1%, respectively. Diagnostic accuracy was 92.2%. EBUS-TBNA is an efficient and effective technique for diagnosis of intrapulmonary and mediastinal/hilar lymph nodes. It becomes significantly invaluable on clinical management for staging in those patients with lung cancer of other metastatic malignancies. This technique enables us to obtain tissue samples for quick diagnoses beyond central airway with minimal complications. Diagn. Cytopathol. 2010. (c) 2009 Wiley-Liss, Inc
— id: 106028, year: 2010, vol: 38, page: 337, stat: Journal Article,

Targeted proteasome inhibition by Velcade induces apoptosis in human mesothelioma and breast cancer cell lines
Wang, Ying; Rishi, Arun K; Puliyappadamba, Vineshkumar T; Sharma, Sunita; Yang, Huanjie; Tarca, Adi; Ping Dou, Q; Lonardo, Fulvio; Ruckdeschel, John C; Pass, Harvey I; Wali, Anil
2010 Aug;66(3):455-466, Cancer chemotherapy & pharmacology
INTRODUCTION: Thoracic malignancies and human breast cancer (HBC) continue to be aggressive solid tumors that are poor responders to the existing conventional standard chemotherapeutic approaches. Malignant pleural mesothelioma (MPM) is an asbestos-related tumor of the thoracic pleura that lacks effective treatment options. Altered ubiquitin proteasome pathway is frequently encountered in many malignancies including HBC and MPM and thus serves as an important target for therapeutic intervention strategies. Although proteasome inhibitor Velcade (Bortezomib) has been under clinical investigation for a number of cancers, limited preclinical studies with this agent have thus far been conducted in HBC and MPM malignancies. PURPOSE: To study the biological and molecular responses of MPM and HBC cells to Velcade treatments, and to identify mechanisms involved in transducing growth inhibitory effects of this agent. METHODS: Flow-cytometric analyses coupled with western immunoblotting and gene-array methodologies were utilized to determine mechanisms of Velcade-dependent growth suppression of five MPM (H2595, H2373, H2452, H2461, and H2714) and two breast cancer (MDA MB-468, SKBR-3) cell lines. RESULTS: Our data revealed significant reduction in cell growth properties that were dose and time dependent. Velcade treatment resulted in G2M phase arrest, increased expression of cyclin-dependent kinase inhibitor p21 and pro-apoptotic protein Bax. Pretreatment of mesothelioma cells with Velcade showed synergistic effect with cisplatin combination regimens. High-throughput gene expression profiling among Velcade treated and untreated mesothelioma cell lines resulted in identification of novel transducers of apoptosis such as CARP-1, XAF1, and Troy proteins. CONCLUSIONS: Velcade targets cell cycle and apoptosis signaling to suppress MPM and HBC growth in part by activating novel transducers of apoptosis. This pilot study has paved way for further in-depth analysis of the downstream target molecules associated with presensitization of mesothelioma cells in finding effective therapeutic treatment options for both mesothelioma and recalcitrant breast cancers
— id: 110887, year: 2010, vol: 66, page: 455, stat: Journal Article,

Programmed necrosis induced by asbestos in human mesothelial cells causes high-mobility group box 1 protein release and resultant inflammation
Yang, Haining; Rivera, Zeyana; Jube, Sandro; Nasu, Masaki; Bertino, Pietro; Goparaju, Chandra; Franzoso, Guido; Lotze, Michael T; Krausz, Thomas; Pass, Harvey I; Bianchi, Marco E; Carbone, Michele
2010 Jul 13;107(28):12611-12616, Proceedings of the National Academy of Sciences of the United States of America
Asbestos carcinogenesis has been linked to the release of cytokines and mutagenic reactive oxygen species (ROS) from inflammatory cells. Asbestos is cytotoxic to human mesothelial cells (HM), which appears counterintuitive for a carcinogen. We show that asbestos-induced HM cell death is a regulated form of necrosis that links to carcinogenesis. Asbestos-exposed HM activate poly(ADP-ribose) polymerase, secrete H(2)O(2), deplete ATP, and translocate high-mobility group box 1 protein (HMGB1) from the nucleus to the cytoplasm, and into the extracellular space. The release of HMGB1 induces macrophages to secrete TNF-alpha, which protects HM from asbestos-induced cell death and triggers a chronic inflammatory response; both favor HM transformation. In both mice and hamsters injected with asbestos, HMGB1 was specifically detected in the nuclei, cytoplasm, and extracellular space of mesothelial and inflammatory cells around asbestos deposits. TNF-alpha was coexpressed in the same areas. HMGB1 levels in asbestos-exposed individuals were significantly higher than in nonexposed controls (P < 0.0001). Our findings identify the release of HMGB1 as a critical initial step in the pathogenesis of asbestos-related disease, and provide mechanistic links between asbestos-induced cell death, chronic inflammation, and carcinogenesis. Chemopreventive approaches aimed at inhibiting the chronic inflammatory response, and especially blocking HMGB1, may decrease the risk of malignant mesothelioma among asbestos-exposed cohorts
— id: 110885, year: 2010, vol: 107, page: 12611, stat: Journal Article,

Tissue Tropism of SV40 Transformation of Human Cells: Role of the Viral Regulatory Region and of Cellular Oncogenes
Zhang, Lei; Qi, Fang; Gaudino, Giovanni; Strianese, Oriana; Yang, Haining; Morris, Paul; Pass, Harvey I; Nerurkar, Vivek R; Bocchetta, Maurizio; Carbone, Michele
2010 Oct;1(10):1008-1020, Genes & cancer
SV40 has been detected prevalently in a limited panel of human tumors: mesothelioma, bone and brain tumors, and lymphoma. These are the same tumor types that are specifically induced by SV40 when injected into hamsters, a finding that has raised concerns about the possible pathogenic role of SV40 in humans. Two different SV40 isolates differing in the number of 72-bp elements in the virus regulatory region, archetypal SV40 (1ESV40), which contains one 72 bp, and nonarchetypal SV40 (wtSV40), which contains two 72 bp, have been detected in human tumors. 1ESV40 has been prevalently detected in brain tumors, with wtSV40 prevalently in mesothelioma. The apparent different cell tropism could be related to the virus (i.e., possibly to the number of 72-bp elements) and to different expression of cellular genes, known to play a critical role in SV40-mediated transformation of human cells, such as Notch-1 and c-Met. To test for possible differences in tissue tropism, we infected primary human mesothelial cells (HM) and primary human astrocytes (Ast) with 1ESV40 and with wtSV40 from 2 different SV40 strains, 776 and Baylor. All viruses transformed astrocytes; only wtSV40 transformed HM. Intracellular signaling of c-Met and Notch-1 was differently induced by these 2 viruses in HM and Ast. Differences in Notch-1 expression and signaling (i.e., downstream effectors, c-Myc, HEY-1, HES-1, and HEY-L) appeared to influence SV40-mediated transformation of primary astrocytes and mesothelial cells. Our results provide a biological rationale to the observation that 1ESV40 is prevalently detected in brain tumors and wtSV40 in mesotheliomas
— id: 149990, year: 2010, vol: 1, page: 1008, stat: Journal Article,

Chemotherapy of malignant pleural mesothelioma
Bertino, Pietro; Carbone, Michele; Pass, Harvey
2009 Jan;10(1):99-107, Expert opinion on pharmacotherapy
BACKGROUND: Owing to worldwide use of asbestos during the past century, the global incidence of mesothelioma is still increasing. Although the outcome for patients remains poor, there has been definite progress in the systemic treatment of this disease within the past 5 years. OBJECTIVE: By examining the clinical trials performed and the role of novel emerging agents, this review aims to provide an 'expert opinion' on evidences that validate chemotherapy as current 'standard of care' for inoperable mesothelioma. METHODS: Relevant literature about clinical trials was reviewed using a PubMed search and other relevant data about novel therapeutic approaches both established and in development. CONCLUSION: The response rates achieved using chemotherapeutic treatments are higher than previous ones, and in the future may be improved by the use of combined and personalized therapies
— id: 101353, year: 2009, vol: 10, page: 99, stat: Journal Article,

Angiogenic impact of HAPLN1 in malignant mesothelioma
Blasberg, JD; Goparaju, CM; Ivanova, AV; Ivanov, SV; Donington, JS; Pass, HI
2009 SEP ;4(9):S753-S753, Journal of thoracic oncology
— id: 102469, year: 2009, vol: 4, page: S753, stat: Journal Article,

Divergent impact of osteopontin isoforms on lung cancer invasion
Blasberg, JD; Goparaju, CM; Pass, HI; Donington, JS
2009 SEP ;4(9):S605-S606, Journal of thoracic oncology
— id: 102468, year: 2009, vol: 4, page: S605, stat: Journal Article,

The International Association for the Study of Lung Cancer Staging Project: prognostic factors and pathologic TNM stage in surgically managed non-small cell lung cancer
Chansky, Kari; Sculier, Jean-Paul; Crowley, John J; Giroux, Dori; Van Meerbeeck, Jan; Goldstraw, Peter; Pass, Harvey I
2009 Jul;4(7):792-801, Journal of thoracic oncology
PURPOSE: To assess the impact of cell type, age, and gender in addition to pathologic tumor, node, metastasis (TNM) stage in surgically managed stage I-IIIA non-small cell lung cancer (NSCLC) cases from the international staging database of the International Association for the Study of Lung Cancer. MATERIAL AND METHODS: From the 67,725 cases of NSCLC submitted to the staging database, 9137 surgically managed cases were selected for which all the following variables were available: pathologic stage, age, gender, and specific histologic cell type. Performance status and smoking history were examined in subsets. Methods used were Cox proportional hazards regression and recursive partitioning and amalgamation (RPA) analyses. RESULTS: Pathologic TNM stage, age, and gender were all independently prognostic for survival. The bronchioloalveolar carcinoma (BAC) subtype had superior survival over other cell types despite the potential for heterogeneity in this group. Adjusted comparisons revealed a small survival advantage for squamous cell carcinomas over non-BAC adenocarcinoma histology and also over large cell, though the effect appeared to be limited to the male patients. RPA revealed the importance of TNM stage primarily, and age was prognostic within stage groups. Cell type was not found to add prognostic value in the RPA analysis. Prognostic groups were formed based on the RPA output, and the prognostic value of these groupings was validated using the North American Surveillance, Epidemiology, and End Results Registries. Performance status and smoking history were prognostic in the subsets where data were available. Effects of other variable were not influenced by the inclusion of smoking status in regression models. CONCLUSIONS: Age and gender are confirmed as important prognostic factors in surgically resected NSCLC. Cell type is less important, although the small population of cases classified as BAC have a survival advantage over other histologies, and there may be a small survival advantage for squamous cell carcinomas over non-BAC adenocarcinomas. Imbalances between stage, gender, and cell type at presentation may lead to a misleading result with respect to cell type in unadjusted analyses. Pathologic TNM category is the most important prognostic factor in this analysis
— id: 110923, year: 2009, vol: 4, page: 792, stat: Journal Article,

Detection and localization of intraepithelial neoplasia and invasive carcinoma using fluorescence-reflectance bronchoscopy: an international, multicenter clinical trial
Edell, Eric; Lam, Stephen; Pass, Harvey; Miller, York E; Sutedja, Thomas; Kennedy, Timothy; Loewen, Gregory; Keith, Robert L; Gazdar, Adi
2009 Jan;4(1):49-54, Journal of thoracic oncology
OBJECTIVES: The primary objective of this study was to evaluate the benefit of using a new fluorescence-reflectance imaging system, Onco-LIFE, for the detection and localization of intraepitheal neoplasia and early invasive squamous cell carcinoma. A secondary objective was to evaluate the potential use of quantitative image analysis with this device for objective classification of abnormal sites. DESIGN: This study was a prospective, multicenter, comparative, single arm trial. Subjects for this study were aged 45 to 75 years and either current or past smokers of more than 20 pack-years with airflow obstruction, forced expiratory volume in 1 second/forced vital capacity less than 75%, suspected to have lung cancer based on either sputum atypia, abnormal chest roentgenogram/chest computed tomography, or patients with previous curatively treated lung or head and neck cancer within 2 years. MATERIALS AND METHODS: The primary endpoint of the study was to determine the relative sensitivity of white light bronchoscopy (WLB) plus autofluorescence-reflectance bronchoscopy compared with WLB alone. Bronchoscopy with Onco-LIFE was carried out in two stages. The first stage was performed under white light and mucosal lesions were visually classified. Mucosal lesions were classified using the same scheme in the second stage when viewed with Onco-LIFE in the fluorescence-reflectance mode. All regions classified as suspicious for moderate dysplasia or worse were biopsied, plus at least one nonsuspicious region for control. Specimens were evaluated by the site pathologist and then sent to a reference pathologist, each blinded to the endoscopic findings. Positive lesions were defined as those with moderate/severe dysplasia, carcinoma in situ (CIS), or invasive carcinoma. A positive patient was defined as having at least one lesion of moderate/severe dysplasia, CIS, or invasive carcinoma. Onco-LIFE was also used to quantify the fluorescence-reflectance response (based on the proportion of reflected red light to green fluorescence) for each suspected lesion before biopsy. RESULTS: There were 115 men and 55 women with median age of 62 years. Seven hundred seventy-six biopsy specimens were included. Seventy-six were classified as positive (moderate dysplasia or worse) by pathology. The relative sensitivity on a per-lesion basis of WLB + FLB versus WLB was 1.50 (95% confidence interval [CI], 1.26-1.89). The relative sensitivity on a per-patient basis was 1.33 (95% CI, 1.13-1.70). The relative sensitivity to detect intraepithelial neoplasia (moderate/severe dysplasia or CIS) was 4.29 (95% CI, 2.00-16.00) and 3.50 (95% CI, 1.63-12.00) on a per-lesion and per-patient basis, respectively. For a quantified fluorescence reflectance response value of more than or equal to 0.40, a sensitivity and specificity of 51% and 80%, respectively, could be achieved for detection of moderate/severe dsyplasia, CIS, and microinvasive cancer. CONCLUSIONS: Using autofluorescence-reflectance bronchoscopy as an adjunct to WLB with the Onco-LIFE system improves the detection and localization of intraepitheal neoplasia and invasive carcinoma compared with WLB alone. The use of quantitative image analysis to minimize interobserver variation in grading of abnormal sites should be explored further in future prospective clinical trial
— id: 101355, year: 2009, vol: 4, page: 49, stat: Journal Article,

Nuclear, compared with combined nuclear and cytoplasmic expression of maspin, is linked in lung adenocarcinoma to reduced VEGF-A levels and in Stage I, improved survival
Frey, Amy; Soubani, Ayman O; Adam, Abdulgadir K; Sheng, Shijie; Pass, Harvey I; Lonardo, Fulvio
2009 Apr;54(5):590-597, Histopathology
AIMS: To evaluate whether there is a correlation between the subcellular localization of maspin and the histological, molecular and biological features of pulmonary adenocarcinoma, particularly addressing the hypothesis that the tumour inhibitor properties of maspin may be linked to a nuclear, compared with a combined nuclear and cytoplasmic expression pattern. METHODS AND RESULTS: The subcellular expression of maspin was determined in 80 resected pulmonary adenocarcinomas (Stage I, 46; Stage II, 10; Stage III, 20; Stage IV, 4) and correlated with histological grade, proliferative rate, p53 expression, vascular endothelial growth factor (VEGF)-A levels, and prognosis (mean follow-up of 41.5 months). Cases with nuclear (N) maspin (n = 47), compared with the [N + cytoplasmic (C)] group (n = 28), showed lower (P <or= 0.05): histological grade, proliferative rate, p53 expression and VEGF-A levels. Cox multivariate analysis revealed in stage I adenocarcinomas (N) maspin as the only predictor of improved survival. CONCLUSIONS: (N) maspin selects lung adenocarcinomas with distinct molecular and clinical features, supporting the hypothesis that its tumour inhibitor properties may be linked to its nuclear localization
— id: 101352, year: 2009, vol: 54, page: 590, stat: Journal Article,

The IASLC Lung Cancer Staging Project: data elements for the prospective project
Giroux, Dorothy J; Rami-Porta, Ramon; Chansky, Kari; Crowley, John J; Groome, Patti A; Postmus, Pieter E; Rusch, Valerie; Sculier, Jean-Paul; Shepherd, Frances A; Sobin, Leslie; Goldstraw, Peter; Pass, Harvey I
2009 Jun;4(6):679-683, Journal of thoracic oncology
The International Association for the Study of Lung Cancer Retrospective Staging Project culminated in a series of recommendations to the International Union Against Cancer and to the American Joint Committee on Cancer regarding the seventh edition of the tumor, node, metastasis (TNM) classification for lung cancer. The International Staging Committee of the International Association for the Study of Lung Cancer now issues this call for participation in the Prospective Project designed to assess the validity of each component of T, N, and M, and other factors relevant to lung cancer staging and prognosis. In the Retrospective Project, the original data acquisition was typically motivated by interests other than staging. In contrast, the Prospective Project offers online data entry. Alternatively, participants may transfer existing data, provided core objectives are addressed. Cancer Research and Biostatistics will coordinate data management and analysis. The study population is newly diagnosed lung cancer patients. Data elements include patient characteristics, baseline laboratory values, first-line treatment, TNM plus supporting evidence, and survival. Pretreatment TNM will be collected for all cases; postsurgical TNM, if resection is attempted. T descriptors include size and degree of tumor extension, with further description of extent of visceral pleural invasion, venous invasion, carcinomatous lymphangitis, and pleural lavage cytology. M descriptors characterize the newly proposed M1a category and sites of distant metastases. Nodal station involvement is described by means of a newly proposed nodal map, facilitating international participation, and allowing further investigation of nodal zones. Successful collection and analysis of these data can be expected to yield unprecedented improvements in the utility and validity of lung cancer staging
— id: 110922, year: 2009, vol: 4, page: 679, stat: Journal Article,

Clinical presentation of asbestosis with intractable pleural pain in the adult child of a taconite miner and radiographic demonstration of the probable pathology causing the pain
Harbut, Michael R; Endress, Carmen; Graff, John J; Weis, Christopher; Pass, Harvey
2009 Jul-Sep;15(3):269-273, International journal of occupational & environmental health
Taconite, although not classified by the United States Government as asbestos or asbestiform material, has been associated with asbestos-related diseases. The mineral is used in the production of steel and as a road-patch material and is mined in Michigan and Minnesota. This report describes the case of a middle-aged Caucasian woman with exposure to taconite mining dust from her miner father's clothing in childhood with a resultant presentation consistent with asbestosis and intractable pleural pain. Intractable pleural pain has been described in asbestos-exposed patients with theorized etiologies. However, no in vivo reported mechanism has demonstrated a plausible, anatomically apparent mechanism for the pain. We utilize an application of the Vitrea software for enhancement of high-resolution computerized tomography which demonstrates at least one likely mechanism for intractable pleural pain
— id: 101348, year: 2009, vol: 15, page: 269, stat: Journal Article,

Redox Regulation of FoxM1 in Malignant Mesothelioma cells
Heintz, NH; Newick, K; Mossman, BT; Hillegass, J; Beuschel, S; Shukla, A; Arbiser, J; Pass, H
2009 OCT ;47(4):S173-S173, Free radical biology & medicine
— id: 105953, year: 2009, vol: 47, page: S173, stat: Journal Article,

Expression profiling of glycosylation pathways in pleural mesothelioma
Ivanov, S; Pass, HI; Huflejt, M
2009 SEP ;4(9):S763-S764, Journal of thoracic oncology
— id: 102470, year: 2009, vol: 4, page: S763, stat: Journal Article,

Tumorigenic properties of alternative osteopontin isoforms in mesothelioma
Ivanov, Sergey V; Ivanova, Alla V; Goparaju, Chandra M V; Chen, Yuanbin; Beck, Amanda; Pass, Harvey I
2009 May 8;382(3):514-518, Biochemical & biophysical research communications
Osteopontin (SPP1) is an inflammatory cytokine that we previously characterized as a diagnostic marker in patients with asbestos-induced malignant mesothelioma (MM). While SPP1 shows both pro- and anti-tumorigenic biological effects, little is known about the molecular basis of these activities. In this study, we demonstrate that while healthy pleura possesses all three differentially spliced SPP1 isoforms (A-C), in clinical MM specimens isoform A is markedly up-regulated and predominant. To provide a clue to possible functions of the SPP1 isoforms we next performed their functional evaluation via transient expression in MM cell lines. As a result, we report that isoforms A-C demonstrate different activities in cell proliferation, wound closure, and invasion assays. These findings suggest different functions for SPP1 isoforms and underline pro-tumorigenic properties of isoforms A and B
— id: 99136, year: 2009, vol: 382, page: 514, stat: Journal Article,

Genomic events associated with progression of pleural malignant mesothelioma
Ivanov, Sergey V; Miller, Jeremy; Lucito, Robert; Tang, Chunlao; Ivanova, Alla V; Pei, Jianming; Carbone, Michele; Cruz, Christina; Beck, Amanda; Webb, Craig; Nonaka, Daisuke; Testa, Joseph R; Pass, Harvey I
2009 Feb 1;124(3):589-599, International journal of cancer
Pleural malignant mesothelioma (MM) is an aggressive cancer with a very long latency and a very short median survival. Little is known about the genetic events that trigger MM and their relation to poor outcome. The goal of our study was to characterize major genomic gains and losses associated with MM origin and progression and assess their clinical significance. We performed Representative Oligonucleotide Microarray Analysis (ROMA) on DNA isolated from tumors of 22 patients who recurred at variable interval with the disease after surgery. The total number of copy number alterations (CNA) and frequent imbalances for patients with short time (<12 months from surgery) and long time to recurrence were recorded and mapped using the Analysis of Copy Errors algorithm. We report a profound increase in CNA in the short-time recurrence group with most chromosomes affected, which can be explained by chromosomal instability associated with MM. Deletions in chromosomes 22q12.2, 19q13.32 and 17p13.1 appeared to be the most frequent events (55-74%) shared between MM patients followed by deletions in 1p, 9p, 9q, 4p, 3p and gains in 5p, 18q, 8q and 17q (23-55%). Deletions in 9p21.3 encompassing CDKN2A/ARF and CDKN2B were characterized as specific for the short-term recurrence group. Analysis of the minimal common areas of frequent gains and losses identified candidate genes that may be involved in different stages of MM: OSM (22q12.2), FUS1 and PL6 (3p21.3), DNAJA1 (9p21.1) and CDH2 (18q11.2-q12.3). Imbalances seen by ROMA were confirmed by Affymetrix genome analysis in a subset of samples. (c) 2008 Wiley-Liss, Inc
— id: 90030, year: 2009, vol: 124, page: 589, stat: Journal Article,

Protumorigenic role of HAPLN1 and its IgV domain in malignant pleural mesothelioma
Ivanova, Alla V; Goparaju, Chandra M V; Ivanov, Sergey V; Nonaka, Daisuke; Cruz, Christina; Beck, Amanda; Lonardo, Fulvio; Wali, Anil; Pass, Harvey I
2009 Apr 15;15(8):2602-2611, Clinical cancer research
PURPOSE: Tumor extracellular matrix (ECM) plays a crucial role in cancer progression mediating and transforming host-tumor interactions. Targeting the ECM is becoming an increasingly promising therapeutic approach in cancer treatment. We find that one of the ECM proteins, HAPLN1, is overexpressed in the majority of mesotheliomas. This study was designed to characterize the protumorigenic role of HAPLN1 in mesothelioma. EXPERIMENTAL DESIGN: Overexpression of HAPLN1 was assessed and validated on a large set of normal/mesothelioma specimens on the RNA and protein levels. We also analyzed DNA copy number alterations in the HAPLN1 genomic locus using the array-based comparative genomic hybridization representational oligonucleotide microarray analysis tool. Tumorigenic activities of the HAPLN1 domains were evaluated in vitro on mesothelioma cells transfected with HAPLN1-expressing constructs. RESULTS: We found that HAPLN1 is 23-fold overexpressed in stage I mesothelioma and confirmed it for 76% samples (n = 53) on RNA and 97% (n = 40) on protein levels. The majority of lung cancers showed no differential expression of HAPLN1. Analysis of DNA copy number alterations identified recurrent gain in the 5q14.3 HAPLN1 locus in approximately 27% of tumors. Noteworthy, high expression of HAPLN1 negatively correlated with time to progression (P = 0.05, log-rank test) and overall survival (P = 0.006). Proliferation, motility, invasion, and soft-agar colony formation assays on mesothelioma cells overexpressing full-length HAPLN1 or its functional domains strongly supported the protumorigenic role of HAPLN1 and its SP-IgV domain. CONCLUSION: Overexpression of HAPLN1 and its SP-IgV domain increases tumorigenic properties of mesothelioma. Thus, targeting the SP-IgV domain may be one of the therapeutic approaches in cancer treatment
— id: 101351, year: 2009, vol: 15, page: 2602, stat: Journal Article,

Mechanisms of FUS1/TUSC2 deficiency in mesothelioma and its tumorigenic transcriptional effects
Ivanova, Alla V; Ivanov, Sergey V; Prudkin, Ljudmila; Nonaka, Daisuke; Liu, Zhandong; Tsao, Anne; Wistuba, Ignacio; Roth, Jack; Pass, Harvey I
2009 ;8:91-91, Molecular cancer
BACKGROUND: FUS1/TUSC2 is a novel tumor suppressor located in the critical 3p21.3 chromosomal region frequently deleted in multiple cancers. We previously showed that Tusc2-deficient mice display a complex immuno-inflammatory phenotype with a predisposition to cancer. The goal of this study was to analyze possible involvement of TUSC2 in malignant pleural mesothelioma (MPM) - an aggressive inflammatory cancer associated with exposure to asbestos. METHODS: TUSC2 insufficiency in clinical specimens of MPM was assessed via RT-PCR (mRNA level), Representational Oligonucleotide Microarray Analysis (DNA level), and immunohistochemical evaluation (protein level). A possible link between TUSC2 expression and exposure to asbestos was studied using asbestos-treated mesothelial cells and ROS (reactive oxygen species) scavengers. Transcripional effects of TUSC2 in MPM were assessed through expression array analysis of TUSC2-transfected MPM cells. RESULTS: Expression of TUSC2 was downregulated in approximately 84% of MM specimens while loss of TUSC2-containing 3p21.3 region observed in approximately 36% of MPMs including stage 1 tumors. Exposure to asbestos led to a transcriptional suppression of TUSC2, which we found to be ROS-dependent. Expression array studies showed that TUSC2 activates transcription of multiple genes with tumor suppressor properties and down-regulates pro-tumorigenic genes, thus supporting its role as a tumor suppressor. In agreement with our knockout model, TUSC2 up-regulated IL-15 and also modulated more than 40 other genes (approximately 20% of total TUSC2-affected genes) associated with immune system. Among these genes, we identified CD24 and CD274, key immunoreceptors that regulate immunogenic T and B cells and play important roles in systemic autoimmune diseases. Finally, clinical significance of TUSC2 transcriptional effects was validated on the expression array data produced previously on clinical specimens of MPM. In this analysis, 42 TUSC2 targets proved to be concordantly modulated in MM serving as disease discriminators. CONCLUSION: Our data support immuno-therapeutic potential of TUSC2, define its targets, and underscore its importance as a transcriptional stimulator of anti-tumorigenic pathways
— id: 108813, year: 2009, vol: 8, page: 91, stat: Journal Article,

Mechanisms of FUS1 deficiency in mesothelioma and its tumorigenic transcriptional effects
Ivanova, AV; Ivanov, SV; Prudkin, L; Nonaka, D; Liu, ZD; Tsao, A; Roth, J; Wistuba, I; Pass, HI
2009 SEP ;4(9):S764-S764, Journal of thoracic oncology
— id: 102471, year: 2009, vol: 4, page: S764, stat: Journal Article,

Multicenter phase II trial of neoadjuvant pemetrexed plus cisplatin followed by extrapleural pneumonectomy and radiation for malignant pleural mesothelioma
Krug, Lee M; Pass, Harvey I; Rusch, Valerie W; Kindler, Hedy L; Sugarbaker, David J; Rosenzweig, Kenneth E; Flores, Raja; Friedberg, Joseph S; Pisters, Katherine; Monberg, Matthew; Obasaju, Coleman K; Vogelzang, Nicholas J
2009 Jun 20;27(18):3007-3013, Journal of clinical oncology
PURPOSE: Neoadjuvant pemetrexed plus cisplatin was administered, followed by extrapleural pneumonectomy (EPP) and hemithoracic radiation (RT), to assess the feasibility and efficacy of trimodality therapy in stage I to III malignant pleural mesothelioma. PATIENTS AND METHODS: Requirements included stage T1-3 N0-2 disease, no prior surgical resection, adequate organ function (including predicted postoperative forced expiratory volume in 1 second > or = 35%), and performance status 0 to 1. Patients received pemetrexed 500 mg/m(2) plus cisplatin 75 mg/m(2) for four cycles. Patients without disease progression underwent EPP followed by RT (54 Gy). The primary end point was pathologic complete response (pCR) rate. RESULTS: Seventy-seven patients received chemotherapy. All four cycles were administered to 83% of patients. The radiologic response rate was 32.5% (95% CI, 22.2 to 44.1). Fifty-seven patients proceeded to EPP, which was completed in 54 patients. Three pCRs were observed (5% of EPP). Forty of 44 patients completed irradiation. Median survival in the overall population was 16.8 months (95% CI, 13.6 to 23.2 months; censorship, 33.8%). Patients completing all therapy had a median survival of 29.1 months and a 2-year survival rate of 61.2%. Radiologic response of complete or partial response was associated with a median survival of 26.0 months compared with 13.9 months for patients with stable disease or progressive disease (P = .05). CONCLUSION: This multicenter trial showed that trimodality therapy with neoadjuvant pemetrexed plus cisplatin is feasible with a reasonable long-term survival rate, particularly for patients who completed all therapy. Radiologic response to chemotherapy, but not sex, histology, disease stage, or nodal status, was associated with improved survival
— id: 101349, year: 2009, vol: 27, page: 3007, stat: Journal Article,

Phase II clinical trial of zileuton in persons with bronchial dysplasia
Kucuk, O; Pass, H; Lonardo, F; Gazdar, A; Madan, S; Abrams, J; Maddipati, KR; Upfal, M; Soubani, AO; Honn, K; Szabo, E
2009 SEP ;4(9):S137-S137, Journal of thoracic oncology
— id: 102463, year: 2009, vol: 4, page: S137, stat: Journal Article,

Diagnostic Assay Based on hsa-miR-205 Expression Distinguishes Squamous From Non-Squamous Non-Small-Cell Lung Carcinoma
Lebanony, Danit; Benjamin, Hila; Gilad, Shlomit; Ezagouri, Meital; Dov, Avital; Ashkenazi, Karin; Gefen, Nir; Izraeli, Shai; Rechavi, Gideon; Pass, Harvey; Nonaka, Daisuke; Li, Junjie; Spector, Yael; Rosenfeld, Nitzan; Chajut, Ayelet; Cohen, Dalia; Aharonov, Ranit; Mansukhani, Mahesh
2009 Apr 20;27(12):2030-2037, Journal of clinical oncology
PURPOSE: Recent advances in treatment of lung cancer require greater accuracy in the subclassification of non-small-cell lung cancer (NSCLC). Targeted therapies which inhibit tumor angiogenesis pose higher risk for adverse response in cases of squamous cell carcinoma. Interobserver variability and the lack of specific, standardized assays limit the current abilities to adequately stratify patients for such treatments. In this study, we set out to identify specific microRNA biomarkers for the identification of squamous cell carcinoma, and to use such markers for the development of a standardized assay. PATIENTS AND METHODS: High-throughput microarray was used to measure microRNA expression levels in 122 adenocarcinoma and squamous NSCLC samples. A quantitative real-time polymerase chain reaction (qRT-PCR) platform was used to verify findings in an independent set of 20 NSCLC formalin-fixed, paraffin-embedded (FFPE) samples, and to develop a diagnostic assay using an additional set of 27 NSCLC FFPE samples. The assay was validated using an independent blinded cohort consisting of 79 NSCLC FFPE samples. RESULTS: We identified hsa-miR-205 as a highly specific marker for squamous cell lung carcinoma. A microRNA-based qRT-PCR assay that measures expression of hsa-miR-205 reached sensitivity of 96% and specificity of 90% in the identification of squamous cell lung carcinomas in an independent blinded validation set. CONCLUSION: Hsa-miR-205 is a highly accurate marker for lung cancer of squamous histology. The standardized diagnostic assay presented here can provide highly accurate subclassification of NSCLC patients
— id: 96873, year: 2009, vol: 27, page: 2030, stat: Journal Article,

Current status of screening for malignant pleural mesothelioma
Pass, Harvey I; Carbone, Michele
2009 Summer;21(2):97-104, Seminars in thoracic & cardiovascular surgery
Malignant mesothelioma is characterized by its association with asbestos, its long latency period, and the propensity for the diagnosis to be obtained in the later stages of the disease. Because the high-risk cohorts for mesothelioma are fairly well defined by the association with asbestos, and the exposure is usually in the workplace, it is hypothesized that early detection of the disease could (1) find patients at an earlier, more treatable stage and (2) result in prolonged survival over the present median 12 months from the start of therapy. Many studies have used standard chest X-ray to characterize changes associated with asbestos-exposed individuals, but the insensitivity of X-ray in screening patients with mesothelioma has never supported the wide-scale adaptation of such an effort. With the advent of computerized tomography, prospective trials, many of which are chiefly prevalence detection studies, have been performed and stress the importance for proper detailing by carefully qualifying suspicious changes, as well as defining the correct cohort to screen. Most recently, serum biomarkers with the potential to discriminate asbestos-exposed, non-cancer-bearing individuals from those with mesothelioma have been investigated both at single institutions and with multi-institutional-blinded trials. These markers, including soluble mesothelin-related protein, osteopontin, and megakaryocyte potentiating factor, may, in the future, be incorporated into a screening algorithm for high-risk asbestos-exposed individuals to help monitor these cohorts in a noninvasive fashion and guide the use of computerized tomography
— id: 104359, year: 2009, vol: 21, page: 97, stat: Journal Article,

Biomarker development: muddy waters
Pass, HI
2009 SEP ;4(9):S7-S7, Journal of thoracic oncology
— id: 102462, year: 2009, vol: 4, page: S7, stat: Journal Article,

Translational research and mesothelioma
Pass, HI
2009 SEP ;4(9):S254-S254, Journal of thoracic oncology
— id: 102464, year: 2009, vol: 4, page: S254, stat: Journal Article,

Preliminary validation of a lung cancer diagnostic biomarker panel identified through mass spectrometry-based discovery in cancer tissues and cell lines
Rom, WN; Pass, HI; FitzHugh, W; Dhariwal, G; Heidbrink, J; Ruben, SM; Birse, CE
2009 SEP ;4(9):S380-S381, Journal of thoracic oncology
— id: 102465, year: 2009, vol: 4, page: S380, stat: Journal Article,

Activated cAMP response element binding protein is overexpressed in human mesotheliomas and inhibits apoptosis
Shukla, Arti; Bosenberg, Marcus W; MacPherson, Maximilian B; Butnor, Kelly J; Heintz, Nicholas H; Pass, Harvey I; Carbone, Michele; Testa, Joseph R; Mossman, Brooke T
2009 Nov;175(5):2197-2206, American journal of pathology
Little is known about the cellular mechanisms contributing to the development and chemoresistance of malignant mesothelioma (MM), an aggressive asbestos-associated tumor. A human mesothelial cell line (LP9/TERT-1) and isolated human pleural mesothelial cells showed rapid and protracted asbestos-induced cAMP response element binding protein (CREB1) phosphorylation, which was inhibited in LP9/TERT-1 cells by small molecule inhibitors of epidermal growth factor receptor phosphorylation and protein kinase A. Asbestos increased expression of several CREB target genes (c-FOS, EGR-1, MKP1, BCL2, and MMP13) and apoptosis, which was enhanced using small interfering CREB. Human MM tissue arrays showed elevated endogenous levels of phosphorylated nuclear CREB1 as compared with reactive mesothelial hyperplasias and normal lung tissue. Significantly increased phosphorylated CREB1 and mRNA levels of BCL2, c-FOS, MMP9, and MMP13 were also observed in MM cells in vitro, which were further augmented after addition of Doxorubicin (Dox). Small interfering CREB inhibited migration of MMs, increased apoptosis by Dox, and decreased BCL2 and BCL-xL expression, suggesting a role for these molecules in CREB-induced MM survival. These data indicate that CREB1 and its target genes are up-regulated in asbestos-exposed human mesothelial cells through an epidermal growth factor receptor/protein kinase A pathway. Since activated CREB1 also is increased endogenously in human MM and modifies migration and resistance to Dox-induced apoptosis, inhibition of CREB1 may be a new strategy for MM therapy
— id: 110888, year: 2009, vol: 175, page: 2197, stat: Journal Article,

Alterations in Gene Expression in Human Mesothelial Cells Correlate with Mineral Pathogenicity
Shukla, Arti; MacPherson, Maximilian B; Hillegass, Jedd; Ramos-Nino, Maria E; Alexeeva, Vlada; Vacek, Pamela M; Bond, Jeffrey P; Pass, Harvey I; Steele, Chad; Mossman, Brooke T
2009 Jul;41(1):114-123, American journal of respiratory cell & molecular biology
Human mesothelial cells (LP9/TERT-1) were exposed to low and high (15 and 75 microm2/cm2 dish) equal surface area concentrations of crocidolite asbestos, nonfibrous talc, fine titanium dioxide (TiO2), or glass beads for 8 or 24 h. RNA was then isolated for Affymetrix microarrays, GeneSifter analysis and QRT-PCR. Gene changes by asbestos were concentration- and time-dependent. At low nontoxic concentrations, asbestos caused significant changes in mRNA expression of 29 genes at 8 h and 205 genes at 24 h, whereas changes in mRNA levels of 236 genes occurred in cells exposed to high concentrations of asbestos for 8 h. Human primary pleural mesothelial cells also showed the same patterns of increased gene expression by asbestos. Nonfibrous talc at low concentrations in LP9/TERT-1 mesothelial cells caused increased expression of 1 gene Activating Transcription Factor 3 (ATF3) at 8 h and no changes at 24 h, whereas expression levels of 30 genes were elevated at 8 h at high talc concentrations. Fine TiO2 or glass beads caused no changes in gene expression. In human ovarian epithelial (IOSE) cells, asbestos at high concentrations elevated expression of 2 genes (NR4A2, MIP2) at 8 h and 16 genes at 24 h that were distinct from those elevated in mesothelial cells. Since ATF3 was the most highly expressed gene by asbestos, its functional importance in cytokine production by LP9/TERT-1 cells was assessed using siRNA approaches. Results reveal that ATF3 modulates production of inflammatory cytokines (IL-1beta, IL-13, G-CSF) and growth factors (VEGF and PDGF-BB) in human mesothelial cells
— id: 96979, year: 2009, vol: 41, page: 114, stat: Journal Article,

A histone deacetylase inhibitor LBH589 downregulates XIAP in mesothelioma cell lines which is likely responsible for increased apoptosis with TRAIL
Symanowski, James; Vogelzang, Nicholas; Zawel, Leigh; Atadja, Peter; Pass, Harvey; Sharma, Sunil
2009 Feb;4(2):149-160, Journal of thoracic oncology
PURPOSE: Tumor necrosis factor-alpha-related apoptosis-inducing ligand (TRAIL) is a member of tumor necrosis factor family and it is important for ligand induced apoptosis in tumor cells. TRAIL has been shown to be synergistic with a variety of chemotherapies and targeted agents. In the study, a combination of TRAIL and a histone deacetylase inhibitor LBH589 was studied in mesothelioma cell lines. EXPERIMENTAL DESIGN: Five mesothelioma cell lines and two normal cell lines were tested for cell growth inhibition and apoptosis using high-throughput assays in the presence of LBH589, TRAIL and a combination of the two. Caspase induction was studied and levels of X-linked inhibitor of apoptosis (XIAP) were tested using Western blotting. A combination of a direct inhibitor of XIAP was also tested in combination with TRAIL. RESULTS: In mesothelioma cell lines, a combination of LBH589 and TRAIL markedly increased cell growth inhibition and apoptosis when compared with the effect on normal cell lines. LBH589 and TRAIL appeared to induce higher levels of caspase 3 and 7 and this appeared to be closely related to ability of LBH589 to degrade XIAP. In addition, a direct inhibitor of XIAP was also sensitized cells to TRAIL apoptosis, providing an indirect confirmation for XIAP degradation as a possible mechanism of synergy. CONCLUSIONS: In mesothelioma cell lines, LBH589 increases the sensitivity to TRAIL. In addition, at least partly, the mechanism of this induction of TRAIL sensitivity is due to LBH589 related degradation of XIAP. These results provide initial evidence for testing this combination in clinical trials
— id: 101354, year: 2009, vol: 4, page: 149, stat: Journal Article,

Local surgical, ablative, and radiation treatment of metastases
Timmerman, Robert D; Bizekis, Costas S; Pass, Harvey I; Fong, Yuman; Dupuy, Damian E; Dawson, Laura A; Lu, David
2009 May-Jun;59(3):145-170, CA: a cancer journal for clinicians
Because local therapies directed toward a specific tumor mass are known to be effective for treating early-stage cancers, it should be no surprise that there has been considerable historical experience using local therapies for metastatic disease. In more recent years, increasing interest in the use of local therapy for metastases likely has arisen from improvements in systemic therapy. In the absence of effective systemic therapies, such local treatments were often considered futile given both the difficulty in eliminating all sites of identifiable metastatic disease as well as realities regarding the rapid natural history of uncontrolled tumor dissemination. However, with a higher likelihood of patients surviving longer after effective systemic therapy, even if not cured, the goal of the eradication of residual metastases via potent local therapies can be rationalized. However, this rationalization should be evidence-based so as to avoid harming patients for no established benefit. Although surgical metastectomy remains the most common and first-line standard among local therapies, nonsurgical alternatives, including thermal ablation and stereotactic body radiotherapy, have become increasingly popular because they are generally less invasive than surgery and have demonstrated considerable promise in eradicating macroscopic tumor. Rather than eliminating the need for local therapies, improvements in systemic therapies appear to be increasing the prudent utilization of modern local therapies in patients presenting with more advanced cancer
— id: 101350, year: 2009, vol: 59, page: 145, stat: Journal Article,

The IASLC Lung Cancer Staging Project: proposals regarding the relevance of TNM in the pathologic staging of small cell lung cancer in the forthcoming (seventh) edition of the TNM classification for lung cancer
Vallieres, Eric; Shepherd, Frances A; Crowley, John; Van Houtte, Paul; Postmus, Pieter E; Carney, Desmond; Chansky, Kari; Shaikh, Zeba; Goldstraw, Peter; Pass, Harvey I
2009 Sep;4(9):1049-1059, Journal of thoracic oncology
INTRODUCTION: For more than 50 years, small cell lung cancer (SCLC) has been staged mainly as either limited or extensive stage disease. Small published series of resected SCLC have suggested that the tumor, node, metastases (TNM) pathologic staging correlates with the survival of resected patients. Recent analysis of the 8088 cases of SCLC in the International Association for the Study of Lung Cancer (IASLC) database demonstrated the usefulness of clinical TNM staging in this malignancy. The IASLC data bank contains an unprecedented number of resected SCLC cases with pathologic staging information. This analysis was undertaken to examine the impact of the TNM system on the pathologic staging of SCLC and to assess the new IASLC proposals in this subtype of lung cancer. METHODS: Using the IASLC database, survival analyses were performed for resected patients with SCLC. Prognostic groups were compared, and the new IASLC TNM proposals were applied to this population and to the Surveillance, Epidemiology, and End Results (SEER) database. RESULTS: The IASLC database contained 349 cases of resected SCLC where pathologic TNM staging was available. Survival after resection correlated with both T and N category with nodal status having a stronger influence on survival. Stage groupings using the 6th edition of TNM clearly identify patient subgroups with different prognoses. The IASLC proposals for the 7th edition of TNM classification also apply to this population and to the SEER database. CONCLUSION: This analysis further strengthens our previous recommendation to use TNM staging for all SCLC cases
— id: 110921, year: 2009, vol: 4, page: 1049, stat: Journal Article,

Correlation between plasma osteopontin levels and aortic valve calcification: potential insights into the pathogenesis of aortic valve calcification and stenosis
Yu, Pey-Jen; Skolnick, Adam; Ferrari, Giovanni; Heretis, Katherine; Mignatti, Paolo; Pintucci, Giuseppe; Rosenzweig, Barry; Diaz-Cartelle, Juan; Kronzon, Itzhak; Perk, Gila; Pass, Harvey I; Galloway, Aubrey C; Grossi, Eugene A; Grau, Juan B
2009 Jul;138(1):196-199, Journal of thoracic & cardiovascular surgery
OBJECTIVE: The inflammatory process of aortic stenosis involves the differentiation of aortic valve myofibroblasts into osteoblasts. Osteopontin, a proinflammatory glycoprotein, both stimulates differentiation of myofibroblasts and regulates the deposition of calcium by osteoblasts. Osteopontin levels are increased in patients with such conditions as end-stage renal disease, ectopic calcification, and autoimmune disease. We hypothesized that increased plasma osteopontin levels might be associated with the presence of aortic valve calcification and stenosis. METHODS: Venous blood from volunteers older than 65 years undergoing routine echocardiographic analysis or aortic valve surgery for aortic stenosis was collected. Plasma osteopontin levels were measured by means of enzyme-linked immunosorbent assay. The presence of aortic stenosis was defined as an aortic valve area of less than 2.0 cm(2). Aortic valve calcification was assessed by using a validated echocardiographic grading system (1, none; 2, mild; 3, moderate; 4, severe). Comparisons were performed with nonpaired t tests. RESULTS: Aortic stenosis was present in 23 patients (mean age, 78 years) and was absent in 7 patients (mean age, 72 years). Aortic valve calcification scores were 3.5 +/- 0.6 and 1.3 +/- 0.5 in patients with and without aortic stenosis, respectively (P < .001). Patients with no or mild aortic valve calcification had lower osteopontin levels compared with patients with moderate or severe aortic valve calcification (406.1 +/- 165.8 vs 629.5 +/- 227.5 ng/mL, P = .01). Similarly, patients with aortic stenosis had higher osteopontin levels compared with patients without aortic stenosis (652.2 +/- 218.7 vs 379.7 +/- 159.9 ng/mL, P < .01). CONCLUSION: Increased levels of plasma osteopontin are associated with the presence of aortic valve calcification and stenosis. These findings suggest that osteopontin might play a functional role in the pathogenesis of calcific aortic stenosis
— id: 100629, year: 2009, vol: 138, page: 196, stat: Journal Article,

National Mesothelioma Virtual Bank: a standard based biospecimen and clinical data resource to enhance translational research
Amin, Waqas; Parwani, Anil V; Schmandt, Linda; Mohanty, Sambit K; Farhat, Ghada; Pople, Andrew K; Winters, Sharon B; Whelan, Nancy B; Schneider, Althea M; Milnes, John T; Valdivieso, Federico A; Feldman, Michael; Pass, Harvey I; Dhir, Rajiv; Melamed, Jonathan; Becich, Michael J
2008 ;8:236-236, BMC cancer
BACKGROUND: Advances in translational research have led to the need for well characterized biospecimens for research. The National Mesothelioma Virtual Bank is an initiative which collects annotated datasets relevant to human mesothelioma to develop an enterprising biospecimen resource to fulfill researchers' need. METHODS: The National Mesothelioma Virtual Bank architecture is based on three major components: (a) common data elements (based on College of American Pathologists protocol and National North American Association of Central Cancer Registries standards), (b) clinical and epidemiologic data annotation, and (c) data query tools. These tools work interoperably to standardize the entire process of annotation. The National Mesothelioma Virtual Bank tool is based upon the caTISSUE Clinical Annotation Engine, developed by the University of Pittsburgh in cooperation with the Cancer Biomedical Informatics Grid (caBIG, see http://cabig.nci.nih.gov). This application provides a web-based system for annotating, importing and searching mesothelioma cases. The underlying information model is constructed utilizing Unified Modeling Language class diagrams, hierarchical relationships and Enterprise Architect software. RESULT: The database provides researchers real-time access to richly annotated specimens and integral information related to mesothelioma. The data disclosed is tightly regulated depending upon users' authorization and depending on the participating institute that is amenable to the local Institutional Review Board and regulation committee reviews. CONCLUSION: The National Mesothelioma Virtual Bank currently has over 600 annotated cases available for researchers that include paraffin embedded tissues, tissue microarrays, serum and genomic DNA. The National Mesothelioma Virtual Bank is a virtual biospecimen registry with robust translational biomedical informatics support to facilitate basic science, clinical, and translational research. Furthermore, it protects patient privacy by disclosing only de-identified datasets to assure that biospecimens can be made accessible to researchers
— id: 95437, year: 2008, vol: 8, page: 236, stat: Journal Article,

Ranpirnase as a potential antitumor ribonuclease treatment for mesothelioma and other malignancies
Beck, Amanda K; Pass, Harvey I; Carbone, Michele; Yang, Haining
2008 Jun;4(3):341-349, Future Oncology
Ranpirnase, originally isolated from oocytes of the northern leopard frog (Rana pipiens), is a member of the pancreatic RNase A superfamily of ribonucleases. Ranpirnase exerts antiproliferative and cytotoxic effects in vitro and in vivo and has been shown to act synergistically with different cancer therapeutic agents. The cytotoxic and cytostatic effects of ranpirnase are the consequence of tRNA degradation that results in the disruption of protein translation and the induction of programmed cell death (apoptosis). Ranpirnase has been shown to target malignant cells both in human cancer cell lines and in animal models, and has demonstrated efficacy in the treatment of several human cancers in clinical studies. Most clinical studies have been conducted in patients with malignant mesothelioma, and a confirmatory Phase IIIb trial is currently underway for the treatment of this disease. Owing to its selective destruction of malignant cells and favorable toxicology profile, ranpirnase is a promising antitumor agent with ideal attributes that are generally lacking in conventional cytotoxic drugs
— id: 80617, year: 2008, vol: 4, page: 341, stat: Journal Article,

Serum mesothelin for early detection of the asbestos-induced cancer malignant mesothelioma
Creaney, J; Robinson, BWS; Segal, A; Musk, AW; de Klerk, N; Pass, HI; Skates, SJ
2008 DEC 11 ;4(3):169-170, Cancer biomarkers : section A of Disease markers
— id: 91476, year: 2008, vol: 4, page: 169, stat: Journal Article,

Extrapleural pneumonectomy versus pleurectomy/decortication in the surgical management of malignant pleural mesothelioma: results in 663 patients
Flores, Raja M; Pass, Harvey I; Seshan, Venkatraman E; Dycoco, Joseph; Zakowski, Maureen; Carbone, Michele; Bains, Manjit S; Rusch, Valerie W
2008 Mar;135(3):620-6, 626.e1, Journal of thoracic & cardiovascular surgery
OBJECTIVE: The optimal procedure for resection of malignant pleural mesothelioma is controversial, partly because previous analyses include small numbers of patients. We performed a multi-institutional study to increase statistical power to detect significant differences in outcome between extrapleural pneumonectomy and pleurectomy/decortication. METHODS: Patients with malignant pleural mesothelioma who underwent extrapleural pneumonectomy or pleurectomy/decortication at 3 institutions were identified. Survival and prognostic factors were analyzed by the Kaplan-Meier method, log-rank test, and Cox proportional hazards analysis. RESULTS: From 1990 to 2006, 663 consecutive patients (538 men and 125 women) underwent resection. The median age was 63 years (range, 26-93 years). The operative mortality was 7% for extrapleural pneumonectomy (n = 27/385) and 4% for pleurectomy/decortication (n = 13/278). Significant survival differences were seen for American Joint Committee on Cancer stages 1 to 4 (P < .001), epithelioid versus non-epithelioid histology (P < .001), extrapleural pneumonectomy versus pleurectomy/decortication (P < .001), multimodality therapy versus surgery alone (P < .001), and gender (P < .001). Multivariate analysis demonstrated a hazard rate of 1.4 for extrapleural pneumonectomy (P < .001) controlling for stage, histology, gender, and multimodality therapy. CONCLUSION: Patients who underwent pleurectomy/decortication had a better survival than those who underwent extrapleural pneumonectomy; however, the reasons are multifactorial and subject to selection bias. At present, the choice of resection should be tailored to the extent of disease, patient comorbidities, and type of multimodality therapy planned
— id: 96982, year: 2008, vol: 135, page: 620, stat: Journal Article,

Opposite effects of Notch-1 and Notch-2 on mesothelioma cell survival under hypoxia are exerted through the Akt pathway
Graziani, Irene; Eliasz, Sandra; De Marco, Melissa A; Chen, Yuanbin; Pass, Harvey I; De May, Richard M; Strack, Peter R; Miele, Lucio; Bocchetta, Maurizio
2008 Dec 1;68(23):9678-9685, Cancer research
Malignant mesothelioma (MM) is a cancer of the lining of the lungs, heart, and intestine and is known to respond poorly to chemotherapy. Here we show that malignant mesothelial cells have an elevated Notch signaling pathway compared with normal human mesothelial cells. We studied the role of Notch in MM under normoxic and hypoxic conditions, the latter condition best recapitulating the MM microenvironment. Genetic and chemical modulation of the Notch pathway indicated that MM cells are dependent on Notch signaling. More specifically, this signaling was Notch-1 dependent as the result of its negative transcriptional regulation on phosphatase and tensin homologue (PTEN), which led to activation of the prosurvival phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling pathway. Our study also provides evidence that whereas Notch-1 is elevated in the malignant setting, Notch-2 is diminished. This differential expression of the two Notch isoforms benefits cancer cell survival because reexpression of Notch-2 was toxic to MM cells. The mechanism of Notch-2 toxicity to MM cells countered that of Notch-1, as it was the result of positive transcriptional regulation of PTEN and inhibition of the PI3K/Akt/mTOR signaling pathway. These results provide new insight into the role of Notch in MM and suggest that Notch pathway inhibitors may be useful in the treatment of this deadly disease
— id: 96980, year: 2008, vol: 68, page: 9678, stat: Journal Article,

Current concepts in malignant pleural mesothelioma
Kaufman, Andrew J; Pass, Harvey I
2008 Feb;8(2):293-303, Expert review of anticancer therapy
Malignant pleural mesothelioma (MPM) is a rare but lethal cancer associated with asbestos exposure. Worldwide, the incidence of MPM is expected to increase over the next 20 years. The molecular and genetic profiling of MPM tumors and patients, and improved understanding of the pathogenesis of MPM may lead to novel diagnostic, preventative and therapeutic strategies. Treatment options for MPM remain limited and no consensus exists at this time. Multimodality therapy that combines surgery, chemotherapy and radiation offers the best chance for long-term survival in select patients
— id: 76469, year: 2008, vol: 8, page: 293, stat: Journal Article,

The aberrant promoter methylation of BMP3b and BMP6 in malignant pleural mesotheliomas
Kimura, Kentaro; Toyooka, Shinichi; Tsukuda, Kazunori; Yamamoto, Hiromasa; Suehisa, Hiroshi; Soh, Junichi; Otani, Hiroki; Kubo, Takafumi; Aoe, Keisuke; Fujimoto, Nobukazu; Kishimoto, Takumi; Sano, Yoshifumi; Pass, Harvery I; Date, Hiroshi
2008 Nov;20(5):1265-1268, Oncology reports
Bone morphogenetic proteins (BMPs) belong to the transforming growth factor-beta superfamily. Recent studies have showed that aberrant methylation of BMP genes is present in several types of human cancer. We examined the expression and methylation status of BMP3b and BMP6 in malignant pleural mesotheliomas (MPMs). The expression status of BMP3b, and BMP6 mRNAs were examined in seven MPM cell lines by RT-PCR assay. The expression of BMP3b was completely suppressed in 2 and partially suppressed in 2 of 7 cell lines and expression of BMP6 was partially suppressed in 2 cell lines. Methylation status of BMP3b in cell lines was determined by methylation-specific assay to find aberrant methylation in 6 cell lines which include 4 cell lines with suppressed BMP3b expression. Partial methylation of BMP6 was found in 2 cell lines whose expression was partially suppressed. Treatment with 5-Aza-dC restored BMP3b expression in methylated cell lines. Next, we examined the methylation status in 57 surgically resected MPM cases and found aberrant methylation of BMP3b in 9 (53%) out of 17 cases from Japan and 3 (8%) of 40 cases from USA and that of BMP6 in 4 (24%) cases from Japan and 12 (30%) cases from USA, showing significant difference in frequency of BMP3b methylation between MPMs of the two countries (P=0.0004). Our study indicated that BMP3b and BMP6 genes were suppressed by DNA methylation and methylation of BMP3b is significantly frequent in Japanese MPMs, suggesting its pathogenic role and the ethnic difference in MPMs
— id: 101363, year: 2008, vol: 20, page: 1265, stat: Journal Article,

The development and deployment of Common Data Elements for tissue banks for translational research in cancer - an emerging standard based approach for the Mesothelioma Virtual Tissue Bank
Mohanty, Sambit K; Mistry, Amita T; Amin, Waqas; Parwani, Anil V; Pople, Andrew K; Schmandt, Linda; Winters, Sharon B; Milliken, Erin; Kim, Paula; Whelan, Nancy B; Farhat, Ghada; Melamed, Jonathan; Taioli, Emanuela; Dhir, Rajiv; Pass, Harvey I; Becich, Michael J
2008 ;8:91-91, BMC cancer
BACKGROUND: Recent advances in genomics, proteomics, and the increasing demands for biomarker validation studies have catalyzed changes in the landscape of cancer research, fueling the development of tissue banks for translational research. A result of this transformation is the need for sufficient quantities of clinically annotated and well-characterized biospecimens to support the growing needs of the cancer research community. Clinical annotation allows samples to be better matched to the research question at hand and ensures that experimental results are better understood and can be verified. To facilitate and standardize such annotation in bio-repositories, we have combined three accepted and complementary sets of data standards: the College of American Pathologists (CAP) Cancer Checklists, the protocols recommended by the Association of Directors of Anatomic and Surgical Pathology (ADASP) for pathology data, and the North American Association of Central Cancer Registry (NAACCR) elements for epidemiology, therapy and follow-up data. Combining these approaches creates a set of International Standards Organization (ISO) - compliant Common Data Elements (CDEs) for the mesothelioma tissue banking initiative supported by the National Institute for Occupational Safety and Health (NIOSH) of the Center for Disease Control and Prevention (CDC). METHODS: The purpose of the project is to develop a core set of data elements for annotating mesothelioma specimens, following standards established by the CAP checklist, ADASP cancer protocols, and the NAACCR elements. We have associated these elements with modeling architecture to enhance both syntactic and semantic interoperability. The system has a Java-based multi-tiered architecture based on Unified Modeling Language (UML). RESULTS: Common Data Elements were developed using controlled vocabulary, ontology and semantic modeling methodology. The CDEs for each case are of different types: demographic, epidemiologic data, clinical history, pathology data including block level annotation, and follow-up data including treatment, recurrence and vital status. The end result of such an effort would eventually provide an increased sample set to the researchers, and makes the system interoperable between institutions. CONCLUSION: The CAP, ADASP and the NAACCR elements represent widely established data elements that are utilized in many cancer centers. Herein, we have shown these representations can be combined and formalized to create a core set of annotations for banked mesothelioma specimens. Because these data elements are collected as part of the normal workflow of a medical center, data sets developed on the basis of these elements can be easily implemented and maintained
— id: 95438, year: 2008, vol: 8, page: 91, stat: Journal Article,

Surgery : basic science and clinical evidence
Norton JA; Barie PS; Bollinger RR; Chang AE; Lowry SF; Mulvihill SJ; Pass HI; Thompson RW
New York : Springer 2008,
— id: 2224, year: 2008, vol: , page: , stat: ,

Invited commentary
Pass, Harvey
2008 Dec;86(6):1744-1744, Annals of thoracic surgery
— id: 101356, year: 2008, vol: 86, page: 1744, stat: Journal Article,

The mets, the scalpels, and possibly the beams
Pass, Harvey
2008 Nov;3(11):1211-1212, Journal of thoracic oncology
— id: 101357, year: 2008, vol: 3, page: 1211, stat: Journal Article,

Lung cancer staging techniques and induction therapy: maybe timing is everything
Pass, Harvey I
2008 Jul 10;26(20):3306-3307, Journal of clinical oncology
— id: 96981, year: 2008, vol: 26, page: 3306, stat: Journal Article,

A phase II trial of tetrathiomolybdate after surgery for malignant mesothelioma: final results
Pass, Harvey I; Brewer, George J; Dick, Robert; Carbone, Michele; Merajver, Sofia
2008 Aug;86(2):383-389, Annals of thoracic surgery
BACKGROUND: Tetrathiomolybdate (TM) is an oral copper-depleting agent that has been shown to inhibit angiogenesis, and angiogenesis is a predictor of poor prognosis in malignant pleural mesothelioma. We hypothesized that cytoreduction of malignant pleural mesothelioma followed by TM will delay time to progression. METHODS: Between November 2000 and August 2003, 30 patients with malignant pleural mesothelioma received postoperative TM beginning 4 to 6 weeks after surgery at a dose adjusted to keep ceruloplasmin between 5 and 15 mg/dL). Time to progression was compared with the 55 stage I and II patients and 109 stage III patients previously treated with cytoreduction by one of us (H.P.). RESULTS: The 30 patients (25 men, 5 women; 13 stage I and II, 17 stage III), median age 67 years (range, 49-81 years), remained on TM a median of 14.9 months (range, 2 to 57 months). All patients reached target ceruloplasmin levels at a mean of 34 +/- 2 days (95% confidence interval, 30 to 39 days), and vascular endothelial growth factor levels at baseline (ceruloplasmin = 45.2 +/- 2 mg/dL) decreased from 2,086 +/- 390 pg/mL to 1,250 +/- 712 pg/mL (p < 0.002) at target ceruloplasmin (13 +/- 2 mg/dL; p < 0.0001 from baseline). The time to progression for all stage I or II TM patients was 20 months whereas that of 55 stage I or II non-TM-treated patients was 10 months (p = 0.046 versus TM). No differences in time to progression for the stage III TM patents from surgery were seen (7 months). CONCLUSIONS: Tetrathiomolybdate has antiangiogenic effects in malignant pleural mesothelioma patients after resection of gross disease, and exhibits minimal toxicity and comparable efficacy to previous multimodality trials. Tetrathiomolybdate should be evaluated for efficacy in combination with standard malignant pleural mesothelioma regimens, as well as for postsurgical maintenance therapy
— id: 82920, year: 2008, vol: 86, page: 383, stat: Journal Article,

Soluble mesothelin-related peptide level elevation in mesothelioma serum and pleural effusions
Pass, Harvey I; Wali, Anil; Tang, Naimei; Ivanova, Alla; Ivanov, Sergey; Harbut, Michael; Carbone, Michele; Allard, Jeffrey
2008 Jan;85(1):265-272, Annals of thoracic surgery
BACKGROUND: Soluble mesothelin-related peptide (SMRP) is a potential marker for malignant pleural mesothelioma (MPM), which may be useful for screening high-risk asbestos-exposed individuals. METHODS: We evaluated SMRP in serum from MPM patients (n = 90), lung cancer patients (n = 170), age and tobacco-matched asbestos-exposed individuals (n = 66), and in MPM pleural effusions (n = 45), benign effusions (n = 30), and non-MPM effusions (n = 20) using the MesoMark enzyme-linked immunosorbent assay kit (Fujirebio Diagnostics, Malvern, PA). Receiver operating characteristic (ROC) curves were used to define true and false positive rates at various cutoffs. RESULTS: Mean serum SMRP levels were higher in MPM compared with lung cancer (5.67 +/- 0.82 nM [mean +/- standard error of the mean vs 1.99 +/- 0.43 nM, p < 0.001), and stage I MPM SMRP levels (n = 12; 2.09 +/- 0.41 nM) were significantly higher than those in asbestos-exposed individuals (0.99 +/- 0.09 nM, p = 0.02, respectively). Stage 2 to 4 SMRP serum levels were significantly higher than those for stage 1 MPM. The area under the ROC curve for serum SMRP was 0.81 for differentiating MPM and asbestos-exposed individuals; cutoff = 1.9 nM (sensitivity = 60%, specificity = 89%). The MPM pleural effusion SMRP was significantly higher than benign or other non-MPM pleural effusions (65.57 +/- 11.33 nM vs 27.46 +/- 11.25 nM [p = 0.003] and 18.99 +/- 7.48 nM [p = 0.044], respectively). CONCLUSIONS: These data support SMRP as a promising marker for MPM in both serum and pleural effusion fluid, and justify prospective screening studies of SMRP in combination with other markers for screening of asbestos-exposed cohorts
— id: 75721, year: 2008, vol: 85, page: 265, stat: Journal Article,

The American-Australian Mesothelioma Consortium: EDRN Mesothelioma Biomarker Discovery Laboratory
Pass, HI; Beck, A; Ianova, A; Ivanov, S; Goparaju, C; Donington, J; Creaney, J; Robinson, B
2008 DEC 11 ;4(3):188-190, Cancer biomarkers : section A of Disease markers
— id: 91477, year: 2008, vol: 4, page: 188, stat: Journal Article,

The American-Australian Mesothelioma Consortium: DRN Mesothelioma Biomarker Discovery Laboratory
Pass, HI; Beck, A; Ivanova, A; Ivanov, S; Goparaju, C; Donington, J; Creaney, J; Robinson, B
2008 DEC 11 ;4(3):155-158, Cancer biomarkers : section A of Disease markers
— id: 91474, year: 2008, vol: 4, page: 155, stat: Journal Article,

Detection of lung cancer using weighted digital analysis of breath biomarkers
Phillips, Michael; Altorki, Nasser; Austin, John H M; Cameron, Robert B; Cataneo, Renee N; Kloss, Robert; Maxfield, Roger A; Munawar, Muhammad I; Pass, Harvey I; Rashid, Asif; Rom, William N; Schmitt, Peter; Wai, James
2008 Jul;393(2):76-84, Clinica chimica acta
BACKGROUND: A combination of biomarkers in a multivariate model may predict disease with greater accuracy than a single biomarker employed alone. We developed a non-linear method of multivariate analysis, weighted digital analysis (WDA), and evaluated its ability to predict lung cancer employing volatile biomarkers in the breath. METHODS: WDA generates a discriminant function to predict membership in disease vs no disease groups by determining weight, a cutoff value, and a sign for each predictor variable employed in the model. The weight of each predictor variable was the area under the curve (AUC) of the receiver operating characteristic (ROC) curve minus a fixed offset of 0.55, where the AUC was obtained by employing that predictor variable alone, as the sole marker of disease. The sign (+/-) was used to invert the predictor variable if a lower value indicated a higher probability of disease. When employed to predict the presence of a disease in a particular patient, the discriminant function was determined as the sum of the weights of all predictor variables that exceeded their cutoff values. The algorithm that generates the discriminant function is deterministic because parameters are calculated from each individual predictor variable without any optimization or adjustment. We employed WDA to re-evaluate data from a recent study of breath biomarkers of lung cancer, comprising the volatile organic compounds (VOCs) in the alveolar breath of 193 subjects with primary lung cancer and 211 controls with a negative chest CT. RESULTS: The WDA discriminant function accurately identified patients with lung cancer in a model employing 30 breath VOCs (ROC curve AUC=0.90; sensitivity=84.5%, specificity=81.0%). These results were superior to multilinear regression analysis of the same data set (AUC=0.74, sensitivity=68.4, specificity=73.5%). WDA test accuracy did not vary appreciably with TNM (tumor, node, metastasis) stage of disease, and results were not affected by tobacco smoking (ROC curve AUC=0.92 in current smokers, 0.90 in former smokers). WDA was a robust predictor of lung cancer: random removal of 1/3 of the VOCs did not reduce the AUC of the ROC curve by >10% (99.7% CI). CONCLUSIONS: A test employing WDA of breath VOCs predicted lung cancer with accuracy similar to chest computed tomography. The algorithm identified dependencies that were not apparent with traditional linear methods. WDA appears to provide a useful new technique for non-linear multivariate analysis of data
— id: 78887, year: 2008, vol: 393, page: 76, stat: Journal Article,

Using high throughput resequencing microarrays to detect mutations in genes involved in lung cancer
Piao, LC; Gunnison, A; Nadas, A; Chen, WC; Nonaka, D; Spivack, S; Pass, H; Rom, WN; Tang, MS
2008 DEC 11 ;4(3):159-159, Cancer biomarkers : section A of Disease markers
— id: 91475, year: 2008, vol: 4, page: 159, stat: Journal Article,

HGF mediates cell proliferation of human mesothelioma cells through a PI3K/MEK5/Fra-1 pathway
Ramos-Nino, Maria E; Blumen, Steven R; Sabo-Attwood, Tara; Pass, Harvey; Carbone, Michele; Testa, Joseph R; Altomare, Deborah A; Mossman, Brooke T
2008 Feb;38(2):209-217, American journal of respiratory cell & molecular biology
The ligand hepatocyte growth factor/scatter factor (HGF) and its receptor tyrosine kinase, c-Met, are highly expressed in most human malignant mesotheliomas (MMs) and may contribute to their increased growth and viability. Based upon our observation that RNA silencing of fos-related antigen 1 (Fra-1) inhibited c-met expression in rat mesotheliomas (1), we hypothesized that Fra-1 was a key player in HGF-induced proliferation in human MMs. In three of seven human MM lines evaluated, HGF increased Fra-1 levels and phosphorylation of both extracellular signal-regulated kinase 5 (ERK5) and AKT that were inhibited by the phosphatidylinositol 3-kinase (PI3K) inhibitor, LY290042. HGF-dependent phosphorylation and Fra-1 expression were decreased after knockdown of Fra-1, whereas overexpression of Fra-1 blocked the expression of mitogen/extracellular signal-regulated kinase kinases (MEK)5 at the mRNA and protein levels. Stable MM cell lines using a dnMEK5 showed that basal Fra-1 levels were increased in comparison to empty vector control lines. HGF also caused increased MM cell viability and proliferating cell nuclear antigen (PCNA) expression that were abolished by knockdown of MEK5 or Fra-1. Data suggest that HGF-induced effects in some MM cells are mediated via activation of a novel PI3K/ERK5/Fra-1 feedback pathway that might explain tumor-specific effects of c-Met inhibitors on MM and other tumors
— id: 101360, year: 2008, vol: 38, page: 209, stat: Journal Article,

The relationship between simian virus 40 and mesothelioma
Rivera, Zeyana; Strianese, Oriana; Bertino, Pietro; Yang, Haining; Pass, Harvey; Carbone, Michele
2008 Jul;14(4):316-321, Current opinion in pulmonary medicine
PURPOSE OF REVIEW: Simian virus 40 is present in some human malignant mesotheliomas. The evidence in favor and against a pathogenic role of simian virus 40 in malignant mesothelioma is discussed in this review. RECENT FINDINGS: When simian virus 40 is injected intracardially into hamsters, 60% develop and die of malignant mesothelioma. Moreover, some human malignant mesotheliomas contain and express simian virus 40 DNA and proteins. To date, over 50 laboratories have detected simian virus 40 in malignant mesotheliomas and in other tumors; however, the variability of the percentage of positivity led to a controversy about the role and significance of simian virus 40 in malignant mesotheliomas. Compared with other cell types, human mesothelial cells are unusually susceptible to simian virus 40-induced malignant transformation. The presence of simian virus 40 in malignant mesothelioma has been associated with the activation of specific oncogene pathways. Cocarcinogenesis between simian virus 40 and asbestos in causing malignant mesotheliomas has been demonstrated in three separate research laboratories using different experimental approaches. Epidemiological data possibly linking simian virus 40 and malignant mesothelioma is lacking owing to unattainable identification of infected from noninfected cohorts. SUMMARY: Available evidence appears sufficient to link simian virus 40 either alone or in conjunction with asbestos in causing malignant mesotheliomas; however, it is still insufficient to speculate about the contribution of simian virus 40 to the overall incidence of malignant mesotheliomas
— id: 101358, year: 2008, vol: 14, page: 316, stat: Journal Article,

The Diagnostic Value of Endobronchial Ultrasound-Guided Needle Biopsy in Lung Cancer and Mediastinal Adenopathy
Sun, W; Zervos, M; Pass, H; Cangiarella, J; Bizekis, C; Crawford, B; Wang, B
2008 OCT 25 ;114(5):415-416, Cancer
— id: 90487, year: 2008, vol: 114, page: 415, stat: Journal Article,

The IASLC Lung Cancer Staging Project: proposals for the inclusion of broncho-pulmonary carcinoid tumors in the forthcoming (seventh) edition of the TNM Classification for Lung Cancer
Travis, William D; Giroux, Dorothy J; Chansky, Kari; Crowley, John; Asamura, Hisao; Brambilla, Elisabeth; Jett, James; Kennedy, Catherine; Rami-Porta, Ramon; Rusch, Valerie W; Goldstraw, Peter; Pass, Harvey I
2008 Nov;3(11):1213-1223, Journal of thoracic oncology
OBJECTIVE: In the 2003 Supplement for tumor, node, metastasis (TNM) Staging classification it states that TNM staging 'applies to all types of carcinoma including small cell carcinoma; however, it does not apply to carcinoids.' Despite this caveat, most publications on typical and atypical carcinoids use the TNM staging system for nonsmall cell carcinoma and are able to demonstrate prognostic significance for the different stages. For this reason, as the next TNM Staging proposal is being considered, we sought to investigate the carcinoid cases submitted to the International Association for the Study of Lung Cancer (IASLC) database, as well as the National Cancer Institute Surveillance Epidemiology and End Results (SEER). MATERIALS AND METHODS: In the data collected for the IASLC Staging Project database over the time period 1990 to 2000, there were 513 broncho-pulmonary carcinoids. A total of 1619 broncho-pulmonary carcinoid cases diagnosed over the period 1990-2002 were analyzed from the SEER database, including 1437 surgical cases. Pathologic slides were not available for histologic review. RESULTS: Most of tumors in both the IASLC and SEER databases were Stage I (82% and 78%, respectively), as defined by the IASLC proposals for the 7th edition of TNM staging system. T status was a statistically significant predictor of survival for both the SEER data (p < 0.0001) and the IASLC database (p = 0.0156), though for different reasons. N status showed significant survival correlations in both data sets (p < 0.0001). The effect of M status was significant (p < 0.0001) within the SEER data and not studied in the IASLC cases, which were almost exclusively M0. We found that all three T, N, and M categories as defined for non-small cell lung cancer are generally useful for staging of pulmonary carcinoid tumors. Significant differences in survival for overall stages I versus II versus III/IV were identified in both data sets. Patients with multiple same lobe nodules had a 100% 5-year survival, which may be a reason to reevaluate their status in the IIB category in future analyses. CONCLUSIONS: In summary, the IASLC proposals for the 7th edition of TNM are helpful in predicting prognosis for broncho-pulmonary carcinoid tumors. It is the recommendation of the IASLC Staging project that TNM be applied to broncho-pulmonary carcinoid tumors. A prospective collection of data through an International Registry of Pulmonary Neuroendocrine Tumors planned by the IASLC will allow for further detailed analysis of staging data for broncho-pulmonary carcinoids
— id: 110924, year: 2008, vol: 3, page: 1213, stat: Journal Article,

Malignant mesothelioma 2008
Zervos, Michael D; Bizekis, Costas; Pass, Harvey I
2008 Jul;14(4):303-309, Current opinion in pulmonary medicine
PURPOSE OF REVIEW: Mesothelioma is an aggressive malignancy of the pleura with poor survival. There will be approximately 3000 cases of mesothelioma in the United States annually. Multimodality treatment including neoadjuvant chemotherapy in selected individuals followed by extrapleural pneumonectomy and radiation has been studied in recent trials for its effects on disease free and overall survival This review provides a general overview of malignant mesothelioma with a summary of the most significant articles from within the past year as well as from the past. RECENT FINDINGS: Areas of recent interest include the evaluation of osteopontin and mesothelin as new tumor markers for mesothelioma. New phase III trials have been performed to evaluate the use of combined chemotherapy regimens. SUMMARY: Malignant mesothelioma is a very difficult malignancy to treat. Patients with the disease usually have an occupational asbestos exposure, and in some, viral exposure with SV40. There have been many historical treatments including combinations of local control with surgery and radiation as well as attempts to prevent systemic failure with chemotherapy. Novel therapies including intrapleural chemotherapy, photodynamic therapy and hyperthermic perfusion have also been used with some success. Finally there are several attempts at immunomodulating and targeted treatments, which are in phase I/II trials
— id: 82916, year: 2008, vol: 14, page: 303, stat: Journal Article,

MET amplification occurs with or without T790M mutations in EGFR mutant lung tumors with acquired resistance to gefitinib or erlotinib
Bean, J; Brennan, C; Shih, JY; Riely, G; Viale, A; Wang, L; Chitale, D; Motoi, N; Szoke, J; Broderick, S; Balak, M; Chang, WC; Yu, CJ; Gazdar, A; Pass, H; Rusch, V; Gerald, W; Huang, SF; Yang, PC; Miller, V; Ladanyi, M; Yang, CH; Pao, W
2007 DEC ;6(12):3333S-3334S, Molecular cancer therapeutics
— id: 75901, year: 2007, vol: 6, page: 3333S, stat: Journal Article,

MET amplification occurs with or without T790M mutations in EGFR mutant lung tumors with acquired resistance to gefitinib or erlotinib
Bean, James; Brennan, Cameron; Shih, Jin-Yuan; Riely, Gregory; Viale, Agnes; Wang, Lu; Chitale, Dhananjay; Motoi, Noriko; Szoke, Janos; Broderick, Stephen; Balak, Marissa; Chang, Wen-Cheng; Yu, Chong-Jen; Gazdar, Adi; Pass, Harvey; Rusch, Valerie; Gerald, William; Huang, Shiu-Feng; Yang, Pan-Chyr; Miller, Vincent; Ladanyi, Marc; Yang, Chih-Hsin; Pao, William
2007 Dec 26;104(52):20932-20937, Proceedings of the National Academy of Sciences of the United States of America
In human lung adenocarcinomas harboring EGFR mutations, a second-site point mutation that substitutes methionine for threonine at position 790 (T790M) is associated with approximately half of cases of acquired resistance to the EGFR kinase inhibitors, gefitinib and erlotinib. To identify other potential mechanisms that contribute to disease progression, we used array-based comparative genomic hybridization (aCGH) to compare genomic profiles of EGFR mutant tumors from untreated patients with those from patients with acquired resistance. Among three loci demonstrating recurrent copy number alterations (CNAs) specific to the acquired resistance set, one contained the MET proto-oncogene. Collectively, analysis of tumor samples from multiple independent patient cohorts revealed that MET was amplified in tumors from 9 of 43 (21%) patients with acquired resistance but in only two tumors from 62 untreated patients (3%) (P = 0.007, Fisher's Exact test). Among 10 resistant tumors from the nine patients with MET amplification, 4 also harbored the EGFR(T790M) mutation. We also found that an existing EGFR mutant lung adenocarcinoma cell line, NCI-H820, harbors MET amplification in addition to a drug-sensitive EGFR mutation and the T790M change. Growth inhibition studies demonstrate that these cells are resistant to both erlotinib and an irreversible EGFR inhibitor (CL-387,785) but sensitive to a multikinase inhibitor (XL880) with potent activity against MET. Taken together, these data suggest that MET amplification occurs independently of EGFR(T790M) mutations and that MET may be a clinically relevant therapeutic target for some patients with acquired resistance to gefitinib or erlotinib
— id: 101359, year: 2007, vol: 104, page: 20932, stat: Journal Article,

MESOMARK: a potential test for malignant pleural mesothelioma
Beyer, Heather L; Geschwindt, Ryan D; Glover, Curtis L; Tran, Ly; Hellstrom, Ingegerd; Hellstrom, Karl-Erik; Miller, M Craig; Verch, Thorsten; Allard, W Jeffrey; Pass, Harvey I; Sardesai, Niranjan Y
2007 Apr;53(4):666-672, Clinical chemistry
BACKGROUND: Soluble mesothelin-related peptides (SMRP)have been reported to be potential biomarkers for malignant pleural mesothelioma (MPM). We report analytical and preliminary clinical studies of MESOMARK, a quantitative assay for SMRP. METHODS: The MESOMARK assay is a 2-step immunoenzymatic assay in an ELISA format with a 6-point calibration curve (0-32 nmol/L). We assessed analytical imprecision, analyte stability, and analytical interferences. We measured SMRP by this assay in 409 apparently healthy individuals (reference interval study), 177 patients with nonmalignant conditions, and 500 cancer patients, including 88 with MPM. RESULTS: The limit of detection was 0.16 nmol/L. At 2-19 nmol/L, intraassay imprecision (CV) was 1.1%-5.3%, and total imprecision was 4.0%-11.0%. The mean dilution recovery for 5 samples was 109% (range, 99%-113%). No interference was seen from added bilirubin (200 mg/L), hemoglobin (500 mg/L), triglycerides (30 g/L), chemotherapeutic agents, or other tested substances. Recombinant mesothelin was stable in serum upon freeze/thaw at -70 degrees C and upon storage for at least 7 days at 2-8 degrees C. The 99(th) percentile of the reference group was 1.5 nmol/L [95% confidence interval (CI), 1.2-1.6 nmol/L; n = 409], and mean SMRP was significantly higher in sera from patients with MPM (7.5 nmol/L; 95% CI, 2.8-12.1 nmol/L; n = 88). SMRP was increased in 52% and 5% of MPM patients and asbestos-exposed individuals, respectively. Concentrations in other nonmalignant and malignant conditions were similar to those in healthy controls. CONCLUSIONS: The MESOMARK assay is analytically robust and may be useful for the detection and management of mesothelioma
— id: 96988, year: 2007, vol: 53, page: 666, stat: Journal Article,

A review of the use of stents for palliation of esophageal and lung cancer
Bizekis CS; Pass HI; Zervos MD
2007 ;3(1):45-60, Current Cancer Therapy Reviews
According to the American Cancer Society, there will be an estimated 14,520 new cases of esophageal cancer and 174,470 new cases of lung cancer in 2005. Close to 60% of these patients with esophageal cancer will present at an advanced stage not amenable to cure, but still will require palliation of their dysphagia. Conventional plastic stents (CPS) were used initially, and with continuous improvement in technology, insertion of self-expanding metal stents (SEMS) has become the palliative treatment of choice in the majority of these patients. SEMS are effective in palliating malignant dysphagia in 85%-100% of patients. More recently, a new self-expanding plastic stent (SEPS) has been designed which in early studies has been very effective in palliating dysphagia. Similarly, the majority of patients with lung cancer will present at an advanced stage and approximately 20% of these patients will have an endobronchial component requiring some form of palliation for relief of airway obstruction. Currently airway stents are either made of self-expanding metal for more permanent use, orl silicone if a more temporary solution is needed. Complications similar to the esophageal stents may arise. The purpose of this article is to provide an evidence based review of stents in the palliative setting for esophageal and lung cancer and briefly explore their potential use and expanding indications in the neoadjuvant setting. copyright 2007 Bentham Science Publishers Ltd
— id: 71626, year: 2007, vol: 3, page: 45, stat: Journal Article,

Eighth international mesothelioma interest group
Carbone, M; Albelda, S M; Broaddus, V C; Flores, R M; Hillerdal, G; Jaurand, M-C; Kjaerheim, K; Pass, H I; Robinson, B; Tsao, A
2007 Oct 25;26(49):6959-6967, Oncogene
The eighth International Mesothelioma Interest Group (IMIG) meeting was held in Chicago, IL, United States, in 19-22 October 2006 to discuss mesothelioma - the cancer often linked to asbestos exposure. It is a very aggressive malignancy with a median survival of less than 1 year from diagnosis. Millions of people have been exposed worldwide to asbestos, especially during the second half of the twentieth century when asbestos use increased significantly. The tons of asbestos utilized in the past remain a health hazard for current and future generations because asbestos is difficult to be disposed off. This makes asbestos and mesothelioma research a public health issue in addition to a medical problem. Moreover, the very high costs of asbestos litigation have a significant impact on the whole economy. In the United States, up until 2001, defendant companies had paid 54 billion dollars in claims and estimated future liabilities ranged from 145 to 210 billion. Therefore, asbestos research is of great interest to a large audience that includes patients, millions of asbestos-exposed individuals, scientists, physicians, public health officials, politicians, unions of asbestos workers, lawyers and the public at large. During the past few years, there has been significant progress in understanding the process of mineral fiber carcinogenesis and mesothelioma pathogenesis. With improved understanding of the pathogenesis of mesothelioma, new diagnostic, preventive and therapeutic options are being developed. A total of 247 papers were presented at the IMIG: the abstracts of these presentations were published in Lung Cancer, Supplement 1, October 2006. Here, experts in different disciplines critically review some of the most exciting presentations of the IMIG meeting. The result is a comprehensive review of the research field of asbestos carcinogenesis and mesothelioma, and of the progress that has been made in recent years in both basic and clinical sciences
— id: 101364, year: 2007, vol: 26, page: 6959, stat: Journal Article,

A mesothelioma epidemic in Cappadocia: scientific developments and unexpected social outcomes
Carbone, Michele; Emri, Salih; Dogan, A Umran; Steele, Ian; Tuncer, Murat; Pass, Harvey I; Baris, Y Izzettin
2007 Feb;7(2):147-154, Nature reviews. Cancer
In Cappadocia, Turkey, an unprecedented mesothelioma epidemic causes 50% of all deaths in three small villages. Initially linked solely to the exposure to a fibrous mineral, erionite, recent studies by scientists from Turkey and the United States have shown that erionite causes mesothelioma mostly in families that are genetically predisposed to mineral fibre carcinogenesis. This manuscript reports, through the eyes of one of the researchers, the resulting scientific advances that have come from these studies and the social improvements that were brought about by both the scientists and members of the Turkish Government
— id: 101361, year: 2007, vol: 7, page: 147, stat: Journal Article,

IMRT treatment for locally advanced non-small cell lung cancer achieves low levels of pulmonary irradiation including the low-dose volume, V 5 Gy, along with low levels of esophageal and cardiac irradiation
Chandra, A; Mitchell, JD; McCarthy, A; Chachoua, A; Jozsef, G; DeWyngaert, K; Pass, HI; Formenti, S
2007 JAN ;69(3):S523-S523, International journal of radiation oncology biology physics
— id: 87195, year: 2007, vol: 69, page: S523, stat: Journal Article,

Osteopontin is linked to p65 and MMP-9 expression in pulmonary adenocarcinoma but not in malignant pleural mesothelioma
Frey, A B; Wali, A; Pass, H; Lonardo, F
2007 May;50(6):720-726, Histopathology
AIMS: Osteopontin (OPN) is a matricellular protein involved in tissue remodelling, cell-mediated immunity and malignant transformation. High OPN serum levels predict poor prognosis in non-small cell carcinoma and set patients with malignant pleural mesothelioma (MM) apart from disease-free asbestos-exposed individuals. Yet neither the spectrum of tissue expression nor the signalling pathways of OPN in MM and pulmonary adenocarcinoma have been characterized, although in vitro evidence links OPN to the epidermal growth factor receptor (EGFR) pathway. The aim of this study was to address these deficiencies. METHODS AND RESULTS: OPN expression was investigated immunohistochemically in 104 adenocarcinomas and 38 MM and correlated with histological features, including tumour type, grade and proliferation and with expression of activated intermediary EGFR signalling pathway molecules p65, p-AKT, p-ERK, p-STAT-3, and of metalloproteinase (MMP)-1, MMP-2 and MMP-9. In MM, OPN expression was widespread (36/38) and independent of the molecular parameters studied. In adenocarcinoma, high OPN expression was correlated with expression of p65, p-ERK and MMP-9. CONCLUSIONS: Frequent OPN expression is typical of, but not specific for MM, whereas it appears to select adenocarcinoma cases with p65 and MMP-9 expression, suggesting a link with EGFR signalling pathways
— id: 110900, year: 2007, vol: 50, page: 720, stat: Journal Article,

Computed tomographic screening for lung cancer: Individualising the benefit of the screening
Henschke C.I.; Yankelevitz D.F.; McCauley D.I.; Sone S.; Hanaoka T.; Markowitz S.; Miller A.; Klingler K.; Scherer T.; Inderbitzi R.; Zulueta J.; Montuenga L.; Bastarrika G.; Giunta S.; Crecco M.; Pugliese P.; Tockman M.; Shaham D.; Rice K.; Aye R.; Roberts H.; Patsios D.; Bauer T.; Lally J.; Austin J.H.M.; Pearson G.D.N.; Naidich D.; McGuinness G.; Rifkin M.; Fiore E.; Kopel S.; Klippenstein D.; Litwin A.; Loud P.A.; Kohman L.J.; Scalzetti E.M.; Khan A.; Shah R.; Smith M.V.; Williams H.T.; Lovett L.; Mendelson D.S.; Thurer R.; Heelan R.T.; Ginsberg M.S.; Sullivan F.; Ottinger M.; Vafai D.; Matalon T.A.S.; Odzer S.-L.; Liu X.; Sheppard B.; Cole E.; Wiernik P.H.; Ray D.; Pass H.; Endress C.; Mullen D.; Kalafer M.; Grannis F.; Rotter A.; Thorsen M.K.; Hansen R.; Camacho E.; Luedke D.
2007 ;30(5):843-847, European respiratory journal
Individuals concerned about their risk of lung cancer are recommended to talk with their physicians about computed tomographic screening for lung cancer. To provide the necessary information, the survival benefit of the screening, specific to a particular person for a particular round of screening, is needed. The probability of survival gain from the first, baseline, round of screening was addressed as the product of: 1) the screening resulting in a diagnosis of lung cancer; 2) not dying from some other cause for a sufficiently long period of time; and 3) cure resulting from pre-symptomatic treatment of lung cancer. These probabilities were estimated using the International Early Lung Cancer Action Program data on individuals aged 40-85 yrs with a cigarette smoking history of 0-150 pack-yrs. The estimated probability of survival gain ranged from 0.4% for a 60-yr-old with a 10-pack-yr smoking history who quit smoking 20 yrs ago, to 3.1% for a 70-yr-old current smoker with a 100 pack-yr history and 2.0% for an 85-yr-old current smoker with a 150-pack-yr history. When seeking counsel about initiation of screening for lung cancer, an estimate of the probability of survival gain from the first round of computed tomographic screening, specific to the person's age and history of smoking, can be provided. CopyrightcopyrightERS Journals Ltd 2007
— id: 76019, year: 2007, vol: 30, page: 843, stat: Journal Article,

High-resolution ROMA analysis of chromosomal rearrangements in mesothelioma patients with poor and good survival
Ivanov, SV; Ivanova, AV; Lucito, R; Pass, HI
2007 AUG ;2(8):S431-S431, Journal of thoracic oncology
— id: 74187, year: 2007, vol: 2, page: S431, stat: Journal Article,

Mechanisms of innate drug sensitivity in malignant pleural mesotheliomas
Ivanova, AV; Ivanov, SV; Cruz, C; Beck, A; Pass, HI
2007 AUG ;2(8):S374-S375, Journal of thoracic oncology
— id: 74186, year: 2007, vol: 2, page: S374, stat: Journal Article,

Surgery and multimodality therapy for mesothelioma
Pass, H
2007 AUG ;2(8):S214-S215, Journal of thoracic oncology
— id: 74185, year: 2007, vol: 2, page: S214, stat: Journal Article,

Prediction of lung cancer using volatile biomarkers in breath
Phillips, Michael; Altorki, Nasser; Austin, John H M; Cameron, Robert B; Cataneo, Renee N; Greenberg, Joel; Kloss, Robert; Maxfield, Roger A; Munawar, Muhammad I; Pass, Harvey I; Rashid, Asif; Rom, William N; Schmitt, Peter
2007 ;3(2):95-109, Cancer biomarkers : section A of Disease markers
BACKGROUND: Normal metabolism generates several volatile organic compounds (VOCs) that are excreted in the breath (e.g. alkanes). In patients with lung cancer, induction of high-risk cytochrome p450 genotypes may accelerate catabolism of these VOCs, so that their altered abundance in breath may provide biomarkers of lung cancer. METHODS: VOCs in 1.0 L alveolar breath were analyzed in 193 subjects with primary lung cancer and 211 controls with a negative chest CT. Subjects were randomly assigned to a training set or to a prediction set in a 2:1 split. A fuzzy logic model of breath biomarkers of lung cancer was constructed in the training set and then tested in subjects in the prediction set by generating their typicality scores for lung cancer. RESULTS: Mean typicality scores employing a 16 VOC model were significantly higher in lung cancer patients than in the control group (p<0.0001 in all TNM stages). The model predicted primary lung cancer with 84.6% sensitivity, 80.0% specificity, and 0.88 area under curve (AUC) of the receiver operating characteristic (ROC) curve. Predictive accuracy was similar in TNM stages 1 through 4, and was not affected by current or former tobacco smoking. The predictive model achieved near-maximal performance with six breath VOCs, and was progressively degraded by random classifiers. Predictions with fuzzy logic were consistently superior to multilinear analysis. If applied to a population with 2% prevalence of lung cancer, a screening breath test would have a negative predictive value of 0.985 and a positive predictive value of 0.163 (true positive rate =0.277, false positive rate =0.029). CONCLUSIONS: A two-minute breath test predicted lung cancer with accuracy comparable to screening CT of chest. The accuracy of the test was not affected by TNM stage of disease or tobacco smoking. Alterations in breath VOCs in lung cancer were consistent with a non-linear pathophysiologic process, such as an off-on switch controlling high-risk cytochrome p450 activity. Further research is needed to determine if detection of lung cancer with this test will reduce mortality
— id: 78891, year: 2007, vol: 3, page: 95, stat: Journal Article,

Cancer Care Ontario and American Society of Clinical Oncology adjuvant chemotherapy and adjuvant radiation therapy for stages I-IIIA resectable non small-cell lung cancer guideline
Pisters, Katherine M W; Evans, William K; Azzoli, Christopher G; Kris, Mark G; Smith, Christopher A; Desch, Christopher E; Somerfield, Mark R; Brouwers, Melissa C; Darling, Gail; Ellis, Peter M; Gaspar, Laurie E; Pass, Harvey I; Spigel, David R; Strawn, John R; Ung, Yee C; Shepherd, Frances A
2007 Dec 1;25(34):5506-5518, Journal of clinical oncology
PURPOSE: To determine the role of adjuvant chemotherapy and radiation therapy in patients with completely resected stage IA-IIIA non-small-cell lung cancer (NSCLC). METHODS: The Cancer Care Ontario Program in Evidence-Based Care and the American Society of Clinical Oncology convened a Joint Expert Panel in August 2006 to review the evidence and draft recommendations for these therapies. RESULTS: Available data support the use of adjuvant cisplatin-based chemotherapy in completely resected NSCLC; however, the strength of the data and consequent recommendations vary by disease stage. Adjuvant radiation therapy appears detrimental to survival in stages IB and II, with a possible modest benefit in stage IIIA. CONCLUSION: Adjuvant cisplatin-based chemotherapy is recommended for routine use in patients with stages IIA, IIB, and IIIA disease. Although there has been a statistically significant overall survival benefit seen in several randomized clinical trials (RCTs) enrolling a range of people with completely resected NSCLC, results of subset analyses for patient populations with stage IB disease were not significant, and adjuvant chemotherapy in stage IB disease is not currently recommended for routine use. To date, very few patients with stage IA NSCLC have been enrolled onto RCTs of adjuvant therapy; adjuvant chemotherapy is not recommended in these cases. Evidence from RCTs demonstrates a survival detriment for adjuvant radiotherapy with limited evidence for a reduction in local recurrence. Adjuvant radiation therapy appears detrimental to survival in stage IB and II, and may possibly confer a modest benefit in stage IIIA
— id: 96983, year: 2007, vol: 25, page: 5506, stat: Journal Article,

Fra-1 governs cell migration via modulation of CD44 expression in human mesotheliomas
Ramos-Nino, Maria E; Blumen, Steven R; Pass, Harvey; Mossman, Brooke T
2007 ;6:81-81, Molecular cancer
Silencing of Fra-1, a component of the dimeric transcription factor, activator protein-1 (AP-1), inhibits mRNA expression of c-met and cd44 in rat mesothelioma cells and is causally linked to maintenance of the transformed phenotype. However, the mechanisms of Fra-1 regulation and Fra-1 regulated gene expression in human malignant mesothelioma (MM) are unclear. We first show in a panel of human MM cells that Fra-1 mRNA expression in MM is complex and regulated by extracellular signal-regulated kinase (ERK1, ERK2), Src, and phosphatidyl-inositol-3-kinase (PI3K) pathways in a tumor-specific fashion. Cell lines with PI3K-dependent Fra-1 expression were SV40 positive and expressed the lowest basal Fra-1 levels. Levels of Fra-1 expression correlated with amounts of CD44 expression that were greater in simian virus 40 negative (SV40-) MM cells. Using dominant negative (dn), short hairpin (sh) and small interference (si) RNA constructs, we next demonstrate that expression of CD44, the principal hyaluronic receptor in MMs, correlates with Fra-expression in both simian virus 40 positive (SV40+) and SV40- MMs. Moreover, both Fra-1 and CD44 expression are linked to cell migration in SV40- MM cells. Lastly, in contrast to normal lung tissue, tissue microarrays revealed that Fra-1 was expressed in 33 of 34 human MMs, and that all CD44+ tumors were SV40-. These results suggest that Fra-1 is associated with cell migration in human MMs and that Fra-1 modulation of CD44 may govern migration of selected MMs
— id: 79129, year: 2007, vol: 6, page: 81, stat: Journal Article,

Aberrant promoter methylation of insulin-like growth factor binding protein-3 gene in human cancers
Tomii, Kunitoshi; Tsukuda, Kazunori; Toyooka, Shinichi; Dote, Hideaki; Hanafusa, Tadashi; Asano, Hiroaki; Naitou, Minoru; Doihara, Hiroyoshi; Kisimoto, Takumi; Katayama, Hideki; Pass, Harvery I; Date, Hiroshi; Shimizu, Nobuyoshi
2007 Feb 1;120(3):566-573, International journal of cancer
Insulin-like growth factor binding protein-3 (IGFBP-3) is postulated to be a mediator of growth suppression signals. Here, we examined the methylation status of IGFBP-3 to correlate to clinicopathological factors in human cancers. The methylation status of IGFBP-3 was determined by bisulfite DNA sequencing and was correlated with expression semi-quantified by real-time RT-PCR to develop a methylation-specific PCR (MSP) assay for IGFBP-3. Using the MSP assay, we examined the methylation status of IGFBP-3 in gastric cancer (GC), colorectal cancer (CRC), breast cancer (BC) and malignant mesothelioma (MM). IGFBP-3 methylation was detected in 6 of 13 (46%) and 16 of 24 (67%) GC cell lines and tumors, respectively; 4 of 8 (50%) and 15 of 26 (58%) CRC cell lines and tumors, respectively; 3 of 11 (27%) and 7 of 39 (18%) BC cell lines and tumors, respectively and 1 of 5 (20%) and 18 of 56 (32%) MM cell lines and tumors, respectively. Interestingly, the methylation status of MM specimens from Japanese patients (75%, 12 out of 16 patients) was significantly higher than those from the USA (15%, 6 out of 40 patients) (p < 0.0001), suggesting the presence of ethnic differences in the IGFBP-3 methylation status. We also found that IGFBP-3 methylation was preferentially present in GCs arising in the lower-third of the stomach (p = 0.079). In summary, our results showed that IGFBP-3 methylation played an important role in the silencing of its expression, suggesting that IGFBP-3 may act as a tumor suppressor gene in several human cancers examined
— id: 101365, year: 2007, vol: 120, page: 566, stat: Journal Article,

DNA methylation profile of 28 potential marker loci in malignant mesothelioma
Tsou, Jeffrey A; Galler, Janice S; Wali, Anil; Ye, Wei; Siegmund, Kimberly D; Groshen, Susan; Laird, Peter W; Turla, Sally; Koss, Michael N; Pass, Harvey I; Laird-Offringa, Ite A
2007 Nov;58(2):220-230, Lung cancer
Patients with malignant mesothelioma (MM), an aggressive cancer associated with asbestos exposure, usually present clinically with advanced disease and this greatly reduces the likelihood of curative treatment. MM is difficult to diagnose without invasive techniques; the development of non-invasively detectable molecular markers would therefore be highly beneficial. DNA methylation changes in cancer cells provide powerful markers that are potentially detectable non-invasively in DNA shed into bodily fluids. Here we examined the methylation status of 28 loci in 52 MM tumors to investigate their potential as molecular markers for MM. To exclude candidate MM markers that might be positive in biopsies/pleural fluid due to contaminating surrounding non-tumor lung tissue/DNA, we also examined the methylation of these markers in lung samples (age- or environmentally induced hypermethylation is frequently observed in non-cancerous lung). Statistically significantly increased methylation in MM versus non-tumor lung samples was found for estrogen receptor 1 (ESR1; p = 0.0002), solute carrier family 6 member 20 (SLC6A20; p = 0.0022) and spleen tyrosine kinase (SYK; p=0.0003). Examination of associations between methylation levels of the 28 loci and clinical parameters suggest associations of the methylation status of metallothionein genes with gender, histology, asbestos exposure, and lymph node involvement, and the methylation status of leucine zipper tumor suppressor 1 (LZTS1) and SLC6A20 with survival
— id: 96984, year: 2007, vol: 58, page: 220, stat: Journal Article,

Evolving aspects of mesothelioma carcinogenesis: SV40 and genetic predisposition
Carbone, Michele; Pass, Harvey I
2006 Feb;1(2):169-171, Journal of thoracic oncology
— id: 96987, year: 2006, vol: 1, page: 169, stat: Journal Article,

Oncology : an evidence-based approach
Chang AE; Ganz PA; Hayes DF; Kinsella T; Pass HI; Schiller JH; Stone RM; Strecher V
New York : Springer 2006,
— id: 1471, year: 2006, vol: , page: , stat: ,

Oncology : an evidence-based approach
Chang, Alfred E; Ganz, Patricia A; Hayes, Daniel F; Kinsella, Timothy J; Pass, Harvey I; Schiller, Joan H; Stone, Richard M; Strecher, Victor J
New York : Springer, 2006,
— id: 2173, year: 2006, vol: , page: , stat: ,

Common EGFR mutations conferring sensitivity to gefitinib in lung adenocarcinoma are not prevalent in human malignant mesothelioma
Cortese, Joseph F; Gowda, Ashok L; Wali, Anil; Eliason, James F; Pass, Harvey I; Everson, Richard B
2006 Jan 15;118(2):521-522, International journal of cancer
— id: 59011, year: 2006, vol: 118, page: 521, stat: Journal Article,

Polio vaccines, SV40 and human tumours, an update on false positive and false negative results
Elmishad, A G; Bocchetta, M; Pass, H I; Carbone, M
2006 ;123:109-117, Developments in biologicals
Simian virus 40 (SV40) has been detected in different human tumours in numerous laboratories. The detection of SV40 in human tumours has been linked to the administration of SV40-contaminated polio vaccines from 1954 until 1963. Many of these reports linked SV40 to human mesothelioma. Some studies have failed to detect SV40 in human tumours and this has caused a controversy. Here we review the current literature. Moreover, we present evidence showing how differences in the sensitivities of methodologies can lead to a very different interpretation of the same study. The same 20 mesothelioma specimens all tested negative, 2/20 tested positive or 7/20 tested positive for SV40 Tag by simply changing the detection method on the same immuno-precipitation/western blot membranes. These results provide a simple explanation for some of the apparent discordant results reported in the literature
— id: 68294, year: 2006, vol: 123, page: 109, stat: Journal Article,

Current treatment options and biology of peritoneal mesothelioma: meeting summary of the first NIH peritoneal mesothelioma conference
Hassan, R; Alexander, R; Antman, K; Boffetta, P; Churg, A; Coit, D; Hausner, P; Kennedy, R; Kindler, H; Metintas, M; Mutti, L; Onda, M; Pass, H; Premkumar, A; Roggli, V; Sterman, D; Sugarbaker, P; Taub, R; Verschraegen, C
2006 Nov;17(11):1615-1619, Annals of oncology
Peritoneal mesothelioma is a rare cancer of the peritoneum with about 250 new cases diagnosed each year in the United States. It is the second most common site for mesothelioma development and accounts for 10-20% of all mesotheliomas diagnosed in the United States. A meeting sponsored by the NIH Office of Rare Diseases was held in Bethesda, Maryland on September 13 and 14, 2004. The objective of this meeting was to review the epidemiology, biology and current surgical and medical management of peritoneal mesothelioma. In addition, the meeting also discussed clinical and pre-clinical evaluation of novel treatments for mesothelioma as well as ongoing laboratory research to better understand this disease. This report summarizes the proceedings of the meeting as well as directions for future clinical and basic research
— id: 110897, year: 2006, vol: 17, page: 1615, stat: Journal Article,

Crocidolite asbestos and SV40 are cocarcinogens in human mesothelial cells and in causing mesothelioma in hamsters
Kroczynska, Barbara; Cutrone, Rochelle; Bocchetta, Maurizio; Yang, Haining; Elmishad, Amira G; Vacek, Pamela; Ramos-Nino, Maria; Mossman, Brooke T; Pass, Harvey I; Carbone, Michele
2006 Sep 19;103(38):14128-14133, Proceedings of the National Academy of Sciences of the United States of America
Only a fraction of subjects exposed to asbestos develop malignant mesothelioma (MM), suggesting that additional factors may render some individuals more susceptible. We tested the hypothesis that asbestos and Simian virus (SV40) are cocarcinogens. Asbestos and SV40 in combination had a costimulatory effect in inducing ERK1/2 phosphorylation and activator protein-1 (AP-1) activity in both primary Syrian hamster mesothelial cells (SHM) and primary human mesothelial cells (HM). Ap-1 activity caused the expression and activation of matrix metalloprotease (MMP)-1 and MMP-9, which in turn led to cell invasion. Experiments using siRNA and chemical inhibitors confirmed the specificity of these results. The same effects were observed in HM and SHM. Experiments in hamsters showed strong cocarcinogenesis between asbestos and SV40: SV40 did not cause MM, asbestos caused MM in 20% of hamsters, and asbestos and SV40 together caused MM in 90% of hamsters. Significantly lower amounts of asbestos were sufficient to cause MM in animals infected with SV40. Our results indicate that mineral fibers and viruses can be cocarcinogens and suggest that lower amounts of asbestos may be sufficient to cause MM in individuals infected with SV40
— id: 68291, year: 2006, vol: 103, page: 14128, stat: Journal Article,

Multicenter phase II trial of neoadjuvant pemetrexed plus cisplatin (PC) followed by extrapleural pneumonectomy (EPP) and radiation (FIT) for malignant pleural mesothelioma (MPM)
Krug, LM; Pass, HI; Ruschl, VW; Kindler, HL; Sugarbaker, DJ; Rosenzweig, KE; Friedberg, JS; Raman, J; Ye, Z; Obasaju, C; Vogelzang, NJ
2006 OCT ;54(2):S42-S42, Lung cancer
— id: 70927, year: 2006, vol: 54, page: S42, stat: Journal Article,

Maspin nuclear localization is linked to favorable morphological features in pulmonary adenocarcinoma
Lonardo, Fulvio; Li, Xiaohua; Siddiq, Fauzia; Singh, Rajendra; Al-Abbadi, Moussa; Pass, Harvey I; Sheng, Shijie
2006 Jan;51(1):31-39, Lung cancer
Maspin, a mammary homologue of Serine Protease Inhibitors, has been shown to inhibit tumor progression and metastasis. Recently, its biological functions have been linked to its subcellular localization. Specifically, a nuclear, opposed to a combined nuclear and cytoplasmic localization has been associated with increased survival in human malignancies, including non-small cell lung cancer (NSCLC). However, it is not known whether transformation affects maspin expression during lung carcinogenesis, and whether its subcellular localization correlates with the morphological features of NSCLC. To address these questions, we studied maspin expression in a model of transformation of bronchial epithelial cells and in resected NSCLC. We found that decreased maspin accompanied chemical transformation of normal immortalized bronchial epithelial cells BEAS 2B. Immunohistochemistry revealed maspin expression to be virtually universal in NSCLC, occurring in 72/77 Adenocarcinoma (ACa), and 46/46 squamous cell carcinoma (SqCCa). SqCCa showed almost exclusively a combined nuclear-cytosolic stain. In contrast, nuclear maspin, but not combined nuclear-cytoplasmic maspin significantly correlated with low histological grade, lower proliferative rate, absence of invasion, and negative p53 stain in ACa. These data support the hypothesis that nuclear localization of maspin may stratify subtypes of NSCLC with favorable clinical-pathological features
— id: 59010, year: 2006, vol: 51, page: 31, stat: Journal Article,

Pleurectomy/decortication for malignant pleural mesothelioma: Technique and comments
Pass, H
2006 OCT ;54(2):S31-S31, Lung cancer
— id: 70925, year: 2006, vol: 54, page: S31, stat: Journal Article,

Genomics for biomarker detection in mesothelioma
Pass, H; Harbut, M; Webb, C; Carbone, M; Wali, A
2006 OCT ;54(2):S2-S3, Lung cancer
— id: 70923, year: 2006, vol: 54, page: S2, stat: Journal Article,

Complications of pulmonary and chest wall sugery
Pass, Harvey I; Yamane, Shane
Complications in surgery Philadelphia PA : Lippincott Williams & Wilkins, 2006,
— id: 5349, year: 2006, vol: , page: ?, stat: Chapter,

Asbestos exposure and serum osteopontin - Reply
Pass, HI; Carbone, M; Wali, A
2006 JAN 19 ;354(3):305-305, New England journal of medicine
— id: 61431, year: 2006, vol: 354, page: 305, stat: Journal Article,

Cellular and molecular parameters of mesothelioma
Ramos-Nino, Maria E; Testa, Joseph R; Altomare, Deborah A; Pass, Harvey I; Carbone, Michele; Bocchetta, Maurizio; Mossman, Brooke T
2006 Jul 1;98(4):723-734, Journal of cellular biochemistry
Malignant mesotheliomas (MM) are neoplasms arising from mesothelial cells that line the body cavities, most commonly the pleural and peritoneal cavities. Although traditionally recognized as associated with occupational asbestos exposures, MMs can appear in individuals with no documented exposures to asbestos fibers, and emerging data suggest that genetic susceptibility and simian virus 40 (SV40) infections also facilitate the development of MMs. Both asbestos exposure and transfection of human mesothelial cells with SV40 large and small antigens (Tag, tag) cause genetic modifications and cell signaling events, most notably the induction of cell survival pathways and activation of receptors, and other proteins that favor the growth and establishment of MMs as well as their resistance to chemotherapy. Recent advances in high-throughput technologies documenting gene and protein expression in patients and animal models of MMs can now be validated in human MM tissue arrays. These have revealed expression profiles that allow more accurate diagnosis and prognosis of MMs. More importantly, serum proteomics has revealed two new candidates (osteopontin and serum mesothelin-related protein or SMRP) potentially useful in screening individuals for MMs. These mechanistic approaches offer new hope for early detection and treatment of these devastating tumors
— id: 68293, year: 2006, vol: 98, page: 723, stat: Journal Article,

Spindle cell tumors of the pleura: differential diagnosis
Rdzanek, Monica; Fresco, Raoul; Pass, Harvey I; Carbone, Michele
2006 Feb;23(1):44-55, Seminars in diagnostic pathology
Spindle cell tumors that arise in or metastasize to the pleura must be thoroughly evaluated to arrive at a definitive diagnosis. Malignant mesothelioma is the most common tumor arising in the pleura, but metastatic tumors to the pleura occur more frequently. Additionally, many tumors arising in the lung and surrounding tissues involve the pleura. It is crucial to arrive at a correct diagnosis since many of these neoplasms show different prognoses and require varying treatment modalities. Sarcomatoid malignant mesothelioma is a rare tumor that arises in the pleura, and can be confused with numerous tumors arising in or metastasizing to the pleura, including synovial sarcoma, metastatic sarcomatoid carcinoma, metastatic melanoma, thymoma, renal cell carcinoma, localized fibrous tumor, leiomyosarcoma, and other types of sarcoma. Desmoplastic malignant mesothelioma is a fibrous sarcomatoid variant of malignant mesothelioma, and is occasionally mistaken for chronic fibrous pleurisy. Here, we review morphological, clinical, histological, immunohistochemical, ultrastructural, and molecular methods that aid in the diagnosis of spindle cell tumors of the pleura, and we provide specific examples of patients in which this multi-modal approach proved to be helpful
— id: 101362, year: 2006, vol: 23, page: 44, stat: Journal Article,

Gene expression profiling in an SV40 large T antigen expressing transgenic mouse mesothelioma model. Implications for a role for SV40 in human mesothelioma?
Robinson, C; Diyagama, D; Pass, H; Webb, C; Robinson, B; Lake, R; Holloway, A
2006 OCT ;54(2):S5-S5, Lung cancer
— id: 70924, year: 2006, vol: 54, page: S5, stat: Journal Article,

Surgery for bronchioloalveolar carcinoma and "very early" adenocarcinoma: an evolving standard of care?
Rusch, Valerie W; Tsuchiya, Ryosuke; Tsuboi, Masahiro; Pass, Harvey I; Grunenwald, Dominique; Goldstraw, Peter
2006 Nov;1(9 Suppl):S27-S31, Journal of thoracic oncology
Lobectomy and mediastinal lymph node dissection is the standard surgical management of early stage non-small cell lung cancer (NSCLC) because more limited resections have been associated with a higher risk of local recurrence. Nevertheless, recent lung cancer screening studies have led to the detection of an increasing number of 'very early' NSCLC (defined as less than 2 cm in size) and of good-prognosis histologic subtypes, bronchioloalveolar carcinoma (BAC), and adenocarcinoma (AC), mixed subtypes that are potentially appropriate for sublobar resection. The precise indications for sublobar resection remain unclear and are the subject of ongoing clinical trials, but it seems that very early, peripherally located, node-negative AC of a predominantly BAC pattern may be adequately treated in this manner. Multifocal AC and BAC, either synchronous or metachronous, are also effectively treated by complete resection, using limited resections whenever possible. The pneumonic form of BAC, the rarest variant of this disease spectrum, continues to have a poor prognosis despite complete resection. Very limited experience suggests that lung transplantation leads to prolonged survival in highly selected patients with this histologic subtype. To improve our management of very early AC, much more information is needed about the molecular abnormalities of AC and their relationship to clinical outcomes
— id: 96985, year: 2006, vol: 1, page: S27, stat: Journal Article,

DNA methylation profile of 28 candidate marker loci in malignant mesothelioma
Tsou, JA; Galler, JS; Wali, A; Pass, HI; Siegmund, KD; Ye, W; Groshen, S; Weisenberger, D; Campan, M; Laird, PW; Turla, S; Koss, MN; Laird-Offringa, IA
2006 OCT ;54(2):S36-S36, Lung cancer
— id: 70926, year: 2006, vol: 54, page: S36, stat: Journal Article,

Newer issues in mesothelioma chemotherapy
Vogelzang, Nicholas; Pass, Harvey I
2006 Feb;1(2):177-179, Journal of thoracic oncology
— id: 96986, year: 2006, vol: 1, page: 177, stat: Journal Article,

TNF-alpha inhibits asbestos-induced cytotoxicity via a NF-kappaB-dependent pathway, a possible mechanism for asbestos-induced oncogenesis
Yang, Haining; Bocchetta, Maurizio; Kroczynska, Barbara; Elmishad, Amira G; Chen, Yuanbin; Liu, Zemin; Bubici, Concetta; Mossman, Brooke T; Pass, Harvey I; Testa, Joseph R; Franzoso, Guido; Carbone, Michele
2006 Jul 5;103(27):10397-10402, Proceedings of the National Academy of Sciences of the United States of America
Asbestos is the main cause of human malignant mesothelioma (MM). In vivo, macrophages phagocytize asbestos and, in response, release TNF-alpha and other cytokines that contribute to carcinogenesis through unknown mechanisms. In vitro, asbestos does not induce transformation of primary human mesothelial cells (HM); instead, asbestos is very cytotoxic to HM, causing extensive cell death. This finding raised an apparent paradox: How can asbestos cause MM if HM exposed to asbestos die? We found that asbestos induced the secretion of TNF-alpha and the expression of TNF-alpha receptor I in HM. Treatment of HM with TNF-alpha significantly reduced asbestos cytotoxicity. Through numerous technical approaches, including chemical inhibitors and small interfering RNA strategies, we demonstrate that, in HM, TNF-alpha activates NF-kappaB and that NF-kappaB activation leads to HM survival and resistance to the cytotoxic effects of asbestos. Our data show a critical role for TNF-alpha and NF-kappaB signaling in mediating HM responses to asbestos. TNF-alpha signaling through NF-kappaB-dependent mechanisms increases the percent of HM that survives asbestos exposure, thus increasing the pool of asbestos-damaged HM that are susceptible to malignant transformation. Cytogenetics supported this hypothesis, showing only rare, aberrant metaphases in HM exposed to asbestos and an increased mitotic rate with fewer irregular metaphases in HM exposed to both TNF-alpha and asbestos. Our findings provide a mechanistic rationale for the paradoxical inability of asbestos to transform HM in vitro, elucidate and underscore the role of TNF-alpha in asbestos pathogenesis in humans, and identify potential molecular targets for anti-MM prevention and therapy
— id: 68292, year: 2006, vol: 103, page: 10397, stat: Journal Article,

SV40 detection in human tumor specimens
Carbone, Michele; Rdzanek, Monica A; Rudzinski, Jennifer J; De Marco, Melissa A; Bocchetta, Maurizio; Ramos Nino, Maria; Mossman, Brooke; Pass, Harvey I
2005 Nov 1;65(21):10120-10121, Cancer research
— id: 59007, year: 2005, vol: 65, page: 10120, stat: Journal Article,

Minority Opinion: CT Screening for Lung Cancer
Henschke, Claudia I; Austin, John H M; Berlin, Nathaniel; Bauer, Thomas; Giunta, Salvatore; Gannis, Fred; Kalafer, Michael; Kopel, Samuel; Miller, Albert; Pass, Harvey; Roberts, Heidi; Shah, Rakesh; Shaham, Dorith; Smith, Michael V; Sone, Shusuke; Turner, Richard; Yankelevitz, David F; Zulueta, Javier
2005 Nov;20(4):324-325, Journal of thoracic imaging
— id: 59006, year: 2005, vol: 20, page: 324, stat: Journal Article,

Malignant mesothelioma : advances in pathogenesis, diagnosis, and translational therapies
Pass HI; Vogelzang NJ; Carbone M
New York : Springer, 2005,
— id: 1466, year: 2005, vol: , page: , stat: ,

Lung cancer : principles and practice
Pass, Harvey I
Philadelphia PA : Lippincott Williams & Wilkins, 2005,
— id: 1464, year: 2005, vol: , page: , stat: ,

Mediastinal staging 2005: pictures, scopes, and scalpels
Pass, Harvey I
2005 Jun;32(3):269-278, Seminars in oncology
Staging of the mediastinum for lung cancer has matured dramatically with the advent of newer technologies in imaging and endoscopic surveillance. Some of these technologies such as positron emission tomography (PET) scanning are becoming mainstream in the evaluation of patients with clinically suspicious mediastinal disease as seen on computed tomography (CT), while others such as endobronchial ultrasound are reserved for specialty expertise and await validation. While much improvement has been made in the accurate preoperative staging of patients having surgery as the primary modality in lung cancer, controversy exists regarding the restaging of locally advanced cases after induction chemotherapy or chemoradiotherapy. A major concentration on these restaging issues is warranted since it is now generally agreed that sterilization of the mediastinum after induction therapy has an impact on the prognosis of patients with stage IIIA disease, and accurate staging after therapy may rationally guide diverse therapeutic interventions in these patients
— id: 59012, year: 2005, vol: 32, page: 269, stat: Journal Article,

Asbestos exposure, pleural mesothelioma, and serum osteopontin levels
Pass, Harvey I; Lott, Dan; Lonardo, Fulvio; Harbut, Michael; Liu, Zhandong; Tang, Naimei; Carbone, Michele; Webb, Craig; Wali, Anil
2005 Oct 13;353(15):1564-1573, New England journal of medicine
BACKGROUND: We investigated the presence of osteopontin in pleural mesothelioma and determined serum osteopontin levels in three populations: subjects without cancer who were exposed to asbestos, subjects without cancer who were not exposed to asbestos, and patients with pleural mesothelioma who were exposed to asbestos. METHODS: A group of 69 subjects with asbestos-related nonmalignant pulmonary disease were compared with 45 subjects without exposure to asbestos and 76 patients with surgically staged pleural mesothelioma. Tumor tissue was examined for osteopontin by immunohistochemical analysis, and serum osteopontin levels were measured by an enzyme-linked immunosorbent assay. RESULTS: There were no significant differences in mean (+/-SE) serum osteopontin levels between age-matched subjects with exposure to asbestos and subjects without exposure to asbestos (30+/-3 ng per milliliter and 20+/-4 ng per milliliter, respectively; P=0.06). In the group with exposure to asbestos, elevated serum osteopontin levels were associated with pulmonary plaques and fibrosis (56+/-13 ng per milliliter) but not with normal radiographic findings (21+/-5 ng per milliliter), plaques alone (23+/-3 ng per milliliter), or fibrosis alone (32+/-7 ng per milliliter) (P=0.004). Serum osteopontin levels were significantly higher in the group with pleural mesothelioma than in the group with exposure to asbestos (133+/-10 ng per milliliter vs. 30+/-3 ng per milliliter, P<0.001). Immunohistochemical analysis revealed osteopontin staining of the tumor cells in 36 of 38 samples of pleural mesothelioma. An analysis of serum osteopontin levels comparing the receiver-operating-characteristic curve in the group exposed to asbestos with that of the group with mesothelioma had a sensitivity of 77.6 percent and a specificity of 85.5 percent at a cutoff value of 48.3 ng of osteopontin per milliliter. Subgroup analysis comparing patients with stage I mesothelioma with subjects with exposure to asbestos revealed a sensitivity of 84.6 percent and a specificity of 88.4 percent at a cutoff value of 62.4 ng of osteopontin per milliliter. CONCLUSIONS: Serum osteopontin levels can be used to distinguish persons with exposure to asbestos who do not have cancer from those with exposure to asbestos who have pleural mesothelioma
— id: 59009, year: 2005, vol: 353, page: 1564, stat: Journal Article,

100 questions & answers about mesothelioma
Pass, Harvey I; Roy, Laura; Vento, Susan
Sudbury MA : Jones and Barlett, 2005,
— id: 1468, year: 2005, vol: , page: , stat: ,

Prediction of lung cancer using volatile biomarkers in breath
Phillips, M; Altorki, N; Austin, JHM; Cameron, RB; Cataneo, RN; Greenberg, J; Kloss, R; Maxfield, RA; Pass, HI; Rom, WN; Tietje, O
2005 JUN 1 ;23(16):839S-839S, Journal of clinical oncology
— id: 57805, year: 2005, vol: 23, page: 839S, stat: Journal Article,

Nuclear estrogen receptor beta in lung cancer: expression and survival differences by sex
Schwartz, Ann G; Prysak, Geoffrey M; Murphy, Valerie; Lonardo, Fulvio; Pass, Harvey; Schwartz, Jan; Brooks, Sam
2005 Oct 15;11(20):7280-7287, Clinical cancer research
PURPOSE: A role for estrogens in determining lung cancer risk and prognosis is suggested by reported sex differences in susceptibility and survival. Archival lung tissue was evaluated for the presence of nuclear estrogen receptor (ER)-alpha and ER-beta and the relationship between ER status, subject characteristics, and survival. EXPERIMENTAL DESIGN: Paraffin-embedded lung tumor samples were obtained from 214 women and 64 men from two population-based, case-control studies as were 10 normal lung autopsy samples from patients without cancer. Nuclear ER-alpha and ER-beta expression was determined by immunohistochemistry. Logistic regression was used to identify factors associated with ER positivity and Cox proportional hazards models were used to measure survival differences by ER status. RESULTS: Neither tumor (0 of 94) nor normal (0 of 10) lung tissue stained positive for ER-alpha. Nuclear ER-beta positivity was present in 61% of tumor tissue samples (170 of 278; 70.3% in men and 58.3% in women) and 20% of normal tissue samples (2 of 10; P = 0.01). In multivariate analyses, females were 46% less likely to have ER-beta-positive tumors than males (odds ratio, 0.54; 95% confidence interval, 0.27-1.08). This relationship was stronger and statistically significant in adenocarcinomas (odds ratio, 0.40; 95% confidence interval, 0.18-0.89). Women with ER-beta-positive tumors had a nonsignificant 73% (P = 0.1) increase in mortality, whereas men with ER-beta-positive tumors had a significant 55% (P = 0.04) reduction in mortality compared with those with ER-beta-negative tumors. CONCLUSIONS: This study suggests differential expression by sex and influence on survival in men of nuclear ER-beta in lung cancer, particularly in adenocarcinomas
— id: 59008, year: 2005, vol: 11, page: 7280, stat: Journal Article,

Aberrant methylation of HIN-1 (high in normal-1) is a frequent event in many human malignancies
Shigematsu, Hisayuki; Suzuki, Makoto; Takahashi, Takao; Miyajima, Kuniharu; Toyooka, Shinichi; Shivapurkar, Narayan; Tomlinson, Gail E; Mastrangelo, Domenico; Pass, Harvey I; Brambilla, Elisabeth; Sathyanarayana, Ubaradka G; Czerniak, Bogdan; Fujisawa, Takehiko; Shimizu, Nobuyoshi; Gazdar, Adi F
2005 Feb 10;113(4):600-604, International journal of cancer
HIN-1 (high in normal-1) is a putative cytokine with growth inhibitory activities and is downregulated by aberrant methylation in breast cancers. We studied HIN-1 methylation status in many types of adult and pediatric malignancies and cell lines. We examined the expression of HIN-1 mRNA in 52 cell lines and the promoter methylation status in the cell lines and in over 800 primary tumors representing 17 tumor types using methylation specific PCR. Promoter methylation was observed in 73% of breast cancer, 67% of nonsmall cell lung cancer (NSCLC), 30% of small cell lung cancer (SCLC) and 57% of malignant mesothelioma (MM) cell lines, and methylation was completely correlated with loss of expression. Expression negative cell lines restored HIN-1 expression after treatment with 5-aza-2'-deoxycytidine. Promoter methylation of HIN-1 was found in 90% of retinoblastomas, 73% of Wilms' tumors, 61% of rhabdomyosarcomas, 57% of breast cancers, 52% of prostate cancers, 40% of MMs, 28% of NSCLCs and 27% of lymphomas. Methylation frequencies in colorectal cancers, cervical cancers, bronchial carcinoids, SCLCs, neuroblastomas, osteosarcomas, leukemia, medulloblastomas and bladder cancers were lower (4-21%), while hepatoblastomas lacked methylation. HIN-1 methylation was rarely detected in nonmalignant tissues (8 of 165, 5%). Aberrant methylation of HIN-1 with loss of expression is a common event and may contribute to the pathogenesis of many types of human malignancies
— id: 59020, year: 2005, vol: 113, page: 600, stat: Journal Article,

Aberrant methylation profile of human malignant mesotheliomas and its relationship to SV40 infection
Suzuki, Makoto; Toyooka, Shinichi; Shivapurkar, Narayan; Shigematsu, Hisayuki; Miyajima, Kuniharu; Takahashi, Takao; Stastny, Victor; Zern, Andrea L; Fujisawa, Takehiko; Pass, Harvey I; Carbone, Michele; Gazdar, Adi F
2005 Feb 10;24(7):1302-1308, Oncogene
Malignant mesothelioma (MM) is associated with asbestos exposure and the presence of SV40 viral sequences. Recently, we reported that SV40 infection of human mesothelial cells (HM) causes aberrant methylation of the tumor suppressor gene (TSG) RASSF1A. We investigated methylation of 12 genes by methylation-specific PCR in 63 MMs, six MM cell lines, and two foci of SV40-infected HM. Methylation percentages of the tested genes ranged from 3 to 65%. The frequencies of HPP1, RASSF1A, Cyclin D2, and RRAD methylation, and the value of the methylation index, were significantly higher in SV40 sequence-positive MMs than in SV40-negative MMs. Methylation of TMS1 and HIC-1 was associated with shortened survival. SV40-infected HM showed progressive aberrant methylation of seven genes (RASSF1A, HPP1, DcR1, TMS1, CRBP1, HIC-1, and RRAD) during serial passage. Our results demonstrate a relationship between SV40 and methylation of multiple genes in MM, indicating that the virus plays a role in the pathogenesis of MM
— id: 59015, year: 2005, vol: 24, page: 1302, stat: Journal Article,

Distinct DNA methylation profiles in malignant mesothelioma, lung adenocarcinoma, and non-tumor lung
Tsou, Jeffrey A; Shen, Linda Y C; Siegmund, Kimberly D; Long, Tiffany I; Laird, Peter W; Seneviratne, Chandrika K; Koss, Michael N; Pass, Harvey I; Hagen, Jeffrey A; Laird-Offringa, Ite A
2005 Feb;47(2):193-204, Lung cancer
DNA methylation markers provide a powerful tool to make diagnoses based on genetic material obtained directly from tumors or from 'remote' locations such as sputum, pleural fluid, or serum. In particular when limited cell numbers are available, amplifyable DNA markers can provide a very sensitive tool for cancer detection and classification. Malignant mesothelioma (MM), an aggressive cancer strongly associated with asbestos exposure, can be difficult to distinguish from adenocarcinoma of the lung when limited material is available. In an attempt to identify molecular markers for MM and adenocarcinoma, we examined the DNA methylation status of 14 loci. Analysis of methylation levels in 10 MM and 8 adenocarcinoma cell lines showed that methylation of APC was significantly elevated in adenocarcinoma compared to MM cell lines (P=0.0003), while methylation of CDH1 was higher in MM (P<0.02). Subsequent examination of the methylation status of the 14 loci in 6 MM and 7 adenocarcinoma primary tumors, which yielded similar methylation profiles, supported these observations. Comparison of methylation in MM cell lines and tumors versus non-tumor lung tissue indicated that APC exhibits less methylation in MM (P=0.003) while RASSF1, PGR1, ESR1, and CDH1 show more methylation in MM, the latter two showing the most significant difference between the two tissue types (P< or = 0.0001). Comparison of methylation in adenocarcinoma cell lines and tumors versus non-tumor lung tissue showed methylation of ESR1, PGR1 and RASSF1 to be significantly elevated in adenocarcinoma, with RASSF1 being most significant (P=0.0002). Thus, with the examination of 14 loci, we have identified 5 candidates that show potential for distinguishing between MM, adenocarcinoma and/or non-cancer lung. Our observations support the strong potential of methylation markers as tools for accurate diagnosis of neoplasms in and around the lung
— id: 59014, year: 2005, vol: 47, page: 193, stat: Journal Article,

Identification of intelectin overexpression in malignant pleural mesothelioma by serial analysis of gene expression (SAGE)
Wali, Anil; Morin, Patrice J; Hough, Colleen D; Lonardo, Fulvio; Seya, Tsukasa; Carbone, Michele; Pass, Harvey I
2005 Apr;48(1):19-29, Lung cancer
Malignant pleural mesothelioma (MPM) is a fatal neoplasm with no acceptable curative approaches. We used serial analysis of gene expression (SAGE) to compare the gene expression pattern of a surgically resected MPM to the autologous normal mesothelium. Intelectin gene overexpression (>139-fold) was found in the tumor. Online SAGE datasets revealed intelectin to be consistently present in mesothelioma(s), ovarian cancer, and colon cancer. Intelectin mRNA expression was found by RT-PCR in 4 of 5 resected MPM tumors, and Intelectin protein expression was confirmed by immunohistochemistry in 28 of 53 MPM tumors, and in 4 of 4 mesothelioma cell lines studied by Western blot. A marked induction in intelectin gene expression was observed among human primary mesothelial cells as a consequence of crocidolite asbestos exposure and simian virus 40 infection. Intelectin overexpression in mesothelioma could have potential screening, and therapeutic implications
— id: 59013, year: 2005, vol: 48, page: 19, stat: Journal Article,

Genomics and proteomic in mesothelioma
Wali, Anil; Pass, Harvey I
Malignant mesothelioma : advances in pathogenesis, diagnosis, and translational therapies New York : Springer, 2005,
— id: 5347, year: 2005, vol: , page: ?, stat: Chapter,

Multistep and multifactorial carcinogenesis: when does a contributing factor become a carcinogen?
Carbone, Michele; Pass, Harvey I
2004 Dec;14(6):399-405, Seminars in cancer biology
Our greatest successes in fighting cancer derive from the identification and removal or inactivation of carcinogenic substances, and from the identification and removal of pre-malignant lesions. In comparison, our successes at treating already formed malignancies have been minimal. Therefore, emphasis should be put in identifying and removing pre-malignant lesions, and in the identification and removal of those agents that cause or contribute to cancer development. It is important to target initiators, co-carcinogens and promoters, since by removing any one of them, tumor growth may be prevented. Identification of these agents is difficult. Epidemiological studies largely study cancer after it has occurred. It would be preferable to identify potential carcinogenic substances at an earlier stage before they have caused a large number of malignancies and thus become identifiable by epidemiology. During the past three decades, we have accumulated an impressive amount of evidence concerning molecular pathways that when altered contribute to malignant growth. It is time that we start applying this knowledge to the identification of human carcinogens. Here, we review the molecular changes that are required for carcinogenesis and propose some criteria that, in the absence of epidemiological evidence, can be used to identify agents that cause or contribute to human cancer development. In the absence of epidemiological evidence, a given agent should be considered a human carcinogen when: (1) the agent causes or contributes to the development of tumors in animals that are of the same type as those tumors associated with exposure to the agent in humans; (2) the agent transforms or contributes to the transformation of human cells in culture and these cells are of the same type from which associated human malignancies arise; (3) there is molecular evidence that the agent interferes with one or more key molecular pathways in human cells which leads to the formation of human cancer
— id: 59019, year: 2004, vol: 14, page: 399, stat: Journal Article,

Mutation analysis of the BRAF codon 599 in malignant pleural mesothelioma by enriched PCR-RFLP
Dote, Hideaki; Tsukuda, Kazunori; Toyooka, Shinichi; Yano, Masaaki; Pass, Harvey I; Shimizu, Nobuyoshi
2004 Feb;11(2):361-363, Oncology reports
BRAF encodes a RAS-regulated serine/threonine kinase that mediates the pathway for cell growth and malignant transformation. Point mutations of BRAF were reported recently in 66% of melanomas, over 30% of thyroid papillary and low-grade ovarian cancers, and a smaller percentage of other human cancers. Mutations in malignant cells were reported to occur only in exons 11 and 15. Among these mutations, BRAF V599E is most frequent and proved to invert its transcript to the dominant active form. To exclude the interference of co-existing normal cells in clinical samples, we developed a new enriched PCR-RFLP assay for detecting mutations of BRAF codon 599 mutation. The sensitivity of this assay was examined to find that one mutant allele among 10(2) wild-type alleles could be detected. We applied this method for 53 cases of primary malignant pleural mesotheliomas (MPMs) and 6 cell lines and found no mutations in these samples. Our results demonstrate that the developed enriched PCR-RFLP is a sensitive assay to detect BRAF codon 599 mutation. However, it may be a rare type of mutation in MPMs. Our new assay is useful and can be applied for screening of BRAF codon 599 mutation in various kinds of clinical samples
— id: 59029, year: 2004, vol: 11, page: 361, stat: Journal Article,

Novel combinations using pemetrexed in malignant mesothelioma
Gadgeel, Shirish M; Pass, Harvey I
2004 Apr;5 Suppl 2:S61-S66, Clinical lung cancer
Malignant mesothelioma is an uncommon malignancy that is locally invasive and rapidly fatal. The majority of patients with mesothelioma are not candidates for curative surgical resection. Chemotherapy has yielded only modest results in these patients. Pemetrexed is a multitargeted antifolate that is being evaluated in many tumor types. Recent single-agent data and data in combination with cisplatin have suggested that pemetrexed has therapeutic benefits in patients with malignant mesothelioma. This article summarizes the data regarding pemetrexed in the treatment of malignant mesothelioma and the potential novel combinations involving the drug that may be used in the future for the treatment of the disease
— id: 59024, year: 2004, vol: 5 Suppl 2, page: S61, stat: Journal Article,

Aberrant methylation of p57KIP2 gene in lung and breast cancers and malignant mesotheliomas
Kobatake, Takaya; Yano, Masaaki; Toyooka, Shinichi; Tsukuda, Kazunori; Dote, Hideaki; Kikuchi, Takefumi; Toyota, Minoru; Ouchida, Mamoru; Aoe, Motoi; Date, Hiroshi; Pass, Harvey I; Doihara, Hiroyoshi; Shimizu, Nobuyoshi
2004 Nov;12(5):1087-1092, Oncology reports
The p57KIP2 gene belongs to the Cip/Kip family of CDK inhibitors and has been demonstrated to be a tumor suppressor gene, being inactivated in various types of human cancers. We analyzed the methylation and expression status of p57KIP2 in lung and breast cancers, and in malignant mesotheliomas (MMs). The promoter region of p57KIP2 was determined by methylation-specific PCR (MSP) in samples of lung and breast cancer, and of MM. The expression of the gene in the cell lines was determined by RT-PCR and correlated with the methylation status. Aberrant methylation was detected by MSP in 9 of 27 (33%) and 25 of 78 (32%) lung cancer cell lines and tumors, respectively, 11 of 18 (61%) and 17 of 38 (45%) breast cancer cell lines and tumors, respectively, and 1 of 25 (4%) MM tumors. DNA methylation was detected but rarely in the corresponding non-malignant tissues. In addition, the gene expression was restored in the methylated cell lines following 5-aza-2'-deoxycytidine treatment, confirming that the methylation was indeed responsible for the gene down-regulation. We also examined the relationship between the p57KIP2 methylation status and the clinicopathological features of the primary tumors, and found that there was no relationship between the p57KIP2 methylation status and any of the examined clinicopathological features. In summary, our results demonstrate that p57KIP2 methylation associated with the gene down-regulation is frequently present in lung and breast cancers and plays an important role at the molecular level in the pathogenesis of these cancers
— id: 59018, year: 2004, vol: 12, page: 1087, stat: Journal Article,

Integration of multimodality approaches in the management of malignant pleural mesothelioma
Martino, Derlis; Pass, Harvey I
2004 Mar;5(5):290-298, Clinical lung cancer
More than half a century after the first descriptions of mesothelioma as a pathologic entity, satisfactory treatment is still elusive. Although relatively uncommon, the incidence of mesothelioma will most likely increase over the next 10-20 years. Advances have been made in understanding the pathogenesis, diagnosis, and staging, but they have not translated into markedly improved survival. Some use palliative treatment as the primary means of therapy even now. On the other hand, a cadre of individuals have studied how surgery, chemotherapy, and radiation therapy affect the disease. Although each individual modality has had limited success by itself, a multimodality approach has been documented to improve survival and quality of life. In addition, intriguing discoveries in immunology and gene profiling and therapy promise hope for further improvement. In this article, we will illustrate the current views on integrating these different approaches and delineate areas of active research
— id: 59025, year: 2004, vol: 5, page: 290, stat: Journal Article,

Computerized tomographic nodule heterogeneity: present and future impact on indications for sublobar resections
Pass, Harvey I; Altorki, Nasser K
2004 Jul;6(1):20-27, Clinical lung cancer
With the advent of lung cancer screening, many nodules are being detected that are subsequently proven to be lung cancer. These nodules have different radiographic appearances and different biologic characteristics regarding their invasiveness and propensity for metastasis. These solid and part-solid nodules are now having surgeons reassess issues of lung sparing for early-stage lung cancer by not only considering smaller nodules as potentially appropriate for wedge resection or segmentectomies, but are also requiring surgeons to stratify these lesions by radiographic appearance. Data that argue for considering lesser resection of selected early-stage lung cancers, as well as the need for more prospectively accumulated facts that arise from trial designs like the original randomized Lung Cancer Study Group Trial, are discussed
— id: 59021, year: 2004, vol: 6, page: 20, stat: Journal Article,

Evidence of an important role for SV40 in mesothelioma
Pass, Harvey I; Bocchetta, Maurizio; Carbone, Michele
2004 Nov;14(4):489-495, Thoracic surgery clinics
The discovery of SV40 DNA in human mesothelioma has evolved from a finding that originally was dismissed as polymerase chain reaction contamination to one that has won approval for a National Cancer Institute Rapid Access to Intervention Development grant to vaccinate SV40-positive tumors with a vaccinia mTag construct. As the credibility of these findings has become imprinted in the literature, the burden of phenomenon dismissal has become more difficult for investigators who have based their arguments on critically flawed validation studies. Mesothelioma is a disease for which novel strategies of detection or treatment should be encouraged, and it is as dangerous as a hungry shark. In the past, the argument always has been whether the finding of SV40 in mesothelioma is credible enough to lead our thinking in another direction to help our patients. Unfortunately, the causality issues have been stuck to the issue like a remora on a shark. It is time to study the remora, but our priorities should be on taming the shark
— id: 59016, year: 2004, vol: 14, page: 489, stat: Journal Article,

Gene expression profiles predict survival and progression of pleural mesothelioma
Pass, Harvey I; Liu, Zhandong; Wali, Anil; Bueno, Raphael; Land, Susan; Lott, Daniel; Siddiq, Fauzia; Lonardo, Fulvio; Carbone, Michele; Draghici, Sorin
2004 Feb 1;10(3):849-859, Clinical cancer research
PURPOSE: Clinical outcomes for malignant pleural mesothelioma (MPM) patients having surgery are imprecisely predicted by histopathology and intraoperative staging. We hypothesized that gene expression profiles could predict time to progression and survival in surgically cytoreduced pleural mesothelioma of all stages. EXPERIMENTAL DESIGN: Gene expression analyses from 21 MPM patients having cytoreductions and identical postoperative adjuvant therapy were performed using the U95 Affymetrix gene chip. Using both dChip and SAM, neural networks constructed a common 27 gene classifier, which was associated with either the high-risk and low-risk group of patients. Data were validated using real-time PCR and immunohistochemical staining. The 27 gene classifier was also used for validation in a separate set of 17 MPM patients from another institution. RESULTS: The groups predicted by the gene classifier recapitulated the actual time to progression and survival of the test set with 95.2% accuracy using 10-fold cross-validation. Clinical outcomes were independent of histology, and heterogeneity of progression and survival in early stage patients was defined by the classifier. The gene classifier had a 76% accuracy in the separate validation set of MPMs. CONCLUSIONS: These data suggest that pretherapy gene expression analysis of mesothelioma biopsies may predict which patients may benefit from a surgical approach
— id: 59027, year: 2004, vol: 10, page: 849, stat: Journal Article,

Malignant pleural mesothelioma
Pass, Harvey I; Vogelzang, Nicholas; Hahn, Steven; Carbone, Michele
2004 May-Jun;28(3):93-174, Current problems in cancer
— id: 59023, year: 2004, vol: 28, page: 93, stat: Journal Article,

Aberrant methylation of trail decoy receptor genes is frequent in multiple tumor types
Shivapurkar, Narayan; Toyooka, Shinichi; Toyooka, Kiyomi O; Reddy, Jyotsna; Miyajima, Kuniharu; Suzuki, Makoto; Shigematsu, Hisayuki; Takahashi, Takao; Parikh, Gunjan; Pass, Harvey I; Chaudhary, Preet M; Gazdar, Adi F
2004 May 1;109(5):786-792, International journal of cancer
TNF-related apoptosis-inducing ligand (TRAIL) selectively induces programmed cell death (apoptosis) in various cancer cells but not in normal cells. TRAIL is known to bind to 4 different receptors, 2 proapoptotic (DR4 and DR5), and 2 potentially antiapoptotic receptors lacking death domains (DcR1 and DcR2). Aberrant promoter methylation and resultant silencing of tumor suppressor genes play an important role in the pathogenesis of many tumor types. Recently aberrant methylation of TRAIL decoy receptors was reported in pediatric tumor cell lines and neuroblastomas. We examined the methylation and expression status of TRAIL receptor genes in cancers of breast, lung, mesothelioma, prostate, bladder, cervix, ovary, brain and in hematopoietic malignancies. Aberrant methylation of DcR1 or DcR2 was present in 70% of primary breast cancers, 31% of primary lung cancers, in 63% of primary malignant mesothelioma (MM), in 60% of prostate cancer, in 42% of bladder cancer, in 100% of cervical cancer, in 43% of ovarian cancer, in 41% of lymphoma, in 26% of leukemia and in 56% of multiple myeloma. Methylation of DR4 and DR5 was rare in all the tumor types examined. Methylation of all the 4 receptors was rare in non malignant tissues. In cell lines, aberrant methylation of DcR1 was present in 11 of 23 (48%) breast, 10 of 27 (37%) lung and 3 of 7 (43%) MM, whereas aberrant methylation of DcR2 was present in 17 of 23 (74%) breast, 13 of 27 (48%) lung and 5 of 7 (71%) MM. The concordance between loss of gene expression and aberrant methylation ranged from 70-100%. Treatment with 5-aza-2'-deoxycytidine restored DcR1 and DcR2 expression in 9 methylated cell lines confirming that aberrant methylation was the cause for silencing of DcR1 and DcR2 expression. Our results demonstrate that DcR1 and DcR2 genes are frequently methylated in various tumor types, and that the role of decoy receptors in tumor pathogenesis needs to be re-evaluated
— id: 59026, year: 2004, vol: 109, page: 786, stat: Journal Article,

Increased osteonectin expression is associated with malignant transformation and tumor associated fibrosis in the lung
Siddiq, Fauzia; Sarkar, Fazlul H; Wali, Anil; Pass, Harvey Ira; Lonardo, Fulvio
2004 Aug;45(2):197-205, Lung cancer
Chemical transformation of the SV-40 immortalized bronchial epithelial cell line BEAS2-B induces alterations in molecules involved in cell cycle control, including up-regulation of EGFR and cyclin E [Oncogene 13 (1996) 1983; Clin Cancer Res 8 (2002) 54]. The finding that these changes also occur in vivo, in both pre-invasive and invasive lung cancer [Cancer Res 55 (1995) 1365; Cancer Res 59 (1999) 2470], proves this to be a suitable model to study lung carcinogenesis. The current study tested the hypothesis that chemical treatment of BEAS2-B with Cigarette Smoke Condensate (CSC) may affect levels of gene products involved in cell adhesion and tissue remodeling. To this end, we studied the extent of changes in osteonectin (ON) protein levels induced in BEAS 2 B-cells by CSC treatment and its timing to changes occurring in the anchorage independent cloning efficiency. ON, a multimodular protein component of the extra-cellular matrix, has been implicated in tissue remodeling occurring in neoplastic and non-neoplastic conditions, but its role in lung carcinogenesis is incompletely characterized. To validate the in vitro findings, as in our previous reports, we studied resected lung tissue, to assess whether ON expression in neoplastic lung tissue differs from normal, and to determine its cellular localization. We found that CSC treatment of BEAS2-B cells results in a 7-16-fold increase in ON protein levels, that is associated with increased colony forming efficiency. ON is absent in normal lung; in contrast it is present in the majority (39/52) of non-small cell lung cancer (NSCLC). Here, its expression is restricted to peritumoral fibroblasts in squamous cell carcinoma and adenocarcinoma. In contrast, it is localized to tumor cells in pulmonary sarcomatoid carcinoma (8/10). Thus, up-regulated ON is linked in vitro to cell transformation and in vivo, it is frequently expressed in tumor-associated fibrosis, compatible with its proposed role in tissue remodelling. Increased ON expression by tumor cells appears to represent a marker of sarcomatoid NSCLC
— id: 59022, year: 2004, vol: 45, page: 197, stat: Journal Article,

Translation research: from accurate diagnosis to appropriate treatment
Webb CP; Pass HI
2004 Oct 21;2(1):35-35, Journal of translational medicine
This review article focuses on the various aspects of translational research, where research on human subjects can ultimately enhance the diagnosis and treatment of future patients. While we will use specific examples relating to the asbestos related cancer mesothelioma, it should be stressed that the general approach outlined throughout this review is readily applicable to other diseases with an underlying molecular basis. Through the integration of molecular-based technologies, systematic tissue procurement and medical informatics, we now have the ability to identify clinically applicable 'genotype'-'phenotype' associations across cohorts of patients that can rapidly be translated into useful diagnostic and treatment strategies. This review will touch on the various steps in the translational pipeline, and highlight some of the most essential elements as well as possible roadblocks that can impact success of the program. Critical issues with regard to Institutional Review Board (IRB) and Health Insurance Portability and Accountability Act (HIPAA) compliance, data standardization, sample procurement, quality control (QC), quality assurance (QA), data analysis, preclinical models and clinical trials are addressed. The various facets of the translational pipeline have been incorporated into a fully integrated computational system, appropriately named Dx2Tx. This system readily allows for the identification of new diagnostic tests, the discovery of biomarkers and drugable targets, and prediction of optimal treatments based upon the underlying molecular basis of the disease
— id: 59017, year: 2004, vol: 2, page: 35, stat: Journal Article,

Disseminated malignant solitary fibrous tumor of the pleura
Zhang, Hongquan; Lucas, David R; Pass, Harvey I; Che, Mingxin
2004 Feb;54(2):111-115, Pathology international
Solitary fibrous tumor (SFT) of the pleura typically forms a localized pleura-based mass, and most are benign. A rare case of disseminated malignant SFT of the pleura is reported. The patient was a 71-year-old man who presented with complaints of shortness of breath to his primary care physician. A diagnosis of malignant mesothelioma was suspected, based on clinical, radiological and needle biopsy findings. He was referred to our institution for surgery. An extrapleural pneumonectomy, encompassing all pleural masses, was performed. Gross examination of the resected specimen was remarkable for numerous masses, ranging in size from 0.2 to 13.5 cm, covering the majority of the visceral pleura. Histologically, the tumor was composed of short spindle cells admixed with variable proportions of collagenous stroma. There were great intra- and intertumoral heterogeneity in tumor growth pattern, cellularity, pleomorphism and mitoses. Histologically malignant areas were present in all of the masses examined. The neoplastic cells were diffusely and intensely positive for bcl-2. Most tumor cells were also strongly stained for CD34 and CD99. Staining for cytokeratin was negative. The tumor also revealed p53 over-expression. Thus, the histological and immunohistochemical features of the tumor were consistent with a disseminated malignant SFT. This report shows that SFT rarely presents with disseminated pleural involvement, and a panel with CD34, bcl-2 and cytokeratin are valuable for differentiating SFT from malignant mesothelioma and other malignant spindle cell neoplasms of the pleura
— id: 59028, year: 2004, vol: 54, page: 111, stat: Journal Article,

Notch-1 induction, a novel activity of SV40 required for growth of SV40-transformed human mesothelial cells
Bocchetta, Maurizio; Miele, Lucio; Pass, Harvey I; Carbone, Michele
2003 Jan 9;22(1):81-89, Oncogene
We show that SV40 infection of human mesothelial cells directly causes overexpression of Notch-1, a key cell regulatory gene. Notch-1 induction is achieved at the transcriptional level and requires both the SV40 large T-antigen and the small t-antigen. Notch-1 upregulation is maintained in SV40-transformed human mesothelial clones and in SV40-positive mesotheliomas and derived cell lines. Activation of Notch-1 promotes cell cycle progression and it is required for the growth of SV40-transformed mesothelial cells. Our finding is relevant to the process of SV40-mediated human cell transformation, an effect that cannot be accounted for solely by SV40-Tag inhibition of Rb and p53
— id: 59035, year: 2003, vol: 22, page: 81, stat: Journal Article,

New developments about the association of SV40 with human mesothelioma
Carbone, M; Pass, H I; Miele, L; Bocchetta, M
2003 Aug 11;22(33):5173-5180, Oncogene
Simian virus 40 (SV40) has been detected in human tumors in over 40 different laboratories. Many of these reports linked SV40 to human mesotheliomas. The Vaccine Safety Committee of the Institute of Medicine (IOM), National Academy of Sciences, USA, recently reviewed the evidence associating polio vaccines and/or SV40 with human tumors. The IOM conclusions about polio vaccines and human cancer were: (1) 'the evidence is inadequate to accept or reject a causal relation between SV40-containing polio vaccines and cancer' because the 'epidemiological studies are sufficiently flawed'; (2) 'the biological evidence is of moderate strength that SV40 exposure from the polio vaccines is related to SV40 infection in humans'. The epidemiological studies were considered flawed because it was not possible to distinguish reliably among exposed and nonexposed cohorts. Concerning SV40, the IOM concluded that (1) 'the evidence is strong that SV40 is a transforming virus; (2) the evidence is of moderate strength that SV40 exposure could lead to cancer in humans under natural conditions' (IOM, 2002). Similar conclusions were reached at an International consensus meeting on SV40 and human tumors held at the University of Chicago in 2001. G Klein and C Croce, who chaired the final panel that reviewed all the published evidence linking SV40 to human tumors, stated that 'the presence of SV40 in human tumors has been convincingly demonstrated' (Klein et al., 2002). In addition, a workshop organized by the Biological Carcinogenesis Branch of the National Cancer Institute, Bethesda, MD, chaired by J Pagano, has reached similar conclusions (Wong et al., 2002). Therefore, three independent scientific panels have all agreed that there is compelling evidence that SV40 is present in some human cancers and that SV40 could contribute to the pathogenesis of some of them. It should be noted that the presence of SV40 in mesothelioma and other human tumor types has been challenged by a research team that has consistently reported negative findings (Strickler et al., 2001). However, a member of this research team has recently acknowledged - in sworn testimony -sensitivity problems and possible irregularities that raise concerns about these negative reports (MacLachlan, 2002). These revelations, together with the conclusions of the three independent panels mentioned above, appear to bring to an end the apparent controversy about the presence of SV40 in human mesotheliomas and brain tumors
— id: 59047, year: 2003, vol: 22, page: 5173, stat: Journal Article,

SV40 and human brain tumors
Carbone, Michele; Bocchetta, Maurizio; Cristaudo, Alfonso; Emri, Salih; Gazdar, Adi; Jasani, Bharat; Lednicky, John; Miele, Lucio; Mutti, Luciano; Pass, Harvey I; Ramael, Marc; Rizzo, Paola; Testa, Joseph R; Weggen, Sascha; Yeung, Anthony
2003 Aug 10;106(1):140-142, International journal of cancer
— id: 59031, year: 2003, vol: 106, page: 140, stat: Journal Article,

Induction treatment before surgery for non-small cell lung cancer
Eberhardt, W E; Albain, K S; Pass, H; Putnam, J B; Gregor, A; Assamura, H; Mornex, F; Senan, S; Belderbos, J; Westeel, V; Thomas, M; Van Schil, P; Vansteenkiste, J; Manegold, C; Mirimanoff, R O; Stuschke, M; Pignon, J; Rocmans, P; Shepherd, F A
2003 Dec;42 Suppl 1:S9-14, Lung cancer
Surgery alone is currently still accepted 'standard of care' for patients with operable NSCLC, this includes stages IA and IIB, as well as selected early subsets of IIIA disease. In more advanced and inoperable stage III disease, combinations of chemotherapy and radiotherapy remain the standard treatment approach for patients with good performance status. The role of surgery following induction therapy in these advanced stage III patients is at the moment not conclusively defined. More evidence from randomized trials is clearly needed to tailor treatment for the large number of patients that present in these locally advanced stages. Enrollment of patients into ongoing prospective clinical trials should be encouraged, whenever possible, to further define prognostic factors and improve multimodality strategies in this clinical setting
— id: 110894, year: 2003, vol: 42 Suppl 1, page: S9, stat: Journal Article,

A phase I study of Foscan-mediated photodynamic therapy and surgery in patients with mesothelioma
Friedberg, Joseph S; Mick, Rosemarie; Stevenson, James; Metz, James; Zhu, Timothy; Buyske, Jo; Sterman, Daniel H; Pass, Harvey I; Glatstein, Eli; Hahn, Stephen M
2003 Mar;75(3):952-959, Annals of thoracic surgery
BACKGROUND: Photodynamic therapy (PDT) is a light-based cancer treatment that, in the correct setting, can be delivered intraoperatively as an adjuvant therapy. A phase I clinical trial combining surgical debulking with Foscan-mediated PDT was performed in patients with malignant pleural mesothelioma. The purpose of the study was to define the toxicities and to determine the maximally tolerated dose (MTD) of Foscan-mediated PDT. METHODS: A total of 26 patients completed treatment. Tumor debulking was accomplished with either an extrapleural pneumonectomy (7 patients) or a lung-sparing pleurectomy-decortication (19 patients). Patients were injected with Foscan before surgery, and 652 nm light was delivered intraoperatively after completion of surgical debulking. Four light sensors were placed in the chest, allowing delivery of light to a uniform measured dose throughout the hemithorax. RESULTS: Four dose levels were explored. The MTD was 0.1 mg/kg of Foscan injected 6 days before surgery in combination with 10 J x cm(-2) 652 nm light. Dose limiting toxicity at the next higher dose was a systemic capillary leak syndrome leading to death in 2 of 3 patients treated at that dose. Other PDT-related toxicities included wound burns and skin photosensitivity. In all, 14 patients were treated at the MTD without significant complications. CONCLUSIONS: Foscan-mediated PDT can be safely combined with surgery at the established MTD. Unlike most other surgery-based multimodal treatments for mesothelioma, Foscan-mediated PDT affords the option, in selected patients, of accomplishing tumor debulking with a lung-sparing procedure rather than an extrapleural pneumonectomy. A phase II study is warranted
— id: 59033, year: 2003, vol: 75, page: 952, stat: Journal Article,

Expression of human MutT homologue (hMTH1) protein in primary non-small-cell lung carcinomas and histologically normal surrounding tissue
Kennedy, Christopher H; Pass, Harvey I; Mitchell, James B
2003 Jun 1;34(11):1447-1457, Free radical biology & medicine
In situ, oxidation of deoxyguanosine yields 8-hydroxy-2'-deoxyguanosine (8-oxo-dG), which is mutation prone and results in a G:C --> T:A transversion following DNA replication. Another pathway to the formation of DNA containing 8-oxo-dG is by the misincorporation of 8-oxo-dGTP via DNA polymerase. Human MutT homologue (hMTH1), an 8-oxo-dGTPase, prevents misincorporation of this oxidized nucleotide by hydrolyzing 8-oxo-dGTP to 8-oxo-dGMP. Previous studies have shown that hMTH1 mRNA is overexpressed in human renal cell carcinomas and breast tumors. Elevated levels of hMTH1 protein have also been detected in brain tumors. In the current study, we determined whether hMTH1 protein is overexpressed in primary non-small-cell lung carcinomas as compared to adjacent histologically normal lung tissue. Twenty matched human lung tumor/normal pairs were examined by Western analysis for expression of hMTH1 protein. Overexpression in the tumors was detected in 4/8 (50%) adenocarcinomas, 4/4 (100%) adenocarcinomas with bronchioalveolar (BAC) features, 2/2 (100%) BACs, and 3/6 (50%) squamous cell carcinomas. The data from Western analysis were validated by immunohistochemical staining for hMTH1 protein. The results of this study indicate that hMTH1 protein may be a potential marker for the detection of persistent oxidative stress in lung cancer
— id: 59032, year: 2003, vol: 34, page: 1447, stat: Journal Article,

Immunohistochemistry frequently detects c-Kit expression in pulmonary small cell carcinoma and may help select clinical subsets for a novel form of chemotherapy
Lonardo, Fulvio; Pass, Harvey Ira; Lucas, David Robert
2003 Mar;11(1):51-55, Applied immunohistochemistry & molecular morphology
The presence of c-Kit immunoreactivity in gastrointestinal stromal tumor (GIST), currently guides treatment with the selective c-Kit inhibitor STI571 (or Gleevec) in clinical trials and establishes a precedent of immunohistochemistry-guided treatment decisions. Thus, the optimization of detection conditions for c-Kit and the determination of its incidence in other malignancies have clinical bearing. Aims of our study were: 1) to determine the incidence of c-Kit expression in formalin-fixed paraffin-embedded tissue (FFPE) in pulmonary small cell carcinoma (SCC) and non small cell carcinoma (NSCC), pulmonary carcinoid, and malignant mesothelioma (MM); and 2) to test the feasibility of c-Kit determination using commercially available antibodies and routine immunohistochemical settings, comparing the performance of two commercially available antibodies, Dako and Santa Cruz. The Dako antibody detected positive stain in 10/22 SCC, 3/8 carcinoids, 1/57 NSCC (1/30 adenocarcinomas, 0/24 squamous cell carcinomas, 0/3 large cell undifferentiated carcinomas), and 7/33 MM. The Santa Cruz antibody detected c-kit in 8/22 SCC, 0/57 NSCC, 1/8 carcinoids, and 0/33 MM. HIER increased the performance of both antibodies. We conclude that c-Kit can routinely be detected in FFPE tissue with commercially available antibodies, and that the Dako anti-c-Kit has a higher sensitivity than the Santa Cruz antibody. C-Kit expression is common in SCC and carcinoids, very rare in NSCC, and infrequent in MM. The frequent c-Kit expression in SCC highlights that this molecule plays an important role in the biology of this malignancy, and that it could be targeted in subsets of patients for therapy with c-Kit inhibitors
— id: 59034, year: 2003, vol: 11, page: 51, stat: Journal Article,

Sarcomatoid mesothelioma and its histological mimics: a comparative immunohistochemical study
Lucas, D R; Pass, H I; Madan, S K; Adsay, N V; Wali, A; Tabaczka, P; Lonardo, F
2003 Mar;42(3):270-279, Histopathology
AIMS: Differentiating sarcomatoid mesothelioma from other pleural-based spindle cell tumours by light microscopy can be challenging, especially in a biopsy. The role of immunohistochemistry in this differential diagnosis is not as well defined as it is for distinguishing epithelioid mesothelioma from adenocarcinoma. In this study, we investigate the utility of diagnostic immunohistochemistry for distinguishing sarcomatoid mesothelioma from its histological mimics, high-grade sarcoma and pulmonary sarcomatoid carcinoma. METHODS: We stained 20 mesotheliomas with sarcomatoid components (10 biphasic and 10 sarcomatoid mesotheliomas) for pan-cytokeratin, cytokeratin 5/6, calretinin, WT-1, thrombomodulin, and smooth muscle actin. Intensity and distribution of staining were assessed using a semiquantitative scale. Only tumours with unequivocal staining were considered positive for tabulation. We compared the immunophenotypic profiles of these tumours with 24 high-grade sarcomas, 10 pulmonary sarcomatoid carcinomas, and 16 epithelioid mesotheliomas. The sarcomatoid carcinomas were also stained for thyroid transcription factor-1 (TTF-1). RESULTS: Pan-cytokeratin stained 70% of sarcomatoid mesotheliomas, 17% of sarcomas, 90% of sarcomatoid carcinomas, and 100% of epithelioid mesotheliomas. Cytokeratin 5/6 and WT-1 stained most epithelioid mesotheliomas, but rarely stained sarcomas, sarcomatoid carcinomas, or the sarcomatoid components of mesothelioma. Calretinin and thrombomodulin each stained 70% of sarcomatoid mesotheliomas. However, calretinin was also positive in 17% of sarcomas and in 60% of sarcomatoid carcinomas, while thrombomodulin was positive in 38% of sarcomas and in 40% of sarcomatoid carcinomas. Smooth muscle actin was expressed in 60% of sarcomatoid mesotheliomas and in 58% of sarcomas, but in only 10% of sarcomatoid carcinomas. All 10 sarcomatoid carcinomas were negative for TTF-1. CONCLUSIONS: Mesothelioma shows decreased expression of epithelial and mesothelial epitopes in its sarcomatoid components. A wide immunophenotypic overlap exists among sarcomatoid mesotheliomas, sarcoma, and sarcomatoid carcinomas. Cytokeratin and calretinin have the most value in differentiating sarcomatoid mesothelioma from sarcoma. However, because sarcomatoid mesothelioma can occasionally be cytokeratin-negative, the distinction between it and sarcoma may become arbitrary. With the exception of smooth muscle actin, all the markers studied showed similar distributions in sarcomatoid mesothelioma and sarcomatoid carcinoma, including frequent calretinin and thrombomodulin expression in both tumours. Thus, immunohistochemistry plays a more limited role in the differential diagnosis of sarcomatoid tumours compared with epithelioid tumours. For sarcomatoid tumours involving the pleural lining, clinicopathological data, especially information about the gross appearance of the tumour (i.e. localized versus diffuse pleural-based mass), should be noted and carefully correlated with microscopic and immunohistochemical findings
— id: 59048, year: 2003, vol: 42, page: 270, stat: Journal Article,

Essential practice of surgery
Norton JA; Bollinger RR; Chang AE; Lowry SF; Mulvihill SJ; Pass HI; Thompson RW; Li M
New York : Springer, 2003,
— id: 1472, year: 2003, vol: , page: , stat: ,

Consensus report IASLC workshop Bruges, September 2002: pretreatment minimal staging for non-small cell lung cancer
Postmus, Pieter E; Rocmans, Pierre; Asamura, Hisao; Ball, David; Belderbos, Jose; Cappello, Matteo; Jassem, Jacek; Novello, Silvia; Pass, Harvey; Passlick, Bernward; Pirker, Robert; Ready, Neal; Sause, William; Scagliotti, Giorgio; Vansteenkiste, Johan; Westeel, Virginie; van Zandwijk, Nico
2003 Dec;42 Suppl 1:S3-S6, Lung cancer
— id: 59030, year: 2003, vol: 42 Suppl 1, page: S3, stat: Journal Article,

SV40 Tag-specific cytotoxic T lymphocytes generated from the peripheral blood of malignant pleural mesothelioma patients
Bright, Robert K; Kimchi, Eric T; Shearer, Michael H; Kennedy, Ronald C; Pass, Harvey I
2002 Feb;50(12):682-690, Cancer immunology immunotherapy
Malignant pleural mesothelioma (MPM) is an aggressive cancer, with survival of less than one year following diagnosis and treatment with current protocols. Recent studies have demonstrated the presence of the simian virus 40 (SV40)-like, large tumor antigen (Tag) in nearly 60% of MPMs. SV40 Tag is a viral-encoded tumor-specific antigen, and thus a potential target for the induction of anti-tumor immunity and the development of therapeutic vaccines. We describe here evidence for the existence of SV40 Tag-specific immune responses in patients with MPM whose tumors express Tag. Humoral immunity was demonstrated by the detection of IgG titers against Tag in serum samples from 1/3 of patients examined. CTLs were generated from the peripheral blood of an HLA-A2(+) MPM patient with a synthetic peptide representing an HLA-A2 binding epitope in SV40 Tag. The CTLs demonstrated epitope fine specificity, in that other peptides from SV40 Tag and a peptide from influenza virus were not recognized in the context of HLA-A2. Moreover, the CTLs were capable of recognizing mesothelioma tumor cells that expressed SV40 Tag, in an MHC class I restricted manner
— id: 59042, year: 2002, vol: 50, page: 682, stat: Journal Article,

Re: Debate on the link between SV40 and human cancer continues
Carbone, Michele; Pass, Harvey I
2002 Feb 6;94(3):229-230, Journal of the National Cancer Institute
— id: 59045, year: 2002, vol: 94, page: 229, stat: Journal Article,

SV40 infection induces telomerase activity in human mesothelial cells
Foddis, Rudy; De Rienzo, Assunta; Broccoli, Dominique; Bocchetta, Maurizio; Stekala, Elizabeth; Rizzo, Paola; Tosolini, Alessandra; Grobelny, Jennifer V; Jhanwar, Suresh C; Pass, Harvey I; Testa, Joseph R; Carbone, Michele
2002 Feb 21;21(9):1434-1442, Oncogene
Mesotheliomas are malignant tumors of the pleural and peritoneal membranes which are often associated with asbestos exposure and with Simian virus 40 (SV40) infection. Telomerase activity is repressed in somatic cells and tissues but is activated in immortal and malignant cells. We evaluated telomerase activity in seven primary malignant mesothelioma biopsies and matched lung specimens and 20 mesothelioma cell lines and eight corresponding primary tumor cultures. All the tumor biopsies, and nearly all primary cell mesothelioma cultures and cell lines were telomerase positive. The findings in cell lines paralleled those observed in primary cultures in cases where paired samples were available. Next, we found that SV40, a DNA tumor virus present in approximately 50% of mesothelioma biopsies in the USA, induced telomerase activity in primary human mesothelial cells, but not in primary fibroblasts. Telomerase activity became detectable as early as 72 h following wild-type (strain 776) SV40 infection, and a clear DNA ladder was detectable 1 week after infection. The amount of telomerase activity increased during passage in cell culture and appeared to parallel increases in the cellular amounts of the SV40 large T-antigen. Thus, SV40 infection leads to telomerase activity before the infected mesothelial cells become transformed and immortalized. SV40 infection of human fibroblasts did not cause detectable telomerase activity. We also determined that the SV40 small t-antigen (tag) plays an important role in inducing telomerase activity because this activity was undetectable or minimal in mesothelial cells infected and/or transformed by SV40 tag mutants. Asbestos alone did not induce telomerase activity, and asbestos did not influence telomerase activity in mesothelial cells infected with SV40. Induction of telomerase activity by SV40 may be related to the very high rate of mesothelial cell immortalization that is characteristically associated with SV40 infection of mesothelial cells
— id: 59043, year: 2002, vol: 21, page: 1434, stat: Journal Article,

Results of lung metastasectomy from breast cancer: prognostic criteria on the basis of 467 cases of the International Registry of Lung Metastases
Friedel, Godehard; Pastorino, Ugo; Ginsberg, Robert J; Goldstraw, Peter; Johnston, Micheal; Pass, Harvey; Putnam, Joe B; Toomes, Heikki
2002 Sep;22(3):335-344, European journal of cardio-thoracic surgery
OBJECTIVE: Metastatic breast cancer is still defined as an incurable disease. Although the prognosis after resection of isolated metastases to the lung is much better than after chemotherapy most oncologists and gynecologists disapprove of lung metastasectomy. METHODS: In order to summarize the experience of pulmonary metastatic surgery and to achieve more relevant data by an increased number of cases, we evaluate the data of the International Registry of Lung Metastases of 467 patients having lung metastases from breast cancer with regard to long-term survival and prognostic factors. RESULTS: In 84% a complete metastatic resection was possible. The survival rates are 38% after 5 years, 22% after 10 years, and 20% after 15 years. Prognostic factors are a disease-free interval of > or = 36 months with 5-year survival of 45%, a 10-year survival of 26% and a 15-year survival of 21% (P=0.0001), solitary lung metastasis is associated with a survival rate of 44% after 5 years and of 23% after 10 and 15 years, but this is not statistically significant compared to multiple metastases. When establishing prognostic groups as suggested by Pastorino and the International Registry of Lung Metastases based on the risk factors disease-free interval, number of metastases and complete resection the group with the best prognosis showed 5-year survival of 50%, 10- and 15-year survival of 26% with a median survival of 59 months. CONCLUSION: Considering the low morbidity and mortality rate, we think that lung metastasectomy today is the best treatment option in selected cases of lung metastases from breast cancer
— id: 59038, year: 2002, vol: 22, page: 335, stat: Journal Article,

Human lung cancer cells and tissues partially recapitulate the homeobox gene expression profile of embryonic lung
Lechner, John F; Wang, Yongxin; Siddiq, Fauzia; Fugaro, Joseph M; Wali, Anil; Lonardo, Fulvio; Willey, James C; Harris, Curtis C; Pass, Harvey I
2002 Jul;37(1):41-47, Lung cancer
The fetal cell features of tumor cells suggest that neoplasia arises through a process of defective ontogeny. Homeobox (HOX) genes code for transcription factors that orchestrate organogenesis patterning and maintain tissue homeostasis. Thus, if detective ontogeny is a mechanism in cancer development, it can be hypothesized that tumor cells should express the HOX genes normally expressed by the embryonic cells of that tissue. Our data herein indicate that some HOX genes, whose expression is normally restricted to pulmonary embryogenesis, are re-expressed in lung cancer cells. However, lung cancer cells also frequently and inappropriately express HOX genes that are not normally expressed in lung tissue, regardless of developmental stage. Thus, whereas re-expression of some of the embryo-specific HOX genes is a common feature of lung cancer, tumors do not faithfully recapitulate the expression pattern of cells that participate in the early stages of lung development
— id: 59040, year: 2002, vol: 37, page: 41, stat: Journal Article,

The role of imaging in malignant pleural mesothelioma
Marom, Edith M; Erasmus, Jeremy J; Pass, Harvey I; Patz, Edward F Jr
2002 Feb;29(1):26-35, Seminars in oncology
Imaging plays an essential role in the diagnosis, staging, and follow-up of patients with malignant pleural mesothelioma (MPM). The diagnosis is often suggested by a unilateral pleural mass with a moderate to large pleural effusion seen on chest radiographs, but computerized tomography (CT) is the most frequently used technique for evaluation of the lungs in patients with MPM. CT not only suggests pulmonary metastases typically manifested as nodules or masses, but also can demonstrate underlying lung disease often caused by prior asbestos exposure. Magnetic resonance (MR) imaging may be helpful in selected patients with potentially resectable disease to further examine the local extent of tumor. Imaging with positron emission tomography (PET) using the radionuclide imaging agent (18)F fluoro-deoxyglucose (FDG) takes advantage of a basic property of tumor cells, increased glucose metabolism to identify malignant lesions. PET provides not only anatomic information, especially regarding mediastinal node metastasis, but also biochemical information about the lesion. These imaging modalities help triage patients to the most appropriate diagnostic and treatment options. Following patients after therapy usually relies on chest radiographs, although CT can more accurately describe response to therapy. This review will focus on radiologic evaluation in diagnosing, staging, and follow-up patients with MPM
— id: 59044, year: 2002, vol: 29, page: 26, stat: Journal Article,

Fei ai = Lung cancer
Pass, Harvey I
Beijing Shi : Ren min wei sheng chu ban she, 2002,
'yuan zhu Harvey I Pass ... ; zhu yi Feng Yulin, Liu Chuntao; zhu shen Shi Yingkang'
— id: 1470, year: 2002, vol: , page: , stat: ,

Biology of metastatic disease
Pass, Harvey I
2002 Jan;14(1):10-17, Seminars in thoracic & cardiovascular surgery
Metastasis development is a complex series of events involving the generation of new blood vessels, growth, invasion with breakdown of the host matrix, transport to other sites with adhesion, and subsequent invasion of the organ that hosts the metastasis. It is only recently that the molecular basis for these events has been studied, and the understanding of this process is now leading to the development of therapies that targets one or more of the components of this series of events
— id: 59041, year: 2002, vol: 14, page: 10, stat: Journal Article,

General thoracic surgery and science: it all takes time
Pass, Harvey I
2002 Oct;8(5):251-252, Annals of thoracic & cardiovascular surgery
— id: 59036, year: 2002, vol: 8, page: 251, stat: Journal Article,

Photodynamic therapy in thoracic surgery
Pass, Harvey I
2002 Jun;73(6):2012-2013, Annals of thoracic surgery
— id: 59039, year: 2002, vol: 73, page: 2012, stat: Journal Article,

Pleural mesothelioma in 2002: going somewhere very slowly
Pass, Harvey I
2002 Dec;124(6):1074-1077, Journal of thoracic & cardiovascular surgery
— id: 59037, year: 2002, vol: 124, page: 1074, stat: Journal Article,

2001 Image-guided percutaneous breast cancer ablation meeting at the American Society of Breast Surgeons
Dowlat, K; Robinson, D; Schwartzberg, B; Singletary, E; Pass, H; Gittleman, M; Edwards, M
2001 Oct;182(4):429-433, American journal of surgery
— id: 110892, year: 2001, vol: 182, page: 429, stat: Journal Article,

Prospects for an SV40 vaccine
Imperiale MJ; Pass HI; Sanda MG
2001 Feb;11(1):81-85, Seminars in cancer biology
The identification of SV40 as a possible cause of human cancer leads to the question of whether the unique properties of the virus can be exploited to treat patients with SV40-positive mesotheliomas, which are otherwise refractory to successful intervention. A modified SV40 T antigen, from which the transforming domains have been removed, has been cloned into a vaccinia virus vector and tested in animal tumor model systems. It has been shown to be effective against both subsequent tumor challenge and pre-existing tumors. Thus, the potential exists for use of such a vaccine in mesothelioma patients
— id: 59051, year: 2001, vol: 11, page: 81, stat: Journal Article,

Perspective: cell differentiation theory may advance early detection of and therapy for lung cancer
Lechner JF; Fugaro JM; Wong Y; Pass HI; Harris CC; Belinsky SA
2001 Jan;155(1 Pt 2):235-238, Radiation research
Many of these deaths could be prevented if there were better screening methods to uncover the disease when it is limited and most responsive to intervention. Novel biomarkers of early-stage disease are therefore needed. By applying the principle of 'oncology recapitulates ontogeny', we have discovered three homeobox (HOX) genes that are inappropriately expressed in the majority of lung tumors. Understanding the role of these inappropriately expressed genes in lung epithelial cell carcinogenesis may not only augment early detection, but may also offer new avenues of treatment of this disease
— id: 59053, year: 2001, vol: 155, page: 235, stat: Journal Article,

Malignant pleural mesothelioma: surgical roles and novel therapies
Pass HI
2001 Nov;3(2):102-117, Clinical lung cancer
Malignant pleural mesothelioma (MPM) is a uniformly fatal disease that has been recalcitrant to curative therapies. Median survivals of 8-18 months have, for the most part, led to a sense of frustration and nihilism in the medical and surgical community with regard to management of the disease, and the relatively small numbers of patients with mesothelioma have made it an orphan among other cancers with regard to research efforts and funding. This review will comment on the clinical presentation of the disease and therapeutic options that are available at this time. The role, timing, degree, and availability of cytoreductive surgery in the context of a multimodality approach for MPM will be highlighted, and various strategies that incorporate adjunctive therapies before, during, or after the operation will be discussed. Newer cytotoxic chemotherapies, either alone or in combination, are reviewed, with an emphasis on the increasing number of options with increased response rates that are becoming available for MPM patients. The results of protocols at selected centers that offer gene therapy, photodynamic therapy, hyperthermic chemotherapeutic perfusion, and intrapleural chemokines will be discussed, as well as newer preclinical approaches that base targeted therapies on novel molecular findings. In considering the newest approaches to the disease, one is encouraged to seek specialty consultation at centers that concentrate programmatic efforts on mesothelioma in order to design translational-based approaches on preclinical findings. By using such an approach, the patient and physician will find that there are considerably more options in the new century for mesothelioma
— id: 59046, year: 2001, vol: 3, page: 102, stat: Journal Article,

Novel molecular and immunotherapeutic strategies for lung cancer
Pass HI; Kalemkerian G; Bright RK
2001 Feb;11(1):189-212, ix, Chest surgery clinics of North America
Lung cancer therapy in the future will be guided by specific characteristics of the individual tumor specimens. The molecular cancer phenotyping will allow for targeted approaches based on the amplification of oncogenes, lack of tumor suppressor genes, dysregulation of growth factors, and angiogenesis or matrix metalloproteinases. Specific immunotherapeutic approaches based on
— id: 59050, year: 2001, vol: 11, page: 189, stat: Journal Article,

SV40 and the pathogenesis of mesothelioma
Rizzo P; Bocchetta M; Powers A; Foddis R; Stekala E; Pass HI; Carbone M
2001 Feb;11(1):63-71, Seminars in cancer biology
Malignant mesothelioma, a tumor of the pleura, pericardium, and peritoneum, is presently a worldwide problem. Current therapy is ineffective in slowing the course of the disease, and median survival from the time of diagnosis is rarely greater than 1 year. While the tumor was almost unknown prior to the second half of the twentieth century, it is presently responsible for more than 2000 deaths per year in the US alone. Mesothelioma is frequently associated with exposure to asbestos, but the incidence of cases involving individuals with low levels of asbestos exposure is increasing. For this reason, there has been much interest in studying whether there are alternative factors that act alone or in conjunction with asbestos in producing this malignancy. In the last decade, simian virus 40 (SV40) has become the most notable suspected agent
— id: 59052, year: 2001, vol: 11, page: 63, stat: Journal Article,

Aberrant methylation and simian virus 40 tag sequences in malignant mesothelioma
Toyooka S; Pass HI; Shivapurkar N; Fukuyama Y; Maruyama R; Toyooka KO; Gilcrease M; Farinas A; Minna JD; Gazdar AF
2001 Aug 1;61(15):5727-5730, Cancer research
Aberrant promoter methylation and resultant silencing of several genes plays an important role in the pathogenesis of many tumor types. We compared the methylation profile of 66 malignant mesotheliomas (MMs) and 40 lung adenocarcinomas using methylation-specific PCR for seven genes frequently methylated in lung cancer. We also compared the methylation frequencies of these genes as well as the methylation index, a reflection of all of the gene frequencies, with the presence of SV40 large T-antigen (Tag) sequences, histological subtype, and patient survival. Our major findings are: (a) with the exception of the RASSF1A promoter of the RASSF1 gene, frequencies of aberrant methylation were significantly lower in MMs than in adenocarcinomas; (b) the frequency of RASSF1A aberrant methylation and the value of the methylation index were significantly higher in SV40 sequence positive MM than in negative MM; and (c) the methylation index was higher in epithelial MM than in sarcomatous/mixed MM. Our results demonstrate a relationship between SV40 and aberrant methylation in MMs
— id: 59049, year: 2001, vol: 61, page: 5727, stat: Journal Article,

Human mesothelial cells are unusually susceptible to simian virus 40-mediated transformation and asbestos cocarcinogenicity
Bocchetta M; Di Resta I; Powers A; Fresco R; Tosolini A; Testa JR; Pass HI; Rizzo P; Carbone M
2000 Aug 29;97(18):10214-10219, Proceedings of the National Academy of Sciences of the United States of America
Mesothelioma, a malignancy associated with asbestos, has been recently linked to simian virus 40 (SV40). We found that infection of human mesothelial cells by SV40 is very different from the semipermissive infection thought to be characteristic of human cells. Mesothelial cells are uniformly infected but not lysed by SV40, a mechanism related to p53, and undergo cell transformation at an extremely high rate. Exposure of mesothelial cells to asbestos complemented SV40 mutants in transformation. Our data provide a mechanistic explanation for the ability of SV40 to transform mesothelial cells preferentially and indicate that asbestos and SV40 may be cocarcinogens
— id: 59055, year: 2000, vol: 97, page: 10214, stat: Journal Article,

Simian virus 40: the link with human malignant mesothelioma is well established
Carbone, M; Rizzo, P; Pass, H
2000 Mar-Apr;20(2A):875-877, Anticancer research
Mesotheliomas are malignancies of the pleural, pericardial, and peritoneal surfaces with a mean survival of less than 1 year from the time of diagnosis (1). While mesotheliomas were extremely rare in the first half of this century, the incidence of these tumors has increased enormously in the last several decades. Presently, 2-3 thousand people in the US develop and die of mesothelioma each year (1). It is estimated that approximately 80% of mesotheliomas develop in people with a history of occupational asbestos exposure or in individuals with family member(s) professionally exposed to asbestos that brought home fibers on their clothing (1). Although conventional wisdom dictates that asbestos is the most commonly associated 'environmental' factor with mesothelioma, asbestos does not transform human mesothelioma cells in tissue culture (2). This suggests that additional carcinogens act in concert with asbestos to cause mesothelioma. Recent evidence indicated that Simian Virus 40 (SV40) preferentially causes mesotheliomas in hamsters, and that SV40 is present in up to 80% of human mesotheliomas in the US and in Europe (reviewed in ref. 3 and 4)
— id: 110891, year: 2000, vol: 20, page: 875, stat: Journal Article,

Human mesothelioma samples overexpress both cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (NOS2): in vitro antiproliferative effects of a COX-2 inhibitor
Marrogi A; Pass HI; Khan M; Metheny-Barlow LJ; Harris CC; Gerwin BI
2000 Jul 15;60(14):3696-3700, Cancer research
Accumulating data demonstrate overexpression of both inducible NO synthase (NOS2) and cyclooxygenase-2 (COX2) in many epithelial neoplasias. In addition, cyclooxygenase inhibitors have been shown to have antineoplastic and prophylactic efficacy against human colon cancer and in mouse models of this disease. Mesothelioma arises in a context of asbestos exposure and chronic inflammation, which would be expected to enhance the expression of these inducible enzymes. This study demonstrates that both inducible enzymes were expressed in 30 human mesothelioma tissues but were not detectable in nonreactive mesothelial tissues from the same individuals. In contrast, areas of reactive mesothelial cells stained positively for these enzymes. In vitro exposure of human mesothelioma cell lines to the COX2 inhibitor, NS398, revealed dose- and time-dependent antiproliferative activity, whereas the NOS2 inhibitor, 1400W, had no detectable inhibitory effect. Surprisingly, nonmalignant human mesothelial isolates expressed both NOS2 and COX2 in vitro at the same level as mesothelioma cell lines but were less sensitive to NS398 inhibition. This finding indicates that these nonmalignant isolates may retain properties of reactive mesothelial cells and suggests that targets in addition to COX2 may be involved in the antiproliferative response of mesothelioma cell lines. These results have clinical significance because of the selective activity of the drug coupled with the therapeutic resistance and poor prognosis of mesothelioma. The findings presented here suggest that further preclinical studies of these inhibitors in animal models of mesothelioma would be of great interest
— id: 59056, year: 2000, vol: 60, page: 3696, stat: Journal Article,

Lung cancer surveillance: new technologies and novel strategies
Pass HI
2000 Apr;7(3):171-173, Annals of surgical oncology
— id: 59057, year: 2000, vol: 7, page: 171, stat: Journal Article,

Lung cancer : principles and practice
Pass, Harvey I
Philadelphia PA : Lippincott Williams & Wilkins, 2000,
— id: 1463, year: 2000, vol: , page: , stat: ,

Thoracic complications of AIDS
Pass, Harvey I
[S.l. : s.n.], 2000,
— id: 2170, year: 2000, vol: , page: , stat: ,

A simple method for generating full length cDNA from low abundance partial genomic clones
Wang Y; Fugaro JM; Siddiq F; Goparaju CM; Lonardo F; Wali A; Lechner JF; Pass HI
2000 ;1:2-2, BMC molecular biology
BACKGROUND: PCR amplification of target molecules involves sequence specific primers that flank the region to be amplified. While this technique is generally routine, its applicability may not be sufficient to generate a desired target molecule from two separate regions involving intron /exon boundaries. For these situations, the generation of full-length complementary DNAs from two partial genomic clones becomes necessary for the family of low abundance genes. RESULTS: The first approach we used for the isolation of full-length cDNA from two known genomic clones of Hox genes was based on fusion PCR. Here we describe a simple and efficient method of amplification for homeobox D13 (HOXD13) full length cDNA from two partial genomic clones. Specific 5' and 3' untranslated region (UTR) primer pairs and website program (primer3_www.cgv0.2) were key steps involved in this process. CONCLUSIONS: We have devised a simple, rapid and easy method for generating cDNA clone from genomic sequences. The full length HOXD13 clone (1.1 kb) generated with this technique was confirmed by sequence analysis. This simple approach can be utilized to generate full-length cDNA clones from available partial genomic sequences
— id: 59054, year: 2000, vol: 1, page: 2, stat: Journal Article,

New molecular and epidemiological issues in mesothelioma: role of SV40
Carbone M; Fisher S; Powers A; Pass HI; Rizzo P
1999 Aug;180(2):167-172, Journal of cellular physiology
Mesotheliomas are malignant tumors usually associated with occupational asbestos exposure. Simian virus 40 (SV40) is a DNA tumor virus that preferentially causes mesotheliomas when injected intracardially and/or intrapleurally into hamsters. SV40 also transforms human cells in tissue culture, and these cells contain extensive DNA damage. In the United States, at least 60% of human mesotheliomas contain and express SV40. In these tumor cells, the SV40 tumor antigen binds and inhibits the cellular tumor suppressors p53 and Rb. These findings suggest that SV40 may contribute to the development of those human mesotheliomas that occur in people not exposed to asbestos. SV40 may also facilitate asbestos-mediated carcinogenicity. The epidemiological data available are insufficient to address the role that SV40 may have played in contributing to the increased incidence of mesothelioma in the second half of this century
— id: 59065, year: 1999, vol: 180, page: 167, stat: Journal Article,

[Resection of lung metastases: long-term results and prognostic analysis based on 5206 cases--the International Registry of Lung Metastases]
Friedel, G; Pastorino, U; Buyse, M; Ginsberg, R J; Girard, P; Goldstraw, P; Johnston, M; McCormack, P; Pass, H; Putnam, J B; Toomes, H
1999 ;124(2):96-103, Zentralblatt fur chirurgie
The International Registry of Lung Metastases was established in 1991 to asses the long-term results of pulmonary metastasectomy. The Registry has accrued 5206 cases of lung metastasectomy, from 18 departments of thoracic surgery in Europe (n = 13), USA (n = 4) and Canada (n = 1). Of these patients 4572 (88%) underwent complete surgical resection. The primary tumor was epithelial in 2260 (43%), sarcoma in 2173 (42%), germ cell in 363 (7%), and melanoma in 328 (6%) patients. The disease-free interval was 0 to 11 months in 1729 (33%) cases, 12 to 35 months in 1857 (36%) and more than 36 months in 1620 (31%). Single metastases accounted for 2383 (46%) cases and multiple lesions for 2726 (52%). Mean follow up was 46 months. Analysis was performed by Kaplan-Meier estimates of survival, relative risk of death and multivariate Cox model. The actuarial survival after complete metastasectomy was 36% at 5 years, 26% at 10 years and 22% at 15 years (median 35 months); the corresponding values for incomplete resection were 13% at 5 years and 7% at 10 years (median 15 months). Among complete resections, the 5-year survival was 33% for patients with a disease free-interval of 0 to 11 months and 45% for those with a disease-free interval of more than 36 months; 43% for single lesions and 27 for four or more lesions. Multivariate analysis showed a better prognosis for patients with germ cell tumors, disease-free interval of 36 months and more and single metastases. These results confirm that lung metastasectomy is a safe and potentially curative procedure
— id: 110889, year: 1999, vol: 124, page: 96, stat: Journal Article,

Modulation of integrin expression on mesotheliomas: the role of different histotypes in invasiveness
Giuffrida A; Vianale G; Di Muzio M; Pass HI; Coletti A; Birarelli P; Procopio A; Modesti A
1999 Sep;15(3):437-442, International journal of oncology
The in vitro and in vivo integrin expression in human pleural malignant mesothelioma (MM) of three different histotypes was studied. Cell lines from MM of epithelioid (E1), fibrous (F1), byphasic histotype (B1) and normal mesothelial cells (NM) were analysed for the surface expression of alpha2, alpha3, alpha4, alpha5, alpha6, alphav, beta1, beta3, beta4 subunits and alphavbeta5 integrins. We found that alpha6, beta4 subunits and alphavbeta5, weakly detectable on NM cells, were expressed on MM cells. The beta3 subunit, well expressed on NM cells, was absent on MM cells. Differential expression among histotypes was observed, the MM-E1 was the least and the MM-B1 the most positive. Specimens for each MM histotype, were analysed by immunohistochemistry. The alpha6 and alphav subunits were more evident on the epithelioid histotype. Intense staining for beta3 and beta4 subunits, was found in all MM, particularly in invading cells, while the alpha5, and alphavbeta5 integrins were variously expressed. The different histotypes can affect the in vitro integrin expression and may indicate a preferential involvement of some subunits in vivo during MM tumor progression
— id: 59064, year: 1999, vol: 15, page: 437, stat: Journal Article,

Principles of chemoradiation: theoretical and practical considerations
Herscher LL; Cook JA; Pacelli R; Pass HI; Russo A; Mitchell JB
1999 Oct;13(10 Suppl 5):11-22, Oncology
Chemotherapy agents known to enhance the effects of radiation in preclinical studies have been used concurrently with radiotherapy in numerous clinical trials with the prospect of further enhancing radiation-induced local tumor control. While some success in several tumor histologies has been achieved using this approach, a major concern has been enhancement in normal tissue toxicity. This brief review addresses both theoretical and practical issues with respect to chemoradiation clinical trials. Recommendations for clinical trials are provided that, if implemented, can increase our understanding of basic mechanisms (in patients) and provide a more rational approach for future trials
— id: 59060, year: 1999, vol: 13, page: 11, stat: Journal Article,

Simian virus 40 (SV40)-like DNA sequences not detectable in finnish mesothelioma patients not exposed to SV40-contaminated polio vaccines
Hirvonen A; Mattson K; Karjalainen A; Ollikainen T; Tammilehto L; Hovi T; Vainio H; Pass HI; Di Resta I; Carbone M; Linnainmaa K
1999 Oct;26(2):93-99, Molecular carcinogenesis
Occupational asbestos exposure can be demonstrated in 80% of mesothelioma cases. A possible role of simian virus 40 (SV40) in the etiology of mesothelioma was raised because several studies reported the presence and expression of SV40-like DNA sequences in human mesotheliomas. It is also known that expression of SV40 large T antigen inhibits cellular Rb and p53. This suggests that SV40 might render infected cells more susceptible to asbestos carcinogenicity. The SV40-like sequences are suggested to have arisen from contaminated polio vaccines. Millions of people in the United States and most European countries were inoculated with SV40-contaminated polio vaccine in 1955-1963. However, in Finland, where polio vaccination started in 1957, no SV40-contaminated vaccine was used. We used a polymerase chain reaction-based method to test for the presence of SV40-like sequences in DNA extracted from the frozen tumor tissues of 49 Finnish mesothelioma patients, most of whom had been occupationally exposed to asbestos. All of the Finnish tumor tissues tested negative for SV40-like sequences. The results suggest that the SV40-like sequences detected in mesothelioma tissue in some previous studies may indeed originate from SV40-contaminated polio vaccines. It is a matter of speculation whether the absence of SV40 infection has contributed to the relatively low incidence of mesothelioma in Finland (1/10(5) in 1990-1995)
— id: 59061, year: 1999, vol: 26, page: 93, stat: Journal Article,

VEGF and VEGF type C play an important role in angiogenesis and lymphangiogenesis in human malignant mesothelioma tumours
Ohta Y; Shridhar V; Bright RK; Kalemkerian GP; Du W; Carbone M; Watanabe Y; Pass HI
1999 Sep;81(1):54-61, British journal of cancer
The vascular endothelial growth factor (VEGF) family is a novel regulator of endothelial cell proliferation. We assessed the mRNA expression of VEGF, VEGF type C (VEGF-C) and their receptors together with the microvessel density (VD) and microlymphatic vessel density (LVD) in pursuit of their connection and prognostic value in malignant pleural mesothelioma (MPM). We used four human MPM cell lines, 54 MPM tumours and five normal pleural tissues. Expression levels for receptors and ligands were assessed by semiquantitative reverse transcriptase polymerase chain reaction analysis. Microvessels were highlighted by immunohistochemical staining for factor VIII. The discrimination of lymphatics was performed by enzyme-histochemistry for 5'-nucleotidase after adequate inhibition of non-specific activity. The expression levels of VEGF, VEGF-C and VEGFRs were high in all MPM cell lines. The percentages of tumours with higher expression compared to the mean values of normal pleural tissues were 31.5% (17/54) for VEGF, 66.7% (36/54) for VEGF-C, 20.4% (11/54) for fms-like tyrosine kinase (flt)-1, 42.6% (23/54) for kinase insert domain-containing recepter (KDR) and 59.3% (32/54) for flt-4. Significant positive correlations were found between VEGF-C and flt-4, VEGF and KDR, VEGF and flt-1 in tumour tissues. The association between LVD and VEGF-C expression level was especially strong (P< 0.0001, r= 0.63). There were also significant correlations between LVD and flt-4, and VD and VEGF. No correlation, however, was found between LVD and nodal metastasis. VD was a negative prognostic indicator in this study. The associations between VEGFNEGF-C and vessel density suggest that these factors play an important role in angiogenesis and lymphangiogenesis in this tumour, and assessment of vascularity may be a useful prognostic indicator for MPM patients
— id: 59062, year: 1999, vol: 81, page: 54, stat: Journal Article,

Thrombospondin-1 expression and clinical implications in malignant pleural mesothelioma
Ohta Y; Shridhar V; Kalemkerian GP; Bright RK; Watanabe Y; Pass HI
1999 Jun 15;85(12):2570-2576, Cancer
BACKGROUND: The role of thrombospondin-1 (TSP-1) in tumor angiogenesis and progression is controversial. The authors assessed the impact of TSP-1 as a prognostic indicator in malignant pleural mesothelioma (MPM). METHODS: TSP-1 expression was assessed by reverse transcriptase-polymerase chain reaction using 5 normal pleural samples, 78 MPM tumors, and 43 surrounding normal lung samples. In MPM tumors, vascular endothelial growth factor (VEGF) expression also was examined. Differences between different valuables were analyzed using the Mann-Whitney U test. Survival curves were obtained by the Kaplan-Meier method and the survival rate was assessed by the log rank test. RESULTS: TSP-1 was highly expressed in 74 of the 78 MPM tumors (95%) with a mean value of 2.27 +/- 0.42 compared with normal pleura (0.50 +/- 0.06) and surrounding normal lung (0.96 +/- 0.20) (P = 0.05 vs. normal pleura and P = 0.0006 vs. surrounding normal lung). The mean TSP-1 expression was significantly greater in high VEGF-expressing tumors (2.63 +/- 0.51) compared with low VEGF-expressing tumors (1.17 +/- 0.39; P < 0.0001) and TSP-1 expression was lower in patients with TNM Stage III/IV disease (n = 60) (1.85 +/- 0.37) than in patients with Stage I/II disease (n = 13) (4.46 +/- 1.74) (P = 0.025). The TSP-1 expression levels in tumors with lymph node metastases were significantly lower than in those without lymph node metastases (P = 0.0305). Although high TSP-1 expression was associated with good prognosis in patients with low VEGF-expressing tumors, TSP-1 itself appeared to have no overall impact on survival. The methylation status of a CpG island associated with the TSP-1 promoter was evident in MPM tumor samples despite high levels of TSP-1 mRNA expression. CONCLUSIONS: TSP-1 is overexpressed in MPM tumors but its expression is of little value as a prognostic indicator in MPM. However, the relations between TSP-1 and VEGF in MPM merit further investigation for possible innovative therapeutic interventions
— id: 59066, year: 1999, vol: 85, page: 2570, stat: Journal Article,

Emerging translational therapies for mesothelioma
Pass HI; Robinson BW; Testa JR; Carbone M
1999 Dec;116(6 Suppl):455S-460S, Chest
Malignant pleural mesothelioma remains a therapeutic and diagnostic problem. Translational mechanisms for treatment of the disease are emerging from newly learned characteristics of the tumor on a molecular, cellular, and extracellular basis. Although slow to reach the clinical arena, these potential strategies do show proof of principle in the in vitro and in vivo settings, and some, including adenoviral molecular chemotherapy, have completed phase I testing. This review describes the rationale and status of these newer treatment ideas
— id: 59059, year: 1999, vol: 116, page: 455S, stat: Journal Article,

Simian virus 40 is present in most United States human mesotheliomas, but it is rarely present in non-Hodgkin's lymphoma
Rizzo P; Carbone M; Fisher SG; Matker C; Swinnen LJ; Powers A; Di Resta I; Alkan S; Pass HI; Fisher RI
1999 Dec;116(6 Suppl):470S-473S, Chest
Simian virus 40 (SV40) causes mesotheliomas, osteosarcomas, ependymomas, choroid plexus tumors, and lymphomas in hamsters. In humans, SV40 has been detected in tumors of the first four types. Using the polymerase chain reaction (PCR), we tested 29 non-Hodgkin's lymphomas (intermediate and high-grade), 25 posttransplant lymphoproliferative disorders, and 5 AIDS lymphomas for SV40 DNA. PCR analysis revealed that 3 of 29 lymphomas, 6 of 25 posttransplant lymphoproliferative disorders, and 2 of 5 AIDS lymphomas contained SV40 sequences corresponding to the retinoblastoma (RB)-pocket binding domain of SV40 tumor antigen (Tag). However, among positive samples, only one posttransplant lymphoproliferative disorder and one AIDS lymphoma contained the SV40 regulatory region, which suggest a higher viral load in these patients. In parallel experiments, 8 of 12 mesotheliomas tested positive for SV40 for both the RB-pocket binding domain of Tag and the SV40 regulatory region. These data confirm the presence of SV40 in most United States mesotheliomas and indicate that in human non-Hodgkin's lymphomas, the prevalence of SV40 is low
— id: 59058, year: 1999, vol: 116, page: 470S, stat: Journal Article,

Migration of mesothelioma cells correlates with histotype-specific synthesis of extracellular matrix
Scarpa S; Giuffrida A; Fazi M; Coletti A; Palumbo C; Pass HI; Procopio A; Modesti A
1999 Jul;4(1):67-71, International journal of molecular medicine
Three human pleural malignant mesothelioma cell cultures (MM) of epithelioid (E1), fibrous (F1) and byphasic (B1) histotype were studied in their synthesis of the extracellular matrix (ECM) components laminin (LM), fibronectin (FN), type IV collagen (cIV), and in their chemotactic and haptotactic migration towards the ECM produced proteins. MM-B1 showed the highest FN synthesis and release; MM-E1 produced the highest quantity of basement membrane constituents LM and cIV; MM-F1 weakly produced and released FN, LM and cIV. MM-B1 had the highest chemotactic and haptotactic motility, MM-F1 migrated toward the lowest concentration of LM while had reduced chemotactic activity toward FN and cIV; MM-E1 had the lowest migratory activity toward each ECM substrate. We demonstrated that three MM of different histotype are characterized by different ECM production and that these differences determine a variable ability of each MM to spread and migrate towards ECM substrates
— id: 59067, year: 1999, vol: 4, page: 67, stat: Journal Article,

Presence of simian virus 40 sequences in malignant mesotheliomas and mesothelial cell proliferations
Shivapurkar, N; Wiethege, T; Wistuba, I I; Salomon, E; Milchgrub, S; Muller, K M; Churg, A; Pass, H; Gazdar, A F
1999 Dec;76(2):181-188, Journal of cellular biochemistry
Malignant mesotheliomas (MMs) are pleural-, pericardial-, or peritoneal-based neoplasms usually associated with asbestos exposure. Mesothelial cells are biphasic and may give rise to epithelial and sarcomatous MMs. In addition, benign or atypical proliferations of mesothelial cells may occur in response to many stimuli. There have been recent reports of simian virus 40 (SV40) DNA large T antigen (Tag) sequences in pleural MMs. To further understand the relationship between SV40, MMs, and mesothelial proliferations, we studied 118 MMs from multiple sites in Germany and North America, including 93 epithelial pleural, 14 sarcomatous or mixed pleural MMs, and 11 peritoneal MMs. In 12 pleural MMs, adjacent noninvasive tumor foci were identified and studied separately. Information about asbestos exposure (detailed history and/or microscopic examination for asbestos bodies) was available from 43 German patients. In addition, 13 examples of reactive mesothelium and 20 lung cancers from the United States were tested. DNA was extracted from frozen tumor and adjacent nontumorous tissues or after microdissection of archival formalin-fixed, paraffin-embedded microslides. Two rounds of PCR were performed with primers SVFor 3 and SVRev, which amplify a 105 bp region specific for SV40 Tag. The specificity of the PCR product was confirmed in some cases by sequencing. Our major findings were: 1) Specific SV40 viral sequences were present in 57% of epithelial invasive MMs, of both pleural and peritoneal origin. No significant geographic differences were found, and frozen and paraffin-embedded tissues were equally suitable for analysis. 2) There was no apparent relationship between the presence of SV40 sequences and asbestos exposure. 3) SV40 sequences were present in the surface (noninvasive) components of epithelial MMs. 4) SV40 sequences were not detected in MMs of sarcomatous or mixed histologies. 5) Viral sequences were present in two of 13 samples (15%) of reactive mesothelium. 6) Lung cancers lacked SV40 sequences, as did non-malignant tissues adjacent to MMs. Our findings demonstrate the presence of SV40 sequences in epithelial MMs of pleural and peritoneal origin and their absence in tumors with a sarcomatous component. Viral sequences may be present in reactive and malignant mesothelial cells, but they are absent in adjacent tissues and lung cancers
— id: 110890, year: 1999, vol: 76, page: 181, stat: Journal Article,

A novel region of deletion on chromosome 6q23.3 spanning less than 500 Kb in high grade invasive epithelial ovarian cancer
Shridhar V; Staub J; Huntley B; Cliby W; Jenkins R; Pass HI; Hartmann L; Smith DI
1999 Jul 1;18(26):3913-3918, Oncogene
Detailed deletion mapping of chromosome 6q sequences in invasive ovarian tumors have implicated several broad regions involving 6q14-16, 6q21-23, 6q25-26, and the telomeric portion in band 6q27 as regions of frequent loss in this malignancy. In order to define regions of loss involved in the development of ovarian cancer, we used 23 polymorphic markers on 6q to examine allelic loss in 25 high-grade, late stage ovarian tumors. Four non-overlapping deletion regions were observed: (1) at 6q21-22.3 (D6S301-D6S292); (2) within a 1 cM region at 23.2-23.3 between markers D6S978-D6S1637 (at D6S311); (3) at 6q26 (between markers D6S411-D6S1277) and (4) at 6q27 with the markers D6S297 and D6S193. The highest region of loss was observed with marker D6S311 (lost in 17 of 19 informative cases, 89%) in 6q23.3, followed by D6S977 and D6S1637 (71 and 55%, respectively). The average fractional allele loss in the high-grade tumors was around 35%. Previous reports have shown 6q27 as the region of most frequent loss in invasive ovarian cancer. However, our results indicate a novel region in 6q23.3 (spanning less than 500 Kb distance between the markers) with the highest loss, implicating this region of chromosome 6q to harbor a putative tumor suppressor gene involved in the development of invasive epithelial ovarian cancer
— id: 59063, year: 1999, vol: 18, page: 3913, stat: Journal Article,

Comparison of simian virus 40 large T antigen recombinant protein and DNA immunization in the induction of protective immunity from experimental pulmonary metastasis
Watts AM; Shearer MH; Pass HI; Bright RK; Kennedy RC
1999 Feb;47(6):343-351, Cancer immunology immunotherapy
In this report we examine the ability of a recombinant tumor antigen preparation to prevent the establishment of experimental pulmonary metastasis. Baculovirus-derived recombinant simian virus 40 (SV40) large tumor antigen (T-Ag) was injected into BALB/c mice followed by challenge with an intravenous injection of syngeneic SV40-transformed tumorigenic cells. The experimental murine pulmonary metastasis model allows for the accurate measurement of metastatic lessions in the lungs at various times after the challenge, using computer-assisted video image analysis. Following challenge, lung metastasis and survival data for the groups of mice were obtained. Animals immunized with recombinant SV40 T-Ag showed no detectable sign of lung metastasis and survived for more than 120 days after challenge. Antibodies specific for SV40 T-Ag were detected in the serum of immunized mice by enzyme-linked immunosorbent assay. Splenocytes obtained from mice immunized with recombinant SV40 T-Ag did not lyse syngeneic tumor cells, indicating that no cytotoxic T lymphocyte response was induced. Control mice developed extensive lung metastasis and succumbed to lethal tumor within 4 weeks after challenge. These data indicate that immunization with the recombinant SV40 T-Ag induces protective, T-Ag-specific immunity in an experimental pulmonary tumor metastasis model
— id: 59069, year: 1999, vol: 47, page: 343, stat: Journal Article,

Asbestos induction of extended lifespan in normal human mesothelial cells: interindividual susceptibility and SV40 T antigen
Xu L; Flynn BJ; Ungar S; Pass HI; Linnainmaa K; Mattson K; Gerwin BI
1999 May;20(5):773-783, Carcinogenesis
Normal human mesothelial cells from individual donors were studied for susceptibility to asbestos-induction of apoptosis and generation of an extended lifespan population. Such populations were generated after death of the majority of cells and arose from a subset of mesothelial cultures (4/16) whereas fibroblastic cells (5/5) did not develop extended lifespan populations after asbestos exposure. All mesothelial cultures were examined for the presence of SV40 T antigen to obtain information on (i) the presence of SV40 T antigen expression in normal human mesothelial cells and (ii) the relationship between generation of an extended lifespan population and expression of SV40 T antigen. Immunostaining for SV40 T antigen was positive in 2/38 normal human mesothelial cultures. These cultures also had elevated p53 expression. However, the two isolates expressing SV40 T antigen did not exhibit enhanced proliferative potential or develop an extended lifespan population. Asbestos-generated extended lifespan populations were specifically resistant to asbestos-mediated but not to alpha-Fas-induced apoptosis. Deletion of p16Ink4a was shown in 70% of tumor samples. All mesothelioma cell lines examined showed homozygous deletion of this locus which extended to exon 1beta. Extended lifespan cultures were examined for expression of p16Ink4a to establish whether deletion was an early response to asbestos exposure. During their rapid growth phase, extended lifespan cultures showed decreased expression of p16Ink4a relative to untreated cultures, but methylation was not observed, and p16Ink4a expression became elevated when cells entered culture crisis. These data extend the earlier observation that asbestos can generate extended lifespan populations, providing data on frequency and cell type specificity. In addition, this report shows that generation of such populations does not require expression of SV40 T antigen. Extended lifespan cells could represent a population expressing early changes critical for mesothelioma development. Further study of these populations could identify such changes
— id: 59068, year: 1999, vol: 20, page: 773, stat: Journal Article,

Immunotherapy of SV40 induced tumours in mice: a model for vaccine development
Bright RK; Shearer MH; Pass HI; Kennedy RC
1998 ;94:341-353, Developments in biological standardization
Various vaccination strategies were compared for their ability to elicit antigen-specific tumour immunity, using the SV40-BALB/c murine tumour system. Specifically, mice were injected with baculovirus-derived recombinant SV40 Tag (rTag), synthetic peptides corresponding to B cell epitopes on SV40 Tag or a plasmid DNA construct encoding the gene for SV40 Tag. In vivo tumour immunity was determined by a lethal tumour challenge with syngeneic SV40-transformed tumour cells. SV40 Tag-specific antibody titres were induced in mice immunized with rTag or Tag synthetic peptides. Partial tumour protection was observed in mice that were immunized with SV40 Tag peptides, where as complete tumour immunity was observed in mice immunized with rTag. Although protective tumour immunity was also observed in mice immunized with DNA, negligible levels of antibodies to SV40 Tag were detected. Examination of the cytotoxic T lymphocyte (CTL) activity in mice injected with the SV40 Tag-DNA construct revealed Tag-specific lysis of syngeneic SV40-transformed tumour cells. Conversely, little to no CTL activity was detected in mice immunized with rTag. However, antigen-specific antibodies from rTag immunized mice were capable of mediating antibody-dependent cell-mediated cytotoxicity against SV40-transformed cells. These data indicate that the immune mechanisms elicited for protection against SV40 induced tumours in mice appeared to be dependent on the vaccination strategy employed and included both humoral and cell-mediated immune responses
— id: 59073, year: 1998, vol: 94, page: 341, stat: Journal Article,

Simian virus 40 oncogenesis in hamsters
Carbone M; Stach R; Di Resta I; Pass HI; Rizzo P
1998 ;94:273-279, Developments in biological standardization
Simian virus 40 (SV40) is a DNA tumour virus which is highly oncogenic in hamsters. Only specific histologic types of tumours develop in hamsters injected with SV40, and these are influenced by the route of virus inoculation. When SV40 is injected systemically to expose most different cell types to the virus, the animals develop mesotheliomas, osteosarcomas, sarcomas, and lymphomas within six months. When the virus is injected subcutaneously, sarcomas at the site of injection develop. If hamsters are injected intracranially with SV40, they develop ependymomas. These same tumour types have been found to contain SV40
— id: 59075, year: 1998, vol: 94, page: 273, stat: Journal Article,

Phase I study of paclitaxel as a radiation sensitizer in the treatment of mesothelioma and non-small-cell lung cancer
Herscher, L L; Hahn, S M; Kroog, G; Pass, H; Temeck, B; Goldspiel, B; Cook, J; Mitchell, J B; Liebmann, J
1998 Feb;16(2):635-641, Journal of clinical oncology
PURPOSE: To determine the maximum-tolerated dose (MTD) and dose-limiting toxicities of paclitaxel with concurrent thoracic irradiation in patients with malignant pleural mesothelioma and locally advanced non-small-cell lung cancer (NSCLC) using a 120-hour continuous infusion regimen. A secondary objective was to assess the effect of paclitaxel on the cell cycle through serial tumor biopsies. PATIENTS AND METHODS: Paclitaxel was administered as a 120-hour (5-day) continuous infusion repeated every 3 weeks during the course of radiation therapy. The starting dose of paclitaxel was 90 mg/m2. Doses were escalated at 15-mg/m2 increments in successive cohorts of three patients. In NSCLC patients, radiation was delivered to the primary tumor and regional lymph nodes for a total tumor dose of 6,120 cGy. In mesothelioma patients, hemithoracic irradiation was delivered as the initial treatment field with a conedown to the tumor volume for a total dose of 5,760 to 6,300 cGy. Tumor biopsies were obtained, if possible, before and during paclitaxel treatment. RESULTS: Thirty patients were entered onto this study through three dose levels (from 90 mg/m2 to 120 mg/m2). The MTD was determined to be 105 mg/m2. The dose-limiting toxicity was grade 4 neutropenia (two patients). Grade 2 gastrointestinal (GI) toxicity (nausea and vomiting) was also observed at 120 mg/m2. Three of 30 patients developed a hypersensitivity reaction. Six patients had grade 2 lung injury manifested by a persistent cough that required antitussives. Five patients underwent tumor biopsies. None of the patients showed a significant block of cells in mitosis (G2/M) after paclitaxel infusion. CONCLUSION: The MTD of paclitaxel, when administered as a 120-hour continuous infusion with concurrent radiotherapy, was determined to be 105 mg/m2. The dose-limiting toxicity was neutropenia. Continuous infusion paclitaxel administered with large field irradiation of the lung is well tolerated and deserves continued evaluation
— id: 110917, year: 1998, vol: 16, page: 635, stat: Journal Article,

The biological activities of simian virus 40 large-T antigen and its possible oncogenic effects in humans
Matker CM; Rizzo P; Pass HI; Di Resta I; Powers A; Mutti L; Kast WM; Carbone M
1998 Apr;53(2):193-197, Monaldi archives for chest disease = Archivio Monaldi per le malattie del torace
Simian virus 40 (SV40) is an oncogenic virus which induces tumors in hamsters and transforms human cells in tissue culture. Between 1955 and 1963, polio vaccines and adenovaccines were contaminated with SV40; therefore, millions of people were exposed to this oncogenic virus. The SV40 proteins responsible for in vivo oncogenesis and in vitro cell transformation are encoded by the early region of the virus. These proteins are called T (tumor) antigens (Tags), because animals with tumors induced by SV40 have antibodies against these viral proteins. Recently, we and other research laboratories have found SV40 in specific types of human tumors: mesothelioma, ependymoma and choroid plexus tumors, osteosarcoma and sarcoma. The same tumor types will develop in hamsters which have been injected systemically with SV40. SV40 causes cell transformation in tissue culture and tumors in animals, because SV40 Tag binds and inactivates the cellular tumor suppressor gene products, Rb and p53. We found that SV40 Tag binds p53 and Rb in human mesotheliomas, possibly contributing to the malignant phenotype
— id: 59078, year: 1998, vol: 53, page: 193, stat: Journal Article,

Pancreatic cancer, gene delivery, and targets: the search for specificity
Pass HI
1998 Dec;5(8):667-669, Annals of surgical oncology
— id: 59071, year: 1998, vol: 5, page: 667, stat: Journal Article,

Surgical management of pulmonary metastases
Pass HI
1998 Mar;10(2):146-150, Current opinion in oncology
The management of pulmonary metastases remains controversial. More information is available, however, on outcomes in larger series of patients undergoing metastasectomy as well as the indications for the procedure. The role of video-assisted thoracic surgery for the diagnosis and management of these patients is being scrutinized carefully. Isolated perfusion techniques for treating patients with unresectable pulmonary metastases have been applied in phase I and II trials at selected institutions. More data regarding clinical outcomes are necessary, however, before widespread adaptation of this experimental form of treatment is accepted as standard practice
— id: 59079, year: 1998, vol: 10, page: 146, stat: Journal Article,

Human mesotheliomas contain the simian virus-40 regulatory region and large tumor antigen DNA sequences
Pass HI; Donington JS; Wu P; Rizzo P; Nishimura M; Kennedy R; Carbone M
1998 Nov;116(5):854-859, Journal of thoracic & cardiovascular surgery
BACKGROUND: A cohort (20%) of patients with mesothelioma will not have an exposure to asbestos. Recently, a DNA tumor virus (simian virus 40) has been shown to cause hamster mesotheliomas; we previously described simian virus 40-like DNA amino terminus sequences in 29 of 48 mesotheliomas. We analyzed an additional 42 mesotheliomas to determine (1) whether our initial observations were durable and (2) the extent to which the simian virus 40 genome is present in mesotheliomas. METHODS: Genomic DNA was extracted from snap frozen mesothelioma tumor samples and from the simian virus 40-induced hamster mesothelioma tumor H9A. Polymerase chain reaction primers were used to amplify various simian virus 40 large T-antigen regions including a 105-base pair amino terminus fragment, a 281-base pair carboxyl terminus fragment, and a 310-base pair fragment of the enhancer promoter region. Endonuclease digestions and Southern blotting were used to verify the expected product. RESULTS: Thirty of the 42 (71%) samples amplified T-antigen amino sequences, and specificity was verified by Southern hybridization. Sixteen of 42 samples (38%) amplified the appropriate size fragment for the carboxyl terminus, and digestion with BsaB1 matched that of H9A. Twenty-two of 42 samples (52%) amplified simian virus 40 regulatory sequences and Fok1 digestion matched that of the hamster control tumor. Sequence analysis (4 patients) revealed 100% homology with the regulatory region of simian virus 40 strain 776. CONCLUSIONS: These data suggest an association between the simian virus 40 virus and human mesothelioma that could be exploited for diagnostic/therapeutic options including early detection and potential vaccination strategies
— id: 59072, year: 1998, vol: 116, page: 854, stat: Journal Article,

The effect of an antisense expression plasmid to the IGF-1 receptor on hamster mesothelioma proliferation
Pass HI; Mew DJ; Carbone M; Donington JS; Baserga R; Steinberg SM
1998 ;94:321-328, Developments in biological standardization
We have evaluated the effect of antisense IGF receptor transcripts on the proliferation and tumorigenicity in an SV40-induced, immunocompetent hamster mesothelioma model (H9A). Expression of IGF-1 and IGF-1 receptor (IGF-1 R) genes was identified from H9A RNA using RT-PCR and Northern blot analysis. H9A cells were electroporated with inducible expression vectors (under the transcriptional control of heat shock promotor HSP70) containing a cDNA fragment corresponding to bp 1-309 of IGF-1 R in the sense or antisense orientation to generate the respective clones A3 sense or B9 antisense. At 39 degrees C, the B9 antisense transfectants demonstrated significantly less proliferation than A3 sense transfectants (p2 < 0.02). At 34 degrees C, cell growth of A3 sense and B9 antisense transfected cells was not significantly different. The A3 sense clones resulted in greater numbers of tumours in vivo compared to the B9 antisense clone (p2 = 0.0001). The inhibitory effect of IGF-1R antisense transcripts on hamster mesothelioma demonstrated in this study by decreased growth and tumorigenicity in vitro and in vivo may have implications for the therapy of human mesothelioma
— id: 59074, year: 1998, vol: 94, page: 321, stat: Journal Article,

Biology of metastatic disease
Pass HI; Temeck BA
1998 Feb;8(1):1-11, Chest surgery clinics of North America
Metastasis is highly organized and organ selective, a process involving multiple sequential steps. It occurs through complex interactions between tumor cells and the host. The surviving metastatic cells have heterogeneous biologic and antigenic or immunogenic properties, and the metastatic cells take over the homeostatic mechanisms of the host. Investigations at the genetic level are necessary to make advances in the early diagnosis, treatment, and prevention of metastatic disease
— id: 59082, year: 1998, vol: 8, page: 1, stat: Journal Article,

Preoperative tumor volume is associated with outcome in malignant pleural mesothelioma
Pass HI; Temeck BK; Kranda K; Steinberg SM; Feuerstein IR
1998 Feb;115(2):310-317, Journal of thoracic & cardiovascular surgery
OBJECTIVES: Our objective was to analyze the impact of preoperative and postresection solid tumor volumes on outcomes in 47 of 48 consecutive patients undergoing resection for malignant pleural mesothelioma who were treated prospectively and randomized to photodynamic therapy or no photodynamic therapy. METHODS: From July 1993 to June 1996, 48 patients with malignant pleural mesothelioma had cytoreductive debulking to 5 mm or less residual tumor by extrapleural pneumonectomy (n = 25) or pleurectomy/decortication (n = 23). Three-dimensional computed tomographic reconstructions of preresection and postresection solid tumor were prospectively performed and the disease was staged postoperatively according to the new International Mesothelioma Interest Group staging. RESULTS: Median survival for all patients is 14.4 months (extrapleural pneumonectomy, 11 months; pleurectomy/decortication, 22 months; p2 = 0.07). Median survival for preoperative volume less than 100 was 22 months versus 11 months if more than 100 cc, p2 = 0.03. Median survival for postoperative volume less than 9 cc was 25 months versus 9 months if more than 9 cc, p2 = 0.0002. Thirty-two of forty-seven (68%) had positive N1 or N2 nodes. Tumor volumes associated with negative nodes were significantly smaller (median 51 cc) than those with positive nodes (median 166 cc, p2 = 0.01). Progressively higher stage was associated with higher median preoperative volume: stage I, 4 cc; stage II, 94 cc; stage III, 143 cc; stage IV, 505 cc; p2 = 0.007 for stage I versus II versus III versus IV. Patients with preoperative tumor volumes greater than 52 cc had shorter progression-free intervals (8 months) than those 51 cc or less (11 months; p2 = 0.02). CONCLUSIONS: Preresection tumor volume is representative of T status in malignant pleural mesothelioma and can predict overall and progression-free survival, as well as postoperative stage. Large volumes are associated with nodal spread, and postresection residual tumor burden may predict outcome
— id: 59084, year: 1998, vol: 115, page: 310, stat: Journal Article,

Further validation of SV40-like DNA in human pleural mesotheliomas
Pass, H; Rizzo, P; Donington, J; Wu, P; Carbone, M
1998 ;94:143-145, Developments in biological standardization
We have confirmed in a second set of patients having human pleural mesothelioma that DNA for regions of the amino terminus of SV40 Tag can be amplified by the polymerase chain reaction. Moreover, other regions, including the carboxy terminus for Tag, and the regulatory region of SV40, are present in these specimens
— id: 110920, year: 1998, vol: 94, page: 143, stat: Journal Article,

Resection of a large, mediastinal germ cell tumor
Pass, Harvey I
St. Louis : Medical Vidoe Productions, 1998,
— id: 2171, year: 1998, vol: , page: , stat: ,

Evidence for and implications of SV40-like sequences in human mesotheliomas and osteosarcomas
Rizzo P; Di Resta I; Stach R; Mutti L; Picci P; Kast WM; Pass HI; Carbone M
1998 ;94:33-40, Developments in biological standardization
Pleural mesotheliomas and osteosarcomas develop in hamsters injected intracardially with SV40. Using primers specific for the RB-pocket binding domain of SV40 we analysed with the polymerase chain reaction frozen specimens from 48 human mesotheliomas and 145 human bone tumours. We found that 60% of human mesotheliomas and 33% of human bone tumours contained SV40-like DNA. Immunostaining, Western blot and RNA in situ hybridization experiments revealed SV40 Tag expression in human mesotheliomas. Osteosarcomas were not studied for Tag expression because not enough material was available. Finally, antibodies anti-Tag were detected in the sera collected from patients with mesothelioma. These data indicate that SV40, or a closely related virus, is/are present in human mesothelioma and osteosarcoma
— id: 59076, year: 1998, vol: 94, page: 33, stat: Journal Article,

The detection of simian virus 40 in human tumors by polymerase chain reaction
Rizzo, P; Di Resta, I; Powers, A; Matker, C M; Zhang, A; Mutti, L; Kast, W M; Pass, H; Carbone, M
1998 Apr;53(2):202-210, Monaldi archives for chest disease = Archivio Monaldi per le malattie del torace
Simian virus (SV) 40 is a deoxyribonucleic acid (DNA) virus that induces mesotheliomas, ependymomas, bone tumors, and lymphomas in hamsters. In recent years SV40 sequences have been detected in approximately 60% of mesotheliomas and ependymomas, in 33% of bone tumors and sarcomas, and in 13% of lymphomas. Because the amount of human specimens available for molecular studies is usually minimal, the method most commonly used to demonstrate SV40 in human specimens is the polymerase chain reaction (PCR). PCR is a highly sensitive and useful technique. In the PCR reaction, different sets of primers are used for targeting different regions of DNA. The regions of the SV40 genome targeted by PCR include the large T-antigen, the small t-antigen, the origin of replication, and viral protein-1 capsid protein. The use of these different sets of primers to test human tumor specimens for SV40 produce a different percentage of positive results. This is because these experiments revealed that some primers are more specific than others which may also detect sequences belonging to other DNA papovaviruses. Therefore, the combined use of different sets of primers is recommended when it is important to distinguish SV40 from other related papovaviruses such as BK and JC, which can also be occasionally present in human cells. Furthermore, these experiments demonstrated that polymerase chain reaction analyses for simian virus 40 can be performed better and easier when using deoxyribonucleic acid extracted from fresh and/or frozen tissue. Deoxyribonucleic acid from paraffin embedded specimens should not be used routinely for simian virus 40 testing because of the high risk of obtaining false negative results. However, these paraffin derived deoxyribonucleic acids can be used reliably in molecular laboratories specialized in these type of analyses. This paper describes the methods that we have developed to test simian virus 40 in human specimens
— id: 110919, year: 1998, vol: 53, page: 202, stat: Journal Article,

Metastatic mesothelioma presenting as a salivary gland neoplasm
Sgrignoli, A; Abati, A; Pass, H; Lebovics, R; Hijazi, Y
1998 May-Jun;42(3):818-820, Acta cytologica
— id: 110918, year: 1998, vol: 42, page: 818, stat: Journal Article,

Genetic polymorphism of CYP2D6 and lung cancer risk
Shaw GL; Falk RT; Frame JN; Weiffenbach B; Nesbitt JC; Pass HI; Caporaso NE; Moir DT; Tucker MA
1998 Mar;7(3):215-219, Cancer epidemiology biomarkers & prevention
Previous reports of the association of extensive debrisoquine metabolism, controlled by the cytochrome P450 CYP2D6, with increased lung cancer risk have been conflicting. We examined the hypothesis that genetic polymorphism at the CYP2D6 locus identifies individuals at increased risk for lung cancer in a case-control study of 98 incident Caucasian lung cancer patients and 110 age-, race-, and sex-matched controls conducted at the National Naval Medical Center, Bethesda, MD. Using germ line DNA, we identified inactivating mutations at the CYP2D6 locus (CYP2D6*3, CYP2D6*4, CYP2D6*5, and CYP2D6*6A), as well as those mutations that impair but do not abolish enzyme activity (CYP2D6*9 and CYP2D6*10A). Compared to subjects with homozygous inactivating mutations, no association with lung cancer was observed for those with homozygous or heterozygous functional alleles (odds ratios were 0.4 and 0.7, respectively). Furthermore, no excess risk was seen in any histological group or smoking category, and adjustment for smoking and sociodemographic characteristics did not alter the findings. Although the concept that genetic polymorphisms may contribute to differential lung cancer susceptibility is sound, these data do not support the role of CYP2D6 as a marker for elevated lung cancer risk
— id: 59080, year: 1998, vol: 7, page: 215, stat: Journal Article,

Reoperative pulmonary metastasectomy for sarcomatous pediatric histologies
Temeck BK; Wexler LH; Steinberg SM; McClure LL; Horowitz MA; Pass HI
1998 Sep;66(3):908-912, Annals of thoracic surgery
BACKGROUND: The role for reoperative pulmonary metastasectomy in patients with 'pediatric sarcomas' (osteosarcoma, nonrhabdomyosarcoma-soft tissue sarcoma, and Ewing's sarcoma) is undefined. METHODS: We reviewed our results for patients with these histologic presentations (median age, 17.5 years; range, 6 to 32 years) having two (70), three (27), or four (10) metastasectomies between January 1965 and March 1995 to define postresection survival and potential prognostic factors. Simple wedges (88 thoracotomies, 84%) were performed more frequently than anatomic (17 thoracotomies, 16%) resections. RESULTS: With a median potential follow-up of 12.7 years, median survival was 2.25, 3.60, and 0.96 years from the second, third, and fourth explorations, respectively. Primary tumor site, sex, histology, age, maximal metastasis size, and systemic chemotherapy did not influence survival. Resectability was the most important prognostic factor (5.6 versus 0.7 years, 5.2 versus 2.5 years, 2.2 versus 0.2 years, resectable versus unresectable, median survival from second, third, and fourth thoracotomy, respectively). Unresectability, disease-free interval less than 6 months between initial (ie, first) pulmonary resection and the second thoracotomy, and two or more preoperative nodules noted on the right were simultaneously negatively associated with survival from the second thoracotomy. Unresectability or finding two or more metastases negatively affected survival from the third thoracotomy. CONCLUSIONS: These data imply that repeat metastasectomy can salvage a subset of patients with sarcomatous pediatric histologic presentations who retain favorable prognostic determinants
— id: 59077, year: 1998, vol: 66, page: 908, stat: Journal Article,

Pharmacokinetics of fentanyl during hyperthermic, isolated lung perfusion
Williams KS; Susla G; Temeck BK; Piscitelli SC; Pass HI
1998 Mar;91(3):261-265, Southern medical journal
BACKGROUND: Hyperthermic, isolated pulmonary perfusion with tumor necrosis factor is a surgical procedure that isolates the pulmonary vasculature from the systemic circulation in patients with unresectable primary or metastatic disease confined to the chest. High drug levels are delivered to the perfused organ, avoiding systemic toxicity, and preventing loss of active drug through metabolism. METHODS: The pharmacokinetics of fentanyl are evaluated in three patients while the operative lung is hyperthermic, ventilated, and perfused with an asanguineous solution during nonpulsatile bypass. A loading dose of fentanyl, 1.5 microg/kg to 2.5 microg/kg, was given during the induction of anesthesia followed by a continuous infusion of 150 microg/hr. RESULTS: Results showed no difference in mean plasma fentanyl concentrations before, during, or after bypass and was consistent with clearance values previously reported in healthy adult surgical patients in the absence of an extracorporeal circuit. CONCLUSIONS: Adjustments in fentanyl dosing are not required before, during, or after hyperthermic, isolated pulmonary perfusion is established and a steady state of fentanyl is achieved
— id: 59081, year: 1998, vol: 91, page: 261, stat: Journal Article,

Detection of aneuploidy in mesothelioma cell lines by fluorescence in situ hybridization (FISH)
Abati, A; Sanford, J; Fetsch, P; Pass, H
1997 Apr;16(4):375-377, Diagnostic cytopathology
— id: 110915, year: 1997, vol: 16, page: 375, stat: Journal Article,

Benign and malignant mesothelioma
Antman KH; Pass HI; Schiff PB
Cancer : principles & practice of oncology Philadelphia PA : Lippincott-Raven, 1997,
— id: 5086, year: 1997, vol: , page: 1853, stat: Chapter,

Simian virus-40 large-T antigen binds p53 in human mesotheliomas
Carbone M; Rizzo P; Grimley PM; Procopio A; Mew DJ; Shridhar V; de Bartolomeis A; Esposito V; Giuliano MT; Steinberg SM; Levine AS; Giordano A; Pass HI
1997 Aug;3(8):908-912, Nature medicine
We found that simian virus 40 (SV40) induces mesotheliomas in hamsters and that 60% of human mesotheliomas contain and express SV40 sequences, results now confirmed by others [ref. 3-5, and presentations by D. Griffiths & R. Weiss, F. Galateau-SallE, and H.I.P. at 'Simian virus 40: A possible human polyoma virus,' NIH workshop, 27-28 January 1997, Bethesda, MD (transcript available through SAG Corp., Washington, DC 20008)]. Mesothelioma, an aggressive malignancy resistant to therapy, originates from the serosal lining of the pleural, pericardial and peritoneal cavities. The incidence of mesothelioma continues to increase worldwide because of exposure to crocidolite asbestos. However, at least 20% of mesotheliomas in the United States are not associated with asbestos exposure, and only a minority of people exposed to high concentrations of asbestos develop mesothelioma. Thus, other carcinogens may induce mesothelioma in individuals not exposed to asbestos, and/or may render particular individuals more susceptible to the carcinogenic effect of asbestos. We investigated whether the expression of the SV40 large T-antigen (Tag) interferes with the normal expression of the tumor suppressor gene p53 in human mesotheliomas. We found that SV40 Tag retains its ability to bind and to inactivate p53, a cellular protein that when normally expressed plays an important role in suppressing tumor growth and in inducing sensitivity to therapy. Our findings do not establish a cause-and-effect relation, but indicate that the possibility that SV40 contributes to the development of human mesotheliomas should be carefully investigated
— id: 59090, year: 1997, vol: 3, page: 908, stat: Journal Article,

Simian virus 40, poliovaccines and human tumors: a review of recent developments
Carbone M; Rizzo P; Pass HI
1997 Oct 16;15(16):1877-1888, Oncogene
Recently, wild-type SV40 and/or DNA sequences indistinguishable from SV40 have been detected in specific types of human tumors: ependymoma and choroid plexus tumors, mesothelioma, osteosarcoma and sarcoma. The same tumor types will develop in hamsters after injection with SV40. These findings are interesting in themselves for they could shed light on the pathogenesis of these tumors. These findings also have public health implications. SV40 was found to have contaminated the poliovaccines and the adenovaccines from 1955 until 1963, therefore resulting in the inadvertent injection of millions of people with this tumor virus. Moreover, our society pays a high cost for asbestos causality, a carcinogen associated with the development of mesothelioma. In addition to asbestos, the potential impact of finding another possible cause for mesothelioma (i.e., SV40), as well as the possible pathogenic role of the contaminated poliovaccines, has generated considerable public interest and concern. To discuss these recent findings, the NIH (National Institutes of Health) and the FDA (Food and Drug Administration), organized an International Conference at the NIH, Bethesda, MD, January 27-28, 1997. The association of SV40 with human mesothelioma was also discussed in a special session at the IV International Mesothelioma Conference that was held at the University of Pennsylvania, Philadelphia, PA, May 13-16, 1997. The purpose of this review is to summarize data, from the discovery of the contaminated poliovaccines, to the most recent findings presented at the meetings in Bethesda and Philadelphia, to discuss technical and other problems associated with this research, and the potential for using these findings to develop new diagnostic and therapeutic approaches for SV40-associated malignancies
— id: 59086, year: 1997, vol: 15, page: 1877, stat: Journal Article,

The retinoblastoma gene family pRb/p105, p107, pRb2/p130 and simian virus-40 large T-antigen in human mesotheliomas
De Luca A; Baldi A; Esposito V; Howard CM; Bagella L; Rizzo P; Caputi M; Pass HI; Giordano GG; Baldi F; Carbone M; Giordano A
1997 Aug;3(8):913-916, Nature medicine
The oncoprotein of simian virus-40, SV40 large T-antigen (Tag), is reported to target and to inactivate growth suppressive proteins such as the retinoblastoma family and p53 (ref. 4, 5), leading to transformation of human cell lines in vitro, tumor production in rodents, and detection of Tag in several human cancers including mesotheliomas. The retinoblastoma family contains three members, pRb, p107 and pRb2/p130 (ref. 9), that are phosphorylated in a cell cycle-dependent manner, have cell growth suppressive properties and bind to specific members of the E2F family and various cyclins. Even though mesotheliomas are among the most aggressive human cancers, alterations of important cell-cycle 'controllers,' such as the Rb family genes, have never been reported in these tumors. We found the presence of SV40-like sequences in 86% of 35 archival specimens of mesothelioma. We also demonstrated that SV40 Tag, isolated from frozen biopsies of human mesothelioma, binds each of the retinoblastoma family proteins, pRb, p107 and pRb2/p130, in four of four specimens. We propose that the tumorigenic potential of SV40 Tag in some human mesotheliomas may arise from its ability to interact with and thereby inactivate several tumor and/or growth suppressive proteins
— id: 59089, year: 1997, vol: 3, page: 913, stat: Journal Article,

Nonsurgical therapy for pulmonary hydatid cyst disease
Mawhorter, S; Temeck, B; Chang, R; Pass, H; Nash, T
1997 Nov 5;112(5):1432-1436, Chest
Therapeutic and diagnostic aspiration of Echinococcus granulosus liver cysts, but not pulmonary cysts, are increasingly being performed. Documented herein is the utility of percutaneous drainage and of albendazole treatment in a patient with a large recurrent, isolated, pulmonary echinococcal cyst for whom traditional therapy would have resulted in severe morbidity. Therapeutic options and possible complications are discussed
— id: 110916, year: 1997, vol: 112, page: 1432, stat: Journal Article,

Surgically debulked malignant pleural mesothelioma: results and prognostic factors
Pass HI; Kranda K; Temeck BK; Feuerstein I; Steinberg SM
1997 Apr-May;4(3):215-222, Annals of surgical oncology
BACKGROUND: We analyzed morbidity and mortality, sites of recurrence, and possible prognostic factors in 95 (78 male, 17 female) patients with MPM on phase I-III trials since 1990. A debulking resection to a requisite, residual tumor thickness of < or = 5 mm was required for inclusion. METHODS: Preoperative tumor volumes were determined by three-dimensional reconstruction of chest computerized tomograms. Pleurectomy (n = 39) or extrapleural pneumonectomy (EPP; n = 39) was performed. Seventeen patients could not be debulked. Preoperative EPP platelet counts (404,000) and mean tumor volume (491 cm3) were greater than that seen for pleurectomy (344,000, 114 cm3). RESULTS: Median survival for all patients was 11.2 months, with that for pleurectomy 14.5 months, that for EPP 9.4 months, and that for unresectable patients 5.0 months. Arrhythmia (n = 14; 15%) was the most common complication, and there were two deaths related to surgery (2.0%). Tumor volume of > 100 ml, biphasic histology, male sex, and elevated platelet count were associated with decreased survival (p < 0.05). Both EPP and pleurectomy had equivalent recurrence rates (27 of 39 [69%] and 31 of 39 [79%], respectively); however, 17 of 27 EPP recurrences as opposed to 28 of 31 pleurectomy recurrences were locoregional (p2 = 0.013). CONCLUSIONS: Debulking resections for MPM can be performed with low operative mortality. Size and platelet count are important preoperative prognostic parameters for MPM. Patients with poor prognostic indicators should probably enter nonsurgical, innovative trials where toxicity or response to therapy can be evaluated
— id: 59091, year: 1997, vol: 4, page: 215, stat: Journal Article,

Phase III randomized trial of surgery with or without intraoperative photodynamic therapy and postoperative immunochemotherapy for malignant pleural mesothelioma
Pass HI; Temeck BK; Kranda K; Thomas G; Russo A; Smith P; Friauf W; Steinberg SM
1997 Dec;4(8):628-633, Annals of surgical oncology
BACKGROUND: Patients with malignant pleural mesothelioma (MPM) usually die of progressive local disease. This report describes the results of a Phase III trial comparing maximum debulking surgery and postoperative cisplatin, interferon alpha-2b, and tamoxifen (CIT) immunochemotherapy with and without intraoperative photodynamic therapy (PDT) to determine (1) whether such a multimodal approach can be performed with minimum morbidity and mortality in malignant pleural mesothelioma (MPM), and (2) whether first-generation (i.e., 630-nm laser light, Photofrin II) intrapleural PDT impacts on local recurrence of survival. METHODS: From July 1993 to June 1996, 63 patients with localized MPM were randomized to either PDT or no PDT. The tumors of 15 patients could not be debulked to 5 mm. Patients assigned to PDT (n = 25) and no PDT (n = 23) were similar with respect to age, sex, tumor volume, and histology. RESULTS: The type of resection (11 pleurectomies and 14 pneumonectomies vs. 12 pleurectomies and 11 pneumonectomies), length postoperative stay, and ICU time were comparable (PDT vs. no PDT). There was one operative death (hemorrhage), and each group had two bronchopleural fistulas. Postoperative staging divided patients into the following categories: stage I: PDT, 2, no PDT, 2; stage II: PDT, 2, no PDT, 2; stage III, PDT, 21; no PDT, 17; stage IV, PDT, 0; no PDT, 2. Comparable numbers of CIT cycles were delivered. Median survival for the 15 non-debulked patients was 7.2 months, compared to 14 months for the 48 patients on protocol. There were no differences in median survival (14.4 vs. 14.1 months) or median progression-free time (8.5 vs. 7.7 months), and sites of first recurrence were similar. CONCLUSIONS: Aggressive multimodal therapy can be delivered for patients with higher stage MPM. First-generation PDT does not prolong survival or increase local control for MPM
— id: 59085, year: 1997, vol: 4, page: 628, stat: Journal Article,

Pulmonary infarcts can mimic pulmonary metastases from renal cancer
Wagner JR; Merino MJ; Pass HI; Linehan WM; Walther MM
1997 Nov;158(5):1688-1690, Journal of urology
PURPOSE: Spontaneous regression of pulmonary metastases from renal cell carcinoma is a rare but well documented event. We present 2 recent cases that were radiographically consistent with pulmonary metastases from renal cell carcinoma but were pathologically shown to be pulmonary infarcts with no evidence of metastatic cells. Stable pulmonary infarcts can be misconstrued as metastatic disease in patients with renal cell carcinoma while resolving pulmonary infarcts may represent a subpopulation of patients with apparent spontaneous regression. Clinical implications of these findings are discussed. MATERIALS AND METHODS: Clinical and pathological data from 2 patients with large primary renal tumors, venous thrombi and lung masses were reviewed. Data from these cases, as well as pertinent urological and pathological literature, are presented. RESULTS: Although preoperative assessment was consistent with stage IV renal cell carcinoma, pathological examination of the lung masses in these patients showed no evidence of tumor cells. CONCLUSIONS: Pulmonary infarcts may mimic resolving or stable pulmonary metastasis in patients with renal cell carcinoma. Accurate clinical staging is crucial for the prognosis and treatment of renal cell carcinoma. Mistaking pulmonary infarcts for metastatic lesions can lead to inaccurate prognoses and inappropriate treatment
— id: 59087, year: 1997, vol: 158, page: 1688, stat: Journal Article,

Cytoreductive surgery before high dose interleukin-2 based therapy in patients with metastatic renal cell carcinoma
Walther MM; Yang JC; Pass HI; Linehan WM; Rosenberg SA
1997 Nov;158(5):1675-1678, Journal of urology
PURPOSE: We defined the outcome of a strategy using cytoreductive surgery before high dose interleukin-2 (IL-2) therapy in patients with metastatic renal cell carcinoma. MATERIALS AND METHODS: During an 11-year period, 195 patients underwent cytoreductive surgery as preparation for high dose IL-2 based therapy. The renal primary and locoregional metastatic disease that could be safely resected was removed. RESULTS: Because of the large size 176 of 195 renal tumors (90%) were resected through transabdominal incision and in 45 patients (23%) a second additional significant procedure was performed. Five cases (2.6%) were unresectable and 2 (1%) perioperative deaths occurred. After surgery 121 of 195 patients (62%) were eligible for treatment with high dose IL-2 based protocols. Overall response rate to IL-2 based protocols was 18%. CONCLUSIONS: Cytoreductive surgery can be performed safely in patients with metastatic renal cell carcinoma. Although the impact of cytoreductive surgery on response to immunotherapy remains undefined, this combination of primary debulking and systemic IL-2 can result in durable complete tumor regression in some patients with metastatic renal cell carcinoma
— id: 59088, year: 1997, vol: 158, page: 1675, stat: Journal Article,

Development of an experimental murine pulmonary metastasis model incorporating a viral encoded tumor specific antigen
Watts AM; Shearer MH; Pass HI; Kennedy RC
1997 Dec;69(1-2):93-102, Journal of virological methods
A SV40 murine tumor model was developed and characterized involving intravenous inoculation of BALB/c mice with syngeneic SV40-transformed kidney fibroblasts (mKSA cells). Following intravenous inoculation with mKSA cells, viable tumor cells were recovered from primary organ cell culture of the brain, spleen, lungs, and kidneys of tumor bearing mice. The presence of mKSA tumor cells in these tissues was confirmed by morphological identification and by immunofluorescence directed to SV40 large tumor antigen (T-ag). Additionally, a computer assisted method was used to enumerate and quantitate the size of tumor foci. Tumor foci were observed in the lungs and were quantifiable based on both size and number. The number and size of foci observed in the lungs of tumor bearing mice was dependent on the dose of mKSA cells and time post-inoculation. Ultimately, the tumor burden in inoculated mice was found to be lethal. Quantification of tumor foci in the lung, survival data, and detection of metastasis to organs at sites distal to tumor cell inoculation, provides specific reference points for use in examining the mechanism(s) of the immune response to tumors expressing viral antigen and in evaluating immunologic based therapies within this new SV40 murine tumor model. The methods described herein can be applied for the development of new animal models of metastasis that express viral encoded tumor-specific antigens
— id: 59083, year: 1997, vol: 69, page: 93, stat: Journal Article,

SV40-like sequences in human bone tumors
Carbone M; Rizzo P; Procopio A; Giuliano M; Pass HI; Gebhardt MC; Mangham C; Hansen M; Malkin DF; Bushart G; Pompetti F; Picci P; Levine AS; Bergsagel JD; Garcea RL
1996 Aug 1;13(3):527-535, Oncogene
Simian virus 40 (SV40) is a monkey virus that induces ependymomas, choroid plexus tumors, mesotheliomas, osteosarcomas, sarcomas and true histiocytic lymphomas when injected in hamsters. Recently, approximately 60% of human ependymomas, choroid plexus tumors and mesotheliomas were reported to contain and express SV40-like sequences (N. Engl. J. Med., 1992, 36, 988-993; Oncogene, 1994, 9, 1781-1790). In this study the presence of SV40-like sequences was investigated in additional types of human tumors. Initially, 200 tumor and normal tissue DNA samples were analysed by polymerase chain reaction (PCR) with primers that amplify a 574 base pair region of SV40 large T antigen (Tag), which includes the Rb-pocket binding domain and the intron of Tag. PCR amplification and Southern blot hybridization with a probe specific for SV40 Tag revealed that 18/200 samples contained SV40-like sequences and, unexpectedly, 11/18 were from patients with osteosarcomas. Additional DNA samples from bone tumors were then analysed. In 40/126 osteosarcomas, and 14/34 other bone-related tumors, Tag sequences could be amplified. Sequence analysis of the DNA amplified from seven different tumors confirmed that the amplified sequences corresponded to SV40 Tag, with some demonstrating deletions in the intron region but not in the Rb-pocket binding domain. The extent of SV40 genome sequences present in the DNA samples was further analysed in two osteosarcomas. PCR amplification, Southern blot hybridization, and sequence analysis revealed that these samples also contained sequences for the carboxy-terminal domain of Tag, the viral regulatory region, and the VP1 capsid protein. These results indicate that SV40-like sequences are present in human bone tumors
— id: 59098, year: 1996, vol: 13, page: 527, stat: Journal Article,

Parathyroid adenomas in the aortopulmonary window
Doppman JL; Skarulis MC; Chen CC; Chang R; Pass HI; Fraker DL; Alexander HR; Niederle B; Marx SJ; Norton JA; Wells SA; Spiegel AM
1996 Nov;201(2):456-462, Radiology
PURPOSE: To describe localization studies in nine patients with ectopic parathyroid adenomas in the aortopulmonary window. MATERIALS AND METHODS: Nine patients with ectopic parathyroid tissue (eight adenomas, one hyperplastic gland) in the aortopulmonary window were examined with ultrasound (US), computed tomography (CT), magnetic resonance (MR) imaging, and scintigraphy. Diagnostic arteriography (n = 4) and venous sampling (n = 3) were performed in the first four patients; arteriography for the purpose of staining was attempted in the last five patients. RESULTS: The results of CT and MR imaging studies were positive in eight of nine patients (89%) and five of eight patients (63%), respectively. The results of thallium/technetium scintigraphy were negative in three patients scanned (0%), but the results of a repeat study in one patient were positive (33%). Sestamibi scans were positive in six of six patients (100%). Single photon emission CT was performed in all six patients and enabled distinction between adenomas in the aortopulmonary window and those in the thymus. CONCLUSION: Ectopic parathyroid glands in the aortopulmonary window are usually detected at sestamibi scintigraphy, and SPECT is helpful in distinguishing these adenomas from more common adenomas in the anterior mediastinum. CT and MR imaging studies can also enable this distinction, but imaging must extend below the aortic arch
— id: 59093, year: 1996, vol: 201, page: 456, stat: Journal Article,

Cytologic effects of photodynamic therapy in body fluids
Garza OT; Abati A; Sindelar WF; Pass HI; Hijazi YM
1996 Jun;14(4):356-361, Diagnostic cytopathology
Photodynamic therapy (PDT) has been used in phase I clinical trials at the National Institutes of Health for the treatment of malignancies disseminated within the peritoneal and pleural cavities. Review of records revealed 18 patients who were treated with PDT between April 1988-June 1993. Sixty-five pleural and peritoneal fluids, 22 pre- and 43 post-PDT, were available for evaluation. Mesothelial cell changes seen post-PDT included: increased nuclear-to-cytoplasmic ratios in 7/18 (39%), cytomegaly in 9/18 (50%), and multinucleation in 12/18 (67%), with Touton-like giant cells in 3/18 (17%). Additional changes noted post-PDT comprised histiocytic aggregates in 9/18 patients (50%), with granuloma-like clusters in 3/18 (17%), acute and chronic inflammation in 13/18 (72%), and eosinophilia in 8/18 (44%). Residual tumor was present in 7/18 (39%) patients post-PDT. In 2 patients with malignant mesothelioma, benign mesothelial cells with cytologic changes post-PDT were difficult to distinguish from malignant cells. Mesothelial cell changes following PDT, specifically increased nuclear-to-cytoplasmic ratios and cytomegaly, should be recognized to avert false-positive diagnoses of tumor. In patients with malignant mesothelioma, and less commonly with adenocarcinoma, benign mesothelial cells with changes secondary to PDT may be difficult to distinguish from tumor cells
— id: 59100, year: 1996, vol: 14, page: 356, stat: Journal Article,

Presence of an insulin-like growth factor I autocrine loop predicts uterine fibroid responsiveness to tamoxifen
Howe SR; Pass HI; Ethier SP; Matthews WJ; Walker C
1996 Sep 1;56(17):4049-4055, Cancer research
Uterine leiomyoma is an estrogen-responsive tumor, and the present studies examine the ability of the antiestrogen tamoxifen to modulate leiomyoma cell growth. Tamoxifen is an effective form of hormonal therapy for breast cancer, although the mechanism by which tamoxifen inhibits tumor growth is not well understood and may involve mechanisms other than the action of tamoxifen as an estrogen antagonist. Tamoxifen was found to inhibit the proliferation of three of five leiomyoma-derived cell lines (ELT cell lines) in vitro, including an estrogen receptor-negative cell line. The ability of tamoxifen to decrease leiomyoma growth was found to correlate with expression of insulin-like growth factor I (IGF-I) by the tumor cells, suggesting that the inhibitory effects of tamoxifen were associated with expression of this growth factor. The existence of an IGF-I autocrine loop in the cells was investigated, because transcripts for both IGF-I and its cognate receptor were expressed in the tamoxifen-responsive cell lines. An IGF-I RIA demonstrated secreted IGF-I protein in serum-free medium conditioned by the IGF-I-expressing cell line ELT 3, and this same medium supported the growth of IGF-requiring MCF-10A cells, indicating the presence of biologically active IGF-I in the conditioned medium. Exogenous IGF-I stimulated ELT 3 cell proliferation, confirming that this growth factor is mitogenic for leiomyoma cells. IGF-I neutralizing antibody inhibited ELT 3 growth, indicating that the levels of IGF-I produced by the leiomyoma cells were physiologically significant. These data demonstrate the existence of an IGF-I autocrine loop in tamoxifen-sensitive leiomyoma cells, supporting the hypothesis that the presence of an IGF-I autocrine loop predicts uterine fibroid responsiveness to tamoxifen
— id: 59096, year: 1996, vol: 56, page: 4049, stat: Journal Article,

Role of tissue diagnosis in pulmonary involvement in pediatric human immunodeficiency virus infection
Izraeli S; Mueller BU; Ling A; Temeck BK; Lewis LL; Chang R; Shad AT; Pass HI; Pizzo PA
1996 Feb;15(2):112-116, Pediatric infectious disease journal
BACKGROUND: Pulmonary complications occur commonly during HIV infection. The aim of this study was to evaluate the clinical value of lung tissue examination in the diagnosis and treatment of pulmonary disorders in children with HIV infection. METHODS: The medical records of 347 children enrolled between January, 1990, and April, 1994, into various antiretroviral therapy protocols were reviewed to identify patients who underwent a lung biopsy. RESULTS: Fourteen patients underwent diagnostic lung biopsies on 16 separate occasions. The most common radiologic findings were nodular infiltrates which were localized in 7 patients and diffuse in 6. Eight patients presented with fever and progressive respiratory distress unresponsive to empiric therapy, whereas the rest had progressive nodular infiltrates. The pathologic diagnoses included opportunistic infection in 7 patients, lymphocytic interstitial pneumonitis in 5, non-Hodgkin's lymphoma in 3 and interstitial fibrosis in 1. The biopsy led to a major change in the treatment of 7 patients which resulted in a significant improvement of the pulmonary process in all of them. In an additional patient the excisional biopsy proved curative. CONCLUSIONS: When patients are selected appropriately, lung biopsy might have a significant impact on therapy and outcome in HIV-infected children with pulmonary infiltrates
— id: 59102, year: 1996, vol: 15, page: 112, stat: Journal Article,

Patients with limited-stage small-cell lung cancer treated with concurrent twice-daily chest radiotherapy and etoposide/cisplatin followed by cyclophosphamide, doxorubicin, and vincristine
Johnson, B E; Bridges, J D; Sobczeck, M; Gray, J; Linnoila, R I; Gazdar, A F; Hankins, L; Steinberg, S M; Edison, M; Frame, J N; Pass, H; Nesbitt, J; Holden, D; Mulshine, J L; Glatstein, E; Ihde, D C
1996 Mar;14(3):806-813, Journal of clinical oncology
PURPOSE: A phase II trial in patients with limited-stage small-cell lung cancer treated with induction etoposide/cisplatin plus twice-daily chest radiotherapy was conducted in an attempt to increase response rates and prolong survival. PATIENTS AND METHODS: Fifty-four previously untreated patients with limited-stage small-cell cancer were treated with etoposide/cisplatin and concurrent radiotherapy at 1.5 Gy twice daily for 3 weeks to a total dose of 45 Gy. Patients then received three more cycles of etoposide/cisplatin followed by four cycles of vincristine, doxorubicin, and cyclophosphamide or an individualized chemotherapy regimen. RESULTS: Nine patients are alive and free of cancer a median of 4 years (range, 2 to 7) from the start of treatment. Thirty-eight have had progression of their cancer at a median of 1.2 years (range, 0.5 to 5.4) and all have died of small-cell cancer. Thirteen of these 38 patients' (34%) only site of initial relapse was in the CNS and all died of CNS metastases. Five patients died during therapy or from its complications and two patients died of causes other than relapsed small-cell lung cancer and toxicity. The median survival time is 21.3 months, with an actual survival rate of 83% at 1 year, and actuarial survival rates of 43% at 2 years and 19% at 5 years. CONCLUSION: This combined modality regimen for patients with limited-stage small-cell lung cancer results in a 2-year survival rate of 43%, but the principal cause of death in these patients is still relapse of the original cancer. Isolated CNS metastases caused more than 30% of the cancer deaths
— id: 110914, year: 1996, vol: 14, page: 806, stat: Journal Article,

Localization by venous sampling of occult chorionic gonadotropin-secreting tumor in a boy with mosaic Klinefelter's syndrome and precocious puberty
Leschek EW; Doppman JL; Pass HI; Cutler GB Jr
1996 Nov;81(11):3825-3828, Journal of clinical endocrinology & metabolism
— id: 59092, year: 1996, vol: 81, page: 3825, stat: Journal Article,

Evidence for and implications of SV40-like sequences in human mesotheliomas
Pass HI; Kennedy RC; Carbone M
1996 ;:89-108, Important advances in oncology
— id: 59105, year: 1996, vol: , page: 89, stat: Journal Article,

In vitro and in vivo studies of mesothelioma
Pass HI; Mew DJ
1996 ;24:142-151, Journal of cellular biochemistry. Supplement
Pleural mesothelioma is an asbestos-related malignancy characterized by progressive local growth, late metastases, and median survivals between 8 and 18 months. It is only recently that the in vitro and in vivo characteristics of the malignancy has been investigated. These investigations have been aided by the development of cell lines from patients with the disease, as well as lines developed from asbestos-exposed animals. Nude mouse models constructed with subcutaneous, intraabdominal, or intrathoracic innoculation of cultured cell lines or fresh tumor have been used for evaluating response to innovative therapies. Karyotyping has been performed on a number of cell lines and multiple abnormalities involving many chromosomes have been identified. Aneuploidy is commonly seen, along with reported non-random patterns of chromosomal aberrations. The role of tumor suppressor genes, including p53 is controversial. Multiple growth factors including PDGF are being investigated for a possible paracrine/autocrine loop, and PDGF receptors seem to be differentially expressed in mesothelioma cells compared to normal mesothelial cells. The role of cytokines in the pathophysiology of the disease, secreted either by the tumor cells themselves or by monocyte/macrophages in the local tumor environment, remains to be defined
— id: 59104, year: 1996, vol: 24, page: 142, stat: Journal Article,

Inhibition of hamster mesothelioma tumorigenesis by an antisense expression plasmid to the insulin-like growth factor-1 receptor
Pass HI; Mew DJ; Carbone M; Matthews WA; Donington JS; Baserga R; Walker CL; Resnicoff M; Steinberg SM
1996 Sep 1;56(17):4044-4048, Cancer research
We evaluated the effect of antisense insulin-like growth factor (IGF) receptor transcripts on the proliferation and tumorigenicity in an SV40-induced, immunocompetent hamster mesothelioma model (H9A). Expression of IGF-1 and IGF-1 receptor (IGF-1R) genes was identified from H9A RNA using reverse transcription-PCR and Northern analysis. H9A cells were electroporated with inducible expression vectors (under the transcriptional control of heat shock promoter HSP70) containing a cDNA fragment corresponding to base pairs 1-309 of IGF-1R in the sense or antisense orientation to generate the respective clones A3 sense or B9 antisense. The expression vector in genomic DNA was detected with PCR analysis as a 173-bp fragment on ethidium bromide gels. The effects of the expression vectors were then evaluated in vitro under active (at 39 degrees C) or inactive (at 34 degrees C) conditions. At 39 degrees C, the B9 antisense transfectants demonstrated significantly less proliferation than A3 sense transfectants (P2 < 0.02). At 34 degrees C, cell growth of A3 sense- and B9 antisense-transfected cells was not significantly different. In vivo tumorigenicity was evaluated in hamsters inoculated with 10(5) A3 sense- or B9 antisense-transfected cells. The A3 sense clones resulted in greater numbers of tumors in vivo compared to the B9 antisense clone (P2 = 0.0001). When genomic DNA from tumors that developed in A3 sense and B9 antisense animals was analyzed for the expression vectors, a 173-bp fragment amplified from the expression vector was identified in the sense tumors but not in antisense B9 or wild-type H9A tumors, indicating a loss of the vector from the antisense clones that proliferated in vivo. The inhibitory effect of IGF-1R antisense transcripts on hamster mesothelioma demonstrated in this study by decreased growth and tumorigenicity in vitro and in vivo may have implications for the therapy of human mesothelioma
— id: 59097, year: 1996, vol: 56, page: 4044, stat: Journal Article,

Isolated lung perfusion with tumor necrosis factor for pulmonary metastases
Pass HI; Mew DJ; Kranda KC; Temeck BK; Donington JS; Rosenberg SA
1996 Jun;61(6):1609-1617, Annals of thoracic surgery
BACKGROUND. A phase I trial was initiated to define the feasibility and safety of single-lung isolation perfusion with tumor necrosis factor-alpha, interferon-gamma, and moderate hyperthermia for patients with unresectable pulmonary metastases. METHODS. Twenty patients with lung metastases (Ewing's, 2; sarcoma, 8; melanoma, 6; other, 4) were considered for single-lung isolation perfusion with 0.3 to 6.0 mg of tumor necrosis factor-alpha and 0.2 mg interferon-gamma delivered through an oxygenated pump circuit. Sixteen perfusions were performed in 15 patients (bilateral in 1). Metastases were completely resected (no single-lung isolation perfusion) in 3 patients, 1 patient had extrapulmonary disease, and one single-lung isolation perfusion was aborted for mechanical reasons. RESULTS. There were no significant changes in systemic arterial blood pressure or cardiac output during perfusion. Systolic pulmonary artery pressure increased with isolation, but returned to pre-single-lung isolation perfusion levels after clamp release. The maximum systemic tumor necrosis factor-alpha level was 8 ng/mL, whereas pump-circuit levels ranged from 200 to 10,976 ng/mL. There were no deaths, and the mean hospitalization period was 9 days (range, 5 to 34 days). A short-term (6 to 9 month) unilateral decrease in perfused nodules was noted in 3 patients (melanoma in 1, adenoid cystic carcinoma in 1, renal cell carcinoma in 1). CONCLUSIONS. Future studies using a combination of biologic modifiers, chemotherapy, and hyperthermia should be pursued to define active cytotoxic agents that will preserve underlying pulmonary function
— id: 59101, year: 1996, vol: 61, page: 1609, stat: Journal Article,

Lung cancer : principles and practice
Pass, Harvey I
Philadelphia PA : Lippincott-Raven, 1996,
— id: 1465, year: 1996, vol: , page: , stat: ,

Oncogene alterations in primary, recurrent, and metastatic human bone tumors
Pompetti F; Rizzo P; Simon RM; Freidlin B; Mew DJ; Pass HI; Picci P; Levine AS; Carbone M
1996 Oct;63(1):37-50, Journal of cellular biochemistry
We investigated the structure and the expression of various oncogenes in three of the most common human bone tumors-osteosarcoma (36 samples from 34 patients), giant cell tumor (10 patients), and chondrosarcoma (18 patients)-in an attempt to identify the genetic alterations associated with these malignancies. Alterations of RB and p53 were detected only in osteosarcomas. Alterations of c-myc, N-myc, and c-fos were detected in osteosarcomas and giant cell tumors. Ras alterations (H-ras, Ki-ras, N-ras) were rare. Chondrosarcomas did not contain any detectable genetic alterations. Our results suggest that alterations of c-myc, N-myc, and c-fos oncogenes occur in osteosarcomas, in addition to those previously described for the tumor suppressor genes RB and p53. Moreover, statistical analyses indicate that c-fos alterations occur more frequently in osteosarcoma patients with recurrent or metastatic disease
— id: 59095, year: 1996, vol: 63, page: 37, stat: Journal Article,

Correlation of in vitro drug sensitivity testing results with response to chemotherapy and survival: comparison of non-small cell lung cancer and small cell lung cancer
Shaw GL; Gazdar AF; Phelps R; Steinberg SM; Linnoila RI; Johnson BE; Oie HK; Russell EK; Ghosh BC; Pass HI; Minna JD; Mulshine JL; Ihde DC
1996 ;24:173-185, Journal of cellular biochemistry. Supplement
Clinical protocols for small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) were devised to prospectively select individualized chemotherapy based on in vitro drug sensitivity testing (DST) of cell lines derived from the patient's SCLC tumor cell lines or the patient's fresh NSCLC tumor. DST data derived from SCLC tumor cell lines were available for 33/115 (29%) patients. The DST-selected chemotherapy regimen was administered to 21 (18%) patients, or 64% of patients with DST. In SCLC< the DST-selected chemotherapy was administered either during weeks 13-24 following 12 weeks of etoposide/cisplatin, or at relapse after complete response to etoposide/cisplatin. Several parameters of in vitro drug sensitivity were significantly associated (two-sided P < 0.05) with clinical response to primary therapy and also with response to the DST-selected chemotherapy regimen, but were not associated with survival (P = 0.24). Five patients treated with their DST-selected chemotherapy attained a complete or partial response, compared to 5 of 68 who received an empiric regimen (P = 0.057). A total of 36/165 (22%) NSCLC patients had DST successfully completed. These results directed management for 21/96 (22%) patients who eventually received chemotherapy, or 58% of patients with DST. Response to chemotherapy for the patients treated prospectively with their DST-selected chemotherapy regimen (2/21; 9%) was not significantly different than the response rate for patients treated empirically with etoposide/cisplatin (10/69; 14%) in the absence of in vitro results to direct chemotherapy (P = 0.73). There was no difference in survival by treatment group for the NSCLC patients. The correlation between in vitro and clinical response was not significant for any individual drug or for all drugs considered together, illustrating the poor predictive value of in vitro testing with currently available chemotherapy in NSCLC
— id: 59103, year: 1996, vol: 24, page: 173, stat: Journal Article,

Somatostatin analogue in the localization and treatment of bronchial carcinoid tumours
Temeck BK; Koong SS; Reynolds JC; Pass HI
1996 Oct-Dec;5(5-6):195-200, Surgical oncology
Octreotide scanning is increasingly being used to detect tumours with somatostatin receptors. Moreover, there is growing interest in the use of somatostatin analogues for the treatment of tumours with somatostatin receptors. This review documents the use at our institution of the octreotide scan in three patients with intrathoracic pathology, and comments on overall experience in the literature with this technology
— id: 59094, year: 1996, vol: 5, page: 195, stat: Journal Article,

Phase II trial of 5-fluorouracil, leucovorin, interferon-alpha-2a, and cisplatin as neoadjuvant chemotherapy for locally advanced esophageal carcinoma
Temeck BK; Liebmann JE; Theodossiou C; Steinberg SM; Cook JA; Metz DC; Shawker TH; Allegra CJ; Russo A; Pass HI
1996 Jun 15;77(12):2432-2439, Cancer
BACKGROUND: Most patients with esophageal carcinoma present with locally advanced disease and a poor prognosis. Surgery or radiation provides palliation for locally advanced esophageal carcinoma. The role of neoadjuvant therapy remains to be defined. We administered neoadjuvant chemotherapy consisting of 5-fluorouracil (5-FU), leucovorin, interferon-alpha, and cisplatin to 11 patients with locally advanced disease. METHODS: Eleven patients with squamous cell or adenocarcinoma of the esophagus were treated peroperatively with two to three cycles of combination chemotherapy. Nine patients underwent resection with curative intent. RESULTS: Six patients received three cycles of chemotherapy, and five received two. Dose reduction was necessary for two patients. One patient achieved a pathologic complete response, histologically confirmed. Of the eleven patients, two did not undergo surgery because of progressive disease during chemotherapy. Seven of the 9 patients relapsed after surgery and 2 have been disease free for 27 months. CONCLUSIONS: The combination 5-FU leucovorin, interferon-alpha-2a, and cisplatin administered in a neoadjuvant setting resulted in a median survival of 11.8 months with a median time to relapse of 7 months
— id: 59099, year: 1996, vol: 77, page: 2432, stat: Journal Article,

Thymidylate Synthase Protein Expression
Alexander HR; Grem JL; Hamilton JM; Pass HI; Hong M; Fraker DL; Steinberg SM; McAtee N; Allegra CJ; Johnston PG
1995 May;1(1):49-49, The cancer journal of Scientific American
PURPOSE: A phase II study of neoadjuvant fluorouracil, leucovorin, and interferon alpha-2a was conducted to determine the feasibility of this regimen's use and the response rates in patients undergoing resection for locally advanced gastric or gastroesophageal adenocarcinoma. Also, tumor protein expression of free, total, or bound thymidylate synthase before and after initial exposure to fluorouracil was quantitated to determine if thymidylate synthase expression is associated with response in this treatment setting. PATIENTS AND METHODS: Twenty-two patients with T3-4N0-2M0 gastric or gastroesophageal adenocarcinoma were treated with three cycles of neoadjuvant fluorouracil (370 mg/m2 intravenously on days 2 through 6), leucovorin (500 mg/m2 intravenously on days 2 through 6), and interferon alpha-2a (5x10(6) U/m2 subcutaneously days 1 through 7), followed by resection and three cycles of consolidation therapy. Endoscopic tumor biopsies were done in 13 patients before therapy and during cycle 2 of the 5-fluorouracil/leucovorin/interferon regimen, and total thymidylate synthase, free thymidylate synthase, bound thymidylate synthase, and percent complexed thymidylate synthase were quantitated by Western blot. Tumor protein expression was evaluated for its association with response to neoadjuvant therapy and patient survival. RESULTS: Eight of 21 (38%) evaluable patients had a partial response, and another 5 of 21 (24%) had a minor response (25% to 49% tumor reduction) after three cycles of neoadjuvant fluorouracil/leucovorin/interferon. The pretreatment total thymidylate synthase level was significantly higher in five nonresponders than in eight responders. After exposure to fluorouracil, levels of free thymidylate synthase were significantly lower and the percent bound thymidylate synthase was higher in responders than in nonresponders. The median potential follow-up period is 24 months, and 11 of 21 patients have died from disease. CONCLUSIONS: These preliminary results indicate that a response to neoadjuvant fluorouracil-based therapy may be associated with decreased levels of total thymidylate synthase before therapy and free thymidylate synthase after exposure to fluorouracil in patients with locally advanced gastric cancer. Quantification of thymidylate synthase protein expression before and after exposure to fluorouracil may provide a method to select patients for fluorouracil therapy in the neoadjuvant, adjuvant, or advanced-disease setting based upon the fundamental sensitivity of the tumor
— id: 59110, year: 1995, vol: 1, page: 49, stat: Journal Article,

Wilms' tumor 1 susceptibility (WT1) gene products are selectively expressed in malignant mesothelioma
Amin KM; Litzky LA; Smythe WR; Mooney AM; Morris JM; Mews DJ; Pass HI; Kari C; Rodeck U; Rauscher FJ 3rd; et al.
1995 Feb;146(2):344-356, American journal of pathology
The distinction between malignant mesothelioma and other neoplastic processes involving the pleura is difficult, partly due to the lack of specific markers expressed on mesothelioma. Because of evidence suggesting that the Wilms' tumor susceptibility gene (WT1), unlike other tumor suppressor genes, is restricted mostly to mesenchymally derived tissues, we hypothesized that the WT1 gene products could serve as a potential marker for mesothelioma. The expression of WT1 mRNA was analyzed in 19 malignant mesothelioma cell lines and 9 tumors and compared with the expression of WT1 in 10 non-small cell lung cancer lines and 9 lung cancer specimens. WT1 mRNA was detectable by Northern analysis in 16 of 19 mesothelioma cell lines and in 5 of 8 malignant mesothelioma tumors. In contrast, WT1 mRNA was not detected by Northern analysis in non-small cell lung cancer lines or carcinomas. Immunoprecipitation with an anti-WT1 monoclonal antibody showed that a 52- to 54-kd protein was present in 4 mesothelioma cell lines. Immunostaining with this antibody localized the WT1 protein to the nucleus in two mesothelioma lines and in 20 of 21 mesothelioma tumors examined. This distinctive pattern of nuclear immunoreactivity was absent in 26 non-mesothelioma tumors involving the lung, including 20 non-small cell lung carcinomas. The detection of WT1 mRNA or protein may thus provide a specific molecular or immunohistochemical marker for differentiation of mesothelioma from other pleural tumors, in particular, adenocarcinoma
— id: 59116, year: 1995, vol: 146, page: 344, stat: Journal Article,

Malignant pleural mesothelioma: newer aspects of carcinogenesis, molecular genetics, and prospects for future therapies
Donington JS; Mew DJ; Pass HI
1995 Aug;4(4):175-185, Surgical oncology
Malignant pleural mesothelioma (MPM) is an asbestos-related disease which, although rare, is having a major social impact, and is, for the majority of cases, an incurable illness. There has been a surge of information regarding data on mesothelial transformation, mesothelioma molecular genetics and somatic gene therapy for this disease. This report summarizes the most recent investigations attempting to characterize the behaviour, on a cellular and molecular level, of MPM, with an emphasis on data from investigations performed at the National Cancer Institute with our collaborators
— id: 59108, year: 1995, vol: 4, page: 175, stat: Journal Article,

Use of photodynamic therapy for the management of pleural malignancies
Pass HI; Donington JS
1995 Sep-Oct;11(5):360-367, Seminars in surgical oncology
Photodynamic therapy (PDT) is a surface oriented, locally cytotoxic intervention being investigated for oncologic therapy. Surfaces such as the pleura or the peritoneum are frequently involved with primary or metastatic cancer, and the chance for cure in such situations is low due to the inability to eradicate all the disease. A series of investigations have been performed at the National Cancer Institute since 1985 studying the possible use of PDT for large cavity treatment. This report details evolution of the methodology, toxicity, and overall feasibility of the delivery of intrapleural PDT to patients after debulking of primary and malignant chest neoplasms, with an emphasis on malignant pleural mesothelioma. These investigations have culminated in an ongoing Phase III trial to define the efficacy of intrapleural PDT
— id: 59107, year: 1995, vol: 11, page: 360, stat: Journal Article,

The macrophage, TNF, and other cytokines
Pass HI; Mew D; Pass HA; Temeck BK
1995 Feb;5(1):73-90, Chest surgery clinics of North America
A complex interplay of peptides known as the cytokines may have a tremendous influence over a number of inflammatory related conditions. Tumor necrosis factor occupies an early and central role in the initiation of cascades that ultimately influences a number of cell types involved in tissue inflammation, tissue rejection, cancer, and injuries from ischemia reperfusion. Only now are the cascades being defined and therapies being designed to interrupt the toxic effects of these cytokines and to treat malignancy
— id: 59117, year: 1995, vol: 5, page: 73, stat: Journal Article,

Characteristics of nine newly derived mesothelioma cell lines
Pass HI; Stevens EJ; Oie H; Tsokos MG; Abati AD; Fetsch PA; Mew DJ; Pogrebniak HW; Matthews WJ
1995 Apr;59(4):835-844, Annals of thoracic surgery
This report characterizes nine new cell lines derived from patients with malignant pleural mesothelioma. The lines were initiated between July 1990 and July 1992 from solid tumors (5 lines) or effusions (4 lines) and had proliferated for a period of at least 2 months without senescence. They were characterized by cell size, doubling time, immunohistochemical analyses, electron microscopy, and chromosomal karyotyping. Growth factor/cytokine elaboration was determined using enzyme-linked immunoassays. The established lines were similar in morphology to their parent tumor (ie, epithelial or sarcomatoid). Cell sizes ranged from 59 to 81 microns, and the doubling times varied from 31 to 65 hours. The lines stained with cytokeratin and showed expected negative staining for adenomarkers including B72.3 and carcinoembryonic antigen. All cell lines exhibited aneuploidy, with modal chromosome numbers between 40 and 81 and had multiple chromosomal aberrations. Significant production of granulocyte-monocyte colony-stimulating factor, leukemia inhibitory factor, platelet-derived growth factor, and interleukin-6 was seen. These new cell lines derived from human mesotheliomas can now be used to aid in the design of innovative treatment strategies
— id: 59112, year: 1995, vol: 59, page: 835, stat: Journal Article,

A phase II trial investigating primary immunochemotherapy for malignant pleural mesothelioma and the feasibility of adjuvant immunochemotherapy after maximal cytoreduction
Pass HW; Temeck BK; Kranda K; Steinberg SM; Pass HI
1995 May;2(3):214-220, Annals of surgical oncology
BACKGROUND: The treatment of malignant pleural mesothelioma (MPM) continues to be inadequate with the use of standard techniques, including surgery, radiotherapy and chemotherapy. We initiated a phase II trial of immunochemotherapy with cisplatinum (25 mg/m2 four times weekly), interferon-alpha (5 mU/m2 s.c. three times weekly, and tamoxifen (20 mg orally twice a day for 35 days) (CIT) based on in vitro and in vivo data suggesting interrelating efficacy of this combination. METHODS: Since July 1991, 36 patients have been evaluable for response after receiving one to five cycles of CIT. Ten additional patients had debulking surgery followed by two cycles of postoperative adjuvant CIT commencing a mean of 6 weeks after surgery. RESULTS: Toxicity was acceptable (4% grade III/IV). One treatment-related death (2%) occurred, from myocardial infarction. A 19% partial response rate, objectively quantified using three-dimensional computerized tomographic (CT) measurement of solid disease volume, was recorded. The median survival for the seven responders was 14.7 months, whereas that of the nonresponders was 8 months (p2 = 0.2). Median survival for the entire group was 8.7 months. Preoperative size, platelet count > 360,000/ml, and nonepithelial histology were associated with shortened survival. CONCLUSIONS: The CIT regimen has some activity in MPM and can be delivered after debulking resection. In good-risk patients, as defined by favorable prognostic factors, a randomized trial using this combination may be warranted
— id: 59111, year: 1995, vol: 2, page: 214, stat: Journal Article,

High CD44 Expression on Human Mesotheliomas Mediates Association with Hyaluronan
Penno MB; Askin FB; Ma H; Carbone M; Vargas MP; Pass HI
1995 Oct;1(3):196-196, The cancer journal of Scientific American
PURPOSE: Malignant pleural mesothelioma is a rare malignancy with major environmental implications regarding passive asbestos exposure. We have conducted an immunohistochemical and functional study to address three questions: (1) What is the representation of CD44 on tumor cells as detected by immunohistochemistry? (2) Do cultured cell lines derived from malignant pleural mesothelioma tissue express the same CD44 phenotypes as the original tumors, and can they serve as a model for the study of CD44 in mesotheliomas? (3) What is the functional status of the CD44 expressed on mesotheliomas, with regard to hyaluronan anchorage? MATERIALS AND METHODS: Thirty-seven samples of pleural mesothelioma were obtained from patients entered on phase I/II protocols conducted in the Surgery Branch of the National Cancer Institute since 1991. The diagnosis was confirmed in all 37 patients by means of a battery of immunohistochemical tests for markers differentiating malignant pleural mesothelioma from adenocarcinoma. Tumor-positive lymph nodes and distant metastases were also examined in six of the patients. Cell lines, established from tumor tissue of six of the patients described above, were used in these experiments. Four (H2596, H2461, H2373, H2452) were derived from primary solid tumors and two (HP-1 and HP-3) were derived from effusions. RESULTS: Immunohistochemical staining with a monoclonal antibody (H4C4) that recognizes a constant region of human CD44 demonstrated that 34 (92%) of the malignant pleural mesotheliomas examined expressed CD44 on 50% to 100% of their cells. The extent of CD44 expression was apparently related to histologic subtype with the highest expression seen in epithelioid mesotheliomas and the least in sarcomatoid tumors. Tumor cell lines established from the primary tumors or effusions of six of the malignant pleural mesothelioma patients showed high expression of the hematopoietic form of CD44. Four of these cell lines exhibited strong attachment to hyaluronan in an in vitro attachment assay, indicating that their CD44 was functional with respect to hyaluronan anchorage. Hyaluronan attachment was specific in that it could be abolished by preincubation with epitope-specific anti-CD44 antibodies or soluble substrate or by hyaluronidase treatment of attachment surfaces. CONCLUSIONS: We conclude that CD44 is highly expressed on human mesotheliomas, that cell lines adequately represent tumor expression, and that CD44 mediates association with hyaluronan, a major component of pleural fluid
— id: 59106, year: 1995, vol: 1, page: 196, stat: Journal Article,

Neurofibromatosis type 2 (NF2) gene is somatically mutated in mesothelioma but not in lung cancer
Sekido Y; Pass HI; Bader S; Mew DJ; Christman MF; Gazdar AF; Minna JD
1995 Mar 15;55(6):1227-1231, Cancer research
We have found 16 of 28 small cell lung cancers, 17 of 31 non-small cell lung cancers, 2 of 3 carcinoids, and 12 of 14 mesotheliomas that had chromosome 22 cytogenetic abnormalities. To determine whether the neurofibromatosis type 2 (NF2) gene located on chromosome 22 participates in the oncogenesis of these malignancies, we studied DNAs from lung cancer cell lines and mesotheliomas using Southern blot analysis and the single-strand conformation polymorphism (SSCP) technique for mutations covering 8 of the 16 known NF2 exons. We detected 7 mutations in 17 mesotheliomas (41%) within the coding region of NF2 but none in 75 lung cancer cell lines (38 small cell lung cancers, 34 non-small cell lung cancers, and 3 carcinoids). These mutations were found to be somatic when normal tissue was available for testing. Four mesothelioma cell lines had relatively large deletions (approximately 10-50 kilobases) in the NF2 gene detectable by Southern blot analysis. Two mesothelioma cell lines had nonsense mutations at codons 57 and 341, respectively. Another mesothelioma obtained as a specimen directly from a patient, had a 10-base pair microdeletion from nucleotide 1004 to nucleotide 1013 causing a frameshift mutation. These results suggest that the NF2 gene participates in the oncogenesis in a subset of mesotheliomas but not in lung cancers
— id: 59113, year: 1995, vol: 55, page: 1227, stat: Journal Article,

Debrisoquine metabolism and lung cancer risk
Shaw GL; Falk RT; Deslauriers J; Frame JN; Nesbitt JC; Pass HI; Issaq HJ; Hoover RN; Tucker MA
1995 Jan-Feb;4(1):41-48, Cancer epidemiology biomarkers & prevention
Previous reports of the association between the debrisoquine metabolic polymorphism and lung cancer risk have been conflicting. We examined the hypothesis that the genetically determined ability to metabolize debrisoquine identifies individuals at increased risk for lung cancer in a study designed to address some of the methodological criticisms of previous studies. A case-control study of 335 incident Caucasian lung cancer patients and 373 controls matched for age, race, sex, and hospital, was conducted at the National Naval Medical Center (Bethesda, MD) and at the Laval Hospital (Sainte-Foy, Quebec, Canada). Debrisoquine metabolic phenotype was determined by debrisoquine administration and analysis of debrisoquine and 4-hydroxydebrisoquine in the subsequent 8-h urine collected. Stratified and logistic regression analyses were used to evaluate the association between extensive or intermediate debrisoquine metabolism and lung cancer risk. We found no increased risk among extensive or intermediate metabolizers (odds ratio, 0.6; 95% confidence interval, 0.3-1.2). The lack of an association was not confounded by control diagnoses, medications used within 1 month of debrisoquine administration, smoking, stage, or histology of lung cancer. No relationship was found among either heavy smokers or light and nonsmokers. Our results do not support the role of debrisoquine metabolism as a marker for lung cancer risk. While the concept that polymorphisms of metabolism may account for differential susceptibility to lung cancer is sound, debrisoquine metabolic phenotype was not associated with lung cancer risk in these data
— id: 59119, year: 1995, vol: 4, page: 41, stat: Journal Article,

Esophagopleural fistula: a complication of photodynamic therapy
Temeck BK; Pass HI
1995 Mar;88(3):271-274, Southern medical journal
Mesothelioma of the pleura remains an incurable disease for which novel treatments are being investigated. One of these is intraoperative photodynamic therapy (PDT), using the principle of cell cytotoxicity produced by light-activated sensitization. We report a complication of this therapy that defined the maximal tolerated dose of PDT, ie, esophagopleural fistula, in two consecutive patients who had received the same dose of PDT at the time of extrapleural pneumonectomy
— id: 59114, year: 1995, vol: 88, page: 271, stat: Journal Article,

Metastasectomy for sarcomatous pediatric histologies: results and prognostic factors
Temeck BK; Wexler LH; Steinberg SM; McClure LL; Horowitz M; Pass HI
1995 Jun;59(6):1385-1389, Annals of thoracic surgery
We reviewed our experience of pediatric metastasectomy to define (1) morbidity/mortality in this population and (2) any preoperative or intraoperative prognostic predictors of survival. One hundred fifty-two patients with median age 19 years (range, 5 to 33 years) had 258 thoracic explorations (Ewing's sarcoma, 28; rhabdomyosarcoma, 6; nonrhabdomyosarcoma soft tissue sarcoma, 42; and osteosarcoma, 76). Resections were accomplished by 218 wedge resections, 19 anatomic resections, 14 wedge and anatomic resections, 4 wedge and chest wall resections, and 3 wedge resections/other procedures. An initial complete resection was accomplished in 121/152 patients (80%). With a median potential follow-up of 10.6 years, median survival from initial thoracotomy is 2.2 years. By the Cox proportional hazards model, three or more positive nodules (p = 0.021), histology other than osteosarcoma (p = 0.0054), and incomplete resection (p < 0.0001) were unfavorable prognostic factors for survival. Two or more positive nodules (p = 0.0049), left location (p = 0.0031), age 14 years or greater at diagnosis (p = 0.0052), or rhabdomyosarcoma (p = 0.0066) predicted shorter pulmonary progression-free survivals after resection. Nonrhabdomyosarcoma pediatric metastasectomy can yield selected long-term survival. Morbidity/mortality is low, and a complete resection, if possible, is paramount. Prognostic factors can be defined that can be used to define the limits of this therapy to the patient and family
— id: 59109, year: 1995, vol: 59, page: 1385, stat: Journal Article,

Pulmonary malignant lymphoma of mucosa-associated lymphoid tissue (MALT) arising in a pediatric HIV-positive patient
Teruya-Feldstein J; Temeck BK; Sloas MM; Kingma DW; Raffeld M; Pass HI; Mueller B; Jaffe ES
1995 Mar;19(3):357-363, American journal of surgical pathology
A malignant lymphoma arising in the lung of a pediatric HIV-positive patient exhibited histologic and clinical features of low-grade B-cell lymphoma of mucosa-associated lymphoid tissue (MALT). Clinically, the neoplasm consisted of a 4-cm mass in the left-upper lobe of the lung of a 7-year-old girl. The lung mass was surgically resected. Monoclonal immunoglobulin heavy and light chain gene rearrangements were shown by Southern blot. Monoclonality of light chain expression was demonstrated by immunohistochemistry. Coexpression of Leu-22 (CD43) by the tumor cells supported the diagnosis of lymphoma. The remainder of the pulmonary parenchyma distal to the mass was associated with pulmonary lymphoid hyperplasia/lymphocytic interstitial pneumonitis, which may have been a predisposing factor. Gastric MALT lymphomas have recently been described in adult HIV-antibody-positive patients. Ours represents the first reported case of a pulmonary MALT lymphoma in a pediatric HIV-positive patient. In addition, at age 7, this is the youngest patient reported with a MALT lymphoma
— id: 59115, year: 1995, vol: 19, page: 357, stat: Journal Article,

Cytomegalovirus enteritis after treatment with 5-fluorouracil, leukovorin, cisplatin, and alpha-interferon
Theodossiou, C; Temeck, B; Vargas, H; Yang, J; Vargas, M; Hahn, S; Pass, H
1995 Jul;90(7):1174-1176, American journal of gastroenterology
— id: 110910, year: 1995, vol: 90, page: 1174, stat: Journal Article,

Isolation perfusion with tumor necrosis factor-alpha, interferon-gamma, and hyperthermia in the treatment of localized and metastatic cancer
Yang JC; Fraker DL; Thom AK; Pass HI; Rosenberg SA
1995 ;138:161-166, Recent results in cancer research = Fortschritte der Krebsforschung = Progres dans les recherches sur le cancer
— id: 59118, year: 1995, vol: 138, page: 161, stat: Journal Article,

Simian virus 40-like DNA sequences in human pleural mesothelioma
Carbone M; Pass HI; Rizzo P; Marinetti M; Di Muzio M; Mew DJ; Levine AS; Procopio A
1994 Jun;9(6):1781-1790, Oncogene
Mesotheliomas are pleural, pericardial, or peritoneal neoplasms frequently associated with asbestos exposure, and it is estimated that over the next twenty years up to 80,000 new cases are expected in the USA alone. We found simian virus 40-like DNA sequences in 29 of 48 mesotheliomas studied (60%) and demonstrated simian virus large-T antigen expression in 13 of 16 specimens. The matching lung samples did not contain simian virus 40-like sequences; however, they contained asbestos. These findings are to our knowledge the first demonstration of a physical link between DNA virus-like sequences and human mesothelioma. We suggest that a simian virus 40-like virus may act independently or as a co-carcinogen with asbestos. Moreover, the selective large T antigen expression by mesothelioma and not by the surrounding pulmonary parenchyma may have both diagnostic and therapeutic implications
— id: 59130, year: 1994, vol: 9, page: 1781, stat: Journal Article,

Postoperative complications in patients receiving suramin therapy
Cole DJ; Ettinghausen SE; Pass HI; Danforth DN; Linehan MW; Myers CW; Cooper MR; Sindelar WF
1994 Jul;116(1):90-95, Surgery
BACKGROUND. Suramin is an antiparasitic agent that is currently being evaluated for antineoplastic activity. Documented toxicities of suramin include adrenal and renal insufficiency, coagulation factor abnormalities, immunosuppression, and polyneuropathy. These adverse effects have potential for contributing to postoperative morbidity in surgical patients. Because no experience with suramin has been reported in the surgical literature, this 5-year retrospective review of postoperative complications in patients receiving suramin was performed. METHODS. From a review of 171 charts, 14 patients were identified who had undergone a major surgical procedure either while receiving intravenous suramin or within 1 year after its administration. Primary diagnoses included prostate cancer (six), lymphoma (four), ovarian cancer (two), colon cancer (one), and glioblastoma (one). All patients received replacement dose hydrocortisone at the initiation of suramin therapy and thereafter. RESULTS. Eighteen major surgical procedures were performed with 18 complications occurring in five patients. The predominant complications encountered were hemorrhage (five), impaired wound healing (three), and bowel dysmotility (two). A highly significant relationship existed between the incidence of complications and interval from completion of suramin therapy to the time of operation (p < 0.0005), with 17 of the 18 morbidities occurring within the first month. The length of operation (p < 0.05) and amount of blood transfused during the procedure were related to postoperative morbidity (p < 0.05). No other factors evaluated were correlated to complications. CONCLUSIONS. This experience suggests the avoidance of elective procedures during the first month after suramin therapy and a heightened awareness of the potential for bleeding and wound healing problems in patients receiving suramin who do require an emergent procedure
— id: 59129, year: 1994, vol: 116, page: 90, stat: Journal Article,

A comparison of the standard high dose dexamethasone suppression test and the overnight 8-mg dexamethasone suppression test for the differential diagnosis of adrenocorticotropin-dependent Cushing's syndrome
Dichek HL; Nieman LK; Oldfield EH; Pass HI; Malley JD; Cutler GB Jr
1994 Feb;78(2):418-422, Journal of clinical endocrinology & metabolism
To improve the overnight 8-mg dexamethasone (DEX) suppression test (DST) for differential diagnosis of Cushing's syndrome and to develop optimal criteria for its interpretation, we increased the number of blood samples and measured the suppression of both plasma ACTH and cortisol. Forty-one patients who were subsequently proven at surgery to have Cushing's syndrome were studied (34 Cushing's disease and 7 ectopic ACTH secretion). DEX (8 mg, orally) was administered at 2300 h. Blood samples for ACTH and cortisol measurements were obtained at 0800, 0830, and 0900 h on the day before and at 0700, 0800, 0900, and 1000 h on the morning after DEX treatment. The conventional 6-day DST was also performed, with measurement of both urinary free cortisol and urinary 17-hydroxysteroids as indices of suppression. Optimal criteria for the diagnosis of Cushing's disease were developed for both the overnight 8-mg and the 6-day tests using receiver operating characteristic curves. The results were compared with those using the previously published criteria for diagnosis of Cushing's disease by the overnight 8-mg test (> 50% suppression of plasma cortisol at 0700-0800 h). In our patients, the previously published criterion for the overnight 8-mg test yielded high sensitivity (88%), but low specificity (57%), in making the diagnosis of Cushing's disease. When the time of cortisol measurement and the diagnostic criteria for Cushing's disease were revised to achieve 100% specificity, the sensitivity of the overnight 8-mg test was 71%, which was not significantly different from that of the 6-day test (79%; P = NS). Addition of plasma ACTH levels to the test did not improve diagnostic accuracy compared to that with measurement of plasma cortisol levels alone. When the revised 8-mg overnight dexamethasone suppression test was combined with the 6-day dexamethasone suppression test, sensitivity increased to 91%, with a specificity of 100%, which was significantly better than that of the overnight 8-mg test alone (P < 0.002). We conclude that the overnight 8-mg DST has low specificity for the diagnosis of Cushing's disease when performed as originally described. However, with revised sampling times and diagnostic criteria, the overnight test has sensitivity and specificity similar to those of the conventional 6-day DST. The diagnostic performance of a criterion that combines the results of both tests is better than the diagnostic performance of either test alone
— id: 59134, year: 1994, vol: 78, page: 418, stat: Journal Article,

Clara cell 10 kDa protein mRNA in normal and atypical regions of human respiratory epithelium
Jensen, S M; Jones, J E; Pass, H; Steinberg, S M; Linnoila, R I
1994 Sep 1;58(5):629-637, International journal of cancer
We used RNA-RNA in situ hybridization to study expression of the human CC10 gene in morphologically normal and atypical areas of 32 non-neoplastic lung specimens resected from 26 non-small cell lung cancer patients. We scored strong, moderate or weak levels of CC10 mRNA expression in 3 distinct lung compartments. In morphologically normal lungs, strong and moderate levels of CC10 mRNA were observed in bronchioli and bronchi, respectively, but the expression was rarely observed in the alveolar region. Distinct alterations in CC10 mRNA expression were noted in specific histologic abnormalities within bronchi and the alveolar region. CC10 hybridization signal decreased markedly in bronchi containing diffuse goblet cell hyperplasia or squamous metaplasia, while CC10 mRNA expression remained unchanged in bronchi with basal cell hyperplasia or focal goblet cell hyperplasia. Bronchiolar CC10 mRNA levels remained unchanged in sections containing abnormalities elsewhere. Interestingly, in alveoli with bronchiolization of the alveoli, high levels of CC10 mRNA were observed. These regions also contained strongly stained keratin 14-positive cells, which may indicate a concurrent metaplastic process. In lungs with morphologic atypias, no correlation was found between abnormalities detected in bronchi and alveoli from the same lung. A comparison of mRNA expression and clinicopathologic features demonstrated that the amount of histologic abnormalities increased with smoking history (pack years); however, no correlation between CC10 mRNA expression and sex, age or smoking history was found
— id: 110909, year: 1994, vol: 58, page: 629, stat: Journal Article,

Surgical pathology of the lung in chronic granulomatous disease
Moskaluk CA; Pogrebniak HW; Pass HI; Gallin JI; Travis WD
1994 Nov;102(5):684-691, American journal of clinical pathology
The pathologic features in pulmonary specimens are reported from 32 open thoracotomies of 20 patients with chronic granulomatous disease (CGD). The pattern of inflammation present in the resected material varied, but a granulomatous component was present in each case. In 78% of the specimens, a distinctive form of granuloma was found: a neutrophilic microabscess surrounded by palisading histiocytes. In four specimens eosinophils were also found within the microabscesses. This feature was found exclusively in cases of fungal infection. Fungal organisms were found by culture in 18 specimens (56%) and in 17 of these specimens (94%), they also were seen by histopathology. In 9 cases (28%) routine bacterial cultures were positive, and in one case an atypical Mycobacterium was cultured. These organisms were not prospectively identified on special stains of histologic sections in any of the cases. Abscess formation was found more commonly in pure fungal infections (41%) than in pure bacterial infections (14%). In contrast to earlier reports, well-formed granulomas with giant cells were not specific for fungal infections. In this series, they were present in 57% of cases with pure bacterial infections. A subset of the patients received gamma interferon therapy or granulocyte transfusions before the surgical procedures. No differences in the histopathology of the inflammation were associated with granulocyte transfusions, but gamma interferon therapy was associated with a reduction in necrotizing granulomatous inflammation. Additionally, one case of severe cytomegalovirus pneumonitis is described in a CGD patient receiving chronic steroid therapy
— id: 59121, year: 1994, vol: 102, page: 684, stat: Journal Article,

Integrated clinical and basic studies related to circumventing non-small cell lung cancer drug resistance
Mulshine, J L; Johnson, B E; Gazdar, A F; Shaw, G L; Kramer, B S; Mitsudomi, T; Minna, J D; Pass, H; Phelps, R; Ghosh, B
1994 Mar;10 Suppl 1:S73-S81, Lung cancer
Consideration of a range of clinical and basic studies conducted at the National Cancer Institute which explore the nature of the tumor biology of lung identify the limitations of using chemotherapy for the treatment of advanced lung cancer. No single mechanistic explanation for lung cancer's chemoresistance is apparent, although considerable information about the biology of lung cancer and some of its clinical consequences have been elucidated. In contrast to previous works from our group, this presentation will focus principally on studies of the nature of drug resistance with non-small cell cancer. An alternative combined modality strategy for lung cancer control is to focus on epithelial progression of lung cancer using local modalities while it is still confined to the bronchial epithelium. Particular high risk populations may be appropriate to determine if local tools such as photodynamic laser therapy can be effective in this application. To deal with the underlying biochemical perturbations resulting from critical exposure of the bronchial epithelium to carcinogens, rational biochemical intervention with 13 cis retinoic acid are being evaluated in several clinical trials. An evolution towards more effective lung cancer control may involve the combined modalities of laser ablation of accessible dysplastic epithelium and chronic administration of intervention agents, such as retinoids, to neutralize cancer promotion dynamics in the more remote areas of the lung epithelium
— id: 110911, year: 1994, vol: 10 Suppl 1, page: S73, stat: Journal Article,

1987: Delivery of intraoperative radiation therapy after pneumonectomy: experimental observations and early clinical results. Updated in 1994
Pass HI
1994 Jul;58(1):269-270, Annals of thoracic surgery
— id: 59128, year: 1994, vol: 58, page: 269, stat: Journal Article,

Contemporary approaches in the investigation and treatment of malignant pleural mesothelioma
Pass HI
1994 Aug;4(3):497-515, Chest surgery clinics of North America
The cellular and molecular biology of mesothelioma is a complicated, multifactorial, incompletely understood process of carcinogenesis. Normal mesothelial cells can be transformed into a malignant phenotype by multiple factors, usually asbestos. Several tumor suppressor genes may be lost, and several oncogenes can be activated. A local environment of inflammation with associated release of cytokines may promote deregulated cell growth. The release of immunosuppressive substances such as nitric oxide may contribute to this process. The interaction of asbestos and viral DNA incorporation is unclear but warrants further investigation. In the majority of mesothelioma patients, present standard therapies have little effect on survival. Clinical trials studying a variety of innovative treatment strategies are being performed at centers with a significant referral base for the disease. Future treatments, however, must be based on understanding of the biology of mesothelioma
— id: 59127, year: 1994, vol: 4, page: 497, stat: Journal Article,

Malignant pleural mesothelioma: the thoracic surgeon and gene therapy
Pass HI
1994 Jun;57(6):1383-1384, Annals of thoracic surgery
— id: 59132, year: 1994, vol: 57, page: 1383, stat: Journal Article,

Intrapleural photodynamic therapy: results of a phase I trial
Pass HI; DeLaney TF; Tochner Z; Smith PE; Temeck BK; Pogrebniak HW; Kranda KC; Russo A; Friauf WS; Cole JW; et al.
1994 Jan;1(1):28-37, Annals of surgical oncology
BACKGROUND: The management of pleural neoplasms, specifically mesothelioma, remains difficult. We performed a phase I trial in 54 patients with isolated hemithorax pleural malignancy to determine (a) the feasibility of intraoperative, intrapleural photodynamic therapy after debulking surgery; (b) the influence of light dose/sensitizer interval on postoperative morbidity in order to define the photodynamic therapy (PDT) maximal tolerated dose (MTD); and (c) whether first order dosimetry could be applied to this complex geometry. METHODS: Cohorts of three patients were given escalating intraoperative light doses of 15-35 J/cm2 48 h after i.v. delivery of 2.0 mg/kg Photofrin II (Quadra Logic Technologies, Vancouver, British Columbia, Canada), and then escalating light doses of 30-32.5 J/cm2 after a 24-h sensitizer/operation interval. Twelve patients could not be debulked to the prerequisite 5 mm residual tumor thickness. The remaining 42 patients underwent 19 modified pleuropneumonectomies, five lobectomy-pleurectomies, and 18 pleurectomies. Intrapleural PDT was delivered using 630 nm light from two argon pump-dye lasers, and real-time and cumulative light doses were monitored using seven uniquely designed, computer-interfaced photodiodes. RESULTS: There was one 30-day mortality from intraoperative hemorrhage. In the 48-h sensitizer/operation group (n = 33), possible PDT-related complications included an empyema with late hemorrhage in one of three patients at 17.5 J/cm2 and a bronchopleural fistula at 35 J/cm2. At each of these light doses, three additional patients were treated without complication. Two patients subjected to 24-h sensitizer dosing and 32.5 J/cm2 developed esophageal perforations after pleuropneumonectomy at identical sites. The MTD was declared as 30 J/cm2 light with a 24-h dosing interval when none of the six patients (three original, three repeat) at that level developed toxicity. CONCLUSIONS: These data demonstrate that resection and intrapleural PDT can be performed safely with currently available sensitizers and lasers. Phase II and III trials are now warranted at this MTD in a homogeneous population of patients with pleural malignancies
— id: 59137, year: 1994, vol: 1, page: 28, stat: Journal Article,

Potential uses of prostaglandin E1 analog for cardiovascular disease
Pass HI; Pogrebniak HW
1994 Oct;108(4):789-790, Journal of thoracic & cardiovascular surgery
— id: 59123, year: 1994, vol: 108, page: 789, stat: Journal Article,

Isolated lung perfusion with tumor necrosis factor: a swine model in preparation of human trials
Pogrebniak HW; Witt CJ; Terrill R; Kranda K; Travis WD; Rosenberg SA; Pass HI
1994 Jun;57(6):1477-1483, Annals of thoracic surgery
Isolated lung perfusion with tumor necrosis factor (TNF) potentially could deliver high doses of drug and avoid systemic toxicity in patients with unresectable lung cancer or metastases. We investigated the feasibility of isolated lung perfusion with TNF in a pig model. Eleven animals had left-sided isolated lung perfusion with no TNF (n = 3), 40 micrograms/kg TNF (n = 2), 80 micrograms/kg TNF (n = 3), and 40 micrograms/kg TNF at moderate (39.5 degrees C) hyperthermia (n = 3). Hemodynamic monitoring and measurement of systemic and pulmonary circuit TNF levels were performed. Surviving animals were electively sacrificed a minimum of 6 months after isolated lung perfusion. All sham-perfused pigs survived. Isolated lung perfusion elevated pulmonary artery pressure, decreased cardiac output, and had minimal effects on mean pressure (15 +/- 0 versus 32 +/- 8 mm Hg, 4.5 +/- 1.1 versus 3.03 +/- 0.03 L/min, 67 +/- 11 versus 61 +/- 2 mm Hg; before versus after 90 minutes of isolated lung perfusion). Both 40 micrograms/kg animals and 2 of the 3 hyperthermic perfusion pigs survived, with 1 requiring pneumonectomy. Of the three 80 micrograms/kg animals, 1 survived, 1 died, and 1 required pneumonectomy. Survivors, compared with dying animals, had lower systemic/pulmonary TNF ratios and lower peak systemic TNF levels. All surviving pigs were electively sacrificed. These data justify phase I human protocols of isolated lung perfusion with TNF and hyperthermia; however, intraoperative leak rates must be monitored to ensure pulmonary isolation because systemic TNF levels may dictate treatment morbidity/mortality
— id: 59131, year: 1994, vol: 57, page: 1477, stat: Journal Article,

Tumor necrosis factor induces doxorubicin resistance to lung cancer cells in vitro
Prewitt TW; Matthews W; Chaudhri G; Pogrebniak HW; Pass HI
1994 Jan;107(1):43-49, Journal of thoracic & cardiovascular surgery
Tumor necrosis factor can alter the cell cycle of tumor cells and protect hematopoietic stem cells from cell cycle-specific chemotherapy, but the ability of tumor necrosis factor to protect cancer cells from chemotherapy by manipulation of the cell cycle is unknown. Twenty-four-hour exposure of A549 human lung cancer cells to tumor necrosis factor shifted cells from S phase to G0/G1 phase as determined by analysis of isolated cell nuclei with an FACScan Cell Sorter. This effect was not seen in cells exposed to interleukin-1 or interleukin-6. Growth assays demonstrated that tumor necrosis factor slowed the doubling time of A549 cells, confirming that tumor necrosis factor caused G0/G1 arrest in these cells. Pretreatment with tumor necrosis factor rendered cells resistant to subsequent 1-hour exposure to doxorubicin, a chemotherapeutic agent active against S phase cells. Tumor necrosis factor did not protect cells against either cisplatin or mitomycin C, drugs not specific for S phase. Measurement of intracellular drug levels indicated that pretreatment with tumor necrosis factor did not affect doxorubicin uptake or efflux. These findings suggest that cells producing tumor necrosis factor within a tumor may render surrounding malignant cells resistant to cell cycle-specific chemotherapy, and this mechanism may explain failure of sequential immunotherapy-chemotherapy protocols
— id: 59135, year: 1994, vol: 107, page: 43, stat: Journal Article,

Pulmonary artery-bronchial fistula during lymphoma treatment
Shilyansky J; Wilson W; Temeck BK; Pass HI
1994 Oct;108(4):790-791, Journal of thoracic & cardiovascular surgery
— id: 59122, year: 1994, vol: 108, page: 790, stat: Journal Article,

A method to facilitate subxiphoid pericardiotomy
Temeck BK; Pass HI
1994 Apr;57(4):1015-1017, Annals of thoracic surgery
Pericardial effusion can be treated effectively by the technique of subxiphoid pericardial window. We present a case in which the Cooper retractor designed for transcervical thymectomy facilitated this operation. When available, the Cooper retractor can be useful in selected patients
— id: 59133, year: 1994, vol: 57, page: 1015, stat: Journal Article,

Thoracotomy for pulmonary mycoses in non-HIV-immunosuppressed patients
Temeck BK; Venzon DJ; Moskaluk CA; Pass HI
1994 Aug;58(2):333-338, Annals of thoracic surgery
Pulmonary mycoses can be life threatening in patients who are in an immunocompromised state stemming from defective host defenses or the use of certain treatment regimens. In 36 immunosuppressed patients undergoing thoracotomy for the treatment of pulmonary fungal disease, the underlying cause of immunosuppression was malignancy (n = 9), Wegener's granulomatosis (n = 4), hematologic disorders (aplastic anemia, 5-Q minus syndrome, or myelofibrosis) (n = 6), or chronic granulomatous disease of childhood (n = 17). The mean age of the patients was 25 years, and 89% were symptomatic (fever, n = 27; cough, n = 20; chest pain, n = 14; and other, n = 13). Chest x-ray studies revealed the presence of cavitary disease (n = 7), a mass (n = 8), infiltrates (n = 20), or cavity and infiltrate (n = 1). A preoperative diagnosis was lacking in 23 of the 36 patients. Procedures included wedge biopsy (n = 13), segmentectomy with or without wedge or chest wall resection (n = 5), lobectomy with or without chest wall resection (n = 16), wedge resection plus completion pneumonectomy (n = 1), and segmentectomy plus completion pneumonectomy (n = 1). Fungi identified included Aspergillus (n = 23), Zygomycetes (n = 4), Cryptococcus (n = 3), and other (n = 6; 1 each), and specific antifungal treatment was instituted in 34 of the patients (94%). The 31% operative (ie, < 30-day or inhospital) mortality was chiefly due to multiorgan system failure (9/11).(ABSTRACT TRUNCATED AT 250 WORDS)
— id: 59126, year: 1994, vol: 58, page: 333, stat: Journal Article,

Intrathoracic photodynamic therapy: a canine normal tissue tolerance study and early clinical experience
Tochner ZA; Pass HI; Smith PD; DeLaney TF; Sprague M; DeLuca AM; Harrington F; Thomas GF; Terrill R; Bacher JD; et al.
1994 ;14(2):118-123, Lasers in surgery & medicine
Surgery with intraoperative photodynamic therapy (PDT) has the potential to improve the treatment of pleural malignancies. Before embarking on such treatment in humans, however, thoracic tissue tolerance to PDT was studied. For each of three (1 week, 1 month, and 6 month) study end-points, one control (no Photofrin II [PII]) and four treated animals underwent thoracotomy 72 hours after I.V. injection (6 mg/kg) PII. Red light (630 nm) was delivered (5-40 J/cm2) to the pleural surface (1 cm diameter) of selected thoracic organs. No clinical differences were observed between PDT and control dogs. The control showed no histological changes; however, in the treated animals focal areas of coagulation necrosis were found at 1 week which progressed to fibrosis at 1 month. The extent and depth of injury was proportional to light dose. The lung was the most sensitive; the chest wall was the most resistant. Myocardium had superficial damage, whereas coronary arteries appeared normal. The results provide the basis for proceeding to phase I human trials in the evaluation of PDT as an intraoperative adjuvant treatment in the management of pleural malignancies
— id: 59136, year: 1994, vol: 14, page: 118, stat: Journal Article,

Wilms' tumor suppressor gene expression in rat and human mesothelioma
Walker, C; Rutten, F; Yuan, X; Pass, H; Mew, D M; Everitt, J
1994 Jun 15;54(12):3101-3106, Cancer research
Induction of mesothelioma in the rat is an important animal model for assessing the carcinogenic potential of fibers and for understanding the molecular basis underlying the development of these tumors. Mesotheliomas and nephroblastoma (Wilms' tumor) have many developmental, biochemical, and histological similarities; however, the expression of the Wilms' tumor suppressor gene, WT-1, has not been well characterized in the rat, and its expression pattern in rat or human mesothelioma has not been described. We report that WT-1 transcripts (3.2 kilobases) could be detected by Northern analysis in adult rat testis, spleen, kidney, lung, heart, and glomerular mesangial cells. Normal adult mesothelial cells also expressed this gene. Rat mesothelioma cell lines expressed WT-1 transcripts of 3.2 kilobases and an additional 2.8-kilobase transcript, previously only reported to be expressed in the testis. Normal and transformed rat mesothelial cells expressed all four of the WT-1 splice variants, except testis, which only expressed WT-1 splice variants containing exon 5. Seven of seven human mesothelioma cell lines examined also expressed WT-1 transcripts, suggesting that expression of this gene may be useful in the diagnosis of these tumors
— id: 110912, year: 1994, vol: 54, page: 3101, stat: Journal Article,

Invasive zygomycosis due to Conidiobolus incongruus
Walsh TJ; Renshaw G; Andrews J; Kwon-Chung J; Cunnion RC; Pass HI; Taubenberger J; Wilson W; Pizzo PA
1994 Sep;19(3):423-430, Clinical infectious diseases
During the past decade, an increasing spectrum of pathogenic Zygomycetes fungi have caused infections in humans. The preponderance of these deeply invasive infections have been caused by members of the order Mucorales. However, deeply invasive zygomycoses due to genera of the order Entomophthorales (Conidiobolus species and Basidiobolus species) have seldom been reported. We describe a granulocytopenic patient with pulmonary and pericardial zygomycosis due to Conidiobolus incongruus, describe this organism's susceptibility to antifungal agents, characterize its diagnostic microbiological characteristics, and review previously reported cases of deeply invasive zygomycosis due to Conidiobolus species. In immunocompromised patients, C. incongruus is an uncommon but highly invasive fungal pathogen that may be resistant to amphotericin B and can be distinguished from other Zygomycetes fungi by characteristic mycological features
— id: 59124, year: 1994, vol: 19, page: 423, stat: Journal Article,

Intrapericardial pheochromocytoma complicated by massive intraoperative hemorrhage
Williams KS; Temeck BK; Pass HI
1994 Nov;87(11):1164-1167, Southern medical journal
Middle mediastinal pheochromocytomas are exceedingly rare. Because so few cases have been reported, consensus has not been reached regarding the anesthetic management of patients with these tumors. The use of cardiopulmonary bypass (CPB) for the resection of intrapericardial pheochromocytomas has met with varied success. We report the first documented case of successful anesthetic and surgical management of an acute, massive hemorrhage during the dissection of an intrapericardial pheochromocytoma, which was managed without cardiopulmonary bypass. Perioperative anesthetic considerations, including the risks and benefits of CPB, are discussed
— id: 59120, year: 1994, vol: 87, page: 1164, stat: Journal Article,

Loss of heterozygosity on the short arm of chromosome 3 in mesothelioma cell lines and solid tumors
Zeiger MA; Gnarra JR; Zbar B; Linehan WM; Pass HI
1994 Sep;11(1):15-20, Genes, chromosomes & cancer
Cytogenetic analysis of mesothelioma cell lines and solid tumors has documented non-random chromosomal abnormalities on the short arm of chromosome 3 from 3p14 to 3p25. We therefore examined nine mesothelioma cell lines, their corresponding tumors, and 15 additional mesothelioma tumors for loss of heterozygosity on 3p from 3p13 to 3p25.5 by polymerase chain reaction and restriction fragment length polymorphism analysis at 8 loci: D3S3, D3S30, D3S6, D3S2, D3S32, D3F15S2, THRB, and VHL. Loss of heterozygosity was documented by loss of one of two alleles in the tumor DNA whose corresponding normal DNA was heterozygous and was documented in four of nine mesothelioma cell lines and six of 15 mesothelioma tumors or a total of 42% of the mesotheliomas evaluated. This study suggests the involvement of a gene on the short arm of chromosome 3 in the development of mesotheliomas
— id: 59125, year: 1994, vol: 11, page: 15, stat: Journal Article,

Neoadjuvant chemotherapy for locally advanced gastric adenocarcinoma
Alexander HR; Grem JL; Pass HI; Hamilton M; McAtee N; Fraker DL; Allegra CJ
1993 May;7(5):37-42, Oncology
Gastric adenocarcinoma is typically diagnosed at an advanced stage, and even with 'curative' gastrectomy, most patients die of recurrent disease. Neoadjuvant chemotherapy for locally advanced gastric cancer is an experimental treatment strategy that may increase resectability and improve survival for patients afflicted with an almost uniformly fatal neoplasm. At our institution, we are evaluating the efficacy of fluorouracil, leucovorin, and interferon alfa-2A administered for three cycles, followed by surgery and consolidation therapy for patients with T3-4, N1-2, M0 gastric adenocarcinoma. The rationale for the use of neoadjuvant therapy combined with radical extirpative surgery in this setting and related issues are discussed
— id: 59147, year: 1993, vol: 7, page: 37, stat: Journal Article,

Pulmonary cryptococcosis presenting as metastases in children with sarcomas
Allende M; Pizzo PA; Horowitz M; Pass HI; Walsh TJ
1993 Mar;12(3):240-243, Pediatric infectious disease journal
— id: 59151, year: 1993, vol: 12, page: 240, stat: Journal Article,

Expression of c-myc in progenitor cells of the bronchopulmonary epithelium and in a large number of non-small cell lung cancers
Broers, J L; Viallet, J; Jensen, S M; Pass, H; Travis, W D; Minna, J D; Linnoila, R I
1993 Jul;9(1):33-43, American journal of respiratory cell & molecular biology
We performed in situ hybridization for c-myc, N-myc, and L-myc mRNA expression using 35S-labeled cRNA probes on frozen sections of 19 pairs of non-small cell lung cancers (NSCLC) and the surrounding non-neoplastic lung tissue. In non-neoplastic lung, c-myc expression was strongest in bronchial epithelium basal cells and hyperplastic alveolar type II pneumocytes, which are potential progenitor cells for bronchopulmonary epithelium and their tumors. In contrast, N-myc and L-myc mRNAs were not detected in non-neoplastic lung. In studies of freshly resected primary tumors, expression of c-myc was detected in 11 of 19 NSCLC (with the highest levels in squamous cell carcinomas), two of which also expressed L-myc, while N-myc expression was never detected. Levels of c-myc expression in tumors were significantly higher than in non-neoplastic lung samples. We conclude that: (1) c-myc expression in non-neoplastic lung tissues is highest in bronchial basal cells and hyperplastic type II cells, and (2) in NSCLC, overexpression of the myc-proto-oncogene is common
— id: 110913, year: 1993, vol: 9, page: 33, stat: Journal Article,

Intraoperative ultrasound in the evaluation of tumor involvement of the inferior vena cava
Long JP; Choyke PL; Shawker TA; Robertson CA; Pass HI; Walther MM; Linehan WM
1993 Jul;150(1):13-17, Journal of urology
The successful excision of genitourinary malignancies extending to the inferior vena cava relies heavily on accurate preoperative imaging. For the majority of these patients magnetic resonance imaging, inferior venacavography, abdominal ultrasound or abdominal computerized tomography will reliably predict the extent of inferior vena caval involvement by tumor. However, occasionally the results of these studies will conflict or be called into question intraoperatively. We report on 8 patients considered to be at risk for inferior vena caval involvement by tumor and for whom intraoperative ultrasound was obtained to clarify the presence or extent of thrombus. Five patients had renal cell carcinoma and 3 had adrenal carcinoma. In all patients concern as to the extent or presence of tumor was based on either inconclusive preoperative studies or unexpected intraoperative findings. In each case intraoperative ultrasound clearly visualized the inferior vena cava and established the presence or extent of tumor invasion. In 4 patients venacavotomy was avoided as a consequence of these findings. Intraoperative ultrasound is a useful tool that can accurately assess the inferior vena cava for possible tumor invasion, especially when the presence or extent of tumor involvement is not definitively established preoperatively
— id: 59145, year: 1993, vol: 150, page: 13, stat: Journal Article,

Photodynamic therapy in oncology: mechanisms and clinical use
Pass HI
1993 Mar 17;85(6):443-456, Journal of the National Cancer Institute
In photodynamic therapy (PDT), a sensitizer, light, and oxygen are used to cause photochemically induced cell death. The mechanism of cytotoxicity involves generation of singlet oxygen and other free radicals when the light-excited sensitizer loses or accepts an electron. Although selective retention of sensitizer by malignant tissue is seen in vivo, the mechanisms for this sensitizer targeting remain unclear. The first-generation sensitizers are porphyrin based and vary in lipophilicity and hydrophilicity. Targeting of the vasculature seems to be a prominent feature of the cytotoxic effect of these sensitizers in vivo, with resulting necrosis. Treatment depth varies with the wavelength of light that activates the sensitizer used, and the second-generation sensitizers are activated at longer wavelengths, allowing for a 30% increase in treatment depths. The selectivity of targeting can be increased when the sensitizer is delivered with the use of liposomes or monoclonal antibodies specific for tumor antigens. Studies have demonstrated direct effects of PDT on immune effector cells, specifically those with lineage from macrophages or other monocytes. Clinically, this therapy has been chiefly used for palliation of endobronchial and esophageal obstruction, as well as for treatment of bladder carcinomas, skin malignancies, and brain tumors. The future of PDT rests in defining its use either as an intraoperative adjuvant to marginal surgical procedures or as a primary treatment for superficial malignancies. Phase III trials in esophageal cancer and lung cancer are in progress and will help in evaluation of whether Photofrin II, the most widely used sensitizer, can be added to the oncologic armamentarium, pending approval from the U.S. Food and Drug Administration
— id: 59149, year: 1993, vol: 85, page: 443, stat: Journal Article,

Malignant pleural mesothelioma
Pass HI; Pogrebniak HW
1993 Oct;30(10):921-1012, Current problems in surgery
— id: 59142, year: 1993, vol: 30, page: 921, stat: Journal Article,

Surgical management of pulmonary infections in chronic granulomatous disease of childhood
Pogrebniak HW; Gallin JI; Malech HL; Baker AR; Moskaluk CA; Travis WD; Pass HI
1993 Apr;55(4):844-849, Annals of thoracic surgery
Chronic granulomatous disease of childhood is an inheritable disorder of phagocytic cell respiratory burst resulting in recurrent, life-threatening, catalase-positive infections. The lung is the most common site of infection, and pulmonary disease is the primary cause of death in greater than 50% of children with chronic granulomatous disease. Still, the role of surgery in management of this disease remains undefined. Between 1974 and 1990, 19 patients with chronic granulomatous disease required 31 thoracic interventions at our institution. Patients ranged in age from 2.5 to 27 years (mean age, 15 years). Seventeen of 19 patients (89%) had had previous pulmonary infections. Patients presented as toxic (temperature > 38.5 degrees C, chest pain, and cough) in 22 instances before the 31 procedures. Aggressive surgical intervention for diagnosis and extirpation of localized infections was undertaken with lobectomy/pneumonectomy with or without other procedures (5), bisegmentectomy (2), segmentectomy with or without other procedures (5), or wedge with or without other procedures (13). In five instances, an empyema was drained; a chest tube for a sterile collection was placed in one instance. There was one intraoperative death, and 3 patients died 22 to 600 days postoperatively with overwhelming sepsis. The mean hospitalization was 101 days (range, 24 to 600 days). Wound complications occurred in 5 patients, requiring 17 separate anesthetic debridements. A change in therapy was dictated by the results of the procedure in 23 of 31 instances (74%). Thoracic surgeons must be aware of this rare cause of immunosuppression in these children and, due to the unusual nature of the pulmonary infections, should follow an aggressive approach in their diagnosis and management
— id: 59148, year: 1993, vol: 55, page: 844, stat: Journal Article,

Differential expression of platelet derived growth factor-beta in malignant mesothelioma: a clue to future therapies?
Pogrebniak HW; Lubensky IA; Pass HI
1993 Aug;2(4):235-240, Surgical oncology
Malignant mesothelioma (MM) is resistant to most standard forms of treatment. Accordingly, novel therapies based on the genetic and autocrine growth characteristics are being investigated. Platelet-derived growth factor (PDGF), a potent mitogen for mesenchymal cells, is produced by several human malignant cell lines including MM and therefore may promote tumourigenesis by an autocrine mechanism. We investigated the expression of PDGF-beta mRNA in tumour specimens excised from 18 patients with MM. Total cellular RNA was successfully extracted from 16/18 frozen tumour specimens with guanidine isothiocyanate and purified by centrifugation through a caesium chloride gradient. Northern blots were prepared and probed sequentially with 32P-labelled PDGF-beta and beta-actin cDNA. Gene expression was quantitated by optical densitometry. Freshly elutriated human peripheral blood monocytes were stimulated to induce PDGF-mRNA expression with transforming growth factor-beta-1. This positive control was assigned an expression index (EI) of 1, with the EI for the tumour sample calculated as: PDGFpatient/Actinpatient/EI positive control. In the 16 tumour specimens with useable RNA, transcripts for PDGF-beta MRNA were detected. Northern blot analyses revealed elevation of PDGF-beta expression above control in 10/16 (63%) of MM patients. A 230% increase in PDGF-beta expression (EI = 1.62 vs. EI = 0.49) was found between the lowest and highest expression samples. The specimens from which the PDGF transcripts were derived were found histologically to contain 87% tumour and 13% contaminating normal cells, predominantly lymphocytes. The elucidation of the transcriptional regulation of growth factors which are implicated in the pathogenesis of MM may guide the development of more effective biologic therapies
— id: 59144, year: 1993, vol: 2, page: 235, stat: Journal Article,

Targetted phototherapy with sensitizer-monoclonal antibody conjugate and light
Pogrebniak HW; Matthews W; Black C; Russo A; Mitchell JB; Smith P; Roth JA; Pass HI
1993 ;2(1):31-42, Surgical oncology
Photodynamic therapy (PDT) was performed in vitro and in vivo using monoclonal antibody conjugated to hematoporphyrin (HP). The antibody (45-2D9) recognized a cell surface glycoprotein on cells derived from NIH 3T3 cells which were transformed with the ras oncogene (45-342). Radionuclide imaging with either In111 or I125 chelated to 45-2D9 or the isotype identical (IgG1) antibody MOPPC-21 revealed selectivity of 45-2D9 for 45-342 flank tumours in nude mice, and minimal targetting for a 45-342 clone which did not express the cell surface glycoprotein. The 45-2D9-HP conjugate resulted in selective killing of the 45-342 line compared with the parent line in vitro. At HP concentrations of 76 micrograms ml-1, the 45-2D9-HP conjugate resulted in significantly more long-term cures of PDT treated flank tumours compared with free HP at the same concentration. 45-2D9 alone had no effect on tumour growth. The antibody-HP conjugate resulted in significantly less local toxicity compared with standard Photofrin II PDT, and also achieved a greater number of long-term cures. This 'photoimmunotherapy' demonstrates the ability to treat established tumours with greater efficacy and decreased morbidity, probably due to specific sensitizer targetting which allows normal surrounding tissue to be spared upon illumination
— id: 59152, year: 1993, vol: 2, page: 31, stat: Journal Article,

Initial and reoperative pulmonary metastasectomy: indications, technique, and results
Pogrebniak HW; Pass HI
1993 Mar-Apr;9(2):142-149, Seminars in surgical oncology
The ability to predict which patients will derive a survival benefit from pulmonary metastasectomy is limited. Most patients remain asymptomatic until the disease becomes advanced, and therefore computerized tomography (CT) of the chest has become the standard of care for follow-up of patients at risk for pulmonary metastases. The most important predictor of post-thoracotomy survival in patients at the National Cancer Institute with soft tissue, osteogenic, and pediatric sarcomas as well as melanoma and renal cell carcinoma has been the ability to render the patient disease-free. Tumor histology, disease-free interval, and possibly number of nodules are also determinants of survival. Median sternotomy is the preferred approach for initial and repeat metastasectomies and every effort should be made to preserve pulmonary parenchyma. Resection of pulmonary metastases has become an accepted therapeutic modality, but selection of surgical candidates, and operative planning needs to be individualized
— id: 59150, year: 1993, vol: 9, page: 142, stat: Journal Article,

Orthotopic implantation of mesothelioma in the pneumonectomized immune-deficient rat: a model for innovative therapies
Prewitt TW; Lubensky IA; Pogrebniak HW; Pass HI
1993 Nov 11;55(5):877-880, International journal of cancer
— id: 59140, year: 1993, vol: 55, page: 877, stat: Journal Article,

Photodynamic therapy for thoracic cancer: biology and applications
Prewitt TW; Pass HI
1993 Jul;5(3):229-237, Seminars in thoracic & cardiovascular surgery
— id: 59146, year: 1993, vol: 5, page: 229, stat: Journal Article,

Individualized chemotherapy for patients with non-small cell lung cancer determined by prospective identification of neuroendocrine markers and in vitro drug sensitivity testing
Shaw GL; Gazdar AF; Phelps R; Linnoila RI; Ihde DC; Johnson BE; Oie HK; Pass HI; Steinberg SM; Ghosh BC; et al.
1993 Nov 1;53(21):5181-5187, Cancer research
We attempted to prospectively select individualized chemotherapy for 165 non-small cell lung cancer patients based on in vitro analysis of neuroendocrine (NE) markers and drug sensitivity testing (DST) using fresh tumor. The chemotherapy used for small cell lung cancer (SCLC) was selected when NE marker expression determined by L-dopa decarboxylase assay was documented. Selection of chemotherapy for other patients was guided by DST results using a modified dye exclusion assay when available; otherwise etoposide and cisplatin was administered. A total of 112 of 165 (68%) specimens were assayed for L-dopa decarboxylase and 36 patients (22%) had DST. In vitro data directed management for 27 of 96 (28%) patients given chemotherapy: 6 with NE markers were treated with the SCLC regimen; and 21 (58% of those with DST) received their DST-selected chemotherapy regimen. There were no significant differences in response rate among all 3 treatment arms (P = 0.076). However, response to chemotherapy for the patients treated prospectively with a SCLC regimen was 3 of 6 (50%), marginally better than patients given their DST-selected chemotherapy regimen (2 of 21; 9%; P = 0.056) or those treated with etoposide and cisplatin (10 of 69; 14%; P = 0.061). When patients whose NE markers were identified retrospectively are included, 4 of 9 (44%) responded to administered chemotherapy, compared to 7 of 55 (13%) with no NE markers present (P = 0.04). There were no differences in survival among the three treatment groups. Cisplatin and etoposide comprised the most active regimen in vitro for tumors from 16 of 36 (44%) patients, potentially limiting the benefit of DST since this is often the empiric therapy for non-SCLC. Furthermore, the correlation between in vitro and clinical response is nonsignificant for all drugs tested, highlighting the overall relative resistance of non-SCLC tumors to currently available chemotherapy
— id: 59141, year: 1993, vol: 53, page: 5181, stat: Journal Article,

Pulmonary metastatic disease in ameloblastoma
Sheppard BC; Temeck BK; Taubenberger JK; Pass HI
1993 Dec;104(6):1933-1935, Chest
Ameloblastoma is a rare disease of odontogenic origin with indeterminate metastatic potential. The first site of metastatic disease is usually the lung. We report aggressive surgical treatment of a patient with bilateral disease with five subsequent recurrences. A review of the literature suggests that in the absence of effective chemotherapy or radiation, surgery should be considered the treatment of choice for metastatic ameloblastoma confined to the lung
— id: 59139, year: 1993, vol: 104, page: 1933, stat: Journal Article,

Cytoreductive surgery prior to interleukin-2