Jonathan Melamed, M.D.

Multilocular cystic renal cell carcinoma: Comparison of imaging and pathologic findings
Hindman N.M.; Bosniak M.A.; Rosenkrantz A.B.; Lee-Felker S.; Melamed J.
2012 ;198(1):W20-W26, American journal of roentgenology
OBJECTIVE. The purpose of this study was to retrospectively correlate the imaging and pathologic features of multilocular cystic renal cell carcinoma (RCC), a low-grade neoplasm that has an excellent prognosis. MATERIALS AND METHODS. Institutional databases were searched for the period between 2001 and 2010 to identify cases of resected renal tumors that had been evaluated with CT or MRI and been analyzed by a uropathologist to confirm the histologic diagnosis of multilocular cystic RCC. The images (nine CT, 14 MRI) were reviewed, and a Bosniak cyst category was assigned. RESULTS. Of 23 confirmed cases of multilocular cystic RCC, imaging revealed seven lesions were Bosniak category IIF, 13 were category III, and three were category IV. Pathologic examination of the category IIF lesions revealed 99% fluid, 0.001-1% clear cells lining the septum, and 0% fibrosis. The category III lesions were 98-99% fluid, 1-2% clear cells, and 0% fibrosis. The category IV lesions were 20-40% fluid, 1-5% clear cells, and 60-80% fibrosis. The patient demographics were similar across groups. Clinical follow-up showed no evidence of recurrent or metastatic disease. CONCLUSION. Multilocular cystic RCC is a rare cystic lesion of the kidney that is low risk to the patient and benign in behavior. It has a variable imaging pattern, the Bosniak category ranging from IIF to IV. As multilocular cystic RCC lesions increase in complexity on images (higher Bosniak category), there is a corresponding increase in the volume of malignant cells lining the tumor and an increase in the presence of vascularized fibrous tissue. Regardless of the imaging appearance, the behavior of these tumors was benign in this study. Clinicians and radiologists should be aware that when this carcinoma is reported to occur, the patient has an excellent prognosis. American Roentgen Ray Society
— id: 149823, year: 2012, vol: 198, page: W20, stat: Journal Article,

Impact of decalcification on receptor status in breast cancer
Darvishian, Farbod; Singh, Baljit; Krauter, Stephanie; Chiriboga, Luis; Gangi, Maryann D; Melamed, Jonathan
2011 Nov;17(6):689-691, Breast journal
— id: 141074, year: 2011, vol: 17, page: 689, stat: Journal Article,

Periprostatic Lymph Node Metastasis in Prostate Cancer and Its Clinical Significance
Deng, F-M; Mendrinos, S. E.; Das, K.; Melamed, J.
2011 FEB ;91(6):188A-188A, Laboratory investigation
— id: 134483, year: 2011, vol: 91, page: 188A, stat: Journal Article,

Periprostatic Lymph Node Metastasis in Prostate Cancer and Its Clinical Significance
Deng, F-M; Mendrinos, S. E.; Das, K.; Melamed, J.
2011 FEB ;24(11):188A-188A, Modern pathology
— id: 132754, year: 2011, vol: 24, page: 188A, stat: Journal Article,

Patch TMA Construction Using Pre-Existing Slides as Source of Tissue When Paraffin Blocks Are Unavailable
Deng, F-M; Zhao, Y.; Kong, X.; Lee, P.; Melamed, J.
2011 FEB ;91(6):449A-449A, Laboratory investigation
— id: 134487, year: 2011, vol: 91, page: 449A, stat: Journal Article,

Patch TMA Construction Using Pre-Existing Slides as Source of Tissue When Paraffin Blocks Are Unavailable
Deng, F-M; Zhao, Y.; Kong, X.; Lee, P.; Melamed, J.
2011 FEB ;24(11):449A-449A, Modern pathology
— id: 132758, year: 2011, vol: 24, page: 449A, stat: Journal Article,

MRI appearance of massive renal replacement lipomatosis in the absence of renal calculus disease
Fitzgerald, E; Melamed, J; Taneja, S S; Rosenkrantz, A B
2011 Feb;84(998):e41-e44, British journal of radiology
Renal replacement lipomatosis is a rare benign entity in which extensive fibrofatty proliferation of the renal sinus is associated with marked renal atrophy. In this report, we present a case of massive renal replacement lipomatosis demonstrated on MRI. The presentation was atypical given an absence of associated renal calculus disease, and an initial CT scan was interpreted as suspicious for a liposarcoma. The differential diagnosis and key MRI findings that served to establish this specific diagnosis are reviewed. Histopathological correlation is also presented, as the patient underwent nephroureterectomy
— id: 121307, year: 2011, vol: 84, page: e41, stat: Journal Article,

microRNA Associated with Aggressive Prostate Cancer in Racial Disparity
Huang, H.; Wu, X.; Zhou, L.; Li, Y.; Basturk, O.; Ostrer, H.; Freedland, S.; Osman, I.; Reuter, V.; Melamed, J.; Lee, P.
2011 FEB ;91(6):199A-199A, Laboratory investigation
— id: 134484, year: 2011, vol: 91, page: 199A, stat: Journal Article,

microRNA Associated with Aggressive Prostate Cancer in Racial Disparity
Huang, H.; Wu, X.; Zhou, L.; Li, Y.; Basturk, O.; Ostrer, H.; Freedland, S.; Osman, I.; Reuter, V.; Melamed, J.; Lee, P.
2011 FEB ;24(11):199A-199A, Modern pathology
— id: 132755, year: 2011, vol: 24, page: 199A, stat: Journal Article,

TPL2/COT/MAP3K8 (TPL2) activation promotes androgen depletion-independent (ADI) prostate cancer growth
Jeong, Joseph H; Bhatia, Ayesha; Toth, Zsolt; Oh, Soohwan; Inn, Kyung-Soo; Liao, Chun-Peng; Roy-Burman, Pradip; Melamed, Jonathan; Coetzee, Gerhard A; Jung, Jae U
2011 ;6(1):e16205-e16205, PLoS ONE
BACKGROUND: Despite its initial positive response to hormone ablation therapy, prostate cancers invariably recur in more aggressive, treatment resistant forms. The lack of our understanding of underlying genetic alterations for the transition from androgen-dependent (AD) to ADI prostate cancer growth hampers our ability to develop target-driven therapeutic strategies for the efficient treatment of ADI prostate cancer. METHODOLOGY/PRINCIPAL FINDINGS: By screening a library of activated human kinases, we have identified TPL2, encoding a serine/threonine kinase, as driving ADI prostate cancer growth. TPL2 activation by over-expressing either wild-type or a constitutively activated form of TPL2 induced ADI growth, whereas the suppression of TPL2 expression and its kinase activity in ADI prostate cancer cells inhibited cell proliferation under androgen-depleted conditions. Most importantly, TPL2 is upregulated in ADI prostate cancers of both the Pten deletion mouse model and the clinical prostate cancer specimens. CONCLUSIONS/SIGNIFICANCE: Together these data suggest that TPL2 kinase plays a critical role in the promotion of ADI prostate cancer progression. Furthermore, the suppression of TPL2 diminishes ADI prostate cancer growth and a high frequency of TPL2 overexpression in human ADI prostate cancer samples validates TPL2 as a target for the treatment of this deadly disease
— id: 134711, year: 2011, vol: 6, page: e16205, stat: Journal Article,

Osteoclast-like Giant Cell Tumor of the Renal Pelvis Associated With Urothelial Carcinoma: Computed Tomography, Gross, and Histologic Appearance
Rosenkrantz AB; Melamed J; Stifelman M
2011 Dec;78(6):1310-1312, Urology
Osteoclastoma-like giant cell tumor of the renal pelvis, similar to the entity more commonly occurring in bone, is very rare, having been reported in twelve previous cases to our knowledge. This is the first report of this entity, to our knowledge, to include its cross-sectional imaging appearance. A hyperdense area within the lesion on non-contrast CT may correspond with extensive hemorrhagic content of the lesion identified histologically. As in most prior cases, an adjacent smaller urothelial carcinoma of the renal pelvis was also identified. In the limited reported cases, this entity has exhibited highly aggressive behavior with poor prognosis
— id: 134891, year: 2011, vol: 78, page: 1310, stat: Journal Article,

MRI findings of sarcomatoid renal cell carcinoma in nine cases
Rosenkrantz, Andrew B; Chandarana, Hersh; Melamed, Jonathan
2011 Nov;35(6):459-464, Clinical imaging
PURPOSE: To assess the magnetic resonance imaging (MRI) features of a series of 9 cases of pathologically proven sarcomatoid renal cell carcinoma (SRCC). METHODS: Two radiologists in consensus retrospectively reviewed a spectrum of MRI features of nine cases of SRCC imaged at our institution between 2003 and 2009. RESULTS: SRCC had a mean diameter of 9.9 cm. All cases had an irregular or infiltrative morphology and demonstrated heterogeneous T2 signal intensity and enhancement. Internal necrosis was present in all cases, with four cases demonstrating >50% necrosis. Evidence of aggressive local behavior and/or distant spread was frequently observed. CONCLUSIONS: We have presented the largest case series to our knowledge of the MRI appearance of SRCC, with the lesions tending to appear as large heterogeneous masses with internal necrosis and evidence of aggressive local or distant behavior. However, these imaging features are non-specific, and histology remains necessary to establish the diagnosis
— id: 140534, year: 2011, vol: 35, page: 459, stat: Journal Article,

Prostate cancer: comparison of tumor visibility on trace diffusion-weighted images and the apparent diffusion coefficient map
Rosenkrantz, Andrew B; Kong, Xiangtian; Niver, Benjamin E; Berkman, Douglas S; Melamed, Jonathan; Babb, James S; Taneja, Samir S
2011 Jan;196(1):123-129, American journal of roentgenology
OBJECTIVE: The purpose of our study was to compare the visibility of prostate cancer on trace diffusion-weighted (DW) images and the apparent diffusion coefficient (ADC) map. MATERIALS AND METHODS: In this retrospective study, 45 patients with prostate cancer underwent preoperative MRI, including DW imaging (DWI) (b values 0, 500, and 1,000 s/mm(2)). A single observer reviewed the images in conjunction with tumor maps constructed from prostatectomy. For 132 peripheral zone (PZ) tumor foci, the visibility and contrast relative to benign PZ were recorded for T2-weighted imaging, trace DWI b500 images, trace DWI b1,000 images, and ADC maps. Trace DWI b1,000 images and ADC maps were compared in terms of Gleason score, size, normalized T2 signal intensity, ADC, and normalized ADC of visible tumors. RESULTS: For each image set, the percentage of visible tumor foci and contrast relative to benign PZ were as follows: T2-weighted imaging, 80.3% and 0.411; trace DWI b500, 26.5% and 0.131; trace DWI b1,000, 46.2% and 0.119; and ADC maps, 62.1% and 0.309. Forty-seven tumor foci were visible on both trace DWI b1,000 images and ADC maps, 14 only on trace DWI b1,000 images, 35 only on ADC maps, and 36 on neither image set. There was no significant difference in Gleason score, size, normalized T2 signal intensity, ADC, or normalized ADC between tumors visible only on trace DWI b1,000 images and those visible only on ADC maps. CONCLUSION: Given a greater proportion of tumors visible on the ADC map than trace DWI and greater contrast relative to benign PZ on the ADC map, we suggest that, when performing DWI of the prostate, careful attention be given to the ADC map for tumor identification
— id: 116225, year: 2011, vol: 196, page: 123, stat: Journal Article,

Prostate cancer: Utility of fusion of T2-weighted and high b-value diffusion-weighted images for peripheral zone tumor detection and localization
Rosenkrantz, Andrew B; Mannelli, Lorenzo; Kong, Xiangtian; Niver, Ben E; Berkman, Douglas S; Babb, James S; Melamed, Jonathan; Taneja, Samir S
2011 Jul;34(1):95-100, Journal of magnetic resonance imaging
PURPOSE: To retrospectively assess the utility of fusion of T2-weighted images (T2WI) and high b-value diffusion-weighted images (DWI) for prostate cancer detection and localization. MATERIALS AND METHODS: In this IRB-approved HIPAA-compliant study, 42 patients with prostate cancer underwent MRI including multiplanar T2WI and axial DWI before prostatectomy. Two independent radiologists first assessed multiplanar T2WI and axial DWI(b-1000) images and recorded whether tumor was present in each sextant. Axial T2WI was then fused with axial DWI(b-1000) images, and the radiologists re-evaluated each sextant for tumor. Accuracy was compared using generalized estimating equations based on a binary logistic regression model. RESULTS: The accuracy, sensitivity, specificity, PPV, and NPV for tumor detection on a sextant-basis using separate and fused image sets was 65.1%, 50.8%, 78.0%, 67.8%, and 63.6% and 71.0%, 60.8%, 80.3%, 73.7%, and 69.3%, respectively, for reader 1, and 54.0%, 42.5%, 64.4%, 52.0%, and 55.2%, and 61.1%, 56.7%, 65.2%, 59.6%, and 62.3%, respectively, for reader 2. The improvements in accuracy, sensitivity, and NPV using fused images were statistically significant for both readers, as was the improvement in PPV for reader 2 (P ranging from <0.0001 to 0.041). With either separate or fused images, there was greater sensitivity for tumors of higher grade or larger size (P ranging from <0.001 to 0.099). CONCLUSION: Fusion of T2WI and high b-value DWI resulted in significant improvements in sensitivity and accuracy for tumor detection on a sextant-basis, with similar specificity. J. Magn. Reson. Imaging 2011;. (c) 2011 Wiley-Liss, Inc
— id: 134472, year: 2011, vol: 34, page: 95, stat: Journal Article,

Regulation of HMGA1 expression by microRNA296 affects prostate cancer growth and invasion
Wei JJ; Wu X; Peng Y; Shi G; Olca B; Yang X; Daniels G; Osman I; Ouyang J; Hernando E; Pellicer A; Rhim J; Melamed J; Lee P
2011 Mar 15;17(6):1297-1305, Clinical cancer research
PURPOSE: High mobility group AT-hook 1 (HMGA1) is a non-histone nuclear binding protein that is developmentally regulated. HMGA1 is significantly overexpressed in and associated with high grade and advance stage of prostate cancer (PC). The oncogenic role of HMGA1 is at least mediated through chromosomal instability and structural aberrations. However, regulation of HMGA1 expression is not well understood. Identification of microRNA mediated HMGA1 regulation will provide a promising therapeutic target in treating PC. Experimental Designs: In this study, we examined the functional relation between miR-296 and HMGA1 expression in several prostate cancer cell lines and a large prostate cancer cohort. We further examined the oncogenic property of HMGA1 regulated by miR-296. RESULTS: Here we report that miR-296, a microRNA predicted to target HMGA1, specifically represses HMGA1 expression by promoting degradation and inhibiting HMGA1translation . Repression of HMGA1 by miR-296 is direct and sequence-specific. Importantly, ectopic miR-296 expression significantly reduced prostate cancer cell proliferation and invasion, in part through the down-regulation of HMGA1. Examining prostate cancer patient samples, we found an inverse correlation between HMGA1 and miR-296 expression: high levels of HMGA1 were associated with low miR-296 expression and strongly linked to more advanced tumor grade and stage. CONCLUSIONS: Our results indicate miR-296 regulates HMGA1 expression and is associated with PC growth and invasion
— id: 115464, year: 2011, vol: 17, page: 1297, stat: Journal Article,

LEF1 Identifies Androgen-Independent Epithelium in the Developing Prostate
Wu, Xinyu; Daniels, Garrett; Shapiro, Ellen; Xu, Kun; Huang, Hongying; Li, Yirong; Logan, Susan; Greco, M Alba; Peng, Yi; Monaco, Marie E; Melamed, Jonathan; Lepor, Herbert; Grishina, Irina; Lee, Peng
2011 Jun;25(6):1018-1026, Molecular endocrinology
Lymphoid enhancer-binding factor (LEF)1 is a major mediator and a target in canonical Wnt/beta-catenin pathway. Interactions between the androgen receptor (AR) and canonical Wnt pathways have been implicated in the development of the genitourinary organs. Here, we investigated the localization and role of LEF1-positive cells during development of the prostate gland in human and in the murine model. We show that during human prostate development, LEF1 is restricted to the basal epithelial layer of the urogenital sinus. During mouse development, Lef1 is also present in the urogenital mesenchyme in addition to the basal epithelial layer of the urogenital sinus. In the course of elongation and branching of the prostatic ducts, Lef1 is localized to the proliferating epithelium at the distal tips of the buds. Notably, during branching morphogenesis, domains of Lef1 and AR are mutually exclusive. We further employed the TOPGAL reporter strain to examine the dynamics of Wnt signaling in the context of prostate regression upon a 7-d treatment with a competitive AR inhibitor, bicalutamide. We found that Wnt/Lef1-positive basal cells are not dependent upon androgen for survival. Furthermore, upon bicalutamide treatment, Wnt/Lef1-positive basal progenitors repopulated the luminal compartment. We conclude that Wnt/Lef1 activity identifies an androgen-independent population of prostate progenitors, which is important for embryonic development and organ maintenance and regeneration in the adult
— id: 132604, year: 2011, vol: 25, page: 1018, stat: Journal Article,

Intraoperative Frozen Section Analysis of Urethral Margin Biopsies During Radical Prostatectomy
Ye H; Kong X; He TW; Jolis T; Choi K; Lepor H; Melamed J
2011 Aug;78(2):399-404, Urology
OBJECTIVES: To evaluate the accuracy and potential clinical value of intraoperative frozen section analysis (FSA) on urethral margin (UM) tissue during radical prostatectomy. Positive surgical margins increase the risk of post-operative cancer recurrence. Positive surgical margins are frequently found at the apex. The utility of intraoperative FSA of the margins is controversial. METHODS: We reviewed a consecutive series of radical prostatectomy cases (n = 1669) performed at our institution, in which UMs were routinely evaluated by intraoperative FSA. RESULTS: The submitted UM tissue contained cancer glands in 111 cases (6.7%). On FSA, the pathologists detected cancer in 55 cases (3.3%), missed cancer in 38 (2.3%), and reported atypical glands in 18 (1.1%). FSA of the UMs had a sensitivity of 59.1%, specificity of 99.8%, and positive and negative predictive value of 94.8% and 97.6%, respectively. The low sensitivity resulted from a substantial false-negative rate (n = 38), which was largely attributed to limited sampling on FSA (n = 31). Of the 55 patients (3.3%) whose positive UMs were detected by FSA, 20 (1.2%) had cancer-free margins after tissue re-excision. A positive final UM was associated with greater biochemical recurrence (P = .0073). However, the few patients limited the statistical analysis of the benefit of margin conversion through tissue re-excision (P = .35). CONCLUSIONS: Although experienced pathologists can evaluate the UMs on FSA with good accuracy, FSA has a relatively low sensitivity. Our data have indicated a low yield and a questionable value of routine FSA during radical prostatectomy
— id: 134890, year: 2011, vol: 78, page: 399, stat: Journal Article,

Measures To Assure Tissue Identification during Intraoperative Consultation: A Patient Safety Measure That Prevents Tissue Mismatch
Arif, F; Melamed, J; Warfield, D; Wang, BY
2010 FEB ;23(3):417A-417A, Modern pathology
— id: 109945, year: 2010, vol: 23, page: 417A, stat: Journal Article,

Measures To Assure Tissue Identification during Intraoperative Consultation: A Patient Safety Measure That Prevents Tissue Mismatch
Arif, F; Melamed, J; Warfield, D; Wang, BY
2010 FEB ;90(11):417A-417A, Laboratory investigation
— id: 109964, year: 2010, vol: 90, page: 417A, stat: Journal Article,

The Expression of Prostate Secretory Protein (PSP) and Hepatocyte Nuclear Factor-1 (HNF) in High Grade Prostate Intrepithelial Neoplasia (HGPIN) and Adenocarcinoma of the Prostate
Blutreich, AM; Sasturkar, S; He, T; Nagar, M; Chiriboga, L; Hayes, R; Melamed, J; Ahn, J
2010 FEB ;23(3):180A-180A, Modern pathology
— id: 109934, year: 2010, vol: 23, page: 180A, stat: Journal Article,

The Expression of Prostate Secretory Protein (PSP) and Hepatocyte Nuclear Factor-1 (HNF) in High Grade Prostate Intrepithelial Neoplasia (HGPIN) and Adenocarcinoma of the Prostate
Blutreich, AM; Sasturkar, S; He, T; Nagar, M; Chiriboga, L; Hayes, R; Melamed, J; Ahn, J
2010 FEB ;90(11):180A-180A, Laboratory investigation
— id: 109953, year: 2010, vol: 90, page: 180A, stat: Journal Article,

Compensatory upregulation of tyrosine kinase Etk/BMX in response to androgen deprivation promotes castration-resistant growth of prostate cancer cells
Dai, Bojie; Chen, Hege; Guo, Shengjie; Yang, Xi; Linn, Douglas E; Sun, Feng; Li, Wei; Guo, Zhiyong; Xu, Kexin; Kim, Oekyung; Kong, Xiangtian; Melamed, Jonathan; Qiu, Shaopeng; Chen, Hegang; Qiu, Yun
2010 Jul 1;70(13):5587-5596, Cancer research
We previously showed that targeted expression of non-receptor tyrosine kinase Etk/BMX in mouse prostate induces prostate intraepithelial neoplasia, implying a possible causal role of Etk in prostate cancer development and progression. Here, we report that Etk is upregulated in both human and mouse prostates in response to androgen ablation. Etk expression seems to be differentially regulated by androgen and interleukin 6 (IL-6), which is possibly mediated by the androgen receptor (AR) in prostate cancer cells. Our immunohistochemical analysis of tissue microarrays containing 112 human prostate tumor samples revealed that Etk expression is elevated in hormone-resistant prostate cancer and positively correlated with tyrosine phosphorylation of AR (Pearson correlation coefficient rho = 0.71, P < 0.0001). AR tyrosine phosphorylation is increased in Etk-overexpressing cells, suggesting that Etk may be another tyrosine kinase, in addition to Src and Ack-1, which can phosphorylate AR. We also showed that Etk can directly interact with AR through its Src homology 2 domain, and such interaction may prevent the association of AR with Mdm2, leading to stabilization of AR under androgen-depleted conditions. Overexpression of Etk in androgen-sensitive LNCaP cells promotes tumor growth while knocking down Etk expression in hormone-insensitive prostate cancer cells by a specific shRNA that inhibits tumor growth under androgen-depleted conditions. Taken together, our data suggest that Etk may be a component of the adaptive compensatory mechanism activated by androgen ablation in prostate and may play a role in hormone resistance, at least in part, through direct modulation of the AR signaling pathway
— id: 110687, year: 2010, vol: 70, page: 5587, stat: Journal Article,

Impact of Decalcification on Receptor Status in Breast Cancer
Darvishian, F; Singh, B; Krauter, S; Chiriboga, L; Melamed, J
2010 FEB ;23(3):43A-43A, Modern pathology
— id: 109930, year: 2010, vol: 23, page: 43A, stat: Journal Article,

Impact of Decalcification on Receptor Status in Breast Cancer
Darvishian, F; Singh, B; Krauter, S; Chiriboga, L; Melamed, J
2010 FEB ;90(11):43A-43A, Laboratory investigation
— id: 109949, year: 2010, vol: 90, page: 43A, stat: Journal Article,

Extensive infiltrating renal cell carcinoma with minimal distortion of the renal anatomy mimicking benign renal vein thrombosis
Hecht, Elizabeth M; Hindman, Nicole; Huang, William C; Rosenkrantz, Andrew B; Melamed, Jonathan
2010 May;55(5):967-971, American journal of kidney diseases
— id: 109555, year: 2010, vol: 55, page: 967, stat: Journal Article,

Higher Expression of Serine-213 Phosphorylated Androgen Receptor Level Is Associated With Prostate Cancer Recurrence
Jain, Shilpa; Ruoff, Rachael; Ha, Susan; Melamed, Jonathan; Wang, Jinhua; Ren, Qinghu; Lee, Peng; Logan, Susan
2010 OCT ;134(4):674-674, American journal of clinical pathology
— id: 113734, year: 2010, vol: 134, page: 674, stat: Journal Article,

The Expression of the Androgen Receptor Coactivator P44 in Proliferative Inflammatory Atrophy
Kabiawu, OE; Melamed, J; Yu, M; Wang, J; Jain, S; Aladhamy, N; Wang, Z; Lee, P
2010 FEB ;23(3):199A-199A, Modern pathology
— id: 109935, year: 2010, vol: 23, page: 199A, stat: Journal Article,

The Expression of the Androgen Receptor Coactivator P44 in Proliferative Inflammatory Atrophy
Kabiawu, OE; Melamed, J; Yu, M; Wang, J; Jain, S; Aladhamy, N; Wang, Z; Lee, P
2010 FEB ;90(11):199A-199A, Laboratory investigation
— id: 109954, year: 2010, vol: 90, page: 199A, stat: Journal Article,

Tumor Suppressor Function of Androgen Receptor Coactivator ARA70{alpha} in Prostate Cancer
Ligr, Martin; Li, Yirong; Zou, Xuanyi; Daniels, Garrett; Melamed, Jonathan; Peng, Yi; Wang, Wei; Wang, Jinhua; Ostrer, Harry; Pagano, Michele; Wang, Zhengxin; Garabedian, Michael J; Lee, Peng
2010 Apr;176(4):1891-1900, American journal of pathology
Androgen receptor (AR), a member of the steroid receptor family, is a transcription factor that has an important role in the regulation of both prostate cell proliferation and growth suppression. AR coactivators may influence the transition between cell growth and growth suppression. We have shown previously that the internally spliced ARA70 isoform, ARA70beta, promotes prostate cancer cell growth and invasion. Here we report that the full length ARA70alpha, in contrast, represses prostate cancer cell proliferation and anchorage-independent growth in vitro and inhibits tumor growth in nude mice xenograft experiments in vivo. Further, the growth inhibition by ARA70alpha is AR-dependent and mediated through induction of apoptosis rather than cell cycle arrest. Interestingly, AR with T877A mutation in LNCaP cells decreased its physical and functional interaction with ARA70alpha, facilitating the growth of LNCaP cells. This is consistent with our previous findings that ARA70alpha expression is decreased in prostate cancer cells compared with benign prostate. ARA70alpha also reduced the invasion ability of LNCaP cells. Although growth inhibition by ARA70alpha is AR-dependent, the inhibition of cell invasion is an androgen-independent process. These results strongly suggest that ARA70alpha functions as a tumor suppressor gene
— id: 107298, year: 2010, vol: 176, page: 1891, stat: Journal Article,

The role of surgical resection of fibrosis in the healing of venous ulcers
Maggi, Jason; Melamed, Jonathan; Onyedika, Chukwuemeka; Labinskyy, Volodymyr; Zimmerman, Karen; Granat, Anna; Tomic-Canic, Marjana; Brem, Harold
2010 SEP ;211(3):S76-S76, Journal of the American College of Surgeons
— id: 113914, year: 2010, vol: 211, page: S76, stat: Journal Article,

Angiomyolipoma with epithelial cysts: mimic of renal cell carcinoma
Rosenkrantz, Andrew B; Hecht, Elizabeth M; Taneja, Samir S; Melamed, Jonathan
2010 Jan-Feb;34(1):65-68, Clinical imaging
Angiomyolipoma with epithelial cysts (AMLEC) is a rare variant of angiomyolipoma with minimal fat that contains epithelial-lined cysts and may mimic a cystic renal cell carcinoma. While 17 cases have been described in the pathology literature since this entity was first described in 2006, the radiologic appearance was not demonstrated in any of these cases. We report the CT and MRI appearance of AMLEC found incidentally in a patient with lupus nephritis
— id: 107271, year: 2010, vol: 34, page: 65, stat: Journal Article,

MRI features of renal oncocytoma and chromophobe renal cell carcinoma
Rosenkrantz, Andrew B; Hindman, Nicole; Fitzgerald, Erin F; Niver, Benjamin E; Melamed, Jonathan; Babb, James S
2010 Dec;195(6):W421-W427, American journal of roentgenology
OBJECTIVE: The purpose of this study was to retrospectively describe the MRI features of the pathologically related entities renal oncocytoma and chromophobe renal cell carcinoma (RCC). MATERIALS AND METHODS: Twenty-eight cases of histologically proven renal oncocytoma and 15 of chromophobe RCC evaluated with preoperative MRI from January 2003 through June 2009 at our institution were independently reviewed for an array of MRI features by two radiologists blinded to the final histopathologic diagnosis. These features were tabulated and compared between chromophobe RCC and renal oncocytoma by use of the Mann-Whitney test and binary logistic regression. RESULTS: Renal oncocytoma and chromophobe RCC showed no significant difference in size or any of 16 qualitative imaging features (p = 0.0842-1.0, reader 1; p = 0.0611-1.0, reader 2). Microscopic fat, hemorrhage, cysts, infiltrative margins, perinephric fat invasion, renal vein invasion, enhancement homogeneity, and hypervascularity were each observed in less than 20% of cases by both readers. A central scar and segmental enhancement inversion (a recently described finding in which early contrast-enhanced images show relatively more enhanced and less enhanced intralesional components with inversion of their relative enhancement on later images) were observed by both readers in at least 10% of cases of both renal oncocytoma and of chromophobe RCC with no significant difference between the two entities (p = 0.2092-0.2960). CONCLUSION: We have presented the largest series to date of the MRI features of both renal oncocytoma and chromophobe RCC. These related entities exhibited similar findings, and no MRI features were reliable in distinguishing between them
— id: 114840, year: 2010, vol: 195, page: W421, stat: Journal Article,

Imaging appearance of solitary fibrous tumor of the abdominopelvic cavity
Rosenkrantz, Andrew B; Hindman, Nicole; Melamed, Jonathan
2010 Mar-Apr;34(2):201-205, Journal of computer assisted tomography
The computed tomographic or magnetic resonance imaging appearance of solitary fibrous tumors of the abdominopelvic cavity has previously only been presented in the English literature as individual case reports. In this article, we present the cross-sectional imaging appearance of 5 such cases, all of which exhibited highly similar imaging features, including well-circumscribed margins, lack of invasion of adjacent structures, and avid enhancement. In view of these shared imaging features, it may be possible to suggest the diagnosis preoperatively. Given their unpredictable biologic behavior with infrequent reports of recurrent or metastatic disease, complete surgical excision and long-term follow-up for these lesions is recommended
— id: 108933, year: 2010, vol: 34, page: 201, stat: Journal Article,

Prostate cancer vs. post-biopsy hemorrhage: diagnosis with T2- and diffusion-weighted imaging
Rosenkrantz, Andrew B; Kopec, Martin; Kong, Xiangtian; Melamed, Jonathan; Dakwar, George; Babb, James S; Taouli, Bachir
2010 Jun;31(6):1387-1394, Journal of magnetic resonance imaging
PURPOSE: To assess the value of quantitative T2 signal intensity (SI) and apparent diffusion coefficient (ADC) to differentiate prostate cancer from post-biopsy hemorrhage, using prostatectomy as the reference. MATERIALS AND METHODS: Forty-five men with prostate cancer underwent prostate magnetic resonance imaging (MRI), including axial T1-weighted imaging (T1WI), T2WI, and single-shot echo-planar image (SS EPI) diffusion-weighted imaging. Two observers measured, in consensus, normalized T2 signal intensity (SI) (nT2, relative to muscle T2 SI), ADC, and normalized ADC (nADC, relative to urine ADC) on peripheral zone (PZ) tumors, benign PZ hemorrhage, and non-hemorrhagic benign PZ. Tumor maps from prostatectomy were used as the reference. Mixed model analysis of variance was performed to compare parameters among the three tissue classes, and Pearson's correlation coefficient was utilized to assess correlation between parameters and tumor size and Gleason score. Receiver-operating characteristic (ROC)-curve analysis was used to determine the performance of nT2, ADC, and nADC for diagnosis of prostate cancer. RESULTS: nT2, ADC, and nADC were significantly lower in tumor compared with hemorrhagic and non-hemorrhagic benign PZ (P < 0.0001). There was a weak but significant correlation between ADC and Gleason score (r = -0.30, P = 0.0119), and between ADC and tumor size (r = -0.40, P = 0.0027), whereas there was no correlation between nT2 and Gleason score and tumor size. The areas under the curve to distinguish tumor from benign hemorrhagic and non-hemorrhagic PZ were 0.97, 0.96, and 0.933 for nT2, ADC, and nADC, respectively. CONCLUSION: Quantitative T2 SI and ADC/nADC values may be used to reliably distinguish prostate cancer from post-biopsy hemorrhage
— id: 109856, year: 2010, vol: 31, page: 1387, stat: Journal Article,

Prostate cancer: Comparison of 3D T2-weighted with conventional 2D T2-weighted imaging for image quality and tumor detection
Rosenkrantz, Andrew B; Neil, Jeffry; Kong, Xiangtian; Melamed, Jonathan; Babb, James S; Taneja, Samir S; Taouli, Bachir
2010 Feb;194(2):446-452, American journal of roentgenology
OBJECTIVE: The purpose of this study was to compare a 3D T2-weighted imaging sequence with a conventional multiplanar 2D turbo spin-echo T2-weighted sequence in terms of tumor detection and staging of prostate cancer, as well as image quality. MATERIALS AND METHODS: Before prostatectomy, 38 men (mean age, 60 years) with prostate cancer underwent MRI of the prostate with multiplanar 2D turbo spin-echo T2-weighted sequences (total acquisition time, approximately 11 minutes 4 seconds) and a 3D T2-weighted sampling perfection with application optimized contrasts sequence with different flip angle evolutions (SPACE) (acquisition time, approximately 3 minutes 52 seconds). Two blinded observers in consensus reviewed 2D turbo spin-echo T2-weighted images and SPACE images for detection of peripheral zone cancer, extracapsular extension, and seminal vesicle invasion. The observers also assessed subjective image quality and measured the signal-to-noise ratio (SNR) of normal peripheral zone and tumor-to-peripheral zone contrast. Prostatectomy was used as the reference standard. The diagnostic accuracy of the two sequences was assessed with generalized estimating equations and McNemar tests. The agreement between sequences was assessed with kappa coefficients. A paired Wilcoxon signed rank test was used to compare the subjective image quality, SNR, and tumor-to-peripheral zone contrast of the two sequences. RESULTS: For tumor detection and diagnosis of extracapsular extension, there was substantial agreement between the two sequences (kappa = 0.79, kappa = 0.76) with no difference in sensitivity, specificity, positive predictive value, negative predictive value, accuracy (p = 0.25-1), or image quality (p = 0.937). Images obtained with the 2D turbo spin-echo sequence had a significantly higher SNR ratio for normal peripheral zone (p = 0.0010), but SPACE images had significantly greater tumor-to-peripheral zone contrast (p < 0.0001). CONCLUSION: In comparison with conventional multiplanar 2D turbo spin-echo MRI of the prostate, 3D T2-weighted SPACE MRI was associated with substantial time saving (nearly 8 minutes), had similar image quality and accuracy in the diagnosis of tumor and extracapsular extension, and had better tumor conspicuity
— id: 106383, year: 2010, vol: 194, page: 446, stat: Journal Article,

Utility of the apparent diffusion coefficient for distinguishing clear cell renal cell carcinoma of low and high nuclear grade
Rosenkrantz, Andrew B; Niver, Benjamin E; Fitzgerald, Erin F; Babb, James S; Chandarana, Hersh; Melamed, Jonathan
2010 Nov;195(5):W344-W351, American journal of roentgenology
OBJECTIVE: The purpose of our study was to assess the utility of the apparent diffusion coefficient (ADC) in distinguishing low-grade and high-grade clear cell renal cell carcinoma (ccRCC). MATERIALS AND METHODS: The cases of 57 patients with pathologically proven ccRCC who underwent preoperative MRI, including diffusion-weighted imaging, were retrospectively assessed. ADC values were obtained from ADC maps calculated using b-value combinations of 0 and 400 s/mm(2) and of 0 and 800 s/mm(2) (hereafter referred to as ADC-400 and ADC-800). Lesions were also evaluated for an array of conventional MRI features. A single expert uropathologist reviewed all slides to determine nuclear grade. The utility of ADC for detecting high-grade ccRCC, alone and in combination with conventional MRI features, was assessed using receiver operating characteristic (ROC) analysis and binary logistic regression. RESULTS: ADC-400 and ADC-800 were significantly lower among high-grade than among low-grade ccRCC (2.24 +/- 0.50 mm(2)/s vs 1.59 +/- 0.57 mm(2)/s for ADC-400, p < 0.001; 1.85 +/- 0.40 mm(2)/s vs 1.28 +/- 0.48 mm(2)/s for ADC-800; p < 0.001). The area under the ROC curve for identifying high-grade ccRCC using ADC-400 and ADC-800 was 0.801 and 0.824 respectively (p = 0.606), with optimal thresholds, sensitivity, and specificity as follows: ADC-400: 2.17 mm(2)/s, 88.5%, 64.5% and ADC-800: 1.20 mm(2)/s, 65.4%, 96.0%. Using multivariate logistic regression, only necrosis (p = 0.0229) and perinephric fat invasion (p = 0.0160) were retained among conventional imaging features as independent risk factors for high-grade ccRCC. The accuracy of the logistic regression model for predicting high-grade ccRCC was significantly improved by inclusion of either ADC-400 (p = 0.0143) or ADC-800 (p = 0.015). CONCLUSION: ADC is significantly lower in high-grade ccRCC compared with low-grade ccRCC and increases the accuracy for detecting high-grade ccRCC compared with conventional MRI features alone
— id: 114050, year: 2010, vol: 195, page: W344, stat: Journal Article,

The Expression of Vitamin D Associated Markers in High Grade Prostatic Intraepithelial Neoplasia (HGPIN)
Sasturkar, S; Blutreich, A; He, TW; Nagar, M; Small, J; Chriboga, L; Hayes, R; Melamed, J; Ahn, J
2010 FEB ;23(3):217A-217A, Modern pathology
— id: 109936, year: 2010, vol: 23, page: 217A, stat: Journal Article,

The Expression of Vitamin D Associated Markers in High Grade Prostatic Intraepithelial Neoplasia (HGPIN)
Saturkar, S; Blutreich, A; He, TW; Nagar, M; Small, J; Chiriboga, L; Hayes, R; Melamed, J; Ahn, J
2010 FEB ;90(11):217A-217A, Laboratory investigation
— id: 109955, year: 2010, vol: 90, page: 217A, stat: Journal Article,

Intraepidermal and dermal Merkel cell carcinoma with squamous cell carcinoma in situ: a case report with review of literature
Sirikanjanapong, Sasis; Melamed, Jonathan; Patel, Rishi R
2010 Aug;37(8):881-885, Journal of cutaneous pathology
Merkel cell carcinoma (MCC), a rare aggressive primary cutaneous neuroendocrine carcinoma, occurs on sun-damaged skin, especially in the elderly. Its unique co-expression of cytokeratin 20 (CK20) and neuroendocrine markers, including neuron-specific enolase (NSE), is diagnostic. Most MCCs are located in the dermis, rarely has an intraepidermal component been reported. We report a case of MCC with an intraepidermal component admixed with squamous cell carcinoma in situ (SCCIS). We were able to identify the differences in the immunohistochemical expression pattern between that of the intraepidermal and the dermal components. Most intraepidermal neoplastic cells of MCC in this case showed a less intense immunoreactivity to CK20 and NSE compared to that of dermal neoplastic cells. This case reports an unusual occurrence of combined SCC and MCC that shows both intraepidermal and dermal components
— id: 138372, year: 2010, vol: 37, page: 881, stat: Journal Article,

Utility of Uroplakin and PAX-2 Immunohistochemistry in the Diagnosis of Primary Adenocarcinoma of the Urinary Bladder
Ye, H; Wu, X; Hansel, DE; Melamed, J; Epstein, JI
2010 FEB ;23(3):229A-230A, Modern pathology
— id: 109937, year: 2010, vol: 23, page: 229A, stat: Journal Article,

Utility of Uroplakin and PAX-2 Immunohistochemistry in the Diagnosis of Primary Adenocarcinoma of the Urinary Bladder
Ye, H; Wu, X; Hansel, DE; Melamed, J; Epstein, JI
2010 FEB ;90(11):229A-230A, Laboratory investigation
— id: 109956, year: 2010, vol: 90, page: 229A, stat: Journal Article,

Activation of Stat3 in renal tumors
Guo, Charles; Yang, Guanyu; Khun, Kyle; Kong, Xiantian; Levy, David; Lee, Peng; Melamed, Jonathan
2009 ;1(3):283-290, American Journal of Translational Research
Signal transducer and activator of transcription 3 (Stat3) plays a vital role in signal transduction pathways that mediate transformation and inhibit apoptosis. Oncogenic Stat3 is persistently activated in several human cancers and transformed cell lines. Previous studies indicate activation of Stat3 in renal cell carcinoma (RCC). However, the detailed characterization of the Stat3 expression pattern in different histologic types of RCC is lacking. We have analyzed the immunoprofile of activated or phosphorylated Stat3 (pStat3) in a tissue microarray of renal tumors of different histologic types, including 42 cases of conventional clear cell type, 24 chromophobe, and 7 papillary, 15 oncocytoma, 7 urothelial carcinoma and 21 normal kidney tissues using an anti-pStat3 antibody (recognizes only activated STAT3). pStat3 nuclear staining was observed in 25 of 42 conventional clear cell RCC (59.5 %), 8 of 24 chromophobe RCC (33.3%), 4 of 7 papillary RCC (57.1%). In the other tumor groups, 4 of 15 oncocytomas (26.7%) and 6 of 7 urothelial carcinomas (85.7%) showed positive nuclear staining. Weak nuclear immunoreactivity for pStat3 was seen in 4 of 21 cases of non-neoplastic kidney tissue (19.0%). The extent of Stat3 activation as determined by nuclear expression of its phosphorylated form is increased in histologic types of renal tumors with greater malignant potential, specifically conventional clear cell RCC, papillary RCC and urothelial carcinoma, only slightly increased in chromophobe RCC, and not increased in oncocytoma. These results suggest a role of Stat3 activation in different types of renal neoplasia, possibly serving as a prognostic marker or therapeutic target
— id: 105529, year: 2009, vol: 1, page: 283, stat: Journal Article,

A Novel Androgen Receptor Splice Variant Is Up-regulated during Prostate Cancer Progression and Promotes Androgen Depletion-Resistant Growth
Guo, Zhiyong; Yang, Xi; Sun, Feng; Jiang, Richeng; Linn, Douglas E; Chen, Hege; Chen, Hegang; Kong, Xiangtian; Melamed, Jonathan; Tepper, Clifford G; Kung, Hsing-Jien; Brodie, Angela M H; Edwards, Joanne; Qiu, Yun
2009 Mar 15;69(6):2305-2313, Cancer research
The androgen receptor (AR) plays a key role in progression to incurable androgen ablation-resistant prostate cancer (PCA). We have identified three novel AR splice variants lacking the ligand-binding domain (designated as AR3, AR4, and AR5) in hormone-insensitive PCA cells. AR3, one of the major splice variants expressed in human prostate tissues, is constitutively active, and its transcriptional activity is not regulated by androgens or antiandrogens. Immunohistochemistry analysis on tissue microarrays containing 429 human prostate tissue samples shows that AR3 is significantly up-regulated during PCA progression and AR3 expression level is correlated with the risk of tumor recurrence after radical prostatectomy. Overexpression of AR3 confers ablation-independent growth of PCA cells, whereas specific knockdown of AR3 expression (without altering AR level) in hormone-resistant PCA cells attenuates their growth under androgen-depleted conditions in both cell culture and xenograft models, suggesting an indispensable role of AR3 in ablation-independent growth of PCA cells. Furthermore, AR3 may play a distinct, yet essential, role in ablation-independent growth through the regulation of a unique set of genes, including AKT1, which are not regulated by the prototype AR. Our data suggest that aberrant expression of AR splice variants may be a novel mechanism underlying ablation independence during PCA progression, and AR3 may serve as a prognostic marker to predict patient outcome in response to hormonal therapy. Given that these novel AR splice variants are not inhibited by currently available antiandrogen drugs, development of new drugs targeting these AR isoforms may potentially be effective for treatment of ablation-resistant PCA. [Cancer Res 2009;69(6):OF1-9]
— id: 95435, year: 2009, vol: 69, page: 2305, stat: Journal Article,

Dysplastic ("in-situ") Lesions in multofocal renal oncocytomas (oncocytosis)
Huang, Jiaoti; Lee, Peng; Mikami, Yoshiki; Melamed, Jonathan
2009 ;2(6):583-587, International journal of clinical & experimental pathology
Preneoplastic lesions for renal oncocytosis have not been well defined. We have attempted to identify the putative in-situ or dysplastic change in nephrectomy specimens with oncocytosis. Cases of multiple oncocytoma previously identified in radical nephrectomy specimens (n = 5) were reviewed for early lesions of renal oncocytosis by light microscopic analysis and by immunohistochemical studies for p53, bcl2 and MIB-1. Microscopic analysis showed that the renal cortical regions in all cases contain isolated groups of tubules partially or completely replaced by oncocytic cells with morphologic features resembling tumor cells in oncocytosis. The oncocytic cells within these tubules are increased in number and are arranged either as solid groups or as single layers in cystically dilated tubules, and may assume a hobnail appearance. They can be distinguished from small foci of oncocytosis as they do not form a coalescent group but are separated in part by intervening normal-appearing tubules. Cytologically, the cells have abundant eosinophilic, granular cytoplasm with a low nuclear/cytoplasmic ratio and demonstrate distinct cell borders. A very characteristic feature of these cells is the retraction space ('windows') between the oncocytic cells. Nuclear features of these cells are not distinctive from normal tubules. Immunostaining with Bcl-2, p53 and MIB-1 antibodies also does not differentiate the putative preneoplastic lesions from normal tubules. Thus, recognition of a putative dysplastic lesion for oncocytosis is possible by routine microscopic analysis. Identification of this lesion in a biopsy or partial nephrectomy specimen should raise the possibility of the existence of renal oncocytosis (multifocality), leading to adequate clinical management
— id: 111607, year: 2009, vol: 2, page: 583, stat: Journal Article,

Renal involvement by chronic myelomonocytic leukemia requiring nephroureterectomy
Hyams, Elias S; Gupta, Raavi; Melamed, Jonathan; Taneja, Samir S; Shah, Ojas
2009 Winter;11(1):33-37, Reviews in urology
Chronic monomyelocytic leukemia (CMML) is a relatively rare clonal hematologic disorder with features of myelodysplastic syndrome and myeloproliferative disease. Renal impairment from CMML is infrequent and can result from both direct (ie, infiltrative) and indirect (eg, vasculitis, infarction) mechanisms. This case report describes a patient with refractory gross hematuria requiring nephroureterectomy with diffuse involvement of the upper tract by CMML and accompanying extramedullary hematopoiesis. Underscored are the need to maintain a broad differential diagnosis for upper tract lesions in the setting of gross hematuria, and the potential need for drastic measures to control upper tract bleeding if conservative measures fail
— id: 108184, year: 2009, vol: 11, page: 33, stat: Journal Article,

MALDI Imaging and LCMS Identification of Colon Cancer Biomarkers in Benign Polyps and Normal Tandem Mucosa
Imanpour, J; Pevsner, P; Kachalov, V; Mathur, S; Moore, H; Melamed, J; Remsen, T; Kanaparthi, C; Mujtaba, G; Kothiya, P; Momin, Z; Vasani, N; Sobel, N; Oprihory, J; Francois, F; Momeni, M; Stern, A; Anand, S
2009 OCT ;104(2):S575-S575, American journal of gastroenterology
— id: 106467, year: 2009, vol: 104, page: S575, stat: Journal Article,

LEF1 in androgen-independent prostate cancer: regulation of androgen receptor expression, prostate cancer growth, and invasion
Li, Yirong; Wang, Longgui; Zhang, Miao; Melamed, Jonathan; Liu, Xiaomei; Reiter, Robert; Wei, Jianjun; Peng, Yi; Zou, Xuanyi; Pellicer, Angel; Garabedian, Michael J; Ferrari, Anna; Lee, Peng
2009 Apr 15;69(8):3332-3338, Cancer research
A major obstacle in treating prostate cancer is the development of androgen-independent disease. In this study, we examined LEF1 expression in androgen-independent cancer as well as its regulation of androgen receptor (AR) expression, prostate cancer growth, and invasion in androgen-independent prostate cancer cells. Affymetrix microarray analysis of LNCaP and LNCaP-AI (androgen-independent variant LNCaP) cells revealed 100-fold increases in LEF1 expression in LNCaP-AI cells. We showed that LEF1 overexpression in LNCaP cells resulted in increased AR expression and consequently enhanced growth and invasion ability, whereas LEF1 knockdown in LNCaP-AI cells decreased AR expression and, subsequently, growth and invasion capacity. Chromatin immunoprecipitation, gel shift, and luciferase assays confirmed LEF1 occupancy and regulation of the AR promoter. Thus, we identified LEF1 as a potential marker for androgen-independent disease and as a key regulator of AR expression and prostate cancer growth and invasion. LEF1 is highly expressed in androgen-independent prostate cancer, potentially serving as a marker for androgen-independent disease
— id: 99128, year: 2009, vol: 69, page: 3332, stat: Journal Article,

Immunohistochemical Panel to Identify the Primary Site of Invasive Micropapillary Carcinoma
Lotan, Tamara L; Ye, Huihui; Melamed, Jonathan; Wu, Xue-Ru; Shih, Ie-Ming; Epstein, Jonathan I
2009 Jul;33(7):1037-1041, American journal of surgical pathology
Invasive micropapillary carcinoma (IMC) is generally an aggressive morphologic variant that has been described in the bladder, lung, breast, salivary gland, gastrointestinal tract, and ovary. Given the morphologic similarities between IMCs arising from different organ systems and the high propensity of this histologic subtype for lymphatic metastasis, it may be necessary to use immunohistochemical (IHC) markers to determine the primary site of an IMC. Few studies have compared the IHC profiles of IMCs originating from different sites. We tested a panel of 11 IHC markers for their ability to distinguish urothelial, lung, breast, and ovarian IMC using a tissue microarray constructed with primary tumor tissue from 47 patients with IMC (13 bladder, 6 lung, 16 breast, and 12 ovarian). For each tumor, correct classification as IMC was verified by reverse polarity MUC1 expression. We found that immunostaining for uroplakin, CK20, TTF-1, estrogen receptor (ER), WT-1 and/or PAX8, and mammaglobin was the best panel for determining the most likely primary site of IMC. The best markers to identify urothelial IMC were uroplakin and CK20, whereas p63, high molecular weight cytokeratin, and thrombomodulin were less sensitive and specific. Lung IMC was uniformly TTF-1 positive. Breast IMC was ER positive, mammaglobin positive, and PAX8/WT-1 negative, while ovarian IMC was ER positive, mammaglobin negative, and PAX8/WT-1 positive. In the metastatic setting, or when IMC occurs without an associated in situ or conventional carcinoma component, staining for uroplakin, CK20, TTF-1, ER and WT-1, and/or PAX8, and mammaglobin is the best panel for accurately classifying the likely primary site of IMC
— id: 95436, year: 2009, vol: 33, page: 1037, stat: Journal Article,

Mass spectrometry MALDI imaging of colon cancer biomarkers: a new diagnostic paradigm
Pevsner, Paul H; Melamed, Jonathan; Remsen, Tiffany; Kogos, Alexander; Francois, Fritz; Kessler, Paul; Stern, Arnold; Anand, Sury
2009 Feb;3(1):55-69, Biomarkers in medicine
Colorectal cancer (CRC), is the second-leading cause of cancer-related deaths in the USA, affecting both men and women. Current projections show little or no change since the publication of a morbidity and mortality study in 2005. The projected number of new cases for 2008 is 154,000, and the projected number of CRC cancer deaths for 2008 is 53,000. The standard diagnostic paradigm is based on histopathology of either biopsy or surgical specimens. This article suggests a new paradigm for colon cancer diagnosis and staging using matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI IMS or IMS). IMS may identify potential tumors in normal tissue of cancer patients and predict those cancer patients who are at risk for recurrent cancer
— id: 110097, year: 2009, vol: 3, page: 55, stat: Journal Article,

Mass Spectrometry MALDI Imaging and LCMS Identification of Colon Cancer Proteins in Benign Polyps
Pevsner, PH; Melamed, J; Kogos, A; Remsen, T; Francois, F; Imanpour, J; Mathur, S; Kachalov, V; Kanaparthi, C; Kessler, P; Moore, HG; Stern, A; Momeni, M; Anand, S
2009 ;136(5):A303-A303, Gastroenterology
— id: 110784, year: 2009, vol: 136, page: A303, stat: Journal Article,

Pseudosarcomatous fibroblastic/myofibroblastic proliferation in perinephric adipose tissue adjacent to renal cell carcinoma: a lesion mimicking well-differentiated liposarcoma
Tanas, Munir R; Sthapanachai, Chalenpoj; Nonaka, Daisuke; Melamed, Jonathan; Oliveira, Andre M; Erickson-Johnson, Michele R; Rubin, Brian P
2009 Sep;22(9):1196-1200, Modern pathology
Cytologically atypical stromal cells were found in the perinephric adipose tissue, mimicking well-differentiated liposarcoma in 12 of 59 (20%) consecutive nephrectomy specimens that were resected for renal cell carcinoma. Morphologically, the atypical cells included enlarged, hyperchromatic spindle cells and floret-type multinucleate cells. Of 59, 10 (17%) renal cell carcinomas invaded through the renal capsule into the perinephric adipose tissue. Of these cases, three (30%) contained the aforementioned atypical cells. In contrast, 9 of 49 cases without extrarenal invasion (18%) contained the atypical stromal cells. Of the 12 cases with atypical stromal cells, 3 (25%) were associated with extrarenal involvement. The atypical spindle cells exhibited focal to variable positivity for smooth muscle actin and desmin in 3 of the 14 cases (including two cases from our consultation files) each. Cytokeratin AE1/AE3, cytokeratin Cam 5.2, cytokeratin 7, epithelial membrane antigen, and S-100 were negative in all cases. Amplification of MDM2 gene region, which is commonly observed in well-differentiated liposarcoma, was absent by fluorescence in situ hybridization (FISH) in the atypical stromal cells. Immunohistochemistry and FISH suggest that the atypical cells are most consistent with reactive fibroblasts/myofibroblasts. Recognition of these atypical fibroblasts/myofibroblasts may help in avoiding the potential pitfall of misdiagnosing them as well-differentiated liposarcoma.Modern Pathology advance online publication, 12 June 2009; doi:10.1038/modpathol.2009.84
— id: 100579, year: 2009, vol: 22, page: 1196, stat: Journal Article,

Regulation of Androgen Receptor Transcriptional Activity and Specificity by RNF6-induced Ubiquitination
Xu, KX; Shimelis, H; Linn, DE; Jiang, RC; Yang, X; Sun, F; Guo, ZY; Chen, HG; Li, W; Chen, HG; Kong, XT; Melamed, J; Fang, SY; Xiao, Z; Veenstra, TD; Qiu, Y
2009 APR 7 ;15(4):270-282, Cancer cell
The androgen receptor (AR) plays a critical role in prostate cancer. We have identified a ubiquitin E3 ligase, RNF6, as an AR-associated protein in a proteomic screen. RNF6 induces AR ubiquitination and promotes AR transcriptional activity. Specific knockdown of RNF6 or mutation of RNF6-induced ubiquitination acceptor sites on AR selectively alters expression of a subset of AR target genes and diminishes recruitment of AR and its coactivators to androgen-responsive elements present in the regulatory region of these genes. Furthermore, RNF6 is overexpressed in hormone-refractory human prostate cancer tissues and required for prostate cancer cell growth under androgen-depleted conditions. Our data suggest that RNF6-induced ubiquitination may regulate AR transcriptional activity and specificity through modulating cofactor recruitment
— id: 97881, year: 2009, vol: 15, page: 270, stat: Journal Article,

Stromal anti-apoptotic androgen receptor target gene c-FLIP in prostate cancer
Ye, Huihui; Li, Yirong; Melamed, Jonathan; Pearce, Patrice; Wei, Jianjun; Chiriboga, Luis; Wang, Zhengxin; Osman, Iman; Lee, Peng
2009 Feb;181(2):872-877, Journal of urology
PURPOSE: The tumor microenvironment significantly influences prostate cancer progression. Androgen receptor exerts its effect through downstream target genes to regulate prostate cancer cell proliferation. The c-FLIP gene was recently shown to be an androgen receptor target gene. c-FLIP is an inactive homologue of caspase-8 and, thus, it inhibits the death receptor mediated apoptosis pathway. c-FLIP over expression was shown to accelerate the progression of prostate cancer cells to androgen independence. We evaluated the role of c-FLIP expression in stromal cells in prostate cancer development. MATERIALS AND METHODS: We examined c-FLIP expression in 53 androgen dependent and 21 androgen independent prostate cancer stromal cells by immunohistochemical analysis. The effects of c-FLIP over expression in stromal cells on the growth and invasion of LNCaP and PC3 prostate cancer cells were determined in indirect coculture systems. RESULTS: At the androgen dependent stage the stromal c-FLIP level was increased in prostate cancer tissue. The expression level of stromal c-FLIP was associated with tumor differentiation. However, stromal c-FLIP expression was not increased in androgen independent human prostate cancer. c-FLIP over expression in stromal cells stimulated the growth and invasion of prostate cancer, including LNCaP and PC3 cells in vitro. CONCLUSIONS: These results indicate the over expression of stromal c-FLIP and its function for promoting prostate cancer growth and invasion
— id: 92157, year: 2009, vol: 181, page: 872, stat: Journal Article,

Lef1 Expression in Androgen-Independent Prostate Cancer
Zhang, M; Li, YR; Wang, LG; Melamed, J; Liu, XM; Wei, JJ; Peng, Y; Pellicer, A; Garabedian, MJ; Ferrari, A; Lee, P
2009 ;89:921-921, Laboratory investigation
— id: 104576, year: 2009, vol: 89, page: 921, stat: Journal Article,

Lef1 Expression in Androgen-Independent Prostate Cancer
Zhang, M; Li, YR; Wang, LG; Melamed, J; Liu, XM; Wei, JJ; Peng, Y; Pellicer, A; Garabedian, MJ; Ferrari, A; Lee, P
2009 ;22(Suppl 1):203A-203A 921, Modern pathology
— id: 104577, year: 2009, vol: 22, page: 203A, stat: Journal Article,

Chemokine signaling via the CXCR2 receptor reinforces senescence
Acosta, Juan C; O'Loghlen, Ana; Banito, Ana; Guijarro, Maria V; Augert, Arnaud; Raguz, Selina; Fumagalli, Marzia; Da Costa, Marco; Brown, Celia; Popov, Nikolay; Takatsu, Yoshihiro; Melamed, Jonathan; d'Adda di Fagagna, Fabrizio; Bernard, David; Hernando, Eva; Gil, Jesus
2008 Jun 13;133(6):1006-1018, Cell
Cells enter senescence, a state of stable proliferative arrest, in response to a variety of cellular stresses, including telomere erosion, DNA damage, and oncogenic signaling, which acts as a barrier against malignant transformation in vivo. To identify genes controlling senescence, we conducted an unbiased screen for small hairpin RNAs that extend the life span of primary human fibroblasts. Here, we report that knocking down the chemokine receptor CXCR2 (IL8RB) alleviates both replicative and oncogene-induced senescence (OIS) and diminishes the DNA-damage response. Conversely, ectopic expression of CXCR2 results in premature senescence via a p53-dependent mechanism. Cells undergoing OIS secrete multiple CXCR2-binding chemokines in a program that is regulated by the NF-kappaB and C/EBPbeta transcription factors and coordinately induce CXCR2 expression. CXCR2 upregulation is also observed in preneoplastic lesions in vivo. These results suggest that senescent cells activate a self-amplifying secretory network in which CXCR2-binding chemokines reinforce growth arrest
— id: 90815, year: 2008, vol: 133, page: 1006, 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,

Interobserver variability in differentiation of nodal nevus from melanoma micrometastasis in sentinel lymph adenectomy specimens
Celin, N; Bannan, M; Darvishian, F; Hajdu, C; Nonaka, D; Ye, W; Pei, Z; Melamed, J
2008 ;21(2):409-409, Modern pathology
— id: 100682, year: 2008, vol: 21, page: 409, stat: Journal Article,

Prospective evaluation of an extended histologic protocol for detection of melanoma micrometastasis
Cetin, N; Bannan, M; Wang, B; Melamed, J
2008 JAN ;21(2):91A-92A, Modern pathology
— id: 75908, year: 2008, vol: 21, page: 91A, stat: Journal Article,

MicroRNA expression in the tumor-associated stroma of prostate cancer
Gellert, LL; Basturk, O; Zon, XY; Wei, JJ; Pellicer, A; Kong, XT; Melamed, J; Lee, P
2008 OCT ;130(4):5-519, American journal of clinical pathology
— id: 98126, year: 2008, vol: 130, page: 5, stat: Journal Article,

A systematic evaluation of histopathologic criteria for adenocarcinoma of prostate using frozen sections as compared with routine permanent sections
Kong, X; Ye, H; Cetin, N; Small, J; Lee, P; Melamed, J
2008 JAN ;21(2):163A-164A, Modern pathology
— id: 75912, year: 2008, vol: 21, page: 163A, stat: Journal Article,

A systematic evaluation of histopathologic criteria for adenocarcinoma of prostate using frozen sections as compared with routine permanent sections
Kong, X; Ye, H; Cetin, N; Small, J; Lee, P; Melamed, J
2008 JAN ;88(2):163A-164A, Laboratory investigation
— id: 75934, year: 2008, vol: 88, page: 163A, stat: Journal Article,

Invasive lobular carcinoma of the breast: role of endothelial lymphatic marker D2-40
Laser, Jordan; Cangiarella, Joan; Singh, Baljit; Melamed, Jonathan; Chiriboga, Luis; Yee, Herman; Darvishian, Farbod
2008 Spring;38(2):99-104, Annals of clinical & laboratory science
Lymphovascular invasion (LVI) of breast cancer is an independent adverse prognosticator that is associated with increased regional and distant tumor recurrence. LVI is infrequently encountered in invasive lobular carcinoma when compared to invasive ductal carcinoma. We employed D2-40 antibody, a novel marker for lymphatic endothelial cells, in an attempt to enhance the detection of LVI in invasive lobular carcinomas. We identified 78 patients with invasive lobular carcinoma with known axillary status, who were studied between 2003 and 2006. D2-40 antibody was applied to one representative paraffin block from each case and the results were compared to LVI on routine histology. LVI was identified in 12 (15%) and 19 (24%) cases by routine histology and D2-40 antibody, respectively. Eleven of 12 patients (92%) with LVI identified by routine histology had axillary nodal metastasis compared to 14 of 19 patients (74%) with LVI identified by D2-40 antibody. LVI was missed by routine histology in 8 cases (10%). D2-40 antibody enhanced the identification of LVI by 9% in node negative patients. D2-40 antibody increased the identification of LVI by 12% in classic invasive lobular carcinoma. In conclusion, D2-40 antibody staining may be useful as an adjunct in detecting LVI in invasive lobular carcinoma, especially in node-negative patients with the classic variant of invasive lobular carcinoma
— id: 78828, year: 2008, vol: 38, page: 99, stat: Journal Article,

Stromal AR inhibition of prostate cancer growth and invasion by stromal AR and association with androgen independent disease
Li, Y; Li, CX; Melamed, J; Walden, P; Peng, Y; Lepor, H; Garabedian, MJ; Lee, P
2008 ;179(4):187-187, Journal of urology
— id: 104578, year: 2008, vol: 179, page: 187, stat: Journal Article,

Decrease in stromal androgen receptor associates with androgen-independent disease and promotes prostate cancer cell proliferation and invasion
Li, Yirong; Li, Caihong X; Ye, Huihui; Chen, Fei; Melamed, Jonathan; Peng, Yi; Liu, Jinsong; Wang, Zhengxin; Tsou, Hui C; Wei, Jianjun; Walden, Paul; Garabedian, Michael J; Lee, Peng
2008 Dec;12(6B):2790-2798, Journal of cellular & molecular medicine
Androgen receptor (AR) is expressed in both stromal and epithelial cells of the prostate. The majority of studies on AR expression and function in prostate cancer is focused on malignant epithelial cells rather than stromal cells. In this study, we examined the levels of stromal AR in androgen-dependent and -independent prostate cancer and the function of stromal AR in prostate cancer growth and invasion. We showed that stromal AR levels were decreased in the areas surrounding cancerous tissue, especially in androgen-independent cancer. Using two telomerase-immortalized human stromal cell lines, one AR-positive and the other AR-negative, we demonstrated that stromal cells lacking AR stimulated cell proliferation of co-cultured prostate cancer cells in vitro and enhanced tumor growth in vivo when co-injected with PC3 epithelial cells in nude mice. In contrast, stromal cells expressing AR suppressed prostate cancer growth in vitro and in vivo. In parallel with cancer growth, in vitro invasion assays revealed that stromal cells lacking AR increased the invasion ability of PC3 cell by one order of magnitude, while stromal cells expressing AR reduced this effect. These results indicate a negative regulation of prostate cancer growth and invasion by stromal AR. This provides potentially new mechanistic insights into the failure of androgen ablation therapy, and the reactivation of stromal AR could be a novel therapeutic approach for treating hormone refractory prostate cancer
— id: 76448, year: 2008, vol: 12, page: 2790, stat: Journal Article,

Management of localized prostate cancer and an incidental ureteral duplication with upper pole ectopic ureter inserting into the prostatic urethra
Marien, Tracy P; Shapiro, Ellen; Melamed, Jonathan; Taouli, Bachir; Stifelman, Michael D; Lepor, Herbert
2008 Fall;10(4):297-303, Reviews in urology
Ectopic ureters are rare congenital malformations of the renal system that most commonly present in females. It is extremely rare to encounter an ectopic ureter in an older man undergoing radical prostatectomy. We report herein a case of a 66-year-old man with prostate cancer and a complete duplication of the left renal collecting system, with an upper pole ectopic ureter and associated normal functioning renal parenchyma entering into the prostatic urethra. This anomaly was incidentally discovered on preoperative magnetic resonance imaging of the prostate. Open radical retropubic prostatectomy and a left ureteroureterostomy were performed
— id: 94870, year: 2008, vol: 10, page: 297, 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,

Distinct nuclear and cytoplasmic functions of androgen receptor cofactor p44 and association with androgen-independent prostate cancer
Peng, Yi; Chen, Fei; Melamed, Jonathan; Chiriboga, Luis; Wei, Jianjun; Kong, Xiangtian; McLeod, Maureen; Li, Yirong; Li, Caihong X; Feng, Alice; Garabedian, Michael J; Wang, Zhengxin; Roeder, Robert G; Lee, Peng
2008 Apr 1;105(13):5236-5241, Proceedings of the National Academy of Sciences of the United States of America
Androgen receptor (AR) mediates transcriptional activation of diverse target genes through interactions with various coactivators that may alter its function and help mediate the switch between prostate cell proliferation and differentiation. We recently identified p44/MEP50 as an AR coactivator and further showed that it is expressed primarily in the nucleus and cytoplasm of benign prostate epithelial and prostate cancer cells, respectively. We also showed that haploinsufficiency in p44(+/-) mice causes prostate epithelial cell proliferation. To establish direct cause-and-effect relationships, we have used p44 fusion proteins that are selectively expressed in the nucleus or cytoplasm of prostate cancer cells (LNCaP), along with RNAi analyses, to examine effects of p44 both in vitro and in vivo (in tumor xenografts). We show that preferential expression of p44 in the nucleus inhibits proliferation of LNCaP cells in an AR-dependent manner, whereas preferential expression of p44 in the cytoplasm enhances cell proliferation. These effects appear to be mediated, at least in part, through the regulation of distinct cell-cycle regulatory genes that include p21 (up-regulated by nuclear p44) and cyclin D2 and CDK6 (up-regulated by cytoplasmic p44). Importantly, we also demonstrate that altered p44 expression is associated with androgen-independent prostate cancer. Our results indicate that nuclear p44 and cytoplasmic p44 have distinct and opposing functions in the regulation of prostate cancer cell proliferation
— id: 76450, year: 2008, vol: 105, page: 5236, stat: Journal Article,

Antiproliferative effects by let-7 repression of high-mobility group A2 in uterine leiomyoma
Peng, Yi; Laser, Jordan; Shi, Guizhi; Mittal, Khush; Melamed, Jonathan; Lee, Peng; Wei, Jian-Jun
2008 Apr;6(4):663-673, Molecular cancer research
High-mobility group A2 (HMGA2) is commonly overexpressed in large leiomyomas. HMGA2 is an important regulator of cell growth, differentiation, apoptosis, and transformation. As a predicted target of Let-7 microRNAs (Let-7s), HMGA2 can be repressed by Let-7s in vitro. MicroRNA profiling analysis revealed that Let-7s were significantly dysregulated in uterine leiomyomas: high in small leiomyomas and lower in large leiomyomas. To evaluate whether Let-7 repression of HMGA2 plays a major role in leiomyomas, we analyzed the molecular relationship of HMGA2 and Let-7s, both in vitro and in vivo. We first characterized that exogenous Let-7 microRNAs could directly repress the dominant transcript of HMGA2, HMGA2a. This repression was also identified for two cryptic HMGA2 transcripts in primary leiomyoma cultures. Second, we found that the endogenous Let-7s were biologically active and played a major role in the regulation of HMGA2. Then, we illustrated that Let-7 repression of HMGA2 inhibited cellular proliferation. Finally, we examined the expression levels of Let-7c and HMGA2 in a large cohort of leiomyomas (n = 120), and we found high levels of Let-7 and low levels of HMGA2 in small leiomyomas, and low levels of Let-7 and high levels of HMGA2 in large leiomyomas. Our findings suggest that the Let-7-mediated repression of HMGA2 mechanism can be an important molecular event in leiomyoma growth. (Mol Cancer Res 2008;6(4):663-73)
— id: 78575, year: 2008, vol: 6, page: 663, stat: Journal Article,

Stimulation of prostate cancer cellular proliferation and invasion by the androgen receptor co-activator ARA70
Peng, Yi; Li, Caihong X; Chen, Fei; Wang, Zhengxin; Ligr, Martin; Melamed, Jonathan; Wei, Jianjun; Gerald, William; Pagano, Michele; Garabedian, Michael J; Lee, Peng
2008 Jan;172(1):225-235, American journal of pathology
ARA70 was first identified as a gene fused to the ret oncogene in thyroid carcinoma and subsequently as a co-activator for androgen receptor (AR). Two isoforms of ARA70 have been identified: a 70-kDa version called ARA70 alpha and an internally spliced 35-kDa variant termed ARA70 beta. We have previously reported that ARA70 alpha expression is reduced in prostate cancer, and its overexpression inhibits proliferation of LNCaP prostate cancer cells. However, the function of the ARA70 beta isoform in prostate cancer is not understood. In this report we examined the effects of ARA70 beta on AR transcriptional regulation as well as prostate cancer cellular proliferation and invasion. Although both ARA70 alpha and ARA70 beta functioned as transcriptional co-activators of AR in cell-based reporter assays, ARA70 beta overexpression, in contrast to ARA70 alpha, promoted prostate cancer cellular proliferation and invasion through Matrigel. Interestingly, genome-wide expression profiling of cells expressing ARA70 beta revealed an increase in the expression of genes involved in the control of cell division and adhesion, compatible with a role for ARA70 beta in proliferation and invasion. Consistent with its function in promoting cell growth and invasion, ARA70 beta expression was increased in prostate cancer. Our findings implicate ARA70 beta as a regulator of tumor cell growth and metastasis by affecting gene expression
— id: 76451, year: 2008, vol: 172, page: 225, stat: Journal Article,

Inflammatory bowel disease (IBD) - Protein profile of active disease
Pevsner, P; Eskaros, S; Melamed, J; Remsen, T; Diamond, I; Francois, F; Momeni, M; Kessler, P; Stern, A; Anand, S
2008 SEP ;103(9):S449-S449, American journal of gastroenterology
— id: 86598, year: 2008, vol: 103, page: S449, stat: Journal Article,

Colon tumor biomarkers-Maldi imaging of tissue microarray
Pevsner, P; Melamed, J; Remsen, T; Duddempudi, S; Francois, F; Momeni, M; Sandar, N; Kessler, P; Stern, A; Anand, S
2008 SEP ;103(9):S196-S197, American journal of gastroenterology
— id: 86597, year: 2008, vol: 103, page: S196, stat: Journal Article,

A tattoo-pigmented node masquerading as the sentinel node in a case of breast cancer
Schlager, Avi; Laser, Alice; Melamed, Jonathan; Guth, Amber A
2008 May-Jun;14(3):299-300, Breast journal
— id: 78829, year: 2008, vol: 14, page: 299, stat: Journal Article,

Androgen receptor overexpression in prostate cancer linked to Pur alpha loss from a novel repressor complex
Wang, Longgui G; Johnson, Edward M; Kinoshita, Yayoi; Babb, James S; Buckley, Michael T; Liebes, Leonard F; Melamed, Jonathan; Liu, Xiao-Mei; Kurek, Ralf; Ossowski, Liliana; Ferrari, Anna C
2008 Apr 15;68(8):2678-2688, Cancer research
Increased androgen receptor (AR) expression and activity are pivotal for androgen-independent (AI) prostate cancer (PC) progression and resistance to androgen-deprivation therapy. We show that a novel transcriptional repressor complex that binds a specific sequence (repressor element) in the AR gene 5'-untranslated region contains Pur alpha and hnRNP-K. Pur alpha expression, its nuclear localization, and its AR promoter association, as determined by chromatin immunoprecipitation analysis, were found to be significantly diminished in AI-LNCaP cells and in hormone-refractory human PCs. Transfection of AI cells with a plasmid that restored Pur alpha expression reduced AR at the transcription and protein levels. Pur alpha knockdown in androgen-dependent cells yielded higher AR and reduced p21, a gene previously shown to be under negative control of AR. These changes were linked to increased proliferation in androgen-depleted conditions. Treatment of AI cells with histone deacetylase and DNA methylation inhibitors restored Pur alpha protein and binding to the AR repressor element. This correlated with decreased AR mRNA and protein levels and inhibition of cell growth. Pur alpha is therefore a key repressor of AR transcription and its loss from the transcriptional repressor complex is a determinant of AR overexpression and AI progression of PC. The success in restoring Pur alpha and the repressor complex function by pharmacologic intervention opens a promising new therapeutic approach for advanced PC
— id: 95063, year: 2008, vol: 68, page: 2678, stat: Journal Article,

Perturbation of transforming growth factor (TGF)-beta1 association with latent TGF-beta binding protein yields inflammation and tumors
Yoshinaga, Keiji; Obata, Hiroto; Jurukovski, Vladimir; Mazzieri, Roberta; Chen, Yan; Zilberberg, Lior; Huso, David; Melamed, Jonathan; Prijatelj, Petra; Todorovic, Vesna; Dabovic, Branka; Rifkin, Daniel B
2008 Dec 2;105(48):18758-18763, Proceedings of the National Academy of Sciences of the United States of America
Transforming growth factor-beta (TGF-beta) activity is controlled at many levels including the conversion of the latent secreted form to its active state. TGF-beta is often released as part of an inactive tripartite complex consisting of TGF-beta, the TGF-beta propeptide, and a molecule of latent TGF-beta binding protein (LTBP). The interaction of TGF-beta and its cleaved propeptide renders the growth factor latent, and the liberation of TGF-beta from this state is crucial for signaling. To examine the contribution of LTBP to TGF-beta function, we generated mice in which the cysteines that link the propeptide to LTBP were mutated to serines, thereby blocking covalent association. Tgfb1(C33S/C33S) mice had multiorgan inflammation, lack of skin Langerhans cells (LC), and a shortened lifespan, consistent with decreased TGF-beta1 levels. However, the inflammatory response and decreased lifespan were not as severe as observed with Tgfb1(-/-) animals. Tgfb1(C33S/C33S) mice exhibited decreased levels of active TGF-beta1, decreased TGF-beta signaling, and tumors of the stomach, rectum, and anus. These data suggest that the association of LTBP with the latent TGF-beta complex is important for proper TGF-beta1 function and that Tgfb1(C33S/C33S) mice are hypomorphs for active TGF-beta1. Moreover, although mechanisms exist to activate latent TGF-beta1 in the absence of LTBP, these mechanisms are not as efficient as those that use the latent complex containing LTBP
— id: 92146, year: 2008, vol: 105, page: 18758, stat: Journal Article,

Midkine is a NF-kappaB-inducible gene that supports prostate cancer cell survival
You, Zongbing; Dong, Ying; Kong, Xiangtian; Beckett, Laurel A; Gandour-Edwards, Regina; Melamed, Jonathan
2008 ;1:6-6, BMC medical genomics
ABSTRACT: BACKGROUND: Midkine is a heparin-binding growth factor that is over-expressed in various human cancers and plays important roles in cell transformation, growth, survival, migration, and angiogenesis. However, little is known about the upstream factors and signaling mechanisms that regulate midkine gene expression. METHODS: Two prostate cancer cell lines LNCaP and PC3 were studied for their expression of midkine. Induction of midkine expression in LNCaP cells by serum, growth factors and cytokines was determined by Western blot analysis and/or real-time quantitative reverse-transcription - polymerase chain reaction (RT-PCR). The cell viability was determined by the trypan blue exclusion assay when the LNCaP cells were treated with tumor necrosis factor alpha (TNFalpha) and/or recombinant midkine. When the LNCaP cells were treated with recombinant midkine, activation of intracellular signalling pathways was determined by Western blot analysis. Prostate tissue microarray slides containing 129 cases (18 normal prostate tissues, 40 early stage cancers, and 71 late stage cancers) were assessed for midkine expression by immunohistochemical staining. RESULTS: We identified that fetal bovine serum, some growth factors (epidermal growth factor, androgen, insulin-like growth factor-I, and hepatocyte growth factor) and cytokines (TNFalpha and interleukin-1beta) induced midkine expression in a human prostate cancer cell line LNCaP cells. TNFalpha also induced midkine expression in PC3 cells. TNFalpha was the strongest inducer of midkine expression via nuclear factor-kappa B pathway. Midkine partially inhibited TNFalpha-induced apoptosis in LNCaP cells. Knockdown of endogenous midkine expression by small interfering RNA enhanced TNFalpha-induced apoptosis in LNCaP cells. Midkine activated extracellular signal-regulated kinase 1/2 and p38 mitogen-activated protein kinase pathways in LNCaP cells. Furthermore, midkine expression was significantly increased in late stage prostate cancer, which coincides with previously reported high serum levels of TNFalpha in advanced prostate cancer. CONCLUSION: These findings provide the first demonstration that midkine expression is induced by certain growth factors and cytokines, particularly TNFalpha, which offers new insight into understanding how midkine expression is increased in the late stage prostate cancer
— id: 95439, year: 2008, vol: 1, page: 6, stat: Journal Article,

EBP1, an ErbB3-binding protein, is decreased in prostate cancer and implicated in hormone resistance
Zhang, Yuexing; Linn, Douglas; Liu, Zhenqiu; Melamed, Jonathan; Tavora, Fabio; Young, Charles Y; Burger, Angelika M; Hamburger, Anne W
2008 Oct;7(10):3176-3186, Molecular cancer therapeutics
Aberrant activation of the androgen receptor (AR) by the ErbB2/ErbB3 heterodimer contributes to the development of hormone resistance in prostate cancer. EBP1, an ErbB3-binding protein, acts as an AR corepressor. As EBP1 is decreased in preclinical models of hormone-refractory prostate cancer, we studied the expression of EBP1 in human prostate cancer. We found that the expression of the EBP1 gene was significantly decreased in prostate cancer tissues compared with benign prostate at both mRNA and protein levels. Restoration of EBP1 expression in the hormone-refractory LNCaP C81 cell line led to an amelioration of the androgen-independent phenotype based on established biological criteria and a reduction in the expression of a cohort of AR target genes. The ability of the ErbB3 ligand heregulin (HRG) to stimulate growth and AKT phosphorylation of hormone-refractory prostate cancer cells was abolished. Abrogation of EBP1 expression by short hairpin RNA in hormone-dependent LNCaP cells, which undergo apoptosis in response to HRG, resulted in HRG-stimulated cell growth. Restoration of EBP1 expression decreased the tumorigenicity of C81 xenografts in female mice, whereas elimination of EBP1 expression enhanced the ability of LNCaP cells to grow in female mice. Our data support a role for EBP1 in the development of hormone-refractory prostate cancer via inhibition of both AR- and HRG-stimulated growth and present a novel strategy for treating androgen-refractory prostate cancer
— id: 90053, year: 2008, vol: 7, page: 3176, stat: Journal Article,

Radiographic determination of tissue thickness in paraffin blocks: application to the construction of tissue microarrays
Kong, Xiangtian; Zhao, Yan; Ksionsk, Marti; Zhou, Meisheng; Walden, Paul; Bosland, Maarten; Pei, Zhiheng; Lee, Peng; Melamed, Jonathan
2007 Mar;15(1):108-112, Applied immunohistochemistry & molecular morphology
The determination of tissue thickness in paraffin blocks in the histology laboratory has been largely based on visual estimates. More accurate methods are required for the construction of tissue microarrays (TMAs) to assure a greater yield of cores in sections through the TMA block. We describe an accurate radiographic method to determine tissue thickness in donor paraffin blocks and have validated its application to TMA construction. Individual radiographic analysis was performed on paraffin donor blocks used for the construction of TMAs for determination of donor block tissue thickness. Consecutive numbered slide sections through the TMA block were then examined for the presence or loss of cores in the 150th TMA slide (from the final third of the TMA block) and correlated with the thickness of the individual donor blocks determined radiographically. At the 150th TMA slide, 202 of 1340 cores (15.1%) were depleted. Radiographic measurement showed a greater thickness of the donor paraffin block tissue (2.02 mm) corresponding to the retained cores as compared with the donor tissue (1.54 mm) of the depleted cores (P < 0.001). With progressive slide sections through a TMA block, the retention of tissue cores shows a significant correlation with donor block tissue thickness. Radiographic determination of tissue thickness in donor paraffin blocks can be used in TMA construction. Prior knowledge of tissue thickness in TMA construction can prompt compensatory steps that can enhance the yield of valuable samples and assure sufficient numbers of adequate cores for statistical analysis in biomarker evaluations
— id: 73238, year: 2007, vol: 15, page: 108, stat: Journal Article,

The expression and function of androgen receptor coactivator p44 and protein arginine methyltransferase 5 in the developing testis and testicular tumors
Liang, John J; Wang, Zhengxin; Chiriboga, Luis; Greco, M Alba; Shapiro, Ellen; Huang, Hongying; Yang, Ximing J; Huang, Jiaoti; Peng, Yi; Melamed, Jonathan; Garabedian, Michael J; Lee, Peng
2007 May;177(5):1918-1922, Journal of urology
PURPOSE: The role of androgen receptor coactivators in testicular development and cancer formation is unclear. p44/Mep50 was identified as an androgen receptor coactivator that functions in a complex with protein arginine methyltransferase 5. We studied the expression of p44 and protein arginine methyltransferase 5 in developing fetal testis and adult testicular tumors, including seminomas and Leydig cell tumors. MATERIALS AND METHODS: A total of 30 human fetal testes from abortuses at a gestational age of 10 to 40 weeks, 33 human seminomas and 11 human Leydig cell tumors were retrieved from the archives of the departments of pathology. Immunohistochemistry was performed with affinity purified p44 and IgG purified protein arginine methyltransferase 5 polyclonal antibodies. RESULTS: Protein arginine methyltransferase 5 and p44 were expressed predominantly as nuclear proteins in fetal Leydig cells and human adult nonneoplastic testes, including germ cells and Leydig cells, while they were expressed in the cytoplasm of germ cells of the fetal testis. Expression was strongest in the fetal testis during the second trimester. Compared to adult nonneoplastic testes, human seminoma and Leydig tumor cells showed a marked decrease in nuclear expression of p44 and protein arginine methyltransferase 5 with a concomitant marked increase in cytoplasmic expression of these proteins. Furthermore, average testicular size was increased by 29% in p44(+/-) heterzygotic mice. CONCLUSIONS: These results suggest distinct functions of the nuclear and the p44/protein arginine methyltransferase 5 complexes in the developing fetal testis and in the oncogenesis of testicular tumors. Further studies are needed to confirm the functional relevance of these findings
— id: 72417, year: 2007, vol: 177, page: 1918, stat: Journal Article,

Two cases of hepatoid adenocarcinoma of the intestine in association with inflammatory bowel disease
Liu, Q; Bannan, M; Melamed, J; Witkin, G B; Nonaka, D
2007 Jul;51(1):123-124, Histopathology
— id: 73000, year: 2007, vol: 51, page: 123, stat: Journal Article,

Immunohistochemical evaluation of necrotic malignant melanomas
Nonaka, Daisuke; Laser, Jordan; Tucker, Rachel; Melamed, Jonathan
2007 May;127(5):787-791, American journal of clinical pathology
We evaluated 35 cases of malignant melanomas with substantial necrosis immunostained with S-100, HMB-45, Melan-A, tyrosinase, PNL2, and microphthalmia transcription factor (MITF). Staining patterns were evaluated in viable and necrotic areas of the tumors. S-100 was the most sensitive marker (97%) in the viable tumors, but necrotic areas demonstrated nonspecific staining. Viable tumors stained variably for HMB-45 (25 [71%]), Melan-A (28 [80%]), tyrosinase (30 [86%]), and PNL2 (23 [66%]). Necrotic areas focally reacted to the same antibodies. The necrotic areas that retained immunoreactivity for these markers corresponded to areas where the outline of the tumor cells could still be recognized as ghost cells on the H&E-stained section. Areas that showed complete coagulative necrosis were negative for melanoma markers. MITF variably stained in the viable tumors but was completely negative in necrotic areas. Our study demonstrated that a combination of antibodies to HMB-45, tyrosinase, and PNL2 detected melanocytic differentiation in necrotic areas in 80% of cases
— id: 71873, year: 2007, vol: 127, page: 787, stat: Journal Article,

Unusual occurrence of a melanoma with intermixed epithelial component: a true melanocarcinoma?: case report and review of epithelial differentiation in melanoma by light microscopy and immunohistochemistry
Wen, Y Hannah; Giashuddin, Shah; Shapiro, Richard L; Velazquez, Elsa; Melamed, Jonathan
2007 Aug;29(4):395-399, American journal of dermatopathology
We report a case of a 27-year-old woman with a nonpigmented lesion on the right scalp. Histological examination showed a malignant nodular neoplasm with 2 distinct but intimately admixed components: a malignant melanoma with a spindle component and an unusual glandular component. Immunohistochemical studies demonstrated epithelial differentiation on the basis of cytokeratin (CAM5.2 and AE1/AE3) expression in the glandular component and melanocytic differentiation (HMB-45, PNL2, MITF, and S-100) of the spindle cell component. A single melanocytic marker (MITF) was expressed in both components, raising the possibility of dual differentiation in a single tumor, rather than the alternative considerations of a collision tumor or a reactive pseudoepitheliomatous hyperplasia with eccrine duct lumen formation within a melanoma. This unusual tumor with both melanocytic and epithelial components may represent a true melanocarcinoma, which becomes a plausible consideration, in view of melanoma plasticity and recent experimental evidence and speculation about the role of stem cells in melanoma
— id: 73902, year: 2007, vol: 29, page: 395, stat: Journal Article,

Differential expression of IL-17RC isoforms in androgen-dependent and androgen-independent prostate cancers
You, Zongbing; Dong, Ying; Kong, Xiangtian; Zhang, Yi; Vessella, Robert L; Melamed, Jonathan
2007 Jun;9(6):464-470, Neoplasia
IL-17RC (interleukin-17 receptor-like) gene codes for a transmembrane protein, the full length of which inhibits apoptosis in prostate cancer cells. IL-17RC gene transcribes over a dozen different splice variants of mRNA. However, it is not known whether there are relevant protein isoforms. Here we report that different IL-17RC protein isoforms were detected by two different antibodies. The isoform as detected byanti-IL-17RC intracellular domain antibodies (anti-ICD) was expressed at higher levels in androgen-independent prostate cancer cell lines (PC3 and DU145) than in androgen-dependent prostatic cell lines (RWPE-1, pRNS-1-1, MLC-SV40, and LNCaP). In contrast, several isoforms as detected by anti-IL-17RC extracellular domain antibodies (anti-ECD) were expressed at significantly higher levels in androgen-dependent prostatic cell lines than in androgen-independent ones. Furthermore, immunohistochemical staining of prostate tissue microarrays showed that IL-17RC protein expression was significantly higher in androgen-independent prostate cancers than in androgen-dependent ones when anti-ICD was used, whereas the trend was reversed using anti-ECD. These observations provide evidence that IL-17RC protein isoforms are differentially expressed in prostatic cells and cancer tissues and may play a negative or positive role in the initiation and progression of prostate cancer
— id: 95440, year: 2007, vol: 9, page: 464, stat: Journal Article,

Tyrosine Kinase Etk/BMX Is Up-regulated in Human Prostate Cancer and Its Overexpression Induces Prostate Intraepithelial Neoplasia in Mouse
Dai, Bojie; Kim, Oekyung; Xie, Yingqiu; Guo, Zhiyong; Xu, Kexin; Wang, Bin; Kong, Xiangtian; Melamed, Jonathan; Chen, Hegang; Bieberich, Charles J; Borowsky, Alexander D; Kung, Hsing-Jien; Wei, Guo; Ostrowski, Michael C; Brodie, Angela; Qiu, Yun
2006 Aug 15;66(16):8058-8064, Cancer research
The nonreceptor tyrosine kinase Etk/BMX was originally identified from the human prostate xenograft CWR22. Here, we report that Etk is up-regulated in human prostate tumor specimens surveyed. Knocking down Etk expression by a specific small interfering RNA (siRNA) in prostate cancer cells attenuates cell proliferation, suggesting an essential role of Etk for prostate cancer cell survival and growth. Targeted expression of Etk in mouse prostate epithelium results in pathologic changes resembling human prostatic intraepithelial neoplasia, indicating that up-regulation of Etk may contribute to prostate cancer development. A marked increase of luminal epithelial cell proliferation was observed in the Etk transgenic prostate, which may be attributed in part to the elevated activity of Akt and signal transducers and activators of transcription 3 (STAT3). More interestingly, the expression level of acetyltransferase cyclic AMP-responsive element binding protein-binding protein (CBP) is also increased in the Etk transgenic prostate as well as in a prostate cancer cell line overexpressing Etk, concomitant with elevated histone 3 acetylation at lysine 18 (H3K18Ac). Down-modulation of Etk expression by a specific siRNA leads to a decrease of H3 acetylation in prostate cancer cell lines. Our data suggest that Etk may also modulate chromatin remodeling by regulating the activity of acetyltransferases, such as CBP. Given that Etk may exert its effects in prostate through modulation of multiple signaling pathways altered in human prostate cancer, the Etk transgenic mouse model may be a useful tool for studying the functions of Etk and identification of new molecular markers and drug targets relevant to human diseases. (Cancer Res 2006; 66(16): 8058-64)
— id: 69646, year: 2006, vol: 66, page: 8058, stat: Journal Article,

Androgen receptor and prostate apoptosis response factor-4 target the c-FLIP gene to determine survival and apoptosis in the prostate gland
Gao, Shen; Wang, Hua; Lee, Peng; Melamed, Jonathan; Li, Caihong X; Zhang, Fahao; Wu, Hong; Zhou, Liran; Wang, Zhengxin
2006 Jun;36(3):463-483, Journal of molecular endocrinology
Androgen receptor (AR) is a ligand-activated transcription factor that mediates the action of androgens and is essential for the growth, function, and cell differentiation of the prostate gland. Here, we demonstrated that the prostate apoptosis response factor-4 (par-4) functions as a novel AR coactivator. Par-4 physically interacted with the DNA-binding domain of AR, enhanced AR interaction with DNA, and increased AR-dependent transcription. Par-4 enhanced the c-FLIP promoter activity and was recruited on to the c-FLIP gene in the presence of androgens, and the dominant-negative par-4 decreased c-FLIP expression. These results suggest that, in addition to its proapoptotic function, par-4 acts as a novel transcription cofactor for AR to target c-FLIP gene expression. In addition, we demonstrated that loss of c-FLIP expression was essential for castration-induced apoptosis in the prostate gland and that enhanced c-FLIP expression was associated with prostate cancer progression to the androgen-resistant stage. Our data shed light on a transcription-mediated mechanism for the effects of the AR pathway on cell survival and apoptosis
— id: 64212, year: 2006, vol: 36, page: 463, stat: Journal Article,

Regulation of androgen receptor activity by tyrosine phosphorylation
Guo, Zhiyong; Dai, Bojie; Jiang, Tianyun; Xu, Kexin; Xie, Yingqiu; Kim, Oekyung; Nesheiwat, Issa; Kong, Xiangtian; Melamed, Jonathan; Handratta, Venkatesh D; Njar, Vincent C O; Brodie, Angela M H; Yu, Li-Rong; Veenstra, Timothy D; Chen, Hegang; Qiu, Yun
2006 Oct;10(4):309-319, Cancer cell
The androgen receptor (AR) is essential for the growth of prostate cancer cells. Here, we report that tyrosine phosphorylation of AR is induced by growth factors and elevated in hormone-refractory prostate tumors. Mutation of the major tyrosine phosphorylation site in AR significantly inhibits the growth of prostate cancer cells under androgen-depleted conditions. The Src tyrosine kinase appears to be responsible for phosphorylating AR, and there is a positive correlation of AR tyrosine phosphorylation with Src tyrosine kinase activity in human prostate tumors. Our data collectively suggest that growth factors and their downstream tyrosine kinases, which are elevated during hormone-ablation therapy, can induce tyrosine phosphorylation of AR and such modification may be important for prostate tumor growth under androgen-depleted conditions
— id: 69645, year: 2006, vol: 10, page: 309, stat: Journal Article,

MTOR/4E-BP1 pathway is a translational regulator of prostate cancer progression
Karpisheva, KV; Xi, QR; Braunstein, S; Melamed, J; Goldberg, J; Schneider, R
2006 MAR 6 ;20(4):A109-A109, FASEB journal
— id: 63857, year: 2006, vol: 20, page: A109, stat: Journal Article,

Appendiceal diverticulitis: A greater susceptibility to perforation of the appendix
Liu, Q; Tao, ZM; Bannan, M; Melamed, J
2006 OCT ;126(4):658-658, American journal of clinical pathology
— id: 68760, year: 2006, vol: 126, page: 658, stat: Journal Article,

An informatics model for tissue banks--lessons learned from the Cooperative Prostate Cancer Tissue Resource
Patel, Ashokkumar A; Gilbertson, John R; Parwani, Anil V; Dhir, Rajiv; Datta, Milton W; Gupta, Rajnish; Berman, Jules J; Melamed, Jonathan; Kajdacsy-Balla, Andre; Orenstein, Jan; Becich, Michael J
2006 ;6:120-120, BMC cancer
BACKGROUND: Advances in molecular biology and growing requirements from biomarker validation studies have generated a need for tissue banks to provide quality-controlled tissue samples with standardized clinical annotation. The NCI Cooperative Prostate Cancer Tissue Resource (CPCTR) is a distributed tissue bank that comprises four academic centers and provides thousands of clinically annotated prostate cancer specimens to researchers. Here we describe the CPCTR information management system architecture, common data element (CDE) development, query interfaces, data curation, and quality control. METHODS: Data managers review the medical records to collect and continuously update information for the 145 clinical, pathological and inventorial CDEs that the Resource maintains for each case. An Access-based data entry tool provides de-identification and a standard communication mechanism between each group and a central CPCTR database. Standardized automated quality control audits have been implemented. Centrally, an Oracle database has web interfaces allowing multiple user-types, including the general public, to mine de-identified information from all of the sites with three levels of specificity and granularity as well as to request tissues through a formal letter of intent. RESULTS: Since July 2003, CPCTR has offered over 6,000 cases (38,000 blocks) of highly characterized prostate cancer biospecimens, including several tissue microarrays (TMA). The Resource developed a website with interfaces for the general public as well as researchers and internal members. These user groups have utilized the web-tools for public query of summary data on the cases that were available, to prepare requests, and to receive tissues. As of December 2005, the Resource received over 130 tissue requests, of which 45 have been reviewed, approved and filled. Additionally, the Resource implemented the TMA Data Exchange Specification in its TMA program and created a computer program for calculating PSA recurrence. CONCLUSION: Building a biorepository infrastructure that meets today's research needs involves time and input of many individuals from diverse disciplines. The CPCTR can provide large volumes of carefully annotated prostate tissue for research initiatives such as Specialized Programs of Research Excellence (SPOREs) and for biomarker validation studies and its experience can help development of collaborative, large scale, virtual tissue banks in other organ systems
— id: 69647, year: 2006, vol: 6, page: 120, stat: Journal Article,

PAX2: a reliable marker for nephrogenic adenoma
Tong, Guo-Xia; Melamed, Jonathan; Mansukhani, Mahesh; Memeo, Lorenzo; Hernandez, Osvaldo; Deng, Fang-Ming; Chiriboga, Luis; Waisman, Jerry
2006 Mar;19(3):356-363, Modern pathology
Nephrogenic adenoma is a rare lesion of the urinary tract. The diagnosis usually is straightforward when characteristic microscopic and clinical findings are present, and the entity is familiar. However, misdiagnosis, in particular of adenocarcinoma of the prostate gland, may occur. Immunohistochemical stains often are needed to make such a distinction, but currently available markers offered only partial help. It recently was demonstrated that nephrogenic adenoma in renal transplant patients originated from the renal tubular epithelium. This newly proved, but long sought information may be helpful in the differential diagnosis of neophrogenic adenoma. In this study, we investigated the expression of a renal transcription factor, PAX2, in 39 nonrenal transplant-related nephrogenic adenomas, 100 adenocarcinomas of the prostate gland, and 47 urothelial carcinomas of the urinary tract. A strong and distinct nuclear staining of PAX2 was found in all 39 cases of nephrogenic adenoma (100%), but not in normal prostate tissue, normal urothelium, adenocarcinomas of the prostate gland, and invasive urothelial carcinomas. Focal CD10 was detected in six of 13 nephrogenic adenomas in the superficial papillary component and in normal prostate epithelium, normal urothelium, lymphocytes, adenocarcinoma of the prostate gland, and urothelial carcinoma. There was no uroplakins detected in nephrogenic adenoma. Therefore, these findings are suggesting that nephrogenic adenoma in nonrenal transplant patients may also arise from the renal epithelium, as did the comparable lesions after transplantation. PAX2 is a specific and sensitive immunohistochemical marker in identification and differential diagnosis of nephrogenic adenoma.Modern Pathology advance online publication, 6 January 2006; doi:10.1038/modpathol.3800535
— id: 62129, year: 2006, vol: 19, page: 356, stat: Journal Article,

Expression of protein arginine methyl transferases in mammary ductal carcinoma
Wang, J; Zhang, XM; Singh, B; Melamed, J; Chen, F; Lee, P; Sun, W
2006 JAN ;19(4):45A-45A, Modern pathology
— id: 61433, year: 2006, vol: 19, page: 45A, stat: Journal Article,

Expression of protein arginine methyl transferases in mammary ductal carcinoma
Wang, J; Zhang, XM; Singh, B; Melamed, J; Chen, F; Lee, P; Sun, W
2006 JAN ;86(4):45A-45A, Laboratory investigation
— id: 62614, year: 2006, vol: 86, page: 45A, stat: Journal Article,

EXPRESSION OF ANDROGEN RECEPTOR ASSOCIATED PROTEIN 55 (ARA55) IN THE DEVELOPING HUMAN FETAL PROSTATE
Cai, Guoping; Huang, Hongying; Shapiro, Ellen; Zhou, Holly; Yeh, Shuyuan; Melamed, Jonathan; Greco, M Alba; Lee, Peng
2005 Jun;173(6):2190-2193, Journal of urology
PURPOSE:: Development and differentiation of the human fetal prostate are androgen dependent and follow a specific pattern of solid bud-ductal morphogenesis, which involves stromal-epithelial interactions. Androgen receptor associated protein 55 (ARA55) an androgen receptor coactivator localized in stromal cells, binds to androgen receptor (AR) and regulates androgen receptor translocation and transcriptional activity. We investigated whether ARA55 has a role in human prostate development. MATERIALS AND METHODS:: ARA55 expression was examined in 25 human prostates from fetuses at gestational ages 10 to 40 weeks and compared to the expression of 34betaE12 (a basal cell marker), smooth muscle actin, desmin (a smooth muscle marker), vimentin (a mesenchymal marker) and Ki-67 (a proliferation marker) by immunohistochemistry. RESULTS:: Prostatic epithelium appeared as solid epithelial buds from the urogenital sinus. It underwent arborization and ductal differentiation from the center to the periphery. ARA55 was expressed in stromal cells with a zonal pattern, primarily in the peripheral zone surrounding the noncanalized acini. Most cells in solid buds were positive for 34betaE12, while only basal layer cells in the centrally located epithelial ducts stained with 34betaE12. Solid buds also had a higher proliferation index than ducts. In addition, ARA55 expressing stromal cells but not ARA55 negative stromal cells showed smooth muscle differentiation. CONCLUSIONS:: The intimate relationship between ARA55 expressing stromal cells and mitotically active, noncanalized acini suggests that ARA55 has a role in the stromal-epithelial interaction involved in fetal prostate development
— id: 51801, year: 2005, vol: 173, page: 2190, stat: Journal Article,

Repair of fractured or thin tissue microarray paraffin blocks
Chiriboga, L; Zhao, Y; Wei, JJ; Melamed, J
2005 DEC ;28(4):245-248, Journal of histotechnology
Tissue microarrays (TMAs) are a valuable resource that have been used for molecular profiling and biomarker development. The high throughput and cost savings make TMAs well suited for the rapid screening of large patient populations and for use in multitissue studies. Construction and casting is time consuming and the most important step in the use of a TMA. Occasionally, improper casting of a TMA leads to failure of the block. Similarly, repeated sectioning can cause the block to become too thin to collect additional sections. Considering the increased use of TMA and their occasional failure, we developed a method to repair fractured blocks or blocks worn thin from repeated sectioning
— id: 62767, year: 2005, vol: 28, page: 245, stat: Journal Article,

Prostate cancer in patients with screening serum prostate specific antigen values less than 4.0 ng/dl: results from the cooperative prostate cancer tissue resource
Datta, Milton W; Dhir, Rajiv; Dobbin, Kevin; Bosland, Maarten C; Melamed, Jonathan; Becich, Michael J; Orenstein, Jan M; Kajdacsy-Balla, Andre A; Patel, Ashok; Macias, Virgilia; Berman, Jules J
2005 May;173(5):1546-1551, Journal of urology
PURPOSE: Prostate cancer can occur in patients with low screening serum prostate specific antigen (PSA) values (less than 4.0 ng/ml). It is currently unclear whether these tumors are different from prostate cancer in patients with high PSA levels (greater than 4.0 ng/ml). MATERIALS AND METHODS: From the Cooperative Prostate Cancer Tissue Resource database through March 2004, 3,416 patients with screening PSA less than 16.0 ng/ml diagnosed with prostate cancer between 1993 and 2004 were stratified in groups based on screening serum PSA. These subsets were compared for race, age at diagnosis, clinical and pathological stage, Gleason score, positive surgical margins, posttreatment recurrent disease, and vital status. RESULTS: We identified 468 (14%) patients with screening PSA less than 4.0 ng/ml, 142 (4.2%) of whom had a PSA of less than 2.0 ng/ml. This group included 40 black and 376 white patients. Men with low screening PSA treated with radical prostatectomy had smaller cancers, lower Gleason scores, lower pathological tumor (T) stage and lower PSA recurrence rates than men with high PSA levels (4 ng/ml or greater). These differences held true for men who were younger than 62 years or were white, whereas older or black men had tumor characteristics and outcomes similar to those with higher PSA levels. CONCLUSIONS: Young (younger than 62 years) or white patients with screening serum PSA less than 4.0 ng/ml had smaller, lower grade tumors and lower recurrence rates than patients with PSA 4.0 ng/ml or greater. This was not true for those older than 62 years and for black men
— id: 51790, year: 2005, vol: 173, page: 1546, stat: Journal Article,

Expression of mucin antigens in renal tumors
Guo, CC; Kong, X; Lee, P; Melamed, J
2005 ;85(Suppl 1):143A-143A, Laboratory investigation
— id: 50459, year: 2005, vol: 85, page: 143A, stat: Journal Article,

Expression of mucin antigens in renal tumors
Guo, CC; Kong, X; Lee, P; Melamed, J
2005 ;18(Suppl 1):143A-143A, Modern pathology
— id: 50430, year: 2005, vol: 18, page: 143A, stat: Journal Article,

Decreased expression of PRMT5 is associated with prostate cancer
Guo, CC; Zhang, X; Yee, H; Chiriboga, L; Melamed, J; Lee, P
2005 ;18(Suppl 1):143A-143A, Modern pathology
— id: 50431, year: 2005, vol: 18, page: 143A, stat: Journal Article,

Decreased expression of PRMT5 is associated with prostate cancer
Guo, CC; Zhang, X; Yee, H; Chiriboga, L; Melamed, J; Lee, P
2005 ;85(Suppl 1):143A-143A, Laboratory investigation
— id: 50460, year: 2005, vol: 85, page: 143A, stat: Journal Article,

The development of common data elements for a multi-institute prostate cancer tissue bank: The Cooperative Prostate Cancer Tissue Resource (CPCTR) experience
Patel, Ashokkumar A; Kajdacsy-Balla, Andre; Berman, Jules J; Bosland, Maarten; Datta, Milton W; Dhir, Rajiv; Gilbertson, John; Melamed, Jonathan; Orenstein, Jan; Tai, Kuei-Fang; Becich, Michael J
2005 Aug 21;5(1):108-108, BMC cancer
BACKGROUND: The Cooperative Prostate Cancer Tissue Resource (CPCTR) is a consortium of four geographically dispersed institutions that are funded by the U.S. National Cancer Institute (NCI) to provide clinically annotated prostate cancer tissue samples to researchers. To facilitate this effort, it was critical to arrive at agreed upon common data elements (CDEs) that could be used to collect demographic, pathologic, treatment and clinical outcome data. METHODS: The CPCTR investigators convened a CDE curation subcommittee to develop and implement CDEs for the annotation of collected prostate tissues. The draft CDEs were refined and progressively annotated to make them ISO 11179 compliant. The CDEs were implemented in the CPCTR database and tested using software query tools developed by the investigators. RESULTS: By collaborative consensus the CPCTR CDE subcommittee developed 145 data elements to annotate the tissue samples collected. These included for each case: 1) demographic data, 2) clinical history, 3) pathology specimen level elements to describe the staging, grading and other characteristics of individual surgical pathology cases, 4) tissue block level annotation critical to managing a virtual inventory of cases and facilitating case selection, and 5) clinical outcome data including treatment, recurrence and vital status. These elements have been used successfully to respond to over 60 requests by end-users for tissue, including paraffin blocks from cases with 5 to 10 years of follow up, tissue microarrays (TMAs), as well as frozen tissue collected prospectively for genomic profiling and genetic studies. The CPCTR CDEs have been fully implemented in two major tissue banks and have been shared with dozens of other tissue banking efforts. CONCLUSION: The freely available CDEs developed by the CPCTR are robust, based on 'best practices' for tissue resources, and are ISO 11179 compliant. The process for CDE development described in this manuscript provides a framework model for other organ sites and has been used as a model for breast and melanoma tissue banking efforts
— id: 57729, year: 2005, vol: 5, page: 108, stat: Journal Article,

Cell-specific regulation of androgen receptor phosphorylation in vivo
Taneja, Samir S; Ha, Susan; Swenson, Nicole K; Huang, Hong Ying; Lee, Peng; Melamed, Jonathan; Shapiro, Ellen; Garabedian, Michael J; Logan, Susan K
2005 Dec 9;280(49):40916-40924, Journal of biological chemistry
The biological ramifications of phosphorylation of the androgen receptor (AR) are largely unknown. To examine the phosphorylation of AR at serine 213, a putative substrate for Akt, a phosphorylation site-specific antibody was generated. The use of this antibody indicated that AR Ser-213 is phosphorylated in vivo and that phosphorylation is tightly regulated in a cell type-specific manner. Furthermore, Ser-213 phosphorylation took place with rapid kinetics and was inhibited by the phosphatidylinositol 3-kinase inhibitor LY294002. Phosphorylation occurred in response to R1881 and dihydrotestosterone but weakly if at all in response to testosterone. It did not occur in response to AR antagonists or growth factor stimulation in the absence of an AR agonist. Transcription assays using an AR-responsive reporter gene construct showed that activated phosphatidylinositol 3-kinase inhibited transcription mediated by wild type AR but not that of a mutant AR variant (S213A), which could not be phosphorylated at Ser-213. By immunohistochemistry, the AR Ser(P)-213 antigen was detected in prostate epithelial but not stromal cells despite the fact that an antibody recognizing both phosphorylated and non-phosphorylated forms of AR demonstrates that AR is present in both cell types as expected. In fetal tissue the AR-Ser(P)-213 antigen was present in epithelial cells of the urogenital sinus when endogenous androgen levels were high and activated Akt was prevalent, but absent at a later stage of development when endogenous androgen levels were low and Akt activation was minimal. Immunoreactivity was evident in differentiated cells lining the lumen of the urogenital sinus but not in rapidly dividing, Ki67 positive cells within the developing prostate or stromal tissue, suggesting that site-specific phosphorylation of AR Ser-213 by cellular kinases occurs in a non-proliferating cellular milieu
— id: 61359, year: 2005, vol: 280, page: 40916, stat: Journal Article,

Sarcomatoid Carcinoma of the Penis: A Clinicopathologic Study of 15 Cases
Velazquez, Elsa F; Melamed, Jonathan; Barreto, Jose E; Aguero, Fatima; Cubilla, Antonio L
2005 Sep;29(9):1152-1158, American journal of surgical pathology
Sarcomatoid carcinomas are uncommon, high-grade tumors, predominantly composed of spindle cells. Only a few cases arising in the penis have been reported. The aim of this study is to better define the clinicopathologic features of this neoplasm. A total of 400 cases of squamous cell carcinoma of the penis were reviewed from which 15 sarcomatoid carcinomas (4%) were identified. Clinical and pathologic features were evaluated in all cases. Immunohistochemical studies for expression of AE1/AE3, Cam 5.2, 34betaE12, EMA, vimentin, muscle specific actin, smooth muscle actin, desmin, S-100, p63, and p53 and in situ hybridization studies for HPV were performed in 5 cases. Information about lymph node status was available in 9 cases, and follow-up in 5 cases. The mean age was 59 years, and mean tumor size was 5 cm. Grossly, most tumors were large, polypoid, and ulcerated masses frequently affecting the glans (93%) and deeply invading corpora cavernosa (80%) and skin. Microscopically, the lesions were predominantly composed of atypical spindle cells disposed in interlacing fascicles, resembling fibrosarcoma or leiomyosarcoma, sometimes admixed with pleomorphic giant cells mimicking malignant fibrous histiocytoma. One case was predominantly composed of myxoid areas. Less frequent and focal patterns were pseudoangiomatous and epithelioid. Mitotic figures were numerous, and necrosis was prominent. Foci of heterologous differentiation toward bone (osteosarcomatous component) were present in 1 case. Four cases showed a minor mixed component of usual, papillary, verrucous, and basaloid carcinoma. Intrapenile metastasis ('satellitosis') was present in 4 tumors. One of the cases was multicentric with a separate independent focus of well-differentiated carcinoma with pseudohyperplastic features. Associated low- and high-grade squamous intraepithelial lesions were noted in 73% of the cases. Immunohistochemical studies and HPV in situ hybridization were done in 5 cases. The spindle cells were diffusely positive for vimentin and p53 and showed at least intermediate expression of 34betaE12 and p63 in all cases. EMA and AE1/AE3 were focally positive in 60% of the cases, and Cam 5.2 was focally positive in 1 case. Tumor cells failed to express muscle specific actin, smooth muscle actin, desmin, and S-100. HPV in situ hybridization was negative in all cases. Inguinal metastases were present in 89% of the cases. Two of five patients with adequate follow-up died of disease within 8 months of the diagnoses. In conclusion, penile sarcomatoid carcinomas are unusual, large, and aggressive tumors usually associated with lymph node metastasis and poor outcome. Differential diagnoses include sarcoma and melanoma. Cytokeratin 34betaE12 and p63 appear to be the more specific and sensitive markers to categorize these tumors as epithelial. Diffuse immunoreactivity for p53, compared with a more basal and focal reactivity in differentiated squamous cell carcinoma, may be indicative of a late mutation in the natural progression of the disease
— id: 57730, year: 2005, vol: 29, page: 1152, stat: Journal Article,

Stromal cell-derived factor-1alpha and CXCR4 expression in hemangioblastoma and clear cell-renal cell carcinoma: von Hippel-Lindau loss-of-function induces expression of a ligand and its receptor
Zagzag, David; Krishnamachary, Balaji; Yee, Herman; Okuyama, Hiroaki; Chiriboga, Luis; Ali, M Aktar; Melamed, Jonathan; Semenza, Gregg L
2005 Jul 15;65(14):6178-6188, Cancer research
The genetic hallmark of hemangioblastomas and clear cell-renal cell carcinomas (CC-RCCs) is loss-of-function of the von Hippel-Lindau (VHL) tumor suppressor protein. VHL is required for oxygen-dependent degradation of hypoxia-inducible factor-1alpha (HIF-1alpha). In hemangioblastomas and CC-RCCs, HIF-1alpha is constitutively overexpressed leading to increased transcription of HIF-1-regulated genes, including vascular endothelial growth factor (VEGF). Because loss of VHL function is associated with increased expression of the chemokine receptor CXCR4 in CC-RCCs, we investigated the expression of HIF-1alpha, CXCR4, and its ligand stromal cell-derived factor-1alpha (SDF-1alpha) in hemangioblastomas and CC-RCCs. Immunohistochemistry revealed overexpression of both CXCR4 and SDF-1alpha within tumor cells and endothelial cells of hemangioblastomas and CC-RCCs. HIF-1alpha was detected in tumor cell nuclei of both hemangioblastomas and CC-RCCs. A specific ELISA showed that hemangioblastomas and CC-RCCs expressed SDF-1alpha protein at levels that were significantly higher than those found in normal tissue. Analysis of the VHL-null RCC line 786-0 revealed that SDF-1alpha mRNA levels were 100-fold higher than in a subclone transfected with the wild-type VHL gene. Expression of CXCR4 and SDF-1alpha mRNA was significantly decreased in HIF-1alpha-null compared with wild-type mouse embryo fibroblasts (MEFs). ELISA and Western blot studies for SDF-1alpha and CXCR4 protein expression confirmed the RNA findings in RCC lines and MEFs. These results suggest that loss-of-function of a single tumor suppressor gene can up-regulate the expression of both a ligand and its receptor, which may establish an autocrine signaling pathway with important roles in the pathogenesis of hemangioblastoma and CC-RCC
— id: 57731, year: 2005, vol: 65, page: 6178, stat: Journal Article,

Upregulated expression of androgen receptor (AR) specific transcription corepressors in prostate cancer
Zhang, XM; Chiu, J; Kong, XT; Melamed, J; Twiss, C; Lee, P
2005 ;85(Suppl 1):174A-175A, Laboratory investigation
— id: 50462, year: 2005, vol: 85, page: 174A, stat: Journal Article,

An accurate method for determination of tissue thickness in paraffin blocks by Faxitron analysis: Application to tissue microarray construction
Zhao, Y; Kong, X; Ksionsk, M; Walden, PD; Bosland, MC; Melamed, J
2005 ;18(Suppl 1):337A-337A, Modern pathology
— id: 50449, year: 2005, vol: 18, page: 337A, stat: Journal Article,

The alveolar soft part sarcoma marker TFE3 is also frequently expressed in granular cell tumor
Zhu, C; Melamed, J; Sidhu, G; Argani, P; Ladanyi, M; Illei, P
2005 ;85(Suppl 1):23A-24A, Laboratory investigation
— id: 50452, year: 2005, vol: 85, page: 23A, stat: Journal Article,

The alveolar soft part sarcoma marker TFE3 is also frequently expressed in granular cell tumor
Zhu, C; Melamed, J; Sidhu, G; Argani, P; Ladanyi, M; Illei, P
2005 ;18(Suppl 1):23A-24A, Modern pathology
— id: 50424, year: 2005, vol: 18, page: 23A, stat: Journal Article,

Up regulation of retinoid acid receptor x (RXR alpha) in uterine leiomyosarcomas
Zhu, H; Mittal, K; Melamed, J; Goswami, S; Chiriboba, L; Wei, JJ
2005 ;18(Suppl 1):210A-210A, Modern pathology
— id: 50437, year: 2005, vol: 18, page: 210A, stat: Journal Article,

Up regulation of retinoid acid receptor x (RXR alpha) in uterine leiomyosarcomas
Zhu, H; Mittal, K; Melamed, J; Goswami, S; Chiriboba, L; Wei, JJ
2005 ;85(Suppl 1):210A-210A abstract #976, Laboratory investigation
— id: 50467, year: 2005, vol: 85, page: 210A, stat: Journal Article,

The tissue microarray data exchange specification: implementation by the Cooperative Prostate Cancer Tissue Resource
Berman, Jules J; Datta, Milton; Kajdacsy-Balla, Andre; Melamed, Jonathan; Orenstein, Jan; Dobbin, Kevin; Patel, Ashok; Dhir, Rajiv; Becich, Michael J
2004 Feb 27;5(1):19-19, BMC bioinformatics
BACKGROUND: Tissue Microarrays (TMAs) have emerged as a powerful tool for examining the distribution of marker molecules in hundreds of different tissues displayed on a single slide. TMAs have been used successfully to validate candidate molecules discovered in gene array experiments. Like gene expression studies, TMA experiments are data intensive, requiring substantial information to interpret, replicate or validate. Recently, an open access Tissue Microarray Data Exchange Specification has been released that allows TMA data to be organized in a self-describing XML document annotated with well-defined common data elements. While this specification provides sufficient information for the reproduction of the experiment by outside research groups, its initial description did not contain instructions or examples of actual implementations, and no implementation studies have been published. The purpose of this paper is to demonstrate how the TMA Data Exchange Specification is implemented in a prostate cancer TMA. RESULTS: The Cooperative Prostate Cancer Tissue Resource (CPCTR) is funded by the National Cancer Institute to provide researchers with samples of prostate cancer annotated with demographic and clinical data. The CPCTR now offers prostate cancer TMAs and has implemented a TMA database conforming to the new open access Tissue Microarray Data Exchange Specification. The bulk of the TMA database consists of clinical and demographic data elements for 299 patient samples. These data elements were extracted from an Excel database using a transformative Perl script. The Perl script and the TMA database are open access documents distributed with this manuscript. CONCLUSIONS: TMA databases conforming to the Tissue Microarray Data Exchange Specification can be merged with other TMA files, expanded through the addition of data elements, or linked to data contained in external biological databases. This article describes an open access implementation of the TMA Data Exchange Specification and provides detailed guidance to researchers who wish to use the Specification
— id: 45289, year: 2004, vol: 5, page: 19, stat: Journal Article,

Altered N-myc downstream-regulated gene 1 protein expression in African-American compared with caucasian prostate cancer patients
Caruso, Robert P; Levinson, Benjamin; Melamed, Jonathan; Wieczorek, Rosemary; Taneja, Samir; Polsky, David; Chang, Caroline; Zeleniuch-Jacquotte, Anne; Salnikow, Konstantin; Yee, Herman; Costa, Max; Osman, Iman
2004 Jan 1;10(1 Pt 1):222-227, Clinical cancer research
PURPOSE: The protein encoded by N-myc downstream-regulated gene 1 (NDRG1) is a recently discovered protein whose transcription is induced by androgens and hypoxia. We hypothesized that NDRG1 expression patterns might reveal a biological basis for the disparity of clinical outcome of prostate cancer patients with different ethnic backgrounds. EXPERIMENTAL DESIGN: Patients who underwent radical prostatectomy between 1990 and 2000 at Veterans Administration Medical Center of New York were examined. We studied 223 cases, including 157 African Americans and 66 Caucasians (T2, n = 144; >/=T3, n = 79; Gleason <7, n = 122; >/=7, n = 101). Three patterns of NDRG1 expression were identified in prostate cancer: (a) intense, predominately membranous staining similar to benign prostatic epithelium; (b) intense, nucleocytoplasmic localization; and (c) low or undetectable expression. We then examined the correlations between patients' clinicopathological parameters and different NDRG1 expression patterns. RESULTS: In this study of patients with equal access to care, African-American ethnic origin was an independent predictor of prostate-specific antigen recurrence (P < 0.05). We also observed a significant correlation between different patterns of NDRG1 expression and ethnic origin. Pattern 2 was less frequent in African Americans (21% versus 38%), whereas the reverse was observed for pattern 3 (60% in African Americans versus 44% in Caucasians; P = 0.03). This association remained significant after controlling for both grade and stage simultaneously (P = 0.02). CONCLUSIONS: Our data suggest that different NDRG1 expression patterns reflect differences in the response of prostatic epithelium to hypoxia and androgens in African-American compared with Caucasian patients. Further studies are needed to determine the contribution of NDRG1 to the disparity in clinical outcome observed between the two groups
— id: 44771, year: 2004, vol: 10, page: 222, stat: Journal Article,

The cooperative prostate cancer tissue resource: a specimen and data resource for cancer researchers
Melamed, Jonathan; Datta, Milton W; Becich, Michael J; Orenstein, Jan M; Dhir, Rajiv; Silver, Sylvia; Fidelia-Lambert, Marie; Kadjacsy-Balla, Andre; Macias, Virgilia; Patel, Ashokkumar; Walden, Paul D; Bosland, Maarten C; Berman, Jules J
2004 Jul 15;10(14):4614-4621, Clinical cancer research
PURPOSE: The Cooperative Prostate Cancer Tissue Resource (CPCTR) is a National Cancer Institute-supported tissue bank that provides large numbers of clinically annotated prostate cancer specimens to investigators. This communication describes the CPCTR to investigators interested in obtaining prostate cancer tissue samples. EXPERIMENTAL DESIGN: The CPCTR, through its four participating institutions, has collected specimens and clinical data for prostate cancer cases diagnosed from 1989 onward. These specimens include paraffin blocks and frozen tissue from radical prostatectomy specimens and paraffin blocks from prostate needle biopsies. Standardized histopathological characterization and clinical data extraction are performed for all cases. Information on histopathology, demography (including ethnicity), laboratory data (prostate-specific antigen values), and clinical outcome related to prostate cancer are entered into the CPCTR database for all cases. Materials in the CPCTR are available in multiple tissue formats, including tissue microarray sections, paraffin-embedded tissue sections, serum, and frozen tissue specimens. These are available for research purposes following an application process that is described on the CPCTR web site (www.prostatetissues.org). RESULTS: The CPCTR currently (as of October 2003) contains 5135 prostate cancer cases including 4723 radical prostatectomy cases. Frozen tissues, in some instances including patient serum samples, are available for 1226 cases. Biochemical recurrence data allow identification of cases with residual disease, cases with recurrence, and recurrence-free cases. CONCLUSIONS: The CPCTR offers large numbers of highly characterized prostate cancer tissue specimens, including tissue microarrays, with associated clinical data for biomarker studies. Interested investigators are encouraged to apply for use of this material (www.prostatetissues.org)
— id: 44707, year: 2004, vol: 10, page: 4614, stat: Journal Article,

A randomized, controlled six-month intervention study soy protein isolate in men with biochemical recurrence after radical prostatectomy
Bosland, MC; Zeleniuch-Jacquotte, A; Melamed, J; Lepor, H; Taneja, SS; Schmoll, J; Watanabe, H; Levinson, B; Walden, PD
2003 NOV ;12(11):1327S-1328S, Cancer epidemiology biomarkers & prevention
— id: 55376, year: 2003, vol: 12, page: 1327S, stat: Journal Article,

The New York University nerve sparing algorithm decreases the rate of positive surgical margins following radical retropubic prostatectomy
Shah, Ojas; Robbins, David A; Melamed, Jonathan; Lepor, Herbert
2003 Jun;169(6):2147-2152, Journal of urology
PURPOSE: We developed an algorithm that prospectively defines when to excise the neurovascular bundles during radical retropubic prostatectomy with the goal of maximizing the performance of nerve sparing procedures while minimizing positive surgical margins. MATERIALS AND METHODS: From January 1 to December 31, 2000 a single surgeon performed 272 radical retropubic prostatectomies and 263 were performed from January 1 to December 31, 2001. A single pathologist analyzed all specimens with positive margins. There were no prospectively defined criteria to guide decisions regarding excision of the neurovascular bundles in the 2000 study cohort. Gleason score, percent tumor volume and perineural invasion were independently analyzed in the biopsy specimens according to the site of origin (right versus left side) for the 2001 group only. The ipsilateral neurovascular bundle was excised for Gleason 6 or less tumors when there were 50% or greater tumor volume in the biopsy specimen and perineural invasion, for Gleason 7 tumors when there was 30% or greater tumor volume, or perineural invasion and for Gleason 8 to 10 tumors when there was 10% or greater tumor volume, or perineural invasion. RESULTS: There were no statistically significant differences between the 2000 and 2001 groups in regard to preoperative prostate specific antigen, clinical and pathological stage, biopsy Gleason score and percent tumor volume in the surgical specimen. There was a statistically significant decrease in the incidence of positive margins between the 2000 and 2001 groups (14% versus 8%, p = 0.027). The lower positive margin rate was not achieved because of a tendency to excise more neurovascular bundles since a significantly greater percent of neurovascular bundles was preserved in the 2001 group. The sensitivity, specificity, positive and negative predictive values, and accuracy of our algorithm were 18%, 93%, 28%, 89% and 84%, respectively. In sides of the prostate with extraprostatic extension ipsilateral wide excision of the neurovascular bundle was associated with positive margins in 33% of cases compared with 22% when the neurovascular bundle was preserved (p = 0.42). CONCLUSIONS: The New York University nerve sparing algorithm prospectively defines when to excise the neurovascular bundle based on Gleason score, perineural invasion and tumor volume in the biopsy specimen. Use of this algorithm decreases positive surgical margin rates, while significantly increasing the preservation of neurovascular bundles
— id: 37582, year: 2003, vol: 169, page: 2147, stat: Journal Article,

Concordant down-regulation of proto-oncogene PML and major histocompatibility antigen HLA class I expression in high-grade prostate cancer
Zhang, Huiming; Melamed, Jonathan; Wei, Ping; Cox, Karen; Frankel, Wendy; Bahnson, Robert R; Robinson, Nikki; Pyka, Ron; Liu, Yang; Zheng, Pan
2003 Feb 14;3:2-2, Cancer imunity
Recognition of tumor cells by cytolytic T lymphocytes depends on cell surface MHC class I expression. As a mechanism to evade T cell recognition, many malignant cancer cells, including those of prostate cancer, down-regulate MHC class I. For the majority of human cancers, the molecular mechanism of MHC class I down regulation is unclear, although it is well established that MHC class I down-regulation is often associated with the down-regulation of multiple genes devoted to antigen presentation. Since the promyelocytic leukemia (PML) proto-oncogene controls multiple antigen-presentation genes in some murine cancer cells, we analyzed the expression of proto-oncogene PML and MHC class I in high-grade prostate cancer. We found that 30 of 37 (81%) prostate adenocarcinoma cases with a Gleason grade of 7-8 had more than 50% down-regulation of HLA class I expression. Among these, 22 cases (73.3%) had no detectable PML protein, while 4 cases (13.3%) showed partial PML down-regulation. In contrast, all 7 cases of prostate cancer with high expression of cell surface HLA class I had high levels of PML expression. Concordant down-regulation of HLA and PML was observed in different histological patterns of prostate adenocarcinoma. These results suggest that in high-grade prostate cancer, malfunction of proto-oncogene PML is a major factor in the down-regulation of cell surface HLA class I molecules, the target molecules essential for the direct recognition of cancer cells by cytolytic T lymphocytes
— id: 57581, year: 2003, vol: 3, page: 2, stat: Journal Article,

Chemoprevention strategies for prostate cancer
Bosland, Maarten C; McCormick, David L; Melamed, Jonathan; Walden, Paul D; Zeleniuch-Jacquotte, Anne; Lumey, L H
2002 Aug;11 Suppl 2(2):S18-S27, European journal of cancer prevention
Prostate cancer is the most common male malignancy in western countries. Although primary prevention of prostate cancer is not possible, screening using prostate-specific antigen (PSA) may eliminate prostate cancers by definitive treatments. Prevention of clinically detectable prostate cancer requires earlier chemoprevention interventions. Because prostate cancer is histologically present in 30-50% of 30- to 50-year-old men, effective chemoprevention needs to inhibit not only prostate carcinogenesis but also growth and progression of these cancers. A prostate carcinogenesis animal model has been used to screen chemopreventive agents; inhibitory effects were found with 9-cis-retinoic acid, dehydroepiandrosterone, fluasterone, and the Bowman-Birk inhibitor and an isoflavone mixture which both occur in soy. Such results can be used to select agents for clinical trials. Besides large-scale long-duration prevention trials, trials of short/intermediate duration using smaller cohorts prior to or following radical prostatectomy may provide excellent and cost-effective approaches for chemopreventive agent efficacy testing. Intervention prior to surgery allows measurements of intervention agents and intermediate end-points in the prostate. These peri-surgical trials only assess inhibition of growth and progression of preexisting cancer, not real preventive effects, but they focus on clinically significant cancers. Such trials are an essential step in the development of antiprostate cancer chemoprevention agents
— id: 34748, year: 2002, vol: 11 Suppl 2, page: S18, stat: Journal Article,

Followup interval prostate biopsy 3 years after diagnosis of high grade prostatic intraepithelial neoplasia is associated with high likelihood of prostate cancer, independent of change in prostate specific antigen levels
Lefkowitz, Gary K; Taneja, Samir S; Brown, Jordan; Melamed, Jonathan; Lepor, Herbert
2002 Oct;168(4 Pt 1):1415-1418, Journal of urology
PURPOSE: Repeat biopsy has been advocated following the diagnosis of high grade prostatic intraepithelial neoplasia to exclude coexisting prostate cancer. We further define the natural history of high grade prostatic intraepithelial neoplasia by determining the incidence of prostate cancer 3 years following diagnosis. MATERIALS AND METHODS: A total of 31 men underwent followup interval biopsy 3 years after high grade prostatic intraepithelial neoplasia diagnosis in 1996 to 1997, regardless of change in serum prostate specific antigen (PSA) or digital rectal examination findings. A single pathologist reviewed all biopsy specimens. All men had a minimum of 12 biopsy cores taken at the time of diagnosis. RESULTS: A 3-year followup interval biopsy eight (25.8%) men had prostate cancer, 11 (35.5%) had high grade prostatic intraepithelial neoplasia only and 12 (38.7%) had no disease. Mean serum PSA at diagnosis and before the followup biopsy was 6.88 and 9.69 ng./dl., respectively (p = 0.008). Of the men 48% had less than a 1.0 unit increase in serum PSA. Upon univariate regression analysis change in serum PSA was not associated with the detection of prostate cancer (p >0.10). All 4 patients who subsequently underwent radical prostatectomy had organ confined disease. CONCLUSIONS: In a high proportion of men with high grade prostatic intraepithelial neoplasia prostate cancer will develop in a 3-year interval. Our findings support the concept that high grade prostatic intraepithelial neoplasia is a precursor to prostate cancer and that repeat biopsy at a delayed interval is recommended regardless of changes in PSA
— id: 68187, year: 2002, vol: 168, page: 1415, stat: Journal Article,

Heterogeneous expression and functions of androgen receptor co-factors in primary prostate cancer
Li, Peng; Yu, Xin; Ge, Kai; Melamed, Jonathan; Roeder, Robert G; Wang, Zhengxin
2002 Oct;161(4):1467-1474, American journal of pathology
The androgen receptor (AR), a ligand-activated transcription factor of the steroid receptor superfamily, plays an important role in normal prostate growth and in prostate cancer. The recent identification of various AR co-factors prompted us to evaluate their possible roles in prostate tumorigenesis. To this end, we analyzed the expression of AR and eight of its co-factors by quantitative in situ RNA hybridization in 43 primary prostate cancers with different degrees of differentiation. Our results revealed nearly constant expression of AR and heterogeneous expression of AR co-factors, with increased expression of PIAS1 and Ran/ARA24, decreased expression of ELE1/ARA70, and no change in TMF1/ARA160, ARA54, SRC1, or TRAP220. Interestingly, whereas TMF1/ARA160, ELE1/ARA70, ARA54, RAN/ARA24, and PIAS1 were preferentially expressed in epithelial cells, another co-factor, ARA55, was preferentially expressed in stromal cells. Although the changes in levels of these co-activators did not correlate with Gleason score, their occurrence in high-grade prostatic intraepithelial neoplasia, suggests their involvement in initiation (or an early stage) of cancer. In addition, human prostate tumor cell proliferation and colony formation were markedly reduced by ELE1/ATRA70. Together, these findings indicate that changes in levels of expression of AR co-factors may play important, yet different, roles in prostate tumorigenesis
— id: 42676, year: 2002, vol: 161, page: 1467, stat: Journal Article,

Expression of B-cell translocation gene 2 protein in normal human tissues
Melamed, J; Kernizan, S; Walden, P D
2002 Feb;34(1):28-32, Tissue & cell
The antiproliferative B-cell translocation gene 2 (BTG2(TIS21/PC3)) is emerging as an important regulator of cell cycle dynamics. BTG2(TIS21/PC3) expression increases in response to the induction of DNA damage, cell differentiation, cell quiescence, cell contact, and as part of a positive feedback mechanism in response to growth stimulation. The objective of the present study was to provide further insight into the biological function of BTG2(TIS21/PC3) by determining the expression levels and cellular localization of BTG2(TIS21/PC3) in a spectrum of normal human tissues and to determine the proliferative indices (based on Ki-67 staining) and apoptotic indices (based on TUNEL assay) in those cell populations where BTG2(TIS21/PC3) was differentially expressed. Highest levels of BTG2(TIS21/PC3) expression were seen in kidney proximal tubules, lung alveolar bronchial epithelium and in the basal cell layer of prostate acini. BTG2(TIS21/PC3) was expressed at significantly different levels within the different epithelial populations of the kidney (proximal vs distal tubules) and prostate (acinar basal cells vs lumenal cells). Moderate levels of expression were seen in the acinar cells of breast and pancreas and in the mucosal epithelium of the intestine. Low levels of expression were seen in neurons, hepatocyctes, the zona granulosa of the ovary, round spermatids and thyroid follicles. Our results therefore indicate an imperfect correlation between the terminally differentiated phenotype and BTG2(TIS21/PC3) expression, but no correlation between basal cellular proliferative or apoptotic indices and BTG2(TIS21/PC3) expression levels
— id: 39655, year: 2002, vol: 34, page: 28, stat: Journal Article,

Placental transmogrification of the lung is a histologic pattern frequently associated with pulmonary fibrochondromatous hamartoma
Xu, Ruliang; Murray, Melissa; Jagirdar, Jaishree; Delgado, Yara; Melamed, Jonathan
2002 May;126(5):562-566, Archives of pathology & laboratory medicine
CONTEXT: Placental transmogrification of the lung is a term introduced to describe a peculiar histologic pattern characterized by formation of placental villuslike structures in the lung parenchyma. It has been reported to occur in association with bullous emphysema and lipomatosis. OBJECTIVES: To study the relationship between placental transmogrification and pulmonary hamartomas. DESIGN AND METHODS: Reports of 38 cases of pulmonary hamartomas during 18 years (1982-1999) were reviewed. All histologic slides of these cases were examined for the presence of villuslike papillary projections and placenta-like structures. Hamartomas with prominent papillary projections or placenta-like structures were further investigated to assess the histogenesis and proliferation of epithelial and stromal cells. Immunohistochemical analysis was performed on paraffin-embedded tissue using monoclonal antibodies against Ki-67 and thyroid transcription factor 1 (TTF-1) and polyclonal antibodies against c-Kit antigen (a stem cell factor receptor/mast cell growth factor receptor) in conjunction with Leder stain for naphthol-ASD-chloroacetate esterase. RESULTS: Placental transmogrification was identified in 6 of 38 cases of pulmonary fibrochondromatous hamartomas. The histologic change consisted of an abundant myxoid or edematous fibroadipose stroma with a respiratory epithelial lining, resulting in papillary projections that resembled immature placental villi. Epithelium lining the papillary projections was positive for TTF-1 (70%-90%) and Ki-67 (3%-5%). In contrast, stromal cells were negative for TTF-1 with only rare cells immunoreactive for Ki-67. A number of stromal spindle cells and occasional cells in epithelium were c-Kit immunoreactive; however, concurrent Leder stain demonstrated that these c-Kit-positive cells were mast cells and not stem cells. CONCLUSIONS: Placental transmogrification is frequently associated with pulmonary fibrochondromatous hamartomas and may be induced by or associated with a proliferation of lining epithelial components in the hamartomas. The significance of numerous mast cells within stroma of placental transmogrification is unclear and their possible role in inducing stromal proliferation needs to be further evaluated
— id: 27561, year: 2002, vol: 126, page: 562, stat: Journal Article,

Chemoprevention trials in men with prostate-specific antigen failure or at high risk for recurrence after radical prostatectomy: Application to efficacy assessment of soy protein
Bosland MC; Kato I; Melamed J; Taneja S; Lepor H; Torre P; Walden P; Zeleniuch-Jacquotte A; Lumey LH
2001 Apr;57(4 Suppl 1):202-204, Urology
This article discusses the basic elements of chemoprevention trial designs using cohorts of men following radical prostatectomy who either have prostate-specific antigen (PSA) failure indicative of recurrence or are at high risk for recurrence (positive surgical margins, extracapsular extension, seminal vesicle invasion, positive lymph nodes, Gleason score of greater than or equal to 8, preoperative serum PSA less than 20 ng/mL). Two ongoing randomized, double-blind, placebo-controlled clinical trials with soy protein as intervention in these 2 populations are described. In the trial with men at high risk for recurrence, participants started intervention within 4 months after surgery and were followed for up to 2 years; primary endpoints were PSA failure rate and time-to-PSA failure. In the trial with men with PSA failure (PSA 0.1 to 2.0 ng/mL), participants received treatment for 8 months and the primary endpoint is rise in PSA over time. The strengths and limitations of these designs are discussed and interim experience using studies with soy protein as the intervention agent are summarized
— id: 18555, year: 2001, vol: 57, page: 202, stat: Journal Article,

Antiproliferative B cell translocation gene 2 protein is down-regulated post-transcriptionally as an early event in prostate carcinogenesis
Ficazzola MA; Fraiman M; Gitlin J; Woo K; Melamed J; Rubin MA; Walden PD
2001 Aug;22(8):1271-1279, Carcinogenesis
B cell translocation gene 2 (BTG2) is a p53 target that negatively regulates cell cycle progression in response to DNA damage and other stress. The objective of this study was to examine the expression, regulation and tumor suppressor properties of BTG2 in prostate cells. By immunohistochemistry BTG2 protein was detected in approximately 50% of basal cells in benign glands from the peripheral zone of the human prostate. BTG2 was expressed in all hyperproliferative atrophic peripheral zone lesions examined (simple atrophy, post-atrophic hyperplasia and proliferative inflammatory atrophy), but was undetectable or detectable at very low levels in the hyperproliferative epithelial cells of HGPIN and prostate cancer. BTG2 mRNA was detected in non-malignant prostate epithelial (PE) cells and in LNCaP cells, but not in PC-3 cells, consistent with p53-dependent regulation. In PE cells BTG2 protein was detected in areas of cell confluence by immunohistochemistry. BTG2 protein in LNCaP cells was undetectable by immunohistochemistry but was detected by immunoblotting at 8- to 9-fold lower levels than in PE cells. BTG2 protein levels were shown to be regulated by the ubiquitin-proteosome system. Forced expression of BTG2 in PC-3 cells was accompanied by a decreased rate of cell proliferation and decreased tumorigenicity of these cells in vivo. Taken together, these findings suggest that BTG2 functions as a tumor suppressor in prostate cells that is activated by cell quiescence, cell growth stimuli as part of a positive feedback mechanism and in response to DNA damage or other cell stress. The low steady-state levels of BTG2 protein in HGPIN and prostate cancer, a potential consequence of increased proteosomal degradation, may have important implications in the initiation and progression of malignant prostate lesions. Furthermore, these findings suggest that a significant component of the p53 G(1) arrest pathway might be inactivated in prostate cancer even in the absence of genetic mutations in p53
— id: 25549, year: 2001, vol: 22, page: 1271, stat: Journal Article,

p53 Mutation in adenocarcinoma arising in retrorectal cyst hamartoma (tailgut cyst)
Moreira AL; Scholes JV; Boppana S; Melamed J
2001 Oct;125(10):1361-1364, Archives of pathology & laboratory medicine
Retrorectal cyst hamartoma (RCH) is a rare benign cystic lesion located in the retrorectal space. Malignancy arising in such lesions is very uncommon. In this study, 2 cases of mucinous adenocarcinoma arising in RCH are presented. In one case, dysplastic epithelium lined the cyst wall, surrounding the area of carcinoma and suggesting a dysplasia-carcinoma progression in RCH. Adenocarcinoma and the dysplastic epithelium were strongly positive for p53 and Ki-67 and showed negative staining for p21 by immunohistochemistry. These findings are suggestive of a mutation in the p53 gene in the adenocarcinoma and in dysplastic epithelium lining the cysts, similar to the dysplasia-carcinoma sequence described for the development of colonic adenocarcinoma
— id: 24346, year: 2001, vol: 125, page: 1361, stat: Journal Article,

Analysis of apical soft tissue margins during radical retropubic prostatectomy
Shah O; Melamed J; Lepor H
2001 Jun;165(6 Pt 1):1943-1948, Journal of urology
PURPOSE: We determine the use of information gained with intraoperative biopsy and frozen section analysis of the apical soft tissue margin during nerve sparing radical retropubic prostatectomy. MATERIALS AND METHODS: A separate 2 to 3 mm. circumferential biopsy was obtained from the apical soft tissue margin, and was sent for frozen and permanent section analysis during radical retropubic prostatectomy in 95 men with clinically localized adenocarcinoma of the prostate. A single pathologist examined the surgical and apical soft tissue margin specimens for evidence and extent of benign or malignant prostate tissue. Urinary continence was evaluated at catheter removal and 3 months postoperatively. RESULTS: Of the patients 26% had positive surgical margins, of which 64% were positive apical margins. Permanent section of the apical soft tissue biopsy revealed no prostate in 39%, benign prostate in 54% and prostate cancer in 7% of patients. Because of the frozen section finding of adenocarcinoma in 3 patients, the apical soft tissue margin was further resected until the specimen was negative for malignancy. The apical soft tissue margin was the only positive margin site in 2 of these 3 patients. Positive surgical and apical margins, and percent tumor volumes greater than 26% on prostatectomy specimen had a significantly higher likelihood for positive apical soft tissue margins. The pathological finding of a positive apical margin on the surgical specimen had sensitivity, specificity, and positive and negative predictive values of 57%, 86%, 25% and 96%, respectively, for detecting prostate cancer on the apical soft tissue biopsy. Of the apical soft tissue biopsies 54% contained an element of benign prostatic tissue, although 92% of them contained benign tissue in less than 25% of the total specimen. Mean continence score in the men with and those without benign prostate tissue on apical soft tissue biopsy was 15.6 and 14.4, respectively (p = 0.15). The percent of men who required no protective pads for urinary continence at 3 months was 53% and 65% for those who had no prostate and those who had benign prostate tissue, respectively, in the apical soft tissue margin. CONCLUSIONS: Excising and submitting an additional 2 to 3 mm. of apical soft tissue margin for permanent section analysis after prostate removal during radical prostatectomy represent an effective method for decreasing residual prostate tissue. Attempts at maximizing urethral length when dividing the prostato-urethral junction likely increases the chance of leaving residual prostate without improving continence
— id: 20647, year: 2001, vol: 165, page: 1943, stat: Journal Article,

BRCA1 germline mutation presenting as an adenocarcinoma of unknown primary
Klein, P; Prolla, G; Wallach, R; Melamed, J; Muggia, FM
2000 MAY-JUN ;6(3):188-190, Cancer journal
BACKGROUND The work-up of adenocarcinoma of unknown primary usually includes history, physical examination, radiographic imaging, tumor markers, and more recently molecular and genetic information. We report here on how the suggestion by family history of a BRCA1 mutation guided the diagnostic and therapeutic approach in a patient with metastatic carcinoma of unknown primary. METHODS BRCA1 mutation was screened for by polymerase chain reaction (PCR) and single-strand conformational polymorphism analysis. Primers for PCR amplification included selected BRCA1 exons 2, 110, 11L, 13, and 20. The PCR product was cloned into a PCRII vector and sequenced with a Sequenase Version 2.0 Sequencing Kit. RESULTS Single-strand conformational polymorphism analysis suggested a mutation in the region of exon 20 and sequencing confirmed the presence of a germline mutation 5382insC. CONCLUSIONS This case illustrates an unusual presentation of adenocarcinoma of unknown primary in a patient with a germline BRCA1 mutation, the use of a suspected germline mutation to guide the work-up and treatment, and finally the value of positive emission tomography scanning in the work-up of an unknown primary
— id: 54549, year: 2000, vol: 6, page: 188, stat: Journal Article,

Basement membrane material in ovarian clear cell carcinoma: correlation with growth pattern and nuclear grade
Mikami Y; Hata S; Melamed J; Moriya T; Manabe T
1999 Jan;18(1):52-57, International journal of gynecological pathology
Stromal hyalinization in ovarian clear cell carcinomas has been suggested to be caused by deposition of basement membrane (BM) material, but the biological and diagnostic significance of this finding remains unknown. The distribution of BM material in 17 primary ovarian clear cell carcinomas was examined semiquantitatively using hematoxylin and eosin-stained sections and immunohistochemistry with antibodies to laminin and type IV collagen. For comparison, other surface epithelial tumors, including 8 serous tumors of low malignant potential, 10 serous adenocarcinomas, 6 mucinous tumors of low malignant potential, 5 mucinous adenocarcinomas, 6 endometrioid carcinomas, 4 Brenner tumors, 1 transitional cell carcinoma, and 3 undifferentiated carcinomas, were examined. Stromal hyalinization was found in all 17 clear cell carcinomas and was immunoreactive for type IV collagen and laminin. Other types of surface epithelial tumor lacked these findings. In clear cell carcinoma, areas showing a papillary pattern tended to show abundant deposition regardless of nuclear grade, whereas in solid, tubular, or cystic areas, the deposition was more prominent in areas showing high-nuclear-grade features (grade 2 and 3) than in areas with low-nuclear-grade features (grade 1). Dense deposition of BM material recognized as stromal hyalinization on hematoxylin and eosin-stained sections in primary ovarian clear cell carcinoma is a characteristic feature that is not seen in other ovarian surface epithelial tumors. This matrix production correlates with high-nuclear-grade features and papillary growth pattern
— id: 7406, year: 1999, vol: 18, page: 52, stat: Journal Article,

Benign proliferative nipple duct lesions frequently contain CAM 5.2 and anti-cytokeratin 7 immunoreactive cells in the overlying epidermis
Zeng Z; Melamed J; Symmans PJ; Cangiarella JF; Shapiro RL; Peralta H; Symmans WF
1999 Nov;23(11):1349-1355, American journal of surgical pathology
Benign proliferative nipple duct lesions (PNDLs) pose a diagnostic problem for clinicians and pathologists. Clinically, they may be associated with skin changes typically present in Paget's disease of the nipple. The identification of numerous scattered cells in the epidermis that are immunoreactive for low-molecular-weight cytokeratin may lead to further confusion with Paget's disease. We studied the nipple epidermis in nine cases of PNDL and compared them with 26 histologically normal nipples from mastectomy specimens. CAM 5.2 and anticytokeratin 7 (CK7) immunoreactive cells were identified in the epidermis of seven of nine nipples associated with PNDL. The cytokeratin-positive cells appeared cytologically benign and were dispersed singly (scattered in seven of seven cases and frequent in four of seven cases) or formed small aggregates with occasional tubular structures (three of seven cases) in the basal and middle layers of the epidermis. In two of seven cases, these epidermal immunoreactive cells showed continuity with the underlying PNDL, suggesting the spread or continuation of lesional cells to the epidermis. Dispersed single immunoreactive cells were identified in small numbers (scattered) in the basal layer of the epidermis in 12 of 26 normal nipples and more frequently in 1 of 12 cases. In all cases, the intraepidermal cells were negative for carcinoembryonic antigen (CEA) and Her-2/neu. We conclude that intraepidermal CAM 5.2 and anti-CK7 immunoreactive cells, which are normally present in the nipple epidermis, may proliferate and form aggregates when there is an underlying PNDL. The presence of these cells does not imply Paget's disease when the intraepidermal cells have a bland cytologic appearance, fail to overexpress Her-2/neu, and there is no carcinoma within the PNDL or elsewhere in the breast
— id: 6232, year: 1999, vol: 23, page: 1349, stat: Journal Article,

Immunohistochemical detection of hepatitis C antigen by monoclonal antibody TORDJI-22 compared with PCR viral detection
Brody RI; Eng S; Melamed J; Mizrachi H; Schneider RJ; Tobias H; Teperman LW; Theise ND
1998 Jul;110(1):32-37, American journal of clinical pathology
We sought to determine the sensitivity and specificity of immunohistochemistry using the TORDJI-22 MoAb (BioGenex, San Ramon, Calif), which is specific for the C-100 protein of the hepatitis C virus, compared with reverse transcriptase-polymerase chain reaction (RT-PCR) of tissue for viral RNA. RT-PCR had been performed on 52 fixed tissue specimens. Immunohistochemistry was performed using prediluted antibody with the alkaline phosphatase/fast red (BioGenex) technique. Predigestion with Protease XXIV (BioGenex) and other procedures followed the manufacturer's protocols. Positive immunohistochemistry was narrowly defined as tightly clumped, perinuclear red granules in hepatocytes. Of the specimens, 28 were positive by RT-PCR. With RT-PCR as the standard of comparison, immunohistochemistry yielded a sensitivity of 70% and specificity of 84%. Positive cells, when present, were usually very rare. With stringent criteria, immunohistochemistry with the TORDJI-22 monoclonal antibody is a very specific, fairly sensitive diagnostic test for hepatitis C virus in fixed liver tissues
— id: 7512, year: 1998, vol: 110, page: 32, stat: Journal Article,

Initial clinical evaluation of radiolabeled MX-DTPA humanized BrE-3 antibody in patients with advanced breast cancer
Kramer EL; Liebes L; Wasserheit C; Noz ME; Blank EW; Zabalegui A; Melamed J; Furmanski P; Peterson JA; Ceriani RL
1998 Jul;4(7):1679-1688, Clinical cancer research
To evaluate radiometal-labeled humanized BrE-3 (huBrE-3) monoclonal antibody as a radioimmunolocalization and therapeutic agent in breast cancer patients, tumor localization, pharmacokinetics, radiation dosimetry, and immunogenicity of (111)In-labeled combined 1-p-isothiocyanatobenzyl 3-methyl- and 1-p-isothiocyanatobenzyl 4-methyldiethylenetriamine pentaacetic acid (MX-DTPA) huBrE-3 were studied. Seven women with BrE-3 antigen-positive, metastatic breast carcinoma underwent (111)In huBrE-3 infusion (5 mCi; 50 mg), followed by serial gamma camera imaging and plasma sampling. Region of interest analysis of images was used to make radiation absorbed dose estimates for (111)In huBrE-3. Data were extrapolated to 90Y huBrE-3. Human anti-human antibody (HAHA) response was measured in serum samples obtained up to 3 months after infusion. Patients tolerated infusions well. Seventy-six percent of 105 known sites of disease were identified on planar and single-photon emission computed tomography scans. For six of seven patients, a biexponential model fit the plasma time-activity curve best with an average T1/2alpha=10.6+/-8.5 (SD) h and average T1/2beta=114.2+/-39.2 h. Radiation absorbed dose estimates for (111)In huBrE-3 for whole body averaged 0.53+/-.08 rads/mCi. Dose estimates for 90Y huBrE-3 for marrow averaged 8.4+/-11.9 rads/mCi, and for tumors, 70+/-31.5 rads/mCi. Liver radioactivity uptake averaged 19.7+/-8.8% injected dose at 24 h after infusion, translating into an average radiation absorbed dose 21.1+/-12 rads/90Y mCi administered. Only one of seven patients demonstrated a low level of HAHA response. Although the plasma half-lives are longer and marrow dose higher for radiolabeled huBrE-3 compared with the murine construct, the excellent tumor localization, good tumor dosimetry, and low immunogenicity support the use of 90Y-huBrE-3 antibody for radioimmunotherapy of breast cancer
— id: 7634, year: 1998, vol: 4, page: 1679, stat: Journal Article,

The role of bladder neck biopsy in men undergoing radical retropubic prostatectomy with preservation of the bladder neck
Lepor H; Chan S; Melamed J
1998 Dec;160(6 Pt 2):2435-2439, Journal of urology
PURPOSE: Radical retropubic prostatectomy is often performed with preservation of the bladder neck. We examine the incidence of benign and malignant prostatic tissue at the bladder neck margin in men undergoing radical retropubic prostatectomy with preservation of the bladder neck for clinically localized prostate cancer. MATERIALS AND METHODS: The study included 100 cases of radical retropubic prostatectomy with preservation of the bladder neck performed by a single surgeon (H. L.). A 2 mm. thick circumferential specimen was excised from the bladder neck, divided into 4 quadrants (anterior, posterior, right and left) and submitted for frozen section examination. The permanent sections from these bladder neck biopsies and the entire surgical specimens were analyzed by a single pathologist (J. M.). RESULTS: The frozen section diagnosis from the bladder neck biopsies were adenocarcinoma, benign prostatic tissue and no prostatic tissue in 3, 38 and 59 cases, respectively. The permanent section diagnosis of the bladder neck biopsies was adenocarcinoma, benign prostatic tissue and no prostatic tissue in 4, 57 and 39 cases, respectively. The sensitivity specificity, and positive and negative predictive values for examination of the surgical specimen to identify benign prostatic tissue was 67, 90, 90 and 65%, respectively. The bladder neck was re-biopsied because of the findings of adenocarcinoma and benign prostatic tissue in 3 and 8 cases, respectively. The initial bladder neck biopsy resulted in pathological down staging to pT2c in only 1 case. Repeat resection of the bladder neck in all cases with 10% or less benign prostatic tissue showed no prostatic tissue, whereas 50% of the cases with more than 10% benign prostatic tissue demonstrated residual benign prostatic tissue. Serum prostate specific antigen was undetectable immediately after radical retropubic prostatectomy in all cases with benign prostatic tissue only. CONCLUSIONS: Preservation of the bladder neck during radical retropubic prostatectomy does not significantly compromise total extirpation of the malignant process. Benign prostatic tissue at the bladder neck margin is relatively common. Examination of the surgical specimen has limited sensitivity, and negative and positive predictive values for the presence of benign prostatic tissue at the bladder neck margin. The impact of benign prostatic tissue as it relates to future malignant transformation is unknown. Submitting frozen section specimens from the bladder neck is reasonable for the younger man who may be at risk from benign prostatic tissue at the bladder neck margin
— id: 12059, year: 1998, vol: 160, page: 2435, stat: Journal Article,

Two consecutive sets of transrectal ultrasound guided sextant biopsies of the prostate for the detection of prostate cancer
Levine MA; Ittman M; Melamed J; Lepor H
1998 Feb;159(2):471-475, Journal of urology
PURPOSE: We investigated the role of performing 2 consecutive sets of transrectal ultrasound guided sextant biopsies of the prostate in a single office visit as the protocol for detecting prostate cancer in men presenting for the first time with an abnormal digital rectal examination and/or elevated serum prostate specific antigen (PSA). MATERIALS AND METHODS: A total of 137 consecutive men presenting for the first time with a clinically localized prostate nodule on digital rectal examination and/or elevated serum PSA based upon age specific reference ranges underwent 2 consecutive sets of sextant prostate biopsies under transrectal ultrasound guidance in a single office visit. The 2 sets of biopsies were processed and analyzed separately by pathologists. RESULTS: Adenocarcinoma of the prostate was diagnosed in 43 of the patients (31%) undergoing biopsy. Adenocarcinoma of the prostate was diagnosed in only the second set of biopsies in 13 cases (10%). High grade prostatic intraepithelial neoplasia without adenocarcinoma of the prostate was observed in 18 of the first set of biopsies (15%). High grade intraepithelial neoplasia without adenocarcinoma of the prostate was the only pathological diagnosis in the second set of biopsies in 3 cases. The second set of biopsies provided important new clinical information related to prostate cancer in 20 cases (28%) and increased the number of cancers detected by 30%. In addition, 14 patients with high grade intraepithelial neoplasia who would have required a second set of biopsies were found not to have adenocarcinoma of the prostate. Prostate cancer was detected in 43, 27 and 24% of men with prostate volumes less than 30, 30 to 50 and greater than 50 cc, respectively. The percentage of prostate cancers detected only in the second set of biopsies was not significantly related to prostate size. CONCLUSIONS: Two consecutive sets of transrectal ultrasound guided sextant biopsies of the prostate performed in a single office visit represent a cost-effective biopsy strategy for men presenting with an abnormal digital rectal examination and/or elevated serum PSA. The benefits include increasing the detection of adenocarcinoma of the prostate and providing the recommended second set of biopsies for high grade intraepithelial neoplasia without increased morbidity or cost
— id: 7653, year: 1998, vol: 159, page: 471, stat: Journal Article,

Pancreatic endocrine tumor with signet ring cell features: a case report with novel ultrastructural observations
Stokes MB; Kumar A; Symmans WF; Scholes JV; Melamed J
1998 Mar-Apr;22(2):147-152, Ultrastructural pathology
The case of a malignant pancreatic endocrine neoplasm with an unusual signet ring cell appearance is reported. The tumor was resected from a 30-year-old man with a 4.0-cm tumor in the body of the pancreas diagnosed by computerized tomographic (CT) scan. The resected tumor had a unique morphology characterized by numerous mucin-negative, signet ring cells, which were argyrophilic and immunoreactive for cytokeratin (CAM 5.2), chromogranin, synaptophysin, neuron specific enolase, and gastrin. Dense-core neurosecretory-type granules and numerous cytoplasmic lamellar inclusions were identified by electron microscopy. These inclusion bodies consisted of multilayered concentric osmiophilic lamellae (myelin figures), which most likely represent an abnormal accumulation of degenerating organelles. Two years later, the patient developed an abdominal recurrence of the tumor, confirming its malignant behavior. This case expands the spectrum of pancreatic endocrine tumors to include an aggressive signet ring cell tumor with a novel ultrastructural basis
— id: 7810, year: 1998, vol: 22, page: 147, stat: Journal Article,

Adenovirus colitis in human immunodeficiency virus infection: an underdiagnosed entity
Yan Z; Nguyen S; Poles M; Melamed J; Scholes JV
1998 Sep;22(9):1101-1106, American journal of surgical pathology
Adenovirus infection of the gastrointestinal tract in human immunodeficiency virus (HIV)-infected patients is rarely reported, probably because of a lack of familiarity of most pathologists with diagnostic criteria during routine light microscopy and possible misidentification as cytomegalovirus infection. We studied colonoscopic biopsy specimens from 135 HIV-infected patients with clinically suspected cytomegalovirus colitis during a 4.5-year period to morphologically identify the presence of adenovirus infection. Immunohistochemical staining for adenovirus was performed for confirmation on all suspected cases. Adenovirus infected cells showed characteristic amphophilic or eosinophilic nuclear inclusions, predominantly affecting the surface epithelium and characteristically involving goblet cells. Sixteen cases showed morphologic features of adenovirus infection, all confirmed by immunohistochemistry. Twelve cases also showed cytomegalovirus infection, whereas 4 showed adenovirus alone. In 10 cases, adenovirus colitis was not recognized during initial routine histopathologic diagnostic evaluation. Adenovirus inclusions also were discovered in the stomach, the duodenum, and the liver in single cases. Conclusions are as follows: (1) Adenovirus colitis has been underdiagnosed at our institution and, we suspect, in general. (2) The morphologic features and nuclear inclusions of adenovirus colitis are characteristic and can be identified reliably by routine light microscopy. (3) Adenovirus infection also may be diagnosed morphologically in extracolonic sites, such as the stomach, the small intestine, and the liver. (4) Coinfection of adenovirus with cytomegalovirus and other agents is seen frequently, but, less frequently, adenovirus may be identified as a sole pathogen
— id: 7949, year: 1998, vol: 22, page: 1101, stat: Journal Article,

Pagetoid spread of CAM5.2 immunoreactive cells into nipple epidermis overlying benign proliferative nipple duct lesions
Zeng, Z; Melamed, J; Cangiarella, J; Symmans, WF
1998 ;11(Suppl 1):31A-31A, Modern pathology
— id: 53568, year: 1998, vol: 11, page: 31A, stat: Journal Article,

Allelic loss on chromosome 13q in human prostate carcinoma
Melamed J; Einhorn JM; Ittmann MM
1997 Oct;3(10):1867-1872, Clinical cancer research
To clarify the role in prostate tumorigenesis played by loss of the three known or putative tumor suppressor loci on the centromeric portion of chromosome 13q, we examined 80 clinically localized and 15 advanced prostate carcinomas for allelic loss at microsatellite markers mapped to this region, including markers tightly linked to the BRCA-2, retinoblastoma (Rb), and DBM (deleted in B-cell malignancy) loci. Among the 80 clinically localized cases, 24 showed allelic loss at one or more 13q loci. In all cases with loss, the Rb and/or DBM loci were lost. No cases were found with loss of Rb without loss of DBM or loss of DBM without loss of Rb, implying a role for both the Rb and DBM loci in clinically localized prostate cancer. Loss of the BRCA-2 locus was less common (4 of 55 informative cases) and was always associated with loss of Rb and/or DBM loci. Thus, the BRCA-2 locus does not appear to play as important a role in clinically localized prostate cancer as the Rb and/or DBM loci. Allelic loss on 13q was extremely common in the clinically advanced cases; it was present in 14 of the 15 cases. The rate of allelic loss at each of the three tumor suppressor loci was increased significantly in the advanced cases (P < 0.01, Fisher's exact test). Thus, loss of heterozygosity on 13q is very common in prostate cancer and occurs at all three known or putative tumor suppressor loci on the centromeric portion of chromosome 13q
— id: 6045, year: 1997, vol: 3, page: 1867, stat: Journal Article,

Morphological and biological characteristics of mammogram-detected invasive breast cancer
Moezzi M; Melamed J; Vamvakas E; Inghirami G; Mitnick J; Quish A; Bose S; Zelman G; Roses D; Harris M; Feiner H
1996 Sep;27(9):944-948, Human pathology
Thirty-nine mammographically detected, (M-detected) small invasive carcinomas of the breast (< or = 5 mm) were compared with 78 consecutive clinical cancers (> or = 10 mm) for a variety of morphological and biological markers of prognostic importance. There were more tubular carcinomas in the M-detected group (12.8% v 3.8%), but this did not reach statistical significance. Incidences of other histological types were similar. The types of associated in situ component were similar in the two groups. M-detected cancers were of lower overall grade (P < .001), lower architectural and nuclear grades (P = .0164 and P < .0001 respectively), and had fewer mitotic cells (P < .0001). None showed positive lymph nodes (P < .0001). Estrogen and progesterone receptor expression was similar in both groups. M-detected cancers expressed p53 nuclear protein less frequently than clinical cancers (P = .0398), had lower levels of microvessel density (P = .0001), and were more often diploid (P = .0131). S-phase of diploid tumors in the two groups was similar, but S-phase of aneuploid tumors was lower in the M-detected group (P = .0057). Ki67 expression was lower in M-detected cancers (P < .0001). In conclusion, M-detected small breast cancers, although invasive, represent an evolutionary phase of breast cancer that generally lacks morphological and biologic markers of aggressive behavior. The presence or absence of these markers, collectively, may explain the influence of tumor size on survival in patients with breast cancer
— id: 7020, year: 1996, vol: 27, page: 944, stat: Journal Article,

Immunohistochemical characterization of the canals of hering: Evidence of bipotent progenitor cells in the liver
Theise, ND; Thung, SN; Kumar, A; Peralta, H; Brody, RI; Gallo, G; Melamed, J; Nalesnik, M
1996 OCT ;24(4):520-520, Hepatology
— id: 98377, year: 1996, vol: 24, page: 520, stat: Journal Article,

Sinus histiocytosis mimicking metastatic melanoma in lymph nodes of a patient with a large joint prosthesis: case report and review of the literature
Charny CK; Jacobowitz G; Melamed J; Tata M; Harris MN
1995 Oct;60(2):128-130, Journal of surgical oncology
Malignant melanoma metastases to regional lymph nodes may be mimicked by several non-neoplastic processes, including sinus histiocytosis induced by fragments shed from joint prostheses. A patient who had an elective lymph node dissection for malignant melanoma and was found to have 'post-prosthesis lymph node histiocytosis' resembling metastatic disease is described. Knowledge of the patient's past history of a total shoulder joint replacement along with the use of polarized light microscopy to identify birefringent particles of prosthetic debris allows for an accurate histologic diagnosis
— id: 12729, year: 1995, vol: 60, page: 128, stat: Journal Article,

Kaposi's sarcoma of internal organs. A multiparameter study of 86 cases
Ioachim HL; Adsay V; Giancotti FR; Dorsett B; Melamed J
1995 Mar 15;75(6):1376-1385, Cancer
BACKGROUND. During the past decade, Kaposi's sarcoma (KS), one of the most common acquired immune deficiency syndrome-defining diseases, has been the subject of sustained research. However, basic questions about its etiology, histogenesis, growth, and dissemination remain unanswered. Even its nature, whether hyperplasia or neoplasia, is still controversial. Most studies and concepts to date have been based on dermatologic KS. The present study, in contrast, examines by various parameters a series of patients with KS of internal organs. MATERIALS AND METHODS. The series includes 86 cases (39 surgical specimens and 47 autopsies) of visceral and disseminated KS. The study is focused on the gross distribution of lesions, the mode of dissemination, the histologic patterns, and the cellular immunophenotypes, which are investigated with the use of 18 monoclonal antibodies. RESULTS. The involvement of various organs, multiplicity of lesions, and progression of tumors were recorded. Seven histologic patterns forming a spectrum of cellular differentiation were distinguished. Immunophenotypes characteristic for different histologic patterns were recognized. Although some cell markers such as those recognized by antibodies against Factor VIII R-Ag, Actin, and Ulex europaeus were restricted to the well differentiated KS cells, others including CD34 and CD31 demonstrated a strong affinity for the entire spectrum of KS cell differentiation. CONCLUSION. The present study of KS of internal organs revealed that poor grades of histologic and immunophenotypic differentiation correlated with invasion and dissemination, which are fundamental characteristics of malignant tumors
— id: 12796, year: 1995, vol: 75, page: 1376, stat: Journal Article,

BIOLOGIC FEATURES OF 45 MAMMOGRAM DETECTED INVASIVE CARCINOMAS (ICS) OF THE BREAST (EXCLUDING MICROINVASIVE CA)
MELAMED, J; QUISH, A; MOEZZI, M; INGHIRAMI, G; FEINER, H
1995 JAN ;72(1):A22-A22, Laboratory investigation
— id: 87426, year: 1995, vol: 72, page: A22, stat: Journal Article,

HISTOLOGIC FEATURES OF 45 MAMMOGRAM DETECTED INVASIVE CARCINOMAS (ICS) OF THE BREAST (EXCLUDING MICROINVASIVE CA)
MOEZZI, M; QUISH, A; MELAMED, J; SEEWAH, V; FELNER, H
1995 JAN ;72(1):A22-A22, Laboratory investigation
— id: 87427, year: 1995, vol: 72, page: A22, stat: Journal Article,

Hepatoid adenocarcinoma in the urinary bladder. Unusual localization of a newly recognized tumor type
Sinard J; Macleay L Jr; Melamed J
1994 Apr 1;73(7):1919-1925, Cancer
A tumor mass resected from the anterior bladder wall of a 68-year-old woman displayed unusual histologic features: sheets of hepatoid cells merging focally with a secondary glandular pattern of adenocarcinoma. Intracytoplasmic hyaline globules and bile production within the solid areas supported the impression of hepatocytic differentiation. Immunoreactivity for alpha-fetoprotein (AFP) and alpha-1-antitrypsin and a striking canalicular immunostaining pattern for carcinoembryonic antigen and epithelial membrane antigen all indicate hepatocellular differentiation within this bladder tumor. This represents a case of a hepatoid adenocarcinoma located in the urinary bladder. The use of the term 'hepatoid' in the literature is reviewed and the reported cases are grouped into two distinct categories of tumors: (1) germ cell tumors with focal hepatoid areas and (2) true hepatoid adenocarcinomas that meet histologic and immunohistochemical criteria for hepatocellular differentiation. AFP-producing tumors without any other feature of hepatocellular differentiation should not be considered as hepatoid tumors. This classification of hepatoid tumors is likely to be important in elucidating the histogenesis and clinicopathologic features of these unusual neoplasms
— id: 6519, year: 1994, vol: 73, page: 1919, stat: Journal Article,

p53 expression in precancerous gastric lesions: an immunohistochemical study of PAb 1801 monoclonal antibody on adenomatous and hyperplastic gastric polyps
Lauwers GY; Wahl SJ; Melamed J; Rojas-Corona RR
1993 Nov;88(11):1916-1919, American journal of gastroenterology
To determine the chronology of p53 mutation in the gastric carcinogenic sequence, we studied p53 overexpression in premalignant lesions, including 17 adenomatous polyps (10/17 surrounded by intestinal metaplasia and 11/17 harboring foci of adenocarcinoma or severe dysplasia), and 18 hyperplastic polyps (4/18 with focal adenomatous changes). Immunohistochemistry with PAb 1801 monoclonal antibody was performed on archival material; p53 nuclear staining was seen in 10/17 adenomas, but was limited to the foci of adenocarcinoma in three cases. Five adenomas with foci of severe dysplasia or carcinoma were nonreactive. Intestinal metaplasia, normal gastric mucosa, and 14/18 hyperplastic polyps were nonreactive. p53 Reactivity observed in four hyperplastic polyps was limited to adenomatous foci. These results suggest that p53 overexpression occurs in dysplastic epithelium of precancerous gastric lesions. Its absence in chronic atrophic gastritis with intestinal metaplasia suggests it is a relatively late event in the gastric carcinogenic sequence
— id: 36463, year: 1993, vol: 88, page: 1916, stat: Journal Article,

Cytomegalovirus, angiomatosis, and Kaposi's sarcoma: new observations of a debated relationship
Ioachim, H L; Dorsett, B; Melamed, J; Adsay, V; Santagada, E A
1992 Mar;5(2):169-178, Modern pathology
Kaposi's sarcoma (KS) encompasses a broad spectrum of lesions ranging from foci of muco-cutaneous angiomatosis to tumor masses of internal organs. Its strong association with immune deficiency and the marked differences in incidence between the various populations at risk are suggestive of an infectious etiology. The agent most often suspected of being implicated in the etiology of KS is cytomegalovirus (CMV); however, despite sustained research on this subject, its role remains controversial. The present work includes six cases of KS with a broad variety of lesions in which, with the use of light and electron microscopy, immunohistochemistry, and in situ hybridization, we investigated the presence of CMV and examined its relationship with KS. CMV was present in all six cases and showed a remarkable propensity for the KS lesions where both intranuclear and intracytoplasmic forms were not only next to but frequently within KS cells. Areas of angiomatosis, hemorrhage, and KS had usually an abundance of CMV. Herpes-like virus particles inside KS nuclei were documented by light and electron microscopy and identified as CMV by immunohistochemistry and in situ hybridization. The selective morphologic presence of this virus within the tumor cells, not previously demonstrated, indicates a strong association between CMV and KS, the significance of which remains to be established
— id: 116284, year: 1992, vol: 5, page: 169, stat: Journal Article,

Pigmented melanocytic schwannoma of the uterine cervix
Terzakis JA; Opher E; Melamed J; Santagada E; Sloan D
1990 Jul-Aug;14(4):357-366, Ultrastructural pathology
A 47-year-old woman had a lesion of the uterine cervix that presented clinically as a protruding or aborted leiomyoma. Grossly the tumor occupied a substantial portion of the cervical and endocervical region. Histologically it showed a spindle cell neoplasm arranged in large fascicles that penetrated deeply into the fibromuscular wall of the cervix. The tumor cells had abundant pink cytoplasm that contained considerable brown melanin granules confirmed by Fontana's stain. Cytologically nuclear pleomorphism, hyperchromatism, and giant nuclear forms were observed. Mitoses were also seen. Localized nuclear palisading was present. Electron microscopic examination of paraffin-embedded material revealed numerous premelanosomes and opaque granules that were compatible with mature melanosomes, thus confirming melanogenesis in the tumor. Tumor cells exhibited focal projections, and the connective tissue showed abnormal spacing of collagen. Basal lamina material was noted focally on tumor cell surfaces. Immunocytochemistry showed a positive reaction to S-100 protein and HMB-45 in tumor cell cytoplasm
— id: 22797, year: 1990, vol: 14, page: 357, stat: Journal Article,