Anna C Pavlick, D.O.

Intra- and Inter-Tumor Heterogeneity of BRAFMutations in Primary and Metastatic Melanoma
Yancovitz, Molly; Litterman, Adam; Yoon, Joanne; Ng, Elise; Shapiro, Richard L; Berman, Russell S; Pavlick, Anna C; Darvishian, Farbod; Christos, Paul; Mazumdar, Madhu; Osman, Iman; Polsky, David
2012 ;7(1):e29336-e29336, PLoS ONE
The rationale for using small molecule inhibitors of oncogenic proteins as cancer therapies depends, at least in part, on the assumption that metastatic tumors are primarily clonal with respect to mutant oncogene. With the emergence of BRAF(V600E) as a therapeutic target, we investigated intra- and inter-tumor heterogeneity in melanoma using detection of the BRAF(V600E) mutation as a marker of clonality. BRAF mutant-specific PCR (MS-PCR) and conventional sequencing were performed on 112 tumors from 73 patients, including patients with matched primary and metastatic specimens (n = 18). Nineteen patients had tissues available from multiple metastatic sites. Mutations were detected in 36/112 (32%) melanomas using conventional sequencing, and 85/112 (76%) using MS-PCR. The better sensitivity of the MS-PCR to detect the mutant BRAF(V600E) allele was not due to the presence of contaminating normal tissue, suggesting that the tumor was comprised of subclones of differing BRAF genotypes. To determine if tumor subclones were present in individual primary melanomas, we performed laser microdissection and mutation detection via sequencing and BRAF(V600E)-specific SNaPshot analysis in 9 cases. Six of these cases demonstrated differing proportions of BRAF(V600E)and BRAF(wild-type) cells in distinct microdissected regions within individual tumors. Additional analyses of multiple metastatic samples from individual patients using the highly sensitive MS-PCR without microdissection revealed that 5/19 (26%) patients had metastases that were discordant for the BRAF(V600E) mutation. In conclusion, we used highly sensitive BRAF mutation detection methods and observed substantial evidence for heterogeneity of the BRAF(V600E) mutation within individual melanoma tumor specimens, and among multiple specimens from individual patients. Given the varied clinical responses of patients to BRAF inhibitor therapy, these data suggest that additional studies to determine possible associations between clinical outcomes and intra- and inter-tumor heterogeneity could prove fruitful
— id: 149812, year: 2012, vol: 7, page: e29336, stat: Journal Article,

A pilot phase II trial of all-trans retinoic acid (Vesanoid) and paclitaxel (Taxol) in patients with recurrent or metastatic breast cancer
Bryan, Margarette; Pulte, E Dianne; Toomey, Kathleen C; Pliner, Lillian; Pavlick, Anna C; Saunders, Tracie; Wieder, Robert
2011 Dec;29(6):1482-1487, Investigational new drugs
PURPOSE: We investigated a combination therapy with weekly paclitaxel and all trans-retinoic acid (ATRA) for tolerability, response to treatment, time to progression and survival in previously treated patients with metastatic or recurrent breast cancer. Our rationale was based on preclinical studies demonstrating potentiation of the cytotoxic effects of taxanes and induction of differentiation by ATRA. PATIENTS AND METHODS: Seventeen patients with previously treated metastatic or recurrent breast cancer were enrolled to a regimen of all-trans retinoic acid (Vesanoid, tretinoin, Hoffman-La Roche, Inc.) 45 mg/m(2) PO daily for 4 days starting 2 days before a 1 h treatment with paclitaxel (Taxol, Bristol-Myers Squibb, Plainsboro, NJ) 80 mg/m(2) IV administered weekly for 3 weeks, repeated in 28 day cycles until disease progression or until no longer tolerated. Patients were evaluated for toxicity, response, time to progression and survival. Patients were primarily African American and Latino, representative of the population served by our Cancer Center. RESULTS: The regimen was relatively well tolerated. There were nine grade 3 and one grade 4 toxic events. We administered 162 treatment cycles with a mean of 7.5 per patient (range 1-22, median 5). Three patients had a partial response (17.6%) and ten patients had stable disease (58.8%), with an overall clinical benefit of 76.4%. Median time to progression was 6.0 months (range 1-21, mean 7.7 months). Fourteen evaluable patients had a median survival of 16 months (range 1-68 months, mean 25.2 months). CONCLUSIONS: The data suggest this is a well tolerated regimen with modest response rates but with time to progression and survival rates similar to those reported for paclitaxel alone and relatively high rates of stable disease in this sample of patients
— id: 141635, year: 2011, vol: 29, page: 1482, stat: Journal Article,

KIT as a therapeutic target in metastatic melanoma
Carvajal, Richard D; Antonescu, Cristina R; Wolchok, Jedd D; Chapman, Paul B; Roman, Ruth-Ann; Teitcher, Jerrold; Panageas, Katherine S; Busam, Klaus J; Chmielowski, Bartosz; Lutzky, Jose; Pavlick, Anna C; Fusco, Anne; Cane, Lauren; Takebe, Naoko; Vemula, Swapna; Bouvier, Nancy; Bastian, Boris C; Schwartz, Gary K
2011 Jun 8;305(22):2327-2334, JAMA
CONTEXT: Some melanomas arising from acral, mucosal, and chronically sun-damaged sites harbor activating mutations and amplification of the type III transmembrane receptor tyrosine kinase KIT. We explored the effects of KIT inhibition using imatinib mesylate in this molecular subset of disease. OBJECTIVE: To assess clinical effects of imatinib mesylate in patients with melanoma harboring KIT alterations. DESIGN, SETTING, AND PATIENTS: A single-group, open-label, phase 2 trial at 1 community and 5 academic oncology centers in the United States of 295 patients with melanoma screened for the presence of KIT mutations and amplification between April 23, 2007, and April 16, 2010. A total of 51 cases with such alterations were identified and 28 of these patients were treated who had advanced unresectable melanoma arising from acral, mucosal, and chronically sun-damaged sites. INTERVENTION: Imatinib mesylate, 400 mg orally twice daily. MAIN OUTCOME MEASURES: Radiographic response, with secondary end points including time to progression, overall survival, and correlation of molecular alterations and clinical response. RESULTS: Two complete responses lasting 94 (ongoing) and 95 weeks, 2 durable partial responses lasting 53 and 89 (ongoing) weeks, and 2 transient partial responses lasting 12 and 18 weeks among the 25 evaluable patients were observed. The overall durable response rate was 16% (95% confidence interval [CI], 2%-30%), with a median time to progression of 12 weeks (interquartile range [IQR], 6-18 weeks; 95% CI, 11-18 weeks), and a median overall survival of 46.3 weeks (IQR, 28 weeks-not achieved; 95% CI, 28 weeks-not achieved). Response rate was better in cases with mutations affecting recurrent hotspots or with a mutant to wild-type allelic ratio of more than 1 (40% vs 0%, P = .05), indicating positive selection for the mutated allele. CONCLUSIONS: Among patients with advanced melanoma harboring KIT alterations, treatment with imatinib mesylate results in significant clinical responses in a subset of patients. Responses may be limited to tumors harboring KIT alterations of proven functional relevance. Trial Registration clinicaltrials.gov Identifier: NCT00470470
— id: 135201, year: 2011, vol: 305, page: 2327, stat: Journal Article,

A phase II multicenter study of ipilimumab with or without dacarbazine in chemotherapy-naive patients with advanced melanoma
Hersh, Evan M; O'Day, Steven J; Powderly, John; Khan, Khuda D; Pavlick, Anna C; Cranmer, Lee D; Samlowski, Wolfram E; Nichol, Geoffrey M; Yellin, Michael J; Weber, Jeffrey S
2011 Jun;29(3):489-498, Investigational new drugs
OBJECTIVE: Ipilimumab is a fully human, anti-cytotoxic T-lymphocyte antigen-4 (CTLA-4) monoclonal antibody that has demonstrated antitumor activity in advanced melanoma. We evaluated the safety and efficacy of ipilimumab alone and in combination with dacarbazine (DTIC) in patients with unresectable, metastatic melanoma. METHODS: Chemotherapy-naive patients were randomized in this multicenter, phase II study to receive ipilimumab at 3 mg/kg every 4 weeks for four doses either alone or with up to six 5-day courses of DTIC at 250 mg/m(2)/day. The primary efficacy endpoint was objective response rate. RESULTS: Seventy-two patients were treated per-protocol (ipilimumab plus DTIC, n = 35; ipilimumab, n = 37). The objective response rate was 14.3% (95% CI, 4.8-30.3) with ipilimumab plus DTIC and was 5.4% (95% CI, 0.7-18.2) with ipilimumab alone. At a median follow-up of 20.9 and 16.4 months for ipilimumab plus DTIC (n = 32) and ipilimumab alone (n = 32), respectively, median overall survival was 14.3 months (95% CI, 10.2-18.8) and 11.4 months (95% CI, 6.1-15.6); 12-month, 24-month, and 36-month survival rates were 62%, 24% and 20% for the ipilimumab plus DTIC group and were 45%, 21% and 9% for the ipilimumab alone group, respectively. Immune-related adverse events were, in general, medically manageable and occurred in 65.7% of patients in the combination group versus 53.8% in the monotherapy group, with 17.1% and 7.7% >/=grade 3, respectively. CONCLUSION: Ipilimumab therapy resulted in clinically meaningful responses in advanced melanoma patients, and the results support further investigations of ipilimumab in combination with DTIC
— id: 134131, year: 2011, vol: 29, page: 489, stat: Journal Article,

Correction: The Novel Gamma Secretase Inhibitor RO4929097 Reduces the Tumor Initiating Potential of Melanoma
Huynh, Chanh; Poliseno, Laura; Segura, Miguel F; Medicherla, Ratna; Haimovic, Adele; Menendez, Silvia; Shang, Shulian; Pavlick, Anna; Shao, Yongzhao; Darvishian, Farbod; Boylan, John F; Osman, Iman; Hernando, Eva
2011 ;6(11):?-?, PLoS ONE
[This corrects the article on p. e25264 in vol. 6.]
— id: 141637, year: 2011, vol: 6, page: ?, stat: Journal Article,

The Novel Gamma Secretase Inhibitor RO4929097 Reduces the Tumor Initiating Potential of Melanoma
Huynh, Chanh; Poliseno, Laura; Segura, Miguel F; Medicherla, Ratna; Haimovic, Adele; Menendez, Silvia; Shang, Shulian; Pavlick, Anna; Shao, Yongzhao; Darvishian, Farbod; Boylan, John F; Osman, Iman; Hernando, Eva
2011 ;6(9):e25264-e25264, PLoS ONE
Several reports have demonstrated a role for aberrant NOTCH signaling in melanoma genesis and progression, prompting us to explore if targeting this pathway is a valid therapeutic approach against melanoma. We targeted NOTCH signaling using RO4929097, a novel inhibitor of gamma secretase, which is a key component of the enzymatic complex that cleaves and activates NOTCH. The effects of RO4929097 on the oncogenic and stem cell properties of a panel of melanoma cell lines were tested both in vitro and in vivo, using xenograft models. In human primary melanoma cell lines, RO4929097 decreased the levels of NOTCH transcriptional target HES1. This was accompanied by reduced proliferation and impaired ability to form colonies in soft agar and to organize in tridimensional spheres. Moreover, RO4929097 affected the growth of human primary melanoma xenograft in NOD/SCID/IL2gammaR-/- mice and inhibited subsequent tumor formation in a serial xenotransplantation model, suggesting that inhibition of NOTCH signaling suppresses the tumor initiating potential of melanoma cells. In addition, RO4929097 decreased tumor volume and blocked the invasive growth pattern of metastatic melanoma cell lines in vivo. Finally, increased gene expression of NOTCH signaling components correlated with shorter post recurrence survival in metastatic melanoma cases. Our data support NOTCH inhibition as a promising therapeutic strategy against melanoma
— id: 138712, year: 2011, vol: 6, page: e25264, stat: Journal Article,

Impact of population genetic substructure on association studies and risk assessment for melanoma
Lobach I; Belitskaya-Levy I; Goldberg JD; Ostrer H; Berman RS; Pavlick AC; Shapiro RL; Osman I; Manga P
2011 ;29(Suppl):?-? #8521, Journal of clinical oncology
Background: Genetic substructure due to varying allele frequencies between populations can confound association studies. Ancestry informative genetic marker (AIMs) data combined with statistical adjustment can reveal spurious associations and identify population specific risk markers. In melanoma, AIMs may also be risk markers, e.g. pigment genes contribute to melanoma susceptibility and segregate with ancestry. We have thus developed a strategy to adjust for population genetic substructure (PGS) using AIMs, while identifying potentially novel genes associated with melanoma. Methods: 326 melanoma patients and 400 controls of European ancestry from the New York area were studied. Tag SNPs spanning 14 candidate genes and 75 AIMs were genotyped and odds ratios (OR), unadjusted and adjusted for PGS, computed. Results: A PGS model based on all AIMs separated cases and controls, suggesting that some AIMs were associated with melanoma. An algorithm was developed to select AIMs least capable of separating cases and controls to infer PGS and validated using simulations. The resulting model, which was reproduced using 49 additional AIMs, separated Northern (NE) and Southern Europeans (SE) and was used to adjust ORs. Three classes of SNPs were identified 1. Associated before and after PGS correction in both groups (10 SNPs localized to MATP, TYR and ERCC5). 2. Not associated in unadjusted analysis, but significantly associated with melanoma in NEs (6 SNPs localized to XPC, ERCC4, OCA2, ASIP and TYR). 3. Associated with melanoma before but not after adjustment. To determine if AIMs that separate cases and controls can identify novel melanoma genes, we genotyped 16 SNPs localized to 4 genes that house candidate AIMs. Four SNPs at 2 different loci were associated with melanoma (e.g. AIM1: OR=0.35, p=0.01; AIM2: OR=1.77, p=0.03). Conclusions: Our approach demonstrated that ancestry is a significant confounding factor in identifying melanoma susceptibility genes. Melanoma risk markers vary significantly between groups and a DNA based risk assessment model will require adjustment for ancestry. We have also identified potentially novel susceptibility melanoma genes for futher study
— id: 132473, year: 2011, vol: 29, page: ?, stat: Journal Article,

Systemic bevacizumab (Avastin) for exudative retinal detachment secondary to choroidal melanoma
Newman H; Finger PT; Chin KJ; Pavlick AC
2011 Mar 23;21(6):796-801 L, European journal of ophthalmology
Purpose. To evaluate the safety and effect of systemic anti-vascular endothelial growth factor bevacizumab (Avastin) in treatment of exudative retinal detachment secondary to choroidal melanoma. Methods. Two patients were definitively treated with ophthalmic plaque radiation therapy and subsequently given 10 mg/kg intravenous bevacizumab every 2 weeks for 3 or 4 cycles. Results. Complete resolution of the exudative retinal detachments occurred 1.2 months and 6.5 months after completion of systemic bevacizumab and 4.7 and 10 months after plaque therapy. The first patient's visual acuity improved from counting fingers at 1 foot to 20/80 (at 40 months), while his tumor regressed from 9.2 to 3.7 mm in apical height. The second patient's initial acuity was 20/20 and final acuity was 20/80 (at 35 months), while her tumor height regressed from 12.2 to 6.3 mm. No exudative retinal detachment, intraocular or systemic tumor recurrence was noted up to 40 and 35 months, respectively. Acute side effects of intravenous bevacizumab therapy included hypertension, headaches, and amenorrhea, which shortly resolved after completion of therapy. Conclusions. This pilot study suggests that systemic bevacizumab was associated with transient systemic effects as well as resolution of choroidal melanoma-related exudative retinal detachment
— id: 139640, year: 2011, vol: 21, page: 796, stat: Journal Article,

Clinical and pharmacologic evaluation of two dose levels of intetumumab (CNTO 95) in patients with melanoma or angiosarcoma
O'Day SJ; Pavlick AC; Albertini MR; Hamid O; Schalch H; Lang Z; Ling J; Mata M; Reddy M; Foster B
2011 Feb 18;:?-?, Investigational new drugs
Purpose In this Phase 1, multicenter, open-label study, intetumumab (CNTO 95), a fully human anti-alphav integrin monoclonal antibody was evaluated for safety, pharmacokinetics, and pharmacodynamic activity in patients with melanoma or angiosarcoma. Patients and methods Patients with histologically-confirmed inoperable melanoma or angiosarcoma refractory to standard treatment were allocated to treatment with 10 mg/kg or 20 mg/kg intetumumab, administered once every 3 weeks for up to four cycles unless unacceptable toxicity or disease progression occurred. Extended dosing was available for patients who responded with stable disease or better. Results Eight patients received 10 mg/kg and 11 received 20 mg/kg intetumumab. Baseline patient characteristics were comparable between treatment groups; 18 patients had metastatic malignant melanoma and one had angiosarcoma. No dose-limiting toxicities were observed. Headache was the most common adverse event across both dose groups. Vomiting, nausea and chills were more common, and uveitic reactions lasted longer, in patients treated with 20 mg/kg compared with 10 mg/kg intetumumab. No patient developed antibodies to intetumumab. Intetumumab drug exposure as assessed by area under the curve and maximum serum concentration appeared to increase approximately dose-proportionally from 10 to 20 mg/kg, while volume of distribution remained constant for both doses. Stable disease was observed in two patients with metastatic malignant melanoma (one in each dose group) for at least 6 weeks. Conclusions In patients with metastatic malignant melanoma and angiosarcoma in this study, intetumumab demonstrated manageable toxicity, was well tolerated, and presented approximately dose-proportional pharmacokinetics for the 10 mg/kg and 20 mg/kg doses
— id: 141636, year: 2011, vol: , page: ?, stat: Journal Article,

Deletion of PTENP1 Pseudogene in Human Melanoma
Poliseno, Laura; Haimovic, Adele; Christos, Paul J; Vega Y Saenz de Miera, Eleazar C; Shapiro, Richard; Pavlick, Anna; Berman, Russell S; Darvishian, Farbod; Osman, Iman
2011 Dec;131(12):2497-2500, Journal of investigative dermatology
— id: 141068, year: 2011, vol: 131, page: 2497, stat: Journal Article,

Integrative genomics identifies molecular alterations that challenge the linear model of melanoma progression
Rose AE; Poliseno L; Wang J; Clark M; Pearlman A; Wang G; Vega Y Saenz de Miera EC; Medicherla R; Christos PJ; Shapiro RL; Pavlick AC; Darvishian F; Zavadil J; Polsky D; Hernando E; Ostrer H; Osman I
2011 Apr 1;71(7):2561-2571, Cancer research
Superficial spreading melanoma (SSM) and nodular melanoma (NM) are believed to represent sequential phases of linear progression from radial to vertical growth. Several lines of clinical, pathological and epidemiologic evidence suggest, however, that SSM and NM might be the result of independent pathways of tumor development. We utilized an integrative genomic approach that combines single nucleotide polymorphism array (SNP 6.0, Affymetrix) with gene expression array (U133A 2.0, Affymetrix) to examine molecular differences between SSM and NM. Pathway analysis of the most differentially expressed genes between SSM and NM (N=114) revealed significant differences related to metabolic processes. We identified 8 genes (DIS3, FGFR1OP, G3BP2, GALNT7, MTAP, SEC23IP, USO1, ZNF668) in which NM/SSM-specific copy number alterations correlated with differential gene expression (P<0.05, Spearman's rank). SSM-specific genomic deletions in G3BP2, MTAP, and SEC23IP were independently verified in two external data sets. Forced overexpression of metabolism-related gene methylthioadenosine phosphorylase (MTAP) in SSM resulted in reduced cell growth. The differential expression of another metabolic related gene, aldehyde dehydrogenase 7A1 (ALDH7A1), was validated at the protein level using tissue microarrays of human melanoma. In addition, we show that the decreased ALDH7A1 expression in SSM may be the result of epigenetic modifications. Our data reveal recurrent genomic deletions in SSM not present in NM, which challenge the linear model of melanoma progression. Furthermore, our data suggest a role for altered regulation of metabolism-related genes as a possible cause of the different clinical behavior of SSM and NM
— id: 124135, year: 2011, vol: 71, page: 2561, stat: Journal Article,

Clinical relevance of SKP2 alterations in metastatic melanoma
Rose, Amy E; Wang, Guimin; Hanniford, Douglas; Monni, Stefano; Tu, Ting; Shapiro, Richard L; Berman, Russell S; Pavlick, Anna C; Pagano, Michele; Darvishian, Farbod; Mazumdar, Madhu; Hernando, Eva; Osman, Iman
2011 Feb;24(1):197-206, Pigment cell & melanoma research
In this study, we investigated the mechanism(s) of altered expression of protooncogene SKP2 in metastatic melanoma and its clinical relevance in patients with metastatic melanoma. The genomic status of SKP2 was assessed in cell lines by sequencing, single nucleotide polymorphism array, and genomic PCR. Copy number status was then evaluated for concordance with SKP2 mRNA and protein expression. SKP2 protein was further evaluated by immunohistochemistry in 93 human metastatic tissues. No mutations were identified in SKP2. Increased copy number at the SKP2 locus was observed in 6/14 (43%) metastatic cell lines and in 9/22 (41%) human metastatic tissues which was associated with overexpression of SKP2 protein. Overexpression of SKP2 protein in human tissues was associated with worse survival in a multivariate model controlling for the site of metastasis. Copy number gain is a major contributing mechanism of SKP2 overexpression in metastatic melanoma. Results may have implications for the development of therapeutics that target SKP2
— id: 138133, year: 2011, vol: 24, page: 197, stat: Journal Article,

A high proliferative index of recurrent melanoma is associated with worse survival
Tu, Ting J; Ma, Michelle W; Monni, Stefano; Rose, Amy E; Yee, Herman; Darvishian, Farbod; Polsky, David; Berman, Russell S; Shapiro, Richard L; Pavlick, Anna C; Mazumdar, Madhu; Osman, Iman
2011 ;80(3-4):181-187, Oncology (New York)
Objective: Previous melanoma studies evaluating prognostic factors of survival at recurrence have focused on primary tumor characteristics and clinical variables at first recurrence. We examined the prognostic relevance of recurrent tumor proliferation. Methods: 114 melanoma patients with available recurrent tissues who were prospectively enrolled at New York University Medical Center were studied. Standard of care prognostic variables (e.g. stage at initial diagnosis and lactate dehydrogenase level) and recurrent tissue expression of proliferative marker Ki-67 were evaluated for their association with overall survival. Results: High Ki-67 expression was observed in 57 (50%) of the 114 recurrent melanomas. On univariate analysis, the median overall survival of patients whose recurrent tumors overexpressed Ki-67 was significantly shorter than that of patients whose recurrent tumors had low Ki-67 expression (3.6 vs. 9.5 years, p = 0.03). On multivariate analysis, a high proliferative index of the recurrent melanoma remained an independent predictor of worse overall survival, controlling for stage at initial diagnosis, disease-free survival, and stage at first recurrence [HR = 2.09 (95% CI 1.24-3.54), p = 0.006]. Conclusions: Our results demonstrate the prognostic relevance of tumor proliferation in recurrent melanoma patients. Data also support restratification of risk assessment upon recurrence that considers tumor biology in addition to clinical variables evaluated as part of the standard of care
— id: 135575, year: 2011, vol: 80, page: 181, stat: Journal Article,

Impact of socioeconomic status and sociodemographic factors on melanoma presentation among ethnic minorities
Wich, Lindsay G; Ma, Michelle W; Price, Leah S; Sidash, Stanislav; Berman, Russell S; Pavlick, Anna C; Miller, George; Sarpel, Umut; Goldberg, Judith D; Osman, Iman
2011 Jun;36(3):461-468, Journal of community health
Minority melanoma patients have worse survival. In this study, we evaluated the impact of socioeconomic and demographic factors on minority melanoma patients presenting to two different New York City hospitals (one public and one private) managed by the same multidisciplinary team. Sociodemographic and clinicopathologic characteristics were retrieved for melanoma patients presenting to Bellevue Hospital Center (BHC), a public hospital, and the New York University Cancer Institute (NYUCI), a private cancer center. Socioeconomic data was obtained from the United States Census Bureau database. The Kruskal-Wallis and chi-square tests were used to evaluate the associations between race/ethnicity and continuous and categorical variables (e.g. income, stage at presentation), respectively. Minorities comprised 2% (27/1296) of melanoma patients at the NYUCI compared to 42% (50/119) at BHC. Those presenting to the NYUCI were more likely to have a higher median household income (P = 0.05), a higher educational level (P = 0.04), and an earlier stage at presentation (P = 0.02) than those at BHC. NYUCI patients were predominantly covered by commercial insurance (70%), whereas Medicaid (62%) was common among BHC patients. Only 19% of Hispanic patients at BHC chose English as their preferred language. Our data demonstrate that language and health care system factors affect melanoma presentation in minorities
— id: 138281, year: 2011, vol: 36, page: 461, stat: Journal Article,

Clinical variables and primary tumor characteristics predictive of the development of melanoma brain metastases and post-brain metastases survival
Zakrzewski, Jan; Geraghty, Laurel N; Rose, Amy E; Christos, Paul J; Mazumdar, Madhu; Polsky, David; Shapiro, Richard; Berman, Russell; Darvishian, Farbod; Hernando, Eva; Pavlick, Anna; Osman, Iman
2011 Apr 15;117(8):1711-1720, Cancer
BACKGROUND: Melanoma patients who develop brain metastases (B-Met) have limited survival and are excluded from most clinical trials. In the current study, the authors attempted to identify primary tumor characteristics and clinical features predictive of B-Met development and post-B-Met survival. METHODS: A prospectively accrued cohort of 900 melanoma patients was studied to identify clinicopathologic features of primary melanoma (eg, thickness, ulceration, mitotic index, and lymphovascular invasion) that are predictive of B-Met development and survival after a diagnosis of B-Met. Associations between clinical variables present at the time of B-Met diagnosis (eg, extracranial metastases, B-Met location, and the presence of neurological symptoms) and post-B-Met survival were also assessed. Univariate associations were analyzed using Kaplan-Meier survival analysis, and the effect of independent predictors was assessed using multivariate Cox proportional hazards regression analysis. RESULTS: Of the 900 melanoma patients studied, 89 (10%) developed B-Met. Ulceration and site of the primary tumor on the head and neck were found to be independent predictors of B-Met development on multivariate analysis (P = .001 and P = .003, respectively). Clinical variables found to be predictive of post-B-Met survival on multivariate analysis included the presence of neurological symptoms (P = .008) and extracranial metastases (P = .04). Ulceration was the only primary tumor characteristic that remained a significant predictor of post-B-Met survival on multivariate analysis (P = .04). CONCLUSIONS: Primary tumor ulceration was found to be the strongest predictor of B-Met development and remained an independent predictor of decreased post-B-Met survival in a multivariate analysis inclusive of primary tumor characteristics and clinical variables. The results of the current study suggest that patients with ulcerated primary tumors should be prospectively studied to determine whether heightened surveillance for B-Met can improve clinical outcome. Cancer 2011. (c) 2010 American Cancer Society
— id: 130314, year: 2011, vol: 117, page: 1711, stat: Journal Article,

Cutaneous melanoma in the elderly: Epidemiology and management
Lam B.; Ott P.A.; Pavlick A.C.
2010 ;6(3):383-392, Aging Health
The incidence of melanoma is on the rise and the elderly population disproportionately accounts for the majority of melanoma cases and melanoma-related deaths. Advanced age is an independent adverse prognostic factor. Surgical resection remains the mainstay of treatment; however, elderly patients receive care that is nonconformant with well-established guidelines. Medical therapy options for high-risk and metastatic melanomas remain limited. New treatment approaches targeting the MAPK pathway, c-kit gene aberrations and novel immune-based therapies will pave the road to individualized and more effective treatment for invasive melanoma. 2010 Future Medicine Ltd
— id: 121344, year: 2010, vol: 6, page: 383, stat: Journal Article,

A phase II trial of the epothilone B analog ixabepilone (BMS-247550) in patients with metastatic melanoma
Ott, Patrick A; Hamilton, Anne; Jones, Amanda; Haas, Naomi; Shore, Tsiporah; Liddell, Sandra; Christos, Paul J; Doyle, L Austin; Millward, Michael; Muggia, Franco M; Pavlick, Anna C
2010 ;5(1):e8714-e8714, PLoS ONE
BACKGROUND: Ixabepilone (BMS-247550), an epothilone B analog, is a microtubule stabilizing agent which has shown activity in several different tumor types and preclinical models in melanoma. In an open label, one-arm, multi-center phase II trial the efficacy and toxicity of this epothilone was investigated in two different cohorts: chemotherapy-naive (previously untreated) and previously treated patients with metastatic melanoma. METHODOLOGY/PRINCIPAL FINDINGS: Eligible patients had histologically-confirmed stage IV melanoma, with an ECOG performance status of 0 to 2. Ixabepilone was administered at a dose of 20 mg/m(2) on days 1, 8, and 15 during each 28-day cycle. The primary endpoint was response rate (RR); secondary endpoints were time to progression (TTP) and toxicity. Twenty-four patients were enrolled and 23 were evaluable for response. Initial serum lactate dehydrogenase (LDH) levels were elevated in 6/11 (55%) of the previously treated and in 5/13 (38%) of the previously untreated patients. No complete or partial responses were seen in either cohort. One patient in the previously treated group developed neutropenia and fatal septic shock. Seventeen patients (8 in the previously untreated group and 9 in the previously treated group) progressed after 2 cycles, whereas six patients (3 in each group) had stable disease after 2-6 cycles. Median TTP was 1.74 months in the previously untreated group (95% CI = 1.51 months, upper limit not estimated) and 1.54 months in the previously treated group (95% CI = 1.15 months, 2.72 months). Grade 3 and/or 4 toxicities occurred in 5/11 (45%) of previously untreated and in 5/13 (38%) of previously treated patients and included neutropenia, peripheral neuropathy, fatigue, diarrhea, and dyspnea. CONCLUSIONS/SIGNIFICANCE: Ixabepilone has no meaningful activity in either chemotherapy-naive (previously untreated) or previously treated patients with metastatic melanoma. Further investigation with ixabepilone as single agent in the treatment of melanoma is not warranted. TRIAL REGISTRATION: Clinical Trials.gov NCT00036764
— id: 106468, year: 2010, vol: 5, page: e8714, stat: Journal Article,

A Phase II Trial of Sorafenib in Metastatic Melanoma with Tissue Correlates
Ott, Patrick A; Hamilton, Anne; Min, Christina; Safarzadeh-Amiri, Sara; Goldberg, Lauren; Yoon, Joanne; Yee, Herman; Buckley, Michael; Christos, Paul J; Wright, John J; Polsky, David; Osman, Iman; Liebes, Leonard; Pavlick, Anna C
2010 ;5(12):e15588-e15588, PLoS ONE
BACKGROUND: Sorafenib monotherapy in patients with metastatic melanoma was explored in this multi-institutional phase II study. In correlative studies the impact of sorafenib on cyclin D1 and Ki67 was assessed. METHODOLOGY/PRINCIPAL FINDINGS: Thirty-six patients treatment-naive advanced melanoma patients received sorafenib 400 mg p.o. twice daily continuously. Tumor BRAF(V600E) mutational status was determined by routine DNA sequencing and mutation-specific PCR (MSPCR). Immunohistochemistry (IHC) staining for cyclin D1 and Ki67 was performed on available pre- and post treatment tumor samples. The main toxicities included diarrhea, alopecia, rash, mucositis, nausea, hand-foot syndrome, and intestinal perforation. One patient had a RECIST partial response (PR) lasting 175 days. Three patients experienced stable disease (SD) with a mean duration of 37 weeks. Routine BRAF(V600E) sequencing yielded 27 wild-type (wt) and 6 mutant tumors, whereas MSPCR identified 12 wt and 18 mutant tumors. No correlation was seen between BRAF(V600E) mutational status and clinical activity. No significant changes in expression of cyclin D1 or Ki67 with sorafenib treatment were demonstrable in the 15 patients with pre-and post-treatment tumor samples. CONCLUSIONS/SIGNIFICANCE: Sorafenib monotherapy has limited activity in advanced melanoma patients. BRAF(V600E) mutational status of the tumor was not associated with clinical activity and no significant effect of sorafenib on cyclin D1 or Ki67 was seen, suggesting that sorafenib is not an effective BRAF inhibitor or that additional signaling pathways are equally important in the patients who benefit from sorafenib. TRIAL REGISTRATION: Clinical Trials.gov NCT00119249
— id: 117357, year: 2010, vol: 5, page: e15588, stat: Journal Article,

Incidence of the V600K mutation among melanoma patients with BRAF mutations, and potential therapeutic response to the specific BRAF inhibitor PLX4032
Rubinstein, Jill C; Sznol, Mario; Pavlick, Anna C; Ariyan, Stephan; Cheng, Elaine; Bacchiocchi, Antonella; Kluger, Harriet M; Narayan, Deepak; Halaban, Ruth
2010 ;8:67-67, Journal of translational medicine
Activating mutations in BRAF kinase are common in melanomas. Clinical trials with PLX4032, the mutant-BRAF inhibitor, show promising preliminary results in patients selected for the presence of V600E mutation. However, activating V600K mutation is the other most common mutation, yet patients with this variant are currently excluded from the PLX4032 trials. Here we present evidence that a patient bearing the BRAF V600K mutation responded remarkably to PLX4032, suggesting that clinical trials should include all patients with activating BRAF V600E/K mutations
— id: 141638, year: 2010, vol: 8, page: 67, stat: Journal Article,

Mucosal melanomas: a case-based review of the literature
Seetharamu, Nagashree; Ott, Patrick A; Pavlick, Anna C
2010 ;15(7):772-781, Oncologist
Mucosal melanoma is a rare cancer that is clearly distinct from its cutaneous counterpart in biology, clinical course, and prognosis. Recent studies have shown important differences in the frequencies of various genetic alterations in different subtypes of melanoma. Activating mutations in the c-KIT gene are detected in a significant number of patients with mucosal melanoma. This observation has resulted in the initiation of several clinical trials aimed at exploring the role of receptor tyrosine kinases that inhibit c-KIT in this patient population. We herein present a comprehensive literature review of mucosal melanoma along with case vignettes of a number of pertinent cases. We further discuss melanomas of the head and neck, the female genital tract, and the anorectum, which are the three most common sites of mucosal melanoma, with a particular focus on the diagnostic, prognostic, and therapeutic data available in the literature
— id: 111620, year: 2010, vol: 15, page: 772, stat: Journal Article,

Melanoma MicroRNA Signature Predicts Post-Recurrence Survival
Segura, Miguel F; Belitskaya-Levy, Ilana; Rose, Amy E; Zakrzewski, Jan; Gaziel, Avital; Hanniford, Douglas; Darvishian, Farbod; Berman, Russell S; Shapiro, Richard L; Pavlick, Anna C; Osman, Iman; Hernando, Eva
2010 Mar 1;16(5):1577-1586, Clinical cancer research
PURPOSE: To identify a melanoma microRNA (miRNA) expression signature that is predictive of outcome and then evaluate its potential to improve risk stratification when added to the standard-of-care staging criteria. EXPERIMENTAL DESIGN: Total RNA was extracted from 59 formalin-fixed paraffin-embedded melanoma metastases and hybridized to miRNA arrays containing 911 probes. We then correlated miRNA expression with post-recurrence survival and other clinicopathologic criteria. RESULTS: We identified a signature of 18 miRNAs whose overexpression was significantly correlated with longer survival, defined as more than 18 months post-recurrence survival. Subsequent cross-validation showed that a small subset of these miRNAs can predict post-recurrence survival in metastatic melanoma with an estimated accuracy of 80.2% (95% confidence interval, 79.8-80.6%). In contrast to standard-of-care staging criteria, a six-miRNA signature significantly stratified stage III patients into 'better' and 'worse' prognostic categories, and a multivariate Cox regression analysis revealed the signature to be an independent predictor of survival. Furthermore, we showed that most miRNAs from the signature also showed differential expression between patients with better and worse prognoses in the corresponding paired primary melanoma. CONCLUSIONS: MiRNA signatures have potential as clinically relevant biomarkers of prognosis in metastatic melanoma. Our data suggest that molecularly based models of risk assessment can improve the standard staging criteria and support the incorporation of miRNAs into such models. Clin Cancer Res; 16(5); 1577-86
— id: 107357, year: 2010, vol: 16, page: 1577, stat: Journal Article,

An open-label, multicenter Phase II study of continuous oral dosing of RG7204 (PLX4032) in previously treated patients with BRAF V600E mutation-positive metastatic melanoma
Sosman J.; Kim K.; Schuchter L.; Gonzalez R.; Pavlick A.; Weber J.; McArthur G.; Hutson T.; Lawrence D.; Moschos S.; Flaherty K.; Hersey P.; Kefford R.; Chmielowski B.; Amaravadi R.; Puzanov I.; Li J.; Bhattacharya S.; Nolop K.; Lee R.; Joe A.; Ribas A.
2010 ;23(6):886-886, Pigment cell & melanoma research
The V600E activating mutation of the BRAF gene occurs in approximately 50% of melanomas and is a potentially important molecular target for therapy in this disease. In a Phase I clinical trial, treatment with RG7204 (PLX4032), a low molecular weight, orally available selective inhibitor of oncogenic BRAF kinase, led to impressive tumor regression in patients whose tumors carried the V600E BRAF mutation. This is the first report of a pivotal open-label, multicenter, Phase II trial in previously treated patients with BRAF V600E mutation-positive metastatic melanoma. The primary endpoint is best overall response rate (BORR). Patients were selected with the cobas 4800 V600 Mutation Assay (Roche, Basel, Switzerland), a PCR-based companion diagnostic assay that is currently under development. Patients are treated with RG7204 (960 mg given twice daily) until they develop progressive disease, unacceptable toxicity, or death, whichever occurs first. A total of 132 patients were enrolled between September 2009 and March 2010. At the time of the presentation (based on the data cut-off date of September 27, 2010), we will report an interim analysis of the primary endpoint of BORR as assessed by independent review committee, as well as the secondary endpoints of BORR (as assessed by the investigator), response duration, median progression-free survival, time to response, and safety (adverse events, serious adverse events, dose reductions). We will also provide the median duration of treatment and the median safety follow up period. These results may provide additional clinical information in a larger sample of patients of the efficacy and safety profile of RG7204 in previously treated patients with BRAF V600Epositive metastatic melanoma
— id: 135620, year: 2010, vol: 23, page: 886, stat: Journal Article,

An open-label, multicenter Phase II study of continuous oral dosing of RG7204 (PLX4032) in previously treated patients with BRAF V600E mutation-positive metastatic melanoma
Sosman J.; Kim K.; Schuchter L.; Gonzalez R.; Pavlick A.; Weber J.; McArthur G.; Hutson T.; Lawrence D.; Moschos S.; Flaherty K.; Hersey P.; Kefford R.; Chmielowski B.; Amaravadi R.; Puzanov I.; Li J.; Bhattacharya S.; Nolop K.; Lee R.; Joe A.; Ribas A.
2010 ;23(6):912-912, Pigment cell & melanoma research
The V600E activating mutation of the BRAF gene occurs in approximately 50% of melanomas and is a potentially important molecular target for therapy in this disease. In a Phase I clinical trial, treatment with RG7204 (PLX4032), a low molecular weight, orally available selective inhibitor of oncogenic BRAF kinase, led to impressive tumor regression in patients whose tumors carried the V600E BRAF mutation. This is the first report of a pivotal open-label, multicenter, Phase II trial in previously treated patients with BRAF V600E mutation-positive metastatic melanoma. The primary endpoint is best overall response rate (BORR). Patients were selected with the cobas-4800 V600 Mutation Assay, a PCR-based companion diagnostic assay that is currently under development. Patients are treated with RG7204 (960 mg given twice daily) until they develop progressive disease, unacceptable toxicity, or death, whichever occurs first. A total of 132 patients were enrolled between September 2009 and March 2010. At the time of the presentation (based on the data cut-off date of September 27, 2010), we will report an interim analysis of the primary endpoint of BORR as assessed by independent review committee, as well as the secondary endpoints of BORR (as assessed by the investigator), response duration, median progression-free survival, time to response, and safety (adverse events, serious adverse events, dose reductions). We will also provide the median duration of treatment and the median safety follow up period. These results may provide additional clinical information in a larger sample of patients of the efficacy and safety profile of RG7204 in previously treated patients with BRAF V600E-positive metastatic melanoma
— id: 135619, year: 2010, vol: 23, page: 912, stat: Journal Article,

Clinical variables and primary tumor characteristics predictive of the development of melanoma brain metastases and post-brain metastases survival
Zakrzewski J; Geraghty LN; Rose AE; Christos PJ; Mazumdar M; Polsky D; Shapiro R; Berman R; Darvishian F; Hernando E; Pavlick A; Osman I
2010 Nov 8;:?-?, Cancer
BACKGROUND:: Melanoma patients who develop brain metastases (B-Met) have limited survival and are excluded from most clinical trials. In the current study, the authors attempted to identify primary tumor characteristics and clinical features predictive of B-Met development and post-B-Met survival. METHODS:: A prospectively accrued cohort of 900 melanoma patients was studied to identify clinicopathologic features of primary melanoma (eg, thickness, ulceration, mitotic index, and lymphovascular invasion) that are predictive of B-Met development and survival after a diagnosis of B-Met. Associations between clinical variables present at the time of B-Met diagnosis (eg, extracranial metastases, B-Met location, and the presence of neurological symptoms) and post-B-Met survival were also assessed. Univariate associations were analyzed using Kaplan-Meier survival analysis, and the effect of independent predictors was assessed using multivariate Cox proportional hazards regression analysis. RESULTS:: Of the 900 melanoma patients studied, 89 (10%) developed B-Met. Ulceration and site of the primary tumor on the head and neck were found to be independent predictors of B-Met development on multivariate analysis (P = .001 and P = .003, respectively). Clinical variables found to be predictive of post-B-Met survival on multivariate analysis included the presence of neurological symptoms (P = .008) and extracranial metastases (P = .04). Ulceration was the only primary tumor characteristic that remained a significant predictor of post-B-Met survival on multivariate analysis (P = .04). CONCLUSIONS:: Primary tumor ulceration was found to be the strongest predictor of B-Met development and remained an independent predictor of decreased post-B-Met survival in a multivariate analysis inclusive of primary tumor characteristics and clinical variables. The results of the current study suggest that patients with ulcerated primary tumors should be prospectively studied to determine whether heightened surveillance for B-Met can improve clinical outcome. Cancer 2010. (c) 2010 American Cancer Society
— id: 141464, year: 2010, vol: , page: ?, stat: Journal Article,

Immune profile and mitotic index of metastatic melanoma lesions enhance clinical staging in predicting patient survival
Bogunovic, Dusan; O'Neill, David W; Belitskaya-Levy, Ilana; Vacic, Vladimir; Yu, Yi-Lo; Adams, Sylvia; Darvishian, Farbod; Berman, Russell; Shapiro, Richard; Pavlick, Anna C; Lonardi, Stefano; Zavadil, Jiri; Osman, Iman; Bhardwaj, Nina
2009 Dec 1;106(48):20429-20434, Proceedings of the National Academy of Sciences of the United States of America
Although remission rates for metastatic melanoma are generally very poor, some patients can survive for prolonged periods following metastasis. We used gene expression profiling, mitotic index (MI), and quantification of tumor infiltrating leukocytes (TILs) and CD3+ cells in metastatic lesions to search for a molecular basis for this observation and to develop improved methods for predicting patient survival. We identified a group of 266 genes associated with postrecurrence survival. Genes positively associated with survival were predominantly immune response related (e.g., ICOS, CD3d, ZAP70, TRAT1, TARP, GZMK, LCK, CD2, CXCL13, CCL19, CCR7, VCAM1) while genes negatively associated with survival were cell proliferation related (e.g., PDE4D, CDK2, GREF1, NUSAP1, SPC24). Furthermore, any of the 4 parameters (prevalidated gene expression signature, TILs, CD3, and in particular MI) improved the ability of Tumor, Node, Metastasis (TNM) staging to predict postrecurrence survival; MI was the most significant contributor (HR = 2.13, P = 0.0008). An immune response gene expression signature and presence of TILs and CD3+ cells signify immune surveillance as a mechanism for prolonged survival in these patients and indicate improved patient subcategorization beyond current TNM staging
— id: 105312, year: 2009, vol: 106, page: 20429, stat: Journal Article,

Effect of mebendazole on melanoma xenograft growth through targeting of bcl-2
Doudican N.A.; Pennell R.; Tu T.; Liebes L.; Pavlick A.; Berman R.; Shapiro R.; Goldberg J.D.; Osman I.; Orlow S.
2009 ;27(15 Suppl 1):9075-9075, Journal of clinical oncology
Background: Defects in apoptosis are thought to contribute to melanoma chemoresistance, making the anti-apoptotic protein Bcl-2 an attractive therapeutic target. We identified mebendazole (MBZ), a microtubule binding agent, as an inducer of melanoma cytotoxicity via a Bcl-2 dependent mechanism in vitro (Mol Cancer Res, Aug 2008). In the present study, we assessed the effect of MBZ on human melanoma tumor growth and progression in a mouse xenograft model and compared the ability of MBZ to inhibit growth of cultured melanoma cells to that of oblimersen (OBL), an antisense drug targeting Bcl-2. Methods: Growth of human M-14 melanoma xenografts in mice administered MBZ orally at doses from 0.1 to 2 mg were compared to tumor growth in mice receiving 100mg/kg intraperitoneal temozolomide (TMZ) or vehicle alone. Tumor diameter, volume, histopathology, and immunohistochemical staining of caspase 3 and Ki67 were assessed. Bcl-2 phosphorylation was determined by immunoblotting. MBZ and OBL-induced melanoma growth inhibition was analyzed by MTT assay. Results: Anti-melanoma effects of MBZ were dose- dependent up to 1 mg which displayed a 72% reduction in tumor volume compared to vehicle treated mice. This reduction in volume was accompanied by a 46% decrease in proliferating cells and an 81% increase in apoptotic cells. Moreover, 1 mg MBZ inhibited tumor growth as effectively as high dose TMZ, the current melanoma standard of care. Orally administered MBZ treatment resulted in Bcl-2 phosphorylation in vivo, further confirming its mechanism of action. MBZ inhibited growth of melanoma cells in culture more effectively than OBL with GI50 values of 0.32 uM and 7.45 uM, respectively. Conclusions: MBZ safely and effectively inhibits melanoma growth and progression in a xenograft model. A phase II clinical trial investigating MBZ's utility as adjuvant therapy in patients with stage IV, resected melanoma is planned
— id: 111807, year: 2009, vol: 27, page: 9075, stat: Journal Article,

Phase II assessment of talabostat and cisplatin in second-line stage IV melanoma
Eager, Robert M; Cunningham, C Casey; Senzer, Neil N; Stephenson, Joe Jr; Anthony, Stephen P; O'Day, Steven J; Frenette, Gary; Pavlick, Anna C; Jones, Barry; Uprichard, Margaret; Nemunaitis, John
2009 ;9:263-263, BMC cancer
BACKGROUND: Metastatic melanoma is an incurable disease with an average survival of less than one year. Talabostat is a novel dipeptidyl peptidase inhibitor with immunostimulatory properties. METHODS: This phase II, open label, single arm study was conducted to evaluate the safety and efficacy of 75-100 mg/m2 cisplatin combined with 300-400 mcg talabostat bid for 6, 21-day cycles. The primary endpoint was overall response. The rate of complete responses, duration of overall objective response, progression-free survival (PFS), and overall survival were the secondary endpoints. RESULTS: Six objective partial responses were recorded in the 74 patients (8.1%) in the intention-to-treat population. Five of these responses involved the 40 evaluable patients (12.5%). Thirty-one percent of patients reported SAEs to the combination of talabostat and cisplatin. CONCLUSION: Acceptable tolerability was observed in the intention-to-treat population and antitumor activity was observed in 12.5% of evaluable patients, which is not greater than historical expectation with cisplatin alone
— id: 141639, year: 2009, vol: 9, page: 263, stat: Journal Article,

Association of MDM2 SNP309, age of onset, and gender in cutaneous melanoma
Firoz, Elnaz F; Warycha, Melanie; Zakrzewski, Jan; Pollens, Danuta; Wang, Guimin; Shapiro, Richard; Berman, Russell; Pavlick, Anna; Manga, Prashiela; Ostrer, Harry; Celebi, Julide Tok; Kamino, Hideko; Darvishian, Farbod; Rolnitzky, Linda; Goldberg, Judith D; Osman, Iman; Polsky, David
2009 Apr 1;15(7):2573-2580, Clinical cancer research
PURPOSE: In certain cancers, MDM2 SNP309 has been associated with early tumor onset in women. In melanoma, incidence rates are higher in women than in men among individuals less than 40 years of age, but among those older than 50 years of age, melanoma is more frequent in men than in women. To investigate this difference, we examined the association among MDM2 SNP309, age at diagnosis, and gender among melanoma patients. EXPERIMENTAL DESIGN: Prospectively enrolled melanoma patients (N = 227) were evaluated for MDM2 SNP309 and the related polymorphism, p53 Arg72Pro. DNA was isolated from patient blood samples, and genotypes were analyzed by PCR-restriction fragment length polymorphism. Associations among MDM2 SNP309, p53 Arg72Pro, age at diagnosis, and clinicopathologic features of melanoma were analyzed. RESULTS: The median age at diagnosis was 13 years earlier among women with a SNP309 GG genotype (46 years) compared with women with TG+TT genotypes (59 years; P = 0.19). Analyses using age dichotomized at each decade indicated that women with a GG genotype had significantly higher risks of being diagnosed with melanoma at ages <50 years compared with women >or=50 years, but not when the comparison was made between women <60 and >or=60 years. At ages <50 years, women with a GG genotype had a 3.89 times greater chance of being diagnosed compared with women with TG+TT genotypes (P = 0.01). Similar observations were not seen among men. CONCLUSIONS: Our data suggest that MDM2 may play an important role in the development of melanoma in women. The MDM2 SNP309 genotype may help identify women at risk of developing melanoma at a young age
— id: 104875, year: 2009, vol: 15, page: 2573, stat: Journal Article,

Detection of BRAF kinase mutations in melanoma, ovarian, and prostate carcinomas: Evidence for tumor heterogeneity in clinical samples
Litterman A.J.; Yancovitz M.; Shapiro R.; Berman R.; Pavlick A.; Daarvishian F.; Blank S.; Lee P.; Osman I.; Polsky D.
2009 ;27(15 Suppl 1):11031-11031, Journal of clinical oncology
Background: Several studies have provided evidence that solid tumors are polyclonal malignancies, an observation which may contribute to difficulties in achieving durable treatment responses. In some patients, molecularly targeted therapies may be compromised due to heterogeneity among tumor subclones. In this study we compared conventional DNA sequencing with a fluorescent-based mutant-specific PCR (MS-PCR) assay to detect the BRAF hotspot mutation V600E in a large panel of patient tumors, including paired primary and metastatic tumors from individual patients. Methods: BRAF MS-PCR and conventional sequencing were performed on DNA from 304 tumors (112 melanoma, 110 ovarian, 82 prostate) to determine the presence of the BRAFV600E hot-spot mutation. Among the melanomas were 18 matched primary and metastatic specimens, and 40 metastatic specimens from 19 patients, each of whom had 2 or more metastases. Results: DNA sequencing detected mutations in 5/110 (4.5%) ovarian tumors, 1/82 (1.2%) prostate tumors, and 36/112 (32%) melanomas. In contrast, the MS-PCR assay detected mutations in 12/110 (11%) ovarian tumors, 15/82 (18%) prostate tumors and 85/112 (76%) melanomas. The presence of contaminating normal tissue was scored for each melanoma sample, but excess normal tissue did not influence the results using either methodology. In all cases mutations detected by sequencing were also detected by MSPCR. Among 18 patients with matched primary and metastatic melanoma, 8/18 (44%) had discordant results including 2 patients with mutant primary tumors and wild-type metastases; among the 19 patients with multiple metastases 5/19 (26%) had discordant (both wild-type and mutant) tumors. Conclusions: Using a highly sensitive BRAF mutation detection method, we observed substantial evidence for heterogeneity within clinical tumor specimens. This was especially true in melanoma samples, where multiple specimens from individual patients differed with respect to the presence of the mutant BRAF allele. These results suggest that failures of molecularly targeted therapies, such as those directed against mutant BRAF, may be due in part to a lack of clonality among the tumors under treatment
— id: 111809, year: 2009, vol: 27, page: 11031, stat: Journal Article,

Developing genetic markers for melanoma risk assessment
Manga P.; Goldberg J.D.; Belitskaya-Levy I.; Lobach I.; Polsky D.; Pavlick A.; Shapiro R.; Berman R.; Osman I.; Ostrer H.
2009 ;27(15 Suppl 1):9046-9046, Journal of clinical oncology
Background: Risk assessment for melanoma is currently based on phenotype, family and exposure history. This approach is subject to recall bias and excludes at-risk groups such as those with darker skin pigmentation. Poorly stratified risk pools also result in unnecessary dermatologist visits and biopsies for those at lower risk. Use of genetic markers may improve risk assessment; however few susceptibility markers have been developed to date. There have been a number of reports of association between melanoma and genetic markers though few have been replicated or validated. In addition, these studies frequently utilized specific coding region variants as markers and failed to test the entire gene. We have therefore assembled a case-control cohort in which to search for potential biomarkers for melanoma risk by interrogating genes using recently developed tools for genetic analysis. A pilot study was performed to test the utility of our cohort. Methods: A cohort of 326 individuals diagnosed with melanoma and treated at the New York University Langone Medical Center and 400 controls obtained from the New York Cancer project was assembled. Candidate genes were selected based on involvement in determining melanoma predisposition factors (skin pigmentation and DNA repair capability) and previous studies showing association. Three genes, ERCC1, ERCC4 (DNA repair) and MATP (skin pigmentation) were selected. Tag Single Nucleotide Polymorphisms (tSNPs) were selected using Haploview (Hapmap.org) and DNA genotyped (Sequenom Inc, San Diego, CA). Odds ratios and confidence intervals were computed for each SNP. Results: An association was found between SNP rs11615 at the ERCC1 locus and melanoma (Odds ratio = 1.718, 95% Confidence interval: 1.259 - 2.343 for TT vs TC/CC). Conclusions: A tSNP approach is thus useful in identifying associations in our melanoma case-control cohort. Sequence variation at the ERCC1 locus contributes to melanoma risk and the gene will now be screened for clinically useful susceptibility biomarkers. Additional DNA repair and pigmentation genes will also be interrogated using this approach. Genes found to be associated with melanoma will be screened by high- density SNP analysis to identify the most appropriate biomarker/s for use in risk assessment
— id: 111805, year: 2009, vol: 27, page: 9046, stat: Journal Article,

Phosphorylated 4E-BP1 is associated with poor survival in melanoma
O'Reilly, Kathryn E; Warycha, Melanie; Davies, Michael A; Rodrik, Vanessa; Zhou, Xi K; Yee, Herman; Polsky, David; Pavlick, Anna C; Rosen, Neal; Bhardwaj, Nina; Mills, Gordon; Osman, Iman
2009 Apr 15;15(8):2872-2878, Clinical cancer research
PURPOSE: Both phosphatidylinositol 3-kinase/AKT and RAS/mitogen-activated protein kinase signal transduction pathways mediate 4E-BP1 phosphorylation, releasing 4E-BP1 from the mRNA cap and permitting translation initiation. Given the prevalence of PTEN and BRAF mutations in melanoma, we first examined translation initiation, as measured by phosphorylated 4E-BP1 (p-4E-BP1), in metastatic melanoma tissues and cell lines. We then tested the association between amounts of total and p-4E-BP1 and patient survival. EXPERIMENTAL DESIGN: Seven human metastatic melanoma cells lines and 72 metastatic melanoma patients with accessible metastatic tumor tissues and extended follow-up information were studied. Expression of 4E-BP1 transcript, total 4E-BP1 protein, and p-4E-BP1 was examined. The relationship between 4E-BP1 transcript and protein expression was assessed in a subset of patient tumors (n = 41). The association between total and p-4E-BP1 levels and survival was examined in the larger cohort of patients (n = 72). RESULTS: 4E-BP1 was hyperphosphorylated in 4 of 7 melanoma cell lines harboring both BRAF and PTEN mutations compared with untransformed melanocytes or RAS/RAF/PTEN wild-type melanoma cells. 4E-BP1 transcript correlated with 4E-BP1 total protein levels as measured by the semiquantitative reverse-phase protein array (P = 0.012). High levels of p-4E-BP1 were associated with worse overall and post-recurrence survival (P = 0.02 and 0.0003, respectively). CONCLUSION: Our data show that translation initiation is a common event in human metastatic melanoma and correlates with worse prognosis. Therefore, effective inhibition of the pathways responsible for 4E-BP1 phosphorylation should be considered to improve the treatment outcome of metastatic melanoma patients
— id: 99295, year: 2009, vol: 15, page: 2872, stat: Journal Article,

Phase II trial of dacarbazine and thalidomide for the treatment of metastatic melanoma
Ott, Patrick A; Chang, Jason L; Oratz, Ruth; Jones, Amanda; Farrell, Kathleen; Muggia, Franco; Pavlick, Anna C
2009 ;55(4):221-227, Chemotherapy
OBJECTIVE: This phase II study evaluated the efficacy and tolerability of dacarbazine in combination with thalidomide in metastatic melanoma patients. METHODS: Chemotherapy-naive patients with histologically confirmed, measurable metastatic melanoma with no evidence of brain metastases and adequate hematologic and organ function received dacarbazine (1,000 mg/m(2) i.v. every 3 weeks) and thalidomide (starting dose of 200 mg/day orally at night, escalated every 3 weeks) as tolerated. The primary endpoint was objective tumor response, evaluated after every 3 cycles of treatment. Fifteen patients, age range 29-77 years, were accrued for this study. All had stage IV disease (1 M1a, 5 M1b, 9 M1c). Nine patients had had no prior adjuvant therapy, 6 had received prior immunotherapy. The median number of cycles was 5 (range 1-18), with 8 patients receiving >or=3 cycles. The median thalidomide dose administered was 200 mg/day with a maximum tolerated dose of 400 mg/day. RESULTS: Of the 13 patients evaluable for response, 1 patient had a partial response, 3 patients had stable disease and 9 patients had progressive disease. No complete responses were seen. Two patients were not evaluable for response: 1 withdrew due to toxicity and 1 died of unrelated causes. Grade III neutropenia, thrombocytopenia and nausea were attributed to dacarbazine. Grade III/IV constipation, peripheral neuropathy, fatigue, edema and rash were attributed to thalidomide. CONCLUSION: The addition of thalidomide to dacarbazine in metastatic melanoma yielded activity insufficient to proceed with additional trials of this combination. Thalidomide dose escalation beyond 200 mg/day was limited by unacceptable toxicity. Therefore, this combination does not warrant further investigation
— id: 100608, year: 2009, vol: 55, page: 221, stat: Journal Article,

Phase I study of bryostatin 1, a protein kinase C modulator, preceding cisplatin in patients with refractory non-hematologic tumors
Pavlick, Anna C; Wu, Jennifer; Roberts, John; Rosenthal, Mark A; Hamilton, Anne; Wadler, Scott; Farrell, Kathleen; Carr, Michelle; Fry, David; Murgo, Anthony J; Oratz, Ruth; Hochster, Howard; Liebes, Leonard; Muggia, Franco
2009 Sep;64(4):803-810, Cancer chemotherapy & pharmacology
PURPOSE: Preclinical data suggested that bryostatin-1 (bryo) could potentiate the cytotoxicity of cisplatin when given prior to this drug. We designed a phase I study to achieve tolerable doses and schedules of bryo and cisplatin in combination and in this sequence. METHODS: Patients with non-hematologic malignancies received bryo followed by cisplatin in several schedules. Bryo was given as an 1 and a 24 h continuous infusion, while cisplatin was always given over 1 h at 50 and 75 mg/m(2); the combined regimen was repeated on an every 3-week and later on an every 2-week schedule. Bryo doses were escalated until recommended phase II doses were defined for each schedule. Patients were evaluated with computerized tomography every 2 cycles. RESULTS: Fifty-three patients were entered. In an every 2-week schedule, the 1-h infusion of bryo became limited by myalgia that was clearly cumulative. With cisplatin 50 mg/m(2) its recommended phase II dose was 30 mug/m(2). In the 3-week schedule, dose-limiting toxicities were mostly related to cisplatin effects while myalgias were tolerable. Pharmacokinetics unfortunately proved to be unreliable due to bryo's erratic extraction. Consistent inhibition of PKC isoform eta (eta) in peripheral blood mononuclear cells was observed following bryo. CONCLUSIONS: Bryo can be safely administered with cisplatin with minimal toxicity; however, only four patients achieved an objective response. Modulation of cisplatin cytotoxicity by bryo awaits further insight into the molecular pathways involved
— id: 97002, year: 2009, vol: 64, page: 803, stat: Journal Article,

Novel therapeutics for melanoma
Seetharamu, Nagashree; Ott, Patrick A; Pavlick, Anna C
2009 Jun;9(6):839-849, Expert review of anticancer therapy
Advanced melanoma has the highest per-death loss of years of potential life expectancy except for adult leukemia. Standard therapy with agents such as dacarbazine, temozolomide and IL-2 is associated with notoriously low response rates. The identification of new active agents is, therefore, critical in this disease. In recent years, better understanding of melanoma biology, as well as cancer and immune biology in general has led to the development of a number of new potential therapeutic agents for advanced melanoma. While many of these compounds are being tested in clinical trials, there are more agents in various stages of preclinical development. These novel therapeutics offer hope for this aggressive and so far largely treatment-resistant disease. In this review we will discuss some of the most promising novel therapeutic agents for advanced melanoma
— id: 99325, year: 2009, vol: 9, page: 839, stat: Journal Article,

A phase 2, randomized study of SB-485232, rhIL-18, in patients with previously untreated metastatic melanoma
Tarhini, Ahmad A; Millward, Michael; Mainwaring, Paul; Kefford, Richard; Logan, Ted; Pavlick, Anna; Kathman, Steven J; Laubscher, Kevin H; Dar, Mohammed M; Kirkwood, John M
2009 Feb 15;115(4):859-868, Cancer
BACKGROUND: Phase 1 studies demonstrated evidence of recombinant human IL-18 (rhIL-18)-mediated immunomodulatory and clinical activity, and defined a biologically active dose range. METHODS: A phase 2 study of rhIL-18 was conducted in untreated AJCC stage IV melanoma. Patients were randomized to 1 of 3 dose groups (0.01, 0.1, and 1.0 mg/kg/d) of rhIL-18 administered as 5 daily intravenous infusions repeated every 28 days. A 2-stage design with a stopping rule was used. RESULTS: A total of 64 patients (median age, 57.5 years) with metastatic melanoma (M1a/b (30), M1c (34)) were accrued to stage I, and randomized to 3 groups (21 [0.01 mg/kg/d], 21 [0.1 mg/kg/d], 22 [1.0 mg/kg/d]). Five patients experienced 10 grade 3 drug-related adverse events (AEs): polyarthritis (1 subject: 0.01 mg/kg); deep vein thrombosis, pulmonary embolism (1:0.01 mg/kg); cognitive disorder (1:0.1 mg/kg); fatigue, dyspnea, pleural effusion, lymphopenia (1:1.0 mg/kg); fatigue, lymphopenia (1:1.0 mg/kg). One patient experienced a grade 4 AE of increased lipase (0.1 mg/kg) that led to permanent discontinuation from the study. Among 63 subjects evaluable for response, 1 (M1c; 0.01 mg/kg) achieved a partial response after 4 cycles. Four subjects (3 at 0.01 mg/kg and 1 at 1.0 mg/kg) had stable disease maintained for 6 months or longer. Due to the low apparent level of clinical efficacy using RECIST criteria, the study was terminated at the end of stage 1. The median progression free survival for the 3 groups was 7.5 (0.01), 7.4 (0.1), and 7.3 (1.0) weeks. CONCLUSIONS: rIL-18 as tested in this trial was well tolerated, but had limited activity as a single agent in patients with metastatic melanoma
— id: 97003, year: 2009, vol: 115, page: 859, stat: Journal Article,

Meta-analysis of sentinel lymph node positivity in thin melanoma (</=1 mm)
Warycha, Melanie A; Zakrzewski, Jan; Ni, Quanhong; Shapiro, Richard L; Berman, Russell S; Pavlick, Anna C; Polsky, David; Mazumdar, Madhu; Osman, Iman
2009 Feb 15;115(4):869-879, Cancer
BACKGROUND:: Despite the lack of an established survival benefit of sentinel lymph node (SLN) biopsy, this technique has been increasingly applied in the staging of thin (</=1 mm) melanoma patients, without clear evidence to support this recommendation. The authors performed a meta-analysis to estimate the risk, potential predictors, and outcome of SLN positivity in this group of patients. METHODS:: MEDLINE, EMBASE, and Cochrane databases were searched for rates of SLN positivity in patients with thin melanoma. The methodologic quality of included studies was assessed using the Methodological Index for Non-Randomized Studies criteria. Heterogeneity was assessed using the Cochran Q statistic, and publication bias was examined through funnel plot and the Begg and Mazumdar method. Overall SLN positivity in thin melanoma patients was estimated using the DerSimonial-Laird random effect method. RESULTS:: Thirty-four studies comprising 3651 patients met inclusion criteria. The pooled SLN positivity rate was 5.6%. Significant heterogeneity among studies was detected (P = .005). There was no statistical evidence of publication bias (P = .21). Eighteen studies reported select clinical and histopathologic data limited to SLN-positive patients (n = 113). Among the tumors from these patients, 6.1% were ulcerated, 31.5% demonstrated regression, and 47.5% were Clark level IV/V. Only 4 melanoma-related deaths were reported. CONCLUSIONS:: Relatively few patients with thin melanoma have a positive SLN. To the authors' knowledge, there are no clinical or histopathologic criteria that can reliably identify thin melanoma patients who might benefit from this intervention. Given the increasing diagnosis of thin melanoma, in addition to the cost and potential morbidity of this procedure, alternative strategies to identify patients at risk for lymph node disease are needed. Cancer 2009. (c) 2008 American Cancer Society
— id: 92156, year: 2009, vol: 115, page: 869, stat: Journal Article,

Developing a multidisciplinary prospective melanoma biospecimen repository to advance translational research
Wich, Lindsay G; Hamilton, Heather K; Shapiro, Richard L; Pavlick, Anna; Berman, Russell S; Polsky, David; Goldberg, Judith D; Hernando, Eva; Manga, Prashiela; Krogsgaard, Michelle; Kamino, Hideko; Darvishian, Farbod; Lee, Peng; Orlow, Seth J; Ostrer, Harry; Bhardwaj, Nina; Osman, Iman
2009 ;1(1):35-43, American Journal of Translational Research
Several challenges face the development and operation of a biospecimen bank linked to clinical information, a critical component of any effective translational research program. Melanoma adds particular complexity and difficulty to such an endeavor considering the unique characteristics of this malignancy. We describe here a review of biospecimen bank and our experience in establishing a multi-disciplinary, prospective, integrated clinicopathological-biospecimen database in melanoma. The Interdisciplinary Melanoma Cooperative Group (IMCG), a prospective clinicopathological and biospecimen database, was established at the New York University (NYU) Langone Medical Center. With patients' informed consent, biospecimens from within and outside NYU, clinicopathological data, and follow-up information are collected using developed protocols. Information pertaining to biospecimens is recorded in 35 fields, and clinicopathological information is recorded in 371 fields within 5 modules in a virtual network system. Investigators conducting research utilizing the IMCG biospecimen resource are blind to clinicopathological information, and molecular data generated using biospecimens are linked independently with clinicopathological data by biostatistics investigators. This translational research enterprise acts as a valuable resource to efficiently translate laboratory discoveries to the clinic
— id: 105566, year: 2009, vol: 1, page: 35, stat: Journal Article,

Immunization of Malignant Melanoma Patients with Full-Length NY-ESO-1 Protein Using TLR7 Agonist Imiquimod as Vaccine Adjuvant
Adams, Sylvia; O'Neill, David W; Nonaka, Daisuke; Hardin, Elizabeth; Chiriboga, Luis; Siu, Kimberly; Cruz, Crystal M; Angiulli, Angelica; Angiulli, Francesca; Ritter, Erika; Holman, Rose Marie; Shapiro, Richard L; Berman, Russell S; Berner, Natalie; Shao, Yongzhao; Manches, Olivier; Pan, Linda; Venhaus, Ralph R; Hoffman, Eric W; Jungbluth, Achim; Gnjatic, Sacha; Old, Lloyd; Pavlick, Anna C; Bhardwaj, Nina
2008 Jul 1;181(1):776-784, Journal of immunology
T cell-mediated immunity to microbes and to cancer can be enhanced by the activation of dendritic cells (DCs) via TLRs. In this study, we evaluated the safety and feasibility of topical imiquimod, a TLR7 agonist, in a series of vaccinations against the cancer/testis Ag NY-ESO-1 in patients with malignant melanoma. Recombinant, full-length NY-ESO-1 protein was administered intradermally into imiquimod preconditioned sites followed by additional topical applications of imiquimod. The regimen was very well tolerated with only mild and transient local reactions and constitutional symptoms. Secondarily, we examined the systemic immune response induced by the imiquimod/NY-ESO-1 combination, and show that it elicited both humoral and cellular responses in a significant fraction of patients. Skin biopsies were assessed for imiquimod's in situ immunomodulatory effects. Compared with untreated skin, topical imiquimod induced dermal mononuclear cell infiltrates in all patients composed primarily of T cells, monocytes, macrophages, myeloid DCs, NK cells, and, to a lesser extent, plasmacytoid DCs. DC activation was evident. This study demonstrates the feasibility and excellent safety profile of a topically applied TLR7 agonist used as a vaccine adjuvant in cancer patients. Imiquimod's adjuvant effects require further evaluation and likely need optimization of parameters such as formulation, dose, and timing relative to Ag exposure for maximal immunogenicity
— id: 79260, year: 2008, vol: 181, page: 776, stat: Journal Article,

Gene expression profile for metastatic melanoma and patient survival
Bogunovic D; O'Neill D; Adams S; Wang J; Darvishian F; Pavlick AC; Shapiro RL; Zavadil J; Osman I; Bhardwaj N
2008 May 20;26(Suppl):?-? #9049, Proceedings (American Society of Clinical Oncology)
Background: Although remission rates for metastatic melanoma are generally very poor, some patients can survive for prolonged periods following metastasis. Here we use gene expression profiling of metastatic melanoma samples to search for a molecular basis for this observation. Methods: We analyzed gene expression profiles of 44 metastatic melanoma specimens collected from 38 patients who were followed clinically for a median of 20 months after surgery. RNA was processed using standard methods and hybridized to Affymetrix Human Genome HU133 Plus 2.0 arrays. Data were analyzed using GeneSpring and PathwayAssist software, normalizing using a PLIER algorithm and utilizing ANOVA statistical tests. Results: Unsupervised clustering yielded 4 distinct groups of subjects, 2 of which had large differences in overall survival. We then used supervised clustering to compare patients whose post-surgery survival was less then 1.5 years (11 subjects, 9.5 month median survival) to those who survived greater than 1.5 years (23 subjects, 26 month median survival, 17 alive at last follow-up). Only genes with changes in expression of > 2 with a p value of < 0.05 were accepted, resulting in a group of approximately 200 genes. Genes associated with immune response (TNFa, IRF1, Granzyme B, CD8a, CXCL11, IL27AR, GBP1, CXCL10, CCBP2, GBP2, CCR9 and IFIT4) or with cell proliferation (FGFR1, MET, MDM2, CDC25A, RFC2, SOS1, HOXA3, MCM4, MCM7, ORC5L, KIF23 and VAV3) were highly represented. Prolonged survival was associated with elevated expression of immune response genes and decreased expression of genes associated with cell proliferation. Conclusions: Gene expression profiling of metastatic melanoma samples identified a set of genes associated with patient survival, and suggests that immune surveillance is a mechanism for prolonged survival in these patients
— id: 106301, year: 2008, vol: 26, page: ?, stat: Journal Article,

Phase I and pharmacokinetic study of imatinib mesylate in patients with advanced malignancies and varying degrees of renal dysfunction: a study by the National Cancer Institute Organ Dysfunction Working Group
Gibbons, Joseph; Egorin, Merrill J; Ramanathan, Ramesh K; Fu, Pingfu; Mulkerin, Daniel L; Shibata, Stephen; Takimoto, Chris H M; Mani, Sridhar; LoRusso, Patricia A; Grem, Jean L; Pavlick, Anna; Lenz, Heinz-Josef; Flick, Susan M; Reynolds, Sherrie; Lagattuta, Theodore F; Parise, Robert A; Wang, Yanfeng; Murgo, Anthony J; Ivy, S Percy; Remick, Scot C
2008 Feb 1;26(4):570-576, Journal of clinical oncology
PURPOSE: This study was undertaken to determine the safety, dose-limiting toxicities (DLT), maximum-tolerated dose (MTD), and pharmacokinetics of imatinib in cancer patients with renal impairment and to develop dosing guidelines for imatinib in such patients. PATIENTS AND METHODS: Sixty adult patients with advanced solid tumors and varying renal function (normal, creatinine clearance [CrCL] >or= 60 mL/min; mild dysfunction, CrCL 40 to 59 mL/min; moderate dysfunction, CrCL 20 to 39 mL/min; and severe dysfunction, CrCL < 20 mL/min) received daily imatinib doses of 100 to 800 mg. Treatment cycles were 28 days long. RESULTS: The MTD was not reached for any group. DLTs occurred in two mild group patients (600 and 800 mg) and two moderate group patients (200 and 600 mg). Serious adverse events (SAEs) were more common in the renal dysfunction groups than in the normal group (P = .0096). There was no correlation between dose and SAEs in any group. No responses were observed. Several patients had prolonged stable disease. Imatinib exposure, expressed as dose-normalized imatinib area under the curve, was significantly greater in the mild and moderate groups than in the normal group. There was a positive correlation between serum alpha-1 acid glycoprotein (AGP) concentration and plasma imatinib, and an inverse correlation between plasma AGP concentration and imatinib clearance. Urinary excretion accounted for 3% to 5% of the daily imatinib dose. CONCLUSION: Daily imatinib doses up to 800 or 600 mg were well tolerated by patients with mild and moderate renal dysfunction, respectively, despite their having increased imatinib exposure
— id: 97004, year: 2008, vol: 26, page: 570, stat: Journal Article,

Phase I/II Study of CR011-vcMMAE, an Antibody-drug Conjugate Targeting GPNMB, for the Treatment of Patients With Advanced Melanoma
Hwu, P; Sznol, M; Pavlick, A; Kluger, H; Kim, KB; Hwu, WJ; Papadopoulos, N; Sanders, D; Boasberg, P; Simantov, R; Hamid, O
2008 NOV-DEC ;31(9):970-971, Journal of immunotherapy (Hagerstown)
— id: 91385, year: 2008, vol: 31, page: 970, stat: Journal Article,

Transfection of dendritic cells (DCs) with mRNA encoding IL-12p70 enhances anti-tumor immunity in melanoma patients
Minkis K; Kavanagh D; O'Neill D; Alter G; Sunderji S; Adams S; Walker B; Pavlick AC; Gandhi R; Bhardwaj N
2008 May 20;26(Suppl):?-? #22217, Proceedings (American Society of Clinical Oncology)
Background: DCs are widely used in experimental immune-based therapies for melanoma. Prior to injection, DCs are matured with a cocktail of recombinant cytokines and PGE-2, which preserves the ability of DCs to migrate to draining lymph nodes. However, PGE-2 also suppresses the ability of DCs to express IL-12p70. To overcome this paradox, we transfected mature DCs with synthetic mRNA encoding IL-12p70 and evaluated both their innate and adaptive immune functions in vitro. Methods: DCs from healthy donors and melanoma patients were cultured in vitro and transfected with IL-12p70 mRNA. The ability of these DCs to secrete bioactive IL-12p70 was tested by ELISA. Bioactivity of the secreted IL-12 was tested using NK cell assays and allogeneic MLRs. T cell assays were also performed to assess TH1 skewing towards melanoma antigens: T cells from healthy donors and melanoma patients were isolated and stimulated with autologous DCs previously transfected with MART-1 and IL-12p70 mRNA. The quantity and quality of the primed MART-1 specific T cells was determined. For comparison, melanoma tumor-infiltrating T cells (TILs) isolated from a resected tumor were used to examine TH phenotype. Results: IL-12p70-transfected DCs produced bioactive IL-12p70, and enhanced the response of NK cells to MHC class I-negative tumor targets. IL-12p70 transfected DC skewed TH responses away from TH2 in allogeneic MLRs. Cotransfection of DCs derived from the blood of healthy donors with IL-12p70 and MART-1 enhanced in vitro priming of melanoma- specific CD8 T cells, enhanced their capacity to secrete IFN? and inhibited the production of the TH2 cytokines IL-4 and IL-5, compared to MART-1 alone. In contrast, TILs from resected tumor exhibited a strong TH2 phenotype. T cell lines primed in vitro from the blood of melanoma patients by autologous DCs also showed strong TH2 skewing that was reversed by IL-12p70 transfection. Conclusions: Clinical DC preparations may be improved by IL-12p70 transfection, which enhances both innate and antigen-specific anti-tumor immune responses in vitro. This approach can be applied in vivo, thereby contributing to effective immune-based therapy against melanoma
— id: 79466, year: 2008, vol: 26, page: ?, stat: Journal Article,

Type 2 Bias of T cells expanded from the blood of melanoma patients switched to type 1 by IL-12p70 mRNA-transfected dendritic cells
Minkis, Kira; Kavanagh, Daniel G; Alter, Galit; Bogunovic, Dusan; O'Neill, David; Adams, Sylvia; Pavlick, Anna; Walker, Bruce D; Brockman, Mark A; Gandhi, Rajesh T; Bhardwaj, Nina
2008 Nov 15;68(22):9441-9450, Cancer research
Melanoma patients may exhibit a T(H)2-skewed cytokine profile within blood and tumor-infiltrating lymphocytes. Therapies that induce beneficial T(H)1-type tumor-specific immune responses, therefore, are highly desirable. Dendritic cells (DC) are widely used as immune adjuvants for cancer. Before their administration, DC are generally induced to mature with a cocktail of recombinant cytokines [interleukin (IL)-1beta, tumor necrosis factor alpha, and IL-6] and prostaglandin E(2) (PGE(2)), which is added to preserve the ability of DC to migrate to draining lymph nodes. However, PGE(2) suppresses the production of IL-12p70, a cytokine essential for differentiation of T(H)1 responses. In this study, human DC were transfected with IL-12p70 mRNA and tested for their ability to alter the T(H)2 type bias manifested by blood T cells of patients with melanoma. Transfected DC secreted high levels of bioactive IL-12p70, as indicated by their capacity to enhance natural killer cell activity, skew T(H)1 responses in allogeneic mixed lymphocyte reactions through reduction of IL-4 and IL-5, and prime CD8(+) T cells to the melanoma-associated antigen Melan A/MART-1. Furthermore, T-cell lines primed in vitro from the blood of melanoma patients showed strong type 2 skewing that was dramatically reversed by IL-12p70 transfection of autologous DC. Thus, IL-12p70 transfection of clinical DC preparations may enhance type 1 antitumor responses and may thereby contribute to effective immune-based therapy
— id: 90929, year: 2008, vol: 68, page: 9441, stat: Journal Article,

Shedding of distinct cryptic collagen epitope (HU177) in sera of melanoma patients
Ng, Bruce; Zakrzewski, Jan; Warycha, Melanie; Christos, Paul J; Bajorin, Dean F; Shapiro, Richard L; Berman, Russell S; Pavlick, Anna C; Polsky, David; Mazumdar, Madhu; Montgomery, Anthony; Liebes, Leonard; Brooks, Peter C; Osman, Iman
2008 Oct 1;14(19):6253-6258, Clinical cancer research
PURPOSE: Extracellular matrix remodeling during tumor growth plays an important role in angiogenesis. Our preclinical data suggest that a newly identified cryptic epitope (HU177) within collagen type IV regulates endothelial and melanoma cell adhesion in vitro and angiogenesis in vivo. In this study, we investigated the clinical relevance of HUI77 shedding in melanoma patient sera. EXPERIMENTAL DESIGN: Serum samples from 291 melanoma patients prospectively enrolled at the New York University Medical Center and 106 control subjects were analyzed for HU177 epitope concentration by a newly developed sandwich ELISA assay. HU177 serum levels were then correlated with clinical and pathologic parameters. RESULTS: Mean HU177 epitope concentration was 5.8 ng/mL (range, 0-139.8 ng/mL). A significant correlation was observed between HU177 concentration and nodular melanoma histologic subtype [nodular, 10.3 +/- 1.6 ng/mL (mean +/- SE); superficial spreading melanoma, 4.5 +/- 1.1 ng/mL; all others, 6.1 +/- 2.1 ng/mL; P = 0.01 by ANOVA test]. Increased HU177 shedding also correlated with tumor thickness (< or =1.00 mm, 3.8 +/- 1.1 ng/mL; 1.01-3.99 mm, 8.7 +/- 1.3 ng/mL; > or =4.00 mm, 10.3 +/- 2.4 ng/mL; P = 0.003 by ANOVA). After multivariate analysis controlling for thickness, the correlation between higher HU177 concentration and nodular subtype remained significant (P = 0.03). The mean HU177 epitope concentration in control subjects was 2.4 ng/mL. CONCLUSIONS: We report that primary melanoma can induce detectable changes in systemic levels of cryptic epitope shedding. Our data also support that nodular melanoma might be biologically distinct compared with superficial spreading type melanoma. As targeted interventions against cryptic collagen epitopes are currently undergoing phase I clinical trial testing, these findings indicate that patients with nodular melanoma may be more susceptible to such targeted therapies
— id: 92160, year: 2008, vol: 14, page: 6253, stat: Journal Article,

Changes in the presentation of nodular and superficial spreading melanomas over 35 years
Warycha, Melanie A; Christos, Paul J; Mazumdar, Madhu; Darvishian, Farbod; Shapiro, Richard L; Berman, Russell S; Pavlick, Anna C; Kopf, Alfred W; Polsky, David; Osman, Iman
2008 Dec 15;113(12):3341-3348, Cancer
BACKGROUND: Nodular melanoma (NM) may be biologically aggressive compared with the more common superficial spreading melanoma (SSM), with recent data suggesting underlying genetic differences between these 2 subtypes. To better define the clinical behavior of NMs, the authors compared their clinical and histopathologic features to those of SSMs at their institution, a tertiary referral center, over 3 decades. METHODS: A total of 1,684 patients diagnosed with 1,734 melanomas were prospectively enrolled. Of these, 1,143 patients (69% SSM, 11% NM, 20% other) were diagnosed between 1972 and 1982; 541 patients (54% SSM, 23% NM, 23% other) were diagnosed between 2002 and the present. Differences between the features of NM and SSM within each time period as well as changes over time were analyzed. RESULTS: The authors found that SSMs are now diagnosed as thinner lesions (P < .0001) with a low incidence of histologic ulceration (P < .0001), whereas there was no significant change in the median tumor thickness or ulceration status of NMs over time (P = .10, P = .30, respectively). The median age at diagnosis of NM, however, did significantly increase over time (51 years to 63 years, P < .01). The median duration of NMs was reported to be only 5 months compared with 9 months in SSM patients. CONCLUSIONS: The authors' data suggest that improvements have been made in the early detection of SSM but not NM. Modifications of current screening practices, including increased surveillance of high-risk patients with an emphasis on the 'E' for 'evolution' criterion of the ABCDE acronym used for early detection of melanoma, are thus warranted
— id: 91976, year: 2008, vol: 113, page: 3341, stat: Journal Article,

Assessing the clinical utility of measuring Insulin-like Growth Factor Binding Proteins in tissues and sera of melanoma patients
Yu, Jessie Z; Warycha, Melanie A; Christos, Paul J; Darvishian, Farbod; Yee, Herman; Kaminio, Hideko; Berman, Russell S; Shapiro, Richard L; Buckley, Michael T; Liebes, Leonard F; Pavlick, Anna C; Polsky, David; Brooks, Peter C; Osman, Iman
2008 ;6:70-70, Journal of translational medicine
BACKGROUND: Different Insulin-like Growth Factor Binding Proteins (IGFBPs) have been investigated as potential biomarkers in several types of tumors. In this study, we examined both IGFBP-3 and -4 levels in tissues and sera of melanoma patients representing different stages of melanoma progression. METHODS: The study cohort consisted of 132 melanoma patients (primary, n = 72; metastatic, n = 60; 64 Male, 68 Female; Median Age = 56) prospectively enrolled in the New York University School of Medicine Interdisciplinary Melanoma Cooperative Group (NYU IMCG) between August 2002 and December 2006. We assessed tumor-expression and circulating sera levels of IGFBP-3 and -4 using immunohistochemistry and ELISA assays. Correlations with clinicopathologic parameters were examined using Wilcoxon rank-sum tests and Spearman-rank correlation coefficients. RESULTS: Median IGFBP-4 tumor expression was significantly greater in primary versus metastatic patients (70% versus 10%, p = 0.01) A trend for greater median IGFBP-3 sera concentration was observed in metastatic versus primary patients (4.9 microg/ml vs. 3.4 microg/ml, respectively, p = 0.09). However, sera levels fell within a normal range for IGFBP-3. Neither IGFBP-3 nor -4 correlated with survival in this subset of patients. CONCLUSION: Decreased IGFBP-4 tumor expression might be a step in the progression from primary to metastatic melanoma. Our data lend support to a recently-described novel tumor suppressor role of secreting IGFBPs in melanoma. However, data do not support the clinical utility of measuring levels of IGFBP-3 and -4 in sera of melanoma patients
— id: 92159, year: 2008, vol: 6, page: 70, stat: Journal Article,

Imiquimod -- a TLR 7 agonist as vaccine adjuvant
Adams S; O'Neill D; Pavlick A; Hardin E; Nonaka D; Chiriboga L; Siu K; Shapiro R; Berman R; Strober B; Cruz C; Angiulli A; Manchez O; Berner N; Mukhi V; Shao Y; Bhardwaj N
2007 ;:- #8545, Proceedings (American Society of Clinical Oncology)
— id: 73377, year: 2007, vol: , page: , stat: Journal Article,

Vaccination with NY-ESO-1 protein and CpG in Montanide induces integrated antibody/Th1 responses and CD8 T cells through cross-priming
Valmori, Danila; Souleimanian, Naira E; Tosello, Valeria; Bhardwaj, Nina; Adams, Sylvia; O'Neill, David; Pavlick, Anna; Escalon, Juliet B; Cruz, Crystal M; Angiulli, Angelica; Angiulli, Francesca; Mears, Gregory; Vogel, Susan M; Pan, Linda; Jungbluth, Achim A; Hoffmann, Eric W; Venhaus, Ralph; Ritter, Gerd; Old, Lloyd J; Ayyoub, Maha
2007 May 22;104(21):8947-8952, Proceedings of the National Academy of Sciences of the United States of America
The use of recombinant tumor antigen proteins is a realistic approach for the development of generic cancer vaccines, but the potential of this type of vaccines to induce specific CD8(+) T cell responses, through in vivo cross-priming, has remained unclear. In this article, we report that repeated vaccination of cancer patients with recombinant NY-ESO-1 protein, Montanide ISA-51, and CpG ODN 7909, a potent stimulator of B cells and T helper type 1 (Th1)-type immunity, resulted in the early induction of specific integrated CD4(+) Th cells and antibody responses in most vaccinated patients, followed by the development of later CD8(+) T cell responses in a fraction of them. The correlation between antibody and T cell responses, together with the ability of vaccine-induced antibodies to promote in vitro cross-presentation of NY-ESO-1 by dendritic cells to vaccine-induced CD8(+) T cells, indicated that elicitation of NY-ESO-1-specific CD8(+) T cell responses by cross-priming in vivo was associated with the induction of adequate levels of specific antibodies. Together, our data provide clear evidence of in vivo cross-priming of specific cytotoxic T lymphocytes by a recombinant tumor antigen vaccine, underline the importance of specific antibody induction for the cross-priming to occur, and support the use of this type of formulation for the further development of efficient cancer vaccines
— id: 72446, year: 2007, vol: 104, page: 8947, stat: Journal Article,

Expression of the cancer/testis antigen NY-ESO-1 in primary and metastatic malignant melanoma (MM)--correlation with prognostic factors
Velazquez, Elsa F; Jungbluth, Achim A; Yancovitz, Molly; Gnjatic, Sacha; Adams, Sylvia; O'Neill, David; Zavilevich, Kira; Albukh, Tatyana; Christos, Paul; Mazumdar, Madhu; Pavlick, Anna; Polsky, David; Shapiro, Richard; Berman, Russell; Spira, Joanna; Busam, Klaus; Osman, Iman; Bhardwaj, Nina
2007 ;7:11-11, Cancer imunity
Cancer/testis (CT) antigens are potential targets for cancer immunotherapy, with NY-ESO-1 being among the most immunogenic. In several clinical trials in malignant melanoma (MM) patients, NY-ESO-1 protein/peptides showed clear evidence of inducing specific immunity. However, little is known about NY-ESO-1 expression in primary and metastatic MM and its relationship to disease progression. We analyzed NY-ESO-1 expression immunohistochemically in a series of primary and metastatic MMs and its relation to prognostic parameters and survival. We studied 61 primary and 63 metastatic MM specimens (from 61 and 56 patients, respectively). The prevalence of NY-ESO-1 expression was significantly higher in metastatic versus primary tumors [18/56 (32%) versus 8/61 (13%), P = 0.015]. There was a significant association between initial stage at presentation and NY-ESO-1 expression [stage I (3.45%), stage II (9.52%) and stage III (45.45%), P = 0.0014]. Primary MMs expressing NY-ESO-1 were significantly thicker than NY-ESO-1 negative cases (median thickness 4.7 mm versus 1.53 mm respectively, P = 0.03). No significant difference was seen in overall survival. In conclusion, NY-ESO-1 is more frequently expressed in metastatic than in primary MM and its expression is associated with thicker primary lesions and a higher frequency of metastatic disease, indicative of a worse prognosis. Our study suggests that patients with metastatic MM who express NY-ESO-1 may benefit from NY-ESO-1-based immunotherapy
— id: 73347, year: 2007, vol: 7, page: 11, stat: Journal Article,

Clinical relevance of neutral endopeptidase (NEP/CD10) in melanoma
Velazquez, Elsa F; Yancovitz, Molly; Pavlick, Anna; Berman, Russell; Shapiro, Richard; Bogunovic, Dusan; O'Neill, David; Yu, Yi-Lo; Spira, Joanna; Christos, Paul J; Zhou, Xi Kathy; Mazumdar, Madhu; Nanus, David M; Liebes, Leonard; Bhardwaj, Nina; Polsky, David; Osman, Iman
2007 ;5:2-2, Journal of translational medicine
BACKGROUND: Overexpression of Neutral Endopeptidase (NEP) has been reported in metastatic carcinomas, implicating NEP in tumor progression and suggesting a role for NEP inhibitors in its treatment. We investigated the role of NEP expression in the clinical progression of cutaneous melanoma. METHODS: We screened 7 melanoma cell lines for NEP protein expression. NEP-specific siRNA was transfected into the lines to examine the role of gene transcription in NEP expression. Immunohistochemistry was done for 93 specimens and correlated with clinicopathologic parameters. Thirty-seven metastatic melanoma specimens were examined for NEP transcript expression using Affymetrix GeneChips. In a subset of 25 specimens for which both transcript and protein expression was available, expression ratios were used to identify genes that co-express with NEP in GeneChip analysis. RESULTS: NEP was overexpressed in 4/7 human melanoma cell lines, and siRNA knock-down of NEP transcripts led to downregulation of its protein expression. NEP protein overexpression was significantly more common in metastatic versus primary tumors (P = 0.002). Twelve of 37 (32%) metastatic tumors had increased NEP transcript expression, and an association was observed between NEP transcript upregulation and protein overexpression (P < 0.0001). Thirty-eight genes were found to significantly co-express with NEP (p < 0.005). Thirty-three genes positively correlated with NEP, including genes involved in the MAP kinase pathway, antigen processing and presentation, apoptosis, and WNT signaling pathway, and 5 genes negatively correlated with NEP, including genes of focal adhesion and the notch signaling pathways. CONCLUSION: NEP overexpression, which seems to be largely driven by increased transcription, is rare in primary melanoma and occurs late in melanoma progression. Functional studies are needed to better understand the mechanisms of NEP regulation in melanoma
— id: 74679, year: 2007, vol: 5, page: 2, stat: Journal Article,

Role of radiologic imaging at the time of initial diagnosis of stage T1b-T3b melanoma
Yancovitz, Molly; Finelt, Nika; Warycha, Melanie A; Christos, Paul J; Mazumdar, Madhu; Shapiro, Richard L; Pavlick, Anna C; Osman, Iman; Polsky, David; Berman, Russell S
2007 Sep 1;110(5):1107-1114, Cancer
BACKGROUND: In patients with T1b-T3b cutaneous melanoma the utility of radiologic imaging at the time of diagnosis is unclear. Whether initial imaging led to a change in stage or treatment plan was investigated. METHODS: The melanoma database was searched for patients with T1b-T3b primary lesions, clinically N0, and asymptomatic for metastatic disease. Radiologic studies conducted before wide local excision +/- sentinel lymph node biopsy as well as all further imaging and investigations were analyzed. Outcome measures included upstaging, change in initial surgical management, true-positive, false-positive, true-negative, and false-negative rates of each imaging modality. RESULTS: In all, 344 preoperative imaging studies (chest x-ray [CXR], computed tomography [CT], positron emission tomography [PET]/CT) were performed on 158 patients, resulting in 49 findings suspicious for metastatic melanoma and 134 findings suggestive of nonmelanoma pathology. Only 1 of 344 (0.3%) studies, a PET/CT, correlated with confirmed metastatic melanoma. The false-positive rates were CXR 5 of 7 (71.4%), chest CT 21 of 24 (87.5%), abdomen/pelvis CT 10 of 11 (90.9%), head CT 2 of 2 (100.0%), PET/CT 3 of 5 (60.0%). No patient was upstaged or had a change in initial surgical management based on preoperative imaging. The cost of all initial imaging and imaging to follow-up abnormal findings was estimated as $555,308 for the 158 patients studied. CONCLUSIONS: Imaging at the time of initial diagnosis of T1b-T3b, clinically N0, M0 melanoma was of low yield with a high false-positive rate, and did not lead to upstaging or change in initial surgical management. These findings suggest that imaging of asymptomatic patients at the time of diagnosis may not be warranted
— id: 74405, year: 2007, vol: 110, page: 1107, stat: Journal Article,

Detection of mutant BRAF alleles in the plasma of patients with metastatic melanoma
Yancovitz, Molly; Yoon, Joanne; Mikhail, Maryann; Gai, Weiming; Shapiro, Richard L; Berman, Russell S; Pavlick, Anna C; Chapman, Paul B; Osman, Iman; Polsky, David
2007 Apr;9(2):178-183, Journal of molecular diagnostics
Mutations in the BRAF oncogene at amino acid 600 have been reported in 40 to 70% of human metastatic melanoma tissues, and the critical role of BRAF in the biology of melanoma has been established. Sampling the blood compartment to detect the mutational status of a solid tumor represents a highly innovative advance in cancer medicine, and such an approach could have advantages over tissue-based techniques. We report the development of a fluorescence-based polymerase chain reaction (PCR) assay to detect mutant BRAF alleles in plasma. A mutant-specific PCR assay was optimized to specifically amplify the mutant BRAF allele without amplifying the wild-type allele. Experiments mixing DNA from a BRAF mutant melanoma cell line with wild-type human placental DNA in varying proportions were performed to determine the threshold of this assay and to compare it with routine DNA sequencing. The assay was then applied to tissue and plasma specimens from patients with metastatic melanoma. The assay detected 0.1 ng of mutant DNA mixed in 100 ng of wild-type DNA and was 500-fold more sensitive than DNA sequencing. The assay detected mutant BRAF alleles in plasma samples from 14 of 26 (54%) metastatic melanoma patients. These data demonstrate the feasibility of blood-based testing for BRAF mutations in metastatic melanoma patients
— id: 71931, year: 2007, vol: 9, page: 178, stat: Journal Article,

Bcl-2 antisense (oblimersen sodium) plus dacarbazine in patients with advanced melanoma: the Oblimersen Melanoma Study Group
Bedikian, Agop Y; Millward, Michael; Pehamberger, Hubert; Conry, Robert; Gore, Martin; Trefzer, Uwe; Pavlick, Anna C; DeConti, Ronald; Hersh, Evan M; Hersey, Peter; Kirkwood, John M; Haluska, Frank G
2006 Oct 10;24(29):4738-4745, Journal of clinical oncology
PURPOSE: Chemotherapy resistance in melanoma has been linked to antiapoptotic effects mediated by Bcl-2 protein. We evaluated whether targeting Bcl-2 using an antisense oligonucleotide (oblimersen sodium) could improve the efficacy of systemic chemotherapy in patients with advanced melanoma. PATIENTS AND METHODS: We randomly assigned chemotherapy-naive patients with advanced melanoma to treatment with dacarbazine (1,000 mg/m2) alone or preceded by a 5-day continuous intravenous infusion of oblimersen sodium (7 mg/kg/d) every 3 weeks for up to eight cycles. Patients were stratified by Eastern Cooperative Oncology Group performance status, liver metastases, disease site, and serum lactate dehydrogenase (LDH). The primary efficacy end point was overall survival. RESULTS: Among 771 patients randomly assigned, the addition of oblimersen to dacarbazine yielded a trend toward improved survival at 24-month minimum follow-up (median, 9.0 v 7.8 months; P = .077) and significant increases in progression-free survival (median, 2.6 v 1.6 months; P < .001), overall response (13.5% v 7.5%; P = .007), complete response (2.8% v 0.8%), and durable response (7.3% v 3.6%; P = .03). A significant interaction between baseline serum LDH and treatment was observed; oblimersen significantly increased survival in patients whose baseline serum LDH was not elevated (median overall survival, 11.4 v 9.7 months; P = .02). Neutropenia and thrombocytopenia were increased in the oblimersen-dacarbazine group; however, there was no increase in serious infections or bleeding events. CONCLUSION: The addition of oblimersen to dacarbazine significantly improved multiple clinical outcomes in patients with advanced melanoma and increased overall survival in patients without an elevated baseline serum LDH
— id: 97005, year: 2006, vol: 24, page: 4738, stat: Journal Article,

Docetaxel more active than paclitaxel as second-line therapy for metastatic breast cancer
Chen A.L.; Pavlick A.
2006 ;6(1-2):99-100, Women's oncology review
— id: 74217, year: 2006, vol: 6, page: 99, stat: Journal Article,

Expression of cancer testis (CT) antigen NY-ESO-1 in primary and metastatic malignant melanoma (MM), correlation with prognostic factors and potential role in a melanoma vaccine
Velazquez, EF; Jungbluth, AA; Osman, I; Yancovitz, M; Adams, S; O'Neill, D; Zavilevich, K; Albukh, T; Pavlick, A; Polsky, D; Shapiro, R; Berman, R; Spira, J; Busam, K; Bhardwaj, N
2006 JAN ;19(4):89A-89A, Modern pathology
— id: 61434, year: 2006, vol: 19, page: 89A, stat: Journal Article,

Expression of cancer testis (CT) antigen NY-ESO-1 in primary and metastatic malignant melanoma (MM), correlation with prognostic factors and potential role in a melanoma vaccine
Velazquez, EF; Jungbluth, AA; Osman, I; Yancovitz, M; Adams, S; O'Neill, D; Zavilevich, K; Albukh, T; Pavlick, A; Polsky, D; Shapiro, R; Berman, R; Spira, J; Busam, K; Bhardwaj, N
2006 JAN ;86(4):89A-89A, Laboratory investigation
— id: 62615, year: 2006, vol: 86, page: 89A, stat: Journal Article,

Neutral endopeptidase (NEP) overexpression is associated with progression in malignant melanoma (MM) and is a potential target of treatment
Velazquez, EF; Yancovitz, M; Sorhaindo, L; Bogunovic, D; O'Neill, D; Shapiro, R; Pavlick, A; Berman, R; Bhardwaj, N; Spira, J; Christos, P; Nanus, D; Polsky, D; Osman, I
2006 JAN ;19(4):89A-89A, Modern pathology
— id: 61435, year: 2006, vol: 19, page: 89A, stat: Journal Article,

Neutral endopeptidase (NEP) overexpression is associated with progression in malignant melanoma (MM)and is a potential target of treatment
Velazquez, EF; Yancovitz, M; Sorhaindo, L; Bogunovic, D; O'Neill, D; Shapiro, R; Pavlick, A; Berman, R; Bhardwaj, N; Spira, J; Christos, P; Nanus, D; Polsky, D; Osman, I
2006 JAN ;86(4):89A-89A, Laboratory investigation
— id: 62616, year: 2006, vol: 86, page: 89A, stat: Journal Article,

Clinical relevance of neutral endopeptidase overexpression in melanoma
Yancovitz, M; Velazquez, E; Christos, P; Pavlick, A; Berman, R; Shapiro, R; Bhardwaj, N; Nanus, D; Polsky, D; Osman, I
2006 JUN 20 ;24(18):459S-459S, Journal of clinical oncology
— id: 69301, year: 2006, vol: 24, page: 459S, stat: Journal Article,

Spontaneous immune reponses to melanoma-associated antigens in melanoma, vitiligo and healthy controls
Adams S; Lowes M; Pavlick A; Schachterle S; O'Neill D; Bhardwaj N
2005 ;23:16S-16S abstact #9682, Proceedings (American Society of Clinical Oncology)
— id: 60240, year: 2005, vol: 23, page: 16S, stat: Journal Article,

Non-Hodgkin's lymphoma presenting as a breast mass in patients with HIV infection: a report of three cases
Chanan-Khan, Asher; Holkova, Beata; Goldenberg, Alec S; Pavlick, Anna; Demopoulos, Rita; Takeshita, Kenichi
2005 Aug;46(8):1189-1193, Leukemia & lymphoma
Breast involvement with non-Hodgkin's lymphoma (NHL) is rare. Patients with AIDS have an increased incidence of NHL, often with high-grade histology, extranodal presentation and aggressive clinical course. Lymphoma of the breast in patients with HIV-1 infection has not been reported. We reviewed our tumor registry database of all AIDS-associated NHL and report on the clinical presentation and long-term outcome of 3 patients with AIDS who presented with lymphomatous involvement of the breast
— id: 76326, year: 2005, vol: 46, page: 1189, stat: Journal Article,

Proteasome inhibition with bortezomib (PS-341): a phase I study with pharmacodynamic end points using a day 1 and day 4 schedule in a 14-day cycle
Hamilton, A L; Eder, J P; Pavlick, A C; Clark, J W; Liebes, L; Garcia-Carbonero, R; Chachoua, A; Ryan, D P; Soma, V; Farrell, K; Kinchla, N; Boyden, J; Yee, H; Zeleniuch-Jacquotte, A; Wright, J; Elliott, P; Adams, J; Muggia, F M
2005 Sep 1;23(25):6107-6116, Journal of clinical oncology
PURPOSE: We performed a phase I study of a day (D) 1 and D4 bortezomib administration once every 2 weeks to determine the recommended phase II dose and toxicity profile, and the extent of 20S proteasome inhibition obtained. PATIENTS AND METHODS: Patients with solid tumors or lymphomas were treated with bortezomib at 0.25 to 1.9 mg/m2 on D1 and D4, every 2 weeks. 20S proteasome levels in blood were assayed at baseline and at 1, 4, and 24 hours postdose in cycle 1. RESULTS: On this D1 and D4 every 2 weeks' schedule, dose-limiting toxicity (DLT) was evident at the 1.75 and 1.9 mg/m2 dose levels, most commonly in patients receiving individual total doses > or = 3.0 mg. The main DLT was peripheral neuropathy evident at the higher doses and in patients previously exposed to neurotoxic agents. Other DLTs included diarrhea and fatigue; grade 3 thrombocytopenia was also noted. Reversible inhibition of 20S proteasome activity was dose dependent and best fit a total dose (mg) per fraction rather than mg/m2; 70% of baseline activity was inhibited by a dose of 3.0 to 3.5 mg given on D1 and on D4 every other week. Antitumor effects short of confirmed partial responses were observed in patients with melanoma, non-small-cell lung cancer, and renal cell carcinoma. CONCLUSION: Bortezomib (PS-341) is a novel antineoplastic agent that is well tolerated at doses not exceeding 3.0 mg (equivalent to 1.75 mg/m2), repeated on D1 and D4 every other week. This dose correlates with 70% inhibition of 20S proteasome activity. DLTs include neuropathy, fatigue, and diarrhea
— id: 57888, year: 2005, vol: 23, page: 6107, stat: Journal Article,

Whole body positron emission tomography/computed tomography staging of metastatic choroidal melanoma
Kurli, Madhavi; Reddy, Shantan; Tena, Lawrence B; Pavlick, Anna C; Finger, Paul T
2005 Aug;140(2):193-199, American journal of ophthalmology
PURPOSE: To evaluate whole-body positron emission tomography (PET)/computed tomography in staging of patients with metastatic choroidal melanoma. DESIGN: Interventional non-randomized clinical study. METHODS: Twenty patients were referred for whole-body 18-fluoro-2-deoxy-D-glucose (FDG) PET/computed tomography imaging because of suspected metastatic choroidal melanoma. PET/computed tomography images were studied for the presence and distribution of metastatic melanoma. Subsequent biopsies were performed to confirm the presence of metastatic disease. RESULTS: Twenty patients underwent PET/computed tomography. Eighteen were imaged because of abnormal clinical, hematologic, or radiographic screening studies during the course of their follow-up after plaque brachytherapy or enucleation. Two were imaged before treatment of their primary tumor. PET/computed tomography revealed or confirmed metastatic melanoma in eight (40%) of these 20 patients. The mean time from initial diagnosis to metastasis was 47 months (range 0 to 154). The most common sites for metastases were the liver (100%), bone (50%), lung (25%), lymph nodes (25%), and subcutaneous tissue (25%). Cardiac, brain, thyroid, and posterior abdominal wall lesions (12.5%) were also noted. Six patients (75%) had multiple organ involvement. No false positives were noted. PET/computed tomography imaging also detected benign lesions of the bone and lymph nodes in three patients (15%). All patients had hepatic metastases and liver enzyme assays were abnormal in only one (12.5%) of eight patients. CONCLUSIONS: PET/computed tomography imaging is a sensitive tool for the detection and localization of hepatic and extra-hepatic (particularly osseous) metastatic choroidal melanoma
— id: 62889, year: 2005, vol: 140, page: 193, stat: Journal Article,

PTEN expression in melanoma: relationship with patient survival, Bcl-2 expression, and proliferation
Mikhail, Maryann; Velazquez, Elsa; Shapiro, Richard; Berman, Russell; Pavlick, Anna; Sorhaindo, Lian; Spira, Joanna; Mir, Carmen; Panageas, Katherine S; Polsky, David; Osman, Iman
2005 Jul 15;11(14):5153-5157, Clinical cancer research
PURPOSE: Inactivation of the tumor suppressor gene, phosphatase and tensin homologue (PTEN), is a major alteration in preclinical melanoma models. We investigated the clinical relevance of PTEN expression in the primary melanoma patients with extended follow-up. EXPERIMENTAL DESIGN: We correlated PTEN expression with clinicopathologic variables and outcome in 127 primary melanomas (median follow-up, 12.8 years). We evaluated the associations between PTEN expression and proliferation and resistance to apoptosis (assessed by Ki-67 and Bcl-2, respectively). We also examined the effect of a favorable phenotype, defined as retained PTEN, low proliferative index, and low expression of Bcl-2 on disease-free survival and overall survival. RESULTS: Altered PTEN, Bcl-2, and Ki-67 expressions were observed in 55 of 127 (43.3%), 61 of 127 (48%), and 43 of 114 (37.7%) of cases, respectively. Decreased PTEN expression correlated significantly with the ulceration (P = 0.01). Rates of disease-free survival and overall survival in patients with favorable phenotype were 72% and 74% at 5 years versus 64% and 64% in patients with an unfavorable phenotype. At 10 years, the rates of disease-free survival and overall survival were 72% and 68% for patients with a favorable phenotype but declined to 60% and 55% in patients with an unfavorable phenotype. However, relationships between both PTEN and Bcl2 and patient survival were not significant as well as the associations between PTEN and Bcl-2 or Ki-67. CONCLUSIONS: Our data suggest that altered PTEN expression is common in primary melanomas and is associated with aggressive tumor behavior. However, PTEN alone provided limited prognostic value. Our findings show the need to examine molecular alterations identified in preclinical studies using an adequately large cohort of patients with extended follow-up to better assess the magnitude of their clinical relevance
— id: 57826, year: 2005, vol: 11, page: 5153, stat: Journal Article,

Whole body PET/CT imaging for detection of metastatic choroidal melanoma
Finger, P T; Kurli, M; Wesley, P; Tena, L; Kerr, K R; Pavlick, A
2004 Aug;88(8):1095-1097, British journal of ophthalmology
— id: 44833, year: 2004, vol: 88, page: 1095, stat: Journal Article,

Randomized multinational phase 3 trial of dacarbazine (DTIC) with or without Bcl-2 antisense (oblimersen sodium) in patients (pts) with advanced malignant melanoma (MM): Analysis of long-term survival
Millward, MJ; Bedikian, AY; Conry, RM; Gore, ME; Pehamberger, HE; Sterry, W; Pavlick, AC; De Conti, RC; Gordon, D; Itri, LM
2004 JUL 15 ;22(14):711S-711S, Journal of clinical oncology
— id: 48689, year: 2004, vol: 22, page: 711S, stat: Journal Article,

A phase I and pharmacokinetic study of docetaxel combined with Doxil (pegylated liposomal doxorubicin) without and with granulocyte colony stimulating factor
Pavlick, Anna C; Chodkiewicz, Catherine; Liebes, Leonard; Hamilton, Anne; Wasserheit, Carolyn; Hochster, Howard; Speyer, James; Phillips, Zoe; Downey, Andrea; Sorich, Joan; Muggia, Franco
2004 Feb;15(2):119-125, Anti-cancer drugs
The purpose of this study was (i) to determine the maximum tolerated dose (MTD) of docetaxel that can be administered in combination with Doxil, given without and with granulocyte colony stimulating factor (G-CSF), (ii) to define the pharmacokinetics (PK) of docetaxel when used in combination with Doxil, and (iii) to make preliminary observations on the anti-tumor activity of this combination in patients with metastatic solid tumors. Thirty-seven patients with metastatic cancer were enrolled. Courses were repeated every 3 weeks. Patients received a fixed dose of Doxil 30 mg/m(2) in combination with escalating doses of docetaxel ranging from 40 to 100 mg/m(2). After encountering dose-limiting febrile neutropenia, subsequent escalation was accomplished with G-CSF support. Selected patients at the recommended phase II dose underwent PK evaluation. The most common toxicity observed was neutropenia. Dose-limiting toxicity (30 mg/m(2) Doxil + 80 mg/m(2) docetaxel) was febrile neutropenia in three of six patients treated without G-CSF. Major non-hematological toxicities included alopecia, mucositis and hand-foot syndrome, and were observed after cumulative doses of chemotherapy. Objective responses (complete/partial) were documented in eight of 37 patients (four with breast cancer) and stable disease was seen in 17 patients. PK studies showed an increased tissue retention (decreased clearance) of docetaxel when given with Doxil. The recommended phase II dose of Doxil/docetaxel is 30/60 mg/m(2), q3 weeks, without G-CSF. Further dose escalation to 30/80 mg/m(2) is safe with G-CSF support. Anti-tumor activity, particularly against breast cancer, was observed at various dose levels. Our observations should provide evidence for phase II studies of this combination in patients with breast cancer and other anthracycline/taxane-sensitive cancers
— id: 44738, year: 2004, vol: 15, page: 119, stat: Journal Article,

Phase I study of amifostine as a cytoprotector of the gemcitabine/cisplatin combination in patients with advanced solid malignancies
Haigentz, Missak Jr; Kim, Mimi; Sorich, Joan; Lee, Janet; Hochster, Howard; Macapinlac, Manuel; Mirchandani, Deepu; Sewak, Sanjeev; Pavlick, Anna; Volm, Matthew; Hamilton, Anne; Muggia, Franco M
2003 Apr;14(4):321-326, Anti-cancer drugs
Our objective was to evaluate the role of amifostine as a cytoprotector in patients with solid tumors receiving the myelosuppressive regimen of gemcitabine/cisplatin combination. Patients with advanced solid tumors were randomized to gemcitabine-amifostine-cisplatin (GAP) or gemcitabine-cisplatin (GP) in Cycle 1 (C1) and then were crossed over to the other treatment in Cycle 2 (C2). Amifostine at 740 mg/m2, followed by gemcitabine and cisplatin, were given for 2 consecutive weeks, every 4 weeks. Two GP combinations were studied: G 1000 mg/m2 and P 40 mg/m2 days 1, 8 (high dose), and G 800 mg/m2 and P 30 mg/m2 days 1, 8 (low dose). Forty patients were enrolled. Of the 19 patients treated with high-dose GP, 11 (nine patients GP in C1 and GAP in C2, two patients GAP in C1 and GP in C2) completed 2 cycles of therapy. Of the eight non-evaluable patients, five patients dropped out due to toxicity or refusal after treatment with amifostine in C1. Of the 21 patients treated with low-dose GP, 15 (eight patients GP in C1 and GAP in C2, seven patients GAP in C1 and GP in C2) were likewise evaluable. The incidence of grade 3 or 4 hematologic toxicities was similar for GP and GAP during the first 2 cycles of treatment, and there were no statistically significant differences in mean absolute neutrophil count, hemoglobin level and platelet levels between the cycles in each arm. We conclude that amifostine, at 740 mg/m2, does not lead to less myelosuppression when combined with gemcitabine/cisplatin chemotherapy regimens and may possibly contribute to subjective intolerance
— id: 44744, year: 2003, vol: 14, page: 321, stat: Journal Article,

Pegylated liposomal doxorubicin (PLD) and carboplatin (C): A phase I study of combination therapy with maintenance PLD
Hamilton AL; Pavlick A; Volm M; Adams S; Hochster H; Moore S; Mozina J; Cordner M; Utate M; Muggia F
2003 ;22:2003-2003 #1986, Proceedings (American Society of Clinical Oncology)
Anthracyclines and platinums have activity in GYN, lung, breast and upper GI tumors, lymphomas and sarcomas. C and PLD (Doxil, Caelyx) have non-overlapping toxicity profiles: C produces myelosuppression, nausea and peripheral neuropathy while PLD causes schedule-dependent mucocutaneous toxicity. This study aimed to define the RPTD of the two agents in combination. Design: Patients (pt) received C and PLD on D1 of a 21 day schedule. 5 dose levels (DL) were studied (C AUC / PLD mg/m2): DL1: 4/20; DL2: 4/25; DL3: 4/30; DL4: 5/30; DL5: 6/30. DLT were febrile neutropenia, G4 heme or G3 non-heme toxicity other than hypersensitivity (HSR). Pt with heme toxicity could omit C in later cycles and continue PLD until disease progression. Pt with mucocutaneous toxicity extended the PLD dosing interval to 28 days. Results: 20 pt were treated: 7M/13F. Age: med 58.5, range 36-85. Tumors: ovarian (EOC)(7), MMT (2), endometrial (1), cervix (2), H&N (3), NPC (2), leiomyosarc (1), breast (1), islet cell (1). Prior chemo: 13. Pt received a median of 4 cycles of C/PLD (range 1-8) and 8 pt received maintenance PLD after cessation of C. No DLT occurred at any DL. At DL5 (n=6 eval), C1 toxicities were G1-2 ANC/Hb (4), G2 vaginal mucositis (1), G2 HSR (1), G1-2 nausea/vom (2), G2 fatigue (1), G2 hand-foot syndrome (1), G1 diarrhea (1). No cardiac events were observed. RECIST responses were observed in 4 pts (MMT 2, NPC 1, EOC 1). In pt with EOC, Ca125 responses were seen in 4/4 evaluable pt. Conclusions: C and PLD can be safely administered together at full dose, and maintenance PLD is feasible. This combination warrants phase III evaluation in ovarian cancer and may be a useful regimen in other solid tumors. Supported by M01 RR00096 and the Lynne Cohen Foundation for Ovarian Cancer Research
— id: 79467, year: 2003, vol: 22, page: 2003, stat: Journal Article,

Treatment of sarcomas: thinking out-of-the-box
Muggia, Franco M; Pavlick, Anna
2003 Apr;21(2):321-322, Cancer investigation
— id: 44824, year: 2003, vol: 21, page: 321, stat: Journal Article,

Novel therapeutic agents under investigation for malignant melanoma
Pavlick, Anna C; Adams, Sylvia; Fink, Matthew A; Bailes, Amanda
2003 Sep;12(9):1545-1558, Expert opinion on investigational drugs
Malignant melanoma presents a therapeutic challenge. Patients at high risk for recurrence (stage III) are eligible for adjuvant treatment with IFN-alpha or may enrol in a clinical trial. Both options offer no meaningful survival advantage. Patients with metastatic disease (stage IV) have a 5-year survival of < 10% and have no effective treatment options. Despite aggressive investigations into vaccine therapy, no vaccine has yet received FDA approval. Biological therapies with IFN-alpha and IL-2 have demonstrated a real but minimal effect. Chemotherapeutic options are even more dismal. Single-agent chemotherapy yields a 15-20% response rate of short lived duration. Combination chemotherapy alone or with immunological adjuvants yields response rates of 35-45% but with significant toxicity and no significant improvement in survival. Novel treatment agents that target metabolic pathways, angiogenesis inhibitors, antisense therapies, gene therapies and innovative vaccines may offer hope for an otherwise grave disease
— id: 44834, year: 2003, vol: 12, page: 1545, stat: Journal Article,

Ewing sarcoma in an octogenarian : a case report
Levine, Richard G; Bono, Christopher M; Hameed, Meera; Blacksin, Marcia; Pavlick, Anna C; Cathcart, Charles; Benevenia, Joseph
2002 Mar;84-A(3):445-448, Journal of bone & joint surgery (American volume)
— id: 25942, year: 2002, vol: 84-A, page: 445, stat: Journal Article,

Chemotherapy approaches to melanoma
Pavlick, Anna C
2002 Oct;20(4):709-712, Dermatologic clinics
Melanoma, if detected early, is a curable malignancy. Unfortunately, however, many melanomas are detected at the stage that puts patients at a high risk of recurrence, if they are not already metastatic. New techniques are being developed to try to detect subclinical disease and allow for early intervention with adjuvant treatment. Because the incidence of melanoma is on the rise, there is a greater demand to improve the current therapy. Revision of the American Joint Committee on Cancer staging system has enabled patients to be stratified better into risk groups, which in turn dictates treatment recommendations. As evidenced by the data provided, the current chemotherapeutic options for metastatic melanoma are far from optimal. Clearly, in this malignancy, enrollment into a clinical trial is an excellent option for patients. The development of novel approaches to treating this disease provide hope for better management and possible cure of a notoriously aggressive disease with a dismal prognosis
— id: 39393, year: 2002, vol: 20, page: 709, stat: Journal Article,

Phase I/II trial of accutane as a potentiator of carboplatin and paclitaxel in squamous cell carcinomas
Wieder, Robert; Pavlick, Anna C; Bryan, Margarette; Hameed, Meera; Baredes, Soly; Pliner, Lillian; Saunders, Tracie; Korah, Reju
2002 Oct;25(5):447-450, American journal of clinical oncology
This study investigated the toxicity and efficacy of a 13-cis retinoic acid, carboplatin, and paclitaxel (Taxol) regimen in 18 patients with recurrent or metastatic squamous cell carcinomas (12 head and neck, 4 cervix, 1 esophagus, and 1 anus). Three patients were treated at each dose level with fenretamide (Accutane) 1 mg/kg/d orally for 14 days, carboplatin AUC of 5 mg/ml.min intravenously (IV) and paclitaxel at a dose of 135, 155, 175, 195, 205, or 225 mg/m(2) IV on day 8 every 4 weeks for 6 cycles. Fifteen evaluable patients had a total of 72 treatment cycles. There were 21 grade III or IV toxicities distributed among all the dose levels, including neutropenia, anemia, thrombocytopenia, elevated prothrombin time/partial thromboplastin time, elevated alkaline phosphatase, weight loss, alopecia, and three deaths from aspiration pneumonia and septic shock. The maximum tolerated dosage included 205 mg/m(2) paclitaxel. There was one complete response, three partial responses, and 2 stable diseases. The three partial responses were in the four patients with cervical cancer. Responses did not correlate with expression of retinoic acid receptor subtypes. Toxicity profiles and overall response rates were comparable to prior studies with similar chemotherapy regimens alone. The data support further study in a phase II trial
— id: 44835, year: 2002, vol: 25, page: 447, stat: Journal Article,

[Commentary on] Weekly docetaxel in the treatment of elderly patients with advanced breast cancer: a Minnie Pearl Cancer Center Research Network phase II trial
Pavlick AC
2001 ;1(4):391-2 Dec, Women's oncology review
— id: 57681, year: 2001, vol: 1, page: 391, stat: Journal Article,

Proteasome inhibition by PS-341: A phase I study
Hamilton, A; Eder, JP; Pavlick, A; Clark, JW; Chachoua, A; Ryan, DP; Farrell, K; Wasserstrom, H; Liebes, L; Wright, J; Elliott, P; Adams, J; Muggia, F
2000 NOV ;6(6):4549S-4549S, Clinical cancer research
— id: 54445, year: 2000, vol: 6, page: 4549S, stat: Journal Article,

Immunoproliferative small intestinal disease: case report and literature review
Trotman BW; Pavlick AC; Igwegbe IC; Goldstein MM
1999 ;10(4):88-93, Journal of the Association for Academic Minority Physicians
Immunoproliferative small intestinal disease (IPSID) is a subtype of lymphoma of mucosa-associated lymphoid tissue. Notable for a high production of alpha-heavy chains, it is designated alpha-heavy-chain disease. IPSID is a debilitating disease that has a predilection for impoverished populations of developing countries. It has been documented primarily in subjects of Middle Eastern countries and thus was previously referred to as Mediterranean lymphoma. We report the case of a 42-year-old man from Senegal who presented with chronic diarrhea, dehydration, and weight loss. The endoscopic, pathologic, and serologic findings before, during, and after treatment with fludarabine phosphate are presented. We review the literature concerning current concepts on the etiology, pathogenesis, and management of IPSID
— id: 25943, year: 1999, vol: 10, page: 88, stat: Journal Article,

Endoscopic ultrasound in the evaluation of gastric small lymphocytic mucosa-associated lymphoid tumors
Pavlick AC; Gerdes H; Portlock CS
1997 May;15(5):1761-1766, Journal of clinical oncology
PURPOSE: Low-grade, small lymphocytic lymphomas of the mucosa-associated lymphoid tissue (MALT) have recently been shown to be associated with Helicobacter pylori infections. Regression of these tumors has been reported with antibiotic therapy. Here we evaluate endoscopic ultrasound (EUS) as on objective method to evaluate pretreatment disease and posttherapy response. MATERIALS AND METHODS: We retrospectively reviewed 20 patients initially diagnosed elsewhere with MALT lymphoma. All patients had their initial endoscopic biopsies (EGDs) reviewed at Memorial Sloan-Kettering Cancer Center (MSKCC). All patients had EUS performed at the time of consultation and on completion of therapy if treated at our center. Antral biopsies were stained with a modified Steiner preparation to determine infection by H pylori. RESULTS: Gastric low-grade lymphoma was confirmed in 16 of 20 patients; 11 of 16 had previously received antibiotic therapy for biopsy-positive H pylori infection. All gastric lymphomas had an abnormal EUS: eight with discrete tumor masses and eight with gastric wall infiltration (submucosa, n = 4; muscularis propria, n = 3; serosa, n = 1). On completion of lymphoma treatment with chemotherapy, radiotherapy, or surgery, 11 of 16 patients underwent follow-up EUS. Five patients received care elsewhere and did not return for posttreatment EUS. The gastric wall was normal with no evidence of disease on EUS-guided biopsy in eight of 11 patients. The remaining three patients had abnormal gastric walls. One was biopsy-negative and two had residual lymphoma. Four patients were found to have benign lymphoid aggregates in association with H pylori on initial EGD and EUS biopsies. All four patients were previously untreated with antibiotics. EUS showed prominent mucosa, but no significant findings within the gastric wall. CONCLUSION: EUS appears useful to stage objectively and evaluate therapeutic outcome in the management of gastric, low-grade MALT lymphomas. It also helps to distinguish benign lymphoid aggregates from lymphoma associated with H pylori infection. EUS findings may have a significant impact on assessment and therapeutic recommendations
— id: 25537, year: 1997, vol: 15, page: 1761, stat: Journal Article,