bluuebunny/crossref_metadata_2025_split huggingface dataset:
Microscopic tumor burden in sentinel lymph nodes (SLNs) best predicts nonsentinel lymph node (NSLN) involvement in patients with melanoma
Authors: Andtbacka R. H. , Gershenwald J. E. , Prieto V. G. , Johnson M. , Diwan H. , Lee J. E. , Mansfield P. F. , Schacherer C. W. , Ross M. I. 
Published: April 2020

8004 Background: Therapeutic lymph node dissection (TLND) has long been the standard of care for melanoma metastatic to the regional LNs and is commonly used for patients (pts) with microscopic disease identified by SLN biopsy. We and others have demonstrated that additional histologically positive (pos) nodes are identified in 8%-33% of completion LN dissection (CLND) specimens. The purpose of this study was to determine predictors of additional LN involvement in pts. with pos SLNs. Methods: Pts with clinically node-negative melanoma who underwent SLN biopsy at our institution between 1991 and 2003 and had pos SLNs were identified. Patient and primary tumor factors, number of pos SLNs, and extent of microscopic disease within the SLN were evaluated as potential predictors of pos NSLNs. Results: Overall, 359 (16%) of 2,203 pts had a pos SLN. Pos NSLNs were identified in 48 (14%) of the 343 pts with pos SLNs who underwent CLND. On univariate analysis, several markers of SLN microscopic tumor burden, tumor thickness >2mm, age >50 years, and Clark level >III were predictive of additional pos nodes in the TLND specimen. Primary tumor ulceration was not predictive. On multivariable logistic regression analysis, markers of microscopic tumor burden (large SLN met focus, large SLN tumor square area, presence of SLN extracapsular extension, and synchronous subcapsular and intramedullary SLN deposits) were the most powerful independent predictors of pos NSLNs; tumor thickness >2mm also predicted additional disease. A model was established using tumor thickness and SLN tumor burden to identify pts with low, intermediate, or high risk for NSLN involvement (Table). Conclusions: In melanoma pts with ≥1 pos SLN, SLN tumor burden and primary tumor thickness may be useful in identifying a group at low risk for pos NSLNs. This information is valuable in designing clinical trials in which pts may be randomly assigned to TLND versus observation alone after removal of a pos SLN. [Table: see text] No significant financial relationships to disclose.
NCOA3: A molecular prognostic marker for melanoma
Authors: Rangel J. , Torabian S. , Shaikh L. , Nosrati M. , Miller J. R. , Sagebiel R. W. , Kashani-Sabet M. 
Published: April 2020

8007 Background: Nuclear receptor coactivator-3 (NCOA3, also known as AIB1 or SRC-3), a member of the steroid receptor coactivator 1 family, has been shown to be amplified in human breast cancer. We recently identified NCOA3 as differentially expressed in metastatic melanomas by gene expression profiling, suggesting its role as a possible molecular prognostic factor. In this study, we assessed the prognostic significance of NCOA3 expression in a large melanoma patient cohort using tissue micro-arrays (TMAs). Methods: We used a commercially available antibody against NCOA3 to perform immunohistochemical analysis of NCOA3 expression in TMAs containing primary melanoma specimens from 353 patients seen at the UCSF Melanoma Center. Cases included clinicopathologic information (e.g., age, sex, tumor location, tumor thickness, Clark level and ulceration), as well as sentinel lymph node (SLN) status, and information regarding relapse-free (RFS) and disease-specific (DSS) survival. NCOA3 expression was assessed on a 4-point scale (0–3) by an observer blinded to patient outcomes. Results: High NCOA3 expression was significantly predictive of SLN metastasis by univariate logistic regression (p=0.015), and associated with a higher mean positive SLN count (p=0.03, Le test). Kaplan-Meier analysis demonstrated a significant association between increased NCOA3 expression and reduced RFS as well as DSS (p=0.024, and p=0.031 by log-rank test, respectively). Multivariate step-wise logistic regression analysis of 12 factors revealed NCOA3 expression, along with tumor thickness, age, vascular involvement, and Clark level to be independent predictors of SLN status. Multivariate Cox regression analysis showed the independent impact of NCOA3 expression on RFS and DSS with the inclusion of the AJCC factors tumor thickness, ulceration, Clark level, tumor location, patient age and sex. Conclusions: These results reveal NCOA3 to be a novel, independent marker of melanoma outcome, with a significant impact on SLN metastasis, RFS and DSS. No significant financial relationships to disclose.
Phase II trial of sorafenib combined with dacarbazine in metastatic melanoma patients
Authors: Lorigan P. , Corrie P. , Chao D. , Nathan P. , Ahmad T. , Marais R. , Burk K. , Erlandsson F. , Gore M. , Eisen T. 
Published: April 2020

8012 Background: Sorafenib inhibits tumor cell proliferation and angiogenesis through blockade of multiple kinases including Raf, VEGFR-2/-3, and PDGFR-β. In Phase I/II trials, sorafenib was generally well tolerated as a monotherapy or in combination with other agents. A Phase I study in combination with dacarbazine (DTIC) showed encouraging activity, which warranted this Phase II study. Methods: This multi-center, open-label, two-stage (30 patients in Stage 1; 52 in Stage 2), uncontrolled Phase II trial was performed to evaluate the primary endpoints of efficacy (according to RECIST) and tolerability of sorafenib in combination with DTIC in patients with advanced metastatic melanoma. Eligibility criteria included ECOG 0 or 1, life expectancy ≥12 weeks, adequate bone marrow, liver, and renal function. Oral sorafenib 400 mg twice daily (bid) was administered with repeated 3-week cycles of DTIC 1000 mg/m2. Results: At this interim end of Stage 1 analysis, 30 patients with metastatic melanoma had been treated (median age 61 years [range 30–78]; 73.3% male; 96.7% white). Five (16.7%) patients had PR as best response (two confirmed, three currently unconfirmed), 13 (43.3%) had SD, 10 (33.3%) had PD, and two (6.7%) were unevaluable for tumor response. The patients with confirmed PR continue on study drug at 6.4 months. Median progression-free survival for all patients was 3.6 months (range 0.9–6.1 months). The most frequently reported drug-related adverse events (AEs) were dermatologic (rash/desquamation [43%], hand-foot skin reaction [HFS, 33%]); gastrointestinal (constipation [47%], nausea [37%], diarrhea [27%]); constitutional (fatigue [43%]); and blood/bone marrow (neutrophils [40%], platelets [30%]). The most common grade 3/4 drug-related AEs were blood/bone marrow (neutrophils [23%], platelets [17%]), and fatigue (7%), while HFS and hypertension were observed in <5%. Conclusions: Continuous sorafenib 400 mg bid is generally well tolerated and shows promising preliminary anti-tumor activity in combination with DTIC. No toxicities were observed above those expected from either agent alone. Updated results will be presented, including the decision whether to proceed to Stage 2 of the study. [Table: see text]
First and final report of a phase II study of the poly(ADP-ribose) polymerase (PARP) inhibitor, AG014699, in combination with temozolomide (TMZ) in patients with metastatic malignant melanoma (MM)
Authors: Plummer R. , Lorigan P. , Evans J. , Steven N. , Middleton M. , Wilson R. , Snow K. , Dewji R. , Calvert H. 
Published: April 2020

8013 Background: Inhibition of PARP and thus Base Excision Repair has been shown to potentiate the cytotoxicity of DNA damaging agents preclinically. A Phase I study of AG014699 + TMZ reported at ASCO 2005 showed that a full dose of TMZ could be given in the presence of profound PARP inhibition. We report the results of a Phase II study of AG014699 12 mg/m2 and TMZ 200 mg/m2 5x daily q 4 weekly in patients with advanced MM. This Phase II study commenced in March 2005 and completed recruitment in December 2005. Methods: Patients with measurable MM who were chemotherapy naïve, performance status ≤ 2, and had standard blood indices for early trials were recruited. Patients with ocular melanoma or brain metastases were excluded. Treatment was given until progression, with repeat imaging every 2 cycles. A two stage phase II design was used, with the hypothesis to be tested that the response rate to TMZ would be increased to 25%. α and β error rates were set at 0.10. 27 patients were recruited into the first stage with continuation to 40 patients if ≥3 partial responses were observed. Results 40 patients who fulfilled the eligibility criteria were recruited and treated. The required 3 responses were seen at an early stage. More enhancement of TMZ associated myelosuppression by the addition of AG014699 has been observed compared to the phase I study (Grade 4 thrombocytopenia 12% cycles, grade 4 neutropenia 15% to date). There has been one toxic death in cycle 1 (febrile neutropenia), 3 further patients hospitalised with myelosuppression and 12 patients in total requiring dose reduction of TMZ to 150 mg/m2 (1 to 100 mg/m2). All of these patients continued treatment at the reduced dose. Other toxicities have been fatigue and mild nausea. Currently there are 4 confirmed partial responses, 4 prolonged disease stabilisations and 20 patients are too early to evaluate. Conclusions The combination of TMZ and AG014666 shows encouraging activity in MM. Myelosuppression is greater than would be expected with single agent TMZ. PARP expression and activity in blood cells and tumour will be correlated with the mature outcome data from the trial. [Table: see text]
Phase II study of the farnesyltransferase inhibitor R115777 in advanced melanoma: CALGB 500104
Authors: Gajewski T. F. , Niedzwiecki D. , Johnson J. , Linette G. , Bucher C. , Blaskovich M. , Sebti S. , Haluska F. 
Published: April 2020

8014 Background: Ras-based signaling is thought to be critical in the genesis of melanoma. Farneslytransferase (FT) inhibitors (FTIs) have been developed as a pharmacologic strategy to inhibit Ras function. Additional farnesylated proteins are also important for the malignant process, and FTIs inhibit melanoma cell line proliferation in vitro. These considerations motivated the development of a phase II trial of the FTI R115777 in patients with melanoma. Farnesylated proteins are also important for T cell activation. The interest in future combinations of targeted agents and immunotherapeutics in this disease prompted analysis of T cell function ex vivo. Methods: A 3-stage design was pursued with a maximum of 40 patients planned and early stopping if there were no responders in the first 14, or fewer than 2 responders in the first 28 patients. Eligibility included intact organ function, PS≤1, no prior chemotherapy, at most 1 prior immunotherapy, no brain metastases, and presence of at least 2 cutaneous lesions amenable to excisional biopsy. R115777 (300 mg orally) was administered twice per day for 21 days of a 28-day cycle. Patients were evaluated every 2 cycles by RECIST criteria. Blood was obtained pre-treatment and during week 7 for analysis of HDJ-2 farnesylation and for T cell IFN-γ production in response to SEA. In addition, tumor biopsies were performed pre- and post-treatment when feasible to directly measure FT activity. Results: 14 patients were enrolled. 2 patients had grade 3 toxicities, which included myelosuppression, nausea/vomiting, elevated BUN, and anorexia. There were no clinical responses, and only 4 patients went on to a second course of treatment. All analyzed patients showed HDJ-2 gel shift in peripheral blood cells, as well as marked inhibition of FT activity (by 85–98%) in tumor tissue. T cell production of IFN-γ was also suppressed. Conclusions: Despite potent target inhibition, the FTI R115777 showed no evidence for clinical activity as a single agent in this cohort of 14 metastatic melanoma patients. Inhibition of T cell function has implications for future combination therapies and suggests the possibility for FTIs as candidate immunosuppressive agents. New therapeutic approaches for melanoma, or logically selected combination therapies, are needed. [Table: see text]
Race, socioeconomic status and survival difference in cutaneous melanoma patients in California
Authors: Mobasher M. , Zell J. A. , Meyskens F. L. , Anton-Culver H. 
Published: April 2020

8023 Background: Survival data for malignant melanoma patients of various ethnic backgrounds are lacking. Furthermore, the modifying effect of socioeconomic status (SES) on survival in melanoma patients is unknown. This study was performed to analyze survival differences for cutaneous melanoma patients of each major ethnicity, including analysis of the effect of SES on outcomes, using a statewide cancer registry. Methods: A case-only analysis of data from the California Cancer Registry database during 1992–2002 was conducted. The primary outcome measured was overall survival for each ethnic group. Univariate survival analyses were conducted using the Kaplan-Meier method and log-rank test; multivariate survival analyses were performed using Cox proportional hazards ratios. Results: 46,218 incident cases of invasive cutaneous melanoma were identified, including 39,741 Caucasians (93.47%), 2263 (5.32%) Hispanics, 331(0.78%) Asians, 172 (0.40%) African-Americans, and 12 (0.03%) Native Americans (P<0.0001). On univariate survival analysis, improved 10-year overall survival rates were noted for Hispanics (63.2%) and Caucasians (60.9%) compared to Asians (51.1%), African-Americans (39.8%), and Native Americans (30.6%) (P<0.0001). A statistically significant survival difference was observed for melanoma patients based on SES (P<0.0001), favoring those with high SES. Multivariate survival analysis revealed an increased hazard ratio (HR) for African-Americans (HR=1.594; P=0.0023) compared to Caucasians, after adjustment for age, sex, stage, Breslow depth, histologic subtype,location, and SES. Increased age, male sex, regional and remote stages, melanoma of the head/face, Breslow depth categories 2, 3, and 4, nodular melanoma, melanoma-NOS, and lowest SES quartile were independently associated with poor survival (P<0.0001). Conclusions: Among patients with invasive cutaneous melanoma, survival is significantly decreased for African-Americans compared to Caucasians. This is not explained by differences in SES, stage, Breslow depth, age, sex, histological subtype, and location. Our epidemiologic observations suggest that intrinsic differences may exist for African-American melanoma patients, adversely affecting survival. No significant financial relationships to disclose.
Targeting Src/Stat3 pathway in malignant melanoma
Authors: Homsi J. , Messina J. , Cubutt C. , Maunglay S. , Scalf L. , Komarla A. , Yu H. , Jove R. , Daud A. 
Published: April 2020

8025 Background: The Src/Stat 3 pathway has been implicated in the pathogenesis of several malignancies including melanoma. In the current study we evaluated the prevalence of Src and Stat3 activation in human melanoma and the effect of Src inhibitors alone or in combination with chemotherapeutic agents on melanoma cell lines. Methods: Activation of Src was measured by staining for Src-phosphotyrosine 416 (P-Src) and Stat3 by phosphotyrosine 705 Stat3 (P-Stat3). Immunohistochemistry was performed with anti-pStat3-Y705 and anti-pSrc-Y416 antibodies (Cell Signaling, Beverly, MA) on 3 melanoma subtypes. Staining of tumor cells for P-Stat3 was scored by percentage of stained cells as follows: 0 (no staining), 1 (1–25%), 2 (26–50%), 3 (>50%), and intensity 0–3 (0: absent, 1: low, 2: moderate, and 3: high). The sum of these was the composite P-Stat3 score: 0 (0), 1 (1–2), 2 (3–4), and 3 (5–6). P-Src staining was scored by intensity. Melanoma cell lines, A-375, SK-Mel-5 and SK-Mel-28 were exposed to Src inhibitors, SKI-606, PD 180970 and BMS 354825 alone or in combination with standard chemotherapy agents and IC-50 was determined by MTT assay at 24 and 72 hours. Results: 35 biopsies were stained. Median age was 66 years (range 23–90); 60% were women. 48% of all melanoma stained express P-Src; all samples express pStat3. We found a positive correlation between P-Src and P-Stat3 (Spearman coefficient=0.346, p=0.042). 46% stained only for pStat3 and 6% did not stain for either P-Src or P-Stat3. Most positively stained biopsies stained weakly for P-Src and moderately or strongly for pStat3. Src inhibitors inhibited the proliferation of melanoma cell lines; furthermore Src inhibitor treatment synergized with platinum and topoisomerase I inhibitors but not temozolomide. Conclusions: 1) Immunohistochemistry shows variable expression of P-Src and P-Stat3 in human melanoma 2) All tumors staining for P-Src also stain for P-Stat3 and the strength of staining is significantly related. 3) This data may be useful in planning future clinical trials with Src inhibitors in melanoma. [Table: see text] [Table: see text]
Methylated estrogen receptor alpha in tumors and sera of melanoma patients
Authors: Martinez S. R. , Mori T. , Umetani N. , Nguyen S. L. , Kitago M. , Tanemura A. , Morton D. L. , O’Day S. J. , Hoon D. S. 
Published: April 2020

8026 Background: The mechanisms regulating the variable expression of estrogen receptor alpha (ER-α) in melanoma are unknown. Silencing of ER-α expression in melanoma may be regulated by the hypermethylation of promoter region CpG islands. To determine the significance of ER-α hypermethylation-induced transcription silencing in melanoma progression, we assessed hypermethylation of ER-α DNA in primary tumors, metastatic tumors, and sera of AJCC stage I-IV melanoma patients. Methods: The methylation status of theER-α DNA promoter region in tumor (n = 107) and sera (n = 119) from AJCC stage I-IV melanoma patients was examined by methylation-specific PCR (MSP) and capillary array electrophoresis (CAE). To determine the significance of free circulating hypermethylated ER-α DNA, we assessed the therapeutic response, progression-free and overall survival among AJCC stage IV melanoma patients receiving biochemotherapy. Results: The frequency of ER-α DNA methylation in AJCC stage I, II, and III primary melanomas was 36% (4 of 11), 26% (5 of 19), and 35% (8 of 23), respectively. The frequency of methylated ER-α DNA detected in stage III and IV metastatic melanomas was 42% (8 of 19) and 86% (30 of 35), respectively. ER-α DNA was methylated in 38 of 54 (70%) metastatic tumors, a more than two-fold increase compared to primaries (p = 0.0003). In the analysis of 109 melanoma patients’ sera, the frequency of methylated ER-α DNA in AJCC stage I, II, III, and IV was 10% (2 of 20), 15% (3 of 20), and 26% (5 of 19), and 32% (16 of 50), respectively. The frequency of methylated ER-α DNA detected in stage III/IV was significantly higher than in stage I/II (p=0.034). In a multivariate analysis, circulating hypermethylated ER-α DNA was the only independent factor predicting progression-free (risk ratio 2.64, 95% CI 1.36–5.13, p = 0.004) and overall survival (risk ratio 2.31, 95% confidence interval 1.41–5.58, p = 0.003) among stage IV patients receiving biochemotherapy. Conclusion: Hypermethylation of ER-α DNA in primary and metastatic melanoma tumors and serum is a significant factor in melanoma progression. The detection of methylated serum ER-α DNA predicts poor response to systemic therapy and is an unfavorable prognostic factor in advanced melanoma. [Table: see text]
Clinical relevance of neutral endopeptidase overexpression in melanoma
Authors: Yancovitz M. , Velazquez E. , Christos P. , Pavlick A. , Berman R. , Shapiro R. , Bhardwaj N. , Nanus D. , Polsky D. , Osman I. 
Published: April 2020

8028 Background: Neutral Endopeptidase (NEP/CD10) is a cell surface peptidase expressed in a variety of normal and neoplastic tissue. Both loss of and overexpression of NEP have been reported in different types of tumors. Defining the role of NEP in the clinical progression of melanoma is particularly relevant given the availability of NEP inhibitors. Our aim was to determine if NEP expression correlated with clinicopathological parameters and survival. We also investigated the upregulation of NEP transcription as a possible mechanism of NEP overexpression. Methods: Eighty-four patients who were prospectively enrolled in the Interdisciplinary Melanoma Cooperative Group database at the New York University School of Medicine were studied. Ninety-three specimens from the 84 patients were examined for NEP protein expression using an immunohistochemical assay, including 33 primary melanoma (thickness <1mm, N=15; 1–4mm, N=15; >4mm, N=3) and 60 metastatic melanoma specimens. NEP overexpression was defined as either moderate or diffuse. NEP transcript expression was assessed using Affymetrix U133Plus2.0 GeneChips in 37 metastatic melanoma cases. NEP transcript upregulation was defined as >2 fold increase compared to NEP transcript expression in normal lymph node tissue. Results: A statistically significant difference was observed between NEP overexpression in primary [1/33 (3%)] versus metastatic disease [18/60 (30%)] (Fisher’s exact test, p=0.002). In addition, there was a statistically observed association between NEP transcript upregulation and NEP protein overexpression (p=0.002). Among patients with metastatic disease, median survival time was shorter for patients who overexpressed NEP compared to those who had normal NEP expression (10.2 yrs. versus 12.7 yrs., respectively); however this difference was not statistically significant (p=0.74 by log-rank test). Conclusions: Our data support a role for increased NEP expression in the progression of melanoma to metastatic disease. Functional studies are needed to better understand the role of NEP upregulation in melanoma pathogenesis and progression and to determine if there is a role for NEP inhibitors in the treatment of melanoma. No significant financial relationships to disclose.