bluuebunny/crossref_metadata_2025_split huggingface dataset:
Use of gene expression profile and mitotic index of metastatic melanoma lesions as an adjunct to TNM staging in predicting patient survival
Authors: Bogunovic D. , O'Neill D. , Belitskaya-Levy I. , Vacic V. , Adams S. , Darvishian F. , Pavlick A. , Zavadil J. , Osman I. , Bhardwaj N. 
Published: August 2020

9014 Background: Although remission rates for metastatic melanoma are generally very poor, some patients can survive for prolonged periods following metastasis. We used gene expression profiling of metastatic lesions to search for a molecular basis for this observation, and to develop improved methods for predicting patient survival. Methods: We analyzed gene expression profiles of 44 metastatic melanoma specimens collected from 38 patients (median follow-up of 20 months after surgery). We used the False Discovery Rate (FDR) approach to identify genes significantly associated with post-recurrence survival. We then evaluated matching H&E stained tissue samples for the presence of tumor-infiltrating leukocytes (TILs) and mitotic index, (MI). Support vector machines and multi-variable Cox regression analysis was used to examine the relative ability of the pre-validated gene expression predictor, TILs, MI and TNM staging to predict survival. Results: We identified a group of approximately 300 genes associated with survival. Genes associated with immune response (ICOS, CD3d, ZAP70, TRAT1, TARP, GZMK, LCK, CD2, CXCL13, CCL19, CCR7, VCAM1 etc.) or with cell proliferation (PDE4D, CDK2, GREF1, NUSAP1, SPC24 etc.) were highly represented .Prolonged survival was associated with the elevated expression of immune response genes and decreased expression of genes associated with proliferation. Furthermore, any of the three additional parameters (pre-validated gene expression signature, TILs or MI) improved the ability of TNM staging to predict post-recurrence survival; MI was the most significant contributor (HR = 2.65, p = 0.003) followed by the gene expression signature (HR = 2.71, p = 0.05). Conclusions: Gene expression profiling and MI of metastatic lesions can both be utilized to improve upon current staging of metastatic melanoma to predict patient survival. Gene expression signature and analysis of TILs indicate immune surveillance as a mechanism for prolonged survival in these patients. No significant financial relationships to disclose.
PLX4032, a highly selective V600EBRAF kinase inhibitor: Clinical correlation of activity with pharmacokinetic and pharmacodynamic parameters in a phase I trial
Authors: Puzanov I. , Nathanson K. L. , Chapman P. B. , Xu X. , Sosman J. A. , McArthur G. A. , Ribas A. , Kim K. B. , Grippo J. F. , Flaherty K. T. 
Published: August 2020

9021 Background: PLX4032 is an oral, highly selective inhibitor of oncogenic V600EBRAF kinase currently in phase I trial. V600EBRAF mutation activates Raf/MEK/ERK pathway in multiple tumor types. We evaluated the relationship between PK, PD (pERK, Ki67, FDG-PET), tumor histology and clinical activity following PLX4032 administration in a phase I trial. Methods: In the phase I trial, 6 melanoma pts with V600EBRAF were treated with PLX4032 daily at several dose levels and tumor biopsies (baseline vs. day 15) were assessed histologically and by semi-quantitative IHC analysis (modified H-score) for pERK and Ki67. The first 4 pts received a crystalline formulation of PLX4032; the last 2 pts received a formulation with increased bioavailability. Plasma PK parameters were collected at frequent time points on Days 1, 8 and 15. FDG-PET was performed on Days 1 and 15 on last 2 pts. Results: In the first 4 pts, no histological changes were observed with treatment and all developed disease progression. All had decreased percentage of Ki67 positive nuclei (pre-Rx, range 20–60%, median 45%; post-Rx, range 5–25%, median 12.5%) and 3 of the 4 had decreased pERK levels (pre-Rx, range 50–100, median 60; post-Rx, range 10–40, median 11). Mean PLX4032 AUC0–24h ∼ 126 μM*h was in the range for preclinical tumor stasis but below the threshold for shrinkage. In the last 2 pts, striking tumor necrosis and tumor melanosis was observed in the post-Rx samples. One pt remains on study with a confirmed PR, the other showed a clinical response before disease progression occurred in cycle 2. The percentage of Ki67 positive nuclei declined substantially (pre-Rx, 30% and 50% to post-Rx, 5% and 3%), as did the levels of pERK in the pt with PR (pre-Rx: 70 to post-Rx: 2). Mean PLX4032 AUC0–24h was well above the preclinical threshold in the range of 500 - 1000 μM*h. Both pts had decreased FDG uptake on D15. Conclusions: Clinical activity of PLX4032 treatment correlates with drug exposure levels as measured by AUC0–24h and was associated with histological changes in V600EBRAF positive melanomas on Day 15. Reduction of pERK, along with evidence of reduced proliferation and FDG uptake was observed. Further analysis of PD markers with additional pts at the MTD is planned. [Table: see text]
Randomized phase II study of the safety and efficacy of a human anti-αv integrin monoclonal antibody (CNTO 95) alone and in combination with dacarbazine in patients with stage IV metastatic melanoma: 12-month results
Authors: Loquai C. , Pavlick A. , Lawson D. , Gutzmer R. , Richards J. , Gore M. E. , de Boer C. J. , Uhlar C. , Lang Z. , O'Day S. 
Published: August 2020

9029 Objectives: Evaluate the safety and efficacy of CNTO 95, a human anti-αv integrin monoclonal antibody, when administered alone or in combination with dacarbazine (DTIC). Methods: Patients with Stage IV metastatic melanoma were randomized 1:1:1:1 to receive 5 or 10mg/kg CNTO 95 alone, or DTIC (1000mg/m2) + either 10mg/kg CNTO 95 or placebo administered intravenously once every 3 weeks for 8 cycles in the absence of disease progression or unacceptable toxicity. DTIC arms were blinded; single-agent arms were open-label. The primary endpoint was progression free survival (PFS); secondary endpoints included partial response (PR), complete response (CR), stable disease (SD) and overall survival (OS). Major safety endpoints included the incidence of adverse events (AEs) and serious AEs (SAEs). Results: Patients were randomized to receive 5mg/kg CNTO 95 (n=32), 10mg/kg CNTO 95 (n=33), CNTO 95+DTIC (n=32), or placebo+DTIC (n=32). Baseline demographics were similar across groups. The median PFS for CNTO 95+DTIC was 75 days, placebo+DTIC was 54 days and both CNTO 95 alone arms were 42 days. Six patients achieved PR (2–10mg/kg CNTO 95, 1-CNTO 95+DTIC, 3-placebo+DTIC); one patient achieved CR (CNTO 95+DTIC). A higher proportion (43.3%) of patients achieved SD ≥ 12 wks in the CNTO 95+DTIC group compared with the other 3 groups (<20.0%). The median survival was 11.0 months for the patients in the CNTO 95+DTIC arm, 9.8 months and 14.9 months for the 5mg/kg and 10mg/kg arms, and 8.0 months for those in the DTIC control arm. The most common AEs were headache, nausea, fatigue, pyrexia, vomiting and transient uveitic reactions. Three patients (1–5mg/kg, 2-CNTO 95+DTIC) discontinued treatment due to AEs. A higher proportion of patients experienced SAEs in the placebo+DTIC group (29.0%) than in the 5mg/kg (12.9%), 10mg/kg (16.2%) or CNTO 95+DTIC (18.8%) groups. Conclusions: CNTO 95 alone or combined with DTIC was generally well tolerated. In patients with Stage IV metastatic melanoma, a trend toward improvement in PFS, OS and disease control was demonstrated with CNTO 95+DTIC. Centocor, Centocor Research and Development, Inc. Centocor Research and Development, Inc. Johnson & Johnson Centocor Research and Development, Inc. No significant financial relationships to disclose.
Evaluation of the effect of systemic corticosteroids for the treatment of immune-related adverse events (irAEs) on the development or maintenance of ipilimumab clinical activity
Authors: Amin A. , DePril V. , Hamid O. , Wolchock J. , Maio M. , Neyns B. , Chin K. , Ibrahim R. , Hoos A. , O'Day S. 
Published: August 2020

9037 Background: Ipilimumab, a fully human monoclonal antibody that inhibits cytotoxic T-lymphocyte antigen-4, has clinical activity at 10 mg/kg in patients (pts) with advanced melanoma. Most grade 3/4 immune-related adverse events (irAEs) associated with ipilimumab can be managed with systemic corticosteroids following established treatment guidelines. However, little has been reported about the effects of corticosteroids used to treat irAEs on ipilimumab antitumor responses. Methods: Across 3 phase II studies with 10 mg/kg ipilimumab monotherapy in advanced melanoma (CA184008, 022, and 007; N=283), 83 pts (29.3%) achieved disease control [complete/partial responses (CR/PR), or stable disease (SD) ≥12 weeks] and 43/83 (52%) received steroids for treatment of irAEs. The pts' ability to develop and maintain disease control in the presence and absence of steroids was analyzed. Disease control was assessed by modified World Health Organization (mWHO) criteria and novel immune-related response criteria (irRC) (Hodi FS, et al. J Clin Oncol 26: 2008 [May 20 suppl; abstr 3008]). The range of follow-up was 5.7–6.3 months. Results: Of 117 pts who received steroids prior to response assessment, 26 pts achieved CR or PR, or maintained SD without disease progression by mWHO, and the remaining 91 pts had PD. Of 166 pts who either never received steroids or received them after response assessment, 31 achieved a CR, PR, or SD (by mWHO). Further, of 26 pts with CR/PR by mWHO, 14 received subsequent steroids and 11 maintained a response, while of 12 pts who received no subsequent steroids, 9 maintained a response. Similar results were obtained if irRC were used (see table ). Conclusions: Systemic corticosteroids for treatment of irAEs do not appear to impact the development or maintenance of ipilimumab clinical activity in advanced melanoma. [Table: see text] [Table: see text]
Effect of ipilimumab at 10 mg/kg on disease control in patients (pts) with M1c-stage melanoma in relation to baseline lactate dehydrogenase (LDH) levels
Authors: Smylie M. , Francis S. , Neyns B. , Maio M. , Minor D. , Verschraegen C. , Chin K. , Ibrahim R. , Hoos A. , Schadendorf D. 
Published: August 2020

9041 Background: Ipilimumab, a fully human, anti-cytotoxic T-lymphocyte antigen-4 monoclonal antibody, enhances antitumor immunity. Ipilimumab is clinically active in advanced melanoma, with a 1-year survival rate of ∼50% in Phase II studies (Wolchok et al. CRI-CVC annual meeting 2008. Oral presentation). Serum LDH level is an independent prognostic factor for malignant melanoma, and is strongly predictive of reduced survival in stage IV disease (Bedikian et al. J Clin Oncol. 2006;24:4738–4745.). This analysis evaluated the association between baseline LDH levels and disease control (stable or reduced measurable tumor burden) in previously treated pts with M1c-stage melanoma (metastasis to vital organs other than the lungs) who received ipilimumab in 2 recently completed Phase II studies (CA184008 and 022). Methods: Ipilimumab at 10 mg/kg was given every 3 weeks (Q3W) × 4; eligible pts could continue to receive ipilimumab Q12W beginning at Week 24. In study 022, pts were randomized to receive ipilimumab induction dosing at 0.3, 3.0, or 10 mg/kg Q3W × 4; study 008 was a single- arm trial of ipilimumab at 10 mg/kg. Disease control data were pooled from the 2 Phase II studies for pts treated with ipilimumab at 10 mg/kg and stratified by normal and elevated (>1× upper normal limit [UNL]) LDH levels. Elevated LDH was not capped. Results: For 227 pts treated at 10 mg/kg, 123 had M1c-stage disease: 42 had normal LDH and 81 had LDH >1 × UNL (of which 32 had LDH 2 × UNL). Among these 123 pts, 17/81 (21.0%) [95% CI 12.7–31.5] with elevated LDH levels experienced disease control, whereas 12/42 (28.6%) [95% CI 15.7–44.6] with LDH levels at or below the UNL experienced disease control. Conclusions: Our data show that ipilimumab exerts similar disease control in pts with normal and elevated LDH levels. Ipilimumab therefore appears to have clinical activity in the form of disease control in pts with a very poor prognosis, i.e., M1c-stage melanoma and elevated LDH levels. [Table: see text]
Ki67 as a prognostic biomarker for patients with vertical growth phase (VGP) melanomas
Authors: Gimotty P. , Guerry D. , VanBelle P. , Montone K. , Guerra M. , Hwang W. , Schuchter L. , Xu X. , Elder D. 
Published: August 2020

9043 Background: In VGP melanomas proliferation is reflected in dermal mitotic figures (“mitogenic” VGP) and/or tumor cell nests larger than any epidermal nest. An alternative to mitotic rate (MR) to characterize cell proliferation is the expression of Ki67 protein. Since Ki67 is expressed in all phases of the cell cycle except G0, it is potentially a more robust biomarker for proliferation and prognosis than mitoses. Methods: To test the hypothesis that Ki67 would replace MR as a prognostic factor, we did a retrospective cohort study of 432 patients with Stage I/II primary VGP melanomas who had at least 10 years of follow up. Tissue sections were stained using the monoclonal antibody MIB-1 to Ki67 and the % of positive melanoma cells were evaluated by two readers. ROC curves for Ki67 and MR were computed. Predicted probabilities (PP) of 10-year melanoma-specific death were computed from 3 multivariate logistic regression models, one for each biomarker (Models 1 and 2) and one with both (Model 3), controlling for established melanoma prognostic factors (thickness, gender, anatomic site, ulceration, regression and tumor infiltrating lymphocytes), and compared. Cross-validation was used to assess differences between using Ki67 and using MR including the differences in PP, Brier scores and the misclassification rates. A decision curve analysis was done to assess the clinical net benefit of the two. Results: The areas under the ROC curve (AUCs) for Ki67 and MR, both continuous factors, were 0.69 and 0.79, respectively. In the multivariate analysis, Ki67 expression was significant in Model 1 (OR=1.03, 95% CI: 1.01–1.05), mitotic rate was not significant in Model 2 (1.05, 0.99–1.1), and only Ki67 was significant in Model 3 (1.03, 1.01–1.05). The AUCs for the three models were 0.84, 0.84, and 0.85, respectively. Based on cross-validation, there was no difference between the two biomarkers in PP, Brier scores, or misclassification rates. The decision cost analysis demonstrated the same net benefit for the two. Conclusions: A prospective study needs to be conducted to confirm that Ki67 and MR are equivalent. No significant financial relationships to disclose.
Developing genetic markers for melanoma risk assessment
Authors: Manga P. , Goldberg J. D. , Belitskaya-Levy I. , Lobach I. , Polsky D. , Pavlick A. , Shapiro R. , Berman R. , Osman I. , Ostrer H. 
Published: August 2020

9046 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. No significant financial relationships to disclose.
Role of circulating angiogenin TGF-β1, VEGF-R1, and VEGF-R2 in metastatic malignant melanoma patients
Authors: Spano J. , Mouawad R. , Vignot S. , Magné N. , Khayat D. 
Published: August 2020

9048 Background: Malignant melanoma is a disease capable of rapid progression and is associated with high angiogenesis. Thus, investigation of mechanisms involved in metastasis is essential to control this tumor. However, the angiogenesis regulators that are biologically relevant for melanoma are still unknown. We have previously reported that high levels of soluble VEGF in metastatic malignant melanoma (MMM) patients may represent a useful biomarker to predict the effect of biochemotherapy in terms of clinical response. In this study, we evaluate whether soluble levels of angiogenin, transforming growth factor-β1 and VEGFR-1 and -2 play a role in metastatic malignant melanoma patients and to determine if they have any relationship with clinicopathological parameters. Methods: Using a sensitive enzyme-linked immunosorbent assays, angiogenin TGF-β1, VEGF-R1 and VEGF-R2 were measured in sera of 70 patients with a fully documented history of metastatic malignant melanoma in comparison with 30 healthy controls. Results: Pretreatment circulating angiogenin, TGF- β1 VEGF-R1 and VEGF-R2 were detectable, variable in all samples from either melanoma patients or healthy donors Only serum transforming growth factor- β1 levels was significantly higher (p=0.005) in patients compared to healthy controls. No relationship was observed between sex, age or LDH level and all studied parameters. When tumor burden has been taken into consideration, a significant relationship was established between high circulating serum TGF-β1 (p= 0.001) levels and tumor burden were found, Similarly, higher serum VEGFR1 levels were correlated with tumor burden (P = 0.02). Conclusions: The presence of high circulating TGF-β1 and VEGF-R1 in metastatic malignant melanoma patients may prospectively identify high-risk patients with a worse prognosis. In addition, these two parameters may be promising targets for new therapeutic strategies in this pathology. No significant financial relationships to disclose.
Evaluation of IL-10 polymorphisms in high-risk melanoma patients receiving adjuvant interferon
Authors: Gogas H. , Metaxas Y. , Polyzos A. , Mantzourani M. , Antoniadis A. , Floudas C. , Fountzilas G. , Pectasides D. , Tsoutsos D. , Spyropoulou-Vlachou M. 
Published: August 2020

9049 Background: Attempts to identify patients who benefit from adjuvant treatment of interferon alfa-2b (IFN) have been disappointing. Interleukin-10 polymorphisms have been implicated with the prognosis of patients with advanced melanoma and associated with response to biochemotherapy. Several polymorphisms have been found within the IL-10 gene. We evaluated three IL-10 Single Nucleotide Polymorphisms (SNPs) in high-risk melanoma patients enrolled in a study of two regimens of high-dose IFN and compared the distribution of SNPs found in healthy controls. Methods: We genotyped DNA from peripheral blood of 280 stage IIb, IIc and III melanoma patients and 288 healthy controls for 592 C/A, 819 C/T and 1082 G/A with PCR and pyrosequencing technology (Biotage, Uppsala, Sweden). Results: At a median follow up of 56.3 months (95% CI 47.4–63.7), 147 patients have recurred and 94 have died. The median DFS was 53 months and the median OS 86 months. There were no statistically significant differences in the incidence of IL-10 polymorphisms between the melanoma patients and healthy controls. The incidence of these polymorphisms is presented in table . RFS and OS did not differ significantly between the alleles of these polymorphisms (p=0.88 and p=0.55 for 592 C/A, p=0.84 and p=0.68 for 819 C/T and p=0.26 and p=0.30 for 1082 G/A respectively). Conclusions: No SNP studied was correlated with improved RFS and OS in this high-risk group of melanoma patients. [Table: see text] [Table: see text]
Biological factors in human cutaneous melanoma correlated to disease stage
Authors: Elias E. G. , Sharma B. K. , Hasskamp J. H. , Avergas A. M. , Beam S. L. , Broussard J. N. , Zapas J. L. , McCarron E. C. , Culpepper W. J. 
Published: August 2020

9053 Background: Cutaneous melanoma cells express a variety of cytokines and growth factors (C/GF) as the tumor progresses. This study was undertaken to identify various C/GF at different stages of the disease with the hope of identifying prognostic factors. Methods: Immunohistochemical (IHC) studies were performed on 62 specimens of parafinized human melanoma comprised of 12 primaries, 10 local recurrences, 6 intransit, 15 regional lymph node and 19 distant metastases. Staining for 17 C/GF was performed using commercially available antibodies on Bond-Max automated IHC system. Results: The overexpression of C/GF in primary lesions was compared to distant metastases with regard to intensity and extent of staining. Data was dichotomized as positive (dark staining) or negative (lesser or no staining). There was simultaneous intense staining of 4–15 C/GF in primaries and 3–14 C/GF in metastatic lesions. Comparing primaries to metastases by Chi-Square using Fisher's exact test, statistical differences were seen in intensities of transforming growth factor-β (p<0.001), β-catenin (p<0.01), Bcl-2 (p<0.01). Staining intensities of IL-8 approached significance (p<0.058). Statistical differences in extent of staining between primaries and metastases were found for insulin-like growth factor-1 (p<0.01), fibroblast growth factor-basic (p<0.05) and IL-15 (p<0.05). Conclusions: Potential dynamic changes in overexpression or loss of expression of C/GF in metastatic melanoma is not clearly understood and may reflect on mutations. Melanoma is an extremely heterogeneous tumor and no single targeted therapeutic agent can control this disease. No significant financial relationships to disclose.