bluuebunny/crossref_metadata_2025_split huggingface dataset:
Toward an miRNA signature for predicting outcome in patients with melanoma.
Authors: Pameijer Colette R 
Published: March 2020

9039 Background: Melanoma remains a clinical challenge, as an aggressive and often unpredictable tumor. The incidence continues to increase, but treatment options are limited. One significant challenge is predicting which patients with stage I or II disease will have a poor outcome. We sought to develop a tool to assist in risk stratifying patients with melanoma. Methods: This is a prospective trial in which patients with melanoma at least 0.5mm deep were enrolled between 2007-2011. Tissue was collected from primary tumors, bulky nodes and metastatic deposits. RNA was extracted, labeled and hybridized to a miRNA microarray (Affymetrix). Hierarchical cluster method was used to find similarities among samples. A clinical patient database was maintained. Results: This study looks at 58 intermediate and high risk subjects. The median depth of melanoma was 3mm. The median age was 69 (range 26-95) and most patients (48/58, 83%) were treated with surgery alone, with ten receiving adjuvant therapy. All patients underwent wide excision, and 43 patients had sentinel node biopsy. Twenty-seven patients developed a recurrence (47%), and 19 (33%) patients have died, 14 from melanoma. The median length of follow-up is 21 months (range 1-76 months). A total of 112 probes are differentially expressed at a p value of 0.005. The largest number of differentially expressed probes relate to location of the tumor. Other significant differences are origin of the specimen (primary versus node), mitotic rate and subject age. High expression of miR-193b was correlated with death from melanoma, p=0.05. Parameters with no differential expression include gender, tumor depth and subtype, and ulceration. Conclusions: Microarray analysis of miRNAs is a reliable platform to obtain prognostic information about melanoma. The miRNA signatures found in this patient population reinforce some well described differences among patients with melanoma, and fail to find a difference between other groups thought to be clinically important. Tumor genetic profiling may provide better risk stratification of patients with melanoma than clinical parameters alone.
Adjusting for treatment crossover in the BREAK-3 metastatic melanoma trial for dabrafenib: Preliminary analysis.
Authors: Latimer Nicholas , Abrams Keith R. , Amonkar Mayur , Stapelkamp Ceilidh , Swann R. Suzanne 
Published: March 2020

9044 Background: In BREAK-3, dabrafenib improved PFS (hazard ratio [HR]=0.30 [95% CI 0.18–0.51; p<0.0001] as of Dec 19, 2011) vs dacarbazine (DTIC) in patients (pts) with previously untreated BRAF V600E+unresectable or metastatic melanoma. In an updated analysis (data as of June 25, 2012), PFS HR=0.37 (95% CI 0.24–0.58; p<0.0001). Overall survival (OS) results may underestimate the effect of dabrafenib as DTIC pts could cross over to dabrafenib at progression. This analysis attempts to adjust for confounding effects of crossover on OS using BREAK-3 results from June 2012 data. Methods: Randomization-based crossover adjustment methods – Rank Preserving Structural Failure Time Models (RPSFTM) and the Iterative Parameter Estimation (IPE) algorithm – were used. We conducted 2 sets of analyses testing different assumptions regarding the durability of the treatment (trt) effect. “Trt group” analyses adjusted for crossover under the assumption that the trt effect is maintained until death regardless of trt duration; “On trt – observed” analyses adjusted for crossover under the assumption that the trt effect disappears upon trt discontinuation. Results are presented as HRs. Results: 187 and 63 pts were randomized to dabrafenib and DTIC, respectively. At the time of this analysis, 55.6% of DTIC pts crossed over to dabrafenib. Median duration of follow-up was 10.5 months and 76 (30.4%) pts died. Median OS has not yet been reached. Crossover adjustment results are presented in the Table. Conclusions: All RPSFTM and IPE analyses resulted in point estimates for the OS HR that represented a substantial increase in trt effect compared with the unadjusted HR of 0.75. Results are exploratory, as the OS data are not mature. Analyses will be updated when further data are available. [Table: see text]
Prognostic implication of KIT mutations in melanoma.
Authors: Roth Katherine G. , Zabor Emily C. , Colgan Marta N. , Wolchok Jedd D. , Chapman Paul B. , Schwartz Gary K. , Panageas Katherine S. , Carvajal Richard D. 
Published: March 2020

9049 Background: The natural history of BRAF and NRAS mutant (mut) melanoma (mel) has been described, but prognostic implications of KIT mut mel have not. Methods: We performed a single-center retrospective review of 180 patients (pts) enriched for mucosal, acral or chronic sun-damaged skin (CSD) mel and screened for KIT, BRAF, and NRAS mut from 4/07 - 4/10 as a part of a phase II imatinib study. Pt/disease characteristics were compared using the Kruskal-Wallis or Chi-square tests. Factors associated with outcomes were assessed by Kaplan-Meier methods and multivariable Cox regression. Results: Median age, 63.7 years; 54.4% male. Primary site: 40% mucosal, 29% acral, 22% CSD, 9% others. Mut rate: 18% KIT, 16% BRAF, 14% NRAS, 52% wild-type (wt). Pathologic subtype differed by genetic subgroup (p<.001) while age, gender, and stage did not (all p>0.05). 18/26 (69%) KIT mut pts received imatinib in the metastatic (met) setting; 6/18 received > 1 other KIT inhibitor. 3/25 (12%) BRAF mut pts received vemurafenib. 8/27 (30%) KIT mut, 4/27 (15%) BRAF mut, 6/20 (30%) NRAS mut, and 6/20 (30%) wt pts received ipilimumab. 149/180 (83%) pts developed mets at a median of 2.15 years (95% CI: 1.72, 2.72). Median follow-up (FU) of pts not developing mets was 3.91 yrs (range: 0.25, 14.34). Older age (HR: 1.02, 95% CI: 1.00, 1.03) and pathologic subtype (mucosal vs CSD HR: 1.70, 95% CI: 1.02, 2.84; non-CSD/unknown vs CSD HR: 2.05, 95% CI: 1.00, 4.21) were associated with increased risk of mets but not with time from mets to death. Of 149 pts who progressed, 123 (83%) died during FU. Median time from met to death was 1.21 years (95% CI: 0.91, 1.67). Median FU from time of mets among those alive at last FU was 2.53 yrs (range: 0.06, 6.85). Mut status including KIT mut was not associated with time to first met or time from met to death. Pts who received ipilimumab from time of first distant met had reduced risk of death (HR: 0.55, 95% CI: 0.36, 0.87) independent of mut status. No impact was observed with KIT inhibition. Conclusions: KIT mut status is not an independent predictor of time to mets or survival in pts with mets. Ipilimumab improved pt outcomes regardless of mut status. The lack of impact of KIT inhibitors is likely due to the heterogeneity of KIT mut in mel but does not preclude efficacy in appropriately selected pts.
Long-term survival in patients with metastatic melanoma who received ipilimumab in four phase II trials.
Authors: Lebbé Celeste , Weber Jeffrey S. , Maio Michele , Neyns Bart , Harmankaya Kaan , Hamid Omid , O'Day Steven , Chin Kevin M. , McDowell Diane Opatt , Cykowski Lori , McHenry Brent , Wolchok Jedd D. 
Published: March 2020

9053 Background: Ipilimumab (Ipi) has shown improved overall survival (OS) in two phase III trials of patients (pts) with metastatic melanoma (MM), with survival follow-up of >4 years in one trial. The present analyses provide survival follow-up of >5 years in four phase II trials of Ipi in MM. Methods: Pts with MM were enrolled in one of four phase II trials: (1) CA184-004, a biomarker study with Ipi at 3 or 10 mg/kg in treatment-naive (TN) and previously treated (PT) pts; (2) CA184-007, with Ipi at 10 mg/kg +/- prophylactic budesonide in TN and PT pts; (3) CA184-008, a single-arm study with Ipi at 10 mg/kg in PT pts; and (4) CA184-022, a dose-ranging study of Ipi at 0.3, 3, or 10 mg/kg in PT pts (crossover from lower dose groups to 10 mg/kg was allowed upon disease progression). Ipi was administered q3 wk x4 (induction), followed by maintenance (q12 wk from week 24) in eligible pts. Some pts were retreated with Ipi at 10 mg/kg upon disease progression. Along with survival data collected through March 2012 for studies 007, 008, and 022, we report updated 5-year OS data for study 004 collected through September 2012. Results: Five-year OS rates for TN and PT pts are reported in studies 007, 008, and 022, with combined analyses for TN and PT pts within each dose group in study 004 (Table). The results show that survival rates reach a plateau beginning at year 3. Conclusions: In pts who received Ipi at 3 or 10 mg/kg in phase II studies, regardless of prior treatment, a proportion (12.3–49.5%) remained alive 5 years after the start of treatment. These results demonstrate long-term survival with Ipi therapy in MM. An ongoing phase III trial will compare OS for Ipi at 3 vs 10 mg/kg in pts with MM. Clinical trial information: NCT00162123. [Table: see text]
Safety and efficacy of adjuvant anti-PD1 therapy (nivolumab) in combination with vaccine in resected high-risk metastatic melanoma.
Authors: Gibney Geoffrey Thomas , Weber Jeffrey S. , Kudchadkar Ragini Reiney , De Conti Ronald C. , Tetteh Leticia , Eysmans Cabell , Yu Bin , Martinez Alberto J , Younos Ibrahim 
Published: March 2020

9056^ Background: Nivolumab (BMS-936558), a fully human monoclonal antibody targeting the programmed death-1 (PD-1) receptor, has demonstrated clinical activity in advanced metastatic melanoma patients (pts). In this phase I study, the safety and activity of nivolumab plus a multipeptide vaccine was investigated as adjuvant therapy in resected stage IIIC and IV melanoma pts. Methods: HLA-A*0201 positive pts with HMB-45, NY-ESO-1, and/or MART-1 positive tumors received nivolumab (1mg/kg, 3mg/kg, or 10mg/kg IV) with a multipeptide vaccine (gp100, MART-1, NY-ESO-1, Montanide ISA 51 VG) every 2 weeks for 12 doses followed by nivolumab maintenance every 3 months (8 doses) or until disease recurrence. The primary objective was safety and determination of maximum tolerated dose (MTD). Secondary objectives were immunologic response and relapse free survival. Results: 33 pts were enrolled: 12 pts at 1mg/kg, 10 pts at 3mg/kg, and 11 pts at 10mg/kg nivolumab. Median age was 47 yrs; 55% male and 52% M1c disease (2 IIIc, 7 M1a, 7 M1b, and 17 M1c pts). As of January 16, 2012, median follow up time was 14 months and median number of doses was 12 (20 pts still receiving therapy). A MTD was not reached. Grade 2-3 related adverse events (AEs) occurred in 27 pts with the most common AEs being fatigue, rash/pruritis, and endocrinopathies. 4 pts experienced grade 3 AEs: (colitis/diarrhea (3), rash (1)). No drug related grade 4 or higher AEs occurred. 7/33 pts have relapsed to date. One pt with biopsy-proven relapse on trial had spontaneous disease regression. Non-relapsing pts had higher pre-treatment PD-1 expression on Treg and TCD4+ cells (p=0.053) and a greater increase in Treg cells after 12 weeks on treatment (p=0.027). Among all pts, treatment led to a rise in Treg cells (p=0.015) and decreased PD-1 expression on TCD4+ and TCD8+cells (p=0.014 and p<0.001, respectively). Conclusions: Nivolumab is well tolerated in combination with vaccine and preliminary data demonstrates immunologic and clinical activity as adjuvant therapy, justifying a randomized phase III study in resected high risk melanoma pts. Clinical trial information: NCT01176474.
BEVATEM: Phase II study of bevacizumab (B) in combination with temozolomide (T) in patients (pts) with first-line metastatic uveal melanoma (MUM): Final results.
Authors: Piperno-Neumann Sophie , Servois Vincent , Bidard Francois-Clement , Mariani Pascale , Plancher Corine , Diallo Alhassane , Vago-Ady Nora , Desjardins Laurence 
Published: March 2020

9057 Background: Overall survival (OS) of MUM pts remains poor (median 12 months), stressing the lack of effective therapies in this rare cancer. Targeting angiogenesis seems to be promising in uveal melanoma (UM). Antiangiogenic agents are used to treat neovascular ocular diseases such as age-related macular degeneration or proliferative diabetic retinopathy. B suppressed in vitro growth and in vivo hepatic establishment of micrometastases in experimental UM. Preclinical data suggest a potential clinical benefit of the combination of dacarbazine and B. Methods: Two-stage phase II trial; expected 6-month progression-free rate (PFR) of 40% with BEVATEM versus 15% with chemotherapy (power 94%, α risk 3%). Primary endpoint: 6-month PFR according to RECIST. Secondary objectives: response and survival rates, safety; liver perfusion CT for functional imaging of response; impact of VEGF-A gene polymorphisms on B pharmacodynamics. Treatment schedule: T 150mg/m2 d1-d7 and d15-d21 oral route, B 10 mg/kg d8 d22 IV infusion, 6 cycles (d1=d28) then B maintenance until toxicity or progression. Results: 35 evaluable pts have been enrolled from May 2010 to May 2012. First step analysis showed 3/17 first patients with disease control at 6 months and good tolerance. The final population consisted of 19 men and 16 women, median age 55 (29-72). PS was 0 in 28 and 1 in 7 pts, and the median time to metastasis was 38 months (17-62). Liver was the sole metastatic site in 29 pts.With an administered dose-intensity similar to the planned schedule, 7 and 9 pts experienced grade 3 (neutropenia 4, thrombocytopenia 1, constipation 1, pruritis 1) or grade 4 toxicities (neutropenia 3, thrombocytopenia 4, thrombosis 1) respectively. Despite no objective response, 9/35 pts showed stable disease, and the 6-month PFR was 26% [95%CI 13-41]. With a median follow-up of 18 months, 5 pts (14%) had long lasting non progressive disease with B maintenance (10+ to 29+ months). Finally, the median PFS and OS were 3 and 12 months respectively. Conclusions: BEVATEM regimen in first line MUM patients showed safety and 6-month PFR of 26% including 14% of pts with durable clinical benefit. Clinical trial information: 2009-011751-46.
Ipilimumab (Ipi) retreatment at 10 mg/kg in patients with metastatic melanoma previously treated in phase II trials.
Authors: Neyns Bart , Weber Jeffrey S. , Lebbé Celeste , Maio Michele , Harmankaya Kaan , Hamid Omid , O'Day Steven , Chin Kevin M. , McDowell Diane Opatt , Cykowski Lori , McHenry Brent , Wolchok Jedd D. 
Published: March 2020

9059 Background: Ipi is a fully human monoclonal antibody that binds to cytotoxic T-lymphocyte antigen-4 to augment antitumor immune responses. In phase III study MDX010-20, where patients (pts) could be retreated if they met safety criteria and achieved an objective response or stable disease ≥3 months from the end of the induction period (q3 weeks for 4 doses), 21 of 31 pts (68%) retreated with Ipi reestablished disease control. CA184-025 is a roll-over study of extended Ipi treatment or survival follow-up in pts who received Ipi in phase II trials, with the primary objective of evaluating safety during extended treatment. We report the safety profile in pts retreated with Ipi in study 025. Methods: Eligible pts in phase II trials CA184-004, -007, -008, -022, MDX010-08, or -015 were enrolled in study 025 (N=248) to receive retreatment (at the time of progression), extended maintenance (if no prior progression), or survival follow-up only. Pts were ineligible for retreatment if they had experienced a grade 3-4 non-skin toxicity during prior Ipi therapy. Ipi was administered at 10 mg/kg, q3 weeks for 4 doses, to 111 pts who initially received Ipi induction at 0.3, 3, or 10 mg/kg in a parent study. Results: In this selected population of eligible pts, the nature and frequency of immune-related adverse events (irAEs) during retreatment were similar to those reported in previous studies, which most commonly affected the GI tract and skin (Table). There were no new types of drug-related irAEs and no grade 5 irAEs upon retreatment. Conclusions: Retreatment with Ipi at 10 mg/kg in these pts was generally well tolerated and the safety profile was similar to that during induction dosing in the parent studies. The higher frequencies of irAEs at lower doses should be interpreted with caution given the small sample sizes. An ongoing, randomized phase II trial will evaluate the clinical benefit of Ipi retreatment. Clinical trial information: NCT00162123. [Table: see text]
Evaluating the safety of anti-CTLA-4 therapy in the elderly with unresectable melanoma.
Authors: Chandra Sunandana , Madden Kathleen M. , Kannan Rajni , Pavlick Anna C. 
Published: March 2020

9063 Background: Anti-CTLA-4 monoclonal antibodies demonstrated an improvement in overall survival in patients with metastatic melanoma and ipilimumab (ipi) was FDA approved in 2011. We performed a retrospective analysis of 74 elderly (age ≥ 65) patients (pts) who were treated with anti-CTLA-4 therapy (tx) and evaluated their treatment related adverse events (AEs) as well as clinical response. Methods: 65 pts were treated with ipi 3 mg/kg x 4, among whom 8 pts were re-treated with ipi 3 mg/kg x 4; 3 pts were treated with ipi 10 mg/kg x 4 with 2 pts who went on to receive maintenance tx; 2 pts were treated with tremelimumab (treme) 15 mg/kg q 3 months; 4 pts are currently undergoing tx with ipi 3 mg/kg x 4. There were 17 treatment naïve pts, and 57 pts were previously treated with 1-4 prior therapies. Thirty-nine pts received all 4 doses of ipi. There were 46 males and 28 females. Ages ranged from 65 to 90, median age 74. Melanoma subtypes included: 55 cutaneous, 8 mucosal, 7 ocular, 3 acral, and 1 unknown primary. Ten pts had M1a, 18 M1b, and 45 M1c disease. One pt had unresectable stage IIIC disease. Results: The most common tx related AEs included rash (33 AEs ≤ grade 3), diarrhea/colitis (21 AEs ≤ grade 3, with 1 grade 4 AE), fatigue (17 AEs ≤ grade 2), and pain at tumor site (17 AEs ≤ grade 2). There were 3 hepatotoxicity-related AEs, including 1 grade 5 AE; and 3 endocrinopathy-related AEs, including 1 grade 4 hypopituitarism. Toxicities were managed with corticosteroids, anti-histamines, anti-motility agents, analgesics, thyroid and cortisol supplementation. Of the 69 pts evaluable for response, 16 pts (23%) had complete response (CR) or partial response (PR), and 9 pts (13%) had stable disease (SD) as measured radiographically using mWHO criteria at least 12 weeks post completion of treatment. When analyzed within melanoma subtypes, 17 cutaneous pts (31%) had tumor response (CR, PR, SD), 6 mucosal (75%), and 2 ocular (29%). Conclusions: Anti-CTLA-4 tx, including ipi and treme, was safe and well tolerated by the elderly population. Reported adverse events and response rates were consistent with published data in younger cohorts.
Gender differences in survival from cutaneous melanoma: Analysis of United States SEER data, 1992 to 2009.
Authors: Dronca Roxana Stefania , Weaver Amy , Brewer Jerry D. , Shuster Lynne T , Kottschade Lisa A. , Morita Shane Young , Markovic Svetomir 
Published: March 2020

9073 Background: An accumulating body of evidence suggests that the outcome of early-stage melanoma is influenced by endocrine and menopausal status. However, it remains controversial as to whether the superior female melanoma-specific survival (MSS) is restricted to early stage disease or if it also pertains to patients with metastatic melanoma (MM). Methods: We analyzed data from the 13 registries that participate in the National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) program. We identified all cases of primary invasive melanoma diagnosed between 1992 and 2009; none of the patients had a prior history of another cancer. MSS was compared between males and females, stratified by stage of disease. Age groups were defined as 18-45y, 46-54y, 55-64y, 65+y as a proxy of female menopausal status. Results: The study population included 87,165primary invasive melanoma cases (unstaged n=2834). MSS was significantly poorer for males compared to females for localized (n=72,456) and regional (n=8,945) disease for all age groups (Hazard ratio (HR) ranging from 1.21 to 2.09, all p<0.001). MSS was not significantly different between males and females for patients with distant disease at diagnosis (n= 2930; HR 0.99, 0.92, 1.11, 1.07 for each age group) and remained non-significant after adjusting for Breslow thickness, histologic subtype, anatomic site, and age group (adjusted HR 1.04 males vs. females; 95% CI 0.95-1.14; p=0.41). Conclusions: While our results were consistent with earlier reports that women have higher MSS rates compared to men for early (stage I-III) melanoma, the intriguing finding of this study was that the female survival advantage does not vary with age or menopausal status as compared to men, which is contrary to previously published reports. Furthermore, we found that the difference in survival was no longer significant for patients with MM, suggesting that sex may influence local and regional, but not distant cancer progression.
Treatment patterns in patients with early and advanced malignant melanoma.
Authors: Gastanaga Victor M. , Lethen Jan E. , Vanderwalde Ari M. , Cyprien Lori A. , Kelsh Michael A. , Kallich Joel D. 
Published: March 2020

9083 Background: We seek to characterize tx patterns for patients (pts) with early stage (ES) and advanced stage (AS) malignant melanoma (MM). MarketScan is a large insurance claims database with complete diagnosis (dx) and tx information. Methods: Using MarketScan data, pts were identified between Jan 2001 and Jun 2011 using ≥1 inpatient or ≥2 outpatient MM ICD9 codes ≥6 weeks apart. Pts with a history of other malignancies or lacking records at least 1 year prior to diagnosis were excluded. Pts were considered AS if they received chemotherapy, interferon, ≥2 days of MM surgery, or a code of secondary metastases. All other pts were classified as ES. Radiotherapy, immunotherapy, chemotherapy, and surgery type were identified with HCPCS, CPT, and ICD9 procedure codes. Pts were categorized by type of progression (ToP): AS at time of dx (AS-D), ES at dx with progression to AS during follow-up (ES-P), and ES at dx with no progression during follow up (ES-NP). Results: Of 30,678 eligible pts, 55% were male, median age was 59 yrs, and median follow-up was 31 months. Initial disease locations were head and neck (21%), torso (27%), upper extremities (17%), and lower extremities (14%). Twenty-five percent (7607 pts) were identified as having AS MM during follow-up. Of these, 2,445 (8%) were AS-D, while 5162 (17%) were ES-P. The remaining 23,071 pts (75%) were ES-NP. Frequency of most extensive surgery type after diagnosis date are shown by ToP (table). No ES-NP pts received systemic tx during follow-up, but 21% of ES-P and 64% of AS-D pts received either chemotherapy, immunotherapy, or both. Agents most commonly prescribed in AS pts were interferon and temozolomide. Conclusions: The tx burden in MM pts is extensive and appears to increase with disease severity. Claims data can be a valuable tool in elucidating MM tx patterns by disease stage. [Table: see text]