bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of Melan-Α/Μart-1-peptide vaccination plus IMP321 on antitumor immunity and clinical benefit in patients receiving autologous PBMCs after lymphodepletion.
Authors: Romano Emanuela , Bichat Helene , Stravodimou Athina , Romero Pedro , Daniel Speiser E , Triebel Frederic , Michielin Olivier , Harari Alexander , Leyvraz Serge 
Published: March 2020

e20011 Background: Immunotherapy offers great promise for cancer treatmet. Strong evidence supports adoptive cell transfer (ACT) and immunemodulation for regression of advanced melanoma. Few studies assessed the potential synergy between these two strategies. Methods: Twelve patients with metastatic melanoma received multiple Melan-A/Mart-1-peptide vaccinations with (n=6) or without (n=6) IMP321 (LAG-3Ig fusion protein) as an adjuvant in combination with lymphodepleting chemotherapy and ACT. All patients were selected on the basis of ex vivo detectable Melan-A-specific CD8 T cell responses and were immunized at day (D) 0, 8, 15, 22, 28, 52, and 74 post-reinfusion. Results: One-week after reinfusion of bulk autologous PBMCs, a significant expansion of Melan-A-specific CD8 T cells was measured in >83% (n=5) and <17% (n=1) of patients from the IMP321 and control groups, respectively (p=0.02). Compared to the control group, the mean fold increase of Melan-A-specific CD8 T cells was respectively >2-, >4-, and >6-fold higher in the IMP321 group at D15, D30, and D60 (p=0.02). A long-lasting Melan-A-specific CD8 T-cell response was significantly associated with IMP321 (p<0.001). A higher proportion of Melan-A-specific CD8 TEMRA (i.e., CD45RA+CCR7-CD127-) cells was observed in the IMP321 group at the peak of the response (p <0.002), whereas no significant difference was observed in the expression of co-inhibitory receptors (i.e., PD-1, 2B4, TIM3, CD160). IMP321 was associated with a significantly (p<0.04) reduced expansion of regulatory T cells (TREGS); we observed a negative correlation between the fold increase of Melan-A-specific CD8 T cells and the relative expansion of TREGS. Clinical benefit (assessed as CR, PR, and SD) was observed in none of the control patients vs 67% (4/6) of patients from the IMP321 group, (p=0.02). Conclusions: Vaccination with IMP321 as an adjuvant in combination with lymphodepleting chemotherapy and ACT provided clinical benefit and this was associated with a more robust and durable cellular antitumor immune response, supporting further development of IMP321 for future immunotherapeutic strategies. Clinical trial information: NCT00324623.
Familial melanoma in Spain: Preliminary report of the FAM-GEM-1 study.
Authors: Martin-Gonzalez Manuel , Cerezuela Pablo , Martin-Carnicero Alfonso , Puertolas Teresa , Martin-Algarra Salvador , Gil-Arnaiz Irene , Maldonado-Seral Cayetana , Gonzalez Cao Maria , Belon Joaquin , Aviles Izquierdo Jose Antonio , Marquez-Rodas Ivan ,   Grupo Español Multidisciplinar de Melanoma
Published: March 2020

e20015 Background: In addition to environmental factors and phenotype, melanoma risk is determined by familial background. It is estimated that 5-10% of melanoma cases occur in a familial setting. High susceptibility genes like CDKN2A and intermediate risk like M1CR are the most known, but explain less than 1/3 of the cases, most of them cases with 2 or more first degree relatives involved, the classical definition for familial melanoma (FM). In Spain there are several local studies about epidemiology and characteristics of FM, but there are no studies that cover all the territory. Methods: FAM-GEM-1 is a national, observational, 2 years-registry study (2011-2013), conducted by the Spanish Multidisciplinary Melanoma Group (GEM), whose principal objective is to assess the rate of melanoma patients with family history of melanoma in Spain. Secondary objectives are to analyze whether patients with family history are different from sporadic melanoma in terms of clinical, pathological and molecular features; and to constitute a registry of FM in order to deeper characterise these patients in further studies. We present the exploratory results of the first 219 patients registered Results: See Table. Conclusions: We have found that almost 9% of patients have family history of melanoma. Of them, almost 3/4 fulfils familial melanoma criteria. It seems that there are not relevant differences among sporadic and familial melanoma in our registry, except for sex, although the preliminary nature of the results makes necessary more patients in order to determine if there are clinical and/or pathological differences between both groups. [Table: see text]
Comparison of mucosal and cutaneous melanoma in the head and neck region: Different clinical features and similar outcomes.
Authors: Ciftci Rumeysa , Keskin Serkan , Karabulut Senem , Yildiz Ibrahim , Kilic Leyla , Sen Fatma , Tastekin Didem , Tas Faruk 
Published: March 2020

e20016 Background: Mucosal melanoma (MM) of head and neck (H&N) is a relatively rare and different disease from cutaneous melanoma (CM). We aimed to define clinical features and outcomes of patients with MM of H&N and to emphasize its differences from CM. Methods: The medical records of patients (n= 41 for MM, n=94 for CM) between 2000 and 2010 were assesed. Results: In MM group, 21 patients had primary oral cavity (OCM) and 20 had sinonasal melanoma (SNM). The median age was 60 years and gender distribution was similar. Thirty-two (78%) of patients had stage I, 4 (10%) had stage II, and 5 (12%) patients had stage III disease. One and 5-year overall survival (OS) rates were 81% and 58%, and similar for SNM and OCM (p=0.67). Among CM patients, primary sites were face (53%), scalp (28%) and ear region (19%). Facial melanoma (FM) patients were older (p=0.001) than scalp (SM) or ear melanoma (EM). Male gender was more frequent among SM patients (81%) than FM (42%, p=0.001) and EM (50%, p=0.03). Most of FM patients had localized disease (84%), while most of EM (72%) and SM (46%) patients had advanced disease. One and 5-year OS rates of CM were 86% and 43%, respectively. Five-year OS rates were 72% for FM, 27% for EM and 17% for SM (FM v SM, p<0.001; FM v EM, p=0,012; EM v SM, p=0.40). Advanced disease (stage III and IV) had significant impact on OS (p=0.001) for only SM patients. In addition, male patients with CM had poorer prognosis than female patients (p=0.034). However, age of patient did not affect OS. MM group was older (median 60 v 54 years, p= 0.008) and had a higher rate of localized disease than CM (78% v 65%, p=0.06). Advanced disease had a significant impact on OS for both MM and CM (p= 0.03). OS rates of CM and MM were similar (p=0.53). Conclusions: Melanoma of H&N region is a very heterogeneous disease. MM has different clinicopathologic features from CM. Primary site of melanoma in this region is also important for prognosis and biological behaviour of tumour. Therefore, approaches to these melanomas should be different.
A phase III trial of nab-paclitaxel versus dacarbazine in chemotherapy-naive patients (pts) with metastatic melanoma: Analysis of peripheral neuropathy.
Authors: Del Vecchio Michele , Hersh Evan , Brown Michael Paul , Clements Arthur , Loquai Carmen , Ferrucci Pier Francesco , Robert Caroline , Li Mingyu , Elias Ilena , Renschler Markus F. , Hauschild Axel 
Published: March 2020

e20025 Background: Peripheral neuropathy (PN) is a common side effect associated with taxane treatment. In a phase III trial, nab-paclitaxel vs dacarbazine demonstrated a significant improvement in progression-free survival (4.8 vs 2.5 months; P = 0.044) and at the interim survival analysis, a trend toward prolonged overall survival (12.8 vs 10.7 months; P = 0.094) for the treatment of chemotherapy-naive patients with metastatic melanoma. Here we report on the PN profile of nab-paclitaxel in this phase III trial. Methods: Pts (median age, 63 years) with chemotherapy-naive stage IV melanoma (M1c stage, 65%; elevated LDH, 28%) and an ECOG performance status 0-1 were randomized to nab-paclitaxel 150 mg/m2 on days 1, 8, and 15 of a 28-day cycle (n = 264) or dacarbazine 1000 mg/m2on day 1 of each 21-day cycle (n = 265). PN events were defined based on the Standardized MedDRA Query (V 12.1, broad scope). Results: As expected, a higher proportion of pts receiving nab-paclitaxel vs dacarbazine had ≥ 1 treatment-related PN event (68% vs 8%; P < 0.001). Treatment-related grade ≥ 3 PN was more frequent with nab-paclitaxel vs dacarbazine (25% vs 0%; P < 0.001); 2 grade 4 events were reported in the nab-paclitaxel arm. Treatment-related grade ≥ 3 PN was 15% in pts who received up to the median of 3 cycles of nab-paclitaxel. PN led to dose reduction in 13% or discontinuation in 15% of nab-paclitaxel–treated pts. The median time to onset of grade ≥ 3 PN was 101 days (95% CI, 85 - 113). Most early-onset PN events, occurring within the first 3 cycles, were grade 1. Grade ≥ 2 PN events peaked by cycle 4 and subsided by cycle 9. Forty-one of the 64 (64%) pts with a grade ≥ 3 PN event had an improvement of ≥ 1 grade, with a median time to improvement of 28 days (95% CI, 17 - 64), and 33 of 64 (52%) pts had improved to grade 1 or better by a median of 67 days from onset (95% CI, 22- upper limit not estimable); 30 of 64 (47%) pts resumed treatment with nab-paclitaxel. Conclusions: In this phase III trial, grade ≥ 3 PN was the main treatment-related toxicity with nab-paclitaxel as observed in other studies. However, PN was rapidly reversible; a majority of pts had improvement of PN symptoms within 1 month and resumed treatment. Clinical trial information: NCT00864253.
Combination therapy with ipilimumab and electrochemotherapy: Preliminary efficacy results and correlation with immunologic parameters.
Authors: Simeone Ester , Benedetto Lucia , Gentilcore Giusy , Caraco Corrado , Di Monta Gianluca , Grimaldi Antonio M , Esposito Assunta , Capone Marilena , Marone Ugo Di , Curvietto Marcello , Madonna Gabriele Di , Di Cecilia Marialuisa , Mori Stefano Di , Mozzillo Nicola , Ascierto Paolo Antonio 
Published: March 2020

e20031 Background: Ipilimumab is the first agent approved for the treatment of advanced melanoma that showed a survival benefit in randomized phase 3 trials. Despite the survival benefit, due to its mechanism of action it is associated with a slow onset and low rate of responses and, in many cases, responses occur after other therapies, like chemotherapy, targeted therapy and radiotherapy. Electrochemotherapy (ECT) has been shown to be effective and well tolerated for local control of metastatic melanoma with superficial lesions. The current challenge is to improve ipilimumab efficacy by combination/sequence with other therapies. We performed a pilot study of combination with ipilimumab and ECT in order to verify the possible increase of response rate. Furthermore, due to the lack of predictive markers, we evaluated the possible predictive role of circulating T-regulatory cells (T-Reg) variations in peripheral blood mononuclear cells (PBMC) of treated patients. Methods: We collected data from 10 patients (pts) with advanced melanoma (6 stage IIIc and 4 stage IV M1c) treated with ipilimumab at 3 mg/kg every 3 weeks for 4 cycles (day 1) and ECT with bleomycine at 15 mg/m2 (day 2) on superficial lesions. Blood draws were collected on day 0, 1 and 2, then on day 15 and 30 from ECT, at each cycle of ipilimumab and at every tumor evaluation (every 12 weeks). PBMC were thawed and labeled with anti-CD4-Pe-Cy-5, CD25-Pe and anti-FoxP3-AlexaFlour488 for T-Reg. Results: 10/10 (100%) pts showed local objective responses (4 CR and 6 PR). 7/10 (70%) pts showed local response (6 PR and 1 CR) after the second ipilimumab dose and 3/10 showed response (3 CR) at week 12. Two pts with PR (28%) out of the group of 7 showed response on distant lesions at week 24 (abscopal effect). All pts are still alive with a median follow up of 11 months (range 6-18). We found in all pts a decrease of T-Reg of 0.10% (range 0.50-2.6%) per cycle and no variation of CD4+ and CD25+ lymphocytes. Conclusions: Our preliminary results show that a combination approach with ipilimumab and ECT may increase responses to ipilimumab. T-Reg decrease in PBMC could be associated with response to treatment. Further studies about this combination are warranted.
Clinical characteristics of melanoma patients with non-V600E/K BRAF mutations.
Authors: Nowroozi Sasan , Zuo Zhuang , Patel Keyur , Patel Sapna Pradyuman , Luthra Rajyalakshmi , Routbort Mark , Lazar Alexander J. F. , Davies Michael A. , Hasanein Hassan , Papadopoulos Nicholas E. , Hwu Wen-Jen , Bedikian Agop Y. , Woodman Scott , Hwu Patrick , Kim Kevin 
Published: March 2020

e20036 Background: BRAF mutations are found in ~50% of melanoma. V600E/K substitutions are the most common and well-characterized. We analyzed the clinical characteristics of patients with non-V600E/K BRAF mutations. Methods: We identified 38 melanoma patients whose tumor contained a non-V600E/K BRAF mutation and reviewed the clinical characteristics. The sequencing analysis was performed with either pyrosequencing or next generation sequencing assay. Results: 38 patients were identified with non-V600E/K BRAF mutations. Mutations detected in more than 1 patient included V600R (n=14, 37%), K601E (5, 13%), G469E (3, 8%); L597S (3, 7%), D594G (2, 5%); 11 other mutations were identified in single patients. Median age was 57 yrs; 82% were men; 95% were white. The common primary subtypes were nodular (26%), superficial spreading (24%), unknown primary (21%); no one were acral, mucosal or uveal melanomas. Ten (26%) of 27 with known ulceration status had ulceration, and 3 (7%) of 22 with known mitosis status had < 1 mitosis /mm2. The sites of primary melanoma were located mostly in the head/neck and the trunk (63%), extremities (16%) and unknown primary (21%). The stage at diagnosis was I /II (29%), III (40%), IV (18%) and unknown (13%). Among 33 (87%) patients who ultimately developed distant metastases, 23(67%) had metastasis in the soft tissue/nodes, 21 (63%) in the lung, 9 (24%) in the brain, 7 (21%) in the liver, 6 (16%) in the bone, and 5 (15%) in the adrenal gland. Among patients (n=25) with initial stage I-III melanoma who later developed distant metastasis, the median duration between the time of initial diagnosis and distant metastases was 36 months. Among the 32 (84%) of the patients who developed stage IV melanoma, the median survival from the time of stage IV diagnosis was 18 months. Five patients received vemurafenib treatment, and 2 patients (K601E; T599_V600ins2) had stable disease and 2 patients (L597Q; G466E) had disease progression and 1 lost to follow up. Conclusions: Unexpectedly higher proportion of the patients with non-V600E/K mutant-melanoma had unknown primary melanoma and higher mitotic rate. In a small number of patients who received vemurafenib, the clinical response appears to be low.
Ipilimumab for advanced, refractory melanoma: A report of the Israeli cohort of expanded access program.
Authors: Shapira-Frommer Ronnie , Stephen Frank , Ben-Ami Eytan , Hamburger Tamar , Markel Gal , Ospovat Inna , Zippel Douglas , Merims Sharon , Apter Sara , Steinberg Hani , Silman-Steiberg Yael , Peretz Tamar , Lotem Michal , Schachter Jacob 
Published: March 2020

e20039 Background: As the first agent to show survival advantage in metastatic melanoma, Ipilimumab (Yervoy, BMS) is being gradually introduced into health services worldwide. It's unique immune mediated side effects requires the incorporation of follow-up guidelines to prevent toxic sequella. We report on safety and efficacy results of refractory melanoma patients (pts) treated on an international expanded access program of Ipilimumab. Methods: Between 4/2010 and 12/2011 183 pts were treated. Pts received Ipilimumab 3 mg/kg q3w for 4 doses. Pts with evidence of clinical benefit at week 12 (CR, PR or SD), were eligible for re-induction upon progression. Results: All pts were pretreated for metastatic disease (median:1 line,range 1-5). 140 pts(77%) had M1c disease, 63 pts(34%) had brain metastasis and 84 (46%) had LDH above ULN, reflecting poor prognostic characteristics of this cohort. Patients received 3.6 doses of Ipilimumab on average. 11% received less than 4 cycles due to toxicity. Grade 3/4 immune-related adverse events were noted in 19.6% with the most common all grades toxicity being diarrhea (17.5%), pruritus (14%) rash (13%) and fatigue (8.7%). Grade 5 toxicity was noted in 4 patients (2%). Five pts were treated with anti TNF antibodies (Infliximab) for steroid resistant toxicity. Objective responses were noted in 16 pts (8.7%;4 CR, 12 PR), 26 pts(14.2%) had stable disease, overall yielding clinical benefit in 23%. Patients with stage IIIc, M1a and M1b were more likely to benefit (52% Vs 23% of the group, p<0.001) as well as patients previously treated by immunotherapy (p=0.026). Median OS was 9.2 months with 1 year survival of 42%. 34 pts (18.6%) are alive beyond 20 months, the majority of them received no further treatment. Factors favoring survival included stage IIIc, M1a and M1b, LDH below ULN and lymphocyte count at week 6 above 1000/ml (p values: <0.001,<0.001, 0.03 respectively). None of the 14 ocular melanoma pts exhibited clinical benefit. Conclusions: Our cohort reflects rapid adoption of this new modality. Ipilimumab had significant clinical benefit, comparable with previous reports, in a heterogenous group of patients, including those with poor prognostic factors.
Outcome and prognostic factors in BRAF mutation positive metastatic melanoma treated with a BRAF inhibitor: A population-based study in British Columbia.
Authors: Vergidis Joanna , Klasa Richard John , Zhou Youwen , Moon Elena , Jepson Debbie , Savage Kerry J. 
Published: March 2020

e20045 Background: BRAF mutations are present in approximately 40-60% of cutaneous melanomas. The BRAF inhibitor vemurafenib has demonstrated dramatic anti-tumour activity in phase III trials in BRAF mutation positive (BRAFm) metastatic/unresectable melanoma; however, there is limited data outside of clinical trials. Methods: All patients > 18 years of age, PS 0-2, with metastatic/unresectable melanoma considered for treatment with vemurafenib in British Columbia between March 2011 to December 2012 were identified. CNS disease, if present, had to be radiographically stable/asymptomatic and treated with radiation and/or surgery. The BRAF V600E mutation status was evaluated centrally on primary or metastatic biopsies using a real-time PCR assay (Cobas 4800 BRAF Mutation Test, Roche Molecular Systems). Vemurafenib was initially provided through an Expanded Access Program/Roche patient assistance program and subsequently through provincial funding. Results: In total, 84 patients were identified that had undergone BRAF mutation screening, 49(58%) were BRAFm, 35(42%) were BRAFwt. For the BRAFm patients 33 have received 1 cycle of vemurafenib and are included in the present analysis (n=21 (64%) 1st line therapy; 12(36%) > 1st line therapy). BRAFm patients: median age 53 y; 64% male; PS 0/1 76%; LDH elevated 51.5%; M1c 91%; 27% history CNS metastases. With a median follow-up of 4.9 m the median PFS, measured from the 1st dose of vemurafenib, was 9 m and the median OS was 12.4 m. The 1 year PFS and OS were 47% and 50%, respectively. The median OS of patients who progressed following vemurafenib was only 2 months. There was an inferior PFS in patients with an elevated LDH (median PFS 5 m vs not reached, p=0.024) prior to receiving vemurafenib. Conclusions: The efficacy of vemurafenibin BRAF + melanoma in this population-based analysis compares favorably to estimates in the clinical trial setting. The survival of patients who progress on vemurafenib is short, highlighting the need to explore combination therapies. An updated analysis will be presented.
A prospective evaluation of vascular endothelial growth factor (VEGF) and the immune system in stage III/IV melanoma.
Authors: Agostino Nicole Marie , Weiss Michael , Shi Wenjing , Nevala Wendy Kay , Hemperly Stephen , Markovic Svetomir , Nair Suresh G 
Published: March 2020

e20046 Background: The immune system and VEGF may play a role in melanoma behavior. We prospectively collected data in 10 stage III and 22 stage IV melanoma patients to observe factors influencing outcomes. Methods: We assessed median survival (MS), LDH, BRAF, VEGF, Th1/Th2 ratio, regulatory T cells (Tregs) and CD4/CD8 ratio, which were measured upon enrollment. LDH and BRAF were measured in standard commercial labs; VEGF via ELISA at LVHN; Th1/Th2 ratio and CD4/CD8 ratio via flow cytometry at Mayo Clinic. Stage III patients were treated with resection and interferon or observation. Stage IV patients were treated with some or all of the following: resection +/- GM-CSF, IL-2, ipilimumab, vemurafenib, carboplatin/paclitaxel/bevacizumab and temazolamide. Results: MS for stage IV patients was 48 months using a Kaplan-Meier survival curve. The only variable associated with survival was LDH, (HR=1.0017, 95%CI: 1.0003-1.0032, p=0.02). In stage IV patients, there was a positive correlation between VEGF and Tregs (r=.485, n=22 p=0.022) and a negative correlation between Tregs and Th1/Th2 (r=-.470, n=22, p=0.027). In stage III/IV patients who were alive at study completion, there was a positive correlation between CD4/CD8 and VEGF (r=.792, n=10, p=0.006). In patients who died, there was a negative correlation between Tregs and Th1/Th2 (r=-.660, n=12, p=0.02). 7 of the stage IV patients are currently disease free, including 5 of the 10 who received IL-2 +/- metastectomy. Conclusions: While a median survival of 48 months was provocative for stage IV patients, it may reflect referral selection at an IL-2 center. Recent advances such as ipilimumab (which lowers Tregs), BRAF inhibitors, and immunotherapy/aggressive resection as initial therapy may have impacted survival. The literature suggests that an elevated CD4/CD8 ratio predicts better outcomes. Higher VEGF levels have also been associated with lower overall survival in patients treated with IL-2. We found an association between higher VEGF levels and increased Tregs in deceased patients but not in living patients. In patients still alive, higher VEGF was balanced by a higher CD4/CD8 ratio. We did not find a correlation between baseline VEGF and survival.