Extended long-term follow-up of metastatic melanoma patients treated with immunotherapy: late relapses and second primary melanomas.

Background: Immunotherapy has revolutionized the treatment of patients with advanced melanoma as well as other cancers. Most studies, whether of interleukin-2 or checkpoint inhibitor therapies, have limited follow-up after 5 years, making the incidence of late relapses uncertain. In addition, the incidence of second primary melanomas in patients with stage IV melanoma treated with immunotherapy has rarely been reported.

A Pilot Study of Hepatic Irradiation with Yttrium-90 Microspheres Followed by Immunotherapy with Ipilimumab and Nivolumab for Metastatic Uveal Melanoma.

Liver metastases from uveal melanoma carry a very poor prognosis. Hepatic artery infusions with Yttrium-90 (Y) resin microspheres have some activity in this disease, and radiation and immunotherapy may be synergistic. The primary objective of this study was to determine the safety and tolerability of sequential Y resin microspheres and immunotherapy with ipilimumab and nivolumab in metastatic uveal melanoma.

Immune adverse events (irAEs) with adjuvant ipilimumab in melanoma, use of immunosuppressants and association with outcome: ECOG-ACRIN E1609 study analysis.

Background: The impact of immune-related adverse events (irAEs) occurring from adjuvant use of immunotherapy and of their management on relapse-free survival (RFS) and overall survival (OS) outcomes is currently not well understood.

Patients And Methods: E1609 enrolled 1673 patients with resected high-risk melanoma and evaluated adjuvant ipilimumab 3 mg/kg (ipi3) and 10 mg/kg (ipi10) versus interferon-α. We investigated the association of irAEs and of use of immunosuppressants with RFS and OS for patients treated with ipilimumab (n=1034).

Prevalence of Homologous Recombination Pathway Gene Mutations in Melanoma: Rationale for a New Targeted Therapeutic Approach.

Homologous recombination DNA damage repair (HR-DDR) deficient patients with various solid tumors have been treated with PARP inhibitors. However, the clinical characteristics of patients with melanoma who have HR-DDR gene mutations and the consequences of PARP inhibition are poorly understood. We compared the commercially available next-generation sequencing data from 84 patients with melanomas from our institution with a dataset of 1,986 patients as well as 1,088 patients profiled in cBioportal.

Sources of contamination in the operating room: A fluorescent particle powder study.

This study utilized fluorescent particle powder to investigate 2 potential sources of sterile field contamination in the operating room (OR): forced-air warming blankets and OR light manipulation. In part 1, sterile draping for knee replacement surgery was performed on a mannequin in a sterile OR, comparing field contamination with the forced-air warming on versus off during draping. In part 2, OR lights coated with fluorescent powder were manipulated over a sterile field.

Phase III Study of Adjuvant Ipilimumab (3 or 10 mg/kg) Versus High-Dose Interferon Alfa-2b for Resected High-Risk Melanoma: North American Intergroup E1609.

Purpose: Phase III adjuvant trials have reported significant benefits in both relapse-free survival (RFS) and overall survival (OS) for high-dose interferon alfa (HDI) and ipilimumab at 10 mg/kg (ipi10). E1609 evaluated the safety and efficacy of ipilimumab at 3 mg/kg (ipi3) and ipi10 versus HDI.

Patients And Methods: E1609 was a phase III trial in patients with resected cutaneous melanoma (American Joint Committee on Cancer 7th edition stage IIIB, IIIC, M1a, or M1b).

Fruit production is influenced by tree size and size-asymmetric crowding in a wet tropical forest.

In tropical forest communities, seedling recruitment can be limited by the number of fruit produced by adults. Fruit production tends to be highly unequal among trees of the same species, which may be due to environmental factors. We observed fruit production for ~2,000 trees of 17 species across 3 years in a wet tropical forest in Costa Rica.

Survival and clinical outcomes of patients with melanoma brain metastasis in the era of checkpoint inhibitors and targeted therapies.

Background: Melanoma brain metastasis is associated with an extremely poor prognosis, with a median overall survival of 4-5 months. Since 2011, the overall survival of patients with stage IV melanoma has been significantly improved with the advent of new targeted therapies and checkpoint inhibitors. We analyze the survival outcomes of patients diagnosed with brain metastasis after the introduction of these novel drugs.

Prolonged survival after intraperitoneal interleukin-2 immunotherapy for recurrent ovarian cancer.

•A case report of a 14 year remission of recurrent ovarian cancer with intraperitoneal aldesleukin (IL-2) is presented.•Intraperitoneal IL-2 was given with little toxicity.•Immunotherapy may have the potential for durable remissions in ovarian cancer.

Non-progressing cancer patients have persistent B cell responses expressing shared antibody paratopes that target public tumor antigens.

There is significant debate regarding whether B cells and their antibodies contribute to effective anti-cancer immune responses. Here we show that patients with metastatic but non-progressing melanoma, lung adenocarcinoma, or renal cell carcinoma exhibited increased levels of blood plasmablasts. We used a cell-barcoding technology to sequence their plasmablast antibody repertoires, revealing clonal families of affinity matured B cells that exhibit progressive class switching and persistence over time.

Overall Survival in Patients With Advanced Melanoma Who Received Nivolumab Versus Investigator's Choice Chemotherapy in CheckMate 037: A Randomized, Controlled, Open-Label Phase III Trial.

Purpose Until recently, limited options existed for patients with advanced melanoma who experienced disease progression while receiving treatment with ipilimumab. Here, we report the coprimary overall survival (OS) end point of CheckMate 037, which has previously shown that nivolumab resulted in more patients achieving an objective response compared with chemotherapy regimens in ipilimumab-refractory patients with advanced melanoma. Patients and Methods Patients were stratified by programmed death-ligand 1 expression, BRAF status, and best prior cytotoxic T-lymphocyte antigen-4 therapy response, then randomly assigned 2:1 to nivolumab 3 mg/kg intravenously every 2 weeks or investigator's choice chemotherapy (ICC; dacarbazine 1,000 mg/m every 3 weeks or carboplatin area under the curve 6 plus paclitaxel 175 mg/m every 3 weeks).

Combined nivolumab and ipilimumab versus ipilimumab alone in patients with advanced melanoma: 2-year overall survival outcomes in a multicentre, randomised, controlled, phase 2 trial.

Background: Results from phase 2 and 3 trials in patients with advanced melanoma have shown significant improvements in the proportion of patients achieving an objective response and prolonged progression-free survival with the combination of nivolumab (an anti-PD-1 antibody) plus ipilimumab (an anti-CTLA-4 antibody) compared with ipilimumab alone. We report 2-year overall survival data from a randomised controlled trial assessing this treatment in previously untreated advanced melanoma.

Methods: In this multicentre, double-blind, randomised, controlled, phase 2 trial (CheckMate 069) we recruited patients from 19 specialist cancer centres in two countries (France and the USA).

Talimogene Laherparepvec in Combination With Ipilimumab in Previously Untreated, Unresectable Stage IIIB-IV Melanoma.

Purpose: Combining immunotherapeutic agents with different mechanisms of action may enhance efficacy. We describe the safety and efficacy of talimogene laherparepvec (T-VEC; an oncolytic virus) in combination with ipilimumab (a cytotoxic T-lymphocyte-associated antigen 4 checkpoint inhibitor) in patients with advanced melanoma.

Methods: In this open-label, multicenter, phase Ib trial of T-VEC in combination with ipilimumab, T-VEC was administered intratumorally in week 1 (10(6) plaque-forming units/mL), then in week 4 and every 2 weeks thereafter (10(8) plaque-forming units/mL).

Nivolumab and ipilimumab versus ipilimumab in untreated melanoma.

Background: In a phase 1 dose-escalation study, combined inhibition of T-cell checkpoint pathways by nivolumab and ipilimumab was associated with a high rate of objective response, including complete responses, among patients with advanced melanoma.

Methods: In this double-blind study involving 142 patients with metastatic melanoma who had not previously received treatment, we randomly assigned patients in a 2:1 ratio to receive ipilimumab (3 mg per kilogram of body weight) combined with either nivolumab (1 mg per kilogram) or placebo once every 3 weeks for four doses, followed by nivolumab (3 mg per kilogram) or placebo every 2 weeks until the occurrence of disease progression or unacceptable toxic effects. The primary end point was the rate of investigator-assessed, confirmed objective response among patients with BRAF V600 wild-type tumors.

Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial.

Background: Nivolumab, a fully human IgG4 PD-1 immune checkpoint inhibitor antibody, can result in durable responses in patients with melanoma who have progressed after ipilimumab and BRAF inhibitors. We assessed the efficacy and safety of nivolumab compared with investigator's choice of chemotherapy (ICC) as a second-line or later-line treatment in patients with advanced melanoma.

Methods: In this randomised, controlled, open-label, phase 3 trial, we recruited patients at 90 sites in 14 countries.

The role of BPTF in melanoma progression and in response to BRAF-targeted therapy.

Background: Bromodomain PHD finger transcription factor (BPTF) plays an important role in chromatin remodeling, but its functional role in tumor progression is incompletely understood. Here we explore the oncogenic effects of BPTF in melanoma.

Methods: The consequences of differential expression of BPTF were explored using shRNA-mediated knockdown in several melanoma cell lines.

Phase 2 Study of Intralesional PV-10 in Refractory Metastatic Melanoma.

Purpose: This international, multicenter, single-arm trial assessed efficacy and safety of intralesional rose bengal (PV-10) in 80 patients with refractory cutaneous or subcutaneous metastatic melanoma.

Methods: Sixty-two stage III and 18 stage IV melanoma patients with disease refractory to a median of six prior interventions received intralesional PV-10 into up to 20 cutaneous and subcutaneous lesions up to four times over a 16-week period and were followed for 52 weeks. Objectives were to determine best overall response rate in injected target lesions and uninjected bystander lesions, assess durability of response, and characterize adverse events.

Phase II trial (BREAK-2) of the BRAF inhibitor dabrafenib (GSK2118436) in patients with metastatic melanoma.

Purpose: Dabrafenib (GSK2118436) is a potent inhibitor of mutated BRAF kinase. Our multicenter, single-arm, phase II study assessed the safety and clinical activity of dabrafenib in BRAF(V600E/K) mutation-positive metastatic melanoma (mut(+) MM).

Patients And Methods: Histologically confirmed patients with stage IV BRAF(V600E/K) mut(+) MM received oral dabrafenib 150 mg twice daily until disease progression, death, or unacceptable adverse events (AEs).

Anesthesia management of patients undergoing hyperthermic isolated limb perfusion with melphalan for melanoma treatment: an analysis of 17 cases.

Background: Hyperthermic isolated limb perfusion (HILP) is used for patients with intractable or extensive in-transit metastatic melanoma of the limb to deliver high concentrations of cytotoxic agents to the affected limb and offers a treatment option in a disease stage with a poor prognosis when no treatment is given.

Methods: In a retrospective chart review of 17 cases, we studied the anesthetic and hemodynamic changes during HILP and its management.

Results: HILP was well tolerated except in one case that is described herein.

Inoperable bulky melanoma responds to neoadjuvant therapy with vemurafenib.

A patient with a bulky inoperable stage IIIC melanoma involving the left axilla and neck from a primary of the left medial elbow received vemurafenib as neo-adjuvant treatment. Based on the molecular analysis, BRAF V600E mutation was present. After 4 months of vemurafinib treatment, the tumours shrank to less than 50% of original clinical size and allowed the surgeons to perform a left modified radical neck dissection and left radical axillary dissection.

Successful desensitization in a case of Stevens-Johnson syndrome due to vemurafenib.

The BRAF inhibitor vemurafenib can cause severe cutaneous reactions, including Stevens-Johnson syndrome, particularly when administered after ipilimumab, which usually prevents further drug administration. We report the case of a patient with Stevens-Johnson syndrome due to vemurafenib, who was retreated with vemurafenib with a program of slow desensitization with dexamethasone and diphenhydramine. Vemurafenib was tolerated at a 50% dose after a 3-week desensitization.