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. In total, 21.4% of patients had ≥1 functional HR-DDR mutation, most commonly involving BRCA1, ARID1A, ATM, ATR, and FANCA. Concurrent NF1, BRAF, and NRAS mutations were found in 39%, 39%, and 22% of cases, respectively. HR-DDR gene mutation was associated with high tumor mutational burden and clinical response to checkpoint blockade. A higher prevalence of HR-DDR mutations was observed in the datasets from Foundation Medicine (Cambridge, CA) and those from the Cancer Genome Atlas. Treatment of HR-DDR‒mutated patient-derived xenograft models of melanoma with PARP inhibitor produced significant antitumor activity in vivo and was associated with increased apoptotic activity. RNA sequencing analysis of PARP inhibitor-treated tumors indicated alterations in the pathways involving extracellular matrix remodeling, cell adhesion, and cell-cycle progression. Melanomas with HR-DDR mutations represent a unique subset, which is more likely to benefit from checkpoint blockade and may be targeted with PARP inhibitor.

A rare case of pulmonary Kaposi sarcoma presented with respiratory failure.

Kaposi sarcoma (KS) is the most commonly diagnosed malignancy in HIV-infected patients. With new treatments, incidence and severity of KS have significantly decreased. A 57-year-old African American male with medical history of AIDS presented with progressively worsening cough, shortness of breath, fever, night sweats, and 60 lb weight loss. On physical examination, he had diffused dark purple skin lesions and decreased air entry in the right lower lung fields. Chest x-ray and subsequent chest computed tomography (CT) showed moderate right lung pleural effusion with scattered bilateral diffuse infiltrates. The patient's absolute CD4 count was 27 cells/microliter. Thoracentesis was negative for infection or malignancy. He was started on chemotherapy paclitaxel along with HAART for extensive pulmonary KS. Since starting the treatment, his condition has significantly improved with near complete resolution of the pleural effusion, oral, and skin lesions. In conclusion, the diagnosis of AIDS-related pulmonary KS is often clinical, typically based on the presence of mucocutaneous disease and compatible features on CT chest. The differential diagnosis of pulmonary KS is broad. A detailed evaluation should exclude an infectious etiology or other tumors. Chemotherapy along with HAART can be used for treatment of severe pulmonary KS.

Role of Elevated PHIP Copy Number as a Prognostic and Progression Marker for Cutaneous Melanoma.

Purpose: Previous studies have indicated an important role for pleckstrin homology domain-interacting protein (PHIP) as a marker and mediator of melanoma metastasis. Here we aimed to confirm the role of PHIP copy number in successive stages of melanoma progression.Experimental Design:PHIP copy number was examined using FISH in three independent cohorts by recording the percentage of cells harboring ≥3 copies of PHIP The impact of PHIP copy number on survival was assessed using Cox regression analysis. The enrichment of PHIP was assessed in various molecular melanoma subtypes. PHIP expression was analyzed in The Cancer Genome Atlas (TCGA) melanoma cohort.Results: Elevated PHIP copy number was significantly predictive of reduced distant metastasis-free survival (DMFS) and disease-specific survival (DSS), and increased prevalence of ulceration in primary melanoma (cohort No. 1). By multivariate analysis, PHIP FISH scores were independently predictive of DMFS and DSS. PHIP copy number was enriched in metastatic melanomas harboring mutant NRAS or expressing PTEN protein (cohort No. 2). PHIP copy number was significantly elevated in metastatic melanomas when compared with matched primary tumors from the same patient (cohort No. 3). Several of these associations were replicated using TCGA cohort analysis.Conclusions: These results underscore the important role of PHIP copy-number elevation in melanoma progression, and identify molecular subtypes of melanoma in which PHIP is enriched. Finally, as elevated PHIP copy number appears to be selected for during the progression of primary to metastatic melanoma, these results confirm PHIP as a promising therapeutic target for melanoma. Clin Cancer Res; 24(17); 4119-25. ©2018 AACR.

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. METHODS: We performed a retrospective analysis of our melanoma center database and identified 79 patients with brain metastasis between 2011 and 2015. RESULTS: The median time from primary melanoma diagnosis to brain metastasis was 3.2 years. The median overall survival duration from the time of initial brain metastasis was 12.8 months. Following a diagnosis of brain metastasis, 39 (49.4%), 28 (35.4%), and 24 (30.4%) patients were treated with anti-CTLA-4 antibody, anti-PD-1 antibody, or BRAF inhibitors (with or without a MEK inhibitor), with a median overall survival of 19.2 months, 37.9 months and 12.7 months, respectively. Factors associated with significantly reduced overall survival included male sex, cerebellar metastasis, higher number of brain lesions, and treatment with whole-brain radiation therapy. Factors associated with significantly longer overall survival included treatment with craniotomy, stereotactic radiosurgery, or with anti-PD-1 antibody after initial diagnosis of brain metastasis. CONCLUSIONS: These results show a significant improvement in the overall survival of patients with melanoma brain metastasis in the era of novel therapies. In addition, they suggest the activity of anti-PD-1 therapy specifically in the setting of brain metastasis.

Efficacy of intralesional amphotericin B for the treatment of cutaneous leishmaniasis.

BACKGROUND: Antimoniate compounds have been used as gold standard treatment for cutaneous leishmaniasis since many years ago, but with increase in incidence of drug as well as individual contraindications, more attention has been given to alternative treatments. AIM: The aim of this study was to evaluate the efficacy of intralesional amphotericin B as an alternative treatment for cutaneous leishmaniasis in Mashhad, Iran, during 2007-2009. MATERIALS AND METHODS: Non-random sampling from both sexes and without any age limitation of cases eligible for this alternative treatment was done. Size and induration of lesions were measured before beginning and weakly during the treatment. Amphotericin B (2 mg/ml) was injected into lesions weekly for up to 12 weeks and the cases were followed up for the treatment responses, possible side effects and recurrence of the disease. RESULTS: A total of 93 patients with a mean age of 20.81 ± 15.26 years were included in this study. At the end of 12(th) week, 61.4% of the patients were recovered completely (more than 90% reduction in size and induration), 21.6% had partial remission (60-90% reduction in size and induration), and 17% had less than 60% reduction in size and induration of skin lesions. Injection side effects were insignificant and did not lead to premature discontinuation of treatment in any patients. CONCLUSION: Weekly intralesional injection of amphotericin B looks promising, considering the fact that most of the patients in this study were resistant to antimoniates.