Intracranial hemorrhage caused by dabrafenib and trametinib therapy for metastatic melanoma.

Although generally well tolerated compared with chemotherapy, molecular targeted therapy used in metastatic melanoma may be associated with life-threatening toxicity. We report the case of a patient with metastatic melanoma treated by dabrafenib plus trametinib who developed intracranial hemorrhage. Physicians should be aware of this rare but life-threatening adverse event of B-rapidly accelerated fibrosarcoma (BRAF) and mitogen-activated protein kinase kinase (MEK) inhibitors. However, they should be also careful about the bleeding origin, which can prove to be a new onset of melanoma metastasis or anticoagulation overdose, or even an uncontrolled arterial hypertension.

Individuals with JAK1 variants are affected by syndromic features encompassing autoimmunity, atopy, colitis, and dermatitis.

Inborn errors of immunity lead to autoimmunity, inflammation, allergy, infection, and/or malignancy. Disease-causing JAK1 gain-of-function (GoF) mutations are considered exceedingly rare and have been identified in only four families. Here, we use forward and reverse genetics to identify 59 individuals harboring one of four heterozygous JAK1 variants. In vitro and ex vivo analysis of these variants revealed hyperactive baseline and cytokine-induced STAT phosphorylation and interferon-stimulated gene (ISG) levels compared with wild-type JAK1. A systematic review of electronic health records from the BioME Biobank revealed increased likelihood of clinical presentation with autoimmunity, atopy, colitis, and/or dermatitis in JAK1 variant-positive individuals. Finally, treatment of one affected patient with severe atopic dermatitis using the JAK1/JAK2-selective inhibitor, baricitinib, resulted in clinically significant improvement. These findings suggest that individually rare JAK1 GoF variants may underlie an emerging syndrome with more common presentations of autoimmune and inflammatory disease (JAACD syndrome). More broadly, individuals who present with such conditions may benefit from genetic testing for the presence of JAK1 GoF variants.

Low risk of embryonic and other cancers in PIK3CA-related overgrowth spectrum: Impact on screening recommendations.

The PIK3CA-related overgrowth spectrum (PROS) encompasses various conditions caused by mosaic activating PIK3CA variants. PIK3CA somatic variants are also involved in various cancer types. Some generalized overgrowth syndromes are associated with an increased risk of Wilms tumor (WT). In PROS, abdominal ultrasound surveillance has been advocated to detect WT. We aimed to determine the risk of embryonic and other types of tumors in patients with PROS in order to evaluate surveillance relevance. We searched the clinical charts from 267 PROS patients for the diagnosis of cancer, and reviewed the medical literature for the risk of cancer. In our cohort, six patients developed a cancer (2.2%), and Kaplan Meier analyses estimated cumulative probabilities of cancer occurrence at 45 years of age was 5.6% (95% CI = 1.35%-21.8%). The presence of the PIK3CA variant was only confirmed in two out of four tumor samples. In the literature and our cohort, six cases of Wilms tumor/nephrogenic rests (0.12%) and four cases of other cancers have been reported out of 483 proven PIK3CA patients, in particular the p.(His1047Leu/Arg) variant. The risk of WT in PROS being lower than 5%, this is insufficient evidence to recommend routine abdominal imaging. Long-term follow-up studies are needed to evaluate the risk of other cancer types, as well as the relationship with the extent of tissue mosaicism and the presence or not of the variant in the tumor samples.

Efficacy of Immune Checkpoint Inhibitor (ICI) Rechallenge in Advanced Melanoma Patients' Responders to a First Course of ICI: A Multicenter National Retrospective Study of the French Group of Skin Cancers (Groupe de Cancérologie Cutanée, GCC).

BACKGROUND: The long-term effectiveness of immune checkpoint inhibitor (ICI) rechallenge for progressive or recurrent advanced melanoma following previous disease control induced by ICI has not been thoroughly described in the literature. PATIENTS AND METHODS: In this retrospective multicenter national real-life study, we enrolled patients who had been rechallenged with an ICI after achieving disease control with a first course of ICI, which was subsequently interrupted. The primary objective was to evaluate tumor response, while the secondary objectives included assessing the safety profile, identifying factors associated with tumor response, and evaluating survival outcomes. RESULTS: A total of 85 patients from 12 centers were included in the study. These patients had advanced (unresectable stage III or stage IV) melanoma that had been previously treated and controlled with a first course of ICI before undergoing rechallenge with ICI. The rechallenge treatments consisted of pembrolizumab (n = 44, 52%), nivolumab (n = 35, 41%), ipilimumab (n = 2, 2%), or ipilimumab plus nivolumab (n = 4, 5%). The best overall response rate was 54%. The best response was a complete response in 30 patients (35%), a partial response in 16 patients (19%), stable disease in 18 patients (21%) and progressive disease in 21 patients (25%). Twenty-eight adverse events (AEs) were reported in 23 patients (27%), including 18 grade 1-2 AEs in 14 patients (16%) and 10 grade 3-4 AEs in nine patients (11%). The median progression-free survival (PFS) was 21 months, and the median overall survival (OS) was not reached at the time of analysis. Patients who received another systemic treatment (chemotherapy, targeted therapy or clinical trial) between the two courses of ICI had a lower response to rechallenge (p = 0.035) and shorter PFS (p = 0.016). CONCLUSION: Rechallenging advanced melanoma patients with ICI after previous disease control induced by these inhibitors resulted in high response rates (54%) and disease control (75%). Therefore, ICI rechallenge should be considered as a relevant therapeutic option.

Nivolumab-induced capillary leak syndrome associated with chylothorax in a melanoma patient: A case report and review of the literature.

Introduction: Adverse events (AEs) of immune checkpoint inhibitors (ICIs) are frequent and mainly due to an overactivity of the immune system leading to excessive inflammatory responses (immune-related AE) that can affect any organ of the body. Beside the most frequent AEs, there are rare AEs whose diagnosis and treatment can be challenging. We report here a singular case of capillary leak syndrome (CLS) associated with chylothorax occurring in a patient who has been treated with adjuvant nivolumab (anti-PD1) for resected AJCC stage IIB primary melanoma. Case presentation: A 43-year-old woman was diagnosed with a nodular stage IIB melanoma of her left thigh, according to the AJCC 8th edition (T3bN0M0). The woman was treated with adjuvant nivolumab. She stopped the treatment after 4 infusions due to thrombopenia. Three months later, she developed facial and leg edema and ascites due to capillary leak syndrome. The CLS was associated with chylothorax and elevated vascular endothelial growth factor. The patient was initially treated with several pleural puncturing and steroids. CLS and chylothorax progressively decreased with intravenous immunoglobulins and fat-free diet without recurrence of melanoma at one-year follow-up. Conclusion: CLS is a rare and potentially life-threatening AE of ICIs such as anti-PD1. This AE may be associated with chylothorax probably related to lymphatic permeability induced by anti-PD1.

Naturally Occurring Telomerase-Specific CD4 T-Cell Immunity in Melanoma.

CD4 T cells play a key role in anticancer immunity. In this study, we investigate the clinical relevance of circulating CD4 T helper type 1 (Th1) response against telomerase (anti-TERT Th1 response) in patients with melanoma. The spontaneous anti-TERT Th1 response was detected in 54.5% (85/156) of patients with melanoma before treatment. The prevalence of this systemic response was inversely related to Breslow thickness >1 mm and American Joint Committee on Cancer stage ≥II (P = 0.001 and 0.032, respectively). In contrast to patients treated with targeted therapies, the anti-TERT Th1 immunity was associated with an objective response after immune checkpoint inhibitors treatment. Hence, 86% (18/21) of responder patients exhibited pre-existing anti-TERT Th1 versus 35% (6/19) in nonresponders (P = 0.001). This response was also associated with increased progression-free survival and overall survival in patients with melanoma treated with immune checkpoint inhibitors (P = 0.0008 and 0.012, respectively). Collectively, the presence of circulating anti-TERT Th1 response is inversely related to melanoma evolution and appears to be a predictive factor of response to immunotherapy. Our results highlight the interest in telomerase-specific CD4 Th1 response as a promising blood-based biomarker of immune checkpoint inhibitors therapy in melanoma.

Dissecting cellulitis of the scalp treated by tumour necrosis factor inhibitors: a case series.

BACKGROUND: Dissecting cellulitis of the scalp (DCS), also known as Hoffmann disease or perifolliculitis capitis abscedens et suffodiens, is a rare disease characterized by chronic inflammation of the scalp. Treatment is difficult and often disappointing. OBJECTIVES: To report our experience of TNF inhibitors in a series of patients with DCS. MATERIALS & METHODS: We conducted a monocentric retrospective study of nine patients with DCS treated with TNF blocker after failure of other conventional treatments. RESULTS: After a mean duration of treatment by TNF inhibitors of 17 ± 16 months, four patients (44% versus 0%) had a Physician's Global Assessment score of 0 or 1. We observed a 67% reduction in the number of inflammatory nodules, an 88% reduction in purulent drainage and a 45% improvement in Dermatology Life Quality Index. The mean treatment satisfaction index was 6.6 ± 1.6 out of 10. CONCLUSION: Our study suggests that TNF inhibitors are effective against disease activity and may improve quality of life in the management of DCS refractory to conventional treatments.

MEK inhibitors combined with programmed cell death-1 blockade immunotherapy for metastatic uveal melanoma: is it warranted?

In the setting of metastatic uveal melanoma (mUM), prognosis is dismal and treatment options are limited. MEK inhibition using selumetinib has led to promising results with improved progression-free survival. While immune checkpoint inhibitors such as programmed cell death-1 (PD-1) blockade therapy (anti-PD-1) has shown discrete efficacy in mUM, combining MEK inhibitors (MEKi) to anti-PD-1 might be an option as such combinations have shown synergistic efficacy in metastatic cutaneous melanoma. We report here and discuss our experience in three patients who received this combination in the absence of suitable alternative treatment. The efficacy was difficult to assess due to early severe toxicities (pneumonitis and Takotsubo syndrome). This case series highlights the need to evaluate the safety and efficacy of new treatment options such as MEKi and anti-PD-1 for mUM.

Long-Term Infliximab Treatment in Psoriasis Patients: A National Multicentre Retrospective Study.

BACKGROUND: Although infliximab (IFX) has been available since 2005, there are very little data on the long-term drug survival of infliximab in real-life. OBJECTIVE: Our aim was to identify and describe psoriasis patients treated with IFX for longer than 6 years. METHODS: Psoriasis patients treated with IFX for longer than 6 years were retrospectively included. Demographic and clinical data were collected in May 2018. RESULTS: Between January 2005 and December 2012, 43 patients were maintained on IFX for 6 years or longer. IFX was introduced as a 4.5 line of systemic therapy. The mean duration of IFX treatment was 8.5 years (6-12). In May 2018, 30 patients (70%) were still maintained on IFX at 4-6 mg/kg every 8-10 weeks with an efficiency of about 100%. IFX was stopped in 13 patients (30%) mainly for loss of efficacy in 6 patients (46%). Three patients developed solid cancer including bladder cancer, lung cancer, and prostate cancer. Limitation. Retrospective study. CONCLUSION: We report the efficacy and safety of IFX maintained for up to 12 years in psoriasis patients. The long-term use of IFX was associated with a high BMI confirming the critical role of weight-based dosing for this drug.

Angiosarcoma: A population-based cancer registry descriptive study of 45 consecutive cases diagnosed between 1979 and 2016.

Angiosarcoma (AS) is a rare aggressive sarcoma with differentiation toward blood or lymphatic endothelium. There are few epidemiological data available on AS. To address this limitation, we investigated the epidemiological and clinical features of angiosarcoma diagnosed in a French administrative area (the Doubs department) from 1979 to 2016. A retrospective cohort study was conducted using the Doubs cancer registry database. A total of 45 patients with invasive AS were diagnosed between 1979 and 2016 in the Doubs department. Among the 45 AS, 51% were either cutaneous AS (27%), including head and neck and extremities, or breast AS (24%) as compared to visceral AS (42%). Eleven patients had metastasis at diagnosis (26%). Age-standardized incidence rate was 0.15 per 100,000 persons-years (95%CI, 0.10-0.20) for the entire study period (1979-2016) and 0.26 (95%CI, 0.15-0.42) for the last decade (2007-2016). Crude survival at 1, 3, 5 years after diagnosis was 44%, 21%, and 12%, respectively. Our population-based study provides updated data on the incidence and overall survival of AS in a French population-based cancer registry.