Clinical experience with combination BRAF/MEK inhibitors for melanoma with brain metastases: a real-life multicenter study.

BRAF and MEK kinase inhibitors can be highly effective in treating BRAF-mutant melanomas, but their safety and activity in patients with active/symptomatic brain metastases are unclear. We sought to shed light on this open clinical question. We conducted a multicenter retrospective study on real-life patients with melanoma and active brain metastases treated with combination BRAF/MEK inhibitors. A total of 65 patients were included (38 men and 27 women; median age: 49 years). Of them, 53 patients received dabrafenib/trametinib, 10 received vemurafenib/cobimetinib, one received encorafenib/binimetinib, and one received vemurafenib/trametinib. We did not observe any unexpected treatment-related safety signals in our cohort. Overall, 17 patients continued on therapy through the cutoff date. After initiation of therapy, steroid dose could be decreased in 22 of 33 patients (11 tapered off entirely), anticonvulsants were stopped in four of 21, and narcotics were stopped in four of 12. Median progression-free survival from the start of therapy was 5.3 months (95% confidence interval: 3.6-6.1), and median overall survival was 9.5 months (95% confidence interval: 7.7-13.5). A total of 20 patients were surviving at the cutoff date. Univariate analysis of age, sex, ulceration status, thickness, stage, location, or lactate dehydrogenase did not reveal significant predictors of progression-free survival or overall survival within our cohort, but multivariate analysis suggested that older age, lower risk location of original lesion, and nodular melanoma are poor prognostic indicators. Combination therapy with BRAF/MEK inhibitors is a viable treatment option for patients with BRAF-mutant melanoma and brain metastases, but further studies should help to define the optimal treatment approach in this population.

Unexpected contribution of lymphatic vessels to promotion of distant metastatic tumor spread.

Tumor lymphangiogenesis is accompanied by a higher incidence of sentinel lymph node metastasis and shorter overall survival in several types of cancer. We asked whether tumor lymphangiogenesis might also occur in distant organs with established metastases and whether it might promote further metastatic spread of those metastases to other organs. Using mouse metastasis models, we found that lymphangiogenesis occurred in distant lung metastases and that some metastatic tumor cells were located in lymphatic vessels and draining lymph nodes. In metastasis-bearing lungs of melanoma patients, a higher lymphatic density within and around metastases and lymphatic invasion correlated with poor outcome. Using a transgenic mouse model with inducible expression of vascular endothelial growth factor C (VEGF-C) in the lung, we found greater growth of lung metastases, with more abundant dissemination to other organs. Our findings reveal unexpected contributions of lymphatics in distant organs to the promotion of growth of metastases and their further spread to other organs, with potential clinical implications for adjuvant therapies in patients with metastatic cancer.

Angioimmunoblastic T-Cell Lymphoma Mimicking Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS Syndrome).

Angioimmunoblastic T-cell lymphoma (AITCL) is a rare, aggressive lymphoma which derives from follicular helper T cells, commonly affecting the elderly population. It accounts for 2% of all non-Hodgkin lymphomas, with a reported 5-year overall survival rate of less than 30%. Very often, the clinical picture of AITCL encompasses systemic symptoms such as generalized lymphadenopathy, hepatosplenomegaly, skin rash, anemia, and polyclonal hypergammaglobulinemia. Here we report on the case of a female patient who presented with clinical features resembling drug reaction with eosinophilia and systemic symptoms (DRESS syndrome) prior to the definitive diagnosis of AITCL. The index of suspicion for cutaneous manifestations of lymphoma, and especially AITCL, must be high, particularly in atypical clinical courses of drug eruptions or if skin lesions relapse and are refractory to standard high-dose systemic corticosteroids.

Multicenter, real-life experience with checkpoint inhibitors and targeted therapy agents in advanced melanoma patients in Switzerland.

Metastatic melanoma is a highly aggressive disease. Recent progress in immunotherapy (IT) and targeted therapy (TT) has led to significant improvements in response and survival rates in metastatic melanoma patients. The current project aims to determine the benefit of the introduction of these new therapies in advanced melanoma across several regions of Switzerland. This is a retrospective multicenter analysis of 395 advanced melanoma patients treated with standard chemotherapy, checkpoint inhibitors, and kinase inhibitors from January 2008 until December 2014. The 1-year survival was 69% (n=121) in patients treated with checkpoint inhibitors (IT), 50% in patients treated with TTs (n=113), 85% in the IT+TT group (n=66), and 38% in patients treated with standard chemotherapy (n=95). The median overall survival (mOS) from first systemic treatment in the entire study cohort was 16.9 months. mOS of patients treated either with checkpoint or kinase inhibitors (n=300, 14.6 months) between 2008 and 2014 was significantly improved (P<0.0001) compared with patients treated with standard chemotherapy in 2008-2009 (n=95, 7.4 months). mOS of 61 patients with brain metastases at stage IV was 8.1 versus 12.5 months for patients without at stage IV (n=334), therefore being significantly different (P=0.00065). Furthermore, a significant reduction in hospitalization duration compared with chemotherapy was noted. Treatment with checkpoint and kinase inhibitors beyond clinical trials significantly improves the mOS in real life and the results are consistent with published prospective trial data.

Activin promotes skin carcinogenesis by attraction and reprogramming of macrophages.

Activin has emerged as an important player in different types of cancer, but the underlying mechanisms are largely unknown. We show here that activin overexpression is an early event in murine and human skin tumorigenesis. This is functionally important, since activin promoted skin tumorigenesis in mice induced by the human papillomavirus 8 oncogenes. This was accompanied by depletion of epidermal γδ T cells and accumulation of regulatory T cells. Most importantly, activin increased the number of skin macrophages via attraction of blood monocytes, which was prevented by depletion of CCR2-positive monocytes. Gene expression profiling of macrophages from pre-tumorigenic skin and bioinformatics analysis demonstrated that activin induces a gene expression pattern in skin macrophages that resembles the phenotype of tumor-associated macrophages in different malignancies, thereby promoting angiogenesis, cell migration and proteolysis. The functional relevance of this finding was demonstrated by antibody-mediated depletion of macrophages, which strongly suppressed activin-induced skin tumor formation. These results demonstrate that activin induces skin carcinogenesis via attraction and reprogramming of macrophages and identify novel activin targets involved in tumor formation.

Sonidegib for the treatment of advanced basal cell carcinoma.

INTRODUCTION: Advanced and metastatic basal cell carcinomas (BCCs) are rare but still present a severe medical problem. These tumors are often disfiguring and impact the quality of life by pain or bleeding. Based on discovery of the hedgehog (Hh) signaling pathway and its role in the pathogenesis of BCCs, smoothened (SMO) inhibitors have been developed with Sonidegib being the 2nd in class. It is the only Hh pathway inhibitor investigated in a randomized trial accompanied by pharmacodynamic investigations. Also, the disease assessment criteria applied were more stringent than those used in trials of 1st developed SMO inhibitor - vismodegib, and required annotated photographs, MRI as well as multiple biopsies in case of regression. AREAS COVERED: All available papers from Medline and the abstracts of the most important dermato-oncology meetings were included. EXPERT OPINION: Sonidegib is a promising medication for advanced BCC and other malignancies, driven by Hh signaling. It presents favorable pharmacokinetic properties and causes class specific toxicity with dose dependent adverse events in muscular and taste bud homeostasis, gastrointestinal symptoms and hair growth. Early after treatment initiation, it impacts the immunesusceptibility of the tumor lesions. Sonidegib deserves further development in combination with other drugs or antibodies, or alternative dosing schedules.

Hypersomnolence in Wilson Disease.

ABSTRACT: Wilson disease (WD) is an autosomal recessive disorder of copper metabolism resulting in copper accumulation in a number of organs including the liver, brain, and cornea, predominantly leading to hepatic, neurologic, and psychiatric manifestations. An association between WD and sleep problems is not commonly recognized, and sleep complaints are often overlooked. Daytime hypersomnolence is even more rarely reported in this population. We report a case of WD and hypersomnolence objectively confirmed by a multiple sleep latency test (MSLT). Consequently, we suggest that increased awareness, assessment, and treatment of sleep disorders, including daytime sleepiness, may help improve patients' quality of life.