Fatal gastrointestinal toxicity with ipilimumab after BRAF/MEK inhibitor combination in a melanoma patient achieving pathological complete response.

Approximately 50% of metastatic melanoma patients harbor BRAF mutations. Several treatment options including the combination of BRAF and MEK inhibitors (BRAF/MEKi) and immunotherapy (mainly anti CTLA-4 and anti PD-1 antibodies), have been shown to improve survival in these patients. Although preclinical data support the synergistic effect of both modalities in combination, data confirming the activity and tolerability of these combinations are not yet available in the clinical setting. Herein, we report the case of a melanoma patient treated with sequential BRAF/MEKi (dabrafenib plus trametinib) followed by the anti CTLA-4 antibody ipilimumab who achieved a pathological complete response. Unfortunately, the patient died due to fatal gastrointestinal (GI) toxicity. Analysis of the BRAFV600E mutation in circulating tumoral DNA (ctDNA) from peripheral blood samples and serial tumor tissue biopsies throughout treatment demonstrated a good correlation with clinical evolution.

Results of clinical trials with anti-programmed death 1/programmed death ligand 1 inhibitors in lung cancer.

One of the main hallmarks of cancer is the capability of evading immune destruction. In order to drive tumor progression, malignant cells are able to promote immunosuppressive mechanisms avoiding recognition and elimination. Increasing knowledge of the mechanisms of immune tolerance has led to the identification of several membrane receptors strongly implicated in this cancer feature: the immune checkpoints. Among them, programmed death 1 (PD-1) receptors and their ligands have been identified as potential targets for a new anti-cancer therapeutic approach: the use of immune-modulatory monoclonal antibodies designed to interrupt the immune escape activated by the interaction of PD-1 receptors and their ligands. Five of these antibodies are now in their late stages of clinical development and this review will summarize their up-to-date efficacy and toxicity data.

Other targeted drugs in melanoma.

Targeted therapy drugs are developed against specific molecular alterations on cancer cells. Because they are "targeted" to the tumor, these therapies are more effective and better tolerated than conventional therapies such as chemotherapy. In the last decade, great advances have been made in understanding of melanoma biology and identification of molecular mechanisms involved in malignant transformation of cells. The identification of oncogenic mutated kinases involved in this process provides an opportunity for development of new target therapies. The dependence of melanoma on BRAF-mutant kinase has provided an opportunity for development of mutation-specific inhibitors with high activity and excellent tolerance that are now being used in clinical practice. This marked a new era in the treatment of metastatic melanoma and much research is now ongoing to identify other "druggable" kinases and transduction signaling networking. It is expected that in the near future the spectrum of target drugs for melanoma treatment will increase. Herein, we review the most relevant potential novel drugs for melanoma treatment based on preclinical data and the results of early clinical trials.

Immune checkpoint inhibitors: therapeutic advances in melanoma.

In recent years, new strategies for treating melanoma have been introduced, improving the outlook for this challenging disease. One of the most important advances has been the development of immunotherapy. The better understanding of the role of the immunological system in tumor control has paved the way for strategies to enhance the immune response against cancer cells. Monoclonal antibodies (mAbs) against the immune checkpoints cytotoxic T-lymphocyte antigen-4 (CTLA-4) and programmed cell death protein 1 (PD-1) and its ligand (PD-L1) have demonstrated high activity in melanoma and other tumors. Ipilimumab, an anti CTLA-4 antibody, was the first drug of this class that was approved. Although the response rate with ipilimumab is low (less than 20% of patients have objective responses), 20% of patients have long survival, with similar results in the first and second line settings. Nivolumab and pembrolizumab, both anti PD-1 inhibitors, have been approved for the treatment of melanoma, with response rates of 40% and a demonstrated survival advantage in phase III trials. This has marked a new era in the treatment of metastatic melanoma and much research is now ongoing with other drugs targeting checkpoint inhibitors. In addition, the agonist of activating molecules on T cells and their combinations are being investigated. Herein we review the clinical development of checkpoint inhibitors and their approval for treatment of metastatic melanoma.

Melanoma: oncogenic drivers and the immune system.

Advances and in-depth understanding of the biology of melanoma over the past 30 years have contributed to a change in the consideration of melanoma as one of the most therapy-resistant malignancies. The finding that oncogenic BRAF mutations drive tumor growth in up to 50% of melanomas led to a molecular therapy revolution for unresectable and metastatic disease. Moving beyond BRAF, inactivation of immune regulatory checkpoints that limit T cell responses to melanoma has provided targets for cancer immunotherapy. In this review, we discuss the molecular biology of melanoma and we focus on the recent advances of molecularly targeted and immunotherapeutic approaches.

Tumor Carcinoide de testículo / Testicular carcinoid tumor

Los tumores carcinoides de testículo son extremadamente raros, representando el 0.23% de los tumores de dicha localización. Se dividen en tres grupos: tumor carcinoide primario de testículo, teratoma de testículo con áreas de carcinoide y tumor carcinoide metastásico de otra localización. Presentamos un paciente de 52 años que consultó por dolor y tumefacción testicular. Se realizó orquiectomía derecha. LDH, alfa feto proteína y beta HCG: normales. Anatomía patológica: tumor blanco amarillento, constituido por células neoplásicas. Inmunohistoquímica: inmunofenotipo correspondiente a tumor neuroendocrino. 5HIAA urinario: normal. Centellografía con (Tc99) octreotide: normal. Se decidió control. Los tumores carcinoides primarios de testículo son infrecuentes, es fundamental descartar localizaciones primarias intestinales para confirmar el diagnóstico. Las herramientas diagnósticas más utilizadas son 5HIAA en orina y centellografía con (TC99) octreotide. El tumor carcinoide primario de testículo presenta un pronóstico favorable luego de la orquiectomía (AU)

Testicular carcinoid tumors are extremely rare. They are divided into three groups: primary testicular carcinoid tumor, testicular teratoma with areas of carcinoid and metastatic carcinoid tumor from another location. We present a 52 years old patient that was admitted with testicular pain and swelling. Right orchiectomy was performed. Serum LDH and alpha, fetoprotein and beta human chorionic gonadotropin were normal. Pathology: white yellowish tumor consisting of neoplastic cells. Immunohistochemistry: immunophenotype corresponding to neuroendocrine tumor. 5HIAA urinary and somatostatin receptor scintigraphy were normal. It was decided to control the patient. Primary testicular carcinoid tumors are uncommon. It is essential to rule out intestinal primary locations to confirm the diagnosis. The diagnostic tools used are 5 HIAA urinary and somatostatin receptor scintigraphy. The primary carcinoid tumor of the testis presents a favorable prognosis after orchiectomy (AU)