High CTLA-4 expression correlates with poor prognosis in thymoma patients

Thymomas, tumors that arise from epithelial cells of the thymus gland, are the most common neoplasms of the anterior mediastinum, with an incidence rate of approximately 2.5 per million/year. Cytotoxic T Lymphocyte Antigen 4 (CTLA-4 or CD152) exerts inhibitory activity on T cells, and since its oncogenic role in the progression of different types of tumors, it has emerged as a potential therapeutic target in cancer patients. In this study, we assessed the expression of CTLA-4 both at mRNA and protein levels in paraffin embedded-tissues from patients with thymomas. Furthermore, we evaluated the relationship between CTLA-4 expression and the clinical-pathologic characteristics and prognosis in patients with thymomas. Sixty-eight patients with median age corresponding to 62 years were included in this analysis. Thymomas were classified accordingly to the WHO and Masaoka-Koga for histochemical analysis and for prognostic significance. A statistical difference was found between CTLA-4 mRNA levels in human normal thymus compared with thymoma specimens. CTLA-4 expression was statistically found to progressively increase in A, B1, B2, AB and it was maximal in B3 thymomas. According to Masaoka-Koga pathological classification, CTLA-4 expression was lower in I, IIA and IIB, and higher in invasive III and IV stages. By confocal microscopy analysis we identified the expression of CTLA-4 both in tumor cells and in CD45+ tumor-infiltrating leukocytes, mainly in B3 and AB thymomas. Finally, CTLA-4 overexpression significantly correlates with reduced overall survival in thymoma patients and in atypical thymoma subgroup, suggesting that it represents a negative prognostic factor

A long-term treatment with taurine prevents cardiac dysfunction in mdx mice

Taurine is an amino acid abundantly present in heart and skeletal muscle. Duchenne muscular dystrophy (DMD) is a genetic disorder in which the absence of dystrophin leads to skeletal muscle wasting and heart failure. An altered taurine metabolism has been described in dystrophic animals and short-term taurine administration exerts promising amelioration of early muscular alterations in the mdx mouse model of DMD. To reinforce the therapeutic and nutraceutical taurine potential in DMD, we evaluated the effects of a long-term treatment on cardiac and skeletal muscle function of mdx mice in a later disease stage. Taurine was administered in drinking water (1 g/kg/day) to wt and mdx mice for 6 months, starting at 6 months of age. Ultrasonography evaluation of heart and hind limb was performed, in parallel with in vivo and ex vivo functional tests and biochemical, histological and gene expression analyses. 12-month-old mdx mice showed a significant worsening of left ventricular function parameters (shortening fraction, ejection fraction, stroke volume), which were significantly counteracted by the taurine treatment. In parallel, histologic signs of damage were reduced by taurine along with the expression of proinflammatory myocardial IL-6. Interestingly, no effects were observed on hind limb volume and percentage of vascularization or on in vivo and ex vivo muscle functional parameters, suggesting a tissue-specific action of taurine in relation to the disease phase. A trend toward increase in taurine was found in heart and quadriceps from treated animals, paralleled by a slight decrease in mdx mice plasma. Our study provides evidences that taurine can prevent late heart dysfunction in mdx mice, further corroborating the interest on this amino acid toward clinical trials

Potential dual synergy between electrochemotherapy and sequence of immunotherapies in metastatic melanoma: A case report

Immune checkpoint inhibitors have changed the natural history of advanced melanoma. Despite this, a notable proportion of patients immediately relapse or develop resistance during immunotherapy, especially with the appearance of superficial metastases and consequently with a dramatic impact on clinical outcomes. Local treatment by electrochemotherapy (ECT), parallel to regional control with palliative aim, seems to release neoantigens potentially determining a significant systemic anticancer immune reactivation. The present study reported a case of a patient with metastatic melanoma receiving Pembrolizumab, electrochemotherapy and then Ipilimumab for in-transit and finally locoregional lymph nodes and distant bone metastases with experience of clinic-radiological remission. Specifically, the present patient progressed during adjuvant treatment with in-transit metastases on the scalp; he underwent two cycle of ECT obtaining partial and then unexpected and very fast nearly complete response with the Ipilimumab treatment. Concomitantly, he developed grade 4 endocrine adverse events (hypophysitis and diabetes mellitus type I) as immune-related toxicities. At 12 months from ECT the patient is in ECOG Performance Status 0 and he has resumed a regular social life. In our experience, ECT in two administrations increased and accelerated the response of Ipilimumab. The present confirmed its promising contribution in inducing a powerful immune response in order to overcome primary or acquired resistance to immune checkpoint inhibitors such as anti-programmed death antigen-1 drugs

New findings on thymic epithelial tumors: Something is changing

Thymic epithelial tumors (TETs) are uncommon neoplasms with a wide range of anatomical, clinical, histological and molecular malignant entities. To date the management of TETs within clinical practice is based on a multimodal therapeutic strategy including surgery, chemotherapy and radiotherapy with a multidisciplinary approach and prognostic evaluation is mainly based on Masaoka staging and World Health Organization classification. Therefore novel strategies are needed, especially for refractory and/or recurrent TETs and for thymic carcinomas that present a poor prognosis. Personalized approaches are currely being developed and molecular targets are emerging from recent integrated genomic analyses. Targeted therapy will represent an important treatment option for TETs with an aggressive histology. To date, data indicate that vascular endothelial growth factor molecules, insulin-like growth factor 1 receptor, cyclin-dependent kinases and mammalian target of rapamycin may be potentially useful as targeted biological therapies

Systemic treatment for lung carcinoids: from bench to bedside

In the huge spectrum of lung neuroendocrine neoplasms, typical and atypical carcinoids should be considered as a separate biological entity from poorly differentiated forms, harboring peculiar molecular alterations. Despite their indolent behavior, lung carcinoids correlate with a worse survival. To date, only limited therapeutic options are available and novel drugs are strongly needed. In this work, we extensively reviewed scientific literature exploring available therapeutic options, new molecular targets and future perspectives in the management of well differentiated neoplasms of bronchopulmonary tree. Systemic therapy represents the main option in advanced and unresectable disease; accepted choices are somatostatin analogs, peptide receptor radionuclide therapy, everolimus and chemotherapy. To date, an univocal treatment strategy has not been identified yet, thus tailored therapeutic algorithms should consider treatment efficacy as well as safety profiles. Several molecular alterations found in carcinoid tumors might act as molecular targets leading to development of new therapeutic options. Further studies are necessary to identify new potential druggable molecular targets in the selected subset of low-grade lung carcinoids. Furthermore, evaluating the available therapies in more homogeneous population might improve their efficacy through a perfect tailoring of treatment options

Potential immune‑related adverse events during dabrafenib and trametinib treatment: A case series of patients with BRAF V600E melanoma

In recent years, BRAF inhibitors (BRAFi) and MEK inhibitors (MEKi), together with immune checkpoint inhibitors (ICIs), have changed the therapeutic strategy of cutaneous melanoma, both in adjuvant and metastatic settings. These inhibitors have significantly improved the clinical outcome for patients with melanoma, including in both BRAF-mutated and BRAF-wild type disease. Some preclinical and clinical studies have revealed that BRAFi and MEKi are able to influence T- and B-cell activation, and to modulate immune system activation within the tumor microenvironment. Dabrafenib and trametinib have been shown to enhance the expression of melanoma antigens on BRAF-mutated cells, and to favor both a cytotoxic and immune response against melanoma cells. Thereby, the present study described a case series of five women treated with BRAFi and MEKi, in both adjuvant and metastatic settings, that experienced potential immune-related adverse events. In particular, these patients exhibited sarcoidosis, mesenteric panniculitis, lymphocytic colitis and neuropathy of phrenic nerve. Considering that T and B cells are responsible for immune-related adverse events, as observed in patients treated with ICIs, the present study suggested a possible role of BRAFi and MEKi as triggers of immune system activation and subsequent immune-related toxicities

Electrolyte disorders in cancer patients: a systematic review

Electrolyte disorders are very common complications in cancer patients. They might be associated to a worsening outcome, influencing quality of life, possibility to receive anticancer drugs, and conditioning survival. In fact, they might provoke important morbidity, with dysfunction of multiple organs and rarely causing life-threatening conditions. Moreover, recent studies showed that they might worsen cancer patients’ outcome, while a prompt correction seems to have a positive impact. Furthermore, there is evidence of a correlation between electrolyte alterations and poorer performance status, delays in therapy commencement and continuation, and negative treatment outcomes. These alterations usually involve sodium, potassium, calcium, and magnesium serum levels. Several causes might contribute to electrolyte disorders in cancer patients: cancer effects, such as paraneoplastic syndrome of inappropriate antidiuresis and tumor lysis syndrome; anti-cancer therapies; and other concomitant clinical conditions or treatments. However, the origin of the electrolyte disorder is often multifactorial, thus identifying and correcting the causes is not always feasible. Furthermore, they are often not recognized or not considered in clinical practice, worsening these alterations and patient condition. An improvement of knowledge about the physiological mechanisms underlying electrolyte disorders is necessary to strengthen their identification and set up a prompt, adequate, and effective treatment. The aim of this systematic review is to provide an analysis of the pathophysiological mechanisms of electrolyte abnormalities in cancer patients to facilitate their identification, management, and therapy to improve patient outcome

Medical therapy for advanced gastro-entero-pancreatic and bronchopulmonary neuroendocrine tumors

Neuroendocrine tumors (NETs) represent a spectrum of rare neoplasms arising in different organism sites. Depending on the site of onset, they also can be distinguished using lab exams (secreting vs. nonsecreting), clinical symptoms (functioning vs. nonfunctioning), behavioral, morphological characteristics (tumor cells’ architectural growth patterns, mitotic and Ki-67 index, presence of necrosis), and grade of cellular differentiation. The aim of this review is to focus on the main signaling pathways targeted by medical treatments of advanced sporadic gastro-entero-pancreatic (GEP) and bronchopulmonary (BP) neuroendocrine neoplasms. The scientific literature regarding treatment of advanced GEP and BP-NETs has been extensively reviewed using MEDLINE and PubMed databases, selecting principal and more recent research articles, clinical trials, and updated guidelines. Somatostatin analogues represent a valid approach to control symptoms in functioning tumors and to inhibit tumor progression in certain categories on the basis of the typical somatostatin receptor expression observed in NETs. The pathogenesis of NETs has been the subject of increased interest in recent years. Many driver mutations pathway genes have been identified as important factors in the carcinogenesis process and, therefore, as potential targets for new anticancer therapies. Activating mutations have been shown in epidermal growth factor receptor, stem cell factor receptor, platelet-derived growth factor receptor, vascular endothelial growth factor, basic-fibroblastic growth factor, transforming growth factor, insulin-like growth factor-1, and their receptors. Effective M-Tor inhibition pathway modulation has led to the approval of drugs in this field such as everolimus. New drugs and several combination regimens with targeted and newer biological agents are being developed and tested in recently conducted and ongoing trials