Effects of Eribulin on the RNA Content of Extracellular Vesicles Released by Metastatic Breast Cancer Cells.

Extracellular vesicles (EVs) are small lipid particles secreted by almost all human cells into the extracellular space. They perform the essential function of cell-to-cell communication, and their role in promoting breast cancer progression has been well demonstrated. It is known that EVs released by triple-negative and highly aggressive MDA-MB-231 breast cancer cells treated with paclitaxel, a microtubule-targeting agent (MTA), promoted chemoresistance in EV-recipient cells. Here, we studied the RNA content of EVs produced by the same MDA-MB-231 breast cancer cells treated with another MTA, eribulin mesylate. In particular, we analyzed the expression of different RNA species, including mRNAs, lncRNAs, miRNAs, snoRNAs, piRNAs and tRNA fragments by RNA-seq. Then, we performed differential expression analysis, weighted gene co-expression network analysis (WGCNA), functional enrichment analysis, and miRNA-target identification. Our findings demonstrate the possible involvement of EVs from eribulin-treated cells in the spread of chemoresistance, prompting the design of strategies that selectively target tumor EVs.

Potential immune­related 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.

Management of lung cancer patients during COVID-19 pandemic: dos, don'ts and don't knows.

Aim: During the coronavirus disease 2019 (COVID-19) pandemic two needs have overlapped: on one hand continuing to provide the best care for patients with lung cancer and preventing the spread of the virus between patients and healthcare professionals on the other hand. Due to the pandemic's unpredictable duration, physicians had to evaluate the risk/benefit ratio of anti-cancer therapeutic strategy to do the best for their patients and to protect patients themselves, as well as healthcare workers. Methods: Systematic literature research was performed with the aim to assess the available guidelines for the management of lung cancer patients during the COVID-19 pandemic. Thirteen potentially relevant articles were selected and recommendations have been divided into three main categories: dos, don'ts and don't knows. Results: All guidelines and recommendations highlighted the relevance of being able to delay, if possible and based on risk stratification, and curative interventions. The selected recommendations should be considered adaptable and flexible because they might be contextualized on the basis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection prevalence and the availability of diagnostic-therapeutic resources. Conclusions: It remains of fundamental importance to discuss each diagnostic and therapeutic decision with the patient taking into account risks and benefits that might vary from case to case.

BRCA mutations and gastrointestinal cancers: When to expect the unexpected?

BRCA1/2 pathogenic variants are widely known as major risk factors mainly for breast and ovarian cancer, while their role in gastrointestinal (GI) malignancies such as colorectal cancer (CRC), gastric cancer and oesophageal cancer (OeC) is still not well established. The main objective of this review is to summarise the available evidence on this matter. The studies included in the review were selected from PubMed/GoogleScholar/ScienceDirect databases to identify published articles where BRCA1/2 pathogenic variants were assessed either as a risk factor or a prognostic/predictive factor in these malignancies. Our review suggests that BRCA1/2 might have a role as a risk factor for colorectal, gastric and OeC, albeit with differences among these diseases: In particular BRCA1 seems to be much more frequently mutated in CRC whereas BRCA2 appears to be much more closely associated with gastric and OeC. Early-onset cancer seems to be also associated with BRCA1/2 mutations and a few studies suggest a positive prognostic role of these mutations. The assessment of a potentially predictive role of these mutations is hampered by the fact that most patients with these diseases have been treated with platinum compounds, where it is expected that a higher probability of response should be seen. A few clinical trials focused on poly (ADP-ribose) polymerase inhibitors use in GI cancers are currently ongoing.

Prognostic Impact of Ki-67 Change in Locally Advanced and Early Breast Cancer after Neoadjuvant Chemotherapy: A Single Institution Experience.

Systemic neoadjuvant chemotherapy (NCT) is a standard treatment for locally advanced breast cancer (LABC) and for selected early breast cancer (EBC). In these settings, the prognostic and predictive role of Ki-67 before and after NCT is unclear. The aim of our study was to investigate the prognostic role of Ki-67 change in patients not achieving pathological complete response (pCR). We retrospectively analyzed data of patients who did not achieve pCR assessing Ki-67 expression pre- and post-NCT. We stratified three groups: high reduction (>20%), low reduction (1-20%), and no reduction in Ki-67. These groups were correlated with clinical and pathological data by χ2 test. We estimated disease-free survival (DFS) and overall survival (OS) using Kaplan-Meier method, and we adopted univariate and multivariate Cox proportional hazard models. We selected 82 patients from a database of 143 patients, excluding those who were metastatic at diagnosis, achieved pCR, or lack data regarding Ki-67. Median age at diagnosis was 54 years (range 30-75); 51 patients were Luminal B, 10 human epidermal growth factor receptor 2 (HER-2) enriched, and 21 triple negative. A significant correlation between high Ki-67 reduction and luminal B HER-2-negative subtype was observed (p = 0,0035). The change in Ki-67 was significantly associated with DFS (p = 0,0596) and OS (p = 0,0120), also at multivariate analysis (p = 0,0256 for DFS; p = 0,0093 for OS). In particular, as compared to patients with low/no reduction of Ki-67, those with high Ki-67 reduction (>20%) after NCT showed better survival (60% vs. 56% vs. 83% after 5 years from diagnosis, respectively; p = 0.01). In conclusion, in our study, Ki-67 change showed a significant prognostic role in breast cancer patients treated with NCT who did not achieve pCR. Crucially, Ki-67 < 20% identifies a high-risk population that may be eligible for clinical trials with novel therapeutic interventions in adjuvant setting.

The Impact of Lifestyle Interventions in High-Risk Early Breast Cancer Patients: A Modeling Approach from a Single Institution Experience.

A healthy lifestyle plays a strategic role in the prevention of BC. The aim of our prospective study is to evaluate the effects of a lifestyle interventions program based on special exercise and nutrition education on weight, psycho-physical well-being, blood lipid and hormonal profile among BC patients who underwent primary surgery. From January 2014 to March 2017, a multidisciplinary group of oncologists, dieticians, physiatrists and an exercise specialist evaluated 98 adult BC female patients at baseline and at different time points. The patients had at least one of the following risk factors: BMI ≥ 25 kg/m2, high testosterone levels, high serum insulin levels or diagnosis of MS. Statistically significant differences are shown in terms of BMI variation with the lifestyle interventions program, as well as in waist circumference and blood glucose, insulin and testosterone levels. Moreover, a statistically significant difference was reported in variations of total Hospital Anxiety and Depression Scale (HADS) score, in the anxiety HADS score and improvement in joint pain. Our results suggested that promoting a healthy lifestyle in clinical practice reduces risk factors involved in BC recurrence and ensures psycho-physical well-being.

Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH): Optimal Management.

Hyponatremia, defined as serum sodium concentration <135 mEq/l, is the most common electrolyte balance disorder in clinical practice. Many causes are listed, but syndrome of inappropriate antidiuretic hormone secretion (SIADH) is certainly the most relevant, mainly in oncological and hospitalized patients. In this review, the pathophysiological and clinical aspects are described in detail. Patients' extensive medical history and structured physical and biochemical tests are considered the milestones marking the way of the SIADH management as to provide early detection and proper correction. We focused our attention on the poor prognostic role and negative effect on patient's quality of life of SIADH-induced hyponatremia in both malignant and non-malignant settings, stressing how optimal management of this electrolyte imbalance can result in improved outcomes and lower health costs.

Benefits and Limitations of a Multidisciplinary Approach in Cancer Patient Management.

Over the years, a growing body of literature has confirmed as beneficial the implementation of a multidisciplinary approach in the so-often-intricate scenario of cancer patients' management. Together with the consolidation of tumor-board experience in clinical practice, certain aspects have emerged as controversial and a source of current debate. In this systematic literature review, we focused our attention on the impact of multidisciplinary tumor boards, assessing benefits and limitations as a result of the dissemination of such approaches. On the bright side, adherence to clinical guidelines, treatment outcomes, and overall improvement in decision-making processes have been recognized as advantages. On the other side, our analysis highlights a few limitations that should be taken into account to optimize cancer patients' management. Of note, some issues, such as costs, legal responsibility, geographic barriers, and treatment delays, have yet to be resolved. In order partly to address this matter, software platforms and novel methods of computational analysis may provide the needed support. Therefore, the aim of our analysis was to describe the multidisciplinary approach in cancer care in terms of adherence to clinical guidelines, treatment outcomes, and overall improvement in decision-making processes through a systematic review of the literature.

Tailored therapy in patients treated with fluoropyrimidines: focus on the role of dihydropyrimidine dehydrogenase.

Fluoropyrimidines are widely used in the treatment of solid tumors, mainly gastrointestinal, head and neck and breast cancer. Dihydropyrimidine dehydrogenase (DPD) is the rate-limiting enzyme for catabolism of 5-FU and it is encoded by DPYD gene. To date, many known polymorphisms cause DPD deficiency and subsequent increase of 5-FU toxicity. In addition, reduced inactivation of 5-FU could lead to increased 5-FU intracellular concentration and augmented efficacy of this drugs. Therefore DPD expression, particularly intratumoral, has been investigated as predictive and prognostic marker in 5-FU treated patients. There also seems to be a tendency to support the correlation between DPD expression and response/survival in patients treated with fluoropyrimidine even if definitive conclusions cannot be drawn considering that some studies are conflicting. Therefore, the debate on intratumoral DPD expression as a potential predictor and prognostic marker in patients treated with fluoropyrimidines is still open. Four DPD-polymorphisms are the most relevant for their frequency in population and clinical relevance. Many studies demonstrate that treating a carrier of one of these polymorphisms with a full dose of fluoropyrimidine can expose patient to a severe, even life-threatening, toxicity. Severe toxicity is reduced if this kind of patients received a dose-adjustment after being genotyped. CPIC (Clinical Pharmacogenetics Implementation Consortium) is an International Consortium creating guidelines for facilitating use of pharmacogenetic tests for patient care and helps clinicians ensuring a safer drug delivery to the patient. Using predictive DPD deficiency tests in patients receiving 5FU-based chemotherapy, in particular for colorectal cancer, has proven to be a cost-effective strategy.

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.