Frontiers and Challenges of Computing ncRNAs Biogenesis, Function and Modulation.

Non-coding RNAs (ncRNAs), generated from nonprotein coding DNA sequences, constitute 98-99% of the human genome. Non-coding RNAs encompass diverse functional classes, including microRNAs, small interfering RNAs, PIWI-interacting RNAs, small nuclear RNAs, small nucleolar RNAs, and long non-coding RNAs. With critical involvement in gene expression and regulation across various biological and physiopathological contexts, such as neuronal disorders, immune responses, cardiovascular diseases, and cancer, non-coding RNAs are emerging as disease biomarkers and therapeutic targets. In this review, after providing an overview of non-coding RNAs' role in cell homeostasis, we illustrate the potential and the challenges of state-of-the-art computational methods exploited to study non-coding RNAs biogenesis, function, and modulation. This can be done by directly targeting them with small molecules or by altering their expression by targeting the cellular engines underlying their biosynthesis. Drawing from applications, also taken from our work, we showcase the significance and role of computer simulations in uncovering fundamental facets of ncRNA mechanisms and modulation. This information may set the basis to advance gene modulation tools and therapeutic strategies to address unmet medical needs.

Label-Free SERS and MD Analysis of Biomarkers for Rapid Point-of-Care Sensors Detecting Head and Neck Cancer and Infections.

For the progress of point-of-care medicine, where individual health status can be easily and quickly monitored using a handheld sensor, saliva serves as one of the best-suited body fluids thanks to its availability and abundance of physiological indicators. Salivary biomarkers, combined with rapid and highly sensitive detection tools, may pave the way to new real-time health monitoring and personalized preventative therapy branches using saliva as a target matrix. Saliva is increasing in importance in liquid biopsy, a non-invasive approach that helps physicians diagnose and characterize specific diseases in patients. Here, we propose a proof-of-concept study combining the unique specificity in biomolecular recognition provided by surface-enhanced Raman spectroscopy (SERS) in combination with molecular dynamics (MD) simulations, which give leave to explore the biomolecular absorption mechanism on nanoparticle surfaces, in order to verify the traceability of two validated salivary indicators, i.e., interleukin-8 (IL-8) and lysozyme (LYZ), implicated in oropharyngeal squamous cell carcinoma (OSCC) and oral infection. This strategy simultaneously assures the detection and interpretation of protein biomarkers in saliva, ultimately opening a new route for the evolution of fast and accurate point-of-care SERS-based sensors of interest in precision medicine diagnostics.

SARS-CoV-2 inhibitory activity of a short peptide derived from internal fusion peptide of S2 subunit of spike glycoprotein.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has posed a great concern in human population. To fight coronavirus emergence, we have dissected the conserved amino acid region of the internal fusion peptide in the S2 subunit of Spike glycoprotein of SARS-CoV-2 to design new inhibitory peptides. Among the 11 overlapping peptides (9-23-mer), PN19, a 19-mer peptide, exhibited a powerful inhibitory activity against different SARS-CoV-2 clinical isolate variants in absence of cytotoxicity. The PN19 inhibitory activity was found to be dependent on conservation of the central Phe and C-terminal Tyr residues in the peptide sequence. Circular dichroism spectra of the active peptide exhibited an alpha-helix propensity, confirmed by secondary structure prediction analysis. The PN19 inhibitory activity, exerted in the first step of virus infection, was reduced after peptide adsorption treatment with virus-cell substrate during fusion interaction. Additionally, PN19 inhibitory activity was reduced by adding S2 membrane-proximal region derived peptides. PN19 showed binding ability to the S2 membrane proximal region derived peptides, confirmed by molecular modelling, playing a role in the mechanism of action. Collectively, these results confirm that the internal fusion peptide region is a good candidate on which develop peptidomimetic anti SARS-CoV-2 antivirals.

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.

The dynamics of t1 adenosine binding on human Argonaute 2: Understanding recognition with conformational selection.

The control of expression in genetic regulation is a fundamental process for cell life. In RNA-mediated silencing, human Argonaute-2 protein (hAgo2) uses sequence information encoded in small RNAs (guide) to identify complementary sites in messenger RNAs (target) for repression. The specificity of this molecular recognition lies at the basis of the mechanisms that control the expression of thousands of genes, which necessarily requires a fine tuning of complex events. Among these, the binding of the first nucleotide of the target RNA (t1) is emerging as an important modulator of hAgo2-mediated machinery. Using atomistic molecular dynamics-derived analyses, we address the mechanism behind t1-dependent regulation and study the impact of different t1 nucleotides (t1A, t1C, t1G, t1U) on the conformational dynamics of both hAgo2 and guide-target RNAs. Only when an adenine is found at this position, t1 directly interacts with a specific hAgo2 binding pocket, favoring the stabilization of target binding. Our findings show that hAgo2 exploits a dynamic recognition mechanism of the t1-target thanks to a modulation of RNA conformations. Here, t1-adenine is the only nucleobase endowed with a dual binding mode: a T-shape and a co-planar conformation, respectively, orthogonal and parallel to the following base-pairs of guide-target duplex. This triggers a composite set of molecular interactions that stabilizes distinctive conformational ensembles. Our comparative analyses show characteristic traits of local and global dynamic interplay between hAgo2 and the RNA molecules and highlight how t1A binding acts as a molecular switch for target recognition and complex stabilization. Implications for future mechanistic studies are discussed.

BRCA-associated protein 1 (BAP1) and miR-31 combination predicts outcomes in epithelioid malignant pleural mesothelioma.

BACKGROUND: Malignant pleural mesothelioma (MPM) is an aggressive disease, with few available treatment options. Identification of novel prognostic and predictive biomarkers is a priority. In MPM patients, BRCA-associated protein 1 (BAP1) alterations are detected in about 60% of cases and miR-31 seems to be involved in BAP1 regulation at post-transcriptional level. The aim of this study was to evaluate the interaction between BAP1 and miR-31 in MPM and their prognostic role in MPM. METHODS: The expression of BAP1 and miR-31 was analyzed in tissues of 55 MPM patients treated with first-line chemotherapy. Overall survival (OS) and progression-free survival (PFS) were assessed by Kaplan-Meier method and Log-rank test was used to investigate differences among subgroups. Multivariate Cox regression analysis was used to evaluate independent predictors of survival. RESULTS: In the whole cohort, loss of BAP1 was associated with a significant improvement in OS, but not in PFS. Lower miR-31 levels were detected in epithelioid MPM (e-MPM) compared to the non-epithelioid subtypes and resulted associated with BAP1 loss. By looking at the e-MPM subgroup, loss of BAP1 was not able to predict clinical outcome. Conversely, miR-31 levels were significantly associated with PFS (P=0.028), but not with OS (P=0.059). By combining the two biomarkers, e-MPM patients with BAP1 loss/low miR-31 levels showed a better prognosis compared to the ones with BAP1 retained/high miR-31 levels (median OS 22.6 vs. 17.0 months, P=0.017 and median PFS 8.7 vs. 5.1 months, P=0.020). The BAP1 and miR-31 combination was confirmed at multivariate analysis as an independent prognostic factor for e-MPM patients. CONCLUSIONS: In this preliminary study, we found that the prognostic stratification of e-MPM patients may be improved by simultaneously assessing of BAP1 status and miR-31 levels. The two-biomarker score is useful to identify a subgroup of e-MPM tumors characterized by BAP1 retained and high miR-31 levels with worse clinical outcome.

Exploring the role of respiratory microbiome in lung cancer: A systematic review.

Giving the potential contribute in cancer initiation and progression, lung microbiota represents a promising topic in cancer research, although still unexplored. We performed a systematic literature search to identify clinical studies evaluating lung microbiota composition, its correlation with lung cancer patients' clinico-pathological features and prognosis. Of the identified 370 studies, 21 were eligible and included. Although studies were heterogeneous, lung cancer resulted to be enriched in peculiar microbial communities, with differences in composition and diversity according to clinico-pathological parameters. Few studies explored how lung microbiota influences cancer outcome. In light of these findings and borrowing the suggestions coming from gut microbiota, we speculate that respiratory microbiome may influence pathogenesis, progression and outcome of lung cancer. Taking advantage of the experience of chronical lung diseases, prospective studies should be designed to evaluate lung microbiota changes throughout any phase of lung cancer course, particularly with the advent of immunotherapy as pivotal treatment.

The Gustave Roussy Immune (GRIm)-Score Variation Is an Early-on-Treatment Biomarker of Outcome in Advanced Non-Small Cell Lung Cancer (NSCLC) Patients Treated with First-Line Pembrolizumab.

BACKGROUND: The Gustave Roussy Immune (GRIm)-Score takes into account neutrophil-to-lymphocyte ratio (NLR), serum albumin concentration and lactate dehydrogenase (LDH) and its prognostic value has been investigated in patients treated with immune check-point inhibitors (ICIs). To further assess the prognostic and predictive value of baseline GRIm-Score (GRImT0) in advanced non-small cell lung cancer (aNSCLC) patients, we separately investigated two cohorts of patients treated with first-line pembrolizumab or chemotherapy. We also investigated whether GRIm-Score at 45 days since treatment initiation (GRImT1) and GRIm-Score difference between the two timepoints may better predict clinical outcomes (GRImΔ = GRImT0 - GRImT1). METHODS: We retrospectively evaluated 222 aNSCLC patients: 135 treated with pembrolizumab and 87 treated with chemotherapy as the first-line regimen. NLR, serum albumin and LDH concentrations were assessed at T0 and at T1. According to the GRIm-Score, patients were assigned 1 point if they had NLR > 6, LDH > upper limit normal or albumin < 3.5 g/dL. Patients with a GRIm-Score < 2 were considered as having a low Score. RESULTS: In both cohorts, no difference in terms of overall survival (OS) between patients with low and high GRImT0 was found. Otherwise, median OS and progression free survival (PFS) of the low GRImT1 group were significantly longer than those of the high GRImT1 group in pembrolizumab-treated patients, but not in the CHT cohort (pembrolizumab cohort: low vs. high; median OS not reached vs. 9.2 months, p = 0.004; median PFS 10.8 vs. 2.3 months, p = 0.002). Patients receiving pembrolizumab with stable/positive GRImΔ had better OS (median OS not reached vs. 12.0 months, p < 0.001), PFS (median PFS 20.6 vs. 2.6 months, p < 0.001) and objective response rate (58.2% vs. 7.6%, p = 0.003) compared to patients with negative GRImΔ. CONCLUSION: Our data shown that GRImT1 and GRImΔ are more reliable peripheral blood biomarkers of outcome compared to GRImT0 in aNSCLC patients treated with pembrolizumab and might represent useful biomarkers to drive clinical decisions in this setting.

Tumor burden as possible biomarker of outcome in advanced NSCLC patients treated with immunotherapy: a single center, retrospective, real-world analysis.

Aim: The role of tumor burden (TB) for patients with non-small cell lung cancer (NSCLC) receiving immunotherapy is still unknown. The aim of this analysis was to analyze the prognostic value of TB in a real-world sample of advanced NSCLC patients. Methods: Sixty-five consecutive patients with advanced NSCLC treated with immunotherapy as first or second line therapy were retrospectively analyzed between August 2015 and February 2018. TB was recorded at baseline considering sites and number of metastases, thoracic vs. extrathoracic disease, measurable disease (MD) vs. not-MD (NMD) and evaluating dimensional aspects as maximum lesion diameter (cut-off = 6.3 cm), sum of the 5 major lesions diameters (cut-off = 14.3 cm), and number of sites of metastases (cut-off > 4). All cut-offs were calculated by receiver operating characteristic curves. Median overall survival (OS) was estimated using Kaplan-Meier method. A Cox regression model was carried out for univariate and multivariate analyses. Results: Median age was 70 years and most patients (86.2%) had a good performance status (PS-Eastern Cooperative Oncology Group < 2). No significant difference in OS was noted between subgroups of patients according to TB. Bone metastases (BM) had a negative prognostic impact [median OS (mOS), 13.8 vs. 70.0 months, P = 0.0009; median progression free survival in the second line (mPFS2) 2.97 vs. 8.63 months; P = 0.0037]. Patients with NMD had a poorer prognosis (mOS, 15.9 months vs. not reached, P < 0.0001; mPFS2 3.8 vs. 12.2 months; P = 0.0199). Patients with disease limited to the thorax had a better prognosis compared to patients with involvement of extrathoracic sites (mOS, 70 vs. 17.3 months; P = 0.0136). Having more than 4 metastatic sites resulted as a negative prognostic factor (mOS, 15.9 vs. 25.2 months; P = 0.0106). At multivariate analysis, BM, NMD, extrathoracic disease and number of sites of metastases > 4 were negative prognostic factors (P < 0.0001). Conclusions: This study underlines the negative prognostic impact of specific metastatic sites, presence of NMD and extrathoracic disease in advanced NSCLC patients treated with immunotherapy. However, TB does not appear to affect the outcome of these patients.

High-intensity statins are associated with improved clinical activity of PD-1 inhibitors in malignant pleural mesothelioma and advanced non-small cell lung cancer patients.

BACKGROUND: In preclinical models, statins showed vaccine adjuvant activities and synergized with PD-1 inhibitors. We analyzed the impact of statin treatment on clinical outcome in thoracic cancer patients treated with PD-1 inhibitors. METHODS: A total of 82 malignant pleural mesothelioma (MPM) and 179 advanced non-small cell lung cancer (aNSCLC) patients treated with PD-1 inhibitors as second or further line treatment were examined. Seventy-seven MPM patients treated with standard chemotherapy were analyzed as control cohort. Objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) were calculated. RESULTS: Among 253 patients with available data, statin use was associated with increased ORR (32% versus 18%, P = .02), PFS (median 6.7 versus 2.9 months, hazard ratio [HR] 0.57, 95% CI 0.39-0.83, P < .01), and OS (median 13.1 versus 8.7 months, HR 0.67, 95% CI 0.45-1.00, P = .05). In the control MPM cohort treated with chemotherapy (n = 77), no association was found. MPM patients who used statins showed improved ORR (22% versus 6%, P = .05), PFS (median 6.7 versus 2.4 months, P < .01), and OS (median not reached versus 6.0 months, P = .01). In aNSCLC patients, statin use was associated with improved ORR (40% versus 22%, P = .04) and PFS (median 7.8 versus 3.6 months, P = .03), but no significant difference in OS was found (median 13.1 versus 10.1 months, P = .30). Multivariable analysis confirmed the correlation between statin use and better PFS and OS in MPM and better PFS in aNSCLC. In the whole cohort, high but not low/moderate-intensity statins were associated with better OS compared to no user (P = .02 and P = .59, respectively). CONCLUSIONS: Our study showed that statins are associated with better clinical outcome in MPM and aNSCLC patients treated with PD-1 inhibitors in an intensity-dependent manner.

Machine Learning of Allosteric Effects: The Analysis of Ligand-Induced Dynamics to Predict Functional Effects in TRAP1.

Allosteric molecules provide a powerful means to modulate protein function. However, the effect of such ligands on distal orthosteric sites cannot be easily described by classical docking methods. Here, we applied machine learning (ML) approaches to expose the links between local dynamic patterns and different degrees of allosteric inhibition of the ATPase function in the molecular chaperone TRAP1. We focused on 11 novel allosteric modulators with similar affinities to the target but with inhibitory efficacy between the 26.3 and 76%. Using a set of experimentally related local descriptors, ML enabled us to connect the molecular dynamics (MD) accessible to ligand-bound (perturbed) and unbound (unperturbed) systems to the degree of ATPase allosteric inhibition. The ML analysis of the comparative perturbed ensembles revealed a redistribution of dynamic states in the inhibitor-bound versus inhibitor-free systems following allosteric binding. Linear regression models were built to quantify the percentage of experimental variance explained by the predicted inhibitor-bound TRAP1 states. Our strategy provides a comparative MD-ML framework to infer allosteric ligand functionality. Alleviating the time scale issues which prevent the routine use of MD, a combination of MD and ML represents a promising strategy to support in silico mechanistic studies and drug design.

High Prevalence and Early Occurrence of Skeletal Complications in EGFR Mutated NSCLC Patients With Bone Metastases.

OBJECTIVES: The prevalence of Skeletal Related Adverse Events (SREs) in EGFR mutated non-small cell lung cancer (NSCLC) patients with bone metastases, treated with modern tyrosine kinase inhibitors (TKIs), has been scarcely investigated. MATERIALS AND METHODS: We retrospectively evaluated the data of EGFR mutated NSCLC patients with bone metastases treated with TKIs in 12 Italian centers from 2014 to 2019, with the primary aim to explore type and frequency of SREs. RESULTS: Seventy-seven out of 274 patients enrolled (28%) developed at least one major SRE: 55/274 (20%) bone fractures, 30/274 (11%) spinal cord compression, 5/274 (2%) hypercalcemia. Median time to the onset of SRE was 3.63 months. Nine patients (3%) underwent bone surgery and 150 (55%) radiation therapy on bone. SREs were more frequently observed within the 12 months from TKI start than afterwards (71 vs 29%, p 0.000). Patient Performance Status and liver metastases where independently associated with the risk of developing SREs. Median TKI exposure and overall survival were 11 and 28 months, respectively. Bone resorption inhibitors were associated with a lower risk of death (HR 0.722, 95% CI: 0.504-1.033, p = 0.075) although not statistically significant at multivariate analysis. CONCLUSION: Bone metastatic NSCLC patients with EGFR mutated disease, treated with EGFR TKIs, have a relatively long survival expectancy and are at high risk to develop SREs. The early SRE occurrence after the TKI start provides the rationale to administer bone resorption inhibitors.

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.

Setup and Validation of a Reliable Docking Protocol for the Development of Neuroprotective Agents by Targeting the Sigma-1 Receptor (S1R).

Sigma-1 receptor (S1R) is a promising molecular target for the development of novel effective therapies against neurodegenerative diseases. To speed up the discovery of new S1R modulators, herein we report the development of a reliable in silico protocol suitable to predict the affinity of small molecules against S1R. The docking method was validated by comparing the computational calculated Ki values of a test set of new aryl-aminoalkyl-ketone with experimental determined binding affinity. The druggability profile of the new compounds, with particular reference to the ability to cross the blood-brain barrier (BBB) was further predicted in silico. Moreover, the selectivity over Sigma-2 receptor (S2R) and N-methyl-D-aspartate (NMDA) receptor, another protein involved in neurodegeneration, was evaluated. 1-([1,1'-biphenyl]-4-yl)-4-(piperidin-1-yl)butan-1-one (12) performed as the best compound and was further investigated for acetylcholinesterase (AchE) inhibitor activity and determination of antioxidant activity mediated by aquaporins (AQPs). With a good affinity against both S1R and NMDA receptor, good selectivity over S2R and favorable BBB penetration potential together with its AChE inhibitory activity and its ability to exert antioxidant effects through modulation of AQPs, 12 represents a viable candidate for further development as a neuroprotective agent.

MALAT1 as a Versatile Regulator of Cancer: Overview of the updates from Predatory role as Competitive Endogenous RNA to Mechanistic Insights

The central dogma of molecular biology, has remained a cornerstone of classical molecular biology. However, serendipitously discovered microRNAs (miRNAs) in nematodes paradigmatically shifted our current knowledge of the intricate mechanisms during transitions from transcription to translation. The discovery of miRNA captured considerable attention and appreciation, and we had witnessed an explosion in the field of non-coding RNAs. Ground-breaking discoveries in the field of non-coding RNAs have helped in better characterization of microRNAs and long non-coding RNAs (LncRNAs). There is an ever-increasing list of miRNA targets that are regulated by MALAT1 to stimulate or repress the expression of target genes. However, in this review, our main focus is to summarize mechanistic insights on MALAT1-mediated regulation of oncogenic signaling pathways. We have discussed how MALAT1 modulated TGF/SMAD and Hippo pathways in various cancers. We have also comprehensively summarized how JAK/STAT and Wnt/ß-catenin pathways stimulated MALAT1 expression and consequentially how MALAT1 potentiated these signaling cascades to promote cancer. MALAT1 research has undergone substantial broadening. However, there is still a need to identify additional mechanisms. MALAT1 is involved in the multi-layered regulation of multiple transduction cascades, and detailed analysis of different pathways will be advantageous in getting a step closer to individualized medicine.

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.

The Role of Hyponatraemia Before Surgery in Patients With Radical Resected Pancreatic Cancer.

OBJECTIVES: Hyponatraemia represents a negative prognostic factor in patients with cancer. The aim of this study was to assess, for the first time, the role of hyponatraemia in patients undergoing radical surgery for pancreatic ductal adenocarcinoma. METHODS: A total of 89 patients with stage I-III pancreatic ductal adenocarcinoma underwent radical surgery between November 2012 and October 2014. Relapse-free survival (RFS) and disease-specific survival (DSS) were estimated using Kaplan-Meier method. A Cox regression model was carried out for univariate and multivariate analyses. Fisher exact test was used to estimate correlation between variables. RESULTS: In total, 12 patients (14%) presented with hyponatraemia at diagnosis. The median DSS was 20 months in patients with hyponatraemia and not reached in patients with eunatraemia (P < .1073), while a statistical significant difference was observed in terms of median RFS (10 months vs 17 months, respectively; P = .0233). Considering clinical features (hyponatraemia, smoke and alcoholic habit, diabetes, pain, and jaundice), patients with 4 or more of these factors had a worse prognosis (mDSS: 30 months vs not reached; hazard ratio [HR]: 0.40, 95% confidence interval [CI] = 0.16-0.80; P = .0120). CONCLUSIONS: The presence of hyponatraemia and its prompt correction at the diagnosis time should be considered for the correct management of patients with pancreatic carcinoma.

Questioning the prognostic role of BAP-1 immunohistochemistry in malignant pleural mesothelioma: A single center experience with systematic review and meta-analysis.

INTRODUCTION: The prognostic role of BRCA1 associated protein-1 (BAP1) expression in malignant pleural mesothelioma (MPM) is a matter of debate. We aimed to clarify whether MPM patients with loss of BAP1 expression have better overall survival (OS) compared to BAP1 positive patients. METHODS: BAP1 immunohistochemical staining of tumor samples from 60 MPM patients treated at our institution with first-line chemotherapy was evaluated. A systematic literature search was also performed. Only cohort studies that investigated BAP1 by immunohistochemistry (IHC) and reported hazard ratio (HR) values for OS obtained through multivariate analysis (or adjusted for histotype) were considered. A dataset comprising 638 MPM patients was added to our cohort and included in the meta-analysis. RESULTS: In our cohort, 23 samples (38 %) were BAP1 positive/retained (≥1 %) and 37 samples (62 %) were BAP1 negative/loss. BAP1 loss was associated with epithelioid histotype (p 0.01). Median OS times were 14.8 months (95 % CI: 10.7-29.3) and 18.1 months (95 % CI: 11.2-25.8) for negative and positive BAP1 expression, respectively (p 0.2). At multivariate analysis, again no differences were observed among the two groups (p 0.81). Similarly, the meta-analysis consisting of 698 patients showed no difference in terms of OS according to BAP1 status (HR 1.11; 95 % CI, 0·76-1·61; p 0.60). CONCLUSIONS: BAP1 expression is not an independent prognostic factor for MPM patients and it should not be considered without taking into account tumor histotype. Future studies should investigate its predictive role in patients treated with new emerging therapies such as immunotherapy.

Prognostic relevance of programmed cell death protein 1/programmed death-ligand 1 pathway in thymic malignancies with combined immunohistochemical and biomolecular approach.

BACKGROUND: The aim of the study was to investigate Programmed cell Death protein 1 (PD-1) and Programmed Death-Ligand 1 (PD-L1) and their mRNA expression in thymic epithelial tumors (TETs). RESEARCH DESIGN AND METHODS: We analyzed 68 samples of formalin-fixed paraffin-embedded tissue (63 thymomas and 5 thymic carcinomas). PD-1 and PD-L1 protein expression were evaluated by immunohistochemistry, and mRNA expression was evaluated by real-time PCR. RESULTS: M/F ratio was 33/35, and median age was 60.5 years. Twenty patients had Myasthenia Gravis (MG). In the subgroup with large tumors (>5 cm), PD-L1 mRNA overexpression was significantly associated with worse prognosis vs. patients with no mRNA overexpression (p = 0.0083) and simultaneous PD-L1 immunostaining (>1%); PD-L1 mRNA overexpression was significantly associated with worse prognosis, respect to patient with PD-L1 negative immunostaining, and no PD-L1 mRNA overexpression (p = 0.0178). The elderly patients (>60 years) with large tumors showed worse prognosis (p = 0.0395). PD-L1 immunostaining (>50%) resulted to be significantly associated with MG. CONCLUSIONS: Our data suggest the potential involvement of the PD-1 and PD-L1 pathway in TETs' progression. According to our results, it may be helpful to design future trials with anti-PD-1 drugs to establish high-risk patients after surgery.

Hyponatremia is a Predictor of Clinical Outcome for Resected Biliary Tract Cancers: A Retrospective Single-Center Study.

INTRODUCTION: Biliary tract cancers (BTC) include both gallbladder cancer and cholangiocarcinoma, both of which have a poor prognosis. The aim of our study was to evaluate the main clinical prognostic factors in this setting and to assess their impact on overall survival (OS). METHODS: We retrospectively analyzed data collected on 64 patients with BTC who underwent surgery with radical intent at our institution. OS was estimated using the Kaplan-Meier method. The Cox regression model was used to perform univariate and multivariate analyses. RESULTS: Preoperative hyponatremia was found to be an independent prognostic factor that correlated negatively with prognosis, with hyponatremic patients having a poor OS compared to the group of patients with normal serum sodium levels (9.44 vs. 15.47 months; p = 0.0215). In addition, high preoperative values for carbohydrate antigen 19-9 (Ca19.9), a tumor marker for some gastrointestinal cancers, and lactate dehydrogenase (LDH) were found to be prognostic factors for a significant reduction in OS (Ca19-9: 7.14 vs. 24.22 months, p = 0.0088; LDH: 1.70 vs. 15.47 months, p = 0.0384). CONCLUSION: Identification of these prognostic factors may support strategies to identify, in clinical practice, those subgroups of patients with a favorable or unfavorable prognosis before surgical treatment and, therefore, to guide therapeutic choices. In particular, to our knowledge, this is the first report of the prognostic role of serum sodium level in BTC. Early detection and careful monitoring of hyponatremia and supportive therapy can help to improve the treatment and prognosis of BTC.