Lynch syndrome-associated lung cancer: pitfalls of an immunotherapy-based treatment strategy in an unusual tumor type.

Lynch syndrome is a hereditary cancer predisposition syndrome caused by germline alterations in mismatch repair (MMR) genes leading to increased risk of colon cancer as well as other cancer types. Non-small cell lung cancer (NSCLC) is not among typical Lynch syndrome-associated tumors: pembrolizumab, an immune checkpoint inhibitor, is actually approved for the treatment of NSCLC patients and represents a promising treatment option for patients with advanced metastatic MMR-deficient cancer, regardless of tumor origin. This case report describes the clinical presentation and management of a 74-year-old female with a history of rectal adenocarcinoma and ovarian cancer, who has a documented frameshift pathogenic variant in the exon 8 of MSH6 gene and an intronic variant in the BRCA2 gene (classified as a variant of uncertain significance), affected by NSCLC with brain metastases. Despite these premises, the patient was treated with pembrolizumab and she did not benefit from this kind of treatment.

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.

Expectations and psychological issues before genetic counseling: analysis of distress determinant factors.

BACKGROUND: Hereditary non-polyposis colorectal cancer (HNPCC) and Hereditary Breast and Ovarian Cancer Syndrome (HBOC) are the most common hereditary cancer syndromes in which a genetic test is available. Potential risks associated with testing include psychological harm, emotional distress and insurance problems. METHODS: The aim of the present study is to investigate determinants of distress in a sample of Italian subjects undergoing genetic counseling. Demographic information and psychological distress were assessed by using a self-reported questionnaire and the "Hospital Anxiety and Depression Scale" (HAD), before attending the first counseling session. RESULTS: Of the all subjects referred for the first time to our Center (January 2012-June 2013), a total of 227 were eligible (female/male = 174/53) for the survey, 134 (59%) were oncologic patients and of these, 116 received genetic test (36 for HNPCC and 80 for HBOC). The remaining 93 (41%) were healthy subjects referred for suspected familiar history and of this group, 65 subjects performed predictive test in a family with a known pathogenic mutation (53 for HBOC and 12 for HNPCC). Affected subjects had a significantly higher level of anxiety (p = 0.02) and HAD global score (p = 0.01) than healthy ones. There was no difference in HAD score between individuals testing for different syndromes (p = 0.3). In the affected subgroup, there was a significant linear correlation between the HAD anxiety score and how much subjects perceived their disease as hereditary (p = 0.01). Female and younger subjects had higher levels of anxiety (p = 0.05). Also healthy single subjects show more general distress (p = 0.02) than those with a partner. CONCLUSIONS: Greater level of distress identified on females, single and younger subjects.

Correction to: Expectations and psychological issues before genetic counseling: analysis of distress determinant factors.

[This corrects the article DOI: 10.1186/s13053-020-00142-1.].

Clinical impact of different exosomes' protein expression in pancreatic ductal carcinoma patients treated with standard first line palliative chemotherapy.

INTRODUCTION: Pancreatic ductal adenocarcinoma is associated to dismal prognosis despite the use of palliative chemotherapy, partly due to the lack of knowledge of biological processes underlying disease progression. Exosomes have been identified as biomarkers sources in different cancer types. Aim of the study was to analyse the contents of circulating exosomes in patients with pancreatic cancer who received palliative chemotherapy. PATIENTS AND METHODS: Patients were submitted to blood sample collection before chemotherapy (T0) and after 3 months (T3). We quantified by an ELISA-based technique specific proteins of cancer-derived exosomes (CD44,CD44v6,EpCAM,CD9,CD81,Tspan8,Integrin α6,Integrin ß4,CD24,CXCR4). We correlated the baseline levels of these factors and changes between T3 and T0 and survival outcomes. Survival analyses were performed by Kaplan-Meier method. Correlation was assessed by log-rank test and level of statistical significance was set at 0.05. Multivariate analysis was performed by logistic regression analysis. RESULTS: Nineteen patients were enrolled. EpCAM T0 levels and increased EpCAM levels from T0 to T3 were those mostly associated with differences in survival. Patients having higher EpCAM had median progression free survival (PFS) of 3.18vs7.31 months (HR:2.82,95%CI:1.03-7.73,p = 0.01). Overall survival (OS) was shorter for patients having higher EpCAM (5.83vs16.45 months,HR:6.16,95%CI:1.93-19.58,p = 0.0001) and also response rates (RR) were worse (20%vs87%,p = 0.015). EpCAM increase during treatment was associated with better median PFS (2.88vs7.31 months,HR:0.24,95%CI:0.04-1.22,p = 0.003). OS was also better (8.75vs11.04 months, HR:0.77,95%CI:0.21-2.73,p = 0.66) and RR were 60%vs20% (p = 0.28). Among clinical factors that might determine changes on PFS and OS, only ECOG PS was associated to significantly worse PFS and OS (p = 0.0137and<0.001 respectively).Multivariate analysis confirmed EpCAM T0 levels and EpCAM T0/T3 changes as independent prognostic factors for PFS. CONCLUSIONS: Pancreatic cancer patients exosomes express EpCAM, whose levels change during treatment. This represents a useful prognostic factor and also suggests that future treatment modalities who target EpCAM should be tested in pancreatic cancer patients selected by exosome EpCAM expression.

Impact of vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor (VEGFR) single nucleotide polymorphisms on outcome in gastroenteropancreatic neuroendocrine neoplasms.

Angiogenesis represents a key event in cancer development, leading to local invasion e metastatization, and might be considered a basic feature in gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) with a high expression of angiogenic molecules. We aimed to analyze the prognostic and predictive role of angiogenic factors in GEP-NENs through the analysis of single nucleotide polymorphisms (SNPs) of VEGF-A, VEGFR2 and VEGFR3. The genomic DNA of 58 consecutive patients with GEP-NENs treated at our Institution was extracted from peripheral blood. Two SNPs were identified respectively in VEGF-A (rs2010963G>C, rs699947A>C), VEGFR-2 (rs2305948C>T, rs1870377T>A), and VEGFR-3 (rs307821T>C, rs307826C>A) gene. Gene polymorphisms were determined by Real-Time PCR using TaqMan assays. Median age was 57 years (range 24-79 years); 32 patients were male and 77.5% of NENs were localized in the pancreas. The allele frequency of VEGFR-2 rs2305948T and of VEGF-A rs2010963C showed a trend of higher frequency than in general population (12.1% vs. 8.0% and 34.5% vs. 31.2%, respectively). Three out SNPs (VEGF-A rs699947C, VEGF-A rs2010963GC and VEGFR-3 rs307821C) showed a correlation with an increased risk of disease relapse. Moreover median PFS changes according to the presence of 0-1 SNPs (20.7% of cases; 61.9 months), 2 SNPs (25.9%; 49.2 months) and 3 SNPs (53.4%; 27.8 months) (p = 0.034). Results suggest, for the first time, that specific SNPs in VEGF-A and VEGFR-3 correlate with poor prognosis in GEP-NENs. The identification of this new prognostic factor might be helpful in order to optimize the management of these heterogeneous neoplasms.