Objectives: Mutations in the gene that encodes epidermal growth factor receptor (EGFR) are biomarkers that predict how non-small cell lung cancer (NSCLC) patients respond to EGFR-targeted therapies collectively known as tyrosine kinase inhibitors (TKIs). Thus, EGFR genotyping provides crucial information for treatment decision. Both Sanger sequencing and real-time PCR methodologies are used for EGFR genotyping. However, methods based on real-time PCR have limitations, as they may not detect rare or novel mutations. The aim of this study was to determine the prevalence of rare mutations in the tyrosine kinase domain (exons 18-21) of the EGFR gene not targeted by the most frequently used real-time PCR approaches, i.e., the cobas® EGFR Mutation Test, and the Idylla™ EGFR Mutation Assay. Methods: A total of 1228 NSCLC patients were screened for mutations in exons 18-21 of the EGFR gene using Sanger sequencing. Results: We observed that 252 patients (∼20%) had at least one mutation in the EGFR gene, and 38 (∼3%) carried uncommon genetic alterations that would not be identified by the cobas® or the Idylla™ tests. We further found six new single mutations and seven previously unreported compound mutations. Clinical information and patient outcome are presented for these cases. Conclusions: This study highlights the value of sequencing-based approaches to identify rare mutations. Our results add to the inventory of known EGFR mutations, thus contributing to improved lung cancer precision treatment.

Genetic polymorphisms in proangiogenic factors did not associate with the risk of ALD in heavy drinkers. However, KDR and VEFGA polymorphisms may confer an increased risk of HCC in patients with ALD.

Background: Liquid biopsy allows the identification of targetable cancer mutations in a minimally invasive manner. In patients with advanced non-small cell lung cancer (NSCLC), droplet digital PCR (ddPCR) is increasingly used to genotype the epidermal growth factor receptor (EGFR) gene in circulating cell-free DNA (cfDNA). However, the sensitivity of this method is still under debate. The aim of this study was to implement and assess the performance of a ddPCR assay for detecting the EGFR T790M mutation in liquid biopsies.Methods: A ddPCR assay was optimized to detect the EGFR T790M mutation in plasma samples from 77 patients with NSCLC in progression.Results: Our ddPCR assay enabled the detection and quantification of the EGFR T790M mutation at cfDNA allele frequency as low as 0.5%. The mutation was detected in 40 plasma samples, corresponding to a positivity rate of 52%. The number of mutant molecules per mL of plasma ranged from 1 to 6,000. A rebiopsy was analyzed for 12 patients that had a negative plasma test and the mutation was detected in 2 cases.A second liquid biopsy was performed for 6 patients and the mutation was detected in 3 cases.Conclusions: This study highlights the value of ddPCR to detect and quantify the EGFR T790M mutation in liquid biopsies in a real-world clinical setting. Our results suggest that repeated ddPCR tests in cfDNA may obviate tissue re-biopsy in patients unable to provide a tumor tissue sample suitable for molecular analysis.

Cerebrospinal fluid (CSF) biomarkers have been extensively investigated in the Alzheimer's disease (AD) field, and are now being applied in clinical practice. CSF amyloid-beta (A␤ 1-42), total tau (t-tau), and phosphorylated tau (p-tau) reflect disease pathology, and may be used as quantitative traits for genetic analyses, fostering the identification of new genetic factors and the proposal of novel biological pathways of the disease. In patients, the concentration of CSF A␤ 1-42 is decreased due to the accumulation of A␤ 1-42 in amyloid plaques in the brain, while t-tau and p-tau levels are increased, indicating the extent of neuronal damage. To better understand the biological mechanisms underlying the regulation of AD biomarkers, and its relation to AD, we examined the association between 36 selected single nucleotide polymorphisms (SNPs) and AD biomarkers A␤ 1-42 , t-tau, and p-tau in CSF in a cohort of 672 samples (571 AD patients and 101 controls) collected within ten European consortium centers. Our results highlighted five genes, APOE, LOC100129500, PVRL2, SNAR-I, and TOMM40, previously described as main players in the regulation of CSF biomarkers levels, further reinforcing a role for these in AD pathogenesis. Three new AD susceptibility loci, INPP5D, CD2AP, and CASS4, showed specific association with CSF tau biomarkers. The identification of genes that specifically influence tau biomarkers point out to mechanisms, independent of amyloid processing, but in turn related to tau biology that may open new venues to be explored for AD treatment.

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Monolithic carbon foams with hierarchical porosity were prepared from polyurethane templates and resol precursors. Mesoporosity was achieved through the use of soft templating with surfactant Pluronic F127, and macroporosity from the polyurethane foams was retained. Conditions to obtain high porosity materials were optimized. The best materials have high specific surface areas (380 and 582 m 2 g -1 , respectively) and high electrical conductivity, which make them good candidates for supports in sensors. These materials showed an almost linear dependence between the potential and the pH of aqueous solutions.

Background: PROs enable direct measurement of the experiences of pts with cancer related to an intervention. Regulators increasingly use PROs to inform the risks and benefits of new drug candidates, focusing on 3 core concepts: physical functioning (PF), disease-related symptoms (DRS), and symptomatic adverse events (AEs). Dostarlimab is an investigational antieprogrammed death-1 monoclonal antibody that has shown activity in pts with advanced dMMR EC (objective response rate, 42%; disease control rate, 58%) and an acceptable safety profile. Here, we report on PROs in pts treated with dostarlimab in the single-arm GARNET trial.Methods: Pts with recurrent or advanced dMMR/MSI-H EC that progressed on a platinum regimen received 500 mg Q3W*4 of dostarlimab, then 1000 mg Q6W until disease progression or discontinuation (DC). PRO assessment, an exploratory endpoint, was measured using the EORTC-QLQ-C30. PROs were collected at baseline (BL), each dose cycle, and after DC. For PF and DRS (pain and fatigue), we conducted multi-item descriptive analyses, including change from BL. For symptomatic AEs and tolerability (nausea, vomiting, constipation, diarrhea, tiredness/fatigue), we conducted item-level analyses to understand response distribution and change in response categories from BL: improved, stable, and 1-, 2-, or 3-category worsening.Results: PRO data were available for 66/104 pts who received 1 dose of dostarlimab. Questionnaire compliance was consistent across domains, ranging from 100% at BL to 45% at cycle 7. Pain, fatigue, and PF were maintained above BL starting at cycles 1, 3, and 4, respectively. Symptomatic AEs were experienced by a minority of pts, with <25% and <6% of pts having 1-or 2-category worsening, respectively. Improved scores were reported by 6% to 37% of pts.Conclusions: PROs from the GARNET trial showed that dostarlimab was generally well tolerated and disease-related symptoms were improved or maintained while on treatment. These data, along with the efficacy and safety profile of dostarlimab, support use of dostarlimab in pts with dMMR/MSI-H advanced EC.Clinical trial identification: NCT02715284.

<b><i>Background and Aims:</i></b> Colorectal cancer (CRC) is a heterogeneous disease with distinctive genetic pathways, such as chromosomal instability, microsatellite instability and methylator pathway. Our aim was to correlate clinical and genetic characteristics of CRC patients in order to understand clinical implications of tumour genotype. <b><i>Methods:</i></b> Single-institution retrospective cohort of patients who underwent curative surgery for CRC, from 2012 to 2014. <i>RAS</i> and <i>BRAF</i> mutations were evaluated with the real-time PCR technique Idylla®. Mismatch repair deficiency (dMMR) was characterized by absence of MLH1, MSH6, MSH2 and/or PMS2 expression, evaluated by tissue microarrays. Overall survival (OS) and disease-free survival (DFS) were assessed using survival analysis. <b><i>Results:</i></b> Overall, 242 patients were included (males 57.4%, age 69.3 ± 12.9 years; median follow-up 49 months). <i>RAS</i>-mutated tumours were associated with reduced DFS (<i>p</i> = 0.02) and OS (<i>p</i> = 0.045) in stage I–III CRC. <i>BRAF</i>-mutated tumours were more predominant in females and in the right colon, similarly to dMMR tumours. BRAF status did not influence OS (4 years)/DFS (3.5 years) in stage I–III disease. However, after relapse, length of survival was 3.5 months in <i>BRAF</i>-mutated tumours in contrast to 18.6 months in <i>BRAF</i> wild-type tumours (<i>p</i> = NS). No germline mutations in mismatch repair genes were so far identified in the patients with dMMR tumours. Molecular phenotype (<i>RAS, BRAF</i> and MMR) did not influence OS in metastatic patients. Our small sample size may be a limitation of the study. <b><i>Conclusion:</i></b> In our cohort, <i>RAS</i>-mutated tumours were associated with worse DFS and OS in early-stage CRC, whereas the remaining molecular variables had no prognostic influence.