A comprehensive analysis of candidate genes in familial pancreatic cancer families reveals a high frequency of potentially pathogenic germline variants.

Background: The 5-year survival rate of patients with pancreatic ductal adenocarcinoma (PDAC) is around 5% due to the fact that the majority of patients present with advanced disease that is treatment resistant. Familial pancreatic cancer (FPC) is a rare disorder that is defined as a family with at least two affected first degree relatives, with an estimated incidence of 4%-10%. The genetic basis is unknown in the majority of families although around 10%-13% of families carry germline mutations in known genes associated with hereditary cancer and pancreatitis syndromes.

Biological Features and Prognostic Impact of Bone Marrow Infiltration in Patients with Diffuse Large B-Cell Lymphoma.

The biology and clinical impact of bone marrow (BM) infiltration in patients with diffuse large B-cell lymphoma (DLBCL) remains unclear in the rituximab era. We retrospectively analyzed 232 patients diagnosed with DLBCL at our center between 1999 and 2014. Concordant-presence of large cells similar to those of the lymph node biopsy- and discordant-infiltration by small cells forming lymphoid aggregates, lacking cytological atypia-BM infiltration was defined by histological criteria and further characterized by flow cytometry (FCM).

Baveno VI and Expanded Baveno VI criteria successfully predicts the absence of high-risk gastro-oesophageal varices in a Chilean cohort.

Background: Baveno VI and expanded Baveno VI criteria have been recommended to circumvent the need for endoscopy screening in patients with a very low probability of varices needing treatment (VNT).

Aim: To validate these criteria in a Latin American population.

Methods: The ability of Baveno VI criteria (liver stiffness measurement (LSM) <20 kPa and platelet count >150 × 103/μL) and expanded Baveno VI criteria (LSM < 25kPa and platelet count >110 × 103/μL) to exclude the presence of VNT was tested in a prospectively recruited cohort of patients with Child-Pugh A liver cirrhosis and with no previous variceal haemorrhage who attended the liver clinics of three major hospitals in Chile.

[Experience of continuing online education in gastroenterology for non specialist medical doctors].

Background: Continuing education is essential for health professions and online courses can be a good way for professional development.

Aim: To describe the experience with online courses for continuing education in hepatology and gastroenterology and to analyze their educational impact.

Material And Methods: A three years' experience in courses on liver diseases and digestive tract is described.

Influence of Dietary Vitamin A and Iron Deficiency on Hematologic Parameters and Body Weight of Young Male Wistar Rats.

Micronutrient deficiency is one of the most prominent public health concerns; in particular, vitamin A and iron are determinants of appropriate development, and vitamin A influences iron homeostasis and metabolism. Here we compared the effects of diets that were sufficient and insufficient in vitamin A and iron on the hematologic parameters and body weight of rats. Male Wistar rats were randomly divided into 5 dietary groups ( = 7 per group): adequate in iron and vitamin A (control); adequate in iron but low in vitamin A (FesvAi); adequate in iron but lacking vitamin A (FesvAd); low in iron but adequate in vitamin A (FeivAs); and low in both iron and vitamin A (FeivAi).

Immune Checkpoint Inhibition in Colorectal Cancer: Microsatellite Instability and Beyond.

Immune checkpoints inhibitors (ICIs) have been a breakthrough, with unique response and survival patterns compared with chemotherapy for patients with advanced Mismatch Repair-deficient/Microsatellite instable (dMMR/MSI) colorectal cancer, but have shown disappointing results in Mismatch Repair-proficient/Microsatellite stable (pMMR/MSS) colorectal cancer. As up to 50% of patients harboring dMMR/MSI advanced cancers will ultimately progress after PD-1 blockade, biomarkers are needed to predict response/resistance to immunotherapy and to select patients for immunomodulating combination therapies. Patients with pMMR/MSS colorectal cancer present with distinct immune profiles compared to dMMR/MSI tumors, giving evidence of different immune escape mechanisms, which could be overcome through individualized immunotherapeutic strategies.

High-intensity sequencing reveals the sources of plasma circulating cell-free DNA variants.

Accurate identification of tumor-derived somatic variants in plasma circulating cell-free DNA (cfDNA) requires understanding of the various biological compartments contributing to the cfDNA pool. We sought to define the technical feasibility of a high-intensity sequencing assay of cfDNA and matched white blood cell DNA covering a large genomic region (508 genes; 2 megabases; >60,000× raw depth) in a prospective study of 124 patients with metastatic cancer, with contemporaneous matched tumor tissue biopsies, and 47 controls without cancer. The assay displayed high sensitivity and specificity, allowing for de novo detection of tumor-derived mutations and inference of tumor mutational burden, microsatellite instability, mutational signatures and sources of somatic mutations identified in cfDNA.

Phase II Open-Label Study of Pembrolizumab in Treatment-Refractory, Microsatellite Instability-High/Mismatch Repair-Deficient Metastatic Colorectal Cancer: KEYNOTE-164.

Purpose: KEYNOTE-164 (NCT02460198) evaluated the antitumor activity of pembrolizumab in previously treated, metastatic, microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) colorectal cancer (CRC).

Methods: This phase II open-label study involved 128 centers worldwide. Eligible patients were age ≥ 18 years and had metastatic MSI-H/dMMR CRC treated with ≥ 2 prior lines of standard therapy, including fluoropyrimidine, oxaliplatin, and irinotecan with or without anti-vascular endothelial growth factor/epidermal growth factor receptor monoclonal antibody (cohort A) or ≥ 1 prior line of therapy (cohort B).

Efficacy of Pembrolizumab in Patients With Noncolorectal High Microsatellite Instability/Mismatch Repair-Deficient Cancer: Results From the Phase II KEYNOTE-158 Study.

Purpose: Genomes of tumors that are deficient in DNA mismatch repair (dMMR) have high microsatellite instability (MSI-H) and harbor hundreds to thousands of somatic mutations that encode potential neoantigens. Such tumors are therefore likely to be immunogenic, triggering upregulation of immune checkpoint proteins. Pembrolizumab, an anti‒programmed death-1 monoclonal antibody, has antitumor activity against MSI-H/dMMR cancer.

Lesion-Level Response Dynamics to Programmed Cell Death Protein (PD-1) Blockade.

Purpose: Response to programmed cell death protein 1 (PD-1) blockade is often conceptualized as resulting from reinvigoration of tumor-infiltrating lymphocytes. However, recruited antitumor immunity from the periphery may also be an important contributor to response. A detailed assessment of the response dynamics of individual metastasis could provide insight to the systemic and local features that mediate response and resistance to immunotherapy.

Assessment of Hepatic Arterial Infusion of Floxuridine in Combination With Systemic Gemcitabine and Oxaliplatin in Patients With Unresectable Intrahepatic Cholangiocarcinoma: A Phase 2 Clinical Trial.

Importance: Unresectable intrahepatic cholangiocarcinoma (IHC) carries a poor prognosis, with a median overall survival (OS) of 11 months. Hepatic arterial infusion (HAI) of high-dose chemotherapy may have potential benefit in these patients.

Objective: To evaluate clinical outcomes when HAI chemotherapy is combined with systemic chemotherapy in patients with unresectable IHC.

Intra-articular Corticosteroid Injections in the Hip and Knee: Perhaps Not as Safe as We Thought?

Osteoarthritis (OA) of the hip and knee is among the most common joint disorders. Intra-articular corticosteroid (IACS) injections are frequently performed to treat OA and other joint-related pain syndromes; however, there is conflicting evidence on their potential benefit. There is a lack of prospective and large retrospective studies evaluating potential joint findings, including increased risk for accelerated OA progression or adverse joint events, after treatment with IACS injection.

First Detection of Madariaga virus in Mosquitoes Collected in a Wild Environment of Northeastern Argentina.

Madariaga virus (MADV), previously known as South American eastern equine encephalitis virus (SA EEEV; family Togaviridae, genus ), is a mosquito-borne virus associated mainly with equine disease. In 2010, the first human outbreak by MADV was reported in Central America, but the mosquito vectors and vertebrate hosts involved in the outbreak were not identified. In Argentina, the first epizootic of MADV was in 1930, and since then, several epizootics by MADV have been reported.

Immunopathologic Stratification of Colorectal Cancer for Checkpoint Blockade Immunotherapy.

Mismatch-repair deficiency in solid tumors predicts their response to PD-1 blockade. Based on this principle, pembrolizumab is approved as standard of care for patients with unresectable or metastatic microsatellite instability-high (MSI-H) cancer. Despite this success, a large majority of metastatic colorectal cancer patients are not MSI-H and do not benefit from checkpoint blockade treatment.

"Hey CIRI, What's My Prognosis?".

Although serial tumor assessments are increasingly performed through imaging and molecular approaches, such evaluations are often considered in isolation, as robust frameworks for integrating multiple biomarkers are currently lacking. Thus, in this issue of Cell, Kurtz et al. present a method (termed CIRI) that integrates pre-treatment and on-treatment risk factors for accurate outcome prediction.

Clinical and Molecular Predictors of Response to Immune Checkpoint Inhibitors in Patients with Advanced Esophagogastric Cancer.

Purpose: Immune checkpoint inhibitors (ICI) are effective in only a minority of patients with esophagogastric cancer (EGC). Here, we aimed to identify predictors of durable clinical benefit to ICI in EGC.

Experimental Design: Patients with advanced EGC treated with ICIs at Memorial Sloan Kettering Cancer Center (New York, NY) were identified.

Intermittent pneumatic compression in patients with ESRD. A systematic review.

Introduction: Patients with end-stage renal disease (ESRD) experience frequent hemodialysis (HD) complications. Intradialytic hypotension (IDH) is a common complication presenting in approximately between 20 and 50% of HD sessions. Available interventions such as volume replacement or vasoactive medications are associated with significant side effects.

Walnut antigens can trigger autoantibody development in patients with pemphigus vulgaris through a "hit-and-run" mechanism.

Background: Environmental factors, as well as genetic predisposition, are known to be critical for the development of autoimmunity. However, the environmental agents that trigger autoimmune responses have remained elusive. One possible explanation is the "hit-and-run" mechanism in which the inciting antigens that initiate autoimmune responses are not present at the time of overt autoimmune disease.

Tumor genomic alterations in severe-combined immunodeficiency bare-lymphocyte syndrome genes are associated with high mutational burden and disproportional neo-antigen rates.

The progression of cancer requires mutational adaptation to permit unrestrained proliferation. A fraction of cancer mutations are oncogenic drivers, while others are putative 'passengers' that do not contribute to oncogenesis. However, altered peptides arising from passenger mutations may bind MHCs and activate non-self immunologic signals (i.

Intratumoral Adaptive Immunosuppression and Type 17 Immunity in Mismatch Repair Proficient Colorectal Tumors.

Purpose: Approximately 10% of patients with mismatch repair-proficient (MMRp) colorectal cancer showed clinical benefit to anti-PD-1 monotherapy (NCT01876511). We sought to identify biomarkers that delineate patients with immunoreactive colorectal cancer and to explore new combinatorial immunotherapy strategies that can impact MMRp colorectal cancer.

Experimental Design: We compared the expression of 44 selected immune-related genes in the primary colon tumor of 19 patients with metastatic colorectal cancer (mCRC) who responded ( = 13) versus those who did not ( = 6) to anti-PD-1 therapy (NCT01876511).

Genetic diversity of tumors with mismatch repair deficiency influences anti-PD-1 immunotherapy response.

Tumors with mismatch repair deficiency (MMR-d) are characterized by sequence alterations in microsatellites and can accumulate thousands of mutations. This high mutational burden renders tumors immunogenic and sensitive to programmed cell death-1 (PD-1) immune checkpoint inhibitors. Yet, despite their tumor immunogenicity, patients with MMR-deficient tumors experience highly variable responses, and roughly half are refractory to treatment.