Lessons learned from 150 total gastrectomies for prevention of cancer.

Background: Prophylactic total gastrectomy (PTG) is performed in carriers of CDH1 pathogenic and likely pathogenic (P/LP) variants and is becoming more frequent with broader use of germline genetic testing. There is an unmet need to standardize care and enhance outcomes among patients undergoing surgery for the prevention of gastric cancer.

Methods: This was a retrospective analysis of 150 individuals with germline CDH1 P/LP variants who underwent PTG as part of a prospective natural history study from October 2017 to May 2023.

Germline CDH1 Variants and Lifetime Cancer Risk.

Importance: Approximately 1% to 3% of gastric cancers and 5% of lobular breast cancers are hereditary. Loss of function CDH1 gene variants are the most common gene variants associated with hereditary diffuse gastric cancer and lobular breast cancer. Previously, the lifetime risk of gastric cancer was estimated to be approximately 25% to 83% and for breast cancer it was estimated to be approximately 39% to 55% in individuals with loss of function CDH1 gene variants.

Tumor-Intrinsic Enhancer of Zeste Homolog 2 Controls Immune Cell Infiltration, Tumor Growth, and Lung Metastasis in a Triple-Negative Breast Cancer Model.

Triple-negative breast cancer (TNBC) is an aggressive and highly metastatic type of tumor. TNBC is often enriched in tumor-infiltrating neutrophils (TINs), which support cancer growth in part by counteracting tumor-infiltrating lymphocytes (TILs). Prior studies identified the enhancer of zeste homolog 2 (EZH2) as a pro-tumor methyltransferase in primary and metastatic TNBCs.

Life-Threatening Airway Obstruction and Septic Shock Due to Submandibular Space Infection: A Case Report.

Submandibular space infection, a rare and aggressive form of cellulitis, affects the floor of the mouth and neck, potentially leading to life-threatening complications. Although commonly associated with oral trauma and contiguous abscesses, the severity of these odontogenic infections often escalates due to underlying comorbidities. This report presents a unique case of a 74-year-old man who developed severe complications following an outpatient oral procedure.

Protocol for isolation of signet ring cells from human gastric mucosa.

More than 90% of individuals with germline pathogenic CDH1 variants will harbor occult, microscopic foci of signet ring cell carcinomas capable of progressing to advanced diffuse-type gastric cancer. Here, we present a protocol for high viability suspension of signet ring cells from human gastric tissue. We describe the steps for gastric mucosa isolation and tissue dissociation.

Costs of Cancer Prevention: Physical and Psychosocial Sequelae of Risk-Reducing Total Gastrectomy.

Purpose: Risk-reducing surgery for cancer prevention in solid tumors is a pressing clinical topic because of the increasing availability of germline genetic testing. We examined the short- and long-term outcomes of risk-reducing total gastrectomy (RRTG) and its lesser-known impacts on health-related quality of life (QOL) in individuals with hereditary diffuse gastric cancer syndrome.

Methods: Individuals who underwent RRTG as part of a single-institution natural history study of hereditary gastric cancers were examined.

Defining features of hereditary lobular breast cancer due to CDH1 with magnetic resonance imaging and tumor characteristics.

Women with germline pathogenic variants in CDH1, which encodes E-cadherin protein, are at increased lifetime risk of invasive lobular carcinoma (ILC). The associated tumor characteristics of hereditary lobular breast carcinoma (HLBC) in this high-risk population are not well-known. A single-center prospective cohort study was conducted to determine the imaging and pathologic features of HLBC compared to population-based ILC using Surveillance, Epidemiology, and End Results (SEER) data.

Early Immune Changes Support Signet Ring Cell Dormancy in CDH1-Driven Hereditary Diffuse Gastric Carcinogenesis.

Unlabelled: Stage IA gastric adenocarcinoma, characterized by foci of intramucosal signet ring cells (SRC), is found in nearly all asymptomatic patients with germline pathogenic CDH1 variants and hereditary diffuse gastric cancer syndrome (HDGC). The molecular steps involved in initiating malignant transformation and promoting SRC dormancy in HDGC are unknown. Here, whole-exome bulk RNA sequencing (RNA-seq) of SRCs and adjacent non-SRC epithelium (NEP) was performed on laser-capture microdissected (LCM) regions of interest found in risk-reducing total gastrectomy specimens from patients with HDGC (Clinicaltrials.

Optimal cancer care pathways - the ideal versus reality for patient-centric cancer care during COVID-19.

Objectives To assess whether compliance with the nationally endorsed Optimal Care Pathways is evident in 75% of patients treated with curative intent treatment and if this compliance was impacted by the COVID-19 pandemic (hereinafter COVID-19). Methods This retrospective study included patients undergoing curative treatment with radiotherapy in head and neck (HN), breast, lung and gastrointestinal malignancies between January 2019 and June 2021 in a single NSW outer metropolitan cancer service. For care delivered within the remit of cancer services, the primary outcome measure was the proportion of patients whose treatment complied with the Optimal Care Pathways recommended time frame.

Micronutrient Supplementation and Bone Health After Prophylactic Total Gastrectomy in Patients With CDH1 Variants.

Introduction: Patients with germline variants in CDH1 who undergo prophylactic total gastrectomy (TG) are at risk of altered nutrient and drug absorption due to modified gastrointestinal anatomy. Bone mineral density loss and micronutrient deficiencies have not been described previously in this patient population.

Methods: In this study we included 94 patients with germline CDH1 variants who underwent prophylactic TG between October 2017 and February 2022.

Association of Germline Variants and Colon Polyp Phenotypes in Patients with Hereditary Diffuse Gastric Cancer.

Background And Aims: Germline variants resulting in E-cadherin loss of function result in an increased risk of diffuse type gastric cancer and lobular type breast cancer. However, the risk of developing other epithelial neoplasms, specifically colorectal cancer, is unknown.

Methods: Patients enrolled in a prospective natural history study of hereditary gastric cancer who underwent at least one colonoscopy were evaluated.

Estimating road traffic impacts of commute mode shifts.

This work considers the sensitivity of commute travel times in US metro areas due to potential changes in commute patterns, for example caused by events such as pandemics. Permanent shifts away from transit and carpooling can add vehicles to congested road networks, increasing travel times. Growth in the number of workers who avoid commuting and work from home instead can offset travel time increases.

An In Vivo Definition of Brain Histamine Dynamics Reveals Critical Neuromodulatory Roles for This Elusive Messenger.

Histamine is well known for mediating peripheral inflammation; however, this amine is also found in high concentrations in the brain where its roles are much less known. In vivo chemical dynamics are difficult to measure, thus fundamental aspects of histamine's neurochemistry remain undefined. In this work, we undertake the first in-depth characterization of real time in vivo histamine dynamics using fast electrochemical tools.

Frequent cleft lip and palate in families with pathogenic germline variants.

Pathogenic and likely pathogenic (P/LP) germline variants in the tumor suppressor gene (E-cadherin) result in increased lifetime risk of diffuse-type gastric cancer and lobular breast cancer. variants are also associated with hereditary cleft lip and palate (CLP), the mechanism of which is not well understood. We sought to determine the prevalence of CLP in families who carry P/LP variants.

Safe reopening of university campuses is possible with COVID-19 vaccination.

We construct an agent-based SEIR model to simulate COVID-19 spread at a 16000-student mostly non-residential urban university during the Fall 2021 Semester. We find that mRNA vaccine coverage at 100% combined with weekly screening testing of 25% of the campus population make it possible to safely reopen to in-person instruction. Our simulations exhibit a right-skew for total infections over the semester that becomes more pronounced with less vaccine coverage, less vaccine effectiveness and no additional preventative measures.

Decision-making and regret in patients with germline variants undergoing prophylactic total gastrectomy.

Introduction: Prophylactic total gastrectomy (PTG) can eliminate gastric cancer risk and is recommended in carriers of a germline pathogenic variant. PTG has established risks and potential life-long morbidity. Decision-making regarding PTG is complex and not well-understood.

Managing public transit during a pandemic: The trade-off between safety and mobility.

During a pandemic such as COVID-19, managing public transit effectively becomes a critical policy decision. On the one hand, efficient transportation plays a pivotal role in enabling the movement of essential workers and keeping the economy moving. On the other hand, public transit can be a vector for disease propagation due to travelers' proximity within shared and enclosed spaces.

Metformin reduces PD-L1 on tumor cells and enhances the anti-tumor immune response generated by vaccine immunotherapy.

Background: PD-L1 is one of the major immune checkpoints which limits the effectiveness of antitumor immunity. Blockade of PD-L1/PD-1 has been a major improvement in the treatment of certain cancers, however, the response rate to checkpoint blockade remains low suggesting a need for new therapies. Metformin has emerged as a potential new drug for the treatment of cancer due to its effects on PD-L1 expression, T cell responses, and the immunosuppressive environment within tumors.

Inflammation-Induced Histamine Impairs the Capacity of Escitalopram to Increase Hippocampal Extracellular Serotonin.

Commonly prescribed selective serotonin reuptake inhibitors (SSRIs) inhibit the serotonin transporter to correct a presumed deficit in extracellular serotonin signaling during depression. These agents bring clinical relief to many who take them; however, a significant and growing number of individuals are resistant to SSRIs. There is emerging evidence that inflammation plays a significant role in the clinical variability of SSRIs, though how SSRIs and inflammation intersect with synaptic serotonin modulation remains unknown.

Biological Role of Arrestin-1 Oligomerization.

Members of the arrestin superfamily have great propensity of self-association, but the physiological significance of this phenomenon is unclear. To determine the biological role of visual arrestin-1 oligomerization in rod photoreceptors, we expressed mutant arrestin-1 with severely impaired self-association in mouse rods and analyzed mice of both sexes. We show that the oligomerization-deficient mutant is capable of quenching rhodopsin signaling normally, as judged by electroretinography and single-cell recording.

Bounded Asymmetry in Road Networks.

Road networks are a classical stage for applications in network science and graph theory. Meanwhile, many combinatorial problems that arise in road networks are computationally intractable. Thus, an attractive way of tackling them is through efficient heuristics with provable performance guarantees, better known as approximation algorithms.