Multi-omic characterization of early-onset esophagogastric cancer.

Using a large real-world database with matched genomic and transcriptomic data, we characterized clinical and molecular differences between patients with early-onset esophagogastric cancer (EOEGC; <50 years), intermediate-onset esophagogastric cancer (IOEGC; 50-65 years), and average-onset esophagogastric cancer (AOEGC; >65 years). We analyzed clinicopathologic, whole transcriptome, and DNA-sequencing data from 5175 patient samples (EOEGC, n = 530; IOEGC, n = 1744; AOEGC, n = 2901) from the Caris Life Sciences database. Immune deconvolution was performed with quanTIseq and pathway enrichment with Gene Set Enrichment Analysis (GSEA).

A CXCR4 partial agonist improves immunotherapy by targeting immunosuppressive neutrophils and cancer-driven granulopoiesis.

Pathologically activated immunosuppressive neutrophils impair cancer immunotherapy efficacy. The chemokine receptor CXCR4, a central regulator of hematopoiesis and neutrophil biology, represents an attractive target. Here, we fuse a secreted CXCR4 partial agonist, trefoil factor 2 (TFF2), to mouse serum albumin (MSA) and demonstrate that TFF2-MSA peptide synergizes with anti-PD-1 to inhibit primary tumor growth and distant metastases and prolongs survival in gastric cancer (GC) mouse models.

Claudin 18 immunohistochemistry in cholangiocarcinoma.

Background: Monoclonal antibodies against claudin (CLDN) 18.2 (a component of tight junctions) in gastric epithelial cells are an emerging therapeutic option for patients with advanced gastric and esophageal adenocarcinoma. Phase 2 and 3 trials have shown clinical efficacy in patients whose tumors show high expression of CLDN18 by immunohistochemistry, and the US Food and Drug Administration has recently approved a drug for patients with advanced gastric and gastroesophageal adenocarcinoma and high CLDN18 expression.

Strengthening Asian/Asian American, Native Hawaiian, and Pacific Islander Leadership in Cancer Research.

Individuals in the United States from Asian and Asian American, Native Hawaiian, and Pacific Islander (AANHPI) backgrounds face a distinct set of cancer-related disparities. In this study, in conjunction with the American Association for Cancer Research Asian/AANHPI Task Force, we highlight the unique disparities faced by AANHPI patients and professionals, and we offer actionable recommendations on how to strengthen AANHPI leadership in cancer research.

Phase I trial of ATR inhibitor elimusertib with FOLFIRI in advanced or metastatic gastrointestinal malignancies (ETCTN 10406).

Background: ATR is an apical DDR kinase activated at damaged replication forks. Elimusertib is an oral ATR inhibitor and potentiates irinotecan in human colorectal cancer models.

Methods: To establish dose and tolerability of elimusertib with FOLFIRI, a Bayesian Optimal Interval trial design was pursued.

Diffuse Gastric Cancer: A Comprehensive Review of Molecular Features and Emerging Therapeutics.

Diffuse-type gastric cancer (DGC) accounts for approximately one-third of gastric cancer diagnoses but is a more clinically aggressive disease with peritoneal metastases and inferior survival compared with intestinal-type gastric cancer (IGC). The understanding of the pathogenesis of DGC has been relatively limited until recently. Multiomic studies, particularly by The Cancer Genome Atlas, have better characterized gastric adenocarcinoma into molecular subtypes.

Molecular Landscape and Clinical Implication of CCNE1-amplified Esophagogastric Cancer.

Unlabelled: Cyclin E overexpression as a result of CCNE1 amplification is a critical driver of genomic instability in gastric cancer, but its clinical implication is largely unknown. Thus, we integrated genomic, transcriptomic, and immune profiling analysis of 7,083 esophagogastric tumors and investigated the impact of CCNE1 amplification on molecular features and treatment outcomes. We identified CCNE1 amplification in 6.

The Present and Future of Neoadjuvant and Adjuvant Therapy for Locally Advanced Gastric Cancer.

Gastric cancer is a highly prevalent and lethal disease worldwide. Given the insidious nature of the presenting symptoms, patients are frequently diagnosed with advanced, unresectable disease. However, many patients will present with locally advanced gastric cancer (LAGC), which is often defined as the primary tumor extending beyond the muscularis propria (cT3-T4) or having nodal metastases (cN+) disease and without distant metastases (cM0).

Patient-Derived Organoids from Locally Advanced Gastric Adenocarcinomas Can Predict Resistance to Neoadjuvant Chemotherapy.

Background: Patients (pts) with locally advanced gastric adenocarcinoma (LAGA) often receive neoadjuvant chemotherapy. A minority of patients do not respond to chemotherapy and thus may benefit from upfront surgery. Patient-derived organoids (PDOs) are an in vitro model that may mimic the chemotherapy response of the original tumors.

Gastric Cancer and the Immune System: The Key to Improving Outcomes?

Gastric adenocarcinoma is by far the most common form of gastric cancer (GC) and is a highly lethal form of cancer arising from the gastric epithelium. GC is an important area of focus of the medical community, given its often late-stage of diagnosis and associated high mortality rate. While surgery and chemotherapy remain the primary treatments, attention has been drawn to the use of immunologic therapies, which have shown promise in the treatment of other malignancies.

Functional genetic screen identifies ITPR3/calcium/RELB axis as a driver of colorectal cancer metastatic liver colonization.

Metastatic colonization is the primary cause of death from colorectal cancer (CRC). We employed genome-scale in vivo short hairpin RNA (shRNA) screening and validation to identify 26 promoters of CRC liver colonization. Among these genes, we identified a cluster that contains multiple targetable genes, including ITPR3, which promoted liver-metastatic colonization and elicited similar downstream gene expression programs.

Defining and Targeting Esophagogastric Cancer Genomic Subsets With Patient-Derived Xenografts.

Purpose: Comprehensive genomic profiling has defined key oncogenic drivers and distinct molecular subtypes in esophagogastric cancer; however, the number of clinically actionable alterations remains limited. To establish preclinical models for testing genomically driven therapeutic strategies, we generated and characterized a large collection of esophagogastric cancer patient-derived xenografts (PDXs).

Materials And Methods: We established a biobank of 98 esophagogastric cancer PDX models derived from primary tumors and metastases.

Phase I/Ib study of crenolanib with ramucirumab and paclitaxel as second-line therapy for advanced esophagogastric adenocarcinoma.

Purpose: Paclitaxel plus ramucirumab is a standard second-line regimen for patients with advanced gastric adenocarcinoma, but clinical benefit remains modest. One potential resistance mechanism to VEGFR2 inhibition is activation of the PDGF/PDGFR pathway, which can be blocked by the selective inhibitor crenolanib. Therefore, we performed a phase I/Ib study of crenolanib in combination with paclitaxel/ramucirumab.

Variable selection methods for predicting clinical outcomes following allogeneic hematopoietic cell transplantation.

Allogeneic hematopoietic cell transplantation (allo-HCT) is a potentially curative procedure for a large number of diseases. However, the greatest barriers to the success of allo-HCT are relapse and graft-versus-host-disease (GVHD). Many studies have examined the reconstitution of the immune system after allo-HCT and searched for factors associated with clinical outcome.

DDX56 Binds to Chikungunya Virus RNA To Control Infection.

DEAD box RNA helicases regulate diverse facets of RNA biology. Proteins of this family carry out essential cellular functions, and emerging literature is revealing additional roles in immune defense. Using RNA interference screening, we identified an evolutionarily conserved antiviral role for the helicase DDX56 against the alphavirus Sindbis virus (SINV), a mosquito-transmitted pathogen that infects humans.

Regorafenib in Combination with First-Line Chemotherapy for Metastatic Esophagogastric Cancer.

Background: Angiogenesis is critical to gastroesophageal adenocarcinoma growth and metastasis. Regorafenib is a multikinase inhibitor targeting angiogenic and stromal receptor tyrosine kinases. We evaluated whether regorafenib augments the antitumor effect of first-line chemotherapy in metastatic esophagogastric cancer.

Immune Checkpoint Inhibition in Hodgkin Lymphoma.

Intricate systems of checkpoints such as the programmed cell death protein 1 (PD-1)/programmed death ligand 1 (PD-L1) axis regulate adaptive immune responses to protect against tissue damage. However, diverse cancers can exploit these pathways to evade or suppress antitumor immunity, leading to tumor progression. Correspondingly, immune checkpoint inhibitors that block PD-1/PD-L1 signaling have shown marked therapeutic efficacy in certain cancers, such as Hodgkin lymphoma.

Clinical and immunologic impact of CCR5 blockade in graft-versus-host disease prophylaxis.

Graft-versus-host disease (GVHD) is a major cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Lymphocyte trafficking via chemokine receptors such as CCR5 plays a critical role in alloreactive responses, and previous data suggest that CCR5 blockade with maraviroc results in a low incidence of visceral GVHD. However, the full scope of clinical and immunologic effects of CCR5 blockade in HSCT has not been described.

A conserved virus-induced cytoplasmic TRAMP-like complex recruits the exosome to target viral RNA for degradation.

RNA degradation is tightly regulated to selectively target aberrant RNAs, including viral RNA, but this regulation is incompletely understood. Through RNAi screening in Drosophila cells, we identified the 3'-to-5' RNA exosome and two components of the exosome cofactor TRAMP (Trf4/5-Air1/2-Mtr4 polyadenylation) complex, dMtr4 and dZcchc7, as antiviral against a panel of RNA viruses. We extended our studies to human orthologs and found that the exosome as well as TRAMP components hMTR4 and hZCCHC7 are antiviral.