Heat shock protein 72 supports extracellular matrix production in metastatic mammary tumors.

This study identified tumorigenic processes most dependent on murine heat shock protein 72 (HSP72) in the mouse mammary tumor virus-PyMT mammary tumor model, which give rise to spontaneous mammary tumors that exhibit HSP72-dependent metastasis to the lung. RNA-seq expression profiling of Hspa1a/Hspa1b (Hsp72) WT and Hsp72-/- primary mammary tumors discovered significantly lower expression of genes encoding components of the extracellular matrix (ECM) in Hsp72 knockout mammary tumors compared to WT controls. In vitro studies found that genetic or chemical inhibition of HSP72 activity in cultured collagen-expressing human or murine cells also reduces mRNA and protein levels of COL1A1 and several other ECM-encoding genes. In search of a possible mechanistic basis for this relationship, we found HSP72 to support the activation of the tumor growth factor-ß-suppressor of mothers against decapentaplegic-3 signaling pathway and evidence of suppressor of mothers against decapentaplegic-3 and HSP72 coprecipitation, suggesting potential complex formation. Human COL1A1 mRNA expression was found to have prognostic value for HER2+ breast tumors over other breast cancer subtypes, suggesting a possible human disease context where targeting HSP72 may have a therapeutic rationale. Analysis of human HER2+ breast tumor gene expression data using a gene set comprising ECM-related gene and protein folding-related gene as an input to the statistical learning algorithm, Galgo, found a subset of these genes that can collectively stratify patients by relapse-free survival, further suggesting a potential interplay between the ECM and protein-folding genes may contribute to tumor progression.

Non-invasive markers of inflammation in alcohol-associated liver disease: A scoping review.

Clinical manifestations of liver inflammation in alcohol-associated liver disease (ALD) can range from asymptomatic to severe alcoholic hepatitis. While biopsy is the gold standard for identifying liver inflammation, it is an invasive procedure with risks of bleeding, visceral damage, and infection. We aim to establish the state of the current literature on non-invasive markers of inflammation in ALD. We searched Ovid MEDLINE, Embase, and the Cochrane Library for original studies on the association between one or more non-invasive biomarker(s) and histological inflammation or hepatitis in ALD patients. Exclusion criteria were lack of histological data, abstract only, non-English-language articles, and animal studies. Two independent reviewers screened abstracts, reviewed full texts, and extracted data from included papers. Our search identified 8051 unique studies. Title and abstract screening resulted in 563 studies, and full-text screening resulted in 31 studies for final inclusion. The majority were single-center observational cohorts with an average sample size of 124. Review of these studies identified 44 unique biomarkers and 8 calculated scores associated with histological inflammation and/or hepatitis, in addition to a metabolomic panel of 468 metabolites. Six studies examined diagnostic accuracy for histological inflammation and/or hepatitis. The highest area under the receiver operating characteristic curve was 0.932 using a model based on four metabolites. This review highlights the available literature on non-invasive markers of inflammation in ALD. There is a dearth of studies that evaluate the diagnostic accuracy of these biomarkers, and larger studies are needed to confirm findings identified in small cohorts.

Outcomes of Endoscopic Ultrasound-guided Fine Needle Biopsy Using a Novel Hydrostatic Stylet Tissue Acquisition Technique.

BACKGROUND: Endoscopic ultrasound-guided fine needle biopsy (EUS-FNB) is frequently used to obtain core samples of solid lesions. Here, we describe and evaluate a novel hydrostatic stylet (HS) technique designed to optimize core sample acquisition, reporting diagnostic yield, efficacy, and safety relative to the conventional stylet slow-pull (SP) technique. METHODS: A novel HS technique was developed and validated retrospectively. Consecutive patients who underwent EUS-FNB with core biopsy of solid lesions through either the HS or SP technique between January 2020 and April 2022 were included. Exclusion criteria included cystic lesions, nonlesional liver biopsies, and specimens sent for cytologic analysis only. Patient and lesion characteristics, number of passes, sample adequacy, and adverse events were compared between the two techniques. RESULTS: A total of 272 patients were included with 138 in the HS group and 134 in the SP group. Lesion size and anatomic distribution were similar in both groups. Compared with the SP approach, the HS technique demonstrated significantly higher sample adequacy (97.8% vs 83.6%, P < 0.001), higher sensitivity (97.1% vs 89.7%, P = 0.03), and lower mean number of passes (1.2 vs 3.3, P < 0.001). Rates and severity of adverse events in the HS group were comparable to the SP group and existing literature. Similar associations were observed in pancreatic and nonpancreatic lesion subanalyses. CONCLUSIONS: The novel HS technique demonstrated excellent biopsy sample adequacy and diagnostic yield while requiring fewer passes to obtain diagnostic specimens compared with a conventional EUS-FNB approach. Further prospective evaluation is needed to confirm these pilot findings and optimize EUS-FNB acquisition techniques.

Prevalence of Enteric Infections in Patients on Immune Checkpoint Inhibitors and Impact on Management and Outcomes.

BACKGROUND: Stool pathogen testing is recommended as part of the initial evaluation for patients with new-onset diarrhea on immune checkpoint inhibitors (ICIs), yet its significance has not been well-studied. We aimed to determine the impact of multiplex gastrointestinal (GI) pathogen PCR testing on the clinical course and use of immunosuppressive therapy in patients who develop diarrhea on ICIs. METHODS: This retrospective cohort included individuals who underwent GI pathogen panel PCR for diarrhea on ICIs at Memorial Sloan Kettering between 7/2015 and 7/2021. The primary outcome was use of immunosuppressive therapy for suspected immunotherapy-related enterocolitis (irEC). Secondary outcomes included diarrhea severity and endoscopic and histologic disease patterns. RESULTS: Among 521 ICI-treated patients tested for GI pathogens, 61 (11.7%) had a positive PCR. Compared to patients without detectable infections, patients with infections had more frequent grades 3-4 diarrhea (37.7% vs. 19.6%, P < .01) and colitis (39.3% vs. 14.7%, P < .01). However, patients with infections did not have higher rates of persistent or recurrent diarrhea and were less likely to receive steroids (P < .01) and second-line immunosuppressive agents (P = .03). In 105 patients with lower endoscopy, similar trends were observed and no differences in endoscopic severity or histologic patterns were noted between groups. CONCLUSIONS: GI infections in ICI-treated patients presenting with diarrhea are linked to more severe but self-limited clinical presentations and may be optimally treated with observation and supportive care alone. Routine and timely stool pathogen testing may help avert unnecessary empiric immunosuppression for suspected irEC, which has been linked to blunted antitumor responses and numerous adverse effects.

Preferred techniques for endoscopic ultrasound-guided gastroenterostomy: a survey of expert endosonographers.

Background and study aims Endoscopic ultrasound-guided gastroenterostomy (EUS-GE) is an emerging procedure that lacks technical standardization with limited adoption beyond expert centers. We surveyed high-volume endosonographers about the technical aspects of EUS-GE to describe how the procedure is currently performed at expert centers and identify targets for standardization. Methods Invitations to complete an electronic survey were distributed to 21 expert EUS practitioners at 19 U.S. centers. Respondents were surveyed about technical aspects of EUS-GE, indications, efficacy, safety, and attitudes toward the procedure. Results All 21 (100%) invited expert endoscopists completed the survey. Nine (42.9%) reported performing >10 EUS-GEs in the last 12 months. About half (47.6%, 10/21) puncture the target loop prior to lumen-apposing metal stent (LAMS) introduction, most often to confirm the loop is jejunum. No respondents reported guidewire placement prior to LAMS introduction. Most (71.4%, 15/21) do not use a guidewire at any time, while 28.6% (6/21) reported wire placement after distal flange deployment to secure the tract during apposition. Eight (38.1%, 8/21) reported at least one major adverse event, most commonly intraperitoneal LAMS deployment (87.5%, 7/8). Factors most often reported as advantageous for EUS-GE over enteral stenting included lack of papilla interference (33.3%, 7/21) and decreased occlusion risk (23.8%, 5/21). Conclusions Significant variation in performance technique for EUS-GE exists among expert US endoscopists, which may hinder widespread adoption and contribute to inconsistencies in reported patient outcomes. The granularity provided by these survey results may identify areas to focus standardization efforts and guide future studies on developing an ideal EUS-GE protocol.

Impact of Helicobacter pylori infection status on outcomes among patients with advanced gastric cancer treated with immune checkpoint inhibitors.

BACKGROUND: Gut microbiota composition can influence cancer immunotherapy response. Recent evidence suggests Helicobacter pylori infection may reduce immune checkpoint inhibitor (ICI) efficacy in lung cancer and melanoma, but thorough characterization of this association in patients with gastric cancer is lacking. We aimed to determine the impact of H. pylori on survival in this population. METHODS: This single-center, retrospective study included all ICI-treated individuals with metastatic gastric cancer and documented H. pylori status at Memorial Sloan Kettering between July 2013 and October 2021. H. pylori-positive status was defined as history of infection obtained via breath test, stool antigen test, histopathology, and/or chart documentation. Negative status was defined as explicitly negative testing, histopathology, and/or chart documentation. Primary outcomes were progression-free survival (PFS) and overall survival (OS). RESULTS: Of 215 included patients, 49 had documented history of H. pylori infection. Compared with H. pylori-negative patients, positive individuals tended to be younger, non-white, and Hispanic with non-cardia and intestinal-type gastric cancer. H. pylori-positive patients had significantly shorter median PFS (3.2 vs 6.8 months, HR 1.96, p<0.01) and OS (9.8 vs 17.9 months, HR 1.54, p=0.02). Multivariable analysis confirmed H. pylori infection as an independent predictor of PFS (HR 3.04, p<0.01) and OS (HR 2.24, p=0.01). CONCLUSIONS: In this largest study of its kind, H. pylori infection was associated with inferior survival in ICI-treated patients with gastric cancer. This suggests H. pylori status may be a prognostic marker of immune responsiveness. Future studies are needed to elucidate immunoregulatory mechanisms and whether treatment of active infections would improve immunotherapy outcomes.

Acute worsening of gastric outlet obstruction following EUS-guided gastrojejunal bypass.

Video 1Presentation and treatment of an unusual acute worsening of gastric outlet obstruction following EUS-guided gastrojejunal bypass.

Factors associated with detection of hereditary diffuse gastric cancer on endoscopy in individuals with germline CDH1 mutations.

BACKGROUND AND AIMS: Individuals with germline pathogenic CDH1 variants have a high risk of hereditary diffuse gastric cancer. The sensitivity of EGD in detecting signet ring cell carcinoma (SRCC) in this population is low. We aimed to identify endoscopic findings and biopsy practices associated with detection of SRCC. METHODS: This retrospective cohort included individuals with a germline pathogenic/likely pathogenic CDH1 variant undergoing at least 1 EGD at Memorial Sloan Kettering Cancer Center between January 1, 2006, and March 25, 2022. The primary outcome was detection of SRCC on EGD. Findings on gastrectomy were also assessed. The study included periods before and after implementation of the Cambridge protocol for endoscopic surveillance, allowing for assessment of a spectrum of biopsy practices. RESULTS: Ninety-eight CDH1 patients underwent at least 1 EGD at our institution. SRCC was detected in 20 (20%) individuals on EGD overall and in 50 (86%) of the 58 patients undergoing gastrectomy. Most SRCC foci were detected in the gastric cardia/fundus (EGD, 50%; gastrectomy, 62%) and body/transition zone (EGD, 60%; gastrectomy, 62%). Biopsy results of gastric pale mucosal areas were associated with detection of SRCC (P < .01). The total number of biopsy samples taken on EGD was associated with increased detection of SRCC (P = .01), with 43% detected when ≥40 samples were taken. CONCLUSIONS: Targeted biopsy sampling of gastric pale mucosal areas and increasing number of biopsy samples taken on EGD were associated with detection of SRCC. SRCC foci were mostly detected in the proximal stomach, supporting updated endoscopic surveillance guidelines. Further studies are needed to refine endoscopic protocols to improve SRCC detection in this high-risk population.

EUS-guided liver biopsy using a novel hydrostatic stylet technique.

Video 1Hydrostatic stylet technique for the performance of EUS-guided liver biopsy.