Helicobacter pylori testing prior to or at gastric cancer diagnosis and survival in a diverse US patient population.

BACKGROUND: Gastric cancer (GC) accounts for the greatest disparity in cancer mortality between Black and White Americans. Although clinical trials have shown that Helicobacter pylori (Hp) treatment reduces risk of GC, Hp testing and treatment is not consistently performed in the US, and may offer an opportunity to improve survival. METHODS: In a diverse retrospective cohort of 99 GC cases diagnosed at Duke University from 2002-2020 (57% Black; 43% white), we examined the association of Hp testing and treatment prior to or at cancer diagnosis with overall survival using Cox regression analyses to calculate adjusted hazards ratios (HRs) and 95% confidence intervals (CIs). RESULTS: Overall, 62% of patients were tested for Hp prior to or at GC diagnosis. Of those, 25% tested positive and were treated < 1 year prior to or at diagnosis, 15% tested positive and were treated ≥ 1 year prior to diagnosis, 6% tested positive without evidence of treatment, and 54% tested negative. Compared to never tested, Hp testing and treatment < 1 year prior to or at diagnosis was associated with a significantly reduced likelihood of death (HR 0.21, 95% CI 0.08-0.58). The benefit of any Hp test and treat prior to or at GC diagnosis was significant even among stage IV patients only (HR, 0.22; 95% CI 0.05-0.96). CONCLUSIONS: These findings support Hp testing and treatment for patients at risk of or diagnosed with GC, and suggest Hp treatment may provide an opportunity to reduce GC mortality disparities in the US.

Proximal ventricular shunt catheter occlusion model.

PURPOSE: Proximal ventricular shunt catheter occlusion remains a problematic cause of shunt malfunction, and there is no consistent in vivo or in vitro model to help clinicians and researchers study this phenomenon. METHODS: An in vitro model utilizing standard proximal ventricular catheter and biological occluding agents mimicking choroid plexus was designed, constructed, and calibrated to occlude consistently within a specified timeframe. Hydrostatic pressure differential of 100 cmH2O was used as a driving force to generate flow through the catheter. Chalaza and vitelline membranes were harvested from avian eggs and used as occluding agents. Successful occlusion was defined as a greater than 90% reduction in volumetric flow rate through distal outlet. Histological sections of occluded catheters were performed and interpreted by a neuropathologist. RESULTS: Initial trials demonstrated successful standard catheter occlusion within 24 h using chalaza, vitelline membrane, and combination treatments. Repeat trials demonstrated consistency in successful occlusion within 5 min utilizing only vitelline membrane treatment. Histopathology demonstrated the vitelline membrane to consist of a thin, superficial layer of extraembryonic ectoderm; the chalaza was observed to consist of strands of mucin protein. CONCLUSIONS: An in vitro model of proximal ventricular shunt catheter occlusion was developed and calibrated for successful occlusion within 5 min. Future studies may utilize this model to rapidly test occlusion-resistant shunt designs and de-obstruction techniques.

Development of a precision medicine pipeline to identify personalized treatments for colorectal cancer.

BACKGROUND: Metastatic colorectal cancer (CRC) continues to be a major health problem, and current treatments are primarily for disease control and palliation of symptoms. In this study, we developed a precision medicine strategy to discover novel therapeutics for patients with CRC. METHODS: Six matched low-passage cell lines and patient-derived xenografts (PDX) were established from CRC patients undergoing resection of their cancer. High-throughput drug screens using a 119 FDA-approved oncology drug library were performed on these cell lines, which were then validated in vivo in matched PDXs. RNA-Seq analysis was then performed to identify predictors of response. RESULTS: Our study revealed marked differences in response to standard-of-care agents across patients and pinpointed druggable pathways to treat CRC. Among these pathways co-targeting of fibroblast growth factor receptor (FGFR), SRC, platelet derived growth factor receptor (PDGFR), or vascular endothelial growth factor receptor (VEGFR) signaling was found to be an effective strategy. Molecular analyses revealed potential predictors of response to these druggable pathways. CONCLUSIONS: Our data suggests that the use of matched low-passage cell lines and PDXs is a promising strategy to identify new therapies and pathways to treat metastatic CRC.

Ductular and proliferative response of esophageal submucosal glands in a porcine model of esophageal injury and repair.

Esophageal injury is a risk factor for diseases such as Barrett's esophagus (BE) and esophageal adenocarcinoma. To improve understanding of signaling pathways associated with both normal and abnormal repair, animal models are needed. Traditional rodent models of esophageal repair are limited by the absence of esophageal submucosal glands (ESMGs), which are present in the human esophagus. Previously, we identified acinar ductal metaplasia in human ESMGs in association with both esophageal injury and cancer. In addition, the SOX9 transcription factor has been associated with generation of columnar epithelium and the pathogenesis of BE and is present in ESMGs. To test our hypothesis that ESMGs activate after esophageal injury with an increase in proliferation, generation of a ductal phenotype, and expression of SOX9, we developed a porcine model of esophageal injury and repair using radiofrequency ablation (RFA). The porcine esophagus contains ESMGs, and RFA produces a consistent and reproducible mucosal injury in the esophagus. Here we present a temporal assessment of this model of esophageal repair. Porcine esophagus was evaluated at 0, 6, 18, 24, 48, and 72 h and 5 and 7 days following RFA and compared with control uninjured esophagus. Following RFA, ESMGs demonstrated an increase in ductal phenotype, echoing our prior studies in humans. Proliferation increased in both squamous epithelium and ESMGs postinjury with a prominent population of SOX9-positive cells in ESMGs postinjury. This model promises to be useful in future experiments evaluating mechanisms of esophageal repair.NEW & NOTEWORTHY A novel porcine model of injury and repair using radiofrequency ablation has been developed, allowing for reproducible injury to the esophagus to study repair in an animal model with esophageal submucosal glands, a key anatomical feature and missing in rodent models but possibly harboring progenitor cells. There is a strong translational component to this porcine model given the anatomical and physiological similarities between pigs and humans.

TGF-ß-induced stromal CYR61 promotes resistance to gemcitabine in pancreatic ductal adenocarcinoma through downregulation of the nucleoside transporters hENT1 and hCNT3.

Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer in part due to inherent resistance to chemotherapy, including the first-line drug gemcitabine. Although low expression of the nucleoside transporters hENT1 and hCNT3 that mediate cellular uptake of gemcitabine has been linked to gemcitabine resistance, the mechanisms regulating their expression in the PDAC tumor microenvironment are largely unknown. Here, we report that the matricellular protein cysteine-rich angiogenic inducer 61 (CYR61) negatively regulates the nucleoside transporters hENT1 and hCNT3. CRISPR/Cas9-mediated knockout of CYR61 increased expression of hENT1 and hCNT3, increased cellular uptake of gemcitabine and sensitized PDAC cells to gemcitabine-induced apoptosis. In PDAC patient samples, expression of hENT1 and hCNT3 negatively correlates with expression of CYR61 . We demonstrate that stromal pancreatic stellate cells (PSCs) are a source of CYR61 within the PDAC tumor microenvironment. Transforming growth factor-ß (TGF-ß) induces the expression of CYR61 in PSCs through canonical TGF-ß-ALK5-Smad2/3 signaling. Activation of TGF-ß signaling or expression of CYR61 in PSCs promotes resistance to gemcitabine in PDAC cells in an in vitro co-culture assay. Our results identify CYR61 as a TGF-ß-induced stromal-derived factor that regulates gemcitabine sensitivity in PDAC and suggest that targeting CYR61 may improve chemotherapy response in PDAC patients.

Ductal metaplasia in oesophageal submucosal glands is associated with inflammation and oesophageal adenocarcinoma.

AIMS: Recent studies have suggested that oesophageal submucosal gland (ESMG) ducts harbour progenitor cells that may contribute to oesophageal metaplasia. Our objective was to determine whether histological differences exist between the ESMGs of individuals with and without oesophageal adenocarcinoma (EAC). METHODS AND RESULTS: We performed histological assessment of 343 unique ESMGs from 30 control patients, 24 patients with treatment-naïve high-grade columnar dysplasia (HGD) or EAC, and 23 non-EAC oesophagectomy cases. A gastrointestinal pathologist assessed haematoxylin and eosin-stained ESMG images by using a scoring system that assigns individual ESMG acini to five histological types (mucous, serous, oncocytic, dilated, or ductal metaplastic). In our model, ductal metaplastic acini were more common in patients with HGD/EAC (12.7%) than in controls (3.5%) (P = 0.006). We also identified greater proportions of acini with dilation (21.9%, P < 0.001) and, to a lesser extent, ductal metaplasia (4.3%, P = 0.001) in non-EAC oesophagectomy cases than in controls. Ductal metaplasia tended to occur in areas of mucosal ulceration or tumour. CONCLUSIONS: We found a clear association between ductal metaplastic ESMG acini and HGD/EAC. Non-EAC cases had dilated acini and some ductal dilation. Because ESMGs and ducts harbour putative progenitor cells, these associations could have significance for understanding the pathogenesis of EAC.

Endogenous elevation of plasma cholecystokinin does not prevent gallstones.

BACKGROUND: Regular gall bladder contraction reduces bile stasis and prevents gallstone formation. Intraduodenal administration of exogenous pancreatic secretory trypsin inhibitor-I (PSTI-I, also known as monitor peptide) causes cholecystokinin (CCK) secretion. DESIGN: We proposed that stimulation of CCK release by PSTI would produce gall bladder contraction and prevent gallstones in mice fed a lithogenic diet. Therefore, we tested the effect of overexpression of rat PSTI-I in pancreatic acinar cells on plasma CCK levels and gall bladder function in a transgenic mouse line (TgN[Psti1]; known hereafter as PSTI-I tg). RESULTS: Importantly, PSTI tg mice had elevated fasting and fed plasma CCK levels compared to wild-type (WT) mice. Only mice fed the lithogenic diet developed gallstones. Both fasting and stimulated plasma CCK levels were substantially reduced in both WT and PSTI-I tg mice on the lithogenic diet. Moreover, despite higher CCK levels PSTI-I tg animals developed more gallstones than WT animals. CONCLUSIONS: Together with the previously observed decrease in CCK-stimulated gall bladder emptying in mice fed a lithogenic diet, our findings suggest that a lithogenic diet causes gallstone formation by impaired CCK secretion in addition to reduced gall bladder sensitivity to CCK.

Phase I study of dasatinib in combination with capecitabine, oxaliplatin and bevacizumab followed by an expanded cohort in previously untreated metastatic colorectal cancer.

PURPOSE: Dasatinib inhibits src family kinases and has anti-angiogenic properties. We conducted a phase I study of dasatinib, capecitabine, oxaliplatin, and bevacizumab (CapeOx/bevacizumab), with an expansion cohort in metastatic colorectal cancer (CRC). METHODS: Patients were enrolled in a dose escalation cohort to establish the maximum tolerated dose (MTD) and the recommended phase II dose (RP2D). Using a "3 + 3" design, twelve patients with advanced solid tumors received dasatinib (50 mg twice daily or 70 mg daily), capecitabine (850 mg/m(2) twice daily, days 1-14), oxaliplatin (130 mg/m(2) on day 1) and bevacizumab (7.5 mg/kg on day1), every 3 weeks. Ten patients with previously untreated metastatic CRC were then enrolled in an expansion cohort. Activated src (src(act)) expression was measured by immunohistochemistry, using an antibody that selectively recognizes the active conformation of src (clone 28). RESULTS: Twenty-two patients were enrolled between June 2009 and May 2011. Two DLTs were observed in the 50 mg bid dasatinib cohort, and one DLT was observed in the 70 mg daily dasatinib cohort. The MTD and RP2D for dasatinib was 70 mg daily. The most common treatment-related adverse events were fatigue (20; 91 %) and diarrhea (18; 82 %). Biomarker analysis of src(act) expression demonstrated that the overall response rate (ORR) was 75 % (6/8) for patients with high src(act) expression (IHC ≥ 2), compared to 0 % (0/8) for patients with low srcact expression (IHC 0 or 1); (p = 0.007). CONCLUSIONS: The RP2D of dasatinib is 70 mg daily in combination with CapeOx/bevacizumab. High levels of srcact expression may predict those patients most likely to benefit from dasatinib.

Prevalence of the cagA Virulence Factor Varies by Race Among Helicobacter pylori -Infected Patients Undergoing Upper Endoscopy.

INTRODUCTION: We designed a race-conscious study to assess the presence of Helicobacter pylori v irulence factor cagA in a retrospective cohort of patients with active H. pylori infection. METHODS: We compared cagA status by race in gastric tissue samples from 473 patients diagnosed with active H. pylori infection from 2015 to 2019. RESULTS: H. pylori + Black patients were 2 times more likely to be cagA + than H. pylori + White patients (82% vs 36%, P < .0001). DISCUSSION: Presence of cagA is common among endoscopy patients with active H. pylori infection; appropriate testing and treatment of H. pylori can both reduce gastric cancer risk and address health disparities.

Treatment Patterns and Clinical Outcomes Among Patients With Metastatic Prostate Cancer Harboring Homologous Recombination Repair Mutations.

BACKGROUND: There is currently limited literature assessing the real-world treatment patterns and clinical outcomes of patients with metastatic castration-resistant prostate cancer (mCRPC) and homologous recombination repair (HRR) mutations. METHODS: Medical charts were abstracted for mCRPC patients with ≥ 1 of 12 HRR somatic gene alterations treated at US oncology centers participating in the American Association for Cancer Research Project Genomics Evidence Neoplasia Information Exchange. Treatment patterns and clinical outcomes were assessed from the initiation of first-line or later (1L+) mCRPC therapy received on or after July 1, 2014. RESULTS: Among 138 patients included in the study, the most common somatic HRR mutations were CDK12 (47.8%), BRCA2 (22.5%), and ATM (21.0%). Novel hormonal therapy and taxane chemotherapy were most commonly used in 1L; taxane use increased in later lines. Median overall survival (95% confidence interval [CI]) was 36.3 (30.7-47.8) months from initiation of 1L therapy and decreased for subsequent lines. Similarly, there was a trend of decreasing progression-free survival and prostate-specific antigen response from 1L to 4L+ therapy. CONCLUSIONS: Treatment patterns identified in this study were similar to those among patients with mCRPC regardless of tumor HRR mutation status in the literature.