Impact of large scale, multicomponent intervention to reduce proton pump inhibitor overuse in integrated healthcare system: difference-in-difference study.

OBJECTIVE: To determine how a large scale, multicomponent, pharmacy based intervention to reduce proton pump inhibitor (PPI) overuse affected prescribing patterns, healthcare utilization, and clinical outcomes. DESIGN: Difference-in-difference study. SETTING: US Veterans Affairs Healthcare System, in which one regional network implemented the overuse intervention and all 17 others served as controls. PARTICIPANTS: All individuals receiving primary care from 2009 to 2019. INTERVENTION: Limits on PPI refills for patients without a documented indication for long term use, voiding of PPI prescriptions not recently filled, facilitated electronic prescribing of H2 receptor antagonists, and education for patients and clinicians. MAIN OUTCOME MEASURES: The primary outcome was the percentage of patients who filled a PPI prescription per 6 months. Secondary outcomes included percentage of days PPI gastroprotection was prescribed in patients at high risk for upper gastrointestinal bleeding, percentage of patients who filled either a PPI or H2 receptor antagonist prescription, hospital admission for acid peptic disease in older adults appropriate for PPI gastroprotection, primary care visits for an upper gastrointestinal diagnosis, upper endoscopies, and PPI associated clinical conditions. RESULTS: The number of patients analyzed per interval ranged from 192 607 to 250 349 in intervention sites and from 3 775 953 to 4 360 868 in control sites, with 26% of patients receiving PPIs before the intervention. The intervention was associated with an absolute reduction of 7.3% (95% confidence interval -7.6% to -7.0%) in patients who filled PPI prescriptions, an absolute reduction of 11.3% (-12.0% to -10.5%) in PPI use among patients appropriate for gastroprotection, and an absolute reduction of 5.72% (-6.08% to -5.36%) in patients who filled a PPI or H2 receptor antagonist prescription. No increases were seen in primary care visits for upper gastrointestinal diagnoses, upper endoscopies, or hospital admissions for acid peptic disease in older patients appropriate for gastroprotection. No clinically significant changes were seen in any PPI associated clinical conditions. CONCLUSIONS: The multicomponent intervention was associated with reduced PPI use overall but also in patients appropriate for gastroprotection, with minimal evidence of either clinical benefits or harms.

Effectiveness of Tofacitinib in Patients With Ulcerative Colitis: A Nationwide Veterans Administration Cohort Study.

INTRODUCTION: There is paucity of data on the effectiveness and safety of tofacitinib among elderly patients with ulcerative colitis (UC). METHODS: Through a retrospective cohort study among the US National Veterans Affairs Healthcare System, we evaluated effectiveness among the elderly (≥65) and young (<65) patients with UC initiated on tofacitinib. RESULTS: Among 158 patients (53 elderly, 105 young), effectiveness at 12 months was 50.94% in the elderly and 33.33% in the young ( P = 0.032). DISCUSSION: In a nationwide cohort of patients with UC initiating tofacitinib, effectiveness was seen in half of the elderly patients.

Exogenous Insulin Therapy Is Associated with the Risk of Advanced Colorectal Adenoma in Patients with Diabetes Mellitus.

BACKGROUND/AIMS: Exogenous insulin therapy increases systemic exposure to insulin which may promote the development of colorectal neoplasia. We sought to evaluate the association between exogenous insulin therapy and the incidence of advanced adenoma in type 2 diabetes mellitus. METHODS: A retrospective cohort study was conducted from January 1, 2007, to January 1, 2018, in a regional health system serving the United States Philadelphia metropolitan area, Central New Jersey, and South Central Pennsylvania. Study patients consisted of a random sample of patients with type 2 diabetes mellitus aged 40-80 years who had undergone two rounds of colonoscopy examinations. The exposure was cumulative duration of insulin therapy (i.e., no use, 1-365 days and > 365 days). The outcome was time to incident advanced adenoma. RESULTS: Of the 975 eligible patients, 184 patients accumulated > 365 days of insulin therapy before the follow-up colonoscopy. The mean (standard deviation) duration between the two rounds of colonoscopy examination was 5.1 (2.9) years among the insulin users and 5.3 (3.9) years among non-users. Compared to no insulin exposure, receiving > 365 days of insulin therapy was associated with an increased incidence of advanced adenoma (adjusted hazard ratio [aHR] 4.84, 95% confidence interval [CI] 2.82-8.30), right-sided advanced adenoma (aHR 5.48, 95% CI 2.90-10.35), and 3 or more adenomas (aHR 2.61, 95% CI 1.46-4.69) at the follow-up colonoscopy examination. CONCLUSION: Insulin therapy is associated with an increased risk of advanced adenoma and may serve as a novel risk-stratification factor to enhance the efficiency of existing colorectal cancer screening and surveillance programs.

Development and Validation of Case-Finding Algorithms to Identify Pancreatic Cancer in the Veterans Health Administration.

BACKGROUND: Survival in pancreatic ductal adenocarcinoma (PDAC) remains poor due to late diagnosis. Electronic Health Records (EHRs) can be used to study this rare disease, but validated algorithms to identify PDAC in the United States EHRs do not currently exist. AIMS: To develop and validate an algorithm using Veterans Health Administration (VHA) EHR data for the identification of patients with PDAC. METHODS: We developed two algorithms to identify patients with PDAC in the VHA from 2002 to 2023. The algorithms required diagnosis of exocrine pancreatic cancer in either ≥ 1 or ≥ 2 of the following domains: (i) the VA national cancer registry, (ii) an inpatient encounter, or (iii) an outpatient encounter in an oncology setting. Among individuals identified with ≥ 1 of the above criteria, a random sample of 100 were reviewed by three gastroenterologists to adjudicate PDAC status. We also adjudicated fifty patients not qualifying for either algorithm. These patients died as inpatients and had alkaline phosphatase values within the interquartile range of patients who met ≥ 2 of the above criteria for PDAC. These expert adjudications allowed us to calculate the positive and negative predictive value of the algorithms. RESULTS: Of 10.8 million individuals, 25,533 met ≥ 1 criteria (PPV 83.0%, kappa statistic 0.93) and 13,693 individuals met ≥ 2 criteria (PPV 95.2%, kappa statistic 1.00). The NPV for PDAC was 100%. CONCLUSIONS: An algorithm incorporating readily available EHR data elements to identify patients with PDAC achieved excellent PPV and NPV. This algorithm is likely to enable future epidemiologic studies of PDAC.

A Clinical Prediction Model to Assess Risk for Pancreatic Cancer Among Patients With Acute Pancreatitis.

OBJECTIVES: We aimed to develop and validate a prediction model as the first step in a sequential screening strategy to identify acute pancreatitis (AP) individuals at risk for pancreatic cancer (PC). MATERIALS AND METHODS: We performed a population-based retrospective cohort study among individuals 40 years or older with a hospitalization for AP in the US Veterans Health Administration. For variable selection, we used least absolute shrinkage and selection operator regression with 10-fold cross-validation to identify a parsimonious logistic regression model for predicting the outcome, PC diagnosed within 2 years after AP. We evaluated model discrimination and calibration. RESULTS: Among 51,613 eligible study patients with AP, 801 individuals were diagnosed with PC within 2 years. The final model (area under the receiver operating curve, 0.70; 95% confidence interval, 0.67-0.73) included histories of gallstones, pancreatic cyst, alcohol use, smoking, and levels of bilirubin, triglycerides, alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, and albumin. If the predicted risk threshold was set at 2% over 2 years, 20.3% of the AP population would undergo definitive screening, identifying nearly 50% of PC associated with AP. CONCLUSIONS: We developed a prediction model using widely available clinical factors to identify high-risk patients with PC-associated AP, the first step in a sequential screening strategy.

Incidence of Pneumonia, Related Hospitalization, and Mortality Among Younger Unvaccinated IBD Patients in a Nationwide Cohort.

BACKGROUND AND GOALS: Community Acquired Pneumonia (CAP) is among the most common infections among Inflammatory Bowel Disease (IBD) patients. Our aim was to determine the absolute and relative risk of CAP, related hospitalization, and death among younger (age < 65) unvaccinated IBD patients exposed and unexposed to immunosuppressive medications. MATERIALS AND METHODS: We conducted a retrospective cohort study among a nationwide cohort of younger IBD unvaccinated patients in the VAHS. Exposure was administration of any immunosuppressive medication. The primary outcome was the first occurrence of pneumonia; secondary outcomes being pneumonia related hospitalization and mortality. We reported event rate per 1000 person-years, hazard ratio, and 95% confidence intervals (CIs) for each outcome. RESULTS: Among a total of 26,707 patients, 513 patients developed pneumonia. Mean age in years (SD) was 51.67 (11.34) for the exposed and 45.91 (12.34) for the unexposed group. The overall crude incidence rate was 3.2 per 1000 patient-years (PYs) [4.04/1000 PYs in the exposed versus 1.45/1000 PYs in the unexposed]. The overall crude incidence rates for pneumonia-related-hospitalization and mortality 1.12 and 0.09 per 1000 PYs, respectively. In Cox regression, the exposed group was associated with an increased risk of pneumonia (AHR 2.85; 95% CI: 2.21 to 3.66, P < 0.001) and pneumonia-related-hospitalization (AHR 3.46; 95% CI: 2.20 to 5.43, P < 0.001). CONCLUSIONS: Overall incidence of CAP among younger unvaccinated IBD patients was 3.2 per 1000 PYs. The overall associated hospitalization rates were low, however, higher amongst those exposed to immunosuppressive medications. This data will help patients and physicians make informed decisions regarding pneumococcal vaccine recommendations.

The Non-Invasive Prediction of Colorectal Neoplasia (NIPCON) Study 1995-2022: A Comparison of Guaiac-Based Fecal Occult Blood Test (FOBT) and an Anti-Adenoma Antibody, Adnab-9.

Given the need to improve the sensitivity of non-invasive methods to detect colorectal neoplasia, particularly adenomas, we compared a fecal test using a monoclonal antibody (Mab) raised against constituents of colonic adenomas designated Adnab-9 (Adenoma Antibody 9), recognizing an N-linked 87 kDa glycoprotein, to gFOBT, which is shown to reduce CRC mortality. p87 immunohistochemistry testing is significantly more sensitive (OR 3.64[CI 2.37-5.58]) than gFOBT (guaiac-based fecal occult blood test) for adenomas (<3 in number), advanced adenomas (OR 4.21[CI 2.47-7.15]), or a combination of the two (OR 3.35[CI 2.47-4.53]). p87 immunohistochemistry shows regional Paneth cell (PC) expression mainly in the right-sided colon and is significantly reduced in the ceca of African Americans (p < 0.0001). In a subset of patients, we obtained other body fluids such as urine, colonic effluent, and saliva. Urine tests (organ-specific neoantigen) showed a significant difference for advanced adenomas (p < 0.047). We conclude that fecal p87 testing is more sensitive than gFOBT and Adnab-9 and could be used to better direct the colonoscopy screening effort.

Amniotic membrane mesenchymal stromal cell-derived secretome in the treatment of acute ischemic stroke: A case report.

BACKGROUND: Stroke is the second and third leading cause of death and disability, respectively. To date, no definitive treatment can repair lost brain function. Recently, various preclinical studies have been reported on mesenchymal stromal cells (MSCs) and their derivatives and their potential as alternative therapies for stroke. CASE SUMMARY: A 45-year-old female suffered an acute stroke, which led to paralysis in the left upper and lower limbs. The amniotic membrane MSC-derived secretome (MSC-secretome) was intravenously transplanted once a week for 4 wk. MSC-secretome-regulated regulatory T cells were investigated for the beneficial effects. The clinical improvement of this patient was accompanied by an increased frequency of regulatory T cells after transplantation. CONCLUSION: Intravenous administration of MSC-secretome can potentially treat patients who suffer from acute ischemic stroke.

Tumor Differentiation as a Prognostic Marker in Clinically Staged T1bN0 Esophageal Adenocarcinoma.

Current guidelines recommend that clinically staged T1N0 esophageal cancers are to be referred to surgery or endoscopic resection. Using the National Cancer Database, we identified 733 individuals with clinically staged T1N0 esophageal carcinoma, who underwent upfront surgery and did not receive any prior treatment. We assessed upstaging, which was defined as ≥ T2 disease or positive lymph nodes. Poorly differentiated adenocarcinomas were associated with upstaging, whereas squamous cell carcinomas were not. Specifically, the percentage of upstaging among individuals with clinically staged T1b and poorly differentiated tumor was 33.8%. Therefore, clinically staged T1bN0 poorly differentiated esophageal adenocarcinomas are at high risk for upstaging following surgery.

Do Polygenic Risk Scores Add to Clinical Data in Predicting Pancreatic Cancer? A Scoping Review.

BACKGROUND: Polygenic risk scores (PRS) summarize an individual's germline genetic risk, but it is unclear whether PRS offer independent information for pancreatic cancer risk prediction beyond routine clinical data. METHODS: We searched 8 databases from database inception to March 10, 2023 to identify studies evaluating the independent performance of pancreatic cancer-specific PRS for pancreatic cancer beyond clinical risk factors. RESULTS: Twenty-one studies examined associations between a pancreatic cancer-specific PRS and pancreatic cancer. Seven studies evaluated risk factors beyond age and sex. Three studies evaluated the change in discrimination associated with the addition of PRS to routine risk factors and reported improvements (AUCs: 0.715 to 0.745; AUC 0.791 to 0.830; AUC from 0.694 to 0.711). Limitations to clinical applicability included using source populations younger/healthier than those at risk for pancreatic cancer (n = 10), exclusively of European ancestry (n = 13), or controls without relevant exposures (n = 1). CONCLUSIONS: While most studies of pancreatic cancer-specific PRS did not evaluate the independent discrimination of PRS for pancreatic cancer beyond routine risk factors, three that did showed improvements in discrimination. IMPACT: For pancreatic cancer PRS to be clinically useful, they must demonstrate substantial improvements in discrimination beyond established risk factors, apply to diverse ancestral populations representative of those at risk for pancreatic cancer, and use appropriate controls.

Brief Report: Second-line treatment outcomes in patients with advanced NSCLC previously treated with first-line immunotherapy regimens.

CLINICAL PRACTICE POINTS: In the United States of America, nearly all patients with advanced NSCLC, absent oncogenic drivers, receive some form of immunotherapy (IO) as part of initial treatment. Current national guidelines currently recommend against IO re-challenge if there is disease progression on IO in the first line, but re-treatment with IO is attractive given its favorable toxicity profile and descriptions of durable clinical benefit in a subset of patients treated beyond disease progression on initial IO (Gandara, J Thorac Oncol, 2018). Data in the non-clinical trial setting on the efficacy of IO in sequential lines of treatment after initial IO are lacking. In our large cohort study of patients with advanced NSCLC treated with immunotherapy regimens in the first-line setting, we find that outcomes after second-line treatment did not differ statistically by type of treatment used in the second line. While current prospective clinical trials are investigating several aspects of the utility of continuing immunotherapy and adding novel agents, our study offers data outside of a clinical trial. In addition, with the increased prevalence of adjuvant immunotherapy we urgently need to wrestle with whether to continue immunotherapy in the first-line metastatic setting if a patient experiences disease progression on adjuvant immunotherapy. While this analysis does not directly investigate that question, it does provide hypothesis-generating evidence for further evaluations.

Prognostic value of systemic immune inflammation index and geriatric nutrition risk index in early-onset colorectal cancer.

Background: Systemic nutritional and inflammatory markers, which are easy to measure are associated with the progression and prognosis of many cancers. Nevertheless, among the various available indicators, optimal prognostic indicators for patients with early-onset colorectal cancer have not been identified. Therefore, the aim of this study was to identify optimal nutritional and inflammatory markers for early-onset colorectal cancer and examine the relationship between systemic nutritional and inflammatory markers before treatment and survival in patients with early-onset colorectal cancer. Methods: We retrospectively collected data from 236 eligible patients with early-onset colorectal cancer. Area under the prognostic curve (AUC) and concordance index (C-index) were used to compare seven systemic nutritional and inflammatory markers to identify the optimal inflammatory immune markers. Univariate and multivariate COX regression analyses were used to evaluate the prognostic value of indicators in the total study population and different subgroups. Results: The AUC and C-index showed that the systemic immune inflammation index (SII) and geriatric nutrition risk index (GNRI) had higher prognostic values than other systemic nutritional and inflammatory indicators. Compared with patients in the low SII group, those in the high SII group had lower overall survival (HR, 4.42, 95% CI, 2.36-8.27, p = 0.000). Compared with patients in the high GNRI group, those in the low GNRI group had lower overall survival (HR, 0.33, 95% CI, 0.19-0.56, p = 0.000). SII was negatively associated with GNRI (R = -0.3, p < 0.001), and both were correlated with the tumor stage. Conclusion: SII and GNRI are suitable nutritional and inflammatory factors for predicting OS in patients with early-onset colorectal cancer; high SII and low GNRI were correlated with worse prognoses. Identifying the high inflammatory state and low nutritional state of patients before surgery and conducting active and timely therapeutic interventions could improve patient prognosis.

Outcomes of hepatocellular carcinoma by etiology with first-line atezolizumab and bevacizumab: a real-world analysis.

PURPOSE: Hepatocellular carcinoma (HCC) is a common and deadly form of liver cancer. Combination atezolizumab and bevacizumab has improved the outcomes for patients with advanced disease. We sought to determine the impact of etiology on outcomes of patients treated with atezolizumab and bevacizumab. METHODS: This study used a real-world database. The primary outcome was overall survival (OS) by etiology of HCC; the secondary outcome was real-world time to treatment discontinuation (rwTTD). Time-to-event analyses was performed by the Kaplan-Meier method; the log-rank test to assess for differences by etiology from date of first receipt of atezolizumab and bevacizumab. The Cox proportional hazards model was used to calculate hazard ratios. RESULTS: In total, 429 patients were included (n = 216 Viral-HCC; n = 68 Alcohol-HCC; n = 145, NASH-HCC). The median overall survival for the entire cohort was 9.4 months (95% CI 7.1-10.9). Compared with Viral-HCC, the hazard ratio (HR) of death was 1.11 (95% CI 0.74-1.68, p = 0.62) for Alcohol-HCC and was 1.34 (95% CI 0.96-1.86, p = 0.08) for NASH-HCC. The median rwTTD for the entire cohort was 5.7 months (95% CI 5.0-7.0 months). The HR of rwTTD was 1.24 (95% CI 0.86-1.77, p = 0.25) for Alcohol-HCC and was 1.31 (95% CI 0.98-1.75, p = 0.06) in reference to TTD with Viral-HCC. CONCLUSIONS: In this real-world cohort of patients with HCC receiving first-line atezolizumab and bevacizumab, we did not identify an association between etiology and OS or rwTTD. This suggests that the efficacy of atezolizumab and bevacizumab may be similar across HCC etiologies. Further prospective studies are needed to confirm these findings.

Antibiotic Exposure is Associated With a Risk of Esophageal Adenocarcinoma.

BACKGROUND & AIMS: Antibiotic exposure leads to changes in the gut microbiota. Our objective was to evaluate the association between antibiotic exposure and esophageal adenocarcinoma (EAC) risk. METHODS: We performed a nested case-control study using data from the Veterans Health Administration from 2004 through 2020. The case group consisted of patients who received an incident diagnosis of EAC. For each case, up to 20 matched controls were selected using incidence density sampling. Our primary exposure of interest was any oral or intravenous antibiotic use. Our secondary exposures included cumulative number of days of exposure and classification of antibiotics by various subgroups. Conditional logistic regression was used to estimate the crude and adjusted odds ratios (aORs) for the risk of EAC associated with antibiotic exposure. RESULTS: The case-control analysis included 8226 EAC cases and 140,670 matched controls. Exposure to any antibiotic was associated with an aOR for EAC of 1.74 (95% confidence interval [CI], 1.65-1.83) vs no antibiotic exposure. Compared with no antibiotic exposure, the aOR for EAC was 1.63 (95% CI, 1.52-1.74; P < .001) for cumulative exposure to any antibiotic for 1 to 15 days; 1.77 (95% CI, 1.65-1.89; P < 0 .001) for 16 to 47 days; and 1.87 (95% CI, 1.75-2.01; P < .001) for ≥48 days, respectively (P for trend < .001). CONCLUSION: Exposure to any antibiotic is associated with an increased risk of EAC, and this risk increases as the cumulative days of exposure increase. This novel finding is hypothesis-generating for potential mechanisms that may play a role in the development or progression of EAC.

Dopamine agonists and risk of lung cancer in patients with restless legs syndrome.

PURPOSE: To examine the association between long-term use of dopamine agonists (DAs) and the risk of lung cancer in patients with restless legs syndrome (RLS). METHODS: We conducted a retrospective cohort study using Optum Clinformatics® database. We included adults ≥40 years diagnosed with RLS during the study period (1/2006-12/2016). Follow-up started with the first RLS diagnosis and ended on the earliest of: incident diagnosis of lung cancer, end of enrollment in the database or end of the study period. The exposure of interest was cumulative duration of DAs use, measured in a time-varying manner. We constructed a multivariable Cox regression model to estimate HRs and 95% CIs for the association between lung cancer and cumulative durations of DA use, adjusting for potential confounding variables. RESULTS: We identified 295 042 patients with a diagnosis of RLS. The mean age of the cohort was 62.9; 66.6% were women and 82.3% were white. The prevalence of any DA exposure was 40.3%. Compared to the reference group (no use and ≤1 year), the crude HRs for lung cancer were 1.16 (95% CI 0.99-1.36) and 1.14 (95% CI 0.86-1.51) for 1-3 years and >3 years of cumulative DA use, respectively. The adjusted HR for lung cancer was 1.05 (95% CI 0.88-1.25) for 1-3 years and 1.02 (95% CI 0.76-1.37) for >3 years of cumulative DA use, respectively. CONCLUSIONS: At typical doses for the clinical management of RLS, long-term DA use was not associated with risk of lung cancer.

Development and validation of case-finding algorithms to identify acute pancreatitis in the Veterans Health Administration.

PURPOSE: Acute pancreatitis (AP) is a frequently encountered adverse drug reaction. However, the validity of diagnostic codes for AP is unknown. We aimed to determine the positive predictive value (PPV) of a diagnostic code-based algorithm for identifying patients with AP within the US Veterans Health Administration and evaluate the value of adding readily available structured laboratory information. METHODS: We identified patients with possible AP events first based on the presence of a single hospital discharge ICD-9 or ICD-10 diagnosis of AP (Algorithm 1). We then expanded Algorithm 1 by including relevant laboratory test results (Algorithm 2). Specifically, we considered amylase or lipase serum values obtained between 2 days before admission and the end of the hospitalization. Medical records of a random sample of patients identified by the respective algorithms were reviewed by two separate gastroenterologists to adjudicate AP events. The PPV (95% confidence interval [CI]) for the algorithms were calculated. RESULTS: Algorithm 2, consisting of one ICD-9 or ICD-10 hospital discharge diagnosis of AP and the addition of lipase serum value ≥200 U/L, had a PPV 89.1% (95% CI 83.0%-95.2%), improving from the PPV of algorithm 1 (57.9% [95% CI 46.8-69.0]). CONCLUSIONS: An algorithm consisting of an ICD-9 or ICD-10 diagnosis of AP with a lipase value ≥200 U/L achieved high PPV. This simple algorithm can be readily implemented in any electronic health records (EHR) systems and could be useful for future pharmacoepidemiologic studies on AP.