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.

Systems approach to enhance Lynch syndrome diagnosis through tumour testing.

BACKGROUND: Guidelines recommend universal mismatch repair (MMR) tumour testing of colorectal adenocarcinomas (CRCs) to screen for Lynch syndrome (LS). However, its implementation remains disjointed and referral for genetic testing dismal, particularly among minorities. We aimed to increase referral, cancer genetic testing and eventually LS diagnosis by developing the CLEAR LS (Closed Loop Enhanced Assessment and Referral for Lynch Syndrome) intervention, a systems approach which in the second phase was automated. METHODS: This is a cohort study of all patients diagnosed with CRC at an academic centre between 1 January 2012, when implementation of universal CRC testing began, and 31 January 2021. The original cohort spanned through 31 May 2015. Tumour testing included MMR immunohistochemistry, followed by BRAF V600E/MLH1 promoter methylation testing when indicated. The intervention included a manual phase (1 June 2015 through 31 July 2018), which systematised pathology screening and cancer genetics (CG) referral mechanisms, and an automated phase (1 August 2018 through 31 January 2021) using computer programming. RESULTS: A total of 249/1541 CRC (17.38%) had MMR loss of expression and 129 (8.37%) qualified for CG evaluation. Referral was 27.58% in the original cohort and 92.1% in the intervention (p<0.001). Patients seen by CG among referred were 27.58% in the original cohort and 74.3% in the intervention (p two-sided<0.001). The distribution of race/ethnicity among patients qualifying and referred for CG evaluation was not significantly different across cohorts. LS diagnosis increased from 0.56% (original cohort) to 1.43% (intervention). Cost per new diagnosis of LS decreased from US$173 675 to $87 960 from original cohort to intervention. CONCLUSION: Implementation of systematic case identification and referral support mechanisms significantly increased the proportion of patients undergoing genetic testing and doubled the percentage of patients diagnosed with LS with no referral differences across racial/ethnic groups.

Depressive symptoms among dementia caregivers: role of mediating factors.

OBJECTIVE: To compare depressive symptoms between caregivers to persons with dementia and other illnesses and determine whether caregiver role captivity and care recipient disruptive behaviors mediate this association. METHODS: Prospective cohort study of older women in four U.S. communities followed from 1999 to 2009. Home-based interviews were used in 345 caregiving participants from the Caregiver-Study of Osteoporotic Fractures. Caregiver status was based on self-report of performing one or more instrumental or basic activities of daily living for a care recipient. Depressive symptoms were measured using the 20-item Center for Epidemiologic Studies Depression Scale. Scores of 16 or greater represented high depressive symptoms. Caregiver role captivity and care recipient problematic behaviors were measured using validated instruments. RESULTS: Approximately one third of the caregivers cared for a person with dementia. High depressive symptoms were more common among dementia caregivers (22.8% versus 11.2%, p <0.001) (unadjusted odds ratio: 2.12; 95% confidence interval [CI]: 1.20-3.74). This association was completely mediated by caregiver role captivity and care recipient problematic behaviors. In adjusted results, high depressive symptoms were associated with middle and highest tertiles of role captivity (adjusted odds ratios [AOR]: 5.01; 95% CI: 2.31-11.05 and AOR: 9.41; 95% CI: 3.95-22.40 for the middle and highest tertiles, respectively) and care recipient problematic behaviors (AOR: 2.52; 95% CI: 1.02-6.19 and AOR: 5.26; 95% CI: 2.00-13.8 for the middle and highest tertiles, respectively). CONCLUSION: Older caregivers to persons with dementia are at increased risk of high depressive symptoms. Targeting problematic behaviors among dementia patients and addressing aspects of dementia care that result in role captivity may ameliorate caregiver depression.

Review of the cost-effectiveness of surveillance for hereditary pancreatic cancer.

Individuals with hereditary pancreatic cancer risk include high risk individuals (HRIs) with germline genetic susceptibility to pancreatic cancer (PC) and/or a strong family history of PC. Previously, studies have shown that PC surveillance in HRIs can downstage PC diagnosis and extend survival leading to pancreatic surveillance being recommended for certain HRIs. However, the optimal surveillance strategy remains uncertain, including which modalities should be used for surveillance, how frequently should surveillance be performed, and which sub-groups of HRIs should undergo surveillance. Additionally, in the ideal world PC surveillance should also be cost-effective. Cost-effectiveness analysis is a valuable tool that can consider the costs, potential health benefits, and risks among various PC surveillance strategies. In this review, we summarize the cost-effectiveness of various PC surveillance strategies for HRIs for hereditary pancreatic cancer and provide potential avenues for future work in this field. Additionally, we include cost-effectiveness studies among individuals with new-onset diabetes (NoD), a high-risk group for sporadic PC, as a comparison.

Community-Level Factors Associated with Hepatocellular Carcinoma Incidence and Mortality: An Observational Registry Study.

BACKGROUND: Hepatocellular carcinoma (HCC) incidence and outcomes vary across populations in the United States, but few studies evaluate local drivers of observed disparities. We measured HCC incidence at the community level and assessed community-level HCC risk factors with the goal of informing resource allocation to improve early case detection, which is associated with improved outcomes. METHODS: Clinical and demographic data including census tract of residence for all adults diagnosed with HCC in the Connecticut Tumor Registry between 2008 and 2019 were combined with publicly available U.S. Census and Centers for Disease Control and Prevention (CDC) data at the ZIP Code tabulation area (ZCTA) level. The average annual incidence of HCC was calculated for each ZCTA and associations between community-level characteristics, HCC incidence, stage at diagnosis, and survival were evaluated. RESULTS: Average annual HCC incidence during the study period was 8.9/100,000 adults and varied from 0 to 97.7 per 100,000 adults by ZCTA. At the community level, lower rates of high school graduation, higher rates of poverty, and rural community type were associated with higher HCC incidence. Persons with HCC living in the highest incidence ZCTAs were diagnosed at a younger age and were less likely to be alive at 1, 2, and 5 years after diagnosis. CONCLUSIONS: Community-level socioeconomic factors are strongly associated with HCC incidence and survival in Connecticut. IMPACT: This reproducible geo-localization approach using cancer registry, Census, and CDC data can be used to identify communities most likely to benefit from health system investments to reduce disparities in HCC.

Detection of hepatocellular carcinoma methylation markers in salivary DNA.

BACKGROUND: Alterations to DNA methylation have been identified in both hepatocellular carcinoma (HCC) tumor and circulating DNA from affected individuals. These markers have potential utility in HCC screening. Adherence to HCC screening is poor and acceptable HCC screening tests are needed. METHODS: A feasibility study was performed on a subset of case patients and control subjects from a prior study of risk factors for HCC. Case patients (n=12) included adults aged 47-85 years with a first diagnosis of HCC between 2011 and 2016 and without viral hepatitis. Control subjects (n=12) were matched on age, sex, and state of residence. Participants provided saliva samples for DNA genotyping. Log fold change in salivary DNA methylation at 1359 CpG sites representing 25 candidate genes previously associated with HCC was compared across case patients and control subjects. RESULTS: The quantity of DNA ranged from 9.65 to 257.79 µg. The purity of DNA isolates was good, with mean OD260/280 ratio of 1.78 (SD: 0.14). Of 25 candidate genes, 16 had at ≥1 CpG site with detectable differences in methylation across HCC case patients and control subjects. Sites differentially methylated in HCC case patients included genes encoding tumor suppressors (PRDM2, RUNX3, p15/16, and RASSF1/5), regulators of cell cycle progression (DAPK1 and TP73), and DNA repair (MGMT and GSTP1). No associations met the significance threshold 3.7 × 10-5 required for multiple comparisons. CONCLUSIONS: Salivary DNA may be a feasible alternative to blood samples in the era of novel DNA-based screening tests for HCC. The ease of saliva-based testing supports further investigation of its potential.

Severe Acute Liver Injury After Hepatotoxic Medication Initiation in Real-World Data.

Importance: Current approaches to classify the hepatotoxic potential of medications are based on cumulative case reports of acute liver injury (ALI), which do not consider the size of the exposed population. There is little evidence from real-world data (data relating to patient health status and/or the delivery of health care routinely collected from sources outside of a research setting) on incidence rates of severe ALI after initiation of medications, accounting for duration of exposure. Objective: To identify the most potentially hepatotoxic medications based on real-world incidence rates of severe ALI and to examine how these rates compare with categorization based on case reports. Design, Setting, and Participants: This series of cohort studies obtained data from the US Department of Veterans Affairs on persons without preexisting liver or biliary disease who initiated a suspected hepatotoxic medication in the outpatient setting between October 1, 2000, and September 30, 2021. Data were analyzed from June 2020 to November 2023. Exposures: Outpatient initiation of any one of 194 medications with 4 or more published reports of hepatotoxicity. Main Outcomes and Measures: Hospitalization for severe ALI, defined by either inpatient: (1) alanine aminotransferase level greater than 120 U/L plus total bilirubin level greater than 2.0 mg/dL or (2) international normalized ratio of 1.5 or higher plus total bilirubin level greater than 2.0 mg/dL recorded within the first 2 days of admission. Acute or chronic liver or biliary disease diagnosis recorded during follow-up or as a discharge diagnosis of a hospitalization for severe ALI resulted in censoring. This study calculated age- and sex-adjusted incidence rates of severe ALI and compared observed rates with hepatotoxicity categories based on cumulative published case reports. Results: The study included 7 899 888 patients across 194 medication cohorts (mean [SD] age, 64.4 [16.4] years, 7 305 558 males [92.5%], 4 354 136 individuals [55.1%] had polypharmacy). Incidence rates of severe ALI ranged from 0 events per 10 000 person-years (candesartan, minocycline) to 86.4 events per 10 000 person-years (stavudine). Seven medications (stavudine, erlotinib, lenalidomide or thalidomide, chlorpromazine, metronidazole, prochlorperazine, and isoniazid) exhibited rates of 10.0 or more events per 10 000 person-years, and 10 (moxifloxacin, azathioprine, levofloxacin, clarithromycin, ketoconazole, fluconazole, captopril, amoxicillin-clavulanate, sulfamethoxazole-trimethoprim, and ciprofloxacin) had rates between 5.0 and 9.9 events per 10 000 person-years. Of these 17 medications with the highest observed rates of severe ALI, 11 (64%) were not included in the highest hepatotoxicity category when based on case reports. Conclusions and Relevance: In this study, incidence rates of severe ALI using real-world data identified the most potentially hepatotoxic medications and can serve as a tool to investigate hepatotoxicity safety signals obtained from case reports. Case report counts did not accurately reflect the observed rates of severe ALI after medication initiation.

Baseline assessment of adult and adolescent primary care delivery in Rwanda: an opportunity for quality improvement.

BACKGROUND: As resource-limited health systems evolve to address complex diseases, attention must be returned to basic primary care delivery. Limited data exists detailing the quality of general adult and adolescent primary care delivered at front-line facilities in these regions. Here we describe the baseline quality of care for adults and adolescents in rural Rwanda. METHODS: Patients aged 13 and older presenting to eight rural health center outpatient departments in one district in southeastern Rwanda between February and March 2011 were included. Routine nurse-delivered care was observed by clinical mentors trained in the WHO Integrated Management of Adolescent & Adult Illness (IMAI) protocol using standardized checklists, and compared to decisions made by the clinical mentor as the gold standard. RESULTS: Four hundred and seventy consultations were observed. Of these, only 1.5% were screened and triaged for emergency conditions. Fewer than 10% of patients were routinely screened for chronic conditions including HIV, tuberculosis, anemia or malnutrition. Nurses correctly diagnosed 50.1% of patient complaints (95% CI: 45.7%-54.5%) and determined the correct treatment 44.9% of the time (95% CI: 40.6%-49.3%). Correct diagnosis and treatment varied significantly across health centers (p = 0.03 and p = 0.04, respectively). CONCLUSION: Fundamental gaps exist in adult and adolescent primary care delivery in Rwanda, including triage, screening, diagnosis, and treatment, with significant variability across conditions and facilities. Research and innovation toward improving and standardizing primary care delivery in sub-Saharan Africa is required. IMAI, supported by routine mentorship, is one potentially important approach to establishing the standards necessary for high-quality care.

Adherence to Tumor Board Recommendations in the Treatment of Patients with Hepatocellular Carcinoma.

Background: Hepatocellular carcinoma (HCC) is a heterogeneous disease that typically arises in the setting of chronic liver disease, making treatment selection complex. Multidisciplinary liver tumor boards (MDLTB) have been shown to improve outcomes in patients with HCC. However, in many cases, patients evaluated by MDLTBs ultimately do not receive the board's recommended treatment. Purpose: This study aims to assess adherence to MDLTB recommendations for the treatment of HCC, the reasons for non-adherence, and the survival of Barcelona Clinic Liver Cancer (BCLC) Stage A patients treated with curative treatment compared to palliative locoregional therapy. Patients and Methods: A single-site, retrospective cohort study was conducted of all patients with treatment-naïve HCC who were evaluated by an MDLTB at a tertiary care center in Connecticut between 2013 and 2016, of which 225 patients met inclusion criteria. Investigators conducted a chart review and recorded adherence to the MDLTB's recommendations, and in cases of discordance, evaluated and recorded the underlying cause; investigators assessed MDLTB recommendations' compliance with BCLC guidelines. Survival data was accrued through February 1st of 2022 and analyzed via Kaplan-Meier analysis and multivariate Cox regression. Results: Treatment adherent to MDLTB recommendations occurred in 85.3% of patients (n=192). The majority of non-adherence occurred in the management of BCLC Stage A disease. In cases where adherence was possible but the recommendation was not followed, most discrepancies were whether to treat with curative or palliative intent (20/24), with almost all discrepancies occurring in patients (19/20) with BCLC Stage A disease. For patients with Stage A unifocal HCC, those who received curative therapy lived significantly longer than patients who received palliative locoregional therapy (5.55 years vs 4.26 years, p=0.037). Conclusion: Most forms of non-adherence to MDLTB recommendations were unavoidable; however, treatment discordance in the management of patients with BCLC Stage A unifocal disease may present an opportunity for clinically significant quality improvement.

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.

HCC is associated with diabetes and longitudinal blood glucose control in a national cohort with cirrhosis.

BACKGROUND: Diabetes is associated with HCC; however, the impact of longitudinal blood glucose (BG) control on HCC risk in cirrhosis is not well known. We investigated this knowledge gap in a cohort of United States Veterans with cirrhosis from 2015 to 2021. METHODS: We used repeated hemoglobin A1c measurements to categorize follow-up time according to BG control (defined as hemoglobin A1c < 7%) state over time: uncontrolled, nonsustained control (≤2 y), or sustained control (>2 y). We performed a sensitivity analysis using hemoglobin A1c < 8% to define BG control. We used Fine and Gray Cox proportional hazards regression with death and transplant as competing events to compare rates of incident HCC. RESULTS: Our study included 81,907 individuals, 56.2% of whom had diabetes at baseline. There were 8,002 incident HCCs. The rate of HCC was 18% higher in diabetes (95% CI: 13% - 24%), and the relative increase in the rate of HCC varied by etiology of cirrhosis from nonsignificant (HCV) to an increase of 120% (HBV). Uncontrolled and nonsustained BG control was associated with 1.80 (95% CI: 1.70-1.91) and 2.34 (95% CI: 2.21-2.48) times the rate of HCC compared to sustained BG control, respectively. Using Hgb A1c < 8% to define BG control, HCC rates in uncontrolled and nonsustained BG control were 2.43 (2.28-2.58) and 2.23 (2.11-2.36) times that observed in sustained BG control. CONCLUSIONS: Associations between diabetes and HCC in cirrhosis vary according to the longitudinal BG control state. Inadequate BG control is consistently associated with a higher risk of HCC, and long-term BG control should be considered in comprehensive cirrhosis care.

Cancer tracking system improves timeliness of liver cancer care at a Veterans Hospital: A comparison of cohorts before and after implementation of an automated care coordination tool.

INTRODUCTION: Hepatocellular carcinoma (HCC) requires complex care coordination. Patient safety may be compromised with untimely follow-up of abnormal liver imaging. This study evaluated whether an electronic case-finding and tracking system improved timeliness of HCC care. METHODS: An electronic medical record-linked abnormal imaging identification and tracking system was implemented at a Veterans Affairs Hospital. This system reviews all liver radiology reports, generates a queue of abnormal cases for review, and maintains a queue of cancer care events with due dates and automated reminders. This is a pre-/post-intervention cohort study to evaluate whether implementation of this tracking system reduced time between HCC diagnosis and treatment and time between first liver image suspicious for HCC, specialty care, diagnosis, and treatment at a Veterans Hospital. Patients diagnosed with HCC in the 37 months before tracking system implementation were compared to patients diagnosed with HCC in the 71 months after its implementation. Linear regression was used to calculate mean change in relevant intervals of care adjusted for age, race, ethnicity, BCLC stage, and indication for first suspicious image. RESULTS: There were 60 patients pre-intervention and 127 post-intervention. In the post-intervention group, adjusted mean time from diagnosis to treatment was 36 days shorter (p = 0.007), time from imaging to diagnosis 51 days shorter (p = 0.21), and time from imaging to treatment 87 days shorter (p = 0.05). Patients whose imaging was performed for HCC screening had the greatest improvement in time from diagnosis to treatment (63 days, p = 0.02) and from first suspicious image to treatment (179 days, p = 0.03). The post-intervention group also had a greater proportion of HCC diagnosed at earlier BCLC stages (p<0.03). CONCLUSIONS: The tracking system improved timeliness of HCC diagnosis and treatment and may be useful for improving HCC care delivery, including in health systems already implementing HCC screening.

Sex Differences in Patients Receiving Left Ventricular Assist Devices for End-Stage Heart Failure.

OBJECTIVES: This study sought to use INTERMACS (Interagency Registry for Mechanically Assisted Circulatory Support) results to evaluate sex differences in the use and clinical outcomes of left ventricular assist devices (LVAD). BACKGROUND: Despite a similar incidence of heart failure in men and women, prior studies have highlighted potential underuse of LVADs in women, and studies of clinical outcomes have yielded conflicting results. METHODS: Patients were enrolled from the INTERMACS study who underwent implantation of their first continuous-flow LVAD between 2008 and 2017, and survival analyses stratified by sex were conducted. RESULTS: Among the 18,868 patients, 3,984 (21.1%) were women. At 1 year, women were less likely to undergo heart transplantation than men (17.9% vs. 20.0%, respectively; p = 0.003). After multivariable adjustments, women had a higher risk of death (hazard ratio [HR]: 1.15; 95% confidence interval [CI]: 1.07 to 1.23; p < 0.001) and were more likely to incur post-implantation adverse events, including rehospitalization, bleeding, stroke, and pump thrombosis or device malfunction. Although women younger than 50 years of age had an increased risk of death compared to men of the same age (HR: 1.34; 95% CI: 1.12 to 1.6), men and women 65 years of age and older had a similar risk of death (HR: 1.09; 95% CI: 0.95 to 1.24). CONCLUSIONS: This study found that women had a higher risk of mortality and adverse events after LVAD. Only 1 in 5 LVADs were implanted in women, and women were less likely to receive a heart transplant than men. Further investigation is needed to understand the causes of adverse events and potential underuse of advanced treatment options in women.

Neurohormonal Blockade and Clinical Outcomes in Patients With Heart Failure Supported by Left Ventricular Assist Devices.

Importance: Left ventricular assist devices (LVADs) improve outcomes in patients with advanced heart failure, but little is known about the role of neurohormonal blockade (NHB) in treating these patients. Objective: To analyze the association between NHB blockade and outcomes in patients with LVADs. Design, Setting, and Participants: This retrospective cohort analysis of the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) included patients from more than 170 centers across the United States and Canada with continuous flow LVADs from 2008 to 2016 who were alive with the device in place at 6 months after implant. The data were analyzed between February and November 2019. Exposures: Patients were stratified based on exposure to NHB and represented all permutations of the following drug classes: angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, ß-blockers, and mineralocorticoid antagonists. Main Outcomes and Measures: The outcomes of interest were survival at 4 years and quality of life at 2 years based on Kansas City Cardiomyopathy Questionnaire scores and a 6-minute walk test. Results: A total of 12 144 patients in INTERMACS met inclusion criteria, of whom 2526 (20.8% ) were women, 8088 (66.6%) were white, 3024 (24.9%) were African American, and 753 (6.2%) were Hispanic; the mean (SD) age was 56.8 (12.9) years. Of these, 10 419 (85.8%) were receiving NHB. Those receiving any NHB medication at 6 months had a better survival rate at 4 years compared with patients not receiving NHB (56.0%; 95% CI, 54.5%-57.5% vs 43.9%; 95% CI, 40.5%-47.7%). After sensitivity analyses with an adjusted model, this trend persisted with patients receiving triple therapy with an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, ß-blocker, and mineralocorticoid antagonist having the lowest hazard of death compared with patients in the other groups (hazard ratio, 0.34; 95% CI, 0.28-0.41). Compared with patients not receiving NHB, use of NHB was associated with a higher Kansas City Cardiomyopathy Questionnaire score (66.6; bootstrapped 95% CI, 65.8-67.3 vs 63.0; bootstrapped 95% CI, 60.1-65.8; P = .02) and a 6-minute walk test (1103 ft; bootstrapped 95% CI, 1084-1123 ft vs 987 ft; bootstrapped 95% CI, 913-1060 ft; P < .001). Conclusions and Relevance: Among patients with LVADs who tolerated NHB therapy, continued treatment was associated with improved survival and quality of life. The optimal heart failure regimen for patients after LVAD implant may be the initiation and continuation of guideline-directed medical therapy.