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.

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.

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.

Is carotid web an arterial wall dysplasia? A histological series.

INTRODUCTION: Described for 60 years under various names, the carotid web is a suspected cause of cryptogenic stroke, especially in young patients. The web creates an intraluminal protrusion that may contribute to turbulent flow and thrombus embolization into cerebral arteries. Although the carotid web has frequently been related to arterial fibrodysplasia, its natural history and pathological description remain unclear. PATIENTS: Among all consecutive patients admitted to the stroke unit of Sainte-Anne Hospital and referred to the vascular surgery department from January 2015 to December 2022, we retrospectively identified 9 patients with a carotid web. The surgical specimens of the 9 patients were submitted to systematic pathological analysis. RESULTS: The patients with a histologically confirmed carotid web were young (median age was 42 years), prominently women (7/9), and presenting with low cardiovascular risk. Eight patients had a stroke proven by a magnetic resonance imaging, and 1 had transient monocular amaurosis. The typical pathological lesion supporting the imaging pattern of the carotid web was a focal eccentric intimal hyperplasia forming a protruding lesion characterized by a population of vascular smooth muscle cells intermingled in an abundant, most often loose extracellular matrix. Pathologically proven thrombus was observed in 4 cases. Importantly atherosclerosis was absent. CONCLUSION: Histological features in our 9 cases strengthen carotid web characterization as a homogeneous pattern of localized intimal hyperplasia. It is a unique entity consistent with intimal fibroplasia, distinct from medial fibromuscular dysplasia and early atherosclerosis.

Summary of the experiences, knowledge, medical management, and family communication of monoallelic MUTYH carriers.

Germline genetic testing for inherited cancer risk is increasingly being performed with multigene panel testing with MUTYH often included on colorectal cancer- and polyposis-focused panels, as well as on broader pan-cancer panels. With up to 1%-2% of the general population being monoallelic MUTYH carriers, pathogenic/likely pathogenic (P/LP) variants in MUTYH are one of the most common findings on multigene cancer panels. However, little is known about patient experience and understanding of monoallelic MUTYH P/LP variants, nor whether such findings influence medical management recommendations and familial communication, which this study aims to better understand. Monoallelic P/LP MUTYH carriers were recruited from the Prospective Registry of Multiplex Testing (PROMPT) and completed a cross-sectional self-report survey on sociodemographic characteristics, medical and family history, experiences with MUTYH genetic testing, genetics and MUTYH knowledge, perceived cancer risk, and familial communication. Of 115 eligible PROMPT participants, 49 (43%) completed the survey who were primarily female (94%), white (96%), had a history of cancer (61%), and a median age of 51.4 years. Most participants (61%) reported satisfaction with how their healthcare provider managed their genetic test result and care, and 65% of survey participants reported their provider recommended colonoscopy based on their genetic test results. Participants' responses also reflected variable levels of knowledge regarding cancer risks and screening recommendations for MUTYH carriers. The majority (98%) of participants shared their genetic test results with at least some of their relatives; however, only 13% of eligible relatives reportedly underwent cascade testing. Taken together, this study provides needed insight into the overall experiences of monoallelic MUTYH carriers and highlights numerous areas for improvement in clinician education, communication, and management of these individuals.

Cost-Effectiveness of a Risk-Tailored Pancreatic Cancer Early Detection Strategy Among Patients With New-Onset Diabetes.

BACKGROUND & AIMS: Screening for pancreatic ductal adenocarcinoma (PDAC) in asymptomatic adults is not recommended, however, patients with new-onset diabetes (NoD) have an 8 times higher risk of PDAC than expected. A novel risk-tailored early detection strategy targeting high-risk NoD patients might improve PDAC prognosis. We sought to evaluate the cost effectiveness of this strategy. METHODS: We compared PDAC early detection strategies targeting NoD individuals age 50 years and older at various minimal predicted PDAC risk thresholds vs standard of care in a Markov state-transition decision model under the health care sector perspective using a lifetime horizon. RESULTS: At a willingness to pay (WTP) threshold of $150,000 per quality-adjusted life-year, the early detection strategy targeting patients with a minimum predicted 3-year PDAC risk of 1% was cost effective (incremental cost-effectiveness ratio, $116,911). At a WTP threshold of $100,000 per quality-adjusted life-year, the early detection strategy at the 2% risk threshold was cost effective (incremental cost-effectiveness ratio, $63,045). The proportion of PDACs detected at local stage, costs of treatment for metastatic PDAC, utilities of local and regional cancers, and sensitivity of screening were the most influential parameters. Probabilistic sensitivity analysis confirmed that at a WTP threshold of $150,000, early detection at the 1.0% risk threshold was favored (30.6%), followed by the 0.5% risk threshold (20.4%) vs standard of care (1.7%). At a WTP threshold of $100,000, early detection at the 1.0% risk threshold was favored (27.3%) followed by the 2.0% risk threshold (22.8%) vs standard of care (2.0%). CONCLUSIONS: A risk-tailored PDAC early detection strategy targeting NoD patients with a minimum predicted 3-year PDAC risk of 1.0% to 2.0% may be cost effective.

Performance of polygenic risk scores for cancer prediction in a racially diverse academic biobank.

PURPOSE: Genome-wide association studies have identified hundreds of single nucleotide variations (formerly single nucleotide polymorphisms) associated with several cancers, but the predictive ability of polygenic risk scores (PRSs) is unclear, especially among non-Whites. METHODS: PRSs were derived from genome-wide significant single-nucleotide variations for 15 cancers in 20,079 individuals in an academic biobank. We evaluated the improvement in discriminatory accuracy by including cancer-specific PRS in patients of genetically-determined African and European ancestry. RESULTS: Among the individuals of European genetic ancestry, PRSs for breast, colon, melanoma, and prostate were significantly associated with their respective cancers. Among the individuals of African genetic ancestry, PRSs for breast, colon, prostate, and thyroid were significantly associated with their respective cancers. The area under the curve of the model consisting of age, sex, and principal components was 0.621 to 0.710, and it increased by 1% to 4% with the inclusion of PRS in individuals of European genetic ancestry. In individuals of African genetic ancestry, area under the curve was overall higher in the model without the PRS (0.723-0.810) but increased by <1% with the inclusion of PRS for most cancers. CONCLUSION: PRS moderately increased the ability to discriminate the cancer status in individuals of European but not African ancestry. Further large-scale studies are needed to identify ancestry-specific genetic factors in non-White populations to incorporate PRS into cancer risk assessment.

Associations of sociodemographic and clinical factors with gastrointestinal cancer risk assessment appointment completion.

Cancer risk assessment services are important for patient care; effective use requires appropriate provider referral, accurate scheduling processes, and completed attendance at booked appointments. Sociodemographic and clinical factors associated with gastrointestinal cancer (GIC)-specific risk assessment appointments remain unstudied; therefore, we aimed to identify factors associated with appointment completion in a GIC risk assessment program at a tertiary academic center. Retrospective chart review was conducted on all patients scheduled for an appointment in the Gastrointestinal Cancer Risk Evaluation Program (GI-CREP) between January 2016 and December 2017. Data collected included demographic and clinical factors. Chi-square and Wilcoxon's rank-sum tests compared variables among patients based on the study outcome of whether a GI-CREP appointment was completed; marginal standardization was used to predict the standardized percentage of patients that had appointment completion. A total of 676 patients had a scheduled GI-CREP appointment; 32 individuals were excluded due to incomplete information or scheduling error, resulting in 644 patients available for final analysis. Our study population was predominantly female (61%), White (77%), and married (64%), had private healthcare insurance (76%), and lacked a personal history of cancer (60%). Referrals internal to the healthcare system were most common (77%), with gastroenterologists as the most frequent referring provider (42%). Seventy-five percent of scheduled individuals had appointment completion, while 25% of individuals did not. Independent predictors for an incomplete GI-CREP appointment included Medicaid insurance (OR 2.45, 95% CI 1.21-4.28, p = .01), self-identified Black race (OR 1.97, 95% CI: 1.20-3.25, p = .008), and personal history of cancer (OR 1.60, 95% CI 1.11-2.31, p = .01). These data highlight existing disparities in GIC risk assessment appointment completion associated with race, health insurance coverage, and medical status. Further studies of these areas are necessary to ensure equitable access to important GIC risk assessment services.

Low Rates of Gastrointestinal and Non-Gastrointestinal Complications for Screening or Surveillance Colonoscopies in a Population-Based Study.

BACKGROUND: The full spectrum of serious non-gastrointestinal post-colonoscopy complications has not been well characterized. We analyzed rates of and factors associated with adverse post-colonoscopy gastrointestinal (GI) and non-gastrointestinal events (cardiovascular, pulmonary, or infectious) attributable to screening or surveillance colonoscopy (S-colo) and non-screening or non-surveillance colonoscopy (NS-colo). METHODS: We performed a population-based study of colonoscopy complications using databases from California hospital-owned and nonhospital-owned ambulatory facilities, emergency departments, and hospitals from January 1, 2005 through December 31, 2011. We identified patients who underwent S-colo (1.58 million), NS-colo (1.22 million), or low-risk comparator procedures (joint injection, aspiration, lithotripsy; arthroscopy, carpal tunnel; or cataract; 2.02 million) in California's Ambulatory Services Databases. We identified patients who developed adverse events within 30 days, and factors associated with these events, through patient-level linkage to California's Emergency Department and Inpatient Databases. RESULTS: After S-colo, the numbers of lower GI bleeding, perforation, myocardial infarction, and ischemic stroke per 10,000-persons were 5.3 (95% confidence interval [CI], 4.8-5.9), 2.9 (95% CI, 2.5-3.3), 2.5 (95% CI, 2.1-2.9), and 4.7 (95% CI, 4.1-5.2) without biopsy or intervention; with biopsy or intervention, numbers per 10,000-persons were 36.4 (95% CI, 35.1-37.6), 6.3 (95% CI, 5.8-6.8), 4.2 (95% CI, 3.8-4.7), and 9.1 (95% CI, 8.5-9.7). Rates of dysrhythmia were higher. After NS-colo, event rates were substantially higher. Most serious complications led to hospitalization, and most GI complications occurred within 14 days of colonoscopy. Ranges of adjusted odds ratios for serious GI complications, myocardial infarction, ischemic stroke, and serious pulmonary events after S-colo vs comparator procedures were 2.18 (95% CI, 2.02-2.36) to 5.13 (95% CI, 4.81-5.47), 0.67 (95% CI, 0.56-0.81) to 0.99 (95% CI, 0.83-1.19), 0.66 (95% CI, 0.59-0.75) to 1.13 (95% CI, 0.99-1.29), and 0.64 (95% CI, 0.61-0.68) to 1.05 (95% CI, 0.98-1.11). Biopsy or intervention, comorbidity, black race, low income, public insurance, and NS-colo were associated with post-colonoscopy adverse events. CONCLUSIONS: In a population-based study in California, we found that following S-colo, rates of serious GI adverse events were low but clinically relevant, and that rates of myocardial infarction, stroke, and serious pulmonary events were no higher than after low-risk comparator procedures. Rates of myocardial infarction are similar to, but rates of stroke are higher than, those reported for the general population.

Health outcomes in US children with abdominal pain at major emergency departments associated with race and socioeconomic status.

OBJECTIVE: Over 9.6 million ED visits occur annually for abdominal pain in the US, but little is known about the medical outcomes of these patients based on demographics. We aimed to identify disparities in outcomes among children presenting to the ED with abdominal pain linked to race and SES. METHODS: Data from 4.2 million pediatric encounters of abdominal pain were analyzed from 43 tertiary US children's hospitals, including 2.0 million encounters in the emergency department during 2004-2011. Abdominal pain was categorized as functional or organic abdominal pain. Appendicitis (with and without perforation) was used as a surrogate for abdominal pain requiring emergent care. Multivariate analysis estimated likelihood of hospitalizations, radiologic imaging, ICU admissions, appendicitis, appendicitis with perforation, and time to surgery and hospital discharge. RESULTS: Black and low income children had increased odds of perforated appendicitis (aOR, 1.42, 95% CI, 1.32- 1.53; aOR, 1.20, 95% CI 1.14 - 1.25). Blacks had increased odds of an ICU admission (aOR, 1.92, 95% CI 1.53 - 2.42) and longer lengths of stay (aHR, 0.91, 95% CI 0.86 - 0.96) than Whites. Minorities and low income also had lower rates of imaging for their appendicitis, including CT scans. The combined effect of race and income on perforated appendicitis, hospitalization, and time to surgery was greater than either separately. CONCLUSIONS: Based on race and SES, disparity of health outcomes exists in the acute ED setting among children presenting with abdominal pain, with differences in appendicitis with perforation, length of stay, and time until surgery.

Cost-effectiveness of universal serologic screening to prevent nontraumatic hip and vertebral fractures in patients with celiac disease.

BACKGROUND & AIMS: Patients with asymptomatic or poorly managed celiac disease can experience bone loss, placing them at risk for hip and vertebral fractures. We analyzed the cost-effectiveness of universal serologic screening (USS) vs symptomatic at-risk screening (SAS) strategies for celiac disease because of the risk of nontraumatic hip and vertebral fractures if untreated or undiagnosed. METHODS: We developed a lifetime Markov model of the screening strategies, each with male or female cohorts of 1000 patients who were 12 years old when screening began. We screened serum samples for levels of immunoglobulin A, compared with tissue transglutaminase and total immunoglobulin A, and findings were confirmed by mucosal biopsy. Transition probabilities and quality of life estimates were obtained from the literature. We used generalizable cost estimates and Medicare reimbursement rates and ran deterministic and probabilistic sensitivity analyses. RESULTS: For men, the average lifetime costs were $8532 and $8472 for USS and SAS strategies, respectively, corresponding to average quality-adjusted life year gains of 25.511 and 25.515. Similarly for women, costs were $11,383 and $11,328 for USS and SAS strategies, respectively, corresponding to quality-adjusted life year gains of 25.74 and 25.75. Compared with the current standard of care (SAS), USS produced higher average lifetime costs and lower quality of life for each sex. Deterministic and probabilistic sensitivity analyses showed that the model was robust to realistic changes in all the variables, making USS cost-ineffective on the basis of these outcomes. CONCLUSIONS: USS and SAS are similar in lifetime costs and quality of life, although the current SAS strategy was overall more cost-effective in preventing bone loss and fractures among patients with undiagnosed or subclinical disease. On the basis of best available supportive evidence, it is more cost-effective to maintain the standard celiac screening practices, although future robust population-based evidence in other health outcomes could be leveraged to reevaluate current screening guidelines.

Novel mechanism of inhibition of HIV-1 reverse transcriptase by a new non-nucleoside analog, KM-1.

2-Naphthalenesulfonic acid (4-hydroxy-7-[[[[5-hydroxy-6-[(4 cinnamylphenyl)azo]-7-sulfo-2-naphthalenyl]amino]-carbonyl]amino]-3-[(4-cinnamylphenyl)]azo (KM-1)) is a novel non-nucleoside reverse transcriptase inhibitor (NNRTI) that was designed to bind at an unconventional site on human immunodeficiency virus type 1 reverse transcriptase (RT) (Skillman, A. G., Maurer, K. W., Roe, D. C., Stauber, M. J., Eargle, D., Ewing, T. J., Muscate, A., Davioud-Charvet, E., Medaglia, M. V., Fisher, R. J., Arnold, E., Gao, H. Q., Buckheit, R., Boyer, P. L., Hughes, S. H., Kuntz, I. D., and Kenyon, G. L. (2002) Bioorg. Chem. 30, 443-458). We have investigated the mechanism by which KM-1 inhibits wild-type human immunodeficiency virus type 1 RT by using pre-steady state kinetic methods to examine the effect of KM-1 on the parameters governing the single nucleotide incorporation catalyzed by RT. Analysis of the pre-steady-state burst phase of dATP incorporation showed that KM-1 decreased the amplitude of the reaction as previously shown for other NNRTIs, because of the slow equilibration of the inhibitor with RT. In the ternary enzyme-DNA-KM-1 complex (E-DNA-I), incorporation of the next nucleotide onto the primer is blocked. However, unlike conventional NNRTIs, the inhibitory effect was caused primarily by weakening the DNA binding affinity and displacing DNA from the enzyme. Wild-type RT binds a 25/45-mer DNA duplex with an apparent K(d) of 3 nm, which was increased to 400 nm upon saturation with KM-1. Likewise, the apparent K(d) for KM-1 binding to RT increased at higher DNA concentrations. We therefore conclude that KM-1 represents a new class of inhibitor distinct from nevirapine and related NNRTIs. KM-1 can bind to RT in both the absence and presence of DNA but weakens the affinity for DNA 140-fold so that it favors DNA dissociation. The data suggest that KM-1 distorts RT conformation and misaligns DNA at the active site.

Purification of salmon thrombin and its potential as an alternative to mammalian thrombins in fibrin sealants.

A method to produce highly purified thrombin from salmon blood is described, and a series of biochemical, cell biologic, and biophysical assays demonstrate the functional similarities and some differences between salmon and human thrombins. Salmon thrombin with specific activity greater than 1000 units/mg total protein can be prepared by modifications of the methods used for purification of human thrombin. Using a synthetic substrate based on the human fibrinogen A-alpha polypeptide sequence as an indicator of enzymatic activity, salmon and human thrombin preparations contain similar specific activities per mass of purified protein. Salmon thrombin activates human fibrinogen and initiates the formation of fibrin clots whose structure and rheologic properties are indistinguishable from those of human fibrin clotted by human thrombin. Salmon thrombin also activates human platelets. Approximately 10 times higher activities are needed for the same rate of platelet aggregation compared to human thrombin, and some aspects of platelet activation, most notably phosphatidylserine exposure, are diminished relative to the effects of human thrombin. This latter finding suggests that salmon thrombin may not activate all of the receptors that are targets of human thrombin, although it does appear to activate signals that are sufficient to produce normal rates of activation and aggregation as measured by conventional aggregometry. Together with the recent purification of salmon fibrinogen and its application in mammalian wound healing, the availability of salmon thrombin allows the formulation of biological sealants devoid of any exogenous mammalian proteins and so may aid the design of materials with increased safety from infectious disease transmission.