Determining the feasibility of calculating pancreatic cancer risk scores for people with new-onset diabetes in primary care (DEFEND PRIME): study protocol.

INTRODUCTION: Worldwide, pancreatic cancer has a poor prognosis. Early diagnosis may improve survival by enabling curative treatment. Statistical and machine learning diagnostic prediction models using risk factors such as patient demographics and blood tests are being developed for clinical use to improve early diagnosis. One example is the Enriching New-onset Diabetes for Pancreatic Cancer (ENDPAC) model, which employs patients' age, blood glucose and weight changes to provide pancreatic cancer risk scores. These values are routinely collected in primary care in the UK. Primary care's central role in cancer diagnosis makes it an ideal setting to implement ENDPAC but it has yet to be used in clinical settings. This study aims to determine the feasibility of applying ENDPAC to data held by UK primary care practices. METHODS AND ANALYSIS: This will be a multicentre observational study with a cohort design, determining the feasibility of applying ENDPAC in UK primary care. We will develop software to search, extract and process anonymised data from 20 primary care providers' electronic patient record management systems on participants aged 50+ years, with a glycated haemoglobin (HbA1c) test result of ≥48 mmol/mol (6.5%) and no previous abnormal HbA1c results. Software to calculate ENDPAC scores will be developed, and descriptive statistics used to summarise the cohort's demographics and assess data quality. Findings will inform the development of a future UK clinical trial to test ENDPAC's effectiveness for the early detection of pancreatic cancer. ETHICS AND DISSEMINATION: This project has been reviewed by the University of Surrey University Ethics Committee and received a favourable ethical opinion (FHMS 22-23151 EGA). Study findings will be presented at scientific meetings and published in international peer-reviewed journals. Participating primary care practices, clinical leads and policy makers will be provided with summaries of the findings.

Improving Adherence to Clinical Practice Guidelines for Managing Gastric Intestinal Metaplasia Among Gastroenterologists at a US Academic Institution.

BACKGROUND: Clinical guidelines reserve endoscopic surveillance after a gastric intestinal metaplasia (GIM) diagnosis for high-risk patients. However, it is unclear how closely guidelines are followed in clinical practice. We examined the effectiveness of a standardized protocol for the management of GIM among gastroenterologists at a US hospital. METHODS: This was a preintervention and postintervention study, which included developing a protocol and education of gastroenterologists on GIM management. For the preintervention study, 50 patients with GIM were randomly selected from a histopathology database at the Houston VA Hospital between January 2016 and December 2019. For the postintervention study, we assessed change in GIM management in a cohort of 50 patients with GIM between April 2020 and January 2021 and surveyed 10 gastroenterologists. The durability of the intervention was assessed in a cohort of 50 GIM patients diagnosed between April 2021 and July 2021. RESULTS: In the preintervention cohort, GIM location was specified (antrum and corpus separated) in 11 patients (22%), and Helicobacter pylori testing was recommended in 11 of 26 patients (42%) without previous testing. Gastric mapping biopsies were recommended in 14% and surveillance endoscopy in 2%. In the postintervention cohort, gastric biopsy location was specified in 45 patients (90%, P <0.001) and H. pylori testing was recommended in 26 of 27 patients without prior testing (96%, P <0.001). Because gastric biopsy location was known in 90% of patients ( P <0.001), gastric mapping was not necessary, and surveillance endoscopy was recommended in 42% ( P <0.001). One year after the intervention, all metrics remained elevated compared with the preintervention cohort. CONCLUSIONS: GIM management guidelines are not consistently followed. A protocol for GIM management and education of gastroenterologists increased adherence to H. pylori testing and GIM surveillance recommendations.

The Impact of Race on Pancreatic Cancer Treatment and Survival in the Nationwide Veterans Affairs Healthcare System.

OBJECTIVES: Among patients with pancreatic cancer, studies show racial disparities at multiple steps of the cancer care pathway. Access to healthcare is a frequently cited cause of these disparities. It remains unclear if racial disparities exist in an integrated, equal access public system such as the Veterans Affairs healthcare system. METHODS: We identified all patients diagnosed with pancreatic adenocarcinoma in the national Veterans Affairs Central Cancer Registry from January 2010 to December 2018. We examined the independent association between race and 3 endpoints: stage at diagnosis, receipt of treatment, and survival while adjusting for sociodemographic factors and medical comorbidities. RESULTS: We identified 8529 patients with pancreatic adenocarcinoma, of whom 79.5% were White and 20.5% were Black. Black patients were 19% more likely to have late-stage disease and 25% less likely to undergo surgical resection. Black patients had 13% higher mortality risk compared with White patients after adjusting for sociodemographic characteristics and medical comorbidities. This difference in mortality was no longer statistically significant after additionally adjusting for cancer stage and receipt of potentially curative treatment. CONCLUSIONS: Equal access to healthcare might have reduced but failed to eliminate disparities. Dedicated efforts are needed to understand reasons underlying these disparities in an attempt to close these persistent gaps.

Emergency Presentations Predict Worse Outcomes Among Patients with Pancreatic Cancer.

BACKGROUND: Emergency presentation (EP) of cancer, a new cancer diagnosis made following an emergency department (ED) visit, is associated with worse patient outcomes and greater organizational stress on healthcare systems. Pancreatic cancer has the highest rate of EPs among European studies but remains understudied in the U.S. AIMS: To evaluate the association between pancreatic cancer EPs and cancer stage, treatment, and survival. METHODS: We conducted a retrospective cohort study among patients with pancreatic adenocarcinoma diagnosed from 2007 to 2019 at a tertiary-care Veterans Affairs medical center. Electronic health records were reviewed to identify EP cases, defined as a new pancreatic cancer diagnosis made within 30 days of an ED visit where cancer was suspected. We used multivariate logistic regression models and Cox proportional hazards models to examine the associations between EPs and cancer stage, treatment, and survival. RESULTS: Of 243 pancreatic cancer patients, 66.7% had EPs. There was no difference in stage by EP status. However, patients diagnosed through EPs were 72% less likely to receive cancer treatment compared to non-emergency presenters (adjusted OR 0.28; 95% CI 0.13-0.57). Patients with EPs also had a 73% higher mortality risk (adjusted HR 1.73; 95% CI 1.29-2.34). This difference in mortality remained statistically significant after adjusting for cancer stage and receipt of cancer treatment (adjusted HR 1.47; 95% CI 1.09-1.99). CONCLUSIONS: Pancreatic cancer EPs are common and independently associated with lower treatment rates and survival. Enhanced understanding of process breakdowns that lead to EPs can help identify care gaps and inform future quality improvement efforts.

Diabetes Status and Pancreatic Cancer Survival in the Nationwide Veterans Affairs Healthcare System.

BACKGROUND: Long-standing type 2 diabetes is a known risk factor for developing pancreatic cancer, however, its influence on cancer-associated outcomes is understudied. AIMS: To examine the associations between diabetes status and pancreatic cancer outcomes. METHODS: We identified patients diagnosed with pancreatic adenocarcinoma in the national Veterans Administration System from 2010 to 2018. We classified each patient by pre-cancer diagnosis diabetes status: no diabetes, new-onset diabetes (NOD) of ≤ 3 years duration, or long-standing diabetes of > 3 years duration. We used Cox proportional hazards models to examine the association between diabetes status and survival. We adjusted the models for age, race, sex, body mass index, tobacco, and alcohol use, coronary artery disease, hypertension, chronic kidney disease, year of cancer diagnosis, and cancer stage and treatment. RESULTS: We identified 6342 patients diagnosed with pancreatic adenocarcinoma. Most had long-standing diabetes (45.7%) prior to their cancer diagnosis, 14.5% had NOD, and 39.8% had no diabetes. Patients with long-standing diabetes had 10% higher mortality risk compared to patients without diabetes after adjusting for sociodemographic factors and medical comorbidities (adjusted HR 1.10; 95% CI 1.03-1.16). This difference in mortality remained statistically significant after additionally adjusting for cancer stage and receipt of potentially curative treatment (adjusted HR 1.09; 95% CI 1.02-1.15). There was no significant difference in mortality between patients with NOD compared to those without diabetes. CONCLUSIONS: Long-standing but not new-onset diabetes is independently associated with increased mortality among patients with pancreatic cancer. This information has implication for prognostication and risk stratification among pancreatic cancer patients.

Baseline Features and Reasons for Nonparticipation in the Colonoscopy Versus Fecal Immunochemical Test in Reducing Mortality From Colorectal Cancer (CONFIRM) Study, a Colorectal Cancer Screening Trial.

Importance: The Colonoscopy Versus Fecal Immunochemical Test in Reducing Mortality From Colorectal Cancer (CONFIRM) randomized clinical trial sought to recruit 50 000 adults into a study comparing colorectal cancer (CRC) mortality outcomes after randomization to either an annual fecal immunochemical test (FIT) or colonoscopy. Objective: To (1) describe study participant characteristics and (2) examine who declined participation because of a preference for colonoscopy or stool testing (ie, fecal occult blood test [FOBT]/FIT) and assess that preference's association with geographic and temporal factors. Design, Setting, and Participants: This cross-sectional study within CONFIRM, which completed enrollment through 46 Department of Veterans Affairs medical centers between May 22, 2012, and December 1, 2017, with follow-up planned through 2028, comprised veterans aged 50 to 75 years with an average CRC risk and due for screening. Data were analyzed between March 7 and December 5, 2022. Exposure: Case report forms were used to capture enrolled participant data and reasons for declining participation among otherwise eligible individuals. Main Outcomes and Measures: Descriptive statistics were used to characterize the cohort overall and by intervention. Among individuals declining participation, logistic regression was used to compare preference for FOBT/FIT or colonoscopy by recruitment region and year. Results: A total of 50 126 participants were recruited (mean [SD] age, 59.1 [6.9] years; 46 618 [93.0%] male and 3508 [7.0%] female). The cohort was racially and ethnically diverse, with 748 (1.5%) identifying as Asian, 12 021 (24.0%) as Black, 415 (0.8%) as Native American or Alaska Native, 34 629 (69.1%) as White, and 1877 (3.7%) as other race, including multiracial; and 5734 (11.4%) as having Hispanic ethnicity. Of the 11 109 eligible individuals who declined participation (18.0%), 4824 (43.4%) declined due to a stated preference for a specific screening test, with FOBT/FIT being the most preferred method (2820 [58.5%]) vs colonoscopy (1958 [40.6%]; P < .001) or other screening tests (46 [1.0%] P < .001). Preference for FOBT/FIT was strongest in the West (963 of 1472 [65.4%]) and modest elsewhere, ranging from 199 of 371 (53.6%) in the Northeast to 884 of 1543 (57.3%) in the Midwest (P = .001). Adjusting for region, the preference for FOBT/FIT increased by 19% per recruitment year (odds ratio, 1.19; 95% CI, 1.14-1.25). Conclusions and Relevance: In this cross-sectional analysis of veterans choosing nonenrollment in the CONFIRM study, those who declined participation more often preferred FOBT or FIT over colonoscopy. This preference increased over time and was strongest in the western US and may provide insight into trends in CRC screening preferences.

Adipose tissue and skeletal muscle wasting precede clinical diagnosis of pancreatic cancer.

Patients with pancreatic cancer commonly develop weight loss and muscle wasting. Whether adipose tissue and skeletal muscle losses begin before diagnosis and the potential utility of such losses for earlier cancer detection are not well understood. We quantify skeletal muscle and adipose tissue areas from computed tomography (CT) imaging obtained 2 months to 5 years before cancer diagnosis in 714 pancreatic cancer cases and 1748 matched controls. Adipose tissue loss is identified up to 6 months, and skeletal muscle wasting is identified up to 18 months before the clinical diagnosis of pancreatic cancer and is not present in the matched control population. Tissue losses are of similar magnitude in cases diagnosed with localized compared with metastatic disease and are not correlated with at-diagnosis circulating levels of CA19-9. Skeletal muscle wasting occurs in the 1-2 years before pancreatic cancer diagnosis and may signal an upcoming diagnosis of pancreatic cancer.

Prediagnostic Inflammation and Pancreatic Cancer Survival.

BACKGROUND: Chronic inflammation may promote initiation and progression of pancreatic cancer, but no studies have examined the association between inflammation in the period before diagnosis and pancreatic cancer survival. METHODS: We prospectively examined the association of prediagnostic plasma levels of C-reactive protein, interleukin-6, and tumor necrosis factor-α receptor 2 with survival among 492 participants from 5 large US prospective cohort studies who developed pancreatic cancer. Using an empirical dietary inflammatory pattern (EDIP) score, we evaluated whether long-term proinflammatory diets were associated with survival among 1153 patients from 2 of the 5 cohorts. Cox proportional hazards regression was used to estimate hazard ratios for death with adjustment for potential confounders. All statistical tests were 2-sided. RESULTS: Higher prediagnostic levels of C-reactive protein, interleukin-6, and tumor necrosis factor-α receptor 2 were individually associated with reduced survival (Ptrend = .03, .01, and .04, respectively). Compared with patients with a combined inflammatory biomarker score of 0 (all 3 marker levels below medians), those with a score of 3 (all 3 marker levels above medians) had a hazard ratio for death of 1.57 (95% confidence interval = 1.16 to 2.12; Ptrend = .003), corresponding to median overall survival times of 8 vs 5 months. Patients consuming the most proinflammatory diets (EDIP quartile 4) in the prediagnostic period had a hazard ratio for death of 1.34 (95% confidence interval = 1.13 to 1.59; Ptrend = .01), compared with those consuming the least proinflammatory diets (EDIP quartile 1). CONCLUSION: Prediagnostic levels of inflammatory biomarkers and long-term proinflammatory diets were inversely associated with pancreatic cancer survival.

Burden of Pancreatic Cancer: From Epidemiology to Practice.

Pancreatic cancer is the seventh leading cause of cancer-related deaths worldwide with 432,242 related deaths in 2018. Unlike other cancers, the incidence of pancreatic cancer continues to increase, with little improvement in survival rates. We review the epidemiologic features of pancreatic cancer, covering surveillance and early detection in high-risk persons. We summarize data on worldwide incidence and mortality and analyze the 1975-2016 data from 9 registries of the National Cancer Institute's Surveillance, Epidemiology, and End Results study, on the overall burden of pancreatic cancer as well as age-, sex-, and race-specific incidence, survival rates and trends. It is important to increase our knowledge of the worldwide and regional epidemiologic features of and risk factors for pancreatic cancer, to identify new approaches for prevention, surveillance, and treatment.

Imaging-Based Subtypes of Pancreatic Ductal Adenocarcinoma Exhibit Differential Growth and Metabolic Patterns in the Pre-Diagnostic Period: Implications for Early Detection.

BACKGROUND: Previously, we characterized subtypes of pancreatic ductal adenocarcinoma (PDAC) on computed-tomography (CT) scans, whereby conspicuous (high delta) PDAC tumors are more likely to have aggressive biology and poorer clinical outcomes compared to inconspicuous (low delta) tumors. Here, we hypothesized that these imaging-based subtypes would exhibit different growth-rates and distinctive metabolic effects in the period prior to PDAC diagnosis. MATERIALS AND METHODS: Retrospectively, we evaluated 55 patients who developed PDAC as a second primary cancer and underwent serial pre-diagnostic (T0) and diagnostic (T1) CT-scans. We scored the PDAC tumors into high and low delta on T1 and, serially, obtained the biaxial measurements of the pancreatic lesions (T0-T1). We used the Gompertz-function to model the growth-kinetics and estimate the tumor growth-rate constant (α) which was used for tumor binary classification, followed by cross-validation of the classifier accuracy. We used maximum-likelihood estimation to estimate initiation-time from a single cell (10-6 mm3) to a 10 mm3 tumor mass. Finally, we serially quantified the subcutaneous-abdominal-fat (SAF), visceral-abdominal-fat (VAF), and muscles volumes (cm3) on CT-scans, and recorded the change in blood glucose (BG) levels. T-test, likelihood-ratio, Cox proportional-hazards, and Kaplan-Meier were used for statistical analysis and p-value <0.05 was considered significant. RESULTS: Compared to high delta tumors, low delta tumors had significantly slower average growth-rate constants (0.024 month-1 vs. 0.088 month-1, p<0.0001) and longer average initiation-times (14 years vs. 5 years, p<0.0001). α demonstrated high accuracy (area under the curve (AUC)=0.85) in classifying the tumors into high and low delta, with an optimal cut-off of 0.034 month-1. Leave-one-out-cross-validation showed 80% accuracy in predicting the delta-class (AUC=0.84). High delta tumors exhibited accelerated SAF, VAF, and muscle wasting (p <0.001), and BG disturbance (p<0.01) compared to low delta tumors. Patients with low delta tumors had better PDAC-specific progression-free survival (log-rank, p<0.0001), earlier stage tumors (p=0.005), and higher likelihood to receive resection after PDAC diagnosis (p=0.008), compared to those with high delta tumors. CONCLUSION: Imaging-based subtypes of PDAC exhibit distinct growth, metabolic, and clinical profiles during the pre-diagnostic period. Our results suggest that heterogeneous disease biology may be an important consideration in early detection strategies for PDAC.

Rapid Rectal Polyposis Development in a Patient With Familial Adenomatous Polyposis.

Familial adenomatous polyposis (FAP) is a well-described genetic condition that results in the development of multiple benign and malignant lesions throughout the gastrointestinal tract. The development of colorectal cancer is nearly universal in classic FAP, and total proctocolectomy after polyp development is recommended. We present a patient with FAP who was unable to undergo proctectomy. Despite careful removal of all rectal polyps before subtotal colectomy with ileorectal anastomosis, he developed 12 rectal polyps, including 4 advanced neoplastic lesions, within 73 days after initial endoscopic removal. This case highlights the rapid regrowth rate of colorectal adenomas in FAP.

Risk prediction rule for advanced neoplasia on screening colonoscopy for average-risk individuals.

BACKGROUND: In resource-limited countries, risk stratification can be used to optimize colorectal cancer screening. Few prospective risk prediction models exist for advanced neoplasia (AN) in true average-risk individuals. AIM: To create and internally validate a risk prediction model for detection of AN in average-risk individuals. METHODS: Prospective study of asymptomatic individuals undergoing first screening colonoscopy. Detailed characteristics including diet, exercise and medications were collected. Multivariate logistic regression was used to elucidate risk factors for AN (adenoma ≥1 cm, villous histology, high-grade dysplasia or carcinoma). The model was validated through bootstrapping, and discrimination and calibration of the model were assessed. RESULTS: 980 consecutive individuals (51% F; 49% M) were enrolled. Adenoma and AN detection rates were 36.6% (F 29%: M 45%; P < 0.001) and 5.1% (F 3.8%; M 6.5%) respectively. On multivariate analysis, predictors of AN [OR (95%CI)] were age [1.036 (1.00-1.07); P = 0.048], BMI [overweight 2.21 (0.98-5.00); obese 3.54 (1.48-8.50); P = 0.018], smoking [< 40 pack-years 2.01 (1.01-4.01); ≥ 40 pack-years 3.96 (1.86-8.42); P = 0.002], and daily red meat consumption [2.02 (0.92-4.42) P = 0.079]. Nomograms of AN risk were developed in terms of risk factors and age separately for normal, overweight and obese individuals. The model had good discrimination and calibration. CONCLUSION: The prevalence of adenoma and AN in average-risk Lebanese individuals is similar to the West. Age, smoking, and BMI are important predictors of AN, with obesity being particularly powerful. Though external validation is needed, this model provides an important platform for improved risk-stratification for screening programs in regions where universal screening is not currently employed.

Diabetes, Weight Change, and Pancreatic Cancer Risk.

Importance: Pancreatic cancer is the third-leading cause of cancer death in the United States; however, few high-risk groups have been identified to facilitate early diagnosis strategies. Objective: To evaluate the association of diabetes duration and recent weight change with subsequent risk of pancreatic cancer in the general population. Design, Setting, and Participants: This cohort study obtained data from female participants in the Nurses' Health Study and male participants in the Health Professionals Follow-Up Study, with repeated exposure assessments over 30 years. Incident cases of pancreatic cancer were identified from self-report or during follow-up of participant deaths. Deaths were ascertained through reports from the next of kin, the US Postal Service, or the National Death Index. Data collection was conducted from October 1, 2018, to December 31, 2018. Data analysis was performed from January 1, 2019, to June 30, 2019. Exposures: Duration of physician-diagnosed diabetes and recent weight change. Main Outcome and Measures: Hazard ratios (HRs) for subsequent development of pancreatic cancer. Results: Of the 112 818 women (with a mean [SD] age of 59.4 [11.7] years) and 46 207 men (with a mean [SD] age of 64.7 [10.8] years) included in the analysis, 1116 incident cases of pancreatic cancers were identified. Compared with participants with no diabetes, those with recent-onset diabetes had an age-adjusted HR for pancreatic cancer of 2.97 (95% CI, 2.31-3.82) and those with long-standing diabetes had an age-adjusted HR of 2.16 (95% CI, 1.78-2.60). Compared with those with no weight loss, participants who reported a 1- to 4-lb weight loss had an age-adjusted HR for pancreatic cancer of 1.25 (95% CI, 1.03-1.52), those with a 5- to 8-lb weight loss had an age-adjusted HR of 1.33 (95% CI, 1.06-1.66), and those with more than an 8-lb weight loss had an age-adjusted HR of 1.92 (95% CI, 1.58-2.32). Participants with recent-onset diabetes accompanied by weight loss of 1 to 8 lb (91 incident cases per 100 000 person-years [95% CI, 55-151]; HR, 3.61 [95% CI, 2.14-6.10]) or more than 8 lb (164 incident cases per 100 000 person-years [95% CI, 114-238]; HR, 6.75 [95% CI, 4.55-10.00]) had a substantially increased risk for pancreatic cancer compared with those with neither exposure (16 incident cases per 100 000 person-years; 95% CI, 14-17). Incidence rates were even higher among participants with recent-onset diabetes and weight loss with a body mass index of less than 25 before weight loss (400 incident cases per 100 000 person-years) or whose weight loss was not intentional judging from increased physical activity or healthier dietary choices (334 incident cases per 100 000 person-years). Conclusions and Relevance: This study demonstrates that recent-onset diabetes accompanied by weight loss is associated with a substantially increased risk for developing pancreatic cancer. Older age, previous healthy weight, and no intentional weight loss further elevate this risk.

Treatment of Esophageal Stricture After Lye Ingestion.

Caustic ingestions represent a well-known public health concern. Ingestion of highly alkali agents (lye ingestion) from the consumption of cleaning products is common, with an estimated 200,000 cases reported annually in the United States. Long-term complications of lye ingestion include esophageal strictures, gastric stenosis, and cancer. We describe a 53-year-old woman who suffered from lye ingestion as a child complicated by refractory esophageal strictures. Twenty years after esophagectomy and colon interposition, she developed debilitating dysphagia with daily regurgitation. The case highlights the long-term gastrointestinal consequences of lye ingestion and the evolution of endoscopic and surgical treatments of known complications.