Environmental drivers of the rising incidence of early-onset colorectal cancer in the United States.

Incidence of early-onset (diagnosed before age 50) colorectal cancer (EOCRC) has increased alarmingly since the 1990s in the United States. This study investigated what environmental exposures may have driven this increase. We obtained EOCRC incidence data from the Surveillance, Epidemiology, and End Results Program, and data for 11 exposures, for example, body mass index (BMI), from long-term national surveys. We aggregated these data for 30 to 49-year-olds during 1992 to 2016 by population subgroups defined by calendar period, age, race and sex, and used negative binomial regression models to identify and estimate associations of EOCRC with multiple exposures. Furthermore, we used counterfactual modeling to quantify contributions of identified risk factors to EOCRC incidence. The top models (with lowest Bayesian Information Criteria) consistently identified excess body weight, represented by overweight and obesity (BMI ≥25) or obesity alone (BMI ≥30), as the strongest risk factor. The best-performing model estimated increased EOCRC incidence due to overweight and obesity, with an incidence rate ratio (95% confidence interval) of 1.20 (1.17-1.22) for white men, 1.04 (1.00-1.08) for black men, 1.17 (1.15-1.21) for white women and 1.03 (0.97-1.08) for black women. Increases in overweight and obesity prevalence contributed to an estimated 30% (standard error: 1%) for men and 28% (standard error: 2%) for women of ECORC incidence during 1992 to 2016. These findings suggest excess body weight substantially contributed to and is likely a primary driver of the rising incidence of EOCRC in the United States. Prevention of excess weight gain may help lower colorectal cancer risk early in life.

Prevalence of Gastric Precursor Lesions in Countries With Differential Gastric Cancer Burden: A Systematic Review and Meta-analysis.

BACKGROUND & AIMS: The prevalence of precursor lesions for gastric cancer (GC) and the differential burden between countries of varying GC risk is not well-understood. We conducted a systematic review and meta-analysis to estimate the global prevalence of precursor lesions. METHODS: We estimated the prevalence of atrophic gastritis (AG), gastric intestinal metaplasia (IM), and dysplasia in regions with low, medium, and high GC incidence. Because IM is an advanced manifestation of AG, we assessed the prevalence of less advanced precursors, regardless of the presence of more advanced lesions. Prevalence was sub-stratified by Helicobacter pylori infection, symptomatology, and period (<2000, 2000-2010, and >2010). RESULTS: Among the 582 articles that underwent full-text review, 166 studies met inclusion criteria. The global prevalence estimates of AG, IM, and dysplasia were 25.4%, 16.2%, and 2.0%, respectively, on the basis of 126 studies that reported the prevalence of less advanced precursors, regardless of the presence of more advanced lesions. The prevalence of all precursor lesions was higher in high and medium compared with low GC incidence countries (P < .01). Prevalence of AG and IM was significantly higher among H pylori-infected individuals (P < .01) but not statistically different between symptomatic and asymptomatic individuals (P > .17). All precursors demonstrated a secular decrease in prevalence over time. CONCLUSIONS: Gastric precursor lesions have differences in prevalence in regions with differential GC incidence and are associated with H pylori infection. Because of the substantial prevalence of precursor lesions in both symptomatic and asymptomatic individuals, symptomatic evaluation may not be sufficient to identify individuals at risk. These estimates provide important insights for tailoring GC prevention strategies.

Endoscopic Surveillance of Intestinal Metaplasia of the Esophagogastric Junction: A Decision Modeling Analysis.

INTRODUCTION: The incidence of esophagogastric junction adenocarcinoma (EGJAC) has been rising. Intestinal metaplasia of the esophagogastric junction (EGJIM) is a common finding in gastroesophageal reflux (irregular Z-line) and may represent an early step in the development of EGJAC in the West. Worldwide, EGJIM may represent progression along the Correa cascade triggered by Helicobacter pylori . We sought to evaluate the cost-effectiveness of endoscopic surveillance of EGJIM. METHODS: We developed a decision analytic model to compare endoscopic surveillance strategies for 50-year-old patients after diagnosis of non-dysplastic EGJIM: (i) no surveillance (standard of care), (ii) endoscopy every 3 years, (iii) endoscopy every 5 years, or (iv) 1-time endoscopy at 3 years. We modeled 4 progression scenarios to reflect uncertainty: A (0.01% annual cancer incidence), B (0.05%), C (0.12%), and D (0.22%). RESULTS: Cost-effectiveness of endoscopic surveillance depended on the progression rate of EGJIM to cancer. At the lowest progression rate (scenario A, 0.01%), no surveillance strategies were cost-effective. In moderate progression scenarios, 1-time surveillance at 3 years was cost-effective, at $30,989 and $16,526 per quality-adjusted life year for scenarios B (0.05%) and C (0.12%), respectively. For scenario D (0.22%), surveillance every 5 years was cost-effective at $77,695 per quality-adjusted life year. DISCUSSION: Endoscopic surveillance is costly and can cause harm; however, low-intensity longitudinal surveillance (every 5 years) is cost-effective in populations with higher EGJAC incidence. No surveillance or 1-time endoscopic surveillance of patients with EGJIM was cost-effective in low-incidence populations. Future studies to better understand the natural history of EGJIM, identify risk factors of progression, and inform appropriate surveillance strategies are required.

Trends in uterine cancer incidence in the United States: The contribution of age, period and cohort effects.

OBJECTIVE: In the U.S., uterine cancer incidence is rising, with racial and ethnic minorities experiencing the largest increases. We performed age-period-cohort analyses using novel methods to examine the contribution of age at diagnosis (age), year of diagnosis (period), and birth cohort (cohort), to trends in uterine cancer incidence. METHODS: We used uterine cancer incidence data from the Surveillance, Epidemiology, and End Result (SEER) 12 database (1992-2019), and performed hysterectomy-correction. We generated hexamaps to visualize age, period, and cohort effects, and used mutual information to estimate the percent contribution of age, period, and cohort effects, individually and combined, on uterine cancer incidence, overall and by race and ethnicity and histology. RESULTS: Hexamaps showed an increase in uterine cancer in later time periods, and a cohort effect around 1933 showing a lower incidence compared with earlier and later cohorts. Age, period, and cohort effects combined contributed 86.6% (95% CI: 86.4%, 86.9%) to the incidence. Age effects had the greatest contribution (65.1%, 95% CI: 64.3%, 65.9), followed by cohort (20.7%, 95% CI: 20.1%, 21.3%) and period (14.2%, 95% CI: 13.7%, 14.8%) effects. Hexamaps showed higher incidence in recent years for non-Hispanic Blacks and non-endometrioid tumors. CONCLUSIONS: Age effects had the largest contribution to uterine cancer incidence, followed by cohort and period effects overall and across racial and ethnic groups and histologies. IMPACT: These findings can inform uterine cancer modeling studies on the effects of interventions that target risk factors which may vary across age, period, or cohort.

Excess morbidity and mortality associated with underuse of estrogen replacement therapy in premenopausal women who undergo surgical menopause.

BACKGROUND: Contrary to clinical guidelines, there has been a decrease over time in estrogen therapy use in premenopausal women undergoing bilateral oophorectomy for benign indications. OBJECTIVE: This study aimed to estimate the excess morbidity and mortality associated with current patterns of estrogen therapy use in women who undergo bilateral oophorectomy with hysterectomy for benign indications. STUDY DESIGN: We developed 2 Bayesian sampling Markov state-transition models to estimate the excess disease incidence (incidence model) and mortality (mortality model). The starting cohort for both models were women who had undergone bilateral oophorectomy with hysterectomy for benign indications at the age of 45 to 49 years. The models tracked outcomes in 5-year intervals for 25 years. The incidence model estimated excess incidence of breast cancer, lung cancer, colorectal cancer, coronary heart disease, and stroke, whereas the mortality model estimated excess mortality due to breast cancer, lung cancer, coronary heart disease, and all-other-cause mortality. The models compared current rates of estrogen therapy use with optimal (100%) use and calculated the mean difference in each simulated outcome to determine excess disease incidence and death. RESULTS: By 25 years after bilateral oophorectomy with hysterectomy, there were an estimated 94 (95% confidence interval, -158 to -23) fewer colorectal cancer cases, 658 (95% confidence interval, 339-1025) more coronary heart disease cases, and 881 (95% confidence interval, 402-1483) more stroke cases. By 25 years after bilateral oophorectomy with hysterectomy, there were an estimated 189 (95% confidence interval, 59-387) more breast cancer deaths, 380 (95% confidence interval, 114-792) more coronary heart disease deaths, and 759 (95% confidence interval, 307-1527) more all-other-cause deaths. In sensitivity analyses where we defined estrogen therapy use as a duration of >2 years of use, these differences increased >2-fold. CONCLUSION: Underuse of estrogen therapy in premenopausal women who undergo oophorectomy is associated with substantial excess morbidity and mortality.

Endoscopic Screening Program for Control of Esophageal Adenocarcinoma in Varied Populations: A Comparative Cost-Effectiveness Analysis.

BACKGROUND & AIMS: Guidelines suggest endoscopic screening for esophageal adenocarcinoma (EAC) among individuals with symptoms of gastroesophageal reflux disease (GERD) and additional risk factors. We aimed to determine at what age to perform screening and whether sex and race should influence the decision. METHODS: We conducted comparative cost-effectiveness analyses using 3 independent simulation models. For each combination of sex and race (White/Black, 100,000 individuals each), we considered 41 screening strategies, including one-time or repeated screening. The optimal strategy was that with the highest effectiveness and an incremental cost-effectiveness ratio <$100,000 per quality-adjusted life-year gained. RESULTS: Among White men, 536 EAC deaths were projected without screening, and screening individuals with GERD twice at ages 45 and 60 years was optimal. Screening the entire White male population once at age 55 years was optimal in 26% of probabilistic sensitivity analysis runs. Black men had fewer EAC deaths without screening (n = 84), and screening those with GERD once at age 55 years was optimal. Although White women had slightly more EAC deaths (n = 103) than Black men, the optimal strategy was no screening, although screening those with GERD once at age 55 years was optimal in 29% of probabilistic sensitivity analysis runs. Black women had a very low burden of EAC deaths (n = 29), and no screening was optimal, as benefits were very small and some strategies caused net harm. CONCLUSIONS: The optimal strategy for screening differs by race and sex. White men with GERD symptoms can potentially be screened more intensely than is recommended currently. Screening women is not cost-effective and may cause net harm for Black women.

Epidemiology of Gastric Malignancies 2000-2018 According to Histology: A Population-Based Analysis of Incidence and Temporal Trends.

BACKGROUND & AIMS: Gastric cancer (GC) remains a leading cause of cancer and cancer-related mortality. Recent reports suggest noncardia GC is increasing in certain U.S. POPULATIONS: However, whether these trends are driven by gastric adenocarcinoma (GA) or other histologies, including neuroendocrine tumors (NETs), lymphoma, or gastrointestinal stromal tumors (GISTs), is unclear. METHODS: We analyzed the Surveillance, Epidemiology and End Results-18 cancer registry (2000-2018) to determine age-standardized incidence rates (ASIR) and annual percentage change (APC) trends for histologically-confirmed GCs, stratified by anatomic location (noncardia vs cardia), age group (20-49 vs 50+ years), sex, race, and ethnicity. Joinpoint regression modeling estimated the statistical significance of trend comparisons. RESULTS: Of 74,520 individuals with noncardia GC, most (66.2%) were GA, with the next largest categories being non-mucosa-associated lymphoid tissue (non-MALT) lymphomas (6.9%), GIST (6.7%), NET (6.4%), and MALT lymphoma (5.6%). Noncardia GA ASIR was significantly higher than other histologies and demonstrated the greatest differences by race and ethnicity. APCs for GA and MALT, both Helicobacter pylori-associated cancers, declined significantly over time, which was driven primarily by trends among individuals ≥50 years-old. NET and GIST APCs significantly increased irrespective of age group, with the highest APCs observed among non-Hispanic white individuals. Cardia GC was rarer than noncardia GC and comprised primarily by GA (87.9%). Cardia GC incidence fell during the study period, which was primarily driven by decline in cardia GA. CONCLUSIONS: GA was the most common histology. On the basis of our findings, the rise in noncardia GC among certain U.S. populations appears predominantly driven by NET and GIST, not GA. Further studies are needed to clarify underlying etiologies for these findings.

Yield of Repeat Endoscopy for Barrett's Esophagus After Normal Index Endoscopy.

INTRODUCTION: Guidelines suggest 1-time screening with esophagogastroduodenoscopy (EGD) for Barrett's esophagus (BE) in individuals at an increased risk of esophageal adenocarcinoma (EAC). We aimed to estimate the yield of repeat EGD performed at prolonged intervals after a normal index EGD. METHODS: We conducted a national retrospective analysis within the U S Veterans Health Administration, identifying patients with a normal index EGD between 2003 and 2009 who subsequently had a repeat EGD. We tabulated the proportion with a new diagnosis of BE, EAC, or esophagogastric junction adenocarcinoma (EGJAC) and conducted manual chart review of a sample. We fitted logistic regression models for the odds of a new diagnosis of BE/EAC/EGJAC. RESULTS: We identified 71,216 individuals who had a repeat EGD between 1 and 16 years after an index EGD without billing or cancer registry codes for BE/EAC/EGJAC. Of them, 4,088 had a new billing or cancer registry code for BE/EAC/EGJAC after the repeat EGD. On manual review of a stratified sample, most did not truly have new BE/EAC/EGJAC. A longer duration between EGD was associated with greater odds of a new diagnosis (adjusted odds ratio [aOR] for each 5 years 1.31; 95% confidence interval [CI] 1.19-1.44), particularly among those who were younger during the index EGD (ages 19-29 years: aOR 3.92; 95% CI 1.24-12.4; ages 60-69 years: aOR 1.19; 95% CI 1.01-1.40). DISCUSSION: The yield of repeat EGD for BE/EAC/EGJAC seems to increase with time after a normal index EGD, particularly for younger individuals. Prospective studies are warranted to confirm these findings.

Dostarlimab for recurrent mismatch repair-deficient endometrial cancer: A cost-effectiveness study.

OBJECTIVE: Patients with recurrent endometrial cancer treated with carboplatin and paclitaxel whose disease progresses have few effective treatment options. Based on promising clinical trial data, the anti-programmed cell death 1 (anti-PD-1) antibody dostarlimab was recently granted accelerated approval for endometrial cancer by the US Food and Drug Administration. We developed a decision model to examine the cost-effectiveness of dostarlimab for patients with progressive/recurrent deficient mismatch repair (dMMR) endometrial cancer whose disease has progressed with first-line chemotherapy. DESIGN: Cost-effectiveness study. POPULATION: Hypothetical cohort of 6000 women with progressive/recurrent dMMR endometrial cancer. METHODS: The initial decision point in the Markov model was treatment with dostarlimab, pembrolizumab or pegylated liposomal doxorubicin (PLD). Model probabilities, and cost and utility values were derived with assumptions drawn from published literature. Effectiveness was estimated as average quality-adjusted life years (QALYs) gained. One-way, two-way and probabilistic sensitivity analyses were performed to vary the assumptions across a range of plausible values. MAIN OUTCOME MEASURES: The primary outcome was the incremental cost-effectiveness ratio (ICER). RESULTS: Pegylated liposomal doxorubicin (PLD) was the least costly strategy, at $55,732, followed by dostarlimab ($151,533) and pembrolizumab ($154,597). Based on a willingness-to-pay threshold of $100,000/QALY, PLD was cost-effective compared with dostarlimab, with an ICER of $331,913 per QALY gained for dostarlimab, whereas pembrolizumab was ruled out by extended dominance (less effective, more costly), compared with dostarlimab. In one-way sensitivity analyses, dostarlimab was cost-effective when its cost was reduced to $4905 (52% reduction). These results were robust in a variety of sensitivity analyses. CONCLUSIONS: Dostarlimab is associated with greater survival compared with other treatments for women with recurrent dMMR endometrial cancer. Although the agent is substantially more costly, dostarlimab became cost-effective when its cost was reduced to $5489 per cycle.

Hysterectomy Trends and Risk of Vaginal Cuff Dehiscence: An Update by Mode of Surgery.

STUDY OBJECTIVE: To analyze hysterectomy trends and vaginal cuff dehiscence (VCD) rates by mode of surgery at a tertiary care medical center and to describe characteristics of VCD cases. DESIGN: Observational retrospective cohort study. SETTING: Large academic hospital and affiliated community hospital. PATIENTS: 4722 patients who underwent hysterectomy at Columbia University Irving Medical Center between January 2010 and August 2021. INTERVENTIONS: Current Procedural Terminology and International Classification of Diseases codes identified hysterectomies and VCD cases. Hysterectomy trends and VCD rates were calculated by mode of surgery. Relative risks of VCD for each mode were compared with total abdominal hysterectomy (TAH). Clinical characteristics of VCDs were reviewed. MEASUREMENTS AND MAIN RESULTS: There were 4059 total hysterectomies. Laparoscopic hysterectomies, including total laparoscopic hysterectomies (TLHs), laparoscopic-assisted vaginal hysterectomies, and robot-assisted TLHs (RA-TLHs), increased from 41.9% in 2010 to 65.9% in 2021 (p <.001). RA-TLH increased from 5.7% in 2010 to 40.2% in 2021. Supracervical hysterectomies followed similar trends and were excluded from VCD analysis. There were 15 VCDs (overall rate 0.37%). VCD was highest after RA-TLH (0.66%), followed by TLH (0.32%) and TAH (0.27%), with no VCDs after laparoscopic-assisted vaginal hysterectomy or total vaginal hysterectomy. Compared with TAH, the relative risk for VCD after RA-TLH was 2.44 (95% confidence interval 0.66-9.00) and after TLH was 1.18 (95% confidence interval 0.24-5.83), which were not statistically significant. The mean time to dehiscence was 39 days (range 8-145 days). The most common trigger event was coitus (41%). CONCLUSION: VCD rates were low (<1%) for all modes of hysterectomy, and rates after robotic and laparoscopic hysterectomy were much lower than previously reported. Although VCD rates trended higher after robotic and laparoscopic hysterectomy compared with abdominal hysterectomy, the difference was not significant. It is difficult to determine whether this finding represents true lack of difference vs a lack of power to detect a significant difference given the rarity of VCD.

Risk of corticosteroid treatment and hospitalization after checkpoint inhibitor and radiation therapy in patients with cancer.

BACKGROUND: Immune checkpoint inhibitors (ICIs) are potent new cancer therapies but can cause serious immune-related adverse events. ICIs have contributed significantly to improved survival and thereby provide more opportunity for the development of local disease symptomatology requiring palliative radiation. Radiation therapy (RT) has also recently shown benefit in the oligometastatic setting. Data on the interaction and safety of concurrent ICIs and RT are limited. METHODS: In this retrospective cohort study using a large medical claims database from 2010 to 2017, the need for corticosteroid therapy and the risk of hospitalization within 180 days of treatment with an ICI were determined for patients with a diagnosis of malignant melanoma or lung cancer. Patients were stratified by the use of RT within the 30 days before and after ICI therapy. RESULTS: In all, 2020 patients (218 with RT and 1802 without RT) met the inclusion criteria for prednisone analysis, whereas 3519 patients (361 with RT and 3158 without RT) met the inclusion criteria for all other analyses. In a univariable analysis, RT was not associated with the need for prednisone (relative risk [RR], 1.2; 95% confidence interval [CI], 0.8-1.9) or methylprednisolone (RR, 1.1; 95% CI, 0.7-2.0). When the end point was hospitalization, RT was significantly associated with hospitalization after ICI therapy for certain cancer/drug combinations (RR for lung cancer/programmed death 1 receptor inhibitors, 1.4; 95% CI, 1.2-1.6; P < .001; RR for melanoma/ipilimumab, 2.0; 95% CI, 1.0-3.5; P = .03). CONCLUSIONS: In patients treated with ICIs, receiving RT was not associated with a higher risk of requiring corticosteroid therapy in comparison with not receiving RT. However, RT was associated with a higher risk of hospitalization, although this finding may be a result of differences in the underlying patient illness severity or oncologic disease burden at the baseline. LAY SUMMARY: Data on the interaction of immunotherapy (immune checkpoint inhibitors) and radiation therapy and the safety of combining them are limited. Using a large database, this study has found that patients treated concurrently with immune checkpoint inhibitors and radiation therapy are not at increased risk for requiring corticosteroid therapy (which is used as a proxy for immune-related adverse events). However, concurrent therapy is associated with a higher risk of hospitalization, although this finding may be due to differences in the underlying patient illness severity (sicker patients may require both immunotherapy and radiation therapy).

Gene-Specific Variation in Colorectal Cancer Surveillance Strategies for Lynch Syndrome.

BACKGROUND AND AIMS: Lynch syndrome is associated with pathogenic variants in 4 mismatch repair (MMR) genes that increase lifetime risk of colorectal cancer. Guidelines recommend intensive colorectal cancer surveillance with colonoscopy every 1-2 years starting at age 25 years for all carriers of Lynch syndrome-associated variants, regardless of gene product. We constructed a simulation model to analyze the effects of different ages of colonoscopy initiation and surveillance intervals for each MMR gene (MLH1, MSH2, MSH6, and PMS2) on colorectal cancer incidence and mortality, quality-adjusted life-years, and cost. METHODS: Using published literature, we developed a Markov simulation model of Lynch syndrome progression for patients with each MMR variant. The model simulated clinical trials of Lynch syndrome carriers, varying age of colonoscopy initiation (5-year increments from 25-40 years), and surveillance intervals (1-5 years). We assessed the optimal strategy for each gene, defined as the strategy with the highest quality-adjusted life-years and incremental cost-effectiveness ratio below a $100,000 willingness-to-pay threshold. RESULTS: Optimal surveillance for patients with pathogenic variants in the MLH1 and MSH2 genes was colonoscopy starting at age 25 years, with 1- to 2-year surveillance intervals. Initiating colonoscopy at age 35 and 40 years, with 3-year intervals, was cost-effective for patients with pathogenic variants in MSH6 or PMS2, respectively. CONCLUSIONS: We developed a simulation model to select optimal surveillance starting ages and intervals for patients with Lynch syndrome based on MMR variant. The model supports recommendations for intensive surveillance of patients with Lynch syndrome-associated variants in MLH1 or MSH2. However, for patients with Lynch syndrome-associated variants of MSH6 or PMS2, later initiation of surveillance at 35 and 40 years, respectively, and at 3-year intervals, can be considered.

Utility and Cost-Effectiveness of a Nonendoscopic Approach to Barrett's Esophagus Surveillance After Endoscopic Therapy.

BACKGROUND & AIMS: A non-endoscopic approach to Barrett's esophagus (BE) surveillance after radiofrequency ablation (RFA) would offer a less invasive method for monitoring. We assessed the test characteristics and cost-effectiveness of the Cytosponge (Medtronic, Minneapolis, MN) in post-RFA patients. METHODS: We performed a multicenter study of dysplastic BE patients after at least one round of RFA. A positive Cytosponge before endoscopy was defined as intestinal metaplasia (IM) on cytological assessment and/or TFF3 immunohistochemistry. Sensitivity, specificity, and receiver operator characteristic (ROC) curves were calculated. Multivariable regression was used to estimate the odds of a positive Cytosponge in BE. A microsimulation cost-effectiveness model was performed to assess outcomes of various surveillance strategies: endoscopy-only, Cytosponge-only, and alternating endoscopy/Cytosponge. RESULTS: Of 234 patients, Cytosponge adequately sampled the distal esophagus in 175 (75%). Of the 142 with both endoscopic and histologic data, 19 (13%) had residual/recurrent BE. For detecting any residual Barrett's, Cytosponge had a sensitivity of 74%, specificity of 85%, accuracy of 84%, and ROC curve showed an area under the curve of 0.74. The adjusted odds of a positive Cytosponge in BE were 17.1 (95% CI, 5.2-55.9). Cytosponge-only surveillance dominated all the surveillance strategies, being both less costly and more effective. Cytosponge-only surveillance required <1/4th the endoscopies, resulting in only 0.69 additional EAC cases/1000 patients, and no increase in EAC deaths when compared to currently-practiced endoscopy-only surveillance. CONCLUSIONS: A positive Cytosponge test was strongly associated with residual BE after ablation. While the assay needs further refinement in this context, it could serve as a cost-effective surveillance examination.

The Optimal Age to Stop Endoscopic Surveillance of Patients With Barrett's Esophagus Based on Sex and Comorbidity: A Comparative Cost-Effectiveness Analysis.

BACKGROUND AND AIMS: Current guidelines recommend surveillance for patients with nondysplastic Barrett's esophagus (NDBE) but do not include a recommended age for discontinuing surveillance. This study aimed to determine the optimal age for last surveillance of NDBE patients stratified by sex and level of comorbidity. METHODS: We used 3 independently developed models to simulate patients diagnosed with NDBE, varying in age, sex, and comorbidity level (no, mild, moderate, and severe). All patients had received regular surveillance until their current age. We calculated incremental costs and quality-adjusted life-years (QALYs) gained from 1 additional endoscopic surveillance at the current age versus not performing surveillance at that age. We determined the optimal age to end surveillance as the age at which incremental cost-effectiveness ratio of 1 more surveillance was just less than the willingness-to-pay threshold of $100,000/QALY. RESULTS: The benefit of having 1 more surveillance endoscopy strongly depended on age, sex, and comorbidity. For men with NDBE and severe comorbidity, 1 additional surveillance at age 80 years provided 4 more QALYs per 1000 patients with BE at an additional cost of $1.2 million, whereas for women with severe comorbidity the benefit at that age was 7 QALYs at a cost of $1.3 million. For men with no, mild, moderate, and severe comorbidity, the optimal ages of last surveillance were 81, 80, 77, and 73 years, respectively. For women, these ages were younger: 75, 73, 73, and 69 years, respectively. CONCLUSIONS: Our comparative modeling analysis illustrates the importance of considering comorbidity status and sex when deciding on the age to discontinue surveillance in patients with NDBE.

Genetic testing to guide screening for pancreatic ductal adenocarcinoma: Results of a microsimulation model.

BACKGROUND: First-degree relatives (FDRs) of patients with pancreatic ductal adenocarcinoma (PDAC) have elevated PDAC risk, partially due to germline genetic variants. We evaluated the potential effectiveness of genetic testing to target MRI-based screening among FDRs. METHODS: We used a microsimulation model of PDAC, calibrated to Surveillance, Epidemiology, and End Results (SEER) data, to estimate the potential life expectancy (LE) gain of screening for each of the following groups of FDRs: individuals who test positive for each of eight variants associated with elevated PDAC risk (e.g., BRCA2, CDKN2A); individuals who test negative; and individuals who do not test. Screening was assumed to take place if LE gains were achievable. We simulated multiple screening approaches, defined by starting age and frequency. Sensitivity analysis evaluated changes in results given varying model assumptions. RESULTS: For women, 92% of mutation carriers had projected LE gains from screening for PDAC, if screening strategies (start age, frequency) were optimized. Among carriers, LE gains ranged from 0.1 days (ATM+ women screened once at age 70) to 510 days (STK11+ women screened annually from age 40). For men, LE gains were projected for all mutation carriers, ranging from 0.2 days (BRCA1+ men screened once at age 70) to 620 days (STK11+ men screened annually from age 40). For men and women who did not undergo genetic testing, or for whom testing showed no variant, screening yielded small LE benefit (0-2.1 days). CONCLUSIONS: Genetic testing of FDRs can inform targeted PDAC screening by identifying which FDRs may benefit.

Short and long-term outcomes of prophylactic total gastrectomy in 54 consecutive individuals with germline pathogenic mutations in the CDH1 gene.

BACKGROUND: Germline mutation of CDH1 is rare and leads to hereditary diffuse gastric cancer (DGC). METHODS: Patients (pts) with CDH1 mutation who underwent multidisciplinary counseling followed by open prophylactic total gastrectomy (PTG) by a single surgeon were reviewed. RESULTS: Fifty-four pts with a median age of 41 years (16-70 years) underwent PTG between 2006 and 2021. Median operative time was 161 min, and median hospital stay was 7 days (range 6-12). There were 5 complications (9.2%) within 30 days, and two complications (pulmonary embolism and pancreatitis) required readmission. There were no anastomotic leaks. The pathologic analysis of the first 10 pts included the entire gastric mucosa, revealing a median of 15 foci of DGC (range 5-136). The subsequent 44 pts with more limited analysis had a median of 2 foci (range 0-5), and two pts (3.7%) had no foci identified. Median maximum weight loss was 19%. In long-term follow-up (median 4.6 years) of 20 pts, median global QOL was 2.0 (very good), the majority had persistent difficulty with certain foods or liquids, and all stated they would again elect PTG over surveillance endoscopy. CONCLUSIONS: PTG can be performed safely at high-volume referral centers with very good QOL but nutritional sequelae persist.

Immunogenetics of gastrointestinal cancers: A systematic review and retrospective survey of inborn errors of immunity in humans.

BACKGROUND AND AIM: Humans with inborn errors of immunity (IEI), or primary immunodeficiencies, may be associated with a potential risk factor for early-onset gastrointestinal (GI) cancer. METHODS: We systematically reviewed all cases with clinical diagnoses of both an IEI and a GI cancer in three databases (MEDLINE, SCOPUS, and EMBASE). In total, 76 publications satisfying our inclusion criteria were identified, and data for 149 cases were analyzed. We also searched our institutional cancer registry for such cases. RESULTS: We identified 149 patients with both an IEI and a GI cancer, 95 presented gastric cancer, 13 small bowel cancer, 35 colorectal cancer, and 6 had an unspecified cancer or cancer at another site. Gastric and colon adenocarcinomas were the most common. For both gastric and colorectal cancers, age at onset was significantly earlier in patients with IEIs than in the general population, based on the SEER database. Common variable immunodeficiency (CVID) was the most common IEI associated with gastrointestinal cancer. About 12% of patients had molecular genetic diagnoses, the three most frequently implicated genes being ATM, CARMIL2, and CTLA4. Impaired humoral immunity and Epstein-Barr virus (EBV) infection were frequently reported as factors potentially underlying early-onset GI cancers in patients with IEIs. We identified one patient with CVID and early-onset gastric adenocarcinoma, recurrent diarrhea, and gastrointestinal CMV infection from a retrospective survey. CONCLUSION: Patients with IEIs should be considered at risk of early-onset GI cancers and should therefore undergo cancer screening at an earlier age.

Deep learning on time series laboratory test results from electronic health records for early detection of pancreatic cancer.

The multi-modal and unstructured nature of observational data in Electronic Health Records (EHR) is currently a significant obstacle for the application of machine learning towards risk stratification. In this study, we develop a deep learning framework for incorporating longitudinal clinical data from EHR to infer risk for pancreatic cancer (PC). This framework includes a novel training protocol, which enforces an emphasis on early detection by applying an independent Poisson-random mask on proximal-time measurements for each variable. Data fusion for irregular multivariate time-series features is enabled by a "grouped" neural network (GrpNN) architecture, which uses representation learning to generate a dimensionally reduced vector for each measurement set before making a final prediction. These models were evaluated using EHR data from Columbia University Irving Medical Center-New York Presbyterian Hospital. Our framework demonstrated better performance on early detection (AUROC 0.671, CI 95% 0.667 - 0.675, p < 0.001) at 12 months prior to diagnosis compared to a logistic regression, xgboost, and a feedforward neural network baseline. We demonstrate that our masking strategy results greater improvements at distal times prior to diagnosis, and that our GrpNN model improves generalizability by reducing overfitting relative to the feedforward baseline. The results were consistent across reported race. Our proposed algorithm is potentially generalizable to other diseases including but not limited to cancer where early detection can improve survival.

Endoscopic Balloon Dilation Is Cost-Effective for Crohn's Disease Strictures.

BACKGROUND: Endoscopic balloon dilation (EBD) has emerged as an alternative intervention to manage Crohn's disease (CD) strictures. We determined the cost-effectiveness of EBD versus resection surgery for patients with short (< 4-5 cm) primary or secondary/anastomotic small or large bowel strictures. METHODS: A microsimulation state-transition model analyzed the benefits and risks of EBD and resection surgery for patients with primary or anastomotic CD strictures. Our primary outcome was quality-adjusted life years (QALYs) over ten years, and strategies were compared using a willingness to pay of $100,000/QALY from a societal perspective. Costs (2021 $US) and incremental cost-effectiveness ratios (ICER) were calculated. Deterministic 1-way and probabilistic analyses assessed model uncertainty. RESULTS: The EBD strategy cost $19,822 and resulted in 6.18 QALYs while the surgery strategy cost $41,358 and resulted in 6.37 QALYs. Surgery had an ICER of $113,332 per QALY, making EBD a cost-effective strategy. The median number of EBDs was 5 in the EBD strategy and 0 in the surgery strategy. The median number of surgeries was 2 in the surgery strategy and 1 in the EBD strategy. Of individuals who initially received EBD, 50.4% underwent subsequent surgery. One-way sensitivity analyses showed that the probabilities of requiring repeated interventions, surgery mortality (< 0.7%), and quality of life after interventions were the most influential model parameters. Probabilistic sensitivity analyses favored EBD in 50.9% of iterations. CONCLUSIONS: EBD is a cost-effective strategy for managing CD strictures. Differences in patient risk and quality of life after intervention impact cost-effectiveness. Intervention decisions should consider cost-effectiveness, patient risks, and quality of life.

Prevalence of Extensive and Limited Gastric Intestinal Metaplasia and Progression to Dysplasia and Gastric Cancer.

BACKGROUND AND AIMS: Guidelines cite extensive gastric intestinal metaplasia (GIM) as a bigger risk factor for gastric cancer (GC) than limited GIM and an indication for endoscopic surveillance. Data on progression of extensive GIM to GC in the USA are limited. This study aimed to estimate the prevalence and progression rates of extensive GIM in a US cohort. METHODS: This retrospective study assessed the prevalence of extensive GIM between 1/1/1990 and 8/1/2019 at a large academic medical center. Multivariable regression was used to identify predictors of extensive GIM. Incidence of GC on follow-up was calculated as number of new diagnoses divided by person-years of follow-up. Presence of GIM on subsequent follow-up endoscopy was assessed. RESULTS: Of 1256 individuals with GIM, 352 (28%) had extensive GIM and 904 (72%) had limited GIM. On multivariable analysis, older age (OR 1.01, 95% CI 1.00-1.02) and Hispanic ethnicity (OR 1.55, 95% CI 1.11-2.16) were predictive of extensive GIM. The annual incidence of GC for GIM overall was 0.09%. There was no difference in progression to GC between extensive or limited GIM (IRR 0, 95% CI 0-2.6), or to advanced lesions overall (IRR 0.37, 95% CI 0.04-1.62). 70% of individuals had persistent GIM on follow-up biopsy, and 22% with limited GIM had extensive GIM on follow-up biopsy. CONCLUSIONS: 28% of individuals with GIM have the extensive subtype, and are more likely to be older and of Hispanic ethnicity. There was no difference in progression to GC between extensive and limited GIM. Further research is needed to better assess risk of GIM in the US context.