How Would You Screen This Patient for Colorectal Cancer?: Grand Rounds Discussion From Beth Israel Deaconess Medical Center: Annals of Internal Medicine: Vol 175, No 10

Colorectal cancer (CRC) is the third leading cause of cancer death for men and women in the United States, with an estimated 52 580 people expected to die in 2022. Most frequently, CRC is diagnosed among persons aged 65 to 74 years. However, among persons younger than 50 years, incidence rates have been increasing since the mid-1990s. In 2021, partially because of the rising incidence, the U.S. Preventive Services Task Force (USPSTF) recommended CRC screening for adults aged 45 to 49 years (Grade B recommendation). Options for CRC screening include stool-based and direct visualization tests. The USPSTF did not recommend a specific screening test; rather, its guidance was to select a test after a discussion with the patient. Here, a primary care physician and a gastroenterologist discuss the recommendation to begin CRC screening at age 45, review options for CRC screening, and discuss how to choose among the available options.

Effectiveness of mRNA COVID-19 Vaccine Boosters Against Infection, Hospitalization, and Death: A Target Trial Emulation in the Omicron (B.1.1.529) Variant Era

Background: The effectiveness of a third mRNA COVID-19 vaccine dose (booster dose) against the Omicron (B.1.1.529) variant is uncertain, especially in older, high-risk populations. Objective: To determine mRNA booster vaccine effectiveness (VE) against SARS-CoV-2 infection, hospitalization, and death in the Omicron era by booster type, primary vaccine type, time since primary vaccination, age, and comorbidity burden. Design: Retrospective matched cohort study designed to emulate a target trial of booster vaccination versus no booster, conducted from 1 December 2021 to 31 March 2022. Setting: U.S. Department of Veterans Affairs health care system. Participants: Persons who had received 2 mRNA COVID-19 vaccine doses at least 5 months earlier. Intervention: Booster monovalent mRNA vaccination (Pfizer–BioNTech's BNT162b2 or Moderna's mRNA-1273) versus no booster. Measurements: Booster VE. Results: Each group included 490 838 well-matched persons, who were predominantly male (88%), had a mean age of 63.0 years (SD, 14.0), and were followed for up to 121 days (mean, 79.8 days). Booster VE more than 10 days after a booster dose was 42.3% (95% CI, 40.6% to 43.9%) against SARS-CoV-2 infection, 53.3% (CI, 48.1% to 58.0%) against SARS-CoV-2–related hospitalization, and 79.1% (CI, 71.2% to 84.9%) against SARS-CoV-2–related death. Booster VE was similar for different booster types (BNT162b2 or mRNA-1273), age groups, and primary vaccination regimens but was significantly higher with longer time since primary vaccination and higher comorbidity burden. Limitation: Predominantly male population. Conclusion: Booster mRNA vaccination was highly effective in preventing death and moderately effective in preventing infection and hospitalization for up to 4 months after administration in the Omicron era. Increased uptake of booster vaccination, which is currently suboptimal, should be pursued to limit the morbidity and mortality of SARS-CoV-2 infection, especially in persons with high comorbidity burden. Primary Funding Source: U.S. Department of Veterans Affairs.

Effect of Calorie-Unrestricted Low-Carbohydrate, High-Fat Diet Versus High-Carbohydrate, Low-Fat Diet on Type 2 Diabetes and Nonalcoholic Fatty Liver Disease: A Randomized Controlled Trial: Annals of Internal Medicine: Vol 176, No 1

Background: It remains unclear if a low-carbohydrate, high-fat (LCHF) diet is a possible treatment strategy for type 2 diabetes mellitus (T2DM), and the effect on nonalcoholic fatty liver disease (NAFLD) has not been investigated. Objective: To investigate the effect of a calorie-unrestricted LCHF diet, with no intention of weight loss, on T2DM and NAFLD compared with a high-carbohydrate, low-fat (HCLF) diet. Design: 6-month randomized controlled trial with a 3-month follow-up. (ClinicalTrials.gov: NCT03068078) Setting: Odense University Hospital in Denmark from November 2016 until June 2020. Participants: 165 participants with T2DM. Intervention: Two calorie-unrestricted diets: LCHF diet with 50 to 60 energy percent (E%) fat, less than 20E% carbohydrates, and 25E% to 30E% proteins and HCLF diet with 50E% to 60E% carbohydrates, 20E% to 30E% fats, and 20E% to 25E% proteins. Measurements: Glycemic control, serum lipid levels, metabolic markers, and liver biopsies to assess NAFLD. Results: The mean age was 56 years (SD, 10), and 58% were women. Compared with the HCLF diet, participants on the LCHF diet had greater improvements in hemoglobin A1c (mean difference in change, −6.1 mmol/mol [95% CI, −9.2 to −3.0 mmol/mol] or −0.59% [CI, −0.87% to −0.30%]) and lost more weight (mean difference in change, −3.8 kg [CI, −6.2 to −1.4 kg]). Both groups had higher high-density lipoprotein cholesterol and lower triglycerides at 6 months. Changes in low-density lipoprotein cholesterol were less favorable in the LCHF diet group than in the HCLF diet group (mean difference in change, 0.37 mmol/L [CI, 0.17 to 0.58 mmol/L] or 14.3 mg/dL [CI, 6.6 to 22.4 mg/dL]). No statistically significant between-group changes were detected in the assessment of NAFLD. Changes were not sustained at the 9-month follow-up. Limitation: Open-label trial, self-reported adherence, unintended weight loss, and lack of adjustment for multiple comparisons. Conclusion: Persons with T2DM on a 6-month, calorie-unrestricted, LCHF diet had greater clinically meaningful improvements in glycemic control and weight compared with those on an HCLF diet, but the changes were not sustained 3 months after intervention. Primary Funding Source: Novo Nordisk Foundation.

Comparison of Over-the-Scope Clips to Standard Endoscopic Treatment as the Initial Treatment in Patients With Bleeding From a Nonvariceal Upper Gastrointestinal Cause: A Randomized Controlled Trial: Annals of Internal Medicine: Vol 176, No 4

Background: Current endoscopic methods in the control of acute nonvariceal bleeding have a small but clinically significant failure rate. The role of over-the-scope clips (OTSCs) as the first treatment has not been defined. Objective: To compare OTSCs with standard endoscopic hemostatic treatments in the control of bleeding from nonvariceal upper gastrointestinal causes. Design: A multicenter, randomized controlled trial. (ClinicalTrials.gov: NCT03216395) Setting: University teaching hospitals in Hong Kong, China, and Australia. Patients: 190 adult patients with active bleeding or a nonbleeding visible vessel from a nonvariceal cause on upper gastrointestinal endoscopy. Intervention: Standard hemostatic treatment (n = 97) or OTSC (n = 93). Measurements: The primary outcome was 30-day probability of further bleeds. Other outcomes included failure to control bleeding after assigned endoscopic treatment, recurrent bleeding after initial hemostasis, further intervention, blood transfusion, and hospitalization. Results: The 30-day probability of further bleeding in the standard treatment and OTSC groups was 14.6% (14 of 97) and 3.2% (3 of 93), respectively (risk difference, 11.4 percentage points [95% CI, 3.3 to 20.0 percentage points]; P = 0.006). Failure to control bleeding after assigned endoscopic treatment in the standard treatment and OTSC groups was 6 versus 1 (risk difference, 5.1 percentage points [CI, 0.7 to 11.8 percentage points]), respectively, and 30-day recurrent bleeding was 8 versus 2 (risk difference, 6.6 percentage points [CI, −0.3 to 14.4 percentage points]), respectively. The need for further interventions was 8 versus 2, respectively. Thirty-day mortality was 4 versus 2, respectively. In a post hoc analysis with a composite end point of failure to successfully apply assigned treatment and further bleeds, the event rate was 15 of 97 (15.6%) and 6 of 93 (6.5%) in the standard and OTSC groups, respectively (risk difference, 9.1 percentage points [CI, 0.004 to 18.3 percentage points]). Limitation: Clinicians were not blinded to treatment and the option of crossover treatment. Conclusion: Over-the-scope clips, as an initial treatment, may be better than standard treatment in reducing the risk for further bleeding from nonvariceal upper gastrointestinal causes that are amenable to OTSC placement. Primary Funding Source: General Research Fund to the University Grant Committee, Hong Kong SAR Government.

Oral ENT-01 Targets Enteric Neurons to Treat Constipation in Parkinson Disease: A Randomized Controlled Trial: Annals of Internal Medicine: Vol 175, No 12

Background: Parkinson disease (PD) is associated with α-synuclein (αS) aggregation within enteric neurons. ENT-01 inhibits the formation of αS aggregates and improved constipation in an open-label study in patients with PD. Objective: To evaluate the safety and efficacy of oral ENT-01 for constipation and neurologic symptoms in patients with PD and constipation. Design: Randomized, placebo-controlled phase 2b study. (ClinicalTrials.gov: NCT03781791) Setting: Outpatient. Patients: 150 patients with PD and constipation. Intervention: ENT-01 or placebo daily for up to 25 days. After baseline assessment of constipation severity, daily dosing was escalated to the prokinetic dose, the maximum dose (250 mg), or the tolerability limit, followed by a washout period. Measurements: The primary efficacy end point was the number of complete spontaneous bowel movements (CSBMs) per week. Neurologic end points included dementia (assessed using the Mini-Mental State Examination [MMSE]) and psychosis (assessed using the Scale for the Assessment of Positive Symptoms adapted for PD [SAPS-PD]). Results: The weekly CSBM rate increased from 0.7 to 3.2 in the ENT-01 group versus 0.7 to 1.2 in the placebo group (P < 0.001). Improvement in secondary end points included SBMs (P = 0.002), stool consistency (P < 0.001), ease of passage (P = 0.006), and laxative use (P = 0.041). In patients with dementia, MMSE scores improved by 3.4 points 6 weeks after treatment in the ENT-01 group (n = 14) versus 2.0 points in the placebo group (n = 14). Among patients with psychosis, SAPS-PD scores improved from 6.5 to 1.7 six weeks after treatment in the ENT-01 group (n = 5) and from 6.3 to 4.4 in the placebo group (n = 6). ENT-01 was well tolerated, with no deaths or drug-related serious adverse events. Adverse events were predominantly gastrointestinal, including nausea (34.4% [ENT-01] vs. 5.3% [placebo]; P < 0.001) and diarrhea (19.4% [ENT-01] vs. 5.3% [placebo]; P = 0.016). Limitation: Longer treatment periods need to be investigated in future studies. Conclusion: ENT-01 was safe and significantly improved constipation. Primary Funding Source: Enterin, Inc.

Evaluation of Harms Reporting in U.S. Cancer Screening Guidelines

Background: Cancer screening should be recommended only when the balance between benefits and harms is favorable. This review evaluated how U.S. cancer screening guidelines reported harms, within and across organ-specific processes to screen for cancer. Objective: To describe current reporting practices and identify opportunities for improvement. Design: Review of guidelines. Setting: United States. Patients: Patients eligible for screening for breast, cervical, colorectal, lung, or prostate cancer according to U.S. guidelines. Measurements: Information was abstracted on reporting of patient-level harms associated with screening, diagnostic follow-up, and treatment. The authors classified harms reporting as not mentioned, conceptual, qualitative, or quantitative and noted whether literature was cited when harms were described. Frequency of harms reporting was summarized by organ type. Results: Harms reporting was inconsistent across organ types and at each step of the cancer screening process. Guidelines did not report all harms for any specific organ type or for any category of harm across organ types. The most complete harms reporting was for prostate cancer screening guidelines and the least complete for colorectal cancer screening guidelines. Conceptualization of harms and use of quantitative evidence also differed by organ type. Limitations: This review considers only patient-level harms. The authors did not verify accuracy of harms information presented in the guidelines. Conclusion: The review identified opportunities for improving conceptualization, assessment, and reporting of screening process–related harms in guidelines. Future work should consider nuances associated with each organ-specific process to screen for cancer, including which harms are most salient and where evidence gaps exist, and explicitly explore how to optimally weigh available evidence in determining net screening benefit. Improved harms reporting could aid informed decision making, ultimately improving cancer screening delivery. Primary Funding Source: National Cancer Institute.

Adenoma Detection Rate and Colorectal Cancer Risk in Fecal Immunochemical Test Screening Programs: An Observational Cohort Study: Annals of Internal Medicine: Vol 176, No 3

Background: Colorectal cancer (CRC) screening programs based on fecal immunochemical tests (FITs) represent the standard of care for population-based interventions. Their benefit depends on the identification of neoplasia at colonoscopy after FIT positivity. Colonoscopy quality measured by adenoma detection rate (ADR) may affect screening program effectiveness. Objective: To examine the association between ADR and postcolonoscopy CRC (PCCRC) risk in a FIT-based screening program. Design: Retrospective population-based cohort study. Setting: Fecal immunochemical test–based CRC screening program between 2003 and 2021 in northeastern Italy. Patients: All patients with a positive FIT result who had a colonoscopy were included. Measurements: The regional cancer registry supplied information on any PCCRC diagnosed between 6 months and 10 years after colonoscopy. Endoscopists' ADR was categorized into 5 groups (20% to 39.9%, 40% to 44.9%, 45% to 49.9%, 50% to 54.9%, and 55% to 70%). To examine the association of ADR with PCCRC incidence risk, Cox regression models were fitted to estimate hazard ratios (HRs) and 95% CIs. Results: Of the 110 109 initial colonoscopies, 49 626 colonoscopies done by 113 endoscopists between 2012 and 2017 were included. After 328 778 person-years follow-up, 277 cases of PCCRC were diagnosed. Mean ADR was 48.3% (range, 23% and 70%). Incidence rates of PCCRC from lowest to highest ADR group were 13.13, 10.61, 7.60, 6.01, and 5.78 per 10 000 person-years. There was a significant inverse association between ADR and PCCRC incidence risk, with a 2.35-fold risk increase (95% CI, 1.63 to 3.38) in the lowest group compared with the highest. The adjusted HR for PCCRC associated with 1% increase in ADR was 0.96 (CI, 0.95 to 0.98). Limitation: Adenoma detection rate is partly determined by FIT positivity cutoff; exact values may vary in different settings. Conclusion: In a FIT-based screening program, ADR is inversely associated with PCCRC incidence risk, mandating appropriate colonoscopy quality monitoring in this setting. Increasing endoscopists' ADR may significantly reduce PCCRC risk. Primary Funding Source: None.

15-Year Benefits of Sigmoidoscopy Screening on Colorectal Cancer Incidence and Mortality: A Pooled Analysis of Randomized Trials: Annals of Internal Medicine: Vol 175, No 11

Background: The effectiveness of screening for colorectal cancer (CRC) by sex and age in randomized trials is uncertain. Objective: To evaluate the 15-year effect of sigmoidoscopy screening on CRC incidence and mortality. Design: Pooled analysis of 4 large-scale randomized trials of sigmoidoscopy screening. Setting: Norway, the United States, the United Kingdom, and Italy. Participants: Women and men aged 55 to 64 years at enrollment. Intervention: Sigmoidoscopy screening. Measurements: Primary end points were cumulative incidence rate ratio (IRR) and mortality rate ratio (MRR) and rate differences after 15 years of follow-up comparing screening versus usual care in intention-to-treat analyses. Stratified analyses were done by sex, cancer site, and age at screening. Results: Analyses comprised 274 952 persons (50.7% women), 137 493 in the screening and 137 459 in the usual care group. Screening attendance was 58% to 84%. After 15 years, the rate difference for CRC incidence was 0.51 cases (95% CI, 0.40 to 0.63 cases) per 100 persons and the IRR was 0.79 (CI, 0.75 to 0.83). The rate difference for CRC mortality was 0.13 deaths (CI, 0.07 to 0.19 deaths) per 100 persons, and the MRR was 0.80 (CI, 0.72 to 0.88). Women had less benefit from screening than men for CRC incidence (IRR for women, 0.84 [CI, 0.77 to 0.91]; IRR for men, 0.75 [CI, 0.70 to 0.81]; P = 0.032 for difference) and mortality (MRR for women, 0.91 [CI, 0.77 to 1.17]; MRR for men, 0.73 [CI, 0.64 to 0.83]; P = 0.025 for difference). There was no statistically significant difference in screening effect between persons aged 55 to 59 years and those aged 60 to 64 years. Limitation: Data from the U.K. trial were less granular because of privacy regulations. Conclusion: This pooled analysis of all large randomized trials of sigmoidoscopy screening demonstrates a significant and sustained effect of sigmoidoscopy on CRC incidence and mortality for 15 years. Primary Funding Source: Health Fund of South-East Norway.

Benefits and Risks Associated With Continuation of Anti–Tumor Necrosis Factor After 24 Weeks of Pregnancy in Women With Inflammatory Bowel Disease: A Nationwide Emulation Trial: Annals of Internal Medicine: Vol 175, No 10

Background: Continuation of biologics for inflammatory disorders during pregnancy is still a difficult decision. Many women with inflammatory bowel diseases (IBDs) stop anti–tumor necrosis factor (anti-TNF) treatment after 24 weeks. Objective: To evaluate the benefits and risks of anti-TNF continuation after 24 weeks of pregnancy for mothers with IBD and their offspring. Design: Target trial emulation between 2010 and 2020. Setting: Nationwide population-based study using the Système National des Données de Santé. Patients: All pregnancies with birth exposed to anti-TNF between conception and 24 weeks of pregnancy in women with IBD. Intervention: Continuation of anti-TNF after 24 weeks of pregnancy. Measurements: Occurrence of maternal IBD relapse up to 6 months after pregnancy, adverse pregnancy outcomes, and serious infections in the offspring during the first 5 years of life was compared according to anti-TNF continuation after 24 weeks of pregnancy using inverse probability–weighted marginal models. Results: A total of 5293 pregnancies were included; among them, anti-TNF treatment was discontinued before 24 weeks for 2890 and continued beyond 24 weeks for 2403. Continuation of anti-TNF was associated with decreased frequencies of maternal IBD relapse (35.8% vs. 39.0%; adjusted risk ratio [aRR], 0.93 [95% CI, 0.86 to 0.99]) and prematurity (7.6% vs. 8.9%; aRR, 0.82 [CI, 0.68 to 0.99]). No difference according to anti-TNF continuation was found regarding stillbirths (0.4% vs. 0.2%; aRR, 2.16 [CI, 0.64 to 7.81]), small weight for gestational age births (13.1% vs. 12.9%; aRR, 1.01 [CI, 0.88 to 1.17]), and serious infections in the offspring (54.2 vs. 50.2 per 1000 person-years; adjusted hazard ratio, 1.08 [CI, 0.94 to 1.25]). Limitation: Algorithms rather than clinical data were used to identify patients with IBD, pregnancies, and serious infections. Conclusion: Continuation of anti-TNF after 24 weeks of pregnancy appears beneficial regarding IBD activity and prematurity, while not affecting neonatal outcomes and serious infections in the offspring. Primary Funding Source: None.

Potential Medicare Part D Savings on Generic Drugs From the Mark Cuban Cost Plus Drug Company

Homozygous Familial Hypobetalipoproteinemia Diagnosed in Adulthood With a New Splicing Variant of the APOB Gene | Annals of Internal Medicine: Clinical Cases

We report a case of familial hypobetalipoproteinemia presenting with severe fat malabsorption, diagnosed in adulthood, with a new splicing variant of the APOB gene.

Ileitis in Adult Multisystem Inflammatory Syndrome: A Case Report | Annals of Internal Medicine: Clinical Cases

Multisystem inflammatory syndrome (MIS) can manifest with nonspecific gastrointestinal symptoms, fever, shock, and cardiovascular dysfunction. Compared with children, MIS in adults (MIS-A) is rare. We present a definitive case of MIS-A (based on the Brighton criteria) in a young adult with fever, erythematous rash, and prominent gastrointestinal (ileitis) features, elevated inflammatory markers with evidence of cardiac involvement, and renal injury 4 weeks after confirmed SARS-CoV-2 infection. We highlight the histopathologic features from an ileal biopsy, which demonstrated reactive lymphocytic infiltrates. To our knowledge, this is the first report describing intestinal histopathologic findings in MIS-A.

Spontaneous Ectopic Paraumbilical Variceal Bleeding in a Patient With Cirrhosis | Annals of Internal Medicine: Clinical Cases

Ectopic variceal hemorrhage is a rare sequela of portal hypertension, accounting for 5% of variceal bleeding events. Although mortality rates are high for this condition, there is no established management protocol. We present a patient case of spontaneous external hemorrhage from an ectopic paraumbilical varicosity in the setting of portal hypertension secondary to decompensated alcoholic cirrhosis that was treated effectively with transjugular intrahepatic portosystemic shunt placement.

A Rare Manifestation of Chronic Gastric Ischemia With Ulceration | Annals of Internal Medicine: Clinical Cases

We present the patient case of a woman with significant cardiovascular disease, chronic abdominal pain, and repeated episodes of gastrointestinal bleeding, who was ultimately diagnosed with chronic gastric ischemia with recurrent gastric ulcers. The current literature suggests that gastric ischemia is more common than previously thought. A higher degree of suspicion for this relatively rare presentation may be required in the clinical setting.

Hyperplastic Polyps Discovered Because of Unprovoked Acute Upper Gastrointestinal Bleeding as an Unusual Presentation of Malignancy | Annals of Internal Medicine: Clinical Cases

Gastric hyperplastic polyps are small (<1 cm), asymptomatic, and found incidentally on esophagogastroduodenoscopy. Patients can present with dyspepsia, abdominal pain, anemia from chronic occult bleeding, and, rarely, acute upper gastrointestinal bleeding. Helicobacter pylori, autoimmune gastritis, and long-term use of proton-pump inhibitors can increase the risk for hyperplastic polyps. Dysplasia and carcinoma in the surrounding gastric mucosa with concomitant hyperplastic polyps can be seen but carcinoma and dysplasia within the hyperplastic polyp itself are extremely rare. We report on a 70-year-old White woman who presented with melena from what appeared to be hyperplastic polyps on esophagogastroduodenoscopy, but pathology reported frank intramucosal adenocarcinoma.