Contributions of Adenocarcinoma and Carcinoid Tumors to Early-Onset Colorectal Cancer Incidence Rates in the United States

Background: Early-onset colorectal cancer (EOCRC) incidence rates (IRs) are rising, according to previous cancer registry analyses. However, analysis of histologic subtypes, including adenocarcinoma (the focus of CRC screening and diagnostic testing) and carcinoid tumors (which are classified as “colorectal cancer” in SEER [Surveillance, Epidemiology, and End Results] databases but have a distinct pathogenesis and are managed differently from adenocarcinoma), has not been reported. Objective: To assess EOCRC IRs and changes in IRs over time, stratified by histology. Design: Retrospective analysis. Setting: Yearly IRs according to SEER 18 data from 2000 to 2016 on age-specific colon-only, rectal-only, and combined-site CRC cases, stratified by histology (“overall” CRC [all histologic subtypes], adenocarcinoma, and carcinoid tumors) and age. Patients: 119 624 patients with CRC. Measurements: IRs per 100 000 population, changes in 3-year average annual IRs (pooled IRs from 2000 to 2002 vs. those from 2014 to 2016), and annual percentage change (APC) in persons aged 20 to 29, 30 to 39, 40 to 49, and 50 to 54 years. Results: The steepest changes in adenocarcinoma 3-year average annual IRs were for rectal-only cases in persons aged 20 to 29 years (+39% [0.33 to 0.46 per 100 000]; P < 0.050) and 30 to 39 years (+39% [1.92 to 2.66 per 100 000]; P < 0.050) and colon-only cases in those aged 30 to 39 years (+20% [3.30 to 3.97 per 100 000]; P < 0.050). Corresponding APCs were 1.6% (P < 0.050), 2.2% (P < 0.050), and 1.2% (P < 0.050), respectively. In persons aged 40 to 49 years, 3-year average annual IRs increased in both colon-only (+13% [12.21 to 13.85 per 100 000]; P < 0.050) and rectal-only (+16% [7.50 to 8.72 per 100 000]; P < 0.050) subsites. Carcinoid tumors were common, representing approximately 4% to 20% of all colorectal and 8% to 34% of all rectal cancer cases, depending on age group and calendar year. Colon-only carcinoid tumors were rare. Colorectal carcinoid tumor IRs increased more steeply than adenocarcinoma in all age groups, thus affecting the contribution of carcinoid tumors to overall cancer cases over time. These changes were driven by rectal subsites and were most pronounced in persons aged 50 to 54 years, in whom rectal carcinoid tumors increased by 159% (2.36 to 6.10 per 100 000) between 2000 to 2002 and 2014 to 2016, compared with 10% for adenocarcinoma (18.07 to 19.84 per 100 000), ultimately accounting for 22.6% of all rectal cancer cases. Limitation: Population-based data. Conclusion: These findings underscore the importance of assessing histologic CRC subtypes independently. Doing so may lead to a better understanding of the drivers of temporal changes in overall CRC incidence and a more accurate measurement of outcomes from efforts to reduce adenocarcinoma risk, and can guide future research. Primary Funding Source: None.

World Health Organization Guidelines on Treatment of Hepatitis C Virus Infection: Best Practice Advice From the American College of Physicians

Utility, Appropriateness, and Content of Electronic Consultations Across Medical Subspecialties: A Cohort Study: Annals of Internal Medicine: Vol 172, No 10

Background: Electronic consultations (e-consults) can facilitate patient access to specialists, minimize travel, and reduce unnecessary in-person visits. However, metrics to enable study of e-consults and their effect on processes and patient care are lacking. Objective: To assess novel metrics of e-consult appropriateness and utility. Design: Retrospective cohort study. Setting: Primary and specialty care practices at 2 large academic and 2 community hospitals of an integrated health system. Participants: Patients with e-consult requests to 5 specialties—hematology, infectious disease, dermatology, rheumatology, and psychiatry—between October 2017 and November 2018. Measurements: The appropriateness of e-consult inquiries was assessed by review of medical records and defined as meeting the following 4 criteria: not answerable by reviewing evidence-based summary sources (“point-of-care resource test”), not merely requesting logistic information, having appropriate clinical urgency, and having appropriate patient complexity. Interrater agreement in assessments of e-consult appropriateness was assessed by the κ statistic. Utility of e-consults was assessed by the rate of avoided visits (AVs), defined by the absence of an in-person visit to the same specialty within 120 days. Results: Overall, 6512 eligible e-consults were made by 1096 referring providers to 121 specialist consultants. Inquiries were characterized as diagnostic, therapeutic, for provider education, or at the request of the patient. Most consultations were answered within 1 day, with variation across specialties (73.1% for psychiatry to 87.8% for infectious disease). Overall, 70.2% of e-consults met all 4 criteria for appropriateness; the frequency of unmet criteria varied among specialties. Raters agreed on the appropriateness of 94% of e-consults (κ = 0.57 [95% CI, 0.36 to 0.79]), indicating moderate agreement. The overall rate of AVs across the 5 specialties was 81.2%; the highest rate was in psychiatry (92.6%) and the lowest in dermatology (61.9%). Limitation: Generalizability is unknown outside a single integrated health system, where requesting and consulting providers share a common electronic health record. Conclusion: Novel metrics to assess the appropriateness and utility of e-consults provide meaningful insight into practice, provide a rubric for comparison in future studies in additional settings, and suggest areas to improve resource use and patient care. Primary Funding Source: None.

Rifabutin-Based Triple Therapy (RHB-105) for Helicobacter pylori Eradication: A Double-Blind, Randomized, Controlled Trial: Annals of Internal Medicine: Vol 172, No 12

Background: Although consensus supports eradication of Helicobacter pylori infections, antimicrobial resistance has substantially reduced eradication rates with most current therapies. Objective: To assess the effectiveness of a novel rifabutin-based therapy (RHB-105) for H pylori eradication. Design: Phase 3, double-blind trial (ERADICATE Hp2). (ClinicalTrials.gov: NCT03198507) Setting: 55 clinical research sites in the United States. Participants: 455 treatment-naive adults with epigastric discomfort and confirmed H pylori infection. Intervention: RHB-105 (amoxicillin, 3 g; omeprazole, 120 mg; and rifabutin, 150 mg) versus active comparator (amoxicillin, 3 g, and omeprazole, 120 mg), given as 4 capsules every 8 hours for 14 days. Measurements: Between-group difference for H pylori eradication rate, demonstrated by 13C urea breath test 4 weeks after treatment, analyzed by using the χ2 test. Results: In the intention-to-treat population, the eradication rate was higher with RHB-105 than with the active comparator (228 vs. 227 patients, respectively; 83.8% [95% CI, 78.4% to 88.0%] vs. 57.7% [95% CI, 51.2% to 64.0%]; P < 0.001). Eradication rates were unaffected by resistance to clarithromycin or metronidazole. No rifabutin resistance was detected. The most commonly reported adverse events (incidence ≥5%) were diarrhea (10.1% with RHB-105 vs. 7.9% with active comparator), headache (7.5% vs. 7.0%), and nausea (4.8% vs. 5.3%). Limitation: Persons of Asian descent were excluded because of their higher prevalence of poor cytochrome P450 2C19 metabolizers. Conclusion: These findings suggest potential for RHB-105 as first-line empirical H pylori therapy, addressing an unmet need in the current environment of increasing antibiotic resistance. Primary Funding Source: RedHill Biopharma Ltd.

Association Between Treatment With Apixaban, Dabigatran, Rivaroxaban, or Warfarin and Risk for Osteoporotic Fractures Among Patients With Atrial Fibrillation: A Population-Based Cohort Study: Annals of Internal Medicine: Vol 173, No 1

Background: It is unclear whether anticoagulant type is associated with the risk for osteoporotic fracture, a deleterious complication of anticoagulants among patients with atrial fibrillation (AF). Objective: To compare the risk for osteoporotic fracture between anticoagulants. Design: Population-based cohort study. Setting: Territory-wide electronic health record database of the Hong Kong Hospital Authority. Participants: Patients newly diagnosed with AF between 2010 and 2017 who received a new prescription for warfarin or a direct oral anticoagulant (DOAC) (apixaban, dabigatran, or rivaroxaban). Follow-up ended on 31 December 2018. Measurements: Osteoporotic hip and vertebral fractures in anticoagulant users were compared using propensity score–weighted cumulative incidence differences (CIDs). Results: There were 23 515 patients identified (3241 apixaban users, 6867 dabigatran users, 3866 rivaroxaban users, and 9541 warfarin users). Overall mean age was 74.4 years (SD, 10.8), ranging from 73.1 years (warfarin) to 77.9 years (apixaban). Over a median follow-up of 423 days, 401 fractures were identified (crude event number [weighted rate per 100 patient-years]: apixaban, 53 [0.82]; dabigatran, 95 [0.76]; rivaroxaban, 57 [0.67]; and warfarin, 196 [1.11]). After 24-month follow-up, DOAC use was associated with a lower risk for fracture than warfarin use (apixaban CID, −0.88% [95% CI, −1.66% to −0.21%]; dabigatran CID, −0.81% [CI, −1.34% to −0.23%]; and rivaroxaban CID, −1.13% [CI, −1.67% to −0.53%]). No differences were seen in all head-to-head comparisons between DOACs at 24 months (apixaban vs. dabigatran CID, −0.06% [CI, −0.69% to 0.49%]; rivaroxaban vs. dabigatran CID, −0.32% [CI, −0.84% to 0.18%]; and rivaroxaban vs. apixaban CID, −0.25% [CI, −0.86% to 0.40%]). Limitation: Residual confounding is possible. Conclusion: Among patients with AF, DOAC use may result in a lower risk for osteoporotic fracture compared with warfarin use. Fracture risk does not seem to be altered by the choice of DOAC. These findings may help inform the benefit–risk assessment when choosing between anticoagulants. Primary Funding Source: The University of Hong Kong and University College London Strategic Partnership Fund.

Reconciling Disparate Guidelines: The American College of Physicians Colorectal Cancer Screening Guidance Statement

Effect of Acupuncture for Postprandial Distress Syndrome: A Randomized Clinical Trial: Annals of Internal Medicine: Vol 172, No 12

Background: Postprandial distress syndrome (PDS) is the most common subtype of functional dyspepsia. Acupuncture is commonly used to treat PDS, but its effect is uncertain because of the poor quality of prior studies. Objective: To assess the efficacy of acupuncture versus sham acupuncture in patients with PDS. Design: Multicenter, 2-group, randomized clinical trial. (ISRCTN registry number: ISRCTN12511434) Setting: 5 tertiary hospitals in China. Participants: Chinese patients aged 18 to 65 years meeting Rome IV criteria for PDS. Intervention: 12 sessions of acupuncture or sham acupuncture over 4 weeks. Measurements: The 2 primary outcomes were the response rate based on overall treatment effect and the elimination rate of all 3 cardinal symptoms: postprandial fullness, upper abdominal bloating, and early satiation after 4 weeks of treatment. Participants were followed until week 16. Results: Among the 278 randomly assigned participants, 228 (82%) completed outcome measurements at week 16. The estimated response rate from generalized linear mixed models at week 4 was 83.0% in the acupuncture group versus 51.6% in the sham acupuncture group (difference, 31.4 percentage points [95% CI, 20.3 to 42.5 percentage points]; P < 0.001). The estimated elimination rate of all 3 cardinal symptoms was 27.8% in the acupuncture group versus 17.3% in the sham acupuncture group (difference, 10.5 percentage points [CI, 0.08 to 20.9 percentage points]; P = 0.034). The efficacy of acupuncture was maintained during the 12-week posttreatment follow-up. There were no serious adverse events. Limitation: Lack of objective outcomes and daily measurement, high dropout rate, and inability to blind acupuncturists. Conclusion: Among patients with PDS, acupuncture resulted in increased response rate and elimination rate of all 3 cardinal symptoms compared with sham acupuncture, with sustained efficacy over 12 weeks in patients who received thrice-weekly acupuncture for 4 weeks. Primary Funding Source: Beijing Municipal Science and Technology Commission.

Preneoplastic Colorectal Polyps: “I Found Them and Removed Them—Now What?”

International Consensus Guidelines for Nonvariceal Gastrointestinal Bleeding: A Step Forward

Linked Color Imaging Focused on Neoplasm Detection in the Upper Gastrointestinal Tract: A Randomized Trial: Annals of Internal Medicine: Vol 174, No 1

Background: Linked color imaging (LCI) is a new image-enhanced endoscopy technique that allows users to recognize slight differences in mucosal color. Objective: To compare the performance of LCI with white light imaging (WLI) in detecting neoplastic lesions in the upper gastrointestinal tract. Design: A controlled, multicenter trial with randomization using minimization. (University Hospital Medical Information Network Clinical Trials Registry: UMIN000023863) Setting: 16 university hospitals and 3 tertiary care hospitals in Japan. Patients: 1502 patients with known previous or current cancer of the gastrointestinal tract and undergoing surveillance for gastrointestinal cancer. Intervention: WLI followed by LCI examination (WLI group) or LCI followed by WLI examination (LCI group). Measurements: Diagnosis of 1 or more neoplastic lesions in the pharynx, esophagus, or stomach in the first examination (primary outcome) and 1 or more neoplastic lesions overlooked in the first examination (secondary outcome). Results: 752 patients were assigned to the WLI group and 750 to the LCI group. The percentage of patients with 1 or more neoplastic lesions diagnosed in the first examination was higher with LCI than with WLI (60 of 750 patients or 8.0% [95% CI, 6.2% to 10.2%] vs. 36 of 752 patients or 4.8% [CI, 3.4% to 6.6%]; risk ratio, 1.67 [CI, 1.12 to 2.50; P = 0.011]). The proportion with overlooked neoplasms was lower in the LCI group than in the WLI group (5 of 750 patients or 0.67% [CI, 0.2% to 1.6%] vs. 26 of 752 patients or 3.5% [CI, 2.3% to 5.0%]; risk ratio, 0.19 [CI, 0.07 to 0.50]). Limitation: Endoscopists were not blinded. Conclusion: LCI is more effective than WLI for detecting neoplastic lesions in the pharynx, esophagus, and stomach. Primary Funding Source: Fujifilm Corporation.