Establishment of standards for the referral of large nonpedunculated colorectal polyps: an international expert consensus using a modified Delphi process.

BACKGROUND AND AIMS: Resection of colorectal polyps has been shown to decrease the incidence and mortality of colorectal cancer. Large nonpedunculated colorectal polyps are often referred to expert centers for endoscopic resection, which requires relevant information to be conveyed to the therapeutic endoscopist to allow for triage and planning of resection technique. The primary objective of this study was to establish minimum expected standards for the referral of large non-pedunculated colonic polyps for potential endoscopic resection. METHODS: A Delphi method was used to establish consensus on minimum expected standards for the referral of large colorectal polyps among a panel of international endoscopy experts. The expert panel was recruited through purposive sampling, and 3 rounds of surveys were conducted to achieve consensus. Quantitative and qualitative data were analyzed for each round. RESULTS: A total of 24 international experts from diverse continents participated in the Delphi study, resulting in consensus on 19 statements related to the referral of large colorectal polyps. The identified factors, including patient demographic characteristics, relevant medications, lesion factors, photodocumentation, and the presence of a tattoo, were deemed important for conveying the necessary information to therapeutic endoscopists. The mean scores for the statements, which were scored on a scale of 1 to 10, ranged from 7.04 to 9.29, with high percentages of experts considering most statements as a very high priority. Subgroup analysis according to continent revealed some variations in consensus rates among experts from different regions. CONCLUSIONS: The identified consensus statements can aid in improving the triage and planning of resection techniques for large colorectal polyps, ultimately contributing to the reduction of colorectal cancer incidence and mortality.

Clinical and pathological predictors of failure of endoscopic therapy for Barrett's related high-grade dysplasia and early esophageal adenocarcinoma.

BACKGROUND AND AIMS: Multimodal endoscopic treatment for Barrett's esophagus (BE) related high-grade dysplasia (HGD) and early esophageal adenocarcinoma (EAC) is safe and effective. However, there is a paucity of data to predict the response to endoscopic treatment. This study aimed to identify predictors of failure to achieve complete eradication of neoplasia (CE-N) and complete eradication of intestinal metaplasia (CE-IM). METHODS: We performed a retrospective analysis of prospectively collected data of all HGD/EAC cases treated endoscopically at a tertiary referral center. Only patients with confirmed HGD/EAC from initial endoscopic mucosal resection (EMR) were included. Potential predictive variables including clinical characteristics, endoscopic features, and index histologic parameters of the EMR specimens were evaluated using multivariate Cox regression. RESULTS: A total of 457 patients were diagnosed with HGD/EAC by initial EMR from January 2008 to January 2019. Of these, 366 patients who underwent subsequent endoscopic treatment with or without RFA were included. Cumulative incidence rates at 3 years for CE-N and CE-IM were 91.4% (95% CI 87.8-94.2%) and 66.8% (95% CI 61.2-72.3%), respectively during a median follow-up period of 35 months. BE segment of 3-10 cm (HR 0.45; 95% CI 0.36-0.57) and > 10 cm (HR 0.25; 95% CI 0.15-0.40) were independent clinical predictors associated with failure to achieve CE-N. With respect to CE-IM, increasing age (HR 0.88; 95% CI 0.78-1.00) was another predictor along with BE segment of 3-10 cm (HR 0.37; 95% CI 0.28-0.49) and > 10 cm (HR 0.15; 95% CI 0.07-0.30). Lymphovascular invasion increased the risk of CE-N and CE-IM failure in EAC cases. CONCLUSION: Failure to achieve CE-N and CE-IM is associated with long-segment BE and other clinical variables. Patients with these predictors should be considered for a more intensive endoscopic treatment approach at expert centers.

Clinical, endoscopic, and histologic characteristics of lymphocytic esophagitis: a systematic review.

OBJECTIVE: Lymphocytic esophagitis (LyE) is a novel, yet poorly described, clinicopathologic entity. The aim of this systematic review was to characterize the demographic, clinical, endoscopic, and histologic features of LyE in observational studies of adult and pediatric patients. DESIGN: We searched the Embase, MEDLINE, and SCOPUS databases for relevant studies in 2018. Two authors reviewed and extracted data from studies that met the inclusion and exclusion criteria. RESULTS: We identified 20 studies for analysis of demographic, clinical, and endoscopic features of LyE. The mean age ranged from 9 to 67 years. When pooled, there were 231 (52.7%) patients with LyE that were female. The most common presenting symptom was dysphagia reported in 191 (48.8%) patients. On endoscopy, most patients with LyE tended to have abnormal findings (69.0%), which included erosive esophagitis, multiple esophageal rings, linear furrows, and narrow-caliber esophagus. In the 31 studies used to assess the histologic definition, the cut-off number of intraepithelial lymphocytes (IELs) was reported in 16 (51.6%) studies, peripapillary IEL specification in 18 (58.1%) studies, and presence of spongiosis in 6 (19.4%) studies. CONCLUSION: We identified a spectrum of demographic, clinical, and endoscopic findings characteristic of patients with LyE. A consensus on the diagnostic criteria of LyE is required.

Hot avulsion may be effective as salvage treatment for focal Barrett's esophagus remaining after endoscopic therapy for dysplasia or early cancer: a preliminary study.

BACKGROUND AND STUDY AIM: Both endoscopic mucosal resection (EMR) and radiofrequency ablation (RFA) are used to treat Barrett's esophagus (BE) complicated by dysplasia and intramucosal cancer. However, focal areas of BE can remain after otherwise successful application of these techniques. We report the results of hot avulsion using a hot biopsy forceps to resect these residual focal areas. PATIENTS AND METHODS: This was a retrospective study from a prospective database in a tertiary reference center from August 2013 to May 2015. All included patients had undergone hot avulsion for eradication of residual focal areas of BE that were ≤ 1 cm and not suspicious for dysplasia, following at least one previous endoscopic treatment for dysplasia or intramucosal cancer. RESULTS: 35 patients harboring 124 residual areas of 1 - 7 mm were treated with hot avulsion. After a mean follow-up of 17.4 months, all patients achieved complete eradication of residual focal BE. One of the patients required a second hot avulsion treatment. Hot avulsion provided samples in all cases but limited the assessment of dysplasia (cautery artifact) in 20.2 % of them. The only complication was bleeding in two patients, which was easily stopped by soft coagulation. CONCLUSIONS: Hot avulsion appears to be effective and safe in removing focal BE ≤ 1 cm at its greatest length remaining after endoscopic treatment for dysplasia or early cancer. Further studies are required before this technique can be considered the standard of care.

Mucosal Th17 cell function is altered during HIV infection and is an independent predictor of systemic immune activation.

Mucosal Th17 cells maintain the gut epithelial barrier and prevent invasion by luminal bacteria through a delicate balance of immunosuppressive and proinflammatory functions. HIV infection is characterized by mucosal Th17 depletion, microbial translocation, and immune activation. Therefore, we assessed the function of blood and sigmoid Th17 cells during both early and chronic HIV infection, as well as the impact of short- and long-term antiretroviral therapy. Th17 cells were defined as IL-17a(+) CD4 T cells, and their functional capacity was assessed by the coproduction of the inflammatory cytokines IL-22, TNF-α, and IFN-γ, as well as the immunoregulatory cytokine IL-10. Gut Th17 cells had a much greater capacity to produce proinflammatory cytokines than did those from the blood, but this capacity was dramatically reduced from the earliest stages of HIV infection. Immunoregulatory skewing of mucosal Th17 cell function, characterized by an increased IL-10/TNF-α ratio, was uniquely seen during early HIV infection and was independently associated with reduced systemic immune activation. Antiretroviral therapy rapidly restored mucosal Th17 cell numbers; however, normalization of mucosal Th17 function, microbial translocation, and mucosal/systemic immune activation was much delayed. These findings emphasize that strategies to preserve or to more rapidly restore mucosal Th17 function may have important therapeutic benefit.

Effect of antiretroviral therapy on HIV reservoirs in elite controllers.

Elite controllers suppress human immunodeficiency virus (HIV) viremia to below the limit of detection in the absence of antiretroviral therapy (ART). However, precise frequencies of CD4(+) T cells carrying replication-competent HIV and/or the dynamics of the infectious viral reservoirs in response to initiation and discontinuation of ART in elite controllers are unknown. We show that the size of the pool of CD4(+) T cells harboring infectious HIV diminished significantly after initiation of ART and rebounded to baseline upon cessation of therapy. Our data provide compelling evidence that persistent viral replication occurs in untreated elite controllers even in the absence of detectable plasma viremia.

Clinical characteristics of young patients with early Barrett's neoplasia.

BACKGROUND: Esophageal adenocarcinoma (EAC) and high-grade dysplasia (HGD) may appear in young patients with Barrett's esophagus (BE). However, characteristics of Barrett's-related neoplasia in this younger population remain unknown. AIM: To identify clinical characteristics that differ between young and old patients with early-stage Barrett's-related neoplasia. METHODS: We conducted a retrospective analysis of a prospectively maintained database comprised of consecutive patients with early-stage EAC (pT1) and HGD at a tertiary-referral center between 2001 and 2017. Baseline characteristics, drug and risk factor exposures, clinicopathological staging of EAC/HGD and treatment outcomes [complete eradication of neoplasia (CE-N), complete eradication of intestinal metaplasia (CE-IM), recurrence of neoplasia and recurrence of intestinal metaplasia] were retrieved. Multivariate analyses were performed to identify factors that differed significantly between older and younger (≤ 50 years) patients. RESULTS: We identified 450 patients with T1 EAC and HGD (74% and 26%, respectively); 45 (10%) were ≤ 50 years. Compared to the older group, young patients were more likely to present with ongoing gastroesophageal reflux disease (GERD) symptoms (55% vs 38%, P = 0.04) and to be obese (body mass index > 30, 48% vs 32%, P = 0.04). Multivariate logistic regression analysis showed that young patients were significantly more likely to have ongoing GERD symptoms [odds ratio (OR) 2.00, 95% confidence interval (CI) 1.04-3.85, P = 0.04] and to be obese (OR 2.06, 95%CI 1.07-3.98, P = 0.03) whereas the young group was less likely to have a smoking history (OR 0.39, 95%CI 0.20-0.75, P < 0.01) compared to the old group. However, there were no significant differences regarding tumor histology, CE-N, CE-IM, recurrence of neoplasia and recurrence of intestinal metaplasia (mean follow-up, 44.3 mo). CONCLUSION: While guidelines recommend BE screening in patients > 50 years of age, younger patients should be considered for screening endoscopy if they suffer from obesity and GERD symptoms.

Clinical characteristics may distinguish patients with esophageal adenocarcinoma arising from long- versus short-segment Barrett's esophagus.

BACKGROUND AND AIMS: Patients with long-segment Barrett's esophagus (LSBE; ≧3 cm) have higher risk of developing esophageal adenocarcinoma (EAC) than those with short-segment Barrett's esophagus (SSBE; <3 cm). However, it is unclear whether patients developing EAC from LSBE or SSBE differ significantly according to baseline clinical characteristics. METHODS: We conducted a retrospective analysis of a prospectively maintained database comprising consecutive patients with early EAC treated by endoscopic mucosal resection at a single, tertiary-referral center. Information regarding baseline clinical characteristics were determined. Univariate and multivariate logistic regression were performed to identify factors that differed significantly between patients with EAC arising from SSBE and LSBE. RESULTS: A total of 145 LSBE EAC and 179 SSBE EAC cases were identified. The LSBE EAC patients had a stronger association with having a hiatal hernia compared to the SSBE EAC patients. In contrast, inverse associations were observed in LSBE EAC patients with statin use and smoking pack-years relative to SSBE EAC patients. CONCLUSIONS: Patients who developed EAC on a background of LSBE were more likely to have a hiatus hernia compared to patients with SSBE EAC, who were more likely to have higher smoking pack-years and higher rates of statin use.

Endoscopic cryotherapy for the management of gastric antral vascular ectasia.

BACKGROUND: Gastric antral vascular ectasia (GAVE) is an uncommon but clinically significant cause of chronic GI bleeding. OBJECTIVE: To assess the efficacy and safety of cryotherapy for endoscopic treatment of GAVE. DESIGN: Patients received 3 sessions of endoscopic cryotherapy at 3-week to 6-week intervals and had a follow-up endoscopy 4 weeks thereafter. They were followed prospectively in terms of clinical and endoscopic response. SETTING: Tertiary-care center, between October 2004 and April 2006. PATIENTS: The patients were 43 to 89 years of age, with a diagnosis of GAVE and documented iron deficiency anemia. Eight patients had a history of overt GI bleeding. Eight patients (67%) had previously been treated with argon plasma coagulation (APC) (median 6 sessions, range 1-10 sessions) and failed to respond or had a recurrence. RESULTS: Twelve patients were enrolled. Six patients (50%) had a complete response, and 6 patients had a partial response. The mean number of units of blood transfused in the period of 3 months before cryotherapy and during the period of follow-up of 3 months was 4.6 and 1.7 units, respectively. An increased mean Hb level, from 9.9 to 11.3 g/dL, was noted. The average duration of the cryotherapy was 5 minutes (range 1-15 minutes). In 32 of 36 cryotherapy treatment sessions performed (89%), it was technically possible to treat more than 90% of GAVE lesions. There were no immediate cryotherapy-related complications, and none of the patients required admission after the procedure. LIMITATIONS: A pilot study from a single center. CONCLUSIONS: Endoscopic cryotherapy is a safe and effective treatment for GAVE. It appears to be effective, even for GAVE refractory to APC therapy. Optimal cryogen, delivery device, and treatment protocols are yet to be determined.

Double-balloon enteroscopy following capsule endoscopy in the management of obscure gastrointestinal bleeding: outcome of a combined approach.

BACKGROUND: There is no consensus on the relative accuracy of capsule endoscopy (CE) versus double-balloon enteroscopy (DBE) to investigate obscure gastrointestinal bleeding (GIB). CE is less invasive, but DBE more directly examines the small bowel, and allows tissue sampling plus therapeutic intervention. OBJECTIVES: To evaluate the yield and outcome of DBE following CE in patients with obscure GIB. METHODS: After DBE became readily available at the Centre for Therapeutic Endoscopy and Endoscopic Oncology (St Michael's Hospital, Toronto, Ontario), all patients with obscure GIB seen from December 2002 to June 2007 were evaluated identically, first with CE, then with DBE (some with further interventions). Findings, adverse outcomes and interventions are reported. RESULTS: Fifty-one patients (25 women) with a mean (range) age of 64.1 years (34 to 83 years) are reported. Eight patients underwent DBE twice, for a total of 59 DBEs. Fourteen patients had overt GIB and the median (range) number of red blood cell unit transfusions was 10 (0 to 100). The positive findings for each type of lesion were compared in these 51 patients: angiodysplasia (CE 64.7% and DBE 61%, P=0.3), ulcers (CE 19.6% and DBE 18.6%, P=0.5), bleeding lesions (CE 43.1% and DBE 15.3%, P=0.0004) and mass (CE 10.2% and DBE 8.5%, P=0.5). DBE provided the advantage of therapeutic intervention: argon plasma coagulation (33 of 59 DBEs), clipping (two of 59), both argon plasma coagulation and clipping (three of 59), polypectomy (two of 59), tattooing (52 of 59) and biopsies (11 of 59). DBE detected lesions not seen by CE in 21 patients; lesions were treated in 18 patients. However, CE detected 31 lesions not seen by DBE. No major complications occurred with either examination. CONCLUSION: Overall detection rates for both techniques are similar. Each technique detected lesions not seen by the other. These data suggest that CE and DBE are complementary and that both evaluate obscure GIB more fully than either modality alone.

Systematic review of strategies to measure HIV-related diarrhea.

INTRODUCTION: In the highly active antiretroviral therapy (HAART) era, HIV-related diarrhea remains common. There is no gold standard to measure diarrhea, making comparison across trials difficult. We conducted a systematic review to determine current research practice in measuring HIV-related diarrhea. METHOD: MEDLINE was searched from 1980 to 2006 for clinical trials of treatment for HIV-related diarrhea. The following data were abstracted: type of trial, treatment studied, definition of diarrhea, and definition of improvement in diarrhea. RESULTS: We reviewed 384 articles; 46 met our inclusion criteria. Forty-two trials were prospective: 25 were open-label and 17 were controlled trials. Antimicrobials were studied most often (15 trials): octreotide was studied in 10 trials, and HAART in 5. Presence of diarrhea was most often defined by duration (33 trials, 72%), stool frequency (29 trials, 63%), and/or stool form (23 trials, 50%); often, more than one parameter was used. Stool frequency was used most often to measure diarrhea improvement (28 trials, 61%). Only one trial used a measure validated for HIV-related diarrhea. CONCLUSION: Investigators rely on non-validated and disparate measures of HIV-related diarrhea. An easy-to-use, well-accepted, and valid tool to measure HIV-related diarrhea would enhance research in this field.

Evaluation of Stool frequency and stool form as measures of HIV-related diarrhea.

PURPOSE: In the highly active antiretroviral therapy (HAART) era, HIV-related diarrhea remains common. Our aim was to evaluate stool frequency and form as measures of HIV-related diarrhea. METHOD: Forty-eight HIV-infected persons with self-reported diarrhea were studied. In Analysis 1, self-reported retrospective and 7-day prospective measurement of stool frequency and form were compared using Spearman's correlation coefficient. In Analysis 2, diarrhea was measured during two 8-hour study periods in a subgroup (n = 20) using stool weight (Wt), diarrhea symptom score (Sx Score), stool frequency (SP-freq), and stool form using the Bristol Stool Form Scale (SP-BSFS). SP-freq and SP-BSFS were modeled alone and in combination to predict Wt and Sx Score. RESULTS: In Analysis 1, correlation between measures of stool frequency was rs = 0.62 (p < .0001) but was rs = 0.16 (p = .26) between measures of stool form. In Analysis 2, the two-predictor model best predicted Wt, whereas the model using SP-freq only performed as well as the two-predictor model to predict Sx Score. CONCLUSION: Prospective measurement of stool frequency performed well; in some situations, it may be used alone to measure severity of HIV-related diarrhea. Our findings may be used to design more rigorous clinical trials in HIV.

The effect of dairy product ingestion on human immunodeficiency virus-related diarrhea in a sample of predominantly gay men: a randomized, controlled, double-blind, crossover trial.

BACKGROUND: In the highly active antiretroviral therapy (HAART) era, chronic diarrhea remains common in human immunodeficiency virus (HIV) illness. Empirical lactose avoidance is often advised despite lack of evidence of benefit in a population at risk for osteopenia and malnutrition. METHODS: The a priori hypothesis was that moderate lactose ingestion would not worsen diarrhea in this population. We used a double-blind, noninferiority, randomized crossover trial in a community setting of primary and tertiary care HIV clinics. The participants all had chronic diarrhea and were a volunteer sample of 49 predominantly white HIV-infected men who have sex with men. They ingested 240 mL of low-fat milk (12 g of lactose) and lactose-free milk during 2 separate study periods. The primary outcome was mean difference in stool weight between the 2 study periods in the 8 hours after milk ingestion. Lactose was judged not to worsen diarrhea if this difference did not exceed 167 g in 8 hours with 95% certainty. RESULTS: Forty-eight (98%) of 49 participants were male. Median age, CD4 cell count, and viral load were 42 years (range, 20-62 years), 390 cells/mL (range, 20-1100 cells/mL), and 112 copies/mL (range, <50 to >500,000 copies/mL), respectively. Thirty-nine participants (80%) were taking HAART medication. Ten participants (20%) were lactase deficient. The mean difference in stool weight between the 2 study periods was -41.3 g/8 h (upper 95% confidence limit, -13.5 g) for the entire group and +11.3 g/8 h (upper 95% confidence limit, +47.4 g) for the lactase-deficient group. CONCLUSIONS: Moderate lactose ingestion does not worsen diarrhea in HIV-infected persons with chronic diarrhea, regardless of lactase status. Therefore, avoidance of modest quantities of milk may not be justified in this population.

Impact of intensified antiretroviral therapy during early HIV infection on gut immunology and inflammatory blood biomarkers.

OBJECTIVE: Standard antiretroviral therapy (ART) is slow to reverse gut mucosal immune defects that cause persistent inflammation and immune activation. We examined whether intensifying early-administered ART through the addition of maraviroc and raltegravir would accelerate their resolution. DESIGN: ART-naïve men with early HIV infection were randomized in a double-blind manner to receive ART (emtricitabine/tenofovir disoproxil fumarate + lopinavir/ritonavir), together with either combined placebo or raltegravir + maraviroc, for 48 weeks. In a predefined substudy, paired blood and sigmoid biopsies were collected at baseline and week 48. Mucosal CD4 T-cell immune subsets (Th1, Th17, and Th22 cells), CD8 T-cell immune activation, and soluble blood markers of inflammation (IL-6, IL-17, macrophage inflammatory protein-1b, soluble CD14, and IL-10) and coagulation (D-dimer) were measured. RESULTS: A total of 22 participants were enrolled, a median of 4 months after HIV acquisition. At baseline, there was substantial systemic and mucosal immune activation, and gut CD4 T-cell numbers, Th22 cell numbers, and Th17 cell function were reduced compared with controls. Early ART restored gut Th22 numbers, improved but did not restore overall CD4 numbers, and had no impact on Th17 function. Plasma levels of soluble CD14 and D-dimer normalized, whereas other inflammatory cytokines were reduced but not normalized. ART intensification had no impact on any blood or gut immune parameters. CONCLUSION: Early HIV infection causes substantial mucosal and systemic immune activation, and gut CD4 T-cell dysfunction. One year of ART improved but did not normalize most parameters, regardless of intensification with raltegravir and maraviroc, and did not restore mucosal Th17 function.