Stratification of Barrett's esophagus surveillance based on p53 immunohistochemistry: a cost-effectiveness analysis by an international collaborative group.

BACKGROUND: Surveillance of nondysplastic Barrett's esophagus (NDBE) is recommended to identify progression to dysplasia; however, the most cost-effective strategy remains unclear. Mutation of TP53 or aberrant expression of p53 have been associated with the development of dysplasia in BE. We sought to determine if surveillance intervals for BE could be stratified based on p53 expression. METHODS: A Markov model was developed for NDBE. Patients with NDBE underwent p53 immunohistochemistry (IHC) and those with abnormal p53 expression underwent surveillance endoscopy at 1 year, while patients with normal p53 expression underwent surveillance in 3 years. Patients with dysplasia underwent endoscopic therapy and surveillance. RESULTS: On base-case analysis, the strategy of stratifying surveillance based on abnormal p53 IHC was cost-effective relative to conventional surveillance and a natural history model, with an incremental cost-effectiveness ratio (ICER) of $8258 for p53 IHC-based surveillance. Both the conventional and p53-stratified surveillance strategies dominated the natural history model. On probabilistic sensitivity analysis, the p53 IHC strategy ($28 652; 16.78 quality-adjusted life years [QALYs]) was more cost-effective than conventional surveillance ($25 679; 16.17 QALYs) with a net monetary benefit of $306 873 compared with conventional surveillance ($297 642), with an ICER <$50 000 in 96% of iterations. The p53-stratification strategy was associated with a 14% reduction in the overall endoscopy burden and a 59% increase in dysplasia detection. CONCLUSION: A surveillance strategy for BE based on abnormal p53 IHC is cost-effective relative to a conventional surveillance strategy and is likely to be associated with higher rates of dysplasia diagnosis.

Genomic Basis for Individual Differences in Susceptibility to the Neurotoxic Effects of Diesel Exhaust.

Air pollution is a known environmental health hazard. A major source of air pollution includes diesel exhaust (DE). Initially, research on DE focused on respiratory morbidities; however, more recently, exposures to DE have been associated with neurological developmental disorders and neurodegeneration. In this study, we investigated the effects of sub-chronic inhalation exposure to DE on neuroinflammatory markers in two inbred mouse strains and both sexes, including whole transcriptome examination of the medial prefrontal cortex. We exposed aged male and female C57BL/6J (B6) and DBA/2J (D2) mice to DE, which was cooled and diluted with HEPA-filtered compressed air for 2 h per day, 5 days a week, for 4 weeks. Control animals were exposed to HEPA-filtered air on the same schedule as DE-exposed animals. The prefrontal cortex was harvested and analyzed for proinflammatory cytokine gene expression (Il1ß, Il6, Tnfα) and transcriptome-wide response by RNA-seq. We observed differential cytokine gene expression between strains and sexes in the DE-exposed vs. control-exposed groups for Il1ß, Tnfα, and Il6. For RNA-seq, we identified 150 differentially expressed genes between air and DE treatment related to natural killer cell-mediated cytotoxicity per Kyoto Encyclopedia of Genes and Genomes pathways. Overall, our data show differential strain-related effects of DE on neuroinflammation and neurotoxicity and demonstrate that B6 are more susceptible than D2 to gene expression changes due to DE exposures than D2. These results are important because B6 mice are often used as the default mouse model for DE studies and strain-related effects of DE neurotoxicity warrant expanded studies.

Chronic Obstructive Pulmonary Disease and the Risk of Esophagitis, Barrett's Esophagus, and Esophageal Adenocarcinoma: A Primary Care Case-Control Study.

BACKGROUND: Chronic gastroesophageal reflux predisposes to the development of esophageal adenocarcinoma (EAC). Asthma and medication to treat it are associated with gastroesophageal reflux and EAC. We studied subjects with chronic obstructive pulmonary disease (COPD) to examine the relationship between COPD and medication used to treat it, and the risk of reflux esophagitis, Barrett's esophagus, and EAC. METHODS: A case-control study from the UK General Practice Research Database was conducted. Cases were aged 50 or above with a diagnosis of COPD and were matched with controls without a diagnosis of COPD by age, general practitioners practice, and time on the database. EAC was confirmed by cross-referencing cancer registry data. Cox-regression analysis was performed to assess the relationship between COPD, reflux esophagitis, Barrett's esophagus, and EAC. RESULTS: A total of 45,141 cases were studied [24,464 male, age 75 (50 to 100) years]. Among COPD cases there were 55 esophageal cancers (30 EAC) and 506 Barrett's esophagus, compared with 62 (34 EAC) and 329 Barrett's esophagus among controls. COPD was not associated with EAC on univariable [0.92 (0.56 to 1.50), P=0.73] and multivariable analysis [0.85 (0.52 to 1.40), P=0.53]. COPD was however, associated with Barrett's esophagus on univariable [0.92 (0.56 to 1.50), P=0.73] and multivariable [1.53 (1.31 to 1.78), P<0.001] analysis and reflux esophagitis on univariable [1.41 (1.36 to 1.48), P<0.001] and multivariable [1.33 (1.27 to 1.40), P<0.001] analysis. CONCLUSION: COPD is associated with an increased risk of reflux esophagitis and Barrett's esophagus but not EAC.

The impact on patients of a nurse-led clinical service in gastroenterology.

Higher rates of chronic liver disease have resulted in a significant increase in the number of patients needing regular abdominal paracentesis for ascites. Waiting times for admission at the Royal Wolverhampton NHS Trust had become longer and delays in intervention and treatment became inevitable. In 2014, the Trust developed a nurse-led abdominal paracentesis day-case service. A qualitative evaluation of the service was conducted using in-depth patient interviews and surveys to determine the impact of the service, including how the new nursing role affected the patient experience. The results show that the nurse-led clinical service in gastroenterology positively impacts patients' experiences. Following this innovation, the service was extended to provide intravenous infusions for gastroenterology patients via the day-case unit. With appropriate training and competency assessments, nurses can now perform selected medical procedures safely and effectively, thereby facilitating nursing staff to expand and develop their roles. This development has substantial implications for nursing and is an important contribution to the debate on the future direction of the nursing profession.

Factors Associated with Upper Gastrointestinal Cancer Occurrence After Endoscopy that Did Not Diagnose Cancer.

BACKGROUND AND AIMS: Up to 14 % of upper gastrointestinal cancer (UGIC) subjects underwent esophago-gastro-duodenoscopy (EGD) in the preceding 3 years, which did not detect UGIC. The frequency of such events and associated risk factors was evaluated. METHODS: UGIC subjects were identified from a UK primary care database. Post-EGD upper gastrointestinal cancers (PEUGIC) cases were subjects undergoing EGD 12-36 months prior to UGIC diagnosis. Controls had not undergone EGD during the same period. Logistic regression analysis examined associations with PEUGIC. RESULTS: 4249 gastric cancer (GC) subjects (44.8 %) and 5238 esophageal cancer (EC) subjects (55.2 %) were analyzed. There were 633 (6.7 %) PEUGIC subjects [279 EC and 354 GC]. Multivariate analysis revealed that younger age [OR 1.02, (95 % CI 1.01-1.03), p < 0.0001], female gender [1.39 (1.17-1.64), p < 0.0001], increasing comorbidity [1.35 (1.13-1.61), p < 0.0001], and greater deprivation [1.31 (1.09-1.59), p = 0.005] were associated with PEUGIC. Alarm symptoms on presentation [0.32 (0.26-0.40), p < 0.0001] were less likely to be associated with PEUGIC. GC was more likely to be associated with PEUGIC than EC [1.33 (1.13-1.58), p = 0.001]. PEUGIC EGDs reported findings associated with UGIC (stricture or ulceration) in 8.3 % of cases, and only 60.9 % had a follow-up EGD within 90 days. PEUGIC rate declined from 7.9 to 2.7 % for EC and 9.0-6.5 % for GC during the study period. CONCLUSIONS: PEUGIC occurs in 6.7 % of UGIC. PEUGIC was associated with GC, younger age, female gender, increasing comorbidity and deprivation, and a lack of alarm symptoms.

Effect of Covered Metallic Stents Compared With Plastic Stents on Benign Biliary Stricture Resolution: A Randomized Clinical Trial.

IMPORTANCE: Endoscopic placement of multiple plastic stents in parallel is the first-line treatment for most benign biliary strictures; it is possible that fully covered, self-expandable metallic stents (cSEMS) may require fewer endoscopic retrograde cholangiopancreatography procedures (ERCPs) to achieve resolution. OBJECTIVE: To assess whether use of cSEMS is noninferior to plastic stents with respect to stricture resolution. DESIGN, SETTING, AND PARTICIPANTS: Multicenter (8 endoscopic referral centers), open-label, parallel, randomized clinical trial involving patients with treatment-naive, benign biliary strictures (N = 112) due to orthotopic liver transplant (n = 73), chronic pancreatitis (n = 35), or postoperative injury (n = 4), who were enrolled between April 2011 and September 2014 (with follow-up ending October 2015). Patients with a bile duct diameter less than 6 mm and those with an intact gallbladder in whom the cystic duct would be overlapped by a cSEMS were excluded. INTERVENTIONS: Patients (N = 112) were randomized to receive multiple plastic stents or a single cSEMS, stratified by stricture etiology and with endoscopic reassessment for resolution every 3 months (plastic stents) or every 6 months (cSEMS). Patients were followed up for 12 months after stricture resolution to assess for recurrence. MAIN OUTCOMES AND MEASURES: Primary outcome was stricture resolution after no more than 12 months of endoscopic therapy. The sample size was estimated based on the noninferiority of cSEMS to plastic stents, with a noninferiority margin of -15%. RESULTS: There were 55 patients in the plastic stent group (mean [SD] age, 57 [11] years; 17 women [31%]) and 57 patients in the cSEMS group (mean [SD] age, 55 [10] years; 19 women [33%]). Compared with plastic stents (41/48, 85.4%), the cSEMS resolution rate was 50 of 54 patients (92.6%), with a rate difference of 7.2% (1-sided 95% CI, -3.0% to ∞; P < .001). Given the prespecified noninferiority margin of -15%, the null hypothesis that cSEMS is less effective than plastic stents was rejected. The mean number of ERCPs to achieve resolution was lower for cSEMS (2.14) vs plastic (3.24; mean difference, 1.10; 95% CI, 0.74 to 1.46; P < .001). CONCLUSIONS AND RELEVANCE: Among patients with benign biliary strictures and a bile duct diameter 6 mm or more in whom the covered metallic stent would not overlap the cystic duct, cSEMS were not inferior to multiple plastic stents after 12 months in achieving stricture resolution. Metallic stents should be considered an appropriate option in patients such as these. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01221311.

Intra-sphincteric botulinum toxin in the management of functional biliary pain.

Background and study aims The management of functional biliary-type pain remains a clinical challenge. Intra sphincteric botulinum toxin putatively exerts an anti-spasmodic and anti-nociceptive effect. The objective of this study was to examine the clinical response to intra sphincteric botulinum toxin in patients with functional biliary-type pain. Patients and methods This was a cross-sectional (hypothesis-generating) study of prospectively collected data from patients referred to a tertiary center from 2014 to 2019. The efficacy of ampullary botulinum toxin injection for relief of pain was recorded at post-procedure outpatient review. Opioid analgesia, neuromodulatory medication, and frequency of hospital admissions were recorded. Results A total of 119 consecutive patients (109 women, 10 men, mean age 45 years; range 17-77) underwent 411 intra-sphincteric botulinum toxin injection procedures (mean 2 procedures; range 1-15). A total of 103 patients (87 %) had a significant improvement in pain on post-procedure review and 77 % and 76 % of patients were opioid and admission free, respectively. Of the patients, 59 % were prescribed tricyclic antidepressants (amitriptyline), 18 % duloxetine, 13 % pregabalin, and 3 % mirtazapine. Loss of response with the initial dose of botulinum toxin occurred in 56 % of patients. Pain control was reestablished in 80 % of patients in this cohort following botulinum toxin injection at a higher dose. Conclusions These data suggest that botulinum toxin may improve outcomes in patients with functional biliary pain. Further controlled studies are needed to clarify the role of Botox and neuromodulatory agents.

Comparative cost-effectiveness of three post-radiofrequency ablation surveillance intervals for Barrett's esophagus.

Background and study aims Radiofrequency ablation (RFA) for dysplastic Barrett's esophagus (BE) has resulted in a paradigm shift in the management of BE. Despite widespread adoption of RFA, the optimal surveillance interval of the ablated zone is unclear. Methods A patient-level discrete time cycle Markov model was developed to model clinical surveillance strategies post-RFA for BE. Three surveillance strategies were examined: the American College of Gastroenterology (ACG) strategy based on ACG guidelines for post-RFA surveillance, the Cotton strategy based on data from the USA and UK RFA registries, and the UK strategy in line with surveillance strategies in UK centers. Monte-Carlo deterministic and probabilistic analyses were performed over 10,000 iterations (i. e., representing 10,000 patient journeys) and sensitivity analyses were carried out on the variables used in the model. Results On base-case analysis, the ACG strategy was the most cost-effective strategy, at a mean cost of £â€Š11,733 ($ 16,396) (standard deviation (SD) 1520.15) and a mean effectiveness of 12.86 (SD 0.07) QALYs. Probabilistic sensitivity analysis demonstrated that the ACG model was the most cost-effective strategy with a net monetary benefit (NMB) of £â€Š5,136 ($ 7177) (SD 241) compared to the UK strategy and a NMB of £â€Š7017 ($ 9,806) (SD 379) compared to the Cotton strategy. At a willingness to pay (WTP) threshold of £â€Š20,000 ($ 27,949), the ACG model was superior to the other strategies as the most cost-effective strategy. Conclusions A post-RFA surveillance strategy based on the ACG guidelines seems to be the most cost-effective surveillance option.

The mechanisms associated with reflux episodes in ambulant subjects with gastro-esophageal reflux disease.

BACKGROUND: The mechanisms associated with gastro-esophageal reflux (GER) episodes were studied using combined High-resolution Impedance Manometry (HRIM) and pH monitoring in ambulant subjects with different patterns of GERD. METHODS: Sixteen subjects with mild-moderate esophagitis (Los Angeles (LA) grade A&B) (group A) and 11 subjects with severe esophagitis (LA grade C&D) or Barrett's esophagus (BE) were studied before and after a meal, resting, while walking, and during standardized exercise, using a HRIM and a pH probe. KEY RESULTS: Post-prandial acid GER episodes were more common in group B (median 10 range (3-18) vs A (6.5 (0-18), p = 0.048). Postprandial acid clearance time was much longer in group B (median 0.71( 0.07-2.66 min) vs A (0.17 (0.04-2.44 min), p = 0.02). Transient lower esophageal sphincter relaxation (TLESR) was the most frequent mechanism associated with GER episodes in both groups. Post-prandial TLESRs with GER were more common in group B (median 17 (9-24) vs A 13.5 (7-34), p = 0.014), particularly during exercise (B 8 (6-9) vs A 6 (5-6.8), p = 0.007). Post-prandially TLESR with acid reflux increased during exercise in both groups (A rest median 2.4 (0-6.4) per hour vs exercise 4.7 (0-17.3), p = 0.005 and B 4 (0.8-9.6) vs 5.3 (2.7-13.3) per hour, p = 0.045). CONCLUSIONS AND INFERENCES: TLESR was the most common mechanism associated with reflux episodes in all subjects. Acid reflux episodes were more common in subjects with severe esophagitis or BE and esophageal acid clearance was much slower. Post-prandial exercise increased TLESR with acid reflux and GERD patients should be encouraged to avoid exercise immediately after a meal.

The role of intrasphincteric botulinum toxin injection in the management of functional biliary pain: a systematic review and meta-analysis.

BACKGROUND: The management of postcholecystectomy functional biliary pain or Type III sphincter of Oddi dysfunction is challenging. The Evaluating Predictors and Interventions in Sphincter of Oddi Dysfunction study has demonstrated the lack of efficacy of endoscopic sphincterotomy in the management of Type III sphincter of Oddi dysfunction. OBJECTIVE AND METHODS: Botulinum toxin injection to the sphincter of Oddi has been reported as being effective in uncontrolled studies. We sought to understand its pooled efficacy in controlling pancreaticobiliary pain in a systematic review and meta-analysis. RESULTS: Our literature review yielded 10 studies (416 patients) and on random effects meta-analysis, the pooled efficacy of intrasphincteric botulinum toxin injection in alleviating symptoms of pancreaticobiliary was 49% (complete response) and 64% (partial response). One patient developed mild pancreatitis postprocedure and five patients needed postprocedure hospital admission for pain management. The effect of botulinum toxin injection was transient and in the majority of studies, and a positive response to botulinum toxin injection was followed by an endoscopic sphincterotomy. In one study, relapse of pain was managed by repeat botulinum toxin injections with success. CONCLUSION: Intermittent botulinum toxin injection could be a potential option in the overall management strategy of patients with Type III sphincter of Oddi dysfunction, in conjunction with medical management with neuromodulatory medication.

Glioma-derived IL-33 orchestrates an inflammatory brain tumor microenvironment that accelerates glioma progression.

Despite a deeper molecular understanding, human glioblastoma remains one of the most treatment refractory and fatal cancers. It is known that the presence of macrophages and microglia impact glioblastoma tumorigenesis and prevent durable response. Herein we identify the dual function cytokine IL-33 as an orchestrator of the glioblastoma microenvironment that contributes to tumorigenesis. We find that IL-33 expression in a large subset of human glioma specimens and murine models correlates with increased tumor-associated macrophages/monocytes/microglia. In addition, nuclear and secreted functions of IL-33 regulate chemokines that collectively recruit and activate circulating and resident innate immune cells creating a pro-tumorigenic environment. Conversely, loss of nuclear IL-33 cripples recruitment, dramatically suppresses glioma growth, and increases survival. Our data supports the paradigm that recruitment and activation of immune cells, when instructed appropriately, offer a therapeutic strategy that switches the focus from the cancer cell alone to one that includes the normal host environment.