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

Background and Aim Surveillance of non-dysplastic Barrett's esophagus (BE) is recommended to identify progression to dysplasia; however, the most cost-effective strategy remains unclear. Mutation or aberrant expression of p53 has 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 non-dysplastic BE. Patients with non-dysplastic BE (NDBE) underwent p53 immunohistochemistry (IHC) and those with abnormal p53 expression underwent surveillance endoscopy at 1 year, whilst 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 ICER of $8,258 for p53 IHC based surveillance. Both conventional and p53 stratified surveillance strategies dominated the natural history model. On probabilistic sensitivity analysis (PSA), the p53 IHC strategy ($28,652, 16.78 QALYs) was more cost-effective than conventional surveillance ($25,679, 16.17 QALYs) with a net monetary benefit (NMB) of $306,873 compared to conventional surveillance ($297,642) with ICER < $50000 in 96% of the iterations. The p53 stratification strategy was associated with a 14.5% reduction in the overall endoscopy burden and a 59% increase in dysplasia. 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 diagnostic rates of dysplasia.

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.

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.

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.

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.

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.

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.

SpHincterotomy for Acute Recurrent Pancreatitis Randomized Trial: Rationale, Methodology, and Potential Implications.

OBJECTIVES: In patients with acute recurrent pancreatitis (ARP), pancreas divisum, and no other etiologic factors, endoscopic retrograde cholangiopancreatography (ERCP) with minor papilla endoscopic sphincterotomy (miES) is often performed to enlarge the minor papillary orifice, based on limited data. The aims of this study are to describe the rationale and methodology of a sham-controlled clinical trial designed to test the hypothesis that miES reduces the risk of acute pancreatitis. METHODS: The SpHincterotomy for Acute Recurrent Pancreatitis (SHARP) trial is a multicenter, international, sham-controlled, randomized trial comparing endoscopic ultrasound + ERCP with miES versus endoscopic ultrasound + sham for the management of ARP. A total of 234 consented patients having 2 or more discrete episodes of acute pancreatitis, pancreas divisum confirmed by magnetic resonance cholangiopancreatography, and no other clear etiology for acute pancreatitis will be randomized. Both cohorts will be followed for a minimum of 6 months and a maximum of 48 months. RESULTS: The trial is powered to detect a 33% risk reduction of acute pancreatitis frequency. CONCLUSIONS: The SHARP trial will determine whether ERCP with miES benefits patients with idiopathic ARP and pancreas divisum. Trial planning has informed the importance of blinded outcome assessors and long-term follow-up.

Large-duct cholangiopathies: aetiology, diagnosis and treatment.

Cholangiopathies describe a group of conditions affecting the intrahepatic and extrahepatic biliary tree. Impairment to bile flow and chronic cholestasis cause biliary inflammation, which leads to more permanent damage such as destruction of the small bile ducts (ductopaenia) and biliary cirrhosis. Most cholangiopathies are progressive and cause end-stage liver disease unless the physical obstruction to biliary flow can be reversed. This review considers large-duct cholangiopathies, such as primary sclerosing cholangitis, ischaemic cholangiopathy, portal biliopathy, recurrent pyogenic cholangitis and Caroli disease.

Preoperative Anemia and Outcomes in Cardiovascular Surgery: Systematic Review and Meta-Analysis.

BACKGROUND: Preoperative anemia is common in patients scheduled for cardiac surgery. However, its effect on postoperative outcomes remains controversial. This meta-analysis aimed to clarify the impact of anemia on outcomes after cardiac surgery. METHODS: A literature search was conducted on MEDLINE, Embase, Cochrane, and Web of Science databases. The primary outcome was 30-day postoperative or in-hospital mortality. Secondary outcomes included acute kidney injury, stroke, blood transfusion, and infection. A meta-analytic model was used to determine the differences in the above postoperative outcomes between anemic and nonanemic patients. RESULTS: Of 1103 studies screened, 22 met the inclusion criteria. Of 114,277 patients, 23,624 (20.6%) were anemic. Anemia was associated with increased mortality (odds ratio [OR], 2.74; 95% confidence interval [CI], 2.32-3.24; I2 = 69.6%; P < .001), acute kidney injury (OR, 3.13; 95% CI, 2.37-4.12; I2 = 71.1%; P < .001), stroke (OR, 1.46; 95% CI, 1.24-1.72; I2 = 21.6%; P < .001), and infection (OR, 2.65; 95% CI, 1.98-3.55; I2 = 46.7%; P < .001). More anemic patients were transfused than nonanemic patients (33.3% vs 11.9%, respectively). No statistically significant association was found between mortality and blood transfusion (OR, 1.35; 95% CI, 0.92-1.98; I2 = 83.7%; P = .12), but we were not able to compare mortality with or without transfusion in those who were or were not anemic. CONCLUSIONS: Preoperative anemia is associated with adverse outcomes after cardiac surgery. These findings support the addition of preoperative anemia to future risk prediction models and as a target for risk modification.

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.

Ocular radiation exposure during endoscopic retrograde cholangiopancreatography: a meta-analysis of studies.

BACKGROUND: The increasing complexity involved in procedures requiring fluoroscopy such as endoscopic retrograde cholangiopancreatography (ERCP) results in heightened screening times with attendant radiation exposure during these procedures. There is increasing awareness of tissue-reactions to the lens of the eye due to radiation exposure, with evidence suggesting that threshold doses may be lower than previously considered. MATERIALS AND METHODS: A literature search was performed to identify studies involving ERCP in which radiation exposure was reported. Demographic data and data on fluoroscopy time and ocular exposure were extracted. Fixed and random-effects meta-analyses were conducted. RESULTS: Twenty-six studies (8016 procedures) were identified, of which 10 studies (818 procedures) contained data on ocular exposure. The mean screening time per procedure was 3.9 min with a mean of three images captured per procedure. On fixed effects meta-analysis, the point estimate for the effective ocular exposure dose per procedure was 0.018 (95% confidence interval: 0.017-0.019) mSv. On random-effects meta-analysis, the effective ocular exposure dose was 0.139 (0.118-0.160) mSv (Q=2590.78, I=99.5, P<0.001). On comparing these point estimates to the ocular dose limit of 20 mSv/year, 1111 ERCPs (using fixed effects data) and 144 ERCPs (using random-effects data), with a mean of 627 ERCPs/individual/year, could deliver an ocular radiation dose equivalent to this dose limit. CONCLUSION: Ocular radiation exposures in high-volume ERCP operators (>200 procedures/year) and operators performing complex ERCPs involving prolonged fluoroscopy, need to exercise caution in relation to ocular exposure. Shielding using lead-lined glasses may be reasonable in this group.

Association between metabolic syndrome and hepatobiliary cancers: A case-control study.

BACKGROUND: The incidence of hepatobiliary cancer is steadily increasing. It is unclear if this rise is related to increasing trends in obesity, metabolic syndrome, and lifestyle changes. METHODS: A case-control study was performed using the Health Improvement Network (THIN) database. Cases with a diagnosis of liver, bile duct, and gallbladder cancers were matched in a 1:2 fashion with controls and analyzed for potential associations between hepatobiliary cancer and obesity/metabolic syndrome. RESULTS: Four thousand two hundred and eighty-seven patients (62% male, 38% female) with hepatobiliary cancers were matched with 8574 controls. On univariate analysis, body mass index (BMI), smoking, diabetes, alcohol consumption, ischemic heart disease, and hypertension were associated with hepatobiliary cancer. Statin use and non-smoking status had an inverse association. On multivariate analysis, BMI, diabetes, hypertension, ischemic heart disease, and insulin use were associated with the risk of hepatobiliary cancer. Statin use and non-smoking status were protective. On modeling BMI, each of diabetes and hypertension as a single covariate, there was a significant association with hepatobiliary cancer (1.59 [1.49-1.69], p < 0.001) which persisted despite adjusting for increasing age (1.006 [1005-1.006], p < 0.001) and background liver cirrhosis (1.037 [1.03-1.044], p < 0.001). CONCLUSIONS: Obesity and metabolic syndrome are associated with the risk of hepatobiliary cancer. Statin use seems to be protective.