Robert W. O'Rourke

The Effect of Antireflux Surgery on Esophageal Carcinogenesis in Patients With Barrett Esophagus: A Systematic Review

Objective:To determine whether patients with Barrett esophagus who undergo antireflux surgery differ from medically treated patients in incidence of esophageal adenocarcinoma and probability of disease regression/progression. Summary Background Data:Barrett esophagus is a risk factor for the development of esophageal adenocarcinoma. A question exists as to whether antireflux surgery reduces this risk. Methods:Query of PubMed (1966 through October 2005) using predetermined search terms revealed 2011 abstracts, of which 100 full-text articles were reviewed. Twenty-five articles met selection criteria. A review of article references and consultation with experts revealed additional articles for inclusion. Studies that enrolled adults with biopsy-proven Barrett esophagus, specified treatment-type rendered, followed up patients with endoscopic biopsies no less than12 months of instituting therapy, and provided adequate extractable data. The incidence of adenocarcinoma and the proportion of patients developing progression or regression of Barrett esophagus and/or dysplasia were extracted. Results:In surgical and medical groups, 700 and 996 patients were followed for a total of 2939 and 3711 patient-years, respectively. The incidence rate of esophageal adenocarcinoma was 2.8 (95% confidence interval, 1.2–5.3) per 1000 patient-years among surgically treated patients and 6.3 (3.6–10.1) among medically treated patients (P = 0.034). Heterogeneity in incidence rates in surgically treated patients was observed between controlled studies and case series (P = 0.014). Among controlled studies, incidence rates were 4.8 (1.7–11.1) and 6.5 (2.6–13.8) per 1000 patient-years in surgical and medical patients, respectively (P = 0.320). Probability of progression was 2.9% (1.2–5.5) in surgical patients and 6.8% (2.6–12.1) in medical patients (P = 0.054). Probability of regression was 15.4% (6.1–31.4) in surgical patients and 1.9% (0.4–7.3) in medical patients (P = 0.004). Conclusions:Antireflux surgery is associated with regression of Barrett esophagus and/or dysplasia. However, evidence suggesting that surgery reduces the incidence of adenocarcinoma is largely driven by uncontrolled studies.

Depot-specific differences in inflammatory mediators and a role for NK cells and IFN-γ in inflammation in human adipose tissue

Background:Adipose tissue is a primary in vivo site of inflammation in obesity. Excess visceral adipose tissue (VAT), when compared to subcutaneous adipose tissue (SAT), imparts an increased risk of obesity-related comorbidities and mortality, and exhibits differences in inflammation. Defining depot-specific differences in inflammatory function may reveal underlying mechanisms of adipose-tissue-based inflammation.Methods:Stromovascular cell fractions (SVFs) from VAT and SAT from obese humans undergoing bariatric surgery were studied in an in vitro culture system with transcriptional profiling, flow cytometric phenotyping, enzyme-linked immunosorbent assay and intracellular cytokine staining.Results:Transcriptional profiling of SVF revealed differences in inflammatory transcript levels in VAT relative to SAT, including elevated interferon-γ (IFN-γ) transcript levels. VAT demonstrated a broad leukocytosis relative to SAT that included macrophages, T cells and natural killer (NK) cells. IFN-γ induced a proinflammatory cytokine expression pattern in SVF and adipose tissue macrophages (ATM). NK cells, which constitutively expressed IFN-γ, were present at higher frequency in VAT relative to SAT. Both T and NK cells from SVF expressed IFN-γ on activation, which was associated with tumor necrosis factor-α expression in macrophages.Conclusion:These data suggest involvement of NK cells and IFN-γ in regulating ATM phenotype and function in human obesity and a potential mechanism for the adverse physiologic effects of VAT.

Office-Based Unsedated Small-Caliber Endoscopy Is Equivalent to Conventional Sedated Endoscopy in Screening and Surveillance for Barrett's Esophagus: A Randomized and Blinded Comparison

OBJECTIVES:A major limitation to screening and surveillance of Barretts esophagus is the complexity, expense, and risk associated with sedation for upper endoscopy. This study examines the feasibility, accuracy, and patient acceptability of office-based unsedated endoscopy as an alternative.METHODS:Of 274 eligible adults scheduled for endoscopic screening for gastroesophageal reflux symptoms or surveillance of Barretts esophagus at a tertiary care center, 121 underwent unsedated small-caliber endoscopy and conventional endoscopy in a randomized crossover study. The two procedures were compared with regard to histological detection of Barretts esophagus and dysplasia and biopsy size. Patients answered questionnaires assessing the tolerability of the procedures.RESULTS:The prevalence of Barretts esophagus was 26% using conventional endoscopy and 30% using unsedated endoscopy (P = 0.503). The level of agreement between the two approaches was “moderate” (κ = 0.591). Each modality detected four cases of low-grade dysplasia with concordance on one case. The tissue samples collected with unsedated endoscopy were smaller than with conventional endoscopy (P < 0.001). The majority of subjects rated their experience with both procedures as being well tolerated with minimal or no difficulty. When asked which procedure they would prefer in the future, 71% (81/114) chose unsedated small-caliber endoscopy.CONCLUSIONS:Office-based unsedated small-caliber endoscopy is technically feasible, well tolerated, and accurate in screening for Barretts esophagus, despite yielding a smaller biopsy specimen. This approach bears the potential to eliminate the infrastructure and cost required for intravenous sedation in this application.

Effect of Reversible Intermittent Intra-abdominal Vagal Nerve Blockade on Morbid Obesity The ReCharge Randomized Clinical Trial

IMPORTANCE Although conventional bariatric surgery results in weight loss, it does so with potential short-term and long-term morbidity. OBJECTIVE To evaluate the effectiveness and safety of intermittent, reversible vagal nerve blockade therapy for obesity treatment. DESIGN, SETTING, AND PARTICIPANTS A randomized, double-blind, sham-controlled clinical trial involving 239 participants who had a body mass index of 40 to 45 or 35 to 40 and 1 or more obesity-related condition was conducted at 10 sites in the United States and Australia between May and December 2011. The 12-month blinded portion of the 5-year study was completed in January 2013. INTERVENTIONS One hundred sixty-two patients received an active vagal nerve block device and 77 received a sham device. All participants received weight management education. MAIN OUTCOMES AND MEASURES The coprimary efficacy objectives were to determine whether the vagal nerve block was superior in mean percentage excess weight loss to sham by a 10-point margin with at least 55% of patients in the vagal block group achieving a 20% loss and 45% achieving a 25% loss. The primary safety objective was to determine whether the rate of serious adverse events related to device, procedure, or therapy in the vagal block group was less than 15%. RESULTS In the intent-to-treat analysis, the vagal nerve block group had a mean 24.4% excess weight loss (9.2% of their initial body weight loss) vs 15.9% excess weight loss (6.0% initial body weight loss) in the sham group. The mean difference in the percentage of the excess weight loss between groups was 8.5 percentage points (95% CI, 3.1-13.9), which did not meet the 10-point target (P = .71), although weight loss was statistically greater in the vagal nerve block group (P = .002 for treatment difference in a post hoc analysis). At 12 months, 52% of patients in the vagal nerve block group achieved 20% or more excess weight loss and 38% achieved 25% or more excess weight loss vs 32% in the sham group who achieved 20% or more loss and 23% who achieved 25% or more loss. The device, procedure, or therapy-related serious adverse event rate in the vagal nerve block group was 3.7% (95% CI, 1.4%-7.9%), significantly lower than the 15% goal. The adverse events more frequent in the vagal nerve block group were heartburn or dyspepsia and abdominal pain attributed to therapy; all were reported as mild or moderate in severity. CONCLUSION AND RELEVANCE Among patients with morbid obesity, the use of vagal nerve block therapy compared with a sham control device did not meet either of the prespecified coprimary efficacy objectives, although weight loss in the vagal block group was statistically greater than in the sham device group. The treatment was well tolerated, having met the primary safety objective. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01327976.

Systemic inflammation and insulin sensitivity in obese IFN-γ knockout mice

Adipose tissue macrophages are important mediators of inflammation and insulin resistance in obesity. IFN-γ is a central regulator of macrophage function. The role of IFN-γ in regulating systemic inflammation and insulin resistance in obesity is unknown. We studied obese IFN-γ knockout mice to identify the role of IFN-γ in regulating inflammation and insulin sensitivity in obesity. IFN-γ-knockout C57Bl/6 mice and wild-type control litter mates were maintained on normal chow or a high fat diet for 13 weeks and then underwent insulin sensitivity testing then sacrifice and tissue collection. Flow cytometry, intracellular cytokine staining, and QRTPCR were used to define tissue lymphocyte phenotype and cytokine expression profiles. Adipocyte size was determined from whole adipose tissue explants examined under immunofluorescence microscopy. Diet-induced obesity induced systemic inflammation and insulin resistance, along with a pan-leukocyte adipose tissue infiltrate that includes macrophages, T-cells, and NK cells. Obese IFN-γ-knockout animals, compared with obese wild-type control animals, demonstrate modest improvements in insulin sensitivity, decreased adipocyte size, and an M2-shift in ATM phenotype and cytokine expression. These data suggest a role for IFN-γ in the regulation of inflammation and glucose homeostasis in obesity though multiple potential mechanisms, including effects on adipogenesis, cytokine expression, and macrophage phenotype.

Hypoxia-induced inflammatory cytokine secretion in human adipose tissue stromovascular cells

AimsHypoxia has been implicated as a cause of adipose tissue inflammation in obesity, although the inflammatory response of human adipose tissue to hypoxia is not well understood. The goal of this study was to define in vitro inflammatory responses of human adipose tissue to hypoxia and identify molecular mechanisms of hypoxia-induced inflammation.MethodsThe inflammatory milieu and responses of visceral (VAT) and subcutaneous (SAT) adipose tissue explants and purified stromovascular cells (SVFs) from obese and lean humans were studied in an in vitro hypoxic culture system using quantitative real-time PCR, ELISA, western blotting, immunofluorescence microscopy, flow cytometry and immunohistochemistry.ResultsHuman adipose tissue in obesity demonstrates an increased leucocyte infiltrate that is greater in VAT than SAT and involves macrophages, T cells and natural killer (NK) cells. Hypoxic culture regulates inflammatory cytokine secretion and transcription of metabolic stress response genes in human adipose tissue SVF. Adipocyte diameter is increased and adipose tissue capillary density is decreased in obese participants. Inhibition of c-Jun terminal kinase (JNK) or p38 significantly attenuates hypoxia-induced SVF inflammatory responses. Hypoxia induces phosphorylation of p38 in adipose tissue.ConclusionsHuman adipose tissue in obesity is characterised by a depot-specific inflammatory cell infiltrate that involves not only macrophages, but also T cells and NK cells. Hypoxia induces inflammatory cytokine secretion by human adipose tissue SVF, the primary source of which is adipose tissue macrophages. These data implicate p38 in the regulation of hypoxia-induced inflammation and suggest that alterations in adipocyte diameter and adipose tissue capillary density may be potential underlying causes of adipose tissue hypoxia.

Alterations in T-Cell Subset Frequency in Peripheral Blood in Obesity

Background: Obesity affects the regulation of immune and inflammatory responses. This study characterizes differences in peripheral blood lymphocyte phenotype in obese humans. Methods: Frequencies of lymphocyte subsets among peripheral blood mononuclear cells were compared between 10 obese (BMI ≥35) and 10 lean subjects, as determined by antibodies directed against cluster differentiation (CD) markers. Results: Obese patients demonstrated an increased frequency of CD3+CD4+ T-cells (mean difference 12%, P=0.004), a decreased frequency of CD3+CD8+ T-cells (mean difference 9.4%, P=0.016) and an increased frequency of CD3+CD8+CD95+ T-cells (mean difference 13.3%, P=0.032). No other differences among T-cell or monocyte subsets were noted. Conclusions: Obesity is associated with alterations in frequencies of peripheral CD4+ and CD8+ T-cells and aberrations in the expression of CD95 among CD8+ T-cells. These data suggest both CD4+ and CD8+ T-cell compartments, as well as the regulation of CD95 expression on CD8+ T-cells, as targets for further study into obesitys effects on the immune system.

Comparison of 30-day outcomes after non-LapBand primary and revisional bariatric surgical procedures from the Longitudinal Assessment of Bariatric Surgery study

BACKGROUND The goals were to compare the morbidity and mortality between primary and revisional bariatric surgery and to identify the clinical predictors of adverse outcomes among patients undergoing revisional surgery in the Longitudinal Assessment of Bariatric Surgery consortium. The study was multi-institutional at university hospitals in the United States. METHODS Data from the LABS-1 (safety) cohort were analyzed, excluding primary gastric banding patients. A total of 3802 LABS-1 patients were included: 3577 who underwent primary surgery and 225 who underwent revisional surgery. The demographic, clinical, operative, and 30-day outcome data were compared between the 2 groups. A nonlinear mixed effects logit model was used to identify independent risk factors for adverse outcomes (death, deep vein thrombosis, pulmonary embolism, reintubation, reoperation, or discharge after 30 days). RESULTS Compared with those undergoing revisional surgery, the primary surgery patients were younger (median age 44 versus 49 years, P <.0001) and more likely to be male (20.5% versus 12.7%, P = .006) and heavier (median body mass index 47.3 versus 41.2 kg/m(2), P <.0001) and to have more co-morbidities (P <.0001), including hypertension (56.0% versus 46.0%, P = .0044), diabetes (35.7% versus 20.0%, P <.0001), and sleep apnea (50.3% versus 27.2%, P <.0001). The operative time for the revisional procedures was longer (median 181 versus 135 min, P <.0001) and associated with greater blood loss (median 100 versus <50 mL, P <.0001). Adverse outcomes were more likely after revisional surgery (15.1% versus 5.3%, P <.0001, odds ratio 2.4, 95% confidence interval 1.6-3.6). After adjusting for patient characteristics previously shown to be associated with adverse outcomes, this difference remained statistically significant (odds ratio 2.3, 95% confidence interval 1.5-3.8). The 30-day mortality rate was similar in the 2 groups (.4%). CONCLUSION Revisional surgery was performed without substantial mortality but with a greater incidence of adverse outcomes than was primary bariatric surgery.

Alterations in peripheral blood lymphocyte cytokine expression in obesity

Obesity is characterized by alterations in immune and inflammatory function. In order to evaluate the potential role of cytokine expression by peripheral blood mononuclear cells (PBMC) in obesity‐associated inflammation, we studied serum protein levels and mRNA levels in PBMC of interleukin (IL)‐6, IL‐1β, tumour necrosis factor (TNF)‐α and IL‐1Ra in nine lean and 10 obese subjects. Serum IL‐1β was undetectable, IL‐1Ra serum levels were elevated, serum levels of TNF‐α were decreased and serum levels of IL‐6 were similar in obese subjects compared to lean subjects, while transcript levels of IL‐6, IL‐1β and TNF‐α, but not IL‐1Ra, were decreased in PBMC from obese subjects. PBMC from obese subjects did, however, up‐regulate cytokine expression in response to leptin. Thus, obesity‐associated changes in IL‐1Ra serum levels and IL‐6 mRNA levels were not correlated with changes in cognate mRNA and serum levels, respectively, while TNF‐α serum levels and PBMC mRNA levels were both decreased in obese patients. While immune alterations in obesity are manifest in peripheral blood lymphocytes, the general lack of correlation between altered serum levels and altered PBMC gene expression suggests that PBMC may not be the source of aberrant serum cytokine levels in obesity.

Adipose tissue fibrosis, hypertrophy, and hyperplasia: Correlations with diabetes in human obesity.

The relationship between adipose tissue fibrosis, adipocyte hypertrophy, and preadipocyte hyperplasia in the context of obesity and the correlation of these tissue‐based phenomena with systemic metabolic disease are poorly defined. The goal of this study was to clarify the relationship between adipose tissue fibrosis, adipocyte hypertrophy, and preadipocyte hyperplasia in human obesity and determine the correlation of these adipose‐tissue based phenomena with diabetes.