Novel intravesical therapeutics in the treatment of non-muscle invasive bladder cancer: Horizon scanning.

Introduction: Non-muscle-invasive bladder cancer (NMIBC) is a common and heterogeneous disease; many patients develop recurrent or progress to muscle-invasive disease. Intravesical drug therapy is a pillar in the current management of NMIBC; notwithstanding, Mitomycin C (MMC) and Bacillus Calmette-Guérin (BCG) have numerous limitations including international supply issues, and local and systemic toxicity. Here we review novel intravesical therapeutic options and drug delivery devices with potential for clinical use in the treatment of NMIBC. Methods: PubMed, ClinicalTrials.gov and Cochrane Library searches were undertaken. Systematic reviews, meta-analyses, randomised controlled trials, single-arm clinical trials and national/international conference proceedings were included. Results: Novel intravesical drugs, including chemotherapeutic agents, immune checkpoint inhibitors, monoclonal antibodies and gene therapies, have demonstrated varying efficacy in the treatment of NMIBC. Current evidence for the majority of treatments is mostly limited to single-arm trials in patients with recurrent NMIBC. Various novel methods of drug delivery have also been investigated, with encouraging preliminary results supporting the intravesical delivery of hyperthermic MMC and MMC hydrogel formulations. Conclusions: Novel therapeutic agents and drug delivery systems will be important in the future intravesical management of NMIBC. As our understanding of the molecular diversity of NMIBC develops, molecular subtyping will become fundamental in the personalisation of intravesical treatments. Further randomised studies are urgently required to investigate the efficacy of novel intravesical treatments and novel regimens, in comparison to current standards-of-care, particularly in the context of international BCG shortages.

Physoxia Influences Global and Gene-Specific Methylation in Pluripotent Stem Cells.

Pluripotent stem cells (PSC) possess unlimited proliferation, self-renewal, and a differentiation capacity spanning all germ layers. Appropriate culture conditions are important for the maintenance of self-renewal, pluripotency, proliferation, differentiation, and epigenetic states. Oxygen concentrations vary across different human tissues depending on precise cell location and proximity to vascularisation. The bulk of PSC culture-based research is performed in a physiologically hyperoxic, air oxygen (21% O2) environment, with numerous reports now detailing the impact of a physiologic normoxia (physoxia), low oxygen culture in the maintenance of stemness, survival, morphology, proliferation, differentiation potential, and epigenetic profiles. Epigenetic mechanisms affect multiple cellular characteristics including gene expression during development and cell-fate determination in differentiated cells. We hypothesized that epigenetic marks are responsive to a reduced oxygen microenvironment in PSCs and their differentiation progeny. Here, we evaluated the role of physoxia in PSC culture, the regulation of DNA methylation (5mC (5-methylcytosine) and 5hmC (5-hydroxymethylcytosine)), and the expression of regulatory enzyme DNMTs and TETs. Physoxia enhanced the functional profile of PSC including proliferation, metabolic activity, and stemness attributes. PSCs cultured in physoxia revealed the significant downregulation of DNMT3B, DNMT3L, TET1, and TET3 vs. air oxygen, accompanied by significantly reduced 5mC and 5hmC levels. The downregulation of DNMT3B was associated with an increase in its promoter methylation. Coupled with the above, we also noted decreased HIF1A but increased HIF2A expression in physoxia-cultured PSCs versus air oxygen. In conclusion, PSCs display oxygen-sensitive methylation patterns that correlate with the transcriptional and translational regulation of the de novo methylase DNMT3B.

Immunotherapy for non-muscle-invasive bladder cancer: from the origins of BCG to novel therapies.

Supplies of intravesical Bacillus Calmette-Guérin (BCG), the first-line treatment for most intermediate- and high-risk non-muscle-invasive bladder cancers (NMIBC), have proven unreliable over the past decade. This review considers the evolution of BCG immunotherapy for NMIBC: from the discovery of the antitumour side effects of tuberculosis and subsequently the BCG vaccine, to recent advances in novel immunotherapeutic agents. We summarize the evidence for alternative options to standard intravesical BCG therapy regimens and describe the potential for immune response manipulating drugs in the treatment of NMIBC. These new agents, including immune checkpoint inhibitors, toll-like receptor agonists and recombinant viral vectors, may provide better options in the management of NMIBC in the future.

Lay abstract Many patients with non-invasive bladder cancers may need treatments into the bladder, including one called Bacillus Calmette-Guérin (BCG). Unfortunately, the supplies of BCG have been interrupted and somewhat unreliable since 2012. Because of this, we have been forced to look at other means of treating our patients using drugs similar to BCG. This has made us think about how BCG treatment was first developed more than 40 years ago and how it has evolved as a treatment for bladder cancer. In this article, we review the current uses of BCG and other treatments for bladder cancer and explore what the future may hold for bladder cancer treatment.

DNMT3B Is an Oxygen-Sensitive De Novo Methylase in Human Mesenchymal Stem Cells.

The application of physiological oxygen (physoxia) concentrations is becoming increasingly commonplace within a mammalian stem cell culture. Human mesenchymal stem cells (hMSCs) attract widespread interest for clinical application due to their unique immunomodulatory, multi-lineage potential, and regenerative capacities. Descriptions of the impact of physoxia on global DNA methylation patterns in hMSCs and the activity of enzymatic machinery responsible for its regulation remain limited. Human bone marrow-derived mesenchymal stem cells (BM-hMSCs, passage 1) isolated in reduced oxygen conditions displayed an upregulation of SOX2 in reduced oxygen conditions vs. air oxygen (21% O2, AO), while no change was noted for either OCT-4 or NANOG. DNA methylation marks 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) showed decreases in 2% O2 environment (workstation) (2% WKS). DNMT3B (DNA methyltransferase 3B) and TET1 (Ten-eleven translocation enzyme 1) displayed reduced transcription in physoxia. Consistent with transcriptional downregulation, we noted increased promoter methylation levels of DNMT3B in 2% WKS accompanied by reduced DNMT3B and TET1 protein expression. Finally, a decrease in HIF1A (Hypoxia-inducible factor 1A) gene expression in 2% WKS environment correlated with protein levels, while HIF2A was significantly higher in physoxia correlated with protein expression levels vs. AO. Together, these data have demonstrated, for the first time, that global 5mC, 5hmC, and DNMT3B are oxygen-sensitive in hMSCs. Further insights into the appropriate epigenetic regulation within hMSCs may enable increased safety and efficacy development within the therapeutic ambitions.

HumanMethylation450K Array-Identified Biomarkers Predict Tumour Recurrence/Progression at Initial Diagnosis of High-risk Non-muscle Invasive Bladder Cancer.

BACKGROUND: High-risk non-muscle invasive bladder cancer (HR-NMIBC) is a clinically unpredictable disease. Despite clinical risk estimation tools, many patients are undertreated with intra-vesical therapies alone, whereas others may be over-treated with early radical surgery. Molecular biomarkers, particularly DNA methylation, have been reported as predictive of tumour/patient outcomes in numerous solid organ and haematologic malignancies; however, there are few reports in HR-NMIBC and none using genome-wide array assessment. We therefore sought to identify novel DNA methylation markers of HR-NMIBC clinical outcomes that might predict tumour behaviour at initial diagnosis and help guide patient management. PATIENTS AND METHODS: A total of 21 primary initial diagnosis HR-NMIBC tumours were analysed by Illumina HumanMethylation450 BeadChip arrays and subsequently bisulphite Pyrosequencing. In all, 7 had not recurred at 1 year after resection and 14 had recurred and/or progressed despite intra-vesical BCG. A further independent cohort of 32 HR-NMIBC tumours (17 no recurrence and 15 recurrence and/or progression despite BCG) were also assessed by bisulphite Pyrosequencing. RESULTS: Array analyses identified 206 CpG loci that segregated non-recurrent HR-NMIBC tumours from clinically more aggressive recurrence/progression tumours. Hypermethylation of CpG cg11850659 and hypomethylation of CpG cg01149192 in combination predicted HR-NMIBC recurrence and/or progression within 1 year of diagnosis with 83% sensitivity, 79% specificity, and 83% positive and 79% negative predictive values. CONCLUSIONS: This is the first genome-wide DNA methylation analysis of a unique HR-NMIBC tumour cohort encompassing known 1-year clinical outcomes. Our analyses identified potential novel epigenetic markers that could help guide individual patient management in this clinically unpredictable disease.

Maternal genome-wide DNA methylation profiling in gestational diabetes shows distinctive disease-associated changes relative to matched healthy pregnancies.

Several recent reports have described associations between gestational diabetes (GDM) and changes to the epigenomic landscape where the DNA samples were derived from either cord or placental sources. We employed genome-wide 450K array analysis to determine changes to the epigenome in a unique cohort of maternal blood DNA from 11 pregnant women prior to GDM development relative to matched controls. Hierarchical clustering segregated the samples into 2 distinct clusters comprising GDM and healthy pregnancies. Screening identified 100 CpGs with a mean ß-value difference of ≥0.2 between cases and controls. Using stringent criteria, 5 CpGs (within COPS8, PIK3R5, HAAO, CCDC124, and C5orf34 genes) demonstrated potentials to be clinical biomarkers as revealed by differential methylation in 8 of 11 women who developed GDM relative to matched controls. We identified, for the first time, maternal methylation changes prior to the onset of GDM that may prove useful as biomarkers for early therapeutic intervention.

Quantitative genome-wide methylation analysis of high-grade non-muscle invasive bladder cancer.

High-grade non-muscle invasive bladder cancer (HG-NMIBC) is a clinically unpredictable disease with greater risks of recurrence and progression relative to their low-intermediate-grade counterparts. The molecular events, including those affecting the epigenome, that characterize this disease entity in the context of tumor development, recurrence, and progression, are incompletely understood. We therefore interrogated genome-wide DNA methylation using HumanMethylation450 BeadChip arrays in 21 primary HG-NMIBC tumors relative to normal bladder controls. Using strict inclusion-exclusion criteria we identified 1,057 hypermethylated CpGs within gene promoter-associated CpG islands, representing 256 genes. We validated the array data by bisulphite pyrosequencing and examined 25 array-identified candidate genes in an independent cohort of 30 HG-NMIBC and 18 low-intermediate-grade NMIBC. These analyses revealed significantly higher methylation frequencies in high-grade tumors relative to low-intermediate-grade tumors for the ATP5G2, IRX1 and VAX2 genes (P<0.05), and similarly significant increases in mean levels of methylation in high-grade tumors for the ATP5G2, VAX2, INSRR, PRDM14, VSX1, TFAP2b, PRRX1, and HIST1H4F genes (P<0.05). Although inappropriate promoter methylation was not invariantly associated with reduced transcript expression, a significant association was apparent for the ARHGEF4, PON3, STAT5a, and VAX2 gene transcripts (P<0.05). Herein, we present the first genome-wide DNA methylation analysis in a unique HG-NMIBC cohort, showing extensive and discrete methylation changes relative to normal bladder and low-intermediate-grade tumors. The genes we identified hold significant potential as targets for novel therapeutic intervention either alone, or in combination, with more conventional therapeutic options in the treatment of this clinically unpredictable disease.

Methylation of HOXA9 and ISL1 Predicts Patient Outcome in High-Grade Non-Invasive Bladder Cancer.

INTRODUCTION: Inappropriate DNA methylation is frequently associated with human tumour development, and in specific cases, is associated with clinical outcomes. Previous reports of DNA methylation in low/intermediate grade non-muscle invasive bladder cancer (NMIBC) have suggested that specific patterns of DNA methylation may have a role as diagnostic or prognostic biomarkers. In view of the aggressive and clinically unpredictable nature of high-grade (HG) NMIBC, and the current shortage of the preferred treatment option (Bacillus:Calmette-Guerin), novel methylation analyses may similarly reveal biomarkers of disease outcome that could risk-stratify patients and guide clinical management at initial diagnosis. METHODS: Promoter-associated CpG island methylation was determined in primary tumour tissue of 36 initial presentation high-grade NMIBCs, 12 low/intermediate-grade NMIBCs and 3 normal bladder controls. The genes HOXA9, ISL1, NKX6-2, SPAG6, ZIC1 and ZNF154 were selected for investigation on the basis of previous reports and/or prognostic utility in low/intermediate-grade NMIBC. Methylation was determined by Pyrosequencing of sodium-bisulphite converted DNA, and then correlated with gene expression using RT-qPCR. Methylation was additionally correlated with tumour behaviour, including tumour recurrence and progression to muscle invasive bladder cancer or metastases. RESULTS: The ISL1 genes' promoter-associated island was more frequently methylated in recurrent and progressive high-grade tumours than their non-recurrent counterparts (60.0% vs. 18.2%, p = 0.008). ISL1 and HOXA9 showed significantly higher mean methylation in recurrent and progressive tumours compared to non-recurrent tumours (43.3% vs. 20.9%, p = 0.016 and 34.5% vs 17.6%, p = 0.017, respectively). Concurrent ISL1/HOXA9 methylation in HG-NMIBC reliably predicted tumour recurrence and progression within one year (Positive Predictive Value 91.7%), and was associated with disease-specific mortality (DSM). CONCLUSIONS: In this study we report methylation differences and similarities between clinical sub-types of high-grade NMIBC. We report the potential ability of methylation biomarkers, at initial diagnosis, to predict tumour recurrence and progression within one year of diagnosis. We found that specific biomarkers reliably predict disease outcome and therefore may help guide patient treatment despite the unpredictable clinical course and heterogeneity of high-grade NMIBC. Further investigation is required, including validation in a larger patient cohort, to confirm the clinical utility of methylation biomarkers in high-grade NMIBC.

Epidrug mediated re-expression of miRNA targeting the HMGA transcripts in pituitary cells.

INTRODUCTION: Transgenic mice overexpressing the high mobility group A (HMGA) genes, Hmga1 or Hmga2 develop pituitary tumours and their overexpression is also a frequent finding in human pituitary adenomas. In some cases, increased expression of HMGA2 but not that of HMGA1 is consequent to genetic perturbations. However, recent studies show that down-regulation of microRNA (miRNA), that contemporaneously target the HMGA1 and HMGA2 transcripts, are associated with their overexpression. RESULTS: In a cohort of primary pituitary adenoma we determine the impact of epigenetic modifications on the expression of HMGA-targeting miRNA. For these miRNAs, chromatin immunoprecipitations showed that transcript down-regulation is correlated with histone tail modifications associated with condensed silenced genes. The functional impact of epigenetic modification on miRNA expression was determined in the rodent pituitary cell line, GH3. In these cells, histone tail, miRNA-associated, modifications were similar to those apparent in human adenoma and likely account for their repression. Indeed, challenge of GH3 cells with the epidrugs, zebularine and TSA, led to enrichment of the histone modification, H3K9Ac, associated with active genes, and depletion of the modification, H3K27me3, associated with silent genes and re-expression of HMGA-targeting miRNA. Moreover, epidrugs challenges were also associated with a concomitant decrease in hmga1 transcript and protein levels and concurrent increase in bmp-4 expression. CONCLUSIONS: These findings show that the inverse relationship between HMGA expression and targeting miRNA is reversible through epidrug interventions. In addition to showing a mechanistic link between epigenetic modifications and miRNA expression these findings underscore their potential as therapeutic targets in this and other diseases.

Medium-term outcomes of patients with insulin-dependent diabetes after laparoscopic adjustable gastric banding.

BACKGROUND: Bariatric surgery is effective in the control of type 2 diabetes mellitus. Laparoscopic adjustable gastric banding is a popular form of bariatric surgery, but very limited data are available on its long-term effect on type 2 diabetes mellitus. The present study examined the effect of gastric banding on a consecutive cohort of unselected patients with insulin-dependent diabetes mellitus at a teaching hospital in Birmingham, United Kingdom. METHODS: From April 2003 to December 2008, 200 patients with diabetes underwent laparoscopic adjustable gastric banding at our unit. All those with insulin-dependent diabetes and ≥1 year of follow-up were included in the present analysis. Data collection included the body mass index, weight, blood pressure, glycosylated hemoglobin, fasting glucose, total cholesterol, triglycerides, and medication dose preoperatively and 1, 2, and 3 years postoperatively. RESULTS: Preoperatively, 69 patients were taking insulin, with a mean daily preoperative dose of 132.3 U (range 15-500). At 1 year, 27 of these patients had discontinued using insulin (34.8%). At 2 years, 34 patients had discontinued using insulin (54.8% of the patients taking insulin preoperatively and who had also completed 2 yr of follow-up). At 3 years, 40 patients had discontinued using insulin (80% of patients who were taking insulin preoperatively and who had also completed 3 yr of follow-up). These changes were accompanied by an improvement in glycosylated hemoglobin, fasting glucose, total serum cholesterol, triglycerides, and mean arterial pressures. CONCLUSION: Laparoscopic gastric banding can be considered a powerful treatment option in the management of obese patients with insulin-dependent diabetes and becomes increasingly effective with time ≤3 years after surgery.

Junior doctors' guide to portfolio learning and building.

BACKGROUND: A portfolio is a collection of evidence supporting an individual's achievement of competencies and learning outcomes. The material included in the portfolio must be reflected upon, as reflection provides the evidence that learning has taken place. CONTEXT: Portfolio learning is important for two principal reasons: assessment of the trainee, and for lifelong learning and reflection. The ability of a portfolio to be used for both summative and formative assessment makes it a flexible and robust assessment method. A portfolio also demonstrates reflection and lifelong learning abilities. Reflective learning is key to postgraduate medical education: it is part of both the Foundation Programme curriculum and General Medical Council guidance on best practice. INNOVATION: To ensure correct learning outcomes are identified and evidenced, the curriculum programme must be referred to and an educational supervisor should be consulted. Once identified, it is necessary to: identify how these outcomes can be met (learning needs); decide what needs to be done to meet these needs; reflect on what has been done; and evidence what has been done in the portfolio. Evidence could include written feedback, certificates of course completion, online learning modules, etc. IMPLICATIONS: A learning portfolio is a necessary tool for every postgraduate medical trainee. The portfolio serves to record and evidence all learning that has taken place, and thereon acts as a guide for future learning needs. The key process to portfolio building and learning is the provision of evidence by reflecting upon the learning that has taken place.

Facilitating small groups: how to encourage student learning.

BACKGROUND: Many clinicians are involved in medical education, with small group teaching (SGT) forming a significant part of their work. Most facilitate these sessions by experience and common sense: less than one-third of them have received formal training in SGT. CONTEXT: Evidence suggests small group productivity depends on good facilitation rather than on topic knowledge. Applying the fundamental concepts of SGT will lead to improvements in the quality of clinicians' teaching and in student learning. Good SGT creates the perfect environment for learning and discussion, without the need for didactic teaching. SGT emphasises the role of students in sharing and discussing their ideas in a safe learning environment, without domination by the tutor. INNOVATION: This article provides clinicians with basic requirements for effective session design and planning, explains how to encourage student participation, how to manage students as a group, how to manage student learning, and how to recognise and deal with problems. IMPLICATIONS: Active facilitation and group management is the key to success in SGT, and consequently better learning outcomes. Improving the facilitation skills of clinical teachers makes teaching more effective, stimulating, and enjoyable for both tutors and students.

Band slippage and erosion after laparoscopic gastric banding: a meta-analysis.

BACKGROUND: Laparoscopic adjustable gastric banding has the lowest morbidity and mortality rates among the common bariatric procedures. Troublesome complications associated with this procedure include band slippage and erosion, often requiring revisionary surgery. Rates of slippage have decreased, and this appears to be due to changes in surgical technique. In the authors' experience, units with a low slippage rate also have a low erosion rate and vice versa. Thus a systematic review was undertaken to investigate this relationship. METHODS: Electronic databases were searched up to 31 December 2008. Publications focusing solely on laparoscopic adjustable gastric banding with at least 500 patients and a minimum follow-up period of 2 years were included in the study. Publications in languages other than English and those that failed to mention erosion and slippage rates were excluded. Multivariate meta-analyses were conducted separately for the pars flaccida group, the perigastric group, and the combined overall group to pool the average rates of both erosion and slippage for each paper included. The correlation between the occurrence rates for both erosion and slippage then was examined. RESULTS: The inclusion criteria were met by 19 studies. The mean rates of erosion and slippage were 1.03 and 4.93, respectively. The results demonstrated a statistically significant overall correlation between erosion and slippage rates (r = 0.48, p = 0.032). A very strong correlation between erosion and slippage was found if the perigastric technique of insertion was used (r = 0.99, p < 0.001). However, this correlation was not statistically significant where the pars flaccida technique of insertion was used (r = 0.34, p = 0.38). CONCLUSIONS: The high correlation rate between erosion and slippage for the perigastric group strongly suggests that these complications share a common pathophysiology. This correlation is reduced with the pars flaccida technique, suggesting that perhaps a different etiology is associated with erosion in these studies. Surgical techniques that help to eliminate lap band slippage should also reduce rates of erosion.

Dietetic-led management of patients undergoing laparoscopic gastric banding: early results.

BACKGROUND: Optimal results of bariatric surgery are achieved when it is performed within a multidisciplinary team. Within this team, the dietician plays a key role before and after surgery in patient education and behaviour change. With long-term follow-up, the number of patients per surgeon increases exponentially. This study evaluated the outcomes of a dietician-only led management program for patients who underwent laparoscopic gastric banding in our unit. METHODS: Between April 2003 and November 2007, 1,335 patients underwent laparoscopic gastric banding in two hospitals by the same surgical team. Weight loss outcomes were compared for patients in a dietician-led management program against a surgeon/nurse specialist follow-up program with more frequent patient visits. For the dietician-led group, a standard protocol of six postoperative visits and two to three fluoroscopic adjustments was developed from referral until 2 years after surgery. RESULTS: There were 316 patients followed up in a dietician-led program. They were compared with the remaining patients who were followed up in a surgeon/ nurse specialist led program. The mean preoperative weight and body mass index (BMI) for the dietetic-led subset was significantly higher (weight: 147.4 +/- 30.2; BMI: 52.8 +/- 8.9) compared with the remaining group (weight: 113.8 +/- 18.7; BMI: 41.6 +/- 5.2; p < 0.001: Mann-Whitney test). Percent BMI loss was initially lower in the dietician-led group, but this difference disappeared at the end of 24 months (p = 0.056). CONCLUSIONS: A patient management program led by specialist dieticians is an effective way to manage large numbers of patients after laparoscopic gastric banding while maintaining comparable weight loss to surgeon/nurse-led series.

Age > or =50 does not influence outcome in laparoscopic gastric banding.

BACKGROUND: Laparoscopic adjustable gastric banding is an accepted treatment for obesity. Age greater than 50 carries a theoretically increased risk from weight loss surgery and perhaps less clinical benefit in the long term. We compare results of gastric banding at age 50 and above with age below 50 in our unit. METHODS: Between April 2003 and November 2007, 1,335 patients, mean weight 121.7 kg (range 73-268 kg), mean body mass index (BMI) 44.1 kg/m(2) (range 35-99), underwent gastric banding. Three hundred and twenty four patients had age > or =50. Band adjustments were usually carried out using fluoroscopy. RESULTS: There was no statistically significant difference in the preoperative weights and BMIs for the two patient groups (age < 50: weight 120.7 +/- 24.9, BMI 43.6 +/- 7.3 kg/m(2); age > or = 50: weight 118 +/- 23.7 kg, BMI 43.8 +/- 7 kg/m(2)). Similarly, there was no statistically significant difference with regards to excess percent BMI loss in the two groups over 36 months (age < 50 = 49 +/- 27.9; age > or = 50 = 47.3 +/- 35.1). There was no difference in the incidence of complications with patient age. CONCLUSION: These results demonstrate that, at age > or =50, this procedure is successful in producing weight loss and, at the same time, has a complication rate comparable to younger patients.

Metabolic outcomes of obese diabetic patients following laparoscopic adjustable gastric banding.

INTRODUCTION: Obesity is an independent risk factor in the development of diabetes. Weight loss surgery is the most effective treatment of morbid obesity. This study examines the effect of gastric banding on metabolic profile in diabetics. METHODS: Between April 2003 and November 2007, 1,335 patients underwent laparoscopic adjustable gastric banding. Metabolic profile was examined on a subset of 254 patients. Of these, 122 were diabetic. Data collection included body mass index, weight, blood pressure, HbA1c, fasting glucose, total serum cholesterol, triglyceride, and medications taken for blood pressure and diabetes both preoperatively and 1 year postoperatively. RESULTS: Comorbid conditions in the diabetic patients included hypercholesterolemia (49.3%), hypertriglyceridemia (53.8%) and hypertension (92%). In 1 year, mean BMI reduced from 52.9 kg/m(2) to 41.5 kg/m(2). Of the patients, 93.1% experienced an improvement in fasting glucose levels and 75.4% patients an improvement in HbA1c levels at the end of 1 year. All patients experienced a decrease in insulin requirements, and 36.6% were able to totally discontinue using it. Of the patients, 100% showed improvement in their triglyceride level, and 90.9% showed improvement in their total cholesterol level. The mean arterial pressure improved in 87.5% of the patients. CONCLUSION: The metabolic syndrome associated with morbid obesity is difficult to adequately control with medication. Laparoscopic gastric banding can be considered a potentially curative treatment option in the management of this syndrome.

The "Birmingham stitch"--avoiding slippage in laparoscopic gastric banding.

BACKGROUND: Slippage rates of 1.4-24 % are frequently quoted after adjustable gastric banding. This complication can be extremely serious and has contributed to many units offering more invasive interventions in the surgical management of morbid obesity. We present results of the first 1,140 Laparoscopic Bands performed in our unit. METHODS: Between April 2003 and June 2007, 1140 consecutive patients, mean weight 121.5 kg (range 73-268 kg), mean body mass index (BMI) 44.3 kg/m(2) (range 35-88) underwent laparoscopic adjustable gastric banding (LAGB). An identical surgical technique of one gastropexy suture in addition to the two routine gastro-gastro tunnel sutures was used in all cases. Fluoroscopy-guided adjustments were performed at 3 and 6 months and fluoroscopic evaluations were performed later if clinically indicated. RESULTS: There was no mortality and only one major septic complication of gastric perforation 1 week postoperatively which was managed conservatively. The mean stay was 1.02 days (range 0-30 days). Excess percent BMI loss in these patients at 3, 6, 12, 18, 24, 30, and 36 months were 25.4%, 34.7%, 38.3%, 41.1%, 43.7%, 44.4%, and 58.9%, respectively. Slippage with urgent readmission occurred in one patient (0.08%) at 5 months. Two partial slippages were noticed at 12 and 18 months, respectively. One patient had the band removed and the other was treated by band deflation and repositioning 6 months later. CONCLUSION: These results demonstrate that in our unit, laparoscopic gastric band insertion is successful in producing weight loss and at the same time has a very low slippage and pouch dilatation rate. This difference is most probably secondary to operative technique.