A Method for Increasing the Robustness of Stable Feature Selection for Biomarker Discovery in Molecular Medicine Developed Using Serum Small Extracellular Vesicle Associated miRNAs and the Barrett's Oesophagus Disease Spectrum.

The biomarker development field within molecular medicine remains limited by the methods that are available for building predictive models. We developed an efficient method for conservatively estimating confidence intervals for the cross validation-derived prediction errors of biomarker models. This new method was investigated for its ability to improve the capacity of our previously developed method, StaVarSel, for selecting stable biomarkers. Compared with the standard cross validation method, StaVarSel markedly improved the estimated generalisable predictive capacity of serum miRNA biomarkers for the detection of disease states that are at increased risk of progressing to oesophageal adenocarcinoma. The incorporation of our new method for conservatively estimating confidence intervals into StaVarSel resulted in the selection of less complex models with increased stability and improved or similar predictive capacities. The methods developed in this study have the potential to improve progress from biomarker discovery to biomarker driven translational research.

Five Year Follow-up of a Randomized Controlled Trial of Laparoscopic Repair of Very Large Hiatus Hernia With Sutures Versus Absorbable Versus Nonabsorbable Mesh.

OBJECTIVE: To determine whether absorbable or nonabsorbable mesh repair of large hiatus hernias is followed by less recurrences at late follow-up compared to sutured repair. SUMMARY OF BACKGROUND DATA: Radiological recurrences have been reported in up to 30% of patients after repair of large hiatus hernias, and mesh repair has been proposed as a solution. Earlier trials have revealed mixed outcomes and early outcomes from a trial reported previously revealed no short-term advantages for mesh repair. METHODS: Multicentre prospective double-blind randomized controlled trial of 3 methods of hiatus hernia repair; sutures versus absorbable mesh versus nonabsorbable mesh. Primary outcome - hernia recurrence assessed by barium meal X-ray and endoscopy at 3-4 years. Secondary outcomes - clinical symptom scores at 2, 3, and 5 years. RESULTS: 126 patients were enrolled - 43 sutures, 41 absorbable mesh, and 42 nonabsorbable mesh. Clinical outcomes were obtained at 5 years in 89.9%, and objective follow-up was obtained in 72.3%. A recurrent hernia (any size) was identified in 39.3% after suture repair, 56.7% - absorbable mesh, and 42.9% - nonabsorbable mesh (P = 0.371). Clinical outcomes were similar at 5 years, except chest pain, diarrhea, and bloat symptoms which were more common after repair with absorbable mesh. CONCLUSIONS: No advantages were demonstrated for mesh repair at up to 5 years follow-up, and symptom outcomes were worse after repair with absorbable mesh. The longer-term results from this trial do not support mesh repair for large hiatus hernias.

Laparoscopic repair of very large hiatus hernia with sutures versus absorbable mesh versus nonabsorbable mesh: a randomized controlled trial.

OBJECTIVE: Determine whether absorbable or nonabsorbable mesh in repair of large hiatus hernias reduces the risk of recurrence, compared with suture repair. BACKGROUND: Repair of large hiatus hernia is associated with radiological recurrence rates of up to 30%, and to improve outcomes mesh repair has been recommended. Previous trials have shown less short-term recurrence with mesh, but adverse outcomes limit mesh use. METHODS: Multicentre prospective double blind randomized controlled trial of 3 methods of repair: sutures versus absorbable mesh versus nonabsorbable mesh. Primary outcome-hernia recurrence assessed by barium meal radiology and endoscopy at 6 months. Secondary outcomes-clinical symptom scores at 1, 3, 6, and 12 months. RESULTS: A total of 126 patients enrolled: 43 sutures, 41 absorbable mesh, and 42 nonabsorbable mesh. Among them, 96.0% were followed up to 12 months, with objective follow-up data in 92.9%. A recurrent hernia (any size) was identified in 23.1% after suture repair, 30.8% after absorbable mesh, and 12.8% after nonabsorbable mesh (P = 0.161). Clinical outcomes were similar, except less heartburn at 3 and 6 months and less bloating at 12 months with nonabsorbable mesh; more heartburn at 3 months, odynophagia at 1 month, nausea at 3 and 12 months, wheezing at 6 months; and inability to belch at 12 months after absorbable mesh. The magnitudes of the clinical differences were small. CONCLUSIONS: No significant differences were seen for recurrent hiatus hernia, and the clinical differences were unlikely to be clinically significant. Overall outcomes after sutured repair were similar to mesh repair.

Phase 1 trial of intraperitoneal paclitaxel in combination with intravenous cisplatin and oral capecitabine in patients with advanced gastric cancer and peritoneal metastases (IPGP study).

AIMS: Gastric cancer with peritoneal involvement has a poor prognosis. Intraperitoneal (IP) paclitaxel has shown promising results in these patients. However, this approach has only been studied in the Asian population, and in combination with S-1. We investigated the maximum tolerated dose of IP paclitaxel, with a standard chemotherapy combination, in the Australian population. METHODS: The study of the population included metastatic human epidermal growth factor receptor 2 (HER2) negative gastric adenocarcinoma with peritoneal involvement. Treatment included six 21-day cycles of cisplatin (80 mg/m2 IV, day 1) plus capecitabine (1000 mg/m2 PO BD, days 1-14) plus IP paclitaxel (days 1 and 8). IP paclitaxel doses for cohort 1-3 were 10, 20, and 30 mg/m2 , respectively, in a 3 + 3 standard dose-escalation design. RESULTS: Fifteen patients were enrolled of which 6 were female and the median age was 63. Two patients developed dose-limiting toxicities. No grade 4/5 toxicities were recorded. The maximum tolerated dose was not reached. Therefore, as defined by the study protocol, the recommended phase-2 dose for IP paclitaxel was determined to be 30 mg/m2 . The 12-month survival rate was 46.7%, and the median survival was 11.5 months (interquartile range [IQR]: 15.3-6.9). CONCLUSIONS: IP paclitaxel is safe in combination with cisplatin and capecitabine and the recommended phase-2 dose is 30 mg/m2 .

New endoscopic and surgical treatment options for early esophageal adenocarcinoma.

Although the outcome for advanced stage esophageal cancer is poor, the early detection and treatment of early stage disease is usually associated with a much better outcome. Until recently, esophagectomy has been the treatment of choice in fit patients. However, morbidity is significant, and this has encouraged the development of newer endoscopic treatments that preserve the esophagus. These techniques include ablation and mucosal resection. Promising results are described, and endoscopic methods might provide a reasonable alternative for the treatment of early esophageal cancer. However, follow-up remains short and endoscopic treatment does not deal with potential lymphatic spread. Hence, careful selection is required. Minimally invasive techniques for esophageal resection have also been shown to be feasible, although there is only limited evidence that they reduce postoperative morbidity. Better data are still required to demonstrate improved outcomes from endoscopic treatment and minimally invasive esophagectomy.

Phase I open-label trial of intraperitoneal paclitaxel in combination with intravenous cisplatin and oral capecitabine in patients with advanced gastric cancer and peritoneal metastases (IPGP study): study protocol.

INTRODUCTION: Gastric cancer with peritoneal metastasis has a poor outcome. Only a few studies have specifically investigated this group of patients. Japanese researchers have shown that chemotherapy with intraperitoneal paclitaxel (IPP) and oral S-1 (tegafur/gimeracil/oteracil) is active and well tolerated. These results have been achieved in a specific genetic pool (Japanese population), using regimens that may not be available in other parts of the world. We have designed this phase I trial to investigate IPP in combination with a standard chemotherapy combination in these patients. METHODS: We use a 3+3 expanded cohort dose escalation until a predefined number of dose-limiting toxicities are reached. Patients will have an intraperitoneal catheter placed surgically after trial enrolment. Chemotherapy includes a maximum of six cycles (21 days) of capecitabine (X) (1000 mg/m2 two times a day, days 1-14)+cisplatin (C) (intravenous 80 mg/m2 day 1) and IPP (days 1 and 8) with the following doses: cohort-1: 10 mg/m2, cohort-2: 20 mg/m2 and cohort-3: 30 mg/m2. Primary endpoint is to determine the maximum tolerated dose of IPP. Secondary endpoints include determining the safety and tolerability of IPP in combination with C and X, overall response rates, ascites response rate, progression-free survival, overall survival and effects on quality of life.Important inclusion criteria include age ≥18 years, human epidermal growth factor receptor 2 non-amplified gastric adenocarcinoma with histological or cytology-proven peritoneal involvement and adequate organ function. Exclusion criteria include previous malignancy within 5 years, recent abdominal or pelvic radiation treatment, significant abdominal adhesions or sepsis. ETHICS AND DISSEMINATION: The study is approved by Southern Adelaide Clinical Human Research Ethics Committee. A manuscript will be prepared for publication on the completion of the trial. This study will be conducted according to the Note for Guidance on Good Clinical Practice (CPMP/ICH/135/95) annotated with TGA comments (Therapeutic Goods Administration DSEB July 2000) and in compliance with applicable laws and regulations. The study will be performed in accordance with the NHMRC Statement on Ethical Conduct in Research Involving Humans (© Commonwealth of Australia 2007), and the NHMRC Australian Code for the Responsible Conduct of Research (©Australian Government 2007), and the principles laid down by the World Medical Assembly in the Declaration of Helsinki 2008. TRIAL REGISTRATION NUMBER: ACTRN12614001063606.

More than meets the eye: subtle but important CT findings in Bouveret's syndrome.

OBJECTIVE: Gallstones are a rare cause of duodenal or gastric outlet obstruction and therefore are not commonly suspected. Rigler's radiographic triad of pneumobilia, bowel obstruction, and an ectopic gallstone is seen in few of these patients. The symptoms are insidious and nonspecific, and the diagnosis is usually made radiologically. Although CT scans are far more sensitive, 25% of cases are still missed, often because the size of the offending gallstone is underestimated. CONCLUSION: Better assessment of stone size, and therefore higher accuracy of diagnosis, could be achieved if attention is paid to more subtle but nonetheless important signs. These include compressed air in dependent areas of the duodenal lumen, an area of soft-tissue rather than fluid density surrounding the calcified rim of the stone, and a faint radiolucency in or beyond this soft-tissue area that could represent laminations of fat or air in the stone.

Self-Reported Hypoglycemia in Insulin-Treated Patients with Diabetes: Results from the Philippine Cohort of the International Operations Hypoglycemia Assessment Tool (IO HAT) Study.

OBJECTIVE: To determine the frequency of hypoglycemia in insulin-treated patients with type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM) in the non-interventional International Operations Hypoglycemia Assessment Tool (IO HAT) study. METHODOLOGY: This sub-analysis included Filipino patients with T1DM or T2DM, aged 18 years and older, treated with insulin for more than 12 months, who completed the two-part self-assessment questionnaires (SAQ1 and SAQ2) and patient diaries that recorded hypoglycemia during retrospective (6 months/4 weeks before baseline) and prospective period (4 weeks after baseline) (ClinicalTrials.gov number: NCT02306681). RESULTS: A total of 671 patients were enrolled and completed the SAQ1 (62 patients with T1DM and 609 patients with T2DM). Almost all patients (100% in T1DM and 99.3% in T2DM) experienced at least 1 hypoglycemic event prospectively. The incidence of any hypoglycemia was also high in the prospective period compared to retrospective period (72.6 [95% CI: 64.8, 80.9] events PPY and 43.6 [95% CI: 37.8, 49.9] events PPY; p=0.001, respectively) in T1DM patients. CONCLUSION: Among insulin-treated patients, higher rates of hypoglycemia were reported prospectively than retrospectively. This indicates that the patients in real-life setting often under-report hypoglycemia. Patient education can help in accurate reporting and appropriate management of hypoglycemia and diabetes.

Efficacy of surgery in the management of obesity-related type 2 diabetes mellitus.

BACKGROUND: It is estimated that up to 80% of persons with diabetes mellitus type 2 are overweight and in these patients it is recognized that effective weight control can lead to improvement or even resolution of their diabetes (Colagiuri et al.). All currently carried out operations for morbid obesity have been shown to improve diabetes, but there appears to be a variable response to surgery depending on several surgical and patient factors. METHODS: In this prospective review, we analysed the change in the diabetic status in 72 patients undergoing three different bariatric procedures in a single institution over 30 months. A review of the published work comparing the efficacy of the various procedures in achieving improvement or resolution of diabetes was also carried out and correlated to our findings. RESULTS: At an average follow up of 13 months, 50% of patients who had placement of laparoscopic adjustable gastric band had an improvement or resolution of their diabetes, compared with 95% of patients who had had laparoscopic sleeve gastrectomy or Roux-en-Y gastric bypass. Two of 12 (17%) laparoscopic adjustable gastric band patients had normal blood glucose levels off all diabetic medications compared with 7 of 21 (33%) laparoscopic sleeve gastrectomy and 27 of 39 (69%) Roux-en-Y gastric bypass patients. There was no significant association between the amount of weight lost and the return to euglycaemia. CONCLUSION: Direct comparison has shown a significant difference in the effects of different forms of bariatric surgery on type 2 diabetes, this is in keeping with evidence that surgery can lead to improvement in diabetes additional to that obtained by weight loss alone.

Safety and effectiveness of biphasic insulin aspart 30 in type 2 diabetes patients switched from biphasic human insulin 30: results from the Filipino cohort of the A1chieve study.

AIM: To evaluate the safety and effectiveness of biphasic insulin aspart 30 (BIAsp 30) in Filipino patients with type 2 diabetes previously treated with biphasic human insulin 30 (BHI 30). METHODS: Safety and effectiveness outcomes were measured in all patients switching from BHI 30 to BIAsp 30 in the Filipino cohort of the 24-week, multinational, prospective, non-interventional A1chieve study. RESULTS: A total of 111 Filipino patients (mean age ± SD, 57.4 ± 12.8 years; BMI, 25.8 ± 5.6 kg/m(2)) with mean diabetes duration of 9.9 ± 7.1 years switched therapy from BHI 30 to BIAsp 30. The mean pre-study BHI 30 dose was 0.65 ± 0.28 IU/kg and the baseline BIAsp 30 dose was 0.65 ± 0.26 U/kg titrated up to 0.70 ± 0.26 U/kg by Week 24. No serious adverse drug reactions were reported. Overall hypoglycaemia was reduced from 5.62 to 1.98 events/patient-year. Minor and nocturnal hypoglycaemia decreased and no major hypoglycaemia was reported at Week 24. Glucose control improved from baseline to Week 24 (HbA1c, -2.2 ± 2.1% [24 ± 23 mmol/mol]; FPG, -72.0 ± 71.8 mg/dL; PPPG, -145.5 ± 125.4 mg/dL). A total of 24 patients achieved HbA1c levels <7.0% at Week 24 compared to 6 patients reporting this target at baseline. Quality of life was positively impacted at Week 24 (change in visual analogue scores, 15.3 ± 16.9 points). CONCLUSION: Switching from BHI 30 to BIAsp 30 improved glycaemic control without increasing the risk of hypoglycaemia.

Challenges in achieving optimal glycemic control in type 2 diabetes patients with declining renal function: The Southeast Asia perspective.

It is well recognised that Asia is at the epicenter of the global type 2 diabetes epidemic. Driven by socioeconomic changes involving industrialization, urbanization and adoption of Western lifestyles, the unprecedented increases in the prevalence of diabetes are particularly evident in Southeast Asia. The impact of diabetes is immense, and despite evidence of the benefit of optimal glucose control in reducing the risk of disease progression and development of macrovascular and microvascular complications, many individuals in this region remain poorly controlled. Chronic kidney disease (CKD) is an increasingly common diabetes-associated complication in Asian patients. Furthermore, Southeast Asia has one of the highest rates of end-stage renal disease (ESRD) in the world. Consequently, CKD in diabetes is associated with considerable morbidity and cardiovascular-related mortality, highlighting the need to screen and assess patients early in the course of the disease. The management of type 2 diabetes patients with declining renal function represents a significant challenge. Many of the older antidiabetic agents, such as metformin and sulfonylureas, are limited in their utility in CKD as a result of contraindications or hypoglycemic episodes. In contrast, dipeptidyl-peptidase IV inhibitors have provided a welcome addition to the therapeutic armamentarium for achieving glycemic control in these special populations. With comparable efficacy to and more favorable pharmacokinetic and side-effect profiles than traditional therapies, agents in this drug class, such as linagliptin, offer a more tailored approach to disease control in type 2 diabetes patients with declining renal function.