Outcomes of the One Anastomosis Gastric Bypass with Various Biliopancreatic Limb Lengths:a Retrospective Single-Center Cohort Study

Introduction: One anastomosis gastric bypass (OAGB) is an effective and safe treatment for morbidly obese patients. Longer biliopancreatic (BP) limb length is suggested to result in better weight loss outcomes, but to date, no data are available for the OAGB to substantiate this. We hypothesized that applying a longer BP-limb length in the higher BMI classes would result in more weight reduction so that the attained BMI would be comparable to patients with a lower BMI, thereby compensating for differences in baseline BMI. Method: A retrospective cohort study in patients who underwent a primary OAGB at a teaching hospital in the Netherlands between January 2015 and December 2016. BP-limb length was tailored based on preoperative BMI. Patients were divided into three different groups depending on the length of the BP-limb: 150, 180, and 200 cm. Weight loss outcomes after 1 and 3 years and resolution of comorbidities were compared between these groups. Results: Of the 632 included patients, a BP-limb length of 150 cm was used in 172 (27.2%), 180 cm in 388 (61.4%), and 200 cm in 72 (11.4%) patients. Despite more BMI loss, %EWL was lower and attained BMI remained higher in the groups with longer BP-limb lengths. After adjustment for the confounder preoperative BMI, longer BP-limb lengths were not associated with higher BMI loss. There was no difference in remission rates of comorbidities. Conclusion: Attained BMI remained higher in spite of tailoring BP-limb length according to baseline BMI with no differences in remission rates of comorbidities

Tailoring limb length based on total small bowel length in one anastomosis gastric bypass surgery (TAILOR study):study protocol for a randomized controlled trial

Background: The one anastomosis gastric bypass (OAGB) is being performed by an increasing number of bariatric centers over the world. However, the optimal length of the biliopancreatic (BP) limb remains a topic of discussion. Retrospective studies suggest the benefit of tailoring BP-limb length; however, randomized trials are lacking. The aim of this study is to investigate whether tailoring the length of the BP-limb based on total small bowel length (TSBL) leads to better results in terms of weight loss, vitamin deficiencies, and bowel movements compared to a fixed BP-limb length. Methods: The TAILOR study is a double-blind single-center randomized controlled trial. Patients scheduled for primary OAGB surgery will be randomly allocated either to a standard BP-limb of 150 cm or to a BP-limb length based on their TSBL: TSBL 700 cm, BP-limb 210 cm. The primary outcome is to compare the percent total weight loss (%TWL) at 5 years between the two groups. Secondary outcomes include nutritional deficiencies, remission of comorbidities, symptoms of dumping, quality of life, and daily bowel movements. The study includes a total of 212 patients and is designed to detect a 5% difference in the primary endpoint. Discussion: The TAILOR study will provide new insights into the effect of different BP-limb lengths and the role of the TSBL in the OAGB. The study is designed to provide guidance for bariatric surgeons to determine the optimal BP-limb length in the OAGB

Laparoscopic Small Bowel Length Measurement in Bariatric Surgery Using a Hand-Over-Hand Technique with Marked Graspers:an Ex Vivo Experiment

Introduction Tailoring limb length in bariatric surgery is a subject of many studies. To acquire the optimal limb length, accurate measurement of the small bowel length is essential. Objective To assess the intra- and inter-individual variability of laparoscopic bowel length measurement using a hand-over-hand technique with marked graspers. Method Four bariatric surgeons and four surgical residents performed measurements on cadaver porcine intestine in a laparoscopic box using marked graspers. Each participant performed 10 times a measurement of three different lengths: 150, 180, and 210 cm. Acceptable percentage deviation from the goal lengths was defined as less than 10%, while unacceptable deviations were defined as more than 15%. Results The bariatric surgeons measured the 150-, 180-, and 210-cm tasks with 4% (CI 0.4, 9), - 6% (CI - 11, - 0.8), and 1% (CI - 4, 6) deviation, respectively. In total, the bariatric surgeons estimated 58 out of 119 times (49%) between the margins of 10% deviation and 36 times (30%) outside the 15% margin. Considerable inter-individual differences were found between the surgeons. The surgical residents underestimated the tasks with 12% (CI - 18, - 6), 16% (CI - 19, - 13), and 18% (CI - 22, - 13), respectively. Conclusion Bariatric surgeons estimated bowel length with on average less than 10% deviation. However, this still resulted in 30% of the measurements with more than 15% deviation. There were considerable inter-individual differences between the surgeons and residents structurally underestimated the bowel length. Ascertainment of measurement accuracy and adequate training is essential for bariatric procedures in which limb length is of importance

Applying an Anti-reflux Suture in the One Anastomosis Gastric Bypass to Prevent Biliary Reflux:a Long-Term Observational Study

INTRODUCTION: The one anastomosis gastric bypass (OAGB) is an effective treatment to induce sustained weight loss in morbidly obese patients. Concerns remain regarding the development of reflux. The aim of this study was to investigate the effect of an "anti-reflux suture" as anti-reflux modification to prevent reflux. METHOD: This is a single-center retrospective cohort study of patients who underwent a primary OAGB at the Center Obesity North-Netherlands (CON) between January 2015 and December 2016. Reflux was defined as symptoms of acid/bilious regurgitation or pyrosis. This was consequently asked and reported at each follow-up visit. Outcomes of patients with an anti-reflux suture were compared to those without. RESULTS: In 414 (59%) of the 703 included patients, an anti-reflux suture was applied. Follow-up at 3 years was 74%. The incidence of reflux did not differ between patients with or without an anti-reflux suture (57 versus 56%, respectively; P = 0.9). The presence of an anti-reflux suture was significantly associated with a lower incidence of conversion to Roux-en-Y gastric bypass (RYGB) for reflux (OR 0.56, 95%CI 0.34-0.91). Patients preoperatively diagnosed with gastroesophageal reflux disease (GERD) were 5.2 times more likely to need a conversion to RYGB for reflux (95%CI 2.7-10.1). CONCLUSION: The presence of preoperative GERD should be weighted heavily in the decision to perform an OAGB as this is a major risk factor for conversion surgery due to reflux. The anti-reflux suture might be a valuable addition to the procedure of the OAGB because it results in fewer conversion surgeries for reflux

Alteration of AKT Activity Increases Chemotherapeutic Drug and Hormonal Resistance in Breast Cancer yet Confers an Achilles Heel by Sensitization to Targeted Therapy

The PI3K/PTEN/Akt/mTOR pathway plays critical roles in the regulation of cell growth. The effects of this pathway on drug resistance and cellular senescence of breast cancer cells has been a focus of our laboratory. Introduction of activated Akt or mutant PTEN constructs which lack lipid phosphatase [PTEN(G129E)] or lipid and protein phosphatase [PTEN(C124S)] activity increased the resistance of the cells to the chemotherapeutic drug doxorubicin, and the hormonal drug tamoxifen. Activated Akt and PTEN genes also inhibited the induction of senescence after doxorubicin treatment; a phenomenon associated with unrestrained proliferation and tumorigenesis. Interference with the lipid phosphatase domain of PTEN was sufficient to activate Akt/mTOR/p70S6K as MCF-7 cells transfected with the mutant PTEN gene lacking the lipid phosphatase activity [PTEN(G129E)] displayed elevated levels of activated Akt and p70S6K compared to empty vector transfected cells. Cells transfected with mutant PTEN or Akt constructs were hypersensitive to mTOR inhibitors when compared with the parental or empty vector transfected cells. Akt-transfected cells were cultured for over two months in tamoxifen from which tamoxifen and doxorubicin resistant cells were isolated that were >10-fold more resistant to tamoxifen and doxorubicin than the original Akt-transfected cells. These cells had a decreased induction of both activated p53 and total p21Cip1 upon doxorubicin treatment. Furthermore, these cells had an increased inactivation of GSK-3β and decreased expression of the estrogen receptor-α. In these drug resistant cells, there was an increased activation of ERK which is associated with proliferation. These drug resistant cells were hypersensitive to mTOR inhibitors and also sensitive to MEK inhibitors, indicating that the enhanced p70S6K and ERK expression was relevant to their drug and hormonal resistance. Given that Akt is overexpressed in greater than 50% of breast cancers, our results point to potential therapeutic targets, mTOR and MEK. These studies indicate that activation of the Akt kinase or disruption of the normal activity of the PTEN phosphatase can have dramatic effects on activity of p70S6K and other downstream substrates and thereby altering the therapeutic sensitivity of breast cancer cells. The effects of doxorubicin and tamoxifen on induction of the Raf/MEK/ERK and PI3K/Akt survival pathways were examined in unmodified MCF-7 breast cells. Doxorubicin was a potent inducer of activated ERK and to a lesser extent Akt. Tamoxifen also induced ERK. Thus a consequence of doxorubicin and tamoxifen therapy of breast cancer is the induction of a pro-survival pathway which may contribute to the development of drug resistance. Unmodified MCF-7 cells were also sensitive to MEK and mTOR inhibitors which synergized with both tamoxifen and doxorubicin to induce death. In summary, our results point to the key interactions between the PI3K/PTEN/Akt/mTOR and Raf/ MEK/ERK pathways in regulating chemotherapeutic drug resistance/sensitivity in breast cancer and indicate that targeting these pathways may prevent drug and hormonal resistance. Orignally published Advances in Enzyme Regulation, Vol. 48, No. 1, 2008

Gender differences in the use of cardiovascular interventions in HIV-positive persons; the D:A:D Study

Peer reviewe

Antidepressant use and risk for mortality in 121,252 heart failure patients with or without a diagnosis of clinical depression

ABSTRACTBackgroundDepression is a risk factor for mortality in patients with heart failure (HF), however, treating depression with antidepressant therapy does not seem to improve survival. We examined the prevalence of antidepressant use in HF patients, the correlates of antidepressant use subsequent to hospital discharge and the relation between antidepressant use, clinical depression and mortality in patients with HF.Methods121,252 HF patients surviving first hospitalization were stratified by antidepressant use and a diagnosis of clinical depression.ResultsIn total, 15.6% (19,348) received antidepressants at baseline, of which 86.7% (16,780) had no diagnosis of clinical depression. Female gender, older age, higher socio-economic status, more comorbidities, increased use of statins, spironolactone and aspirin, lower use of beta-blockers and ACE-inhibitors, greater HF severity and a diagnosis of clinical depression were independently associated with antidepressant use. Patients using no antidepressants with clinical depression and patients using antidepressants, with or without clinical depression, had a significantly higher risk for all-cause mortality (HR, 1.25; 95% CI, 1.15–1.36; HR, 1.24; 95% CI, 1.22–1.27; HR, 1.21; 95% CI, 1.16–1.27, respectively) and CV-mortality (HR: 1.17; 95% CI, 1.14–1.20, P<.001; HR: 1.20; 95% CI, 1.08–1.34, P<.001; HR: 1.21; 95% CI, 1.12–1.29, P<.001, respectively) as compared to patients not using antidepressants without depression in adjusted analysis.ConclusionPatients with HF taking antidepressants had an increased risk for all-cause and CV-mortality, irrespectively of having clinical depression. These results highlight the importance of further examining the antidepressant prescription pattern in patients with HF, as this may be crucial in understanding the antidepressant effects on cardiac function and mortality

Preclinical lead optimization of a 1,2,4-triazole based tankyrase inhibitor

Abstract Tankyrases 1 and 2 are central biotargets in the WNT/β-catenin signaling and Hippo signaling pathways. We have previously developed tankyrase inhibitors bearing a 1,2,4-triazole moiety and binding predominantly to the adenosine binding site of the tankyrase catalytic domain. Here we describe a systematic structure-guided lead optimization approach of these tankyrase inhibitors. The central 1,2,4-triazole template and trans-cyclobutyl linker of the lead compound 1 were left unchanged, while side-group East, West, and South moieties were altered by introducing different building blocks defined as point mutations. The systematic study provided a novel series of compounds reaching picomolar IC₃₀ inhibition in WNT/β-catenin signaling cellular reporter assay. The novel optimized lead 13 resolves previous atropisomerism, solubility, and Caco-2 efflux liabilities. 13 shows a favorable ADME profile, including improved Caco-2 permeability and oral bioavailability in mice, and exhibits antiproliferative efficacy in the colon cancer cell line COLO 320DM in vitro

Development of a 1,2,4-triazole-based lead tankyrase inhibitor:part II

Abstract Tankyrase 1 and 2 (TNKS1/2) catalyze post-translational modification by poly-ADP-ribosylation of a plethora of target proteins. In this function, TNKS1/2 also impact the WNT/β-catenin and Hippo signaling pathways that are involved in numerous human disease conditions including cancer. Targeting TNKS1/2 with small-molecule inhibitors shows promising potential to modulate the involved pathways, thereby potentiating disease intervention. Based on our 1,2,4-triazole-based lead compound 1 (OM-1700), further structure–activity relationship analyses of East-, South- and West-single-point alterations and hybrids identified compound 24 (OM-153). Compound 24 showed picomolar IC₅₉ inhibition in a cellular (HEK293) WNT/β-catenin signaling reporter assay, no off-target liabilities, overall favorable absorption, distribution, metabolism, and excretion (ADME) properties, and an improved pharmacokinetic profile in mice. Moreover, treatment with compound 24 induced dose-dependent biomarker engagement and reduced cell growth in the colon cancer cell line COLO 320DM