OBJECTIVE:To examine associations of laparoscopic sleeve gastrectomy with maternal and perinatal outcomes.
METHODS:We conducted a retrospective case–control study of deliveries that occurred from ...2006 to 2016 at two university hospitals. The study group comprised all women who had undergone laparoscopic sleeve gastrectomy and who delivered during the study period. If a woman had more than one pregnancy during the study period, data from only her first pregnancy were used. A control group was established by matching preoperative body mass index (BMI), age, parity, delivery history, and delivery year.
RESULTS:Data from 238 women were analyzed, 119 post–laparoscopic sleeve gastrectomy and 119 matched control parturients. Among the post–laparoscopic sleeve gastrectomy patients, the median preoperative BMI was 41.7 (interquartile range 39.9–44.4) and the median postoperative BMI was 28.9 (26.6–32.0). Compared with the control group, the study group had lower rates of gestational diabetes mellitus (3.4% vs 17.6%, P=.001), large-for-gestational-age neonates (1.7% vs 19.3%, P=.001), and birth weight greater than 4,000 g (0.8% vs 7.6%, P=.02) but higher proportions of small-for-gestational-age (SGA) neonates (14.3% vs 4.2%, P=.01) and low-birth-weight neonates (12.6% vs 4.2%, P=.03). Rates of gestational hypertensive disorders and prematurity were comparable between the groups. For the study group, hemoglobin levels were lower in early pregnancy (median 12.6 vs 13.2 g/dL, P=.001) and after delivery (10.5 vs 10.8 g/dL, P=.002), and a higher proportion of patients were treated with intravenous iron supplementation during pregnancy (14.3% vs 0.8%, P=.001). Cesarean delivery rates during labor were lower in the study group (10.1% vs 20.2%, P=.04).
CONCLUSION:Laparoscopic sleeve gastrectomy was associated with reduced rates of gestational diabetes mellitus, excessive fetal growth, and cesarean delivery and an increased rate of SGA and low-birth-weight neonates.
Mutant KRAS is a druggable target for pancreatic cancer Khvalevsky, Elina Zorde; Gabai, Racheli; Rachmut, Itzhak Haim ...
Proceedings of the National Academy of Sciences - PNAS,
12/2013, Volume:
110, Issue:
51
Journal Article
Peer reviewed
Open access
Pancreatic ductal adenocarcinoma (PDA) represents an unmet therapeutic challenge. PDA is addicted to the activity of the mutated KRAS oncogene which is considered so far an undruggable therapeutic ...target. We propose an approach to target KRAS effectively in patients using RNA interference. To meet this challenge, we have developed a local prolonged siRNA delivery system (Local Drug EluteR, LODER) shedding siRNA against the mutated KRAS (siG12D LODER). The siG12D LODER was assessed for its structural, release, and delivery properties in vitro and in vivo. The effect of the siG12D LODER on tumor growth was assessed in s.c. and orthotopic mouse models. KRAS silencing effect was further assessed on the KRAS downstream signaling pathway. The LODER-encapsulated siRNA was stable and active in vivo for 155 d. Treatment of PDA cells with siG12D LODER resulted in a significant decrease in KRAS levels, leading to inhibition of proliferation and epithelial–mesenchymal transition. In vivo, siG12D LODER impeded the growth of human pancreatic tumor cells and prolonged mouse survival. We report a reproducible and safe delivery platform based on a miniature biodegradable polymeric matrix, for the controlled and prolonged delivery of siRNA. This technology provides the following advantages: (i) siRNA is protected from degradation; (ii) the siRNA is slowly released locally within the tumor for prolonged periods; and (iii) the siG12D LODER elicits a therapeutic effect, thereby demonstrating that mutated KRAS is indeed a druggable target.
Liver cancer is one of the most lethal malignancies with very poor prognosis once diagnosed. The most common form of liver cancer is hepatocellular carcinoma (HCC). The WW domain-containing ...oxidoreductase (WWOX) is a large gene that is often perturbed in a wide variety of tumors, including HCC. WWOX has been shown to act as a tumor suppressor modulating cellular metabolism via regulating hypoxia-inducible factor 1α (HIF-1α) levels and function. Given that WWOX is commonly inactivated in HCC, we set to determine whether specific targeted deletion of murine Wwox affects liver biology and HCC development. WWOX liver-specific knockout mice (Wwox
) showed more potent liver regeneration potential and enhanced proliferation as compared with their control littermates. Moreover, WWOX deficiency in hepatocytes combined with diethylnitrosamine treatment increased the tumor burden, which was associated with increased HIF1α levels and target gene transactivation. Inhibition of HIF1α by systemic treatment with digoxin significantly delayed HCC formation. Our work suggests that WWOX inactivation has a central role in promoting HCC through rewiring of cellular metabolism and modulating proliferation.
Nutritional deficiencies are common among morbidly obese patients. Data are scarce for patients who have undergone laparoscopic sleeve gastrectomy (LSG).
The aim of the study is to clarify the ...prevalence of deficiencies and to identify risk factors for postoperative deficiencies.
Hebrew University, Israel.
Preoperative and 1-year postoperative data were collected. We included anthropometric parameters, obesity-related co-morbidities, and laboratory findings.
There were 192 candidates. Seventy-seven of them completed follow-ups at 12 months. Before surgery, 15% had anemia. Deficiencies of iron, folate, and B12 were 47%, 32%, and 13%, respectively. Women were more deficient in iron (56% women, 26% men, P<.001). Before surgery, low levels of vitamin D and elevated parathyroid hormone (PTH) were 99% and 41%, respectively. One year postsurgery, the deficiencies of hemoglobin and vitamin B12 worsened (20% and 17%, P<.001, P = .048, respectively). One year postsurgery, deficiencies of iron, folate, vitamin D, and PTH improved (28%, 21%, 94%, and 10%, respectively). Deficiencies of hemoglobin, folate, and B12 before surgery were predictors for deficiencies 1 year after surgery (P = .006 OR = .090; P = .012 OR = .069; P = .062 OR = .165, respectively).
LSG had a modest effect on nutritional deficiencies in our patients at 1-year postsurgery. Focusing on the preoperative nutritional status and tailoring a specific supplemental program for each individual should prevent postoperative deficiencies.
Background
Food addiction and binge eating are common among individuals with obesity. However, a paucity of studies prospectively examined the prevalence and implications of food addiction before and ...post-bariatric surgery. We aimed to examine the prevalence of food addiction and binge eating before and after sleeve gastrectomy (SG) and to assess their associations with behavioral and weight loss outcomes.
Methods
We followed at 3 (M3), 6 (M6), and 12 (M12) months postoperative, 54 women who underwent SG. Data collected including anthropometrics, nutritional intake, food tolerance, and physical activity measures. The Yale Food Addiction Scale and the Binge Eating Scale were used to characterize food addiction and binge eating, respectively.
Results
The mean baseline age and BMI were 32.1 ± 11.1 years and 44.9 ± 4.9 kg/m
2
, respectively. Pre-surgery, food addiction, and binge eating were identified in 40.7% and 48.1% of patients, respectively. The prevalence of food addiction decreased significantly up to M6, but increased to 29.3% at M12. The prevalence of binge eating decreased significantly through the follow-up up to 17.4% at M12. Those who met criteria for food addiction at M12 achieved significantly lower excess weight loss at M12 compared with those not meeting this criterion (
P
= 0.005). Food addiction scores at M12 negatively correlated with weekly physical activity (
r
= − 0.559;
P
< 0.001) and food tolerance scores (
r
= − 0.428;
P
= 0.005).
Conclusions
The reduction in food addiction observed at M6 was not maintained at M12. Food addiction at M12 was associated with poorer weight loss, eating, and lifestyle behaviors. Clinical practice should focus on the psychological aspects associated with obesity.
Purpose
Sleeve gastrectomy (SG) is an effective treatment for extreme obesity; however, long-term weight loss outcomes remain largely understudied. We aimed to examine the long-term weight changes ...following SG and patient characteristics and lifestyle patterns related to weight loss outcomes.
Materials and Methods
Data from medical records of patients operated in a tertiary university medical center between 2008 and 2014 were reviewed, along with information derived from a telephone questionnaire. Information included the following: current medical status, medications, side effects, behavior, lifestyle habits, and weight changes.
Results
A total of 212 patients (69.3% females) were included, with a median follow-up duration of 8 years post-SG. Mean age and baseline body mass index (BMI) of participants were 39.7 ± 12.0 years and 42.2 ± 4.9 kg/m
2
, respectively. Mean BMI, percentage excess weight loss, and percentage total body weight loss were 33.1 ± 6.1, 55.5 ± 27.5%, and 21.7 ± 10.7%, respectively. Higher baseline BMI was found to be the strongest independent predictor for insufficient weight loss (
OR
= 0.90,
P
= 0.001, 95% CI 0.85, 0.96). Sweetened beverage intake, usage of psychiatric medications, higher initial BMI, and lower age were significant predictors for increased weight gain from nadir weight (
P
< 0.0001,
P
= 0.005,
P
= 0.035, and
P
< 0.0001, respectively).
Conclusions
SG patients were found to maintain a notable long-term weight loss. Nevertheless, weight regain and insufficient weight loss were prevalent in the long-term post-operative period, and were related to certain lifestyle patterns. Clinical practice should emphasize the relationship between post-operative weight loss outcomes and specific behaviors. Efforts should be made to educate patients on the need for lifelong follow-up and support.
Graphical abstract
The appropriate strategies to minimize skeletal deterioration following bariatric surgeries are inconclusive. This randomized controlled trial evaluated the effect of preoperative vitamin ...supplementation on bone mineral density (BMD) and biochemical parameters in females post-sleeve gastrectomy (SG).
Participants were randomized to a 2-month preoperative treatment with a multivitamin and vitamin D 4000 IU/d (intervention arm) or 1200 IU/d (control arm). Preoperative and 12-month postoperative follow-up evaluations included anthropometrics, biochemical parameters, and dual energy X-ray absorptiometry (DEXA).
Sixty-two females (median age 29.7 years and median BMI 43.4 kg/m
) were recruited, 87% completed the 12-month follow-up. For the intervention and control arms, significant and similar reductions at 12-months post-surgery were observed in BMD of the hip (-6.8 ± 3.7% vs. -6.0 ± 3.6%; P = 0.646) and of the femoral neck (-7.1 ± 5.8% vs. -7.2 ± 5.5%; P = 0.973). For the intervention compared to the control arm, the 25 hydroxyvitamin D (25(OH)D) increment was greater after 2 months treatment, and vitamin D deficiency rates were lower at 3 and 6-months follow-up (P < 0.016). However, at 12-months postoperative, 25(OH)D values and vitamin D deficiency were comparable between the arms (P > 0.339). Predictors for BMD decline in the total hip were the percentage of excess weight-loss, age>50 years, and lower initial BMI (P ≤ 0.003).
SG was associated with a significant decline in BMD of the hip and femoral neck in young and middle-aged women, and was unaffected by preoperative vitamin D supplementation. Females who are peri-menopausal or with greater postoperative weight-loss should be particularly followed for BMD decline.
Objective Growing evidence suggests that a phenotypic switch converting pancreatic acinar cells to duct-like cells can lead to pancreatic intraepithelial neoplasia and eventually to invasive ...pancreatic ductal adenocarcinoma. Histologically, the onset of this switch is characterised by the co-expression of acinar and ductal markers in acini, a lesion called acinar-to-ductal metaplasia (ADM). The transcriptional regulators required to initiate ADM are unknown, but need to be identified to characterise the regulatory networks that drive ADM. In this study, the role of the ductal transcription factors hepatocyte nuclear factor 6 (HNF6, also known as Onecut1) and SRY-related HMG box factor 9 (Sox9) in ADM was investigated. Design Expression of HNF6 and Sox9 was measured by immunostaining in normal and diseased human pancreas. The function of the factors was tested in cultured cells and in mouse models of ADM by a combination of gain and loss of function experiments. Results Expression of HNF6 and Sox9 was ectopically induced in acinar cells in human ADM as well as in mouse models of ADM. HNF6 and, to a lesser extent, Sox9 were required for repression of acinar genes, for modulation of ADM-associated changes in cell polarity and for activation of ductal genes in metaplastic acinar cells. Conclusions HNF6 and Sox9 are new biomarkers of ADM and constitute candidate targets for preventive treatment in cases when ADM may lead to cancer. This work also shows that ectopic activation of transcription factors may underlie metaplastic processes occurring in other organs.
The signaling pathways that mediate the development of pancreatic ductal adenocarcinoma (PDAC) downstream of mutant Kras remain incompletely understood. Here, we focus on ribosomal protein S6 (rpS6), ...an mTOR effector not implicated previously in cancer. Phosphorylation of rpS6 was increased in pancreatic acinar cells upon implantation of the chemical carcinogen 7,12-dimethylbenz(a)anthracene (DMBA) or transgenic expression of mutant Kras. To examine the functional significance of rpS6 phosphorylation, we used knockin mice lacking all five phosphorylatable sites in rpS6 (termed rpS6(P-/-) mice). Strikingly, the development of pancreatic cancer precursor lesions induced by either DMBA or mutant Kras was greatly reduced in rpS6(P-/-) mice. The rpS6 mutants expressing oncogenic Kras showed increased p53 along with increased staining of γ-H2AX and 53bp1 (Trp53bp1) in areas of acinar ductal metaplasia, suggesting that rpS6 phosphorylation attenuates Kras-induced DNA damage and p53-mediated tumor suppression. These results reveal that rpS6 phosphorylation is important for the initiation of pancreatic cancer.
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