Identification of functional pathways and molecular signatures in neuroendocrine neoplasms by multi-omics analysis.

BACKGROUND: Neuroendocrine neoplasms (NENs) represent a heterogeneous class of rare tumors with increasing incidence. They are characterized by the ability to secrete peptide hormones and biogenic amines but other reliable biomarkers are lacking, making diagnosis and identification of the primary site very challenging. While in some NENs, such as the pancreatic ones, next generation sequencing technologies allowed the identification of new molecular hallmarks, our knowledge of the molecular profile of NENs from other anatomical sites is still poor. METHODS: Starting from the concept that NENs from different organs may be clinically and genetically correlated, we applied a multi-omics approach by combining multigene panel testing, CGH-array, transcriptome and miRNome profiling and computational analyses, with the aim to highlight common molecular and functional signatures of gastroenteropancreatic (GEP)-NENs and medullary thyroid carcinomas (MTCs) that could aid diagnosis, prognosis and therapy. RESULTS: By comparing genomic and transcriptional profiles, ATM-dependent signaling emerged among the most significant pathways at multiple levels, involving gene variations and miRNA-mediated regulation, thus representing a novel putative druggable pathway in these cancer types. Moreover, a set of circulating miRNAs was also selected as possible diagnostic/prognostic biomarkers useful for clinical management of NENs. CONCLUSIONS: These findings depict a complex molecular and functional landscape of NENs, shedding light on novel therapeutic targets and disease biomarkers to be exploited.

It is really time to retire laparoscopic gastric banding? Positive outcomes after long-term follow-up: the management is the key.

After the initial widespread diffusion, laparoscopic adjustable gastric banding (LAGB) has been progressively abandoned and laparoscopic sleeve gastrectomy (LSG) has become the worldwide most adopted procedure. Nevertheless, recent reports raised concerns about the long-term weight regain after different bariatric techniques. Considering the large LAGB series recorded in our multicentric bariatric database, we analysed the anthropometric and surgical outcomes of obese patients underwent LAGB at a long-term follow-up, focusing on LAGB management. Between January 2008 to January 2018, demographics, anthropometric and post-operative data of obese patients undergone LAGB were retrospectively evaluated. To compare the postoperative outcomes, the cohort was divided in two groups according to the quantity of band filling (QBF): low band filling group (Group 1) with at most 3 ml of QBF, and patients in the high band filling group (Group 2) with at least 4 ml. 699 obese patients were considered in the analysis (351 in Group 1 and 348 in Group 2). Patients in Group 1 resulted significantly associated (p < 0.05) to higher % EWL and quality of life score (BAROS Score), 49.1 ± 11.3 vs 38.2 ± 14.2 and 5.9 ± 1.8 vs 3.8 ± 2.5, respectively. Moreover, patients with lower band filling (Group 1) complained less episodes of vomiting, epigastric pain and post-prandial reflux and significantly decreased slippage and migration rate (p < 0.001 for all parameters). LAGB is a safe and reversible procedure, whose efficacy is primarily related to correct postoperative handling. Low band filling and strict follow-up seem the success' key of this technique, which deserves full consideration among bariatric procedures.

Esophagogastric junction function and gastric pressure profile after minigastric bypass compared with Billroth II.

BACKGROUND: Minigastric bypass (MGB) is being performed widely with effective weight loss and improvement in co-morbidities. Because of similarity to Billroth II (BII), there are concerns about bile reflux. OBJECTIVES: To assess the esophagogastric junction (EGJ) function, esophageal peristalsis, and reflux exposure after MGB and BII. SETTING: University Hospital, Italy; Public Hospital, Italy. METHODS: Obese patients underwent symptom questioning, endoscopy, high-resolution impedance manometry, and impedance-pH monitoring, before and 1 year after MGB. Esophageal motor function, EGJ, EGJ-contractile integral, intragastric pressure (IGP), and gastroesophageal pressure gradient were determined. Acid exposure time, number of refluxes, and symptom-association probability were assessed. A group of patients who underwent BII were studied with the same protocol and served as controls. RESULTS: Twenty-two MGB and 20 BII patients were studied. After surgery, none of the patients reported de novo heartburn or regurgitation. At endoscopic follow-up, esophagitis and bile findings were absent in all. High-resolution impedance manometry features did not vary significantly after MGB, whereas IGP and gastroesophageal pressure gradient statistically diminished (P < .01). BII patients had significantly lower values in IGP, sphincter pressure, and EGJ-contractile integral. In MGB patients, a marked decrease in number of refluxes (from median 41 to 7, P < .01) was observed, whereas BII patients had statistically significant higher acid exposure and number of refluxes (57, P < .001). CONCLUSIONS: In contrast to BII, MGB does not increase any kind of reflux. Also, the differences in IGP and gastroesophageal pressure gradient suggest that bile reflux occurs more readily after BII than after MGB, and that these 2 operations share more differences than similarities.

Complications Following the Mini/One Anastomosis Gastric Bypass (MGB/OAGB): a Multi-institutional Survey on 2678 Patients with a Mid-term (5 Years) Follow-up.

BACKGROUND: In recent years, several articles have reported considerable results with the Mini/One Anastomosis Gastric Bypass (MGB/OAGB) in terms of both weight loss and resolution of comorbidities. Despite those positive reports, some controversies still limit the widespread acceptance of this procedure. Therefore, a multicenter retrospective study, with the aim to investigate complications following this procedure, has been designed. PATIENTS AND METHODS: To report the complications rate following the MGB/OAGB and their management, and to assess the role of this approach in determining eventual complications related especially to the loop reconstruction, in the early and late postoperative periods, the clinical records of 2678 patients who underwent MGB/OAGB between 2006 and 2015 have been studied. RESULTS: Intraoperative and early complications rates were 0.5 and 3.1%, respectively. Follow-up at 5 years was 62.6%. Late complications rate was 10.1%. A statistical correlation was found for perioperative bleeding both with operative time (p < 0.001) or a learning curve of less than 50 cases (p < 0.001). A statistical correlation was found for postoperative duodenal-gastro-esophageal reflux (DGER) with a preexisting gastro-esophageal-reflux disease (GERD) or with a gastric pouch shorter than 9 cm, (p < 0.001 and p = 0.001), respectively. An excessive weight loss correlated with a biliopancreatic limb longer than 250 cm (p < 0.001). CONCLUSIONS: Our results confirm MGB/OAGB to be a reliable bariatric procedure. According to other large and long-term published series, MGB/OAGB seems to compare very favorably, in terms of complication rate, with two mainstream procedures as standard Roux-en-Y gastric bypass (RYGBP) and laparoscopic sleeve gastrectomy (LSG).

Effects of omega-loop bypass on esophagogastric junction function.

BACKGROUND: At present, no objective data are available on the effect of omega-loop gastric bypass (OGB) on gastroesophageal junction and reflux. OBJECTIVES: To evaluate the possible effects of OGB on esophageal motor function and a possible increase in gastroesophageal reflux. SETTING: University Hospital, Italy; Public Hospital, Italy. METHODS: Patients underwent clinical assessment for reflux symptoms, and endoscopy plus high-resolution impedance manometry (HRiM) and 24-hour pH-impedance monitoring (MII-pH) before and 1 year after OGB. A group of obese patients who underwent sleeve gastrectomy (SG) were included as the control population. RESULTS: Fifteen OGB patients were included in the study. After surgery, none of the patients reported de novo heartburn or regurgitation. At endoscopic follow-up 1 year after surgery, esophagitis was absent in all patients and no biliary gastritis or presence of bile was recorded. Manometric features and patterns did not vary significantly after surgery, whereas intragastric pressures (IGP) and gastroesophageal pressure gradient (GEPG) statistically diminished (from a median of 15 to 9.5, P<.01, and from 10.3 to 6.4, P<.01, respectively) after OGB. In contrast, SG induced a significant elevation in both parameters (from a median of 14.8 to 18.8, P<.01, and from 10.1 to 13.1, P<.01, respectively). A dramatic decrease in the number of reflux events (from a median of 41 to 7; P<.01) was observed after OGB, whereas in patients who underwent SG a significant increase in esophageal acid exposure and number of reflux episodes (from a median of 33 to 53; P<.01) was noted. CONCLUSIONS: In contrast to SG, OGB did not compromise the gastroesophageal junction function and did not increase gastroesophageal reflux, which was explained by the lack of increased IGP and in GEPG as assessed by HRiM.

Smoking Habit in Severe Obese after bariatric procedures.

BACKGROUND: Bariatric procedures provide an effective means of short term weight loss and sustained weight control for the morbidly obese. The effect of bariatric procedures on smoking habit in obese subjects is not well known. Therefore, we examined the short term effect of bariatric surgery on smoking habit of severe obese patients up to 12 months from the intervention. PATIENTS AND METHODS: Smoking habit was assessed in a cohort of 78 morbid smoking obese patients followed at our clinic for bariatric procedures. They underwent non surgical intra-gastric balloon (IB) or surgical procedures such as lap-band laparoscopic surgery (LAGB) or sleeve gastrectomy/gastric by-pass (SPG). Subjects were administered a written questionnaire about their smoking habit before and 3, 6 and 12 months after the procedures. RESULTS: No differences were found among the three groups at 6 and 12 months after the procedures (IB 21 %, LAGB 6 %, SPG 5 %; and IB 14 %, LAGB 3 %, SPG 5 %). Only after 3 months, the rate of quitting of the IB group was higher than LAGB and SPG groups (36 %, 6 % and 5 %, respectively; p = 0.02). CONCLUSIONS: Bariatric procedures have no effects on smoking habit of moderate-to-heavy smoker severe obese patients. The use of other traditional smoking cessation methods in patients undergone to bariatric procedures should be implemented.

Low alveolar and bronchial nitric oxide in severe uncomplicated obesity.

BACKGROUND: Fractional concentration of exhaled nitric oxide (FeNO) is a recognized biomarker of the lower respiratory tract, where it is produced by the proximal conducting airways and the expansible peripheral bronchoalveolar compartment. We have previously shown that large increase in body mass decreases FeNO. Here we evaluated bronchial and alveolar components of the NO output of the lower respiratory tract in subjects with severe uncomplicated obesity (OB). METHODS: Fifteen OB subjects (BMI 45.3 ± 5.6 kg/m(2)), 15 healthy controls (HC) (BMI 22.4 ± 2.4 kg/m(2)) and 10 obese subjects who experienced weight loss after bariatric surgery (OBS) (BMI 31.2 ± 3.4 kg/m(2)), were examined. Anthropometry and respiratory lung tests were performed. Exhaled NO was assessed using multiple single-breath NO analysis at different constant expiratory flow rates. From the fractional NO concentration measured at each flow-rate, the total NO flux between tissue and gas phase in the bronchial lumen (J'awNO), and the alveolar NO concentration (CANO) were extrapolated. RESULTS: Measured FeNO levels at 50 mL/s were lower in OB compared with HC and OBS (11.6 ± 2.8 ppb, 18.0 ± 4.1 ppb and 17.6 ± 2.9 ppb, respectively, p < 0.05). In OB, both J'awNO and CANO resulted significantly lower than OBS and HC values. CONCLUSIONS: Respiratory NO output is decreased in severe uncomplicated obesity for the reduction of both large/central airway maximal NO flux and alveolar NO concentration. The pathophysiological relevance of airway NO abnormalities in severe obese phenotype remains to be investigated.

Weight loss and asthma control in severely obese asthmatic females.

BACKGROUND: Obesity is proposed to represent an important predisposing condition to serious respiratory disturbances including asthma. The effects of consistent weight loss on asthma control are not well known. We investigated the effect of weight reduction induced by bariatric surgery on asthma control in severely obese asthmatic patients. PATIENTS AND METHODS: A consecutive series of 12 asthmatic obese females who had laparoscopic adjustable gastric banding (OB group) and 10 non-operated asthmatic obese females as control group (CG). Body mass index (BMI), Asthma Control Test (ACT), pulmonary function test (PFT), exhaled nitric oxide (NO) were evaluated at baseline and after 1 year. RESULTS: Mean BMI (kg/m(2)) of OB group decreased from 45.2+/-4.7 before surgery to 34.8+/-4.2 post-operatively. After surgery the overall ACT score in OB group significantly improved from 18.7 to 22.2 (p<0.001), while it remained unchanged in CG (from 18.8 to 18.6, p=0.73). In particular, in OB group the parameters of shortness of breath and rescue medication use were significantly improved respectively from 3.2 and 3.9 before surgery to 4.2 and 4.6 after surgery (always p<0.05). Accordingly, none of the CG who did not experience any weight loss was able to obtain a full asthma control. In the OB group after the surgery PFT significantly improved as compared to CG. No significant difference in exhaled NO was found both in OB group after surgery as compared to before surgery. CONCLUSION: Consistent weight loss in severely obese patients with asthma is associated to improvement in respiratory symptoms and lung function. However, the mechanisms underlying the effect of large body mass changes on asthma would require further studies.

Exhaled nitric oxide in severe obesity: effect of weight loss.

Exhaled nitric oxide (NO) is a recognized biomarker in the lower respiratory tract. The effect of large variation in body mass on exhaled NO in the same individuals is not well known. The aim of the study was to evaluate both the effect of severe obesity and the influence of weight reduction on exhaled NO. A consecutive series of 24 uncomplicated obese patients (OB), who had laparoscopic adjustable gastric banding (LAGB) and 15 healthy controls (HC) were studied. Body mass index (BMI), exhaled NO and respiratory function tests were assessed. Exhaled NO was lower in obese in comparison to HC (12.0+/-3.6ppb versus 15.8+/-4.0ppb, p=0.0035). A significant positive correlation was found between exhaled NO and BMI in HC, which was not evident in OB. Among the respiratory indexes, functional residual capacity was significantly associated to exhaled NO. After 1 year, 12 obese patients undergone to LAGB were re-evaluated. Mean BMI (kg/m(2)) decreased from 44.8 before surgery to 32.3 post-operatively. The exhaled NO increased from 11.8+/-3.2ppb before surgery to 14.9+/-3.1ppb 1 year post-operatively (p=0.0023, n=12). In conclusion exhaled NO is consistently reduced in severe obesity and it is restored after weight reduction. The relationship between exhaled NO, large body mass excess and decrease of resting lung volume in severe obesity deserves further studies.

Effect of bariatric surgery on the six-minute walk test in severe uncomplicated obesity.

BACKGROUND: The six-minute walk test (6mWT) is a simple index of functional capacity in healthy people, and it has been used to estimate exercise capacity in obese subjects. The aim of this study was to determine whether weight reduction induced by laparoscopic adjustable gastric banding (LAGB) improves the functional capacity in the severely obese on the 6mWT. METHODS: A prospective 1-year study was carried out at the Hospital Casoria, Naples, involving 15 consecutive severely obese patients who underwent the 6mWT before and 1 year after LAGB. BMI, walking distance, heart rate, dyspnea, and respiratory function tests were also measured. Patients served as their own controls. RESULTS: 15 patients (all females) were evaluated. Mean BMI decreased from 42.1 (range 39-49) before to 31.9 (range 25-38) postoperatively. The distance walked increased from 475.7 meters (range 380-580) before LAGB to 626.3 meters (range 435-880) 1 year postoperatively (P < 0.0001), and the dyspnea score after the 6mWT was significantly reduced postoperatively. All functional variables after the 6mWT showed improvement postoperatively at 1 year study. CONCLUSION: Weight reduction in the obese increases the functional capacity during walking. The improvements are refected in the patients' own assessment.

Ultrasound diagnosis of intragastric balloon complications in obese patients.

PURPOSE: Our study describes ultrasonography (US) aspects of complications related to the use of the Bioenterics intragastric balloon (BIB) system for the treatment of moderate obesity. MATERIALS AND METHODS: Over the last three years 151 BIBs were endoscopically placed and inflated with 500-600 ml of saline plus 10 ml of methylene blue in 131 patients (mean age 38.4 years, range 18-72; 46 males, 85 females, mean body mass index 43.8 kg/m(2)). In all cases abdominal US was carried out before and 1-2 days after endoscopy and thereafter at scheduled follow-up visits and/or whenever the patient complained of heartburn, vomiting, a sensation of ''absence of the BIB'' with or without staining of urine and/or faeces. RESULTS: The BIB appeared as a round anechoic structure, with a thick hyperechoic wall and a hyperechoic band-like valve inside. In 8 cases staining of urine and/or faeces prompted immediate endoscopic removal. In 10 patients US findings of BIB-related complications were: 1) decreased volume with a visible valve (5 cases; in two of these staining of urine was reported); 2) multiple hyperechoic streaks regularly spaced due to a completely collapsed BIB, not modified by decubitus changes (3 cases; one patient reported staining of urine); 3) migration through the bowel (2 cases): in one patient the BIB was passed after 4 days, whereas in the other case bowel obstruction required laparoscopic surgery. CONCLUSIONS: In conclusion, US provides a quick and accurate method for the assessment of BIB-related complications in obese patients.

Ultrasound as the imaging method of choice for monitoring the intragastric balloon in obese patients: normal findings, pitfalls and diagnosis of complications.

BACKGROUND: The authors studied ultrasound (U/S) monitoring of the BioEnterics intragastric balloon (BIB) for treatment of moderate obesity by describing normal U/S aspects, diagnostic pitfalls and assessment of complications. METHODS: Over the last 3 years, 151 BIB systems have been endoscopically placed and filled with 500-700 ml of saline plus 10 ml of methylene blue in 131 patients (mean age 38.4 years, range 18-72); males/females 46/85; mean BMI 43.8 kg/m(2)). In all patients abdominal U/S was carried out before and 12 days after endoscopy and thereafter at scheduled follow-up examinations, and/or whenever the subject complained of epigastric burning/ache, vomiting, and lack of sensation of a BIB with or without staining of urine and/or feces. RESULTS: The BIB appeared as a round anechoic structure, with a thick hyperechoic wall and a hyperechoic band-like valve inside. Complications occurred in 18 patients: in 8, staining of urine and/or feces prompted immediate endoscopic removal. In 10 patients, U/S findings were: 1) decreased volume, loss of the spherical shape with the valve still visible (5 cases); 2) multiple hyperechoic streaks regularly spaced due to a completely collapsed BIB, not modified by decubitus changes (3 cases); 3) migration through the intestine (2 cases): in one patient the BIB was passed in the stools after 4 days, whereas in the other case large bowel obstruction required laparoscopic surgery. CONCLUSION: U/S affords a quick, safe and accurate method for assessing both BIB status after endoscopic deployment and the most frequently-occurring complications (partial/complete deflation, migration through the pylorus with intestinal obstruction) in obese patients.

Gastric perforation in an obese patient with an intragastric balloon, following previous fundoplication.

BACKGROUND: The Bioenterics Intragastric Balloon (BIB) has been a safe and effective method used in treatment of moderate obesity. Gastric perforation is a rare complication, and its possible sequelae are dangerous. METHODS: A 52-year-old women (BMI 37 kg/m(2)), with hiatal hernia, moderate hypertension and dyspnea, 1 year ago underwent laparoscopic fundoplication. She now underwent positioning of a BIB filled with 500 cc of saline. After 8 days, 6 kg weight loss occurred and her clinical condition was satisfactory. On day 11, severe abdominal pain and vomiting occurred, which spontaneously regressed in the following 6-8 hours. Ultrasound confirmed the correct position of the BIB, and showed widespread abdominal meteorism. On day 18, acute abdomen with paralytic ileus occurred. On admission, CT scan documented hydropneumoperitonitis. At operation, a large perforation of the lesser curvature was found, with undigested food in the abdomen. She underwent peritoneal lavage, removal of the BIB, and suture of the gastric laceration. RESULTS: She was discharged in good condition after 11 days. CONCLUSION: According to our experience, fundoplication represents an absolute contraindication to positioning of a BIB.