Phenotypic characterisation of SMAD4 variant carriers.

BACKGROUND: Both hereditary haemorrhagic telangiectasia (HHT) and juvenile polyposis syndrome (JPS) are known to be caused by SMAD4 pathogenic variants, with overlapping symptoms for both disorders in some patients. Additional connective tissue disorders have also been reported. Here, we describe carriers of SMAD4 variants followed in an HHT reference centre to further delineate the phenotype. METHODS: Observational study based on data collected from the Clinical Investigation for the Rendu-Osler Cohort database. RESULTS: Thirty-three participants from 15 families, out of 1114 patients with HHT, had an SMAD4 variant (3%).Regarding HHT, 26 out of 33 participants (88%) had a definite clinical diagnosis based on Curaçao criteria. Complication frequencies were as follows: epistaxis (n=27/33, 82%), cutaneous telangiectases (n=19/33, 58%), pulmonary arteriovenous malformations (n=17/32, 53%), hepatic arteriovenous malformations (AVMs) (n=7/18, 39%), digestive angiodysplasia (n=13/22, 59%). No cerebral AVMs were diagnosed.Regarding juvenile polyposis, 25 out of 31 participants (81%) met the criteria defined by Jass et al for juvenile polyposis syndrome. Seven patients (21%) had a prophylactic gastrectomy due to an extensive gastric polyposis incompatible with endoscopic follow-up, and four patients (13%) developed a digestive cancer.Regarding connective tissue disorders, 20 (61%) had at least one symptom, and 4 (15%) participants who underwent echocardiography had an aortic dilation. CONCLUSION: We describe a large cohort of SMAD4 variant carriers in the context of HHT. Digestive complications are frequent, early and diffuse, justifying endoscopy every 2 years. The HHT phenotype, associating pulmonary and hepatic AVMs, warrants systematic screening. Connective tissue disorders broaden the phenotype associated with SMAD4 gene variants and justify systematic cardiac ultrasound and skeletal complications screening.

Mesenteric sparing approach for advanced nodal extent in small intestinal neuroendocrine tumors. Is there a limit to the vascular resection in order to avoid creating a short small bowel syndrome? An anatomic research study.

PURPOSE: By selectively perfusing the first three jejunal arteries (JA), we aim to assess the individual perfusion length of small bowel (SB) and its impact on nodal resection in stage III-up small-intestinal neuroendocrine tumors (SI-NET). METHODS: Our anatomical research protocol implies a midline laparotomy and three measures of the SB length. We then perform a classical anterior approach of the superior mesenteric vessels. We carry on with the complete dissection and checking of the superior mesenteric artery (SMA) in order to identify the first three JA. Then we selectively perfuse each artery with colored latex solutions and measure the length of small bowel perfused respectively. RESULTS: We conducted our protocol on six cadaveric subjects. Mean(SD) SB length was 413(5.7), 535(13.2), 485(15), 353(25.1), 730(17.3) and 525(16° cm respectively from subject one to six. Most JA originated from the left side of the SMA. The first JA originated from its posterior wall in two subjects. Mean(SD) distance of origin of the first three JA was 4.6(1.3)cm, 6(1.1)cm and 7.1(0.9)cm respectively. Mean(SD) diameter of SMA was 10.8(3.3)mm. Mean diameter of the three first JA was 4(1.4)mm, 4(1.5)mm and 5(1.2)mm respectively. Mean(SD) SB length perfused by first and second JA was 224(14.9)cm, 175(8.6)cm, 238.3(7.6)cm, 84.3(5.1)cm, 233.3(5.8)cm and 218.3(10.4)cm respectively from subject one to six. CONCLUSION: We observed a trend suggesting that the first and second JA may sustain a SB length beyond the viable 1.5 m limit, implying the feasibility of stage III-up SI-NET resection with just two JA.

The Need for Centralization for Small Intestinal Neuroendocrine Tumor Surgery: A Cohort Study from the GTE-Endocan-RENATEN Network, the CentralChirSINET Study.

BACKGROUND: The concept of surgical centralization is becoming more and more accepted for specific surgical procedures. OBJECTIVE: The aim of this study was to evaluate the relationship between procedure volume and the outcomes of surgical small intestine (SI) neuroendocrine tumor (NET) resections. METHODS: We conducted a retrospective national study that included patients who underwent SI-NET resection between 2019 and 2021. A high-volume center (hvC) was defined as a center that performed more than five SI-NET resections per year. The quality of the surgical resections was evaluated between hvCs and low-volume centers (lvCs) by comparing the number of resected lymph nodes (LNs) as the primary endpoint. RESULTS: A total of 157 patients underwent surgery in 33 centers: 90 patients in four hvCs and 67 patients in 29 lvCs. Laparotomy was more often performed in hvCs (85.6% vs. 59.7%; p < 0.001), as was right hemicolectomy (64.4% vs. 38.8%; p < 0.001), whereas limited ileocolic resection was performed in 18% of patients in lvCs versus none in hvCs. A bi-digital palpation of the entire SI length (95.6% vs. 34.3%, p < 0.001), a cholecystectomy (93.3% vs. 14.9%; p < 0.001), and a mesenteric mass resection (70% vs. 35.8%; p < 0.001) were more often performed in hvCs. The proportion of patients with ≥8 LNs resected was significantly higher (96.3% vs. 65.1%; p < 0.001) in hvCs compared with lvCs, as was the proportion of patients with ≥12 LNs resected (87.8% vs. 52.4%). Furthermore, the number of patients with multiple SI-NETs was higher in the hvC group compared with the lvC group (43.3% vs. 25.4%), as were the number of tumors in those patients (median of 7 vs. 2; p < 0.001). CONCLUSIONS: Optimal SI-NET resection was significantly more often performed in hvCs. Centralization of surgical care of SI-NETs is recommended.

Management strategies of anastomotic ulcer after gastric bypass and risk factors of recurrence.

BACKGROUND: Marginal ulcers (MU) after gastric bypass are a challenging problem. The first-line treatment is a medical therapy with eviction of risk factors but is sometimes insufficient. The management strategies of intractable ulcers are still not clearly defined. The aim of our study was to analyse the risk factors for recurrence, the management strategies used and their efficiencies. METHODS: Based on a retrospective analysis of all MU managed in our tertiary care centre of bariatric surgery during the last 14 years, a descriptive analysis of the cohort, the management strategies and their efficiency were analysed. A logistic regression was done to identify the independent associated risk factors of intractable ulcer. RESULTS: Fifty-six patients matched inclusion criteria: 30 were referred to us (13 Roux-en-Y Gastric Bypass-RYGB and 17 One Anastomosis Gastric Bypass-OAGB), 26 were operated on in our institution (24 RYGB and 2 OAGB). 11 patients had a complicated inaugural MU requiring an interventional procedure in emergency: 7 perforations, 4 haemorrhages. The majority of MU were treated medically as a first-line therapy (n = 45; 80.4%). 32 MU recurred: 20 patients required surgery as a 2nd line therapy, 6 were operated on as a 3rd line therapy and 1 had a surgery as a 5th line therapy. The OAGB was the only risk factor of recurrence (p = 0.018). We found that the Surgical management was significantly more frequent for patients with a OAGB (84% versus 35% for RYGB, p = 0.001); the most performed surgical procedure was a conversion of OAGB to RYGB (n = 11, 37.9%). CONCLUSION: Surgery was required for a large number of MU especially in case of recurrence, but recurrence can still occur after the surgery. The OAGB was the only risk factor of recurrence identified and conversion to RYGB seemed to be effective for the healing.

Unifocal versus Multiple Ileal Neuroendocrine Tumors Location: An Embryological Origin.

INTRODUCTION: Small-intestinal neuroendocrine tumors (SI-NET) are situated preferentially within the ileum. The aim was to describe a potential difference in location between unifocal and multiple ileal-NET. PATIENTS AND METHODS: Between December 2010 and December 2019, all consecutive patients who underwent resection in our European Neuroendocrine Tumor Society Center of Excellence, of at least 1 non-duodenal SI-NET, were retrospectively included. The main objective was to prove that multiple ileal-NET were mostly located on the left side of the superior mesenteric artery (SMA) axis (defined as 40 cm from the ileocecal valve), and unifocal ones on the right side. RESULTS: Ninety-four patients were included, 6 with unifocal jejunal-NET located 35 cm (range, 10-60) from the duodenojejunal angle (DJA), 44 (47%) with unifocal ileal-NET and 44 (47%) with multiple ileal-NET. The median number of tumors in multiple ileal-NET was 7 (range, 2-95), within a median small bowel segment of 105 cm (10-240). The median length between the proximal tumor and the DJA was 428 cm (300-635) and 540 cm (350-725) for the distal one; 40 (91%) of them were located on the left side of the SMA axis. In contrast, unifocal ileal-NET were located at a median distance of 577 cm (305-820) from the DJA (p < 0.001, compared to multiple ileal-NET); 30 (68%) of them were on the right side of the SMA axis (p < 0.001). CONCLUSION: Multiple ileal-NET are mostly located on the left side of the SMA axis. Further studies are warranted to explore the embryological origin of unifocal versus multiple ileal-NET.

Neuropilin-2 contributes to tumor progression in preclinical models of small intestinal neuroendocrine tumors.

The identification of novel regulators of tumor progression is a key challenge to gain knowledge on the biology of small intestinal neuroendocrine tumors (SI-NETs). We recently identified the loss of the axon guidance protein semaphorin 3F as a protumoral event in SI-NETs. Interestingly the expression of its receptor neuropilin-2 (NRP-2) was still maintained. This study aimed at deciphering the potential role of NRP-2 as a contributor to SI-NET progression. The role of NRP-2 in SI-NET progression was addressed using an approach integrating human tissue and serum samples, cell lines and in vivo models. Data obtained from human SI-NET tissues showed that membranous NRP-2 expression is present in a majority of tumors, and is correlated with invasion, metastatic abilities, and neovascularization. In addition, NRP-2 soluble isoform was found elevated in serum samples from metastatic patients. In preclinical mouse models of NET progression, NRP-2 silencing led to a sustained antitumor effect, partly driven by the downregulation of VEGFR2. In contrast, its ectopic expression conferred a gain of aggressiveness, driven by the activation of various oncogenic signaling pathways. Lastly, NRP-2 inhibition led to a decrease of tumor cell viability, and sensitized to therapeutic agents. Overall, our results point out NRP-2 as a potential therapeutic target for SI-NETs, and will foster the development of innovative strategies targeting this receptor. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Long-term Follow-up of MEN1 Patients Who Do Not Have Initial Surgery for Small ≤2 cm Nonfunctioning Pancreatic Neuroendocrine Tumors, an AFCE and GTE Study: Association Francophone de Chirurgie Endocrinienne & Groupe d'Etude des Tumeurs Endocrines.

OBJECTIVE: To report long-term follow-up of patients with multiple endocrine neoplasia type 1 (MEN1) and nonfunctioning pancreatic neuroendocrine tumors (NF-PET). BACKGROUND: Pancreaticoduodenal tumors occur in almost all patients with MEN1 and are a major cause of death. The natural history and clinical outcome are poorly defined, and management is still controversial for small NF-PET. METHODS: Clinical outcome and tumor progression were analyzed in 46 patients with MEN1 with 2 cm or smaller NF-PET who did not have surgery at the time of initial diagnosis. Survival data were analyzed using the Kaplan-Meier method. RESULTS: Forty-six patients with MEN1 were followed prospectively for 10.7 ±â€Š4.2 (mean ±â€Šstandard deviation) years. One patient was lost to follow-up and 1 died from a cause unrelated to MEN1. Twenty-eight patients had stable disease and 16 showed significant progression of pancreaticoduodenal involvement, indicated by increase in size or number of tumors, development of a hypersecretion syndrome, need for surgery (7 patients), and death from metastatic NF-PET (1 patient). The mean event-free survival was 13.9 ±â€Š1.1 years after NF-PET diagnosis. At last follow-up, none of the living patients who had undergone surgery or follow-up had evidence of metastases on imaging studies. CONCLUSIONS: Our study shows that conservative management for patients with MEN1 with NF-PET of 2 cm or smaller is associated with a low risk of disease-specific mortality. The decision to recommend surgery to prevent tumor spread should be balanced with operative mortality and morbidity, and patients should be informed about the risk-benefit ratio of conservative versus aggressive management when the NF-PET represents an intermediate risk.

Laparoscopic total colectomy for ulcerative colitis after liver transplantation is feasible.

Ulcero-haemorrhagic rectocolitis can occur after liver transplantation for sclerosing cholangitis. Total colectomy with or without proctectomy may be indicated in case of chronic drug-resistant colitis, dysplasia or cancer. Today, laparoscopic approach is the standard for such procedure in non-operated patients. We performed a completely laparoscopic total colectomy 5 years after a liver transplantation. There were a few peritoneal adherences, and we could safely perform the procedure almost as usual. It provided all the advantages of the laparoscopic approach in the post-operative course.

Lymphadenectomy during Small Bowel Neuroendocrine Tumor Surgery: The Concept of Skip Metastases.

BACKGROUND: More than half of small bowel neuroendocrine tumors (SB-NETs) are metastatic at diagnosis, but complete resection of the primary tumor and lymph node (LN) is recommended by most authors. Our aim was to describe the pattern of involved LN after an extensive LN resection. MATERIALS AND METHODS: Between July 2013 and December 2015, all consecutive patients who underwent resection of at least one SB-NET in our European Neuroendocrine Tumor Society Center of Excellence were prospectively included, while patients with duodenal SB-NETs were excluded. The resection and pathological analysis of LNs were standardized using three groups (group 1, along the small intestine; group 2, along the mesenteric vessel; and group 3, retropancreatic and mesenteric vessel origin). RESULTS: Twenty-eight patients with SB-NET resection were prospectively enrolled in the study, with seven patients being excluded from the analysis because it was impossible to divide the operative piece into nodal groups due to retractile mesenteritis. Among the remaining 21 patients, 20 (95 %) had LNs involved; 8 (38 %) in group 1, 13 (62 %) in group 2, and 12 (57 %) in group 3. Skip metastases were found in 14 patients (67 %): 4 (19 %) with an invasion pattern of group 3+ without group 2+, and 12 (57 %) with an invasion pattern of group 2+ or group 3+ without group 1+. CONCLUSION: As a result of skip metastases, systematic, extensive LN resection in retropancreatic portion may be required to prevent unresectable locoregional recurrence.

Endoscopic submucosal dissection with the Nestis® jet injector system with a bifunctional catheter: first prospective clinical trial (NCT: 2012-A00272-41).

BACKGROUND: The Enki-2 water jet system (Nestis SAS®, Lyon, France) with dual injection and dissection capability significantly reduced ESD procedure time and perforation rates in animal studies. The study aim was to evaluate its efficacy and safety in patients with superficial neoplastic lesions. METHODS: A prospective study including 18 patients with esophageal, gastric and rectal superficial neoplasms treated by ESD using Enki-2 was designed. RESULTS: Eighteen lesions (6 esophageal, 3 gastric, 9 rectal, mean diameter 43.5 mm) in 17 patients (10 men, mean age 65.9) were included. The mean procedure time was 65.6 min. One patient needed clipping for an incomplete muscle tear during procedure; there were neither delayed bleedings nor perforation. The "en bloc" resection rate was 100 %, the R0 resection rate was 88.9 % (16/18 lesions), and the curative resection rate was 77.8 %. The 3-month disease-free rate was 92.3 % (12/13 patients, 13/14 lesions, 1 patient lost to follow-up). The 12-month disease-free rate was 69.2 % (9/13 patients, 10/14 lesions, 4 patients lost to follow-up). CONCLUSIONS: ESD with Enki-2 water jet system is effective and safe for superficial neoplastic digestive lesions.

Surgical Management of Small Bowel Neuroendocrine Tumors: Specific Requirements and Their Impact on Staging and Prognosis.

BACKGROUND: Small bowel neuroendocrine tumors (SB-NETs) are characterized by two main features: they usually are metastatic at diagnosis and multiple in 30 % of cases. As such, SB-NETs require specific surgical management. This retrospective study examined local recurrence, survival, and prognosis of SB-NETs after adapted surgery. METHODS: All consecutive patients with SB-NETs who underwent resection of at least one primary tumor between 1 January 2000 and 1 January 2013 were analyzed. The preoperative morphologic workup, histologic classification, and metastatic lymph node (LN) ratio (LNs involved/removed) were recorded. RESULTS: The study enrolled 107 patients, 35 (33 %) of whom had multiple SB-NETs (range 1-44; mean 3.1). Preoperative imaging and perioperative surgical examination missed 61 and 33 % of SB-NETs, respectively, in contrast to pathologic examination. Of the 107 patients, 43 % had carcinoid syndrome, 70 % had metastatic disease, and 90 % had LN involvement. The median number of LNs retrieved was 12 (range 1-69). The LN ratio (LNs involved/removed) was 0.25. The highest tumoral grades were G1 (in 61 % of patients) and G2 (in 37 % of patients). Of the 107 patients, 13 (12 %) had local LN recurrence. The rate of LN recurrence-free survival at 5 years was 88 %. The median overall survival (OS) time was 128 months (range 91-165 months). In the multivariate analysis, high chromogranin A (CgA) levels and peritoneal carcinomatosis were significantly associated with shorter OS. CONCLUSIONS: Systematic palpation of the entire small bowel detects more multiple NETs than preoperative imaging. Systematic surgery with extensive LN resection is associated with low local recurrence. High CgA levels and carcinomatosis are linked with shorter survival.

Impact of neoadjuvant chemoradiotherapy on postoperative outcomes after esophageal cancer resection: results of a European multicenter study.

OBJECTIVES: To assess the impact of neoadjuvant chemoradiotherapy (NCRT) on anastomotic leakage (AL) and other postoperative outcomes after esophageal cancer (EC) resection. BACKGROUND: Conflicting data have emerged from randomized studies regarding the impact of NCRT on AL. METHODS: Among 2944 consecutive patients operated on for EC between 2000 and 2010 in 30 European centers, patients treated by NCRT after surgery (n=593) were compared with those treated by primary surgery (n=1487). Multivariable analyses and propensity score matching were used to compensate for the differences in some baseline characteristics. RESULTS: Patients in the NCRT group were younger, with a higher prevalence of male sex, malnutrition, advanced tumor stage, squamous cell carcinoma, and surgery after 2005 when compared with the primary surgery group. Postoperative AL rates were 8.8% versus 10.6% (P=0.220), and 90-day postoperative mortality and morbidity rates were 9.3% versus 7.2% (P=0.110) and 33.4% versus 32.1% (P=0.564), respectively. Pulmonary complication rates did not differ between groups (24.6% vs 22.5%; P=0.291), whereas chylothorax (2.5% vs 1.2%; P=0.020), cardiovascular complications (8.6% vs 0.1%; P=0.037), and thromboembolic events (8.6% vs 6.0%; P=0.037) were higher in the NCRT group. After propensity score matching, AL rates were 8.8% versus 11.3% (P=0.228), with more chylothorax (2.5% vs 0.7%; P=0.030) and trend toward more cardiovascular and thromboembolic events in the NCRT group (P=0.069). Predictors of AL were high American Society of Anesthesiologists scores, supracarinal tumoral location, and cervical anastomosis, but not NCRT. CONCLUSIONS: Neoadjuvant chemoradiotherapy does not have an impact on the AL rate after EC resection (NCT 01927016).

Operating room organization and surgical performance: a systematic review.

BACKGROUND: Organizational factors may influence surgical outcomes, regardless of extensively studied factors such as patient preoperative risk and surgical complexity. This study was designed to explore how operating room organization determines surgical performance and to identify gaps in the literature that necessitate further investigation. METHODS: We conducted a systematic review according to PRISMA guidelines to identify original studies in Pubmed and Scopus from January 1, 2000 to December 31, 2019. Studies evaluating the association between five determinants (team composition, stability, teamwork, work scheduling, disturbing elements) and three outcomes (operative time, patient safety, costs) were included. Methodology was assessed based on criteria such as multicentric investigation, accurate population description, and study design. RESULTS: Out of 2625 studies, 76 met inclusion criteria. Of these, 34 (44.7%) investigated surgical team composition, 15 (19.7%) team stability, 11 (14.5%) teamwork, 9 (11.8%) scheduling, and 7 (9.2%) examined the occurrence of disturbing elements in the operating room. The participation of surgical residents appeared to impact patient outcomes. Employing specialized and stable teams in dedicated operating rooms showed improvements in outcomes. Optimization of teamwork reduced operative time, while poor teamwork increased morbidity and costs. Disturbances and communication failures in the operating room negatively affected operative time and surgical safety. CONCLUSION: While limited, existing scientific evidence suggests that operating room staffing and environment significantly influences patient outcomes. Prioritizing further research on these organizational drivers is key to enhancing surgical performance.

Neuropilin 2 and soluble neuropilin 2 in neuroendocrine neoplasms.

Neuropilin 2 (NRP2), a transmembrane non-tyrosine kinase receptor, has been described as a potential critical player in the tumourigenesis of several solid cancers and particularly in neuroendocrine neoplasms (NENs). A soluble form of NRP2 (sNRP2) has been previously described and corresponds to a truncated splice isoform. Its prognostic value has never been studied in NEN. NRP2 expression was studied by immunochemistry on tissue microarrays (n = 437) and on circulating tumour cells (CTCs, n = 5 patients with neuroendocrine carcinoma, NEC). We described the levels of sNRP2 in 229 patients with NEN using the ELISA method to identify the factors associated with sNRP2 levels and to evaluate its prognostic role; 90 blood donors represented the healthy control group. NRP2 was found in 97% of neuroendocrine tumours (396/410) and in 74% of NEC (20/27). NRP2 was also expressed in CTC of all the studied patients. The receiver operating characteristic (ROC) analysis showed that sNRP2 had a weak capacity to discriminate between NEN patients and healthy controls (area under curve (AUC) = 0.601, P = 0.053). Abnormal sNRP2 levels were associated with inflammatory syndrome, bone and peritoneal metastases, and abnormal chromogranin A levels. Patients with high sNRP2 levels (sNRP2Q3-Q4) had significantly poorer overall survival in multivariate analysis (HR 0.16, 95% CI (0.04-0.67), P = 0.015). In conclusion, the present study found that sNRP2 and NRP2 could represent a new prognostic biomarker and a therapeutic target, respectively, particularly in aggressive NEN.

Antitumor effect of everolimus in preclinical models of high-grade gastroenteropancreatic neuroendocrine carcinomas.

BACKGROUND/AIMS: While the range of therapeutic options for well-differentiated gastroenteropancreatic neuroendocrine tumors has recently increased with the emergence of targeted therapies, such as mTOR inhibitors, there is no recent progress in the treatment of poorly differentiated neuroendocrine carcinomas (PDNECs). Since PDNECs have been shown to strongly express mTOR pathway components, the aim of the present study was to assess the antitumor effect of the mTOR inhibitor everolimus in preclinical models of PDNECs. METHODS: The expression of mTOR pathway components and their response to everolimus were assessed in two neuroendocrine cell lines: STC-1 and GluTag. A xenograft model of intrahepatic dissemination in the nude mouse, based on the intrasplenic injection of either STC-1 and GluTag tumor cells, was used. Animals were started on everolimus treatment 3 days after injection. The effects of treatment on tumor growth, proliferative capacities, apoptosis and in situ expression of mTOR pathway components were assessed. RESULTS: The expression of mTOR pathway components was comparable in STC-1 and GluTag cells and in human PDNECs and could be inhibited in vitro by everolimus. In vivo, the tumor volume of STC-1 and GluTag xenografts was significantly reduced in treated animals (6.05 ± 1.84% as compared to 21.76 ± 3.88% in controls). Everolimus treatment also induced a significant decrease in Ki67 index and in the phosphorylation levels of the two major effectors of mTOR, p70S6K and 4E-BP1. CONCLUSION: Our experimental data suggest that mTOR inhibition could be considered a therapeutic option for high-grade gastroenteropancreatic neuroendocrine tumors.

Targeting the PI3K/mTOR pathway in murine endocrine cell lines: in vitro and in vivo effects on tumor cell growth.

The mammalian target of rapamycin (mTOR) inhibitors, such as rapalogues, are a promising new tool for the treatment of metastatic gastroenteropancreatic endocrine tumors. However, their mechanisms of action remain to be established. We used two murine intestinal endocrine tumoral cell lines, STC-1 and GLUTag, to evaluate the antitumor effects of rapamycin in vitro and in vivo in a preclinical model of liver endocrine metastases. In vitro, rapamycin inhibited the proliferation of cells in the basal state and after stimulation by insulin-like growth factor-1. Simultaneously, p70S6 kinase and 4EBP1 phosphorylation was inhibited. In vivo, rapamycin substantially inhibited the intrahepatic growth of STC-1 cells, irrespectively of the timing of its administration and even when the treatment was administered after cell intrahepatic engraftment. In addition, treated animals had significantly prolonged survival (mean survival time: 47.7 days in treated animals versus 31.8 days in controls) and better clinical status. Rapamycin treatment was associated with a significant decrease in mitotic index and in intratumoral vascular density within STC-1 tumors. Furthermore, the antitumoral effect obtained after treatment with a combination of rapamycin and phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 was more significant than with rapamycin alone in both cell lines. Our results suggest that the antitumor efficacy of rapamycin in neuroendocrine tumors results from a combination of antiproliferative and antiangiogenic effects. Interestingly, a more potent antitumor efficiency could be obtained by simultaneously targeting several levels of the PI3K/mTOR pathway.

Impaired postoperative EGJ relaxation as a determinant of post laparoscopic fundoplication dysphagia: a study with high-resolution manometry before and after surgery.

BACKGROUND: Laparoscopic fundoplication (FP) reduces gastroesophageal reflux (GER) efficiently. Dysphagia is its main complication, but no clear data have been published in literature to evaluate risk factors associated with it. The goal of this retrospective study was to identify factors associated with dysphagia occurring after FP for GER disease, with high-resolution manometry (HRM) performed before and after surgery. METHODS: Twenty patients (11 women; mean age, 49 (range, 19-68 years) underwent HRM before and 2-3 months after laparoscopic Nissen-Rossetti FP. Analysis was performed with esophageal pressure topography according to the Chicago Classification. RESULTS: Before FP, ten patients had a manometric hiatal hernia (none after FP). Esophagogastric junction (EGJ) pressures increased after surgery (p < 0.01). Bolus pressurization was present in 2% of all swallows before FP and in 22% after (p = 0.01). Postoperative bolus pressurization percentage was significantly correlated with EGJ relaxation as measured with integrated relaxation pressure (IRP) (r = 0.79, p < 0.01). Eight patients reported dysphagia after FP. The only pre- or post-operative parameter significantly associated with dysphagia was postoperative IRP (5.1 mmHg without vs. 10.3 with dysphagia, p < 0.02). CONCLUSIONS: FP establishes an efficient antireflux mechanism by correcting hiatal hernia and increasing EGJ pressures. EGJ relaxation as measured by IRP is significantly altered after surgery, leading to more frequent motility disorders, and bolus pressurization. Postoperative dysphagia was associated with higher values of IRP.