Gilles Poncet

Low Microvessel Density Is an Unfavorable Histoprognostic Factor in Pancreatic Endocrine Tumors

BACKGROUND AND AIMS In many malignant tumors, intratumoral microvascular density (MVD) has been suggested to be a prognostic parameter. We aimed to provide a quantitative evaluation of intratumoral microvascular density in a large series of resected endocrine tumors of the pancreas and to evaluate the potential prognostic significance of this parameter. METHODS Eighty-two tumors from 77 patients have been studied. MVD was evaluated by 2 observers after CD34 immunostaining and correlated with the following parameters: WHO classification, hormonal profile, tumor size, vascular endothelial growth factor expression, occurrence of metastasis, duration of survival. RESULTS MVD ranged from 5 to 92 vessels/field. MVD was significantly higher in well-differentiated benign endocrine tumors than in tumors of uncertain behavior and in carcinomas. No close correlation was found between MVD and the hormonal profile. MVD was significantly higher in tumors characterized by the following histoprognostic parameters: size <2 cm, proliferation index <2%, no evidence of metastasis. No close correlation was observed between MVD and VEGF expression. Finally, a MVD <30 vessels/field was associated with the occurrence of metastasis in tumors <2 cm and/or with a proliferation index <2% and with a significantly shorter survival after surgery. CONCLUSIONS The quantitative analysis of microvessel density in pancreatic endocrine tumors may identify patients who, despite favorable conventional histoprognostic factors, are at risk of unfavorable evolution.

Eversion Thrombectomy for Portal Vein Thrombosis During Liver Transplantation

Portal vein thrombosis (PVT) has been seen as an obstacle to orthotopic liver transplantation (OLT), but recent data suggest that favorable results may be achieved in this group of patients. The aim of this study was to analyze the incidence, management, and survival of patients with PVT undergoing primary OLT with thrombectomy. Between October 1990 and August 2000, 468 liver transplantations were performed in our center and portal vein thrombosis was present in 38 patients (8.1%). Preoperative diagnosis, extension, intraoperative management, postoperative recurrence of portal vein thrombosis, and 1‐year actuarial survival rates were retrospectively studied. Preoperative diagnosis was made in 17 cases (44.7%). In all patients, portal flow was restored after portal vein thrombectomy, followed by usual end‐to‐end portal anastomosis. All patients received preventive low‐weight heparin from day 2 to hospital discharge, and then aspirin. Rethrombosis was observed in one patient with extended splanchnic thrombus. The 1‐year actuarial patient survival rate was 83.7%, and did not significantly differ from the patients without portal vein thrombosis (86.7%). Our results suggest that portal vein thrombosis is often partial and thus difficult to diagnose preoperatively; it can be managed successfully during surgery by thrombectomy, except when there is complete splanchnic veins thrombosis; and it did not affect 1‐year survival.

Doppler-guided hemorrhoidal artery ligation and rectoanal repair (HAL-RAR) for the treatment of grade IV hemorrhoids: long-term results in 100 consecutive patients.

BACKGROUND: Doppler-guided hemorrhoidal artery ligation is a minimally invasive technique for the treatment of symptomatic hemorrhoids that has been applied successfully for grade II and III hemorrhoids but is less effective for grade IV hemorrhoids. Development of a special proctoscope enabled the combination of hemorrhoidal artery ligation with transanal rectoanal repair (mucopexy), which serves to lift and then secure the protruding hemorrhoids in place. OBJECTIVE: The purpose of this study was to describe our experience with this combined procedure in the treatment of grade IV hemorrhoids. DESIGN: Prospective observational study. SETTING: Outpatient colorectal surgery unit. PATIENTS: Consecutive patients with grade IV hemorrhoids treated from April 2006 to December 2008. INTERVENTION: Hemorrhoidal artery ligation–rectoanal repair. MAIN OUTCOME MEASURES: Operating time, number of ligations, number of mucopexies and associated procedures, and postoperative symptoms were recorded. Pain was graded on a visual analog scale. Follow-up was at 2, 6, and 12 months after surgery, and then annually. RESULTS: A total of 100 consecutive patients (64 women, 36 men) with grade IV hemorrhoids were included. Preoperative symptoms were bleeding in 80 and pain in 71 patients; 19 patients had undergone previous surgical treatment for the disease. The mean operative time was 35 (range, 17–60) minutes, with a mean of 9 (range, 4–14) ligations placed per patient. Eighty-four patients were discharged on the day of the operation. Nine patients developed early postoperative complications: pain in 6, bleeding in 4, dyschezia in 1, and thrombosis of residual hemorrhoids in 3. Late complications occurred in 4 patients and were managed conservatively. Recurrence was observed in 9 patients (9%), with a mean follow-up of 34 (range, 14–42) months. LIMITATIONS: The 2 main weaknesses of the study were the lack of very long-term follow-up and the absence of a comparison with hemorrhoidectomy or hemorrhoidopexy. CONCLUSION: Doppler-guided hemorrhoidal artery ligation with rectoanal repair is safe, easy to perform, and should be considered as an effective option for the treatment of grade IV hemorrhoids.

Partial recovery of peristalsis after myotomy for achalasia; more the rule than the exception

IMPORTANCE Although successful treatment of achalasia depends on alleviating the obstruction at the esophagogastric junction, the postintervention contractile and pressurization pattern may also play a role in outcome. OBJECTIVE To determine whether myotomy that alleviates the esophagogastric junction outflow obstruction in achalasia might improve peristalsis. DESIGN Retrospective study from August 1, 2004, through January 30, 2012. SETTING Two tertiary care hospitals in Chicago and Lyon. PATIENTS We included 30 patients (18 male; mean age [range], 43 [17-78] years), of whom 8 had type 1 (26.6%), 17 had type 2 (56.7%), and 5 (16.7%) had type 3 achalasia according to the Chicago classification. INTERVENTIONS Esophageal high-resolution manometry before and after laparoscopic or endoscopic myotomy. MAIN OUTCOMES MEASURE The integrity of peristalsis, characterized as intact, weak contractions; frequent failed peristalsis; or premature contractions. RESULTS Although peristaltic fragments were evident only in patients with type 3 achalasia before treatment, intact, weak, or frequent failed peristalsis was encountered in 5 patients with type 1 (63%), 8 with type 2 (47%), and 4 with type 3 (80%) achalasia after myotomy. One patient with type 3 achalasia had distal esophageal spasm after treatment. In patients with a postmyotomy integrated relaxation pressure of less than 15 mm Hg, only 10 (40%) had persistent absent peristalsis. Panesophageal pressurization disappeared after myotomy in 16 of 19 patients. In the 5 patients with postmyotomy integrated relaxation pressure of more than 15 mm Hg, 4 had weak peristalsis and 1 had absent peristalsis. CONCLUSIONS AND RELEVANCE Reduction or normalization of the esophagogastric junction relaxation pressure achieved by myotomy in achalasia is associated with partial recovery of peristalsis in some patients, suggesting that the disease process progresses from the esophagogastric junction to the esophageal body. Whether the return of peristalsis is predictive of an improved therapeutic outcome requires further study.

Original article: Natural history of acute colonic diverticular bleeding: prospective study in 133 consecutive patients

Aliment Pharmacol Ther 2010; 32: 466–471

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.

Achalasia-Like Disorder After Laparoscopic Adjustable Gastric Banding: a Reversible Side Effect?

Literature data concerning the effect of laparoscopic adjustable gastric banding (LAGB) on esophageal motility are conflicting. Achalasia-like disorder involving the absence of esophageal peristalsis and impaired esophago-gastric junction (EGJ) is probably under-estimated and can result in failure and band removal. The aim of our study was to focus on cases of achalasia-like disorder and study its evolution after band deflating or removal. LAGB patients with food intolerance and whose esophageal manometry confirmed dysmotility were selected from our database. Achalasia-like disorder was defined as the absence of esophageal peristalsis (< 20 % contraction waves) with impairment of EGJ relaxation. Manometric control was performed after removal or band deflating; functional results were assessed. Eleven patients among 20 (55 %) with esophageal motility disorders (EMD) fitted the manometric criteria of achalasia-like disorder with a mean EGJ resting pressure of 32.1 cmH2O and a EGJ relaxation pressure of 24.2. Nine patients out of 11 underwent band removal which resulted in the resolution of their symptoms. The other two underwent band deflation. Manometric control after band removal showed both a decrease in resting and relaxation EGJ pressures (mean of 9.5 and 6.5 cmH2O) and a recovery of wave contractions in 87.5 % of cases. Four patients underwent revision surgery due to weight regain with a successful outcome. Achalasia-like disorder is a manometric diagnosis and accounts for a significant part of symptomatic EMD after LAGB. It often results in band removal, allowing some reversibility of the disorders.

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.

Neuroendocrine neoplasms of the jejunum: a heterogeneous group with distinctive proximal and distal subsets

Neuroendocrine tumors (NETs) of the jejunum are rare and usually grouped with either duodenal or ileal NETs. We aimed at better evaluating their characteristics by studying 116 cases of small-bowel NETs for which a precise anatomical location was available. Thirty-four cases were duodenal. Eighty-two were located after the duodenojejunal ligament, including ten cases in the first 50 cm, four cases between 50 and 100 cm, and six cases between 100 and 250 cm. All tumors located after 50 cm from the duodenojejunal ligament were enterochromaffin neoplasms. In contrast, the ten tumors located before this point formed a heterogeneous group. They included two cases of gastrin-expressing tumors in the first 10 cm and one case of enterochromaffin tumor located at 45 cm. The seven remaining cases were large tumors, located between 10 and 50 cm, of intermediate or high histological grade (four out of seven G2 or G3), locally invasive and usually metastatic (five out of seven with liver metastases); their survival was comparable to that of duodenal NETs. Patients with tumors located in the duodenum or the first 50 cm of the jejunum had longer survivals than those with lower jejunal and ileal tumors (p = 0.024). In conclusion, our study underlines the heterogeneity of jejunal NETs and supports the distinction between “upper” and “lower” jejunal tumors, which, for prognostic purposes, might be grouped with, respectively, duodenal and ileal NETs. Our data suggest that the arbitrary limit between upper and lower jejunal tumors might be fixed at 50 cm from the duodenojejunal ligament.

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 ± 4.2 (mean ± standard 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 ± 1.1 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.