Endoscopic treatment of sporadic small duodenal and ampullary neuroendocrine tumors.

Background and study aim: As duodenal neuroendocrine tumors (NETs) are rare, their optimal management has not been clearly established. The aim of this study was to evaluate the feasibility and outcome of endoscopic treatment of duodenal NETs. Patients and methods: We reviewed the files of all patients who underwent endoscopic resection of a sporadic duodenal or ampullary NET between 1996 and 2014 at two centers. Results: A total of 29 patients with 32 uT1N0M0 NETs < 20 mm were included. Treatment consisted of endoscopic mucosal resection in 19 cases, and cap aspiration in 13 cases. Prior submucosal saline injection was used in 15 cases. Mortality was 3 % (one severe bleeding). Morbidity was 38 % (11/29). At post-resection analysis, mean tumor size was 8.9 mm (range 3 - 17 mm), 29 lesions were stage pT1, one was pT2, and 2 were pTx because of piecemeal resection. All NETs were well differentiated. A total of 27 lesions were classified as grade 1 and 5 were grade 2. The resection was R0, R1, and Rx for 16, 14, and 2 lesions, respectively. Three R1 patients underwent additional surgical treatment, with no residual tumor on the surgical specimen but with positive metastatic lymph nodes in two cases. One patient was lost to follow-up. Finally, 24 patients were included in the follow-up analysis. The median follow-up period was 56 months (range 6 - 175 months). Two patients presented a tumor recurrence during the follow-up period. Conclusions: Endoscopic treatment of small duodenal NETs was associated with significant morbidity, a difficulty in obtaining an R0 specimen, and the risk of lymph node metastasis. Nevertheless, it represents an interesting alternative in small grade 1 duodenal lesions and in patients at high surgical risk.

Endoscopic treatment of severe duodenal polyposis as an alternative to surgery for patients with familial adenomatous polyposis.

BACKGROUND: Patients with familial adenomatous polyposis (FAP) and severe (stage IV) duodenal polyposis are candidates for pancreaticoduodenectomy, which has high morbidity. Little information is available about the feasibility of therapeutic endoscopy for these patients. OBJECTIVE: To evaluate the long-term efficiency and risks of endoscopic therapy. DESIGN: Retrospective study. SETTING: A 2-referral center long-term cohort study. PATIENTS: Thirty-five FAP patients (15 men, mean age 48 years) presenting with stage IV duodenal polyposis were included. Patients had a mean Spigelman classification score of 9.8 points (range 9-12 points) at their first examination. INTERVENTIONS: Patients underwent a surveillance endoscopy, including lateral and axial viewing with chromoendoscopy while under sedation, along with 7 ± 4.8 therapeutic endoscopic sessions during a follow-up period of 9 ± 4.5 years (range 1-19 years) after their first endoscopy. MAIN OUTCOME MEASUREMENTS: Treatment modalities, adverse events, and efficiency (evolution of the Spigelman score) were reviewed. RESULTS: A total of 245 therapeutic endoscopies were performed and 15 adverse events (6%) occurred. During the follow-up period, Spigelman scores decreased in 95% of patients by 6 ± 2.2 points (P = .002). Modeling analysis showed that the mean Spigelman score decreased by 60% after 150 months. LIMITATIONS: Retrospective study and the duration of the follow-up, even though this is the longest follow-up reported in medical literature. CONCLUSION: Endoscopic treatment of severe duodenal polyposis in patients with FAP produces few adverse events and allows efficient downstaging of the polyposis. Long-term follow-up data did not reveal a high risk of invasive duodenal cancer in these patients.

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.

Contrast-enhanced ultrasound after devascularisation of neuroendocrine liver metastases: functional and morphological evaluation.

OBJECTIVE: To evaluate morphological and perfusion changes in liver metastases of neuroendocrine tumours by contrast-enhanced ultrasound (CEUS) after transarterial embolisation with bead block (TAE) or trans-arterial chemoembolisation with doxorubicin-eluting beads (DEB-TACE). METHODS: In this retrospective study, seven patients underwent TAE, and ten underwent DEB-TACE using beads of the same size. At 1 day before embolisation, 2 days, 1 month and 3 months after the procedure, a destruction-replenishment study using CEUS was performed with a microbubble-enhancing contrast material on a reference tumour. Relative blood flow (rBF) and relative blood volume (rBV) were obtained from the ratio of values obtained in the tumour and in adjacent liver parenchyma. Morphological parameters such as the tumour's major diameter and the viable tumour's major diameter were also measured. A parameter combining functional and morphological data, the tumour vitality index (TVI), was studied. The Wilcoxon rank-sum test and Fisher's test were used to compare treatment groups. RESULTS: At 3 months rBF, rBV and TVI were significantly lower (P = 0.005, P = 0.04 and P = 0.03) for the group with doxorubicin. No difference in morphological parameters was found throughout the follow-up. CONCLUSIONS: One parameter, TVI, could evaluate the morphological and functional response to treatments.

Is the combination of chromogranin A and pancreatic polypeptide serum determinations of interest in the diagnosis and follow-up of gastro-entero-pancreatic neuroendocrine tumours?

INTRODUCTION: Chromogranin A (CgA) is the principal tumour marker for gastroenteropancreatic neuroendocrine tumours (GEPNET). Combining serum CgA and pancreatic polypeptide (PP) levels may increase the sensitivity of tumour markers in the diagnosis of GEPNET. OBJECTIVES: (1) To evaluate the sensitivity of PP and CgA in GEPNET. (2) To compare changes in serum CgA and PP levels with the morphological evolution of the tumours. PATIENTS AND METHODS: Sixty-six pancreatic and 49 gastrointestinal NET, with at least one serum determination of CgA and PP at the same time were retrieved from an institutional data base. Secondly, the variations in serum CgA or PP at successive determinations were compared to Response Evaluation Criteria in Solid Tumours (RECIST) criteria in 57 patients (112 follow-up visits) with high serum CgA levels and in 21 patients (37 follow-up visits) with high serum PP levels. RESULTS: Among the 115 patients included in the study group, an increase in serum CgA (normal <98 µg/L) or PP (normal <100 pmol/L) was found in respectively 79 (69%) and 36 (31%) cases. Seven patients had normal CgA and elevated PP levels. Both markers were significantly more elevated in metastatic disease (74% versus 51% for CgA and 37% versus 18% for PP). The concordance rates between serum markers and RECIST criteria were 51% for CgA and 54% for PP. CONCLUSIONS: Serum PP determination identify few false-negative results of serum CgA determination in GEPNET. Our study does not validate the use of CgA or PP as surrogate markers for detecting changes in tumour burden.

Management of gastrointestinal stromal tumours of limited size: proposals from a French panel of physicians.

A number of guidelines on the management of gastro-intestinal stromal tumours (GISTs) have been published, mostly based on expert consensus. However, these guidelines have generally failed to address the specific problem of GISTs of limited size (i.e. those measuring a few centimetres in diameter) with which gastroenterologists are increasingly confronted. The aim of the present work was to draw up proposals for the diagnosis and treatment of GISTs measuring less than 5 cm in diameter. For this purpose, a number of practical questions were put to a panel of French experts.

Primary neuroendocrine tumors of the main pancreatic duct: a rare entity.

Very few cases of primary neuroendocrine tumors of the main pancreatic duct have been reported. This paucity has hampered an accurate description of the distinctive clinical and pathological features of these tumors and the correct evaluation of the diagnostic and therapeutic problems which they may raise. We report here five additional cases in order to underline the clinical, histological, and immunohistochemical features of this tumor entity. There were three male and two female, aged 43-72 years; in all patients, but one, who presented with epigastric pain, the diagnosis was made after the incidental discovery of a dilatation of the main pancreatic duct. The preoperative diagnosis was ductal adenocarcinoma in one case, IPMN in one case and neoplastic stenosis of unknown etiology in four cases. Surgical resection was performed in all cases. The diagnosis of neuroendocrine tumor was made at histological examination. All lesions were small, ranging from 5 to 15 mm. They had a predominantly intramural growth. The growth pattern was nodular in three cases, circumferential in two; there was no intra-luminal component. All cases were well-differentiated neuroendocrine neoplasms of low histological grade (G1); four cases expressed serotonin. One case was associated with regional lymph node metastases. All cases were cured by surgery alone; no recurrence was observed at the end of the follow-up period. In conclusion, despite their rarity, primary neuroendocrine tumors of the main pancreatic duct deserve recognition and must be considered in the etiological diagnosis of ductal stenosis.

Neuroendocrine tumors of Meckel's diverticulum: lessons from a single institution study of eight cases.

INTRODUCTION: Endocrine tumors of Meckel's diverticulum are rare. Their clinical and pathological characteristics are not well known, making it difficult to assess the best strategy for therapeutic management. MATERIALS AND METHODS: Eight cases of endocrine tumors of Meckel's diverticulum, submitted to surgical resection in our institution between 1977 and 2009, were studied. Clinical charts were reviewed; classification, grading, and staging were performed according to recent international recommendations. Five cases, including two associated with the carcinoid syndrome, were revealed by mesenteric mass or liver metastases; three cases were diagnosed incidentally at laparotomy or laparoscopy. RESULTS: All cases presented as typical well-differentiated midgut endocrine tumors. Five cases were associated with mesenteric lymph node metastases; three presented with liver metastases. Seven cases were classified as well-differentiated endocrine carcinomas, one as well-differentiated endocrine tumor of benign behavior. DISCUSSION: All tumors >1 cm, but one, had regional or distant disease. All patients had complete surgical resection of the primary. One patient deceased after 25 months; the others were alive after 12-101 months. CONCLUSION: In conclusion, endocrine tumors of Meckel's diverticulum are rarely symptomatic and often diagnosed at an advanced stage. All tumors measuring more than 1 cm in diameter must be resected according to oncological principles.

Perfusion characterization of liver metastases from endocrine tumors: Computed tomography perfusion.

AIM: To assess prospectively parameters of computed tomography perfusion (CT p) for evaluation of vascularity of liver metastases from neuroendocrine tumors. METHODS: This study was approved by the hospital's institutional review board. All 18 patients provided informed consent. There were 30 liver metastases from neuroendocrine tumors. Patients were divided into three groups depending on the appearance of the liver metastases at the arterial phase of morphological CT (hyperdense, hypodense and necrotic). Sequential acquisition of the liver was performed before and for 2 min after intravenous injection of 0.5 mg/kg contrast medium, at 4 mL/s. Data were analyzed using deconvolution analysis to calculate blood flow (BF), blood volume (BV), mean transit time (MTT), hepatic arterial perfusion index (HAPI) and a bi-compartmental analysis was performed to obtain vascular permeability-surface area product (PS). Post-treatment analysis was performed by a radiologist and regions of interest were plotted on the metastases, normal liver, aorta and portal vein. RESULTS: At the arterial phase of the morphological CT scan, the aspects of liver metastases were hyperdense (n = 21), hypodense (n = 7), and necrotic (n = 2). In cases of necrotic metastases, none of the CT p parameters were changed. Compared to normal liver, a significant difference in all CT p parameters was found in cases of hyperdense metastases, and only for HAPI and MTT in cases of hypodense metastases. No significant difference was found for MTT and HAPI between hypo- and hyperdense metastases. A significant decrease of PS, BV and BF was demonstrated in cases of patients with hypodense lesions PS (23 ± 11.6 mL/100 g per minute) compared to patients with hyperdense lesions; PS (13.5 ± 10.4 mL/100 g per minute), BF (93.7 ± 75.4 vs 196.0 ± 115.6 mL/100 g per minute) and BV (9.7 ± 5.9 vs 24.5 ± 10.9 mL/100 g). CONCLUSION: CT p provides additional information compared to the morphological appearance of liver metastases.

Evaluation of the combination 5-fluorouracil, dacarbazine, and epirubicin in patients with advanced well-differentiated neuroendocrine tumors.

INTRODUCTION: The aim of this study was to retrospectively analyze the efficacy and safety of the combination of 5-fluorouracil (5-FU), dacarbazine, and epirubicin (FDE) in 39 patients with advanced, well-differentiated neuroendocrine tumors (NETs). PATIENTS AND METHODS: The primary sites of the disease were the pancreas (16 cases), gastrointestinal tract (12 cases), and extradigestive sites (11 cases). Out of these, 54% of the patients were chemotherapy naive and 74% were progressive. The treatment was a combination of 5-FU 500 mg/m²/day, dacarbazine 250 mg/m²/day for 5 days, and epirubicin 50 mg/m² on day 1, administered every 21 days. Tumoral response was assessed with response evaluation criteria in solid tumors. RESULTS: Partial response was seen in 17 out of the 39 patients (44%) and the median response duration was 12 months. The median progression-free survival and overall survival were 11 and 21 months, respectively. Disease control was achieved in 83% of the 29 patients in progression at the beginning of the treatment. Objective responses were 58%, 25%, and 36%, for pancreatic, gastrointestinal, and extradigestive NETs, respectively. The sole grade 3/4 toxicity was hematologic. CONCLUSION: The FDE regimen is effective in advanced well-differentiated NETs and represents an interesting alternative to streptozocin-based regimens as first- or second-line therapy.

Is caseinomacropeptide from milk proteins, an inhibitor of gastric secretion?

The aim of this work was to study, in vivo, the effect of the ingestion of not glycosylated caseinomacropeptide (CMP) on gastric secretion. In Experiments #1 and #2, 7 calves fitted with a gastric pouch received either a diet without CMP (C diet) or C diet in which CMP was introduced (equal to and 5 folds that of CMP quantity contained in cow milk, diets CMP1 and CMP5, respectively). In Experiment #3, 2 calves (with gastric pouch) were fed C diet followed by an "iv perfusion" of CMP. In Experiment #4, 25 calves fed either C, CMP1 or CMP5 diets were fitted with a blood catheter for sample collections. The quantities of daily gastric secretions seemed few modified by CMP ingestion but the profile of these secretions was changed along the day. The most important result is that CMP can inhibit gastric secretions (mainly hydrochloric acid) stimulated by the meal, but there was no dose-dependent response. No similar observations were obtained after perfusion of CMP in jugular vein. CMP was not detected in blood. Results obtained in our experiments are not in favor of its significant intestinal absorption. Gastrin, somatostatin and VIP could be implicated in the mechanisms of regulation.

A new role of phosphopeptides as bioactive peptides released during milk casein digestion in the young mammal: regulation of gastric secretion.

The aim of this work was to study in vivo the effect of ingestion of phosphopeptides (PP) alone or associated with caseinomacropeptide (CMP) on gastric secretion and to elucidate some possible mechanisms involved. Seven calves fitted with a gastric pouch received either a diet based on whey proteins without PP and CMP (C diet) or C diet in which PP or PP+CMP was introduced at concentrations similar to that of PP or PP+CMP in cow milk (PP diet and PP+CMP diet, respectively). Gastric juice secretion was measured during successive periods throughout the day. Twenty-four calves were fitted with a catheter introduced in one external jugular vein for blood sample collections. The daily secretion of electrolytes decreased with the presence of PP or PP+CMP in the diet. During the day, peptide supplementation in the diet resulted in (1) short term (1st-2nd postprandial h), a decrease of secreted quantities of gastric juice, enzymes and electrolytes, (2) long term (7-24h after the morning meal), a decrease of electrolyte secretions. Intervention of gastrin, CCK, somatostatin and BPP could be probable. Globally, inhibition of gastric secretions seemed more important when PP was given in association with CMP in the diet rather than alone. CMP and PP may have short and long term action respectively over the 24h day. To our knowledge, it is the first time that phosphopeptides coming from milk casein digestion are demonstrated to inhibit gastric secretion. Therapeutic uses are suggested.

Major hyperghrelinemia in advanced well-differentiated neuroendocrine carcinomas: report of three cases.

OBJECTIVE: We aimed to gain insight into the functional consequences of ghrelin overproduction in patients with neuroendocrine tumors and its relations with disease characteristics and evolution. DESIGN: We retrospectively analyzed three cases of neuroendocrine carcinomas associated with very high levels of circulating ghrelin. METHODS: Between February and October 2007, serum ghrelin levels were determined in all patients with well-differentiated endocrine carcinoma referred to our center (n=72). Three patients were found to have circulating ghrelin levels >10-fold the upper limit of normal. The clinical, biochemical, and pathological characteristics of these three patients were reviewed. The ratio between circulating acyl and total ghrelin was determined, and tumor tissue expression of ghrelin was assayed by immunohistochemistry. RESULTS: The three patients had massive hyperghrelinemia (respectively 49 028, 63 711, and 101 996 pg/ml), with <10% of acyl ghrelin. The corresponding primary tumors were located in the pancreas, rectum, and gallbladder; all were metastatic. There was no acromegaly; there was a decrease in appetite; and body mass index was low. Serum GH levels were only slightly increased and serum IGF1 levels were normal. Immunoreactive ghrelin was detected in the tumor tissue in the two cases in which tissue material was available. All three patients died before 12 months after the diagnosis of hyperghrelinemia. CONCLUSION: Well-differentiated neuroendocrine carcinomas of various origins may produce markedly high levels of circulating ghrelin, without evidence of clinical or functional consequences.

Long-term survival after pancreaticoduodenectomy for endocrine tumors of the ampulla of Vater and minor papilla.

OBJECTIVE: Endocrine tumors of the ampullary region are rare, and accurate indications for their management are lacking. We aimed to evaluate the outcome of surgical treatment in this indication. METHOD: We reviewed all patients who submitted to a pancreaticoduodenectomy for ampullary endocrine tumors between 1982 and 2003 in our center. RESULTS: Eight patients, 3 men and 5 women, with a mean age of 47.8 years (range, 37-57 years) were included. Two patients presented with Zollinger-Ellison syndrome, and 1 had neurofibromatosis. Operative mortality was nil. The mean size of the tumors was 17.4 mm (range, 5-40 mm). There were 7 well-differentiated and 1 poorly differentiated endocrine carcinomas. Seven patients had satellite lymph node metastases, and 1 had diffuse liver metastases. Median follow-up was 131 months (range, 17-315 months). At the end of the follow-up period, 5 patients were alive and disease-free; 1 patient was alive with stable liver metastases. Two patients died 17 months and 13 years after surgery, respectively, from metastasis and an unrelated cause. CONCLUSION: This study demonstrates the high frequency of lymph node invasion in these uncommon tumors, even at an early clinical stage. Pancreaticoduodenectomy may result in prolonged survival of patients with well-differentiated tumors.

Gemcitabine and oxaliplatin combination chemotherapy for metastatic well-differentiated neuroendocrine carcinomas: a single-center experience.

BACKGROUND: Beyond the usual regimens based on streptozocin and doxorubicin or 5-fluorouracil, no second-line therapy of metastatic neuroendocrine tumor has gained wide acceptance. Gemcitabine and oxaliplatin are generally well tolerated and have shown activity against a wide range of malignancies. The authors assessed the efficacy of gemcitabine-oxaliplatin combination (GEMOX) in the treatment of patients with metastatic neuroendocrine tumors. METHODS: Twenty consecutive patients with progressive disease were treated with GEMOX, in most cases after failure of other chemotherapy regimens (median=2). Patients were followed for evidence of toxicity, response, and survival. Two patients were chemotherapy-naive at treatment initiation and were excluded from the efficacy analysis. RESULTS: Toxicity was manageable overall; however, 6 (30%) patients had to discontinue treatment because of oxaliplatin-induced neurotoxicity (grade 2). Three (17%) of 18 patients had a partial response, median progression-free survival was 7.0 months, and median overall survival was 23.4 months. CONCLUSIONS: Gemcitabine-oxaliplatin combination shows interesting activity and is well tolerated in pretreated patients with neuroendocrine tumors.

Well-differentiated endocrine carcinoma of the renal pelvis: report of a case with sustained objective response to octreotide.

Endocrine tumors of the upper urogenital tract are extremely rare. We report the case of a patient with a primary well-differentiated endocrine carcinoma of the renal pelvis metastatic to the liver, in whom an objective response was obtained under octreotide treatment. A 36-year-old woman without symptoms was admitted for exploration of a solid nodule in the right kidney. A right nephrectomy was performed. The histological examination of the surgical specimen diagnosed a primary well-differentiated endocrine tumor of the renal pelvis. Tumor cells strongly expressed synaptophysin and were focally positive for chromogranin A; they displayed faint reactivity for PSAP. Three months later, multiple liver metastases, proved by biopsy, were diagnosed. After two lines of chemotherapy, octreotide treatment was initiated because of persistent high activity at scintigraphic examination. A marked decrease in tumor volume and in chromogranin A serum levels was obtained. Two years later, there was no further progression. The patient was treated with octreotide. Our report points out the unusual immunophenotypic features which may be encountered in well-differentiated endocrine carcinoma of the upper urogenital tract and the potential interest in somatostatin analogues in the treatment of metastatic cases.

MEN1 missense mutations impair sensitization to apoptosis induced by wild-type menin in endocrine pancreatic tumor cells.

BACKGROUND & AIMS: Missense mutations account for 30% of mutations identified in patients with the multiple endocrine neoplasia type 1 (MEN1) syndrome. They raise several issues: the distinction between pathogenic mutations and polymorphisms is sometimes difficult and the functional effects of missense mutations are unclear. We aimed to evaluate the functional consequences of missense MEN1 mutations in an appropriate endocrine cellular context. METHODS: From the INS-1 insulinoma cell line, we established clones conditionally over expressing wild-type (WT) menin or its A160T, H317Y, and A541T variants. We compared the consequences of WT or variant menin over expression on apoptotic response after gamma-irradiation and analyzed the interactions of these proteins with p53. RESULTS: WT menin over expression sensitized INS-r3 cells to apoptosis through amplification of caspase-3 activation, increased p53 acetylation, and accelerated p21 activation; moreover, over expressed WT menin could be recovered in p53-containing complexes. For all 3 missense mutations tested, the functional effects observed with WT were impaired significantly and only low amounts of variant menin proteins were recovered in p53-containing complexes. CONCLUSIONS: Taking advantage of a new endocrine cellular model, we show a loss of function for 2 missense disease-related menin mutants and for a controversial variant as well. Furthermore, our results suggest the existence of functional interactions between p53 and menin for the control of apoptosis, which may cast new light on the mechanisms of endocrine tumorigenesis.