Elettra Merola

Type I gastric carcinoids: a prospective study on endoscopic management and recurrence rate.

Background: Type I gastric carcinoids (TIGCs) are neuroendocrine neoplasms arising from enterochromaffin-like cells in atrophic body gastritis. Data regarding their evolution in prospective series are scarce, thus treatment and follow-up are not codified. Our aim was to evaluate clinical outcome and recurrence in TIGCs managed by endoscopic approach. Methods: 33 patients (24 females; median age 65 years, range 23–81) were included and managed through endoscopic follow-up every 6–12 months, with lesion removal and multiple gastric biopsies. Baseline clinical and histological features were analyzed as risk factors by Cox regression. Results: At diagnosis, 7 tumors were intramucosal carcinoids and 26 were polyps (median diameter 5 mm, range 2–20), multiple in 17 patients. Associated severe atrophy was present in 21 cases (63.6%), while mild atrophy was found in 6 cases (18.2%). During a 46-month median follow-up, survival was 100% and no metastases occurred. One patient developed a less-differentiated carcinoid that was radically treated by surgery. 21 patients (63.6%) had recurrence after a median of 8 months, 14 of these (66.6%) had a second recurrence after a median of 8 months following the previous carcinoid removal. Median recurrence-free survival was 24 months. Neither clinical nor biochemical recurrence-predicting factors were found. Conclusions: Although about 60% of TIGCs had recurrence after endoscopic resection, endoscopic management may be considered safe and effective.

Advanced digestive neuroendocrine tumors: Metastatic pattern is an independent factor affecting clinical outcome

Objectives The objective of this study was to determine the impact of different metastatic spread patterns on outcome in advanced digestive neuroendocrine tumors (NETs). Methods This was a retrospective analysis of patients with stage IV NETs, classified as group 1 (unilobar liver metastases), group 2 (bilobar liver metastases), group 3 (extra-abdominal metastases). End points were overall survival (OS) and progression-free survival (PFS). Risk factor analysis was performed using Cox proportional hazard model. Results Of the 229 patients, 135 (58.9%) had pancreatic, and 94 (41.1%) small bowel NETs: 32 (13.9%) were included in group 1, 179 (78.2%) in group 2, and 18 (7.9%) in group 3. Median Ki67 was 4.5%. Overall, 5-year OS was 55%. Different OS was observed among the 3 groups: median survival not reached, 81 and 8 months, respectively (P < 0.001). Median PFS was 18 months. Both OS and PFS were significantly affected by Ki67 and metastatic spread pattern. Conclusions The stratification of stage IV NET patients based on metastatic patterns, alongside Ki67, predicts the clinical outcome. The extent of metastatic disease is a previously unrecognized variable, which should be considered when evaluating the results of treatments in NET patients with advanced disease.

Antiproliferative effect of somatostatin analogs in advanced gastro-entero-pancreatic neuroendocrine tumors: a systematic review and meta-analysis

A meta-analysis has systematically investigated the antineoplastic efficacy and safety of somatostatin analogs (SSAs) in advanced gastro-entero-pancreatic neuroendocrine tumors (GEP-NETs). Randomized controlled trials (RCTs) reporting the hazard ratio (HR) for disease progression (DP) were evaluated. Response rate and risk ratio (RR) for adverse events were also analyzed. A total of 289 patients (143 receiving SSAs vs. 146 placebo) were evaluated from two RCTs. A significant benefit from SSAs in terms of disease control was observed (HR 0.41, 95% CI: 0.29 to 0.58, P < 0.01; I20%), response rate being 58.0% vs. 32.2%, respectively. The occurrence of adverse events significantly differed from the placebo arm only in terms of biliary stones (RR 3.79, 95% CI: 1.28 to 11.17, P = 0.02; I20%). In conclusion, SSAs showed an antiproliferative effect in advanced GEP-NETs, with a good safety profile.

Probiotics and severe acute pancreatitis.

Acute pancreatitis (AP) is an acute inflammatory process ranging from mild forms to severe disease with high rates of mortality. In this disease, enteral nutrition helps in maintaining the integrity of the gut barrier, with consequent decreased bacterial translocation, a key factor in limiting the complications in severe AP. Modulation of the intestinal flora through the administration of probiotics (PBs) has thus an intriguing rationale as possible treatment option. Their role in this setting has been investigated both in animal models and clinical trials in the last few years; however, their use has never been recommended or even cited by existing guidelines. We analyzed the literature in search of the existing data from human and animal models studies evaluating the effect of PB administration in AP to highlight existing evidence. An interesting scenario emerges from the the papers that have been evaluated. The adjunct of PBs in the treatment of AP may show some advantage in terms of the reduction of infectious complications. Nevertheless, more data on efficacy and safety from a larger and stringently designed study are eagerly waited.

Acute leukaemia following low dose peptide receptor radionuclide therapy for an intestinal carcinoid.

Gastroenteropancreatic neuroendocrine tumours (GEP NETs) re rare, but their incidence seems to be on the rise. 90% of hem express cell surface somatostatin receptors, and somatotatin analogues are used in order to control both symptoms and umour growth [1]. Peptide receptor radionuclide therapy (PRRT) pplies the somatostatin analogue octreotide chelated to differnt radioisotopes, delivering tumouricidal radiotherapeutic agent n loco thanks to receptor-mediated endocytosis into cancer cells, hus having cytoreductive effect [2,3]. Reported side effects include renal failure (although the use of rophylactic amino acid infusion is protective), and, in patients ith multiple liver metastases, hepatic failure [3]. Bone marrow (BM) also is sensitive to PRRT, as somatostatin is nvolved in haematopoiesis, and both blood lymphocytes and some ubsets of BM cells express somatostatin receptor subtype 2 (sst2) 4]. Indeed, during PRRT, a reversible decrease in blood cells count is requent. While [177Lu-DOTA0,Tyr3]-octreotate seems less haemaotoxic, Myelodysplastic Syndrome (MDS) has been described ith [111In-DTPA]-octreotide and 90Y-DOTA-TOC, and myeloblasic leukaemia has been reported with total radiation cumulative oses >100 Gbq. However, most of these patients have had previus chemotherapy, and it is difficult to dissect adverse effects of RRT from those of other agents [3]. We hereby report a case of acute lymphoblastic leukaemia (ALL) n a 78-year-old man treated with low dose PRRT for metastatic ileal ndocrine carcinoma. The patient had an accidental ultrasound finding of multiple epatic nodules (max diameter 35 mm); liver biopsy diagnosed etastases from well-differentiated neuroendocrine carcinoma positive for serotonin and sst2; Ki67: 6%). Abdominal CT-scan and PET 68Ga-DOTANOC identified a 20 mm esion in the medium ileum as the primary site. Lab tests showed normal blood cell count and renal function haemoglobin 14 g/dl, creatinine clearance 100 ml/min). The patient was treated with lanreotide for 3 months, then tarted PRRT with three cycles of 90Y-DOTA-TOC (October 2007, ebruary 2008 and April 2008), each with radioactive activity of .56 GBq for a total of 7.68 GBq. Two weeks after the last treatment, he came to our observation. aboratory tests showed lymphocytosis (70,000/ l). Blood smear nd BM biopsy diagnosed T-lineage ALL, but cytogenetics was not valuable because of low rate of metaphases. A further CT-scan howed new bone lesions and increased number and size of hepatic nd lymph node metastases. The patient was treated for ALL with three cycles of vincristine nd daunoblastin. In November 2008 he was alive, although his

Functional Imaging in the Follow-Up of Enteropancreatic Neuroendocrine Tumors: Clinical Usefulness and Indications

Context Functional imaging tests (FITs) detecting somatostatin receptor expression [i.e., somatostatin receptor scintigraphy, 68Ga-DOTA positron emission tomography/computed tomography (CT)] have a pivotal role in the diagnosis of neuroendocrine tumors (NETs), although their indication during follow-up still needs to be clarified. Objective Investigate the role of FITs after diagnosis of metastatic enteropancreatic NETs, identifying patients who might benefit from these exams. Design Multicenter retrospective analysis of metastatic enteropancreatic NETs. Setting Analysis of imaging tests performed between January 1995 and December 2015 in Rome, Berlin, Milan, Marburg, or Graz. Subjects One hundred forty-three patients with metastatic pancreatic NETs and small intestine NETs, at least 2-year follow-up, and positive FITs. Interventions Patients had received CT every 6 months (unless clinical conditions and tumor behavior required shorter intervals) and FIT every 12 months. Main Outcome Measures Clinical usefulness of FITs, defined as changes in patient management (indication to biopsy, medical therapy, surgery, or further imaging tests) due only to FITs. Results FITs affected management in 73.4% of patients, mostly when G2 vs G1 [odds ratio (OR), 2.40; 95% confidence interval (CI), 1.09 to 5.27; P = 0.03]. Changes were observed in a 12-month time frame especially with pancreatic NETs vs small intestine NETs (OR, 2.89; 95% CI, 1.09 - 7.67; P = 0.03) or metastases since diagnosis vs developed during follow-up (OR, 4.00; 95% CI, 1.43 to 11.17; P < 0.01). Conclusions FITs used in addition to CT in the follow-up of stage IV enteropancreatic NETs improve patient management (especially for G2 tumors). Follow-up program should be tailored according to tumor features.

Stage IV Gastro-Entero-Pancreatic Neuroendocrine Neoplasms: A Risk Score to Predict Clinical Outcome.

BACKGROUND Several risk factors predict clinical outcome in gastro-entero-pancreatic neuroendocrine neoplasms (GEP-NENs); however, the impact of their combination has not been investigated so far. PATIENTS AND METHODS A retrospective analysis of stage IV GEP-NENs was performed. Multivariate analysis for progression of disease (PD) was performed by Cox proportional hazards method to obtain a risk score. Area under the curve obtained by receiver operating characteristic analysis was used to assess the score performance. Progression-free survival analysis was performed by Kaplan-Meier method. RESULTS Two hundred eighty-three stage IV GEP-NENs were evaluated, including 93 grade 1 neuroendocrine tumors (32.9%), 153 grade 2 neuroendocrine tumors (54%), and 37 grade 3 neuroendocrine carcinomas (13.1%). Independent risk factors for PD were Ki67, proportion of metastatic liver involvement, and presence of extra-abdominal metastases. The risk score was calculated as follows: (0.025 × Ki67) + [(0 if no liver metastases or liver involvement <25%) OR (0.405 if liver involvement 25%-50%) OR (0.462 if liver involvement >50%)] + [(0 if no extra-abdominal metastases) OR (0.528 if extra-abdominal metastases present)]. The risk score accuracy to predict PD was superior compared with the G grading system (area under the curve: 0.705 and 0.622, respectively). Three subgroups of patients with low, intermediate, and high risk of PD according to risk score were identified, median progression-free survival being 26 months, 19 months, and 12 months, respectively. CONCLUSION In stage IV GEP-NENs, a risk score able to predict PD was obtained by combining Ki67, proportion of metastatic liver involvement, and presence of extra-abdominal metastases. The score may help to discriminate patients with different progression risk level to plan tailored therapeutic approaches and follow-up programs. The Oncologist 2017;22:409-415Implications for Practice: Clinical outcome of patients with advanced gastro-entero-pancreatic neuroendocrine neoplasms is affected by several risk factors, including the proliferative index Ki67, extension of liver metastases, and the presence of distant extra-abdominal lesions. A risk score that combines these variables may help physicians dealing with these diseases to plan the optimal therapeutic approach and follow-up program.

Clinical Usefulness of 18F‐Fluorodeoxyglucose Positron Emission Tomography in the Diagnostic Algorithm of Advanced Entero‐Pancreatic Neuroendocrine Neoplasms

BACKGROUND The role of 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET) in the diagnostic algorithm of entero-pancreatic neuroendocrine neoplasms (EP NENs) is unclear because most available data derive from heterogeneous populations in terms of tumor biology and disease status at time of examination. The aim of this study was to determine the ability of 18F-FDG PET to identify patients with more aggressive disease among those with advanced EP NENs. Subjects, Materials, and Methods . Patients with advanced EP NENs and known disease status (progressive disease [PD] or stable disease [SD]) according to imaging procedures, who received 18F-FDG PET and computed tomography scans during a time frame of 1 month, were included. RESULTS A total of 93 patients, including 69 patients with pancreatic NENs and 24 patients with small-intestine NENs, were included. At the time of study entry, 64 patients (68.8%) had PD, and the remaining 29 patients (31.2%) had SD. A total of 62 patients (66.7%) had positive 18F-FDG PET, whereas 18F-FDG PET was negative in the remaining 31 patients (33.3%). Overall, 18F-FDG PET sensitivity and specificity to detect PD were 90.6% and 86.2%, respectively, resulting in a diagnostic accuracy of 89.2%. A positive 18F-FDG PET was significantly associated with PD at the time of study entry (p < .0001 at multivariate analysis). Although a higher proportion of 18F-FDG PET-positive examinations were observed in patients with higher tumor grade (p = .01), 53.8% of patients with grade 1 neuroendocrine tumors (NETs) had positive 18F-FDG PET, and 37.5% of patients with grade 2 NETs had negative 18F-FDG PET. Overall survival was significantly shorter in 18F-FDG PET-positive patients (median: 60 months) in comparison with 18F-FDG PET-negative patients (median not reached; p = .008). CONCLUSION 18F-FDG PET has a high diagnostic accuracy to identify progression of disease with unfavorable clinical outcome in patients with advanced EP NENs. Knowledge of disease status and G grading are key factors for physicians to better select patients for whom 18F-FDG PET is clinically useful. IMPLICATIONS FOR PRACTICE The findings of the present study may help physicians dealing with advanced neuroendocrine neoplasms to select patients for whom 18F-fluorodeoxyglucose positron emission tomography is useful to predict poor clinical outcome.

Impact of Ki67 re-assessment at time of disease progression in patients with pancreatic neuroendocrine neoplasms

Background Although re-assessment of proliferative activity by K67 evaluation during the course of neuroendocrine neoplasms (NENs) is recommended in selected patients, its impact on patients’ management is not clear due to the lack of data supporting this practice. Aim To investigate Ki67 change at time of progressive disease (PD) in entero-pancreatic NENs (EP-NENs). Patients and methods Retrospective analysis of sporadic EP-NENs which received histological re-assessment after PD once radiologically documented. Results Forty-three patients were evaluated, including 24 pancreatic NENs (PNENs), and 19 small intestine NENs (SI-NENs). At time of initial histological evaluation, 19 patients had grade 1 (G1) NETs (44.2%), and 24 grade 2 (G2) NETs (55.8%), overall median Ki67 being 3% (range 1%-20%). At time of PD, 13 patients had G1 NETs (30.2%), 26 G2 NETs (60.5%), and 4 had grade 3 (G3) NECs (9.3%), thus resulting in a significant median Ki67 increase (8%, range 1%-70%; p = 0.0006), and a G upgrading in 12 patients (27.9%). A statistically significant Ki67 increase and G grading change at time of PD was observed in PNENs (p = 0.0005 and p = 0.028, respectively). Conversely, no statistically significant change occurred in non-PNENs. Conclusions In PNENs with documented PD, Ki67 increase occurs in a significant proportion of patients, providing useful information necessary to choose appropriate therapeutic options.

Functional imaging tests and CT scan: Detection of new metastases and clinical usefulness in digestive neuroendocrine neoplasms follow-up.

219 Background: Digestive Neuroendocrine Neoplasms (DNENs) express in up to 80% of cases somatostatin receptors (SSTRs), which can be detected by Functional Imaging Tests (FITs). FITs are needed at DNENs first diagnosis to define therapy but their role in follow-up (FU) is unclear. Moreover, with the introduction of targeted therapies, RECIST criteria are showing difficulties to assess tumor response to these drugs. The aim of this study was to evaluate, in metastatic DNENs FU, the diagnostic yield of FITs associated to Computed Tomography scan (CT) in terms of detecting new distant metastases (primary outcome) and of clinical usefulness (secondary outcome). Methods: Retrospective analysis of stage IV DNENs expressing SSTRs and with at least 24 month-FU. From 1995 to 2008 FIT performed was Octreoscan (OCT), subsequently it was 68Ga-DOTA- PET/CT (GaPET). CT was repeated every 6-12 months, FIT yearly. FU time was divided into 12 month-“units”, in which each patient had faced at least 1 CT and 1 FIT. Units w...