Gianfranco Delle Fave

Gastroenteropancreatic neuroendocrine tumours

Gastroenteropancreatic (GEP) neuroendocrine tumours (NETs) are fairly rare neoplasms that present many clinical challenges. They secrete peptides and neuroamines that cause distinct clinical syndromes, including carcinoid syndrome. However, many are clinically silent until late presentation with mass effects. Investigation and management should be highly individualised for a patient, taking into consideration the likely natural history of the tumour and general health of the patient. Management strategies include surgery for cure (which is achieved rarely) or for cytoreduction, radiological intervention (by chemoembolisation and radiofrequency ablation), chemotherapy, and somatostatin analogues to control symptoms that result from release of peptides and neuroamines. New biological agents and somatostatin-tagged radionuclides are under investigation. The complexity, heterogeneity, and rarity of GEP NETs have contributed to a paucity of relevant randomised trials and little or no survival increase over the past 30 years. To improve outcome from GEP NETs, a better understanding of their biology is needed, with emphasis on molecular genetics and disease modeling. More-reliable serum markers, better tumour localisation and identification of small lesions, and histological grading systems and classifications with prognostic application are needed. Comparison between treatments is currently very difficult. Progress is unlikely to occur without development of centers of excellence, with dedicated combined clinical teams to coordinate multicentre studies, maintain clinical and tissue databases, and refine molecularly targeted therapeutics.

Pancreatic endocrine tumors: improved TNM staging and histopathological grading permit a clinically efficient prognostic stratification of patients.

Pancreatic endocrine tumors are rare diseases and devising a clinically effective prognostic stratification of patients is a major clinical challenge. This study aimed at assessing whether the tumor-node-metastasis (TNM)-based staging and proliferative activity-based grading recently proposed by the European NeuroEndocrine Tumors Society (ENETS) have clinical value. TNM was applied to 274 patients with histologically diagnosed pancreatic endocrine tumors operated from 1991 to 2005, with last follow-up at December 2007. According to World Health Organization (WHO) classification, 246 were well-differentiated neoplasms (51 benign, 56 uncertain behavior, 139 carcinomas) and 28 poorly differentiated carcinomas. Grading was based on Ki67 immunohistochemistry. Survival analysis not only ascertained the prognostic value of the TNM system but also highlighted that in the absence of nodal and distant metastasis, infiltration and tumor dimensions over 4 cm had prognostic significance. T parameters were then appropriately modified to reflect this weakness. The 5-year survival for modified TNM stages I, II, III and IV were 100, 93, 65 and 35%, respectively. Multivariate analysis identified TNM stages as independent predictors of death, in which stages II, III and IV showed a risk of death of 7, 29 and 58 times higher than stage I tumors (P<0.0001). Ki67-based grading resulted an independent predictor of survival with cut-offs at 5 and 20%. In conclusion, WHO classification assigns clinically significant diagnostic categories to pancreatic endocrine tumors that need prognostic stratification by applying a staging system. The ENETS–TNM provides the best option, but it requires some modifications to be fully functional. The modified TNM described in this study ameliorates the clinical applicability and prediction of outcome of the ENETS–TNM; it (i) assigns a risk of death proportional to the stage at the time of diagnosis, and (ii) allows a clinically based staging of patients, as the T parameters as modified permit their clinical-radiological recognition. Ki67-based grading discerns prognosis of patients with same stage diseases.

Everolimus for the treatment of advanced, non-functional neuroendocrine tumours of the lung or gastrointestinal tract (RADIANT-4): a randomised, placebo-controlled, phase 3 study

BACKGROUND Effective systemic therapies for patients with advanced, progressive neuroendocrine tumours of the lung or gastrointestinal tract are scarce. We aimed to assess the efficacy and safety of everolimus compared with placebo in this patient population. METHODS In the randomised, double-blind, placebo-controlled, phase 3 RADIANT-4 trial, adult patients (aged ≥18 years) with advanced, progressive, well-differentiated, non-functional neuroendocrine tumours of lung or gastrointestinal origin were enrolled from 97 centres in 25 countries worldwide. Eligible patients were randomly assigned in a 2:1 ratio by an interactive voice response system to receive everolimus 10 mg per day orally or identical placebo, both with supportive care. Patients were stratified by tumour origin, performance status, and previous somatostatin analogue treatment. Patients, investigators, and the study sponsor were masked to treatment assignment. The primary endpoint was progression-free survival assessed by central radiology review, analysed by intention to treat. Overall survival was a key secondary endpoint. This trial is registered with ClinicalTrials.gov, number NCT01524783. FINDINGS Between April 3, 2012, and Aug 23, 2013, a total of 302 patients were enrolled, of whom 205 were allocated to everolimus 10 mg per day and 97 to placebo. Median progression-free survival was 11·0 months (95% CI 9·2-13·3) in the everolimus group and 3·9 months (3·6-7·4) in the placebo group. Everolimus was associated with a 52% reduction in the estimated risk of progression or death (hazard ratio [HR] 0·48 [95% CI 0·35-0·67], p<0·00001). Although not statistically significant, the results of the first pre-planned interim overall survival analysis indicated that everolimus might be associated with a reduction in the risk of death (HR 0·64 [95% CI 0·40-1·05], one-sided p=0·037, whereas the boundary for statistical significance was 0·0002). Grade 3 or 4 drug-related adverse events were infrequent and included stomatitis (in 18 [9%] of 202 patients in the everolimus group vs 0 of 98 in the placebo group), diarrhoea (15 [7%] vs 2 [2%]), infections (14 [7%] vs 0), anaemia (8 [4%] vs 1 [1%]), fatigue (7 [3%] vs 1 [1%]), and hyperglycaemia (7 [3%] vs 0). INTERPRETATION Treatment with everolimus was associated with significant improvement in progression-free survival in patients with progressive lung or gastrointestinal neuroendocrine tumours. The safety findings were consistent with the known side-effect profile of everolimus. Everolimus is the first targeted agent to show robust anti-tumour activity with acceptable tolerability across a broad range of neuroendocrine tumours, including those arising from the pancreas, lung, and gastrointestinal tract. FUNDING Novartis Pharmaceuticals Corporation.

ENETS Consensus Guidelines for the Standards of Care in Neuroendocrine Tumors: Towards a Standardized Approach to the Diagnosis of Gastroenteropancreatic Neuroendocrine Tumors and Their Prognostic Stratification

ENETS Consensus Guidelines for the Standards of Care in Neuroendocrine Tumors : towards a standardized approach to the diagnosis of gastroenteropancreatic neuroendocrine tumors and their prognostic stratification

Reversal of Iron Deficiency Anemia after Helicobacter pylori Eradication in Patients with Asymptomatic Gastritis

Standard care for men and postmenopausal women with iron deficiency anemia is use of gastrointestinal evaluation to exclude gastrointestinal tract abnormality (1, 2). Nevertheless, even when the gastrointestinal tract is investigated thoroughly, a large proportion of patients (around 30%) remain without a diagnosis (2, 3). Recent epidemiologic studies have suggested an association between Helicobacter pylori infection and iron deficiency (4, 5). Infection with H. pylori is recognized as a major risk factor in peptic ulcer disease and gastric cancer, in which lesions are likely to bleed either overtly or in an occult manner, eventually leading to iron deficiency anemia. However, most people infected with H. pylori only have chronic gastritis that is not associated with gastrointestinal bleeding or with any other specific disease (6). It has been suggested that infection with H. pylori may lead to iron deficiency or iron deficiency anemia by impairing iron uptake or increasing iron demand (4). Reversal of iron deficiency anemia after successful eradication of H. pylori was recently observed in children (7, 8) and in a young adult (9). We performed a prospective open study to verify the effects of eradication of H. pylori infection on iron deficiency anemia in patients with H. pylori-associated gastritis. Methods Patients Patients were observed from September 1994 to December 1997. A total of 189 consecutive adult outpatients who were older than 20 years of age and had iron deficiency anemia (158 women and 31 men; median age, 47 years [range, 20 to 79 years]) were referred to our gastroenterology department from the hematology department. Iron-deficiency anemia was defined as a hemoglobin concentration less than 14 g/L for men and less than 12 g/L for women, a mean corpuscular volume less than 80 fL, and a serum ferritin level less than 30 g/L (3). Outpatients with an obvious cause of blood loss, such as a heavy menstrual period (cycles>6 days), epistaxis, active gastrointestinal hemorrhage, or evidence of fecal occult blood positivity, were excluded from the study. Other exclusion criteria were gastrointestinal or hematologic cancer at the time of observation, chronic renal failure, severe cardiopulmonary disease, reported or suspected pica, hemolysis, aplastic anemia or thalassemia, alcoholism or liver cirrhosis, and pregnancy. After this selection, patients who were taking nonsteroidal anti-inflammatory drugs; had had gastric surgery; or had atrophic body gastritis and celiac disease, as described elsewhere (3), were excluded from the study. An iron-poor diet as a cause of iron deficiency anemia was excluded by a hospital dietitian (3). A double-contrast barium enema or colonoscopy plus radiographic examination of the small bowel, or Meckel scintigraphy, were also carried out if indicated. Interventions Patients were treated for 2 weeks with omeprazole, 40 mg, in the morning; amoxicillin, 1g; and metronidazole, 250 mg three times daily after meals, for the first week. Patients were also instructed to discontinue any iron replacement therapy, including over-the-counter iron-containing medication. A clinical evaluation was performed 3 months after eradication therapy to check for clinical signs of anemia. Two follow-up visits at 6 and 12 months were planned. At each visit, a complete blood count was done and ferritin levels were measured. Baseline and 12-month transferrin saturation indexes were also calculated. The 6-month follow-up examination included endoscopy with biopsy to evaluate H. pylori eradication. Patients were considered cured of H. pylori infection if both rapid urease testing and histologic examination of the gastric antral and body biopsy samples were negative. Successful eradication therapy for iron deficiency anemia was defined as no need for iron replacement therapy, recovery from anemia, or both. All patients gave full informed consent to participate the study, which was approved by the local ethical committee. Measurements History of anemia, expressed as length of time from first laboratory diagnosis of iron deficiency anemia to referral to the gastroenterology department, was assessed. Serum ferritin levels were measured by using commercial kits (Ciba-Corning Diagnostic Corp., Milan, Italy) (3). Hemoglobin concentrations and mean corpuscular volume were determined by an automated Coulter counter (Technicon H1, Bayer Corp., Tarrytown, New York) (3). Serum transferrin levels were measured by using a commercial kit (Beckman Analytical, Milan, Italy) (10). Serum iron levels were measured and the transferrin saturation index (normal value, 16% to 45%) was calculated as described elsewhere (10). Patients underwent gastroscopy with gastric antral (n=3) or body (n=3) biopsy. One sample was tested by using a rapid urease test, and the others were examined by conventional histology (3, 9). Duodenal biopsy specimens were also obtained to exclude celiac disease. The pathologist was unaware of clinical and endoscopic data. Gastritis status was described according to the Updated Sydney System classification (8). Helicobacter pylori status was considered positive when the organism was detected on histologic examination, by rapid urease testing, or both. Statistical Analysis Data are expressed as the mean ( SE) or median (range) as appropriate and were analyzed by using the t-test for paired data. Subgroups (percentages of patients) were compared by using the McNemar test. A P value less than 0.05 was considered statistically significant. Role of the Funding Sources Our funding sources had no role in the collection, analysis, or interpretation of the data or in the decision to submit the paper for publication. Results Of the 189 patients referred to our gastroenterology department, 30 (15.9%) had iron deficiency anemia: 4 men and 26 women (of whom 3 were postmenopausal) with a median age of 35.5 years (range, 20 to 65 years). In these patients, H. pylori-associated gastritis was the only pathologic finding. Gastroscopy did not reveal any sign of current or past mucosal erosion or ulcer disease. All patients had a suboptimal response to oral iron therapy; they needed continuous or intermittent oral iron treatment to prevent the decrease of hemoglobin levels. All patients denied having any specific gastrointestinal symptom or having used antisecretory drugs. Occasional, nonpersistent, mild dyspeptic symptoms were considered nonspecific. Anamnestic interview and evaluation of previous medical records documented moderate to severe iron deficiency anemia in all patients (hemoglobin level, 9.5 0.25 g/L; mean corpuscular volume, 69 1.15 fL; and serum ferritin level, 6.2 0.8 g/L) associated with clear clinical signs of anemia, such as fatigue, pallor, and decreased exercise capacity. Median history of anemia and of oral iron therapy in these patients was 4.8 years (range, 2 to 20 years). All patients underwent an eradication regimen. At the 3-month clinical evaluation, no patients reported anemia-related symptoms. Twenty-eight patients underwent endoscopy at 6 months to verify H. pylori eradication. Two female patients (27 and 36 years of age) declined further follow-up because they were in good general health. Helicobacter pylori infection was cured in 25 patients (89.3% [95% CI, 72% to 98%]); at this point, one female 31-year-old patient was excluded from further follow-up because she had developed heavy menstrual periods due to a uterine myoma that was not present at the initial diagnosis. Thus, 24 patients (3 men and 21 women; median age, 35.7 years [range, 20 to 65 years]) in whom H. pylori infection was cured and 3 patients (1 man 21 years of age and 2 women 22 and 37 years of age) in whom H. pylori infection was not cured were eligible for evaluation. Effects of Helicobacter pylori Eradication on Iron Deficiency Anemia At 6 months of follow-up, 18 of 24 (75%) patients recovered from anemia (P<0.001) and had a significant increase in the hemoglobin concentration, mean corpuscular volume, and ferritin level (Table). Table. Hematologic Data from 24 Patients with Iron Deficiency Anemia At 12 months of follow-up, 4 more patients (22 of 24 [91.7%]) showed recovery from anemia without resuming iron supplementation. The mean values of all measurements obtained were similar to those seen at the 6-month evaluation (Table). Even though ferritin levels returned to normal in only 4 patients at the 12-month follow-up visit, we observed a significant increase of more than 300% over baseline values (5.7 0.7 g/L compared with 24.1 5.0 g/L [P=0.0018]; mean increase, 18.4 g/L [CI, 8.08 to 29.44 g/L]). Mean transferrin saturation index also significantly increased from baseline (from 5.5% 0.8% to 18.7% 1.8% [P<0.001]; mean increase, 13.2 percentage points [CI, 8.92 to 17.46 percentage points]), even though values in 5 patients were still below the normal range. Eight patients were followed for 1 more year. Hemoglobin levels returned to normal in the two patients who were still anemic at the previous 12-month examination. In these patients, ferritin levels further increased from those measured at the 12-month follow-up (23.9 6.7 g/L and 30.5 7.4 g/L [P=0.047]; mean increase, 6.6 g/L [CI, 0.5 to 12.6 g/L]). In the three patients who were not cured, the hemoglobin level at 6 months of follow-up was stable in the male patient and was slightly decreased in the two female patients. These three patients experienced mild fatigue. However, in all patients, a clear decrease in ferritin levels was observed (data not shown). Helicobacter pylori Gastritis At diagnosis, 7 patients had mild antral atrophic gastritis, of whom 4 had associated chronic, body nonatrophic gastritis; 1 patient had only body nonatrophic gastritis; and 22 patients had chronic antral nonatrophic gastritis, 20 of whom had a similar pattern in the gastric body mucosa. Thus, considering the involvement of both gastric compartments, 24 of 30 (80%) patients with iron de

ENETS Consensus Guidelines for the Management of Patients with Gastroduodenal Neoplasms

a Department of Digestive and Liver Disease, Ospedale Sant’Andrea, Rome , Italy; b Department of Oncology, Royal Free University UFR Bichat-Beaujon-Louis Mourier, Colombes , France; c Digestive Oncology, University Hospital Gasthuisberg/Leuven, Leuven , Belgium; d Institute of Pathology, Catholic University – Policlinic A. Gemelli, Rome , Italy; e Department of Endocrinology, Medical University of Silesia, Katowice , Poland; f Department of Surgery, Rigshospitalet, Copenhagen University Hospital, Copenhagen , Denmark; g Department of Pathology, Tohoku University Graduate School of Medicine, Sendai , Japan; h Department of Internal Medicine and Gastroenterology, St. Orsola Hospital, University of Bologna, Bologna , Italy; i Institut Catala d’Oncologia (IDIBELL), Barcelona , Spain; j Department of Gastroenterology, Beaujon Hospital, Clichy , France

ENETS Consensus Guidelines for the Standards of Care in Neuroendocrine Tumors : biochemical markers

Biomarkers have been the mainstay in the diagnosis and follow-up of patients with neuroendocrine tumors (NETs) over the last few decades. In the beginning, secretory products from a variety of subtype

Metastatic and Locally Advanced Pancreatic Endocrine Carcinomas: Analysis of Factors Associated With Disease Progression

PURPOSE Knowledge of clinical course of pancreatic endocrine carcinomas (PECs) is poor. This study aimed to determine the time to progression of advanced PECs, and to identify predictors capable of selecting subgroups with higher risk of progression. PATIENTS AND METHODS In this multicenter retrospective analysis, patients with advanced PECs were enrolled. Staging was according to European Neuroendocrine Tumors Society guidelines. Grading was based on proliferation index using Ki67 immunohistochemistry. The primary end point was progression-free survival (PFS), which was assessed using the Kaplan-Meier method. The Cox regression proportional hazard model was used to identify predictors for tumor progression. RESULTS Two hundred two patients with PECs were enrolled, including 172 with well-differentiated and 30 with poorly differentiated endocrine carcinomas. There were 34 patients with stage III and 168 with stage IV tumors. G1 tumors were present in 19.7% of patients, whereas 60.1% of patients had G2 tumors, and the remaining 20.2% had G3 tumors. Disease progression occurred in 166 patients (82.2%), at a median interval of 10 months (interquartile range, 5 to 22) from diagnosis. Median PFS was 14 months. Different PFS were observed depending on G grade (P < .001) and tumor differentiation (P < .001) and in patients who did not receive any antitumor treatment (P = .002). The major risk factor for progression was the proliferation index Ki67 (hazard ratio, 1.02 for each increasing unit; P < .001). Overall 5-year survival was 44.1%. CONCLUSION The vast majority of patients with advanced PECs undergo disease progression. The major risk factor for progression is Ki67 index, which should lead physicians dealing with PECs to plan appropriate follow-up programs and therapeutic strategies.

ENETS consensus guidelines for the standards of care in neuroendocrine tumors: Somatostatin receptor imaging with IIIIn-pentetreotide

ENETS Consensus Guidelines for the Standards of Care in Neuroendocrine Tumors : Somatostatin Receptor Imaging with In-111-Pentetreotide

Well-differentiated gastric tumors/carcinomas

a Department of Gastroenterology, Beaujon Hospital, Clichy , France; b Department of Digestive and Liver Disease, Ospedale S. Andrea, Rome , Italy; c Department of Hepatology and Gastroenterology, CHU Bichat – B. Claude Bernard University, Paris , France; d Department of Pathology, Kantonsspital Baden , Switzerland; e Department of Gastroenterology, Massachussetts General Hospital, Boston , Mass. , USA; f B. Kos-Kudla, Department of Endocrinology, Slaska University, Zabrze , Poland; g Department of Surgery, UFR Bichat-Beaujon-Louis Mourier Hospital, Colombes , France; h Department of Oncology, Royal Free University, London , UK; i Department of Gastroenterology, Philipps University, Marburg , Germany; j Department of Surgery, Gothenburg University, Gothenburg , Sweden; k Department of Nuclear Medicine, Catholique de Louvain University, Brussels , Belgium; l Department of Nuclear Medicine, Erasmus MC University, Rotterdam , The Netherlands; m Department of Pathology and Laboratory Medicine, Universita degli Studi, Parma , Italy