Guido Rindi

Lanreotide in Metastatic Enteropancreatic Neuroendocrine Tumors

BACKGROUNDnSomatostatin analogues are commonly used to treat symptoms associated with hormone hypersecretion in neuroendocrine tumors; however, data on their antitumor effects are limited.nnnMETHODSnWe conducted a randomized, double-blind, placebo-controlled, multinational study of the somatostatin analogue lanreotide in patients with advanced, well-differentiated or moderately differentiated, nonfunctioning, somatostatin receptor-positive neuroendocrine tumors of grade 1 or 2 (a tumor proliferation index [on staining for the Ki-67 antigen] of <10%) and documented disease-progression status. The tumors originated in the pancreas, midgut, or hindgut or were of unknown origin. Patients were randomly assigned to receive an extended-release aqueous-gel formulation of lanreotide (Autogel [known in the United States as Depot], Ipsen) at a dose of 120 mg (101 patients) or placebo (103 patients) once every 28 days for 96 weeks. The primary end point was progression-free survival, defined as the time to disease progression (according to the Response Evaluation Criteria in Solid Tumors, version 1.0) or death. Secondary end points included overall survival, quality of life (assessed with the European Organization for Research and Treatment of Cancer questionnaires QLQ-C30 and QLQ-GI.NET21), and safety.nnnRESULTSnMost patients (96%) had no tumor progression in the 3 to 6 months before randomization, and 33% had hepatic tumor volumes greater than 25%. Lanreotide, as compared with placebo, was associated with significantly prolonged progression-free survival (median not reached vs. median of 18.0 months, P<0.001 by the stratified log-rank test; hazard ratio for progression or death, 0.47; 95% confidence interval [CI], 0.30 to 0.73). The estimated rates of progression-free survival at 24 months were 65.1% (95% CI, 54.0 to 74.1) in the lanreotide group and 33.0% (95% CI, 23.0 to 43.3) in the placebo group. The therapeutic effect in predefined subgroups was generally consistent with that in the overall population, with the exception of small subgroups in which confidence intervals were wide. There were no significant between-group differences in quality of life or overall survival. The most common treatment-related adverse event was diarrhea (in 26% of the patients in the lanreotide group and 9% of those in the placebo group).nnnCONCLUSIONSnLanreotide was associated with significantly prolonged progression-free survival among patients with metastatic enteropancreatic neuroendocrine tumors of grade 1 or 2 (Ki-67 <10%). (Funded by Ipsen; CLARINET ClinicalTrials.gov number, NCT00353496; EudraCT 2005-004904-35.).

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

Diagnostic performance of Gallium-68 somatostatin receptor PET and PET/CT in patients with thoracic and gastroenteropancreatic neuroendocrine tumours: a meta-analysis

Gallium-68 somatostatin receptor (SMSR) positron emission tomography (PET) and positron emission tomography/computed tomography (PET/CT) are valuable diagnostic tools for patients with neuroendocrine tumours (NETs). To date, a meta-analysis about the diagnostic accuracy of these imaging methods is lacking. Aim of our study is to meta-analyse published data about the diagnostic performance of SMSR PET or PET/CT in patients with thoracic and/or gastroenteropancreatic (GEP) NETs. A comprehensive computer literature search of studies published in PubMed/MEDLINE, Scopus and Embase databases through October 2011 and regarding SMSR PET or PET/CT in patients with NETs was carried out. Only studies in which SMSR PET or PET/CT were performed in patients with thoracic and/or GEP NETs were selected (medullary thyroid tumours and neural crest derived tumours were excluded from the analysis). Pooled sensitivity, pooled specificity and area under the ROC curve were calculated to measure the diagnostic accuracy of SMSR PET and PET/CT in NETs. Results: Sixteen studies comprising 567 patients were included in this meta-analysis. The pooled sensitivity and specificity of SMSR PET or PET/CT in detecting NETs were 93% (95% confidence interval [95% CI]: 91–95%) and 91% (95% CI: 82–97%), respectively, on a per patient-based analysis. The area under the ROC curve was 0.96. In patients with suspicious thoracic and/or GEP NETs, SMSR PET and PET/CT demonstrated high sensitivity and specificity. These accurate techniques should be considered as first-line diagnostic imaging methods in patients with suspicious thoracic and/or GEP NETs.

Neuroendocrine neoplasms of the gut and pancreas: new insights

Neuroendocrine neoplasms arise in almost every organ of the body and are variably defined according to the site of origin. This Review focuses on neuroendocrine neoplasms of the digestive tract and pancreas. The 2010 WHO classification of tumors of the digestive system introduces grading and staging tools for neuroendocrine neoplasms. A carcinoid is now defined as a grade 1 or 2 neuroendocrine tumor and grade 3, small-cell or large-cell carcinomas are defined as neuroendocrine carcinoma. Epidemiological data show a worldwide increase in the prevalence and incidence of gastroentero-pancreatic neuroendocrine tumors in the past few decades, which is probably due to improved methods of detection of these tumors. The current diagnostic procedures and treatment options for neuroendocrine neoplasms are defined and summarized in the Review, although evidence-based data are lacking. Surgery remains the treatment mainstay and somatostatin analogues the basis for both diagnosis and therapy as the only theranostic tool. Emerging compounds including chemotherapeutic agents, small molecules and biological therapies may provide new hope for patients.

Grading the neuroendocrine tumors of the lung: an evidence-based proposal.

Lung neuroendocrine tumors are catalogued in four categories by the World Health Organization (WHO 2004) classification. Its reproducibility and prognostic efficacy was disputed. The WHO 2010 classification of digestive neuroendocrine neoplasms is based on Ki67 proliferation assessment and proved prognostically effective. This study aims at comparing these two classifications and at defining a prognostic grading system for lung neuroendocrine tumors. The study included 399 patients who underwent surgery and with at least 1 year follow-up between 1989 and 2011. Data on 21 variables were collected, and performance of grading systems and their components was compared by Cox regression and multivariable analyses. All statistical tests were two-sided. At Cox analysis, WHO 2004 stratified patients into three major groups with statistically significant survival difference (typical carcinoid vs atypical carcinoid (AC), P=0.021; AC vs large-cell/small-cell lung neuroendocrine carcinomas, P<0.001). Optimal discrimination in three groups was observed by Ki67% (Ki67% cutoffs: G1 <4, G2 4-<25, G3 ≥25; G1 vs G2, P=0.021; and G2 vs G3, P≤0.001), mitotic count (G1 ≤2, G2 >2-47, G3 >47; G1 vs G2, P≤0.001; and G2 vs G3, P≤0.001), and presence of necrosis (G1 absent, G2 <10% of sample, G3 >10% of sample; G1 vs G2, P≤0.001; and G2 vs G3, P≤0.001) at uni and multivariable analyses. The combination of these three variables resulted in a simple and effective grading system. A three-tiers grading system based on Ki67 index, mitotic count, and necrosis with cutoffs specifically generated for lung neuroendocrine tumors is prognostically effective and accurate.

Follicular thyroid neoplasms can be classified as low- and high-risk according to HBME-1 and Galectin-3 expression on liquid-based fine-needle cytology

DESIGNnFine-needle aspiration biopsy (FNAB) is the most reliable diagnostic tool in the diagnosis of thyroid nodules. A cytologic diagnosis of follicular neoplasm with atypical cells of undetermined significance (FN/AUS) implies that the selection of patients between surgery and follow-up is difficult. In this setting immunocytochemical stainings might be helpful. The efficacy of a panel made up of HBME-1 and Galectin-3 antibodies is evaluated in cases processed by liquid-based cytology (LBC).nnnMETHODSnOut of 7091 thyroid FNAB processed by LBC method, 120 cases undergoing surgery successively were selected. These cases were classified as benign lesion (BL, eight cases), FN, including the ACUS category of the Bethesda classification (FN/AUS, 50 cases), suspicious for malignancy (SM, 59 cases), and malignant neoplasm (MN, three cases). Immunostains for HBME-1 and Galectin-3 were carried out on the LBC slides.nnnRESULTSnAll MN and BL were histologically confirmed. FN/AUS and SM showed a malignancy risk of 24 and 72.9% respectively. The complete immunocytochemical panel was positive in 83.3% of the cases resulting in malignancy and negative in 87.5% of cases resulting in benign histology. Among the FN/AUS, the complete positive immunocytochemical panel was detected in 76.9% of cases resulting as malignant and the complete negative immunocytochemical panel was observed in 96.8% of cases resulting as benign at histology.nnnCONCLUSIONSnThe expression of HBME-1 and Galectin-3 in cases classified as FN/AUS on LBC-processed FNABs can effectively distinguish lesions, which need immediate surgery (high risk or FNH or Thy 3h) from those which can be followed-up (low risk or FNL or Thy 3l).

Epidemiology of carcinoid neoplasms in Vaud, Switzerland, 1974–97

In Vaud, Switzerland, the incidence of carcinoids based on 218 malignant and 215 benign cases rose from 19.6/106in 1974–85 to 28.2/106in 1986–97, more so among males and malignant neoplasms. Lung was the commonest site for malignant and large intestine for benign carcinoids. Sixty-eight (16%) carcinoids had another neoplasm.

3. The ENETS guidelines: the new TNM classification system

The WHO definition of the 3 classes of well differentiated endocrine tumor, well differentiated endocrine carcinoma and poorly differentiated carcinoma, allows an efficient general classification of GEP NETs fitting European Union (EU) current clinical use. The ENETS grading and TNM staging systems are complementary tools allowing to improve patients stratification, and their adoption is strongly recommended. However, the prognostic value of these tools is still under investigation and more data are needed to support their usefulness at all gut sites and in perspective series. Similarly, the four classes system adopted by the WHO for the endocrine tumors of the lung allows a prognostically effective stratification of patients. A common grading system is advocated for lung and GEP NETS.

The 2010 WHO Classification of Digestive Neuroendocrine Neoplasms: a Critical Appraisal four years after Its Introduction

This paper briefly illustrates the basis, rules of application, and present outcome of the current World Health Organization (WHO) classification for neuroendocrine neoplasms. Established in 2010 upon the proposal from the European Neuroendocrine Tumor Society (ENETS), the WHO 2010 fostered some definitional changes (most notably the use of neuroendocrine tumor (NET) instead of carcinoid) and indicated the tools of grading and staging. Specific rules for its application were also defined. The data generated from the use of WHO 2010 classification substantially endorsed its rules and prognostic efficacy. In addition, the application demonstrated some issues, among which are the possible re-definition of the cutoff for grading G1 vs G2, as well as the possible identification of cases with somewhat different clinical behavior within the G3 neuroendocrine cancer class. Overall, since the recent introduction of WHO 2010 grading and staging, it appears wise to keep the current descriptors to avoid unnecessary confusion and to generate comparable data. Homogenous data on large series are ultimately needed to solve such issues.