Digestive Neuroendocrine Tumors Research Articles

Ki67 proliferation index, hepatic tumor load, and pretreatment tumor growth predict the antitumoral efficacy of lanreotide in patients with malignant digestive neuroendocrine tumors

An antiproliferative effect of somatostatin analogs was recently demonstrated. To identify factors associated with tumor control in a group of patients with well-differentiated malignant digestive neuroendocrine tumors treated with lanreotide. A retrospective study was conducted in 68 patients treated with lanreotide alone, with progression-free survival as the primary endpoint. The role of the following factors was searched for by univariate and multivariate analyses: age, sex, mode of discovery, site of the primary tumor, metastatic spread, Ki67 proliferation index, uptake on somatostatin receptor scintigraphy, pretreatment tumor growth, extent of liver involvement, resection of primary tumor, previous treatments, and tumor markers. Tumor progression was observed in 39/68 patients (57.4%). Median progression-free survival was 29 months. On multivariate analysis, a Ki67 proliferation index of up to 5% [hazard ratio (HR)=0.262, P=0.009], pretreatment stability (HR=0.241, P=0.008), and hepatic tumor load of up to 25% (HR=0.237, P=0.004) were significantly associated with disease stability under lanreotide therapy. In patients with well-differentiated malignant digestive neuroendocrine tumors, Ki67 proliferation index of up to 5%, stable disease before treatment, and low-to-moderate hepatic tumor involvement (≤ 25%) are associated with tumor control during lanreotide treatment. These data if confirmed in prospective trials will help in rationalizing the use of somatostatin analogs with antiproliferative intent.

Endocrine Tumours: Epidemiology of malignant digestive neuroendocrine tumours

Little is known about patients with malignant digestive neuroendocrine tumours (MD-NETs). Although their incidence is increasing, MD-NETs remain a rare cancer, representing 1% of digestive cancers. Most MD-NETs are well-differentiated. MD-NET poorly differentiated carcinomas account for 20% of cases on average. Anatomical localisation of MD-NETs varied according to geographic region. Stage at diagnosis and prognosis for patients with MD-NETs in the general population are considerably worse than often reported from small hospital case series. Prognosis varies with tumour differentiation, anatomic site and histological subtype. There are significant differences in survival from MD-NETs among European countries, independent of other prognostic factors. Early diagnosis is difficult; new therapeutic options appear to represent the best approach to improving prognosis.

Methylguanine DNA methyl transferase (MGMT) expression predicts response to temozolomide (TMZ) in patients with digestive neuroendocrine tumors (NETs)

La place de la radiothérapie chez les patients atteints de cancer du pancréas opérable ou localement évolué est actuellement controversée. En situation adjuvante, le traitement standard est une chimiothérapie par gemcitabine et capécitabine pendant six mois. En association avec une chimiothérapie concomitante, la radiothérapie postopératoire permettrait d’améliorer la probabilité de survie des patients après une résection tumorale incomplète (R1). Ceci reste à démontrer dans un essai prospectif. La chimioradiothérapie néoadjuvante est une approche prometteuse de plus en plus utilisée pour les tumeurs à la limite de la résécabilité (borderline). Pour les tumeurs localement évoluées, il n’existe pas de standard thérapeutique. Une chimiothérapie première suivie chez les patients en situation de non progression d’une chimioradiothérapie permet de diminuer le taux de rechute locale. Alors que dans les premiers essais de radiothérapie pancréatique étaient utilisés de grands faisceaux d’irradiation, les volumes traités ont été réduits afin d’améliorer la tolérance. Les mouvements de la tumeur liés à la respiration doivent être pris en compte. La radiothérapie conformationnelle avec modulation d’intensité permet de diminuer les doses reçues par les organes à risque. Bien que de plus en plus utilisée, elle n’est pas encore validée dans cette indication.Currently, the use of radiation therapy for patients with pancreatic cancer is subject to discussion. In adjuvant setting, the standard treatment is 6 months of chemotherapy with gemcitabine and capecitabine. Chemoradiation (CRT) may improve the survival of patients with incompletely resected tumors (R1). This should be confirmed by a prospective trial. Neoadjuvant CRT is a promising treatment especially for patients with borderline resectable tumors. For patients with locally advanced tumors, there is no a standard. An induction chemotherapy followed by CRT for non-progressive patients reduces the rate of local relapse. Whereas in the first trials of CRT large fields were used, the treated volumes have been reduced to improve tolerance. Tumor movements induced by breathing should be taken in account. Intensity modulated radiation therapy allows a reduction of doses to the organs at risk. Whereas widely used, this technique is not recommended.

ENETS Consensus Guidelines for the Management of Patients with Digestive Neuroendocrine Neoplasms of the Digestive System

Панкреатические нейроэндокринные опухоли (П-НЭО) представлены как функционирующими опухолями, так и новообразованиями без определенной функциональной активности [1–4]. Нефункционирующие П-НЭО часто секретируют панкреатический полипептид (ПП), хромогранин А, нейроспецифическую энолазу (НСЭ), хорионический гонадотропин (ХГ), кальцитонин, нейротензин и другие пептиды, обычно не проявляются клиническими симптомами и в связи с этим считаются нефункционирующими опухолями [2, 3, 5–7]. В этой части рекомендаций рассматриваются только функционирующие П-НЭО. Отдельно обсуждаются две группы: наиболее часто встречающиеся опухоли (инсулинома и гастринома) и другие опухоли (подробно описанные и реже встречающиеся), так называемые редкие функционирующие П-НЭО (см. таблицу) [1–4].

209P - Predictive Value of Circulating Endothelial Cell (CEC) Levels in Metastatic or Locally Advanced Neuroendocrine Digestive Tumor Patients Treated With Chemotherapy and Bevacizumab

ABSTRACT Background The efficacy/safety of bevacizumab in combination with chemotherapy was investigated in patients (pts) with advanced progressive digestive neuroendocrine tumors (DigNET) (phase II BETTER study (ML20383)). Circulating endothelial cell levels were explored as potential prognostic or predictive marker. Methods Pts were enrolled in two arms depending on tumor primary localisation. Pts with duodeno-pancreatic NET were treated with 5-FU/streptozocin combined to bevacizumab (arm 1, n = 34). Patients with other digNET received capecitabine combined to bevacizumab (arm 2, n = 49). In 50 dig NET patients, CEC levels were monitored at several time points: -before treatment (baseline, BL), -on day 2 (d2) of cycle 1 (C1), -on day 22 (d22) of cycle 1 (C1) for arm 1 and day 1 (d1) of cycle 2 (C2) for arm 2, -at day 1 of each of the subsequent cycles and at the end of treatment. CECs were measured in 1ml erythocyte lysed whole blood by four color flow cytometry (FCM) and identified by a CD45-CD31+CD1467-amino-actinomycin (7AAD)- phenotype. Relation between CEC levels and clinico-biological characteristics, response to treatment and progression/death at 1 or 2 years (1 yr-, 2 yr-PFS) was examined. Non parametric Wilcoxon tests were used to analyze change from baseline and to evaluate the association beteween CEC values and efficacy parameters. Results Median CEC values were low at BL (4 CEC/mL) and similar for the 2 arms. CEC levels significantly increased on C1d2 onlv (media value: 7CEC/mL for the 2 pooled arms, p = 0.019). A trend towards an association between changes in CEC levels between BL and C1d2, and progression/death during the first two years of treatment was observed (p = 0.078). Conclusions Increased CECs at baseline could be an indicator of shorter PFS in digNET treated with the combination of bevacizumab and chemotherapy. The mechanism of increased CECs at day 2 of treatment remains to be understood. Disclosure E. Mitry: Honoraries: Roche. K. Joly: Employment: Roche. M. Ducreux: Consultant: Roche, Merck Serono Honoraries: Roche, Merck Serono, Amgen, Bayer, Fresenus, Pfizer, Sanofi Clinical research project: Pfizer, Chugai, Merck Serono. E. Baudin: Honoraries : Scientific committee of BETTER Trial. All other authors have declared no conflicts of interest.

New treatment options with cytotoxic agents in neuroendocrine tumours

There are numerous treatment options for patients with advanced digestive neuroendocrine tumours (NETs). Medical treatment includes systemic chemotherapies, targeted therapies, somatostatin analogs, liver-directed therapies such as (chemo)embolization or thermoablation, and peptide receptor radionuclide therapy. Cytotoxic chemotherapies can help control tumour progression in patients with non-resectable tumours and may improve symptoms by reducing tumour bulk. In addition, tumour response is usually greater than that obtained with targeted therapies. This should be taken into consideration in neoadjuvant strategies. Efficacy of temozolomide depends on the O(6) methylguanine DNA methyl transferase status, and thus, this drug will likely have to be considered in the future in patients with a favourable enzyme profile. Because numerous treatment options are available for patients with advanced digestive NETs, and thanks to their long survival, successive drugs should be used. Careful attention should be paid to the adverse events in order to maintain the quality of life in these patients who have with a long life expectancy.

Overview of neuroendocrine liver metastases treatment

Although surgical resection is the only way to induce remission (if not cure) in patients with liver metastases (LM) of digestive neuroendocrine tumours (NETS), it cannot be performed in the vast majority of the patients due to the diffusion of hepatic disease. Indeed, despite evolving techniques that may include twostep resection procedures and liver transplantation, the proportion of patients who receive liver resection barely exceeds 15% in specialised centres. Medical and interventional radiological anti-tumour treatments are the mainstay for the management of patients with malignant NETS. The treatment approach is determined by: the tumour biology, location of the primary, natural history and extent of liver involvement. In patients with nonprogressive disease on 2 consecutive CT scans performed at 6-month intervals, with limited (<50% of the liver parenchyma), well-differentiated grade 1 or 2 LM, and

Methylguanine DNA methyl transferase (MGMT) expression to predict response to temozolomide (TMZ) in patients with digestive neuroendocrine tumors (NETs).

4133 Background: TMZ is an orally given drug used in patients (pts) with NETs, with encouraging results in pancreatic NETs in a recent study (Strosberg et al, 2011). Higher treatment efficacy seems to be correlated to MGMT tumor deficiency (Kulke et al, 2010). Aim-To assess MGMT expression in digestive NETs and to correlate with the efficacy of TMZ-based therapies. Methods: All pts with well differentiated, progressive, non resectable NETs treated with TMZ-based chemotherapy were included. Treatment efficacy was defined according to RECIST. Pts with progression or only stable disease were considered as “non-responders”. Nuclear expression of MGMT was assessed by immunohistochemistry on primary tumors or metastases and graded according the product of the intensity of staining (0 to 3) and the rate of positive cells (%), leading to a score comprised between 0 and 300. A score ≥ 80 was defined as “high” staining. Results: 22 pts (age 59 years (36-81)) with pancreatic (14 pts), small bowel (5 pts) or other (3 pts) NETs, grade 1 (5 pts) or 2 (17 pts) (WHO 2010 classification) were included. They received TMZ alone (19 pts) or combined with capecitabine (3 pts) as first line (3 pts) or 2+ line (19 pts).After a median of 6 cycles (3-16), objective response, stable disease and progression rates were seen in 32 % (7 pts, all with pancreatic NETs), 41% (9 pts, 5 pancreatic) and 27% (6 pts, 4 small bowel), respectively. Median (range) MGMT score was 10 (0-300). A “High” MGMT score was seen in 36% of pts (small bowel 4, pancreas 3 pts) ; it was correlated with primary tumor location (more frequent in small bowel NETs, p=0.02) and predictive of the absence of response (p=0.02). A “Low “MGMT score tended to be associated with objective response (p=0.06) whereas none of the pts with “high” score had tumor response. Response rate in pts with “low” MGMT score was 50%. Conclusions: MGMT deficiency is more frequent in pancreatic than small bowel NETs. Patients with pancreatic NET and low MGMT score are good candidates for TMZ, whereas those with high score should be treated with other drug in first intention. In patients with small bowel NET with most often high MGMT score, tumor stabilization using TMZ seems to be rare.

Well-differentiated grade 3 digestive neuroendocrine tumors: Myth or reality? The PRONET study group.

4129 Background: In contrast to the 2000 World Health Organization (WHO) classification of digestive neuroendocrine tumors (NET) in which morphologic differentiation was the first criterion, the 2010 WHO classification of NET is based mostly on histologic grade. NET are now classified into three main categories: NET G1 (mitotic count &lt;2/10 HPF and/or ≤2% Ki67 index), NET G2 (2-20/10 HPF and/or 3-20%), and neuroendocrine carcinoma (NEC) of small or large cell type. While NET G1 and G2 are well-differentiated tumors, NEC are considered poorly differentiated G3 tumors. We looked at the agreement between grade and differentiation to determine whether all NET can be readily classified according to the 2010 WHO classification. Methods: We designed a 1-year prospective, epidemiologic study to assess the characteristics of newly diagnosed NET, including diagnostic pathology. From August 2010 to July 2011, all pathology laboratories in France were invited to register all incident cases of gastroenteropancreatic (GEP) and thoracic NET, excluding small cell carcinoma. For GEP-NET, investigators were asked to indicate morphologic differentiation (according to WHO 2000) and elements of histologic grade (mitotic index, Ki67 index), according to ENETS. Results: Of 500 invited centers, 80 participated; 1417 incidental cases were included and 77 excluded (duplicates or exclusion criteria), totaling 1340 cases; 778 (58.1%) were GEP-NET; 660/778 (85%) were well differentiated, 72 (9%) poorly differentiated, and 46 (6%) adenocarcinoid, nonclassified, or not evaluable; 422 (54.2%) were G1, 220 (28%) G2, 104 (13.5%) G3, and 32 (4.1%) had missing grades. Of those deemed G3, 72 (69%) were described as poorly differentiated, 21 (20%) as well differentiated (mean Ki67 index 35%, range 25%-60%), and 11 (10.5%) as adenocarcinoid. Conclusions: In this prospective, epidemiologic study, overall agreement between grade and differentiation was good. However, a significant proportion of G3 NET were classified as well differentiated and thus unclassifiable by 2010 WHO classification. This group of tumor deserves to be included in future classifications to help the clinician decide whether they should be treated as NET G1/G2 or NEC G3.

Neuroendocrine tumours of the pancreas: recent developments in staging and grading

A new classification of digestive neuroendocrine neoplasms, including pancreas, has been formulated in the 2010 revision of the WHO classification of tumours of the digestive system. The terminology and principles of this novel classification are different from those used previously. Three main grading categories are recognized (neuroendocrine tumour G1, neuroendocrine tumour G2 and neuroendocrine carcinoma of small and of large cell types) combined with a site-specific TNM staging, which was published in 2009 by the AJCC–UICC following a 2006 TNM proposal by the European Neuroendocrine Tumor Society. This review describes the different classifications that have been used in the last 10 years, in order to better understand the sequential modifications which have been progressively added. It highlights problems of terminology that could lead to confusion and also gives some recommendations for the formulation of pathological reports.

ENETS 2011 Consensus Guidelines for the Management of Patients with Digestive Neuroendocrine Tumors: An Update

intermediateand high-grade tumors; (iii) the term ‘tumor’ (neuroendocrine tumor, NET) is meant for lowto intermediate-grade neoplasms, as previously defined either ‘carcinoid’ or ‘atypical carcinoid’; (iv) the word ‘carcinoma’ (neuroendocrine carcinoma, NEC) is meant only for high-grade neoplasms, as previously defined poorly differentiated carcinomas. This terminology is adopted by the ENETS 2011 Guidelines.

Hepatic Arterial Embolization Versus Chemoembolization in Patients With Liver Metastases of a Digestive Neuroendocrine Tumors

Background Presence of liver metastases (Mets) is a pejorative prognostic factor in patients with digestive neuroendocrine tumors (NET). Surgical resection is the best treatment but it is often not feasible due to the extension of the disease. Systemic chemotherapy has limited efficacy. Promising results have been reported using hepatic arterial chemoembolization (CE) or embolization (E) alone. However, these methods have never been compared thus the role of combining chemotherapy to E during the procedure remains unclear. Patients and methods:In this prospective study, CE (with doxorubicin 50 mg/m2) was compared to E in patients with unresectable and progressive liver Mets of a carcinoid tumor. Two procedures were performed with a 3-month interval. The main objective assessed was the rate of progression free survival (PFS) at 2 years. Secondary objectives were overall survival (OS), tumor response (morphological and biological), and safety of the treatment. Results:Among the 26 patients included (median age 58 years, range 38-79), 12 patients had CE and 14 had E. All patients but 3 underwent the two procedures. Characteristics of patients in the two groups were similar. Median follow-up was of 16.9 months (1-28.5). One-year and 2-year PFS were 90%/38% in the arm CE, and 92%/44% in the arm E (p= 0.90). Age, sex, resection of primary tumor, extension of liver Mets, presence of a carcinoid syndrome, use of somatostatin analogs and disease duration before inclusion were not correlated with PFS. In contrast, high levels of urinary 5HIAA and serum chromogranin A were correlated with a shortened PFS. One-year and 2-year OS were 92%/80% in the arm CE, and 100%/100% in the arm E (p=0.16). A tumor control (response+stable) or a biological response were obtained in 95% (arm CE) and 90% (arm E), without significant difference. A toxicity grade 3 occurred in 21% and 14%, respectively (no significant difference). Conclusion:CE and E alone allow controlling tumor growth in 95% of patients with carcinoid and liver Mets, without major toxicity. SSP is not increased using CE, thus additional chemotherapy during the procedure does not likely increase efficacy compared to E alone.

Une nouvelle classification OMS des tumeurs (neuro)endocrines digestives

A new classification of digestive neuroendocrine neoplasms has been formulated in the 2010 revision of the WHO classification of digestive tumors. The principles of this new classification are different from those used in the previous one and the terminology is quite novel. Five main categories are recognized: neuroendocrine tumor G1; neuroendocrine tumor G2; neuroendocrine carcinoma, small cell type; neuroendocrine carcinoma, large cell type; mixed adenoneuroendocrine carcinoma (a new term for mixed tumors). This new classification will change the habits of the clinicians, familiar with the previous classification, which formed the basis for deciding the therapeutic strategy and the type of patient management. Attention must be paid when establishing the concordance between the new classification and the previous one and when reclassifying a previously diagnosed case, now under follow-up. Recommendations are proposed for the redaction of the pathological reports in this period of transition.

Developments in Digestive Tract Neuroendocrine Tumors and Pheochromocytomas/Paragangliomas—A Narrative Review

Digestive neuroendocrine tumors (carcinoids) derive from serotonin-producing enterochromaffin cells. Biochemical screening (and follow-up) is performed with measurements of 5-hydroxyindoloacetic acid in urine. Other markers are also useful. Most digestive neuroendocrine tumors are better localized with functional imaging, i.e. nuclear medicine, compared with other modalities. The treatment of choice is surgical; non-resectable tumors are treated with somatostatin analogs (unlabelled and for more advanced disease radiolabelled) or chemotherapy. Most pheochromocytomas/paragangliomas are sporadic, however, and genetically caused tumors are much more common than previously thought. Biochemical proof of disease is best carried out with measurement of plasma metadrenaline. Imaging with computed tomography or magnetic resonance imaging (MRI) should be followed by functional imaging. Chromaffin tumor-specific methods are preferred.18F-fluoro-deoxyglucose positron emission tomography (18F-DOPA PET) should be used in patients with succinate-dehydrogenase-B-related metastatic pheochromocytoma/paraganglioma.18F-DOPA PET may become a modality of choice for the localization of head and neck paragangliomas. If possible, treatment is surgical. For non-operable disease, other options are available and new drugs are under investigation or in clinical trials.

4. Pathological Diagnosis and Tumor Markers

Pulmonary and digestive neuroendocrine tumors (NETs) are a group of neoplasms whose incidence and prevalence has been constantly increasing over the last years thanks to the significant improvements in instrumental diagnostic techniques. Because NETs are extremely heterogeneous a correct histopathological diagnosis is essential for appropriate treatment. More specifically, the histopathological diagnosis of NETs can be regarded as a multistep: identification of the neuroendocrine nature of the neoplasm, determination of tumor grading; identification of unknown primary. Laboratory biomarkers for the study of gastroenteropancreatic neuroendocrine tumors include both specific markers and non-specific or general markers. At the moment, chromogranin A is the best available and most frequently used biomarker for the diagnosis of NETs, offering the highest overall sensitivity. CgA has also demonstrated some utility in the assessment of response to treatment and as indicator of tumor recurrence.

Developments in Digestive Tract Neuroendocrine Tumours and Pheochromocytomas/Paragangliomas – A Narrative Review

Digestive neuroendocrine tumours (carcinoids) derive from serotonin-producing enterochromaffin cells. Biochemical screening (and follow-up) is performed with measurements of 5-hydroxyindoloacetic acid in urine. Other markers are also useful. Most digestive neuroendocrine tumours are better localised with functional imaging, i.e. nuclear medicine, compared with other modalities. The treatment of choice is surgical; non-resectable tumours are treated with somatostatin analogues (unlabelled and for more advanced disease radiolabelled) or chemotherapy. Most pheochromocytomas/paragangliomas are sporadic, however, and genetically caused tumours are much more common than previously thought. Biochemical proof of disease is best carried out with measurement of plasma metadrenaline. Imaging with computed tomography or magnetic resonance imaging (MRI) should be followed by functional imaging. Chromaffin tumour-specific methods are preferred.18F-fluoro-deoxyglucose positron emission tomography (18F-DOPA PET) should be used in patients with succinate-dehydrogenase-B-related metastatic pheochromocytoma/paraganglioma.18F-DOPA PET may become a modality of choice for the localisation of head and neck paragangliomas. If possible, treatment is surgical. For non-operable disease, other options are available and new drugs are under investigation or in clinical trials.

Angiogenesis and Tumor Progression in Neuroendocrine Digestive Tumors

Clinical observations suggest that in neuroendocrine digestive tumors a high intratumoral microvascular density is associated with good prognosis. We used an experimental orthotopic xenograft model to analyze the relations between angiogenic activity and tumor progression in this tumor subset. We compared 2 endocrine cell lines: STC-1, a low vascular endothelial growth factor (VEGF)-producing cell line, and INS-r3, a high VEGF-producing cell line. Tumor cells were grafted in the adventitial layer of the caecal wall of nude mice, sacrificed after 8 wk. At 8 wk, "primary" tumors were present in all animals. STC-1 derived tumors were morphologically moderately differentiated, with high proliferative and apoptotic activities; in contrast, INS-r3 derived tumors were well differentiated, with low proliferative and apoptotic activities. VEGF was expressed in <50% grafted STC-1 cells but in >90% of grafted INS-r3 cells. Microvascular density was significantly higher in INS-r3 derived tumors than in STC-1 derived tumors. All STC-1 derived tumors (n = 8) have invaded the mucosa, in contrast to none of the INS-r3 derived tumors (n = 8); liver metastases were detected in 7/8 animals bearing STC-1 derived tumors and in 0/8 animals with INS-r3 derived tumors, despite the presence of lymph node metastases. Our experimental data concur with clinical findings to suggest that in well differentiated digestive neuroendocrine tumors angiogenesis is disconnected from tumor progression: the development of a highly vascular tumor microenvironment is correlated with VEGF secretion but is not associated with invasive and metastatic properties; it must therefore be regarded as an indirect marker of differentiation.

Consensus Guidelines for the Management of Patients with Digestive Neuroendocrine Tumors: The Second Event and Some Final Considerations

Fifty-six experts active in the field of digestive endocrine tumors from 18 countries attended the second Consensus Conference. Attendees were invited on the basis of their acumen (proven publication track and clinical practice) in the field on NETs. The attendees represented all medical branches involved in managing patients with gastroenteropancreatic NETs. They were assigned to four working groups according to their specific clinical expertise: (1) Pathology and Genetics (11 participants); (2) Surgery (8 participants); (3) Imaging and Radiology (6 participants), and (4) Medicine and Clinical Pathology (31 participants). The complete list is provided at the end of this commentary, as well as at the end of each of the five following papers. The Conference was divided sequentially into five sessions devoted to specific topics on an anatomical basis (Small Intestine; Colon and Rectum; Appendix; Metastatic Liver, and Poorly-Differentiated Endocrine Carcinomas of Hindgut and Midgut Origin). The Organizing Committee (the four front authors) prepared in advance a working booklet, reporting the text of the ENETS guidelines with specific questions for different working groups. The booklet was provided to all the participants at the conference venue. The work was organized such that, after a short case presentation in a plenary session, each working group The Second Event

Chemotherapy and role of the proliferation marker Ki-67 in digestive neuroendocrine tumors

Neuroendocrine tumors (NETs) of the digestive tract are a heterogeneous group of rare malignancies. Three major subgroups can be defined: pancreatic endocrine tumors, carcinoid tumors, and poorly differentiated gastroenteropancreatic NETs. Classically, digestive NETS have been considered to have an indolent course characterized for prolonged stabilizations or slow progressions, but there are clear differences in terms of aggressiveness, clinical course, and response to treatment among them. Retrospective studies have identified several clinicopathological and immunohistochemical factors as angioinvasion and proliferative index assessed by Ki-67 expression, which predict biological behavior and correlate with survival. Chemotherapy regimens based on the combination of several active drugs such as streptozocin, doxorubicin, 5-fluorouracil, dacarbazine, and temozolomide show low response rates, which sets the need to improve the results of the medical treatment of these malignancies. This review will analyze the role of Ki-67 in digestive NETs under a clinical perspective and will suggest future fields for development of this approach that enable a better patient selection for chemotherapy. Also a comprehensive review of the literature about chemotherapy in NETs is presented.

Consensus Guidelines for the Management of Patients with Digestive Neuroendocrine Tumors: Why Such Guidelines and How We Went about It

Sixty-two experts active in the field of digestive NETs from 20 different countries attended the first Consensus Conference. Attendees were invited on the basis of their proven expert scientific and clinical experience in NETs. The attendees represented all medical disciplines involved in managing patients with digestive NETs. They were assigned to four working groups according to their specific clinical expertise: (1) Pathology and Genetics (11 participants); (2) Surgery (10 participants); (3) Imaging and Radiology (10 participants), and (4) Medicine and Clinical Pathology (31 participants). The complete list of delegates is provided at the end of this commentary, as well as at the end of each of the six following papers. The Conference was divided sequentially into 8 sessions devoted to specific topics on an anatomical basis (Gastric NET, Sessions 1 and 2; Duodenal NET; Pancreatic NET, Sessions 1–4; Poorly Differentiated Endocrine Carcinomas of foregut origin). A working booklet was prepared in advance by the organizing committee, using as a basis the published text of the ENETS Guidelines so that specific questions could be prepared and presented to different working groups. The booklet was provided to the participants only at the conference venue. The Starting Point