Natural history of gastro-entero-pancreatic and thoracic neuroendocrine tumors. Data from a large prospective and retrospective Italian epidemiological study: the NET management study.

BACKGROUND: The few epidemiological data available in literature on neuroendocrine tumors (NET) are mainly based on Registry databases, missing therefore details on their clinical and natural history. AIM: To investigate epidemiology, clinical presentation, and natural history of NET. DESIGN AND SETTING: A large national retrospective survey was conducted in 13 Italian referral centers. Among 1203 NET, 820 originating in the thorax (T-NET), in the gastro-enteropancreatic tract (GEP-NET) or metastatic NET of unknown primary origin (U-NET) were enrolled in the study. RESULTS: 93% had a sporadic and 7% a multiple endocrine neoplasia type 1 (MEN1)-associated tumor; 63% were GEP-NET, 33% T-NET, 4% U-NET. Pancreas and lung were the commonest primary sites. Poorly differentiated carcinomas were <10%, all sporadic. The incidence of NET had a linear increase from 1990 to 2007 in all the centers. The mean age at diagnosis was 60.0 ± 16.4 yr, significantly anticipated in MEN1 patients (47.7 ± 16.5 yr). Association with cigarette smoking and other non-NET cancer were more prevalent than in the general Italian population. The first symptoms of the disease were related to tumor burden in 46%, endocrine syndrome in 23%, while the diagnosis was fortuity in 29%. Insulin (37%) and serotonin (35%) were the most common hormonal hypersecretions. An advanced tumor stage was found in 42%, more frequently in the gut and thymus. No differences in the overall survival was observed between T-NET and GEP-NET and between sporadic and MEN1-associated tumors at 10 yr from diagnosis, while survival probability was dramatically reduced in U-NET. CONCLUSIONS: The data obtained from this study furnish relevant information on epidemiology, natural history, and clinico-pathological features of NET, not available from the few published Register studies.

Imaging of NETs with PET radiopharmaceuticals.

Neuroendocrine tumours (NET) diagnosis has represented a major challenge in the past decades. The introduction of somatostatin receptor scintigraphy in the diagnostic work-up led to a significant improvement of accuracy. However with the advent of positron emission tomography (PET) that presents a higher spatial resolution as compared to the gamma camera and an array of different radiotracers, it is now possible to image NET with an even higher accuracy. In fact, PET imaging of NET is a rapidly evolving field closely connected to the development of novel beta-emitting radiopharmaceuticals. NET can be easily visualized on PET scans using an array of both metabolic and receptor-based tracers. [18F]DOPA and [68Ga]DOTA-peptides (DOTA-TOC, DOTA-NOC, DOTA-TATE) are very promising to image well differentiated NET and were reported to be superior to other imaging modalities (computed tomography [CT], somatostatin receptor scintigraphy). On the contrary, the role of [18F]FDG is limited in well differentiated NET, due to their low glucose metabolism and growth rate, while it still can provide valuable information in less differentiated tumours. On-going studies are investigating the potential role of new imaging agents (bombesin, GLP-1, CCK) that specifically bind to receptors expressed on NET cells.

Animal-sediment relationships: evaluating the 'Pearson-Rosenberg paradigm' in Mediterranean coastal lagoons.

We investigated the applicability of the Pearson-Rosenberg (P-R) conceptual model describing a generalized pattern of response of benthic communities in relation to organic enrichment to Mediterranean Sea coastal lagoons. Consistent with P-R model predictions, benthic diversity and abundance showed two different peaks at low (>2.5-5 mg g(-1)) and high (>25-30 mg g(-1)) total organic carbon (TOC) ranges, respectively. We identified TOC thresholds indicating that risks of reduced benthic diversity should be relatively low at TOC valuesabout 28 mg g(-1), and intermediate at values in-between. Predictive ability within these ranges was high based on results of re-sampling simulation. While not a direct measure of causality, it is anticipated that these TOC thresholds should serve as a general screening-level indicator for evaluating the likelihood of reduced sediment quality and associated bioeffects in such eutrophic systems of the Mediterranean Sea.

Gastric endocrine tumors type I: treatment with long-acting somatostatin analogs.

Gastric endocrine tumors associated with autoimmune chronic atrophic gastritis (gastric carcinoid type I) are almost exclusively benign lesions with little risk of deep invasion of the gastric parietal wall. For this reason, the role of octreotide in the treatment of these neoplastic lesions is controversial. Nine patients with more than five type I gastric endocrine tumors each <1 cm in size, without invasion of the muscularis propria and with Ki-67 index lower than 3%, were treated with long-acting somatostatin analogs for 12 months. After 6 months and again after 12 months, all the patients underwent upper gastrointestinal (GI) endoscopy with multiple biopsies. The plasma chromogranin A (CgA) levels and the gastrin levels in the serum were also determined. In all patients, the gastric neoplastic lesions disappeared after 12 months of somatostatin analog therapy. We also observed a significant reduction of CgA and gastrin levels at 6 and at 12 months of therapy as compared with the baseline values. We demonstrate that somatostatin analog treatment provokes the pathological regression of type I gastric carcinoids. This therapeutic approach should be considered as a valid option in selected patients with multiple type I gastric endocrine tumors.

Comparison between two methods in the determination of circulating chromogranin A in neuroendocrine tumors (NETs): results of a prospective multicenter observational study.

Several methods for analyzing CgA using either monoclonal or polyclonal antibodies have been developed, which differ in their diagnostic performance. The present paper describes the results of a prospective multicenter study aimed at comparing the clinical value of the two most widely used commercially available CgA assay kits in patients affected by neuroendocrine tumors (NETs). Two hundred sixty-one patients from 40 different centers and 99 healthy subjects were evaluated. CgA levels were measured with two different methods, a two-step immunoradiometric assay (IRMA) and an enzyme-linked immunosorbent assay (ELISA). CgA was measured centrally by two reference laboratories, one of which used IRMA and the other ELISA, and it was measured by the participating institutions with the method routinely used by each of them. The major findings of the present study were: (i) the two assays for the determination of CgA present good diagnostic performance; (ii) both assays are robust and guarantee comparable results when applied in different settings (central vs local laboratory); (iii) the negative/positive cutoff points (87 ng/mL for IRMA and 21.3 U/L for ELISA) were established according to standardized criteria; (iv) the results obtained with the two assays in basal clinical samples of patients affected by NETs show an apparently satisfactory correlation (rs = 0.843, p < 0.0001). However, a possibly clinically meaningful 36% discordance rate was found. These findings support the hypothesis that the two CgA kits might provide partially different information.

Zollinger-Ellison syndrome. Diagnosis and therapy.

Zollinger-Ellison syndrome (ZES) is characterised by refractory peptic ulcer disease, severe diarrhoea and gastric acid hypersecretion associated with an islet-cell tumor of the pancreas (gastrinoma). ZES is sporadic in 62-80% of cases and in 20-38% of cases is associated with multiple endocrine neoplasia type 1 (MEN 1). The diagnosis of ZES is certain when the plasma gastrin is >1000 pg/mL and the basal acid output is >15 mEq/h in patients with an intact stomach, >5 mEq/h in gastrectomised patients, or when the hypergastrinemia is associated with a pH <2. Treatment is based on the control of gastric acid hypersecretion and of the malignant tumor and its possible metastases. Proton pump inhibitors are the most effective antisecretory drugs and can be administered at high dosages without drug-related adverse effects. All sporadic, localised gastrinomas should be excised if possible. When liver metastases are also present, their debulking may improve symptoms and survival, and facilitate medical treatment. There is some controversy as to the surgical approach for gastrinomas associated with MEN 1. Somatostatin analogues can be useful in reducing gastric acid hypersecretion, serum gastrin and gastric enterochromaffin-like cells, and can thus contribute to treating the disease more effectively. Their antiproliferative effect can be used in treating liver metastases. Chemotherapy and/or interferon are indicated only in patients with malignant progressive disease. Embolisation and chemoembolisation are effective in controlling clinical symptoms; however, they do not seem to improve survival.

Endocrine pancreatic tumors: factors correlated with survival.

BACKGROUND: The aim of this study was to evaluate the survival rate of patients with endocrine tumors of the pancreas, functioning or non-functioning, associated or not with MEN 1 syndrome. PATIENTS AND METHODS: Eighty-three patients with pancreatic endocrine tumors diagnosed in our department from 1978 to 2003 were studied. RESULTS: The study included 37 men (44.6%) and 46 women (55.4%). The median age of patients at diagnosis was 55 years (range 19-81 years). Fifty-two patients (62.7%) had non-functioning endocrine tumors, 16 (19.3%) had functioning endocrine tumors and 15 (18.1%) had MEN 1 disease with pancreatic involvement. Twenty-seven patients (32.5%) had liver metastases at the time of diagnosis, involvement of the lymph nodes was found in 47 out of 79 patients (59.5%). Forty patients (48.2%) had radical surgery, 20 (24.1%) had palliative surgery and 53 were treated medically. The survival rate was significantly related to the presence of metastases, lymph node involvement, and the type of tumor and treatment. CONCLUSIONS: Tumor resection, the absence of liver and lymph node metastases, and the presence of MEN 1 syndrome are related to a better survival rate. Radical surgery continues to have a central role in the therapeutic approach to endocrine tumors of the pancreas.

Oil-lubricated colonoscopy: easier and less painful?

BACKGROUND AND STUDY AIMS: Methods of lubrication are rarely considered to be a matter for study in gastrointestinal endoscopy. We evaluated a new technique, i. e. the release of seed oil in discrete amounts from the tip of the scope during colonoscopy. PATIENTS AND METHODS: 346 consecutive patients prospectively underwent colonoscopy with a standard lubricating method (using water-soluble jelly; group A) or with the standard method plus seed oil (corn oil) instillations through the biopsy channel (group B). The following variables were evaluated in the two groups: the success rate for total intubation, and the time required to reach the cecum; the time needed to examine the colon at withdrawal; the detection rates for colorectal diseases; the level of pain and degree of difficulty associated with the examination. Patients in whom total colonoscopy was not achieved were asked to undergo a further examination in which the other lubricating technique was used. RESULTS: Successful intubation to the cecum was significantly more frequent ( P < 0.005) in the oil lubrication group (group B, 159/168) than in the control group (group A, 145/170), and less time was needed ( P < 0.001). No significant differences were found with regard to time for examination at withdrawal and detection rates for colorectal diseases. Level of pain and degree of difficulty during colonoscopy were significantly lower in the oil group ( P < 0.001). In the cross-over examinations done in patients in whom total colonoscopy was not achieved, no statistical difference was found between the two groups. We observed no side effects for patients or damage to the instrument. CONCLUSIONS: The proposed technique could be a simple, safe, and inexpensive method for easier and less painful colonoscopy; moreover, it might facilitate difficult examinations. Further studies are needed to confirm our data and to ensure that the use of this technique is not liable to damage the scope.

Thymic neuroendocrine carcinoma (carcinoid) in multiple endocrine neoplasia type 1 syndrome: the Italian series.

Neuroendocrine tumors may occur in the setting of multiple endocrine neoplasia type 1 (MEN1) syndrome. Among these, a probably underestimated prevalence of well differentiated neuroendocrine thymic carcinoma (carcinoid), a neoplasm characterized by very aggressive behavior, has been described. We report characterization of the seven Italian cases in which this association occurred among a series of 221 MEN1 patients (41 sporadic and 180 familial cases; prevalence, 3.1%). All of the patients were male, and six of seven (85%) were heavy smokers. No associated hormonal hypersecretion was detected. The first diagnosis was between the second and fifth decades. Familial clusters were present in three of seven (42.8%). No genotype-phenotype correlation was found. All seven cases were associated with hyperparathyroidism. In one patient, prophylactic thymectomy revealed a small nodular lesion suggestive of a thymic carcinoid, providing evidence that preventive thymectomy might prevent additional growth of an occult thymic carcinoid. These findings confirm that thymic carcinoids are associated with a very high lethality, with a near-total prevalence in smoker males. Therefore, prophylactic thymectomy should be considered at neck surgery for primary hyperparathyroidism in MEN1 male patients, especially for smokers, and, due to the frequent familial clusters distribution of this pathology, in subjects with affected relatives presenting this feature. Thus, we recommend screening every patient affected with a neuroendocrine thymic neoplasm for MEN1 syndrome.

Basis for treatment of functioning neuroendocrine tumours.

A general characteristic of GEP endocrine tumours is that vast majority produce and secrete a multitude of peptide hormones and amines. The rarity of these types of tumours, their possible episodic expression and the variable clinical symptoms, are the reasons why patients are often diagnosed late in the advanced stages of the disease. For these reasons, the patients with advanced metastatic disease should be treated aggressively with medical and surgical therapies aimed at reducing both symptoms and complications through strategies that reduce tumour bulk and block hormonal effects. The medical treatment of functioning endocrine tumours of the gastrointestinal tract must be based on the growth properties of the tumour and includes chemotherapy, somatostatin analogs, alpha-interferon alone and associated with somatostatin analogs, chemoembolization and radiolabelled somatostatin analogs. Even if chemotherapy has been basis of therapy for these types of tumours for a long time, it is currently reserved for progressive disease and anaplastic tumours. Biotherapy, with interferon and somatostatin analogs has been demonstrated to have a significant antitumor effect and causes an improvement of symptoms in patients with functioning neuroendocrine tumours. Furthermore, these drugs produce a notable improvement in the quality of life. Radioactive targeting therapy is the most promising new treatment modality for patients who have SST receptor positive tumours.

Pancreatic hyperenzymaemia and hypertransaminasaemia in healthy subjects. Report of three cases.

Three healthy subjects, two from Italy and one from the United States, showing a chronic increase in serum pancreatic enzymes and transaminases are described. The enzyme elevations reached very high levels but were not constant; rather, they fluctuated and sometimes returned to normal. Furthermore, tests for non-hepatic diseases that can be accompanied by an increase in serum transaminases, such as coeliac disease, were normal. The intervals between the first finding of the pancreatic hyperenzymaemia and the hypertransaminasaemia and this study ranged from 2 to 6 years (mean 4.3 years), during which the three subjects remained healthy, with no clinical, laboratory or imaging evidence of disease. These data support the conclusion that these increases in enzymes are benign; however, monitoring of these three subjects is already underway. Awareness of this anomaly is important, both to relieve the distress of the persons involved, as well as to avoid the numerous, sometimes invasive, complex and expensive examinations that might otherwise be unnecessarily performed.

A meal stimulation test in the diagnosis of pancreatic endocrine tumors in multiple endocrine neoplasia type 1.

BACKGROUND: The diagnostic value of the determination of the serum pancreatic polypeptide (PP) and gastrin concentrations after a standard meal for early diagnosis of patients with multiple endocrine neoplasia type 1 (MEN 1) is controversial. The aim of this study was to clarify this issue. Thirteen patients with MEN 1, seven healthy family members, and eight healthy controls were studied. Plasma PP and serum gastrin were measured before and after the ingestion of a standardized meal. The meal caused a statistically significant (p < 0.05) increase of both PP and gastrin in all three groups studied. Concerning PP, no statistically significant difference was observed between patients and controls. In family members, the values were significantly (p < 0.05) lower than in the other two groups. On the whole, no significant differences in gastrin levels were noted between patients and controls; in family members, the values were significantly (p < 0.05) lower than in patients. All patients who had abnormally high postprandial values of PP and gastrin also had abnormally high basal values of these two peptides. The determination of serum PP and gastrin levels after a meal stimulation test in patients with MEN 1 adds no information about the presence of pancreatic endocrine tumors over that provided by basal values of the two peptides.

Endoscopic markers in adult coeliac disease.

BACKGROUND: Various endoscopic markers have been described in coeliac disease, particularly in the second part of the duodenum, with minor attention generally being paid to the duodenal bulb. AIMS: To evaluate, prospectively, the presence of all endoscopic markers in the bulb and the second part of the duodenum on a large series of patients submitted to endoscopy for duodenal biopsy. PATIENTS AND METHODS. A total of 367 consecutive patients, submitted to endoscopy with duodenal biopsy for various indications, were considered. Biopsies were graded as normal, with partial villous atrophy (mild, moderate, severe) or with subtotal villous atrophy. Endoscopic markers and corresponding locations evaluated were: micronodular pattern [bulb and descending duodenum], mosaic appearance (bulb and descending duodenum), scalloped folds (descending duodenum), reduced or absent folds (descending duodenum). RESULTS: In 78 patients, a diagnosis of untreated coeliac disease was made. Endoscopic markers were seen in 73/78 patients, with only a single sign present (bulb or descending duodenum) in 12 patients. In the remaining 289 patients, normal histology and normal endoscopic findings were observed, except in two patients with reduced folds. Sensitivity, specificity, positive and negative predictive values and diagnostic accuracy regarding all endoscopic markers were 93.6%, 99.3%, 97.3%, 98.3% and 98.1%, respectively CONCLUSIONS: This study confirms the usefulness of endoscopic markers in detecting coeliac disease, underlining the importance of evaluating also abnormalities in the bulb and endoscopic single signs; although endoscopy may not detect all cases of coeliac disease, the recognition of endoscopic markers allows the selection for biopsy of unsuspected patients submitted to endoscopy for non-specific symptoms.

Guidelines for diagnosis and therapy of MEN type 1 and type 2.

This is a consensus statement from an international group, mostly of clinical endocrinologists. MEN1 and MEN2 are hereditary cancer syndromes. The commonest tumors secrete PTH or gastrin in MEN1, and calcitonin or catecholamines in MEN2. Management strategies improved after the discoveries of their genes. MEN1 has no clear syndromic variants. Tumor monitoring in MEN1 carriers includes biochemical tests yearly and imaging tests less often. Neck surgery includes subtotal or total parathyroidectomy, parathyroid cryopreservation, and thymectomy. Proton pump inhibitors or somatostatin analogs are the main management for oversecretion of entero-pancreatic hormones, except insulin. The roles for surgery of most entero-pancreatic tumors present several controversies: exclusion of most operations on gastrinomas and indications for surgery on other tumors. Each MEN1 family probably has an inactivating MEN1 germline mutation. Testing for a germline MEN1 mutation gives useful information, but rarely mandates an intervention. The most distinctive MEN2 variants are MEN2A, MEN2B, and familial medullary thyroid cancer (MTC). They vary in aggressiveness of MTC and spectrum of disturbed organs. Mortality in MEN2 is greater from MTC than from pheochromocytoma. Thyroidectomy, during childhood if possible, is the goal in all MEN2 carriers to prevent or cure MTC. Each MEN2 index case probably has an activating germline RET mutation. RET testing has replaced calcitonin testing to diagnose the MEN2 carrier state. The specific RET codon mutation correlates with the MEN2 syndromic variant, the age of onset of MTC, and the aggressiveness of MTC; consequently, that mutation should guide major management decisions, such as whether and when to perform thyroidectomy.

Do early symptoms of pancreatic cancer exist that can allow an earlier diagnosis?

Diagnosis of pancreatic cancer is made late, and prognosis remains extremely poor. This study was carried out to investigate whether symptoms exist before pain or jaundice that could suggest pancreatic cancer and favor earlier diagnosis. The study involved 305 patients with confirmed pancreatic cancer and 305 controls. All subjects were interviewed personally at least twice about their clinical history; pancreatic cancer patients were asked about any disturbances before abdominal pain or jaundice. Of the 305 pancreatic cancer patients, 151 (49.5%) had some prior disturbances, 108 (35.4%) 6 months or less before pain or jaundice and 43 (14.1%) more than 6 months before. Among the latter, 14 (4.6% of all patients) had had anorexia and/or early satiety and/or asthenia (7-20 months before pain or jaundice), 11 (3.6%) had disgust for coffee and/or smoking and/or wine (7-20 months before), 14 (4.6%) had diabetes (7-24 months before), and four (1.3%) had acute pancreatitis (8-26 months before). Among the controls, the only reports of these symptoms were two (0.7%) cases of asthenia (4 and 6 years earlier), 22 (7.2%) cases of diabetes (of which only two [0.7%] were diagnosed 7-24 months before the interview), and one (0.33%) case of acute pancreatitis (10 years earlier). Apart from acute pancreatitis, all the other differences between patients and controls were statistically significant. In approximately 15% of patients, disturbances existed more than 6 months before pain or jaundice, which, although not specific, could raise suspicion of the possibility of pancreatic cancer. These disturbances could represent the one current opportunity for an earlier diagnosis in a significant minority of pancreatic cancer patients.