Italian journal of gastroenterology and hepatology最新文献

The efficacy of chemotherapy on digestive neuro-endocrine tumours is not yet fully established and depends on the tumour type and on the differentiation of the neuro-endocrine tumours. Reports have indirectly suggested the superior activity of chemotherapy for pancreatic neuro-endocrine tumours than for metastatic carcinoid tumours (response rates around 60% vs 20%). Neuro-endocrine tumour differentiation is also a major factor and a higher chemotherapy efficacy (tumour responses: 69%) has been suggested in undifferentiated or poorly differentiated neuro-endocrine tumours which respond to chemotherapy, a little like small cell lung carcinomas. The efficacy of interferons has also been reported in phase II trials only, with symptomatic and biological responses in about 50% of the cases and tumour responses in 10 to 15%; some studies have suggested an interesting tumour growth control with prolonged survival but this efficacy has still to be investigated to clearly establish the best indications. The role of chemotherapy has to be discussed with surgeons and, in slowly progressing tumours, after the use of somatostatin analogues.

Factors affecting natural history of gastrinoma (Zollinger-Ellison Syndrome) are not yet entirely understood, although much valid information has been gained in the last two decades. Prognostic factors are: a) adequate reduction of gastric acid overproduction insuring symptomatic control and healing of ulcerative lesions; b) inclusion in multiple endocrine neoplasia-1 syndrome rendering gastrinoma surgery rarely indicated and scarcely efficacious; c) size location and spread of the tumoural process(es) conditioning resectability and risk of metachronous liver and extra-abdominal metastases; d) hepatic and bone metastases, major determinants of death; e) development of paraneoplastic Cushing rapidly out of control and causing death within a short period of time; f) development of fundic EC-Lomas in Zollinger-Ellison Syndrome-multiple endocrine neoplasia-1 patients, generally undergoing benign course but possibly leading to lymph node and (exceptionally) to liver metastases and, sometimes, to total gastrectomy; g) experience of medical and surgical teams which are also most important in order to achieve no operative mortality and minimal post-operative complications.

Somatostatin has represented a significant breakthrough in the treatment of patients with hormonally-acting, neuroendocrine gastroenteropancreatic neoplasms, even if its short half-life made it impractical in the clinic. In recent years, new long-acting formulations have been developed from the native peptide. The long-lasting formulation of the somatostatin analogue octreotide (octreotide-LAR) can be administered once-monthly and has been shown to provide similar efficacy to subcutaneous octreotide administered three times a day in the control of flushing and diarrhoea associated with the carcinoid syndrome. Another-long acting somatostatin analogue, lanreotide, is available in a slow-release form, lanreotide-SR. In a multicentre 6-month trial on carcinoid tumour patients, 30 mg lanreotide-SR were administered intramuscularly every 14 days, obtaining the control of symptoms in the majority of subjects. Thus, both octreotide-LAR administered monthly, and lanreotide-SR administered every 10-14 days, have been shown to be an effective tool in the treatment of carcinoid tumours, providing, in addition, a substantial improvement in patient compliance.

Among various newly synthesized chelator-linked octreotide analogues 90Y-[DOTA-DPhe1, Thyr3]-octreotide (90Y-SMT 487) was finally selected for clinical development. In vitro, SMT 487 binds selectively with nanomolar affinity to the somatostatin receptor subtype 2 (IC30 = 0.39 nM +/- 0.02). In vivo, 90Y-[DOTA-DPhe1, Thyr3]-octreotide shows a rapid blood clearance (T1/2 alpha < 5 min) and high accumulation in somatostatin subtype 2 receptor expressing tumours. The in vivo administration of 90Y-[DOTA-DPhe1, Thyr3]-octreotide induces a rapid tumour shrinkage in three different somatostatin receptor positive tumour models: CA20948 rat pancreatic tumours grown in normal rats, AR42J rat pancreatic tumours and NCI-H69 human small cell lung cancer both grown in nude mice. The radiotherapeutic efficacy of 90Y-SMT 487 was enhanced in combination with standard anticancer drugs, such as mitomycin C, which resulted in a tumour decrease of 70% of the initial volume. In the CA 20948 syngeneic rat tumour model, a single treatment with 10 microCi/kg 90Y-SMT 487 resulted in the disappearance of 5 out of 7 tumours. Thus the new radiotherapeutic agent showed its curative potential for the selective treatment of SRIF receptor-expression tumours. Clinical Phase I studies with 90Y-SMT 487 were started in September 1997.

Somatostatin exerts its actions through interaction with specific heptahelical G-protein coupled plasma membrane receptors. Five different somatostatin receptor subtypes have been cloned in man. Different receptor subtypes are coupled to different intracellular transmission cascades in a cell type-dependent manner. In general, somatostatin affects cell proliferation either directly: reducing mitogen-activated protein kinase cascade, activating phosphoproteinphosphatase, stimulating EGF-receptors and adenylate cyclase activity; or indirectly reducing the release of autocrine- and/or paracrine-acting growth factors. Somatostatin can exert cytotoxic (G1 phase cell arrest) or cytostatic (apoptosis induction) effects, also depending on the receptor subtype expressed on the target cell. In gastroenteropancreatic neuroendocrine tumours predominance of sst1 and sst2 with a lesser extent of sst3 and sst5 subtype receptors have been demonstrated using sensitive methods. Synthetic analogues with specific decreasing affinity for sst2 > sst5 > sst3 receptor subtypes have been used as antiproliferative drug in the treatment of gastroenteropancreatic tumours. These compounds (octreotide, lanreotide) resulted in a modest growth-inhibition activity either in functioning or in non-functioning tumours. Combination of somatostatin analogues with alpha-interferon produced a more pronounced antiproliferative effect overcoming therapy resistance developed to either single drug. Finally, the development of radio-labelled somatostatin analogue scintigraphy has contributed to gastroenteropancreatic-tumours lesion localization and future more detailed knowledge of somatostatin receptor mechanisms could improve both the diagnostic and therapeutic application of somatostatin analogues.

This article focuses on the classification of neuroendocine tumours with particular emphasis on pancreatic and gastrointestinal neoplasms.

Placing the endoscopic ultrasound transducer in the descending duodenum, the duodenal bulb and the stomach, all the pancreas can be imaged. Endoscopic ultrasonography is a sophisticated imaging technique able to accurately diagnose and localize primary endocrine tumours of the pancreas (mostly insulinoma and gastrinoma) which may not be detectable with other imaging modalities. Furthermore, endoscopic ultrasonography-guided fine needle aspiration allows cytology and/or biopsy specimens to be obtained, that are crucial for clinicians in decision making. In the case of extrapancreatic endocrine tumours, which are often localized in the second and third part of the duodenum, endoscopic ultrasonography may have difficulty in localizing small and flat lesions. In this case, the initial step would be identification of duodenal nodules by duodenoscopy and thereafter, a catheter echoprobe can be inserted to identify the extent of submucosal lesion. Then gastroduodenal nodules found by endoscopy and confirmed by endoscopic ultrasonography can be removed endoscopically using the technique of mucosectomy. In the case of large pancreatic lesions, endoscopic tattoo with dye-India ink or methylene blue may become helpful for the surgeon to perform local resection via duodenostomy.

Neuroendocrine tumours of the gastro-entero-pancreatic tract are an uncommon clinical entity and are believed to arise from the endocrine cells of the gastrointestinal tract. Somatostatin receptor imaging is a diagnostic tool which allows visualization of somatostatin receptor bearing tumours. This scintigraphic procedure is performed with indium-111 labelled octreotide, a somatostatin analogue, chelated with diethylene triamine penta-acetic acid. Radionuclide imaging consists in detecting the biodistribution of somatostatin receptors, normally expressed on the cell surface of neuroendocrine gastro-entero-pancreatic tumours. To date, five types of this receptor have been cloned: indium-111-labelled-pentetreotide can visualize tumours expressing type 2 and 5 receptors. The results of our study, which involved 81 neuroendocrine gastro-entero-pancreatic tumour patients, confirm the superior sensitivity of somatostatin receptor imaging (61%) for primary tumour evaluation with respect to conventional imaging modalities such as computed tomography (40%) or ultrasound (28%). Scintigraphic findings in metastatic liver disease proved to have a sensitivity of 89% for somatostatin receptor imaging, versus 81% and 88% for computed tomography and ultrasound, respectively. In 23% of patients, lesions were found with somatostatin receptor imaging which had been missed using the other diagnostic modalities; in 26% of the patients the therapeutic approach was modified after somatostatin receptor imaging.

The diagnosis of entero-neuropancreatic tumours different from Zollinger-Ellison syndrome and carcinoid syndrome require an high index of suspicion and even when they are associated to virulent syndromes such as VIPoma or insulinoma syndrome the mean delay in diagnosis is of 4 years. Symptomatic hypoglycaemia due to inappropriate insulin release from insulinoma and watery diarrhoea leading to dehydration caused by elevated circulant vaso-intestinal peptide levels are present in the 90% and 100% of the patients at presentation of the respective syndrome. Somatostatinoma syndrome has a far more subtle presentation and it tends to present much later during the disease course. The diagnosis is based on the presence of gallstones, diabetes, weight loss, diarrhoea and steatorrhoea. Growth hormone releasing factor neuroendocrine tumours (GRFoma) present with acromegaly and account for less than 2% of the acromegalic patients in which the growth hormone is from an ectopic source located in the pancreas. The Cushing's syndrome diagnosis due to rare ectopic neuroendocrine tumour adrenocorticotropic hormone secretion can be made only with selective angiography, whereas non-functional and pancreatic polypeptide producing neuroendocrine tumours (PPoma) present without any symptoms. Finally, multiple endocrine neoplasia type one occurs more commonly with somatostatinoma or GRFoma, conversely patients with multiple endocrine neoplasia type one can develop insulinoma (20%) or PPoma (60%).