Appetecchia and Baldelli Journal of Experimental & Clinical Cancer Research 2010, 29:19 http://www.jeccr.com/content/29/1/19 Page 6 of 12 lengthened time to tumour progression compared with placebo in patients with functionally active and inactive metastatic midgut NETs [80]. Midgut carcinoids express somatostatin receptors in 80 to 100% of cases. SSTR 2 is the most frequently expressed [34]. The antiproliferative effect of somatosta- tin analogues on the growth of the midgut carcinoids is unknown. A partial or complete responses were observed in less than 10% of the patients, while stabilisa- tion of tumour growth was noticed in 24-57% of the patients [6]. Few data are available regarding the role of somatosta- tin analogues in the treatment of gastrinomas. In a study of 15 malignant gastrinoma, in about 50% of these patients, octreotide had an antiproliferative effect, including one patient with tumour regression and seven patients with tumour stabilisation [mean period 25 months] patients [81]. The long-acting somatostatin analogue octreotide-LAR was administered in a patient with multiple type A gas- tric carcinoids for a period of 9 months with a normali- sation of serum gastrin levels and permanent disappearance of the tumour [82]. Fykse et al. treated five patients with hypergastrinaemia and gastric carci- noids for a period of 1 year with monthly injections of octreotide-LAR with a significant reduction in tumour load, ECL cell density and normalisation of circulating chromogranin A levels, indicating a possible direct anti- proliferative effect of the treatment [83]. These results suggest that the somatostatin analogues could have an important antiproliferative effect. However, data on the effect of somatostatin analogues on tumour growth in patients with gastric carcinoids type C or poorly differ- entiated endocrine carcinomas are scanty. In poorly dif- ferentiated gastric carcinomas, treatment with somatostatin analogs is not considered. As surgical excision is the definitive treatment of insu- linoma, there are few contrasting data in the literature regarding the inhibitory effect of the somatostatin analo- gues on the growth of these tumours. Grozinsky-Glas- berg et al have conducted a study regarding the effects of somatostatin analogues on cell proliferation in the rat-derived insulinoma cell line (INS1). Their prelimin- ary data show that octreotide has a significant inhibitory effect on cell proliferation, as assessed by cell counting and MTS assay, and on phosphorylation states of a number of proteins in the PI3K/Akt/mTOR pathway [84,85]. In his work, Vezzosi founded that despite achieving hypoglycaemic control, insulinoma size remained unchanged or increased moderately despite normal blood glucose levels, concluding that somatosta- tin analogues, as medical treatment is not sufficient to prevent tumour growth in patients with malignant insu- linomas [36]. In 2006, Romeo et al reported a complete clinical remission with regression of the metastatic lesions in the liver after one year in a patient affected by meta- static insulinoma with severe hypoglycaemia treated with octreotide LAR [85].A more controversial area con- cerns the treatment of patients with non-functioning endocrine tumours of the pancreas as few studies have been published in these patients. The prospective Ger- man Sandostatin multicentre phase II trial investigated the effects of octreotide for one year on tumour growth in 103 patients and included 15 patients with diagnosed non-functional pancreatic tumours [74]. Only 3 out of these 15 patients had a stable disease, in 8 patients a tumour progression occurred while the outcome of the remaining four patients was not clear. As previously said, the SST analogue efficacy depends on the tumour receptor expression patterns, but these are rarely assessed, even if there is evidence of better results on survival obtained with selective treatments. An antiproli- ferative effect was achieved on hepatic metastatic cells in a patient with a carcinoid tumour, selected for the treatment with SST analogues after the immunohisto- chemical identification of the SSTR 1, 2 and 5 subtypes expression on the neoplastic cell surface [86]. A com- plete clinical remission with regression of the metastatic lesions in the liver after one year of treatment was observed in a patient affected by metastatic insulinoma with severe hypoglycaemia treated with octreotide LAR expressing at immunohistochemical analysis of tissue specimens a strong membrane immunoreactivity for SSTR 2 in both the primary nodule and the metastases [85]. However, another study showed neither an anti- neoplastic effect nor an increase in survival percentage of treated patients [87]. It has been reported that in glucagonoma patients there are no data available on their SSTR expression patterns [45]. In 2006 we demonstrated, for the first time, a scattered immunopositivity for somatostatin receptors in a case of malignant glucagonoma.We had access to polyclonal antibodies specifically targeted against SSTR5 and SSTR2 and we were therefore able to localise these two receptors in our histological sec- tions. The immunopositivity was detected for both receptor subtypes in the membrane and in the cyto- plasm of glucagonoma cells. We then treated our patient with a combination therapy consisting of the somatosta- tin analogue octreotide and interferon-a. The patient had a complete resolution of skin rash, normalisation of plasma glucagon, chromogranin A and neuron specific enolase levels, and metastatic disease stabilisation. The patient’s quality of life significantly improved, and she was alive 40 months after debulking surgery [46]. In conclusion, in many cases authors did not stratify patients in treatment arms, according to the histological