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Gastroenteropancreatic neuroendocrine tumors (NETs) are a relatively rare group of heterogeneous neoplasms. The most significant advance in therapy of NETs has been the advent of the somatostatin analog octreotide, which represents a cornerstone in their management and dramatically changed the therapeutic landscape. Octreotide long-acting release (LAR) was developed to overcome some of the limitations of octreotide. Several clinical studies, including PROMID and RADIANT-2, have validated the clinical benefits of octreotide LAR in NETs, with tumor shrinkage in about 10% of patients and tumor stabilization in roughly half of cases. While the use of octreotide LAR is well-consolidated in NETs, some open questions remain. These include the use of high-dose octreotide LAR, as there is evidence that higher dose may provide longer disease control, and nonstandard treatment schedules, with administration every 21 days instead of 28 days, as well as their use in combination with targeted agents or peptide receptor radiotherapy in clinical practice. After 3 decades of clinical experience with octreotide LAR, the drug has a well-established safety profile. It is well-tolerated and treatment discontinuations due to adverse events are uncommon. One exception is cholelithiasis, which may increase with longer duration of treatment. According to the literature data, octreotide LAR is currently recommended in both functioning and nonfunctioning advanced NETs. This review summarizes the available clinical data with octreotide LAR and also provides future perspectives on its possible uses in patients with NETs.

Abnormal PI3K-AKT-mTOR pathway signalling and autocrine activation of the mTOR pathway, mediated through insulin-like growth factor-1, have been implicated in the proliferation of pancreatic neuroendocrine tumor (pNET) cells. Everolimus, an mTOR inhibitor, has shown antitumor benefit in pNETs alone and in combination with octreotide LAR in RADIANT-1 and RADIANT-3 studies. Although everolimus-based phase II/III trials have improved progression-free survival for pNET, its use has not impacted on prolonging overall survival. Metformin has recently shown some anti-cancer activity in both in vitro and in vivo studies by its indirect properties to decrease insulin and insulin-like growth factor-1 (IGF-1) levels and by its antitumour effect to promote AMPK activation and consequently inhibition to TSC1–2/mTOR complex. In light of even more retrospective evidence of metformin's anticancer activity, a prospective evaluation is required to either confirm or discard these preliminary findings. With the aim to evaluate the antiproliferative effect of metformin in combination with everolimus and octreotide LAR in pancreatic well-differentiated neuroendocrine tumor patients, a single arm, prospective, single center phase II study was designed (MetNET-1 trial, NCT 02294006). Forty-three patients are expected to be evaluated. The study is ongoing, and recruitment is estimated to be completed in August 2016. The results will be anticipated in 2017.

From 1970 to 1980, 171 consecutive cases with non-Hodgkin's lymphomas (NHL) of Waldeyer's ring were admitted to this Institute. The cases were reviewed to evaluate whether involvement of Waldeyer's ring might represent a distinct clinicopathologic entity. Adequate pathologic staging was performed in 86% of cases. All slides were reviewed, and the histologic diagnosis given according to the Rappaport classification, the Kiel classification, and the recent Working Formulation of NHL for Clinical Usage. Waldeyer's ring alone was involved in 12.3% of the cases at presentation; regional nodes were positive in one-third (35.7%), and distant involvement was detected in half of the patients (52%). The tonsils represented the most frequent site of involvement by NHL within Waldeyer's ring. Treatments employed were heterogeneous, but most of the patients with stage I-II received radiotherapy alone. The present series shows that the association of involvement of Waldeyer's ring and the stomach by NHL occurs in less than 10% of the cases. Treatment results and patterns of recurrence fail to differentiate NHL involving Waldeyer's ring from those of other sites. Prognosis remains related to the classical variables and is independent of the site of onset.

The medical records of women taking part in the first 2 prospective adjuvant CMF (cyclophosphamide, methotrexate, fluorouracil) programs were reviewed to evaluate the incidence of liver damage which could be attributable to prolonged methotrexate administration. In 802 evaluable patients abnormal liver studies occurred in 7 of 170 controls (4.1 %) and 20 of 632 CMF-treated patients (3.2 %). In 22 of 27 patients they were reversible, while the persistence of enzyme abnormalities in 2 patients treated with 12 CMF cycles was followed by the occurrence of viral hepatitis and osseous metastases, respectively. Adjuvant CMF was never discontinued in the presence of liver function abnormalities. In 22 women liver biopsies through laparoscopy were performed for various diagnostic purposes. They yielded an incidence of aspecific histologic changes (fatty metamorphosis, subcapsular fibrosis) which was similar between controls and CMF-treated patients. Present analysis failed to demonstrate a higher incidence of acute and/or chronic liver changes in patients treated with cyclical CMF compared to controls treated with surgery alone.