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Purpose: Many different treatments are suggested by guidelines to treat grade 1−2 (G1−G2) neuroendocrine tumors (NET). However, a precise therapeutic algorithm has not yet been established. This study aims at identifying and comparing the main therapeutic sequences in G1−G2 NET. Methods: A retrospective observational Italian multicenter study was designed to collect data on therapeutic sequences in NET. Median progression-free survival (PFS) was compared between therapeutic sequences, as well as the number and grade of side effects and the rate of dose reduction/treatment discontinuation. Results: Among 1182 patients with neuroendocrine neoplasia included in the ELIOS database, 131 G1–G2 gastroenteropancreatic, lung and unknown primary NET, unresectable or persistent/relapsing after surgery, treated with ≥2 systemic treatments, were included. Four main therapeutic sequences were identified in 99 patients: (A) somatostatin analogs (SSA) standard dose to SSA high dose (n = 36), (B) SSA to everolimus (n = 31), (C) SSA to chemotherapy (n = 17), (D) SSA to peptide receptor radionuclide therapy (PRRT) (n = 15). Median PFS of the second-line treatment was not reached in sequence A, 33 months in sequence B, 20 months in sequence C, 30 months in sequence D (p = 0.16). Both total number and severity of side effects were significantly higher in sequences B and C than A and D (p = 0.04), as well as the rate of dose reduction/discontinuation (p = 0.03). Conclusions: SSA followed by SSA high dose, everolimus, chemotherapy or PRRT represent the main therapeutic sequences in G1−G2 NET. Median PFS was not significantly different between sequences. However, the sequences with SSA high dose or PRRT seem to be better tolerated than sequences with everolimus or chemotherapy. [ABSTRACT FROM AUTHOR]

Purpose: Thymic epithelial tumors (TETs) are rare tumors of the mediastinum, with an estimated incidence of about 3 cases per 100,000 inhabitants. Although anthracycline- and platinum-based chemotherapy is an active treatment for TETs, novel systemic therapeutic options are especially needed for metastatic disease, which is virtually incurable. On the basis of the radiographic response obtained with imatinib (Novartis Pharma, Basel, Switzerland) in a patient with thymic carcinoma harboring the V560del c-KIT mutation, a phase II trial was initiated at the Department of Molecular and Clinical Oncology and Endocrinology of University 'Federico II of Naples' with the purpose to test imatinib in TETs. Methods: Imatinib was daily delivered at the dose of 400 mg to patients affected by TETs, who had progressed after at least one chemotherapy regimen. Positivity of c-KIT on immunohistochemistry was not mandatory for study entry. Radiographic responses were measured by CT scans performed every 3 months, according to the RECIST criteria. Toxicity was graded according to the Common Toxicity Criteria of the National Cancer Institute, version 3.0. Results: Fifteen patients with advanced TETs were enrolled from March 2008 to May 2010. Three patients presented with thymic carcinomas. Two of these three patients presented c-kit expression on immunohistochemistry. No patient harbored a known c-kit activating mutation. Imatinib was very well tolerated, with no toxicity-related death. Diarrhea and migraine were the most frequent events, occurring both in 20% of patients, but were manageable and mild. No radiographic responses were recorded. Median progression-free survival was 3 months (interquartile range, 2.5-4). Median overall survival was not reached. The study was terminated before it reached its target accrual of 42 patients, because of the lack of responses and low accrual rate. Conclusions: This trial indicates the lack of effectiveness of imatinib in unselected patients with thymic epithelial tumors. Nevertheless, imatinib may represent a valuable option in selected patients with TETs, such as those harboring the V560del c-KIT mutation. [ABSTRACT FROM AUTHOR]

Advanced hepatocellular carcinoma (HCC) not eligible for local therapies has limited chances of cure. Sorafenib is a multikinase inhibitor with proven activity in advanced HCC. Octreotide is used in this setting with conflicting results. Treatment with sorafenib and long-acting octreotide was tested in advanced HCC to evaluate safety and activity. Fifty patients with advanced HCC, Child-Pugh A or B, received sorafenib at a dosage of 800 mg/day for 28 days with a following week of rest and long-acting octreotide at a dose of 40 mg, administered every 28 days. All patients were assessable for safety and efficacy. Sixteen patients out of 50 (34%) were naïve from other therapies, while all the others were previously treated with local and/or systemic treatments. We achieved 5 partial responses (10%), 33 stable diseases (66%) and 12 progressions of disease (24%). Median time to progression was 7.0 months (95% CI, 3.0–10.9 months), and median overall survival was 12 months (95% CI, 6.3–17.4 months). Treatment was well tolerated. Diarrhoea (6%) and hypertension (4%) were the most frequent grade 3 toxicities. Our data suggest that the combination between sorafenib and long-acting octreotide is active and well tolerated in patients with advanced HCC and could represent another efficacious chance for the management of this population. [ABSTRACT FROM AUTHOR]

The survival of patients with hepatocellular carcinoma (HCC) has improved with advancements in various diagnostic tools and treatment modalities. Consequently, bone metastases from HCC are diagnosed more frequently. The aims of the present study was to describe the clinical features and treatment of HCC patients presenting with bone metastases. In particular, we evaluated the role of zoledronic acid in these patients especially with regard to pain reduction, analgesic drug consumption and safety. Between December 2006 and July 2008, we recruited 17 (male:female, 12:5, median age, 68 years; age range, 62–85 years) consecutive patients. Spinal metastases were present in 11 patients (64.7%). Zoledronic acid was administered in all patients (total number of administrations, 107; mean number of administrations, 6.29). A total of 15 patients received at least three administrations of zoledronic acid and reported clinical benefit with pain reduction and tapering of analgesic drugs. Before starting treatment, the mean VAS for patients who received at least three administrations (15/17 patients) of zoledronic acid was 7.1 (±0.24), and after 3 months 5.3 (±0.20). This improvement was independent of the sex, the extent of metastasis and the concomitant anticancer treatment. No significant side effects were registered in this series of patients. Median survival was 10 months (CI 6,353–13,647). Zoledronic acid may be helpful in treating bone metastases in HCC patients. Patients regularly receiving zoledronic acid showed significant pain relief. [ABSTRACT FROM AUTHOR]

Langerhans cell histiocytosis (LCH) is a rare disease, probably an atypical myeloproliferative syndrome, with variable clinical presentation and behavior. In this report, we focus on bone involvement by LCH and treatment with zoledronic acid in six patients as they progressed after chemotherapy and radiotherapy. Zoledronic acid appeared safe and produced significant relief in pain. [ABSTRACT FROM AUTHOR]

Human melanoma cells are sensitive to the lytic activity of natural killer (NK) and lymphokine-activated killer (LAK) cells in vitro. The events resulting in tumour cell killing by lymphocytic effectors have not been completely clarified, and the same target cell determinants regulating responsiveness to immune cytolysis have not yet been identified. Indeed, changes in the differentiative status of leukemia cells as well as in the expression of major histocompatibility complex (MHC) antigens have been described to modulate sensitivity to cytotoxic effectors; moreover surface expression of adhesion factors or extracellular matrix proteins by the cancer cells can promote the activation of the cytolytic effectors and has been described to correlate with tumour cell sensitivity to cytolytic cells. We reasoned that treatment with differentiation inducers could modulate melanoma cell sensitivity to NK and LAK cells. The present study demonstrates that human melanoma GLL-19 cells, when treated with the phorbol diester phorbol 12-myristate 13-acetate (PMA) in vitro, undergo growth inhibition and neuron-like differentiation. Moreover PMA treatment induces an evident inhibition of GLL-19 cell sensitivity to NK- and LAK-mediated cytotoxicity. GLL-19 cells express constitutively MHC class I antigens. PMA treatment, however, does not modify the expression of MHC class I and class II DR antigens in human melanoma GLL-19 cells. We have finally evaluated the effects of PMA on the expression at the cell surface of adhesion factors such as ICAM-1, and extracellular matrix proteins such as collagen IV, laminin and fibronectin; we have also studied the expression of the integrin vitronectin receptor, a membrane receptor for adhesive proteins. While adhesion factors and extracellular matrix proteins appear to play an important role in the interaction between immune effector and tumour target, it can be supposed that the modulation of such membrane-associated proteins or glycoproteins induces NK and LAK resistance in cancer cells. We indeed found that PMA treatment induced in GLL-19 a marked reduction of membrane expression of collagen IV and ICAM-1; moreover PMA reduced the cell membrane expression of the integrin vitronectin receptor. On the other hand, membrane expression of fibronectin and laminin was not affected by PMA. These data indicate that the acquisition of a NK- and LAK-resistant phenotype by GLL-19 cells occurs together with cell differentiation, down-regulation of membrane expression of collagen IV, ICAM-1 and vitronectin receptor, but in the absence of changes in MHC antigens. [ABSTRACT FROM AUTHOR]

A total of 72 patients with metastatic stage IV non-small-cell lung cancer (NSCLC) were treated with combination chemotherapy comprising the MEV regimen (mitomycin C, 8 mg/m2 given i.v. on day 1; etoposide, 100 mg/m2 given i.v. on days 1-3; and vindesine, 3 mg/m2 given i.v. on day 1; treatment repeated every 3 weeks). In 65 evaluable patients, the objective response rate was 37% (complete responses, 4.7%; partial responses, 32.3%). The median survival was 7.6 months for all patients. The treatment was very well tolerated. MEV proved to be an active and non-toxic regimen for the treatment of metastatic NSCLC. [ABSTRACT FROM AUTHOR]

Background: Patients with advanced or recurrent thymic epithelial tumors (TETs) often need several consecutive lines of chemotherapy. The aim of this retrospective monocentric study was to test whether 18 F-Fluorodeoxyglucose positron emission tomography-computed tomography ( 18 F-FDG PET-CT) is able to monitor standard chemotherapy efficacy in those patients and whether metabolic response correlates with morphovolumetric response as assessed by Response Evaluation Criteria in Solid Tumor (RECIST)., Methods: We evaluated 27 consecutive patients with advanced (16 patients) or recurrent (11 patients) TETs. All patients underwent 18 F-FDG PET-CT before and after at least 3 cycles of chemotherapy. Maximum standardized uptake value (SUV max ) of all detected lesions was recorded and the most 18 F-FDG avid lesion in each patient was selected for determination of percentage change of SUV max (ΔSUV max ) in pre- and post-treatment scans. Tumor response was assessed by contrast-enhanced computed tomography (CE-CT) using RECIST criteria. Receiver operating characteristic (ROC) curve analysis was performed to define the optimal threshold of ΔSUV max discriminating responders from non-responders., Results: Metabolic response expressed as ΔSUV max was significantly correlated with morphovolumetric response (Spearman's rank correlation, r = 0.64, p = 0.001). ROC curve analysis showed that a ΔSUV max value of -25% could discriminate responders from non-responders with a sensitivity of 88% and a specificity of 80%. Conversely, basal SUV max values were not predictive of morphovolumetric tumor response., Conclusions: Our findings indicate that metabolic response assessed by 18 F-FDG PET-CT, through evaluation of ΔSUV max , may allow identification of responders and non-responders thus guiding adaptation of therapy in patients with advanced or recurrent TETs.