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// Alessandro Ottaiano 1, * , Valerio Scotti 2, * , Chiara De Divitiis 3 , Monica Capozzi 3 , Carmen Romano 3 , Antonino Cassata 3 , Rossana Casaretti 3 , Lucrezia Silvestro 3 , Anna Nappi 3 , Valeria Vicario 3 , Alfonso De Stefano 3 , Salvatore Tafuto 3 , Massimiliano Berretta 4 , Guglielmo Nasti 1 and Antonio Avallone 3 1 Department of Abdominal Oncology, SSD–Innovative Therapies for Abdominal Metastases, Istituto Nazionale Tumori di Napoli G. Pascale IRCCS, National Cancer Institute, 80131, Naples, Italy 2 San Rossore Clinic, Viale delle Cascine, 56122, Pisa, Italy 3 Department of Abdominal Oncology, Experimental Clinical Oncology, Istituto Nazionale Tumori di Napoli G. Pascale IRCCS, National Cancer Institute, 80131, Naples, Italy 4 Department of Medical Oncology, CRO Aviano, National Cancer Institute, 33081, Aviano, Italy * These authors have contributed equally to this work Correspondence to: Guglielmo Nasti, email: g.nasti@istitutotumori.na.it , ale.otto@libero.it Keywords: colorectal cancer; radiation therapy; chemotherapy; metastatic colorectal cancer Received: April 26, 2018 Accepted: June 23, 2018 Published: October 16, 2018 ABSTRACT Background: There are very few clinical or prognostic studies on the role of SRT (Stereotactic Radiation Therapy) in the continuum of care of metastatic colorectal cancer (mCRC) patients. Patients and methods: Patients affected by oligo-mCRC were treated with SRT before or after front-line standard treatments. SRT was delivered according to a risk-adapted protocol. Total body CT (Computed Tomography) scan was done before therapy and every three months thereafter. The radiologic responses to therapy were evaluated by RECIST (Response Evaluation Criteria In Solid Tumors). FDG-PET (FluoroDeoxyGlucose - Positron Emission Tomography) was done before and after SRT; metabolic responses were evaluated by using the EORTC (European Organization for Research and Treatment of Cancer) criteria. The Kaplan-Meier product limit method was applied to graph Overall Survival (OS) and Progression-Free Survival (PFS). Results: Forty-seven patients were included. Twenty-one patients had disease limited to lungs, 9 to lung and liver, 7 only to liver, 10 to multiple sites. The median prescription SRT dose was 60 Gy per organ in 3 fractions (median biological effective dose of 180 Gy). The reduction of delta SUVmax (maximum Standardized Uptake Value) correlated with the local control (p

Aim The purpose of the present multicentric study was to review stereotactic body radiotherapy (SBRT) with or without chemotherapy (CHT) experience in locally advanced pancreatic cancer (LAPC). Endpoints were overall survival (OS), local control (LC), and distant metastasis-free survival (DMFS). Several parameters' impact on these outcomes was assessed. Materials and methods Fifty-six patients with LAPC undergoing SBRT+/-CHT were included. SBRT median BEDα/β10Gy was 48.0 Gy (range=28.0-78.7). Survival curves were calculated by Kaplan-Meier method. A Cox regression model was fitted. Results At a median follow-up of 15.0 months, 2-year OS, LC, DMFS were: 33.8% 55.4%, and 22.9%, respectively. Patients treated with BEDα/β10Gy≥48 Gy showed improved OS (p=0.020) and LC (p=0.024). At multivariate analysis, BEDα/β10Gy≥48 Gy was significantly associated to both higher OS (p=0.042) and LC (p=0.045), while post-SBRT CHT improved DMFS (p=0.003). Conclusion SBRT proved to be tolerable and effective in LAPC. Moreover, BEDα/β10Gy≥48 Gy was significantly correlated with improved OS and LC.

The present study aims to assess the feasibility and the effectiveness of a second-line Fotemustine chemotherapy in patients with recurrent Glioblastoma after standard primary treatment. Between 2005 and 2007, 50 patients with relapsed malignant glioma (median age = 56.8 years; median KPS = 90) underwent a second-line chemotherapy with Fotemustine. Selected patients were previously treated with a standard 60 Gy Radiotherapy course and Temozolomide Chemotherapy. Patients were stratified into classes according to the prognostic Recursive Partition Analysis. Endpoints of the study were Progression Free Survival at 6 months, duration of Objective Response and Stabilization, Overall Survival and toxicity. At analysis, 36 patients were dead and 14 were alive. Median follow-up from primary diagnosis was 26.6 months. The Efficacy control of the disease was 62%. PFS was 6.1 months; PFS-6 was 52% and median overall survival from primary diagnosis was 24.5 months, with few manageable haematological toxicities. Fotemustine was safe and effective as second-line chemotherapy in recurrent glioblastoma.

Diffuse malignant pleural mesothelioma (MPM) is an aggressive tumor that originates from the surface of the pleura. Approximately 70% of cases are associated with chronic asbestos exposure. MPM is regarded as an incurable disease, with a median survival of similar to 2 years following intensive multimodality treatment. Pancreatic cancer is a malignancy also associated with a poor prognosis, with only 2% of patients surviving for 5 years. The majority of patients with pancreatic cancer are diagnosed with an advanced stage of disease and experience a poor response to therapy. The development of synchronous MPM and other types of cancer is rare. The present study describes a patient with synchronous, biphasic MPM and pancreatic adenocarcinoma, who was treated with a multimodal therapeutic approach with stereotactic body radiation therapy. Due to a suspected diagnosis of 'acute abdomen', an emergency small intestine resection was performed and a. subsequent diagnosis of moderately-differentiated adenocarcinoma was confirmed. During a further immunohistochemical examination, pathologists determined that the small bowel metastasis descended from pancreatic cancer. The onset of bowel metastasis is an event rarely associated with MPM, and has not been previously described in the literature for cases of pancreatic cancer. Therefore, to the best of our knowledge, the present study describes the first case of intestinal metastasis from pancreatic cancer in a long-term survival patient with biphasic MPM.

Radiotherapy is one of the most effective therapeutic strategies for breast cancer patients, although its efficacy may be reduced by intrinsic radiation resistance of cancer cells. Recent investigations demonstrate a link between cancer cell radio-resistance and activation of sphingosine kinase (SphK1), which plays a key role in the balance of lipid signaling molecules. Sphingosine kinase (SphK1) activity can alter the sphingosine-1-phosphate (S1P)/ceramide ratio leading to an imbalance in the sphingolipid rheostat. Fingolimod (FTY720) is a novel sphingosine analog and a potent immunosuppressive drug that acts as a SphK1 antagonist, inhibits the growth, and induces apoptosis in different human cancer cell lines. We sought to investigate the in vitro radiosensitizing effects of FTY720 on the MDA-MB-361 breast cancer cell line and to assess the effects elicited by radiation and FTY720 combined treatments. We found that FTY720 significantly increased anti-proliferative and pro-apoptotic effects induced by a single dose of ionizing radiation while causing autophagosome accumulation. At the molecular level, FTY720 significantly potentiated radiation effects on perturbation of signaling pathways involved in regulation of cell cycle and apoptosis, such as PI3K/AKT and MAPK. In conclusion, our data highlight a potent radiosensitizing effect of FTY720 on breast cancer cells and provide the basis of novel therapeutic strategies for breast cancer treatment.

Malignant glioma is a primary tumor of the central nervous system, representing a major cause of mortality in a young, productive subset of population. The management of this neoplasm requires aggressive treatments, including radiotherapy. Accurate imaging plays a central role in treatment planning process with curative intent based on radiation therapy. In order to maximize the radiation dose to the tumor and to minimize the damage to the normal surrounding tissue, a reliable identification of viable tumor margins is indeed required. The use of PET in the treatment planning process has become more promising over the years, although many important questions must be addressed. The aim of this article is to critically review the evidence supporting PET in radiotherapy planning, with special emphasis on the role of novel radiopharmaceuticals, comparing its sensitivity and specificity with respect to 18F-FDG and other anatomic imaging modalities.

The treatment of hepatitis C has dramatically improved over the last decade. The association between pegylated interferon and ribavirin is the first-line gold standard but it has some limitations: (i) a limited efficacy in patients with hepatitis C virus (HCV) genotype 1 and (ii) an unfavorable side effect profile. Development of new therapeutic approaches is warranted (Manns et al., 2006). Generally, the treatment of chronic HCV infection is focuses (i) to achieve sustained eradication of HCV [sustained virologic response (SVR): persistent absence of HCV RNA in serum 6 months or more after completing antiviral treatment] and (ii) to prevent progression to cirrhosis and hepatocellular carcinoma (HCC). Currently, the most promising drugs against HCV infection (genotype 1) are protease inhibitors. They are peptidomimetic inhibitors of the HCV non-structural (NS) 3/4A serine protease. NS3 protease plays an important role in the HCV life-cycle by causing cleavage of HCV polyprotein at the NS3-NS4A and other downstream junctions (Tomei et al., 1993; Romano et al., 2012). Telaprevir and boceprevir were approved by the Food and Drug Administration (FDA) in May 2011 for the treatment of HCV genotype 1 in combination with peginterferon and ribavirin (triple therapy) in adult patients with compensated liver disease, including cirrhosis, who have not been treated before or who have failed a previous treatment (Asselah, 2012; Popescu et al., 2012). In Italy, telaprevir and boceprevir were approved in December 2012 after a complicated prescriptive pathway (definition of the AIFA—Agenzia Italiana del FArmaco—register for the intensive monitoring, identification of authorized centers for prescription, definition of dispensing modalities). The first prescriptions of telaprevir and boceprevir in the Local Sanitary Agency (LSA) Naples 3 South Italy (i.e., LSA, NA 3 South, 1.200.000 inhabitants, Campania Region) were done in March 2013. Currently (June 2013), patients treated with the protease inhibitors are 87: 58 with telaprevir (51 naive and 7 null responders) and 29 with boceprevir (24 naive and 5 null responders). During the observed 4 months, 8 treatment interruptions have occurred, all with telaprevir. Reasons for interruption were: 2 cases of severe anemia, 1 case of severe allergy with rush. Five patients were lost at follow-up. No interruption occurred among patients receiving boceprevir. This first survey of pharmacoutilization clearly shows that telaprevir is more frequently prescribed than boceprevir. Probably, this is due to different therapy protocols. In fact telaprevir is indicated in triple therapy for the first 12 weeks followed by a dual therapy (only with peginterferon and ribavirin) for 36 weeks. Boceprevir is started after 4 weeks of a dual therapy with peginterferon alfa and ribavirin. The combination therapy (boceprevir, peginterferon and ribavirin) is administered for 24 weeks if the virus is undetectable at week 8 and 24 or for 44 weeks if the virus is detectable at week 8 but undetectable at week 24. Both drugs achieve similar SVR rates but treatment strategies are completely different. The therapy with telaprevir appears easier and faster. In this first 4 months, the total pharmaceutical spending to acquire protease inhibitors for 87 patients was approximately € 1.700.000. In particular, € 1.350.000 were spent for telaprevir and € 350.000 for boceprevir. The choice on a specific protease inhibitor should weigh several factors including the treatment strategy, the duration of therapy, the likelihood of achieving a SVR, the safety profile and the costs (Esteban and Buti, 2012). We are really concerned about the high cost of the therapy with protease inhibitors. In our series we observed that among patients who interrupted the treatment 1 was male and 7 female; this could suggest that gender could be associated with treatment compliance. However, we cannot rule out any conclusion and studies on large series are warranted to find predictive factors for response to protease inhibitors in HCV.

Interaction between different transmitter receptor systems is an emerging feature of neurotransmission at central synapses. G protein-coupled receptors' ability to form dimers or larger hetero-oligomers probably serves to facilitate the integration of diverse signals within the cell. We found that, in nerve terminals isolated from the cerebral cortices of rats, co-application of the GABAB agonist, baclofen, and of the non-selective mGlu agonist, L-CCG-I, potentiates the basal and depolarization-evoked release of [(3)H]GABA via a mechanism that involves mobilization of intracellular Ca(2+) ions. The effect of L-CCG-I + baclofen was abolished by the phospholipase C inhibitor U73122, reduced by Xestospongin C (an IP3 receptor blocker), and blocked by 2-APB, an IP3 receptor antagonist. Pretreatment of the synaptosomes with the lipid-soluble Ca(2+) chelator BAPTA-AM also inhibited the effects of L-CCG-I + baclofen. Subtype-selective non-competitive group I mGlu receptor antagonists, MPEP and CPCCOEt, had no effect on the release enhancement produced by baclofen + L-CCG-I. The enhancement was reversed by the GABAB receptor antagonist, CGP54626, and by the group I/group II mGlu receptor antagonist (R,S)-MCPG. The GABA release-enhancing effects of L-CCG-I + baclofen in our model might reflect the presence on cortical nerve endings of GABAB/group I mGlu receptor heteromers with pharmacological properties distinct from those of the component receptors. Activation of these heteromeric receptors might modify the function of the GABAB receptor in such a way that it facilitates GABAergic transmission, an effect that might be useful under conditions of excessive glutamatergic activity.

The aims of radiotherapeutic treatment of brain metastases include maintaining neurocognitive function and improvement of survival. Based on these premises, we present a case report in which the role of repeat stereotactic radiosurgery (SRS) was investigated in a patient with a recurrent brain metastasis from non-small cell lung cancer in the same area as previously treated with radiosurgery. A 40-year-old male caucasian patient was diagnosed with brain metastasis from non-small cell lung cancer (NSCLC) and underwent SRS. The patient developed a recurrence of the disease and a second SRS on the same area was performed. After 8 months, tumor restaging demonstrated a lesion compatible with a recurrence and the patient underwent surgery. Histological diagnosis following surgery revealed only the occurrence of radionecrosis. Radiotherapy was well-tolerated and no grade 3/4 neurological toxicity occurred. To date, no consensus exists on the efficacy of retreatment with SRS. Despite the limited number of studies in this field, in the present case report, we outline the outcomes of this unconventional approach.