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Background: The present study investigated the efficacy and safety of nivolumab in pre-treated patients with advanced NSCLC harbouring KRAS mutations.Methods: Clinical data and KRAS mutational status were analysed in patients treated with nivolumab within the Italian Expanded Access Program. Objective response rate, progression-free survival and overall survival were evaluated. Patients were monitored for adverse events using the National Cancer Institute Common Terminology Criteria for Adverse Events.Results: Among 530 patients evaluated for KRAS mutations, 206 (39%) were positive while 324 (61%) were KRAS wild-type mutations. KRAS status did not influence nivolumab efficacy in terms of ORR (20% vs 17%, P = 0.39) and DCR (47% vs 41%, P = 0.23). The median PFS and OS were 4 vs 3 months (P = 0.5) and 11.2 vs 10 months (P = 0.8) in the KRAS-positive vs the KRAS-negative group. The 3-months PFS rate was significantly higher in the KRAS-positive group as compared to the KRAS-negative group (53% vs 42%, P = 0.01). The percentage of any grade and grade 3-4 AEs were 45% vs 33% (P = 0.003) and 11% vs 6% (P = 0.03) in KRAS-positive and KRAS-negative groups, respectively.Conclusions: Nivolumab is an effective and safe treatment option for patients with previously treated, advanced non-squamous NSCLC regardless of KRAS mutations. [ABSTRACT FROM AUTHOR]

Background: The treatment of refractory metastatic colorectal cancer (rmCRC) and the lack of predictive variables are matters of debate.Patients and methods: We conducted a multicentre phase II trial assessing the disease control rate (DCR) of the combination of tegafur/uracil and mitomycin C in rmCRC. The number of previous lines of chemotherapy, carcinoembryonic antigen (CEA) levels, progression-free survival of the last chemotherapy regimen (PPFS), and the neutrophil/lymphocyte ratio (NLR) and platelet/lymphocyte ratio at the time of study entry were evaluated as indicators of early progression.Results: We enrolled 42 patients. The combination was well tolerated with a DCR of 26.2% and median overall survival of 6.9 months. Low CEA levels, PPFS >6 months and low NLR were significantly associated with better prognosis.Conclusion: The study failed its primary endpoint. However, some putative indicators of early progressive patients have been described. [ABSTRACT FROM AUTHOR]

From the thymus to the peripheral lymph nodes, integrin-mediated interactions with neighbor cells and the extracellular matrix tune T cell behavior by organizing cytoskeletal remodeling and modulating receptor signaling. LFA-1 (αLβ2 integrin) and VLA-4 (α4β1 integrin) play a key role throughout the T cell lifecycle from thymocyte differentiation to lymphocyte extravasation and finally play a fundamental role in organizing immune synapse, providing an essential costimulatory signal for the T cell receptor. Apart from tuning T cell signaling, integrins also contribute to homing to specific target organs as exemplified by the importance of α4β7 in maintaining the gut immune system. However, apart from those well-characterized examples, the physiological significance of the other integrin dimers expressed by T cells is far less understood. Thus, integrin-mediated cell-to-cell and cell-to-matrix interactions during the T cell lifespan still represent an open field of research. [ABSTRACT FROM AUTHOR]

Purpose: Non-small cell lung cancer (NSCLC) is a condition with significant clinical burden for patients and relevant economic impact. Limited evidence exists on the management costs of NSCLC patients, especially in the late phases of the disease. The main objective of this analysis was to evaluate the economic impact of clinical management of NSCLC patients in the Italian population. Methods: This evaluation was an economic analysis of the observational and multicentre study LIFE, which described the therapeutic approach in routine clinical practice for NSCLC patients, progressing after first-line treatment. This study evaluated resource consumption in different Italian hospitals, including specialist visits, hospitalizations, accesses to first aid, pharmacological treatment, laboratory tests and palliative care. The National Healthcare Service perspective was adopted. Results: In this study, N = 191 patients enrolled in the LIFE study were included. Patients were aged 64.2 years and were predominantly males (66%). In the different line of treatments, monthly costs of patients ranged between €1471 (first line) and €1788 (third line). The overall healthcare cost over the average period of observation (16.4 months) was €25,859 per patient. Overall, oncology therapy was the cost driver, although the composition of medical costs changed across the different lines of treatment, with costs for concomitant medication and palliative care being predominant in late phase of the disease. Conclusions: The economic burden of NSCLC is extremely high during the overall period of treatment, and a significant level of care is required in each stage of the disease. [ABSTRACT FROM AUTHOR]

Cetuximab improves efficacy when added to chemotherapy for metastatic colorectal cancer ( mCRC). Effective management of skin reactions from cetuximab improves quality of life (QoL), and treatment compliance in clinical trials. No data are available from real-world settings. The ObservEr observational, multicenter, prospective study evaluated QoL, the incidence of skin reactions, and management of chemotherapy plus cetuximab in first-line for mCRC. The primary endpoint was QoL measured with the Dermatology Life Quality Index ( DLQI) and EORTC QLQ-C30. Secondary endpoints were the incidence of skin and serious adverse events, median overall and progression-free survival, tumor response, and resection rates. Between May 2011 and November 2012, 228 patients with KRASwt mCRC were enrolled at 28 Italian centers, 225 evaluable, median age 65 years. QoL did not change during treatment and was not affected by the choice of prophylactic or reactive skin management. The incidence of cetuximab-specific grade ≥3 skin reactions was 14%, with no grade 4/5 events. Skin reactions correlated with survival ( P = 0.016), and their incidence was influenced by chemotherapy regimen (oxaliplatin vs. irinotecan-Incidence rate ratio [ IRR] 1.72, P < 0.0001) and gender (male vs. female- IRR 1.38, P = 0.0008). Compliance at first postbaseline evaluation was 97.75%. Median overall survival was 23.6 months, median progression-free survival 8.3 months. Cetuximab plus chemotherapy did not compromise QoL in the routine clinical setting when patients receive close monitoring plus prophylactic or reactive management of skin reactions. We observed the same correlation between overall survival ( OS) and skin reactions reported in controlled clinical trials, also in this setting. [ABSTRACT FROM AUTHOR]

Thyroid cancer is the most common cancer of the endocrine system and is responsible for the majority of deaths from endocrine malignancies. Although a large proportion of thyroid cancers belong to well differentiated histologic subtypes, which in general show a good prognosis after surgery and radioiodine ablation, the treatment of radio-resistant papillarytype, of undifferentiated anaplastic, and of medullary-type thyroid cancers remains unsatisfactory. Autophagy is a vesicular process for the lysosomal degradation of protein aggregates and of damaged or redundant organelles. Autophagy plays an important role in cell homeostasis, and there is evidence that this process is dysregulated in cancer cells. Recent in vitro preclinical studies have indicated that autophagy is involved in the cytotoxic response to chemotherapeutics in thyroid cancer cells. Indeed, several oncogenes and oncosuppressor genes implicated in thyroid carcinogenesis also play a role in the regulation of autophagy. In addition, some epigenetic modulators involved in thyroid carcinogenesis also influence autophagy. In this review, we highlight the genetic and epigenetic factors that mechanistically link thyroid carcinogenesis and autophagy, thus substantiating the rationale for an autophagy-targeted therapy of aggressive and radio-chemo-resistant thyroid cancers. [ABSTRACT FROM AUTHOR]

Autophagy is dysregulated in cancer and might be involved in ovarian carcinogenesis. BECLIN-1, a protein that interacts with either BCL-2 or PI3k class III, plays a critical role in the regulation of both autophagy and cell death. Induction of autophagy is associated with the presence of vacuoles characteristically labelled with the protein LC3.We have studied the biological and clinical significance of BECLIN 1 and LC3 in ovary tumours of different histological types. The positive expression of BECLIN 1 was well correlated with the presence of LC3-positive autophagic vacuoles and was inversely correlated with the expression of BCL-2. The latter inhibits the autophagy function of BECLIN 1.We found that type I tumours, which are less aggressive than type II, were more frequently expressing high level of BECLIN 1. Of note, tumours of histologic grade III expressed lowlevel of BECLIN 1. Consistently, high level of expression of BECLIN1 and LC3 in tumours is well correlated with the overall survival of the patients. The present data are compatible with the hypotheses that a low level of autophagy favours cancer progression and that ovary cancer with upregulated autophagy has a less aggressive behaviour and is more responsive to chemotherapy. [ABSTRACT FROM AUTHOR]

Venous thromboembolism (VTE) is the leading cause of mortality and morbidity in patients with cancer. The estimated risk of VTE in cancer patients is 0.5% per year and 0.04% per month. In small cell lung cancer and non-small cell lung cancer (NSCLC) the cumulative incidence is 3% per year and it seems to be associated with advanced stage and histotype. We performed a retrospective analysis on data from all NSCLC treated at the Oncology Day Hospital in Novara, Italy, northern Italy, to assess the incidence of thromboembolic events in patients undergoing systemic cancer treatments. All patients diagnosed with NSCLC who were treated at the Oncology Day Hospital in Novara from January 2008 to May 2011 have been assessed. Many variables related to VTE were analyzed: age, gender, different NSCLC histotype, Eastern Cooperative Oncology Group (ECOG) performance status, body mass index, stage of disease, treatment and chemotherapy regimen, development of a VTE event and its temporal correlation with chemotherapy, central venous catheter presence, use of erythropoietin, use of low molecular weight heparin at baseline, use of acetyl salicylic acid. A total of 355 patients were evaluated, 307 of whom were considered to be eligible for analysis. Median age was 68 years. Histology was as follows: 7% not otherwise specified, 60% adenocarcinoma, 31% squamous cell carcinoma and 2% large cell carcinoma. Thirty-six cases of deep vein thrombosis (DVT) have been reported (incidence 12%). Thirty-one DVT were recorded in patients who were candidates for or undergoing chemotherapy: 14 during treatment, 7 at the end of chemotherapy, and 10 before treatment. The incidence was significantly higher for patients treated with cisplatin (CDDP), both during chemotherapy and after chemotherapy. A correlation with disease stage was documented: 26.5% of total VTE occurred in locally advanced and metastatic stages (IIIB and IV); 18.8% in stage IIIA (N2). A significant correlation between non-squamous histology was also highlighted (P=0.015) and ECOG 0-1 (P=0.010). According to the high incidence of VTE in patients with NSCLC, especially adenocarcinoma, and the correlation highlighted in this study with ECOG performance status 0-1 and CDDP-based treatment, we believe that outpatients undergoing chemotherapy for advanced stage (IIIB-IV) lung cancer should receive thromboembolic prophylaxis at least for the duration of chemotherapy. It is, therefore, essential to propose a thrombo-prophylaxis clinical trial that recruits only lung cancer patients to evaluate the benefit of prophylaxis in this population and to assess the real risk of bleeding during antithrombotic treatment. [ABSTRACT FROM AUTHOR]

Background and Objective: First-line bevacizumab-based therapy has been shown to improve outcomes in patients with advanced non-squamous non-small-cell lung cancer (NSCLC). The recent international phase IV SAiL study (a Study of Avastin [bevacizumab] in combination with platinum-containing chemotherapy in patients with advanced or recurrent non-squamous cell Lung cancer) evaluated the safety and efficacy of bevacizumab combined with standard chemotherapy regimens in routine clinical practice. Here we report the results of a subanalysis of baseline characteristics and efficacy data for Italian patients enrolled in SAiL. Methods: In the SAiL study, patients with untreated locally advanced, metastatic or recurrent non-squamous NSCLC received bevacizumab (7.5 or 15 mg/kg) every 3 weeks plus chemotherapy for up to six cycles, followed by single-agent bevacizumab until disease progression. Efficacy was assessed in terms of time to disease progression (TTP) and overall survival (OS). Results: The Italian intent-to-treat population comprised 215 patients from a SAiL population of 2212 patients. At baseline, Italian patients tended to have less advanced disease than the overall population. Thus, the proportion of patients at enrollment with tumour stage IIIb and IV was 23.7 and 76.3 %, respectively, for the Italian population versus 19.7 and 80.3 % for the whole SAiL population. In addition, a higher proportion of Italian patients had an Eastern Cooperative Oncology Group performance status of 0 (72.6 vs. 37.2 %) and the prevalence of co-morbid conditions was lower in Italian patients (59.5 % of Italian patients reported a co-morbid condition and 60.0 % were receiving non-oncological treatment compared with 73.3 and 73.4 %, respectively, of SAiL patients overall). The mean exposures to bevacizumab and to chemotherapy were comparable between the Italian patient group and overall patient population, although cisplatin doublets were more commonly employed in Italian patients whereas carboplatin doublets were more commonly employed in the overall SAiL population. The median TTP and OS times for Italian and SAiL populations were comparable (TTP, 7.8 months vs. 7.8 months; OS, 14.8 months vs. 14.6 months). Conclusion: The results of this subanalysis of the SAiL study of bevacizumab treatment in routine clinical practice suggest that Italian oncologists tend to prescribe bevacizumab to a selected population of patients with less advanced disease than is the case in the overall population. Nevertheless, the first-line use of bevacizumab in combination with chemotherapy offers clinical benefits to Italian patients with advanced or recurrent non-squamous NSCLC. [ABSTRACT FROM AUTHOR]

Background. The role of surgery for lung metastases (LM) secondary to colorectal cancer (CRC) remains controversial. The bulk of evidence is derived from single surgical series, hampering any definitive conclusions. The aim of this study was to compare the outcomes of CRC patients with LM submitted to surgery with those who were not. Patients and Methods. Data from 409 patients with LM as the first evidence of advanced disease were extracted from a database of 1,411 patients. Patients were divided into three groups: G1, comprised of 155 patients with pulmonary and extrapulmonary metastases; G2, comprised of 104 patients with LM only and no surgery; G3, comprised of 50 patients with LM only and submitted to surgery. Results. No difference in response rates emerged between G1 and G2. Median progression-free survival (PFS) times were: 10.3 months, 10.5 months, and 26.2 months for G1, G2, and G3, respectively. No difference in PFS times was observed between G1 and G2, whereas there was a statistically significant difference between G2 and G3. Median overall survival times were 24.2 months, 31.5 months, and 72.4 months, respectively. Survival times were longer in resected patients: 17 survived >5 years and three survived >10 years. In patients with LM only and no surgery, four survived for 5 years and none survived >10 years. Conclusions. Even though patients with resectable LM are more likely to be those with a better outcome, our study provides evidence suggesting an active role of surgery in improving survival outcomes in this patient subset. [ABSTRACT FROM AUTHOR]

Autophagy is a lysosomal-driven catabolic process that contributes to preserve cell and tissue homeostases through the regular elimination of damaged, aged and redundant self-constituents. In normal cells, autophagy protects from DNA mutation and carcinogenesis by preventive elimination of pro-oxidative mitochondria and protein aggregates. Mutations in oncogenes and oncosuppressor genes dysregulate autophagy. Up-regulated autophagy may confer chemo- and radio-resistance to cancer cells, and also a pro-survival advantage in cancer cells experiencing oxygen and nutrient shortage. This fact is the rationale for using autophagy inhibitors along with anti-neoplastic therapies. Yet, aberrant hyper-induction of autophagy can lead to cell death, and this phenomenon could also be exploited for cancer therapy. The actual level of autophagy in the cancer cell is greatly affected by vascularization,inflammation, and stromal cell infiltration. In addition, small non-coding microRNAs have recently emerged as important epigenetic modulators of autophagy. The present review focuses on the potential involvement of macroautophagy, and on its genetic and epigenetic regulation, in ovarian cancer pathogenesis and progression. [ABSTRACT FROM AUTHOR]

Post-transplant lymphoproliferative disorders (PTLD) derive from antigen-experienced B-cells and represent a major complication of solid organ transplantation. We characterized usage, mutation frequency and mutation pattern of immunoglobulin variable (IGV) gene rearrangements in 50 PTLD (polymorphic PTLD, n=10; diffuse large B-cell lymphoma, n=35; and Burkitt/Burkitt-like lymphoma, n=5). Among PTLD yielding clonal IGV amplimers, a functional IGV heavy chain (IGHV) rearrangement was found in 40/50 (80.0%) cases, whereas a potentially functional IGV light chain rearrangement was identified in 36/46 (78.3%) PTLD. By combining IGHV and IGV light chain rearrangements, 10/50 (20.0%) PTLD carried crippling mutations, precluding expression of a functional B-cell receptor (BCR). Immunohistochemistry showed detectable expression of IG light chains in only 18/43 (41.9%) PTLD. Failure to detect a functional IGV rearrangement associated with lack of IGV expression. Our data suggest that a large fraction of PTLD arise from germinal centre (GC)-experienced B-cells that display impaired BCR. Since a functional BCR is required for normal B-cell survival during GC transit, PTLD development may implicate rescue from apoptosis and expansion of B-cells that have failed the GC reaction. The high frequency of IGV loci inactivation appears to be a peculiar feature of PTLD among immunodeficiency-associated lymphoproliferations. Copyright © 2006 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Background: To test safety and activity of 3-weekly doses of docetaxel and a weekly dose of trastuzumab in women with HER2-overexpressing advanced breast cancer. Patients and Methods: Forty-two women, median age 53 years (range 36–73 years), with HER2-overexpressing advanced breast cancer were enrolled in a study of docetaxel, 75 mg/m[sup 2] q3w for 6 cycles, and trastuzumab, 4 mg/kg loading dose, 2 mg/kg weekly thereafter. Thirty-four patients (81%) had visceral metastatic involvement. Thirty-five patients had received prior chemotherapy as part of their treatment: adjuvant/neoadjuvant (26), metastatic (2) and both (7). Thirty-one patients had been previously exposed to an anthracycline and 11 to paclitaxel. Four patients had previously received high-dose chemotherapy followed by autologous stem cell transplant. Results: 226 cycles (median 6, range 1–6) were administered. The median delivered dose intensity for docetaxel was 24 mg/m[sup 2] /week (range 16–25 mg/m[sup 2] /week). The intent to treat overall response rate was 67% (95% confidence interval, 52–79%). Median progression-free survival, time to treatment failure, and duration of response were 9, 8 and 12 months, respectively. Symptomatic cardiotoxicity (grade 3) occurred in 1 patient. The most common grade 3/4 toxicity was neutropenia (76% of the patients), although febrile neutropenia did not occur. Conclusions: Three-weekly doses of docetaxel and a weekly dose of trastuzumab is an active and safe combination in patients with HER2-overexpressing advanced breast cancer. Copyright © 2004 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background. Systemic chemotherapy does not satisfactorily improve the poor prognosis of pancreas and biliary tract cancer unresectable or metastatic to the liver. Intra-arterial infusion of antineoplastic agents can give higher concentrations to the tumor and slighter concentrations to the whole body, with a potential of efficacy and lower toxicity, due to the hepatic clearance. Methods. Based on a safe and ambulatorial technique of transcutaneous arterial port implantation, this study was designed to evaluate feasibility and toxicity of 5-fluorouracil (5-FU) intra-arterial continuous infusion combined with systemic gemcitabine with dose escalation. Seventeen patients affected by pancreatic (14) or biliary tract (3) cancer received up to six cycles of treatment. Treatment consisted of intravenous gemcitabine on d 1 and 8 and intra-arterial 5-FU continuous infusion on d 1–14 every 21 d. Dose-escalation levels were 900 and 1000 mg/m2 for gemcitabine and 8, 10, 12, 15, and 17 mg/kg/d for 5-FU. Consecutive cohorts of three patients were planned at each dose level. Results. Gastrointestinal toxicity (vomiting and diarrhea [3rd–4th degree] and gastritis), constituted the dose-limiting toxicity, with a maximum-tolerated dose of 1000 mg/m2 for gemcitabine and 15 mg/kg/d for 5-FU. Hematological toxicity was present in a minority of patients. No patient had acute or later complications such as arterial thrombosis related to the implanted arterial port, sclerosis cholangitis, or chemical cholecistitis. Conclusion. 5-Fluorouracil intra-arterial continuous infusion, combined with systemic gemcitabine, seems to be a feasible and safe regimen that could give interesting results in pancreatic cancer. [ABSTRACT FROM AUTHOR]

Purpose: The incorrect positioning of the arterial Port-a-Cath or the presence of anatomic or functional hepatic arteriovenous shunting may explain the occurrence of systemic toxicity of hepatic arterial infusion of floxuridine in patients with liver metastases. The aim of our study was to predict the occurrence of systemic toxic effects from this treatment using a scintigraphic and pharmacokinetic approach. Methods: A group of 26 patients were studied. Before treatment, Tc-99m-labelled macroaggregated albumin arterial perfusion scintigraphy was performed to verify the correct positioning of the catheter, to evaluate the percentage of pulmonary uptake of the tracer, reflecting intrahepatic arteriovenous anatomic shunting, and to qualitatively assess the perfusion pattern of the metastases with respect to the normal liver parenchyma (SPECT images). Hepatic arteriovenous functional shunting was assessed through the bioavailability of intraarterially administered D-sorbitol. Treatment was then started and systemic toxic effects were evaluated according to WHO recommendations. Results: No correlation was found between anatomic shunting (≤10% in all patients) and systemic toxicity of treatment. The 9 patients with hypoperfused metastases experienced a significantly lower level of toxic effects (1 low-grade toxicity and 8 no toxicity) than the 17 with hyperperfused metastases (6 high-grade toxicity, 5 low-grade and 6 no toxicity; χ2 = 7.170, P = 0.028). Functional shunting was significantly different in patients with high-grade, low-grade and no toxicity (46.5 ± 19.9%, 15.8 ± 12.7% and 16.5 ± 10.3%, respectively; P<0.001 by analysis of variance). Moreover, functional shunting was significantly greater only in patients with hyperperfused metastases who developed high-grade toxicity. Conclusions: A protocol combining scintigraphic and pharmacokinetic methods is of value in the individual patient in assessing the risk of high-grade systemic toxicity during hepatic arterial infusion of floxuridine. A flow-chart used in our ongoing prospective study for the evaluation of patients undergoing regional chemotherapy for liver metastases is included. [ABSTRACT FROM AUTHOR]