Real Life Clinical Management and Survival in Advanced Cutaneous Melanoma: The Italian Clinical National Melanoma Registry Experience

background: cutaneous melanoma (CM) is one of the most aggressive types of skin cancer. currently, innovative approaches such as target therapies and immunotherapies have been introduced in clinical practice. data of clinical trials and real life studies that evaluate the outcomes of these therapeutic associations are necessary to establish their clinical utility. the aim of this study is to investigate the types of oncological treatments employed in the real-life clinical management of patients with advanced CM in several Italian centers, which are part of the clinical national melanoma registry (CNMR). methods: melanoma-specific survival and overall survival were calculated. multivariate cox regression models were used to estimate the hazard ratios adjusting for confounders and other prognostic factors. results: the median follow-up time was 36 months (range 1.2-185.1). 787 CM were included in the analysis with completed information about therapies. all types of immunotherapy showed a significant improved survival compared with all other therapies (p=0.001). 75% was the highest reduction of death reached by anti-PD-1 (HR=0.25), globally immunotherapy was significantly associated with improved survival, either for anti-CTLA4 monotherapy or combined with anti-PD-1 (HR=0.47 and 0.26, respectively) and BRAFI+MEKI (HR=0.62). conclusions: the nivolumab/pembrolizumab in combination of ipilimumab and the addition of ant-MEK to the BRAFi can be considered the best therapies to improve survival in a real-world-population. the CNMR can complement clinical registries with the intent of improving cancer management and standardizing cancer treatment

Risk-Driven Behavioral Biometric-based One-Shot-cum-Continuous User Authentication Scheme

The paper presents a risk-driven behavioral biometric-based user authentication scheme for smartphones. Our scheme delivers one-shot-cum-continuous authentication, thus not only authenticates users at the start of the application sign-in process but also, throughout the active user session. The scheme leverages the widely used PIN/password-based authentication technology by giving flexibility to users to enter any random 8-digit alphanumeric text, instead of pre-configured PIN/Passwords. Internally, the scheme exploits two behavioral biometric traits, i.e., touch-timing-differences of the entered strokes and the hand-movement gesture recorded during the random text entry, to authenticate users. And, for the entire user session, the scheme continuously authenticates the user by computing the risk-score every time the user initiates a sensitive activity. If the risk-score is higher than the predefined threshold, the current user session terminates. Afterward, the scheme requests the user to re-authenticate. Thus, our scheme serves three main objectives: Firstly, it offers users the flexibility to enter an 8 - digit random alphanumeric text as their secret enhancing the usability of PIN/password-based schemes. Secondly, it strengthens the security of PIN/password-based schemes as verification decision is not binary, and mimicking the invisible touch-timings and hand-movements simultaneously, could be extremely difficult as our security analysis determined. Lastly, the scheme does not require any dedicated device (e.g., a smart token for OTP generation) for 2-factor authentication. The results obtained on 11,400 user-samples (collected by 3 days in-the-wild testing) and user-experience responses (received from the Software Usability Scale(4) survey) of 95 testers demonstrate our scheme as an accurate and acceptable user authentication scheme

Role of Reactive Oxygen Species in the Neural and Hormonal Regulation of the PNMT Gene in PC12 Cells

The stress hormone, epinephrine, is produced predominantly by adrenal chromaffin cells and its biosynthesis is regulated by the enzyme phenylethanolamine N-methyltransferase (PNMT). Studies have demonstrated that PNMT may be regulated hormonally via the hypothalamic-pituitary-adrenal axis and neurally via the stimulation of the splanchnic nerve. Additionally, hypoxia has been shown to play a key role in the regulation of PNMT. The purpose of this study was to examine the impact of reactive oxygen species (ROS) produced by the hypoxia mimetic agent CoCl2, on the hormonal and neural stimulation of PNMT in an in vitro cell culture model, utilizing the rat pheochromocytoma (PC12) cell line. RT-PCR analyses show inductions of the PNMT intron-retaining and intronless mRNA splice variants by CoCl2 (3.0- and 1.76-fold, respectively). Transient transfection assays of cells treated simultaneously with CoCl2 and the synthetic glucocorticoid, dexamethasone, show increased promoter activity (18.5-fold), while mRNA levels of both splice variants do not demonstrate synergistic effects. Similar results were observed when investigating the effects of CoCl2-induced ROS on the neural stimulation of PNMT via forskolin. Our findings demonstrate that CoCl2-induced ROS have synergistic effects on hormonal and neural activation of the PNMT promoter

Tel-eVax: a genetic vaccine targeting telomerase for treatment of canine lymphoma

Background: we have recently shown that Tel-eVax, a genetic vaccine targeting dog telomerase (dTERT) and based on Adenovirus (Ad)/DNA Electro-Gene-Transfer (DNA–EGT) technology can induce strong immune response and increase overall survival (OS) of dogs affected by multicentric Diffuse Large B cell Lymphoma (DLBCL) when combined to COP therapy in a double-arm study. Here, we have utilized a clinically validated device for veterinary electroporation called Vet-ePorator , based on Cliniporator technology currently utilized and approved in Europe for electro- chemotherapy applications and adapted to electrogenetransfer (EGT). Methods: 17 dogs affected by DLBCL were vaccinated using two Ad vector injections (Prime phase) followed by TM DNA–EGT (Boost phase) by means of a Vet-ePorator device and treated in the same time with a 27-week Madison Wisconsin CHOP protocol. The immune response was measured by ELISA assays using pool of peptides. Results: No significant adverse effects were observed. The OS of vaccine/CHOP animals was 64.5 weeks, in line with the previous study. Dogs developed antibodies against the immunizing antigen. Conclusions: Tel-eVax in combination with CHOP is safe and immunogenic in lymphoma canine patients. These data confirm the therapeutic efficacy of dTERT vaccine and hold promise for the treatment of dogs affected by other cancer types. More importantly, our findings may translate to human clinical trials and represent new strategies for cancer treatment

Dietary Patterns in Italy and the Risk of Renal Cell Carcinoma

Background: Conclusive evidence on foods, nutrients, or dietary patterns and the risk of renal cell carcinoma (RCC) is lacking in the literature. Methods: We considered data from an Italian hospital-based case\u2013control study (1992\u20132004) on 767 incident RCC cases and 1534 controls. A posteriori dietary patterns were identified by applying principal component factor analysis on 28 nutrients derived from a 78-item food-frequency questionnaire. We estimated the odds ratios (ORs) of RCC and corresponding 95% confidence intervals (CIs) for each quartile category (compared to the lowest one) using conditional multiple logistic regression models providing adjustment for major confounding factors. Results: We identified four dietary patterns, named \u201cAnimal products\u201d, \u201cStarch-rich\u201d, \u201cVitamins and fiber\u201d, and \u201cCooking oils and dressings\u201d. Higher intakes of the \u201cStarch-rich\u201d pattern were positively associated with RCC risk (OR = 1.38, 95% CI: 1.04\u20131.82 for the highest quartile, p = 0.018). The association was inverse with the \u201cCooking oils and dressings\u201d pattern (OR = 0.61, 95% CI: 0.47\u20130.80, p < 0.001), whereas no association was found with \u201cAnimal products\u201d and \u201cVitamins and fiber\u201d patterns. Conclusions: Higher intakes of starch-related foods may increase RCC risk, whereas consumption of olive and seed oils may favorably influence RCC risk

Dietary intake of branched-chain amino acids and colorectal cancer risk

ABSTACTAn adequate intake of branched-chain amino acids (BCAAs) is required for protein synthesis and metabolic functions, including insulin metabolism. Emerging studies found positive associations between BCAAs and the risk of various diseases sharing etiological aspects with colorectal cancer (CRC), including type 2 diabetes, obesity, and pancreatic cancer.We investigated the relation between dietary BCAAs and CRC using data from a multicentric Italian case-control study, including 1953 cases of CRC (of these, 442 of sigmoid colon) and 4154 hospital controls with acute, non-neoplastic diseases. A validated food-frequency questionnaire was used to estimate the participants' usual diet and to assess dietary intakes of various nutrients, including energy, BCAAs and calcium. Odds ratio (ORs) and corresponding confidence intervals (CI) were computed by multiple logistic regression models adjusted for age, sex and other confounding factors, including total energy intake.BCAA intake was inversely related to CRC risk (OR for the highest versus the lowest quintile, 0.73; 95% CI, 0.55-0.97), but the association was attenuated after adjustment for calcium intake (OR, 0.90; 95% CI, 0.65-1.25). A linear inverse association with sigmoid colon cancer risk remained also after adjustment for other dietary factors, including calcium intake (OR, 0.49; 95% CI, 0.27-0.87).This study provides supporting evidence that higher levels of dietary BCAA intake are not associated with an increase of CRC risk, but confirms that they may be related to a reduced risk of sigmoid colon cancer

An elementary proof of uniqueness of the particle trajectories for solutions of a class of shear-thinning non-Newtonian 2D fluids

We prove some regularity results for a class of two dimensional non-Newtonian fluids. By applying results from [Dashti and Robinson, Nonlinearity, 22 (2009), 735-746] we can then show uniqueness of particle trajectories

Use of complementary and alternative medicine (CAM) in cancer patients. An italian multicenter survey

INTRODUCTION: Complementary and Alternative Medicine (CAM) include a wide range of products (herbs, vitamins, minerals, and probiotics) and medical practices, developed outside of the mainstream Western medicine. Patients with cancer are more likely to resort to CAM first or then in their disease history; the potential side effects as well as the costs of such practices are largely underestimated. PATIENTS AND METHOD: We conducted a descriptive survey in five Italian hospitals involving 468 patients with different malignancies. The survey consisted of a forty-two question questionnaire, patients were eligible if they were Italian-speaking and receiving an anticancer treatment at the time of the survey or had received an anticancer treatment no more than three years before participating in the survey. RESULTS: Of our patients, 48.9% said they use or have recently used CAM. The univariate analysis showed that female gender, high education, receiving treatment in a highly specialized institute and receiving chemotherapy are associated with CAM use; at the multivariate analysis high education (Odds Ratio, (OR): 1.96 95% Confidence Interval, CI, 1.27-3.05) and receiving treatment in a specialized cancer center (OR: 2.75 95% CI, 1.53-4.94) were confirmed as risk factors for CAM use. CONCLUSION: Roughly half of our patients receiving treatment for cancer use CAM. It is necessary that health professional explore the use of CAM with their cancer patients, educate them about potentially beneficial therapies in light of the limited available evidence of effectiveness, and work towards an integrated model of health-care provision

Diabetes risk reduction diet and endometrial cancer risk

Diabetes increases endometrial cancer risk. We investigated the role of a diabetes risk reduction diet (DRRD) on the risk of endometrial cancer using data from a multicentric, Italian hospital-based case–control study (1992–2006) enrolling 454 histologically confirmed cases of endometrial cancer and 908 controls matched by age and center. We derived a DRRD score assigning higher scores for higher intakes of cereal fiber, fruit, coffee, polyunsaturated:saturated fatty acid ratio, and nuts and for lower glycemic load and lower intakes of red/processed meat and sugar-sweetened beverages/fruit juices. The odds ratios (OR) of endometrial cancer according to the DRRD score were derived by multiple conditional logistic regression models. The OR for high (DRRD score >24, i.e., third tertile) versus medium–low adherence to the DRRD was 0.73 (95% confidence interval, CI, 0.55–0.97). Similar results were observed after the exclusion of diabetic women (OR 0.75; 95% CI, 0.56–1.00) and allowance for total vegetable consumption (OR 0.80; 95% CI, 0.60–1.07). Inverse associations were observed in most of the analyzed subgroups. The OR for high DRRD combined with high vegetable consumption was 0.45 (95% CI, 0.28–0.73). Our results suggest that diets able to reduce diabetes risk may also reduce endometrial cancer risk. High vegetable consumption combined with high adherence to the DRRD may provide additional benefit in endometrial cancer prevention

Transgenic mouse model harboring the transcriptional fusion Ccl20-luciferase as a novel reporter of pro-inflammatory response

The chemokine CCL20, the unique ligand of CCR6 functions as an attractant of immune cells. Expression of CCL20 is induced by Toll-like Receptor (TLR) signaling or proinflammatory cytokine stimulation. However CCL20 is also constitutively produced at specific epithelial sites of mucosa. This expression profile is achieved by transcriptional regulation. In the present work we characterized regulatory features of mouse Ccl20 gene. Transcriptional fusions between the mouse Ccl20 promoter and the firefly luciferase (luc) encoding gene were constructed and assessed in in vitro and in vivo assays. We found that liver CCL20 expression and luciferase activity were upregulated by systemic administration of the TLR5 agonist flagellin. Using shRNA and dominant negative form specific for mouse TLR5, we showed that this expression was controlled by TLR5. To address in situ the regulation of gene activity, a transgenic mouse line harboring a functional Ccl20-luc fusion was generated. The luciferase expression was highly concordant with Ccl20 expression in different tissues. Our data indicate that the transgenic mouse model can be used to monitor activation of innate response in vivo.Laboratorio de Investigaciones del Sistema InmuneFacultad de Ciencias Exacta