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Background Immunotherapy has brought clinical benefits to patients with metastatic renal cell cancer (mRCC). Most patients tolerate immunotherapy but serious immune-related adverse events (irAEs) have been reported. Some studies indicate a correlation between irAEs and clinical response in other cancer types (eg, lung cancer and melanoma). For patients with mRCC, the impact of irAE on clinical outcome is unknown. Patients and Methods A retrospective review of 167 patients with mRCC treated with nivolumab as standard of care between March 2017 and January 2018 in 16 Italian centers was performed. irAEs were assessed using Common Terminology Criteria for Adverse Events (CTCAE) v.4.0. Results Any grade and grade 3/4 irAEs occurred in 46% and 8.9% of patients, respectively. The median time to appearance of irAEs was 10 weeks; 38.8% of patients required steroid treatment. The most common irAEs were cutaneous (33.7%) and gastrointestinal (23.3%). The median overall survival and progression-free survival were 20.13 and 7.86 months, respectively. Patients with irAEs showed a greater overall survival (hazard ratio, 0.38; 95% confidence interval [CI], 0.23-0.63) and progression-free survival (hazard ratio, 0.44; 95% CI, 0.29-0.66) benefit as well as better overall response rate (27.3% vs. 13.7%; odds ratio, 2.36; 95% CI, 1.03-5.44) and disease control rate (68.8% vs. 48%; odds ratio, 2.4; 95% CI, 1.23-4.67) if compared with those without irAEs. No correlation was found between steroid use and clinical outcomes. Conclusions Our analysis revealed that the appearance of irAEs was associated with better outcomes in patients treated with nivolumab. This data may be limited by sample size and the retrospective nature of the study.

Background Although statin use has been associated with favorable effects in various solid malignancies, no conclusive evidence is available at present. Statins are safe and inexpensive, and may synergize with novel antiandrogen agents abiraterone via pharmacokinetic interactions and decrease substrate availability for de novo androgen biosynthesis. Objective To determine whether statin use affects survival in patients with metastatic castration-resistant prostate cancer (mCRPC) treated with abiraterone. Design, setting, and participants Medical records of patients with documented mCRPC between September 2011 and August 2016 were reviewed at multiple participating centers. This research was conducted in ten institutions, including both referral centers and local hospitals. A total of 187 patients receiving abiraterone for mCRPC between September 2011 and August 2016 were eligible for inclusion in this retrospective study. Outcome measurements and statistical analysis Patients were assessed for overall survival (OS), statin use at the time of treatment initiation, prostate-specific antigen (PSA) variations, and other variables of interest. Univariable and multivariable analysis was used to explore the association of variables of interest with OS and PSA declines. Results and limitations Statin use was a significant prognostic factor for longer OS in univariable (hazard ratio [HR] 0.51, 95% confidence interval [CI] 0.37–0.72; p p 50% decline at 12 wk: 72.1% in statin users vs 38.5% in non-users; p Conclusions Our study suggests a prognostic impact of statin use in patients receiving abiraterone for mCRPC. The mechanism of this interaction warrants elucidation, but may include enhancement of the antitumor activity of abiraterone as well as cardioprotective effects. Patient summary We assessed the effects of statin use in patients with advanced prostate cancer receiving abiraterone. Patients treated with a statin plus abiraterone appeared to live longer than those treated with abiraterone only. Since no negative drug-drug interaction is known and statins are widely used and inexpensive, further studies assessing the use of abiraterone plus statins are warranted.

Immune checkpoint inhibitor (ICI)-based combinations have become the first-line standard of care in metastatic renal cell carcinoma (mRCC), but their activity on the primary tumor is still one of the most debated issues.The aim of our analysis was to evaluate the primary tumor's response to first-line therapy with cabozantinib or nivolumab+ipilimumab, and its correlation with metastatic response and with patient outcomes.Sixty-seven mRCC patients met the criteria for inclusion in the final analysis (30 treated with cabozantinib and 37 with nivolumab+ipilimumab). In the overall population, the primary tumor control rate (PTCR) was 90.9%; no complete responses (CR) were achieved. A significant correlation was found between the baseline size of the primary tumor's longest diameter and its response according to RECIST v1.1 criteria at the time of the second radiological assessment (rs = -0.351; P = .049). Moreover, a significant correlation between the type of primary tumor response and the response of the metastases was observed in the overall population (rs = 0.50; two-sided P 0.001). There was also a significant correlation between primary tumor response and 1-year survival rate (P = .002), even when adjusted for the IMDC prognostic group and type of therapy (HR = 8.70; 95%CI, 2.52-30.05; P = .001).Extension of the primary tumor did not affect patient survival, while its response was significantly related to the response on metastatic disease and survival. No significant differences in terms of primary tumor shrinkage were identified between treatment with nivolumab+ipilimumab or cabozantinib in this cohort.

Nowadays, the demand for devices capable of efficiently identifying the presence of various biomarkers in human body, connected to a wide variety of pathologies, is progressively increasing. Chemoresistive semiconductor sensors, capable of changing their conductance depending on the chemical reactions between their surface and gaseous analytes, could be a suitable choice for medical devices implementation. In this work, a prototype based on an array of nanostructured sensors was tested, in order to detect the presence of airborne tumor markers in blood samples. These chemicals were conveyed to sensors with an air-flow circuit, equipped with antibacterial filters to maintain the sterility of the system. Resulting signals were acquired, processed and plotted thanks to a custom-made software, realized in Labview®. Statistics on these signals was performed by means of Principal Component Analysis. Both male and female subjects, ranging between 21 to 91 years of age, have accepted to participate in this study, donating their blood samples. Donors were patients affected by colorectal and stomach cancers, at different stages of evolution, and/or having differently localized metastasis, and a healthy control group. The results have shown that the processed sensor responses, well discriminate healthy and tumor affected subjects. Obtained results can be also employed to assess the level of tumor growth and vascularization.

BACKGROUND AND AIMS: Self-expandable metal stent (SEMS) positioning is the recommended method for palliation of dysphagia from esophageal cancer, although it is not adverse event-free. The present study was aimed at identifying predictors for adverse events and at proposing a statistical model to predict them. METHODS: We performed a retrospective analysis of a prospectively collected database. All patients who underwent SEMS placement for stricture due to esophageal cancer between 2002 and 2011 in a tertiary-care center were identified. Multivariable regression analysis in the presence of competing risk events was used to identify factors associated with SEMS-related adverse events and to build a prediction model. RESULTS: A total of 267 patients were included. According to the competing risk regression analysis, only 2 variables were significantly associated with the risk of SEMS-related adverse events: prior chemoradiotherapy (CRT), yielding a hazard ratio (HR) of 1.687 (95% confidence interval [CI], 1.076-2.644), and the SEMS length (HR 0.884; 95% CI, 0.798-0.980) for every 10-mm length increase. Based on the estimated probability curves, after 4 months from SEMS placement, the probability of an adverse event in patients who did receive prior CRT was 50.9% compared with 34.4% in those who did not receive prior therapy, which was reduced to 9.2% and 15.1%, respectively, if a 180 mm-length stent was used. The ability of the predictive model to differentiate between patients who did and did not experience the adverse event was moderate (c-index: 0.617). CONCLUSION: The rate of SEMS-related adverse events was higher in patients with previous CRT and lower in patients receiving longer stents. Both factors were used to build an accurate predictive model. Background and Aims Self-expandable metal stent (SEMS) positioning is the recommended method for palliation of dysphagia from esophageal cancer, although it is not adverse event-free. The present study was aimed at identifying predictors for adverse events and at proposing a statistical model to predict them. Methods We performed a retrospective analysis of a prospectively collected database. All patients who underwent SEMS placement for stricture due to esophageal cancer between 2002 and 2011 in a tertiary-care center were identified. Multivariable regression analysis in the presence of competing risk events was used to identify factors associated with SEMS-related adverse events and to build a prediction model. Results A total of 267 patients were included. According to the competing risk regression analysis, only 2 variables were significantly associated with the risk of SEMS-related adverse events: prior chemoradiotherapy (CRT), yielding a hazard ratio (HR) of 1.687 (95% confidence interval [CI], 1.076-2.644), and the SEMS length (HR 0.884; 95% CI, 0.798-0.980) for every 10-mm length increase. Based on the estimated probability curves, after 4 months from SEMS placement, the probability of an adverse event in patients who did receive prior CRT was 50.9% compared with 34.4% in those who did not receive prior therapy, which was reduced to 9.2% and 15.1%, respectively, if a 180 mm-length stent was used. The ability of the predictive model to differentiate between patients who did and did not experience the adverse event was moderate (c-index: 0.617). Conclusion The rate of SEMS-related adverse events was higher in patients with previous CRT and lower in patients receiving longer stents. Both factors were used to build an accurate predictive model.

We propose numerical simulations of viscoelastic fluids based on a hybrid algorithm combining Lattice-Boltzmann models (LBM) and Finite Differences (FD) schemes, the former used to model the macroscopic hydrodynamic equations, and the latter used to model the polymer dynamics. The kinetics of the polymers is introduced using constitutive equations for viscoelastic fluids with finitely extensible non-linear elastic dumbbells with Peterlin's closure (FENE-P). The numerical model is first benchmarked by characterizing the rheological behaviour of dilute homogeneous solutions in various configurations, including steady shear, elongational flows, transient shear and oscillatory flows. As an upgrade of complexity, we study the model in presence of non-ideal multicomponent interfaces, where immiscibility is introduced in the LBM description using the "Shan-Chen" model. The problem of a confined viscoelastic (Newtonian) droplet in a Newtonian (viscoelastic) matrix under simple shear is investigated and numerical results are compared with the predictions of various theoretical models. The proposed numerical simulations explore problems where the capabilities of LBM were never quantified before., Comment: 32 Pages, 11 Figures

Canine distemper virus (CDV) is a contagious and multisystemic viral disease that affects domestic and wild canines as well as other terrestrial and aquatic carnivores. The disease in dogs is often fatal and no specific antiviral therapy is currently available. In this study, we evaluated the in vitro antiviral activity against CDV of proanthocyanidin A2 (PA2), a phenolic dimer belonging to the class of condensed tannins present in plants. Our results showed that PA2 exerted in vitro antiviral activity against CDV with a higher selectivity index compared to ribavirin, included in our study for the previously tested anti-CDV activity. The time of addition assay led us to observe that PA2 was able to decrease the viral RNA synthesis and to reduce progeny virus liberation, at different times post infection suggesting multiple mechanisms of action including inhibition of viral replicative complex and modulation of the redox milieu. These data suggest that PA2, isolated from the bark of Aesculus hippocastanum, has potential usefulness as an anti-CDV compound inhibiting viral replication.

Canine distemper virus (CDV) is a highly contagious pathogen of carnivores. In dogs, the disease is characterized by high lethality rates and no specific antiviral therapy is available. In this study, the aim was to verify the in vitro antiviral activity of the 5-ethynyl-1-β-D-ribofuranosylimidazole-4-carboxamide (EICAR) and to compare it with the 1-(β-D-ribofuranosil)-1,2,4-triazole-3-carboxamide (Ribavirin, RBV). EICAR was more active than RBV against CDV replication, while both molecules exhibited low selectivity indexes. A reversal of their antiviral activity was observed after addition of guanosine, suggesting their involvement in the inhibition of the inosine monophosphate dehydrogenase enzyme (IMPDH). RBV and EICAR had a time- and concentration-dependent anti-CDV activity, mainly displayed during the first 10 h post-infection. The involvement of the inhibition of the viral RNA polymerase RNA dependent (vRdRp) is discussed, as well as the role of CDV as a model to study more potent and selective antiviral molecules active against other paramyxoviruses.

Background Many complications have been reported after orf infection, including lymphadenopathy, secondary bacterial infection, and erythema multiforme. Rare associations with papulovesicular eruptions, including a bullous pemphigoid-like eruption, have also been described. Objectives Our purpose was to clinically, histologically, and immunologically characterize two cases of orf-induced blistering disease, and to determine whether this condition represented a novel disease entity distinct from known immunobullous diseases. Methods Two patients were clinically described and skin biopsy specimens were collected for routine histology, direct immunofluorescence studies, and polymerase chain reaction analysis to detect orf viral DNA. Patients' sera were assessed for autoantibodies by indirect immunofluorescence studies using normal-appearing human salt-split skin, by Western blot analysis using keratinocyte extracts, dermal extracts, and recombinant type VII collagen, and immunoprecipitation studies of extracts from biosynthetically radiolabeled human keratinocytes. Results Two distinctive cases of severe, diffuse blistering eruptions after orf infection are described. In one patient, orf virus DNA was detected in the inciting orf lesion, but not in blistered skin, ruling out disseminated orf infection as a cause of the blisters. In both cases, histology revealed subepidermal blisters with mixed inflammatory cell infiltrates containing neutrophils and eosinophils, direct immunofluorescence microscopy studies demonstrated IgG and C3 deposited at the dermoepidermal junctions of perilesional skin, and indirect immunofluorescence studies demonstrated circulating antibasement membrane IgG that bound the dermal side of salt-split skin. Extensive immunoblot and immunoprecipitation studies failed to reveal a consistent, identifiable autoantigen. Limitations We describe only two cases. The autoantigen recognized by circulating autoantibodies was not identified. Conclusions Orf-induced immunobullous disease is a unique disease entity that is clinically and immunologically distinct from bullous pemphigoid, epidermolysis bullosa acquisita, and other known immunobullous conditions.

The alkylation of phenol with methanol was studied using a Bronsted-type acid catalyst (a H-mordenite) and basic/dehydrogenating catalysts (MgO, Fe2O3 and Mg/Fe/O), with the aim of investigating the reaction mechanism. The main difference between the two classes of catalysts concerned the transformations occurring on methanol. Specifically, in the former case the acid-type activation of methanol led to the development of an electrophylic species that gave rise to the formation of anisole and of C-alkylated compounds. With basic catalysts, methanol dehydrogenated to formaldehyde, which then underwent transformation to methylformate and to decomposition products, i.e., CO, CO2, CH4 and H2. In this case, the prevailing compounds obtained by reaction with phenol were o-cresol and 2,6-xylenol. The dehydrogenation of methanol was found to be the key-step in the generation of the active methylating species with basic catalysts.

Orf virus (ORFV), the type species of Parapoxvirus , is responsible for contagious ecthyma in sheep and goats. In the present report, sequence analysis of major envelope gene (B2L) of four Indian orf virus isolates originating two each from sheep and goats was carried out. These recent isolates belonged to different outbreaks that occurred in Kumaon hills and adjoining plains during 2004–2005. Preliminary screening of the scab samples was carried out by diagnostic PCR. Full-length B2L gene encoding for immunogenic major envelope protein from all the four ORFV isolates was amplified by PCR and the amplicons (1206 bp) were cloned and sequenced. Comparative sequence analysis revealed an open reading frame of 1137 nucleotides (nt) encoding a polypeptide of 378 amino acids (aa). Indian isolates were highly related amongst themselves with sequence identity of over 97% at the nt and aa level. Further, they showed 97–98% sequence identity with sequences of other ORFV isolates from around the world; while 94–95 and 82.7–83.8% sequence identity was observed, respectively, with pseudocowpox and bovine papular stomatitis viruses—the other members of the genus. Phylogenetic analysis also showed that these Parapoxviruses from sheep and goats are closely related to other orf viruses reported worldwide.

This study reports the detection of co-infection by multiple CPV variants and the high genetic complexity of a CPV-2 strain detected in a domestic cat. The CPV variants selected by cloning the VP2 gene were sequenced, and genetic diversity and selection pressure were investigated. Comparison of the nucleotide sequences has evidenced 10 different viral populations, and, in the same animal, more CPV variants coexist. Our analysis excludes the possibility that the recombination events took place during infection and that negative selection acted on the VP2 gene. These findings confirm that CPV-2 shows high genetic heterogeneity resembling the quasispecies found in RNA viruses.

The orf virus is the type species of the Parapoxvirus genus and is the causative agent of contagious echtyma, a debilitating skin disease of sheep and goats, which can also affect man. The virus exhibits a restricted host range, even if it has been shown to bind to a wide range of tissues of non-permissive species. This ability is an argument for its potential use as an expression vector. Since most mammalian cell types express heparan sulfate (HS) surface receptors, we assumed that HS could serve as receptors to mediate orf virus binding. In this study, we showed that orf virus is inhibited by the addition of soluble heparin in cell cultures. Affinity chomatography using heparin agarose demonstrated that orf virus F1L is the major heparin binding protein. Furthermore, the recombinant F1L protein was visualised on the cell surface by confocal microscopy, and rabbits immunised with recombinant F1L protein produced virus neutralising antibodies. These results confirm that the F1L immunodominant protein is also involved in virus binding to cells as for the vaccinia homologue H3L protein. Heparin also inhibited the binding of the F1L protein to cells showing that this protein has a role in the early stages of infection.