Genetic interaction of P2X7 receptor and VEGFR-2 polymorphisms identifies a favorable prognostic profile in prostate cancer patients

VEGFR-2 and P2X7 receptor (P2X7R) have been described to stimulate the angiogenesis and inflammatory processes of prostate cancer. The present study has been performed to investigate the genetic interactions among VEGFR-2 and P2X7R SNPs and their correlation with overall survival (OS) in a population of metastatic prostate cancer patients. Analyses were performed on germline DNA obtained from blood samples and SNPs were investigated by real-time PCR technique. The survival dimensionality reduction (SDR) methodology was applied to investigate the genetic interaction between SNPs. One hundred patients were enrolled. The SDR software provided two genetic interaction profiles consisting of the combination between specific VEGFR-2 (rs2071559, rs11133360) and P2X7R (rs3751143, rs208294) genotypes. The median OS was 126 months (95% CI, 115.94-152.96) and 65.65 months (95% CI, 52.95-76.53) for the favorable and the unfavorable genetic profile, respectively (p < 0.0001). The genetic statistical interaction between VEGFR-2 (rs2071559, rs11133360) and P2X7R (rs3751143, rs208294) genotypes may identify a population of prostate cancer patients with a better prognosis

Initial therapy with FOLFOXIRI and bevacizumab for metastatic colorectal cancer

A fluoropyrimidine plus irinotecan or oxaliplatin, combined with bevacizumab (a monoclonal antibody against vascular endothelial growth factor), is standard first-line treatment for metastatic colorectal cancer. Before the introduction of bevacizumab, chemotherapy with fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) showed superior efficacy as compared with fluorouracil, leucovorin, and irinotecan (FOLFIRI). In a phase 2 study, FOLFOXIRI plus bevacizumab showed promising activity and an acceptable rate of adverse effects

Clinical, pharmacokinetic and pharmacodynamic evaluations of metronomic UFT and cyclophosphamide plus celecoxib in patients with advanced refractory gastrointestinal cancers

Aims. To evaluate UFT and cyclophosphamide (CTX) based metronomic chemotherapy plus celecoxib (CXB) for the treatment of patients with heavily pre-treated advanced gastrointestinal malignancies. Methods. Thirty-eight patients received 500 mg/mq2 CTX i.v bolus on day 1 and, from day 2, 50 mg/day CTX p.o. plus 100 mg/twice a day UFT p.o. and 200 mg/twice a day CXB p.o. Tegafur, 5-FU, 5-FUH2, GHB and uracil pharmacokinetics were assessed. Plasma vascular endothelial growth factor (VEGF), soluble VE-cadherin (sVE-C) and thrombospondin-1 (TSP-1) levels were detected by ELISA and real-time PCR of CD133 gene expression on peripheral blood mononuclear cell was also performed. Results Seventeen patients (45%) obtained stable disease (SD) with a median duration of 5.8 ms (range, 4.2–7.4). Median progression free survival (PFS) and overall survival (OS) were 2.7 ms (95% CI, 1.6–3.9 ms) and 7.1 ms (95% CI, 4.3–9.9 ms), respectively. No toxicities of grade >1 were observed. Pharmacokinetics of 27 patients (13/14, SD/progressive disease, PD) after the first treatment of UFT revealed that 5-FU AUC and Cmax values greater than 1.313 h x microg/ml and 0.501 microg/ml, respectively, were statistically correlated with stabilization of disease and prolonged PFS/OS. VEGF and sVE-C plasma levels were greater in the PD group when compared to SD group. CD133 expression increased only in the PD patients. Conclusion. Metronomic UFT and CTX with CXB in heavily pre-treated gastrointestinal patients were well tolerated and associated with interesting activity. Potential predictive pharmacokinetic parameters and pharmacodynamic biomarkers have been found

Prognostic and predictive role of neutrophil/lymphocytes ratio in metastatic colorectal cancer: a retrospective analysis of the TRIBE study by GONO.

Background Neutrophil/lymphocyte ratio (NLR), defined as absolute neutrophils count divided by absolute lymphocytes count, has been reported as poor prognostic factor in several neoplastic diseases but only a few data are available about unresectable metastatic colorectal cancer (mCRC) patients (pts). The aim of our study was to evaluate the prognostic and predictive role of NLR in the TRIBE trial. Patients and methods Pts enrolled in TRIBE trial were included. TRIBE is a multicentre phase III trial randomizing unresectable and previously untreated mCRC pts to receive FOLFOXIRI or FOLFIRI plus bevacizumab. A cut-off value of 3 was adopted to discriminate pts with low (NLR < 3) versus high (NLR ≥ 3) NLR, as primary analysis. As secondary analysis, NLR was treated as an ordinal variable with three levels based on terciles distribution. Results NLR at baseline was available for 413 patients. After multiple imputation at univariate analysis, patients with high NLR had significantly shorter progression-free survival (PFS) [hazard ratio (HR) 1.27 (95% CI 1.05-1.55), P = 0.017] and overall survival (OS) [HR 1.56 (95% CI 1.25-1.95), P < 0.001] than patients with low NLR. In the multivariable model, NLR retained a significant association with OS [HR 1.44 (95% CI 1.14-1.82), P = 0.014] but not with PFS [HR 1.18 (95% CI 0.95-1.46), P = 0.375]. No interaction effect between treatment arm and NLR was evident in terms of PFS (P for interaction = 0.536) or OS (P for interaction = 0.831). Patients with low [HR 0.84 (95% CI 0.64-1.08)] and high [HR 0.73 (95% CI 0.54-0.97)] NLR achieved similar PFS benefit from the triplet and consistent results were obtained in terms of OS [HR 0.83 (95% CI 0.62-1.12) for low NLR; HR 0.82 (95% CI 0.59-1.12) for high NLR]. Conclusion This study confirmed the prognostic role of NLR in mCRC pts treated with bevacizumab plus chemotherapy in the first line, showing the worse prognosis of pts with high NLR. The advantage of the triplet is independent of NLR at baseline

Real World Estimate of Vaccination Protection in Individuals Hospitalized for COVID-19

Whether vaccination confers a protective effect against progression after hospital admission for COVID-19 remains to be elucidated. Observational study including all the patients admitted to San Paolo Hospital in Milan for COVID-19 in 2021. Previous vaccination was categorized as: none, one dose, full vaccination (two or three doses >14 days before symptoms onset). Data were collected at hospital admission, including demographic and clinical variables, age-unadjusted Charlson Comorbidity index (CCI). The highest intensity of ventilation during hospitalization was registered. The endpoints were in-hospital death (primary) and mechanical ventilation/death (secondary). Survival analysis was conducted by means of Kaplan-Meier curves and Cox regression models. Effect measure modification by age was formally tested. We included 956 patients: 151 (16%) fully vaccinated (18 also third dose), 62 (7%) one dose vaccinated, 743 (78%) unvaccinated. People fully vaccinated were older and suffering from more comorbidities than unvaccinated. By 28 days, the risk of death was of 35.9% (95%CI: 30.1–41.7) in unvaccinated, 41.5% (24.5–58.5) in one dose and 28.4% (18.2–38.5) in fully vaccinated (p = 0.63). After controlling for age, ethnicity, CCI and month of admission, fully vaccinated participants showed a risk reduction of 50% for both in-hospital death, AHR 0.50 (95%CI: 0.30–0.84) and for mechanical ventilation or death, AHR 0.49 (95%CI: 0.35–0.69) compared to unvaccinated, regardless of age (interaction p > 0.56). Fully vaccinated individuals in whom vaccine failed to keep them out of hospital, appeared to be protected against critical disease or death when compared to non-vaccinated. These data support universal COVID-19 vaccination

TRIBE-2: A phase III, randomized, open-label, strategy trial in unresectable metastatic colorectal cancer patients by the GONO group

Background: Chemotherapy plus bevacizumab is a standard first-line treatment for unresectable metastatic colorectal cancer patients. Different chemotherapy backbones may be chosen, including one to three drugs, based on patients' general conditions and comorbidities, treatments' objectives, and disease characteristics. TRIBE trial demonstrated a significant advantage in terms of progression-free survival and overall survival for FOLFOXIRI plus bevacizumab as compared with FOLFIRI plus bevacizumab. Based on recent evidence, the de-intensification of the upfront regimen after 4-6 months of treatment is nowadays regarded as a valuable option. Moreover, the prolonged inhibition of angiogenesis, and in particular the continuation of bevacizumab beyond the evidence of disease progression, is an efficacious strategy in the treatment of metastatic colorectal cancer patients. Methods/design: TRIBE-2 is a prospective, open-label, multicentric phase III randomized trial in which unresectable and previously untreated metastatic colorectal cancer patients are randomized to receive first-line FOLFOX plus bevacizumab followed by FOLFIRI plus bevacizumab after disease progression or FOLFOXIRI plus bevacizumab followed by the re-introduction of the same regimen after disease progression. The primary endpoint is to compare the efficacy of the two proposed treatment strategies in terms of Progression Free Survival 2. Discussion: The TRIBE-2 study aims at answering the question whether the upfront use of FOLFOXIRI improves the clinical outcome of metastatic colorectal cancer patients, when compared with the pre-planned, sequential use of oxaliplatin-based and irinotecan-based doublets. Both proposed treatment strategies are designed to exploit the effectiveness of the prolonged inhibition of angiogenesis, alternating short (up to 4 months) induction periods and less intensive maintenance phases. Trial registration: TRIBE2 is registered at Clinicaltrials.gov: NCT02339116. January 12, 2015. TRIBE-2 is registered at EUDRACT 2014-004436-19, October 10, 2014

ANXIOUS SYMPTOMS IN ADOLESCENTS WITH AUTISM SPECTRUM DISORDER: THE ROLE OF GENDER DIFFERENCES, COGNITIVE STRATEGIES OF EMOTION REGULATION AND PERCEIVED SOCIAL SUPPORT

reservedNegli ultimi anni, la letteratura internazionale ha evidenziato che i soggetti con Disturbo dello Spettro dell’Autismo sembrano mostrare una maggiore vulnerabilità per l’insorgenza di problematiche di salute mentale rispetto alla popolazione generale; tra queste, l’ansia rappresenta una delle condizioni maggiormente frequenti nei soggetti appartenenti allo spettro (Conner et al., 2020; McCauley et al., 2020). Emergono, inoltre, importanti differenze di genere in relazione alla sintomatologia ansiosa: la letteratura ha infatti evidenziato che le donne con ASD presentano livelli di ansia significativamente superiori agli uomini (Sedgewick et al., 2020). Un filone di ricerca ipotizza che le vulnerabilità mostrate dagli individui con ASD possano essere in parte riconducibili alle difficoltà che questi mostrano nei processi di regolazione emotiva (Franciosi, 2017; Cai et al., 2018). È stato inoltre evidenziato che gli individui autistici ricorrerebbero maggiormente a strategie cognitive di regolazione emotiva disfunzionali; tale elemento potrebbe contribuire all’instaurarsi e al mantenersi delle problematiche emotive e comportamentali degli individui con ASD (Samson et al., 2014). Oltre a ciò, la ricerca ha rilevato che bassi livelli di supporto sociale possono rappresentare un importante fattore di rischio per l’esordio di problematiche ansiose; questo parrebbe particolarmente vero in età adolescenziale, periodo in cui le richieste di sviluppo possono aumentare le vulnerabilità dell’individuo (Moeller & Seehuus, 2019). Il ruolo del supporto sociale percepito negli adolescenti con ASD appare ad oggi poco indagato; le poche ricerche in merito hanno evidenziato che gli individui autistici riportano livelli di supporto sociale percepito inferiore ai soggetti a sviluppo tipico (Alvarez‐Fernandez et al., 2017). Il presente studio si propone dunque di analizzare i livelli di ansia in un campione di adolescenti (13-22 anni) con Disturbo dello Spettro Autistico senza associazione di Disabilità Intellettiva (ASD, N=14, 7M e 7F); i risultati saranno confrontati con quelli rivelati su un campione di coetanei a sviluppo tipico (TD, N=14, 7M e 7F). Si indagherà poi il ruolo ricoperto dalle strategie cognitive di regolazione emotiva e dal supporto sociale percepito nell’insorgenza e nel mantenimento dei livelli di ansia rilevati nel campione clinico. Si prenderanno inoltre in considerazione eventuali possibili differenze legate al genere dei partecipanti. Si discuteranno, infine, i risultati dello studio e le implicazioni cliniche ad esso associate

All-optical pulsed writing in azobenzene copolymer films in the sub-millisecond regime

Block copolymers P(MA4-block -MMA)10 and P(MA4- block -MMA)20 and a random copolymer P(MA4-ran-MMA)10 were prepared from azobenzene methacrylate (MA4) and methyl methacrylate (MMA). The former monomer was introduced as both a photoresponsive and a mesogenic component, and the latter as a transparent non-mesogenic component. Thin films of the copolymers were used to investigate all-optical writing by linear-polarized illumination in the pulsed regime to modify the local birefringence at the microscopic scale. The optical properties of P(MA4- block -MMA)10 were compared with those of P(MA4- ran-MMA)10 having the same chemical composition (10 mol% MA4) but different distributions of the two components. It was found that in the block copolymers relatively intense pulses as short as 100 ms produced a remarkable local increase in the birefringence, stable in the time-scale (up to several days) explored in the experiment. In contrast, efficient and stable optical modifications could not be achieved in the random copolymer

Merkel cell carcinoma arising in inguinal lymph node in a patient with von Willebrand disease after multiple blood transfusions

Merkel cell carcinoma (MCC) is an uncommon neuroendocrine tumour of the skin; rare cases have been reported within the lymph nodes without a primary site. The detection of Merkel cell polyomavirus (MCPyV) DNA, integrated within the genome of MCC, suggests its role for the onset of this tumour. We report a case of MCC in an inguinal lymph node of a patient with Von Willebrand disease (VWD), who underwent multiple blood transfusions following haemorrhoidectomy. The diagnosis was performed on the bases of morphology and immunohistochemistry; genomic sequences of LT and VP1 regions of MCPyV were amplified from MCC using a quantitative polymerase chain reaction (qPCR) assay. High levels of MCPyV antibodies were detected in the patient's serum by ELISA method. We discuss the role of MCPyV in the development of this tumour, the use of viral DNA detection for confirming the diagnosis of MCC in unusual sites and the possibility of MCPyV transmission from blood donors