Translationally controlled tumor protein in prostatic adenocarcinoma: correlation with tumor grading and treatment-related changes

12Prostate cancer is the second leading cause of cancer-related death. The androgen deprivation therapy is the standard treatment for advanced stages. Unfortunately, virtually all tumors become resistant to androgen withdrawal. The progression to castration-resistance is not fully understood, although a recent paper has suggested translationally controlled tumor protein to be implicated in the process. The present study was designed to investigate the role of this protein in prostate cancer, focusing on the correlation between its expression level with tumor differentiation and response to treatment. We retrieved 292 prostatic cancer specimens; of these 153 had been treated only by radical prostatectomy and 139 had undergone radical prostatectomy after neoadjuvant treatment with combined androgen blockade therapy. Non-neoplastic controls were represented by 102 prostatic peripheral zone specimens. In untreated patients, the expression of the protein, evaluated by RT-qPCR and immunohistochemistry, was significantly higher in tumor specimens than in non-neoplastic control, increasing as Gleason pattern and score progressed. In treated prostates, the staining was correlated with the response to treatment. An association between protein expression and the main clinicopathological factors involved in prostate cancer aggressiveness was identified. These findings suggest that the protein may be a promising prognostic factor and a target for therapy.openopenRocca, Bruno Jim; Ginori, Alessandro; Barone, Aurora; Calandra, Calogera; Crivelli, Filippo; De Falco, Giulia; Gazaneo, Sara; Tripodi, Sergio; Cevenini, Gabriele; Del Vecchio, Maria Teresa; Ambrosio, Maria Raffaella; Tosi, PieroRocca, BRUNO JIM; Ginori, Alessandro; Barone, Aurora; Calandra, Calogera; Crivelli, Filippo; DE FALCO, Giulia; Gazaneo, Sara; Tripodi, Sergio; Cevenini, Gabriele; DEL VECCHIO, MARIA TERESA; Ambrosio, MARIA RAFFAELLA; Tosi, Pier

Putative role of circulating human papillomavirus DNA in the development of primary squamous cell carcinoma of the middle rectum: a case report

Here we present the case of a patient affected by rectal squamous cell carcinoma in which we demonstrated the presence of Human Papillomavirus (HPV) by a variety of techniques. Collectively, the virus was detected not only in the tumor but also in some regional lymph nodes and in non-neoplastic mucosa of the upper tract of large bowel. By contrast, it was not identifiable in its common sites of entry, namely oral and ano-genital region. We also found HPV DNA in the plasma-derived exosome. Next, by in vitro studies, we confirmed the capability of HPV DNA-positive exosomes, isolated from the supernatant of a HPV DNA positive cell line (CaSki), to transfer its DNA to human colon cancer and normal cell lines. In the stroma nearby the tumor mass we were able to demonstrate the presence of virus DNA in the stromal compartment, supporting its potential to be transferred from epithelial cells to the stromal ones. Thus, this case report favors the notion that human papillomavirus DNA can be vehiculated by exosomes in the blood of neoplastic patients and that it can be transferred, at least in vitro, to normal and neoplastic cells. Furthermore, we showed the presence of viral DNA and RNA in pluripotent stem cells of non-tumor tissue, suggesting that after viral integration (as demonstrated by p16 and RNA in situ hybridization positivity), stem cells might have been activated into cancer stem cells inducing neoplastic transformation of normal tissue through the inactivation of p53, p21, and Rb. It is conceivable that the virus has elicited its oncogenic effect in this specific site and not elsewhere, despite its wide anatomical distribution in the patient, for a local condition of immune suppression, as demonstrated by the increase of T-regulatory (CD4/CD25/FOXP3 positive) and T-exhausted (CD8/PD-1positive) lymphocytes and the M2 polarization (high CD163/CD68 ratio) of macrophages in the neoplastic microenvironment. It is noteworthy that our findings depicted a static picture of a long-lasting dynamic process that might evolve in the development of tumors in other anatomical sites. Copyright © 2019 Ambrosio, Vernillo, De Carolis, Carducci, Mundo, Ginori, Rocca, Nardone, Lucenti Fei, Carfagno, Lazzi, Cricca and Tosi

Benda-BEAM High-Dose Therapy Prior to Auto-SCT is Effective in Resistant/Relapsed DLBCL

Abstract Background: The most important drawback of clinical trials of high-dose therapy (HDT) followed by autologous stem cell transplant (ASCT) in lymphomas is the high heterogeneity of histological entities. Therefore, the statistical power is reduced, and data are not conclusive. We previously demonstrated the safety of a new conditioning regimen with bendamustine, etoposide, cytarabine, and melphalan (BeEAM) prior to ASCT in resistant/relapsed lymphoma patients. This combination of drugs was able to induce a high CR rate in a population that did not have an opportunity of being cured with other therapies. However, that study enrolled both Hodgkin and non-Hodgkin lymphoma patients. Aims: We designed a phase II study to evaluate the efficacy of the BeEAM conditioning in resistant/relapsed diffuse large B-cell non-Hodgkin lymphoma (DLBCL) patients. Patients and methods: The study was registered at European Union Drug Regulating Authorities Clinical Trials (EudraCT) N. 2011-001246-14. Until now, 61 patients (median age 54 years, range 19-69) with resistant/relapsed DLBCL were enrolled. The primary end-point of the study is to evaluate the 1-year complete remission rate. Results: Briefly, 46/61 patients had advanced stage disease (III-IV); 20 were primary refractory and 41 had relapsed after a median number of 2 lines of therapy (range: 1-3). Twenty-one patients had 1 or more relevant comorbidities (range: 1- 5). 30 patients were in II or subsequent CR after salvage therapy, whereas 27 were in PR and 4 had stable or progressive disease. A median number of 5.72x106 CD34+/kg cells (range 2.21-10.60) collected from peripheral blood was reinfused to patients. All patients engrafted, with a median time to ANC>0.5x109/l of 10 days. Median times to achieve a platelet count >20x109/l and >50x109/l were 12 and 17 days respectively. Twenty-two out of 61 patients presented a fever of unknown origin (36%), whereas 24 patients (39%) presented a clinically documented infection. All patients received G-CSF after transplant for a median time of 8 days (range: 8-13). One patient died due to an incomplete hematological recovery after transplant, producing an overall transplant related mortality of 2.7%. Fifty-seven patients are evaluable for response: 48/57 (84%) obtained a CR, 3/57 (5%) a PR, whereas 6/57 (11%) did not respond to therapy. After a median follow-up of 10.5 months after transplant (range 3-37), 6/57 (11%) patients were refractory, 12/57 (21%) relapsed and 39/57 (68%) are still alive, in continuous CR. Conclusion: Our clinical trial was designed to closely resemble real-world treatment for these patients. During the study, we transplanted a similar proportion of the patients that would have received ASCT in a real-world scenario. While we cannot make sound comparisons without head-to-head trials, results from previous studies using HDT regimens in DLCBL have not been as encouraging as ours. Accordingly, our data preliminary provide the evidence that the Benda-BEAM regimen is safe and has promising high efficacy in resistant-relapsed aggressive DLBCL patients. Acknowledgments: The study was supported in part by AIL Pesaro Onlus. Mundipharma Italy is grateful acknowledged for providing Bendamustine free of charge. Disclosures Patriarca: Janssen-Cilag, Celgene, Merck Sharp & Dohme: Honoraria. Zinzani:Gilead: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; J&J: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees

INCB84344-201: Ponatinib and steroids in frontline therapy for unfit patients with Ph+ acute lymphoblastic leukemia

Tyrosine kinase inhibitors have improved survival for patients with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL). However, prognosis for old or unfit patients remains poor. In the INCB84344-201 (formerly GIMEMA LAL 1811) prospective, multicenter, phase 2 trial, we tested the efficacy and safety of ponatinib plus prednisone in newly diagnosed patients with Ph+ ALL 6560 years, or unfit for intensive chemotherapy and stem cell transplantation. Forty-four patients received oral ponatinib 45 mg/d for 48 weeks (core phase), with prednisone tapered to 60 mg/m2/d from days-14-29. Prophylactic intrathecal chemotherapy was administered monthly. Median age was 66.5 years (range, 26-85). The primary endpoint (complete hematologic response [CHR] at 24 weeks) was reached in 38/44 patients (86.4%); complete molecular response (CMR) in 18/44 patients (40.9%) at 24 weeks. 61.4% of patients completed the core phase. As of 24 April 2020, median event-free survival was 14.31 months (95% CI 9.30-22.31). Median overall survival and duration of CHR were not reached; median duration of CMR was 11.6 months. Most common treatment-emergent adverse events (TEAEs) were rash (36.4%), asthenia (22.7%), alanine transaminase increase (15.9%), erythema (15.9%), and \u3b3-glutamyltransferase increase (15.9%). Cardiac and vascular TEAEs occurred in 29.5% (grade 653, 18.2%) and 27.3% (grade 653, 15.9%), respectively. Dose reductions, interruptions, and discontinuations due to TEAEs occurred in 43.2%, 43.2%, and 27.3% of patients, respectively; 5 patients had fatal TEAEs. Ponatinib and prednisone showed efficacy in unfit patients with Ph+ ALL; however, a lower ponatinib dose may be more appropriate in this population. This trial was registered at www.clinicaltrials.gov as #NCT01641107

Development and Implementation of the AIDA International Registry for Patients with Non-Infectious Scleritis

Introduction This article points out the design, methods, development and deployment of the international registry promoted by the AutoInflammatory Disease Alliance (AIDA) Network with the aim to define and assess paediatric and adult patients with immune-mediated scleritis. Methods This registry collects both retrospective and prospective real-world data from patients with non-infectious scleritis through the Research Electronic Data Capture (REDCap) tool and aims to promote knowledge and real-life evidence from patients enrolled worldwide; the registry also allows the collection of standardised data, ensuring the highest levels of security and anonymity of patients' data and flexibility to change according to scientific acquisitions over time. The communication with other similar registries has been also ensured in order to pursue the sustainability of the project with respect to the adaptation of collected data to the most diverse research projects. Results Since the launch of the registry, 99 centres have been involved from 20 countries and four continents. Forty-eight of the centres have already obtained a formal approval from their local ethics committees. At present, the platform counts 259 users (95 principal investigators, 160 site investigators, 2 lead investigators, and 2 data managers); the platform collects baseline and follow-up data using 3683 fields organised into 13 instruments, including patient's demographics, history, symptoms, trigger or risk factors, therapies and healthcare utilization. Conclusions The development of the AIDA International Registry for patients with non-infectious scleritis will allow solid research on this rare condition. Real-world evidence resulting from standardised real-life data will lead to the optimisation of routine clinical and therapeutic management, which are currently limited by the rarity of this ocular inflammatory condition

Development and Implementation of the AIDA International Registry for Patients with Non-Infectious Uveitis

Introduction: The aim of this paper is to point out the design, development and deployment of the AutoInflammatory Disease Alliance (AIDA) International Registry for paediatric and adult patients with non-infectious uveitis (NIU). Methods: This is a physician-driven, population- and electronic-based registry implemented for both retrospective and prospective collection of real-world demographics, clinical, laboratory, instrumental and socioeconomic data of patients with uveitis and other non-infectious inflammatory ocular diseases recruited through the AIDA Network. Data recruitment, based on the Research Electronic Data Capture (REDCap) tool, is thought to collect standardised information for real-life research and has been developed to change over time according to future scientific acquisitions and potentially communicate with other similar instruments. Security, data quality and data governance are cornerstones of this platform. Results: Ninety-five centres have been involved from 19 countries and four continents from 24 March to 16 November 2021. Forty-eight out of 95 have already obtained the approval from their local ethics committees. At present, the platform counts 259 users (95 principal investigators, 160 site investigators, 2 lead investigators, and 2 data managers). The AIDA Registry collects baseline and follow-up data using 3943 fields organised into 13 instruments, including patient's demographics, history, symptoms, trigger/risk factors, therapies and healthcare utilization for patients with NIU. Conclusions: The development of the AIDA Registry for patients with NIU will facilitate the collection of standardised data leading to real-world evidence and enabling international multicentre collaborative research through inclusion of patients and their families worldwide

Clinical characteristics and risk factors associated with COVID-19 severity in patients with haematological malignancies in Italy: a retrospective, multicentre, cohort study

Several small studies on patients with COVID-19 and haematological malignancies are available showing a high mortality in this population. The Italian Hematology Alliance on COVID-19 aimed to collect data from adult patients with haematological malignancies who required hospitalisation for COVID-19

ECMO for COVID-19 patients in Europe and Israel

Since March 15th, 2020, 177 centres from Europe and Israel have joined the study, routinely reporting on the ECMO support they provide to COVID-19 patients. The mean annual number of cases treated with ECMO in the participating centres before the pandemic (2019) was 55. The number of COVID-19 patients has increased rapidly each week reaching 1531 treated patients as of September 14th. The greatest number of cases has been reported from France (n = 385), UK (n = 193), Germany (n = 176), Spain (n = 166), and Italy (n = 136) .The mean age of treated patients was 52.6 years (range 16–80), 79% were male. The ECMO configuration used was VV in 91% of cases, VA in 5% and other in 4%. The mean PaO2 before ECMO implantation was 65 mmHg. The mean duration of ECMO support thus far has been 18 days and the mean ICU length of stay of these patients was 33 days. As of the 14th September, overall 841 patients have been weaned from ECMO support, 601 died during ECMO support, 71 died after withdrawal of ECMO, 79 are still receiving ECMO support and for 10 patients status n.a. . Our preliminary data suggest that patients placed on ECMO with severe refractory respiratory or cardiac failure secondary to COVID-19 have a reasonable (55%) chance of survival. Further extensive data analysis is expected to provide invaluable information on the demographics, severity of illness, indications and different ECMO management strategies in these patients

Differential cross section measurements for the production of a W boson in association with jets in proton–proton collisions at √s = 7 TeV

Measurements are reported of differential cross sections for the production of a W boson, which decays into a muon and a neutrino, in association with jets, as a function of several variables, including the transverse momenta (pT) and pseudorapidities of the four leading jets, the scalar sum of jet transverse momenta (HT), and the difference in azimuthal angle between the directions of each jet and the muon. The data sample of pp collisions at a centre-of-mass energy of 7 TeV was collected with the CMS detector at the LHC and corresponds to an integrated luminosity of 5.0 fb[superscript −1]. The measured cross sections are compared to predictions from Monte Carlo generators, MadGraph + pythia and sherpa, and to next-to-leading-order calculations from BlackHat + sherpa. The differential cross sections are found to be in agreement with the predictions, apart from the pT distributions of the leading jets at high pT values, the distributions of the HT at high-HT and low jet multiplicity, and the distribution of the difference in azimuthal angle between the leading jet and the muon at low values.United States. Dept. of EnergyNational Science Foundation (U.S.)Alfred P. Sloan Foundatio

Penilaian Kinerja Keuangan Koperasi di Kabupaten Pelalawan

This paper describe development and financial performance of cooperative in District Pelalawan among 2007 - 2008. Studies on primary and secondary cooperative in 12 sub-districts. Method in this stady use performance measuring of productivity, efficiency, growth, liquidity, and solvability of cooperative. Productivity of cooperative in Pelalawan was highly but efficiency still low. Profit and income were highly, even liquidity of cooperative very high, and solvability was good