Real-world efficacy and safety of nivolumab in previously-treated metastatic renal cell carcinoma, and association between immune-related adverse events and survival: the Italian expanded access program

Background: The Italian Renal Cell Cancer Early Access Program was an expanded access program that allowed access to nivolumab, for patients (pts) with metastatic renal cell carcinoma (mRCC) prior to regulatory approval. Methods: Pts with previously treated advanced or mRCC were eligible to receive nivolumab 3 mg/kg every 2 weeks. Pts included in the analysis had received ≥1 dose of nivolumab and were monitored for drug-related adverse events (drAEs) using CTCAE v.4.0. Immune-related (ir) AEs were defined as AEs displaying a certain, likely or possible correlation with immunotherapy (cutaneous, endocrine, hepatic, gastro-intestinal and pulmonary). The association between overall survival (OS) and irAEs was assessed, and associations between variables were evaluated with a logistic regression model. Results: A total of 389 pts were enrolled between July 2015 and April 2016. Overall, the objective response rate was 23.1%. At a median follow-up of 12 months, the median progression-free survival was 4.5 months (95% CI 3.7-6.2) and the 12-month overall survival rate was 63%. Any grade and grade 3-4 drAEs were reported in 124 (32%) and 27 (7%) of pts, respectively, and there were no treatment-related deaths. Any grade irAEs occurred in 76 (20%) of patients, 8% cutaneous, 4% endocrine, 2% hepatic, 5% gastro-intestinal and 1% pulmonary. Of the 22 drAEs inducing treatment discontinuation, 10 (45%) were irAEs. Pts with drAEs had a significantly longer survival than those without drAEs (median OS 22.5 versus 16.4 months, p = 0.01). Pts with irAEs versus without irAEs had a more significant survival benefit (median OS not reached versus 16.8 months, p = 0.002), confirmed at the landmark analysis at 6 weeks. The occurrence of irAEs displayed a strong association with OS in univariable (HR 0.48, p = 0.003) and multivariable (HR 0.57, p = 0.02) analysis. Conclusions: The appearance of irAEs strongly correlates with survival benefit in a real-life population of mRCC pts treated with nivolumab

Duration of adjuvant chemotherapy for stage III colon cancer

BACKGROUND Since 2004, a regimen of 6 months of treatment with oxaliplatin plus a fluoropyrimidine has been standard adjuvant therapy in patients with stage III colon cancer. However, since oxaliplatin is associated with cumulative neurotoxicity, a shorter duration of therapy could spare toxic effects and health expenditures. METHODS We performed a prospective, preplanned, pooled analysis of six randomized, phase 3 trials that were conducted concurrently to evaluate the noninferiority of adjuvant therapy with either FOLFOX (fluorouracil, leucovorin, and oxaliplatin) or CAPOX (capecitabine and oxaliplatin) administered for 3 months, as compared with 6 months. The primary end point was the rate of disease-free survival at 3 years. Noninferiority of 3 months versus 6 months of therapy could be claimed if the upper limit of the two-sided 95% confidence interval of the hazard ratio did not exceed 1.12. RESULTS After 3263 events of disease recurrence or death had been reported in 12,834 patients, the noninferiority of 3 months of treatment versus 6 months was not confirmed in the overall study population (hazard ratio, 1.07; 95% confidence interval [CI], 1.00 to 1.15). Noninferiority of the shorter regimen was seen for CAPOX (hazard ratio, 0.95; 95% CI, 0.85 to 1.06) but not for FOLFOX (hazard ratio, 1.16; 95% CI, 1.06 to 1.26). In an exploratory analysis of the combined regimens, among the patients with T1, T2, or T3 and N1 cancers, 3 months of therapy was noninferior to 6 months, with a 3-year rate of disease-free survival of 83.1% and 83.3%, respectively (hazard ratio, 1.01; 95% CI, 0.90 to 1.12). Among patients with cancers that were classified as T4, N2, or both, the disease-free survival rate for a 6-month duration of therapy was superior to that for a 3-month duration (64.4% vs. 62.7%) for the combined treatments (hazard ratio, 1.12; 95% CI, 1.03 to 1.23; P=0.01 for superiority). CONCLUSIONS Among patients with stage III colon cancer receiving adjuvant therapy with FOLFOX or CAPOX, noninferiority of 3 months of therapy, as compared with 6 months, was not confirmed in the overall population. However, in patients treated with CAPOX, 3 months of therapy was as effective as 6 months, particularly in the lower-risk subgroup. (Funded by the National Cancer Institute and others.

“Randomised, open-label, phase II trial of paclitaxel, gemcitabine and cisplatin versus gemcitabine and cisplatin as first-line chemotherapy in advanced transitional cell carcinoma of the urothelium”

The purpose of the study was to evaluate the antitumor activity and the safety of paclitaxel combined with gemcitabine and cisplatin in patients affected by advanced transitional cell carcinoma of the urothelium (TCC). Eighty-five patients affected by advanced TCC and measurable disease were randomized to receive either paclitaxel at dosage of 70 mg/m2, gemcitabine 1000 mg/m2 and cisplatin 35 mg/m2 on days 1 and 8 every 3 weeks (GCP) or gemcitabine 1000 mg/m2 on days 1, 8, 15 and cisplatin 70 mg/m2 on day 2 every 4 weeks (GC). All enrolled patients were considered evaluable for response and toxicity (intention to treat). The observed response rate was 43% for GCP and 44% for GC combination, respectively. Median time to treatment failure was 32 weeks for GCP and 26 weeks for GC and overall survival 61 vs 49 weeks, respectively (p-value not significant). Grade 3-4 neutropenia was observed in 49% of patients treated with GCP vs 35% of those treated with GC (P=0.05) and grade 3-4 thrombocytopenia was observed in 36% of GCP treated patients as compared to 21% of those treated with GC (P=0.01). Seven patients over 70 years old or with poor PS were removed from the study: 6 patients from GCP group (2 toxic deaths, 2 grade 4 myelotoxicity and 2 grade 3 asthenia) and 1 from GC group was lost to follow-up after the first cycle. The combination of paclitaxel, gemcitabine and cisplatin is effective in the treatment of TCC. However, the addition of paclitaxel to the combination of gemcitabine plus cisplatin seems to increase toxicity, therefore it seems not suitable for poor PS patients and those over 70 years old. Larger and more powered studies are needed to exactly define the role of paclitaxel in this combination

Adaptive remodeling of the bacterial proteome by specific ribosomal modification regulates Pseudomonas infection and niche colonisation

Post-transcriptional control of protein abundance is a highly important, underexplored regulatory process by which organisms respond to their environments. Here we describe an important and previously unidentified regulatory pathway involving the ribosomal modification protein RimK, its regulator proteins RimA and RimB, and the widespread bacterial second messenger cyclic-di-GMP (cdG). Disruption of rimK affects motility and surface attachment in pathogenic and commensal Pseudomonas species, with rimK deletion significantly compromising rhizosphere colonisation by the commensal soil bacterium P. fluorescens, and plant infection by the pathogens P. syringae and P. aeruginosa. RimK functions as an ATP-dependent glutamyl ligase, adding glutamate residues to the C-terminus of ribosomal protein RpsF and inducing specific effects on both ribosome protein complement and function. Deletion of rimK in P. fluorescens leads to markedly reduced levels of multiple ribosomal proteins, and also of the key translational regulator Hfq. In turn, reduced Hfq levels induce specific downstream proteomic changes, with significant increases in multiple ABC transporters, stress response proteins and non-ribosomal peptide synthetases seen for both ΔrimK and Δhfq mutants. The activity of RimK is itself controlled by interactions with RimA, RimB and cdG. We propose that control of RimK activity represents a novel regulatory mechanism that dynamically influences interactions between bacteria and their hosts; translating environmental pressures into dynamic ribosomal changes, and consequently to an adaptive remodeling of the bacterial proteome

The diagnosis and management of gastric cancer: expert discussion and recommendations from the 12th ESMO/World Congress on Gastrointestinal Cancer, Barcelona, 2010

Well-recognized experts in the field of gastric cancer discussed during the 12th European Society Medical Oncology (ESMO)/World Congress Gastrointestinal Cancer (WCGIC) in Barcelona many important and controversial topics on the diagnosis and management of patients with gastric cancer. This article summarizes the recommendations and expert opinion on gastric cancer. It discusses and reflects on the regional differences in the incidence and care of gastric cancer, the definition of gastro-esophageal junction and its implication for treatment strategies and presents the latest recommendations in the staging and treatment of primary and metastatic gastric cancer. Recognition is given to the need for larger and well-designed clinical trials to answer many open question

The IDEA (International Duration Evaluation of Adjuvant Chemotherapy) Collaboration: Prospective Combined Analysis of Phase III Trials Investigating Duration of Adjuvant Therapy with the FOLFOX (FOLFOX4 or Modified FOLFOX6) or XELOX (3 versus 6 months) Regimen for Patients with Stage III Colon Cancer: Trial Design and Current Status

The International Duration Evaluation of Adjuvant Chemotherapy (IDEA) collaboration was established to prospectively combine and analyze data from several randomized trials conducted around the world to answer whether a three-month course of oxaliplatin-based adjuvant therapy (FOLFOX4/modified FOLFOX6 or XELOX) is non-inferior to the current standard six-month treatment for patients with stage III colon cancer, with a primary endpoint of three years disease-free survival. The IDEA steering committee comprises two members from each group coordinating an individual trial and two members from a secretariat who coordinate combining of the data and management of the joint analysis. Members of the IDEA agreed to combine the data from their individual trials to enable definitive analysis consisting of at least 10,500 patients. With accrual of 8,797 patients at the end of February 2013, the IDEA is on track to achieve its accrual objective of at least 10,500 patients by the end of 2013

L’ORALITÀ A SCUOLA, DA PLATONE AL PORTFOLIO EUROPEO DELLE LINGUE

L'oralità risulta primaria rispetto alla scrittura sia per quanto riguarda la razza umana (filogenesi) sia per quanto riguarda lo sviluppo individuale (ontogenesi), tuttavia essa ha sempre goduto di minor prestigio della scrittura. Nella prima parte di questo articolo sono ricostruiti i diversi momenti in cui questa gerarchia è stata fondata e si è affermata stabilmente: dai contrasti epocali tra Socrate e  Platone da una parte e i Sofisti dall'altra all'affermazione della centralità della scrittura da parte di Aristotele e degli aristotelici; fino, poi, all'Illuminismo, in cui l'oralità veniva ormai identificata con l'inciviltà, la rozzezza e l'arretratezza, posizione che in qualche misura permane ancora oggi. Nella seconda parte dell'articolo si ricostruisce il graduale recupero del valore dell'oralità nell'insegnamento linguistico, attraverso un'analisi dei programmi scolastici italiani, dalla Legge Casati del 1859 ai Programmi della scuola media e di quella elementare rispettivamente del 1979 e del 1985, alle più recenti "Indicazioni Moratti e infine alle "Indicazioni Fioroni". In queste ultime si sottolinea la necessità di finalizzare l'insegnamento dell'oralità anche a scopi interculturali più ampi, prioritari nella società attuale, quali il rispetto e la promozione delle differenze linguistiche e culturali, lo sviluppo del plurilinguismo; la centralità e l'autonomia dell'apprendente.   Historically, the oral tradition has been more important than writing, both in human history (philogenesis) and in individual, personal history (onthogenesis), but it has always had far less prestige. The first part of this paper surveys important moments in the formation and establishment of this hierarchy, starting from the fundamental contrast between the Sophists on the one hand, and Socrates and Plato from the other, to the centrality of Aristotle and Aristotelianism, up to the Age of Enlightenment and the identification between orality, barbarism and roughness, still common today. In the second part, the gradual rediscovery and positive reevaluation of the oral tradition in language teaching is mapped out. Italian school programmes are analyzed, from Legge Casati (1859)  to the Programmes of 1979 and 1985, up to the recent 'Indicazioni Moratti' and 'Indicazioni Fioroni'. These latest pieces of legislation underline the need to highlight the oral tradition within didactics to meet the wider intercultural  goals that today have become real priorities.  This in order to promote respect for linguistic and cultural diversity, the development of plurilingualism as well as the centrality and autonomy of learners within the learning process. &nbsp

Scuola e alfabetizzazione in Italia. Caratteri e limiti di una correlazione spuria

The functional alphabetical competence and the competence in the matter of citizenship are closely interconnected in the training of the young person: their close functional link is well expressed and well-argued by the Recommendations of the Council of the European Union (in particular from that of 2018) within the general framework of key competences for learning, but in reality it occupies a strand of western thought that goes back so far as to be considered traditional, and takes up ideas and proposals advanced in the last half century mainly by Tullio De Mauro, through the principles of democratic linguistic education. The current cultural climate brings to the fore the link between language and citizenship and outlines a framework of educational obligations which the school cannot escape. But an examination of the limits and difficulties of the Italian school leads to downsizing the most advanced objectives, while aiming to respect the basic objectives indicated by the Council of the European Union. In conclusion, we propose a Decalogue of operational choices that take into account both the essential objectives that cannot be renounced and the current difficulties of the Italian school