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Contains fulltext : 235433.pdf (Publisher’s version ) (Open Access), BACKGROUND: Innovative strategies to fully exploit the antitumor activity of multitargeted tyrosine kinase inhibitors (TKIs) are urgently needed. Higher concentrations of TKIs at their target site, i.e. intratumorally, may lead to broader kinase inhibition, which might be essential for the optimal suppression of tumor growth and induction of apoptosis. To reach these higher intratumoral concentrations, without encountering dose limiting toxicity, alternative TKI dosing strategies employing higher daily and high intermittent doses have been studied. In this systematic review, we evaluated the current clinical evidence to support (intermittent) high TKI dosing regimens. METHODS: A systematic review was conducted in the following databases: PubMed®, EMBASE® and Cochrane Library©, to evaluate efficacy of alternatively scheduled high-dosed regimen (a higher dose in a regular daily schedule than registered or a higher dose in an alternative intermittent schedule) of TKIs in (haemato-)oncology. Data were extracted independently by two authors according to predefined criteria. Extracted data were tabulated to summarize key findings. RESULTS: Out of twenty studies that met the inclusion criteria, thirteen investigated higher daily dose schedules of either afatinib, axitinib, erlotinib, gefitinib, imatinib, sorafenib, and sunitinib. Five of these studies included pharmacokinetic analyses, reporting marginal higher maximum drug concentrations (C(max)) in plasma (1.3-4-fold higher) compared to the standard dose schedules. Seven clinical trials investigated intermittent high-dose schedules requiring treatment breaks, with the following TKIs: afatinib, erlotinib, gefitinib, lapatinib, sorafenib, and sunitinib. Six of these included pharmacokinetic results, all reporting higher (2-21-fold) C(max) in plasma compared to the standard daily dose schedule, with manageable toxicity. No data on tumor concentrations were presented. Data on the efficacy outcomes were limited due to small s

BACKGROUND: Emerging data suggest that metastasis is a spectrum of disease burden rather than a binary state, and local therapies, such as radiation, might improve outcomes in oligometastasis. However, current definitions of oligometastasis are solely numerical. OBJECTIVE: To characterize the somatic mutational landscape across the disease spectrum of metastatic castration-sensitive prostate cancer (mCSPC) to elucidate a biological definition of oligometastatic CSPC. DESIGN, SETTING, AND PARTICIPANTS: This was a retrospective study of men with mCSPC who underwent clinical-grade sequencing of their tumors (269 primary tumor, 25 metastatic sites). Patients were classified as having biochemically recurrent (ie, micrometastatic), metachronous oligometastatic (≤5 lesions), metachronous polymetastatic (>5 lesions), or de novo metastatic (metastasis at diagnosis) disease. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We measured the frequency of driver mutations across metastatic classifications and the genomic associations with radiographic progression-free survival (rPFS) and time to castrate-resistant prostate cancer (CRPC). RESULTS AND LIMITATIONS: The frequency of driver mutations in TP53 (p = 0.01), WNT (p = 0.08), and cell cycle (p = 0.04) genes increased across the mCSPC spectrum. TP53 mutation was associated with shorter rPFS (26.7 vs 48.6 mo; p = 0.002), and time to CRPC (95.6 vs 155.8 mo; p = 0.02) in men with oligometastasis, and identified men with polymetastasis with better rPFS (TP53 wild-type, 42.7 mo; TP53 mutated, 18.5 mo; p = 0.01). Mutations in TP53 (incidence rate ratio [IRR] 1.45; p = 0.004) and DNA double-strand break repair (IRR 1.61; p < 0.001) were associated with a higher number of metastases. Mutations in TP53 were also independently associated with shorter rPFS (hazard ratio [HR] 1.59; p = 0.03) and the development of CRPC (HR 1.71; p = 0.01) on multivariable analysis. This study was limited by its retrospective nature, sample size

Questa epoca in cui già siamo come condizione permanente, e che abbiamo co-costruito proprio con la nostra modernità e libertà del carbonio, apre una riflessione profonda sulla condizione umana e sulle relazioni che intratteniamo con altri esseri viventi a cui siamo interdipendenti: ciò che era distanziato come “roba” (Illich,1988) a disposizione riemerge come molteplicità di soggetti vibranti, pulsanti, caotici o in via di estinzione o collasso. La natura, come campo di “oggetti” di gestione della modernità capitalistica, pullula tutto ad un tratto di soggetti che riemergono, tra cui le stesse dimensioni atmosferiche, tanto da assoggettare l’uomo e mettere a repentaglio le forme di vivibilità. Da un unico, solitario, soggetto umano del cambiamento e della padronanza, unico attore con potere di valutazione, altri soggetti mai sopiti emergono come interdipendenti. L’idea dell’uomo come misura di ogni cosa si rivela rappresentazione perturbante nel momento in cui si ritrova di fronte ad altri attori non-umani a cui è intimamente interdipendente senza saperne leggere e accogliere le relazioni e le misure della terra come organismo vivente. La terra stessa si impone come soggetto diritto accanto agli uomini, facendo tremare il nostro antropocentrismo nel momento in cui ci accorgiamo di limiti, di essere coinvolti in relazioni di interdipendenza o a fronte di scenari di collasso ambientale. L’ambiente, compresa l’atmosfera, mostra tutto ad un tratto la sua agency, i suoi cambiamenti così interdipendenti dalle forme di surriscaldamento globale: ciò destabilizza, rende incerte le categorie ben ordinate e sempre più sgretolate tra cultura e natura, tra saperi dell’uomo e saperi della natura, aprendo un temporale di incertezze, un terremoto quindi nel mondo e nel modo di comprendere il mondo. «La materia dell’Antropocene si è animata, si è presa lei la nostra in/capacità di agency» (Beugleux, 2017: 92), dove ciò che avevamo tradotto in magazzino e discarica si

Background Aurora kinase overexpression or amplifications are associated with high proliferation, poor prognosis, and therapeutic resistance in human tumors. AMG 900 is an investigational, oral, selective pan-Aurora kinase inhibitor. Methods This first-in-human trial included dose-escalation and dose-expansion phases (ClinicalTrials.gov: NCT00858377). Dose escalation evaluated the safety, tolerability, and pharmacokinetics of AMG 900 in advanced solid tumors and determined the maximum tolerated dose (MTD) with/without granulocyte colony-stimulating factor (G-CSF) prophylaxis. Dose expansion evaluated clinical activity in three tumor types: taxane- and platinum-resistant ovarian cancer, taxane-resistant triple-negative breast cancer (TNBC), and castration-resistant and taxane- or cisplatin/etoposide-resistant prostate cancer (CRPC). AMG 900 was administered 4 days on/10 days off at 1-50 mg/day during escalation and at the MTD with G-CSF during expansion. Results AMG 900 showed rapid absorption with fast clearance, supporting once-daily dosing. The MTD was 25 mg/day, increasing to 40 mg/day with G-CSF. Grade >= 3 treatment-related adverse events included neutropenia (37%), anemia (23%), leukopenia (14%), and thrombocytopenia (12%). During dose expansion, 3/29 (10.3%, 95% CI: 2.0%-28.0%) evaluable patients with ovarian cancer experienced partial response by central imaging per RECIST 1.1; median duration of response was 24.1 weeks (95% CI: 16.1-34.1). Seven patients (24.1%, 95% CI: 10.3%-43.5%) experienced partial response per Gynecologic Cancer InterGroup criteria; 5/9 patients positive for p53 expression responded to treatment. No objective responses were observed in patients with TNBC or CRPC per RECIST 1.1. Conclusions AMG 900 40 mg/day with G-CSF had manageable toxicity and demonstrated single-agent activity in patients with heavily pretreated, chemotherapy-resistant ovarian cancer.Copyright © 2018, Springer Science+Business Media, LLC, part of Springer Nature.