Search

Background: Increased success in the treatment of hematological cancers contributed to the increase of 5-year survival for most adolescent and young adults (AYAs) with these tumours. However, as 5-year survival increased, it became clear that AYA long-term survivors were at increased risk for severe late effects. Moreover, limited information on long-term cancer impact is available for AYAs, since most studies focused on children and adolescents. We aimed to assess various long-term outcomes on AYA survivors of hematological cancers. Methods: We selected patients diagnosed with a first primary hematological cancer between 1997 and 2006, in the Italian nationwide population-based cohort of AYA cancer survivors (i.e. alive at least 5 years after cancer diagnosis). Long-term outcomes of interest were: second malignant neoplasms (SMNs), hospitalizations and overall mortality. We calculated standardized incidence ratios (SIRs), standardized hospitalization rate ratios (SHRs) and standardized mortality rate ratios (SMRs). To study morbidity patterns over time, we modeled observed incidence rates by fitting flexible parametric models for nonlinear patterns and we used linear regression for linear patterns. Results: The study cohort included 5,042 AYA hematological cancer survivors of which 1,237 and 3,805 had a leukaemia and lymphoma diagnosis, respectively. AYA survivors were at substantially increased risk for SMN (SIR=2.1; 95%CI=1.7; 2.6), hospitalisation (SHR=1.5; 95%CI=1.5; 1.6), and mortality (SMR=1.4; 95%CI=1.2; 1.6) with differences between leukaemia and lymphoma survivors. The highest excess risks of hospitalisations were for infectious diseases, respiratory diseases, and diseases of blood and blood-forming organs. The morbidity pattern differs over time by morbidity type. Conclusions: Our results support the need for strict follow-up plans for survivors, and call for further study to better personalised follow-up plans for AYA cancer survivors.

Contains fulltext : 251611.pdf (Publisher’s version ) (Open Access)

The XPO1/CRM1 inhibitor selinexor (KPT-330), is currently being evaluated in multiple clinical trials as an anticancer agent. XPO1 participates in the nuclear export of FoxO-1, which we previously found to be decreased in platinum-resistant ovarian carcinoma. The aim of this study was to determine whether enriching FoxO-1 nuclear localization using selinexor would increase ovarian cancer cell sensitivity to cisplatin. Selinexor, as a single agent, displayed a striking antiproliferative effect in different ovarian carcinoma cell lines. A schedule-dependent synergistic effect of selinexor in combination with cisplatin was found in cisplatin-sensitive IGROV-1, the combination efficacy being more evident in sensitive than in the resistant cells. In IGROV-1 cells, the combination was more effective when selinexor followed cisplatin exposure. A modulation of proteins involved in apoptosis (p53, Bax) and in cell cycle progression (p21WAF1) was found by Western blotting. Selinexor-treated cells exhibited enriched FoxO-1 nuclear staining. Knock-down experiments with RNA interference indicated that FOXO1-silenced cells displayed a reduced sensitivity to selinexor. FOXO1 silencing also tended to reduce the efficacy of the drug combination at selected cisplatin concentrations. Selinexor significantly inhibited tumor growth, induced FoxO-1 nuclear localization and improved the efficacy of cisplatin in IGROV-1 xenografts. Taken together, our results support FoxO-1 as one of the key factors promoting sensitivity towards selinexor and the synergistic interaction between cisplatin and selinexor in ovarian carcinoma cells with selected molecular backgrounds, highlighting the need for treatment regimens tailored to the molecular tumor features.

Cerebral amyloid angiopathy (CAA) is one of the major types of cerebral small vessel disease, and a leading cause of spontaneous intracerebral hemorrhage and cognitive decline in elderly patients. Although increasingly detected, a number of aspects including the pathophysiology, the clinical and neuroradiological phenotype, and the disease course are still under investigation. The incomplete knowledge of the disease limits the implementation of evidence-based guidelines on patient’s clinical management and the development of treatments able to prevent or reduce disease progression. The SENECA (SEarchiNg biomarkErs of Cerebral Angiopathy) project is the first Italian multicenter cohort study aimed at better defining the disease natural history and identifying clinical and neuroradiological markers of disease progression. By a multidisciplinary approach and the collection of a large and well-phenotyped series and biorepository of CAA patients, the study is ultimately expected to improve the diagnosis and the knowledge of CAA pathophysiological mechanisms.

Background: Scant real-world data exist on the clinical outcomes associated with the use of bevacizumab-containing chemotherapy (B+CT) in patients with metastatic colorectal cancer (mCRC). The primary objective of the GRETA cohort study was to compare the overall survival (OS) of patients with mCRC treated with first-line B+CT versus chemotherapy (CT) alone, in an Italian clinical practice setting. Materials and Methods: Incident patients with mCRC were identified during the period 2010–2012 from five population-based cancer registries in Italy. Cases were linked to regional health care utilization databases to obtain the entire spectrum of health services provided to each patient. Patients starting a first-line treatment with B+CT or CT alone within 90 days from the diagnosis were included in the study cohort. A propensity score (PS) method was applied to account for residual confounding. Results: Of 480 patients with mCRC included in the study cohort, 21.0 received first-line B+CT, and 79.0% received CT. Patients receiving B+CT were younger (p <.001) and underwent surgery more frequently (p =.001). The median OS was 22.5 and 14.6 months for B+CT and CT, respectively (p =.011). The corresponding hazard ratios adjusted by multivariate modeling and PS matched analysis were 0.82 (95% confidence interval [CI], 0.62–1.08) and 0.86 (95% CI, 0.56–1.33), respectively. Similar results were observed after subgrouping by age and surgery. Conclusion: In this Italian real-world setting of unselected mCRC, the OS of patients treated with B+CT was consistent with previous observational and patient-registry studies. However, definitive evidence of an improvement in OS cannot be drawn. Implications for Practice: Bevacizumab is a well-established first-line treatment for metastatic colorectal cancer. However, there is scarce evidence in the literature about its effectiveness in clinical practice. Evaluating this topic should be of interest for both clinicians and regulatory agenc

The occurrence of drug resistance limits the efficacy of platinum compounds in the cure of ovarian carcinoma. Since microRNAs (miRNAs) may contribute to this phenomenon by regulating different aspects of tumor cell response, the aim of this study was to exploit the analysis of expression of miRNAs in platinum sensitive/resistant cells in an attempt to identify potential regulators of drug response. MiR-483-3p, which may participate in apoptosis and cell proliferation regulation, was found up-regulated in 4 platinum resistant variants, particularly in the IGROV-1/Pt1 subline, versus parental cells. Transfection of a synthetic precursor of miR-483-3p in IGROV-1 parental cells elicited a marked up-regulation of the miRNA levels. Growth-inhibition and colony-forming assays indicated that miR-483-3p over-expression reduced cell growth and conferred mild levels of cisplatin resistance in IGROV-1 cells, by interference with their proliferative potential. Predicted targets of miR-483-3p included PRKCA (encoding PKC-alpha), previously reported to be associated to platinum-resistance in ovarian carcinoma. We found that miR-483-3p directly targeted PRKCA in IGROV-1 cells. In keeping with this finding, cisplatin sensitivity of IGROV-1 cells decreased upon molecular/pharmacological inhibition of PKC-alpha. Overall, our results suggest that overexpression of miR-483-3p by ovarian carcinoma platinum-resistant cells may interfere with their proliferation, thus protecting them from DNA damage induced by platinum compounds and ultimately representing a drug-resistance mechanism. The impairment of cell growth may account for low levels of drug resistance that could be relevant in the clinical setting.