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Overweight is an established risk factor of the colorectal cancer initiation and progression. Aim of this study is to investigate the prognostic role of visceral fat (VAT) in metastatic colorectal cancer (MCRC). We retrospectively analyzed 71 consecutive MCRC patients (2013-2017) at the Oncology Department of CRO Aviano (Italy). VAT area was measured as of cross-sectional area (cm2) at the L3 level divided by the square of the height (m2). A ROC analysis was performed to define a threshold capable to identify distinct prognostic categories of patients according to VAT. Subsequently, the value of VAT in predicting overall survival (OS) was evaluated with uni- and multivariate Cox regression analyses and estimated with Kaplan-Meier curves. Patients’ characteristics before first-line chemotherapy are reported in table 1. Interestingly, 40 pts (56%) had a body mass index (BMI)>25 and 42 (59%) had median VAT of 51.94. LDH level>=480 UI/L was recorded in 12 patients (27%) reflecting the inflammatory response. The optimal cut-off value for VAT was 44. Median OS was 30.97 months. At univariate analysis, older age (HR 2.46, p=0.013), primary tumor resection (HR 0.40, p=0.029), VAT>=44 (HR 2.85, p=0.011) and metastasectomy (HR 0.22, p=0.005), were significantly associated with OS (Table 2 and Figure1). By multivariate analysis, only VAT>=44 (HR2.64; p=0.030) was significantly associated with OS (Table 2). This exploratory study supported the prognostic role of VAT evaluation in patients with MCRC. In particular, high VAT was predictor of worse outcome. Further investigations are needed to confirm these preliminary data.

Cancer patients (CP) typically experiment cachexia and malnutrition due to cancer type and systemic inflammation, that may cause greater treatment toxicities, impacting on prognosis, response to treatment, hospitalization and quality of life. We retrospectively analyzed consecutive data of 190 CP treated from February 2017 to July 2018 at the Anesthesia and Intensive Care Unit of National Cancer Institute, Aviano. At nutritional assessment we evaluated the rate of weight loss (WL) compared to self-reported usual weight (UW) and at 6 and 1 months before the visit, performed by an expert physician and a certified dietitian. We explored the association of WL≥10% with inflammation biomarkers, total protein, albumin, diagnosis and nutritional intervention through chi-squared or Kruskal-Wallis test, as statistically appropriate (Tab.2). Patients’ characteristics were summarized through descriptive analysis (Tab.1). Noteworthy 48% of CP was ≥65 years old, 20% had BMI<18.49; 21% had BMI≥25, 51% of them had a WL≥10%. About 63%, 44% and 13% of patients had a WL≥10% from UW, at 6 months and at 1 month, respectively. Moreover, 57% received oral supplementation after nutritional counseling. Conversely, 31% received artificial nutrition. Interestingly, WL≥10% from UW was associated with neutrophils-to-lymphocytes ratio (P=0.049) (Fig.1), cholesterol level (P=0.016) (Fig.2) and cancer type both from UW (P=0.003) (Fig.3) and at 6 months (P=0.007) before evaluation. A trend was observed with artificial nutrition (P=0.067). Prevention and treatment of cachexia still remain a critical need in CP. Therefore, integrating nutritional supportive care to oncologic treatments is crucial.

Introduction/BackgroundPatients (pts) with ovarian cancer experiencing a platinum-sensitive (PS) recurrence are generally re-exposed to platinum agents (PCT). The addition of bevacizumab (BEV) or PARP inhibitors (PARPi) as concomitant and/or maintenance therapy has shown to improve progression free survival (PFS). In the absence of direct comparisons coming from randomized trials (RCTs), we have performed a network meta-analysis to evaluate differences in terms of efficacy between BEV and PARPi in pts with PS recurrent ovarian cancer (rOC), according to BRCA status.MethodologyWe searched PubMed, Embase and Medline for RCTs involving pts with PS rOC treated with BEV (n=3, 1563 pts) or PARPi (n=5, 1839 pts). Only trials with PFS as primary endpoint were included. Analyses have been done pooling pts who had received PARPi in three groups, according to the available data on BRCA genes status: all comers (AC), BRCA mutated pts (BRCAm) and BRCA wild-type pts (BRCAwt). A frequentist approach has been used with R statistical software. To rank the effect size of treatments, surface under the cumulative ranking value (SUCRA) has been applied.ResultsIn AC pts, PARPi improved PFS compared to BEV (hazard ratio [HR]=0.70, 95% CI 0.54–0.91). In BRCAm pts the gain in PFS for PARPi was even higher compared to BEV (HR=0.46, 95% CI 0.36–0.59). In BRCAwt pts the benefit of PARPi over BEV was not statistically significant (HR=0.87, 95% CI 0.63–1.20) but PARPi had the highest likelihood of being ranked as the best treatment in terms of efficacy according to SUCRA (90% and 60%, respectively for PARPi and BEV).ConclusionAccording to indirect comparisons, PARPi performed the best for the treatment of PS rOC, especially in BRCAm pts who had not previously received PARPi. BEV could be still an option in BRCAwt pts.DisclosureFabio Puglisi: Roche, AstraZeneca (honoraria and research founding). No conflict of interest is to be declared for the remaining authors. The authors receive no financial support for this study.

Introduction/BackgroundWomen aged ≥65 represent nearly 50% of ovarian cancer (OC) patients (pts). However, elderly OC pts are less likely to receive optimal treatment. Furthermore, they are significantly under-represented in clinical trials and multidimensional geriatric assessment is still underused. The present study aims to provide an overview of real-life treatment strategies for elderly advanced-OC pts and to investigate clinico-pathological features that could potentially drive choice of first-line treatment.MethodologyA retrospective analysis was conducted on a consecutive series of 45 OC pts aged ≥69 treated with first-line chemotherapy (1L_CT) from 2011 to 2018 at CRO Aviano National Cancer Institute (Italy). Factors associated with treatment choice and rate of adverse events were investigated through Fisher-exact test; differences in progression free survival (PFS) and overall survival (OS) were tested by log-rank test.Results67% of pts received 1L_CT with a standard carboplatin-paclitaxel combination (CPC). Conversely, 33% received a monotherapy (MT) (31% with carboplatin, 2% with paclitaxel). ECOG PS ≥1 was the only factor significantly associated with choice of MT (P=0.021). No differences were observed between CPC and CPC with dose reductions (CPCdr), neither in terms of PFS (HR=1.29 P=0.59) nor OS (HR=1.40 P=0.56). On the other hand, MT was associated with shorter PFS (HR=4.35 P=0.001) and OS (HR=4.48 P=0.005). No differences in treatment discontinuation rate, neutropenia, thrombocytopenia, neuropathy, constipation, diarrhoea and asthenia in CPC, CPCdr and MT were detected (P>0.05).ConclusionThe present study confirms CPC as the standard first-line chemotherapy also in advanced OC elderly pts and suggests that CPCdr is preferable to MT regimens. Notwithstanding the limitations due to the small sample size, the evaluated regimens showed a comparable toxicity profile. Notably, clinical decision-making was mainly driven by PS ECOG highlighting the pivotal role of multidimensional geriatric assessment for pts stratification. Further prospective studies are needed to investigate improved tailored strategies.DisclosureNothing to disclose.

Chronic myelomonocytic leukemia (CMML) is a complex clonal hematological disorder classified among myelodysplastic (MDS)/myeloproliferative neoplasms. Prognosis is poor and there is a lack of effective treatments. The hypomethylating agent decitabine has shown activity against MDS and elderly acute myeloid leukemia, but there is little data focusing specifically on its efficacy in CMML. In this prospective, phase 2 Italian study, CMML patients received intravenous decitabine 20 mg/m2 per day on Days 1-5 of a 28-day treatment cycle. Response was evaluated after four and six cycles; patients responding at the end of six cycles could continue treatment with decitabine. Forty-three patients were enrolled; >50% were high-risk according to four CMML-specific scoring systems. In the intent-to-treat population (n=42), the overall response rate after six cycles was 47.6%, with seven complete responses (16.6%), eight marrow responses (19%), one partial response (2.4%) and four hematological improvements (9.5%). After a median follow-up of 51.5 months (range: 44.4-57.2), median overall survival was 17 months, with responders having a significantly longer survival than non-responders (P=0.02). Grade 3/4 anemia, neutropenia and thrombocytopenia occurred in 28.6%, 50% and 38% of patients, respectively. Decitabine appears to be an effective and well-tolerated treatment for patients with high-risk CMML.

Background Pancreatic cancer (PC) patients have multiple risk factors for sarcopenia and loss of skeletal muscle mass (LSMM), which may cause greater treatment toxicities, reduced response to cancer therapy, prolonged hospitalization, impaired quality of life, and worse prognosis. Methods This is a retrospective study on advanced PC patients treated at the Department of Oncology of Udine, Italy, from January 2012 to November 2017. Among 162 patients who received chemotherapy, 94 consecutive patients with an available computed tomography (CT) scan were retrospectively analyzed. The primary objective of our study was to explore if an early LSMM ≥ 10% (measured at first radiological evaluation and compared with baseline) and/or baseline sarcopenia may impact prognosis. Baseline sarcopenia was defined according to Prado's criteria. Skeletal muscle area was measured as cross‐sectional areas (cm2) using CT scan data through the Picture archiving and communication system (PACS) image system. Results In the whole cohort, 48% of patients were ≤70 years old, and 50% had metastatic disease. At baseline, 73% of patients had sarcopenia, and 16% presented a visceral fat area ≥ 44 cm2/m2. Overall, 21% experienced an early LSMM ≥ 10%. Approximately 33% of sarcopenic patients at baseline and ~35% of patients with early LSMM ≥ 10% had a body mass index > 25 kg/m2. Of note, 71% of patients were evaluated by a nutritionist, and 56% received a dietary supplementation (oral and/or parenteral). After a median follow‐up of 30.44 months, median overall survival (OS) was 11.28 months, whereas median progression‐free survival (PFS) was 5.72 months. By multivariate analysis, early LSMM ≥ 10% was significantly associated with worse OS [hazard ratio (HR): 2.16; 95% confidence interval (CI) 1.23–3.78; P = 0.007] and PFS (HR: 2.31; 95% CI 1.30–4.09; P = 0.004). Moreover, an exploratory analysis showed that inflammatory indexes, such as neutrophil–lymphocyte ratio variation, impact early LSMM ≥ 10% (odds ratio 1.31, 95% CI 1.06–1.61, P = 0.010). Conclusions Early LSMM ≥ 10% has a negative prognostic role in advanced PC patients. Further prospective investigations are needed to confirm these preliminary data.

In this study the Peak Stress Method (PSM) has been applied to the fatigue assessment of the welds of an axle equipped in an off-road vehicle. In the fatigue design of welded joints, the PSM is a FE-based method to rapidly evaluate the NSIFs relevant to the opening, sliding and tearing modes by means of the linear elastic peak stresses extracted from the FE model. First, an axle, which consists of a central body and two lateral branches composed by several plates welded to a tube, has been fatigue tested under a vertical load in a test bench designed to replicate the frame-axle interface. Then, an FE model of the axle has been calibrated to simulate the behaviour observed during the fatigue test, where the reaction forces and the strains at pre-defined locations have been considered. Once the FE model has been calibrated, the PSM has been applied to the welds of the axle, taking advantage of an automatic procedure, and the crack initiation location has been estimated. Finally, the theoretical estimations have been compared with the experimental datum.

Background: Mutations in CALR observed in myeloproliferative neoplasms (MPN) were recently shown to be pathogenic via their interaction with MPL and the subsequent activation of the Janus Kinase – Signal Transducer and Activator of Transcription (JAK-STAT) pathway. However, little is known on the impact of those variant CALR proteins on endoplasmic reticulum (ER) homeostasis. Methods: The impact of the expression of Wild Type (WT) or mutant CALR on ER homeostasis was assessed by quantifying the expression level of Unfolded Protein Response (UPR) target genes, splicing of X-box Binding Protein 1 (XBP1), and the expression level of endogenous lectins. Pharmacological and molecular (siRNA) screens were used to identify mechanisms involved in CALR mutant proteins degradation. Coimmunoprecipitations were performed to define more precisely actors involved in CALR proteins disposal. Results: We showed that the expression of CALR mutants alters neither ER homeostasis nor the sensitivity of hematopoietic cells towards ER stress-induced apoptosis. In contrast, the expression of CALR variants is generally low because of a combination of secretion and protein degradation mechanisms mostly mediated through the ER-Associated Degradation (ERAD)-proteasome pathway. Moreover, we identified a specific ERAD network involved in the degradation of CALR variants. Conclusions: We propose that this ERAD network could be considered as a potential therapeutic target for selectively inhibiting CALR mutant-dependent proliferation associated with MPN, and therefore attenuate the associated pathogenic outcomes.