461 research outputs found
Il controllo dell’interazione fra strutture sincinematiche a diversa orientazione nella genesi ed evoluzione dei processi sismogenetici: l’esempio della Val di Sangro (Abruzzo).
No full textThe “Val di Sangro” earthquake (May 7th, 1984 Ms5.8) and related aftershock sequence are analysed from a seismotectonic point of view. The study is carried out by a carefully relocation of the aftershock sequence and by comparing seismological data with detailed geological information. The aftershocks are located in the hangingwall of the two major normal fault systems of the southeastern Marsica area (Abruzzo, central Italy): the Barrea normal fault system (NNW-SSE trending, WSW-dipping) and the Valle del Sangro right-lateral normal-oblique fault (N100°E trending, SSW-dipping). The CMT focal mechanisms of the main shock (M5.8) and of the largest aftershock (M5.2) point to a NNW-SSE trending extensional main seismogenetic structure. Aftershock epicentres are mostly concentrated within a cluster oriented ENE-WSW. Hypocentres deepen about 60° toward SW in a SW-NE section and about 80° toward S in a N-S section.
The anomalous ENE-WSW distribution of the aftershock volume appears to be controlled by the interference between two non-coaxial, but kinematically compatible, structures: the Barrea fault and the Valle del Sangro fault. The aftershocks are clustered within the rock volume at the hangingwall of both the faults, along the zone of intersection between the two structures. The Barrea fault would also have acted as the main seismogenetic fault structure; the Valle del Sangro fault would have acted as a barrier to the seismogenic rupture process and also as transfer fault for accumulated strain induced by the main shock rupture
Abstract IA25: Targeted therapies for hepatocellular carcinoma
No full textAbstract
In 2008, the multikinase inhibitor Sorafenib consistently proved to extend the survival of patients with Hepatocellular Carcinoma (HCC) that were treated in the advanced stage and had a good liver function, and it became the first agent to be specifically approved for this indication (ref). Although Sorafenib was a paradigm shift in the field, systemic therapy of HCC remains a major unmet need. The mechanism of action of Sorafenib is still poorly understood and the same is true for the mechanism of resistance after initial response, which usually reveals as disease stabilization for a few months. Molecular biomarkers predicting response and resistance to Sorafenib are also hardly defined. Furthermore, all subsequent novel targeted agents or regimens tested in large randomized controlled trials both in the first-line and second-line setting have been unable to reach or improve the magnitude of benefit obtained with Sorafenib. Strategies under study have included the blockade of other pro-angiogenic signals such as the FGFR pathway using Brivanib, proliferative signals such as the EGFR pathway using Erlotinib, or cell growth, proliferation, angiogenesis and apoptosis signals arising from the PI3K-Akt-mTOR pathway using Everolimus. The relevance of targeting these pathways is still not completely understood since biomarker data have not been reported, including EGFR and FGFR expression in tumor specimens.
Besides, a number of trials have definitively shown the lack of efficacy of Doxorubicin, used for decades as a systemic therapy for HCC patients without formal scientific evidence. And no survival benefit was proven for combination chemotherapy based on 5-fluorouracil and oxaliplatin.
The door was then opened to a more focused approach in which only patients with an altered targeted pathway are deemed candidates for a given agent. The anticancer activity of the c-met tyrosine kinase inhibitor Tivantinib was suggested in a randomized, placebo-controlled trial in the second-line setting where patients with high c-met expression survived significantly longer if they received Tivantinib. Patient enrichment based on molecular targets has been incorporated into the clinical development of other agents such as a monoclonal antibody that binds to glypican-3 or Refametinib a tyrosine kinase inhibitor that targets the MAPK (Ras-Raf-MEK-ERK) pathway. Agents targeting novel signaling pathways including TGF-β and FGF19, but also less explored pathways such as Wntβ-catenin, Hedgehog or Notch are being studied for the treatment of HCC.
We will soon learn whether or not this more selective approach translates into positive results. Identification of driver molecular events in an individual patient using markers from tumor biopsies has proven successful in other tumors including breast or lung cancer. However, the reliability of this strategy has been challenged by studies showing intratumoural heterogeneity in various malignancies at advanced stages. HCC needs to be explored in this regard.
Citation Format: Bruno Sangro. Targeted therapies for hepatocellular carcinoma [abstract]. In: Proceedings of the AACR International Conference: New Frontiers in Cancer Research; 2017 Jan 18-22; Cape Town, South Africa. Philadelphia (PA): AACR; Cancer Res 2017;77(22 Suppl):Abstract nr IA25.</jats:p
Heterogeneity of patients with intermediate (BCLC B) Hepatocellular Carcinoma: proposal for a subclassification to facilitate treatment decisions
No full textThe intermediate stage of hepatocellular carcinoma (HCC) comprises a highly heterogeneous patient population and therefore poses unique challenges for therapeutic management, different from the early and advanced stages. Patients classified as having intermediate HCC by the Barcelona Clinic Liver Cancer (BCLC) staging system present with varying tumor burden and liver function. Transarterial chemoembolization (TACE) is currently recommended as the standard of care in this setting, but there is considerable variation in the clinical benefit patients derive from this treatment.In April 2012, a panel of experts convened to discuss unresolved issues surrounding the application of current guidelines when managing patients with intermediate HCC. The meeting explored the applicability of a subclassification system for intermediate HCC patients to tailor therapeutic interventions based on the evidence available to date and expert opinion. The present report summarizes the proposal of the expert panel: four substages of intermediate HCC patients, B1 to B4
Transarterial radioembolization in patients with hepatocellular carcinoma of intermediate B2 substage
No full textPurpose: Patients with hepatocellular carcinoma (HCC) of intermediate stage (BCLC-B according to the Barcelona Clinic Liver Cancer classification) are a heterogeneous group with different degrees of liver function impairment and tumour burden. The recommended treatment is transarterial chemoembolization (TACE). However, patients in this group may be judged as poor candidates for TACE because the risk-benefit ratio is low. Such patients may receive transarterial radioembolization (TARE) only by entering a clinical trial. Experts have proposed that the stage could be further divided into four substages based on available evidence of treatment benefit. We report here, for the first time, the outcome in patients with BCLC-B2 substage HCC treated with TARE. Methods: A retrospective analysis of the survival of 126 patients with BCLC-B2 substage HCC treated with TARE in three European hospitals was performed. Results: Overall median survival in patients with BCLC-B2 substage was not significantly different in relation to tumour characteristics; 19.35 months (95% CI 8.27–30.42 months) in patients with a single large (>7 cm) HCC, and 18.43 months (95% CI 15.08–21.77 months) in patients with multinodular HCC (p = 0.27). However, there was a higher proportion of long-term survivors at 36 months among those with a single large tumour (29%) than among those with multiple tumours (16.8%). Conclusion: Given the poor efficacy of TACE in treating patients with BCLC-B2 substage HCC, TARE treatment could be a better choice, especially in those with a large tumour
Radioembolization versus chemoembolization for unresectable hepatocellular carcinoma: a meta-analysis of randomized trials
No full textPURPOSE:
This study aimed to compare clinically relevant outcomes following transarterial chemoembolization (TACE) and transarterial radioembolization (TARE) in patients with unresectable hepatocellular carcinoma (HCC) using only prospective randomized clinical trials as a source of information.
MATERIALS AND METHODS:
A meta-analysis was performed to compare the efficacy of TARE and TACE in treating patients with unresectable HCC. Only prospective randomized trials were included in the quantitative analysis. Overall and progression-free survival, disease control rate, and transplantation rate were the variables under analysis.
RESULTS:
Overall survival at 1 year was similar between the two treatment groups (OR =1.31, 95% CI: 0.56-3.04, P=0.53). Progression-free survival at 1 year was also not statistically different between the two treatments (OR =0.23, 95% CI: 0.02-2.45, P=0.22). Although a higher proportion of patients underwent transplantation in the TARE group (30% vs 20.8%), this difference was not statistically significant (OR =0.68, 95% CI: 0.23-2.01; P=0.49).
CONCLUSION:
TARE and TACE provide similar outcomes in unresectable HCC. The role of TARE should be explored in selected patient subpopulations in future clinical trials
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