Maintaining angiogenesis inhibition and switching the chemotherapy backbone represent the current second-line therapy in patients with RAS-mutant metastatic colorectal cancer (mCRC). Regorafenib, an ...oral multikinase inhibitor, prolonged overall survival (OS) in the chemorefractory setting.
STREAM was an academic, multicenter, single-arm phase II trial, evaluating the activity of regorafenib in RAS-mutant mCRC, in terms of the rate of patients who were progression-free after 6 months from study entry (6mo-PF). Patients were pretreated with fluoropyrimidine, oxaliplatin, and bevacizumab. According to Simon’s two-stage design, ≥18 patients 6mo-PF were needed in the overall population (N = 46). Secondary endpoints were safety, objective response rate (ORR), progression-free survival (PFS), and OS. Early metabolic response by 18F2-fluoro-2-deoxy-D-glucose-positron emission tomography/computed tomography (18F-FDG PET/CT) scan was an exploratory endpoint. EudraCT Number: 2015-001105-13.
The number of patients 6mo-PF was 8/22 at the first stage and 14/46 in the overall population. The ORR was 10.9%, disease control rate was 54.6%, median (m)PFS was 3.6 months 95% confidence interval (CI) 1.9-6.7 months, mOS was 18.9 months (95% CI 10.3-35.3 months), and mPFS2 (from study entry to subsequent-line progression) was 13.3 months (95% CI 8.4-19.7 months). Long benefiter patients (>6mo-PF) significantly more often had a single metastatic site and lung-limited disease. No unexpected toxicity was reported. Grade ≥3 events occurred in 39.1% of patients, with hand–foot syndrome (13%), fatigue, and hyperbilirubinemia (6.5%) occurring mostly. Baseline metabolic assessment was associated with OS in the multivariate analysis, while early metabolic response was not associated with clinical outcomes.
The study did not meet its primary endpoint. However, regorafenib was well tolerated and did not preclude subsequent treatments. Patients with good prognostic features (single metastatic site and lung-limited disease) reported clinical benefit with regorafenib. The exploratory metabolic analysis suggests that baseline 18F-FDG PET/CT might be useful to select patients with a favorable outcome. A chemotherapy-free interval with regorafenib was associated with durable disease control in a selected group of patients with favorable clinical characteristics.
•Early-lines treatment of patients with RAS-mutant mCRC consists of chemotherapy and antiangiogenic agents.•STREAM evaluated regorafenib as second line for RAS-mutant mCRC, in terms of rate of patients progression-free at 6 months.•The primary endpoint of STREAM was not met. Regorafenib had no unexpected toxicity and did not preclude subsequent therapies.•A chemotherapy-free interval with regorafenib was beneficial in patients with good prognostic features.•Baseline 18F-FDG PET/CT might be useful to select patients with favorable outcomes.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
12.
One-Way Carsharing Di Febbraro, Angela; Sacco, Nicola; Saeednia, Mahnam
Transportation research record,
01/2012, Volume:
2319, Issue:
1
Journal Article
Peer reviewed
Carsharing services allow users to benefit from the advantages of a private car without the costs of owning one. One-way systems provide users with a higher level of service than traditional ...carsharing systems in terms of flexibility because users do not need to return to the station of origin. Moreover, the added option to leave the vehicle at any free parking area, which is not necessarily a station, increases the flexibility offered by the one-way system. Introduction of such improvements to the carsharing system, however, leads to a vehicle relocation problem, which should be addressed carefully to avoid concentration of vehicles in certain areas. This paper reports on a study of this issue with the use of discrete event systems (DESs), which allowed an easy representation of the complex dynamics of the carsharing system. A user-based methodology was proposed on the basis of an optimal relocation policy in a rolling horizon framework. This methodology not only offers greater flexibility to users, it also maximizes operator benefits by reducing the number of required staff to relocate vehicles among the stations and determines the minimum number of vehicles needed to satisfy system demand. The DES model was applied to a case study to evaluate the proposed approach. The results showed a significant decrease in the rejection rate from the worst scenario (no relocation) to the best (relocation of all vehicles by their users). The paper concludes with suggestions for additional research and improvements to this study.
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NUK, OILJ, SAZU, UKNU, UL, UM, UPUK
We report a novel
PPARG germline mutation in a patient affected by colorectal cancer that replaces serine 289 with cysteine in the mature protein (S289C). The mutant has impaired transactivation ...potential and acts as dominant negative to the wild type receptor. In addition, it no longer restrains cell proliferation both in vitro and in vivo. Interestingly, the S289C mutant poorly activates target genes and interferes with the inflammatory pathway in tumor tissues and proximal normal mucosa. Consistently, only mutation carriers exhibit colonic lesions that can evolve to dysplastic polyps. The proband presented also dyslipidemia, hypertension and overweight, not associated to type 2 diabetes; of note, family members tested positive for the mutation and display only a dyslipidemic profile at variable penetrance with other biochemical parameters in the normal range. Finally, superimposing the mutation to the crystal structure of the ligand binding domain, the new Cys289 becomes so closely positioned to Cys285 to form an S–S bridge. This would reduce the depth of the ligand binding pocket and impede agonist positioning, explaining the biological effects and subcellular distribution of the mutant protein. This is the first
PPARG germline mutation associated with dyslipidemia and colonic polyp formation that can progress to full-blown adenocarcinoma.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Anthracyclines and platinum derivates are active drugs for advanced endometrial carcinoma (AEC), but new schedules with higher efficacy and better tolerability are needed. A phase II study was ...conducted to describe activity and tolerability of carboplatin (C)+pegylated liposomal doxorubicin (PLD) in patients with AEC. Patients with chemonaive AEC, PS < or = 2, aged < 75 years, with at least one measurable lesion were eligible. Treatment was C (area under curve 5)+PLD (40 mg m(-2)) on day 1 every 4 weeks, up to six cycles. Forty-two patients were needed in a single-stage design, with at least 13 objective responses to define the treatment active. Forty-two patients were enrolled. Median age was 64 years (31-74). A total of 64% of patients were recurrent while 36% were advanced. Three complete (7%) and 22 partial responses (52%) were observed, for an overall response rate of 59.5% (95% exact CI: 43.3-74.3). One death potentially related to treatment was recorded (death at home for unknown reasons after 6th cycle). Other relevant toxicities (% of patients) were grade 3/4 neutropaenia 33%/14%, febrile neutropaenia 5%, grade 3/4 thrombocytopaenia 17%/5%, grade 3/4 anaemia 31%/2%. Skin toxicity was mild: grade 1 14%, grade 2 10%, grade 3 5%. Hair loss: complete 5%, partial 12%. The combination of carboplatin and PLD shows good activity and favourable toxicity as first-line chemotherapy of patients with AEC, deserving further studies in this setting.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, SIK, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
•Develops an agent-based modeling framework for planning of intermodal freight transport chains.•Each actor keeps its independent decision-making process.•The dynamics of operations are modeled using ...discrete event systems.•Cooperation improves efficiency significantly in systems operating close to capacity.
The recent development of Intelligent Transportation Systems offers the possibility of cooperative planning of multi-actor systems in a distributed framework, by enabling prompt exchange of information among actors. This paper proposes a modeling framework for cooperation in intermodal freight transport chains as multi-actor systems. In this framework, the problem of optimizing freight transportation is decomposed into a suitable set of sub-problems, each representing the operations of an actor which are connected using a negotiation scheme. A Discrete Event model is developed which optimizes the system on a rolling horizon basis to account for the dynamics of intermodal freight transport operations. This framework allows for an event driven short/medium term planning of intermodal freight transport chains. The proposed methodology is evaluated using a realistic case study, and the results are compared against the First-Come-First-Served strategy, highlighting the significance of cooperation in systems operating close to capacity.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
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