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Purpose Tasquinimod, a novel oral therapy targeting the tumor microenvironment, significantly improved progression-free survival (PFS) in a randomized, placebo-controlled phase II trial in men with metastatic castration-resistant prostate cancer (mCRPC). This phase III study was conducted to confirm the phase II results and to detect an overall survival (OS) benefit. Patients and Methods Men with chemotherapy-naïve mCRPC and evidence of bone metastases were assigned (2:1) to receive tasquinimod once per day or placebo until progression or toxicity. The primary end point was radiographic PFS (rPFS; time from random assignment to radiologic progression or death) per Prostate Cancer Working Group 2 criteria and RECIST 1.1. The study had 99.9% power to detect an rPFS hazard ratio (HR) of 0.6 with a two-sided alpha error of .05 and 80% power to detect a target HR of 0.8 for OS, the key secondary end point. Results In all, 1,245 patients were randomly assigned to either tasquinimod (n = 832) or placebo (n = 413) between March 2011 and December 2012 at 241 sites in 37 countries. Baseline characteristics were balanced between groups: median age, 71 years; Karnofsky performance status ≥ 90%, 77.3%; and visceral metastases, 21.1%. Estimated median rPFS by central review was 7.0 months (95% CI, 5.8 to 8.2 months) with tasquinimod and 4.4 months (95% CI, 3.5 to 5.5 months) with placebo (HR, 0.64; 95% CI, 0.54 to 0.75; P < .001). Median OS was 21.3 months (95% CI, 19.5 to 23.0 months) with tasquinimod and 24.0 months (95% CI, 21.4 to 26.9 months) with placebo (HR, 1.10; 95% CI, 0.94 to 1.28; P = .25). Grade ≥ 3 adverse events were more frequent with tasquinimod (42.8% v 33.6%), the most common being anemia, fatigue, and cancer pain. Conclusion In chemotherapy-naïve men with mCRPC, tasquinimod significantly improved rPFS compared with placebo. However, no OS benefit was observed.

Background: \ud \ud Tasquinimod is a small molecule with immunomodulatory, anti-angiogenic, and anti-metastatic properties that targets the tumor microenvironment. This study aimed to obtain a clinical proof of concept that tasquinimod was active and tolerable in patients with advanced solid tumors.\ud \ud Patients and Methods: \ud \ud This early stopping design, open-label, proof-of-concept clinical trial evaluated the clinical activity of tasquinimod in four independent cohorts of patients with advanced hepatocellular (n = 53), ovarian (n = 55), renal cell (n = 38), and gastric (n = 21) cancers. Tasquinimod was given orally every day (0.5 mg/day for at least 2 weeks, with dose increase to 1 mg/day) until radiological progression according to Response Evaluation Criteria in Solid Tumor (RECIST) 1.1 criteria, intolerable toxicity, or patient withdrawal. The primary efficacy endpoint was progression-free survival (PFS) rate according to RECIST 1.1 by central assessment.\ud \ud Results: \ud \ud Interim futility analyses at 8 weeks (6 weeks for the gastric cancer cohort) found adequate clinical activity of tasquinimod only in the hepatocellular cohort and recruitment to the other three cohorts was stopped. PFS rates were 26.9% at 16 weeks, 7.3% at 24 weeks, 13.2% at 16 weeks, and 9.5% at 12 weeks, respectively, in hepatocellular, ovarian, renal cell, and gastric cancer cohorts. The pre-defined PFS threshold was not reached in the hepatocellular cancer cohort at the second stage of the trial. The most common treatment-related adverse events were fatigue (48.5%), nausea (34.1%), decreased appetite (31.7%), and vomiting (24.6%).\ud \ud Conclusions: \ud \ud This study failed to demonstrate clinical activity of tasquinimod in heavily pre-treated patients with advanced hepatocellular, ovarian, renal cell, and gastric cancer.\ud \ud Trial registration: \ud \ud NCT01743469.

RESUME La forte croissance socio-economique de Quito a conduit a d’importants projets de transferts interbassins, intensifiant la mobilisation des ressources d’altitude situees dans des zones ecologiques sensibles et connaissant une fonte acceleree des glaciers. Afin d’etudier divers scenarios d’evolutions, nous proposons une modelisation du continuum climat/glacier/hydrologie/gestion des ressources en eau. Utilisant l’outil Water Evaluation and Planning (WEAP), nous avons developpe : (1) une modelisation hydro-climatologique semi-distribuee avec des donnees mensuelles homogeneisees par vectorisation regionale ; (2) une modelisation de la production en eau des glaciers et de leur evolution interannuelle ; (3) une modelisation en unites hydrologiques distinguant differentes couvertures de sols ; et (4) une modelisation de la gestion distinguant droits, allocation et usages de l’eau. Nous presentons les resultats du calage hydrologique mensuel (1963–2006), en etudiant particulierement l’equifinalite de dive...

Introduction Vinflunine (Javlor) has shown significant antitumour activity in advanced non-small cell lung cancer (NSCLC). We propose to define the recommended dose of vinflunine in combination with gemcitabine for treatment of advanced NSCLC in chemonaive patients. Methods A phase I and pharmacokinetic study was conducted to determine the maximum tolerated dose and to establish the recommended dose of vinflunine (VFL) administered on day 1 every 21 days combined with gemcitabine given on days 1 and 8 every 3 weeks. Results Nineteen patients were included in this study. Three patients experienced a dose limiting toxicity, with constipation in one patient, hypertension in one patient, and constipation and febrile neutropenia in one patient. The combination of VFL 320 mg/m 2 and gemcitabine 1250 mg/m 2 was defined as the maximum tolerated dose. The recommended dose was established at the dose of VFL 320 mg/m 2 combined with gemcitabine 1000 mg/m 2 . Neither VFL nor gemcitabine seemed to be influencing the pharmacokinetics of each other. All patients were evaluable for tumor response. Seven presented a partial response and eight experienced a stable disease. Conclusions The combination of VFL 320 mg/m 2 administered on day 1 combined with gemcitabine 1000 mg/m 2 given on days 1 and 8 every 3 weeks is established as the RD and was shown to be active in these chemonaive NSCLC patients.

Background A multicenter phase I/II trial of vinflunine administered in combination with cisplatin at 80 mg/m2 was conducted in order to determine the dose-limiting toxicities, the maximum tolerated dose, and the recommended dose of the combination. An eventual mutual pharmacokinetic drug-drug interaction when vinflunine and cisplatin were coadministered was also evaluated. The study was also intended to define the response rate of vinflunine in combination with cisplatin as first-line chemotherapy in patients with advanced non–small-cell lung cancer (NSCLC) at the recommended dose. Patients and Methods Patients were required to have a histologically confirmed diagnosis of NSCLC not amenable to curable treatment or stage IV disease. Patients may have had previous surgery for NSCLC but were to be chemonaive and have at least 1 bidimensional measurable lesion outside an irradiated area. Results The recommended dose was established at cisplatin 80 mg/m2 combined with vinflunine 320 mg/m2. No unexpected adverse events were seen. Pharmacokinetic analysis supported the absence of mutual pharmacokinetic interaction when vinflunine and cisplatin are given in combination. Treatment of 53 patients at this recommended dose demonstrated a tumor response rate of 32.1% in the intent-to-treat population; disease control was achieved in 79.2% of the patients. The median progression-free survival and overall survival were estimated at 5 months and 10.4 months, respectively, and the 1-year survival rate was 43.4%. Conclusion These results place the vinflunine/cisplatin combination among the most active doublets in this treatment setting and warrant further development in phase III trials of first-line treatment of patients with advanced metastatic NSCLC.

A multicenter, open-label, phase 2 study evaluated the efficacy and safety of intravenous vinflunine as third-line treatment in patients with progressing metastatic breast cancer (MBC) after failure of anthracycline- and taxane-based chemotherapy.Fifty-six patients with MBC, relapsing after receiving 2 previous treatments for advanced disease, including both anthracyclines and taxanes, received 320 mg/m(2) of vinflunine once every 3 weeks (median number of 2.5 cycles, range: 1-13).According to an independent radiologist, the response rate was 12.5% (95% CI: 5.2-24.1) and 14% (95% CI: 5.3-27.9) (6 partial responses) in the treated and evaluable populations, respectively. Disease control was achieved in 42.9% and 51.2% of the patients, respectively. Median progression-free survival was 2.6 months (95% CI: 1.6-4.0 months) with a median overall survival of 11.4 months (95% CI: 7.4-14.2 months). Duration of response was 6.8 months (95% CI: 5.6 months, upper limit not reached). Leukopenia was the most frequent hematologic toxicity, with grade 3/4 severity in 49.1% of the patients. Grade 3 neutropenia in 30.9%, grade 4 in 40.0% of patients, febrile neutropenia (5.4%), and 1 case of neutropenia infection (1.8%) were reported. Other grade 3 toxicities included anemia (5.5%), fatigue (14.3%), and constipation (7.1%), which were noncumulative. The adverse events associated with vinflunine were predictable and manageable.Vinflunine is an active and well-tolerated agent as third-line treatment of patients with MBC after failure of anthracycline- and taxane-based therapy. These results warrant further investigation of vinflunine monotherapy or in combination for the treatment of MBC.

Combination of intravenous (i.v.) vinorelbine and docetaxel was shown to be feasible and effective in metastatic breast cancer (MBC). In an effort to improve patient convenience, we investigated in first-line treatment a regimen alternating i.v. and oral vinorelbine in combination with docetaxel.Forty-nine patients (median age, 53 years) with MBC received a maximum of 6 cycles consisting of i.v. vinorelbine 20 mg/m(2) plus docetaxel 60 mg/m(2) given on day 1, and oral vinorelbine 60 mg/m(2) on day 15 every 3 weeks in an open-label, multicentre phase II study (recommended dose established in phase I study [1]).Sixty-three percent of the patient had received prior adjuvant chemotherapy and 78% presented visceral involvement. Twenty-four responses were documented and validated by an independent panel review, yielding response rates of 49% (95% CI: 34-64) in the 49 enrolled patients and 55.8% (95% CI: 40-71) in the 43 evaluable patients. Median duration of response was 9.4 months. Median progression-free survival and median overall survival were 5.5 and 33.2 months, respectively. Neutropenia was the main dose-limiting toxicity but complications were uncommon, four patients having experienced febrile neutropenia and one having developed neutropenic infection. Other frequently reported adverse events included alopecia, fatigue, stomatitis, constipation, diarrhoea and nausea, which were rarely severe.This regimen alternating oral and i.v. vinorelbine in combination with docetaxel is effective and manageable. Vinorelbine i.v. per oral day 1 per day 15-docetaxel day 1 every 3 weeks represents a convenient option to combine docetaxel and vinorelbine for the palliative treatment of MBC.

This paper presents a model of Andean glacier hydrology which can be used to assess the water management implications of possible future glacier retreat. The approach taken uses the Water Evaluation and Planning (WEAP) system and integrates both hydrologic processes and representations of the operations of built infrastructure. The model is applied in the Rio Santa watershed in Peru to illustrate how alternative water management strategies can be simulated. The WEAP platform built for this study has been used to engage with local stakeholders for water management.

To design integrated water management for a whole region, all agricultural activities need to be taken into account together with their irrigation water requirements and agricultural outputs. The aim of this paper is to present a modeling environment, called ZonAgri, that allows agricultural activities to be represented at regional scale and enables prospective scenarios concerning these activities to be tested. The modeling of agricultural activities is based on typologies of farms and production units (i.e. plant cropping systems) using a simple framework. A region is designated as a set of “sectors” that correspond to geographical spaces; each sector is designated as a weighted (by strength) sum of “farms”. A “farm” is designated as a weighted (by size) sum of “production units” that can be linked with specific geographical “sites” in the region. Each “production unit” consumes inputs and produces outputs that can have prices. This framework allows the aggregated calculation of inputs and outputs, as well as of the incomes of farms, sites or sectors. Scenarios can be built to change the original values or to envisage changes that may occur over a period of several years. The results of multi-year simulations make up the database. The information contained in the database can be requested by area or by sector, and can be mapped and exported to be used in a GIS. Maps of agricultural activities or water demand can then be superimposed on maps of water resources and hydraulic facilities to check if they are consistent. ZonAgri software was used to model agricultural activities in a plain in central Tunisia where irrigation depends on pumping from the water table. The resulting model enabled estimation of water demand for irrigation from public and private wells and the valorization of the water through agricultural outputs. In our case, the model was then used in collaboration with stakeholders to evaluate the effects of water tariffs or market prices on farm incomes. It could be also used to simulate farmers’ reactions concerning their crop choices or irrigation practices. Interactions between activities or between resources and uses cannot be modeled using the framework. However, representing these interactions would result in intricate models, and in addition, such interactions would change as a function of changes in production systems. It is thus more efficient to build simple models that enable stakeholders to understand the consequences of possible changes in their activities and the interactions between end uses of the water resource.

International audience; Il est proposé de concevoir un environnement de modélisation permettant d'envisager différentes alternatives de gestion du bassin correspondant à divers objectifs : valorisation, équité, durabilité. Cet environnement est fondé sur un système d'information à référence spatiale et temporelle, et propose une interface conviviale pour définir et activer différents modèles. Pour répondre à des questions concrètes de gestion, les thématiciens et acteurs du projet auront à définir les liaisons entre modèles de natures différentes, en assurant la cohérence des échelles d'étude spatiale et temporelle. Par exemple, sur la nappe de Kairouan il est intéressant de tester l'impact de politiques de taxation ou d'évolution du marché sur les dynamiques d'extension des exploitations agricoles privées et publiques en liaison avec l'état des réserves en eau. Afin de capitaliser les travaux effectués, il est proposé de développer un modèle de demande basé sur une représentation technico-économique des exploitations agricoles. Sur le bassin amont, il convient de développer des modèles hydrologiques afin d'évaluer l'impact d'aménagements du territoire comme les banquettes, les lacs collinaires. Des modèles d'allocation, basés sur une représentation de type arcs-noeuds, vont être utilisés afin d'explorer les limites des aménagements. Il est ainsi possible de simuler l'évolution de l'occupation du territoire, en activant le modèle d'allocation couplé au modèle hydrologique et au modèle de demande, et de tester la faisabilité de réallocations de l'eau au sein du bassin, issues d'une modélisation économétrique. Les tests des scénarios d'évolution nécessitent de nombreuses simulations, pertinentes en terme d'évolutions socio-économiques et représentatives de l'aléa hydrologique.

River networks are structural and functional backbones of river basins. They frequently display general scaling properties through their hierarchical topology. Their mathematical description further feeds geomorphology-based hydrological analyses and modelling approaches that require little calibration. Nevertheless, particular river basins display widely diverse geomorphometic structures in relation to relief, geology, climate and anthropogenic constraints, as well as various hydrological structure-function relationships. A robust, flexible and systematic approach is thus needed to allow for joint spatial, topological and scaling analyses, in order to explore the hydro-geomorphological diversity. The HydroStruct software application is dedicated to such analyses, and to easily link geomorphometric observations with hydrological analysis and modelling approaches, such as geomorphology-based transfer functions, accounting for rainfall variability within rainfall-runoff modelling, and impact assessment of landscape and hydraulic changes. HydroStruct was developed within the generic Ode-fiX framework, which provides Java software components to allow co-development and interfacing of object-oriented models.; Les réseaux hydrographiques sont les ossatures structurelles et fonctionnelles des bassins versants. Ils présentent fréquemment des propriétés d’échelles à travers leur topologie de hiérarchie. De plus, leur description mathématique alimente une hydrologie à base géomorphologique, à travers des analyses et des modélisations peu exigeantes en calage. Cependant, les bassins versants présentent des structures géomorphométriques très variées, en lien avec le relief, la géologie, le climat et des contraintes anthropiques ainsi qu’une diversité de relations structure-fonction hydrologiques. Une approche robuste, flexible et systématique est par conséquent nécessaire pour faciliter des analyses conjointes spatiales, topologiques et scalantes et, ainsi, explorer la diversité hydro-géomorphologique. L’application logicielle HydroStruct est dédiée à de telles analyses, mais aussi à l’articulation des observations géomorphométriques avec des analyses et des modélisations hydrologiques telles que des approches basées sur des fonctions de transfert à base géomorphologique, la prise en compte de la variabilité de la pluie au sein de la modélisation pluie-débit et l’évaluation de l’impact de changements paysagers et hydrauliques. HydroStruct a été développé au sein du cadre générique OdefiX, qui fournit des composants logiciels en Java, dans l’optique de faciliter le co-développement et l’interfaçage de modèles orientés objet.