Glutathione precursor N-acetyl-cysteine modulates EEG synchronization in schizophrenia patients: a double-blind, randomized, placebo-controlled trial.

Glutathione (GSH) dysregulation at the gene, protein, and functional levels has been observed in schizophrenia patients. Together with disease-like anomalies in GSH deficit experimental models, it suggests that such redox dysregulation can play a critical role in altering neural connectivity and synchronization, and thus possibly causing schizophrenia symptoms. To determine whether increased GSH levels would modulate EEG synchronization, N-acetyl-cysteine (NAC), a glutathione precursor, was administered to patients in a randomized, double-blind, crossover protocol for 60 days, followed by placebo for another 60 days (or vice versa). We analyzed whole-head topography of the multivariate phase synchronization (MPS) for 128-channel resting-state EEGs that were recorded at the onset, at the point of crossover, and at the end of the protocol. In this proof of concept study, the treatment with NAC significantly increased MPS compared to placebo over the left parieto-temporal, the right temporal, and the bilateral prefrontal regions. These changes were robust both at the group and at the individual level. Although MPS increase was observed in the absence of clinical improvement at a group level, it correlated with individual change estimated by Liddle's disorganization scale. Therefore, significant changes in EEG synchronization induced by NAC administration may precede clinically detectable improvement, highlighting its possible utility as a biomarker of treatment efficacy. TRIAL REGISTRATION: ClinicalTrials.gov NCT01506765.

Neoadjuvant treatment with docetaxel plus lapatinib, trastuzumab, or both followed by an anthracycline-based chemotherapy in HER2-positive breast cancer: results of the randomised phase II EORTC 10054 study.

BACKGROUND: Neoadjuvant trials conducted using a double HER2 blockade with lapatinib and trastuzumab, combined with different paclitaxel-containing chemotherapy regimens, have shown high pathological complete response (pCR) rates, but at the cost of important toxicity. We hypothesised that this toxicity might be due to a specific interaction between paclitaxel and lapatinib. This trial assesses the toxicity and activity of the combination of docetaxel with lapatinib and trastuzumab. PATIENTS AND METHODS: Patients with stage IIA to IIIC HER2-positive breast cancer received six cycles of chemotherapy (three cycles of docetaxel followed by three cycles of fluorouracil, epirubicin, cyclophosphamide). They were randomised 1 : 1 : 1 to receive during the first three cycles either lapatinib (1000 mg orally daily), trastuzumab (4 mg/kg loading dose followed by 2 mg/kg weekly), or trastuzumab + lapatinib at the same dose. The primary end point was pCR rate defined as ypT0/is. Secondary end points included safety and toxicity. pCR rate defined as ypT0/is ypN0 was assessed as an exploratory analysis. In June 2012, arm A was closed for futility based on the results from other studies. RESULTS: From October 2010 to January 2013, 128 patients were included in 14 centres. The percentage of the 122 assessable patients with pCR in the breast, and pCR in the breast and nodes, was numerically highest in the lapatinib + trastuzumab group (60% and 56%, respectively), intermediate in the trastuzumab group (52% and 52%), and lowest in the lapatinib group (46% and 36%). Frequency (%) of the most common grade 3-4 toxicities in the lapatinib /trastuzumab/lapatinib + trastuzumab arms were: febrile neutropenia 23/15/10, diarrhoea 9/2/18, infection (other) 9/4/8, and hepatic toxicity 0/2/8. CONCLUSIONS: This study demonstrates a numerically modest pCR rate increase with double anti-HER2 blockade plus chemotherapy, but suggests that the use of docetaxel rather than paclitaxel may not reduce toxicity. CLINICALTRIALSGOV: NCT00450892.

Randomised trial of oral versus sequential intravenous/oral cephalosporins in children with pyelonephritis.

The hypothesis was tested that oral antibiotic treatment in children with acute pyelonephritis and scintigraphy-documented lesions is equally as efficacious as sequential intravenous/oral therapy with respect to the incidence of renal scarring. A randomised multi-centre trial was conducted in 365 children aged 6 months to 16 years with bacterial growth in cultures from urine collected by catheter. The children were assigned to receive either oral ceftibuten (9 mg/kg once daily) for 14 days or intravenous ceftriaxone (50 mg/kg once daily) for 3 days followed by oral ceftibuten for 11 days. Only patients with lesions detected on acute-phase dimercaptosuccinic acid (DMSA) scintigraphy underwent follow-up scintigraphy. Efficacy was evaluated by the rate of renal scarring after 6 months on follow-up scintigraphy. Of 219 children with lesions on acute-phase scintigraphy, 152 completed the study; 80 (72 females, median age 2.2 years) were given ceftibuten and 72 (62 females, median age 1.6 years) were given ceftriaxone/ceftibuten. Patients in the intravenous/oral group had significantly higher C-reactive protein (CRP) concentrations at baseline and larger lesion(s) on acute-phase scintigraphy. Follow-up scintigraphy showed renal scarring in 21/80 children treated with ceftibuten and 33/72 with ceftriaxone/ceftibuten (p = 0.01). However, after adjustment for the confounding variables (CRP and size of acute-phase lesion), no significant difference was observed for renal scarring between the two groups (p = 0.2). Renal scarring correlated with the extent of the acute-phase lesion (r = 0.60, p < 0.0001) and the grade of vesico-ureteric reflux (r = 0.31, p = 0.03), and was more frequent in refluxing renal units (p = 0.04). The majority of patients, i.e. 44 in the oral group and 47 in the intravenous/oral group, were managed as out-patients. Side effects were not observed. From this study, we can conclude that once-daily oral ceftibuten for 14 days yielded comparable results to sequential ceftriaxone/ceftibuten treatment in children aged 6 months to 16 years with DMSA-documented acute pyelonephritis and it allowed out-patient management in the majority of these children.

Efficacy of an adjunctive brief psychodynamic psychotherapy to usual inpatient treatment of depression: rationale and design of a randomized controlled trial.

BACKGROUND: A few recent studies have found indications of the effectiveness of inpatient psychotherapy for depression, usually of an extended duration. However, there is a lack of controlled studies in this area and to date no study of adequate quality on brief psychodynamic psychotherapy for depression during short inpatient stay exists. The present article describes the protocol of a study that will examine the relative efficacy, the cost-effectiveness and the cost-utility of adding an Inpatient Brief Psychodynamic Psychotherapy to pharmacotherapy and treatment-as-usual for inpatients with unipolar depression. METHODS/DESIGN: The study is a one-month randomized controlled trial with a two parallel group design and a 12-month naturalistic follow-up. A sample of 130 consecutive adult inpatients with unipolar depression and Montgomery-Asberg Depression Rating Scale score over 18 will be recruited. The study is carried out in the university hospital section for mood disorders in Lausanne, Switzerland. Patients are assessed upon admission, and at 1-, 3- and 12- month follow-ups. Inpatient therapy is a manualized brief intervention, combining the virtues of inpatient setting and of time-limited dynamic therapies (focal orientation, fixed duration, resource-oriented interventions). Treatment-as-usual represents the best level of practice for a minimal treatment condition usually proposed to inpatients. Final analyses will follow an intention-to-treat strategy. Depressive symptomatology is the primary outcome and secondary outcome includes measures of psychiatric symptomatology, psychosocial role functioning, and psychodynamic-emotional functioning. The mediating role of the therapeutic alliance is also examined. Allocation to treatment groups uses a stratified block randomization method with permuted block. To guarantee allocation concealment, randomization is done by an independent researcher. DISCUSSION: Despite the large number of studies on treatment of depression, there is a clear lack of controlled research in inpatient psychotherapy during the acute phase of a major depressive episode. Research on brief therapy is important to take into account current short lengths of stay in psychiatry. The current study has the potential to scientifically inform appropriate inpatient treatment. This study is the first to address the issue of the economic evaluation of inpatient psychotherapy. TRIAL REGISTRATION: Australian New Zealand Clinical Trial Registry (ACTRN12612000909820).

The frequency and prognostic impact of dic(9;20)(p13.2;q11.2) in childhood B-cell precursor acute lymphoblastic leukemia: results from the NOPHO ALL-2000 trial.

The dic(9;20)(p13.2;q11.2) is reported to be present in ∼2% of childhood B-cell precursor acute lymphoblastic leukemia (BCP ALL). However, it easily escapes detection by G-banding analysis and its true prevalence is hence unknown. We performed interphase fluorescence in situ hybridization analyses-in a three-step manner-using probes for: (i) CDKN2A at 9p21, (ii) 20p and 20q subtelomeres and (iii) cen9 and cen20. Out of 1033 BCP ALLs diagnosed from 2001 to 2006, 533 were analyzed; 16% (84/533) displayed 9p21 deletions, of which 30% (25/84) had dic(9;20). Thus, dic(9;20)-positivity was found in 4.7% (25/533), making it the third most common genetic subgroup after high hyperdiploidy and t(12;21)(p13;q22). The dic(9;20) was associated with a female predominance and an age peak at 3 years; 18/25 (72%) were allocated to non-standard risk treatment at diagnosis. Including cases detected by G-banding alone, 29 dic(9;20)-positive cases were treated according to the NOPHO ALL 2000 protocol. Relapses occurred in 24% (7/29) resulting in a 5-year event-free survival of 0.69, which was significantly worse than for t(12;21) (0.87; P=0.002) and high hyperdiploidy (0.82; P=0.04). We conclude that dic(9;20) is twice as common as previously surmised, with many cases going undetected by G-banding analysis, and that dic(9;20) should be considered a non-standard risk abnormality.

Long-term results of a multicenter SAKK trial on high-dose ifosfamide and doxorubicin in advanced or metastatic gynecologic sarcomas.

BACKGROUND: Dose intensive chemotherapy has not been tested prospectively for the treatment of gynecologic sarcomas. We investigated the antitumor activity and toxicity of high-dose ifosfamide and doxorubicin, in the context of a multidisciplinary strategy for the treatment of advanced and metastatic, not pretreated, gynecologic sarcomas. PATIENTS AND METHODS: Thirty-nine patients were enrolled onto a phase I-II multicenter trial of ifosfamide, 10 g/m2 as a continuous infusion over 5 days, plus doxorubicin intravenously, 25 mg/m2/day for 3 days with Mesna and granulocyte-colony-stimulating factor every 21 days. Salvage therapy was allowed after chemotherapy. RESULTS: Among the 37 evaluable patients, the tumor was locally advanced (n = 11), with concomitant distant metastases (n = 5) or with distant metastases only (n = 21). After a median of three (range 1-7) chemotherapy cycles, six patients experienced a complete response and 12 a partial response for an overall response rate of 49% (95% CI 32% to 66%). The response rate was higher in poorly differentiated tumors (62%) compared with moderately well differentiated ones (18%), but was not different according to histology subtypes. Eleven patients had salvage therapy, either immediately following chemotherapy (n = 7) or at time of progression (n = 4). With a median follow-up time of 5 years, the median overall survival was 30.5 months. Hematological toxicity was as expected neutropenia, thrombopenia and anemia > or = grade 3 at 50%, 34% and 33% of cycles respectively. No toxic death occurred. CONCLUSIONS: High-dose ifosfamide plus doxorubicin is an active regimen for all subtypes of gynecological sarcomas. Its toxicity was manageable in a multicentric setting. The prolonged survival might be due to the multidisciplinary strategy that was possible in one-third of the patients.

Evaluation des Nationalen Krebsbekämpfungsprogrammes, Phase I, 1999. Studie 2: Inventar der vorhandenen Datenquellen und Indikatoren

[Table des matières] 1. Allgemeine Schlussforschungen und Empfehlungen. 2. Einleitung. 3. Methodik. 4. Ergebnisse. 4.1. Zentrale Datenquellen : Kontinuierliche und periodische Erhabungen, Mortalitätsstatistik, Spitalstatistik, Vereinigung Schweizerischer Krebsregister, Schweizerische Gesundheitsbefragung, Trendstudie zum Konsum von Alkohol, Tabak, Medikamenten und illegalen Drogen SFA, SChülerbefragung SFA, Warenkorb BFS, Schweizer Haushalt-Panel, Traditioneller Haushaltspanel IHA-GfM, Pharmaabsatzzahlen IHA-GfM, Sonnenexposition und Sonnenschutz, Indikatoren für den Tabakkonsum in der Schweiz, Statistische Erhebungen und Schätzungen über Landwirtschaft und Ernährung, Participants' Report SIAK, Trial guide SAKK, Guidelines, Berufskrankheiten SUVA, Krebstelefon SKL. 4.2. Weitere Datenquellen : Kontinuierliche und periodische Erhebungen, Statistik der verteilten Broschüren SKL, Jahresbericht von im Bereich Krebs tätigen Institutionen, Invalidenversicherung BSV, Andere Statistiken des BSV, Konkordat der Schweizerischen Krankenversicherer, Nestlé-Studie. 4.3. Zentrale Einzelerhebungen : Frauen und Krebs, Vorstudie für eine nationale Kampagne zur Früherfassung des kolorektalen Karzinoms, Ausmass und Intensität von Krebsschmerzen in der Schweiz. 4.4. Weitere Einzelerhebungen : IUMSP : die Gesundheit Jugendlicher in der Schweiz, Stillhäufigkeit und Stilldauer in der Schweiz 1994, Kohortenstudie Alkohol- und Drogenkonsum SFA. 4.5. Abgeschlossene Erhebungen : Krebsvorsorge, MONICA-Studie und Basler Ernährungsstudie. 5. Schlussfolgerungen und Empfehlungen : Zusammenfassende Schlussfolgerungen und Empfehlungen. 6. Anhang. 6.1. Zentrale Datenquellen im Uberblick : Globalkonzept, Brustkrebsprogramm, Lungenkrebsprogramm, Hautkrebsprogramm, Darmkrebsprogramm. 6.2. Zieltabelle : formulierte Ziele des nationalen Krebsbekämpfungsprogramms. 6.3. Abkürzungen.

The release of antidiuretic hormone is appropriate in response to hypovolemia and/or sodium administration in children with severe head injury: a trial of lactated Ringer's solution versus hypertonic saline.

We conducted an open, randomized, and prospective study to determine the effect of hypertonic saline on the secretion of antidiuretic hormone (ADH) and aldosterone in children with severe head injury (Glasgow coma scale <8). Thirty-one consecutive patients at a level III pediatric intensive care unit at a children's hospital received either lactated Ringer's solution (Ringer's group, n = 16) or hypertonic saline (Hypertonic Saline group, n = 15) over a 3-day period. Serum ADH levels were significantly larger in the Hypertonic Saline group as compared with the Ringer's group (P = 0.001; analysis of variance) and were correlated to sodium intake (Ringer's group: r = 0.39, R(2) = 0.15, P = 0.02; Hypertonic Saline group: r = 0.42, R(2) = 0.18, P = 0.02) and volume of fluids given IV (Ringer's group: r = 0.38, R(2) = 0.15, P = 0.02; Hypertonic Saline group: r = 0.32, R(2) = 0.1, P = not significant). Correlation of ADH to plasma osmolality was significant if plasma osmolality was >280 mOsm/kg (r = 0.5, R(2) = 0.25, P = 0.06), indicating an osmotic threshold for ADH release. Serum aldosterone levels were larger on the first day than during Days 2 and 3 in both groups and inversely correlated to serum sodium levels only in the Ringer's group (r = -0.55, R(2) = 0.3, P < 0.001). This group received a significantly larger fluid volume on Day 1 (P = 0.05, Mann-Whitney U-test) than did patients in the Hypertonic Saline group, indicating hypovolemia during the first day. Head-injured children have appropriate levels of ADH. They may be hypovolemic during the first day of treatment, especially if they receive lactated Ringer's solution. IMPLICATIONS: In head-injured patients, we recommend fluid restriction to avoid inappropriate secretion of antidiuretic hormone. In a prospective, randomized, and controlled study in 31 children, we were able to show that the antidiuretic hormone levels are appropriate in response to hypovolemia, sodium load, or both.

Phase I safety and pharmacodynamic of inecalcitol, a novel VDR agonist with docetaxel in metastatic castration-resistant prostate cancer patients.

PURPOSE: We conducted a phase I multicenter trial in naïve metastatic castrate-resistant prostate cancer patients with escalating inecalcitol dosages, combined with docetaxel-based chemotherapy. Inecalcitol is a novel vitamin D receptor agonist with higher antiproliferative effects and a 100-fold lower hypercalcemic activity than calcitriol. EXPERIMENTAL DESIGN: Safety and efficacy were evaluated in groups of three to six patients receiving inecalcitol during a 21-day cycle in combination with docetaxel (75 mg/m2 every 3 weeks) and oral prednisone (5 mg twice a day) up to six cycles. Primary endpoint was dose-limiting toxicity (DLT) defined as grade 3 hypercalcemia within the first cycle. Efficacy endpoint was ≥30% PSA decline within 3 months. RESULTS: Eight dose levels (40-8,000 μg) were evaluated in 54 patients. DLT occurred in two of four patients receiving 8,000 μg/day after one and two weeks of inecalcitol. Calcemia normalized a few days after interruption of inecalcitol. Two other patients reached grade 2, and the dose level was reduced to 4,000 μg. After dose reduction, calcemia remained within normal range and grade 1 hypercalcemia. The maximum tolerated dose was 4,000 μg daily. Respectively, 85% and 76% of the patients had ≥30% PSA decline within 3 months and ≥50% PSA decline at any time during the study. Median time to PSA progression was 169 days. CONCLUSION: High antiproliferative daily inecalcitol dose has been safely used in combination with docetaxel and shows encouraging PSA response (≥30% PSA response: 85%; ≥50% PSA response: 76%). A randomized phase II study is planned.

Conservation of the Eurasian Lynx (Lynx lynx) in a fragmented landscape - habitat models, dispersal and potential distribution

Abstract: The expansion of a recovering population - whether re-introduced or spontaneously returning - is shaped by (i) biological (intrinsic) factors such as the land tenure system or dispersal, (ii) the distribution and availability of resources (e.g. prey), (iii) habitat and landscape features, and (iv) human attitudes and activities. In order to develop efficient conservation and recovery strategies, we need to understand all these factors and to predict the potential distribution and explore ways to reach it. An increased number of lynx in the north-western Swiss Alps in the nineties lead to a new controversy about the return of this cat. When the large carnivores were given legal protection in many European countries, most organizations and individuals promoting their protection did not foresee the consequences. Management plans describing how to handle conflicts with large predators are needed to find a balance between "overabundance" and extinction. Wildlife and conservation biologists need to evaluate the various threats confronting populations so that adequate management decisions can be taken. I developed a GIS probability model for the lynx, based on habitat information and radio-telemetry data from the Swiss Jura Mountains, in order to predict the potential distribution of the lynx in this mountain range, which is presently only partly occupied by lynx. Three of the 18 variables tested for each square kilometre describing land use, vegetation, and topography, qualified to predict the probability of lynx presence. The resulting map was evaluated with data from dispersing subadult lynx. Young lynx that were not able to establish home ranges in what was identified as good lynx habitat did not survive their first year of independence, whereas the only one that died in good lynx habitat was illegally killed. Radio-telemetry fixes are often used as input data to calibrate habitat models. Radio-telemetry is the only way to gather accurate and unbiased data on habitat use of elusive larger terrestrial mammals. However, it is time consuming and expensive, and can therefore only be applied in limited areas. Habitat models extrapolated over large areas can in turn be problematic, as habitat characteristics and availability may change from one area to the other. I analysed the predictive power of Ecological Niche Factor Analysis (ENFA) in Switzerland with the lynx as focal species. According to my results, the optimal sampling strategy to predict species distribution in an Alpine area lacking available data would be to pool presence cells from contrasted regions (Jura Mountains, Alps), whereas in regions with a low ecological variance (Jura Mountains), only local presence cells should be used for the calibration of the model. Dispersal influences the dynamics and persistence of populations, the distribution and abundance of species, and gives the communities and ecosystems their characteristic texture in space and time. Between 1988 and 2001, the spatio-temporal behaviour of subadult Eurasian lynx in two re-introduced populations in Switzerland was studied, based on 39 juvenile lynx of which 24 were radio-tagged to understand the factors influencing dispersal. Subadults become independent from their mothers at the age of 8-11 months. No sex bias neither in the dispersal rate nor in the distance moved was detected. Lynx are conservative dispersers, compared to bear and wolf, and settled within or close to known lynx occurrences. Dispersal distances reached in the high lynx density population - shorter than those reported in other Eurasian lynx studies - are limited by habitat restriction hindering connections with neighbouring metapopulations. I postulated that high lynx density would lead to an expansion of the population and validated my predictions with data from the north-western Swiss Alps where about 1995 a strong increase in lynx abundance took place. The general hypothesis that high population density will foster the expansion of the population was not confirmed. This has consequences for the re-introduction and recovery of carnivores in a fragmented landscape. To establish a strong source population in one place might not be an optimal strategy. Rather, population nuclei should be founded in several neighbouring patches. Exchange between established neighbouring subpopulations will later on take place, as adult lynx show a higher propensity to cross barriers than subadults. To estimate the potential population size of the lynx in the Jura Mountains and to assess possible corridors between this population and adjacent areas, I adapted a habitat probability model for lynx distribution in the Jura Mountains with new environmental data and extrapolated it over the entire mountain range. The model predicts a breeding population ranging from 74-101 individuals and from 51-79 individuals when continuous habitat patches < 50 km2 are disregarded. The Jura Mountains could once be part of a metapopulation, as potential corridors exist to the adjoining areas (Alps, Vosges Mountains, and Black Forest). Monitoring of the population size, spatial expansion, and the genetic surveillance in the Jura Mountains must be continued, as the status of the population is still critical. ENFA was used to predict the potential distribution of lynx in the Alps. The resulting model divided the Alps into 37 suitable habitat patches ranging from 50 to 18,711 km2, covering a total area of about 93,600 km2. When using the range of lynx densities found in field studies in Switzerland, the Alps could host a population of 961 to 1,827 residents. The results of the cost-distance analysis revealed that all patches were within the reach of dispersing lynx, as the connection costs were in the range of dispersal cost of radio-tagged subadult lynx moving through unfavorable habitat. Thus, the whole Alps could once be considered as a metapopulation. But experience suggests that only few disperser will cross unsuitable areas and barriers. This low migration rate may seldom allow the spontaneous foundation of new populations in unsettled areas. As an alternative to natural dispersal, artificial transfer of individuals across the barriers should be considered. Wildlife biologists can play a crucial role in developing adaptive management experiments to help managers learning by trial. The case of the lynx in Switzerland is a good example of a fruitful cooperation between wildlife biologists, managers, decision makers and politician in an adaptive management process. This cooperation resulted in a Lynx Management Plan which was implemented in 2000 and updated in 2004 to give the cantons directives on how to handle lynx-related problems. This plan was put into practice e.g. in regard to translocation of lynx into unsettled areas. Résumé: L'expansion d'une population en phase de recolonisation, qu'elle soit issue de réintroductions ou d'un retour naturel dépend 1) de facteurs biologiques tels que le système social et le mode de dispersion, 2) de la distribution et la disponibilité des ressources (proies), 3) de l'habitat et des éléments du paysage, 4) de l'acceptation de l'espèce par la population locale et des activités humaines. Afin de pouvoir développer des stratégies efficaces de conservation et de favoriser la recolonisation, chacun de ces facteurs doit être pris en compte. En plus, la distribution potentielle de l'espèce doit pouvoir être déterminée et enfin, toutes les possibilités pour atteindre les objectifs, examinées. La phase de haute densité que la population de lynx a connue dans les années nonante dans le nord-ouest des Alpes suisses a donné lieu à une controverse assez vive. La protection du lynx dans de nombreux pays européens, promue par différentes organisations, a entraîné des conséquences inattendues; ces dernières montrent que tout plan de gestion doit impérativement indiquer des pistes quant à la manière de gérer les conflits, tout en trouvant un équilibre entre l'extinction et la surabondance de l'espèce. Les biologistes de la conservation et de la faune sauvage doivent pour cela évaluer les différents risques encourus par les populations de lynx, afin de pouvoir rapidement prendre les meilleuresmdécisions de gestion. Un modèle d'habitat pour le lynx, basé sur des caractéristiques de l'habitat et des données radio télémétriques collectées dans la chaîne du Jura, a été élaboré afin de prédire la distribution potentielle dans cette région, qui n'est que partiellement occupée par l'espèce. Trois des 18 variables testées, décrivant pour chaque kilomètre carré l'utilisation du sol, la végétation ainsi que la topographie, ont été retenues pour déterminer la probabilité de présence du lynx. La carte qui en résulte a été comparée aux données télémétriques de lynx subadultes en phase de dispersion. Les jeunes qui n'ont pas pu établir leur domaine vital dans l'habitat favorable prédit par le modèle n'ont pas survécu leur première année d'indépendance alors que le seul individu qui est mort dans l'habitat favorable a été braconné. Les données radio-télémétriques sont souvent utilisées pour l'étalonnage de modèles d'habitat. C'est un des seuls moyens à disposition qui permette de récolter des données non biaisées et précises sur l'occupation de l'habitat par des mammifères terrestres aux moeurs discrètes. Mais ces méthodes de- mandent un important investissement en moyens financiers et en temps et peuvent, de ce fait, n'être appliquées qu'à des zones limitées. Les modèles d'habitat sont ainsi souvent extrapolés à de grandes surfaces malgré le risque d'imprécision, qui résulte des variations des caractéristiques et de la disponibilité de l'habitat d'une zone à l'autre. Le pouvoir de prédiction de l'Analyse Ecologique de la Niche (AEN) dans les zones où les données de présence n'ont pas été prises en compte dans le calibrage du modèle a été analysée dans le cas du lynx en Suisse. D'après les résultats obtenus, la meilleure mé- thode pour prédire la distribution du lynx dans une zone alpine dépourvue d'indices de présence est de combiner des données provenant de régions contrastées (Alpes, Jura). Par contre, seules les données sur la présence locale de l'espèce doivent être utilisées pour les zones présentant une faible variance écologique tel que le Jura. La dispersion influence la dynamique et la stabilité des populations, la distribution et l'abondance des espèces et détermine les caractéristiques spatiales et temporelles des communautés vivantes et des écosystèmes. Entre 1988 et 2001, le comportement spatio-temporel de lynx eurasiens subadultes de deux populations réintroduites en Suisse a été étudié, basé sur le suivi de 39 individus juvéniles dont 24 étaient munis d'un collier émetteur, afin de déterminer les facteurs qui influencent la dispersion. Les subadultes se sont séparés de leur mère à l'âge de 8 à 11 mois. Le sexe n'a pas eu d'influence sur le nombre d'individus ayant dispersés et la distance parcourue au cours de la dispersion. Comparé à l'ours et au loup, le lynx reste très modéré dans ses mouvements de dispersion. Tous les individus ayant dispersés se sont établis à proximité ou dans des zones déjà occupées par des lynx. Les distances parcourues lors de la dispersion ont été plus courtes pour la population en phase de haute densité que celles relevées par les autres études de dispersion du lynx eurasien. Les zones d'habitat peu favorables et les barrières qui interrompent la connectivité entre les populations sont les principales entraves aux déplacements, lors de la dispersion. Dans un premier temps, nous avons fait l'hypothèse que les phases de haute densité favorisaient l'expansion des populations. Mais cette hypothèse a été infirmée par les résultats issus du suivi des lynx réalisé dans le nord-ouest des Alpes, où la population connaissait une phase de haute densité depuis 1995. Ce constat est important pour la conservation d'une population de carnivores dans un habitat fragmenté. Ainsi, instaurer une forte population source à un seul endroit n'est pas forcément la stratégie la plus judicieuse. Il est préférable d'établir des noyaux de populations dans des régions voisines où l'habitat est favorable. Des échanges entre des populations avoisinantes pourront avoir lieu par la suite car les lynx adultes sont plus enclins à franchir les barrières qui entravent leurs déplacements que les individus subadultes. Afin d'estimer la taille de la population de lynx dans le Jura et de déterminer les corridors potentiels entre cette région et les zones avoisinantes, un modèle d'habitat a été utilisé, basé sur un nouveau jeu de variables environnementales et extrapolé à l'ensemble du Jura. Le modèle prédit une population reproductrice de 74 à 101 individus et de 51 à 79 individus lorsque les surfaces d'habitat d'un seul tenant de moins de 50 km2 sont soustraites. Comme des corridors potentiels existent effectivement entre le Jura et les régions avoisinantes (Alpes, Vosges, et Forêt Noire), le Jura pourrait faire partie à l'avenir d'une métapopulation, lorsque les zones avoisinantes seront colonisées par l'espèce. La surveillance de la taille de la population, de son expansion spatiale et de sa structure génétique doit être maintenue car le statut de cette population est encore critique. L'AEN a également été utilisée pour prédire l'habitat favorable du lynx dans les Alpes. Le modèle qui en résulte divise les Alpes en 37 sous-unités d'habitat favorable dont la surface varie de 50 à 18'711 km2, pour une superficie totale de 93'600 km2. En utilisant le spectre des densités observées dans les études radio-télémétriques effectuées en Suisse, les Alpes pourraient accueillir une population de lynx résidents variant de 961 à 1'827 individus. Les résultats des analyses de connectivité montrent que les sous-unités d'habitat favorable se situent à des distances telles que le coût de la dispersion pour l'espèce est admissible. L'ensemble des Alpes pourrait donc un jour former une métapopulation. Mais l'expérience montre que très peu d'individus traverseront des habitats peu favorables et des barrières au cours de leur dispersion. Ce faible taux de migration rendra difficile toute nouvelle implantation de populations dans des zones inoccupées. Une solution alternative existe cependant : transférer artificiellement des individus d'une zone à l'autre. Les biologistes spécialistes de la faune sauvage peuvent jouer un rôle important et complémentaire pour les gestionnaires de la faune, en les aidant à mener des expériences de gestion par essai. Le cas du lynx en Suisse est un bel exemple d'une collaboration fructueuse entre biologistes de la faune sauvage, gestionnaires, organes décisionnaires et politiciens. Cette coopération a permis l'élaboration du Concept Lynx Suisse qui est entré en vigueur en 2000 et remis à jour en 2004. Ce plan donne des directives aux cantons pour appréhender la problématique du lynx. Il y a déjà eu des applications concrètes sur le terrain, notamment par des translocations d'individus dans des zones encore inoccupées.

Prognostic factors affecting long-term outcomes in patients with resected stage IIIA pN2 non-small-cell lung cancer: 5-year follow-up of a phase II study.

The aim was to investigate the efficacy of neoadjuvant docetaxel-cisplatin and identify prognostic factors for outcome in locally advanced stage IIIA (pN2 by mediastinoscopy) non-small-cell lung cancer (NSCLC) patients. In all, 75 patients (from 90 enrolled) underwent tumour resection after three 3-week cycles of docetaxel 85 mg m-2 (day 1) plus cisplatin 40 or 50 mg m-2 (days 1 and 2). Therapy was well tolerated (overall grade 3 toxicity occurred in 48% patients; no grade 4 nonhaematological toxicity was reported), with no observed late toxicities. Median overall survival (OS) and event-free survival (EFS) times were 35 and 15 months, respectively, in the 75 patients who underwent surgery; corresponding figures for all 90 patients enrolled were 28 and 12 months. At 3 years after initiating trial therapy, 27 out of 75 patients (36%) were alive and tumour free. At 5-year follow-up, 60 and 65% of patients had local relapse and distant metastases, respectively. The most common sites of distant metastases were the lung (24%) and brain (17%). Factors associated with OS, EFS and risk of local relapse and distant metastases were complete tumour resection and chemotherapy activity (clinical response, pathologic response, mediastinal downstaging). Neoadjuvant docetaxel-cisplatin was effective and tolerable in stage IIIA pN2 NSCLC, with chemotherapy contributing significantly to outcomes.

Biases on the administered parenteral doses of an experimental drug during phase I clinical trials

Introduction: The pharmaceutical aspects of drug administration in clinical trials receive poor consideration compared with the important attention devoted to the analytical and mathematical aspects of biological sample exploitation. During PK calculations, many researchers merely use for dose the nominal amount declared, overlooking the noticeable biases that may result in the assessment of PK parameters. The aim of this work was to evaluate the biases related to doses injected of a biosimilar drug in 2 Phase I clinical trials. Patients (or Materials) and Methods: In trial A, 12 healthy volunteers received different doses of a biosimilar of interferon beta-1a by either subcutaneous (SC) or intravenous (IV) injection. The doses were prepared by partially emptying 0.5-mL syringes supplied by the manufacturer (drop count procedure). In trial B, 12 healthy volunteers received 3 different formulations of the drug by IV injection (biosimilar without albumin [HSA], biosimilar with HSA and original brand [Rebif®]) and 2 different formulations as multiple SC injections (biosimilar HSA-free and original brand). In both trials, the actual dose administered was calculated as: D = C·V - losses. The product titer C was assessed by ELISA. The volume administered IV was assessed by weighting. Losses were evaluated by in vitro experiments. Finally, the binding of 125I-interferon to HSA was evaluated by counting the free and HSA complexed molecule fractions separated by gel filtration. Results: Interferon was not significantly adsorbed onto the lines used for its IV administration. In trial A, the titer was very close to the one declared (96 ± 7%). In trial B, it differed significantly (156 ± 10% for biosimilar with/without HSA and 123 ± 5% for original formulation). In trial A, the dose actually administered showed a large variability. The real injected volume could be biased up to 75% compared with the theoretical volume (for the lower dose administered [ie, 0.03 mL]). This was mainly attributed to a partial re-aspiration of the drug solution before withdrawing the syringe needle. A strict procedure was therefore applied in trial B to avoid these inaccuracies. Finally, in trial B, 125I-Interferon beta-1a binding to HSA appeared time dependent and slow, reaching 50% after 16-hour incubation, which is close to steady state reported for the comparator Rebif®. Conclusion: These practical examples (especially biases on actual titer and volume injected) illustrate that actual dose assessment deserves attention to ensure accuracy for estimates of clearance and distribution volume in the scientific literature and for registration purposes, especially for bioequivalence studies.

Vaccines safety; effect of supervision or SMS on reporting rates of adverse events following immunization (AEFI) with meningitis vaccine (MenAfriVac?): a randomized controlled trial.

BACKGROUND: To ensure vaccines safety, given the weaknesses of the national pharmacovigilance system in Cameroon, there is a need to identify effective interventions that can contribute to improving AEFI reporting. OBJECTIVE: To assess the effect of: (i) sending weekly SMS, or (ii) weekly supervisory visits on AEFI reporting rate during a meningitis immunization campaign conducted in Cameroon in 2012 using the meningitis A conjugate vaccine (MenAfriVac?). METHODS: Health facilities that met the inclusion criteria were randomly assigned to receive: (i) a weekly standardized SMS, (ii) a weekly standardized supervisory visits or (iii) no intervention. The primary outcome was the reported AEFI incidence rate from week 5 to 8 after the immunization campaign. Poisson regression model was used to estimate the effect of interventions after adjusting for health region, type of health facility, type and position of health workers as well as the cumulative number of AEFI reported from weeks 1 to 4. RESULTS: A total of 348 (77.2%) of 451 health facility were included, and 116 assigned to each of three groups. The incidence rate of reported AEFI per 100 health facility per week was 20.0 (15.9-24.1) in the SMS group, 40.2 (34.4-46.0) in supervision group and 13.6 (10.1-16.9) in the control group. Supervision led to a significant increase of AEFI reporting rate compared to SMS [adjusted RR=2.1 (1.6-2.7); p<0.001] and control [RR=2.8(2.1-3.7); p<0.001)] groups. The effect of SMS led to some increase in AEFI reporting rate compared to the control group, but the difference was not statistically significant [RR=1.4(0.8-1.6); p=0.07)]. CONCLUSION: Supervision was more effective than SMS or routine surveillance in improving AEFI reporting rate. It should be part of any AEFI surveillance system. SMS could be useful in improving AEFI reporting rates but strategies need to be found to improve its effectiveness, and thus maximize its benefits.

A pilot feasibility, safety and biological efficacy multicentre trial of therapeutic hypercapnia after cardiac arrest: study protocol for a randomized controlled trial.

BACKGROUND: Cardiac arrest causes ischaemic brain injury. Arterial carbon dioxide tension (PaCO2) is a major determinant of cerebral blood flow. Thus, mild hypercapnia in the 24 h following cardiac arrest may increase cerebral blood flow and attenuate such injury. We describe the Carbon Control and Cardiac Arrest (CCC) trial. METHODS/DESIGN: The CCC trial is a pilot multicentre feasibility, safety and biological efficacy randomized controlled trial recruiting adult cardiac arrest patients admitted to the intensive care unit after return of spontaneous circulation. At admission, using concealed allocation, participants are randomized to 24 h of either normocapnia (PaCO2 35 to 45 mmHg) or mild hypercapnia (PaCO2 50 to 55 mmHg). Key feasibility outcomes are recruitment rate and protocol compliance rate. The primary biological efficacy and biological safety measures are the between-groups difference in serum neuron-specific enolase and S100b protein levels at 24 h, 48 h and 72 h. Secondary outcome measure include adverse events, in-hospital mortality, and neurological assessment at 6 months. DISCUSSION: The trial commenced in December 2012 and, when completed, will provide clinical evidence as to whether targeting mild hypercapnia for 24 h following intensive care unit admission for cardiac arrest patients is feasible and safe and whether it results in decreased concentrations of neurological injury biomarkers compared with normocapnia. Trial results will also be used to determine whether a phase IIb study powered for survival at 90 days is feasible and justified. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12612000690853 .

Two cilengitide regimens in combination with standard treatment for patients with newly diagnosed glioblastoma and unmethylated MGMT gene promoter: results of the open-label, controlled, randomized phase II CORE study.

BACKGROUND: Survival outcomes for patients with glioblastoma remain poor, particularly for patients with unmethylated O(6)-methylguanine-DNA methyltransferase (MGMT) gene promoter. This phase II, randomized, open-label, multicenter trial investigated the efficacy and safety of 2 dose regimens of the selective integrin inhibitor cilengitide combined with standard chemoradiotherapy in patients with newly diagnosed glioblastoma and an unmethylated MGMT promoter. METHODS: Overall, 265 patients were randomized (1:1:1) to standard cilengitide (2000 mg 2×/wk; n = 88), intensive cilengitide (2000 mg 5×/wk during wk 1-6, thereafter 2×/wk; n = 88), or a control arm (chemoradiotherapy alone; n = 89). Cilengitide was administered intravenously in combination with daily temozolomide (TMZ) and concomitant radiotherapy (RT; wk 1-6), followed by TMZ maintenance therapy (TMZ/RT→TMZ). The primary endpoint was overall survival; secondary endpoints included progression-free survival, pharmacokinetics, and safety and tolerability. RESULTS: Median overall survival was 16.3 months in the standard cilengitide arm (hazard ratio [HR], 0.686; 95% CI: 0.484, 0.972; P = .032) and 14.5 months in the intensive cilengitide arm (HR, 0.858; 95% CI: 0.612, 1.204; P = .3771) versus 13.4 months in the control arm. Median progression-free survival assessed per independent review committee was 5.6 months (HR, 0.822; 95% CI: 0.595, 1.134) and 5.9 months (HR, 0.794; 95% CI: 0.575, 1.096) in the standard and intensive cilengitide arms, respectively, versus 4.1 months in the control arm. Cilengitide was well tolerated. CONCLUSIONS: Standard and intensive cilengitide dose regimens were well tolerated in combination with TMZ/RT→TMZ. Inconsistent overall survival and progression-free survival outcomes and a limited sample size did not allow firm conclusions regarding clinical efficacy in this exploratory phase II study.