Premier épisode thymique: cas particulier de l'intervention dans la phase précoce des troubles bipolaires [First episode of mood disorders: an opportunity for early intervention in bipolar disorders].

While early intervention strategies have been developed for psychotic disorders, affective psychoses and bipolar disorders have been neglected by this movement. However, when considering that outcome of bipolar disorders is often not as favorable as previously thought and that delay between illness onset and introduction of an adequate treatment is often very long, such developments seem clearly justified. In this paper we briefly review arguments supporting early intervention in bipolar disorders, the practical and theoretical obstacles that still need to be overcome, the strategies that may already now contribute to decrease treatment delay, and we describe current state of research regarding identification of the prodromal phase of bipolar disorders.

The role of dentritic cells in leishmania infection : use of novel DC lines for the development of monoclonal antibodies

Les cellules dendritiques (DCs) sont des cellules multifonctionnelles qui font le lien entre le sytème immunitaire inné et adaptatif chez les mammifères. Il existe plusieurs sous-types de DCs basés sur leurs fonctions et l'endroit où elles se situent dans le corps. Dans le cadre de cette thèse, nous avons étudié le rôle de ces cellules face à une infection parasitaire. La Leishmania est un parasite causant une maladie appelée Leishmaniose, maladie endémique de l'Afrique, de l'Asie et de certaines régions de l'Amérique du Sud. Certaines espèces causent des lésions cutanées, alors que d'autres causent des lésions dans les muqueuses ou dans les organes internes. Le système immunitaire répond en générant une réponse inflammatoire qui élimine l'infection. Lors d'une réponse non-inflammatoire (de type cytokines, chemokines), cela va amener à une persistance du parasite sur le long terme. Les DC s'activant en présence du parasite dans la peau, vont le transporter vers un ganglion. A cet endroit, se trouvent différents sous-types de DC qui ont la particularité de présenter l'antigène (spécifique à la Leishmaniose) aux lymphocytes T, ce qui va alors amener à une réponse immunitaire puissante contre le parasite. Nous avons comparé différentes espèces de Leishmaniose dans leur façon d'activer les DC et différents modèles de souris ont été utilisé dans ce but-là. Les souris du type C57BL/6 sont connues pour être résistantes à L. major et sensibles à L. mexicana, alors qu'au contraire, les souris Balb/c sont connues pour être sensibles à ces deux espèces. En utilisant des parasites fluorescents transgéniques, nous avons comparé ces deux espèces de parasites (L. major et L. mexicana) en recherchant quelles cellules elles sont capables d'infecter in-vivo dans un modèle murin. Le rôle général des DC dans une infection à L. major a déjà été décrit. Dans notre étude, nous avons étudié le besoin en DC CD8a+ dans les ganglions afin d'engendrer une réponse face à une infection à L. major. Les souris qui n'ont pas ce sous-type de DC sont beaucoup plus sensibles à l'infection : elles ont des marqueurs inflammatoires plus bas et des lésions plus grandes. Nous avons également remarqué que les DC CD8a+ jouent un rôle crucial dans une phase plus avancée de l'infection. Dans notre laboratoire, nous avons la chance d'avoir une source illimitée de DCs de sous-type CD8a+ provenant d'une souris génétiquement modifiée par nos soin. Grâce à cela, nous avons utilisé ces cellules CD8a+ pour immuniser des rats afin de produire des anticorps monoclonaux ayant des propriétés spécifiques comme l'identification de protéines uniques présentes à la surface des DC et qui ensuite, modulent une réponse immunitaire in-vivo. Nous sommes actuellement en phase de caractérisation de plus de 750 hybridomes générés dans notre laboratoire. - Les cellules dendritiques (DCs) constituent le lien entre le système inné et adaptatif de la réponse immunitaire, car elles sont capables de présenter l'antigène, de donner la co- stimulation et de relâcher des cytokines et chimokines. Au cours de cette thèse, nous avons exploré différentes familles de DC lors d'infections parasitaires, telles que la Leishmaniose, parasite intracellulaire qui infecte les mammifères. La plupart des lésions cutanées résistantes sont caractérisées par une réponse pro-inflammatoire générée par l'IL-12. A l'inverse, pour la forme non résistante, la réponse est générée par l'IL-4 et l'IL-10, dans les modèles murins vulnérables. L'infection avec Lmajor a été caractérisée chez la souris C57BL/6 (Thl) et chez la souris Balb/c (Th2). Chez la souris C57BL/6 la lésion guérit, alors que chez la souris Balb/c, la lésion est au contraire non-cicatrisante. Nous avons comparé l'activation causée dans l'ensemble des DC par différentes espéces de Leishmania, et plus spécifiquement dans les DC CD8a+ présentes dans les ganglions lymphatiques et leur rôle dans la vulnérabilité à L. major. Ces cellules sont spécialisées dans la présentation croisée d'antigènes exogènes par le CMH-I et le haut taux de production d'IL-12 après activation. En utilisant des DC dérivées de moelle osseuse, nous avons constaté que L. guyanensis V+ (transportant un retrovirus) était le plus efficace pour l'activation des DC in-vitro comparé à L. major, L. mexicana et L. guyanensis (V-). Toutefois, in-vivo, les souris infectées avec L. major ont vu la taille de leur ganglions lymphatiques drainants augmentée, 3-6 semaines après l'infection dans les deux espèces de souris (les C57BL/6 résistantes et les Balb/c sensibles). En utilisant un parasite fluorescent transgénique, nous avons trouvé que les souris C57BL/6 sensibles à Lmexicana ont un nombre plus important de cellules Β infectées et un plus petit nombre de DC dérivées des monocytes inflammatoires, comparé au souris infectées avec L. major. Les conséquences de ces observations sont encore à l'étude. Des souris déficientes en CD8ct+DC et CD103+ sont plus sensibles à L. major que les souris WT: leurs lésions sont plus grandes et la charge parasitaire est plus importante. Nous avons généré une chimère de moelles osseuse CD11-DTR et Batf3-/- en mélangeant les moelles de ces deux souris, afin de déterminer le temps après infection où le manque de DC's CD8a+ contribue le plus à l'augmentation de la vulnérabilité chez la souris KO. Ces souris produisent plus d'IgG1 et IgE, font une réponse Th2 plus forte et Thl moins forte. Nous avons constaté que les souris déficientes en DC CD8a+ au début de la réponse immunitaire adaptive (trois semaines après injection) maintiennent un haut taux de lésions de grande taille, semblable à celui des souris chez qui les cellules ont été déplétées avant l'injection. Cela indique que les DC CD8a+ sont nécessaires pour l'efficacité de l'immunité dans la phase chronique de l'infection à L. major. Parallèlement à cela, nous avons aussi commencé une génération d'anticorps monoclonaux dirigés contre les DC CD8a+ activés en utilisant des souches établies dans notre laboratoire. En partant d'une librairie de 763 hybridomes, nous avons identifié plusieurs clones dignes d'intérêt avec une capacité fonctionnelle à moduler la prolifération et la sécrétion de cytokines des cellules T, ainsi que les molécules de co-stimulation présentes à la surface des DC activées elle-même. - Dendritic cells (DCs) are the bridge between the innate and the adaptive arms of the immune systems. They are professional antigen presentation cells and have important cytokine/chemokine release functions. In this dissertation we have focussed on the study of the different subsets of DCs in parasitic infection immunity. Leishmania are intra-cellular parasites of many different species that infect mammals. Most cutaneous lesions that are self- healing are characterized with a pro-inflammatory response with IL-12 while high levels of cytokines such as IL-4 and IL-10 characterized in susceptible mouse models. In mice L. major infection has been well characterized in C57BL/6 mice (Thl) that form healing lesions while Balb/c mice (Th2) form non-healing lesions. This thesis is focussed on comparing DC activation at large by different strains of Leishmania and more specifically, dLN resident CD8a+ DCs and their role in L. major susceptibility. This subset is specialized in cross- presentation of exogenous antigens in the MHC-I pathway and produce high levels of EL-12. Using bone marrow derived DCs we found that L. guyanensis V+ (carrying a retro-virus) was the most efficient at activating DCs in-vitro. In-vivo however L. major infected mice had the largest dLNs 3-6 weeks after infection in both genetically resistant C57BL/6 and susceptible Balb/c mice. Using transgenic fluorescent parasites, we found that C57BL/6 mice which are susceptible to L. mexicana had more number of infected Β cells and fewer number of infected inflammatory monocyte derived DCs in contrast to L. major infection. Using mice deficient in CD8a+ DCs, we found that these mice were more susceptible to L. major than their WT counterparts. They made larger lesions, had higher parasite burdens, higher levels of Th2 indicating immunolgloblins as measured by higher serie IgE levels and lower CD4+ IFNy+ cells. A mixed bone marrow chimera system of CDllc-DTR and Batf3~'~ was generated to determine the time point at which the lack of CD8a+ DCs most contributes to the increased susceptibility in KO mice. We found that mice depleted of CD8a+ DCs at the advent of the adaptive response (3 weeks after infection) maintained the significantly higher lesion size similar to mice whose cells were depleted from the onset of infection. This indicates that CD8a+ DCs are required for effective immunity in the chronic phase of L. major infection. We also began the generation of a valuable tool of monoclonal antibodies against activated CD8a+ DCs using our in-house DC line. From a library of 763 hybridomas we have identified several interesting clones with a functional ability to modulate Τ cell proliferation and cytokine secretion as well as down-modulating co-stimulatory molecules on activated DC cells themselves.

Daptomycin plus fosfomycin versus daptomycin monotherapy in treating MRSA: protocol of a multicentre, randomised, phase III trial.

INTRODUCTION Despite the availability of new antibiotics such as daptomycin, methicillin-resistant Staphylococcus aureus (MRSA) bacteraemia continues to be associated with high clinical failure rates. Combination therapy has been proposed as an alternative to improve outcomes but there is a lack of clinical studies. The study aims to demonstrate that combination of daptomycin plus fosfomycin achieves higher clinical success rates in the treatment of MRSA bacteraemia than daptomycin alone. METHODS AND ANALYSIS A multicentre open-label, randomised phase III study. Adult patients hospitalised with MRSA bacteraemia will be randomly assigned (1:1) to group 1: daptomycin 10 mg/kg/24 h intravenous; or group 2: daptomycin 10 mg/kg/24 h intravenous plus fosfomycin 2 gr/6 g intravenous. The main outcome will be treatment response at week 6 after stopping therapy (test-of-cure (TOC) visit). This is a composite variable with two values: Treatment success: resolution of clinical signs and symptoms (clinical success) and negative blood cultures (microbiological success) at the TOC visit. Treatment failure: if any of the following conditions apply: (1) lack of clinical improvement at 72 h or more after starting therapy; (2) persistent bacteraemia (positive blood cultures on day 7); (3) therapy is discontinued early due to adverse effects or for some other reason based on clinical judgement; (4) relapse of MRSA bacteraemia before the TOC visit; (5) death for any reason before the TOC visit. Assuming a 60% cure rate with daptomycin and a 20% difference in cure rates between the two groups, 103 patients will be needed for each group (α:0.05, ß: 0.2). Statistical analysis will be based on intention to treat, as well as per protocol and safety analysis. ETHICS AND DISSEMINATION The protocol was approved by the Spanish Medicines and Healthcare Products Regulatory Agency (AEMPS). The sponsor commits itself to publishing the data in first quartile peer-review journals within 12 months of the completion of the study. TRIAL REGISTRATION NUMBER NCT01898338.

Primary dengue haemorrhagic fever in patients from northeast of Brazil is associated with high levels of interferon-β during acute phase

Dengue is an acute febrile disease caused by the mosquito-borne dengue virus (DENV) that according to clinical manifestations can be classified as asymptomatic, mild or severe dengue. Severe dengue cases have been associated with an unbalanced immune response characterised by an over secretion of inflammatory cytokines. In the present study we measured type I interferon (IFN-I) transcript and circulating levels in primary and secondary DENV infected patients. We observed that dengue fever (DF) and dengue haemorrhagic fever (DHF) patients express IFN-I differently. While DF and DHF patients express interferon-α similarly (52,71 ± 7,40 and 49,05 ± 7,70, respectively), IFN- β were associated with primary DHF patients. On the other hand, secondary DHF patients were not able to secrete large amounts of IFN- β which in turn may have influenced the high-level of viraemia. Our results suggest that, in patients from our cohort, infection by DENV serotype 3 elicits an innate response characterised by higher levels of IFN- β in the DHF patients with primary infection, which could contribute to control infection evidenced by the low-level of viraemia in these patients. The present findings may contribute to shed light in the role of innate immune response in dengue pathogenesis.

A combination of ascorbic acid and α-tocopherol to test the effectiveness and safety in the fragile X syndrome: study protocol for a phase II, randomized, placebo-controlled trial.

BACKGROUND Fragile X syndrome (FXS) is an inherited neurodevelopmental condition characterised by behavioural, learning disabilities, physical and neurological symptoms. In addition, an important degree of comorbidity with autism is also present. Considered a rare disorder affecting both genders, it first becomes apparent during childhood with displays of language delay and behavioural symptoms.Main aim: To show whether the combination of 10 mg/kg/day of ascorbic acid (vitamin C) and 10 mg/kg/day of α-tocopherol (vitamin E) reduces FXS symptoms among male patients ages 6 to 18 years compared to placebo treatment, as measured on the standardized rating scales at baseline, and after 12 and 24 weeks of treatment.Secondary aims: To assess the safety of the treatment. To describe behavioural and cognitive changes revealed by the Developmental Behaviour Checklist Short Form (DBC-P24) and the Wechsler Intelligence Scale for Children-Revised. To describe metabolic changes revealed by blood analysis. To measure treatment impact at home and in an academic environment. METHODS/DESIGN A phase II randomized, double-blind pilot clinical trial. SCOPE male children and adolescents diagnosed with FXS, in accordance with a standardized molecular biology test, who met all the inclusion criteria and none of the exclusion criteria. INSTRUMENTATION clinical data, blood analysis, Wechsler Intelligence Scale for Children-Revised, Conners parent and teacher rating scale scores and the DBC-P24 results will be obtained at the baseline (t0). Follow up examinations will take place at 12 weeks (t1) and 24 weeks (t2) of treatment. DISCUSSION A limited number of clinical trials have been carried out on children with FXS, but more are necessary as current treatment possibilities are insufficient and often provoke side effects. In the present study, we sought to overcome possible methodological problems by conducting a phase II pilot study in order to calculate the relevant statistical parameters and determine the safety of the proposed treatment. The results will provide evidence to improve hyperactivity control and reduce behavioural and learning problems using ascorbic acid (vitamin C) and α-tocopherol (vitamin E). The study protocol was approved by the Regional Government Committee for Clinical Trials in Andalusia and the Spanish agency for drugs and health products. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT01329770 (29 March 2011).

Segmentation and grid generation for numerical simulations of vad connections with patient-specific data

Objectives: We are interested in the numerical simulation of the anastomotic region comprised between outflow canula of LVAD and the aorta. Segmenta¬tion, geometry reconstruction and grid generation from patient-specific data remain an issue because of the variable quality of DICOM images, in particular CT-scan (e.g. metallic noise of the device, non-aortic contrast phase). We pro¬pose a general framework to overcome this problem and create suitable grids for numerical simulations.Methods: Preliminary treatment of images is performed by reducing the level window and enhancing the contrast of the greyscale image using contrast-limited adaptive histogram equalization. A gradient anisotropic diffusion filter is applied to reduce the noise. Then, watershed segmentation algorithms and mathematical morphology filters allow reconstructing the patient geometry. This is done using the InsightToolKit library (www.itk.org). Finally the Vascular Model¬ing ToolKit (www.vmtk.org) and gmsh (www.geuz.org/gmsh) are used to create the meshes for the fluid (blood) and structure (arterial wall, outflow canula) and to a priori identify the boundary layers. The method is tested on five different patients with left ventricular assistance and who underwent a CT-scan exam.Results: This method produced good results in four patients. The anastomosis area is recovered and the generated grids are suitable for numerical simulations. In one patient the method failed to produce a good segmentation because of the small dimension of the aortic arch with respect to the image resolution.Conclusions: The described framework allows the use of data that could not be otherwise segmented by standard automatic segmentation tools. In particular the computational grids that have been generated are suitable for simulations that take into account fluid-structure interactions. Finally the presented method features a good reproducibility and fast application.

An in vitro iron superoxide dismutase inhibitor decreases the parasitemia levels of Trypanosoma cruzi in BALB/c mouse model during acute phase.

In order to identify new compounds to treat Chagas disease during the acute phase with higher activity and lower toxicity than the reference drug benznidazole (Bz), two hydroxyphthalazine derivative compounds were prepared and their trypanocidal effects against Trypanosoma cruzi were evaluated by light microscopy through the determination of IC50 values. Cytotoxicity was determined by flow cytometry assays against Vero cells. In vivo assays were performed in BALB/c mice, in which the parasitemia levels were quantified by fresh blood examination; the assignment of a cure was determined by reactivation of blood parasitemia levels after immunosuppression. The mechanism of action was elucidated at metabolic and ultra-structural levels, by (1)H NMR and TEM studies. Finally, as these compounds are potentially capable of causing oxidative damage in the parasites, the study was completed, by assessing their activity as potential iron superoxide dismutase (Fe-SOD) inhibitors. High-selectivity indices observed in vitro were the basis of promoting one of the tested compounds to in vivo assays. The tests on the murine model for the acute phase of Chagas disease showed better parasitemia inhibition values than those found for Bz. Compound 2 induced a remarkable decrease in the reactivation of parasitemia after immunosuppression. Compound 2 turned out to be a great inhibitor of Fe-SOD. The high antiparasitic activity and low toxicity together with the modest costs for the starting materials render this compound an appropriate molecule for the development of an affordable anti-Chagas agent.

Motivation des patients à participer à un essai clinique de phase I en oncologie

Chaque année en Suisse, 15000 personnes meurent du cancer, ce qui en fait la deuxième cause de mortalité [1]. Il est donc nécessaire d'introduire sur le marché de nouveaux traitements plus efficaces. Ces derniers doivent passer par une période d'essais cliniques qui comporte plusieurs phases, dont la phase I. Celle-ci sert principalement à déterminer la dose maximale tolérable d'un médicament, en exposant le patient à des doses croissantes. Déterminer les motivations des patients à participer à la phase I d'un essai clinique, alors que les bénéfices personnels sont relativement faibles [3].

Extracellular protease and phospholipase C are controlled by the global regulatory gene gacA in the biocontrol strain Pseudomonas fluorescens CHA0.

Pseudomonas fluorescens strain CHA0 protects plants from various root diseases. Antibiotic metabolites synthesized by this strain play an important role in disease suppression; their production is mediated by the global activator gene gacA. Here we show by complementation that the gacA gene is also essential for the expression of two extracellular enzymes in P. fluorescens CHA0: phospholipase C and a 47-kDa metalloprotease. In contrast, the production of another exoenzyme, lipase, is not regulated by the gacA gene. Protease, phospholipase and antibiotics of P. fluorescens are all known to be optimally produced at the end of exponential growth; thus, the gacA gene appears to be a general stationary-phase regulator.

Tonotopic gradients in human primary auditory cortex: concurring evidence from high-resolution 7 t and 3 t FMRI.

The tonotopic representations within the primary auditory cortex (PAC) have been successfully mapped with ultra-high field fMRI. Here, we compared the reliability of this tonotopic mapping paradigm at 7 T with 1.5 mm spatial resolution with maps acquired at 3 T with the same stimulation paradigm, but with spatial resolutions of 1.8 and 2.4 mm. For all subjects, the mirror-symmetric gradients within PAC were highly similar at 7 T and 3 T and across renderings at different spatial resolutions; albeit with lower percent signal changes at 3 T. In contrast, the frequency maps outside PAC tended to suffer from a reduced BOLD contrast-to-noise ratio at 3 T for a 1.8 mm voxel size, while robust at 2.4 mm and at 1.5 mm at 7 T. Overall, our results showed the robustness of the phase-encoding paradigm used here to map tonotopic representations across scanners.

A Multi-Center Phase II Study (SAKK 36/06) of Single Agent Everolimus (RAD001) In Patients with Relapsed or Refractory Mantle Cell Lymphoma

Introduction: Mantle cell lymphoma (MCL) accounts for 6% of all B-cell lymphomas and remains incurable for most patients. Those who relapse after first line therapy or hematopoietic stem cell transplantation have a dismal prognosis with short response duration after salvage therapy. On a molecular level, MCL is characterised by the translocation t[11;14] leading to Cyclin D1 overexpression. Cyclin D1 is downstream of the mammalian target of rapamycin (mTOR) kinase and can be effectively blocked by mTOR inhibitors such as temsirolimus. We set out to define the single agent activity of the orally available mTOR inhibitor everolimus (RAD001) in a prospective, multi-centre trial in patients with relapsed or refractory MCL (NCT00516412). The study was performed in collaboration with the EU-MCL network. Methods: Eligible patients with histologically/cytologically confirmed relapsed (not more than 3 prior lines of systemic treatment) or refractory MCL received everolimus 10 mg orally daily on day 1 - 28 of each cycle (4 weeks) for 6 cycles or until disease progression. The primary endpoint was the best objective response with adverse reactions, time to progression (TTP), time to treatment failure, response duration and molecular response as secondary endpoints. A response rate of 10% was considered uninteresting and, conversely, promising if 30%. The required sample size was 35 pts using the Simon's optimal two-stage design with 90% power and 5% significance. Results: A total of 36 patients with 35 evaluable patients from 19 centers were enrolled between August 2007 and January 2010. The median age was 69.4 years (range 40.1 to 84.9 years), with 22 males and 13 females. Thirty patients presented with relapsed and 5 with refractory MCL with a median of two prior therapies. Treatment was generally well tolerated with anemia (11%), thrombocytopenia (11%), neutropenia (8%), diarrhea (3%) and fatigue (3%) being the most frequent complications of CTC grade III or higher. Eighteen patients received 6 or more cycles of everolimus treatment. The objective response rate was 20% (95% CI: 8-37%) with 2 CR, 5 PR, 17 SD, and 11 PD. At a median follow-up of 6 months, TTP was 5.45 months (95% CI: 2.8-8.2 months) for the entire population and 10.6 months for the 18 patients receiving 6 or more cycles of treatment. Conclusion: This study demonstrates that single agent everolimus 10 mg once daily orally is well tolerated. The null hypothesis of inactivity could be rejected indicating a moderate anti-lymphoma activity in relapsed/refractory MCL. Further studies of either everolimus in combination with chemotherapy or as single agent for maintenance treatment are warranted in MCL.

Safety, pharmacokinetics, and preliminary clinical activity of inotuzumab ozogamicin, a novel immunoconjugate for the treatment of B-cell non-Hodgkin's lymphoma: results of a phase I study.

PURPOSE Inotuzumab ozogamicin (CMC-544) is an antibody-targeted chemotherapy agent composed of a humanized anti-CD22 antibody conjugated to calicheamicin, a potent cytotoxic agent. This was a phase I study to determine the maximum-tolerated dose (MTD), safety, and preliminary efficacy of inotuzumab ozogamicin in an expanded MTD cohort of patients with relapsed or refractory CD22(+) B-cell non-Hodgkin's lymphoma (NHL). PATIENTS AND METHODS Inotuzumab ozogamicin was administered intravenously as a single agent once every 3 or 4 weeks at doses ranging from 0.4 to 2.4 mg/m(2). Outcomes included MTD, safety, pharmacokinetics, response, progression-free survival (PFS), and overall survival. Results Seventy-nine patients were enrolled. The MTD was determined to be 1.8 mg/m(2). Common adverse events at the MTD were thrombocytopenia (90%), asthenia (67%), and nausea and neutropenia (51% each). The objective response rate at the end of treatment was 39% for the 79 enrolled patients, 68% for all patients with follicular NHL treated at the MTD, and 15% for all patients with diffuse large B-cell lymphoma treated at the MTD. Median PFS was 317 days (approximately 10.4 months) and 49 days for patients with follicular NHL and diffuse large B-cell lymphoma, respectively. CONCLUSION Inotuzumab ozogamicin has demonstrated efficacy against CD22(+) B-cell NHL, with reversible thrombocytopenia as the main toxicity.

RTOG 0525: A randomized phase iii trial comparing standard adjuvant temozolomide (tmz) with a dose-dense (dd) schedule in newly diagnosed glioblastoma (gbm)

Radiotherapy with concomitant and adjuvant TMZ is the standard of care for newly diagnosed GBM. MGMT methylation status may be an important determinant of treatment response. This trial, conducted by the RTOG, EORTC, and NCCTG, determined if intensified TMZ improves survival (OS) or progression free survival (PFS) in all patients or specific to MGMT status. Eligibility criteria included age . 18 yrs, KPS ≥ 60, and existence of a tissue block with . 1cm2 tumor for prospective MGMT and retrospective molecular analysis. Patients were randomized to Arm 1: standard TMZ (150-200 mg/m2 x 5 d) or Arm 2: dd TMZ (75-100 mg/m2 x 21 d) q 4 wks for 6-12 cycles. Symptom burden, quality of life (QOL), and neurocognition were prospectively and longitudinally assessed in a patient subset. 833 patients were randomized (1173 registered). Inadequate tissue (n ¼ 144) was the most frequent reason for nonrandomization.No statistical difference was observed between Arms 1 and 2 for median OS (16.6, 14.9 mo, p ¼ 0.63), median PFS (5.5, 6.7 mo, p ¼ 0.06), or methylation status. MGMT methylation was associated with improved OS (21.2, 14 mo, p , 0.0001), PFS (8.7, 5.7 mo, p , 0.0001), and treatment response (p ¼ 0.012). Cox modeling identifiedMGMT status and RPA class as significant predictors of OS; treatment arm and radiation technique (EORTC vs. RTOG) were not. There was increased grade ≥ 3 toxicity in Arm 2 (19%, 27%, p ¼ 0.008), which was mostly lymphopenia and fatigue. This study did not demonstrate improved efficacy for dd TMZ for newly diagnosed GBM regardless of methylation status. However, it confirmed the prognostic significance of MGMT methylation in GBM, demonstrated the feasibility of tumor tissue collection, molecular stratification, and collection of patient outcomes in a large transatlantic intergroup trial, thereby establishing a viable clinical trial paradigm. Support: NCI U10 CA 21661 and U10 CA37422.

Value of PET/CT versus contrast-enhanced CT in identifying chest wall invasion (T3) by NSCLC [B-671]

Purpose: To determine the diagnostic value of 18F-FDG PET/CT versus contrastenhanced CT in identifying chest wall invasion by NSCLC. Methods and Materials: The primary selection criterion was a peripheral tumor of any size with contact to the chest wall. A total of 25 patients with pathologically proven NSCLC satisfied these criteria. Chest wall invasion was interpreted upon PET/CT when a frank costal or intercostal 18F-FDG uptake was identified with or without concomitant morphologic alterations. On the other hand, the existence of periosteal rib reaction/erosion, chest wall thickening or obliteration of the pleural fat layer either separately or combined were considered essential diagnostic criteria for disease extension into the chest wall upon contrast-enhanced CT. The results were correlated with the final histological analysis. Results: Among the studied cohort, 13/25 (52%) patients had chest wall invasion consistent with T3 disease. Both PET/CT and contrast-enhanced CT successfully identified 12/13 (92%) of these patients. The single false-negative result was due to parietal pleural invasion. On the other hand, one false-positive result was encountered by PET/CT in a dyspneic patient; whereas, CT analysis revealed false-positive results in six patients. In these patients, periosteal rib reaction (n = 2) or asymmetric enlargement of adjacent chest wall muscles (n = 1) were identified along with an obliterated pleural fat layer (n = 6). The sensitivity, specificity, and accuracy of PET/CT and contrast-enhanced CT were 92, 91 and 92% versus 92, 50 and 72%. Conclusion: 18F-FDG PET/CT is an accurate diagnostic modality in identifying.