Three-phase 18F-fluorocholine PET/CT in the evaluation of prostate cancer recurrence.

AIM: Contribution of 3-phase 18F-fluorocholine PET/CT in suspected prostate cancer recurrence at early rise of PSA. PATIENTS, METHODS: Retrospective analysis was performed in 47 patients after initial treatment with radiotherapy (n=30) or surgery (n=17). Following CT, 10 minutes list-mode PET acquisition was done over the prostate bed after injection of 300 MBq of 18F-fluorocholine. Three timeframes of 3 minutes each were reconstructed for analysis. All patients underwent subsequent whole body PET/CT. Delayed pelvic PET/CT was obtained in 36 patients. PET/CT was interpreted visually by two observers and SUVmax determined for suspicious lesions. Biopsies were obtained from 13 patients. RESULTS: Biopsies confirmed the presence of cancer in 11 of 13 patients with positive PET for a total of 15 local recurrences in which average SUVmax increased during 14 minutes post injection and marginally decreased in delayed scanning. Conversely inguinal lymph nodes with mild to moderate metabolic activity on PET showed a clearly different pattern with decreasing SUVmax on dynamic images. Three-phase PET/CT contributed to the diagnostic assessment of 10 of 47 patients with biological evidence of recurrence of cancer. It notably allowed the discrimination of confounding blood pool or urinary activity from suspicious hyperactivities. PET/CT was positive in all patients with PSA>or=2 ng/ml (n=34) and in 4/13 patients presenting PSA values<2 ng/ml. CONCLUSION: 18F-fluorocholine 3-phase PET/CT showed a progressively increasing SUVmax in biopsy confirmed cancer lesions up to 14 minutes post injection while decreasing in inguinal lymph nodes interpreted as benign. Furthermore, it was very useful in differentiating local recurrences from confounding blood pool and urinary activity.

Identifying and Implementing Effective Training for Hispanic Craft Workers, American Supervisors, and DOT Inspectors: Phase III of the Hispanic Workforce Research Project, May 2006

The number of Hispanic workers in the U.S. construction industry has been steadily increasing, and language and cultural barriers have sometimes arisen on the jobsite. Due in part to these barriers, the number of fatalities among Hispanics at construction sites in 2001 jumped 24%, while construction fatalities overall dropped 3%. This study, which constitutes Phase III of the Hispanic Workforce Research Project, addresses these language and cultural barriers by investigating the most effective way to deliver training material developed in Phases I and II to Hispanic workers, American supervisors, and department of transportation (DOT) inspectors. The research methodology consisted of assessing the needs and interests of potential and current course participants in terms of exploring innovative ways to deliver the training. The training courses were then adapted and delivered to fit the specific needs of each audience. During Phase III of this project, the research team delivered the courses described in the Phase I and II reports to eight highway construction companies and two DOT groups. The courses developed in Phases I and II consist of four construction-focused language training courses that can be part of an effective training program to facilitate integration among U.S. and Hispanic workers, increase productivity and motivation at the jobsite, and decrease the existing high mortality rate for Hispanic workers. Moreover, the research team developed a course for the construction season called Toolbox Integration Course for Hispanic workers and American supervisors (TICHA), which consists of nine 45-minute modules delivered to one construction company over 11 weeks in the summer of 2005.

ECG interpretation during the acute phase of coronary syndromes: in need of improvement?

QUESTION UNDER STUDY: Emergency room (ER) interpretation of the ECG is critical to assessment of patients with acute coronary syndromes (ACS). Our aim was to assess its reliability in our institution, a tertiary teaching hospital. METHODS: Over a 6-month period all consecutive patients admitted for ACS were included in the study. ECG interpretation by emergency physicians (EPs) was recorded on a preformatted sheet and compared with the interpretation of two specialist physicians (SPs). Discrepancies between the 2 specialists were resolved by an ECG specialist. RESULTS: Over the 6-month period, 692 consecutive patients were admitted with suspected ACS. ECG interpretation was available in 641 cases (93%). Concordance between SPs was 87%. Interpretation of normality or abnormality of the ECG was concordant between EPs and SPs in 475 cases (74%, kappa = 0.51). Interpretation of ischaemic modifications was concordant in 69% of cases, and as many ST segment elevations were unrecognised as overdiagnosed (5% each). The same findings occurred for ST segment depressions and negative T waves (12% each). CONCLUSIONS: Interpretation of the ECG recorded during ACS by 2 SPs was discrepant in 13% of cases. Similarly, EP interpretation was discrepant from SP interpretation in 25% of cases, equally distributed between over- and underdiagnosing of ischaemic changes. The clinical implications and impact of medical education on ECG interpretation require further study.

EuroCMR (European Cardiovascular Magnetic Resonance) registry: results of the German pilot phase.

OBJECTIVES: During its German pilot phase, the EuroCMR (European Cardiovascular Magnetic Resonance) registry sought to evaluate indications, image quality, safety, and impact on patient management of routine CMR. BACKGROUND: CMR has a broad range of applications and is increasingly used in clinical practice. METHODS: This was a multicenter registry with consecutive enrollment of patients in 20 German centers. RESULTS: A total of 11,040 consecutive patients were enrolled. Eighty-eight percent of patients received gadolinium-based contrast agents. Twenty-one percent underwent adenosine perfusion, and 11% high-dose dobutamine-stress CMR. The most important indications were workup of myocarditis/cardiomyopathies (32%), risk stratification in suspected coronary artery disease/ischemia (31%), as well as assessment of viability (15%). Image quality was good in 90.1%, moderate in 8.1%, and inadequate in 1.8% of cases. Severe complications occurred in 0.05%, and were all associated with stress testing. No patient died during or due to CMR. In nearly two-thirds of patients, CMR findings impacted patient management. Importantly, in 16% of cases the final diagnosis based on CMR was different from the diagnosis before CMR, leading to a complete change in management. In more than 86% of cases, CMR was capable of satisfying all imaging needs so that no further imaging was required. CONCLUSIONS: CMR is frequently performed in clinical practice in many participating centers. The most important indications are workup of myocarditis/cardiomyopathies, risk stratification in suspected coronary artery disease/ischemia, and assessment of viability. CMR imaging as used in the centers of the pilot registry is a safe procedure, has diagnostic image quality in 98% of cases, and its results have strong impact on patient management.

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.

An European Organisation for Research and Treatment of Cancer phase I study of lapatinib and docetaxel as neoadjuvant treatment for Human Epidermal Growth Factor Receptor 2 (HER2) positive locally-advanced/inflammatory or large operable breast cancer.

BACKGROUND: Lapatinib is an effective anti-HER2 therapy in advanced breast cancer and docetaxel is one of the most active agents in breast cancer. Combining these agents in pre-treated patients with metastatic disease had previously proved challenging, so the primary objective of this study aimed to determine the maximum tolerated dose (MTD) in treatment-naive patients, by identifying acute dose-limiting toxicities (DLT) during cycle 1 in the first part of a phases 1-2 neoadjuvant European Organisation for Research and Treatment of Cancer (EORTC) trial. PATIENTS AND METHODS: Patients with large operable or locally-advanced HER2 positive breast cancer were treated with continuous lapatinib, and docetaxel every 21days for 4 cycles. Dose levels (DLs) were: 1000/75, 1250/75, 1000/85, 1250/85, 1000/100 and 1250/100 (mg/day)/(mg/m(2)). RESULTS: Twenty-one patients were included. Two DLTs occurred at dose level 5 (1000/100); one grade 4 neutropenia ⩾7days and one febrile neutropenia. A further 3 patients were therefore treated at the same dose with prophylactic granulocyte-colony stimulating factor (G-CSF), and 3 patients at dose level 6. No further DLTs were observed. CONCLUSIONS: Our recommended dose for phase II is lapatinib 1000mg/day and docetaxel 100mg/m(2) with G-CSF in HER2 positive non-metastatic breast cancer. The dose of lapatinib should have been 1250mg/day but we were mindful of the high rate of treatment discontinuation in GeparQuinto with lapatinib 1250mg/day combined with docetaxel. No grade 3-4 diarrhoea was observed. Pharmacodynamics analysis suggests that concomitant medications altering P-glycoprotein activity (in addition to lapatinib) can modify toxicity, including non-haematological toxicities. This needs verification in larger trials, where it may contribute to understanding the sources of variability in clinical toxicity and treatment discontinuation.

Concomitant Cisplatin and Hyperfractionated Radiotherapy in Locally Advanced Head and Neck Cancer: Ten-year Follow-up of a Randomized Phase III Trial (SAKK 10/94)

Purpose/Objective(s): To analyze the long-term outcome of treatment with concomitant cisplatin and hyperfractionated radiotherapy in locally advanced head and neck cancer compared with hyperfractionated radiotherapy alone.Materials/Methods: From July 1994 to July 2000 a total of 224 patients with squamous cell carcinoma of the head and neck were randomized to either hyperfractionated radiotherapy (median dose 74.4 Gy; 1.2 Gy twice daily) or the same radiotherapy combined with two cycles of concomitant cisplatin (20mg/m2 for 5 consecutive days of weeks 1 and 5). The primary endpoint was time to any treatment failure; secondary endpoints were locoregional failure, metastatic failure, overall survival, and late toxicity assessed according to RTOG criteria. The trial was registered at the National Institutes of Health (www.clinicaltrials.gov; identifier number: NCT00002654).Results: Median follow-up was 9.5 years (range, 0.1 - 15.4 years). Median time to any treatment failure was not significantly different between treatment arms (p = 0.19). Locoregional control (p\0.05), distant metastasis-free survival (p = 0.02) and cancer specific survival (p = 0.03) were significantly improved in the combined treatment arm, with no difference in late toxicity between treatment arms. However, overall survival was not significantly different (p = 0.19). Conclusions: After long-term follow-up combined treatment with cisplatin and hyperfractionated, radiotherapy maintained an improved locoregional control, distant metastasis-free survival, and cancer specific survival as compared to hyperfractionated radiotherapy alone with no difference in late toxicity.Author Disclosure: P. Ghadjar, None; M. Simcock, None; G. Studer, None; A.S. Allal, None; M. Ozsahin, None; J. Bernier, None; M. To¨ pfer, None; F. Zimmermann, None; C. Glanzmann, None; D.M. Aebersold, None.

Investigating barriers in HIV-testing oncology patients. The IBITOP study: phase I.

BACKGROUND: Since the advent of combined antiretroviral therapy (ART), the incidence of non-AIDS-defining cancers (non-ADCs) among HIV-positive patients is rising. We previously described HIV testing rates of <5% in our oncology centre, against a local HIV prevalence of 0.4% (1). We have since worked with the Service of Oncology to identify, how HIV testing can be optimized, we have conducted a study on investigating barriers in HIV-testing oncology patients (IBITOP) among treating oncologists and their patients. METHODS: After an initial two-month pilot study to examine feasibility (2), we conducted the first phase of the IBITOP study between 1st July and 31st October 2013. Patients of unknown HIV status, newly diagnosed with solid-organ non-AIDS-defining cancer, and treated at Lausanne University Hospital were invited to participate. Patients were offered HIV testing as a part of their initial oncology work-up. Oncologist testing proposals and patient acceptance were the primary endpoints. RESULTS: Of 235 patients with a new oncology diagnosis, 10 were excluded (7 with ADCs and 3 of known HIV-positive status). Mean age was 62 years; 48% were men and 71% were Swiss. Of 225 patients, 75 (33%) were offered HIV testing. Of these, 56 (75%) accepted, of whom 52 (93%) were tested. A further ten patients were tested (without documentation of being offered a test), which gave a total testing rate of 28% (62/225). Among the 19 patients who declined testing, reasons cited included self-perceived absence of HIV risk, previous testing and palliative care. Of the 140 patients not offered HIV testing and not tested, reasons were documented for 35 (25%), the most common being previous testing and follow-up elsewhere. None of the 62 patients HIV tested had a reactive test. CONCLUSIONS: In this study, one third of patients seen were offered testing and the HIV testing rate was fivefold higher than that of previously observed in this service. Most patients accepted testing when offered. As HIV-positive status impacts on the medical management of cancer patients, we recommend that HIV screening should be performed in settings, where HIV prevalence is >0.1%. Phase II of the IBITOP study is now underway to explore barriers to HIV screening among oncologists and patients following the updated national HIV testing guidelines which recommend testing in non-ADC patients undergoing chemotherapy.

LAPATAX: A randomized phase II trial of FEC-docetaxel combined with lapatinib and/or trastuzumab as neoadjuvant therapy of HER2- positive breast cancer-EORTC 10054 trial.

Background: Patients with HER2 +ve breast cancer suitable for neoadjuvant chemotherapy (NAC) have been shown in a series of clinical trials to have the best outcome when treated with anthracyclines (A), taxanes (T), and trastuzumab (Tz). Recent evidence confirms that adjuvant Tz is more effective when given concomitantly rather than sequentially with T (Perez SABCS 2009). Whilst there remains uncertainty as to the most efficacious A-T regimen and duration of Tz, there is widespread use in Europe of FEC-D [3 cycles of 5-FU 500 mg/m2, epirubicin 100 mg/m2 and cyclophosphamide 500 mg/m2 (FEC100) followed by 3 cycles of docetaxel 100 mg/m2 (D) q3w] following the results of PACS-01. The advent of TKI anti-HER2 agents such as L could offer superior outcomes if combined with NAC. However, a phase I study in heavily pre-treated advanced breast cancer reported difficulties in combining lapatinib (L) with D 100 mg/m2 (LoRusso JCO 2008). Methods: EORTC 10054 is designed as a two-part study to compare FEC-D with either Tz, L or their combination as NAC for patients with HER2 +ve large operable or locally advanced breast cancer. Before and on-treatment frozen tumor and blood samples will be taken to better define which tumours are particularly sensitive to either Tz and/or L. Stage 1: (complete) a dose- finding study has confirmed that with primary prophylactic G-CSF, D 100 mg/m2 can be safely and effectively given with L 1,250 mg daily continuously. The dose-limiting toxicity was myelosuppression, and there was no significant diarrhoea or cardiac toxicity (ESMO 2009 abstr P- 5073). Stage 2: (opening Q1 2010) will enroll 150 patients from European centres into a 3-arm randomized trial whose primary endpoint is pathological complete response. All patients will receive FEC-D before primary surgery: 3 cycles of FEC (without anti-HER2 therapy) followed by 3 cycles of D plus either Tz (conventional weekly schedule), monotherapy L, or the combination of Tz and L, using doses based on the EGF100161 dose-finding study in 1st line metastatic therapy of D+L+Tz. After surgery all patients will receive standard 3-weekly Tz, radiotherapy and endocrine therapy as per local guidelines.

Partial melting of basic dykes in the contact aureoles of two shallow-level, gabbro-pyroxenite intrusions, Fuerteventura

THESIS ABSTRACT Low-pressure anatexis of basic dykes gave rise to unusual, zebra-like migmatites, in the contact metamorphic aureoles of two layered gabbro-pyroxenite intrusions, PXl and PX2, in the root zone of an ocean island, Fuerteventura Basal Complex (Canary Islands). This thesis focuses on the understanding of processes attributing to the partial melting and formation of these migmatites, characterised by a dense network of closely spaced, millimetre-wide leucocratic segregations with perfectly preserved igneous textures. The presence of fluids are required to decrease the solidus of basic igneous lithologies, to allow partial melting in such aloes-pressure (1-2 kb) environment. An oxygen isotope study was thus carried out on dykes inside and beyond the PX2 aureole, in order to decipher the nature and origin of such fluids. Low or negative δ18O values were obtained for whole rocks and mineral-separates, decreasing towards the contact, with the intrusion itself retaining fairly high values. This trend has been attributed to the advection of meteoric water during magma emplacement, with increasing fluid/rock ratios (higher dyke intensities towards the intrusion acting as fluid-pathways) and higher temperatures promoting increasing exchange during recrystallisation. A comparison of whole rock and mineral major- and trace- element data allowed the redistribution of elements .between different mineral phases and generations, during contact metamorphism and partial melting to be assessed. Certain trace-elements, e.g. Zr, Hf, Y, and REEs, were internally redistributed during contact metamorphic recrystallisation, causing- the enrichment of neocrystallised diopsides compared to relict phenocrysts. This has been assigned to the liberation of trace elements on the breakdown of primary minerals, kaersutite and sphene, on entering the thermal aureole. Major and trace element compositions of minerals in migmatite melanosomes and leucosomes are almost identical, pointing to a syn- or post- solidus reequilibration on cooling of the migmatite terrain. The mineralogical, textural and geochemical evolution of dykes in a contact metamorphic aureole, is recorded around an apophysis of the PX1 intrusion, where there is evidence of incipient partial melting. Hydrothermal mineral pseudomorphs in the outer parts of the aureole are progressively replaced by dry mineral assemblages, with increasingly recrystallised diopside and evidence of partial melting -the extent of which varies from one lithology to another. The appearance of more mafic lithologies towards the intrusion, with lower whole rock SiO2 and mobile element abundances, e.g. Rb, Cs, K, has been explained by the migration and accumulation of feldspathic material into leucosomes outside the samples. A micro-structural study of leucosomes and leucocratic pods, with the aid of high-resolution X-ray computed micro-tomography (HRXµCT), allowing the visualization and quantification of shapes and orientations, was carried out in order to better understand the processes of melt segregation in the PX1 aureole. Leucocratic pods, representing former amygdales, are considered as natural strain ellipsoids. Their short axes are oriented perpendicular to leucosome planes, which sub-parallel the intrusive contact. Leucosomes thus effectively represent foliation planes. This implies that the direction of maximum shortening, during migmatisation, was perpendicular to the orientation of leucosomes, contradicting earlier models that suggest leucosomes represent tension veins. RESUME DE LA THESE Un phénomène rare de fusion partielle de filons basiques à basse pression a été étudié dans les auréoles de contact de deux intrusions litées de gabbro-pyroxénite, PX1 et PX2, localisées dans le soubassement de l'île volcanique de Fuerteventura aux Canaries. Cette anatexie a engendré des migmatites finement zébrées d'aspect très inhabituel, dont les processus de formation ont été étudiés dans le présent travail. Ces roches sont caractérisées par un réseau dense de veinules leucocrates d'épaisseur millimétrique, dont les textures ignées sont parfaitement préservées. La fusion partielle de roches basiques à basse pression (1-2 kbar) requiert la présence d'eau afin d'abaisser le solidus du système à des températures géologiquement réalistes. Une étude comparative des isotopes de l'oxygène a ainsi été menée sur des filons respectivement affectés et non affectés par le métamorphisme de contact, afin de confirmer la présence de ces fluides, de déterminer l'importance de leur interaction avec les roches et leur origine. Des valeurs de δ180 basses ou négatives ont été mesurées sur roche totale et minéraux séparés, décroissantes en direction du contact, alors que l'intrusion elle-même a conservé des valeurs élevées. Ce gradient a été attribué à l'advection d'eau météorique durant la mise en place du magma, les températures les plus élevées favorisant d'autant plus la circulation des fluides et les échanges isotopiques durant la recristallisation des roches. Cette recristallisation engendré une redistribution chimique complète des éléments entre les différentes générations de minéraux résultant du métamorphisme de contact et de l'anatexie, mise en évidence par microanalyse. Certains éléments traces comme Zr, Hf, Y et les REE ont été concentrés dans le diopside néoformé consécutivement à la déstabilisation de minéraux primaires riches en ces éléments comme la kaersutite ou le sphène. Les compositions en éléments majeurs et traces des minéraux des mélanosomes et leucosomes des migmatites sont pratiquement identiques, indiquant une rééquilibration syn- à postsolidus lors du refroidissement de l'auréole de contact. La transformation progressive des filons basiques au niveau de leur minéralogie, textures et composition chimique a pu être observée en détail à l'approche du contact d'une apophyse de l'intrusion PX1. La paragenèse magmatique initiale n'est jamais préservée, les faciès les plus distants du contact étant constitués d'un assemblage pseudomorphique hydrothermal. Ce dernier est progressivement remplacé par des assemblages anhydres incluant du diopside néoformé, puis apparaissent les premiers signes de fusion partielle, dont l'importance varie fortement d'une lithologie à l'autre. L'apparition de faciès plus basiques en direction du contact, avec des teneurs réduites en SiO2 et en éléments incompatibles tels Rb, Cs, K, a été attribuée à l'échappement de leucosomes feldspathiques hors du système. Une étude microstructurale de la distribution spatiale du matériel leucocrate au sein des migmatites par microtomographie X de haute résolution (HRXµCT) a été menée pour mieux comprendre les processus de ségrégation des liquides dans l'auréole de PX1. De petites entités ovoïdes, représentant d'anciennes structures amygdalaires au sein des filons, ont été considérées comme des ellipsoïdes marqueurs de la déformation finie. Leur petit axe est orienté perpendiculairement aux plans définis par les leucosomes, eux-mêmes subparallèles au contact intrusif. Les leucosomes matérialisent donc des plans de clivage. Ainsi, la direction de raccourcissement maximum durant la fusion partielle était perpendiculaire à l'orientation des leucosomes, contrairement à ce qui a été dit dans de précédentes publications, qui suggéraient que les leucosomes représentaient des veines de tension. RESUME DE LA THESE (POUR LE GRAND PUBLIC) L'observation directe du soubassement d'une île volcanique est une occasion rare, accessible dans le «complexe de base » de l'île canarienne de Fuerteventura. Ce dernier a enregistré divers phénomènes magmatiques, métamorphiques et de fusion partielle induits par l'intrusion répétée de magmas alimentant des appareils volcaniques sus jacents, sous forme de petits plutons, essaims de filons et complexes annulaires de gabbros alcalins, pyroxénites, syénites et carbonatites. Dans ce contexte de flux de chaleur élevé, des filons basiques ont subi une fusion partielle au contact de deux intrusions de gabbro-pyroxénite, un phénomène extrêmement rare à une profondeur aussi réduite, estimée à quelque 3-6 km. Les produits de cette fusion partielle sont des liquides très riches en feldspath, concentrés en un réseau dense de veinules blanches (leucosomes) au sein du matériau résiduel sombre non fondu (mélanosome) pour former ce qu'on appelle des migmatites. Outre les aspects pétrologiques liés à la formation de ces migmatites, l'intérêt majeur du phénomène réside dans le fait qu'il puisse représenter la source des magmas évolués parfois observés sur les îles océaniques. A des pressions aussi faibles que dans le soubassement de Fuerteventura (1-2 Kbar), la présence de fluides abondants est nécessaire pour abaisser la température de début de fusion des roches (solidus) à des valeurs géologiquement réalistes. Des expériences ont montré que même en présence de plusieurs %-poids d'eau, une température de 1000°C était encore nécessaire pour obtenir une proportion de liquide équivalente à celle observée sur le terrain, soit 25%. Or les magmas alcalins des îles océaniques, bien qu'hydratés, n'en contiennent de loin pas autant, ce qui implique une source d'eau externe. Une étude isotopique de l'oxygène a été entreprise afin de tester cette hypothèse. Les valeurs obtenues en 5180 sont basses ou négatives et indiquent l'influence d'eau d'origine météorique. Cette eau de pluie se serait infiltrée le long des filons depuis la surface du volcan et les aurait complètement hydrothermalisés en profondeur (situation encore visible à l'extérieur de l'auréole de contact), leur permettant ainsi de stocker l'eau nécessaire à leur fusion partielle ultérieure. L'interaction entre eau de pluie et filons a été d'autant plus importante que ces derniers étaient proches du contact avec l'intrusion, ce qui suggère que la circulation de ces eaux et leur interaction avec les roches a été favorisée par la chaleur fournie par l'intrusion elle-même. Un autre aspect de ce travail s'est focalisé sur la redistribution des éléments traces au sein des minéraux des filons basiques durant le métamorphisme de contact et la fusion partielle. Ainsi, le pyroxène de seconde génération est-il sensiblement enrichi en traces telles Zr, Hf, Y et les terres rares, par rapport au pyroxène magmatique originel, en relation avec la déstabilisation de minéraux primaires riches en ces éléments tels le sphène et la kaersutite. Cependant, les compositions en éléments majeurs et traces des minéraux recristallisés des migmatites sont pratiquement les mêmes dans les leucosomes et les mélanosomes, suggérant une rééquilibration chimique complète durant le refroidissement de ces lithologies. Si certaines migmatites se sont comportées en système chimiquement fermé (hormis l'eau météorique), d'autres filons ont manifestement perdu une partie de leurs leucosomes, ainsi qu'en témoigne leur composition progressivement appauvrie en silice et autres éléments incompatibles mobiles, tels K et Rb à l'approche du contact de l'intrusion. Parallèlement à cette évolution chimique, les paragenèses hydrothermales distantes du contact sont progressivement remplacées par des paragenèses anhydres, puis par l'apparition des premiers leucosomes, tandis que les textures magmatiques initiales sont complètement effacées au profit d'une combinaison de textures magmatique dans les leucosomes et en mosaïque dans les mélanosomes. Enfin, la distribution spatiale des liquides de fusion partielle a été étudiée par microtomographie X de haute résolution, dans des filons contenant des entités ovoïdes leucocrates, sans doute d'anciennes amygdales à zéolites. Ces dernières ont été considérées comme des ellipsoïdes de la déformation finie. L'orientation de leur petit axe, perpendiculaire au plan défini par les veinules de leucosomes, indique que ces derniers représentent des plans de clivage perpendiculaires à la direction de raccourcissement maximum. Ainsi, la ségrégation des liquides de fusion partielle se serait faite dans les plans de compression et non dans des plans de dilatation, contrairement à ce que laisserait penser le sens commun.

Tertiary Himalayan structures and metamorphism in the Kulu Valley (Mandi-Khoksar transect of the Western Himalaya) - Shikar-Beh-nappe and crystalline nappe

The Crystalline Nappe of the High Himalayan Crystalline has been examined along the Kulu Valley and its vicinity (Mandi-Khoksar transect). This nappe was believed to have undergone deformation related only to its transport towards the SW essentially during the `'Main Central Thrust event''. New data has led to the conclusion that during the Himalayan orogeny, two distinctive phases, related to two opposite transport directions, characterize the evolution of this part of the chain, before the creation of the late NE-vergent backfolding. The first phase corresponds to an early NE-vergent folding and thrusting, creating the Tandi Syncline and the NE-oriented Shikar Beh Nappe stack, with a displacement amplitude of about 50 km. Two schistosities, together with a strong stretching lineation are developed at a deep tectonic level under amphibolite facies conditions (kyanite-staurolite-garnet-two mica schists). At a higher tectonic level and in the southern part of the section (Tandy Syncline and southern Kulu Valley between Kulu and Mandi) one or two schistosities are developed in the greenschist facies grade rocks (garnet-biotite and biotite schists). These structures and the associated Barrovian type metamorphism are all related to the NE-verging Shikar Beh Nappe. The creation of the NE-verging Shikar Beh Nappe may be explained by the reactivation of a SW dipping listric normal fault of the N Indian flexural passive margin, during the early stages of the Himalayan orogeny. In the second phase, the still hot metamorphic rocks of the Shikar Beh Nappe were folded and thrust towards the SW (mainly along the MBT and the MCT with a displacement in excess of 100 km) onto the cold, low-grade metamorphic rocks of the Larji-Kulu-Rampur Window or, near Mandi, on the non-metamorphic sandstones of the Ganges Molasse (Siwaliks). Sense of shear criteria and a strong NE-SW stretching-lineation indicate that the Crystalline Nappe has been overthrusted towards the SW. Thermometry on synkinematically crystallised garnet-biotite and garnet-hornblende pairs reveals the lower amphibolite facies temperature conditions related to the Crystalline Nappe formation. From the muscovite and biotite Rb-Sr cooling ages, the Shikar Beh Nappe emplacement occurred before 32 Ma and the southwestward thrusting of the Crystalline Nappe began before 21 Ma. Our model involving two opposite directions of thrusting goes against the conventional idea of only one main SW-oriented transport direction in the High Himalayan Crystalline Nappes.

Phase I safety and immunogenicity trial of Plasmodium vivax CS derived long synthetic peptides adjuvanted with montanide ISA 720 or montanide ISA 51.

We assessed the safety, tolerability, and immunogenicity of a mixture of three synthetic peptides derived from the Plasmodium vivax circumsporozoite protein formulated in Montanide ISA 720 or Montanide ISA 51. Forty healthy malaria-naive volunteers were allocated to five experimental groups (A-E): four groups (A-D) were immunized intramuscularly with 50 and 100 μg/dose injections of a mixture of N, R, and C peptides formulated in the two different adjuvants at 0, 2, and 4 months and one group was administered placebo. Vaccines were immunogenic, safe, well tolerated, and no serious adverse events related to the vaccine occurred. Seroconversion occurred in > 90% of the vaccines and antibodies recognized the sporozoite protein on immunofluorescent antibody test. Vaccines in Montanide ISA 51 showed a higher sporozoite protein recognition and interferon production. Results encourage further testing of the vaccine protective efficacy.

Panitumumab plus radiotherapy versus chemoradiotherapy in patients with unresected, locally advanced squamous-cell carcinoma of the head and neck (CONCERT-2): a randomised, controlled, open-label phase 2 trial.

BACKGROUND: We aimed to compare panitumumab, a fully human monoclonal antibody against EGFR, plus radiotherapy with chemoradiotherapy in patients with unresected, locally advanced squamous-cell carcinoma of the head and neck. METHODS: In this international, open-label, randomised, controlled, phase 2 trial, we recruited patients with locally advanced squamous-cell carcinoma of the head and neck from 22 sites in eight countries worldwide. Patients aged 18 years and older with stage III, IVa, or IVb, previously untreated, measurable (≥10 mm for at least one dimension), locally advanced squamous-cell carcinoma of the head and neck (non-nasopharygeal) and an Eastern Cooperative Oncology Group performance status of 0-1 were randomly assigned (2:3) by an independent vendor to open-label chemoradiotherapy (two cycles of cisplatin 100 mg/m(2) during radiotherapy) or to radiotherapy plus panitumumab (three cycles of panitumumab 9 mg/kg every 3 weeks administered with radiotherapy) using a stratified randomisation with a block size of five. All patients received 70-72 Gy to gross tumour and 54 Gy to areas of subclinical disease with accelerated fractionation radiotherapy. The primary endpoint was local-regional control at 2 years, analysed in all randomly assigned patients who received at least one dose of their assigned protocol-specific treatment (chemotherapy, radiation, or panitumumab). The trial is closed and this is the final analysis. This study is registered with ClinicalTrials.gov, number NCT00547157. FINDINGS: Between Nov 30, 2007, and Nov 16, 2009, 152 patients were enrolled, and 151 received treatment (61 in the chemoradiotherapy group and 90 in the radiotherapy plus panitumumab group). Local-regional control at 2 years was 61% (95% CI 47-72) in the chemoradiotherapy group and 51% (40-62) in the radiotherapy plus panitumumab group. The most frequent grade 3-4 adverse events were mucosal inflammation (25 [40%] of 62 patients in the chemoradiotherapy group vs 37 [42%] of 89 patients in the radiotherapy plus panitumumab group), dysphagia (20 [32%] vs 36 [40%]), and radiation skin injury (seven [11%] vs 21 [24%]). Serious adverse events were reported in 25 (40%) of 62 patients in the chemoradiotherapy group and in 30 (34%) of 89 patients in the radiotherapy plus panitumumab group. INTERPRETATION: Panitumumab cannot replace cisplatin in the combined treatment with radiotherapy for unresected stage III-IVb squamous-cell carcinoma of the head and neck, and the role of EGFR inhibition in locally advanced squamous-cell carcinoma of the head and neck needs to be reassessed. FUNDING: Amgen.

Phase 3 randomized trial on larynx preservation comparing sequential vs alternating chemotherapy and radiotherapy.

BACKGROUND: Both induction chemotherapy followed by irradiation and concurrent chemotherapy and radiotherapy have been reported as valuable alternatives to total laryngectomy in patients with advanced larynx or hypopharynx cancer. We report results of the randomized phase 3 trial 24954 from the European Organization for Research and Treatment of Cancer. METHODS: Patients with resectable advanced squamous cell carcinoma of the larynx (tumor stage T3-T4) or hypopharynx (T2-T4), with regional lymph nodes in the neck staged as N0-N2 and with no metastasis, were randomly assigned to treatment in the sequential (or control) or the alternating (or experimental) arm. In the sequential arm, patients with a 50% or more reduction in primary tumor size after two cycles of cisplatin and 5-fluorouracil received another two cycles, followed by radiotherapy (70 Gy total). In the alternating arm, a total of four cycles of cisplatin and 5-fluorouracil (in weeks 1, 4, 7, and 10) were alternated with radiotherapy with 20 Gy during the three 2-week intervals between chemotherapy cycles (60 Gy total). All nonresponders underwent salvage surgery and postoperative radiotherapy. The Kaplan-Meier method was used to obtain time-to-event data. RESULTS: The 450 patients were randomly assigned to treatment (224 to the sequential arm and 226 to the alternating arm). Median follow-up was 6.5 years. Survival with a functional larynx was similar in sequential and alternating arms (hazard ratio of death and/or event = 0.85, 95% confidence interval = 0.68 to 1.06), as were median overall survival (4.4 and 5.1 years, respectively) and median progression-free interval (3.0 and 3.1 years, respectively). Grade 3 or 4 mucositis occurred in 64 (32%) of the 200 patients in the sequential arm who received radiotherapy and in 47 (21%) of the 220 patients in the alternating arm. Late severe edema and/or fibrosis was observed in 32 (16%) patients in the sequential arm and in 25 (11%) in the alternating arm. CONCLUSIONS: Larynx preservation, progression-free interval, and overall survival were similar in both arms, as were acute and late toxic effects.

Differences in Frontal Activation in Adult Patients with Schizophrenia and in Psychotic Adolescents with Schizophrenic Symptoms in Two Fmri Tasks

Background: Language processing abnormalities and inhibition difficulties are hallmark features of schizophrenia. The objective of this study is to asses the blood oxygenation level-dependent (BOLD) response at two different stages of the illness and compare the frontal activity between adolescents and adults with schizophrenia. Methods: 10 adults with schizophrenia (mean age 31,5 years) and 6 psychotic adolescents with schizophrenic symptoms (mean age 16,2 years) underwent functional magnetic resonance imaging while performing two frontal tasks. Regional activation is compared in the bilateral frontal areas during a covert verbal fluency task (letter version) and a Stroop task (inhibition task). Results: Preliminary results show poorer task performance and less frontal cortex activation during both tasks in the adult group of patients with schizophrenia. In the adolescent patients group, fMRI analysis show significant and larger activity in the left frontal operculum (Broca's area) in the verbal fluency task and greater activity in the medium cingulate during the inhibition phase of the Stroop task. Conclusions: These preliminary findings suggest a decrease of frontal activity in the course of the illness. We assume that schizophrenia contributes to frontal brain activity reduction.