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.

Effets bénéfiques du ranélate de strontium compare à l'alendronate sur le TBS chez les femmes ostéoporotiques ménopausées: une étude de 2 ans.

Introduction. - Le TBS ou Score Trabéculaire Osseux (TBS, Med- Imaps, France) est un index d'architecture osseuse apportant des informations indépendantes de la densité minérale osseuse (DMO), et calculé par la quantification des variations locales des niveaux de gris à partir d'examen de densitométrie (DXA) lombaire. Dans des études antérieures prospectives et cas-témoins, cet index a été considéré comme associé aux fractures. Nous avons comparé les effets du ranélate de strontium (RanSr) et de l'alendronate (ALN) sur l'architecture vertébrale à l'aide du TBS, chez des femmes ostéoporotiques ménopausées. Patients et méthodes. - Une analyse post hoc a été réalisée sur des DXA (Hologic and GE Lunar Devices) de 79 des 189 femmes incluses dans une étude en double aveugle et double placebo et réparties de façon randomisée entre un groupe à 2 g/jour de RanSr et un groupe à 70 mg/semaine d'ALN pendant 2 ans. Les paramètres de TBS ont été évalués en aveugle par TBS iNsight (v1,9) au niveau vertébral après 12 et 24 mois de traitement. Nous avons appliqué les règles de l'ISCD (International Society for Clinical Densitometry) pour chaque exclusion de vertèbre, de façon indépendante respectivement pour la DMO et le TBS. Des doubles mesures ayant été réalisées initialement, la reproductibilité est exprimée en % CV. Résultats. - Les caractéristiques initiales (moyenne ± DS) étaient identiques entre les groupes en termes d'âge, 69,2 ± 4,4 ans ; d'IMC, 23,8 ± 4,4 kg/m2 ; de T-score L1-L4, - 2,9 ± 0,9 et de TBS, 1,230 ± 0,09. Comme prévu, le coefficient de détermination entre la DMO et le TBS au niveau du rachis était très basse r2 = 0,12. Les reproductibilités brutes étaient respectivement de 1,1 et 1,6 % pour la DMO et le TBS au niveau vertébral. Après 1 et 2 ans, la DMO en L1-L4 a augmenté de façon significative de respectivement 5,6 % et 9 % dans le groupe RanSr et de respectivement 5,2 % et 7,6 % dans le groupe ALN. De même, le TBS au niveau vertébral a augmenté respectivement de 2,3 % (p < 0,001) et de 3,1 % (p < 0,001) dans le groupe RanSr et de 0,5 % (NS) et de 1 % (NS) dans le groupe ALN avec une différence entre groupe significative en faveur du RanSr (p = 0,04 et p = 0,03). Il n'y avait aucune corrélation entre la différence de DMO et de TBS à 1 ou 2 ans. Les deux traitements étaient bien tolérés. Discussion. - Ces résultats sur le TBS confortent des études précédentes qui sont en faveur de l'effet bénéfique du RanSr sur l'architecture osseuse. Conclusion. - Le ranélate de strontium a des effets plus importants que l'alendronate sur le score trabéculaire osseux, indice d'architecture osseuse au niveau vertébral, chez les femmes ayant une ostéoporose post-ménopausique, après 2 ans de traitement.

A phase 2 randomized trial of radiotherapy (RT) plus panitumumab compared to chemoradiotherapy in patients with unresected, locally advanced squamous cell carcinoma of the head and neck (SCCHN): interim pooled safety analysis

Background: Panitumumab (pmab), a fully human monoclonal antibody against the epidermal growth factor receptor (EGFR), is indicated as monotherapy for treatment of metastatic colorectal cancer. This ongoing study is designed to assess the efficacy and safety of pmab in combination with radiotherapy (PRT) compared to chemoradiotherapy (CRT) as initial treatment of unresected, locally advanced SCCHN (ClinicalTrials.gov Identifier: NCT00547157). Methods: This is a phase 2, open-label, randomized, multicenter study. Eligible patients (pts) were randomized 2:3 to receive cisplatin 100 mg/m2 on days 1 and 22 of RT or pmab 9.0 mg/kg on days 1, 22, and 43. Accelerated RT (70 to 72 Gy − delivered over 6 to 6.5 weeks) was planned for all pts and was delivered either by intensity-modulated radiation therapy (IMRT) modality or by three-dimensional conformal (3D-CRT) modality. The primary endpoint is local-regional control (LRC) rate at 2 years. Key secondary endpoints include PFS, OS, and safety. An external, independent data monitoring committee conducts planned safety and efficacy reviews during the course of the trial. Results: Pooled data from this planned interim safety analysis includes the first 52 of the 150 planned pts; 44 (84.6%) are male; median (range) age is 57 (33−77) years; ECOG PS 0: 65%, PS 1: 35%; 20 (39%) pts received IMRT, and 32 (61%) pts received 3D-CRT. Fifty (96%) pts completed RT, and 50 pts received RT per protocol without a major deviation. The median (range) total RT dose administered was 72 (64−74) Gy. The most common grade _ 3 adverse events graded using the CTCAE version 3.0 are shown (Table). Conclusions: After the interim safety analysis, CONCERT-2 continues per protocol. Study enrollment is estimated to be completed by October 2009.

Deviant trajectories of cortical maturation in 22q11.2 deletion syndrome (22q11DS): a cross-sectional and longitudinal study.

22q11.2 deletion syndrome (22q11DS) is associated with an increased susceptibility to develop schizophrenia. Despite a large body of literature documenting abnormal brain structure in 22q11DS, cerebral changes associated with brain maturation in 22q11DS remained largely unexplored. To map cortical maturation from childhood to adulthood in 22q11.2 deletion syndrome, we used cerebral MRI from 59 patients with 22q11DS, aged 6 to 40, and 80 typically developing controls; three year follow-up assessments were also available for 32 patients and 31 matched controls. Cross-sectional cortical thickness trajectories during childhood and adolescence were approximated in age bins. Repeated-measures were also conducted with the longitudinal data. Within the group of patients with 22q11DS, exploratory measures of cortical thickness differences related to COMT polymorphism, IQ, and schizophrenia were also conducted. We observed deviant trajectories of cortical thickness changes with age in patients with 22q11DS. In affected preadolescents, larger prefrontal thickness was observed compared to age-matched controls. Afterward, we observed greater cortical loss in 22q11DS with a convergence of cortical thickness values by the end of adolescence. No compelling evidence for an effect of COMT polymorphism on cortical maturation was observed. Within 22q11DS, significant differences in cortical thickness were related to cognitive level in children and adolescents, and to schizophrenia in adults. Deviant trajectories of cortical thickness from childhood to adulthood provide strong in vivo cues for a defect in the programmed synaptic elimination, which in turn may explain the susceptibility of patients with 22q11DS to develop psychosis.

Polymorphisms in TLR2 are associated with increased viral shedding and lesional rate in patients with genital herpes simplex virus Type 2 infection.

Clinical and virologic manifestations of genital herpes simplex virus type 2 (HSV-2) infection vary widely. We examined frequencies of single-nucleotide polymorphisms (SNPs) in Toll-like receptors (TLRs) 2, 3, 4, and 9 in a prospective cohort of 128 HSV-2-infected persons whose viral shedding and lesion frequency was measured by daily sampling from genital secretions. Two TLR2 haplotypes (2 and 4) were associated with increased lesional (P=.008 and P=.03) and shedding (P=.02 and P=.001) rates. An SNP in haplotype 2 (-15607A/G) was also associated with shedding (P=.01) and lesional (P=.008) rates. Polymorphisms in TLR2 may be in part responsible for differences in the severity of HSV-2 infection.

Production et évaluation de l'anticorps NIMP-R14 pour dépléter chroniquement les neutrophiles chez un modèle expérimental d'athérosclérose avancée : la souris ApoE-/- 2 reins-1clip (2K1C)

L'athérosclérose (ATS) est une maladie artérielle inflammatoire chronique à l'origine des nombreuses maladies cardiovasculaires que sont l'infarctus du myocarde, l'accident vasculaire cérébral ou encore l'artériopathie oblitérante des membres inférieurs. L'ATS se définit comme la formation de plaques fibro-lipidiques dans l'intima des artères. Les facteurs de risque majeurs associés à l'ATS sont l'hypertension, l'hypercholestérolémie, le tabagisme, le diabète, la sédentarité, ou encore des prédispositions génétiques. L'ATS peut être asymptomatique durant des années ou alors engendrer des complications aiguës pouvant parfois mettre le pronostic vital en jeu. Les complications les plus graves surviennent principalement lors de la rupture d'une plaque athéromateuse dite vulnérable ou instable. En effet, cette dernière peut se rompre et entraîner la formation d'un thrombus artériel occlusif avec, pour conséquence, l'ischémie/nécrose des tissus en aval. Prévenir le développement de la plaque vulnérable et/ou la « stabiliser » permettrait donc de prévenir les complications cliniques de l'ATS. Cet objectif requiert une connaissance éclairée des mécanismes cellulaires et moléculaires impliqués dans la physiopathologie de l'ATS et de la plaque vulnérable. Les travaux expérimentaux menés au sein du laboratoire du service d'angiologie du CHUV sous la direction du Prof. Lucia Mazzolai ont montré que l'angiotensine II (ang II), produit final de la cascade du système rénine-angiotensine, joue un rôle majeur dans la « vulnérabilité » des plaques athéromateuses (1). Ces travaux ont été réalisés à partir d'un modèle animal original développant des plaques d'ATS vulnérables dépendantes de l'ang II: la souris ApoE-/- 2 reins-1 clip (2K1C). Plus récemment, le laboratoire d'angiologie a mis en évidence une implication directe des leucocytes, plus précisément des macrophages et des lymphocytes T CD4+, dans l'athérogenèse ang II-dépendante (2,3). Dernièrement, des travaux ont également suggéré un rôle possible des granulocytes neutrophiles dans l'ATS (4,5,6,7). Toutefois, les études sont encore limitées de sorte que le rôle exact des neutrophiles dans l'ATS et plus spécialement dans l'ATS induite par l'ang II reste à démontrer. Une des recherches actuelles menée dans le laboratoire est donc d'étudier le rôle des neutrophiles dans le développement de la plaque athéromateuse vulnérable à partir du modèle animal, la souris ApoE-/- 2K1C. Pour évaluer le rôle direct des neutrophiles chez notre modèle animal, nous avons choisi comme méthode la déplétion des neutrophiles circulants par l'utilisation d'un anticorps spécifique. Il a été reporté dans la littérature que l'anticorps monoclonal NIMP-R14 3 permettait de dépléter sélectivement in vivo les neutrophiles dans différents modèles murins (8,9). Cependant, ces études ont utilisé cet anticorps anti-neutrophiles majoritairement sur des périodes expérimentales de durées relativement limitées (12-14 jours) et la question s'est donc posée de savoir si cet anticorps pouvait aussi dépléter les neutrophiles chez notre modèle animal, qui requiert une période expérimentale de 4 semaines pour développer des plaques vulnérables (1). Le but de ce travail a donc été de produire l'anticorps NIMP-R14 et d'évaluer son efficacité chez la souris ApoE-/- 2K1C qui développe des plaque d'ATS vulnérables dépendantes de l'ang II.

Bonded, Thin-Lift, Non-Reinforced Portland Cement Concrete Resurfacing, MLR-77-2, 1977

A research project involving 2, 3, 4, and 5 in. (5.1, 7.6, 10.2, and 12.7 cm) of bonded portland cement concrete (PCC) overlay on a 1.3 mile (2.1 km) PCC pavement was conducted in Clayton County, Iowa, during September 1977, centering on the following objectives: (1) Determine the mixing and proportioning procedures required in using a conventional, central mix proportioning plant to produce a dense PCC mixture using standard mixes with super water reducing admixtures; (2) Determine the economics, longevity and maintenance performance of a bonded, thin-lift, non-reinforced PCC resurfacing course using conventional procedures, equipment and concrete paving mixtures both with and without super water reducing admixtures; and (3) Determine if an adequate bond between the existing pavement and an overlay of thin-lift, dense, non-reinforced PCC can be obtained with only special surface cleaning and no surface removal or grinding. The conclusions are as follows: (1) Normal mixing equipment and proportioning procedures could be used using a conventional central-mix proportioning plant. This was successful when used with super water reducing admixtures. Only minor changes need be made in procedures and timing. (2) The time has been too short since the completion of the project to determine how the new pavement will perform, however, initially it appears that the method is economical and no reason is seen at this time why the life of the pavement should not be comparable to an all new pavement. (3) The initial test results show that bond strength, regardless of which method of cleaning is used, scarifying, sand blasting or water blasting, far exceed what is considered the minimum bond strength of 200 psi (1379 kPa) except where the paint stripes were intentionally left, thus showing that the paint must be removed. (4) It appears that either cement and water grout or sand, cement and water grout may be used and still obtain the required bond.

Diurnal inhibition of NMDA-EPSCs at rat hippocampal mossy fibre synapses through orexin-2 receptors.

Diurnal release of the orexin neuropeptides orexin-A (Ox-A, hypocretin-1) and orexin-B (Ox-B, hypocretin-2) stabilises arousal, regulates energy homeostasis and contributes to cognition and learning. However, whether cellular correlates of brain plasticity are regulated through orexins, and whether they do so in a time-of-day-dependent manner, has never been assessed. Immunohistochemically we found sparse but widespread innervation of hippocampal subfields through Ox-A- and Ox-B-containing fibres in young adult rats. The actions of Ox-A were studied on NMDA receptor (NMDAR)-mediated excitatory synaptic transmission in acute hippocampal slices prepared around the trough (Zeitgeber time (ZT) 4-8, corresponding to 4-8 h into the resting phase) and peak (ZT 23) of intracerebroventricular orexin levels. At ZT 4-8, exogenous Ox-A (100 nm in bath) inhibited NMDA receptor-mediated excitatory postsynaptic currents (NMDA-EPSCs) at mossy fibre (MF)-CA3 (to 55.6 ± 6.8% of control, P = 0.0003) and at Schaffer collateral-CA1 synapses (70.8 ± 6.3%, P = 0.013), whereas it remained ineffective at non-MF excitatory synapses in CA3. Ox-A actions were mediated postsynaptically and blocked by the orexin-2 receptor (OX2R) antagonist JNJ10397049 (1 μm), but not by orexin-1 receptor inhibition (SB334867, 1 μm) or by adrenergic and cholinergic antagonists. At ZT 23, inhibitory effects of exogenous Ox-A were absent (97.6 ± 2.9%, P = 0.42), but reinstated (87.2 ± 3.3%, P = 0.002) when endogenous orexin signalling was attenuated for 5 h through i.p. injections of almorexant (100 mg kg(-1)), a dual orexin receptor antagonist. In conclusion, endogenous orexins modulate hippocampal NMDAR function in a time-of-day-dependent manner, suggesting that they may influence cellular plasticity and consequent variations in memory performance across the sleep-wake cycle.

Eighty-Sixth General Assembly Senate Rules (Senate Resolution 1 — Adopted 2/4/15), February 6, 2015

Eighty-Sixth General Assembly House Rules (House Resolution 4-Adopted 2-3-2015)

Histoire universelle du règne végétal, ou Nouveau dictionnaire physique et oeconomique de toutes les plantes qui croissent sur la surface du globe... par M. Buc'hoz,.... Texte, t. 1-3

Le t. 1 est publié chez Costard en 1774, les t. 2-3 chez Brunet en 1775

Seroepidemiology of herpes simplex virus type 1 and 2 in pregnant women in Switzerland: an obstetric clinic based study.

OBJECTIVE: To assess the seroprevalence of herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) IgG antibodies and the seroincidence of HSV-1 and HSV-2 infections in pregnant women attending the maternity clinic of the University Hospital Lausanne. STUDY DESIGN: Blood samples from 1030 women were taken at the usual pregnancy visit in the first trimester to assess the prevalence rate of IgG antibodies against HSV-1 and HSV-2 using a type-specific assay. A second blood sample was taken 6-8 weeks postpartum from returning women who were seronegative for HSV-2 or HSV-1 to assess the incidence of seroconversion (primary infection). RESULTS: The seroprevalence rates were 79.4% (95% CI: 76.9-81.9) for HSV-1 and 21.2% (18.7-23.7) for HSV-2 in women 14-46 years old. Type-specific serostatus patterns were as follows: 17.3% HSV-1/-2: +/+, 62.1% HSV-1/-2: +/-, 3.9% HSV-1/-2: -/+, 16.7% HSV-1/-2: -/-. Two hundred and sixty five women (59 of the 212 seronegative for HSV-1 (27.8%) and 265 of the 812 seronegative for HSV-2 (32.6%)) returned to the outpatient clinic for the post-delivery check and a second blood sample was obtained. One HSV-1 seroconversion was detected (HSV-1 seroconversion rate 2.4%/100 patient×year (95% CI: 0.06-13.4)) in a patient who had symptoms compatible with primary genital herpes. No HSV-2 seroconversion was detected (HSV-2 seroconversion rate: 0/100 patient×year (97.5% one-sided CI: 0-2)). CONCLUSION: Compared to a previous population-based study, our study results suggest a rise in the prevalence of HSV-2 among pregnant women in Switzerland. The low incidence of seroconversion detected during pregnancy is consistent with the very low reported incidence of neonatal herpes in Switzerland. CONDENSATION: This study in a public hospital in Western Switzerland suggests an increasing prevalence of HSV-2, but a low incidence of primary infections in women of childbearing age.