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We describe how to estimate progression-free survival while dealing with interval-censored data in the setting of clinical trials in oncology. Three procedures with SAS and R statistical software are described: one allowing for a nonparametric maximum likelihood estimation of the survival curve using the EM-ICM (Expectation and Maximization-Iterative Convex Minorant) algorithm as described by Wellner and Zhan in 1997; a sensitivity analysis procedure in which the progression time is assigned (i) at the midpoint, (ii) at the upper limit (reflecting the standard analysis when the progression time is assigned at the first radiologic exam showing progressive disease), or (iii) at the lower limit of the censoring interval; and finally, two multiple imputations are described considering a uniform or the nonparametric maximum likelihood estimation (NPMLE) distribution. Clin Cancer Res; 22(23); 5629–35. ©2016 AACR.

International audience; BACKGROUND:Despite multimodality treatments including neurosurgery, radiotherapy and chemotherapy, glioblastoma (GBM) prognosis remains poor. GBM is classically considered as a radioresistant tumor, because of its high local recurrence rate, inside the irradiation field. The development of new radiosensitizer is crucial to improve the patient outcomes. Pre-clinical data showed that Poly (ADP-ribose) polymerase inhibitors (PARPi) could be considered as a promising class of radiosensitizer. The aim of this study is to evaluate Olaparib, a PARPi, as radiosensitizing agent, combined with the Stupp protocol, namely temozolomide (TMZ) and intensity modulated radiotherapy (IMRT) in first line treatment of partially or non-resected GBM.METHODS:The OLA-TMZ-RTE-01 study is a multicenter non-randomized phase I/IIa trial including unresectable or partially resectable GBM patients, from 18 to 70 years old. A two-step dose-escalation phase I design will first determine the recommended phase 2 dose (RP2D) of olaparib, delivered concomitantly with TMZ plus conventional irradiation for 6 weeks and as single agent for 4 weeks (radiotherapy period), and second, the RP2D of olaparib combined with adjuvant TMZ (maintenance period). Phase IIa will assess the 18-month overall survival (OS) of this combination. In both phase I and IIa separately considered, the progression-free survival, the objective response rate, the neurocognitive functions of patients, emotional disorders among caregivers, the survival without toxicity, degradation nor progression, the complications onset and the morphologic and functional MRI (magnetic resonance imaging) parameters will be also assessed as secondary objectives. Ancillary objectives will explore alteration of the DNA repair pathways on biopsy tumor, proton magnetic resonance spectroscopy parameters to differentiate tumor relapse and radionecrosis, and an expanded cognition evaluation. Up to 79 patients will be enrolled: 30 patients in the phase I and 49 patients in the phase IIa.DISCUSSION:Combining PARP inhibitors, such as olaparib, with radiotherapy and chemotherapy in GBM may improve survival outcomes, while sparing healthy tissue and preserving neurocognitive function, given the replication-dependent efficacy of olaparib, and the increased PARP expression in GBM as compared to non-neoplastic brain tissue. Ancillary studies will help to identify genetic biomarkers predictive of PARPi efficacy as radiosensitizer.TRIAL REGISTRATION:NCT03212742 , registered June, 7, 2017. Protocol version: Version 2.2 dated from 2017/08/18.

Aim Cetuximab is an anti-epidermal growth factor receptor antibody used for the treatment of metastatic colorectal cancer and head and neck cancer. Hypersensitivity reactions (HSRs) are associated with cetuximab use. The aim of the study was to evaluate the utility of anti-cetuximab immunoglobulin E (IgE) detection in order to identify patients at risk of HSR to cetuximab. Methods We included patients ready to receive a first cetuximab infusion in a prospective cohort carried out at nine French centres. Pretreatment anti-cetuximab IgE levels were measured. We compared the proportion of severe HSRs in the low anti-cetuximab IgE levels (≤29 IgE arbitrary units) subgroup with that in a historical cohort of 213 patients extracted from a previous study. Results Of the 301 assessable patients (mean age: 60.9 ± 9.3 years, head-and-neck cancer: 77%), 66 patients (22%) had high anti-cetuximab IgE levels, and 247 patients received cetuximab (including 38 with high anti-cetuximab levels). Severe HSRs occurred in eight patients (five grade 3 and three grade 4). The proportion of severe HSRs was lower in the low anti-cetuximab IgE levels subgroup vs. the historical cohort (3/209 [1.4%] vs. 11/213 [5.2%], odds ratio, 0.27, 95% confidence interval, 0.07–0.97), and higher in high vs. low anti-cetuximab IgE levels subgroup (5/38 [13.2%] vs. 3/209 [1.4%]; odds ratio, 10.4, 95% confidence interval, 2.4–45.6). Patients with severe HSRs had higher anti-cetuximab IgE levels than patients without reaction (median, 45 vs. 2 IgE arbitrary units, P = 0.006). Conclusions Detection of pretreatment anti-cetuximab IgE is feasible and helpful to identify patients at risk of severe cetuximab-induced HSRs.

OBJECTIVE We implemented the two-step OPTIMA program to anticipate chemotherapy prescription which aims to assess the discrepancy rate between anticipated and real prescription and its impact on waiting time and quality of care. METHODS This prospective study included cancer patients receiving any intravenous chemotherapy. The OPTIMA program consists in a nurse phone call and a blood sample two days before the planned treatment. Collected information and biological results were used by a physician to issue a non-effective (step 1) or effective (step 2) anticipated prescription the day before the consultation. The real prescription was given as usual by another physician on the day of the consultation. Waiting time was collected, and patients' satisfaction with care was assessed with the OUT-PATSAT35 questionnaire. RESULTS Respectively, 540 and 979 consultations (283 and 294 patients) were analysed in both steps. The discrepancy rate was 8.7% (step 1). In routine practice, the OPTIMA program (step 2) reduced patients' waiting time (median time 55 vs. 95 min, p

This study aimed to evaluate the usefulness of combining fluorine-18 choline (F-FCH) and fluorine-18 fluorodeoxyglucose (F-FDG) PET/computed tomography (CT) in patients with rising prostate-specific antigen and known or suspected second malignancy.F-FCH and F-FDG PET/CT were performed 15±9 days apart on the same PET/CT system and acquisition and reconstruction parameters. A mean standardized uptake value (SUVmean) was computed for every lesion that could be discriminated with both tracers. PET results were confirmed by histology (eight patients) and clinical and imaging follow-up (mean±SD: 15±9 months).Of 77 consecutive patients who underwent F-FCH PET/CT scans for suspected prostate cancer recurrence, 10 (13%) were suspected to have a second malignancy because of F-FCH PET pattern inconsistency with that of prostate cancer (n=6), because of a history of a second malignancy with similar metastatic patterns (n=2) or inconsistency between disease burden and prostate-specific antigen value (n=2). Seventy lesions were studied, with a final diagnosis of prostate cancer, other cancers and benign disease in 55, nine and six lesions, respectively. F-FCH SUVmean and F-FCH/F-FDG SUVmean ratios were significantly different between prostate cancer, nonprostate cancer and benign disease (P0.0001 and P=0.04, respectively). Receiving operating characteristic analysis showed that the F-FCH/F-FDG ratios were not better than F-FCH SUVmean in discriminating prostate cancer from nonprostate cancer and benign diseases (sensitivity, specificity and area under the curve were 69%, 80%, 0.71 and 84%, 80% and 0.89, respectively).We found that F-FCH/F-FDG SUVmean ratios cannot differentiate prostate cancer recurrences from other cancer types when both diagnoses are suspected. Doubtful lesions should be biopsied.

Chemotherapy-induced nausea and vomiting (CINV) still remain frequent. The procedure for announcing the diagnosis (PAD) was an emblematic measure of the first French Plan Cancer aiming at providing patients with time to listen, information after cancer diagnosis, and discussion on treatments and their side effects. We aimed at assessing the risk factors of CINV, focusing on patients’ satisfaction with the PAD. This prospective multicentre study assessed the frequency and intensity of CINV among chemonaive patients during the first cycle of treatment. CINV was defined by ≥1 emetic episode or reported nausea intensity ≥3 on a 0–10 scale. Multivariate analysis was used to identify factors related to global CINV onset including satisfaction with the PAD (satisfaction score ≥the median on a 0–10 scale). Data from 291 patients (women, 85.2 %; mean age, 57 years) were analyzed. Most patients (69.4 %) received highly emetogenic chemotherapy regimens and 77.7 % received antiemetic drugs consistent with international guidelines. Acute, delayed and overall CINV were experienced by 40.4, 34.8 and 52.4 % of patients, respectively. Sixty-seven per cent of patients were satisfied with the PAD. No relation was noted between PAD satisfaction and CINV onset. The nausea and vomiting dimension of the QLQ-C30 questionnaire before chemotherapy (OR 3.62), motion sickness history (OR 2.73), highly emetogenic CT (OR 2.73), anxiety (OR 1.99) and younger age (OR 1.96) were independent predictive factors. Although patients were mostly satisfied with the PAD, half of them experienced CINV. A state of anxiety could be identified during the PAD to be managed.

At the end of the dose escalation step of phase I trials in oncology, it is increasingly frequent to include patients in expansion cohorts. However, the objective of the expansion cohorts, the number of patients included and their justification are insufficiently explained in the protocols. These cohorts are sometimes of considerable size. The aim of this article is to outline the methodology of expansion cohorts in order to provide recommendations for their planning in practice. This work has been undertaken in collaboration with the statisticians of the early phase investigation centers (CLIP(2)), supported by INCA. First, we have outlined the recent articles published on the expansion cohorts in phase I. We then proposed recommendations, in terms of objectives and number of patients to be included, to guide investigators and facilitate the use of these expansion cohorts in practice. Manji et al. have identified 149 phase I clinical trials using expansion cohorts in oncology with a review of the literature between 2006 and 2011 (Manji et al., 2013). Objectives of the expansion cohort were reported in 111 trials (74%). In these trials, safety was the most reported objective (80% of trials), followed by efficacy (45%). According to this review, the number of patients included in these cohorts was insufficiently justified. This result was confirmed by the study of literature that we conducted over the period 2011-2014. We propose to define the number of patients to be included in expansion cohorts in terms of (1) their objectives, (2) the statistical criteria and (3) the clinical context of the trial. The toxicity study remains the primary objective to evaluate in the expansion phase. In some contexts, the activity study is considered as co-primary objective, either for identifying preliminary signs of activity in studies like screening, or for studying the activity when the target population is known. This study is then considered as phase I/II, and experience plans of phase II can be adapted for planning expansion cohorts. Recommendations for the size of expansion cohorts are proposed. Despite the exploratory character of the expansion cohort, a justification of their size based on assumptions statistically defined is recommended in order to provide an interpretable conclusion and to quantify the risk of errors.

Background Brain metastases (BMs) are associated with a poor prognosis. Standard treatment comprises whole-brain radiation therapy (WBRT). As neo-angiogenesis is crucial in BM growth, combining angiogenesis inhibitors such as bevacizumab with radiotherapy is of interest. We aimed to identify the optimal regimen of bevacizumab combined with WBRT for BM for phase II evaluation and provide preliminary efficacy data. Patients and methods In this multicentre single-arm phase I study with a 3 + 3 dose-escalation design, patients with unresectable BM from solid tumours received three cycles of bevacizumab at escalating doses [5, 10 and 15 mg/kg every 2 weeks at dose levels (DL) 0, 1 and 2, respectively] and WBRT (30 Gy/15 fractions/3 weeks) administered from day 15. DL3 consisted of bevacizumab 15 mg/kg with WBRT from day 15 in 30 Gy/10 fractions/2 weeks. Safety was evaluated using NCI-CTCAE version 3. BM response (RECIST 1.1) was assessed by magnetic resonance imaging at 6 weeks and 3 months after WBRT. Results Nineteen patients were treated, of whom 13 had breast cancer. There were no DLTs. Grade 1–2 in-field and out-field toxicities occurred for five and nine patients across all DLs, respectively, including three and six patients (including one patient with both, so eight patients overall) of nine patients in DL3. One patient experienced BM progression during treatment (DL0). At the 3-month post-treatment assessment, 10 patients showed a BM response: one of three treated at DL0, one of three at DL1, two of three at DL2 and six of seven at DL3, including one complete response. BM progression occurred in five patients, resulting in two deaths. The remaining patient died from extracranial disease progression. Conclusion Bevacizumab combined with WBRT appears to be a tolerable treatment of BM. DL3 warrants further efficacy evaluation based on the favourable safety/efficacy balance. Clinical trials.gov Identifier NCT01332929.

Three-dimensional echocardiography (3DE) is a reliable and reproducible tool for assessing left ventricular (LV) function but remains sensitive to patient echogenicity. Contrast-enhanced 3DE (C3DE) has the potential to improve quantification in challenging patients. The aim of this study was to evaluate the impact of temporal resolution, spatial resolution, and image dynamic range on LV function assessed using C3DE compared with cardiac magnetic resonance imaging (MRI) in patients with poor echogenicity.Forty-one patients with poor echogenicity who underwent two-dimensional echocardiography (2DE), 3DE, C3DE, and MRI were retrospectively investigated.Before contrast injection, 24 patients had three or more nonvisible segments. Three cases of 2DE and 12 cases of 3DE were not suitable for quantification. LV end-diastolic volumes were systematically underestimated by 2DE (142 ± 58 mL), 3DE (146 ± 69 mL), and C3DE (172 ± 61 mL) compared with MRI (216 ± 85 mL) (P.001). Similar results were found for LV end-systolic volumes (81 ± 65 mL for 2DE, 82 ± 69 mL for 3DE, and 102 ± 80 mL for C3DE vs 129 ± 94 mL for MRI; P.001). C3DE provided the best agreement with MRI (Lin concordance correlation coefficients of 0.67, 0.93, and 0.99, respectively, for end-diastolic volume, end-systolic volume, and ejection fraction) as well as the best measurement reproducibility. Finally, ultrasound settings had no significant effect on LV volumes and ejection fraction measurements.In these patients with poor ultrasound image quality, C3DE, regardless of instrument settings, outperformed 2DE and 3DE to assess LV volumes and ejection fraction and can thus be proposed as an acceptable alternative when MRI cannot be performed in this subgroup.

Background Axitinib is used after failure of first line treatment for metastatic renal cell carcinoma (mRCC). A known side effect is the increase of haemoglobin level (HbL) during treatment with a suspected correlation with better outcome. Our objective was to examine whether HbL increase during the first three months of axitinib treatment is associated with better prognosis. Methods Retrospective multicentre analysis including patients with mRCC treated with axitinib for at least three months from 2012 to 2014. Progression-free survival (PFS) was analysed by a Cox model according to gender, International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) prognostic score, high blood pressure (hBP), and maximum increase in HbL within the first three months of treatment. Results Ninety-eight patients were analysed (71% men; median age at treatment initiation: 62 years; IMDC: 24%, 50%, and 26% in the favourable, intermediate, and poor-risk group, respectively). Patients received axitinib for a median of 8 months. During the first three months, the median increase of HbL was +2.3 g/dL (−1.1; 7.2). Fifty-six (57%) patients developed hBP. In multivariate analysis, after adjustment for performance status (P

Radiotherapy associated with cetuximab (Cet-RT) is an alternative treatment to platinum-based chemoradiotherapy in locally advanced head and neck carcinoma (LAHNC). Reviews suggest that the use of cetuximab is associated with poorer tolerance in patients unfit for chemotherapy than in pivotal trial. We retrospectively studied patients first treated by Cet-RT for LAHNC presenting contraindications to chemoradiotherapy. Objectives were treated population description, acute tolerance, progression-free survival (PFS), overall survival (OS), and 3-month clinical response. Eighty-eight patients were included. Treatment was completed without delay for 43 patients. Grade 3–4 acute toxicity was described in 44.3%: mucositis (n = 20), radiodermatitis (n = 25) folliculitis (n = 10), and anaphylaxis (n = 6). Fourteen patients died during treatment. Median PFS and OS were 6.3 and 18.7 months, respectively. We confirm that Cet-RT tolerance in unfit patients is poorer than that in trials. Survival data illustrate patients’ frailty and suggest that balanced use of Cet-RT is required in this population.

Ovarian cancers are addicted to Bcl-xL and Mcl-1, antiapoptotic members of the Bcl-2 family. Bcl-xL can be inhibited by the BH3-mimetic ABT-737. In vitro, ABT-737 can induce apoptosis of cancer cells, and its activity is potentiated by Mcl-1 inactivation. Herein, we assessed the sensitivity of human ovarian tumor nodes to ABT-737 when combined with carboplatin, which can indirectly inhibit Mcl-1. Fresh samples from 25 patients with high-grade serous ovarian cancer (HGSOC) who were chemo-naive and had undergone surgery were prospectively exposed ex vivo to ABT-737 ± carboplatin. The treatment effect was studied on sliced tumor nodes by assessment of cleaved-caspase 3 immunostaining. We also studied the association between baseline Bcl-2 family protein expression (via immunohistochemistry) and the response of nodes to treatment. ABT-737 induced apoptosis as a single agent but its efficacy was not improved by the addition of carboplatin. Bim was frequently expressed (20/25) and its absence or low expression was associated with the absence of response to ABT-737, p value = 0.019 by Fisher's test and sensitivity = 93%, (95% confidence interval, 66–100). Moreover, we observed that in tumors in which Bim was expressed, a low expression of phospho-Erk1/2 or Mcl-1 improved the proportion of responses. This pilot study showed that ABT-737 has promise as monotherapy for HGSOC in a specific subgroup of tumors. Bim, Mcl-1, and phospho-Erk1/2 appeared to be relevant biomarkers that could be used for the selection of patients in the design of clinical trials using Navitoclax (an orally available compound related to ABT-737).

Purpose Point spread function (PSF) reconstruction improves spatial resolution throughout the entire field of view of a PET system and can detect smaller metastatic deposits than conventional algorithms such as OSEM. We assessed the impact of PSF reconstruction on quantitative values and diagnostic accuracy for axillary staging of breast cancer patients, compared with an OSEM reconstruction, with emphasis on the size of nodal metastases. Methods This was a prospective study in a single referral centre in which 50 patients underwent an 18F-FDG PET examination before axillary lymph node dissection. PET data were reconstructed with an OSEM algorithm and PSF reconstruction, analysed blindly and validated by a pathologist who measured the largest nodal metastasis per axilla. This size was used to evaluate PET diagnostic performance. Results On pathology, 34 patients (68 %) had nodal involvement. Overall, the median size of the largest nodal metastasis per axilla was 7 mm (range 0.5 – 40 mm). PSF reconstruction detected more involved nodes than OSEM reconstruction (p = 0.003). The mean PSF to OSEM SUVmax ratio was 1.66 (95 % CI 1.01 – 2.32). The sensitivities of PSF and OSEM reconstructions were, respectively, 96 % and 92 % in patients with a largest nodal metastasis of >7 mm, 60 % and 40 % in patients with a largest nodal metastasis of ≤7 mm, and 92 % and 69 % in patients with a primary tumour ≤30 mm. Biggerstaff graphical comparison showed that globally PSF reconstruction was superior to OSEM reconstruction. The median sizes of the largest nodal metastasis in patients with nodal involvement not detected by either PSF or OSEM reconstruction, detected by PSF but not by OSEM reconstruction and detected by both reconstructions were 3, 6 and 16 mm (p = 0.0064) respectively. In patients with nodal involvement detected by PSF reconstruction but not by OSEM reconstruction, the smallest detectable metastasis was 1.8 mm. Conclusion As a result of better activity recovery, PET with PSF reconstruction performed better than PET with OSEM reconstruction in detecting nodal metastases ≤7 mm. However, its sensitivity is still insufficient for it to replace surgical approaches for axillary staging. PET with PSF reconstruction could be used to perform sentinel node biopsy more safely in patients with a primary tumour ≤30 mm and with unremarkable PET results in the axilla. Electronic supplementary material The online version of this article (doi:10.1007/s00259-014-2689-7) contains supplementary material, which is available to authorized users.

Background The objective of this study is to explore the impact of PSA nadirs on detection rates of prostate cancer (PCa) recurrence with 18F-choline (CH) PET/CT after external beam radiation therapy (EBRT). Methods In this retrospective study, data were collected from 54 patients with suspicion of PCa biochemical recurrence after EBRT (28 patients treated initially with EBRT and 26 as salvage therapy in the absence of PSA decrease after initial treatment), who underwent 18F-CH PET/CT between 2010 and 2015. PSA nadir and trigger PSA were collected from patient files. Relative PSA was calculated by subtracting the nadir from the trigger PSA. Results Median PSA nadir was 0.31 (0.01–13.31) ng/mL, trigger PSA was 7.85 (0.47–111.60) ng/mL, and relative PSA was 6.05 (0.24–104.59) ng/mL. Overall, 40 (74%) PET/CT scans were positive: recurrence was local and/or regional in 29 patients, distant in 15 and combined both in four, with no association between PSA values and sites of recurrence. In univariate analysis, trigger (p = 0.015) and relative (p = 0.0005) PSA values and PSA velocity (p = 0.01) were significantly linked to positive PET/CT, but PSA nadir was not. In subgroup analysis, these significant differences were only found in the salvage EBRT group. Akaike Information Criterion multivariate model comparison found that relative PSA was a better predictor of positive PET/CT than trigger PSA (PSAt). 18F-CH PET/CT detection rates increased with trigger and relative PSA: 0% (0/4 patients), 71% (5/7 patients), and 81% (35/43 patients) for PSAt 4 ng/mL, respectively, and 14% (1/7 patients), 50% (5/10 patients), and 92% (34/37 patients) when relative PSA was taken into account instead of trigger PSA, with seven (13%) patients changing subgroups. Conclusions We found a high overall detection rate and an increase in detection rates proportional to trigger and relative PSAs. Although relative PSA, taking into account PSA nadir, was a better predictive factor of PET/CT positivity in univariate analysis, this was most noticeable for high PSAs. For low PSAs, trigger PSA remains most relevant. Larger series with intermediate PSA values need to be studied to fully apprehend nadir impact.

Germline allele specific expression (ASE), resulting in a lowered expression of one of the BRCA1 alleles, has been described as a possible predisposition marker in Hereditary Breast or Ovarian Cancer (HBOC), usable for molecular diagnosis in HBOC. The main objective of this prospective case-control study was to compare the proportion of ASE between controls without familial history of breast or ovarian cancer, and HBOC cases without BRCA1 or BRCA2 deleterious mutation. BRCA1 ASE evaluated on three SNPs among controls and HBOC patients without deleterious mutation were assessed by pyrosequencing. The allelic ratios and the proportion of ASE were compared between controls and cases using a Student's t test and a Fisher exact test, respectively. The linearity and reproducibility of the ASE dosage was demonstrated with R2 > 0.99 and a coefficient of variation below 10 %, and ASE was detected in two positive controls harbouring BRCA1 truncated mutations. In the heterozygote population, composed of 99/264 controls (37.5 %) and 96/227 patients (42.3 %), we detected a 5 % ASE without truncated mutations, in each population. We failed to detect any significant difference of ASE between controls and patients. So far, BRCA1 Allelic specific expression is not usable in routine diagnosis as a possible predisposition marker in HBOC patients except for the detection of truncated mutations.

Introduction OLA-TMZ-RTE-01 (PHRC-K15-135, Clinicaltrial NCT03212742 ), en cours de recrutement, est un essai de Phase I/IIa dont l’objectif est de determiner la dose optimale puis l’efficacite de l’association de l’olaparib au protocole Stupp (six semaines de temozolomide et radiotherapie, suivi, apres quatre semaines de pause, de six cycles de temozolomide en traitement de maintenance), chez les patients atteints d’un gliome de haut grade non resecable. Il repose sur deux designs innovants, la « Time-to-event Continual Reassessment Method » (Tite-CRM) et le design de Case & Morgan. Nous presentons ces designs et les difficultes rencontrees par leur mise en œuvre dans l’essai. Methodes La Phase I se scinde en deux escalades de dose successives (pendant la radiotherapie puis la periode de maintenance), chacune selon une Tite-CRM [1] . Cette methode permet d’inclure les patients sans attendre un delai fixe d’observation des toxicites en leur attribuant un poids proportionnel au delai d’apparition de l’evenement, pour guider l’escalade de dose. L’efficacite, en termes de survie, de la dose d’olaparib definie lors de la Phase I sera evaluee en utilisant un design de Case & Morgan en deux etapes [2] . Ce design donne la possibilite de poursuivre l’inclusion pendant l’analyse intermediaire. Resultats Chez les patients a esperance de vie limitee, la Tite-CRM autorise une escalade de dose plus rapide qu’un design de type CRM ou 3 + 3, permettant de faire beneficier plus vite d’un traitement novateur. Les contraintes de securite liees a la dose administree restent neanmoins primordiales, que ce soit pour des toxicites a court ou a plus long terme. Le rythme d’inclusion se definit au fur et a mesure des observations en utilisant les proprietes mathematiques du design qui permettent une inclusion au jour le jour, tout en s’accordant un temps d’observation acceptable entre chaque inclusion, en partie guide par la periode definie d’observation des TDL (toxicites dose-limitantes). Mais comment definir ce rythme ? Combien de patients observer ? Et comment gerer de facon efficace le processus d’inclusion dans le cadre d’une etude multicentrique ? Telles sont les questions auxquelles nous avons ete confrontes par l’utilisation de la Tite-CRM. Les designs classiques d’essais de Phase II, tels que Simon ou Fleming, sont concus pour repondre a une problematique d’efficacite lorsque la variable d’interet est binaire, generalement la reponse au traitement, en se basant sur le fait que sa loi est binomiale. Lorsque l’efficacite est mesuree par un taux de survie, cette propriete ne tient plus. Le design de Case & Morgan repond alors a cette problematique, dans lequel le taux de survie est evalue par l’estimateur de Nelson–Aalen. Les regles de decisions sont accompagnees d’un test statistique, rendant l’utilisation et l’interpretation de ce design moins intuitives. Conclusion Au-dela des nombreux avantages que conferent les deux methodologies, elles suscitent de nombreuses questions, que ce soit des la conception de l’etude ou pendant son deroulement. Ces limites peuvent generer un frein a leur developpement, ce qui peut expliquer qu’elles soient encore peu utilisees dans les essais cliniques.

Aims After an old myocardial infarction (MI), patients are at risk for reentrant ventricular tachycardia (VT) due to scar tissue that can be accurately identified by late gadolinium enhancement cardiac magnetic resonance (LGE-CMR). Although the ability of LGE-CMR to predict sustained VT in implantable cardioverter-defibrillator (ICD) recipients has been well established, its use to predict monomorphic VT (sustained or not) cycle length (CL) and so, optimize ICD programming has never been investigated. Methods and results We included retrospectively 49 consecutive patients with an old MI who had undergone LGE-CMR before ICD implantation over a 4-year period (2006–09). Patients with amiodarone used were excluded. Scar extent was assessed by measuring scar mass, percent scar, and transmural scar extent. The endpoint was the occurrence of monomorphic VT, requiring an ICD therapy or not. The endpoint occurred in 26 patients. The median follow-up duration was 31 months. Scar extent parameters were significantly correlated with the study endpoint. With univariate regression analysis, the scar mass had the highest correlation with the VT CL ( R = 0.671, P = 0.0002). Receiver-operating characteristic curve showed that scar mass can predict VT CL (area under the curve = 0.977, P < 0.0001). For a cut-off value of scar mass at 17.6 g, there is 100% specificity and 94.4% sensitivity. Conclusion In this observational and retrospective study, scar mass studied by LGE-CMR was specific and sensitive to predict VT CL and so could be a promising option to improve ICD post-implantation programming and decrease appropriate and inappropriate shocks. These conclusions must now be confirmed in a large and prospective study.

Fatigue is a common but complex symptom of multiple sclerosis. A central origin is now suggested as a key feature of its pathophysiology and gray matter (GM) structure seems to be (particularly) involved in the neurobiological basis of fatigue in multiple sclerosis (MS) patients.We investigated, in a cohort of 17 Relapsing-Remitting-MS patients recruited within three years of disease diagnosis, the link between fatigue severity evaluated by the EMIF-SEP (a validated self-report questionnaire in French), and metabolic and density alterations of GM using positron emission tomography (PET) and magnetic resonance (MR) imaging using SPM5 (statistical parametric morphometry) analysis and voxel-based-morphometry.Compared to patients without fatigue-MS (NF-MS) group, patients with fatigue-MS (F-MS) had significant reduction (with correctedp0.05) of GM density in clusters located in the bilateral middle, superior and inferior frontal cortex and in left temporal and parietal cortex. In addition, the total score for fatigue was negatively correlated with GM density in the same regional areas for the whole group. Total fatigue score was negatively correlated with GM density in bilateral thalamus (correctedp=0.04) and with rest cerebral metabolic rate of glucose (rCMRglu) in the basal ganglia (correctedp0.05). Juxtacortical and/or overlapping corticosubcortical lesion volume in frontal and temporal areas were significantly higher in the F-MS group compared to NF-MS patients.These results add new data suggesting that fatigue is associated with functional and structural changes of cerebral gray matter especially in frontal cortex and basal ganglia.

Objectif Les primates hominoides (humain, Chimpanze, Gorille, Orang-outang et Gibbons) possedent des orbites convergentes qui favorisent la vision binoculaire et stereoscopique (vision precise) mais limite le champ visuel lateral. Cependant, une etude recente montre que l’humain elargit son champ visuel de plus de 60° grâce aux mouvements oculaires (champs visuel dynamique). Nous cherchons a comprendre les bases anatomiques de cette performance et savoir si elles sont presentes chez les autres primates hominoides. Methode Les orbites de 100 humains (47 hommes/36 femmes), 30 Chimpanzes, 30 Gorilles, 30 Orangs-outangs, et 30 Gibbons ont ete analysees en mesurant leur angle de convergence et leur angle d’ouverture laterale ainsi que le rapport largeur/hauteur. Ces parametres sont compares selon les genres et modelises pour evaluer le retentissement sur le champ visuel dynamique. Resultats Le genre humain possede une orbite significativement bien plus large (largeur/hauteur = 1,19) que les autres hominoides (p Discussion La forme de l’orbite humaine se distingue des autres hominoides et permet a la fois une vision binoculaire precise et un champ visuel elargi lors des mouvements oculaires. Cette caracteristique pourrait resulter de l’evolution de l’homme dans un milieu ouvert ou la detection des predateurs est essentielle a la survie, tandis que l’orbite des hominoides arboricoles est plus fermee lateralement, protegeant mieux l’œil face aux traumatisme des branches.

Objectives The aim of this study was to appreciate the safety and effectiveness of transradial percutaneous coronary intervention (PCI) with rotational atherectomy for highly calcified left main coronary artery (LMCA) disease in octogenarians. Background Conventional surgery is still considered the preferred management for LMCA disease; but, when the lesion is severely calcified, and the patient is unsuitable for surgery, the interventional cardiologist faces a complex PCI traditionally approached by femoral access. Methods Between June 2004 and December 2010, octogenarians with calcified LMCA disease who were primary denied for surgical revascularization were enrolled. Procedural success and major adverse cerebral and cardiovascular events (MACCE) including death, nonfatal myocardial infarction, target lesion revascularization (TLR), or stroke during long-term follow-up were evaluated. Results Forty-two consecutive patients≥80 years had undergone stenting for calcified LMCA disease (13 with rotational atherectomy, the “Rota” group, and 29 without rotational atherectomy, the “without Rota” group). Procedural success was good (92.3% vs. 96.6%, respectively, p = NS). Mean follow-up time was 25.7 ± 21.4 and 28 ± 32.3 months, respectively. There was a TLR in 25% and 11.1%, respectively; p = NS. No difference was detected in terms of overall in-hospital or long-term mortality or MACCE. Conclusion Rotational atherectomy followed by stent implantation by transradial approach, when applied to heavily calcified lesions, appeared to be a safe and effective strategy for the treatment of LMCA disease in octogenarians who were refused for surgery. (J Interven Cardiol 2013;26:173–182)

Aims Obesity may have implications in the myocardial structural change, which may contribute to mechanical consequences. Using 2D speckle echocardiography, we looked for myocardial changes and investigated their relation to obesity, inflammation, insulin resistance and physical capacity in children with isolated obesity. Methods and results Standard echocardiography and 2D strain were prospectively performed in obese children and compared them with age- and sex-matched controls. Z-score body mass index (BMI Z-score), ultra-sensitive C reactive protein, indices of insulin resistance (HOMA-IR) and metabolic stress test were assessed in obese children. Thirty-two consecutive obese patients [age: 12.8 (8–17) years; 15 males; BMI Z -score: 5.8 [2.05–8.6)] were compared with 32 controls. Longitudinal strain and circumferential strain were significantly lower in the obese group (respectively −18.0 ± 2.4% vs. −20.6 ± 2.5%; P = 0.0001 and −18.2 ± 3.5% vs. −20.1 ± 2.3%; P = 0.013), while radial strain did not differ. Longitudinal strain was correlated with HOMA-IR (Pearson's rho = −0.39) and with the exercise capacity (Pearson's rho = 0.62). In the multivariate analysis, after adjusting for age, the mean arterial pressure and left ventricular (LV) mass, the BMI Z -score remained independently related to the longitudinal and circumferential strain. Conclusion Childhood obesity may be associated with an early alteration of the longitudinal and circumferential LV strain. These findings have potentially significant clinical implications for the outcomes and follow-up of obese children meriting further studies.

Scientific Reports 5: Article number: 1152810.1038/srep11528; published online: June252015; updated: July202016 This Article contains typographical errors. In the Methods section under subheading ‘Measurement error evaluation’, “Measurement errors were 1.33° degree for OA, 0.93° for OA; 1.12° for OA-CA; 0.44 mm for orbital width; 0.35 mm for orbital height; 0.015 for the orbital width/height ratio.” should read: “Measurement errors were 1.33° degree for CA, 0.93° for OA; 1.12° for OA-CA; 0.44 mm for orbital width; 0.35 mm for orbital height; 0.015 for the orbital width/height ratio.”

We thank Lou and Sperduto (1) for their comments regarding the results of our REBECA trial [a phase I study designed to assess the safety of bevacizumab (BEV) in combination with whole brain radiation therapy (WBRT) for brain metastases (BM) of solid tumors (2)]. They highlighted the interest of exploring VEGF-based therapy in the context of radiation therapy of BM, as well as the issues of such an approach.

Viral respiratory infections are common in infants and can be severe. The new pandemic influenza virus H1N1v2009 was feared to cause particularly severe outcomes.This study aimed at evaluating the impact of H1N1v2009 on the viral epidemiology, the clinical presentation and the severity of respiratory infections in infants.This prospective epidemiologic study included all infants2 years of age, both inpatients and outpatients, presenting with respiratory symptoms, from November 2009 through April 2010, at the pediatric emergency department of the University Hospital of Caen, France. A nasal swab was taken for viral detection and analyzed by immunofluorescence and, if negative, polymerase chain reaction. Severe respiratory infection was defined by a score of respiratory severity.One thousand twenty-one infectious episodes with a respiratory sample met inclusion criteria. Eight hundred thirty-four samples (81.7%) were positive. The viruses with the highest incidence were the respiratory syncytial virus (34.2%), the rhinoviruses (23.9%), the coronaviruses (9.3%) and H1N1v2009 (7.7%). Of all infections, 28.6% were severe and more frequent in infants with risk factors. H1N1v2009 infections had a low risk of severe respiratory disease (odds ratios = 0.15) and hospitalization (odds ratios = 0.40) compared with the other viruses. Respiratory syncytial virus infections had a high risk of respiratory severity (odds ratios = 7.85) and were responsible for 71.4% of admissions to the intensive care unit.Despite the modest impact of H1N1v2009 observed in this study, further surveillance is needed to detect virological factors that may increase its severity.

Background Tail vein injection under short anesthesia is the most commonly used route for administering radiopharmaceuticals. However, the small caliber of the vein in rodents may lead to tracer extravasation and thereby compromise quantitative accuracy of PET. We aimed to evaluate a method for correction of interstitial radiotracer leakage in the context of pre-clinical therapeutic response assessment. Methods In two separate studies involving 16 nude rats, a model of human ovarian cancer was xenografted and each was treated with a Phosphoinositide 3-kinase/mammalian target of rapamycin inhibitor or used as a control. Tracer injections were performed via the tail vein by a single operator. Two observers qualitatively evaluated the resulting images and if appropriate drew a volume of interest (VOI) over the injection site to record extravasated activities. Uncorrected and corrected tumors’ mean standardized uptake value (SUV)mean was computed (corrected injected activity = calibrated activity − decay corrected residual syringe activity − decay corrected tail extravasated activity). Molecular analyses were taken as a gold standard. The frequency and magnitude of extravasation were analyzed, as well as the inter-observer agreement and the impact of the correction method on tumor uptake quantification. Results Extravasation never exceeded 20 % of the injected dose but occurred in more than 50 % of injections. It was independent of groups of animals and protocol time points with p values of 1.00 and 0.61, respectively, in the first experiment and 0.47 and 0.13, respectively, in the second experiment. There was a good inter-observer agreement for qualitative analysis (kappa = 0.72) and a moderate agreement when using quantitative analysis (ρc= 0.94). In both experiments, there was significant difference between uncorrected and corrected SUVmean. Despite this significant difference, mean percent differences between uncorrected and corrected SUVmean in the first and the second experiments were -3.61 and -1.78, respectively. Concerning therapy assessment, in both experiments, significant differences in median %SUVmean between control and treated groups were observed over all time points with either uncorrected and corrected data (p

Objectifs Les resultats a long terme de l’angioplastie transluminale (ATL) de l’artere sous-claviere prevertebrale (ASCPV) sont mal connus. Le but de ce travail est de presenter l’analyse retrospective d’une serie consecutive de 81 ATL de l’artere ASCPV avec un suivi moyen d’environ 7 ans (82 mois). Materiel et methodes De janvier 1984 a mai 2007, 81 ATL d'arteres ASCPV ont ete realisees consecutivement chez 72 malades (64% d'hommes ; âge median = 56,7 ans) pour traiter 71 stenoses serrees et 10 occlusions. L’ATL a ete realisee sous anesthesie locale dans 58 cas (71,6%), par abord femoral 65 fois et humeral 16 fois. L'abord a ete percutane 72 fois (89%). Un stent a ete mis en place 18 fois (22,2%). Resultats Le taux de succes technique immediat est de 96,3%. Une monoplegie transitoire a ete notee apres ATL, et 4 complications de ponction, statistiquement plus nombreuses par abord humeral percutane ( p = 0,024). Une restenose est survenue 28 fois (34,6%), symptomatique dans 3 cas. Avec un suivi moyen de 82 mois (3 a 299 mois), la permeabilite primaire a 10 ans est de 85,2% et la permeabilite primaire assistee de 92,6%. Aucune restenose n’est survenue apres le 25 eme mois de suivi. Aucun facteur n'etait statistiquement predictif de restenose. Conclusion L'ATL de l’artere ASCPV est un traitement peu invasif et efficace. Les restenoses precoces sont frequentes, mais restent accessibles a une nouvelle ATL, avec des resultats stables a long terme.

Background Long-term results of transluminal angioplasty (TLA) of the prevertebral subclavian artery (PVSA) are not well known. The aim of this work was to present a retrospective analysis of a consecutive series of 81 TLAs of the PVSA, with a mean follow-up of approximately 7 years (82 months). Material and Methods From January 1984 to May 2007, 81 TLAs of PVSA were consecutively performed in 72 patients (64% men; median age = 56.7 years) to treat 71 tight stenoses and 10 occlusions. In 58 cases, TLA was carried out under local anesthesia (71.6%), 65 times by femoral approach, and 16 times by humeral approach. A percutaneous approach was used 72 times (89%). A stent was placed in 18 cases (22.2%). Results Immediate technical success rate was 93%. One transient monoplegia was noticed after TLA and four puncture complications were observed, which occurred significantly more frequently with percutaneous humeral approach (p = 0.024). A recurrent stenosis occurred 28 times (34.6%) and was symptomatic in three cases. With a mean 82-month follow-up (3-299 months), primary patency at 10 years was 85.2% and primary assisted patency was 92.6%. No restenosis occurred after the 25th month of the follow-up. No restenosis factor was statistically predictive. Conclusion TLA of the PVSA is a mildly invasive and efficient treatment. Early restenoses are frequent but remain accessible to a new TLA with stable long-term results.

Little is known about the risks of catheter-related infections in patients undergoing intermittent hemodialysis (IHD) as compared with continuous renal replacement therapy (CRRT) techniques. We compared the two modalities among critically ill adults requiring acute renal replacement therapy (RRT).We used the multicenter Cathedia study cohort of 736 critically ill adults requiring RRT. Cox marginal structural models were used to compare time to catheter-tip colonization at removal (intent-to-treat, primary endpoint) among patients who started IHD (n = 470) versus CRRT (n = 266). On-treatment analysis was also conducted to take into account changes in prescription of RRT modality.Hazard rate of catheter-tip colonization did not increase within the first 10 days of catheter use. Predictors of catheter-tip colonization were higher lactate levels and hypertension, while systemic antibiotics, antiseptics-impregnated catheters, and mechanical ventilation were associated with decreased risk. The incidence of catheter-tip colonization per 1000 catheter-days was 42.7 in the IHD group and 27.7 in the CRRT group (P0.01). This association was no longer significant after correction for channeling bias (weighted HR, 0.96; 95% CI: 0.77 to 1.20, P = 0.73). On-treatment analysis revealed an increased risk of primary endpoint during CRRT exposure as compared with IHD exposure (weighted HR, 0.71; 95% CI: 0.56 to 0.92, P0.009).Our results do not support the use of CRRT when IHD could be an alternative to reduce the risk of catheter-related infection.

Objectives In advanced non-small cell lung cancer (NSCLC), maintenance therapy has emerged as a novel therapeutic reference for patients with non-progressive disease after platinum-based induction chemotherapy. However, the use of double maintenance (DM) with pemetrexed and bevacizumab is still being evaluated in terms of its clinical benefits and safety profile. The objective of this retrospective study was to describe the reasons for DM discontinuation in a real-world setting. Materials and methods Patients with advanced non-squamous NSCLC were eligible if they had received at least 4 cycles of induction chemotherapy, followed by at least 1 cycle of DM. They were identified by using the oncology pharmacy database of 17 French centers. Results Eighty-one patients who began a DM after induction chemotherapy were identified from September 2009 to April 2013. Among the 78 patients who had stopped DM at the time of the analysis, the main reasons for discontinuation were disease progression (42%), adverse events (33%), and personal preference (8%). The most frequent toxicity responsible for DM discontinuation was renal insufficiency (54%). Conclusion For patients with advanced NSCLC eligible for DM therapy, a particular attention should be paid to potential renal failure. Kidney function should be monitored carefully before and during DM to detect and manage early this adverse event.

We compared conventional filtered back-projection (FBP), two-dimensional-ordered subsets expectation maximization (OSEM) and maximum a posteriori (MAP) NEMA NU 4-optimized reconstructions for therapy assessment.Varying reconstruction settings were used to determine the parameters for optimal image quality with two NEMA NU 4 phantom acquisitions. Subsequently, data from two experiments in which nude rats bearing subcutaneous tumors had received a dual PI3K/mTOR inhibitor were reconstructed with the NEMA NU 4-optimized parameters. Mann-Whitney tests were used to compare mean standardized uptake value (SUV(mean)) variations among groups.All NEMA NU 4-optimized reconstructions showed the same 2-deoxy-2-[(18)F]fluoro-D-glucose ([(18)F]FDG) kinetic patterns and detected a significant difference in SUV(mean) relative to day 0 between controls and treated groups for all time points with comparable p values.In the framework of therapy assessment in rats bearing subcutaneous tumors, all algorithms available on the Inveon system performed equally.

Introduction Lors d’un essai de phase 1 d’oncologie dont l’objectif principal est de definir la dose a recommander a l’aide d’une escalade de dose, il est necessaire de recuperer l’information des toxicites dose-limitante (DLT) en temps reel, dans un contexte ou les cahiers d’observations sont majoritairement remplis a posteriori. Plusieurs centres promoteurs ont concu et utilisent une fiche specifique au recueil des DLT, en sus de la declaration des toxicites attendues, inattendues et evenements indesirables dans le cahier d’observation. L’objectif de ce travail collaboratif etait d’harmoniser les pratiques de recueil des DLT dans les essais cliniques academiques de phase I. Methodes Au sein du Hub phase 1 du groupe des statisticiens des CLCC, nous avons recueilli et centralise plusieurs exemples de fiches et leurs procedures associees afin de creer une trame de fiche harmonisee. La validation de ces items s’est faite lors d’une teleconference reunissant huit CLCC. Resultats La fiche harmonisee est composee de quatre chapitres : « identification du patient », « traitement administre », « toxicite dose-limitante » et « signature » avec un total de 16 items a remplir (dont deux optionnels). Les seules dates demandees sont la date de premiere prise du traitement (ou date de debut de la fenetre d’observation des DLT), la date de derniere visite pour les patients n’ayant aucune DLT (optionnelle), la date de survenue des DLT et la date a laquelle la fiche a ete remplie. En plus du type de DLT et de son grade, il a ete convenu qu’un champ texte devait apparaitre sur la fiche pour decrire la DLT en clair. Enfin, il a semble important d’inserer une question oui/non a propos de l’evaluabilite du patient pour les DLT (c’est-a-dire son eligibilite, son suivi et son traitement). En ce qui concerne la procedure associee aux fiches, il a ete decide de demander aux centres d’envoyer la fiche au promoteur soit des l’apparition d’une DLT, soit a la fin du delai d’observation si aucune DLT n’est apparue. Dans le cadre d’une methodologie evaluant un delai d’apparition des DLT comme lors d’une time to event-continuous reassessment method (TITE-CRM) par exemple, la fiche peut etre utilisee mais necessite que la date de derniere visite soit obligatoire pour les patients ne presentant aucune DLT et qu’un calendrier d’envoi de ces fiches soit defini a priori. Conclusion L’harmonisation des pratiques sur le recueil des DLT pour les phases 1 d’oncologie a pu se faire grâce au reseau actif du Hub phase 1. Nous allons egalement recueillir les retours d’experience d’utilisation des fiches de DLT (lors des cinq dernieres annees) ainsi que les attentes des promoteurs academiques d’essais cliniques de phase 1 a ce sujet. Un retour sur l’utilisation de cette fiche harmonisee est prevu.

Introduction: In therapeutic research, the safety and efficacy of pharmaceutical products are necessarily tested on humans via clinical trials after a very long and expensive development period. Alternative methodologies such as computer modeling and Clinical Trial Simulation (CTS) are a valuable option to reduce animal and human assays. The relevance of these methods is well recognized in pharmacokinetics and pharmacodynamics from the pre-clinical phase to post-marketing. However, they are seldom used and are poorly regarded for drug approval, despite FDA and EMA recommendations. We propose to discuss the principle behind, and the interest of, CTS approaches in drug development in oncology. Our work is based on a systematic review using two electronic literature databases (Medline and Web of Science). Key components of CTS: We will explain why and how to successfully develop CTS. Why developing CTS? To obtain a better knowledge of pharmacology and/or better prediction of safety and efficacy To evaluate disease progression dynamics and to test the potential impact of biomarkers To analyze subpopulations and extend the post-marketing authorization to help in the choice of the best outcome To optimize experimental designs in order to better anticipate the progress of the study How to develop CTS? CTS project must follow three steps: 1/The constitution of pharmacometricians team who elaborates clinical model and simulation plan that must contain three components: Input/output model: How do covariates impact outcomes? Covariate distribution Model: How can we generate virtual patients? Execution model: What can happen during the clinical trial? 2/Obtaining data for simulations. We will present the contribution of machine learning for CTS 3/The use of specialized software to realize simulations Limitations of CTS: We will present the features that can slow down or accelerate the development of CTS. The generalization of CTS could be greatly facilitated by the availability of software for modeling biological systems, by the clinical trials studies and hospital databases. Data-sharing and data-merging raise legal, policy and technical issues that will need to be addressed. CTS challenges and prospects: Development of future molecules will have to use CTS for faster development and thus enable better patient management. Drug activity modeling coupled with disease modeling, optimal use of medical data and increase of the computing speed should allow this leap forward. The realization of CTS requires not only the bioinformatics tools to allow interconnection and global integration of all clinical data, but also a universal legal framework to protect the privacy of every patient. CTS will have to be used to provide quantitative support for drug development decisions but will never replace real clinical trials. This in silico medicine opens the way to the 4P medicine: predictive, preventive, personalized and participatory. Citation Format: Jocelyn Gal, Gerard Milano, Julien Viotti, Renaud Schiappa, Audrey Dugue, Agnes Paquet, Sylvie Chabaud, Jean-Marc Ferrero, Emmanuel Chamorey. Optimizing drug regimens in oncology by clinical trial simulations: Why and how [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 773. doi:10.1158/1538-7445.AM2017-773

Introduction Des reactions d’hypersensibilite graves (HSI) mediees par des IgE anti-galactose-α-1,3-galactose (αGal) peuvent survenir a la premiere injection de cetuximab chez certains patients. Le depistage des IgE anti-cetuximab realise au laboratoire d’immunologie du CHU de Caen (technique Elisa [1] ) est a disposition des cliniciens pour adapter la prise en charge dans le but de diminuer ce risque. L’objectif de l’etude est de comparer les performances de l’ImmunoCap® o215/αGal a ce test. Methodes Une premiere cohorte de 90 patients [1] , ayant permis la mise au point de l’Elisa, a ete analysee pour comparer les performances des 2 tests. Tous les echantillons ont ete analyses sur Phadia 250 avec un seuil de positivite > 0,1 kUA/L. Un test d’inhibition par cetuximab atteste de la reactivite du Cap o215 envers le cetuximab. Puis, 95 patients, tires au sort dans une cohorte prospective de 247 patients [2] , ont ete utilises pour etudier la prediction du risque d’HSI. Resultats Dans la premiere cohorte, 7/8 HSI ont ete detectees par les 2 tests. La sensibilite et la valeur predictive negative sont egales (Se = 88 %, VPN = 99 %). Cependant, le Cap o215 possede une meilleure specificite et valeur predictive positive que l’Elisa (Sp = 94 % vs 80 %, VPP = 58 % vs 30 %, respectivement). L’analyse ROC permet d’optimiser un seuil de positivite a 0,525 kUA/L. Dans la seconde cohorte, 5/8 HSI sont detectees par les deux tests (Se = 62,5 %). La prediction d’HSI est meilleure avec le Cap o215 (seuil > 0,1 kUA/L : risque d’HSI = 50 %, p = 0,00021 ; seuil ≥ 0,525 kUA/L : risque d’HSI = 80 %, p = 0,0011) qu’avec le test Elisa (risque d’HSI = 25 %, p = 0,0095). Conclusion Le Cap o215 permet une meilleure prediction du risque d’HSI au cetuximab lors de la premiere injection. Son utilisation est adaptee en routine pour les laboratoires equipes d’un automate Phadia. Le seuil de positivite de ce test meriterait cependant d’etre valide dans une etude prospective elargie.

The aim of this study was to appreciate the safety and effectiveness of transradial percutaneous coronary intervention (PCI) with rotational atherectomy for highly calcified left main coronary artery (LMCA) disease in octogenarians.Conventional surgery is still considered the preferred management for LMCA disease; but, when the lesion is severely calcified, and the patient is unsuitable for surgery, the interventional cardiologist faces a complex PCI traditionally approached by femoral access.Between June 2004 and December 2010, octogenarians with calcified LMCA disease who were primary denied for surgical revascularization were enrolled. Procedural success and major adverse cerebral and cardiovascular events (MACCE) including death, nonfatal myocardial infarction, target lesion revascularization (TLR), or stroke during long-term follow-up were evaluated.Forty-two consecutive patients ≥80 years had undergone stenting for calcified LMCA disease (13 with rotational atherectomy, the "Rota" group, and 29 without rotational atherectomy, the "without Rota" group). Procedural success was good (92.3% vs. 96.6%, respectively, p = NS). Mean follow-up time was 25.7 ± 21.4 and 28 ± 32.3 months, respectively. There was a TLR in 25% and 11.1%, respectively; p = NS. No difference was detected in terms of overall in-hospital or long-term mortality or MACCE.Rotational atherectomy followed by stent implantation by transradial approach, when applied to heavily calcified lesions, appeared to be a safe and effective strategy for the treatment of LMCA disease in octogenarians who were refused for surgery.

Our aim was to compare the impact of two types of sunglasses on visual field and glare: one ("thick sunglasses") with a thick plastic frame and wide temples and one ("thin sunglasses") with a thin metal frame and thin temples.Using the Goldmann perimeter, visual field surface areas (cm²) were calculated as projections on a 30-cm virtual cupola. A V4 test object was used, from seen to unseen, in 15 healthy volunteers in the primary position of gaze ("base visual field"), then allowing eye motion ("eye motion visual field") without glasses, then with "thin sunglasses," followed by "thick sunglasses." Visual field surface area differences greater than the 14% reproducibility error of the method and having a p0.05 were considered significant. A glare test was done using a surgical lighting system pointed at the eye(s) at different incidence angles.No significant "base visual field" or "eye motion visual field" surface area variations were noted when comparing tests done without glasses and with the "thin sunglasses." In contrast, a 22% "eye motion visual field" surface area decrease (p0.001) was noted when comparing tests done without glasses and with "thick sunglasses." This decrease was most severe in the temporal quadrant (-33%; p0.001). All subjects reported less lateral glare with the "thick sunglasses" than with the "thin sunglasses" (p0.001).The better protection from lateral glare offered by "thick sunglasses" is offset by the much poorer ability to use lateral space exploration; this results in a loss of most, if not all, of the additional visual field gained through eye motion.

Devic's neuromyelitis optica (NMO) is a severe inflammatory and autoimmune disease producing demyelinating lesions. Recent data suggest that a complex genetic component could be involved. While impairment of glutamate homeostasis has emerged as a contributing etiological factor in NMO, a genetic alteration of Excitatory Amino Acid Transporter 2 ( EAAT2/SLC 1 A2 ), the major glutamate transporter in the Central Nervous System (CNS), could contribute to glutamate excitotoxicity and then must be considered. We evaluated whether mutations and/or single nucleotide polymorphisms (SNPs) in EAAT2 gene, are associated with susceptibility to NMO. We studied a cohort of NMO sporadic cases including afro-caribbean patients ( n= 81; French cohort of Devic's neuromyelitis optica—NOMADMUS cohort) and compared to control subjects ( n= 56). We sequenced the whole coding region of EAAT2 gene and splicing consensus sequences flanking each exon. The results obtained from all NMO samples did not show any novel mutations and/or SNPs both in the coding region and splicing sites of EAAT2 gene compared to controls subjects. We reported three synonymous SNPs (rs752949, rs1042113 and rs7102949) but only rs7102949 was found in afro-caribbean. Genotype frequencies did not differ between patients and controls for the three SNPs in caucasians and afro-caribbeans (rs752949: p =0.71 and p =0.37, respectively; rs1042113: p =0.73 and p =0.35, respectively; rs7102949: p =0.08 in afro-caribbeans). Our data showed no evidence for a genetic association between EAAT2 gene and Devic's neuromyelitis optica.

e16105Background: RCC is considered as radioresistant and radiation therapy of metastases is usually reserved only to palliate symptoms. However, by delivering ablative doses, SRT may increase loca...

580 Background: Axitinib is used after failure of first line treatment for metastatic renal cell carcinoma (mRCC). A common side effect of axitinib is the increase of hemoglobin level (HbL) during treatment with a suspected correlation with better outcome. We examined whether HbL increase during the first 3 months of axitinib treatment is associated with better prognosis. Methods: Retrospective multicenter analysis including patients with mRCC treated with axitinib for at least 3 months from 2012 to 2014 as part of the French temporary use authorization cohort. Progression-free survival (PFS) was analyzed according to the following factors: gender, International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) prognostic score at axitinib initiation, polycythemia (HbL above 16.5/18.5 g/dL or hematocrit above 56/60% for women/men), and maximum increase in HbL within the first 3 months of treatment. Results: 97 patients were analyzed (71% men; median age at diagnosis: 54.7 years [22; 80]; IMDC: 23%, 49%, and 27% in the favorable, intermediate, and poor-risk group, respectively). Patients received axitinib for a median of 8 months [3; 30]. Grade 2-3 toxicities were observed in 81% of patients. Objective response rate was 32%. The median PFS and OS were 8.9 [7.4; 9.3] and 22 [19.4; not reached] months, respectively. During the first 3 months, 81 patients (84%) experienced HbL increase with a median increase of +2.3g/dL [-1.1; 7.2] and 40 of them (51%) had an increase above this median. Eight patients (8%) presented polycythemia. In univariate analysis, significantly longer PFS was observed for men (p = 0.02), for patients who had a better IMDC prognostic score (p = 0.004), and for patients who experienced an increase of HbL ≥ 2.3 g/dL (with a median PFS of 11.7 vs. 7.4 months; p = 0.025), but not for patients with polycythemia. In a multivariate analysis, after adjustment for IMDC score (p < 0.0001) and gender (p = 0.029), an increase in HbL ≥ 2.3 g/dL was significantly associated with a longer PFS (HR = 0.57, 95%CI [0.34; 0.95]). Conclusions: HbL increase ≥ 2.3g/dL in the first 3 months of axitinib treatment was associated with longer PFS. These results require validation in a prospective trial setting.

Objective: To study the prognostic impact of O 6 -methylguanine-DNA methyltransferase (MGMT) on newly diagnosed glioblastoma patients being treated with carmustine-releasing wafers (Gliadel®) along with temozolomide (TMZ). Background MGMT promoter methylation status was proposed as a prognostic biomarker for glioblastoma patients. However, the prognostic impact of MGMT on newly diagnosed glioblastoma patients treated using surgical resection and Gliadel® implants followed by Stupp9s protocol is still unknown. Design/Methods: MGMT promoter methylation status and protein expression were analyzed in formalin-fixed, paraffin-embedded tumor specimens obtained from 111 French patients with newly diagnosed glioblastoma. Patients received Gliadel® followed by radiotherapy plus concomitant and adjuvant TMZ chemotherapy, while being enrolled in a French multicenter prospective study. Results: For the whole cohort, median overall survival (OS) and progression-free survival (PFS) were 17.5 and 10.3 months, respectively. Patients with tumors harboring MGMT methylation displayed a significantly longer OS compared to those with wild-type MGMT (21.7 vs . 15.1 months, p=0.025). Similarly, patients with low MGMT protein expression (≤15%) exhibited significantly improved OS compared to those with high MGMT expression (27.0 vs. 15.1 months, p=0.021). The extent of resection was the strongest clinical outcome predictor. In multivariate Cox models adjusted for gender, performance status, and extent of surgery, both MGMT methylation and protein expression were found to be independent prognosticators, which was internally validated using bootstrap resampling techniques. However, no significant correlation was found between protein expression and MGMT methylation status, thus suggesting that the two assays probably assess different biological features. Conclusions: MGMT promoter methylation status and low MGMT expression were both found to be positive prognosticators in newly diagnosed glioblastoma patients treated using surgical resection and Gliadel® implants followed by Stupp9s protocol. Disclosure: Dr. Guillamo has nothing to disclose. Dr. Levallet has nothing to disclose. Dr. Dugue has nothing to disclose. Dr. Vital has nothing to disclose. Dr. Diebold has nothing to disclose. Dr. Menei has nothing to disclose. Dr. Colin has nothing to disclose. Dr. Peruzzy has nothing to disclose. Dr. Emery has nothing to disclose. Dr. Bernaudin has nothing to disclose. Dr. Chapon has nothing to disclose. Dr. Lechapt-Zalcman has nothing to disclose.

Management of lateral no necks in papillary thyroid carcinoma (PTC) is very controversial. The aim of this study was to find predictive factors of lateral neck involvement in N0 PTC to help the clinician in his decision to treat the lateral compartment. We retrospectively analysed 173 patients who underwent thyroidectomy and lateral prophylactic neck dissection for PTC >10 mm. Predictive factors for occult lateral lymph node metastasis including sex, age, tumour size, multifocality and bilaterality, tumour extracapsular spread, vascular invasion and presence of a tumour capsule were examined by multivariate analysis. There were three independent predictive factors for occult lateral lymph node metastases in multivariate analysis: tumour extracapsular spread (p < 0.0001), vascular invasion (p < 0.001) and age

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