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Validated biomarkers predictive of response/resistance to anthracyclines in breast cancer are currently lacking. The neoadjuvant Trial of Principle (TOP) study, in which patients with estrogen receptor (ER)–negative tumors were treated with anthracycline (epirubicin) monotherapy, was specifically designed to evaluate the predictive value of topoisomerase II-alpha (TOP2A) and develop a gene expression signature to identify those patients who do not benefit from anthracyclines. Here we describe in details the contents and quality controls for the gene expression and clinical data associated with the study published by Desmedt and colleagues in the Journal of Clinical Oncology in 2011 (Desmedt et al., 2011). We also provide R code to easily access the data and perform the quality controls and basic analyses relevant to this dataset.

L’intérêt de santé publique des médicaments (ISP) est un critère d’évaluation récent (décret d’octobre 1999) et spécifiquement français qui, faute d’éléments disponibles au moment de son appréciation, reste à ce jour souvent incomplètement documenté dans les dossiers de transparence. En effet, lors de la demande de première inscription d’un médicament sur la liste des spécialités remboursables, les données cliniques dont on dispose sont en général les seules contenues dans le dossier d’enregistrement. Ces données sont issues d’un programme de développement désormais global, construit bien longtemps avant le dépôt du dossier d’inscription au remboursement, qui ne prévoit pas de façon systématique de renseigner les données nécessaires à l’évaluation de l’ISP. On comprend donc la difficulté d’anticipation et de documentation de ce critère récent et hexagonal. En France, l’ISP est à la fois l’un des critères d’admission au remboursement des médicaments et un élément de pilotage d’une politique de santé nationale. Son évaluation permet par ailleurs d’identifier les besoins et les objectifs des études post-inscription qui font l’objet d’une clause conventionnelle lors du passage au Comité Économique des Produits de Santé (CEPS). Située en aval de l’évaluation de l’autorisation de mise sur le marché (AMM), l’évaluation du critère ISP lui fait suite et la complète.

The Public Health Benefit (PHB) of new medicines is a recent and French-specific criterion (October 1999 decree) which is often only partially documented in the transparency files due to a lack of timely information. At the time of the first reimbursement application for a new medicine to the “Transparency Committee”, the file is exclusively based on data from randomised clinical trials. These data are generated from a global clinical development plan which was designed a long time before the new medicine’s submission for reimbursement. And this plan does not systematically provide the data needed to assess the PHB. Thus, one easily understands the difficulty to anticipate and document this recent French criterion. In France, the PHB is both one of the necessary criteria for the reimbursement submission and an indicator for the national health policy management. Its assessment also helps to identify the needs and objectives of the post-registration studies (nowadays in the scope of responsibilities of the “Drug Economics Committee”). The assessment of the PHB criterion is carried through after the marketing authorization process and is an addition to it.

Background & Aims:Leptin production has been reported in the rat and in human stomach. It initiates intestinal nutrient absorption. In this study, we analyzed the effect of vagal stimulation on leptin release in the human stomach. Methods:We studied the secretion of gastric acid and leptin on stimulation with insulin (a stimulant of vagal pathways via hypoglycemia) and pentagastrin in 11 healthy men (normal endoscopy and normal histological gastric mucosa), 5 with previous highly selective vagotomy (HSV), and 6 without HSV. Fundic biopsies were performed for immunostaining of leptin. Results:There was no difference between the 2 groups with respect to age, body mass index, basal leptin (4.8 +/- 1.2 ng/15 minutes) and gastric acid (0.7 +/- 0.2 mmol/15 minutes) outputs. Leptin-immunoreactivity was found in the fundic glands, and its distribution and density were similar in 2 groups. Insulin caused a rapid (15-minute) increase in leptin output in men without HSV (31 +/- 9 ng/15 minutes), but not in those with HSV (7.7 +/- 3.2 ng/15 minutes). Insulin-stimulated gastric leptin was biphasic, with a rapid increase (15 minutes after injection) followed by a second steady and sustained increase (39.9 +/- 7.6 ng/15 minutes at 120 minutes after injection). Pentagastrin increased gastric leptin output in individuals with (30 +/- 4.9 ng/15 minutes) and without (26 +/- 3.2 ng/15 minutes) HSV. Insulin and pentagastrin did not modify plasma leptin, whatever HSV status. Conclusions:Vagal stimulation of leptin release in the human stomach suggests that leptin is released during the cephalic phase of gastric secretion. Luminal leptin may be involved in vagus-mediated intestinal functions.

The validation of surrogate endpoints has been studied by Prentice (1989). He presented a definition as well as a set of criteria, which are equivalent only if the surrogate and true endpoints are binary. Freedman et al. (1992) supplemented these criteria with the so-called 'proportion explained'. Buyse and Molenberghs (1998) proposed replacing the proportion explained by two quantities: (1) the relative effect linking the effect of treatment on both endpoints and (2) an individual-level measure of agreement between both endpoints. The latter quantity carries over when data are available on several randomized trials, while the former can be extended to be a trial-level measure of agreement between the effects of treatment of both endpoints. This approach suggests a new method for the validation of surrogate endpoints, and naturally leads to the prediction of the effect of treatment upon the true endpoint, given its observed effect upon the surrogate endpoint. These ideas are illustrated using data from two sets of multicenter trials: one comparing chemotherapy regimens for patients with advanced ovarian cancer, the other comparing interferon-alpha with placebo for patients with age-related macular degeneration.

Chemo-occlusion of the liver increases the tumour concentration of drugs. Thirty-nine patients with colorectal liver metastases received a monthly bolus administration of mitomycin C (10 mg/m2on day 1) plus a continuous infusion of 5-fluorouracil (500 mg/m2daily from days 1 to 5). Drugs were given via both portal (one-third of the dose) and arterial (two-thirds) routes to control large and small metastases. Arterially administered mitomycin C was mixed with individualized doses of degradable starch microspheres. In 16 patients treatment was not started or was interrupted early because of arterial or portal catheter problems. In 23 patients who received two or more cycles of treatment the mean (s.d.) microsphere dose was 835(399) mg. Toxicity was mild, consisting mainly of pain. Five complete and five partial responses were seen, and six patients had stable disease. The median time to progression and length of survival were 6 and 16 months respectively. The relatively high rates of complete and overall response in hypovascular tumours (six of 12 lesions) may support the rationale of chemo-occlusion.

From 1978 to 1985, 297 patients were entered in a double-blind randomized trial comparing levamisole to placebo as adjuvant therapy of Dukes' C carcinoma of the colon. Therapy consisted of from two to five tablets of 50 mg levamisole (or placebo) twice a week, depending on bodyweight for 1 year. Levamisole was generally well tolerated, with only four reversible cases of agranulocytosis reported among 129 patients. The trial failed to show a benefit of levamisole on disease-free survival (P = 0·53) or on survival (P = 0·35). There was no difference between the two treatment groups in terms of number of disease relapses, sites of relapse, or time to relapse. The proportion of patients still alive at 5 years was 51 per cent (standard error, 5·5 per cent) in the levamisole group versus 39 per cent (standard error, 5·4 per cent) in the placebo group.

Summary To test the hypothesis that the initial response to corticosteroid treatment makes it possible to predict the further course of patients with polymyalgia rheumatica (PMR), 20 patients with PMR were prospectively given a therapeutic challenge with 15 mg of prednisolone (PDN) per day. The erythrocyte sedimentation rate (ESR), the fibrinogen and the C-reactive protein (CRP) were measured before and after 7 days of therapy. At the end of the challenge, the CRP had normalized in 11 patients (Group I), whereas it had remained elevated in 9 (Group II). The dose of PDN was thereafter tapered according to a strict and standard schedule integrating clinical and laboratory parameters, and was used as the index of disease control. The statistical analysis was made using a generalized linear model.

Hydroxyurea (HU) enhances the synthesis of fetal hemoglobin (HbF) and can improve the clinical course of some adult patients with sickle cell anemia (SCA). In a randomized trial, we studied the biologic effects and the clinical benefit of HU in children and young adults with severe SCA. Twenty-five patients (median age, 9 years) were randomized to receive either HU (at the initial dosage of 20 mg/kg/d) or a placebo for 6 months and were then switched to the other arm for the next 6 months. Among the 22 evaluable patients (median age, 8 years), significant increases in HbF and mean corpuscular volume occurred during the HU treatment period. The white blood cell and reticulocytes counts decreased significantly, but these changes were not clinically relevant. Sixteen of 22 patients (73%) experienced a complete disappearance of events requiring hospitalization. The number of days of hospitalization as well as the number of hospitalizations for patients on HU, as compared with those for the patients receiving placebo, were significantly reduced. We conclude that treatment with HU in children and young adults is feasible, well-tolerated, and improves the clinical course of SCA. The long-term effects of HU require further investigation.

The addition of dipyridamole, an antiplatelet agent, to conventional anticoagulant regimens has been shown to reduce the frequency of embolization after valve replacement with a mechanical prosthesis. The purpose of this meta-analysis was to reevaluate the benefit of dipyridamole by analyzing the evidence from all randomized clinical trials. Summary data were extracted from the application to the Food and Drug Administration. Six randomized clinical trials had accrued 1141 patients, of whom 582 received anticoagulant therapy alone and 559 received additional dipyridamole at dosages ranging from 225 to 400 mg per day. The events analyzed were all thromboembolic events, both fatal and nonfatal; hemorrhagic events, both fatal and nonfatal; and the overall mortality. The combination of dipyridamole with anticoagulants reduced the risk of thromboembolic events (fatal or nonfatal) by 56% when compared with the use of anticoagulants alone ( p = 0.0001). The risk reduction was seen in fatal and in nonfatal thromboembolic events (risk reduction for fatal events, 64%, p = 0.008; for nonfatal events, 50%, p = 0.005). The overall mortality rate was also significantly reduced by 40% in the group receiving dipyridamole ( p = 0.013). There was no difference between treatment groups with respect to hemorrhagic events (risk reduction, -1%, p = 0.94). This meta-analysis supports the use of dipyridamole in this setting and warrants further trials with new antiplatelet agents. (J THORAC CARDIOVASC SURG 1995;110:463-72)

Objectives: The International Registry of Lung Metastases was established in 1991 to assess the long-term results of pulmonary metastasectomy. Methods: The Registry has accrued 5206 cases of lung metastasectomy, from 18 departments of thoracic surgery in Europe (n = 13), the United States (n = 4) and Canada (n = 1). Of these patients, 4572 (88%) underwent complete surgical resection. The primary tumor was epithelial in 2260 cases, sarcoma in 2173, germ cell in 363, and melanoma in 328. The disease-free interval was 0 to 11 months in 2199 cases, 12 to 35 months in 1857, and more than 36 months in 1620. Single metastases accounted for 2383 cases and multiple lesions for 2726. Mean follow-up was 46 months. Analysis was performed by Kaplan-Meier estimates of survival, relative risks of death, and multivariate Cox model. Results: The actuarial survival after complete metastasectomy was 36% at 5 years, 26% at 10 years, and 22% at 15 years (median 35 months); the corresponding values for incomplete resection were 13% at 5 years and 7% at 10 years (median 15 months). Among complete resections, the 5-year survival was 33% for patients with a disease-free interval of 0 to 11 months and 45% for those with a disease-free interval of more than 36 months; 43% for single lesions and 27% for four or more lesions. Multivariate analysis showed a better prognosis for patients with germ cell tumors, disease-free intervals of 36 months or more, and single metastases. Conclusions: These results confirm that lung metastasectomy is a safe and potentially curative procedure. Resectability, disease-free interval, and number of metastases enabled us to design a simple system of classification valid for different tumor types. (J Thorac Cardiovasc Surg 1997;113:37-49)

Hydroxyurea (HU) enhances the synthesis of fetal hemoglobin (HbF) and can improve the clinical course of some adult patients with sickle cell anemia (SCA). In a randomized trial, we studied the biologic effects and the clinical benefit of HU in children and young adults with severe SCA. Twenty-five patients (median age, 9 years) were randomized to receive either HU (at the initial dosage of 20 mg/kg/d) or a placebo for 6 months and were then switched to the other arm for the next 6 months. Among the 22 evaluable patients (median age, 8 years), significant increases in HbF and mean corpuscular volume occurred during the HU treatment period. The white blood cell and reticulocytes counts decreased significantly, but these changes were not clinically relevant. Sixteen of 22 patients (73%) experienced a complete disappearance of events requiring hospitalization. The number of days of hospitalization as well as the number of hospitalizations for patients on HU, as compared with those for the patients receiving placebo, were significantly reduced. We conclude that treatment with HU in children and young adults is feasible, well-tolerated, and improves the clinical course of SCA. The long-term effects of HU require further investigation.

Abstract: In spite of the improvements in surgical techniques and intensive care therapy, no appreciable improvement in the prognosis for patients with colorectal cancer has been made in recent years. Several types of adjuvant treatment, including radiotherapy, chemotherapy, and immunotherapy, have therefore been proposed and used in clinical trials, mainly in the United States and western Europe. The results obtained by the Gastrointestinal Group of the European Organization for Research and Treatment of Cancer (EORTC), using preoperative radiation therapy with 3450 rads, are reported here; this therapy results in a reduction in the number of local recurrences and also appears to prolong the five-year survival period, although a longer follow-up is required to confirm this. According to the Gastrointestinal Tumor Study Group (GITSG), postoperative radiation therapy with chemotherapy seems to prolong the tumor-free interval in stages B2 and C when compared to surgery alone. Nonspecific immunotherapy does not appear to improve surgical results either in terms of local recurrences or survival. Some clinical trials suggest that systemic polychemotherapy benefit subgroups of patients with colorectal cancer. Toxicity is still very high, however; 5-FU is the more active and safe single agent but, due to the low response rate, it appears essential to identify new, more active drugs. Particular attention has been focused recently on prophylactic infusion chemotherapy of the liver, and clinical trials are now being made by several groups, including the EORTC. Preliminary results seem to show a reduced incidence of liver metastases in patients infused with 5-FU after radical surgery. Adjuvant therapy in colorectal cancer patients undergoing radical surgery has so far given encouraging results. Future results are awaited with optimism, but they must be achieved through prospective clinical trials conducted by well-organized cooperative groups.

Until now advanced gastric cancer has been generally treated with the FAM chemotherapy protocol. Due to the relatively low response rates with this protocol we decided to start a randomized prospective phase II trial comparing the FAM with the FAMTX protocol. The primary aim of our trial was to compare the toxicity in both protocols. The FAMTX protocol has been demonstrated to be fully comparable with the toxicity of the FAM protocol. The trial has been extended to a phase III study. With respect to response rates and survival times it is too early for evaluation.

The distribution pattern of muscarinic receptors in N1E 115 mouse neuroblastoma cells after linear and non-linear gradient centrifugation was investigated. In untreated cells, at least two forms of the receptors, with different densities, were found.

The purpose of this systematic study was to provide an up to date and reliable quantitative summary of the relative benefits of various types of chemotherapy (non-platinum vs platinum, single-agent vs combination and carboplatin vs cisplatin) in the treatment of advanced ovarian cancer. Also, to investigate whether well-defined patient subgroups benefit more or less from cisplatin- or carboplatin-based therapy. Meta-analyses were based on updated individual patient data from all available randomized controlled trials (published and unpublished), including 37 trials, 5667 patients and 4664 deaths. The results suggest that platinum-based chemotherapy is better than non-platinum therapy, show a trend in favour of platinum combinations over single-agent platinum, and suggest that cisplatin and carboplatin are equally effective. There is no good evidence that cisplatin is more or less effective than carboplatin in any particular subgroup of patients.

Mature explants of mouse spinal cord and ganglia have been infected with Herpes virus hominis type 2. After 48 h, a high titer of virus was detected in the explant and typical herpes-like particles were seen by electron microscopy. They were more numerous in sensory neurons and Schwann cells than in the CNS possibly because of a more rapid propagation through the extracellular space in spinal ganglia. In the infected nuclei, besides the naked particles, numerous tubular formations were found, apparently resulting from virus infection and specific for herpes type 2. Their dimensions and fine structure are illustrated and compared to other microtubular formations.

Les syndromes lipodystrophiques sont caractérisés par une lipoatrophie généralisée ou partielle responsable d’un morphotype stigmatisant. Le traitement par leptine recombinante (une injection sous-cutanée quotidienne) améliore les complications métaboliques associées à l’hypoleptinémie (insulino-résistance, diabète, hypertriglycéridémie). L’effet sur la qualité de vie n’a pas été évalué.

L’insulino-résistance est associée à une augmentation adaptative de la sécrétion d’insuline et de la masse des cellules bêta. Récemment, il a été montré chez l’homme que cette augmentation était due à la différenciation de cellules bêta à partir de précurseurs, ou néogénèse, dont les signaux inducteurs sont encore inconnus. Notre étude a pour but de caractériser l’adaptation des cellules bêta dans un modèle murin d’insulino-résistance sévère.

L’identification de nouvelles adipokines faisant le lien entre obésité et insulino-résistance représente un enjeu majeur. Nous avons montré récemment que NOV/CCN3, une protéine matricellulaire multifonctionnelle est synthétisée et sécrétée par le tissu adipeux, avec des taux plasmatiques corrélés avec l’IMC. NOV a été antérieurement impliquée dans les processus de réparation tissulaire, la fibrose, les maladies inflammatoires et le cancer. Cependant, son rôle dans l’homéostasie énergétique restait inconnu. Nous avons ainsi étudié le phénotype de souris NOV-/- soumises à un régime normal ou hyperlipidique (HFD). De façon très nette, le poids des souris NOV-/- est nettement plus faible que celui des souris témoins, mais seulement en HFD. Ceci est lié à une réduction de masse grasse, avec des adipocytes plus petits, et une plus forte expression des acteurs de la thermogenèse au sein des dépôts adipeux blancs, et en particulier d’UCP1. Ceci va de pair avec une dépense énergétique accrue des souris invalidées. Les souris NOV-/- en HFD améliorent par ailleurs leur tolérance au glucose et leur sensibilité à l’insuline. De façon remarquable, les animaux NOV-/- ont un changement de phénotype macrophagique (M1 vers M2) et lymphocytaire dans leur tissu adipeux épididymaire, associé à une chute d’expression des cytokines pro-inflammatoires. Les animaux invalidés ont également une amélioration de leur signalisation insulinique in vivo. L’ensemble de ces données montre que NOV est une nouvelle adipokine impliquée dans la résistance à l’insuline associée à l’obésité.

À fortes doses, les glucocorticoïdes sont à l’origine d’effets secondaires tels qu’un diabète cortico-induit et une lipodystrophie caractérisée par une hypertrophie du tissu adipeux viscéral (TAV) aux dépens du TA sous-cutané. Les GC exercent des actions pléiotropes sur la biologie du TA, cependant, les mécanismes moléculaires des effets différentiels des GC ne sont pas encore élucidés. Nous formulons l’hypothèse que le récepteur aux glucocorticoïdes (GR) des tissus adipeux participe au phénotype de lipodystrophie et au développement d’une résistance à l’insuline.

L’inflammation de bas grade caractéristique de l’obésité joue un rôle important dans le développement de la résistance à l’insuline. Les glucocorticoïdes possèdent une activité anti-inflammatoire puissante mais provoquent fréquemment une obésité ainsi qu’une insulino-résistance. Notre travail visait à caractériser la population macrophagique au sein des différents tissus adipeux après traitement par les corticoïdes et à étudier l’impact de l’infiltration des macrophages sur la sensibilité à l’insuline.

Les glucocorticoïdes (GC) font partie des médicaments les plus prescrits en raison de leurs propriétés anti-inflammatoires et immunosuppressives. À fortes doses, ils sont responsables d’effets secondaires tels qu’un diabète cortico-induit et une lipodystrophie caractérisée par une hypertrophie du tissu adipeux viscéral aux dépens du tissu adipeux sous-cutané. Les GC exercent des actions pléïotropes sur la physiologie et la pathologie du tissu adipeux, cependant, les mécanismes moléculaires des effets différentiels des GC ne sont pas encore élucidés. Nous formulons l’hypothèse que le phénotype de lipodystophie et d’insulino-résistance induit par les GC implique de façon intrinsèque le GR adipocytaire.

L’efficacité et la tolérance sont les deux aspects principaux évalués lors d’un essai randomisé évaluant une nouvelle thérapeutique. Nous proposons d’utiliser la méthode de comparaison par paire généralisée pour évaluer la balance bénéfice-risque de l’erlotinib associé à la gemcitabine dans le traitement de l’adénocarcinome du pancréas avancé sur les données de l’essai PA-3 du NCIC.

la physiopathologie de l’insulino-résistance associée à l’obésité reste encore mal comprise. L’identification de nouvelles adipokines impliquées dans ce phénomène reste ainsi un enjeu essentiel. Nos résultats récents suggèrent que NOV, une protéine matricielle multi-fonctionnelle, est synthétisée et sécrétée par le tissu adipeux, avec des taux plasmatiques corrélés à l’IMC et à la masse grasse, et réduits après chirurgie bariatrique (Pakradouni et al., PlosOne 2013). NOV est impliquée dans les processus de cicatrisation, fibrose, inflammation, et tumorigenèse. Cependant, son rôle dans le tissu adipeux et l’homéostasie énergétique demeure inconnu.

Une exposition prolongée aux glucocorticoïdes provoque des effets secondaires graves tels que prise de poids, lipodystrophie, et insulinorésistance. L’objectif était de préciser les mécanismes par lesquels les glucocorticoïdes perturbent le métabolisme glucidique.

Les antipsychotiques induisent des effets secondaires métaboliques majeurs, notamment obésogènes et diabétogènes. Bien qu’ils soient prescrits chez la femme enceinte et passent la barrière placentaire, leur conséquences métaboliques sur la descendance sont actuellement inconnues.