MGMT promoter methylation in malignant gliomas: ready for personalized medicine?

The DNA repair enzyme O(6)-methylguanine-DNA methyltransferase (MGMT) antagonizes the genotoxic effects of alkylating agents. MGMT promoter methylation is the key mechanism of MGMT gene silencing and predicts a favorable outcome in patients with glioblastoma who are exposed to alkylating agent chemotherapy. This biomarker is on the verge of entering clinical decision-making and is currently used to stratify or even select glioblastoma patients for clinical trials. In other subtypes of glioma, such as anaplastic gliomas, the relevance of MGMT promoter methylation might extend beyond the prediction of chemosensitivity, and could reflect a distinct molecular profile. Here, we review the most commonly used assays for evaluation of MGMT status, outline the prerequisites for standardized tests, and evaluate reasons for difficulties in reproducibility. We critically discuss the prognostic and predictive value of MGMT silencing, reviewing trials in which patients with different types of glioma were treated with various chemotherapy schedules, either up-front or at recurrence. Standardization of MGMT testing requires comparison of different technologies across laboratories and prospectively validated cut-off values for prognostic or predictive effects. Moreover, future clinical trials will need to determine, for each subtype of glioma, the degree to which MGMT promoter methylation is predictive or prognostic, and whether testing should become routine clinical practice.

Associations between psychiatric disorders and cardiovascular risk factors

Bien que de nombreuses études suggèrent des liens entre les troubles psychiatriques et les maladies cardiovasculaires (MCV), peu ont utilisé des investigations somatique, biologique et psychiatrique adéquates. Pour déterminer les potentiels mécanismes impliqués dans ces associations, plusieurs études ont investigué le lien entre les troubles psychiatriques et les facteurs de risque des maladies cardiovasculaires (FRCV) (surpoids, diabète, dyslipidémie, hypertension artérielle, inactivité, consommation de cigarettes). De plus, des biomarqueurs (régulateurs du métabolisme, marqueurs hépatiques et inflammatoires) pouvant être associés à la fois aux troubles psychiatriques et aux FRCV ont été étudiés mais avec des résultats contradictoires. Basée sur un large échantillon de la population générale de la Ville de Lausanne et des investigations somatique et psychiatrique adéquates, cette thèse comporte deux articles: le premier étudie l'association entre les troubles psychiatriques majeurs et les FRCV; le second établit les liens entre certains biomarqueurs et le développement du diabète de type 2. Appliquant une méthodologie rigoureuse sur un échantillon de 3716 sujets de la population lausannoise âgés de 35 à 66 ans, les résultats du premier article ont montré que 1) le sous-type atypique de la dépression était associé à une augmentation du risque de souffrir de plusieurs FRCV (surpoids, diabète et syndrome métabolique), contrairement à d'autres sous-types de dépression, 2) les problèmes d'alcool étaient associés à un risque accru de souffrir de diabète et de dyslipidémie, 3) presque tous les troubles psychiatriques étaient associés à une consommation régulière de cigarettes. Quant au deuxième article, parmi les différents biomarqueurs testés, seul un niveau bas d'adiponectine (une hormone produite par le tissu adipeux qui affecte la sensibilité à l'insuline) était associé à un risque accru de souffrir de diabète par la suite. Ces résultats soulignent la nécessité pour les spécialistes de distinguer les sous-types de dépression pour le risque cardiovasculaire et de donner une attention particulière au sous-type atypique. Un problème d'alcool comorbide pourrait accroître le risque cardiovasculaire. De plus, des efforts pour diminuer la cigarette chez les sujets souffrant de troubles psychiatriques seraient une mesure préventive importante contre le développement des MCV. Le rôle de l'adiponectine dans l'association entre les troubles psychiatriques et les FRCV restant incertain, une prochaine analyse devrait déterminer le lien entre ce biomarqueur et la dépression atypique. - Despite the fact that several studies have highlighted associations between psychiatric disorders and cardiovascular diseases (CVD), few have used adequate somatic, biological and psychiatric measures. To determine potential mechanisms implicated in these associations, several studies have assessed the relationship between psychiatric disorders and cardiovascular risk factors (CVRFs), such as overweight, diabetes, dyslipidemia, hypertension, physical inactivity and smoking. Moreover, biomarkers such as metabolic regulators, hepatic and inflammatory markers, which could be associated with both psychiatric disorders and CVRFs, have been studied yielding contradictory results. Based on a population-based sample from the city of Lausanne and using adequate somatic and psychiatric investigations, this dissertation encompasses two articles: the first studies the associations between major psychiatric disorders established for lifetime and CVRFs; the second studies the associations between certain biomarkers and the development of type 2 diabetes. Using standardized contemporary methodology in a sample composed of 3716 individuals aged from 35 to 66 years, the first article revealed associations between 1) the atypical depression subtype and an increased risk of several CVRFs (overweight, diabetes and the metabolic syndrome) in contrast to other depression subtypes; 2) alcohol disorders and an increased risk of diabetes and dyslipidemia; 3) almost all psychiatric disorders and a lifetime history of regular cigarette smoking. The second article showed, among the various biomarkers tested, that only lower levels of adiponectin (a hormone produced by adiposity which affects sensitivity to insulin) were associated with an increased risk of subsequent type 2 diabetes. Our results highlight the need for specialists to subtype depression when studying the cardiovascular risk and to pay particular attention to the atypical subtype. A comorbid alcohol misuse may further increase the cardiovascular risk. Moreover, efforts to diminish smoking in subjects suffering from psychiatric disorders could be an important tool for preventing subsequent CVD. The role of adiponectin in the association between psychiatric disorders and CVRFs should still be elucidated, and future analyses should focus in particular on the relationship between this biomarker and atypical depression.

HIV-1 co/super-infection in intravenous drug users.

BACKGROUND: The frequency of HIV-1 co/super-infection is unknown despite their implications for public health and vaccine development. This issue was addressed during an epidemic of both CRF11 and B subtype among intravenous drug users (IVDUs). METHODS: Bulk sequencing of reverse transcriptase, protease and C2V3 regions and subtype-specific nested polymerase chain reaction (PCR) in plasma and proviral DNA were performed using baseline and follow-up samples collected in recently infected IVDUs between 1998-2002 and in IVDUs with chronic infection living in the same area and presenting an unexpected rise of viremia (> 1 log10). RESULTS: In 58 recently infected patients, three B/CRF-11 co-infections, 25 B, 28 CRF-11 and two other subtypes were detected at baseline. In the three co-infected patients, both CRF-11 and B were detected in plasma and proviral DNA and persisted during follow-up. B- and CFR-11-specific PCR performed on follow-up samples of 40 of 58 recently infected patients (median follow-up, 14.5 months) revealed a transient B super-infection in a patient initially infected by CRF-11. Five of 156 chronic IVDUs (total follow-up: 346 years) had an unexpected rise of viremia. In two of them, aviremic without treatment for years after an initial B infection, a symptomatic CRF-11 super-infection occurred and was associated with high viral load and a fall of CD4 cell count. CONCLUSIONS: In recently infected IVDUs, co-infection B/CRF-11 is relatively frequent (5%). In chronically infected IVDUs super-infection may be transient and may occur in patients controlling efficiently HIV infection by the initial strain.

Intrinsically photosensitive retinal ganglion cells: classification, function and clinical implications.

PURPOSE OF REVIEW: The discovery of a new class of intrinsically photosensitive retinal ganglion cells (ipRGCs) revealed their superior role for various nonvisual biological functions, including the pupil light reflex, and circadian photoentrainment. RECENT FINDINGS: Recent works have identified and characterized several anatomically and functionally distinct ipRGC subtypes and have added strong new evidence for the accessory role of ipRGCs in the visual system in humans. SUMMARY: This review summarizes current concepts related to ipRGC morphology, central connections and behavioural functions and highlights recent studies having clinical relevance to ipRGCs. Clinical implications of the melanopsin system are widespread, particularly as related to chronobiology.

Gene deletion of dopamine beta-hydroxylase and alpha1-adrenoceptors demonstrates involvement of catecholamines in vascular remodeling.

In vitro studies have shown that stimulation of alpha1-adrenoceptors (ARs) directly induces proliferation, hypertrophy, and migration of arterial smooth muscle cells and adventitial fibroblasts. In vivo studies confirmed these findings and showed that catecholamine trophic activity becomes excessive after experimental balloon injury and contributes to neointimal growth, adventitial thickening, and lumen loss. However, past studies have been limited by selectivity of pharmacological agents. The aim of this study, in which mice devoid of norepinephrine and epinephrine synthesis [dopamine beta-hydroxylase (DBH-/-)] or deficient in alpha1-AR subtypes expressed in murine carotid (alpha1B-AR-/- and alpha1D-AR-/-) were used, was to test the hypothesis that catecholamines contribute to wall hypertrophy after injury. At 3 wk after injury of wild-type mice, lumen area and carotid circumference increased significantly, and hypertrophy of media and adventitia was in excess of that needed to restore circumferential wall stress to normal. In DBH-/- and alpha1B-AR-/- mice, increases in lumen area, circumference, and hypertrophy of the media and adventitia were reduced by 50-91%, resulting in restoration of wall tension to nearly normal (DBH-/-) or normal (alpha1B-AR-/-). In contrast, in alpha1D-AR-/- mice, increases in lumen area, circumference, and wall hypertrophy were unaffected and wall thickening remained in excess of that required to return tension to normal. When examined 5 days after injury, proliferation and leukocyte infiltration were inhibited in DBH-/- mice. These studies suggest that the trophic effects of catecholamines are mediated primarily by alpha1B-ARs in mouse carotid and contribute to hypertrophic growth after vascular injury.

Factors associated with comorbidity patterns in full and partial PTSD: Findings from the PsyCoLaus study.

Subtypes of comorbid conditions and their associated trauma and clinical characteristics in full and partial PTSD were examined. Data from 289 subjects from the general population that met criteria for full or partial PTSD were analyzed. Latent class analyses (LCA) were performed to derive homogeneous patterns of DSM-IV Axis-I disorders and anti-social personality comorbid to PTSD. Logistic regression models were conducted to characterize these classes by trauma-related and clinical features. The LCA revealed three classes: (1) low comorbidity; (2) high comorbidity with primarily substance-related disorders and a higher proportion of males; and (3) more severe PTSD-symptomatology and higher comorbid anxiety disorders and depression, almost entirely represented by females. Exposure to sexual abuse was more likely in the substance-dependent class and contributed strongly to the distinction between classes. Affective disorders tended to precede the onset of PTSD in the substance-dependent class, whereas phobias were more likely to follow PTSD in the depressed-anxious class. Posttrauma onset of alcohol use disorders in the substance dependent class confirmed the self-medication hypothesis. The three classes of comorbidity and their sequence of onset with PTSD suggest different mechanisms involved in their development. Our findings suggest that PTSD-related comorbidity subtypes also apply to individuals with partial PTSD.

Fatty acids, eicosanoids, and hypolipidemic agents identified as ligands of peroxisome proliferator-activated receptors by coactivator-dependent receptor ligand assay.

Peroxisome proliferator-activated receptors (PPARs) are nuclear hormone receptors controlling the expression of genes involved in lipid homeostasis. PPARs activate gene transcription in response to a variety of compounds including hypolipidemic drugs as well as natural fatty acids. From the plethora of PPAR activators, Scatchard analysis of receptor-ligand interactions has thus far identified only four ligands. These are the chemotactic agent leukotriene B4 and the hypolipidemic drug Wy 14,643 for the alpha-subtype and a prostaglandin J2 metabolite and synthetic antidiabetic thiazolidinediones for the gamma-subtype. Based on the hypothesis that ligand binding to PPAR would induce interactions of the receptor with transcriptional coactivators, we have developed a novel ligand sensor assay, termed coactivator-dependent receptor ligand assay (CARLA). With CARLA we have screened several natural and synthetic candidate ligands and have identified naturally occurring fatty acids and metabolites as well as hypolipidemic drugs as bona fide ligands of the three PPAR subtypes from Xenopus laevis. Our results suggest that PPARs, by their ability to interact with a number of structurally diverse compounds, have acquired unique ligand-binding properties among the superfamily of nuclear receptors that are compatible with their biological activity.

Psychotherapeutic case conceptualization using plan analysis for bipolar affective disorder.

Valid individualized case conceptualization methodologies, such as plan analysis, are rarely used for the psychotherapeutic treatment conceptualization and planning of bipolar affective disorder (BD), even if data do exist showing that psychotherapy interventions might be enhanced by applying such analyses for treatment planning for several groups of patients. We applied plan analysis as a research tool (Caspar, 1995) to N=30 inpatients presenting BD, who were interviewed twice. Our study aimed at producing a prototypical plan structure encompassing the most relevant data from the 30 individual case conceptualizations. Special focus was given to links with emotions and coping plans. Inter-rater reliability of these plan analyses was considered sufficient. Results suggest the presence of two subtypes based on plananalytic principles: emotion control and relationship control, along with a mixed form. These subtypes are discussed with regard to inherent plananalytic conflicts, specific emotions and coping plans, as well as symptom level and type. Finally, conclusions are drawn for enhancing psychotherapeutic practice with BD patients, based on the motive-oriented therapeutic relationship.

ITMIG consensus statement on the use of the WHO histological classification of thymoma and thymic carcinoma: refined definitions, histological criteria, and reporting.

INTRODUCTION: The 2004 version of the World Health Organization classification subdivides thymic epithelial tumors into A, AB, B1, B2, and B3 (and rare other) thymomas and thymic carcinomas (TC). Due to a morphological continuum between some thymoma subtypes and some morphological overlap between thymomas and TC, a variable proportion of cases may pose problems in classification, contributing to the poor interobserver reproducibility in some studies. METHODS: To overcome this problem, hematoxylin-eosin-stained and immunohistochemically processed sections of prototypic, "borderland," and "combined" thymomas and TC (n = 72) were studied by 18 pathologists at an international consensus slide workshop supported by the International Thymic Malignancy Interest Group. RESULTS: Consensus was achieved on refined criteria for decision making at the A/AB borderland, the distinction between B1, B2, and B3 thymomas and the separation of B3 thymomas from TCs. "Atypical type A thymoma" is tentatively proposed as a new type A thymoma variant. New reporting strategies for tumors with more than one histological pattern are proposed. CONCLUSION: These guidelines can set the stage for reproducibility studies and the design of a clinically meaningful grading system for thymic epithelial tumors.

AUTOIMMUNE PANCREATITIS

Autoimmune Pancreatitis (AIP) is a new nosological entity that was first reported by Sarles et al. in 1961 and then named by Yoshida et al. in 1995 in Japan. It was then ignored by many Western researchers and now, in the last decade; it appears to have been recognized worldwide. AIP is a distinct form a chronic pancreatitis with an immune mediated fibroinflammatory process that has unique histopathologic features that makes it distinguishable from other forms of pancreatitis. Moreover, AIP is the only type of pancreatitis that responds to steroid administration. The Honolulu consensus document that has recently been published by Chari et al. described the histopathologic and clinical subtypes of AIP. Indeed, it appears that there are two forms of AIP, with different prevalence in Europe and Asia and distinct clinical profiles. The first subtype, the most common type in Asia, has recently been named Lymphoplasmocytic sclerosing pancreatitis (LPSP) or type I AIP because of its histological features and its association with elevated IgG serum levels and various autoantibodies. The second one is called idiopathic duct centric pancreatitis, IDCP, or type II AIP, that barely exists in Japan, but more accounted in Caucasian people. IDCP is recognized by its particular histology that is a granulocytic epithelial lesion (GEL) which makes some people call it AIP with GEL. Still nowadays, the diagnosis of AIP is a challenge. AIP can only be definitively diagnosed by histological examination. The main differential diagnosis of AIP is, except chronic pancreatitis, pancreatic cancer. That explains why there are still some unnecessary resections. Several groups have proposed diagnostic criteria for AIP as in Japan, Korea, Germany, Italy and the United States. Thus, it is important to find an international consensus. Above all, it is important to find new criteria as specific markers in the serum and the pancreatic tissues, for example using proteomics, to be able to diagnosis both types of AIP, and distinguish AIP from pancreatic cancer in order to avoid surgical resection in patients with AIP. The aim of this project is to review all relevant studies about AIP and to document all the available diagnostic tools.

Mental disorders in offspring of parents with bipolar and major depressive disorders.

OBJECTIVES: There is limited information on the specificity of associations between parental bipolar disorder (BPD) and major depressive disorder (MDD) and the risk of psychopathology in offspring. The chief aim of the present study was to investigate the association between mood disorder subtypes in the two parents and mental disorders in the offspring. METHODS: A total of 376 offspring (aged 6.0-17.9 years; mean=11.5years) of 72 patients with BPD (139 offspring), 56 patients with MDD (110 offspring), and 66 controls (127 offspring) participated in a family study conducted in two university hospital centers in Switzerland. Probands, offspring, and biological co-parents were interviewed by psychologists blind to proband diagnoses, using a semi-structured diagnostic interview. RESULTS: Rates of mood and anxiety disorders were elevated among offspring of BPD probands (34.5% any mood; 42.5% any anxiety) and MDD probands (25.5% any mood; 44.6% any anxiety) as compared to those of controls (12.6% any mood; 22.8% any anxiety). Moreover, recurrent MDD was more frequent among offspring of BPD probands (7.9%) than those of controls (1.6%). Parental concordance for bipolar spectrum disorders was associated with a further elevation in the rates of mood disorders in offspring (64.3% both parents versus 27.2% one parent). CONCLUSIONS:   These findings provide unique information on the broad manifestations of parental mood disorders in their offspring. The earlier onset and increased risk of recurrent MDD in the offspring of parents with BPD compared to those of controls suggests that the episodicity characterizing BPD may emerge in childhood and adolescence.

Patterns and trends in esophageal cancer mortality and incidence in Europe (1980-2011) and predictions to 2015

BACKGROUND: Over the last few decades, esophageal cancer incidence and mortality trends varied substantially across Europe, with important differences between sexes and the two main histological subtypes, squamous cell carcinoma (ESCC) and adenocarcinoma (EAC). PATIENTS AND METHODS: To monitor recent esophageal cancer mortality trends and to compute short-term predictions in the European Union (EU) and selected European countries, we analyzed data provided by the World Health Organization (WHO) for 1980-2011. We also analyzed incidence trends and relative weights of ESCC and EAC across Europe using data from Cancer Incidence in Five Continents. RESULTS: Long-term decreasing trends were observed for male esophageal cancer mortality in several southern and western European countries, whereas in central Europe mortality increased until the mid-1990s and started to stabilize or decline over the last years. In some eastern and northern countries, the rates were still increasing. Mortality among European women remained comparatively low and showed stable or decreasing trends in most countries. Between 2000-2004 and 2005-2009, esophageal cancer mortality declined by 7% (from 5.34 to 4.99/100 000) in EU men, and by 3% (from 1.12 to 1.09/100 000) in EU women. Predictions to 2015 show persistent declines in mortality rates for men in the EU overall, and stable rates for EU women, with rates for 2015 of 4.5/100 000 men (about 22 300 deaths) and 1.1/100 000 women (about 7400 deaths). In northern Europe, EAC is now the predominant histological type among men, while for European women ESCC is more common and corresponding rates are still increasing in several countries. CONCLUSION(S): The observed trends reflect the variations in alcohol drinking, tobacco smoking and overweight across European countries.

Radioimmunotherapy confers long-term survival to lymphoma patients with acceptable toxicity: registry analysis by the international radioimmunotherapy network.

The Radioimmunotherapy Network (RIT-N) is a Web-based, international registry collecting long-term observational data about radioimmunotherapy-treated patients with malignant lymphoma outside randomized clinical studies. The RIT-N collects unbiased data on treatment indications, disease stages, patients' conditions, lymphoma subtypes, and hematologic side effects of radioimmunotherapy treatment. Methods: RIT-N is located at the University of Gottingen, Germany, and collected data from 14 countries. Data were entered by investigators into a Web-based central database managed by an independent clinical research organization. Results: Patients (1,075) were enrolled from December 2006 until November 2009, and 467 patients with an observation time of at least 12 mo were included in the following analysis. Diagnoses were as follows: 58% follicular lymphoma and 42% other B-cell lymphomas. The mean overall survival was 28 mo for follicular lymphoma and 26 mo for other lymphoma subtypes. Hematotoxicity was mild for hemoglobin (World Health Organization grade II), with a median nadir of 10 g/dL, but severe (World Health Organization grade III) for platelets and leukocytes, with a median nadir of 7,000/mu L and 2.2/mu L, respectively. Conclusion: Clinical usage of radioimmunotherapy differs from the labeled indications and can be assessed by this registry, enabling analyses of outcome and toxicity data beyond clinical trials. This analysis proves that radioimmunotherapy in follicular lymphoma and other lymphoma subtypes is a safe and efficient treatment option.

Performance evaluation of a new fourth-generation HIV combination antigen-antibody assay.

Education and diagnostic tests capable of early detection represent our most effective means of preventing transmission of human immunodeficiency virus (HIV). The importance of early detection is underlined by studies demonstrating increased life expectancy following early initiation of antiviral treatment. The Elecsys(®) HIV combi PT assay is a fourth-generation antigen-antibody combination assay developed to allow earlier detection of seroconversion, and to have increased sensitivity and improved specificity. We aimed to determine how early the assay could detect infection compared with existing assays; whether all HIV variants could be detected; and the assay's specificity using samples from blood donors, routine specimens, and patients with potential cross-reacting factors. Samples were identified as positive by the Elecsys(®) assay 4.9 days after a positive polymerase chain reaction result (as determined by the panel supplier), which was earlier than the 5.3-7.1 days observed with comparators. The analytical sensitivity of the Elecsys(®) HIV combi PT assay for the HIV-1 p24 antigen was 1.05 IU/mL, which compares favorably with the comparator assays. In addition, the Elecsys(®) assay identified all screened HIV subtypes and displayed greater sensitivity to HIV-2 homologous antigen and antibodies to HIV-1 E and O and HIV-2 than the other assays. Overall, the specificity of the Elecsys(®) assay was 99.88 % using samples from blood donors and 99.81 % when analyzing unselected samples. Potential cross-reacting factors did not interfere with assay performance. The Elecsys(®) HIV combi PT assay is a sensitive and specific assay that has been granted the CE mark according to Directive 2009/886/EC.

Cardiovascular influences of alpha1b-adrenergic receptor defect in mice.

BACKGROUND: The alpha1-adrenergic receptors (alpha1-ARs) play a key role in cardiovascular homeostasis. However, the functional role of alpha1-AR subtypes in vivo is still unclear. The aim of this study was to evaluate the cardiovascular influences of alpha1b-AR. METHODS AND RESULTS: In transgenic mice lacking alpha1-AR (KO) and their wild-type controls (WT), we evaluated blood pressure profile and cardiovascular remodeling induced by the chronic administration (18 days via osmotic pumps) of norepinephrine, angiotensin II, and subpressor doses of phenylephrine. Our results indicate that norepinephrine induced an increase in blood pressure levels only in WT mice. In contrast, the hypertensive state induced by angiotensin II was comparable between WT and KO mice. Phenylephrine did not modify blood pressure levels in either WT or KO mice. The cardiac hypertrophy and eutrophic vascular remodeling evoked by norepinephrine was observed only in WT mice, and this effect was independent of the hypertensive state because it was similar to that observed during subpressor phenylephrine infusion. Finally, the cardiac hypertrophy induced by thoracic aortic constriction was comparable between WT and KO mice. CONCLUSIONS: Our data demonstrate that the lack of alpha1b-AR protects from the chronic increase of arterial blood pressure induced by norepinephrine and concomitantly prevents cardiovascular remodeling evoked by adrenergic activation independently of blood pressure levels.