Systems biology in the development of HIV vaccines.

PURPOSE OF REVIEW: In the present review, we will provide the scientific rationale for applying systems biology to the development of vaccines and particularly HIV vaccines, the predictive power of systems biology on the vaccine immunological profile, the correlation between systems biology and the immunological functional profiles of different candidate vaccines, and the value of systems biology in the selection process of identifying the best-in-class candidate vaccines and in the decision process to move into in-vivo evaluation in clinical trials. RECENT FINDINGS: Systems biology has been recently applied to the characterization of the protective yellow fever vaccine YF17D and of seasonal flu vaccines. This has been instrumental in the identification of the components of the immune response that need to be stimulated by the vaccine in order to generate protective immunity. It is worth noting that a systems biology approach is currently being performed to identify correlates of immune protection of the RV144 Thai vaccine, the only known vaccine that showed modest protection against HIV reacquisition. SUMMARY: Systems biology represents a novel and powerful approach to predict the vaccine immunological profile, to identify the protective components of the immune response, and to help in the selection process of the best-in-class vaccines to move into clinical development.

Place de l'aspirine en prévention primaire des maladies cardiovasculaires [The role of aspirin in the primary prevention of cardiovascular disease]

For persons without cardiovascular disease, the benefit of aspirin in primary prevention has been controversial until the recent publication of several major randomized controlled trials. Since then, several medical societies recommend that clinicians discuss aspirin prevention with adults at high cardiovascular risk. Patients with low cardiovascular risk are unlikely to benefit from aspirin, as potential harms (hemorrhagic strokes, gastrointestinal bleedings) may outweigh benefits. Aspirin should be recommended in primary prevention only in patients with a 10-year cardiovascular risk > or = 10% or in diabetic patients aged > or = 40 years with a concomitant cardiovascular risk factor, after assessing contraindications for aspirin and individual's preferences for the risks and benefits associated with aspirin.

Sepsis: time to reconsider the concept.

OBJECTIVE: To discuss the difficulty in using the concept of sepsis for clinical trials and propose new ways for designing future trials for severe infections. DESIGN: Short position statement. METHODS AND MAIN RESEARCH: Using a thorough evaluation of the recent literature in the field of severe sepsis and septic shock, the authors challenge the concept of sepsis as used in the past two decades and propose new ideas for designing future trials in this setting. The two main proposals are first to use a systematic assessment of the targeted inflammatory mediators when the study intends to counteract or replace those mediators (e.g., anti-tumor necrosis factor-alpha, activated protein C) and, second, to select more homogeneous populations, coming back to "precise infectious diseases," such as severe community-acquired pneumonia, severe peritonitis, or meningitis. CONCLUSIONS: The concept of sepsis has been useful to help clinicians to suspect and detect severe infections. Due to a considerable heterogeneity in the patients and type of infections included in the trials performed in the last two decades, it has not been useful in demonstrating the efficacy of new compounds. The authors propose a dramatic change in the design of future trials dealing with severe infections.

Clinical management and burden of bipolar disorder: a multinational longitudinal study (WAVE-bd Study)

BACKGROUND: Studies in bipolar disorder (BD) to date are limited in their ability to provide a whole-disease perspective--their scope has generally been confined to a single disease phase and/or a specific treatment. Moreover, most clinical trials have focused on the manic phase of disease, and not on depression, which is associated with the greatest disease burden. There are few longitudinal studies covering both types of patients with BD (I and II) and the whole course of the disease, regardless of patients' symptomatology. Therefore, the Wide AmbispectiVE study of the clinical management and burden of Bipolar Disorder (WAVE-bd) (NCT01062607) aims to provide reliable information on the management of patients with BD in daily clinical practice. It also seeks to determine factors influencing clinical outcomes and resource use in relation to the management of BD. METHODS: WAVE-bd is a multinational, multicentre, non-interventional, longitudinal study. Approximately 3000 patients diagnosed with BD type I or II with at least one mood event in the preceding 12 months were recruited at centres in Austria, Belgium, Brazil, France, Germany, Portugal, Romania, Turkey, Ukraine and Venezuela. Site selection methodology aimed to provide a balanced cross-section of patients cared for by different types of providers of medical aid (e.g. academic hospitals, private practices) in each country. Target recruitment percentages were derived either from scientific publications or from expert panels in each participating country. The minimum follow-up period will be 12 months, with a maximum of 27 months, taking into account the retrospective and the prospective parts of the study. Data on demographics, diagnosis, medical history, clinical management, clinical and functional outcomes (CGI-BP and FAST scales), adherence to treatment (DAI-10 scale and Medication Possession Ratio), quality of life (EQ-5D scale), healthcare resources, and caregiver burden (BAS scale) will be collected. Descriptive analysis with common statistics will be performed. DISCUSSION: This study will provide detailed descriptions of the management of BD in different countries, particularly in terms of clinical outcomes and resources used. Thus, it should provide psychiatrists with reliable and up-to-date information about those factors associated with different management patterns of BD. TRIAL REGISTRATION NO: ClinicalTrials.gov: NCT01062607.

Vascular Integrins: Therapeutic and Imaging Targets of Tumor Angiogenesis

Cells, including endothelial cells, continuously sense their surrounding environment and rapidly adapt to changes in order to assure tissues and organs homeostasis. The extracellular matrix (ECM) provides a physical scaffold for cell positioning and represents an instructive interface allowing cells to communicate over short distances. Cell surface receptors of the integrin family emerged through evolution as essential mediators and integrators of ECM-dependent communication. In preclinical studies, pharmacological inhibition of vascular integrins suppressed angiogenesis and inhibited tumor progression. alpha(V)beta(3) and alpha(V)beta(5) were the first integrins targeted to suppress tumor angiogenesis. Subsequently, additional integrins, in particular alpha(1)beta(1), alpha(2)beta(1), alpha(5)beta(1), and alpha(6)beta(4), emerged as potential therapeutic targets. Integrin inhibitors are currently tested in clinical trials for their safety and antiangiogenic/antitumor activity. In this chapter, we review the role of integrins in angiogenesis and present recent advances in the use of integrin antagonists as potential therapeutics in cancer and discuss future perspectives.

Effectiveness of psychotropic medications in the maintenance phase of bipolar disorder:a meta-analysis of randomized controlled trials

The purpose of this meta-analysis was to examine the efficacy of maintenance treatments for bipolar disorder. Placebo-controlled or active comparator bipolar maintenance clinical trials of ≥6 months' duration with at least 15 patients/treatment group were identified using Medline, EMBASE, clinicaltrials.gov, and Cochrane databases (1993 to July 2010). The main outcome measure was relative risk for relapse for patients in remission. Twenty trials (5,364 patients) were identified. Overall, lithium and quetiapine were the most studied agents (eight and five trials, respectively). The majority of studies included patients who had previously responded to treatment for an acute episode. All interventions, with the exception of perphenazine+mood stabilizer, showed a relative risk for manic/mixed or depressive relapse below 1.0, although there was variation in the statistical significance of the findings vs. placebo. No monotherapy was associated with a significantly reduced risk for both manic/mixed and depressed relapse. Of the combination treatments, only quetiapine+lithium/divalproex, was associated with a significantly reduced risk vs. comparator (placebo+lithium/valproate) for relapse at both the manic/mixed and depressed poles of bipolar illness. Limitations for the analysis include differences in study durations and definitions of relapse. In conclusion, available maintenance therapies show considerable variation in efficacy. The efficacy of lithium and divalproex has been confirmed, but newer therapies, such as a number of atypical antipsychotics were also shown to be effective in bipolar disorder. Efficacy of all maintenance interventions needs to be balanced against the safety and tolerability profiles of individual agents.

Clinical effectiveness of direct class II restorations: a meta-analysis.

Purpose: More than five hundred million direct dental restorations are placed each year worldwide. In about 55% of the cases, resin composites or compomers are used, and in 45% amalgam. The longevity of posterior resin restorations is well documented. However, data on resin composites that are placed without enamel/dentin conditioning and resin composites placed with self-etching adhesive systems are missing. Material and Methods: The database SCOPUS was searched for clinical trials on posterior resin composites without restricting the search to the year of publication. The inclusion criteria were: (1) prospective clinical trial with at least 2 years of observation; (2) minimum number of restorations at last recall = 20; (3) report on dropout rate; (4) report of operative technique and materials used; (5) utilization of Ryge or modified Ryge evaluation criteria. For amalgam, only those studies were included that directly compared composite resin restorations with amalgam. For the statistical analysis, a linear mixed model was used with random effects to account for the heterogeneity between the studies. P-values under 0.05 were considered significant. Results: Of the 373 clinical trials, 59 studies met the inclusion criteria. In 70% of the studies, Class II and Class I restorations had been placed. The overall success rate of composite resin restorations was about 90% after 10 years, which was not different from that of amalgam. Restorations with compomers had a significantly lower longevity. The main reason for replacement were bulk fractures and caries adjacent to restorations. Both of these incidents were infrequent in most studies and accounted only for about 6% of all replaced restorations after 10 years. Restorations with macrofilled composites and compomer suffered significantly more loss of anatomical form than restorations with other types of material. Restorations that were placed without enamel acid etching and a dentin bonding agent showed significantly more marginal staining and detectable margins compared to those restorations placed using the enamel-etch or etch-and-rinse technique; restorations with self-etching systems were between the other groups. Restorations with compomer suffered significantly more chippings (repairable fracture) than restorations with other materials, which did not statistically differ among each other. Restorations that were placed with a rubber-dam showed significantly fewer material fractures that needed replacement, and this also had a significant effect on the overall longevity. Conclusion: Restorations with hybrid and microfilled composites that were placed with the enamel-etching technique and rubber-dam showed the best overall performance; the longevity of these restorations was similar to amalgam restorations. Compomer restorations, restorations placed with macrofilled composites, and resin restorations with no-etching or self-etching adhesives demonstrated significant shortcomings and shorter longevity.

Impact of 3 different short-term chemotherapy regimens on lymphocyte-depletion and reconstitution in melanoma patients.

Recent immunotherapy trials have shown that lymphodepletion induced by short-term chemotherapy favors subsequent expansion of adoptively transferred T cells, by homeostatic mechanisms. To take advantage of this effect, novel regimens are being developed with the aim to enhance tumor immunity and reduce treatment toxicity. We have designed a clinical phase I trial combining chemotherapy, reinfusion of PBMC containing Melan-A(MART-1)-specific T cells, and vaccination with Melan-A peptide in Incomplete Freund's Adjuvant. Treatment with Busulfan plus Fludarabine depleted lymphocytes only weakly. Cyclophosphamide (CTX) plus Fludarabine depleted lymphocytes more profoundly, with a maximal effect using high doses of CTX. It is interesting to note that, the degree of homeostatic T-cell proliferation correlated tightly with the extent of lymphodepletion. As compared with CD4 T cells, CD8 T cells showed higher susceptibility to chemotherapy, followed by more rapid homeostatic proliferation and recovery, resulting in strong inversions of CD4/CD8 ratios. Despite efficient homeostatic proliferation of total CD4 and CD8 T cells, the frequency of CD8 T cells specific for Melan-A and cancer-testis antigens remained relatively low. In contrast, EBV-specific T cells expanded and reached high numbers. We conclude that short-term chemotherapy promoted homeostatic lymphocyte proliferation depending on the intensity of lymphocyte depletion, however without preferential expansion of tumor antigen-specific T cells.

Available evidence and outcome of off-label use of rituximab in clinical practice

Purpose: To analyze the therapeutic indications for off-label use of rituximab, the available evidence for its use, the outcomes, and the cost. Methods: This was a retrospective analysis of patients treated with rituximab for off-label indications from January 2007 to December 2009 in two tertiary hospitals. Information on patient characteristics, medical conditions, and therapeutic responses was collected from medical records. Available evidence for the efficacy of rituximab in each condition was reviewed, and the cost of treatment was calculated. Results: A total of 101 cases of off-label rituximab use were analyzed. The median age of the patients involved was 53 [interquartile range (IQR) 37.568.0] years; 55.4 % were women. The indications for prescribing rituximab were primarily hematological diseases (46 %), systemic connective tissue disorders (27 %), and kidney diseases (20 %). Available evidence supporting rituximab treatment for these indications mainly came from individual cohort studies (53.5 % of cases) and case series (25.7 %). The short-term outcome (median 3 months, IQR 24 months) was a complete response in 38 % of cases and partial response in 32.6 %. The highest short-term responses were observed for systemic lupus erythematosus and membranous glomerulonephritis, and the lowest was for neuromyelitis optica, idiopathic thrombocytopenic purpura, and miscellaneous indications. Some response was maintained in long-term follow-up (median 23 months IQR 1230months) in 69.2%of patients showing a short-term response. Median cost per patient was 5,187.5 (IQR 5,187.57,781.3). Conclusions: In our study, off-label rituximab was mainly used for the treatment of hematological, kidney, and systemic connective tissue disorders, and the response among our patient cohort was variable depending on the specific disease. The level of evidence supporting the use of rituximab for these indications was low and the cost was very high. We conclude that more clinical trials on the off-label use of rituximab are needed, although these may be difficult to conduct in some rare diseases. Data from observational studies may provide useful information to assist prescribing in clinical practice.

Stratégies thérapeutiques pour le traitement des gliomes [Therapeutic strategies for the management of gliomas]

The management of gliomas remains challenging and requires a multidisciplinary approach that involves neurosurgeons, radiation therapists and oncologists. For patients with glioblastomas, progress has been made in recent years with the introduction of a combined modality treatment associating radiation therapy and concomitant chemotherapy with the novel alkylating agent temozolomide. This combination resulted in a significant prolongation of survival and increase in the number of patients with survival well beyond two years. Since then, interest in developing new agents in this disease has dramatically increased. In parallel, molecular markers, such as methylation status of MGMT or identification of the translocation of 1p and 19q in oligodendrogliomas have allowed to identify distinct subtypes with exquisite response to treatment or different prognosis. These developments have implications for the development of clinical trials of new potential drug treatments. In this article, we provide a review of the current management of low- and high-grade gliomas, including astrocytomas, oligodendrogliomas and glioblastomas and provide an outlook into future potential therapies.

Addressing current treatment challenges in Crohn's disease in real life: A physician's survey.

BACKGROUND: In recent years several trials have addressed treatment challenges in Crohn's disease. Clinical trials however, represent a very special situation. AIMS: To perform a cross-sectional survey among gastroenterologists on the current clinical real life therapeutic approach focussing on the use of biologics. METHODS: A survey including six main questions on clinical management of loss of response, diagnostic evaluation prior to major treatment changes, preference for anti-tumour necrosis factor (TNF) agent, (de-)escalation strategies as well as a basic section regarding personal information was sent by mail to all gastroenterologists in Switzerland (n=318). RESULTS: In total, 120 questionnaires were analysed (response rate 37.7%). 90% of gastroenterologists in Switzerland use a thiopurine as the first step-up strategy (anti-TNF alone 7.5%, combination 2.5%). To address loss of response, most physicians prefer shortening the interval of anti-TNF administration followed by dose increase, switching the biologic and adding a thiopurine. In case of prolonged remission on combination therapy, the thiopurine is stopped first (52.6%) after a mean treatment duration of 15.7 months (biologic first in 41.4%). CONCLUSIONS: Everyday clinical practice in Crohn's disease patients appears to be incongruent with clinical data derived from major trials. Studies investigating reasons underlying these discrepancies are of need to optimize and harmonize treatment.

Safety concerns about CCR5 as an antiviral target.

PURPOSE OF REVIEW: Clinical trials of CCR5 antagonists attest to their efficacy and tolerance in HIV treatment. However, there has been debate on their long-term safety because of the role of CCR5 in innate immunity. This review highlights gaps in our understanding of epidemiology of infections that are modulated by CCR5, in particular, in HIV-infected individuals. RECENT FINDINGS: In the mouse model, CCR5 has a role in the response against pathogens as diverse as Toxoplama gondii, West Nile virus, Mycobacterium tuberculosis, herpes simplex virus, Trypanosoma cruzi, Cryptococcus neoformans, Chlamydia trachomatis, Listeria, and plasmodia. In human cohorts, individuals carrying the defective CCR5Delta32 allele present an increased susceptibility to flavivirus (West Nile virus and tickborne encephalitis virus). The selective pressures that led to the spread of loss-of-function CCR5 mutations in humans (CCR5Delta32), and in mangabeys (CCR5Delta24) are not understood. SUMMARY: The recent availability of CCR5 antagonists has raised concern that genetic, biological, or chemical CCR5 knockout, although beneficial against some pathogens (i.e. HIV), could be deleterious for other processes implicated in pathogen response. The consequences of long-term pharmaceutical intervention on CCR5 should be carefully assessed through rigorous postmarketing surveillance.

Treatment of brain metastases from non-small cell lung cancer with whole-brain radiotherapy (wbrt) in combination with gefitinib (gft) or temozolomide (tmz): a randomized multicenter phase ii trial of the swiss group of clinical cancer research (sakk #70/03)

BACKGROUND: Patients with BM rarely survive .6 months and are commonly excluded from clinical trials. We aimed at improving outcome by exploring 2 combined modality regimens with at the time novel agents for which single-agent activity had been shown. METHODS: NSCLC patients with multiple BM were randomized to WBRT (10 × 3 Gy) and either GFT 250 mg p.o. daily or TMZ 75 mg/m2 p.o. daily ×21/28 days, starting on Day 1 of RT and to be continued until PD. Primary endpoint was overall survival, a Simon's optimal 2-stage design was based on assumptions for the 3-month survival rate. Cognitive functioning and quality of life were also evaluated. RESULTS: Fifty-nine patients (36 M, 23 F; 9 after prior chemo) were included. Median age was 61 years (range 46-82), WHO PS was 0 in 18 patients, 1 in 31 patients, and 2 in 10 patients. All but 1 patients had extracranial disease; 33 of 43 (TMZ) and 15 of 16 (GFT) had adenocarcinoma histology. GFT arm was closed early after stage 1 analysis when the prespecified 3-mo survival rate threshold (66%) was not reached, causes of death were not GFT related. Main causes of death were PD in the CNS 24%, systemic 41%, both 8%, and toxicity 10% [intestinal perforation (2 patients), pneumonia (2), pulmonary emboli (1), pneumonitis NOS (1), seizure (1)]. We summarize here other patients' characteristics for the 2 trial arms: TMZ (n ¼ 43)/GFT (n ¼ 16); median treatment duration: 1.6 /1.8 mo; Grade 3-4 toxicity: lymphopenia 5 patients (12%)/0; fatigue 8 patients (19%)/2 patients (13%). Survival data for TMZ/GFT arms: 3-month survival rate: 58.1% (95% CI 42.1-73)/62.5% (95% CI 35- 85); median OS: 4.9 months (95% CI 2.5-5.6)/6.3 months (95% CI 2.2- 14.6); median PFS: 1.8 months (95% CI 1.5-1.8)/1.8 (95% CI 1.1-3.9); median time to neurol. progr.: 8.0 months (95% CI 2.2-X)/4.8 (95% CI 3.9-10.5). In a model to predict survival time including the variables' age, PS, number of BM, global QL, total MMSE score, and subjective cognitive function, none of the variables accounted for a significant improvement in survival time. CONCLUSIONS: The combinations of WBRT with GFT or TMZ were feasible. However, in this unselected patient population, survival remains poor and a high rate of complication was observed. Four patients died as a result of high-dose corticosteroids. Preliminary evaluation of cognitive function andQL failed to show significant improvement. Indications and patient selection for palliative treatment should be revisited and careful monitoring and supportive care is required. Research and progress for this frequent clinical situation is urgently needed. Trial partly supported by AstraZeneca (Switzerland), Essex Chemie (Switzerland) and Swiss Federal Government.

Cellules gliales et douleur chronique: du laboratoire a l'espoir clinique [Glial cells and chronic pain: from the laboratory to clinical hope].

Despite their high prevalence, associated disability and seemingly rich pharmacopeia, the various forms of chronic pain remain frequently intractable. The past decade witnessed the rise of a concept stating that non-neuronal cells of the central nervous system, astrocytes and microglia, are crucial elements in pathological pain. This review gathers and summarizes the experimental data underpinning this theory in animal models and addresses their pertinence in humans. The potential opportunities and constraints of glial inhibition are exposed and compared to more moderate strategies of selective modulation. This therapeutic hope is particularly highlighted in our discussion of the first completed clinical trials employing glial inhibitors in the treatment of chronic pain.

Clinical implications in the shift of syndecan-1 expression from the cell membrane to the cytoplasm in bladder cancer

Background To determine the diagnostic and prognostic capability of urinary and tumoral syndecan-1 (SDC-1) levels in patients with cancer of the urinary bladder. Methods SDC-1 levels were quantitated by enzyme-linked immunosorbent assay (ELISA) in 308 subjects (102 cancer subjects and 206 non-cancer subjects) to assess its diagnostic capabilities in voided urine. The performance of SDC-1 was evaluated using the area under the curve of a receiver operating characteristic curve. In addition, immunohistochemical (IHC) staining assessed SDC-1 protein expression in 193 bladder specimens (185 cancer subjects and 8 non-cancer subjects). Outcomes were correlated to SDC-1 levels. Results Mean urinary levels of SDC-1 did not differ between the cancer subjects and the non-cancer subjects, however, the mean urinary levels of SDC-1 were reduced in high-grade compared to low-grade disease (p < 0.0001), and in muscle invasive bladder cancer (MIBC) compared to non-muscle invasive bladder cancer (NMIBC) (p = 0.005). Correspondingly, preliminary data note a shift from a membranous cellular localization of SDC-1 in normal tissue, low-grade tumors and NMIBC, to a distinctly cytoplasmic localization in high-grade tumors and MIBC was observed in tissue specimens. Conclusion Alone urinary SDC-1 may not be a diagnostic biomarker for bladder cancer, but its urinary levels and cellular localization were associated with the differentiation status of patients with bladder tumors. Further studies are warranted to define the potential role for SDC-1 in bladder cancer progression.