Disease activity in rheumatoid arthritis patients at initiation of biologic agents and 1 year of treatment: results from the Swiss SCQM registry.

OBJECTIVE: In Switzerland, the prescription of biologic antirheumatic agents in rheumatoid arthritis (RA) patients is not limited by stringent requirements from health authorities. The goals of this study were to: determine the characteristics of the Swiss patients at the initiation of biologics, compare them with other countries and evaluate whether different disease activity levels at initiation of therapy, resulting from distinct access to these treatment, influence their effectiveness. METHODS: This is a retrospective cohort study of RA patients followed in the Swiss register (SCQM-RA). Two thousand and sixty patients treated with biologics were retrieved. We present the disease characteristics and the patients' demographic data, at initiation and some effectiveness data after 1 year of treatment. RESULTS: Two thousand and sixty patients treated with biologics were retrieved. At initiation of treatment, the mean disease activity DAS (SD): 4.4 (1.4), number of previous antirheumatic treatments: 1.1, functional status HAQ: 1.1 (0.7) and median duration of illness: 5.5 years were significantly lower than in other published registries. The mean DAS: 3.3 (1.4) 1 year after initiation of therapy also appears lower than in other countries. Additionally, patients treated more recently (after 2005) had a significantly higher improvement in mean DAS. CONCLUSIONS: Data from the Swiss RA registry demonstrate that biologics are prescribed at a lower level of disease activity and after fewer prior DMARD failures than in most other countries, a practice that seems to correlate with overall lower absolute levels of disease activity and better patient outcomes after 1 year of treatment.

Novel Agents Targeting the IGF-1R/PI3K Pathway Impair Cell Proliferation and Survival in Subsets of Medulloblastoma and Neuroblastoma.

The receptor tyrosine kinase (RTK)/phosphoinositide 3-kinase (PI3K) pathway is fundamental for cancer cell proliferation and is known to be frequently altered and activated in neoplasia, including embryonal tumors. Based on the high frequency of alterations, targeting components of the PI3K signaling pathway is considered to be a promising therapeutic approach for cancer treatment. Here, we have investigated the potential of targeting the axis of the insulin-like growth factor-1 receptor (IGF-1R) and PI3K signaling in two common cancers of childhood: neuroblastoma, the most common extracranial tumor in children and medulloblastoma, the most frequent malignant childhood brain tumor. By treating neuroblastoma and medulloblastoma cells with R1507, a specific humanized monoclonal antibody against the IGF-1R, we could observe cell line-specific responses and in some cases a strong decrease in cell proliferation. In contrast, targeting the PI3K p110α with the specific inhibitor PIK75 resulted in broad anti-proliferative effects in a panel of neuro- and medulloblastoma cell lines. Additionally, sensitization to commonly used chemotherapeutic agents occurred in neuroblastoma cells upon treatment with R1507 or PIK75. Furthermore, by studying the expression and phosphorylation state of IGF-1R/PI3K downstream signaling targets we found down-regulated signaling pathway activation. In addition, apoptosis occurred in embryonal tumor cells after treatment with PIK75 or R1507. Together, our studies demonstrate the potential of targeting the IGF-1R/PI3K signaling axis in embryonal tumors. Hopefully, this knowledge will contribute to the development of urgently required new targeted therapies for embryonal tumors.

Agents and intermediaries

Managing Football is the first book to directly respond to the rapid managerial, commercial and global development of the sport and offers a thorough analysis of how the football industry can meet the challenges that flow from these developments. Expertly edited by two well known specialists in football business management, it draws together the work of a world-class contributor team to form a comprehensive analysis of the most important issues facing the managers of football businesses across the world. The cutting edge analysis examines all the important business challenges in the football industry and the management of football businesses and covers all of the key football markets including England, Spain, France, Italy, Germany, Australia, North America, China, South Africa, South Korea, the Netherlands & Belgium, and Mexico. Managing Football is simply a must-read for anyone studying or working in football business management and is set to be an important landmark in this rapidly moving and globally expansive field.

Development, optimization, and validation of novel anti-TEM1/CD248 affinity agent for optical imaging in cancer.

Tumor Endothelial Marker-1 (TEM1/CD248) is a tumor vascular marker with high therapeutic and diagnostic potentials. Immuno-imaging with TEM1-specific antibodies can help to detect cancerous lesions, monitor tumor responses, and select patients that are most likely to benefit from TEM1-targeted therapies. In particular, near infrared(NIR) optical imaging with biomarker-specific antibodies can provide real-time, tomographic information without exposing the subjects to radioactivity. To maximize the theranostic potential of TEM1, we developed a panel of all human, multivalent Fc-fusion proteins based on a previously identified single chain antibody (scFv78) that recognizes both human and mouse TEM1. By characterizing avidity, stability, and pharmacokinectics, we identified one fusion protein, 78Fc, with desirable characteristics for immuno-imaging applications. The biodistribution of radiolabeled 78Fc showed that this antibody had minimal binding to normal organs, which have low expression of TEM1. Next, we developed a 78Fc-based tracer and tested its performance in different TEM1-expressing mouse models. The NIR imaging and tomography results suggest that the 78Fc-NIR tracer performs well in distinguishing mouse- or human-TEM1 expressing tumor grafts from normal organs and control grafts in vivo. From these results we conclude that further development and optimization of 78Fc as a TEM1-targeted imaging agent for use in clinical settings is warranted.

Current multiple myeloma treatment strategies with novel agents: a European perspective.

The treatment of multiple myeloma (MM) has undergone significant developments in recent years. The availability of the novel agents thalidomide, bortezomib, and lenalidomide has expanded treatment options and has improved the outcome of patients with MM. Following the introduction of these agents in the relapsed/refractory setting, they are also undergoing investigation in the initial treatment of MM. A number of phase III trials have demonstrated the efficacy of novel agent combinations in the transplant and nontransplant settings, and based on these results standard induction regimens are being challenged and replaced. In the transplant setting, a number of newer induction regimens are now available that have been shown to be superior to the vincristine, doxorubicin, and dexamethasone regimen. Similarly, in the front-line treatment of patients not eligible for transplantation, regimens incorporating novel agents have been found to be superior to the traditional melphalan plus prednisone regimen. Importantly, some of the novel agents appear to be active in patients with high-risk disease, such as adverse cytogenetic features, and certain comorbidities, such as renal impairment. This review presents an overview of the most recent data with these novel agents and summarizes European treatment practices incorporating the novel agents.

Les connectivites: progrès thérapeutiques et place de la biothérapie [Connective tissue diseases: news in therapy, role of biologics agents].

Systemic lupus erythematosus and primary Sjögren's syndrom are the two major connective tissue diseases. A better knowledge of their physiopathology allows us today to propose an adapted therapy. Moreover progress concerns the oldest treatment, hydroxychloroquine, and biotherapy. Hydroxychloroquine is still an actual treatment for lupus, its positive effects are better understood today. Nevertheless it does not seem to be efficient to treat primitive Sjögren. Biotherapy targeting B lymphocytes seems efficient in these two connective tissue diseases. Anti TNF therapy is not recommended and seems to induce connective tissue diseases. The real news is the recent approval and reimbursement in Switzerland of the new drug belimumab (Benlysta) in case of moderate lupus.

Strategies for the development of tdm for targeted anticancer agents

Most of the novel targeted anticancer agents share classical characteristics that define drugs as candidates for blood concentration monitoring: long-term therapy; high interindividual but restricted intraindividual variability; significant drug-drug and drug- food interactions; correlations between concentration and efficacy/ toxicity with rather narrow therapeutic index; reversibility of effects; and absence of early markers of response. Surprisingly though, therapeutic concentration monitoring has received little attention for these drugs despite reiterated suggestions from clinical pharmacologists. Several issues explain the lack of clinical research and development in this field: global tradition of empiricism regarding treatment monitoring, lack of formal conceptual framework, ethical difficulties in the elaboration of controlled clinical trials, disregard from both drug manufacturers and public funders, limited encouragement from regulatory authorities, and practical hurdles making dosage adjustment based on concentration monitoring a difficult task for prescribers. However, new technologies are soon to help us overcome these obstacles, with the advent of miniaturized measurement devices able to quantify circulating drug concentrations at the point-of-care, to evaluate their plausibility given actual dosage and sampling time, to determine their appropriateness with reference to therapeutic targets, and to advise on suitable dosage adjustment. Such evolutions could bring conceptual changes into the clinical development of drugs such as anticancer agents, while increasing the therapeutic impact of population PK-PD studies and systematic reviews. Research efforts in that direction from the clinical pharmacology community will be essential for patients to receive the greatest benefits and the least harm from new anticancer treatments. The example of imatinib, the first commercialized tyrosine kinase inhibitor, will be outlined to illustrate a potential research agenda for the rational development of therapeutic concentration monitoring.

Research recommendations for selected IARC-classified agents.

OBJECTIVES: There are some common occupational agents and exposure circumstances where evidence of carcinogenicity is substantial but not yet conclusive for humans. The objectives are to identify research gaps and needs for twenty agents prioritized for review based on evidence of widespread human exposures and potential carcinogenicity in animals or humans. DATA SOURCES: A systematic review was conducted of new data published since the most recent pertinent IARC monograph meeting. DATA EXTRACTION: Reviewers were charged with identifying data gaps and general and specific approaches to address them, focusing on research that would be important in resolving classification uncertainties. An expert meeting brought reviewers together to discuss each agent and the identified data gaps and approaches. DATA SYNTHESIS: Several overarching issues were identified that pertained to multiple agents; these included the importance of recognizing that carcinogenic agents can act through multiple toxicity pathways and mechanisms, including epigenetic mechanisms, oxidative stress and immuno- and hormonal modulation. CONCLUSIONS: Studies in occupational populations provide important opportunities to understand the mechanisms through which exogenous agents cause cancer and intervene to prevent human exposure and/or prevent or detect cancer among those already exposed. Scientific developments are likely to increase the challenges and complexities of carcinogen testing and evaluation in the future, and epidemiologic studies will be particularly critical to inform carcinogen classification and risk assessment processes.[Authors]

Intravitreal ranibizumab for age-related macular degeneration : optical coherence tomography guided retreatment intervals and their intra- and inter-individual variability

Purpose: To determine whether the need for retreatment after an initial phase of 3 monthly intravitreal injections of ranibizumab shows an intra-individual regular rhythm and to what degree it varies between different patients. Methods: Prospective study with 42 patients with exudative AMD, treatment naïve. Loading dose of 3 monthly doses of ranibizumab (0,5 mg), followed by a 12 months pro re nata (PRN) regimen according to early exudative signs on HD-OCT Cirrus, Zeiss. The follow-up visits were intensified (week 4, 5, 6, 7, 8, 10, 12, 14, 16, 20, etc after each injection) in order to detect recurrences early, and injection followed within 3 days in cases of subretinal fluid, cysts, or central thickness increase of>50microns. Intervals were calculated between injections for the 12 month follow-up with PRN treatment. Variability was expressed as standard deviation (SD). Results: Visual acuity (VA) improved from a mean ETDRS score of 61.6 (SD 10.8) at baseline to 68.0 (SD 10.2) at month 3 and to 74.7(SD 9.0) at month 12. The 15 patients who have already completed the study showed maintenance of the VA improvement. Central foveal thickness improved from a mean value of 366 microns (baseline) to 253 microns (month 3), well maintained thereafter. Mean number of injections was 8.8 (SD 3.5,range 0-12) per 12 months of follow-up (after 3 doses), with mean individual treatment-recurrence (TR) intervals ranging from 28->365 days (mean 58). Intraindividual variability of TR intervals (SD) was 7.1 days as a mean value (range 1.7¡V22.6). It ranged within 20% of the mean intra-individual interval for 30 (91%) and within 15% for 21 patients (64%). The first interval was within 1 week of the mean intra-individual interval in 64% and within 2 weeks in 89% of patients. Conclusions: The majority of AMD patients showed a relatively stable rhythm for PRN injections of ranibizumab after initial loading phase, associated with excellent functional/anatomical results. The initial interval last loading dose-first recurrence may have a predictive value for further need of treatment, potentially facilitating follow-up and patient care.

Identification of infectious agents in onychomycoses by PCR-terminal restriction fragment length polymorphism.

A fast and reliable assay for the identification of dermatophyte fungi and nondermatophyte fungi (NDF) in onychomycosis is essential, since NDF are especially difficult to cure using standard treatment. Diagnosis is usually based on both direct microscopic examination of nail scrapings and macroscopic and microscopic identification of the infectious fungus in culture assays. In the last decade, PCR assays have been developed for the direct detection of fungi in nail samples. In this study, we describe a PCR-terminal restriction fragment length polymorphism (TRFLP) assay to directly and routinely identify the infecting fungi in nails. Fungal DNA was easily extracted using a commercial kit after dissolving nail fragments in an Na(2)S solution. Trichophyton spp., as well as 12 NDF, could be unambiguously identified by the specific restriction fragment size of 5'-end-labeled amplified 28S DNA. This assay enables the distinction of different fungal infectious agents and their identification in mixed infections. Infectious agents could be identified in 74% (162/219) of cases in which the culture results were negative. The PCR-TRFLP assay described here is simple and reliable. Furthermore, it has the possibility to be automated and thus routinely applied to the rapid diagnosis of a large number of clinical specimens in dermatology laboratories.

Intravitreal ranibizumab (Lucentis) in the treatment of retinal angiomatous proliferation (RAP).

BACKGROUND: Retinal angiomatous proliferation (RAP) is a distinct variant of neovascular age-related macular degeneration (AMD). The aim of this study is to evaluate the functional and anatomic outcome after intravitreal ranibizumab (Lucentis) treatment in patients with RAP. METHODS: Prospective study of consecutive patients with newly diagnosed or recurrent RAP treated with intravitreal ranibizumab at the Jules Gonin Eye Hospital between March 2006 and December 2007. Baseline and monthly follow-up visits included best-corrected visual acuity (BCVA), fundus exam and optical coherence tomography. Fluorescein and indocyanine green angiography were performed at baseline and repeated at least every 3 months. RESULTS: Thirty-one eyes of 31 patients were treated with 0.5 mg of intravitreal ranibizumab for RAP between March 2006 and December 2007. The mean age of the patients was 82.6 years (SD:4.9). The mean number of intravitreal injections administered for each patient was 5 (SD: 2.4, range 3 to 12). The mean follow up was 13.4 months (SD: 3, range 10 to 22). The baseline mean logMAR BCVA was 0.72 (SD: 0.45) (decimal equivalent of 0.2). The mean logMAR BCVA was improved significantly (P < 0.0001) at the last follow-up to 0.45, SD: 0.3 (decimal equivalent 0.35). The visual acuity (VA) improved by a mean of 2.7 lines (SD 2.5). Mean baseline central macular thickness (CMT) was 376 microm, and decreased significantly to a mean of 224 microm (P < 0.001) at the last follow-up. Mean reduction of CMT was 152 microm (SD: 58). An average of 81.5% of the total visual improvement and 85% of the total CMT reduction occurred during the first post-operative month after one intravitreal injection of ranibizumab. During follow-up, an RPE tear occurred in one eye (3.2%) of the study group. No injection complications or systemic drug-related side-effects were noted during the follow-up period. CONCLUSIONS: Intravitreal ranibizumab injections appeared to be an effective and safe treatment for RAP, resulting in visual gain and reduction in macular thickness. Further long-term studies to evaluate the efficacy of intravitreal ranibizumab in RAP are warranted.

Hyperpolarized lithium-6 as a sensor of nanomolar contrast agents.

Lithium is widely used in psychotherapy. The (6)Li isotope has a long intrinsic longitudinal relaxation time T(1) on the order of minutes, making it an ideal candidate for hyperpolarization experiments. In the present study we demonstrated that lithium-6 can be readily hyperpolarized within 30 min, while retaining a long polarization decay time on the order of a minute. We used the intrinsically long relaxation time for the detection of 500 nM contrast agent in vitro. Hyperpolarized lithium-6 was administered to the rat and its signal retained a decay time on the order of 70 sec in vivo. Localization experiments imply that the lithium signal originated from within the brain and that it was detectable up to 5 min after administration. We conclude that the detection of submicromolar contrast agents using hyperpolarized NMR nuclei such as (6)Li may provide a novel avenue for molecular imaging.