Defining responses to therapy and study outcomes in clinical trials of invasive fungal diseases: Mycoses Study Group and European Organization for Research and Treatment of Cancer consensus criteria.

Invasive fungal diseases (IFDs) have become major causes of morbidity and mortality among highly immunocompromised patients. Authoritative consensus criteria to diagnose IFD have been useful in establishing eligibility criteria for antifungal trials. There is an important need for generation of consensus definitions of outcomes of IFD that will form a standard for evaluating treatment success and failure in clinical trials. Therefore, an expert international panel consisting of the Mycoses Study Group and the European Organization for Research and Treatment of Cancer was convened to propose guidelines for assessing treatment responses in clinical trials of IFDs and for defining study outcomes. Major fungal diseases that are discussed include invasive disease due to Candida species, Aspergillus species and other molds, Cryptococcus neoformans, Histoplasma capsulatum, and Coccidioides immitis. We also discuss potential pitfalls in assessing outcome, such as conflicting clinical, radiological, and/or mycological data and gaps in knowledge.

An analysis of protocols and publications suggested that most discontinuations of clinical trials were not based on preplanned interim analyses or stopping rules.

OBJECTIVES: To investigate the frequency of interim analyses, stopping rules, and data safety and monitoring boards (DSMBs) in protocols of randomized controlled trials (RCTs); to examine these features across different reasons for trial discontinuation; and to identify discrepancies in reporting between protocols and publications. STUDY DESIGN AND SETTING: We used data from a cohort of RCT protocols approved between 2000 and 2003 by six research ethics committees in Switzerland, Germany, and Canada. RESULTS: Of 894 RCT protocols, 289 prespecified interim analyses (32.3%), 153 stopping rules (17.1%), and 257 DSMBs (28.7%). Overall, 249 of 894 RCTs (27.9%) were prematurely discontinued; mostly due to reasons such as poor recruitment, administrative reasons, or unexpected harm. Forty-six of 249 RCTs (18.4%) were discontinued due to early benefit or futility; of those, 37 (80.4%) were stopped outside a formal interim analysis or stopping rule. Of 515 published RCTs, there were discrepancies between protocols and publications for interim analyses (21.1%), stopping rules (14.4%), and DSMBs (19.6%). CONCLUSION: Two-thirds of RCT protocols did not consider interim analyses, stopping rules, or DSMBs. Most RCTs discontinued for early benefit or futility were stopped without a prespecified mechanism. When assessing trial manuscripts, journals should require access to the protocol.

Validity, reliability and responsiveness of the French language translation of the Western Ontario Shoulder Instability Index (WOSI).

BACKGROUND: The WOSI (Western Ontario Shoulder Instability Index) is a self-administered quality of life questionnaire designed to be used as a primary outcome measure in clinical trials on shoulder instability, as well as to measure the effect of an intervention on any particular patient. It is validated and is reliable and sensitive. As it is designed to measure subjective outcome, it is important that translation should be methodologically rigorous, as it is subject to both linguistic and cultural interpretation. OBJECTIVE: To produce a French language version of the WOSI that is culturally adapted to both European and North American French-speaking populations. MATERIALS AND METHODS: A validated protocol was used to create a French language WOSI questionnaire (WOSI-Fr) that would be culturally acceptable for both European and North American French-speaking populations. Reliability and responsiveness analyses were carried out, and the WOSI-Fr was compared to the F-QuickDASH-D/S (Disability of the Arm, Shoulder and Hand-French translation), and Walch-Duplay scores. RESULTS: A French language version of the WOSI (WOSI-Fr) was accepted by a multinational committee. The WOSI-Fr was then validated using a total of 144 native French-speaking subjects from Canada and Switzerland. Comparison of results on two WOSI-Fr questionnaires completed at a mean interval of 16 days showed that the WOSI-Fr had strong reliability, with a Pearson and interclass correlation of r=0.85 (P=0.01) and ICC=0.84 [95% CI=0.78-0.88]. Responsiveness, at a mean 378.9 days after surgical intervention, showed strong correlation with that of the F-QuickDASH-D/S, with r=0.67 (P<0.01). Moreover, a standardized response means analysis to calculate effect size for both the WOSI-Fr and the F-QuickDASH-D/S showed that the WOSI-Fr had a significantly greater ability to detect change (SRM 1.55 versus 0.87 for the WOSI-Fr and F-QuickDASH-D/S respectively, P<0.01). The WOSI-Fr showed fair correlation with the Walch-Duplay. DISCUSSION: A French-language translation of the WOSI questionnaire was created and validated for use in both Canadian and Swiss French-speaking populations. This questionnaire will facilitate outcome assessment in French-speaking settings, collaboration in multinational studies and comparison between studies performed in different countries. TYPE OF STUDY: Multicenter cohort study. LEVEL OF EVIDENCE: II.

Readiness to participate in psychiatric research.

BACKGROUND: The feasibility of clinical trials depends, among other factors, on the number of eligible patients, the recruitment process, and the readiness of patients to participate in research. Seeking patients' views about their experience in research projects may allow investigators to develop more effective recruitment and retention strategies. METHODS: A total of 100 patients consecutively admitted to a psychiatric university hospital were interviewed with respect to their willingness to participate in a study. For a different study scenario, patients were asked whether they would be ready to participate if such a study were organized in the service and to indicate their reasons for refusing or for participating. RESULTS: The general readiness to participate in a study ranged between 70% and 96%. The prospect of remuneration did not notably augment the potential consent rate. The most common and spontaneous motivation for agreeing to take part in a study was to help science progress and to allow future patients to benefit from improved diagnosis and treatment (87%). The presence or lack of a financial incentive was rarely chosen as an argument to agree (23%) or to refuse (7%) to participate. Patients relied mainly on their treating physicians when contemplating possible participation in a study (family physician [65%] and hospital physician [54%]). CONCLUSIONS: Clinicians and, in particular, treating doctors can play an important role in facilitating the recruitment process.

Epidermal growth factor receptor: a re-emerging target in glioblastoma.

PURPOSE OF REVIEW: Amplification and overexpression of the epidermal growth factor receptor (EGFR) gene are a hallmark of primary glioblastoma (45%), making it a prime target for therapy. In addition, these amplifications are frequently associated with oncogenic mutations in the extracellular domain. However, efforts at targeting the EGFR tyrosine kinase using small molecule inhibitors or antibodies have shown disappointing efficacy in clinical trials for newly diagnosed or recurrent glioblastoma. Here, we review recent insights into molecular mechanisms relevant for effective targeting of the EGFR pathway. RECENT FINDINGS: Molecular workup of glioblastoma tissue of patients under treatment with small molecule inhibitors has established drug concentrations in the tumor tissue, and has shed light on the effectiveness of target inhibition and respective effects on pathway signaling. Further, functional analyses of interaction of small molecule inhibitors with distinct properties to bind to the active or inactive form of EGFR have provided new insights that will impact the choice of drugs. Finally, vaccination approaches targeting the EGFRvIII mutant featuring a tumor-specific antigen have shown promising results that warrant larger controlled clinical trials. SUMMARY: A combination of preclinical and clinical studies at the molecular level has provided new insights that will allow refining strategies for targeting the EGFR pathway in glioblastoma.

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Primary ciliary dyskinesia (PCD) is an autosomal recessive disease with an incidence estimated between 1:2,000 and 1:40,000. Ciliated epithelia line the airways, nasal and sinus cavities, Eustachian tube and fallopian tubes. Congenital abnormalities of ciliary structure and function impair mucociliary clearance. As a consequence, patients present with chronic sinopulmonary infections, recurrent glue ear and female subfertility. Similarities in the ultrastructure of respiratory cilia, nodal cilia and sperm result in patients with PCD also presenting with male infertility, abnormalities of left-right asymmetry (most commonly situs inversus totalis) and congenital heart disease. Early diagnosis is essential to ensure specialist management of the respiratory and otological complications of PCD. Diagnostic tests focus on analysis of ciliary function and electron microscopy structure. Analysis is technically difficult and labour intensive. It requires expertise for interpretation, restricting diagnosis to specialist centres. Management is currently based on the consensus of experts, and there is a pressing need for randomised clinical trials to inform treatment.

Ambulatory blood pressure measurement and antihypertensive therapy.

The traditional basis for assessing the effect of antihypertensive therapy is the blood pressure reading taken by a physician. However, several recent trials have been designed to evaluate the blood pressure lowering effect of various therapeutic agents during the patients' normal daytime activities, using a portable, semi-automatic blood pressure recorder. The results have shown that in a given patient, blood pressure measured at the physician's office often differs greatly from that prevailing during the rest of the day. This is true both in treated and untreated hypertensive patients. The difference between office and ambulatory recorded pressures cannot be predicted from blood pressure levels measured by the physician. Therefore, a prospective study was carried out in patients with diastolic blood pressures that were uncontrolled at the physician's office despite antihypertensive therapy. The purpose was to evaluate the response of recorded ambulatory blood pressure to treatment adjustments aimed at reducing office blood pressure below a pre-set target level. Only patients with high ambulatory blood pressures at the outset appeared to benefit from further changes in therapy. Thus, ambulatory blood pressure monitoring can be used to identify those patients who remain hypertensive only when facing the physician, despite antihypertensive therapy. Ambulatory monitoring could thus help to evaluate the efficacy of antihypertensive therapy and allow individual treatment.

Correlation of wear in vivo and six laboratory wear methods.

OBJECTIVE: We examined the correlation between clinical wear rates of restorative materials and enamel (TRAC Research Foundation, Provo, USA) and the results of six laboratory test methods (ACTA, Alabama (generalized, localized), Ivoclar (vertical, volumetric), Munich, OHSU (abrasion, attrition), Zurich). METHODS: Individual clinical wear data were available from clinical trials that were conducted by TRAC Research Foundation (formerly CRA) together with general practitioners. For each of the n=28 materials (21 composite resins for intra-coronal restorations [20 direct and 1 indirect], 5 resin materials for crowns, 1 amalgam, enamel) a minimum of 30 restorations had been placed in posterior teeth, mainly molars. The recall intervals were up to 5 years with the majority of materials (n=27) being monitored, however, only for up to 2 years. For the laboratory data, the databases MEDLINE and IADR abstracts were searched for wear data on materials which were also clinically tested by TRAC Research Foundation. Only those data for which the same test parameters (e.g. number of cycles, loading force, type of antagonist) had been published were included in the study. A different quantity of data was available for each laboratory method: Ivoclar (n=22), Zurich (n=20), Alabama (n=17), OHSU and ACTA (n=12), Munich (n=7). The clinical results were summed up in an index and a linear mixed model was fitted to the log wear measurements including the following factors: material, time (0.5, 1, 2 and 3 years), tooth (premolar/molar) and gender (male/female) as fixed effects, and patient as random effect. Relative ranks were created for each material and method; the same was performed with the clinical results. RESULTS: The mean age of the subjects was 40 (±12) years. The materials had been mostly applied in molars (81%) and 95% of the intracoronal restorations were Class II restorations. The mean number of individual wear data per material was 25 (range 14-42). The mean coefficient of variation of clinical wear data was 53%. The only significant correlation was reached by OHSU (abrasion) with a Spearman r of 0.86 (p=0.001). Zurich, ACTA, Alabama generalized wear and Ivoclar (volume) had correlation coefficients between 0.3 and 0.4. For Zurich, Alabama generalized wear and Munich, the correlation coefficient improved if only composites for direct use were taken into consideration. The combination of different laboratory methods did not significantly improve the correlation. SIGNIFICANCE: The clinical wear of composite resins is mainly dependent on differences between patients and less on the differences between materials. Laboratory methods to test conventional resins for wear are therefore less important, especially since most of them do not reflect the clinical wear.

MET: a promising anticancer therapeutic target.

The MET pathway is dysregulated in many human cancers and promotes tumour growth, invasion and dissemination. Abnormalities in MET signalling have been reported to correlate with poor clinical outcomes and drug resistance in patients with cancer. Thus, MET has emerged as an attractive target for cancer therapy. Several MET inhibitors have been introduced into the clinic, and are currently in all phases of clinical trials. In general, initial results from these studies indicate only a modest benefit in unselected populations. In this Review, we discuss current challenges in developing MET inhibitors--including identification of predictive biomarkers--as well as the most-efficient ways to combine these drugs with other targeted agents or with classic chemotherapy or radiotherapy.

Outpatient treatment of pulmonary embolism.

Pulmonary embolism (PE) is traditionally treated in hospital. Growing evidence from non randomized prospective studies suggests that a substantial proportion of patients with non-massive PE might be safely treated in the outpatient setting using low molecular weight heparins. Based on this evidence, professional societies started to recommend outpatient care for selected patients with non-massive PE. Despite these recommendations, outpatient treatment of non-massive PE appears to be uncommon in clinical practice. The major barriers to PE outpatient care are, firstly, the uncertainty as how to identify low risk patients with PE who are candidates for outpatient care and secondly the lack of high quality evidence from randomized trials demonstrating the safety of PE outpatient care compared to traditional inpatient management. Also, although clinical prognostic models, echocardiography and cardiac biomarkers accurately identify low risk patients with PE in prospective studies, the benefit of risk stratification strategies based on these instruments should be demonstrated in prospective management studies and clinical trials before they can be implemented as decision aids to guide PE outpatient treatment. Before high quality evidence documenting the safety of an outpatient treatment approach is published, outpatient management of non-massive PE cannot be generally recommended.

Cilengitide: an integrin-targeting arginine-glycine-aspartic acid peptide with promising activity for glioblastoma multiforme.

BACKGROUND: Glioblastoma multiforme (GBM), a highly invasive and vascular cancer, responds poorly to conventional cytotoxic therapy. Integrins, widely expressed in GBM and tumor vasculature, mediate cell survival, migration and angiogenesis. Cilengitide is a potent alphavbeta3 and alphavbeta5 integrin inhibitor. OBJECTIVE: To summarize the preclinical and clinical experience with cilengitide for GBM. METHODS: Preclinical studies and clinical trials evaluating cilengitide for GBM were reviewed. RESULTS/CONCLUSIONS: Cilengitide is active and synergizes with external beam radiotherapy in preclinical GBM models. In clinical trials for recurrent GBM, single-agent cilengitide has antitumor benefits and minimal toxicity. Among newly diagnosed GBM patients, single-arm studies incorporating cilengitide into standard external beam radiotherapy/temozolomide have shown encouraging activity with no increased toxicity and have led to a planned randomized Phase III trial.

Dipeptidyl peptidase IV and its inhibitors: therapeutics for type 2 diabetes and what else?

The proline-specific dipeptidyl aminopeptidase IV (DPP IV, DPP-4, CD26), widely expressed in mammalians, releases X-Pro/Ala dipeptides from the N-terminus of peptides. DPP IV is responsible of the degradation of the incretin peptide hormones regulating blood glucose levels. Several families of DPP IV inhibitors have been synthesized and evaluated. Their positive effects on the degradation of the incretins and the control of blood glucose levels have been demonstrated in biological models and in clinical trials. Presently, several DPP IV inhibitors, the "gliptins", are approved for type 2 diabetes or are under clinical evaluation. However, the gliptins may also be of therapeutic interest for other diseases beyond the inhibition of incretin degradation. In this Perspective, the biological functions and potential substrates of DPP IV enzymes are reviewed and the characteristics of the DPP IV inhibitors are discussed in view of type 2 diabetes and further therapeutic interest.

Fructose toxicity: is the science ready for public health actions?

PURPOSE OF REVIEW: The assumption that fructose may be toxic and involved in the pathogenesis of noncommunicable diseases such as obesity, diabetes mellitus, dyslipidemia, and even cancer has resulted in the call for public health action, such as introducing taxes on sweetened beverages. This review evaluates the scientific basis for such action. RECENT FINDINGS: Although some studies hint towards some potential adverse effects of excessive fructose consumption especially when combined with excess energy intake, the results from clinical trials do not support a significant detrimental effect of fructose on metabolic health when consumed as part of a weight-maintaining diet in amounts consistent with the average-estimated fructose consumption in Western countries. However, definitive studies are missing. SUMMARY: Public health policies to eliminate or limit fructose in the diet should be considered premature. Instead, efforts should be made to promote a healthy lifestyle that includes physical activity and nutritious foods while avoiding intake of excess calories until solid evidence to support action against fructose is available. Public health is almost certainly to benefit more from policies that are aimed at promoting what is known to be good than from policies that are prohibiting what is not (yet) known to be bad.

The Swiss regulatory framework for pædiatric health research

Medical research on minors entails both risks and benefits. Under Swiss law, clinical trials on children, including nontherapeutic drug trials, are permissible. However, ethics committees must systematically verify that all clinical studies have a favorable risk-benefit profile. Additional safeguards are designed to ensure that children are not unnecessarily involved in research and that proper consent is always obtained. Federal Swiss law is undergoing revision to extend these protections beyond clinical trials to a broad array of health research. The Swiss drug agency also seeks to improve the incentives for pharmaceutical firms to develop new paediatric drugs and relevant paediatric drug labels.