[Recombinant proteins as therapeutic compounds in clinical oncology]

The in vitro production of recombinant protein molecules has fostered a tremendous interest in their clinical application for treatment and support of cancer patients. Therapeutic proteins include monoclonal antibodies, interferons, and haematopoietic growth factors. Clinically established monoclonal antibodies include rituximab (targeting CD20-positive B-cell lymphomas), trastuzumab (active in HER-2 breast and gastric cancer), and bevacizumab (blocking tumor-induced angiogenesis through blockade of vascular-endothelial growth factor and its receptor). Interferons have lost much of their initial appeal, since equally or more effective treatments with more pleasant side effects have become available, for example in chronic myelogenous leukaemia or hairy cell leukaemia. The value of recombinant growth factors, notably granulocyte colony stimulating factor (G-CSF) and erythropoietin is rather in the field of supportive care than in targeted anti-cancer therapy. Adequately powered clinical phase III trials are essential to estimate the true therapeutic impact of these expensive compounds, with appropriate selection of clinically relevant endpoints and sufficient follow-up. Monoclonal antibodies, interferons, and growth factors must also, and increasingly so, be subjected to close scrutiny by appropriate cost-effectiveness analyses to ensure that their use results in good value for money. With these caveats and under the condition of their judicious clinical use, recombinant proteins have greatly enriched the therapeutic armamentarium in clinical oncology, and their importance is likely to grow even further.

Structural modification of DNA--a therapeutic option in SLE?

Systemic lupus erythematosus (SLE) is an autoimmune disease that affects multiple organs, with glomerulonephritis representing a frequent and serious manifestation. SLE is characterized by the presence of various autoantibodies, including anti-DNA antibodies that occur in approximately 70% of patients with SLE and which contribute to disease pathogenesis. Consequently, immunosuppressive therapies are applied in the treatment of SLE to reduce autoantibody levels. However, increasing evidence suggests that DNA--especially double--stranded DNA-constitutes an important pathogenic factor that is able to activate inflammatory responses by itself in autoimmune diseases. Therefore, modifying the structure of DNA to reduce its pathogenicity might be a more targeted approach for the treatment of SLE than immunosuppression. This article presents information in support of this strategy, and discusses the potential methods of DNA structure manipulation--in light of data obtained from mouse models of SLE--including topoisomerase I inhibition, administration of DNase I, or modification of histones using heparin or histone deacetylase inhibitors.

Future trials of endovascular mechanical recanalisation therapy in acute ischemic stroke patients - A position paper endorsed by ESMINT and ESNR : Part II: methodology of future trials

Based on current data and experience, the joint working group of the European Society of Minimally Invasive Neurological Therapy (ESMINT) and the European Society of Neuroradiology (ESNR) make suggestions on trial design and conduct aimed to investigate therapeutic effects of mechanical thrombectomy (MT). We anticipate that this roadmap will facilitate the setting up and conduct of successful trials in close collaboration with our neighbouring disciplines.

Hereditary angioedema (HAE) in children and adolescents--a consensus on therapeutic strategies

Hereditary angioedema due to C1 inhibitor (C1 esterase inhibitor) deficiency (types I and II HAE-C1-INH) is a rare disease that usually presents during childhood or adolescence with intermittent episodes of potentially life-threatening angioedema. Diagnosis as early as possible is important to avoid ineffective therapies and to properly treat swelling attacks. At a consensus meeting in June 2011, pediatricians and dermatologists from Germany, Austria, and Switzerland reviewed the currently available literature, including published international consensus recommendations for HAE therapy across all age groups. Published recommendations cannot be unconditionally adopted for pediatric patients in German-speaking countries given the current approval status of HAE drugs. This article provides an overview and discusses drugs available for HAE therapy, their approval status, and study results obtained in adult and pediatric patients. Recommendations for developing appropriate treatment strategies in the management of HAE in pediatric patients in German-speaking countries are provided.Conclusion Currently, plasma-derived C1 inhibitor concentrate is considered the best available option for the treatment of acute HAE-C1-INH attacks in pediatric patients in German-speaking countries, as well as for short-term and long-term prophylaxis.

Therapeutic approaches to patients with hypereosinophilic syndromes

Hypereosinophilic syndromes (HES) are a heterogeneous group of disorders that range from asymptomatic eosinophilia > 1,500/mL to aggressive disease complicated by life-threatening end organ involvement, including endomyocardial fibrosis and thromboembolism. To complicate matters further, similar clinical manifestations can occur in the setting of marked eosinophilia due to helminth infection, drug hypersensitivity, and other causes. In the past, therapy was guided only by the exclusion of these secondary causes of eosinophilia and the severity of the clinical manifestations. More recently, the availability of novel targeted therapies and a better understanding of the etiologies of some subtypes of HES have necessitated a more structured approach.

Involvement of autophagy in the response of tumor cells to PtdIns3K inhibitors: therapeutic implications

The phosphoinositide 3-kinase (PI3K) pathway plays a crucial role in cell proliferation and survival and is frequently activated by genetic and epigenetic alterations in human cancer. An arsenal of pharmacological inhibitors of key signaling enzymes in this pathway, including class I(A) PI3K isoforms, has been developed in the past decade and several compounds have entered clinical testing in cancer patients. The PIK3CA/p110α isoform is the most studied enzyme of the family and a validated cancer target. The induction of autophagy by PI3K pathway inhibitors has been documented in various cancers, although a clear picture about the significance of this phenomenon is still missing, especially in the in vivo situation. A better understanding of the contribution of autophagy to the action of PI3K inhibitors on tumors cells is important, since it may limit or enhance the action of these compounds, depending on the cellular context.

Metzincins, including matrix metalloproteinases and meprin, in kidney transplantation

Chronic allograft nephropathy, including chronic rejection, remains one of the major causes of renal allograft failure. Amongst other mediators, metzincins, such as matrix metalloproteinases (MMP), direct extracellular matrix metabolism and cell proliferation. Thus, we hypothesized, that these proteolytic enzymes are differentially regulated in chronic renal transplant rejection in rats and in human renal allograft nephropathy. Our studies demonstrated on the experimental level and in humans an overall up-regulation of MMP, tissue inhibitors of metalloproteinases (TIMP) and related enzymes as a result of rejection processes. Thus, metzincins may represent novel markers and therapeutic targets with respect to renal allograft rejection.

Differential regulation of metzincins in experimental chronic renal allograft rejection: potential markers and novel therapeutic targets

Chronic renal allograft rejection is characterized by alterations in the extracellular matrix compartment and in the proliferation of various cell types. These features are controlled, in part by the metzincin superfamily of metallo-endopeptidases, including matrix metalloproteinases (MMPs), a disintegrin and metalloproteinase (ADAM) and meprin. Therefore, we investigated the regulation of metzincins in the established Fisher to Lewis rat kidney transplant model. Studies were performed using frozen homogenates and paraffin sections of rat kidneys at day 0 (healthy controls) and during periods of chronic rejection at day +60 and day +100 following transplantation. The messenger RNA (mRNA) expression was examined by Affymetrix Rat Expression Array 230A GeneChip and by real-time Taqman polymerase chain reaction analyses. Protein expression was studied by zymography, Western blot analyses, and immunohistology. mRNA levels of MMPs (MMP-2/-11/-12/-14), of their inhibitors (tissue inhibitors of metalloproteinase (TIMP)-1/-2), ADAM-17 and transforming growth factor (TGF)-beta1 significantly increased during chronic renal allograft rejection. MMP-2 activity and immunohistological staining were augmented accordingly. The most important mRNA elevation was observed in the case of MMP-12. As expected, Western blot analyses also demonstrated increased production of MMP-12, MMP-14, and TIMP-2 (in the latter two cases as individual proteins and as complexes). In contrast, mRNA levels of MMP-9/-24 and meprin alpha/beta had decreased. Accordingly, MMP-9 protein levels and meprin alpha/beta synthesis and activity were downregulated significantly. Members of metzincin families (MMP, ADAM, and meprin) and of TIMPs are differentially regulated in chronic renal allograft rejection. Thus, an altered pattern of metzincins may represent novel diagnostic markers and possibly may provide novel targets for future therapeutic interventions.

Reporting of randomized controlled trials in Hodgkin lymphoma in biomedical journals

BACKGROUND: Randomized controlled trials (RCTs) are the best tool to evaluate the effectiveness of clinical interventions. The Consolidated Standards for Reporting Trials (CONSORT) statement was introduced in 1996 to improve reporting of RCTs. We aimed to determine the extent of ambiguity and reporting quality as assessed by adherence to the CONSORT statement in published reports of RCTs involving patients with Hodgkin lymphoma from 1966 through 2002. METHODS: We analyzed 242 published full-text reports of RCTs in patients with Hodgkin lymphoma. Quality of reporting was assessed using a 14-item questionnaire based on the CONSORT checklist. Reporting was studied in two pre-CONSORT periods (1966-1988 and 1989-1995) and one post-CONSORT period (1996-2002). RESULTS: Only six of the 14 items were addressed in 75% or more of the studies in all three time periods. Most items that are necessary to assess the methodologic quality of a study were reported by fewer than 20% of the studies. Improvements over time were seen for some items, including the description of statistics methods used, reporting of primary research outcomes, performance of power calculations, method of randomization and concealment allocation, and having performed intention-to-treat analysis. CONCLUSIONS: Despite recent improvements, reporting levels of CONSORT items in RCTs involving patients with Hodgkin lymphoma remain unsatisfactory. Further concerted action by journal editors, learned societies, and medical schools is necessary to make authors even more aware of the need to improve the reporting RCTs in medical journals to allow assessment of validity of published clinical research.

Herbal medicine in the treatment of liver diseases

Herbal drugs have become increasingly popular and their use is widespread. Licensing regulations and pharmacovigilance regarding herbal products are still incomplete and clearcut proof of their efficacy in liver diseases is sparse. Nevertheless, a number of herbals show promising activity including silymarin for antifibrotic treatment, phyllantus amarus in chronic hepatitis B, glycyrrhizin to treat chronic viral hepatitis, and a number of herbal combinations from China and Japan that deserve testing in appropriate studies. Apart from therapeutic properties, reports are accumulating about liver injury after the intake of herbals, including those advertised for liver diseases. Acute and/or chronic liver damage occurred after ingestion of some Chinese herbs, herbals that contain pyrrolizidine alkaloids, germander, greater celandine, kava, atractylis gummifera, callilepsis laureola, senna alkaloids, chaparral and many others. Since the evidence supporting the use of botanicals to treat chronic liver diseases is insufficient and only few of them are well standardised and free of potential serious side effects, most of these medications are not recommended outside clinical trials. Particularly with regard to the latter, adequately powered randomised-controlled clinical trials with well-selected end points are needed to assess the role of herbal therapy for liver diseases.

Insulin resistance, obesity and the metabolic syndrome. Is there a therapeutic role for endothelin-1 antagonists?

There is increasing evidence to suggest that chronic activation of the endothelin-1 system can lead to heterologous desensitization of the glucose-regulatory and mitogenic actions of insulin with subsequent development of glucose intolerance, hyperinsulinemia, impaired endothelial function and exacerbation of cardiovascular disease. Effects are mediated through a variety of mechanisms that include attenuation of key insulin signalling pathways and decreased tyrosine phosphorylation of insulin receptor substrates IRS-1, SHC and G alpha q/11. Other actions involve hemodynamic changes leading to reduced delivery of insulin and glucose to peripheral tissues as well as enhanced hepatic glycogenolysis, decreased glucose-transporter translocation and modulation of various adipokines that regulate insulin action. Overall the data suggest that ET-1 antagonists may provide an effective means of improving cardiac dysfunction and favourably influencing glucose tolerance in obese humans and patients with early insulin sensitivity where there is clear evidence for activation of the ET-1 system. Although most effects of ET-1 that modulate mechanisms leading to glucose intolerance appear to involve the ETA receptor subtype recent data indicates that combined ETA/ETB receptor antagonists may function as effectively as selective ETA blockers. Prospective trials are needed to assess whether ET-1 antagonists, either alone or in combination, are superior to other more conventional therapies such as insulin sensitizers and to evaluate effects of combined treatments on the development of insulin resistance and the progression of diabetes. Early screening of patients at risk for evidence of ET-1 activation would help to identify subjects who may benefit most from such treatment.

Clinical end points in coronary stent trials: a case for standardized definitions

BACKGROUND: Although most clinical trials of coronary stents have measured nominally identical safety and effectiveness end points, differences in definitions and timing of assessment have created confusion in interpretation. METHODS AND RESULTS: The Academic Research Consortium is an informal collaboration between academic research organizations in the United States and Europe. Two meetings, in Washington, DC, in January 2006 and in Dublin, Ireland, in June 2006, sponsored by the Academic Research Consortium and including representatives of the US Food and Drug Administration and all device manufacturers who were working with the Food and Drug Administration on drug-eluting stent clinical trial programs, were focused on consensus end point definitions for drug-eluting stent evaluations. The effort was pursued with the objective to establish consistency among end point definitions and provide consensus recommendations. On the basis of considerations from historical legacy to key pathophysiological mechanisms and relevance to clinical interpretability, criteria for assessment of death, myocardial infarction, repeat revascularization, and stent thrombosis were developed. The broadly based consensus end point definitions in this document may be usefully applied or recognized for regulatory and clinical trial purposes. CONCLUSION: Although consensus criteria will inevitably include certain arbitrary features, consensus criteria for clinical end points provide consistency across studies that can facilitate the evaluation of safety and effectiveness of these devices.

Peripheral endovascular revascularization trials: high noon for uniform reporting standards

In the era of evidence based medicine, proof of clinical benefits and cost-effectiveness need to be firmly based on transparent comparisons between various therapeutic alternatives. Standards for reports are a prerequisite for comparisons across reports and should reflect the patient's perspective. According standards have been successfully introduced in many fields of modern medicine, but not yet for peripheral endovascular interventions. Given the overwhelmingly increasing importance of endovascular revascularization in patients with chronic lower limb ischemia, this report provides an updated outline of the heterogeneity of current reporting practice and highlights the need for uniform reporting standards.

Cardiovascular risk factors impair native collateral development and may impair efficacy of therapeutic interventions

Animal and early clinical studies of gene therapy for tissue ischaemia suggested that this approach might provide benefit to patients with coronary artery disease not amenable to traditional revascularization. This enthusiasm was then tempered by the subsequent disappointing results of randomized clinical trials and led researchers to develop strategies using progenitor cells as an alternative to improve collateral function. However, the recent publication of several randomized clinical trials reporting either negative or weakly positive results using this approach have led to questions regarding its effectiveness. There are several factors that need to be considered in explaining the discordance between the positive studies of such treatments in animals and the disappointing results seen in randomized patient trials. Aside from the practical issues of arteriogenic therapies, such as effective delivery, vascular remodelling is an extraordinarily complex process, and the administration of a single agent or cell in the hope that it would lead to lasting physiological effects may be far too simplistic an approach. In addition, however, evidence now suggests that many of the traditional cardiovascular risk factors-such as age and hypercholesterolemia-may impair the host response not only to ischaemia but, critically, also to treatment as well. This review discusses the evidence and mechanisms for these observations and highlights future directions that might be taken in an effort to provide more effective therapies.

Effect of therapeutic exercise for hip osteoarthritis pain: results of a meta-analysis

OBJECTIVE: Recommendations for lower extremity osteoarthritis (OA) and exercise have been primarily based on knee studies. To provide more targeted recommendations for the hip, we gathered evidence for the efficacy of exercise for hip OA from randomized controlled trials. METHODS: A bibliographic search identified trials that were randomized, controlled, completed by >or=60% of subjects, and involved an exercise group (strengthening and/or aerobic) versus a non exercise control group for pain relief in hip OA. Two reviewers independently performed the data extraction and contacted the authors when necessary. Effect sizes (ES) of treatment versus control and the I(2) statistic to assess heterogeneity across trials were calculated. Trial data were combined using a random-effects meta-analysis. RESULTS: Nine trials met the inclusion criteria (1,234 subjects), 7 of which combined hip and knee OA; therefore, we contacted the authors who provided the data on hip OA patients. In comparing exercise treatment versus control, we found a beneficial effect of exercise with an ES of -0.38 (95% confidence interval [95% CI] -0.68, -0.08; P = 0.01), but with high heterogeneity (I(2) = 75%) among trials. Heterogeneity was caused by 1 trial consisting of an exercise intervention that was not administered in person. Removing this study left 8 trials (n = 493) with similar exercise strategy (specialized hands-on exercise training, all of which included at least some element of muscle strengthening), and demonstrated exercise benefit with an ES of -0.46 (95% CI -0.64, -0.28; P < 0.0001). CONCLUSION: Therapeutic exercise, especially with an element of strengthening, is an efficacious treatment for hip OA.