Polymer-drug conjugates: towards a novel approach for the treatment of endrocine-related cancer

The last decade has seen successful clinical application of polymer–protein conjugates (e.g. Oncaspar, Neulasta) and promising results in clinical trials with polymer–anticancer drug conjugates. This, together with the realisation that nanomedicines may play an important future role in cancer diagnosis and treatment, has increased interest in this emerging field. More than 10 anticancer conjugates have now entered clinical development. Phase I/II clinical trials involving N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-doxorubicin (PK1; FCE28068) showed a four- to fivefold reduction in anthracycline-related toxicity, and, despite cumulative doses up to 1680 mg/m2 (doxorubicin equivalent), no cardiotoxicity was observed. Antitumour activity in chemotherapy-resistant/refractory patients (including breast cancer) was also seen at doxorubicin doses of 80–320 mg/m2, consistent with tumour targeting by the enhanced permeability (EPR) effect. Hints, preclinical and clinical, that polymer anthracycline conjugation can bypass multidrug resistance (MDR) reinforce our hope that polymer drugs will prove useful in improving treatment of endocrine-related cancers. These promising early clinical results open the possibility of using the water-soluble polymers as platforms for delivery of a cocktail of pendant drugs. In particular, we have recently described the first conjugates to combine endocrine therapy and chemotherapy. Their markedly enhanced in vitro activity encourages further development of such novel, polymer-based combination therapies. This review briefly describes the current status of polymer therapeutics as anticancer agents, and discusses the opportunities for design of second-generation, polymer-based combination therapy, including the cocktail of agents that will be needed to treat resistant metastatic cancer.

Data-driven treatment selection for seamless phase II/III trials incorporating early-outcome data

Seamless phase II/III clinical trials are conducted in two stages with treatment selection at the first stage. In the first stage, patients are randomized to a control or one of k > 1 experimental treatments. At the end of this stage, interim data are analysed, and a decision is made concerning which experimental treatment should continue to the second stage. If the primary endpoint is observable only after some period of follow-up, at the interim analysis data may be available on some early outcome on a larger number of patients than those for whom the primary endpoint is available. These early endpoint data can thus be used for treatment selection. For two previously proposed approaches, the power has been shown to be greater for one or other method depending on the true treatment effects and correlations. We propose a new approach that builds on the previously proposed approaches and uses data available at the interim analysis to estimate these parameters and then, on the basis of these estimates, chooses the treatment selection method with the highest probability of correctly selecting the most effective treatment. This method is shown to perform well compared with the two previously described methods for a wide range of true parameter values. In most cases, the performance of the new method is either similar to or, in some cases, better than either of the two previously proposed methods.

Flexible selection of a single treatment incorporating short-term endpoint information in a phase II/III clinical trial

Seamless phase II/III clinical trials in which an experimental treatment is selected at an interim analysis have been the focus of much recent research interest. Many of the methods proposed are based on the group sequential approach. This paper considers designs of this type in which the treatment selection can be based on short-term endpoint information for more patients than have primary endpoint data available. We show that in such a case, the familywise type I error rate may be inflated if previously proposed group sequential methods are used and the treatment selection rule is not specified in advance. A method is proposed to avoid this inflation by considering the treatment selection that maximises the conditional error given the data available at the interim analysis. A simulation study is reported that illustrates the type I error rate inflation and compares the power of the new approach with two other methods: a combination testing approach and a group sequential method that does not use the short-term endpoint data, both of which also strongly control the type I error rate. The new method is also illustrated through application to a study in Alzheimer's disease. © 2015 The Authors. Statistics in Medicine Published by John Wiley & Sons Ltd.

Stopping rules for phase II studies

This paper, the second in a series of three papers concerned with the statistical aspects of interim analyses in clinical trials, is concerned with stopping rules in phase II clinical trials. Phase II trials are generally small-scale studies, and may include one or more experimental treatments with or without a control. A common feature is that the results primarily determine the course of further clinical evaluation of a treatment rather than providing definitive evidence of treatment efficacy. This means that there is more flexibility available in the design and analysis of such studies than in phase III trials. This has led to a range of different approaches being taken to the statistical design of stopping rules for such trials. This paper briefly describes and compares the different approaches. In most cases the stopping rules can be described and implemented easily without knowledge of the detailed statistical and computational methods used to obtain the rules.

Ximelagatran versus warfarin for prophylaxis of venous thromboembolism in major orthopedic surgery: systematic review of randomized controlled trials

INTRODUÇÃO: O ximelagatrano foi recentemente estudada para profilaxia do tromboembolismo venoso (TEV). OBJETIVO: Avaliar se o ximelagatrano comparado com a varfarina melhora a profilaxia do TEV em pacientes submetidos à cirurgia ortopédica do joelho. FONTE DE DADOS: Estudos randomizados identificados por pesquisa eletrônica na literatura médica, até 2006, cujos dados foram compilados no programa Review Manager, versão 4.2.5. RESULTADOS: Foram incluídos três estudos randomizados bem conduzidos envolvendo 4.914 participantes. Foram definidos dois sub-grupos com dosagens diferentes de ximelagatrano (24 mg and 36 mg, duas vezes ao dia). O tratamento com ximelagatrano mostrou freqüência significantemente menor de TEV que o tratamento com varfarina, mas somente na dosagem de 36-mg [risco relativo, RR 0.72 ([intervalo de confiança, IC, 95% 0.64, 0.81), p < 0.00001]. A freqüência de TEV no sub-grupo de 24-mg foi similar a da varfarina [RR 0.86 (IC 95% 0.73, 1.01), p = 0.06]. Para TEV maior, embolia pulmonar, sangramento e sangramento maior não houve diferença entre varfarina e a ximelagatrano. Ao final do tratamento, a elevação da alanino-aminotransferase (ALT) foi menos freqüente no sub-grupo de 24 mg de ximelagatrano que no grupo da varfarina [RR 0.33 (IC 95% 0.12, 0.91) p = 0.03], mas no período de acompanhamento essa elevação foi maior com 36 mg de ximelagatrano [RR 6.97 (IC 95% 1.26, 38.50) p = 0.03]. CONCLUSÃO: O ximelagatrano foi mais efetivo que a varfarina quando usado em dosagens maiores (36 mg, 2 vezes ao dia), mas às expensas de aumento de enzimas hepáticas no período de acompanhamento.

Consenso brasileiro para a abordagem clínica e tratamento do hipotireoidismo subclínico em adultos: recomendações do Departamento de Tireoide da Sociedade Brasileira de Endocrinologia e Metabologia

INTRODUÇÃO: O hipotireoidismo subclínico (HSC), definido por concentrações elevadas do TSH em face de níveis normais dos hormônios tireoidianos, tem elevada prevalência no Brasil, particularmente entre mulheres e idosos. Embora um número crescente de estudos venha associando o HSC com maior risco de doença arterial coronariana e de mortalidade, não há ensaio clínico randomizado sobre o benefício do tratamento com levotiroxina na redução dos riscos e o tratamento permanece controverso. OBJETIVO: Este consenso, patrocinado pelo Departamento de Tireoide da Sociedade Brasileira de Endocrinologia e Metabologia e desenvolvido por especialistas brasileiros com vasta experiência clínica em tireoide, apresenta recomendações baseadas em evidências para uma abordagem clínica do paciente com HSC no Brasil. MATERIAIS E MÉTODOS: Após estruturação das questões clínicas, a busca das evidências disponíveis na literatura foi realizada inicialmente na base de dados do MedLine-PubMed e posteriormente nas bases Embase e SciELO - Lilacs. A força da evidência, avaliada pelo sistema de classificação de Oxford, foi estabelecida a partir do desenho de estudo utilizado, considerando-se a melhor evidência disponível para cada questão e a experiência brasileira. RESULTADOS: Os temas abordados foram definição e diagnóstico, história natural, significado clínico, tratamento e gestação, que resultaram em 29 recomendações para a abordagem clínica do paciente adulto com HSC. CONCLUSÃO: O tratamento com levotiroxina foi recomendado para todos os pacientes com HSC persistente com níveis séricos do TSH > 10 mU/L e para alguns subgrupos especiais de pacientes.

The Pediatric Rheumatology International Trials Organization American-College-of-Rheumatology provisional criteria for the evaluation of response to therapy in juvenile systemic lupus erythematosus: Prospective validation of the definition of improvement

Objective. To use the Pediatric Rheumatology International Trials Organization (PRINTO) core set of outcome measures to develop a validated definition of improvement for the evaluation of response to therapy in juvenile systemic lupus erythematosus (SLE).Methods. Thirty-seven experienced pediatric rheumatologists from 27 countries, each of whom had specific experience in the assessment of juvenile SLE patients, achieved consensus on 128 patient profiles as being clinically improved or not improved. Using the physicians' consensus ratings as the gold standard measure, the chi-square, sensitivity, specificity, false-positive and false-negative rates, area under the receiver operating characteristic curve, and kappa level of agreement for 597 candidate definitions of improvement were calculated. Only definitions with a kappa value greater than 0.7 were retained. The top definitions were selected based on the product of the content validity score multiplied by its kappa statistic.Results. The definition of improvement with the highest final score was at least 50% improvement from baseline in any 2 of the 5 core set measures, with no more than 1 of the remaining worsening by more than 30%.Conclusion. PRINTO proposes a valid and reproducible definition of improvement that reflects well the consensus rating of experienced clinicians and that incorporates clinically meaningful change in core set measures in a composite end point for the evaluation of global response to therapy in patients with juvenile SLE. The definition is now proposed for use in juvenile SLE clinical trials and may help physicians to decide whether a child with SLE responded adequately to therapy.

Longitudinal clinical evaluation of adjunct minocycline in the treatment of chronic periodontitis

Background: the clinical benefits of minocycline in combination with thorough scaling and root planing (SRP) have been examined in multicenter studies. The aim of this longitudinal investigation was to evaluate the clinical response to scaling and root planing combined with the use of locally delivered minocycline microspheres for 720 days in individuals with advanced chronic periodontitis.Methods: A total of 26 individuals aged 26 to 69 years (mean: 46.8 +/- 12.1 years) were included in this double-blind randomized clinical trial. After randomization, 13 individuals were selected for the test group (TG) and treated with SRP plus subgingival minocycline at baseline and 90, 180, and 270 days, and 13 individuals were selected for the control group (CG) and received SRP plus vehicle at the same time-points. Two homologous sites with probing depth (PD) >= 6 mm were chosen in each subject. To evaluate the clinical response after treatment, PD, plaque index (PI), and gingival index (GI) were assessed at baseline and 90, 180, 270, 360, and 720 days.Results: No statistical differences were found between test and control groups in relation to PD at the different timepoints. The mean values of PD demonstrated a higher reduction in the test group at 270 and 360 days. No statistical differences were observed at 90, 180, and 720 days between TG and CG (P < 0.05; Wilcoxon test). There were no statistically significant differences between TG and CG concerning PI and GI (P < 0.05; analysis of variance and t test) at all evaluated timepoints.Conclusion: Our findings demonstrated that both therapies reduced mean PD from 90 to 360 days; however, SRP combined with the use of subgingival minocycline showed a higher reduction at 270 and 360 days following therapy.

Structural Basis for Interaction of Inhibitors with Cyclin-Dependent Kinase 2

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Cryoablation vs radiofrequency ablation for the treatment of renal cell carcinoma: a meta-analysis of case series studies

OBJECTIVETo determine the current status of the literature regarding the clinical efficacy and complication rates of cryoablation vs radiofrequency ablation in the treatment of small renal tumours.METHODSA review of the literature was conducted. There was no language restriction. Studies were obtained from the following sources: MEDLINE, EMBASE and LILACS.Inclusion criteria were (i) case series design with more than one case reported, (ii) use of cryoablation or radiofrequency ablation, (iii) patients with renal cell carcinoma and, (iv) outcome reported as clinical efficacy.When available, we also quantified the complication rates from each included study.Proportional meta-analysis was performed on both outcomes with a random-effects model. The 95% confidential intervals were also calculated.RESULTSThirty-one case series (20 cryoablation, 11 radiofrequency ablation) met all inclusion criteria.The pooled proportion of clinical efficacy was 89% in cryoablation therapy from a total of 457 cases. There was a statistically significant heterogeneity between these studies showing the inconsistency of clinical and methodological aspects.The pooled proportion of clinical efficacy was 90% in radiofrequency ablation therapy from a total of 426 cases. There was no statistically significant heterogeneity between these studies.There was no statistically significant difference regarding complications rate between cryoablation and radiofrequency ablation.CONCLUSIONSThis review shows that both ablation therapies have similar efficacy and complication rates.There is urgency for performing clinical trials with long-term data to establish which intervention is most suitable for the treatment of small renal masses.

Efficacy of hormone therapy with and without methyltestosterone augmentation of venlafaxine in the treatment of postmenopausal depression: A double-blind controlled pilot study

Objective: This study evaluated the augmentation of venlafaxine with hormone therapy in the treatment of postmenopausal depression. The hormones evaluated were estrogen (0.625 mg) in combination with medroxyprogesterone acetate (2.5 mg) and methyltestosterone (2.5 mg). Design: Seventy-two menopausal women (mean age: 53.6 ± 4.27 years) diagnosed with depression (Montgomery-Åsberg Depression Rating Scale [MADRS] scores ≥ 20) were treated with venlafaxine and one of the following hormone therapy combinations, in a double-blind regimen: estrogen + medroxyprogesterone + methyltestosterone (group 1, n = 20); estrogen + medroxyprogesterone acetate (group 2, n = 20); methyltestosterone only (group 3, n = 16); and no hormone therapy (group 4, n = 16). Study duration was 24 weeks. Primary efficacy outcome was remission according to the MADRS, whereas secondary efficacy measures included the Clinical Global Impression (CGI), Blatt-Kupperman Index, and Women's Health Questionnaire (WHQ). Results: Forty-eight patients completed the study. All groups showed significant improvement from baseline. Group 3 demonstrated significant improvement on the MADRS compared with placebo (group 4) at weeks 20 (P = 0.048) and 24 (P = 0.030); effect size 8.04 (0.83; 15.26) (P = 0.029), but also had the highest dropout rate. Groups 1 and 3 had significant CGI improvement rates compared with placebo: 42.23% (P = 0.012) and 44.45% (P = 0.08), respectively. There were no differences in the WHQ or BKI scores among the groups. Conclusions: Methyltestosterone 2.5 mg had the highest effect size compared with placebo, but the high dropout rate prevented its efficacy from being determined. Estrogen plus medroxyprogesterone, combined with methyltestosterone or otherwise, demonstrated a trend toward increased efficacy of venlafaxine. Further larger-scale clinical trials are needed to elucidate the findings of this pilot study. © 2006 by The North American Menopause Society.

A comparison between diuretics and angiotensin-receptor blocker agents in patients with stage I hypertension (PREVER-treatment trial): Study protocol for a randomized double-blind controlled trial

Background: Cardiovascular disease is the leading cause of death in Brazil, and hypertension is its major risk factor. The benefit of its drug treatment to prevent major cardiovascular events was consistently demonstrated. Angiotensin-receptor blockers (ARB) have been the preferential drugs in the management of hypertension worldwide, despite the absence of any consistent evidence of advantage over older agents, and the concern that they may be associated with lower renal protection and risk for cancer. Diuretics are as efficacious as other agents, are well tolerated, have longer duration of action and low cost, but have been scarcely compared with ARBs. A study comparing diuretic and ARB is therefore warranted.Methods/design: This is a randomized, double-blind, clinical trial, comparing the association of chlorthalidone and amiloride with losartan as first drug option in patients aged 30 to 70 years, with stage I hypertension. The primary outcomes will be variation of blood pressure by time, adverse events and development or worsening of microalbuminuria and of left ventricular hypertrophy in the EKG. The secondary outcomes will be fatal or non-fatal cardiovascular events: myocardial infarction, stroke, heart failure, evidence of new subclinical atherosclerosis and sudden death. The study will last 18 months. The sample size will be of 1200 participants for group in order to confer enough power to test for all primary outcomes. The project was approved by the Ethics committee of each participating institution.Discussion: The putative pleiotropic effects of ARB agents, particularly renal protection, have been disputed, and they have been scarcely compared with diuretics in large clinical trials, despite that they have been at least as efficacious as newer agents in managing hypertension. Even if the null hypothesis is not rejected, the information will be useful for health care policy to treat hypertension in Brazil. Clinical trials registration number: ClinicalTrials.gov: NCT00971165. © 2011 Fuchs et al; licensee BioMed Central Ltd.

Clinical evaluation of a composite resin and a resin-modified glass-ionomer cement in non-carious cervical lesions: One-year results

Objectives: The objective of this study was to evaluate the clinical performance of 124 non-carious cervical lesion restorations at 12 months. Materials And Methods: Three study groups were formed according to the material and technique used. All teeth received 37% phosphoric acid etching in enamel and dentin. The teeth of Group I received the conventional adhesive system Scotch Bond Multi Purpose, followed by resin composite Filtek Z350; teeth of Group II were restored with resin-modified glassionomer cement Fuji II LC; teeth of Group III were restored with the same resin-modified glass-ionomer cement-however, before it was inserted, 2 coats of primer of the Scotch Bond Multi Purpose adhesive system were applied to dentinal tissue. The teeth were evaluated by 2 examiners with regard to the factors of retention, marginal adaptation, marginal discoloration, color alteration, presence of marginal caries lesion, anatomic shape, and sensitivity. Results: Application of the Kruskal-Wallis test showed no statistically significant difference for anatomic shape, marginal discoloration, color alteration, caries lesion, marginal adaptation, and sensitivity among the three study groups, but the variable retention presented statistically significant difference at 12 months, with Group III presenting a behavior superior to that of Group II but similar to that of Group I. Conclusion: The analyzed restorations of non-carious cervical lesions presented a good clinical performance at 12 months. © 2012 Nova Science Publishers, Inc.

Como desenhar e escrever um protocolo de pesquisa clínica em Cosmiatria

Cosmetic Dermatology is a growing subspecialty. High-quality basic science studies have been published; however, few double-blind, randomized controlled clinical trials, which are the major instrument for evidence-based medicine, have been conducted in this area. Clinical research is essential for the discovery of new knowledge, improvement of scientific basis, resolution of challenges, and good clinical practice. Some basic principles for a successful researcher include interest, availability, persistence, and honesty. It is essential to learn how to write a protocol research and to know the international and national regulatory rules. A complete clinical trial protocol should include question, background, objectives, methodology (design, variable description, sample size, randomization, inclusion and exclusion criteria, intervention, efficacy and safety measures, and statistical analysis), consent form, clinical research form, and references. Institutional ethical review board approval and financial support disclosure are necessary. Publication of positive or negative results should be an authors' commitment. © 2013 by Anais Brasileiros de Dermatologia.