The complexity of chronic graft-versus-host disease (GVHD) and the lack of established research methods have made it difficult to design, conduct, and analyze clinical trials involving subjects with this disease, even when promising treatment options are available. This consensus document was developed to offer an approach for overcoming these obstacles. Clinical trials in chronic GVHD should adhere to principles of good trial design and practice. Inclusion and exclusion criteria should allow as many subjects to participate as possible without compromising the interpretation of results. Pre-enrollment assessment of chronic GVHD characteristics should be standardized. The protocol should provide clear guidance about administration of study medication and other interventions. Methods of assessing response should be defined and validated in advance. Efficacy endpoints should be selected to reflect clinical benefit. Expert biostatistical support is needed to ensure the validity and reliability of trial results. The use of consistent standards in clinical trial designs to evaluate agents that have activity in pathogenic pathways could facilitate advances in the treatment of chronic GVHD.
Biochemistry H-2RIIBP, a member of the nuclear hormone receptor superfamily that binds to both the regulatory element of major histocompatibility class I genes and the estrogen response element (H-2 genes/zinc-finger protein/trans-acting factor/steroid hormone receptor) KAZUSHIGE Major histocompatibility complex (MHC) class I genes are expressed in a tissue-specific and developmentally dependent fashion and are inducible by interferons. Their transcription is controlled by two conserved upstream cis-acting sequences, the MHC class I regulatory element (CRE) and the interferon consensus sequence (ICS) (refs. 1-3; Fig. la). These elements elicit positive and negative regulation as well as interferon-mediated induction of the MHC class I genes. In the MHC CRE there are at least three sequences, regions I-III, that bind nuclear factors (4). Region I, composed of a palindrome, binds KbF1 (5) and NF-KB and H2TF1 (6) and has an enhancer activity in fibroblasts. The upstream region II binds another factor and also exerts an enhancer activity (7). Region I binding activity is expressed in tissues that express MHC class I genes at high levels, while the region II factor is detected in various tissues irrespective of the MHC class I gene expression (7). To isolate genes encoding transacting factors for the MHC CRE, we screened a phage expression library by a method that relies on the detection of Table 1
Children deserve medicines that are adapted to their needs. The need to include children in drug development has been recognised increasingly over the past few decades. Legal and regulatory frameworks are well established in the EU and US. The amount of work done to study medicines for children is significantly greater than it was 10 years go. Proof-of-concept has been demonstrated for all segments of the paediatric drug development pipeline. It is now time to examine how the practice of developing medicines for children has evolved within those frameworks and to determine how that work should be generalised. This review describes the development of medicines for children and critically appraises the work that has been done within those frameworks. Significant effort is needed to realize the potential provided by the current regulatory framework. Using the work programme of the Global Research in Paediatrics (GRiP) Network of Excellence as a template we outline current work and future growing points.
The purpose of this report is to summarize information on oxaliplatin, a drug recently approved by the U.S. Food and Drug Administration. Information provided includes regulatory history, study design, efficacy and safety results, and pertinent literature references.A single, multicenter, randomized trial, enrolling 463 patients with metastatic colorectal carcinoma whose disease had recurred or progressed during or within 6 months of completion of therapy with the combination of bolus 5-fluorouracil (FU)/leucovorin (LV) and irinotecan, was submitted. Study arms included infusional 5-FU/LV alone (arm A), oxaliplatin alone (arm B), and the combination of oxaliplatin and infusional 5-FU/LV(arm C). Oxaliplatin, at a dose of 85 mg/m 2 , was administered to patients in arms B and C intravenously over 2 hours in 250-500 ml of dextrose 5% in water (D5W) on day 1 only. A 200-mg/m 2 dose of LV was administered simultaneously to arm C patients, in a separate bag using a Y-line, or alone to arm A patients, by i.v. infusion, over 2 hours. 5-FU was then administered to arms A and C patients, first as a bolus injection over 2-4 minutes at a dose of 400 mg/m 2 , then as a continuous infusion in 500 ml of D5W over 22 hours at a dose of 600 mg/m 2 . LV was repeated on day 2 of the cycle (arms A and C) followed by a 400-mg/m 2 5-FU bolus and a 600-mg/m 2 22-hour infusion. Treatment was repeated every 2 weeks.Response rate was the prespecified end point for accelerated approval. Time to progression (TTP) was a secondary end point. The prespecified primary comparison was between the 5-FU/LV regimen and the 5-FU/LV/ oxaliplatin combination regimen. The three arms were well balanced for patient prognostic factors.There were no complete responders. The partial response rates were 0%, 1%, and 9% for the 5-FU/LV, oxaliplatin, and oxaliplatin plus 5-FU/LV treatments, respectively (p = 0.0002, arm C versus arm A). The median times to radiographic tumor progression, based LEARNING OBJECTIVESAfter completing this course, the reader will be able to:1. Describe the safe and effective use of oxaliplatin in patients with metastatic carcinoma of the colon or rectum whose disease has recurred or progressed during or within 6 months of completion of first-line therapy with the combination of bolus 5-FU/LV and irinotecan.2. List the major common toxicities of oxaliplatin. Discuss the limitations of the results of the reviewed trial.Access and take the CME test online and receive one hour of AMA PRA category 1 credit at CME.TheOncologist.com CME CMEThis material is protected by U.S. Copyright law. Unauthorized reproduction is prohibited. For reprints contact: Reprints@AlphaMedPress.com Ibrahim, Hirschfeld, Cohen et al. 9 on available radiographs, were 2.7 months, 1.6 months, and 4.6 months, respectively (p < 0.0001, arm C versus arm A).Common adverse events associated with the combination treatment included peripheral neuropathy, fatigue, diarrhea, nausea, vomiting, stomatitis, and abdominal pain. Neutropenia was the major hematologic t...
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