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Biomedical subjects

Malcolm A Smith

Publications and source records attributed to Malcolm A Smith.

16 recordsLinked to original sources
PubMed2008

SK-NEP-1 and Rh1 are Ewing family tumor lines.

The utility of preclinical models of childhood cancers is contingent upon reliably classifying them with their corresponding clinical counterparts. Molecular tools such as gene expression profiling allow researchers to confirm the similarity between clinical tumors and preclinical models. We describe the use of gene expression profiling to show that SK-NEP-1, a cell line previously thought to represent anaplastic Wilms tumor, is instead related to Ewing sarcoma. RT-PCR confirmed that SK-NEP-1 expresses EWS-FLI1 gene fusion transcripts characteristic of Ewing sarcoma, and DNA sequencing demonstrated the joining of exon 7 of EWS with exon 5 of FLI1 for these transcripts. Rh1, which was previously categorized as an alveolar rhabdomyosarcoma cell line, also has a gene expression profile suggestive of Ewing sarcoma and expresses EWS-FLI1 fusion transcripts in which exon 7 of EWS is joined with exon 6 of FLI1. These examples illustrate the importance of molecularly characterizing pediatric preclinical models used for testing new agents.

Adult↗
PubMed2007

Credentialing preclinical pediatric xenograft models using gene expression and tissue microarray analysis.

Human tumor xenografts have been used extensively for rapid screening of the efficacy of anticancer drugs for the past 35 years. The selection of appropriate xenograft models for drug testing has been largely empirical and has not incorporated a similarity to the tumor type of origin at the molecular level. This study is the first comprehensive analysis of the transcriptome of a large set of pediatric xenografts, which are currently used for preclinical drug testing. Suitable models representing the tumor type of origin were identified. It was found that the characteristic expression patterns of the primary tumors were maintained in the corresponding xenografts for the majority of samples. Because a prerequisite for developing rationally designed drugs is that the target is expressed at the protein level, we developed tissue arrays from these xenografts and corroborated that high mRNA levels yielded high protein levels for two tested genes. The web database and availability of tissue arrays will allow for the rapid confirmation of the expression of potential targets at both the mRNA and the protein level for molecularly targeted agents. The database will facilitate the identification of tumor markers predictive of response to tested agents as well as the discovery of new molecular targets.

Cell Line, Tumor↗
PubMed2007

The pediatric preclinical testing program: description of models and early testing results.

BACKGROUND: The Pediatric Preclinical Testing Program (PPTP) is an initiative supported by the National Cancer Institute (NCI) to identify novel therapeutic agents that may have significant activity against childhood cancers. The PPTP has established panels of childhood cancer xenografts and cell lines to be used for in vivo and in vitro testing. These include panels for Wilms tumor, sarcomas (rhabdomyosarcoma, Ewing sarcoma, and osteosarcoma), neuroblastoma, brain tumors (glioblastoma, ependymoma, and medulloblastoma), rhabdoid tumors (CNS and renal), and acute lymphoblastic leukemia (ALL). Here, we describe the characteristics of the in vivo tumor panels and report results for the in vivo evaluation of two standard agents, vincristine and cyclophosphamide. PROCEDURES: Solid tumors were grown subcutaneously in immune-deficient mice and tumor dimensions were measured weekly. ALL xenografts were inoculated intravenously and human CD45-positive cells were enumerated weekly. RESULTS: Vincristine-induced objective responses in 6 of 24 (25%) and cyclophosphamide-induced objective responses in 18 of 28 (64%) solid tumor models. Comparable assessments of high levels of activity for these two agents were obtained using a tumor growth delay (TGD) measure. Both agents induced regressions in each of the ALL models evaluated. CONCLUSIONS: We have established 51 solid tumor and 10 ALL in vivo models. The models identify vincristine and cyclophosphamide as having broad-spectrum activity. The PPTP tumor panels appear to generally recapitulate the activity of these agents against specific childhood cancers and to have the potential for identifying novel agents having significant clinical activity.

Animals↗
PubMed2005

Design issues of randomized phase II trials and a proposal for phase II screening trials.

Future progress in improving cancer therapy can be expedited by better prioritization of new treatments for phase III evaluation. Historically, phase II trials have been key components in the prioritization process. There has been a long-standing interest in using phase II trials with randomization against a standard-treatment control arm or an additional experimental arm to provide greater assurance than afforded by comparison to historic controls that the new agent or regimen is promising and warrants further evaluation. Relevant trial designs that have been developed and utilized include phase II selection designs, randomized phase II designs that include a reference standard-treatment control arm, and phase II/III designs. We present our own explorations into the possibilities of developing "phase II screening trials," in which preliminary and nondefinitive randomized comparisons of experimental regimens to standard treatments are made (preferably using an intermediate end point) by carefully adjusting the false-positive error rates (alpha or type I error) and false-negative error rates (beta or type II error), so that the targeted treatment benefit may be appropriate while the sample size remains restricted. If the ability to conduct a definitive phase III trial can be protected, and if investigators feel that by judicious choice of false-positive probability and false-negative probability and magnitude of targeted treatment effect they can appropriately balance the conflicting demands of screening out useless regimens versus reliably detecting useful ones, the phase II screening trial design may be appropriate to apply.

Clinical Trials, Phase II as Topic↗
PubMed2005

Preliminary data release for randomized clinical trials of noninferiority: a new proposal.

Noninferiority trials often require a long follow-up period for the data to reach the maturity needed for definitive analysis. A proposal is presented that allows for early release of outcome data from a carefully specified subset of noninferiority trials. This subset is defined so that the early release of the data will be potentially useful to patients who face a treatment decision but will not compromise the integrity of the trial or interfere with the completion of the trial to its definitive analysis. In particular, the release of the data will only occur after the last participant has been randomly assigned and is off treatment-arm-specific therapy and only if it is unlikely that subsequent treatment and/or follow-up practices will change based on the knowledge of released data. In contrast to standard interim monitoring, (1) the release of the data would be automatic and independent of the observed data, and (2) the trial would continue on to its planned final analysis and not be stopped. Examples are given demonstrating how the proposal would work, along with a discussion of possible objections to the proposal.

Clinical Trials Data Monitoring Committees↗
PubMed2004

Tissue collection for correlative studies in childhood cancer clinical trials: ethical considerations and special imperatives.

Federal regulations prescribe distinct protections for children participating in research studies. Procedures for collecting tissue specimens from children solely for research purposes must pose no more than a minor increase over minimum risk, thereby limiting the approvable correlative biologic studies to evaluate molecularly targeted agents in children with cancer. Ethical issues arise when approvable correlative studies are a mandatory component of an early-phase pediatric clinical trial of new anticancer agents. The National Cancer Institute Cancer Therapy Evaluation Program sponsored a workshop in 2002 to discuss tissue collection for correlative biologic studies in early-phase childhood cancer clinical studies of molecularly targeted agents. Workshop participants recommended the following: (1) tissue specimens for correlative studies should provide vital clinical and scientific results to qualify for early-phase pediatric study consideration; (2) parents should receive a realistic appraisal of the risks, requirements, and potential for benefit of phase I protocol participation; (3) investigators should clearly distinguish clinically necessary procedures from research procedures of no benefit to the child to improve correlative study informed consent; and (4) participation in correlative research studies included in clinical trials generally should be voluntary. The need to acquire important biologic data regarding new molecular agents will challenge the ingenuity of pediatric cancer researchers, necessitating the application of highly sensitive laboratory assay methods, new imaging procedures, and preclinical models of childhood cancer. Such innovative methods can allow necessary scientific information to be obtained while simultaneously respecting the protections appropriately afforded to children participating in research studies and minimizing the burden of research participation for children with cancer and their families.

Child↗
PubMed2004

A window on reality?

Explore the source record for details and available documents.

Antineoplastic Agents↗
PubMed2004

Commentary on "European collaboration in trials of new agents for children with cancer" by Ablett et al.

Recent progress in establishing a European network to conduct paediatric oncology phase I/II clinical trials calls attention to the challenges facing researchers developing new agents for children with cancer. These challenges include: ensuring that effective infrastructures are in place to safely and efficiently conduct early phase clinical trials in children while meeting all ethical and regulatory requirements associated with such trials; obtaining timely access to new agents from pharmaceutical sponsors for both preclinical testing and for phase I and phase II testing; and effectively prioritizing new agents for evaluation in children so that those agents most likely to benefit children with specific cancers are brought forward for clinical testing. The use of public funds to develop and maintain clinical trials infrastructures devoted to paediatric oncology drug development can help in addressing these challenges and can facilitate the timely paediatric evaluation of new agents, thereby contributing to the goal of identifying more effective treatments for children with cancer.

Antineoplastic Agents↗
PubMed2003

Biology of childhood osteogenic sarcoma and potential targets for therapeutic development: meeting summary.

Childhood osteogenic sarcoma (OS) is a rare bone cancer occurring primarily in adolescents. The North American pediatric cooperative groups have performed a series of clinical treatment trials in this disease over the past several decades, and biology studies of tumor tissue have been an important study component. A meeting was held in Bethesda, Maryland on November 29-30, 2001, sponsored by the NIH Office of Rare Diseases, the Children's Oncology Group, and the National Cancer Institute-Cancer Therapy Evaluation Program with the general objectives: (a) to review the current state of knowledge regarding OS biology; (b) to identify, prioritize, and support the development of biology studies of potential clinical relevance in OS; and (c) to discuss the available tissue resources and the appropriate methods for analysis of OS samples for the conduct of biology studies. This report summarizes the information presented and discussed by the meeting participants.

Angiogenesis Inhibitors↗
PubMed2002

Study design and cohort characteristics of the Childhood Cancer Survivor Study: a multi-institutional collaborative project.

BACKGROUND: Increased attention has been directed toward the long-term health outcomes of survivors of childhood cancer. To facilitate such research, a multi-institutional consortium established the Childhood Cancer Survivor Study (CCSS), a large, diverse, and well-characterized cohort of 5-year survivors of childhood and adolescent cancer. PROCEDURE: Eligibility for the CCSS cohort included a selected group of cancer diagnoses prior to age 21 years between 1970-1986 and survival for at least 5 years. RESULTS: A total of 20,276 eligible subjects were identified from the 25 contributing institutions, of whom 15% are considered lost to follow-up. Currently, 14,054 subjects (69.3% of the eligible cohort) have participated by completing a 24-page baseline questionnaire. The distribution of first diagnoses includes leukemia (33%), lymphoma (21%), neuroblastoma (7%), CNS tumor (13%), bone tumor (8%), kidney tumor (9%), and soft-tissue sarcoma (9%). Abstraction of medical records for chemotherapy, radiation therapy, and surgical procedures has been successfully completed for 98% of study participants. Overall, 78% received radiotherapy and 73% chemotherapy. CONCLUSION: The CCSS represents the largest and most extensively characterized cohort of childhood and adolescent cancer survivors in North America. It serves as a resource for addressing important issues such as risk of second malignancies, endocrine and reproductive outcome, cardiopulmonary complications, and psychosocial implications, among this unique and ever-growing population.

Adolescent↗
PubMed2002

Testing of new agents in childhood cancer preclinical models: meeting summary.

A workshop on pediatric preclinical testing, sponsored by the National Cancer Institute and the Children's Oncology Group Phase 1 Consortium, was held on June 26-27, 2001 in Bethesda, Maryland. Drs. Peter Adamson, Peter Houghton, and Malcolm Smith organized and hosted the meeting. There were 20 participants from 12 institutions. The primary objectives of the workshop included: (a) development of a working inventory of available preclinical models (including human tumor xenografts in immunodeficient mice, transgenic and syngeneic tumors, and selected in vitro models), with a basic understanding of the strengths and weaknesses of each as possible components of a preclinical testing program; (b) identification of the key scientific issues related to establishment of a program for preclinical testing of new agents for their applicability to childhood cancers; and (c) identification of the key infrastructure requirements for a program for preclinical testing of new agents for their applicability to childhood cancers. This report is a synthesis of the workshop's presentations and discussions.

Animals↗