Temozolomide pharmacodynamics in patients with metastatic melanoma: dna damage and activity of repair enzymes O6-alkylguanine alkyltransferase and poly(ADP-ribose) polymerase-1.

PURPOSE: Temozolomide, a DNA methylating agent used to treat melanoma, induces DNA damage, which is repaired by O6-alkylguanine alkyltransferase (ATase) and poly(ADP-ribose) polymerase-1 (PARP-1)-dependent base excision repair. The current study was done to define the effect of temozolomide on DNA integrity and relevant repair enzymes as a prelude to a phase I trial of the combination of temozolomide with a PARP inhibitor. EXPERIMENTAL DESIGN: Temozolomide (200 mg/m2 oral administration) was given to 12 patients with metastatic malignant melanoma. Peripheral blood lymphocytes (PBL) were analyzed for PARP activity, DNA single-strand breakage, ATase levels, and DNA methylation. PARP activity was also measured in tumor biopsies from 9 of 12 patients and in PBLs from healthy volunteers. RESULTS: Temozolomide pharmacokinetics were consistent with previous reports. Temozolomide therapy caused a substantial and sustained elevation of N7-methylguanine levels, a modest and sustained reduction in ATase activity, and a modest and transient increase in DNA strand breaks and PARP activity in PBLs. PARP-1 activity in tumor homogenates was variable (828 +/- 599 pmol PAR monomer/mg protein) and was not consistently affected by temozolomide treatment. CONCLUSIONS: The effect of temozolomide reported here are consistent with those documented in previous studies with temozolomide and similar drug, dacarbazine, demonstrating that a representative patient population was investigated. Furthermore, PARP activity was not inhibited by temozolomide treatment and this newly validated pharmacodynamic assay is therefore suitable for use in a proof-of-principle phase I trial a PARP-1 inhibitor in combination with temozolomide.     

Phase I and pharmacologic study of infusional topotecan and Carboplatin in relapsed and refractory acute leukemia.

PURPOSE: To assess the maximum tolerated dose, toxicities, pharmacokinetics, and antileukemic activity of topotecan and carboplatin in adults with recurrent or refractory acute leukemias. EXPERIMENTAL DESIGN: Patients received topotecan and carboplatin by 5-day continuous infusion at nine dose levels. Patients achieving a complete remission received up to two additional courses for consolidation. Plasma topotecan and ultrafilterable platinum were assayed on days 1 to 5. In addition, pretreatment levels of various polypeptides in leukemic cells were examined by immunoblotting to assess possible correlations with response. RESULTS: Fifty-one patients received a total of 69 courses of therapy. Dose-limiting toxicity consisted of grade 4/5 typhlitis and grade 3/4 mucositis after one course of therapy or grade 4 neutropenia and thrombocytopenia lasting >50 days when a second course was administered on day 21. Among 45 evaluable patients, there were 7 complete remissions, 2 partial remissions, 1 incomplete complete remission, and 1 reversion to chronic-phase chronic myelogenous leukemia. Topotecan steady-state plasma concentrations increased with dose. No accumulation of topotecan or ultrafilterable platinum occurred between days 1 and 5 of therapy. Leukemic cell levels of topoisomerase I, checkpoint kinase 1, checkpoint kinase 2, and Mcl-1 correlated with proliferating cell nuclear antigen but not with response. In contrast, low Bcl-2 expression correlated with response (P = 0.014, Mann-Whitney U test). CONCLUSIONS: The maximum tolerated dose was 1.6 mg/m(2)/d topotecan plus 150 mg/m(2)/d carboplatin. The complete remission rate in a heavily pretreated population was 16% (33% at the highest three dose levels). Responses seem to correlate with low pretreatment blast cell Bcl-2 expression.     

Rehabilitation of ataxic gait following cerebellar lesions: Applying theory to practice

Damage to the cerebellum can result in ataxic gait, which affects the ability to walk safely and independently. Physiotherapy is the main treatment for ataxic gait, but there is limited high-quality evidence for interventions used. This review explores the neural mechanisms of the symptoms of ataxic gait, by discussing the cerebellum’s role in coordination, motor learning, anticipatory postural control, balance reactions and adapting gait to meet environmental demands. It discusses mechanisms that occur at cellular level throughout the whole cerebellum and then focuses on difficulties that arise from damage to specific lobes of the cerebellum. Physiotherapy-based interventions, such as balance training, developing postural control, specific gait training, and use of compensatory orthotics and aids, are discussed in relation to the theoretical understanding of cerebellar functioning. Consideration is given to difficulties of using trial-and-error–based learning, which will impact on teaching techniques and strategies used during gait rehabilitation. This theoretical understanding will aid physiotherapists to target their assessment, treatment, management, and goal setting with individuals who have difficulties with ataxic gait following a cerebellar lesion.     

Book reviews

History

The End of History and the Last Man By Francis Fukuyama. Hamish Hamilton, London, 1992, 418 pp., £20.00, ISBN 0–24–1301–1

Aeskulap oder Mars? [Asdepius or Mars] (subtitle: Doctors against War) Edited by T.M. Ruprecht and C. Jenssen. (In German). Donat Verlag, Bremen, 1991, 604pp., 48.00DM, ISBN 3–924444–51‐X.

The Gulf War

Hidden Casualties, Volume II: The Environmental, Health and Political Consequences of the Persian Gulf War Edited by Saul Bloom, John M. Miller and Philippa Winkler, with Ross Mirkarimi. ARC/Arms Control Research Center, 942 Market St, Suite 202, San Francisco CA 94102, USA, 1993, 350pp.

Medicine and War

Wounded Healthy Cities: Searching for Health and Human Dignity A report by the Croatian Healthy Cities Network. Compiled by Ivana Eterovi?, Selma Sogori?, and Slobodan Lang. Edited by John Middleton. Sandwell Public Health Publications, 1992, PO Box 1953, Lyndon, West Bromwich, West Midlands, B71 4NA, pp. 68, £5.95 incl. p&;p, ISBN 0–9517035–4–4.

Public Health

Health through Public Policy, the Greening of Public Health Edited by Peter Draper. Greenprint, London, 1991, x + 258 pp., £9.99, ISBN 1–85425–045–0.

Economics

The Culture of Contentment By John Kenneth Galbraith. Sinclair Stevenson, London, 1992, 195pp., £14.95, ISBN 1–85619–147–8.

Beyond the Limits: Global Collapse or a Sustainable Future By Donella Meadows, Dennis Meadows and Jorgen Randers. Earthscan, London, 1992, xix + 300 pp., £19.95, ISBN 1–85383–130–1 (hbk), £11.95, ISBN 1–85383–131‐X (pbk).

Human Rights

Refugees: Rationing the Right to Life By David Keen. Zed Books, London, 1992, 86pp., £29.9S(hbk), ISBN 1–85649–091–2, £9.95(pbk), ISBN 1–85649–092–0.

Deadly Silence: Black Deaths in Custody Institute of Race Relations, London, 1991, 75pp., £4 (pbk), ISBN 085001–038–1.

Torture and Its Consequences: Current Treatment Approaches Edited by Metin Ba?o?lu. Cambridge University Press, Cambridge, 1992, xxiii + 527pp., £55.00, ISBN 0–521–39299–3

Militarism and the Environment

Taking Stock: The Impact of Militarism on the Environment Working Group on Militarism and the Environment. Science for Peace, 1992, 30pp., Can$ 4.00 (available from WGME, University College, University of Toronto, Ontario, Canada M5S 1A1).

AIDS

The AIDS Epidemic: Economic, Political and Security Implications By Alan Whiteside and David FitzSimons. Research Institute for the Study of Conflict and Terrorism, London, 1992, 43pp., £9.00, ISSN 0069–8792 (available from 136 Baker Street, London W1M 1FH)     

Validation of the National Institute of Neurological Disorders and Stroke Spinal Cord Injury MRI Common Data Elements Instrument

BACKGROUND AND PURPOSE:The National Institute of Neurological Disorders and Stroke common data elements initiative was created to provide a consistent method for recording and reporting observations related to neurologic diseases in clinical trials. The purpose of this study is to validate the subset of common data elements related to MR imaging evaluation of acute spinal cord injury.MATERIALS AND METHODS:Thirty-five cervical and thoracic MR imaging studies of patients with acute spinal cord injury were evaluated independently in 2 rounds by 5 expert reviewers. Intra- and interrater agreement were calculated for 17 distinct MR imaging observations related to spinal cord injury. These included ordinal, categoric, and continuous measures related to the length and location of spinal cord hemorrhage and edema as well as spinal canal and cord measurements. Level of agreement was calculated using the interclass correlation coefficient and kappa.RESULTS:The ordinal common data elements spinal cord injury elements for lesion center and rostral or caudal extent of edema or hemorrhage demonstrated agreement ranging from interclass correlation coefficient 0.68 to 0.99. Reproducibility ranged from 0.95 to 1.00. Moderate agreement was observed for absolute length of hemorrhage and edema (0.54 to 0.60) with good reproducibility (0.78 to 0.83). Agreement for the Brain and Spinal Injury Center score showed the lowest interrater agreement with an overall kappa of 0.27 (0.20, 0.34). For 7 of the 8 variables related to spinal cord injury, agreement improved between the first and second evaluation. Continuous diameter measures of the spinal cord and spinal canal using interclass correlation coefficient varied substantially (0.23 to 0.83).CONCLUSIONS:Agreement was more consistent for the ordinal measures of spinal cord injury than continuous measures. Good to excellent agreement on length and location of spinal cord hemorrhage and edema can be achieved with ordinal measures alone.

In 2006, the National Institute of Neurological Disorders and Stroke (NINDS) began a process to develop common data elements (CDEs) to provide a standardized method for the collection of clinical data related to neurologic diseases.^1-3 Recognizing that there is a lack of clear and consistent terminology for spine disorders, particularly spinal cord injury (SCI), in 2014, the NINDS convened a workgroup comprising expert stakeholders for the development of SCI CDE instruments that included clinical care assessments and imaging.^3-8 This new set of SCI CDE instruments aimed to increase the efficiency and value of clinical research studies and treatment, increase data quality, facilitate data sharing, and help educate new clinical investigators.³ Investigators are expected to incorporate the CDE modules in grant applications and National Institutes of Health–funded research.The MR imaging SCI CDE subset was created to be a comprehensive and standardized terminology for describing MR imaging findings in patients with SCI. This collection consists of a case report form (CRF) containing 35 discrete measures and responses divided into 4 main categories: general imaging characteristics, spinal injury features, canal and cord measurements, and chronic SCI features. The responses are of 3 types: Boolean, categoric, and an ordinal range representing specific anatomic locations. These measures were chosen to represent both objective and subjective assessment derived from routine clinical MR images. The workgroup codified these features using existing CDEs that have proved value in the published literature, and when ones did not exist, the workgroup developed the feature and the response parameters.As with the development of any CRF used for a clinical trial or research, the goal is to provide an instrument that provides useful data representations that are reproducible across trained observers and institutions, require minimal cognitive effort, minimize ambiguity, and are both accurate and precise. Reproducibility of the observations through rigorous testing by multiple observers is a needed step to validate the instrument before clinical or research use. However, the evaluation process may not entirely reproduce the clinical environment in which it is meant to be used such that datasets and observers are overly prepared or optimized. Therefore, the goal of this study is to determine the inter- and intrarater reliability of the NINDS MR imaging CDEs when assessed by MR imaging experts with familiarity with SCI. We hypothesize that there will be good to excellent agreement (kappa >0.4) among the expert raters after limited training.