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Biomedical subjects

Mark Bernstein

Publications and source records attributed to Mark Bernstein.

At least 37 records · Page 2Linked to original sources
PubMed2004

Imatinib mesylate (STI571) for treatment of children with Philadelphia chromosome-positive leukemia: results from a Children's Oncology Group phase 1 study.

The purpose of this study was to determine dose-limiting toxicities and pharmacokinetics of imatinib in children with refractory or recurrent Philadelphia chromosome-positive (Ph(+)) leukemias. Oral imatinib was administered daily at dose levels ranging from 260 to 570 mg/m(2). Plasma pharmacokinetic studies were performed on days 1 and 8 of course 1. There were 31 children who received 479 courses of imatinib. The most common toxicities encountered, which occurred in less than 5% of courses, were grade 1 or 2 nausea, vomiting, fatigue, diarrhea, and reversible increases in serum transaminases. One patient at the 440-mg/m(2) dose level had dose-limiting weight gain. There were no other first-course dose-limiting toxicities. A maximum tolerated dosage was not defined. Among 12 chronic myeloid leukemia (CML) patients evaluable for cytogenetic response, 10 had a complete response and 1 had a partial response. Among 10 acute lymphoblastic leukemia (ALL) patients evaluable for morphologic response, 7 achieved an M1 and 1 achieved an M2 bone marrow. We observed marked interpatient variability in the pharmacokinetic parameters. In conclusion, we found that daily oral imatinib is well tolerated in children at doses ranging from 260 to 570 mg/m(2). Doses of 260 and 340 mg/m(2) provide systemic exposures similar to those of adults who are treated with daily doses of 400 and 600 mg, respectively.

Adolescent↗
PubMed2004

Phase I trial of tirapazamine and cyclophosphamide in children with refractory solid tumors: a pediatric oncology group study.

PURPOSE: To determine the dose limiting toxicity (DLT), maximum-tolerated dose (MTD), and pharmacokinetic profile of tirapazamine (Sanofi Synthelabo Research, Malvern, PA) combined with cyclophosphamide in children with recurrent solid tumors. PATIENTS AND METHODS: Patients received a 2-hour infusion of tirapazamine, followed by 1,500 mg/m(2) cyclophosphamide, and mesna once every 3 weeks. Dose escalation of tirapazamine began at 250 mg/m(2) and was increased by 30% in subsequent cohorts. If DLT was hematologic, less-heavily pretreated patients were to be enrolled until their DLTs were encountered, and MTDs defined. Pharmacokinetic profiles were also characterized. RESULTS: Twenty-three patients were enrolled onto the study. Pharmacokinetic data were calculated for 22 patients. Prolonged neutropenia was the DLT at 420 mg/m(2) in heavily pretreated patients. Grade 3, reversible ototoxicity was the DLT in less-heavily pretreated patients at 420 mg/m(2). Two (one with neuroblastoma and one with rhabdomyosarcoma) had partial responses. One child with neuroblastoma had prolonged stable disease (10 cycles) at a dose of 250 mg/m(2). This patient had disease detectable in the bone marrow only and all evidence of bone marrow involvement resolved for 17 cycles of therapy. Four other patients had stable disease. An apparent dose-proportional increase in tirapazamine maximal concentration and area under the curve(last) was observed. Tirapazamine clearance, volume of distribution at steady-state, and terminal half-life did not appear to be dose-dependent. CONCLUSION: The recommended dose of tirapazamine given with 1,500 mg/m(2) of cyclophosphamide once every 3 weeks is 325 mg/m(2). Neutropenia and ototoxicity were dose-limiting. Based on early evidence of antitumor activity, additional studies appear warranted.

Adolescent↗
PubMed2004

Doctors' duty to disclose error: a deontological or Kantian ethical analysis.

Medical (surgical) error is being talked about more openly and besides being the subject of retrospective reviews, is now the subject of prospective research. Disclosure of error has been a difficult issue because of fear of embarrassment for doctors in the eyes of their peers, and fear of punitive action by patients, consisting of medicolegal action and/or complaints to doctors' governing bodies. This paper examines physicians' and surgeons' duty to disclose error, from an ethical standpoint; specifically by applying the moral philosophical theory espoused by Immanuel Kant (ie. deontology). The purpose of this discourse is to apply moral philosophical analysis to a delicate but important issue which will be a matter all physicians and surgeons will have to confront, probably numerous times, in their professional careers.

Bioethical Issues↗
PubMed2004

A qualitative study of attitudes toward error in patients facing brain tumour surgery.

BACKGROUND: Medical error is an extremely important component of patient safety and requires intense study. The present investigation undertook to examine patients' perceptions and attitudes regarding medical error. METHODS: Qualitative case study methodology was used. We conducted 30 face-to-face interviews with patients within one week of undergoing a neurosurgical operation for a brain tumour. Interviews were audiotaped and transcribed and the data subjected to thematic analysis. RESULTS: Three overarching themes emerged from the data: 1) trust in the patient's surgeon was of paramount importance; 2) patients' views toward medical error varied between fear and vulnerability to no concern; and 3) discussion of error was felt to be beneficial as it could help the medical profession decrease future errors and could help dispel the patient's fear and anxiety about the upcoming surgery. CONCLUSIONS: Patients' trust in their physician/surgeon is of paramount importance in allaying their fears about the possible occurrence and impact of medical error during their treatment. The level of concern about error varies among patients, but most felt that discussion of error was a good thing.

Adolescent↗
PubMed2004

Enhancement of antineoplastic action of 5-aza-2'-deoxycytidine by phenylbutyrate on L1210 leukemic cells.

Epigenetic changes, such as aberrant DNA methylation that silences tumor suppressor genes (TSGs), can play an important role in the development of leukemia. The DNA methylation inhibitor, 5-aza-2'-deoxycytidine (5-AZA-CdR), can reactivate these silent TSGs and is an interesting agent to investigate for therapy of leukemia. It has been reported that the effectiveness of 5-AZA-CdR to reactivate TSG can be enhanced by inhibitors of histone deacetylase (HDIs). HDIs can convert a compact chromatin structure to an open configuration that facilitates gene expression. An interesting HDI is phenylbutyrate (PB), which has shown some clinical activity for the therapy of leukemia. In this report we have investigated the antineoplastic activity of 5-AZA-CdR and PB alone and in combination on murine L1210 lymphoid leukemic cells. The in vitro treatment of 5-AZA-CdR and PB in combination produced a greater inhibition of growth, DNA synthesis, and also a greater reduction on colony formation on both L1210 and human HL-60 leukemic cells as compared to either drug alone. The combination also produced a synergistic activation of the TSG, p15CDN2B, in the L1210 cells. In mice with L1210 leukemia the combination showed enhanced antineoplastic activity. We also observed an enhancement of the antineoplastic activity of this combination in mice with L1210 leukemia. These data provide a rationale to investigate 5-AZA-CdR and PB in patients with advanced leukemia.

Animals↗
PubMed2004

Surgical innovation or surgical evolution: an ethical and practical guide to handling novel neurosurgical procedures.

OBJECT: Surgical innovation is an important driver of improvements in technique and technology, which ultimately translates into improvements in patients' outcomes. Nevertheless, patients may face new risks of morbidity and mortality when surgical innovation is used, and well-intentioned surgical "experimentation" on patients must be regulated and monitored. In this paper the authors examine the challenges of defining surgical innovation and briefly review the literature on this challenging subject. METHODS: Using examples from the field of neurosurgery and in part from the personal experience of the senior author, the authors develop a model of levels of experimental acuity of surgical procedures and offer recommendations on how these procedures would best be regulated. CONCLUSIONS: The authors propose guidelines for determining the need for regulation of innovation. The potential role of institutional review boards in this process is highlighted.

Diffusion of Innovation↗
PubMed2004

Surgical outreach clinics in Canada: one neurosurgeon's experience.

In this short paper, I present my 3-year experience, from January 2000 to September 2002, with a neurosurgery consultation outreach clinic in Huntsville, Ont. I describe the logistics, advantages, disadvantages and implications for surgeons of outreach clinics and their patients. The clinic was highly successful for the area physicians and the patients, but was discontinued in September 2002 owing to restrictions on my time available for the clinic. New surgical outreach clinics should be carefully planned. The specialist surgeon must have adequate flexibility and time for this activity and the success of the clinic must be assessed regularly.

Ambulatory Care↗
PubMed2004

Antineoplastic action of 5-aza-2'-deoxycytidine (Dacogen) and depsipeptide on Raji lymphoma cells.

Epigenetic alterations, such as aberrant DNA methylation and histone deacetylation, can silence genes that suppress leukemogenesis. The objective of our study was to investigate the in vitro antineoplastic and gene re-activation activity of 5-aza-2'-deoxycytidine (5AZA), a potent inhibitor of DNA methylation, and depsipeptide (depsi), an inhibitor of histone deacetylase, on Raji lymphoma cells. The combination of 5AZA with depsi produced a significantly greater inhibition of growth and colony formation than either agent alone. Using RT-PCR, we observed that combination also produced a synergistic activation of E-cadherin, a gene that is silenced by aberrant DNA methylation in Raji cells. This latter interaction indicates that there is cross-talk between DNA methylation and histone modifications in chromatin for E-cadherin in this cell line. 5AZA and depsi may be an interesting drug combination to investigate in patients with lymphoma.

Antimetabolites, Antineoplastic↗
PubMed2004

The nursing role in patient education regarding outpatient neurosurgical procedures.

The shift towards patient-centred care is the priority in health care today. Providing quality care that is highly efficient and patient-friendly while also being cost-effective is a difficult, but not impossible task. Since 1996, awake, image-guided day surgery for resection of brain tumors has been performed at Toronto Western Hospital in an attempt to combine the concept of patient-centred care with responsible resource allocation. Nurses can play a vital role in facilitating a shift in outpatient neurosurgery towards a more patient-care focused environment. By providing information and education to patients and families, nurses have enormous potential to improve satisfaction and outcomes for patients undergoing these procedures. Thoroughly preparing patients for their surgery and helping them manage their care post-operatively are the keys to decreased complications and re-admission. This would undoubtedly improve cost-effectiveness for the system while simultaneously improving the patients' quality of life.

Ambulatory Surgical Procedures↗
PubMed2004

Ethical issues in molecular medicine of relevance to surgeons.

The technology associated with the care of surgical patients and the level of sophistication of biomedical research accompanying it are evolving at a rapid pace. Both new and old bioethical issues are assuming increasing levels of prominence and importance, particularly in this age of molecular medicine. The authors explore bioethical issues pertinent and relevant to surgeons. Four specific areas that are exemplary by presenting both major scientific and ethical challenges are briefly addressed: privacy of information, stem cells, gene therapy, and conflict of interest in biomedical research. All of these can be generalized to all surgeons. As bioethical issues today play a greater role in surgical practice than they did even a decade ago, it is hoped that this brief review on ethical issues in molecular medicine will help stimulate present and future generations of surgeons in thinking about the ethical dimensions of their work.

Conflict of Interest↗
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↗