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Mark Bernstein

Publications and source records attributed to Mark Bernstein.

At least 19 recordsLinked to original sources
PubMed2005

Etoposide, vincristine, and cyclosporin A with standard-dose radiation therapy in newly diagnosed diffuse intrinsic brainstem gliomas: a pediatric oncology group phase I study.

BACKGROUND: Brainstem gliomas (BSGs) are resistant to all therapy. Based on their imaging characteristics, we postulated that inhibition of P-glycoprotein (P-gp) associated with endothelial cells of the blood-brain barrier might enhance penetration of xenobiotic antineoplastics. PROCEDURE: Seven patients were enrolled in a Phase I study of etoposide, continuous infusion cyclosporine A given with and escalating doses of vincristine and concomitant standard-dose irradiation. RESULTS: Six patients were entered at the first level and one at the second. Closure of the study was mandated by dose-limiting neurotoxicity, consisting of seizures associated with white-matter changes, and alteration of consciousness with bulbar signs. One patient had tumor necrosis at 6 weeks, suggesting some tumor effect. Median survival for the group was 11 months, and for the patients who completed more than 1 month of therapy it was 11 months. CONCLUSION: This regimen proved excessively toxic.

Adolescent↗
PubMed2005

Health and economic benefits of well-designed evaluations: some lessons from evaluating neuroblastoma screening.

BACKGROUND: Well-designed evaluations of health services are frequently made today. However, the extent of the evaluations' benefits and costs is not well documented, creating uncertainty whether their use is optimal from society's perspective. We examined these costs and benefits using data from one well-designed evaluation, the Quebec Neuroblastoma Screening Project (QNSP). It screened most Quebec newborns between 1989 and 1994 for neuroblastoma. As previously reported, the screening did not reduce neuroblastoma mortality and caused adverse health effects. METHODS: We compared the cost of doing the QNSP with its benefits. Had the QNSP not been undertaken, neuroblastoma screening would have been implemented throughout North America. We assume that screening would have started in 1989 and ended in 2002. The QNSP's benefits include the health costs and adverse health effects averted by not using ineffective screening during those 14 years. In our calculations we used neuroblastoma incidence data for the QNSP and for Ontario where there was no screening, detailed data describing the health services used by the patients, and Quebec cost data for those services. RESULTS: The QNSP cost 8.77 million dollars (2002 US dollars). By not implementing similar screening programs between 1989 and 2002, the United States and Canada avoided 574.1 million dollars in health costs, the unnecessary treatment of 9223 children, and false-positive findings for 5003 children screened. CONCLUSIONS: The health care costs and adverse health effects averted by the QNSP justify its costs. These results show that well-designed evaluations can yield--at least sometimes--benefits substantially greater than their high costs. This raises an important policy issue: are these evaluations now being under- or over used?

Canada↗
PubMed2005

Phase II study of nelarabine (compound 506U78) in children and young adults with refractory T-cell malignancies: a report from the Children's Oncology Group.

PURPOSE: Nelarabine (compound 506U78), a water soluble prodrug of 9-b-d-arabinofuranosylguanine, is converted to ara-GTP in T lymphoblasts. We sought to define the response rate of nelarabine in children and young adults with refractory or recurrent T-cell disease. PATIENTS AND METHODS: We performed a phase II study with patients stratified as follows: stratum 1: > or = 25% bone marrow blasts in first relapse; stratum 2: > or = 25% bone marrow blasts in > or = second relapse; stratum 3: positive CSF; stratum 4: extramedullary (non-CNS) relapse. The initial nelarabine dose was 1.2 g/m2 daily for 5 consecutive days every 3 weeks. There were two dose de-escalations due to neurotoxicity on this or other studies. The final dose was 650 mg/m2/d for strata 1 and two patients and 400 mg/m2/d for strata 3 and four patients. RESULTS: We enrolled 121 patients (106 assessable for response) at the final dose levels. Complete plus partial response rates at the final dose levels were: 55% in stratum 1; 27% in stratum 2; 33% in stratum 3; and 14% in stratum 4. There were 31 episodes of > or = grade 3 neurologic adverse events in 27 patients (18% of patients). CONCLUSION: Nelarabine is active as a single agent in recurrent T-cell leukemia, with a response rate more than 50% in first bone marrow relapse. The most significant adverse events associated with nelarabine administration are neurologic. Further studies are planned to determine whether the addition of nelarabine to front-line therapy for T-cell leukemia in children will improve survival.

Adolescent↗
PubMed2005

Phase I trial and pharmacokinetic study of raltitrexed in children with recurrent or refractory leukemia: a pediatric oncology group study.

PURPOSE: To evaluate the toxicity, antileukemic activity, and pharmacology of raltitrexed administered weekly for 3 weeks to patients with refractory or recurrent leukemia. EXPERIMENTAL DESIGN: Raltitrexed was administered as a 15-minute infusion for 3 consecutive weeks every 5 weeks, at doses ranging from 1.3 to 2.8 mg/m(2). The first course was used to determine the dose-limiting toxicities and maximum tolerated dose. Correlative studies included an assessment of raltitrexed pharmacokinetics and measurement of plasma 2'-deoxyuridine concentrations, a surrogate measure of thymidylate synthase inhibition. RESULTS: Twenty-one children (18 evaluable) with refractory leukemia received 25 courses of raltitrexed. The dose-limiting toxicity was reversible elevation in liver transaminases at the 2.8-mg/m(2) dose level and the maximum tolerated dose was 2.1 mg/m(2) per dose. Pharmacokinetics were best characterized by a two-compartment model with a clearance of 139 mL/min/m(2) (8.3 L/h/m(2)), a 2.4-L volume of distribution, an initial half-life (t(1/2alpha)) of 6 minutes, and a terminal half-life (t(1/2beta)) of 45 minutes. There were three objective responses. CONCLUSIONS: Raltitrexed was well tolerated when administered as a single agent to children with recurrent or refractory leukemia. We observed preliminary evidence of antileukemia activity using this weekly dosing schedule and these observations support further evaluation of raltitrexed in this population.

Adolescent↗
PubMed2005

Patterns of care for adults with newly diagnosed malignant glioma.

CONTEXT: Patients with malignant glioma (grade III or IV) face a poor prognosis, and few evidence-based treatment guidelines are available. There is a dearth of prospective data on patterns of care for these patients. OBJECTIVE: To provide benchmark data to enable comparison of individual practice patterns and outcomes. DESIGN, SETTING, AND PATIENTS: The Glioma Outcomes (GO) Project enrolled 788 patients at 52 clinical sites, both academic and community practices, between December 1997 and July 2000. The enrollment criteria included adult patients with primary grade III or IV glioma undergoing a first or second operation for diagnosis or treatment. The data collection instruments included questionnaire forms given at enrollment, during the perioperative period, and at follow-up intervals of 3 months until death or a maximum of 24 months. Of the patients recorded in the GO database, 565 patients with newly diagnosed tumors were used for this analysis. MAIN OUTCOME MEASURES: Patterns of care (surgical management, perioperative care, postoperative management). RESULTS: Most patients underwent magnetic resonance imaging (n = 518; 92%) and an attempt at tumor resection (n = 425; 75%). Cortical mapping (n = 107; 19%) and intraoperative image guidance (n = 161; 29%) were uncommon. Most received perioperative corticosteroids (n = 535; 99%) and antiepileptic medications (n = 497; 88%), but few received antidepressants (n = 38; 8%) or prophylactic heparin (n = 42; 7%). Most received adjuvant radiation therapy (n = 479; 87%), but fewer received chemotherapy (n = 300; 54%). Practice patterns varied significantly between academic and community settings. CONCLUSIONS: Reliance on magnetic resonance imaging, surgery, and radiation is generally accepted; however, relatively infrequent chemotherapy use may conflict with published literature, and frequent use of prophylactic antiepileptic medications contradicts established practice guidelines. Other practice patterns involving surgical adjuncts, prophylactic heparin, and antidepressants require further investigation to clarify appropriateness. Establishing further clinical guidelines may help reduce variability in practice patterns.

Adult↗
PubMed2005

A phase I and pharmacokinetic study of ecteinascidin-743 (Yondelis) in children with refractory solid tumors. A Children's Oncology Group study.

PURPOSE: To determine the dose-limiting toxicity (DLT) and the maximum tolerated dose of ecteinascidin-743 (ET-743, Yondelis) in children with refractory solid tumors, to establish the recommended dose for pediatric phase II trials, and to characterize the pharmacokinetics of ET-743 in children. EXPERIMENTAL DESIGN: ET-743 was administered as a 3-hour i.v. infusion every 21 days. The starting dose was 1,100 microg/m(2) with planned dose escalation of 200 microg/m(2) increments. Pharmacokinetic sampling was done during the first treatment course. RESULTS: Twelve evaluable patients received a total of 29 courses. One grade 4 DLT (prolonged grade 4 neutropenia) was noted at the first dose level. At the second dose level (1,300 microg/m(2)), there were two DLTs (reversible grade 4 elevations of hepatic transaminase); hence the maximum tolerated dose was defined as 1,100 microg/m(2). Overall, reversible hepatic toxicity, manifested as grade 3 or 4 elevations in hepatic transaminase, occurred in more than 50% of the patients. No grade 3 or 4 thrombocytopenia was reported at either dose level and only one episode of isolated creatine phosphokinase grade 4 elevation was observed. One complete response was documented after six courses in a patient with metastatic Ewing sarcoma. The pharmacokinetics of ET-743 in 8 children was characterized by a terminal disposition phase with a mean half-life of 43.8 +/- 18.4 hours, a total body clearance of 28.2 +/- 10.5 L/h/m(2), and a 959 +/- 807 L/m(2) steady-state apparent volume of distribution. CONCLUSION: ET-743 is safe. The phase II recommended dose of ET-743 administered as a 3-hour i.v. infusion following premedication with dexamethasone is 1,100 microg/m(2).

Adolescent↗
PubMed2005

Tension pneumoventricle after placement of a ventriculoperitoneal shunt: a novel treatment strategy. Case report.

A case of pneumoventricle following insertion of a ventriculoperitoneal shunt for hydrocephalus is described. The pneumoventricle was associated with significant morbidity, which improved with treatment. The authors propose a rational treatment for this condition, which, as far as they know, has not previously been described. They also discuss potential mechanisms involved in the pathogenesis of pneumoventricle.

Central Nervous System Cysts↗
PubMed2005

Safety of intracranial aneurysm surgery performed in a postgraduate training program: implications for training.

OBJECT: Patient care and educational experience have long formed a dichotomy in modem surgical training. In neurosurgery, achieving a delicate balance between these two factors has been challenged by recent trends in the field including increased subspecialization, emerging technologies, and decreased resident work hours. In this study the authors evaluated the experience profiles of neurosurgical trainees at a large Canadian academic center and the safety of their practice on patient care. METHODS: Two hundred ninety-three patients who underwent surgery for intracranial aneurysm clipping between 1993 and 1996 were selected. Prospective data were available in 167 cases, allowing the operating surgeon to be identified. Postoperative data and follow-up data were gathered retrospectively to measure patient outcomes. In 167 cases, a total of 183 aneurysms were clipped, the majority (91%) by neurosurgical trainees. Trainees performed dissections on aneurysms that were predominantly small (< 1.5 cm in diameter; 77% of patients) and ruptured (64% of patients). Overall mortality rates for the patients treated by the trainee group were 4% (two of 52 patients) and 9% (nine of 100 patients) for unruptured and ruptured aneurysm cases, respectively. Patient outcomes were comparable to those reported in historical data. Staff members appeared to be primary surgeons in a select subset of cases. CONCLUSIONS: Neurosurgical trainees at this institution are exposed to a broad spectrum of intracranial aneurysms, although some case selection does occur. With careful supervision, intracranial aneurysm surgery can be safely delegated to trainees without compromising patient outcomes. Current trends in practice patterns in neurosurgery mandate ongoing monitoring of residents' operative experience while ensuring continued excellence in patient care.

Adult↗
PubMed2005

Postoperative recovery of complete sudden paraplegia due to lumbar schwannoma. Case report.

The authors present a rare case of acute complete paraplegia due to a lumbar schwannoma. The clinical presentation, magnetic resonance imaging features, and management strategy are discussed. A 29 year-old man presented with acute complete paraplegia and bladder and bowel incontinence. He had a history of stable back pain and a 4-year history of lower-extremity numbness bilaterally. Magnetic resonance imaging revealed an enhancing extraaxial mass filling the spinal canal over two segments below the conus medullaris. An L1-3 laminectomy was performed and the tumor was completely removed. Pathological evaluation showed features characteristic of a schwannoma. The patient regained almost complete motor function after 6 months. To the authors' knowledge, this is the first reported case of acute complete paraplegia secondary to lumbar schwannoma. Possible mechanisms of this occurrence are discussed.

Acute Disease↗
PubMed2004

SARS and hospital priority setting: a qualitative case study and evaluation.

BACKGROUND: Priority setting is one of the most difficult issues facing hospitals because of funding restrictions and changing patient need. A deadly communicable disease outbreak, such as the Severe Acute Respiratory Syndrome (SARS) in Toronto in 2003, amplifies the difficulties of hospital priority setting. The purpose of this study is to describe and evaluate priority setting in a hospital in response to SARS using the ethical framework 'accountability for reasonableness'. METHODS: This study was conducted at a large tertiary hospital in Toronto, Canada. There were two data sources: 1) over 200 key documents (e.g. emails, bulletins), and 2) 35 interviews with key informants. Analysis used a modified thematic technique in three phases: open coding, axial coding, and evaluation. RESULTS: Participants described the types of priority setting decisions, the decision making process and the reasoning used. Although the hospital leadership made an effort to meet the conditions of 'accountability for reasonableness', they acknowledged that the decision making was not ideal. We described good practices and opportunities for improvement. CONCLUSIONS: 'Accountability for reasonableness' is a framework that can be used to guide fair priority setting in health care organizations, such as hospitals. In the midst of a crisis such as SARS where guidance is incomplete, consequences uncertain, and information constantly changing, where hour-by-hour decisions involve life and death, fairness is more important rather than less.

Attitude of Health Personnel↗
PubMed2004

Phase I study of the proteasome inhibitor bortezomib in pediatric patients with refractory solid tumors: a Children's Oncology Group study (ADVL0015).

PURPOSE: To determine the maximum-tolerated dose, dose-limiting toxicity (DLT), and pharmacodynamics of the proteasome inhibitor bortezomib (formerly PS-341) in children with recurrent or refractory solid tumors. PATIENTS AND METHODS: An intravenous bolus of bortezomib was administered twice weekly for 2 consecutive weeks at either 1.2 or 1.6 mg/m2/dose followed by a 1-week rest. The pharmacodynamics of bortezomib were evaluated by measurement of whole blood 20S proteasome activity. RESULTS: Fifteen patients, 11 assessable, were enrolled between November 2001 and February 2003. Dose-limiting thrombocytopenia, which prevented administration of a complete course (four doses in 2 weeks) of therapy, occurred in two of five assessable children enrolled at the 1.6 mg/m2 dose level. There were no other DLTs. Inhibition of 20S proteasome activity seemed to be dose dependent. The average inhibition 1 hour after drug administration on day 1 was 67.2% +/- 7.6% at the 1.2 mg/m2/dose and 76.5% +/- 3.3% at the 1.6 mg/m2/dose. There were no objective antitumor responses. CONCLUSION: Bortezomib is well tolerated in children with recurrent or refractory solid tumors. The recommended phase II dose of bortezomib for children with solid tumors is 1.2 mg/m2/dose, administered as an intravenous bolus twice weekly for 2 weeks followed by a 1-week break.

Biological Availability↗
PubMed2004

Pharmacokinetics of O(6)-benzylguanine in pediatric patients with central nervous system tumors: a pediatric oncology group study.

PURPOSE: To report the results of the first pharmacokinetic study in pediatric patients of O(6)-benzylguanine (O(6)BG), which irreversibly inactivates the DNA repair protein alkylguanine-alkyltransferase, thus enhancing the cytotoxicity of nitrosoureas. EXPERIMENTAL DESIGN: As part of a Pediatric Oncology Group Phase I study, 120 mg/m(2) of O(6)BG was administered i.v. over 1 h, before 1,3-bis(2-chloroethyl)-1-nitrosourea administration in children with recurrent or refractory brain tumors. Serial blood samples for plasma pharmacokinetic studies were obtained. Concentrations of O(6)BG and its active metabolite O(6)-benzyl-8-oxoguanine (8-oxo-O(6)BG) were measured by high-performance liquid chromatography. A pharmacokinetic model and additional first-order elimination rate constants for each compound were developed. RESULTS: O(6)BG concentration versus time data were evaluated for 25 patients. The peak concentration of O(6)BG (mean +/- SD) was 11 +/- 4 microm, and the peak concentration of its active metabolite, 8-oxo-O(6)BG, was 35 +/- 10 microm. O(6)BG was rapidly eliminated with a half-life of 85 +/- 140 min, area under the curve of 795 +/- 320 microm. min and clearance of 760 +/- 400 ml/min/m(2). The area under the curve of 8-oxo-O(6)BG when extrapolated to infinity was 22,700 +/- 11,800 microm. min. The clearance and terminal half-life of 8-oxo-O(6)BG were 30 +/- 15 ml/min/m(2) and 360 +/- 220 min, respectively. CONCLUSIONS: There is rapid elimination of O(6)BG after i.v. administration over 1 h. In contrast, the terminal half-life for the active metabolite, 8-oxo-O(6)BG, is 4-fold longer. The pharmacokinetic parameters for O(6)BG and 8-oxo-O(6)BG are similar to those reported previously in adults.

Adolescent↗
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↗