Assessing the bioethical integrity of a clinical trial in surgery.
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Biomedical subjects
Publications and source records attributed to Mark Bernstein.
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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.
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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.
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Error in medicine is becoming a well recognized phenomenon. The U.S. Institute of Medicine's publication in 1999 included estimations that medical error is the eighth leading cause of death in the United States and results in up to 100,000 deaths annually. Retrospective studies and a few prospective studies are shedding more light on this challenging problem. Strategies to reduce error and increase patient safety have not been widely developed or embraced by surgeons for a variety of reasons. We provide a review on patient safety aimed at surgeons that includes definitions, incidence of errors including those in the surgical literature, causes of error, methods of error detection, and strategies to minimize errors and maximize patient safety.
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PURPOSE: To report a non-fatal case of intraoperative venous air embolism (VAE) during an awake craniotomy. VAE presented with unusual clinical features. CLINICAL FEATURES: VAE during an awake craniotomy has not been reported frequently. The patient we describe presented with persistent coughing followed by tachypnea, hypoxia and reduction in end-tidal CO(2) during dural opening while undergoing an awake craniotomy in the supine position. Cardiovascular variables were stable during the episode except for transient hypertension. Having ruled out airway obstruction and low cardiac output, we concluded that air embolism was the cause. The patient responded immediately to the standard treatment of air embolism and recovered without any complication. CONCLUSION: This case illustrates a VAE during an awake craniotomy and emphasizes the importance of early diagnosis in the management.
OBJECTIVE: Nowadays, microsurgical discectomy is being performed as an outpatient procedure. A retrospective chart review was done to document factors that delayed discharge or led to unanticipated admission. METHODS: After Institutional Review Board approval, the hospital medical records of 106 patients who underwent microsurgical discectomy on an ambulatory basis were reviewed. All patients were operated upon by a single surgeon at the Toronto Western Hospital. Perioperative data were collected on specifically designed data sheets. All anesthetic and surgical factors that affected discharge were noted. RESULTS: Of the 106 patients reviewed, only six required unanticipated admission. Two patients were admitted due to nausea and vomiting, one due to severe pain, one due to urinary retention and two were surgical causes (dural tear). Eight patients had delayed discharge. Anesthesia causes were severe nausea, severe pain, low oxygen saturation, sore throat and dry eyes. Two patients had surgical causes. The incidence of postoperative nausea was 61% and postoperative vomiting was 9.4%. Eighty patients (75.4%) complained of pain in the postanesthesia care unit. Of these, 33.9% had visual analogue pain scale scores more than 6. CONCLUSION: Ambulatory lumbar microdiscectomy can be carried out as an ambulatory procedure with an acceptably low unanticipated admission rate (5.7%). The percentage of patients with severe nausea (16%) and pain (33.9%) is high. Adequate perioperative pain management and effective control of nausea and vomiting may further improve the patients' experience after anesthesia for ambulatory microdiscectomy.
During the development of leukemia, genes that suppress growth and induce differentiation can be silenced by aberrant DNA methylation and by changes in chromatin structure that involve histone deacetylation. It has been reported that a positive interaction between DNA methylation and histone deacetylation takes place to inhibit transcription. Based on this observation, our working hypothesis was that a combination of inhibitors of these processes should produce an enhancement of their antineoplastic activity on leukemic cells. The cytosine nucleoside analog, 5-aza-2'-deoxycytidine (5AZA), is a potent inhibitor of DNA methylation, which can activate tumor suppressor genes in leukemic cells that have been silenced by aberrant methylation. In clinical trials, 5AZA was demonstrated to be an active antileukemic agent. Histone deacetylase inhibitors (HDI) can also activate gene expression in leukemic cell lines by producing changes in chromatin configuration, and show antineoplastic activity in preclinical studies. In this report, we investigated the in vitro antineoplastic activity of 5AZA, alone and in combination with the HDI, trichostatin A (TSA) and depsipeptide (FR901228, depsi), on the human myeloid leukemic cell lines, HL-60 and KG1a. The results showed that the combination of 5AZA with TSA or depsi produced a greater inhibition of growth and DNA synthesis and a greater loss of clonogenicity than either agent alone. These results suggest that 5AZA used in combination with HDI may be an interesting chemotherapeutic regimen to investigate in patients with acute myeloid leukemia that is resistant to conventional chemotherapy.
BACKGROUND: Meningiomas of the anterior cranial fossa frequently present with impaired visual function. Recognition of this entity in the differential diagnosis of painless, progressive, and asymmetric optic neuropathy is important since reversal of visual loss is possible given timely surgical excision of the tumour. METHODS: A 76-year-old man presented with no perception of light in his right eye and a reduced visual acuity of 20/60 in his left eye with a markedly constricted visual field. His visual deterioration had progressed over the previous three months and was not associated with headache. Ophthalmoscopy showed normal optic discs. MRI scanning showed a large frontal basal meningioma, which was subsequently resected. RESULTS: The patient noticed an immediate improvement in his vision in his right eye. Visual acuity in his right eye improved to 20/50 at six weeks postoperatively and to 20/25 at five months, with corresponding improvement of the visual field. CONCLUSION: Complete monocular blindness due to tumour compressing or distorting the anterior visual pathways does not preclude recovery following timely decompressive surgery, especially when the appearance of the optic disc is normal.
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PURPOSE: To conduct a phase 1 trial of rebeccamycin analog (NSC #655649) in children with solid tumors to establish the dose-limiting toxicity (DLT) and maximum-tolerated dose (MTD); to establish the pharmacokinetic profile in children, and to document any evidence of antitumor activity. METHODS: A 1-hour infusion of NSC #655649 was administered every 21 days to 17 patients younger than 21 years who had malignant tumors refractory to conventional therapy. Doses ranged from 450 mg/m2 to 760 mg/m2. Pharmacokinetics were done in at least three patients per dose level. The first course was used to determine DLT and MTD. RESULTS: Sixteen patients on three dose levels were assessable for toxicities. At 760 mg/m2, four patients had dose-limiting neutropenia and thrombocytopenia. Pharmacokinetics were assessable in 13 patients. Plasma concentrations declined triexponentially and concentrations above the range of in vitro antitumor activity were maintained for 3 days. Analysis of urine extracts revealed the presence of an N-de-ethylated metabolite and probable involvement of cytochrome P450 isoenzyme(s) in the metabolism of NSC #655649. Pharmacodynamic studies showed a relationship between the area under the curve and percentage change in absolute neutrophil count in the E(max) model (r2 = 0.56, P = 0.001). CONCLUSIONS: The recommended phase 2 dose of NSC #655649 administered as a 1-hour infusion every 21 days to children with solid tumors is 585 mg/m2. Both neutropenia and thrombocytopenia were found to be dose-limiting toxicities.
SARS is a devastating disease that caused widespread morbidity and mortality, as well as tremendous fear and uncertainty across the global village. There are numerous challenging medical aspects of this disease. Methods required to control it also raised significant ethical challenges for decision-markers both in real time, and for the future. A group at the Joint Centre for Bioethics (JCB) at the University of Toronto formally explored the ethical dimensions of this outbreak. The author briefly reviews the analysis by the JCB group and further examines how bioethical principles and theories relate to the numerous ethical issues raised by SARS and the methods used in its containment.
Capillary hemangiomas are rare benign vascular tumors that tend to occur in children. Whereas the majority of hemangiomas may regress spontaneously, those associated with functional sequelae or severe symptoms may require treatment. Two patients with capillary hemangiomas of the cavernous sinus that caused neurological symptoms were treated with fractionated stereotactic radiation therapy. Both hemangiomas had shown a progressive increase in size during observation before radiation therapy; both tumors regressed after radiotherapy. Up to the time of the last follow-up evaluation both patients experienced symptomatic relief after radiation. One patient's tumor remains in complete remission and the second tumor continues to demonstrate minor residual contrast enhancement without progression. The authors conclude that fractionated stereotactic radiation therapy is a useful treatment modality in the management of symptomatic capillary hemangiomas when these tumors arise in regions of the brain or skull base in which a complete resection cannot be accomplished.