Assessing fitness to drive in brain tumour patients: a grey matter of law, ethics, and medicine.

BACKGROUND: Neurocognitive deficits from brain tumours may impair the ability to safely operate a motor vehicle. Although certain jurisdictions in Canada legally require that physicians report patients who are unfit to drive, criteria for determining fitness are not clearly defined for brain tumours. METHODS: Patients receiving brain radiotherapy at our institution from January to June 2009 were identified using the Oncology Patient Information System. In addition to descriptive statistics, details of driving assessment were reviewed retrospectively. The Fisher exact test was used to determine factors predictive of reporting a patient to the Ontario Ministry of Transportation (mto) as unfit to drive. A logistic regression model was constructed to further determine factors predictive of reporting. RESULTS: Of the 158 patients available for analysis, 48 (30%) were reported to the mto, and 64 (41%) were advised to stop driving. With respect to the 53 patients with seizures, a report was submitted to the mto for 30 (57%), and a documented discussion about the implications of driving was held with 35 (66%). On univariate analysis, younger age, a central nervous system primary, higher brain radiotherapy dose, unifocal disease, and the presence of seizures were predictive of physician reporting (p < 0.05). On logistic regression modelling, the presence of seizures (odds ratio: 3.9) and a higher radiotherapy dose (odds ratio: 1.3) remained predictive of reporting. INTERPRETATION: Physicians frequently do not discuss the implications of driving with brain tumour patients or are not properly documenting such advice (or both). Clear and concise reporting guidelines need to be drafted given the legal, medical, and ethical concerns surrounding this public health issue.

Multidisciplinary assessment of fitness to drive in brain tumour patients in southwestern Ontario: a grey matter.

BACKGROUND: Neurocognitive impairments from brain tumours may interfere with the ability to drive safely. In 9 of 13 Canadian provinces and territories, physicians have a legal obligation to report patients who may be medically unfit to drive. To complicate matters, brain tumour patients are managed by a multidisciplinary team; the physician most responsible to make the report of unfitness is often not apparent. The objective of the present study was to determine the attitudes and reporting practices of physicians caring for these patients. METHODS: A 17-question survey distributed to physicians managing brain tumour patients elicited Respondent demographicsKnowledge about legislative requirementsExperience of reportingBarriers and attitudes to reporting Fisher exact tests were performed to assess differences in responses between family physicians (fps) and specialists. RESULTS: Of 467 physicians sent surveys, 194 responded (42%), among whom 81 (42%) were specialists and 113 (58%) were fps. Compared with the specialists, the fps were significantly less comfortable with reporting, less likely to consider reporting, less likely to have patients inquire about driving, and less likely to discuss driving implications. A lack of tools, concern for the patient-physician relationship, and a desire to preserve patient quality of life were the most commonly cited barriers in determining medical fitness of patients to drive. CONCLUSIONS: Legal requirements to report medically unfit drivers put physicians in the difficult position of balancing patient autonomy and public safety. More comprehensive and definitive guidelines would be helpful in assisting physicians with this public health issue.

Neurocytomas: long-term experience of a single institution.

There is a lack of studies reporting on outcomes of control and treatment toxicities for neurocytomas. A 25-year retrospective review of a tertiary center's experience with neurocytomas was completed to report on these outcomes. All cerebral neurocytoma cases (19 patients; median age, 31 years; range, 18-62 years; 18 intraventricular and 1 extraventricular) treated between 1984 and 2009 were analyzed, including central pathology and radiology reviews. Median follow-up was 104.5 months (range, 0.75-261.7 months). Primary treatment was surgery alone (n = 18 patients), followed by surgery and adjuvant radiotherapy (n = 1). The crude local control rate after surgery was 68% for all cases (cerebral neurocytomas) and 74% for central neurocytomas. Salvage therapies included further surgery (n = 4), radiation (n = 3), and chemotherapy (n = 1). Ten-year Kaplan-Meier overall and relapse-free survival rates were 82% and 62% and 81% and 57%, respectively, for all cases and for central neurocytomas only. The median overall survival and relapse-free survival were 104.5 and 79.3 months, respectively, for all cases and for central neurocytomas. Ten patients had grade 3/4 toxicity, and 1 patient had a grade 5 perioperative hemorrhage that resulted in death 23 days after surgery. Late grade 3/4 toxicities occurred in 9 patients. Three patients had permanent grade 2 motor or cognitive deficits. We provide the first report outlining toxicities and survival outcomes in a series of 19 patients. Our experience suggests that initial surgery provides durable local control rates in two-thirds of patients, with low risk for significant permanent deficits. Salvage therapy with surgery and/or radiation provides durable local control in tumors that recur after surgery.

Can a moral reasoning exercise improve response quality to surveys of healthcare priorities?

OBJECTIVE: To determine whether a moral reasoning exercise can improve response quality to surveys of healthcare priorities METHODS: A randomised internet survey focussing on patient age in healthcare allocation was repeated twice. From 2574 internet panel members from the USA and Canada, 2020 (79%) completed the baseline survey and 1247 (62%) completed the follow-up. We elicited respondent preferences for age via five allocation scenarios. In each scenario, a hypothetical health planner made a decision to fund one of two programmes identical except for average patient age (35 vs 65 years). Half of the respondents (intervention group) were randomly assigned to receive an additional moral reasoning exercise. Responses were elicited again 7 weeks later. Numerical scores ranging from -5 (strongest preference for younger patients) to +5 (strongest preference for older patients); 0 indicates no age preference. Response quality was assessed by propensity to choose extreme or neutral values, internal consistency, temporal stability and appeal to prejudicial factors. RESULTS: With the exception of a scenario offering palliative care, respondents preferred offering scarce resources to younger patients in all clinical contexts. This preference for younger patients was weaker in the intervention group. Indicators of response quality favoured the intervention group. CONCLUSIONS: Although people generally prefer allocating scarce resources to young patients over older ones, these preferences are significantly reduced when participants are encouraged to reflect carefully on a wide range of moral principles. A moral reasoning exercise is a promising strategy to improve response quality to surveys of healthcare priorities.

The potential impact of decision role and patient age on end-of-life treatment decision making.

BACKGROUND: Recent research demonstrates that people sometimes make different medical decisions for others than they would make for themselves. This finding is particularly relevant to end-of-life decisions, which are often made by surrogates and require a trade-off between prolonging life and maintaining quality of life. We examine the impact of decision role, patient age, decision maker age and multiple individual differences on these treatment decisions. METHODS: Participants read a scenario about a terminally ill cancer patient faced with a choice between an aggressive chemotherapy regimen that will extend life by two years and palliative treatments to control discomfort for one remaining month. Participants were randomly assigned to one of three decision roles (patient, physician, or an abstract other) and the scenario randomly varied whether the patient was described as 25 or 65-years old. RESULTS: When deciding for a 65-year old patient, approximately 60% of participants selected aggressive chemotherapy regardless of decision role. When deciding for a 25-year old patient, however, participants were more likely to select chemotherapy for a patient (physician role) or another person (abstract other) than for themselves (70%, 67%, and 59%, respectively). In addition, confidence that powerful others (eg, physicians) control one's health, as well as respondents' age and race, consistently predicted treatment choices. CONCLUSIONS: Patient age appears to influence medical decisions made for others but not those that we make for ourselves. These findings may help to explain the discord that often occurs when younger cancer patients refuse life-extending treatments.

Knowledge of blood pressure targets among patients with diabetes.

INTRODUCTION: Tight blood pressure (BP) control is the single most important intervention to prevent cardiovascular mortality among patients with diabetes mellitus (DM). However, little is known about how many patients have specific target BP levels or the factors associated with patients' knowledge of these targets. OBJECTIVES: (1) To determine what proportion of patients with diabetes have BP targets; (2) To determine patient characteristics associated with having a BP target. METHODS: Cross-sectional, anonymous survey of 500 randomly selected outpatients with hypertension and DM receiving care in any Veterans Health Administration outpatient clinic in 2003. We examined multivariate associations between patient characteristics and having targets for BP. Covariates included age, race, gender, and education level; and factors specific to diabetes and BP treatment, including medication use, diabetes duration, and number of visits to diabetes healthcare providers in the previous year. RESULTS: Three hundred and seventy-eight (80%) patients responded. Although most (91%) had blood glucose targets, fewer than 60% reported having a BP target. In multivariate analyses, college education was associated with having a BP target (AOR 1.97 [95% CI: 1.16-3.34]). CONCLUSIONS: Less than two-thirds of diabetic, hypertensive patients had BP targets. Encouraging patients to set target BPs may promote hypertension self-management in this high-risk patient population. Less educated patients may especially benefit from interventions to increase awareness of BP targets.

Results of a policy of surveillance alone after surgical management of pediatric low grade gliomas.

PURPOSE: To document the incidence of tumor progression in pediatric patients with low-grade gliomas (LGGs), with particular emphasis on those patients who did not receive postoperative chemotherapy or radiotherapy (RT). METHODS AND MATERIALS: A database of 128 patients with histologically confirmed LGGs (World Health Organization Grade I-II), age

Pulmonary sequelae after electron spinal irradiation.

We measured pulmonary function in 21 patients, after craniospinal irradiation with a posterior spinal electron beam. The median age at treatment was 7.5 years. Nine patients (43%) demonstrated abnormal pulmonary function tests, five with restrictive changes, one with isolated diminished diffusion capacity, and three with obstructive disease. These changes were mild and predominantly asymptomatic.

Redox imbalance in Crohn's disease intestinal smooth muscle cells causes NF-kappaB-mediated spontaneous interleukin-8 secretion.

Interleukin-8 (IL-8), a chemokine secreted by cells at injury sites, has recently been recognized as involved in the pathogenesis of Crohn's disease. However, the pathogenesis of enhanced spontaneous transcription of IL-8 by the bowel in patients with Crohn's disease is undefined. Although IL-8 is secreted primarily by neutrophils, macrophages, and endothelial and epithelial cells, we observed the involvement of mesenchymal cells in the inflammatory process. A smooth muscle cell line isolated from the ileum of a patient with Crohn's disease (CDISM) and maintained in culture exhibited spontaneous transcription and secretion of IL-8 when compared with intestinal smooth muscle cells obtained from a normal subject (NHISM). Furthermore, IL-8 transcription from CDISM cells was associated with remarkable spontaneous activation of the oxidant-sensitive transcription factor NF-kappaB, as assessed by transient transfection assays with an IL-8 promoter reporter construct, Western blot analysis, and electrophoretic mobility shift assays (EMSA). Finally, we report here that CDISM cells exhibit significantly altered redox balance. The antioxidant pyrrolidine dithiocarbamate (PDTC) restored the redox equilibrium by mechanisms that inhibit binding of NF-kappaB to its cognate site on the IL-8 promoter. These findings suggest that restoration of the redox balance could hold promise for therapeutic intervention in Crohn's disease.

Nitric oxide suppresses IL-8 transcription by inhibiting c-Jun N-terminal kinase-induced AP-1 activation.

The role of activator protein-1 (AP-1) in tumor necrosis factor-alpha (TNF-alpha)-induced interleukin-8 (IL-8) gene expression was evaluated. We showed that TNF-alpha activates AP-1 in the transformed endothelial cell line ECV304 by transient transfections of IL-8 promoter construct pGL-3BF(2). Mutation of either the AP-1 site or the NF-IL-6 site on the IL-8 promoter suppressed the TNF-alpha-induced activation, suggesting cooperation between these transcription factors and transcription factor NF-kappaB. Overexpression of dominant negative mutants of c-Jun suppressed AP-1-driven transcription of the IL-8 promoter following stimulation by TNF-alpha, suggesting that cooperative interaction between AP-1 and NF-kappaB is essential for IL-8 transcription in the presence of TNF-alpha. We also showed that nitric oxide (NO), in the form of an exogenous NO donor, suppressed the level of activation of the AP-1 subunit, c-Jun, by down-regulation of c-Jun NH2 terminal kinase. This down-regulation could be the putative mechanism of action for NO-mediated inhibition of IL-8 secretion in activated endothelium. These observations suggest for the first time that NO has broad suppressive activities on various proinflammatory effectors in activated endothelium.

Phase I study of topotecan plus cranial radiation for glioblastoma multiforme: results of Radiation Therapy Oncology Group Trial 9507.

PURPOSE: A phase I trial was conducted by the Radiation Therapy Oncology Group (RTOG) to determine the maximum-tolerated dose of topotecan that could be safely combined with standard cranial radiation for glioblastoma multiforme. A secondary objective was to document the acute and late toxicities of this combination of chemotherapy and radiation. PATIENTS AND METHODS: Forty-seven patients with histologically confirmed glioblastoma multiforme were entered onto this phase I trial. Three cycles of topotecan were administered at 21-day intervals commencing at day 1 of cranial radiotherapy (60 Gy/30 fractions). Each cycle consisted of daily 30-minute intravenous (IV) infusions for 5 days. The dose of topotecan was escalated in three-dose increments from 0.5 mg/m(2)/d to 1.0 mg/m(2)/d to 1.5 mg/m(2)/d in different patient groups. RESULTS: The majority of patients were over age 50. Three dose levels of topotecan were tested. Fifteen patients accrued to level 1 (topotecan dose 0.5 mg/m(2)/d). No grade 4 toxicities were seen. Sixteen patients accrued to level 2 (topotecan dose 1.0 mg/m(2)/d), five of whom had brief episodes of grade 4 neutropenia. Seventeen patients accrued to level 3 (1.5 mg/m(2)/d). Six of these patients had brief episodes of grade 4 neutropenia and four developed grade 3 thrombocytopenia. No serious nonhematologic or late toxicities were seen. Median survival for all patients was 9.7 months. There was no apparent difference in survival by topotecan dose schedule. CONCLUSION: Toxicity was acceptable at an IV topotecan dose of 1.5 mg/m(2)/d administered daily for 5 days every 21 days for three cycles. A phase II trial has been performed using this dose of topotecan.

Suicidal intent in patients with chronic pain.

Suicidal ideation among individuals suffering from chronically painful conditions has not been widely studied, although rates of completed suicide are believed to be elevated in this population relative to the general population. The psychiatric literature on suicide documents the importance of controlling for the severity of depression when studying factors associated with suicidal ideation, attempts, or completion. The present study examined the relationships between suicidal ideation and the experience of pain, pain-related disability, and pain coping efforts among a sample of individuals experiencing chronically painful conditions. Of 200 patients evaluated on an inpatient rehabilitation unit in a psychiatric service, 13 individuals (6.5%) reported suicidal intent on a commonly used self-report measure of symptoms of depression, the Beck Depression Inventory. This group was compared to a matched (age, sex, pain duration) group of similarly depressed individuals (N=13) and a matched group of non-depressed individuals (N=13) on measures of pain, disability, pain beliefs, and pain coping strategies. A history of a suicide attempt was associated with suicidal intent. Family history of substance abuse was significantly more prevalent among the depressed groups, regardless of suicidal thinking. The depressed/suicidal group and depressed/non-suicidal groups reported higher levels of pain, higher levels of pain-related disability, lower use of active coping, and higher use of passive coping compared to the non-depressed group. The depressed groups did not differ from one another on any of the measures of pain experience. Depression, not suicidal status, consistently predicted level of functioning. The prevalence of suicidal intent was comparable to rates observed in other studies and relatively low. When individuals with chronic pain report suicidal intent, it is imperative that measures preventing self-harm be implemented immediately and the patient's depression be treated aggressively.

Allelic loss of chromosome 1p and radiotherapy plus chemotherapy in patients with oligodendrogliomas.

INTRODUCTION: Allelic loss of the short arm of chromosome 1 predicts radiographic response to chemotherapy and long overall survival times in patients with anaplastic oligodendrogliomas. Using a database of patients with oligodendrogliomas in whom chromosome 1p status was known, we explored whether allelic loss of 1p also predicted longer duration of tumor control when radiotherapy was part of the initial treatment of these patients. MATERIALS AND METHODS: We measured progression-free survival following radiotherapy in a cohort of patients with World Health Organization (WHO) Grade II and WHO Grade III oligodendrogliomas. The effects on progression-free survival of patient age, Karnofsky performance score (KPS), tumor grade when irradiated and chromosome 1p status were examined by univariate and multivariate statistical analyses. For the subset of patients with newly diagnosed anaplastic oligodendrogliomas, relationships between use of chemotherapy, chromosome 1p status and progression-free survival were also examined. RESULTS: Fifty-five patients (29 male, 26 female; ages 18-75 years; median, 44 years; KPS 50-90, median 80) were irradiated for either a WHO Grade II (n = 19) or Grade III (n = 36) oligodendroglioma. Twenty-eight patients had chemotherapy immediately prior to radiotherapy, and 27 had chemotherapy at progression following radiotherapy. The median radiation dose was 54 Gy in 30 fractions. Loss of heterozygosity (LOH) at chromosome 1p was evident in 36 tumors and absent in 19. Overall median progression-free survival after radiotherapy was 40.4 months. Median progression-free survival was 55.0 months for patients whose tumors harbored 1p loss vs. 6.2 months for those patients whose tumors retained both copies of chromosome 1p (p < 0.001). On both univariate and multivariate analyses, chromosome lp loss was the principal independent predictor of longer progression-free survival for patients with Grade II and III oligodendrogliomas. For Grade III oligodendrogliomas, chemotherapy as an adjunct to radiotherapy prolonged tumor control for those patients whose tumors harbored allelic loss of chromosome 1p (p = 0.004). CONCLUSION: These data suggest allelic loss of chromosome 1p in patients with oligodendroglial neoplasms predicts longer progression-free survival among patients receiving radiotherapy +/- chemotherapy as part of their initial treatment. Chromosome 1p loss may be an important stratification variable in future therapeutic trials of oligodendroglioma.

Anal sphincter conservation for patients with adenocarcinoma of the distal rectum: long-term results of radiation therapy oncology group protocol 89-02.

PURPOSE: To assess the outcome of a multi-institutional, national cooperative group study attempting functional preservation of the anorectum for patients with limited, distal rectal cancer. METHODS AND MATERIALS: Between September 21, 1989 and November 1, 1992, a Phase II trial of sphincter-sparing therapy was conducted for patients with clinically mobile rectal cancers located below the pelvic peritoneal reflection. Protocol treatment was designed for patients who were, in the judgement of their attending surgeon, unsuitable for anal sphincter conservation in the context of anterior resection, and would have required abdominoperineal resection (APR) as conventional surgical therapy. Primary cancers were estimated to be 4 cm or less in largest clinical diameter, and occupied 40% or less of the rectal circumference. Chest radiography and computerized axial tomography (CT) of the abdomen and pelvis excluded patients with overt lymphatic or hematogenous metastases. Protocol surgery was intended to remove the primary cancer by en-bloc, transmural excision of an ellipse of rectal wall by transanal, transcoccygeal, or trans-sacral technique, while conserving the anal sphincter. Based on tumor size, T classification, grade, and adequacy of surgical margins, patients were allocated to one of three treatment assignments: observation, or adjuvant treatment with 5-fluorouracil (5-FU) and one of two different dose levels of local-regional radiation. After completion of protocol therapy, patients were observed with follow-up that included periodic general physical and rectal examination, determinations of CEA, abdominopelvic CT, chest radiography, and surveillance endoscopy. Sixty-five eligible and analyzable patients were registered. RESULTS: With minimum follow-up of 5 years and median follow-up of 6.1 years, 11 patients have failed: 3 patients recurred local-regionally only, 3 patients had distant failure alone, and 5 patients manifested local-regional and distant failure. Eight patients died of intercurrent illness. Local-regional failure correlated with T-category revealed: T1 1/27 (4%), T2 4/25 (16%), and T3 3/13 (23%). Local-regional failure escalated with percentage involvement of the rectal circumference: 2/31 (6%) among patients with cancers involving 20% or less of the rectal circumference, and 6/34 (18%) among patients with cancers involving 21-40% of the circumference. Distant dissemination rose with T-category with 1/27 (4%) T1, 3/25 (12%) T2, and 4/13 (31%) T3 patients manifesting hematogenous spread. Eight patients (12%) required temporary or permanent colostomy. Five of 8 patients with local-regional recurrence achieved local-regional control with management including surgery, although 4 of these patients subsequently developed distant dissemination. Three patients (5%) had persistent, uncontrolled, local disease. Actuarial freedom from pelvic relapse at 5 years is 88% based on the entire study population, and 86% for the less favorable patients treated with adjuvant radiation and 5-FU. CONCLUSION: Conservative, sphincter-sparing therapy is a feasible alternative treatment for selected patients with limited cancer involving the middle and lower rectum. Risk of both local and distant failure appears to escalate with increasing T-category (depth of invasion). Results achieved in the multi-institutional, cooperative group setting approximate results reported from single institutions.

Effects of radiation on a three-dimensional model of malignant glioma invasion.

An experimental model of malignant glioma growth involving implantation of spheroids into a gel matrix of collagen type I has been developed. This model has been used to characterize changes in glioma cell invasion in response to single dose and fractionated radiation treatment. Suspensions of C6 astrocytoma cells were grown in spinner culture flasks to yield spheroids of varying size (300-1000 microm). Implantation of spheroids into a gel matrix of collagen type I was associated with measurable invasion of the surrounding gel by individual tumor cells. Changes in the distance of invasion in response to single dose and fractionated radiation were measured. Changes in apoptosis and proliferative indices in different regions of the spheroids in response to radiation were also assessed. In unirradiated gels, maximum depth of invasion, 1300-1750 microm, was achieved by 5 days after implantation. A radiation dose-dependent inhibition of invasion was noted and was most profound for larger spheroids. Fractionation of the radiation dose was associated with a partial recovery of invasion. Changes in apoptotic and proliferative indices in response to radiation depended on the region of the spheroid examined. Increases in apoptosis were noted for cells at the surface of the spheroid and invading cells while cells at the centre of the spheroid demonstrated virtually no increase in apoptosis. Likewise, a dose-dependent decrease in proliferative indices following radiation was noted among the invading cells and cells at the surface of the spheroid but not at the centre of the spheroid. We have described a model of malignant glioma invasion which possesses many of the qualities of in vivo malignant gliomas. Within this model, invasion appeared to be inhibited by radiation in a dose- and fractionation-dependent fashion. Measurement of apoptotic and cell proliferation indices favour a direct cytotoxic effect on the invading cells as the most likely mechanism for this phenomenon.

Nitric oxide regulates interleukin-8 gene expression in activated endothelium by inhibiting NF-kappaB binding to DNA: effects on endothelial function.

Nuclear factor-kappaB (NF-kappaB) binds to nucleotide sequences between -80 and -70 bp upstream of the transcriptional start site in the interleukin-8 (IL-8) promoter and is crucial for transcription of the IL-8 gene. We showed that exogenous nitric oxide in the form of a nitric oxide donor significantly reduced IL-8 mRNA in cytokine-activated ECV304. Similarly, nitric oxide significantly reduced migration of polymorphonuclear neutrophils through cytokine-activated ECV304 monolayers, an IL-8-dependent process. Using a luciferase reporter construct containing the NF-kappaB site of the IL-8 gene, we showed that exposing cytokine-activated ECV304 to exogenous nitric oxide resulted in significant reduction of NF-kappaB binding. Follow-up studies using a luciferase reporter construct possessing a mutated NF-kappaB site confirmed that the luciferase activity observed in the NF-kappaB reporter resulted from NF-kappaB binding. These studies demonstrate that nitric oxide, supplied exogenously into reactions containing activated endothelium, down-regulates pro-inflammatory activity, such as the secretion of chemokines, and functional activity, such as transendothelial migration of neutrophils.

Analysis of the clinical benefit of 5-fluorouracil and radiation treatment in locally advanced pancreatic cancer.

PURPOSE: To assess the palliative benefit of 5-fluorouracil (5-FU) and radiotherapy in patients with surgically unresectable localized pancreatic cancer. METHODS AND MATERIALS: Twenty-five patients with locally advanced surgically unresectable symptomatic pancreatic cancer received 5-FU chemotherapy and local radiation therapy. They were retrospectively reviewed in regard to their clinical benefit response (a composite of measurement of pain assessment, weight, and Karnofsky performance status [KPS]), as well as radiological response, time to progression, and overall survival. RESULTS: Median survival for the 25 patients was 9 months and median progression-free survival was 6 months. Thirty-two percent of patients survived in excess of 1 year. Analgesic requirements increased >50% in 2 patients and KPS deteriorated in 10 patients. Of the 13 remaining patients, 2 sustained a >7% weight loss and 2 gained weight post-treatment. Six patients improved in one parameter of analgesic consumption, weight loss or KPS without deteriorating in any others. Thus, the clinical benefit response index for 5-FU-radiation was 6/25 (24%). In terms of tumor response, 8 patients (44%) demonstrated a reduction in tumor volume post-treatment, 4 of whom (22%) experienced a >50% reduction. Four additional patients had radiologically stable disease. CONCLUSION: In this retrospective analysis, the clinical benefit response index for 5-FU-radiation was 24%, a value similar to the 23.8% reported for single agent gemcitabine. The median survival of 7 months was also similar to the 5.65 months reported for gemcitabine. The radiological partial response rate of 22% and the 1-year survival of 32% were higher for 5-FU-radiation than the reported values for gemcitabine. A randomized trial would be necessary to compare 5-FU-radiation to gemcitabine directly; however, from this review it did not appear that the overall palliative benefit of 5-FU-radiation was inferior to gemcitabine.

Design of biplanar gradient coils for magnetic resonance imaging of the human torso and limbs.

A method is described for design of gradient coils of unconventional geometry for MRI that is based on the superpositions of magnetic fields arising from individual current elements calculated by the Biot-Savart Law. Use of an optimization method based on a genetic algorithm enables a wide diversity in the shapes of coil that can be modeled. To exemplify this a two axis, biplanar gradient set is presented; this geometry offers good access for rectangular objects whilst holding the coils closer to the region of interest than is possible for cylindrical configurations. The inner dimensions of the gradient set were 40.0 x 24.4 x 40.0 cm and the gradient efficiencies were 0.3 and 0.4 mT m(-1) A(-1) in the z- and y- directions respectively over a 15 cm diameter region. Correction of signals arising from regions for which gradient linearity was not optimized was successful for the monotonic region within the set; the largest cuboid from which the MR signal could be processed to produce an undistorted image is of dimensions 36.3 x 17.2 x 24.4 cm.

Effects of radiation on a model of malignant glioma invasion.

We sought to characterize the effects of radiation alone and in combination with BCNU and dexamethasone on malignant glioma invasion. A model of malignant glioma invasion into a gel matrix of collagen type I was used to characterize response to radiation treatment for four malignant glioma cell lines (C6, U251, U373, A172) and nine primary human glioblastoma explants. A radiation dose dependent inhibition of invasion was noted for the C6 astrocytoma cell line but not the other cell lines or explants. Addition of BCNU and dexamethasone to radiation produced additional inhibition of invasion among the cell lines and explants but could not suppress invasion entirely.

Preoperative radiation with concurrent 5-fluorouracil continuous infusion for locally advanced unresectable rectal cancer.

BACKGROUND AND PURPOSE: To determine the percentage of complete responders and the resectability rate for patients with locally advanced carcinoma of the rectum treated by 5-fluorouracil (5-FU) infusional chemotherapy and pelvic radiation. MATERIALS AND METHODS: Between October 1992 and June 1996, 29 patients with a diagnosis of locally advanced unresectable rectal cancer received preoperative 5 FU by continuous intravenous infusion at a dose of 225 mg/m2/day concurrent with pelvic radiation (median 54 Gy/28 fractions). All patients were clinical stage T4 on the bases of organ invasion or tumor fixation. Median time for surgical resection was 6 weeks. RESULTS: Median follow-up for the group was 28 months (range 5-57 months). Six patients were felt to be persistently unresectable or developed distant metastases and did not undergo surgical resection. Of the 29 patients, 23 proceeded to surgery, 18 were resectable for cure, 13 by abdominoperineal resection, 3 by anterior resection and 2 by local excision. Of the 29 patients, 4 (13%) had a complete response, and 90% were clinically downstaged. Of the 18 resected patients, 1 has died of his disease, 17 are alive, and 15 disease-free. The regimen was well tolerated; there was only one treatment-related complication, a wound dehiscence. CONCLUSION: The combination of 5 FU infusion and pelvic radiation in the management of locally advanced rectal cancer is well tolerated and provides a baseline for comparison purposes with future combinations of newer systemic agents and radiation.