Biomedical subjects
H Hugenholtz
Publications and source records attributed to H Hugenholtz.
A randomized trial to assess the efficacy of surgery in addition to radiotherapy in patients with a single cerebral metastasis.
BACKGROUND: Cerebral metastasis is a common oncologic problem that occurs in 15-30% of cancer patients; approximately half such metastases are single. Previous retrospective studies and two randomized trials reported that the addition of surgical extirpation prior to radiation therapy increased survival, neurologic function, and quality of life compared with radiation alone in patients with a single brain metastasis. METHODS: A randomized controlled trial was conducted in which patients with a single brain metastasis were allocated to undergo radiation alone or surgery plus radiation. Radiation consisted of 3000 centigray to the whole brain in 10 fractions. RESULTS: Forty-three patients received radiation alone and 41 patients surgery plus radiation. All but two of the study patients died. No difference in survival was detected between the groups; the median survival for the radiation group was 6.3 months (95% confidence interval, 3-11.4) compared with 5.6 months for the surgery plus radiation group (95% confidence interval, 3.9-7.2) (P = 0.24). Most patients died within the first year (69.8% in the radiation arm vs. 87.8% in the surgery plus radiation arm). There were no significant differences in the 30-day mortality, morbidity, or causes of death. Extracranial metastases was an important predictor of mortality (relative risk, 2.3). The mean proportion of days that the Karnofsky performance status was > or = 70% did not differ between the 2 groups. CONCLUSIONS: This trial failed to demonstrate that the addition of surgery to radiation therapy improved outcome of patients with a single brain metastasis. Thus, the efficacy of surgery plus radiation compared with radiation alone needs to be addressed by further clinical trials and/or a meta-analysis.
Neurosurgery workforce in Canada, 1996 to 2011. Canadian Neurosurgical Society.
OBJECTIVE: To determine the number of neurosurgeons in clinical practice in Canada on Jan. 1, 1996, and their practice profile and to determine requirements for 2001 and 2011. DESIGN: Telephone survey and national mail survey. SETTING: Canada. PARTICIPANTS: All 174 neurosurgeons in Canada engaged in active clinical practice on Jan. 1, 1996, and all residents enrolled in neurosurgery training programs in Canada during the 1995-96 academic year. OUTCOME MEASURES: Demographic characteristics, full-time equivalents, workload, attrition, reasons for exit, vacancies, supply and shortfall. RESULTS: All 174 neurosurgeons responded to the survey. There is a chronic shortage of 25 neurosurgeons in Canada. Sixty-two established neurosurgeons will have stopped practice by 2001 and 181 by 2011. They will need to be replaced, for a total requirement of 87 and 206 neurosurgeons by 2001 and 2011 respectively. Canadian neurosurgery training programs can currently generate only up to 69 and 177 graduates by 2001 and 2011 respectively. During the period 1985-95, 50% of neurosurgery graduates emigrated from Canada within 2 years of obtaining certification, creating potential deficits of up to 52 and 117 neurosurgeons by 2001 and 2011 respectively. CONCLUSIONS: Strategies need to be developed quickly to address not only the chronic shortfall but also the attrition of established neurosurgeons. Strategies to increase and retain the number of Canadian neurosurgery graduates are also needed.
PROMACE-MOPP and intrathecal chemotherapy for CNS lymphomas.
UNLABELLED: We conducted a Phase II study of PROMACE-MOPP and intrathecal (IT) therapy followed by cranial radiation in 7 patients (4 male, 3 females) with diffuse large cell lymphomas (including one T cell) involving the central nervous system (CNS). Median age was 47 years (range, 25-78). Median performance status was 2 (range, 2 to 3). Two patients had positive CSF cytology. No patients had prior chemotherapy or radiotherapy. Treatment consisted of PROMACE (cyclophosphamide 650 mg/m2, etoposide 120 mg/m2 days 1 and 8, methotrexate (MTX) 1.5 g/m2 and folinic acid 50 mg/m2 (x 5) day 15, and prednisone 60 mg/m2 days 1-14) x 3-4 courses. MOPP consisted of mustargen 6 mg/m2 and vincristine 1.4 mg/m2 days 1 and 8, procarbazine 100 mg/m2 and prednisone 40 mg/m2 po days 1-14 x 3-4 courses. IT drugs were MTX 20 mg and hydrocortisone 20 mg day 1 and cytosine arabinoside 100 mg day 8, courses 2 to 6, or more frequently if CSF cytology was positive. Following MOPP, 4000 cGy whole brain radiation (XRT) and 2000 cGy boost was given. Response was evaluated before XRT. Two patients declined XRT, 3 declined MOPP and 2 declined IT drugs. Two patients had extracerebral disease and 5 were primary CNS lymphomas. Response after PROMACE was CR: 3 patients; PR 2: stable 1. One patient, with extracerebral disease, experienced PR in the abdomen and CR by CT scan in the brain, but had persistent positive CSF cytology. This patient died from pneumocystis pneumonia 10 weeks after her last CSF cytology and 17 weeks after her diagnosis. After PROMACE +/- MOPP 6 patients experienced CR's. Median (range) survival was 100 (17-334) weeks, with 1 patient lost to follow up at 32 weeks. Toxicity included febrile neutropenia; 6 patients; pneumocystis pneumonia: 1 (fatal); thrombocytopenia; 5; stomatitis: 3; diarrhea; 2; nausea; 3. CONCLUSION: This regimen is active in the treatment of CNS lymphomas, although toxicity is substantial.
Intraarterial cisplatin plus intravenous doxorubicin for inoperable recurrent meningiomas.
The majority of meningiomas are cured by surgical resection. There is little information in the literature on the use of chemotherapy in meningiomas. We report 2 patients with inoperable recurrences of meningiomas that responded (1 patient) or stabilized (1 patient) when treated with the combination of intracarotid cisplatin plus intravenous doxorubicin.
Factors affecting platinum concentrations in human surgical tumour specimens after cisplatin.
We assessed factors which affect cisplatin concentrations in human surgical tumour specimens. Cisplatin 10 mg m-2 was given i.v. to 45 consenting patients undergoing surgical resection of neoplasms, and platinum was assayed in resected tumour and in deproteinated plasma by flameless atomic absorption spectrophotometry. By multiple stepwise regression analysis of normalised data, patient characteristics that emerged as being most closely associated (P < 0.05) with tumour platinum concentrations (after correcting for associations with other variables) were tumour 'source' [primary brain lymphomas, medulloblastomas and meningiomas ('type LMM') > 'others' > lung cancer > head/neck cancer > gliomas) or tumour 'type' (LMM > brain metastases > extracerebral tumours > gliomas), serum calcium and chloride (positive correlations) and bilirubin (negative). Tumour location (intracranial vs extracranial) did not correlate with platinum concentrations. If values for a single outlier were omitted, high-grade gliomas had significantly higher platinum concentrations (P < 0.003) than low-grade gliomas. For intracranial tumours, the computerised tomographic scan feature that correlated most closely with platinum concentrations in multivariate analysis was the darkness of peritumoral oedema. Tumour source or type is a much more important correlate of human tumour cisplatin concentrations than is intracranial vs extracranial location. Serum calcium, chloride and bilirubin levels may affect tumour cisplatin uptake or retention. CT scan characteristics may help predict cisplatin concentrations in intracranial tumours.
Classification of brain tumors by ex vivo 1H NMR spectroscopy.
Ex vivo biopsy samples (n = 42) from human brain tumors and normal brain have been examined by high-resolution proton magnetic resonance spectroscopy. Parameters from one-dimensional 1H spectra, two-dimensional COSY spectra, and transverse relaxation time (T2) data were used to classify the tumors according to the histopathological diagnoses. The ratio of the area between 3.4 and 3.1 ppm to that between 1.5 and 1.1 ppm distinguished glioblastomas from astrocytomas and normal brain, and appeared to be indicative of malignant potential. In support of the one-dimensional data, cross-peaks in the COSY spectra of brain specimens classified glioblastomas and metastases into one group and the more benign tumors, meningiomas, astrocytomas, and normal brain into a second group. The transverse relaxation of the resonance at 1.3 ppm was fitted by a model with two T2 values. The longer T2 value could be used to distinguish glioblastomas from normal brain, the latter having a much longer long T2 value. Astrocytomas showed a continuum of T2 values between glioblastomas and normal brain, with the grade of the astrocytoma correlating roughly with the value of the long T2 component.
One-dimensional phosphorus-31 chemical shift imaging of human brain tumors.
RATIONALE AND OBJECTIVES: Phosphorus magnetic resonance spectroscopy has been used noninvasively to determine characteristic spectral parameters for untreated human brain tumors as a prelude to its use in clinical diagnosis. METHODS: The spectra, which reflect the relative amounts of phosphorus-containing compounds, and the pH within and surrounding the tumors, were obtained in vivo using the localization technique of one-dimensional chemical shift imaging applied with a surface coil. Phosphorus-31 chemical shift imaging was performed successfully in vivo on 9 volunteers and 27 patients with untreated brain tumors, including 7 with astrocytoma, 4 with glioblastoma, 3 with meningioma, and 11 with metastases. This study provides spectra from within and surrounding the brain tumors, and allows accountability for the heterogeneity of brain tumors by the selection of the maximum data point for each parameter. RESULTS: The ratios of resonance areas, phosphodiesters over nucleoside triphosphate (NTP), and phosphomonoesters over NTP, were found to be higher in glioblastomas (2.55 +/- 0.22, 1.06 +/- 0.09) and astrocytomas (3.04 +/- 0.36, 1.28 +/- 0.36) than in normal brain (2.00 +/- 0.32, 0.79 +/- 0.22). The ratios of areas due to inorganic phosphate and NTP, and phosphocreatine and NTP, also were higher in astrocytomas (1.16 +/- 0.40, 1.17 +/- 0.41) compared with glioblastomas (0.68 +/- 0.01, 0.88 +/- 0.19) and normal brain (0.61 +/- 0.03, 0.77 +/- 0.03). The pH of brain tumors ranged from alkaline to neutral, with meningiomas consistently having alkaline pH. CONCLUSIONS: These data show that there are statistically significant differences in the magnetic resonance parameters of the affected brain hemispheres of patients with astrocytomas, glioblastomas, meningiomas, and normal brain tissue, and underline the need for a multisite clinical trial to establish clinical criteria for diagnosis.
The Canadian health care system in the nineties.
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Feasibility study of intraarterial vs intravenous cisplatin, BCNU, and teniposide combined with systemic cisplatin, teniposide, cytosine arabinoside, glycerol and mannitol in the treatment of primary and metastatic brain tumors.
Sixteen patients with intracerebral tumors received intraarterial cisplatin, teniposide, and BCNU combined with intravenous cisplatin, teniposide, and cytosine arabinoside. Oral glycerol and intravenous mannitol were given along with the intravenous chemotherapy in an attempt to increase drug delivery to tumor by augmenting tumor blood flow. Thirteen additional patients were treated with the same regimen, but received all the chemotherapy intravenously. Of the 16 patients receiving intraarterial chemotherapy (median survival, 14 weeks), none responded, 5 (31%) were stable for > 8 weeks, 8 (50%) failed, and 3 (19%) were unevaluable due to early death. Of the 13 patients receiving all their treatment intravenously (median survival, 13 weeks), 3 (23%) responded, 1 (8%) was stable, 7 (54%) failed, and 2 (15%) were unevaluable due to early death. In the patients receiving intraarterial chemotherapy, toxicity included ipsilateral retinal toxicity (2 patients), ocular pain or headache (10), periorbital swelling and flushing (6), increased brain edema with focal neurological deficits and drowsiness (5), and catheter-related carotid artery thrombosis followed by fatal herniation (1). Myelosuppression was worse in patients who received all their treatment intravenously than in those receiving intraarterial chemotherapy (p < 0.05). Neutropenic sepsis developed in 4 patients on the intraarterial arm (1 fatal) and in 5 patients on the intravenous arm (2 fatal). Other toxic effects were similar whether or not patients received intraarterial treatment or only intravenous treatment. Overall, toxicity of this regimen was excessive, and response rates were lower than would have been expected with single agent therapy.
Intrathecal baclofen--the importance of catheter position.
In a patient receiving intrathecal baclofen injections for intractable trunk and leg spasms, positioning the subarachnoid catheter tip just caudal to the spinal segments innervating the spastic muscles enhanced the spasmolytic effect of bolus injections of intrathecal baclofen on the affected muscles. Such selective positioning of subarachnoid catheters may facilitate segmental spasmolysis with lower intrathecal doses of baclofen and provide an important alternative to relying only on ascending CSF concentration gradients of baclofen from chronic lumbar intrathecal infusion.
Phase II study of weekly intravenous menogaril in the treatment of recurrent astrocytomas in adults.
Twenty patients with astrocytomas recurrent after surgery +/- radiation were treated on a phase II protocol of the new anthracycline derivative menogaril 115 mg/m2 administered intravenously once per week. Sixteen patients were evaluable for treatment efficacy. No patient achieved a major therapeutic response. Three patients (19%) had stable disease for greater than 8 weeks, including one who showed minor evidence of tumor regression, but less than 50%. Thirteen patients failed. Treatment was well tolerated. One patient developed granulocytopenia, while none developed thrombocytopenia. Four patients required an interruption in their treatment for one to two weeks because of development of granulocytopenia (one patient) or other reasons. Other toxic effects included arm vein phlebitis and skin irritation, skin discoloration of the infused arm, mild to moderate nausea and vomiting, diarrhea, stomatitis, and a fatal central venous catheter infection. Despite the fact that menogaril appeared to have therapeutic activity against recurrent astrocytomas in our phase I studies, we could not document any activity in this phase II study.
Phase I study of intracarotid administration of carboplatin.
Fifteen patients were treated in a Phase I study of intracarotid carboplatin (200-400 mg/m2) in 5% dextrose and water infused over 15 to 30 minutes through a transfemoral catheter with a 0.2-micron inline filter. This study was done because intravenous carboplatin has less neurotoxicity than cisplatin and is active against brain tumors. Eleven men and four women ranging in age from 37 to 72 years (median, 59 years) were treated. The Eastern Cooperative Oncology Group performance status was 1 in 3, 2 in 4, and 3-4 in 8 patients. Eight patients had one to three previous chemotherapy regimens; previous radiotherapy had failed in 13 patients. The response of patients in the Phase I study follows: glioblastoma, 6 failed; not evaluated because of early death from pulmonary embolus, 1; recurrent Grade II and III glioma, 1 stable (minor response with neurologic improvement) and 2 failed; malignant oligodendroglioma, 1 failed; brain metastases from nonsmall cell lung cancer, 1 partial remission, 1 stable (minor response), and 1 failed; brain metastases from unknown primary, 1 stable (minor response with neurological improvement). Median survival was 9 weeks. Nausea was mild to moderate. One patient had granulocytopenia, and 2 had thrombocytopenia (mild). At 200 mg/m2 (2 patients), 1 had a focal seizure. At 300 mg/m2 (9 patients), 2 with abnormally small arteries had severe pain early in the treatment and posttreatment ipsilateral conjunctival edema, decreased vision, and cerebral edema (with partially reversible increased hemiparesis); 1 other had mild decrease in ipsilateral vision and 1 had transient aphasia on removal of the catheter (possibly the result of a vascular spasm).(ABSTRACT TRUNCATED AT 250 WORDS)
Intrathecal baclofen for intractable spinal spasticity--a double-blind cross-over comparison with placebo in 6 patients.
A group of six subjects with intractable spinal spasticity completed a double-blind cross-over paradigm in which they received two intrathecal bolus injections of baclofen solution five hours apart on two different days and two intrathecal bolus injections of placebo saline five hours apart on two other days. Each subject was repeatedly tested with a battery of clinical and physiological tests. In contrast to the placebo injections, the group responded to the baclofen injections with subjective and objective, clinically significant improvement in parameters of spasticity in their lower limbs, including muscle tone, frequency of spasms, hyperreflexia and passive range of joint motion. Furthermore, this improvement was maintained following thirty consecutive days of intrathecal bolus injections of baclofen at a fixed dose.
Reaction time after head injury: fatigue, divided and focused attention, and consistency of performance.
Three groups of patients who had suffered head injury were compared with matched control subjects on reaction time (RT) tasks. Group I consisted of outpatients previously hospitalised for head injury of wide ranging degrees of severity, assessed at varying intervals after injury. Group II was composed of non-hospitalised mildly concussed patients. Group III was made up of head injured patients of varying degrees of severity assessed 7-10 months after initial hospitalisation for their injury. The reaction time tests were graded in difficulty, from a simple RT response to a complex choice RT test. In addition, subjects were compared in their ability to ignore redundant information during one of the choice RT tests. The findings indicate that traumatic brain injury causes slower information processing, deficits in divided attention, an impairment of focused attention, and inconsistency of performance.
Human central nervous system and plasma pharmacology of mitoxantrone.
Mitoxantrone 5-6 mg/m2 was administered IV to 10 consenting patients prior to surgical resection of an intracerebral tumor. Plasma pharmacokinetic parameters were calculated and concentration of mitoxantrone in intracerebral tumors was determined. Concentrations of mitoxantrone were also determined in autopsy tissues of one of the patients who expired 192 days after receiving the drug. The plasma pharmacokinetics were best described by a 3 compartment model, with a tl/2 gamma of 4.74 +/- 5.53 h. Mitoxantrone concentrations in the intracerebral tumors were potentially cytotoxic and ranged from 4 to 322 ng/g. In all but one case, mitoxantrone concentration was higher in tumor than in concurrent plasma samples. There was no obvious relation between tumor mitoxantrone concentration and peak plasma mitoxantrone concentration or time from mitoxantrone administration to tumor removal. Low grade gliomas and viable tumors tended to have lower mitoxantrone concentrations than did other tumor types and necrotic tumors. In the patient undergoing autopsy, highest mitoxantrone concentrations were found in liver, thyroid and heart.
Multiple noncontiguous fractures of the cervical spine.
Multiple noncontiguous fracture-subluxations of the cervical spine are fractures and subluxations separated by at least one normal intervening cervical vertebra. A review of all 66 consecutive cervical spine fractures treated by the Division of Neurosurgery at the University of Ottawa during 26 consecutive months revealed six such cases (9%). These injuries are more common than previously recognized. Special consideration is required in their treatment because of the presence of a mobile intermediate segment in some of these patients.
Cervical spinal cord stimulation for spasticity in cerebral palsy.
A prospective double-blind study of high cervical spinal cord stimulation conducted in eight moderately disabled, spastic, cerebral palsied children failed to demonstrate any significant improvement over base line function during chronic spinal cord stimulation at either optimal stimulation parameters or random placebo parameters. Chronic stimulation included 4 consecutive months of stimulation for 24 hours each day. Stimulators were randomly programmed at optimal parameters for 2 of the 4 months and at placebo parameters for the remaining 2 months. At the end of each month of chronic stimulation, subjects were assessed with a multidisciplinary test battery that included a self-assessment, specific clinical examinations, tests of gross and fine motor control, neuropsychological and neurophysiological tests, a detailed gait analysis, and video recordings. By 6 months after the completion of the study, only 1 of the 8 subjects continued to use his stimulator on a regular basis, with minimal benefit.