James S. Nelson

Comparison of postoperative radiotherapy and combined postoperative radiotherapy and chemotherapy in the multidisciplinary management of malignant gliomas. A joint radiation therapy oncology group and eastern cooperative oncology group study

Recently, the RTOG and ECOG concluded a joint randomized study on malignant gliomas that was in progress for the past five years. A total of 626 patients entered this protocol. Sixty‐seven percent of the 535 evaluable patients have died and thus this represents a preliminary report of a major joint clinical trial. The objective of this study was to evaluate the efficacy after neurosurgery of three new treatment options as compared with control treatment of radiotherapy alone. The four options were: (1) control radiation; 6000 rad/6–7 weeks to whole brain; (2) a higher radiation dose; Control dose plus a booster dose of 1000 rad/1–2 weeks to the tumor; (3) control radiation dose plus BCNU (80 mg/m2/day IV X 3 and repeat BCNU every 8 weeks); (4) Control radiation dose plus combination methyl‐CCNU (125 mg/m2/day orally X 1 and repeat methyl‐CCNU every 8 weeks), and DTIC (150 mg/m2/day IV X 5 and repeat DTIC every 4 weeks). All pertinent patient characteristics were studied and several important prognostic factors have been identified. Notably, age, histologic type (Astrocytoma with anaplastic foci, versus glioblastoma multiforme), initial performance status, time since first symptoms and presence or absence of seizure. At this time, it appeared that there was no treatment option which was significantly better than the control. The study identified that age was the most important prognostic factor. Patients who were younger than age 40 years had an 18‐month survival of 64%, patients who were age 40–60 years had an 18‐month survival of 20%, and patients who were older than age 60 had an 18‐month survival of 8%. The study also demonstrated that a modified histologic classification of anaplastic astrocytoma versus glioblastoma provided better prognostic information than the astrocytoma grading system of Kernohan. Patients with anaplastic astrocytoma had a median survival of 27 months as compared to 8 months for patients with glioblastoma. In further evaluation of any beneficial effect of chemotherapy, it was identified that only among the 40–60‐year‐old groups, BCNU treated patients appeared to have significantly increased survival than patients in the control groups (P = 0.01, one‐sided). Similarly, methyl‐CCNU + DTIC was suggestively better than the control (P = 0.08, one‐sided). The higher radiation dose, 7000 rad/8–9 weeks appeared to give no significantly better survival over the control dose option. Both BCNU and methyl‐CCNU + DTIC produced some toxicity. The combination of methyl‐CCNU + DTIC was more toxic than BCNU, producing severe or worse thrombocytopenia in 23% of the patients as compared to 6% on BCNU.

Excessive daytime sleepiness and subsequent development of Parkinson disease

Objective: To determine if excessive daytime sleepiness (EDS) can predate future Parkinson disease (PD). Methods: EDS was assessed in 3,078 men aged 71 to 93 years in the Honolulu-Asia Aging Study from 1991 to 1993. All were free of prevalent PD and dementia. Follow-up for incident PD was based on three repeat neurologic assessments from 1994 to 2001. Results: During the course of follow-up, 43 men developed PD (19.9/10,000 person-years). After age adjustment, there was more than a threefold excess in the risk of PD in men with EDS vs men without EDS (55.3 vs 17.0/10,000 person-years; odds ratio [OR] = 3.3; 95% CI = 1.4 to 7.0; p = 0.004). Additional adjustment for insomnia, cognitive function, depressed mood, midlife cigarette smoking and coffee drinking, and other factors failed to alter the association between EDS and PD (OR = 2.8; 95% CI = 1.1 to 6.4; p = 0.014). Other sleep related features such as insomnia, daytime napping, early morning grogginess, and frequent nocturnal awakening showed little relation with the risk of PD. Conclusions: Excessive daytime sleepiness may be associated with an increased risk of developing Parkinson disease.

A randomized comparison of misonidazole sensitized radiotherapy plus BCNU and radiotherapy plus BCNU for treatment of malignant glioma after surgery: final report of an RTOG study.

This randomized RTOG study evaluated misonidazole radiosensitized radiation therapy in the treatment of malignant glioma. One hundred and forty-six evaluable patients were treated with conventional radiation therapy to 60.00 Gy in 6-7 weeks plus BCNU 80 mg/m2/d for 3 days every 8 weeks (XRT + BCNU). One hundred and forty-seven evaluable patients were treated with misonidazole 2.5 gm/m2 once a week for 6 weeks, radiation therapy to 60 Gy and BCNU (MISO + XRT + BCNU). Patients were stratified according to the prognostic factors of age, performance status, and histology. Distribution of these characteristics was comparable among the treatment groups. The median survival for XRT + BCNU was 55.0 weeks, and for MISO + XRT + BCNU 46.0 weeks (p = 0.35). With patients on a minimum dose of dexamethasone of 3 mg/d, misonidazole neurotoxicity included 8.8% peripheral neuropathy, 2.7% CNS toxicity, and a 0.68% ototoxicity. BCNU pulmonary toxicity occurred in 9.3% of patients who received 902-2062 mg/m2 of BCNU.

Progressive neuropathologic lesions in vitamin E-deficient rhesus monkeys.

A consistent group of progressive central and peripheral nervous system lesions developed in seven rhesus monkeys maintained on a vitamin E-deficient diet for 30 to 33 months. These lesions were absent from vitamin E-supplemented monkeys. The principal neuropathologic alteration was loss of sensory axons in the posterior columns, sensory roots, and peripheral nerves. Morphologic and morphometric studies indicated that the distal segments of the axons were affected most severely and large-caliber myelinated fibers are selectively involved. Swollen, dystrophic axons (spheroids) occurred infrequently. Degeneration and phagocytosis of small numbers of neuronal perikarya were observed in the dorsal root ganglia and the anterior horns. The number of affected neurons was not proportional to the number of affected axons. Accumulation of lipopigment was evident in neuronal perikarya and CNS endothelial cells. The nervous system lesions were usually accompanied by a chronic necrotizing myopathy. The neuropathologic lesions in vitamin E-deficient monkeys are compared with those in vitamin E-deficient rats and in humans with low serum vitamin E concentrations. A similar type of sensory axonopathy is associated with chronic deficiency of vitamin E in these three species.

Accuracy of clinical criteria for AD in the Honolulu–Asia Aging Study, a population-based study

Objective: To determine diagnostic accuracy for AD in a population-based study of Japanese–American men. AD is neuropathologically confirmed for more than 80% of cases at major referral centers (primarily Caucasians); however, information on diagnostic accuracy in population-based studies and studies of different ethnic groups is limited. Methods: There were 3,734 men who participated in the Honolulu–Asia Aging Study 1991 through 1993 dementia examination and 2,603 in the 1994 through 1996 examination. Diagnoses were based on published criteria. Neuropathologists blinded to clinical data quantified neurofibrillary tangles (NFT) and neuritic plaques (NP). Results: Of 220 autopsied subjects, clinical evaluation revealed 68 with normal cognition, 73 intermediate, and 79 with dementia: 20 AD, 27 vascular dementia, 19 AD + other, and 13 other dementia. Among 20 cases with pure AD, the median value for maximum neocortical NFT density was 6.9/mm2 and for neocortical NP density was 8.0/mm2. Corresponding densities for other groups were <3.0/mm2. Using established neuropathologic criteria, 25% (5/20) of clinical AD cases had enough NP to meet definite AD criteria, whereas 65% (13/20) had sufficient NP to meet neuropathologic definite or probable AD criteria. Among nine AD cases with moderately severe dementia, only two (22%) had NP densities great enough to meet definite neuropathologic criteria, whereas seven (78%) met neuropathologic criteria for probable AD. Conclusions: Neuropathologic confirmation and NP density among decedents with clinical AD in this population-based study were lower than reported by referral centers and similar to reports from two other community studies. Ethnic differences in propensity for amyloid deposition as well as differences in clinical severity and representativeness of cases might contribute to these findings.

Survival and prognosis of patients with astrocytoma with atypical or anaplastic features

SummaryThis study confirms the importance of histologic tumor necrosis as a major prognostic variable in malignant glioma. Necrosis is present in glioblastoma multiforme (GBM), and absent in astrocytoma with atypical or anaplastic features (AAF). This paper evaluates 94 patients with AAF and 462 patients with GBM treated with radiation therapy with or without BCNU on 3 consecutive randomized protocols of the Radiation Therapy Oncology Group (RTOG) between 1974 and 1983. Multivariate analyses of the 556 patients confirmed histology as a significant independent variable that is prognostically relatively more important than Karnofsky performance status (KPS) and extent of surgery, and somewhat less important than age. The median survival for AAF was 36.2 months and for GBM was 8.6 months. In addition, separate multivariate analyses of AAf cases determined that the extent of surgery is a significant independent variable that is relatively more important than KPS, but less important than age. The median survival of AAF patients who underwent surgical excision was 46.8 months compared with 15.2 months for those biopsied (p < .001).

Midlife adiposity and the future risk of Parkinson’s disease

Background Evidence suggests that nigrostriatal system disorders are associated with PD and adiposity. Whether patterns of adiposity coexist or predate clinical PD is unknown. This report examines the relation between midlife adiposity and the risk of PD. Methods Measurement of adiposity occurred from 1965 to 1968 in 7,990 men in the Honolulu Heart Program (aged 45 to 68 years and without PD). Adiposity measures included body mass index (BMI), subscapular skinfold thickness (SSF), and triceps skinfold thickness (TSF). Follow-up for incident PD occurred over a 30-year period. Results During the course of follow-up, PD was observed in 137 men. Among the measures of adiposity, age-adjusted incidence of PD increased threefold from 3.7/10,000 person-years in the bottom quartile of TSF (1 to 5 mm) to 11.1/10,000 person-years in the top quartile (11 to 32 mm, p < 0.001). Effects of TSF on PD were independent of cigarette smoking, coffee consumption, physical activity, daily caloric and fat intake, and the other measures of adiposity (p < 0.001). Whereas rates of PD were lowest in the bottom quartile of BMI and SSF vs higher quartiles, associations with PD were weaker than they were for TSF. The effect of TSF on clinical onset before age 65 years was similar to the effect that was observed in later life. Conclusions Increased triceps skinfold thickness measured in midlife is associated with an elevated risk of future PD. Whether patterns of adiposity reflect a unique metabolic pathology in individuals at a high risk of PD warrants further study.

Consumption of milk and calcium in midlife and the future risk of Parkinson disease

Objective: To examine the relation between milk and calcium intake in midlife and the risk of Parkinson disease (PD). Methods: Findings are based on dietary intake observed from 1965 to 1968 in 7,504 men ages 45 to 68 in the Honolulu Heart Program. Men were followed for 30 years for incident PD. Results: In the course of follow-up, 128 developed PD (7.1/10,000 person-years). Age-adjusted incidence of PD increased with milk intake from 6.9/10,000 person-years in men who consumed no milk to 14.9/10,000 person-years in men who consumed >16 oz/day (p = 0.017). After further adjustment for dietary and other factors, there was a 2.3-fold excess of PD (95% CI 1.3 to 4.1) in the highest intake group (>16 oz/day) vs those who consumed no milk. The effect of milk consumption on PD was also independent of the intake of calcium. Calcium from dairy and nondairy sources had no apparent relation with the risk of PD. Conclusions: Findings suggest that milk intake is associated with an increased risk of Parkinson disease. Whether observed effects are mediated through nutrients other than calcium or through neurotoxic contaminants warrants further study.

Randomized neutron dose searching study for malignant gliomas of the brain: Results of an RTOG study

From September 1980 through January 1985, the Radiation Therapy Oncology Group (RTOG) conducted a randomized, dose-searching study testing the efficacy of a concomitant neutron boost along with whole brain photon irradiation in the treatment of malignant gliomas of the brain. Patients had to have biopsy-proven, supratentorial, anaplastic astrocytoma or glioblastoma multiforme (Nelson schema) to be eligible for the study. The whole brain photon irradiation was given at 1.5 Gy per treatment, 5 days-a-week to a total dose of 45 Gy. Two days-a-week the patients were to receive neutron boost irradiation to the tumor volume as determined on CT scans. The neutron irradiation was to be given prior to and within 3 hours of the photon irradiation on that day. The rationale for this particular treatment regime is discussed. A total of 190 evaluable patients were randomized among 6 different neutron dose levels: 3.6, 4.2, 4.8, 5.2, 5.6 and 6.0 Gyn gamma. There was no difference in overall survival among the 6 different dose levels, but for patients having less aggressive tumor histology (anaplastic astrocytoma), there was a suggestion that patients on the higher dose levels had poorer overall survival than patients on the lower dose levels and also did worse than historical photon controls. Important prognostic factors were identified using a Cox stepwise regression analysis. Tumor histology, Karnofsky performance status, and patient age were found to be related to survival while extent of surgery and neutron dose had no significant impact. Autopsies were performed on 35 patients and the results correlated with the actual neutron dose as determined by central-axis isodose calculations. At all dose levels there were some patients with both radiation damage to normal brain tissue and evidence of viable tumor. No evidence was found for a therapeutic window using this particular treatment regimen.

Adaptive decreases in amino acids (taurine in particular), creatine, and electrolytes prevent cerebral edema in chronically hyponatremic mice: Rapid correction (experimental model of central pontine myelinolysis) causes dehydration and shrinkage of brain

The experimental model of central pontine myelinolysis—chronic (4-day) hyponatremia induced by daily injections of hypotonic dextrose solutions and vasopressin followed by rapid correction with saline—was used in young fasted and thirsted mice. In normal controls, chronic fasting and thirsting lowered plasma and brain glucose levels and cerebral glycolytic and tricarboxylic acid cycle metabolic fluxes. The fasting state had little effect on brain amino acids. Clinically, the animals became semistuporous; about one-third died. Chronic hyponatremia in fasted mice almost tripled the plasma glucose concentrations and increased the brain carbohydrate reserve. Levels of other brain glycolytic and Krebs citric acid cycle intermediates were similar to those of controls. Severe hyponatremia and hypoosmolality induced profound decreases in levels of brain electrolytes, amino acids (especially taurine), and creatine. These changes permitted a new osmotic balance between blood and brain and a normal brain water content. The behavior and mortality of the hyponatremic animals were not different from those of the fasted control mice. Correction of hyponatremia to normonatremic levels over a 9-hr period returned brain Na+ and K+ levels to normal but the contents of the measured amino acids and creatine were still reduced one-third or more. As a result, treatment produced a significant degree of dehydration and shrinkage of the brain. The findings stress the importance of amino acids (taurine in particular) and creatine levels, as well as electrolytes, in brain osmoregulation and suggest a role for an osmotic disequilibrium—blood osmolality higher than brain—in the production of brain lesions following rapid correction of chronic hyponatremia in animals and possibly in humans. Replenishment of depleted brain K+ and amino acid levels, as well as slow elevation of the chronically depressed level of plasma Na+, is recommended.