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Glioblastoma multiforme (GBM) is the most common adult primary malignant brain tumor. Ninety percent of adult GBM patients die within 24 months after diagnosis. The etiology of GBM is unknown. The Honolulu Heart Program (HHP) and Honolulu-Asia Aging Study (HAAS) are prospective, cohort studies of cardiovascular and neurodegenerative disease based on 8,006 Japanese-American men followed since 1965. The Japan Hawaii Cancer Study provides data on incident cancer cases in the HHP/HAAS cohort. We used data from these studies to obtain epidemiologic information about GBM. GBM cases were identified by searching the 1965-1998 databases using International Classification of Diseases (ICD-9) codes. Nine histologically confirmed GBM cases, 58-80 years old, were identified. The incidence rate was 6.2/100,000 person-years. Records of each case were reviewed. Selected variables from the first three examinations (1965-1968; 1968-1970; 1971-1974) were used to identify potential candidate GBM risk factors. A multivariate Cox proportional hazards model showed sugar intake and occupational exposure to carbon tetrachloride were independently and significantly associated with development of GBM.

A seven-week-old infant presented with an acute flaccid paraparesis. Her subsequent course was punctuated by numerous exacerbations, in association with minor intercurrent illness and remissions produced by corticosteroid treatment. Postmortem examination revealed a chronic inflammatory polyradiculopathy. She represents the youngest patient yet described with a chronic, relapsing, steroid-responsive polyneuropathy.

Religious experience is conditioned and influenced by our understanding of reality, and scientific knowledge contributes to that understanding. Spirituality will be related to knowledge of nature in that experience of God will be mediated in and through a relation to the universe and out of the fulfillment of the creation. Thus a mystical knowledge of God is experienced in and out of a developing evolution of nature, society, and culture. Ralph Burhoe and Teilhard de Chardin share a vision of mystical unity with God as arising out of an integration involving the systems of nature and society.

This study attempts to show that brain research brings to light religious meanings. There is a physical basis of religion in that the way the brain has evolved makes possible the religious meanings of human experience. The brain grows out of and reflects the universe. The brain is an icon of God. In the analysis of the brain's various parts and functions the relational dimensions of reality are uncovered in their physical basis. This points to ultimate reality as social and to a social God. As such, the structures of reality, experienced through the brain, reflect the reality of God.

Continuous quality improvement activities are mandated by the Joint Commission on Accreditation of Healthcare Organizations and the College of American Pathologists. In a recent Needs Assessment Survey of neuropathologists undertaken by the College of American Pathologists, in cooperation with the American Association of Neuropathologists, neuropathologists indicated the need for information regarding continuous quality improvement for neuropathology laboratories. This article suggests activities that may be incorporated in a continuous quality improvement program, including suggested monitors in surgical and autopsy neuropathology, as well as an example of a continuous quality improvement plan.

BACKGROUND. Efforts to improve local control and survival by increasing the dose of once-daily radiation therapy beyond 70 Gray (Gy) for patients with malignant gliomas have as yet been unsuccessful. Hyperfractionated radiation therapy (HF) should allow for delivery of a higher total dose without increasing normal tissue late effects, whereas accelerated hyperfractionated radiation therapy (AHF) may minimize tumor repopulation by shortening overall treatment time. The Radiation Therapy Oncology Group (RTOG) conducted a randomized Phase I/II study of escalating doses of HF and AHF with carmustine (bis-chloroethyl nitrosourea [BCNU]) for adults with supratentorial glioblastoma multiforme (GBM) or anaplastic astrocytoma (AA). Primary study endpoints were overall survival and acute and chronic treatment-related toxicity. METHODS. From 1983 to 1989, 786 patients with supratentorial gliomas (81% with GBM and 19% with AA) were stratified by histology, age, and performance status and randomized to receive partial brain irradiation, utilizing either HF (1.2 Gy twice daily to doses of 64.8, 72, 76.8, or 81.6 Gy) or AHF (1.6 Gy twice daily to doses of 48 or 54.4 Gy). All patients received carmustine. The distribution of prognostic factors was similar in all arms. RESULTS. There were 747 eligible and analyzable patients among 786 enrolled patients (95%). Two patients had a Grade 5 and 65 patients had a Grade 4 chemotherapy toxicity. Two patients in the 81.6 Gy arm experienced late Grade 4 radiation toxicity and there was 1 late radiation-associated death in the 54.4 Gy arm. The rate of Grade 3 or worse radiation toxicity at 5 years, calculated by the delivered dose level, was 3% in the lowest total dose arms (48 and 54.4 Gy), 4% in the intermediate dose arms (64.8 and 72 Gy), and 5% in the highest dose arms (76.8 and 81.6 Gy) (P = 0.54). Survival rates at 2 and 5 years were: 21% and 11%, respectively, for all patients; 62% and 41%, respectively, for AA patients; and 10% and 4%, respectively, for GBM patients. There were no significant differences between the treatment arms with regard to median survival time (MST), when analyzed by the originally assigned dose. The MST for all patients varied between 10.8 months and 12.7 months (P = 0.59); between 9.6 months and 11 months for patients with GBM (P = 0.43); and between 30.4 months and 85.8 months for patients with AA (P = 0.78). Analysis of the survival rates for all patients by dose received rather than by dose assigned revealed a 14% 5-year survival rate for the lower HF doses (64.8 and 72 Gy), 11% for the higher doses (76.8 and 81.6 Gy), and 10% for the AHF doses (48 and 54.4 Gy)(P = 0.1). The subgroup of AA patients had a better MST (49.9 months) in the lower received HF doses than in the higher HF doses (34.6 months)(P = 0.35). In contrast, GBM patients who received the higher HF doses had survival superior to the patients in the AHF arms (MST of 11.6 months and 10.2 months, respectively; P = 0.04). CONCLUSIONS. The use of HF with BCNU and dose escalation up to 81.6 Gy is both feasible and tolerable, although late toxicity increases slightly with increasing dose. The best MST with the least toxicity were observed for AA in the lower received HF doses (72 and 64.8 Gy). Accordingly, 72 Gy in two 1.2 Gy fractions was used as the investigational arm of a completed Phase III trial (RTOG 90-06).

The neurocutaneous diseases are a collection of more than 40 hereditary and spontaneously occurring disorders, many of which have prominent lesions involving the nervous system and skin. In this article, the classification of the neurocutaneous diseases is briefly reviewed, and the neuropathologic characteristics of four of these diseases (neurofibromatosis, tuberous sclerosis, von Hippel-Lindau disease, and Sturge-Weber disease) are summarized.

Background. Confounding biologic factors, including histologic grade, may influence the outcome of adult patients with malignant gliomas more than may modifications in therapeutic approach. Any clinical trial design for malignant gliomas in adults must account for such biologic factors, including the accurate identification of the two histologic subgroups astrocytoma with anaplastic foci (AAF) or glioblastoma multiforme (GBM), which are associated with distinctly different survival outcomes. This paper examines the need for a central pathology review before entry of patients in cooperative group clinical trials stratified by histologic grade. Methods. Pathology slides from Radiation Therapy Oncology Group (RTOG) trial 83-02, a randomized Phase II study of hyperfractionated and accelerated hyperfractionated radiation therapy and carmustine for malignant gliomas, provided 747 analyzable cases, with 680 (91%) available for central pathology review. This review was performed by a single pathologist according to RTOG/Eastern Cooperative Oncology Group histopathologic criteria. The kappa statistic was used to measure agreement between the institutional and central classification of AAF and GBM. The influence of misclassification was examined using computer simulation of varying clinical trial sizes (n = 25, 50, or 200). The effect on the statistical power of trials (n = 200) with varying mixtures of AAF and GBM tumors was investigated using computer simulations. Results. Of 159 tumors classified as AAF by institutional pathology review, only 66% (105) were classified as AAF (AAF/AAF) by central review, and 54 of these cases (34%) were classified as GBM (GBM/AAF), whereas 96% (501) of 521 institutionally classified as GBM (GBM/GBM) were similarly classified by central review. Computer simulations demonstrated a 59% underestimation in the median survival (1.82 vs. 4.49 years) for trials of patients with institutionally defined AAF compared to patients with centrally defined AAF in studies of 200 patients, resulting from the addition of poor prognosis of GBM in the trial. Misclassification can also substantially reduce the statistical power of a clinical trial. In one of the simulation studies, statistical power was reduced from 65% to 14% if 50% of the patients were to receive an inaccurate histologic classification. Even greater losses in power are possible in many plausible clinical settings. Conclusions. This examination of a central versus an institutional pathology review demonstrates a low level of agreement on AAF classification and a high level of concordance on GBM classification. The results indicate the need to adjust sample size for trials of both AAF and GBM tumors to have adequate statistical power. A central pathology review remains essential for trial entry for patients with AAF and could be omitted for trials enrolling patients with GBM only

Background. The third and final randomization of Radiation Therapy Oncology Group (RTOG) 83–02 was performed to identify the maximal tolerated dose and potential efficacy of accelerated hyperfractionated radiation therapy (AHRT) in 1.6 Gy twice-daily fractions for adult malignant glioma. Methods. From December 1987 to July 1989, 304 patients with malignant glioma were stratified by age, performance status, and histologic findings and randomized to receive total AHRT doses of 48.0 or 54.4 Gy, with 80 mg/m2 of bis-chlorethyl nitrosourea (BCNU) for 3 days every 8 weeks. Distribution of other prognostic factors, including neurologic function, extent of surgery, tumor size, and sex, was comparable in each treatment arm. Results. One Grade 5 radiation therapy (RT)-related toxic effect was reported (in the 54.4-Gy treatment arm), and the incidence of late Grade 3–5 RT-related toxic effects at 18 months was 1% at 48.0 Gy and 4% at 54.4 Gy. The median survival times (MST) for the 48.0 Gy and 54.4 Gy treatment arms were 11.7 and 10.8 months, respectively, comparable to the MST in prior RTOG trials with a similar proportion of patients with glioblastoma multi-forme (79%). For the 123 patients who were 60 years of age or older, the MST for the 48.0 Gy and 54.4 Gy treatment arms were 8.9 and 10.4 months, respectively, and compare favorably with the MST of 6.0 months reported with standard RT and BCNU treatment used for 101 patients who were 60 years of age or older in two prior RTOG malignant glioma trials (74–01 and 79–18). Although these results differ significantly (P < 0.0015), this contrast is not significant when adjusted by performance status. Conclusions. The maximum tolerated dose of AHRT has yet to be identified, and pursuit of this information may most benefit patients with malignant glioma who are 60 years of age or older.

Between 1983 and 1987 the Radiation Therapy Oncology Group conducted a prospective phase II study to evaluate survival in primary non-Hodgkin's lymphoma of the brain treated with whole brain irradiation to 40 Gy and a 20 Gy boost to tumor plus a 2 cm margin. Forty-one patients are reported. Full follow-up is available on 35/41 who have died. Six are alive at 8.8-67.2 months from start of radiation therapy with a median followup of 53.9 months. Overall median survival was 11.6 months from start of radiation therapy and 12.2 months from diagnosis, with 48% surviving 1 year and 28% surviving 2 years. Karnofsky Performance Status and age were significant prognostic factors. Patients with a Karnofsky Performance Status of 70-100 had a median survival of 21.1 months compared to 5.6 months for patients with a status of 40-60 (p less than .001). Fourteen patients less than 60 years of age had a median survival of 23.1 months, while 27 patients greater than or equal to 60 years of age had a median survival of 7.6 months (log-rank p = .001). Disease recurred in the brain in 25/41 (61%) of the patients, (21/41 in the brain only and 4/41 in the brain plus distant metastases). Despite high dose and large volume irradiation, primary Central Nervous System lymphoma still exhibits excessive mortality, especially in older patients. This paradox of the relative radioresistance of primary Central Nervous System lymphoma remains unresolved.

Central to the work of Arthur Peacocke on science and religion is the intention to develop a reasonable faith within an intelligible framework of meaning. Showing the inadequacy of reductionism is necessary for this purpose. Knowledge of God is related to what science can tell us about creation. From an evolutionary framework, characterized as a delicate balance that issued in humans, and manifested through contingency and chance, God's actions are expressed as exploring the potentialities of creation. The creation is understood to be in God, but God is more than the world, as in panentheism. God suffers with the creation in love, and the focus of human meaning is expressed in Jesus Christ, the Incarnation, the sacrament of God.

Twenty-six cases are reported of gliosarcoma (GS) retrieved from a series of 1479 glioblastomas (GBM) that were part of five consecutive, randomized Phase II or III malignant glioma protocols initiated by the Radiation Therapy Oncology Group between 1974 and 1983. The clinicopathologic features of these 26 cases, including actuarial survival times, were compared with the remaining 1453 GBM. The minimal qualitative and quantitative histologic criteria required to diagnose GS are presented. In most cases the sarcomatous component was a malignant fibrous histiocytoma; a minority were fibrosarcoma. No significant differences between GS and GBM were found with regard to age, sex, pretreatment Karnofsky performance status, tumor location, size, median survival (8.3 and 9.6 months, respectively), and actuarial survival. None of the treatment regimens, which included various combinations of radiation therapy and chemotherapy, improved the survival of GS over GBM. Selective involvement of the temporal lobe by GS was not found, and the frequency of GS was determined to be only 1.8% of all GBM.

Lesions in the nervous system and skeletal muscles of vitamin E-deficient rats, monkeys and humans were studied morphologically and morphometrically. The experimental animals were fed purified, vitamin E-deficient diets for periods from two months to six years. In some studies deficient animals were repleted by feeding 200 mg all-rac-alpha-tocopheryl acetate/kg diet. The humans were children with congenital biliary atresia, low serum levels of vitamin E, and a consistent, progressive neurological syndrome. These studies demonstrate that chronic vitamin E deficiency in rats, monkeys and humans is characterized by a progressive, systematic degeneration of large calibre, myelinated sensory axons in spinal cord and peripheral nerves. The axonopathy is most severe in the rostral segments of the posterior or dorsal columns. Dystrophic axons are numerous in the sensory relay nuclei of cord and medulla in rats and humans, and infrequent in monkeys. Primary, necrotizing myopathy occurs regularly in vitamin E-deficient rats and monkeys. Regenerative changes in the peripheral nerves and skeletal muscles of deficient animals are morphologically typical and develop promptly, despite the deficiency. Repletion of deficient animals with vitamin E interrupts both the axonopathy and the myopathy, indicating the direct role of vitamin E deficiency in the pathogenesis of both lesions.

Lhermitte-Duclos disease (LDD) is a rare cerebellar tumor associated with Cowden disease (CD) and germline mutations in the PTEN gene. To further define these relationships, we reviewed clinical and pathologic findings in 31 LDD cases and analyzed the status of the PTEN pathway in 11 of them. We hypothesized that the granule cell hypertrophy in LDD is secondary to activation of mammalian target of rapamycin (mTOR), a downstream effector in the PTEN/AKT pathway and a major regulator of cell growth. Histopathologically, in addition to the classical findings of LDD, we observed prominent vascular proliferation and vacuolization of the white matter in many of the lesions. Four patients met diagnostic criteria for CD, and many of the remaining patients had some clinical features of CD. Immunohistochemical analysis showed high levels of phospho-AKT and phospho-S6 in the large ganglionic cells forming the lesions, indicating activation of the PTEN/AKT/mTOR pathway and suggesting a central role for mTOR in the pathogenesis of LDD. These data support recommendations for genetic testing and screening for CD in patients with LDD and suggest a novel therapy for LDD through pharmacologic inhibition of mTOR.

Context.—Alzheimer disease (AD) and glioblastoma multiforme (GBM) have similar peak, age-specific incidence rates; however, to my knowledge, only 1 case of GBM associated with AD has been reported to date. The frequency of AD pathology, including neuritic plaques, diffuse plaques, neurofibrillary tangles, and cerebral amyloid angiopathy in patients with GBM is unknown. Studies of cancer occurrence in patients with AD are contradictory, with frequencies reported as equal to and as less than that in the general population. The GBM/AD nonconcordance may reflect underreporting of AD pathology or other factors. Objective.—To compare the frequency and extent of neocortical AD pathology in autopsy cases involving patients aged 60 to 82 years, both with and without GBM. Design.—Case-control study. Setting.—Pathology department of a university hospital. Patients.—Thirty-six autopsy cases of GBM patients aged 60 to 82 years; 54 cases of patients in the same age group without GBM or other primary brain tumors. Methods.—Examination of tumor sections for GBM and of neocortical sections for AD pathology according to Consortium to Establish a Registry for Alzheimer Disease (CERAD) guidelines. Results.—Glioblastoma multiforme was confirmed in all tumor cases. Alzheimer disease pathology was present in 42% of cases with GBM and in 48% of cases without GBM; 28% of GBM cases had CERAD age-related plaque scores indicative or suggestive of AD; 43% of cases without GBM had CERAD age-related plaque scores indicative or suggestive of AD. Conclusions.—Alzheimer disease pathology was underreported in both GBM and non-GBM patients. The influence of neurodegenerative processes on GBM symptoms and therapy in elderly patients requires further study.

We present the clinical, anatomic, and laboratory findings in a 4-month-old child with desmosplastic infantile ganglioglioma. Microtubule-associated protein-2 (AP18) and neuron-specific B-tubulin (TUJ-1) were more sensitive in detecting immature neural elements than synaptophysin. Despite the immature neuroblastic component, focal intermediate proliferation indices, microinvasion, presence of secondary features (extension into Virchow Robin spaces, perineuronal satellitosis), and subtotal resection, the child has done well, with striking improvement of the magnetic resonance imaging (MRI) image, head size improvement, no tumor recurrence, and minimal neurological deficits.

Purpose: Seven percent of patients with high grade gliomas enrolled in RTOG 83-02 had mixed astrocytoma/oligodenroglial elements on central pathology review. It has often been assumed that the most aggressive histologic component of a tumor determines biologic behavior; however in this trial, the survival of patients who had mixed glioblastomas/oligodenrogliomas was significantly longer than that of patients with pure glioblastomas (GBM). We therefore evaluated the effect of an oligodendroglial component on the survival of patients who had anaplastic astrocytomas (AAF) treated in the same trial. Methods and Materials: One hundred nine patients who had AAF and 24 patients with mixed AAF/oligodendrogliomas (AAF/OL) were enrolled in a Phase I/II trial of randomized dose-escalation hyperfractioned radiotherapy plus BCNU. AAF/OL patients were older and more likely to have had more aggressive surgery than AAF patients. Other pretreatment characteristics were balanced between groups, as was assigned treatment. Results: The median survival time for AAF was 3.0 years versus 7.3 years for AAF/OL ( p = 0.019). In a multivariate analysis, adjusting for extent of surgical resection and age, an oligodendroglial component was an independent prognostic factor for survival. Conclusion: The results support the concept that AAFs with an oligodendroglial component have a better prognosis than pure AAF tumors, similar to the effect seen among patients with glioblastoma multiforme tumors. This better survival outcome should be taken into consideration in the design and stratification of future trials. Additionally, in contrast to patients with GBMs, patients who have AAF/OL have the potential for prolonged survival; therefore, late sequelae of treatment (both radiation and chemotherapy) must be weighed more heavily in the benefits to risks analysis.

The influence of tumor site, size, and extent of surgery on the survival of patients with glioblastoma multiforme treated on three consecutive prospectively randomized Radiation Therapy Oncology Group trials employing surgery and irradiation plus or minus chemotherapy was studied.Six hundred forty-five patients with a diagnosis of glioblastoma multiforme on central pathological review were analyzed for survival with respect to known prognostic factors, that is, age and Karnofsky Performance Status, as well as extent of surgery, site, and size. Surgical treatment consisted of biopsy only in 17%, partial resection in 64%, and total resection in 19%. Tumors were located in frontal lobe in 43%, temporal lobe in 28%, and parietal lobe in 25%. Maximum tumor diameter as determined on computed tomography or magnetic resonance imaging scans was less than 5 cm for 38%, between 5-10 cm for 56% and greater than 10 cm for 6% of patients. The extent of surgical therapy was the same for tumors greater than 5 or greater than 10 cm, whereas total resection was more often performed for tumors less than 5 cm. The extent of surgery did not appear to vary with age or site.Patients undergoing total resection had a median survival of 11.3 months compared to 6.6 months for patients with a biopsy only. A significant difference in median survival was also found for partial resection versus biopsy only treatment (10.4 vs. 6.6 months). There was no difference in survival for the different tumor sizes. Patients with frontal lobe tumors survived longer than those with temporal or parietal lobe lesions (11.4 months, 9.1 months, and 9.6 months, respectively) (p = 0.01). A Cox multivariate model confirmed a significant correlation of age, Karnofsky Performance Status, extent of surgery, and primary site with survival. The best survival rates occurred in patients who had at least three of the following features:40 years of age, high Karnofsky Performance Status, frontal tumors, and total resection (17 months median).We conclude that biopsy only yields inferior survival to more extensive surgery for patients with glioblastoma multiforme treated with surgery and radiation therapy.

BACKGROUND Despite notable technical advances in therapy for malignant gliomas during the past decade, improved patient survival has not been clearly documented, suggesting that pretreatment prognostic factors influence outcome more than minor modifications in therapy. Age, performance status, and tumor histopathology have been identified as the pretreatment variables most predictive of survival outcome. However, an analysis of the association of survival with both pretreatment characteristics and treatment-related variables is necessary to assure reliable evaluation of new approaches for treatment of malignant glioma. PURPOSE This study of malignant glioma patients used a non-parametric statistical technique to examine the associations of both pretreatment patient and tumor characteristics and treatment-related variables with survival duration. This technique was used to identify subgroups with survival rates sufficiently different to create improvements in the design and stratification of clinical trials. METHODS We used a recursive partitioning technique to analyze survival in 1578 patients entered in three Radiation Therapy Oncology Group malignant glioma trials from 1974 to 1989 that used several radiation therapy (RT) regimens with and without chemotherapy or a radiation sensitizer. This approach creates a regression tree according to prognostic variables that classifies patients into homogeneous subsets by survival. Twenty-six pretreatment characteristics and six treatment-related variables were analyzed. RESULTS The years). Patients younger than 50 years old were categorized by histology (astrocytomas with anaplastic or atypical foci [AAF] versus glioblastoma multiforme [GBM]) and subsequently by normal or abnormal mental status for AAF patients and by performance status for those with GBM. For patients aged 50 years or older, performance status was the most important variable, with normal or abnormal mental status creating the only significant split in the poorer performance status group. Treatment-related variables produced a subgroup showing significant differences only for better performance status GBM patients over age 50 (by extent of surgery and RT dose). Median survival times were 4.7-58.6 months for the 12 subgroups resulting from this analysis, which ranged in size from 32 to 256 patients. CONCLUSIONS This approach permits examination of the interaction between prognostic variables not possible with other forms of multivariate analysis. IMPLICATIONS The recursive partitioning technique can be employed to refine the stratification and design of malignant glioma trials.

Between January 1983 and November 1987, the Radiation Therapy Oncology Group conducted a prospective, randomized, multi-institutional, dose searching Phase I/II trial to evaluate hyperfractionated radiation therapy in the treatment of supratentorial malignant glioma. Patients with anaplastic astrocytoma, or glioblastoma multiforme, age 18-70 years with a Karnofsky performance status of 40-100 were stratified according to age, Karnofsky performance status, and histology, and were randomized. Initially randomization was to one of three arms: 64.8 Gy, 72.0 Gy, and 76.8 Gy. Fractions of 1.2 Gy were given twice daily, 5 days per week, with intervals of 4 to 8 hr. All patients received bis-chlorethyl nitrosourea (BCNU) 80 mg/m2 on days 3, 4, 5 of radiation therapy and then every 8 weeks for 1 year. After acceptable rates of acute and late effects were found, the randomization was changed to 81.6 Gy and 72.0 Gy with a weighting of 2:1. Out of 466 patients randomized, 435 were analyzed. The distribution of prognostic factors was comparable among the 76.8 Gy arm, 81.6 Gy arm, and the final randomization of the 72 Gy arm. The 64.8 Gy arm and the initial randomization of the 72 Gy arm had somewhat worse prognostic variables. Late radiation toxicity occurred in 1.3-6.8% of the patients, with a modest increase with increasing radiation dose. The best survival occurred in those patients treated with 72 Gy (median survival of 12.8 months overall, and 14 months for the final 72 Gy randomization). The Cox proportional hazards model confirmed the prognostic variables of age, histology and Karnofsky performance status. In addition, the longer interval of 4.5-8 hr was associated with a worse prognosis than the 4-4.4 hr interval (p = 0.0011). The difference in survival between the 81.6 Gy arm and the lower three arms approached significance (p = 0.078) with inferior survival observed in the 81.6 Gy arm. When therapy was evaluated by radiation therapy dose received (60-74.4 Gy compared with 74.5-84.0 Gy), the p value was 0.062 in favor of the lower dose range. Patients with anaplastic astrocytoma treated with 72 Gy by hyperfractionation + BCNU had at least as good a survival as those treated with 60 Gy by conventional fractionation + BCNU on Radiation Therapy Oncology Group protocols 7401 and 7918. This suggests that 72 Gy delivered by 1.2 Gy twice daily is no more toxic than 60 Gy delivered by conventional fractionation.

This report evaluates the long-term survival of patients with histologically confirmed anaplastic astrocytoma on several combined RTOG (Radiation Therapy Oncology Group) studies. Included in this analysis are the following studies: RTOG/ECOG (Eastern Cooperative Oncology Group) 74-01, RTOG 76-11, and RTOG 79-18, with the various treatment arms separated into radiation therapy (RT) only (47 patients) radiation therapy and chemotherapy (Chemo) (78 patients) and radiation therapy, chemotherapy, and misonidazole (Mizo) (24 patients). Pretreatment characteristics of age, prior surgery, performance status, and neurological function classification are identified. Median survival for patients treated with RT only is 3.0 years. Median survival for patients treated with RT + Chemo is 2.3 years, and for patients treated with RT + Chemo/Miso is 1.2 years. Five-year survival rates are 35% for patients treated with RT only, 29% for patients treated with RT + Chemo, and 24% for patients treated with RT + Chemo/Miso. Age and performance status have been identified in previous studies as important prognostic variables and are confirmed in this analysis. Patients treated with misonidazole had a significantly worse prognosis after adjustment for differences in prognostic factors. Addition of chemotherapy did not improve survival except in less favorable prognostic categories. In general, more aggressive treatment regimens are associated with decreased survival compared to conventional postoperative irradiation.

Chronic vitamin E deficiency results in the premature and exaggerated development of neuroaxonal dystrophy (NAD) in primary sensory axon terminals in rat medullary gracile/cuneate nuclei, sites in which NAD develops normally with age. In the current study we determined if chronic Vitamin E deprivation had a similar effect on the development of NAD in the celiac/superior mesenteric sympathetic ganglia (C/SMG), another site with age-dependent NAD. The frequency of NAD failed to increase in the SMG of the same vitamin-E deficient animals in which a marked increase in severity of NAD was found in the gracile nucleus. These findings indicate that different populations of neurons are selectively involved in vitamin E deficiency and that the distribution of axonopathy in the E-deficient C/SMG does not duplicate the pattern of experimental diabetes and aging.

Central nervous system (CNS) infarcts were present at autopsy in 10 of 23 alcoholic patients and in 9 of 36 nonalcoholic patients. There were more males than expected in the infarct population and in the alcoholic population. Male subjects comprised the entire population of alcoholics with infarcts. In addition, a history of alcohol abuse was present in every case of cerebral infarction dying before age 75. The incidence of cardiomegaly was increased among the alcoholics. There were no differences between alcoholics and nonalcoholics in the incidence of diagnosed hypertension, moderate-to-severe coronary atherosclerosis, or adult onset diabetes. However, CNS infarction was more likely to occur at an earlier age in alcoholics than in nonalcoholics. Excessive alcohol consumption may be a risk factor in the premature development of cerebrovascular disease in males.

Leukostasis and leukemic nodules are found in the central nervous system (CNS) of at least 75% of guinea pigs during the terminal stages of untreated L2C/NB leukemia, a transmissible, acute lymphocytic leukemia. The CNS lesions develop after extensive visceral leukemic infiltration at a time when the white cell count is rising to 10(5)-5 x 10(5) cells/mm3, and the differential examination shows predominantly blasts. Leukostasis precedes formation of the nodule. Both lesions may be found in any part of the central nervous system including the spinal cord, but are most numerous in the diencephalon and rostral brain-stem. Ultrastructural studies demonstrate that parenchymal leukostasis develops chiefly within capillaries, and is associated with endothelial cell degeneration and necrosis. Fibrin deposits are not seen within affected capillaries. The sequence of development, pathologic and hematologic characteristics of leukostasiss and leukemic nodules in human and L2C/NB leukemia are virtually identical. The CNS lesions of untreated L2C/NB leukemia are a precise, convenient model for the study of intracerebral leukostasis and leukemic nodules.

Neurologic disease is reported to occur in just 10% of patients with mixed connective tissue disease (MCTD). Most commonly, this is manifested by mild trigeminal neuralgia. This report details the clinical and neuropathologic findings of transverse myelitis in a patient with MCTD. Neurologic features include progressive areflexic paraplegia with loss of bowel and bladder function. Neuropathologically there was thinning of the thoracic cord, widespread loss of axons and myelin sheaths, reactive astrocytosis, macrophage formation, vascular thickening with perivascular chronic inflammatory cell infiltration, and calcium deposits. This case demonstrates that severe neurologic disease unresponsive to therapy can occur in MCTD.

CNS infarcts were demonstrated in 12 of 24 autopsied patients with sickle cell anemia. The infarcts occurred most extensively in the territory supplied by the distal branches of the internal carotid artery, especially the anterior-middle cerebral artery boundary zone. They were regularly associated with organizing and recanalizing thrombi involving the distal cervical and proximal intracranial divisions of the internal carotid system. On the basis of these findings, we infer that the pathogenesis of the infarction involves perfusion failure or intraarterial embolization in addition to intravascular sickling.

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 Gyo nγ . 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.

Surgical specimens of malignant, supratentorial, astrocytic gliomas from 503 patients randomized on an RTOG-ECOG treatment protocol were examined by central pathologic review. The diagnosis of glioblastoma multiforme (GBM) was made only when one or more foci of coagulation necrosis involving astrocytic tumor cells were identified histologically. Malignant astrocytic neoplasms without necrosis were classified as astrocytoma with atypical or anaplastic features (AAF). The median survival stratifying for treatment for patients with GBM was eight months compared to 28 months for patients with AAF. In most cases the specimens were received with a Kernohan grade. On the basis of these grades, patients with astrocytoma Grade 3 had a median survival of ten months as compared to a median survival of nine months for those with astrocytoma Grade 4. Observations demonstrate that necrosis is a reliable, decisive prognostic factor associated with malignant, supratentorial, astrocytic gliomas. The Kernohan system is of limited value in assessing prognosis for this group of tumors.

The identification of intracerebellar hemorrhage in a living premature infant by real-time ultrasound scan and confirmation of the findings at autopsy are described. This represents the first demonstration of the value of this noninvasive, convenient, and safe means of brain imaging in diagnosis of this lesion. Previous studies have described the role of the computed tomography (CT) scan in identification of intracerebellar hemorrhage in the newborn. Because infants with intracerebellar hemorrhage are usually critically ill, a means of identification of the lesion that could be utilized at the bedside rather than an approach that requires transport to a CT scanner is needed. This study indicates that portable real-time ultrasound scanning can satisfy that need.

Autopsy examination confirmed the diagnosis of subacute necrotizing encephalomyelopathy (SNE) in a 7-month-old male infant who underwent several metabolic studies before death. Intermittent lactic acidemia and fumaric aciduria, an extreme hyperglycemic response to an intravenous bolus of alanine, and an elevated total body flux rate of glucose (58.4 mumoles . kg-1 . min-1) suggested a disturbance in the oxidative decarboxylation of pyruvate. Enzymological studies of postmortem samples revealed low nonactivated pyruvate dehydrogenase activity in liver (19.4%) and brain (53.8%). The lowest brain pyruvate dehydrogenase activities were noted in the midbrain and pontine regions. Supramaximal activation of the hepatic pyruvate dehydrogenase complex (135% of control values) occurred in vitro. Spontaneous reactivation following in vitro inactivation of the complex with adenosine triphosphate was significantly less (p less than 0.02) in the patient's samples compared to controls. The biochemical defect was not apparent in fibroblasts. These enzymological observations point to an in vivo defect in the activation mechanism of the pyruvate dehydrogenase complex as the biochemical disturbance in SNE. The findings suggest that dichloroacetate may be beneficial in treating SNE.

The treatment of supratentorial malignant gliomas has continued to be a major problem for neurosurgeons and oncologists. Post-operative conventional radiotherapy is known to prolong survival and to enhance the quality of life. Local persistence of tumor kills the majority of patients. Fast neutron irradiation is being utilized to treat malignant gliomas based on its reputed radiobiological advantages for treatment of large tumors and the encouraging preliminary reports showing tumor eradication in post-radiation biopsy and autopsy specimens. This paper reviews the results of fast neutron irradiation alone and in combination with photons and hypoxic cell sensitizers. Survival comparisons do not show any superiority for neutrons compared to conventional radiation. However, post-neutron radiation tissue samples have shown less aggressive and minimal residual tumor in many instances. At the same time radiation necrosis has emerged as a significant problem. In summary, even though neutron irradiation can eradicate malignant gliomas a therapeutic window has yet to be identified.

Between January 1977 and September 1980, 166 patients were entered on a RTOG protocol comparing neutron-boost radiotherapy with standard treatment for patients with glioblastomas. Eighty-three patients were randomized to receive a neutron boost and 83 to receive a photon boost after 50 Gy photon, whole-brain irradiation. Of these, six were ineligible and two were cancelled, leaving 158 patients available for analysis. The median survival for the neutron-boost group was 9.8 months, compared to 8.6 months for the photon-boost group. The difference is not statistically significant. Autopsies revealed actively growing persistent tumor in all photon-treated patients compared to no evidence of actively growing tumor in the majority of neutron-treated patients.

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.

The dose limiting toxicity of the nitroimidazole radiosensitizers is peripherial neuropathy. Improved pharmacology of newer drugs has eliminated the encephalopathy. Peripheral neuropathies are predominently mild to moderate paresthesias of both hands and feet. Subjective changes occur with or without minimal objective changes on neurologic exam. All of the neuropathies occurred within 30 days of the last drug dose and are of variable duration. Sural nerve biopsies from patients indicate progressive axonal degeneration affecting both large and small caliber myelinated fibers. Axonal damage appears to be more severe in the distal portion of the nerves. More data are needed for correlation of clinical and pathological changes.

The activities of enzymes from the citric acid cycle, pentose phosphate pathway and glycogen cycle were measured in collections of sympathoadrenal cells and compared with other neuronal groups. Enzymes from each pathway are found in groups of sympathetic neurons and adrenal medullary cells. The citric acid cycle has the highest capacity among glucose pathways in sympathoadrenal cells. Differences in glycolytic and citric acid cycle capacities between sympathetic ganglion and the other neuronal groups may be related to differences in capillary density. The capacity of the pentose phosphate pathway and reduced nicotinamide adenine dinucleotide phosphate-linked isocitric dehydrogenase is higher in sympathoadrenal cells than in the other cells surveyed. The enzyme activities in sympathetic ganglion are in excess of those needed to sustain the rates of glucose metabolism previously observed in this structure.

Chicks on an enccphalomalacia-inducing diet (EID), lacking in tocopherol and augmented with Iinoleic acid, exhibit the following triad of fluorescence, light and electron microscopic changes, selectively affecting the endothelium of brain capillaries: 1. development of a gradually intensifying fluorescence, 2. increased deposition of acid phosphatase reaction products, 3. accumulation of electron-dense structures within the endothelial cytoplasm. These changes develop contemporaneously and coincide morphologically. The alterations precede the onset of pathologic lesions. They represent metabolic disturbances induced in cerebral endothelium by feeding the EID. Excessive ingestion of Iinoleic acid without antioxidant coverage could lead to peroxida-tive damage and degradation of subcellular constituents. Possibly the alterations reflect an early stage of ceroid formation associated with activation of endothelial lysosomes. The vascular changes may be a determining factor in the pathogenesis of nutritional encephalomalacia.

Quantitative histochemical methods were used to measure the activities of four glycolytic enzymes, hexokinase (HE), phosphoglucoisomerase (PGI), phosphofructokinase (PFK) and lactic dehydrogenase (LDH), in sympathetic ganglion, adrenal medulla, dorsal root ganglion and cerebellar granular layer. Based upon HIK activity the capacity of the glycolytic pathway in sympathetic ganglion and cerebellar granular layer is 2-2.5 times greater than in adrenal medulla or dorsal root ganglion. Direct regulation of glycolysis probably occurs at the HK and PFK steps in all four tissues. Indirect regulation may possibly be mediated through LDH in sympathetic ganglion.

Summary Persistent blanching in and around the cutaneous metastases of a neuroblastoma was observed in a newborn infant girl. Catecholamines were demonstrated in the tumor cells from a skin metastasis by electron microscopy and fluorescence histochemistry. The blanching is believed to result from local vasoconstriction following release of catecholamines from the tumor cells. The blanching phenomenon may be a useful diagnostic sign characteristic of the skin metastases of neuroblastoma.

INTRODUCTION IN THE course of studying vitamin E deficiency induced in chicks it became apparent that the lack of detailed information about the pathogenesis of the disorder inhibits the development of precise methods of treatment and control of the condition, impairs the understanding of the metabolic role of vitamin E, and precludes the utilization of the disease in chicks as a convenient experimental model for elucidating certain pathobiologic phenomena. An increased susceptibility to lysis in non-physiologic solutions of red blood cells from mammals with subclinical vitamin E deficiency has been well substantiated in reports by Gyorgy (1949), and Horwitt et al. (1956), and others; however, the in vitro lytic susceptibility of erythrocytes from vitamin E-deficient chicks has been incompletely studied (Christensen et al., 1955). Since substantial differences exist among various vertebrate species with regard to other manifestations of avitaminosis E, a study was made of hydrogen peroxide-induced hemolysis of red cells. . .