Studies of collisional selection rules in thioformaldehyde (H2CS) by microwave-optical double resonance.

Individual rotational levels in the A 1A2,v4=1 state of thioformaldehyde (H2CS) are excited by a cw laser and microwave transitions in the region of 8-12 GHz are measured. Some of the microwave frequencies are found to be characteristic of rotational levels other than the level being pumped. Since the microwave frequencies are characteristic of individual rotational levels in the excited state and the excited-state lifetime is approximately 170 micros, information is obtained concerning rotational selection rules during collisions. It is found that J can change by several units and Ka by 0, +/-2, +/-4, and +/-6. The latter result confirms that o-H2CS is not converted to p-H2CS by collisions. Observation of Ka doublets indicates that there are no appreciable differences between the two components.

Molecular subtypes of anaplastic oligodendroglioma: implications for patient management at diagnosis.

PURPOSE: In a prior study of anaplastic oligodendrogliomas treated with chemotherapy at diagnosis or at recurrence after radiotherapy, allelic loss of chromosome 1p correlated with better chemotherapeutic response and overall survival. However, in this group of patients in whom therapeutic management was not uniform, loss of 1p did not identify all chemosensitive tumors, nor did all patients whose tumors harbor a 1p loss have long survival. EXPERIMENTAL DESIGN: To clarify the clinical relevance of molecular genetic testing at the time of diagnosis for patients with anaplastic oligodendrogliomas, we studied a larger, more homogeneous group of 50 patients with histologically defined anaplastic oligodendrogliomas treated with a chemotherapeutic regimen as the principal initial therapy. RESULTS: We demonstrate that these tumors can be divided genetically into four therapeutically and prognostically relevant subgroups. Patients whose tumors have combined but isolated losses of 1p and 19q have marked and durable responses to chemotherapy associated with long survival, with or without postoperative radiation therapy. Other tumors with chromosome 1p alterations also respond to chemotherapy, but with shorter duration of response and patient survival. Tumors lacking 1p loss can also be divided into two subgroups: those with TP53 mutations, which may also respond to chemotherapy but recur quickly, and those without TP53 mutations, which are poorly responsive, aggressive tumors that are clinically and genotypically similar to glioblastomas. CONCLUSIONS: These data raise the possibility, for the first time, that therapeutic decisions at the time of diagnosis might be tailored to particular genetic subtypes of anaplastic oligodendroglioma.

Long survival and therapeutic responses in patients with histologically disparate high-grade gliomas demonstrating chromosome 1p loss.

OBJECT: Allelic loss of chromosome 1p is a powerful predictor of tumor chemosensitivity and prolonged survival in patients with anaplastic oligodendrogliomas. Chromosome 1p loss also occurs in astrocytic and oligoastrocytic gliomas, although less commonly than in pure oligodendroglial tumors. This observation raises the possibility investigated in this study that chromosome 1p loss might also provide prognostic information for patients with high-grade gliomas with astrocytic components. METHODS: The authors report on seven patients with high-grade gliomas composed of either pure astrocytic or mixed astrocytic-oligodendroglial phenotypes, who had remarkable neuroradiological responses to therapy or unexpectedly long survivals. All of the tumors from these seven patients demonstrated chromosome 1p loss, whereas other genetic alterations characteristic of high-grade gliomas (p53 gene mutations, EGFR gene amplification, chromosome 10 loss, chromosome 19q loss, or CDKN2A/p16 deletions) were only found in occasional cases. The authors also assessed the frequency of chromosome 1p loss in a series of anonymous high-grade astrocytoma samples obtained from a tumor bank and demonstrate that this genetic change is uncommon, occurring in only 10% of cases. CONCLUSIONS: Although any prognostic importance of chromosome 1p loss in astrocytic or mixed astrocytic-oligodendroglial gliomas can only be determined in larger and prospective series, these findings raise the possibility that some high-grade gliomas with chromosome 1p loss, in addition to pure anaplastic oligodendrogliomas, may follow a more favorable clinical course.

Genetic background influences timing, morphology and dissemination of lymphomas in p53-deficient mice.

To examine the influence of genetic background on tumorigenesis in p53-deficient mice, we used selective breeding to produce congenic mice with a null p53 gene mutation introduced into the VM inbred strain. Cohorts of homozygous p53 null (-/-) mice from the original C57B6/129Sv mixed strain and the VM congenic strain were monitored for spontaneous tumor development, as were control cohorts of wild-type (+/+) and heterozygous (+/-) animals. Twenty-six of 28 C57B6/129Sv (-/-) mice died by the study end date (median survival =184.5 days). Twenty-three of 26 VM (-/-) mice died and their survival was significantly shorter (111 days, P<0.0001). Of 26 C57B6/129Sv (-/-) mice that died, 21 were autopsied: all 21 had lymphomas. Of 26 VM mice that died (23 -/-, 3 +/-), 21 were autopsied: 19 developed lymphoma and two had sarcomas. Several mice had additional neoplasms. Lymphomas in VM mice were distinct from those in C57B6/129Sv mice in that they i) arose on average more than two months earlier, ii) involved thymus more often than spleen or lymph nodes and iii) were more often poorly differentiated, high grade tumors. These results demonstrate that genetic background alone influences the onset, morphology and dissemination of lymphomas in p53-deficient mice and suggest the presence of genes which modify the timing and biological nature of lymphomas in these mice.

Specific genetic predictors of chemotherapeutic response and survival in patients with anaplastic oligodendrogliomas.

BACKGROUND/METHODS: Gliomas are common malignant neoplasms of the central nervous system. Among the major subtypes of gliomas, oligodendrogliomas are distinguished by their remarkable sensitivity to chemotherapy, with approximately two thirds of anaplastic (malignant) oligodendrogliomas responding dramatically to combination treatment with procarbazine, lomustine, and vincristine (termed PCV). Unfortunately, no clinical or pathologic feature of these tumors allows accurate prediction of their response to chemotherapy. Anaplastic oligodendrogliomas also are distinguished by a unique constellation of molecular genetic alterations, including coincident loss of chromosomal arms 1p and 19q in 50%-70% of tumors. We have hypothesized that these or other specific genetic changes might predict the response to chemotherapy and prognosis in patients with anaplastic oligodendrogliomas. Therefore, we have analyzed molecular genetic alterations involving chromosomes 1p, 10q, and 19q and the TP53 (on chromosome 17p) and CDKN2A (on chromosome 9p) genes, in addition to clinicopathologic features in 39 patients with anaplastic oligodendrogliomas for whom chemotherapeutic response and survival could be assessed. RESULTS/CONCLUSIONS: Allelic loss (or loss of heterozygosity) of chromosome 1p is a statistically significant predictor of chemosensitivity, and combined loss involving chromosomes 1p and 19q is statistically significantly associated with both chemosensitivity and longer recurrence-free survival after chemotherapy. Moreover, in both univariate and multivariate analyses, losses involving both chromosomes 1p and 19q were strongly associated with longer overall survival, whereas CDKN2A gene deletions and ring enhancement (i.e., contrast enhancement forming a rim around the tumor) on neuroimaging were associated with a significantly worse prognosis. The inverse relationship between CDKN2A gene deletions and losses of chromosomes 1p and 19q further implies that these differential clinical behaviors reflect two independent genetic subtypes of anaplastic oligodendroglioma. These results suggest that molecular genetic analysis may aid therapeutic decisions and predict outcome in patients with anaplastic oligodendrogliomas.

Therapy-related chromosomal changes and cytogenetic heterogeneity in human gliomas.

The karyotypes of 18 primary 'untreated' gliomas, 6 recurrent gliomas treated with radiotherapy and/or chemotherapy and 2 gliomas before and after treatment are described, based on observations using standard cytogenetic techniques. In comparison to the untreated gliomas there were relatively consistent chromosome differences in the treated gliomas, including (1) deletions of the long arm of chromosome 7 with breakpoint at q22, possibly induced by alkylating agents, and (2) numerous single cell abnormalities or unrelated clones of structural abnormalities, presumably induced by radiotherapy.

Classification of astrocytomas and malignant astrocytomas by principal components analysis and a neural net.

The classification of astrocytomas, astrocytomas with anaplastic foci and glioblastoma multiformes is not always straightforward because the tumors form a histological continuum. The use of principal component analysis (PCA) and neural nets in the classification of these tumors is explored. PCA was performed on 14 histological features recorded from 52 gliomas classified by the Radiation Therapy Oncology Group method (17 astrocytomas, 18 astrocytomas with anaplastic foci, 17 glioblastoma multiformes). Four of the 14 possible 'scores' derived from this analysis were selected to summarize the histological variability seen in all the tumors. These scores were mostly significantly different between tumor types and were thus used to successfully train a neural net to correctly classify these tumors. The first principal component (score) supported the use of increasing cellularity, mitoses, endothelial proliferation, and necrosis in differentiating between the tumor categories, but accounted for only 39% of the variability seen. Other histological features that were significant components of the other scores included the presence of multinucleated or giant cells, gemistocytes, atypical mitoses and changes in nuclear chromatin. Computer programs derived from the methodology described provide a way of standardizing glioma diagnosis and may be extended to assist with management decisions.

Isolated sulfite oxidase deficiency.

Isolated sulfite oxidase (SO) deficiency is an autosomal recessively inherited inborn error of sulfur metabolism. In this report of a ninth patient the clinical history, laboratory results, neuropathological findings and a mutation in the sulfite oxidase gene are described. The data from this patient and previously published patients with isolated sulfite oxidase deficiency and molybdenum cofactor deficiency are summarized to characterize this rare disorder. The patient presented neonatally with intractable seizures and did not progress developmentally beyond the neonatal stage. Dislocated lenses were apparent at 2 months. There was increased urine excretion of sulfite and S-sulfocysteine and a decreased concentration of plasma cystine. A lactic acidemia was present for 6 months. Liver sulfite oxidase activity was not detectable but xanthine dehydrogenase activity was normal. The boy died of respiratory failure at 32 months. Neuropathological findings of cortical necrosis and extensive cavitating leukoencephalopathy were reminiscent of those seen in severe perinatal asphyxia suggesting an etiology of energy deficiency. A point mutation that resulted in a truncated protein missing the molybdenum-binding site has been identified.

Motor neuron disease presenting as acute respiratory failure: a clinical and pathological study.

Respiratory failure is rarely a presenting symptom of motor neuron disease. Seven patients with motor neuron disease who presented with acute respiratory failure of unknown cause and required mechanical ventilation were studied. They all had symptoms and signs suggestive of diaphragmatic weakness. Respiratory involvement seemed disproportionately severe, as six were ambulatory and only three noted limb weakness. Only one had tongue weakness and none had swallowing difficulty. Electrophysiological studies showed widespread denervation and, in particular, diaphragmatic involvement to explain the severe respiratory failure. Weaning from the ventilator was unsuccessful in all cases. The four patients examined at necropsy showed severe loss of anterior horns cells in the cervical cord, with only minimal upper motor neuron involvement. Motor neuron disease should be recognised as a cause of acute respiratory failure, secondary to diaphragmatic paralysis from involvement of phrenic motor neurons.

Pleomorphic xanthoastrocytoma: case report and analysis of the literature concerning the efficacy of resection and the significance of necrosis.

The case of a patient with a pleomorphic xanthoastrocytoma (PXA), a low-grade glioma of adolescence, is presented. A literature review of 79 patients with PXAs is described and confirms a favorable prognosis in 80% of patients. The sex ratio in the reported cases was almost equal, and the median age at time of diagnosis was 14 years. Seventy-nine percent of the patients presented with seizures. Nine of the 15 deaths from PXA are associated with histological evidence of necrosis at initial presentation or in a recurrent tumor, confirming the poor prognosis associated with the presence of necrosis in these neoplasms. Survival curves confirm that the optimal treatment for PXAs without necrosis is primary surgical resection with subsequent operation for recurrent tumor. The roles of surgery or radiotherapy in necrotic PXA are not clear from the literature.

Medulloblastomas in late middle age and the elderly: report of 2 cases.

Medulloblastomas may be difficult to recognize in late middle age and the elderly because of their rarity and their histological similarity, particularly in frozen sections, to common, poorly differentiated, metastatic tumors, notably the small cell carcinoma of lung. This report describes the occurrence of medulloblastomas in a 66-year-old male (case 1) and a 65-year-old female (case 2). Both tumors appeared radiologically as cystic cerebellar masses of irregular shape and variable intensity on magnetic resonance imaging; in each case microscopic examination revealed a primitive neuroectodermal tumor with focal astrocytic differentiation and desmoplasia. Case 1 died 23 months after surgery; an autopsy revealed extensive dissemination of the tumor to the bone marrow, small collections of malignant cells in the spinal subarachnoid space, and no evidence of local recurrence. Case 2 is well 29 months after her operation. The possibility of a medulloblastoma should be considered when a solitary cerebellar lesion is discovered in a middle-aged or elderly patient without a demonstrable extraneural primary site.

Declaring pediatric brain death: current practice in a Canadian pediatric critical care unit.

OBJECTIVE: To document the criteria used to declare brain death in a pediatric critical care unit (PCCU). DESIGN: Retrospective chart review. SETTING: Regional PCCU in southwestern Ontario. PATIENTS: Sixty patients 16 years of age or less declared brain dead from January 1987 through December 1992. OUTCOME MEASURES: Presence or absence of documentation of irreversible deep coma, nonresponsive cranial nerves, absent brain-stem reflexes, persistent apnea after removal from ventilator, presence or absence of blood flow detected by radioisotope scanning, presence or absence of electroencephalographic evidence of electrocerebral activity. RESULTS: The 60 patients accounted for 1.5% of all PCCU admissions; 17 were under 1 year of age. In 39 cases brain death was diagnosed using clinical criteria ("certified brain death"), which could not be fully applied in the remaining 21 cases ("uncertifiable but suspected brain death"). Electroencephalography and cerebral blood-flow studies with technetium-99m hexamethyl-propyleneamine oxime were used as ancillary tests in 16 patients with certified brain death and in 17 with uncertifiable but suspected brain death who survived long enough to be tested. Electrocerebral silence was demonstrated in all nine patients who underwent electroencephalography. Cerebral blood flow was undetectable in 26 of the 30 patients tested, and an abnormal pattern of blood flow was seen in the remaining 4, all of whom received a diagnosis of certified brain death. CONCLUSIONS: Pediatricians in this large tertiary care referral centre are using clinical criteria based on the 1987 guidelines of the CMA to diagnose brain death in pediatric patients, including neonates. When clinical criteria cannot be fully applied, ancillary methods of investigation are consistently used. Although the soundness of this pattern of practice is established for adults and older children, its applicability to neonates and infants still needs to be validated.

Primary diffuse leptomeningeal oligodendroglioma. Case report.

The authors describe a case of a diffuse primary leptomeningeal oligodendroglioma in a 17-year-old girl who presented with raised intracranial pressure and hydrocephalus. She underwent imaging studies and a left frontotemporal craniotomy that revealed a cystic oligodendroglioma in the suprasellar cistern and spread of neoplastic cells to the spinal leptomeninges. The tumor showed little response to maximum radiotherapy and chemotherapy, and the patient died from complications of high-dose chemotherapy 2 years after diagnosis. Postmortem examination of the brain and spinal cord revealed diffuse meningeal infiltration by neoplastic cells and no evidence of an intraparenchymal origin. Glial heterotopias were noted at several sites along the brain base, adding circumstantial support to the theory that leptomeningeal gliomas are derived from ectopic glial tissue in the subarachnoid space.

Cytogenetic evidence that a tumor suppressor gene in the long arm of chromosome 1 contributes to glioma growth.

In a patient with a rare subtype of glioma, pleomorphic xanthoastrocytoma, cytogenetic studies revealed that both homologues of chromosome 1 were involved in translocations at the same band 1q42 but with different partner chromosomes. In addition, 5 glioblastomas out of 25 gliomas karyotyped in our laboratory had lost at least one copy of band 1q42 through deletions, unbalanced rearrangements, or chromosome losses. Twenty-one gliomas that had lost at least one copy of chromosome band 1q42 were identified in the literature; all were astrocytic tumors and the majority were glioblastomas. It indicates a covert tumor suppressor gene in the region that is involved in astrocytic gliomas.

Homicidal blunt head trauma, diffuse axonal injury, alcoholic intoxication, and cardiorespiratory arrest: a case report of a forensic syndrome of acute brainstem dysfunction.

Sudden death can occur in drunk individuals who are severely beaten about the face. The structural basis for this forensic syndrome is unknown. We herein describe the case of an intoxicated 23-year-old man (blood alcohol 234 mg%, 51 mmol/l) who was involved in an altercation and received blows and kicks to his head. A cardiorespiratory arrest occurred during the assault. He was resuscitated in hospital 23 min later but died 90 h after admission of severe ischemic encephalopathy and bronchopneumonia. Postmortem examination revealed diffuse scalp bruising, no evidence of a skull fracture, multiple small hemispheric contusions, severe cerebral edema secondary to ischemic encephalopathy, and axonal swellings in the corpus callosum, subcortical white matter, midbrain, right rostral inferior cerebellar peduncle, and medulla. This case of near sudden death confirms that blunt head trauma sustained during an assault can cause mild diffuse axonal injury. In addition, it is possible that sudden, alcohol intoxication-associated, craniofacial traumatic death is caused by acute dysfunction of the brainstem cardiorespiratory centers, whose capacity to correct potentially fatal dysrhythmias or apnea, induced by injury to their afferent axons, can be compromised by alcohol ingestion.

Loss of heterozygosity analysis of chromosomes 9, 10 and 17 in gliomas in families.

BACKGROUND: Studies of sporadic malignant gliomas have identified structural abnormalities in a number of chromosomal regions, especially losses of DNA on 9p, 10 and 17p. PURPOSE: We undertook the following molecular analysis in families with glioma to determine the frequency of chromosomal losses in these regions and to test the utility of microsatellite markers in demonstrating losses of heterozygosity. METHODS: Genomic DNA was extracted from tumor tissue and venous blood from 20 patients with a family history of glioma. Dinucleotide repeat polymorphisms (microsatellites) were analyzed by polymerase chain reaction to assess loss of constitutional heterozygosity (LOH) on 9p, 10 and 17p. Three polymorphic markers on chromosome 9 (D9S104, D9S161, D9S165), one on chromosome 10 (D10S209), and two on 17p (D17S786, D17S796) were used. Autoradiographic films were analyzed for LOH after radioactively labelled polymerase chain reaction products were resolved on denaturing formamide-acrylamide gels. RESULTS: Of 20 patients informative for at least one of three chromosome 9 markers, 12 (60%) showed LOH at one or more loci; of 9 informative for the chromosome 10 marker, 4 (44%) showed LOH; and of 16 informative for at least one of two chromosome 17 markers, 7 (44%) showed LOH at one or both loci. These LOH rates do not include instances of tumor nullizygosity (0-35%) and therefore represent minimum frequencies of chromosomal losses at these loci. CONCLUSIONS: Microsatellite markers can be used to detect LOH in archival glioma tissue. As in sporadic gliomas, frequent LOH was observed on 9p (9p21-22), 10 and 17p, supporting the notion that these regions may harbour tumor suppressor genes important in glioma development. Further work will be required to determine whether the proportion of LOH in these chromosomal regions is higher in familial gliomas than sporadic ones, as might occur with an inherited suppressor gene conferring susceptibility to gliomas in families.

Alpha, theta and alpha-theta coma: a clinical outcome study utilizing serial recordings.

Alpha coma (AC), theta coma (TC) and alpha-theta coma (ATC) are transient clinical-electroencephalographic phenomena which do not differ from each other in etiology or outcome and are indicative of a severe disturbance in thalamo-cortical physiology. Although most patients do poorly, these patterns are not reliably predictive of outcome, regardless of etiology. We found that AC, TC or ATC usually change to a more definitive pattern by 5 days from coma onset. EEG reactivity in subsequent patterns is relatively favorable, while a burst-suppression pattern without reactivity is unfavorable in anoxic-ischemic encephalopathy.