Prevalence of antibodies to four herpesviruses among adults with glioma and controls.

The authors previously reported statistically significant inverse associations between adult onset glioma and histories of chickenpox and shingles among 462 cases and 443 controls in the San Francisco Bay Area Adult Glioma Study (1991--1995) and a suggestive but nonsignificant inverse association with immunoglobulin G antibodies to varicella-zoster virus in a small subset of these cases. This report considers antibodies to four common herpesviruses (varicella zoster, herpes simplex, cytomegalovirus, and Epstein Barr) among 134 cases and 165 controls that represent all subjects for whom usable blood specimens were available. The prevalences of immunoglobulin G antibodies to varicella-zoster virus, herpes simplex virus, cytomegalovirus, and Epstein-Barr virus were 90%, 71%, 57%, and 90%, respectively. After adjustment for age, White versus non-White ethnicity, and gender, glioblastoma cases were less likely than controls to have immunoglobulin G antibodies to varicella-zoster virus (odds ratio = 0.4; 95% confidence interval: 0.1, 0.9). They were also somewhat less likely to have antibodies to Epstein-Barr virus but somewhat more likely to have antibodies to herpes simplex virus and cytomegalovirus. Antibody prevalences to all four herpesviruses were similar between cases with other glioma histologies and controls. These results corroborate our previously suggestive findings of an inverse association of varicella-zoster virus antibodies with adult onset glioma.

Discrepancies in diagnoses of neuroepithelial neoplasms: the San Francisco Bay Area Adult Glioma Study.

BACKGROUND: Valid and reliable diagnoses of disease are key both to meaningful epidemiologic and clinical investigations and to decision-making about appropriate treatment. One previous study highlighted the lack of precision in diagnosing primary brain tumors in a neuropathology referral practice. The current study explores diagnostic discrepancies in a population-based adult glioma series by hospital of origin, specialty training of the original diagnosing pathologist, and clinical significance. METHODS: To confirm patients' eligibility for the San Francisco Adult Glioma Study, the authors obtained participants' pathology specimens and conducted a uniform secondary neuropathology review. Eligible patients were all adults age 20 years or older newly diagnosed with glioma between August 1, 1991, and March 31, 1994, who resided in 1 of 6 San Francisco Bay Area counties. RESULTS: Overall, the original and secondary diagnoses were the same (concordant) for 352 (77%) of the 457 cases available for study. Twenty-six percent of the cases from community hospitals were discordant, compared with 12% of the cases from academic hospitals P= 0.004. Of the 105 discordant diagnoses, 17 (16%) were determined to be clinically significant, defined as a difference that could significantly alter patient management and/or prognosis. Sixteen of these 17 cases originated at community hospitals, and only 1 originated at a hospital with a neuropathologist. Based on the distribution of review diagnoses, subjects presenting at nonacademic hospitals were more likely than those presenting at academic hospitals to have glioblastoma (61% vs. 52%; P = 0.07). CONCLUSIONS: The percentage of cases with discrepant original and review diagnoses was higher among those originally diagnosed at community hospitals without a neuropathologist than among those originally diagnosed at an academic hospital with a neuropathologist. Clinically significant discrepancies were much more likely to have originated at a community hospital without a neuropathologist. These data highlight the importance of review of brain tumors by a neuropathologist prior to decision-making regarding treatment. A separate implication of this study is that glioma cases selected exclusively from academic or nonacademic institutions in a particular geographic area are unlikely to be representative of all cases occurring in that area.

Adoptive immunotherapy in patients with recurrent malignant glioma: preliminary results of using autologous whole-tumor vaccine plus granulocyte-macrophage colony-stimulating factor and adoptive transfer of anti-CD3-activated lymphocytes.

OBJECT: This trial was designed to determine the ability of autologous whole-tumor cell vaccines to induce cell mediated immune responses in patients with recurrent malignant glioma, as well as to determine whether combining such vaccination with adoptive transfer of in vitro activated T lymphocytes prolongs patient survival. METHODS: Nineteen patients with recurrent malignant glioma, in whom previous external beam radiotherapy and at least one course of chemotherapy had failed were vaccinated twice with irradiated autologous whole tumor cells by using granulocyte-marcrophage colony-stimulating factor as an adjuvant. Patients then underwent leukapheresis followed by adoptive transfer of peripheral blood lymphocytes activated in vitro with anti-CD3 and interleukin-2. In vivo immune response, radiological response, clinical outcome, and survival were monitored. Seventeen patients developed a delayed-type hypersensitivity (DTH) response to vaccination that appeared to be directed against the autologous tumor. In eight patients there was radiological evidence of a response and in five there was evidence of clinical improvement. Median survival was 12 months (range 6-28 months), and both the presence of a DTH response and the radiological response correlated with survival (p < 0.02 and p < 0.04, respectively). CONCLUSIONS: These preliminary results suggest that autologous whole-tumor cell vaccines induce a cell-mediated immune response, which appears to be tumor specific in most patients. Furthermore, vaccination combined with adoptive immunotherapy with in vitro activated cells may induce a radiologically demonstrated tumor response and improved survival despite a condition of advanced disease and immunosuppression resulting from previous treatment or tumor burden. Further studies of immunotherapy are warranted.

Familial and personal medical history of cancer and nervous system conditions among adults with glioma and controls.

The causes of glioma, the most common type of primary malignant brain tumor, are poorly understood. This study compared the personal and first-degree familial medical histories of 462 adults newly diagnosed with glioma in the San Francisco Bay Area between August 1, 1991, and March 31, 1994, with those of 443 controls who were frequency-matched on age, sex, and ethnicity. Cases and controls had equivalent personal histories of cancers other than brain cancer and most nervous system conditions, but they differed significantly regarding histories of epilepsy, seizures, or convulsions 3 or more years prior to diagnosis (odds ratio = 3.3, 95% confidence interval (CI) 1.4-7.9), chickenpox (odds ratio = 0.4, 95% CI 0.3-0.6), and shingles (odds ratio = 0.5, 95% CI 0.3-0.8). Four cases (less than 1%) and no controls had known genetic disorders (three had neurofibromatosis and one had tuberous sclerosis). Cases and controls had similar family histories of cancer and seizures. However, the odds ratio for a validated family history of primary brain tumor was 2.3 (95% CI 1.0-5.8). These results suggest that although family history of any cancer probably is not an important risk factor for adult glioma, a family history of brain tumors may play a role. Variation in exposure to or biologic response to common viral infections might play a greater role in the etiology of adult glioma than family history.

Does prior infection with varicella-zoster virus influence risk of adult glioma?

To evaluate a possible association between varicella-zoster virus infection and glioma, the authors asked adults with glioma (n = 462) whose tumors were diagnosed between August 1, 1991, and March 31, 1994, and age-, sex-, and ethnicity-matched controls (n = 443) about their histories of chickenpox or shingles. Cases were significantly less likely than controls to report a history of either chickenpox (odds ratio = 0.4, 95% confidence interval (CI) 0.3-0.6) or shingles (odds ratio = 0.5, 95% CI 0.3-0.8). To obtain serologic support for these findings, the authors conducted double-blind enzyme-linked immunosorbent assays for immunoglobulin G antibodies to varicella-zoster virus among 167 self-reporting subjects for whom blood samples were available. Cases and controls reporting no history of chickenpox were equally likely to test positive (73% vs. 75%), but among those reporting a positive history, cases were less likely than were controls to test positive (71% vs. 85%). Despite the misclassification, an odds ratio of 0.6 was obtained using either serologic data (95% CI 0.3-1.3) or reported history of chickenpox (95% CI 0.3-1.1) in this subgroup of subjects. This suggests that adults with glioma were less likely than controls either to have had prior varicella-zoster virus infection or to have an immunoglobulin G antibody response adequate to indicate positivity. Since either explanation suggests novel mechanisms for brain tumor pathogenesis, these findings require corroboration and elaboration.

Comparison of DNA fingerprinting and serotyping for identification of avian Pasteurella multocida isolates.

The DNA fingerprint profiles and serotypes of 63 avian Pasteurella multocida field isolates, 13 attenuated vaccine isolates (propagated from vaccines manufactured by five companies), and 16 somatic reference strains were compared. DNA fingerprinting established the relationship of isolates that could not be distinguished by serotyping. Of the 76 isolates, 28 DNA fingerprint profiles and 12 somatic types were recognized. One isolate was nonreactive with 16 reference somatic and 5 reference capsule-type antisera. Thirty-one field isolates and seven vaccine isolates were identified as capsule type A. Twenty-nine field isolates and six vaccine isolates were nonencapsulated. Three field isolates were capsule type F. Isolates of capsule types B, D, and E were not found. One field isolate, identified as somatic type 7, had a DNA fingerprint identical to that of the somatic reference type 6 profile. Twelve field isolates had profiles identical to the somatic reference type 3 strain profile; 11 of these were identified as somatic type 3, 4, and 1 was identified as somatic type 3. The DNA fingerprint profiles of 50 field isolates and 13 attenuated vaccine isolates did not match profiles of the 16 somatic type reference strains. Twenty-five DNA fingerprint profiles were recognized from 30 of these field isolates. The DNA fingerprint profiles of 20 field isolates and 13 attenuated vaccine isolates were identical. Three somatic types (3; 3,4; and 4,16) were identified from the field isolates, and two somatic types (3 and 3,4) were identified from the attenuated vaccine isolates. DNA fingerprinting is useful for accurate identification and epidemiologic study of P. multocida isolates.

Familial factors associated with malignant gliomas.

Family histories of male patients with histologically confirmed malignant gliomas were compared to family histories of controls (wives). Included were 77 case families with 892 relatives and 77 control families with 719 relatives. Cases had significantly more siblings than controls (P = 0.02), although cases were not preferentially the oldest or the youngest sibs. Odds ratios of two or more were found for mental retardation, Parkinson's disease, and meningitis for the relatives of cases versus controls, but none were statistically significant. The excesses of Parkinson's disease and meningitis were explained by the family of one particularly interesting case containing three relatives with meningitis and two relatives with Parkinson's disease. Noteworthy age-adjusted odds ratios for cancer among relatives of cases compared to relatives of controls were 1.6 (95% confidence interval (CI) = 1.0-2.3) for cancer of any site, 2.4 (95% CI = 0.8-6.1) for breast cancer, and 4.0 (95% CI = 0.6-10.7) for lung cancer. Only the odds ratio for cancer of any site was statistically significant. Overall, 6 of 77 (8%) of cases came from families that included two or more relatives with breast or lung cancer in addition to the proband with malignant glioma. These three cancer sites may form familial clusters worthy of further evaluation in future studies by pedigree and genetic linkage analyses.

Improving patient care through problem-solving groups.

In a competitive healthcare environment where as much attention must be given to quality of care as to cost containment, hospitals must learn to involve their lowest-paid paraprofessionals in decision making, since often these people have as much or more contact with patients than do physicians and nurses. One effective employee-involvement technique is the problem-solving group (PSG), which works to identify, analyze, choose, and implement solutions to various problems that influence the quality of patient care. A PSG project involving a typical paraprofessional unit was begun in spring 1985 at Emory University Hospital, Atlanta. The project's developmental stages were the following: Gathering data; Identifying problems; Providing feedback; Selecting PSG members; Focusing on problems; Generating solutions; Choosing the best solution; Implementing solutions; Managing successful outcomes. The PSG project was successful in addressing almost all the 15 identified problems in the department. Involving the staff in the PSG project resulted in higher morale, greater satisfaction with management, and a more favorable attitude toward their jobs.

Arthritis care in older-adult centers. A controlled study of an education program for public health nurses.

In this study, we evaluated an inservice training program for public health nurses. The training program concerned arthritis screening and management of the disease in elderly subjects. Twenty-nine nurses were assigned randomly to experimental (training) or control conditions. Evaluation data from 158 interviews with patients showed that screening for arthritis was done twice as frequently by nurses in the experimental group, compared with that done by nurses who were not in the experimental group (P less than 0.01). Recommended management of arthritis was not correspondingly improved. Stronger inservice programs are discussed in light of the need to anticipate seasonal conflicts between arthritis care and preventive care for the elderly, to change habitual practice patterns, and to increase access to arthritis health professionals.

The institutional chaplain: constructing a role definition.

Reports on a questionnaire survey of members of the Omaha Nebraska Area Institutional Chaplains' Association and the Nebraska State Chaplain's Association. Develops a typology of the role of the hospital chaplain based on findings which indicate that chaplains see themselves as (1) counselors, (2) professionals, and (3) religious functionaries. Notes that these perceptions are often at dissensus with relevant publics, and interprets the role of definitions in terms of secularization and social structure principles. Discusses and suggests ways of addressing role differences in view of current changes in health care developments.

Improvement in survival produced by sequential therapies in the treatment of recurrent medulloblastoma.

Thirty-six patients with recurrent medulloblastoma were treated with various combination chemotherapy protocols after initial treatment (usually irradiation) failed. Use of systemic chemotherapy was limited by depressed bone marrow reserves secondary to previous craniospinal irradiation. Intraventricular and intrathecal therapies included cytosine arabinoside (Ara-C), methotrexate, and thio-tepa given as single agents. Major systemic agents used alone or in combination included CCNU, procarbazine, vincristine, and the hexitol epoxides. Patients were reirradiated with or without misonidazole when there was definite tumor progression after all other therapies failed and/or because myelosuppression was so severe that further chemotherapy was not possible. Sequential systemic or intrathecal chemotherapy and reirradiation produced median survivals of two years and 25% quartile survivals of 2.9 years. The prognosis for patients harboring recurrent medulloblastoma has improved considerably over the years because of the therapeutic approaches reported here.

Stem cell studies of human malignant brain tumors. Part 1: Development of the stem cell assay and its potential.

A stem cell assay for human malignant gliomas has been developed. Cells obtained from tumor biopsies grew into colonies composed of malignant glial cells, as documented by histochemical, immunohistochemical, and immunobiological techniques. Studies suggest that the disaggregated cells are representative of the cells within the solid tumor. Clonogenic cells were obtained from 48 tumors and analyzed for their in vitro sensitivity to graded doses of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). The in vitro anti-tumor activity of BCNU at clinically achievable doses was compared to clinical response to the agent based on changes in computerized tomographic scan, radionuclide brain scan, and neurological examinations. Twenty-two patients received nitrosoureas before or after tumor specimen analysis, and were eligible for in vitro-in situ correlations. Clinical tumor sensitivity to nitrosoureas was predicted by culture results in 42% of all evaluable patients, and clinical resistance was predicted in 100%. The capability of the assay can be appreciated best for the 13 patients not treated with BCNU prior to culture; the in vitro prediction of clinical sensitivity and resistance was 71% and 100%, respectively. Preliminary findings show that clinical tumor resistance to BCNU may result from "intrinsic" cell resistance in some patients and from inadequate delivery of drug to tumor cells in other cases. The potential utility of this method to study the reason(s) for tumor cell resistance to drugs, to screen new chemotherapeutic agents, to individualize patient treatment, and to investigate tumor biology is discussed.

Age-related chemosensitivity of stem cells from human malignant brain tumours.

After radiation therapy and chemotherapy for malignant glioma, patients aged 50 or under survive longer than patients over 50. Data from Brain Tumor Study Group trials show that, without treatment, these age groups have similar survival; therefore unperturbed tumour growth does not account for the difference. Sixteen consecutive patients with malignant glioma were studied, half of whom were less than or equal to 50 years of age; none had been treated before initial surgery, and all were subsequently treated with radiation and chemotherapeutic agents (in all but two patients, with nitrosoureas). Median survival of those aged greater than 50 was less than or equal to 50 years was 54 + weeks whereas that of those aged greater than 50 was 37 weeks. The longer survival for younger patients could not be attributed to tumour type, size, or location, pretreatment Karnofsky status, or mode of treatment. In-vitro sensitivity testing of clonogenic cells obtained from biopsy specimens showed that tumour cells from seven of eight patients aged less than or equal to 50 years were sensitive to 1,3-bis (2-chloroethyl)-1-nitrosourea (greater than 40% cell kill at clinically achievable concentrations) compared with only one patient with sensitive cells out of eight older patients. Patient age was inversely correlated with in-vitro cell kill, and patients with sensitive cells were significantly younger than those with resistant cells. Therefore influence of age on survival after treatment of malignant gliomas is probably due to inherent differences in the sensitivity of clonogenic cells to radiation and/or chemotherapeutic agents.

The association of periodic alternating nystagmus with periodic alternating gaze. A case report.

A 26-year-old man with a recurrent cerebellar medulloblastoma developed periodic alternating nystagmus. During radiation treatment, a bilateral voluntary horizontal gaze paresis appeared, and the periodic alternating nystagmus was replaced by periodic alternating gaze. Several days later, full eye movements returned, as did the periodic alternating nystagmus which had an identical periodicity to the periodic alternating gaze. The underlying pathophysiology of periodic alternating nystagmus and periodic alternating gaze is discussed.