Distribution and severity of weakness among patients with polymyositis, dermatomyositis and juvenile dermatomyositis.

OBJECTIVE: To describe the distribution and severity of muscle weakness using manual muscle testing (MMT) in 172 patients with PM, DM and juvenile DM (JDM). The secondary objectives included characterizing individual muscle group weakness and determining associations of weakness with functional status and myositis characteristics in this large cohort of patients with myositis. METHODS: Strength was assessed for 13 muscle groups using the 10-point MMT and expressed as a total score, subscores based on functional and anatomical regions, and grades for individual muscle groups. Patient characteristics and secondary outcomes, such as clinical course, muscle enzymes, corticosteroid dosage and functional status were evaluated for association with strength using univariate and multivariate analyses. RESULTS: A gradient of proximal weakness was seen, with PM weakest, DM intermediate and JDM strongest among the three myositis clinical groups (P < or = 0.05). Hip flexors, hip extensors, hip abductors, neck flexors and shoulder abductors were the muscle groups with the greatest weakness among all three clinical groups. Muscle groups were affected symmetrically. CONCLUSIONS: Axial and proximal muscle impairment was reflected in the five weakest muscles shared by our cohort of myositis patients. However, differences in the pattern of weakness were observed among all three clinical groups. Our findings suggest a greater severity of proximal weakness in PM in comparison with DM.

Association of cytokine polymorphic inheritance and in vitro cytokine production in anti-CD3/CD28-stimulated peripheral blood lymphocytes.

BACKGROUND: Genetic variations in cytokine genes are thought to regulate cytokine protein production. However, studies using T cell mitogens have not always demonstrated a significant relationship between cytokine polymorphisms and in vitro protein production. Furthermore, the functional consequence of a polymorphism at position -330 in the IL-2 gene has not been described. We associated in vitro protein production with cytokine gene polymorphic genotypes after costimulation of cultured peripheral blood lymphocytes. METHODS: PBL were isolated from forty healthy volunteers. Cytokine protein production was assessed by enzyme-linked immunosorbent assay. Polymorphisms in interleukin- (IL) 2, IL-6, IL-10, tumor necrosis factor (TNF-alpha), tumor growth factor (TGF-beta), and interferon (IFN-gamma) were determined by polymerase chain reaction (PCR). RESULTS: Statistical difference between protein production and cytokine polymorphic variants in the IL-10, IFN-gamma, and TNF-alpha genes was not evident after 48-hour stimulation with concanavalin-A. In contrast, after anti-CD3/CD28 stimulation significant differences (P<0.05) were found among high and low producers for IL-2, IL-6, and among high, intermediate, and low producers for IFN-gamma, and IL-10. Augmented levels of IL-2 in individuals that were homozygous for the polymorphic IL-2 allele were due to an early and sustained enhancement of IL-2 production. No association was found among TNF-alpha and TGF-beta genotypes and protein production. CONCLUSION: Polymorphisms in IL-2, IL-6, IL-10, and IFN-gamma genes are associated with their protein production after anti-CD3/CD28 stimulation. The profound effect of the IL-2 gene polymorphism in homozygous individuals may serve as a marker for those that could mount the most vigorous allo- or autoimmune responses, or perhaps become tolerant more easily.

Increased CD8(+) T cells associated with Chlamydia pneumoniae in symptomatic carotid plaque.

BACKGROUND AND PURPOSE: The presence of Chlamydia pneumoniae has been reported in carotid atheroma, but its causative effect in the activation of an atherosclerotic plaque to a prothrombotic state remains unproved. Antigen- mediated activation of T lymphocytes within plaque may represent a mechanism by which infection can result in plaque conversion. The goal of the present study was to characterize the T-cell subtype profile related to the presence of C pneumoniae in patients with symptomatic versus asymptomatic carotid atherosclerosis. METHODS: We studied 14 plaques (5 symptomatic and 9 asymptomatic) positive for C pneumoniae confirmed by polymerase chain reaction and 14 plaques (6 symptomatic and 8 asymptomatic) from age- and stenosis-matched patients negative for C pneumoniae by polymerase chain reaction. T-cell subpopulations of T-helper, T-cytotoxic, and T-memory lymphocytes were identified through indirect enzyme immunohistochemistry with anti-CD3+, anti-CD4+, anti-CD8+, and anti-CD45RO+ monoclonal antibodies, respectively. Results are expressed as the number of positive cells per millimeter squared. RESULTS: In the absence of C pneumoniae, symptomatic plaques had a modest but significant increase of CD3+ (89.6 versus 55.3, P=0.013), CD4+ (57.3 versus 32.7, P=0.01), and CD45RO+ (82.8 versus 43.7, P=0.007), but not CD8+ T cells (28.5 versus 25.5, P=0.245) compared with asymptomatic. However, in the presence of C pneumoniae, there was significant increase of all T-lymphocyte subtypes in symptomatic plaques, including CD8+ (76.8 versus 30.3, P=0.03), CD3+ (192.1 versus 80.4, P=0.004), CD4+ (111.9 versus 37.9, P=0.003), and CD45RO+ (120.2 versus 72.9, P=0.003) cells compared with asymptomatic plaques. With use of 2-way ANOVA, both the presence of chlamydia and symptoms were associated with significantly higher T-cell counts (P<0.005 for all subtypes). CONCLUSIONS: Although all patients with symptomatic disease show a modest elevation in the concentration of intraplaque lymphocytes, a preferential increase in CD8+ class I-restricted T cells is observed in symptomatic carotid plaque positive for C pneumoniae. These data provide incentive to further explore the role of Chlamydia in the modification of immune-mediated mechanisms in active atherosclerotic plaque.

Presence of Chlamydia pneumoniae in human symptomatic and asymptomatic carotid atherosclerotic plaque.

BACKGROUND: Chlamydia pneumoniae has been identified in atherosclerotic plaques of patients with cerebrovascular and cardiovascular disease. However, the direct causative effect of C pneumoniae infection in the activation of atherosclerotic plaque to a prothrombotic state remains to be established. The aim of the present study is to examine the correlation between intraplaque presence of chlamydiae and symptomatic carotid disease in humans. METHODS: Plaques from 37 symptomatic and 57 asymptomatic consenting patients undergoing carotid endarterectomy were snap-frozen, and the tissue was prepared for polymerase chain reaction analysis for Chlamydia pneumoniae per Institutional Review Board-approved protocol. Blood was drawn from each patient at the time of surgery for serological analysis. RESULTS: The overall rate of plaques positive for C pneumoniae was 14.82%, with 5 of 37 (13.5%) plaques from symptomatic patients and 9 of 57 (15.8%) from asymptomatic patients, which revealed a definitive presence of the organism. No association existed between C pneumoniae presence and symptomatic disease (P:=1.0). Also, no association existed between presence of C pneumoniae and severity of stenosis. Finally, seropositivity for anti-chlamydial IgG, IgA, and IgM anti-chlamydial antibodies did not correlate with identification of C pneumoniae in the plaques. However, high-serum anti-chlamydial IgA levels (>/=1:128) were associated with occurrence of symptomatic disease (P=0.03; odds ratio, 2.86; 95% CI, 1.12 to 7.28). CONCLUSIONS: Presence of C pneumoniae as a single factor does not appear to be sufficient to explain the occurrence of cerebrovascular symptoms. Low sensitivity of seropositivity for IgG, IgA, or IgM associated with PCR-identified C pneumoniae presence in the plaque makes it unlikely to be valuable as the single determining factor for actively infected plaque. Association of high-level anti-chlamydial IgA with symptomatic disease suggests that chronic or acute chlamydial infection anywhere in the body could play a role in atherosclerotic plaque activation and be used as a marker to target populations in future stroke prevention trials.

Genotype-phenotype assessment of common genotypes among patients with familial Mediterranean fever.

OBJECTIVE: To study genotype-phenotype correlation for the 4 most common genotypes found among patients with familial Mediterranean fever (FMF). METHODS: Thirty patients with the M694V/M694V genotype, 32 with M694V/V726A genotype, 25 with M694V/E 148Q genotype, and 21 with V726A/V726A genotype were assessed for various clinical manifestations of FMF, and overall disease severity. RESULTS: Patients with the M694V/M694V genotype were found to have an earlier age of onset, higher frequency of joint involvement, higher frequency of erysipelas-like erythema, and required higher doses of colchicine to control the disease compared to the other 3 genotypes. CONCLUSION: The M694V/M694V genotype is associated with more severe disease compared to other common genotypes in patients with FMF.

Temporal association between implementation of universal precautions and a sustained, progressive decrease in percutaneous exposures to blood.

To evaluate whether implementation of universal precautions was temporally associated with a decrease in reported parenteral exposures to blood, we analyzed data on self-reported parenteral injuries that were prospectively collected at the Clinical Center, National Institutes of Health (Bethesda, MD), from 1985 through 1991. We also assessed whether implementation of universal precautions, in concert with initiation of a program of postexposure chemoprophylaxis with zidovudine, was associated with decreased time to reporting of occupational exposures. Our data, possibly confounded by the occurrence of an occupational infection due to human immunodeficiency virus infection in 1988, nonetheless demonstrate a temporal association between a progressive, significant decrease in percutaneous injuries and the implementation of universal precautions that has been sustained through subsequent years. The analysis remains significant, regardless of the surrogate denominator chosen for analysis. No trend toward more rapid reporting of exposures was identified. Implementation of universal precautions appears to have contributed to decreased parenteral injuries in our hospital but did not affect reporting efficiency.

Measles immunity in a population of healthcare workers.

OBJECTIVES: To evaluate measles seroprevalence among cohorts of new employees and to evaluate vaccine responses of susceptible adult healthcare workers. DESIGN: New employees were screened for measles susceptibility as part of employee evaluations. Anti-IgG measles antibody tests were completed on 2,473 workers. Demographic, measles history, and measles vaccination information was collected using a short questionnaire. Susceptible workers were vaccinated and screened for vaccine responses following vaccination. RESULTS: Ninety-three workers (4%) were seronegative, and 56 (2%) were equivocal. Individuals in the youngest cohort (born after 1956) were significantly more likely to be susceptible than those in the middle cohort (born 1951 to 1956) and those in the oldest cohort (born before 1951) (P < 0.01). The middle cohort included eight (5%) of the 149 seronegative or equivocal workers. Among the members of the youngest cohort, those from the United States were more likely to be susceptible (P < 0.01) than those from outside the United States. Of the 106 vaccinated susceptible workers whose follow-up serologies were determined, 90 (85%) developed positive IgG serologies, six had equivocal results, and 10 were seronegative. Eleven of the 16 non- or hyporesponders were revaccinated and re-evaluated; nine developed low positive IgG antimeasles levels, one exhibited an equivocal response, and one failed to respond. CONCLUSIONS: A small but important proportion of healthcare workers are susceptible to measles. Whenever feasible, measles immunity programs for healthcare workers should include workers born before 1957. Of workers born after 1956, those from outside the United States are more likely to be immune than workers from inside the United States. Using the currently available vaccine, revaccination of initial non- or hyporesponders appears to be effective.

A comparison of risk factors for human immunodeficiency virus and hepatitis B virus infections in homosexual men.

We analyzed cross-sectional data from 1062 homosexual men recruited in Baltimore during 1984, to directly compare risk factors for human immunodeficiency virus (HIV) and hepatitis B virus (HBV). Using polychotomous logistic regression, risk factor odds ratios (ORs) and 95% confidence intervals were determined for men with HIV alone, men with HBV alone, and men with both HIV and HBV, compared to seronegative men, and paired comparisons among these subgroups. Factors associated with the serologic prevalence of HIV alone and HBV alone (with respective ORs) included and receptive intercourse (HIV OR = 1.23; HBV OR = 1.12), history of gonorrhea (HIV OR = 4.58; HBV OR = 2.52), and rectal douching (HIV OR = 1.41; HBV OR = 1.20). Additional factors associated with HBV alone were years of homosexual activity (OR = 1.65), sexual activity with a person who developed acquired immunodeficiency syndrome (AIDS) (OR = 1.98), and lifetime number of male sex partners (OR = 1.25). HIV and HBV coprevalence was associated with anal receptive intercourse (OR = 1.36), history of gonorrhea (OR = 2.94), rectal douching (OR = 1.45), sexual activity with a person who developed AIDS (OR = 3.87), lifetime number of male sex partners (OR = 1.21), and the lifetime sum of sexually transmitted diseases (OR = 1.47). These findings reinforce the need for following safer-sex guidelines to prevent both infections and in the case of HBV, the prevention strategies should include vaccination.

Nosocomial human parvovirus B19 infection: lack of transmission from a chronically infected patient to hospital staff.

OBJECTIVE: To assess the potential for nosocomial spread of parvovirus B19 from a chronically infected patient. DESIGN: Employees exposed to the index case and control (unexposed) employees were evaluated by baseline and follow up parvovirus B19 serologies and hematologic assessments, and completed baseline and follow up epidemiologic questionnaires. SETTING: A chronically infected patient was hospitalized on a hematology ward in a research referral hospital for 3.5 weeks prior to a diagnosis of parvovirus B19 infection and the institution of isolation precautions. METHODS: Sera were screened for parvovirus B19 DNA (dot blot analysis), and IgG and IgM anti-B19 antibodies (capture immunoassay). Hematologic assessment included CBC, differential, and reticulocyte count. RESULTS: The index case had parvovirus B19 DNA at approximately 10(6) genome copies per ml of serum, elevated IgM and low levels of IgG B19 antibodies. Of the 21 exposed staff, 11 (52%) had IgG B19 antibodies and were immune; of the 8 unexposed staff, 6 (75%) had IgG B19 antibodies. No employees developed IgM B19 antibodies, B19 DNA, hematologic abnormalities, or clinical symptoms. CONCLUSIONS: In contrast to reports of documented nosocomial transmission of B19 parvovirus from patients in transient aplastic crisis, nosocomial transmission did not occur--even in the absence of isolation precautions--presumably from the lower level of B19 viremia in our chronically infected (rather than acutely infected) patient.

Evolving epidemiology of HIV infection among adults.

Whereas new, or changes in existing, routes of transmission of HIV have not been identified in the 11 years since AIDS was identified as a clinical syndrome, changes in the epidemiology of HIV infection in the US have been identified during that period. The role of injection drug use as a risk for both parenteral and sexual transmission of HIV has increased substantially during this period. Heterosexual transmission is becoming more prominent as the epidemic continues to "mature" in the US. The likelihood that heterosexual transmission will become progressively more important in the spread of HIV in the US in the next several years seems high. The ability of individuals in some populations at risk for infection to modify risk behaviors has led to a reduction in transmission of HIV in those populations. The addition of nucleoside analog antiretrovirals and effective chemoprophylaxis for Pneumocystis carinii pneumonia has led to increases in both the quality and duration of life for some populations of HIV-infected patients. Neither a chemotherapeutic cure nor a vaccine is on the immediate horizon; education and behavior modification remain the cornerstones of current prevention efforts. For a variety of complex reasons, inappropriate scrutiny has been focused on the remote risks of health-care provider-to-patient transmission of HIV. In the past 11 years medical science has made remarkable progress in understanding the etiology, biology, epidemiology, pathogenesis, and prevention of HIV infection. Despite this progress, a great deal of work remains to be done not only in the medical and basic science arenas but also in the behavioural and sociological sciences.

Frequency of nonparenteral occupational exposures to blood and body fluids before and after universal precautions training.

PURPOSE: During annual periods before and after Universal Precautions training, we compared the frequency of health care workers' self-reported cutaneous exposures to blood and various body substances from any patient and from patients presumed infected with human immunodeficiency virus type 1 (HIV-1). SUBJECTS AND METHODS: Self-reported cutaneous exposures to blood, sputum, urine, feces, and other body substances were evaluated separately in 559 workers during the first survey and 269 workers during the second. RESULTS: Mean annual blood exposures decreased from 35.8 to 18.1, and mean annual exposures to all substances decreased from 77.8 to 40.0 (p less than 0.001 for both determinations). Two matched analyses of a subset of 200 participants who completed both surveys had similar results. Reported exposures to blood, presumably infectious blood, sputum, presumably infectious sputum, and urine were significantly decreased. Participants were tested for antibodies to HIV-1; no participant reporting cutaneous exposures acquired HIV-1 infection. The upper bound for the 95% confidence interval for the risk of HIV-1 infection associated with a single cutaneous exposure was 0.04% for blood presumed to contain HIV-1 and 0.02% for any body substance presumed to contain HIV-1. CONCLUSIONS: These data suggest that Universal Precautions training significantly decreased but did not eliminate cutaneous exposures to blood and body substances. The results further suggest that the risk for HIV-1 infection associated with cutaneous exposures is substantially lower than the risk associated with parenteral exposures.

Risk for occupational transmission of human immunodeficiency virus type 1 (HIV-1) associated with clinical exposures. A prospective evaluation.

OBJECTIVES: To summarize the results of a 6-year, ongoing, prospective study of the risk for human immunodeficiency virus type 1 (HIV-1) transmission among health care workers, and to estimate the magnitude of the risk for HIV-1 infection associated with different types of occupational exposures. DESIGN: Prospective cohort study; the median follow-up for employees sustaining parenteral exposures was 30.2 months (range, 6 to 69 months). SUBJECTS: Health care workers at the Clinical Center, National Institutes of Health, including those reporting parenteral and nonparenteral occupational exposures to HIV-1. MEASUREMENTS AND MAIN RESULTS: One thousand three hundred and forty-four clinical health care workers reported 179 percutaneous and 346 mucous membrane exposures to fluids from HIV-1-infected patients during a 6-year period. Responding to a supplementary questionnaire, 559 of these workers reported 2712 cutaneous exposures to blood from HIV-1-infected patients and more than 10,000 cutaneous exposures to blood from all patients during a 12-month period. Occupational transmission of HIV-1 occurred in a single worker after a parenteral exposure to blood from an HIV-1-infected patient. No infections occurred after either mucous membrane or cutaneous exposures to blood from HIV-1-infected patients. Use of newer diagnostic technologies (for example, antigen detection, gene amplification) has not resulted in the identification of occupationally transmitted seronegative infections. CONCLUSIONS: Combining our results with those of other prospective studies, the risk for HIV-1 transmission associated with a percutaneous exposure to blood from an HIV-1-infected patient is approximately 0.3% per exposure (95% CI, 0.13% to 0.70%); the risks associated with occupational mucous membrane and cutaneous exposures are likely to be substantially smaller. These data support the use of barrier precautions and suggest a need for strategies that change health care providers' attitudes and behaviors.

Decreasing seroprevalence of human immunodeficiency virus type 1 in a regional blood donor population.

Blood banks have intensified their efforts to discourage donations from individuals at risk for the human immunodeficiency virus (HIV-1). Since the onset of HIV-1 donor screening in April 1985, a marked reduction in seroprevalence has been seen at the authors' institutions: from 51 cases per 100,000 donors in 1985 to 13 per 100,000 in the first 6 months of 1988. Data from 3.5 years have been analyzed for temporal trends in the association of HIV-1 seroprevalence with donation site (urban vs. non-urban) and donor gender. The association of HIV-1 seropositivity with an urban donation site decreased through 1987 as the urban-to-nonurban donation odds ratio declined from 6.48 in 1985 to 2.54 in 1987. Despite this decrease, both men and women who donated in urban areas had a significantly higher seroprevalence than those in nonurban areas. Male donors had a higher overall HIV-1 seroprevalence than female donors. However, the male-to-female odds ratio declined from 2.94 in 1985 to 1.96 in 1988, and male gender was no longer significantly associated with HIV-1 seropositivity. This change in the donor profile appears to reflect declining numbers of seropositive men who acknowledge risk factors and greater numbers of women with no identified risks for HIV-1. This study documents a dramatic decrease in HIV-1-seropositive donors and suggests that the deferral of high-risk individuals has become increasingly successful.

Nosocomial transmission of hepatitis A in an adult population.

Nosocomial transmission of hepatitis A from patients to staff members is an unusual event. Recently, several cases of occupational transmission of hepatitis A to health care workers have been reported in the literature. Most of these have occurred as a result of transmission from an infected child to a staff member involved in his or her care. We report an additional case of transmission of hepatitis A from an infected adult to a staff member and review the literature regarding nosocomial hepatitis A transmission. The review emphasizes several points that nearly all instances of nosocomial transmission of hepatitis A have in common, including the role of asymptomatic infection, the timing of hospitalization, and the fact that index patients often have an underlying illness that obscures the early diagnosis of hepatitis A. In addition, several other areas of controversy with respect to hepatitis A are discussed.

Skull x-ray examinations after head trauma. Recommendations by a multidisciplinary panel and validation study.

The value of skull radiography in identifying intracranial injury has not yet been satisfactorily defined. A multidisciplinary panel of medical experts was assembled to review the issue of skull radiography for head trauma. The panel identified two main groups of patients--those at high risk of intracranial injury and those at low risk of such injury--and developed a management strategy for imaging in the two groups. The high-risk group consists primarily of patients with severe open or closed-head injuries who have a constellation of findings that are usually clinically obvious. These patients are candidates for emergency CT scanning, neurosurgical consultation, or both. The low-risk group includes patients who are asymptomatic or who have one or more of the following: headache, dizziness, scalp hematoma, laceration, contusion, or abrasion. Radiographic imaging is not recommended for the low-risk group and should be omitted. An intermediate moderate-risk group is less well defined, and skull radiography in this group may sometimes be appropriate. A prospective study of 7035 patients with head trauma at 31 hospital emergency rooms was conducted to validate the management strategy. No intracranial injuries were discovered in any of the low-risk patients. Therefore, no intracranial injury would have been missed by excluding skull radiography for low-risk patients, according to the protocol. We conclude that use of the management strategy is safe and that it would result in a large decrease in the use of skull radiography, with concomitant reductions in unnecessary exposure to radiation and savings of millions of dollars annually.

Antibody to hepatitis B core antigen as a paradoxical marker for non-A, non-B hepatitis agents in donated blood.

The relationship between the presence of antibody to hepatitis B core antigen (anti-HBc) in donor blood and the development of hepatitis in recipients of that blood was studied in 6293 blood donors and 481 recipients who were followed for 6 to 9 months after transfusion. Of 193 recipients of at least 1 unit of blood positive for anti-HBc, 23 (11.9%) developed non-A, non-B hepatitis compared with 12 (4.2%) of 288 recipients of only anti-HBc-negative blood (p less than 0.001). Donor anti-HBc status was not significantly associated with the development of hepatitis B in the recipient and was negatively associated with the development of cytomegalovirus hepatitis. The relationship of donor anti-HBc status and the development of non-A, non-B hepatitis in the recipient was independent of transfusion volume and elevated donor transaminase level. Although 88% of anti-HBc-positive blood units were not associated with recipient non-A, non-B hepatitis, calculation of maximal corrected efficacy predicted that exclusion of anti-HBc-positive donors might have prevented 43% of the cases of non-A, non-B hepatitis with a donor loss of 4%. Because of the serious chronic consequences of non-A, non-B hepatitis, surrogate tests for non-A, non-B virus carriers must be seriously considered.

High dose misonidazole with dexamethasone rescue: a possible approach to circumvent neurotoxicity.

With a view to modifying misonidazole (MISO) neurotoxicity, we initiated a randomized clinical study to assess a possible drug interaction and toxicity protection when dexamethasone (DXM) is administered concomittantly with MISO. The ongoing study consists of: 1. Pharmacokinetic evaluation; 2. Assessment of toxicity. Fourteen patients undergoing radiation therapy for different types of malignant neoplasia (excluding brain tumors) have been randomized to receive either MISO alone, or DXM one week prior and during treatment with MISO. Five of seven patients receiving MISO alone developed peripheral neuropathies while only one out of 7 patients that received MISO with DXM coverage developed a transient and mild neuropathy. Pharmacokinetic evaluation of MISO in plasma and urine of those patients receiving DXM has shown no evidence of drug interaction. It is postulated that the mechanism of action of DXM is at the nerve cell membrane level, restoring and stabilizing cell surface properties. In future studies we will investigate the use of DXM with increasing doses of MISO above the recommended maximum dose of 12 gm/m2, hoping to achieve a higher tumor tissue level of MISO while avoiding unacceptable toxicity. The effect of Allopurinol on the plasma kinetics of MISO was studied in four additional patients, observing also no evidence of drug interaction.

Pharmacokinetic interaction of BCNU and misonidazole in humans.

Although considerable laboratory in vitro and in vivo evidence is now available suggesting that misonidazole (MISO) enhances chemotherapy tumor responses, experience with human tumors is limited. Further, the mechanism of this enhancement is not definitely known. One possible mechanism is that MISO alters the pharmacokinetics of the chemotherapeutic agent, vice versa or both. We studied a group of patients with recurrent malignant gliomas, following radiotherapy. After proven recurrence, they were treated with i.v. BCNU in combination with oral MISO in an 8 week cycle. Our aims were: 1. To obtain a second remission; 2. To assess the toxicity of this combination; 3. To assess the plasma pharmacokinetics of each drug alone and in combination. Six patients entered the protocol. Four of six patients obtained either a partial or subpartial response. Prolonged moderate myelosuppression was observed in 2/6 patients after 3 cycles; 2/6 patients experienced seizures after the first cycle of chemotherapy for the first time in the course of their disease. The plasma pharmacokinetic data indicates no evidence of a MISO-BCNU drug interaction.