Diffusion magnetic resonance imaging: an early surrogate marker of therapeutic efficacy in brain tumors.

BACKGROUND: A surrogate marker for treatment response that can be observed earlier than comparison of sequential magnetic resonance imaging (MRI) scans, which depends on relatively slow changes in tumor volume, may improve survival of brain tumor patients by providing more time for secondary therapeutic interventions. Previous studies in animals with the use of diffusion MRI revealed rapid changes in tumor water diffusion values after successful therapeutic intervention. METHODS: The present study examined the sensitivity of diffusion MRI measurements in orthotopic rat brain tumors derived from implanted rat 9L glioma cells. The effectiveness of therapy for individual brain cancer patients was evaluated by measuring changes in tumor volume on neuroimaging studies conducted 6--8 weeks after the conclusion of a treatment cycle. RESULTS: Diffusion MRI could detect water diffusion changes in orthotopic 9L gliomas after doses of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU or carmustine) that resulted in as little as 0.2 log cell kill, a measure of tumor cell death. Mean apparent diffusion coefficients in tumors were found to be correlated with and highly sensitive to changes in tumor cellularity (r =.78; two-sided P =.041). The feasibility of serial diffusion MRI in the clinical management of primary brain tumor patients was also demonstrated. Increased diffusion values could be detected in human brain tumors shortly after treatment initiation. The magnitude of the diffusion changes corresponded with clinical outcome. CONCLUSIONS: These results suggest that diffusion MRI will provide an early surrogate marker for quantification of treatment response in patients with brain tumors.

Variability of 5-bromo-2'-deoxyuridine incorporation into DNA of human glioma cell lines and modulation with fluoropyrimidines.

Human glioma-derived cell lines were found to vary in their ability to incorporate the radiosensitizer 5-bromo-2'-deoxyuridine (BrdUrd) into DNA after one cell doubling. The U-251 cell line was the best incorporator of BrdUrd, whereas U-118 and D-54 demonstrated poor incorporation with respective C50 (BrdUrd concentration required for 50% of the maximum amount of BrdUrd incorporation into DNA) values of 2.8- and 6-fold greater than that of U-251 (P less than 0.001). Modulation of radiosensitizer uptake into DNA could be achieved using the thymidylate synthase inhibitors 5-fluorouracil or 5-fluoro-2'-deoxyuridine (FdUrd). Incorporation into U-251 cells increased only slightly in the presence of the fluoropyrimidines. The BrdUrd concentration required for 50% of the maximum amount of BrdUrd incorporation into DNA changed (P less than 0.001) from 1.8 +/- 0.11 microM (SD) in the absence of a modulator to 1.1 +/- 0.09 or 1.1 +/- 0.16 microM in the presence of 10 microM 5-fluorouracil or 5 nM FdUrd, respectively. The D-54 cell line, which was the worst incorporator of BrdUrd, was found to have an extensive amount of BrdUrd into DNA following biomodulation. The C50 in the absence of modulation was 7.3 +/- 1.3 microM, which was reduced (P less than 0.001) to 0.62 +/- 0.04 and 0.32 +/- 0.13 microM, respectively, in the presence of 10 microM 5-fluorouracil and 5 nM FdUrd. This represents a 12- to 22-fold reduction in the concentration of radiosensitizer required to achieve the same level of BrdUrd incorporation into DNA. Furthermore, this enhancement of BrdUrd DNA incorporation seen in the presence of the fluoropyrimidines is observed at clinically achievable concentrations. The degree of radiosensitization was solely dependent upon the amount of BrdUrd incorporated into DNA. D-54 cells grown in the presence of 0.18 microM BrdUrd plus 5 nM FdUrd or 2.8 microM BrdUrd alone yielded a similar level of BrdUrd incorporation into DNA and radiosensitization, though a 15-fold lower BrdUrd concentration was used in the presence of FdUrd. The combined use of a radiosensitizer with a fluoropyrimidine may overcome poor incorporation of BrdUrd into DNA that may exist among resistant subpopulations of cells within malignant glioma.

A comparison of the predictive power for survival in gliomas provided by MIB-1, bromodeoxyuridine and proliferating cell nuclear antigen with histopathologic and clinical parameters.

The purpose of this prospective study of 65 patients was to compare side-by-side the predictive power for survival of (a) MIB-1, (b) bromodeoxyuridine (BUDR), and (c) proliferating cell nuclear antigen (PCNA). They were compared (a) with each other, (b) with several clinical predictors, and (c) with histopathologic grade under actual clinical biopsy conditions in a study of 1993 World Health Organization (WHO) grade II to IV adult supratentorial gliomas. There was a strong positive relationship between MIB-1 and BUDR by Spearman Rank correlation. In univariate analysis, MIB-1 (logrank p = 0.06) was more predictive of survival than BUDR or PCNA. Longer survivors were distinguished from others by the lowest MIB-1 labeling indices (LI < or = 2.5%) better than by the lowest histopathologic grade. However, histopathologic grades were highly predictive among the entire group (logrank p < 0.0001). Young age (p < 0.0001) and high Karnofsky performance status (p < 0.0001) were the clinical factors most predictive of longer survival. Female gender correlated with longer survival (logrank p = 0.02). In multivariate Cox proportional hazards models, age, Karnofsky performance status, and histopathologic grading remained statistically significant after full reduction of the model. We conclude that Ki-67 measured by MIB-1 monoclonal antibody was superior to other markers of proliferation. When all factors are considered simultaneously over all 3 grades of malignancy, greatest predictive power resides in histopathologic grade and clinical variables. MIB-1 is expected to be most important in cases where clinical or histopathologic factors are ambiguous or where they cannot be fully assessed.

Nuclear parameters as prognostic indicators in glioblastoma patients.

The objective of this study was to determine whether nuclear parameters were associated with prognosis in glioblastoma multiforme. DNA indices, cell cycle parameters, and nuclear population densities were compared with patient survival. Selection criteria included the pathologic diagnosis of a cerebral glioblastoma multiforme, absence of therapy before surgery, and adequate tissue to measure each nuclear parameter studied. Nine cases accrued over a two year period. The amount of DNA per nucleus was quantified in fresh tissue specimens by nuclear-isolation flow cytometry in Vindelov's solution. One particular association was significant when tested by Cox models: The percentage of nuclei with S-phase amounts of nuclear DNA was a significant predictor of decreased survival (regression coefficient = 0.20, p = 0.04). The percentage of nuclei in the G0/G1 peak was marginally associated with longer survival. These data are evidence of an association between nuclei in certain phases of the DNA cell cycle and postoperative survival.

Mixing in the human carotid artery during carotid drug infusion studied with PET.

The safety and efficacy of drug infusion into the carotid artery require adequate mixing of the infused solution with carotid blood. Using positron emission tomography (PET), we studied the mixing of solutions infused into the human carotid artery in seven patients by analyzing the distribution of [15O]H2O infused into the carotid artery and by vein. At four infusion rates ranging from 0.5 to 10 ml/min, the variability in distribution averaged 16.5-17.8% among the pixels in a large volume of interest, without dependence on the infusion rate. The overall correlation between [15O]H2O influx with arterial infusion and [15O]H2O influx with venous injection was 0.78-0.82 at the four infusion rates, with no trend toward higher correlations at the faster infusion rates. The distribution into the anterior, middle, and posterior cerebral artery territories differed from distribution throughout the entire carotid territory by an average of 6.2-9.6% at the four infusion rates, with no trend toward smaller differences at the faster infusion rates. Infusions performed into a vinyl tube simulating the carotid artery indicated that at 0.5 ml/min, the velocity of fluid exiting the catheter makes no apparent contribution to mixing. We conclude that with infusions at the carotid bifurcation, mixing in the human carotid artery is complete or nearly complete over a wide range of infusion rates. The mixing appears to result from the patterns of blood flow within the artery, and not from jet effects at the catheter tip.

Short-term effects of smoking marijuana on balance in patients with multiple sclerosis and normal volunteers.

A double-blind randomized placebo-controlled study of inhaled marijuana smoke on postural responses was performed in 10 adult patients with spastic multiple sclerosis (MS) and 10 normal volunteers matched as closely as possible for age, sex, and weight. A computer-controlled dynamic posturographic platform with a video line scan camera measured shoulder displacement in response to pseudorandom platform movements. Premarijuana smoking patient tracking was inferior to that of the normal volunteers as indicated by the higher noise variance of the former. Smoking one marijuana cigarette containing 1.54% delta 9-tetrahydrocannabinol increased postural tracking error in both the patients and normal control subjects with both eyes open and closed; this untoward effect was greatest for the patients. The tracking error was also accompanied by a decrease in response speed for the patients with their eyes closed. Marijuana smoking further impairs posture and balance in patients with spastic MS.

Carnitine metabolism in Macaca arctoides: the effects of dietary change and fasting on serum triglycerides, unesterified carnitine, esterified (acyl) carnitine, and beta-hydroxybutyrate.

Serum triglycerides and serum total, esterified, and free (unesterified) carnitine were measured in 21 male Macaca arctoides that were switched from a low fat (5.2% w/w), high carbohydrate diet to a high fat (15.9% w/w), low carbohydrate diet for 90 days and then returned to the original low fat diet for a subsequent 76-day period. Serum triglycerides and total carnitine levels fell significantly (p less than 0.05) during the initial 2 wk of feeding the high fat diet and the ratio of esterified/unesterified carnitine rose significantly (P less than 0.05) on the high fat diet. A return to the low fat diet reversed these changes; triglycerides rose significantly (p less than 0.05) within 3 days and the ratio of esterified/unesterified carnitine fell significantly (p less than 0.05) within 3 days and the ratio of esterified/unesterified carnitine fell significantly (p less than 0.05) during the same period. A return of total carnitine levels to those initially observed on the low fat diet was slower to develop. Fasting for 24 to 48 h resulted in increases of 65 to 75% in total serum carnitine. This increase reflected elevations of both the esterified and unesterified carnitine fractions but was largely attributable to increases in esterified carnitine which rose from 10 to 41 nmol/ml by 48 h while unesterified carnitine rose from 55 to 72 nmol/ml during the same period. In addition, the ratio of esterified/unesterified carnitine ratio rose from 0.183 +/- 0.023 to 0.583 +/- 0.069 (n = 8) with a 48-h fast and was significantly correlated with serum beta-hydroxybutyrate levels at both 24 and 48 h.

Clinical outcome in aggressively treated meningeal carcinomatosis.

OBJECTIVE: To critically evaluate the clinical outcome of patients with cytologically proved meningeal carcinomatosis and to identify factors associated with an improved outcome. DESIGN: A consecutive series of patients was identified from a cytopathology data base. The study period was from 1985 to 1990. Case records and results of radiologic investigations were reviewed; all patients were followed up until their deaths. SETTING: University hospital with a cancer center. PATIENTS: Thirty-six consecutive patients with cytologically proved meningeal carcinomatosis. Patients with lymphoma or leukemia were excluded. INTERVENTIONS: External beam radiation therapy, intrathecal chemotherapy via a ventricular catheter, and intravenous chemotherapy. MAIN OUTCOME MEASURES: Clinical assessment and survival. RESULTS: Symptoms improved in 15% of 33 treated patients. Response to treatment had no clear relationship with the age, site of involvement, or tumor type. Median survival for treated patients was only 9 weeks. Patients who received more than five intrareservoir chemotherapy treatments had a median survival of 23 weeks. Median survival for patients with breast carcinoma who received intravenous chemotherapy was 20 weeks, significantly better than that of patients not receiving intravenous chemotherapy. CONCLUSIONS: Survival is poor despite aggressive treatment. Intravenous chemotherapy may improve survival in patients with chemoresponsive primary tumors and deserves further study.

Intracerebral hemorrhage complicating intravenous tissue plasminogen activator treatment.

Tissue plasminogen activator's thrombolytic action is relatively specific for fibrin; however, systemic bleeding can occur in patients, especially when heparin is simultaneously administered. We describe two cases of intracerebral hemorrhage from a cohort of 450 patients (0.44%) treated at one institution with tissue plasminogen activator and heparin for acute myocardial infarction. A pooled worldwide review of 5258 cases from several clinical protocols for treatment of acute myocardial infarction, using tissue plasminogen activator from one source, revealed a similar overall incidence of 0.68%. The incidence of intracerebral hemorrhage may be reduced by lowering the total dose of tissue plasminogen activator or by reducing the infusion rate and duration. The incidence of central nervous system hemorrhage with tissue plasminogen activator is within the range reported with streptokinase, but because equal coronary artery thrombolytic doses are not known, no definitive comparison is possible.

Adult medulloblastoma: multiagent chemotherapy.

In this study, the records of 17 adult patients with medulloblastoma treated with craniospinal radiation and 1 of 2 multiagent chemotherapy protocols were reviewed for progression-free survival, overall survival, and toxicity, and the patients were compared with each other and with similarly treated children and adults. Records of patients treated at 3 institutions were reviewed. Seventeen medulloblastoma patients (11 female, 6 male) with a median age of 23 years (range, 18-47 years) were treated with surgery, craniospinal radiation (CSRT) plus local boost, and 1 of 2 adjuvant chemotherapy regimens. All tumors were infratentorial (10 in 4th ventricle and 7 in left or right hemisphere). Ten patients presented with hydrocephalus, and 7 of them were shunted. Eight patients had gross total resection, 7 had subtotal resection (>50% removed), and 2 had partial resection (<50% removed). Postoperatively, 3 patients had positive cytology and 3 had positive spinal MRI. Five patients were classified as good risk and 12 were classified as poor risk (Chang staging system). Ten patients were treated with the "Packer protocol," consisting of CSRT plus weekly vincristine followed by 8 cycles of cisplatin, lomustine, and vincristine. Seven patients were treated with the Pediatric Oncology Group (POG) protocol, consisting of alternating courses of cisplatin/etoposide and cyclophosphamide/vincristine, followed by CSRT. Eight of 17 patients relapsed, with all 8 relapsing at the primary site. Other relapse sites included the leptomeninges (5), bone (1), and brain (1). The estimated median relapse-free survival (Kaplan-Meier) for all patients was 48 months (95% confidence interval, >26 months to infinity). Median relapse-free survival for patients on the Packer protocol was 26 months, and for those on the POG regimen was 48 months (P = 0.410). Five of 10 on the Packer protocol were relapse-free, while 4 of 7 were relapse-free on the POG regimen. Two patients relapsed during chemotherapy and 6 relapsed after completing all therapy at 18, 18, 26, 30, 40, and 48 months. The estimated median survival of all patients was 56 months (95% confidence interval, 27 to infinity) with 11 patients alive; for the Packer protocol, median survival was 36 months, and for the POG protocol, it was 57 months (P = 0.058). The hazard ratio was 0 (95% confidence interval, 0 to infinity). Toxicity during the Packer protocol was moderately severe, with only 1 of 10 patients able to complete all therapy. Two patients had severe abdominal pain during CSRT + vincristine, and 5 had peripheral neuropathy during vincristine therapy. Hearing loss (>20 dB) occurred in 7, neutropenia (<500 microl) in 6, thrombocytopenia (<50,000 microl) in 6, nephrotoxicity (>25% decrease by creatinine clearance) in 2, and decreased pulmonary function (diffusing capacity for carbon monoxide decrease >40%) in 1. On the POG protocol, only 1 patient had persistent nausea and vomiting, 2 had peripheral neuropathy, and 3 had hearing deficit (>20 dB) or tinnitus. The POG and Packer protocols did not have a statistically significant difference in relapse-free or overall survival because of the small sample size. The POG protocol seemed to have less nonhematologic toxicity. Adults on the Packer protocol appeared to have shorter median survival and greater toxicity than did children. To know whether adding adjuvant chemotherapy to craniospinal radiation in adult therapy increases relapse-free and overall survival, we must await the results of a larger randomized controlled clinical trial.

5-FU multifocal inflammatory leukoencephalopathy and dihydropyrimidine dehydrogenase deficiency.

Multifocal inflammatory leukoencephalopathy (MIL) is a cerebral demyelinating syndrome that develops after chemotherapy with 5-fluorouracil (5-FU) and levamisole. The authors report a patient who developed MIL after 5-FU administration not in association with levamisole. She was subsequently diagnosed with partial deficiency of dihydropyrimidine dehydrogenase, an enzyme necessary for 5-FU catabolism. The authors suggest that MIL is a direct result of 5-FU chemotherapy and that patients with dihydropyrimidine dehydrogenase deficiency are at increased risk for this and other toxic effects of 5-FU.

CT scanning and diagnosis of adrenoleukodystrophy.

On computerized tomography scanning, two patients with adrenoleukodystrophy had low-density abnormalities in the parieto-occipital lobes, which enhanced anteriorly with contrast infusion. Computerized tomographic correlation with the published pathology is discussed. CT scanning may be an important diagnostic procedure in the early diagnosis of adrenoleukodystrophy.

Clinical outcome in aggressively treated meningeal gliomatosis.

We reviewed 11 consecutive patients with an antemortem cytologic diagnosis of meningeal gliomatosis. In three patients, meningeal gliomatosis was diagnosed before surgical resection of the glioma. Three of five patients with anaplastic astrocytoma and one with oligodendroglioma improved with treatment. Patients with glioblastoma multiforme did not respond and had a median survival from the diagnosis of meningeal gliomatosis of only 8 weeks. Meningeal gliomatosis can be an early finding in gliomas. Treatment response is probably related to tumor histology and grade.

Age influences chemotherapy response in astrocytomas.

OBJECTIVE: In patients with cerebral astrocytomas treated with nitrosourea-based chemotherapy, to determine whether age is predictive of response, time to progression, survival, or rate of complications. DESIGN: Retrospective analysis of neuroimaging studies and clinical data. SETTING: University hospital with a busy neuro-oncology service. PATIENTS: One hundred forty-eight patients with pathologically confirmed malignant astrocytomas or recurrent astrocytomas. RESULTS: Partial response occurred in 39% of patients aged < 40 years, in 17% of those aged 40 to 59, and in only 5% of those aged > or = 60 (p < 0.001). Median time to progression after chemotherapy was 23 weeks in patients aged < 60 and 6 weeks in patients aged > or = 60 (p < 0.001). Median survival after chemotherapy was 43 weeks in patients aged < 60 but only 24 weeks in patients aged > or = 60 (p < 0.001). Differences between age groups in response rate, time to progression, and survival persisted with adjustment for tumor grade. The risk of myelosuppressive complications requiring hospitalization was significantly related to age (p = 0.03); such complications occurred in 35% of patients aged > or = 60 and 16% of patients under 60 years. CONCLUSION: Age is strongly predictive of the likelihood of a response to chemotherapy, time to progression, survival, and risk of myelosuppressive complications. Patients aged > or = 60 have a lower change of benefit and an increased risk of myelosuppressive complications from chemotherapy for astrocytomas compared with younger patients.

Evidence of allelic imbalance of chromosome 6 in human astrocytomas.

Transfer of human chromosome 6 can suppress the malignant phenotype of melanoma. Because of the neural ectoderm origin of melanoma and since up to 30% of gliomas have abnormalities involving chromosome 6, we performed restriction fragment length polymorphism analysis to determine the importance of allelic loss on chromosome 6 in gliomas. DNA samples from tumor and white blood cells were obtained from patients with pathologically verified gliomas. Of the 20 paired samples, there were two gangliogliomas and one grade I, four grade II, two tumors labeled "low grade," two grade III, and nine grade IV astrocytomas. DNA was hybridized with polymorphic probes D6S29 (6p21), c-myb (6q23.3-24), SOD2 (6q25), D6S37 (6q26), and ESR (6q27). All grades of tumor revealed areas of genetic loss. Allelic imbalance (AI) was present in 11 of 47 (23%) of informative loci on 6q and four of seven (57%) on 6p. Loci at 6p21 and 6q26 were most often lost. In contrast, probes from three non-chromosome 6 loci demonstrated a combined total of 11% allelic loss. Genetic loss from chromosome 6 is a frequent event in glial neoplasms.

Metastasis to the base of the skull: clinical findings in 43 patients.

We studied 43 patients with metastases to the base of the skull to determine whether clinical symptoms localized the lesions accurately. We identified five clinical syndromes: orbital, parasellar, middle fossa, jugular foramen, and occipital condyle. The orbital and parasellar syndromes were characterized by frontal headache, diplopia, and first-division trigeminal sensory loss. Proptosis occurred with the orbital but not the parasellar syndrome. The middle-fossa syndrome was characterized by facial pain or numbness. The jugular foramen syndrome was characterized by hoarseness and dysphagia, with paralysis of the ninth through eleventh cranial nerves. The occipital condyle syndrome was characterized by unilateral occipital pain and unilateral tongue paralysis.

Procarbazine chemotherapy in the treatment of recurrent malignant astrocytomas after radiation and nitrosourea failure.

The Brain Tumor Study Group has shown procarbazine (PCB) to be as effective an adjuvant treatment as 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). We treated 35 patients with recurrent malignant astrocytomas after radiation and nitrosourea failure with successive courses of PCB 150 mg/m2/d for 28 days every 8 weeks. After 2 courses, 2 patients had complete responses, 7 had partial responses, 11 had stable disease, and 15 had progression. Significantly more patients receiving PCB had complete or partial responses or stable disease than a similar group of patients in a previous trial who received intra-arterial (IA) cisplatin (DDP). There is a significant advantage in time to disease progression for those receiving PCB compared with those receiving IA diaziquone (AZQ). Our results suggest that PCB is a more effective 2nd agent than IA DDP or AZQ following radiation and nitrosourea failure.

Chemotherapy response criteria in malignant glioma.

No one has ever proven a relationship between the extent of response to chemotherapy in malignant glioma and time to progression or survival. We studied the predictive value of "imaging response" following two courses of nitrosourea-based chemotherapy in 136 patients with recurrent astrocytoma/malignant glioma. We performed image analysis by blinded side-to-side comparison of sequential studies, and categorized response into: partial response (PR) (>50% reduction), minor response (MR) (25-50% reduction), stable disease (SD) (<25% change), progressive disease (PD) (>25% increase). Patients with PR, MR, and SD did not differ with respect to time to progression (TTP) (p > 0.2) or survival (p > 0.2). Median TTP was 27 weeks for SD, 43 weeks for MR, and 30 weeks for PR. Patients with PD had a significantly reduced survival (p < 0.001). Median survival was 21 weeks for PD, 53 weeks for SD, 63 weeks for MR, and 48 weeks for PR. The lack of relationship between response and TTP may be due to early relapses in patients with response, a cytostatic benefit of chemotherapy in some patients who do not have an objective response, or a relatively favorable natural history in some tumors that do not respond to chemotherapy. Our data do not support the validity of current response grading, assessed after two courses of chemotherapy. Further research and validation of response criteria is necessary.

Acute sensory neuropathy-neuronopathy from pyridoxine overdose.

We report two patients who developed an acute, profound, and permanent sensory deficit after treatment with massive doses of parenteral pyridoxine. Aside from rapid onset, their clinical picture resembles that described in chronic pyridoxine neurotoxicity. It also is consonant with experimental models of acute pyridoxine intoxication and is probably secondary to a sensory ganglion neuronopathy. These patients also had transient autonomic dysfunction, mild weakness, nystagmus, lethargy, and respiratory depression. These previously undocumented features may be attributable to either the preservative used in the parenteral pyridoxine preparation or to the exceptionally high doses of pyridoxine these patients received.

Gangliosides GM1 and GD1b are antigens for IgM M-protein in a patient with motor neuron disease.

We studied a patient with an IgM M-protein and lower motor neuron disease to identify the antigens to which the M-protein bound. Gangliosides from peripheral nerve and spinal cord were separated by high-performance thin-layer chromatography and immunostained with the patient's serum. The serum IgM immunostained two gangliosides identified as GM1 and GD1b, and immunostaining was specific for the M-protein light chain type. IgM-binding to the two gangliosides was detectable by ELISA at serum dilutions of greater than 1:10,000, and the M-protein was selectively immunoabsorbed by liposomes containing GM1 or GD1b. The IgM M-protein also bound to asialo-GM1, indicating reactivity to the galactosyl(beta 1-3)N-acetylgalactosaminyl moiety shared by GM1, GD1b, and asialo-GM1.