Neurologists
37 years of experience
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Accepting new patients
Central Ann Arbor
University of Michigan Medical School
1500 E Medical Center Dr
Ann Arbor, MI 48109
734-936-9055
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Education ?

Medical School Score
Upstate Medical University Physical Medicine and Rehabilitation (1973)
  • Currently 2 of 4 apples

Awards & Distinctions ?

Associations
American Board of Psychiatry and Neurology

Affiliations ?

Dr. Greenberg is affiliated with 3 hospitals.

Hospital Affilations

Score

Rankings

  • University of Michigan Hospitals & Health Centers
    1500 E Medical Center Dr, Ann Arbor, MI 48109
    • Currently 4 of 4 crosses
    Top 25%
  • University of Michigan Health System
  • Vail Valley Medical Center
  • Publications & Research

    Dr. Greenberg has contributed to 61 publications.
    Title Phase Iii Randomized Study of Radiotherapy Plus Procarbazine, Lomustine, and Vincristine with or Without Budr for Treatment of Anaplastic Astrocytoma: Final Report of Rtog 9404.
    Date March 2004
    Journal International Journal of Radiation Oncology, Biology, Physics
    Excerpt

    PURPOSE: This study was an open-label, randomized Phase III trial in newly diagnosed patients with anaplastic glioma other than glioblastoma multiforme comparing external beam radiotherapy (EBRT) plus adjuvant procarbazine, cyclohexylchloroethylnitrosurea (lomustine), and vincristine (PCV) chemotherapy with or without bromodeoxyuridine (BUdR) given as a 96-h infusion each week of RT. METHODS AND MATERIALS: Only patients 18 years or older with newly diagnosed anaplastic glioma were eligible. A central pathology review was accomplished for most patients, but was not mandated before registration. The study had initially opened as a Northern California Oncology Group trial in 1991, becoming an Intergroup Radiation Therapy Oncology Group (RTOG), Southwestern Oncology Group and the North Central Cancer Treatment Group study in July 1994. A total accrual of 293 patients was planned for the sample size, using survival as the primary end point. The experimental arm (RT/BUdR + PCV) was to be compared with the control arm (RT + PCV) using a one-sided alpha = 0.05, with a power of 85% for detecting an increase in median survival from 160 to 240 weeks, assuming a 3-year follow-up after enrollment completion. RESULTS: Between July 1994 and August 1996, 134 patients were randomized to EBRT + PCV (non-BUdR patients) and 134 to EBRT/BUdR + PCV (BUdR patients). The study was closed before the full-anticipated accrual on the basis of an interim analysis that predicted no survival benefit for the BUdR arm. Of the 268 patients, 41 and 37, respectively, were ineligible or canceled primarily on the basis of the central pathology review findings. Thus, 93 patients and 97 patients were eligible/analyzable in the non-BUdR and BUdR arms, respectively. Patient characteristics were well balanced in both arms, with most <50 years old and in the RTOG recursive partitioning analysis (RPA) Class I category. The minimal potential follow-up was 4.6 years. The median survival for non-BUdR patients was 4.1 years compared with 4.6 years for the BUdR patients (p = 0.61). The 4-year overall survival rate was 51% in both arms. For RPA Class I patients (the best prognostic class), the median survival had not been reached for non-BUdR patients (4-year survival rate 61%) and was 5.6 years for BUdR patients (4-year survival rate 64%; p = 0.91). Each arm was also compared with the RTOG historical database for RPA Class I patients with no statistically significant difference found in overall survival (BUdR vs. historical, p = 0.31 and non-BUdR vs. historical, p = 0.48). Grade 4 toxicity occurred in 15 and 17 patients in the non-BUdR and BUdR arms, respectively, with one treatment-related death in the BUdR group. CONCLUSION: No survival advantage was noted by adding BUdR to EBRT and PCV in this patient population

    Title Phase 2 Study of Bcnu and Temozolomide for Recurrent Glioblastoma Multiforme: North American Brain Tumor Consortium Study.
    Date March 2004
    Journal Neuro-oncology
    Excerpt

    The purpose of this study was to evaluate the activity, measured in terms of progression-free survival (PFS) and response rates, of 1,3-bis(chloro-ethyl)-1-nitrosourea (BCNU) plus temozolomide in adult patients with recurrent glioblastoma multiforme. The phase 2 dose and schedule for this trial was BCNU 150 mg/m(2) i.v. followed in 2 h by temozolomide 550 mg/m(2) as a single oral dose. Treatment was repeated every 6 weeks for up to 8 cycles unless tumor progression was documented. The primary end point was PFS at 6 months (PFS-6). Response was a secondary end point, measured by MR imaging, neurological status, and steroid requirements prior to each 6-week cycle. The median age of eligible patients was 53, and 89.5% had no prior chemotherapy. All patients were evaluable for toxicity and time to progression. The PFS-6 was 21%. Overall survival was 68% at 6 months and 26% at 1 year. The MRI response for 36 patients was 2 partial responses, 2 minor responses, 19 cases of stable disease, and 13 immediate progressions. Median survival was 34 weeks, and median PFS was 11 weeks. Toxicity was primarily myelosuppression; no toxic deaths occurred. Historical phase 2 study data in this patient population show a PFS-6 of 15%. Recent data for use of temozolomide alone have shown a PFS-6 of 21%. We conclude that BCNU plus temozolomide when used in these doses and schedule has only modest activity, with significant toxicity, and appears to be no more effective than single-agent temozolomide.

    Title Phase 1 Trial of Irinotecan (cpt-11) in Patients with Recurrent Malignant Glioma: a North American Brain Tumor Consortium Study.
    Date March 2004
    Journal Neuro-oncology
    Excerpt

    This study was conducted to determine the maximum tolerated dose and dose-limiting toxicity of irinotecan (CPT-11) administered every 3 weeks to adults with progressive malignant glioma who were treated with enzyme inducing antiepileptic drug (EIAED) therapy, and to compare the pharmacokinetics with those in patients not on EIAED therapy treated at the recommended phase 2 dose for other cancers. The CPT-11 dose was 350 mg/m(2) i.v. every 3 weeks and remained fixed in patients not on EIAED therapy, but the dose was escalated by 50-mg/m(2) increments in patients on EIAED therapy. CPT-11 and its metabolites SN-38, SN-38 glucuronide (SN-38G), and APC (7-ethyl-10[4-N-(5 aminopentanoic acid)-1-piperidine]-carbonyloxycamptothecin) were characterized in both groups. Patients on EIAEDs received 350 to 800 mg/m(2) of CPT-11. Dose-limiting toxicity was due to grade 3 diarrhea despite maximal doses of loperamide. The systemic levels of CPT-11, APC, SN-38G, and SN-38 were all lower in the EIAED group. There was a moderate-to-fair relationship between CPT-11 dose and the area under the curve (AUC) for CPT-11 and APC over the 2, but no relationship dosage range of 350 to 800 mg/m between CPT-11 dose and the AUC for SN-38 or SN-38G. At the 750-mg/m(2) dose, the AUC for CPT-11 (21.6 microg x h/ml) matched the AUC (21.6 microg x h/ml) in the non-EIAED group treated with 350 mg/m(2) of CPT-11. We conclude that the recommended phase 2 dose of CPT-11 for patients on EIAEDs is 750 mg/m(2) when given every 3 weeks. A phase 2 study of patients with recurrent malignant glioma is ongoing to assess the efficacy of CPT-11 when the dose is stratified according to the use of EIAEDs.

    Title Survival and Failure Patterns of High-grade Gliomas After Three-dimensional Conformal Radiotherapy.
    Date April 2002
    Journal Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
    Excerpt

    PURPOSE: The goal of three-dimensional (3-D) conformal radiation is to increase the dose delivered to tumor while minimizing dose to surrounding normal brain. Previously it has been shown that even escalated doses of 70 to 80 Gy have failure patterns that are predominantly local. This article describes the failure patterns and survival seen with high-grade gliomas given 90 Gy using a 3-D conformal intensity-modulated radiation technique. PATIENTS AND METHODS: From April 1996 to April 1999, 34 patients with supratentorial high-grade gliomas were treated to 90 Gy. For those that recurred, failure patterns were defined in terms of percentage of recurrent tumor located within the high-dose region. Recurrences with more than 95% of their volume within the high-dose region were considered central; those with 80% to 95%, 20% to 80%, and less than 20% were considered in-field, marginal, and distant, respectively. RESULTS: The median age was 55 years, and median follow-up was 11.7 months. At time of analysis, 23 (67.6%) of 34 patients had developed radiographic evidence of recurrence. The patterns of failure were 18 (78%) of 23 central, three (13%) of 23 in-field, two (9%) of 23 marginal, and zero (0%) of 23 distant. The median survival was 11.7 months, with 1-year survival of 47.1% and 2-year survival of 12.9%. No significant treatment toxicities were observed. CONCLUSION: Despite dose escalation to 90 Gy, the predominant failure pattern in high-grade gliomas remains local. This suggests that close margins used in highly conformal treatments do not increase the risk of marginal or distant recurrences. Our results indicate that intensification of local radiotherapy with dose escalation is feasible and deserves further evaluation for high-grade gliomas.

    Title Adult Medulloblastoma: Multiagent Chemotherapy.
    Date May 2001
    Journal Neuro-oncology
    Excerpt

    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.

    Title Diffusion Magnetic Resonance Imaging: an Early Surrogate Marker of Therapeutic Efficacy in Brain Tumors.
    Date May 2001
    Journal Journal of the National Cancer Institute
    Excerpt

    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.

    Title Intrathecal Treatment of Neoplastic Meningitis Due to Breast Cancer with a Slow-release Formulation of Cytarabine.
    Date March 2001
    Journal British Journal of Cancer
    Excerpt

    DepoCyte is a slow-release formulation of cytarabine designed for intrathecal administration. The goal of this multi-centre cohort study was to determine the safety and efficacy of DepoCyte for the intrathecal treatment of neoplastic meningitis due to breast cancer. DepoCyte 50 mg was injected once every 2 weeks for one month of induction therapy; responding patients were treated with an additional 3 months of consolidation therapy. All patients had metastatic breast cancer and a positive CSF cytology or neurologic findings characteristic of neoplastic meningitis. The median number of DepoCyte doses was 3, and 85% of patients completed the planned 1 month induction. Median follow up is currently 19 months. The primary endpoint was response, defined as conversion of the CSF cytology from positive to negative at all sites known to be positive, and the absence of neurologic progression at the time the cytologic conversion was documented. The response rate among the 43 evaluable patients was 28% (CI 95%: 14-41%); the intent-to-treat response rate was 21% (CI 95%: 12-34%). Median time to neurologic progression was 49 days (range 1-515(+)); median survival was 88 days (range 1-515(+)), and 1 year survival is projected to be 19%. The major adverse events were headache and arachnoiditis. When drug-related, these were largely of low grade, transient and reversible. Headache occurred on 11% of cycles; 90% were grade 1 or 2. Arachnoiditis occurred on 19% of cycles; 88% were grade 1 or 2. DepoCyte demonstrated activity in neoplastic meningitis due to breast cancer that is comparable to results reported with conventional intrathecal agents. However, this activity was achieved with one fourth as many intrathecal injections as typically required in conventional therapy. The every 2 week dose schedule is a major advantage for both patients and physicians.

    Title A Phase 3 Randomized Study of Radiotherapy Plus Procarbazine, Ccnu, and Vincristine (pcv) with or Without Budr for the Treatment of Anaplastic Astrocytoma: a Preliminary Report of Rtog 9404.
    Date January 2000
    Journal International Journal of Radiation Oncology, Biology, Physics
    Excerpt

    PURPOSE: This study was an open label, randomized Phase 3 trial in newly diagnosed patients with anaplastic glioma comparing radiotherapy plus adjuvant procarbazine, CCNU, and vincristine (PCV) chemotherapy with or without bromodeoxyuridine (BUdR) given as a 96-hour infusion each week of radiotherapy. METHODS AND MATERIALS: Only patients 18 years or older with newly diagnosed anaplastic glioma were eligible; central pathology review was accomplished, but was not mandated prior to registration. The study had initially opened as a Northern California Oncology Group (NCOG) trial in 1991, becoming an Intergroup RTOG, SWOG, and NCCTG study in July 1994. Total accrual of 293 patients was planned as the sample size, using survival and time to tumor progression as the primary endpoints. The experiment arm (RT/BUdR plus PCV) was to be compared to the control arm (RT plus PCV) using an alpha = 0.05, one-tailed, with a power of 85% for detecting an increase in median survival from 160 to 240 weeks, assuming a 3-year follow-up after completion of enrollment. RESULTS: As of July 1996, 281 patients had been randomized; 53 (20%) were ineligible, primarily based upon central pathology review, and another 39 cases were canceled. In total, 30% of cases were excluded from analysis. The treatment arms were well balanced despite this rate of exclusion. The RTOG Data Monitoring Committee recommended suspension of enrollment in July 1996 based upon a stochastic curtailment analysis which strongly suggested that the addition of BUdR would not be associated with increased survival. In February 1997, the study was closed prior to full enrollment. At that time, the 1-year survival estimates were 82% versus 68% for RT plus PCV and RT/BUdR plus PCV respectively (one-sided, p = 0.96). The conditional power analysis indicated that even with an additional 12 months of additional accrual and follow-up the probability of detecting the prespecified difference was less than 0.01%. The differences in the two arms seem to be due to early deaths in the BUdR arm, not related to toxicity of the treatment. CONCLUSIONS: Despite encouraging Phase 2 results with BUdR, it is unlikely that a survival benefit will be seen. A final study analysis will not be done for at least 3 more years.

    Title Correlation of Intraluminal Thrombosis in Brain Tumor Vessels with Postoperative Thrombotic Complications: a Preliminary Report.
    Date August 1998
    Journal Journal of Neurosurgery
    Excerpt

    OBJECT: Thrombotic complications (deep vein thrombosis and/or pulmonary embolization [DVT/PE]) occur in 18 to 50% of patients harboring brain tumors who undergo neurosurgical procedures. Such patients are at risk for DVT/PE because of immobility, paresis, hypovolemia, and lengthy surgery. The present study was undertaken to see whether tumor patients at highest risk for DVT/PE could be identified so that augmentation of prophylactic measures might be used to reduce the incidence of thrombotic complications. METHODS: The authors conducted a retrospective analysis of 488 patients enrolled in their brain tumor registries between 1988 and 1995, identifying 57 patients (12%) with recorded symptomatic DVT, PE, or both postoperatively. In 24 of these 57 cases histological specimens were retrievable for review, allowing an in-depth analysis. Forty-five patients were lost to follow-up review, and the remaining 386 patients had no record of systemic thrombosis. Slides of pathological specimens were retrievable in 50 cases in which there was no DVT/PE. From these 50 cases, 25 were selected at random to represent the control group by a blinded observer. Seventeen (71%) of the 24 brain tumor specimens obtained in patients with DVT/PE stained positively for intraluminal thrombosis (ILT) after hematoxylin and eosin had been applied. The odds ratio associated with the presence of ILT was 17.8, with a confidence interval ranging from 4 to 79.3. No evidence of ILT was found in 22 patients (88%) within the control group (p < 0.0001, Fisher's exact test). Other factors that may predispose patients with brain tumors to DVT/PE-limb paresis, extent of tumor removal, and duration of the surgery-were also analyzed and found not to be statistically significant. Therefore, these factors were not the basis for differences seen between the study and control groups. CONCLUSIONS: These preliminary observations suggest that the presence of ILT within malignant glioma or glioblastoma tumor vessels may represent a marker of tumor-induced hypercoagulability.

    Title Local Recurrence of Breast Cancer After Cytological Evaluation of Lumpectomy Margins.
    Date June 1998
    Journal The American Surgeon
    Excerpt

    Successful breast conservation therapy with optimal cosmesis requires adequate tumor excision and negative tumor margins. Therefore, more sensitive techniques are being developed to identify lumpectomy margins intraoperatively with greater accuracy. Unidentified microscopic disease is seemingly responsible for a local recurrence rate of up to 25 per cent 3 to 5 years after lumpectomy and radiotherapy for breast cancer patients. As a result, Moffitt Cancer Center has routinely used an intraoperative touch preparation cytology (TPC) protocol to evaluate the entire resected surface of all lumpectomies. In addition, resection margins were also evaluated by gross examination and by standard histology. In rare instances frozen sections were used to evaluate tumor margins. In this study 701 consecutive lumpectomy specimens were evaluated by TPC during the period of 9 years with a mean follow-up of 3.5 years. Local cancer recurrence was 2.7 per cent (mean recurrence, 2.53 years), in women whose lumpectomy margins were evaluated by TPC. Of interest, a local recurrence rate of 14.6 per cent was observed in patients who had referral lumpectomies evaluated by conventional histopathology. This study suggests that accurate margin assessment with TPC plays an important role in the control of local recurrence after breast conservation therapy. Therefore, we conclude the routine use of intraoperative TPC provides rapid, reliable, topographically accurate identification of residual microscopic disease at lumpectomy margins.

    Title Results of Re-irradiation of Primary Intracranial Neoplasms with Three-dimensional Conformal Therapy.
    Date September 1997
    Journal American Journal of Clinical Oncology
    Excerpt

    We evaluated the potential of three-dimensional conformal therapy for re-irradiation of selected intracranial neoplasms and reviewed the retreatment of 20 patients at the University of Michigan between May 1988 and August 1991. All patients had previously undergone a full course of external beam radiotherapy (RT) to a median dose of 5,940 cGy (range 5,100-6,500 cGy), including five whole brain treatments. All recurrences were unsuitable for brachytherapy or radiosurgery. Various histologies were retreated, including 14 high-grade gliomas. Median time to re-irradiation was 38 months (range 9 months to 19 years, 6 months). RT was delivered with complex plans designed using fully integrated computed tomography/magnetic resonance imaging (CT/ MRI) tumor volume information, and regions of previous parenchymal treatment were avoided if possible. Composite (initial+retreatment) dose-volume histograms (DVH) of dose to nontarget brain allowed comparison of alternative plans to select beam orientations which minimized normal brain irradiation. Mean target dose of re-irradiation was 3,600 cGy (range 3,060-5,940 cGy). Total cumulative dose ranged from 8,060 to 11,940 cGy. Median survival was 9 months, and 1-year actuarial survival was 26%. After retreatment, 8 of 12 patients (67%) had steroid dose decrement and neurologic improvement at 4-48 months (median duration 14 months). Radiographic regression or stabilization of disease was noted in 11 of 16 patients (68%). Re-irradiation with highly conformal three-dimensional planning provides frequent clinical improvement with acceptable morbidity and should be considered in selected patients with recurrent intracranial neoplasms.

    Title 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.
    Date August 1997
    Journal Journal of Neuropathology and Experimental Neurology
    Excerpt

    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.

    Title Chemotherapy Response Criteria in Malignant Glioma.
    Date June 1997
    Journal Neurology
    Excerpt

    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.

    Title Age Influences Chemotherapy Response in Astrocytomas.
    Date June 1995
    Journal Neurology
    Excerpt

    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.

    Title Low Grade Gliomas: Preliminary Analysis of Failure Patterns Among Patients Treated Using 3d Conformal External Beam Irradiation.
    Date March 1995
    Journal International Journal of Radiation Oncology, Biology, Physics
    Excerpt

    PURPOSE: The pattern of failure of low grade gliomas following radiotherapy is less well known than that of the high grade gliomas. Stereotactic histologic studies have suggested that tumor cells extend beyond imaging abnormalities, and that large margins would be required for radiotherapy target volumes to encompass all of the neoplasm. Our experience using computerized tomography (CT)- and magnetic resonance (MR)-planned irradiation of low grade gliomas was reviewed to determine the pattern of tumor recurrence, in an effort to clinically define the minimum margin required. METHODS AND MATERIALS: Forty-six patients with low grade supratentorial gliomas were treated between April 1985 and November 1992 using three-dimensional (3D) conformal CT- or MR-planned external beam radiotherapy. Fields were designed to encompass a target volume created by adding a margin to the tumor in three dimensions. Generally, patients were treated using shrinking fields with an initial target (tumor plus a 1 to 3 cm margin) treated to a dose of 45 to 50.4 (median 50.4) Gy, and a boost (tumor plus a 0 to 2 cm margin) treated to a total of 54 to 59.4 (median 59.4) Gy. Median follow-up was 32.9 months. RESULTS: There have been 11 failures; all of these occurred within the radiographic abnormality (either T2 prolongation or CT hypodensity) visualized at the time of treatment planning (i.e., all failures were within the boost volume). Median time to failure was 53 months. Because all failures were local, there was no relationship between the amount by which the tumor volumes were expanded to create target volumes and the eventual outcome. CONCLUSION: Despite pathologic data suggesting that low grade glioma cells can be found outside the MR T2-signal abnormality in many cases, our results demonstrate that conformal external beam radiotherapy, in which the high dose volume is limited, does not result in increased marginal or out-of-field failures. Until control of tumor within the radiographically abnormal volume can be achieved, the need for large fields to treat prophylactically microscopic disease beyond the visualized tumor volume is questionable. The use of conformal fields might be associated with reduced toxicity, and thereby allow delivery of higher total doses to the central tumor.

    Title Metastatic Epidural Spinal Cord Compression: Current Concepts and Treatment.
    Date February 1995
    Journal Journal of Neuro-oncology
    Excerpt

    Metastatic epidural spinal cord compression (MESCC) is a medical emergency complicating the course of 5-10% of patients with cancer [1]. When diagnosis and treatment is early with the patient ambulatory prognosis for continued ambulation is good [2]. If the patient is nonambulatory or paraplegic, prognosis for meaningful recovery of motor and bladder function is markedly decreased. In the last decade, significant advances in the understanding, management and treatment of metastatic epidural spinal cord compression have occurred. Recent pathophysiological and pharmacological animals studies have afforded insights into disease mechanisms [3-9]. The audit of standard methods of investigation and magnetic resonance imaging have resulted in revision of guidelines for patient evaluation [10-17]. Finally, new surgical philosophies and technical advances have generated interest and controversy [18-25]. With improved clinical awareness, new imaging modalities will help us diagnose epidural spinal cord compression earlier and institute appropriate treatment.

    Title Bromodeoxyuridine-mediated Radiosensitization in Human Glioma: the Effect of Concentration, Duration, and Fluoropyrimidine Modulation.
    Date November 1994
    Journal International Journal of Radiation Oncology, Biology, Physics
    Excerpt

    PURPOSE: To define the relative influence of duration of exposure, concentration, and modulation by fluorodeoxyuridines (FdUrd) on the incorporation of 5-bromo-2-deoxyuridine (BrdUrd) into DNA of a human malignant glioma line (D-54) in vitro and in vivo. MATERIALS AND METHODS: In vitro studies: an established human malignant glioma line (D-54) was exposed to a clinically achievable concentration of BrdUrd to model intravenous (1 microM BrdUrd) and intraarterial (4 microM BrdUrd) conditions. The influence of modulation was assessed using 1 nM FdUrd. Incorporation of BrdUrd, radiosensitization, and cytotoxicity were determined after 24, 72, and 120 h drug exposures. In Vivo studies: nude mice bearing D-54 xenografts were infused with BrdUrd at 100 mg/kg/day for 7 and 14 days or BrdUrd at 400 mg/kg/day for 5 days. The influence of modulation was assessed by combining 100 mg/kg/day of BrdUrd with 0.1, 0.3, and 1 mg/kg/day FdUrd for 7 days. Incorporation of BrdUrd into the DNA of tumor, gut, and marrow were determined. RESULTS: In Vitro: thymidine replacement and radiosensitization were a function of concentration, and incorporation began to plateau after 2 to 3 population doublings. Modulation with 1 nM FdUrd significantly increased incorporation. Radiosensitization was a linear function of thymidine replacement under all conditions tested. In Vivo: infusion with 400 mg/kg/day for 5 days resulted in greater tumor incorporation (10.3 +/- 0.4% thymidine replaced) than treatment with 100 mg/kg/day for 14 days (6.0 +/- 0.6% of thymidine replaced). Infusion of FdUrd with BrdUrd increased normal tissue incorporation of BrdUrd, but failed to increase BrdUrd incorporation in tumor cells. CONCLUSION: These results suggest that relatively short, high dose rate infusions may be preferable to long, low dose rate infusions. The potential benefit of FdUrd modulation demonstrated in vitro may be difficult to realize using continuous systemic infusions.

    Title Radiosensitization with Carotid Intra-arterial Bromodeoxyuridine +/- 5-fluorouracil Biomodulation for Malignant Gliomas.
    Date October 1994
    Journal Neurology
    Excerpt

    Bromodeoxyuridine (BUdR), a nonhypoxic radiosensitizing drug, is a halogenated pyrimidine analog that is incorporated into the DNA of dividing cells in a competitive process with thymidine. BUdR sensitizes cells to radiation therapy. 5-Fluorouracil (5-FU) inhibits the endogenous synthesis of thymidine, resulting in increased incorporation of the BUdR. Neurons and glial cells have a very low mitotic rate; they will not incorporate BUdR and will not be sensitized. BUdR and 5-FU are best delivered intra-arterially (IA) because of their regional advantage. We infused BUdR +/- 5-FU over 8 1/2 weeks, before and during 59.4-Gy focal conformal external beam radiation therapy, through a permanently implanted pump with a catheter placed retrograde through the external carotid artery to the carotid bifurcation. Sixty-two patients with grades III or IV glioma were entered into one of two trials, with 23 patients receiving BUdR alone and 39 patients receiving BUdR + 5-FU. The maximum tolerated dose (MTD) of BUdR alone was 400 mg/m2/d for 8 1/2 weeks. The Kaplan-Meier median survival (KMS) was 20 months. In the BUdR + 5-FU trial, the MTD of BUdR was also 400 mg/m2/d and 5-FU was 5 mg/m2/d with a KMS of 17 months. The KMS of all 62 patients in both trials 1 and 2 was 18 months. Pathologic grading used both the original World Health Organization (WHO) and 1993 modified WHO systems. The KMS of grade IV patients was 13.8 months (48 patients) with the original system and 17 months (58 patients) with the modified system.(ABSTRACT TRUNCATED AT 250 WORDS)

    Title Evidence of Allelic Imbalance of Chromosome 6 in Human Astrocytomas.
    Date April 1994
    Journal Neurology
    Excerpt

    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.

    Title Short-term Effects of Smoking Marijuana on Balance in Patients with Multiple Sclerosis and Normal Volunteers.
    Date April 1994
    Journal Clinical Pharmacology and Therapeutics
    Excerpt

    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.

    Title Comparison Between Bcnu and Procarbazine Chemotherapy for Treatment of Gliomas.
    Date September 1993
    Journal Journal of Neuro-oncology
    Excerpt

    We compared sequential single-agent BCNU and procarbazine (PCB) chemotherapy in 31 patients with gliomas [grade IV (10), grade III (15), grade II (6)]. Patients had failed surgical biopsy +/- resection and radiation therapy. All patients were treated initially with BCNU 150-300 mg/m2 by intra-arterial or intravenous route every 6 weeks. After CT evidence of tumor progression, all patients received PCB 150 mg/m2/day for 28 days every 8 weeks. Patient responses to BCNU were CR (0), PR (7), SD (12), progression (12), and to PCB CR (2), PR (9), SD (6), and progression (14). Kaplan-Meier estimates of median time to failure for all patients were shorter for BCNU, 5.0 months (range 1.5-20), than for PCB, 6.0 months (range 2-50+). There was a statistically significant difference (Mantel-Cox test, p = 0.02) in the distribution of time to disease progression between the two drugs, especially for grade III tumors (p = 0.02). The cumulative proportion of patients without disease progression at 6 months was 26% while on BCNU, compared to 48% while on PCB; at 12 months the cumulative proportions were 3% for BCNU compared to 35% for PCB. Although there was no formal washout period between administration of the two drugs, no carryover effect was evident. These data provide further evidence that PCB has significant activity against malignant glioma and may, in fact, be more effective than BCNU.

    Title Halogenated Pyrimidine Sensitization of Low Dose Rate Irradiation in Human Malignant Glioma.
    Date August 1993
    Journal International Journal of Radiation Oncology, Biology, Physics
    Excerpt

    PURPOSE: To determine the potential advantage of combining halogenated pyrimidine radiosensitization and continuous low dose rate irradiation in human malignant glioma. METHODS AND MATERIALS: An established glioma line (U-251) was incubated with 5-bromo-2-doxyuridine (BrdUrd) at clinically achievable concentrations at three dose rates of interest--100 cGy/min (typical of external beam therapy), 43 cGy/hr (typical of temporary afterloaded implants), and 12 cGy/hr (typical of permanent implants). RESULTS: After exposure to 1 microM BrdUrd, the greatest enhancement ratio was seen at the 12 cGy/hr dose rate, implying a BrdUrd induced inverse dose rate effect independent of a G2M block. Under these conditions, the mean inactivation dose after 1 microM BrdUrd exposure was equivalent for 100 cGy/min and 12 cGy/hr. CONCLUSION: These results support the use of halopyrimidines as sensitizers of temporary afterloaded and permanent implants.

    Title Metastatic Epidural Spinal Cord Compression.
    Date February 1992
    Journal Neurologic Clinics
    Excerpt

    It is important to remember that ESCC is a complication of systemic malignancy and usually denotes disseminated disease with poor survival rates. Early diagnosis is crucial. The initial symptom is almost always back pain, which is local, radicular, or both. Following neurologic examination and radiography, MRI scanning or myelography/CT is immediately indicated if radiculopathy or myelopathy is present or if the radiographs of the spine are abnormal. In cancer patients with local back pain and normal findings on neurologic examination and radiography of the spine, there is still a probability of 0.1 of significant ESCC. Therefore, urgent CT/MRI scanning is justified. At present, the best treatment for ESCC remains unknown. In the majority of patients, radiotherapy is the most readily available and appropriate option because it is equal in effect to posterior decompressive laminectomy in both radiosensitive and radioresistant tumors. In patients with posterior epidural disease without tissue diagnosis, laminectomy with or without stabilization should be performed. Posterior decompressive laminectomy alone is contraindicated in patients with vertebral collapse. In selected instances of anterior epidural compression without tissue diagnosis or after failure of radiotherapy, an anterior surgical approach or synchronous vertebral decompression with posterior stabilization may be indicated. In the future, after appropriate clinical trials, vertebral body resection may be the optimal approach in de novo selected patients with ESCC with radioresistant tumors and limited systemic spread of the disease.

    Title Protracted Lhermitte's Sign Following Head and Neck Irradiation.
    Date January 1992
    Journal Archives of Otolaryngology--head & Neck Surgery
    Excerpt

    Lhermitte's sign is a rare complication of head and neck irradiation involving the delivery of dose to the cervical spinal cord. Although uncommon, symptoms of lightning-like electric sensations spreading into both arms, down the dorsal spine, and into both legs on neck flexion following head and neck irradiation, causes great concern in both the patient and the physician. This spontaneously reversible phenomenon is important for the otolaryngologist and radiation oncologist to recognize and discuss. A particularly severe and protracted case of Lhermitte's sign involving a patient recently completing a radical course of radiation for nasopharyngeal carcinoma is described in detail, including a review of the literature surrounding the cause and management of this condition.

    Title Malignant Astrocytomas: Focal Tumor Recurrence After Focal External Beam Radiation Therapy.
    Date October 1991
    Journal Journal of Neurosurgery
    Excerpt

    Hochberg and Pruitt have reported glioblastomas recurring within 2 cm of the primary site in 90% of patients after whole-brain radiation therapy. They suggested that computerized tomography (CT) scan accuracy would permit smaller radiation fields. A treatment protocol with smaller-field focal brain irradiation following surgical resection is reported. The first 4500 cGy of radiation is focused to within a 3-cm margin around the tumor, with a 1500-cGy boost within a 1.5-cm margin. Forty-two patients with grade III or IV astrocytoma, treated with focal brain radiation therapy were reviewed retrospectively to assess patterns of tumor recurrence. Thirty patients received intra-arterial bromodeoxyuridine (BUdR) radiosensitization with focal brain radiation therapy, and 12 patients underwent conventional focal brain radiation therapy. Tumor margin was defined on preoperative and recurrence CT scans as the contrast-enhanced area; these were traced on acetate templates and compared with each other and with the actual scans. In all 42 patients, the lesion recurred within a 2-cm margin of the original tumor. Four patients had two recurrent areas: the second area was within the 2-cm margin in two, and outside this margin in two. These results are similar to those of Hochberg and Pruitt. It is suggested that focal irradiation is now the optimal treatment for malignant astrocytoma. Since recurrences continue to be within the irradiated volumes, it appears that higher focal doses of radiation are appropriate for clinical treatment trials of malignant astrocytomas.

    Title Three-dimensional Treatment Planning of Astrocytomas: a Dosimetric Study of Cerebral Irradiation.
    Date July 1991
    Journal International Journal of Radiation Oncology, Biology, Physics
    Excerpt

    To demonstrate that 3-dimensional planning is both practical and applicable to the treatment of high-grade astrocytomas, 50 patients over a 2-year period have received cerebral irradiation delivered in focussed, non-axial techniques employing from 2 to 5 beams. Astrocytomas have been planned using rapid, practical incorporation of CT data to define appropriate tumor volumes. Tumor + 3.0 cm and tumor + 1.5 cm volumes have been treated to conventional doses of 4500 cGy and 5940 cGy, respectively, using beam orientations that maximally spared normal remaining parenchyma. Analyses of 3-dimensionally calculated plans have been performed using integral dose-volume histograms (DVH) to help select treatment techniques. Using identical CT-based volumetric data as input for generation of Beam's Eye View (BEV) designed blocks, DVH curves demonstrate dosimetric advantages of non-axial techniques over conventional parallel-opposed orientations. Assessment of the non-axial techniques in selected cases indicates that uniform target volume coverage could be maintained with a typical reduction of 30% in the total amount of brain tissue treated to high dose (95% isodose line).

    Title Variability of 5-bromo-2'-deoxyuridine Incorporation into Dna of Human Glioma Cell Lines and Modulation with Fluoropyrimidines.
    Date February 1991
    Journal Cancer Research
    Excerpt

    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.

    Title Procarbazine Chemotherapy in the Treatment of Recurrent Malignant Astrocytomas After Radiation and Nitrosourea Failure.
    Date December 1990
    Journal Neurology
    Excerpt

    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.

    Title Random Sampling by Glitter Drop Method.
    Date March 1990
    Journal Life Sciences
    Excerpt

    In the course of a study on glioblastoma tissue and cultured cell lines, a glitter drop technique for random sampling was introduced (1). Here, we report the initial description of the details of this procedure and its application to cell counts from explant slides and to determining bromodeoxyuridine (BUdR) labeling indices (LI) in tissues. The method is without bias, easy to perform and takes only a short time. It compares well with three other generally used random sampling procedures.

    Title Nuclear Parameters As Prognostic Indicators in Glioblastoma Patients.
    Date February 1990
    Journal Journal of Neuropathology and Experimental Neurology
    Excerpt

    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.

    Title Mucocutaneous Complications of Intraarterial 5-bromodeoxyuridine and Radiation.
    Date January 1990
    Journal Journal of the American Academy of Dermatology
    Excerpt

    5-Bromodeoxyuridine (BUDR), a halopyrimidine thymidine analogue, is incorporated into the DNA of dividing cells and causes photoradiosensitization. Twenty-five patients with malignant astrocytomas were treated with continuous intracarotid BUDR radiosensitization and radiotherapy for 8 1/2 weeks. Unique dose-limiting mucocutaneous complications were encountered. Ipsilateral facial dermatitis with epilation of eyebrows and eyelashes, ocular irritation, and bilateral nail dystrophy developed in all patients. Less common reactions included oral ulceration in six patients, body exanthem on the trunk in five, and atypical erythema multiforme major in one.

    Title Intra-arterial Cisplatin for the Treatment of Malignant Gliomas.
    Date August 1989
    Journal Journal of Neuro-oncology
    Excerpt

    Cisplatin (DDP) is a chemotherapeutic agent that has shown efficacy against primary CNS malignancies. Intra-arterial (IA) administration of DDP to patients with brain tumors should produce higher peak levels of drug than intravenous (IV) administration of an identical dose and reduce systemic toxicity. Twelve patients with malignant glioma were entered into the study. All had failed irradiation, 11 had failed IA BCNU. Each patient received IA DDP, 58-100 mg/m2, into the internal carotid artery at four to six week intervals. One of 12 patients had a partial response of 6 months. The remaining 11 patients had progressive disease or severe complications. Toxicity included seizures in four patients, weakness and/or aphasia in four patients, coma in two patients, and visual deterioration in two patients. IA DDP has very limited efficacy in patients with malignant gliomas after failure of nitrosoureas and is associated with an unacceptable level of toxicity. IA DDP may be more effective when used as initial chemotherapy of malignant gliomas.

    Title Variance in Ldh Isozyme Patterns in a Chinese Hamster (cricetulus Griseus) Colony.
    Date July 1989
    Journal Comparative Biochemistry and Physiology. B, Comparative Biochemistry
    Excerpt

    1. LDH activity and isozyme pattern were examined in the liver and epididymal fat pad of animals in 12 different sublines of the Upjohn Chinese hamster colony, which was established to produce animals with spontaneous diabetes. 2. Considerable divergence was observed and the animals could be divided into 3 groups according to LDH-H activity. Each group was significantly different from the other in epididymal fat pad LDH-1, 2,3 and 5 and liver LDH-3, 4 and 5. 3. The variance in LDH isozyme pattern bore no relationship to the state of diabetes but appeared to arise from other genetic determinants. However, within a single subline, a significant correlation between blood sugar and epididymal fat pad LDH-5 was observed.

    Title Psychologic Functioning in 8- to 16-year-old Cancer Survivors and Their Parents.
    Date April 1989
    Journal The Journal of Pediatrics
    Excerpt

    This study presents data on psychologic adjustment (self-concept, depression, locus of control, family environment, and parental distress) for a sample of 8- to 16-year-old long-term cancer survivors (n = 138) and their mothers, and for a sample consisting of a matched group of healthy children (n = 92) and their mothers. The null hypothesis of no group differences between survivors and control subjects was tested with respect to these variables. It was hypothesized that survivors with severe late effects would have poorer self-concepts, a more external locus of control, and more depressive symptoms than children with no or mild-to-moderate late effects. The children completed the Piers-Harris Self-Concept Scale, the Nowicki-Strickland Locus of Control Scale, and the Children's Depression Inventory. Mothers completed the Family Environment Scale and the Derogatis Stress Profile. The majority of former patients are functioning within normative limits on these standardized measures, although their scores were lower than those in the comparison group. One-way analyses of variance on the dependent measures indicate that the children with severe medical late effects have a poorer total self-concept, more depressive symptoms, and a more external locus of control than those with no or mild-to-moderate late effects. Therapies for childhood cancer are now well standardized and many long-term deleterious effects are known, so children at risk can be identified readily and steps taken early in treatment to prevent or mitigate future psychologic problems.

    Title Intra-arterial 5-bromo-2-deoxyuridine (budr) Radiosensitization with External Beam Radiation in Rhesus Monkeys: Toxicity Study.
    Date March 1989
    Journal Journal of Neuro-oncology
    Excerpt

    A primate toxicity study was performed to test the hypothesis that BUdR does not increase the likelihood of unilateral or bilateral central nervous system damage secondary to radiation therapy. BUdR, a halogenated pyrimidine analog is incorporated into DNA of dividing cells and sensitizes them to radiation. It is best given unilaterally, intra-arterially by continuous infusion because of its regional advantage (Rd) estimated to be between 11 and 16. Six rhesus monkeys were implanted with a Model 400 Infusaid pump perfusing the right internal carotid artery. Three of the six monkeys received intra-arterial (IA) BUdR infusion plus whole brain external beam radiation (6,000 R over 6 weeks) and three received radiation alone. The two BUdR treated animals completing radiation developed symmetric bilateral high signal aberrations on MRI in the frontal, parietal, and occipital centrum semiovale and corona radiata at nine months. At autopsy, confluent microinfarcts were found to correspond topographically to the MRI abnormalities. In the radiation alone group, two animals had normal MRI and autopsy while the third animal had bilateral MRI high signal aberrations develop sequentially with corresponding microinfarcts at autopsy. These changes were greater in severity than those seen in the BUdR treated animals. We support previous evidence that there is differential intraspecies sensitivity to radiation. We find that BUdR produces no unilateral potentiation of radiation toxicity.

    Title Intra-arterial Bromodeoxyuridine Radiosensitization and Radiation in Treatment of Malignant Astrocytomas.
    Date October 1988
    Journal Journal of Neurosurgery
    Excerpt

    Bromodeoxyuridine (BUdR), a nonhypoxic radiosensitizing drug, is a halogenated pyrimidine analog that is incorporated into the deoxyribonucleic acid of dividing cells in a competitive process with thymidine; BUdR also sensitizes these cells to radiation therapy. Neurons and glial cells have a very low mitotic rate. They will not incorporate BUdR and will not be sensitized. Bromodeoxyuridine is best delivered intra-arterially because of its regional advantage, calculated to be between 6 and 16. An 8-week BUdR infusion is delivered before and during radiation therapy through a permanently implanted pump with a catheter placed retrograde into the external carotid artery. Eighteen patients with malignant glioma (15 grade IV, and three grade III) were entered into a Phase I dose-escalation protocol with BUdR dosages ranging from 400 to 600 mg/sq m/day. The maximum dose that can be tolerated appears to be 400 mg/sq m/day for 8 weeks. The 18 patients entered in this study have a median Kaplan-Meier estimated survival time (+/- standard error of the mean) of 22 +/- 5 months with 11 patients still alive. Three patients are alive at 30, 29, and 21 months after diagnosis with no evidence of tumor on computerized tomography. There have been no vascular complications. Side effects in all patients have included anorexia, fatigue, ipsilateral forehead dermatitis, blepharitis, iritis, and nail ridging. Myelosuppression requiring dose reduction occurred in one patient. One patient had a Stevens-Johnson syndrome requiring termination of BUdR. It is concluded that intra-arterial BUdR may improve survival times in patients with malignant gliomas.

    Title Possible Treatment of Parkinson's Disease with Intrathecal Medication in the Mptp Model.
    Date July 1988
    Journal Annals of the New York Academy of Sciences
    Title Use of Implantable Pump Systems for Intraarterial, Intraventricular and Intratumoral Treatment of Malignant Brain Tumors.
    Date July 1988
    Journal Annals of the New York Academy of Sciences
    Title Primary Cerebellar Glioblastoma Multiforme.
    Date January 1988
    Journal Journal of Neuro-oncology
    Excerpt

    Glioblastoma multiforme in adults arising in the cerebellum is a rare tumor, well documented in only 13 cases in the literature. We report a fourteenth case, an 80-year-old female, and reassess the clinical and CT aspects of this tumor based on review of the world's literature. The median age of patients is 53 years with a median survival of three months, which is less than adult cerebral hemisphere malignant gliomas.

    Title Acute Sensory Neuropathy-neuronopathy from Pyridoxine Overdose.
    Date December 1987
    Journal Neurology
    Excerpt

    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.

    Title Acute Arsenic Intoxication Presenting As Guillain-barré-like Syndrome.
    Date April 1987
    Journal Muscle & Nerve
    Excerpt

    Arsenic-induced polyneuropathy is traditionally classified as an axonal-loss type, electrodiagnostically resulting in low amplitude or absent sensory and motor responses, relatively preserved proximal and distal motor conduction rates, and distal denervation. We report four patients with a subacute onset progressive polyradiculoneuropathy following high-dose arsenic poisoning. In three patients, early electrodiagnostic testing demonstrated findings suggestive of an acquired segmental demyelinating polyradiculoneuropathy. Serial testing confirmed evolution into features of a distal dying-back neuropathy. We hypothesize that arsenic toxicity and the resultant biochemical derangement of the peripheral nerve cell leads to subtle changes in axonal function that produce, initially, segmental demyelination and eventually distal axonal degeneration. Acute arsenic toxicity must be suspected in patients with clinical and electrodiagnostic features supporting Guillain-Barré syndrome.

    Title Phase I-ii Evaluation of Intra-arterial Diaziquone for Recurrent Malignant Astrocytomas.
    Date May 1986
    Journal Cancer Treatment Reports
    Excerpt

    Diaziquone (AZQ) is a lypophilic alkylating agent that crosses the blood-brain barrier and has shown broad activity in animal tumor models. Five of 12 patients with malignant astrocytoma treated with iv AZQ had clinical and/or radiographic improvement (Schold, Neurology 34:615, 1984). Intra-arterial administration of AZQ to patients with brain tumors should produce higher peak levels of drug in the tumor and should reduce systemic toxicity. Twenty-one patients with astrocytoma (grade II, four; grade III, 11; and grade IV, six), in all of whom irradiation and intra-arterial carmustine chemotherapy failed, received intra-arterial AZQ as a single dose every 28 days. Two of 20 evaluable patients experienced partial responses of 5 and 8+ months, respectively. Four patients had disease stabilization of 3, 4, 5, and 8 months' duration, respectively, and one of these patients had tumor shrinkage (partial response) after seven courses of AZQ. The initial dose in the first three patients was 10 mg/m2, and doses in subsequent groups of three patients were begun at increases of 5 mg/m2. The within-group dose escalation was 5 mg/m2 per course if there was no hematologic toxicity. Dose-limiting toxicity was myelosuppression, which occurred at doses greater than 15 mg/m2. The maximum tolerated dose was 25 mg/m2. Intra-arterial AZQ appears to be of marginal effectiveness in patients refractory to carmustine and offers no advantage over iv AZQ in efficacy or toxicity.

    Title Gangliosides Gm1 and Gd1b Are Antigens for Igm M-protein in a Patient with Motor Neuron Disease.
    Date May 1986
    Journal Neurology
    Excerpt

    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.

    Title Intra-arterial Bcnu Chemotherapy for Treatment of Malignant Gliomas of the Central Nervous System.
    Date September 1984
    Journal Journal of Neurosurgery
    Excerpt

    Because of the rapid systemic clearance of BCNU (1,3-bis-(2-chloroethyl)-1-nitrosourea), intra-arterial administration should provide a substantial advantage over intravenous administration for the treatment of malignant gliomas. Thirty-six patients were treated with BCNU every 6 to 8 weeks, either by transfemoral catheterization of the internal carotid or vertebral artery or through a fully implantable intracarotid drug delivery system, beginning with a dose of 200 mg/sq m body surface area. Twelve patients with Grade III or IV astrocytomas were treated after partial resection of the tumor without prior radiation therapy. After two to seven cycles of chemotherapy, nine patients showed a decrease in tumor size and surrounding edema on contrast-enhanced computerized tomography scans. In the nine responders, median duration of chemotherapy response from the time of operation was 25 weeks (range 12 to more than 91 weeks). The median duration of survival in the 12 patients was 54 weeks (range 21 to more than 156 weeks), with an 18-month survival rate of 42%. Twenty-four patients with recurrent Grade I to IV astrocytomas, whose resection and irradiation therapy had failed, received two to eight courses of intra-arterial BCNU therapy. Seventeen of these had a response or were stable for a median of 20 weeks (range 6 to more than 66 weeks). The catheterization procedure is safe, with no immediate complication in 111 infusions of BCNU. A delayed complication in nine patients has been unilateral loss of vision secondary to a retinal vasculitis. The frequency of visual loss decreased after the concentration of the ethanol diluent was lowered.

    Title Bcnu Solubility and Toxicity in the Treatment of Malignant Astrocytomas.
    Date July 1984
    Journal Journal of Neurosurgery
    Excerpt

    Administration of BCNU into the carotid artery as treatment for malignant astrocytomas has produced retinal and brain toxicity. It is unclear whether the BCNU diluent, ethanol, is the cause of the toxicity, but the elimination of the ethanol is an attractive possibility. Clinically, decreasing the ethanol from 2.0 ml/100 mg BCNU to 0.75 ml/100 mg BCNU resulted in a marked decrease in eye toxicity. To simulate this clinical situation, three 500-mg solutions of BCNU, ethanol, and saline were prepared, decreasing the ethanol concentration from 3.0 ml to 2.0 ml to 0.75 ml/100 mg BCNU. The amount of BCNU recovered in vitro after simulated clinical administration of the three solutions decreased from 84.9% to 38.3% as the diluent decreased. Therefore, drug delivery at a fixed BCNU dose will decrease with the amount of ethanol diluent used. The clinical decrease in eye toxicity must be partly attributed to a decrease in the amount of BCNU delivered to the retina. Simulated administration of a solution of 500 mg BCNU/150 ml of 5% dextrose in water (D5W) gave 83.7% BCNU recovery. The D5W gives solubility comparable to that provided by 3.0 ml ethanol to each 100 mg BCNU, and its use eliminates ethanol as a potential retinal and brain toxin.

    Title Chiari Malformation Presenting As Loss of Cerebellar Substance on Computed Tomography.
    Date June 1984
    Journal Surgical Neurology
    Excerpt

    Cerebral computed tomography (CT) is the primary imaging modality in the investigation of suspected cerebellar degeneration. A case is presented in which an inaccurate clinical and radiologic diagnosis of olivo-pontocerebellar degeneration resulted from CT imaging demonstrating loss of cerebellar substance. Subsequent clinical recognition of downbeat nystagmus led to a diagnosis of Chiari malformation. This malformation was classified as a "severe" Chiari type I via clivomyelography and angiography. Surgical decompression resulted in marked clinical improvement. Visualization of the loss of cerebellar substance should not be considered to exclude Chiari malformation.

    Title Resolution of Stiff-man Syndrome with Cortisol Replacement in a Patient with Deficiencies of Acth, Growth Hormone, and Prolactin.
    Date June 1984
    Journal The New England Journal of Medicine
    Title Peripheral Neuropathy in Osteosclerotic Myeloma: Clinical and Electrodiagnostic Improvement with Chemotherapy.
    Date May 1984
    Journal Muscle & Nerve
    Excerpt

    A patient with a severe remote-effect polyneuropathy and other paraneoplastic features of osteosclerotic myeloma improved dramatically with melphalan and prednisone treatment. Serial electrodiagnostic studies provided an objective means of following the response to therapy and documented the improvement. We believe this represents the first reported patient with multifocal osteosclerotic myeloma and a myelomatous polyneuropathy responding to melphalan and prednisone.

    Title Orbital Angiographic Changes After Intracarotid Bcnu Chemotherapy.
    Date March 1984
    Journal Ajnr. American Journal of Neuroradiology
    Excerpt

    Seven patients treated with intraarterial internal carotid 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) chemotherapy for malignant gliomas of the brain had postinjection angiographic demonstration of increased orbital vascularity and vasodilatation, sometimes associated with arteriovenous shunting. Subjective orbital discomfort reported by the patients during chemotherapy correlated with this orbital hyperemia. Some therapeutic suggestions for managing this undesirable effect of BCNU chemotherapy are discussed.

    Title Episodic Hyperhidrosis, Hypothermia, and Agenesis of Corpus Callosum.
    Date October 1983
    Journal Neurology
    Excerpt

    Episodic hyperhidrosis and hypothermia are the primary symptoms of a rare central nervous system disorder of thermoregulation which is often associated with agenesis of the corpus callosum and can present in childhood or adult years. During attacks, patients may exhibit confused, withdrawn, and lethargic behavior and ataxia or other neurologic symptoms. A 21-year-old man with temperature chronically between 30 and 32 degrees C transiently responded to phenobarbital and to cyproheptadine therapy. A 34-year-old woman with frequent, brief episodes of hypothermia and hyperhidrosis improved with chlorpromazine treatment. Episodic thermoregulatory disturbance has been attributed to "vagal attacks" or "diencephalic epilepsy," but the pathophysiology remains undefined.

    Title A Breeding Study to Control Chronic Progressive Nephrosis in Rats.
    Date April 1983
    Journal Laboratory Animal Science
    Excerpt

    Breeder male Sprague-Dawley rats were categorized as potential low and high protein excretors at 4 months of age. The average selection values of these two groups were 0.59 and 1.75 mg/ml, respectively. Paris of females were mated to these males in two breeding cycles in the fashion of a diallele cross. The heritability index based on protein excretion values of 263 male offspring at 6 months of age from both cycles of high and low excretor males was 0.526 with approximate variance of 0.0668. Significantly different (p less than 0.01) survival distributions were shown. The mean and median survival times of the high excretor offspring were 611.1 and 652 days, respectively, compared to 651.4 and 680.5 days, respectively, in low excretor offspring. The proportion of offspring with marked chronic progressive nephrosis was significantly greater (p less than 0.01) in the high excretor group, both prior to and after 700 days of age, than that of offspring in the low excretor group. The selection of low excretor males for breeding stock appears to offer a practical basis for minimizing the total expression of chronic progressive nephrosis in this strain of rat.

    Title Ocular Toxicity Associated with High-dose Carmustine.
    Date December 1982
    Journal Archives of Ophthalmology
    Excerpt

    The ocular side effects of carmustine (a nitrosurea) are not well established. Evidence of delayed bilateral ocular toxicity developed in two of 50 patients treated with high dose intravenous (IV) carmustine (800 mg/sq m) with autologous bone marrow rescue. Symptoms or signs of ocular toxicity became apparent four weeks following IV treatment. Evidence of delayed ocular toxicity ipsilateral to the side of the infusion developed in seven of ten patients treated with intra-arterial carotid doses of carmustine to a cumulative minimum of 450 mg/sq m in two treatments. The ocular toxicity began two to 14 weeks (mean, six weeks) following intra-arterial treatment. In three of these patients, the visual loss progressed over one week to no light perception. The funduscopic manifestations of both groups included arterial narrowing, nerve fiber-layer infarcts, and intraretinal hemorrhages. Fluorescein angiography demonstrated segmental perivascular staining, wide-spread late capillary leakage, and optic disc hyperfluorescence. One patient had light and microscopic confirmation of cilioretinal artery occlusion and choroidal fibrin thrombi.

    Title New Implantable Continuous Administration and Bolus Dose Intracarotid Drug Delivery System for the Treatment of Malignant Gliomas.
    Date December 1982
    Journal Neurosurgery
    Excerpt

    A totally implantable system for the continuous and bolus delivery of intra-arterial chemotherapeutic agents to patients with malignant gliomas is described. The system utilizes an Infusaid pump (Infusaid Corp., Sharon, Massachusetts), which discharges the drug directly into the internal carotid artery and is percutaneously refillable. This system has been utilized experimentally in primates and in the treatment of six patients with malignant gliomas. It seems that this system can be utilized safely as an experimental technique in the treatment of malignant gliomas.

    Title Benefit from and Tolerance to Continuous Intrathecal Infusion of Morphine for Intractable Cancer Pain.
    Date September 1982
    Journal Journal of Neurosurgery
    Excerpt

    A patient with painful bilateral metastatic lumbosacral plexopathy from cervical cancer was treated with levorphanol tartrate (Levo-Dromoran), 4 mg orally every 4 hours, with poor pain relief. A lumbar subarachnoid catheter was then placed percutaneously. A bolus of 1 mg of morphine gave complete pain relief for 17 hours. Over the next week, the dose requirement increased to 10 mg/day, infused by an external pump. A permanently implantable infusion pump with a 50-cc drug chamber and flow rate of 3.4 cc/day was placed in the abdomen and attached to the lumbar subarachnoid catheter. The pump was refilled by percutaneous injection. Morphine was infused continuously at 15 mg/day, affording the patient increased mobility and no pain for 7 days. When the pain returned, the morphine dose was increased to 17.5 mg/day, and the patient was allowed to take oral Levo-Dromoran for pain. The intrathecal morphine dose was constant within 2-week periods, but was increased from 17.5 to 96 mg/day because of inadequate pain relief. Oral Levo-Dromoran intake averaged 3.4 mg/day. Levo-Dromoran intake was less during the 1st week of each 2-week cycle than the last week (mean 15.0 versus 38.0 mg/wk, p less than 0.05). No sedation or respiratory depression was seen.

    Title Carnitine Metabolism in Macaca Arctoides: the Effects of Dietary Change and Fasting on Serum Triglycerides, Unesterified Carnitine, Esterified (acyl) Carnitine, and Beta-hydroxybutyrate.
    Date August 1982
    Journal The American Journal of Clinical Nutrition
    Excerpt

    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.

    Title Intra-arterial Bcnu Chemotherapy for the Treatment of Malignant Gliomas of the Central Nervous System: a Preliminary Report.
    Date November 1981
    Journal Cancer Treatment Reports
    Excerpt

    We treated six patients with unilateral malignant astrocytomas with pulse doses of intra-arterial BCNU (200 mg/m2 initially, with escalating doses every 6-8 weeks) via transfemoral selective internal carotid catheterization. Four patients had had partial resections without prior radiation therapy and received no steroids. They had decreased tumor stain and surrounding edema after two to four cycles of chemotherapy. For one patient, results of the neurologic examination returned to normal, with total disappearance of her tumor as assessed by computerized tomographic scan. Objective tumor response continued for 7 months in three patients and for 3 months in one. In two of the four patients, chemotherapy was discontinued because of retinal toxicity and not because of treatment failure. Two patients had had partial resections and radiation therapy. One patient had stable disease for 4 months, and the second had progressive disease with gradual visual loss beginning in the infused eye 3 weeks after the second treatment. The catheterization procedure is safe; it was without immediate complication in 17 BCNU infusions. In summary, high-dose intra-arterial BCNU is well-tolerated and is an effective initial chemotherapeutic modality.

    Title Metastasis to the Base of the Skull: Clinical Findings in 43 Patients.
    Date July 1981
    Journal Neurology
    Excerpt

    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.

    Title Treatment of Odontoid Fractures in Cancer Patients.
    Date March 1981
    Journal Journal of Neurosurgery
    Excerpt

    A series of 18 patients with odontoid fractures due to metastatic cancer were treated at Memorial Sloan-Kettering Cancer Center between 1974--1980. The primary source of cancer was breast (12 cases), lung (two cases), nasopharynx (one case), multiple myeloma (one case), colon (one case), and rhabdomyosarcoma (one case). The clinical features consisted of severe neck pain and neck stiffness in 17 patients; signs of cord compression were noted in only four patients. Tomography and computerized tomography were useful in identifying both the osseous and soft-tissue involvement by tumor. Initial treatment in all patients except those with myelopathy consisted of high-dose steroids, and immobilization in a hard collar. Ten patients were treated with radiation therapy alone; six patients underwent surgical fusion (four before and two after radiation therapy); and two patients died before completion of treatment. Conservatively treated patients were allowed to walk with the support of only a collar following radiation therapy. We believe that the initial management of patients with odontoid fractures secondary to cancer should be high-dose steroids and radiation therapy, unless displacement is marked. Assessment for surgical fusion should be made following radiation therapy, since conservative treatment may suffice in most patients. Early recognition is important so that treatment can be instituted before C1--2 subluxation becomes severe.

    Title Epidural Spinal Cord Compression from Metastatic Tumor: Results with a New Treatment Protocol.
    Date January 1981
    Journal Annals of Neurology
    Excerpt

    Eighty-three patients with epidural spinal cord compression, from metastatic cancer were treated with high-dose adrenocorticosteroids and a new radiation fractionation protocol. Only those patients were included who had complete or almost complete block on myelography and who had not received prior radiation therapy to the area of compression. Patients were given 100 mg of dexamethasone intravenously at the time of diagnosis and 500 rads of radiation on each of the first three days. After a four-day rest, radiation therapy was continued at 300 rads to a total dose of 3,000 rads. The effects of this new protocol on the patient's motor abilities did not differ from those of previous protocols, namely, 47 of 83 patients (57%) were ambulatory after treatment, with no responses in patients totally paraplegic before treatment. However, early administration of high doses of dexamethasone substantially ameliorated pain in the majority of patients, with relief often coming within hours after the drug was given. On the basis of these data, we recommend high doses of adrenocorticosteroids combined with radiation therapy for acute treatment of spinal cord compression. The optimum fractionation schedule for radiation therapy is not established.

    Title Renal Glucosyltransferase Activity in Highly-inbred Spontaneously Diabetic Chinese Hamsters.
    Date September 1980
    Journal Diabetologia
    Excerpt

    A modified glucosyltransferase assay using degraded gelatin as acceptors was found to be enzyme concentration- and time-dependent in the Chinese hamster kidney extracts. In 54 Chinese hamsters selected from 7 highly inbred sublines with or without spontaneous glycosuria, the glucosyltransferase activity (0.78-3.25 unit/g) in the kidney was found to be significantly correlated (P = 0.0002) to blood sugar concentrations (60-475 mg/dl). However, subline-dependent variation in glycosyltransferase activity was also evident and, in animals from 2 of the 5 diabetic sublines, similar activity of glucosyltransferase was found in their kidneys as in those of nondiabetic animals. It was concluded that renal glucosyltransferase activity was affected by blood sugar level as well as by genetically determined factor(s).

    Title Acid Glycohydrolase in Chinese Hamster with Spontaneous Diabetes. Iii. Line-dependent Variance.
    Date November 1978
    Journal Biochimica Et Biophysica Acta

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