✓ Multidrug resistance for many types of cancer outside the central nervous system (CNS) has been found to be due to the overexpression of the multidrug resistance gene MDR1, of which the gene-product P-glycoprotein acts as a membrane-bound efflux pump for many anticancer drugs. To examine whether brain tumors overexpress the MDR1 gene, 25 brain-tumor specimens were subjected to Northern blot analysis: 10 gliomas, eight meningiomas, three schwannomas, one malignant lymphoma, and three tumors metastatic to the brain. Ten fresh-frozen autopsy specimens of various parts of normal brain were also analyzed. Blots were hybridized with 32P-labeled Chinese hamster complementary deoxyribonucleic acid (cDNA) and 32P-labeled human MDR1 cDNA. The MDR1 gene messenger ribonucleic acid (mRNA) was detected in two tumors using the Chinese hamster probe (one sphenoid wing meningioma and one metastatic prostate tumor) and in one CNS lymphoma using the human probe. Intact mRNA could not be extracted from the fresh-frozen autopsy specimens of normal brain. Seventeen tumors were examined for P-glycoprotein by immunohistochemical staining using murine monoclonal antibody C219: eight gliomas, eight meningiomas, and one craniopharyngioma. The neoplastic cells from two gliomas and three meningiomas and the blood vessels within six gliomas and two meningiomas stained positively for P-glycoprotein. Seven of 10 normal brain specimens stained positively for P-glycoprotein in blood vessels but no specimen demonstrated staining of parenchymal cells. This study demonstrates that the MDR1 gene can be detected in normal brain, and in malignant, benign, and metastatic lesions. P-glycoprotein can be present in tumor blood vessels even when it is not seen in neoplastic cells. Although the role of P-glycoprotein in tumor blood vessels needs to be further examined and more clearly defined, drug resistance in malignant primary brain tumors may result from characteristics not solely of neoplastic cells but also tumor vasculature.
Michael W. Nabors, Constance A. Griffin, Barbara A. Zehnbauer, Ralph H. Hruban, Peter C. Phillips, Stuart A. Grossman, Henry Brem and O. Michael Colvin
Stuart A. Grossman, Carla Reinhard, O. Michael Colvin, Mark Chasin, Robert Brundrett, Rafael J. Tamargo and Henry Brem
✓ The local concentration and distribution of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) within normal brain tissue were studied following surgical implantation of biodegradable polymer containing BCNU in New Zealand White rabbits. Cylindrical discs of poly(bis(p-carboxyphenoxy)-propane:sebacic acid) copolymer in a 20:80 formulation were made containing [3H]-inulin or [3H]-BCNU labeled in the methylene hydrogens of the chloroethyl groups. These were implanted in the brains of 56 New Zealand White rabbits. The animals were sacrificed 3, 7, 14, or 21 days later and the brains were rapidly removed, frozen, and prepared for quantitative autoradiography. Autoradiographs from coronal sections bisecting the polymer were analyzed to determine both the proportion of the brain section exposed to the tracer and the local drug concentrations as a function of distance from the polymer. Tritiated BCNU was also injected directly into the brains of eight additional rabbits, and local brain concentrations were studied over time.
The results of this study demonstrate that approximately 50% of the area of the brain sections was exposed to radiolabeled compound 3 days after BCNU-polymer implantation, 15% at 7 days, and less than 10% at 14 and 21 days. Polymer discs containing 600 µg BCNU generated 6 mM concentrations of BCNU in brain tissue 10 mm from the polymer at 3 and 7 days. Pharmacological studies demonstrated that approximately 25% of the tritium label was associated with intact BCNU 3 days following polymer implantation. Radiolabeled inulin delivered by polymer remained dispersed throughout the ipsilateral hemisphere for 14 days. Direct injection of [3H]-BCNU into brain parenchyma resulted in widely distributed tracer at 1 and 3 hours with rapid disappearance thereafter. It is concluded that local delivery of BCNU to brain tissue with this polymeric drug delivery system results in sustained high local concentrations of BCNU which may be of value in the treatment of patients with brain tumors.
Adham M. Khalafallah, Adrian E. Jimenez, Carlos G. Romo, David Olayinka Kamson, Lawrence Kleinberg, Jon Weingart, Henry Brem, Stuart A. Grossman and Debraj Mukherjee
There has been limited research on the efficacy of multidisciplinary tumor boards (MDTBs) in improving the treatment of patients with tumors affecting the nervous system. The objective of the present study was to quantify the utility of MDTBs in providing alternative diagnostic interpretations and treatment plans for this patient population.
The authors performed a prospective study of patients in 4 hospitals whose cases were discussed at MDTBs between July and November 2019. Patient demographic data, diagnoses, treatment plans, and eligibility for clinical trials were recorded, among other variables.
A total of 176 cases met eligibility criteria for study inclusion. The majority (53%) of patients were male, and the mean patient age was 52 years. The most frequent diagnosis was glioblastoma (32.4%). Among the evaluable cases, MDTBs led to 38 (21.6%) changes in image interpretation and 103 (58.2%) changes in patient management. Additionally, patients whose cases were discussed at MDTBs had significantly shorter referral times than patients whose cases were not discussed (p = 0.024).
MDTB discussions led to significant numbers of diagnostic and treatment plan changes as well as shortened referral times, highlighting the potential clinical impact of multidisciplinary care for patients with nervous system tumors.
Stephen B. Tatter, Edward G. Shaw, Mark L. Rosenblum, Kastytis C. Karvelis, Lawrence Kleinberg, Jon Weingart, Jeffrey J. Olson, Ian R. Crocker, Steven Brem, James L. Pearlman, Joy D. Fisher, Kathryn A. Carson, Stuart A. Grossman and other members of The New Approaches to Brain Tumor Therapy Central Nervous System Consortium
Object. In this study the authors evaluated the safety and performance of the GliaSite Radiation Therapy System (RTS) in patients with recurrent malignant brain tumors who were undergoing tumor resection.
Methods. The GliaSite is an inflatable balloon catheter that is placed in the resection cavity at the time of tumor debulking. Low-dose-rate radiation is delivered with an aqueous solution of organically bound iodine-125 (Iotrex [sodium 3-(125I)-iodo-4-hydroxybenzenesulfonate]), which are temporarily introduced into the balloon portion of the device via a subcutaneous port. Adults with recurrent malignant glioma underwent resection and GliaSite implantation. One to 2 weeks later, the device was filled with Iotrex for 3 to 6 days, following which the device was explanted. Twenty-one patients with recurrent high-grade astrocytomas were enrolled in the study and received radiation therapy. There were two end points: 1) successful implantation and delivery of brachytherapy; and 2) safety of the device.
Implantation of the device, delivery of radiation, and the explantation procedure were well tolerated. At least 40 to 60 Gy was delivered to all tissues within the target volume. There were no serious adverse device-related events during brachytherapy. One patient had a pseudomeningocele, one patient had a wound infection, and three patients had meningitis (one bacterial, one chemical, and one aseptic). No symptomatic radiation necrosis was identified during 21.8 patient-years of follow up. The median survival of previously treated patients was 12.7 months (95% confidence interval 6.9–15.3 months).
Conclusions. The GliaSite RTS performs safely and efficiently. It delivers a readily quantifiable dose of radiation to tissue at the highest risk for tumor recurrence.
Matthew J. McGirt, Khoi D. Than, Jon D. Weingart, Kaisorn L. Chaichana, Frank J. Attenello, Alessandro Olivi, John Laterra, Lawrence R. Kleinberg, Stuart A. Grossman, Henry Brem and Alfredo Quiñones-Hinojosa
Gliadel (BCNU) wafer and concomitant temozolomide (TMZ) therapy, when used individually as adjuvant therapies, extend survival from that achieved by resection and radiation therapy (XRT) for glioblastoma multiforme (GBM). It remains unstudied whether combining Gliadel and TMZ therapy is safe or further improves survival in patients with newly diagnosed GBM. The authors reviewed their initial experience utilizing combined Gliadel, TMZ, and radiation therapy for the treatment of GBM.
All cases involving patients undergoing primary resection of GBM with or without Gliadel wafer (3.85% BCNU) implantation and adjuvant XRT over a 10-year period (1997–2006) were retrospectively reviewed. Beginning in 2004, concomitant TMZ became the standard of care at the authors' institution and all patients with Gliadel implantation also received concomitant TMZ (Stupp protocol). Overall survival and treatment-related morbidity were assessed for all patients treated with Gliadel plus concomitant TMZ (XRT + Gliadel + TMZ). Age-matched (≤ 70 years) comparison of survival and morbidity was performed between the XRT + Gliadel + TMZ (post-2003) and XRT + Gliadel (pre-2004) cohorts.
Thirty-three patients were treated with XRT + Gliadel + TMZ. The median survival in this group was 20.7 months, with a 2-year survival rate of 36%. Six-month morbidity included surgical site infection in 1 case (3%), perioperative seizures in 2 cases (6%), deep-vein thrombus in 1 (3%), pulmonary embolism in 3 (9%), and cerebral edema requiring admission for intravenous dexamethasone in 1 case (3%). Myelosuppression required premature termination of TMZ in 7 patients (21%) (thrombocytopenia in 5, neutropenia in 2 cases). In patients ≤ 70 years of age, XRT + Gliadel + TMZ (30 patients, post-2003) was independently associated with improved median survival (21.3 vs 12.4 months, p = 0.005) versus XRT + Gliadel (78 patients, pre-2004), with 2-year survival of 39 versus 18%, respectively. In these patients, XRT + Gliadel + TMZ was not associated with an increase in perioperative morbidity in comparison with XRT + Gliadel.
In this experience, concomitant TMZ therapy in addition to Gliadel wafer implantation was associated with a median survival of nearly 21 months without increased perioperative morbidity. Temozolomide can be safely administered to patients receiving Gliadel wafers after resection of GBM.
Bizhan Aarabi, James S. Harrop, Charles H. Tator, Melvin Alexander, Joseph R. Dettori, Robert G. Grossman, Michael G. Fehlings, Stuart E. Mirvis, Kathirkamanathan Shanmuganathan, Katie M. Zacherl, Keith D. Burau, Ralph F. Frankowski, Elizabeth Toups, Christopher I. Shaffrey, James D. Guest, Susan J. Harkema, Nader M. Habashi, Penny Andrews, Michele M. Johnson and Michael K. Rosner
Pulmonary complications are the most common acute systemic adverse events following spinal cord injury (SCI), and contribute to morbidity, mortality, and increased length of hospital stay (LOS). Identification of factors associated with pulmonary complications would be of value in prevention and acute care management. Predictors of pulmonary complications after SCI and their effect on neurological recovery were prospectively studied between 2005 and 2009 at the 9 hospitals in the North American Clinical Trials Network (NACTN).
The authors sought to address 2 specific aims: 1) define and analyze the predictors of moderate and severe pulmonary complications following SCI; and 2) investigate whether pulmonary complications negatively affected the American Spinal Injury Association (ASIA) Impairment Scale conversion rate of patients with SCI. The NACTN registry of the demographic data, neurological findings, imaging studies, and acute hospitalization duration of patients with SCI was used to analyze the incidence and severity of pulmonary complications in 109 patients with early MR imaging and long-term follow-up (mean 9.5 months). Univariate and Bayesian logistic regression analyses were used to analyze the data.
In this study, 86 patients were male, and the mean age was 43 years. The causes of injury were motor vehicle accidents and falls in 80 patients. The SCI segmental level was in the cervical, thoracic, and conus medullaris regions in 87, 14, and 8 patients, respectively. Sixty-four patients were neurologically motor complete at the time of admission. The authors encountered 87 complications in 51 patients: ventilator-dependent respiratory failure (26); pneumonia (25); pleural effusion (17); acute lung injury (6); lobar collapse (4); pneumothorax (4); pulmonary embolism (2); hemothorax (2), and mucus plug (1). Univariate analysis indicated associations between pulmonary complications and younger age, sports injuries, ASIA Impairment Scale grade, ascending neurological level, and lesion length on the MRI studies at admission. Bayesian logistic regression indicated a significant relationship between pulmonary complications and ASIA Impairment Scale Grades A (p = 0.0002) and B (p = 0.04) at admission. Pulmonary complications did not affect long-term conversion of ASIA Impairment Scale grades.
The ASIA Impairment Scale grade was the fundamental clinical entity predicting pulmonary complications. Although pulmonary complications significantly increased LOS, they did not increase mortality rates and did not adversely affect the rate of conversion to a better ASIA Impairment Scale grade in patients with SCI. Maximum canal compromise, maximum spinal cord compression, and Acute Physiology and Chronic Health Evaluation–II score had no relationship to pulmonary complications.