Perry Black

Malignant astrocytomas treated with iodine-125 labeled monoclonal antibody 425 against epidermal growth factor receptor: A phase II trial☆

Twenty-five patients with primary presentation of malignant astrocytoma, astrocytoma with anaplastic foci, and glioblastoma multiforme were treated with surgical resection and definitive radiation therapy followed by intravenous or intra-arterial administration of Iodine-125 labeled monoclonal antibody-425, which binds specifically to human epidermal growth factor receptor. The patients presented with primary untreated disease, positive contrast enhanced computed tomography scans of the brain, and compatible clinical symptoms. In this Phase II clinical trial, the patients had surgical debulking or biopsy followed by definitively administered external beam radiation therapy and one or multiple doses (35 to 90 mCi per infusion) of radiolabeled antibody. The total cumulative doses ranged from 40 to 224 mCi. The administrations of the radiolabeled antibody were performed in most cases 4-6 weeks following completion of the primary surgery and radiation therapy. Ten patients had astrocytoma with anaplastic foci and 15 had glioblastoma multiforme. No significant life-threatening toxicities were observed during this trial. At 1 year 60% of the patients with astrocytoma with anaplastic foci or glioblastoma multiforme are alive. The median survival for both groups was 15.6 months.

Models of spinal cord injury: Part 3. Dynamic load technique.

Having previously studied a static load model of cord injury in rats, we report here an evaluation of a dynamic (weight drop) technique. Under general anesthesia, Sprague-Dawley rats were subjected to a laminectomy at T12, after which a 10-g weight was dropped onto a force transducer and impounder resting on the spinal cord; the weight drop distances varied in different groups from 0 (control) in increments of 2.5 cm to a maximal height of 17.5 cm. A strain gauge attached to the force transducer yielded an oscilloscopic wave form from which force of impact (peak force and impulse) was calculated. Eighty-six animals were used in this parametric study. The animals were observed for 4 weeks postinjury with two tests of motor recovery (Tarlov score for locomotion and the inclined plane test). After sacrifice at 4 weeks, the spinal cords were removed and, with the use of preset criteria, qualitative histopathological scoring of the extent of tissue damage was carried out. We found that the variable height of weight drop was capable of producing a graded injury that correlated with the force of injury (as measured by the force transducer) and with the outcome parameters of functional recovery and degree of morphological damage in the spinal cord. Histopathologically, there was a tendency to central cavitation of the cord. Both the static load and the dynamic load techniques seem to be valid models of spinal cord injury. Pathologically, however, the tissue damage after static load injury involved primarily the dorsal half of the cord. By contrast, the dynamic load technique produced central cavitation comparable to that observed in human spinal cord injury. In this respect, the dynamic model seems to be superior and its use is therefore recommended for studies of therapeutic intervention for spinal cord injury.

A Phase II study of anti–epidermal growth factor receptor radioimmunotherapy in the treatment of glioblastoma multiforme

OBJECT This single-institution Phase II study tests the efficacy of adjuvant radioimmunotherapy with (125)I-labeled anti-epidermal growth factor receptor 425 murine monoclonal antibody ((125)I-mAb 425) in patients with newly diagnosed glioblastoma multiforme (GBM). METHODS A total of 192 patients with GBM were treated with (125)I-mAb 425 over a course of 3 weekly intravenous injections of 1.8 GBq following surgery and radiation therapy. The primary end point was overall survival, and the secondary end point was toxicity. Additional subgroup analyses were performed comparing treatment with (125)I-mAb 425 (RIT, 132 patients), (125)I-mAb 425 and temozolomide (TMZ+RIT, 60 patients), and a historical control group (CTL, 81 patients). RESULTS The median age was 53 years (range 19-78 years), and the median Karnofsky Performance Scale score was 80 (range 60-100). The percentage of patients who underwent debulking surgery was 77.6% and that of those receiving temozolomide was 31.3%. The overall median survival was 15.7 months (95% CI 13.6-17.8 months). The 1- and 2-year survivals were 62.5 and 25.5%, respectively. For subgroups RIT and TMZ+RIT, the median survivals were 14.5 and 20.2 months, respectively. No Grade 3 or 4 toxicity was seen with the administration of (125)I-mAb 425. The CTL patients lacked Karnofsky Performance Scale scores, had poorer survival, were older, and were less likely to receive radiation therapy. On multivariate analysis, the hazard ratios for RIT versus CTL, TMZ+RIT versus CTL, and TMZ+RIT versus RIT were 0.49 (p < 0.001), 0.30 (p < 0.001), and 0.62 (p = 0.008), respectively. CONCLUSIONS In this large Phase II study of 192 patients with GBM treated with anti-epidermal growth factor receptor (125)I-mAb 425 radioimmunotherapy, survival was 15.7 months, and treatment was safe and well tolerated.

Radioiodinated (I-125) monoclonal antibody 425 in the treatment of high grade glioma patients: ten-year synopsis of a novel treatment.

The present report is the follow-up of patients enrolled in a phase II clinical trial using 125I-MAb 425 as an adjuvant treatment for high grade gliomas. Patient median survivals support published data from an earlier preliminary report. From January 29, 1987 to January 25, 1997, 180 patients diagnosed with astrocytoma with anaplastic foci (AAF) and glioblastoma multiforme (GBM) were treated as outpatients with an average of three weekly intravenous or intraarterial injections of radiolabeled MAb 425. The mean dose was 140 mCi (5.2 GBq). Only one patient who received a single dose of more than 60 mCi (2.2 GBq) experienced acute toxicity. Patients received prior surgery and radiation therapy, with and without chemotherapy. Overall median survival for patients with GBM and AAF was 13.4 and 50.9 months, respectively, with Karnofsky Performance Status (KPS) ranging from 40 to 100 and age ranging from 11 to 75 years. Prognostic factors (KPS and age) correlated positively with increased survival, with KPS the most important determinant of median survival. Data analysis was performed on patients followed 5 years or longer. We conclude that the administration of 125I-MAb 425 with intensive medical management demonstrates a significant increase in median survival and should be considered a therapeutic regimen for the management of patients with high grade gliomas.

Test for chemotherapeutic sensitivity of cerebral gliomas: use of colorimetric MTT assay.

SummaryThis study was undertaken to evaluate the colorimetric MTT [3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H tetrazolium bromide] assay as a means of testing the sensitivity of gliomas to chemotherapeutic agents in vitro. Eight human glioma established cell lines were plated in 96-well tissue culture plates and incubated for 4 days with 10 different anti-cancer agents; 5 different concentrations of each drug were tested. The MTT dye was then added to the wells, and the resulting formazan precipitate was solubilized with dimethylsulfoxide (DMSO). The spectrophotometric absorbance (measured at 570 nm) of control and experimental wells was used to calculate the cytotoxicity index (CI). Values with a CI greater than 50% growth inhibition indicated cytotoxic efficacy (sensitivity to the chemotherapeutic drug).Six of the seven (85.7%) glioma cell lines were highly sensitive at varying concentrations to mitomycin C, cisplatin, and doxorubicin. Four of the seven (57.1%) cell lines demonstrated intermediate sensitivity to mitoxantrone and vinblastine. Five of the seven (71.4%) cell lines exhibited resistance to etoposide, bleomycin, cosmegen, and BCNU. One of the cell lines tested, U-138MG, failed to produce the MTT formazan precipitate, so that the sensitivity of this cell line to the panel chemotherapeutic drugs could not be determined. The variability of the results indicates the need for an in vitro screening method to evaluate the effectiveness of clinical and experimental chemotherapeutic agents. The MTT assay provides a rapid method of screening antineoplastic agents against gliomas for cytotoxicity.

Clinical experience with a fiberoptic intracranial pressure monitor

Retrospective clinical experience with our first 46 patients monitored with a fiberoptic intracranial pressure device is described. In 43 of 46 patients, the transducer was introduced into brain parenchyma. A ventriculostomy system was used in 3 of 46 patients. The monitoring system was generally characterized by ease of placement and system maintenance and by technical simplicity. Several problems were encountered, including breakage of system components (12%), erroneous readings requiring transducer repositioning (8.6%), epidural hematoma (3.4%), and infection (1.7%). No infections or hematomas occurred in the 3 cases in which the ventriculostomy system was used. Overall, our experience with the Camino intracranial pressure fiberoptic monitoring system confirms previous reports of its favorable features.

Naloxone and experimental spinal cord injury: Part 2. Megadose treatment in a dynamic load injury model

We previously reported that high dose naloxone (10 mg/kg) failed to promote recovery of motor function after a static load injury of the spinal cord in rats. In the present experiments, using the more traditional dynamic weight drop model, we tested megadose naloxone administered by the intraperitoneal route in 23 rats, including saline controls (Experiment 1). Thirty minutes after a cord injury at T-12, naloxone was given i.p. in a bolus of 100 mg/kg, followed by a continuous i.p. infusion of 50 mg/kg/hour for 23 hours. Again, no benefit was observed; this raised a question regarding naloxone and its absorption and serum levels. In another study, reported separately, we found that naloxone administered by the subcutaneous route affords higher and more sustained serum levels than by i.p. administration. Consequently, in 20 rats (Experiment 2), we repeated the protocol, using subcutaneous naloxone in a bolus dose of 150 mg/kg, followed by continuous infusion of 75 mg/kg/hour for 23 hours; the result was again negative. Morphometric determination of the residual (normal) cross sectional areas of gray and white matter at the epicenter of the cord lesion showed no statistically significant difference between treated and control animals in either Experiment 1 or Experiment 2. In view of the negative findings at high dose (10 mg/kg) and megadose naloxone, it seems that a reasonable next step would be an evaluation of lower doses using a factorial research design, incorporating a range of doses of naloxone in relation to a variety of intensities of cord injury. This question will be addressed in future experiments.

Spontaneous Spinal Cord “Injury Potential” in the Rat

A marked ionic change in both the intra- and the extracellular space at the site of an acute spinal cord lesion has been reported in the literature. The present study was undertaken to measure spontaneous electrical potentials that might be associated with the previously observed ionic shifts. With the use of an impact (weight drop) model of cord injury in rats, lesions were induced at T-8. DC potentials were measured simultaneously both rostrally and caudally with respect to site of injury over a time course of 4 hours after injury. The potentials were positive with respect to lesion site, and the intensity decreased with time during 4 hours of observation. These results seem to support reported ionic shifts and migrations in injured cords and represent, to our knowledge, the first reported measurement of spontaneous injury potential in the cord of a mammal.

Naloxone and experimental spinal cord injury: Part 1. High dose administration in a static load compression model.

Previous studies by other investigators using a dynamic weight drop injury model in cats or rats have demonstrated a beneficial effect of naloxone in promoting motor recovery after experimental spinal cord injury. The effective doses ranged from 0.8 mg (total dose) in rats to a high dose of 10 mg/kg in cats. We report here an evaluation of high dose naloxone (10 mg/kg) in a model of cord injury in rats using a static load compression technique. After induction of injury at T-12, naloxone (10 mg/kg) was administered by the intraperitoneal route, followed by five additional bolus injections over the course of the next 2 days. Animals were randomly assigned to this treatment regimen (n = 10) or to a saline control group (n = 10). The animals were observed for 4 weeks, with testing of recovery of hind limb motor function (Tarlov score and on an inclined plane). Although there were slight differences in recovery, the overall evaluation showed no statistically significant difference between the naloxone-treated and control groups. The spinal cords of the sacrificed animals were studied morphometrically; there was no statistically significant difference between the residual gray and white matter at the site of cord injury between the treated and control groups. Naloxone did not seem to promote recovery of motor function in this model of spinal cord injury.

Surgical Management of Radiated Scalp in Patients with Recurrent Glioma

Patients with malignant brain tumors requiring multiple craniotomies and external beam radiotherapy are at risk of scalp wound breakdown secondary to fibrosis and radiation damage. We present three cases to illustrate the nature of the problem and the surgical approaches to scalp repair. When a bicoronal incision has been used for the initial craniotomy, the plastic repair can be performed with a bipedicle visor scalp flap and split-thickness skin graft to cover the pericranium at the donor site. When a curvilinear (U-shaped or horseshoe) flap has been used for the initial craniotomy, a single-pedicle flap may be rotated to achieve closure without tension. In anticipation of the risk of scalp wound breakdown in patients with malignant brain tumors, the planning of the operative incision for the first craniotomy needs to take into account the long-term viability of the scalp. We recommend linear scalp incisions parallel to the arterial distribution instead of the traditional curvilinear (U-shaped or horseshoe) flaps; linear incisions are less likely to break down, and in the event of breakdown, linear wounds offer better therapeutic surgical options for plastic repair.