Local convection enhanced delivery of IL4-Pseudomonas exotoxin (NBI-3001) for treatment of patients with recurrent malignant glioma.

PURPOSE: This was an open-label, dose-escalation trial of intratumoral administration of IL-4 Pseudomonas Exotoxin (NBI-3001) in patients with recurrent malignant glioma. PATIENTS AND METHODS: A total of 31 patients with histologically verified supratentorial grade 3 and 4 astrocytoma were studied. Of these, twenty-five patients were diagnosed with glioblastoma multiforme (GBM) while six were diagnosed with anaplastic astrocytoma (AA). Patients were over 18 years of age and had Karnofsky performance scores > or = 60. Patients were assigned to one of four dose groups in a dose-escalation fashion: 6 microg/ml x 40 ml, 9 microg/ml x 40 ml, 15 microg/ml x 40 ml, or 9 microg/ml x 100 ml of NBI-3001 administered intratumorally via stereotactically placed catheters. Patients were followed with serial MRI scans and clinical assessments every four weeks for the first 16 weeks and then every eight weeks until week 26. RESULTS: No drug-related systemic toxicity, as evident by lack of hematological or serum chemical changes, was apparent in any patients; treatment-related adverse effects were limited to the central nervous system. No deaths were attributable to treatment. Drug-related Grade 3 or 4 toxicity was seen in 39% of patients in all dose groups and 22% of patients at the maximum tolerated dose of 6 microg/ml x 40 ml. The overall median survival was 8.2 months with a median survival of 5.8 months for the GBM patients. Six-month survival was 52% and 48%, respectively. Gadolinium-enhanced magnetic resonance imaging of the brain showed areas of decreased signal intensity within the tumor consistent with tumor necrosis following treatment in many patients. CONCLUSIONS: NBI-3001 appears to have an acceptable safety and toxicity profile when administered intratumorally in patients with recurrent malignant glioma.

Intratumoral administration of recombinant circularly permuted interleukin-4-Pseudomonas exotoxin in patients with high-grade glioma.

Human glioblastoma but not normal brain cells express numerous receptors for the cytokine interleukin (IL)-4. To target these receptors, we have investigated the safety and activity of directly infusing IL-4(38-37)-PE38KDEL, a chimeric protein composed of circularly permuted IL-4 and a truncated form of Pseudomonas exotoxin (PE), into recurrent malignant high-grade gliomas. IL-4(38-37)-PE38KDEL (IL-4-toxin) was infused over a 4-8-day period into gliomas of nine patients by one to three stereotactically placed catheters. No apparent systemic toxicity occurred in any patient. The infusion of IL-4-toxin in six of nine patients showed glioma necrosis as evidenced by diminished gadolinium enhancement on magnetic resonance imaging. Seven of nine patients underwent craniotomy because of increased intracranial pressure at 16-101 days after the beginning of infusion. In six of these seven patients, partial-to-extensive tumor necrosis with edema was confirmed pathologically. No histological evidence of neurotoxicity to normal brain was identified in any patient. Two patients were not operated on; by magnetic resonance imaging, one showed mottled gadolinium enhancement, and the other showed extensive necrosis of tumor leading to complete remission; this patient remains disease-free > 18 months after the procedure. We conclude that direct glioma injection of IL-4(38-37)-PE38KDEL is safe without systemic toxicity. Local toxicity seemed attributable mainly to tumor necrosis or occasionally to the volume of infusion. Histological evidence of toxicity to normal brain was not observed and in many patients, could be pathologically excluded. Additional patients are being treated to determine the maximal tolerated concentration and volume of IL-4(38-37)-PE38KDEL.

Leksell Gamma Knife treatment of tic douloureux.

Stereotactic radiosurgery with the Leksell Gamma Knife under local anesthesia can effectively treat patients with recurrent tic douloureux after unsuccessful medical/surgical procedures. Eight of 12 patients have shown complete relief or improvement of their trigeminal neuralgia after 3 to 4 year follow-up. No complications have been observed, with the exception of 1 patient who developed a small area of radionecrosis in the medial temporal lobe.

Preclinical development of a recombinant toxin containing circularly permuted interleukin 4 and truncated Pseudomonas exotoxin for therapy of malignant astrocytoma.

Effective treatment is lacking for malignant glioblastoma/astrocytoma. We have identified interleukin-4 receptors (IL-4R) on human malignant astrocytoma. We demonstrate that 16 of 21 surgical samples of high-grade astrocytoma and glioblastoma but not normal brain tissues expressed IL-4R as assessed by reverse transcriptase PCR. We further demonstrate that human malignant astrocytoma cell lines express high-affinity IL-4R. Using a chimeric protein composed of circularly permuted IL-4 and a truncated form of Pseudomonas exotoxin A, we observed that this toxin IL4(38-37)-PE38KDEL) is highly cytotoxic to IL-4R-bearing glioblastoma cells. Compared with a previously reported IL4-PE chimeric protein (IL-PE4E), IL4(38-37)-PE38KDEL bound with higher affinity and was 3-30-fold more cytotoxic to glioblastoma cell lines. Upon intrathecal administration in monkeys, high cerebrospinal fluid IL4(38-37)-PE38KDEL levels were achieved using 2- and 6-microg/kg doses without any central nervous system or other abnormalities. IL4(38-37)-PE38KDEL levels were not detectable in the serum of any monkey studied. When IL4(38-37)-PE38KDEL was injected into the right frontal cortex of rats, localized necrosis was observed at 1000-ng/ml doses but not at < or = 100-ng/ml doses. We conclude that by localized administration, nontoxic levels of IL4(38-37)-PE38KDEL can be achieved, which may have significant cytotoxic activity against malignant astrocytoma.

Stereotactic radiosurgery for trigeminal neuralgia: a multiinstitutional study using the gamma unit.

A multiinstitutional study was conducted to evaluate the technique, dose-selection parameters, and results of gamma knife stereotactic radiosurgery in the management of trigeminal neuralgia. Fifty patients at five centers underwent radio-surgery performed with a single 4-mm isocenter targeted at the nerve root entry zone. Thirty-two patients had undergone prior surgery, and the mean number of procedures that had been performed was 2.8 (range 1-7). The target dose of the radiosurgery used in the current study varied from 60 to 90 Gy. The median follow-up period after radiosurgery was 18 months (range 11-36 months). Twenty-nine patients (58%) responded with excellent control (pain free), 18 (36%) obtained good control (50%-90% relief), and three (6%) experienced treatment failure. The median time to pain relief was 1 month (range 1 day-6.7 months). Responses remained consistent for up to 3 years postradiosurgery in all cases except three (6%) in which the patients had pain recurrence at 5, 7, and 10 months. At 2 years, 54% of patients were pain free and 88% had 50% to 100% relief. A maximum radiosurgical dose of 70 Gy or greater was associated with a significantly greater chance of complete pain relief (72% vs. 9%, p = 0.0003). Three patients (6%) developed increased facial paresthesia after radiosurgery, which resolved totally in one case and improved in another. No patient developed other deficits or deafferentation pain. The proximal trigeminal nerve and root entry zone, which is well defined on magnetic resonance imaging, is an appropriate anatomical target for radiosurgery. Radiosurgery using the gamma unit is an additional effective surgical approach for the management of medically or surgically refractory trigeminal neuralgia. A longer-term follow-up review is warranted.

Technique of stereotactic medial thalamotomy with the Leksell Gamma Knife for treatment of chronic pain.

Nineteen patients underwent a total of 24 medial thalamic lesions made with the Leksell Gamma Knife for the treatment of chronic intractable pain after extensive prior medical and surgical intervention had failed to provide pain relief. The lesion locations were based on prior experience with open radiofrequency medial thalamotomies for the treatment of pain and were directed at the intralaminar, mediodorsal, centromedian, and parafascicular nuclei. All lesions were made with the 4 mm collimator helmet at radiosurgical doses from 140-180 Gray. Follow-up MRI scans indicated anatomically distinct lesions which developed 3-6 weeks after the procedure and were fully formed by 8-12 weeks. The lesion volumes averaged 300-400 mm3 for a single isocentre, 600-900 mm3 for two isocentres, and 900-1100 mm3 for three isocentres. One patient developed a lesion 5500 mm3 in volume after a two isocentre lesion at 160 Gray. Of 15 patients who have been followed for more than 3 months (average follow-up 12 months) four patients (27%) are virtually pain free and functioning normally, whereas five other patients (33%) achieved greater than 50% pain relief. Thus 9/15 patients (60%) have had worthwhile benefit from medial thalamotomy with the Gamma Knife. Medial thalamotomy with the Gamma Knife produces thalamic lesions which are reliable in size, shape and location with a low complication rate and offers a minimally invasive, cost effective treatment for certain selected patients with chronic intractable pain.

Gamma knife radiosurgery for metastatic brain tumors.

Sixty-three patients with metastatic brain tumors have had stereotactic radiosurgery 90 times with the Leksell Gamma Knife over a 29-month period. Initially, a single treatment of 35 to 45 Gy was delivered to the enhanced CT margin. This dose was found to be inadequate for tumor control. We then raised the marginal dose to 50 to 55 Gy, but even this radiosurgical dose did not appear to control tumor growth. However, we have found that metastatic brain tumors can be controlled successfully using enhanced MR scans and a peripheral dose of 60 Gy or even 65 Gy adjacent to the enhanced margins of the metastatic brain tumors, especially melanomas.

Gamma Knife thalamotomy for the treatment of persistent pain.

Twenty patients who suffered persistent intractable pain from a variety of disorders underwent medial thalamotomy with the Leksell Gamma Knife. The lesions were directed at the intralaminar nuclei, the lateral portion of the medial dorsal nucleus, the centromedian and the parafascicular nuclei. Lesions were made with radiation doses from 140 to 180 Gy using a 4-mm beam collimator helmet and either a single isocenter (1 patient), two isocenters (17 patients) or three isocenters (2 patients). Two thirds of the patients experienced either excellent or good pain relief in a follow-up period between 1 and 22 months. One patient showed temporary complications which resolved, and 2 other patients also suffered complications which currently are improving. One patient died due to radiation necrosis following a bilateral thalamotomy. Gamma Knife thalamotomy may offer a potentially safe and effective alternative for the treatment of certain difficult persistent pain problems.

Role of cryosurgery and MRI for Parkinson's disease.

Three basic principles underlie the techniques of stereotactic cryosurgery for Parkinson's disease: (1) high-resolution MRI of the surgical target using thin sequential coronal, axial and sagittal views: (2) clinical-physiological verification of localization of the surgical target by reversible inhibition test, and (3) production of the cryosurgical freezing lesion in a conscious, cooperative patient. The cryosurgical lesion is created in the ventrolateral nucleus of the thalamus for control of tremor and rigidity, or in the posterior ventral area of the pallidum for control of rigidity and bradykinesia. An initially reversible inhibition is produced by cooling the probe tip to -10 degrees C. This cools the brain tissue within 3 mm of the probe to 2-15 degrees C. If parkinsonian symptoms are suppressed, the cryoprobe tip temperature is then lowered incrementally, resulting in a gradually enlarging lesion surrounded by a reversible buffer zone. The final temperature is that in which parkinsonian symptoms are abolished and/or side effects appear. After performing and evaluating over 1,000 cryothalamotomies and cryopallidotomies on patients for whom medical treatments had failed, the author concludes that cryosurgical techniques are safer and produce lesions that are better controlled for size and location than other techniques, resulting in lasting, successful therapeutic results.

Four-year follow-up of adrenal-to-brain transplants in Parkinson's disease.

OBJECTIVE: Evaluate long-term efficacy of autologous adrenal-to-caudate transplants in idiopathic Parkinson's disease refractory to medical treatment. DESIGN: Subjects underwent evaluations several times preoperatively on the University of California-Los Angeles Parkinson's Disease Disability Scale and the Hoehn and Yahr stage of disease. Postoperatively, they were also repeatedly rated on the Unified Parkinson's Disease Rating Scale. SETTING: Clinical visits and surgery took place at the University of California-Los Angeles Center for the Health Sciences. PATIENTS: Three men and one woman, ages 44 to 55 years, were followed up for several years preoperatively. At surgery, disease durations ranged from 7 to 16 years. Originally, all patients had a good response to levodopa, but for several years preoperatively, they had had fluctuating responses and a short duration of drug action. INTERVENTION: Right adrenalectomy was performed through a midline abdominal incision. Open craniotomy exposed the head of the right caudate into which pieces of adrenal medulla, 1 to 2 mm in size, were implanted. MAIN OUTCOME MEASURES: Scores on the three major scales (see "Design") were augmented with the number of hours "off" per day and severity of abnormal involuntary movements. Disease progression of each patient was compared with his own preoperative course and with those of a cohort of patients with Parkinson's disease followed up for 14 years who had received medical treatment without transplant surgery. RESULTS: After 4 years, transplants continued to be beneficial to three patients and had been of brief transient benefit to the fourth. The course of disease was more benign postoperatively than preoperatively and was more slowly progressive than that in the cohort. CONCLUSION: Improvement was not sufficient to justify adrenal transplants as routine therapy but does point the way to the use of other dopamine tissue transplantation.

Medial thalamotomy with the Leksell Gamma Knife for treatment of chronic pain.

The authors describe 10 patients who underwent stereotactic medial thalamotomy with the Leksell Gamma Knife for treatment of chronic intractable pain. The pain was related to structural spinal disorders (4), postherpetic neuralgia (2), spinal cord injury (1), thalamic syndrome (1), anesthesia dolorosa of the face (1), and brainstem infarction (1). All patients had undergone extensive treatment with a variety of modalities prior to gamma thalamotomy. Nine patients underwent unilateral and one patient bilateral lesions. Magnetic resonance imaging (MRI) was used for target localization and the lesions were directed toward the intralaminar nuclei, the lateral portion of the medial dorsal nucleus, the centrum medianum and parafascicular nuclei. The lesions were made with radiation doses of 160-180 Gy using a 4 mm beam collimator and either a single isocenter (1 patient) or two isocenters (9 patients). Follow-up MRI scans in all patients showed well localized lesions. Three patients experienced excellent pain relief, four had good pain relief and three were failures. No complications were seen in any of the patients. In the past gamma thalamotomy was used mainly for treatment of pain related to malignancies but our results indicate that it may also be a safe and effective treatment for pain of nonmalignant origin as well.

Transplantation of fetal mesencephalic tissue in Parkinson's patients.

Patients with idiopathic Parkinson's disease who had become refractory to medical treatment underwent unilateral stereotactic transplantation of mesencephalic tissue obtained from 7- to 9-week-old postconception fetuses. Small pieces of tissue, less than 1 mm, were deposited in 9 sites in the putamen and 3 in the caudate. Patients were 4 men and 3 women and aged from 42 to 59 years (mean 50). Symptom durations were from 9 to 21 years (mean 14). The examinations were done at 3- to 4-month intervals pre- and postoperatively. Patients were examined for a minimum of 1 year postoperatively. The examinations consisted of neurological and general physical examinations, UCLA Parkinson's Disability Scale, Hoehn and Yahr rating and United Parkinson's Disease Rating Scale (PDRS), all in both 'on' and 'off' states. Video recordings and timed tests of a number of motor tests were performed. Patients also completed 7 consecutive days of hourly self-assessments prior to each visit. Fluorodopa PET scans were obtained pre- and 6 and 15 months postoperatively. The operations took place from mid-July 1992 to January 1993. Postoperative states have been free of complications. All have been on immunosuppressants. Levodopa was transiently decreased in the postoperative period, but raised to approximately the preoperative level thereafter. In late March 1993, 3 patients appeared to show modest improvement in the UCLA and UPDRS scales and in the patients' self-assessments.

MR imaging findings after transplant surgery for Parkinson disease.

The authors describe the magnetic resonance (MR) imaging appearance of the head of the right caudate nucleus in patients who have undergone adrenal medullary transplant surgery for Parkinson disease. All four patients examined showed some clinical improvement after surgery. The MR images acquired 4-6 months postoperatively showed no evidence of caudate atrophy. Three of the four patients showed some increase in size of the operated caudate head relative to preoperative studies. Neither cavitation nor high signal intensity on T2-weighted images was evident within the caudate head. The one patient studied after administration of gadopentetate dimeglumine showed no abnormal enhancement. These images provided a description of the transplant site and also suggested that the clinical improvement seen was not due to simple ablation of caudate tissue or to postoperative inflammation. The increase in size of the caudate head also suggested that some implanted tissue may have remained in these patients at the time the MR images were acquired.

Gamma Knife thalamotomy and pallidotomy in patients with movement disorders: preliminary results.

The Leksell Gamma Knife is a useful and safe method to perform thalamotomy and pallidotomy in selected older patients with Parkinson's disease and related movement disorders. In this preliminary report, 2 of 3 patients with severe intention tremor were relieved of their symptoms by thalamotomy, as were 4 of 7 patients with Parkinson's tremor. Four of 8 patients had significant improvement of contralateral rigidity following pallidotomy.

Leksell Gamma Knife treatment of tic douloureux.

Stereotactic radiosurgery under local anesthesia with the Leksell Gamma Knife can effectively treat some patients with recurrent tic douloureux after unsuccessful medical/surgical procedures. Seven of 12 patients have shown complete relief or improvement of their trigeminal neuralgia. No complications have been observed.

Thrombogenic microballoon for cerebral aneurysms, arteriovenous malformations, and carotid cavernous fistula occlusion. Preliminary technical note.

A thrombogenic microballoon was developed to overcome the problems of cerebral aneurysm rupture during microballoon inflation and incomplete aneurysm obliteration by microballoons with subsequent fatal rupture. These complications occur in about 35% of reported series with current microballoon embolization techniques. The wall of the new thrombogenic microballoon allows 80% aneurysm occlusion by inflation, thus avoiding mechanical rupture, and at the same time it produces a blood clot in the space remaining between the microballoon and the aneurysm wall. This clot undergoes fibrosis with firm adherence of the microballoon to the aneurysm wall. Experimental evidence is presented to support these conclusions. This thrombogenic microballoon system is also applicable to carotid-cavernous fistulas and arteriovenous malformations.

Immunotherapy for recurrent malignant glioma: an interim report on survival.

We present interim survival data for a group of 83 adult patients with recurrent malignant glioma treated by implanting stimulated autologous lymphocytes into the tumour bed following surgical debulking. The patients were treated 6 months or more prior to data analysis. Fifty-nine patients were male and 24 female. The mean age for the entire group was 48.4 years and the mean Karnofsky rating (KR) was 67.2. Eight of the patients had grade II tumours, 33 had grade III tumours and 42 had grade IV tumours. Statistical analysis focuses on tumour grade, KR and patient age, factors that have been shown to affect survival in previous studies. Multifactorial analyses are employed to identify interrelationships among factors related to survival. Seven patients (8%) did not respond to immunotherapy, 76 (92%) had a good initial response. Twenty-five patients (30.1%) are living and 18 (22%) have shown no evidence of recurrence. Results are evaluated in the light of those obtained in trials of other experimental therapies for recurrent malignant gliomas. It is concluded that the present protocol offers a safe and comparatively effective treatment option.

Ischemic brain rescue by transvenous perfusion in baboons with venous sinus occlusion.

We studied brain retroperfusion in nine adult baboons. Experiments in four baboons determined techniques and the safety of retroperfusion, and experiments in three baboons determined the ability of retroperfusion to reverse cerebral ischemia. Two baboons died before retroperfusion. Arterial blood was continuously circulated by an external pumping system from one femoral artery into the intracranial sinuses through specially designed balloon-tipped catheters placed percutaneously into the sigmoid sinuses bilaterally. The balloons intermittently occluded the sinuses. Ischemia was produced by occluding the left middle cerebral artery. Standard and computed electroencephalography with topographic mapping monitored the onset and reversal of ischemia. Retroperfusion rate exceeded 50 ml/min with a mean intrasinus pressure increase of 27 (0-149) mm Hg in all seven experiments. Venograms demonstrated complete or partial filling of the superior sagittal sinus in each experiment. Four experiments without ischemia established maximal balloon occlusion cycles, retroperfusion rates, and sinus pressure changes. These four baboons were neurologically normal after retroperfusion; two had normal magnetic resonance imaging scans. Ischemic changes, detected by electroencephalography following middle cerebral artery occlusion, were reversed with retroperfusion in all three ischemia experiments. Autopsies in the seven baboons demonstrated no parenchymal hemorrhage or edema. Our results suggest that further investigation of retroperfusion, and possibly retroinfusion of agents for cerebral protection, is warranted.