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.

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.

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.

Hematogenous candida osteomyelitis. Report of three cases and review of the literature.

Candida osteomyelitis of the spine and intervertebral disc developed in three patients without evidence of back trauma of overlying cutaneous infection. Two patients were prone to the development of disseminated candidiasis by the use of multiple antibiotics and other predisposing modalities following abdominal surgery. One patient had no identifiable cause for development of the infection. The diagnosis was established in all three cases by x-ray evidence of osteomyelitis and culture from needle aspirate. Two patients had bone scans consistent with infection. Each patient received different therapy. One was treated with amphotericin B, one with spinal fusion and 5-fluorocytosine, and one with no antifungal therapy. All patients had complete healing of the involved vertebrae. Candida organisms have the potential to cause destructive bone infection following hematogenous dissemination. The presence of Candida osteomyelitis may be helpful in diagnosing disseminated candidiasis.

Scanning electron microscopic observations of the common carotid artery of the rat. III. Heparin effect on platelets.

After administration of high systemic doses of heparin verified by assay, common carotid arteries in the rat were divided and sutured. Scanning electron microscope observations of endothelial surfaces showed a decrease in platelet adhesion, as well as a reduction in the adherence of other circulatory blood elements when compared to controls. This is the first report indicating the in vivo effect of high dose systemic heparin on platelets.

Lack of effect of thyroid hormones on the growth hormone response to thyrotropin-releasing hormone in acromegaly.

Serum growth hormone (GH) responses to thyrotropin-releasing hormone (TRH) were evaluated in 14 patients with acromegaly following treatment with thyroid hormones. After an initial TRH test, seven patients received L-triiodothyronine, 100 mug daily for seven days; the GH response to TRH was not significantly altered by this treatment. Similar findings were noted in two acromegalic subjects who were tested with TRH before and after longer periods of administration of L-thyroxine. Four of five additional subjects with acromegaly who had received replacement doses of thyroid hormones for an average of 6.6 yr demonstrated GH responses to TRH which were similar to those seen in subjects not receiving thyroid hormones. Acute or long-term administration of replacement doses of thyroid hormones seems to have minimal effect on the GH response to TRH in acromegaly.

Intraoperative digital subtraction neuroangiography: a diagnostic and therapeutic tool.

We report our experience with intraoperative digital subtraction neuroangiography to demonstrate its application as a diagnostic and therapeutic technique. Intraoperative neuroangiography was performed on 53 occasions in 43 patients using a portable imaging system. Thirty-two procedures were performed for diagnostic purposes after resection of arteriovenous malformations, clipping of aneurysms, or carotid endarterectomy. Unexpected problems were disclosed in seven cases and were surgically remedied immediately in four. In addition, angiography was used as a therapeutic tool in 21 cases to facilitate intraoperative embolization of a vascular lesion or to enable the angioplasty of a vessel inaccessible without direct surgical exposure. We found that by allowing a combined interventional neuroangiographic and neurosurgical approach, intraoperative angiography opened new avenues for treatment of intracranial vascular abnormalities.

Efficacy of cryohypophysectomy in the treatment of acromegaly. Evaluation of 54 cases.

Between 1963 and 1974, 54 patients with acromegaly (28 men and 26 women) ranging in age from 23 to 61 years were evaluated. Each patient underwent thorough preperative neurological, roentgenographic, and endocrinological surveys; most demonstrated mild-to-severe abnormalities in growth hormone immunoassay and oral glucose tolerance. Of those who underwent stereotaxic cryohypophysectomy, approximately 80% were considered to have a beneficial result. The efficacy of this form of therapy was judged on the basis of: 1) significant overall clinical improvement and regression of acromegalic features; 2) improvement in the glucose tolerance curve; and 3) a fall of serum growth hormone below 10 ng/ml. Complications including rhinorrhea, meningitis, and hemorrhage occurred in only a small number of cases. A comparison is made between this technique and other, including craniotomy, radiotherapy, and transnasal transsphenoidal hypophysectomy. The efficacy, low morbidity, and the ease with which the procedure may be performed make this our treatment of choice when dealing with growth-hormone-producing pituitary adenomas with no suprasellar extension.

The cryoprobe retractor in the microsurgical dissection of tumors. Technical note.

A technique is outlined for retraction of tumors under the operating microscope using the microcyoprobe. The method depends on temperatures settings in the--20 degrees to--30 degrees C range to produce a small ice bond uniting tumor and cryoprobe. No attempt is made to create a solid frozen tumor. The locally avascular field and retraction provided ideal circumstances for microdissection. Examples of this approach are outlined with case summaries for spinal cord ependymoma and hemangioblastoma.

Detachable balloon catheter. Its application in experimental arteriovenous fistulae.

Recent Russian reports have described the use of balloon occlusion in both the diagnosis and treatment of various pathological processes affecting intracranial vessels. This intraluminal approach has demonstrated successful results in vascular problems such as carotid-cavernous fistulae, arteriovenous malformations, and large inoperable aneurysms. Despite widespread interest in the neurosurgical community, the application of a similar technique in the Western hemisphere has been hindered by lack of an adequate, functional, inflatable apparatus. The authors describe their experience with the prototype of a safe, reliable, detachable balloon. Because of a unique development, the apparatus may be filled with liquid and detached from its parent catheter without subsequent leakage. In order to satisfy variable requirements, balloons are available in several sizes ranging from 0.5 to 4.0 mm in diameter. When fully inflated these devices will hold from 1 to 3 cc of fluid. The authors' study involved 18 dogs with artificially created carotid-jugular fistulae that were visualized by angiography. Under fluoroscopic control, detachment of inflated balloons on the venous side of the defect not only successfully occluded the fistulae but also preserved the arterial vasculature. X-ray films taken several weeks later failed to show any change either in size or position of the inflated devices.

A critical comparison of neurosurgical and otolaryngological approaches to acoustic neuromas.

Neurosurgeons have traditionally advocated the transmeatal suboccipital craniectomy as the procedure of choice in treating acoustic neuromas of all sizes. With this technique, complete tumor removal was achieved in 91% of our patients. Facial motor activity was fully preserved in 59% and it was only partially deficient in an additional 29%. Conversely, recent otological reports have proposed a more flexible attitute in which the size of the tumor dictates the form of surgical therapy. In that scheme, the universally applicable and clinically proven suboccipital craniectomy is replaced by a series of procedures (translabyrinthine, middle fossa, transsigmoidal), each of which differs in its anatomical and technical requirements. This necessity for several operations seems to stem from the failure of any particular approach either to provide adequate visualization of the entire pathological process, or to afford maximum opportunity for complete tumor removal. By employing these various techniques, total capsular removal has been generally achieved in only 71% of cases. A careful comparison and analysis of these individual procedures reaffirms the superiority of the posterior fossa approach.

Comparison of fascicular, interfascicular and epineural suture techniques in the repair of simple nerve lacerations.

Simple lacerations of dog anterior tibial nerves were repaired utilizing fascicular interfascicular, and epineural suture techniques. Two months following repair, the involved regions of the nerve were removed and stained with hematoxylin and eosin, Weil, Bielschowsky, and Masson trichrome stains. An independent, unbiased observer rated proximal and distal myelin, connective tissue responses, and proximal to distal axon counts. The proportion of proximal to distal axons revealed no significant difference between fascicular (77%) and epineural (67%) neurorrhaphy, but showed a significant beneficial effect of fascicular suture to the interfascicular (52%) repair (significance at less than 0.02). Masson stain revealed dense connective tissue responses, but the axon counts were adversely affected only when the separate fascicles showed internal disruption by connective tissue. In general, distal myelinization was mildly superior with the fascicular neurorrhaphy technique. It appears that in simple lacerations in nerves which are repaired via direct end-to-end suture, there is no significant advantages to fascicular over epineural repair; however, there is a definite deleterious effect of interfascicular neurorrhaphy. The theoretical and technical implications of these findings are discussed.

Fascicular nerve allograft evaluation. Part 1: comparison with autografts by light microscopy.

In a comparative experiment, transplantation of orthotopic nerve fascicle was performed on 100 sciatic nerves between inbred, antigenically identified rats. The authors studied cellular response, macrophage reaction, connective-tissue reaction, myelination, and distal/proximal axonal ratios, but no difference could be established between allografted and autografted fascicles after 2 months. Moreover, there was no evidence of any graded rejection phenomenon dependent on differences of tissue typing. Theories for the decreased antigenic reaction of nerve fascicles are proposed.

Fascicular nerve allograft evaluation. Part 2: comparison with whole-nerve allograft by light microscopy.

Orthotopic whole-nerve and fascicular nerve grafts were transplanted between inbred rats with known histocompatibility antigen structure. In general, the whole sciatic nerves demonstrated a graded rejection response dependent upon the degree of tissue histocompatibility differences. The fascicular grafts, however, had evidence of greatly decreased rejection and no stigma of a graded response dependent on degree of variability of tissue typing. Limitations of the experiment are outlined, and the possible avenues of further research are briefly discussed.

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.

Leksell stereotactic radiosurgery in the treatment of eye melanoma.

Current experiments indicate that a focussed single radiation treatment with a dose of 6000 to 9000 rads delivered to the 90% zone through a collimator of the Leksell stereotactic radiosurgical unit or 'gamma knife' to the rabbit eye melanoma model is capable of destroying the cancer totally and thus effecting a cure. The beneficial effect in these rabbit eye melanoma experiments appears to be similar to the results obtained by physicians using the Harvard and Berkeley cyclotrons in treating malignant neoplasms in the human eye. Therefore, it is proposed that a properly designed stereotactic radiosurgical unit can be used in patients with eye tumours similar to those selected for the cyclotron systems.

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.

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.

Current adjuncts for surgery of the sphenoid sinus and pituitary gland.

Surgical intervention in the region of the sphenoid sinus pituitary gland requires extreme precision because of enveloping vital structures. The rhinologic approach to the pituitary gland, once abandoned due to limited visibility and the risk of meningitis, has experienced a renaissance as a result of recent medical and technical advances. Antibiotics have almost eliminated the risk of meningitis, and the operating microscope and televised radiofluoroscope now provide sufficient illumination, magnification, and orientation that injury to nearby structures can be avoided. A mid-line rhinologic approach provides ample exposure and further minimizes operative hazards.

Ischemic paralysis of the facial nerve: a possible etiologic factor in Bell's palsy.

Numerous causes of peripheral facial nerve paralyses have been described; however, none has satisfactorily explained the genesis of the most common type of paralysis, Bell's palsy. Two patients undergoing an experimental embolization of vascular intracranial tumors suffered a total peripheral facial nerve paralysis when occlusion of the middle meningeal artery had been accomplished. It is speculated that this paralysis resulted from ischemia of the horizontal portion of the facial nerve, an observation that has not previously been described and that might be applicable as well to the etiology of Bell's palsy.