Robert W. Rand

Safety, Tolerability, and Tumor Response of IL4-Pseudomonas Exotoxin (NBI-3001) in Patients with Recurrent Malignant Glioma

SummaryPurpose: This was an open-label, dose-escalation trial of intratumoral administration of IL-4Pseudomonas exotoxin (NBI-3001) in patients with recurrent malignant glioma. Patients and methods: A total of 31 patients with histologically verified supratentorial grades 3 and 4 astrocytoma were studied. Of these, 25 patients were diagnosed with glioblastoma multiforme (GBM) while six were diagnosed with anaplastic astrocytoma. Patients were over 18 years of age and had Karnofsky performance scores ≥60. Patients were assigned to one of four dose groups in a dose-escalation fashion: 6 µg/ml × 40 ml, 9 µg/ml × 40 ml, 15 µg/ml × 40 ml, or 9 µg/ml × 100 ml of NBI-3001 administered via convection-enhanced delivery intratumorally using 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 µg/ml × 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.

Cryolumpectomy for breast cancer: an experimental study.

The effects of cryosurgical procedures and surgical excision in preventing the local recurrence of mammary adenocarcinoma were studied in BALB/cfC3H mice carrying syngeneic, virus-induced mammary adenocarcinomas transplanted into the fourth mammary fat pad. In this report we present evidence demonstrating that cryosurgical procedures involving multiple freeze-thaw cycles followed by tumor excision markedly reduce the local recurrence rate of mouse mammary cancer. Surgical resection without cryotreatment resulted in an 80% local recurrence rate; in contrast, cryotreatment consisting of three freeze-thaw cycles before excision prevented local tumor recurrence in 70% of the animals. The use of cryotherapy and local excision (cryolumpectomy) in the treatment of human breast cancer is discussed.

Ferromagnetic Silicone Necrosis of Hypernephromas by Selective Vascular Occlusion to the Tumor: A New Technique

Arterial vascular occlusion of hypernephromas may be performed by obstructiing the tumor vascular tree with the injection of ferromagnetic silicone microspheres. The powerful superconducting electromagnet confines the embolized iron-silicone compound to the neoplastic target organ. Radioactive material may or may not be added to the iron-silicone compound to give local direct radioactive radiation therapy to the tumor area. In experimental dogs up to 70,000 rad of beta radiation from the P32 source had been delivered homogeneously within the kidney when mixed with the ferrosilicone. This technique may well be used in cases in which a major operation is contraindicated or when preoperative necrosis of the tumor is advisable. Since the entire procedure can be done with the patient under local anesthesia in a radiology department it may be a valuable new technique in the future management of urological tumors, unilateral renal hypertension, solitary kidney pathology and so forth. Ferrosilicone material has not been found to be toxic. The application of a powerful superconducting electromagnet to the technique provides a means of confining the embolized iron-silicone compound to the target organ.

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.

Thermomagnetic surgery for cancer.

Thermomagnetic Surgery is a unique technique that takes advantage of the phenomenon of hysteresis heating of a ferromagnetic material to produce intense but controlled temperatures within solid organs or tumors to cause coagulation necrosis. By controlling the power of the electromagnetic coil system, the degree of heating of the tumor can be controlled through temperature monitoring that allows limitation of the area of destruction to the disease process and avoids damage to surrounding structures. If the ferromagnetic material is delivered by the arterial route to the tumor or organ, there is an additional beneficial effect of ischemic necrosis of the tissue and in time more concentration of the ferromagnetic particles. This new technique is applicable to selected cases of human cancer because no ill effect has been shown to exposure of the electromagnetic field or the ferromagnetic material in experimental animals.

Birth injuries to the spinal cord: A report of 2 cases and review of the literature

Abstract Two personally studied examples of injuries to the cervical spinal cord attendant upon breech extraction prompted a review of the mechanisms whereby such lesions are produced, their frequency, and the clinical aspects. From 1923 to the present time 53 reasonably well-documented examples of birth injury to the spinal cord have been reported. Forceful breech extraction is the commonest obstetrical situation, although cephalic presentation may also be associated with cord injury. The cervicothoracic spinal cord is the predominant site of injury which may be complete or patchy. Forceful traction plus angulation of the vertebral column offers the greatest chance of damage to the cord with or without attendant vertebral column trauma. The disparity between the very pliable beny ligamentous column and the less elastic spinal cord and meninges explains the often severe cord lesions without bone or point injury. Therapy is directed to the supportive care of a paraparetic or paraplegic infant with high mortality and severe morbidity. Only rarely will operative measures be applicable. Prevention of the condition requires an alertness to its potential occurrence and a cognizance of the vulnerability of the spinal cord to stretch and angulation so that the physician is sensitized to the spinal cord as well as to the umbilical cord when vigorous extractive methods are needed.

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, Bells 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 Bells palsy.

Central Spinal Cord Syndrome in Hyper-extension Injuries of the Cervical Spine

The syndrome of acute central cervical spinal-cord damage, as originally described by Bailey and subsequently by Schneider, Cherry, and Pantek, consists of disproportionately greater weakness in the upper extremities as compared with the lower, with various sensory changes at or below the site of the lesion, and urinary bladder dysfunction. Three patients with this problem are presented. The mechanism of injury is discussed and related to pre-existing conditions such as cervical spondylosis as well as acute pathological entities causing central cord damage, such as hematomyelia, contusion, cord swelling, and ischemia. The treatment and prognosis of patients with this type of spinal-cord injury is outlined.

Thermomagnetic surgery for cancer

Thermomagnetic Surgery is a unique technique that takes advantage of the phenomenon of hysteresis heating of a ferromagnetic material to produce intense but controlled temperatures within solid organs or tumors to cause coagulation necrosis. By controlling the power of the electromagnetic coil system, the degree of heating of the tumor can be controlled through temperature monitoring that allows limitation of the area of destruction to the disease process and avoids damage to surrounding structures. If the ferromagnetic material is delivered by the arterial route to the tumor or organ, there is an additional beneficial effect of ischemic necrosis of the tissue and in time more concentration of the ferromagnetic particles. This new technique is applicable to selected cases of human cancer because no ill effect has been shown to exposure of the electromagnetic field or the ferromagnetic material in experimental animals.

Preoperative vascular embolization as an adjunct to successful resection of large retroperitoneal hemangiopericytoma.

A large retroperitoneal hemangiopericytoma was resected successfully with the aid of preoperative control of the blood supply of the lesion with percutaneous intra-arterial gelfoam and ferromagnetic silicone embolization. We believe that this resection would not have been possible without this adjuvant technique. Future application of this combined technique will enable more aggressive surgical intervention in unresectable vascular tumors and arteriovenous malformations.