The use of swine in brain interstitial radiation studies.

Swine offer an excellent, but previously unused, model for brain interstitial ionizing and non-ionizing radiation research. Significant advantages include size, cost, maneuverability, availability and conditioning. The methodology and some experimental results from studies of the effects of interstitial microwave hyperthermia and iridium-192 irradiation are presented.

Removable high intensity iridium-192 brain implants. Technique and in vivo measurements in canine brain.

A preclinical evaluation of the technical details and dosimetry for temporary high intensity 192Ir brain implants is presented. The canine brain was used for this quality assurance study in which direct in vivo dose measurements were done by thermoluminescent dosimetry (TLD rods). Precise and reproducible positioning of the TLD rods and 192Ir ribbons were assured by simple accessories which can be utilized in the clinical situation. The neurosurgical procedure for this non-routine interstitial implant of the brain, suitability of type and size of afterloading cannulas and facility for firmly anchoring them to the scalp, and comparison of measured doses with computer-predicted values are details assured by the canine study. Agreement between the in vivo determination and computer-generated doses was consistently in the range 2-5%. Data derived from this preclinical evaluation are currently used in both stereotactic and non-stereotactic brain implants at our institution. Details are presented for the implant procedure, dose measurements and brachytherapy planning for multiple ribbons. The latter incorporates direct interaction on computed tomography (CT) images for a hypothetical patient case.

Correction of microwave-induced thermistor sensor errors.

Accurate and reliable thermometry is essential in the development of microwave-induced hyperthermal cancer therapy. While temperature measurements in strong electromagnetic fields usually require special sensors, this does not hold true for interstitial radiator/sensor systems. Miniature thermistors (with metallic leads) bonded to invasive microwave applicators exhibit a sensor error linearly related to the radiator's transmitted power. This relationship permits thermistor sensor error correction and temperature measurements to within +/- 0.1 degrees C or better. The instrumental methods and empirical validation are presented.

Sympathetic neural prosthesis for managing orthostatic hypotension.

A prototype electromechanical analogue of the sympathetic division of the baroreceptor reflex arc was used to maintain blood pressure automatically in two patients with neurogenic orthostatic hypotension. The device prevented significant and sustained reductions in mean blood pressure when the patients were tilted up to 85 degrees. Upon achieving the preset mean blood pressure, the device maintained this pressure with a standard error of less than 2 mm Hg. Similar results were obtained when the patients were walking. The device did not cause supine hypertension during the trials.

Interstitial microwave hyperthermia for brain tumors. Results of a phase-1 clinical trial.

The technical feasibility and clinical safety of interstitial microwave hyperthermia was evaluated in six patients with glioblastoma and malignant astrocytoma. Prior to entry into the study, each patient had received surgery, radiation and nitrosourea chemotherapy. All patients were implanted at open craniotomy with a flexible microwave radiator/sensor (o.d. 1.5 mm) and transcutaneously connected to a 245- MHz microwave generator. Intraoperative thermal field plots and cooling curves were obtained with the aid of non-perturbing probes (o.d. 1.2 mm) perpendicularly driven into the tumor at fixed radial distances from the central antenna. In comparison to similar measurements carried out in normal feline brains, human gliomas were unable to efficiently dissipate heat as demonstrated by doubling of the effective diameter of the thermal field to 4 cm and by prolongation of the decay time in all cooling curves. Patients were also implanted with subarachnoid ICP monitors over the contralateral hemisphere. Two postoperative treatments were given at 45 degrees C for 60 min on the night of surgery and 48 hr later. No patient was aware of power on/power off, there were no permanent neurologic sequelae and there were no significant changes in the ICP. Power was manually controlled with visual feedback in the first three patients and automatically controlled by a computer-based system in the final three patients. Four of the six patients have lived 18 months after implantation and two of these have negative CT scans at 18 and 27 months since recurrence. It appears that interstitial microwave hyperthermia is both feasible and safe within the intracranial cavity and that combined interstitial irradiation and hyperthermia deserves clinical study.

Aggressive multimodality therapy based on a multicompartmental model of glioblastoma.

Glioblastoma multiforme is composed of multiple cellular compartments with different morphologic, kinetic, metabolic, vascular, and genetic properties. Optimal therapy may consist of a variety of therapeutic strategies designed for individual compartments, administered in close temporal relation. These concepts may turn out to be valid for other solid tumors as well. Microwave-induced hyperthermia can be used to treat metabolically quiescent, relatively hypoxic, nondividing cells (Go) otherwise resistant to radiation and chemotherapy. Similarly, polychemotherapy can treat a broad spectrum of cell types if the blood-brain barrier can be circumvented. Radical surgery, repetitively applied, can be safely used to "set up" experimental agents if the operation microscope and laser are employed. A consecutive series of 74 adult patients with malignant astrocytoma were treated with primary resection, radiation therapy, and 1,3,-bis(2 chloroethyl) 1 nitrosourea chemotherapy. At recurrence, all patients were offered reoperation with the microscope and the laser prior to administration of phase-I agents--hyperthermia via an implantable miniature microwave antenna (6 cases); aziridinylbenzoquinone chemotherapy (13 cases); and blood-brain barrier reversal with dimethyl sulfoxide (DMSO) and polychemotherapy (9 cases). It was concluded that temperatures of 45 degrees C could be safely achieved and human tumors could not efficiently dissipate heat; that DMSO plus drug therapy could be tolerated but blood-brain barrier reversal demonstrated by us in animals could not be shown in humans; and that aggressive multimodality therapy and reoperation could produce a 40% 2-year survival rate for patients younger than 40 years.

Clinical local heating by microwaves.

The advantages and limitations of microwave heating in clinical thermotherapy are reviewed on the basis of the clinical experiences of various investigators who used microwave-induced hyperthermia. Also discussed are the clinical engineering system requirements necessary for conducting controlled clinical trials, as well as appropriate thermal treatment planning. Lastly, we present the future prospects for complex antennas and treatment control systems.

Hyperthermia for brain tumors: biophysical rationale.

Hyperthermia has great potential as an antineoplastic agent because: (a) it is effective against relatively radioresistant hypoxic cells and cells in S phase; (b) unlike most chemotherapeutic agents, it is effective against poorly vascularized and metabolically quiescent tissues; (c) as a physical agent, its biological effect is related to the duration and intensity of its application; (d) it seems to have no cumulative toxicity; and (e) it potentiates the effects of both chemotherapy and ionizing radiation at the cellular level. The use of hyperthermia for malignant brain tumors is constrained by a relatively narrow therapeutic index and the considerable thermal sensitivity of normal neural tissue. Glioblastoma multiforme, by virtue of its low growth fraction and heterogeneous cell populations, seems to be an ideal candidate for hyperthermia administered as part of a combined modality treatment program. Focal hyperthermia can be produced by a number of energy sources, including those utilizing ultrasound, microwave, and radiofrequency generators. The clinical safety and feasibility of a miniature microwave radiator/sensor system for direct implantation have been demonstrated. In comparison to normal feline brain, malignant brain tumors in humans are unable to dissipate heat efficiently.

Dielectric properties of animal tissues in vivo at frequencies 10 MHz--1 GHz.

An open-ended coaxial line sensor in conjunction with an automatic network analyzer was used to measure in vivo the permittivity of several feline tissues (skeletal and smooth muscle, liver, kidney, spleen, and brain--gray and white matter) at frequencies between 10 MHz and 1 GHz. The estimated uncertainties of measurement were between 1.5% and 5%. The data are in general agreement with previously obtained data in vitro and in vivo. Significant differences in the properties of different types of the same tissue (eg, skeletal and smooth muscle) were observed. Many tissues were found to be non-homogeneous in its permittivity.

Neurosurgery and clinical engineering.

Modern technology has profoundly altered the clinical practice of neurosurgery. For a wide variety of conditions, patients are being implanted with active and passive devices or treated with advanced microsurgical instrumentation. After surgery, such patients are sent to modern intensive-care units employing the latest advances in patient monitoring and computer technology. We contend that the responsibilities of the Clinical Engineer extend beyond simple installation and maintenance of equipment and systems. It is essential that he take part in the continuing education of non-technical personnel who must make use of the equipment in ways that are meaningful in the care of the patient and to the progress of clinical science. This point is illustrated by our experience with a neurosurgical intensive-care unit. It is also the thesis of this paper that the design and maintenance of increasingly sophisticated biomedical systems will benefit from the use of an interdisciplinary approach at the very inception of a project. This approach is illustrated by our current development of a multibeam microwave hyperthermia system for possible use in the treatment of brain tumors.