Henry Hirschberg

Intratumoral immunotoxin treatment of human malignant brain tumors in immunodeficient animals

Treatment of malignant brain tumors remains a clinical challenge. New treatment modalities are under investigation and among these are intratumoral infusion of immunotoxins that bind to specific cell surface molecules on the malignant cells. We have compared the efficacy of the 425.3‐PE immunotoxin (which targets the epidermal growth factor [EGF] receptor) with the well‐known immunotoxin Tfn‐CRM107 (which targets the transferrin receptor), for the treatment of subcutaneous and intracranial human gliomas in nude animals. Bolus intratumoral administration of 1 μg Tfn‐CRM107 or 425.3‐PE into sc U87Mg tumors in nude mice reduced the tumor volume to 29 and 79%, respectively, of that in the control group 18 days after start of treatment. Higher doses of Tfn‐CRM107 were toxic to the animals, whereas 425.3‐PE was tolerated, with a dose‐response relationship of up to 8 μg, a dose that reduced the tumor volume to 2% of control. In nude rats, treatment of intracerebral U87Mg tumors with Tfn‐CRM107 proved ineffective and doses above 10 ng/animal were toxic to tumor‐bearing rats. In contrast, intratumoral administration of 4 μg 425.3‐PE increased symptom‐free survival from 23 days to 40 days, with 2/9 surviving more than 90 days. We have recently shown that immunodeficient rats inoculated intracerebrally with precultured glioblastoma biopsy specimens develop highly infiltrative brain tumors. Direct interstitial infusion of immunotoxins into such tumors reduced the number of animals with detectable tumors at autopsy after 3 months, from 8/9 in the control animals to 4/6 and 2/6 in animals treated with Tfn‐CRM107 and 425.3‐PE, respectively. In conclusion, the anti‐EGF receptor immunotoxin 425.3‐PE exhibited promising efficacy, comparable to or better than that of Tfn‐CRM107, an immunotoxin that in early clinical trials has been found to give responses in patients with brain tumors.

Neuronavigation in intraoperative MRI

OBJECTIVE We describe the development and implementation of an image-guided surgical system combining the best features of conventional frameless stereotactic systems and the recently developed superconductive vertically configured intraoperative magnetic resonance scanner. The incorporation of intraoperatively updated magnetic resonance imaging (MRI) data sets into the neuronavigation computer overcomes one of the main disadvantages of these systems, i.e., intraoperative brain shift. METHODS The integrated system consists of a 0.5-T MRI scanner (Signa SP General Electric Medical Systems, Milwaukee, WI), a neuronavigation computer with associated software (OTS Radionics, Burlington, MA), and an emulation program linking the two. The scanner has a 60-cm-wide vertical gap where both imaging and surgery are conducted, in-bore infrared linear cameras and monitors for interactive surgical neuronavigation, and flexible surface coils specially designed for surgery. RESULTS Phantom studies showed navigational accuracy to be better than that obtained using conventional preoperative images and surface markers for patient registration. Our initial 17 cases using this integrated system comprised 16 craniotomies and one biopsy, and demonstrated decreased operative duration, greater frequency of interactive image guidance utilization, and better assessment of the progress of surgery compared to the cases previously done in the intraoperative MRI. CONCLUSION This initial study of the addition of frameless stereotactic systems to the basic intraoperative MRI concept has demonstrated its clinical usefulness. The use of the intraoperative MRI greatly reduces the basic weakness of neuronavigation inaccuracy due to target shift. The surgical procedure performed in the imaging volume of the MRI scanner eliminates the problems of patient or scanner transport during the procedure. Immobilization of the patient throughout the procedure eliminated the need for reregistration of the patient, by taking advantage of the fixed camera system in the bore of the MRI system.

Characterization of optical and thermal distributions from an intracranial balloon applicator for photodynamic therapy

An indwelling balloon applicator developed for postoperative intracavity brachytherapy was evaluated for photodynamic therapy. Measurements of light distributions in a brain phantom show that the applicator can be used to deliver sufficiently uniform light doses during PDT. The light distribution is uniform to within 5% when the balloon is filled with a scattering medium. Based on simple assumptions, it is shown that the applicator can be used to deliver a threshold optical dose to brain tissue at depths of 1.4 cm in less than 90 minutes. A mathematical model of the thermal distribution around the applicator suggests that tissue temperatures will be below the hyperthermic threshold at the input powers required for treatments to depths of 1.4 cm in the resection cavity. The delivery of threshold light doses to depths exceeding 1.4 cm is likely to result in hyperthermic effects to tissues near the applicator surface.

Stereotactic target localization accuracy in interventional magnetic resonance imaging.

Objective: To compare stereotactic target determination, based on images obtained from interventional MRI (iMRI), conventional closed MR and CT. Methods: Stereotactic coordinates for 55 targets in an artificial scull were derived from iMRI scans and compared using CT as the standard. Stereotactic coordinates were also derived from iMRI scans in a series of patients and compared using iMRI fused with CT as the standard. Results: The mean difference between targets in the skull phantom determined from iMRI and CT images was 0.90 ± 0.28 mm, with a maximum difference of 1.57 mm. The mean difference between targets in the patients derived from iMRI alone and interventional MR fused with CT was 1.39 ± 0.54 mm, with a maximum difference of 2.47 mm. Discussion: The results indicate that iMRI can be used for stereotactic target localization.

Photodynamic therapy of human glioma spheroids: a comparative study of the effectiveness of 5-aminolevulinic acid and its esters

Although 5-aminolevulinic acid (ALA) has several advantages over other photosensitizers, its hydrophilic nature gives rise to relatively poor transport across cell membranes. Esterification of ALA is a commonly used strategy to improve the effectiveness of ALA. In this study, the effectiveness of photodynamic therapy (PDT) in human glioma spheroids incubated in ALA, or ALA esters, is investigated. Spheroid survival and growth are monitored following PDT at representative drug concentrations and light fluences. It is shown that the response of human glioma spheroids to PDT with lipophilic ester derivatives, such as benzyl-ALA and hexyl-ALA, is equivalent to that observed with ALA, however, this equivalency is observed for ester concentrations 10 to 20 times lower than the parent compound.

Fluence rate effects in human glioma spheroids: Implications for photodynamic therapy of brain tumors

The effects of fluence rate are investigated in human glioma spheroids incubated in 5-aminolevulinic acid (ALA). It is shown that the response of glioma spheroids to ALA-mediated PDT depends strongly on the rate at which the light dose is delivered. At low doses, lower fluence rates are more effective. For example, at a dose of 50 JIcm2, near total spheroid kill is observed at fluence rates of as low as 1 0 mW/cm2. Below 1 0 mW/cm2, however, treatments are not as effective. The fluence rate effect is not as pronounced at higher doses where a favorable response is observed throughout the range of fluence rates investigated. The clinical implications ofthese findings are discussed.