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Charged particle radiotherapy for lesions encircling the brain stem or spinal cord.

Since 1981, a specialized technique has been under development at the University of California Lawrence Berkeley Laboratory for charged particle irradiation of tumors partially or completely encircling the brain stem or spinal cord. By dividing the target volume into two or more portions and using a combination of beams, a reasonably homogeneous irradiation of the target volume can be obtained which protects critical CNS structures from over-irradiation. This technique requires knowledge of the physical and biological effects of charged particles, precise, reproducible patient immobilization, careful treatment planning based upon Metrizamide contrast CT and/or MRI scanning, compensation for tissue inhomogeneities, and accurate, verifiable radiation delivery. Uncertainties in the dose distribution must be taken into account when prescribing treatment. We have used this technique in 47 patients with a variety of tumors abutting the brain stem and spinal cord, including chordoma, chondrosarcoma, meningioma, osteosarcoma and metastatic tumors. The results have shown a significant local control rate (62%) and the incidence of serious complications has been acceptable (13%). The median follow-up is 20 months with a range of 6-90 months. We conclude that charged particles can be safely and effectively used to irradiate lesions encircling the brain stem or spinal cord to doses higher than can be achieved with low-LET irradiation.

Brain Neoplasms↗

Stereotactic frame for neuroradiology and charged particle Bragg peak radiosurgery of intracranial disorders.

The application of heavy charged particle Bragg peak radiosurgery for the treatment of intracranial vascular and other disorders requires a system of precise patient immobilization and stereotactic localization of defined intracranial targets. The process of using stereotactic neuroradiological procedures (including cerebral angiography, CT scanning and magnetic resonance imaging) for target definition and localization, and complex treatment planning constrain such a system to be adaptable and reusable. This paper describes a removable stereotactic frame-mask system that is used to immobilize and reposition the patient during stereotactic neuroradiological procedures and charged particle radiosurgery. It consists of four parts--(a) a plastic mask for immobilizing the patient's head; (b) a lucite-graphite mounting frame; (c) a set of fiducial markers; and (d) interfaces between the frame for immobilization and fixation to various diagnostic and therapeutic patient couches. The relationship between each component and the radiosurgical procedure is discussed. This system has proven to be safe, reliable, and noninvasive and it does not require fixation to the bones of the face or skull. When integrated into the radiosurgical treatment planning and localization procedures developed at Lawrence Berkeley Laboratory, it is capable of reliably repositioning the patient to 1 mm in each of three planes and contouring the intracranial target reliably to this accuracy. The application of this stereotactic system in heavy charged particle radiosurgery of intracranial arteriovenous malformations is described in other reports.

Cerebral Angiography↗

Comparison of different radiation types and irradiation geometries in stereotactic radiosurgery.

Recent interest in stereotactic radiosurgery of intracranial lesions, and the development of stereotactic irradiation techniques has led to the need for a systematic and complete comparison of these methods. A method for conducting these comparisons is proposed and is applied to a set of currently-used stereotactic radiosurgical techniques. Three-dimensional treatment planning calculations are used to compare dose distributions for several different radiation types and irradiation geometries. Calculations were performed using charged particles (H, He, C, and Ne ions) and the irradiation geometry currently used at Lawrence Berkeley Laboratory. Photons in the Gamma Knife configuration and the Heidelberg Linac arc method are used. The 3-dimensional dose distributions were evaluated by means of dose-volume histograms and integral doses to the target volume and to normal brain. The effects of target volume, shape and location are studied. The charged particle dose distributions are more favorable than those of the photon methods. The differences between charged particles and photons increase with increasing target volume. The differences between different charged particle species are small, as are the effects of target shape and location.

Humans↗

Long-term results of helium ion irradiation of uveal melanoma.

Between 1978 and 1988, 307 patients with uveal melanoma were irradiated using helium ions at Lawrence Berkeley Laboratory. The length of follow-up ranged from 1-115 months (median 42 months). The 5-year actuarial treatment results were: local control rate, 96.8%, determinate survival rate, 81%, freedom from distant metastases, 76%, eye retention rate, 83%, and risk of developing neovascular glaucoma, 36%. Long-term vision outcome was analyzed in 81 patients with a minimum follow-up of 5 years. Forty-seven percent of patients retained vision of 20/200 or better. The median change in vision was a loss of four lines on the standard eye chart. Thirty-eight percent of patients had visual acuity either improve or remain within two lines of their pretreatment vision. A multivariate analysis identified tumor size as the only independently significant risk factor affecting survival, development of neovascular glaucoma, or the risk of enucleation; no risk factor correlated with local recurrence. Tumor size, tumor-fovea distance, and pretreatment visual acuity were independently significant risk factors influencing vision outcome. These results confirm that helium ion irradiation is an effective treatment for uveal melanoma which combines high rates of local control, survival, and eye retention with a substantial likelihood of long-term vision preservation.

Adult↗

Neon ion radiotherapy: results of the phase I/II clinical trial.

Neon ion radiotherapy possesses biologic and physical advantages over megavoltage X rays. Biologically, the neon beam reduces the oxygen enhancement ratio and increases relative biological effectiveness. Cells irradiated by neon ions show less variation in cell-cycle related radiosensitivity and decreased repair of radiation injury. The physical behavior of heavy charged particles allows precise delivery of high radiation doses to tumors while minimizing irradiation of normal tissues. In 1979 a Phase I-II clinical trial was started at Lawrence Berkeley Laboratory using neon ions to irradiate patients for whom conventional treatment modalities were ineffective. By the end of 1988 a total of 239 patients had received a minimum neon physical dose of 1000 cGy (median follow-up for survivors 32 months). Compared with historical results, the 5-year actuarial disease-specific survival (DSS5) and local control (LC5) rates suggest that neon treatment improves outcome for several types of tumors: a) advanced or recurrent macroscopic salivary gland carcinomas (DSS5 59%; LC5 61%); b) paranasal sinus tumors (DSS5 69%; LC5 69% for macroscopic disease); c) advanced soft tissue sarcomas (DSS5 56%, LC5 56% for macroscopic disease); d) macroscopic sarcomas of bone (DSS5 45%; LC5 59%); e) locally advanced prostate carcinomas (DSS5 90%; LC5 75%); and f) biliary tract carcinomas (DSS5 28%; LC5 44%). Treatment of malignant gliomas, pancreatic, gastric, esophageal, lung, and advanced or recurrent head and neck cancer has been less successful; results for these tumors appear no better than those achieved with conventional x-ray therapy. These findings suggest that Phase III trials using the neon beam should be implemented for selected malignancies.

Drug Evaluation↗

Charged particle radiotherapy of paraspinal tumors.

Between 1976 and 1987, 52 patients with tumors adjacent to and/or involving the cervical, thoracic, or lumbar spinal cord were treated with charged particles at the University of California Lawrence Berkeley Laboratory. The histologies included chordoma and chondrosarcoma (24 pts), other bone and soft tissue sarcoma (14 pts), and metastatic or unusual histology tumors (14 pts). Radiation doses ranged from 29 to 80 Gray-equivalent (GyE), with a median dose of 70 GyE. Twenty-one patients received a portion of their treatment with photons. Median followup was 28 months. For 36 previously untreated patients, local control was achieved in 21/36 patients and the 3-year actuarial survival was 61%. Of 16 patients treated for recurrent disease, 7/16 were locally controlled and the 3-year actuarial survival was 51%. For patients treated for chordoma and chondrosarcoma, probability of local control was influenced by tumor volume (less than 100 cc or greater than 150 cc) and whether disease was recurrent or previously untreated. Complications occurred in 6/52 patients, including one spinal cord injury, one cauda equina and one brachial plexus injury, and three instances of skin or subcutaneous fibrosis. Charged particle radiotherapy can safely deliver high tumor doses to paraspinal tumors with good local control.

Adolescent↗

Recurrent locally advanced nasopharyngeal carcinoma treated with heavy charged particle irradiation.

Between June 1981 and May 1990, 11 patients with recurrent locally advanced nasopharyngeal carcinoma were treated with heavy charged particle radiation at Lawrence Berkeley Laboratory. All patients had previously undergone full course radiotherapy to a median dose of 70.2 Gy [range 61-81 Gy]. Median time to recurrence was 18.2 months. At the time of heavy charged particle radiotherapy treatment, all had evidence of invasion of the base of skull and 7 of 11 had cranial nerve deficits. None of the patients were candidates for brachytherapy because of tumor extent or poor geometry. The tumor histology was squamous cell carcinoma in 10 patients and lymphoepithelioma in one patient. Ten of the 11 patients had received chemotherapy prior to re-irradiation. The heavy charged particle tumor dose delivered ranged from 31.80 GyE to 62.30 GyE (average 50.25 GyE, median 50 GyE). Local control was achieved in 45%. Median survival was 42 months. Actuarial survival was 59% at 3 years and 31% at 5 years (Kaplan-Meier). There were no fatal complications. The results in treating locally advanced recurrent nasopharyngeal carcinoma with heavy charged particles appear superior to those reported by others using photon therapy.

Carcinoma, Squamous Cell↗

Preliminary results in heavy charged particle irradiation of bone sarcoma.

Between 1979 and 1989, 17 patients with unfavorable bone sarcoma were treated wholly or in part with heavy charged particle irradiation (helium and/or neon ions) at the University of California Lawrence Berkeley Laboratory. The majority of tumors were located near critical structures such as the spinal cord or brain. Gross tumor was present in all but two patients at the time of irradiation. Six patients were treated for recurrent disease. Histologies included osteosarcoma, Ewing's sarcoma, and recurrent osteoblastoma. Four of the osteosarcomata were believed to have been induced by previous therapeutic irradiation for various tumors. Follow-up time since initiation of radiation ranged from 7 to 118 months (median 40 months). The 5-year Kaplan-Maier local control rate was 48%; the corresponding survival rate was 41%. Over half the patients succumbed to distant metastases despite the majority of patients receiving chemotherapy. In this preliminary study, we have shown that heavy charged particle irradiation can be effectively used for control of bone sarcoma. A Phase II trial is warranted to determine optimal treatment for unresectable or gross residual disease.

Antineoplastic Combined Chemotherapy Protocols↗

Charged particle irradiation of sacral chordomas.

PURPOSE: The purpose of this report is determine the impact of charged particle irradiation at Lawrence Berkeley Laboratory (LBL) in treating patients with sacral chordomas. Overall survival, local control, complications, and predictive parameters are analyzed. METHODS AND MATERIALS: Fourteen patients with sacral chordomas were treated with the charged particles helium and neon between 1977 and 1989. The median dose was 7565 cGyE and the median follow up is 5 years. All patients were treated post-operatively; ten had gross residual disease. RESULTS: Kaplan-Meier survival at 5 years is 85%. Overall 5-year local control is 55%. A trend to improved local control at 5 years was seen in patients treated with neon when compared to patients treated with helium (62% vs 34%), in patients following complete resection versus patients with gross residual tumor (75% vs 40%), and in patients who had treatment courses under 73 days (61% vs 21%). Distant metastases were seen in two patients (14%). No patient developed neurologic sequelae or pain syndromes. One previously irradiated patient required colostomy, one patient had delayed wound healing following a negative post-radiation biopsy, and one patient developed a second malignancy. There were no genitourinary complications. CONCLUSION: Our experience indicates that post-operative charged particle irradiation of sacral chordomas appears to result in reasonable local control and survival with acceptable risk, and that additional evaluation on the use of heavy charged particles is warranted.

Adult↗

Evaluation of a pencil-beam dose calculation technique for charged particle radiotherapy.

PURPOSE: The purpose of this article is to evaluate a pencil-beam dose calculation algorithm for protons and heavier charged particles in complex patient geometries defined by computed tomography (CT) data and to compare isodose distributions calculated with the new technique to those calculated with conventional algorithms in selected patients with skull-base tumors. METHODS AND MATERIALS: Monte Carlo calculations were performed to evaluate the pencil-beam algorithm in patient geometries for a modulated 150-MeV proton beam. A modified version of a Monte Carlo code described in a previous publication (18) was used for these comparisons. Tissue densities were inferred from patient CT data on a voxel-by-voxel basis, and calculations were performed with and without tissue compensators. A dose calculation module using the new algorithm was written, and treatment plans using the new algorithm were compared to plans using standard ray-tracing techniques for 10 patients with clival chordoma and three patients with nasopharyngeal carcinoma who were treated with helium lons at Lawrence Berkeley National Laboratory (LBL). RESULTS: Pencil beam calculations agreed well with Monte Carlo calculations in the patient geometries. The pencil-beam algorithm predicted several multiple-scattering effects that are not modeled by conventional ray-tracing calculations. These include (a) the widening of the penumbra as a function of beam penetration, (b) the degradation in the sharpness of the dose gradient at the end of the particle range in highly heterogeneous regions, and (c) the appearance of hot and cold dose regions in the shadow of complex heterogeneities. In particular, pencil-beam calculations indicated that the dose distribution within the target was not as homogeneous as expected on the basis of ray-tracing calculations. On average, for the 13 patients considered, only about 72% of the conedown target volume received at least 99% of the prescribed dose, whereas, 93% of the conedown volume was contained within the 95% isodose surface. This may be significant because in standard charged particle dose calculations, the dose across the spread-Bragg peak is assumed to be uniform and equal to the maximum or prescribed dose. CONCLUSIONS: Dose distributions computed with the pencil-beam model are more accurate than ray-tracing calculations, providing additional information to clinicians, which may influence the doses they prescribe. In particular, these calculations indicate that for some patients with skull-base tumors, it may be advantageous to prescribe proton doses to a lower isodose level than is commonly done.

Algorithms↗

Genetics and ethanol tolerance.

This paper reviews some of the research on genetic bases of individual differences in ethanol tolerance of mice conducted at the Institute for Behavioral Genetics and at its predecessor laboratory at the University of California, Berkeley. Tolerance is, of course, a complex concept. Theoretical distinctions are made between tachyphylaxis and more slowly acquired tolerance and between dispositional and tissue tolerance. Pragmatically, a variety of measures (such as locomotor activity, sleep time, hypothermia) can be used to define these processes, and the different indices may yield quite different results even when they presumably indicate the same process. It is clear that an understanding of genetic influence in "ethanol tolerance" will require wide sampling of this complex domain. The work described here represents only a beginning, but it may illustrate the general approaches that are available for addressing the issue.

Alcohol Drinking↗

Evaluation of a new herpes simplex virus typing reagent for tissue culture confirmation.

Monoclonal antibody typing reagents for herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) from California Integrated Diagnostics, Inc. (Berkeley, CA) were compared to two other commercially available HSV monoclonal antibody typing reagents. Of the 105 specimens tested, of which 81 were positive for HSV, there was 100% agreement with all three typing reagents.

Antibodies, Monoclonal↗

Confirmation of high blood flow rates through 150 mu filter/high-flow tubing.

Many new products designed to assist in rapid blood infusion are appearing. Some highly touted and routinely used devices for intravenous (IV) infusion have recently been shown to be, at least in part, defective. A tubing with an in-line 150 mu filter (150 mu High-Flow Blood Filter; Saftifilter Blood Administration Sets; Cutter Biological, Berkeley, CA 94710) has recently been introduced to facilitate rapid blood transfusion. It is claimed that at least 8.5 units of blood can be rapidly run through each set before replacement is necessary. To test this under simulated clinical conditions, four sets of ten random units of outdated erythrocytes at 4 to 9 degrees C were each admixed with 250 mL 70 degrees C 0.9 NaCl and infused through the system under a constant 300 mmHg pressure. Two sets infused through unmodified tubing flowed at an average of 25 mL/sec (1500 mL/min) before there was an appreciable slowing of the flow rate. Two sets with 8 Fr catheters attached infused at an average of 22 mL/sec (1320 mL/min) before there was an appreciable slowing of the flow rate. Even after the flow slowed, the 9th and 10th units infused at an average greater than 10 mL/sec (600 mL/min). The tubing/filter exceeded the manufacturer's published claims. This tubing/filter appears to be one element that could be an effective component of a high-flow infusion system.

Blood Transfusion↗

Phylogenetic relationships in the honeybee (genus Apis) as determined by the sequence of the cytochrome oxidase II region of mitochondrial DNA.

The complete nucleotide sequence of the mitochondrial cytochrome oxidase II (COII) gene was determined for five species of the honeybee (Genus: Apis): A. andreniformis, A. cerana, A. dorsata, A. florea, and A. koschevnikovi; these were then compared to the known sequence of the A. millifera gene from Crozier et al. (1989, Mol. Biol. Evol., 6: 399-411) and the wasp Excristes roborator (Liu and Beckenbach, 1992, Mol. Phylogenet. Evol., 1:41-52). Phylogenetic relationships were derived using the parasimony methods DNAPARS and PROTPARS of Felsenstein ("PHYLIP Manual Version 3.4, "University Herbarium, Univ. of California, Berkeley). The results suggest that A. dorsata is the most ancestral species, followed by the branching of A. florea/A. andreniformis and A. koschevnikovi, and then A. mellifera and A. cerana. This inference differs from the currently accepted view that considers the A. florea/A. andreniformis line to be the most ancestral.

Amino Acid Sequence↗

Retinal change induced in the primate (Macaca mulatta) by oxygen nuclei radiation.

Retinas of primates (Macaca mulatta) were exposed to oxygen nuclei at the Bevatron, Berkeley, California. Color fundus photographs and fluorescein angiograms were taken of the retinas prior to irradiation and up to 5 weeks post exposure. Animals were sacrificed at post exposure intervals for histopathologic examination of the retinas. A series of animals were exposed to 200 kVp X-ray and examined on the same regime as the first series. The results showed a low rad equivalent dose for retinal damage as compared with the X-ray series, i.e., a high quality factor, and a marked compression of the latency between exposure and onset of the retinal pathology.

Animals↗

Experimental methods of correlation between the trajectories of cosmic heavy ions and biological objects: dosimetric results from the Biostack experiment on Apollo 16 and 17.

The biological objects in the Biostack are stacked alternately between physical detectors of HZE particle tracks which include nuclear emulsions. The pattern of the biological objects is transferred to the upper side of the adjacent emulsion by optical illumination. On each sheet of nuclear emulsion a coordinate grid is transferred to the bottom side by optical illumination. The visible track left by the passage of the heavy ion can then be very clearly localized. The charge of the ions is determined by photometric measurements of the tracks. These measurements are calibrated with known tracks of heavy ions accelerated at the Bevatron at Berkeley. The results are given as: flux, number of stars per cm3, charge of the ions, comparison with other detectors (plastics, AgCl crystals, LiF), energy loss, hit region in the biological objects.

Cosmic Radiation↗

Comparative study of lesions in the brain of rats exposed to heavy ions: accelerator and stratospheric flight research.

Irradiations of rat's brain with heavy ionized particles (12/6C, 291 Mev/nucleon, 100 to 300 ions/mm2) have been carried out at the Lawrence Berkeley Laboratory. Exposures were made with slowed ions which stopped within the brain as well as with more energetic particles which passed through. Histological examination of irradiated encephalons by optical microscopy showed zones of glial reaction and an increased number of darkly staining cells. By electron microscopy, intercellular edema, various alterations of nervous cells and macrophagy were observed, especially with stopped ions.

Animals↗

Measuring nigrescence attitudes in school-aged adolescents.

In this study, we examined the reliability and validity of Cross Racial Identity Scale (CRIS; Vandiver, B. J., Cross Jr., W. E., Fhagen-Smith, P. E., Worrell, F. C., Swim, J. K., & Caldwell, L. D. (2000). The Cross Racial Identity Scale. Unpublished scale; Worrell, F. C., Vandiver, B. J., & Cross Jr., W. E., (2004). The Cross Racial Identity Scale: Technical manual (2nd ed.). Berkeley, CA: Author) scores in 143 middle and high school students. Exploratory factor analyses provided support for the six-factor structure of the CRIS, reliability estimates for the scores were in the moderate to high range, and subscale intercorrelations were low. Multicultural Inclusive scores were significantly correlated with age with high school students reporting significantly higher multicultural attitudes than middle school students. The authors concluded that the CRIS is appropriate for use with adolescent populations.

Adolescent↗