Technical note: using calcium carbonate as an osmolar control treatment for acid-base studies in horses.

The efficacy of using calcium carbonate as an osmolar control treatment for acid-base studies in horses receiving alkalizing compounds was evaluated. Six mares were nasogastrically intubated with isomolar quantities of sodium or calcium as sodium bicarbonate or calcium carbonate or with water during three treatment periods. Doses of the carbonic acid salts were 500 mg/kg sodium bicarbonate mixed with 4 L of distilled water (positive control) and 595 mg/kg calcium carbonate mixed with 2 L of distilled water to yield isoosmolar treatments. Four liters of distilled water served as the negative control. Jugular venous blood samples were drawn before intubation and at hourly intervals for 6 h after intubation. The serum electrolytes Na+ and K+, blood pH, and HCO3- were determined. The sodium bicarbonate treatment increased blood pH and HCO3- (P < 0.01) above both the water and CaCO3 treatments. No differences (P > 0.05) were found between the water and CaCO3 treatments. These data indicate that calcium carbonate may serve as a suitable osmolar control treatment for studying the effects of treatments that affect acid-base status of horses.

Handling individual mammalian embryos using microfluidics.

We have designed, built, and tested microfluidic systems capable of transporting individual, preimplantation mouse embryos (100-microm to 150-microm diameter) through a network of channels. Typical channels are 160 to 200 microm deep, 250 to 400 microm wide at the top, and narrower at the bottom (0 to 250 microm wide) due to the fabrication process. In these channels, a pressure gradient of 1 Pa/mm causes the medium to flow on the order of 10(-10) m3/s (100 nl/s), with an average speed of 1 to 2 mm/s. Under these flow conditions the embryos roll along the bottoms of the channels, traveling at 1/2 the speed of the fluid. By manipulating the pressure at the wells connected to the ends of the channels, the embryos can be transported to (and retained at) specific locations including culture compartments and retrieval wells.

Radiation physics for particle beam radiosurgery.

For the particles and energies considered suitable for radiosurgery, with increasing particle charge, the Bragg peak height reaches a maximum with helium and then decreases, the Bragg peak width narrows, the distal fall-off steepens, and the exit dose increases (Table 1). The helium-ion beam is superior to a proton beam because of the higher peak-plateau ratio, more rapid dose fall-off, and smaller beam deflection, and it suffers only in the modest exit dose. Comparison of the therapeutically useful parameters of these beams is complicated by the change in beam quality (LET) with depth. Considerations of RBE values, which change with the ion species and with depth of penetration, may alter the relative rankings based on one or more of these beam characterization values. For all these beams, the RBE increases with increasing LET. The effect for protons is small and occurs just at the end of range of the particles. Effective isodose distributions based on modeled beams have been reported for helium, carbon, and neon ions. These distributions include the effects of a varying RBE with changes in the beam quality (as measured by a dose-weighted LET) and the change in dose fraction size with depth (the dose per fraction is a function of the depth of penetration). These calculations suggest that the optimal charged-particle beam for radiosurgery might be carbon. Heavy charged-particle beams can produce dose distributions superior to those obtainable with photon or electron beams. In clinical trials, these dose distributions have proved to be useful for the treatment of human diseases, including neoplasia and life-threatening intracranial disorders.(ABSTRACT TRUNCATED AT 250 WORDS)

Charged-particle radiosurgery for intracranial vascular malformations.

Heavy charged-particle radiation has unique physical characteristics that offer several advantages over photons and protons for stereotactic radiosurgery of intracranial AVMs. These include improved dose distributions with depth in tissue, small angle of lateral scattering, and sharp distal fall-off of dose in the Bragg ionization peak. Under multi-institutionally approved clinical trials, we have used stereotactic helium-ion Bragg peak radiosurgery to treat approximately 400 patients with symptomatic, surgically inaccessible vascular malformations at the UCB-LBL 184-in synchrocyclotron and bevatron. Treatment planning for stereotactic heavy charged-particle radiosurgery for intracranial vascular disorders integrates anatomic and physical information from the stereotactic cerebral angiogram and stereotactic CT and MR imaging scans for each patient, using computerized treatment-planning calculations for optimal isodose contour distribution. The shape of an intracranial AVM is associated strongly with its treatability and potential clinical outcome. In this respect, heavy charged-particle radiosurgery has distinct advantages over other radiosurgical methods; the unique physical properties allow the shaping of individual beams to encompass the contours of large and complexly shaped AVMs, while sparing important adjacent neural structures. We have had a long-term dose-searching clinical protocol in collaboration with SUMC and UCSF and have followed up over 300 patients for more than 2 years. Initially, treatment doses ranged from 45 GyE to 35 GyE. Currently, total doses up to 25 GyE are delivered to treatment volumes ranging from 0.1 cm3 to 70 cm3. This represents a relatively homogeneous dose distribution, with the 90% isodose surface contoured to the periphery of the lesion; there is considerable protection of normal adjacent brain tissues, and most of the brain receives no radiation exposure. Dose selection depends on the volume, shape, and location of the AVM and several other factors, including the volume of normal brain that must be traversed by the plateau portion of the charged-particle beam. The first 230 patients have been evaluated clinically to the end of 1989. Using the clinical grading of Drake, about 90% of the patients had an excellent or good neurologic grade, about 5% had a poor grade, and about 5% had progression of disease and died, or died as a result of unrelated intercurrent illness. Neuroradiologic follow-up to the end of 1989 indicated the following rates of complete angiographic obliteration 3 years after treatment: 90% to 95% for AVM treatment volumes less than 4 cm3, 90% to 95% for volumes 4 to 14 cm3, and 60% to 70% for volumes greater than 14 cm3.(ABSTRACT TRUNCATED AT 400 WORDS)

The use of 3-D dose volume analysis to predict radiation hepatitis.

Although it is well known that the tolerance of the liver to external beam irradiation depends on the volume of liver irradiated, few data exist which quantify this dependence. Therefore, a review was carried out of our clinical trial for the treatment of intrahepatic malignancies in which the dose of radiation delivered depended on the volume of normal liver treated. Three dimensional treatment planning using dose-volume histogram analysis of the normal liver was used for all patients. Nine of the 79 patients treated developed clinical radiation hepatitis. None of the patient related variables assessed were associated with radiation hepatitis. All patients who developed radiation hepatitis received whole liver irradiation, as all or part of their treatment, which produced a mean dose greater than or equal to 37 Gy. Dose volume histograms were used to calculate normal tissue complication probabilities based on parameters derived from the literature. The risk of complication was greatly overestimated among patients receiving a high dose of radiation to part of the liver without whole liver treatment. An estimation of model parameters based on the clinical results indicated a larger magnitude for the "volume effect parameter" than the literature estimate (n = 0.69 +/- 0.05 vs 0.32; p less than 0.001). Computation of the normal tissue complication probabilities using the larger value of n produced a good description of the observed risk of radiation hepatitis. These findings suggest that dose volume histogram analysis can be used to quantify the tolerance of the liver to radiation. The predictive value of this parameterization of the normal tissue complication probability model will need to be tested with liver tolerance and dose volume histogram data from an independent clinical trial.

Normal tissue complication probabilities: variable dose per fraction.

Because of the large amount of data generated by 3D treatment planning, new tools are being developed for the evaluation and optimization of the plans. Estimates of the probability of local control of the tumor and for the probability of specific normal tissue complications are among the new tools. The normal tissue complication probability (NTCP) is based on clinical estimates of the tolerance doses for specific tissues/organs. These tolerance doses are assumed to apply for uniform partial and full volume irradiations delivered at 2 Gy per fraction and 5 fractions per week. A different tolerance dose may apply when the dose is delivered at a different dose per fraction and over a different period of time. This study evaluates the maximum change expected in the NTCP when the normal structure receives the dose at a different dose per fraction than the target volume due to different choices in the delivery of the daily fraction.

Sensitivity of helium beam-modulator design to uncertainties in biological data.

The goal in designing beam-modulating devices for heavy charged-particle therapy is to achieve uniform biological effects across the spread-peak region of the beam. To accomplish this, the linear-quadratic model for cell survival has been used to describe the biological response of the target cells to charged-particle radiation. In this paper, the sensitivity of the beam-modulator design in the high-dose region to the values of the linear-quadratic variables alpha and beta has been investigated for a 215-MeV/u helium beam, and implications for higher LET beams are discussed. The major conclusions of this work are that, for helium over the LET range of 2 to 16 keV/mu, uncertainties in measuring alpha and beta for a given cell type which are of the order of 20% or less have a negligible effect on the beam-modulator design (i.e., on the slope of the spread Bragg peak); uncertainties less than or equal to 10% in the dose-averaged LET at each depth are unimportant; and, if the linear-quadratic variables for the tumor differ from those used in the beam-modulator design by a constant factor between about 0.5 and 3, then the resultant nonuniformity in the photon-equivalent dose delivered to the tumor is within +/- 25%. It is also shown that for any ion, if the nominal values of alpha or beta used by the beam-modulator design program differ from their actual values by a constant factor, then the maximum errors possible in the beam-modulator design may be characterized by two limiting depth-dose curves such that the ratio of the dose at the proximal end of the spread Bragg curve to the dose at the distal end of the spread peak is given by alpha distal/alpha prox for the steepest curve, and square root of beta distal/beta prox for the flattest curve.

Design of beam-modulating devices for charged-particle therapy.

The computer modeling program used to design beam-modulating devices for charged-particle therapy at Lawrence Berkeley Laboratory has been improved to allow a more realistic description of the beam. The original program used a single calculated Bragg peak to design the spread Bragg peak. The range of this curve was shifted so that Bragg curves of varying ranges could be superimposed. The new version of the program allows several measured Bragg curves with different ranges to be used as input, and interpolates between them to obtain the required data for the superposition calculation. The experimental configuration for measuring these input curves simulated therapy conditions. Seven beam-modulating propellers with spread Bragg-peak widths ranging from 2.2 to 14.4 cm were designed and constructed for a 215-MeV/u helium beam using this new design program. Depth-dose distributions produced by these new propellers were in good agreement with predicted distributions, and these propellers are currently being used clinically.

Image correlation of MRI and CT in treatment planning for radiosurgery of intracranial vascular malformations.

Magnetic resonance imaging (MRI) has been incorporated with stereotactic cerebral angiography and computed tomography (CT) in the treatment planning process of heavy ion radiosurgery of intracranial arteriovenous malformations (AVM's). Correlation of the images of the AVM and normal tissue on each of these neuroradiological imaging modalities is achieved by means of fiducial markers. The computerized transfer of angiographic information to the CT images regarding the size, shape, and location of the abnormal vasculature has been described in an earlier report. A separate computer program calculates a fit between individual fiducial markers on the CT and MR images that enables the transfer of contours between the two imaging modalities. The MR images aid in the determination of the 3-dimensional shape of the AVM, adding to the information derived from the two angiographic projections. Currently, MRI cannot replace cerebral angiography in delineating the entire arterial phase of the AVM. Magnetic resonance imaging is invaluable in the treatment planning of angiographically-occult AVM's, determining the location, size, and shape of the volume to be treated. Correlation of the CT and MRI images allows for the transfer of CT-calculated isodose contours to the MRI images to aid in the determination of optimal treatment plans.

Heavy-charged-particle radiosurgery of the pituitary gland: clinical results of 840 patients.

Since 1954, 840 patients have been treated at Lawrence Berkeley Laboratory with stereotactic charged-particle radiosurgery of the pituitary gland. The initial 30 patients were treated with proton beams; the subsequent 810 patients were treated with helium ion beams. In the great majority of the 475 patients treated for pituitary tumors, marked and sustained biochemical and clinical improvement was observed. Variable degrees of hypopituitarism developed in about one-third of patients treated solely with radiosurgery. In the earlier years of the program, 365 patients underwent radiosurgery to treat selected systemic diseases by inducing hypopituitarism. Focal temporal lobe necrosis and cranial nerve injury occurred in about 1% of patients who were treated with doses less than 230 Gy.

Heavy-charged-particle radiosurgery for intracranial arteriovenous malformations.

We have treated over 400 patients with symptomatic inoperable intracranial arteriovenous malformations (AVMs) with stereotactic heavy-charged-particle Bragg peak radiosurgery at the University of California at Berkeley in a collaborative program with Stanford University Medical Center and the University of California Medical Center, San Francisco. A long-term dose-searching clinical trial protocol has been developed and we have followed more than 250 patients for more than 2 years. Initially, radiation doses ranged from 45 to 35 GyE, and now doses of 25, 20, 15 and, under special circumstances, 10 GyE, depending on a number of factors, are being evaluated. The characteristics of charged-particle beams provide a relatively homogeneous dose distribution with the 90% isodose contour to the periphery of the lesion. When the entire arterial phase of the AVM core is included in the treatment field, the rates for complete obliteration 3 years after treatment are: 90-95% for volumes less than or equal to 4 cm3; 90-95% for volumes greater than 4 and less than or equal to 14 cm3; and 60-70% for volumes greater than 14 cm3. The total obliteration rate for all volumes up to 70 cm3 is approximately 80-85%. For complete radiation-induced obliteration there is a relationship of dose and volume primarily, and location secondarily. Results on relationships between dose, AVM obliteration, and complications and sequelae of the radiosurgical procedure are presented and discussed.

Charged-particle radiosurgery of the brain.

Charged-particle beams (e.g., protons and helium, carbon and neon ions) manifest unique physical properties which offer advantages for neurosurgery and neuroscience research. The beams have Bragg ionization peaks at depth in tissues, and finite range and are readily collimated to any desired cross-sectional size and shape by metal apertures. Since 1954 nearly 6000 neurosurgical patients worldwide have been treated with stereotactic charged-particle radiosurgery of the brain for various localized and systemic malignant and nonmalignant disorders. Experimental studies with charged-particle beams have been carried out in laboratory animals to characterize anatomic and physiologic correlates of various behavioral and functional properties in the brain. Highly focused charged-particle beams have been used to induce sharply delineated laminar lesions or discrete focal ablation of deep-seated brain structures for the study of the functional anatomy of selected intracranial sites. Charged-particle beam irradiation for stereotactic radiosurgery and radiation oncology of intracranial disorders has achieved increasing importance internationally. More than 30 biomedical accelerator facilities on four continents are currently fully operational, under construction, or in an active planning stage; this last group consists primarily of dedicated biomedical hospital-based facilities. Therapeutic efficacy has been demonstrated clearly for the treatment of selected intracranial sites, e.g., pituitary adenomas and intracranial arteriovenous malformations. Heavier charged particles (e.g., carbon and neon ions) have been found to manifest a number of valuable radiobiologic properties and appear to be of potential advantage in the radiosurgical treatment of those primary or metastatic brain tumors that are radioresistant. The optimal dose and choice of charged-particle species must be determined for the treatment of the different intracranial disorders to improve the cure rate and to minimize potential adverse sequelae of the reaction of the brain to radiation injury.

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.

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.

Heavy charged-particle stereotactic radiosurgery: cerebral angiography and CT in the treatment of intracranial vascular malformations.

A method is described for stereotactic localization of intracranial arteriovenous malformations (AVM) and for calculating treatment plans for heavy charged-particle Bragg peak radiosurgery. A stereotactic frame and head immobilization system is used to correlate the images of multivessel cerebral angiography and computed tomography. The AVM is imaged by angiography, and the frame provides the stereotactic coordinates for transfer of this target to CT images for the calculation of treatment plans. The CT data are used to calculate the residual ranges and compensation for the charged-particle beam required for each treatment port. Three-dimensional coordinates for the patient positioner are calculated, and stereotactic radiosurgery is performed. Verification of the accuracy of the stereotactic positioning is obtained with computer-generated overlays of the vascular malformation, stereotactic fiducial markers, and bony landmarks on orthogonal radiographs immediately prior to treatment. Using these procedures, the accuracy of the repositioning of the patient at each of a series of imaging and treatment procedures is typically within 1 mm in each of three orthogonal planes.

Optimization of radiation therapy, IV: A dose-volume histogram reduction algorithm.

A general formalism for estimating the complication probability for non-uniform irradiation of a normal tissue structure has been developed and used by the NCI-sponsored committee on "Evaluation of Treatment Planning for Particle Beam Radiotherapy." The approach involves reducing an N-step dose-volume histogram for the tissue (obtained from the 3D treatment plan) to an equivalent (N-1)-step histogram; this procedure is repeated until there remains a single-step histogram, the complication probability of which can readily be determined. This note provides technical details concerning the histogram-reduction algorithm. Results obtained using it are compared with those for two alternative histogram-reduction algorithms.

Stereotactic heavy-charged-particle Bragg peak radiosurgery for the treatment of intracranial arteriovenous malformations in childhood and adolescence.

Forty patients aged 6 to 18 years have now been treated for inoperable intracranial arteriovenous malformations (AVMs) using stereotactic heavy-charged-particle Bragg peak radiosurgery at the Lawrence Berkeley Laboratory 184-inch Synchrocyclotron at the University of California, Berkeley. This paper describes the procedures for selection of patients, the treatment protocol, and the neurological and neuroradiological responses to stereotactic radiosurgery in this age group. The volumes of the treated AVMs ranged from 265 mm3 to 60,000 mm3. The results are favorable: thus far, 20 of 25 patients have experienced greater than or equal to 50% obliteration of their AVMs within 1 year after treatment, and 14 of 18 patients have experienced total obliteration of the AVM by 2 years after treatment. Two patients hemorrhaged from radiosurgically treated AVMs within 12 months after treatment, but none thereafter. Complications include vasogenic edema and arterial occlusion; three patients have had neurological worsening as definite or possible sequelae of treatment. The strengths and limitations of the method are discussed.

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.

Treatment planning study for carcinoma of the esophagus: helium ions versus photons.

Helium ion radiotherapy significantly reduces dose to adjoining critical structures in the treatment of carcinoma of the esophagus when the same treatment plan is compared with megavoltage photon therapy. A five-field 18 MV photon treatment plan, selected to minimize lung dose, is compared with helium ions using the same field configuration. Dose volume histograms show target coverage, as well as dose delivered to critical structures lung, heart, mediastinum, and spinal cord. Although both helium ions and photons deliver approximately the same lung dose for this treatment plan, radiation to the heart and spinal cord from this field arrangement is significantly reduced with the helium ion beam. The concentration of dose at the tumor site, while sparing surrounding normal tissue, is characteristic of charged particle therapy, particularly with light ions, which includes particles with Z from that of protons (Z = 1) through that of neon (Z = 10).