Brain Tumor Working Group Report on the 9th International Conference on Brain Tumor Research and Therapy. Organ System Program, National Cancer Institute.
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Biomedical subjects
J R Fike
Publications and source records attributed to J R Fike.
Cerebrovascular response after interstitial irradiation.
To characterize the role of the cerebrovascular response in the development of brain injury after focal irradiation, 125I sources were implanted in frontal white matter of the brain of normal dogs; dose was 20 Gy, 7.5 mm from the source. Cerebral blood flow, vascular volume and mean transit time of blood were quantified in irradiated tissues relative to tissues in the contralateral hemisphere and analyzed with respect to previously determined volumetric measurements of damage and the blood-to-brain transfer constant. Blood flow and vascular volume within the radiation-induced focal lesion were maximally reduced 3 weeks after implant, when necrosis volume was maximal. By 6 weeks, vascular volume and mean transit time were increased, suggesting a strong neovascular response. In tissues surrounding the lesion, blood flow and vascular volume were reduced 1-4 weeks after irradiation and approached normal at 6 weeks; average mean transit time was not altered significantly. Alterations in blood flow and mean transit time were significantly related to edema volume and transfer constant, but alterations in vascular volume were not, suggesting that edema-induced vascular compression was not responsible for changes in blood flow. Reductions of radiation-induced permeability of the blood-brain barrier and/or edema might limit radiation-induced changes in blood flow and the extent of tissue injury.
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Measurement of regional cerebral blood flow using ultrafast computed tomography. Theoretical aspects.
Theoretical and practical limitations have prevented the measurement of regional cerebral blood flow using dynamic x-ray computed tomography. Development of the ultrafast computed tomography scanner has made it possible to overcome the practical limitations and measure changes in contrast concentration in the brain with excellent time and spatial resolution. By applying modifications of indicator dilution theory, we have derived a method to use these changes in contrast concentration determined using ultrafast computed tomography to measure the fractional vascular volume, mean transit time of blood, and blood flow within specific regions of the brain in a relatively simple and practical manner. This method could theoretically be used in the evaluation of physiological and pathophysiological alterations in cerebral blood flow.
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Measurement of regional cerebral blood flow in the dog using ultrafast computed tomography. Experimental validation.
The applicability, feasibility, reproducibility, and accuracy of the method of measuring regional cerebral blood flow using ultrafast computed tomography were evaluated in 25 dogs under varying physiological and pathophysiological conditions. Regional cerebral blood flow values were 75.6 +/- 29.4 ml/100 g/min (mean +/- standard deviation) for the hemisphere, 68.4 +/- 28.2 ml/100 g/min for the basal ganglia, 41.2 +/- 15.0 ml/100 g/min for the internal capsule, and 80.8 +/- 37.2 ml/100 g/min for the neocortex. Measurements made 10 minutes apart were significantly (p less than 0.05) correlated. Simultaneous measurements of regional cerebral blood flow by the microsphere and ultrafast computed tomography methods showed a significant (p less than 0.05) correlation for the hemisphere (r = 0.95), basal ganglia (r = 0.95), and neocortex (r = 0.94) but not for the internal capsule (r = 0.51). Microsphere and ultrafast computed tomography regional cerebral blood flow values were also in agreement in radiation-damaged brain with appreciable blood-brain barrier breakdown, and the two methods demonstrated similar responsiveness of regional cerebral blood flow to alterations in arterial carbon dioxide tension. The accuracy and sensitivity of the ultrafast computed tomography technique suggests that it affords a useful new tool for studying normal and abnormal regional cerebral blood flow.
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Modification of radiation-induced brain injury by alpha-difluoromethylornithine.
The effect of alpha-difluoromethylornithine (DFMO) on 125I-induced brain injury was investigated in a dog model. Cerebrospinal putrescine levels were reduced from baseline levels 1-2 weeks after irradiation in animals treated with 125I and DFMO, while putrescine levels were elevated in 125I and saline-treated animals. In addition, the time course of changes in the volumes of edema, necrosis, and tissue showing evidence of blood-brain barrier breakdown was altered significantly by DFMO treatment. The most significant alterations occurred 2-4 weeks after irradiation, at which times the average volumes of damage in DFMO-treated animals were reduced compared to saline-treated animals. The time course of alterations in blood-to-brain transfer, brain-to-blood transfer, and vascularity following irradiation was also altered by DFMO treatment. Analysis of variance demonstrated a strong relationship of blood-to-brain transfer and vascularity to volume of edema, suggesting that the effect of DFMO on edema may be partially mediated by its effects on blood-brain barrier breakdown.
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Radiation dose response of normal brain.
Dose response relationships were determined after hemibrain x-irradiation of normal beagle dogs. Radiation doses of 11.5, 13.5, 14.3, and 17 Gy were delivered in a single dose and results were compared to previous studies using doses of 15 and 30 Gy. Brain injury was quantified using computed tomography (CT), with serial studies obtained monthly up to 1 year following irradiation. Quantitative endpoints included low density volume and contrast enhancement. Doses above 14.3 Gy resulted in high lethality 5-8 months following irradiation, and an LD50 of 14.9 Gy was calculated. At these lethal doses, low density volume representing edema, demyelination, and necrosis had a similar response with an ED50 of 14.6 Gy. Radiation-induced decreases in white matter density appeared 5-6 months after sublethal doses (less than or equal to 14.3 Gy) and the volume of tissue characterized by this low density increased with time and dose. This sublethal low density change had an ED50 of 12.8 Gy, and may reflect a loss or generalized atrophy of glial cells and/or myelin. These results show that: (a) the dose response curves obtained after hemibrain x-irradiation are extremely steep; and (b) at least two processes may be involved in the development of late radiation damage, one that is rapid upon onset (a "delayed acute" reaction) and the other which is a slower and more degenerative process.
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Thermal distribution studies of helical coil microwave antennas for interstitial hyperthermia.
An implantable 915 MHz helical coil antenna was developed for improved localization and control of interstitial microwave hyperthermia. The radiating element consisted of a fine wire coil wound back over the inner conductor of a miniature semi-rigid coaxial cable in place of the terminal portion of outer conductor. The power deposition profiles from single helical coil antennas were studied both in homogeneous phantom and in muscle tissue in vivo and compared to those of single half-wavelength linear dipole antennas. The effects of variable coil length, turn density, and antenna insertion depth in tissue were characterized. The helical coil antennas produced a well-localized heating pattern with a sharp falloff of temperature in both directions axially from the coil element. One of the best heating patterns was obtained with a 35 turn, 35 mm long helical coil element which was separated from the antenna feedline outer conductor by a 1 mm gap (HCS-35(1)/36). This antenna showed a marked shift of the effectively heated volume toward the antenna tip and essentially no dependence of the heating pattern on insertion depth. In contrast, the axial power deposition profiles of dipole antennas were strongly affected by insertion depth and exhibited an inadequately heated area at the antenna tip even with 1/2-3/4 wavelength insertion. Thermal distribution studies showed that the single helical coil microwave antenna provided more predictable, well-localized heating of deep-seated tissues, with minimal requirement for over-implanting of the treatment volume.
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Interstitial helical coil microwave antenna for experimental brain hyperthermia.
A helical coil 2450-MHz microwave antenna was used to induce interstitial hyperthermia in normal dog brain. The HCS-10(1)/11 antenna consisted of a miniature semirigid coaxial cable around which a fine wire coil with 10 turns per 1-cm length was wound. A single antenna and two or three temperature probes were implanted stereotactically, and the temperature distributions surrounding the antenna were measured and compared to those induced using a dipole antenna. The helical coil antenna produced well-localized temperature distributions at depths that were symmetrical around the coil and that extended to the antenna tip. There was minimal variation of the heating patterns with insertion depth using the HCS-10(1)/11 antenna and no excessive heating of extracerebral tissues. In contrast, 2450-MHz dipole antennas induced temperatures of 43 to 46 degrees C at the brain surface and extracerebral tissues (skull, muscle, and scalp), with a relatively uniform but lower temperature in the targeted brain volume. One week after hyperthermia treatment, the thermal lesions induced by the helical coil antenna were visualized using computed tomography. The heating patterns correlated well with the location of the heat lesions and were reproducible among animals. The results indicated that the helical coil antenna could be used to induce localized hyperthermia at specific depths in normal brain without inducing unacceptable heating of the brain surface or extracerebral tissues. Consequently, this antenna seems to be suitable for studying the response of normal brain after a heat insult and may be effective in the application of interstitial microwave brain hyperthermia for malignant brain tumors.
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[Characterization of helical coil microwave antenna for interstitial hyperthermia].
Implantable microwave antennas for interstitial hyperthermia have been constructed by using a fine wire helical coil extension of the coax feedline inner conductor. The effects of the variable coil length the winding density, and the antenna insertion depth in the tissue on the heating patterns from a single antenna were characterized in phantom models. Results indicated that the helical coil microwave antenna provided localized heat at depth near the antenna tip, and the heating patterns were easily modified by minor changes in the coil length, winding density, and altering the separation gap. The characteristics of the helical coil microwave antenna may increase its potential application to cases of interstitial hyperthermia.
Hyperthermia, Induced↗
Pathology of delayed radiation brain damage: an experimental canine model.
Delayed radiation damage of normal brain can be a devastating complication of radiation therapy and generally occurs months to years after the initiation of therapy. Primarily restricted to the white matter, radiation damage is characterized by a number of histopathologic changes including coagulation necrosis, vascular alterations with fibrinoid necrosis, edema, and demyelination. Normal dogs were exposed to either 10, 15, or 30 Gy of X rays to a single hemisphere and the gross and histopathologic changes were evaluated qualitatively. A spectrum of changes was observed ranging from white matter edema to extensive white matter necrosis, and the extent, location, and type of damage were dependent upon radiation dose. Histopathologic changes were separated into three major categories based on the character and size of the lesions, with the most severe changes being similar to the types of changes described in human patients who have developed delayed radiation necrosis. Less severe forms of damage such as multifocal, sometimes confluent areas of microscopic necrosis with spongiotic borders and edema with severe axonal swelling were also observed. These latter changes are not well recognized as being due to radiation. The findings of this study also indicate that many of the changes ascribed to combined treatment with methotrexate and radiation in humans are induced in the normal dog brain by radiation alone. The results of his study show that the dog is a suitable model of the human brain for studying radiation brain injury and may be useful for investigation of drug-radiation interactions.
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Computed tomographic characteristics of primary brain tumors in 50 dogs.
Fifty histologically identified primary brain tumors in the dog were analyzed by computed tomography to establish criteria for identifying tumor types by computed tomography characteristics. Meningiomas could be distinguished from tumors within the brain parenchyma because they usually were broad-based, peripherally located masses that were enhanced homogeneously with contrast material. Among parenchymal tumors, astrocytomas were not distinguished easily from oligodendrogliomas because both tumors had similar features of ring-like and nonuniform enhancement, and poorly defined tumor margins. Choroid plexus tumors were seen as well-defined, hyperdense masses that had marked, uniform contrast enhancement. Pituitary tumors were distinguished readily by their location, minimal peritumoral edema, uniform contrast enhancement, and well-defined margins. Distinguishing features of other less frequently seen tumors (ependymoma, primitive neuroectodermal tumor, glioma, and neoplastic reticulosis) were not identified.
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Contrast enhancement of brain tumors and irradiated normal brain: a comparison of iohexol and iothalamate.
The nonionic contrast agent iohexol was compared with the ionic agent iothalamate for contrast enhancement of brain tumors and radiation brain damage in dogs. Tissue enhancement during infusion of contrast and 5, 10, 15 and 30 min later was measured using quantitative computed tomography. Blood iodine was measured using x-ray fluorescence. Peak contrast enhancement occurred during infusion in tumors and after 5 min in irradiated normal brain for both contrast agents. Absolute uptake of contrast in each lesion was the same for both agents when normalized to total grams of iodine administered. Blood iodine levels were slightly but not significantly higher using iohexol. The reduced osmotic load and similar contrast enhancement of lesions suggest that the nonionic contrast medium iohexol may be a useful agent for routine CT of the brain.
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Interstitial microwave hyperthermia in a canine brain model.
A dual frequency microwave system was constructed for interstitial heating of brain tissue. Single-junction dipole antennas were tested in a phantom model and in normal dog brain to determine how variations in physical factors affected temperature distributions. Non-survival studies were performed at both 915 and 2450 MHz to determine heating patterns that could be achieved within normal brain using this system. Chronic survival studies were performed using a single dipole antenna inserted laterally into one hemisphere of brain and driven at 2450 MHz. Temperatures of 43 or 44 degrees C for 30 min at a reference point 0.5 cm from the antenna junction were used to induce a thermal lesion of approximately 1 cm diameter in the right cerebral hemisphere of dogs. Neurologic and physical changes in dogs were monitored daily for up to 16 weeks after induction of cerebral lesions. The extent and development of thermal lesions was monitored with weekly computed tomographic (CT) examinations and, after death, at histopathologic examination. Results of the phantom studies showed that the longitudinal heating pattern was bell-shaped at both frequencies used and that there was some variation in heating length that depended on insertion depth. Acute studies in dog brain showed that 915 MHz antennas implanted less than 6.5 cm deep produced erratic heating patterns that usually included excessive heating of the surface of the brain. Conversely, 2 cm-long antennas driven at 2450 MHz gave reproducible temperature distributions both longitudinally along and radially away from the antenna. The steepest gradients--about 1 degree C/mm--occurred in the radial direction away from the antenna junction. A single 30 min heat treatment produced a large focal lesion that consisted of central coagulation necrosis surrounded by a sharply demarcated hypervascular zone. Edematous changes were minimal and were observed only during the first week after treatment. As assessed by serial CT scans, thermal lesions reached a maximum size by the first week after treatment and were essentially resolved by 16 weeks after treatment.
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Normal brain iodine-125 radiation damage: effect of dose and irradiated volume in a canine model.
High-activity iodine-125 sources in plastic catheters were surgically placed in the cerebral white matter of healthy beagle dogs and later removed. Reference doses, calculated at a point 0.75 mm from the source, ranged from 10 to 40 Gy. Necrosis, vascular-related damage, and edema were quantified by computed tomography. Volumetric analyses were used to derive the relationship of dose and dose rate to necrosis and contrast enhancement. The extent of necrosis was related to irradiated volume; a minimum effective dose averaging 180-200 Gy was required to induce this type of damage. Contrast enhancement was less dependent on irradiated volume or total dose. The extent of radiation-induced edema was directly related to the volumes of necrosis plus contrast enhancement. Noninvasive serial studies in a well-characterized in vivo model can address specific clinically related questions on damage to normal tissue after interstitial irradiation.
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[Hyperthermia in malignant brain tumors. Interstitial microwave hyperthermia in a canine brain model].
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Animals↗
[Hyperthermia of malignant brain tumors--development of an interstitial microwave hyperthermia system and study of thermodosimetry and heat toxicity in a canine brain model].
Hyperthermia is a promising important adjunct to conventional treatment of malignant brain tumors and available data suggest a strong biological rationale for its use. Hyperthermia has been shown to sensitize tumors to radiation, particularly radiation delivered at low dose rates typical of brachytherapy. To complement our clinical study of interstitial brachytherapy of malignant brain tumors, a microwave interstitial heating system with data acquisition has been constructed at UCSF. This system was evaluated in a phantom and in a series of non-survival and survival experiments for heating patterns and heat toxicity in 24 adult canine brains. A single 2450 MHz microwave heating antenna and 3 fiberoptic thermometry probes were placed stereotaxically into the frontal white matter of 24 dogs. Temperature measurements were made at 1 mm increments along the antenna length 5 mm from the antenna axis and radially away from the antenna junction. For the survival studies, minimum temperatures 43 degrees C, 44 degrees C, and 45 degrees C were maintained at points 5 mm from the antenna junction for 30 minutes. Hyperthermia-induced tissue damage was measured weekly following the heat treatment using CT. In general, it was easy to maintain a steady temperature state for a long time period. Heating patterns tended to be ellipsoidal, corresponding relatively well with those predicted by the phantom trials. Heat toxicity was examined by sequential quantitative CT scans in chronic trials and correlated with histopathology following sacrifice at 1-16 weeks. Neurological deficits were minimal and were restricted to the first day after treatment.(ABSTRACT TRUNCATED AT 250 WORDS)
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Radiation brain damage induced by interstitial 125I sources: a canine model evaluated by quantitative computed tomography.
The canine brain is a good model of the human brain for studying radiation damage after megavoltage x-irradiation for brain tumors. We have further developed this model to study radiation damage induced by high activity interstitial 125I sources. Removable 125I sources were implanted in normal canine brains, and doses of 1,000 to 10,000 rads were delivered to a reference point at a 10-mm radius from the source; dose rates were 35 to 40 rads/hour at the reference point. Serial quantitative analysis of tissue damage (tissue density and contrast enhancement) was done using computed tomographic scanning up to 6 months after implantation and was compared to histopathological findings after the animals were killed. At doses greater than 19,000 rads (i.e., inside the reference point), frank coagulation necrosis was observed. Pronounced vessel-related changes, manifest as areas of contrast enhancement, corresponded to tissues receiving a minimum of 6,000 rads and a maximum of 19,000 rads. These results indicate that this model can be used in serial noninvasive studies to quantify the development of damage induced by interstitial irradiation and to provide dose-response information in individual animals.
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Radiotherapy of brain tumors in dogs.
Brain tumors in 4 dogs were treated with external beam, megavoltage radiation. X-ray computed tomography was used to localize and characterize brain tumors and to assess treatment response. Total radiation doses were 3,000 or 3,600 rad, given in 5 or 6 fractions over 14 to 19 days. Complete tumor regression, as determined from computed tomography scans, improvement in clinical signs, and reduction in medication, were documented in all irradiated dogs. The median survival time for irradiated dogs was 322 days, which was significantly (P less than 0.05) longer than the median survival time of 56 days in 8 dogs with brain tumors treated symptomatically. The one-year survival rate for the irradiated dogs, after correcting for deaths from intercurrent disease, was 100%. It was concluded that canine brain tumors may be treated effectively by use of megavoltage radiation.
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