Radiation enhancement of metastasis: a review.

Virtually every modality employed in the treatment of cancer has demonstrated an adverse effect upon metastasis under some conditions. This review surveys the experimental and clinical literature pertaining to the untoward effects of ionizing radiation upon metastatic processes. Two processes are described: (1) enhancement of metastases following local tumor irradiation; (2) localization of metastasis in previously irradiated normal tissues. In the first process the experimental evidence indicates a local effect of irradiation upon the tumor-stroma interface. It predominates under conditions of non-curative radiation doses. There is no proof that this process occurs in clinical practice, but a review of data provides suggestive evidence for its existence following non-curative therapy. The second process is documented both experimentally and clinically. It requires the presence of viable, circulating tumor cells and appears mediated through vascular damage. The few clinical reports suggest that this effect is rare in practice. The clinical significance of both processes appears small under conditions of effective tumor therapy, but it is speculated that inadequate tumor irradiation, or irradiation of normal tissues with uncontrolled tumor elsewhere, may be deleterious.

Long-term results of pion therapy at Los Alamos.

Two hundred twenty-eight patients were treated at the Los Alamos Meson Physics Facility (LAMPF) with negative pi-mesons (pions) between 1974 and 1981. Of these, 19 patients with metastatic disease were treated in pilot studies. Following the clinical determination of relative biological effectiveness (RBE) of pions, 209 patients were treated in site and dose searching studies beginning in 1977. Advanced but regionally localized cancers that were considered poorly responsive to conventional therapy were selected for treatment. A wide range of treatment fractions (22 to 45) and of total dose (1800 to 4200 cGy at the 80% isodose level) to the prescribed target volumes was explored. A follow-up observation period of between 4.5 and 9 years has been completed. The analysis focuses on 129 patients receiving pion therapy alone. Thirty-six (28%) had persisting local tumor control of which 12 (9%) suffered complications of treatment. The results varied among treatment sites, for example: prostate cancer, 18/21 (86%) locally controlled, 6/21 (29%) complications; head and neck, 8/31 (26%) locally controlled, 1/31 (3%) complications; and pancreas, none controlled and no complications. Analysis of dose-fraction response suggests a steep rising curve of complications beyond the dose level of 3750 cGy minimum, 4700 cGy maximum, in 38 fractions. The tumor control response has a broader and ill-defined curve possibly due to the heterogeneity of tumor types. The RBE for late effects in normal tissues appeared to be higher than that for acute effects although the mixture of tumor types, sites, dose, and fractionation made this estimate highly uncertain. No late secondary neoplastic changes in pion irradiated tissues were seen. It is concluded that pions can locally ablate some advanced cancers, often without significant sequelae, but that the optimum therapeutic range is critical. The Los Alamos data may be of use to ongoing pion studies in Canada and Switzerland.

High-dose-rate afterloading brachytherapy in carcinoma of the uterine cervix.

The Brachytron has been used in the University of California at San Diego Medical Center since 1970 as one method of treating gynecological malignancies. This machine contains a high intensity cobalt 60 remote afterloading cycling source used for intracavitary brachytherapy. One hundred twenty-seven patients with epithelial carcinoma of the cervix are available for analysis of 5-year survival, and 176 are analyzed for treatment complications two years following therapy. Five year survival figures for FIGO-staged patients treated with external beam pelvic irradiation and intracavitary Brachytron treatments are as follows: Stage I, 89%; Stage II, 58%; Stage III, 33%, and two of five patients Stage IVa. Rectal complications graded moderate or severe (M, S) were dose-related and gradually decreased over the years as techniques improved. Complications from early results in 1970-1972 (24% M, 10% S) were reduced to lower levels in 1976-1979 (14% M, 4% S). The Brachytron offers the advantage of rapid dose delivery. Thus, patients can be treated in an outpatient setting, avoiding the cost of hospitalization and the risks of anesthesia. The Brachytron also offers virtually complete radiation safety to all attending medical personnel. With survival and complication figures similar to those reported for patients treated with conventional low-dose-rate brachytherapy, the Brachytron represents an effective alternate mode of therapy for uterine carcinoma.

The Piotron: II. Methods and initial results of dynamic pion therapy in phase II studies.

Negative pi-meson (pion) therapy employing dynamic scanning with a focused spot of convergent beams has been in use since 1981 at SIN. Three-dimensional conformation of the treatment volume to the target volume can thus be achieved. Following previously reported Phase I and Ib clinical trials, a Phase II trial was initiated with the goal of treating primary deep-seated tumors in a dose optimization schedule which included stepwise increase of total pion dose and of target volume. Patients with multicentric superficial bladder tumors who were cystectomy candidates were initially selected. Since then, more invasive cases have been treated. A graded scoring of acute tissue reactions was employed. Follow-up periods were from 10 to 20 months. The pion dose escalation ranged from 3000 rad (minimum) to 3600 rad (minimum) in 20 fractions over 5 weeks. The treatment volumes encompassed 190 cc for local to 1,820 cc for extended volume therapy. Treatment reactions ranged from a faint erythema and increase of bladder frequency to dry desquamation, mild nausea, moderate dysuria, and moderate proctitis or diarrhea with mucus. These reactions were closely related to treatment volume and site. One severe late cystitis has occurred in a patient treated with 2 courses of pions (4475 rad). Mild to moderate late proctitis has been seen in 4 patients. Ten of 13 bladder cancer patients had local control of disease while all 3 pancreas or biliary tract cancer patients had microscopic residual disease locally at time of death from metastasis. A total of 11 of 17 patients are thus clinically or pathologically free of local tumor to time of last observation.

The PIOTRON: initial performance, preparation and experience with pion therapy.

The PIOTRON is a large solid angle superconducting channel built for the use of negative pi-mesons in radiotherapy. The pions are produced by protons of 590 MeV striking a target of molybdenum or beryllium. The pions are divided into 60 channels and deflected twice to enter the treatment volume radially. The momentum and the momentum band for all 60 channels can be chosen and the beam spot of Bragg peak pions at the isocenter of the applicator is a few centimeters in each direction. Dynamic scanning can thus achieve 3-dimensionally shaped treatment volumes. Two different methods are available: the ring scan, using changes of pion range; and the spot scan, involving translation of the patient through the fixed beam spot. Dose distributions of individual and multiple beams were plotted in a cylindrical water phantom. Radiobiological experiments with mammalian cells in gel and with mouse feet were performed. A special beam geometry using a sector of 15 beams was selected for the first treatments of patients with metastatic skin nodules. Six patients were treated. Acute skin reactions were scored and compared with those from orthovoltage therapy with comparable beam geometry. The RBE for 10 fractions is between 1.4 and 1.5. The next step involved treatment of patients inside water-bolus rings in preparation for dynamic therapy. Patients were then treated with the spot scan dynamic mode in the water bolus. The initial responses and reactions are favorable and confirm the feasibility and accuracy of dynamic pion therapy.

Dynamic pion irradiation of unresectable soft tissue sarcomas.

Since November 1981, when pion irradiation was introduced for deep seated tumors at the Swiss Institute for Nuclear Research (SIN, now Paul Scherrer Institute, PSI) a dynamic, 3-dimensional spot scan treatment technique has been in use. To exploit this technique a special optimization treatment planning system has been designed. Of a total of 331 patients treated with pions from November 1981-December 1987, 35 were irradiated for unresectable soft tissue sarcomas. In 32/35 patients, tumor sites were retroperitoneal, pelvic or in the groin or thigh. Twenty-nine tumors had a maximum diameter of greater than 10 cm, 18 tumors of greater than 15 cm; 30 tumors had grade 2/3 and 32 Stage III B/IV A/IV B. Eight of 35 patients received a low pion total dose, 7-27 Gy. Twenty-seven patients received a total dose of 30-36 Gy, fraction size 150-170 cGy (90%-isodose), 20 fractions, 4 times per week. Of these 27 patients, severe late reactions appeared in five: 2/8 patients with extremity/groin sarcomas (1/2 caused by biopsy) and 3/19 patients with retroperitoneal/pelvic sarcomas (one a skin reaction after Actinomycin-D, one a small bowel reaction after 36 Gy, a dose no longer used). Seven of 27 patients had metastases at the beginning of irradiation. Three of 27 were treated with excisional biopsy, 9 with incisional biopsy or partial resection and in 15 patients biopsies were performed for histology only. The median follow-up of these 27 patients was 17 months (5-66). There was no progression in eight extremity/groin tumors but in 4 of 19 retroperitoneal/pelvic tumors. Three of these were marginal progressions. The actuarial 5-year rate of local tumor control is 64%; the actuarial 5-year survival rate of patients without metastases at the beginning of treatment is 58%. Dynamic spot scan pion irradiation proves to be a successful treatment technique for unresectable sarcomas with a high rate of tumor control and a very low rate of severe late reactions.

Anaplastic astrocytoma and glioblastoma: pion irradiation with the dynamic conformation technique at the Swiss Institute for Nuclear Research (SIN).

Clinical phase I/II studies have been performed at the Swiss Institute for Nuclear Research (SIN) since February 1982. Fifty-two out of 249 patients accepted for pion treatment by the end of 1986 were treated for malignant glioma with high dose pion irradiation. A substantial influence of their radioresistance was expected from increased radiation quality due to the contribution of high LET particles from pion capture, and by the possibility of target volume shaping and dose distribution related to the dynamic spot-scan conformation technique. The patients' treatment followed a dose escalation program with total doses from 2720-3420 cGy, fraction sizes from 170 to 205 cGy (90% isodose, minimum target dose), and treatment times from 4 to 5 weeks. 12/52 patients received an accelerated treatment with 3280 cGy in 14-22 days. 49/52 patients are eligible: 3 with astrocytoma of clinical aggressive behaviour, 14 with anaplastic astrocytoma (median age 42 years), and 32 patients with glioblastoma (median age 52 years). 8/49 patients had total/subtotal tumour resection, 19 patients a stereotactic biopsy. The patients were divided into three groups according to total dose, and a fourth group which received the accelerated treatment. There was no statistically significant difference in the median survival rate between the four groups, which was 13 months for the non-glioblastoma patients and 9 months for the glioblastoma patients. No radiation necrosis and no demyelination was found in 17 patients (6 recraniotomies, 11 autopsies). In 10/17 patients, clearly identifiable tumour cells were not demonstrated. NMR findings showed the tumour-surrounding oedema mostly stimulated by tumour necrosis and tumour progression. From these findings, further dose escalation programs, together with a shaping of the target volume close to the tumour, are not contraindicated.

Atypical pyramidal cells in epileptic human cortex: CFLS and 3-D reconstructions.

Epileptic temporal cortices, removed from 3 patients with intractable partial epilepsy (IPE) during neurosurgery, were studied. Pyramidal neurons (40-50 per slice) in laminae III, V and white matter, were injected with lucifer yellow. Samples were examined in a confocal laser scanning microscope (Biorad 600) and individual cells scanned at 0.1-1 microns incremental levels. 2-D maximal linear projection was used for overview. Frames (50-60) of scanned neurons were transformed into 3-D volumes, using VoxelView software on a Silicone Graphics workstation and rotated. All samples contained neurons with duplicated apical dendrites, additional basal dendrites or were misplaced in a horizontal position in the white matter. The relation between these preliminary observations and the disease is discussed.

Separation of cerebrospinal fluid-enriched proteins. A methodological study, Part 2.

Beta-trace protein, beta2-microglobulin and prealbumin were identified in a cerebrospinal fluid fraction containing proteins enriched in CSF-characteristic proteins obtained through affinity chromatography. The prealbumin amount was somewhat higher among CSF-enriched proteins from ventricular CSF than in the same fraction from lumbar CSF. Otherwise no variations in the CSF-enriched protein pattern were found in a ventriculo-spinal CSF-gradient analysed with isoelectric focusing. Affinity chromatography was done using insolubilized antisera against human serum proteins or against human cerebrum. Soluble brain proteins were analysed similarly and compared to the CSF-enriched protein pattern.

Early aneurysm surgery and preventive therapy with intravenously administered nimodipine: a multicenter, double-blind, dose-comparison study.

A European, multicenter, prospective, randomized, double-blind, dose-comparison study on preventive therapy with intravenously administered nimodipine was performed to evaluate the efficacy and tolerability of two different doses: 2 and 3 mg/h. Two hundred four patients fulfilled the criteria for enrollment in the study: surgery within 72 hours after the last subarachnoid hemorrhage, and age between 16 and 72 years. All patients who had Hunt and Hess grades of I to III were operated upon; patients who had poor Hunt and Hess grades (IV-V) were operated on according to the surgeon's choice. This treatment regimen was associated with a low incidence of delayed neurological dysfunction with no significant difference between the two dosage groups: three patients (1.5%) remained severely disabled and two (1%) moderately disabled due to vasospasm with or without additional complications. Among the patients with Hunt and Hess grades of IV or V, the long-term outcome was favorable (good-fair) for 40% and unfavorable for 60%. Among the patients with grades of I to III, the long-term outcome was favorable for 89% and unfavorable for 11%.

Dendritic morphology in epileptogenic cortex from TRPE patients, revealed by intracellular Lucifer Yellow microinjection and confocal laser scanning microscopy.

Biopsy material was obtained from cortical epileptogenic zones (eight temporal, one occipital, one parietal and one frontal) of eleven patients aged 1.5-47 years with therapy-resistant partial epilepsy (TRPE) undergoing epilepsy surgery. Control autopsy material (two temporal, two occipital, one parietal and one frontal) was removed from six neurologically healthy cases within 6-10 hours postmortem delay. In each specimen, 100-300 pyramidal and non-pyramidal neurons were visualized by intracellular Lucifer Yellow microinjection. Single neurons were imaged using CLSM generated serial optical sections; 2-D reconstruction of each neuron was made using z-projection of serial optical images, and 3-D reconstructions and rotations were computerized. Neuronal maps from TRPE biopsies, compared to control autopsies, show markedly increased numbers of dendritic abnormalities of single pyramidal and non-pyramidal neurons in layers I, II-III, V-VII, and in the subcortical white matter. The abnormalities include: (1) increased number of non-pyramidal cells in layer I; (2) many pyramidal cells with two or three dendrites originating apically, rather than one single apical dendrite, in layers II-III; (3) atypical orientation of oblique apical and basal dendrites in pyramidal neurons of layers II-VII; (4) increased number of atypical 'dinosaur-like' and fusiform cells in layers V-VII; (5) numerous neurons in the white matter. These abnormalities may be etiological in cases with early onset, and predisposing in cases with late onset.

Surgically created fourth-third cranial nerve communication: temporary success in a child with bilateral third nerve hamartomas. Case report.

Shortly after birth, an otherwise healthy infant developed eye deviation and ptosis due to a hamartomatous lesion of the interpeduncular segment of the right oculomotor nerve. The left nerve became similarly involved when the child was 1.5 years of age. Direct nerve repair was not possible. Instead, the trochlear nerve was divided and its proximal end was attached to the distal end of the third nerve. Elevation of the upper eyelid and partial adduction of the eye developed gradually over the ensuing 3 to 5 months. Both functions were lost after an additional 2 months, presumably as a result of tumor recurrence or neuroma formation. This case report shows that surgically created fourth-third cranial nerve communication is feasible and may merit consideration under similar circumstances.

Significance of "ultra-early" rebleeding in subarachnoid hemorrhage.

Knowledge of the local incidence of aneurysm rupture permits the conclusion that almost every patient in the population of 933,800 persons served by the authors' institution who was stricken by this catastrophe and survived long enough to be transported was treated at this center (121 patients during 34 months). Of these, 9.1% were admitted late (greater than 72 hours after subarachnoid hemorrhage (SAH]; of the remaining cases, 94.5% were seen within 24 hours and 50% within 6 hours post-SAH. Of the 121 patients, 10% were neurologically devastated on arrival, a late operation was planned for 19%, and the earliest possible surgery and nimodipine administration was selected for 71%. In this latter group, 50% of the operations were begun within 24 hours and 76% within 48 hours post-SAH. Sixty percent of all mortality and morbidity could be linked to the initial aneurysm bleed. The remaining 40% could be ascribed to potentially avoidable causes of unfavorable outcome. No less than 9.6% of all patients admitted within 24 hours after SAH suffered from "ultra-early" rebleeding during transportation or preparation for operation. The mortality rate from such rebleeding was 7.4%, compared with the 9.1% combined mortality rate from complications and late ischemia.

Variations in red blood cell polyamines in brain tumour patients treated with stereotactic radiosurgery.

Red blood cell polyamine levels were followed in 13 patients treated with stereotactic radiosurgery for various types of brain tumours. In the most malignant tumours radiosurgery resulted in a decrease in spermine and an increase in spermidine levels. This discrepancy between variations in polyamine levels was not found after conventional radiotherapy. The results may indicate a change in tumour polyamine activity induced by high energy radiotherapy.

Extracellular glial fibrillary acidic protein and amino acids in brain regions of patients with subarachnoid hemorrhage--correlation with level of consciousness and site of bleeding.

The extracellular fluid of two cortical regions was investigated in eight patients who underwent surgery for subarachnoid hemorrhage within 7-96 h after the rupture of an arterial aneurysm. Microdialysis samples, collected from the cortex of the ipsilateral gyrus rectus and temporal lobe for 52-127 h, were analyzed with respect to amino acids and the glial fibrillary acidic protein. In agreement with a previous study, an inverse relation was observed between total amino acid concentration and the level of consciousness. We also found that the concentration of glial fibrillary acidic protein was higher close to the bleeding site. Furthermore, we observed specific changes in the concentration of the protein and certain amino acids which coincided with clinical events such as increased intracranial pressure, vasospasm, ischemia and infarction. Finally, the concentrations of taurine may corroborate its function as an osmoequivalent.

Subarachnoid blood infusion versus raised intracranial pressure: effects on the amino acid pattern in the extracellular fluid of the rabbit hippocampus.

In order to evaluate the role of a hemorrhage versus that of a transient increase in intracranial pressure in subarachnoid hemorrhage, the two components were induced separately in rabbits. Extracellular glutamate, sampled from the hippocampus with microdialysis, was used to evaluate the degree of CNS tissue damage. In four rabbits, autologous arterial blood was infused in the cisterna magna in a volume that would not affect the intracranial pressure. The other group of animals was infused with saline to elevate the intracranial pressure from 10 to > 100 mmHg. The increase of intracranial pressure per se did not induce significant changes in extracellular glutamate. However, 20-60 min after infusion of blood, a significant glutamate increase was recorded. Furthermore, aspartate, alanine, glycine and serine were also raised. The results indicate that blood in the subarachnoid space damages the brain primarily by inducing ischemia. Furthermore, the parameters employed gave no indication that an increase in intracranial pressure had a deleterious effect on CNS tissue.

Analysis of interobserver disagreement in the assessment of subarachnoid blood and acute hydrocephalus on CT scans.

The purpose of this study was to analyse factors for interobserver disagreements in two scales used for the assessments of the amount of blood in subarachnoid space (Fisher grading) and of acute hydrocephalus on computerized tomographic (CT) scans. The assessments made by four neuroradiologists on 59 CT scans obtained in the acute stage after subarachnoid hemorrhage were analysed by a statistical method by Svensson and Holm. This method permits the separation of the inter-observer disagreements in their random and systematic components. The overall consistency of the assessments was significant (p < 0.0005) but the neuroradiologists disagreed on half of the CT-scans. The kappa values were 0.50-0.63. The analysis showed that the main reason for disagreements was systematic inter-observer differences in their use of the clinically most important parts of staging, i.e. subarachnoid clot or intraventricular blood (Fisher grading) and too low categories (hydrocephalus). The main conclusion from this study is that the proper remedy for Fisher grading and for grading of hydrocephalus is a sharpening of the criteria of specific category levels and given this improvement both grading systems will show a high level of reliability.

The neuronal environment after subarachnoid haemorrhage--correlation of amino acid and nucleoside levels with post-operative recovery.

The study explores biochemically the neuronal environment adjacent to a subarachnoid haemorrhage in 11 patients after neurosurgical clipping of an arterial aneurysm. Extracellular fluid (ECF) from the rectus gyrus and subarachnoid fluid (SAF) were sampled with microdialysis probes. The concentrations of amino acids and nucleosides were monitored in 60 min samples collected over 2-4 days. The patients were 33-67 years of age. Surgery was performed 0-5 days after rupture of the aneurysm in 8 patients. One patient was operated on after 15 months. Clipping of aneurysms without prior haemorrhage was performed in two cases. Markedly elevated concentrations of the excitatory amino acid glutamate was observed in the ECF of only one patient who underwent surgery within 8 hours after the haemorrhage. Moderate glutamate elevations were seen in two patients and of aspartate in another patient. Five patients displayed periods of varying length of specifically elevated taurine concentrations in ECF or SAF. Transient periods of high concentrations of glycine and serine were seen in two patients. Even though average concentrations of all amino acids were fairly similar in the ECF and SAF, the pattern of changes vs. time differed markedly in the two compartments. Presently, we conclude that the level of consciousness in the post-operative phase was inversely related to total amino acid concentration in the ECF. Furthermore, while the ECF concentrations of taurine and glycine increased both specifically and transiently in several patients, excitatory amino acid levels were not appreciably elevated subsequent to the neurosurgical intervention.(ABSTRACT TRUNCATED AT 250 WORDS)

Local cerebral blood flow in the dog during intravenous infusion of dopamine.

Local cerebral blood flow was measured in anaesthetized beagle dogs by the hydrogen clearance method. Dopamine was administered as a continuous intravenous infusion of varying doses. The changes in local cerebral blood flow induced by dopamine were similar at the different locations; i.e., the caudate nucleus, thalamus, frontal and parietal cortex. Blood flow responded to dopamine in the following ways: low dose (less than 2 micrograms/kg/min): blood flow decreased or remained unchanged; moderate doses (2--6 micrograms/kg/min): blood flow increased at all electrodes; high doses (7--20 micrograms/kg/min): blood flow decreased once again. The decrease in blood flow could be inhibited by the alpha-adrenergic receptor antagonist phentolamine or by the serotonin receptor antagonist methysergide. This indicates that the constrictor effect of dopamine on cerebral blood vessels is mediated via alpha-adrenergic receptors as well as via serotonin receptors. The increase in cerebral flow could be inhibited by the dopamine receptor antagonist haloperidol, indicating vascular dopamine receptors in the brain with a dilating effect. When the vasoconstrictor activity of dopamine is blocked, the single response to a dopamine infusion is a blood flow increase. This might be beneficial in the clinical situation of symptomatic vasospasm.

Vestibulo-oculomotor disturbances in trigeminal neuralgia and hemifacial spasm.

Patients with hemifacial spasm and trigeminal neuralgia later treated with microvascular decompression and surgical interposition for their vascular loop disturbance were investigated preoperatively with electronystagmography, saccade test and audiometry. Some of them underwent an extended investigation including computerized broad-frequency rotatory test with visual suppression and a computerized smooth pursuit test, both tests using sinusoidal as well as randomized movement patterns as stimulus. The patients showed a high frequency of vestibulo-oculomotor disturbances indicating that the vascular loop, in addition to pressure on the trigeminal and facial nerves, also exerted pressure on the statoacoustic nerve and/or the brain-stem. It can be deduced that the vascular loop may give purely VIII nerve disturbances treatable with surgery, the problem being, however, to establish the diagnosis.