Metastatic testicular cancer presenting as spinal cord compression: report of two cases.

BACKGROUND: Testicular cancers are heterogenous neoplasms often found in young adults. They tend to metastasize to the chest, retroperitoneum, or neck, but rarely to the long bones or skeleton. However, they can cause neurologic compromise and should be considered in young male patients who present with symptoms of a spine lesion and no known primary cancer. METHODS: Two patients presented with back pain and a rapid progression of lower extremity weakness. Both underwent radiographic workup and emergency surgery. Metastatic workup revealed testicular cancer and widespread metastases. RESULTS: Both patients improved neurologically after surgery, but neither regained the ability to ambulate independently. They both underwent chemotherapy. One patient is alive at 1 year follow-up; the other died 9 months after surgery of widespread metastases. CONCLUSIONS: Vertebral metastases from testicular tumors, although rare, should be considered in young men presenting with spinal cord compression. Work-up should include magnetic resonance imaging (MRI) of the spine and computed tomography (CT) of the chest, abdomen, and pelvis. Urgent intervention may be required, as these two cases show that loss of neurologic function can be rapid and permanent.

A multi-institutional analysis of complication outcomes after arteriovenous malformation radiosurgery.

PURPOSE: To better understand radiation complications of arteriovenous malformation (AVM) radiosurgery and factors affecting their resolution. METHODS AND MATERIALS: AVM patients (102/1255) who developed neurological sequelae after radiosurgery were studied. The median AVM marginal dose (Dmin) was 19 Gy (range: 10-35). The median volume was 5.7 cc (range: 0.26-143). Median follow-up was 34 months (range: 9-140). RESULTS: Complications consisted of 80/102 patients with evidence of radiation injury to the brain parenchyma (7 also with cranial nerve deficits, 12 also with seizures, 5 with cyst formation), 12/102 patients with isolated cranial neuropathies, and 10/102 patients with only new or worsened seizures. Severity was classified as minimal in 39 patients, mild in 40, disabling in 21, and fatal in 2 patients. Symptoms resolved completely in 42 patients for an actuarial resolution rate of 54% +/- 7% at 3 years post-onset. Multivariate analysis identified significantly greater symptom resolution in patients with no prior history of hemorrhage (p = 0.01, 66% vs. 41%), and in patients with symptoms of minimal severity: headache or seizure as the only sequelae of radiosurgery (p < 0.0001, 88% vs. 34%). CONCLUSION: Late sequelae of radiosurgery manifest in varied ways. Further long-term studies of these problems are needed that take into account symptom severity and prior hemorrhage history.

Gliomatosis cerebri. Results with radiation therapy.

BACKGROUND: This review was undertaken to determine the outcome for patients diagnosed in the modern era and treated with radiation therapy. METHODS: Using the tumor registries of six institutions in a large metropolitan area, cases of gliomatosis were identified and retrospectively reviewed. RESULTS: The clinical course for each patient was unique. Deterioration during treatment, brief stabilization, and reversal of the clinical signs and symptoms with stability and high quality of life at 16 months from diagnosis characterized Patients 1, 2, and 3, respectively. CONCLUSIONS: Radiotherapy for gliomatosis appears to stabilize or improve neurologic function in some patients. Its impact on survival will await additional reports and longer follow-up.

Preradiation chemotherapy in advanced medulloblastoma. A Pediatric Oncology Group pilot study.

BACKGROUND: Children diagnosed with medulloblastoma whose tumor involves the brain stem or has spread through the cerebrospinal fluid pathways to other areas of the brain or spinal cord have a poor prognosis despite therapy with surgery, craniospinal irradiation (CSI), and chemotherapy. Preradiation chemotherapy may improve the outlook for these patients. METHODS: To further study the role and feasibility of preradiation chemotherapy, children between the ages of 4 and 21 years diagnosed with advanced medulloblastoma and measurable disease were enrolled in the Pediatric Oncology Group 8695 study. Patients were treated with a 9-week course of vincristine, cisplatin, and cyclophosphamide followed by CSI. Imaging films were reviewed centrally for eligibility and response to chemotherapy. Toxicity to chemotherapy and radiation as well as delays and modifications in subsequent CSI were recorded. RESULTS: Thirteen of 30 fully evaluable patients achieved complete or partial response (43%) to chemotherapy. Toxicity was mostly fever and neutropenia after cyclophosphamide, which is predictable and tolerable. Radiation therapy was delivered in full doses and volumes in most patients but was delayed in its start in most patients. Central review of films revealed frequent use of different imaging modalities at baseline and after therapy, making accurate assessment of tumor response difficult. CONCLUSION: Preradiation chemotherapy with vincristine, cisplatin, and cyclophosphamide is active in patients with advanced medulloblastoma but should be modified to minimize the risk of progressive disease while on therapy and to avoid delays in starting radiation therapy. Consistent use of the same neuroimaging modality is essential in documenting response.

Effect of pentobarbital on normal brain protection and on the response of 9L rat brain tumor to radiation therapy.

The authors attempted to confirm published reports that pentobarbital protects against radiation-induced damage to normal rat brain, as well as enhances radiotherapeutic efficacy in a rat brain tumor model. They evaluated animal survival in 9L gliosarcoma-burdened rats that received whole-brain radiation therapy (16, 24, 32, or 40 Gy) while under intraperitoneal pentobarbital (60 mg/kg) or intramuscular ketamine (60 mg/kg) sedation. The animals were examined at autopsy to attribute death to either intracranial tumor growth or normal brain toxicity in the absence of discernible tumor. There was no difference between the two anesthesia groups regarding the survival of unirradiated animals. Radiation therapy produced a significant dose-dependent prolongation in animal survival, which was limited by the development of normal tissue toxicity at the higher doses. When compared to ketamine anesthesia, pentobarbital anesthesia appeared to offer some protection (not statistically significant) against early (but not late) toxicity at selected radiation doses. A reduction in the number of deaths from tissue toxicity suggested an increased antitumor effect, but again this was not statistically significant. Only in one case was there even a marginal significant difference (p = 0.045) between overall therapeutic efficacy in rats sedated with pentobarbital versus ketamine. While there may be a radioprotective effect of pentobarbital in rat brains without intracranial tumor, there is no conclusive evidence for either radioprotection or significant improvement of radiotherapeutic efficacy in this 9L rat brain tumor model.

Increased levels of plasminogen activator inhibitor-1 (PAI-1) in human brain tumors.

Considerable interest in the roles of serine proteases and serine protease inhibitors (serpins) in regulating physiologic and pathologic tissue remodeling has led to studies that indicate their critical participation in development and diseases of the brain. Plasminogen activator inhibitor-1 (PAI-1) is the most significant regulator of fibrinolysis in plasma, but little is known of the levels or activities of this important serpin in normal brain and brain tumors. For this reason, we estimated qualitative and quantitative levels of PAI-1 in normal human brain and various brain tumors. Western-blot results indicated that a 51 kDa band recognized with polyclonal anti-PAI-1 was more prominently in metastatic and glioblastoma than in meningiomas and low-grade gliomas; normal human brain lacked any detectable band. Reverse zymography also showed high levels of PAI-1 in malignant brain tumors. The complex formation with 125I-urokinase demonstrated that PAI-1 complex levels were increased in metastatic and glioblastoma when compared with low-grade gliomas and meningiomas. Since PAI-1 acts as a modulator of fibrinolysis, a better understanding of the balance between serine proteases and PAI-1 is likely to enhance our knowledge of brain tumor biology.

Lack of complications in long-term survivors after treatment with Fluosol and oxygen as an adjuvant to radiation therapy for high-grade brain tumors.

PURPOSE: A Phase I/II trial was initiated in 1987 to determine the toxicity/efficacy of the perfluorochemical emulsion Fluosol-DA 20% and 100% oxygen as an adjuvant to conventional radiation therapy for high-grade brain tumors. METHODS AND MATERIALS: Three grade 3 and 15 grade 4 patients received 1 Fluosol administration (8 mL/kg) per week with daily oxygen breathing prior to and during radiation therapy. Megavoltage radiation was delivered to the whole brain at 25 x 1.8 Gy, followed by 10 x 2 Gy to a boost volume, resulting in a total tumor bed dose of 65 Gy in 7 weeks. RESULTS: Of the 18 patients, 10 (nine grade 4, one grade 3) survived more than 1 year postsurgery, six (all grade 4) lived more than 2 years, four of these patients lived more than 3 years, and three patients are alive at times ranging from 250 to 276 weeks. The median survival of the Fluosol group was 75 weeks, not statistically different from 54 weeks for a historical, matched control group. However, a Gehan-Wilcoxon test applied to those patients that survived > 1 year revealed a significant difference (p = 0.0013) in favor of the Fluosol group. Periodic clinical evaluations showed no evidence of any functional or neurological defects that could be attributed to radiation therapy and/or Fluosol. Radiographic studies (computed tomography and magnetic resonance imaging) revealed no structural alterations outside the original tumor volume, and changes within the tumor region were easily assignable to expected effects of tumor, surgery, or radiation alone. CONCLUSION: These results indicate that, although Fluosol/oxygen added to conventional radiation therapy does not enhance survival of patients who succumb to their disease early, it does confer a significant benefit to patients that survive past 1 year. The minimal acute side effects and no long-term deleterious effects suggest that Fluosol/oxygen sensitizes only hypoxic cells, with no effect on well-oxygenated normal tissues within the brain. We have been impressed by the quality of life of the surviving patients following radiation therapy with adjuvant Fluosol+oxygen.

A randomized trial of radiotherapy versus radiotherapy plus CCNU for incompletely resected low-grade gliomas: a Southwest Oncology Group study.

Sixty adult patients with incompletely excised low-grade gliomas were randomly assigned to receive radiotherapy (55 Gy over a total of 6 1/2 to 7 weeks) either alone or with 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU; 100 mg/sq m every 6 weeks). Pathological review showed that six patients were ineligible for the study. Evaluation of patient age, extent of surgery, tumor grade, and performance status showed no significant differences between the treatment arms. The response rate, as judged by the disappearance or reduction in size of the tumor on computerized tomography scans, was 79% for radiation therapy alone versus 54% for irradiation plus CCNU. The median survival time was 4.45 years for all patients, with no significant difference between treatment arms (p = 0.7). For the group as a whole, patient age and performance status were the most important prognostic parameters. The majority of patients receiving chemotherapy experienced moderate hematological toxicity. This study demonstrates that CCNU chemotherapy does not improve the results of radiation therapy in the treatment of incompletely excised low-grade gliomas.

Combination of aziridinylbenzoquinone and cis-platinum with radiation therapy in the 9L rat brain tumor model.

PURPOSE: We evaluated the potentiating effects of aziridinylbenzoquinone (AZQ) and cis-platinum on the prolongation of survival by radiation therapy in a rat brain tumor model. METHODS AND MATERIALS: On day 10 following intracranial inoculation of the 9L gliosarcoma, Fischer 344 rats were treated with radiation therapy (Cesium-137 source irradiator) and/or chemotherapy delivered either systemically (intraperitoneal or intravenous), or intracranially directly into the tumor in a volume of 5 microliters. Increased life spans were calculated relative to the median survival time for the control (ILS-C) or to the median survival time for radiation therapy only (ILS-RT) group. RESULTS: Median survival time for untreated rats was 22 +/- 3 days for seven experiments. Radiation therapy (16 Gy) produced a significant (p < 0.002) improvement in survival, with an average ILS-C of 75 +/- 19%. Systemic AZQ (1 or 5 intravenous injections of 0.5 mg/kg) produced ILS's of 0 and 23%, the latter being significant (p = 0.002). When added to radiation therapy, there were further improvements (ILS-RT's of 47 and 72%), but these were not significant. Intratumor AZQ (40 or 50 micrograms intracranially) produced significant ILS-C's of 30 and 33% (p = 0.01 and 0.0002, respectively). Added to radiation therapy, intracranial AZQ produced improvements (ILS-RT's of 5 and 102%), with only the latter being significantly improved (p = 0.009). Cis-platinum (3 micrograms intracranially) produced ILS-C's of 13 and 6%, neither significantly different from controls. Added to radiation therapy, cisplatinum caused improvements (ILS-RT's of 18 and 64%), with only the latter significant (p = 0.049). CONCLUSION: These results demonstrate that AZQ delivered systemically, and AZQ and cis-platinum delivered intracranially, can produce statistically significant improvements in the survival of rats burdened with the 9L brain tumor. The agents delivered intracranially significantly potentiated the prolongation of survival obtained by radiation therapy. This preclinical evidence suggests that combining radiation therapy with these cytotoxic chemotherapeutic agents may benefit patients with high-grade malignant brain tumors.

Immune adjuvants for chemotherapy or radiotherapy in the 9L rat brain tumor model.

The therapeutic efficacy and toxicity of three biological response modifiers, Corynebacterium parvum (Cp), Chinese blister beetle extract (CBBE), recombinant human IL-1 alpha (rhIL-1 alpha), used alone or in combination with chemotherapy or radiotherapy, were investigated in the intracerebral (ic) rat 9L brain tumor model. Used alone, Cp (2 mg/rat, ip plus 70 micrograms/rat, ic), CBBE (5 microliters of an ethanol extract, ic), or IL-1 alpha (1 microgram/rat, ic or 1 microgram/rat x 3, q 3 d, ic), had no effect on animal survival compared to the untreated or saline treated controls. When combined with chemotherapy or radiotherapy, the three immunotherapeutic agents did not show any additive effects on survival compared to that observed with systemic BCNU (12 mg/kg), local ic bleomycin (0.25 unit), or local radiotherapy (16 Gy). While ic IL-1 alpha did not produce evident toxicity, there was fatal toxicity caused by ic Cp or CBBE treatment in a few animals. The combination of Cp and bleomycin produced severe neurotoxicity, resulting in the early death of animals. This study demonstrates a lack of efficacy of the nonspecific immune adjuvants IL-1 alpha, Cp or CBBE, used either alone or combined with cytotoxic chemotherapy or radiotherapy, in this rat brain tumor model.

Intracerebral chemotherapy in the 9L rat brain tumor model.

We have used the 9L rat brain tumor model to search for effective chemotherapeutic approaches to the management of brain tumors. Several antineoplastic agents which have been proposed or are currently being used for human brain tumors, including 1,3-bis (2-chloroethyl)-1-nitrosourea (BCNU), bleomycin, aziridinylbenzoquinone (AZQ), cis-Platinum, and acivicin, were administered intravenously (iv), intraperitoneally (ip), or intracerebrally (ic) to rats burdened with the intracranial 9L gliosarcoma. The results confirm that BCNU is the most effective systemic agent among the chemotherapeutic agents tested as indicated by its ability to significantly increase the median survival time (MST) and life span of the tumor-burdened animals. Bleomycin is an effective agent against the intracranial 9L tumor when administered ic. While neither systemic single iv dose AZQ (0.5-2.5 mg/kg) nor multiple ip treatments (0.5-1.0 mg/kg x 5, q 6 h) were effective in prolonging the survival, single ic dose AZQ (5-50 micrograms/rat) treatment significantly increased the MST of the treated animals (P < 0.05). Systemic AZQ treatments using higher doses produced a hematological toxicity, resulting in a decrease in MST of the treated animals. Cis-Platinum, either administered ip or ic, produced only a marginal effect on survival, although acute neurologic toxicity limited the dose of cis-Platinum that could be administered ic. Acivicin, either administered ip or ic, produced no effect on the survival of treated animals. Our results suggest that local treatment with certain antineoplastic agents may be an efficient therapy in the management of brain tumors.

Generation of cytotoxic immune responses against a rat glioma by in vivo priming and secondary in vitro stimulation with tumor cells.

Cytotoxic T lymphocyte (CTL) responses to most antigens are generated by in vivo priming and secondary stimulation with antigen in vitro. The present studies were designed to determine whether that strategy could be used to stimulate development of CTL against brain tumors. Rats were primed with one of two tumors, RT2, an astrocytoma, or 9L, a gliosarcoma, and Corynebacterium parvum. Spleen cells from primed rats were stimulated with tumor cells and interleukin-2 in vitro to generate CTL. CTL generated against RT2 killed RT2 and 9L, but not allogeneic or histopathologically unrelated tumor cells, suggesting that the killing was brain tumor-specific and major histocompatibility complex gene product-restricted. Similar results were obtained with rats primed and secondarily stimulated with 9L. Specific cytotoxic cells only developed when syngeneic brain tumor cells were used for both priming and secondary stimulation. The cytotoxic cell populations were composed of OX-19+ T cells with a mixed CD4/CD8 phenotype. Controls consisting of spleen cells from unprimed or primed rats tested before culture exhibited low levels of cytotoxicity against brain tumor targets. Culturing unprimed or primed cells with interleukin-2 alone stimulated cell proliferation, but the cells that grew out exhibited only low levels of cytotoxicity for brain tumor cells. Cell populations exhibited consistent cytotoxicity against natural killer cell targets. None of the cell populations killed lymphokine-activated killer cell targets. The results demonstrated that brain tumor-specific CTL could be produced by priming in vivo followed by secondary stimulation with brain tumor cells in vitro. The results further demonstrated that RT2 and 9L share antigens that both induce and serve as target structures for specific cytotoxic cells.

High incidence of cardiopulmonary complications associated with implantation of adrenal medullary tissue into the caudate nucleus in patients with advanced neurologic disease.

OBJECTIVE: The purpose of our study was to examine the cardiopulmonary complications of a group of patients who had undergone implantation of adrenal medullary tissue into the caudate nucleus for treatment of neurologic disease. DESIGN: Prospective study with partially matched historical controls. SETTING: Tertiary care community medical center. PATIENTS AND METHODS: Seven patients with advanced Parkinson's disease and three patients with progressive supranuclear palsy underwent implantation of adrenal medullary tissue into the caudate nucleus. These patients were compared with respect to their cardiopulmonary complications with a control group who had undergone craniotomy and then compared with a control group who had undergone only abdominal surgery. RESULTS: In the study group, six patients developed major postoperative complications including development of large pleural effusions, lobar atelectasis, pneumonia, upper airway obstruction, and cardiac arrest. Three patients had minor complications including development of small pleural effusions, subsegmental atelectasis, purulent bronchitis, mild congestive heart failure, and atrial flutter/fibrillation. One patient had an unremarkable postoperative course. The first control group, whose only surgery was a craniotomy, had only one major complication. The second control group, the abdominal surgery control group, had one major and five minor complications. CONCLUSION: The particular neurologic disease, its severity, and the type of surgery performed appear to be causative factors in the high incidence of complications in the study group.

Association of brain cancer with dental X-rays and occupation in Missouri.

This investigation of a brain cancer cluster in Missouri used two approaches to investigate associations with potential risk factors. In a case-control study in a rural town, we interviewed surrogates of cases and controls about potential risk factors. We found a statistically significant positive association of brain cancer with reported exposure to dental X-rays. Occupation was not associated with the cluster in the rural town. In a standardized proportional mortality study for the state of Missouri, we calculated the observed and expected proportion of brain cancers by occupation and industry in Missouri decedents. We found that motor vehicle manufacturers, beauty shop workers, managers and administrators, elementary school teachers, and hairdressers and cosmetologists had significantly elevated proportions of brain cancer. Brain tumors are inconsistently associated with occupation in the literature. Further study of brain cancer etiology with respect to dental X-ray exposures seems warranted.

Nutritional aspects and swallowing function of patients with Parkinson's disease.

Seven patients with Parkinson's disease and three patients with progressive supranuclear palsy underwent adrenal medullary transplant to the caudate nucleus for treatment of their neurologic disease. Preoperative nutritional assessment demonstrated that a significant number of the Parkinson's patients had mild to moderate nutritional depletion. Motility problems, manifest by dysphagia and delayed gastric emptying causing problems over a number of years, were probably responsible. Of the 10 patients studied, 6 were studied by videofluoroscopy. All patients had variable dysphagia of variable servility with or without aspiration. Etiologic factors included the basic underlying neurologic disease, delay in resumption of anti-parkinsonian medications, use of metoclopramide, and postoperative medical complications leading to a debilitated clinical state.

A phase I/II study of the use of Fluosol as an adjuvant to radiation therapy in the treatment of primary high-grade brain tumors.

The main objective of this study was to evaluate the safety and efficacy of a perfluorochemical emulsion, Fluosol, with short-term high inspired oxygen tension as an adjuvant to radiation therapy in the treatment of high-grade tumors of the brain. Radiation was delivered to the whole brain at 1.8 Gy per daily treatment for 5 weeks to a total dose of 45 Gy. The radiation portals were then reduced in size to encompass the known volume of tumor, as determined by the presurgical contrast-enhancing ring on computed tomography (CT), plus a 3-cm margin. An additional 10 treatments of 2 Gy each were given to the smaller volume, to bring the total tumor dose to 65 Gy in 7 weeks. This report describes the experience of the first 18 patients treated at the University of Kansas Medical Center on this study, whose median follow-up time from the date of surgery is 77 weeks (62-115 w). Immediately following Fluosol administration on a Monday, patients breathed 100% oxygen for at least 45 minutes prior to and throughout their radiation treatment. On each subsequent day of the weeks in which they received Fluosol, patients breathed 100% oxygen. Hematology and blood chemistries were also drawn prior to Fluosol treatment each Friday during treatment and at the 2-week, 3-month, and 6-month follow-up visits. The median age of the patients was 45 years (16-72); 13 patients were male and 15 carried the diagnosis of glioblastoma multiforme (3 had anaplastic astrocytoma). Two thirds of the patients had an initial allergic reaction to the Fluosol consisting of back pain, shortness of breath, and flushing, but all responded to 50-100 mg of Benadryl. During radiation therapy, all patients developed scalp erythema and complete alopecia by the end of 3 weeks, but no patient required a treatment rest. The serum levels of SGOT, SGPT, and alkaline phosphatase were examined before and throughout the Fluosol treatment and, by week 5, 11/18 of the patients had increased values of all three enzymes above the upper range of normal. These increases persisted through the end of treatment, but most values returned to essentially normal by the 3-month follow-up visit. We conclude that Fluosol, given in the manner described above, appears to be associated with minimal significant side effects and no changes could be detected in the white matter of any of the patients at the time of their magnetic resonance imaging study at 6 months follow-up.(ABSTRACT TRUNCATED AT 400 WORDS)

Serpin inhibitors of urokinase and thrombin in normal rat brain and the 9L brain tumor: evidence for elevated expression of protease nexin I-like inhibitor and a novel sodium dodecyl sulfate-activated tumor antithrombin.

Increasing attention is being paid to alterations of the hemostatic balance in tumors, in general, and brain tumors, in particular. Apparently divergent results, showing excess fibrinolysis (i.e., increased plasminogen activator activity) or its inhibition (i.e., increased inhibitor activity), have been reported. The 9L rat brain tumor is a gliosarcoma and a model used to study treatment paradigms for human gliomas. To study the roles of fibrin and fibrinolysis in this brain tumor model, we used these features to investigate the nature of the plasminogen activator (PA) and thrombin inhibitors in normal rat brain and in the 9L rat brain tumor, growing both in vitro and in vivo in rat brain. The results indicate that cells cultured from the tumor in vitro express PA inhibitory activity which is both of the protease nexin I and PA inhibitor 1 types. However, the serpin PA inhibitory activity in extracts of both the normal brain and tumor is of the protease nexin I/PA inhibitor 3 type. This activity is higher in the tumor than in the surrounding "normal" tissue. In addition, we present evidence for a novel thrombin inhibitor which (a) is present only in the tumor growing in rat brain and undetectable either in the normal brain tissue or in vitro, (b) is in a latent, but sodium dodecyl sulfate-activatable, state, and (c) does not bind urokinase. In current studies, investigators are exploring the roles of these molecules and the target serine proteases they inhibit in the pathogenesis of gliomas.

Combination of radiation therapy and intracranial bleomycin in the 9L rat brain tumor model.

The rat 9L brain tumor model was used to investigate the therapeutic potential of a combined modality approach using intracranial Bleomycin and radiation therapy. Bolus Bleomycin was delivered intracranially into the tumor volume via cannula guides; for continuous infusions, osmotic mini-pumps were implanted subcutaneously between the scapulae with flexible tubing to deliver the drug directly into the tumor and brain. Two to six bolus injections of Bleomycin (1 unit/kg each) over 5-11 days produced modest (usually statistically significant, p less than 0.05) increases in the median survival time compared to controls. Continuous infusion of Bleomycin by osmotic pump (10 units/kg over 7 days or 15 units/kg over 14 days) was also effective at significantly increasing median survival times compared to that of controls. Radiation therapy schedules of 10 daily fractions in 12 days (2 weeks) or 10 twice-daily fractions in 5 days produced dose-dependent increases in median survival time. Multiple bolus injections of Bleomycin when combined with fractionated radiation therapy significantly increased the median survival time due to fractionated radiation therapy alone for low doses (40 or 50 Gy). However, at higher radiation doses, the addition of Bleomycin either had no effect on median survival time or actually shortened it. Continuous infusion of Bleomycin by osmotic pump was effective when added to low dose radiation therapy in several experiments, twice for a total radiation dose of 50 Gy and once for radiation therapy of 60 Gy. However, it was also observed (once for 60 Gy and twice for 70 Gy) that the addition of continuous infusion Bleomycin either had no effect or served to decrease the improvement of median survival time obtained by radiation therapy alone. Thus, we conclude that increases in normal tissue toxicity can prevent full attainment of improved therapeutic advantage from the addition of Bleomycin to fractionated radiation therapy in the rat 9L model. These results should be considered when attempts are made to combine radiation therapy and intracranial Bleomycin for the treatment of patients with primary malignant brain tumors.

Cerebellar astrocytomas in elderly patients with very long preoperative histories: report of three cases.

Three patients, ages 69, 67, and 74 years, respectively, underwent surgical removal of cystic cerebellar astrocytomas. All three had past histories pointing to the existence of a cerebellar lesion for many decades prior to surgery: Patient 1 had had nystagmus on lateral gaze on the side of the tumor since early childhood; Patient 2 had had sensorineural hearing loss on the side of her neoplasm for 38 years preceding the operation; and Patient 3 was diagnosed as having a brain tumor 51 years before the operation. (He has been blind because of pressure hydrocephalus for half a century, but otherwise managed to live a productive farming and family life until he sustained a head injury in a car accident, which forced him to undergo removal of his cerebellar tumor.) The neoplasms in all three instances were found by histological examination to be low-grade astrocytomas. These cases indicate that low-grade cerebellar astrocytomas, which are well known for their characteristically long postoperative courses, may at times manifest a slow growth potential with an exceptionally long preoperative course.

Effect of spirogermanium and radiation therapy on the 9L rat brain tumor model.

Spirogermanium (SPG) was investigated in the 9L rat brain tumor model in vivo and in vitro. Used at a single ip dose of 50 or 60 mg/kg or at 5 daily doses of 10 mg/kg, SPG was ineffective in prolonging survival of rats burdened with the intracerebrally implanted tumor, i.e., the median survival time (MST) was the same as that for the controls. Only a schedule of 3 X 20 mg SPG/kg every other day improved the MST compared with controls. Single-dose (20-Gy) radiation therapy (RT, cesium-137 whole-head irradiation) did prolong survival. However, when single-dose SPG was combined with RT (1 hr or 1 day before, or 1 hr after RT), the survival response was worse than after RT alone. When the daily SPG was combined with daily RT (5 doses of 6 Gy), survival was no better than after daily RT alone. In vitro, SPG produces a concentration-dependent, exponential decrease in cell survival as measured by colony formation assay. When combined with radiation, there is an additive effect on cell lethality. Aside from the possibility that SPG does not penetrate the rat brain tumor itself, we have no explanation why SPG shows some activity against human brain tumors and is cytotoxic against 9L cells in vitro, yet is both ineffective by itself and fails to potentiate RT in the 9L rat brain tumor model.