Boron neutron capture therapy of brain tumors: enhanced survival following intracarotid injection of either sodium borocaptate or boronophenylalanine with or without blood-brain barrier disruption

The purpose of the present study was to determine whether the efficacy of boron neutron capture therapy could be enhanced by means of intracarotid (i.c.) injection of sodium borocaptate (BSH) or boronophenylalanine (BPA) with or without blood-brain barrier disruption (BBB-D). For biodistribution studies, F98 glioma-bearing rats were injected i.v. or i.c. with either BSH (30 mg of boron/kg of body weight) or BPA (24 mg of boron/kg of body weight) with or without mannitol-induced, hyperosmotic BBB-D and killed 2.5 h later. The highest tumor boron concentrations for BSH and BPA were attained following i.c. injection with BBB-D (48.6 and 94.0 microg/g, respectively) compared to i.c. (30.8 and 42.7 microg/g) and i.v. injection (12.9 and 20.8 microg). Using the same doses of BSH and BPA, therapy experiments were initiated 14 days after intracerebral implantation of F98 glioma cells. Animals were irradiated 2.5 h after i.v. or i.c. administration of the capture agent with or without BBB-D using a collimated beam of thermal neutrons at the Brookhaven Medical Research Reactor. The median survival times of rats given BSH or BPA i.c. were 52 and 69 days, respectively, for rats with BBB-D; 39 and 48 days for rats without BBB-D; 33 and 37 days for i.v. injected rats; 29 days for irradiated controls; and 24 days for untreated controls. i.c. injection of either BSH or BPA resulted in highly significant enhancement (P = 0.01 and P = 0.0002, respectively) of survival times compared to i.v. injection, and this was further augmented by BBB-D (P = 0.02 and P = 0.04, respectively) compared to i.c. injection. Normal brain tissue tolerance studies were carried out with non-tumor-bearing rats, which were treated in the same way as tumor-bearing animals. One year after irradiation, the brains of these animals showed only minimal radiation-induced changes in the choroid plexus, but no differences were discernible between irradiated controls and those that had BBB-D followed by i.c. injection of either BSH or BPA. Our data clearly show that the route of administration, as well as BBB-D, can enhance the uptake of BSH and BPA, and, subsequently, the efficacy of boron neutron capture therapy.     

The role of brain cholinergic system in renal sodium, potassium and water excretion in rats

In anesthetized rats intracerebroventricular (i. c. v.) injection of cholinergic agonist carbachol induced significant natriuresis, kaliuresis and diuresis (P < 0.05). Among them, the degree of natriuresis was changed with carbachol in a dose-dependent manner (r = 0.9997, P < 0.05). These responses were completely blocked by cholinergic M receptor antagonist atropine or N receptor antagonist hexamethonium pretreatment. Such effects of carbachol were inhibited in part by pretreatment with adrenergic alpha receptor antagonist phentolamine. These results indicate that the natriuresis, kaliuresis and diuresis induced by i. c. v. injection of carbachol were primarily mediated by both muscarinic and nicotinic receptors in the brain, while the effect was in part mediated secondarily via adrenergic alpha receptor.     

CCNU chemotherapy in adult patients with tumors of the basal ganglia and brain stem

The present investigation evaluates those few patients of our series with basal ganglia and brain-stem tumor who refused either surgical decompression and biopsy or radiation therapy. Four patients were suffering from tumors of the basal ganglia and three from brain-stem tumors; all the tumors were diagnosed by classical neuroradiological investigations and computerized tomography. The patients were given CCNU by mouth, 13 mg/sq m every 6 weeks. No toxicity was recorded. Mean survival was 19 weeks for patients with basal ganglia tumors and 48 weeks for those with brain-stem tumors. All patients were evaluated with respect to the quality of survival. Results were compared with those obtained in a control group of patients who received methylprednisolone therapy only.     

Electroporation increases the effect of borocaptate (10B-BSH) in neutron capture therapy

Patients with colorectal cancer were entered into a clinical phase I trial of immunotherapy with an autologous tumour cell/bacillus Calmette-Guerin (BCG) vaccine. We attempted to describe the possible effects and side effects of the immunisation, and further to investigate whether expression of immune-response-related surface molecules on the tumour cells in the vaccine correlated with survival. The first and second vaccine comprised of 107 irradiated tumour cells mixed with BCG, the third of irradiated tumour cells only. Thirty-nine patients were considered, but only 6 patients fulfilled the criteria for inclusion. No serious side effects were observed. With three years of observation time, two patients are healthy, while the rest have had recurrence, and two of them have died. In all vaccines, all tumour cells expressed HLA class I, some expressed HLA class II and none expressed CD80. There was an inverse relation between survival and HLA class II expression. This highlights an essential problem, in the absence of CD80 expression the expression of HLA class II may induce anergy. In future attempts to develop improved vaccines this problem should be addressed.     

Safety and use of gadobutrol in patients with brain tumors (phase III trial)

PURPOSE: The purpose of the study was to investigate the use and safety of Gadobutrol, a new low-osmolar, non-ionic contrast agent for MRI using a total dose of 0.3 mmol/kg b.w. on the basis of a clinical phase 3 study. METHODS: 30 patients with primary brain tumours (n = 15) or cerebral metastases (n = 15) were examined via MRI before and after application of a total of 0.3 mmol/kg b.w. given in two fractions (0.1 and 0.2 mmol/kg b.w.). T2-weighted images were performed before, T1-weighted images before, between and after application of contrast material. RESULTS: In this study one-molar Gadobutrol showed a good tolerance. In half of the cases the contrast between lesion and brain was improved comparing single and triple dose, but this means only a slightly improvement of information for the primary brain tumours compared with single dose. The detected metastatic lesions increased in 40% of the patients after the single dose and in 53% of the patients after cumulative triple dose. There was a consecutive change in therapy in 20% of the patients. CONCLUSION: For the differentiation of primary brain tumours the single dose was sufficient, in metastatic lesions triple dose was essential for the detection or exclusion of multifocality.     

A randomized, blinded, placebo-controlled trial of divalproex sodium prophylaxis in adults with newly diagnosed brain tumors

BACKGROUND: Seizures occur after the diagnosis of brain tumors in up to 40% of patients. Prophylactic anticonvulsants are widely advocated despite a lack of convincing evidence of their efficacy in preventing first seizures. We conducted a randomized, double-blind, placebo-controlled study comparing the incidence of first seizures in divalproex sodium- and placebo-treated patients with newly diagnosed brain tumors. PATIENTS AND METHODS: Patients who had not previously had a seizure were randomized within 14 days of diagnosis of their brain tumor to receive either divalproex sodium or placebo. All patients had at least one supratentorial brain lesion, a Karnofsky Performance Score (KPS) > or = 50%, and no previous anticonvulsant use or other brain disease. Compliance and adequacy of dosing were assessed by pill counts and monthly blood levels. RESULTS: Seventy-four of 75 consecutive eligible patients were entered in this study. Median follow-up was 7 months. The drug and placebo groups did not differ significantly in age, sex, KPS, primary tumor type, number or location of brain lesions, frequency of brain surgery, or pretreatment EEG. Thirteen of 37 patients (35%) receiving divalproex sodium and 9 of 37 patients (24%) on placebo had seizures. The odds ratio for a seizure in the divalproex sodium arm relative to the placebo arm was 1.7 (95% CI 0.6 to 4.6; p = 0.3). The hypothesis that anticonvulsant prophylaxis provides a reduction in the frequency of first seizure as small as 30% was rejected (p = 0.05). CONCLUSIONS: Anticonvulsant prophylaxis with divalproex sodium is not indicated for patients with brain tumors who have not had seizures.     

The effect of steroid contraceptives on the concentrations of brain monoamines in rats and mice

The effect of three estrogen-progestin combinations on biogenic amines in discrete brain areas of rats and mice has been investigated. With the exception of a significant decrease of brain 5-hydroxyindolacetic acid in the rats treated for 30 days with the combination norethynodrel + mestranol, no significant changes in the levels of serotonin, noradrenaline or dopamine in the rat brain were found following the administration of the compounds under study. On the other hand, in mice moderate but significant changes in the levels of serotonin, dopamine, noradrenaline and 5-hydroxyindolacetic acid were found in various brain areas depending on the estrogen-progestin combination used. The potential importance of these effects for the contraceptive as well as for some central actions of these compounds is discussed.     

The effect of metal ions on free radical formation in lung and brain of rats

The influence of 14 metal ions on free radical (FR) formation in subcellular systems of lung mitochondria and brain synaptosomes (cortex and cerebellum) of rats was investigated. Iron and manganese showed a highly significant increase in FR formation in lung, whereas other investigated metal ions showed relatively slight, insignificant decreases in FR. The significant enhancement effects of iron and manganese increased with their content in the media. Scandium exhibited an insignificant enhancement effect at a low concentration of 0.01 microM, but also an insignificant decrease in FR formation in lung at higher concentrations. In brain cerebellum only iron significantly increased FR formation but manganese, as well as trivalent metals (Al, La, Sc), showed insignificant changes in FR formation. The possible causes of differences induced by metal ions at various concentrations, as well as the biological functions of the investigated tissues, were considered in the explanation of obtained results.     

Changes in QOL in patients with brain tumors measured by mood changes during and after treatment

Patients with brain tumors are exposed to severe stress which may have an influence on their quality of life (QOL). To measure QOL in those patients, we measure their mood state during and after the treatments. MATERIALS: 16 patients who were admitted to our department for treatment of brain tumors, were included in the study. The tumors included 5 gliomas, 6 meningiomas and others. They were 7 males and 9 females, and age distributed from 19 to 74 years old. All patients presented more than 90% of the Karnofsky performance score (KPS) on discharge, so they were expected to return to their previous social life. METHOD: The self-answering tests were performed on admission (Pre), on discharge (Post 1), and at more than 5 months after the discharge (Post 2). The tests included an original questionnaire asking consent to admission and treatment, and concerning the feeling of disability to cope with conditions of living, Cornell Medical Index (CMI) which measured the neurosis, and Profile of mood state (POMS) which measured the 6 subscales of patients mood states including tension-anxiety (TA), depression (D), anger-hostility (AH), vigor (V), fatigue (F), and confusion (C). RESULTS: The questionnaire showed that the patients feel satisfied with having consented to the treatment. The feeling of disability to cope with living became stronger in Post 2 than in Pre. CMI showed a borderline of neurosis in three patients on admission, and in four patients in Post 2. Only the TA of POMS subscale improved significantly in Post 2. However, other subscales were unchanged. It is characteristic that all of the subscales of POMS showed less disturbance on discharge compared with that on admission, but, they returned to the Prelevel after they returned to social life. CONCLUSIONS: Patients with brain tumors have satisfactory consent to the treatment, however, they feel disability to cope with social life. On discharge, they showed a better mood state compared to that on admission, but the mood state turned for the worse again during the follow-up period. It is evident that patients with brain tumors are exposed to severe stress even after the completion of the treatment. The results necessitate our taking patients' mental health into consideration for our treatment protocol.     

The effect of thyrotropin-releasing hormone on gonadotropin and free alpha-subunit secretion in patients with acromegaly and functionless pituitary tumors

Paradoxical response of luteinizing hormone (LH), follicle-stimulating hormone (FSH), and alpha-subunits (alpha-SU) to thyrotropin-releasing hormone (TRH) have previously been reported in individuals with clinically nonfunctioning pituitary tumors (NFT). In the present study, we assessed the in vivo responses of LH, FSH, alpha-SU to TRH in 34 patients with NFT and 29 patients with agromegaly. Twenty-three clinically NFT were postoperatively analyzed by immunocytochemistry and 21 stained positive for beta-FSH and/or beta-LH. Two patients with NFT had elevated basal circulating levels of FSH (41.5 IU/L) and thus were characterized as FSH-secreting adenomas. TRH in these patients increased LH from basal 1.6 IU/L to 32.6 IU/L. In other patients with NFT, circulating levels of glycoprotein peptides were not elevated. TRH induced significant rise of LH in 8 (23.5%), FSH in 5 (14.7%), and alpha-SU in 10 (29.4%) patients with NFT. Thus, a bolus dose of TRH elicited a notable increment in FSH, LH or alpha-SU in 23 of 34 patients with NFT. Among 29 patients with acromegaly, LH rose in 6 (20.7%), FSH in 5 (17.2%), and alpha-SU in 3 (10.3%) patients. In conclusion: (1) We confirm that most NFTs are capable of synthesizing gonadotropin hormones and subunits (beta-FSH, beta-LH). (2) Most patients in our study responded by either FSH, LH or alpha-SU secretion after TRH, independent of basal hormone levels. Furthermore, recent studies show that by measurement of TRH stimulated beta-FSH and beta-LH one might further improve the diagnostic tools. (3) Gonadotropin response and possibly alpha-SU to TRH are also found in some patients with acromegaly. This could be a marker of a plurihormonal pituitary tumor.     

The use of SPECT with 201Tl in the evaluation of brain tumors

There is increasing interest in the literature regarding the use of SPECT (single photon emission computed tomography) with 201Tl in the evaluation of cerebral tumours. Thallium (201Tl) is one of the isotopes most commonly used in studies of the myocardium and in the diagnosis of various tumours. Normal brain takes up very little 201Tl, but in viable tumour tissue the 201Tl becomes intracellular and is rapidly cleared from the blood stream. Such cerebral tumour uptake is related to changes in the permeability of the blood-brain barrier, regional blood flow and transport by means of the Na(+)-K+ adenosine triphosphate pump. Once the SPECT images have been obtained following administration of the radioisotope, one can calculate the indices of early and of late uptake together with the retention index. The usefulness of SPECT in the preoperative detection of malignant expansive pathology, choice of tumour region during stereotaxic biopsy, control of tumour reproduction and their differentiation from post-radiotherapy necrotic tissue, and evaluation of chemotherapy in treatment of cerebral tumours are analyzed. Finally the application of SPECT in metastatic conditions and the differential diagnosis of expansive lesions is considered.     

The chemotherapy of adult primary brain tumors

Adult patients with primary malignant brain tumors are a heterogeneous group. Most patients will have high-grade astrocytomas and can be expected to obtain minimal benefit from current standard chemotherapy regimens. Intra-arterial chemotherapy, high-dose chemotherapy with autologous bone marrow rescue, and new chemotherapeutic agents designed to penetrate the blood-brain barrier have not resulted in significant advances to date. However, there are exciting new directions in the chemotherapy of high-grade astrocytomas which are entering clinical trials. Two potentially promising approaches include interstitial chemotherapy using surgically implanted polymers and the continuous infusion of combinations of active chemotherapeutic agents. Other therapeutic modalities such as radioactive seed implants, stereotactic radiosurgery, and gene therapy are also being evaluated. Hopefully, this intense activity by subspecialists with a wide range of interests and expertise will produce novel and effective treatments for the large number of patients with malignant astrocytomas. In contrast, patients with many of the less common neoplasms of the central nervous system may benefit from the addition of chemotherapy to their treatment. Primary germ cell tumors or lymphomas of the central nervous system are very sensitive to chemotherapy. The germ cell tumors respond to the cisplatin-containing regimens developed for testicular malignancies. The optimal chemotherapy for CNS lymphoma is not clear but exciting results have been reported with a combination of radiation, systemic and intrathecal methotrexate, and systemic cytosine arabinoside. Although limited, the available literature suggests that patients with anaplastic oligodendrogliomas may also benefit from chemotherapy at diagnosis or at relapse. Studies in children suggest a benefit for adjuvant chemotherapy and radiation therapy in poor risk patients with medulloblastomas although these findings have not been confirmed in adults. Finally, anecdotal reports suggest that chemotherapy may be useful in the very rare patient who presents with a pineal tumor or an ependymoma.     

Cytological effect of nogalamycin in mammals and regression of methylcholanthrene-induced and spontaneous tumors in rats

In experiments carried out on Wistar rats ultrastructrual charges of hepatocytes were studied during long-term carcinogenesis due to N-Nitrosomorpholine administered as a 20 mg% solution in drinking water. Carcinoma usually developed after the 20th week of the experiment. The development of the tumour was preceded by early dystrophic changes and, later, by a precancerous posttoxic "glycogenosis". The structural alterations as observed during the precancerous stage were rather noncharacteristic so that they did not permit to disclose the exact point of neoplastic change of the hepatocytes. Nevertheless, the model of carcinogenesis as demonstrated here appears to be a rather standard one and seems to be suitable for studying oncological problems of general character.     

Inhibitory effect of combined treatment with the aromatase inhibitor exemestane and tamoxifen on DMBA-induced mammary tumors in rats

The antitumor effect of exemestane (FCE 24304), an irreversible aromatase inhibitor, given alone or in combination with tamoxifen, was investigated in rats with 7,12-dimethylbenzanthracene (DMBA)-induced mammary tumors. The compounds were given once daily, 6 days a week for 4 weeks. Exemestane, given at the dose of 20 mg/kg/day s.c., induced 26% complete (CR) and 18% partial (PR) tumor regressions, compared to 0% CR and 6% PR observed in controls. Tamoxifen, given at 1 mg/kg/day p.o., induced 16% CR and 13% PR. The combined treatment caused 41% CR and 16% PR, thus resulting in a higher antitumor effect than either single treatment. The appearance of new tumors was reduced by each single treatment and almost totally prevented by the combined treatment. Serum prolactin (PRL) levels, assayed 4 h after the last dose, were unchanged in the group treated with the combination, whereas tamoxifen alone caused a slight increase of serum PRL. These results indicate that estrogen deprivation through aromatase inhibition and estrogen receptor antagonism causes a better inhibition of DMBA-induced mammary tumors than either treatment modality alone.     

Connexins are expressed in primary brain tumors and enhance the bystander effect in gene therapy

OBJECTIVE: Experimental brain tumor gene therapy with the herpes simplex virus thymidine kinase (HSV-tk) gene has demonstrated that not only HSV-tk transduced but surrounding non-HSV-tk transduced cells are killed when given ganciclovir. This so-called bystander effect has recently been shown to be dependent on connexin-mediated intercellular communication. To assess potential susceptibility to the bystander effect, we examined levels of connexin-26 and connexin-43 expression in a series of primary brain tumors. Connexin-26 expression has not previously been studied in primary brain tumors and connexin-43 expression has not been studied in nonastrocytic primary brain tumors. We also attempted to enhance the bystander effect in vitro by overexpressing connexin in tumor cells with high basal levels of connexin expression. METHODS: Western blot analysis and immunohistochemistry were used to determine levels of connexin-26 and connexin-43 expression in a series of primary brain tumors. Wild-type 9L gliosarcoma cells were transfected in vitro with the connexin-43 gene and the HSV-tk gene or the HSV-tk gene alone. The bystander effect of each transfectant was then assessed and compared. RESULTS: Most of the primary brain tumors tested, including low-grade astrocytomas, anaplastic astrocytomas, glioblastomas, oligodendrogliomas, gangliogliomas, meningiomas, and medulloblastomas, showed connexin-26 and connexin-43 expression. Bystander experiments revealed a significant enhancement of the bystander effect in the gliosarcoma cells transfected with connexin-43 and HSV-tk, as compared with gliosarcoma cells transfected with HSV-tk alone. CONCLUSION: Most primary brain tumors express connexin-26 and connexin-43. This suggests that most primary brain tumors may be susceptible to the bystander effect of HSV-tk gene therapy. The bystander effect can be enhanced in vitro by overexpression of connexin-43 in a cell line with a high basal level of connexin-43 expression.     

The induction of lipid peroxidation in human brain glial tumors

Tissue examinations of glial tumors in the human brain revealed that therein lipid peroxidation could be induced by using bivalent iron salts, which is indicated by higher malonic dialdehyde levels. The authors have demonstrated that the glioma tissue levels of iron were statistically lower than those in the brain tissue. The induction in tumor tissue does not depend upon the degree of its malignancy, but it significantly differs from this parameter in the rabbit brain tissue. The induction of lipid peroxidation processes is accompanied by a lower cumulative antioxidative activity. The findings open new prospects for affecting tumor growth.