Actions of nitric oxide on renal epithelial transport

A 55-year-old male who had a remote history of occupational asbestos exposure consulted us because of chest pain. Chest X-ray revealed diffuse pleural thickening and pleural effusion on the right. A diagnosis of malignant mesothelioma, biphasic type was made by needle pleural biopsy. Fourteen months later, the patient died of brain metastasis. At autopsy, malignant mesothelioma of the pleura with metastasis to the brain and bilateral adrenal glands was observed. Brain metastases proven by autopsy are rare in cases of malignant mesothelioma. The ferruginous body count in the lung tissue was 16 per gram of wet weight.     

Childhood tumors

Slowly, advances are being made in the understanding and treatment of primary childhood brain tumors. The addition of chemotherapy has resulted in better survival for children with medulloblastoma. For other tumor types, therapeutic advances have been slower. High-dose chemotherapy is increasingly being employed to treat malignant childhood tumors with variable results. Chemotherapy has been effective in low-grade glial tumors.     

Production of urokinase-type plasminogen activator (u-PA) and plasminogen activator inhibitor-1 (PAI-1) in human brain tumours

We investigated the role of plasminogen activators (PAs) and their inhibitor (plasminogen activator inhibitor-1, PAI-1) in human brain tumours. The amounts of urokinase-type plasminogen activator (u-PA), tissue-type plasminogen activator (t-PA), and plasminogen activator inhibitor-1 (PAI-1), and the activity of u-PA and t-PA were determined by enzyme-linked immunosorbent assay (ELISA), and u-PA and PAI-1 were immunolocalized using monoclonal antibodies in human brain tumours and normal brain tissues. The tissues were surgically removed from 64 patients; normal brain tissue (5 cases), low-grade glioma (4 cases), high-grade glioma (17 cases), metastatic tumour (9 cases), meningioma (benign 12 cases, malignant 6 cases), acoustic schwannoma (11 cases). u-PA activity and u-PA and PAI-1 antigen levels were significantly elevated in malignant brain tumours (malignant meningiomas, high-grade gliomas, and metastatic tumours) and acoustic schwannomas but very low in benign meningiomas, low-grade gliomas and normal brain. There was no difference in t-PA antigen levels among normal and malignant tissues, however levels of t-PA activity were markedly decreased in metastastic tumours. All malignant brain tumour tissues showed positive immunostaining for u-PA and PAI-1, however, some tumour cells showed negative intensity while others showed strong intensity for these antibodies. This contrasts to the homogeneous staining pattern found in acoustic schwannoma. These findings indicate that malignancy in human brain tumours is associated with elevated levels of u-PA and PAI-1 and that an imbalance between these proteins in a micro-environment contributes (ascribes) to tumour cell invasion.     

Translational research models in neuro-oncology

Tumor development and progression in the nervous system are poorly understood. Consequently, even though there seems to be little possibility of major advances in existing clinical modalities used to treat malignant brain tumors, no targeted molecular therapies have risen to take their place. The variability and plasticity of brain neoplasms make them an illusive target for study and therapeutic intervention. Further complicated by infiltration of vital nervous tissue, clinical studies have serious practical limitations and the ability to assess tumor progression in vivo is still a developing technology. Evaluation of potential new therapies for brain tumors is heavily dependent on the development of more informative and cognate experimental models. To develop and validate new models, it is particularly important to integrate clinical, pathological, and cell biological characterizations of malignant brain tumors. This discussion provides an overview of developments in tumor cell culture and the impact of animal models on brain tumor research. Studies of malignant glial neoplasms associated with a dismal prognosis in patients receive particular attention.     

Correlation of B-FABP and GFAP expression in malignant glioma

The murine brain fatty acid binding protein (B-FABP) is encoded by a developmentally regulated gene that is expressed in radial glial cells and immature astrocytes. We have cloned the human B-FABP gene and have mapped it to chromosome 6q22-23. We show that B-FABP mRNA is expressed in human malignant glioma tumor biopsies and in a subset of malignant glioma cell lines, as well as in human fetal retina and brain. Malignant glioma tumors are characterized by cytoplasmic bundles of glial fibrillary acidic protein (GFAP), a protein normally expressed in mature astrocytes. Establishment of malignant glioma cell lines often results in loss of GFAP. The subset of malignant glioma cell lines that express GFAP mRNA also express B-FABP mRNA. Co-localization experiments in cell lines indicate that the same cells produce both GFAP and B-FABP. We suggest that some malignant gliomas may be derived from astrocytic precursor cells which can express proteins that are normally produced at different developmental stages in the astrocytic differentiation pathway.     

Trends in reported incidence of primary malignant brain tumors in children in the United States

BACKGROUND: The reported incidence of primary malignant brain tumors among children in the United States increased by 35% during the period from 1973 through 1994. The purpose of our study was twofold: 1) to determine whether the reported incidence rates for this period are better represented by a linear increase over the entire period ("linear model") or, alternatively, by a step function, with a lower rate in the years preceding 1984-1985 and a constant higher rate afterward ("jump model"); and 2) to identify the specific brain regions and histologic subtypes that have increased in incidence. METHODS: Incidence data from the Surveillance, Epidemiology, and End Results Program of the National Cancer Institute for the period from 1973 through 1994 for primary malignant brain tumors in children were used to model the number of cases in a year as a random variable from a Poisson distribution by use of either a linear model or a jump model. RESULTS/CONCLUSIONS: The increase in reported incidence of childhood primary malignant brain tumors is best explained by the jump model, with a step increase in incidence occurring in the mid-1980s. The brain stem and the cerebrum are the primary sites for which an increase in tumor incidence has been reported. The increase in reported incidence of low-grade gliomas in the cerebrum and the brain stem (unaccompanied by an increase in mortality for these sites) supports the substantial contribution of low-grade gliomas to the overall increase in reported incidence for childhood brain tumors. IMPLICATIONS: The significantly better fit of the data to a jump model supports the hypothesis that the observed increase in incidence somehow resulted from changes in detection and/or reporting of childhood primary malignant brain tumors during the mid-1980s.     

Chemotherapy of primary malignant brain tumors in adults

Chemotherapy of primary malignant brain tumors (PMBT) is palliative, except for germinomas. It is used as adjuvant therapy or alone at recurrence. The chemosensitivity of PMBT differs among tumors of different histological types. The role of chemotherapy in the treatment strategy will be reviewed by tumor type (malignant astrocytic gliomas, anaplastic oligodendrogliomas and mixed gliomas, anaplastic ependymomas, medulloblastomas, germinomas, primary malignant cerebral lymphoma).     

Percutaneous treatment of bronchial artery aneurysm with use of transcatheter coil embolization and thoracic aortic stent-graft placement

Lactic acidosis due to thiamine deficiency is known to complicate chemotherapy and radiotherapy treatment of malignant extracranial tumors, but to the authors' knowledge, this complication has not been reported in patients treated for malignant brain tumors. They report three such cases, demonstrating that this complication can occur during treatment of brain tumors. In all patients, consciousness levels deteriorated within 1 to 2 days. Serum lactic acid levels increased to concentrations between 62 and 96.7 mg/dl, resulting in severe metabolic acidosis. A low blood thiamine level (9 ng/ml) was demonstrated at the onset in one case, and high-dose thiamine infusions dramatically improved lactic acidemia as well as impairment of consciousness in two cases. In the other case, hydrocephalus was suspected initially, resulting in a delay in thiamine supplementation. Clinical differentiation of this form of lactic acidosis from hydrocephalus or tumor progression can be very difficult in a patient undergoing treatment for a malignant brain tumor. Demand for thiamine is thought to be increased in patients with malignant brain tumors, and supplemental thiamine during treatment is necessary to prevent lactic acidosis. When this complication occurs, immediate treatment with sufficient thiamine is essential, together with normalization of pH by using sodium bicarbonate. With timely intervention, the level of consciousness can recover to the preacidotic state with no new neurological deficits.     

Intrathecal 5-fluoro-2'-deoxyuridine (FdUrd) for the treatment of solid tumor neoplastic meningitis: an in vivo study

To evaluate the possible intrathecal use of 5-fluoro-2'-deoxyuridine (FdUrd) for neoplastic meningitis, its antitumor activity and neurotoxicity in vivo were assessed. FdUrd at doses in the range 5-100 microg/animal was effective against meningeal carcinomatosis using Walker 256 carcinoma cells in rats and MM46 mammary cancer cells in mice and against meningeal gliomatosis using 203 glioma cells in mice. After four intrathecal injections, FdUrd at these doses also showed minimal neurotoxicity in the C57BL/6 mouse brain. To estimate the mechanism of FdUrd efficacy, thymidine phosphorylase (TPase) and thymidine kinase (TK), key enzymes in the metabolism of FdUrd, were measured in rat, mouse and normal human brain tissue, and in human brain tumor tissues and cerebrospinal fluid (CSF) from patients with malignant brain tumors including meningeal carcinomatosis. TPase levels were lower in brain and malignant brain tumors than in other organs and their tumors. Moreover, the activity of TPase in the gray matter of human brain, which faces the cerebrospinal fluid across the cortical surface and into which malignant cells invade in meningeal carcinomatosis, was lower than that in the white matter. TK was undetectable, and TPase was detected (at very low concentrations) in only 4 of 56 patients with brain tumors or meningeal carcinomatosis. These findings indicate that brain tissue and CSF are favorable sites for FdUrd chemotherapy because the rate of conversion of FdUrd to 5-FU would be minimal. In conclusion, FdUrd is potentially useful for intrathecal treatment of neoplastic meningitis from primary brain tumors and systemic cancer.     

The creation of protection and hope in patients with malignant brain tumours

The malignant brain tumour disease condenses much of the anguish of cancer diseases. The brain is a vital and delicate organ, and the prognosis is generally unfavourable. The patient is exposed and has to rely on cognitive manoeuvres to manage the mental stress. The purpose of this study was to generate new insights into how the patient constructs a new sense of reality when confronted with the malignant brain tumour diagnosis. Within grounded theory methodology, 30 patients with malignant gliomas were interviewed twice, in direct connection with diagnosis, surgery and radiotherapy. In addition, their partners were interviewed, and quantitative instruments (SMMSE, RDCQ) were used as additional references for assessing the patients cognitively and emotionally. Eleven patients were excluded from the final analysis because of cognitive impairment of personality change. Most of the patients were aware of the fact that the brain tumour exposed them to grave danger, but they were also able to use various cognitive manoeuvres to create protection and hope. This process originated from different sources: the body; helpful relations; cognitive schemata; and the handling of information. The importance of the body to raise hope is emphasized. In the discussion we consider this process as an expression of how the patient brings together reality and hope, thus creating her/his own illusion. These findings are also related to adjacent psychoanalytic theory, proposing a theoretical reference with clinical implications when discussing "What to tell cancer patients."     

A quantitative study of the EMI values obtained for normal brain cerebral infarction and certain tumours

A quantitative study has been made of the EMI numbers of normal brain, cerebral infarction and certain tumours. The scans were recorded on magnetic tape and analysed using a minicomuter linked to a graphic display unit. This system not only yielded 16 grey scales compared with the ten currently available, but was programmed to allow selected regions of the scans to be outlined. From these regions the computer calculated the area, the mean EMI number and its standard deviation. It was found that in 15 normal brain scans, the EMI values obtained for normal frontal and temporal lobes were similar, but that the values for the basal ganglia and occipital lobes were significantly different from the first two regions and from each other. Ten cases of cerebral infarction and 30 cases of cerebral tumour were analysed, and it was shown that analysing representative areas was more informative than surveying the whole lesion. Whilst only half of the scans of brain tumours had a significantly altered EMI number compared with that of normal brain, enhancement of tumour density with sodium iothalamate revealed a consistent and significant elevation of the EMI number for all tumours. In particular, the value for enhanced meningiomas was almost double and malignant tumours more than a third larger than normal brain. It was not possible to differentiate quantitatively between astrocytomas and metastases.     

Port site recurrences after laparoscopic surgery. A review

The diagnosis of meningeal carcinomatosis hinges on the cytologic examination of cerebrospinal fluid (CSF), which has a known low sensitivity for the identification of malignant cells. Often only 'suspicious' or 'atypical' diagnoses can be rendered, and specimens are commonly unsatisfactory for evaluation due to poor morphologic preservation. Telomerase is widely expressed in most brain metastases, medulloblastomas, lymphomas, oligodendrogliomas, and is expressed focally in glioblastomas. Little is known about the level of telomerase expression in these tumors, except for brain metastases, where a four-fold variation in telomerase levels exists. In our laboratory, as few as ten carcinoma cells can be detected by a sensitive polymerase chain reaction-based assay, the telomeric repeat amplification protocol (TRAP), for telomerase, but it was unclear whether varying levels of telomerase expressed by different types of metastases would influence detection. Using the TRAP protocol, we studied 281 CSF samples from a wide variety of patients with neurologic and non-neurologic conditions for telomerase expression. An adjusted specificity of 90% and a sensitivity of 64% were achieved for detection of malignant cells in CSF by telomerase expression. The TRAP assay for telomerase detection may serve as an adjunct to the traditional examination of CSF. Neither previously documented four-fold variation in the levels of telomerase expression in brain metastases, high CSF protein levels nor high white blood cell counts precluded detection of malignant cells in CSF.     

Local spread of malignant neuroepithelial tumors

A short review of invasiveness of primary malignant neoplasms in the nervous system is given. Invasiveness implies progressive spread and destruction locally, which eventually leads to a fatal outcome in the patient. In particular, the malignant cells are able to rapidly migrate over large parts of the brain. This process includes the capacity to adhere to a substratum, usually constituted by the various components of the extracellular matrix, followed by detachment and migration. Anatomical structures and local regulatory factors in the brain influence the direction and extent of this migration. Several model systems are now available for monitoring the aggressiveness of such tumours both in vivo and in vitro, and different phenotypic properties characteristic of invasive cells have been elucidated. Although still in its infancy, and currently as an experimental approach, anti-invasive therapy may in the future be an interesting alternative to conventional chemotherapy of brain tumours.     

Spontaneous regression of brain metastasis secondary to renal cell carcinoma

Spontaneous regression of malignant tumors is a rare event. A case involving brain metastasis from renal cell carcinoma (RCC) is presented. Nine years after the diagnosis of metastasis the patient is alive without evidence of recurrence. We have only found three previous RCC cases in the literature involving spontaneous regression of brain metastasis (4, 16, 17).     

A case of an adult patient of tetralogy of Fallot having malignant hyperthermia during surgery

An episode of malignant hyperthermia occurring in a 42-year-old man undergoing hypothermic cardiopulmonary bypass is reported. Malignant hyperthermia is a syndrome initiated by a hypermetabolic state of skeletal muscle. A patient presented for correction of an acyanotic tetralogy of Fallot. The coincidental usage of hypothermic cardiopulmonary bypass obscured the classical presenting sings and symptoms of the malignant hyperthermia. And the disease of tetralogy of Fallot made the syndrome difficult to manage. Although the clinical diagnosis of malignant hyperthermia is difficult to be confirmed, when it is suspected, it is prudent for the case to be initially treated as malignant hyperthermia.     

Treatment of human breast cancer in a brain metastatic model by G207, a replication-competent multimutated herpes simplex virus 1

We investigated the therapeutic efficacy of G207, a replication-competent multimutated herpes simplex virus type 1, for the treatment of human malignant mammary tumors metastatic to the brain. In vitro studies demonstrated that G207 efficiently destroyed three of four human malignant breast cancer cell lines. MDA-MB-435 was most susceptible and MDA-MB-231 was least susceptible to G207. In athymic mice harboring subcutaneous or intracerebral MDA-MB-435 cells, intraneoplastic inoculation of G207 caused growth inhibition and/or prolonged survival. In contrast, G207 had minimal effects on MDA-MB-231 subcutaneous tumor growth or survival in the intracerebral tumor model. The efficacy of G207 therapy in vivo correlated well with the susceptibility of the human cancer cells to G207 in vitro. Histological studies indicate that G207 replication is restricted to tumor cells in vivo and does not occur in the surrounding brain tissue. These results suggest that G207 shows particular promise for use as a novel antineoplastic agent for metastatic brain tumors and that in vitro testing may predict which tumors will be most responsive in vivo.     

Influence of hyperthyroidism on the activity of liver nitric oxide synthase in the rat

Previous studies of associations of metabolic polymorphisms with the occurrence of malignant brain tumors have suggested that there is a significantly increased risk of development of adult gliomas in individuals who carry a poor metabolizer CYP2D6 variant allele and the GSTT1 null genotype. To investigate this further, a population-based case control study of adult glioma in the San Francisco Bay area was conducted. Patients (n = 188) diagnosed with brain tumors and controls (n = 166) were enrolled using random digit dialing and were frequency matched for age, ethnicity and gender. Genotyping for the polymorphisms was performed using standard PCR-based techniques. The analysis of the data was restricted to Caucasians because the prevalence of these traits is known to vary by ethnicity. No overall association of either the GSTT1 null genotype or CYP2D6 homozygous variant PM genotype was observed with the occurrence of brain tumors. However, when stratified by histopathologic subtype, there was a significantly increased risk for oligodendroglioma associated with the GSTT1 null genotype, with an OR of 3.2 (95% CI 1.1-9.2). These data suggest that the GSTT1 polymorphism may play a role in the development of a subset of malignant brain tumors in adults, and indicate the need for further studies.     

Pseudoaldosteronism induced by administration of a massive dose of glycyrrhizin]

Formalin-fixed tissues from 100 endometria and 50 brains were grouped and studied by the technic of mixed-cell agglutination reaction (MCAR) for studying isoantigens A, B, and H (O). MCAR's were negative in all 45 of the endometria from subjects with endometrial carcinomas, where as MCAR's were positive in the epithelium of endometrial glands of the remaining 55 subjects (cyclic phases of endometrium and benign lesions). MCAR's were negative in all benign and malignant brain tumors and normal brain tissues used in this study. In view of the present findings and in the light of previous observations, the isonatigen loss in adenocarcinomas is greater than such losses in other types of malignancies so far studied. The cause of the negative MCAR's in normal brain tissue and brain tumours is not known, but they may be attributable to lack of isoantigens in normal brain tissue.     

In vitro stability of polymerase chain reaction-generated DNA fragments in serum and cell extracts

1. The identification of cytokine genes expressed in the central nervous system is critical to understanding the immune network in various diseases of brain, such as infection, degeneration, and malignancy. 2. Expression of cytokine genes in human astrocytoma cell lines and in fresh brain specimens was studied by the reverse-transcribed/polymerase chain reaction method. 3. The correlation between clinical malignancy and cytokine gene expression within malignant glioma was examined, especially regarding the relevancy of inhibitory cytokines, such as transforming growth factor-beta and interleukin-10.     

A novel gene, LGI1, from 10q24 is rearranged and downregulated in malignant brain tumors

Loss of heterozygosity for 10q23-26 is seen in over 80% of glioblastoma multiforme tumors. We have used a positional cloning strategy to isolate a novel gene, LGI1 (Leucine-rich gene-Glioma Inactivated), which is rearranged as a result of the t(10;19)(q24;q13) balanced translocation in the T98G glioblastoma cell line lacking any normal chromosome 10. Rearrangement of the LGI1 gene was also detected in the A172 glioblastoma cell line and several glioblastoma tumors. These rearrangements lead to a complete absence of LGI1 expression in glioblastoma cells. The LGI1 gene encodes a protein with a calculated molecular mass of 60 kD and contains 3.5 leucine-rich repeats (LRR) with conserved flanking sequences. In the LRR domain, LGI1 has the highest homology with a number of transmembrane and extracellular proteins which function as receptors and adhesion proteins. LGI1 is predominantly expressed in neural tissues, especially in brain; its expression is reduced in low grade brain tumors and it is significantly reduced or absent in malignant gliomas. Its localization to the 10q24 region, and rearrangements or inactivation in malignant brain tumors, suggest that LGI1 is a candidate tumor suppressor gene involved in progression of glial tumors.