Molecular genetics of brain tumors

As many as 40000 patients are newly diagnosed each year as having brain tumors. About half of these are metastatic foci of tumors originating outside the central nervous system, while the other half are primary tumors of central nervous system tissues. These are a diverse group of neoplasms. Currently, primary brain tumors are classified in a manner that reflects their histological appearance and location. The identification of cancer as a disorder of genes, however, has opened the possibility of classifying tumors according to the genetic alterations that underlie their pathogenesis and that regulate their malignant behavior. Two major classes of genes critical for the development of all types of cancer, including brain tumors, are now recognized: tumor suppressor genes, which encode genes that function to inhibit cell proliferation and tumor development, and oncogenes, which encode proteins that stimulate proliferation and mediate biological activities important for invasion, neoangiogenesis, immune escape, and other characteristics of malignancy. While in most cases the specific pathways regulating tumor characteristics such as tumor neoangiogenesis and tissue invasion remain to be defined, recognition of the genetic changes characteristic of individual tumor types should provide opportunities to develop more effective, less toxic therapies.     

Morphine-induced changes in cyclic AMP metabolism and protein kinase activity in the brain.

The effects of consecutive oral administration of morphine on the cyclic AMP synthesizing system and cyclic AMP dependent protein kinase activity in the cerebral cortex of mice were examined. The administration of morphine (2--4 weeks) induced an increase of the cyclic AMP formation by activating adenylate cyclase, whereas responses of the cyclic AMP synthesizing system to biogenic amines (norepinephrine, dopamine and histamine) added in vitro was found to be significantly attenuated in these animals. Cyclic AMP dependent protein kinase activity in the cerebral cortex was also increased following a consecutive oral administration of morphine. These changes in the activities of adenylate cyclase and protein kinase were found mainly in crude mitochondrial and/or synaptosomal fractions. Morphine induced decrease in the response of the cyclic AMP synthesizing system to biogenic amines was rapidly reversed, and a significant increase of the cyclic AMP formation in the presence of added norepinephrine compared with that found in morphinized animals was observed following the administration of levallorphan, a narcotic antagonist. On the other hand, the changes in adenylate cyclase and cyclic AMP dependent protein kinase activities were not affected significantly by levallorphan administration. These results suggest that alterations in activities of cyclic AMP synthesizing system and of cyclic AMP dependent protein kinase may be involved in processes of the formation of morphine dependence. Possible involvement of abrupt increments in the sensitivity of "norepinephrine receptor-adenylate cyclase" system and a subsequent increase in cerebral cyclic AMP is also suggested as a cause of morphine withdrawal syndrome.     

Immunological comparison between prostate-specific antigen and γ-seminoprotein

Summary Prostate-specific antigen (PA) and -seminoprotein (-Sm) were compared by immunocytochemical, immunodiffusion and immunoblotting methods using rabbit anti-PA antibody and rabbit anti--Sm antibody. Enzyme immunoassys (EIAs) were developed for measurements of PA and -Sm to determine a correlation between serum PA and -Sm levels in patients with prostate cancer. The patterns of localization and distribution of PA and -Sm were identical in prostate tissue sections, including benign and cancerous human prostacs. The immunodiffusion study showed that the antigens with which anti-PA antibody and anti--Sm antibody reacted in seminal plasma and prostate tissue homogenates were identical to each other. In the immunoblotting study, anti-PA antibody and anti--Sm antibody recognized a single antigen corresponding to a molecular weight of approximately 33,000 both in seminal plasma and prostate tissue homogenates. The EIAs developed in this study were sensitive, specific, and reproducible, and the correlation between serum PA and -Sm values determined by these EIAs was highly significant (r=0.99, P(0.001). These results indicated that PA and -Sm were immunologically identical and that serum PA and -Sm determined by immunoassays using anti-PA antibody and anti--Sm antibody should be evaluated as identical tumor markers for serodiagnosis of prostate cancer.     

Comparative study on the cardio-respiratory change during prostaglandin E1-induced hypotension in the patients in the supine and prone position

Prostaglandin E₁-induced hypotension (25% reduction from the preadministration level in mean arterial pressure) was applied to thirteen patients. Eight patients among them were operated in the supine position (group I) and other five in the prone position (group II). The maintenance dose of PGE₁ was considerably lower in group II than in group I (0.067µg·kg^–1·min^–1 vs. 0.119µg·kg^–1·min^–1). In group I, there was a significant increase in CI, with a significant decrease in SVRI and PVRI during PGE₁-induced hypotension. Such a high dose of PGE₁ (0.119µg·kg^–1·min^–1) was considered to have a direct dilating action on the systemic resistance bed as well as on the pulmonary vasculature. It was considered that the suppression of hypoxic pulmonary vasoconstriction could be a mechanism to increase venous admixture during PGE₁-induced hypotension. In group II, there was no significant increase in CI, and no significant decrease in SVRI and PVRI. PGE₁-induced hypotension can be safely applied to the anesthetized patients, but we should be careful to apply it to the patients in the prone position, because lower dose of PGE₁ can induce severe hypotension, which is not accompanied by the increase in CI as occures in the patients in the supine position.(Hirose M, Yoda K, Sakai K, et al.: Comparative Study on the cardio-respiratory change during prostaglandin E₁-induced hypotention in the patients in the supine and prone position. J Anesth 5: 30–35, 1991)     

Ambulatory blood pressure monitoring in hypertensive CAPD patients

The periodic structure of 24-hour blood pressure variation(circadian rhythm of blood pressure by ambulatory blood pressure monitoring(ABPM) in hypertensive CAPD patients was investigated by a new method of analysis based upon the maximum entropy method(MEM). In addition, this method allows the adequacy of antihypertensive therapies to be evaluated in such patients. The results were as follows; 1) The frequency of non-dipper type hypertension was 88%(36/41 cases), and the remaining 12% (5/41) were dipper type hypertension patients. The rise in morning blood pressure(morning surge: MS) was noted in 64% of the former. 2) Night time systolic blood pressure(182 +/- 22 mmHg, n = 36) was higher in patients with non-dipper type hypertension than in those with the dipper type(151 +/- 17 mmHg, n = 5, p < 0.01). 3) The standardized level of systolic blood pressure(SLSBP) calculated by MEM analysis in patients with non-dipper type hypertension(177 +/- 7 mmHg) was comparable with that in those with dipper type hypertension(168 +/- 13 mmHg, ns). 4) Treatment with long-acting Ca antagonist alone significantly reduced both SLSBP and the area over the SLSBP from 188 +/- 18 mmHg to 160 +/- 7 mmHg(p < 0.01, n = 8), and area over the SLSBP from 2,735 +/- 340 mmHg.hr to 1,945 +/- 298 mmHg.hr(p < 0.01, n = 8). 5) In addition to long-acting Ca antagonist, administration of alpha 1-blocker given at bed time was significantly efficacious in reducing the rise in morning blood pressure, MS. The present study using MEM analysis of ABPM suggests that the blood pressure profile of hypertensive CAPD patients is characterized by a non-dipper type dominance and a frequent morning surge. Furthermore, the combined therapy with long-acting Ca antagonist and alpha 1-blocker was substantially effective both in reducing the overall blood pressure level, and in inhibiting the MS. This combined antihypertensive therapy may be potentially useful to prevent CAPD patients from the future development of cardiovascular complications.     

Changes in levels of serum erythropoietin, serum iron and unsaturated iron binding capacity during chemotherapy for lung cancer

BACKGROUND: The serum erythropoietin level increases markedly during chemotherapy for leukemia. A number of hypotheses have been built for the mechanism, none of them satisfactory. Difficulty in evaluating bone marrow activity hampers the elucidation. Therefore, we focused on patients who had non-hematological cancer and no evidence of bone marrow suppression. METHODS: Twelve patients, who had lung cancer (four with small cell cancer and eight with non-small cell cancer) and who had not undergone any chemotherapy, were studied. During chemotherapy, we measured serum erythropoietin, serum iron, unsaturated iron binding capacity and hemoglobin concentration in these patients. RESULTS: The serum erythropoietin level before chemotherapy (10.8 +/- 7.4 mU/ml) was within the normal range but the peak values after the first treatment (73.4 +/- 90.4 mU/ml) increased in all patients. In the patients with small cell cancer, a transient but marked increase in erythropoietin value (204.6 +/- 167.3 mU/ml) was observed after each session of chemotherapy while hemoglobin concentration decreased gradually. Throughout treatments, elevation of the serum iron concentration and concomitant reduction of unsaturated iron binding capacity were observed after each session of chemotherapy. They regained their original values whilst the serum erythropoietin level decreased after each chemotherapy session was completed. CONCLUSIONS: It is suggested that the suppression of erythroid marrow by chemotherapeutic agents causes the changes in serum erythropoietin level during chemotherapy in patients with lung cancer.      

Cytomegalovirus reactivation in patients with multiple myeloma

The introduction of novel antimyeloma agents has improved the outcome of multiple myeloma (MM) dramatically. However, it has also led to an increasing incidence of Herpesviridae family virus infections, including a high incidence of post‐transplant cytomegalovirus (CMV) reactivation after treatment with novel agents. We herein retrospectively assessed the CMV reactivation in all 120 newly diagnosed patients with MM consecutively seen and treated at our hospital. CMV antigenemia tests were ordered in 58 patients depending on the clinical context, and the incidence of CMV reactivation and proven/suspected CMV disease requiring antiviral therapy was 20% (24 of 120) and 11% (13 of 120) respectively, including those without stem cell transplantation (SCT). The clinical and laboratory characteristics of these patients were compared with those in 34 CMV antigenemia‐negative (CMV‐negative) patients. Patients with extramedullary disease or a low absolute lymphocyte count (ALC) had a higher risk of developing CMV reactivation. In addition, the median duration from the time of MM diagnosis to CMV reactivation was 5.0 months. These results suggest that, regardless of whether or not undergoing SCT, elderly patients with MM receiving novel agents should be monitored for CMV reactivation to allow for the timely diagnosis and treatment, especially for those with extramedullary disease.     

Maximum Standard Uptake Value at the Biopsy Site during F-Fluorodeoxyglucose Positron Emission Tomography Does Not Predict the Proliferation Potential of Tumor Cells in Extranodal Natural Killer/T Cell Lymphoma, Nasal Type

No abstract available.