Pathological classification of malignant lymphoma

The classification of malignant lymphoma is an important factor in treatment. Hodgkin's disease (HD) and non-Hodgkin's lymphoma (NHL) should be clearly differentiated from each other, since their clinical behavior and response to treatment are quite different. Although four histological subtypes of HD has been recognized, the subclassification is not so important clinically. Many classifications of NHL have been devised, but most of them are based on morphological features only and do not incorporate recent advances in understanding of origin, function and differentiation of lymphoma cells. Further improvement is necessary to establish a reproducible, histogenetically accurate and clinically meaningful classification.     

Characterization of temperature rise of the brain and the rectum following intracerebroventricular administration of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate and kainate in rats

Intracerebroventricular administration of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) or kainate caused a rise of the temperature of the brain and the rectum in urethane-anesthetized rats. An AMPA–kainate receptor antagonist, 6,7-dinitroquinoxaline-2,3-dione (DNQX), significantly suppressed the AMPA- and kainate-induced rises of brain and rectal temperatures. An N-methyl- -aspartate receptor antagonist, MK-801, also suppressed the rises of the brain and rectal temperatures induced by AMPA or kainate, but the profiles of the suppressive effects of MK-801 were different between rats treated with AMPA and kainate. An antipyretic agent, indomethacin, completely suppressed the AMPA-induced rises of brain and rectal temperatures. Although indomethacin completely suppressed the kainate-induced rise of the rectal temperature as well, the brain temperature was still raised. These findings suggest that distinct mechanisms may be involved in the temperature rise of the brain and the rectum mediated through AMPA and kainate receptor stimulation.     

Lymphocyte subsets in pulmonary venous and arterial blood of lung cancer patients

Lymphocyte subsets in pulmonary venous blood (PVB) smears from 42 patients with lung cancer were immunocytochemically determined. In four patients, pulmonary arterial blood (PAB) smears were also studied for comparison with PVB. Seven healthy donor peripheral blood (PB) smears were used as controls. The percentage of T cells, helper/inducer T (Th) cells and B cells were significantly lower (P less than 0.01) than in normal controls but those of suppressor/cytotoxic T (Ts) cells, natural killer (NK) cells (P less than 0.01) and S100+ small lymphoid cells (P less than 0.05) were higher. This resulted in a decrease in the Th:Ts value in cancer patients (1.46 vs. 2.28 for normal controls; P less than 0.01). The Th and Ts value of PVB from patients in pathological Stages III and IV was lower than from those in Stages I and II because of the increase in Ts cells in the former (P less than 0.05). S100+ small lymphoid cells were increased in cancer patients, especially in those with adenocarcinoma. The present study demonstrates immunoregulation abnormalities in cancer bearing hosts, the results correlating well with the stage of the cancer. Determining lymphocyte subset alterations in PVB did not, however, enable us to detect the changes associated with local immune responses against cancer.     

Quantitative assessment of ventilation-perfusion mismatch by radioxenon imaging of the lung

By the use of xenon-133 and a scintillation camera with digital data storage and processing system, a topographic relationship between ventilation distribution (V) and perfusion distribution (Q) was examined quantitatively in two groups of normal nonsmokers and one of older smokers, all healthy. In addition, subjects with a variety of cardiopulmonary disease were tested. The fractional regional ventilation (VR) and regional perfusion (QR) were plotted against the V/Q ratio on a logarithmic abscissa for the normal subjects; both were distributed log-normally with a narrow standard deviation, and were dissociated slightly from each other. However, with smoking and with increasing age, the s.d. and the dissociation became wider, suggesting an impairment of gas exchange as estimated by alveolar-atrial gas-pressure differences (A-aD), which were calculated by putting these topographic relationships into a gas-exchange program in a computer. In various cardiopulmonary diseases a good correlation was found between the estimated A-aDO2 thus obtained and the actual A-aDO2 derived from analysis of the blood gases.     

Involvement of protein kinase PKN1 in G2/M delay caused by arsenite

PKN1 is a serine/threonine protein kinase that has been reported to mediate cellular response to stress. We show here that in response to arsenite exposure, PKN1 kinase activity was stimulated, which was associated with increased binding of PKN1 to Cdc25C and delayed mitotic entry. A role for PKN1 in mediating arsenite-induced G(2)/M delay was supported by the finding that expression of a constitutively active form of PKN1 (PKN1AF3) in HeLa cells delayed the mitotic entry of cell cycle. Further experiments indicate that PKN1 directly phosphorylated serine 216 (Ser216) in Cdc25C, which then facilitated association between Cdc25C and 14-3-3. Significantly, expression of a phosphorylation mutant of Cdc25C (S216A) partially abrogated the cell-cycle arrest in response to arsenite. Together, our results suggest that PKN1 mediates arsenite-induced delay of the G(2)/M transition by binding to and phoshorylating Cdc25C.     

Clinical usefulness of serum and immunohistochemical markers in patients with stage Ia and Ic ovarian cancer

We compared the preoperative serum tumor marker values and diameters of ovarian tumors between 14 stage Ia ovarian cancer patients with a good prognosis and 14 stage Ic patients with a poor prognosis. The aim was to examine the usability of tumor markers and diameter of ovarian tumors for prognostic diagnosis of clinically advanced phases. In occult neoplastic cells (ONCs), a tumor marker indicative of recurrence and metastasis, the cytokeratin-positive cells in lymph node biopsies, were also compared. In a preoperative comparison of serum tumor markers, CA125 levels in stage Ia and Ic patients were 47.1+/-15.9 (median, 31.9 U/ml) and 370.6+/-146.2 U/ml (median, 135.6 U/ml), respectively (p=0.0457), and CA19-9 levels were 25.5+/-5.5 (median, 20.4 U/ml) and 564.5+/-192.4 U/ml (median, 248.0 U/ml), respectively (p=0.0131). In a comparison of tumor diameters during surgery, diameters of stage Ia and Ic patients were 117.3+/-11.4 (median, 100.0 mm) and 182.0+/-29.2 mm (median, 145.0 mm), respectively (p=0.0457). ONCs were not detected in any stage Ia patients, but detected in 3 (30%) stage Ic patients. In conclusion, clinical progression was evaluated using CA125 and CA19-9 serum markers and tumor diameters in stage Ia and Ic patients, and demonstrated significant differences between stage. ONCs were only detected in the lymph nodes of stage Ic patients.     

Association of neuroendocrine differentiation with neoadjuvant hormone therapy effects in prostatic cancer

Histological therapeutic effects of neoadjuvant hormone therapy (NHT) in prostatic cancer were examined, focusing on the association with neuroendocrine differentiation (NED), using 69 radical prostatectomy cases. The effects of NHT were classified into 3 grades based on the extent of tumor degeneration as observed with hematoxylin and eosin staining. NED cells in the cancer were semi-quantified into 4 grades (negative, 1+, 2+, and 3+) by immunohistochemical staining of chromogranin A (CgA). According to the therapeutic effects, the cases are divided as follows: good response in 26 patients, intermediate in 20, poor in 23. The histological therapeutic effects were significantly weaker in the CgA-positive group than the CgA-negative group (p=0.02). A close relationship between the extent of CgA expression and the histological response was also demonstrated (p=0.007). In the biopsy specimens before NHT, CgA was positive in 46% (32/69) and there was no significant difference in histological therapeutic effects between the positive and negative groups. However, the therapeutic effects were significantly weaker in 22 CgA-positive cases for both biopsy and prostatectomy specimens than in 18 CgA-negative cases for both specimens (p=0.001). In conclusion, although it seems difficult to predict the therapeutic effects of NHT using the biopsy specimens of prostatic cancer, we believe that NED is negatively associated with histological response of prostatic cancer to NHT.     

QT PRODACT: in vivo QT assay with a conscious monkey for assessment of the potential for drug-induced QT interval prolongation

In safety pharmacology studies, the effects on the QT interval of electrocardiograms are routinely assessed using a telemetry system in cynomolgus monkeys. However, there is a lack of integrated databases concerning in vivo QT assays in conscious monkeys. As part of QT Interval Prolongation: Project for Database Construction (QT PRODACT), the present study examined 10 positive compounds with the potential to prolong the QT interval and 6 negative compounds considered to have no such effect on humans. The experiments were conducted at 7 facilities in accordance with a standard protocol established by QT PRODACT. The vehicle or 3 doses of each test compound were administered orally to male cynomolgus monkeys (n=3-4), and telemetry signals were recorded for 24 h. None of the negative compounds prolonged the corrected QT using Bazett's formula (QTcB) interval. On the other hand, almost all of the positive compounds prolonged the QTcB interval, but haloperidol, terfenadine, and thioridazine did not. The failure to detect the QTcB interval prolongation appeared to be attributable for the differences in metabolism between species and/or disagreement with Bazett's formula for tachycardia. In the cynomolgus monkeys, astemizole induced Torsade de Pointes and cisapride caused tachyarrhythmia at lower plasma concentrations than those observed in humans and dogs. These results suggest that in vivo QT assays in conscious monkeys represent a useful model for assessing the risks of drug-induced QT interval prolongation.