Between 1986 and 1991, 45 patients with intermediate- or high-grade non-Hodgkin's lymphoma, including 30 patient with large cell lymphoma (including both diffuse large cell and large cell, immunoblastic), were treated with CHOPB-POEMB chemotherapy. The regimen consisted POEMB (a combination of prednisolone, vincristine, etoposide and bleomycin) alternating every 3 weeks with a variant of CHOP-Bleo. None of the patients had received prior chemotherapy. The overall complete response (CR) rate was 80% and 20 patients (57%) were disease free for a median follow up time of 48 months. In cases of large cell lymphoma, the CR rate and disease free rate were 73% and 65%, respectively. Toxic effects were well-tolerated. Alternating CHOPB-POEMB was useful for treatment of intermediate- or high-grade non-Hodgkin's lymphomas.
An equation was developed to describe the kinetics of leukemic cell destruction in bone marrow during induction chemotherapy for acute nonlymphocytic leukemia (logZ=K1t4+K2t3+K3t2+K4, where Z=leukemic cell number, t=time, and K=a constant). The leukemic cell destruction curve was biphasic; phase I was the period from the initiation of a decrease in cells to the maximum velocity of the decrease, and phase II was the subsequent period to the cessation of decrease. The following parameters were established: duration and acceleration of decrease in phases I and II, maximum velocity of decrease, duration of reduction, and residual volume of leukemic cells. 1. Patients who achieved CR showed a longer duration of phases I and II, a lower acceleration of the decrease in phase II, and smaller residual leukemic cell volume than patients who did not achieve CR. there were no significant differences of parameters related to FAB classification, type of induction therapy, or the age of the patients. 2. This equation could be adapted to explain erythroblast kinetics during induction chemotherapy. There were no significant differences of the parameters with respect to the effect of induction therapy and patient age. 3. Patients with high acceleration of the decrease in phase II had a short duration of CR and survival. The leukemic cell destruction curve was thought to be useful not only for evaluation of the effect of induction therapy, but also for establishment of post-remission chemotherapy.
Myelodysplastic syndrome (MDS) are hematological disorders with the potential of progressing to acute leukemia. MDS patients occasionally die of infection despite the absence of severe pancytopenia prior to overt leukemia. Superoxide anion (O2-) production leads to intracellular bactericidal activity by neutrophils, particularly in an oxygen-dependent system. In this paper, O2- production by neutrophils in 15 MDS patients [11 patients with refractory anemia with excess of blasts (RAEB) and 4 patients with RAEB in transformation (RAEB-t)] was examined to evaluate possible causes of enhanced susceptibility to infection and to gain information concerning the pathophysiology and prognosis. The following results were obtained: (1) The O2- production by neutrophils (O2-production) in 15 MDS patients was lower than that in healthy controls (3.75±2.93 vs 6.20±1.53 nmol/min/106 neutrophils, p<0.05). Three of the 15 MDS patients showed little O2- production. (2) There was inverse correlation between O2- production and the percentage of leukemic cells in the marrow in acute leukemia (r=0.55, p<0.01), but not in MDS. (3) The O2- production in 5 MDS patients showing morphological anomalies in a high percentage of neutrophils significantly lower than that in 10 MDS patients showing morphological anomalies in a low percentage of neutrophils (1.04±1.37 vs 5.15±2.50 nmol/min/106 neutrophils, p<0.05). (4) The O2- production in 5 patients with frequent fever (≥38°C) -episodes was significantly lower than that in 10 MDS patients with infrequent fever-episodes (2.22±2.15 vs 4.49±2.83 nmol/min 106 neutrophils, p<0.05). (5) Comparison of the O2- production between MDS patients with and without progression to overt leukemia showed no significant difference (4.25±3.26 vs 3.28±2.76 nmol/min/106 neutrophils). These findings suggest that impaired O2- production by neutrophils, probably due to the faulty differentiation from abnormal hematopoietic clones, is one possible cause of enhanced susceptibility to infection in MDS, and may provide clues for clinical management of infection, but is not useful for early detection of progression to overt leukemia.
The ability of horseradish peroxidase (HRP) to cross the blood-brain barrier (BBB) was studied in dogs by electron microscopy after 18 minutes of complete global brain ischemia (CGBI). The first BBB opening occurred 30 minutes after the recirculation was established; This was associated with the increase of HRP-containing pinocytotic vesicles (HRP-PV), but there was no endothelial cell damage. There was no BBB opening 3, 6, and 24 hours after the recirculation; This was determined by absence of increase in HRP-PV and lack of endothelial cell damage. The second BBB opening occurred 48 hours after the recirculation; This was associated with disruption of the tight junction of the endothelial cell, lack of increased HRP-PV and destruction of the endothelial cell menbrane. These results suggest that the first BBB opening is due to increased pinocytotic transport by reactive hyperemia and the second BBB opening is due to endothelial cell damage by CGBI itself.
To clarify the pathogenesis of respiratory disease induced by drug allergy, clinical features and allergic examinations were evaluated in 9 patients (10 episodes). The ten episodes were classified as a case with bronchospasm, 7 cases with PIE (pulmonary infiltration with eosinophilia) syndrome and 2 cases with IP (interstitial pneumonia) according to clinical features and chest X-ray findings. In the case of bronchospasm, serum IgE level was low and Prausnitz-Küstner reaction was negative. However, increased LTC4 and LTD4 production in peripheral leukocytes and a normal level of histamine release in whole blood induced by the causative drug were shown. All cases of PIE syndrome revealed positive DLST (drug lymphocyte stimulation test). Four of 7 cases with PIE syndrome had high levels of serum IgE. One case showed decreased serum IgE level as the pulmonary infiltrtation shadow improved. In cases of IP, positive DLST and increased lymphocytes in BAL (bronchoalveolar lavage) fluid were shown. Four cases of PIE syndrome and a case of IP underwent BAL revealing an increase of eosinophils in all cases and an increase of lymphocytes of 3/5 cases. DLST using BAL lymphocyte revealed a higher stimulation index compared to that using peripheral lymphocyte. These results suggest that non-IgE-mediated allergic reaction in bronchospasm, IgE-mediated allergic reaction in PIE syndrome, and cell-mediated allergic reaction in PIE syndrome and IP are involved in pulmonary changes induced by drug allergy.
To clarify the pathogenesis of respiratory disease induced by drug allergy, an animal model of eosinophilic lung disease induced by drug was developed. Administration of an aerosol of piperacillin (PIPC) to guinea pigs immunized with emulsion of PIPC and complete Freund's adjuvant (CFA) produced diffuse interstitial lung disease with alveolar wall thickening and alveolitis characterized by marked increase in eosinophils and mononuclear cells. A significant increase of eosinophils in bronchoalveolar lavage fluid was shown in PIPC+CFA-sensitized animals compared with that in non-sensitized, PIPC-sensitized and CFA-sensitized animals. Using lymphocytes from BAL fluid, drug lymphocyte stimulation test (DLST) revealed a higher stimulation index (S. I.) than that using lymphocytes from peripheral blood in 5 of seven animals. These findings suggest that eosinophils and lymphocytes (especially lymphocytes sensitized by antigen) play important roles in drug-induced respiratory disease. Furthermore, it is considered that lung lymphocytes were more active than lymphocytes in peripheral blood in the experiment, and local lymphocytes in BAL contributed to the pathogenesis of the respiratory disease induced by drug allergy.
The nonciliated bronchiolar epithelial (Clara) cells are principally distributed in the distal airway, and characterized by the presence of abundant agranular endoplasmic reticulum and electron-dense granules. In the present study, changes in the glycogen, intracellular organella and cytoskeleton occurred in perinatal rat Clara cells were studied by H.E. staining, PAS staining, transmission electron microscopy and detergent perfusion method. The cytoplasm of Clara cells in the prenatal rat contained glycogen and was intensely positive on PAS staining. In 1 to 3-day-old rat, Clara cells with abundant mitochondria, smooth-surfaced endoplasmic reticulum, and filaments in supranuclear area appeared among glycogen-rich Clara cells. In 4 to 7-day-old rat, almost all Clara cells showed no PAS reaction, increased electrondense granules concomitant with the increase of rough-surfaced endoplasmic reticulum. Abundant filaments and microtubules were observed in the supranuclear area. These results suggest that Clara cells mature after birth and filament formation in these cells occurs with cell maturation and function.
El mice manifest epileptiform seizures which are gradually elicited by tossing stimulation once a week from 5 to 10 weeks of ages. It was reported that brain monoamines, especially serotonin (5-HT), are important factors in seizure susceptivity. In this study, we observed changes in brain 5-HT and its metabolite, 5-hydroxyindolacetic acid (5-HIAA), and its metabolic enzymes, tryptophan hydroxylase (Trp-OHase) and monoamine oxidase-A (MAO-A), during growth with and without tossing stimulation. In non-stimulated El mice, the 5-HT level was lower at 6 and 7 weeks than that in other ages, and the 5-HIAA level was generally lower in older mice. In stimulated El mice, the 5-HT level was higher after the first stimulation, lower at 8 weeks, and then higher again at 10 weeks. However, 5-HIAA levels were generally higher in older mice. The Trp-OHase activity was higher at 8 and 10 weeks, and the MAO-A activity was higher at 8 weeks compared to that of non-stimulated El mice. These findings suggest that a disordered release and metabolism of 5-HT influences the development of the epileptiform seizures induced by tossing stimulation.
A multivariate analysis of the clinical and radiographic findings of 70 patients with rheumatoid arthritis (RA) was studied. Linear multiple regression analysis was performed on 23 clinical variables. The factors that contributed highly to the progression of vertical atlanto-axial subluxation (VS) were gender, presence of arthritis mutilans, blood hemoglobin level, carpal height ratio (CHR) and the number of joints treated by arthroplasty. This result suggests that the natural progression of VS may well relate to the indicators of the severity of destructive conditions. In contrast, anterior atlanto-axial subluxation (AAS) showed no statistical correlation with any factors. Therefore, the severity of AAS does not appear to be related to the factors that were closely related to VS. A follow-up study of the radiological changes in the cervical spine and hand was performed. There was a high correlation between the severity of VS and the reduction of CHR. As destructive changes in the hands were common and irreversible findings in RA, CHR was the most objective of the factors correlated with VS. Therefore, the measurement of CHR is useful in evaluating the progression of VS.
Adenosine, a potent vasodilator, may be involved in the metabolic control of coronary blood flow. However, the site of adenosine formation remains unclear. Evidence has demonstrated that L-homocysteine (L-homo) can decrease the cytosolic adenosine level and α, β-methylene adenosine 5'-diphosphate (AOPCP) can inhibit ect 5'-nucleotidase which catalyzes the formation of adenosine from 5'-AMP at the myocyte membrane. We examined the effects of L-homo and AOPCP on coronary reactive hyperemia following transient coronary occlusion in the open chest dog. Intracoronary L-homo infusion with coronary plasma concentration of 223±54.3↔ M did not affect myocardial reactive hyperemia. Intracoronary AOPCP infusion, which produced coronary plasma concentration of 43.8±20.6μM and had no effect on hemodynamics or myocardial oxygen consumption, significantly attenuated repayment of flow debt by approximately 30% following coronary occlusions longer than 15s. Concomitant infusion of L-homo and AOPCP did not change the attenuation of the repayment by AOPCP infusion alone. Percent peak reactive hyperemic response was not affected by L-homo or AOPCP infusion. These results indicated that ect 5'-nucleotidase contributed to adenosine formation during transient ischemia and adenosine is involved in approximately 1/3 of metabolic vasodilation following transient coronary occlusion.
Twenty six patients with non-Hodgkin's lymphoma (NHL), who failed to achieve complete remission or had relapsed after conventional chemotherapy (CHOP or CHOP-Bleo) were treated with a four-drug combination of mitoxantrone, etoposide, cisplatin and prednisolone (MEPP). Of 24 patients evaluated, five (21%) achieved complete remission and seven (29%) responded partially. The median duration of remission was 25 weeks, 38 weeks for complete responders (CRs), 24 weeks for partial responders (PRs). The median survival time after initiation of therapy was 93 weeks for CRs, 50 weeks for PRs and 25 weeks for non-responders (NRs). The difference in survival time between CRs and NRs was statistically significant. Myelosuppression was the major dose-limiting toxicity; WBC nadir below 1, 000/μl occurred in 66.2% of evaluable courses. Two patients with bone marrow involvement died of infection due to granulocytopenia. Renal toxicity of cisplatin was moderate and there was no cardiotoxicity of mitoxantrone detected. Despite severe myelotoxicity, these results indicate that MEPP regimen is useful as a salvage therapy for relapsed or refractory NHL.
To establish an effective combination chemotherapy for hematologic malignancies, the combined effects of four anthracycline-anthraquinones and five other drugs were assessed in vitro. The anthracycline-anthraquinones were adriamycin (ADM), aclarubicin (ACR), THP-adriamycin (THP-ADM), mitoxantrone (MXT) and five other drugs were 4-hydroperoxycyclophosphamide (4HO2-CTX), cytarabine (Ara-C), vincristine (VCR), etoposide (ETP), cisplatin (CDDP). Median effect analysis presented by Chou and Talalay was used to assess the combined effects of these drugs on two cell lines (HL-60 and Raji). In addition, the ratio of maximal tolerable dose (MTD) to the dose that produced 50% growth inhibition (Dm) was calculated to estimate the clinical activity of each drug. Data of MTD/Dm indicated that THP-ADM and MXT might be clinically superior to ADM and ACR. The results of median effect analysis shown by a combination index were as follows: As to HL-60 cells that were derived from acute promyelocytic leukemia cells, synergistic effects were seen in the combination of ACR and Ara-C, THP-ADM and CDDP, MXT and 4HO2-CTX, MXT and Ara-C, MXT and VCR, MXT and ETP, indicating that MXT showed efficient synergistic effects when combined with other drugs. As to Raji cells that were derived from Burkitt's lymphoma cells, synergistic effects were observed in the combinations of ADM and ETP, ADM and CDDP, ACR and VCR, THP-ADM and VCR, THP-ADM and ETP, THP-ADM and CDDP, MXT and VCR, indicating that THP-ADM showed efficient synergistic effects when combined with other drugs.