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A total of 64 newly diagnosed acute myelogenous leukemia patients (except FAB M3 and/or Down syndrome) under 18 years of age were consecutively enrolled into the study. Patients having an HLA-identical sibling (allo group) were assigned to undergo allogeneic bone marrow transplantation (allo BMT) in the first complete remission (CR). Others (non-allo group) were assigned to undergo autologous peripheral blood stem cell transplantation (PBSCT) or autologous BMT (auto BMT). Conditioning regimen was busulfan + melphalan for all transplantation. Of 64 patients (allo group 24; non-allo group 40), 59 (92.2%) achieved a CR. Eighteen relapses occurred (allo group 4; non-allo group 14) and 6 died during the first CR. The 5-year event-free survival (EFS) rate was 53.3 +/- 6.4% at a median follow-up period of 45 months. The 5-year EFS rates of allo and non-allo groups were 70.8 +/- 9.3% and 43.0 +/- 8.1%, respectively (p = .08). The EFS rates at 5 years post-transplant for allo BMT from an HLA-identical sibling (n = 18), PBSCT (11), and auto BMT (6) were 88.1 +/- 7.9%, 41.6 +/- 19.7%, and 83.3 +/- 15.2%, respectively. The outcome of allo BMT was superior to that of autograft. Auto BMT rather than PBSCT might contribute to a long-term survival in case of no available HLA-identical siblings.

To address the issue of salvageability in relapsed children with NHL who had all received the same frontline therapy, we retrospectively studied the treatment response and the outcome of 27 children who relapsed following the CCLSG-NHL890 protocol. The reinduction rates and 3-year survival rates (mean +/- SD) were as follows: lymphoblastic lymphoma (LB, n = 9), 44% & 17 +/- 14%; leukemia lymphoma syndrome (LLS, n = 8), 25% & 0%; large cell lymphoma (LC, n = 3) 100% & 67 +/- 27%; Burkitt's lymphoma (B, n = 7) 0% & 0%. Thus, the salvageability of LC lymphoma was good, but the outcome of Burkitt's lymphoma was very poor. CCLSG-NHL960 protocol for LB lymphomas and intensive multiagent regimens for LC lymphomas produced favorable response rates, but the effect of the high-dose Ara-C regimen for Burkitt's lymphoma was not determined. The initial stages of the disease seemed to be associated with the patient outcome: the outcome of the patients in stage IV was inferior to that of patients in stages II or III. Other clinical variables, such as relapse sites, relapse time and BM rescue did not affect the patients' outcome.

Background: Prevention of central nervous system (CNS) leukemia by early introduction of therapy to this sanctuary site is an essential component of modern treatment strategy for acute lymphoblastic leukemia (ALL). However, the optimal form of preventive CNS therapy remains debatable., Procedure: To address this issue, we evaluated the efficacy of CNS preventive therapy for 572 children with ALL who achieved complete remission in the Children's Cancer and Leukemia Study Group (CCLSG) ALL874 (1987-1990) and ALL911 (1991-1993) studies. They received risk-directed therapy based on age and leukocyte count. In the ALL 874 study, the non-high-risk (low-risk [LR] + intermediate risk [IR]) patients were randomly assigned to the conventional cranial irradiation (CRT) regimen (L874A and I874A) and the high-dose methotrexate (HDMTX) regimen without CRT (L874B and I874B). The former patients received 18-Gy CRT plus 3 doses of intrathecal (i.t.) MTX and the latter patients received 3 courses of HDMTX at 2 g/m2 plus 13 doses of ITMTX (L874B) or 4 courses of HDMTX at 4.5 g/m2 plus 1 dose of ITMTX (I874B)., Results: The 7-year probabilities (+/- SE) of CNS relapse-free survival were 97.3% +/- 2.6% (L874A, n = 41) vs. 90.3% +/- 5.3% (L874B, n = 39) (P = 0.25) in the LR patients, and 100% (I874A, n = 55) vs. 78.5% +/- 6.5% (I874B, n = 54) (P = 0.002) in the IR patients. The corresponding disease-free survival (DFS) rates were 79.4% +/- 6.5% vs. 74.4% +/- 7.3% (P = 0.62) in the LR group and 63.3% +/- 6.8% vs. 58.3% +/- 7.2% (P = 0.66) in the IR group. Thus, the HDMTX regimen could not provide better protection of CNS relapse as compared with the CRT regimen, although their overall efficacy was not significantly different. In the ALL 911 study, intensive systemic chemotherapy with extended i,t, injections of MTX plus cytarabine achieved a high CNS relapse-free survival (98% +/- 1.9% at 7 years) and a favorable DFS (85.5% +/- 5% at 7 years) in the IR patients. The patients in the high-risk (HR) group in both ALL874 and ALL911 studies received the 18-Gy or 24-Gy CRT with intensive systemic chemotherapy. Their 7-year probabilities of CNS relapse-free survival ranged from 88% to 95%, among which the T-ALL patients had a risk of CNS leukemia, which was 3-4 times higher compared with B-precursor ALL patients., Conclusions: These results indicate that long-term intrathecal CNS prophylaxis as well as appropriate systemic therapy for the non-high-risk patients can provide protection against CNS relapse equivalent to that provided by cranial irradiation.

We report here on the preliminary treatment findings of a CCLSG NHL 960 study that was initiated in March 1996. In this study, 37 patients with non-Hodgkin's lymphoma were assigned to 4 different treatment groups according to disease stage and histology: (1) localized disease; (2) advanced disease, lymphoblastic type; (3) advanced disease, large cell type; and (4) advanced disease, Burkitt type. The first three groups received the modified protocols of the NHL 890 study. Groups 1 and 3 received COPADM induction therapy (CPM, VCR, PRD, ADR, and MTX). After achieving remission, Group 1 received only maintenance therapy consisting of alternate administration of 7 drugs, while Group 3 received additional intensification therapy with combination chemotherapy consisting of MTX and Ara-C, followed by a maintenance phase involving the administration of 9 drugs. Group 2 received COPADL induction therapy (CPM, VCR, PRD, ADR, and LASP) and consolidation/intensification therapies followed by a maintenance phase. Group 4 received short-term intensive COPADM polychemotherapy. Twelve patients with localized with localized disease (stage I-II) and 25 patients with advanced disease (stage III-IV) were enrolled in this study. Except for 2 patients in the advanced disease stages who died earlier in the course of the study, all patients remained in remission.

To clarify the efficacy of modern intensive chemotherapy for ALL patients with unfavorable features, we compared the time to failure and initial clinical features of children who relapsed in the bone marrow or combined sites, as documented by early CCLSG studies (H811 and H851; 1981-1987) and later studies (H874 and H/HH911; 1987-1993) concerning high-risk ALL patients. In the later studies patients outcomes with new intensive regimens employing early intensification and reinduction therapy were apparently better than those of patients in the early studies with conventional regimens. When we compared the number of relapsed patients based on duration of first remission, we found that the improved outcomes for patients in the later studies were due to a decrease in the number who relapsed 7-36 months after the start of treatment (intermediate relapse), and that the percentage of those who relapsed within the first 6 months of therapy (early relapse) was higher. Patients with high initial WBC counts tended to relapse much earlier than those with low initial WBC counts. However, in the later studies, patients with high WBC counts often relapsed after the termination of therapy (late relapse). These results suggest that the intensive chemotherapy regimens used in the later studies can prevent the development of drug resistant leukemic clones, except in extremely high-risk patients likely to relapse within the first 6 months of therapy.

The authors report an 85-year-old man with schizophrenia, who had undergone bilateral frontal gyrectomy at the age of 44 and had a single series of convulsions 6 months after the psychosurgery. Forty-one years later, he had developed partial seizures with secondary generalized seizures, and died of partial status epilepticus. Ictal EEG showed generalized high-amplitude spikes or sharp waves spreading from the left frontal region. Interictal EEG showed slowing of background activity and high-amplitude paroxysmal discharges on the left frontal and central regions. Postmortem examination of the brain revealed tissue defects in the superior and middle frontal gyri caused by resection at the time of gyrectory and old cysts in the deep frontal white matter as late sequelae of the psychosurgery. There was fibrillary gliosis in the surrounding cerebral convolutions and the deep white matter. We considered that the glial scar in the frontal lobes, on the left side in particular, had developed the epileptogenic focus. The pathophysiological mechanism by which the intractable epileptic seizures appeared 41 years after psychosurgery is discussed.

We describe a case of a 15 year old boy who developed acute megakaryoblastic leukemia (AMKL) while receiving treatment with human growth hormone (hGH) for idiopathic growth hormone deficiency (GHD). He was diagnosed as having idiopathic GHD and given hGH from December 1991. The examination of his peripheral blood showed mild pancytopenia 2 months before the start of the hGH therapy. Since January 1992, paleness of the skin, general fatigue and fervescence progressed gradually. In February 1992, because of the occurrence of acute leukemia, administration of hGH was discontinued. Judging from the results of surface marker analysis of the blast cells, the patient was diagnosed as having AMKL. He was treated with chemotherapy for acute non-lymphoblastic leukemia from March 1992. A complete remission was obtained after 4 weeks of treatment. The chemotherapy was completed in July 1993. He remains in complete remission 26 months after diagnosis. This case suggests the importance of hematological examination and, when there is any abnormality which is not caused by GHD, such as pancytopenia, more detailed medical examinations (for example bone marrow examination) are necessary.

A newly synthesized anti-inflammatory agent, Y-8004 demonstrated a greater inhibition than did indomethacin (IM). on inflammatory response such as ultraviolet erythema in guinea pigs, carrageenin edema, evans blue and carrageenin-induced pleuritis and acetic acid-induced peritonitis in rats. On the other hand, the inhibition of Y-8004 was to the same extent as IM regarding granuloma formation around cotton pellet and the development of adjuvant arthritis in rats, however, Y-8004 was only half as effective as IM regarding exudation in granuloma pouch. In addition, the agent was effective in alleviating established adjuvant arthritis, the anti-inflammatory activity was not mediated by stimulation of the adrenals, and glucocorticoid-like activity could not be demonstrated. Furthermore, analgesic and antipyretic activities were to the degree as seen with IM, and the analgesic property of Y-8004 was considered to be peripheral as is the case with IM. The ulcerogenic activity of Y-8004 was observed to be mainly in the jejunum and ileum of the rat, but compared to IM, there were considerable differences between the ulcerogenic and the effective doses. As Y-8004 has a wider therapeutic margin than IM, this non-steroidal anti-inflammatory agent should be quite applicable for clinical purposes.

The effects of Y-8894 on experimental amnesia in rats induced by transient cerebral ischemia (600 sec) according to the method of Pulsinelli and Brierley were studied using the one trial passive avoidance response and the pole climbing discrete avoidance response. All drugs were administered to the rats immediately after recirculation. The following results were obtained: 1) In the one trial passive avoidance response test, Y-8894 (2.5, 5 and 10 mg/kg, i.p.) improved significantly the decreased latency induced by the ischemia, and it was most effective at 5 mg/kg. Calcium-hopantenate (100, 250 and 500 mg/kg, i.p.) and dihydroergotoxine (5 and 10 mg/kg, i.p.) tended to increase the latency. On the other hand, physostigmine (0.025, 0.05 and 0.1 mg/kg, i.p.), a cholinesterase inhibitor, increased the latency significantly, and it was most effective at 0.05 mg/kg. 2) The pole climbing discrete avoidance response was significantly decreased by the ischemia compared with the sham operated group, and Y-8894 (5 mg/kg, i.p.) tended to improve this decreased avoidance response. 3) Y-8894 (5 mg/kg, i.p.) facilitated recovery from the changes in glycolytic metabolism, and inhibited the accumulation of choline due to the dysfunction of the neuronal membranes induced by the ischemia. These results show that Y-8894 has beneficial effects on experimental amnesia induced by transient cerebral ischemia.

The effect of Y-8894 on the abnormal electrocorticogram (ECoG) of alcuronium-immobilized rats, induced by destruction of the internal capsule with heat, was compared with that produced by imipramine, amantadine and Ca-hopantenate. ECoG power in the delta + theta (1-7 Hz), alpha (7.5-12.5 Hz) and beta (13-30 Hz) bands was used as an index. Delta + theta power increased following destruction of the internal capsule with heat. The increased delta + theta power (abnormal ECoG) lasted for 60 min following the injection of saline at 60 degrees C for 3 min. Y-8894 (0.1-1 mg/kg, i.v.) apparently improved the abnormal ECoG dose-dependently by significantly reducing the increased delta + theta power. Similar results were obtained with amantadine (10 mg/kg, i.v.), but its potency was weaker than that of Y-8894. Imipramine (1 mg/kg, i.v.) and Ca-hopantenate (30 mg/kg, i.v.), however, both failed to modify the abnormal ECoG. All drugs, except Ca-hopantenate, decreased the magnitudes of the alpha and beta bands. The above results suggest that Y-8894 may be effective in ameliorating cerebral dysfunction induced experimentally by the lesion of the internal capsule.

The effect of Y-8894 (+/-) 2-[[o-(2-thenyl)phenoxy]methyl] morpholine maleate, which has been shown to improve experimentally induced learning and memory deficits, on cerebral monoamine uptake and turnover was studied in the mouse. The following results were obtained: 1) It inhibited in vitro norepinephrine (NE) uptake to the mouse cerebral synaptosomal fractions about 800 and 1250 times more potently than it did those of dopamine (DA) and serotonin (5-HT), respectively. 2) It dose-dependently inhibited in vivo NE uptake, but not DA or 5-HT uptake. 3) It reduced the accumulation of the NE metabolite, 3-methoxy-4-hydroxyphenylglycol (MHPG), increased that of the 5-HT metabolite, 5-hydroxyindoleacetic acid (5-HIAA), and had no effect on that of the DA metabolite, homovanillic acid (HVA). These effects were compared with those of imipramine, calcium hopantenate (Ca-hopantenate) and dihydroergotoxine. Y-8894 appeared to act by stimulating the noradrenergic receptor, and it acts to a lesser extent by blocking the serotonergic receptor in the brain.

The effects of long-term dosing with acetyl-L-carnitine (ALC) were examined in aged rats, and they were compared with those in young rats. ALC significantly reduced the lipofuscin deposition in the brain of aged rats. Emotional parameters such as locomotor activity and rearing behavior are lower in aged rats than in young rats, and these behaviors decreased in both age groups during the experiments. ALC diminished the decrease of these emotional behaviors, especially in rearing behavior in the aged rats. Furthermore, ALC had no effect on body weight gain. These results might reflect one of the main beneficial pharmacological mechanisms of ALC in clinical use.

Analgesic and antipyretic activities of 2-(4-(2-imidazo-[1,2-a]pyridylphenyl)propionic acid (Y-9213) were studied with various experimental models. The analgesic activity of Y-9213 was found to be more potent than that of indometacin and morphine in the silver nitrate, Randall-Selitto, and phenylquinone writhing tests. Y-9213 also showed an analgesia in the tail pinch and electric stimulation test. On the warm water induced foot withdrawal reflex, Y-9213 was more effective in spinal-sectioned mice than in intact mice similarly to mephenesin and diazepam. Y-9213 was also proved to possess antipyretic activity as potent as indometacin and to be devoid of morphine-like property. Y-9213 exhibited little effect on the respiration and cardiovascular system in dogs. Y-9213 was found to be rapidly absorbed and eliminated from the blood with a half-life of about 2.5 h in rats. These findings indicate that Y-9213 may be an effective and well tolerated antipyretic and analgesic agent.

The amelioration of energy metabolic disturbance in cerebral anoxia is valuable for the treatment of various cerebral ischemic diseases and insufficiency. In this study, the effect of Y-8894 on the cerebral energy metabolism was investigated using a KCN-induced cerebral anoxia model with mice. The intravenous injection of a lethal dose of KCN (2.5 mg/kg) induced rapid and marked decreases of brain glucose, phosphocreatine and ATP contents, with a remarkable enhancement of lactate and AMP levels, indicating a severe disorder of the cerebral energy metabolism. This phenomenon was also shown by an irreversible deterioration of the energy charge potential (ECP), an index of the cerebral energy state. The treatment with Y-8894 (30 mg/kg, i.p.) remarkably ameliorated this KCN-induced energy metabolic disturbance: markedly reducing the changes in brain phosphocreatine, glucose and lactate contents, while keeping ATP, AMP and ECP at nearly their normal levels. In addition, these changes in the Y-8894 treated group recovered promptly to normal, whereas those in the control group were irreversible. In normal mice, Y-8894 induced a significant increase in the cerebral glucose content without affecting either the cerebral glycolytic metabolism or the energy state. The present findings suggest that Y-8894 has an ameliorative effect on the cerebral energy metabolic disturbance, and this effect likely plays an important role in the improvement of amnesia and other neurological deficits related to cerebral anoxia.

The effects of Y-8894 on learning and memory were studied using the pole climbing avoidance (PCA) response in intact and experimentally induced amnesic rats. The following results were obtained: A single administration of Y-8894 (2.5 mg/kg, i.p.) to experimentally induced amnesic rats significantly antagonized the decrease in the mean number of PCA responses induced by an electroconvulsive shock (ECS). At a higher dose (10 mg/kg, i.p.), however, this effect was reduced. Repeated administration of Y-8894 (5 mg/kg, i.p.) significantly antagonized the facilitation of the extinction of the PCA response induced by exposure to CO2. Repeated administration of Y-8894 (2.5 mg/kg, i.p.) significantly facilitated the learning of the PCA response in intact rats. At a higher dose (5 mg/kg, i.p.), however, this effect was reduced. A single administration of Y-8894 (5 mg/kg, i.p. and 25 mg/kg, p.o.) significantly delayed the extinction of the PCA response in intact rats. These results suggest that Y-8894 has an ameliorative and facilitative effect on learning and memory in experimentally induced amnesic and intact rats.

Effects of Y-8894 on learning and memory were studied using a radial maze task in intact and scopolamine-induced amnesic mice. The following results were obtained: 1) Repeated administration of Y-8894 (1, 2.5 and 5 mg/kg, i.p.) significantly increased the number of initial correct responses (ICR) in the training session in intact mice, facilitating the learning of the maze task. Dihydroergotoxine (5 mg/kg, i.p.) significantly facilitated the learning of this task in the initial stage of the training session, but non-specifically inhibited the performance in the late stage of training. Ca-hopantenate did not modify the learning of this task. 2) A single administration of Y-8894 (2.5 or 5 mg/kg, i.p.) showed an antagonistic effect on scopolamine (1 mg/kg, s.c.)-induced amnesic mice. Dihydroergotoxine (5 mg/kg, i.p.) and Ca-hopantenate (500 mg/kg, i.p.) also significantly antagonized the ICR-decreasing effect of scopolamine. These results suggest that Y-8894 has an ameliorative and/or facilitative effect on learning and memory in the radial maze task, and Y-8894 is more potent than dihydroergotoxine and Ca-hopantenate.

Anti-inflammatory activity of 2-[p-(2-imidazo[1,2-a]pyridyl) phenyl]propionic acid (Y-9213, miroprofen) was studied on various experimental models. Miroprofen was found to be as active as indomethacin against the exudative inflammation such as pleuritis in rats induced by Evans blue-carrageenin and the peritonitis in mice induced by acetic acid, and against the local Shwartzman reaction in rabbits. Miroprofen also inhibited the formation of edema induced by carrageenin or kaolin in rats' paws at lower doses. Against the proliferation of connective tissues, miroprofen showed the inhibitory action at higher doses. The ulcerogenic activity of miroprofen in rats was less potent than that of indomethacin, and as active as that of phenylbutazone. These findings indicate that miroprofen may be more effective in suppressing pain responses and acute inflammation accompanied with increased vascular permeability.

The effects of sufoxazine on various experimental amnesia models were studied using passive avoidance behavior in mice. Sufoxazine had no influence on learning and memory in intact mice. Sufoxazine, administered either immediately after CO2 exposure or 30 min prior to the acquisition trial, improved CO2 induced amnesia. It also improved both electroconvulsive shock (ECS) induced amnesia (administered immediately after the amnestic treatment) and scopolamine induced amnesia (administered immediately after the acquisition trial). The anti-depressant drugs, imipramine and desipramine had no ameliorative activity in any of these experimental amnesia models. These results suggest that sufoxazine improves amnesia experimentally induced by various methods.