Recent Trends in the Treatment and Prognosis of Adult Leukemia with Characteristics of Patients in Japan: Transition during the Fifteen Years from 1971 to 1985

Patients with acute (2,569) and chronic (957) leukemia diagnosedat 19 institutes took part in the study on the "MultidisciplinaryTreatment of Leukemia" between 1971 and 1985 and were investigatedretrospectively. By dividing the 15 years into three five-yearperiods, we were able to compare patient ratios in the differentperiods. The proportions of acute to chronic leukemia casesshowed no obvious change; however, the proportions of casesdiagnosed as acute lymphocytic leukemia in acute leukemia showeda significant increase. The main chemotherapeutic drugs usedduring the three time periods were cytarabine or its analogues,the anthracyclines, 6-mercaputopurine and prednisolone, againstacute myelogenous leukemia, and the vinca alkaloids, prednisoloneand the anthracyclines against acute lymphocytic leukemia. Therate of complete remission from acute myelogenous leukemia mademarked progress, from 45.1% during 1971–1975 to 62.3%during 1981–1985, but that of acute lymphocytic leukemiashowed no significant progress, being 65% during 1971–1975and 69.7% during 1981–1985. The durations of remission,however, and the survival times for patients with acute lymphocyticleukemia, as well as for those with acute myelogenous leukemia,became significantly longer over the three periods. Median survivaltimes from chronic myelocytic leukemia were 37–40 mo inall three periods, showing no progress. There was a better prognosisin cases of chronic myelocytic leukemia with, than without,Philadelphia chromosome. Except for a low incidence of chroniclymphocytic leukemia in Japan, adult leukemia patients' characteristicsand prognoses seem to be almost the same in Japan as in theU.S.A. and Europe.     

Phase I clinical and pharmacokinetic study ofN 4-behenoyl-1-β-d-arabinofuranosylcytosine

A phase I study ofN ⁴-behenoyl-1-β-d-arabinofuranosylcytosine (BHAC) was conducted in 66 patients, 41 with solid tumors and 25 with hematological malignancies. The patients received either a 2-h single intravenous (i.v.) drip infusion (Schedule 1) or consecutive daily 2-h i.v. infusions (Schedule 2). In Schedule 1 the daily dose was initiated with 1.5 mg kg^?1 which was escalated up to 7 mg kg^?1. Side-effects were mild, and included nausea, vomiting, epilation, and hot flushes. Because of the presence of the solvent vehicle, HCO-60 and in consideration of the mechanism of action of BHAC, the dose escalation was stopped at 7 mg kg^?1. In Schedule 2, the daily dose was started with 1.5 mg kg^?1 which was escalated up to 8 mg kg^?1 and given for 2–16 days. Myelosuppression was found to be dose-limiting toxicity. The maximum tolerated dose (MTD) in patients with non-hematological solid tumors was assumed to be 5 mg kg^?1 daily × 5 days. The plasma disappearance curve of BHAC looked biphasic, and when 4 mg kg^?1 of BHAC were administered the half-lives of the initial phase (t _1/2α) and the second phase (t _1/2β) were calculated as 0.798 and 5.76 h respectively. In Schedule 2 complete remission was observed in 5 out of 21 patients with acute leukemia, one partial remission in Hodgkin’s disease, and one 1-B response (Karnofsky) in thyroid papillary adenocarcinoma.     

Plasma Factor Triggering Alternative Complement Pathway Activation by Liposomes

Several plasma components, such as complement (C) components, play a role in the clearance of liposomes from the circulation. The interactions between liposomes and the C system were investigated in this study. Multilamellar vesicle (MLV) liposomes, which were damaged by activation of the complement, became susceptible depending on the density of cetylmannoside (Man) on the liposome membrane, and activation proceeded through the alternative C pathway as observed for liposomes without Man (PC-MLV) (K. Funato et al, Biochim. Biophys. Acta 1103:198–204, 1992). In addition, the capacity of Man-modified liposomes (Man-MLV) to activate the alternative C pathway was abolished by preadsorption of plasma with Man-MLV but not with PC-MLV. The results suggest that a specific plasma factor adsorbed with Man-MLV was responsible for the augmentation of the C activation and, further, that the rapid clearance of Man-MLV from the circulation is caused by both enhanced C-mediated liposome permeability and enhanced C-mediated phagocytosis of liposomes.     

A Targeted Biopsy during Menstruation for the Definitive Diagnosis of Rectovaginal Endometriosis: A Report of Two Cases

We herein report the definitive diagnosis of rectovaginal endometriosis in two cases. Case 1 involved a 46-year-old woman with abdominal pain and hematochezia. The diagnosis after the first and second examinations using lower gastrointestinal (GI) endoscopy was unclear. Differential diagnoses included mucosa-associated lymphoid tissue and colorectal cancer. The third lower GI endoscopy with a targeted biopsy, performed during menstruation, confirmed rectovaginal endometriosis. Case 2 involved a 38-year-old woman with hematochezia. Lower GI endoscopy during menstruation revealed rectovaginal endometriosis. When rectovaginal or bowel endometriosis is suspected, lower GI endoscopy and a targeted biopsy during menstruation can prevent unnecessary surgery.     

Effectiveness of the Imugard E Leukocyte Removal Filter for Preparation of Leukocyte-Poor Concentrated Red Cells

Concentrated red cells (CRC) were filtered through a new leukocyte removal filter, the Imugard E, which consists of a polyvinyl alcohol porous sheet. CRC were filtered through the Imugard E with neither priming before filtration nor rinsing after filtration. Leukocyte removal was 99.1 +/- 0.6, 99.6 +/- 0.3 and 99.6 +/- 0.4% on the 1st, 5th and 10th day after blood collection, respectively. Platelet removal was 96 +/- 2, 81 +/- 6 and 85 +/- 3% on the 1st, 5th and 10th day, respectively. Red cell recovery was 86 +/- 2, 86 +/- 1 and 86 +/- 1% on the 1st 5th and 10th day, respectively. Filtration time was 3.9 +/- 0.8, 5.8 +/- 0.9 and 6.1 +/- 0.8 min on the 1st, 5th and 10th day, respectively. Direct filtration of CRC through the Imugard E resulted in no significant changes in the ATP or 2,3-DPG concentrations, and no hemolysis due to filtration was noticed. It may be concluded that the Imugard E is a good filter that is simple to use and effective in leukocyte removal.     

Enhancing effect of cetylmannoside on targeting of liposomes to Kupffer cells in rats

In order to evaluate whether surface modification of liposomes by cetylmannoside (Man) could be useful for targeting to Kupffer cells, the effect of Man on disposition of liposomes was examined after intravenous administration to rats. In the case of small unilamellar vesicles (SUV), no difference in disposition was observed between control liposomes (PC-SUV) and modified liposomes (Man-SUV). On the other hand, in the case of multilamellar vesicles (MLV), modified liposomes (Man-MLV) were rapidly eliminated from the circulation, and showed higher accumulation (51.4% of dose) in the liver as compared with control liposomes (PC-MLV, 25.7% of dose). In the spleen, splenic clearance of Man-MLV (0.068 ml/min) was comparable to that of PC-MLV (0.068 ml/min), although Man-MLV showed lower accumulation (5.7% of dose) than PC-MLV (14.7% of dose). This lower accumulation in the spleen of Man-MLV might be due to the low blood concentration caused by the high accumulation in the liver. Thus, it is considered that liposomal size is important in revealing the effects of Man, and Man-MLV is able to enhance only the affinity for the liver. The cellular distribution in the liver of Man-MLV 2 h after intravenous administration to rats gave encouraging evidence that Kupffer cells might be involved in the enhanced hepatic uptake of the liposomes. These results suggest the usefulness of Man-MLV for targeting to Kupffer cells. Furthermore, the involvement of plasma protein(s) in the uptake of Man-MLV is suspected.     

Induction of mucosal immunity by pulmonary administration of a cell-targeting nanoparticle

We previously found that a nanoparticle constructed with an antigen, benzalkonium chloride (BK) and γ-polyglutamic acid (γ-PGA) showed high Th1 and Th2-type immune induction after subcutaneous administration. For prophylaxis of respiratory infections, however, mucosal immunity should be induced. In this study, we investigated the effect of pulmonary administration of a nanoparticle comprising ovalbumin (OVA) as a model antigen, BK, and γ-PGA on induction of mucosal immunity in the lungs and serum. The complex was strongly taken up by RAW264.7 and DC2.4cells. After pulmonary administration, lung retention was longer for the OVA/BK/γ-PGA complex than for OVA alone. OVA-specific serum immunoglobulin (Ig)G was highly induced by the complex. High IgG and IgA levels were also induced in the bronchoalveolar lavage fluid, and in vivo toxicities were not observed. In conclusion, we effectively and safely induced mucosal immunity by pulmonary administration of an OVA/BK/γ-PGA complex.