Clinical outcome of high-dose chemotherapy combined with peripheral blood stem cell transplantation for male germ cell tumors

Peripheral blood stem cell transplantation (PBSCT) is widely performed currently instead of bone marrow transplantation (BMT) because bone marrow reconstruction is better and the procedure is less invasive. We applied 26 courses of high-dose chemotherapy (1250 mg/m2 of carboplatin, 1500 mg/m2 of etoposide and 7.5 g/m2 of ifosfamide) to 14 male patients with germ cell tumors. Eleven patients underwent high-dose chemotherapy as induction after two to three courses of conventional BEP therapy. The remaining three patients had recurrent disease after conventional chemotherapies. Peripheral blood stem cells were harvested during previous chemotherapy and sufficient CD34+ cells were harvested for transplantation. Although all patients had grade 4 hematotoxicity, the white blood cell count recovered to more than 1000/microl within 8-11 days after PBSCT. No treatment-related death was found. Nine of 14 patients (64.3%) remain disease free at 18 months of median follow up time (range 12-60). We conclude that high-dose chemotherapy is a safe and effective means of treating advanced or refractory germ cell tumors in male patients.     

重组人粒细胞集落刺激因子注射液动员外周血干细胞10例

目的 :探讨重组人粒细胞集落刺激因子(rhG CSF)注射液动员外周血造血干细胞 (PBSC)的效果。方法 :对 6例恶性血液病病人 ,1d内静脉注射长春新碱 1～ 2mg·m- 2 及环磷酰胺 4～ 7g·m- 2 (分 4次 ,间隔 4h) ,外周血白细胞降至 1×10 9·L- 1以下时 ,加rhG CSF 6～ 8μg·kg- 1,皮下注射 ,qd× 5～ 7d ;对 4例健康供者在采集PBSC前 5d予rhG CSF 6～ 8μg·kg- 1,皮下注射 ,qd× 5d。白细胞升至 10× 10 9·L- 1以上时采集PSBC ,并进行CD+ 34 及粒 巨噬细胞集落形成单位 (CFU GM )检测。结果 :一次收集单个核细胞计数 (3.9±s 1.7)×10 8·kg- 1;CD+ 34 (4 .8± 2 .3)× 10 8·kg- 1;粒 巨噬细胞集落形成单位 (5± 3)× 10 4 ·kg- 1。未出现严重不良反应。结论 :rhG CSF无论对病人自体还是对健康供者均能安全、高效地动员PBSC ,满足移植所需要。     

Feasibility and usefulness of high-dose chemotherapy (high-dose ifosfamide, carboplatin and etoposide) combined with peripheral blood stem cell transplantation for male germ cell tumor: a single-institute experience

Although the usefulness of high-dose chemotherapy with peripheral blood stem cell transplantation for advanced germ cell tumor is still under evaluation in phase III randomized controlled studies, this approach is currently used as one treatment option for relapsed or advanced male germ cell tumor. Clinical outcomes of high-dose chemotherapy for a single institute from Japan are presented herein. We administered 63 courses of high-dose ifosfamide, carboplatin and etoposide chemotherapy (1250 mg/m carboplatin; 1500 mg/m etoposide; 7.5 g/m ifosfamide) to 34 men with germ cell tumors. Of these, 27 patients underwent high-dose ifosfamide, carboplatin and etoposide as first-line therapy after 2-3 courses of conventional bleomycin, etoposide and cisplatin chemotherapy, and seven patients underwent high-dose ifosfamide, carboplatin and etoposide for relapsed germ cell tumor. Peripheral blood stem cells were harvested during previous chemotherapy and sufficient CD34 cells were harvested for transplantation. Although all patients experienced grade 4 hemotoxicity, leukocyte counts recovered to above 1000/mul within 8-11 days after peripheral blood stem cell transplantation. No treatment-related deaths occurred. After a mean follow-up of 45 months (range 12-118 months), 23 of 34 patients (67.6%) remained disease-free. High-dose ifosfamide, carboplatin and etoposide could be performed safely, and could offer an effective means of treating advanced or refractory germ cell tumors in men.     

BI-L-239, a 5-lipoxygenase inhibitor, blocks inhaled antigen-induced airway hyperresponsiveness in conscious guinea pigs.

Male Hartley guinea pigs were actively sensitized to ovalbumin (OA). Respiratory system resistance (Rrs) was measured by forced oscillations superimposed on tidal breathing. Airway responsiveness (inhaled methacholine PC100) was determined three days prior and three days after (day 10) three alternate day inhalations of OA. Airway cell composition was assessed on day 10 by lung lavage. Three groups (n = 5-6) were studied: A) vehicle challenged, B) OA challenged/placebo treated, C) OA challenged/BI-L-239 (2,6-dimethyl-4-[2-(4-fluorophenyl)ethenyl]phenol) treated (10 x 0.75 mg/actuation, 10 minutes prior to each OA challenge). Animals were treated with pyrilamine and indomethacin (10 mg/kg i.p.) 30 minutes prior to each OA challenge. OA induced acute increases in Rrs of 143 +/- 29%, 238 +/- 73% and 102 +/- 43% in placebo and 86 +/- 34%, 45 +/- 35% (p, 0.05 vs. placebo) and 102 +/- 31% in BI-L-239 treated. OA induced a significant (p less than 0.05) increase in airway leukocytes in placebo (487 +/- 36 to 1615 +/- 421 x 10(3)/ml) but not BI-L-239 treated (to 881 +/- 155 x 10(3)/ml) and decrease in methacholine PC100 in placebo (1.487 +/- 0.49 to 0.39 +/- 0.18 mg/ml) but not BI-L-239 treated (0.99 +/- 34 to 1.04 +/- 0.39 mg/ml). We conclude that BI-L-239 attenuates the airway constriction, inflammation and hyperresponsiveness induced by repeated antigen inhalations in conscious guinea pigs.     

Mobilization of peripheral blood stem cells by granulocyte-colony stimulating factors: comparison of a standard dose of glycosylated and mutated granulocyte-colony stimulating factor in non-Hodgkin's lymphoma patients following CHOP therapy

The effects of granulocyte-colony stimulating factor (G-CSF) have been studied in several clinical settings. G-CSFs are widely used to stimulate the production of granulocytes and are well known to mobilize peripheral blood stem cells (PBSCs). However, very few studies have examined differences among G-CSFs. The aim of this study was to compare the mobilization of PBSCs induced by a standard dose of two G-CSFs following biweekly cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) therapy. Using a standard dose of G-CSF, we conducted a randomized, crossover trial that compared the efficacy of two kinds of G-CSF, glycosylated [lenograstim (2 micrograms/kg)] and mutated [nartograstim (1 microgram/kg)], on PBSC mobilization in 10 patients with non-Hodgkin's lymphoma after biweekly CHOP chemotherapy. Lenograstim (2 micrograms/kg) was more effective in shortening the duration of neutropenia than nartograstim (1 microgram/kg) (3.8 days vs. 5.0 days, p < 0.05, the number of days for the neutrophil count to reach 5 x 10(9)/l from nadir). The number of CD34+ cells and granulocyte-macrophage colony forming units (GM-CFU) was higher for lenograstim but no statistically significant difference between the two groups was found. Glycosylated G-CSF is more effective than mutated G-CSF in shortening the duration of neutropenia. As for the mobilization of CD34+ cells and the number of CFU-GM, there was a tendency to increase in the lenograstim group but no statistically significant differences were found.     

脐血细胞生物学特性的研究

目的 :研究单份脐血造血干 /祖细胞 (HSC/ HPC)的质和量 ,脐血中的干细胞、免疫细胞的表型特征。方法 :收集 2 0份脐血 ,采用 6 %的羟乙基淀粉沉淀去除红细胞 (RBC) ,利用甲基纤维素半固体培养法培养和观察 HSC/ HPC的集落生成情况 ,以了解增殖能力 ,用流式细胞仪检测脐血 CD34 + CD38- 、CD34 + 、CD34 + CD38+ 细胞量及免疫细胞的表型特性。结果 :2 0份脐血采集量在 4 0 m L～ 16 5 m L 之间 ,均数为 (78± 2 3) m L。每次收集的有核细胞 (NC)数在 4 .8×10 8～ 4 .6× 10 9之间 ,均数为 (1.4 3± 0 .96 )× 10 9,NC的回收率为 86 .6 %。脐血中 CD34 + CD35-细胞数占 NC总数的 (0 .10 2± 0 .0 70 ) % ,平均为 (0 .12 0± 0 .0 90 )× 10 7/份 ,CD34 + 细胞占 NC总数的 (1.2 9± 0 .31) % ,平均为 (1.4 2± 0 .92 )×10 7个 /份 ,CFU- GM为 (2 .5 4± 2 .0 2 )× 10 6个 ,BFU- E为 (1.4 1± 1.39)× 10 6个 ,CFU- GEMM(1.6 0± 2 .30 )× 10 5个 ,CD4 + T细胞表达 CD4 5RA为 (89.95± 7.86 ) % ,CD8+ T细胞表达 CD4 5RA为 (99.5 8± 3.4 6 ) % ,均显著高于成人外周血 T淋巴细胞 (P<0 .0 1) ,结论 :单份脐血的 HSC/ HPC含量可以满足体重较轻的 (<5 0 kg成人和儿童患者移植的需要 ,体重 ) ,5 0 kg以上的     

Treatment of acute myeloid leukemia during the second and third trimesters of pregnancy

Fortunately, the occurrence of acute myeloid leukemia (AML) during pregnancy is rare. We report a case of successful fetal outcome with standard induction and consolidation treatment in the second and third trimesters, respectively. A 37-year-old woman in her second trimester (21 wks) of pregnancy was found to have acute myeloid leukemia. She elected to maintain the pregnancy and underwent induction with cytarabine and idarubicin. Her hospital course was complicated by Pseudomonas vesicularis and gram-positive bacilli (not Bacillus anthracis) septicemia, but she obtained complete remission. After discharge, a fetal echocardiogram at 26 weeks revealed a mildly dilated right ventricle with mild systolic dysfunction, and the left ventricle appeared smaller than normal with mild systolic dysfunction. The patient then received consolidation therapy with high-dose cytarabine. On day 14 of consolidation, filgrastim 16 mug/kg was added to improve stem cell mobilization. A total of 19.8x10(6) CD34+ cells/kg were collected with a single apheresis session. At 37 weeks, she delivered a viable female infant weighing 3 lbs 12 oz. Fetal abnormalities included acrocyanosis, shallow sacral dimple, short digits and limbs, and prominent frontal skull with mild macrognathia. A postnatal echocardiogram revealed a moderate-sized membranous ventricular septal defect. The ventricular septal defect proved significant and required surgical repair at 5 months. Approximately 4 weeks after delivery, the mother underwent autologous peripheral stem cell transplantation. Unfortunately, 100 days after transplantation, she had a relapse of AML. After a brief remission from a second induction, the patient died.     

自身免疫病患者外周血CD34+细胞动员、采集和纯化研究

目的：探讨自身免疫病患外周血造血干细胞动员、采集和纯化的效果及安全性。方法：对17例确诊自身免疫病患予环磷酰胺＋粒细胞集落刺激因子（G－CSF）动员外周血干细胞，CliniMACS系统对其中11例患外周血单个核细胞进行CD34^ 细胞阳性分选，流式细胞仪检测分选前后CD34^ 细胞纯度及淋巴细胞各亚群。结果：1例动员中并发尿崩症，2例动员失败。11例分选后CD34^ 细胞纯度平均96．1％，回收率70．14％；CD3^ 、CD19^ 、CD14^ 细胞分别去除10^3/kg,10^2/kg,10^3/kg。结论：对自身免疫病患采用环磷酰胺＋G－CSF方案动员外周血干细胞方法可靠，安全性好；外周血干细胞的纯化方法可获得高纯度和高回收率的CD34^ 细胞，并极大限度的去除T、B等细胞。     

Comparison of growth of the follicle and mesenchymal stem cells to urothelial cells and fibroblasts on collagen scaffold

To develop a tissue-engineered bladder wall replacement with elements obtained from non-urinary tract components is an atractive idea. The aim of this study was to compare growth of hair follicles epithelial stem cells and mesenchymal stem cells to urothelial cells and fibroblasts cells on scaffold prepared from rat collagen type I. MATERIALS AND METHODS: Wistar rats were used in experiment. Rat urothelial cells, hair follicles epithelial stem cells, mesenchymal stem cells and 3T3 cells were cultivated in DMEM (Sigma) supplemented with 10% (or 20% for hair follicles cells) of Fetal Bovine Serum (FBS). Epithelial cell cultures were suplemented with EGF (10 ng/ml; Sigma). Cells were stained using anti-cytokeratine (Clone MMF) and anti-cytokeratine 7. Anti-CD34 and anti-p63 staining were done. Collagen scaffold was prepared from tendoms of Wistar rat's tails. 6-well plates were covered with collagen scaffold. 25 x 10(3) of cells were seeded on each well and cultured for a week. Cells in the controls were seeded on polystyrene surface. After a week cell viability was assessed using MTT test (Sigma). Each experiment was triplicated. Photo documentation was prepared. The differences between means were compared using t-Student test. RESULTS: There were 106.5 +/- 23.4 x 10(3) and 310.7 +/- 60.7 x 10(3) of 3T3 fibroblasts growing on polystyrene and collagen, respectively (p < 0.05). The initial cell number was 25.0 x 10(3). Urothelial cells expressed epithelial markers. There were 40.0 +/- 4.2 x 10(3) and 4.5 +/- 1.8 x 10(3) urothelial cells growing on polystyrene and collagen, respectively after 7 days of culture (p < 0.01). There were 118.5 +/- 19.7 x 10(3) and 114.1 +/- 33.2 x 0(3) of mesenchymal stem cells growing on polystyrene and collagen, respectively (NS). Hair follicles epithelial cells expressed epithelial markers and were slightly positive for CD34 and p63. There were 292.5 +/- 33.3 x 10(3) and 167.4 +/- 24.9 x 10(3) of hair follicles epithelial cells growing on polystyrene and collagen, respectively (p < 0.05). Collagen scaffold decreased proliferation of follicle epithelial and urothelial cells. CONCLUSIONS: Hair follicles epithelial stem cells and mesenchymal stem cells can be potentially used in tissue-engineering, with the guarantee of the sufficient cell number for transplantation. It seems that construction in vitro of urinary bladder walls from elements obtained from non-urinary tract tissues is feasible.     

Comparison of lenograstim and filgrastim on haematological effects after autologous peripheral blood stem cell transplantation with high-dose chemotherapy

OBJECTIVE: To compare the efficacy of lenograstim and filgrastim on haematological recovery following an autologous peripheral blood stem cell transplantation (PBSCT) with high-dose chemotherapy. METHODS: A retrospective case-controlled study. RESULTS: Absolute neutrophil count (ANC) recovery above 0.5 x 10(9)/l and white blood cell (WBC) recovery above 4 x 10(9)/l for 3 consecutive days was achieved earlier with filgrastim than with lenograstim ((13.2 +/- 8.0 vs 19.0 +/- 10.0 days, p = 0.004), (16.9 +/- 9.7 vs 29.9 +/- 16.6 days, p = 0.001), respectively). The platelet recovery above 20 x 10(9)/l was also achieved earlier with filgrastim than with lenograstim (19.5 +/- 11.6 vs 27.2 +/- 13.8 days, p = 0.006). Furthermore, filgrastim-treated patients received fewer days of granulocyte colony simulating factor (G-CSF) administration (12.5 +/- 7.0 vs 18.6 +/- 8.5 days, p = 0.001) and spent less time in hospital (23.7 +/- 10.9 vs 32.0 +/- 17.6 days, p = 0.009). Duration of antibiotic administration was also significantly shorter in the filgrastim group (13.6 +/- 7.6 vs 29.1 +/- 19.8 days, p = 0.001). CONCLUSION: In patients undergoing PBSCT following high-dose chemotherapy, filgrastim significantly reduced the duration of neutropenia, thrombocytopenia and days of G-CSF administration, and led to earlier hospital discharge compared with lenograstim.     

自体外周造血干细胞移植治疗继发进展型多发性硬化的疗效与安全性

目的：评价自体外周造血干细胞移植（APBSCT）治疗继发进展型多发性硬化（MS）的疗效及安全性。方法：回顾性分析2001-2010年在首都医科大学宣武医院接受APBSCT治疗的41例继发进展型MS患者的临床资料。女性31例,男性10例,年龄24～56岁,中位年龄36岁。所有患者连续5d皮下注射粒细胞集落刺激因子（G-CSF）5μg/kg动员造血干细胞。应用细胞分离机采集外周血单个核细胞（PBMC）,对28例患者应用CliniMACS免疫磁珠系统分选CD34^＋细胞,将PBMC或CD34^＋细胞置-80℃冰箱冻存。患者采用BEAM[becenum（camustine）;etoposide（teniposide）;cytosine arabinoside;melphalan]预处理方案：卡莫司汀300mg/m^2×1d;替尼泊苷150mg/m^2×4d;阿糖胞苷200mg/m^2×4d;美法仑140mg/m^2×1d。预处理后经静脉回输低温保存复苏的自体CD34^＋细胞或PBMC。应用扩充神经功能残疾量表评判患者APBSCT后神经系统功能的恢复程度,根据不良事件常用术语标准3.0版评判APBSCT的不良反应。结果：2例患者失访。39例患者治疗后随访6～100个月,平均51个月,其中16例缓解,8例稳定,15例移植后复发且病情进展。100个月累计疾病无进展生存率为55.5%。预处理后41例患者的中性粒细胞均〈0.5×10^9/L,血小板均〈25×10^9/L。经支持治疗后所有患者均获得造血重建;37例发生腹泻;3例发生替尼泊苷过敏反应;26例发生感染,其中发热性中性粒细胞减少19例,会阴肛门周围皮肤软组织脓肿2例,败血症2例,肺部真菌感染、静脉置管处皮肤感染和消化道感染各1例;6例发生植入综合征;无移植相关死亡。结论：APBSCT是治疗继发进展型MS较安全有效的方法,但使用期间应严密观察可能出现的不良反应。     

粒系集落刺激因子对进展型多发性硬化患者造血干细胞的动员效果及安全性

目的：观察粒系集落刺激因子（G-CSF）对进展型多发性硬化（MS）患者造血干细胞动员效果及安全性。方法：34例继发进展型MS患者纳入研究,给予G-CSF5μg/（kg·d）4～6d动员自体造血干细胞。动员后经血细胞分离机收集外周血单个核细胞。应用流式细胞术检测CD34^＋细胞和单个核细胞绝对数,并观察应用G-CSF后不良反应的类型和发生率。于动员前及动员后分别评定患者的扩展残疾状态评分（expanded disability status scale,EDSS）。结果：采集物中CD34＋细胞为（2.68±0.89）×106/kg,单个核细胞为（2.98±1.19）×108/kg。移植后中性粒细胞恢复至〉0.5×10^9/L的中位时间为13d（9～17d）,血小板恢复至〉50×10^9/L的中位时间为16d（11～21d）。移植相关死亡率为0。在G-CSF动员过程中有17例患者（50%）出现肌痛及乏力症状,未用药物治疗症状消退。2例患者在用药期间EDSS评分增加0.5分,与动员前相比差异无统计学意义（P=0.16）。结论：对于自体造血干细胞移植治疗进展型多发性硬化患者,单用G-CSF动员可以达到有效安全的临床要求。     

Tolerance to the neurotoxic effects of methamphetamine in young rats

The present study examined whether exposure to methamphetamine during adolescence (as determined in post-natal day 40 rats) might alter its effects when used in young adulthood (as assessed in post-natal day 90 rats). Results confirm that high-dose methamphetamine administration (4x10 mg/kg/injection, s.c., 2-h intervals) decreases striatal dopamine uptake and transporter ligand binding in post-natal day 90 rats; effects that were blocked if animals received six biweekly methamphetamine pretreatments (15 mg/kg; s.c.) beginning at post-natal day 40. This neuroprotection was not likely due to pharmacokinetic tolerance, since brain methamphetamine concentrations did not differ 1 h after the high-dose methamphetamine regimen among treated rats regardless of pretreatment. The methamphetamine biweekly pretreatment attenuated the hyperthermia caused by the neurotoxic methamphetamine regimen; a phenomenon that may have contributed to the neuroprotection.     

Immune reconstitution after autologous hematopoietic transplantation with Lin-, CD34+, Thy-1lo selected or intact stem cell products

In sequential studies, we compared immune reconstitution following high-dose chemotherapy (HDT) and stem cell transplantation (SCT) using intact mobilized peripheral blood stem cell (PSC) in intermediate grade non-Hodgkin's lymphoma (NHL) patients and CD34(+), lineage-negative (Lin(-)), Thy-1(lo) (CD34(+)Lin(-)Thy-1(lo)) stem cells in low-grade NHL patients. Cytokine expression and cellular phenotype and function were used as the basis of comparison. Despite differences in cellular composition of the stem cell grafts, immune reconstitution in both groups was similar. Significantly higher levels of type 1- and 2-associated cytokine messenger ribonucleic acid (mRNA) were observed both prior to and following transplant in the peripheral blood (PB) of both cohorts as compared to normal individuals. Similar levels of interleukin (IL)-4, IL-10, interferon-gamma (IFN-gamma), and tumor necrosis factor-alpha (TNF-alpha) messenger ribonucleic acid (mRNA) were seen in PB mononuclear cells following transplant with either product. In contrast, patients receiving isolated CD34(+)Lin(-)Thy-1(lo) cells expressed significantly higher IL-2 levels at all times examined post-transplant. Despite the high levels of cytokine gene expression and rapid restoration to pretransplant levels of CD3 cell number by day 30, T cell function and CD4:CD8 and CD4(+)CD45RA:CD4(+)CD45RO(+) ratios were significantly depressed in both cohorts compared to normal donors, and significantly lower in patients transplanted with CD34(+)Lin(-)Thy-1(lo) compared to patients receiving an intact PSC product. These data suggest that the peripheral tolerance in patients receiving HDT and an autologous SCT occurs independent of graft composition, although immune function and CD4 recovery are better facilitated by transplantation of an intact product.     

Quantification of busulfan in saliva and plasma in haematopoietic stem cell transplantation in children : validation of liquid chromatography tandem mass spectrometry method

BACKGROUND AND OBJECTIVE: Busulfan pharmacokinetic studies suggest that an individual dosing strategy may be necessary to optimise systemic exposure in order to decrease toxicity and improve outcome in haematopoietic stem cell transplantation. Therapeutic and toxic effects of the busulfan/cyclophosphamide regimen have been related to the area under the busulfan plasma concentration-time curve. Because of practical limitations in obtaining blood from children, saliva was evaluated as an alternative matrix for therapeutic drug monitoring, offering the advantages of a non-invasive, rapid and easy sampling procedure. Another objective was to evaluate an easy and robust liquid chromatography- tandem mass spectrometry method for plasma and saliva busulfan determination. METHODS: An online extraction cartridge with column-switching technique, analytical liquid chromatography over a Chromolith RP 18 e column, and tandem mass spectrometry were used to quantify busulfan concentrations in matched plasma and saliva samples. The study population consisted of ten patients, aged 1.3-19 years (median age 11.8 years, seven females, three males), undergoing haematopoietic stem cell transplantation. All patients received busulfan 0.8-1.3 mg/kg orally every 6 hours for a total of 16 doses, followed by two doses of cyclophosphamide (60 mg/kg/day). RESULTS: The lowest limit of detection was 2 microg/L and the lower limit of quantification was 10 microg/L. Only 100 microL of plasma/saliva was needed. The mean recoveries (SD) of busulfan were 97.2% (2.7) in plasma and 100.4% (1.3) in saliva. Intra- and inter-assay imprecision was 2-3% and 2-4% for plasma, and 1-2% and 2-4% for saliva (concentration range 30-1,500 microg/L). The bias was <4% for both plasma and saliva. The correlation between the busulfan concentration in plasma and saliva was highly significant (r=0.958; p<0.0001; saliva/plasma ratio=1.09+/-0.04; n=69 sample pairs). The apparent plasma clearance was slightly higher than the apparent saliva clearance (202+/-31 mL/h/kg vs 189+/-28 mL/h/kg; p=0.001). The mean elimination half-life was found to be 2.31+/-0.46 hours for plasma and 2.30+/-0.36 hours for saliva; these were not significantly different (p=0.83). CONCLUSION: The present study demonstrated that busulfan analysis in saliva could be a valuable and reliable alternative to plasma analysis.     

Overall clinical evaluation of panipenem/betamipron against infections in pediatric field]

To conduct a basic-clinical study on newly developed panipenem/betamipron (CS-533/CS-443, PAPM/BP) against various infections in pediatrics, a study group was organized and a joint research by 17 institutions and their related hospitals was undertaken. The obtained results are as follows. 1. Blood concentrations and urinary excretion Pharmacokinetics of PAPM/BP in children was studied using 30 minutes intravenous drip infusion of 10 mg/10 mg/kg, 20 mg/20 mg/kg and 30 mg/30 mg/kg, respectively. Maximum blood levels of PAPM/BP were observed at the completion of drip infusion and were 26.72 +/- 8.78 micrograms/ml/18.33 +/- 8.54 micrograms/ml (mean +/- S.D.) with administration of 10 mg/10 mg, 64.80 +/- 18.50 micrograms/ml/38.74 +/- 16.41 micrograms/ml with administration of 20 mg/20 mg and 91.70 +/- 29.42 micrograms/ml/50.08 +/- 22.41 micrograms/ml with administration of 30 mg/30 mg. Dose dependency was noted with these doses. The half-life was about 1 hour for PAPM and about 0.5 hour for BP. As for urinary excretion, PAPM was excreted about 30% and BP about 70% in the first 6 hours after the start of drip infusion. 2. Clinical results Twenty-five cases of exclusion and drop-out were deducted from a total of 391 cases and 8 cases having 2 diseases concurrently were added to the remaining 366 cases, hence 374 cases were evaluated in the study as the subjects of analysis of clinical effects. As for clinical effects in cases where pathogenic bacteria were detected, 215 out of 221 cases were rated as effective or above, hence the efficacy rate of 97.3% was obtained. In cases where pathogenic bacteria were not detected, 145 out of 153 cases were rated as effective or above, thus the efficacy rate was 94.8% which is similar to that in the cases where pathogenic bacteria were detected. The daily dose levels most commonly employed were 30 to 60 mg/kg (as PAPM) administered in 3 divided doses a day, and this regimen method accounted for 52.7% of the total cases, and the efficacy rate with this regimen was 97.0%. As for the bacteriological effect 87 (96.7%) out of 90 strains of Gram-positive bacteria (GPB) disappeared and 136 (91.3%) out of 149 strains of Gram-negative bacteria (GNB) disappeared upon the treatment. The overall bacterial eradication rate for the pathogenic bacteria was 93.4%.(ABSTRACT TRUNCATED AT 400 WORDS)     

Fatal adenovirus infection indistinguishable from thrombotic microangiopathy after allogeneic CD34+ peripheral progenitor cell transplantation

A 10-year-old boy with acute lymphoblastic leukemia in second relapse received CD34+ purified allogeneic peripheral blood stem cell transplantation (PBSCT) from his HLA-haploidentical father. The patient developed grade II acute GVHD and received high-dose methyl-prednisolone starting on day + 13 posttransplant. Renal dysfunction followed by massive gastrointestinal bleeding was observed from day + 14. The laboratory findings including elevated serum LDH, increased RBC fragmentation, higher level of thrombomodulin and undetectable haptoglobin corresponded with the diagnosis of thrombotic microangiopathy (TMA). In spite of various treatments, the patient died of multiple organ failure on day + 93. Post-mortem examination revealed systemic adenovirus infection without histological findings of TMA. Severe adenovirus infection may be confused with TMA, and should be distinguished by rapid virological assay.     

Pharmacokinetics of intravenous etoposide in patients with breast cancer: influence of dose escalation and cyclophosphamide and doxorubicin coadministration

This study investigates the impact of dose escalation and of doxorubicin and cyclophosphamide coadministration on the pharmacokinetics of etoposide (ETO). Pharmacokinetics of ETO were analyzed in seven patients with breast cancer receiving 3-4 cycles of conventional-dose (CD) and one final course of high-dose (HD) chemotherapy including ETO (450 mg/m(2) and 2100 mg/m(2), respectively, fractionated over 3 consecutive days). ETO was given as monoinfusion apart from day 1 of CD, where cyclophosphamide and doxorubicin were coadministered. Plasma samples obtained on day 1 and day 2 of CD- and HD-therapy, respectively, were analyzed for ETO by HPLC. Data from a total of 25 cycles of CD- and 7 cycles of HD-therapy are given as means +/- SD for CD-day 1, CD-day 2, HD-day 1 and HD-day 2, respectively. Following administration of 210+/-29, 278+/-41, 1143+/-79 and 1143+/-79 mg ETO, the AUC (0-24 h, normalized to 150 mg/m(2)) was 123+/-23, 113+/-22, 92+/-11 and 100+/-22 microgxh/ml. The AUC and CL of single-agent ETO were not significantly different between CD (day 2) and both days of HD ETO. However, we observed a modest but significant difference for AUC and CL between day 1 of CD (coadministration of doxorubicin and cyclophosphamide) and day 2 of CD (ETO monoinfusion), the AUC and CL being 9% higher (see above) and 10% lower (21.1 vs. 23.3 ml/minxm(2)) ( P<0.05), respectively, on day 1. The fraction of unbound ETO was similar on all occasions (range: 5.5%-6.6%). Interpatient variability for AUC and CL during CD-therapy was moderate with coefficients of variation (CV) of 17%-20%, while intraindividual variability was comparatively high and almost in the same range (CV of 13%-16%). Pharmacokinetics of etoposide were not significantly altered following fivefold dose escalation in the same patients. A 10% decrease in systemic clearance of etoposide was observed during doxorubicin and cyclophosphamide coadministration, which could result from drug interactions affecting renal and/or metabolic elimination of etoposide. The magnitude of the decrease, however, is unlikely to be of clinical significance.