Phase II study of continuous-infusion high-dose ifosfamide in advanced and/or metastatic pretreated soft tissue sarcomas

Background: Ifosfamide has important activity in pretreated soft tissue sarcomas (STS), and recent data support a clinically significant dose-response relationship for this agent. Administration by continuous infusion and hematopoietic support have rendered dose intensification regimens possible by reducing both hematologic and non-hematologic toxicities. The optimal dose and schedule of ifosfamide when given at high doses remain to be defined. In a previous phase I study, we demonstrated the feasibility of a continuous infusion (c.i.) high-dose ifosfamide (HDI) regimen in the ambulatory setting for patients with advanced solid tumors. The objective of the present phase II study was to assess the antitumor activity and toxicity of such a schedule in patients with advanced pretreated STS.Patients and methods: Thirty-eight patients with advanced and/or metastatic STS, all pretreated with an anthracycline with or without standard-dose ifosfamide, were treated. Ifosfamide was given by c.i. at a dose of 3.5 g/m²/day over four consecutive days, with equidose mesna uroprotection over five days. G-CSF was added at a dose of 200 µg/m²/day subcutaneously from day 6 to day 12. Cycles were repeated every three weeks in the outpatient setting.Results: A total of 159 cycles of therapy were given (median 4 per patient, range 3–6). Treatment compliance was generally satisfactory. The major toxicity was hematologic, with six febrile neutropenic episodes requiring hospitalisation and parenteral antibiotics. Acute renal failure occurred in one patient after three cycles of therapy; central nervous system toxicity was mild. An overall response rate of 39% was observed (95% confidence interval, 26% to 55%), with one complete and 14 partial remissions. All but one of the responder patients had previously received standard-dose ifosfamide. The median response duration was nine months (range 5–21+ months), and the overall median survival ranged from 6–30+ months (median 13 months).Conclusions: High-dose ifosfamide is an active regimen in anthracycline- pretreated STS. Future clinical trials should be aimed at evaluating the impact of different administration schedules on clinical response and outcome. The potential role of HDI as front-line chemotherapy as well as in the adjuvant treatment of STS needs to be investigated in randomized trials.     

动脉化疗在中晚期膀胱癌治疗中应用的初步报告

自1996年1月至今，我科为12例晚期膀胱癌患者施行了髂内动脉灌注化疗。结果：1例T4期降至T2期后给予膀胱部分切除；7例经手术＋动脉化疗，2年复查未发现复发现象；4例带瘤生存，病灶无进展。动脉化疗毒性反应较轻，疗效是肯定的，为中晚期膀胱癌开辟了一条新的治疗途径。     

Donor Lymphocyte Infusion for the Treatment of Relapse after Allogeneic Hematopoietic Stem Cell Transplantation

The results of donor lymphocyte infusion (DLI) for treatment of relapse after bone marrow transplantation (BMT) are reviewed. Durable complete remission can be achieved at the molecular level for a majority (more than 70%) of patients with CML, when treated at early relapse. Results are less favourable for acute leukemias, although useful responses have been reported. Data are scarce though promising for myelodysplastic syndromes and multiple myeloma. Major treatment-associated toxicities are GVHD and bone marrow aplasia. The latter complication can be predicted by evaluating the level of residual donor-derived hematopoiesis. Modification of infused cells (CD8 negative selection or transduction with a suicide gene), addition of peripheral blood stem cells, and early implementation of escalating doses may counteract the complications and increase the response rate. Response rate is variably influenced by the presence of chronic GVHD after initial BMT, T-cell depleted BMT, underlying disease and stage at relapse, and the level of mixed chimerism. DLI is a direct demonstration of the graft-versus-leukemia effect (GVL). Because GVL after BMT is sometimes the predominant cause of cure, it may be advisable in such situations to redirect the conditioning regimens for BMT towards engraftment and less immediate cytotoxicity.     

Randomized trial comparing monthly low-dose leucovorin and fluorouracil bolus with weekly high-dose 48-hour continuous-infusion fluorouracil for advanced colorectal cancer: A Spanish Cooperative Group for Gastrointestinal Tumor Therapy (TTD) study

Purpose: The objective of this multicenter study was to compare the efficacy and toxicity profiles of a combination of 5-fluorouracil (5-FU) given by bolus injection together with intravenous leucovorin (LV) versus high-dose 5-FU in continuous infusion (CI) in the treatment of advanced colorectal cancer.Patients and methods: A total of 306 patients were randomized to receive either 5-FU 425 mg/m² given by bolus injection on days 1–5 plus intravenous (i.v.) LV 20 mg/m² every four to five weeks or 5-FU 3.5 g/m²/week in a 48-hour CI. Therapy was continued until disease progression. Second-line chemotherapy was allowed in both arms.Results: The response rates in 306 patients with measurable lesions were 19.2% (modulated arm) and 30.3% (CI arm, P < 0.05). The median progression-free survival times were 23.5 weeks (modulated arm) and 25 weeks (CI arm, P = NS). Median survival times were 42.5 weeks (modulated arm) and 48 weeks (CI arm, P = NS). There were no significant differences in grade 3–4 toxicity profiles but if we consider all grades we observed more mucositis in the modulated arm and more hand-foot syndrome in the CI arm.Conclusions: In terms of response rate, the continuous infusion regimen was more effective than the modulated regimen. There was no significant difference in survival and time to progression, and none in grade 3–4 toxicity.     

胃癌术前卡铂腹腔化疗肿瘤组织浓度测定及药代动力学研究

作者采用高效液相色谱法对１０例可切除进展期胃癌进行腹腔卡铂术前化疗药代动力学研究。卡铂３００ｍｇ／ｍ２加生理盐水７５０ｍｌ快速腹腔注射，１６０～１８０ｍｉｎ取腹腔液、门静脉及外周血，２４０～２７０ｍｉｎ取癌组织、癌旁正常组织、腹膜、大网膜、阴性淋巴结，测定总铂浓度。结果表明，腹腔液浓度最高，平均４８．１４μｌ／ｍｌ，门静脉次之为１０．１μｌ／ｍｌ，分别是外周血的８、１．６倍。被测组织中，腹膜浓度超出其它组织浓度（Ρ＜０．０５），癌组织含量高于正常组织。研究证明，卡铂术前腹腔化疗不仅提高腹腔、门静脉药物浓度，而且，在腹膜、癌组织内有一定聚积性，对于杀灭腹腔亚临床病灶，改善临床分期，控制医源性转移，提高治愈性手术切除率发挥重要作用。     

自体癌性胸腹腔积液蛋白质回输临床疗效观察

目的观察浓缩分离的癌性胸腹腔积液蛋白质自体静脉回输的临床疗效.方法采用透析、冷凝、变速离心和抽滤等技术对癌性积液中的蛋白质进行分离提取,将可溶性蛋白稀释在盐水中用于静脉回输.结果该方法提取的蛋白质可浓缩9.78倍,蛋白质浓度可达(262.32±52.36)g/L,其中IL-2、IL-4、IFN 和TNF的浓度(pg/L)分别达到53.34±9.67,47.55±9.25,57.43±15.75和73.50±15.17,提取后浓度明显增加(P<0.05).自体蛋白液回输后无一例发生发热、过敏等副反应,同时水肿也得到一定程度的控制.CD3 、CD8 细胞百分率,总蛋白及IgG浓度均无明显改变(P>0.05),但CD4 细胞百分率和CD4 /CD8 比值明显增加(P<0.05 ).结论通过透析、变速离心及抽滤等技术,可从癌性胸、腹腔积液中浓缩分离出适于静脉输注的蛋白质提取液.自体蛋白质回输以后,水肿得到一定程度的控制,并使CD4 细胞百分率和CD4 /CD8 比值提高.     

一次性输液连接管和输液针对硝酸甘油的吸附作用研究

目的:研究微泵维持静脉注射时一次性输液连接管和输液针对硝酸甘油的吸附作用。方法:模拟临床微泵维持静脉注射,用高效液相色谱法、紫外分光光度法定量分析硝酸甘油在注射过程中的浓度变化。结果:一次性输液连接管和输液针对硝酸甘油具有显著的吸附作用,8h内平均吸附率为(73 .88±2. 05) %。结论:硝酸甘油经微泵维持静脉注射时,不宜使用对硝酸甘油具有吸附作用的一次性输液连接管和输液针     

门冬氨酸左氧氟沙星与其他左氧氟沙星盐的药动学比较

目的对门冬氨酸左氧氟沙星与其他左氧氟沙星盐在大鼠体内进行了药动学比较。方法以替硝唑为内标,血浆样品经乙腈沉淀蛋白后,采用高效液相的方法进行了测定。结果线性范围0.5~25μg/m l,日内、间精密度RSD均<6%,平均回收率大于89%。大鼠腹腔注射门冬氨酸左氧氟沙星、盐酸左氧氟沙星、乳酸左氧氟沙星和左氧氟沙星,测定不同时间的药物浓度,所得的主要药物动力学参数:门冬氨酸左氧氟沙星t1/2K a=7.461m in、t1/2α=16.499m in、t1/2β(m in)=218.989m in、tm ax=22.600m in、AUC=1202.262(μg.m in)/m l;盐酸左氧氟沙星t1/2K a=0.064m in、t1/2K e=24.155m in、tm ax=3.433m in、Cm ax=10.946μg/m l、AUC=420.925(μg.m in)/m l;乳酸左氧氟沙星t1/2K a=0.409m in、t1/2K e=13.576m in、tm ax=2.131m in、Cm ax=13.042μg/m l、AUC=282.797(μg.m in)/m l;左氧氟沙星t1/2K a=0.977m in、t1/2K e=8.519m in、tm ax=3.448m in、Cm ax=13.624μg/m l、AUC=221.667(μg.m in)/m l。结论门冬氨酸左氧氟沙星在大鼠体内的生物利用度比左氧氟沙星及其盐有所提高。     

术中液体治疗量对100例妇科腔镜患者术后恶心呕吐的观察

目的　比较术中补充30 ml/kg乳酸林格液与10 ml/kg乳酸林格液的妇科腔镜患者术后恶心呕吐的发生率。方法　选择100名ASAⅠ~Ⅱ级择期行妇科腔镜不孕查因的患者, 随机分为两组, Ⅰ组患者入手术室至手术结束出麻醉恢复室前共接受30 ml/kg 乳酸林格液, Ⅱ组患者入手术室至手术结束出麻醉恢复室前接受10 ml/kg乳酸林格液, 观察术后发生恶心呕吐的患者例数及需要补救止吐药例数。结果　两组患者年龄、体重、禁食时间、手术操作时间差异无显著性; 术后48h恶心呕吐发生率, 30 ml/kg组较10 ml/kg组明显降低(P<0 05),需要补救止吐药人数30 ml/kg组较10 ml/kg组明显降低(P<0 05)。结论　与输注10 ml/kg乳酸林格液相比,术中输注30 ml/kg乳酸林格液可以降低妇科腔镜患者术后恶心呕吐的发生率。     

The effect of two low-dose propofol infusions on the relationship between six-pulse transcranial electrical stimulation and the evoked lower extremity muscle response

BACKGROUND: Transcranial stimulation of the motor cortex using high-voltage electrical stimuli given in train is a method of monitoring the integrity of the motor pathways during thoracoabdominal aortic aneurysm surgery. The purpose of this study was to assess the relationship between the stimulus intensity and the corresponding amplitude of the myogenic motor evoked potential (tcMEP) in response to six-pulse transcranial electrical stimulation during two levels of low-dose propofol infusion and stable fentanyl/nitrous oxide anaesthesia. METHODS: Nine patients (37-78 yr) scheduled to undergo surgery on the thoracoabdominal aorta were studied. After achieving a stable anaesthetic state the output voltage was decreased with 50 V intervals from 350 V to 200 V during a target propofol infusion aimed at a plasma steady-state concentration of 0.7 microg x ml(-1) and increased with 50 V intervals from 200 V to 450 V during a target propofol infusion aimed at a plasma steady-state concentration of 1.4 microg x ml(-1). TcMEPs were recorded from the right tibialis anterior muscle. RESULTS: Doubling the target propofol infusion to 1.4 microg x ml(-1) resulted in a 30-50% decrease in tcMEP amplitude. The largest tcMEP amplitude using the six-pulse paradigm was found during a propofol infusion aimed at a plasma concentration of 0.7 microg x ml(-1) and demanded a stimulus output of 350 V, corresponding to a charge density of 7.5 microC x cm(-2) per phase. CONCLUSION: Doubling the target propofol infusion to 1.4 microg x ml(-1) provides less robust, but still recordable tcMEPs in response to six-pulse electrical stimulation. Safety guidelines are discussed.