Important factors improving outcome of young adults with acute lymphoblastic leukemia (ALL)

Four categories of important factors improving outcome of young adults and older adolescents with acute lymphoblastic leukemia (ALL) are biologic type, clinical trials, pediatric vs. adult treatment regimen, and psychosocial challenges. Overall, the outcome of ALL in the age group has improved and beginning to catch up with that in children, as exemplified by CALGB 10403, a pediatric treatment regimen. Each is dependent for optimum development, however, on progress in the others. Without adequate psychosocial support and improvement, progress in clinical trials, translational research, and pediatric regimen application is impaired. Without clinical trials, advances in translational research, optimal pediatric regimen application and adequate psychosocial research are restricted. Overall, we have improved the outcome and outlook of ALL in AYAs, as exemplified by CALGB 10403, but we and our current and future patients still have a long way to go.     

Upfront Consolidation Combining Yttrium-90 Ibritumomab Tiuxetan and High-Dose Therapy with Stem Cell Transplantation in Poor-Risk Patients with Diffuse Large B Cell Lymphoma

We evaluated the safety and efficacy of standard-dose yttrium-90 (Y⁹⁰) ibritumomab tiuxetan combined with high-dose BEAM (carmustine, etoposide, cytarabine, and melphalan) after first-line induction treatment in young patients with poor prognoses diffuse large B cell lymphoma (DLBCL) (clinicaltrials.gov: NCT00689169). Seventy-five high-risk (≥2 International Prognostic Index [IPI] factors) consecutive DLBCL patients (≤65 years old) in complete remission (CR) or partial remission (PR) after rituximab chemotherapy were treated with Y⁹⁰ ibritumomab tiuxetan and BEAM regimen followed by autologous stem cell transplantation (ASCT). The median follow-up was 34 months. Of the 75 patients, 71 underwent ASCT and were eligible for analysis. Median time to reach a neutrophil count of >500/μL and platelet count of >20,000/μL was 11 days. Mucositis ≥3 (51%) occurred in most patients. Other adverse events were similar to those seen with BEAM alone. The overall response rate was 86%; 59 patients (83%) achieved a CR or unconfirmed CR. The 2-year event-free survival (EFS), overall survival (OS), and disease-free survival were 79%, 83%, and 91%, respectively. Disease status (CR/PR) and positron emission tomography (PET) findings before transplantation did not predict treatment failure. The IPI (2 versus >2) and maximum tumor diameter of ≥10 cm at diagnosis appeared to be prognosis factors for OS but not for EFS. Adding Y⁹⁰ ibritumomab tiuxetan to BEAM is safe and does not increase transplantation-related toxicity. First-line consolidation with Y⁹⁰ ibritumomab tiuxetan and high-dose chemotherapy induced high rates of EFS and OS in poor-prognosis patients with DLBCL, regardless of PET status after induction treatment and warrants a randomized study.     

A phase I trial to assess the value of recombinant human granulocyte colony stimulating factor (r-MetHuG-CSF,filgrastim) in accelerating the dose rate of chemotherapy for intermediate and high-grade non-Hodgkin's lymphoma (NHL)

In a multi-centre phase I study we investigated the possibility of reducing the interval between courses of standard CHOP (cyclophosphamide 750 mg/mdoxorubicin 50 mg/mvincristine 2 mgs day 1, and prednisolone 40 mg/m² days 1–8) from 21 days to 15 days and then 10 days using granulocyte colony stimulating factor (r-MetHuG-CSF (Amgen)-filgrastim) to accelerate neutrophil recovery. Patients received CHOP followed by G-CSF 5 μg/kg s.c. from day 2 to the day before the next course (e.g. days 2–14 for the 15-day interval). A total of 28 patients with newly diagnosed intermediate grade or high grade NHL were studied. Four patients were studied at a 21-day interval, six patients were treated at a 15-day interval and subsequently six patients at a 10-day interval. Following analysis of this initial cohort, a further 12 patients were evaluated; four at the 15-day interval, and eight at the 10-day interval. No dose-limiting toxicity was seen in the four patients receiving 21-day CHOP. Dose-limiting toxicity was seen in 4/10 patients treated at the 15-day interval (M:F 7:3, median age 55·5, range 39–67 years). This consisted of infection in two patients, recurrent infection and debility in a third, and mucositis in a fourth. Seven patients experienced one or more infectious episodes requiring antibiotics (median number of episodes: 2, range 1–4). Fourteen patients (M:F 4:3, median age 47·5, range 25–63 years) were treated at the 10-day interval. Dose-limiting toxicity was seen in six patients. This consisted of severe mucositis in three patients, neutropenia and thrombocytopenia on two separate occasions in one patient, and steroid-induced gastritis in two patients. Nine patients had one or more documented infections (median: 2, range 1–3) requiring antibiotics, of which six were severe (WHO grade 3 or 4). One patient died of Pneumocystis carinii (PCP) pneumonia. In summary, G-CSF (filgrastim) will facilitate the shortening of the dosage interval between cycles of CHOP chemotherapy due to accelerated hematological recovery. However, non-hematological toxicity due to the shorter dosage interval is increased and infective episodes are frequent. © 1996 John Wiley & Sons, Ltd.     

Ag85B DNA/H37Ra序贯免疫效果的探讨

目的：初步探讨含结核分枝杆菌Ag85B成熟蛋白的DNA（pTB30m）和结核菌H37Ra序贯免疫小鼠产生的特异性免疫应答。方法：重组质粒pTB30m用碱裂解法制备后进行质量鉴定。用pTB30m肌注初次免疫小鼠2周后,H37Ra皮内加强免疫作为DNA-85B/H37Ra组,同时设定DNA-85B/BCG组、H37Ra组、BCG组及未免疫组。免疫4周或8周后,用ELISA法检测小鼠血清中抗PPD IgG抗体的水平和MTT法检测其脾淋巴细胞的刺激指数（SI）。结果：酶切鉴定pTB30m所含外源基因片段大小正确,并且纯度较高。DNA-85B/H37Ra组小鼠血清中抗PPD IgG水平、脾淋巴细胞的SI均显著高于未免疫组（P〈0.05）;其抗PPD IgG水平稍高于DNA-85B/BCG组、H37Ra组及BCG组,但它们之间无显著性差异（P〉0.05）;其脾淋巴细胞的SI显著高于H37Ra、BCG组（P〈0.05）,而与DNA-85B/BCG组比较,仅在4周有显著性差异。在DNA-85B/H37Ra组内,SI在4周显著高于8周（P〈0.05）,而血清中抗PPD IgG水平8周均显著高于4周（P〈0.05）。结论：DNA-85B/H37Ra序贯免疫策略可以诱导小鼠产生特异性体液免疫和细胞免疫,初步证明其免疫效果略优于BCG。     

IMRT联合TP方案治疗晚期食管鳞癌的临床疗效及对患者血清MMP2、TIMP2、nm23-H1及不良反应的影响

目的分析调强放射治疗(IMRT)联合TP方案治疗晚期食管鳞癌的临床疗效及对患者血清基质金属蛋白酶2(MMP2)、组织金属蛋白酶抑制剂2(TIMP2)、nm23-H1及不良反应的影响。方法选取晚期食管鳞癌患者80例为研究对象,按随机数字表法将其分为观察组(n=40,采用IMRT联合TP方案化疗)、对照组(n=40,单纯采用IMRT治疗),比较2组临床疗效、治疗前后血清MMP2、TIMP2、nm23-H1表达阳性率、局控率与生存情况及不良反应。结果观察组治疗有效率(85.00%)明显高于对照组(65.00%)(P<0.05)。治疗后2组血清MMP2表达阳性率下降,而TIMP2、nm23-H1表达阳性率上升,且观察组治疗后血清MMP2表达阳性率低于对照组,而TIMP2、nm23-H1表达阳性率高于对照组(P<0.05)。观察组治疗后1年、2年局控率高于对照组,但2组治疗后1年、2年生存率差异无统计学意义(P>0.05)。观察组白细胞减少、放射性食管炎发生率高于对照组(P<0.05),2组其他不良反应发生率差异无统计学意义(P>0.05)。结论晚期食管癌患者采用IMRT联合TP方案治疗可获得较好的疗效,对患者血清MMP2、TIMP2、nm23-H1有明显改善,但可能会较单纯IMRT治疗具有更多不良反应,需加以监测。     

CyclOBEAP (cyclophosphamide, vincristine, bleomycin, etoposide, doxorubicin, prednisolone) regimen with granulocyte colony-stimulating factor (G-CSF) for patients with aggressive non-Hodgkin's lymphoma: a pilot study. The Adult Lymphoma Treatment Study Group (ALTSG)

We conducted a multi-institutional collaborative study to examine the usefulness and safety of third-generation chemotherapy CyclOBEAP (cyclophosphamide, vincristine, bleomycin, etoposide, doxorubicin, prednisolone) combined with granulocyte colony-stimulating factor (G-CSF) in the treatment of aggressive non-Hodgkin's lymphoma (NHL). Subjects included patients with aggressive NHL who were 60 yr of age or younger and had been diagnosed as having a low-intermediate, high-intermediate, or high risk using the International Prognostic Index (IPI). A total of 24 patients were enrolled in the study between May 1997 and March 1998, including 9 low-intermediate-risk cases, 13 high-intermediate-risk cases and 2 high-risk cases. Although all 24 patients were originally enrolled in the study, one adult T-cell leukemia/lymphoma case was subsequently excluded. Thus, in the end, 23 cases were evaluated. Evaluation of the efficacy of therapy revealed complete remission in 20 patients (87%). Of these 20 patients, 8 were low-intermediate-risk cases (89%) and 12 were either high-intermediate- or high-risk cases (86%). Partial remission was achieved in 2 patients (8.7%). The 2-yr survival rate was 91.3%, and the 2-yr disease-free survival rate was 81.8%. Grade 3 or higher adverse reactions were granulocytopenia (87%), thrombocytopenia (17.4%) and liver dysfunction (4.3%). CyclOBEAP therapy has been associated with a high remission rate for aggressive NHL. When combined with G-CSF, a high relative dose intensity was maintained for each drug administered (0.94-0.97). Furthermore, although the observation period was short, both the survival rate and disease-free survival rate were good. Hence, we concluded that there were no problems associated with the procedure in terms of safety.     

NGF和CGRP对局灶性脑缺血再灌注后大鼠皮质CHOP蛋白表达的影响

目的探讨外源性神经生长因子(NGF)和降钙素基因相关肽(CGRP)对局灶性脑缺血再灌注后大鼠顶叶皮质神经元CHOP蛋白表达的影响及其作用机制。方法用线栓法制备大鼠大脑中动脉阻塞(MCAO)模型,应用免疫组织化学方法,免疫印迹法(W estern B lotting)测定CHOP蛋白表达;M etamoph图像分析系统对结果进行分析。结果假手术组大鼠顶叶皮质未见CHOP蛋白表达;缺血组CHOP蛋白在缺血再灌注后12 h明显表达,24 h达高峰,72 h显著下降,缺血组较假手术组CHOP蛋白表达显著增加(P<0.01);NGF组和CGRP组CHOP蛋白表达分别弱于缺血组(P<0.01);NGF和CGRP合用组CHOP蛋白表达明显弱于缺血组(P<0.01),也分别弱于NGF组和CGRP组(P<0.01)。结论NGF和CGRP能分别下调局灶性脑缺血再灌注大鼠顶叶皮质CHOP蛋白表达,联合应用则作用更强,二者对保护脑缺血神经元可能有协同作用。     

促红细胞生成素对横纹肌溶解大鼠急性肾损伤时内质网应激相关蛋白的影响

目的探讨促红细胞生成素(EPO)能否通过减轻内质网应激相关蛋白葡萄糖调节蛋白78(GRP78)和C/EBP同源蛋白(CHOP)的表达以及减轻横纹肌溶解致急性肾损伤。方法将SD大鼠随机分为4组:对照组(control,n=6)、单纯EPO组(EPO,n=18)、急性肾损伤组(AKI,n=18)和EPO干预组(AKI+EPO,n=18),EPO组、AKI组和AKI+EPO组又分为3个亚组,即1,6和24 h组(均为n=6)。在各自的时间点留取标本,检测血中尿素氮、肌酐和肌红蛋白水平;HE染色法观察肾脏病理;免疫组化观察GRP78和CHOP蛋白表达,实时荧光定量PCR检测GRP78和CHOP mRNA的表达。结果与对照组比较,AKI和AKI+EPO组大鼠尿素氮、肌酐和肌红蛋白水平升高,GRP78和CHOP蛋白及mRNA表达水平均显著上调(P0.05);AKI组肾脏结构出现损伤;与AKI组比较,AKI+EPO组6和24 h血肌酐水平,GRP78、CHOP蛋白和mRNA表达水平较同期均下降(P0.05)。结论 EPO可以通过影响横纹肌溶解致大鼠急性肾损伤时内质网应激相关蛋白的表达,发挥肾脏保护作用,其机制可能与调节未折叠蛋白反应有关。