Insights into oxazaphosphorine resistance and possible approaches to its circumvention.

The oxazaphosphorines cyclophosphamide, ifosfamide and trofosfamide remain a clinically useful class of anticancer drugs with substantial antitumour activity against a variety of solid tumors and hematological malignancies. A major limitation to their use is tumour resistance, which is due to multiple mechanisms that include increased DNA repair, increased cellular thiol levels, glutathione S-transferase and aldehyde dehydrogenase activities, and altered cell-death response to DNA damage. These mechanisms have been recently re-examined with the aid of sensitive analytical techniques, high-throughput proteomic and genomic approaches, and powerful pharmacogenetic tools. Oxazaphosphorine resistance, together with dose-limiting toxicity (mainly neutropenia and neurotoxicity), significantly hinders chemotherapy in patients, and hence, there is compelling need to find ways to overcome it. Four major approaches are currently being explored in preclinical models, some also in patients: combination with agents that modulate cellular response and disposition of oxazaphosphorines; antisense oligonucleotides directed against specific target genes; introduction of an activating gene (CYP3A4) into tumor tissue; and modification of dosing regimens. Of these approaches, antisense oligonucleotides and gene therapy are perhaps more speculative, requiring detailed safety and efficacy studies in preclinical models and in patients. A fifth approach is the design of novel oxazaphosphorines that have favourable pharmacokinetic and pharmacodynamic properties and are less vulnerable to resistance. Oxazaphosphorines not requiring hepatic CYP-mediated activation (for example, NSC 613060 and mafosfamide) or having additional targets (for example, glufosfamide that also targets glucose transport) have been synthesized and are being evaluated for safety and efficacy. Characterization of the molecular targets associated with oxazaphosphorine resistance may lead to a deeper understanding of the factors critical to the optimal use of these agents in chemotherapy and may allow the development of strategies to overcome resistance.     

从八纲辨证的形成看八纲在中医辨证学中的作用与地位

通过回顾八纲辨证问世的历史沿革,分析八纲在辨证学中的作用主要为辨证逻辑思维的方法学,对其它辨证方法起规范与指导作用;认为八纲在辨证学中的地位是首要的,是各种辨证方法的总纲.     

带锁滑动鹅头钉治疗粉碎性股骨转子间骨折的临床研究

为了总结分析运用自行研制的带锁滑动鹅头钉治疗粉碎性股骨转子间骨折的疗效,随机将69例Evan'sⅢ型、Ⅳ型的患者分为两组,一组采用自制带锁滑动鹅头钉治疗(观察组);一组采用DHS治疗(对照组).分别对两组患者的一般资料、手术资料及术后功能恢复情况进行评估比较.结果骨折平均愈合时间观察组为3.65±0.97个月,对照组为4.32±1.38个月,两组比较,术后9个月观察组患侧较健侧平均缩短0.82±0.36cm,对照组平均缩短1.08±0.51cm,两组比较差异有显著性意义(P＜0.05).观察组显效率91.1%,对照组显效率71.1%,两组比较,具有非常显著性差异(P＜0.01).提示带锁滑动鹅头钉治疗粉碎性股骨转子间骨折具有防止骨不连及各种畸形愈合.     

Pivotal study of iodine-131-labeled chimeric tumor necrosis treatment radioimmunotherapy in patients with advanced lung cancer.

PURPOSE: Tumor necrosis treatment (TNT) uses degenerating tumor cells and necrotic regions of tumors as targets for radioimmunotherapy. Previous studies in animal tumor models and clinical trials have demonstrated that when linked to the therapeutic radionuclide iodine-131, recombinant chimeric TNT antibody ((131)I-chTNT) can deliver therapeutic doses to tumors regardless of the location or type of malignancy. Therapeutic efficacy and toxicity of (131)I-chTNT in advanced lung cancer patients were studied in this pivotal registration trial. PATIENTS AND METHODS: Patients with advanced lung cancer were treated with systemic or intratumoral injection of (131)I-chTNT in eight oncology centers in China. The objective response rate (ORR) was assessed as the primary end point. RESULTS: All 107 patients who were entered onto the study and completed therapy had experienced treatment failure after prior radiotherapy or chemotherapy a mean of three times. The results showed an ORR of 34.6% (complete response, 3.7%; partial response, 30.8%; no change, 55.1%; and progressive disease, 10.3%) in all patients and 33% in 97 non-small-cell lung cancer patients. A biodistribution study demonstrated excellent localization of the radioactivity in tumors in both systemically and intratumorally injected patients. The most obvious adverse side effect was mild and reversible bone marrow suppression. CONCLUSION: Radioimmunotherapy with (131)I-chTNT was well tolerated and can be used systemically or locally to treat refractory tumors of the lung.     

胸苷酸合成酶在膀胱癌组织中的表达及意义

目的探讨膀胱癌（BC）中胸苷酸合成酶（TS）的表达对膀胱癌患者预后的影响。方法采用免疫组化S-P法检测50例膀胱癌石蜡标本中的TS蛋白表达情况。结果TS蛋白在膀胱癌与正常膀胱黏膜中的表达有显著性差异（P＜0．01），与肿瘤低分化、临床病理分期晚期、淋巴结转移密切相关（P＜0．05）。结论TS在膀胱癌中的表达增强可能是膀胱癌患者一个重要的预后指标。     

靶向Survivin基因的短发卡RNA在体内对U251细胞移植瘤的影响

Surivin基因属于凋死蛋白抑制因子（inhibitor of apoptosis,IAP）家族，具有抗细胞凋亡、促细胞增殖和促血管形成等多种生物学活性，其在脑胶质瘤发生和发展过程中的作用尚不完全明确，本研究结盟在观察稳定转染靶向Survivin基因的特异性短发卡RNA（shRNA）真核表达载体对人脑胶质母细胞瘤U251细胞裸鼠体内肿瘤生长和血管形成的影响。方法：将U251细胞，稳定转染Survivin基因shRNA真核表达载体pWHI-SR的U251-SR细胞，以及稳定转染空载体pWHI的U251-P细胞，分别接种于裸鼠背部皮下，建立人脑胶质瘤裸鼠皮下移植瘤模型，定期观察肿瘤生长情况，测定肿瘤体积、绘制肿瘤生长曲线，观察45天后处死动物、称瘤重，采用免疫组化SABC法检测Survivin、增殖细胞核抗原（proliferating cell muclear antigen，PCNA）以及八因子相关抗原（factor Ⅷ related antigen,FⅧRAg）在各组肿瘤标本中的表达，采用TUNEL法检测凋亡细胞，分别计算各组肿瘤标本的增殖指数（proliferative index,PI），凋亡指数（apoptotie index,AI）以及微血管密度（microvessel density,MVD）。结果：与U251、U251-SR组肿瘤标本，U251-SR组裸鼠肿瘤形成时间延迟，肿瘤生长缓慢，肿瘤体积及瘤重均明显减小（P〈0.01）；U251-P组裸鼠相丝，U251-SR组肿瘤标本Survivin蛋白表达明显下调：PI和MVD明显减少，AI明显升高（P〈0.001）。结论：靶向Survivin基因的sbRNA能够在体内明显抑制U251细胞的肿瘤生长和血管形成，Survivn基因可作为脑胶质瘤基因治疗的一个良好靶点，而RNA干涉（RNA interference,RNAi）技术可为脑胶瘤基因治疗的一个良好靶点，而RNA干涉（RNA interference，RNAi）技术可为脑胶质瘤的基因治疗提供新的重点手段。     

丹地剂对去卵巢高脂雌鼠雌激素受体α、βmRNA表达的影响

目的：观察丹地剂对去卵巢高脂雌鼠ER（α、β）mRNA表达的影响。方法：采用8周龄雌性大鼠建立去卵巢高脂模型，将24只大鼠随机分为三组：去卵巢＋丹地剂组（丹地组），去卵巢＋苯甲酸雌二醇组（雌二醇组），去卵巢＋生理盐水组（对照组），每组8只，丹地组每天每只大鼠灌饲丹地剂，含生药量6g，共6周；雌二醇组用苯甲酸雌二醇注射液按每鼠每3天1次皮下注射0．2mg，共12次；对照组给予生理盐水，早晚各一次灌胃，共6周。RT-PCR法分析ERα、ERβmRNA表达，应用全自动生化仪测血脂、放免法测FSH、E2，硝酸还原酶法测NO。结果：与对照组比较，丹地组能明显降低TC、TG，差异有显著性（P〈0．01），升高HDL—C（P〈0．05），E2上升（P〈0．05），NO明显上升（P〈0．01），ERα、ERβmRNA表达均明显高于对照组（P〈0．01）。结论：丹地剂具有调高去卵巢高脂大鼠主动脉ERα、ERβmRNA的表达及升高血清NO的作用，并可改善血脂，该作用为其在绝经女性防治动脉粥样硬化和冠心病等应用提供了依据。     

钙化型腰椎间盘突出症手术体会

钙化型腰椎间盘突出是一种特殊类型的腰椎间盘突出症，在病程较长或年龄较大的患者中并不少见。其临床表现及治疗都有一定特殊性，本文介绍作者近年来手术治疗钙化型腰椎间盘突出症的体会。     

Predictors of a positive baseline bone scan in breast cancer

The aim of this retrospective study was to determine the predictors of a positive bone scan in female patients with breast carcinoma. The participants were 126 females with newly diagnosed breast carcinoma and a baseline bone scan. Patients who had started treatment before their bone scan were excluded. Bone scans were assessed as ‘no metastases’ or ‘definite skeletal metastases’ without knowledge of the patient's predictor variables. Those with ‘possible metastases’ were correlated with other available imaging and clinical information, and recategorized as ‘no metastases’ or ‘definite skeletal metastases’. Results were compared with predictor variables. Significant predictors were increasing age, a higher histopathological grading and positive progesterone receptor status following a forward-stepwise logistic regression analysis. Axillary nodal status, tumour size and oestrogen receptor status did not correlate with a positive bone scan. Not every patient needs a staging bone scan. This study is important because it predicts the need for baseline scintigraphy for specific patients in whom skeletal metastases are more likely to be present or to develop. The findings are particularly valuable in times of worldwide resource scarcity and evolving surgical practice.