卵巢癌中P-gp与GST-π的表达对化疗耐药的预测价值

目的 探讨卵巢癌内在性的耐药机制及其对化疗反应的影响。方法 运用免疫组织化学方法对74例术前未经治疗的上皮性卵巢癌进行P－糖蛋白（P-gp)与谷胱甘肽S－转移酶－π（GST－π）检测。结果（1）30例正常卵巢组织中,P－gp与GST－π染色无一例阳性;而74例卵巢癌组织中,P－gp阳性者为14例（18．9％）,GST－π阳性者为55例（74．3％）,这两种指标的表达具有显著的相关性（P＜0．01）。（2）P－gp与GST－π的表达与临床分期、组织学类型及细胞分级等临床病理参数均无相关性（P均＞0．05）。（3）对首次术后有残余病变的27例患者进行化疗评价,P－pg阳性组与阴性组对化疗的反应率为0及57．1%,GST－π阳性组与阴性组对化疗的反应率为13．3％和83．3％,两组比较,差异有显著性（P＜0．01）。GST－π阳性对耐药的预测值为86．7％,GST－π阴性对化疗反应的预测值为83．3％。（4）P－gp与GST－π阳性组的生存率也显著低于阴性组（P＜0．01,P＜0．05）。结论 术前未经治疗的卵巢癌中有一定程度上存在着由P－gp与GST－π介导的内在性的耐药机制,P－gp与GST－π的表达能较好地预测化疗反应及耐药,对预后也有一定的判断价值。     

MDR1和GST-π在骨软组织肉瘤中的表达及其与化疗耐药的关系

目的 探讨多药耐药基因1（MDR1）和谷胱苷肽-S-转移酶-π（GST-π）在骨软组织肉瘤组织中的表达及其与化疗耐药的关系。方法应用荧光定量PCR（FQ-PCR）和流式细胞术（FCM）,分别在mRNA水平和蛋白水平检测MDR1和GST-π的表达;以四甲基偶氮唑盐法（MTT）法检测瘤组织对阿霉素（ADM）、顺铂（DDP）、5-氟脲嘧啶（5-Fu）、丝裂霉素C（MMC）、氮烯咪胺（DTIC）、长春新碱（VCR）和氨甲喋呤（MTX）的敏感性。结果 患者瘤组织对ADM、DDP、5-Fu、MMC、lyric、VCR和MTX的不敏感率分别为41．18％、17．65％、47．06％、50．00％、76．47％、61．76％和52．94％。瘤组织中P-gp和GST-π相对荧光强度的表达分别为1．54和为2．58。X^2分析显示,P-gp的表达与ADM耐药、GST-π的表达与ADM、DDP、MMC耐药均呈正相关（P〈0．05）。MDR1和GST-π的表达与患者年龄、性别、病理类型、肿瘤大小均无关（P〉0．05）。GST-π在术前化疗患者的瘤组织中表达升高,且术前表达升高者,术后复发率高于术前GST-π表达水平较低者（P〈0．05）。结论 骨软组织肉瘤患者的MDR1、GST-π表达及化疗敏感性存在个体差异;化疗引起GST-π表达上调;原发GST-π高表达是骨软组织肉瘤耐药的主要机制,并与患者预后不良有关。     

GSTP1、MRP mRNA表达与胃癌辅助化疗预后的关系

[目的]探讨谷胱甘肽S转移酶（GST）P1、多药耐药相关蛋白（MRP）mRNA表达与胃癌铂类药物辅助化疗预后的关系。[方法]经病理学确诊的胃癌患者66例，采用5-Fu／铂类药物为主的方案进行辅助化疗。采用反转录-聚合酶链反应（RT—PCR）检测胃癌组织中GSTP1和MRP mRNA表达水平。[结果]66例胃癌患者中，MRP和GSTP1 mRNA的表达水平中位值分别为1．214和0．434。GSTP1 mRNA高表达组无复发生存率和总生存率均显著低于低表达组（P〈0．05）。调整年龄、性别、分化程度、淋巴结状态、分期后，多因素分析结果显示GSTP1 mRNA水平是影响患者预后的独立危险因素（P〈0．05），而MRP表达水平与预后无关（P〉0．05）。[结论]GSTP1 mRNA表达水平可以在一定程度上判断术后胃癌患者接受铂类药物化疗后的预后。     

A change in microsatellite instability caused by cisplatin-based chemotherapy of ovarian cancer

To clarify the mechanism of acquired CDDP resistance in ovarian cancer, we compared the microsatellite instability (MSI) by the amplification of 10 microsatellite loci and immunohistochemical detection of hMSH2 and hMLH1 expression between the primary resected tumours and the secondary resected residual tumours after 5 or 6 courses of CDDP-based chemotherapy in the 24 cases of ovarian cancer. Of the 24 primary resected tumours, 9 (37.5%) showed MSI (7 cases of MSI-L, 2 cases of MSI-H), while 15 (72.5%) were microsatellite stable tumours (MSS). The primary tumours also had MSI in the residual tumours after CDDP-based chemotherapy. However, all of the cases with MSS in the primary resected tumours exhibited MSI (2 cases were MSI-L, and 13 cases were MSI-H) in the residual tumours after CDDP-based chemotherapy (P< 0.001). Furthermore, 11 (73.3%) of these cases which changed from MSS to MSI also had a change in the expression of hMLH1 from positive to undetectable (P< 0.001). Our data suggest that tumour MSI changes during CDDP-based chemotherapy, and that the loss of hMLH1 expression is one of the factors that has the greatest effect on this transformation.     

宫颈癌术后脾多肽注射液联合化疗的临床疗效观察

目的:观察脾多肽注射液对宫颈癌术后化疗患者的毒副反应、免疫功能变化、生活质量的影响.方法:将60例宫颈癌术后需要化疗的患者随机分为试验组(化疗联合使用脾多肽)及对照组(单纯化疗),每组30例,分别检测患者T淋巴细胞亚群、毒副反应及KPS评分.结果:试验组较对照组的毒副反应发生率明显降低,T淋巴细胞亚群较对照组有显著改善,KPS评分增加(P＜0.05).结论:宫颈癌术后化疗中应用脾多肽注射液,不但可以减轻化疗的毒副反应,而且可调节免疫功能,改善患者生活质量.     

Efficacy of postoperative adjuvant therapy for resected non-small cell lung cancer--an evidence-based review

Efficacy of postoperative adjuvant therapy for non-small cell lung cancer (NSCLC) was examined based on recent evidence. In 2003, when a clinical guideline for lung cancer had been published, the efficacy of postoperative adjuvant therapy had not been established. However, results of randomized controlled studies and metaanalysis on the efficacy of postoperative chemotherapy, platinum-based chemotherapy or UFT, were presented at the annual meetings of the American Society of Clinical Oncology (ASCO) held in 2003-2005. Thus, postoperative adjuvant chemotherapy for completely resected NSCLC cases is now a standard care of therapy.     

Treatment of recurrent ovarian cancer]

Significant prolongation of survival time among the patients with advanced ovarian cancer has been brought under the development of surgery and chemotherapy, but even those with clinical remission shows sometimes recurrence. For the recurrent ovarian cancer patients at present there are no definite strategy to treat the recurrent cases. Under these circumstance, we have reviewed the current treatment of cytoreductive surgery and chemotherapy for the recurrent cases. 1) surgical treatment Generally, in the cases of recurrent ovarian cancer, cytoreductive surgery is required to minimize the residual tumour in the abdomen. But sometimes we can find the distant metastasis including liver, lung, and lymph node. This means that surgery is not sufficient for control of recurrent tumor. Further adjuvant chemotherapy will be required to control metastatic tumors. 2) chemotherapy After the detail assessment of the initial treatment of cases, at first we should think about retreatment with CDDP-based regimen and secondly about dose-intensification of CDDP or CBDCA for the CDDP-resistant cases. And as combination regimens, topoisomerase inhibitors, etoposide or CPT-11 are also preferable to use, alkylating agents such as ifosfamide, 5-fluorouracil, and some current trials with new drug, taxol are effective for recurrent cases. In conclusion, further active chemotherapy using platinum compounds, topoisomerase inhibitors, taxol will be achieved for the control of the recurrent cases of ovarian cancer.     

Postoperative adjuvant therapy for completely resected early-stage non-small cell lung cancer

Consensus on adjuvant therapy for completely resected non-small cell lung cancer until 2002 was as follows. (1) There was no significant impact of postoperative adjuvant chemotherapy based on meta-analysis and previous clinical trials. (2) Confirmatory studies are necessary in large-scale prospective clinical trials. However, recent mega trials have introduced epoch-making changes for postoperative adjuvant chemotherapy in clinical practice since ASCO 2003. The effectiveness of UFT in N0 patients was confirmed. Patients with completely resected stage I non-small cell lung cancer, especially T2N0 adenocarcinoma, will benefit from adjuvant chemotherapy with UFT. The results of the International Adjuvant Lung Trial (IALT) have confirmed the meta-analysis in 1995. Also, both the JBR10 and Cancer and Leukemia Group B (CALGB) 9633 studies have also confirmed positive IALT results of the benefit for postoperative platinum-based chemotherapy in completely resected non-small cell lung cancer. Adjuvant chemotherapy for pathological stage IB to II, completely resected non-small cell lung cancer is standard care based on clinical trials. UFT showed the strongest evidence for IB in Japan. Platinum doublet chemotherapy with third-generation anticancer agents is also recommended. Adjuvant chemotherapy should be offered as standard care to patients after completely resected early stage non-small cell lung cancer. However, there is no evidence of the feasibility and efficacy for adjuvant chemotherapy with the platinum-based regimen in Japan. Careful management should be necessary in such treatment.The ASCO-JSCO Joint Symposium was held in Kyoto, Japan, on October 29, 2004.     

Heat shock protein 70 as a predictive marker for platinum-based adjuvant chemotherapy in patients with resected non-small cell lung cancer

Objectives

Although adjuvant platinum-based chemotherapy improves survival in completely resected non-small cell lung cancer (NSCLC), its effect is limited. We evaluated whether the expression of heat shock protein 70 (Hsp70) is associated with clinical outcomes in patients with completely resected NSCLC who were treated with or without adjuvant platinum-based chemotherapy.

Patients and methods

Patients who underwent curative resection for NSCLC and diagnosed as stage IIA through IIIA were included. Immunohistochemical staining for Hsp70 was performed on surgical specimens and survival rates were compared by Hsp70 expression and adjuvant platinum-based chemotherapy.

Results

Of 327 enrolled patients, Hsp70 expression was positive in 220 (67.3%). For patients who did not receive adjuvant chemotherapy, Hsp70 expression did not significantly affect survival. However, for patients who received adjuvant chemotherapy, those with Hsp70-positive tumors had a longer disease-free survival outcome than cases with Hsp70-negative tumors (not reached vs. 27.3 months; P = 0.002), although there was no significant difference in overall survival (97.0 vs. 58.9 months, P = 0.080). In the adjuvant chemotherapy group, multivariate modeling showed that patients with Hsp70-postitive tumors had a lower risk of recurrence and death after adjusting for age, sex, performance status, pathologic stage, and histological type (disease-free survival: adjusted hazard ratio, 0.537; 95% CI, 0.362–0.796; P = 0.002; overall survival: adjusted hazard ratio, 0.663; 95% CI, 0.419–1.051; P = 0.080).

Conclusion

Hsp70 is a positive predictive factor in completely resected NSCLC with received platinum-based adjuvant chemotherapy.     

Expression of ERCC1, MSH2 and PARP1 in Non-small Cell Lung Cancer and Prognostic Value in Patients Treated with Platinum-based Chemotherapy

Purpose: To evaluate the prognostic value of the expression of excision repair cross-complementation groupl (ERCC1), MutS protein homolog 2 (MSH2) and poly ADP-ribose polymerase 1 (PARP1) in non-small-cell lungcancer patients receiving platinum-based postoperative adjuvant chemotherapy. Methods: Immunohistochemistrywas applied to detect the expression of ERCC1, MSH2 and PARP1 in 111 cases of non-small cell lung cancerparaffin embedded surgical specimens. Through og-rank survival analysis, we evaluated the prognostic valueof the ERCC1, MSH2, PARP1 and the related clinicopathological factors. COX regression analysis was used todetermine whether ERCC1, MSH2 and PARP1 were independent prognostic factors. Results: In the enrolled111 non-small cell lung cancer patients, the positive expression rate of ERCC1, MSH2 and RARP1 was 33.3%,36.9% and 55.9%, respectively. ERCC1 (P<0.001) and PARP1 (P=0.033) were found to be correlated with thesurvival time while there was no correlation for MSH2 (P=0.298). Patients with both ERCC1 and PARP1 negativecancer had significantly longer survival time than those with ERCC1 (P=0.042) or PARP1 (P=0.027) positivealone. Similalry, the survival time of patients with both ERCC1 and PARP1 positive cancer was shorter thanthose with ERCC1 (P=0.048) or PARP1 (P=0.01) positive alone. Conclusion: Patients with ERCC1 or PARP1negative non-small cell lung cancer appear to benefit from platinum-based postoperative adjuvant chemotherapy.     

右肺PN2非小细胞肺癌术后无复发转移及预后因素探讨

 目的分析影响右肺PN2非小细胞肺癌术后无复发转移及预后的因素,探讨最佳治疗方案。方法分析1999年9月～2002年3月24例术后病理确诊的右肺PN2非小细胞肺癌,随机分为辅助化疗组(术前或术后)与直接手术组,手术均为完全性切除,采用右肺叶或右全肺+系统性纵隔淋巴结清扫术。术后标本采用免疫组化法行抑癌基因p53,癌基因HER2,表皮生长因子受体(EGFR)等基因表达检测。分析病理分型,手术方式,术前辅助治疗,基因表达,淋巴结转移区域,肺门淋巴结转移,最高纵隔淋巴结转移等因素对预后的影响。结果24例患者2年生存率46%。辅助化疗,EGFR为影响术后无复发转移的重要因素。KaplanMeier生存分析显示辅助化疗与生存有影响,多变量COX回归分析未发现影响预后的独立因素。结论以手术为主的综合治疗是右肺PN2非小细胞肺癌较好的治疗模式。EGFR高表达与术后复发转移有关,对此类患者术后是否应加用靶点治疗需进一步的研究。     

ＢＲＣＡ１表达与术后非小细胞肺癌化疗及预后关系的研究

目的　探讨非小细胞肺癌（ＮＳＣＬＣ）组织中人乳腺癌易感基因１（ＢＲＣＡ１）的表达与铂类化疗远期疗效之间的关系,并观察该指标对患者预后的影响。方法　应用免疫组化染色法对６３例ＮＳＣＬＣ手术切除标本的石蜡包埋组织中ＢＲＣＡ１蛋白表达进行测定,并与相关临床病理指标共同纳入生存分析。结果　ＮＳＣＬＣ组织中ＢＲＣＡ１阳性表达率为４６.０％;ｐＴＮＭ分期、ＢＲＣＡ１表达为影响术后ＮＳＣＬＣ预后的独立因素,ＢＲＣＡ１阴性表达者的术后生存优于阳性表达者;ＢＲＣＡ１阴性表达者术后使用铂类药物辅助化疗组的生存时间优于术后未行辅助化疗组。结论　ＢＲＣＡ１表达与化疗疗效及术后生存呈负相关,可作为术后ＮＳＣＬＣ铂类化疗敏感性及生存预测的指标。     

Elevated expression of glutathione S-transferase pi and p53 confers poor prognosis in head and neck cancer patients treated with chemoradiotherapy but not radiotherapy alone

PURPOSE: To examine the prognostic significance of expression of glutathione s-transferase pi (GST-pi) and p53 in patients treated with radiation alone for locally advanced head and neck cancer [Radiation Therapy Oncology Group (RTOG), trial 9003] or radiation +/- concomitant chemotherapy as postoperative adjuvant therapy (RTOG trial 9501). EXPERIMENTAL DESIGN: Immunohistochemical staining for p53 and GST-pi was done on tissue samples from 393 patients in RTOG 9003 and 142 patients in RTOG 9501. Kaplan-Meier survival analyses were done. RESULTS: Patients who had low expression of both markers had longer survival than patients who had high expression of both markers. In trial 9003, median survival was 2.4 years for patients with low expression of both markers versus 1.4 years for patients who had elevated expression of both markers (P = 0.07). These differences were highly significant in trial 9501 and were accounted for by the chemotherapy treated arm. In this group, patients with low expression of both markers had a median survival of 7.0 years compared with 1.4 years for patients with elevated expression of both markers (P = 0.006). In both trials, black patients had lower survival rates than did white patients and there was a trend toward higher expression of both markers in blacks compared with whites. CONCLUSION: Given the poor outcome of chemoradiotherapy treatment patients with elevated expression of both p53 and GST-pi, these patients may not be appropriate candidates for chemoradiotherapy based on standard protocols. Some of the adverse outcome for black patients in both studies may be attributed to elevated expression of p53 and GST-pi.     

老年乳腺癌患者的临床特点及治疗模式的研究

目的：总结老年乳腺癌患者的临床特点,分析其对所采取治疗模式的影响。方法根据患者所处的年龄阶段（60~69岁和≥70岁）将178例接受治疗的老年乳腺癌患者分为A组（103例）和B组（75例）。分析两组患者所采取的治疗方式、疗效及不良反应等差异。结果 A组进行术后辅助化疗的患者比例明显高于B组,差异有统计学意义（P<0.05）;年龄在60~69岁、雌性激素受体阴性及淋巴结转移阳性是术后采取辅助化疗的影响因素（P<0.05）;A组的总有效率高于B组,但差异无统计学意义（P>0.05）;两组均无严重不良反应发生。结论年龄在60~69岁的乳腺癌患者术后宜采取辅助化疗,≥70岁的乳腺癌患者可采取内分泌辅助治疗。     

RCN3 Expression Indicates Prognosis in Colorectal Cancers

Background: Reticulocalbin 3 (RCN3) has been associated with several malignancies. However, its role in colorectal cancer (CRC) remains controversial. Thus, this study aimed to investigate the role of RCN3 in CRC prognosis. Methods: The clinical significance of RCN3 expression in CRC was evaluated in a large cohort of 483 patients. Normal tissues, carcinoma, para-carcinoma, adenoma, and metastatic tissues were evaluated by immunohistochemistry. We investigated the association between RCN3 expression and CRC occurrence in tumors and other tissues. Prognostic factors were also evaluated by Kaplan-Meier survival analysis and the Cox regression model. Results: RCN3 was significantly overexpressed in CRC and metastatic tissues. Patients with high RCN3 expression had shorter disease-free survival than those with low RCN3 expression. Multivariate Cox regression analysis showed a risk ratio HR], 0.607; confidence interval [CI], 0.362–1.016; p < 0.05 after adjusting for other prognostic factors. HighRCN3 expression was also associated with a worse chemotherapeutic response in the colon (p < 0.01) or rectal (p < 0.05) cancer patients who received adjuvant chemotherapy. Conclusion: RCN3 expression level is an independent risk factor and serves as a prognostic biomarker for CRC. High RCN3 expression predicts poor prognosis and chemotherapeutic response.     

Impact of single nucleotide polymorphisms in glutathione S transferase gene GSTP1 in the treatment with oxaliplatin based chemotherapy

Oxaliplatin has been the main treatment of choice in colorectal cancer in advanced settings. However, cellular mechanisms for the uptake, intracellular distribution and efflux of oxaliplatin are unknown. GST(glutathione S transferase)is member of a superfamily of metabolic enzymes that play an important role in the cell defense system. Current data suggest that GST-pi is associated with increased resistance to platinum-based chemotherapy. Specific roles for the single nucleotide polymorphisms in GST-pi gene GSTP1 in the treatment with oxaliplatin based chemotherapy, have been demonstrated in recent years.     

谷胱甘肽硫转移酶—π在人食管鳞癌中的表达

目的 研究谷胱甘肽硫转移酶－π（GST-π）在人食管鳞癌中的表达及其与食管鳞癌临床病理的相互关系。方法 应用免疫组织化学方法和sandwich酶联免疫吸附测定法（enzyme linked immunosorbent assay,ELISA)对143例食管鳞癌石蜡标本和43例食管鳞癌患者的术前及术后血清标本进行检测。结果 GST－π在人食管鳞癌组织及癌旁上皮的表达阳性率分别为58．7％和79．6％,差异有极显著性（P＜0．01）。GST－π在高分化食管鳞癌中的表达显著高于其在低分化食管鳞癌中的表达（P＜0．05）。GST－π在高分化食管鳞癌中的表达显著高于其在低分化食管鳞癌中的表达（P＜0．05）。GST－π的表达与食管鳞癌的淋巴结转移、TNM分期及患者术后生存率差异无显著性（P＞0．05）。食管鳞癌患者术前和术后血清GST－π含量平均值均显著高于正常人GST－π含量平均值（P＜0．05,P＜0．025）;食管鳞癌患者术后血清GST－π含量平均值低于术前血清GST-π含量平均值,但两者差异无显著性（P＞0．05）。结论 GST－π是食管鳞癌的一个有应用价值的标志物,其与食管鳞癌的发生有关,可能是食管上皮癌变前的一个早期标志物。     

Meta-analysis of postoperative adjuvant chemotherapy with tegafur-uracil in non-small-cell lung cancer.

PURPOSE: Recent clinical trials have shown the efficacy of platinum-based adjuvant chemotherapy for completely resected non-small-cell lung cancer (NSCLC). In Japan, many clinical trials of adjuvant chemotherapy with tegafur-uracil (UFT) have been conducted, and some trials showed positive results while others showed negative results. Thus, we performed a meta-analysis to assess the efficacy of postoperative adjuvant chemotherapy with UFT in NSCLC. METHODS: Among nine trials of postoperative adjuvant UFT-containing chemotherapy, six trials comparing surgery alone with surgery plus UFT were identified. Of six trials, two were three-arm trials including cisplatin-based chemotherapy followed by UFT, and data from that arm were not included in the meta-analysis. RESULTS: Of 2,003 eligible patients, most (98.8%) had squamous cell carcinoma or adenocarcinoma, and most had stage I disease; the tumor classification was T1 in 1,308 (65.3%), T2 in 674 (33.6%), and the nodal status was N0 in 1,923 (96.0%). The two treatment groups did not differ significantly in major prognostic factors. The median duration of follow-up was 6.44 years. The survival rates at 5 and 7 years were significantly higher in the surgery plus UFT group (81.5% and 76.5%, respectively) than in the surgery alone group (77.2% and 69.5%, respectively; P = .011 and .001, respectively). The overall pooled hazard ratio was 0.74, and its 95% CI was 0.61 to 0.88 (P = .001). CONCLUSION: This meta-analysis showed that postoperative adjuvant chemotherapy with UFT was associated with improved 5- and 7-year survival in a Japanese patient population composed primarily of stage I adenocarcinoma patients.