cyclin D 1 表达对cN2 口腔鳞癌患者TPF 诱导化疗的预测性研究*

目的：探讨cyclinD1 在局部晚期口腔鳞癌患者中预后价值以及能否作为多西他赛联合顺铂、5- 氟尿嘧啶（TPF）诱导化疗的预测生物标志物。方法：2008年3 月至2010年12月上海交通大学医学院附属第九人民医院局部晚期口腔鳞状细胞癌患者256 例行TPF 诱导化疗的前瞻性随机临床试验为研究对象。随机分为试验组（术前TPF 诱导化疗+ 手术+ 术后放疗）和对照组（手术+ 术后放疗）。 采用免疫组织化学法检测患者活检标本中cyclinD1 蛋白的表达情况,分析cyclinD1 表达与行TPF 诱导化疗患者预后的关系。结果：256 例患者中232 例符合cyclinD1 检测条件,其中cyclinD1 低表达者比高表达者有较高的总生存率（P =0.001）、无病生存率（P = 0.003）、无局部复发生存率（P = 0.004）和无远处转移生存率（P = 0.001）。 试验组和对照组之间的患者预后无差异,cyclinD1 表达水平与患者行TPF 诱导化疗后的疗效无显著相关性,但cN2 患者中cyclinD1 高表达者可从TPF 诱导化疗在总生存率（P = 0.024）和无远处转移生存率（P = 0.024）中获益。结论：cyclinD1 可作为局部晚期口腔鳞癌患者的预后生物标志物,cyclinD1 高表达的cN2 口腔鳞癌患者可从TPF 诱导化疗中获益。     

新辅助化疗在老年中晚期口腔鳞状细胞癌治疗中的临床意义

目的：探讨分析新辅助化疗在治疗老年中晚期口腔鳞状细胞癌中的临床效果。方法收集46例老年中晚期口腔鳞状细胞癌行新辅助化疗患者作为研究组,选取同期收治的60例未行新辅助化疗老年中晚期口腔鳞状细胞癌患者作为对照组,统计入组患者新辅助化疗后临床有效率、病理有效率,对比新辅助化疗前后细胞凋亡及增殖指数,肿瘤组织Ki-67、EGFR、p53及RARβ的表达变化,并分析新辅助化疗后手术及生存情况,比较两组生存率差异。结果研究组化疗后临床有效率和病理有效率分别为80.43%和69.57%。化疗后细胞凋亡指数明显高于化疗前,细胞增殖指数低于化疗前,差异均具有统计学意义（P=0.007、0.015）。化疗后Ki-67、EGFR、p53均低于化疗前,RARβ高于化疗前,差异均具有统计学意义（P=0.004、0.027、0.021、0.013）。研究组患者的中位生存期为28个月,新辅助化疗3、4个疗程患者远期生存率高于2个疗程患者,差异有统计学意义（P=0.021、0.017）。3个疗程和4个疗程化疗患者远期生存率比较差异无统计学意义（P=0.117）。对照组患者中位生存期为17个月,两组患者生存率差异具有统计学意义（P=0.015）。结论新辅助化疗可从多方面改善老年中晚期口腔鳞状细胞癌的临床效果,应成为其综合治疗的重要组成部分。     

口腔鳞癌卡铂,平阳霉素,氨甲喋呤术前诱导化疗的临床研究

目的：探讨卡铂,平阳霉素,氨甲喋呤术前诱导化疗对口腔鳞癌的临床效应。方法：45例32-72岁的口腔鳞癌患者,采用卡铂,平阳霉素,氨甲喋呤术前诱导化疗1个周期,化疗后3-5天,对常规检查正常者再进行手术治疗,对其近期疗效进行评价,随访3-5年。结果：诱导化疗后80%的患者肿瘤缩小50%以上,39例手术患者近期疗效评价中,完全缓解1例,部分缓解14例,无效16例;术后3、5年生存率分别为71.2%、66.7%。结论：卡铂,平阳霉素,氨甲喋呤用于口腔鳞癌术前诱导化疗,具有较满意的临床效果,与相应的手术相结合可以提高患者远期生存率。     

Survivin expression in oral squamous cell carcinoma

A series of 110 cases of oral squamous cell carcinoma (SCC) together with six lymph node and one distant metastatic lesions was analysed for expression of survivin, a recent apoptosis inhibitor, by immunohistochemistry and Western blotting. In total, 91 cases (82.7%) of carcinoma and all metastasis (seven cases, 100%) were positive for survivin expression, with weighted survivin scores ranging from 1 to 4. In contrast, normal oral epithelium did not express survivin. There was no significant correlation between survivin expression and age, sex, tumour size, the presence of lymph node and distant metastases. Survivin expression was increased in poorly differentiated tumours, even if differences were not statistically significant. In contrast, when analysed for prognostic significance, patients with low survivin expression had statistically significant better survival rates than the group with high survivin expression (P<0.05). These data suggest that survivin expression may identify cases of oral SCC with more aggressive and invasive phenotype.     

Long-term results of a randomized phase III trial of TPF induction chemotherapy followed by surgery and radiation in locally advanced oral squamous cell carcinoma

Previously, we conducted a randomized phase III trial of TPF (docetaxel, cisplatin, and 5-fluorouracil) induction chemotherapy in surgically managed locally advanced oral squamous cell carcinoma (OSCC) and found no improvement in overall survival. This study reports long-term follow-up results from our initial trial. All patients had clinical stage III or IVA locally advanced OSCC. In the experimental group, patients received two cycles of TPF induction chemotherapy (75mg/m² docetaxel d1, 75mg/m² cisplatin d1, and 750mg/m²/day 5-fluorouracil d1-5) followed by radical surgery and post-operative radiotherapy; in the control group, patients received upfront radical surgery and post-operative radiotherapy. The primary endpoint was overall survival. Among 256 enrolled patients with a median follow-up of 70 months, estimated 5-year overall survival, disease-free survival, locoregional recurrence-free survival, and distant metastasis-free survival rates were 61.1%, 52.7%, 55.2%, and 60.4%, respectively. There were no significant differences in survival rates between experimental and control groups. However, patients with favorable pathologic responses had improved outcomes compared to those with unfavorable pathologic responses and to those in the control group. Although TPF induction chemotherapy did not improve long-term survival compared to surgery upfront in patients with stage III and IVA OSCC, a favorable pathologic response after induction chemotherapy may be used as a major endpoint and prognosticator in future studies. Furthermore, the negative results observed in this trial may be represent type II error from an underpowered study. Future larger scale phase III trials are warranted to investigate whether a significant benefit exists for TPF induction chemotherapy in surgically managed OSCC.     

Emerging personalized approaches for the management of advanced urothelial carcinoma

Urothelial carcinoma of the bladder comprises a spectrum of illnesses ranging from nonmuscle-invasive to muscle-invasive to advanced/metastatic disease. Each of these clinical states is characterized by a unique pathogenesis, prognosis and approach to treatment. However, given the heterogeneity of urothelial carcinoma, differences in biology and outcomes exist not only among these clinical states but also within each state. Personalized medicine, also commonly referred to as individualized or stratified medicine, offers the potential to optimize treatment for a given patient, based on the ability to accurately predict prognosis, response to treatment and tolerability of treatment. This review will discuss recent efforts, current challenges and future opportunities, for the personalized management of urothelial carcinoma.     

口腔鳞癌卡铂,平阳霉素,氨甲喋呤术前诱导化疗的临床研究

目的:探讨卡铂,平阳霉素,氨甲喋呤术前诱导化疗对口腔鳞癌的临床效应.方法:45例32-72岁的口腔鳞癌患者,采用卡铂,平阳霉素,氨甲喋呤术前诱导化疗1个周期,化疗后3-5天,对常规检查正常者再进行手术治疗,对其近期疗效进行评价,随访3-5年.结果:诱导化疗后80%的患者肿瘤缩小50%以上,39 例手术患者近期疗效评价中,完全缓解 1例,部分缓解14例,无效16例;术后3、5年生存率分别为71.2%、66.7%.结论:卡铂,平阳霉素,氨甲喋呤用于口腔鳞癌术前诱导化疗,具有较满意的临床效果,与相应的手术相结合可以提高患者远期生存率.     

口腔鳞癌细胞增殖和细胞凋亡的相关性研究

目的：通过观察口腔鳞癌中细胞增殖和细胞凋亡之间的关系,探讨细胞凋亡在口腔鳞癌发生中的作用。方法：利用脱氧核糖核酸末端转移酶介导的dUTP缺口末端标记（TUNEL）技术及增殖细胞核抗原（PC—NA）免疫组织化学染色,对69例（维族36例、汉族33例）口腔鳞癌中的凋亡细胞和增殖细胞进行原位观察和比较。结果：口腔鳞癌不同组织学分级比较,高分化口腔鳞癌与中低分化口腔鳞癌之间增殖指数及凋亡指数均有显著性差异（P〈0．05）,不同部位的口腔鳞癌其增殖指数无显著差异,而舌癌组凋亡指数低于唇癌组和牙龈癌组（P〈0．05）,增殖指数与凋亡指数在口腔鳞癌中呈负相关关系（r=-0．663,P〈0．05）。结论：口腔鳞癌癌变过程不仅存在活跃的细胞增殖,而且存在细胞凋亡之异常,细胞增殖和细胞凋亡平衡失调在舌癌发病中可能起重要作用。     

The emerging era of personalized therapy in squamous cell carcinoma of the head and neck

Over the past three decades there has been a move toward organ preservation protocols in the management of locally advanced mucosal head and neck squamous cell carcinomas (LAHNSCC) with combinations of radiotherapy (RT), chemotherapy and, more recently, biological agents. Current standard chemoradiation strategies have reached the upper limits of toxicity. In addition, the traditional one size fits all approach of grouping patients according to traditional clinicopathological features fails to take into account the vast underlying biological heterogeneity of tumors and their host. A number of recent advances such as highly conformal RT, molecular profiling and targeted agents, and improvements in treatment response assessment have set the scene for a fundamental paradigm shift toward greater tailoring of therapy with the aim of improving outcomes and reducing the burden of survivorship. This review focuses on the recognition of the prognostic value of tumor human papillomavirus (HPV) status, the incorporation of biologically targeted therapies and the evolving role of molecular imaging in predicting tumor response and prognosis in the curative management of LAHNSCC.     

钆血卟啉单甲醚介导的光动力疗法治疗口腔舌鳞状细胞癌移植瘤的实验研究

目的:探讨钆血卟啉单甲醚（gadolinium coordinated hemetoporphyrin monomethyl ether,Gd-HMME）介导的光动力疗法（photodynamic therapy,PDT）对裸鼠口腔舌鳞状细胞癌（oral tongue squamous cell carcinoma,OTSCC）移植瘤的治疗效果,为今后的临床治疗提供理论依据。方法:选取36只BALB/c-nu裸鼠随机分为4组,分别为对照组、PDT组、Gd-HMME组和Gd-HMME-PDT组,每组9只。治疗后定期测量裸鼠体重以及肿瘤体积,14 d后各组随机处死裸鼠6只,计算抑瘤率和生命延长率,行苏木精-伊红（hematoxylin-eosin staining,HE）染色后病理形态学观察,评估Gd-HMME-PDT对移植瘤的治疗效果。结果:实验结果显示,各处理组的肿瘤体积均小于对照组,Gd-HMME-PDT组肿瘤体积减小最明显（P＜0.01）;PDT组、Gd-HMME组、Gd-HMME-PDT组的抑瘤率分别为3.17%、6.13%、59.62%。HE染色可见Gd-HMME-PDT组肿瘤细胞坏死和空泡性变,对照组及PDT组、Gd-HMME组均未见明显改变;PDT组、Gd-HMME组、Gd-HMME-PDT组的生命延长率分别为2.82%、7.04%、73.24%。结论:Gd-HMME-PDT对口腔舌鳞状细胞癌移植瘤的生长具有抑制作用,并且可以延长裸鼠的生存时间。     

Development and validation of a seven-immune-feature-based prognostic score for oral squamous cell carcinoma after curative resection

Immune infiltrates have been increasingly recognized as robust prognostic factors for human cancer. Here, we developed and validated a seven-immune-feature-based prognostic score (7IFBPS) for patients with oral squamous cell carcinoma (OSCC) after curative resection. Fourteen immune features regarding detailed locations and densities of seven types of tumor-infiltrating immune cells (TIIs) were characterized in clinical samples from 269 eligible patients in three independent cohorts by immunohistochemistry coupled with digital quantitation. Optimal cutoff values for individual immune features were yielded using X-tile software. The 7IFBPS was constructed by Kaplan–Meier and Cox regression model in training cohort and verified in testing, validation and combined cohorts. Concordance index (C-index), receiver operating characteristics and calibration curves were employed to define the performance of 7IFBPS in prognostic prediction. High CD3 IM (invasive margin), CD3 CT (center of tumor), CD8 CT, CD45RO IM, CD45RO CT, FOXP3 IM and FOXP3 CT significantly associated with improved survival. The 7IFBPS score was calculated using the formula: 1.041 × CD3 IM + 1.24 × CD3 CT + 1.701 × CD8 CT + 1.127 × CD45RO IM + 1.348 × CD45RO CT + 1.089 × FOXP3 IM + 1.483 FOXP3 CT. High 7IFBPS significantly associated with improved survival in all cohorts and served as an independent prognostic predictor. The C-index of 7IFBPS for predicting survival was 0.668 (95% CI, 0.609–0.726). Calibration curves for survival probability showed good agreement between prediction by 7IFBPS and actual observation. Collectively, our findings established the 7IFBPS as a novel powerful prognostic classifier for resectable OSCC. It holds potentials to be incorporated into current prognostic regime to better patient stratification.     

朗氏细胞在口腔鳞状细胞癌中的作用(英文)

During the initiation, promotion, and progression of multi-step carcinogenesis, changes in specific host immunological factors have been observed. Although immunology of oral cancer has long been focused on antigens and lymphocytes, the fact remains that the antigen presenting cells, like the Langerhans cells (LCs) of the epithelium are initiators and modulators of the immune response. LCs as sentinels of immune response, have been investigated in several oral mucosal diseases, including cancer. Inadequate presentation of tumor antigens by host dendritic cells is one potential mechanism that allows tumor progression. In this review, the role of LCs in OSCC is discussed. Elucidation of the role of APCs, in particular LCs, may help to better understand the mechanisms underlying anti-tumour immune responses and, improve the effectiveness of anti-cancer immunity in tumour-bearing hosts. This section focuses on the roles LCs in the immunity of cancer and how cancer bypasses the dendritic cell-mediated immune responses, are discussed. Subsequently, the effects of tumor microenviornment on LC’s and their therapeutic implications are elaborated.     

Inhibition of ICAM2 induces radiosensitization in oral squamous cell carcinoma cells

We recently identified genes and molecular pathways related to radioresistance of oral squamous cell carcinoma (OSCC) using Affymetrix GeneChip. The current study focused on the association between one of the target genes, intercellular adhesion molecule 2 (ICAM2), and resistance to X-ray irradiation in OSCC cells, and evaluated the antitumor efficacy of combining ICAM2 small interfering RNA (siRNA) and X-ray irradiation. Downregulation of ICAM2 expression by siRNA enhanced radiosensitivity of OSCC cells with the increased apoptotic phenotype via phosphorylation (ser473) of AKT and activation of caspase-3. Moreover, overexpression of ICAM2 induced greater OSCC cell resistance to the X-ray irradiation with the radioresistance phenotype. These results suggested that ICAM2 silencing is closely related to sensitivity of OSCC cells to radiotherapy, and that ICAM2 may be an effective radiotherapeutic target for this disease.     

口腔鳞状细胞癌及癌旁组织中抑癌基因PTEN mRNA表达的定量研究

目的定量研究蛋白酪氨酸磷酸酶（PTEN）mRNA在口腔鳞状细胞癌及对应癌旁正常组织中的表达。了解PTEN基因的表达与口腔癌发生、发展的关系。材料和方法应用实时荧光定量PCR方法检测42例口腔鳞状细胞癌及对应癌旁正常组织中PTENmRNA的表达,Rotor-Gene Real-TimePCRAnalysisSoftware6．0软件进行mRNA定量分析,在SPSS14．0统计软件平台上用配对t检验方法统计检验。结果42例口腔鳞状细胞癌和对应癌旁正常组织中均有PTENmRNA表达。口腔鳞状细胞癌组织中PTENmRNA表达量[1．10±0．13（10gPTEN／logβ-actin）]低于相应癌旁正常组织（1．48±0．28）,差异有统计学意义（P〈0．01）。结论口腔鳞状细胞癌的发生与PTENmRNA表达水平降低有一定关系。