A prognostic role for Nm23-H1 in laryngeal carcinoma treated with postoperative radiotherapy: an introductory investigation

Postoperative RT is generally recommended for laryngeal carcinomas (LSCCs) at high risk of recurrence after surgery. There are currently no clinicopathological parameters available to predict response to such adjuvant RT in LSCC, and only a few potentially predictive biomarkers have been investigated. Nm23-H1 protein is reportedly related to the tumor cells’ metastatic potential, and low Nm23-H1 expression levels in human carcinomas often correlate with a poor prognosis. The novel aim of the present preliminary study was to investigate the prognostic value of Nm23-H1 expression and subcellular localization in a series of patients given postoperative RT for LSCC. A retrospective clinicopathological investigation was conducted at an academic tertiary referral center of 28 consecutive patients given postoperative RT for LSCC. Image analysis of immunohistochemical reactions was performed to measure Nm23-H1 total and nuclear expression levels. Disease-free survival (DFS) was significantly shorter among LSCC patients with total Nm23-H1 levels <50.0 % (p = 0.03); the mean total Nm23-H1 expression was lower in patients with recurrent disease than in patients without it (statistical trend, p = 0.07). The disease recurrence rate was significantly higher (p = 0.021) and the DFS shorter (statistical trend, p = 0.052) among LSCC patients with nuclear Nm23-H1 levels <5.0 %. The locoregional recurrence-risk ratio in LSCC patients with nuclear Nm23-H1 levels <5.0 % was 9.16. Nm23-H1 warrants further investigation of its potential role as a predictive biomarker with a view to providing tailored treatments after surgery, such as combinations of chemotherapy and RT instead of RT alone, in patients whose LSCCs have low or no Nm23-H1 expression.     

缺氧诱导因子1α和环氧化酶2在喉鳞癌组织中的表达及意义

目的 探讨喉鳞癌组织中缺氧诱导因子1α(hypoxia-inducible factor-1 alpha,HIF-1α)和环氧化酶2(cyclooxygenage-2,COX-2)的表达情况及其与患者临床病理资料的关系和对预后的影响.方法 免疫组化Envision二步法检测60例喉鳞癌标本中HIF-1α和COX-2蛋白的表达,15例不典型增生、10例声带白斑、10例声带息肉标本作对照.结合喉鳞癌患者临床和病理资料进行分析.结果 60例喉鳞癌组织中HIF-1α呈高表达为35.0%(21/60),COX-2高表达为38.3%(23/60).两者阳性表达率与不典型增生、声带白斑及声带息肉组相比差异均具有统计学意义(Fisher确切概率法,P值均<0.01).喉鳞癌组织中HIF-1α和COX-2的表达结果 呈正相关(r=0.526,P<0.01).喉癌HIF-1α高、低表达组在临床分期(X2=4.331,P<0.05)及淋巴转移方面(Fisher确切概率法,P<0.05)组间差异具统计学意义;COX-2高、低表达组在T分期及临床分期方面组间差异具统计学意义(X2值分别为6.792和8.539,P值均<0.01).单因素分析HIF-1α高、低表达组间生存率及无瘤生存率差异均具统计学意义(X2值分别为6.003和5.010,P值均<0.05),COX-2高、低表达组生存率差异及无瘤生存率差异均具统计学意义(X2值分别为9.489和6.102,P值均<0.05).多因素分析提示复发及COX-2表达是影响喉癌患者预后的重要危险因素(相对危险度分别为7.104和5.714,P值均<0.01).结论 HIF-1α和COX-2在喉鳞癌发生、发展中起重要作用,两者可能有协同关系.COX-2表达及肿瘤复发情况可能作为评估喉鳞癌预后的重要危险因素.     

喉鳞状细胞癌患者预后的多因素分析

目的：探讨影响喉鳞状细胞癌患者预后的主要因素。方法：采用免疫组织化学SP法检测79例喉鳞状细胞癌患者肿瘤组织和10例癌旁正常组织中细胞s期激酶相关蛋白（Skp2）、p27、上皮细胞钙黏素（E-cad）、r连环素（α-cat）的表达,并对可能影响喉鳞状细胞癌患者预后的12项临床病理因素进行单因素和多因素分析。结果：①Skp2在喉鳞状细胞癌和癌旁正常组织中的表达率分别为53,16％和0,p27分别为30．38％和90．00％,E-cad分别为34．18％和100,00％,α-cat分别为40．51％和100,00％,其差异均有统计学意义（P〈0．05或P〈0．01）。②本组患者总的5年生存率为58．75％,Skp2蛋白低表达组的5年生存率（72．18％）显著高于高表达组（44．17％）（P〈0.01）;p27蛋白高表达组的5年生存率（72．98％）显著高于低表达组（51．13％）（P〈O．01）;E-cad及α-cat阳性表达组的5年生存率（分别为63．80％和81．74％）显著高于阴性表达组（分别为50.68％和41．09％）（P〈0．05和P〈0．01）。③单因素分析显示：病理分级,颈淋巴结转移,临床分期,T分期,复发,Skp2、p27、E-cad及α-cat表达对患者预后的影响均有统计学意义（P〈0．05或P〈0．01）;多因素分析显示：复发、Skp2及α-cat表达为影响患者预后的独立因素（P〈0．05或P〈O．01）。④Skp2和p27蛋白表达之间存在着负相关关系（P〈0.01）;p27和α-cat蛋白表达之间、E-cad和α-cat蛋白表达之间存在正相关关系（均P〈0．01）。结论：复发、Skp2及α-cat表达为影响喉鳞状细胞癌患者预后的重要因素。     

Supracricoid partial laryngectomy cricohyoidoepiglottopexy (SCPL-CHEP) versus vertical partial laryngectomy for the treatment of glottic carcinoma

The study aimed to compare the survival rate and functional outcome of supracricoid partial laryngectomy cricohyoidoepiglottopexy (SCPL-CHEP) and vertical partial laryngectomy (VPL) in the treatment of glottic carcinoma. Thirty-nine patients underwent SCPL-CHEP and 45 patients underwent VPL between 2002 and 2007. Post-operative clinical staging were performed according to the UICC staging criteria (2002). The primary endpoints were survival time and recurrence rate. The secondary endpoints were the laryngeal functions including pronunciation, swallowing, and respiration. Overall, the estimated mean survival time was 75.6 months. There was no significant difference in survival times between the two groups (P = 0.496). The SCPL-CHEP group had a significantly lower post-operative local recurrence rate than VPL group (2.6 vs. 17.8 %, P = 0.033). Significantly longer nasogastric tube removal (22 vs. 14 days, P < 0.001) and tracheostomy decannulation (38.5 vs. 15 days, P < 0.001) times in SCPL-CHEP group was observed with the VPL group, respectively. Significantly higher aspiration rates were observed at 3, 6, and 12 months in the SCPL-CHEP group compared with the VPL group (P < 0.001, P < 0.001, P < 0.05, respectively). Although the survival rate was not significantly different between the two groups, the local regional control rate and organ preservation in the supracricoid partial laryngectomy cricohyoidoepiglottopexy group was better than those observed in the vertical partial laryngectomy group.     

Clinical significance of neuropilin-2 expression in laryngeal squamous cell carcinoma

PurposeThe purpose of the study is to evaluate the expression of NRP-2 and explore its role in Laryngeal squamous cell carcinoma (LSCC).Materials and methodsNRP-2 expression in 70 primary LSCC tissue specimens were analyzed by immunohistochemistry and correlated with clinicopathological parameters and patients´ survival rate. Additionally, 9 paired LSCC tissues were evaluated for NRP-2 expression by Western blotting.ResultsThe Western blotting indicated that NRP-2 expression levels in LSCC were significantly higher than those in the paraneoplastic tissues (P < 0.05). Immunohistochemistry staining revealed that NRP-2 was detected in all primary tumor samples, moreover, high expression of NRP-2 was significantly correlated with TNM stage (P < 0.05), clinical stage (P < 0.05), histological classification (P < 0.05), lymph node metastasis (P < 0.05) and recurrence (P = 0.001). Survival curves determined by the Kaplan-Meier method showed that high expression of NRP-2 can reduce overall survival (both group P < 0.05). Then we combined the NRP-2 expression and lymph node status, and Kaplan–Meier survival showed patients with high expression of NRP-2 or lymph node metastasis (+) had both shorter disease-free and overall survival than others (both P < 0.05). Multivariate Cox proportional hazards model analysis confirmed that histological grade (P = 0.045), lymph node metastasis (P = 0.020) and high expression of NRP-2 (P = 0.033) were statistically significant, independent predictor of prognosis.ConclusionsNRP-2 may contribute to LSCC progression and represents as a novel prognostic indicator as well as a potential therapeutic target for LSCC.     

High Gpx1 expression predicts poor survival in laryngeal squamous cell carcinoma

Objective

Several studies have demonstrated that abnormal glutathione peroxidases 1 (Gpx1) expression can influence the biological behavior of malignant cells. However, the roles of Gpx1 in laryngeal squamous cell carcinoma (LSCC) remain unknown. The purpose of this study is to analyze the Gpx1 expression and prognostic significance in LSCC patients.

环氧化酶2和基质金属蛋白酶7在喉癌中的表达

目的探讨环氧化酶2(cycloxygenase-2,COX-2)和基质金属蛋白酶7(matrix metalloprotei- nase-7,MMP-7)在喉鳞状细胞癌(简称喉癌)组织中的表达及临床意义。方法采用免疫组化SP法检测65例喉癌组织及34例癌旁组织中COX-2和MMP-7的表达情况。结果COX-2和MMP-7在LSCC组织中的阳性表达率分别为72.3%和75.4 %,与癌旁组织比较(20.6%,23.5%),其表达均显著增高(P<0.05),且COX-2和MMP-7的表达呈正相关(P<0.05)。两者的表达水平随临床分期的进展显著增高(P<0.05)。COX-2阳性表达组总生存率和无瘤生存率较COC-2阴性表达组明显降低(P<0.05)。结论喉癌组织中存在COX-2和MMP-7的过度表达,其促进了喉癌的发生和侵袭,两者在喉癌发生和进展过程中可能存在协同作用,COX-2的过度表达提示预后不良。     

The EGFR-mTOR pathway and laryngeal cancer angiogenesis

Epidermal growth factor receptor (EGFR) is a trans-membrane tyrosine kinase taking part in cell transformation and tumor progression. One of the downstream pathways controlled by EGFR involves the mammalian target of rapamycin (mTOR), a proto-oncogene activated in several cell functions. Recent evidence seems to confirm that both EGFR and mTOR regulate angiogenesis. The aim of this study was to investigate the expression of EGFR and mTOR in laryngeal squamous cell carcinoma (LSCC) cells in a retrospective clinical setting and their correlation with tumor neo-angiogenesis, judged on the grounds of CD105-assessed microvascular density (MVD), and prognosis. We considered 76 consecutive patients with LSCC treated with surgery alone. Immunohistochemical expressions of EGFR, mTOR, and CD105 were measured using image analysis and findings underwent statistical analysis using univariate and multivariate models. We found that nodal status correlated significantly with patient prognosis in terms of disease-free survival (DFS) (p = 0.01). There was a strong direct correlation between mTOR and EGFR expression (p = 0.0003), and between mTOR and CD105-assessed MVD (p = 0.0025). Patients with a CD105-assessed MVD >5.28 % had a significantly higher recurrence rate (RR) (p = 0.026), and a significantly shorter DFS (p = 0.025). On multivariate analysis, only N stage [hazard ratio (HR) 3.54, p = 0.009] and CD105-assessed MVD (HR 2.87, p = 0.027) maintained their independent prognostic significance in terms of DFS. Judging from our promising findings, the EGFR-mTOR pathway should be investigated further to understand its role in LSCC neo-angiogenesis.     

Reduced E-cadherin expression is associated with lymph node metastases in laryngeal squamous cell carcinoma

Objective

To investigate the expression of E-cadherin and its relationship with clinicopathological parameters in laryngeal squamous cell carcinoma (LSCC).

Methods

Sixty-four patients who had previously undergone complete resection of tumor for LSCC were studied retrospectively. The level of E-cadherin expression in tumor tissues and paired nontumor tissues were determined by immunohistochemistry.

Results

The expression of E-cadherin in tumor tissues was significantly lower than nontumor tissues (P < 0.001). Reduced E-cadherin expression was significantly correlated with lymph node metastases (P < 0.001). Kaplan–Meier survival estimates showed a significant correlation between E-cadherin expression and patient survival rate (log-rank P < 0.05). Multivariate Cox proportional hazards model analysis confirmed that lymph node metastases (P = 0.001) and tumor stage (P = 0.013) were statistically significant, independent predictor of prognosis.

Conclusion

Expression of E-cadherin is an independent predictor of lymph node metastases in LSCC. However, it does not appear to be a better prognostic predictor than other established markers in LSCC.     

COX-2和iNOS在喉鳞癌中的表达及其与血管生成的相关研究

目的探讨喉鳞癌组织中环氧合酶-2（COX-2）和诱导型一氧化氮合酶（iNOS）的表达及其相关性,同时探讨二者与喉鳞癌血管生成的关系。方法应用免疫组化检测48例喉鳞癌组织、20例癌旁组织及20例声带息肉组织中COX-2和iNOS的表达,并观察微血管密度（MVD）。结果COX-2和iNOS在喉鳞癌组织中表达上调,与癌旁组织及声带息肉组织相比均有统计学意义（P〈0．05）。COX-2蛋白表达与喉鳞癌患者肿瘤临床分期有关。iNOS蛋白表达与喉鳞癌患者淋巴结转移、肿瘤病理分期有关。COX-2和iNOS蛋白表达之间呈正相关,两种蛋白在喉鳞癌中的表达有协同关系。喉鳞癌组织中MVD表达与声带息肉组织、癌旁组织有显著差异,且COX-2、iNOS与MVD显著正相关。结论COX-2和iNOS可能在喉鳞癌发生发展中起一定的促进作用。喉鳞癌组织MVD增高与COX-2及iNOS有关,COX-2与iNOS可能通过促进新生血管形成共同影响喉鳞癌的发生发展。     

MGMT和EGFR蛋白在喉鳞状细胞癌中的表达及临床意义

目的 探讨喉鳞状细胞癌组织中O6-甲基鸟嘌呤DNA甲基转移酶(MGMT)、表皮生长因子受体(EGFR)的表达与临床病理特征及其相互之间的关系,研究其在肿瘤发生发展以及治疗中的作用。 方法 采用免疫组织化学染色法检测MGMT、EGFR的表达,分析103例喉癌组织标本与临床病理特征的关系。 结果 MGMT的表达与分化程度、T分期以及临床分期呈正相关(χ2为13.302、8.394、11.403,P值分别为0.001、0.039、0.010<0.05);EGFR的表达与T分期以及临床分期呈正相关(χ2为14.933、16.603,P值分别为0.002、 0.001<0.05)。分层分析发现,MGMT、EGFR 两者的表达强度存在正相关(χ2=5.369, P=0.019<0.05)。 结论 喉鳞状细胞癌中 MGMT、EGFR的表达与T分期、临床分期均有相关性,测定两者的表达水平可评估喉鳞状细胞癌的恶性程度并指导喉癌的治疗。     

Tiam1蛋白在喉癌中的表达及其临床意义

目的检测T淋巴细胞侵袭转移诱导因子1（Tiam1）蛋白在喉癌组织中的表达,并探讨其表达水平与喉癌临床病理特征和预后之间的关系。方法采用免疫组织化学染色技术检测Tiam1蛋白在98例喉癌石蜡组织切片中的表达,并统计分析Tiam1蛋白表达水平与喉癌临床病理特征和预后之间的关系。结果Tiam1蛋白的表达与喉癌的淋巴结转移（P<0.001）、临床分期（Ⅰ期、Ⅱ期/Ⅲ期、Ⅳ期）（P=0.027）、组织病理学分级（P=0.020）及复发（P=0.003）密切相关;Kaplan Meier生存曲线分析结果显示Tiam1高表达组的5年无复发生存率（P=0.001）和5年总生存率（P<0.001）均明显低于Tiam1低表达组;而且通过Kaplan Meier生存曲线分析Tiam1蛋白表达和淋巴结转移情况与头颈鳞癌患者预后之间的关系,发现Tiam1高表达并有淋巴结转移组的5年无复发生存率和5年总生存率明显低于其它（Tiam1低表达或无淋巴结转移）组（P均<0.001）;多因素Cox比例风险回归模型进一步显示,淋巴结转移（P=0.001）及Tiam1表达水平（P=0.020）为喉癌的独立预后因素。结论Tiam1在喉癌组织中表达显著升高,且其高表达与喉癌患者的淋巴结转移、复发及预后密切相关。Tiam1可能在喉癌的发生、发展中起重要作用,其表达水平对喉癌的复发及预后具有评估价值。     

G3BP在喉鳞状细胞癌的表达及其临床意义

目的研究GTP酶激活蛋白SH3功能区结合蛋白（G3BP）在喉鳞癌组织中的表达情况及其与喉鳞癌生物学行为之间的关系。方法采用免疫组织化学方法检测91例喉鳞癌组织中G3BP的表达情况,并探讨他们与喉鳞癌的肿瘤组织分化程度、TNM分期、淋巴结转移和预后的关系。结果G3BP在喉鳞癌的阳性表达率为84.7％。其表达水平与肿瘤分化程度（P=0.008）、临床分期（P=0.005）、淋巴结转移（P=0.000）及肿瘤复发转移（P=0.000）均有密切关。G3BP表达水平越高,患者术后生存时间越短（P=0.000）。结论G3BP在喉鳞癌表达与肿瘤分化程度、临床分期、淋巴结转移、肿瘤复发转移情况及患者的预后有密切关系。G3BP可作为判断喉鳞癌患者预后的有效参考指标。     

喉鳞癌中P糖蛋白表达与细胞增殖、凋亡及预后的关系

目的 探讨P糖蛋白在喉鳞癌组织中表达与肿瘤细胞的增殖、凋亡活性,及其临床病理特征与患者预后的关系。方法 应用免疫组化技术检测86例患者喉鳞癌组织中P糖蛋白、Ki 67的表达,TUNEL法测定喉鳞癌细胞凋亡率。结果 P糖蛋白在喉鳞癌组织中的阳性表达率为39.5％(34/86),与喉鳞癌的临床分期、组织学分级、淋巴结转移及患者术后生存率有关(均P＜0.05);P糖蛋白表达阳性组的肿瘤细胞凋亡率比阴性组低(P＜0.05),而增殖率差异无统计学意义(P＞0.05)。结论 P糖蛋白可能对喉鳞癌细胞的凋亡活性具有一定抑制作用;P糖蛋白阳性表达率对于评估喉鳞癌病程进展及预后具有一定价值。     

Prognostic value of hypoxia-inducible factors (angiogenin and endoglin) in open partial laryngectomies: uni- and multivariate analyses

Purpose

Advances in transoral laser microsurgery, radiotherapy, and chemotherapy (and their combinations) have reduced the indications for open partial laryngectomies, although they have replaced total laryngectomies in selected advanced or recurrent laryngeal squamous cell carcinomas (LSCCs). Tissue hypoxia in malignancies appears to be strongly associated with tumor cell invasiveness and metastases. Whether hypoxia-inducible factors can contribute to a rational recommendation of open partial laryngectomy should be investigated.

Materials and methods

Fifty consecutive patients who had undergone primary open partial laryngectomy (supraglottic and supracricoid laryngectomies) were investigated, measuring the immunohistochemical expression of the hypoxia-inducible proteins angiogenin and endoglin in their primary LSCCs also with image analysis.

Results

Univariate analysis showed a significantly higher recurrence rate (P = .007) and shorter disease-free survival (P = .0047) in patients with LSCC with endoglin expression more than 9.0%. Multivariate analysis found endoglin expression independently prognostic in terms of disease-free survival (P = .012). Angiogenin expression (in carcinoma or endothelial cells) was not associated with prognosis.

Conclusions

Endoglin should be further studied as a biomarker of patients with LSCC at higher risk for recurrence after open partial laryngectomy who may benefit from more aggressive treatments. Endoglin expression in positive laryngeal biopsies may prove useful as a parameter for choosing between different surgical and multimodality approaches to controversial LSCC cases.     

EphA2与VEGF蛋白在喉鳞癌组织中的表达及相关性研究

目的探讨沉默促红细胞生成素产生肝细胞受体(erythropoietin-producing hepatocellular re-ceptor,EphA2)与促血管生成因子(VEGF)蛋白在喉鳞状细胞癌(喉鳞癌)组织中的表达及相关性。方法采用免疫组织化学技术检测EphA2、VEGF蛋白在69例喉鳞癌组织及15例癌旁黏膜组织中的表达,分析二者表达水平与临床病理特征的关系。结果 EphA2和VEGF蛋白在喉鳞癌组织中的阳性率均高于癌旁黏膜组织(P均<0.05),EphA2蛋白表达尚与肿瘤原发部位相关(P<0.05),且EphA2和VEGF蛋白表达均与喉鳞癌患者的临床分期(P均<0.05)及转移(P均<0.05)密切相关,而二者表达与患者年龄、性别、组织学分级均无明显相关(P均>0.05)。喉鳞癌组织中EphA2及VEGF蛋白表达存在正相关性(P<0.05)。生存分析结果显示EphA2及VEGF蛋白表达水平与患者5年总生存率密切相关(P<0.05)。多因素Cox比例风险回归模型进一步显示,淋巴结有无转移及EphA2蛋白表达水平为喉鳞癌患者预后的独立影响因素。结论 EphA2与VEGF蛋白在喉鳞癌组织中表达均上调,提示二者可能存在相互作用,共同在喉鳞癌的发生、发展中起作用。     

DJ-1蛋白在喉鳞状细胞癌中的表达及其与复发和转移的关系

目的 探讨喉鳞状细胞癌(简称鳞癌)中DJ-1蛋白表达水平与喉鳞癌临床病理特征的关系.方法 将1995年1月至2006年1月收治的71例喉鳞癌患者术后肿瘤组织和9例非喉癌者喉黏膜组织应用免疫组织化学法检测,分析其DJ-1蛋白表达水平与临床病理特征的关系.结果 喉鳞癌组织中DJ-1蛋白阳性表达率为85.9%(61/71),与非喉痛的喉黏膜组织55.5%(5/9)比较,差异有统计学意义(精确概率法P<0.05).分别就患者的性别、年龄、原发部位、T分期、临床分期、淋巴转移和肿瘤的病理学分级等情况进行分组比较,各组间喉鳞癌组织中DJ-1蛋白表达水平的差异均无统计学意义;DJ-1蛋白高表达患者其肿瘤复发率(53.3%)明显高于DJ-1蛋白低表达患者的复发率(26.8%;x2=5.164,P<0.05).Kaplan-Meier法和Cox回归分析发现喉鳞癌患者的肿瘤原发部位、性别、年龄、T分期、临床分期和肿瘤病理学分级对术后累积生存率影响均无统计学意义;DJ-1蛋白表达水平和淋巴转移对术后累积生存率影响有统计学意义(X2值分别为6.20和3.97,P值均<0.05).结论 DJ-1蛋白在喉鳞癌组织的表达水平高于喉黏膜组织.DJ-1蛋白表达水平较高的喉癌患者生存率可能低.     

uPA及nm23-H1蛋白表达与喉鳞癌侵袭转移的关系

目的探讨喉鳞癌中uPA及nm23-H1的表达与喉鳞癌侵袭转移的关系。方法采用免疫组织化学方法检测uPA及nm23-H1在55例喉癌中蛋白水平的的表达。结果喉癌中uPA及nm23-H1的阳性表达率分别为67．3％（37／55）和54．5％（30／55），且二者表达呈负相关（P〈0．05）。uPA的表达与临床分期、颈淋巴结转移呈正相关（P〈0．05）。nm23-H1的表达与临床分期、颈淋巴结转移呈负相关（P〈0．05）。uPA阳性同时nm23-H1阴性表达者，颈淋巴结转移率明显高于uPA阴性同时nm23-H1阳性表达者（P〈0．05）。结论uPA及nm23-H1的表达与喉癌的颈淋巴结转移及临床分期密切相关，联合检测具有一定的临床意义。