头颈鳞状细胞癌相关致病基因的筛选和临床分析

目的筛选头颈鳞状细胞癌（head and neck squamous cell carcinoma, HNSCC）差异表达基因（differentially expressed genes, DEGs）,进一步探究其潜在分子机制。方法从Gene Expression Omnibus（GEO）数据库下载HNSCC基因芯片数据集,通过GEO2R鉴定HNSCC与正常样本间的DEGs,并对DEGs进行基因本体(gene ontology, GO)功能注释和京都基因与基因组百科全书（kyoto encyclopedia of genes and genomes, KEGG）通路分析,应用Cytoscape进行蛋白质-蛋白质相互作用（protein protein interaction, PPI）网络构建,最后通过UALCAN数据库进行生存分析。结果筛选出143个DEGs,其中上调基因50个,下调基因93个。GO分析显著富集在胶原分解代谢过程、细胞粘附及蛋白水解等生物过程,KEGG通路分析显著富集在药物代谢、核因子 κB（muclear factor κB,NF κB）信号通路、ECM 受体相互作用、补体和凝血级联等通路。PPI网络构建筛选出15个HNSCC相关核心基因,其中PLAU、SPP1、TIMP1被鉴定为临床相关基因。结论SPP1是抗癌治疗的良好靶标,也是指导放射治疗的标志物。PLAU和TIMP1可能是HNSCC的关键基因,有望成为分子靶向治疗的新靶点,PLAU和SPP1可能通过NF κB信号通路调节HNSCC发展。     

Zwint-1蛋白在头颈部鳞状细胞癌中表达上调及其与临床特征的相关性

目的探讨Zeste white 10（ZW10）相互作用着丝粒蛋白1 (ZW10 interacting kinetochore protein 1,Zwint 1),在头颈部鳞状细胞癌（head and neck squamous cell carcinoma,HNSCC）肿瘤组织中的蛋白表达情况,以及其与临床病理特征之间的关系。方法采用免疫组织化学检测的方法,对16例HNSCC患者的肿瘤组织样本,以及7例相应的癌旁正常组织样本中Zwint 1蛋白进行检测。同时,分析HNSCC相关组织芯片中Zwint 1蛋白表达与HNSCC临床特征的相关性。结果临床样本与组织芯片的检测结果显示,Zwint 1蛋白在HNSCC肿瘤组织中的蛋白表达高于正常组织,其差异具有统计学意义（t=2.399, P<0.05）。组织芯片的检测结果显示,Zwint 1蛋白表达量与HNSCC患者的肿瘤大小（F=2.889,P<0.05）、淋巴结转移（t=2.110,P<0.05）、分化（F=3.667,P<0.05）以及临床分期（F= 2.864,P<0.05）均具有相关性。但是卡方检验结果显示,Zwint 1蛋白阳性表达与肿瘤大小（χ2=3.236,P>0.05）、淋巴结转移（χ2=1.463,P>0.05）、分化（χ2=1.271,P>0.05）、临床分期（χ2=4.179,P>0.05）,差异无统计学意义。结论Zwint 1蛋白在HNSCC的发生发展过程中发挥有重要作用,可能是HNSCC潜在的靶向治疗目标。     

Lateral semicircular canal plugging with endolymphatic sac decompression as new surgical treatment for intractable Meniere's disease

Conclusion. Patients showing a complete response on computed tomography (CT) can be spared from neck dissection. Objective. To determine whether CT or fluorine-18-fluorodeoxyglucose positron emission tomography (¹⁸F-FDG PET) is superior in the evaluation of persistent nodal disease after chemoradiotherapy in patients with node-positive head and neck squamous cell carcinoma (HNSCC). Patients and methods. Study entry criteria included node-positive HNSCC treated with definitive chemoradiotherapy, a local complete response, and post-treatment CT and ¹⁸F-FDG PET studies 7 weeks after chemoradiotherapy. Forty-eight patients with 60 node-positive necks were eligible. Nodes larger than 1 cm, or with central necrosis on CT, or any visually hypermetabolic nodes on ¹⁸F-FDG PET were considered positive. Regardless of PET findings, necks with positive CT were subjected to neck dissection, whereas those with negative CT were observed without neck dissection. Results. Twenty-two necks showed positive CT, 20 and 2 of which underwent neck dissection and fine needle aspiration cytology, respectively, resulting in pathologic evidence of persistent nodal disease in 13 necks. Five of 38 necks with negative CT developed regional recurrence. Diagnostic accuracy was equivalent between CT and ¹⁸F-FDG PET. There was no difference in 3-year cause-specific survival between patients with positive and negative CT (79% and 81%, respectively).     

头颈部鳞状细胞癌的靶向治疗研究进展

头颈部肿瘤是常见肿瘤之一,超过95%的病理类型是鳞状细胞癌,手术与放化疗结合的综合治疗方案是头颈部鳞状细胞癌(HNSCC)的主要治疗方案,但是总体生存率并不高,主要原因是肿瘤复发和/或转移;同时复发性或转移性HNSCC常无法进行手术治疗,放化疗效果也差。靶向治疗的发现为HNSCC、特别是复发性或转移性HNSCC的治疗提供了新的方法。为了进一步认识靶向治疗的临床治疗作用,就HNSCC的靶向治疗研究进展做一综述。     

Basaloid squamous cell carcinoma of the larynx

Basaloid squamous cell carcinoma is a variant of squamous cell carcinoma that was first described in 1986. In the English-language literature, only 26 cases of this infrequent histopathological entity have been reported in the larynx. Tumors have an aggressive biological behavior, justifying combined surgical treatment with radiotherapy. Two new cases are presented and the literature reviewed.     

Identification of Genes Overexpressed in Head and Neck Squamous Cell Carcinoma Using a Combination of Complementary DNA Subtraction and Microarray Analysis

Objectives/Hypothesis To discover unique genes specific for squamous cell carcinoma of the head and neck for eventual development as tumor markers and vaccine candidates. Study Design Molecular biological analysis of fresh‐frozen head and neck squamous cell cancer (HNSCC). Methods A subtractive library was made from two HNSCC and six normal tissues using a polymerase chain reaction (PCR)–based approach. Genes from this library were PCR amplified and placed on a microarray glass slide. RNA was prepared or obtained from 16 fresh‐frozen HNSCC and 22 normal tissue sources. Fluorescent probes were made from the polyA+ RNA derived from the tumor and normal tissues. The probes were hybridized to the glass slides and excited by a tuneable laser. One hundred seven of the genes showing the highest differential fluorescence value between tumor and normal tissue were identified by sequence analysis. Results Thirteen independent genes were found to be overexpressed in tumor tissues. Of these, nine were previously known: keratins K6 and K16, laminin‐5, plakophilin‐1, matrix metalloproteinase‐2 (MMP), vascular endothelial growth factor, connexin 26, 14–3‐3 sigma, and CaN19. The level of polyA+ RNA of these genes in the tumors was significantly different from the levels in normal tissue (P < .05). Four previously unidentified genes were also discovered to have increased expression in tumor tissue. Comparing the total tumor group (n = 16) to the normal group (n = 22), only one of these genes showed significant overexpression. Conclusion We report the identification of nine known genes that are significantly overexpressed in HNSCC as compared to normal tissue using subtractive and microarray technology. In addition, we present four previously unidentified genes that are overexpressed in a subset of tumors. These genes will be developed as tumor markers and vaccine candidates.     

Outcome analysis of patients with squamous cell carcinoma of the head and neck and hepatitis C virus

Objective/Hypothesis: Infection with the hepatitis C virus (HCV) is a global problem with over 170 million people infected. Recently, we have noticed that a large number of patients diagnosed with squamous cell carcinoma of the head and neck (SCCHN) have also been diagnosed with HCV. A review of the literature reveals little information concerning this patient population. The objective of this study was to compare the outcome of SCCHN patients who have been exposed to HCV with naïve SCCHN patients. Study Design: Retrospective chart review. Methods: A retrospective chart review from June 1991 through December 2002 was performed to identify patients diagnosed with SCCHN who were screened for HCV. Patients were stratified into two groups (HCV positive and HCV negative). Data were recorded on patients for status of disease at last clinic visit, pretreatment serum albumin and hematocrit levels, and RNA quantities of HCV. Statistical analysis was performed using paired t test to compare serum albumin and hematocrit levels. Kaplan‐Meier survival curves were used to compare outcomes. The log‐rank test was used to determine significance. Cox regression was used to examine the association of prognostic predictor variables with overall survival and disease‐free survival. Results: There was no difference noted in 5 year survival between hepatitis C positive and hepatitis C negative groups in overall outcomes (66.7% vs. 67.9%, P = 1.000) or 5 year disease‐free survival (90.5% vs. 80.8%, P = .514). The two groups, HCV positive versus HCV negative, also had similar serum albumin levels (3.62 g/dL vs. 3.72 g/dL, P = .37) as well as serum hematocrit levels (42.9% vs. 41.0%, P = .12). Serum levels of hepatitis C RNA were obtained in seven patients, with only one being undetectable. The only prognostic predictor variable that was significantly associated with overall survival was age. None of the predictor variables were significantly associated with disease‐free survival. Conclusion: Co‐infection with HCV, although prevalent in the Veterans Administration Hospital population, did not affect patient outcome as defined by disease‐free survival. Patients who were seropositive for HCV had comparable serum albumin levels as well as serum hematocrit when compared with HCV negative patients.     

鉴定头颈部鳞癌中异常甲基化的差异表达基因及其通路

目的 基于头颈部鳞癌(HNSCC)的生物标记物及其通路尚不明确的现状,研究旨在分析和鉴定HNSCC中异常甲基化的差异表达基因,探讨其关键基因和潜在通路。 方法 从GEO数据库下载基因表达的数据集GSE107591和甲基化数据集GSE33202。通过R软件筛选异常甲基化基因和差异表达基因,两者取交集后获得低甲基化高表达基因(Hypo-HGs)和高甲基化低表达基因(Hyper-LGs)。利用Enrichr对两组基因进行功能富集分析。蛋白互作(PPI)网络由STRING构建并在Cytoscape中可视化,最后利用生存分析来鉴定出关键基因。此外,还进行了免疫组化分析,利用CMap寻找可能逆转HNSCC基因表达的候选小分子。 结果 共鉴定出28个低甲基化高表达基因,GO富集分析显示其主要参与T细胞趋化性的正调节,表皮发育、细胞-基底连接组件及调节T细胞趋化性等方面。Wiki通路分析的结果表明,其主要参与典型和非典型TGF-β信号传导、血液凝结级联反应、α6β4信号通路、补体和凝血级联反应及癌症中的衰老和自噬途径。同时,发现了24个高甲基化低表达基因,主要富集于血管生成及发育的调节,对干扰素-γ反应的负调节,对干扰素-γ介导的信号通路的负调节和上皮发育的生物学过程。Wiki通路分析显示其主要参与哺乳动物含黄素单加氧酶(FMOs)的催化循环,HIF1A和PPARG调节糖酵解以及苯和黄曲霉毒素B1的代谢。此外,鉴定出与HNSCC预后相关的关键基因,分别是SERPINE1、PLAU、MMRN1、LAMB3、LAMC2、PDPN和CXCL13。 结论 通过生物信息学分析并鉴定出HNSCC中异常甲基化差异表达的基因和作用途径,为揭示HNSCC发病机制提供了重要的分子学基础。包括SERPINE1、PLAU、MMRN1、LAMB3、LAMC2、PDPN和CXCL13在内的关键基因可能作为基于甲基化的异常生物标志物,为未来寻找HNSCC诊断和治疗靶点提供了新的思路。     

新辅助免疫治疗在头颈部鳞状细胞癌中的研究进展

头颈部鳞状细胞癌(HNSCC)是全球第八大常见癌症,超过一半的HNSCC患者可出现局部复发或远处转移。随着医学的发展,免疫治疗药物的陆续问世为复发/转移性HNSCC患者带来了新的希望。目前多项研究已经证实,以程序性死亡受体1(PD-1)检查点抑制剂为代表的新辅助免疫治疗具有较好的疗效,且安全性良好,而以新辅助免疫治疗为基础的联合治疗也成为研究热点,包括新辅助免疫治疗联合化疗、放疗、放化疗、靶向治疗以及新辅助双免疫联合治疗等新型治疗模式。本文将对新辅助免疫治疗在HNSCC中的研究进展作一综述。     

Patterns of bone metastases from head and neck squamous cell carcinoma

ObjectiveTo report clinical features of bone metastases (BM) from head and neck squamous cell carcinoma (HNSCC).MethodsAmong 772 patients with HNSCC diagnosed at our hospital over 9 years, 30 patients (3.9%) had clinical evidence of BM (24 men and 6 women; mean age: 63 years). We assessed the time interval from the primary diagnosis to BM development, symptoms attributable to BM, presence of distant metastases to other organs, number of BM, sites of BM, morphologic changes on computed tomography (CT) images, treatment for BM, and overall survival (OS).ResultsBM at the initial stage were found in 9 patients with HNSCC (30%), and in 21 patients (70%) with HNSCC during the course of the disease. In the later patients, the median time interval from the primary diagnosis was 11.5 months. Nineteen patients (63%) did not have BM-related symptoms, 6 (20%) had pain, 3 (10%) had neurologic symptoms resulting from vertebral or skull metastases, and 2 (7%) had hypercalcemia. Seventeen patients (57%) showed bone-exclusive metastases, and 13 (43%) had distant metastases in other organs. Eleven patients (37%) had monostotic metastases (solitary BM), and 19 patients (63%) had polyostotic metastases (multiple BM). When combined, 9 patients (30%) showed bone-exclusive and monostotic metastases. The most commonly affected site was the thoracolumbar spine, accounting for 34% of total BM, followed by the pelvis (24%), shoulder and thorax (21%), and the extremities (17%). Notably, metastases to bones above the clavicle (craniofacial bones and cervical spine) accounted for only 3% of all bone lesions. CT images showed variable morphologic patterns with osteolytic type in 17 patients (57%), intertrabecular in 7 (23%), osteoblastic in 4 (13%), and mixed in 2 (7%). Systematic chemotherapy for BM was performed in 19 patients and radiotherapy in 18. The median survival time for patients with bone-exclusive and monostotic metastases was significantly longer than that for patients with multi-organ metastases or polyostotic metastases at 18.2 months vs. 5.7 months (p = 0.02). Neither chemotherapy nor radiotherapy extended OS.ConclusionThirty percent of BM cases from HNSCC showed bone-exclusive and monostotic metastases. These patients tended to show a more favorable prognosis than patients with multi-organ metastases or polyostotic metastases.     

Comparison of tonsillar biofilms between patients with recurrent tonsillitis and a control group

Abstract Conclusion: The results of the study suggest that biofilms play a causative role in recurrent tonsillitis. Objective: To analyze the association between tonsillar biofilms and recurrent tonsillitis. Methods: The recurrent tonsillitis group comprised patients with a history of at least five episodes of tonsillitis per year over the previous 2 years. The control group comprised volunteers scheduled for laryngeal microsurgery with no history of tonsillitis over the previous 2 years. Between October 2009 and August 2010, specimens were obtained from 20 patients with recurrent tonsillitis and 20 volunteers (controls). Scanning electron microscopy (SEM) was used to confirm the presence of biofilms. Biofilms were graded at a magnification of ×500 by SEM and classified into five grades. The percentages of subjects affected and biofilm grades were compared between the recurrent tonsillitis and control groups. Results: The two groups were matched for age and sex. SEM revealed that biofilms were significantly more prevalent in the recurrent tonsillitis group than in the control group. Furthermore, the biofilms in the recurrent tonsillitis group were of significantly higher grade than those in the control group.     

Serum levels of vascular endothelial growth factor in patients with head and neck cancer

Angiogenesis is now considered to be crucial for tumor growth and metastasis. In several tumors, microvascular density has been shown to be correlated with metastasis and aggressiveness. Vascular endothelial growth factor (VEGF) is a secreted endothelial cell-specific mitogen, which is induced by hypoxia and is angiogenic in vivo. VEGF has been identified in a wide variety of malignancies including head and neck squamous cell carcinomas (HNSCC). We investigated the circulating level of VEGF in sera from patients with various head and neck squamous cell carcinomas (n = 71) as well as from healthy normal controls (n = 47). Serum VEGF concentrations were determined as serum immunoreactivity by using a quantitative sandwich enzyme immunoassay technique. For statistical analysis, the Wilcoxon 2-sample test and Kruskal-Wallis test were performed. The majority of the patients with HNSCC were found to have high concentrations of serum VEGF. The levels of VEGF in the sera of patients with cancer ranged from below the detection limit to 937.1 pg/ml (mean, 144.5 pg/ml). In contrast, the VEGF serum levels in 47 healthy individuals ranged from below the detection limit to 168.1 pg/ml (mean, 32.7 pg/ml), VEGF serum concentration being significantly higher in HNSCC patients (P = < 0.001). These findings indicate that a positive angiogenesis regulator such as VEGF might function as an endocrine growth factor, particularly for solid HNSCC tumors and may be a useful marker for clinical monitoring. Received: 12 April 1999 / Accepted: 30 September 1999     

Basaloid squamous cell carcinoma of the larynx--A systematic review

Objectives

This study pools all the cases of Basaloid squamous cell carcinoma of the larynx in the English literature to investigate the clinical course of this rare clinico-pathological disease entity.

Methods

We found and analyzed 100 cases with individual patient data from 36 publications spanning 20 years.

Results

It is a rare disease of the elderly with strong male predominance and more common in the supraglottis. Patients typically present with locoregionally advanced stage. Surgery alone or combined with radiotherapy is commonly reported. It has a worse survival outcome when compared to laryngeal cancers in general. Twenty-two percent eventually develop distant metastases with the lung being the predominant site.

Conclusions

Given the rarity of this clinical condition and the lack of data from studies with adequate number of cases, this systematic literature analysis provides the best possible relevant evidence.     

Use, accuracy, and implications for patient management of [18F]-2-fluorodeoxyglucose-positron emission/computerized tomography for head and neck tumors

OBJECTIVES/HYPOTHESIS: Positron emission tomography (PET) has shown promise for early detection and accurate staging of cancer patients. A limited number of studies suggest PET/computed tomography (CT) may improve these variables; however, no published study has specifically evaluated clinical outcomes with PET/CT for head and neck (HN) tumors. The current study evaluates the use, accuracy, and implications for patient management of PET/CT scans in patients with HN tumors. STUDY DESIGN: Retrospective cohort outcomes study at a tertiary care center. METHODS: The authors identified 795 consecutive PET/CT at our institution. A total of 113 were obtained for HN tumors; 97 were used in the final analysis. Accuracy, use, and implications for patient care management decisions were correlated with each PET/CT scan. Multiple regression analysis was performed. RESULTS: Accuracy, sensitivity, and specificity were measured by comparing the PET/CT results at the primary tumor site, cervical node sites, and distant sites with either pathologic or definitive clinical diagnoses. PET/CT had an overall per scan accuracy of 72% and a per patient accuracy of 69%. When stratification for rationale of obtaining the scan was performed, accuracy was 80% for staging distant disease, 67% for primary tumor evaluation, 72% for evaluation for recurrence, and 60% for unknown primary tumor evaluation. CONCLUSIONS: PET/CT imaging is a promising tool for evaluating HN tumors; however, in clinical practice, the proper use of such technology is not well studied. In our study, PET/CT had an overall accuracy of 72% in evaluating HN tumors, and PET/CT had the most accuracy in the detection of distant metastasis.     

头颈部鳞癌颈淋巴结转移诸因素对预后的影响

对382例头颈部原发鳞癌病人颈清扫标本连续切片病理观察结果和临床资料进行回顾性分析，探讨淋巴结转移的各项临床和病理学因素与病人预后的关系。发现总体5年生存率为46.1％，口腔癌、口咽癌、下咽癌和喉癌的5年生存率分别为49．7％，39．7％，35．0％和60．3％。表明颈淋巴结的临床分期、触诊淋巴结大小、病理转移淋巴结情况、颈淋巴解剖分区受累数和最低受累平面与病人5年生存率有密切关系（均P＜0．01），而阳性淋巴的个数对病人预后无明显影响。提示针对影响预后的淋巴结因素应采取相应的治疗措施，以提高病人的5年生存率。     

Prevalence and epidemiology of hepatitis C virus in patients with squamous cell carcinoma of the head and neck

OBJECTIVE: Recently, we have noticed that a large number of patients with squamous cell carcinoma of the head and neck (SCCHN) are also infected with the hepatitis C virus (HCV). A review of the literature has revealed no published studies examining this association. The objective of this study was to determine the incidence and epidemiology of HCV infection in patients with SCCHN. STUDY DESIGN: A retrospective chart review. METHODS: Patients diagnosed with SCCHN were analyzed to determine whether they were screened for HCV. Patients were then stratified into two groups (HCV positive and HCV negative). The patient's age at onset, site and stage of the tumor at presentation were determined, and statistical analysis was performed. RESULTS: Ninety-nine (26%) patients were screened, and 21 (21.2%) were HCV positive. This incidence was increased when compared with previously published data (9.9%) (P < .0038). HCV-positive patients presented at an earlier age (51 years) versus the HCV-negative group (60 years) (P < .0002). There were no significant differences in the site or stage at presentation. CONCLUSIONS: In this study, 21% of patients diagnosed with SCCHN were found to be infected with HCV. These patients presented at an earlier age but had similar presentation with respect to site and stage. More research is needed to determine the significance of HCV infection in this patient population.     

AZD5582, an IAP antagonist that leads to apoptosis in head and neck squamous cell carcinoma cell lines and is eligible for combination with irradiation

Conclusion: On the one hand, AZD5582, an inhibitor of inhibitor of apoptosis family proteins (IAP), leads to cellular growth arrest and induction of apoptosis in head and neck squamous cell carcinoma (HNSCC) cell lines. On the other hand, it is a viable candidate for combination therapy with irradiation.

Objectives: The aim and purpose of this study was to evaluate the effects of AZD5582 on HNSCC cell lines.

Methods: HNSCC cell lines SCC25, Cal27, and FaDu were used for all cell culture experiments. Proliferation assays were used to assess a potential inhibitory effect of AZD5582 and a combination therapy of the IAP inhibitor and irradiation. Colony forming assays were used to determine long-term effects of a combined treatment. Apoptosis was measured via flow cytometry and wound-healing assays were performed.

Results: All three cell lines showed a dose-dependent cytotoxic effect after treatment with AZD5582. It was possible to observe a synergistic and additive effect after short-term treatment of AZD5582 and irradiation in Ca27 and FaDu cells, respectively. All test cell lines showed a significant inhibition of colony formation after combined treatment. Treatment of AZD5582 resulted in apoptosis in SCC25, Cal27, and FaDu cells.