Human papillomavirus 16 and head and neck squamous cell carcinoma

Evidence suggests that human papillomavirus (HPV)16 seropositivity reflects past HPV16 exposure and is associated with risk for head and neck squamous cell carcinoma (HNSCC). Our objectives were to test the hypothesis that HPV16 seropositivity is associated with risk for HNSCC, to correlate HPV16 seropositivity with HPV16 tumor DNA, and to correlate HPV16 seropositivity and HPV16 DNA with sexual history and patient survival. In a case-control study of approximately 1,000 individuals, we assessed serology to the HPV16 L1 protein and in cases only, assayed tumors for HPV16 DNA. HPV16 seropositivity was associated with 1.5- and 6-fold risks for tumors of the oral cavity and pharynx, respectively. There was a dose response trend for HPV16 titer and increasing risk of HNSCC (p < 0.0001) and HPV16 tumor DNA (p < 0.0001). In cases, HPV16 DNA and seropositivity were significantly associated with sexual activity; odds ratios (ORs) of 12.8 and 3.7 were observed for more than 10 oral sexual partners and ORs of 4.5 and 3.2 were associated with a high number of lifetime sexual partners, respectively. Finally, HPV16 seropositivity and HPV16 tumor DNA were associated with hazard ratios of 0.4 and 0.5, respectively, indicating better survival for HPV positive individuals. HPV16 seropositivity was associated with risk for HNSCC, with greatest risk for pharyngeal cancer. We observed dose response relationships between serology titer and both risk for HNSCC and HPV16 tumor DNA. In cases, HPV16 tumor DNA and positive serology were associated with sexual history and improved disease free survival.     

头颈部鳞状细胞癌靶向治疗进展

每年全世界大约有65万例新的头颈癌病例出现,其中绝大多数是头颈部鳞状细胞癌.晚期头颈部鳞状细胞癌的治疗需要综合治疗,尽管放化疗及手术治疗手段在不断发展,但是预后仍不理想且具有一定的毒副反应.靶向治疗是目前治疗研究头颈部鳞癌的热点,其在针对头颈部鳞癌的治疗特别是对局部晚期或复发/转移性头颈部鳞癌治疗中展现出了希望.本文综...     

NM23-H1 expression of head and neck squamous cell carcinoma in association with the response to cisplatin treatment

We recently reported that low NM23-H1 expression of head and neck squamous cell carcinoma (HNSCC) correlated with poor patients'' prognosis. Growing evidence has indicated that high tumor NM23-H1 expression contributes to a good response to chemotherapy. Therefore, we investigated the role of NM23-H1 in susceptibility of HNSCC cells to cisplatin and its clinical significance, as well as the in vitro study for validation was performed. Using immunohistochemistry, we analyzed NM23-H1 expression in surgical specimens from 46 HNSCC patients with cervical metastases receiving surgery and adjuvant chemoradiotherapy. Low tumor NM23-H1 expression correlated with locoregional recurrence of HNSCC following postoperative cisplatin-basedtherapy (p = 0.056) and poor patient prognosis (p = 0.001). To validate the clinical observation and the effect of NM23-H1 on cisplatin cytotoxicity, we established several stable clones derived from a human HNSCC cell line (SAS) by knockdown and overexpression. Knockdown of NM23-H1 attenuated the chemosensitivity of SAS cells to cisplatin, which was associated with reduced cisplatin-induced S-phase accumulation and downregulation of cyclin E1 and A. Overexpression of NM23-H1 reversed these results, indicating the essential role of NM23-H1 in treatment response to cisplatin. NM23-H1 may participate in HNSCC cell responses to cisplatin and be considered a potential therapeutic target.     

PD-1/PD-L1单克隆抗体治疗头颈部鳞癌的研究进展

头颈部鳞癌是以转移和局部侵袭为特征的恶性肿瘤,手术及放疗后复发率高,疾病预后及患者生存质量差。近年来,程序性死亡分子-1(programmed death-1,PD-1)抑制剂被新版美国国立综合癌症网络(NCCN)指南推荐用于治疗复发、不可切除和转移性头颈部鳞癌,其疗效引人瞩目。PD-1单抗为铂类化疗难治性的晚期头颈部鳞癌患者提供了新的治疗手段,降低术后功能丧失的风险,实现改善患者生存质量的目的。本文就免疫检查点PD-1/程序性细胞死亡分子配体-1(programmed death-ligand 1,PD-L1)的结构、作用机制和其抑制剂在治疗头颈部鳞癌中的研究进展等方面进行综述。     

DKK1 在头颈部鳞状细胞癌中的临床价值及其调控因子分析

目的：探讨Dickkopf-1（DKK1）在头颈部鳞状细胞癌（head and neck squamous cell carcinoma,HNSCC）组织中的表达及其调控机制。方法：基于TCGA数据库分析DKK1 在HNSCC组织中的表达水平及其甲基化位点与预后的关系。用GO和KEGG基因富集法分析DKK1 富集基因的信号通路。用STRING 分析DKK1 蛋白与其他蛋白质之间的相互作用。利用TargetScan 分析调控DKK1 表达的miRNA,并通过TRRUST网站分析DKK1 的转录因子。结果：DKK1 基因在HNSCC组织中高表达（P<0.01）,其表达水平与患者HPV状态、年龄、病理分级、临床分期显著相关（均P<0.05）;DKK1 高表达HNSCC患者的预后较低表达者差（P<0.01）。DKK1 存在19 个甲基化位点,其中12 个在癌组织与正常组织间表达差异有统计学意义（P<0.05）,11 个与HNSCC的预后显著关联（P<0.05）。此外,miRNA、circRNA、lincRNA、转录因子等也参与DKK1 的调控,共获取5 个DKK1 相关的PPI 网络可能参与HNSCC的发生、发展、侵袭和转移。结论：DKK1 在HNSCC组织中高表达,并且是HNSCC患者预后差的危险因素,DKK1在HNSCC发病过程中起重要作用,有望成为HNSCC治疗的潜在靶标。     

头颈部鳞癌相关生物标志物与免疫治疗预后的关系

头颈部鳞癌(HNSCC)是世界上第六大常见的恶性肿瘤,每年发病超过55万,死亡超过30万人,吸烟和饮酒是其主要危险因素.HNSCC的治疗方案主要是基于TNM分期、以外科手术为主的综合疗法(放疗、化疗及生物治疗).对于HNSCC的治疗,其5年生存率近年来一直没有改善,因此,需要新的治疗方法提高患者生存率,改善患者生活质量...     

Implications of understanding cancer stem cell (CSC) biology in head and neck squamous cell cancer

Head and neck squamous cell cancer (HNSCC) is the sixth most common cancer in the world. Effective therapeutic modalities such as surgery, radiation, chemotherapy and combinations of each are used in the management of this disease. Efforts are ongoing throughout the world to improve early detection and prevention of HNSCCs. Often, treatment fails to obtain total cancer cure and this is more likely with advanced stage disease. In recent years it appears that one of the key determinants of treatment failure may be the presence of cancer stem cells (CSC) that 'escape' currently available therapies. CSCs form a minute portion of the total tumour burden but may play a disproportionately important role in determining outcomes. Molecular mechanisms which underlie the genesis of CSCs are yet not fully understood and their detection within the total tumour bulk remains a challenge. Specific markers like Aldehyde dehydrogenase 1 (ALDH1), CD44 and Bmi-1 have shown early promising results both in CSC detection and in guiding treatment protocols. CSCs have been shown to be relatively resistant to standard treatment modalities. It is hoped that developing robust in vitro and in vivo experimental models of CSCs might provide a means of devising more effective therapeutic strategies.     

头颈部鳞癌TNM分期的进展与展望

头颈部鳞癌的第8版TNM分期在前版基础上做出了许多重要改进,进一步提高了该分期在评估患者预后、指导治疗方案方面的价值.但很多研究表明,该分期的某些方面仍存在改进的空间.该文将对第8版与第7版TNM分期的主要差异、仍旧存在的不足之处,头颈部鳞癌分期的最新研究进展以及未来的发展方向作简要综述.     

Role of miRNA in head and neck squamous cell carcinoma

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common malignancy worldwide. Evidence suggests that miRNAs play an important role in progression, recurrence, metastasis and postoperative survival of HNSCC. Studies have investigated the utility of miRNAs as diagnostic/prognostic tools and as potential therapeutic targets and biomarkers that may improve the management and outcomes of HNSCC. The aim of this article is to review the current literature on aberrant expression profiles of miRNAs in biopsy samples of HNSCC and their role in cancer development, metastasis, prognosis and survival of these patients. This review gives an overview that miRNAs deregulation play major role in the development of HNSCC. They offer the potential to be used as biomarkers or novel therapeutic targets. Future research is required to test their use in both of these fields.     

Smoking modifies the relationship between XRCC1 haplotypes and HPV16‐negative head and neck squamous cell carcinoma

Reports on the relationship between head and neck squamous cell carcinoma (HNSCC) and polymorphisms in X‐ray cross complementing group 1 (XRCC1) have been inconsistent. We hypothesized this may be due to not accounting for Human papillomavirus type‐16 (HPV16) and thus examined whether smoking modified the association between XRCC1 haplotypes and HNSCC risk within HPV16 serologic strata. Cases were diagnosed in Greater Boston, Massachusetts. Controls were matched to cases on age, gender and residential town. Genotyping was conducted on three XRCC1 polymorphisms (Arg194Trp, Arg280His and Arg399Gln) and serology was used to determine HPV16 exposure. Unconditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs), adjusting for age, sex, race, education, smoking, alcohol consumption and HPV16 serology. There was no overall association between XRCC1 polymorphisms and HNSCC risk. Smoking did not modify the association between XRCC1 polymorphisms and HNSCC risk among the HPV16 seropositive (p_interaction = 0.89) but it did for the HPV16 seronegative (p_interaction=0.04). Among the HPV16 seronegative, heavy smokers with a haplotype containing a variant allele had an increased HNSCC risk (haplotype with 399Gln: OR, 1.35; 95% CI, 0.97–1.86), whereas never/light smokers with variant alleles may have a reduced risk. In sum, the association between XRCC1 and HNSCC risk differed by HPV16 status and smoking. Among the HPV16 seronegative, heavy smokers with XRCC1 variant alleles had an increased HNSCC risk. There was no relationship between XRCC1 and HPV16‐related HNSCC, regardless of smoking. Our findings underscore the importance of accounting for HPV16 exposure even when studying susceptibility to HNSCC. © 2009 Wiley‐Liss, Inc.     

Decreased SMAD4 expression is associated with induction of epithelial-to-mesenchymal transition and cetuximab resistance in head and neck squamous cell carcinoma

Epidermal growth factor receptor (EGFR) is frequently overexpressed in head and neck squamous cell carcinoma (HNSCC) and cetuximab, a monoclonal antibody targeting this receptor, is widely used to treat these patients. In the following investigation, we examined the role of SMAD4 down-regulation in mediating epithelial-to-mesenchymal transition (EMT) and cetuximab resistance in HNSCC. We determined that SMAD4 downregulation was significantly associated with increased cell motility, increased expression of vimentin, and cetuximab resistance in HNSCC cell lines. In the HNSCC genomic dataset obtained from The Cancer Genome Atlas, SMAD4 was altered in 20/279 (7%) of HNSCC via homozygous deletion, and nonsense, missense, and silent mutations. When SMAD4 expression was compared with respect to human papillomavirus (HPV) status, HPV-positive tumors had higher expression compared to HPV-negative tumors. Furthermore, higher SMAD4 expression also correlated with higher CDKN2A (p16) expression. Our data suggest that SMAD4 down-regulation plays an important role in the induction of EMT and cetuximab resistance. Patients with higher SMAD4 expression may benefit from cetuximab use in the clinic.     

Hyperfractionated radiotherapy in advanced squamous cell carcinoma of the head and neck

From January, 1976 to January, 1980, 141 patients (135 males and 6 females) with Stage III and IV squamous cell carcinoma of the head and neck received a split course of hyperfractionated radiotherapy (HFR). In the first group, involving 91 patients, the therapeutic schedule was as follows: first and fourth week, 7.2 Gy per day in 8 sessions of .9 Gy from Monday to Friday, the second and third week no irradiation was given. Thus, patients were given 72 Gy total dose, fractionated into 80 sessions. Mucosal necrosis and severe hemorrhage were responsible for the death of 26 patiens (28%). Therefore the therapeutic protocol was altered for the 50 patients of the second group: during the first and sixth week 6.6 Gy per day in 6 sessions of 1.1 Gy from Monday to Friday. The total dose was thus reduced to 66 Gy fractionated into 60 sessions, resulting in the decrease of toxicity. Regardless of the therapeutic protocol and site of primary, 114 patients (80%) achieved a complete remission and 8 showed a partial remission (>50%), whereas no change was seen for the 19 remainders. Local recurrence appeared in 60 patients (48%). Acute mucositis and laryngeal edema regularly occurred a week after every course of HFR and were considered severe in 40 patients. In spite of toxicity, the median survival is 14 months and 22 patients are still alive in November 1981: 19 without disease, and 8 of these patients have a survival time of at least 3 years.     

Phase II study of pemetrexed in combination with cisplatin and cetuximab in recurrent or metastatic squamous cell carcinoma of the head and neck

PurposePlatinum/5-fluorouracil plus cetuximab is a standard systemic treatment for recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN). Pemetrexed has shown activity in SCCHN. This phase II study evaluated pemetrexed with cisplatin and cetuximab in recurrent/metastatic SCCHN.MethodsPatients received cetuximab 250 mg/m² (loading dose: 400 mg/m²) days 1, 8 and 15; pemetrexed 500 mg/m² + cisplatin 75 mg/m² on day 1, q3w up to six cycles and folic acid, vitamin B₁₂ and prophylactic medications. After a minimum of four cycles, responding patients were eligible for maintenance with pemetrexed and cetuximab, or either as monotherapy, until progression or toxicity. Efficacy (primary end-point: progression-free survival [PFS]) and toxicity were evaluated.ResultsSixty-six patients received ?1 cycle of the triplet. Most patients were male (80.3%), with a median age of 62 years and Eastern Cooperative Oncology Group (ECOG) performance status of 1 (71.2%). Diagnoses included oropharynx (45.5%) and larynx (24.2%) cancers, with locoregional disease (51.5%) alone, or combined with distant metastases (48.5%). Median (m) PFS was 4.4 months (95% confidence interval [CI]: 3.6, 5.4); median overall survival was 9.7 months (95% CI: 6.5, 13.1). Objective response rate was 29.3%; 23 patients had stable disease (39.7%). Drug-related grade 3/4 toxicities included neutropaenia (33.3%), fatigue (24.2%), anorexia (12.1%) and infection (10.6%). Five treatment-related deaths (7.6%) occurred.ConclusionsEfficacy results were consistent with current standard treatment for this patient population, but the pre-specified mPFS of 5.5 months was not achieved. Grade 3/4 toxicities were also consistent with standard treatment, although treatment-related deaths were higher than expected.     

CD39 在头颈部鳞状细胞癌组织中的表达及其预后价值

目的：检测CD39 在头颈鳞状细胞癌（head and neck squamous cell carcinoma,HNSCC）组织中的表达,分析其表达与患者临床病理特征的关系及其预后意义。方法：选用2012 年5 月至2013 年12 月在天津市肿瘤医院接受外科手术的85 例HNSCC患者的组织标本及病例资料,Oncomine 数据库获取的基因芯片,以及HNSCC细胞系SCC15、UM1 和Cal25。在线分析CD39 在HNSCC组织与正常颊黏膜组织转录水平的差异性,用Western blotting 和免疫组化法检测HNSCC组织中CD39 蛋白的表达。采用Spearman’s 检验分析HNSCC组织中CD39 的表达与患者临床病理特征的相关性,Kaplan-Meier 曲线法和Log rank 检验分析HNSCC组织CD39 表达与生存的关系,Cox风险比例回归模型评价CD39 表达与复发风险的关系。结果：CD39 在HNSCC组织的转录水平显著高于正常颊黏膜组织（P<0.01）,其在HNSCC细胞Cal25、SCC-15 和UM1 中均有表达,UM1 细胞中CD39的表达呈地塞米松（dexamethasone, DXM）剂量依赖性。CD39 高表达患者53（62.4%）例,其高表达与术前化疗正相关（r=0.234,P<0.05）,CD39 高表达患者的无复发生存期较低表达组显著缩短（P<0.05）,CD39 高表达是HNSCC 复发的独立风险因素（HR=2.328,95%CI=1.091~4.967;P<0.05）。结论：CD39 在HNSCC中呈DXM诱导性表达和组成性表达,其在癌组织中过表达是HNSCC患者不良预后的独立预测因子,提示其在HNSCC进展过程中可能发挥重要作用。     

Cyclin L1 (CCNL1) gene alterations in human head and neck squamous cell carcinoma

We evaluated the expression and amplification of cyclin L1 (CCNL1) gene, a potential oncogene localised in the commonly amplified 3q25-28 region, in human head and neck squamous cell carcinomas (HNSCCs). Overexpression was observed in 55 out of 96 cases (57%) and amplification in nine out of 35 tumours (26%) with no relationships to the clinico-pathological parameters. The Cyclin L1 antibody we developed labels nuclear speckles in tumour cells compatible with a role for CCNL1 in RNA splicing.     

Cancer stem cell related markers of radioresistance in head and neck squamous cell carcinoma

Despite recent advances in understanding of the molecular pathogenesis and improvement of treatment techniques, locally advanced head and neck squamous cell carcinoma (HNSCC) remains associated with an unfavorable prognosis. Compelling evidence suggests that cancer stem cells (CSC) may cause tumor recurrence if they are not eradicated by current therapies as radiotherapy or radio-chemotherapy. Recent in vitro studies have demonstrated that CSCs may be protected from treatment-induced death by multiple intrinsic and extrinsic mechanisms. Therefore, early determination of CSC abundance in tumor biopsies prior-treatment and development of therapeutics, which specifically target CSCs, are promising strategies to optimize treatment. Here we provide evidence that aldehyde dehydrogenase (ALDH) activity is indicative for radioresistant HNSCC CSCs. Our study suggests that ALDH⁺ cells comprise a population that maintains its tumorigenic properties in vivo after irradiation and may provide tumor regrowth after therapy. We found that ALDH activity in HNSCC cells can be attributed, at least in part, to the ALDH1A3 isoform and inhibition of the ALDH1A3 expression by small interfering RNA (siRNA) decreases tumor cell radioresistance. The expression dynamic of ALDH1A3 upon irradiation by either induction or selection of the ALDH1A3 positive population correlates to in vivo curability, suggesting that changes in protein expression during radiotherapy are indicative for tumor radioresistance. Our data indicate that ALDH1A3⁺ HNSCC cells may contribute to tumor relapse after irradiation, and inhibition of this cell population might improve therapeutic response to radiotherapy.