DNA repair gene polymorphisms and risk of second primary neoplasms and mortality in oral cancer patients

OBJECTIVES/HYPOTHESIS: We tested the hypothesis that polymorphisms in genes involved in DNA repair pathways are associated with the development of second primary neoplasms of the upper aerodigestive tract (UADT), as well as mortality, in patients previously diagnosed with oral squamous cell cancer (OSCC). METHODS: DNA specimens from 279 OSCC patients who had participated in two previous population-based case-control studies were assayed for the following polymorphisms: X-ray repair cross-complementing (XRCC) 1 Arg399Gln, XRCC3 Thr241Met, xeroderma pigmentosum complementing group D (XPD) Lys751Gln, and O-methylguanine- DNA methyltransferase (MGMT) Leu84Phe and Val143Ile. Baseline demographic information was obtained from personal interviews and tumor characteristics and treatment were obtained from cancer registry files. Cox proportional hazards models were used to calculate hazards ratio (HR) estimates for each polymorphism in relation to the risk of developing second primary neoplasms at any site, UADT, and head and neck. HRs were also determined for associations with all-cause mortality and oral cancer specific mortality. RESULTS: A significant increased risk of second neoplasms (all sites combined, as well as for UADT sites and for head and neck squamous cell cancers) was observed among XRCC3 241Met allele homozygotes (HR 2.65-3.44, P < .02). No significant association with the development of second neoplasms was observed for the XRCC1 399Gln, XPD 751Gln, or MGMT 84Phe or 143Ile alleles. Although no associations with oral cancer-specific mortality were observed, we found a significant inverse association between all-cause mortality and possessing at least one copy of the XRCC1 399Gln allele (HR 0.68, 95% confidence interval [CI] 0.47-0.97, P = .03), as well as a suggestion of a direct association between all-cause mortality and having one copy of the XRCC3 241Met allele (HR 1.39, 95% CI 0.95-2.03, P = .09). CONCLUSIONS: Polymorphisms in the DNA repair enzyme gene XRCC3 241Met was associated with an increased risk of second neoplasms, and polymorphisms of the XRCC1 399Gln gene were associated with a decreased risk of all-cause mortality in patients with primary OSCC. These findings require confirmation in other populations before the clinical implications can be considered.     

ATM相关信号通路在鼻咽癌中的作用研究进展

鼻咽癌是一种与EB病毒感染密切相关的头颈部恶性肿瘤,其发病机制尚未完全阐明。放射治疗是鼻咽癌最主要的治疗手段,而放疗抵抗则容易使肿瘤复发或转移并最终导致放疗失败。共济失调毛细血管扩张突变(ATM)基因主要在DNA双键断裂时被激活,可参与调控DNA损伤修复、细胞周期阻滞和凋亡等过程。研究表明,ATM在鼻咽癌发生发展的不同阶段以及治疗干预的过程中发挥不同的作用,并在鼻咽癌的放疗抵抗中扮演着重要的角色。近年来,通过抑制ATM活性来降低放疗抵抗已成为学者们研究的热点。本文就ATM相关信号通路在鼻咽癌中的作用研究进展进行简要综述,为鼻咽癌的治疗提供参考。     

Cisplatin induces cytoplasmic to nuclear translocation of nucleotide excision repair factors among spiral ganglion neurons

Genomic DNA is a high-affinity target for the antineoplastic molecule cisplatin. Cell survival from cisplatin DNA damage is dependent on removal of cisplatin-DNA adducts by nucleotide excision repair (NER) pathways. The rate-limiting steps in the NER pathways are DNA damage identification and verification. These steps are accomplished by xeroderma pigmentosum complementation group C and A (XPC and XPA) and RNA polymerase II. Unlike RNA polymerase II, XPC and XPA have no known cellular function beyond DNA repair. Cisplatin is known to damage spiral ganglion neurons at the basal coil of the cochlea therefore it was posited that cisplatin may target their DNA and mobilize XPC and XPA. Female Fisher344 rats were given two, four day cycles of cisplatin (2 mg/kg) or saline, separated by a 10 day rest period. A 2 × 3 × 2 factorial design, consisting of two treatment conditions (cisplatin and saline treatment), three survival times (5, 19 and 22 days) and two analysis methods (quantitative RT-PCR and immunohistochemistry) was employed to evaluate the expression and distribution of XPC and XPA. Quantitative RT-PCR revealed statistically significant differences in cochlear XPC and XPA mRNA levels after cisplatin treatment at all times except day 22 for XPA. Immunohistochemistry revealed that a proportion (50%) of spiral ganglion neurons in control rats showed cytoplasmic expression of XPC and XPA. After cisplatin treatment, a similar proportion (50%) of spiral ganglion neurons showed increased nuclear expression of XPC and XPA, which appears to represent translocation from the cytoplasm. Basal coil spiral ganglion neurons translocated XPC and XPA at later treatment cycles and with less magnitude than apical coil neurons after cisplatin treatment. Therefore, it is suggested that cisplatin treatment induces nuclear translocation of NER proteins among spiral ganglion neurons and that this nuclear translocation is less efficient at the base relative to the apex.     

SIRT1激动剂白藜芦醇在眼部疾病中的研究进展

Sirtuins是一类组蛋白去乙酰化酶,它通过控制基因表达、DNA修复、代谢、氧化应激反应、线粒体功能等生物学进程来调节多种活动,而这类酶中,被研究最多的是沉默信息调节因子-1(sirtuin 1, SIRT1)。白藜芦醇作为上调SIRT1活性的天然多酚类化合物,具有很强的抗氧化和抗炎作用,在心脏保护、神经保护、化疗和延缓衰老等方面被广泛研究。而氧化应激和炎症在眼部疾病的发生和发展中起着关键的作用,这些疾病会导致视力渐进性丧失和(或)致盲。综述白藜芦醇在眼部疾病中的潜在用途及其应用的限制性。     

Repair strategy usage by hearing-impaired adults and changes following communication therapy

This investigation documented how hearing-impaired individuals use communication repair strategies in structured settings and determined whether these strategies could be changed by communication therapy. Eight hearing-impaired adults with mild to severe sensorineural hearing losses practiced using five repair strategies when they did not correctly speechread a videotaped sentence. The strategies included asking the talker to (a) repeat the sentence, (b) simplify it, (c) rephrase it, (d) say an important key word, and (e) speak two sentences. Therapy consisted of computerized interactive activities and role-playing with a clinician. Seven hearing-impaired adults served as control subjects and received no therapy. Before and during therapy, subjects usually wanted a misperceived sentence to be repeated. On average, subjects changed their use of repair strategies following therapy. They utilized the repeat strategy less often and other strategies more often.     

Relative effectiveness of three repair strategies on the visual-identification of misperceived words

Experimental videotapes were used to assess the effectiveness of three repair strategies: (1) repetitions, (2) synonyms, and (3) paraphrases. Three groups of normal-hearing adults viewed one of three videotapes. The same 50 test-words were used on each videotape. Each test-item consisted of three stimuli: a test-word, a stimulus that incorporated the repair strategy under investigation, and a repetition of the initial test-word. Each videotape displayed one of the three repair strategies under investigation. The subjects were required to identify test-words presented in a visual-only mode. The results indicated that the performance of the subjects who were provided with synonyms or paraphrases was significantly better than the performance of the subjects who were shown repetitions. Also, subjects who were shown paraphrases performed significantly better than those who were shown synonyms. These findings indicate that repair strategies that incorporate the use of substitute stimuli such as synonyms and paraphrases may be more effective than the simple repetition of the misperceived stimulus.     

Evidence for a causal association for HPV in head and neck cancers

Current data have now attributed a viral etiology and causality of Human papillomavirus (HPV). Epidemiological analysis of the last decade demonstrates a rapid increase of HPV-associated HNSCC. Genomic detection of HPV DNA in the nuclei of certain oro-pharyngeal cancer cells gives strong evidence of a viral etiology in HNSCC. Non-smokers, non-drinkers, and a sexual debut at a younger age and other sexual risk factors have an increased risk of HPV-positive oropharyngeal cancer. Sexual transmission is considered to play a causal role. In contrast to HPV-negative HNSCC most studies reveal a favorable prognosis for HPV-positive tumors. There is evidence of alterations in the p53 pathway through expression of E6 oncogene with subsequent induction of tumor cell proliferation. Synergies between viral oncogenes and other carcinogens are hypothesized. HPV alone appears to be insufficient as the sole cause of HNSCC; this may explain the long latency period between HPV infection and cancer development. There is now sufficient evidence for a causal role for HPV in HNSCC. As in cervical cancer, HPV requires oncogenes and co-factors for tumor development. Thus, inhibition or loss of such co-factors may lead to tumor regression. The vast amounts of epidemiological, molecular pathological and in vitro experimental data are consistent with the hypothesis that HPV does indeed have a causal role. We await final validation from animal experimentation in which regression of HPV-positive tumors will follow from loss or inhibition of E6 and E7.     

DNA ploidy of primary and metastatic squamous cell head and neck cancers.

Regional metastases are a major determinant in the treatment outcome of patients with squamous cell carcinoma of the head and neck. Metastases do not respond as well to cytotoxic therapy as do primary tumors. DNA diploid tumors or tumor components also respond poorly to intermittent cytotoxic therapy. In our series of 497 patients with squamous cell carcinoma of the head and neck, the percentage of pure DNA diploid tumors and the mean DNA indexes in 497 primary tumors and 82 regional metastases were 34% and 1.54 and 50% and 1.34, respectively. Paired comparisons were performed in 61 patients and revealed a statistically significant increase in the frequency of DNA diploid tumors (27.4% to 41.2%) in associated lymph node metastases. The clinical observation that patients with squamous cell carcinoma of the head and neck and regional lymph node metastases have a poorer prognosis and a poorer response to cytotoxic therapy may in part be explained by the increased incidence of DNA diploid tumors in their regional lymph nodes, and the poorer response of such tumors to cytotoxic therapy.     

Transforming growth factor beta 1 genotype and p16 as prognostic factors in head and neck squamous cell carcinoma

Abstract Conclusion: Transforming growth factor β1 gene (TGFβ1) genotype is a potential p16 independent prognostic factor predicting response to chemoradiotherapy in head and neck squamous cell carcinoma (HNSCC). Objectives: Expression of p16 and epidermal growth factor receptor (EGFR) has been reported to be associated with survival in HNSCC. We have previously reported that genetic polymorphism of TGFβ1 is linked with survival in HNSCC patients who have undergone chemoradiotherapy. We evaluate here whether TGFB1 genotype can serve as a prognostic factor independent of tumor p16 and EGFR expression. Methods: Expression of p16 and EGFR was studied by immunohistochemistry in tumors from 130 HNSCC patients. Peripheral blood DNA was used to genotype 95 patients for single nucleotide polymorphism rs1800470 within the TGFβ1 gene. The minimum follow-up time was 31 months. Results: p16 overexpression was associated with an improved disease-free survival (hazard ratio (HR) = 0.39, 95% CI 0.19-0.78), whereas no evident association was observed between EGFR expression and disease-free survival (HR = 0.90, 95% CI 0.68-1.19). Among the 37 patients who had received chemoradiotherapy, TGFβ1 genotype was associated with disease-free (HR = 0.44, 95% CI 0.19-1.02) and overall survival (HR = 0.31, 95% CI 0.12-0.80) independent of tumor p16 expression.     

Resolution of airflow obstruction on polysomnography after laryngotracheal reconstruction with anterior tracheal wall suspension in a patient with DiGeorge Syndrome

DiGeorge Syndrome (DGS) may be associated with airway abnormalities including laryngomalacia and suprastomal collapse of the trachea (SCT), which may lead to sleep disordered breathing (SDB). We present a 4-year-old boy with DGS, SCT, and SDB by polysomnography (PSG) while the tracheostomy tube was capped. The patient underwent anterior tracheal wall suspension (ATWS) with concurrent tracheostomy decannulation. Following the repair, the patient experienced improved airway patency visually and by PSG with resolution of obstructive sleep apnea and hypoventilation. ATWS is an effective method to repair SCT in selected patients and may lead to early decannulation and improvement of SDB.     

Intravestibular space occupying lesions of lipoma and schwannoma

Intravestibular lipoma (IVL) and intravestibular schwannoma (IVS) are rare tumors occupying the intravestibular space. Patients with IVL or IVS complain of hearing impairment, tinnitus or recurrent rotatory vertigo. Therefore, the clinical practitioner could misdiagnose them as sudden sensorineural hearing loss or Meniere's disease. Since delayed diagnosis and treatment could lead to more severe and refractory symptoms, clinicians should have a high index of suspicion for early diagnosis. Recent advancements in imaging diagnostic tools such as computed tomography and magnetic resonance imaging have facilitated the correct diagnosis of these intravestibular tumors without surgical removal. Presently, we report two different kinds of intravestibular tumors of lipoma and schwannoma which manifest different clinical course and treatment strategies.     

Two cases of malignant tumors of the face after hematopoietic stem cell transplantation

INTRODUCTION: Malignant solid tumors are a complication of hematopoietic stem cell transplantation (HSCT). OBSERVATION: Two patients underwent HSCT for acute leukemia. Chronic graft-versus-host disease (GVHD) developed. At 5 years one patient developed squamous cell carcinoma of the tongue and the other mucoepidermoid carcinoma of the parotid gland. DISCUSSION: Several factors are involved in the development of secondary malignant tumors after HSCT. Pre- and post-graft immunosuppressive treatment inhibits the defence system and cell repair and can trigger chronic GVHD with chronic inflammation of the epithelial tissue leading to accelerated cell turn over and a risk of genetic anomalies favoring penetration of viral particles. Squamous cell carcinoma of the oral cavity after HSCT presents the same clinical, histological and prognostic features as in the non-grafted patient. These patients require prolonged surveillance. Improved grafting and ant-HPV vaccination techniques may reduce the risk of cancer after HSCT.     

口咽部鳞状细胞癌与性行为和人乳头状瘤病毒感染

高危型人乳头状瘤病毒感染(high risk human papillomavirus, HR HPV)是头颈部鳞状细胞癌发生的一个重要相关因素,特别是原发口咽部、缺少烟酒等危险因素的患者。口咽肿瘤中确认发现HR HPV,以及流行病学病例对照研究明确HR HPV与口咽癌发病风险的关系,已阐明了二者的联系。重点论述口咽癌患者与非口咽癌患者在口腔、喉腔和下咽部位的比较及性行为方式的影响。明确头颈肿瘤的性行为危险因素对未来肿瘤预防是必不可少的,同时以利于理解现有的HPV疫苗对未来头颈肿瘤预防的潜在作用。同时还扩展到性行为作为口咽癌发生的一个危险因素以及其作为HPV暴露标记的作用,强调HR HPV是通过性行为传播到上呼吸消化道,增加HPV相关的口咽癌的发病风险。     

Increased cytotoxicity of squamous cell carcinoma of the head and neck by combining cisplatin with VP-16 and ciprofloxacin

Chemotherapeutic treatment of squamous cell carcinoma (SCC) of the head and neck has been largely ineffective because of tumor cell resistance. This study examined combinations of cisplatin, 4′ demethylepipodophyllotoxin ethylidene D-glucoside (VP-16), and ciprofloxacin, a quinolone antibiotic. VP-16 and ciprofloxacin were used in an effort to inhibit DNA repair and increase cytotoxicity. Chemotherapeutic agents often have a direct damaging effect on cellular DNA. Cytotoxicity may be the result of incomplete DNA repair mechanisms; whereas tumor cell resistance to drugs may be due to efficient DNA recovery. A nuclear enzyme especially important to DNA repair and cell growth is topoisomerase II (topo II). Targeted inhibition of topo II by VP-16 and ciprofloxacin may cause increased cisplatin cytotoxicity. SCC cell lines of head and neck origin were treatd with a combination of cisplatin, VP-16, and/or ciprofloxacin with cell viability being assessed by the MTT colorimetric assay. Four of five SCC lines examined demonstrated significant augmentation of cisplatin cytotoxicity with the addition of both VP-16 and ciprofloxacin. These in vitro data suggest methods may exist for improving the chemotherapeutic treatment of SCC of the head and neck.     

人乳头状瘤病毒及pRb在头颈鳞状细胞癌中的表达

目的：探讨人乳头状瘤病毒(HPV)和视网膜母细胞瘤蛋白(pRb)在头颈鳞状细胞癌中的表达及其临床意义。方法：对首选手术治疗的73例头颈鳞状细胞癌患者，用GP5( )bioGP6( )介导的酶联吸附免疫PCR和type-specific PCR检测HPV；免疫组织化学法检测pRb在肿瘤组织中的表达。结果：HPV DNA在73例肿瘤组织中的阳性率为12．3％，均为HPV 16 DNA；口咽癌患者HPV阳性率为18．0％，口腔癌患者HPV阳性率为7．5％。pRb在73例肿瘤组织中的阴性率为12．3％。结论：尽管HPV阳性肿瘤临床多为进展期，常伴有颈淋巴结转移，但HPV阳性患者预后较阴性患者为好．提示HPV阳性、pRb阴性的头颈鳞状细胞癌对放疗反应敏感．     

Mutagen sensitivity in patients with multiple primary tumors (MPT) of the head and neck region--quantitative and qualitative assessment based on bleomycin assay

The occurrence of second primary tumors after curative treatment or simultaneous multiple malignancies are current problem in head and neck cancer. The mutagen sensitivity is well known marker to predict patient proneness to develop the second tumor. The frequency and localization of spontaneous and mutagen induced chromatid breaks in peripheral blood lymphocytes (PBLs) in patients with multiple primary tumors (MPT) may help in defining regions involved in cancerogenesis process. The case control study using the bleomycin sensitivity assay (number of chromatid breaks per cell (b/c) was performed in 36 patients with MPT and two control groups: 52 patients with one malignancy and 47 healthy individuals. The differences between examined patients and control groups were estimated using U Mann-Whitney test. The b/c level in PBLs of patients with MPT ranged from 0.26 to 4.12 (mean 1.53) and was significantly higher (p<0.000006) both compared with patients with one malignancy (b/c ranged from 0.02 to 3.08; mean 0.74) and healthy controls (b/c ranged from 0.04 to 1.14; mean 0.41). An increase of b/c index was observed in almost all chromosomal arms. The majority of chromosomal locations with the increased proportion of breaks in the group of patients with multiple tumors were identified as regions where loci involved in DNA repair, cell cycle regulation suppressor genes and oncogenes were found. Statistically higher induced individual susceptibility in MPT patients compared with single tumor and healthy controls was confirmed. Comparable induced mean b/c was found in patients with two smoking-related cancers as well as with not smoking related tumors.     

Craniopharyngioma

Craniopharyngiomas are rare epithelial tumors arising along the path of the craniopharyngeal duct; therefore, they occur in the sellar or suprasellar regions. These tumors commonly lead to neurologic, endocrinological, or visual symptoms. Radical surgery is the treatment of choice in craniopharyngiomas. The transnasal/transsphenoidal endoscopic approach offers the possibility of removing the tumor without retracting brain and optic pathways, with good results. The rate of cerebrospinal fluid fistula has improved due to the use of vascularized mucosal flaps for cranial base reconstruction.