Prospect of Functional Salivary Gland Enhancement with Biomedical Strategies for Head and Neck Cancers

Xerostomia is the main complication inflicting head and neck cancer patients treated with radiotherapy.Conventional treatment is not very effective in alleviating this morbidity.Biomedical strategies such as gene transfer and tissue engineering have made substantial progress that will potentially lead to successful new treatment options for this condition.This report reviews the process of radiation damage to the salivary glands and the advances in functional salivary gland enhancement with these two brand-new technologies.     

Safety and efficacy of adenovirus-mediated transfer of the human aquaporin-1 cDNA to irradiated parotid glands of non-human primates

This study evaluated the safety and efficacy of a single administration of a recombinant adenovirus encoding human aquaporin-1 (AdhAQP1) to the parotid glands of adult rhesus monkeys. In anticipation of possible clinical use of this virus to correct irradiation damage to salivary glands, AdhAQP1 was administered (at either 2 x 10(9) or 1 x 10(8) plaque-forming units/gland) intraductally to irradiated glands and to their contralateral nonirradiated glands. Radiation (single dose, 10 Gy) significantly reduced salivary flow in exposed glands. Virus administration resulted in gene transfer to irradiated and nonirradiated glands and was without untoward local (salivary) or systemic (sera chemistry, complete blood count) effects in all animals. However, the effect of AdhAQP1 administration varied and did not result in a consistent positive effect on salivary flow rates for all animals under these experimental conditions. We conclude that a single adenoviral-mediated gene transfer to primate salivary glands is well-tolerated, although its functional utility in enhancing fluid secretion from irradiated parotid glands is inconsistent.     

Prevention of radiation induced xerostomia by surgical transfer of submandibular salivary gland into the submental space.

BACKGROUND AND PURPOSE: Xerostomia is a significant morbidity of radiation treatment in the management of head and neck cancers. We hypothesized that the surgical transfer of one submandibular salivary gland to the submental space, where it can be shielded from radiation treatment (XRT), would prevent xerostomia. MATERIALS AND METHODS: We conducted a prospective Phase II clinical trial and the patients were followed clinically with salivary flow studies and the University of Washington Quality of Life questionnaire. RESULTS: We report the results on 76 evaluable patients. The salivary gland transfer was done in 60 patients. Nine patients (of 60) did not have postoperative XRT and in eight patients (of 60) the transferred gland was not shielded from XRT due to proximity of disease. The median follow up is 14 months. Of the 43 patients with the salivary gland transfer and post-operative XRT with protection of the transferred gland, 81% have none or minimal xerostomia, and 19% developed moderate to severe xerostomia. Three patients (6.9%) developed local recurrence, five patients (11.6%) developed distant metastases and five patients (11.6%) have died. There were no complications attributed to the surgical procedure. CONCLUSION: Surgical transfer of a submandibular salivary gland to the submental space preserves its function and prevents the development of radiation induced xerostomia.     

Radiation-induced xerostomia in patients with head and neck cancer: a literature review

A dry mouth or xerostomia is one of the most common complications during and after radiotherapy for head and neck cancer, because irreparable damage is caused to the salivary glands, which are included in the radiation fields. Xerostomia not only significantly impairs the quality of life of potentially cured cancer patients, it may also lead to severe and long-term oral disorders. Because management of xerostomia is rarely effective, prevention is paramount. Several strategies have been developed to avoid radiation-induced salivary dysfunction without compromising definitive oncologic treatment. These include salivary gland-sparing radiation techniques, such as 3-dimensional conformal or intensity-modulated radiotherapy, concomitant cytoprotectants, and surgical salivary gland transfer. However, these preventive approaches are not applicable to all patients, and comprehensive scientific research that incorporates new biological insights is warranted to optimize the therapeutic index of radiotherapy for head and neck cancer.     

颌下腺移位预防鼻咽癌放疗后口干燥症安全性评价的临床对照研究

目的:评价颌下腺移位术预防鼻咽癌放疗后口干燥症的安全性.方法:选择符合入选标准的鼻咽癌患者70例,分为试验组36例和对照组34例.试验组放疗前将颌下腺移位至颏下区,术后接受常规放疗,放疗时颏下区设置挡块.对照组直接行常规放疗.比较试验组和对照组的口干程度、5年颈淋巴结复发率及5年生存率.结果:放疗后60个月,对照组中度至重度口干燥症的发生率高于试验组(78.6% vs 12.9%),差异有统计学意义,P=0.000.试验组和对照组颈部淋巴结复发率分别为11.1%(4/36)和11.8%(4/34) ,两者之间差异无统计学意义,P=0.93.复发部位均在Ⅱ区.5年生存率试验组为86.1%(31/36),对照组82.4%(28/34),两者之间差异无统计学意义,P=0.67.结论:颌下腺移位术可预防鼻咽癌放疗后口干燥症,改善鼻咽癌患者放疗后的生存质量.颌下腺移位术预防鼻咽癌放疗后口干燥症不影响鼻咽癌远期疗效且安全可行.     

唾液腺放射性损伤及其防护

放射治疗在头颈肿瘤的地位已得到广泛认同,但放疗并发症不容忽视,最常见的是放射性口干。其主要机制为放射诱导的唾液腺损伤,早期和晚期损伤的机制不同。目前对唾液腺放射防护的研究主要集中在放射防护剂、放射技术、基因转移技术等多个方面。     

Salivary gland sparing in the treatment of head and neck cancer

Radiotherapy is an important component of the multimodality treatment of head and neck cancer. Although an effective treatment for many patients, it can have significant long-term sequelae. In particular, xerostomia - or dry mouth - caused by salivary gland injury is a serious problem suffered by most patients and leads to problems with oral comfort, dental health, speech and swallowing. This article explores the mechanisms behind radiation injury to the major salivary glands, as well as different strategies to minimize and alleviate xerostomia. This includes technical approaches to minimize radiation dose to salivary tissue, such as intensity-modulated radiotherapy and surgical transfer of salivary glands, as well as pharmacologic approaches to stimulate or protect the salivary tissue. The scientific literature will be critically examined to see what works and what strategies have been less effective in attempting to minimize xerostomia in head and neck cancer patients.     

Salivary gland sparing in the treatment of head and neck cancer

Radiotherapy is an important component of the multimodality treatment of head and neck cancer. Although an effective treatment for many patients, it can have significant long-term sequelae. In particular, xerostomia – or dry mouth – caused by salivary gland injury is a serious problem suffered by most patients and leads to problems with oral comfort, dental health, speech and swallowing. This article explores the mechanisms behind radiation injury to the major salivary glands, as well as different strategies to minimize and alleviate xerostomia. This includes technical approaches to minimize radiation dose to salivary tissue, such as intensity-modulated radiotherapy and surgical transfer of salivary glands, as well as pharmacologic approaches to stimulate or protect the salivary tissue. The scientific literature will be critically examined to see what works and what strategies have been less effective in attempting to minimize xerostomia in head and neck cancer patients.     

Progress in Cancer Gene Therapy

Many technical difficulties have to be overcome before effective gene therapy can be achieved. Strategies for gene therapy include 'suicide' gene therapy, transfer of a tumor suppressor gene, inhibition of activated oncogenes by antisense mechanisms, and cytokine gene transfer and tumor cell vaccination. Gene therapy will have a major impact on the healthcare of our population only when vectors are developed that can safely and efficiently be injected directly into patients as drugs. One of the most promising areas of vector development is that of non-viral vectors, which consist of liposomes, molecular conjugates, and naked DNA delivered by mechanical methods. Future research should be focused on modifying viral vectors to reduce toxicity and immunogenicity, increasing the transduction efficiency of non-viral vectors, enhancing vector targeting and specificity, regulating gene expression, and identifying synergies between gene-based agents and other cancer therapeutics. The evaluation of gene therapy combinations is another important area for future research. The identification of tumor rejection antigens from a variety of cancers and the immune response that is defective in cancer patients are important topics for future studies. A universal gene delivery system has yet to be identified, but the further optimization of each of these vectors should result in each having a unique application. Gene therapy has still a long way to go and requires the efforts of investigators in the basic and clinical sciences. Despite substantial progress, a number of key technical issues need to be resolved before gene therapy can be effectively applied in the clinic.     

颌下腺移位术预防鼻咽癌放疗后口干燥症的长期效果

目的:评价颌下腺移位术预防鼻咽癌放疗后口干燥症的长期效果.方法:70例鼻咽癌患者随机分为试验组36例和对照组34例.试验组在行常规放疗前将颌下腺移位至颏下区,放疗时颏下区设置挡块.~(99)T_c核素扫描检测放疗前后颌下腺功能,测定放疗前后唾液分泌量,放疗后60个月进行口干程度问卷调查,统计5年生存率.结果:放疗后60个月:试验组颌下腺摄取、分泌功能均明显较对照组好,两者之间有显著性差异,P值分别为0.000和0.000;试验组和对照组唾液量的平均值分别为1.65g和0.73g(P=0.000);试验组中度至重度口干燥症的发生率亦显著低于对照组(12.9% vs 78.6%,P=0.000);试验组和对照组的5年生存率分别为86.1%和82.4%,两者之间无显著性差异(P=0.67).结论:颌下腺移位术不影响鼻咽癌远期疗效,预防鼻咽癌放疗后口干燥症的长期效果良好,可改善鼻咽癌患者放疗后的生存质量.     

Upfront submandibular salivary gland transfer in pharyngeal cancers

Head and neck irradiation results in salivary dysfunction and subsequent xerostomia. Twenty two patients with squamous cancer of oropharynx or hypopharynx underwent contralateral submandibular salivary gland transfer (SMSGT) to submental triangle to shield it from subsequent radiotherapy. Resting salivary outputs of transferred and untransferred gland (control) were measured before and after SMSGT and following radiotherapy, by cannulating individual submandibular duct. They were compared by paired samples t-test. Following radiation therapy transferred gland retained 73% and untransferred gland (control) retained 27% of baseline salivary output. This significant difference in post-radiation salivary outputs suggests preservation of function of transferred salivary gland.     

Carcinogenesis ofnasopharyngeal carcinoma：an alternate hypothetical mechanism

Current proposed mechanisms implicate both early and latent Epstein–Barr virus (EBV) infection in the carcinogenic cascade, whereas epidemiological studies have always associated nasopharyngeal carcinoma (NPC) with early child-hood EBV infection and with chronic ear, nose, and sinus conditions. Moreover, most patients with NPC present with IgA antibody titers to EBV capsid antigen (VCA-IgA), which can precede actual tumor presentation by several years. If early childhood EBV infection indeed constitutes a key event in NPC carcinogenesis, one would have to explain the inability to detect the virus in normal nasopharyngeal epithelium of patients at a high risk for EBV infection. It is perhaps possible that EBV resides within the salivary glands, instead of the epithelium, during latency. This claim is indirectly supported by observations that the East Asian phenotype shares the characteristics of an increased sus-ceptibility to NPC and immature salivary gland morphogenesis, the latter of which is inlfuenced by the association of salivary gland morphogenesis with an evolutionary variant of the human ectodysplasin receptor gene (EDAR), EDARV370A. Whether the immature salivary gland represents a more favorable nidus for EBV is uncertain, but in patients with infectious mononucleosis, EBV has been isolated in this anatomical organ. The presence of EBV-induced lymphoepitheliomas in the salivary glands and lungs further addresses the possibility of submucosal spread of the virus. Adding to the fact that the fossa of Rosen Müller contains a transformative zone active only in the ifrst decade of life, one might be tempted to speculate the possibility of an alternative carcinogenic cascade for NPC that is perhaps not dissimilar to the model of human papillomavirus and cervical cancer.     

Clinical update of Ad-p53 gene therapy for lung cancer

These preliminary Phase I and II gene therapy trials in NSCLC have demonstrated that Ad-p53 gene transfer is associated with low toxicity and evidence of antitumoral activity at the locoregional site. Effort to enhance antitumoral efficacy with chemotherapy and radiation therapy have not increased Ad-p53 toxicity and appear to be feasible. Randomized Phase III studies are now needed to determine the potential of Ad-p53 to improve overall survival in selected subsets of NSCLC patients. Future gene therapy research is required to develop systemic delivery systems and to overcome p53 tumor resistance. It is hoped that these efforts will ultimately lead to a novel mode of therapy to complement conventional chemotherapy, radiation therapy, and surgical treatment strategies.     

Estimation of long-term salivary gland damage induced by radiotherapy

A classification is proposed for estimating salivary gland damage induced by radiotherapy to the head and neck. The volume of salivary glands irradiated was evaluated, and their relative proportions of whole saliva output were calculated. Stimulated salivary flow rate was measured in 61 patients treated with radiotherapy for head and neck malignancies. A highly significant negative correlation was found between the classification of salivary gland damage and stimulated salivary flow rate. The volume of the major salivary glands irradiated seems to be the most important factor affecting the postirradiation salivary flow after a curative dose of radiotherapy. If possible, partial sparing of the salivary glands may help to keep the patient's salivary secretion at an acceptable level and promote protection against dental caries. Most patients irradiated to the head and neck, however, need an effective prophylactic programme for the rest of their lives in order to preserve their teeth.     

Prevention of Radiation Induced Xerostomia and Improved Quality of Life: Submandibular Salivary Gland Transfer

Over 60,000 new cases of head and neck cancers, and approximately 15,000 deaths occur every year in the United States (1). Head and neck cancers affect more men then women by a factor of 2:1, although the incidence of women is increasing as a result of increased tobacco use (2). Over 90% of all head and neck cancers are squamous cell carcinomas; most of the remaining cancers are adenocarcinomas. A combination of radiation therapy and surgery is used as the standard, primary treatment modality. Xerostomia occurs when the salivary glands are affected by irradiation. Patients experiencing xerostomia are at an increased risk for a wide variety of oral problems; all adversely affecting one's quality of life. Currently patients make lifestyle changes, dietary modifications, and use artificial salivas, sprays, gels, and lozenges to help mask their xerostomia. However, none of these products stimulate natural salivary production and act as a replacement therapy rather then a cure for xerostomia. A new protocol, RTOG 1083 has been approved by the Radiation Therapy Oncology Group, which involves a surgical transfer of a submandibular salivary gland to the submental space (where it can be easily shielded) as a method of prevention of radiation induced xerostomia.     

涎腺腺样囊性癌中Runx3基因启动子区5'-CpG岛的甲基化演进规律

目的 研究涎腺腺样囊性癌(SGACC)中Runx3基因启动子区5'-CpG岛甲基化的关键位点和演进规律.方法 以定量甲基化特异性PCR(qMSP)检测41例SGACC及配对的癌旁正常涎腺组织中Runx3基因启动子区5'-CpG岛(3478 bp)10个位点的甲基化状态,分析Runx3基因甲基化与SGACC临床病理特征的关系,用Logistic模型分析Runx3基因及各位点甲基化在SGACC中发生的危险度.用Western blot法检测19例SGACC及其相应癌旁正常涎腺组织中Runx3蛋白的表达,分析Runx3基因甲基化对Runx3蛋白表达的影响.结果 SGACC及其相应癌旁正常涎腺组织中,Runx3基因启动子区CpG岛(3478 bp)第1～10个位点的甲基化阳性率分别为42.69%～85.69%和22.17%～59.43%,正常涎腺组织中Runx3基因各位点的甲基化率均显著低于SGACC(P＜0.01).其中第1、2位点甲基化程度最高,向转录起始点方向甲基化程度逐渐减弱,在转录起始点位置(第7、8位点)甲基化程度最低,向3'端方向甲基化程度又略微升高.Logistic模型分析结果显示,Runx3甲基化是SGACC发生的一个重要因素,Runx3甲基化从5'端向转录起始点方向演进,转录起始点区可能是Runx3甲基化的关键位点.Western blot检测结果显示,SGACC组织中Runx3蛋白的表达量显著低于相应的癌旁正常涎腺组织(P＜0.01).结论 SGACC组织中Runx3基因甲基化从5'端向转录起始点方向演进,转录起始点部位可能是Runx3基因甲基化的关键位点.Runx3基因甲基化是引起Runx3蛋白表达下调的原因之一,与SGACC的发生有关.     

颌下腺移位术预防鼻咽癌放疗后口干燥症的近期效果

背景与目的:口干燥症是鼻咽癌放疗后最常见的后遗症之一,它严重影响患者放疗后的生存质量。本研究旨在探讨颌下腺移位术预防鼻咽癌放疗后口干燥症的临床效果。方法:共选择70例病例进行前瞻性非随机临床对照研究。试验组选择符合入选标准的鼻咽癌患者36例,在放疗前将颌下腺移位至颏下区,术后接受常规放疗,放疗时颏下区设置挡块。观察放疗中急性口腔粘膜反应,应用锝-99核素扫描检测放疗前后颌下腺功能的变化,测定放疗前后唾液分泌量的变化,放疗后3个月进行口干程度问卷调查。对照组(34例)不行颌下腺移位术,其余处理方法同试验组。将试验组的术侧与非术侧以及试验组与对照组的上述观察指标进行比较。结果:试验组急性口腔粘膜反应明显轻于对照组(P=0.007)。试验组放疗后3个月移位术侧颌下腺摄取、排泌功能均明显较未移位术侧者好,两者之间有非常显著性差异(P值分别为0.001和0.000);试验组颌下腺摄取、排泌功能均明显较对照组者好,两者之间有非常显著性差异(P值分别为0.004和0.000)。试验组放疗后唾液分泌量的平均值为1.41g,而对照组放疗后唾液分泌量平均值为0.71g。对照组76.5%的患者有中度至重度的口干燥症,试验组仅13.9%的患者有中度至重度的口干燥症,两者之间有非常显著性差异(P=0.000)。结论:颌下腺移位     

Partial irradiation of the parotid gland

Recent efforts to reduce xerostomia associated with irradiation (RT) of head and neck cancer include the use of conformal and intensity-modulated RT (IMRT) to partly spare the major salivary glands, notably the parotid glands, from a high radiation dose while treating adequately all the targets at risk of disease. Knowledge of the dose-volume-response relationships in the salivary glands would determine treatment planning goals and facilitate optimization of the RT plans. Recent prospective studies of salivary flows following inhomogeneous irradiation of the parotid glands have utilized dose-volume histograms (DVHs) and various models to assess these relationships. These studies found that the mean dose to the gland is correlated with the reduction of the salivary output. This is consistent with a pure parallel architecture of the functional subunits (FSUs) of the salivary glands. The range of the mean doses, which have been found in these studies to cause significant salivary flow reduction is 26 to 39 Gy.