臺灣博碩士論文加值系統

對放射線特別敏感的頭頸部腫瘤，尤其如扁桃腺癌、鼻咽癌等而言，放射治療常為臨床治療之首選，可單獨、合併化學治療或為輔助療法；但患者易因放療後遺症，如唾液腺功能障礙和猛爆性齲齒等，嚴重影響生活品質，對牙醫師和腫瘤科醫師都是一長期挑戰。另一方面，建立動物研究模式將有助於放射腫瘤學的長期發展。
本研究之第一單元為頭頸癌放射治療患者之口腔照護模式研究。收集高醫口腔病理科放治化療門診370位頭頸癌中的232位鼻咽癌和62位口腔癌患者(共佔所有頭頸癌患之79.5 %)為主要研究對象。對鼻咽癌患者而言，放療後齲齒數增加極為顯著(7.18 ±7.10 與2.45±2.85; c2= 46.32, p < 0.0001)，而氟托的配製與否和回診率具極顯著之相關性(c2=48.56, p < 0.0001)。相對之，口腔癌患者放療後齲齒並未增加，且回診率與氟托配製與否亦無關，但其存活率雖較鼻咽癌為低，回診率卻與其存活狀況有顯著相關。因此，鼻咽癌與口腔癌患者應有不同的照顧模式。鼻咽癌的口腔照護應以完整的長期照護，減少因口乾引起之齲齒等口腔疾病為主，鼓勵居家塗氟與定期回診，口腔癌則以減輕口腔症狀為主，避免感染，提高其口腔舒適度。
第二單元為建立癌症動物的放療模式。將53隻倉鼠隨機分為治療組A與B及控制組C到G後，A與B組於頰囊塗抹誘癌劑7, 12-dimethyl benz[a]anthrance(DMBA)，每週三次，共12週，再以分次照射方式，以6MV直線加速器每週二次，每次7Gy，分別給予放射量21與42 Gy；未塗抹誘癌劑的C與D組亦給予放射量21與42 Gy，E組與F組分別於頰囊塗抹DMBA與礦物油；而G組則未給予任何處置。
實驗結果發現：倉鼠頰囊袋於癌化後及放射治療後，頰囊袋容積明顯減少三分之一與二分之一。分次放射的模式下，C與D組倉鼠頰囊並無明顯的黏膜炎產生。照射21Gy可使倉鼠在外觀上有殘餘腫瘤的動物數減少(5/9，55.55% )，但鏡檢下之內生型腫瘤數卻顯著增多；照射42Gy時，外觀留有殘餘腫瘤的動物數更少(1/9，11.11% )，且鏡檢下的外生型腫瘤數及總腫瘤數均明顯減少。放療前後鏡檢下的外生型腫瘤數及總腫瘤數於三組間具極顯著之統計差異(p<0.0001, p<0.001)。放療的主要機制為壞死，但鏡檢下仍有殘餘腫瘤細胞，顯示腫瘤復發之可能性。
免疫組織化學染色之結果顯示：放射引發的自戕反應，部份與p53及一氧化氮合成酶的表現有關；而對腫瘤細胞自戕反應的影響，抑制細胞自戕蛋白質survivin 於殘餘腫瘤細胞中呈陽性反應，證實其與放射抗性有關； 42Gy下，p53不表現，可能由於iNOS的作用使放射敏感性增加。此外，由TUNEL染色可觀察唾液腺的早期幅射損傷。頷下腺中的漿液細胞及管道細胞的自戕現象較高，但黏液細胞幾乎不表現，且頷下腺的放射敏感度高於耳下腺，並伴隨劑量而增。
總括以上，本研究之結論如下：(1) 放療前的牙科治療計劃
應同時納入頭頸癌患者的放療計劃中；(2) 倉鼠頰囊袋癌模型可應用於正常組織與癌細胞之分次放射效應之研究。

Radiotherapy (RT) is an effective treatment for radiosensitive head and neck (H&N) cancers, especially for carcinomas of nasopharynx(NPC) and tonsil. It is wildly used either alone or concurrent with chemotherapy. The side effects of RT, particularly the irreversible salivary gland damage and rampant caries severely affects the quality of life of surviving patients, these complications present long-term challenges to both dentists and oncologists. On the other hand, the establishment of an animal caner model for RT will facilitate the development on radiooncological sciences.
Therefore, the aim of the fist part of this study was to construct an oral care model of H&N radiotherapy patients. A total of 232 NPC and 62 oral cancer patients underwent regular recall dental examinations and treatments according to a standard protocol of our Dental Department. The mean number of carious tooth of the NPC patient population during/after RT was significantly higher than the population before RT (7.18±7.10 vs. 2.45±2.85; c2= 46.32, p<0.0001). As compared patients using fluoride trays to those without using, the former had a significantly higher rate of dental follow-up compliance (c2=48.56, p<0.0001). Therefore, fluoride tray fabrication is recommended for dentate NPC patients receiving RT. By contrast, the oral cancer RT patients, their caries rate was not related to radiation experience, and their dental compliances were related to their survival condition rather than fluoride trays. Therefore, the oral care model should be modified for NPC and oral cancer patients according to their different treatment modalities.
The objective of the second part study was to establish an animal cancer model for RT. Fifty-three hamsters was divided randomly into the experimental groups A, B and control groups C to G. After treating the pouches of groups A and B animals with 7, 12-dimethyl benz[a]anthrance (DMBA) thrice a week for 12 weeks, the heads of the animals received fractionated radiation (7Gy/twice/week) of a total dose of 21Gy and 42Gy with a 6 MV linear accelerator, respectively. The untreated pouches of groups C and D animals were similarly irradiated. The pouches of groups E and F animals were treated with DMBA or mineral oil for 12 weeks, respectively. The pouches of group G animals remained untreated throughout the experiment.
The volume of buccal pouches were significantly decreased to 2/3 and less than 1/2 after carcinoma induction and RT in both groups A and B when comparing with group G. There were no obvious mucositis after fractionated radiation in groups C and D. 55.55% in groups A (5 in 9 animals) and 11.11% in B (1 in 9 animals) have visible residual exophytic tumors after RT. Microscopically, the endophytic tumor numbers in group A was significant increased when compared with group E. Both the exophytic tumor and total tumor numbers were decreased for group B animal. There were significant differences on the exophytic tumor and total tumor numbers among groups A, B and E (p<0.0001, p<0.001). Moreover, the main radiogenic killing effect is necrosis, but the residual tumor cells indicating the possibilities of recurrence.
Immunohistological examinations showed p53 and iNOS were associated with the radiation-induced apoptosis of the hamster buccal pouches. The radioresistancy of DMBA-induced buccal pouch carcinoma of hamster may be related to over-expression of survivin, an antiapoptosis protein. Although p53 was not expressed in animals receiving high radiation dose, iNOS may increase the radiosensitivity. Furthermore, via TUNEL staining, the early apoptosis was found in serous cells and ductal cells rather than mucous cells of the parotid and submandibular glands, but submandibular glands were more radiosensitive than parotid counterparts.
In conclusion, our study indicate that, (1) a pre-RT dental care regimen should be conducted simultaneously with the H&N cancer patient’s treatment plan to treat the disease; (2) the hamster pouch cancer model could be employed to study the fractionated radiation effect on both cancer cells and normal tissues.

第一單元 頭頸癌放射治療患者之口腔照護模式研究
The study of oral care model for head and neck cancer radiotherapy patients 1
第一章 前 言 2
第一節 研究的重要性 2
第二節 研究目的 3
第二章 文獻回顧 4
第一節 鼻咽癌與口腔癌 4
1.鼻咽癌 4
2.口腔癌 5
第二節 放射治療的起源、種類及方式 7
第三節 頭頸癌放射線治療的後遺症 8
第三章 材料與方法 10
第一節 樣本收集 10
第二節 放治化療口腔照護臨床路徑 11
第三節 統計方法 12
第四章 結 果 13
第一節 頭頸癌患者之基本資料 13
第二節 鼻咽癌與口腔癌患者之基本資料 13
1-1.鼻咽癌患者之基本資料 13
1-2.口腔癌患者之基本資料 14
1-3.鼻咽癌與口腔癌患者於基本資料之比較 15
2.口腔癌患者之口內病灶分布 15
第三節 鼻咽癌與口腔癌患者之到診狀況與口腔狀況 16
1.患者到診狀況 16
1-1.鼻咽癌患者至牙科就診時之狀態 16
1-2.口腔癌患者至牙科就診時之狀態 17
1-3.鼻咽癌與口腔癌患者於腫瘤治療狀況之比較 17
2.牙齒狀況 18
2-1.鼻咽癌患者之牙齒狀況 18
2-2.口腔癌患者之牙齒狀況 18
2-3.鼻咽癌與口腔癌患者於牙齒狀況之比較 19
3.鼻咽癌與口腔癌患者於放射療程中之口腔狀況 19
第四節 影響牙科回診合作度之相關因素探討 20
1.牙科回診合作度 20
2.配製氟托與否與牙科回診合作度之關係 20
3.存活狀況和牙科回診合作度之關係 21
第五章 討 論 23
第一節 研究限制 23
第二節 鼻咽癌與口腔癌患者之比較 23
1.基本資料之比較 24
2.牙齒狀況之比較 25
3.放療中口腔變化之比較 25
第三節 頭頸部放射治療後口腔照護所面臨的難題 27
1.口腔癌與鼻咽癌患者在口腔照護上的差異 28
2.定期回診的必要性 29
第四節 牙醫師在頭頸癌患者放射治療團隊中的角色 30
第六章 結 論 33
參考文獻 34
附 表 40
附 圖 46
第二單元 以分次放射治療DMBA誘發倉鼠頰嚢癌之成效評估
Therapeutic effect of fractionated radiation on DMBA-induced hamster buccal-pouch squamous- cell carcinomas 47
第一章 前 言 48
第一節 研究的重要性 48
第二節 研究目的 50
第二章 文獻回顧 52
第一節 細胞的輻射效應-細胞的壞死與自戕 52
第二節 p53與放射治療的關係 54
第三節 survivin與癌化及癌症治療的關係 56
第四節 一氧化氮(NO) 與癌化過程及在放射治療中的角色 59
第五節 放射線對唾液腺的影響 61
第三章 材料與方法 65
第一節 實驗設計 65
第二節 分次放射 65
第三節 檢體收集 66
第四節 放射療效的評估 67
第五節 免疫組織化學檢查 68
第六節 統計方法 72
第四章 結 果 73
第一節 倉鼠頰囊袋癌之放療效應 73
1.外部觀察 73
2.頰囊袋容積之變化與可能的影響因子 74
3.外部放療效應 75
4.常規組織學檢查 76
5.鏡檢下的放療效應評估-腫瘤殘存情形 77
6.免疫組織化學檢查 77
6-1.以TUNEL stain 觀察細胞自戕變化 77
6-2. p53 78
6-3. Survivin 78
6-4.誘發性一氧化氮合成酶 (iNOS) 78
第二節 倉鼠唾液腺之放療變化 79
1.外部觀察 79
2.常規組織學檢查 79
3.免疫組織化學檢查 80
第五章 討 論 82
第一節 動物模型的設計-實驗動物與劑量選擇 82
第二節 倉鼠頰囊袋癌之放療過程 83
1.外部觀察－與人類口腔癌放療過程比較 83
2.組織病理上之發現 88
3.以TUNEL 與p53, survivin,一氧化氮合成酶觀察
放射線對細胞自戕的影響 89
4.放射治療對p53, survivin及iNOS的影響 90
5.腫瘤標記於鱗狀細胞癌放射治療後的意義 91
6.與其他實驗之差異 92
第三節 唾液腺的放射損傷 93
第六章 結 論 95
參考文獻 97
附 表 121
附 圖 124
附 錄 (已發表於期刊之部份成果) 131
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induced hamster buccal pouch squamous cellcarcinomas.
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