本文選題：前列腺癌 + 手術(shù)去勢(shì)�。� 參考：《復(fù)旦大學(xué)》2014年博士論文

【摘要】：第一部分 高血糖及超重與前列腺癌預(yù)后關(guān)系目的：代謝異常,如高血糖和超重,與前列腺癌的發(fā)生和進(jìn)展存在聯(lián)系。本研究通過(guò)隨訪接受雙側(cè)睪丸切除術(shù)的前列腺癌患者,來(lái)探討高血糖及超重與前列腺癌患者預(yù)后之間的關(guān)系。材料與方法：我們以復(fù)旦大學(xué)附屬華山醫(yī)院為病人來(lái)源,采用歷史前瞻性研究方式,納入了自2003年1月至2012年8月期間323例接受手術(shù)去勢(shì)的前列腺癌患者,其年齡介于50-91歲之間。所有病人均有詳盡的臨床信息,如血清前列腺特異性抗原(Prostate Specific Antigen, PSA)水平、Gleason評(píng)分、超聲數(shù)據(jù)、CT或MRI及骨掃描等。所有納入研究者對(duì)象都是漢族中國(guó)人。每個(gè)納入研究者對(duì)象都被告知了本研究有關(guān)的目標(biāo)要求,并簽署了知情同意書(shū)。納入的研究對(duì)象根據(jù)其是否具有高血糖、超重進(jìn)行分組,分為對(duì)照組、高血糖組、超重組及超重+高血糖組。高血糖是指空腹血糖水平升高(≥5.6mmol/L)或經(jīng)確診為2型糖尿病。根據(jù)世界衛(wèi)生組織(WHO)的定義,超重是指體質(zhì)指數(shù)(BMI)≥25kg/m2。病人隨訪從手術(shù)去勢(shì)之日開(kāi)始,直至死亡之日或最后一次隨訪的患者仍然存活的日期。我們以電話隨訪的方式,每三個(gè)月電話詢問(wèn)患者或患者家屬有關(guān)患者的生存情況。患者死亡經(jīng)過(guò)疾病防治中心確認(rèn),對(duì)于有上海市醫(yī)保的患者,我們將再通過(guò)上海市城鎮(zhèn)醫(yī)保系統(tǒng)進(jìn)行二次確認(rèn)。我們利用Fisher精確或卡方檢驗(yàn)評(píng)價(jià)四組之間的臨床病理特征以及總體生存率。四組的生存分析采用Kaplan-Meier法。統(tǒng)計(jì)軟件采用SPSS 17.0版本,P0.05認(rèn)為具有顯著的統(tǒng)計(jì)學(xué)差異。結(jié)果：在平均為期43個(gè)月的隨訪期間,共有23例患者失訪,失訪率為7.1%。最后納入研究共300例患者,包括對(duì)照組共166人(55.33%),超重組58人(19.33%),高血糖組50人(16.67%),超重+高血糖組26人(8.67%)。在本研究中共有122例患者死亡,其中對(duì)照組62人(37.35%),超重組25人(43.10%),高血糖組22人(44%),超重+高血糖組13人(50%)。死因包括前列腺癌、心臟病發(fā)作、中風(fēng)和呼吸衰竭等。300例患者1年總體生存率為97%,而5年生存率為65.33%。四組之間1年生存率無(wú)顯著的統(tǒng)計(jì)學(xué)差異,超重+高血糖組的5年生存率為50%,顯著低于對(duì)照組的生存率的70.48%(P=0.038)。對(duì)照組、超重組及高血糖組之間的生存曲線無(wú)顯著性差異,而超重+高血糖組生存曲線與對(duì)照組相比,其生存時(shí)間顯著較短,P=0.044。結(jié)論：通過(guò)對(duì)接受雙側(cè)睪丸切除術(shù)的前列腺癌患者的隨訪,我們發(fā)現(xiàn)同時(shí)超重又有高血糖者其預(yù)后較差,5年總體生存率顯著較低,生存時(shí)間較短,代謝異常與前列腺癌的預(yù)后結(jié)局有著一定聯(lián)系,代謝異常對(duì)前列腺癌的發(fā)生及進(jìn)展有重要影響。第二部分 IGF-1相關(guān)通路在高脂飲食促進(jìn)TRAMP小鼠前列腺癌進(jìn)展中的作用目的：通過(guò)比較高脂飲食TRAMP小鼠與普通飲食TRAMP小鼠的成瘤率與死亡率,研究高脂飲食對(duì)前列腺癌發(fā)生及進(jìn)展的影響,并檢驗(yàn)IGF-1相關(guān)通路在高脂飲食對(duì)前列腺癌發(fā)生及進(jìn)展影響中發(fā)揮的作用。材料與方法：采用TRAMP轉(zhuǎn)基因前列腺癌小鼠模型,隨機(jī)分為實(shí)驗(yàn)組——高脂飲食組(n=42),對(duì)照組——普通飲食組(n=42)。高脂飲食TRAMP小鼠喂以高脂飼料誘導(dǎo)肥胖及胰島素抵抗。兩組TRAMP小鼠均于20周齡、24周齡和28周齡處死取材,每組每次各14只。TRAMP小鼠處死前一晚斷糧。處死抽血后測(cè)定TRAMP小鼠空腹血糖值,留取血清利用ELISA法檢測(cè)胰島素、IGF-1、IGF-2,留取前列腺組織進(jìn)行HE染色及免疫組化染色,測(cè)定指標(biāo)包括IGF-1Rα、IGF-1R β、IGFBP1、IGFBP2、IGFBP3、IGFBP5、IGFBP6和Akt。結(jié)果：在TRAMP小鼠飼養(yǎng)期間共觀察到13例小鼠死亡,包括普通飲食組3只(7.14%)及高脂飲食組10只(23.81%),高脂飲食組TRAMP小鼠的死亡率顯著高于普通飲食組(P=0.035)。在TRAMP小鼠20周齡時(shí),高脂飲食組已有11只(78.57%)TRAMP、鼠具有典型的前列腺癌,而普通飲食TRAMP小鼠只有5只(35.71%)發(fā)生了典型的前列腺癌,高脂飲食組TRAMP小鼠的20周齡時(shí)的成瘤率顯著高于普通飲食組(P=0.022)。普通飲食與高脂飲食TRAMP小鼠在20周、24周及28周時(shí),其血糖、血清胰島素及IGF-2水平并無(wú)顯著性差異。而在24周及28周時(shí),高脂飲食TRAMP、鼠的血清IGF-1水平顯著高于普通飲食組,其中以28周時(shí)最為明顯(P=0.011)。另外,高脂飲食TRAMP小鼠隨著周齡的增加,血清IGF-1的濃度也呈上升趨勢(shì)。TRAMP小鼠前列腺免疫組化染色提示IGF-1Rα、IGF-1Rβ、IGFBP3及Akt在高脂飲食TRAMP小鼠中的陽(yáng)性染色率均顯著高于普通飲食組,其他IGF結(jié)合蛋白(IGFBP1、IGFBP2、IGFBP5和IGFBP6)雖然在TRAMP小鼠前列腺中也有表達(dá),但是在兩組小鼠中沒(méi)有顯著性差異。結(jié)論：高脂飲食TRAMP小鼠成瘤率及死亡率均明顯高于普通飲食TRAMP小鼠,高脂飲食能夠促進(jìn)前列腺癌的發(fā)生及進(jìn)展。通過(guò)ELISA和免疫組化研究胰島素、IGF-1通路相關(guān)蛋白發(fā)現(xiàn),多個(gè)蛋白分子,包括IGF-1、IGF-1Rα、IGF-1Rβ、IGFBP3及Akt在高脂飲食TRAMP小鼠中的表達(dá)量均顯著高于普通飲食組,提示IGF-1相關(guān)通路在高脂飲食促進(jìn)前列腺癌發(fā)生及進(jìn)展中發(fā)揮重要作用。
[Abstract]:Part 1 Relationship between hyperglycemia and overweight and prognosis of prostate cancer: metabolic abnormalities, such as hyperglycemia and overweight, are associated with the development and progression of prostate cancer. This study was conducted to investigate the relationship between hyperglycemia and overweight and the prognosis of prostate cancer patients. Methods: We used a historical prospective study in Huashan Hospital Affiliated to Fudan University for 323 patients with surgical castration between January 2003 and August 2012, whose age was between the age of 50-91. All patients had detailed bed information, such as serum prostate specific antigen (Prostate). Specific Antigen, PSA) level, Gleason score, ultrasound data, CT or MRI, and bone scan. All the participants were Han Chinese. Each participant was informed of the objectives of the study and signed an informed consent. The subjects included in the study were based on whether they had hyperglycemia and were overweight. Group, divided into control group, hyperglycemia group, super recombinant and overweight + hyperglycemia group. Hyperglycemia refers to higher level of fasting blood glucose (more than 5.6mmol/L) or type 2 diabetes. According to the definition of WHO (WHO), overweight refers to the body mass index (BMI) of patients with more than 25kg/m2. from the day of the surgical castration until the day of death or the last time The patients who were followed up were still alive. We call every three months by telephone to inquire about the survival of the patient or the patient's family. The patient's death is confirmed by the disease control center. For patients with medical insurance in Shanghai, we will make a two confirmation through the medical insurance system in the city of Shanghai city. We use Fishe R accurate or chi square test was used to evaluate the clinicopathological features and overall survival rate between the four groups. The four group's survival analysis adopted the Kaplan-Meier method. The statistical software adopted the SPSS 17 version, and the P0.05 thought there was a significant statistical difference. Results: during the average period of 43 months of follow-up, there were 23 patients who lost their visits and the loss rate was 7.1%. final. A total of 300 patients were included in the study, including 166 (55.33%) in the control group, 58 in the super recombinant (19.33%), 50 in the hyperglycemia group (16.67%), and 26 in the hyperglycemic group (8.67%). In this study, 122 patients were killed, including 62 (37.35%) in the control group, hyperglycemic 25 (43.10%), hyperglycemic group, overweight and hyperglycemic group. The total 1 year survival rate of.300 patients with prostate, heart attack, stroke, and respiratory failure was 97%, while the 5 year survival rate was no significant difference between the group 65.33%. four and the 1 year survival rate. The 5 year survival rate of the overweight + hyperglycemia group was 50%, significantly lower than that of the control group (70.48% (P=0.038). The control group, the super recombination and hyperglycemia group) There was no significant difference between the survival curve and the survival curve of the overweight + hyperglycemia group compared with the control group, and the survival time was significantly shorter than those in the control group. P=0.044. conclusion: by follow-up to the prostate cancer patients receiving bilateral testicle excision, we found that the prognosis of those with both overweight and hyperglycemia was poor, and the overall survival rate was significantly lower in 5 years. Short storage time and metabolic abnormalities have a certain relationship with the prognosis of prostate cancer. Metabolic abnormalities have important effects on the development and progression of prostate cancer. Second the role of the IGF-1 related pathway in promoting the progression of prostate cancer in TRAMP mice by high fat diet: by comparing the high fat diet TRAMP mice with the common diet TRAMP The effect of high fat diet on the occurrence and progression of prostate cancer and the role of IGF-1 related pathway in the development and progression of prostate cancer in high fat diet. Materials and methods: the model of TRAMP transgenic prostate cancer mice was divided into experimental group, high fat diet group (n=42), and the effect of high fat diet on the development and progression of prostate cancer was examined. Group (n=42). High fat diet TRAMP mice were fed with high fat diet induced obesity and insulin resistance. Two groups of TRAMP mice were sacrificed at 20 weeks of age, 24 weeks old and 28 weeks old, and 14.TRAMP mice in each group were sacrificed a night before death. The fasting blood glucose values of TRAMP mice were determined and ELISA method was used to determine the use of serum. Detection of insulin, IGF-1, IGF-2, and retained prostate tissue for HE staining and immunohistochemical staining. The indicators included IGF-1R alpha, IGF-1R beta, IGFBP1, IGFBP2, IGFBP3, IGFBP5, IGFBP6 and Akt.. During the feeding of mice, 13 mice were killed, including 3 (7.14%) and 10 (23.81%), high fat diet group, and high fat diet. The mortality of TRAMP mice in the diet group was significantly higher than that in the normal diet group (P=0.035). In the 20 week old TRAMP mice, there were 11 (78.57%) TRAMP in the high fat diet group, and the rat had typical prostate cancer, while only 5 (35.71%) of the normal diet TRAMP mice had a typical prostate cancer, and the high fat diet group TRAMP mice had a significant tumorigenesis rate at the age of 20 weeks. Higher than normal diet group (P=0.022). There was no significant difference in blood glucose, serum insulin and IGF-2 levels between normal diet and high fat diet TRAMP mice at 20 weeks, 24 weeks and 28 weeks. At 24 and 28 weeks, high fat diet TRAMP, the serum IGF-1 level of rats was significantly higher than that of ordinary drinking group, which was most obvious at 28 weeks (P=0.011). With the increase of age, the concentration of serum IGF-1 in the serum of TRAMP mice increased with the increase of the serum level in.TRAMP mice. The positive staining rates of IGF-1R alpha, IGF-1R beta, IGFBP3 and Akt in the high fat diet TRAMP mice were significantly higher than those in the normal diet group, while the other IGF nodal proteins (IGFBP1, IGFBP2, IGFBP5, and Akt) were in spite of There is also expression in the prostate of mice, but there is no significant difference in the two groups of mice. Conclusion: the rate of tumor formation and mortality in the high fat diet TRAMP mice is significantly higher than that of the normal diet TRAMP mice. The high fat diet can promote the development and progression of the prostate cancer. The study of insulin by ELISA and immunohistochemistry and the discovery of IGF-1 pathway related proteins are found. The expression of protein molecules, including IGF-1, IGF-1R a, IGF-1R beta, IGFBP3 and Akt in high fat diet TRAMP mice were significantly higher than those in the normal diet group, suggesting that the IGF-1 related pathway plays an important role in promoting the development and progression of prostate cancer in high fat diet.

【學(xué)位授予單位】：復(fù)旦大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2014
【分類(lèi)號(hào)】：R737.25

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本文編號(hào)：1798663