本文選題：纖維蛋白原 + 乳腺癌　； 參考：《山東大學(xué)》2016年博士論文

【摘要】：研究背景與目的乳腺癌是全球女性中最常見(jiàn)的惡性腫瘤,亦是全球女性癌癥相關(guān)死亡的主要原因。乳腺癌的發(fā)病危險(xiǎn)因素包括生育及激素因素,如長(zhǎng)月經(jīng)史、口服避孕藥及不生育,潛在可改變的危險(xiǎn)因素包括肥胖(尤其是絕經(jīng)后肥胖)、絕經(jīng)后激素替代治療、運(yùn)動(dòng)減少及酗酒。在我國(guó),尤其是在城市地區(qū),乳腺癌也是女性中最常見(jiàn)的惡性腫瘤,自上世紀(jì)90年代,其發(fā)病率每年便以全球同期發(fā)病率的兩倍水平在上升,是中國(guó)女性癌癥相關(guān)死亡的第六位因素。隨著我國(guó)經(jīng)濟(jì)的不斷增長(zhǎng),越來(lái)越多的乳腺癌相關(guān)治療手段被引進(jìn)并應(yīng)用于臨床,使乳腺癌患者的預(yù)后得到明顯改善。并且隨著對(duì)乳腺癌的研究深入,各種用于乳腺癌診斷及治療的分子標(biāo)記物被發(fā)現(xiàn),使乳腺癌的治療趨向于個(gè)體化的精準(zhǔn)治療。但乳腺癌新輔助化療、新輔助內(nèi)分泌治療等的廣泛應(yīng)用,有可能造成上述分子標(biāo)記物在治療后出現(xiàn)變化,從而在手術(shù)后因?yàn)橹笜?biāo)改變失去對(duì)患者預(yù)后的準(zhǔn)確判斷,影響治療策略的決定；此外,多種指標(biāo)的聯(lián)合檢測(cè)費(fèi)用昂貴,在我國(guó)大部分經(jīng)濟(jì)欠發(fā)達(dá)地區(qū)難以實(shí)現(xiàn),這將導(dǎo)致對(duì)高�；颊叩暮Y選出現(xiàn)困難,使術(shù)后的治療及隨訪失去針對(duì)性。因而,我們需要確定一種簡(jiǎn)單的、具有指導(dǎo)意義的標(biāo)記物,來(lái)篩選高危患者并且能檢測(cè)接受新輔助化療患者術(shù)后復(fù)發(fā)及轉(zhuǎn)移的風(fēng)險(xiǎn)。纖維蛋白原是一種糖蛋白,分子量為340kDa,經(jīng)肝臟產(chǎn)生。在凝血系統(tǒng)中,纖維蛋白原由活化的凝血酶作用而轉(zhuǎn)化為纖維蛋白,是一種重要的凝血因子。越來(lái)越多的報(bào)道證實(shí)纖維蛋白原及其降解產(chǎn)物具有廣泛的生物活性,不僅參與凝血過(guò)程,還在血管損傷修復(fù)、刺激遷移、各種細(xì)胞增殖、血管形成及創(chuàng)傷修復(fù)中起重要作用。此外,纖維蛋白原及其衍生物還影響血管收縮和舒張,刺激毛細(xì)血管的通透性和調(diào)節(jié)血小板活化,這些在惡性腫瘤的發(fā)生及進(jìn)展中起著極其重要的作用。本研究中,首先將乳腺癌患者分為可直接手術(shù)組與新輔助化療組,分別探討血清中纖維蛋白原水平或化療前后纖維蛋白原水平的變化與各組患者臨床病理學(xué)指標(biāo)及預(yù)后的關(guān)系,然后對(duì)乳腺癌組織中纖維蛋白原的沉積與癌旁正常乳腺組織的差別及其與臨床病理學(xué)指標(biāo)的關(guān)系進(jìn)行探討,并研究血清中纖維蛋白原的水平與組織中纖維蛋白原沉積的相關(guān)性以及乳腺癌和其轉(zhuǎn)移淋巴結(jié)纖維蛋白原的表達(dá)情況。最后通過(guò)對(duì)以上實(shí)驗(yàn)結(jié)論的分析總結(jié),初步闡明纖維蛋白原與乳腺癌的關(guān)系及其在乳腺癌治療中的應(yīng)用前景。研究方法本研究共分為三部分,第一部分回顧性分析山東大學(xué)齊魯醫(yī)院2009年1月—2011年1月共485例可手術(shù)乳腺癌患者的臨床資料,經(jīng)過(guò)入組條件篩選及去除資料不完整患者,最終入組223例可手術(shù)乳腺癌患者,并隨訪患者至2015年3月,將臨床資料及隨訪資料進(jìn)行統(tǒng)計(jì)學(xué)分析。探討可手術(shù)乳腺癌患者血清中纖維蛋白原水平與患者臨床病理學(xué)指標(biāo)之間的關(guān)系,并對(duì)該樣本進(jìn)行生存分析,闡述血清中纖維蛋白原水平對(duì)可手術(shù)乳腺癌患者預(yù)后的意義。第二部分回顧性分析山東大學(xué)齊魯醫(yī)院2010年1月—2013年1月共92例行術(shù)前新輔助化療的進(jìn)展期乳腺癌患者,經(jīng)過(guò)入組條件篩選及去除資料不完整患者,最終入組67例乳腺癌患者,并隨訪患者至2016年3月,將所得臨床資料及隨訪資料進(jìn)行統(tǒng)計(jì)學(xué)分析,探討行術(shù)前新輔助化療的乳腺癌患者血清中化療前纖維蛋白原水平、手術(shù)前纖維蛋白原水平以及新輔助化療前后血清纖維蛋白原水平變化與患者各臨床病理學(xué)指標(biāo)之間的關(guān)系,尤其與新輔助化療療效之間的關(guān)系；并對(duì)該樣本進(jìn)行生存分析,闡述血清中新輔助化療前、新輔助化療后手術(shù)前纖維蛋白原水平及纖維蛋白原水平的變化對(duì)新輔助化療乳腺癌患者預(yù)后的意義。第三部分隨機(jī)選取山東大學(xué)齊魯醫(yī)院2010年度85例可手術(shù)乳腺癌患者的病理切片標(biāo)本,并同時(shí)隨機(jī)選取其中10例乳腺癌患者癌旁正常乳腺組織病理切片標(biāo)本作對(duì)照,使用兔多克隆抗纖維蛋白原抗體進(jìn)行免疫組化檢測(cè),對(duì)所得結(jié)果進(jìn)行計(jì)分并分級(jí)處理,比較乳腺癌組織、癌旁正常乳腺組織中纖維蛋白原表達(dá)的差異,回顧性分析患者的臨床資料,探討纖維蛋白原在乳腺癌組織中的表達(dá)水平與患者臨床病理學(xué)指標(biāo)之間的關(guān)系,組織中纖維蛋白原水平與血清中纖維蛋白原水平的相關(guān)性；另隨機(jī)選取其中8例乳腺癌合并腋淋巴結(jié)轉(zhuǎn)移患者的轉(zhuǎn)移淋巴結(jié)的病理切片行免疫組化檢測(cè),初步探討纖維蛋白原與乳腺癌淋巴轉(zhuǎn)移之間的關(guān)系。可手術(shù)乳腺癌患者及新輔助化療后的乳腺癌患者均接受乳腺癌改良根治術(shù)或乳腺癌根治術(shù),術(shù)后輔以系統(tǒng)治療。新輔助化療方案采用表柔比星60 mg/m2搭配多西他賽75 mg/m2的化療方案4-6周期,每21天為1周期。隨訪策略為三年內(nèi)每3個(gè)月隨訪一次,三年后每年隨訪一次。臨床資料中患者血清纖維蛋白原水平測(cè)定均為化療前或手術(shù)前7天內(nèi)清晨空腹抽取外周靜脈血后,利用克勞斯法于自動(dòng)血凝分析儀進(jìn)行檢測(cè)所得。血清纖維蛋白原水平的參考值范圍為2-4g/L。利用PASS 14.0.2、CRAN網(wǎng)站的R程序及SAS 9.4對(duì)所得數(shù)據(jù)進(jìn)行統(tǒng)計(jì)學(xué)分析。結(jié)果1.第一部分研究結(jié)果顯示：術(shù)前可手術(shù)乳腺癌患者血清纖維蛋白原水平的升高與發(fā)病年齡、絕經(jīng)與否、腫瘤大小、腫瘤TNM分期和淋巴結(jié)轉(zhuǎn)移數(shù)目相關(guān),而與組織學(xué)分級(jí)、分子分型及其他免疫組化指標(biāo)無(wú)關(guān)；其中因血清纖維蛋白原水平受年齡增高的影響,可將發(fā)病年齡及絕經(jīng)與否的影響舍棄。在單因素COX回歸分析中,腫瘤TNM分期、腫瘤大小、腋窩淋巴結(jié)轉(zhuǎn)移數(shù)目及血清纖維蛋白原水平與無(wú)病生存率及總生存率均相關(guān),而在多因素分析中僅腋窩淋巴結(jié)轉(zhuǎn)移數(shù)目及血清纖維蛋白原水平與預(yù)后相關(guān)。2.第二部分研究結(jié)果顯示：行術(shù)前新輔助化療的患者,其血清纖維蛋白原水平在新輔助化療前后的變化與患者絕經(jīng)與否、新輔助化療的臨床療效以及術(shù)后轉(zhuǎn)移有關(guān)。血清纖維蛋白原水平在新輔助化療過(guò)程中出現(xiàn)降低的患者表現(xiàn)出更好的對(duì)新輔助化療的療效反應(yīng),具有更高的臨床緩解率,并且術(shù)后出現(xiàn)遠(yuǎn)處臟器轉(zhuǎn)移的幾率減小。在對(duì)新輔助化療的進(jìn)展期乳腺癌患者的單因素及多因素COX回歸分析中,我們發(fā)現(xiàn),乳腺癌的分子分型、新輔助化療的臨床療效及新輔助化療過(guò)程中血清纖維蛋白原水平的變化與患者的無(wú)病生存率及總生存率均相關(guān),HER2過(guò)表達(dá)型及三陰型乳腺癌患者、新輔助化療反應(yīng)差的患者以及纖維蛋白原水平在新輔助化療前后穩(wěn)定或出現(xiàn)升高的患者的預(yù)后較差,并且三者均為行新輔助化療的進(jìn)展期乳腺癌患者的獨(dú)立預(yù)后因子。3.第三部分研究結(jié)果顯示：纖維蛋白原在乳腺癌組織中呈現(xiàn)不同程度的表達(dá),而癌旁正常乳腺組織中未見(jiàn)表達(dá)；癌組織中纖維蛋白原的表達(dá)與年齡、絕經(jīng)與否、組織學(xué)分級(jí)、ER、PR及Ki-67有關(guān),而與臨床常見(jiàn)指標(biāo)腫瘤長(zhǎng)徑、淋巴結(jié)轉(zhuǎn)移及腫瘤TNM分期無(wú)關(guān),年齡越大、絕經(jīng)、組織學(xué)分級(jí)升高、細(xì)胞增長(zhǎng)迅速及ER、PR表達(dá)減少均會(huì)導(dǎo)致纖維蛋白原表達(dá)升高。乳腺癌組織中的纖維蛋白原水平與血清中纖維蛋白原水平無(wú)相關(guān)性；乳腺癌組織及其轉(zhuǎn)移的腋窩淋巴結(jié)均見(jiàn)纖維蛋白原表達(dá)。結(jié)論1.可手術(shù)乳腺癌患者血清中纖維蛋白原水平的升高與腫瘤大小、腫瘤TNM分期及腋窩淋巴結(jié)轉(zhuǎn)移數(shù)目有關(guān),其升高導(dǎo)致患者無(wú)病生存率及總生存率下降,是獨(dú)立預(yù)后影響因子,這說(shuō)明纖維蛋白原水平與腫瘤進(jìn)展及轉(zhuǎn)移密切相關(guān)。2.行新輔助化療的乳腺癌患者,化療前后出現(xiàn)血清中纖維蛋白原水平升高的患者新輔助化療的臨床緩解率、術(shù)后無(wú)病生存率及總生存率均下降,使其可以作為新輔助化療療效及預(yù)后判斷的可行標(biāo)記物。3.纖維蛋白原在乳腺癌組織中沉積并且其表達(dá)與血清中纖維蛋白原水平無(wú)相關(guān)性證實(shí)乳腺癌細(xì)胞可自行產(chǎn)生纖維蛋白原,并且癌細(xì)胞自行產(chǎn)生的纖維蛋白原與血清中纖維蛋白原在癌的發(fā)展及轉(zhuǎn)移過(guò)程中作用可能不同；其表達(dá)水平與乳腺癌組織學(xué)分級(jí)相關(guān),證實(shí)其與乳腺癌細(xì)胞周圍空間結(jié)構(gòu)穩(wěn)定性、乳腺癌細(xì)胞周圍血管形成及細(xì)胞遷移有關(guān)；癌組織及腋窩轉(zhuǎn)移淋巴結(jié)中同步表達(dá)證實(shí)其參與乳腺癌的淋巴轉(zhuǎn)移。意義多年來(lái),有關(guān)凝血系統(tǒng)與癌癥關(guān)系的探討從基礎(chǔ)實(shí)驗(yàn)到臨床研究不斷完善,凝血蛋白不僅在機(jī)體凝血過(guò)程中起重要作用,其在惡性腫瘤的進(jìn)展過(guò)程中同樣扮演重要角色。不僅參與腫瘤細(xì)胞周圍空間結(jié)構(gòu)的構(gòu)建、新生血管的形成,而且使血管通透性增加并幫助腫瘤細(xì)胞跨膜遷移,并在其轉(zhuǎn)移過(guò)程中通過(guò)形成血栓栓子來(lái)幫助其逃避免疫監(jiān)視。我們的研究在基礎(chǔ)實(shí)驗(yàn)方面驗(yàn)證了纖維蛋白原在腫瘤周圍的沉積與腫瘤惡性程度的關(guān)系,并在對(duì)不同分期、不同處理的乳腺癌患者的分組回顧性生存分析中,發(fā)現(xiàn)血清中纖維蛋白原水平與乳腺癌淋巴轉(zhuǎn)移、血行轉(zhuǎn)移的相關(guān)性及對(duì)預(yù)后判斷的指導(dǎo)意義。由于血清纖維蛋白原水平檢測(cè)方便、快捷、價(jià)格低廉以及可重復(fù)性,使其成為極具臨床應(yīng)用價(jià)值的判斷預(yù)后的血清標(biāo)記物,并且因?yàn)槠湓谀[瘤轉(zhuǎn)移過(guò)程中的重要作用,使其有望成為新的抗腫瘤轉(zhuǎn)移治療的靶點(diǎn)。最近已有研究證實(shí)抗凝治療及低分子肝素的應(yīng)用可延長(zhǎng)癌癥患者的生存期,雖然抗凝劑應(yīng)用的安全性及有效性尚需更多臨床研究的支持,但此種治療手段在提高癌癥患者預(yù)后上的表現(xiàn)還是值得期待的。
[Abstract]:Background and objective breast cancer is the most common malignancy among women in the world. It is also the main cause of cancer related deaths in women worldwide. The risk factors for breast cancer include reproductive and hormonal factors such as long menstrual history, oral contraceptives and childbearing, and potentially possible changes in risk factors including obesity (especially postmenopausal obesity). In China, especially in urban areas, breast cancer is the most common malignant tumor in China, especially in urban areas. Since 90s, the incidence of breast cancer was two times as high as the global incidence of the same period. It was the sixth factor of cancer related death in Chinese women. More and more breast cancer related treatments have been introduced and applied to the clinic to improve the prognosis of breast cancer patients. And with the study of breast cancer, various molecular markers used for the diagnosis and treatment of breast cancer have been found, and the treatment of breast cancer tends to be individualized and accurate. The extensive application of neoadjuvant chemotherapy and neoadjuvant endocrine therapy may result in the changes in the molecular markers after treatment, thereby losing the accurate judgment of the prognosis of the patients after the operation, and affecting the decision of the treatment strategy. In addition, the combined detection of various indicators is expensive and most of the economy is in our country. The difficult implementation of developed areas will lead to difficulties in screening high-risk patients and the loss of post-operative treatment and follow-up. Therefore, we need to identify a simple, instructive marker to screen high-risk patients and to be able to detect the risk of postoperative recurrence and metastasis in patients with neoadjuvant therapy. It is a glycoprotein whose molecular weight is 340kDa and is produced by the liver. In the coagulation system, fibrin is converted into fibrin by activated thrombin action. It is an important coagulation factor. More and more reports have confirmed that fibrinogen and its degradation products have extensive biological activity, not only in coagulation process, but also in vascular damage. Injury repair, stimulation of migration, various cell proliferation, angiogenesis and trauma repair play an important role. In addition, fibrinogen and its derivatives also affect vasoconstriction and relaxation, stimulate capillary permeability and regulate platelet activation. These play an important role in the development and progression of malignant tumors. First, the breast cancer patients were divided into a direct operation group and a new adjuvant chemotherapy group. The relationship between the changes of fibrinogen level in serum and the changes of fibrinogen level before and after chemotherapy and the relationship between the clinicopathological indexes and prognosis of each group were discussed, and the difference between fibrinogen deposition in breast cancer and normal breast tissue adjacent to the cancer was also discussed. The relationship between the serum levels of fibrinogen and fibrinogen deposition in the tissue and the expression of fibrinogen in breast cancer and its metastatic lymph nodes were investigated. Finally, the relationship between fibrinogen and breast cancer was preliminarily clarified by the analysis of the above conclusions. Department and its application in the treatment of breast cancer. The research method is divided into three parts. The first part is a retrospective analysis of the clinical data of 485 patients with surgical breast cancer in the Qilu Hospital of Shandong University from January 2009 to January 2011. Through the screening and removal of incomplete data, 223 cases of surgical breast can be included. The patients were followed up to March 2015, and the clinical data and follow-up data were statistically analyzed. The relationship between the serum fibrinogen level and the clinicopathological indexes of the patients with operable breast cancer was investigated, and the survival analysis of the sample was carried out. The serum fibrinogen level was predefined for the patients with surgical breast cancer. The second part of the second part retrospective analysis of the 92 cases of advanced breast cancer patients in Qilu Hospital of Shandong University from January 2010 to January 2013. After screening and removing the incomplete data, 67 cases of breast cancer patients were finally enrolled and followed up to March 2016, the clinical data and follow-up were followed up. The data were statistically analyzed to explore the level of fibrinogen before chemotherapy in the serum of breast cancer patients with neoadjuvant chemotherapy, the level of fibrinogen before and after the operation and the relationship between the changes of serum fibrinogen level before and after the neoadjuvant chemotherapy and the relationship between the clinical and pathological indexes of the patients, especially with the therapeutic effect of neoadjuvant chemotherapy. The survival analysis of the sample was carried out, and the significance of the changes of fibrinogen level and fibrinogen level before neoadjuvant chemotherapy before neoadjuvant chemotherapy in sera before neoadjuvant chemotherapy on the prognosis of neoadjuvant chemotherapy for breast cancer patients. The third part randomly selected 85 cases of surgical breast cancer patients in Qilu Hospital of Shandong University in 2010. The specimens of 10 patients with breast cancer were randomly selected as control, and the rabbit polyclonal anti fibrinogen antibody was used for immunohistochemical detection. The results were graded and graded to compare the expression of fibrinogen in the breast cancer tissue and the normal breast tissue near the cancer. The difference, retrospective analysis of the patient's clinical data, the relationship between the expression of fibrinogen in the breast cancer tissue and the clinicopathological indexes, the correlation between fibrinogen level and serum fibrinogen level in the tissue, and the random selection of 8 cases of breast cancer with axillary lymph node metastasis. The pathological sections of the lymph nodes were detected by immunohistochemistry. The relationship between fibrinogen and lymphatic metastasis of breast cancer was preliminarily investigated. All patients with breast cancer and breast cancer after neoadjuvant chemotherapy were treated with modified radical mastectomy or radical mastectomy with systematic treatment after operation. The new adjuvant chemotherapy regimen was treated with epirubicin 60 m G/m2 was paired with a chemotherapy regimen of 75 mg/m2 of docetaxel with a period of 1 cycles per 21 days. The follow-up strategy was followed up every 3 months in three years and one year after three years. The serum fibrinogen levels were measured before or after the early morning empty abdominal extraction in the 7 days before the operation, and the Claus method was used. The reference range of serum fibrinogen level was 2-4g/L. using PASS 14.0.2, R program of CRAN website and SAS 9.4 for statistical analysis. Results 1. the first part of the study showed that the level of blood clearing fibrinogen in patients with surgical breast cancer and the age of onset of preoperatively Menopause or not, tumor size, tumor TNM staging and number of lymph node metastases, but not related to histological classification, molecular typing and other immunohistochemical markers. The effect of age increases on serum fibrinogen levels, and the rejection of age and menopause. In the single factor COX regression analysis, the TNM staging of the tumor The size of the tumor, the number of axillary lymph node metastases, and the serum fibrinogen level were related to the disease-free survival and the total survival rate. In the multifactor analysis, the number of axillary lymph nodes and the serum fibrinogen level were related to the prognosis of the.2. second parts. The changes in the protein level before and after the neoadjuvant chemotherapy are related to the patient's menopause, the clinical efficacy of the neoadjuvant chemotherapy and the postoperative metastasis. The patients with the serum fibrinogen level in the neoadjuvant chemotherapy show a better response to the neoadjuvant chemotherapy, with a higher clinical remission rate, and after the operation. The probability of distant visceral metastasis is reduced. In the single factor and multiple factor COX regression analysis of the advanced breast cancer patients with neoadjuvant chemotherapy, we found that the molecular classification of the breast cancer, the clinical efficacy of neoadjuvant chemotherapy and the changes of serum fibrin leveling during the neoadjuvant chemotherapy and the patient's disease free survival and total survival Rates are correlated, HER2 overexpressed and three yin type breast cancer patients, patients with poor response to neoadjuvant chemotherapy and patients with stable or elevated fibrinogen levels before and after neoadjuvant chemotherapy are poor, and the three are the third part of the independent prognostic factor of the advanced breast cancer patients with neoadjuvant chemotherapy. The results of the study are the result of the third part of the study. The expression of fibrinogen in breast cancer tissues is different, but the expression of fibrinogen is not expressed in normal breast tissue. The expression of fibrinogen is related to age, menopause, histologic classification, ER, PR and Ki-67, and is not related to the common clinical indicators of tumor length, lymph node metastasis and tumor TNM staging. Large, menopause, histopathological grading, rapid cell growth and decreased expression of ER and PR could lead to increased fibrinogen expression. There was no correlation between fibrinogen level in breast cancer tissue and serum fibrinogen level; breast cancer tissue and its metastatic axillary lymph nodes were all fibrinogen expression. Conclusion 1. can be operated in mammary gland. The increase of fibrinogen level in the serum of cancer patients is related to the size of tumor, TNM staging and the number of axillary lymph node metastasis, which leads to the decrease of disease survival and total survival rate, which is an independent prognostic factor, which indicates that the level of fibrinogen is closely related to the progression and metastasis of tumor and.2. is closely related to the breast neoadjuvant chemotherapy. In cancer patients, the clinical remission rate of neoadjuvant chemotherapy in patients with elevated serum fibrinogen levels before and after chemotherapy, the postoperative survival rate and total survival rate decreased, which could be used as a viable marker for the therapeutic effect and prognosis of neoadjuvant chemotherapy,.3. fibrinogen was deposited in the breast cancer tissue and expressed in the serum. No correlation between fibrinogen level confirms that breast cancer cells can produce fibrinogen on its own, and the role of fibrinogen and fibrinogen in cancer cells may be different in the development and metastasis of cancer, and its expression level is related to the histological grade of breast cancer, which confirms its surrounding space in breast cancer cells. Structural stability is related to angiogenesis and cell migration around breast cancer cells; synchronous expression of cancer tissue and axillary metastasis confirms its involvement in lymphatic metastasis of breast cancer. The significance of the relationship between coagulation system and cancer has been perfected from basic experiment to clinical study for many years. Coagulation protein is not only clotting in the body. It plays an important role in the progression of malignant tumor. It not only participates in the construction of the space structure around the tumor cells, the formation of the new blood vessels, but also increases the permeability of the blood vessels and helps the tumor cells to transmigrate across the membrane. In the process of metastasis, the thrombus is formed to help them escape from the immune surveillance. Our study verified the relationship between the deposition of fibrinogen around the tumor and the malignancy of the tumor, and in the retrospective subsistence analysis of patients with different stages and treatment of breast cancer, we found the correlation between serum fibrinogen level and lymph node metastasis, blood metastasis and prognosis. Because the serum fibrinogen level is convenient, fast, cheap and repeatable, it makes it a serum marker for judging prognosis of clinical value, and it is expected to be a new target for tumor metastasis treatment because of its important role in the process of tumor metastasis. Studies have shown that anticoagulant therapy and the application of low molecular weight heparin can prolong the survival of cancer patients. Although the safety and effectiveness of anticoagulants need more support from clinical research, it is still worth looking forward to improving the prognosis of cancer patients.

【學(xué)位授予單位】：山東大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2016
【分類號(hào)】：R737.9

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