46例下咽癌的臨床病理分析及GLUT-1、HIF-1α在頭頸部鱗狀細胞癌中的表達及臨床意義
發(fā)布時間：2018-09-06 13:19
【摘要】：背景和目的：下咽癌的確切病因至今并不清楚,其發(fā)病率較其他頭頸部位者低,但因下咽位置比較深在、隱蔽,下咽癌早期癥狀沒有特異性,其早期診斷較為困難,患者就診時多已是晚期,較早常見頸部轉(zhuǎn)移,常浸潤喉、口咽、頸段食管和咽旁間隙等,5年生存率通常低于50%,是預(yù)后最差的頭頸部惡性腫瘤之一,對于下咽癌的治療,目前主要還是手術(shù)、放療和化療,而且更趨向于綜合治療。但是,不管是何種治療,目前預(yù)后都不是很理想,影響其預(yù)后的真正原因尚不明了。本課題擬分析46例下咽癌患者臨床病理因素和生存率的相關(guān)性,尋求影響預(yù)后的相關(guān)臨床病理因素。 材料與方法：收集2006.1～2012.1期間我院耳鼻咽喉科收治的46例下咽癌病例進行回顧性分析,觀察患者年齡、性別、腫瘤分化程度、TNM分級、臨床分期、治療方式、隨訪結(jié)果,分析與預(yù)后之間的關(guān)系。 結(jié)果 一、46例下咽癌的臨床特點 男性44例,女性2例,年齡43～77歲,平均61.3歲。病史(到就診住院時間)從1個月～10年,腫瘤位于35例位于梨狀窩,1例位于環(huán)后區(qū),9例位于咽后壁,原發(fā)腫瘤不能評估1例。TNM分級：TjNoMo8例,T2NoMo5例,T3NoMo6例,T4NoMo2例,T1N1Mo2例,T2N1Mo8例,T3N1Mo6例,T2N2Mo3例,T3N2M01例,T4aN1Mo2例,T4aN2Mo2例,TxNoMo1例；臨床分期Ⅰ期8例,Ⅱ期5例,Ⅲ期22例,Ⅳa期11例。46例中手術(shù)切除21例,手術(shù)+術(shù)后放化療20例,5例僅放化療,其中31例(67.4%)保留喉功能。26例行保留喉功能手術(shù),術(shù)后1例(3.8%)出現(xiàn)出血再次手術(shù)止血；24例手術(shù)后14天能正常進食無嗆咳,2例(7.7%)出現(xiàn)嗆咳,經(jīng)進食訓練1～3周后恢復(fù)吞咽功能；25例(96.2%)術(shù)后2～3周拔除氣管套管,1例(3.8%)因雙側(cè)聲帶固定于正中位未能拔管,戴管出院。 隨訪時間3個月～75個月,平均31個月。46例中11例死亡,失訪4例,平均中位生存時間為57.5個月。其中11例(23.9%)患者復(fù)發(fā),4例(8.7%)發(fā)生遠處轉(zhuǎn)移4例均為肺轉(zhuǎn)移,其中1例合并骨轉(zhuǎn)移。8例(17.4%)為多原發(fā)癌。單因素分析,生存率與臨床資料的關(guān)系中：T分期與總的生存率有關(guān),T1+T2總生存率為55.6%,T3+T4總生存率為35.0%(p=0.029,),T1+T2期3年、5年生存率分別為83.5%、55.6%,T3+T4期3年、5年生存率分別為46.6%、35.0%；復(fù)發(fā)與生存率有關(guān),復(fù)發(fā)的總生存率為29.1%,無復(fù)發(fā)的生存率為51.8%(p=0.005,),無復(fù)發(fā)的3年、5年生存率分別為80.6%、51.8%,復(fù)發(fā)的3年、5年生存率分別為29.1%、29.1%；其它指標年齡、腫瘤位置、臨床分期、病理分級、有無遠處轉(zhuǎn)移、有無多原發(fā)癌、治療方法與總體生存率無統(tǒng)計學差異。采用Cox Regression多因素分析,發(fā)現(xiàn)僅T分級與總體生存率有統(tǒng)計學差異(p=0.033)。 結(jié)論 1.本組資料顯示,46例下咽癌23.6%出現(xiàn)復(fù)發(fā),17.4%出現(xiàn)多原發(fā)癌； 2.單因素分析,46例下咽癌總的生存率與T分期、復(fù)發(fā)有關(guān),多因素分析顯示僅T分期是獨立的預(yù)后影響因素； 3.保留喉功能與否的治療,對下咽癌的生存率沒有影響,提示下咽癌的保留喉功能手術(shù)切實可行 背景和目的隨著免疫學、分子生物學技術(shù)的進步和不斷發(fā)展,現(xiàn)在大多數(shù)學者認為腫瘤的浸潤和轉(zhuǎn)移是多因素、多步驟的發(fā)展過程,基因表達是其重要的機制之一因此,從分子水平探討頭頸部鱗狀細胞癌發(fā)生、發(fā)展的機制,對于認識頭頸部鱗狀細胞癌的發(fā)病機制、判斷預(yù)后、發(fā)現(xiàn)潛在的治療靶點具有重要意義。 我們前期研究發(fā)現(xiàn)葡萄糖轉(zhuǎn)運蛋白-1(glucose transporter-1,Glut-1)的表達與頭頸部癌的一些生物性行為有關(guān),但這種結(jié)果同樣存在著爭議。因此,Glut-1在頭頸部鱗狀細胞癌中的意義,需進一步研究。缺氧誘導(dǎo)因子(Hypoxia inducible factor, HIF)是Glut-1的調(diào)節(jié)基因,HIF-1α和Glut-1均為腫瘤缺氧的標記,兩者共同表達是癌預(yù)后差的標記。在頭頸部鱗癌中很少見兩者聯(lián)合表達與生物性行為之間相互關(guān)系的報道的,而在下咽癌未見的類似報道。采用免疫組織化學方法檢測下咽癌組織及喉癌組織中HIF-1α和Glut-1蛋白的表達,分析兩者與頭頸部鱗狀細胞癌的預(yù)后及其它生物性行為之間的關(guān)系,探討HIF-1α和Glut-1影響HNSCC預(yù)后的可能作用。 材料與方法69例病理確診的頭頸部癌,其中23例下咽鱗癌、46例喉癌。免疫組織化學EliVisionTM法檢測上述標本的HIF-1α和Glut-1蛋白表達情況分析各臨床病理因素以及HIF-1α和Glut-1表達與生存率的相關(guān)性。 結(jié)果：頭頸部鱗癌Glut-1免疫組化染色陽性率(72.5%)顯著高于聲帶息肉和黏膜白斑病(33.3%)(P0.01)。頭頸部鱗癌HIF-1α免疫組化染色陽性率(71.0%)顯著高于聲帶息肉和黏膜白斑病(13.3%)(P0.01)。Pearson Chi-Square分析：單因素分析年齡、性別、部位、T分期、N分期、病例分型、復(fù)發(fā)和遠處轉(zhuǎn)移這8個臨床因素與GLUT-1、HIF-1α的相關(guān)性,結(jié)果顯示Glut-1表達與腫瘤位置、N分期和遠處轉(zhuǎn)移有關(guān)(P0.05),HIF-1α陽性表達與復(fù)發(fā)、遠處轉(zhuǎn)移有統(tǒng)計學意義(P0.05)69例HNSCC中Glut-1、HIF-1α兩者共同陽性表達37例,經(jīng)Pearson相關(guān)性分析：兩者的表達有一定的相關(guān)性(r=0.338,P=0.004) 69例頭頸部鱗狀細胞癌的總生存率與腫瘤的原發(fā)部位、T分級、臨床分期、淋巴結(jié)轉(zhuǎn)移、復(fù)發(fā)、遠處轉(zhuǎn)移、Glut-1陽性表達、HIF-1α陽性表達有關(guān)。Glut-1陽性表達的HNSCC患者的3年、5年生存率分別為：46.7%、37.3%,無Glut-1表達的HNSCC患者的3年、5年生存率分別為：87.5%、82.4%；HIF-1α陽性表達的HNSCC患者的3年、5年生存率分別為：61.0%、42.7%,無HIF-1α表達的HNSCC患者的3年、5年生存率分別為：85.0%、78.5%。Cox Regression比例風險模型多因素分析：發(fā)現(xiàn)腫瘤原發(fā)位置(p=0.031)、腫瘤局部復(fù)發(fā)(p=0.000)與總體生存率有統(tǒng)計學差異。 結(jié)論 1.本組資料顯示Glut-1、HIF-1α表達增高與頭頸部鱗狀細胞癌的發(fā)生可能有關(guān)：與炎性病變組織、癌前病變組織相比,頭頸部鱗狀細胞癌組織中Glut-1表達增高明顯； 2. Glut-1表達增高與頭頸部鱗狀細胞癌位置、N分期和遠處轉(zhuǎn)移有關(guān)；HIF-1α表達增高與頭頸部鱗狀細胞癌的復(fù)發(fā)、遠處轉(zhuǎn)移有關(guān)； 3.單因素預(yù)后分析：Glut-1表達及HIF-1α表達,連同腫瘤的原發(fā)部位、T分級、臨床分期、淋巴結(jié)轉(zhuǎn)移、復(fù)發(fā)、遠處轉(zhuǎn)移與頭頸部鱗狀細胞癌的預(yù)后有關(guān)；多因素分析,腫瘤原發(fā)位置、腫瘤局部復(fù)發(fā)與頭頸部鱗狀細胞癌的預(yù)后有關(guān)。
[Abstract]:BACKGROUND AND OBJECTIVE: The exact etiology of hypopharyngeal carcinoma is still unclear. The incidence of hypopharyngeal carcinoma is lower than that of other head and neck cancers. However, because the hypopharyngeal position is deep and concealed, the early symptoms of hypopharyngeal carcinoma are not specific, it is difficult to make early diagnosis. The 5-year survival rate is usually less than 50%. It is one of the worst prognosis head and neck malignancies. At present, the treatment of hypopharyngeal cancer is mainly surgery, radiotherapy and chemotherapy, and more inclined to comprehensive treatment. However, no matter what kind of treatment, the prognosis is not very good, the real reason affecting the prognosis is still unknown. To analyze the correlation between clinicopathological factors and survival rate in 46 patients with hypopharyngeal carcinoma, and to explore the related clinicopathological factors affecting prognosis.
Materials and Methods: 46 cases of hypopharyngeal carcinoma admitted to our department of Otolaryngology from January 2006 to January 2012 were retrospectively analyzed. Age, sex, tumor differentiation, TNM classification, clinical stage, treatment, follow-up results, and the relationship between prognosis and prognosis were observed.
Result
Clinical characteristics of 46 cases of hypopharyngeal carcinoma
There were 44 males and 2 females with an average age of 61.3 years, ranging from 43 to 77 years. History (to hospital stay) ranged from 1 month to 10 years. The tumors were located in the pyriform fossa in 35 cases, in the posterior ring area in 1 case, in the posterior pharyngeal wall in 9 cases, and primary tumors could not be evaluated in 1 case. TNM grading: TjNoMo8 cases, T2NoMo5 cases, T3NoMo6 cases, T4NoMo2 cases, T1N1Mo8 cases, T2N1Mo8 cases, T3N1Mo6 cases, and T2N2Mo cases. T3N2M01 cases, T4aN1Mo2 cases, T4aN2Mo2 cases, TxNoMo 1 case, clinical stage I 8 cases, stage II 5 cases, stage III 22 cases, stage IVa 11 cases.46 cases of surgical resection, surgery + postoperative radiochemotherapy 20 cases, 5 cases only radiochemotherapy, of which 31 cases (67.4%) retained laryngeal function surgery, postoperative bleeding occurred in 1 case (3.8%) reoperation hemostasis; One patient could eat normally 14 days after operation without coughing, two patients (7.7%) had cough and recovered swallowing function after 1-3 weeks of training, 25 patients (96.2%) had tracheal cannula removed 2-3 weeks after operation, and one patient (3.8%) was discharged from hospital because bilateral vocal cords were fixed in the median.
The follow-up time ranged from 3 months to 75 months, with an average of 31 months. 11 of 46 patients died and 4 were lost to follow-up. The median survival time was 57.5 months. T stage was associated with overall survival rate, which was 55.6% for T1+T2, 35.0% for T3+T4, 83.5% for T1+T2, 55.6% for T1+T2, 46.6% for T3+T4, 35.0% for T3+T4, and 29.1% for recurrence, 51.8% for non-recurrence, and 51.8% for non-recurrence. The 3-year and 5-year survival rates were 80.6% and 51.8%, respectively. The 3-year and 5-year survival rates were 29.1% and 29.1% respectively. Other indicators, such as age, tumor location, clinical stage, pathological grade, distant metastasis, multiple primary cancer, treatment method and overall survival rate were not significantly different. The survival rate was statistically different (p=0.033).
conclusion
1. according to the data of the group, 23.6% of the 46 hypopharyngeal carcinomas recurred, and 17.4% showed multiple primary cancers.
2. Univariate analysis showed that the overall survival rate of 46 cases of hypopharyngeal carcinoma was related to T stage and recurrence. Multivariate analysis showed that only T stage was an independent prognostic factor.
3. The preservation of laryngeal function has no effect on the survival rate of hypopharyngeal carcinoma, suggesting that the preservation of laryngeal function surgery for hypopharyngeal carcinoma is feasible.
BACKGROUND AND OBJECTIVE With the progress and development of immunology and molecular biology technology, most scholars think that tumor invasion and metastasis is a multi-factor, multi-step process of development, and gene expression is one of the important mechanisms. Therefore, to explore the mechanism of the occurrence and development of head and neck squamous cell carcinoma from the molecular level, for understanding the head and neck. The pathogenesis of squamous cell carcinoma of the body, the prognosis, and the potential therapeutic targets are of great significance.
Our previous study found that the expression of glucose transporter-1 (Glut-1) is related to some biological behaviors of head and neck cancer, but this result is also controversial. Therefore, the significance of Glut-1 in head and neck squamous cell carcinoma needs further study. Hypoxia inducible factor (HIF) is Glut-1. HIF-1a and Glut-1 are both markers of tumor hypoxia and co-expression are markers of poor prognosis in head and neck squamous cell carcinoma. The expression of HIF-1a and Glut-1 proteins in human head and neck squamous cell carcinoma tissues was analyzed. The relationship between the expression of HIF-1a and Glut-1 proteins and the prognosis of head and neck squamous cell carcinoma was analyzed. The possible role of HIF-1a and Glut-1 in the prognosis of HNSCC was discussed.
Materials and Methods The expression of HIF-1a and Glut-1 in 69 cases of head and neck carcinoma confirmed by pathology, including 23 cases of hypopharyngeal squamous cell carcinoma and 46 cases of laryngeal carcinoma, was detected by immunohistochemical EliVisionTM method.
Results: The positive rate of Glut-1 immunohistochemical staining in head and neck squamous cell carcinoma (72.5%) was significantly higher than that in vocal cord polyps and leukoplakia (33.3%) (P 0.01). The positive rate of HIF-1a immunohistochemical staining in head and neck squamous cell carcinoma (71.0%) was significantly higher than that in vocal cord polyps and leukoplakia (13.3%) (P 0.01). Pearson Chi-Square analysis: Univariate analysis of age, sex, location, T. GLUT-1 and HIF-1a were correlated with the clinical factors of stage, N stage, case classification, recurrence and distant metastasis. The results showed that Glut-1 expression was correlated with tumor location, N stage and distant metastasis (P 0.05). The positive expression of HIF-1a was correlated with recurrence and distant metastasis (P 0.05). Pearson correlation analysis showed that there was a certain correlation between the two expressions (r=0.338, P=0.004).
The overall survival rate of 69 cases of head and neck squamous cell carcinoma was related to the primary site, T grade, clinical stage, lymph node metastasis, recurrence, distant metastasis, Glut-1 positive expression and HIF-1a positive expression. The 3-year and 5-year survival rates of Glut-1 positive HNSCC patients were 46.7%, 37.3%, respectively, and those without Glut-1 expression were 3-year and 5-year survival rates. The 3-year and 5-year survival rates were 61.0% and 42.7% for HIF-1a positive HNSCC patients and 85.0% and 78.5% for non-HIF-1a positive HNSCC patients respectively. The survival rate was statistically different.
conclusion
1. The increased expression of Glut-1 and HIF-1a may be related to the occurrence of head and neck squamous cell carcinoma. Compared with inflammatory lesions and precancerous lesions, the expression of Glut-1 in head and neck squamous cell carcinoma increased significantly.
2. The increased expression of Glut-1 was related to the location, N stage and distant metastasis of head and neck squamous cell carcinoma, and the increased expression of HIF-1a was related to the recurrence and distant metastasis of head and neck squamous cell carcinoma.
3. Univariate prognostic analysis: Glut-1 expression and HIF-1a expression were associated with the prognosis of head and neck squamous cell carcinoma, including the primary site, T-grade, clinical stage, lymph node metastasis, recurrence and distant metastasis; Multivariate analysis showed that the primary location and local recurrence of the tumor were associated with the prognosis of head and neck squamous cell carcinoma.
【學位授予單位】：浙江大學
【學位級別】：碩士
【學位授予年份】：2012
【分類號】：R739.63
本文編號：2226469
[Abstract]:BACKGROUND AND OBJECTIVE: The exact etiology of hypopharyngeal carcinoma is still unclear. The incidence of hypopharyngeal carcinoma is lower than that of other head and neck cancers. However, because the hypopharyngeal position is deep and concealed, the early symptoms of hypopharyngeal carcinoma are not specific, it is difficult to make early diagnosis. The 5-year survival rate is usually less than 50%. It is one of the worst prognosis head and neck malignancies. At present, the treatment of hypopharyngeal cancer is mainly surgery, radiotherapy and chemotherapy, and more inclined to comprehensive treatment. However, no matter what kind of treatment, the prognosis is not very good, the real reason affecting the prognosis is still unknown. To analyze the correlation between clinicopathological factors and survival rate in 46 patients with hypopharyngeal carcinoma, and to explore the related clinicopathological factors affecting prognosis.
Materials and Methods: 46 cases of hypopharyngeal carcinoma admitted to our department of Otolaryngology from January 2006 to January 2012 were retrospectively analyzed. Age, sex, tumor differentiation, TNM classification, clinical stage, treatment, follow-up results, and the relationship between prognosis and prognosis were observed.
Result
Clinical characteristics of 46 cases of hypopharyngeal carcinoma
There were 44 males and 2 females with an average age of 61.3 years, ranging from 43 to 77 years. History (to hospital stay) ranged from 1 month to 10 years. The tumors were located in the pyriform fossa in 35 cases, in the posterior ring area in 1 case, in the posterior pharyngeal wall in 9 cases, and primary tumors could not be evaluated in 1 case. TNM grading: TjNoMo8 cases, T2NoMo5 cases, T3NoMo6 cases, T4NoMo2 cases, T1N1Mo8 cases, T2N1Mo8 cases, T3N1Mo6 cases, and T2N2Mo cases. T3N2M01 cases, T4aN1Mo2 cases, T4aN2Mo2 cases, TxNoMo 1 case, clinical stage I 8 cases, stage II 5 cases, stage III 22 cases, stage IVa 11 cases.46 cases of surgical resection, surgery + postoperative radiochemotherapy 20 cases, 5 cases only radiochemotherapy, of which 31 cases (67.4%) retained laryngeal function surgery, postoperative bleeding occurred in 1 case (3.8%) reoperation hemostasis; One patient could eat normally 14 days after operation without coughing, two patients (7.7%) had cough and recovered swallowing function after 1-3 weeks of training, 25 patients (96.2%) had tracheal cannula removed 2-3 weeks after operation, and one patient (3.8%) was discharged from hospital because bilateral vocal cords were fixed in the median.
The follow-up time ranged from 3 months to 75 months, with an average of 31 months. 11 of 46 patients died and 4 were lost to follow-up. The median survival time was 57.5 months. T stage was associated with overall survival rate, which was 55.6% for T1+T2, 35.0% for T3+T4, 83.5% for T1+T2, 55.6% for T1+T2, 46.6% for T3+T4, 35.0% for T3+T4, and 29.1% for recurrence, 51.8% for non-recurrence, and 51.8% for non-recurrence. The 3-year and 5-year survival rates were 80.6% and 51.8%, respectively. The 3-year and 5-year survival rates were 29.1% and 29.1% respectively. Other indicators, such as age, tumor location, clinical stage, pathological grade, distant metastasis, multiple primary cancer, treatment method and overall survival rate were not significantly different. The survival rate was statistically different (p=0.033).
conclusion
1. according to the data of the group, 23.6% of the 46 hypopharyngeal carcinomas recurred, and 17.4% showed multiple primary cancers.
2. Univariate analysis showed that the overall survival rate of 46 cases of hypopharyngeal carcinoma was related to T stage and recurrence. Multivariate analysis showed that only T stage was an independent prognostic factor.
3. The preservation of laryngeal function has no effect on the survival rate of hypopharyngeal carcinoma, suggesting that the preservation of laryngeal function surgery for hypopharyngeal carcinoma is feasible.
BACKGROUND AND OBJECTIVE With the progress and development of immunology and molecular biology technology, most scholars think that tumor invasion and metastasis is a multi-factor, multi-step process of development, and gene expression is one of the important mechanisms. Therefore, to explore the mechanism of the occurrence and development of head and neck squamous cell carcinoma from the molecular level, for understanding the head and neck. The pathogenesis of squamous cell carcinoma of the body, the prognosis, and the potential therapeutic targets are of great significance.
Our previous study found that the expression of glucose transporter-1 (Glut-1) is related to some biological behaviors of head and neck cancer, but this result is also controversial. Therefore, the significance of Glut-1 in head and neck squamous cell carcinoma needs further study. Hypoxia inducible factor (HIF) is Glut-1. HIF-1a and Glut-1 are both markers of tumor hypoxia and co-expression are markers of poor prognosis in head and neck squamous cell carcinoma. The expression of HIF-1a and Glut-1 proteins in human head and neck squamous cell carcinoma tissues was analyzed. The relationship between the expression of HIF-1a and Glut-1 proteins and the prognosis of head and neck squamous cell carcinoma was analyzed. The possible role of HIF-1a and Glut-1 in the prognosis of HNSCC was discussed.
Materials and Methods The expression of HIF-1a and Glut-1 in 69 cases of head and neck carcinoma confirmed by pathology, including 23 cases of hypopharyngeal squamous cell carcinoma and 46 cases of laryngeal carcinoma, was detected by immunohistochemical EliVisionTM method.
Results: The positive rate of Glut-1 immunohistochemical staining in head and neck squamous cell carcinoma (72.5%) was significantly higher than that in vocal cord polyps and leukoplakia (33.3%) (P 0.01). The positive rate of HIF-1a immunohistochemical staining in head and neck squamous cell carcinoma (71.0%) was significantly higher than that in vocal cord polyps and leukoplakia (13.3%) (P 0.01). Pearson Chi-Square analysis: Univariate analysis of age, sex, location, T. GLUT-1 and HIF-1a were correlated with the clinical factors of stage, N stage, case classification, recurrence and distant metastasis. The results showed that Glut-1 expression was correlated with tumor location, N stage and distant metastasis (P 0.05). The positive expression of HIF-1a was correlated with recurrence and distant metastasis (P 0.05). Pearson correlation analysis showed that there was a certain correlation between the two expressions (r=0.338, P=0.004).
The overall survival rate of 69 cases of head and neck squamous cell carcinoma was related to the primary site, T grade, clinical stage, lymph node metastasis, recurrence, distant metastasis, Glut-1 positive expression and HIF-1a positive expression. The 3-year and 5-year survival rates of Glut-1 positive HNSCC patients were 46.7%, 37.3%, respectively, and those without Glut-1 expression were 3-year and 5-year survival rates. The 3-year and 5-year survival rates were 61.0% and 42.7% for HIF-1a positive HNSCC patients and 85.0% and 78.5% for non-HIF-1a positive HNSCC patients respectively. The survival rate was statistically different.
conclusion
1. The increased expression of Glut-1 and HIF-1a may be related to the occurrence of head and neck squamous cell carcinoma. Compared with inflammatory lesions and precancerous lesions, the expression of Glut-1 in head and neck squamous cell carcinoma increased significantly.
2. The increased expression of Glut-1 was related to the location, N stage and distant metastasis of head and neck squamous cell carcinoma, and the increased expression of HIF-1a was related to the recurrence and distant metastasis of head and neck squamous cell carcinoma.
3. Univariate prognostic analysis: Glut-1 expression and HIF-1a expression were associated with the prognosis of head and neck squamous cell carcinoma, including the primary site, T-grade, clinical stage, lymph node metastasis, recurrence and distant metastasis; Multivariate analysis showed that the primary location and local recurrence of the tumor were associated with the prognosis of head and neck squamous cell carcinoma.
【學位授予單位】：浙江大學
【學位級別】：碩士
【學位授予年份】：2012
【分類號】：R739.63
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