软性膀胱镜减少患者痛苦,窄带光成像膀胱镜镜检能够早期发现膀胱肿瘤膀胱肿瘤是泌尿系统发病第一位的恶性肿瘤,每年有近1000例患者在天津医科大学第二医院接受手术。其中有30%的患者在接受术后规律的治疗后两年内出现肿瘤的复发甚至进展。目前非肌层浸润性膀胱癌(浅表膀胱癌)的首选治疗方法是经尿道肿瘤切除术。手术经过尿道进行,没有手术切口,患者恢复快。很多患者和家属在手术后第一个想到的问题就是:“医生,我的肿瘤切除干净了吗?”其实这个问题同样是手术医生十分关注的问题。膀胱肿瘤术后复发率高不是医生的手术操作存在问题,而是很多异常粘膜及疾病的早期病变应用现有手段不能够及时发现,未发现早期肿瘤异常病变是导致膀胱肿瘤术后复发的主要因素。但由于早期的膀胱肿瘤与正常粘膜几乎无法分辨,甚至在病理学上尚未发展至恶性阶段。因而近年来临床不断发展处多种高科技手段用于提高膀胱肿瘤及异常粘膜的检出率。其中窄带光成像技术提高了肿瘤检出率的同时不需要对患者增加额外的操作,得到了医患的广泛认可。NBI是近几年临床出现的新型的成像技术,能更加细微地反映毛细血管和黏膜的表面变化,改善图像的对比性和可视性,大大提高了微小肿瘤和原位癌的检出率,更加清晰地显示了肿瘤的边界。患者术后规律的复查对于早期发现肿瘤复发、早期治疗肿瘤、预防肿瘤进展至关重要。但很多患者一想到应用普通的膀胱镜设备进行膀胱镜检查就会不寒而栗、岁膀胱镜检查有很大的抵触心理。天津医科大学第二医院泌尿外科A区团队已经成功的应用NBI膀胱软镜进行膀胱肿瘤的手术前活检及术后复查。因膀胱软镜纤细、柔软,患者在不麻醉的情况下就能够顺利的实施。大大减轻了膀胱硬镜操作下的疼痛不适及术后血尿。同时膀胱软镜能够在膀胱内360度无死角的观察膀胱粘膜,一定程度上避免了肿瘤的遗漏。普通膀胱镜下图像①NBI镜下图像①普通膀胱镜下图像②NBI镜下图像②膀胱软镜可以轻松看到膀胱颈内口③
【摘要】目的:探讨非肌层浸润性膀胱癌(non-muscle-invasive bladder cancer, NMIBC)伴术前脓尿患者的临床特点及脓尿对其预后方面的临床意义。方法:回顾性分析2009年11月至2011年3月我院278例首发非肌层浸润性膀胱癌患者的临床病理资料。定义脓尿为每高倍视野下尿白细胞数量大于等于5个,根据术前尿白细胞值,将患者分为脓尿(-)组(尿白细胞<5)和脓尿(+)组(尿白细胞≥5),运用卡方检验分析脓尿和各临床病理特点之间的关系,运用Kaplan-Meier法比较两组之间无复发生存期(recurrence-free survival,RFS)和无进展生存期(progression-free survival,PFS)的区别, 并用Log-rank检验评估其统计学意义。结果:278例NMIBC患者中,有98例(35.3%)出现术前脓尿,平均随访48.6(3-72)个月。在随访期间内,脓尿的出现与大体积、多发、高TNM分期、高级别肿瘤以及高复发率和高进展率显著相关,且经Kaplan-Meier法分析发现,脓尿(+)组患者无复发生存率明显低于脓尿(-)组患者(58.2% vs71.7%, p=0.016);同样,脓尿(+)组患者无进展生存率也明显低于脓尿(-)组患者(74.5% vs85.6%, p=0.018)。结论:非肌层浸润性膀胱癌伴术前脓尿患者肿瘤多发且体积大,组织学分级和临床分期高,预后较差,应积极手术治疗并术后密切随访。【关键词】膀胱癌;非肌层浸润;脓尿;预后。The prognostic significanceof preoperative pyuria in patients withnon-muscle-invasive bladder cancerWu Zhou-liang,Xu Hao,Sha Nan, Zhang Yu, Shen Zhong-hua,XingChen, Liu Xiao-teng, WuChangli ,HuHai-long. Department of Urology, the Second Hospital of Tianjin Medical University, National Key Specialty Construction of Clinical Projects, Tianjin Urology Institute, Tianjin Key Laboratory of Basic Urology, Tianjin 300211,China.【Abstract】Objective:To evaluate the prognostic significance of preoperativepyuria in patients with non-muscle-invasive bladder cancer.Methods:Weretrospectively reviewed data from 278patients diagnosed with non-muscle-invasive bladder cancerin our institute from November 2009 to March 2011. Pyuria was defined as urine containing ≥5 white bloodcells per high power field.We divided the 278consecutivepatients into two groups named as pyuria(-) and pyuria(+). Correlations amongpyuria with other clinical and pathological features were assessed by chi-square.Recurrence-freesurvival(RFS) and progression-free survival(PFS) curveswere estimated using the Kaplan-Meier method. Log-ranktest was conducted to evaluate the statistically significance. Results:Among 278consecutive patients,98(35.3%) patients had preoperative pyuria.The mean follow-up time is 48.6(3-72)months. During the follow-up, pyuria was significantlyassociated with large tumor size,multiple tumors, T1 tumors,high-grade tumors, high recurrence rate and high progression rate. The recurrence-free survival rate for patients with pyuria was significantlylower than for patients without pyuria (58.2% vs71.7%,p=0.016).Similarly, the progression-free survival rate waslowerin the pyuria(+) group(74.5% vs85.6%, p=0.018).Conclusion: Preoperative pyuria seems to be significantly associated with poor clinical outcomes inpatients with non-muscle-invasive bladder cancer.These patients should be treated actively and follow up closely.Key words:bladder cancer;non-muscle-invasive bladder cancer;pyuria;prognosis.膀胱尿路上皮癌在泌尿生殖系肿瘤发病率占第二位[1],而非肌层浸润性膀胱癌(non-muscle-invasive bladder cancer,NMIBC)占每年新发膀胱癌的80%。通常采用经尿道膀胱肿瘤电切术(transurethral resection of thebladder tumor,TURBT)来治疗NMIBC,然而,大约15%-70%的NMIBC患者会在术后1年内复发[2],7%-40%的患者会在术后5年内进展为肌层浸润性膀胱癌(muscle-invasive bladder cancer,MIBC)[3]。已经有报道指出,肿瘤大小、数量、病理分期、分级、存在原位癌以及早期复发率是NMIBC复发和进展的预后因子[4]。然而,像IL-8、IL6/IL-10,MMP-9等最新发现的NMIBC预后因子却很少有人提及。近年来,随着分子生物学技术的发展,炎症和肿瘤的关系正成为肿瘤研究领域的热点,事实上,在一些肿瘤中,炎症和肿瘤发生发展之间的关系已经得到了具体的阐述[5, 6]。肿瘤相关炎性细胞能够分泌一系列的炎性介质、细胞因子,促进肿瘤的增殖、侵袭及转移,进而影响患者的预后。而脓尿作为全身炎症反应的表现之一,其存在与否与膀胱肿瘤之间的关系鲜有人报道。因此,本研究回顾性分析了我院278例首发NMIBC患者的临床病理资料,探讨术前脓尿与NMIBC患者预后的关系。1. 资料与方法 1.1 一般资料 回顾性分析我院自2009年11月至2011年3月收治的389例非肌层浸润性膀胱癌患者的临床病理资料。排除复发病例(79例)和术前有尿路感染症状病例(32例)后,将余下的278例NMIBC患者纳入研究。其中男227(81.65%)例,女51(18.35%)例,平均62.8岁(24岁~88岁)。行TURBT 272例,膀胱部分切 6例。1.2 尿液标本采集及脓尿定义 收集患者术前早晨清洁中段尿或女性尿管导尿标本10-50ml送检,定义脓尿为每高倍视野下尿白细胞数量大于等于5个;根据术前尿白细胞值,将患者分为脓尿(-)组(尿白细胞<5)和脓尿(+)组(尿白细胞≥5),所有脓尿(+)组尿液标本均行尿培养药敏实验,以排除泌尿系感染可能;采集相关临床病理资料及术前尿常规化验检查结果。1.3 随访和术后治疗 所有患者均在术后前2年每3个月行一次B超、尿脱落细胞及膀胱镜检查,随后两年每6个月行上述检查1次,然后每年行膀胱 镜检查1次直至终身。术后患者规律行膀胱内灌注表比星50mg或羟喜树碱20mg(每周1次,连续8次,后改为每2周1次,连续8次,最后改为每月1次,连续8次)。1.4 纳入研究项目 该研究中纳入的因素包括性别、年龄、肿瘤大小和数目(术中确定肿瘤大小及数量,直径小于或等于3cm者定义为较小肿瘤,大于3cm者为较大肿瘤。肿瘤数量为1个者定义为单发肿瘤,2个及以上者定义为多发肿瘤)、TNM分期(UICC-TNM,2009)、病理分级(WHO2004)、有无原位癌、灌注药物、以及是否复发和进展。1.5 统计学方法 采用SPSS 20.0对数据进行分析。运用卡方检验分析脓尿和各临床病理特点之间的关系,运用Kaplan-Meier法比较两组之间无复发生存期(recurrence-free survival,RFS)和无进展生存期(progression-free survival,PFS)的区别, 并用Log-rank检验评估其统计学意义。所有差异均以p﹤0.05定义为有统计学意义。其中对于RFS我们定义为首次诊断为NMIBC到首次复发的时间;PFS被定义为首次诊断为NMIBC到首次肿瘤进展(任意肿瘤分级分期的提高)的时间,未复发或进展者截止到末次随访日期。2. 结果 共有278例NMIBC患者纳入研究,其临床病理情况见表1,其中98例(35.3%)出现术前脓尿。平均随访48.6(3-72)个月,在随访期间内,脓尿(+)组有41(41.84%)例出现复发,25(25.51%)出现进展,均较脓尿(-)组复发率和进展率高(p﹤0.05)。通过卡方检验将各临床病理资料进行组间分析可见:脓尿(+)与大体积、多发、高TNM分期、高级别肿瘤以及高复发率和高进展率显著相关(p﹤0.05)。同样,经比较Kaplan-Meier生存曲线可见,脓尿(+)组患者平均RFS为48.62(3-72)个月,平均PFS为49.4(4-72)个月,均较脓尿(-)组RFS和PFS短,且差异有统计学意义(p﹤0.05)(见图1和2)。3. 讨论 自从1863 年Vichow 等[7]首次把肿瘤和炎症细胞联系起来,越来越多的研究证实肿瘤微环境中的炎症反应可以通过提升肿瘤细胞增殖、生存、迁移和血管生成能力来促进肿瘤的生长和侵袭[8, 9]。肿瘤相关炎症因子作为宿主相关因素包括生化和血液学指标,如CA125、白细胞、中性粒细胞、血小板等。肿瘤相关的巨噬细胞、调节性T细胞、浸润性淋巴细胞和骨髓来源的抑制细胞[10, 11],以及外周血中中性粒细胞/淋巴细胞比率[12]在肿瘤发生发展中的作用已经得到了广泛的阐述。已经有文献证明瘤内中性粒细胞数量是肝癌、胃癌、肾癌和黑色素瘤的独立预后因子[13-15],中性粒细胞是机体中最多的白细胞,可以通过释放血管内皮生长因子(VEGF)、细胞生长因子(CXCL8)、基质金属蛋白酶(MMP-9)以及抗凋亡因子(NF-κB)等一系列的炎症介质促进肿瘤的生长、转移和侵袭[16]。过量的炎性介质释放导致氧化损伤、DNA突变和肿瘤微环境的改变,进一步促进了细胞转化、瘤细胞生长和增殖[10]。其中,肿瘤浸润中性粒细胞释放的MMP-9和趋化因子-4(CCL-4)是肿瘤进展的关键介质[17],MMP-9通过分泌促血管生成因子诱导肿瘤内血管的形成,而CCL-4可能是调控骨髓样和淋巴样免疫细胞平衡的关键因子。另外,CCL-4的过表达还和肿瘤的复发和进展明显相关[17]。也有人报道过炎性反应和肌层浸润性膀胱癌(MIBC)进展之间的关系。Gondo 等[18]提出中性粒-淋巴细胞比是行根治性膀胱癌切除术患者的独立预后因子。考虑到MIBC的进展性,中性粒-淋巴细胞比作为全身炎症反应的一种标志物,可以精确的反映炎症严重程度,相反,对于NMIBC却不那么容易。但也同样有人研究证实NMIBC患者术前脓尿预示着不良的预后。Azuma等[19]通过回顾性分析805例NMIBC患者术前尿中白细胞数量及临床病理资料,发现脓尿(+)患者预后明显较差,且脓尿是NMIBC患者复发和进展的独立预后因子。Satake等[20]人也有类似的发现。因此,NMIBC患者尿中白细胞或许能成为指导临床医生选择治疗方案的一个指标。然而,脓尿不仅仅是由于肿瘤炎性反应导致,由于膀胱肿瘤好发于老年男性,尿路梗阻也可以导致脓尿,因此,无泌尿系感染症状(尿培养药敏实验阴性)的NMIBC患者才是我们的研究对象。术前脓尿导致膀胱肿瘤复发的机制尚未完全解释清楚,许多观点认为,肿瘤炎性反应中的白细胞扮演了重要角色[21, 22],肿瘤浸润性单核-巨噬细胞和骨髓粒细胞可能导致膀胱癌的炎性反应和免疫功能失调,其中,骨髓粒细胞释放的各种趋化因子和细胞因子更是发挥了重要作用[23]。另外,Tachibana等[24]通过研究发现,膀胱肿瘤细胞可以产生粒细胞集落刺激因子,持续刺激机体产生白细胞,导致宿主出现类白血病反应 ,同时也发现抗粒细胞集落刺激因子抗体可以抑制肿瘤细胞增殖。因此,NMIBC和脓尿之间的具体关系仍模糊不清,仍待进一步的基础研究阐明。在本研究中,我们回顾性分析了278例NMIBC患者术前尿中白细胞数量和患者临床病理特征及预后的关系,结果发现脓尿(+)与大体积、多发、高TNM分期、高级别肿瘤以及高复发率和高进展率显著相关,且其RFS、PFS均明显低于脓尿(-)组患者,因此可以认为,NMIBC患者术前出现脓尿具有较差的预后。然而不得不承认,本研究存在一些缺陷。首先,本研究作为回顾性非随机分析,有可能引入固有偏倚和缺失值;其次,样本量较小,需要多中心大样本来证实脓尿对NMIBC的临床意义; 另外,根据Hooker [25]的报道,本研究定义脓尿为每高倍视野下白细胞大于等于5个,然而这个界限值仍需进一步证实。4. 结论非肌层浸润性膀胱癌伴术前脓尿患者肿瘤多发且体积大,组织学分级和临床分期高,预后较差,应积极手术治疗并术后密切随访。参考文献[1] Siegel R, Naishadham D, Jemal A. 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J Am Board Fam Med,2014,27(1):97-103.表1:术前脓尿与膀胱癌临床病理特征的关系:脓尿(-)脓尿(+)p值患者数量n=180(%)n=98(%)年龄(岁)(Mean±SD)62.71±12.0362.99±13.330.184﹤6594(52.22)43(43.88)≧6586(47.78)55(56.12)性别(%)0.103男152(84.44)75(76.53)女28(15.56)23(23.47)肿瘤大小*0.016≦3155(86.11)73(74.49)﹥325(13.89)25(25.51)肿瘤数量0.003单发124(68.89)50(51.02)多发56(31.11)48(48.98)TNM分期0.005Ta103(57.22)39(39.80)T177(42.78)59(60.20)病理分级0.001低级别128(71.11)50(51.02)高级别52(28.89)48(48.98)原位癌0.497无156(86.67)82(83.67)有24(13.33)16(16.33)膀胱灌注0.182表比星81(45.00)36(36.73)羟喜树碱99(55.00)62(63.27)是否复发0.022是51(28.33)41(41.84)否129(71.67)57(58.16)是否进展0.023是26(14.44)25(25.51)否154(85.56)73(74.49)*选用肿瘤最大直径为参考值图1:脓尿(—)组和脓尿(+)组NNMIBC患者RFS的比较:图2:脓尿(—)组和脓尿(+)组MMIBC患者PFS的比较:作者:吴周亮
非肌层浸润性膀胱癌术后要进行长达一年至三年的膀胱内灌注药物治疗,膀胱内灌注药物治疗是至关重要的。如果不进行膀胱灌注治疗,术后两年内膀胱肿瘤复发率高达75%,而进行膀胱灌注治疗者复发率则降至15%,所以膀胱癌术后灌注治疗是膀胱癌治疗中的重要一环。但是膀胱灌注化疗药物有一定副作用,需要患者注意事项如下: 1、 坚持规律规范灌药 1 术后第1-8次每周一次,术后第9-18次每月一次,可每月一次维持一至三年。 2 每次灌药前要排空膀胱,化疗药物灌注后尽量坚持60分钟左右(具体药物具体对待)再排尿。排尿后大量喝水,冲刷膀胱! 2、 膀胱灌注期间并发症处理 1 下尿路感染:尤其是术后1-8周,每次灌药前要复查尿常规,如出现下尿路感染要及时治疗,给予抗生素甚至暂停一次灌注治疗以防止感染加重,造成长期不能灌注治疗 2 下尿路刺激症状:绝大部分患者在早期膀胱灌注治疗(1-8周)时,都会出现或轻或重的下尿路刺激症状如尿频、尿急、尿不尽,这是化疗药物造成的刺激症状,请不要慌张,对于轻微症状可不用特殊处理,建议多饮水即可;对于症状较重影响生活或不能耐受的患者,在多饮水的基础上可加用一些对症处理药物如止痛、解痉药物,具体要咨询手术医师,甚至可停用化疗药物 3 血尿:术后化疗药物灌注期间早期轻微血尿(1-3个月)大多数为药物刺激或感染造成,不必太过慌张,如果出现严重血尿则有可能为术后延迟出血,要马上急症就医防止出现膀胱填塞可能,3个月以后如果出现无症状血尿则要引起重视,不能排除肿瘤复发出血,可能要联系手术医师复查以明确诊断 总结:非肌层浸润性膀胱癌手术切除肿瘤只是治疗中的一小环,而膀胱化疗灌注才是重中之重,希望各位患者重视。
一. 生活 1.禁烟:吸烟是目前已知的膀胱癌患病原因之一 2.禁辛辣:少食辛辣刺激食物可降低膀胱前列腺刺激症状,减轻因化疗药物灌注引起的下尿路刺激症状 3.多饮水:大量饮水有利于降低化疗药物对膀胱粘膜的刺激症状,同时降低下尿路感染风险。 4.观察自身排尿症状,包括尿液颜色以及是否有尿频、尿急、尿痛及排尿困难等症状。 二.疾病随访(非肌层浸润膀胱癌) 低危膀胱癌患者: 1. 低危膀胱癌患者需要在TURBT术后第一年分别在术后3个月和第12个月复查2次膀胱镜 2. 低危膀胱癌患者TURBT术后第2-5年每年复查一次膀胱镜检查,如出现血尿或影像学复查异常或复发需随时加做膀胱镜检查。 3. 影像学检查:CTU、静脉肾盂造影、逆行造影、MRU核磁水造影第一年做一次为基线,第一年后如出现临床症状需要随时行影像学检查 高危膀胱癌患者: 1. 高危膀胱癌患者需要在TURBT术后的第1-2年每3个月复查一次膀胱镜检查;第3-5年每半年复查一次膀胱镜检查;5年以上每年复查一次膀胱镜检查 2. 影像学检查:术后第一年行CTU、MRU、IVP等检查,以后每年需要检查一次 3. 尿脱落细胞学检查:高危患者需要在术后第1-2年每3个月复查一次脱落细胞学,2年以后每半年复查一次尿脱落细胞学 三. 治疗 1. 膀胱灌注治疗术后第1-8次,每周灌注一次并检查尿常规,术后第9-18次,每4周灌注一次.术后18次以后可每月一次,维持至3年 膀胱灌注治疗需要注意:a.灌药前排空膀胱 b.灌药后尽量保留60分钟再排空膀胱 2. 手术治疗 二次电切: a.术后病理提示边缘或基底病理呈阳性 b.术后病理提示为T1G3或原位癌建议二次电切治疗 复查过程中膀胱镜检查或影像学检查发现新发肿瘤需要及时就诊并行手术治疗。
最近总有患者咨询我经尿道膀胱肿瘤电切术(TURBT)后如何进行规律的膀胱软镜复查?查阅了国内外指南后总结如下,希望给广大患者带来小小的帮助! 1、高危患者术后前2年每3个月复查一次(3,6,9,12,15,18,21,24),术后3-4年每6个月一次(30,36,42,48),术后第五年每12个月一次(60)。 2、中危患者术后前半年每3个月复查一次(3,6),术后1-4年半年一次(12,18,24,30,36,42,48),术后第五年每12个月一次(60)。
Girdin protein is a novel prognosis predictor for patients with non-muscle invasive bladder cancerZhouliang Wu1,2, , Wenlu Zhao3,, Bo Zhang1,2,, Wanqin Xie4, Dawei Tian1,2,YuZhang1,2, Feiran Cheng1,2, Zhonghua Shen1,2, Xiaoteng Liu1,2, Hao Xu1,2, Nan Sha1,2, Changli Wu1,2, Hailong Hu1,2,*1 Department of Urology, Second Hospital of Tianjin Medical University, Pingjiang Road 23, Hexi District, Tianjin 300211, China;2 Tianjin Key Laboratory of Urology, Tianjin Institute of Urology, Second Hospital of Tianjin Medical University,Pingjiang Road 23, Hexi District, Tianjin 300211, China;3Department ofvascularsurgery,Tianjin Hospital, Tianjin 300211, China;4Key Laboratory of genetics and birth health of Hunan province, the family planning research institute of Hunan province, Changsha, Hunan 410126, China These authors contributed equally to this work.*Corresponding:E-mailaddresses:hhllove2004@163.com;Tel:+86-22-88328603; Fax: +86-22-28273211Abstract:This study aimed to determine the expression status of actin-binding protein Girdin innon-muscle invasive bladder cancer(NMIBC)tissues, and to explore the relationships between Girdin expression and the clinicopathological characteristics of bladder carcinoma. The correlations between Girdin expression and the clinicopathological parameters were examined by Chi-square test. Recurrence-free survival (RFS) and progression-free survival (PFS) were analyzed using Kaplan-Meier method. The prognostic significance of Girdin expression was assessed using univariate and multivariate Cox regression analysis models. Results showed that 69 (43.1%) of the 160 NMIBC tissue samples displayed positive expression of Girdin; Girdin positivity was more frequently seen in high-grade tumors than in low-grade tumors (P=0.019), and in undifferentiated tumors than in differentiated tumors (p=0.028). In Kaplan–Meier analysis, expression of Girdin was significantly associated with lower RFS (p = 0.007) and PFS (p = 0.024) rates. The univariate analysis revealed that Girdin expression was a risk factor for both recurrence and progression of NMIBC. Further multivariate analysis identified Girdin as an independent predictor of tumor recurrence (hazard ratio [HR]: 2.056, 95% CI: 1.213-3.483, p = 0.007). The present study suggests that Girdin is differentially expressed in bladder tumors and may represent an independent predictor of prognosis for patients with NMIBC.Keywords: Girdin; bladder cancer; NMIBC; recurrence; progressionRunning title:The expressionof Girdin proteinnon-muscle invasive bladder cancer1.IntroductionBladder cancer is the most common malignancy of the urinary tract worldwide (1). Approximately 75% of patients with bladder cancer are diagnosed as non-muscle-invasive bladder cancer(NMIBC) (2), and routinely treated with transurethral resection of bladder tumor (TURBT) with or without intravesical therapy. As NMIBC is characterized by high probability of recurrence and progression, with a 5-year recurrence rate ranging from 15% to 90% and a 5-year progression rate from 7% to 50%(3-5), stratification of patients into distinct prognostic groups will greatly contribute to personalized treatment and follow-up plan. Although previous studies identified the clinicopathological factors including gender, tumor stage, lymph node involvement, lymphovascular invasion, and surgical margin status as prognostic factors of NMIBC, inconsistencies exist between the studies regarding the performance of these factors on prognosis prediction(6-8). Hence, novel predictors of prognosis are eagerly anticipated for NMIBC. In addition to the conventional clinicolpathological factors, the newly emerging molecular markers have shown their clinic significance in evaluation of prognosis(9-11).Intracellular signaling pathways are involved in almost all aspects of cellular functions,such as proliferation, differentiation, apoptosis, and etc. Therefore, dysregulation of key components in signaling pathways may lead to initiation and progression of cancers. For instance, the Girdin protein, which serves as a scaffold protein and locates at the crossroad of G protein signaling and tyrosine kinase receptor signaling(12), is abnormally expressed in malignant tumors derived from various types of tissues including the uterine cervix, breast, lung, and thyroid gland. Moreover, it has been shown that expression of Girdin predicts patient survival in colon cancer and that Girdin may be a useful biomarker for tumor stage in colorectal carcinoma(13). Although our knowledge about the roles of Girdin in cancer is accumulating, the relationships between expression of Girdin and the clinicopathological factors of bladder tumors remain unknown. In the present study, we aimed to determine the expression status of Girdin protein in tumor tissues from patients with NMIBC, as well as the clinical implications of Girdin protein in NMIBC.2. Experimental Section2.1. Patients and tissue specimensThis study included 160 patients with NMIBC who underwent surgery from January 2006 to January 2011 at Second Hospital of Tianjin Medical University. All patients were pathologically confirmed to have urothelial bladder carcinoma. 153 out of the 160 tissue specimens were acquired via TURBT, and the other 7 specimens via cystoscopy biopsy. None of the patients had received chemotherapy or radiotherapy before surgery. Two pathologists who were blind to patient information independently reviewed all sections for tumor staging and grading. The tumors were graded in accordance with the World Health Organization (WHO)/International Society of Urological Pathology (ISUP) (2004). Pathological stages were determined according to the Union for International Cancer Control (UICC) TNM classification (2002). Nodal and metastatic profiles were not included in this study due to the incomplete clinical history of patients2.2.Follow-up and clinical outcomesPostoperative follow-up was conducted with rigid cystoscopyevery 3 months for the first two years, every 6 months thereafter, and annually after the fifth year according to the US and European guidelines. The end points for patients in this study were tumor recurrence and progression. Outcomes of interest were recurrence-free survival (RFS) and progression-free survival (PFS). The period for RFS was estimated from the date of surgery to the date of initial recurrence confirmed (any grade, stage category or CIS). The PFS duration was calculated from the date of surgery to the date of disease confirmed with development into higher histological or pathological stage and/ or to metastasis. For patients without recurrence and progression, the end point was the date of the last available follow-up cystoscopy. No patients died until the last available follow-up in the study. The present study was approved by the Ethics Committee of Second Hospital of Tianjin Medical University.2.3.Immunohistochemistry(IHC)Polyclonal rabbit anti-human Girdin antibody (T-13: sc-133371; dilution 1:100) was from Santa Cruz Biotechnology (Santa Cruz, Biotechnology, CA, USA).Thin slices of tumor tissue of all cases, which were fixed in 4% formaldehyde solution (pH 7.0), were from the histopathology unit at the hospital. The fixation for all slices did not exceed 24 h. The tissues were processed routinely for paraffin embedding, and 4 μm-thick sections were cut and placed on glass slides coated with 3-aminopropyl triethoxysilane for immunohistochemistry. Tissue samples were stained with hematoxylin and eosin to determine the histological type and grade of tumors.The number of immunoreactive cellswas quantified as ‘proportion score’, including 0; noimmunoreactive cells, 1; the numbers of immunoreactive cells were less than 1%, 2; less than 10%, 3;less than one-thirds, 4; less than two-thirds, 5; morethan two-thirds. The highest number of immunoreactive tumor cells was graded as ‘intensity score’,including 0; no immunoreactivity, 1; weak stainingintensity, 2; intermediate, 3; strong. The IHC results were grouped based onthe IHC score (proportion score plus intensity score):0–2, negative(); 3–8, positive(+)(14)2.4.Statistical analysisStatistical analysis was performed using SPSS software (IBM company, version20.0). Relationships between Girdin expression and the clinic parameters were studied using the Chi-square test and Fisher’s extract test or independent t test. RFS and PFS rates were analyzed using the Kaplan–Meier method. The log-rank test was used to analyze the differences in survival between groups. The prognostic significance of Girdin expression was assessed using univariate and multivariate Cox regression analysis models. P value < 0.05 was considered statistically significant.3. Results and Discussion3.1.The expression of Girdin in tumors from patients with NMIBCWe detected the Girdin expression in tumors from an independent primary NMIBC cohort comprising 160 patients by using immunohistochemical staining with polyclonal antibodies against human Girdin protein. As depicted in Figure 1,Protein expression of Girdin was mainly evident in the cytoplasm or membrane with yellow or brown-yellow staining. Additionally, the demographic characteristics of the cohort are summarized in Table 1. Girdin expression was dichotomized (negative versus positive) based on the staining area and intensity, with 69 (43.1%) and 91(56.9%) tissue samples showing positive and negative expression of Girdin, respectively.3.2. The association of Girdin expression with clinicopathological factors The relationships between the expression of Girdin and clinicopathological characteristics are summarized in Table 1. Girdin expression was significantly associated with histologic differentiation (p=0.028), tumor grade (p=0.019), recurrence (p=0.008), and progression to MIBC (p=0.022), but not related to age, gender, tumor size, multiplicity, smoking history,tumor stage, or intravesical therapy.3.3. Prognostic significance of Girdin expression in NMIBCThe overall median follow-up duration was 65.0 months (interquartile range (IQR) 29.0–97.8). With respect to patients with Girdin-positive and Girdin-negative tumor, the median follow-up time was 49.0 months (IQR 20.5–90.0) and 74.0 months (IQR49.0–98.0), respectively. The overall RFS and PFS rates of the cohort were 63.8% and 84.4%, respectively.The Kaplan–Meier analysis showed that the Girdin-positive patients had significantly lower RFS (p=0.007) and PFS (p=0.024) rates than did the Girdin-negative patients (Figure 2(A)and 2(B)). The univariate Cox regression analyses showed that Girdin expression was a significant risk factor for tumor recurrence and progression (Table 2 and Table 3). Compared with Girdin-negative tumor, Girdin-positive tumor was associated with a 2.024-fold (95% confidence interval, 1.202–3.408) and 2.481-fold (95% confidence interval, 1.096–5.616) increased risk for recurrence (p = 0.008) and progression (p = 0.029), respectively.Inmultivariate analysis with adjustment for Girdin expression and multiple clinicopathological factors, Girdin expression remained to be a significant predictor of tumor recurrence(Table 2). Patients with Girdin-positive tumor were associated with a 2.056-fold (95% confidence interval, 1.213–3.483) increased risk for tumor recurrence, compared with those with Girdin-negative tumor (p = 0.007). Although the analysis also implied the correlation of Girdin-positive tumor with a 2.272-fold (95% confidence interval, 0.999–5.171) increased risk for tumor progression, the association was marginally significant (p = 0.050) (Table 3).4. DiscussionGirdin is a novel protein identified in 2005, of which the encoding gene locates at chromosome 2p16.1(12, 15). Previous studies have demonstrated Girdin interactions with the key components in intracellular signaling pathways that regulate a number of biological processes, such as Akt, Gαi/s, dynamin, and guanosine triphosphate hydrolase enzyme (GTPase)(16, 17). Accumulating evidence support that Girdin plays an important role in tumor development and progression, which implies its potential as a biomarker for diagnosis and prognosis in clinic oncology. In breast cancer, Girdin has been reported to be a potential predictor for distant metastasis(18). Wang et al. (19)determined the Girdin expression in 105 gastric cancer tissues and 72 para-cancer tissues. Based on the results, Girdin might be considered as a novel biomarker for metastasis and prognosis in gastric cancer. To determine the expression of Girdin in tumor tissues from patients with NMIBC, we performed immunohistochemistry analysis. We observed the positive expression of Girdin in 43.1% of tumor tissues in the cohort. In a previous study, Jiang et al(20)detected high expression of Girdin in breast, colorectal, lung, cervical and thyroid cancer tissues. The positive ratio of Girdin expression varied between 10 and 50% among different types of cancer. Basically, our observation was in accordance with Jiang et al.’s. To the best of our knowledge, this is the first study that explored the relationships between expression of Girdin and the clinicopathological parameters of NMIBC. Because patients with NMIBC are of high probability suffering from tumor recurrence and progression to muscle invasive cancers(21), we focused on the prognostic implication of Girdin in NMIBC. The univariate analysis shows that Girdin expression is a risk factor for both tumor recurrence and progression in the cohort. Further, multivariate analysis indicates that Girdin is an independent predictor of tumor recurrence for patients with NMIBC. However, the prognostic significance of Girdin in the present study should be interpreted with cautions because of the single-institution retrospective study design and the relatively small sample size of the cohort. Future prospective studies in collaboration with multiple centers should be performed to validate our results.Although the association between Girdin expression and tumor recurrence of NMIBC has been shown in this study, the detailed mechanism by which Girdin acts in NMIBC remains largely unknown. To be noticed, the studyby Zhang et al.(22)showed that knockdown of Girdin enhanced chemosensitivity of colorectal cancers cells to oxaliplatin. This finding projects a potential correlation between Girdin protein and the chemoresistance of cancer cells. We reason that high expression of Girdin may confer the survival advantages of bladder tumor cells under the intravesical chemotherapy, thereby resulting in a higher rate of recurrence in patients with Girdin-positive tumors. Although Girdin-G protein-AKT axis has been shown to be associated with anti-apoptotic effects and chemoresistance in cancers(23)the impact of this axis on prognosis of NMIBC remains to be evaluated. 5. ConclusionsIn conclusion, the present study demonstrates that overexpression of Girdin correlates with the tumor recurrence and malignant progression in patients with NMIBC. Moreover, Girdin may represent a novel independent predictor of tumor recurrence for patients with NMIBC.Acknowledgments: This study was supported by grants from Natural Science Foundation of Tianjin (No.12ZCDZSY16600), the Natural Science Foundation of Tianjin (No.14JCYBJC26300), the Natural Science Foundation of Tianjin (No. 15JCYBJC24600) and National Key Specialty Construction of Clinical Projects.Conflict of Interest: The authors declare no conflict of interest.References:1.Ferlay J, Soerjomataram I and Dikshit R, et al.: Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer 136: E359-E386, 2015.2.Nieder AM, Mackinnon JA, Huang Y, Fleming LE, Koniaris LG and Lee DJ: Florida bladder cancer trends 1981 to 2004: minimal progress in decreasing advanced disease. J Urol 179: 491-495, 495, 2008.3.Kurth KH, Denis L and Bouffioux C, et al.: Factors affecting recurrence and progression in superficial bladder tumours. 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J Cell Biol 182: 381-393, 2008.13.Garcia-Marcos M, Jung BH, Ear J, Cabrera B, Carethers JM and Ghosh P: Expression of GIV/Girdin, a metastasis-related protein, predicts patient survival in colon cancer. Faseb J 25: 590-599, 2011.14.Song SY, Lee SK and Kim DH, et al.: Expression of maspin in colon cancers: its relationship with p53 expression and microvessel density. Dig Dis Sci 47: 1831-1835, 2002.15.Asai M, Asai N and Murata A, et al.: Similar phenotypes of Girdin germ-line and conditional knockout mice indicate a crucial role for Girdin in the nestin lineage. Biochem Biophys Res Commun 426: 533-538, 2012.16.Enomoto A, Murakami H and Asai N, et al.: Akt/PKB regulates actin organization and cell motility via Girdin/APE. Dev Cell 9: 389-402, 2005.17.Enomoto A, Ping J and Takahashi M: Girdin, a novel actin-binding protein, and its family of proteins possess versatile functions in the Akt and Wnt signaling pathways. Ann N Y Acad Sci 1086: 169-184, 2006.18.Liu C, Zhang Y and Xu H, et al.: Girdin protein: a new potential distant metastasis predictor of breast cancer. Med Oncol 29: 1554-1560, 2012.19.Wang LC, Xylinas E and Kent MT, et al.: Combining smoking information and molecular markers improves prognostication in patients with urothelial carcinoma of the bladder. Urol Oncol 32: 433-440, 2014.20.Jiang P, Enomoto A and Jijiwa M, et al.: An actin-binding protein Girdin regulates the motility of breast cancer cells. Cancer Res 68: 1310-1318, 2008.21.Cookson MS, Herr HW, Zhang ZF, Soloway S, Sogani PC and Fair WR: The treated natural history of high risk superficial bladder cancer: 15-year outcome. J Urol 158: 62-67, 1997.22.Zhang YJ, Li AJ, Han Y, Yin L and Lin MB: Inhibition of Girdin enhances chemosensitivity of colorectal cancer cells to oxaliplatin. World J Gastroenterol 20: 8229-8236, 2014.23.Garcia-Marcos M, Ghosh P and Farquhar MG: GIV is a nonreceptor GEF for G alpha i with a unique motif that regulates Akt signaling. Proc Natl Acad Sci U S A 106: 3178-3183, 2009.Figure legendsFigure 1.Immunohistochemical staining of Girdin protein in human bladder carcinoma tissue samples. Protein expression of Girdin was mainly evident in the cytoplasm or membrane with yellow or brown-yellow staining. A showed negative(IHC score1) stain of Girdin in NMIBC sample; Bshowedpositive(IHC score3) stain of Girdin in NMIBC sample;Cshowedpositive(IHC score6) stain of Girdin in NMIBC sample; Dshowedpositive(IHC score8) stain of Girdin in NMIBC sample(A, B, Cand D, magnification, ×200)Figure 2. Kaplan–Meier survival curves for recurrence-free survival(A)and progression-free survival (B)according toGirdin expression. Expression was dichotomized appropriately according to the IHCscorewhich was based on staining area and intensity.
在众多的医学观点里,如美国儿科学会、澳洲小儿外科学会、加拿大小儿医学会及小儿泌尿教科书中,都认为新生儿的龟头及包皮粘膜是一个复杂的融合体,还未发育成熟,应谨慎是否行包皮环切术。在青少年期,最好也能清楚
1.什么是膀胱灌注化疗?膀胱灌注化疗属于腔内化疗的一种。医生利用导尿管将化疗药物注入膀胱内,保留一定时间后,患者自然排尽尿液即完成。不同药物保留时间有所不同,但应该注意,保留时间需要严格按照说明书,从