免疫检查点抑制剂治疗尿路上皮癌的临床经验

  目的  探讨使用免疫检查点抑制剂（immune checkpoint inhibitors,ICIs）治疗尿路上皮癌的临床有效性与安全性。  方法  回顾性分析2016年7月至2019年4月32例于辽宁省肿瘤医院使用ICIs治疗尿路上皮癌患者的临床资料。  结果  32例患者中4例完全缓解（complete remission,CR）、7例部分缓解（partial remission,PR）、5例疾病稳定（stable disease,SD）、9例疾病进展（progressiondisease,PD）、7例尚未评估。总客观有效率（overall response rate,ORR）为44.0%（11/25）,总疾病控制率（disease control rate,DCR）为64.0%（16/25）。至少经一种含铂类化疗失败患者的ORR为33.3%（5/15）,未经铂类化疗患者ORR达60.0%（6/10）。患者最多接受23个周期的ICIs治疗、约15个月,中位治疗周期为6个周期、约3.5个月。使用ICIs治疗患者通常耐受性良好,常见的免疫相关不良事件（immune-related adverse events,irAEs）为乏力、皮疹、甲减等。32例患者中5例出现irAEs,行静脉滴注皮质类固醇治疗。  结论  ICIs用于铂类化疗失败的局部晚期或转移性尿路上皮癌疗效明确,对于不能耐受或不愿意接受化疗的患者,或不适合手术的原发性尿路上皮癌患者,一线使用ICIs也是临床中可行的治疗方案,对irAEs需早期识别和给予持续治疗。      

尿路上皮癌免疫治疗的研究进展

尿路上皮癌(UC)是泌尿系统常见的恶性肿瘤之一,其发病率及死亡率较高,几十年来,标准的治疗方案仍是基于顺铂的化学疗法,但是不良反应较大且疗效不佳.目前越来越多的免疫检查点抑制剂在治疗UC中显示出良好的疗效和安全性,在精密医学时代,UC的未来在于使用疗效更确切、不良反应更小、更有针对性的治疗.同样,开发可靠的预测生物标志...     

特瑞普利单抗联合化疗治疗尿路上皮癌多发肺转移1例

尿路上皮癌是全球十大肿瘤死亡原因之一。基于顺铂的全身化疗仍然是转移性尿路上皮癌患者的主要治疗手段,但仍有30%~50%的晚期尿路上皮癌患者对顺铂化疗无效。由于化疗的不良反应较严重,迫切需要一种新的尿路上皮癌的治疗方法。免疫检查点抑制剂(check-point inhibitor,CPI)的研发为局部进展性、不可切除性和转移性尿路上皮癌患者的治疗提供了一种新可能,但不同的免疫检查点抑制剂如何选择使用,及其预测疗效标志物仍未确定。本文报道了1例化疗联合特瑞普利单抗治疗尿路上皮癌多发肺转移的患者,为临床医生用药选择及生物标志物检测提供一定参考,现报道如下。     

肌层浸润性膀胱尿路上皮癌MDM2扩增与PD-1/PD-L1抑制剂耐药机制TCGA数据库资料分析

目的免疫检测点抑制剂能延长晚期膀胱尿路上皮癌患者的生存,但仍面临耐药问题,其机制是目前的研究热点。本研究通过分析癌症基因组图谱(The Cancer Genome Atlas,TCGA)数据库中肌层浸润性膀胱尿路上皮癌的鼠双微基因2(murine double minute 2,MDM2)扩增情况及相关基因表达,寻找免疫检查点抑制剂耐药的潜在机制。方法于2019-04-01从TCGA数据库下载自建库至2014-11-15肌层浸润性膀胱尿路上皮癌数据包"bladder cancer(TCGA,cell2017)",含临床信息、基因拷贝数变异与核糖核酸测序数据,共412例患者,其中408例患者有基因拷贝数信息。对比MDM2扩增(36例)和未扩增(372例)的2组患者间临床特征和预后差异;利用cBioportal和DAVID6.8在线分析mRNA表达与MDM2扩增相关基因,并进行功能富集分析;进一步采用cBioportal和GeneSpringGX软件筛选出MDM2扩增和未扩增组间表达有差异的基因。结果肌层浸润性膀胱尿路上皮癌中MDM2扩增发生率为8.8%(36/408)。MDM2基因扩增组和未扩增组,总人群的中位生存期为33.1和35.0个月(χ^2=0.759,P=0.384),根治术后患者的中位无疾病生存期为18.0和35.7个月(χ^2=2.921,P=0.087),差异均无统计学意义。对mRNA水平与MDM2扩增相关的357个基因进行KEGG功能富集分析显示,36个基因富集于代谢通路(校正P=0.090),14个基因富集于内吞作用通路(校正P=0.280),但差异无统计学意义。MDM2扩增时自身mRNA水平增高,并与FRS2、RAB3IP、YEATS4、RAP1B和CPSF6mRNA水平中度正相关;其中FRS2、RAB3IP、RAP1B、CPSF6与MDM2常同时扩增。MDM2扩增与常见免疫抑制因子PD-1(PDCD1)、PD-L1(PDCD1LG2)、CTLA4、LAG3和IDO1的mRNA水平低度负相关。结论MDM2扩增与非扩增肌层浸润性膀胱尿路上皮癌患者的多个基因mRNA表达水平存在差异,可能为研究免疫检测点抑制剂耐药机制提供线索。     

尿路上皮癌的免疫靶向治疗进展

尿路上皮癌的发病率逐年增加,而复发转移性尿路上皮癌(mUC)的治疗一直以化疗为主,低毒、高效的治疗药物一直是专家们努力寻找的方向.近几年,针对肿瘤免疫检查点及其抑制剂的研究层出不穷,已寻找到一部分免疫检查点,研制出了相应的抑制剂,并发现了一些可能的疗效预测因子,由此开启了肿瘤治疗的新里程.对于mUC,免疫靶向治疗的研究非常多且进展快.因此,本文对肿瘤免疫检查点、疗效预测因子和免疫靶向药物在mUC的主要研究结果作一综述.     

晚期尿路上皮癌的治疗进展

转移性尿路上皮癌(metastatic urothelial carcinoma,mUC)预后差,中位总生存时间约为14个月。近年来免疫治疗快速发展,治疗有效的患者可长久获益,极大地改善m UC患者的预后。此外,Ⅰ/Ⅱ期试验公布的数据更是突出显示成纤维细胞生长因子受体(fibroblast growth factor receptor,FGFR)抑制剂和抗体偶联药物(antibody-drug conjugate,ADC)令人印象深刻的治疗效果。本文将对目前mUC的治疗进展作一全面总结,并对近期临床试验进展作简要介绍,以助于更好地了解尿路上皮癌。     

浸润性尿路膀胱上皮癌中人类表皮生长因子受体-2表达与扩增的研究*

  目的   探讨不同分期（T2~T4）的尿路膀胱上皮癌（urothelial bladder carcinoma,UBC）中人类表皮生长因子受体-2（HER2）蛋白表达和基因扩增状态。   方法   将49例不同分期的膀胱癌患者的肿瘤组织进行HER2免疫组织化学染色,以及HER2基因的双色荧光原位杂交（FISH）检测。   结果   膀胱癌患者男性居多。而且分期越高,HER2染色阳性率越高。但所有患者均未出现基因扩增,有12例患者出现17号染色体多倍体。分期越高,多倍体发生越多。   结论   膀胱癌患者HER2蛋白增高不是由于基因扩增所致,其它的转录和后转录机制参与并调节了蛋白的表达。       

膀胱微乳头型尿路上皮癌1例报告

膀胱浸润性尿路上皮癌微乳头型(infiltrating urothelialcarcinoma,micropapilly variant)是1种新近提出的尿路上皮癌的独特亚型,它不仅具有独特的组织学结构,在临床上也具有自己的特点,有很高的转移率和复发率。对临床病理医师而言,加强对此亚型肿瘤的正确认识,并与其它类型膀     

吉西他滨联合奥沙利铂治疗浸润性和转移性尿路上皮癌的临床研究

目的：评价吉西他滨联合奥沙利铂治疗浸润性和转移性尿路上皮癌的疗效以及毒副作用。方法：入选病例20例经病理证实尿路上皮癌, 其中膀胱癌14例,输尿管癌3例,肾盂癌3例, 均为浸润性或转移性尿路上皮癌,化疗前Karnofsky评分≥60分,化疗方案： 吉西他滨1 250mg/m2,静脉滴注d1,8,奥沙利铂50mg/m2静脉滴注d2,3,4周为1个周期, 连续治疗2个周期以上进行评估。该方案分别运用于姑息性化疗、新辅助化疗、 辅助化疗。结果： 按WHO疗效评定标准,完全缓解 （CR） 5例 （25%）, 部分缓解（PR） 6例 （30%）, 稳定 （SD） 5例 （25%）,进展 （PD）4例 （20%）, 近期有效率55%。主要不良反应为血小板下降, 白细胞下降, 恶心呕吐和便秘, 大多为轻中度, 且化疗停止后很快缓解, 未发生治疗相关死亡。结论： 吉西他滨联合奥沙利铂治疗局部晚期和转移性尿路上皮癌的疗效满意, 毒副作用较轻。     

A role for neoadjuvant gemcitabine plus cisplatin in muscle-invasive urothelial carcinoma of the bladder: a retrospective experience

BACKGROUND: Neoadjuvant cisplatin-based chemotherapy improves survival in muscle-invasive urothelial cancer, with MVAC (methotrexate, vinblastine, doxorubicin and cisplatin) considered the standard regimen. Gemcitabine plus cisplatin (GC) has similar efficacy and less toxicity than MVAC in metastatic disease, but is untested as neoadjuvant treatment. METHODS: The authors retrospectively evaluated patients with muscle-invasive urothelial carcinoma who received neoadjuvant GC before radical cystectomy between November 2000 and December 2006 at Memorial Sloan-Kettering Cancer Center. Post-therapy pathological downstaging to either residual disease at cystectomy (pT0) or no residual muscle-invasion (相似文献   

The clinicopathological characteristics of muscle-invasive bladder recurrence in upper tract urothelial carcinoma

This study aimed to clarify the clinical characteristics and oncological outcomes of patients with upper tract urothelial carcinoma (UTUC) who developed muscle-invasive bladder cancer (MIBC) after radical nephroureterectomy (RNU). We identified 966 pTa-4N0-2M0 patients with UTUC who underwent RNU and clarified the risk factors for MIBC progression after initial intravesical recurrence (IVR). We also identified 318 patients with primary pT2-4N0-2M0 MIBC to compare the oncological outcomes with those of patients with UTUC who developed or progressed to MIBC. Furthermore, immunohistochemical examination of p53 and FGFR3 expression in tumor specimens was performed to compare UTUC of MIBC origin with primary MIBC. In total, 392 (40.6%) patients developed IVR after RNU and 46 (4.8%) developed MIBC at initial IVR or thereafter. As a result, pT1 stage on the initial IVR specimen, concomitant carcinoma in situ on the initial IVR specimen, and no intravesical adjuvant therapy after IVR were independent factors for MIBC progression. After propensity score matching adjustment, primary UTUC was a favorable indicator for cancer-specific death compared with primary MIBC. Subgroup molecular analysis revealed high FGFR3 expression in non-MIBC and MIBC specimens from primary UTUC, whereas low FGFR3 but high p53 expression was observed in specimens from primary MIBC tissue. In conclusion, our study demonstrated that patients with UTUC who develop MIBC recurrence after RNU exhibited the clinical characteristics of subsequent IVR more than those of primary UTUC. Of note, MIBC subsequent to UTUC may have favorable outcomes, probably due to the different molecular biological background compared with primary MIBC.     

Treatment of muscle-invasive and advanced bladder cancer in 2020

Bladder cancer accounts for nearly 170,000 deaths worldwide annually. For over 4 decades, the systemic management of muscle-invasive and advanced bladder cancer has primarily consisted of platinum-based chemotherapy. Over the past 10 years, innovations in sequencing technologies have led to rapid genomic characterization of bladder cancer, deepening our understanding of bladder cancer pathogenesis and exposing potential therapeutic vulnerabilities. On the basis of its high mutational burden, immune checkpoint inhibitors were investigated in advanced bladder cancer, revealing durable responses in a subset of patients. These agents are now approved for several indications and highlight the changing treatment landscape of advanced bladder cancer. In addition, commonly expressed molecular targets were leveraged to develop targeted therapies, such as fibroblast growth factor receptor inhibitors and antibody-drug conjugates. The molecular characterization of bladder cancer and the development of novel therapies also have stimulated investigations into optimizing treatment approaches for muscle-invasive bladder cancer. Herein, the authors review the history of muscle-invasive and advanced bladder cancer management, highlight the important molecular characteristics of bladder cancer, describe the major advances in treatment, and offer future directions for therapeutic development.     

Contemporary management of muscle-invasive bladder cancer

The current standard treatment for muscle-invasive nonmetastatic bladder cancer is neoadjuvant platinum-based chemotherapy followed by radical cystectomy. However, neoadjuvant chemotherapy is not widely accepted even with level 1 evidence. Adjuvant chemotherapy should be discussed if patients have not received neoadjuvant chemotherapy before surgery and have high-risk pathologic features. Although not considered standard of care, bladder-sparing therapy can be considered for highly selected patients and for those medically unfit for surgery. Even though there are no level 1 data, the treatment outcomes for highly select patients given bladder-sparing therapy appear promising, with many patients retaining a functional bladder. Personalized chemotherapy is currently being actively pursued to target the underlying molecular changes and tailor to individual needs.     

Pembrolizumab for the treatment of bladder cancer

Introduction: Until recently, patients with locally advanced or metastatic urothelial carcinoma after progression on cisplatin-containing chemotherapy had limited systemic treatment options with no significant survival benefit and poor tolerability. Advances in the field of immunotherapy with the introduction of checkpoint inhibitors have led to paradigm shifts in the treatment of various malignancies.

Areas covered: The current review will summarize the clinical evidence of checkpoint inhibitors in bladder cancer, with a focus on pembrolizumab.

Expert commentary: Category 1 evidence indicates that the checkpoint inhibitor pembrolizumab improves overall survival in patients with locally advanced or metastatic urothelial carcinoma who progressed after or during cisplatin-containing therapy as compared to current standard of care chemotherapy. Phase 1 and 2 evidence also indicates that checkpoint inhibitors are active in first line in patients who are ineligible for cisplatin-containing chemotherapy.     

Practice change in the management of metastatic urothelial carcinoma after ASCO 2020

Metastatic urothelial carcinoma (mUC) is an incurable and aggressive disease. In the past decades there have been few effective treatment options that have impacted the prognosis of mUC patients. However, in the last few years, several drugs have emerged as new treatment choices that are changing the therapeutic landscape of mUC. Immune checkpoint inhibitors (ICIs) and targeted agents are useful treatment strategies that have been incorporated into our clinical practice. Nevertheless, cisplatin-based chemotherapy is still the standard of care in the first-line of metastatic disease. The results of the JAVELIN Bladder 100 phase 3 trial were presented at ASCO 2020, this trial evaluated the role of avelumab, an ICI, as maintenance therapy in patients who had not progressed after first-line platinum-based chemotherapy. The trial met its primary endpoint demonstrating an overall survival benefit with avelumab maintenance. In addition, new drugs and combinations are being evaluated to improve the outcomes of second and subsequent lines. Fibroblast growth factor receptor (FGFR) inhibitors and immunotherapy combinations were some of the strategies presented at ASCO 2020 that have shown promising results. Finally, the development of predictive biomarkers that help us in the decision-making process will be one of the most important challenges in the next years.     

尿外泌体在膀胱尿路上皮细胞癌中的表达及临床意义

目的:探讨尿外泌体(exosome)在膀胱尿路上皮细胞癌中的表达情况及其临床意义。方法:采用超速离心法提取30例膀胱尿路上皮细胞癌患者和15例健康人群的尿外泌体。利用投射电镜观察形态,BCA法进行蛋白定量,Western blot检测尿外泌体表面分子CD9。结果:健康人群尿外泌体水平[(125.99±47.71)μg/μL]与膀胱尿路上皮细胞癌患者尿外泌体表达水平[(259.74±57.47)μg/μL]差异有统计学意义。根据肿瘤的浸润程度,非肌层浸润性膀胱癌患者尿外泌体水平与肌层浸润性膀胱癌患者尿外泌体水平差异有统计学意义。而肌层浸润性膀胱癌各期患者尿外泌体水平差异无统计学意义。结论:尿外泌体检测可能为膀胱癌的早期诊断提供一种可行的方案。     

MEK5在膀胱尿路上皮癌组织中的表达及预后相关性分析北大核心

目的:探究膀胱尿路上皮癌组织中丝裂原活化蛋白激酶5(mitogen-activated protein kinase 5,MEK5)表达水平及其与预后相关性。方法:选取2015年06月至2017年06月本院收治的膀胱尿路上皮癌患者93例作为研究对象,术中收集入组患者癌组织及癌旁组织。采用qRT-PCR法、免疫组化染色法检测膀胱尿路上皮癌组织及癌旁组织中MEK5表达;Kaplan-Meier法绘制生存曲线分析膀胱尿路上皮癌组织中MEK5表达与患者预后相关性;Cox比例风险回归模型分析影响膀胱尿路上皮癌患者不良预后发生的危险因素;受试者工作特征(ROC)曲线分析膀胱尿路上皮癌组织中MEK5 mRNA对患者预后不良预测价值。结果:膀胱尿路上皮癌组织中MEK5 mRNA表达水平及MEK5蛋白阳性率明显高于癌旁组织(P<0.05)。高级别、T_(2)-T_(4) TNM分期、浸润性及淋巴结转移膀胱尿路上皮癌患者癌组织中MEK5蛋白高表达率明显高于低级别、T_(a)-T_(1) TNM分期、非浸润性及无淋巴结转移患者(P<0.05)。MEK5蛋白高表达患者中无复发生存16例,无复发生存率为31.37%;MEK5蛋白低表达患者中无复发生存28例,无复发生存率为66.67%,两组比较差异有统计学意义(P<0.05)。浸润性、低级别、T_(2)-T_(4) TNM分期、淋巴结转移、MEK5高表达是影响膀胱尿路上皮癌患者不良预后发生的独立危险因素(P<0.05)。结论:膀胱尿路上皮癌组织中MEK5呈高表达,与患者TNM分期、病理分型、病理分级、淋巴结转移等密切相关,可能作为临床评估患者预后的参考指标。