Sunitinib in urothelial cancer: clinical, pharmacokinetic, and immunohistochemical study of predictors of response

Background

Sunitinib has activity in patients with metastatic urothelial cancer (UC), but most patients do not respond.

Objective

To identify predictors of response to sunitinib.

Design, setting, and participants

Seventy-seven patients with advanced UC received sunitinib on one of two schedules at a single institution. Blood pressure (BP), immunohistochemistry (IHC), and pharmacokinetic (PK) results were correlated with response to sunitinib.

Measurements

BP was assessed on day 1 and 28 of each cycle and on day 14 of cycle 1. IHC was performed on 55 samples from 38 cases using mammalian target of rapamycin and hypoxia-inducible factor (HIF) pathway marker antibodies. Blood samples for PK analysis were collected from 15 patients at three time points. Response was assessed using Response Evaluation Criteria in Solid Tumors criteria.

Results and limitations

Sunitinib-induced hypertension predicted improved response when hypertension was categorized as a discrete (p = 0.02) or continuous variable (p = 0.005 [systolic BP] and p = 0.007 [diastolic BP]). The odds ratio of response was 12.5 (95% confidence interval, 1.95-246.8) for grade 3/4 hypertension compared with grade 0. Response was associated with low HIF-1α expression in primary (p = 0.07) tissue. A nonstatistically significant trend was seen for an association between greater drug concentration and best response. A correlation between expression markers within the same pathways was identified, phosphorylated-4EBP1 and phosphorylated-S6 (p = 6.5 × 10⁻⁹), and vascular endothelial growth factor receptor 2 and HIF-1α (p = 0.008). Results are limited by small numbers.

Conclusions

Clinical and molecular biomarkers of response to sunitinib may have clinical relevance and require prospective validation. There is an urgent need for predictive biomarkers to guide the management of UC.     

Targeting urothelial carcinoma cells by combining cisplatin with a specific inhibitor of the autophagy-inducing class III PtdIns3K complex

Background

Cisplatin-based regimens are routinely employed for the treatment of urothelial carcinoma. However, therapeutic success is hampered by the primary presence of or the development of cisplatin resistance. This chemoresistance is executed by multiple cellular pathways. In recent years, the cellular process of autophagy has been identified as a prosurvival pathway of cancer cells. On the one hand, autophagy enables cancer cells to survive conditions of low oxygen or nutrient supply, frequently found in tumors. On the other hand, autophagy supports chemoresistance of cancer cells. Here, we aimed at investigating the involvement of autophagy for cisplatin resistance in different urothelial carcinoma cell lines.

Low expression of TMEM67 is a critical predictor of poor prognosis in human urothelial carcinoma of the bladder

Objectives

The aim of the study was to evaluate the expression of TMEM67 in urothelial carcinoma of the bladder (UCB) tissues and to determine the potential relevance between the expression of TMEM67 and prognosis of UCB.

前列腺尿路上皮癌的诊疗分析

目的:总结前列腺尿路上皮癌的诊断与治疗方法。方法:回顾性分析2011年1月至2019年11月郑州大学第一附属医院收治的25例前列腺尿路上皮癌患者的临床资料。平均年龄(63.4±11.2)(39~85)岁。就诊原因：肉眼血尿13例,排尿困难9例,膀胱刺激征3例。25例PSA均<4 ng/ml。17例MRI检查提示膀胱及前...     

Gemcitabine and cisplatin neoadjuvant chemotherapy for muscle-invasive urothelial carcinoma: Predicting response and assessing outcomes

PurposeTo evaluate gemcitabine-cisplatin (GC) neoadjuvant cisplatin-based chemotherapy (NAC) for pathologic response (pR) and cancer-specific outcomes following radical cystectomy (RC) for muscle-invasive bladder cancer and identify clinical parameters associated with pR.Materials and methodsWe studied 150 consecutive cases of muscle-invasive bladder cancer that received GC NAC followed by open RC (2000–2013). A cohort of 121 patients treated by RC alone was used for comparison. Pathologic response and cancer-specific survival (CSS) were compared. We created the Johns Hopkins Hospital Dose Index to characterize chemotherapeutic dosing regimens and accurately assess sufficient neoadjuvant dosing regarding patient tolerance.ResultsNo significant difference was noted in 5-year CSS between GC NAC (58%) and non-NAC cohorts (61%). The median follow-up was 19.6 months (GC NAC) and 106.5 months (non-NAC). Patients with residual non–muscle-invasive disease after GC NAC exhibit similar 5-year CSS relative to patients with no residual carcinoma (P = 0.99). NAC pR (≤pT1) demonstrated improved 5-year CSS rates (90.6% vs. 27.1%, P<0.01) and decreased nodal positivity rates (0% vs. 41.3%, P<0.01) when compared with nonresponders (≥pT2). Clinicopathologic outcomes were inferior in NAC pathologic nonresponders when compared with the entire RC-only–treated cohort. A lower pathologic nonresponder rate was seen in patients tolerating sufficient dosing of NAC as stratified by the Johns Hopkins Hospital Dose Index (P = 0.049), congruent with the National Comprehensive Cancer Network guidelines. A multivariate classification tree model demonstrated 60 years of age or younger and clinical stage cT2 as significant of NAC response (P< 0.05).ConclusionsPathologic nonresponders fare worse than patients proceeding directly to RC alone do. Multiple predictive models incorporating clinical, histopathologic, and molecular features are currently being developed to identify patients who are most likely to benefit from GC NAC.     

T_1期高级别尿路上皮癌术后复发的影响因素分析

目的通过对T1期高级别尿路上皮癌患者的术后随访,了解影响这类患者复发的因素。方法回顾性分析78例T1期高级别尿路上皮癌患者,对其年龄、性别、肿瘤多发或单发、肿瘤大小、有无吸烟史等因素进行了χ^2检验及多因素分析。结果78例患者术后复发率34.6%（27/78）,术后2年内复发者19例。吸烟患者46例,均为男性,45.7%（21/46）出现术后复发。χ^2检验示肿瘤大小（P=0.012）和吸烟史（P=0.014）对肿瘤复发的影响有统计学差异,多因素分析示肿瘤数目（P=0.027）、肿瘤大小（P=0.018）和吸烟史（P〈0.001）有统计学差异。结论除了肿瘤数目、肿瘤大小是影响膀胱肿瘤患者预后的重要因素外,有吸烟史的T1期高级别尿路上皮癌患者可能更容易复发。     

Plasmacytoid urothelial carcinoma of the urinary bladder report of seven new cases

INTRODUCTION: Plasmacytoid urothelial carcinoma (PUC) is a rare tumor of the urinary bladder. Its clinical and histopathological features have not been well characterized. In this study we report seven cases of PUC from our institution. MATERIALS AND METHODS: A pilot case of PUC was recently diagnosed at our institution. Cases of urothelial carcinoma (UC) were reviewed for a period of seven years to identify PUC. Representative sections from each case of PUC were submitted for immunohistochemical studies. Clinical charts were reviewed. RESULTS: There were a total of seven cases of PUC out of 260 cases of invasive urothelial carcinoma. The common type of urothelial carcinoma (CUC) was present in focal areas in five cases. Cases with extensive PUC showed coarse and indurated mucosal folds and thickened bladder walls, with no grossly identifiable tumor. Urine cytology showed a scant number of atypical single cells, frequently without tumor diathesis, leading to a shortfall in the positive cytological diagnosis. Histologically, PUC appeared as dyscohesive, plasmacytoid cells with eccentric nuclei, extending widely into the bladder walls and extensively into adjacent pelvic organs. CONCLUSION: PUC is a distinct clinical and pathological subtype of urothelial carcinoma. The clinical presentation is frequently late due to the frequent absence of hematuria and indurated mucosal surface at cystoscopy. The disease followed an ominous course with recurrence in all the patients, and with patient death.     

Applying the chicken embryo chorioallantoic membrane assay to study treatment approaches in urothelial carcinoma

Background

Rapid development of novel treatment options demands valid preclinical screening models for urothelial carcinoma (UC). The translational value of high-throughput drug testing using 2-dimensional (2D) cultures is limited while for xenograft models handling efforts and costs often become prohibitive for larger-scale drug testing. Therefore, we investigated to which extent the chicken chorioallantoic membrane (CAM) assay might provide an alternative model to study antineoplastic treatment approaches for UC.

膀胱尿路上皮癌中VEGF、DC的表达及其临床意义

目的:探讨血管内皮生长因子(VEGF)及树突状细胞(DC)在膀胱尿路上皮癌(UC)组织中的表达及其临床意义.方法:采用免疫组织化学EliVision二步法检测49例UC患者病理组织中VEGF蛋白及S100蛋白标记DC的表达情况,并以8例癌旁正常组织作为对照.结果:VEGF阳性组织DC计数为(8.35±3.25)个,阴性组织计数为(13.75±4.56)个;VEGF表达阳性的癌组织内,DC数目明显减少(P<0.05).结论:VEGF和DC在UC组织中的表达具有负相关性,VEGF可能通过对DC的抑制途径,帮助UC逃避机体的肿瘤免疫反应.     

荧光原位杂交技术在尿路上皮癌诊断中的应用

目的 探讨荧光原位杂交技术( FISH)在尿路上皮癌诊断中的应用价值.方法 采用FISH检测100例血尿患者尿脱落细胞中第3、7、17号染色体和第9号染色体p16位点异常,以组织病理学确诊尿路上皮癌为金标准,评估FISH诊断的敏感度和特异度,并与尿细胞学检查结果进行比较.结果 FISH检测和尿细胞学检查诊断尿路上皮癌的敏感度分别为82.5％和49.2％, 差异有统计学意义(P＜0.05);特异度分别为86.7％和96.6％,差异无统计学意义(P＞0.05).结论 与尿细胞学比较,FISH诊断尿路上皮癌具有较高的敏感度和相似的特异度.     

Detection of urothelial carcinoma,upper tract urothelial carcinoma,bladder carcinoma,and urothelial carcinoma with gross hematuria using selected urine-DNA methylation biomarkers: A prospective,single-center study

Introduction

Hematuria is the most common symptom of urothelial carcinomas (UC) but is often idiopathic. Cystoscopy is expensive which involves considerable patient discomfort, and conventional urine cytology for noninvasive UC detection and disease monitoring suffers from poor sensitivity. We aim to evaluate the performance of genes selected from a previous study in detecting UC, especially among patients with gross hematuria, as well as upper tract urothelial carcinoma (UTUC) and bladder carcinoma separately, in voided urine samples.

The emerging role of lymphadenectomy in upper tract urothelial carcinoma

Within the last decade, there has been an increased focus on lymphadenectomy or lymph node dissection (LND) in patients with upper tract urothelial carcinoma (UTUC). Although the data with regards to LND in UTUC are sparse, investigators are beginning to evaluate the role and define the anatomy to understand how LND may affect outcomes in patients with UTUC. This article reviews the history of LND for UTUC, outlines the relative anatomy, and evaluates the arguments and evidence for, and against, LND in patients with UTUC.     

Infrequent microsatellite instability in urothelial cell carcinoma of the bladder in young patients

OBJECTIVE: Defects in the DNA mismatch repair result in microsatellite instability (MSI), which characterise most tumours related to the hereditary non-polyposis colorectal cancer syndrome and some sporadic tumours. Several studies have reported the occurrence of MSI in urothelial cell carcinoma (UCC) of the bladder with a particularly high incidence in tumours from young patients. In this study, we have evaluated the occurrence of MSI in primary bladder UCC arising in seventeen young patients selected for being below 45 years of age at diagnosis. METHODS: Microsatellite analysis has been performed using the panel of five quasimonomorphic mononucleotide repeats (BAT-25, BAT-26, NR-21, NR-24, NR-27) recently recommended to detect MSI tumours. The original Bethesda panel including BAT-25, BAT-26 and three dinucleotide repeats (D2S123, D5S346, D17S250) has further been studied in 10 UCC samples. RESULTS: MSI has been observed in only one of the 17 bladder UCC studied. Using the original Bethesda panel, identical results were obtained, indicating that the panel of five mononucleotide markers adequately detected MSI in UCC tumours. CONCLUSIONS: Our data indicate that classical MSI affecting mono- or di-nucleotides are rarely involved in bladder UCC developing in young patients. Further studies using gold standard criteria would help clarifying the involvement of MSI in the pathogenesis of bladder UCC.     

Thromboembolic events in patients with urothelial carcinoma undergoing neoadjuvant chemotherapy and radical cystectomy

ObjectivesPatients receiving cisplatin are at high risk of thromboembolic events (TEEs). The objective of this study was to assess the effect of cisplatin-based neoadjuvant chemotherapy (NCT) on the incidence of perioperative TEEs in patients undergoing radical cystectomy.Methods and materialsWe analyzed a consecutive sample of 202 patients with urothelial carcinoma treated with radical cystectomy between 2005 and 2013. Data were collected retrospectively by reviewing medical records. Median follow-up was 16.9 months. Events of interest were defined as venous or arterial TEEs occurring from the date of diagnosis to 30 days after surgery. TEE incidence among patients treated with NCT and cystectomy was compared with that among patients treated with cystectomy alone using Fisher exact test and Cox proportional hazards regression. Proportional hazards regression was also used to assess whether TEE is a predictor of cancer progression and survival.ResultsOf 202 patients, 17 (8.4%) developed a TEE, including 8 of 42 (19.1%) treated with NCT and cystectomy and 9 of 160 (5.6%) treated with cystectomy alone (risk ratio = 3.39, 95% CI: 1.39–8.24). After adjustment for observation time, there remained an association between treatment with NCT and risk of TEE (hazard ratio = 2.40; 95% CI: 0.92–6.27; P = 0.07). Overall, 7 events occurred before cystectomy and 10 occurred postoperatively. Among patients treated with NCT, 6 of 8 events occurred before cystectomy. Detection of TEE was clinically significant as preoperative TEE was found to be an independent predictor of progression and cancer-specific mortality (adjusted hazard ratio = 3.91, 95% CI: 1.34–11.45). The main limitations of our study are its retrospective data collection and small absolute number of events.ConclusionsTEE occurs commonly in patients with urothelial carcinoma undergoing NCT. Preoperative TEE is an independent predictor of progression and cancer-specific mortality.     

GC化疗方案在不同转移性尿路上皮癌中的临床疗效观察

目的总结吉西他滨+顺铂(Gemcitabine+Cisplatin,GC)化疗方案在尿路上皮癌(urothelialcellcarcinoma,UCC)中的临床治疗效果,以期提高晚期UCC患者的生存质量。方法回顾分析52例转移性UCC患者接受GC方案化疗后的临床资料。化疗效果参照实体瘤的疗效评价标准进行评价,化疗毒副作用按照WHO化疗毒副作用分级标准进行评价。结果 GC方案对转移性UCC患者总有效率为48.1%,其中单纯淋巴结转移患者的化疗有效率为64.3%,脏器转移者仅为29.2%。化疗中44.2%的患者出现Ⅱ度以上的骨髓抑制。随访时间平均17.6个月。统计分析表明单纯淋巴结转移较脏器转移患者化疗效果更好,生存期更长。结论 GC方案对晚期UCC的化疗效果肯定,化疗毒副作用小,但是要准确评估患者的体能状态和肾功能,谨慎选择合适的化疗对象。     

Preoperative prognostic nutritional index is a significant predictor of survival in patients with localized upper tract urothelial carcinoma after radical nephroureterectomy

Background

Patient's nutritional and immunological status have a potentially significant role in survival outcome in patients with malignant tumors. We investigated the prognostic value of preoperative prognostic nutritional index (PNI) in patients with localized upper tract urothelial carcinoma (UTUC) undergoing radical nephrouretectomy (RNU).

舒尼替尼对晚期肾癌患者血脂和尿酸代谢的影响及相关因素分析

目的：探讨舒尼替尼治疗晚期肾癌患者过程中血脂硬尿酸代谢的变化,分析其与甲状腺机能减退、血雎及心脏功能异常的相关性。方法：收集2008年7月～2012年12月74例接受舒尼替尼治疗的晚期肾癌患哲的血清甘油三酯、总胆同醇、尿酸的资料,同时监测其甲状腺功能、血压及心脏功能情况。分析血脂及尿酸代谢异常的可能原因及与心血管系统不良反应的相关性。结果：74例患者治疗期间发生高甘油三酯血症30例,高胆固醇血症23例,高尿酸血症21例。甲状腺功能减退30例,高血压38例、心脏功能异常22例。统计学分析显示,舒尼替尼治疗期间出现的血脂及尿酸代谢异常与甲状腺功能减退具有显著相关性。血脂代谢及甲状腺功能减退的发生与心脏功能异常具有显著相关性,而与高血压的发生无显著相关性。尿酸升高与高血压的发生有显著相火性．而与心脏功能异常无显著相关性。通过药物治疗纠正甲状腺功能减退后,大部分患者的血清甘油三酯和总胆阎醇出现降低或恢复正常。结论：舒尼替尼治疗期间引发的甲状腺功能减退可能是血脂及尿酸代谢异常的主要原因,甲状腺功能减退、血脂及尿酸代鲥异常与心脏功能减低的发生具有密切关系,治疗中应首先纠正甲状腺功能减退,     

The role of WNT signalling in urothelial cell carcinoma

Urothelial cell carcinoma (UCC) of the bladder is one of the most common malignancies, causing considerable morbidity and mortality worldwide. It is unique among the epithelial carcinomas as two distinct pathways to tumourigenesis appear to exist: low grade, recurring papillary tumours usually contain oncogenic mutations in FGFR3 or HRAS whereas high grade, muscle invasive tumours with metastatic potential generally have defects in the pathways controlled by the tumour suppressors p53 and retinoblastoma. Over the last two decades, a number of transgenic mouse models of UCC, containing deletions or mutations of key tumour suppressor genes or oncogenes, have helped us understand the mechanisms behind tumour development. In this summary, I present my work investigating the role of the WNT signalling cascade in UCC.