A Phase 2 Trial of Sunitinib in Patients with Advanced Non–clear Cell Renal Cell Carcinoma

Background

Sunitinib is a standard-of-care treatment in advanced clear cell renal cell carcinoma (ccRCC). Retrospective and expanded access data suggest sunitinib has activity in advanced non–clear cell renal cell carcinoma (nccRCC).

Objective

To prospectively determine the clinical efficacy and safety of sunitinib in patients with advanced nccRCC.

Design, setting, and participants

This is a single-arm phase 2 trial with a two-stage design. Eligibility criteria included pathologically confirmed nccRCC or ccRCC with ≥20% sarcomatoid histology, performance status 0–2, measurable disease, a maximum of two prior systemic therapies, and no prior treatment with tyrosine kinase inhibitors directed against the vascular endothelial growth factor receptors.

Intervention

Patients received sunitinib 50 mg daily on a 4-wk on, 2-wk off schedule.

Outcome measurements and statistical analysis

Primary end points were objective response rate (ORR) and progression-free survival (PFS). Secondary end points were safety and overall survival (OS).

Results and limitations

Fifty-seven patients were eligible (nccRCC histology: papillary, 27; chromophobe, 5; unclassified, 8; collecting duct or medullary carcinoma, 6; sarcomatoid, 7; and others, 4). Median PFS for 55 evaluable patients was 2.7 mo (95% confidence interval [CI], 1.4–5.4). Two patients with chromophobe and one patient with unclassified histology had a confirmed partial response (5% ORR). Median PFS for patients with papillary histology was 1.6 mo (95% CI, 1.4–5.4). Median PFS for patients with chromophobe histology was 12.7 mo (95% CI, 8.5–NA). Median OS for all patients was 16.8 mo (95% CI, 10.7–26.3). Treatment-emergent adverse events were consistent with sunitinib's mechanism of action. The nonrandomized design and small number of patients are limitations of this study.

Conclusions

The differential response of chromophobe histology to sunitinib suggests a therapeutically relevant biological heterogeneity exists within nccRCC. The low ORR and short PFS with sunitinib in the other nccRCC subtypes underscore the need to enroll patients with these diverse tumors in clinical trials.     

Histologic variants of renal cell carcinoma: does tumor type influence outcome?

Each histologic type of renal cell carcinoma (RCC) has different pathologic and clinical parameters; however, the independent role of histologic type in outcome prediction remains contested. Most studies show relevance for outcome of each histologic type when correlated with survival by univariate analysis, whereas few studies show differences in outcome once other key prognostic factors, such as stage and grade, are considered. These studies highlight the challenges to prove outcome relevance. Despite the contested independent value of type for outcome prediction, separation of RCC into types is well accepted and can be substantiated on clinical, pathologic, molecular, and general outcome differences.     

关木通对大鼠的致肿瘤作用及丹参的干预

目的：观察丹参对马兜铃酸诱导的大鼠胃及膀胱肿瘤病变的影响。方法：给大鼠灌服关木通浸膏（含马兜铃酸10mg·kg^-1·d^-1）12～24周,并给予不同剂量丹参水溶液（5、10、15g·kg^-1·d^-1）,于实验第12、16、20、24周处死大鼠,留取胃、膀胱及肾脏标本,观察其病理学改变。结果：实验第12周开始,所有马兜铃酸诱导的大鼠前胃均出现不同程度的病理改变,胃黏膜可见乳头状增生或乳头状瘤,并伴有上皮轻-重度异型增生,以模型组病变明显,并随实验进展而程度加重、范围扩大,出现原位癌病变。模型组大鼠膀胱黏膜内可见乳头状增生或乳头状瘤,至实验第24周,病变加重,可见多发性乳头状瘤伴局灶上皮异型增生,并有淋巴细胞浸润,部分大鼠膀胱组织表现为高分化原位癌。丹参干预后胃及膀胱病变有所减轻。马兜铃酸诱导的大鼠肾组织主要表现为肾小管间质病变,未出现癌变表现。结论：丹参干预后可减轻马兜铃酸诱导的大鼠胃组织及膀胱病变,具有一定的抗肿瘤作用。     

马兜铃酸-Ⅰ所致大鼠急性肾损伤的实验研究

目的 了解马兜铃酸-Ⅰ肾毒性特点及其在关木通肾毒性中的作用。方法 从关木通中提取纯品马兜铃酸－Ｉ，用马兜铃酸－１２００ｍｇ·ｋｇ~(-１)·ｄ~(－１)、１００ｍｇ·ｋｇ~(－１)·ｄ~(－１)和５０ｍｇ·ｋｇ~(－１)·ｄ~(－１)给大鼠连续灌胃３ｄ，引起大鼠急性肾功能损伤。分别于实验第４、第８ｄ留取血、尿和肾组织标本，检测相关肾功能指标，进行组织形态学观察，并与关木通所致大鼠急性肾损伤进行比较。结果 马兜铃酸－Ⅰ作用后，大鼠主要肾功能改变为氮质血症、大量蛋白尿、糖尿、低渗尿、尿ＮＡＧ酶升高。组织形态学病变主要表现为以皮髓质交界为主的急性肾小管坏死。这些病理表现与关木通所致急性肾损伤极为相似。结论 马兜铃酸－Ⅰ所致大鼠急性肾损伤在肾功能和肾组织形态学表现上与关木通所致急性肾损伤非常相似，这提示马兜铃酸－Ｉ是关木通中主要的毒性成分。     

肾结石合并肾盂癌17例报告

本文报告肾结石合并肾盂癌17例,占同期泌尿系恶性肿瘤的6.7％(17/254)。占同期尿路上皮癌的10.7％(17/59),占同期肾结石的0.73％(17/2344)。其中移行上皮癌11例,鳞状上皮癌5例,非典型性增生1例。作者认为,肾盂鳞状细胞癌和移行上皮癌与肾结石都有密切关系。结石、感染、梗阻的症状往往掩盖了肿瘤的征象,延误了治疗的时机。结石长期刺激肾盂粘膜,致使组织发生乳头样增生,鳞状化生和非典型性增生,进而导致癌变。     

膀胱混合癌的临床特征

目的:探讨膀胱混合癌的临床特征。方法:回顾性分析1990年6月~2004年8月收治的16例膀胱混合癌患者的临床资料,对该病的临床表现,诊断和治疗以及预后情况进行讨论。结果:膀胱混合癌16例,占同期230例膀胱恶性肿瘤的6.9%,其中移行、鳞状细胞混合癌7例,移行、腺细胞混合癌4例,移行、鳞状、腺细胞混合癌3例,鳞状、腺细胞混合癌2例。多数患者以膀胱刺激症为主要临床表现,治疗以膀胱全切为主,术后1、3和5年的生存率分别为81.3%、56.3%和12.5%。结论:膀胱混合癌以膀胱刺激症状为主要临床表现,恶性程度高,早期诊断困难。根治性全膀胱切除术有助于提高生存率。     

慢性马兜铃酸肾病大鼠模型的早期贫血机制探讨

目的 探讨慢性马兜铃酸肾病(CAAN)大鼠模型的早期贫血机制。方法 将78只Wistar雌性大鼠随机分为3组:(1)关木通组(n=30):予关木通水煎剂灌胃连续用药8周；(2)正常对照组(n=24):予饮用水灌胃，连续用药8周；(3)5/6肾切除组(n=24):自由饮水。在第8、12、16周分别随机处死各组大鼠总数的1/3，留取尿、血和骨髓组织标本，分别作生化、ELISA、HE染色、免疫组化、电镜、红细胞生成素(EPO)定量等检查。结果 关木通组大鼠和5/6肾切除组大鼠BUN和Scr从第8周开始升高，但关木通组大鼠肾功能损伤进展迅速。关木通组大鼠第12周开始出现贫血，第16周贫血加重，与正常对照组和5/6肾切除组相比，P < 0.01。关木通组大鼠早期血清和骨髓组织TNF-α和IL-1β表达明显增多，与正常对照组和5/6肾切除组相比，P<0.01。随着病情进展血窦内皮损伤加重，骨髓组织CD34表达、微血管密度MVD和造血组织面积逐渐下降，与正常对照组和5/6肾切除组相比差异有统计学意义，P < 0.01。各组大鼠血清EPO定量比较，差异没有统计学意义。 结论 CAAN大鼠模型血清和骨髓组织早期TNF-α和IL-1β表达明显增多，骨髓微血管损伤可能是其贫血发生早且较严重的原因。     

关木通浸膏加低盐饮食建立大鼠慢性马兜铃酸肾病模型

目的:探讨用关木通浸膏加低盐饮食建立大鼠慢性马兜铃酸肾病动物模型的方法.方法:制备关木通浸膏剂,并测定其中马兜铃酸(AA)含量.实验分为正常对照组、低剂量组(AA 5 mg·kg-1·d-1)、中剂量组(AA10 mg·kg-1·d-1)、高剂量组(AA 20 mg·kg-1·d-1).给药前一次性腹腔注射速尿4 mg/kg,然后分别灌胃不同浓度的关木通浸膏,给药组给予低盐饮食(钠含量＜0.05%);对照组灌胃同体积自来水.连续给药1周,停药1周,隔周给药.各组每周测量体重,每2周代谢笼法留取24 h尿液;每组分别于第10 d、30 d处死大鼠各2只,第56 d处死其余大鼠,腹主动脉采血,测定相关肾功能指标;取肾组织进行形态学检查.结果:AA用药组尿量均明显增多,体重明显降低,尿蛋白、尿酶排泄量、肌酐等均升高.肾脏病理出现明显的小管间质损伤和典型的早期间质纤维化表现.结论:表明成功建立了大鼠慢性AAN模型,且本方法造价低廉,造模时间短,成功率高.     

术前用药对儿童心肺的影响

本文就儿童术前用药不同的给药途径和药物对心肺的影响进行研究。6～84(32±25)个月儿童61例,ASAⅠ～Ⅱ级,不包括有心、肺疾病及应用CNS药物者。按不同用药途径随机分为口眼(哌替啶3mg·kg~(-1)+戊巴比妥钠4mg·kg~(-1))、鼻腔(氯胺酮5mg·kg~(-1)+咪唑安定0.2mg·kg~(-1))二组,另一组为直肠给药(美索比妥30mg·kg~(-1))。除外3例查体不合作和心律失常病儿。     

消癃通闭对前列腺平滑肌中NOS神经的影响

目的 探讨一氧化氮合酶(NOS)与良性前列腺增生(BPH)发病的关系以及中药消癃通闭对前列腺平滑肌中NOS神经的影响。方法 去势雄性大鼠,皮下注射丙酸睾酮5mg·kg~(-1)·d~(-1),分别给予消癃通闭、保列治灌胃,21天后断髓处死,应用NADPH组化染色结合形态学定量分析方法,检测各组前列腺中NOS神经含量。结果 NOS神经纤维主要分布在前列腺平滑肌细胞周围,泪癃通闭高剂量组在治疗3周后,前列腺组织中NOS神经的长度密度(L_v)为0.11349±0.023296,与其它三组相比均有显著性差异(p<0.001)。结论 中药消癃通闭可增加实验性BPH大鼠前列腺中NOS神经含量,为该药治疗前列腺增生,改善临床症状提供了科学依据。     

药典法定剂量关木通对大鼠肾功能及间质结构影响的研究

目的观察药典法定剂量关木通水煎剂对大鼠肾功能及肾间质结构的影响.方法用药典规定剂量的关木通水煎剂给大鼠灌胃(1g/kg,约相当于人类剂量0.1g/kg),每日1次,共两个月.期间观察各项肾功能指标、肾脏组织形态学改变及细胞外基质(纤连蛋白)分布情况.结果关木通给药组的血肌酐水平、尿酶(NAG和γ-GT)活性、尿蛋白、尿糖与正常组大鼠相比无统计学差异.关木通给药组大鼠的肾组织形态结构在光镜下未见明显异常改变,其纤连蛋白的分布与正常组完全相同.结论药典法定剂量的关木通水煎剂对大鼠肾功能及肾间质结构无明显的不利影响.     

错配修复基因hMLH1在膀胱移行细胞癌中的表达及其意义

目的 观察错配修复基因hMLH1在膀胱移行细胞癌中的表达,探讨hMLH1与膀胱移行细胞癌的关系.方法 通过免疫组织化学方法 测定hMLH1在80例膀胱移行细胞癌中及20例正常膀胱组织中的表达.结果 hMLH1在膀胱移行细胞癌中的低表达率(32.5%)明显高于在正常膀胱组织中的低表达率(0%),差异有统计学意义(P＜0.05),且hMLH1在膀胱移行细胞癌中的低表达与肿瘤的分期分级有关(P＜0.05).结论 hMLH1的低表达与膀胱移行细胞癌的发生有关,与肿瘤的高分期和高分级有关,hMLH1的低表达在浸润性及分化差的膀胱移行细胞癌多见.     

Synchronous ipsilateral conventional renal cell and transitional cell carcinoma

Simultaneous occurrence of renal cell carcinoma (RCC) and transitional cell carcinoma (TCC) in the same kidney is unusual. We report a 61-year-old man with ipsilateral synchronous renal adenocarcinoma and renal pelvic TCC. He was referred to our department for gross hematuria and right flank pain. CT and MRI studies revealed a 57 × 50 mm irregular and infiltrative upper right kidney mass with necrotic components. A right radical nephrectomy was done. Pathological diagnosis was a high grade tumor originating from just beneath the intact urothelium of renal pelvis and infiltrating through the parenchyma showing solid and occasional tubular growth patterns. A second tumor in close proximity to the first was reported as well differentiated RCC. This is a rare case of combined renal malignancies.     

Adenoendocrine Cell Carcinoma of the Gallbladder: Report of a Case

Adenoendocrine cell carcinoma of the gallbladder is an uncommon form of cancer. We treated a 36-year-old woman who came to us with a chief complaint of abdominal pain. The abnormality was diagnosed to be a tumor-like mass in the gallbladder, and adenomyomatosis of the gallbladder was strongly suspected. A laparoscopic cholecystectomy was successfully performed, and the histopathological finding was adenoendocrine cell carcinoma of the gallbladder. The tumor cells of the small round cell carcinoma partly stained positively for synaptophysin, neuron-specific enolase, and CD 56, while adenocarcinoma cells showed positive reactions to keratin, which was thus suggestive of adenoendocrine cell carcinoma. The patient is alive and doing well at 12 months after the treatment.     

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目的　总结原发性胆囊鳞癌、腺鳞癌的诊治经验。方法　回顾性分析了浙江大学医学院附属第二医院 1994～ 2 0 0 3年收治的少见胆囊癌 9例 (鳞癌 1例 ,腺鳞癌 8例 )。结果　行根治性手术 4例 ,姑息性手术 5例。9例中有 8例得到随访 ,均在术后半年内死亡 ,术后中位生存期 5 1d。结论　胆囊鳞癌腺鳞癌恶性程度较高 ,但淋巴结转移相对较晚。对于合适病例应尽可能行根治性胆囊切除 ,必要时行扩大根治性切除 ,术后放疗可能是一个较好的治疗方式。     

肾嫌色细胞癌(附15例报告)

目的　提高肾嫌色细胞癌的诊治水平和对此类型肾癌的认识。　方法　回顾性分析15例肾嫌色细胞癌的临床资料。男 10例 ,女 5例。年龄 4 7～ 74岁 ,平均 5 7岁。均行根治性肾切除术。　结果　术后病理证实为肾嫌色细胞癌。病理分期 :pT1N0 M0 6例 ,pT2 N0 M0 5例 ,pT3bN0 M0 2例 ,pT1N2 M0 1例 ,pT2 N2 M0 1例。病理分级 :G2 10例 ,G3 5例。 11例获随访 ,随访 2～ 31个月 ,平均19个月 ,1例死于心脏病 ,1例局部复发 ,9例无瘤生存。　结论　肾嫌色细胞癌是一种具有特殊形态的少见肾癌类型。肾根治性切除术是治疗肾嫌色细胞癌的首选方法。与同期、同级的其他类型肾癌相比 ,肾嫌色细胞癌预后较好。