埃兹蛋白和上皮型钙黏蛋白在肾透明细胞癌的表达及意义

目的:探讨埃兹蛋白(Ezrin)和上皮型钙黏蛋白(E-cadherin)在肾透明细胞癌及癌旁正常肾组织中的表达及与肿瘤侵袭、转移的关系.方法:采用免疫组织化学Elivision方法检测45例肾透明细胞癌组织及相应癌旁正常肾组织中Ezrin和E-cadherin的表达情况.结果:45例癌组织Ezrin异常表达率84.4%(38/45),癌旁正常肾组织Ezrin异常表达率40%(18/45),Ezrin在癌组织中的异常表达明显高于癌旁正常肾组织(χ2=18.9,P<0.005);45例癌组织E-cadherin异常表达率73.3%(33/45),癌旁正常肾组织E-cadherin异常表达率35.6%(16/45),E-cadherin在肾透明细胞癌中的异常表达明显高于癌旁正常肾组织(χ3=12.9,P<0.05);两者呈负相关;Ezrin和E-cadherin的表达与淋巴结转移、静脉瘤栓形成有关(P<0.05),与患者年龄、性别、肿瘤大小、病理分期无相关性(P>0.05).结论:Ezrin和E-cadherin与肾透明细胞癌的浸润转移有关,可能作为预测肾癌转移和判断预后的肿瘤标志物.     

Phase II trial of lenalidomide in patients with metastatic renal cell carcinoma

Summary Lenalidomide (CC-5013) is a structural derivative of thalidomide, with antiangiogenic and immunomodulatory effects. Fourteen patients with metastatic renal cell carcinoma (RCC) were enrolled on a phase 2 trial of lenalidomide administered orally at 25 mg daily for 21 days followed by a rest period of 7 days. The best response was stable disease in eight patients (57%) of the 14 evaluable patients. Toxicities included fatigue, hyperglycemia, dyspnea, and myelosuppression with decreased hemoglobin, lymphopenia, and neutropenia. Lenalidomide is tolerable, but no objective responses were observed in this clinical trial.     

乳头状肾细胞癌的影像学表现

目的探讨乳头状肾细胞癌的影像学特点,以提高其诊断符合率。方法利用16排螺旋CT和MRI,回顾性复习25例手术病理证实的乳头状肾细胞癌的CT、MRI表现,对肿块的边界、大小、均匀度及强化度等因素进行分析。结果 25例乳头状肾细胞癌平扫期密度较均匀,增强后强化程度较低。核磁肿瘤信号均匀或不均匀;呈混杂信号、中低信;呈轻中度强化;实性肿瘤为不均匀强化或均匀轻度强化。结论乳头状肾细胞癌体积小时一般密度均匀、边界光整,增强后强化程度较肾实质明显偏低,但也可出现体积较大、强化明显、囊变坏死或周边侵犯及转移等表现。CT、MRI表现为平扫肿瘤密度/信号较均匀,内有灶状出血坏死和钙化,增强扫描肿瘤呈较均匀或不均匀强化。CT和MRI对乳头状肾癌的早期诊断帮助很大,尤其是16排螺旋CT,对乳头状肾细胞癌的诊断准确性较高。     

Phase II study of vinflunine in patients with metastatic renal cell carcinoma

Summary Purpose: An open-label, multicentre, non-comparative phase II trial to determine the response rate of intravenous vinflunine as first line chemotherapy in patients with metastatic renal cell carcinoma (RCC). Patients and methods: Patients with metastatic RCC were treated with vinflunine 350 mg/m² (n = 11) or 320 mg/m² (n = 22) administered intravenously every 21 days. Results: Out of 33 patients included in this study, one partial response was observed in the group treated at 350 mg/m² and none in the group receiving 320 mg/m² resulting in a response rate in this population of 9.1% (95% CI: 0.2–41.3). Median progression free survival was 5.6 months (95% CI: 2.8–14.4) for patients treated at 350 mg/m², and 3.3 months (95% CI: 1.6–6.4) for those treated at 320 mg/m².The median survival time was 10.4 months (95% CI: 6.8–12.4) for the whole study population. The principal toxicities were grade 3/4 neutropaenia —90.9% at 350 mg/m² and 68.1% at 320 mg/m², febrile neutropaenia was recorded in 3 patients (27.3%) at 350 mg/m² and in 5 patients (22.7%) at 320 mg/m². One episode of thromboembolic event was reported in 1 patient at each dose level. Conclusion: Vinflunine given intravenously once every 3 weeks has not shown any clinically relevant activity in the management of patients with metastatic renal cell carcinoma; tolerance of the treatment was better at a dose of 320 mg/m² than at 350 mg/m². Supported by Institute de Recherche Pierre Fabre Oncologie, Boulogne-Billancourt, France.     

A phase II study of pyrazoloacridine in patients with advanced renal cell carcinoma

The aim of this study was to determine the antitumor activity of pyrazoloacridine in patients with renal cell carcinoma. Eligible patients had advanced renal cell carcinoma with bidimensionally measurable disease, a Karnofsky performance status of at least 70, life expectancy of greater than three months, no prior treatment with chemotherapy, and no evidence of brain metastases. Patients were treated intravenously with 750 mg/m² every three weeks. Twelve patients were enrolled in this study and all were evaluable for response and toxicity. Of the twelve patients, no major responses were achieved. Toxicity was mild, with three patients requiring a 20% dose reduction. At the dose and schedule used in this trial, pyrazoloacridine is inactive in renal cell carcinoma.     

A phase II study of rebeccamycin analog (NSC-655649) in metastatic renal cell cancer

Objective: Rebeccamycin analog (NSC-655649) is an antibiotic with antitumor properties demonstrated in preclinical and phase I studies. We conducted a phase II trial to evaluate the efficacy and toxicity of this agent in patients with advanced renal cell cancer (RCC). Methods: Eligible patients had histologically or cytologically confirmed diagnosis of RCC that was either locally advanced unresectable, locally recurrent, or metastatic. Patients had to have measurable disease, no prior chemotherapy, life expectancy of greater than 12 weeks, an Eastern Cooperative Oncology Group (ECOG) performance status of 0–2, adequate-organ function, and be 18 years old. Patients were treated with NSC-655649 at a dose of 165mg/m² daily i.v. over 30–60min for 5 days. Treatment was repeated every 21 days. Response was assessed every two courses. Results: Twenty-four patients were enrolled. There were sixteen males and eight females with a median age of 60.5 years (range 42–76). Nineteen were Caucasians, seventeen had prior nephrectomy, and thirteen had prior immunotherapy. The major toxicity was myelosuppression with grade 3 and 4 neutropenia in 38% of patients and anemia in 33% of patients. There were two partial responses (2/24, 8%) and 11 patients (46%) achieved stable disease (SD). The 6-month progression-free rate for patients with SD was 30%. Of the seventeen patients with progressive disease at registration, one had a PR and eight had SD. The overall median survival time for all 24 patients was 10.0 months (90% CI=5.2, 17.4 months). The 12-month survival rate was 39%, with 90% CI=(0.21, 0.58). Nine patients are still alive with survival times ranging from 3.8 to 24.2 months, at a median follow-up time of 11.9 months. Conclusion: Rebeccamycin analog (NSC-655649) is well tolerated and has modest antitumor activity in patients with advanced RCC.     

Phase II trial of topotecan in patients with advanced renal cell carcinoma

Summary Fifteen patients with advanced renal cell carcinoma were treated on a phase II trial with topotecan. None of the fourteen evaluable patients achieved a complete or partial response. Myelosuppression was the most common toxicity. Eighty percent (12 of 15) of patients experienced grade III or IV neutropenia and/or anemia. Topotecan is not efficacious in the treatment of advanced renal cell carcinoma.     

Development and validation of a prognostic immune-associated gene signature in clear cell renal cell carcinoma

BackgroundRecent studies have demonstrated that immune-associated genes (IAGs) play an important role in the occurrence and progression of clear renal clear cell carcinoma (ccRCC). Novel biomarkers and a reliable prognostic prediction model for ccRCC patients are still limited. The objective of this study was to develop a IAGs signature and validate its prognostic value in ccRCC using bioinformatic methods and publicly database.MethodsIn the present study, we identified differentially expressed IAGs in ccRCC based on The Cancer Genome Atlas (TCGA) database. A prognostic IAGs risk model was further developed and its prognostic and predictive value was evaluated by survival analysis and nomogram.ResultsA total of 681 differentially expressed IAGs were identified and seven IAGs (IFI30, WNT5A, IRF9, AGER, PLAUR, TEK, BID) were finally selected in a IAGs signature. Survival analysis revealed that high IAGs risk scores were significantly related to poor survival outcomes. The IAGs signature was demonstrated as an independent prognostic factor and closely related to the metastasis status of ccRCC. A nomogram with clinicopathologic characteristics and IAGs signature was also constructed to superiorly predict prognosis of ccRCC patients.ConclusionsWe identified seven IAGs as a potential signature for reflecting the prognosis of ccRCC based on TCGA database. Further clinical trials are needed to validate our observations and the mechanisms underlying the prognostic value of IAGs signature in ccRCC also deserve further experimental exploration.     

Pharmacotherapy for treating metastatic clear cell renal cell carcinoma

Introduction: Over the past decade metastatic renal cell carcinoma (RCC) treatment landscape has dramatically evolved from the era of cytokines-based immunotherapy (which benefited very few patients, at the expenses of high toxicities) to the present era of targeted agents and novel immunotherapeutics, greatly improving the prognosis of our patients.

Areas covered: Here we have reviewed the present status of the medical treatment of metastatic RCC. To do this, we interrogated the Medline database, as well as the proceedings of the main Oncological and Urological conferences for the relevant trials coducted so far.

Expert opinion: Despite all the advances made in these relatively few years, further improvements are needed, since none of the available agents proved able to cure even a sigle metastatic RCC patient. In particular, advances are awaited from the results of ongoing trial of combinations of different immune checkpoint inhibitors and of immune checkpoint inhibitors with anti-VEGF/VEGFRs agents. Furthermore, a better understanding of the molecular escape pathways used by the tumor to overcome VEGFR blockade or immune activation will hopefully bring soon to the clinic more active, tailored treatments, to be used in second line and beyond.     

Phase II trial of Didemnin B in patients with advanced renal cell carcinoma

Summary Twenty-three patients with advanced renal cell cancer were treated with Didemnin B. One partial response was achieved (5%) in 21 evaluable patients. An allergic reaction was noted in four patients including one patient with anaphylaxis. Didemnin B is not recommended in the treatment of renal cell carcinoma.     

MicroRNA-497-5p down-regulation increases PD-L1 expression in clear cell renal cell carcinoma

Recent advances in immunotherapy are raising hope to treat clear cell renal cell carcinoma (ccRCC) with PD-L1 inhibitors, but only a small portion of patients are PD-L1 positive. The heterogeneous expression pattern of PD-L1 in patient population suggests that PD-L1 expression is under the control of diverse regulatory mechanisms. Although recent studies have identified numerous novel PD-L1 regulators, reports on microRNAs which modulate PD-L1 expression are much scarce. In this study, we confirmed that PD-L1 expression was up-regulated in ccRCC compared to paired normal tissues. Using miRDB and miRTarBase, 11 microRNAs were predicted to target PD-L1. After measuring the microRNA panel with TaqMan assays, we found that microRNA-497-5p down-regulation was associated with PD-L1 up-regulation. In TCGA-KIRC dataset, microRNA-497-5p down-regulation was also associated with PD-L1 up-regulation as well as shorter survival. We further validated that PD-L1 was a direct target of microRNA-497-5p in two RCC cell lines. In addition, microRNA-497-5p inhibited cell proliferation, clone formation and migration, while promoted apoptosis in in-vitro assays. Our study reveals a novel regulatory mechanism of PD-L1 expression and the potential of miR-497-5p as therapeutic target and biomarker deserves further investigation.     

Phase II trial of irofulven (6-hydroxymethylacylfulvene) for patients with advanced renal cell carcinoma

The aim of this study was to determine the antitumor activityof irofulven (6-hydroxymethylacylfulvene) in patients withadvanced renal cell carcinoma (RCC). Eligible patients hadadvanced renal cell carcinoma with bidimensionally measurabledisease, a Karnofsky performance status of at least 70, lifeexpectancy of greater than three months, no prior treatmentwith chemotherapy, and no evidence of brain metastases.Irofulven was administered at a dose of 11 mg/m² by 5-minintravenous infusion, on 5 consecutive days. Cycles wererepeated every 28 days. Thirteen patients were enrolled inthis study and 12 were evaluable for response. Of the twelveevaluable patients, no major responses were achieved. Eightpatients had stable disease as best response. Toxicityincluded myelosuppression and gastrointestinal side effects.At the dose and schedule used in this trial, irofulven did notproduce clinical response in RCC.     

A phase II trial of interferon alpha-2A plus fluorouracil in advanced renal cell carcinoma

Summary In vitro studies have documented the synergistic activity of interferon (IFN) and fluorouracil (5-FU) in human cancer cell lines, and recent clinical trials have demonstrated the efficacy of this combination in metastatic colon cancer. The current study was undertaken to evaluate the combination of IFN alpha-2a plus 5-FU in previously untreated patients with metastatic renal cell carcinoma. From May 1990 through August 1990, 14 patients with metastatic renal cell carcinoma were treated with 5-FU 750 mg/m² day continuous infusion IV days 1–5, followed by weekly IV infusions of 5-FU 750 mg/m² beginning on day 12. Patients concurrently received IFN alpha-2a 9×10⁶ IU subcutaneously 3 times per week beginning on day 1. The median age of patients treated was 57 (range 38–80) with a median Karnofsky performance status of 90 (range 60–100). Sites of metastases included lung only in 6 patients, liver only in 1 patient, 1 patient had bilateral disease at presentation, and the remaining patients had multiple sites of metastases. The median duration of therapy was 2 months. The predominant toxicities seen were stomatitis, nausea, flu-like symptoms and neurotoxicity. The only grade IV toxicity observed was severe vomiting in 1 patient, though 5 patients discontinued therapy within 2 months because of poor subjective response. With a minimum follow-up of 13 months no objective responses were seen. Thirteen of the 14 patients have had progressive disease and 11 have died. The median time to progression was 2 months (range 0.5–6 months) and the median survival was 5 months (range 2–14.5+months). We conclude that at this dose and schedule, IFN alpha-2a plus 5-FU is ineffective in the treatment of advanced renal cell carcinoma.From the Hoosier Oncology Group, the Walter Cancer Institute, Indianapolis, Indiana and the Department of Medicine, Indiana University, Indianapolis, USA.     

A randomized phase II trial of interleukin-2 in combination with four different doses of bryostatin-1 in patients with renal cell carcinoma

Summary Purpose: Bryostatin-1 is a PKC modulator with direct anti-tumor activity and immunomodulatory properties. We combined different doses of Bryostatin-1 with IL-2 to determine effects on clinical response rate and T cell phenotype in patients with advanced kidney cancer. Experimental Design: IL-2 na?ve patients were given 11×10⁶ IU subcutaneously of IL-2 on days 1–4, 8–11, and 15–18 of every 28-day cycle. Twenty four patients were randomized to treatment cohorts of 5, 15 or 25 mcg/m² of Bryostatin-1 on days 1, 8 and 15, starting in the second cycle. An additional nine, non-randomized patients were given 35 mcg/m². Lymphocytes were analyzed for number, activation status, and production of IL-2, IL-4 and IFN-γ. Response evaluation was performed every 3 cycles. Results: Common grade 3 toxicities included fatigue (5), nausea/vomiting (5), myopathy (3), dyspnea (3), and syncope (3). Four patients, in the two highest dose cohorts, demonstrated evidence of tumor shrinkage, although there was only 1 objective PR. The median time to progression was 104 days (95% CI 88–120) and the median survival was 452 days (95% CI = 424–480). There was no significant boosting effect of Bryostatin-1 on lymphocytes. Conclusions: The addition of Bryostatin-1 to IL-2 was well tolerated, but the overall response rate was low (3.2%), indicating that further studies with this combination are not warranted. for the University of Chicago Phase II Consortium     

Phase II trial of liposomal encapsulated doxorubicin in patients with advanced renal cell carcinoma

Summary Fourteen patients with advanced renal cell carcinoma were treated on a phase II trial with liposomal encapsulated doxorubicin (Lipodox, LED). None of the fourteen evaluable patients achieved a complete or partial response. Myelosuppression was the most common toxicity and no cardiac toxicity was evident. Seventynine percent (11 of 14) of patients experienced grade III or IV neutropenia. In summary, LED did not show antitumor activity in the treatment of advanced renal cell carcinoma.     

Phase II trial of arsenic trioxide in patients with metastatic renal cell carcinoma

Fourteen patients with metastatic renal cell carcinoma (RCC)were treated on a Phase II trial with arsenic trioxide(As₂O₃). Eligible patients had metastatic renal cellcarcinoma with bidimensionally measurable disease, a Karnofskyperformance status of at least 70%, life expectancy ofgreater than three months, and no evidence of brainmetastases. Arsenic trioxide was given intravenously at a doseof 0.3 mg/kg/day for five consecutive days every four weeks.The most common toxicity observed was grade II elevation inliver function tests (36%), anemia (21%), renalinsufficiency (14%), rash (7%), and diarrhea (7%). Bestresponse was stable disease in 3 patients with one patientremaining on study at 8+ months At the dose and schedule usedin this trial, arsenic trioxide did not achieve a complete orpartial response in metastatic renal cell carcinoma.     

P38与JNK在肾透明细胞癌中的表达及其临床意义

目的:探讨在肾透明细胞癌中丝裂原活化蛋白激酶P38(p38MAPK,p38)和c-Jun氨基末端激酶(c-Jun N-terminal kinase,JNK)的表达及其临床意义.方法:采用免疫组织化学方法,研究癌旁正常组织(20例)、肾透明细胞癌组织(52例)中P38和JNK蛋白的表达情况.结果:P38和JNK在肾透明细胞癌中的阳性表达率分别为75.00％和63.49％,而在癌旁正常组织中阳性表达率分别为30.00％和25.00％.P38和JNK在肾透明细胞癌中的阳性表达率明显高于癌旁正常组织(P＜0.01和P＜0.05),与肿瘤的临床TNM分期、病理分化相关(P＜0.05),而与患者性别、年龄无关(P＞0.05).对肾透明细胞癌中P38和JNK进行相关性分析呈正相关(r＝0.484,P＜0.001).结论:在肾透明细胞癌中P38和JNK的表达高于癌旁组织,且与肿瘤的临床TNM分期、病理分化相关,提示P38和JNK与肾组织癌变、侵袭和转移过程有关.     

A phase II study of vinblastine in combination with acrivastine in patients with advanced renal cell carcinoma

Summary Renal cell carcinoma exhibits chemoresistance attributable in part to the P-glycoprotein drug efflux mechanism. Acrivastine is a hydrophylic antihistamine that has been shownin vitro to reverse this form of resistance. After five patients were treated on a dose-finding study, seventeen patients with metastatic or unresectable renal cell carcinoma were entered into a phase II study of vinblastine in combination with acrivastine. Patients received oral acrivastine at doses of 400 mg every 4 hours for 6 days and a 96-hour continuous infusion of vinblastine at a dose of 1.6 mg/m²/24 h. Of 15 evaluable patients, no tumor responses were seen. The regimen was well-tolerated with the majority of toxicities being gastrointestinal and hematologic. Serum levels of acrivastine, its principal metabolite (270C81) and vinblastine were measured during the study. Based onin vitro data, the plasma levels of acrivastine were within a range adequate to block P-glycoprotein activity. High doses of acrivastine were well-tolerated clinically, however, the combination of acrivastine and vinblastine was not active against renal cell carcinoma.     

GNAS1基因T393C多态性与肾透明细胞癌临床分期和病理分级的关系

目的研究GNAS1基因T393C多态性与肾透明细胞癌的临床分期和病理分级的关系。方法收集42例手术切除肾透明细胞癌的标本,应用PCR-限制性片段长度多态性法,对肾透明细胞癌患者和健康查体者进行基因多态性的比较。结果在GNAS1基因T393C多态性与肾透明细胞癌的病理分级及临床分期无明显相关性(P>0.05)。结论 GNAS1基因T393C多态性与肾透明细胞癌的临床分期及病理分级无明显相关关系。     

人肾透明细胞癌组织中增殖细胞核抗原表达与肾癌的关系

目的 通过检测人肾透明细胞癌组织中增殖细胞核抗原（PCNA）表达的变化,研究其表达与肾癌的关系.方法 标本离体后分成肾透明细胞癌组、癌旁组织组、正常肾组织组,均用10%的甲醛固定48 h,常规石蜡包埋、切片5 μm,同时应用免疫组织化学方法进行观察研究.结果 PCNA免疫组化染色：正常肾组织内的细胞核有弱阳性表达,癌旁阳性表达增加,高于正常肾组织,肾癌组织阳性表达明显增强, 明显高于癌旁组织,两两比较差异均有统计学意义（P＜0.01）.肾癌4个期之间比较差异无统计学意义（P＞0.05）.结论 PCNA在正常组、癌旁组、癌组织组的表达呈明显加强趋势,癌组织细胞增殖旺盛,是肿瘤形成的重要机制.