Nodal蛋白在肾细胞癌组织中的表达及意义

目的研究胚胎成形素Nodal蛋白在肾细胞癌组织中的表达情况,并探讨其临床意义．方法采用免疫组织化学、Westernblot及Realtime PCR方法分别检测25例肾细胞癌组织及16例正常肾组织中NodalmRNA、蛋白的表迭,并检测微血管密度（MVD）指教,分析比较不同临床分期、组织学分级肾细胞癌组织中Nodal的表达情况及其与MVD之间的相关关系。结果肾细胞癌高表迭Nodal mRNA基因及蛋白,且随着临床分期的升高及组织学分级的恶化,NodalmRNA基因及蛋白表达水平不断上升;不同的临床分期及组织学分级中,Nodal蛋白的表达与MVD的变化趋势之间均存在明显的正相关关系。结论肾细胞癌高表达Nodal基因及蛋白,Nodal可能通过促进新生肿瘤血管生成促进肾癌的发展。     

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.     

Emerging oral VEGF inhibitors for the treatment of renal cell carcinoma

Introduction: The incidence of renal cell carcinoma (RCC) has increased in recent years and, unfortunately, many patients initially present with metastatic disease. When surgery is not an option, treatment involves administration of targeted therapies. The vascular endothelial growth factor (VEGF) pathway has been identified as an important mediator for the development of RCC. Numerous agents target VEGF-mediated signaling, yet resistance and progressive disease still persists. Novel small molecule VEGF inhibitors with high affinity for the VEGF receptor (VEGFR) have been discovered and are currently under investigation for the management of RCC.

Areas covered: The VEGFR pathway, its aberrant signaling, and the agents under development that inhibit VEGFR signaling are discussed. The mechanism(s), pharmacokinetics, pharmacodynamics, efficacy, and toxicity of these investigational agents are also reviewed.

Expert opinion: Management of metastatic RCC involves combination immunotherapy or administration of oral VEGFR inhibitors and largely depends on risk stratification. Emerging and investigational oral VEGFR inhibitors, given as monotherapy or in combination with immunotherapy, could augment current treatment approaches and may mitigate toxicities associated with VEGFR inhibition.     

Evaluation of deoxycoformycin in patients with advanced renal cell carcinoma

This study was conducted by the Eastern Cooperative Oncology Group (Paul P. Carbone, M.D., Chairman, CA 21115) and supported by Public Health Service Grants from the NCI, National Institutes of Health, and the Department of Health and Human Services.     

Safety and treatment patterns of angiogenesis inhibitors in patients with advanced renal cell carcinoma in Spain

Objective: To examine real-world safety and treatment patterns of angiogenesis inhibitors for advanced renal cell carcinoma (aRCC) using observational data from two Spanish hospitals.

Methods: A retrospective medical record review was performed for 93 patients with a histological diagnosis of aRCC who received sunitinib, sorafenib, bevacizumab or temsirolimus as first-line angiogenesis inhibitor therapy, between January 2005 and September 2010 at two Spanish hospitals. Data were collected on adverse events (AEs), dosing to calculate relative dose intensity (RDI), treatment modifications and reasons for modifications.

Results: Sixty patients received sunitinib, 23 received sorafenib, 6 received bevacizumab, 1 received temsirolimus and 3 received a bevacizumab-temsirolimus combination. 91.7 and 100.0% of patients receiving sunitinib and sorafenib, respectively, experienced ≥ 1 AE; 40.0% and 43.5% had ≥ 1 grade 3/4 AE. Mean RDI for sunitinib and sorafenib were 0.866 (standard deviation (std) = 0.903) and 0.798 (std = 2.154), respectively. Among patients receiving sunitinib, 15.0% discontinued treatment, 43.3% had an interruption and 33.3% had a reduction due to AEs. For sorafenib, these rates were 4.3, 56.5 and 34.8%, respectively.

Conclusions: High rates of AEs were observed which resulted in high rates of treatment interruptions and dose reductions. These results suggest the need for additional treatment options for aRCC with improved tolerability.     

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.     

Building on a foundation of VEGF and mTOR targeted agents in renal cell carcinoma

Since late 2005 six new drugs have been approved by the Food and Drug Administration (FDA) for the treatment of metastatic renal cell carcinoma (RCC). However, the similarity of these agents with regard to mechanism of action makes it unclear if each agent has unique clinical utility. This flurry of drug development activity stems from the understanding of the central role that loss of von Hippel Lindau (VHL) gene function plays in the pathophysiology of clear cell RCC. The first agent to establish the therapeutic value of targeting the downstream consequences of VHL loss of function was a vascular endothelial growth factor (VEGF) directed monoclonal antibody, bevacizumab. Following the initial observations with bevacizumab, three VEGF receptor (VEGFR) tyrosine kinase inhibitors, with varied spectra beyond VEGFR, have been successfully developed clinically. Unanticipated clinical activity was observed with inhibitors of mTOR, a central component of the nutrient-sensing PI3 kinase pathway, in RCC. Subsequent work identified that mTOR also regulates the expression of hypoxia inducible factor (HIF), which is regulated by VHL outside of the setting of inactivating mutations or deletions. This appears to tie all of the six approved therapies to the direct consequences of loss of VHL function in clear cell RCC. It remains poorly understood to what extent these therapies differ from one another. Although the outcome of patients with metastatic RCC has been substantially altered with administration of the currently available therapies, the proper selection of currently available therapy, rational development of agents with novel mechanism of action and development of predictive biomarkers of response remains a challenge.     

Present and future therapeutic options for locally advanced and metastatic renal cell carcinoma

Introduction: Locally advanced or metastatic renal cell carcinoma (RCC) is notoriously chemo- and radioresistant, leaving immunotherapy as the only treatment option. In recent years, targeted therapies have offered significant increases in progression-free survival (PFS). Despite this, the majority of patients soon develops resistant disease and finally succumbs. The need to implement treatment strategies that improve overall survival while having an acceptable safety profile is imperative.

Areas covered: This review provides information on the efficacy of recently studied treatment strategies for advanced RCC. These include sequential and combination therapy of established drugs as well as data on agents in early clinical development. The Medline and ASCO database were searched for clinical trials on medical therapy of advanced RCC from 2004 until May 2010. Data on targeted therapies, including tyrosine kinase inhibitors, vascular endothelial growth factor inhibitors, mammalian target of rapamycin inhibitors, and antiepidermal growth factor receptor agents are summarized.

Expert opinion: Improvements in response rates and PFS in patients with advanced RCC have been observed with new treatment strategies. The benefit in overall survival is less clear and needs further evaluation. Toxicity represents a concern especially in combination regiments.     

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.     

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.     

肾癌术后应用α-干扰素的疗效观察

目的观察肾癌术后应用α-干扰素(α-IFN)的治疗效果。方法肾癌患者102例随机分为治疗组52例和对照组50例。治疗组肾癌切除术后应用α-IFN治疗,对照组单纯行肾癌切除术治疗。比较2组治疗效果。结果 2组早期(Robson分期Ⅰ～Ⅱ期)肾癌患者5年生存率差异无统计学意义(P>0.05);治疗组晚期(Ⅲ期)肾癌患者5年生存率明显高于对照组,差异有统计学意义(P<0.05)。结论晚期(Ⅲ期)肾癌切除术后应用α-IFN治疗能延长患者生存期,提高长期生存率,值得临床推广应用。     

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.     

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.     

精液凝固蛋白在肾癌中的表达及其临床意义

目的探讨精液凝固蛋白(Sg)在肾癌患者癌旁组织及癌组织中的表达及临床意义。方法收集具有明确病理诊断的20例肾癌组织及癌旁组织,应用qRT-PCR和Western blot方法检测Sg基因和蛋白水平的表达,并进一步研究了Sg与临床分期之间的相关性。结果肾癌组织标本中Sg mRNA的相对表达量为(0.71±0.48),明显低于癌旁组织中的(1.07±0.44)(P<0.05)。在Ⅲ/Ⅳ期癌组织中Sg mRNA的表达量为(0.40±0.19),明显低于Ⅰ/Ⅱ期癌组织的(0.92±0.51)(P<0.05);Sg蛋白表达亦表现出相同趋势。结论 Sg基因在肾癌中的异常表达与肾癌的发生发展关系密切。     

Cost-effectiveness of pembrolizumab with axitinib as first-line treatment for advanced renal cell carcinoma

Abstract

Objective

Pembrolizumab/axitinib significantly prolonged overall survival (OS) and progression-free survival (PFS), and increased objective response rate versus sunitinib in the phase III trial KEYNOTE-426 among previously untreated patients with advanced renal cell carcinoma (RCC). This study assessed the cost-effectiveness of pembrolizumab/axitinib versus other first-line treatments of advanced RCC from a US public healthcare payer perspective.     

32例小肾癌诊治分析

目的：探讨小肾癌的诊断和治疗。方法：对32例直径小于3cm的小肾癌的临床资料进行回顾性分析。结果：32例中因体检或其他疾病检查时发现15例（46．8％）,腰痛6例（15．6％）,血尿2例（6．2％）,腰痛伴血尿3例（9．3％）,无症状6例（18．7％）。行根治性肾切除术12例,行保留肾单位手术20例。术后均经病理证实,术中快速冰冻切片证实2例。结论：小肾癌多为偶然发现．其早期诊断主要依靠B超、CT、肾血管造影等影像学检查：手术视患者具体情况行根治性肾切除术或保留肾单位手术：小肾癌病理分期低,肿瘤体积小,预后较好,生存率高。     

Optimizing treatment for patients with metastatic renal cell carcinoma in the central and Eastern European region

Introduction: Belarus, Bulgaria, Croatia, Czech Republic, Estonia, Hungary, Latvia, Lithuania, Poland, Republic of Moldova, Romania, Russian Federation, Serbia, Slovakia, Slovenia and the Ukraine represent a collection of Central and Eastern European (CEE) countries in which the epidemiology and treatment of cancer varies greatly between and within countries. Current challenges include non-adherence to current treatment guidelines, restrictions in access and reimbursement for new therapies, and a lack of basic oncology programs. Metastatic renal cell carcinoma (mRCC) is a malignancy with historically poor prognosis. In CEE countries, the incidence and mortality rates of mRCC are among the highest in the world. Fortunately, mRCC represents a cancer for which a number of new targeted therapies have recently demonstrated benefit, resulting in new evidence-based treatment guidelines. Incorporating these mRCC treatment recommendations into the routine care of patients with mRCC in CEE countries would represent a major step forward for cancer care in this region.

Areas covered: This review discusses the unique challenges faced by the aforementioned Eastern European countries in the treatment of metastatic renal cell cancer, in an attempt to assist health-care providers in providing the best care possible for their European patients.

Expert opinion: Despite a wealth of clinical trial data supporting the use of targeted therapies for first-line treatment of mRCC, cytokine-based immunotherapy is still used in some of these European countries. With implementation and adherence to existing guidelines, treatment can be clinically and economically optimized in patients with mRCC from this region.