Sequential Therapy in Metastatic Renal Cell Carcinoma

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Bradford R Hirsch

2016-04-01

Full Text Available The treatment of metastatic renal cell carcinoma (mRCC has changed dramatically in the past decade. As the number of available agents, and related volume of research, has grown, it is increasingly complex to know how to optimally treat patients. The authors are practicing medical oncologists at the US Oncology Network, the largest community-based network of oncology providers in the country, and represent the leadership of the Network's Genitourinary Research Committee. We outline our thought process in approaching sequential therapy of mRCC and the use of real-world data to inform our approach. We also highlight the evolving literature that will impact practicing oncologists in the near future.

Novel immunotherapy approaches for metastatic urothelial and renal cell carcinoma

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Zhiying Shao

2016-10-01

Full Text Available The treatment of metastatic renal cell carcinoma (RCC and urothelial carcinoma (UC remains a major challenge. Past research has implicated the immune system in tumor surveillance of both malignancies, leading to the application of immunotherapy agents for both cancers. Among them, the most promising agents are the checkpoint blockade drugs, such as antibodies targeting the cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4, programmed death receptor 1 (PD-1, and PD-1 ligand (PD-L1. In normal physiology, these immune checkpoints act as inhibitory signals to fine-tune the duration and strength of immune reactions, which is pivotal for maintaining self-tolerance. However, tumor cells also utilize immune checkpoint pathways to evade anti-tumor immune response, leading to disease progression and metastasis. Thus, there has been intense preclinical and clinical effort focused on the application of checkpoint inhibitors in metastatic RCC and UC. To date, nivolumab (anti-PD-1 and atezolizumab (anti-PD-L1 have been approved for the treatment of metastatic RCC and UC, respectively. Despite these successes, challenges remain in how to further improve response rates to immunotherapy and how to select patients that will benefit from this approach. In this report, we review existing data and research on immunotherapy in metastatic RCC and UC.

Long-term response to nivolumab and acute renal failure in a patient with metastatic papillary renal-cell carcinoma and a PD-L1 tumor expression increased with sunitinib therapy: A case report.

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Juan Ruiz-Bañobre

2016-11-01

Full Text Available Introduction: Papillary renal-cell carcinoma, which represents around 20% of renal cell carcinomas, is a heterogeneous disease that includes different tumor types with several clinical and molecular phenotypes. Nivolumab, a fully human IgG4 programmed cell death protein 1 immune checkpoint inhibitor antibody, has shown not only an overall survival advantage when compared to everolimus, but also a relatively good side-effect profile among patients with previously treated advanced or metastatic renal-cell carcinoma. Case report: We describe a case of a young man diagnosed with papillary renal-cell carcinoma that achieved a durable response to nivolumab despite a temporary suspension of the treatment due to a renal function side effect. To our knowledge, it is the first renal failure secondary to nivolumab in a metastatic renal-cell carcinoma patient.Concluding Remarks: Nivolumab is a promising drug in patients with metastatic papillary renal-cell carcinoma and long-term responses can be achieved. In case of acute renal failure secondary to this treatment, temporary therapy suspension and a low dose of systemic corticosteroids can recover renal function without a negative impact on treatment efficacy.

Differential Expression of Ccn4 and Other Genes Between Metastatic and Non-metastatic EL4 Mouse Lymphoma Cells.

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Chahal, Manpreet S; Ku, H Teresa; Zhang, Zhihong; Legaspi, Christian M; Luo, Angela; Hopkins, Mandi M; Meier, Kathryn E

Previous work characterized variants of the EL4 murine lymphoma cell line. Some are non-metastatic, and others metastatic, in syngenic mice. In addition, metastatic EL4 cells were stably transfected with phospholipase D2 (PLD2), which further enhanced metastasis. Microarray analyses of mRNA expression was performed for non-metastatic, metastatic, and PLD2-expressing metastatic EL4 cells. Many differences were observed between non-metastatic and metastatic cell lines. One of the most striking new findings was up-regulation of mRNA for the matricellular protein WNT1-inducible signaling pathway protein 1 (CCN4) in metastatic cells; increased protein expression was verified by immunoblotting and immunocytochemistry. Other differentially expressed genes included those for reproductive homeobox 5 (Rhox5; increased in metastatic) and cystatin 7 (Cst7; decreased in metastatic). Differences between PLD2-expressing and parental cell lines were limited but included the signaling proteins Ras guanyl releasing protein 1 (RGS18; increased with PLD2) and suppressor of cytokine signaling 2 (SOCS2; decreased with PLD2). The results provide insights into signaling pathways potentially involved in conferring metastatic ability on lymphoma cells. Copyright© 2016, International Institute of Anticancer Research (Dr. John G. Delinasios), All rights reserved.

Metastatic Renal Cell Carcinoma versus Pancreatic Neuroendocrine Tumor in von Hippel-Lindau Disease: Treatment with Interleukin-2

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Christopher Williams

2005-01-01

Full Text Available Differentiating between clear cell neuroendocrine tumor (NET of the pancreas and renal cell carcinoma (RCC metastatic to the pancreas can be challenging in patients with von Hippel-Lindau disease (VHL. The clear cell features of both NET and RCC in VHL patients may lead to misdiagnosis, inaccurate staging, and alternative treatment. We present a patient in which this occurred. As clear cell NETs closely resembling metastatic RCC are distinctive neoplasms of VHL and metastatic RCC to the pancreas in the VHL population is rare, careful pathologic examination should be performed prior to subjecting patients to definitive surgical or medical therapies.

RECORD-4 multicenter phase 2 trial of second-line everolimus in patients with metastatic renal cell carcinoma: Asian versus non-Asian population subanalysis.

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Yang, Lin; Alyasova, Anna; Ye, Dingwei; Ridolfi, Antonia; Dezzani, Luca; Motzer, Robert J

2018-02-17

RECORD-4 assessed everolimus in patients with metastatic renal cell carcinoma (mRCC) who progressed after 1 prior anti-vascular endothelial growth factor (VEGF) or cytokine and reinforced the clinical benefit of second-line everolimus. Because of the high percentage of patients from China enrolled in RECORD-4 (41%) and some reported differences in responses to certain targeted agents between Chinese and Western patients, this subanalysis evaluated outcomes in Asian versus non-Asian patients. RECORD-4 enrolled patients with clear cell mRCC into 3 cohorts based on prior first-line therapy: sunitinib, other anti-VEGF (sorafenib, bevacizumab, pazopanib, other), or cytokines. Patients received everolimus 10 mg/d until progression of disease (RECIST, v1.0) or intolerance. Primary end point was progression-free survival per investigator review. Data cutoff was Sept 1, 2014. Among Asian (n = 55) versus non-Asian (n = 79) patients, 98% versus 84% had good/intermediate MSKCC prognosis; 73% versus 65% were men, and 85% versus 73% were < 65 years of age. All (100%) Asian patients were of Chinese ethnicity. Median duration of exposure was 5.5 mo for Asian and 6.0 mo for non-Asian patients. Among Asian versus non-Asian patients, median progression-free survival (months) was 7.4 versus 7.8 overall, 7.4 versus 4.0 with prior sunitinib, and 5.7 versus 9.2 with prior other anti-VEGFs. Clinical benefit rate was similar between populations: 74.5% (95% CI 61.0-85.3) for Asian patients and 74.7% (95% CI 63.6-83.8) for non-Asian patients. Most patients achieved stable disease as best overall response (Asian, 63.6%; non-Asian, 69.6%). Overall rate of grade 3/4 adverse events appeared similar for Asian (58%) and non-Asian patients (54%). This RECORD-4 subanalysis demonstrated comparable efficacy and adverse event profiles of second-line everolimus in Asian and non-Asian patients. Efficacy and safety outcomes by prior therapy should be interpreted with caution because of small

Everolimus-induced pneumonitis associates with favourable outcome in patients with metastatic renal cell carcinoma

DEFF Research Database (Denmark)

Penttilä, P; Donskov, F; Rautiola, J

2017-01-01

BACKGROUND: Mammalian target of rapamycin inhibitors may induce pneumonitis. We analysed the association of pneumonitis with outcomes in everolimus treated metastatic renal cell carcinoma (mRCC) patients. PATIENTS AND METHODS: Eighty-five mRCC patients received everolimus at Helsinki University...

Renal Cell Carcinoma Metastatic to Thyroid Gland, Presenting Like Anaplastic Carcinoma of Thyroid

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Khalid Riaz

2013-01-01

Full Text Available Background. Renal cell carcinoma (RCC has unpredictable and diverse behavior. The classic triad of hematuria, loin pain, and abdominal mass is uncommon. At time of diagnosis, 25%–30% of patients are found to have metastases. Bones, lungs, liver, and brain are the frequent sites of metastases. RCC with metastasis to the head and neck region and thyroid gland is the rarest manifestation and anaplastic carcinoma behaving metastatic thyroid mass is an extremely rare presentation of RCC. Case Presentation. A 56-year-old Saudi man with past history of right radical nephrectomy 5 years back presented with 3 months history of rapid increasing neck mass with dysphagia, presenting like anaplastic thyroid carcinoma. Tru-cut biopsy turned out to be metastatic renal cell carcinoma. Patient was treated with radiation therapy 30 Gy in 10 fractions to mass. Patient died 4 months after the discovery of anaplastic thyroid looking metastasis. Conclusion. Rapidly progressing thyroid metastases secondary to RCC are rare and found often unresectable which are not amenable to surgery. Palliative radiotherapy can be considered for such patients.

Comparative proteomic investigation of metastatic and non-metastatic osteosarcoma cells of human and canine origin.

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Jahnabi Roy

Full Text Available Osteosarcoma is the most common bone cancer in dogs and people. In order to improve clinical outcomes, it is necessary to identify proteins that are differentially expressed by metastatic cells. Membrane bound proteins are responsible for multiple pro-metastatic functions. Therefore characterizing the differential expression of membranous proteins between metastatic and non-metastatic clonal variants will allow the discovery of druggable targets and consequently improve treatment methodology. The objective of this investigation was to systemically identify the membrane-associated proteomics of metastatic and non-metastatic variants of human and canine origin. Two clonal variants of divergent in vivo metastatic potential from human and canine origins were used. The plasma membranes were isolated and peptide fingerprinting was used to identify differentially expressed proteins. Selected proteins were further validated using western blotting, flow cytometry, confocal microscopy and immunohistochemistry. Over 500 proteins were identified for each cell line with nearly 40% of the proteins differentially regulated. Conserved between both species, metastatic variants demonstrated significant differences in expression of membrane proteins that are responsible for pro-metastatic functions. Additionally, CD147, CD44 and vimentin were validated using various biochemical techniques. Taken together, through a comparative proteomic approach we have identified several differentially expressed cell membrane proteins that will help in the development of future therapeutics.

Comparative proteomic investigation of metastatic and non-metastatic osteosarcoma cells of human and canine origin.

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Roy, Jahnabi; Wycislo, Kathryn L; Pondenis, Holly; Fan, Timothy M; Das, Aditi

2017-01-01

Osteosarcoma is the most common bone cancer in dogs and people. In order to improve clinical outcomes, it is necessary to identify proteins that are differentially expressed by metastatic cells. Membrane bound proteins are responsible for multiple pro-metastatic functions. Therefore characterizing the differential expression of membranous proteins between metastatic and non-metastatic clonal variants will allow the discovery of druggable targets and consequently improve treatment methodology. The objective of this investigation was to systemically identify the membrane-associated proteomics of metastatic and non-metastatic variants of human and canine origin. Two clonal variants of divergent in vivo metastatic potential from human and canine origins were used. The plasma membranes were isolated and peptide fingerprinting was used to identify differentially expressed proteins. Selected proteins were further validated using western blotting, flow cytometry, confocal microscopy and immunohistochemistry. Over 500 proteins were identified for each cell line with nearly 40% of the proteins differentially regulated. Conserved between both species, metastatic variants demonstrated significant differences in expression of membrane proteins that are responsible for pro-metastatic functions. Additionally, CD147, CD44 and vimentin were validated using various biochemical techniques. Taken together, through a comparative proteomic approach we have identified several differentially expressed cell membrane proteins that will help in the development of future therapeutics.

The use of prognostic factors in metastatic renal cell carcinoma.

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Li, Haoran; Samawi, Haider; Heng, Daniel Y C

2015-12-01

Over the last decade, the treatment landscape of metastatic renal cell carcinoma (mRCC) has evolved tremendously. The outcome of patients with mRCC has been improved since the advent of targeted therapy. In this review, we address the use of prognostic schema in the era of targeted treatment. This article summarizes the current available prognostic models and the evidence to support their use in clinical settings. Prognostic models can help guide clinicians in their decision making, as they have been validated in the first- and second-line targeted therapy settings as well as in non-clear cell mRCC. Prognostic factors are important in patient counseling, clinical trial stratification, and therapy planning. Very selected favorable-risk patients with minimal bulk and slow-growing disease could potentially be observed before needing treatment. Patients with poor-risk disease may be eligible for treatment with temsirolimus. Patients with a very poor prognosis may not be suitable candidates for cytoreductive nephrectomy. New biomarkers are on the horizon, though their roles need to be validated and their additive contribution to improve existing prognostic models examined. Copyright © 2015 Elsevier Inc. All rights reserved.

Treatment of Metastatic Renal Cell Carcinoma With CAIX CAR-engineered T cells: Clinical Evaluation and Management of On-target Toxicity

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Lamers, C.H.; Sleijfer, S.; Steenbergen, S. van; Elzakker, P. van; Krimpen, B. van; Groot, C. de; Vulto, A.; Bakker, M. den; Oosterwijk, E.; Debets, R.; Gratama, J.W.

2013-01-01

Autologous T cells genetically modified to express a chimeric antibody receptor (CAR) against carboxy-anhydrase-IX (CAIX) were administered to 12 patients with CAIX-expressing metastatic renal cell carcinoma (RCC). Patients were treated in three cohorts with a maximum of 10 infusions of a total of

Third-line Targeted Therapy in Metastatic Renal Cell Carcinoma: Results from the International Metastatic Renal Cell Carcinoma Database Consortium.

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Wells, J Connor; Stukalin, Igor; Norton, Craig; Srinivas, Sandy; Lee, Jae Lyun; Donskov, Frede; Bjarnason, Georg A; Yamamoto, Haru; Beuselinck, Benoit; Rini, Brian I; Knox, Jennifer J; Agarwal, Neeraj; Ernst, D Scott; Pal, Sumanta K; Wood, Lori A; Bamias, Aristotelis; Alva, Ajjai S; Kanesvaran, Ravindran; Choueiri, Toni K; Heng, Daniel Y C

2017-02-01

The use of third-line targeted therapy (TTT) in metastatic renal cell carcinoma (mRCC) is not well characterized and varies due to the lack of robust data to guide treatment decisions. This study examined the use of third-line therapy in a large international population. To evaluate the use and efficacy of targeted therapy in a third-line setting. Twenty-five international cancer centers provided consecutive data on 4824 mRCC patients who were treated with an approved targeted therapy. One thousand and twelve patients (21%) received TTT and were included in the analysis. Patients were analyzed for overall survival (OS) and progression-free survival using Kaplan-Meier curves, and were evaluated for overall response. Cox regression analyses were used to determine the statistical association between OS and the six factors included in the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) prognostic model. Subgroup analysis was performed on patients stratified by their IMDC prognostic risk status. Everolimus was the most prevalent third-line therapy (27.5%), but sunitinib, sorafenib, pazopanib, temsirolimus, and axitinib were all utilized in over ≥9% of patients. Patients receiving any TTT had an OS of 12.4 mo, a progression-free survival of 3.9 mo, and 61.1% of patients experienced an overall response of stable disease or better. Patients not receiving TTT had an OS of 2.1 mo. Patients with favorable- (7.2%) or intermediate-risk (65.3%) disease had the highest OS with TTT, 29.9 mo and 15.5 mo, respectively, while poor-risk (27.5%) patients survived 5.5 mo. Results are limited by the retrospective nature of the study. TTT remains highly heterogeneous. The IMDC prognostic criteria can be used to stratify third-line patients. TTT use in favorable- and intermediate-risk patients was associated with the greatest OS. Patients with favorable- and intermediate-prognostic criteria disease treated with third-line targeted therapy have an associated

Reactive Hypertrophy of an Accessory Spleen Mimicking Tumour Recurrence of Metastatic Renal Cell Carcinoma

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Christin Tjaden

2011-01-01

Full Text Available De novo occurrence of an accessory spleen after splenectomy is worth noting for two reasons. First, it is known that splenectomy can cause reactive hypertrophy of initially inactive and macroscopically invisible splenic tissue. Second, it can mimic tumour recurrence in situations in which splenectomy has been performed for oncological reasons. This might cause difficulties in differential diagnosis and the clinical decision for reoperation. We report the case of a patient with suspected recurrence of renal cell carcinoma after total pancreatectomy and splenectomy for metastatic renal cell carcinoma, which finally revealed an accessory spleen as the morphological correlate of the newly diagnosed mass in the left retroperitoneum.

Synchronous Oligometastatic Non-Small Cell Lung Cancer and Isolated Renal Cell Carcinoma: A Case Report and Literature Review.

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Nguyen, Timothy K; Louie, Alexander V

2015-10-27

A 58-year-old gentleman presenting with a progressive headache, visual disturbance, decreased appetite, and weight loss was found to have a localized clear cell carcinoma of the kidney and synchronous Stage IV non-small cell lung cancer with a solitary brain metastasis. This case illustrates the challenges in distinguishing between primary and metastatic disease in a patient with both renal cell carcinoma and lung cancer. We highlight the uncertainties in the diagnosis and management of this unique clinical scenario and the potential implications on prognosis.

Cost-Effectiveness of Everolimus for Second-Line Treatment of Metastatic Renal Cell Carcinoma in Serbia

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Mihajlovic, Jovan; Pechlivanoglou, Petros; Sabo, Ana; Tomic, Zdenko; Postma, Maarten J.

2013-01-01

Background: New targeted therapeutics for metastatic renal cell carcinoma (mRCC) enable an increment in progression-free survival (PFS) ranging from 2 to 6 months. Compared with best supportive care, everolimus demonstrated an additional PFS of 3 months in patients with mRCC whose disease had

Efficacy of Second-line Targeted Therapy for Renal Cell Carcinoma According to Change from Baseline in International Metastatic Renal Cell Carcinoma Database Consortium Prognostic Category

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Davis, Ian D; Xie, Wanling; Pezaro, Carmel

2017-01-01

BACKGROUND: We hypothesized that changes in International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) prognostic category at start of second-line therapy (2L) for metastatic renal cell carcinoma (mRCC) might predict response. OBJECTIVE: To assess outcomes of 2L according to type...... of therapy and change in IMDC prognostic category. DESIGN, SETTING, AND PARTICIPANTS: We performed a retrospective review of the IMDC database for mRCC patients who received first-line (1L) VEGF inhibitors (VEGFi) and then 2L with VEGFi or mTOR inhibitors (mTORi). IMDC prognostic categories were defined......% confidence interval [CI] 12.0-19.0 for VEGFi; 20.2 mo, 95% CI 14.3-26.1 for mTORi; AHR 1.53, 95% CI 1.04-2.24; adjusted p=0.03). CONCLUSIONS: Changes in IMDC prognostic category predict the subsequent clinical course for patients with mRCC and provide a rational basis for selection of subsequent therapy...

Management of metastatic renal cell carcinoma in patients with poor prognosis

International Nuclear Information System (INIS)

Bullock, Andrea; McDermott, David F; Atkins, Michael B

2010-01-01

An improved understanding of renal cell carcinoma (RCC) biology has translated into major advances in the treatment of patients with metastatic RCC in recent years. Clinical and pathologic criteria can be used to identify RCC patients with poor prognoses. Such patients, however, are often excluded from the cancer clinical trials that guide treatment recommendations. This article reviews available information on the management of patients with metastatic RCC and poor risk features, focusing on the role of vascular endothelial growth factor (VEGF) pathway and mammalian target of rapamycin (mTOR) inhibitors. While patients with poor risk features have a more guarded outcome, treatment with temsirolimus has produced meaningful improvements in overall survival for this population. Definitive phase III trial data are lacking for the VEGF pathway inhibitors in patients with poor prognostic features. However, available data suggest that such patients tolerate VEGF pathway blockade reasonably well and are likely to achieve some benefit relative to treatment with interferon. Ongoing translational research efforts may help to define novel treatment approaches specific for patients with metastatic RCC and poor prognostic features

Extracranial stereotactic radiotherapy for primary and metastatic renal cell carcinoma

International Nuclear Information System (INIS)

Wersaell, Peter J.; Blomgren, Henric; Lax, Ingmar; Kaelkner, Karl-Mikael; Linder, Christina; Lundell, Goeran; Nilsson, Bo; Nilsson, Sten; Naeslund, Ingemar; Pisa, Pavel; Svedman, Christer

2005-01-01

Background and purpose: We investigated the results of using stereotactic radiotherapy (SRT) for 58 patients with renal cell carcinomas (RCC) who were evaluated restrospectively for response rates, local control rates and side effects. Patients and methods: From October 1997 to January 2003, 50 patients suffering from metastatic RCC and eight patients with inoperable primary RCC received high-dose fraction SRT while placed in a stereotactic body-frame. The most common dose/fractionation schedules used were 8 Gyx4, 10 Gyx4 and 15 Gyx3 during approximately 1 week. Results: SRT-treated tumor lesions regressed totally in 30% of the patients at 3-36 months, whereas 60% of the patients had a partial volume reduction or no change after a median follow-up of 37 months (SD 17.4) for censored and 13 months (SD 12.9) for uncensored patients. Side effects were generally mild. Of 162 treated tumors, only three recurred, yielding a local control rate of 90-98%, considering the 8% non-evaluable sites as defined here. For patients with one to three metastases, the time to new spread was 9 months. Conclusions: Our use of SRT for patients with primary and metastatic RCC yielded a high local control rate with low toxicity. Patients with one to three metastases, local recurrences after nephrectomy or inoperable primary tumors benefited the most, i.e. had fewer distant recurrences (13/23) and longer survival times compared to patients with >3 metastases (24/27 recurrences)

Cost utility analysis of everolimus in the treatment of metastatic renal cell cancer in the Netherlands

NARCIS (Netherlands)

Mihajlović, J.; Minović, I.; Bruinsma, A.; Postma, M.J.

2013-01-01

Objectives: Metastatic renal cell cancer (mRCC) is becoming an important part of Dutch health care expenditure due to expensive pharmaceutical options for disease control and lack of adequate prevention methods. New targeted therapeutics, such as sunitinib, sorafenib and everolimus, have recently

Opposite prognostic roles of HIF1β and HIF2β expressions in bone metastatic clear cell renal cell cancer

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Szendroi, Attila; Szász, A. Marcell; Kardos, Magdolna

2016-01-01

BACKGROUND: Prognostic markers of bone metastatic clear cell renal cell cancer (ccRCC) are poorly established. We tested prognostic value of HIF1β/HIF2β and their selected target genes in primary tumors and corresponding bone metastases. RESULTS: Expression of HIF2β was lower in mRCC both at m...

Overall survival after immunotherapy, tyrosine kinase inhibitors and surgery in treatment of metastatic renal cell cancer

DEFF Research Database (Denmark)

de Lichtenberg, Trine Honnens; Hermann, Gregers G.; Rorth, Mikael

2014-01-01

Abstract Objective. The aim of this study was to evaluate overall survival (OS) after treatment of metastatic renal cell carcinoma (mRCC) following the introduction of tyrosine kinase inhibitors (TKIs) and mammalian target of rapamycin (mTOR) inhibitors. Material and methods. One-hundred and forty...

Lack of retroperitoneal lymphadenopathy predicts survival of patients with metastatic renal cell carcinoma.

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Vasselli, J R; Yang, J C; Linehan, W M; White, D E; Rosenberg, S A; Walther, M M

2001-07-01

Patients with metastatic renal cell carcinoma have a reported 5-year survival of 0% to 20%. The ability to predict which patients would benefit from nephrectomy and interleukin-2 (IL-2) therapy before any treatment is initiated would be useful for maximizing the advantage of therapy and improving the quality of life. A retrospective analysis of the x-rays and charts of patients treated at the National Institutes of Health Surgery Branch between 1985 and 1996, who presented with metastatic renal cancer beyond the locoregional area and the primary tumor in place, was performed. Preoperative computerized tomography or magnetic resonance imaging, or radiological reports if no scans were available, were used to obtain an estimate of the volume of retroperitoneal lymphadenopathy. Operative notes were used to evaluate whether all lymphadenopathy was resected or disease left in situ, or if any extrarenal resection, including venacavotomy, was performed. Mean survival rate was calculated from the time of nephrectomy to the time of death or last clinical followup. If patients received IL-2 therapy, the response to treatment was recorded. Mean survival and response rate for IL-2 were compared among patients in 3 separate analyses. Patients without preoperatively detected lymphadenopathy were compared with those with at least 1 cm.3 retroperitoneal lymphadenopathy. Also, the patients who had detectable lymphadenopathy were divided into subgroups consisting of all resected, incompletely resected, unresectable and unknown if all disease was resected. Each subgroup was compared with patients without detectable preoperative lymphadenopathy. Patients with less than were compared to those with greater than 50 cm.3 retroperitoneal lymphadenopathy. Patients undergoing extrarenal resection at nephrectomy (complex surgery) due to direct invasion of the tumor into another intra-abdominal organ were compared with those undergoing radical nephrectomy alone, regardless of lymph node status

Weekly 24-hour continuous infusion interleukin-2 for metastatic melanoma and renal cell carcinoma: a phase I study.

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Perez, E A; Scudder, S A; Meyers, F A; Tanaka, M S; Paradise, C; Gandara, D R

1991-02-01

Twenty-nine patients with biopsy-confirmed metastatic melanoma (17) or metastatic renal cell carcinoma (12) were treated with escalating doses or recombinant human interleukin-2 (IL-2) administered as weekly 24-h intravenous infusions. Patients received from 3 to 12 x 10(6) C.U./m2 (18-72 x 10(6) I.U./m2) weekly over a treatment period of 1 to 16 weeks, with a median of eight weekly cycles administered. Patients in all treatment groups experienced non-life-threatening systemic side effects consisting of fever, nausea, vomiting, fluid retention, and diarrhea. Grade III hypotension was seen in four of six patients (67%) at 12 x 10(6) C.U./m2, and represented the dose-limiting toxicity. Grade IV hypotension occurred in 1 of 14 patients at 6 x 10(6) C.U./m2; no other grade IV toxicities were observed. Grade III fever occurred in 3 of 11 patients (27%) treated at 3 x 10(6) C.U./m2, 3 of 14 patients (21%) at 6 x 10(6) C.U./m2, and 3 of 6 patients (50%) at 9 x 10(6) C.U./m2. An objective response was observed in 3 of 28 evaluable patients (10%): 1 complete response and 1 partial response in renal cell cancer, and 1 partial response in a melanoma patient. We conclude that for future studies, the recommended dose of IL-2 given as a weekly 24-h infusion is 9 x 10(6) C.U./m2 and that a low rate of objective tumor response can be obtained in patients with melanoma and renal cell carcinoma using this regimen.

Axitinib with or without dose titration for first-line metastatic renal-cell carcinoma: a randomised double-blind phase 2 trial.

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Rini, Brian I; Melichar, Bohuslav; Ueda, Takeshi; Grünwald, Viktor; Fishman, Mayer N; Arranz, José A; Bair, Angel H; Pithavala, Yazdi K; Andrews, Glen I; Pavlov, Dmitri; Kim, Sinil; Jonasch, Eric

2013-11-01

Population pharmacokinetic data suggest axitinib plasma exposure correlates with efficacy in metastatic renal-cell carcinoma. Axitinib dose titration might optimise exposure and improve outcomes. We prospectively assessed the efficacy and safety of axitinib dose titration in previously untreated patients with metastatic renal-cell carcinoma. In this randomised, double-blind, multicentre, phase 2 study, patients were enrolled from 49 hospitals and outpatient clinics in the Czech Republic, Germany, Japan, Russia, Spain, and USA. Patients with treatment-naive metastatic renal-cell carcinoma received axitinib 5 mg twice daily during a 4 week lead-in period. Those patients with blood pressure 150/90 mm Hg or lower, no grade 3 or 4 treatment-related toxic effects, no dose reductions, and no more than two antihypertensive drugs for 2 consecutive weeks were stratified by Eastern Cooperative Oncology Group performance status (0 vs 1), and then randomly assigned (1:1) to either masked titration with axitinib to total twice daily doses of 7 mg, and then 10 mg, if tolerated, or placebo titration. Patients who did not meet these criteria continued without titration. The primary objective was comparison of the proportion of patients achieving an objective response between randomised groups. Safety analyses were based on all patients who received at least one dose of axitinib. Between Sept 2, 2009, and Feb 28, 2011, we enrolled 213 patients, of whom 112 were randomly assigned to either the axitinib titration group (56 patients) or the placebo titration group (56 patients). 91 were not eligible for titration, and ten withdrew during the lead-in period. 30 patients (54%, 95% CI 40-67) in the axitinib titration group had an objective response, as did 19 patients (34%, 22-48]) in the placebo titration group (one-sided p=0·019). 54 (59%, 95% CI 49-70) of non-randomised patients achieved an objective response. Common grade 3 or worse, all-causality adverse events in treated patients

Axitinib with or without dose titration for first-line metastatic renal-cell carcinoma: a randomised double-blind phase 2 trial

Science.gov (United States)

Rini, Brian I; Melichar, Bohuslav; Ueda, Takeshi; GrÜnwald, Viktor; Fishman, Mayer N; Arranz, José A; Bair, Angel H; Pithavala, Yazdi K; Andrews, Glen I; Pavlov, Dmitri; Kim, Sinil; Jonasch, Eric

2014-01-01

Summary Background Population pharmacokinetic data suggest axitinib plasma exposure correlates with efficacy in metastatic renal-cell carcinoma. Axitinib dose titration might optimise exposure and improve outcomes. We prospectively assessed the efficacy and safety of axitinib dose titration in previously untreated patients with metastatic renal-cell carcinoma. Methods In this randomised, double-blind, multicentre, phase 2 study, patients were enrolled from 49 hospitals and outpatient clinics in the Czech Republic, Germany, Japan, Russia, Spain, and USA. Patients with treatment-naive metastatic renal-cell carcinoma received axitinib 5 mg twice daily during a 4 week lead-in period. Those patients with blood pressure 150/90 mm Hg or lower, no grade 3 or 4 treatment-related toxic effects, no dose reductions, and no more than two antihypertensive drugs for 2 consecutive weeks were stratified by Eastern Cooperative Oncology Group performance status (0 vs 1), and then randomly assigned (1:1) to either masked titration with axitinib to total twice daily doses of 7 mg, and then 10 mg, if tolerated, or placebo titration. Patients who did not meet these criteria continued without titration. The primary objective was comparison of the proportion of patients achieving an objective response between randomised groups. Safety analyses were based on all patients who received at least one dose of axitinib. This ongoing trial is registered with ClinicalTrials.gov, number NCT00835978. Findings Between Sept 2, 2009, and Feb 28, 2011, we enrolled 213 patients, of whom 112 were randomly assigned to either the axitinib titration group (56 patients) or the placebo titration group (56 patients). 91 were not eligible for titration, and ten withdrew during the lead-in period. 30 patients (54%, 95% CI 40–67) in the axitinib titration group had an objective response, as did 19 patients (34%, 22–48]) in the placebo titration group (one-sided p=0·019). 54 (59%, 95% CI 49–70) of non

Sustained systemic response paralleled with ovarian metastasis progression by sunitinib in metastatic renal cell carcinoma: Is this an anti-angiogenic potentiation of cancer?

Directory of Open Access Journals (Sweden)

Uttam K Mete

2015-01-01

Full Text Available Metastatic renal cell cancer is associated with poor prognosis and survival and is resistant to conventional chemotherapy. Therapeutic targeting of molecular pathways for tumor angiogenesis and other specific activation mechanisms offers improved tumor response and prolonged survival. A 48-year-old, female patient presented with large right renal mass with features suggesting of renal cell cancer without metastasis on contrast enhanced computed tomography (CT. Right radical nephrectomy was done. After 9 months of surgery, she got metastasis in lung, liver and ovary. The patient received sunitinib via an expanded access program. After eight 6-week cycles of sunitinib, a reassessment CT scan confirmed an excellent partial response with the almost complete disappearance (90% of liver and lung metastasis but the adnexal mass had increased in size (>10 times and the possibility was thought of second malignancy. Excision of the mass performed. Histopathology of the mass depicted metastatic renal cell cancer. There is possibility of a ′site-specific anti-angiogenic potentiation mechanism′ of malignancy in relation to sunitinib based upon the preclinical studies, in reference to the index case. Regression of one site with concurrent progression is possible. The exact mechanism of site-specific response, especially organ specific progression by vascular endothelial growth factor inhibitors in metastatic renal cell cancer warrants further study.

Efficacy and Safety of Axitinib Versus Sorafenib in Metastatic Renal Cell Carcinoma: Subgroup Analysis of Japanese Patients from the Global Randomized Phase 3 AXIS Trial

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Ueda, Takeshi; Uemura, Hirotsugu; Tomita, Yoshihiko; Tsukamoto, Taiji; Kanayama, Hiroomi; Shinohara, Nobuo; Tarazi, Jamal; Chen, Connie; Kim, Sinil; Ozono, Seiichiro; Naito, Seiji; Akaza, Hideyuki

2013-01-01

Objective Axitinib is a potent and selective second-generation inhibitor of vascular endothelial growth factor receptors 1, 2 and 3. The efficacy and safety of axitinib in Japanese patients with metastatic renal cell carcinoma were evaluated. Methods A subgroup analysis was conducted in Japanese patients enrolled in the randomized Phase III trial of axitinib versus sorafenib after failure of one prior systemic therapy for metastatic renal cell carcinoma. Results Twenty-five (of 361) and 29 (o...

High-dose interleukin 2 in patients with metastatic renal cell carcinoma with sarcomatoid features.

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Achkar, Tala; Arjunan, Ananth; Wang, Hong; Saul, Melissa; Davar, Diwakar; Appleman, Leonard J; Friedland, David; Parikh, Rahul A

2017-01-01

High-dose interleukin-2 (HD IL-2) is used in the treatment of metastatic renal cell carcinoma (mRCC) and has an overall response rate (ORR) of 12-20% and a complete response rate (CR) of 8% in unselected populations with predominantly clear cell type renal cell carcinoma. Nearly 10-15% of patients with renal cell carcinoma exhibit sarcomatoid differentiation, a feature which correlates with a median overall survival (OS) of 9 months and overall poor prognosis. We report a single institution experience with 21 patients with mRCC with sarcomatoid features post-nephrectomy who were treated with HD IL-2. Twenty one patients with mRCC with sarcomatoid features post-nephrectomy who underwent therapy with HD IL-2 were identified at the University of Pittsburgh Medical Center from 2004 to 2016. Baseline patient characteristics, HD IL-2 cycles, time to progression, and subsequent therapies were evaluated. OS and progression-free survival (PFS) in the cohort were calculated using the Kaplan-Meier method. Disease characteristics were evaluated for significance using the Fischer's exact test and Wilcoxon rank sum test. Patients were predominantly Caucasian males with a median age of 54 years. A majority, 86% of these patients, had metastatic disease at time of initial presentation, primarily with lung and lymph node involvement. The ORR and CR with HD IL-2 was 10% and 5%, respectively. Initial localized disease presentation is the only variable that was significantly associated with response to HD IL-2 (p = 0.0158). Number of HD IL-2 doses did not correlate with response with a mean of 16.5 and 15.0 total doses in responders and non-responders, respectively (p = 0.53). Median PFS with HD IL-2 was 7.9 months (95% CI, 5.0-21.3). Median OS was 30.5 months (95% CI 13.3-57.66). Within the subset of patients who had progression on IL-2, median OS was 19.4 months (95% CI, 13.3-35.3). In patients who received second-line therapy, median PFS was 7.9 months (95% CI 2.4-10.2). In

MET Expression in Primary and Metastatic Clear Cell Renal Cell Carcinoma: Implications of Correlative Biomarker Assessment to MET Pathway Inhibitors

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Brian Shuch

2015-01-01

Full Text Available Aims. Inhibitors of the MET pathway hold promise in the treatment for metastatic kidney cancer. Assessment of predictive biomarkers may be necessary for appropriate patient selection. Understanding MET expression in metastases and the correlation to the primary site is important, as distant tissue is not always available. Methods and Results. MET immunofluorescence was performed using automated quantitative analysis and a tissue microarray containing matched nephrectomy and distant metastatic sites from 34 patients with clear cell renal cell carcinoma. Correlations between MET expressions in matched primary and metastatic sites and the extent of heterogeneity were calculated. The mean expression of MET was not significantly different between primary tumors when compared to metastases (P=0.1. MET expression weakly correlated between primary and matched metastatic sites (R=0.5 and a number of cases exhibited very high levels of discordance between these tumors. Heterogeneity within nephrectomy specimens compared to the paired metastatic tissues was not significantly different (P=0.39. Conclusions. We found that MET expression is not significantly different in primary tumors than metastatic sites and only weakly correlates between matched sites. Moderate concordance of MET expression and significant expression heterogeneity may be a barrier to the development of predictive biomarkers using MET targeting agents.

In vivo assessment of the antiproliferative properties of interferon-alpha during immunotherapy: Ki-67 (MIB-1) in patients with metastatic renal cell carcinoma

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Donskov, F; Marcussen, N; Hokland, M

2004-01-01

The aim of the present study was to investigate the in vivo antiproliferative effect of interferon alpha (IFN-alpha) in patients with metastatic renal cell carcinoma (mRCC). Core needle biopsies of metastatic and/or the primary kidney cancer were obtained before interleukin-2 (IL-2)- and IFN...

Semiinvasive Aspergillosis Case Coexisting to Metastatic Renal Cell Cancer

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Hatice Kilic

2013-10-01

Full Text Available Chronic necrotizing pulmonary aspergillosis (CNPA is defined as an cavity or mass lesion in the lung due to invasion of lung tissue by a fungus of the Aspergillosis species. It was described also as semiinvasive aspergillosis. Semiinvasive pulmonary aspergillosis is generally seen in patients with primer immunocompromised and it can be fatal in the event of late diagnose. We present 60 years old patient who had had renal cell cancer admitted to hospital with metastatic nodules in his chest X-ray and Thorax computed tomography. We have seen yellow colour of bronchial secretion in his bronchoscopy. Multipl mantar hyphae by A. Fumigatus was detected in his bronchial lavage cytology. Itrakonazol was administred to this patient. We review to this cases due to a semiinvasive aspergillosis was detected randomly when this case who had not both symptomatic and clinical sign by Aspergillosis is investigated.

A national, multicenter, non-interventional, observational study on treatment patterns in patients with metastatic renal cell carcinoma in Turkey – NOTES study

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Yalcin Ş

2018-03-01

Full Text Available Şuayib Yalçın,1 Ramazan Yildiz,2 Faysal Dane,3 Aziz Karaoğlu,4 Berna Öksüzoğlu,5 Özgür Özyılkan,6 Alper Sevinç,7 Feyyaz Özdemir,8 Hande Turna,9 Rüçhan Uslu,10 Esat Ulay11 1Hacettepe University, Department of Medical Oncology, Ankara, Turkey; 2Gazi University, Department of Medical Oncology, Ankara, Turkey; 3Marmara University, Department of Medical Oncology, İstanbul, Turkey; 4Dokuz Eylül University, Department of Medical Oncology, İzmir, Turkey; 5Ankara Oncology Hospital, Clinic of Medical Oncology, Ankara, Turkey; 6Başkent University, Department of Medical Oncology, Ankara, Turkey; 7Medical Park Gaziantep Hospital, Medical Oncology Unit, Gaziantep, Turkey; 8Karadeniz Technical University, Department of Medical Oncology, Trabzon, Turkey; 9İstanbul University, Department of Medical Oncology, İstanbul, Turkey; 10Ege University, Department of Medical Oncology, İzmir, Turkey; 11Novartis Oncology, İstanbul, Turkey Introduction: The introduction of targeted therapies in renal cell carcinoma has significantly improved its prognosis and treatment outcomes in recent years. Such treatment options are targeted therapies of the vascular endothelial growth factor (VEGF pathway and the mammalian target of the rapamycin pathway. With the use of tyrosine kinase inhibitors (TKIs and mammalian target of the rapamycin inhibitors, overall survival has increased up to 2 years. In Turkey, due to applicable reimbursement conditions for patients with metastatic renal cell carcinoma (mRCC, interferon use is mandated as a first-line treatment, thus providing information on the use of everolimus only after initial interferon and second-line VEGF-targeted treatments such as VEGF-TKI. Patients and methods: To provide a first real-life data set in Turkey, we conducted a prospective, non-interventional, observational study and assessed the efficacy and safety of everolimus after two lines of treatment including interferon. A total of 100 patients with

Improved overall survival after implementation of targeted therapy for patients with metastatic renal cell carcinoma: Results from the Danish Renal Cancer Group (DARENCA) study-2

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Sørensen, Anne V.; Donskov, Frede; Hermann, Gregers G.

2014-01-01

AbstractAim To evaluate the implementation of targeted therapy on overall survival (OS) in a complete national cohort of patients with metastatic renal cell carcinoma (mRCC). Methods All Danish patients with mRCC referred for first line treatment with immunotherapy, TKIs or mTOR-inhibitors between...

Tissue Biomarkers in Predicting Response to Sunitinib Treatment of Metastatic Renal Cell Carcinoma.

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Trávníček, Ivan; Branžovský, Jindřich; Kalusová, Kristýna; Hes, Ondřej; Holubec, Luboš; Pele, Kevin Bauleth; Ürge, Tomáš; Hora, Milan

2015-10-01

To identify tissue biomarkers that are predictive of the therapeutic effect of sunitinib in treatment of metastatic clear cell renal cell carcinoma (mCRCC). Our study included 39 patients with mCRCC treated with sunitinib. Patients were stratified into two groups based on their response to sunitinib treatment: non-responders (progression), and responders (stable disease, regression). The effect of treatment was measured by comparing imaging studies before the initiation treatment with those performed at between 3rd and 7th months of treatment, depending on the patient. Histological samples of tumor tissue and healthy renal parenchyma, acquired during surgery of the primary tumor, were examined with immunohistochemistry to detect tissue targets involved in the signaling pathways of tumor growth and neoangiogenesis. We selected mammalian target of rapamycine, p53, vascular endothelial growth factor, hypoxia-inducible factor 1 and 2 and carbonic anhydrase IX. We compared the average levels of biomarker expression in both, tumor tissue, as well as in healthy renal parenchyma. Results were evaluated using the Student's t-test. For responders, statistically significant differences in marker expression in tumor tissue versus healthy parenchyma were found for mTOR (4%/16.7%; p=0.01031), p53 (4%/12.7%; p=0.042019), VEGF (62.7%/45%; p=0.019836) and CAIX (45%/15.33%; p=0.001624). A further significant difference was found in the frequency of high expression (more than 60%) between tumor tissue and healthy parenchyma in VEGF (65%/35%; p=0.026487) and CAIX (42%/8%; p=0.003328). CAIX was expressed at high levels in the tumor tissue in both evaluated groups. A significantly higher expression of VEGF in CRCC in comparison to healthy parenchyma can predict a better response to sunitinib. Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

Metastatic Renal Cell Carcinoma Presenting as Gastric Ulcer: Case Report and Literature Review

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Alhareth Al Juboori

2017-01-01

Full Text Available Renal cell carcinoma (RCC accounts for approximately 3% of all adult malignancies. True gastrointestinal metastases, specifically to gastric wall, have been rarely observed. Herein we describe a case of delayed metastasis to gastric wall occurring more than a decade after previously curative nephrectomy for RCC. A 67-year-old male with history of right radical nephrectomy in 2001 for RCC was found to have an asymptomatic right lower lobe solitary lung mass upon routine follow-up in 2011, with final biopsy results showing metastatic RCC for which he was treated accordingly. In 2014, patient was evaluated for dyspepsia with microcytic anemia and underwent an esophagogastroduodenoscopy and colonoscopy. EGD revealed a solitary one-centimeter atypical ulcer in the posterior mid gastric body with biopsy results being consistent with metastatic RCC. Our literature review has yielded thirty-six reported cases of RCC in association with gastric wall metastases.

Differential expression of c-Met between primary and metastatic sites in clear-cell renal cell carcinoma and its association with PD-L1 expression.

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Lalani, Aly-Khan A; Gray, Kathryn P; Albiges, Laurence; Callea, Marcella; Pignon, Jean-Christophe; Pal, Soumitro; Gupta, Mamta; Bhatt, Rupal S; McDermott, David F; Atkins, Michael B; Woude, G F Vande; Harshman, Lauren C; Choueiri, Toni K; Signoretti, Sabina

2017-11-28

In preclinical models, c-Met promotes survival of renal cancer cells through the regulation of programmed death-ligand 1 (PD-L1). However, this relationship in human clear cell renal cell carcinoma (ccRCC) is not well characterized. We evaluated c-Met expression in ccRCC patients using paired primary and metastatic samples and assessed the association with PD-L1 expression and other clinical features. Areas with predominant and highest Fuhrman nuclear grade (FNG) were selected. c-Met expression was evaluated by IHC using an anti-Met monoclonal antibody (MET4 Ab) and calculated by a combined score (CS, 0-300): intensity of c-Met staining (0-3) x % of positive cells (0-100). PD-L1 expression in tumor cells was previously assessed by IHC and PD-L1+ was defined as PD-L1 > 0% positive cells. Our cohort consisted of 45 pairs of primary and metastatic ccRCC samples. Overall, c-Met expression was higher in metastatic sites compared to primary sites (average c-Met CS: 55 vs. 28, p = 0.0003). Higher c-Met expression was associated with higher FNG (4 vs. 3) in primary tumors (average c-Met CS: 52 vs. 20, p = 0.04). c-Met expression was numerically greater in PD-L1+ vs. PD-L1- tumors. Higher c-Met expression in metastatic sites compared to primary tumors suggests that testing for biomarkers of response to c-Met inhibitors should be conducted in metastases. While higher c-Met expression in PD-L1+ tumors requires further investigation, it supports exploring these targets in combination clinical trials.

Discontinuing VEGF-targeted Therapy for Progression Versus Toxicity Affects Outcomes of Second-line Therapies in Metastatic Renal Cell Carcinoma

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De Velasco, Guillermo; Xie, Wanling; Donskov, Frede

2017-01-01

BACKGROUND: A significant subgroup of metastatic renal cell carcinoma (mRCC) patients discontinue vascular endothelial growth factor-targeted therapies (VEGF-TT) because of toxicity. Whether clinical outcomes differ in patients who receive second-line (2L) targeted therapy on the basis of reason ...

Prognostic impact of the pretreatment aspartate transaminase/alanine transaminase ratio in patients treated with first-line systemic tyrosine kinase inhibitor therapy for metastatic renal cell carcinoma.

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Kang, Minyong; Yu, Jiwoong; Sung, Hyun Hwan; Jeon, Hwang Gyun; Jeong, Byong Chang; Park, Se Hoon; Jeon, Seong Soo; Lee, Hyun Moo; Choi, Han Yong; Seo, Seong Il

2018-05-13

To examine the prognostic role of the pretreatment aspartate transaminase/alanine transaminase or De Ritis ratio in patients with metastatic renal cell carcinoma receiving first-line systemic tyrosine kinase inhibitor therapy. We retrospectively searched the medical records of 579 patients with metastatic renal cell carcinoma who visited Samsung Medical Center, Seoul, Korea, from January 2001 through August 2016. After excluding 210 patients, we analyzed 360 patients who received first-line tyrosine kinase inhibitor therapy. Cancer-specific survival and overall survival were defined as the primary and secondary end-points, respectively. A multivariate Cox proportional hazards regression model was used to identify independent prognosticators of survival outcomes. The overall population was divided into two groups according to the pretreatment De Ritis ratio as an optimal cut-off value of 1.2, which was determined by a time-dependent receiver operating characteristic curve analysis. Patients with a higher pretreatment De Ritis ratio (≥1.2) had worse cancer-specific survival and overall survival outcomes, compared with those with a lower De Ritis ratio (<1.2). Notably, a higher De Ritis ratio (≥1.2) was found to be an independent predictor of both cancer-specific survival (hazard ratio 1.61, 95% confidence interval 1.13-2.30) and overall survival outcomes (hazard ratio 1.69, 95% confidence interval 1.19-2.39), along with male sex, multiple metastasis (≥2), non-clear cell histology, advanced pT stage (≥3), previous metastasectomy and the Memorial Sloan Kettering Cancer Center risk classification. Our findings show that the pretreatment De Ritis ratio can provide valuable information about the survival outcomes of metastatic renal cell carcinoma patients receiving first-line tyrosine kinase inhibitor therapy. © 2018 The Japanese Urological Association.

Interleukin-2 based immunotherapy in patients with metastatic renal cell carcinoma

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Donskov, Frede

2007-01-01

The present thesis consists of 8 published articles focusing on interleukin-2 based immunotherapy in metastatic renal cell carcinoma (mRCC). This disease represents a significant challenge, as the tumor is resistant to current chemotherapy, hormonal therapy and radiation therapy. However, IL-2...... based immunotherapy may induce dramatic durable tumor regression by manipulating the immune system, however, only in a minority of patients. Two critical questions have driven the present thesis. First, which properties of the immune system are responsible for the dramatic tumor regression seen in some...... patients with mRCC following IL-2 administration? And second, can histamine increase the efficacy of IL-2 based immunotherapy by ending the immune suppression induced by phagocyte-generation of reactive oxygen species? 120 Danish patients, 41 UK patients and 20 Swedish patients were treated with low...

Incorporating Neutrophil-to-lymphocyte Ratio and Platelet-to-lymphocyte Ratio in Place of Neutrophil Count and Platelet Count Improves Prognostic Accuracy of the International Metastatic Renal Cell Carcinoma Database Consortium Model

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Chrom, Pawel; Stec, Rafal; Bodnar, Lubomir; Szczylik, Cezary

2017-01-01

Purpose The study investigated whether a replacement of neutrophil count and platelet count by neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) within the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) model would improve its prognostic accuracy. Materials and Methods This retrospective analysis included consecutive patients with metastatic renal cell carcinoma treated with first-line tyrosine kinase inhibitors. The IMDC and modified-IMDC m...

Nivolumab-Induced Encephalitis in Hereditary Leiomyomatosis and Renal Cell Cancer Syndrome

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Benjamin Chaucer

2018-01-01

Full Text Available The treatment of cancer is a rapidly evolving field. As more chemotherapeutic agents become available, reporting the side effects of these agents in clinical practice becomes increasingly important. Nivolumab is one of the chemotherapeutic agents commonly used for treatment of renal cell carcinoma, metastatic melanoma, and metastatic non-small cell lung cancer. While common side effects are known and well documented, encephalitis is documented as an extremely rare side effect. We present the case of an extremely rare side effect to a common chemotherapeutic agent.

FDG and FLT-PET for Early measurement of response to 37.5 mg daily sunitinib therapy in metastatic renal cell carcinoma.

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Horn, Kevin P; Yap, Jeffrey T; Agarwal, Neeraj; Morton, Kathryn A; Kadrmas, Dan J; Beardmore, Britney; Butterfield, Regan I; Boucher, Kenneth; Hoffman, John M

2015-09-03

Metastatic renal cell carcinoma has a poor prognosis and an intrinsic resistance to standard treatment. Sunitinib is an oral receptor tyrosine kinase inhibitor that has been used as a first-line targeted therapy in metastatic renal cell carcinoma. While computed tomography (CT) is currently the gold standard for response assessment in oncological trials, numerous studies have shown that positron emission tomography (PET) imaging can provide information predictive of tumor response to treatment earlier than the typical interval for standard of care follow-up CT imaging. In this exploratory study we sought to characterize early tumor response in patients with metastatic renal cell carcinoma treated with continuous daily 37.5 mg sunitinib therapy. Twenty patients underwent dynamic acquisition positron emission tomography (PET) imaging using (18) F-fluorodeoxyglucose (FDG) and (18) F-fluorothymidine (FLT) at baseline and early in treatment (after 1, 2, 3 or 4 weeks) with 37.5 mg continuous daily dosing of sunitinib. Semi-quantitative analyses were performed to characterize the tumor metabolic (FDG) and proliferative (FLT) responses to treatment. Proliferative responses were observed in 9/19 patients and occurred in 2 patients at one week (the earliest interval evaluated) after the initiation of therapy. A metabolic response was observed in 5/19 patients, however this was not observed until after two weeks of therapy were completed. Metabolic progression was observed in 2/19 patients and proliferative progression was observed in 1/19 patients. Baseline FDG-PET tumor maximum standardized uptake values correlated inversely with overall survival (p = 0.0036). Conversely, baseline (18) F-fluorothymidine PET imaging did not have prognostic value (p = 0.56) but showed a greater early response rate at 1-2 weeks after initiating therapy. While preliminary in nature, these results show an immediate and sustained proliferative response followed by a delayed

Severe paraneoplastic hypereosinophilia in metastatic renal cell carcinoma

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Todenhöfer Tilman

2012-03-01

Full Text Available Abstract Background Renal cell carcinoma can cause various paraneoplastic syndromes including metabolic and hematologic disturbances. Paraneoplastic hypereosinophilia has been reported in a variety of hematologic and solid tumors. We present the first case in the literature of severe paraneoplastic hypereosinophilia in a patient with renal cell carcinoma. Case presentation A 46 year-old patient patient with a history of significant weight loss, reduced general state of health and coughing underwent radical nephrectomy for metastasized renal cell carcinoma. Three weeks after surgery, the patient presented with excessive peripheral hypereosinophilia leading to profound neurological symptoms due to cerebral microinfarction. Systemic treatment with prednisolone, hydroxyurea, vincristine, cytarabine, temsirolimus and sunitinib led to reduction of peripheral eosinophils but could not prevent rapid disease progression of the patient. At time of severe leukocytosis, a considerable increase of cytokines associated with hypereosinophilia was measurable. Conclusions Paraneoplastic hypereosinophilia in patients with renal cell carcinoma might indicate poor prognosis and rapid disease progression. Myelosuppressive therapy is required in symptomatic patients.

Kinase Gene Expression Profiling of Metastatic Clear Cell Renal Cell Carcinoma Tissue Identifies Potential New Therapeutic Targets.

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Pooja Ghatalia

Full Text Available Kinases are therapeutically actionable targets. Kinase inhibitors targeting vascular endothelial growth factor receptors (VEGFR and mammalian target of rapamycin (mTOR improve outcomes in metastatic clear cell renal cell carcinoma (ccRCC, but are not curative. Metastatic tumor tissue has not been comprehensively studied for kinase gene expression. Paired intra-patient kinase gene expression analysis in primary tumor (T, matched normal kidney (N and metastatic tumor tissue (M may assist in identifying drivers of metastasis and prioritizing therapeutic targets. We compared the expression of 519 kinase genes using NanoString in T, N and M in 35 patients to discover genes over-expressed in M compared to T and N tissue. RNA-seq data derived from ccRCC tumors in The Cancer Genome Atlas (TCGA were used to demonstrate differential expression of genes in primary tumor tissue from patients that had metastasis at baseline (n = 79 compared to those that did not develop metastasis for at least 2 years (n = 187. Functional analysis was conducted to identify key signaling pathways by using Ingenuity Pathway Analysis. Of 10 kinase genes overexpressed in metastases compared to primary tumor in the discovery cohort, 9 genes were also differentially expressed in TCGA primary tumors with metastasis at baseline compared to primary tumors without metastasis for at least 2 years: EPHB2, AURKA, GSG2, IKBKE, MELK, CSK, CHEK2, CDC7 and MAP3K8; p<0.001. The top pathways overexpressed in M tissue were pyridoxal 5'-phosphate salvage, salvage pathways of pyrimidine ribonucleotides, NF-kB signaling, NGF signaling and cell cycle control of chromosomal replication. The 9 kinase genes validated to be over-expressed in metastatic ccRCC may represent currently unrecognized but potentially actionable therapeutic targets that warrant functional validation.

Exosomes from metastatic cancer cells transfer amoeboid phenotype to non-metastatic cells and increase endothelial permeability: their emerging role in tumor heterogeneity.

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Schillaci, Odessa; Fontana, Simona; Monteleone, Francesca; Taverna, Simona; Di Bella, Maria Antonietta; Di Vizio, Dolores; Alessandro, Riccardo

2017-07-05

The goal of this study was to understand if exosomes derived from high-metastatic cells may influence the behavior of less aggressive cancer cells and the properties of the endothelium. We found that metastatic colon cancer cells are able to transfer their amoeboid phenotype to isogenic primary cancer cells through exosomes, and that this morphological transition is associated with the acquisition of a more aggressive behavior. Moreover, exosomes from the metastatic line (SW620Exos) exhibited higher ability to cause endothelial hyperpermeability than exosomes from the non metastatic line (SW480Exos). SWATH-based quantitative proteomic analysis highlighted that SW620Exos are significantly enriched in cytoskeletal-associated proteins including proteins activating the RhoA/ROCK pathway, known to induce amoeboid properties and destabilization of endothelial junctions. In particular, thrombin was identified as a key mediator of the effects induced by SW620Exos in target cells, in which we also found a significant increase of RhoA activity. Overall, our results demonstrate that in a heterogeneous context exosomes released by aggressive sub-clones can contribute to accelerate tumor progression by spreading malignant properties that affect both the tumor cell plasticity and the endothelial cell behavior.

Breast cancer metastatic to the kidney with renal vein involvement.

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Nasu, Hatsuko; Miura, Katsutoshi; Baba, Megumi; Nagata, Masao; Yoshida, Masayuki; Ogura, Hiroyuki; Takehara, Yasuo; Sakahara, Harumi

2015-02-01

The common sites of breast cancer metastases include bones, lung, brain, and liver. Renal metastasis from the breast is rare. We report a case of breast cancer metastatic to the kidney with extension into the renal vein. A 40-year-old woman had undergone left mastectomy for breast cancer at the age of 38. A gastric tumor, which was later proved to be metastasis from breast cancer, was detected by endoscopy. Computed tomography performed for further examination of the gastric tumor revealed a large left renal tumor with extension into the left renal vein. It mimicked a primary renal tumor. Percutaneous biopsy of the renal tumor confirmed metastasis from breast cancer. Surgical intervention of the stomach and the kidney was avoided, and she was treated with systemic chemotherapy. Breast cancer metastatic to the kidney may present a solitary renal mass with extension into the renal vein, which mimics a primary renal tumor.

Carbon anhydrase IX specific immune responses in patients with metastatic renal cell carcinoma potentially cured by interleukin-2 based immunotherapy

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Rasmussen, Susanne; Donskov, Frede; Pedersen, Johannes W

2013-01-01

Abstract The majority of clear-cell renal cell carcinomas (ccRCC) show high and homogeneous expression levels of the tumor associated antigen (TAA) carbonic anhydrase IX (CAIX), and treatment with interleukin-2 (IL-2) based immunotherapy can lead to cure in patients with metastatic renal cell...... of disease (NED) following treatment with IL-2 based immunotherapy, and thus potentially cured. Immune reactivity in these patients was compared with samples from patients with dramatic tumor response obtained immediately at the cessation of therapy, samples from patients that experienced progressive disease...... interest in future cancer vaccines, but more studies are needed to elucidate the immunological mechanisms of action in potentially cured patients treated with an immunotherapeutic agent....

Large cell non-Hodgkin's lymphoma masquerading as renal carcinoma with inferior vena cava thrombosis: a case report

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Weissman Alan

2011-06-01

Full Text Available Abstract Introduction Many cancers are associated with inferior vena cava (IVC obstruction, but very few cancers have the ability to propagate within the lumen of the renal vein or the IVC. Renal cell carcinoma is the most common of these cancers. Renal cancer with IVC extension has a high rate of recurrence and a low five year survival rate. Case presentation A 62-year-old Caucasian woman previously in good health developed the sudden onset of severe reflux symptoms and right-sided abdominal pain that radiated around the right flank. A subsequent ultrasound and CT scan revealed a right upper pole renal mass with invasion of the right adrenal gland, liver, left renal vein and IVC. This appeared to be consistent with stage III renal cancer with IVC extension. Metastatic nodules were believed to be present in the right pericardial region; the superficial anterior abdominal wall; the left perirenal, abdominal and pelvic regions; and the left adrenal gland. The pattern of these metastases, as well as the invasion of the liver by the tumor, was thought to be atypical of renal cancer. A needle biopsy of a superficial abdominal wall mass revealed a surprising finding: The malignant cells were diagnostic of large-cell, B-cell non-Hodgkin's lymphoma. The lymphoma responded dramatically to systemic chemotherapy, which avoided the need for nephrectomy. Conclusion Lymphomas only rarely progress via intraluminal vascular extension. We have been able to identify only one other case report of renal lymphoma with renal vein and IVC extension. While renal cancer would have been treated with radical nephrectomy and tumor embolectomy, large-cell B-cell lymphomas are treated primarily with chemotherapy, and nephrectomy would have been detrimental. It is important to remember that, rarely, other types of cancer arise from the kidney which are not derived from the renal tubular epithelium. These may be suspected if an atypical pattern of metastases or unusual

Tumor mutational load and immune parameters across metastatic Renal Cell Carcinoma (mRCC) risk groups

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de Velasco, Guillermo; Miao, Diana; Voss, Martin H.; Hakimi, A. Ari; Hsieh, James J.; Tannir, Nizar M.; Tamboli, Pheroze; Appleman, Leonard J.; Rathmell, W. Kimryn; Van Allen, Eliezer M.; Choueiri, Toni K.

2016-01-01

Patients with metastatic renal cell carcinoma (mRCC) have better overall survival when treated with nivolumab, a cancer immunotherapy that targets the immune checkpoint inhibitor programmed cell death 1 (PD-1), rather than everolimus (a chemical inhibitor of mTOR and immunosuppressant). Poor-risk mRCC patients treated with nivolumab seemed to experience the greatest overall survival benefit, compared to patients with favorable or intermediate-risk, in an analysis of the CheckMate-025 trial subgroup of the Memorial Sloan Kettering Cancer Center (MSKCC) prognostic risk groups. Here we explore whether tumor mutational load and RNA expression of specific immune parameters could be segregated by prognostic MSKCC risk strata and explain the survival seen in the poor-risk group. We queried whole exome transcriptome data in RCC patients (n = 54) included in The Cancer Genome Atlas that ultimately developed metastatic disease or were diagnosed with metastatic disease at presentation and did not receive immune checkpoint inhibitors. Nonsynonymous mutational load did not differ significantly by MSKCC risk group, nor was the expression of cytolytic genes –granzyme A and perforin – or selected immune checkpoint molecules different across MSKCC risk groups. In conclusion, this analysis found that mutational load and expression of markers of an active tumor microenvironment did not correlate with MSKCC risk prognostic classification in mRCC. PMID:27538576

Immunochemotherapy with interleukin-2, interferon- α and 5-fluorouracil for progressive metastatic renal cell carcinoma: a multicenter phase II study

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Herpen, C M L van; Jansen, R L H; Kruit, W H J; Hoekman, K; Groenewegen, G; Osanto, S; Mulder, P H M De

2000-01-01

In patients with metastatic renal cell carcinoma response rates of 7–26% have been achieved with immunotherapy. A high response rate of 48% in 35 patients has been reported for treatment with the combination of interferon-α (IFN-α), interleukin-2 (IL-2) and 5-fluorouracil (5-FU) (Atzpodien et al (1993 a) Eur J Cancer29A: S6–8). We conducted a multicentre phase II study to confirm these results. Metastatic renal cell carcinoma patients were treated as outpatients with an 8-week treatment cycle. Recombinant human IL-2 20 MU m−2was administered subcutaneously (s.c.) three times a week (t.i.w) in weeks 1 and 4 and 5 MU m−2t.i.w. in weeks 2 and 3. Recombinant human IFN-α 2a 6 MU m−2was administered s.c. once in weeks 1 and 4 and t.i.w. in weeks 2 and 3, and 9 MU m−2t.i.w. in weeks 5–8. 5-FU (750 mg m−2) was given as a bolus injection intravenous once a week in weeks 5–8. The treatment cycle was repeated once in case of response or minor response. Fifty-two patients entered the study. All had undergone a nephrectomy and had progressive metastatic disease. The median WHO-performance status was 1, the median number of metastatic sites was 2 (range 1–5) and the median time between the diagnosis of the primary tumour and the start of treatment was 12.9 months (range 1–153). Among the 51 patients, including four patients with early progressive disease, who were evaluable for response, the response rate was 11.8% (95% confidence interval (CI) 2.9–20.7%), with no complete responses. Median duration of response was 8.3 (range 3.8–22.4+) months. Median survival was 16.5 (range 1.8–30.5+) months. Grade 3/4 toxicity (WHO) occurred in 29/52 (55.8%) of the patients in cycle 1 and in 6/16 (37.5%) of the patients in cycle 2. It consisted mainly of anorexia, fatigue, nausea, fever and leucocytopenia. We cannot confirm the high response rate in patients with metastatic renal cell carcinoma treated with the combination of IFN-α, IL-2 and 5-FU, as described

Functionalization of nanotextured substrates for enhanced identification of metastatic breast cancer cells

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Mansur, Nuzhat; Raziul Hasan, Mohammad; Kim, Young-tae; Iqbal, Samir M.

2017-09-01

Metastasis is the major cause of low survival rates among cancer patients. Once cancer cells metastasize, it is extremely difficult to contain the disease. We report on a nanotextured platform for enhanced detection of metastatic cells. We captured metastatic (MDA-MDB-231) and non-metastatic (MCF-7) breast cancer cells on anti-EGFR aptamer modified plane and nanotextured substrates. Metastatic cells were seen to change their morphology at higher rates when captured on nanotextured substrates than on plane substrates. Analysis showed statistically different morphological behaviors of metastatic cells that were very pronounced on the nanotextured substrates. Several distance matrices were calculated to quantify the dissimilarity of cell shape change. Nanotexturing increased the dissimilarity of the metastatic cells and as a result the contrast between metastatic and non-metastatic cells increased. Jaccard distance measurements found that the shape change ratio of the non-metastatic and metastatic cells was enhanced from 1:1.01 to 1:1.81, going from plane to nanotextured substrates. The shape change ratio of the non-metastatic to metastatic cells improved from 1:1.48 to 1:2.19 for the Hausdorff distance and from 1:1.87 to 1:4.69 for the Mahalanobis distance after introducing nanotexture. Distance matrix analysis showed that nanotexture increased the shape change ratios of non-metastatic and metastatic cells. Hence, the detectability of metastatic cells increased. These calculated matrices provided clear and explicit measures to discriminate single cells for their metastatic state on functional nanotextured substrates.

Review of the Interaction Between Body Composition and Clinical Outcomes in Metastatic Renal Cell Cancer Treated With Targeted Therapies

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Steven M Yip

2016-03-01

Full Text Available Treatment of metastatic renal cell cancer (mRCC currently focuses on inhibition of the vascular endothelial growth factor pathway and the mammalian target of rapamycin (mTOR pathway. Obesity confers a higher risk of RCC. However, the influence of obesity on clinical outcomes in mRCC in the era of targeted therapy is less clear. This review focuses on the impact of body composition on targeted therapy outcomes in mRCC. The International Metastatic Renal Cell Carcinoma Database Consortium database has the largest series of patients evaluating the impact of body mass index (BMI on outcomes in mRCC patients treated with targeted therapy. Overall survival was significantly improved in overweight patients (BMI ≥ 25 kg/m2, and this observation was externally validated in patients who participated in Pfizer trials. In contrast, sarcopenia is consistently associated with increased toxicity to inhibitors of angiogenesis and mTOR. Strengthening patients with mRCC and sarcopenia, through a structured exercise program and dietary intervention, may improve outcomes in mRCC treated with targeted therapies. At the same time, the paradox of obesity being a risk factor for RCC while offering a better overall survival in response to targeted therapy needs to be further evaluated.

Optical imaging of metabolic adaptability in metastatic and non-metastatic breast cancer

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Rebello, Lisa; Rajaram, Narasimhan

2018-02-01

Accurate methods for determining metastatic risk from the primary tumor are crucial for patient survival. Cell metabolism could potentially be used as a marker of metastatic risk. Optical imaging of the endogenous fluorescent molecules nicotinamide adenine dinucleotide (NADH) and flavin adenine dinucleotide (FAD) provides a non-destructive and label-free method for determining cell metabolism. The optical redox ratio (FAD/FAD+NADH) is sensitive to the balance between glycolysis and oxidative phosphorylation (OXPHOS). We have previously established that hypoxia-reoxygenation stress leads to metastatic potential-dependent changes in optical redox ratio. The objective of this study was to monitor the changes in optical redox ratio in breast cancer cells in response to different periods of hypoxic stress as well various levels of hypoxia to establish an optimal protocol. We measured the optical redox ratio of highly metastatic 4T1 murine breast cancer cells under normoxic conditions and after exposure to 30, 60, and 120 minutes of 0.5% O2. This was followed by an hour of reoxygenation. We found an increase in the optical redox ratio following reoxygenation from hypoxia for all durations. Statistically significant differences were observed at 60 and 120 minutes (p˂0.01) compared with normoxia, implying an ability to adapt to OXPHOS after reoxygenation. The switch to OXPHOS has been shown to be a key promoter of cell invasion. We will present our results from these investigations in human breast cancer cells as well as non-metastatic breast cancer cells exposed to various levels of hypoxia.

The occurrence of non-melanoma malignant skin lesions and non-cutaneous squamous-cell carcinoma among metastatic melanoma patients: an observational cohort study in Denmark.

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Li, Haojie; Pedersen, Lars; Nørgaard, Mette; Ulrichsen, Sinna P; Thygesen, Sandra K; Nelson, Jeanenne J

2016-05-03

Inhibitors of mutant BRAF are emerging as standard of care in patients with metastatic melanoma who carry relevant oncogenic mutations. However, BRAF inhibitors are found to induce cutaneous squamous cell carcinoma (cuSCC). Population-based background rates of cuSCC and non-cutaneous squamous cell carcinoma (non-cuSCC) in the metastatic melanoma population may contextualize safety signals from randomized clinical trials or the clinics. However, these background rates are lacking. We conducted a historical cohort study to evaluate the background rates of new-onset non-melanoma skin lesions and non-cuSCC among 2,814 metastatic malignant melanoma patients diagnosed in 1997-2010, identified through the Danish Cancer Registry and the National Pathology Registry. Patients were excluded if they had a history of cancer before the metastatic melanoma diagnosis, other than skin cancers. We determined the incidence of non-melanoma malignant skin lesions and non-cuSCC that occurred post metastatic melanoma diagnosis, censoring patients at death, emigration, or December 31, 2011 (end of study period), whichever came first. The median age at metastatic melanoma diagnosis was 64 years. Over 40% of patients died within one year of metastatic diagnosis and ~70% died within 5 years. The percentages of patients with prior history or prevalent disease at metastatic melanoma diagnosis included: 8.6% with cuSCC or basal cell carcinoma (BCC), 3.9% with actinic keratosis (AK), and 0.7% with Bowen's disease. No patients had past or current non-cuSCC per study exclusion criterion. The incidence of non-melanoma skin lesions during the 6 months post-metastatic melanoma diagnosis was as follows: BCC, 1.8% (42.5 per 1000 person-years [PY]); AK, 0.8% (18.6 per 1000 PY); cuSCC, 0.1% (1.7 per 1000 PY); Bowen's disease, 0.04% (0.8 per 1000 PY); and keratoacanthoma (KA), 0%. Non-cuSCC was observed in 3 patients (0.1%; 2.5 per 1000 PY) at 3 sites: bronchi, heart and lung. CuSCC and non-cuSCC were

The occurrence of non-melanoma malignant skin lesions and non-cutaneous squamous-cell carcinoma among metastatic melanoma patients: an observational cohort study in Denmark

International Nuclear Information System (INIS)

Li, Haojie; Pedersen, Lars; Nørgaard, Mette; Ulrichsen, Sinna P.; Thygesen, Sandra K.; Nelson, Jeanenne J.

2016-01-01

Inhibitors of mutant BRAF are emerging as standard of care in patients with metastatic melanoma who carry relevant oncogenic mutations. However, BRAF inhibitors are found to induce cutaneous squamous cell carcinoma (cuSCC). Population-based background rates of cuSCC and non-cutaneous squamous cell carcinoma (non-cuSCC) in the metastatic melanoma population may contextualize safety signals from randomized clinical trials or the clinics. However, these background rates are lacking. We conducted a historical cohort study to evaluate the background rates of new-onset non-melanoma skin lesions and non-cuSCC among 2,814 metastatic malignant melanoma patients diagnosed in 1997–2010, identified through the Danish Cancer Registry and the National Pathology Registry. Patients were excluded if they had a history of cancer before the metastatic melanoma diagnosis, other than skin cancers. We determined the incidence of non-melanoma malignant skin lesions and non-cuSCC that occurred post metastatic melanoma diagnosis, censoring patients at death, emigration, or December 31, 2011 (end of study period), whichever came first. The median age at metastatic melanoma diagnosis was 64 years. Over 40 % of patients died within one year of metastatic diagnosis and ~70 % died within 5 years. The percentages of patients with prior history or prevalent disease at metastatic melanoma diagnosis included: 8.6 % with cuSCC or basal cell carcinoma (BCC), 3.9 % with actinic keratosis (AK), and 0.7 % with Bowen’s disease. No patients had past or current non-cuSCC per study exclusion criterion. The incidence of non-melanoma skin lesions during the 6 months post-metastatic melanoma diagnosis was as follows: BCC, 1.8 % (42.5 per 1000 person-years [PY]); AK, 0.8 % (18.6 per 1000 PY); cuSCC, 0.1 % (1.7 per 1000 PY); Bowen’s disease, 0.04 % (0.8 per 1000 PY); and keratoacanthoma (KA), 0 %. Non-cuSCC was observed in 3 patients (0.1 %; 2.5 per 1000 PY) at 3 sites: bronchi, heart and lung. CuSCC and

Inherent characteristics of metachronous metastatic renal cell carcinoma in the era of targeted agents.

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Han, Jang Hee; Lee, Seung Hwan; Ham, Won Sik; Han, Woong Kyu; Rha, Koon Ho; Choi, Young Deuk; Hong, Sung Joon; Yoon, Young Eun

2017-10-03

To assess the prognostic and predictive factors of time to treatment failure (TTF) and overall survival (OS), respectively, in patients with metachronous metastatic renal cell carcinoma (mRCC) who were treated with targeted agents. We retrospectively reviewed metachronous mRCC patients, defined as individuals diagnosed with metastatic disease >3 months after initial nephrectomy, treated at an institute since 2005. Cox proportional hazard regression analysis was performed to discover the most determinant variables associated with TTF and OS. Sarcomatoid features, absence of metastasectomy, multiple site metastasis, time to metastasis risk group (0-1 risk factors) did not reach the median OS, whereas the OS for the intermediate (2 risk factors) and high risk groups (3-5 risk factors) were 58.6 and 23.6 months, respectively (prisk criteria models. Initial tumor size or T stage did not affect TTF or OS. Patients who could not undergo metastasectomy and rapidly developed multiple metastases with higher corrected calcium and initial tumors with sarcomatoid features were less likely to benefit from targeted therapy; thus, the new agents under development or clinical trials could be more helpful than the use of standard targeted agents.

The Role of Everolimus in Renal Cell Carcinoma

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Malek Meskawi

2015-12-01

Full Text Available Everolimus (RAD001 is an orally administered agent that inhibits the mammalian target of rapamycin serine-threonine kinase. A phase III pivotal trial on everolimus, published in 2008, provided the first evidence for the efficacy of sequential therapy for patients with metastatic clear cell renal cell carcinoma (RCC. In this study, everolimus was used after failure of one or several previous lines of therapy, and it demonstrated a 3-month survival benefit relative to placebo. Currently, based on the level 1 evidence, everolimus represents the molecule of choice for third-line therapy after failure of previous two tyrosine kinase inhibitors (TKIs. However, second-line use after failure of one TKI is challenged by two new molecules (nivolumab and cabozantinib, which proved to have better efficacy with similar toxicity profile. In non-clear cell metastatic RCC, the current evidence recommends everolimus as a second-line therapy after failure of previous first-line sunitinib.

Renin-angiotensin system (RAS) blockade attenuates growth and metastatic potential of renal cell carcinoma in mice.

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Araújo, Wedson F; Naves, Marcelo A; Ravanini, Juliana N; Schor, Nestor; Teixeira, Vicente P C

2015-09-01

Renal cell carcinoma (RCC) is the most frequent type of cancer among renal neoplasms in adults and responds poorly to radiotherapy and chemotherapy. There is evidence that blockade of the renin-angiotensin system (RAS) might have antineoplastic effects. The aim of this study was to investigate the effects of RAS blockade on RCC in a murine model. Murine renal cancer cells (Renca) were injected (1 × 10(5)) into the subcapsular space of the left kidney of BALB/c mice (8 wk of age). The animals were divided into 4 groups: a control group (no treatment), angiotensin-receptor blockers group (losartan 100mg/kg/d), angiotensin-converting enzyme inhibitor group (captopril 10mg/kg/d), and angiotensin-receptor blockers +angiotensin-converting enzyme inhibitor group (losartan 100mg/kg/d +captopril 10mg/kg/d). The animals received the drugs by gavage for 21 days after inoculation, beginning 2 days before tumor induction, and were then euthanized. After killing the animals, the kidneys and lungs were removed, weighed, and processed for histopathological and immunohistochemical analyses. Angiogenesis and vascular microvessels were assessed with the antibodies anti-vascular endothelial growth factor and anti-CD34. Angiotensin II-inoculated animals developed renal tumors. Treated animals presented smaller tumors, regardless of the therapeutic regimen, and far fewer lung metastases in both quantity and dimension compared with the controls. The expression of vascular endothelial growth factor and CD34 were significantly decreased in renal tumors of treated animals compared with the controls. Our findings suggest that blockade of RAS decreases tumor proliferation and metastatic capacity of RCC in this experimental model. Copyright © 2015 Elsevier Inc. All rights reserved.

Metastatic renal cell carcinoma in the thyroid gland: ultrasonographic features and the diagnostic role of core needle biopsy

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Song, Ok Kyu; Koo, Ja Seung; Kwak, Jin Young; Moon, Hee Jung; Yoon, Jung Hyun; Kim, Eun Kyung [Severance Hospital, Yonsei University College of Medicine, Seoul(Korea, Republic of)

2017-07-15

The aims of this study were to present the ultrasonographic (US) features of metastatic renal cell carcinoma (RCC) in the thyroid gland and to evaluate the diagnostic utility of fine needle aspiration (FNA) and core needle biopsy (CNB). Eight patients with nine metastatic RCC nodules in the thyroid glands who were treated from January 2002 to March 2015 in a single tertiary hospital were consecutively selected and retrospectively reviewed. US features and clinical history were obtained from the institution’s medical database. FNA was performed nine times on eight nodules and CNB was performed six times on six nodules. The diagnostic utility of FNA and CNB was evaluated. All nine nodules showed mass formation without diffuse thyroid involvement. On ultrasonography, metastatic RCC nodules were solid (100%), hypoechoic (100%), and ovalshaped nodules with a well-defined smooth margin (88.9%) and increased vascularity (100%, with 55% showing extensive vascularity). No calcifications were noted in any nodules. Lymph node metastasis and direct extension to nearby structures beyond the thyroid gland were not found. One FNA (11%) was able to confirm metastatic RCC, whereas all six CNBs confirmed metastatic RCC. Metastatic RCC appears as oval-shaped hypoechoic solid nodules with well-defined smooth margins, no calcifications, and increased vascularity on ultrasonography. Characteristic US features along with a previous history of RCC should raise clinical suspicion, and CNB should be performed to make an accurate diagnosis.

Results of a Phase 1/2 Study in Metastatic Renal Cell Carcinoma Patients Treated with a Patient-specific Adjuvant Multi-peptide Vaccine after Resection of Metastases.

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Rausch, Steffen; Gouttefangeas, Cécile; Hennenlotter, Jörg; Laske, Karoline; Walter, Kerstin; Feyerabend, Susan; Chandran, Premachandran Anoop; Kruck, Stephan; Singh-Jasuja, Harpreet; Frick, Annemarie; Kröger, Nils; Stevanović, Stefan; Stenzl, Arnulf; Rammensee, Hans-Georg; Bedke, Jens

2017-10-04

Treatment of metastatic renal cell carcinoma comprises metastasectomy±systemic medical treatment. Specific immunotherapy after metastasectomy could be a complementary option. In this phase 1/2 study, safety and tolerability of an adjuvant multi-peptide vaccine (UroRCC) after metastasectomy was evaluated together with immune response and efficacy, compared with a contemporary cohort of patients (n=44) treated with metastasectomy only. Nineteen metastatic renal cell carcinoma patients received UroRCC via intradermal or subcutaneous application randomized to immunoadjuvants (granulocyte-macrophage colony-stimulating factor or Montanide). Adverse events of UroRCC were mainly grade I and II; frequency of immune response was higher for major histocompatibility complex class II peptides (17/19, 89.5%) than for major histocompatibility complex class I peptides (8/19, 42.1%). Median overall survival was not reached in the UroRCC group (mean: 112.6 mo, 95% confidence interval [CI]: 92.1-133.1) and 58.0 mo (95% CI: 32.7-83.2) in the control cohort (p=0.015). UroRCC was an independent prognosticator of overall survival (hazard ratio=0.19, 95% CI: 0.05-0.69, p=0.012). Adjuvant UroRCC multi-peptide vaccine after metastasectomy was well tolerated, immunogenic, and indicates potential clinical benefit when compared with a contemporary control cohort (NCT02429440). The application of a patient-specific peptide vaccine after complete resection of metastases in metastatic renal cell carcinoma patients resulted in favorable tolerability and outcome. Copyright © 2017 European Association of Urology. Published by Elsevier B.V. All rights reserved.

Increase of circulating CD4+CD25highFoxp3+ regulatory T cells in patients with metastatic renal cell carcinoma during treatment with dendritic cell vaccination and low-dose interleukin-2

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Berntsen, Annika; Brimnes, Marie Klinge; thor Straten, Per

2010-01-01

Regulatory T cells (Treg) play an important role in the maintenance of immune tolerance and may be one of the obstacles of successful tumor immunotherapy. In this study, we analyzed the impact of administration of dendritic cell (DC) vaccination in combination with low-dose interleukin (IL)-2...... in patients with metastatic renal cell carcinoma on the frequency of CD4+CD25highFoxp3+ Treg cells in peripheral blood. We found that the treatment increased the frequency of Treg cells more than 7-fold compared with pretreatment levels (P...

FDG-PET as a predictive biomarker for therapy with everolimus in metastatic renal cell cancer

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Chen, James L; Appelbaum, Daniel E; Kocherginsky, Masha; Cowey, Charles L; Kimryn Rathmell, Wendy; McDermott, David F; Stadler, Walter M

2013-01-01

The mTOR (mammalian target of rapamycin) inhibitor, everolimus, affects tumor growth by targeting cellular metabolic proliferation pathways and delays renal cell carcinoma (RCC) progression. Preclinical evidence suggests that baseline elevated tumor glucose metabolism as quantified by FDG-PET ([ 18 F] fluorodeoxy-glucose positron emission tomography) may predict antitumor activity. Metastatic RCC (mRCC) patients refractory to vascular endothelial growth factor (VEGF) pathway inhibition were treated with standard dose everolimus. FDG-PET scans were obtained at baseline and 2 weeks; serial computed tomography (CT) scans were obtained at baseline and every 8 weeks. Maximum standardized uptake value (SUVmax) of the most FDG avid lesion, average SUVmax of all measured lesions and their corresponding 2-week relative changes were examined for association with 8-week change in tumor size. A total of 63 patients were enrolled; 50 were evaluable for the primary endpoint of which 48 had both PET scans. Patient characteristics included the following: 36 (72%) clear cell histology and median age 59 (range: 37–80). Median pre- and 2-week treatment average SUVmax were 6.6 (1–17.9) and 4.2 (1–13.9), respectively. Response evaluation criteria in solid tumors (RECIST)-based measurements demonstrated an average change in tumor burden of 0.2% (−32.7% to 35.9%) at 8 weeks. Relative change in average SUVmax was the best predictor of change in tumor burden (all evaluable P = 0.01; clear cell subtype P = 0.02), with modest correlation. Baseline average SUVmax was correlated with overall survival and progression-free survival (PFS) (P = 0.023; 0.020), but not with change in tumor burden. Everolimus therapy decreased SUVs on follow-up PET scans in mRCC patients, but changes were only modestly correlated with changes in tumor size. Thus, clinical use of FDG-PET-based biomarkers is challenged by high variability. In this phase II trial, FDG-PET was explored as a predictive biomarker

Cytoreductive nephrectomy vs medical therapy as initial treatment: a rational approach to the sequence question in metastatic renal cell carcinoma.

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Spiess, Philippe E; Fishman, Mayer N

2010-10-01

Renal cell carcinoma (RCC) can be considered as two distinct entities: localized and metastatic disease. We conducted a review of the scientific literature published within the past decade pertaining to cytoreductive nephrectomy for metastatic RCC. Retrospective data and historical prospective series have demonstrated the survival benefit of debulking nephrectomy in well-selected RCC patients. New medical therapies, including vascular endothelial growth factor and mTOR pathway blocking drugs, are active biological agents, with survival improvement and potential regression of metastatic and primary tumors. Our current therapeutic challenge is the optimal integration of multimodal therapy consisting of systemic therapy and surgery including cytoreductive nephrectomy, debulking, and metastasectomy. Empiric data to guide this decision are limited. The decision concerning whether medical or surgical therapy should be the primary treatment approach selected must be made on an individual basis, taking into account patient performance status, clinical parameters, and physician expertise and recommendations, thus making each case a unique therapeutic challenge.

A case of treatment in a patient with synchronous bilateral renal cell carcinoma and simultaneous metastatic involvement of both adrenal glands: Clinical observation

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V. R. Latypov

2014-11-01

Full Text Available Synchronous bilateral renal cell carcinoma occurs in 1.4 % of cases. The probability of bilateral adrenal metastases from renal cell carcinoma is less than 0.5 %. The clinical observation presents a case of synchronous bilateral renal cell carcinoma and simultaneous metastatic involvement of both adrenal glands. A 55‑year-old male patient was adm tted with the signs of hematuria and anemia to the Unit of Urology, Clinic of General Surgery, Siberian State Medical University. He was found to have synchronous bilateral renal cell carcinoma and simultaneous bilateral adrenal involvement. Sequential surgical treatment – radical nephrectomy (with adrenal gland removal on the right side and, after 3 months, adrenalectomy and kidney resection on the left side were performed. All the organs removed displayed tumors that proved to be renal cell carcinomas (a clear cell variant. There were lymph node metastases in the right-sided renal portal. Postoperatively, the investigators performed hormone replacement therapy for adrenal insufficiency, an immunotherapy cycle, three cycles of targeted therapy withsorafenib and sunitinib (at an interval of 0.5–2 years, and insulin therapy for new-onset diabetes mellitus. The duration of a follow-up was 6.2 years. When describing the case, the patient was alive and showed a generalized tumorous process with extensive tumor involvement of the solitary kidney. Sunitinib therapy was used.

A case of treatment in a patient with synchronous bilateral renal cell carcinoma and simultaneous metastatic involvement of both adrenal glands: Clinical observation

Directory of Open Access Journals (Sweden)

V. R. Latypov

2014-01-01

Full Text Available Synchronous bilateral renal cell carcinoma occurs in 1.4 % of cases. The probability of bilateral adrenal metastases from renal cell carcinoma is less than 0.5 %. The clinical observation presents a case of synchronous bilateral renal cell carcinoma and simultaneous metastatic involvement of both adrenal glands. A 55‑year-old male patient was adm tted with the signs of hematuria and anemia to the Unit of Urology, Clinic of General Surgery, Siberian State Medical University. He was found to have synchronous bilateral renal cell carcinoma and simultaneous bilateral adrenal involvement. Sequential surgical treatment – radical nephrectomy (with adrenal gland removal on the right side and, after 3 months, adrenalectomy and kidney resection on the left side were performed. All the organs removed displayed tumors that proved to be renal cell carcinomas (a clear cell variant. There were lymph node metastases in the right-sided renal portal. Postoperatively, the investigators performed hormone replacement therapy for adrenal insufficiency, an immunotherapy cycle, three cycles of targeted therapy withsorafenib and sunitinib (at an interval of 0.5–2 years, and insulin therapy for new-onset diabetes mellitus. The duration of a follow-up was 6.2 years. When describing the case, the patient was alive and showed a generalized tumorous process with extensive tumor involvement of the solitary kidney. Sunitinib therapy was used.

Non-lethal heat treatment of cells results in reduction of tumor initiation and metastatic potential

International Nuclear Information System (INIS)

Kim, Yoo-Shin; Lee, Tae Hoon; O'Neill, Brian E.

2015-01-01

Non-lethal hyperthermia is used clinically as adjuvant treatment to radiation, with mixed results. Denaturation of protein during hyperthermia treatment is expected to synergize with radiation damage to cause cell cycle arrest and apoptosis. Alternatively, hyperthermia is known to cause tissue level changes in blood flow, increasing the oxygenation and radiosensitivity of often hypoxic tumors. In this study, we elucidate a third possibility, that hyperthermia alters cellular adhesion and mechanotransduction, with particular impact on the cancer stem cell population. We demonstrate that cell heating results in a robust but temporary loss of cancer cell aggressiveness and metastatic potential in mouse models. In vitro, this heating results in a temporary loss in cell mobility, adhesion, and proliferation. Our hypothesis is that the loss of cellular adhesion results in suppression of cancer stem cells and loss of tumor virulence and metastatic potential. Our study suggests that the metastatic potential of cancer is particularly reduced by the effects of heat on cellular adhesion and mechanotransduction. If true, this could help explain both the successes and failures of clinical hyperthermia, and suggest ways to target treatments to those who would most benefit. - Highlights: • Non-lethal hyperthermia treatment of cancer cells is shown to cause a reduction in rates of tumor initiation and metastasis. • Dynamic imaging of cells during heat treatment shows temporary changes in cell shape, cell migration, and cell proliferation. • Loss of adhesion may lead to the observed effect, which may disproportionately impact the tumor initiating cell fraction. • Loss or suppression of the tumor initiating cell fraction results in the observed loss of metastatic potential in vivo. • This result may lead to new approaches to synergizing hyperthermia with surgery, radiation, and chemotherapy

Non-lethal heat treatment of cells results in reduction of tumor initiation and metastatic potential

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Kim, Yoo-Shin; Lee, Tae Hoon; O' Neill, Brian E., E-mail: BEOneill@houstonmethodist.org

2015-08-14

Non-lethal hyperthermia is used clinically as adjuvant treatment to radiation, with mixed results. Denaturation of protein during hyperthermia treatment is expected to synergize with radiation damage to cause cell cycle arrest and apoptosis. Alternatively, hyperthermia is known to cause tissue level changes in blood flow, increasing the oxygenation and radiosensitivity of often hypoxic tumors. In this study, we elucidate a third possibility, that hyperthermia alters cellular adhesion and mechanotransduction, with particular impact on the cancer stem cell population. We demonstrate that cell heating results in a robust but temporary loss of cancer cell aggressiveness and metastatic potential in mouse models. In vitro, this heating results in a temporary loss in cell mobility, adhesion, and proliferation. Our hypothesis is that the loss of cellular adhesion results in suppression of cancer stem cells and loss of tumor virulence and metastatic potential. Our study suggests that the metastatic potential of cancer is particularly reduced by the effects of heat on cellular adhesion and mechanotransduction. If true, this could help explain both the successes and failures of clinical hyperthermia, and suggest ways to target treatments to those who would most benefit. - Highlights: • Non-lethal hyperthermia treatment of cancer cells is shown to cause a reduction in rates of tumor initiation and metastasis. • Dynamic imaging of cells during heat treatment shows temporary changes in cell shape, cell migration, and cell proliferation. • Loss of adhesion may lead to the observed effect, which may disproportionately impact the tumor initiating cell fraction. • Loss or suppression of the tumor initiating cell fraction results in the observed loss of metastatic potential in vivo. • This result may lead to new approaches to synergizing hyperthermia with surgery, radiation, and chemotherapy.

T-cell Responses in the Microenvironment of Primary Renal Cell Carcinoma-Implications for Adoptive Cell Therapy

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Andersen, Rikke; Westergaard, Marie Christine Wulff; Kjeldsen, Julie Westerlin

2018-01-01

In vitro expansion of large numbers of highly potent tumor-reactive T cells appears a prerequisite for effective adoptive cell therapy (ACT) with autologous tumor-infiltrating lymphocytes (TIL) as shown in metastatic melanoma (MM). We therefore sought to determine whether renal cell carcinomas (RCC...

Dynamic Contrast-Enhanced Computed Tomography-Derived Blood Volume and Blood Flow Correlate With Patient Outcome in Metastatic Renal Cell Carcinoma

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Mains, Jill Rachel; Donskov, Frede; Pedersen, Erik Morre

2017-01-01

= 7). Using a prototype software program (Advanced Perfusion and Permeability Application, Philips Healthcare, Best, the Netherlands), blood volume (BV), blood flow (BF), and permeability surface area product (PS) were calculated for each tumor at baseline, week 5, and week 10. These parameters......OBJECTIVES: The aim was to explore the potential for using dynamic contrast-enhanced computed tomography as a noninvasive functional imaging biomarker before and during the early treatment of metastatic renal cell carcinoma (mRCC). MATERIALS AND METHODS: Dynamic contrast-enhanced computed...

Whole Blood mRNA Expression-Based Prognosis of Metastatic Renal Cell Carcinoma.

Science.gov (United States)

Giridhar, Karthik V; Sosa, Carlos P; Hillman, David W; Sanhueza, Cristobal; Dalpiaz, Candace L; Costello, Brian A; Quevedo, Fernando J; Pitot, Henry C; Dronca, Roxana S; Ertz, Donna; Cheville, John C; Donkena, Krishna Vanaja; Kohli, Manish

2017-11-03

The Memorial Sloan Kettering Cancer Center (MSKCC) prognostic score is based on clinical parameters. We analyzed whole blood mRNA expression in metastatic clear cell renal cell carcinoma (mCCRCC) patients and compared it to the MSKCC score for predicting overall survival. In a discovery set of 19 patients with mRCC, we performed whole transcriptome RNA sequencing and selected eighteen candidate genes for further evaluation based on associations with overall survival and statistical significance. In an independent validation of set of 47 patients with mCCRCC, transcript expression of the 18 candidate genes were quantified using a customized NanoString probeset. Cox regression multivariate analysis confirmed that two of the candidate genes were significantly associated with overall survival. Higher expression of BAG1 [hazard ratio (HR) of 0.14, p < 0.0001, 95% confidence interval (CI) 0.04-0.36] and NOP56 (HR 0.13, p < 0.0001, 95% CI 0.05-0.34) were associated with better prognosis. A prognostic model incorporating expression of BAG1 and NOP56 into the MSKCC score improved prognostication significantly over a model using the MSKCC prognostic score only ( p < 0.0001). Prognostic value of using whole blood mRNA gene profiling in mCCRCC is feasible and should be prospectively confirmed in larger studies.

A brief symptom index for advanced renal cell carcinoma

Directory of Open Access Journals (Sweden)

Cella David

2006-09-01

Full Text Available Abstract Background Our objective was to test a brief, symptom index for advanced renal cell carcinoma, a disease affecting over 38,000 Americans each year and often diagnosed in late stages. Methods We conducted secondary data analyses on patient-reported outcomes of 209 metastatic renal cell carcinoma patients participating in a Phase III clinical trial. Patient-reported outcomes, obtained from the FACT-Biological Response Modifier (FACT-BRM scale, were available at baseline, 2, and 8 weeks. We analyzed data from eight FACT-BRM items previously identified by clinical experts to represent the most important symptoms of advanced renal cell carcinoma. Items comprising this index assess nausea, pain, appetite, perceived sickness, fatigue and weakness, with higher scores indicating fewer symptoms. We determined reliability and validity of the index and estimated a minimally important difference. Results The index had excellent internal reliability at all three time points (alphas ≥ 0.83. Baseline scores were able to discriminate patients across Karnofsky performance status, number of metastatic sites, and risk group categories (ps Conclusion The 8-item index of patient-reported symptoms of renal cell carcinoma appears to be a psychometrically sound measure. It is a brief, reliable, and valid measure that can easily be adapted for use in clinical trials and observational studies.

Understanding familial and non-familial renal cell cancer

NARCIS (Netherlands)

Bodmer, Daniëlle; van den Hurk, Wilhelmina; van Groningen, Jan J. M.; Eleveld, Marc J.; Martens, Gerard J. M.; Weterman, Marian A. J.; van Kessel, Ad Geurts

2002-01-01

Molecular genetic analysis of familial and non-familial cases of conventional renal cell carcinoma (RCC) revealed a critical role(s) for multiple genes on human chromosome 3. For some of these genes, e.g. VHL, such a role has been firmly established, whereas for others, definite confirmation is

Understanding familial and non-familial renal cell cancer.

NARCIS (Netherlands)

Bodmer, D.; Hurk, W.H. van den; Groningen, J.J.M. van; Eleveld, M.J.; Martens, G.J.M.; Weterman, M.A.J.; Geurts van Kessel, A.H.M.

2002-01-01

Molecular genetic analysis of familial and non-familial cases of conventional renal cell carcinoma (RCC) revealed a critical role(s) for multiple genes on human chromosome 3. For some of these genes, e.g. VHL, such a role has been firmly established, whereas for others, definite confirmation is

Cardiac Metastasis in Renal Cell Carcinoma

African Journals Online (AJOL)

abp

2015-10-21

Oct 21, 2015 ... Metastatic disease of the heart is over twenty times more common than primary heart tumors [1]. They are among the least known and highly debated issues in oncology, and few systematic studies are devoted to this topic. Cardiac involvement in renal cell carcinoma (RCC) commonly arises from direct ...

Active smoking may negatively affect response rate, progression-free survival, and overall survival of patients with metastatic renal cell carcinoma treated with sunitinib.

Science.gov (United States)

Keizman, Daniel; Gottfried, Maya; Ish-Shalom, Maya; Maimon, Natalie; Peer, Avivit; Neumann, Avivit; Hammers, Hans; Eisenberger, Mario A; Sinibaldi, Victoria; Pili, Roberto; Hayat, Henry; Kovel, Svetlana; Sella, Avishay; Boursi, Ben; Weitzen, Rony; Mermershtain, Wilmosh; Rouvinov, Keren; Berger, Raanan; Carducci, Michael A

2014-01-01

Obesity, smoking, hypertension, and diabetes are risk factors for renal cell carcinoma development. Their presence has been associated with a worse outcome in various cancers. We sought to determine their association with outcome of sunitinib treatment in metastatic renal cell carcinoma (mRCC). An international multicenter retrospective study of sunitinib-treated mRCC patients was performed. Multivariate analyses were performed to determine the association between outcome and the pretreatment status of smoking, body mass index, hypertension, diabetes, and other known prognostic factors. Between 2004 and 2013, 278 mRCC patients were treated with sunitinib: 59 were active smokers, 67 were obese, 73 were diabetic, and 165 had pretreatment hypertension. Median progression-free survival (PFS) was 9 months, and overall survival (OS) was 22 months. Factors associated with PFS were smoking status (past and active smokers: hazard ratio [HR]: 1.17, p = .39; never smokers: HR: 2.94, p non-clear cell histology (HR: 1.62, p = .011), pretreatment neutrophil-to-lymphocyte ratio >3 (HR: 3.51, p smoking status (past and active smokers: HR: 1.25, p = .29; never smokers: HR: 2.7, p 3 (HR: 2.95, p smoking may negatively affect the PFS and OS of sunitinib-treated mRCC. Clinicians should consider advising patients to quit smoking at initiation of sunitinib treatment for mRCC.

A Unique Presentation of an Undiagnosed Renal Cell Carcinoma

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Georgios Kravvas

2014-01-01

Full Text Available We describe a 58-year-old lady who presented initially to her general practitioner with a palpable warty urethral nodule. She was subsequently referred to the urology department for further investigations. She underwent flexible cystoscopy and imaging, followed by rigid cystoscopy and excision of the nodule. Histological analysis was consistent with renal cell carcinoma (RCC. CT imaging confirmed the presence of an invading metastatic left renal cell carcinoma with bilateral metastatic deposits to the lungs and adrenal glands. The patient was enlisted on the Panther Trial and received a course of Pazopanib before undergoing radical nephrectomy. Two years later she is still alive with metastases remaining reduced in size and numbers. During this study we have performed a literature review of similar cases with this unusual presentation of RCC.

Postoperative evaluation of renal cell carcinoma in the abdominal computed tomography

International Nuclear Information System (INIS)

Kurihara, Noriko; Tazawa, Satoru; Suzuki, Yasuyoshi; Kato, Masakazu

1993-01-01

Two hundred one abdominal CT scans were performed in 93 patients who had undergone previous nephrectomy for renal cell carcinoma. Three had local recurrence and nine had metastatic lesions. Local recurrence and metastatic lesions were detected from 7 months to 6 years and 4 months after nephrectomy (median 2 years and 9 months). Local recurrent lesions were detected as masses in the vacant renal fossa. Metastatic lesions of the abdomen were seen in adrenal gland, liver, contralateral kidney, bone, etc. Administration of oral contrast material was useful to differentiate these recurrent lesions from intestine. It was important to fully understand the anatomical change after nephrectomy, and ultrasonography might be especially helpful for evaluating the liver and contralateral kidney. (author)

Renal cell carcinoma presenting as mandibular metastasis

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Hassan Ahmadnia

2013-01-01

Full Text Available Renal clear cell carcinoma (RCC has different manifestations, including uncommon metastasis and paraneoplastic syndromes. Here we report a rare case of RCC presenting as metastasis to the mandible. A 57-year-old patient with mandibular swelling was referred to the dentist. After necessary evaluations, an incisional biopsy of mandible showed metastatic RCC. The patient was referred to the urologist. The patient underwent right radical nephrectomy. Pathological examination showed clear renal cell carcinoma. Every abnormal bone lesion in the oral cavity should be evaluated carefully and the possibility of a malignant lesion should always be considered.

Intrinsic resistance to tyrosine kinase inhibitors is associated with poor clinical outcome in metastatic renal cell carcinoma

International Nuclear Information System (INIS)

Busch, Jonas; Grünwald, Viktor; Seidel, Christoph; Weikert, Steffen; Wolff, Ingmar; Kempkensteffen, Carsten; Weinkauf, Lisa; Hinz, Stefan; Magheli, Ahmed; Miller, Kurt

2011-01-01

Data on sequential therapy in patients with metastatic renal cell carcinoma (mRCC) and intrinsic resistance to receptor tyrosine kinase inhibitor (rTKI) treatment remains vague. We retrospectively studied treatment characteristics and outcome of mRCC patients refractory to first rTKI therapy. Thirty-five mRCC patients (male, 18; female, 11) with primary resistance to first rTKI therapy (sunitinib, n = 28; sorafenib, n = 7) and a median treatment interval of 2.4 months (1 - 4.6) were identified. In 22 patients, progressive disease (PD) was determined by a new metastatic lesion. Of these, 16 patients received subsequent therapy with 12 patients remaining refractory and 4 patients achieving disease stabilization. In 13 patients continuous growth of existing metastatic lesions determined PD. Of these, 9 received sequential therapy with 6 achieving disease stabilization. Altogether, 25 patients were treated sequentially (rTKI: n = 15; mTOR-inhibitor: n = 10) and achieved a median PFS of 3.2 months (range, 1-16.6). Fifteen patients failed to respond to either line of therapy. Disease control was not associated with type of subsequent therapy. Median OS was 14.9 months (CI: 5.5-24.4). Intrinsic resistance to rTKI is associated with a low chance of response to sequential therapy and a poor prognosis in mRCC patients

Dynamic contrast-enhanced computed tomography as a potential biomarker in patients with metastatic renal cell carcinoma: preliminary results from the Danish Renal Cancer Group Study-1

DEFF Research Database (Denmark)

Mains, Jill Rachel; Donskov, Frede; Pedersen, Erik Morre

2014-01-01

OBJECTIVES: The aim of this study was to explore the impact of dynamic contrast-enhanced (DCE) computer tomography (CT) as a biomarker in metastatic renal cell carcinoma (mRCC). MATERIALS AND METHODS: Twelve patients with favorable or intermediate Memorial Sloan Kettering Cancer Center risk group...... blinded to treatment group. The DCE-CT scans were performed at baseline, at weeks 5 and 10, and thereafter every third month. Blood flow (BF; mL/min/100 mL), peak enhancement (Hounsfield units), time to peak (seconds), and blood volume (BV; mL/100 g) were calculated. Parameters for DCE-CT were correlated...

Patients with advanced and metastatic renal cell carcinoma treated with targeted therapy in the Czech Republic: twenty cancer centres, six agents, one database.

Science.gov (United States)

Poprach, Alexandr; Bortlíček, Zbyněk; Büchler, Tomáš; Melichar, Bohuslav; Lakomý, Radek; Vyzula, Rostislav; Brabec, Petr; Svoboda, Marek; Dušek, Ladislav; Gregor, Jakub

2012-12-01

The incidence and mortality of renal cell carcinoma (RCC) in the Czech Republic are among the highest in the world. Several targeted agents have been recently approved for the treatment of advanced/metastatic RCC. Presentation of a national clinical database for monitoring and assessment of patients with advanced/metastatic RCC treated with targeted therapy. The RenIS (RENal Information System, http://renis.registry.cz ) registry is a non-interventional post-registration database of epidemiological and clinical data of patients with RCC treated with targeted therapies in the Czech Republic. Twenty cancer centres eligible for targeted therapy administration participate in the project. As of November 2011, six agents were approved and reimbursed from public health insurance, including bevacizumab, everolimus, pazopanib, sorafenib, sunitinib, and temsirolimus. As of 10 October 2011, 1,541 patients with valid records were entered into the database. Comparison with population-based data from the Czech National Cancer Registry revealed that RCC patients treated with targeted therapy are significantly younger (median age at diagnosis 59 vs. 66 years). Most RenIS registry patients were treated with sorafenib and sunitinib, many patients sequentially with both agents. Over 10 % of patients were also treated with everolimus in the second or third line. Progression-free survival times achieved were comparable to phase III clinical trials. The RenIS registry has become an important tool and source of information for the management of cancer care and clinical practice, providing comprehensive data on monitoring and assessment of RCC targeted therapy on a national level.

Computed tomography scans of metastatic hepatic tumors

Energy Technology Data Exchange (ETDEWEB)

Takemoto, Kazumasa; Fukuda, Haruyuki; Nemoto, Yutaka [Osaka City Univ. (Japan). Faculty of Medicine

1984-01-01

Computed tomography scans of 114 metastatic hepatic tumors were reviewed. Central low density was found in 82 cases (71.9%) and seems to be characteristic to metastatic hepatic tumors. Dynamic CT was performed on 34 cases, and 21 (61.8%) of these had ring enhancement at the arterial phase. Most of metastatic hepatic tumors could be differentiated from hepatocellular carcinoma. However, metastatic hepatic tumors from renal cell carcinoma, renal rhabdomyosarcoma, malignant melanoma and leiomyosarcoma could not be differentiated from hepatocellular carcinoma, even with use of dynamic study.

Whole Blood mRNA Expression-Based Prognosis of Metastatic Renal Cell Carcinoma

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Karthik V. Giridhar

2017-11-01

Full Text Available The Memorial Sloan Kettering Cancer Center (MSKCC prognostic score is based on clinical parameters. We analyzed whole blood mRNA expression in metastatic clear cell renal cell carcinoma (mCCRCC patients and compared it to the MSKCC score for predicting overall survival. In a discovery set of 19 patients with mRCC, we performed whole transcriptome RNA sequencing and selected eighteen candidate genes for further evaluation based on associations with overall survival and statistical significance. In an independent validation of set of 47 patients with mCCRCC, transcript expression of the 18 candidate genes were quantified using a customized NanoString probeset. Cox regression multivariate analysis confirmed that two of the candidate genes were significantly associated with overall survival. Higher expression of BAG1 [hazard ratio (HR of 0.14, p < 0.0001, 95% confidence interval (CI 0.04–0.36] and NOP56 (HR 0.13, p < 0.0001, 95% CI 0.05–0.34 were associated with better prognosis. A prognostic model incorporating expression of BAG1 and NOP56 into the MSKCC score improved prognostication significantly over a model using the MSKCC prognostic score only (p < 0.0001. Prognostic value of using whole blood mRNA gene profiling in mCCRCC is feasible and should be prospectively confirmed in larger studies.

Pattern of Care Study in Metastatic Renal-Cell Carcinoma in the Preimmunotherapy Era in Switzerland.

Science.gov (United States)

Sandmeier, Nadja; Rothschild, Sacha I; Rothermundt, Christian; Cathomas, Richard; Schardt, Julian; Berthold, Dominik; von Burg, Philippe; Müller, Beat; Beyer, Jörg; Vogt, Deborah R; Stenner, Frank

2018-02-02

In metastatic renal-cell carcinoma (mRCC), physicians have a plethora of therapeutic choices, with the latest addition of checkpoint inhibitors. However, many questions regarding the best use of the respective drugs remain unanswered. Therefore, it is important to examine and summarize the outcome of real-world experiences to understand the practical value of the various drugs in daily use and foster optimal treatment algorithms for patients with renal-cell carcinoma. We sought to describe the pattern of care in mRCC under circumstances with access to all therapeutic options for patients. We examined the outcome of patients with mRCC who were treated at 8 major centers in Switzerland, mainly with vascular endothelial growth factor-targeted therapy and mammalian target of rapamycin inhibitors. Data from 110 patients with mRCC who had undergone more than one systemic therapy were collected and analyzed. We assessed the pattern of care for patients with mRCC in an unrestricted health care system and outcomes with regard to the respective treatment sequences. We also studied the compliance of individual therapies with published guidelines and correlated the adherence to outcome. Finally, immediate versus deferred treatment and the number of received therapeutic drug lines were analyzed. Median survival of patients treated with targeted agents for mRCC was 2.0 years. Exposure to more than 2 lines of systemic drugs did not improve outcome of patients with mRCC. Copyright © 2018 Elsevier Inc. All rights reserved.

Temsirolimus Is Highly Effective as Third-Line Treatment in Chromophobe Renal Cell Cancer

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Dimitrios Zardavas

2011-01-01

Full Text Available We report unexpectedly high efficacy of temsirolimus as third-line treatment in a patient with metastatic chromophobe renal cell carcinoma. After failure of two sequentially administered tyrosine kinase inhibitors, treatment with temsirolimus resulted in a prolonged partial remission of 14 months, and the response is still continuing. Up to now, no data from randomized clinical studies have been published addressing the question of efficacy of temsirolimus as third-line treatment after failure of tyrosine kinase inhibitors. The case presented here implies that temsirolimus could be a viable option for patients with metastatic chromophobe renal cell carcinoma.

Examining the bleeding incidences associated with targeted therapies used in metastatic renal cell carcinoma.

Science.gov (United States)

Crist, MacKenzie; Hansen, Elizabeth; Chablani, Lipika; Guancial, Elizabeth

2017-12-01

A systematic review was conducted to illustrate the bleeding risks associated with targeted therapies used in the treatment of metastatic renal cell carcinoma (mRCC). Eligible studies included phase II, III, or IV clinical trials using pazopanib, sunitinib, cabozantinib, lenvatinib, everolimus, temsirolimus, bevacizumab, axitinib, and/or sorafenib in the setting of mRCC. Types of bleeding event(s), bleeding event frequency, and incidence of thrombocytopenia were collected from the relevant articles. ClinicalTrials.gov was also searched for incidence of "Serious bleeding adverse effects" reported in these trials. The incidences of bleeding events ranged from 1 to 36%, and incidences of thrombocytopenia ranged from 2 to 78%. Available serious bleeding adverse events ranged from 1 to 7%. The highest percentage of bleeding incidences were seen with bevacizumab, while the lowest percentage of bleeding incidences were seen with axitinib. All of the included trials were of high quality per Jadad scoring. Copyright © 2017 Elsevier B.V. All rights reserved.

PRIMARY SQUAMOUS CELL CARCINOMA OF RENAL PELVIS ASSOCIATED WITH RENAL CALCULUS AND RECURRENT PYONEPHROSIS

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Hoti Lal

2015-11-01

Full Text Available Primary Squamous Cell Carcinoma in the kidney is a rare malignant neoplasm associated with nephrolithiasis, typically monobacterial pyonephrosis and rarely Xanthogranulomatous pyelonephritis. It is an aggressive disease with a poor prognosis mostly due to lack of presenting clinical features like a palpable mass, gross haematuria and pain. We report a case presenting with renal calculus and pyonephrosis managed initially with percutaneous nephrostomy followed by nephrectomy due to complete loss of renal function. Histopathological evaluation revealed poorly differentiated squamous cell carcinoma which is managed by chemotherapy, although initially beneficial, patients later develop disseminated metastatic disease which holds a poor prognosis.

CD147 and matrix-metalloproteinase-2 expression in metastatic and non-metastatic uveal melanomas.

Science.gov (United States)

Lüke, Julia; Vukoja, Vlatka; Brandenbusch, Tim; Nassar, Khaled; Rohrbach, Jens Martin; Grisanti, Salvatore; Lüke, Matthias; Tura, Aysegül

2016-06-03

Extracellular matrix remodelling regulated by matrix-metalloproteinase (MMP) inducer (CD147) is a crucial process during tumor cell invasion and regulation of blood supply. In this study, we evaluated the correlation of CD147 and MMP-2 expression with major prognostic factors for uveal melanoma and the development of metastasis. The expression of CD147 and MMP-2 was analyzed in 49 samples of uveal melanomas. Triple immunofluorescence stainings using markers against glial cells (GFAP), endothelial cells (CD34) and macrophages (CD68) were performed to further analyse the exact localisation of CD147 and MMP-2 positivity. In 28 cases clinical metastatic disease were found. The remaining 21 cases showed no signs of metastatic disease for an average follow-up of 10 years. Correlation analysis (Pearson correlation) was performed to analyse the association of CD147 and MMP-2 expression with known prognostic factors, vasculogenic mimicry (VM), the mature vasculature (von Willebrand Factor) and tumor induced angiogenesis (by means of Endoglin expression). CD147 and MMP-2 were expressed in 47 (96.0 %) of the uveal melanomas. CD147 up-regulation was significantly correlated with a higher MMP-2 expression. The overall expression analysis revealed no significant difference in the metastatic (p = 0.777) and non-metastatic subgroup (p = 0.585). No correlation of CD147 expression and any system of blood supply was evident. In the non-metastatic sub-group a significant correlation of clustered CD147 positive cells with largest basal diameter (p = 0.039), height (p = 0.047) and TNM-stage (p = 0.013) was evident. These data may indicate that CD147 regulates MMP-2 expression in uveal melanoma cells.

Phase II trial of Modified Vaccinia Ankara (MVA virus expressing 5T4 and high dose Interleukin-2 (IL-2 in patients with metastatic renal cell carcinoma

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Mitcham Josephine

2009-01-01

Full Text Available Abstract Background Interleukin-2 (IL-2 induces durable objective responses in a small cohort of patients with metastatic renal cell carcinoma (RCC but the antigen(s responsible for tumor rejection are not known. 5T4 is a non-secreted membrane glycoprotein expressed on clear cell and papillary RCCs. A modified vaccinia virus Ankara (MVA encoding 5T4 was tested in combination with high-dose IL-2 to determine the safety, objective response rate and effect on humoral and cell-mediated immunity. Methods 25 patients with metastatic RCC who qualified for IL-2 were eligible and received three immunizations every three weeks followed by IL-2 (600,000 IU/kg after the second and third vaccinations. Blood was collected for analysis of humoral, effector and regulatory T cell responses. Results There were no serious vaccine-related adverse events. While no objective responses were observed, three patients (12% were rendered disease-free after nephrectomy or resection of residual metastatic disease. Twelve patients (48% had stable disease which was associated with improved median overall survival compared to patients with progressive disease (not reached vs. 28 months, p = 0.0261. All patients developed 5T4-specific antibody responses and 13 patients had an increase in 5T4-specific T cell responses. Although the baseline frequency of Tregs was elevated in all patients, those with stable disease showed a trend toward increased effector CD8+ T cells and a decrease in Tregs. Conclusion Vaccination with MVA-5T4 did not improve objective response rates of IL-2 therapy but did result in stable disease associated with an increase in the ratio of 5T4-specific effector to regulatory T cells in selected patients. Trial registration number ISRCTN83977250

Longterm results in the therapy of 100 cases of metastatic renal cell carcinoma (RCC)

International Nuclear Information System (INIS)

Falk, W.; Halama, J.M.; Halama, J.

1990-01-01

The success of renal cell carcinoma (RCC)-nephrectomy with radical lymph node dissection in stage I and II disease is undisputed. Through these measures 23% of metastases are controlled. The five-year survival time in stage III disease, however, stagnates at 35%±14% despite radical surgery. Also, the additional tumor-vaccine-therapy of the Mainz-Joint-Study-Group was successful only in stage I and II disease, whereas stage III disease did not benefit from this therapy. As 50% of all radically operated patients developed metastases within three years after surgery, the call by radiooncologists for supplementary radiotherapy beginning with stage III disease must be put foreward. The problems of therapy and chances of survival in generalized disease are demonstrated in 100 of our cases treated by surgery, radiotherapy and with MPA (medroxyprogesteroneacetate). Whereas Schmiedt et al. show a total survival time of 10.3 months after diagnosis of metastatic disease, the Offenbach patients achieved 16.5 months with a median survival time of 11.75 months. The necessity of therapeutic intervention is confirmed by the fact that the most favorable median survival time, 15.75 months, was achieved in metastatic disease involving three organs. We present here the special features of the individual organ manifestations and point out that not only the mean and median survival time, but also the very widely varying survival times in individual cases, make conscientious oncological post-treatment follow up and management a requirement. (orig.) [de

Metastatic clear cell carcinoma of the kidney: therapeutic role of bevacizumab

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Ronald M Bukowski

2010-03-01

Full Text Available Ronald M BukowskiCleveland Clinic Taussig Cancer Center, CCF Lerner College of Medicine of CWRU Cleveland, OH, USAAbstract: The biology and pathogenesis of clear cell carcinoma of the kidney has been extensively investgated, and the role of von Hipple-Landau gene inactivation and tumor associated angiogenesis is now recognized. Development of vascular endothelial growth factor inhibitors and phase 3 clinical trials utilizing this class of agents has produced a new treatment paradigm for patients with metastatic renal cell carcinoma (RCC. One of the active regimens identified is the combination of bevacizumab and interferon-α. Recently published reports provided evidence of the clinical and biologic activity of this therapy. The current manuscript reviews the background and rationale for the activity of bevacizumab in RCC, and results from recent clinical trials with this agent alone or in combination with targeted agents or cytokines. The role of this therapy in contrast to other targeted agents is reviewed, and the potential utility as well as questions raised by recent studies are discussed.Keywords: metastatic renal cell carcinoma, bevacizumab, interferon-α

Cabozantinib versus Everolimus in Advanced Renal-Cell Carcinoma

DEFF Research Database (Denmark)

Choueiri, Toni K; Escudier, Bernard; Powles, Thomas

2015-01-01

BACKGROUND: Cabozantinib is an oral, small-molecule tyrosine kinase inhibitor that targets vascular endothelial growth factor receptor (VEGFR) as well as MET and AXL, each of which has been implicated in the pathobiology of metastatic renal-cell carcinoma or in the development of resistance to an...

Circulating Tumor Cell Count Correlates with Colorectal Neoplasm Progression and Is a Prognostic Marker for Distant Metastasis in Non-Metastatic Patients

Science.gov (United States)

Tsai, Wen-Sy; Chen, Jinn-Shiun; Shao, Hung-Jen; Wu, Jen-Chia; Lai-Ming, Jr.; Lu, Si-Hong; Hung, Tsung-Fu; Chiu, Yen-Chi; You, Jeng-Fu; Hsieh, Pao-Shiu; Yeh, Chien-Yuh; Hung, Hsin-Yuan; Chiang, Sum-Fu; Lin, Geng-Ping; Tang, Reiping; Chang, Ying-Chih

2016-04-01

Enumeration of circulating tumor cells (CTCs) has been proven as a prognostic marker for metastatic colorectal cancer (m-CRC) patients. However, the currently available techniques for capturing and enumerating CTCs lack of required sensitivity to be applicable as a prognostic marker for non-metastatic patients as CTCs are even more rare. We have developed a microfluidic device utilizing antibody-conjugated non-fouling coating to eliminate nonspecific binding and to promote the multivalent binding of target cells. We then established the correlation of CTC counts and neoplasm progression through applying this platform to capture and enumerate CTCs in 2 mL of peripheral blood from healthy (n = 27), benign (n = 21), non-metastatic (n = 95), and m-CRC (n = 15) patients. The results showed that the CTC counts progressed from 0, 1, 5, to 36. Importantly, after 2-year follow-up on the non-metastatic CRC patients, we found that those who had ≥5 CTCs were 8 times more likely to develop distant metastasis within one year after curable surgery than those who had marker for the non-metastatic CRC patients who are at high risk of early recurrence.

Phase I-II study of everolimus and low-dose oral cyclophosphamide in patients with metastatic renal cell cancer

International Nuclear Information System (INIS)

Huijts, Charlotte M; Santegoets, Saskia J; Eertwegh, Alfons J van den; Pijpers, Laura S; Haanen, John B; Gruijl, Tanja D de; Verheul, Henk M; Vliet, Hans J van der

2011-01-01

For patients with metastatic renal cell cancer (mRCC) who progressed on vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitor therapy, the orally administered mammalian target of rapamycin (mTOR) inhibitor everolimus has been shown to prolong progression free survival. Intriguingly, inhibition of mTOR also promotes expansion of immunosuppressive regulatory T cells (Tregs) that can inhibit anti-tumor immune responses in a clinically relevant way in various tumor types including RCC. This study intends to investigate whether the antitumor efficacy of everolimus can be increased by preventing the detrimental everolimus induced expansion of Tregs using a metronomic schedule of cyclophosphamide. This phase I-II trial is a national multi-center study of different doses and schedules of low-dose oral cyclophosphamide in combination with a fixed dose of everolimus in patients with mRCC not amenable to or progressive after a VEGF-receptor tyrosine kinase inhibitor containing treatment regimen. In the phase I part of the study the optimal Treg-depleting dose and schedule of metronomic oral cyclophosphamide when given in combination with everolimus will be determined. In the phase II part of the study we will evaluate whether the percentage of patients progression free at 4 months of everolimus treatment can be increased from 50% to 70% by adding metronomic cyclophosphamide (in the dose and schedule determined in the phase I part). In addition to efficacy, we will perform extensive immune monitoring with a focus on the number, phenotype and function of Tregs, evaluate the safety and feasibility of the combination of everolimus and cyclophosphamide, perform monitoring of selected angiogenesis parameters and analyze everolimus and cyclophosphamide drug levels. This phase I-II study is designed to determine whether metronomic cyclophosphamide can be used to counter the mTOR inhibitor everolimus induced Treg expansion in patients with metastatic renal cell

Phase I-II study of everolimus and low-dose oral cyclophosphamide in patients with metastatic renal cell cancer

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Huijts Charlotte M

2011-11-01

Full Text Available Abstract Background For patients with metastatic renal cell cancer (mRCC who progressed on vascular endothelial growth factor (VEGF receptor tyrosine kinase inhibitor therapy, the orally administered mammalian target of rapamycin (mTOR inhibitor everolimus has been shown to prolong progression free survival. Intriguingly, inhibition of mTOR also promotes expansion of immunosuppressive regulatory T cells (Tregs that can inhibit anti-tumor immune responses in a clinically relevant way in various tumor types including RCC. This study intends to investigate whether the antitumor efficacy of everolimus can be increased by preventing the detrimental everolimus induced expansion of Tregs using a metronomic schedule of cyclophosphamide. Methods/design This phase I-II trial is a national multi-center study of different doses and schedules of low-dose oral cyclophosphamide in combination with a fixed dose of everolimus in patients with mRCC not amenable to or progressive after a VEGF-receptor tyrosine kinase inhibitor containing treatment regimen. In the phase I part of the study the optimal Treg-depleting dose and schedule of metronomic oral cyclophosphamide when given in combination with everolimus will be determined. In the phase II part of the study we will evaluate whether the percentage of patients progression free at 4 months of everolimus treatment can be increased from 50% to 70% by adding metronomic cyclophosphamide (in the dose and schedule determined in the phase I part. In addition to efficacy, we will perform extensive immune monitoring with a focus on the number, phenotype and function of Tregs, evaluate the safety and feasibility of the combination of everolimus and cyclophosphamide, perform monitoring of selected angiogenesis parameters and analyze everolimus and cyclophosphamide drug levels. Discussion This phase I-II study is designed to determine whether metronomic cyclophosphamide can be used to counter the mTOR inhibitor everolimus

Renal malignancies with normal excretory urograms

International Nuclear Information System (INIS)

Kass, D.A.; Hricak, H.; Davidson, A.J.

1983-01-01

Four patients with malignant renal masses showed no abnormality of excretory urograms with tomography. Of the four lesions, two were primary renal cell carcinomas, one was a metastatic focus from a contralateral renal cell carcinoma, and one was a metastatic lesion from rectal adenocarcinoma. A normal excretory urogram should not be considered sufficient to exclude a clinically suspected malignant renal mass. In such an instance, diagnostic evaluation should be pursued using a method capable of topographic anatomic display, such as computed tomography or sonography

Disease-specific survival in de novo metastatic renal cell carcinoma in the cytokine and targeted therapy era.

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Sumanta K Pal

Full Text Available Recent phase III studies of targeted agents for metastatic renal cell carcinoma (mRCC have generated median survival estimates that far exceed those observed during the cytokine era. However, substantial population-based data does not exist to confirm this trend. We sought to determine whether survival has improved for patients with mRCC diagnosed in the era of targeted therapies, as compared to the era of immunotherapy.The Surveillance, Epidemiology, and End Results (SEER Registry was used to identify patients aged 18 and older diagnosed stage IV RCC between 1992 and 2009. Patients had documented clear cell, papillary or chromophobe histology. The Kaplan Meier method and log-rank test were used to compare disease-specific survival (DSS for patients diagnosed from 1992-2004 (i.e., the cytokine era and 2005-2009 (i.e., the targeted therapy era. Univariate and multivariate analyses of relevant clinicopathologic characteristics were also performed.Of 5,176 patients identified using the above characteristics, 2,392 patients were diagnosed from 1992-2004 and 2,784 from 2005-2009. Median DSS was improved in those patients diagnosed from 2005-2009 (16 months vs 13 months; P<0.0001. A similar temporal trend towards improving survival was noted in patients with clear cell (P = 0.0006, but not in patients with non-clear cell disease (P = 0.32. Notable findings on multivariate analysis include an association between shorter DSS and the following characteristics: (1 diagnosis from 1992-2004, (2 advanced age (80+, and (3 absence of cytoreductive nephrectomy.These data reflect progress in the management of mRCC, specifically in the era of targeted therapies. Notably, it was inferred that certain treatment strategies were employed during pre-specified time periods, representing a major caveat of the current analysis. Further studies related to the influence of age and race/ethnicity are warranted, as are studies exploring the role of cytoreductive nephrectomy

Non-metastatic squamous cell carcinoma in two Hermann’s tortoises (Testudo hermanni

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Marie-Charlotte von Deetzen

2012-02-01

Full Text Available Squamous cell carcinomas (SCC are malignant tumors of the epidermal cells with varying degrees of keratinocyte differentiation. They are common tumors in mammalian and avian species but there are, however, only two description of SCC in tortoises. In this case report we describe two cases of non-metastatic squamous cell carcinomas of the carapax and the plastron in Hermann’s tortoises with evidence of humoral hypercalcemia of malignancy (HHM in one case. HHM is thought to be associated with SCC in mammals due to de novo secretion of parathyroid hormone-related protein (PTHrP by the tumor cells or tumor induced osteolysis but has not been described in reptiles so far.

Late pancreatic metastasis of renal cell carcinoma with absence of FDG-uptake in PET-CT

Directory of Open Access Journals (Sweden)

Elif Karadeli

2016-03-01

Full Text Available The primary tumors, which raise isolated pancreas metastases are frequently of renal origin, where colorectal cancer, melanoma, breast and lung cancers and sarcoma are the following causes of metastatic pancreas cancer . In this article, we present a case of pancreas-metastatic renal cell carcinoma with its radiological features, which did not exert anF-18 FDG-uptake in the whole-body positron emission tomography (PET. [Cukurova Med J 2016; 41(0.100: 92-94

Cardiac Murmur Prompting Diagnosis of Metastatic Nonseminomatous Germ Cell Testicular Neoplasia in an 18-Year-Old Patient

Directory of Open Access Journals (Sweden)

Steve Y. Chung

2005-01-01

Full Text Available Most retroperitoneal tumors such as renal cell carcinoma have been associated with tumor thrombus extending into the renal vein, inferior vena cava (IVC, and heart. The retroperitoneal metastatic potential of testicular tumors is well known. We report here the first instance of a cardiac murmur prompting diagnosis of metastatic testicular neoplasia in an 18-year-old patient. Chemotherapy was delayed and after successful surgical resection of the ventricular mass, the patient recovered uneventfully. This case underscores the need to pursue abnormal cardiac exams in newly diagnosed testicular cancer patients.

Increase of Circulating CD4(+)CD25(high)Foxp3(+) Regulatory T Cells in Patients With Metastatic Renal Cell Carcinoma During Treatment With Dendritic Cell Vaccination and Low-Dose Interleukin-2

DEFF Research Database (Denmark)

Berntsen, Annika; Brimnes, M.K.; Straten, P.T.

2010-01-01

Regulatory T cells (Treg) play an important role in the maintenance of immune tolerance and may be one of the obstacles of successful tumor immunotherapy. In this study, we analyzed the impact of administration of dendritic cell (DC) vaccination in combination with low-dose interleukin (IL)-2...... in patients with metastatic renal cell carcinoma on the frequency of CD4(+) CD25(high)Foxp3(+) Treg cells in peripheral blood. We found that the treatment increased the frequency of Treg cells more than 7-fold compared with pretreatment levels (P cells decreased when patients...... had been off IL-2 treatment for only 8 days, but remained higher than pretreatment levels. A functional assay showed that isolated Treg cells were capable of inhibiting proliferation of responder cells. Also, in vitro studies showed that coculture of mature DCs, autologous T cells and IL-2 leads...

Metastatic Mantle Cell Lymphoma to the Pituitary Gland: Case Report and Literature Review

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Arthur Wang

2016-01-01

Full Text Available We present an unusual case of a metastatic mantle cell lymphoma (MCL to the pituitary gland. The patient had a known history of MCL for which she previously received chemotherapy. She presented with new-onset diplopia and confusion, and reported a history of progressive vision blurriness associated with headache, nausea, and vomiting. MRI of the brain showed an enhancing lesion within the sella turcica involving the cavernous sinuses bilaterally, extending into Meckel's cave on the left, and abutting the optic nerves bilaterally. Following surgical excision, histopathology revealed the tumor to be a MCL. Metastatic pituitary tumors are rare and have been estimated to make up 1% of tumors discovered in the sellar region. The two most common secondary metastatic lesions to the sella are breast and lung carcinoma followed by prostate, renal cell, and gastrointestinal carcinoma. Metastatic lymphoma to the pituitary gland is especially rare and is estimated to constitute 0.5% of all metastatic tumors to the sella turcica. To our knowledge, this is the first reported case of MCL metastasizing to the pituitary gland.

Triiodothyronine regulates cell growth and survival in renal cell cancer.

Science.gov (United States)

Czarnecka, Anna M; Matak, Damian; Szymanski, Lukasz; Czarnecka, Karolina H; Lewicki, Slawomir; Zdanowski, Robert; Brzezianska-Lasota, Ewa; Szczylik, Cezary

2016-10-01

Triiodothyronine plays an important role in the regulation of kidney cell growth, differentiation and metabolism. Patients with renal cell cancer who develop hypothyreosis during tyrosine kinase inhibitor (TKI) treatment have statistically longer survival. In this study, we developed cell based model of triiodothyronine (T3) analysis in RCC and we show the different effects of T3 on renal cell cancer (RCC) cell growth response and expression of the thyroid hormone receptor in human renal cell cancer cell lines from primary and metastatic tumors along with human kidney cancer stem cells. Wild-type thyroid hormone receptor is ubiquitously expressed in human renal cancer cell lines, but normalized against healthy renal proximal tube cell expression its level is upregulated in Caki-2, RCC6, SKRC-42, SKRC-45 cell lines. On the contrary the mRNA level in the 769-P, ACHN, HKCSC, and HEK293 cells is significantly decreased. The TRβ protein was abundant in the cytoplasm of the 786-O, Caki-2, RCC6, and SKRC-45 cells and in the nucleus of SKRC-42, ACHN, 769-P and cancer stem cells. T3 has promoting effect on the cell proliferation of HKCSC, Caki-2, ASE, ACHN, SK-RC-42, SMKT-R2, Caki-1, 786-0, and SK-RC-45 cells. Tyrosine kinase inhibitor, sunitinib, directly inhibits proliferation of RCC cells, while thyroid hormone receptor antagonist 1-850 (CAS 251310‑57-3) has less significant inhibitory impact. T3 stimulation does not abrogate inhibitory effect of sunitinib. Renal cancer tumor cells hypostimulated with T3 may be more responsive to tyrosine kinase inhibition. Moreover, some tumors may be considered as T3-independent and present aggressive phenotype with thyroid hormone receptor activated independently from the ligand. On the contrary proliferation induced by deregulated VHL and or c-Met pathways may transgress normal T3 mediated regulation of the cell cycle.

Understanding familial and non-familial renal cell cancer.

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Bodmer, Daniëlle; van den Hurk, Wilhelmina; van Groningen, Jan J M; Eleveld, Marc J; Martens, Gerard J M; Weterman, Marian A J; van Kessel, Ad Geurts

2002-10-01

Molecular genetic analysis of familial and non-familial cases of conventional renal cell carcinoma (RCC) revealed a critical role(s) for multiple genes on human chromosome 3. For some of these genes, e.g. VHL, such a role has been firmly established, whereas for others, definite confirmation is still pending. Additionally, a novel role for constitutional chromosome 3 translocations as risk factors for conventional RCC development is rapidly emerging. Also, several candidate loci have been mapped to other chromosomes in both familial and non-familial RCCs of distinct histologic subtypes. The MET gene on chromosome 7, for example, was found to be involved in both forms of papillary RCC. A PRCC-TFE3 fusion gene is typically encountered in t(X;1)-positive non-familial papillary RCCs and results in abrogation of the cell cycle mitotic spindle checkpoint in a dominant-negative fashion, thus leading to RCC. Together, these data turn human RCC into a model system in which different aspects of both familial and non-familial syndromes may act as novel paradigms for cancer development.

Metastasis Targeted Therapies in Renal Cell Cancer

OpenAIRE

K. Fehmi Narter; Bora Özveren

2018-01-01

Metastatic renal cell cancer is a malignant disease and its treatment has been not been described clearly yet. These patients are generally symptomatic and resistant to current treatment modalities. Radiotherapy, chemotherapy, and hormonal therapy are not curative in many of these patients. A multimodal approach consisting of cytoreductive nephrectomy, systemic therapy (immunotherapy or targeted molecules), and metastasectomy has been shown to be hopeful in prolonging the survival and improvi...

Lymph node non-Hodgkin's lymphoma incidentally discovered during a nephrectomy for renal cell carcinoma.

Science.gov (United States)

Fernandez-Pello, Sergio; Rodriguez Villamil, Luis; Gonzalez Rodriguez, Ivan; Venta, Victoria; Cuervo, Javier; Menéndez, Carmen Luz

2013-06-16

We report the case of a left laparoscopic nephroureterectomy with the incidental discovery of a non-Hodgkin's lymphoma in one of the lymph nodes of the renal hilum. A laparoscopic nephroureterectomy was decided on for a 64-year-old man. Renal cell carcinoma in the kidney and one lymph node of the renal hilum with non-Hodgkin's lymphoma was found. Chemotherapy was not started for the lymphoma discovery. There are no signs of relapse after two years of follow up. Coexistence in the same patient is an extremely rare condition. We review the literature about this issue to clarify this association.

Non-small cell lung cancer: Spectral computed tomography quantitative parameters for preoperative diagnosis of metastatic lymph nodes

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Yang, Fengfeng [Department of Radiology, The Fourth Affiliated Hospital, Harbin Medical University, Harbin 150001 (China); Dong, Jie [Department of Geriatrics, The First Affiliated Hospital, Harbin Medical University, Harbin 150001 (China); Wang, Xiuting; Fu, Xiaojiao [Department of Radiology, The Fourth Affiliated Hospital, Harbin Medical University, Harbin 150001 (China); Zhang, Tong, E-mail: zt415@sina.com [Department of Radiology, The Fourth Affiliated Hospital, Harbin Medical University, Harbin 150001 (China)

2017-04-15

Objective: To investigate the application value of spectral computed tomography (CT)quantitative parameters for preoperative diagnosis of metastatic lymph nodes in patients with non-small cell lung cancer (NSLC). Methods: 84 patients with suspected lung cancer who underwent chest dual-phase enhanced scan with gemstone spectral CT imaging (GSI) mode were selected. GSI quantitative parameters including normalized iodine concentrations (NIC), water concentration, slope of the spectral Hounsfield unit curve (λHU) were measured. The two-sample t test was used to statistically compare these quantitative parameters. Receiver operating characteristic (ROC) curves were drawn to establish the optimal threshold values. Results: A total of 144 lymph nodes were included, with 48 metastatic lymph nodes and 96 non-metastatic lymph nodes. The slope of the spectral Hounsfeld unit curve (λHU) measured during both arterial and venous phases were signifcantly higher in metastatic than in benign lymph nodes (P < 0.05). The area under the ROC curve (AUC = 0.951) of λHU of the arterial phase (AP) was the largest. When the optimal threshold values of λHU was 2.75, the sensitivity, specificity, and overall accuracy in the diagnosis of metastatic lymph nodes were 88.2%, 88.4%, 87.0%, respectively. Conclusion: Conventional CT diagnostic criteria established in accordance with size (lymph node maximal short axis diameter ≥10 mm) as the basis for judging metastatic lymph node. In quantitative assessment using spectral CT imaging, quantitative parameters showed higher accuracy than qualitative assessment of conventional CT based on the size for preoperative diagnosis of metastatic lymph nodes.

Changing costs of metastatic non small cell lung cancer in the Netherlands.

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Keusters, W R; de Weger, V A; Hövels, A; Schellens, J H M; Frederix, G W J

2017-12-01

The primary objective of this study was to identify the total intramural cost of illness of metastatic non-small cell lung cancer (NSCLC) in the Netherlands between 2006-2012. Secondary objective was to identify whether changes in cost patterns of metastatic NSCLC have occurred over the last years. Patients diagnosed with metastatic NSCLC between 1-1-2006 and 31-12-2012, who had follow-up to death or the date of data cut-off and no trial participation were included. A structured chart review was performed using a case report form. Data collection started after diagnosis of metastatic NSCLC and ended at death or April first, 2015. Data regarding outpatient visits, clinical attendance, oncolytic drug use, imaging, lab tests, radiotherapy and surgery were collected. Sixty-seven patients were included with a median age of 67 years. The median follow-up was 234days. On average patients had 28 outpatient visits and 11 inpatient days. Oncolytic drugs were administered to 76% of the patients. Mean per patient expenditures amounted up to €17,463, with oncolytic drugs (€6,390) as the main cost driver. In comparison with the time-period of 2003-2005 total per patient per year expenses decreased by 44%. The contribution to total yearly costs of oncolytic drugs increased from 18% to 35%, while costs for inpatient stay decreased from 52% to 28% of total expenditures. Outcomes in this study demonstrate that average treatment costs for metastatic NSCLC in the Netherlands Cancer Institute amount to €17,463. Compared to a prior study the average cost for metastatic NSCLC over time in the Netherlands has decreased. A shift of main cost drivers seems to have occurred from inpatient stay, to oncolytic drugs as main contributor. The shift towards treatment cost might become more visible with the introduction of immunotherapy. These results mark the importance of up-to-date cost of illness studies. Copyright © 2017 Elsevier B.V. All rights reserved.

Monocytes and neutrophils as 'bad guys' for the outcome of interleukin-2 with and without histamine in metastatic renal cell carcinoma--results from a randomised phase II trial

DEFF Research Database (Denmark)

Donskov, F; Hokland, M; Marcussen, N

2006-01-01

Histamine (HDC) inhibits formation and release of phagocyte-derived reactive oxygen species, and thereby protects natural killer (NK) and T cells against oxidative damage. Thus, the addition of histamine may potentially improve the efficacy of interleukin-2 (IL-2). We have explored this potential...... mechanism clinically in two randomised phase II trials in metastatic renal cell carcinoma (mRCC). In parallel with the clinical trial in Denmark (n=63), we obtained serial blood samples and tumour biopsies searching for a potential histamine effect in situ. At baseline and on-treatment weeks 3 and 8, we...

Differentiation of Metastatic and Non-Metastatic Mesenteric Lymph Nodes by Strain Elastography in Surgical Specimens

DEFF Research Database (Denmark)

Havre, R F; Leh, S M; Gilja, O H

2016-01-01

Purpose: To investigate if strain elastography could differentiate between metastatic and non-metastatic mesenteric lymph nodes ex-vivo. Materials and Methods: 90 mesenteric lymph nodes were examined shortly after resection from 25 patients including 17 patients with colorectal cancer and 8...... patients with Crohn's disease. Ultrasound-based strain elastography was performed with a linear probe. Tissue hardness in lymph nodes was assessed using visual scales and measuring the strain ratio. B-mode characteristics were also recorded. Pathological diagnosis with grading of fibrosis served...... non-metastatic nodes, but the difference was not significant (65.5 vs. 55.0, p = 0.055). There was no difference between lymph nodes in Crohn's and non-metastatic cancer specimens. The metastatic lymph nodes were significantly more fibrotic than the non-metastatic lymph nodes by the ordinal fibrosis...

Sciatica leading to the discovery of a renal cell carcinoma | Lakmichi ...

African Journals Online (AJOL)

Metastatic renal cell cancer is not exceptional in kidney cancer (30% of patients with kidneyl cancer). Its prognosis is particularly severe. However, sciatic neuralgia (sciatica) remains an exceptional revealing clinical sign of this disease. The authors report the case of a patient admitted with right sciatica as chief complain, ...

Breast Cancer with Synchronous Renal Cell Carcinoma: A Rare Presentation.

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Arjunan, Ravi; Kumar, Durgesh; Kumar, K V Veerendra; Premlatha, C S

2016-10-01

Primary cancer arising from multiple organs is a well known fact. Synchronous tumours have been most commonly associated with kidney cancer. Bladder, prostate, colorectal and lung cancer are the most common synchronous primaries with Renal Cell Carcinoma (RCC) identified till date. We found metachronous tumours of breast with RCC in literature search which included both metastatic tumours as well second primaries. Overall, 25 cases of metastatic breast tumours and eight cases of second primary in previously treated RCC have been reported in the literature. Here, we are reporting a case of synchronous presentation of carcinoma breast with RCC which is very rare because most of the multiple malignancies reported in the literature are metastatic tumours or metachronous breast malignancy with RCC.

Brain natriuretic peptide precursor (NT-pro-BNP) levels predict for clinical benefit to sunitinib treatment in patients with metastatic renal cell carcinoma

International Nuclear Information System (INIS)

Papazisis, Konstantinos T; Kortsaris, Alexandros H; Kontovinis, Lukas F; Papandreou, Christos N; Kouvatseas, George; Lafaras, Christos; Antonakis, Evangelos; Christopoulou, Maria; Andreadis, Charalambos; Mouratidou, Despoina

2010-01-01

Sunitinib is an oral, multitargeted tyrosine kinase inhibitor that has been approved for the treatment of metastatic renal cell carcinoma. Although the majority of sunitinib-treated patients receive a clinical benefit, almost a third of the patients will not respond. Currently there is no available marker that can predict for response in these patients. We estimated the plasma levels of NT-pro-BNP (the N-terminal precursor of brain natriuretic peptide) in 36 patients that were treated with sunitinib for metastatic clear-cell renal carcinoma. From the 36 patients, 9 had progressive disease and 27 obtained a clinical benefit (objective response or disease stabilization). Increases in plasma NT-pro-BNP were strongly correlated to clinical outcome. Patients with disease progression increased plasma BNP at statistically significant higher levels than patients that obtained a clinical benefit, and this was evident from the first 15 days of treatment (a three-fold increase in patients with progressive disease compared to stable NT-pro-BNP levels in patients with clinical benefit, p < 0.0001). Median progression-free survival was 12.0 months in patients with less than 1.5 fold increases (n = 22) and 3.9 months in patients with more than 1.5 fold increases in plasma NT-pro-BNP (n = 13) (log-rank test, p = 0.001). This is the first time that a potential 'surrogate marker' has been reported with such a clear correlation to clinical benefit at an early time of treatment. Due to the relative small number of accessed patients, this observation needs to be further addressed on larger cohorts. More analyses, including multivariate analyses are needed before such an observation can be used in clinical practice

The option value of innovative treatments for non-small cell lung cancer and renal cell carcinoma.

Science.gov (United States)

Thornton Snider, Julia; Batt, Katharine; Wu, Yanyu; Tebeka, Mahlet Gizaw; Seabury, Seth

2017-10-01

To develop a model of the option value a therapy provides by enabling patients to live to see subsequent innovations and to apply the model to the case of nivolumab in renal cell carcinoma (RCC) and non-small cell lung cancer (NSCLC). A model of the option value of nivolumab in RCC and NSCLC was developed and estimated. Data from the Surveillance, Epidemiology, and End Results (SEER) cancer registry and published clinical trial results were used to estimate survival curves for metastatic cancer patients with RCC, squamous NSCLC, or nonsquamous NSCLC. To estimate the conventional value of nivolumab, survival with the pre-nivolumab standard of care was compared with survival with nivolumab assuming no future innovation. To estimate the option value of nivolumab, long-term survival trends in RCC and squamous and nonsquamous NSCLC were measured in SEER to forecast mortality improvements that nivolumab patients may live to see. Compared with the previous standard of care, nivolumab extended life expectancy by 6.3 months in RCC, 7.5 months in squamous NSCLC, and 4.5 months in nonsquamous NSCLC, according to conventional methods. Accounting for expected future mortality trends, nivolumab patients are likely to gain an additional 1.2 months in RCC, 0.4 months in squamous NSCLC, and 0.5 months in nonsquamous NSCLC. These option values correspond to 18%, 5%, and 10% of the conventional value of nivolumab, respectively. Option value is important when valuing therapies like nivolumab that extend life in a rapidly evolving area of care.

HLA class I expression predicts prognosis and therapeutic benefits from tyrosine kinase inhibitors in metastatic renal-cell carcinoma patients.

Science.gov (United States)

Wang, Jiajun; Liu, Li; Qu, Yang; Xi, Wei; Xia, Yu; Bai, Qi; Xiong, Ying; Long, Qilai; Xu, Jiejie; Guo, Jianming

2018-01-01

Classical HLA class I antigen is highly involved in antigen presentation and adaptive immune response against tumor. In this study, we explored its predictive value for treatment response and survival in metastatic renal-cell carcinoma (mRCC) patients. A TKI cohort of 111 mRCC patients treated with sunitinib or sorafenib and a non-TKI cohort of 160 mRCC patients treated with interleukin-2 or interferon-α-based immunotherapy at a single institution were retrospectively enrolled. HLA class I expression and cytotoxic T lymphocyte (CTL) density was assessed by immunohistochemistry on tissue microarrays. Association between HLA class I and CTL was also assessed in the TCGA KIRC cohort. In the TKI cohort, down-regulated HLA class I was associated with lower objective response rate of TKI therapy (P = 0.004), shorter overall survival (OS) (P = 0.001), and shorter progression free survival (PFS) (P class I was not significantly associated with survival. HLA class I expression was associated with CTL infiltration and function, and its prognostic value was more predominant in CTL high-density tumors (P class I expression can serve as a potential predictive biomarker for TKI therapy in mRCC patients. Its predictive value was restricted in CTL high-density tumors. However, further external validations and functional investigations are still required.

Dual energy CT allows for improved characterization of response to antiangiogenic treatment in patients with metastatic renal cell cancer

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Hellbach, K.; Sterzik, A.; Sommer, W.; Karpitschka, M.; Hummel, N.; Ingrisch, M.; Graser, A. [Ludwig-Maximilians-University Hospital Munich, Department of Clinical Radiology, Muenchen (Germany); Casuscelli, J.; Staehler, Michael [Ludwig-Maximilians-University Hospital Munich, Department of Urology, Muenchen (Germany); Schlemmer, M. [Krankenhaus Barmherzige Brueder Muenchen, Department of Palliative Care, Muenchen (Germany)

2017-06-15

To evaluate the potential role of dual energy CT (DECT) to visualize antiangiogenic treatment effects in patients with metastatic renal cell cancer (mRCC) while treated with tyrosine-kinase inhibitors (TKI). 26 patients with mRCC underwent baseline and follow-up single-phase abdominal contrast enhanced DECT scans. Scans were performed immediately before and 10 weeks after start of treatment with TKI. Virtual non-enhanced (VNE) and colour coded iodine images were generated. 44 metastases were measured at the two time points. Hounsfield unit (HU) values for VNE and iodine density (ID) as well as iodine content (IC) in mg/ml of tissue were derived. These values were compared to the venous phase DECT density (CTD) of the lesions. Values before and after treatment were compared using a paired Student's t test. Between baseline and follow up, mean CTD and DECT-derived ID both showed a significant reduction (p < 0.005). The relative reduction measured in percent was significantly greater for ID than for CTD (49.8 ± 36,3 % vs. 29.5 ± 20.8 %, p < 0.005). IC was also significantly reduced under antiangiogenic treatment (p < 0.0001). Dual energy CT-based quantification of iodine content of mRCC metastases allows for significantly more sensitive and reproducible detection of antiangiogenic treatment effects. (orig.)

Effect of ABO blood type on the outcomes of patients with metastatic renal cell carcinoma treated with first-line tyrosine kinase inhibitors.

Science.gov (United States)

Omae, Kenji; Fukuma, Shingo; Ikenoue, Tatsuyoshi; Kondo, Tsunenori; Takagi, Toshio; Ishihara, Hiroki; Tanabe, Kazunari; Fukuhara, Shunichi

2017-09-01

To assess the effect of blood type on survival outcomes and adverse events (AEs) in patients treated with tyrosine kinase inhibitors (TKIs) for metastatic renal cell carcinoma (mRCC). Patients who received TKIs as first-line therapy for mRCC between 2008 and 2015 at our hospital were included in the study (n = 136). Patients were divided into 2 groups based on their blood type as O and non-O. Survival outcomes and AEs were compared according to blood type. Cox regression models were used for univariate and multivariate survival analyses. Of the 136 patients, 34 (25%) and 102 (75%) had O and non-O blood types, respectively. Blood type O was associated with an increased number of disease sites. There were no differences between the 2 groups with respect to other baseline characteristics. The progression-free survival in patients with O and non-O blood types was 12.1 and 11.6 months, respectively; the overall survival was 34.4 and 24.8 months, respectively. On univariate and multivariate analyses, the ABO blood type was not a significant prognostic factor for progression-free survival or overall survival. Furthermore, the incidences of serious AEs were similar in the 2 blood groups. ABO blood type was not associated with survival outcomes or incidences of serious AEs in mRCC patients treated with TKIs. However, blood type O may be associated with an increased number of disease sites. Copyright © 2017. Published by Elsevier Inc.

Exposure-response relationships in patients with metastatic renal cell carcinoma receiving sunitinib: maintaining optimum efficacy in clinical practice.

Science.gov (United States)

Ravaud, Alain; Bello, Carlo L

2011-06-01

Targeted agents such as sunitinib, an oral, multitargeted receptor tyrosine kinase inhibitor, have greatly improved the prognosis for patients with metastatic renal cell carcinoma (mRCC). In this review we analyse data from sunitinib preclinical and clinical studies in detail and consider the key implications for the effective use of sunitinib in clinical practice. Sunitinib has shown efficacy and acceptable tolerability in patients with mRCC in phase II and III clinical studies. In a pivotal phase III study in treatment-naïve patients with mRCC, median progression-free survival for sunitinib-treated patients was double of that with interferon-α (P relationship between clinical end points and sunitinib exposure showed that increased sunitinib exposure was associated with a greater probability of objective response, longer time to tumour progression and overall survival, as well as some increased risk of specific adverse events. It is important to consider the relationship between exposure and response to maximize clinical benefit from sunitinib treatment.

Metastatic renal cell carcinoma – a case report

Directory of Open Access Journals (Sweden)

Grzegorz Wróbel

2017-09-01

Full Text Available Renal cell carcinoma (RCC is not a single uniform entity but a group of related neoplasms in which the histologic findings, cytogenetic abnormalities, biologic behavior and imaging appearances of the tumors are subtype dependent. PET-CT is the fusion of functional and anatomic information acquired almost simultaneously that lets us see the body and disease in a way that is diagnostically very powerful. The case concerns the result imaging 18F-fluorodeoxyglucose positron emission tomography (PET-CT to patient 47 years old (women is diagnosed with numerous changes in both lungs, the liver and the skeletal system in the abdominal lymph nodes. Primary change in left kidney is indicated. Metastasis is a process consisting of cells spreading from the primary site of the cancer to distant parts of the body. Functional imaging, particularly with PET–CT, might improve the accuracy of diagnosis and provide essential information that could allow clinicians to make more appropriate therapeutic decisions than they previously could without this technique.

Detection of Thyroid Metastasis pf Renal Transitional Cell Carcinoma Using FDG PET/CT

Energy Technology Data Exchange (ETDEWEB)

Kim, Yong Il; Kim, Yu Kyeong; Kim, Sang Eun [Seoul National Univ. Bundang Hospital, Seoul (Korea, Republic of); Lee, Jong Jin [Univ. of Ulsan College of Medicine, Seoul (Korea, Republic of); Paik, Jin Ho [Seoul National Univ. Bundang Hospital, Seoul (Korea, Republic of)

2011-06-15

A 69 year old man who was diagnosed with renal transitional cell carcinoma (TCC) underwent F 18 fluorodeoxyglucose (FDG) positron emission tomography with computed tomography (PET/CT) for detecting recurrence after chemotherapy. FDG PET/CT revealed multiple new hypermetabolic lesions in many places, including the right thyroid gland. Biopsy of the thyroid lesion was performed,and a diagnosis of metastatic TCC was made. We could detect thyroid metastasis of renal TCC by FDG PET/CT.

Validation of a short questionnaire to measure symptoms and functional limitations associated with hand-foot syndrome and mucositis in patients with metastatic renal cell carcinoma.

Science.gov (United States)

Lai, Jin-Shei; Beaumont, Jennifer L; Diaz, Jose; Khan, Sadya; Cella, David

2016-01-15

Hand-foot syndrome and mucositis/stomatitis are frequent adverse events (AEs) of treatment with tyrosine kinase inhibitors in cancer therapy. Quality-of-life instruments that measure the functional consequences of these AEs are needed to assess the impact of therapeutic interventions and to guide patient care. The Hand-Foot and Mucositis Symptom and Impact Questionnaire (HAMSIQ [formerly the Supplementary Quality of Life Questionnaire]) was used in the COMPARZ trial (Pazopanib vs Sunitinib in the Treatment of Locally Advanced and/or Metastatic Renal Cell Carcinoma [national clinical trial no. NCT00720941]) and the PISCES study (Patient Preference Study of Pazopanib vs Sunitinib in Advanced or Metastatic Kidney Cancer [clinicaltrials.gov NCT01064310]) to assess mouth/throat and hand/foot soreness symptoms and subsequent limitations in patients receiving pazopanib or sunitinib for metastatic renal cell carcinoma. The objective of the current analysis was to validate the HAMSIQ using data from the PISCES study. The HAMSIQ was administered in the PISCES study at baseline and every 2 weeks over two 10-week periods to patients who were receiving pazopanib or sunitinib. Data from the first 10-week period were used to assess the feasibility, validity, and responsiveness of the HAMSIQ. In total, ≥85% of 169 patients completed the HAMSIQ (excluding the item concerning days off work). Correlations among items within the same limitation subscale generally were high (Cronbach α ≥ .80). HAMSIQ limitation scores differentiated patients according to their baseline performance status and severity of soreness. Small-to-moderate correlations were observed for the symptoms/limitation scores and for changes from baseline scores between the HAMSIQ and the Functional Assessment of Chronic Illness Therapy fatigue survey. The HAMSIQ demonstrated responsiveness to changes in clinical status and the development of hand-foot syndrome AEs over time. The HAMSIQ is a feasible, valid

Editor’s Pick: Targeted Agents in Patients with Metastatic Renal Cell Carcinoma on Dialysis: Myths and Reality

Directory of Open Access Journals (Sweden)

Annalisa Guida

2016-07-01

Full Text Available Agents targeting the vascular endothelial growth factor (VEGF/VEGF receptor (VEGFR pathway, as well as mammalian target of rapamycin (mTOR inhibitors have revolutionised the therapeutic landscape of metastatic renal cell carcinoma (mRCC in the past decade, greatly improving the survival rates of these patients. However, translating results of registrative Phase III trials into everyday clinical practice is often troublesome, since real-world patients are completely different from those enrolled in randomised controlled Phase III trials. Prospective data on active oncological treatments in mRCC patients on dialysis are dramatically lacking. This literature review summarises and critically comments on available data relative to mRCC patients on dialysis receiving either VEGF/VEGFR-targeting agents, or mTOR inhibitors. Although prospective studies would definitely be warranted in these specific patient populations, all the available data suggest that mRCC patients on dialysis have the same outcome, both in terms of efficacy and safety, as mRCC patients with normal or marginally impaired kidney function, when treated with VEGF/VEGFR-targeting agents and/or mTOR inhibitors.

mTOR inhibitors in the treatment of advanced renal cell carcinoma

International Nuclear Information System (INIS)

Barilla, R.; Sycova-Mila, Z.

2009-01-01

Renal Cell Carcinoma (RCC) accounts for approximately 4 % of all malignancies. Much is known about the pathogenesis of RCC because of studies examining its close relationship with dysfunction of the Von Hippel-Lindau gene (VHL) and hypoxia inducible factor (HIF). Mammalian target of rapamycin (mTOR) regulates nutritional needs, cell growth, and angiogenesisi in cells by down regulating or up regulating a variety of proteins including HIF. Until 2005, only a single agent high dose interleukin 2 was approved by Food and Drug Administration (FDA) for treatment of advanced renal cell carcinoma. More recently thanks to better knowledge in the field of molecular biology new treatment options appeared. Sunitinib and bevacizumab are currently considered to be treatment of first choice for patients in good and intermediate prognostic group and sorafenib is preferred second line treatment in the same patient population pretreated with cytokines after disease progression. Temsirolimus and everolimus, rapamycin analouges, have recently been tested in III trials in first and second line treatment in patients with advanced metastatic clear cell renal cell carcinoma. (author)

Evaluation of resectability of renal cell carcinoma by computed tomography

International Nuclear Information System (INIS)

Hiramatsu, Yoshihiro; Matsumoto, Kunihiko; Tatezawa, Takashi; Kikuchi, Yoichi; Akisada, Masahiro; Kitagawa, Ryuichi

1982-01-01

Renal cell carcinoma is one of the unique neoplasm which is characterized by disappearing of the metastatic tumors after removal of the primary lesion. Angiography has been performed to evaluate the resectability of the primary tumor by nephrectomy in the past. With the use of computed tomography, detailed evaluation of the retroperitoneal structures is now possible. We have evaluated the resectability of renal cell tumor by computed tomography and compared the results with the angiographic findings and operative findings. Computed tomography is very accurate in determining the extent of the tumor especially in evaluation of tumor and the Gerota's fascia, which is essential to determine the resectability of the tumor. Informations about lymph node metastasis and invasion to the renal veins or inferior vena cava are also obtained.FIn most of the cases, angiography can be spared if computed tomography is properly performed. (author)

Role of everolimus in the treatment of renal cell carcinoma

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Saby George

2009-08-01

Full Text Available Saby George1, Ronald M Bukowski21University of Texas Health Sciences Center, MC-8221, Division of Hematology and Oncology, San Antonio, Texas, USA; 2CCF Lerner College of Medicine Division of Hematology and Oncology, Cleveland, Ohio, USAAbstract: The therapeutic options in metastatic renal cell carcinoma have been recently expanded by the discovery of the VHL gene, the mutation of which is associated with development of clear cell carcinoma, and overexpression of the angiogenesis pathway, resulting in a very vascular tumor. This breakthrough in science led to the development of a variety of small molecules inhibiting the VEGF-dependent angiogenic pathway, such as sunitinib and sorafenib. These agents prolong overall and progression-free survival, respectively. The result was the development of robust front-line therapies which ultimately fail and are associated with disease progression. In this setting, there existed an unmet need for developing second-line therapies for patients with refractory metastatic renal cell carcinoma (MRCC. Everolimus (RAD 001 is an oral inhibitor of the mammalian target of rapamycin (mTOR pathway. The double-blind, randomized, placebo-controlled phase III trial of everolimus (RECORD-1 conducted in MRCC patients after progression on sunitinib or sorafenib, or both, demonstrated a progression-free survival benefit favoring the study drug (4.9 months vs 1.9 months, HR 0.33, 95% CI 0.25 to 0.43, P ≤ 0 0.001. Everolimus thus established itself as a standard of care in the second-line setting for patients with MRCC who have failed treatment with VEGF receptor inhibitors.Keywords: mTOR inhibitor, mammalian target of rapamycin inhibitor, signal transduction inhibitor, renal cell carcinoma, targeted therapy

Adjuvant sunitinib or sorafenib for high-risk, non-metastatic renal-cell carcinoma (ECOG-ACRIN E2805): a double-blind, placebo-controlled, randomised, phase 3 trial

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Haas, Naomi B; Manola, Judith; Uzzo, Robert G; Flaherty, Keith T; Wood, Christopher G; Kane, Christopher; Jewett, Michael; Dutcher, Janice P; Atkins, Michael B; Pins, Michael; Wilding, George; Cella, David; Wagner, Lynne; Matin, Surena; Kuzel, Timothy M; Sexton, Wade J; Wong, Yu-Ning; Choueiri, Toni K; Pili, Roberto; Puzanov, Igor; Kohli, Manish; Stadler, Walter; Carducci, Michael; Coomes, Robert; DiPaola, Robert S

2016-01-01

Summary Background Renal-cell carcinoma is highly vascular, and proliferates primarily through dysregulation of the vascular endothelial growth factor (VEGF) pathway. We tested sunitinib and sorafenib, two oral anti-angiogenic agents that are effective in advanced renal-cell carcinoma, in patients with resected local disease at high risk for recurrence. Methods In this double-blind, placebo-controlled, randomised, phase 3 trial, we enrolled patients at 226 study centres in the USA and Canada. Eligible patients had pathological stage high-grade T1b or greater with completely resected non-metastatic renal-cell carcinoma and adequate cardiac, renal, and hepatic function. Patients were stratified by recurrence risk, histology, Eastern Cooperative Oncology Group (ECOG) performance status, and surgical approach, and computerised double-blind randomisation was done centrally with permuted blocks. Patients were randomly assigned (1:1:1) to receive 54 weeks of sunitinib 50 mg per day orally throughout the first 4 weeks of each 6 week cycle, sorafenib 400 mg twice per day orally throughout each cycle, or placebo. Placebo could be sunitinib placebo given continuously for 4 weeks of every 6 week cycle or sorafenib placebo given twice per day throughout the study. The primary objective was to compare disease-free survival between each experimental group and placebo in the intention-to-treat population. All treated patients with at least one follow-up assessment were included in the safety analysis. This trial is registered with ClinicalTrials.gov, number NCT00326898. Findings Between April 24, 2006, and Sept 1, 2010, 1943 patients from the National Clinical Trials Network were randomly assigned to sunitinib (n=647), sorafenib (n=649), or placebo (n=647). Following high rates of toxicity-related discontinuation after 1323 patients had enrolled (treatment discontinued by 193 [44%] of 438 patients on sunitinib, 199 [45%] of 441 patients on sorafenib), the starting dose of each

Decline in peripheral blood NKG2D+CD3+CD56+ NKT cells in metastatic colorectal cancer patients.

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Gharagozloo, M; Rezaei, A; Kalantari, H; Bahador, A; Hassannejad, N; Maracy, M; Nouri, N; Sedghi, M; Ghazanfari, H; Bayat, B

2018-01-01

Colorectal cancer (CRC) is one of the main causes of cancer deaths in the world. This cancer can be divided into non-metastatic and metastatic CRC stages. CD3+CD56+ NKT cell subsets are a minor T cell subset in peripheral blood and conduct the killing of tumor cells in direct manner. Little is obvious about levels and surface markers of these cells such as NKG2D in different cancers, especially in CRC. We included 15 non-metastatic (low-grade), 11 non-metastatic (high-grade), 10 metastatic colorectal cancer patients and 18 healthy controls. The percentages of CD3+CD56+ NKT cells and NKG2D+CD56+ NKT cells from samples were analyzed by flow cytometry in peripheral blood mononuclear cells (PBMCs) of samples. We found that there was a significantly lower number of NKG2D+CD3+CD56+ cells in peripheral blood of patients with metastatic colorectal cancer compared with normal controls (77.53 ± 5.79 % vs 90.74 ± 9.84 %; pNKT cells was significantly lower in patients with metastatic colorectal cancer compared to healthy controls strengthens the hypothesis that NKT cells can play a substantial role in the protection against human colorectal cancer, and this opens up avenues for novel studies about elucidating the other aspects of tumor surveillance in CRC progression and immunotherapy (Tab. 2, Fig. 2, Ref. 46).

Progression of renal cell carcinoma is inhibited by genistein and radiation in an orthotopic model

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Hillman, Gilda G; Wang, Yu; Che, Mingxin; Raffoul, Julian J; Yudelev, Mark; Kucuk, Omer; Sarkar, Fazlul H

2007-01-01

We have previously reported the potentiation of radiotherapy by the soy isoflavone genistein for prostate cancer using prostate tumor cells in vitro and orthotopic prostate tumor models in vivo. However, when genistein was used as single therapy in animal models, it promoted metastasis to regional para-aortic lymph nodes. To clarify whether these intriguing adverse effects of genistein are intrinsic to the orthotopic prostate tumor model, or these results could also be recapitulated in another model, we used the orthotopic metastatic KCI-18 renal cell carcinoma (RCC) model established in our laboratory. The KCI-18 RCC cell line was generated from a patient with papillary renal cell carcinoma. Following orthotopic renal implantation of KCI-18 RCC cells and serial in vivo kidney passages in nude mice, we have established a reliable and predictable metastatic RCC tumor model. Mice bearing established kidney tumors were treated with genistein combined with kidney tumor irradiation. The effect of the therapy was assessed on the primary tumor and metastases to various organs. In this experimental model, the karyotype and histological characteristics of the human primary tumor are preserved. Tumor cells metastasize from the primary renal tumor to the lungs, liver and mesentery mimicking the progression of RCC in humans. Treatment of established kidney tumors with genistein demonstrated a tendency to stimulate the growth of the primary kidney tumor and increase the incidence of metastasis to the mesentery lining the bowel. In contrast, when given in conjunction with kidney tumor irradiation, genistein significantly inhibited the growth and progression of established kidney tumors. These findings confirm the potentiation of radiotherapy by genistein in the orthotopic RCC model as previously shown in orthotopic models of prostate cancer. Our studies in both RCC and prostate tumor models demonstrate that the combination of genistein with primary tumor irradiation is a more

Store-Operated Ca2+ Entry Does Not Control Proliferation in Primary Cultures of Human Metastatic Renal Cellular Carcinoma

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Turin, Ilaria; Potenza, Duilio Michele; Bottino, Cinzia; Glasnov, Toma N.; Ferulli, Federica; Mosca, Alessandra; Guerra, Germano; Rosti, Vittorio; Luinetti, Ombretta; Porta, Camillo; Pedrazzoli, Paolo

2014-01-01

Store-operated Ca2+ entry (SOCE) is activated following depletion of the inositol-1,4,5-trisphosphate (InsP3)-sensitive Ca2+ pool to regulate proliferation in immortalized cell lines established from either primary or metastatic lesions. The molecular nature of SOCE may involve both Stim1, which senses Ca2+ levels within the endoplasmic reticulum (ER) Ca2+ reservoir, and a number of a Ca2+-permeable channels on the plasma membrane, including Orai1, Orai3, and members of the canonical transient receptor (TRPC1–7) family of ion channels. The present study was undertaken to assess whether SOCE is expressed and controls proliferation in primary cultures isolated from secondary lesions of heavily pretreated metastatic renal cell carcinoma (mRCC) patients. SOCE was induced following pharmacological depletion of the ER Ca2+ store, but not by InsP3-dependent Ca2+ release. Metastatic RCC cells express Stim1-2, Orai1–3, and TRPC1–7 transcripts and proteins. In these cells, SOCE was insensitive to BTP-2, 10 µM Gd3+ and Pyr6, while it was inhibited by 100 µM Gd3+, 2-APB, and carboxyamidotriazole (CAI). Neither Gd3+ nor 2-APB or CAI impaired mRCC cell proliferation. Consistently, no detectable Ca2+ signal was elicited by growth factor stimulation. Therefore, a functional SOCE is expressed but does not control proliferation of mRCC cells isolated from patients resistant to multikinase inhibitors. PMID:25126575

Store-Operated Ca2+ Entry Does Not Control Proliferation in Primary Cultures of Human Metastatic Renal Cellular Carcinoma

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Silvia Dragoni

2014-01-01

Full Text Available Store-operated Ca2+ entry (SOCE is activated following depletion of the inositol-1,4,5-trisphosphate (InsP3-sensitive Ca2+ pool to regulate proliferation in immortalized cell lines established from either primary or metastatic lesions. The molecular nature of SOCE may involve both Stim1, which senses Ca2+ levels within the endoplasmic reticulum (ER Ca2+ reservoir, and a number of a Ca2+-permeable channels on the plasma membrane, including Orai1, Orai3, and members of the canonical transient receptor (TRPC1–7 family of ion channels. The present study was undertaken to assess whether SOCE is expressed and controls proliferation in primary cultures isolated from secondary lesions of heavily pretreated metastatic renal cell carcinoma (mRCC patients. SOCE was induced following pharmacological depletion of the ER Ca2+ store, but not by InsP3-dependent Ca2+ release. Metastatic RCC cells express Stim1-2, Orai1–3, and TRPC1–7 transcripts and proteins. In these cells, SOCE was insensitive to BTP-2, 10 µM Gd3+ and Pyr6, while it was inhibited by 100 µM Gd3+, 2-APB, and carboxyamidotriazole (CAI. Neither Gd3+ nor 2-APB or CAI impaired mRCC cell proliferation. Consistently, no detectable Ca2+ signal was elicited by growth factor stimulation. Therefore, a functional SOCE is expressed but does not control proliferation of mRCC cells isolated from patients resistant to multikinase inhibitors.

ROLE OF THE MORPHOMETRIC PARAMETERS OF INTRATUMORAL MICROVESSELS AND THE PROLIFERATIVE ACTIVITY OF TUMOR CELLS IN RENAL CELL CARCINOMA

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N. A. Gorban

2014-08-01

Full Text Available Tumor cell proliferation and angiogenesis are essential factors for tumor growth, progression, and metastasis.Objective: to assess the relationship between the values of proliferative activity and the morphometric parameters of intratumoral microvessels in metastatic and localized carcinomas of the kidney.Materials and methods. Surgical specimens taken from 54 patients (32 men and 22 women aged 26 to 69 years (mean age 55 ± 1.5 years with the verified diagnosis of clear-cell renal cell carcinoma (RCC were studied.Conclusion. Proliferative activity and angioarchitectonics are an important biological characteristic of a tumor of unequal clinical value in RCC. Metastatic carcinoma has a higher proliferative activity and a low tumor vascularization than those of localized carcinoma.

Metastatic and non-metastatic lymph nodes. Quantification and different distribution of iodine uptake assessed by dual-energy CT

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Rizzo, Stefania [European Institute of Oncology, Department of Radiology, Milan (Italy); Radice, Davide [Department of Epidemiology and Biostatistics, Milan (Italy); Femia, Marco; Vigorito, Raffaella [Universita di Milano, Department of Health Sciences, Milan (Italy); De Marco, Paolo; Origgi, Daniela [Medical Physics, European Institute of Oncology, Milan (Italy); Preda, Lorenzo [Division of Radiology, National Centre of Oncological Hadrontherapy (CNAO Foundation), Pavia (Italy); University of Pavia, Department of Clinical, Surgical, Diagnostic and Paediatric Sciences, Pavia (Italy); Barberis, Massimo [European Institute of Oncology, Department of Pathology, Milan (Italy); Mauri, Giovanni [European Institute of Oncology, Division of Interventional Radiology, Milan (Italy); Mauro, Alberto [GE Medical Systems Italia SpA, Milan (Italy); Bellomi, Massimo [European Institute of Oncology, Department of Radiology, Milan (Italy); Universita di Milano, Department of Oncology, Milan (Italy)

2018-02-15

To evaluate quantification of iodine uptake in metastatic and non-metastatic lymph nodes (LNs) by dual-energy CT (DECT) and to assess if the distribution of iodine within LNs at DECT correlates with the pathological structure. Ninety LNs from 37 patients (23 with lung and 14 with gynaecological malignancies) were retrospectively selected. Information of LNs sent for statistical analysis included Hounsfield units (HU) at different energy levels; decomposition material densities fat-iodine, iodine-fat, iodine-water, water-iodine. Statistical analysis included evaluation of interobserver variability, material decomposition densities and spatial HU distribution within LNs. Interobserver agreement was excellent. There was a significant difference in iodine-fat and iodine-water decompositions comparing metastatic and non-metastatic LNs (p < 0.001); fat-iodine and water-iodine did not show significant differences. HU distribution showed a significant gradient from centre to periphery within non-metastatic LNs that was significant up to 20-30% from the centre, whereas metastatic LNs showed a more homogeneous distribution of HU, with no significant gradient. DECT demonstrated a lower iodine uptake in metastatic compared to non-metastatic LNs. Moreover, the internal iodine distribution showed an evident gradient of iodine distribution from centre to periphery in non-metastatic LNs, and a more homogeneous distribution within metastatic LNs, which corresponded to the pathological structure. (orig.)

The relationship of mast cells and angiogenesis with prognosis in renal cell carcinoma

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Guldur, M.E.; Kocarslan, S.; Dincoglu, D.

2014-01-01

Objective: To evaluate the effects of mast cell count and angiogenesis on the prognosis of renal cell carcinoma. Methods: The retrospective study was conducted at the Harran University, Sanliurfa, Turkey, and included 64 cases with diagnosis of renal cell carcinoma between 2002 and 2012. Immunohistochemical analysis was performed on paraffin sections using the standard streptavidin-biotin immunoperoxidase method. CD31 antibodies were used to identify microvessels in tumoural tissues. The microvessel density was calculated using a serological method. The mean vascular density was equivalent to the vascular surface area (in mm) per unit tissue volume (in mm) (MVD=mm). Mast cells tryptase antibody was used to evaluate the mast cell count in tumoural and non-tumoural tissues. The relationship between mast cell count and microvessel density was evaluated and compared with stage, grade, tumour diameter, and age. Results: The mast cell count in the tumoral tissue of renal cell carcinoma was significantly higher compared with non-neoplastic renal tissue (p 0.05). The intratumoural mast cell count in clear cell renal carcinoma was significantly higher compared with non-clear variety (p=0.001). No significant relationship was found between microvessel density, age, stage, diameter, or grade of the tumour and tumoral mast cell count (p>0.05). Conclusion: No significant association was found between the number of mast cells in tumoral tissue and microvessel density. Further studies are needed to demonstrate the effect of mast cells on angiogenesis in renal cell carcinoma. (author)

Transforming Growth Factor-β1 as a Novel Marker of Response to Therapy for Renal Cell Carcinoma.

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Adler, H L

2001-01-01

Renal cell carcinoma is expected to account for 30,000 new cancer cases and 11,900 cancer deaths in the United States in 1999 (1). At the time of initial presentation, up to one-third of patients with renal cell carcinoma (RCC) have metastatic disease; furthermore, almost half of the patients resected for cure will relapse (2). Due to the poor results of cytotoxic chemotherapy in the management of metastatic RCC (3), physicians have explored the use of new therapies including immunotherapy and gene therapy. Some of these therapies are discussed in other chapters of this textbook. The use of these new therapies allows for the identification and utilization of new tumor markers that may allow investigators to identify patients at risk for advanced disease as well as establish new definitions of tumor response.

Implications of Von Hippel-Lindau Syndrome and Renal Cell Carcinoma

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Kenan Ashouri

2015-09-01

Full Text Available Von Hippel-Lindau syndrome (VHLS is a rare hereditary neoplastic disorder caused by mutations in the vhl gene leading to the development of tumors in several organs including the central nervous system, pancreas, kidneys, and reproductive organs. Manifestations of VHLS can present at different ages based on the affected organ and subclass of disease. In the subclasses of VHLS that cause renal disease, renal involvement typically begins closer to the end of the second decade of life and can present in different ways ranging from simple cystic lesions to solid tumors. Mutations in vhl are most often associated with clear cell renal carcinoma, the most common type of renal cancer, and also play a major role in sporadic cases of clear cell renal carcinoma. The recurrent, multifocal nature of this disease presents difficult challenges in the long-term management of patients with VHLS. Optimization of renal function warrants the use of several different approaches common to the management of renal carcinoma such as nephron sparing surgery, enucleation, ablation, and targeted therapies. In VHLS, renal lesions of 3 cm or bigger are considered to have metastatic potential and even small lesions often harbor malignancy. Many of the aspects of management revolve around optimizing both oncologic outcome and long-term renal function. As new surgical strategies and targeted therapies develop, the management of this complex disease evolves.  This review will discuss the key aspects of the current management of VHLS.

Radiofrequency ablation of renal cell carcinoma under CT guidance. Present and Future status

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Nasu, Yasutomo; Kobayashi, Yasuyuki; Uematsu, Katsutoshi; Saika, Takashi; Kumon, Hiromi; Gohara, Hideo; Mimura, Hidefumi; Kanazawa, Susumu

2011-01-01

At Okayama University, radiofrequency ablation (RFA) of renal cell carcinoma was performed in May 2002 as the initial case in Japan. In 2004, it was regarded as an advanced medical technique by the Japanese authority. Since then, RFA has been actively performed for renal cell carcinoma not only at the primary site but also at the metastatic site, including the lung and bone. The clinical outcome has been compatible with other institutes and no serious adverse events have occurred. From the view paint of fusing technical innovation with medical safety, this treatment is a potent therapeutic option for renal cell carcinoma. In the era of laparoscopic surgery, RFA is indicated for cases with von Hippel-Lindau disease (VHL), recurrence after partial nephrectomy, a single kidney and intolerance to general anesthesia, due to its technical advantage in that RFA can be repeated. In this review, the current clinical outcome is reported and future prospects are discussed as to whether it can be the safest and most concrete treatment for renal cell carcinoma in the 21 st century. (author)

Radiotherapy as an immunological booster in patients with metastatic melanoma or renal cell carcinoma treated with high-dose Interleukin-2: evaluation of biomarkers of immunologic and therapeutic response.

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Ridolfi, Laura; de Rosa, Francesco; Ridolfi, Ruggero; Gentili, Giorgia; Valmorri, Linda; Scarpi, Emanuela; Parisi, Elisabetta; Romeo, Antonino; Guidoboni, Massimo

2014-09-23

Tumor cells killed by radiation therapy (RT) are a potentially good source of antigens for dendritic cell (DC) uptake and presentation to T-cells. RT upregulates cell death receptors such as Fas/CD95 and MHC-I, induces the expression of co-stimulatory molecules on tumor cells, and promotes production of pro-inflammatory cytokines. High-dose interleukin-2 (HD-IL-2) bolus has been shown to obtain objective response rates ranging from 15% to 17% in patients with metastatic melanoma or renal cell carcinoma (RCC), with 6% to 8% of cases experiencing a durable complete response. However, HD-IL-2 is also associated with severe side-effects; if it is to remain a component of the curative treatment strategy in patients with metastatic melanoma or RCC, its therapeutic efficacy must be improved and patients who are most likely to benefit from treatment must be identified a priori. We designed a clinical study combining immunomodulating RT and HD-IL-2 to evaluate their clinical and immunological efficacy and to explore the predictive and prognostic value of 1) tumor-specific immune response and 2) serum levels of proangiogenic cytokines. The primary endpoint of this proof-of-principle phase II study is immune response. Secondary endpoints are the identification of biomarkers potentially predictive of response, toxicity, response rate and overall survival. Three daily doses of booster radiotherapy (XRT) at 6-12 Gy will be administered to at least one metastatic field on days -3 to -1 before the first and third cycle. Treatment with IL-2 (dose 18 MIU/m2/day by continuous IV infusion for 72 hours) will start on day +1 and will be repeated every 3 weeks for up to 4 cycles and then every 4 weeks for a further 2 cycles. Immune response against tumor antigens expressed by melanoma and/or RCC will be evaluated during treatment. Circulating immune effectors and regulators, e.g. cytotoxic T lymphocytes and regulatory T cells, as well as serum levels of proangiogenic

Evaluation of dual energy spectral CT in differentiating metastatic from non-metastatic lymph nodes in rectal cancer: Initial experience

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Liu, Huanhuan [Department of Radiology, Ruijin Hospital Affiliated to Shanghai Jiaotong University, School of Medicine, Shanghai 200025 (China); Department of Radiology, Xinhua Hospital affiliated to Shanghai Jiaotong University School of Medicine (China); Yan, Fuhua; Pan, Zilai; Lin, Xiaozhu; Luo, Xianfu; Shi, Cen [Department of Radiology, Ruijin Hospital Affiliated to Shanghai Jiaotong University, School of Medicine, Shanghai 200025 (China); Chen, Xiaoyan [Department of Pathology, Ruijin Hospital Affiliated to Shanghai Jiaotong University, School of Medicine, Shanghai 200025 (China); Wang, Baisong [Department of Biomedical Statistics, Shanghai Jiaotong University, School of Medicine, Shanghai 200025 (China); Zhang, Huan, E-mail: huanzhangy@126.com [Department of Radiology, Ruijin Hospital Affiliated to Shanghai Jiaotong University, School of Medicine, Shanghai 200025 (China)

2015-02-15

Highlights: • Colorectal cancer is the third most prevalent cancer and the status of the regional lymph nodes in rectal cancer is considered to be one of the most powerful prognostic factor in the absence of distant metastatic disease. Detecting LNs metastasis is still a challenging problem due to the presence of microscopic metastasis or inflammatory swelling of LNs. • We investigated the value of dual energy spectral CT in differentiating metastatic from non-metastatic lymph nodes in rectal cancer. Our study demonstrated that the quantitative normalized iodine concentration (nIC) could be useful for differentiating metastatic and non-metastatic lymph nodes. The combination of nIC in portal venous phase and conventional size criterion could improve the diagnostic accuracy, sensitivity, specificity, positive predictive value and negative predictive value of rectal cancer. - Abstract: Objectives: To investigate the value of dual energy spectral CT (DEsCT) imaging in differentiating metastatic from non-metastatic lymph nodes in rectal cancer. Methods: Fifty-five patients with rectal cancer underwent the arterial phase (AP) and portal venous phase (PP) contrast-enhanced DEsCT imaging. The virtual monochromatic images and iodine-based material decomposition images derived from DEsCT imaging were interpreted for lymph nodes (LNs) measurement. The short axis diameter and the normalized iodine concentration (nIC) of metastatic and non-metastatic LNs were measured. The two-sample t test was used to compare the short axis diameters and nIC values of metastatic and non-metastatic LNs. ROC analysis was performed to assess the diagnostic performance. Results: One hundred and fifty two LNs including 92 non-metastatic LNs and 60 metastatic LNs were matched using the radiological-pathological correlation. The mean short axis diameter of metastatic LNs was significantly larger than that of the non-metastatic LNs (7.28 ± 2.28 mm vs. 4.90 ± 1.64 mm, P < 0.001). The mean n

Nivolumab versus Cabozantinib: Comparing Overall Survival in Metastatic Renal Cell Carcinoma.

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Witold Wiecek

Full Text Available Renal-cell carcinoma (RCC affects over 330,000 new patients every year, of whom 1/3 present with metastatic RCC (mRCC at diagnosis. Most mRCC patients treated with a first-line agent relapse within 1 year and need second-line therapy. The present study aims to compare overall survival (OS between nivolumab and cabozantinib from two recent pivotal studies comparing, respectively, each one of the two emerging treatments against everolimus in patients who relapse following first-line treatment. Comparison is traditionally carried out using the Bucher method, which assumes proportional hazard. Since OS curves intersected in one of the pivotal studies, models not assuming proportional hazards were also considered to refine the comparison. Four Bayesian parametric survival network meta-analysis models were implemented on overall survival (OS data digitized from the Kaplan-Meier curves reported in the studies. Three models allowing hazard ratios (HR to vary over time were assessed against a fixed-HR model. The Bucher method favored cabozantinib, with a fixed HR for OS vs. nivolumab of 1.09 (95% confidence interval: [0.77, 1.54]. However, all models with time-varying HR showed better fits than the fixed-HR model. The log-logistic model fitted the data best, exhibiting a HR for OS initially favoring cabozantinib, the trend inverting to favor nivolumab after month 5 (95% credible interval <1 from 10 months. The initial probability of cabozantinib conferring superior OS was 54%, falling to 41.5% by month 24. Numerical differences in study-adjusted OS estimates between the two treatments remained small. This study evidences that HR for OS of nivolumab vs. cabozantinib varies over time, favoring cabozantinib in the first months of treatment but nivolumab afterwards, a possible indication that patients with poor prognosis benefit more from cabozantinib in terms of survival, nivolumab benefiting patients with better prognosis. More evidence, including real

Drug Holiday in Metastatic Renal-Cell Carcinoma Patients Treated With Vascular Endothelial Growth Factor Receptor Inhibitors.

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Mittal, Kriti; Derosa, Lisa; Albiges, Laurence; Wood, Laura; Elson, Paul; Gilligan, Timothy; Garcia, Jorge; Dreicer, Robert; Escudier, Bernard; Rini, Brian

2018-01-04

Tyrosine kinase inhibitor (TKI) therapy in metastatic renal-cell carcinoma (mRCC) is noncurative and may be associated with significant toxicities. Some patients may receive treatment breaks as a result of TKI-related adverse effects or planned drug holidays. In this retrospective study, mRCC patients who underwent drug holidays during TKI therapy at 2 different institutions were analyzed. A drug holiday was defined as a period of drug cessation for ≥ 3 months for reasons other than progressive disease. Of the 112 patients, the median duration of the first drug holiday for the overall cohort was 16.8 months (95% confidence interval, 12.5-26.4), and 40 patients (36%) remain on the first drug holiday. Overall, patients received a median of 2 lines of treatment. Complete response before the initial drug holiday (n = 14) was associated with a longer surveillance period (P = .0004). The observed median survival of this cohort was 71.7 months (range, 1.3 to 93+ months). Some selected mRCC patients with a favorable response to TKIs may be eligible for drug holidays. The cohort evaluated in this retrospective study represents a highly selected group of patients with indolent disease biology. Copyright © 2018 Elsevier Inc. All rights reserved.

New advancements and developments in treatment of renal cell carcinoma: focus on pazopanib

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C Lance Cowey

2010-09-01

Full Text Available C Lance Cowey1, Guru Sonpavde2, Thomas E Hutson11Baylor-Sammons Cancer Center/Texas Oncology, PA, GU Oncology Program, Dallas, 2Baylor College of Medicine/Texas Oncology, PA, Houston, Texas, USAAbstract: With the recent approval of pazopanib, an oral multitargeted tyrosine kinase inhibitor which potently targets vascular endothelial growth factor receptors 1–3, platelet-derived growth factor, and c-kit, six agents are now available for use in the management of metastatic renal cell carcinoma (RCC. Pazopanib has shown improved progression-free survival compared with placebo in treatment-naïve or cytokine-treated patients with metastatic RCC in large Phase II and Phase III clinical trials. Pazopanib has demonstrated a tolerable side effect profile and is currently being compared with sunitinib in a Phase III noninferiority trial. In this review, the outcomes of the clinical testing of pazopanib are discussed, as well as a perspective on the placement of pazopanib among other approved agents.Keywords: renal cell carcinoma, targeted agents, vascular endothelial growth factor ­inhibitors, pazopanib

Metastasis in renal cell carcinoma: Biology and implications for therapy

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Jun Gong

2016-10-01

Full Text Available Although multiple advances have been made in systemic therapy for renal cell carcinoma (RCC, metastatic RCC remains incurable. In the current review, we focus on the underlying biology of RCC and plausible mechanisms of metastasis. We further outline evolving strategies to combat metastasis through adjuvant therapy. Finally, we discuss clinical patterns of metastasis in RCC and how distinct systemic therapy approaches may be considered based on the anatomic location of metastasis.

Bevacizumab Demonstrates Prolonged Disease Stabilization in Patients with Heavily Pretreated Metastatic Renal Cell Carcinoma: A Case Series and Review of the Literature

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Nicole M. Agostino

2010-01-01

Full Text Available There are now a variety of therapies approved for the treatment of metastatic renal cell carcinoma (RCC. These include the immunotherapeutics, alfa-interferon, and interleukin-2, and agents that target the vascular endothelial growth factor receptor (VEGFR via its tyrosine kinase, such as sorafenib, sunitinib, and pazopanib, or the mammalian target of rapamycin (mTOR, such as temsirolimus and everolimus. Bevacizumab, a monoclonal antibody directed against the ligand, VEGF, has shown activity against RCC as a single agent in patients who had failed prior cytokine therapy and as first line therapy in combination with interferon. The activity of bevacizumab in patients who had received and failed prior therapy has not been described. We report our experience in 4 patients with metastatic RCC who had failed prior cytokine, TKI, and mTOR inhibitors who were treated with bevacizumab as single agent therapy. These heavily pretreated patients sustained very prolonged periods of stable disease (median of 12 months with very little toxicity and excellent quality of life. The activity of this agent in patients who had failed prior therapies directed against the VEGFR and mTOR suggests that therapy targeting the ligand, VEGF, is still a viable approach in these patients and deserves further study.

Identification of tissue microRNAs predictive of sunitinib activity in patients with metastatic renal cell carcinoma.

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Celia Prior

Full Text Available To identify tissue microRNAs predictive of sunitinib activity in patients with metastatic renal-cell-carcinoma (MRCC and to evaluate in vitro their mechanism of action in sunitinib resistance.We screened 673 microRNAs using TaqMan Low-density-Arrays (TLDAs in tumors from MRCC patients with extreme phenotypes of marked efficacy and resistance to sunitinib, selected from an identification cohort (n = 41. The most relevant differentially expressed microRNAs were selected using bioinformatics-based target prediction analysis and quantified by qRT-PCR in tumors from patients presenting similar phenotypes selected from an independent cohort (n = 101. In vitro experiments were conducted to study the role of miR-942 in sunitinib resistance.TLDAs identified 64 microRNAs differentially expressed in the identification cohort. Seven candidates were quantified by qRT-PCR in the independent series. MiR-942 was the most accurate predictor of sunitinib efficacy (p = 0.0074. High expression of miR-942, miR-628-5p, miR-133a, and miR-484 was significantly associated with decreased time to progression and overall survival. These microRNAs were also overexpressed in the sunitinib resistant cell line Caki-2 in comparison with the sensitive cell line. MiR-942 overexpression in Caki-2 up-regulates MMP-9 and VEGF secretion which, in turn, promote HBMEC endothelial migration and sunitinib resistance.We identified differentially expressed microRNAs in MRCC patients presenting marked sensitivity or resistance to sunitinib. MiR-942 was the best predictor of efficacy. We describe a novel paracrine mechanism through which high miR-942 levels in MRCC cells up-regulates MMP-9 and VEGF secretion to enhance endothelial migration and sunitinib resistance. Our results support further validation of these miRNA in clinical confirmatory studies.

Human metastatic melanoma cell lines express high levels of growth hormone receptor and respond to GH treatment

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Sustarsic, Elahu G. [Edison Biotechnology Institute, 1 Watertower Drive, Athens, OH (United States); Department of Biological Sciences, Ohio University, Athens, OH (United States); Junnila, Riia K. [Edison Biotechnology Institute, 1 Watertower Drive, Athens, OH (United States); Kopchick, John J., E-mail: kopchick@ohio.edu [Edison Biotechnology Institute, 1 Watertower Drive, Athens, OH (United States); Department of Biological Sciences, Ohio University, Athens, OH (United States); Department of Biomedical Sciences, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH (United States)

2013-11-08

Highlights: •Most cancer types of the NCI60 have sub-sets of cell lines with high GHR expression. •GHR is highly expressed in melanoma cell lines. •GHR is elevated in advanced stage IV metastatic tumors vs. stage III. •GH treatment of metastatic melanoma cell lines alters growth and cell signaling. -- Abstract: Accumulating evidence implicates the growth hormone receptor (GHR) in carcinogenesis. While multiple studies show evidence for expression of growth hormone (GH) and GHR mRNA in human cancer tissue, there is a lack of quantification and only a few cancer types have been investigated. The National Cancer Institute’s NCI60 panel includes 60 cancer cell lines from nine types of human cancer: breast, CNS, colon, leukemia, melanoma, non-small cell lung, ovarian, prostate and renal. We utilized this panel to quantify expression of GHR, GH, prolactin receptor (PRLR) and prolactin (PRL) mRNA with real-time RT qPCR. Both GHR and PRLR show a broad range of expression within and among most cancer types. Strikingly, GHR expression is nearly 50-fold higher in melanoma than in the panel as a whole. Analysis of human metastatic melanoma biopsies confirmed GHR gene expression in melanoma tissue. In these human biopsies, the level of GHR mRNA is elevated in advanced stage IV tumor samples compared to stage III. Due to the novel finding of high GHR in melanoma, we examined the effect of GH treatment on three NCI60 melanoma lines (MDA-MB-435, UACC-62 and SK-MEL-5). GH increased proliferation in two out of three cell lines tested. Further analysis revealed GH-induced activation of STAT5 and mTOR in a cell line dependent manner. In conclusion, we have identified cell lines and cancer types that are ideal to study the role of GH and PRL in cancer, yet have been largely overlooked. Furthermore, we found that human metastatic melanoma tumors express GHR and cell lines possess active GHRs that can modulate multiple signaling pathways and alter cell proliferation. Based on

Cytological diagnosis of a rare case of cutaneous metastasis from transitional cell carcinoma, renal pelvis

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Pragya Singh

2017-12-01

Full Text Available Transitional cell carcinoma (TCC arising from renal pelvis rarely gives rise to cutaneous metastasis. Due to the insufficient literature, the exact incidence is not known till date. Moreover, the diagnosis is confirmed on histopathological examination with the aid of immunohistochemistry wherever needed. We are presenting a case of a 70-year-old female with metastatic TCC from the renal pelvis to the abdominal skin, which was diagnosed on cytology alone along with the cell block preparation. We also highlight the important cytomorphological and immunohistochemical features noted, which need to be known to avoid any diagnostic delay.

Management of Locally Advanced Renal Cell Carcinoma with Invasion of the Duodenum

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Andrew T. Schlussel

2013-01-01

Full Text Available Renal cell carcinoma (RCC is rare but aggressive, with greater than 20% of patients presenting with stage III or IV, disease. Surgical resection of the primary tumor regardless of stage is the treatment of choice, and en bloc resection of involved organs provides the only potential chance for cure. This case report describes a patient with metastatic right-sided RCC with invasion of the inferior vena cava and duodenum managed by en block resection and pancreaticoduodenectomy. This report will review the workup and treatment of locally advanced RCC, as well as the role of cytoreductive nephrectomy in the setting of metastatic disease.

Disseminated breast cancer cells acquire a highly malignant and aggressive metastatic phenotype during metastatic latency in the bone.

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Carolyn G Marsden

Full Text Available BACKGROUND: Disseminated tumor cells (DTCs in the bone marrow may exist in a dormant state for extended periods of time, maintaining the ability to proliferate upon activation, engraft at new sites, and form detectable metastases. However, understanding of the behavior and biology of dormant breast cancer cells in the bone marrow niche remains limited, as well as their potential involvement in tumor recurrence and metastasis. Therefore, the purpose of this study was to investigate the tumorigenicity and metastatic potential of dormant disseminated breast cancer cells (prior to activation in the bone marrow. METHODOLOGY/PRINCIPAL FINDINGS: Total bone marrow, isolated from mice previously injected with tumorspheres into the mammary fat pad, was injected into the mammary fat pad of NUDE mice. As a negative control, bone marrow isolated from non-injected mice was injected into the mammary fat pad of NUDE mice. The resultant tumors were analyzed by immunohistochemistry for expression of epithelial and mesenchymal markers. Mouse lungs, livers, and kidneys were analyzed by H+E staining to detect metastases. The injection of bone marrow isolated from mice previously injected with tumorspheres into the mammary fat pad, resulted in large tumor formation in the mammary fat pad 2 months post-injection. However, the injection of bone marrow isolated from non-injected mice did not result in tumor formation in the mammary fat pad. The DTC-derived tumors exhibited accelerated development of metastatic lesions within the lung, liver and kidney. The resultant tumors and the majority of metastatic lesions within the lung and liver exhibited a mesenchymal-like phenotype. CONCLUSIONS/SIGNIFICANCE: Dormant DTCs within the bone marrow are highly malignant upon injection into the mammary fat pad, with the accelerated development of metastatic lesions within the lung, liver and kidney. These results suggest the acquisition of a more aggressive phenotype of DTCs during

Percutaneous Cryoablation of Solitary, Sporadic Renal Cell Carcinoma: Outcome Analysis Based on Clear-Cell versus Papillary Subtypes.

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Haddad, Mustafa M; Schmit, Grant D; Kurup, A Nicholas; Schmitz, John J; Boorjian, Stephen A; Geske, Jennifer; Thompson, R Houston; Callstrom, Matthew R; Atwell, Thomas D

2018-06-07

To evaluate treatment outcomes with percutaneous cryoablation (PCA) based on renal cell carcinoma (RCC) histology. Patients treated with PCA for a solitary, sporadic stage T1a RCC from 2003 to 2016 were identified from a single institution's renal ablation registry. Patients with multiple tumors, history of RCC, or genetic syndromes associated with RCC (n = 60); no specific RCC subtype determined from core biopsy (n = 66); RCC subtype other than clear-cell or papillary (n = 7); or less than 3 mo of follow-up imaging (n = 5) were excluded. In total, 173 patients met study inclusion criteria. Oncologic outcomes, clinical outcomes, and complications were evaluated based on tumor subtype. Of the 173 patients who underwent PCA for a stage T1a RCC, 130 (75%) had clear-cell RCC (ccRCC) and 43 (25%) had papillary RCC (pRCC). Median tumor size was 2.9 cm (range, 1.3-4.0 cm). Technically successful cryoablation was achieved in all 173 patients. Local tumor recurrence developed in 6 patients with ccRCC (4.6%), new renal tumors developed in 1 patient (0.8%), and metastatic RCC developed in 1 patient (0.8%) who also had local tumor recurrence. No patients with pRCC showed local tumor recurrence, new renal tumors, or metastatic disease. The 5-year disease-free survival rate in patients with ccRCC was 88%, compared with 100% in patients with pRCC (P = .48). Nine patients (5.2%), all with ccRCC, experienced major complications (P = .11). Percutaneous ablation is a viable treatment option for patients with clinical stage T1a pRCC and ccRCC. Percutaneous ablation may be a very favorable treatment strategy particularly for pRCC. Copyright © 2018 SIR. Published by Elsevier Inc. All rights reserved.

Renal cell carcinoma: histological classification and correlation with imaging findings

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Muglia, Valdair F., E-mail: fmuglia@fmrp.usp.br [Universidade de Sao Paulo (CCIFM/FMRP/USP), Ribeirao Preto, SP (Brazil). Centro de Ciencias das Imagens e Fisica Medica. Faculdade de Medicina; Prando, Adilson [Universidade Estadual de Campinas (UNICAMP), SP (Brazil); Hospital Vera Cruz, Campinas, SP (Brazil). Dept. de Imaginologia

2015-05-15

Renal cell carcinoma (RCC) is the seventh most common histological type of cancer in the Western world and has shown a sustained increase in its prevalence. The histological classification of RCCs is of utmost importance, considering the significant prognostic and therapeutic implications of its histological subtypes. Imaging methods play an outstanding role in the diagnosis, staging and follow-up of RCC. Clear cell, papillary and chromophobe are the most common histological subtypes of RCC, and their preoperative radiological characterization, either followed or not by confirmatory percutaneous biopsy, may be particularly useful in cases of poor surgical condition, metastatic disease, central mass in a solitary kidney, and in patients eligible for molecular targeted therapy. New strategies recently developed for treating renal cancer, such as cryo and radiofrequency ablation, molecularly targeted therapy and active surveillance also require appropriate preoperative characterization of renal masses. Less common histological types, although sharing nonspecific imaging features, may be suspected on the basis of clinical and epidemiological data. The present study is aimed at reviewing the main clinical and imaging findings of histological RCC subtypes. (author)

Metastases of Renal Cell Carcinoma to the Thyroid Gland with Synchronous Benign and Malignant Follicular Cell-Derived Neoplasms

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Carlos Zamarrón

2013-01-01

Full Text Available Clear cell renal cell carcinoma (CCRCC is the most common origin for metastasis in the thyroid. A 51-year-old woman was referred to our hospital for a subcarinal lesion. Ten years before, the patient had undergone a nephrectomy for CCRCC. Whole-body fluorodeoxyglucose positron emission tomography revealed elevated values in the thyroid gland, while the mediastinum was normal. An endoscopic ultrasonography-guided fine-needle aspiration biopsy of the mediastinal mass was consistent with CCRCC, and this was confirmed after resection. The thyroidectomy specimen also revealed lymphocytic thyroiditis, nodular hyperplasia, one follicular adenoma, two papillary microcarcinomas, and six foci of metastatic CCRCC involving both thyroid lobes. Curiously two of the six metastatic foci were located inside two adenomatoid nodules (tumor-in-tumor. The metastatic cells were positive for cytokeratins, CD10, epidermal growth factor receptor, and vascular endothelial growth factor receptor 2. No BRAF gene mutations were found in any of the primary and metastatic lesions. The patient was treated with sunitinib and finally died due to CCRCC distant metastases 6 years after the thyroidectomy. In CCRCC patients, a particularly prolonged survival rate may be achieved with the appropriate therapy, in contrast to the ominous prognosis typically found in patients with thyroid metastases from other origins.

Long-term survival in an adolescent with widely metastatic renal cell carcinoma with rhabdoid features.

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Ettinger, L J; Goodell, L A; Javidian, P; Hsieh, Y; Amenta, P

2000-01-01

Renal cell carcinoma is rarely seen in children and adolescents. Patients with widespread disease at diagnosis have a particularly poor survival rate. Currently, all known chemotherapy has been ineffective in improving the median survival in patients with advanced disease. A 13-year-old black boy with stage IV renal cell carcinoma with rhabdoid features is a long-term disease-free survivor after aggressive multiagent chemotherapy. After the initial evaluation and histologic diagnosis of renal cell carcinoma, the patient received three courses of an aggressive chemotherapy regimen consisting of vincristine, doxorubicin, cyclophosphamide with mesna uroprotection, granulocyte colony-stimulating factor and erythropoietin (Epogen). After an almost complete response, a radical nephrectomy was performed and results demonstrated a solitary small nodule with viable tumor. After surgery, he received floxuridine infusion for 14 days by circadian schedule at 28-day intervals for a total of 1 year. The patient is well and free of disease 5 years after initial presentation. The dramatic response to treatment and long-term disease-free survival of this patient suggest this chemotherapeutic approach warrants additional investigation.

Conditionally reprogrammed cells (CRC) methodology does not allow the in vitro expansion of patient-derived primary and metastatic lung cancer cells.

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Sette, Giovanni; Salvati, Valentina; Giordani, Ilenia; Pilozzi, Emanuela; Quacquarini, Denise; Duranti, Enrico; De Nicola, Francesca; Pallocca, Matteo; Fanciulli, Maurizio; Falchi, Mario; Pallini, Roberto; De Maria, Ruggero; Eramo, Adriana

2018-07-01

Availability of tumor and non-tumor patient-derived models would promote the development of more effective therapeutics for non-small cell lung cancer (NSCLC). Recently, conditionally reprogrammed cells (CRC) methodology demonstrated exceptional potential for the expansion of epithelial cells from patient tissues. However, the possibility to expand patient-derived lung cancer cells using CRC protocols is controversial. Here, we used CRC approach to expand cells from non-tumoral and tumor biopsies of patients with primary or metastatic NSCLC as well as pulmonary metastases of colorectal or breast cancers. CRC cultures were obtained from both tumor and non-malignant tissues with extraordinary high efficiency. Tumor cells were tracked in vitro through tumorigenicity assay, monitoring of tumor-specific genetic alterations and marker expression. Cultures were composed of EpCAM+ lung epithelial cells lacking tumorigenic potential. NSCLC biopsies-derived cultures rapidly lost patient-specific genetic mutations or tumor antigens. Similarly, pulmonary metastases of colon or breast cancer generated CRC cultures of lung epithelial cells. All CRC cultures examined displayed epithelial lung stem cell phenotype and function. In contrast, brain metastatic lung cancer biopsies failed to generate CRC cultures. In conclusion, patient-derived primary and metastatic lung cancer cells were negatively selected under CRC conditions, limiting the expansion to non-malignant lung epithelial stem cells from either tumor or non-tumor tissue sources. Thus, CRC approach cannot be applied for direct therapeutic testing of patient lung tumor cells, as the tumor-derived CRC cultures are composed of (non-tumoral) airway basal cells. © 2018 UICC.

A pooled analysis of sequential therapies with sorafenib and sunitinib in metastatic renal cell carcinoma.

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Stenner, Frank; Chastonay, Rahel; Liewen, Heike; Haile, Sarah R; Cathomas, Richard; Rothermundt, Christian; Siciliano, Raffaele D; Stoll, Susanna; Knuth, Alexander; Buchler, Tomas; Porta, Camillo; Renner, Christoph; Samaras, Panagiotis

2012-01-01

To evaluate the optimal sequence for the receptor tyrosine kinase inhibitors (rTKIs) sorafenib and sunitinib in metastatic renal cell cancer. We performed a retrospective analysis of patients who had received sequential therapy with both rTKIs and integrated these results into a pooled analysis of available data from other publications. Differences in median progression-free survival (PFS) for first- (PFS1) and second-line treatment (PFS2), and for the combined PFS (PFS1 plus PFS2) were examined using weighted linear regression. In the pooled analysis encompassing 853 patients, the median combined PFS for first-line sunitinib and 2nd-line sorafenib (SuSo) was 12.1 months compared with 15.4 months for the reverse sequence (SoSu; 95% CI for difference 1.45-5.12, p = 0.0013). Regarding first-line treatment, no significant difference in PFS1 was noted regardless of which drug was initially used (0.62 months average increase on sorafenib, 95% CI for difference -1.01 to 2.26, p = 0.43). In second-line treatment, sunitinib showed a significantly longer PFS2 than sorafenib (average increase 2.66 months, 95% CI 1.02-4.3, p = 0.003). The SoSu sequence translates into a longer combined PFS compared to the SuSo sequence. Predominantly the superiority of sunitinib regarding PFS2 contributed to the longer combined PFS in sequential use. Copyright © 2012 S. Karger AG, Basel.

Is post-operative radiation for renal cell carcinoma justified?

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Aref, Ibrahim; Bociek, R. Gregory; Salhani, Douglas

1997-01-01

Purpose: To identify the pattern of failure in patients with resected renal cell carcinoma (RCC). Materials and methods: The records of 116 patients with unilateral, non-hematogenous metastatic RCC who were treated with definitive surgery and referred to the Ottawa Regional Cancer Centre between 1977 and 1988 were reviewed. Distribution by stage included T1 (3 patients), T2 (42 patients) and T3 (71 patients). The median follow-up was 44 months, with a range of 4-267 months. Results: Local regional failure (LRF) developed in 8 patients. Nine patients developed local or regional recurrence, plus distant failure. Fifty-eight patients had distant metastases (DM) only. The 7-year actuarial rate for LRF and DM were 12%, and 67%, respectively. The overall 7-year actuarial survival rate was 35%, and cause-specific survival was 42%. Conclusions: LRF alone is rare following nephrectomy. DM is the main pattern of failure. This data does not support the role of adjuvant radiation therapy in this disease

Hepatoma SK Hep-1 cells exhibit characteristics of oncogenic mesenchymal stem cells with highly metastatic capacity.

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Jong Ryeol Eun

Full Text Available SK Hep-1 cells (SK cells derived from a patient with liver adenocarcinoma have been considered a human hepatoma cell line with mesenchymal origin characteristics, however, SK cells do not express liver genes and exhibit liver function, thus, we hypothesized whether mesenchymal cells might contribute to human liver primary cancers. Here, we characterized SK cells and its tumourigenicity.We found that classical mesenchymal stem cell (MSC markers were presented on SK cells, but endothelial marker CD31, hematopoietic markers CD34 and CD45 were negative. SK cells are capable of differentiate into adipocytes and osteoblasts as adipose-derived MSC (Ad-MSC and bone marrow-derived MSC (BM-MSC do. Importantly, a single SK cell exhibited a substantial tumourigenicity and metastatic capacity in immunodefficient mice. Metastasis not only occurred in circulating organs such as lung, liver, and kidneys, but also in muscle, outer abdomen, and skin. SK cells presented greater in vitro invasive capacity than those of Ad-MSC and BM-MSC. The xenograft cells from subcutaneous and metastatic tumors exhibited a similar tumourigenicity and metastatic capacity, and showed the same relatively homogenous population with MSC characteristics when compared to parental SK cells. SK cells could unlimitedly expand in vitro without losing MSC characteristics, its tumuorigenicity and metastatic capacity, indicating that SK cells are oncogenic MSC with enhanced self-renewal capacity. We believe that this is the first report that human MSC appear to be transformed into cancer stem cells (CSC, and that their derivatives also function as CSCs.Our findings demonstrate that SK cells represent a transformation mechanism of normal MSC into an enhanced self-renewal CSC with metastasis capacity, SK cells and their xenografts represent a same relative homogeneity of CSC with substantial metastatic capacity. Thus, it represents a novel mechanism of tumor initiation, development and

The role of radiation therapy in multimodality treatment for renal-cell cancer

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Semikoz, N.G.; Kudryashov, O.G.; Ponomar'ov, V.V.; Osipenkov, R.A.; Anyishchenko, A.O.; Kudryashova, S.M.

2011-01-01

The authors report the results of multimodality treatment for renal-cell cancer (pT any, N any, M0) using pre- operative large-fraction irradiation. Our findings demonstrate that radiation therapy does not aggravate the conditions for surgery and improves long-term results. The data about efficacy of multimodality treatment (palliative nephrectomy with radiation therapy) in patients with primary metastatic kidney cancer T any, N any, M1) are also reported.

Unusual Upper Gastrointestinal Bleeding due to Late Metastasis from Renal Cell Carcinoma: A Case Report

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Wen-Tsan Chang

2004-03-01

Full Text Available A case of recurrent massive upper gastrointestinal bleeding originating from metastatic renal cell carcinoma is reported. A 63-year-old woman underwent right nephrectomy 9 years previously and experienced no recurrence during follow-up. A gradually enlarging ulcerative tumor over the bulb of the duodenum and four subsequent episodes of massive bleeding from this tumor occurred between June 2001 and March 2002. The patient underwent surgery in April 2002 for intractable bleeding from the tumor. Renal cell carcinoma metastasis to the duodenum was confirmed from the surgical specimen. Upper gastrointestinal bleeding due to malignancy is very rare and the duodenum is the least frequently involved site. Furthermore, a solitary late renal cell carcinoma metastasis 9 years after a nephrectomy is extremely uncommon. This case suggests that life-long follow-up of renal cell carcinoma patients is necessary, owing to unpredictable behavior and the possibility of long disease-free intervals. In nephrectomized patients suffering from gastrointestinal bleeding, complete evaluation, especially endoscopic examination, is indicated. The possibility of late recurrent renal cell carcinoma metastasis to the gastrointestinal tract should be kept in mind, although it is rare. If the patient is fit for surgery, metastatectomy is the first choice of treatment.

Neutrophil-to-lymphocyte Ratio, Platelet-to-lymphocyte Ratio, and C-reactive Protein as New and Simple Prognostic Factors in Patients With Metastatic Renal Cell Cancer Treated With Tyrosine Kinase Inhibitors: A Systemic Review and Meta-analysis.

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Semeniuk-Wojtaś, Aleksandra; Lubas, Arkadiusz; Stec, Rafał; Syryło, Tomasz; Niemczyk, Stanisław; Szczylik, Cezary

2018-02-02

Inflammation plays a crucial role in cancer development. In this study, we evaluate the prognostic values of systemic inflammation markers such as neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and C-reactive protein (CRP) for the progression-free survival and overall survival in patients with metastatic renal cell carcinoma treated with tyrosine kinase inhibitors. PubMed and the Cochrane Library databases were searched for published studies on the effect of NLR, PLR, and CRP in patients with metastatic renal cell carcinoma treated with tyrosine kinase inhibitors. In the meta-analysis, NLR (hazard ratio [HR], 2.01; 95% confidence interval [CI], 1.27-3.18; P = .003) and PLR (HR, 6.96; 95% CI, 5.04-9.62; P < .001) had a significant influence on progression-free survival, whereas all considered proinflammatory markers had a significant impact on overall survival: NLR (HR, 2.14; 95% CI, 1.67-2.73; P < .001), PLR (HR, 14.67; 95% CI, 11.10-19.57; P < .001), and CRP (HR, 1.96; 95% CI, 1.26-3.05; P = .003). Inflammation markers such as NLR, PLR, and CRP are predictors of clinical outcome and could provide additional information to individualize treatment. Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.

COMBINED TREATMENT OF RENAL CELL CARCINOMA METASTASIS LOCATED IN THE HUMERUS WITH RECONSTRUCTIVE PLASTIC SURGERY STAGE

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S. A. Ivanov

2014-01-01

Full Text Available In the recent years, the effectiveness of the treatment of even advanced cases of metastatic renal cell carcinoma is relatively high due to the possibility of targeted therapy, removal of metastatic lesions. Therefore, the issue of the quality of life of such patients often comes to the fore. This paper presents a clinical case of radical surgical treatment of metastasis located in the humerus, resulting in partial recovery of the limb function which eventually led to the improvement of the patient’s quality of life.

Outcomes of Patients with Renal Cell Carcinoma and Sarcomatoid Dedifferentiation Treated with Nephrectomy and Systemic Therapies: Comparison between the Cytokine and Targeted Therapy Eras.

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Keskin, Sarp K; Msaouel, Pavlos; Hess, Kenneth R; Yu, Kai-Jie; Matin, Surena F; Sircar, Kanishka; Tamboli, Pheroze; Jonasch, Eric; Wood, Christopher G; Karam, Jose A; Tannir, Nizar M

2017-09-01

We studied overall survival and prognostic factors in patients with sarcomatoid renal cell carcinoma treated with nephrectomy and systemic therapy in the cytokine and targeted therapy eras. This is a retrospective study of patients with sarcomatoid renal cell carcinoma who underwent nephrectomy and received systemic therapy at our center in the cytokine era (1987 to 2005) or the targeted therapy era (2006 to 2015). Multivariate regression models were used to determine the association of covariables with survival. Of the 199 patients with sarcomatoid renal cell carcinoma 167 (83.9%) died (median overall survival 16.5 months, 95% CI 15.2-20.9). Survival of patients with clear cell histology was significantly longer vs those with nonclear cell histology (p = 0.034). Patients with synchronous metastatic disease had significantly shorter survival than patients with metachronous metastatic disease (median 12.1 vs 23.3 months, p = 0.0064). Biopsy of the primary tumor or a metastatic site could detect the presence of sarcomatoid features in only 7.5% of cases. Although a significant improvement in survival rate was observed in the first year in patients treated in the targeted therapy era (p = 0.011), this effect was attenuated at year 2, disappeared at years 3 to 5 after diagnosis and was not evident in patients with poor risk features. Patients with sarcomatoid renal cell carcinoma still have poor prognosis with no clear long-term benefit of targeted therapy. This underscores the need to develop more effective systemic therapies for these patients. Copyright © 2017 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

TAZ is required for metastatic activity and chemoresistance of breast cancer stem cells.

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Bartucci, M; Dattilo, R; Moriconi, C; Pagliuca, A; Mottolese, M; Federici, G; Benedetto, A Di; Todaro, M; Stassi, G; Sperati, F; Amabile, M I; Pilozzi, E; Patrizii, M; Biffoni, M; Maugeri-Saccà, M; Piccolo, S; De Maria, R

2015-02-05

Metastatic growth in breast cancer (BC) has been proposed as an exclusive property of cancer stem cells (CSCs). However, formal proof of their identity as cells of origin of recurrences at distant sites and the molecular events that may contribute to tumor cell dissemination and metastasis development are yet to be elucidated. In this study, we analyzed a set of patient-derived breast cancer stem cell (BCSC) lines. We found that in vitro BCSCs exhibit a higher chemoresistance and migratory potential when compared with differentiated, nontumorigenic, breast cancer cells (dBCCs). By developing an in vivo metastatic model simulating the disease of patients with early BC, we observed that BCSCs is the only cell population endowed with metastatic potential. Gene-expression profile studies comparing metastagenic and non-metastagenic cells identified TAZ, a transducer of the Hippo pathway and biomechanical cues, as a central mediator of BCSCs metastatic ability involved in their chemoresistance and tumorigenic potential. Overexpression of TAZ in low-expressing dBCCs induced cell transformation and conferred tumorigenicity and migratory activity. Conversely, loss of TAZ in BCSCs severely impaired metastatic colonization and chemoresistance. In clinical data from 99 BC patients, high expression levels of TAZ were associated with shorter disease-free survival in multivariate analysis, thus indicating that TAZ may represent a novel independent negative prognostic factor. Overall, this study designates TAZ as a novel biomarker and a possible therapeutic target for BC.

A Continuation Study Using Sunitinib Malate For Patients Leaving Treatment On A Previous Sunitinib Study.

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2015-10-07

Metastatic Breast Cancer [F]; Advanced Breast Cancer; Metastatic Castration Resistant Prostate Cancer; Metastatic Renal Cell Cancer; Non-Small Cell Lung Cancer; Thyroid Cancer; Advanced/Metastatic Non-Small Cell Lung Cancer; Advanced Gastric Cancer; Gastrointestinal Stromal Tumor; Hepatocellular Carcinoma; Pancreatic Islet Cell Carcinoma; Pancreatic Neuroendocrine Tumor

Corosolic Acid Induces Non-Apoptotic Cell Death through Generation of Lipid Reactive Oxygen Species Production in Human Renal Carcinoma Caki Cells

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Seon Min Woo

2018-04-01

Full Text Available Corosolic acid is one of the pentacyclic triterpenoids isolated from Lagerstroemia speciose and has been reported to exhibit anti-cancer and anti-proliferative activities in various cancer cells. In the present study, we investigated the molecular mechanisms of corosolic acid in cancer cell death. Corosolic acid induces a decrease of cell viability and an increase of cell cytotoxicity in human renal carcinoma Caki cells. Corosolic acid-induced cell death is not inhibited by apoptosis inhibitor (z-VAD-fmk, a pan-caspase inhibitor, necroptosis inhibitor (necrostatin-1, or ferroptosis inhibitors (ferrostatin-1 and deferoxamine (DFO. Furthermore, corosolic acid significantly induces reactive oxygen species (ROS levels, but antioxidants (N-acetyl-l-cysteine (NAC and trolox do not inhibit corosolic acid-induced cell death. Interestingly, corosolic acid induces lipid oxidation, and α-tocopherol markedly prevents corosolic acid-induced lipid peroxidation and cell death. Anti-chemotherapeutic effects of α-tocopherol are dependent on inhibition of lipid oxidation rather than inhibition of ROS production. In addition, corosolic acid induces non-apoptotic cell death in other renal cancer (ACHN and A498, breast cancer (MDA-MB231, and hepatocellular carcinoma (SK-Hep1 and Huh7 cells, and α-tocopherol markedly inhibits corosolic acid-induced cell death. Therefore, our results suggest that corosolic acid induces non-apoptotic cell death in cancer cells through the increase of lipid peroxidation.

Pattern of failure following surgical resection of renal cell carcinoma

International Nuclear Information System (INIS)

Aref, I.; Bociek, G.; Salhani, D.

1996-01-01

Purpose/objective: To identify the pattern of failure in patients with resected renal cell carcinoma (RCC). Materials and Methods: The records of 116 patients with unilateral non-metastatic RCC, who were treated with definitive surgery and referred to the Ottawa Regional Cancer Centre between 1977 and 1988, were reviewed. Distribution by stage included: T1 = 3 patients, T2 = 42 patients, T3 =71 patients. The median follow-up was 44 months, with a range of 4-267 months. Results: Loco-regional failure (LRF) developed in 8 patients, yielding a 7-year actuarial incidence of 8% for LRF, as first event. Nine patients developed local or regional recurrence + distant failure, and 58 patients had distant metastases only. Seven-year actuarial incidence of distant failure was 55%. The overall 7-year actuarial survival rate was 40%, and cause-specific survival was 45%. Conclusion: LRF was rare following nephrectomy. This data does not support the role of adjuvant radiation therapy in this disease

Clinical efficacy of sunitinib combined with autologous DC and CIK for patients with metastatic renal cell carcinoma

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Liang ZHANG

2014-01-01

Full Text Available Objective　To analyze the clinical efficacy and safety of sunitinib combined with autologous dentritic cell (DC and cytokine induced killer cell (CIK for patients suffering from metastatic renal cell carcinoma (mRCC. Methods　Clinical data of 27 mRCC patients treated with sunitinib combined with autologous DC and CIK were reviewed retrospectively. Efficacy, quality of life, immunology and safety of this treatment were evaluated. Results　Follow-up time ranged from 4 to 25 months. Out of all the patients, sunitinib was reduced in 1 and discontinued in 2 due to side effects; 1 patient quit for personal reasons; 14 patients developed progressive disease. The progression-free survival (PFS was 4 to 19.5 months. Ten patients died from tumor, the overall survival time (OS was 6 to 21 months. The median PFS was 16 months (95%CI 12.5-19.5. The OS was not achieved. The efficacy was evaluated according to Response Evaluation Criteria in Solid Tumors (RECIST. All the patients received treatment over 1 cycle. After one course of treatment, among 27 patients, 0 had complete remission (CR, 4 had partial remission (PR, 17 had stable disease (SD, and 6 had progressive disease (PD. The overall objective remission rate (ORR and disease control rate (DCR were 14.8% (4/27 and 77.8% (21/27, respectively. Sunitinib and autologous transfusion of DC and CIK improved the immune function and quality of life. The major adverse events were fatigue, hand-foot syndrome, hypertension, hypothyroidism, thrombocytopenia, neutropenia and fever. Most of the adverse events were ameliorated by supportive treatment or dose reduction. Conclusions　 Sunitinib combined with autologous DC and CIK may be beneficial in the treatment of mRCC with acceptable toxic reactions, and it may be considered as a new approach for the comprehensive treatment of RCC. DOI: 10.11855/j.issn.0577-7402.2013.12.06

C-reactive protein in patients with advanced metastatic renal cell carcinoma: Usefulness in identifying patients most likely to benefit from initial nephrectomy

International Nuclear Information System (INIS)

Ito, Hiroki; Kishida, Takeshi; Miura, Takeshi; Kubota, Yoshinobu; Yao, Masahiro; Shioi, Koichi; Murakami, Takayuki; Takizawa, Akitoshi; Sano, Futoshi; Kawahara, Takashi; Mizuno, Nobuhiko; Makiyama, Kazuhide; Nakaigawa, Noboru

2012-01-01

C-reactive protein (CRP) is considered a useful serum marker for patients with RCC. However, its clinical utility in advanced metastatic renal cell carcinoma (AM-RCC), particularly in deciding whether to perform nephrectomy at the onset, is not well studied. We retrospectively evaluated 181 patients with AM-RCC, including 18 patients underwent potentially curative surgery, 111 underwent cytoreductive nephrectomy, and 52 received medical treatment only. CRP cutoff points were determined by receiver operating characteristic (ROC) curve analysis. Kaplan-Meier and Cox regression analyses were used for survival tests. ROC analysis suggested that grouping patients according to 3 CRP ranges was a rational model. Patients with highly elevated CRP (≥67.0 mg/L) presented remarkably poor prognosis despite treatment (nephrectomy or medical treatment only). Cox regression models demonstrated that risk factors of overall survival for patients who underwent nephrectomy were the CRP ranges defined in this study (≤18.0 mg/L, >18.0 and <67.0 mg/L, and ≥67.0 mg/L), ECOG PS (0, 1, and ≥2), and number of metastatic organ sites (0–1 and ≥2). The retrospective design is a limitation of this study. Our study demonstrated that the serum CRP level is a statistically significant prognostic parameter for patients with AM-RCC. The data also indicated that pretreatment serum CRP level provides useful prognostic information that helps in deciding whether to perform initial nephrectomy for patients with AM-RCC

Hereditary leiomyomatosis and renal cell cancer presenting as metastatic kidney cancer at 18 years of age : implications for surveillance

NARCIS (Netherlands)

van Spaendonck-Zwarts, Karin Y.; Badeloe, Sadhanna; Oosting, Sjoukje F.; Hovenga, Sjoerd; Semmelink, Harry J. F.; van Moorselaar, R. Jeroen A.; van Waesberghe, Jan Hein; Mensenkamp, Arjen R.; Menko, Fred H.

Hereditary leiomyomatosis and renal cell cancer (HLRCC) is an autosomal dominant syndrome characterized by skin piloleiomyomas, uterine leiomyomas and papillary type 2 renal cancer caused by germline mutations in the fumarate hydratase (FH) gene. Previously, we proposed renal imaging for FH mutation

Role of bone marrow-derived stem cells, renal progenitor cells and stem cell factor in chronic renal allograft nephropathy

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Hayam Abdel Meguid El Aggan

2013-09-01

Full Text Available Introduction: Chronic allograft nephropathy (CAN is a poorly understood clinico-pathological entity associated with chronic allograft loss due to immunologic and non-immunologic causes. It remains the leading cause of late allograft loss. Bone marrow derived stem cells are undifferentiated cells typically characterized by their capacity for self renewal, ability to give rise to multiple differentiated cellular population, including hematopoietic (HSCs and mesenchymal stem cells (MSCs. Characterization of HSCs includes their multipotency, expression of typical surface markers such as CD34 and CD45, while characterization of MSC includes their multipotency, expression of typical surface markers such as CD90 and CD105, and the absence of hemopoietic lineage markers. Aim & methods: The aim of the present work was to study the role of bone marrow-derived HSCs and MSCs, renal progenitor cells and SCF in chronic renal allograft nephropathy in relation to renal hemodynamics and histopathological changes. We studied 30 patients with kidney transplantation for more than 6 months, divided into 15 patients with stable serum creatinine and 15 patients who developed CAN. Detection of HSCs and MSCs in the peripheral blood using flow cytometry via detection of CD34, CD45, CD117 and CD106, as well as immunohistochemical detection of CD34, CD133, VEGF and αSMA in transplanted kidney biopsies of patients with CAN were done. Results: There was a significant increase in the levels of SCF, number of peripheral blood HSCs and MSCs in both transplanted patient groups than the controls and they were higher in patients of group Ia than patients of group Ib, (F = 39.73, P < 0.001, (F = 13.28, P < 0.001, (F = 11.94, P < 0.001, respectively and this was accompanied by evident expression of markers of renal repair. Conclusion: Stem cells might have a role in renal regeneration in CAN and this may pave the way toward the use of stem cells in correction of CAN. KEYWORDS

Recommendations from the Spanish Oncology Genitourinary Group for the treatment of metastatic renal cancer.

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Bellmunt, Joaquim; Calvo, Emiliano; Castellano, Daniel; Climent, Miguel Angel; Esteban, Emilio; García del Muro, Xavier; González-Larriba, José Luis; Maroto, Pablo; Trigo, José Manuel

2009-03-01

For almost the last two decades, interleukin-2 and interferon-alpha have been the only systemic treatment options available for metastatic renal cell carcinoma. However, in recent years, five new targeted therapies namely sunitinib, sorafenib, temsirolimus, everolimus and bevacizumab have demonstrated clinical activity in these patients. With the availability of new targeted agents that are active in this disease, there is a need to continuously update the treatment algorithm of the disease. Due to the important advances obtained, the Spanish Oncology Genitourinary Group (SOGUG) has considered it would be useful to review the current status of the disease, including the genetic and molecular biology factors involved, the current predicting models for development of metastases as well as the role of surgery, radiotherapy and systemic therapies in the early- or late management of the disease. Based on this previous work, a treatment algorithm was developed.

Superior target delineation for stereotactic body radiotherapy of bone metastases from renal cell carcinoma on MRI compared to CT

NARCIS (Netherlands)

Prins, Fieke M.; Van Der Velden, Joanne M.; Gerlich, Anne S.; Kotte, Alexis N.T.J.; Eppinga, Wietse S.C.; Kasperts, Nicolien; Verlaan, Jorrit J.; Pameijer, Frank A.; Kerkmeijer, Linda G.W.

2017-01-01

Background: In metastatic renal cell carcinoma (mRCC) there has been a treatment shift towards targeted therapy, which has resulted in improved overall survival. Therefore, there is a need for better local control of the tumor and its metastases. Image-guided stereotactic body radiotherapy (SBRT) in

Renal cell carcinoma metastases to the pancreas - Value of arterial phase imaging at MDCT

International Nuclear Information System (INIS)

Corwin, Michael T.; Lamba, Ramit; McGahan, John P.; Wilson, Machelle

2013-01-01

Background: The pancreas is an increasingly recognized site of renal cell carcinoma metastases. It is important to determine the optimal MDCT protocol to best detect RCC metastases to the pancreas. Purpose: To compare the rate of detection of renal cell carcinoma metastases to the pancreas between arterial and portal venous phase MDCT. Material and Methods: A retrospective review of CTs of the abdomen yielded six patients with metastatic RCC to the pancreas. Five of six patients had pathologically proven clear cell RCC. Two blinded reviewers independently reported the number of pancreatic lesions seen in arterial and venous phases. Each lesion was graded as definite or possible. The number of lesions was determined by consensus review of both phases. Attenuation values were obtained for metastatic lesions and adjacent normal pancreas in both phases. Results: There were a total of 24 metastatic lesions to the pancreas. Reviewer 1 identified 20/24 (83.3%) lesions on the arterial phase images and 13/24 (54.2%) lesions on the venous phase. Seventeen of 20 (85.0%) arterial lesions were deemed definite and 9/13 (69.2%) venous lesions were definite. Reviewer 2 identified 19/24 (79.2%) lesions on the arterial phase and 14/24 (58.3%) on the venous phase. Seventeen of 19 (89.5%) arterial lesions were definite and 7/14 (50%) venous lesions were definite. Mean attenuation differential between lesion and pancreas was 114 HU and 39 HU for arterial and venous phases, respectively (P<0.0001). Conclusion: Detection of RCC metastases to the pancreas at MDCT is improved using arterial phase imaging compared to portal venous phase imaging

The notch and TGF-β signaling pathways contribute to the aggressiveness of clear cell renal cell carcinoma.

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Jonas Sjölund

Full Text Available BACKGROUND: Despite recent progress, therapy for metastatic clear cell renal cell carcinoma (CCRCC is still inadequate. Dysregulated Notch signaling in CCRCC contributes to tumor growth, but the full spectrum of downstream processes regulated by Notch in this tumor form is unknown. METHODOLOGY/PRINCIPAL FINDINGS: We show that inhibition of endogenous Notch signaling modulates TGF-β dependent gene regulation in CCRCC cells. Analysis of gene expression data representing 176 CCRCCs showed that elevated TGF-β pathway activity correlated significantly with shortened disease specific survival (log-rank test, p = 0.006 and patients with metastatic disease showed a significantly elevated TGF-β signaling activity (two-sided Student's t-test, p = 0.044. Inhibition of Notch signaling led to attenuation of both basal and TGF-β1 induced TGF-β signaling in CCRCC cells, including an extensive set of genes known to be involved in migration and invasion. Functional analyses revealed that Notch inhibition decreased the migratory and invasive capacity of CCRCC cells. CONCLUSION: An extensive cross-talk between the Notch and TGF-β signaling cascades is present in CCRCC and the functional properties of these two pathways are associated with the aggressiveness of this disease.

Optimal management of renal cell carcinoma in the elderly: a review

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Quivy A

2013-04-01

Full Text Available Amandine Quivy,1,2 Amaury Daste,1 Asma Harbaoui,1 Sophie Duc,2,4 Jean-Christophe Bernhard,2,3 Marine Gross-Goupil,1 Alain Ravaud1,2 1Department of Medical Oncology, Hôpital Saint-André, Bordeaux University Hospital, Bordeaux, France; 2University of Bordeaux 2 (Victor Ségalen, Bordeaux, France; 3Department of Urology, Hôpital Pellegrin, Bordeaux University Hospital, Bordeaux, France; 4Department of Geriatrics, Hôpital Saint-André, Bordeaux University Hospital, Bordeaux, France Abstract: Both the aging population and the incidence of renal cell carcinoma (RCC are growing, making the question of tumor management in the elderly a real challenge. Doctors should be aware of the importance of assessing this specific subpopulation. An aggressive therapeutic approach may be balanced by the benefit of the treatment – care or cure – and the life expectancy and willingness of the patient. The treatment for local disease can be surgery (radical or partial nephrectomy or ablative therapies (radiofrequency, cryotherapy. Even if in most cases surgery is safe, complications such as alteration of renal function may occur, especially in the elderly, with physiological renal impairment at baseline. More recently, another option has been developed as an alternative: active surveillance. In the past decade, new drugs have been approved in the metastatic setting. All the phase 3 trials have included patients without a limit on age. Nevertheless, data concerning the elderly are still poor and concern only a very selective subpopulation. The toxicity profile of targeted agents may interfere with pre-existent comorbidities. Furthermore, the metabolism of several agents via cytochrome P450 can cause drug interaction. The importance of quality of life is a major factor with regard to management of therapy. Finally, to date, there is no recommendation of systematic a priori dose reduction in the elderly. In this review we describe the various possibilities of

Metastatic squamous cell non-small-cell lung cancer (NSCLC: disrupting the drug treatment paradigm with immunotherapies

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Sarah L Scarpace

2015-10-01

Full Text Available Lung cancer is the third most commonly diagnosed cancer and the leading cause of cancer-related death in the United States. Unlike non-squamous NSCLC, squamous NSCLC rarely harbor epidermal growth factor receptor (EGFR and anaplastic lymphoma kinase (ALK mutations for which there are directed therapies, and until the recent approval of immunotherapies for squamous NSCLC, a limited number of traditional cytotoxic chemotherapy drugs have been FDA-approved for use in the treatment of advanced and metastatic squamous NSCLC. Immunotherapies directed at the programmed cell death-1 receptor (PD-1 or its ligand (PD-L1 (nivolumab and pembrolizumab have demonstrated efficacy in both nonsquamous and squamous cell NSCLC. Because of their similar mechanism of action against the PD-L1/PD-1 pathway, both drugs have similar toxicity profiles related to immune-mediated adverse reactions that can generally be monitored and managed with oral corticosteroids. This paper provides an overview of drug therapy options for squamous cell NSCLC with a focus on the evidence and clinical application of the anti-PD1 therapies. A comparison of the dosing, administration, indications, and differences in the measurement of PD-L1 expression in the clinical trials of nivolumab and pembrolizumab is also provided.

[Small renal mass].

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Prokofiev, D; Kreutzer, N; Kress, A; Wissing, F; Pfeifer, H; Stolzenburg, J-U; Dietel, A; Schwalenberg, T; Do, M; Truß, M C

2012-10-01

The frequent application of ultrasound and radiological imaging for non-urological indications in recent years has resulted in an increase in the diagnosis of small renal masses. The treatment options for patients with a small renal mass include active surveillance, surgery (both open and minimally invasive) as well as ablative techniques. As there is a risk for metastatic spread even in small renal masses surgical extirpation remains the treatment of choice in most patients. Ablative procedures, such as cryoablation and radiofrequency ablation are appropriate for old and multi-morbid patients who require active treatment of a small renal mass. Active surveillance is an alternative for high-risk patients. Meticulous patient selection by the urologist and patient preference will determine the choice of treatment option in the future.

Treatment of non-neoplastic renal hemorrhage with segmental embolization of renal artery

International Nuclear Information System (INIS)

Zhu Bing

2007-01-01

Objective: To explore the value of segmental embolization of renal artery in dealing with non- neoplastic renal hemorrhage. Methods: Four cases of non-neoplastic hemorrhage, including 2 with bleeding after renal acupuncture biopsy, 2 with bleeding after nephrolithotomy and 1 with congenital renal arteriovenous malformation, were treated with superselective segmental embolization of renal artery. 2 were embolized with coil, 1 with alcohol plus coil and 1 with PVA parcels. Results: Hematuria disappeared in 1-3 days. There was no recurrence in 7-45 months follow up and no complications induced by embolization. Conclusion: It is a safe and reliable therapy to treat non-neoplastic renal hemorrhage with segmental embolization of renal artery. (authors)

An update on current management of advanced renal cell cancer, biomarkers, and future directions

OpenAIRE

Zhi, Wanqing Iris; Kim, Jenny J.

2014-01-01

In the past decade, metastatic renal cell carcinoma (mRCC) treatment underwent significant advancement that resulted in an unprecedented improvement in the prognosis of this disease. This review will provide an updated review of currently approved treatment options, namely antiangiogenic and immunotherapy, as well as treatment guideline recommended by the National Comprehensive Cancer Network (NCCN). We will summarize studies ongoing in determining prognostic and predictive biomarkers in maxi...

Expressions of topoisomerase IIα and BCRP in metastatic cells are associated with overall survival in small cell lung cancer patients.

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Rijavec, Matija; Silar, Mira; Triller, Nadja; Kern, Izidor; Cegovnik, Urška; Košnik, Mitja; Korošec, Peter

2011-09-01

The aim of this study was to investigate the mRNA expression levels of multidrug resistance-associated proteins in chemo-naïve metastatic lung cancer cells and to determine the correlation with response to chemotherapy and overall survival. Metastatic cells were obtained by transbronchial fine needle aspiration biopsy of enlarged mediastinal lymph nodes in 14 patients with small cell lung cancer (SCLC) and 7 patients with non-small cell lung cancer (NSCLC). After cytological confirmation of lung cancer type, total RNA was extracted from biopsy samples and reverse transcribed to cDNA, and real-time PCR for the genes of interest [P-glycoprotein (P-gp), multidrug resistance protein 1 (MRP1), breast cancer resistance protein (BCRP), lung resistance protein (LRP) and topoisomerase IIα (TOPIIα)], was performed. We observed significantly decreased expression of BCRP and significantly increased expression of TOPIIα in metastatic SCLC cells compared to NSCLC. Furthermore, in SCLC high topoisomerase IIα and low BCRP expression levels positively correlated with longer overall survival. Our results showed higher expression levels of BCRP as well as lower levels of topoisomerase IIα in chemo-naïve metastatic cells in NSCLC than in SCLC. These results correlate with previous observations that metastatic SCLC cells at the beginning of chemotherapy are potentially more sensitive to chemotherapeutic agents while in metastatic NSCLC cells resistance is usually inherent. We also showed that altered levels of topoisomerase IIα and BCRP in SCLC are important factors that contribute to resistance to chemotherapeutics that interfere with the enzyme and/or DNA and are highly associated with overall survival.

The Refusal of Palliative Radiation in Metastatic Non-Small Cell Lung Cancer and Its Prognostic Implications.

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Stavas, Mark J; Arneson, Kyle O; Ning, Matthew S; Attia, Albert A; Phillips, Sharon E; Perkins, Stephanie M; Shinohara, Eric T

2015-06-01

Patients with metastatic non-small cell lung cancer (NSCLC) have limited survival. Population studies have evaluated the impact of radiation refusal in the curative setting; however, no data exist concerning the prognostic impact of radiation refusal in the palliative care setting. To investigate the patterns of radiation refusal in newly diagnosed patients with metastatic NSCLC. Patients with Stage IV NSCLC diagnosed between 1988 and 2010 were identified in the Surveillance, Epidemiology, and End Results database. Univariate and multivariate analyses were used to identify predictors for refusal of radiation and the impact of radiation and refusal on survival in the palliative setting. A total of 285,641 patients were initially included in the analysis. Palliative radiation was recommended in 42% and refused by 3.1% of patients. Refusal rates remained consistent across included years of study. On multivariate analysis, older, nonblack/nonwhite, unmarried females were more likely to refuse radiation (P refusing radiation was three months vs. five months for those receiving radiation and two months for those whom radiation was not recommended. Patients with metastatic NSCLC who refuse recommended palliative radiation have a poor survival. Radiation refusal or the recommendation against treatment can serve as a trigger for integrating palliative care services sooner and contributes greatly to prognostic awareness. Further investigation into this survival difference and the factors behind refusal are warranted. Copyright © 2015 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.

Tumor biology of non-metastatic stages of clear cell renal cell carcinoma; overexpression of stearoyl desaturase-1, EPO/EPO-R system and hypoxia-related proteins.

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Stoyanoff, Tania Romina; Rodríguez, Juan Pablo; Todaro, Juan Santiago; Espada, Joaquín Diego; Colavita, Juan Pablo Melana; Brandan, Nora Cristina; Torres, Adriana Mónica; Aguirre, María Victoria

2016-10-01

Clear cell renal cell carcinoma (ccRCC) is the most common subtype of renal carcinomas. There is great interest to know the molecular basis of the tumor biology of ccRCC that might contribute to a better understanding of the aggressive biological behavior of this cancer and to identify early biomarkers of disease. This study describes the relationship among proliferation, survival, and apoptosis with the expression of key molecules related to tumoral hypoxia (hypoxia-inducible factor (HIF)-1α, erythropoietin (EPO), vascular endothelial growth factor (VEGF)), their receptors (EPO-R, VEGFR-2), and stearoyl desaturase-1 (SCD-1) in early stages of ccRCC. Tissue samples were obtained at the Urology Unit of the J.R. Vidal Hospital (Corrientes, Argentina), from patients who underwent radical nephrectomy for renal cancer between 2011 and 2014. Four experimental groups according to pathological stage and nuclear grade were organized: T1G1 (n = 6), T2G1 (n = 4), T1G2 (n = 7), and T2G2 (n = 7). The expression of HIF-1α, EPO, EPO-R, VEGF, VEGFR-2, Bcl-x L , and SCD-1 were evaluated by immunohistochemistry, Western blotting, and/or RT-PCR. Apoptosis was assessed by the TUNEL in situ assay, and tumor proliferation was determined by Ki-67 immunohistochemistry. Data revealed that HIF-1α, EPO, EPO-R, VEGF, and VEGF-R2 were overexpressed in most samples. The T1G1 group showed the highest EPO levels, approximately 200 % compared with distal renal tissue. Bcl-x L overexpression was concomitant with the enhancement of proliferative indexes. SCD-1 expression increased with the tumor size and nuclear grade. Moreover, the direct correlations observed between SCD-1/HIF-1α and SCD-1/Ki-67 increments suggest a link among these molecules, which would determine tumor progression in early stages of ccRCC. Our results demonstrate the relationship among proliferation, survival, and apoptosis with the expression of key molecules related to tumoral hypoxia (HIF-1α, EPO, VEGF), their

Predicting survival in patients with metastatic kidney cancer by gene-expression profiling in the primary tumor.

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Vasselli, James R; Shih, Joanna H; Iyengar, Shuba R; Maranchie, Jodi; Riss, Joseph; Worrell, Robert; Torres-Cabala, Carlos; Tabios, Ray; Mariotti, Andra; Stearman, Robert; Merino, Maria; Walther, McClellan M; Simon, Richard; Klausner, Richard D; Linehan, W Marston

2003-06-10

To identify potential molecular determinants of tumor biology and possible clinical outcomes, global gene-expression patterns were analyzed in the primary tumors of patients with metastatic renal cell cancer by using cDNA microarrays. We used grossly dissected tumor masses that included tumor, blood vessels, connective tissue, and infiltrating immune cells to obtain a gene-expression "profile" from each primary tumor. Two patterns of gene expression were found within this uniformly staged patient population, which correlated with a significant difference in overall survival between the two patient groups. Subsets of genes most significantly associated with survival were defined, and vascular cell adhesion molecule-1 (VCAM-1) was the gene most predictive for survival. Therefore, despite the complex biological nature of metastatic cancer, basic clinical behavior as defined by survival may be determined by the gene-expression patterns expressed within the compilation of primary gross tumor cells. We conclude that survival in patients with metastatic renal cell cancer can be correlated with the expression of various genes based solely on the expression profile in the primary kidney tumor.

Androgen receptor expression on circulating tumor cells in metastatic breast cancer.

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Takeo Fujii

Full Text Available Androgen receptor (AR is frequently detected in breast cancers, and AR-targeted therapies are showing activity in AR-positive (AR+ breast cancer. However, the role of AR in breast cancers is still not fully elucidated and the biology of AR in breast cancer remains incompletely understood. Circulating tumor cells (CTCs can serve as prognostic and diagnostic tools, prompting us to measure AR protein expression and conduct genomic analyses on CTCs in patients with metastatic breast cancer.Blood samples from patients with metastatic breast cancer were deposited on glass slides, subjected to nuclear staining with DAPI, and reacted with fluorescent-labeled antibodies to detect CD45, cytokeratin (CK, and biomarkers of interest (AR, estrogen receptor [ER], and HER2 on all nucleated cells. The stained slides were scanned and enumerated by non-enrichment-based non-biased approach independent of cell surface epithelial cell adhesion molecule (EpCAM using the Epic Sciences CTC platform. Data were analyzed using established digital pathology algorithms.Of 68 patients, 51 (75% had at least 1 CTC, and 49 of these 51 (96% had hormone-receptor-positive (HR+/HER2-negative primary tumors. AR was expressed in CK+ CTCs in 10 patients. Of these 10 patients, 3 also had ER expression in CK+ CTCs. Single cell genomic analysis of 78 CTCs from 1 of these 3 patients identified three distinct copy number patterns. AR+ cells had a lower frequency of chromosomal changes than ER+ and HER2+ cells.CTC enumeration and analysis using no enrichment or selection provides a non-biased approach to detect AR expression and chromosomal aberrations in CTCs in patients with metastatic breast cancer. The heterogeneity of intrapatient AR expression in CTCs leads to the new hypothesis that patients with AR+ CTCs have heterogeneous disease with multiple drivers. Further studies are warranted to investigate the clinical applicability of AR+ CTCs and their heterogeneity.

Variation in use of targeted therapies for metastatic renal cell carcinoma: Results from a Dutch population-based registry

International Nuclear Information System (INIS)

De Groot, S.; Sleijfer, S.; Redekop, W. K.; Oosterwijk, E.; Haanen, J. B. A. G.; Kiemeney, L. A. L. M.; Uyl-de Groot, C. A.

2016-01-01

For patients with metastatic renal cell carcinoma (mRCC), targeted therapies have entered the market since 2006. The aims of this study were to evaluate the uptake and use of targeted therapies for mRCC in The Netherlands, examine factors associated with the prescription of targeted therapies in daily clinical practice and study their effectiveness in terms of overall survival (OS). Two cohorts from PERCEPTION, a population-based registry of mRCC patients, were used: a 2008–2010 Cohort (n = 645) and a 2011–2013 Cohort (n = 233). Chi-squared tests for trend were used to study time trends in the use of targeted therapy. Patients were grouped based on the eligibility criteria of the SUTENT trial, the trial that led to sunitinib becoming standard of care, to investigate the use of targeted therapies amongst patients fulfilling those criteria. Multi-level logistic regression was used to identify patient subgroups that are less likely to receive targeted therapies. Approximately one-third of patients fulfilling SUTENT trial eligibility criteria did not receive any targeted therapy (29 % in the 2008–2010 Cohort; 35 % in the 2011–2013 Cohort). Patients aged 65+ years were less likely to receive targeted therapy in both cohorts and different risk groups (odds ratios range between 0.84–0.92); other factors like number of metastatic sites were of influence in some subgroups. Amongst treated patients, there was a decreasing trend in sunitinib use over time (p = 0.0061), and an increasing trend in pazopanib use (p = 0.0005). Targeted therapies have largely replaced interferon-alfa as first-line standard of care. Nevertheless, many eligible patients in Dutch daily practice did not receive targeted therapies despite their ability to improve survival. Reasons for their apparent underutilisation should be examined more carefully. The online version of this article (doi:10.1186/s12885-016-2395-x) contains supplementary material, which is available to authorized users

Glomerular Filtration Rate Estimation in Renal and Non-Renal Solid Organ Transplantation

DEFF Research Database (Denmark)

Hornum, Mads; Feldt-Rasmussen, Bo

2017-01-01

Following transplantation (TX) of both renal and non-renal organs, a large proportion of patients have renal dysfunction. There are multiple causes for this. Chronic nephrotoxicity and high doses of calcineurin inhibitors are important factors. Preoperative and perioperative factors like...... or estimates of renal function in these patients, in order to accurately and safely dose immunosuppressive medication and perform and adjust the treatment and prophylaxis of renal dysfunction. This is a short overview and discussion of relevant studies and possible caveats of estimated glomerular filtration...... rate methods for use in renal and non-renal TX....

Incorporating Neutrophil-to-lymphocyte Ratio and Platelet-to-lymphocyte Ratio in Place of Neutrophil Count and Platelet Count Improves Prognostic Accuracy of the International Metastatic Renal Cell Carcinoma Database Consortium Model.

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Chrom, Pawel; Stec, Rafal; Bodnar, Lubomir; Szczylik, Cezary

2018-01-01

The study investigated whether a replacement of neutrophil count and platelet count by neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) within the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) model would improve its prognostic accuracy. This retrospective analysis included consecutive patients with metastatic renal cell carcinoma treated with first-line tyrosine kinase inhibitors. The IMDC and modified-IMDC models were compared using: concordance index (CI), bias-corrected concordance index (BCCI), calibration plots, the Grønnesby and Borgan test, Bayesian Information Criterion (BIC), generalized R 2 , Integrated Discrimination Improvement (IDI), and continuous Net Reclassification Index (cNRI) for individual risk factors and the three risk groups. Three hundred and twenty-one patients were eligible for analyses. The modified-IMDC model with NLR value of 3.6 and PLR value of 157 was selected for comparison with the IMDC model. Both models were well calibrated. All other measures favoured the modified-IMDC model over the IMDC model (CI, 0.706 vs. 0.677; BCCI, 0.699 vs. 0.671; BIC, 2,176.2 vs. 2,190.7; generalized R 2 , 0.238 vs. 0.202; IDI, 0.044; cNRI, 0.279 for individual risk factors; and CI, 0.669 vs. 0.641; BCCI, 0.669 vs. 0.641; BIC, 2,183.2 vs. 2,198.1; generalized R 2 , 0.163 vs. 0.123; IDI, 0.045; cNRI, 0.165 for the three risk groups). Incorporation of NLR and PLR in place of neutrophil count and platelet count improved prognostic accuracy of the IMDC model. These findings require external validation before introducing into clinical practice.

P38 pathway as a key downstream signal of connective tissue growth factor to regulate metastatic potential in non-small-cell lung cancer.

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Kato, Shinichiro; Yokoyama, Satoru; Hayakawa, Yoshihiro; Li, Luhui; Iwakami, Yusuke; Sakurai, Hiroaki; Saiki, Ikuo

2016-10-01

Although the secretory matricellular protein connective tissue growth factor (CTGF) has been reported to be related to lung cancer metastasis, the precise mechanism by which CTGF regulates lung cancer metastasis has not been elucidated. In the present study, we show the molecular link between CTGF secretion and the p38 pathway in the invasive and metastatic potential of non-small-cell lung cancer (NSCLC). Among three different human NSCLC cell lines (PC-14, A549, and PC-9), their in vitro invasiveness was inversely correlated with the level of CTGF secretion. By supplementing or reducing CTGF secretion in NSCLC culture, dysregulation of the invasive and metastatic potential of NSCLC cell lines was largely compensated. By focusing on the protein kinases that are known to be regulated by CTGF, we found that the p38 pathway is a key downstream signal of CTGF to regulate the metastatic potential of NSCLC. Importantly, a negative correlation between CTGF and phosphorylation status of p38 was identified in The Cancer Genome Atlas lung adenocarcinoma dataset. In the context of the clinical importance of our findings, we showed that p38 inhibitor, SB203580, reduced the metastatic potential of NSCLC secreting low levels of CTGF. Collectively, our present findings indicate that the CTGF/p38 axis is a novel therapeutic target of NSCLC metastasis, particularly NSCLC secreting low levels of CTGF. © 2016 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

Stereotactic body radiotherapy for primary renal cell carcinoma and adrenal metastases.

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Kothari, Gargi; Louie, Alexander V; Pryor, David; Vela, Ian; Lo, Simon S; Teh, Bin S; Siva, Shankar

2017-09-01

The incidence of renal cell carcinoma (RCC) and metastatic adrenal lesions continues to rise and present evolving complexities in terms of management. Technical challenges in treatment delivery are compounded by the setting of an ageing patient population with multiple medical co-morbidities. While the standard of care treatment for both primary RCC and oligometastatic adrenal lesions has typically been surgery, a number of patients may be medically or surgically inoperable, and for whom alternative options require consideration. Additionally, in metastatic disease, surgery presents an invasive option, sometimes with unacceptable risks of perioperative morbidity and therefore is considered a less desirable option to some. Stereotactic body radiotherapy (SBRT) is an established radiotherapy technique that is rapidly being incorporated into many radiotherapy departments, particu-larly with the increasing availability and capabilities of modern linear accelerators to deliver precise image guided treatment. There are considerable advantages of SBRT including its ability to provide a non-invasive ablative treatment with very few treatment sessions, with emerging evidence showing promising rates of local control (LC) and low associated mor-bidity. This review details the use of SBRT for primary RCC as well as adrenal metastases, focusing on issues including patient selection, technical considerations, and patient out-comes. Furthermore, this review explores some recent insights into the radiobiology of RCC, the immunomodulatory effects of SBRT, and the use of systemic agents with SBRT.

Glomerular Filtration Rate Estimation in Renal and Non-Renal Solid Organ Transplantation

DEFF Research Database (Denmark)

Hornum, Mads; Feldt-Rasmussen, Bo

2017-01-01

Following transplantation (TX) of both renal and non-renal organs, a large proportion of patients have renal dysfunction. There are multiple causes for this. Chronic nephrotoxicity and high doses of calcineurin inhibitors are important factors. Preoperative and perioperative factors like hyperten......Following transplantation (TX) of both renal and non-renal organs, a large proportion of patients have renal dysfunction. There are multiple causes for this. Chronic nephrotoxicity and high doses of calcineurin inhibitors are important factors. Preoperative and perioperative factors like...... hypertension, hypotension, drugs and infections may play a causative role as well. Organ-specific causes include hepatorenal syndrome, cirrhosis, low cardiac function, low respiratory function and diabetes developed both before and after TX. It is important to be able to perform precise and valid measurements...... rate methods for use in renal and non-renal TX....

Patterns of metastatic progression after definitive radiation therapy for early-stage and locally advanced non-small cell lung cancer.

Science.gov (United States)

Jensen, Garrett L; Tang, Chad; Hess, Kenneth R; Liao, Zhongxing; Gomez, Daniel R

2017-06-01

Current preclinical models of metastatic disease (particularly oligometastases) suggest that metastases appear in a hierarchical order. We attempted to identify systematic patterns of metastasis in non-small cell lung cancer (NSCLC) after radiation therapy (XRT). We analyzed 1074 patients treated from 12/21/1998 through 8/20/2012 with ≥60 Gy definitive radiation for initially non-metastatic NSCLC. Location and time of metastases were recorded. Regional nodal failure was noted, as was subsequent distal failure. For further analysis, we considered only the five most common sites of metastasis (bone, brain, liver, adrenal, and lung). Metastatic progression over time was defined and patterns elucidated with Chi square tests. Histologic findings were analyzed with Wilcoxon rank sum tests. A significant multistep linear progression was not apparent. Having a first metastasis in lung or bone was associated with respective 16% (median 2.4 months) and 15% likelihoods (median 7.9 months) of secondary brain metastasis. Initial metastasis in the brain led to metastasis in another organ 29.3% of the time, most often in the lung, bone, and liver (medians 3.6, 7.9, and 3.1 months). Adenocarcinoma was more likely than squamous to metastasize to the brain (18 vs. 9%) and any of the five major sites (41 vs. 27%). We did not appreciate dominant patterns suggesting a multi-step hierarchical order of metastasis. Rather, our findings suggest that certain subgroups may develop different patterns of spread depending on a variety of factors.

Metastatic calcification of the stomach imaged on a bone scan

Energy Technology Data Exchange (ETDEWEB)

Goldstein, R.; Ryo, U.Y.; Pinsky, S.M.

1984-10-01

A whole body bone scan obtained on a 21-year-old woman with sickle cell disease and chronic renal failure showed localization of the radionuclide diffusely in the stomach. The localization of the radionuclide represented metastatic calcification of the stomach caused by secondary hyperparathyroidism.

A HIF-regulated VHL-PTP1B-Src signaling axis identifies a therapeutic target in Renal Cell Carcinoma

OpenAIRE

Suwaki, Natsuko; Vanhecke, Elsa; Atkins, Katelyn M.; Graf, Manuela; Swabey, Katherine; Huang, Paul; Schraml, Peter; Moch, Holger; Cassidy, Amy; Brewer, Daniel; Al-Lazikani, Bissan; Workman, Paul; De-Bono, Johann; Kaye, Stan B.; Larkin, James

2011-01-01

Metastatic renal cell carcinoma (RCC) is a molecularly heterogeneous disease that is intrinsically resistant to chemotherapy and radiotherapy. While VEGF and mTOR targeted therapies have shown clinical activity, their effects are variable and short-lived, underscoring the need for improved treatment strategies for RCC. Here, we used quantitative phosphoproteomics and immunohistochemical profiling of 346 RCC specimens to determine that Src kinase signaling is elevated in RCC cells that retain ...

Volumetric FDG-PET predicts overall and progression- free survival after 14 days of targeted therapy in metastatic renal cell carcinoma

International Nuclear Information System (INIS)

Farnebo, Jacob; Grybäck, Per; Harmenberg, Ulrika; Laurell, Anna; Wersäll, Peter; Blomqvist, Lennart K; Ullén, Anders; Sandström, Per

2014-01-01

To determine whether changes in the metabolism of metastatic renal cell carcinoma (mRCC) assessed by F18-FDG-PET after 14 and 28 days of treatment with tyrosine kinase inhibitors can predict overall and progression- free patient survival. Thirty-nine consecutive patients with mRCC were included prospectively and underwent PET examinations prior to and after 14 and 28 days of standard treatment with sunitinib (n = 18), sorafenib (n = 19) or pazopanib (n = 2). The PET response was analyzed in terms of SUVmax, SULpeak, and total lesion glycolysis and a positive response (defined as a 30% reduction) compared to overall and progression- free survival. Thirty-five patients with at least one metabolically active metastatic lesion prior to treatment underwent additional FDG-PET examinations after 14 (n = 32) and/or 28 days (n = 30) of treatment. Changes in either SULpeak or total lesion glycolysis were correlated to both progression-free and overall survival (for TLG2.5 responders, HR = 0.38 (95% CI: 0.18-0.83) and 0.22 (95% CI: 0.09-0.53), and for TLG50 responders, HR = 0.25 (0.10-0.62) and 0.25 (95% CI: 0.11-0.57) and for SULpeak responders, HR = 0.39 (95% CI: 0.17-0.91) and 0.38 (95% CI: 0.15-0.93), respectively). In contrast SUVmax response did not predict progression- free or overall survival (HR = 0.43 (95% CI: 0.18-1.01) and 0.50 (95% CI: 0.21-1.19), respectively). Assessment of early changes in SULpeak and total lesion glycolysis undergoing treatment with tyrosine kinase inhibitors by FDG-PET can possibly predict progression- free and overall survival in patients with mRCC

Total-Body Irradiation and Fludarabine Phosphate Followed by Donor Peripheral Blood Stem Cell Transplant in Treating Patients With Hematologic Malignancies or Kidney Cancer

Science.gov (United States)

2017-12-11

Adult Acute Myeloid Leukemia in Remission; Childhood Acute Lymphoblastic Leukemia in Remission; Childhood Acute Myeloid Leukemia in Remission; Childhood Myelodysplastic Syndrome; Childhood Renal Cell Carcinoma; Chronic Myelomonocytic Leukemia; Clear Cell Renal Cell Carcinoma; de Novo Myelodysplastic Syndrome; Metastatic Renal Cell Cancer; Previously Treated Myelodysplastic Syndrome; Progression of Multiple Myeloma or Plasma Cell Leukemia; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Recurrent Adult Hodgkin Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Adult Non-Hodgkin Lymphoma; Recurrent Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Recurrent Childhood Lymphoblastic Lymphoma; Recurrent Childhood Non-Hodgkin Lymphoma; Refractory Anemia; Refractory Anemia With Ringed Sideroblasts; Refractory Childhood Hodgkin Lymphoma; Refractory Chronic Lymphocytic Leukemia; Renal Medullary Carcinoma; Type 1 Papillary Renal Cell Carcinoma; Type 2 Papillary Renal Cell Carcinoma; Untreated Adult Acute Lymphoblastic Leukemia; Untreated Adult Acute Myeloid Leukemia; Untreated Childhood Acute Lymphoblastic Leukemia

Evaluating the safety and efficacy of axitinib in the treatment of advanced renal cell carcinoma

Directory of Open Access Journals (Sweden)

Gunnarsson O

2015-02-01

Full Text Available Orvar Gunnarsson,1 Nicklas R Pfanzelter,2 Roger B Cohen,1 Stephen M Keefe1 1Department of Medicine, Division of Hematology and Oncology, Hospital of the University of Pennsylvania, Philadelphia, PA, 2Department of Medicine, Division of Hematology and Oncology, Rush University Medical Center, Chicago, IL, USA Abstract: Axitinib is a tyrosine kinase inhibitor of vascular endothelial growth factor receptor, platelet-derived growth factor receptor-α, and c-kit. Phase I studies demonstrated 5 mg twice daily as the recommended starting dose with notable effects seen in renal cell carcinoma, an observation confirmed in Phase II trials. The trial of comparative effectivess of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS was an international randomized Phase III study designed for registration purposes, compared axitinib to sunitinib. This trial randomized 723 patients with metastatic kidney cancer to axitinib or sunitinib in the second-line setting and demonstrated a median progression-free survival of 6.7 months for axitinib versus 4.7 months for sorafenib (P<0.0001. Clinical benefit was detected regardless of prior therapy, but no overall survival benefit has been observed. Axitinib is well tolerated without a significant effect on quality of life. The most common grade 3 toxicities are hypertension (16%, diarrhea (11%, and fatigue (11%, with other notable side effects being anorexia, nausea, hand–foot syndrome, and rash. Patients who developed diastolic blood pressure >90 mmHg were noted to have significantly longer median overall survival and overall response rates when compared to normotensive patients. Therefore, the manufacturer recommends escalating the twice-daily dose to 7 mg and 10 mg, as tolerated, if there is no significant increase in blood pressure on treatment. Currently, axitinib is approved for use in the second-line setting for patients with metastatic renal cell carcinoma. Research is ongoing in other disease

Renal cell carcinoma in patient with crossed fused renal ectopia

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Ozgur Cakmak

2016-01-01

Full Text Available Primary renal cell carcinomas have rarely been reported in patients with crossed fused renal ectopia. We presented a patient with right to left crossed fused kidney harbouring renal tumor. The most frequent tumor encountered in crossed fused renal ectopia is renal cell carcinoma. In this case, partial nephrectomy was performed which pave way to preservation of the uninvolved both renal units. Due to unpredictable anatomy, careful preoperative planning and meticulous delineation of renal vasculature is essential for preservation of the uninvolved renal units.

Robotic partial nephrectomy for renal cell carcinomas with venous tumor thrombus.

Science.gov (United States)

Abaza, Ronney; Angell, Jordan

2013-06-01

To describe the first report of robotic partial nephrectomies (RPNs) for renal cell carcinoma (RCC) with venous tumor thrombus (VTT). Partial nephrectomy for RCC extending into the renal vein has been described in limited fashion, but such a complex procedure has not previously been reported in minimally-invasive fashion. We demonstrate the feasibility of robotic nephron-sparing surgery despite vein thrombi and the results of the initial four highly-selected patients to have undergone this novel procedure. Two patients underwent RPN for RCC with VTT involving intraparenchymal vein branches, and 2 others had VTT involving the main renal vein. Mean patient age was 65 years (range 50-74 years). Mean tumor size was 7.75 cm (range 4.3-12.8 cm) with mean RENAL (radius, exophytic/endophytic, nearness to collecting system, anterior/posterior, and location) nephrometry score of 9.75 (range 8-12). Mean warm ischemia time was 24.2 minutes (range 19-27 minutes) and mean estimated blood loss was 168.8 mL (range 100-300 mL). No patients required transfusion, and there were no intraoperative complications. No patients required conversion to open or standard laparoscopic surgery. All 4 patients were discharged home on the first postoperative day. A single postoperative complication occurred in 1 patient who was readmitted with an ileus that resolved spontaneously. All patients had negative surgical margins. Two patients developed metastatic disease on surveillance imaging. RPN in patients with VTT is safe and feasible in selected patients. Given the risk of metastatic disease in patients with pathologic stage T3a RCC, the role of nephron sparing requires further evaluation such that radical nephrectomy remains the standard of care. Copyright © 2013 Elsevier Inc. All rights reserved.

Metastatic clear cell carcinoma of the kidney: therapeutic role of bevacizumab

International Nuclear Information System (INIS)

Bukowski, Ronald M

2010-01-01

The biology and pathogenesis of clear cell carcinoma of the kidney has been extensively investgated, and the role of von Hipple-Landau gene inactivation and tumor associated angiogenesis is now recognized. Development of vascular endothelial growth factor inhibitors and phase 3 clinical trials utilizing this class of agents has produced a new treatment paradigm for patients with metastatic renal cell carcinoma (RCC). One of the active regimens identified is the combination of bevacizumab and interferon-α. Recently published reports provided evidence of the clinical and biologic activity of this therapy. The current manuscript reviews the background and rationale for the activity of bevacizumab in RCC, and results from recent clinical trials with this agent alone or in combination with targeted agents or cytokines. The role of this therapy in contrast to other targeted agents is reviewed, and the potential utility as well as questions raised by recent studies are discussed

Stages of Renal Cell Cancer

Science.gov (United States)

... Tumors Treatment Genetics of Kidney Cancer Research Renal Cell Cancer Treatment (PDQ®)–Patient Version General Information About Renal Cell Cancer Go to Health Professional Version Key Points Renal ...

Everolimus-associated acute kidney injury in patients with metastatic breast cancer

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A Chandra

2017-01-01

Full Text Available Recently, everolimus (Evl has been introduced in the management of hormone receptor-positive metastatic breast cancer, in combination with aromatase inhibitors. Evl-induced acute kidney injury has hitherto been described in other malignancies, especially renal cell cancer, but only once before in a patient with breast cancer. We describe two cases of Evl-associated nephrotoxicity in patients with breast cancer, one of whom underwent a renal biopsy showing acute tubular necrosis. Both our patients improved after withdrawal of the offending agent and have normal renal functions on follow-up.

Trials with TALL-1O4 Cells for Treatment of Metastatic Breast Cancer

Science.gov (United States)

1999-10-01

Cesano, A.*, Jeglum, K. A., and Santoli, D. Adjuvant treatment of canine osteosarcoma with the human cytotoxic T cell line TALL-104. Clin. Cancer... canine malignant histiocytosis with the human MHC non-restricted cytotoxic T cell line TALL-104. Clin. Cancer Res., 3: 1789-1797, 1997. 14. Visonneau, S...Visonneau, S., Cesano, A., Jeglum, K. A., and Santoli, D. Adoptive therapy of canine metastatic mammary carcinoma with the human MHC non-restricted

Nanotechnology combined therapy: tyrosine kinase-bound gold nanorod and laser thermal ablation produce a synergistic higher treatment response of renal cell carcinoma in animal model

Science.gov (United States)

Immunologically naïve nude mice (Athymic Nude-Foxn1nu) were injected bilaterally on the flanks (n=36) with 2.5 x 106 cells of a human metastatic renal cell carcinoma cell line (RCC 786-O). Subcutaneous xenograft tumors developed 1 cm palpable nodules. AuNR encapsulated in Human Serum Albumin (HSA) P...

Effect of two tumors (metastatic and non-metastatic) on tissue distribution of Ga-67 citrate in the rat

International Nuclear Information System (INIS)

Durakovic, A.

1985-01-01

The effect of metastatic and non-metastatic mammary adenocarcinoma on tissue distribution of Ga-67 citrate in Fischer female rats was studied. The homogenate (0.1 ml) of each tumor was injected subcutaneously in separate groups of rats and the animals were studied from day 2-30 after tumor homogenate implantation. All animals were injected with 30 μCi of Ga-67 citrate and sacrificed by halothane anethesia 48 hours later. Tissue samples of blood, lung, heart, liver, spleen, kidney, adrenal, stomach, small and large intestine, ovaries, and lymph nodes (popliteal, lumbar, and mediastinal) were obtained and counted in a gamma well counter. The control group consisted of four animals and tumor bearing groups of seven to eight animals at each time. Ga-67 uptake was increased in the liver (24 days) and in the popliteal lymph nodes on days 7, 10, and 18 in the metastatic tumor group (P<0.05). This probably represents Ga-67 uptake in the metastatic deposits in these organs. No difference was observed in non-metastatic tumor group

Present and future perspectives on immunotherapy for advanced renal cell carcinoma: Going to the core or beating around the bush?

Directory of Open Access Journals (Sweden)

Hidenori Kawashima

2015-03-01

Full Text Available Metastatic lesions of renal cell carcinoma (RCC occasionally regress spontaneously after surgical removal of the primary tumor. Although this is an exceptionally rare occurrence, RCC has thus been postulated to be immunogenic. Immunotherapies, including cytokine therapy, peptide-based vaccines, and immune checkpoint inhibitors have therefore been used to treat patients with advanced, metastatic RCC. We review the history, trends, and recent progress in immunotherapy for advanced RCC and discuss future perspectives, with consideration of our experimental work on galectin 9 and PINCH as promising specific immunotherapy targets. 

Bilateral papillary renal cell carcinoma

International Nuclear Information System (INIS)

Gossios, K.; Vazakas, P.; Argyropoulou, M.; Stefanaki, S.; Stavropoulos, N.E.

2001-01-01

Papillary renal cell carcinoma is a subgroup of malignant renal epithelial neoplasms. We report the clinical and imaging findings of a case with multifocal and bilateral renal cell carcinoma which are nonspecific. (orig.)

Dabrafenib plus trametinib in patients with previously untreated BRAF(V600E)-mutant metastatic non-small-cell lung cancer : An open-label, phase 2 trial

NARCIS (Netherlands)

Planchard, David; Smit, Egbert F.; Groen, Harry J. M.; Mazieres, Julien; Besse, Benjamin; Helland, Aslaug; Giannone, Vanessa; D'Amelio, Anthony M.; Zhang, Pingkuan; Mookerjee, Bijoyesh; Johnson, Bruce E.

2017-01-01

Background: BRAF(V600E) mutation occurs in 1-2% of lung adenocarcinomas and acts as an oncogenic driver. Dabrafenib, alone or combined with trametinib, has shown substantial antitumour activity in patients with previously treated BRAF(V600E)-mutant metastatic non-small-cell lung cancer (NSCLC). We

Previously unidentified changes in renal cell carcinoma gene expression identified by parametric analysis of microarray data

International Nuclear Information System (INIS)

Lenburg, Marc E; Liou, Louis S; Gerry, Norman P; Frampton, Garrett M; Cohen, Herbert T; Christman, Michael F

2003-01-01

Renal cell carcinoma is a common malignancy that often presents as a metastatic-disease for which there are no effective treatments. To gain insights into the mechanism of renal cell carcinogenesis, a number of genome-wide expression profiling studies have been performed. Surprisingly, there is very poor agreement among these studies as to which genes are differentially regulated. To better understand this lack of agreement we profiled renal cell tumor gene expression using genome-wide microarrays (45,000 probe sets) and compare our analysis to previous microarray studies. We hybridized total RNA isolated from renal cell tumors and adjacent normal tissue to Affymetrix U133A and U133B arrays. We removed samples with technical defects and removed probesets that failed to exhibit sequence-specific hybridization in any of the samples. We detected differential gene expression in the resulting dataset with parametric methods and identified keywords that are overrepresented in the differentially expressed genes with the Fisher-exact test. We identify 1,234 genes that are more than three-fold changed in renal tumors by t-test, 800 of which have not been previously reported to be altered in renal cell tumors. Of the only 37 genes that have been identified as being differentially expressed in three or more of five previous microarray studies of renal tumor gene expression, our analysis finds 33 of these genes (89%). A key to the sensitivity and power of our analysis is filtering out defective samples and genes that are not reliably detected. The widespread use of sample-wise voting schemes for detecting differential expression that do not control for false positives likely account for the poor overlap among previous studies. Among the many genes we identified using parametric methods that were not previously reported as being differentially expressed in renal cell tumors are several oncogenes and tumor suppressor genes that likely play important roles in renal cell

CT differentiation of infiltrating renal cell carcinoma and renal urothelial tumor

International Nuclear Information System (INIS)

Choi, Hyo Kyeong; Goo, Dong Erk; Bang, Sun Woo; Lee, Moon Gyu; Cho, Kyoung Sik; Auh, Yong Ho

1994-01-01

It may be difficult to differentiate renal cell carcinoma involving collecting system from renal urothelial tumor invading into renal parenchyma. The purpose of this study was to assess the differences of CT findings between two conditions. CT findings of 5 cases of renal cell carcinoma involving the renal collecting systems and 10 cases of renal urothelial tumors invading the renal parenchyma were compared, and analyzed about the presence or absence of hydronephrosis, normal or abnormal CT nephrogram, renal contour changes due to mass and tentative diagnosis. The diagnoses were confirmed at surgery. Renal cell carcinoma showed hydronephrosis in only 20% and normal CT nephrogram and outward contour bulging in all cases. In contrast, renal urothelial tumor showed hydronephrosis(70%), abnormal CT nephrogram(60%), and preservation of reinform shape(100%). Renal contour changes and CT nephrogram may be useful in distinguishing both disease entities

Nanoroughened adhesion-based capture of circulating tumor cells with heterogeneous expression and metastatic characteristics

International Nuclear Information System (INIS)

Chen, Weiqiang; Allen, Steven G.; Reka, Ajaya Kumar; Qian, Weiyi; Han, Shuo; Zhao, Jianing; Bao, Liwei; Keshamouni, Venkateshwar G.; Merajver, Sofia D.; Fu, Jianping

2016-01-01

Circulating tumor cells (CTCs) have shown prognostic relevance in many cancer types. However, the majority of current CTC capture methods rely on positive selection techniques that require a priori knowledge about the surface protein expression of disseminated CTCs, which are known to be a dynamic population. We developed a microfluidic CTC capture chip that incorporated a nanoroughened glass substrate for capturing CTCs from blood samples. Our CTC capture chip utilized the differential adhesion preference of cancer cells to nanoroughened etched glass surfaces as compared to normal blood cells and thus did not depend on the physical size or surface protein expression of CTCs. The microfluidic CTC capture chip was able to achieve a superior capture yield for both epithelial cell adhesion molecule positive (EpCAM+) and EpCAM- cancer cells in blood samples. Additionally, the microfluidic CTC chip captured CTCs undergoing transforming growth factor beta-induced epithelial-to-mesenchymal transition (TGF-β-induced EMT) with dynamically down-regulated EpCAM expression. In a mouse model of human breast cancer using EpCAM positive and negative cell lines, the number of CTCs captured correlated positively with the size of the primary tumor and was independent of their EpCAM expression. Furthermore, in a syngeneic mouse model of lung cancer using cell lines with differential metastasis capability, CTCs were captured from all mice with detectable primary tumors independent of the cell lines’ metastatic ability. The microfluidic CTC capture chip using a novel nanoroughened glass substrate is broadly applicable to capturing heterogeneous CTC populations of clinical interest independent of their surface marker expression and metastatic propensity. We were able to capture CTCs from a non-metastatic lung cancer model, demonstrating the potential of the chip to collect the entirety of CTC populations including subgroups of distinct biological and phenotypical properties. Further

Profile of ramucirumab in the treatment of metastatic non-small-cell lung cancer

Directory of Open Access Journals (Sweden)

Cooper MR

2016-04-01

Full Text Available Maryann R Cooper,1 Chelsea Binkowski,2,3 Jessica Hartung,2,4 Jennifer Towle1 1Department of Pharmacy Practice, School of Pharmacy – Worcester/Manchester, MCPHS University, Manchester, NH, 2School of Pharmacy – Boston, MCPHS University, Boston, MA, 3North America Medical Affairs, 4Global Medical Affairs, Sanofi Oncology, Cambridge, MA, USA Abstract: The interaction between vascular endothelial growth factor and its receptor is an important therapeutic target due to the importance of this pathway in carcinogenesis. In particular, this pathway promotes and regulates angiogenesis as well as increases endothelial cell proliferation, permeability, and survival. Ramucirumab is a fully human monoclonal antibody that specifically targets the vascular endothelial growth factor receptor-2, the key receptor implicated in angiogenesis. Currently, ramucirumab is approved for the second-line treatment of metastatic non-small-cell lung cancer (NSCLC in combination with docetaxel. In a Phase III clinical trial, ramucirumab was shown to improve the overall survival in patients with disease progression, despite platinum-based chemotherapy for advanced NSCLC. This review describes the pharmacology, pharmacokinetics and dynamics, adverse event profile, and the clinical activity of ramucirumab observed in Phase II and III trials in NSCLC. Keywords: NSCLC, antiangiogenesis, VEGF-targeted therapy

Long-term benefit of sunitinib in patients with metastatic renal cell carcinoma in Latin America: retrospective analysis of patient clinical characteristics

Directory of Open Access Journals (Sweden)

Smaletz O

2016-11-01

Full Text Available Oren Smaletz,1 Matias Chacón,2 Ludmila de Oliveira Koch,1 Daniela R de Carvalho Rocha,1 Fernanda C Cardoso1 1Department of Oncology, Hospital Israelita Albert Einstein, São Paulo, Brazil; 2Medical Oncology Department, Alexander Fleming Institute, Buenos Aires, Argentina Objective: To describe the clinical characteristics of Latin American patients with metastatic renal cell carcinoma (mRCC who experienced a progression-free survival (PFS for at least 15 months following treatment with sunitinib. Patients and methods: In this retrospective analysis, mRCC patients in two institutions in Latin America received sunitinib at a starting dose of either 50 mg/day for 4 weeks followed by 2 weeks off treatment (Schedule 4/2 in repeated 6-week cycles or sunitinib 37.5 mg on a continuous daily dosing schedule. Clinical characteristics, tolerability, and PFS data were collected. Results: Twenty-nine patients with long-term clinical benefit from sunitinib were identified between September 2005 and August 2009. Median PFS was 23 months (range: 15–54 months. Two of the 29 patients with prolonged PFS achieved a complete response and additional eleven had a partial response. Most patients were aged <60 years, had good performance status, favorable or intermediate Memorial Sloan Kettering Cancer Center prognostic risk, and disease limited to one or two sites. Dose reduction was necessary in all patients who started sunitinib at 50 mg/day administered on Schedule 4/2. Adverse events leading to dose reduction included grade 3 hand–foot syndrome, mucositis, fatigue, and hypertension. At the time of data cutoff, four patients were still receiving sunitinib treatment. Conclusion: Extended PFS can be achieved in Latin American patients with mRCC treated with sunitinib. Although the small sample size and retrospective nature of this evaluation preclude the identification of pretreatment predictive factors contributing to this benefit, the current analysis warrants

Quantitative Secretomic Analysis Identifies Extracellular Protein Factors That Modulate the Metastatic Phenotype of Non-Small Cell Lung Cancer.

Science.gov (United States)

Hu, Rongkuan; Huffman, Kenneth E; Chu, Michael; Zhang, Yajie; Minna, John D; Yu, Yonghao

2016-02-05

Lung cancer is the leading cause of cancer-related deaths for men and women in the United States, with non-small cell lung cancer (NSCLC) representing 85% of all diagnoses. Late stage detection, metastatic disease and lack of actionable biomarkers contribute to the high mortality rate. Proteins in the extracellular space are known to be critically involved in regulating every stage of the pathogenesis of lung cancer. To investigate the mechanism by which secreted proteins contribute to the pathogenesis of NSCLC, we performed quantitative secretomic analysis of two isogenic NSCLC cell lines (NCI-H1993 and NCI-H2073) and an immortalized human bronchial epithelial cell line (HBEC3-KT) as control. H1993 was derived from a chemo-naïve metastatic tumor, while H2073 was derived from the primary tumor after etoposide/cisplatin therapy. From the conditioned media of these three cell lines, we identified and quantified 2713 proteins, including a series of proteins involved in regulating inflammatory response, programmed cell death and cell motion. Gene Ontology (GO) analysis indicates that a number of proteins overexpressed in H1993 media are involved in biological processes related to cancer metastasis, including cell motion, cell-cell adhesion and cell migration. RNA interference (RNAi)-mediated knock down of a number of these proteins, including SULT2B1, CEACAM5, SPRR3, AGR2, S100P, and S100A14, leads to dramatically reduced migration of these cells. In addition, meta-analysis of survival data indicates NSCLC patients whose tumors express higher levels of several of these secreted proteins, including SULT2B1, CEACAM5, SPRR3, S100P, and S100A14, have a worse prognosis. Collectively, our results provide a potential molecular link between deregulated secretome and NSCLC cell migration/metastasis. In addition, the identification of these aberrantly secreted proteins might facilitate the development of biomarkers for early detection of this devastating disease.

Merkel Cell Carcinoma Metastatic to Pleural Fluid: A Case Report

Directory of Open Access Journals (Sweden)

Ye-Young Rhee

2018-05-01

Full Text Available Merkel cell carcinoma (MCC is a rare aggressive neuroendocrine carcinoma of the skin that shows locoregional or distant metastasis. Metastasis of MCC to body cavity effusion is extremely rare; only three cases have been reported so far. Metastatic MCC in effusion cytology shows small blue round cells with fine stippled chromatin like other small blue round cell tumors such as small cell lung carcinoma or lymphoma. The diagnosis of metastatic MCC can grant patients good chances at recently advanced therapeutic options. Here, we present a case of metastatic MCC to pleural effusion with characteristic single file-like pattern.

Merkel Cell Carcinoma Metastatic to Pleural Fluid: A Case Report.

Science.gov (United States)

Rhee, Ye-Young; Kim, Soo Hee; Kim, Eun Kyung; Kim, Se Hoon

2018-05-01

Merkel cell carcinoma (MCC) is a rare aggressive neuroendocrine carcinoma of the skin that shows locoregional or distant metastasis. Metastasis of MCC to body cavity effusion is extremely rare; only three cases have been reported so far. Metastatic MCC in effusion cytology shows small blue round cells with fine stippled chromatin like other small blue round cell tumors such as small cell lung carcinoma or lymphoma. The diagnosis of metastatic MCC can grant patients good chances at recently advanced therapeutic options. Here, we present a case of metastatic MCC to pleural effusion with characteristic single file-like pattern.

Role of RPLND and Metastasectomy in the Management of Oligometastatic Renal Cell Carcinoma.

Science.gov (United States)

Nagaraja, H; Srivatsa, N; Hemalatha, S; Shweta, S; Raghunath, S K

2018-03-01

Although lymphadenectomy is currently accepted as most accurate and reliable staging procedure for lymph node metastases, its therapeutic benefit in renal cell carcinoma (RCC) still remains controversial. Although the new, targeted therapy paradigms have changed the treatment of patients with advanced RCC and offer prolonged survival, cure is extremely uncommon in the absence of surgical resections. In this paper, the current role of metastasectomy is reviewed. Review the available literature concerning the role of retroperitoneal lymph node dissection and metastasectomy in outcome of oligometastatic RCC. A PubMed search was conducted to identify original articles, review articles, and editorials addressing the role of retroperitoneal lymph node dissection and metastasectomy in outcome of oligometastatic RCC. Keywords included renal tumors, renal cell cancer, kidney cancer, lymphadenectomy, metastasectomy, and oligometastases. While there is no randomized study available, recent large observational studies have better defined the prognosis of patients with metastatic RCC with or without metastasectomy and RPLND. To date, the available evidence suggests that RPLND and metastasectomy may be beneficial when technically feasible in patients with locally advanced (unfavorable clinical and pathologic characteristics) and oligometastatic disease. A proportion of patients will achieve long-term survival with aggressive surgical resection.

Protective, elective lung irradiation in non-metastatic Ewing's sarcoma.

Science.gov (United States)

Marinova, L; Hristozova, I; Mihaylova, I; Perenovska, P

2015-07-01

Ewing's sarcoma in childhood is a disease from family of the peripheral primitive neuroectodermal tumours. For a period of 16 y (1984-2000), 34 children with Ewing's sarcoma were treated and followed in our department. Twenty-seven of these patients were without distant metastases. Complex treatment was applied to all these patients-chemotherapy VACA (vincristine, actinomycin D, cyclophosphamide, adriamycin), local radiotherapy to a total dose of 50-56 Gy +/- surgery. After, a local tumour control was achieved in 11 children with non-metastatic Ewing's sarcoma, elective whole lung irradiation to a total dose of 12-15 Gy was applied. Our experience in these 11 patients with non-metastatic Ewing's sarcoma, in whom elective lung irradiation was applied, showed significant reduction in the lung metastases, improved free of disease survival and overall survival. The achieved good treatment results necessitate extending this treatment approach through defining the risk groups of patients, suitable for elective lung radiotherapy combined with chemotherapy in non-metastatic Ewing's sarcoma. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

CT differentiation of renal tumor invading parenchyma and pelvis: renal cell carcinoma vs transitional cell carcinoma

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Lee, Chang Hee; Cho, Seong Beum; Park, Cheol Min; Cha, In Ho; Chung, Kyoo Byung

1994-01-01

The differentiation between renal cell carcinoma(RCC) and transitional cell carcinoma(TCC) is important due to the different methods of treatment and prognosis. But occasionally it is difficult to draw a distinction between the two diseases when renal parenchyma and renal collecting systems are invaded simultaneously. We reviewed CT scans of 37 cases of renal cell carcinoma and 12 cases of transitional cell carcinoma which showed involvement of renal parenchyma and renal sinus fat on CT. Retrospective analysis was performed by 3 abdominal radiologists. Check points were renal contour bulging or reinform shape, location of mass center, intact parenchyma overlying the tumor, cystic change, calcification, LN metastasis, vessel invasion, and perirenal extention. There were renal contour bulging due to the tumor mass in 33 out of 37 cases of renal cell carcinoma, where a and nine of 12 cases of transitional cell carcinoma maintained the reinform appearance. This is significant statiscal difference between the two(P<0.005). Center of all TCCs were located in the renal sinus, and 24 out of 35 cases of RCC were located in the cortex(P<0.005). Thirty-six out of 37 cases of RCC lost the overlying parenchyma, where as 4 out of 9 cases of well enhanced TCC had intact overlying parenchyma(P<0.005) RCC showed uptic change within the tumor mags in 31 cases which was significanity higher than the 4 cases in TCC(P<0.05). CT findings of renal cell carcinoma are contour bulging, peripheral location, obliteration of parenchyma, and cystic change. Findings of transitional cell carcinoma are reinform appearance, central location within the kidney, intact overlying parenchyma, and rare cystic change

Regorafenib Induces Apoptosis and Inhibits Metastatic Potential of Human Bladder Carcinoma Cells.

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Hsu, Fei-Ting; Sun, Cho-Chin; Wu, Chia-Hsing; Lee, Yen-Ju; Chiang, Chih-Hung; Wang, Wei-Shu

2017-09-01

The aim of the present study was to verify the effects of regorafenib on apoptosis and metastatic potential in TSGH 8301 human bladder carcinoma cells in vitro. Cells were treated with different concentration of regorafenib for different periods of time. Effects of regorafenib on cell viability, apoptosis pathways, metastatic potential, and expression of metastatic and anti-apoptotic proteins were evaluated with the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium (MTT) assay, flow cytometry, cell migration and invasion assay, and western blotting. We found regorafenib significantly reduced cell viability, cell migration and invasion, and expression of metastatic and anti-apoptotic proteins. In addition, regorafenib significantly induced accumulation of sub-G 1 phase cells, loss of mitochondrial membrane potential, and expression of active caspase-3 and caspase-8. These results show that regorafenib not only induces apoptosis, but also inhibits metastatic potential in bladder cancer TSGH 8301 cells in vitro. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

mTOR-inhibitor treatment of metastatic renal cell carcinoma: contribution of Choi and modified Choi criteria assessed in 2D or 3D to evaluate tumor response

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Lamuraglia, M. [Laboratoire d' Imagerie Biomedicale, Sorbonne Universites, UPMC Univ Paris 06, INSERM, CNRS, Paris (France); Raslan, S.; Penna, R.R.; Wagner, M. [Groupe Hospitalier Pitie-Salpetriere, APHP UPMC, Service de Radiologie Polyvalente et Oncologique, Paris Cedex 13 (France); Elaidi, R.; Oudard, S. [APHP, Oncology Unit, Georges-Pompidou Hospital, Paris (France); Escudier, B. [Gustave-Roussy Institute, Medical Oncology Department, Villejuif (France); Slimane, K. [Novartis Pharma, Rueil-Malmaison (France); Lucidarme, O. [Groupe Hospitalier Pitie-Salpetriere, APHP UPMC, Service de Radiologie Polyvalente et Oncologique, Paris Cedex 13 (France); Laboratoire d' Imagerie Biomedicale, Sorbonne Universites, UPMC Univ Paris 06, INSERM, CNRS, Paris (France)

2016-01-15

To determine whether 2D or 3D Choi and modified Choi (mChoi) criteria could assess the efficacy of everolimus against metastatic renal cell carcinoma (mRCC). RECIST-1.1, Choi, and mChoi criteria were applied retrospectively to analyse baseline and 2-month contrast-enhanced computed tomography (CECT) images in 48 patients with mRCC enrolled in the everolimus arm of the French randomized double-blind multicentre phase III trial comparing everolimus versus placebo (RECORD-1). The primary endpoint was centrally reviewed progression-free survival (PFS) calculated from the initial RECORD-1 analysis. Mean attenuation was determined for 2D target lesion regions of interest drawn on CECT sections whose largest diameters had been measured, and for the 3D whole target lesion. The median PFS was 5.5 months. The median PFS for everolimus responders defined using 3D mChoi criteria was significantly longer than for non-responders (7.6 versus 5.4 months, respectively), corresponding to a hazard ratio for progression of 0.45 (95 % CI: 0.22-0.92), with respective 1-year survival rates of 31 % and 9 %. No other 2D or 3D imaging criteria at 2 months identified patients who would benefit from everolimus. At 2 months, only 3D mChoi criteria were able to identify mRCC patients with a PFS benefit from everolimus. (orig.)

Tumor signatures of PTHLH overexpression, high serum calcium, and poor prognosis were observed exclusively in clear cell but not non clear cell renal carcinomas

International Nuclear Information System (INIS)

Yao, Masahiro; Murakami, Takayuki; Shioi, Koichi; Mizuno, Nobuhiko; Ito, Hiroki; Kondo, Keiichi; Hasumi, Hisashi; Sano, Futoshi; Makiyama, Kazuhide; Nakaigawa, Noboru; Kishida, Takeshi; Nagashima, Yoji; Yamanaka, Shoji; Kubota, Yoshinobu

2014-01-01

High serum calcium (Ca) due to aberrant secretion of tumor parathyroid hormone-like hormone (PTHLH) is a well-known paraneoplastic sign and is associated with poor prognosis in patients with renal cell carcinoma (RCC). However, the status of serum Ca and tumor PTHLH expression have not been verified using the 2004 World Health Organization (WHO) renal tumor classification. We retrospectively reviewed corrected serum Ca levels at initial onset (n = 683) and/or as of recurrence (n = 71) in patients with RCC. We also examined a total of 623 renal parenchymal tumor samples for PTHLH mRNA expressions by quantitative real-time PCR. High serum Ca concomitant with PTHLH overexpression in tumors was observed exclusively in clear cell RCC but not in other non clear cell subtype tumors, including papillary, chromophobe, collecting-duct, unclassified, and other rare subtype RCCs or in benign oncocytomas and angiomyolipomas. In clear cell RCC, PTHLH expression was significantly high in male patients, and was associated with a symptomatic presentation, higher grade, and higher stage cases, whereas it was not associated with VHL gene status. Univariate analyses demonstrated that high PTHLH expression was strongly associated with poor outcome both in overall survival (OS) and disease-free survival (DFS) for patients who underwent standard nephrectomy. Further multivariate Cox analyses revealed that the PTHLH expressions remained as independent prognostic parameters for OS but not for DFS. These data suggest that the previously characterized tumor signatures of high serum Ca due to high PTHLH expression and poor prognosis are clear cell RCC-specific features, whereas these characteristics are rare in non clear cell RCCs

Renal cell carcinomas mass of <4 cm are not always indolent

DEFF Research Database (Denmark)

Azawi, Nessn H; Lund, Lars; Fode, Mikkel

2017-01-01

CONTEXT: The rate of progression to metastatic disease in patients undergoing active surveillance for small renal tumors varies in the literature between 1% and 8%. AIMS: This study aims to examine the incidence of metastasis in small renal tumors of cm in a Danish cohort. SETTINGS AND DESIGN......: Retrospective. MATERIALS AND METHODS: Data on 106 patients who were diagnosed with renal cancer (RCC) of cm by CT scan from January 2005 to December 2013 were collected retrospectively in January 2016 from patient charts and analyzed. STATISTICAL ANALYSIS USED: The cancer-specific survival (CSS) and overall...

Emerging growth factor receptor antagonists for the treatment of renal cell carcinoma.

Science.gov (United States)

Zahoor, Haris; Rini, Brian I

2016-12-01

The landscape of systemic treatment for metastatic renal cell carcinoma (RCC) has dramatically changed with the introduction of targeted agents including vascular endothelial growth factor (VEGF) inhibitors. Recently, multiple new agents including growth factor receptor antagonists and a checkpoint inhibitor were approved for the treatment of refractory metastatic RCC based on encouraging benefit shown in clinical trials. Areas covered: The background and biological rationale of existing treatment options including a brief discussion of clinical trials which led to their approval, is presented. This is followed by reviewing the limitations of these therapeutic options, medical need to develop new treatments and major goals of ongoing research. We then discuss two recently approved growth factor receptor antagonists i.e. cabozantinib and lenvatinib, and a recently approved checkpoint inhibitor, nivolumab, and issues pertaining to drug development, and future directions in treatment of metastatic RCC. Expert opinion: Recently approved growth factor receptor antagonists have shown encouraging survival benefit but associated drug toxicity is a major issue. Nivolumab, a programmed death 1 (PD-1) checkpoint inhibitor, has similarly shown survival benefit and is well tolerated. With multiple options now available in this patient population, the right sequence of these agents remains to be determined.

The HDAC inhibitor Vorinostat diminishes the in vitro metastatic behavior of Osteosarcoma cells.

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Mu, Xiaodong; Brynien, Daniel; Weiss, Kurt R

2015-01-01

Osteosarcoma (OS) is the most common primary malignancy of bone and affects patients in the first two decades of life. The greatest determinant of survival is the presence of pulmonary metastatic disease. The role of epigenetic regulation in OS, specifically the biology of metastases, is unknown. Our previous study with the murine OS cell populations K7M2 and K12 demonstrated a significant correlation of metastatic potential with the DNA methylation level of tumor suppressor genes. In the current study, we investigated if the histone deacetylase (HDAC) inhibitor, vorinostat, could regulate the metastatic potential of highly metastatic OS cells. Our results revealed that vorinostat treatment of highly metastatic K7M2 OS cells was able to greatly reduce the proliferation and metastatic potential of the cells. Morphological features related to cell motility and invasion were changed by vorinostat treatment. In addition, the gene expressions of mTOR, ALDH1, and PGC-1 were downregulated by vorinostat treatment. These data suggest that vorinostat may be an effective modulator of OS cell metastatic potential and should be studied in preclinical models of metastatic OS.

The HDAC Inhibitor Vorinostat Diminishes the In Vitro Metastatic Behavior of Osteosarcoma Cells

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Xiaodong Mu

2015-01-01

Full Text Available Osteosarcoma (OS is the most common primary malignancy of bone and affects patients in the first two decades of life. The greatest determinant of survival is the presence of pulmonary metastatic disease. The role of epigenetic regulation in OS, specifically the biology of metastases, is unknown. Our previous study with the murine OS cell populations K7M2 and K12 demonstrated a significant correlation of metastatic potential with the DNA methylation level of tumor suppressor genes. In the current study, we investigated if the histone deacetylase (HDAC inhibitor, vorinostat, could regulate the metastatic potential of highly metastatic OS cells. Our results revealed that vorinostat treatment of highly metastatic K7M2 OS cells was able to greatly reduce the proliferation and metastatic potential of the cells. Morphological features related to cell motility and invasion were changed by vorinostat treatment. In addition, the gene expressions of mTOR, ALDH1, and PGC-1 were downregulated by vorinostat treatment. These data suggest that vorinostat may be an effective modulator of OS cell metastatic potential and should be studied in preclinical models of metastatic OS.

Body composition by computed tomography as a predictor of toxicity in patients with renal cell carcinoma treated with sunitinib.

LENUS (Irish Health Repository)

Cushen, Samantha J

2014-04-21

Sunitinib is a standard first-line option for metastatic renal cell carcinoma (mRCC). Body composition is a prognostic factor in cancer patients and patients with loss of skeletal muscle mass and fat-free mass (FFM) are prone to dose-limiting toxicity (DLT) during targeted drug therapy. We investigated whether body composition by computed tomography predicted DLT from sunitinib in mRCC.

Nuclear expression of Lyn, a Src family kinase member, is associated with poor prognosis in renal cancer patients.

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Roseweir, Antonia K; Qayyum, Tahir; Lim, Zhi; Hammond, Rachel; MacDonald, Alasdair I; Fraser, Sioban; Oades, Grenville M; Aitchison, Michael; Jones, Robert J; Edwards, Joanne

2016-03-16

8000 cases of renal cancer are diagnosed each year in the UK, with a five-year survival rate of 50%. Treatment options are limited; a potential therapeutic target is the Src family kinases (SFKs). SFKs have roles in multiple oncogenic processes and promote metastases in solid tumours. The aim of this study was to investigate SFKs as potential therapeutic targets for clear cell renal cell carcinoma (ccRCC). SFKs expression was assessed in a tissue microarray consisting of 192 ccRCC patients with full clinical follow-up. SFK inhibitors, dasatinib and saracatinib, were assessed in early ccRCC cell lines, 786-O and 769-P and a metastatic ccRCC cell line, ACHN (± Src) for effects on protein expression, apoptosis, proliferation and wound healing. High nuclear expression of Lyn and the downstream marker of activation, paxillin, were associated with decreased patient survival. Conversely, high cytoplasmic expression of other SFK members and downstream marker of activation, focal adhesion kinase (FAK) were associated with increased patient survival. Treatment of non-metastatic 786-O and 769-P cells with dasatinib, dose dependently reduced SFK activation, shown via SFK (Y(419)) and FAK (Y(861)) phosphorylation, with no effect in metastatic ACHN cells. Dasatinib also increased apoptosis, while decreasing proliferation and migration in 786-O and 769-P cell lines, both in the presence and absence of Src protein. Our data suggests that nuclear Lyn is a potential therapeutic target for ccRCC and dasatinib affects cellular functions associated with cancer progression via a Src kinase independent mechanism.

Evaluation of the efficiency of combination palliative treatment in patients with metastatic clear-cell renal cell carcinoma

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P. S. Borisov

2015-01-01

Full Text Available Background. Experience with combination treatment, i.e. systemic therapy in combination with palliative surgery, in the treatment of metastatic kidney cancer is very rarely described in world literature.Objective: to evaluate the efficiency of combination treatment in combination with palliative cytoreductive surgery and targeted therapy and to define optimal indications for combination treatment.Subjects and methods. Data on 47 patients with metastatic renal cell carcinoma (mRCC who received systemic (targeted therapy in combination or after incomplete cytoreduction (iCR were analyzed in this retrospective study. The proportion of men and women was 72.3 % and 27.7 %, respectively; their ratio was 2.6:1. All the patients (100% underwent surgical treatment as nephrectomy or kidney resection for primary tumor. In the patients who had received radical treatment in different periods, the median relapse-free survival was 25.3 (0-187 months; the mean follow-up duration in the study was 33.2 (27.4–39.0 months. Out of the histological characteristics of a primary tumor, its Fuhrman grade was studied. Prior to initiation of mRCC therapy, Memorial Sloan Kettering Cancer Center (MSKCC prognosis groups were assessed; the patients were divided into good (n = 9 (19.1 %, interim (n = 28 (59.6 %, and bad (n = 10 (21.3 % prognosis groups. Their total somatic status was separately rated using the ECOG scale: 0, (n = 10 (21.3%, 1 (n = 24 (51.1 %, and 2, (n = 13 (27.6 %. The sites of metastases were as follows: the lung (n = 29, bones (n = 18, adrenals (n = 11, recurrence in the removed kidney bed (n = 10, and liver (n = 10. Multiple organ involvements were detected in 22 (46.8 % patients. There were more than 5 metastases in one organ in 18 (40.0 % patients and only 15 (33.3 % were found to have a single focus in one organ. Whether iCR might be used as a separate line treatment was studied. A comparative analysis was made between 2 groups of

miR-192, miR-194 and miR-215: a convergent microRNA network suppressing tumor progression in renal cell carcinoma.

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Khella, H W Z; Bakhet, M; Allo, G; Jewett, M A S; Girgis, A H; Latif, A; Girgis, H; Von Both, I; Bjarnason, G A; Yousef, G M

2013-10-01

MicroRNAs (miRNAs) play a crucial role in tumor progression and metastasis. We, and others, recently identified a number of miRNAs that are dysregulated in metastatic renal cell carcinoma compared with primary renal cell carcinoma. Here, we investigated three miRNAs that are significantly downregulated in metastatic tumors: miR-192, miR-194 and miR-215. Gain-of-function analyses showed that restoration of their expression decreases cell migration and invasion in renal cell carcinoma cell line models, whereas knockdown of these miRNAs resulted in enhancing cellular migration and invasion abilities. We identified three targets of these miRNAs with potential role in tumor aggressiveness: murine double minute 2, thymidylate synthase, and Smad Interacting protein 1/zinc finger E-box binding homeobox 2. We observed a convergent effect (the same molecule can be targeted by all three miRNAs) and a divergent effect (the same miRNA can control multiple targets) for these miRNAs. We experimentally validated these miRNA-target interactions using three independent approaches. First, we observed that miRNA overexpression significantly reduces the mRNA and protein levels of their targets. In the second, we observed significant reduction of the luciferase signal of a vector containing the 3'UTR of the target upon miRNA overexpression. Finally, we show the presence of inverse correlation between miRNA changes and the expression levels of their targets in patient specimens. We also examined the prognostic significance of miR-215 in renal cell carcinoma. Lower expression of miR-215 is associated with significantly reduced disease-free survival time. These findings were validated on an independent data set from The Cancer Genome Atlas. These results can pave the way to the clinical use of miRNAs as prognostic markers and therapeutic targets.

Renal Tubular Acidosis an Adverse Effect of PD-1 Inhibitor Immunotherapy

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Sandy El Bitar

2018-01-01

Full Text Available Immune checkpoint blockade therapy is gaining popularity among oncologists for treatment of solid and hematologic malignancies. The widespread use of these agents resulted in increasing incidence of renal immune-related adverse events. Reported renal toxicity described so far includes acute interstitial nephritis, minimal change disease, and immune complex glomerulonephritis. We report the case of a 79-year-old female with metastatic non-small cell lung cancer on anti-PD-1 therapy nivolumab. After the 4th administration of nivolumab, the treatment course was complicated with normal anion gap metabolic acidosis. Urine and blood studies were in favor of distal renal tubular acidosis (RTA. Following a negative workup for an underlying etiology, immunotherapy-induced RTA was suspected. Withholding of the offending agent and initiation of steroid therapy resulted in adequate response. The present report provides the first presentation of RTA as a renal immune-related adverse event secondary to nivolumab. Nephrologists and oncologists should be familiar with potentially life-threatening renal side effects induced by immune checkpoint inhibitors.

General Information about Renal Cell Cancer

Science.gov (United States)

... Tumors Treatment Genetics of Kidney Cancer Research Renal Cell Cancer Treatment (PDQ®)–Patient Version General Information About Renal Cell Cancer Go to Health Professional Version Key Points Renal ...

Treatment Option Overview (Renal Cell Cancer)

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... Tumors Treatment Genetics of Kidney Cancer Research Renal Cell Cancer Treatment (PDQ®)–Patient Version General Information About Renal Cell Cancer Go to Health Professional Version Key Points Renal ...

Tracking Cancer Evolution Reveals Constrained Routes to Metastases: TRACERx Renal.

Science.gov (United States)

Turajlic, Samra; Xu, Hang; Litchfield, Kevin; Rowan, Andrew; Chambers, Tim; Lopez, Jose I; Nicol, David; O'Brien, Tim; Larkin, James; Horswell, Stuart; Stares, Mark; Au, Lewis; Jamal-Hanjani, Mariam; Challacombe, Ben; Chandra, Ashish; Hazell, Steve; Eichler-Jonsson, Claudia; Soultati, Aspasia; Chowdhury, Simon; Rudman, Sarah; Lynch, Joanna; Fernando, Archana; Stamp, Gordon; Nye, Emma; Jabbar, Faiz; Spain, Lavinia; Lall, Sharanpreet; Guarch, Rosa; Falzon, Mary; Proctor, Ian; Pickering, Lisa; Gore, Martin; Watkins, Thomas B K; Ward, Sophia; Stewart, Aengus; DiNatale, Renzo; Becerra, Maria F; Reznik, Ed; Hsieh, James J; Richmond, Todd A; Mayhew, George F; Hill, Samantha M; McNally, Catherine D; Jones, Carol; Rosenbaum, Heidi; Stanislaw, Stacey; Burgess, Daniel L; Alexander, Nelson R; Swanton, Charles

2018-04-19

Clear-cell renal cell carcinoma (ccRCC) exhibits a broad range of metastatic phenotypes that have not been systematically studied to date. Here, we analyzed 575 primary and 335 metastatic biopsies across 100 patients with metastatic ccRCC, including two cases sampledat post-mortem. Metastatic competence was afforded by chromosome complexity, and we identify 9p loss as a highly selected event driving metastasis and ccRCC-related mortality (p = 0.0014). Distinct patterns of metastatic dissemination were observed, including rapid progression to multiple tissue sites seeded by primary tumors of monoclonal structure. By contrast, we observed attenuated progression in cases characterized by high primary tumor heterogeneity, with metastatic competence acquired gradually and initial progression to solitary metastasis. Finally, we observed early divergence of primitive ancestral clones and protracted latency of up to two decades as a feature of pancreatic metastases. Crown Copyright © 2018. Published by Elsevier Inc. All rights reserved.

Adenocarcinoma renal metastático em uma Codorna Japonesa (Coturnix coturnix japonica Metastatic renal adenocarcinoma in a Japanese Quail (Coturnix coturnix japonica

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Renata Assis Casagrande

2011-11-01

parenchyma and part of ovary and oviduct. Histologically, epithelial cells proliferation with formation of tubules, sometimes without lumen supported by mild fibrovascular stroma and multifocal necrosis was observed in the renal mass. The neoplastic cells were cuboidal, with round to oval nuclei, and evident nucleolus, abundant eosinophilic cytoplasm, moderated pleomorphism. Mitotic figures were rare. Metastasis was seen diffuse in ovary, oviduct, left lung, multifocal in intestinal serosa, focal in liver and serosal and muscular layer in gizzard. Immunohistochemically, tumors cells were positive for cytokeratin (clones AE1+AE3 and negative for cytokeratin 5/6, CD10 and placental alkaline phosphatase. According to localization, morphology features and immunohistochemistry evaluation, the present study reports a metastatic renal adenocarcinoma.

Adjuvant Sunitinib in High-Risk Renal-Cell Carcinoma after Nephrectomy.

Science.gov (United States)

Ravaud, Alain; Motzer, Robert J; Pandha, Hardev S; George, Daniel J; Pantuck, Allan J; Patel, Anup; Chang, Yen-Hwa; Escudier, Bernard; Donskov, Frede; Magheli, Ahmed; Carteni, Giacomo; Laguerre, Brigitte; Tomczak, Piotr; Breza, Jan; Gerletti, Paola; Lechuga, Mariajose; Lin, Xun; Martini, Jean-Francois; Ramaswamy, Krishnan; Casey, Michelle; Staehler, Michael; Patard, Jean-Jacques

2016-12-08

Sunitinib, a vascular endothelial growth factor pathway inhibitor, is an effective treatment for metastatic renal-cell carcinoma. We sought to determine the efficacy and safety of sunitinib in patients with locoregional renal-cell carcinoma at high risk for tumor recurrence after nephrectomy. In this randomized, double-blind, phase 3 trial, we assigned 615 patients with locoregional, high-risk clear-cell renal-cell carcinoma to receive either sunitinib (50 mg per day) or placebo on a 4-weeks-on, 2-weeks-off schedule for 1 year or until disease recurrence, unacceptable toxicity, or consent withdrawal. The primary end point was disease-free survival, according to blinded independent central review. Secondary end points included investigator-assessed disease-free survival, overall survival, and safety. The median duration of disease-free survival was 6.8 years (95% confidence interval [CI], 5.8 to not reached) in the sunitinib group and 5.6 years (95% CI, 3.8 to 6.6) in the placebo group (hazard ratio, 0.76; 95% CI, 0.59 to 0.98; P=0.03). Overall survival data were not mature at the time of data cutoff. Dose reductions because of adverse events were more frequent in the sunitinib group than in the placebo group (34.3% vs. 2%), as were dose interruptions (46.4% vs. 13.2%) and discontinuations (28.1% vs. 5.6%). Grade 3 or 4 adverse events were more frequent in the sunitinib group (48.4% for grade 3 events and 12.1% for grade 4 events) than in the placebo group (15.8% and 3.6%, respectively). There was a similar incidence of serious adverse events in the two groups (21.9% for sunitinib vs. 17.1% for placebo); no deaths were attributed to toxic effects. Among patients with locoregional clear-cell renal-cell carcinoma at high risk for tumor recurrence after nephrectomy, the median duration of disease-free survival was significantly longer in the sunitinib group than in the placebo group, at a cost of a higher rate of toxic events. (Funded by Pfizer; S-TRAC Clinical

Renal osteodystrophy in non-dialysed patients with chronic renal failure

International Nuclear Information System (INIS)

Andresen, J.; Nielsen, H.E.

1980-01-01

Radiologic bone lesions in 92 non-dialysed patients with chronic renal failure are described. The bone disease increased with the severity of renal failure. In a prospective series of 20 patients progression of osteodystrophy and decrease in metacarpal bone mass were demonstrated. (Auth.)

Changes in cytoskeletal dynamics and nonlinear rheology with metastatic ability in cancer cell lines

International Nuclear Information System (INIS)

Coughlin, Mark F; Fredberg, Jeffrey J

2013-01-01

Metastatic outcome is impacted by the biophysical state of the primary tumor cell. To determine if changes in cancer cell biophysical properties facilitate metastasis, we quantified cytoskeletal biophysics in well-characterized human skin, bladder, prostate and kidney cell line pairs that differ in metastatic ability. Using magnetic twisting cytometry with optical detection, cytoskeletal dynamics was observed through spontaneous motion of surface bound marker beads and nonlinear rheology was characterized through large amplitude forced oscillations of probe beads. Measurements of cytoskeletal dynamics and nonlinear rheology differed between strongly and weakly metastatic cells. However, no set of biophysical parameters changed systematically with metastatic ability across all cell lines. Compared to their weakly metastatic counterparts, the strongly metastatic kidney cancer cells exhibited both increased cytoskeletal dynamics and stiffness at large deformation which are thought to facilitate the process of vascular invasion. (paper)

Timing the Landmark Events in the Evolution of Clear Cell Renal Cell Cancer: TRACERx Renal

DEFF Research Database (Denmark)

Mitchell, Thomas J.; Turajlic, Samra; Rowan, Andrew

2018-01-01

Clear cell renal cell carcinoma (ccRCC) is characterized by near-universal loss of the short arm of chromosome 3, deleting several tumor suppressor genes. We analyzed whole genomes from 95 biopsies across 33 patients with clear cell renal cell carcinoma. We find hotspots of point mutations in the...

ERK Regulates Renal Cell Proliferation and Renal Cyst Expansion in inv Mutant Mice

International Nuclear Information System (INIS)

Okumura, Yasuko; Sugiyama, Noriyuki; Tanimura, Susumu; Nishida, Masashi; Hamaoka, Kenji; Kohno, Michiaki; Yokoyama, Takahiko

2009-01-01

Nephronophthisis (NPHP) is the most frequent genetic cause of end-stage kidney disease in children and young adults. Inv mice are a model for human nephronophthisis type 2 (NPHP2) and characterized by multiple renal cysts and situs inversus. Renal epithelial cells in inv cystic kidneys show increased cell proliferation. We studied the ERK pathway to understand the mechanisms that induce cell proliferation and renal cyst progression in inv kidneys. We studied the effects of ERK suppression by administering PD184352, an oral mitogen-activated protein kinase kinase (MEK) inhibitor on renal cyst expansion, extracellular signal-regulated protein kinase (ERK) activity, bromo-deoxyuridine (BrdU) incorporation and expression of cell-cycle regulators in invΔC kidneys. Phosphorylated ERK (p-ERK) level increased along with renal cyst enlargement. Cell-cycle regulators showed a high level of expression in invΔC kidneys. PD184352 successfully decreased p-ERK level and inhibited renal cyst enlargement. The inhibitor also decreased expression of cell-cycle regulators and BrdU incorporation in renal epithelial cells. The present results showed that ERK regulated renal cell proliferation and cyst expansion in inv mutants

Diagnosis value of dual-phase contrast enhancement CT combined with virtual non-enhanced images by dual-energy CT in clear cell renal cell carcinoma

International Nuclear Information System (INIS)

Ma Zhoupeng; Zhou Jianjun; Liu Xueling; Wang Chun; Zhang Shunzhuang

2012-01-01

Objective: To explore the diagnostic value of dual-phase contrast enhancement CT combined with virtual non-enhanced images by dual-energy CT in clear cell renal cell carcinoma. Methods: Sixty patients who were suspected of clear cell renal cell carcinoma underwent non-enhanced CT and contrast enhancement CT of early interface-phase between cortex -medulla and parenchymal phase on a dual-energy CT. The true non-enhanced kidney CT (TNCT) was performed in a single-energy acquisition mode, but the dual-phase contrast enhancement CT were performed in a dual-energy mode of 80 kV and 140 kV respectively. The virtual non-enhanced CT (VNCT) images were derived from the data of early interface phase using liver virtual non-contrast software. The diagnose according to VNCT combined dual-phase contrast enhancement CT and dual-phase contrast enhancement CT only were made respectively and compared with χ 2 test. Between the true non-contrast CT and the virtual non-contrast CT, the image quality was compared with Wilcoxon test; The radiation dose of volume CT dose index (CTDIvol) and dose length product(DLP) in a single-phase and total examination, the mean CT HU values of the tumours were compared with t test. Results: The accuracy of VNCT combined dual-phase contrast enhancement CT was higher than that of dual-phase contrast enhancement CT only [93.3% (56/60) vs.78.3% (47/60); χ 2 =5.6, P<0.05]. The detective ability (score) of VNCT was near to that of TNCT and the difference was not obvious (Z=0.00, P>0.05). The radiation dose of volume CT dose index (CTDIvol) and dose length product (DLP) in a single phase and total examination of VNCT [(8.85 ± 1.28) mGy, (196.45 ±21.12) mGy·cm, (17.69±2.35) mGy, (392.90±42.25) mGy · cm] were lower than that of TNCT [(10.20 ± 1.44) mGy,(218.29 ± 29.60) mGy · cm, (30.61 ± 3.27) mGy and (654.86 ± 88.81) mGy ·cm], t=4.21, 3.58, 23.63, 16.12 respectively, P<0.05. The mean CT HU values of tumours on VNCT images was higher than that

The role of surgery in renal cell carcinoma with pancreatic metastasis

Directory of Open Access Journals (Sweden)

Ying-Hsu Chang

2015-04-01

Full Text Available Metastasis of renal cell carcinoma to the pancreas is uncommon and, in most cases, presents as a single pancreatic mass that shows a more favorable prognosis than primary pancreatic tumors. We examined patients with renal cell carcinoma metastatic to the pancreas, and discuss the clinical findings, treatment administered, and final outcomes. The present study is a retrospective analysis of renal cell carcinoma patients with pancreatic metastasis. Pancreatic tumor specimens were obtained by surgical excision, surgical biopsy, fine-needle biopsy, or endoscopic ultrasound biopsy. The surgical approaches included distal splenopancreatectomy, total pancreatectomy, or distal pancreatectomy. The physician determined the postoperative treatment regimen with interferon-α or targeted therapy on the basis of patient's performance. A total of six patients with median age of 50 years were included in the study. The median time from the primary nephrectomy to the development of pancreatic metastasis was 16 years. In the biopsy-only group, the mean stable disease period was 16.5 months. In the patients treated with surgery combined with interferon-α or targeted therapy, the mean stable disease period was 29.5 months. The patients treated with repeat mastectomy showed a mean stable disease period of 33.3 months. Aggressive surgical management is more effective than observation or immunotherapy. Recent advances in the design of targeted therapies may provide alternative treatment strategies. Combination therapy may play an important role in the future. Considering patient compliance and cost-effectiveness, resection of pancreatic metastasis is currently the first choice of treatment.

Computed tomography of renal cell carcinoma in patients with terminal renal impairment

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Ferda, Jiri; Hora, Milan; Hes, Ondrej; Reischig, Tomas; Kreuzberg, Boris; Mirka, Hynek; Ferdova, Eva; Ohlidalova, Kristyna; Baxa, Jan; Urge, Tomas

2007-01-01

Purpose: An increased incidence of renal tumors has been observed in patients with end-stage-renal-disease (ESRD). The very strong association with acquired renal cystic disease (ACRD) and increased incidence of the renal tumors (conventional renal cell carcinoma (CRCC), papillary renal cell carcinoma (PRCC) or papillary renal cell adenoma (PRCA)) was reported. This study discusses the role of computed tomography (CT) in detecting renal tumors in patients with renal impairment: pre-dialysis, those receiving dialysis or with renal allograft transplants. Materials and methods: Ten patients (nine male, one female) with renal cell tumors were enrolled into a retrospective study; two were new dialysis patients, three on long-term dialysis, and five were renal transplant recipients with history of dialysis. All patients underwent helical CT, a total of 11 procedures were performed. Sixteen-row detector system was used five times, and a 64-row detector system for the six examinations. All patients underwent nephrectomy of kidney with suspected tumor, 15 nephrectomies were performed, and 1 kidney was assessed during autopsy. CT findings were compared with macroscopic and microscopic assessments of the kidney specimen in 16 cases. Results: Very advanced renal parenchyma atrophy with small cysts corresponding to ESRD was found in nine patients, chronic pyelonephritis in remained one. A spontaneously ruptured tumor was detected incidentally in one case, patient died 2 years later. In the present study, 6.25% (1/16) were multiple PRCA, 12.5% (2/16) were solitary PRCC, 12.5% tumors (2/16) were solitary conventional renal cell carcinomas (CRCC's), 12.5% tumors (2/16) were multiple conventional renal cell carcinomas (CRCC's), 25% (4/16) were CRCC's combined with multiple papillary renal cell carcinomas with adenomas (PRCC's and PRCA's), and 25% (4/16) of the tumors were multiple PRCC's combined with PRCA's without coexisting CRCC's. Bilateral renal tumors were found in our study

The role of lymph node dissection in the contemporary management of renal cell carcinoma: A critical appraisal of the evidence.

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Brito, Joseph; Gershman, Boris

2017-11-01

The role of lymph node dissection (LND) in the management of renal cell carcinoma has been controversial. Older studies provided initial support to a potential survival benefit in resection of lymph node metastases, and several predictive models were developed to identify patients with lymph node involvement. However, the only randomized trial on the subject did not report a survival benefit to LND in the nonmetastatic setting. Several studies have recently reexplored the therapeutic benefit of LND. In both nonmetastatic and metastatic settings, LND does not appear to be associated with a survival benefit. Moreover, it does not appear that LND confers a survival advantage to patients at increased risk of lymph node metastases, such as those with preoperative radiographic lymphadenopathy or across increasing probability of lymph node disease. Among patients with clinically isolated lymph node metastases, the majority develop disease progression following surgical resection, suggesting a high prevalence of occult systemic disease. Lymph node metastases appear to have prognostic value in both nonmetastatic and metastatic settings. LND may, therefore, have an increasingly important staging role in the management of renal cell carcinoma. Copyright © 2017 Elsevier Inc. All rights reserved.

Sarcomatoid differentiation in renal cell carcinoma: prognostic implications

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Marcos F. Dall'Oglio

2005-02-01

Full Text Available INTRODUCTION: Renal cell carcinoma with sarcomatoid differentiation is a tumor with aggressive behavior that is poorly responsive to immunotherapy. The objective of this study is to report our experience in the treatment of 15 patients with this tumor. MATERIALS AND METHODS: We retrospectively analyzed 15 consecutive cases of renal cell carcinoma with sarcomatoid differentiation diagnosed between 1991 and 2003. The clinical presentation and the pathological stage were assessed, as were the tumor's pathological features, use of adjuvant immunotherapy and survival. The study's primary end-point was to assess survival of these individuals. RESULTS: The sample included 8 women and 7 men with mean age of 63 years (44 - 80; follow-up ranged from 1 to 100 months (mean 34. Upon presentation, 87% were symptomatic and 4 individuals had metastatic disease. Mean tumor size was 9.5 cm (4 - 24 with the following pathological stages: 7% pT1, 7% pT2, 33% pT3, and 53% pT4. The pathological features showed high-grade tumors with tumoral necrosis in 87% of the lesions and 80% of intratumoral microvascular invasion. Disease-free and cancer-specific survival rates were 40 and 46% respectively, with 2 cases responding to adjuvant immunotherapy. CONCLUSIONS: Patients with sarcomatoid tumors of the kidney have a low life expectancy, and sometimes surgical resection associated with immunotherapy can lead to a long-lasting therapeutic response.

Experience with renal cell carcinoma-a single centre study from Khyber Pakhtunkhwa

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Khan, H. S.; Mahmood, A.

2017-01-01

Objective: To analyze the clinical characteristics, management and outcome of renal cell carcinoma (RCC) and its variants in patients treated at CMH Peshawar, from Aug 2011 to Aug 2014. Study Design: Retrospective descriptive. Place and Duration of Study: Combined Military Hospital (CMH) Peshawar, from Aug 2011 to Aug 2014. Material and Methods: All patients who underwent nephrectomy for renal masses at our institution between Aug 2011 and Aug 2014 were included in the study. The demographic distribution, symptoms, tumour characteristics, operative findings and histopathology reports were extracted from the hospital records and analysed via SPSS version 20.0. Results: Among 27 patients male to female ratio was 1.25:1. Mean age was 55.5 ± 11.7 years. Flank pain was the commonest symptom reported. Mean maximum diameter of the tumour was 13.6 ± 4.6 cm. All the tumours were malignant and most common histopathological type was conventional/clear cell RCC. All patients were treated by radical nephrectomy through transperitoneal approach. One patient developed post operative thrombosis of inferior vena cava. Two patients developed metastatic deposit during follow up. Conclusion: Renal tumours in the study population of Khyber Pakhtunkhwa at our centre presented late with large sizes, and incidental diagnosis is rare. Health education and availability of advanced diagnostic facilities will improve outcomes. (author)

Chromophobe Renal Cell Carcinoma is the Most Common Nonclear Renal Cell Carcinoma in Young Women: Results from the SEER Database.

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Daugherty, Michael; Blakely, Stephen; Shapiro, Oleg; Vourganti, Srinivas; Mollapour, Mehdi; Bratslavsky, Gennady

2016-04-01

The renal cell cancer incidence is relatively low in younger patients, encompassing 3% to 7% of all renal cell cancers. While young patients may have renal tumors due to hereditary syndromes, in some of them sporadic renal cancers develop without any family history or known genetic mutations. Our recent observations from clinical practice have led us to hypothesize that there is a difference in histological distribution in younger patients compared to the older cohort. We queried the SEER (Surveillance, Epidemiology and End Results) 18-registry database for all patients 20 years old or older who were surgically treated for renal cell carcinoma between 2001 and 2008. Patients with unknown race, grade, stage or histology and those with multiple tumors were excluded from study. Four cohorts were created by dividing patients by gender, including 1,202 females and 1,715 males younger than 40 years old, and 18,353 females and 30,891 males 40 years old or older. Chi-square analysis was used to compare histological distributions between the cohorts. While clear cell carcinoma was still the most common renal cell cancer subtype across all genders and ages, chromophobe renal cell cancer was the most predominant type of nonclear renal cell cancer histology in young females, representing 62.3% of all nonclear cell renal cell cancers (p renal cell cancer remained the most common type of nonclear renal cell cancer. It is possible that hormonal factors or specific pathway dysregulations predispose chromophobe renal cell cancer to develop in younger women. We hope that this work provides some new observations that could lead to further studies of gender and histology specific renal tumorigenesis. Copyright © 2016 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

Outcomes in Patients With Metastatic Renal Cell Carcinoma Who Develop Everolimus-Related Hyperglycemia and Hypercholesterolemia: Combined Subgroup Analyses of the RECORD-1 and REACT Trials.

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Bono, Petri; Oudard, Stephane; Bodrogi, Istvan; Hutson, Thomas E; Escudier, Bernard; Machiels, Jean-Pascal; Thompson, John A; Figlin, Robert A; Ravaud, Alain; Basaran, Mert; Porta, Camillo; Bracarda, Sergio; Brechenmacher, Thomas; Lin, Chinjune; Voi, Maurizio; Grunwald, Viktor; Motzer, Robert J

2016-10-01

Hyperglycemia and hypercholesterolemia are class effects of mammalian target of rapamycin inhibitors. The purpose of this study was to characterize safety and efficacy of patients with metastatic renal cell carcinoma (mRCC) treated with everolimus in RECORD-1 (REnal Cell cancer treatment with Oral RAD001 given Daily) and REACT (RAD001 Expanded Access Clinical Trial in RCC) who developed these events. Adults with vascular endothelial growth factor-refractory mRCC received everolimus 10 mg/d in the randomized RECORD-1 (n = 277) and open-label REACT (n = 1367) studies. Outcomes included safety, treatment duration, overall response, and progression-free survival for patients who developed hypercholesterolemia or hyperglycemia. In RECORD-1, 12% (33 of 277) and 20% (55 of 277) of patients developed any grade hyperglycemia or hypercholesterolemia, respectively, with only 6% (78 of 1367) and 1% (14 of 1367) of the same events, respectively, in REACT. Median everolimus treatment duration was similar for patients with hyperglycemia or hypercholesterolemia (RECORD-1, 6.2 and 6.2 months, respectively; REACT, 4.4 and 4.5 months, respectively), but longer than the overall populations (RECORD-1, 4.6 months; REACT, 3.2 months). In RECORD-1/REACT, 82%/68% of patients with hyperglycemia and 75%/71% of patients with hypercholesterolemia achieved partial response or stable disease. The incidence of clinically notable Grade 3 or 4 adverse events, other than anemia and lymphopenia, appeared to be similar across trials and subgroups. Although there was a trend for improved progression-free survival with development of hyperglycemia or hypercholesterolemia, the association was not statistically significant. Hyperglycemia and hypercholesterolemia were observed in low numbers of patients, and although these events might be associated with improved response to everolimus, the differences were not significant. These findings should be validated with prospective biomarker studies. Copyright

Primary renal carcinoid tumor mimicking non-clear cell renal cell carcinoma: A case report

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Joo, Lee Hi; Kim, See Hyung; Kim, Mi Jeong; Choe, Mi Sun [Keimyung University School of Medicine, Dongsan Medical Center, Daegu (Korea, Republic of)

2016-07-15

Carcinoid tumors are neoplasms with neuroendocrine differentiation, and they are most commonly found in the gastrointestinal and respiratory systems. Primary renal carcinoid tumor has rarely been reported. Here, we present a case of primary renal carcinoid tumor manifesting as a small but a gradually enhancing mass with calcification and a cystic component.

MicroRNAs Associated with Von Hippel-Lindau Pathway in Renal Cell Carcinoma: A Comprehensive Review.

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Schanza, Lisa-Maria; Seles, Maximilian; Stotz, Michael; Fosselteder, Johannes; Hutterer, Georg C; Pichler, Martin; Stiegelbauer, Verena

2017-11-22

Renal cell carcinoma (RCC) are the most common renal neoplasia and can be divided into three main histologic subtypes, among which clear cell RCC is by far the most common form of kidney cancer. Despite substantial advances over the last decade in the understanding of RCC biology, surgical treatments, and targeted and immuno-therapies in the metastatic setting, the prognosis for advanced RCC patients remains poor. One of the major problems with RCC treatment strategies is inherent or acquired resistance towards therapeutic agents over time. The discovery of microRNAs (miRNAs), a class of small, non-coding, single-stranded RNAs that play a crucial role in post-transcriptional regulation, has added new dimensions to the development of novel diagnostic and treatment tools. Because of an association between Von Hippel-Lindau (VHL) genes with chromosomal loss in 3p25-26 and clear cell RCC, miRNAs have attracted considerable scientific interest over the last years. The loss of VHL function leads to constitutional activation of the hypoxia inducible factor (HIF) pathway and to consequent expression of numerous angiogenic and carcinogenic factors. Since miRNAs represent key players of carcinogenesis, tumor cell invasion, angiogenesis, as well as in development of metastases in RCC, they might serve as potential therapeutic targets. Several miRNAs are already known to be dysregulated in RCC and have been linked to biological processes involved in tumor angiogenesis and response to anti-cancer therapies. This review summarizes the role of different miRNAs in RCC angiogenesis and their association with the VHL gene, highlighting their potential role as novel drug targets.

MicroRNAs Associated with Von Hippel–Lindau Pathway in Renal Cell Carcinoma: A Comprehensive Review

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Lisa-Maria Schanza

2017-11-01

Full Text Available Renal cell carcinoma (RCC are the most common renal neoplasia and can be divided into three main histologic subtypes, among which clear cell RCC is by far the most common form of kidney cancer. Despite substantial advances over the last decade in the understanding of RCC biology, surgical treatments, and targeted and immuno-therapies in the metastatic setting, the prognosis for advanced RCC patients remains poor. One of the major problems with RCC treatment strategies is inherent or acquired resistance towards therapeutic agents over time. The discovery of microRNAs (miRNAs, a class of small, non-coding, single-stranded RNAs that play a crucial role in post-transcriptional regulation, has added new dimensions to the development of novel diagnostic and treatment tools. Because of an association between Von Hippel–Lindau (VHL genes with chromosomal loss in 3p25-26 and clear cell RCC, miRNAs have attracted considerable scientific interest over the last years. The loss of VHL function leads to constitutional activation of the hypoxia inducible factor (HIF pathway and to consequent expression of numerous angiogenic and carcinogenic factors. Since miRNAs represent key players of carcinogenesis, tumor cell invasion, angiogenesis, as well as in development of metastases in RCC, they might serve as potential therapeutic targets. Several miRNAs are already known to be dysregulated in RCC and have been linked to biological processes involved in tumor angiogenesis and response to anti-cancer therapies. This review summarizes the role of different miRNAs in RCC angiogenesis and their association with the VHL gene, highlighting their potential role as novel drug targets.

Polychlorinated biphenyls (PCBs enhance metastatic properties of breast cancer cells by activating Rho-associated kinase (ROCK.

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Sijin Liu

Full Text Available BACKGROUND: Polychlorinated biphenyls (PCBs are a family of structurally related chlorinated aromatic hydrocarbons. Numerous studies have documented a wide spectrum of biological effects of PCBs on human health, such as immunotoxicity, neurotoxicity, estrogenic or antiestrogenic activity, and carcinogenesis. The role of PCBs as etiologic agents for breast cancer has been intensively explored in a variety of in vivo, animal and epidemiologic studies. A number of investigations indicated that higher levels of PCBs in mammary tissues or sera correlated to breast cancer risk, and PCBs might be implicated in advancing breast cancer progression. METHODOLOGY/PRINCIPAL FINDINGS: In the current study, we for the first time report that PCBs greatly promote the ROCK activity and therefore increase cell motility for both non-metastatic and metastatic human breast cancer cells in vitro. In the in vivo study, PCBs significantly advance disease progression, leading to enhanced capability of metastatic breast cancer cells to metastasize to bone, lung and liver. Additionally, PCBs robustly induce the production of intracellular reactive oxygen species (ROS in breast cancer cells; ROS mechanistically elevate ROCK activity. CONCLUSIONS/SIGNIFICANCE: PCBs enhance the metastatic propensity of breast cancer cells by activating the ROCK signaling, which is dependent on ROS induced by PCBs. Inhibition of ROCK may stand for a unique way to restrain metastases in breast cancer upon PCB exposure.

Avelumab: A Review in Metastatic Merkel Cell Carcinoma.

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Shirley, Matt

2018-05-24

Avelumab (Bavencio ® ) is a fully human IgG1 monoclonal antibody that is directed against programmed cell death ligand 1 (PD-L1). Avelumab functions as an immune checkpoint inhibitor and has recently been approved in the USA, the EU and Japan for the treatment of metastatic Merkel cell carcinoma (MCC). It is thus the first therapeutic agent specifically approved for use in this indication, and is approved for use independent of line of treatment. Approval for avelumab in metastatic MCC was based on the two-part, single-arm, phase II trial, JAVELIN Merkel 200. In Part A of the study, confirmed objective responses were observed in approximately one-third of patients with chemotherapy-refractory metastatic MCC treated with avelumab. The responses were observed early and appeared to be durable, with an estimated 74% of responses having a duration ≥ 12 months. Furthermore, interim results from a separate cohort of patients (Part B) indicate an objective response rate for avelumab of > 60% in patients who were chemotherapy-naïve in the metastatic disease setting. Avelumab is associated with a risk of immune-related adverse events but, overall, has an acceptable and manageable safety and tolerability profile. In conclusion, currently available data suggest that avelumab presents a clinically beneficial new treatment option for metastatic MCC, a rare but aggressive cancer associated with a poor prognosis.

RNA interference suppression of A100A4 reduces the growth and metastatic phenotype of human renal cancer cells via NF-kB-dependent MMP-2 and bcl-2 pathway.

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Yang, X-C; Wang, X; Luo, L; Dong, D-H; Yu, Q-C; Wang, X-S; Zhao, K

2013-06-01

S100A4 is a well established marker and mediator of metastatic disease, but the exact mechanisms responsible for the metastasis promoting effects are less well defined. We tested a hypothesis that the S100A4 gene plays a role in the proliferation and invasiveness of human renal cancer cells (RCC) and may be associated with its metastatic spread. The small interference RNA vector pcDNA3.1-S100A4 siRNA was transfected in to the human renal cancer cell lines ACHN, Ketr-3, OS-RC-2, CaKi-2 and HTB-47, then treated with ABT-737 or BB94. Cell apoptosis and cell viability was detected by flow cytometry and MTT assay. Matrigel was used for cell motility and invasion assay. MMP-2, bcl-2 and S100A4 was detected by RT-PCR and western blot assay. NF-kB subunit p65 activity was detected by confocal microscopy assay. We then determine the effect S100A4 sliencing on tumor growth, lung metastasis development in vivo. Immunohistochemistry was used to detected the expression of S100A4, bcl-2, MMP-2, p65 and CD31. S100A4 silencing in ACHN cells by RNA interference significantly inhibited NF-kB and NF-kB-mediated MMP-2 and bcl-2 activation and cellular migration, proliferation, and promoted apoptosis. Furthermore, re-expression of S100A4 in S100A4-siRNA-transfected ACHN cells by transient S100A4 cDNA transfection restored the NF-kB and NF-kB-mediated MMP-2 and bcl-2 activation and their high migratory and cellular proliferative ability. An inhibitor ABT-737 (the Bcl-2 antagonist targets Bcl-2) against Bcl-2 suppressed cellular proliferation and promoted apoptosis induced by S100A4 re-expression in S100A4-siRNA-transfected ACHN cells. A inhibitor BB94 against MMPs to neutralize MMP-2 protein suppressed cellular invasion and migration induced by S100A4 re-expression in S100A4-siRNA-transfected ACHN cells. In the prevention model, S100A4 silencing inhibited primary tumor growth by (tumor weight) (76 ± 8%) and (tumor volum) (78 ± 4%) respectively and promoted apoptosis and the formation

Axitinib in the treatment of renal cell carcinoma: design, development, and place in therapy

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Bellesoeur A

2017-09-01

Full Text Available Audrey Bellesoeur, Edith Carton, Jerome Alexandre, Francois Goldwasser, Olivier Huillard Department of Medical Oncology, Hopital Cochin AP-HP, Paris, France Abstract: Since 2005, the approved first-line treatment of metastatic renal cell carcinoma consists in tyrosine kinase inhibitors (TKIs targeting the vascular endothelial growth factor receptors (VEGFRs. Axitinib is an oral second-generation TKI and a potent VEGFR inhibitor with a half maximal inhibitory concentration for the VEGF family receptors 10-fold lower than other TKIs. Axitinib activity in renal cell carcinoma (RCC patients has been studied in various settings and particularly as second-line treatment. In this setting, axitinib with clinically based dose escalation compared to sorafenib has demonstrated an improvement in progression-free survival in a randomized Phase III trial leading to US Food and Drug Administration approval. In the first-line setting, axitinib failed to demonstrate improved efficacy over sorafenib, but the field of RCC treatment is rapidly changing with novel TKIs as cabozantinib or the emergence of check point inhibitors as nivolumab and the place of axitinib in therapy is therefore challenged. In this review, we focus on axitinib pharmacological and clinical properties in RCC patients and discuss its place in the treatment of patients with RCC. Keywords: renal cell carcinoma, tyrosine kinase inhibitors, vascular endothelial growth factor, axitinib, pharmacology

Rapid Progression of Metastatic Pulmonary Calcification and Alveolar Hemorrhage in a Patient with Chronic Renal Failure and Primary Hyperparathyroidism

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Yoon, Eun Joo; Kim, Dong Hun; Yoon, Seong Ho; Suk, Eun Ha

2013-01-01

Metastatic pulmonary calcification (MPC) is common in patients with chronic renal failure. The authors experienced a patient with chronic renal failure and primary hyperparathyroidism by parathyroid adenoma accompanied with rapid progressions of MPC and alveolar hemorrhage. Recent chest radiographs, compared with previous chest radiographs, showed rapid accumulation of calcification in both upper lungs. Following up on the high-resolution CT scan after five years demonstrates more increased nodules in size and ground glass opacity. The patient was diagnosed with MPC and alveolar hemorrhage by transbronchial lung biopsy. We assumed rapid progression of MPC and alveolar hemorrhage in underlying chronic renal failures could be a primary hyperparathyroidism which may be caused by parathyroid adenoma detected incidentally. Therefore parathyroid adenoma was treated with ethanol injections. Herein, we have reported on CT findings of MPC with alveolar hemorrhage and reviewed our case along with other articles.

An aggressive merkel cell carcinoma in a patient with chronic renal failure

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Sevda Gizlenti

2014-12-01

Full Text Available Merkel cell carcinoma (MCC is a rare cutaneous tumor arising from neuroendocrine cells and Merkel cells. Early diagnosis and treatment is important because of its aggressive course. We here report a 61 years old man with chronic renal failure, 3x5 cm mass on his right leg and inguinal-paraaortic lymph node metastases and resulting in death. MCC in the literature of the AIDS disease, organ transplantation, immunosuppressive therapy areas, and additional malignancies (multiple myeloma, chronic lymphocytic leukemia, non-Hodgkin's lymphoma, and melanoma have been reported in patients with increased incidence. Up to date a patient with renal transplantation and Merkel cell carcinoma have been reported in the literature, Merkel cell carcinoma with chronic renal failure have not been reported.

Pharmacoeconomics of bisphosphonates for skeletal-related event prevention in metastatic non-breast solid tumours.

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Carter, John A; Joshi, Avani D; Kaura, Satyin; Botteman, Marc F

2012-05-01

Bisphosphonates reduce the risk of skeletal-related events (SREs; i.e. spinal cord compression, pathological fracture, radiation or surgery to the bone, and hypercalcaemia) in patients with metastatic cancer. A number of analyses have been conducted to assess the cost effectiveness of bisphosphonates in patients with bone metastases secondary to breast cancer, but few in other solid tumours. This is a review of cost-effectiveness analyses in patients with non-breast solid tumours and bone metastases. A literature search was conducted to identify cost-effectiveness analyses reporting the cost per QALY gained of bisphosphonates in patients with metastatic bone disease secondary to non-breast solid tumours. Four analyses met inclusion criteria. These included two in prostate cancer (one of which used a global perspective but expressed results in $US, and the other reported from a multiple country perspective: France, Germany, Portugal and the Netherlands). The remaining analyses were in lung cancer (in the UK, France, Germany, Portugal and the Netherlands), and renal cell carcinoma (in the UK, France and Germany). In each analysis, the cost effectiveness of zoledronic acid versus placebo was analysed. Zoledronic acid was found to be cost effective in all European countries across all three indications but not in the sole global prostate cancer analysis. Across countries and indications, assumptions regarding patient survival, drug cost and baseline utility (i.e. patient utility with metastatic disease but without an SRE) were the most robust drivers of modelled estimates. Assumptions of SRE-related costs were most often the second strongest cost driver. Further review indicated that particular attention should be paid to the inclusion or exclusion of nonsignificant survival benefits, whether health state utilities were elicited from community or patient samples or author assumptions, delineation between symptomatic and asymptomatic SREs, and the methods with which SRE

Single incision laparoscopic pancreas resection for pancreatic metastasis of renal cell carcinoma.

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Barbaros, Umut; Sümer, Aziz; Demirel, Tugrul; Karakullukçu, Nazlı; Batman, Burçin; Içscan, Yalın; Sarıçam, Gülay; Serin, Kürçsat; Loh, Wei-Liang; Dinççağ, Ahmet; Mercan, Selçuk

2010-01-01

Transumbilical single incision laparoscopic surgery (SILS) offers excellent cosmetic results and may be associated with decreased postoperative pain, reduced need for analgesia, and thus accelerated recovery. Herein, we report the first transumbilical single incision laparoscopic pancreatectomy case in a patient who had renal cell cancer metastasis on her pancreatic corpus and tail. A 59-year-old female who had metastatic lesions on her pancreas underwent laparoscopic subtotal pancreatectomy through a 2-cm umbilical incision. Single incision pancreatectomy was performed with a special port (SILS port) and articulated equipment. The procedure lasted 330 minutes. Estimated blood loss was 100mL. No perioperative complications occurred. The patient was discharged on the seventh postoperative day with a low-volume (20mL/day) pancreatic fistula that ceased spontaneously. Pathology result of the specimen was renal cell cancer metastases. This is the first reported SILS pancreatectomy case, demonstrating that even advanced surgical procedures can be performed using the SILS technique in well-experienced centers. Transumbilical single incision laparoscopic pancreatectomy is feasible and can be performed safely in experienced centers. SILS may improve cosmetic results and allow accelerated recovery for patients even with malignancy requiring advanced laparoscopic interventions.

Late simultaneous metastasis of renal cell carcinoma to the submandibular and thyroid glands seven years after radical nephrectomy.

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Miah, Mohammed S; White, Sharon J; Oommen, George; Birney, Esther; Majumdar, Samit

2010-01-01

Background. Renal cell carcinoma (RCC) metastasis to the salivary glands is extremely rare. Most cases reported previously have involved the parotid gland and only six cases involving the submandibular gland exist in the current literature. Metastasis of RCC to thyroid gland is also rare but appears to be more common than to salivary glands. Methods and Results. We present the first case of simultaneous metastasis to the submandibular and thyroid glands from clear cell RCC in a 61-year-old woman who presented seven years after the primary treatment. The submandibular and thyroid glands were excised completely with preservation of the marginal mandibular and recurrent laryngeal nerves, respectively. Conclusion. Metastatic disease should always be considered in the differential diagnosis for patients who present with painless salivary or thyroid gland swelling with a previous history of RCC. If metastatic disease is confined only to these glands, prompt surgical excision can be curative.

Microarray gene expression profiling and analysis in renal cell carcinoma

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Sadhukhan Provash

2004-06-01

Full Text Available Abstract Background Renal cell carcinoma (RCC is the most common cancer in adult kidney. The accuracy of current diagnosis and prognosis of the disease and the effectiveness of the treatment for the disease are limited by the poor understanding of the disease at the molecular level. To better understand the genetics and biology of RCC, we profiled the expression of 7,129 genes in both clear cell RCC tissue and cell lines using oligonucleotide arrays. Methods Total RNAs isolated from renal cell tumors, adjacent normal tissue and metastatic RCC cell lines were hybridized to affymatrix HuFL oligonucleotide arrays. Genes were categorized into different functional groups based on the description of the Gene Ontology Consortium and analyzed based on the gene expression levels. Gene expression profiles of the tissue and cell line samples were visualized and classified by singular value decomposition. Reverse transcription polymerase chain reaction was performed to confirm the expression alterations of selected genes in RCC. Results Selected genes were annotated based on biological processes and clustered into functional groups. The expression levels of genes in each group were also analyzed. Seventy-four commonly differentially expressed genes with more than five-fold changes in RCC tissues were identified. The expression alterations of selected genes from these seventy-four genes were further verified using reverse transcription polymerase chain reaction (RT-PCR. Detailed comparison of gene expression patterns in RCC tissue and RCC cell lines shows significant differences between the two types of samples, but many important expression patterns were preserved. Conclusions This is one of the initial studies that examine the functional ontology of a large number of genes in RCC. Extensive annotation, clustering and analysis of a large number of genes based on the gene functional ontology revealed many interesting gene expression patterns in RCC. Most

Maslinic acid inhibits proliferation of renal cell carcinoma cell lines and suppresses angiogenesis of endothelial cells

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Parth Thakor

2017-03-01

Full Text Available Despite the introduction of many novel therapeutics in clinical practice, metastatic renal cell carcinoma (RCC remains a treatment-re-sistant cancer. As red and processed meat are considered risk factors for RCC, and a vegetable-rich diet is thought to reduce this risk, research into plant-based therapeutics may provide valuable complementary or alternative therapeutics for the management of RCC. Herein, we present the antiproliferative and antiangiogenic effects of maslinic acid, which occurs naturally in edible plants, particularly in olive fruits, and also in a variety of medicinal plants. Human RCC cell lines (ACHN, Caki-1, and SN12K1, endothelial cells (human umbilical vein endothelial cell line [HUVEC], and primary cultures of kidney proximal tubular epithelial cells (PTEC were treated with maslinic acid. Maslinic acid was relatively less toxic to PTEC when compared with RCC under similar experimental conditions. In RCC cell lines, maslinic acid induced a significant reduction in proliferation, proliferating cell nuclear antigen, and colony formation. In HUVEC, maslinic acid induced a significant reduction in capillary tube formation in vitro and vascular endothelial growth factor. This study provides a rationale for incorporating a maslinic acid–rich diet either to reduce the risk of developing kidney cancer or as an adjunct to existing antiangiogenic therapy to improve efficacy.

Increased diacylglycerol kinase ζ expression in human metastatic colon cancer cells augments Rho GTPase activity and contributes to enhanced invasion

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Cai, Kun; Mulatz, Kirk; Ard, Ryan; Nguyen, Thanh; Gee, Stephen H

2014-01-01

Unraveling the signaling pathways responsible for the establishment of a metastatic phenotype in carcinoma cells is critically important for understanding the pathology of cancer. The acquisition of cell motility is a key property of metastatic tumor cells and is a prerequisite for invasion. Rho GTPases regulate actin cytoskeleton reorganization and the cellular responses required for cell motility and invasion. Diacylglycerol kinase ζ (DGKζ), an enzyme that phosphorylates diacylglycerol to yield phosphatidic acid, regulates the activity of the Rho GTPases Rac1 and RhoA. DGKζ mRNA is highly expressed in several different colon cancer cell lines, as well as in colon cancer tissue relative to normal colonic epithelium, and thus may contribute to the metastatic process. To investigate potential roles of DGKζ in cancer metastasis, a cellular, isogenic model of human colorectal cancer metastatic transition was used. DGKζ protein levels, Rac1 and RhoA activity, and PAK phosphorylation were measured in the non-metastatic SW480 adenocarcinoma cell line and its highly metastatic variant, the SW620 line. The effect of DGKζ silencing on Rho GTPase activity and invasion through Matrigel-coated Transwell inserts was studied in SW620 cells. Invasiveness was also measured in PC-3 prostate cancer and MDA-MB-231 breast cancer cells depleted of DGKζ. DGKζ protein levels were elevated approximately 3-fold in SW620 cells compared to SW480 cells. There was a concomitant increase in active Rac1 in SW620 cells, as well as substantial increases in the expression and phosphorylation of the Rac1 effector PAK1. Similarly, RhoA activity and expression were increased in SW620 cells. Knockdown of DGKζ expression in SW620 cells by shRNA-mediated silencing significantly reduced Rac1 and RhoA activity and attenuated the invasiveness of SW620 cells in vitro. DGKζ silencing in highly metastatic MDA-MB-231 breast cancer cells and PC-3 prostate cancer cells also significantly attenuated

Clinical Studies Applying Cytokine-Induced Killer Cells for the Treatment of Renal Cell Carcinoma

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Clara E. Jäkel

2012-01-01

Full Text Available Metastatic renal cell carcinoma (RCC seems to be resistant to conventional chemo- and radiotherapy and the general treatment regimen of cytokine therapy produces only modest responses while inducing severe side effects. Nowadays standard of care is the treatment with VEGF-inhibiting agents or mTOR inhibition; nevertheless, immunotherapy can induce complete remissions and long-term survival in selected patients. Among different adoptive lymphocyte therapies, cytokine-induced killer (CIK cells have a particularly advantageous profile as these cells are easily available, have a high proliferative rate, and exhibit a high antitumor activity. Here, we reviewed clinical studies applying CIK cells, either alone or with standard therapies, for the treatment of RCC. The adverse events in all studies were mild, transient, and easily controllable. In vitro studies revealed an increased antitumor activity of peripheral lymphocytes of participants after CIK cell treatment and CIK cell therapy was able to induce complete clinical responses in RCC patients. The combination of CIK cell therapy and standard therapy was superior to standard therapy alone. These studies suggest that CIK cell immunotherapy is a safe and competent treatment strategy for RCC patients and further studies should investigate different treatment combinations and schedules for optimal application of CIK cells.

Renal Cell Carcinoma Metastasis to Ipsilateral Parotid and Submandibular Glands: Report of a Case with Sonoelastographic Findings

International Nuclear Information System (INIS)

Balaban, Mehtap; Dogruyol, Sureyya Vudali; Idilman, Ilkay S.; Unal, Ozlem; Ipek, Ali

2016-01-01

Renal cell carcinoma (RCC) – also known as hypernephroma or grawitz tumor – accounts for 3% of the adulthood malignancies. Approximately 30–40% of the patients have metastasis at the time of the diagnosis and most common sites for metastasis are lung, regional lymph nodes, bone and liver. A total of 8–14% of the patients with RCC has head and neck metastasis. However, metastasis to major salivary glands is rarely seen. In this paper, we aimed to report a RCC case with metastasis to parotid and submandibular glands that has the same sonographic and sonoelastographic findings with the primary tumor. 66-year old woman with RCC history was referred to our radiology department for neck ultrasound (US) with painful swelling in the right parotid gland region. A well-defined, 37×21 mm sized hypoechoic heterogeneous solid mass was detected in the superficial-deep lobe of the right parotid gland. The mass was prominently hypervascular in color Doppler ultrasonography scan. Coincidentally, a 13×13 mm hypoechoic lobulated solid mass was detected in the right submandibular gland with similar sonographic findings. Real-time sonoelastography (SEL) was performed to the masses and both of them were blue-green colored that indicates hard tissue. An US and SEL evaluation was also performed to the renal mass (RCC) of the patient. The primary mass was also similar in sonographic and SEL appearance as salivary gland masses. In the patient history, she revealed chemotherapy-radiotherapy treatment 1.5 years ago due to inoperable mass in the mid-lower pole of the left kidney diagnosed as clear cell RCC with vascular invasion, liver, lung and brain metastasis. Because of known primary tumor, the masses in the salivary glands were suspected to be metastatic and a tru-cut biopsy was performed. Pathological result was reported as clear cell RCC metastasis. The etiology of RCC is still unknown and metastatic involvement can be seen at unexpected tissue and organs. Metastatic disease

Levels of circulating CD45dimCD34+VEGFR2+ progenitor cells correlate with outcome in metastatic renal cell carcinoma patients treated with tyrosine kinase inhibitors

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Farace, F; Gross-Goupil, M; Tournay, E; Taylor, M; Vimond, N; Jacques, N; Billiot, F; Mauguen, A; Hill, C; Escudier, B

2011-01-01

Background: Predicting the efficacy of antiangiogenic therapy would be of clinical value in patients (pts) with metastatic renal cell carcinoma (mRCC). We tested the hypothesis that circulating endothelial cell (CEC), bone marrow-derived CD45dimCD34+VEGFR2+ progenitor cell or plasma angiogenic factor levels are associated with clinical outcome in mRCC pts undergoing treatment with tyrosine kinase inhibitors (TKI). Methods: Fifty-five mRCC pts were prospectively monitored at baseline (day 1) and day 14 during treatment (46 pts received sunitinib and 9 pts received sorafenib). Circulating endothelial cells (CD45−CD31+CD146+7-amino-actinomycin (7AAD)− cells) were measured in 1 ml whole blood using four-color flow cytometry (FCM). Circulating CD45dimCD34+VEGFR2+7AAD− progenitor cells were measured in progenitor-enriched fractions by four-color FCM. Plasma VEGF, sVEGFR2, SDF-1α and sVCAM-1 levels were determined by ELISA. Correlations between baseline CEC, CD45dimCD34+VEGFR2+7AAD− progenitor cells, plasma factors, as well as day 1–day 14 changes in CEC, CD45dimCD34+VEGFR2+7AAD− progenitor, plasma factor levels, and response to TKI, progression-free survival (PFS) and overall survival (OS) were examined. Results: No significant correlation between markers and response to TKI was observed. No association between baseline CEC, plasma VEGF, sVEGFR-2, SDF-1α, sVCAM-1 levels with PFS and OS was observed. However, baseline CD45dimCD34+VEGFR2+7AAD− progenitor cell levels were associated with PFS (P=0.01) and OS (P=0.006). Changes in this population and in SDF-1α levels between day 1 and day 14 were associated with PFS (P=0.03, P=0.002). Changes in VEGF and SDF-1α levels were associated with OS (P=0.02, P=0.007). Conclusion: Monitoring CD45dimCD34+VEGFR2+ progenitor cells, plasma VEGF and SDF-1α levels could be of clinical interest in TKI-treated mRCC pts to predict outcome. PMID:21386843

Testicular Metastasis from Renal Cell Carcinoma: A Case Report and Review of the Literature

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Keren Rouvinov

2017-04-01

Full Text Available Testicular metastases from renal cell carcinoma (RCC are extremely rare. To the best of our knowledge, only 33 cases have been described in the literature. Most of the reported cases are of unilateral testicular metastasis from RCC. We report a case of metachronous ipsilateral testicular metastasis from RCC in a 78-year-old man 6 years after nephrectomy. Scrotal ultrasonography showed a 4 × 5 cm mass in the right testis. Right inguinal orchiectomy was performed for diagnosis. Computed tomography revealed liver and lung metastases. First-line therapy with sunitinib was started in November 2016 for metastatic RCC.

[Immunotherapy for renal cell carcinoma - current status].

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Grimm, Marc-Oliver; Foller, Susan

2018-04-01

Systemic treatment of metastatic renal cell carcinoma (mRCC) has substantially changed during the last 2 years due to approval of the immune-checkpoint inhibitor Nivolumab (Opdivo ® ) and new multikinase inhibitors (Cabozantinib, Lenvatinib, Tivozanib). The german kidney tumor guideline strongly recommends Nivolumab and Cabozantinib as 2nd line treatments after prior VEGF targeted therapy. CheckMate 025, the prospective randomized trial which led to approval of Nivolumab demonstrated improved overall survival (26 month vs. 19.7 month; hazard ratio 0.73; p = 0.0006) and response rate (26 % vs. 5 %) as well as a favorable toxicity profile compared with Everolimus. Currently, numerous combinations with PD-1/PD-L1 inhibitors are compared to Sunitinib as first line treatment of mRCC. Out of these CheckMate 214, a randomized phase-3 trial is the first to demonstrate a significant higher objective response rate (42 % vs. 27 %, p < 0.0001) and overall survival (Sunitinib 26.0 month, median for Nivo + Ipi has been not yet reached (28.2 - NR); Hazard ratio 0.63) for the combination of Nivolumab and the CTLA-4 antibody Ipilimumab in IMDC intermediate and high risk patients. Furthermore, CheckMate 214 shows better side effect profile and quality of life in patients receiving Nivolumab and Ipilimumab compared with Sunitinib. However, a considerable increase of immune related adverse events is associated with the immune combination therapy. Another randomized trial demonstrates improved progression-free survival for the combination of the PD-L1 inhibitor Atezolizumab and the VEGF antibody Bevacizumab in patients with PD-L1 positive tumors; this was found in all IMDC risk groups. Further phase-3 trials with "new" VEGFR-TKIs (Axitinib, Cabozantinib, Lenvatinib) and PD-1/PD-L1 inhibitor combinations are ongoing.In conclusion, the PD-1 immune checkpoint inhibitor Nivolumab will remain a standard treatment for patients with metastatic renal cell carcinoma

Spotlight on nivolumab in the treatment of renal cell carcinoma: design, development, and place in therapy

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Venur VA

2017-04-01

Full Text Available Vyshak Alva Venur,1 Monika Joshi,2 Kenneth G Nepple,3 Yousef Zakharia1 1Division of Hematology Oncology and Bone Marrow Transplant, Department of Internal Medicine, University of Iowa Hospitals and Clinics, Iowa City, IA, 2Division of Hematology-Oncology, Penn State Cancer Institute, Hershey, PA, 3Department of Urology, University of Iowa Hospitals and Clinics, Iowa City, IA, USA Abstract: Several tyrosine kinase inhibitors targeting the vascular endothelial growth factor receptors and molecules inhibiting the mammalian target of rapamycin are being used for management of metastatic renal cell carcinoma (mRCC; however, there is still a potential for improvement. Immune checkpoint inhibitors like nivolumab and other PD-1/PD-L1 inhibitors provide an alternative approach for patients with mRCC. In this article, the authors review the safety profile and outcomes of phase 1, 2, and 3 clinical trials of nivolumab in mRCC. Keywords: renal cell carcinoma, kidney cancer, PD-1, nivolumab, immunotherapy

Non-Toxic Metabolic Management of Metastatic Cancer in VM Mice: Novel Combination of Ketogenic Diet, Ketone Supplementation, and Hyperbaric Oxygen Therapy.

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A M Poff

Full Text Available The Warburg effect and tumor hypoxia underlie a unique cancer metabolic phenotype characterized by glucose dependency and aerobic fermentation. We previously showed that two non-toxic metabolic therapies - the ketogenic diet with concurrent hyperbaric oxygen (KD+HBOT and dietary ketone supplementation - could increase survival time in the VM-M3 mouse model of metastatic cancer. We hypothesized that combining these therapies could provide an even greater therapeutic benefit in this model. Mice receiving the combination therapy demonstrated a marked reduction in tumor growth rate and metastatic spread, and lived twice as long as control animals. To further understand the effects of these metabolic therapies, we characterized the effects of high glucose (control, low glucose (LG, ketone supplementation (βHB, hyperbaric oxygen (HBOT, or combination therapy (LG+βHB+HBOT on VM-M3 cells. Individually and combined, these metabolic therapies significantly decreased VM-M3 cell proliferation and viability. HBOT, alone or in combination with LG and βHB, increased ROS production in VM-M3 cells. This study strongly supports further investigation into this metabolic therapy as a potential non-toxic treatment for late-stage metastatic cancers.

Kidney (Renal Cell) Cancer—Health Professional Version

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Kidney cancer has three main types. Renal cell cancer, or renal cell adenocarcinoma, forms in the tubules of the kidney. Transitional cell carcinoma forms in the renal pelvis and ureter. Wilms tumors are common in children. Find evidence-based information on kidney cancer treatment, research, genetics, and statistics.

gamma-Glutamyl transpeptidase overexpression increases metastatic growth of B16 melanoma cells in the mouse liver.

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Obrador, Elena; Carretero, Julian; Ortega, Angel; Medina, Ignacio; Rodilla, Vicente; Pellicer, José A; Estrela, José M

2002-01-01

B16 melanoma (B16M) cells with high glutathione (GSH) content show rapid proliferation in vitro and high metastatic activity in the liver in vivo. gamma-Glutamyl transpeptidase (GGT)-mediated extracellular GSH cleavage and intracellular GSH synthesis were studied in vitro in B16M cells with high (F10) and low (F1) metastatic potential. GGT activity was modified by transfection with the human GGT gene (B16MF1/Tet-GGT cells) or by acivicin-induced inhibition. B16MF1/Tet-GGT and B16MF10 cells exhibited higher GSH content (35 +/- 6 and 40 +/- 5 nmol/10(6) cells, respectively) and GGT activity (89 +/- 9 and 37 +/- 7 mU/10(6) cells, respectively) as compared (P <.05) with B16MF1 cells (10 +/- 3 nmol GSH and 4 mU GGT/10(6) cells). Metastasis (number of foci/100 mm(3) of liver) increased in B16MF1 cells pretreated with GSH ester ( approximately 3-fold, P <.01), and decreased in B16MF1/Tet-GGT and B16MF10 cells pretreated with the GSH synthesis inhibitor L-buthionine (S,R)-sulphoximine ( approximately 5-fold and 2-fold, respectively, P <.01). Liver, kidney, brain, lung, and erythrocyte GSH content in B16MF1/Tet-GGT- or B16MF10-bearing mice decreased as compared with B16MF1- and non-tumor-bearing mice. Organic anion transporting polypeptide 1-independent sinusoidal GSH efflux from hepatocytes increased in B16MF1/Tet-GGT- or B16MF10-bearing mice ( approximately 2-fold, P <.01) as compared with non-tumor-bearing mice. Our results indicate that tumor GGT activity and an intertissue flow of GSH can regulate GSH content of melanoma cells and their metastatic growth in the liver.

Oncogenic micro-RNAs and Renal Cell Carcinoma

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Cristina eGrange

2014-03-01

Full Text Available Tumor formation is a complex process that occurs in different steps and involves many cell types, including tumor cells, endothelial cells, and inflammatory cells, which interact to promote growth of the tumor mass and metastasization. Epigenetic alterations occurring in transformed cells result in de-regulation of miRNA expression (a class of small non-coding RNA that regulates multiple functions which contributes to tumorigenesis. The specific miRNAs, which have an aberrant expression in tumors, are defined as oncomiRNAs, and may be either over- or under-expressed, but down-regulation is most commonly observed.Renal cell carcinoma is a frequent form of urologic tumor, associated with an alteration of multiple signaling pathways. Many molecules involved in the progression of renal cell carcinomas, such as HIF, VEGF or mTOR, are possible targets of deregulated miRNAs. Within tumor mass, the cancer stem cell population is a fundamental component that promotes tumor growth. The cancer stem cell hypothesis postulates that cancer stem cells have the unique ability to self-renew and to maintain tumor growth and metastasis. Cancer stem cells present in renal cell carcinoma were shown to express the mesenchymal stem cell marker CD105 and to exhibit self-renewal and clonogenic properties, as well as the ability to generate serially transplantable tumors. The phenotype of cancer stem cell has been related to the potential to undergo the epithelial-mesenchymal transition, which has been linked to the expression pattern of tumorigenic miRNAs or down-regulation of anti-tumor miRNAs. In addition, the pattern of circulating miRNAs may allow discrimination between healthy and tumor patients. Therefore, a miRNA signature may be used as a tumor biomarker for cancer diagnosis, as well as to classify the risk of relapse and metastasis, and for a guide for therapy.

Protective, elective lung irradiation in non-metastatic Ewing's sarcoma

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Marinova, L.; Hristozova, I.; Mihaylova, I.; Perenovska, P.

2015-01-01

Ewing's sarcoma in childhood is a disease from family of the peripheral primitive neuroectodermal tumours. For a period of 16 y (1984-2000), 34 children with Ewing's sarcoma were treated and followed in our department. Twenty-seven of these patients were without distant metastases. Complex treatment was applied to all these patients-chemotherapy VACA (vincristine, actinomycin D, cyclophosphamide, adriamycin), local radiotherapy to a total dose of 50-56 Gy ± surgery. After, a local tumour control was achieved in 11 children with non-metastatic Ewing's sarcoma, elective whole lung irradiation to a total dose of 12-15 Gy was applied. Our experience in these 11 patients with non-metastatic Ewing's sarcoma, in whom elective lung irradiation was applied, showed significant reduction in the lung metastases, improved free of disease survival and overall survival. The achieved good treatment results necessitate extending this treatment approach through defining the risk groups of patients, suitable for elective lung radiotherapy combined with chemotherapy in non-metastatic Ewing's sarcoma. (authors)

Radiotherapy may improve overall survival of patients with T3/T4 transitional cell carcinoma of the renal pelvis or ureter and delay bladder tumour relapse

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Wu Li-Li

2011-07-01

Full Text Available Abstract Background Since transitional cell carcinoma (TCC of the upper urinary tract is a relatively uncommon malignancy, the role of adjuvant radiotherapy is unknown. Methods We treated 133 patients with TCC of the renal pelvis or ureter at our institution between 1998 and 2008. The 67 patients who received external beam radiotherapy (EBRT following surgery were assigned to the radiation group (RT. The clinical target volume included the renal fossa, the course of the ureter to the entire bladder, and the paracaval and para-aortic lymph nodes, which were at risk of harbouring metastatic disease in 53 patients. The tumour bed or residual tumour was targeted in 14 patients. The median radiation dose administered was 50 Gy. The 66 patients who received intravesical chemotherapy were assigned to the non-radiation group (non-RT. Results The overall survival rates for the RT and non-RT groups were not significantly different (p = 0.198. However, there was a significant difference between the survival rates for these groups based on patients with T3/T4 stage cancer. A significant difference was observed in the bladder tumour relapse rate between the irradiated and non-irradiated bladder groups (p = 0.004. Multivariate analysis indicated that improved overall survival was associated with age grade 3 hematologic symptoms also occurred. Conclusion EBRT may improve overall survival for patients with T3/T4 cancer of the renal pelvis or ureter and delay bladder tumour recurrence in all patients.

Radiological evaluation of response to treatment: Application to metastatic renal cancers receiving anti-angiogenic treatment

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Ammari, S.; Hernigou, A.; Grataloup, C.; Thiam, R.; Cuenod, C.A.; Siauve, N.; Fournier, L.S.; Oudard, S.; Medioni, J.

2014-01-01

Targeted therapies have considerably improved the prognosis of patients with metastatic renal cancer (mRCC) but there are no reliable response assessment criteria reflecting the clinical benefits, because there is no regression in size, or it is delayed. Such criteria would help early identification of non-responders, who would then benefit from a change of treatment, and would avoid their being subjected to unnecessary side effects related to the treatment. We will review the imaging techniques currently available for evaluating tumour response in mRCC patients, including the response evaluation criteria in solid tumours (RECIST), the Choi criteria, the modified Choi criteria, and the CT size and attenuation criteria (SACT). We will also discuss functional imaging techniques, which are based on the physiological characteristics of the tumours, such as perfusion CT, magnetic resonance imaging or ultrasound (DCE-CT, DCE-MRI, DCE-US), diffusion MRI, BOLD MRI and new positron emission tomography (PET) tracers. It is not possible at present to propose a unanimously acknowledged criterion for evaluating tumour response to targeted therapy. However, there is a real need for this according to oncologists and the pharmaceutical industry, and radiologists need to be involved in reflecting on the subject. (authors)

CheckMate 025 Randomized Phase 3 Study: Outcomes by Key Baseline Factors and Prior Therapy for Nivolumab Versus Everolimus in Advanced Renal Cell Carcinoma

DEFF Research Database (Denmark)

Escudier, Bernard; Sharma, Padmanee; McDermott, David F

2017-01-01

/kg every 2 wk or everolimus 10mg once daily. RESULTS AND LIMITATIONS: The minimum follow-up was 14 mo. Baseline subgroup distributions were balanced between nivolumab and everolimus arms. Nivolumab demonstrated an OS improvement versus everolimus across subgroups, including Memorial Sloan Kettering Cancer...... Center (MSKCC) and International Metastatic Renal Cell Carcinoma Database Consortium risk groups; age

Ethnic disparities in renal cell carcinoma: An analysis of Hispanic patients in a single-payer healthcare system.

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Suarez-Sarmiento, Alfredo; Yao, Xiaopan; Hofmann, Jonathan N; Syed, Jamil S; Zhao, Wei K; Purdue, Mark P; Chow, Wong-Ho; Corley, Douglas; Shuch, Brian

2017-10-01

To investigate differences between Hispanics and non-Hispanic whites diagnosed with and treated for renal cell carcinoma in an equal access healthcare system. We carried out a retrospective cohort study within the Kaiser Permanente healthcare system using records from renal cell carcinoma cases. Ethnicity was identified as Hispanic or non-Hispanic whites. Patient characteristics, comorbidities, tumor characteristics and treatment were compared. Overall and disease-specific survival was calculated, and a Cox proportion hazard model estimated the association of ethnicity and survival. A total of 2577 patients (2152 non-Hispanic whites, 425 Hispanic) were evaluated. Hispanics were diagnosed at a younger age (59.6 years vs 65.3 years). Clear cell renal cell carcinoma was more prevalent, whereas papillary renal cell carcinoma was less common among Hispanics. Hispanics had a lower American Joint Committee on Cancer stage (I/II vs III/IV) than non-Hispanic whites (67.4% vs 62.2%). Hispanics were found to have a greater frequency of comorbidities, such as chronic kidney disease and diabetes, but were more likely to receive surgery. The presence of metastases, nodal involvement, increased tumor size, non-surgical management, increasing age and Hispanic ethnicity were independent predictors of worse cancer-specific outcome. Within an equal access healthcare system, Hispanics seem to be diagnosed at younger ages, to have greater comorbidities and to present more frequently with clear cell renal cell carcinoma compared with non-Hispanic white patients. Despite lower stage and greater receipt of surgery, Hispanic ethnicity seems to be an independent predictor of mortality. Further work is necessary to confirm these findings. © 2017 The Japanese Urological Association.

The impact of repeated cycles of radioligand therapy using [{sup 177}Lu]Lu-PSMA-617 on renal function in patients with hormone refractory metastatic prostate cancer

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Yordanova, Anna; Becker, Anja; Eppard, Elisabeth; Kuerpig, Stefan; Essler, Markus; Ahmadzadehfar, Hojjat [University Hospital Bonn, Department of Nuclear Medicine, Bonn (Germany); Fisang, Christian [University Hospital Bonn, Department of Urology, Bonn (Germany); Feldmann, Georg [University Hospital Bonn, Department of Internal Medicine, MED3, Bonn (Germany)

2017-08-15

[{sup 177}Lu]Lu-PSMA-617 is a well-tolerated therapy for the treatment of metastatic prostate cancer. However, because of the mainly renal excretion of the tracer, the kidneys are one of the most limiting organs. The purpose of this study was to examine the post-therapeutic changes in renal function over time and to identify risk factors for developing renal toxicity. We also tested the reliability of markers for renal function monitoring. Fifty-five patients with castrate-resistant metastatic prostate cancer treated with at least three cycles of [{sup 177}Lu]Lu-PSMA-617 were investigated. Renal function was assessed through laboratory tests (creatinine, GFR, cystatin C) and Tc-99 m-MAG3 measurements. Adverse events were classified according to the Common Terminology Criteria for Adverse Events (CTCAE) v4.0. To identify risk factors for renal toxicity, we used Pearson's correlation coefficient and the corresponding p values. None of the 55 patients experienced severe nephrotoxicity (grade 3/4). In 14 patients (25%), we observed increased creatinine levels of CTC 1 or 2 . There were 16 cases of increased GFR (grade 1/2). At the baseline, only 14 patients had elevated cystatin C. However, post-therapeutic cystatin C was elevated in 32 patients (58%). A significant effect on renal function was found for age (p = 0.049), hypertension (p = 0.001) and pre-existing kidney disease (p = 0.001). The most reliable predictive markers of nephrotoxicity were TER-MAG3 and cystatin C. Renal toxicity in patients treated with [{sup 177}Lu]Lu-PSMA-617 was low. There was no (sub)acute grade 3 or 4 nephrotoxicity. (orig.)

Renal Ultrasound in the Diagnosis of the Non-functioning Kidney

International Nuclear Information System (INIS)

Kang, Ik Won; Suh, Jeong Soo

1982-01-01

Renal ultrasound is independent of renal function and capable of renal imaging in impaired or dysplastic renal diseases. Authors reviewed renal ultrasonographic findings of 36 cases which showed non-visualization in intravenous pyelography from Feb. 1979 to Sep. 1982 at Seoul National university Hospital. The results are as follows: 1. Causes of non-visualization of the kidney in IVP were unilateral hydronephrosis(18 cases), renal tuberculosis(7), renal failure(6), renal agenesis(3), tumor(1),and pyonephrosis(1) 2. The sonographic findings were diagnostic in all the cases of unilateral hydronephrosis, renal agenesis and renal tumor. 3. The sonographic findings were not diagnostic but suggestive in more than half cases of renal tuberculosis. 4. Renal ultrasound was not helpful in the diagnosis of renal failure, but useful in delineation of renal size and shape

Renal Replacement Therapy in End-Stage Sickle Cell Nephropathy: Presentation of Two Cases and Literature Review

International Nuclear Information System (INIS)

Al-Mueilo, Samir H.

2005-01-01

Chronic renal failure develops in 4-18% of patients with sickle cell anemia. Hemodialysis and kidney transplant are viable options in the management of end-stage renal disease in patients with sickle cell diseases (SCD). Information on kidney disease among Saudi patients with SCD is non-existing. In this report, the clinical course of two adult males with end-stage sickle cell nephropathy from Eastern Saudi Arabia is described. Literature on renal replacement therapy in sickle cell anemia (SCA) is discussed. (author)

Prognostic significance of overexpressed long non-coding RNA TUG1 in patients with clear cell renal cell carcinoma.

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Wang, P-Q; Wu, Y-X; Zhong, X-D; Liu, B; Qiao, G

2017-01-01

The long non-coding RNAs (lncRNAs) study has gradually become one of the hot topics in the field of RNA biology. However, little is known about the pathological role of lncRNA TUG1 in clear cell renal cell carcinoma (ccRCC) patients. This study attempted to investigate the association of lncRNA TUG1 expression with progression and prognosis in ccRCC patients. Using qRT-PCR, the expression of TUG1 was measured in 203 ccRCC tissues and 45 adjacent non-cancerous tissues. Then, the relationships between TUG1 level and the clinicopathological factors of patients with ccRCC were analyzed. The prognostic significance was evaluated using Kaplan-Meier and Cox regression analyses. The relative level of TUG1was significantly higher in ccRCC tissues compared to the adjacent non-tumor tissues (p TUG1 was associated significantly with histological grade, tumor stage, lymph node metastasis and distant metastasis (all p TUG1 expression levels were associated with a shorter overall survival (p TUG1 expression was an independent prognostic marker of poor outcome. These findings suggested that TUG1 may act as a tumor promoter in ccRCC and could serve as a potential therapeutic target for this tumor.

Non-Hodgkin's lymphoma presenting with uterine and renal enlargement in a young girl

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Moon, L.D.; Brenner, C.; McHugh, K.; DeBruyn, R.; Ancliff, P.

2004-01-01

Non-Hodgkin's lymphoma (NHL) is the fourth most common childhood malignancy. Uterine involvement with NHL is well described in adults, rare in children and has not been described in the first 2 years of life. While renal involvement in NHL is well recognised, diffuse renal enlargement is an uncommon finding. We report a unique case of B-cell lymphoma of primitive phenotype in a 15-month-old girl with uterine and renal involvement at presentation. We describe the US and MRI features at presentation that helped in the prospective diagnosis of this condition. (orig.)

Peripheral White Blood Cell Subsets in Metastatic Colorectal Cancer Patients Treated with Cetuximab: The Potential Clinical Relevance

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Ivana Z. Matić

2018-01-01

Full Text Available It was demonstrated that cetuximab-induced tumor regression is based on the effects exerted by immune cells included mainly in the innate immune response. Therefore, the focus of this study was to explore the alterations in the percentages of CD16+, and/or CD56+ lymphocytes, which are comprised of NK cells, and minority of CD56+CD3+ cells, in patients with metastatic colorectal cancer before or 2 months after the treatment with cetuximab-based regimens associated with the response to therapy. The changes in the percentages of lymphocytes and granulocytes in these patients were evaluated as well. We enrolled 50 patients with wild-type KRAS metastatic colorectal cancer. Disease progression was observed in 11/50 patients (non-responders, while other patients achieved partial response or stable disease (responders. Control groups included up to 72 healthy individuals. A significant decrease in the percentages of CD56+ and CD16+CD56+ lymphocytes together with a significant decrease in the percentage of lymphocytes and an increase in the ratio of granulocyte to lymphocyte percentages were observed in patients with metastatic colorectal cancer before therapy, compared with those in the healthy individuals. In contrast to those in the responders, the percentage of CD16+ lymphocytes in the overall white blood cell pool was shown to be significantly decreased in the non-responders, together with a significantly decreased percentage of lymphocytes, a significantly increased percentage of granulocytes, and an increased ratio of granulocyte to lymphocyte percentages before treatment compared with those in the healthy controls. Two months after the initiation of the treatment, significantly decreased percentages of CD16+, CD56+, and CD16+CD56+ lymphocytes were observed in patients, compared with those determined in the healthy controls. The same changes in the amounts of circulating immune cells were also observed in the responder subgroup, but the

Vinorelbine and paclitaxel for locoregional advanced or metastatic non-small-cell lung cancer.

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Pérez, Juan E; Machiavelli, Mario R; Romero, Alberto O; Romero Acuña, Luis A; Domínguez, María E; Fasce, Hebe; Flores Acosta, Luis; Marrone, Nora; Romero Acuña, Juan M; Langhi, Mario J; Amato, Sonia; Bologna, Fabrina; Ortiz, Eduardo H; Leone, Bernardo A; Lacava, Juan A; Vallejo, Carlos T

2002-08-01

A phase II trial was performed to evaluate the efficacy and toxicity of the novel combination of vinorelbine and paclitaxel as first-line chemotherapy in patients with stages IIIB and IV non-small-cell lung cancer. From January 1997 to September 1999, 34 patients (9 stage IIIB and 25 stage IV) received a regimen consisting of the following: vinorelbine 30 mg/m2 20 minutes intravenous (i.v.) infusion, days 1 and 8; and paclitaxel 135 mg/m2 3-hour i.v. (starting 1 hour after vinorelbine) on day 1. Cycles were repeated every 28 days until progression of disease or unacceptable toxicity development. The median age was 57 years (range 41-70 years); median performance status was 1. Histology was as follows: squamous cell in 24 (71%), large cell in 1 (3%), and adenocarcinoma in 9 (26%). All patients are evaluable for toxicity, whereas 30 are evaluable for response (4 patients refused treatment). Objective response was recorded in 4 of 30 patients (13%, 95% CI 1-25%). No complete response was observed. Partial response was recorded in 4 patients (13%), no change in 10 patients (34%), and progressive disease in 16 patients (53%). The median time to treatment failure was 4 months and median survival was 9 months. The limiting toxicity was myelosuppression: leukopenia in 23 patients (68%), whereas neutropenia was observed in 25 patients (78%). Peripheral neurotoxicity developed in 14 patients (41%) (without G3 or G4 episodes), and constipation (G1-G2: 10 patients), myalgia (G1-G2: 11 patients), diarrhea (G1-G2: 7 patients), and stomatitis were observed in 7 patients. Vinorelbine-paclitaxel combination showed only modest activity against locoregionally advanced or metastatic NSCLC.

Treatment of Renal Cell Carcinoma with 2-Stage Total en bloc Spondylectomy after Marked Response to Molecular Target Drugs

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Yasuhiro Inoue

2013-01-01

Full Text Available Metastatic renal cell carcinoma of the bone occurs at a high rate, and the prognosis is poor. In general, total en bloc spondylectomy is considered when there is only one vertebral metastasis and the primary disease is treated. However, palliative surgery is selected when the primary disease is not being treated or metastasis occurs to an important organ. We encountered a patient in whom lung and vertebra metastases were already present at the time of the first examination at our department and the prognosis was considered poor. However, molecular targeted therapy was markedly effective and enabled 2-stage total en bloc spondylectomy. As of one year after total en bloc spondylectomy, the condition has improved to cane gait, and surgery for lung metastasis is planned. Molecular target drugs might markedly change the current therapeutic strategy for renal cell carcinoma.

Role of Radiation Therapy in the Management of Renal Cell Cancer

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Blanco, Angel I.; Teh, Bin S.; Amato, Robert J.

2011-01-01

Renal cell carcinoma (RCC) is traditionally considered to be radioresistant; therefore, conventional radiotherapy (RT) fraction sizes of 1.8 to 2 Gy are thought to have little role in the management of primary RCC, especially for curative disease. In the setting of metastatic RCC, conventionally fractionated RT has been an effective palliative treatment in 50% of patients. Recent technological advances in radiation oncology have led to the clinical implementation of image-guided radiotherapy, allowing biologically potent doses to the tumors intra- and extra-cranially. As predicted by radiobiologic modeling, favorable outcomes have been observed with highly hypofractionated schemes modeled after the experience with intracranial stereotactic radiosurgery (SRS) for RCC brain metastases with reported local control rates averaging 85%. At present, both primary and metastatic RCC tumors may be successfully treated using stereotactic approaches, which utilize steep dose gradients to maximally preserve function and avoid toxicity of adjacent organs including liver, uninvolved kidney, bowel, and spinal cord regions. Future endeavors will combine stereotactic body radiation therapy (SBRT) with novel targeted therapies, such as tyrosine kinase inhibitors and targeted rapamycin (mTOR) inhibitors, to maximize both local and systemic control

Role of Radiation Therapy in the Management of Renal Cell Cancer

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Blanco, Angel I.; Teh, Bin S. [Department of Radiation Oncology, The Methodist Hospital, The Methodist Hospital Research Institute, Houston, TX 77030 (United States); Department of Radiation Oncology, The Methodist Hospital, Houston, TX 77030 (United States); Amato, Robert J., E-mail: Robert.amato@uth.tmc.edu [Division of Oncology, University of Texas Health Science Center at Houston, Memorial Hermann Cancer Center, Houston, TX 77030 (United States)

2011-10-26

Renal cell carcinoma (RCC) is traditionally considered to be radioresistant; therefore, conventional radiotherapy (RT) fraction sizes of 1.8 to 2 Gy are thought to have little role in the management of primary RCC, especially for curative disease. In the setting of metastatic RCC, conventionally fractionated RT has been an effective palliative treatment in 50% of patients. Recent technological advances in radiation oncology have led to the clinical implementation of image-guided radiotherapy, allowing biologically potent doses to the tumors intra- and extra-cranially. As predicted by radiobiologic modeling, favorable outcomes have been observed with highly hypofractionated schemes modeled after the experience with intracranial stereotactic radiosurgery (SRS) for RCC brain metastases with reported local control rates averaging 85%. At present, both primary and metastatic RCC tumors may be successfully treated using stereotactic approaches, which utilize steep dose gradients to maximally preserve function and avoid toxicity of adjacent organs including liver, uninvolved kidney, bowel, and spinal cord regions. Future endeavors will combine stereotactic body radiation therapy (SBRT) with novel targeted therapies, such as tyrosine kinase inhibitors and targeted rapamycin (mTOR) inhibitors, to maximize both local and systemic control.

Type-I interferon receptor expression: its circadian rhythm and downregulation after interferon-alpha administration in peripheral blood cells from renal cancer patients.

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Shiba, Masahiro; Nonomura, Norio; Nakai, Yasutomo; Nakayama, Masashi; Takayama, Hitoshi; Inoue, Hitoshi; Tsujimura, Akira; Nishimura, Kazuo; Okuyama, Akihiko

2009-04-01

To investigate the regulation of interferon-alpha (IFN-alpha) receptor expression in metastatic renal cell carcinoma (RCC) after IFN-alpha administration. Blood sampling was carried out in eight patients with metastatic RCC and six healthy volunteers. Flow-cytometric analysis using a monoclonal antibody against the active subunit of the type-I IFN-alpha receptor (IFNAR2) was carried out to examine the circadian rhythm of IFNAR2 expression in peripheral blood mononuclear cells (PBMC) as well as its downregulation after IFN-alpha administration. According to its circadian rhythm IFNAR2 in PBMC had a peak expression at night. Once IFN-alpha is administered, IFNAR2 levels in PBMC showed downregulation within 48 h and recovered within another 48 h. Our findings might support the establishment of an optimal schedule for IFN-alpha administration.

Renal and perirenal non-Hodgkin's lymphoma: CT findings

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Lee, Seon Kyu; Kim, Seung Hyup; Lee, Goo; Choi, Byeung In; Han, Man Chung

1992-01-01

CT findings of 19 kidneys in 12 patients with renal and perirenal non-Hodgkin's lymphoma were retrospectively reviewed to determine distinguishing characteristic and specific findings. CT manifestation of the renal and perirenal lymphoma included multiple nodules in five kidneys(26.3%), trans-capsular infiltration in three kidneys(15.8%), trans-sinus infiltration in nine kidneys(47.4%) and diffuse infiltration in two kidneys(10.5%). Perirenal changes were thickening of the renal fascia in ten kidneys(52.6%) and crescent lesion of low attenuation in the subcapsular area in five kidneys(26.3%) Retroperitoneal lymphadenopathy was evident in eleven patient(57.9%). Renal calyceal dilatation without renal pelvic dilatation(selective calycelal dilatation) was noted in three kidneys. Familiarity with these CT findings of renal and perirenal lymphoma may be helpful in the diagnosis and management of patient with non-Hodgkin's lymphoma

Metabolic Plasticity of Metastatic Breast Cancer Cells: Adaptation to Changes in the Microenvironment

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Rui V. Simões

2015-08-01

Full Text Available Cancer cells adapt their metabolism during tumorigenesis. We studied two isogenic breast cancer cells lines (highly metastatic 4T1; nonmetastatic 67NR to identify differences in their glucose and glutamine metabolism in response to metabolic and environmental stress. Dynamic magnetic resonance spectroscopy of 13C-isotopomers showed that 4T1 cells have higher glycolytic and tricarboxylic acid (TCA cycle flux than 67NR cells and readily switch between glycolysis and oxidative phosphorylation (OXPHOS in response to different extracellular environments. OXPHOS activity increased with metastatic potential in isogenic cell lines derived from the same primary breast cancer: 4T1 > 4T07 and 168FARN (local micrometastasis only > 67NR. We observed a restricted TCA cycle flux at the succinate dehydrogenase step in 67NR cells (but not in 4T1 cells, leading to succinate accumulation and hindering OXPHOS. In the four isogenic cell lines, environmental stresses modulated succinate dehydrogenase subunit A expression according to metastatic potential. Moreover, glucose-derived lactate production was more glutamine dependent in cell lines with higher metastatic potential. These studies show clear differences in TCA cycle metabolism between 4T1 and 67NR breast cancer cells. They indicate that metastases-forming 4T1 cells are more adept at adjusting their metabolism in response to environmental stress than isogenic, nonmetastatic 67NR cells. We suggest that the metabolic plasticity and adaptability are more important to the metastatic breast cancer phenotype than rapid cell proliferation alone, which could 1 provide a new biomarker for early detection of this phenotype, possibly at the time of diagnosis, and 2 lead to new treatment strategies of metastatic breast cancer by targeting mitochondrial metabolism.

Renal Cell Cancer: What Can We Learn from Pre-Operative Studies?

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Fisher, Rosalie; Larkin, James, E-mail: james.larkin@rmh.nhs.uk [Department of Medical Oncology, Royal Marsden Hospital, London (United Kingdom)

2011-12-08

Renal cell carcinoma (RCC) affects approximately 60,000 people in Europe and in the United States each year (Ferlay et al., 2007; Jemal et al., 2010), and is associated with high rates of morbidity and mortality. The incidence of RCC is rising, perhaps because of the widespread use of abdominal imaging, resulting in an increased detection of small renal masses, and surgical intervention for these (Hollingsworth et al., 2006; Falebita et al., 2009). Surgery remains an integral part of the management of RCC, and is the only curative treatment in patients with disease confined to the kidney and its regional vasculature and lymph nodes. However, about 30% of patients are diagnosed with metastatic renal cell carcinoma (mRCC) at presentation (Motzer et al., 1996) and a similar proportion will later develop metastases (Leibovich et al., 2003). Until 2007, a combination of cytoreductive nephrectomy (CN) and immunotherapy, usually interferon-α, was considered to be the standard of care for those patients presenting with mRCC deemed fit enough, although cytokine therapy was associated with modest benefits and much toxicity (Coppin et al., 2005). The basis for nephrectomy in the context of metastatic disease was provided by two similar prospective trials which randomized patients to CN plus interferon or interferon alone. Combined analysis of the two trials demonstrated a median survival of 13.6 months for surgery plus interferon, and 7.8 months for interferon alone (HR = 0.69, 95% CI = 0.55–0.87, p = 0.002; Flanigan et al., 2004). The simplest rationale for why CN might improve survival in mRCC is a reduction in overall tumor burden, thus delaying time to a lethal burden of disease; other theories include a decrease in the amount of tumor shedding and systemic signaling from the primary renal mass, effective palliation of pain, bleeding and paraneoplastic syndromes, and removal of a source of significant immunosuppression. The latter was proposed on the basis of reports

Skeletal metastasis in renal cell carcinoma: A review

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Masood Umer

2018-03-01

Conclusion: Incidence of metastatic renal carcinoma is increasing. Overall prognosis of patient with advanced RCC is poor, emphasizing the importance of early detection and prompt treatment of primary lesion in its early stage. Advancement in targeted therapy in recent decades had made some improvement in treatment of SREs and has helped in improving patent's quality of life but still we are in need of further improvement in treatment modalities to cure disease thereby decreasing morbidity and mortality.

Metastatic Basal Cell Carcinoma Accompanying Gorlin Syndrome

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Yeliz Bilir

2014-01-01

Full Text Available Gorlin-Goltz syndrome or basal cell nevus syndrome is an autosomal dominant syndrome characterized by skeletal anomalies, numerous cysts observed in the jaw, and multiple basal cell carcinoma of the skin, which may be accompanied by falx cerebri calcification. Basal cell carcinoma is the most commonly skin tumor with slow clinical course and low metastatic potential. Its concomitance with Gorlin syndrome, resulting from a mutation in a tumor suppressor gene, may substantially change morbidity and mortality. A 66-year-old male patient with a history of recurrent basal cell carcinoma was presented with exophthalmus in the left eye and the lesions localized in the left lateral orbita and left zygomatic area. His physical examination revealed hearing loss, gapped teeth, highly arched palate, and frontal prominence. Left orbital mass, cystic masses at frontal and ethmoidal sinuses, and multiple pulmonary nodules were detected at CT scans. Basal cell carcinoma was diagnosed from biopsy of ethmoid sinus. Based on the clinical and typical radiological characteristics (falx cerebri calcification, bifid costa, and odontogenic cysts, the patient was diagnosed with metastatic skin basal cell carcinoma accompanied by Gorlin syndrome. Our case is a basal cell carcinoma with aggressive course accompanying a rarely seen syndrome.

Notch Signaling Is Associated With ALDH Activity And An Aggressive Metastatic Phenotype In Murine Osteosarcoma Cells

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Xiaodong eMu

2013-06-01

Full Text Available Osteosarcoma (OS is the most common primary malignancy of bone, and pulmonary metastatic disease accounts for nearly all mortality. However, little is known about the biochemical signaling alterations that drive the progression of metastatic disease. Two murine OS cell populations, K7M2 and K12, are clonally related but differ significantly in their metastatic phenotypes and therefore represent excellent tools for studying metastatic OS molecular biology. K7M2 cells are highly metastatic, whereas K12 cells display limited metastatic potential. Here we report that the expression of Notch genes (Notch1, 2, 4 are up-regulated, including downstream targets Hes1 and Stat3, in the highly metastatic K7M2 cells compared to the less metastatic K12 cells, indicating that the Notch signaling pathway is more active in K7M2 cells. We have previously described that K7M2 cells exhibit higher levels of aldehyde dehydrogenase (ALDH activity. Here we report that K7M2 cell ALDH activity is reduced with Notch inhibition, suggesting that ALDH activity may be regulated in part by the Notch pathway. Notch signaling is also associated with increased resistance to oxidative stress, migration, invasion, and VEGF expression in vitro. However, Notch inhibition did not significantly alter K7M2 cell proliferation. In conclusion, we provide evidence that Notch signaling is associated with ALDH activity and increased metastatic behavior in OS cells. Both Notch and ALDH are putative molecular targets for the treatment and prevention of OS metastasis.

Fibroblast-Derived Extracellular Matrices: An Alternative Cell Culture System That Increases Metastatic Cellular Properties.

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Michael T Scherzer

Full Text Available Poor survival rates from lung cancer can largely be attributed to metastatic cells that invade and spread throughout the body. The tumor microenvironment (TME is composed of multiple cell types, as well as non-cellular components. The TME plays a critical role in the development of metastatic cancers by providing migratory cues and changing the properties of the tumor cells. The Extracellular Matrix (ECM, a main component of the TME, has been shown to change composition during tumor progression, contributing to cancer cell invasion and survival away from the primary cancer site. Although the ECM is well-known to influence the fate of tumor progression, little is known about the molecular mechanisms that are affected by the cancer cell-ECM interactions. It is imperative that these mechanisms are elucidated in order to properly understand and prevent lung cancer dissemination. However, common in vitro studies do not incorporate these interactions into everyday cell culture assays. We have adopted a model that examines decellularized human fibroblast-derived ECM as a 3-dimensional substrate for growth of lung adenocarcinoma cell lines. Here, we have characterized the effect of fibroblast-derived matrices on the properties of various lung-derived epithelial cell lines, including cancerous and non-transformed cells. This work highlights the significance of the cell-ECM interaction and its requirement for incorporation into in vitro experiments. Implementation of a fibroblast-derived ECM as an in vitro technique will provide researchers with an important factor to manipulate to better recreate and study the TME.

Radiotherapy for Metastatic Merkel Cell Carcinoma: A Review of the Literature

International Nuclear Information System (INIS)

Khan, L.; Barnes, E. A.

2012-01-01

Merkel cell carcinoma is a rare form of non-melanoma skin cancer of neuroendocrine origin. Optimal management of patients is controversial and the role of radiotherapy is unclear. Purpose. The purpose of this study was to review the efficacy of RT in the treatment of both local and distant metastatic disease from MCC. Methods. A literature search was conducted in MEDLINE (1946-January Week 1 2012) and Embase (1980-2012 Week 2). Articles of interest analyze the efficacy of radiotherapy for treatment of metastatic MCC and did not exclude case reports. Results. All articles except one focusing on the role of radiotherapy were of retrospective origin or case series. Significant limitations applied in all studies due to limited sample sizes and the retrospective nature of these studies. Radiotherapy improves locoregional control in the adjuvant setting, and many series suggest an improvement in overall survival. In cases where surgery is not possible, definitive radiotherapy may be an as-efficacious alternative. The radiosensitive nature of MCC coupled with existing reports suggests that treatment via current protocols for other primary tumors is adequate. Conclusion. Further studies should be conducted prospectively to clarify the true role of radiotherapy in metastatic MCC.

Renal haemodynamics, sodium and water reabsorption during continuous intravenous infusion of recombinant interleukin-2

DEFF Research Database (Denmark)

Geertsen, P F; von der Maase, H; Olsen, Niels Vidiendal

1998-01-01

1. Renal haemodynamics, lithium and sodium clearance were measured in 14 patients treated with recombinant interleukin-2 for metastatic renal cell carcinoma. 2. Patients were studied before and after 72 h of continuous intravenous infusion of recombinant interleukin-2 (18x10(6) i.u..24 h-1.m-2) a...... effect. Changes in renal prostaglandin synthesis may contribute to the decrease in renal blood flow. The lithium clearance data suggest that an increased proximal tubular reabsorption rate may contribute to the decreased sodium clearance during recombinant interleukin-2 treatment....

A bioartificial renal tubule device embedding human renal stem/progenitor cells.

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Anna Giovanna Sciancalepore

Full Text Available We present a bio-inspired renal microdevice that resembles the in vivo structure of a kidney proximal tubule. For the first time, a population of tubular adult renal stem/progenitor cells (ARPCs was embedded into a microsystem to create a bioengineered renal tubule. These cells have both multipotent differentiation abilities and an extraordinary capacity for injured renal cell regeneration. Therefore, ARPCs may be considered a promising tool for promoting regenerative processes in the kidney to treat acute and chronic renal injury. Here ARPCs were grown to confluence and exposed to a laminar fluid shear stress into the chip, in order to induce a functional cell polarization. Exposing ARPCs to fluid shear stress in the chip led the aquaporin-2 transporter to localize at their apical region and the Na(+K(+ATPase pump at their basolateral portion, in contrast to statically cultured ARPCs. A recovery of urea and creatinine of (20±5% and (13±5%, respectively, was obtained by the device. The microengineered biochip here-proposed might be an innovative "lab-on-a-chip" platform to investigate in vitro ARPCs behaviour or to test drugs for therapeutic and toxicological responses.

Culture in embryonic kidney serum and xeno-free media as renal cell carcinoma and renal cell carcinoma cancer stem cells research model.

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Krawczyk, Krzysztof M; Matak, Damian; Szymanski, Lukasz; Szczylik, Cezary; Porta, Camillo; Czarnecka, Anna M

2018-04-01

The use of fetal bovine serum hinders obtaining reproducible experimental results and should also be removed in hormone and growth factor studies. In particular hormones found in FBS act globally on cancer cell physiology and influence transcriptome and metabolome. The aim of our study was to develop a renal carcinoma serum free culture model optimized for (embryonal) renal cells in order to select the best study model for downstream auto-, para- or endocrine research. Secondary aim was to verify renal carcinoma stem cell culture for this application. In the study, we have cultured renal cell carcinoma primary tumour cell line (786-0) as well as human kidney cancer stem cells in standard 2D monolayer cultures in Roswell Park Memorial Institute Medium or Dulbecco's Modified Eagle's Medium and Complete Human Kidney Cancer Stem Cell Medium, respectively. Serum-free, animal-component free Human Embryonic Kidney 293 media were tested. Our results revealed that xeno-free embryonal renal cells optimized culture media provide a useful tool in RCC cancer biology research and at the same time enable effective growth of RCC. We propose bio-mimic RCC cell culture model with specific serum-free and xeno-free medium that promote RCC cell viability.

Non-metastatic 2 (NME2)-mediated suppression of lung cancer metastasis involves transcriptional regulation of key cell adhesion factor vinculin

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Thakur, Ram Krishna; Yadav, Vinod Kumar; Kumar, Akinchan; Singh, Ankita; Pal, Krishnendu; Hoeppner, Luke; Saha, Dhurjhoti; Purohit, Gunjan; Basundra, Richa; Kar, Anirban; Halder, Rashi; Kumar, Pankaj; Baral, Aradhita; Kumar, MJ Mahesh; Baldi, Alfonso; Vincenzi, Bruno; Lorenzon, Laura; Banerjee, Rajkumar; Kumar, Praveen; Shridhar, Viji; Mukhopadhyay, Debabrata; Chowdhury, Shantanu

2014-01-01

Tumor metastasis refers to spread of a tumor from site of its origin to distant organs and causes majority of cancer deaths. Although >30 metastasis suppressor genes (MSGs) that negatively regulate metastasis have been identified so far, two issues are poorly understood: first, which MSGs oppose metastasis in a tumor type, and second, which molecular function of MSG controls metastasis. Herein, integrative analyses of tumor-transcriptomes (n = 382), survival data (n = 530) and lymph node metastases (n = 100) in lung cancer patients identified non-metastatic 2 (NME2) as a key MSG from a pool of >30 metastasis suppressors. Subsequently, we generated a promoter-wide binding map for NME2 using chromatin immunoprecipitation with promoter microarrays (ChIP-chip), and transcriptome profiling. We discovered novel targets of NME2 which are involved in focal adhesion signaling. Importantly, we detected binding of NME2 in promoter of focal adhesion factor, vinculin. Reduced expression of NME2 led to enhanced transcription of vinculin. In comparison, NME1, a close homolog of NME2, did not bind to vinculin promoter nor regulate its expression. In line, enhanced metastasis of NME2-depleted lung cancer cells was found in zebrafish and nude mice tumor models. The metastatic potential of NME2-depleted cells was remarkably diminished upon selective RNA-i-mediated silencing of vinculin. Together, we demonstrate that reduced NME2 levels lead to transcriptional de-repression of vinculin and regulate lung cancer metastasis. PMID:25249619

Murine macrophage heparanase: inhibition and comparison with metastatic tumor cells

International Nuclear Information System (INIS)

Savion, N.; Disatnik, M.H.; Nevo, Z.

1987-01-01

Circulating macrophages and metastatic tumor cells can penetrate the vascular endothelium and migrate from the circulatory system to extravascular compartments. Both activated murine macrophages and different metastatic tumor cells attach, invade, and penetrate confluent vascular endothelial cell monolayer in vitro, by degrading heparan sulfate proteoglycans in the subendothelial extracellular matrix. The sensitivity of the enzymes from the various sources degrading the heparan sulfate proteoglycan was challenged and compared by a series of inhibitors. Activated macrophages demonstrate a heparanase with an endoglycosidase activity that cleaves from the [ 35 S]O 4 - -labeled heparan sulfate proteoglycans of the extracellular matrix 10 kDa glycosaminoglycan fragments. The degradation of [ 35 S]O 4 - -labeled extracellular matrix proteoglycans by the macrophages' heparanase is significantly inhibited in the presence of heparan sulfate (10μg/ml), arteparon (10μg/ml), and heparin at a concentration of 3 μg/ml. Degradation of this heparan sulfate proteoglycan is a two-step sequential process involving protease activity followed by heparanase activity. B16-BL6 metastatic melanoma cell heparanase, which is also a cell-associated enzyme, was inhibited by heparin to the same extent as the macrophage haparanase. On the other hand, heparanase of the highly metastatic variant (ESb) of a methylcholanthrene-induced T lymphoma, which is an extracellular enzyme released by the cells to the incubation medium, was more sensitive to heparin and arteparon than the macrophages' heparanase. These results may indicate the potential use of heparin or other glycosaminoglycans as specific and differential inhibitors for the formation in certain cases of blood-borne tumor metastasis

CD47 regulates renal tubular epithelial cell self-renewal and proliferation following renal ischemia reperfusion.

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Rogers, Natasha M; Zhang, Zheng J; Wang, Jiao-Jing; Thomson, Angus W; Isenberg, Jeffrey S

2016-08-01

Defects in renal tubular epithelial cell repair contribute to renal ischemia reperfusion injury, cause acute kidney damage, and promote chronic renal disease. The matricellular protein thrombospondin-1 and its receptor CD47 are involved in experimental renal ischemia reperfusion injury, although the role of this interaction in renal recovery is unknown. We found upregulation of self-renewal genes (transcription factors Oct4, Sox2, Klf4 and cMyc) in the kidney of CD47(-/-) mice after ischemia reperfusion injury. Wild-type animals had minimal self-renewal gene expression, both before and after injury. Suggestive of cell autonomy, CD47(-/-) renal tubular epithelial cells were found to increase expression of the self-renewal genes. This correlated with enhanced proliferative capacity compared with cells from wild-type mice. Exogenous thrombospondin-1 inhibited self-renewal gene expression in renal tubular epithelial cells from wild-type but not CD47(-/-) mice, and this was associated with decreased proliferation. Treatment of renal tubular epithelial cells with a CD47 blocking antibody or CD47-targeting small interfering RNA increased expression of some self-renewal transcription factors and promoted cell proliferation. In a syngeneic kidney transplant model, treatment with a CD47 blocking antibody increased self-renewal transcription factor expression, decreased tissue damage, and improved renal function compared with that in control mice. Thus, thrombospondin-1 via CD47 inhibits renal tubular epithelial cell recovery after ischemia reperfusion injury through inhibition of proliferation/self-renewal. Copyright © 2016 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.

Anti-metastatic effects of viral and non-viral mediated Nk4 delivery to tumours.

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Buhles, Alexandra; Collins, Sara A; van Pijkeren, Jan P; Rajendran, Simon; Miles, Michelle; O'Sullivan, Gerald C; O'Hanlon, Deirdre M; Tangney, Mark

2009-03-09

The most common cause of death of cancer sufferers is through the occurrence of metastases. The metastatic behaviour of tumour cells is regulated by extracellular growth factors such as hepatocyte growth factor (HGF), a ligand for the c-Met receptor tyrosine kinase, and aberrant expression/activation of the c-Met receptor is closely associated with metastatic progression. Nk4 (also known as Interleukin (IL)32b) is a competitive antagonist of the HGF c-Met system and inhibits c-Met signalling and tumour metastasis. Nk4 has an additional anti-angiogenic activity independent of its HGF-antagonist function. Angiogenesis-inhibitory as well as cancer-specific apoptosis inducing effects make the Nk4 sequence an attractive candidate for gene therapy of cancer. This study investigates the inhibition of tumour metastasis by gene therapy mediated production of Nk4 by the primary tumour. Optimal delivery of anti-cancer genes is vital in order to achieve the highest therapeutic responses. Non-viral plasmid delivery methods have the advantage of safety and ease of production, providing immediate transgene expression, albeit short-lived in most tumours. Sustained presence of anti-angiogenic molecules is preferable with anti-angiogenic therapies, and the long-term expression mediated by Adeno-associated Virus (AAV) might represent a more appropriate delivery in this respect. However, the incubation time required by AAV vectors to reach appropriate gene expression levels hampers efficacy in many fast-growing murine tumour models. Here, we describe murine trials assessing the effects of Nk4 on the spontaneously metastatic Lewis Lung Carcinoma (LLC) model when delivered to primary tumour via plasmid lipofection or AAV2 vector. Intratumoural AAV-Nk4 administration produced the highest therapeutic response with significant reduction in both primary tumour growth and incidence of lung metastases. Plasmid-mediated therapy also significantly reduced metastatic growth, but with moderate

Higher cell stiffness indicating lower metastatic potential in B16 melanoma cell variants and in (-)-epigallocatechin gallate-treated cells.

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Watanabe, Tatsuro; Kuramochi, Hiromi; Takahashi, Atsushi; Imai, Kazue; Katsuta, Naoko; Nakayama, Tomonobu; Fujiki, Hirota; Suganuma, Masami

2012-05-01

To understand how nanomechanical stiffness affects metastatic potential, we studied the relationship between cell migration, a characteristic of metastasis, and cell stiffness using atomic force microscopy (AFM), which can measure stiffness (elasticity) of individual living cells. Migration and cell stiffness of three metastatic B16 melanoma variants (B16-F10, B16-BL6, and B16-F1 cells), and also effects of (-)-epigallocatechin gallate (EGCG), were studied using Transwell assay and AFM. Migration of B16-F10 and B16-BL6 cells was 3 and 2 times higher than that of B16-F1 cells in Transwell assay, and cell stiffness determined by AFM was also different among the three variants, although they have similar morphologies and the same growth rates: Means of Young's modulus were 350.8 ± 4.8 Pa for B16-F10 cells, 661.9 ± 16.5 Pa for B16-BL6 cells, and 727.2 ± 13.0 Pa for B16-F1 cells. AFM measurements revealed that highly motile B16-F10 cells have low cell stiffness, and low motile and metastatic B16-F1 cells have high cell stiffness: Nanomechanical stiffness is inversely correlated with migration potential. Treatment of highly motile B16-F10 cells with EGCG increased cell stiffness 2-fold and inhibited migration of the cells. Our study with AFM clearly demonstrates that cell stiffness is a reliable quantitative indicator of migration potential, and very likely metastatic potential, even in morphologically similar cells. And increased cell stiffness may be a key nanomechanical feature in inhibition of metastasis.

Comprehensive Molecular Characterization of Papillary Renal Cell Carcinoma

Science.gov (United States)

Linehan, W. Marston; Spellman, Paul T.; Ricketts, Christopher J.; Creighton, Chad J.; Fei, Suzanne S.; Davis, Caleb; Wheeler, David A.; Murray, Bradley A.; Schmidt, Laura; Vocke, Cathy D.; Peto, Myron; Al Mamun, Abu Amar M.; Shinbrot, Eve; Sethi, Anurag; Brooks, Samira; Rathmell, W. Kimryn; Brooks, Angela N.; Hoadley, Katherine A.; Robertson, A. Gordon; Brooks, Denise; Bowlby, Reanne; Sadeghi, Sara; Shen, Hui; Weisenberger, Daniel J.; Bootwalla, Moiz; Baylin, Stephen B.; Laird, Peter W.; Cherniack, Andrew D.; Saksena, Gordon; Haake, Scott; Li, Jun; Liang, Han; Lu, Yiling; Mills, Gordon B.; Akbani, Rehan; Leiserson, Mark D.M.; Raphael, Benjamin J.; Anur, Pavana; Bottaro, Donald; Albiges, Laurence; Barnabas, Nandita; Choueiri, Toni K.; Czerniak, Bogdan; Godwin, Andrew K.; Hakimi, A. Ari; Ho, Thai; Hsieh, James; Ittmann, Michael; Kim, William Y.; Krishnan, Bhavani; Merino, Maria J.; Mills Shaw, Kenna R.; Reuter, Victor E.; Reznik, Ed; Shelley, Carl Simon; Shuch, Brian; Signoretti, Sabina; Srinivasan, Ramaprasad; Tamboli, Pheroze; Thomas, George; Tickoo, Satish; Burnett, Kenneth; Crain, Daniel; Gardner, Johanna; Lau, Kevin; Mallery, David; Morris, Scott; Paulauskis, Joseph D.; Penny, Robert J.; Shelton, Candace; Shelton, W. Troy; Sherman, Mark; Thompson, Eric; Yena, Peggy; Avedon, Melissa T.; Bowen, Jay; Gastier-Foster, Julie M.; Gerken, Mark; Leraas, Kristen M.; Lichtenberg, Tara M.; Ramirez, Nilsa C.; Santos, Tracie; Wise, Lisa; Zmuda, Erik; Demchok, John A.; Felau, Ina; Hutter, Carolyn M.; Sheth, Margi; Sofia, Heidi J.; Tarnuzzer, Roy; Wang, Zhining; Yang, Liming; Zenklusen, Jean C.; Zhang, Jiashan (Julia); Ayala, Brenda; Baboud, Julien; Chudamani, Sudha; Liu, Jia; Lolla, Laxmi; Naresh, Rashi; Pihl, Todd; Sun, Qiang; Wan, Yunhu; Wu, Ye; Ally, Adrian; Balasundaram, Miruna; Balu, Saianand; Beroukhim, Rameen; Bodenheimer, Tom; Buhay, Christian; Butterfield, Yaron S.N.; Carlsen, Rebecca; Carter, Scott L.; Chao, Hsu; Chuah, Eric; Clarke, Amanda; Covington, Kyle R.; Dahdouli, Mahmoud; Dewal, Ninad; Dhalla, Noreen; Doddapaneni, HarshaVardhan; Drummond, Jennifer; Gabriel, Stacey B.; Gibbs, Richard A.; Guin, Ranabir; Hale, Walker; Hawes, Alicia; Hayes, D. Neil; Holt, Robert A.; Hoyle, Alan P.; Jefferys, Stuart R.; Jones, Steven J.M.; Jones, Corbin D.; Kalra, Divya; Kovar, Christie; Lewis, Lora; Li, Jie; Ma, Yussanne; Marra, Marco A.; Mayo, Michael; Meng, Shaowu; Meyerson, Matthew; Mieczkowski, Piotr A.; Moore, Richard A.; Morton, Donna; Mose, Lisle E.; Mungall, Andrew J.; Muzny, Donna; Parker, Joel S.; Perou, Charles M.; Roach, Jeffrey; Schein, Jacqueline E.; Schumacher, Steven E.; Shi, Yan; Simons, Janae V.; Sipahimalani, Payal; Skelly, Tara; Soloway, Matthew G.; Sougnez, Carrie; Tam, Angela; Tan, Donghui; Thiessen, Nina; Veluvolu, Umadevi; Wang, Min; Wilkerson, Matthew D.; Wong, Tina; Wu, Junyuan; Xi, Liu; Zhou, Jane; Bedford, Jason; Chen, Fengju; Fu, Yao; Gerstein, Mark; Haussler, David; Kasaian, Katayoon; Lai, Phillip; Ling, Shiyun; Radenbaugh, Amie; Van Den Berg, David; Weinstein, John N.; Zhu, Jingchun; Albert, Monique; Alexopoulou, Iakovina; Andersen, Jeremiah J; Auman, J. Todd; Bartlett, John; Bastacky, Sheldon; Bergsten, Julie; Blute, Michael L.; Boice, Lori; Bollag, Roni J.; Boyd, Jeff; Castle, Erik; Chen, Ying-Bei; Cheville, John C.; Curley, Erin; Davies, Benjamin; DeVolk, April; Dhir, Rajiv; Dike, Laura; Eckman, John; Engel, Jay; Harr, Jodi; Hrebinko, Ronald; Huang, Mei; Huelsenbeck-Dill, Lori; Iacocca, Mary; Jacobs, Bruce; Lobis, Michael; Maranchie, Jodi K.; McMeekin, Scott; Myers, Jerome; Nelson, Joel; Parfitt, Jeremy; Parwani, Anil; Petrelli, Nicholas; Rabeno, Brenda; Roy, Somak; Salner, Andrew L.; Slaton, Joel; Stanton, Melissa; Thompson, R. Houston; Thorne, Leigh; Tucker, Kelinda; Weinberger, Paul M.; Winemiller, Cythnia; Zach, Leigh Anne; Zuna, Rosemary

2016-01-01

Background Papillary renal cell carcinoma, accounting for 15% of renal cell carcinoma, is a heterogeneous disease consisting of different types of renal cancer, including tumors with indolent, multifocal presentation and solitary tumors with an aggressive, highly lethal phenotype. Little is known about the genetic basis of sporadic papillary renal cell carcinoma; no effective forms of therapy for advanced disease exist. Methods We performed comprehensive molecular characterization utilizing whole-exome sequencing, copy number, mRNA, microRNA, methylation and proteomic analyses of 161 primary papillary renal cell carcinomas. Results Type 1 and Type 2 papillary renal cell carcinomas were found to be different types of renal cancer characterized by specific genetic alterations, with Type 2 further classified into three individual subgroups based on molecular differences that influenced patient survival. MET alterations were associated with Type 1 tumors, whereas Type 2 tumors were characterized by CDKN2A silencing, SETD2 mutations, TFE3 fusions, and increased expression of the NRF2-ARE pathway. A CpG island methylator phenotype (CIMP) was found in a distinct subset of Type 2 papillary renal cell carcinoma characterized by poor survival and mutation of the fumarate hydratase (FH) gene. Conclusions Type 1 and Type 2 papillary renal cell carcinomas are clinically and biologically distinct. Alterations in the MET pathway are associated with Type 1 and activation of the NRF2-ARE pathway with Type 2; CDKN2A loss and CIMP in Type 2 convey a poor prognosis. Furthermore, Type 2 papillary renal cell carcinoma consists of at least 3 subtypes based upon molecular and phenotypic features. PMID:26536169

Skull metastasis revealing a renal tumor: A case report and review of the literature

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Mohamed Badri

Full Text Available Background: Renal cell carcinomas represent 85% of malignant renal tumors. Typically, the tumor remains asymptomatic a long time before the appearance of urologic clinical signs. In some cases, metastasis can precede the manifestations of the primary tumor. Different sites are potential metastatic localizations for renal tumors, including skull metastases who represent a very rare location. Case description: We report the case of a 65-year-old man presented after the appearance of a skull mass. This tumefaction developed and had progressively grown up during 9 months. Neurological examination was normal. Brain imaging showed a soft tissue lesion in the left parietal bone with marked osteolysis. Peroperative was found a huge oval-shape hemorrhagic and firm mass associated with scalp invasion and bone destruction that was totally resected. Histopathology revealed renal cell carcinoma (RCC. Pelvic and abdominal CT scan was performed, revealing a large mass on the left kidney with irregular contours and poor definition. The patient was then transferred to urology where he underwent nephrectomy. The patient went then through adjuvant chemotherapy. Clinical and radiological follow up of 12 months did not bring to light tumor recurrence. Conclusions: Although metastases to the head and neck occur infrequently, they should be considered when evaluating any unusual subcutaneous mass in the head and neck. RCC should not be discounted when sites as unlikely as the calvaria are evaluated. Treatment of metastatic renal cell carcinoma is complex, and the optimal regimen for achieving a lasting response without severe toxicity has not yet been defined. Keywords: Renal tumor, Skull metastasis, Neurosurgery

CT staging of renal cell carcinoma

International Nuclear Information System (INIS)

Spina, Juan C.; Garcia, Adriana T.; Rogondino, Jose; Spina, Juan C. h; Vidales, Valeria; Troiani, Guillermo; Iotti, Alejandro; Venditti, Julio

2002-01-01

Objective: To assess the usefulness of computerized tomography (CT) in the characterization of renal masses, in order to stage them, determine their prognosis and their appropriate clinical and/or surgical management. Material and Methods: Between 1988 and 2001, we selected 63 patients with renal tumors that had been examined by pathology. Patient's ages ranged from 16 to 88 years (25 women, 38 men). The studies were performed with a sequential helical CT, using 5 mm thickness sections every 5mm evaluating the cortico medullar and nephrographic phases. Renal tumors were characterized and staged without any knowledge about the pathological findings; subsequently the tomographic characteristics were compared to such findings. The following characteristics were evaluated: 1) mixed solid-cystic nature; 2) size; 3) borders; 4) enhancement; 5) necrosis; 6) hemorrhage; 7) central scar; 8) presence of fat; 9) collecting system; 10) capsular invasion; 11) perirenal fat invasion; 12) vessels; 13) Gerota's fascia; 14) lymph nodes; and 15) local and/or distant metastases. Results: Of the 63 tumors, 2 were complicated cysts; of the 61 remaining tumors, 10 were angiomyolipomas, 1 was a renal lymphoma, 1 was a focal xantogranulomatose pyelonephritis, 1 was a metanephric adenoma, 3 papillary renal cell carcinoma (RCC), 4 transitional cell tumors, 4 oncocytomas, 37 clear cell renal carcinoma. The CT could correctly characterize the 2 cystic tumors as such, as well as the 9 angiomyolipomas and the 4 transitional cell tumors. The 48 other tumors (1 angiomyolipoma, 1 lymphoma, 1 focal xantogranulomatose pyelonephritis, 1 metanephric adenoma, 3 papillary RCC, 4 oncocytomas, and 37 cell renal carcinomas) remaining were characterized as renal adenocarcinomas and CT staged. Conclusion: CT is a useful method to characterize renal masses since it determines their solid-cystic or fatty structure; aiding in many cases to define a surgical treatment. For the CT staging of renal tumors, the

Comprehensive Molecular Characterization of Papillary Renal-Cell Carcinoma.

Science.gov (United States)

Linehan, W Marston; Spellman, Paul T; Ricketts, Christopher J; Creighton, Chad J; Fei, Suzanne S; Davis, Caleb; Wheeler, David A; Murray, Bradley A; Schmidt, Laura; Vocke, Cathy D; Peto, Myron; Al Mamun, Abu Amar M; Shinbrot, Eve; Sethi, Anurag; Brooks, Samira; Rathmell, W Kimryn; Brooks, Angela N; Hoadley, Katherine A; Robertson, A Gordon; Brooks, Denise; Bowlby, Reanne; Sadeghi, Sara; Shen, Hui; Weisenberger, Daniel J; Bootwalla, Moiz; Baylin, Stephen B; Laird, Peter W; Cherniack, Andrew D; Saksena, Gordon; Haake, Scott; Li, Jun; Liang, Han; Lu, Yiling; Mills, Gordon B; Akbani, Rehan; Leiserson, Mark D M; Raphael, Benjamin J; Anur, Pavana; Bottaro, Donald; Albiges, Laurence; Barnabas, Nandita; Choueiri, Toni K; Czerniak, Bogdan; Godwin, Andrew K; Hakimi, A Ari; Ho, Thai H; Hsieh, James; Ittmann, Michael; Kim, William Y; Krishnan, Bhavani; Merino, Maria J; Mills Shaw, Kenna R; Reuter, Victor E; Reznik, Ed; Shelley, Carl S; Shuch, Brian; Signoretti, Sabina; Srinivasan, Ramaprasad; Tamboli, Pheroze; Thomas, George; Tickoo, Satish; Burnett, Kenneth; Crain, Daniel; Gardner, Johanna; Lau, Kevin; Mallery, David; Morris, Scott; Paulauskis, Joseph D; Penny, Robert J; Shelton, Candace; Shelton, W Troy; Sherman, Mark; Thompson, Eric; Yena, Peggy; Avedon, Melissa T; Bowen, Jay; Gastier-Foster, Julie M; Gerken, Mark; Leraas, Kristen M; Lichtenberg, Tara M; Ramirez, Nilsa C; Santos, Tracie; Wise, Lisa; Zmuda, Erik; Demchok, John A; Felau, Ina; Hutter, Carolyn M; Sheth, Margi; Sofia, Heidi J; Tarnuzzer, Roy; Wang, Zhining; Yang, Liming; Zenklusen, Jean C; Zhang, Jiashan; Ayala, Brenda; Baboud, Julien; Chudamani, Sudha; Liu, Jia; Lolla, Laxmi; Naresh, Rashi; Pihl, Todd; Sun, Qiang; Wan, Yunhu; Wu, Ye; Ally, Adrian; Balasundaram, Miruna; Balu, Saianand; Beroukhim, Rameen; Bodenheimer, Tom; Buhay, Christian; Butterfield, Yaron S N; Carlsen, Rebecca; Carter, Scott L; Chao, Hsu; Chuah, Eric; Clarke, Amanda; Covington, Kyle R; Dahdouli, Mahmoud; Dewal, Ninad; Dhalla, Noreen; Doddapaneni, Harsha V; Drummond, Jennifer A; Gabriel, Stacey B; Gibbs, Richard A; Guin, Ranabir; Hale, Walker; Hawes, Alicia; Hayes, D Neil; Holt, Robert A; Hoyle, Alan P; Jefferys, Stuart R; Jones, Steven J M; Jones, Corbin D; Kalra, Divya; Kovar, Christie; Lewis, Lora; Li, Jie; Ma, Yussanne; Marra, Marco A; Mayo, Michael; Meng, Shaowu; Meyerson, Matthew; Mieczkowski, Piotr A; Moore, Richard A; Morton, Donna; Mose, Lisle E; Mungall, Andrew J; Muzny, Donna; Parker, Joel S; Perou, Charles M; Roach, Jeffrey; Schein, Jacqueline E; Schumacher, Steven E; Shi, Yan; Simons, Janae V; Sipahimalani, Payal; Skelly, Tara; Soloway, Matthew G; Sougnez, Carrie; Tam, Angela; Tan, Donghui; Thiessen, Nina; Veluvolu, Umadevi; Wang, Min; Wilkerson, Matthew D; Wong, Tina; Wu, Junyuan; Xi, Liu; Zhou, Jane; Bedford, Jason; Chen, Fengju; Fu, Yao; Gerstein, Mark; Haussler, David; Kasaian, Katayoon; Lai, Phillip; Ling, Shiyun; Radenbaugh, Amie; Van Den Berg, David; Weinstein, John N; Zhu, Jingchun; Albert, Monique; Alexopoulou, Iakovina; Andersen, Jeremiah J; Auman, J Todd; Bartlett, John; Bastacky, Sheldon; Bergsten, Julie; Blute, Michael L; Boice, Lori; Bollag, Roni J; Boyd, Jeff; Castle, Erik; Chen, Ying-Bei; Cheville, John C; Curley, Erin; Davies, Benjamin; DeVolk, April; Dhir, Rajiv; Dike, Laura; Eckman, John; Engel, Jay; Harr, Jodi; Hrebinko, Ronald; Huang, Mei; Huelsenbeck-Dill, Lori; Iacocca, Mary; Jacobs, Bruce; Lobis, Michael; Maranchie, Jodi K; McMeekin, Scott; Myers, Jerome; Nelson, Joel; Parfitt, Jeremy; Parwani, Anil; Petrelli, Nicholas; Rabeno, Brenda; Roy, Somak; Salner, Andrew L; Slaton, Joel; Stanton, Melissa; Thompson, R Houston; Thorne, Leigh; Tucker, Kelinda; Weinberger, Paul M; Winemiller, Cynthia; Zach, Leigh Anne; Zuna, Rosemary

2016-01-14

Papillary renal-cell carcinoma, which accounts for 15 to 20% of renal-cell carcinomas, is a heterogeneous disease that consists of various types of renal cancer, including tumors with indolent, multifocal presentation and solitary tumors with an aggressive, highly lethal phenotype. Little is known about the genetic basis of sporadic papillary renal-cell carcinoma, and no effective forms of therapy for advanced disease exist. We performed comprehensive molecular characterization of 161 primary papillary renal-cell carcinomas, using whole-exome sequencing, copy-number analysis, messenger RNA and microRNA sequencing, DNA-methylation analysis, and proteomic analysis. Type 1 and type 2 papillary renal-cell carcinomas were shown to be different types of renal cancer characterized by specific genetic alterations, with type 2 further classified into three individual subgroups on the basis of molecular differences associated with patient survival. Type 1 tumors were associated with MET alterations, whereas type 2 tumors were characterized by CDKN2A silencing, SETD2 mutations, TFE3 fusions, and increased expression of the NRF2-antioxidant response element (ARE) pathway. A CpG island methylator phenotype (CIMP) was observed in a distinct subgroup of type 2 papillary renal-cell carcinomas that was characterized by poor survival and mutation of the gene encoding fumarate hydratase (FH). Type 1 and type 2 papillary renal-cell carcinomas were shown to be clinically and biologically distinct. Alterations in the MET pathway were associated with type 1, and activation of the NRF2-ARE pathway was associated with type 2; CDKN2A loss and CIMP in type 2 conveyed a poor prognosis. Furthermore, type 2 papillary renal-cell carcinoma consisted of at least three subtypes based on molecular and phenotypic features. (Funded by the National Institutes of Health.).

Spontaneous regression of metastatic Merkel cell carcinoma.

LENUS (Irish Health Repository)

Hassan, S J

2010-01-01

Merkel cell carcinoma is a rare aggressive neuroendocrine carcinoma of the skin predominantly affecting elderly Caucasians. It has a high rate of local recurrence and regional lymph node metastases. It is associated with a poor prognosis. Complete spontaneous regression of Merkel cell carcinoma has been reported but is a poorly understood phenomenon. Here we present a case of complete spontaneous regression of metastatic Merkel cell carcinoma demonstrating a markedly different pattern of events from those previously published.

How Kidney Cell Death Induces Renal Necroinflammation.

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Mulay, Shrikant R; Kumar, Santhosh V; Lech, Maciej; Desai, Jyaysi; Anders, Hans-Joachim

2016-05-01

The nephrons of the kidney are independent functional units harboring cells of a low turnover during homeostasis. As such, physiological renal cell death is a rather rare event and dead cells are flushed away rapidly with the urinary flow. Renal cell necrosis occurs in acute kidney injuries such as thrombotic microangiopathies, necrotizing glomerulonephritis, or tubular necrosis. All of these are associated with intense intrarenal inflammation, which contributes to further renal cell loss, an autoamplifying process referred to as necroinflammation. But how does renal cell necrosis trigger inflammation? Here, we discuss the role of danger-associated molecular patterns (DAMPs), mitochondrial (mito)-DAMPs, and alarmins, as well as their respective pattern recognition receptors. The capacity of DAMPs and alarmins to trigger cytokine and chemokine release initiates the recruitment of leukocytes into the kidney that further amplify necroinflammation. Infiltrating neutrophils often undergo neutrophil extracellular trap formation associated with neutrophil death or necroptosis, which implies a release of histones, which act not only as DAMPs but also elicit direct cytotoxic effects on renal cells, namely endothelial cells. Proinflammatory macrophages and eventually cytotoxic T cells further drive kidney cell death and inflammation. Dissecting the molecular mechanisms of necroinflammation may help to identify the best therapeutic targets to limit nephron loss in kidney injury. Copyright © 2016 Elsevier Inc. All rights reserved.

[Molecular biology of renal cancer: bases for genetic directed therapy in advanced disease].

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Maroto Rey, José Pablo; Cillán Narvaez, Elena

2013-06-01

There has been expansion of therapeutic options in the management of metastatic renal cell carcinoma due to a better knowledge of the molecular biology of kidney cancers. There are different tumors grouped under the term renal cell carcinoma, being clear cell cancer the most frequent and accounting for 80% of kidney tumors. Mutations in the Von Hippel-Lindau gene can be identified in up to 80% of sporadic clear cell cancer, linking a genetically inheritable disease where vascular tumors are frequent, with renal cell cancer. Other histologic types present specific alterations in molecular pathways, like c-MET in papillary type I tumors, and Fumarase Hydratase in papillary type II tumors. Identification of the molecular alteration for a specific tumor may offer an opportunity for treatment selection based on biomarkers, and, in the future, for developing an engineering designed genetic treatment.

Metastatic transitional cell carcinoma of the tibia radiologically mimicking osteosarcoma.

LENUS (Irish Health Repository)

Cunningham, Laurence Patrick

2013-01-01

We report a case of a 73-year-old lady with transitional cell carcinoma and no evidence of metastatic disease presenting with gradual weight loss, pretibial swelling and painful weightbearing. Investigations revealed a lesion of the right tibial diaphysis. The radiological and clinical appearance was that of primary osteosarcoma. Biopsy results revealed metastatic transitional cell carcinoma of the tibia. Intramedullary nailing was performed which relieved pain on weightbearing. The patient declined radiotherapy and was started on a palliative care regimen. This case illustrates the importance of histological diagnosis in the treatment of diaphyseal lesions.

Pattern multiplicity and fumarate hydratase (FH)/S-(2-succino)-cysteine (2SC) staining but not eosinophilic nucleoli with perinucleolar halos differentiate hereditary leiomyomatosis and renal cell carcinoma-associated renal cell carcinomas from kidney tumors without FH gene alteration.

Science.gov (United States)

Muller, Marie; Guillaud-Bataille, Marine; Salleron, Julia; Genestie, Catherine; Deveaux, Sophie; Slama, Abdelhamid; de Paillerets, Brigitte Bressac; Richard, Stéphane; Benusiglio, Patrick R; Ferlicot, Sophie

2018-02-06

Hereditary leiomyomatosis and renal cell carcinoma syndrome is characterized by an increased risk of agressive renal cell carcinoma, often of type 2 papillary histology, and is caused by FH germline mutations. A prominent eosinophilic macronucleolus with a perinucleolar clear halo is distinctive of hereditary leiomyomatosis and renal cell carcinoma syndrome-associated renal cell carcinoma according to the 2012 ISUP and 2016 WHO kidney tumor classification. From an immunohistochemistry perspective, tumors are often FH-negative and S-(2-succino)-cysteine (2SC) positive. We performed a pathology review of 24 renal tumors in 23 FH mutation carriers, and compared them to 12 type 2 papillary renal cell carcinomas from FH wild-type patients. Prominent eosinophilic nucleoli with perinucleolar halos were present in almost all FH-deficient renal cell carcinomas (23/24). Unexpectedly, they were also present in 58% of type 2 papillary renal cell carcinomas from wild-type patients. Renal cell carcinoma in mutation carriers displayed a complex architecture with multiple patterns, typically papillary, tubulopapillary, and tubulocystic, but also sarcomatoid and rhabdoid. Such pattern diversity was not seen in non-carriers. FH/2SC immunohistochemistry was informative as all hereditary leiomyomatosis and renal cell carcinoma-associated renal cell carcinomas were either FH- or 2SC+. For FH and 2SC immunohistochemistries taken separately, sensitivity of negative anti-FH immunohistochemistry was 87.5% and specificity was 100%. For positive anti-2SC immunohistochemistry, sensitivity, and specificity were 91.7% and 91.7%, respectively. All FH wild-type renal cell carcinoma were FH-positive, and all but one were 2SC-negative. In conclusion, multiplicity of architectural patterns, rhabdoid/sarcomatoid components and combined FH/2SC staining, but not prominent eosinophilic nucleoli with perinucleolar halos, differentiate hereditary leiomyomatosis and renal cell carcinoma-associated renal

Radiotherapy for Metastatic Merkel Cell Carcinoma: A Review of the Literature

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Luluel Khan

2012-01-01

Full Text Available Introduction. Merkel cell carcinoma is a rare form of non-melanoma skin cancer of neuroendocrine origin. Optimal management of patients is controversial and the role of radiotherapy is unclear. Purpose. The purpose of this study was to review the efficacy of RT in the treatment of both local and distant metastatic disease from MCC. Methods. A literature search was conducted in MEDLINE (1946—January Week 1 2012 and Embase (1980–2012 Week 2. Articles of interest analyze the efficacy of radiotherapy for treatment of metastatic MCC and did not exclude case reports. Results. All articles except one focusing on the role of radiotherapy were of retrospective origin or case series. Significant limitations applied in all studies due to limited sample sizes and the retrospective nature of these studies. Radiotherapy improves locoregional control in the adjuvant setting, and many series suggest an improvement in overall survival. In cases where surgery is not possible, definitive radiotherapy may be an as-efficacious alternative. The radiosensitive nature of MCC coupled with existing reports suggests that treatment via current protocols for other primary tumors is adequate. Conclusion. Further studies should be conducted prospectively to clarify the true role of radiotherapy in metastatic MCC.

Metastatic tumours to hypophysis: a report of three cases and review of literature

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Tomaž Šmigoc

2016-10-01

Full Text Available Background. Metastatic tumours to pituitary are rare. The most frequent are metastases from breast and lung.Methods. In this paper, three cases of metastatic tumours to the pituitary are presented with panhypopituitarism as a common symptom: I a 60-year-old gentleman with metastasis of diffuse large B cell lymphoma, who presented with diabetes insipidus, II a 54-year-old lady with metastatic renal clear cell carcinoma and consequent disturbances in visual acuity, brain nerve paresis and III a 57-year-old lady with breast cancer metastasis, visual impairment and brain nerve paresis.Results. A transnasal endoscopic resection of the tumours was performed in all cases, followed by oncological treatment. All patients improved after the treatment.Conclusions. Despite the rarity of the disease, a metastatic tumour to the pituitary gland must be included in the differential diagnosis when symptoms such as diabetes insipidus, ophthalmoplegy due to brain nerve palsies, rapid course of the disease and headache are observed. In 20% to 30%, pituitary metastases are the first manifestation of a tumour of unknown origin. Surgical and adjuvant therapy may improve the quality of life. The survival and prognosis are generally poor.

Stimulation of Hepatoma Cell Invasiveness and Metastatic Potential by Proteins Secreted From Irradiated Nonparenchymal Cells

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Zhou Leyuan [Department of Radiation Oncology, Zhongshan Hospital, Fudan University, Shanghai (China); Wang Zhiming [Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai (China); Gao Yabo [Department of Radiation Oncology, Zhongshan Hospital, Fudan University, Shanghai (China); Wang Lingyan [Experimental Research Center, Zhongshan Hospital, Fudan University, Shanghai (China); Zeng Zhaochong, E-mail: zeng.zhaochong@zs-hospital.sh.cn [Department of Radiation Oncology, Zhongshan Hospital, Fudan University, Shanghai (China)

2012-11-01

Purpose: To determine whether factors secreted by irradiated liver nonparenchymal cells (NPCs) may influence invasiveness and/or metastatic potential of hepatocellular carcinoma (HCC) cells and to elucidate a possible mechanism for such effect. Methods and Materials: Primary rat NPCs were cultured and divided into irradiated (10-Gy X-ray) and nonirradiated groups. Forty-eight hours after irradiation, conditioned medium from irradiated (SR) or nonirradiated (SnonR) cultures were collected and added to sublethally irradiated cultures of the hepatoma McA-RH7777 cell line. Then, hepatoma cells were continuously passaged for eight generations (RH10Gy-SR and RH10Gy-SnonR). The invasiveness and metastatic potential of McA-RH7777, RH10Gy-SnonR, and RH10Gy-SR cells were evaluated using an in vitro gelatinous protein (Matrigel) invasion and an in vivo metastasis assay. In addition, SR and SnonR were tested using rat cytokine antibody arrays and enzyme-linked immunosorbent assay (ELISA). Results: In vitro gelatinous protein invasion assay indicated that the numbers of invading cells was significantly higher in RH10Gy-SR (40 {+-} 4.74) than in RH10Gy-SnonR (30.6 {+-} 3.85) cells, and lowest in McA-RH7777 (11.4 {+-} 3.56) cells. The same pattern was observed in vivo in a lung metastasis assay, as evaluated by number of metastatic lung nodules seen with RH10Gy-SR (28.83 {+-} 5.38), RH10Gy-SnonR (22.17 {+-} 4.26), and McA-RH7777 (8.3 {+-} 3.8) cells. Rat cytokine antibody arrays and ELISA demonstrated that metastasis-promoting cytokines (tumor necrosis factor-{alpha} and interleukin-6), circulating growth factors (vascular endothelial growth factor and epidermal growth factor), and metalloproteinases (MMP-2 and MMP-9) were upregulated in SR compared with SnonR. Conclusions: Radiation can increase invasiveness and metastatic potential of sublethally irradiated hepatoma cells, and soluble mediators released from irradiated NPCs promote this potential. Increased secretion of

Pemetrexed combined with paclitaxel in patients with advanced or metastatic non-small-cell lung cancer: a phase I-II trial.

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Stathopoulos, George P; Dimitroulis, John; Toubis, Michael; Katis, Costas; Karaindros, Dimitris; Stathopoulos, John; Koutandos, John

2007-07-01

Pemetrexed, a novel multi-targeted agent established for the treatment of mesothelioma, has been under investigation for other malignancies, and in recent years particularly for non-small-cell lung cancer (NSCLC). In the present trial we investigated pemetrexed in combination with paclitaxel as front-line treatment in advanced or metastatic NSCLC. Our objectives were to determine the response rate, median and overall survival and toxicity. From April 2005 until May 2006, 51 patients with advanced or metastatic NSCLC were enrolled and 48 were considered evaluable. There were 39 males and nine females, median age 62 years (range 37-81 years), one patient stage IIIA N(2), 23 patients, IIIB and 24, stage IV. All patients had a cytologically- or histologically-confirmed diagnosis. Pemetrexed was administered at a standard dose of 500mg/m(2) and paclitaxel at an escalating dose starting at 135mg/m(2), then 150mg/m(2) and ending at a dose of 175mg/m(2); the level was increased every three patients. Both agents were administered on day 1, repeated every 3 weeks for six courses. A 39.6% partial response rate was observed with a median survival of 14 months. Toxicity was mild with 8.3% grade 3 and 4 neutropenia and other very mild hematologic and non-hematologic adverse reactions. The combination of pemetrexed and paclitaxel at doses of 500mg/m(2) and 175mg/m(2), respectively, has been shown to be an effective combination with very limited toxicity.

Treatment options for renal cell carcinoma in renal allografts: a case series from a single institution.

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Swords, Darden C; Al-Geizawi, Samer M; Farney, Alan C; Rogers, Jeffrey; Burkart, John M; Assimos, Dean G; Stratta, Robert J

2013-01-01

Renal cell carcinoma (RCC) is more common in renal transplant and dialysis patients than the general population. However, RCC in transplanted kidneys is rare, and treatment has previously consisted of nephrectomy with a return to dialysis. There has been recent interest in nephron-sparing procedures as a treatment option for RCC in allograft kidneys in an effort to retain allograft function. Four patients with RCC in allograft kidneys were treated with nephrectomy, partial nephrectomy, or radiofrequency ablation. All of the patients are without evidence of recurrence of RCC after treatment. We found nephron-sparing procedures to be reasonable initial options in managing incidental RCCs diagnosed in functioning allografts to maintain an improved quality of life and avoid immediate dialysis compared with radical nephrectomy of a functioning allograft. However, in non-functioning renal allografts, radical nephrectomy may allow for a higher chance of cure without the loss of transplant function. Consequently, radical nephrectomy should be utilized whenever the allograft is non-functioning and the patient's surgical risk is not prohibitive. © 2013 John Wiley & Sons A/S.

Enhanced Metastatic Recurrence Via Lymphatic Trafficking of a High-Metastatic Variant of Human Triple-Negative Breast Cancer After Surgical Resection in Orthotopic Nude Mouse Models.

Science.gov (United States)

Yano, Shuya; Takehara, Kiyoto; Tazawa, Hiroshi; Kishimoto, Hiroyuki; Kagawa, Shunsuke; Bouvet, Michael; Fujiwara, Toshiyoshi; Hoffman, Robert M

2017-03-01

We previously developed and characterized a highly invasive and metastatic triple-negative breast cancer (TNBC) variant by serial orthotopic implantation of MDA-MB-231 human breast cancer cells in nude mice. Eventually, a highly invasive and metastatic variant of human TNBC was isolated after lymph node metastases was harvested and orthotopically re-implanted into the mammary gland of nude mice for two cycles. The variant thereby isolated is highly invasive in the mammary gland and metastasized to lymph nodes in 10 of 12 mice compared to 2 of 12 of the parental cell line. In the present report, we observed that high-metastatic MDA-MB-231H-RFP cells produced significantly larger subcutaneous tumors compared with parental MDA-MB-231 cells in nude mice. Extensive lymphatic trafficking by high-metastatic MDA-MB-231 cells was also observed. High-metastatic MDA-MB-231 developed larger recurrent tumors 2 weeks after tumor resection compared with tumors that were not resected in orthotopic models. Surgical resection of the MDA-MB-231 high-metastatic variant primary tumor in orthotopic models also resulted in rapid and enhanced lymphatic trafficking of residual cancer cells and extensive lymph node and lung metastasis that did not occur in the non-surgical mice. These results suggest that surgical resection of high metastatic TNBC can greatly increase the malignancy of residual cancer. J. Cell. Biochem. 118: 559-569, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Metastatic tonsillar squamous cell carcinoma masquerading as a pancreatic cystic tumor and diagnosed by EUS-guided FNA.

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Glass, Ryan; Andrawes, Sherif A; Hamele-Bena, Diane; Tong, Guo-Xia

2017-11-01

Metastatic carcinoma to the pancreas is uncommon and head and neck squamous carcinoma metastatic to the pancreas is extremely rare. Metastatic squamous cell carcinoma to the pancreas presents a unique diagnostic challenge: in addition to mimicking the rare primary squamous cell carcinoma of the pancreas based on cytologic, histologic, and immunohistochemical features, it may be mistaken for a cystic neoplasm of the pancreas because of its high predilection for cystic degeneration in metastatic sites. Herein, we report a case of tonsillar squamous cell carcinoma with a cystic pancreatic metastasis diagnosed by ultrasound-guided fine needle aspiration biopsy (EUS-FNA). This represents a third reported case of metastatic squamous cell carcinoma to the pancreas from the head and neck region. Metastatic squamous cell carcinoma should be considered in the differential diagnosis of EUS-FNA during evaluation of pancreatic cystic lesion. © 2017 Wiley Periodicals, Inc.

Drugs Approved for Kidney (Renal Cell) Cancer

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... Your Treatment Research Drugs Approved for Kidney (Renal Cell) Cancer This page lists cancer drugs approved by the ... not listed here. Drugs Approved for Kidney (Renal Cell) Cancer Afinitor (Everolimus) Aldesleukin Avastin (Bevacizumab) Axitinib Bevacizumab Cabometyx ( ...

Radiation therapy following targeted therapy in oligometastatic renal cell carcinoma.

Science.gov (United States)

Gravis, Gwenaelle; Faure, Marjorie; Rybikowski, Stanislas; Dermeche, Slimane; Tyran, Marguerite; Calderon, Benoit; Thomassin, Jeanne; Walz, Jochen; Salem, Naji

2015-11-01

Up to 40% of patients with renal cell carcinoma (RCC) with initially localized disease eventually develop metastasis following nephrectomy. The current standard of care for metastatic RCC (mRCC) is targeted therapy. However, complete response remains rare. A state of oligometastatic disease may exist, in which metastases are present in a limited number of locations; such cases may benefit from metastasis-directed local therapy, based on the evidence supporting resection of limited-volume metastases, allowing for improved disease control. We retrospectively analyzed 7 cases of response of RCC metastases, in patients treated with targeted therapies followed by radiation therapy (RT) of residual metastatic lesions in Paoli-Calmettes Institute (Marseille, France). We analyzed disease response rates, response to sequential strategy, relapse at the irradiated locations and disease evolution. The median follow-up was 34.1 months (range, 19.2-54.5 months). No progression at the irradiated sites was observed. A total of 5 patients had stable disease at the irradiated locations at the last follow-up; 3 remained in complete remission at the assessment, and 2 were stable. Excellent local response and clinical benefit may be achieved without added toxicity. In conclusion, sequential therapeutic strategies with RT following systemic treatment using sunitinib appear to be highly effective in patients with progressive mRCC and prompt the conduction of further confirmatory trials.

Durable Clinical Benefit in Metastatic Renal Cell Carcinoma Patients Who Discontinue PD-1/PD-L1 Therapy for Immune-Related Adverse Events.

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Martini, Dylan J; Hamieh, Lana; McKay, Rana R; Harshman, Lauren C; Brandao, Raphael; Norton, Craig K; Steinharter, John A; Krajewski, Katherine M; Gao, Xin; Schutz, Fabio A; McGregor, Bradley; Bossé, Dominick; Lalani, Aly-Khan A; De Velasco, Guillermo; Michaelson, M Dror; McDermott, David F; Choueiri, Toni K

2018-04-01

The current standard of care for treatment of metastatic renal cell carcinoma (mRCC) patients is PD-1/PD-L1 inhibitors until progression or toxicity. Here, we characterize the clinical outcomes for 19 mRCC patients who experienced an initial clinical response (any degree of tumor shrinkage), but after immune-related adverse events (irAE) discontinued all systemic therapy. Clinical baseline characteristics, outcomes, and survival data were collected. The primary endpoint was time to progression from the date of treatment cessation (TTP). Most patients had clear cell histology and received anti-PD-1/PD-L1 therapy as second-line or later treatment. Median time on PD-1/PD-L1 therapy was 5.5 months (range, 0.7-46.5) and median TTP was 18.4 months (95% CI, 4.7-54.3) per Kaplan-Meier estimation. The irAEs included arthropathies, ophthalmopathies, myositis, pneumonitis, and diarrhea. We demonstrate that 68.4% of patients ( n = 13) experienced durable clinical benefit off treatment (TTP of at least 6 months), with 36% ( n = 7) of patients remaining off subsequent treatment for over a year after their last dose of anti-PD-1/PD-L1. Three patients with tumor growth found in a follow-up visit, underwent subsequent surgical intervention, and remain off systemic treatment. Nine patients (47.4%) have ongoing irAEs. Our results show that patients who benefitted clinically from anti-PD-1/PD-L1 therapy can experience sustained beneficial responses, not needing further therapies after the initial discontinuation of treatment due to irAEs. Investigation of biomarkers indicating sustained benefit to checkpoint blockers are needed. Cancer Immunol Res; 6(4); 402-8. ©2018 AACR . ©2018 American Association for Cancer Research.

Solitary metastatic cancer to the thyroid: a report of five cases with fine-needle aspiration cytology

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Batoroev Yuri

2007-01-01

Full Text Available Abstract Three men and 2 women with ages ranging from 37 to 70 years, clinically and histologically confirmed solitary, palpable metastatic cancers to the thyroid (SMCT and preoperative cytologic investigation of their thyroid lesions by fine-needle aspiration (FNA, were reviewed. Four patients were known to have a solid cancer treated by radical surgery 1 to 4 years prior [1 bronchogenic squamous cell carcinoma, 1 parotid adenoid cystic carcinoma, 1 renal cell carcinoma (RCC and 1 cutaneous melanoma], and 1 patient had no past history of cancer. Direct smears prepared from the patients' thyroid FNAs were fixed in 95% ethanol and stained with the Papanicolaou method. In 3 cases, immunostaining of the aspirated tumor cells with thyroglobulin antibody was performed, and in 1 case an aspiration smear was stained with commercial HMB-45 antibody. A correct cytodiagnosis of metastatic cancer to the thyroid was made in all 5 cases. In 1 patient the thyroid FNA revealed a metastatic RCC that led to the discovery of a clinically occult RCC. All 5 patients died of metastatic disease 27 to 40 months after surgical resection of their SMCTs.

Colony, hanging drop, and methylcellulose three dimensional hypoxic growth optimization of renal cell carcinoma cell lines.

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Matak, Damian; Brodaczewska, Klaudia K; Lipiec, Monika; Szymanski, Łukasz; Szczylik, Cezary; Czarnecka, Anna M

2017-08-01

Renal cell carcinoma (RCC) is the most lethal of the common urologic malignancies, comprising 3% of all human neoplasms, and the incidence of kidney cancer is rising annually. We need new approaches to target tumor cells that are resistant to current therapies and that give rise to recurrence and treatment failure. In this study, we focused on low oxygen tension and three-dimensional (3D) cell culture incorporation to develop a new RCC growth model. We used the hanging drop and colony formation methods, which are common in 3D culture, as well as a unique methylcellulose (MC) method. For the experiments, we used human primary RCC cell lines, metastatic RCC cell lines, human kidney cancer stem cells, and human healthy epithelial cells. In the hanging drop assay, we verified the potential of various cell lines to create solid aggregates in hypoxic and normoxic conditions. With the semi-soft agar method, we also determined the ability of various cell lines to create colonies under different oxygen conditions. Different cell behavior observed in the MC method versus the hanging drop and colony formation assays suggests that these three assays may be useful to test various cell properties. However, MC seems to be a particularly valuable alternative for 3D cell culture, as its higher efficiency of aggregate formation and serum independency are of interest in different areas of cancer biology.

Management of non-small cell lung cancer with oligometastasis.

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Villaruz, Liza C; Kubicek, Gregory J; Socinski, Mark A

2012-08-01

Patients with oligometastatic Non-Small Cell Lung Cancer (NSCLC) present a potential opportunity for curative therapy; however, the challenge remains the definitive treatment of their localized disease and ablation of their limited overt metastatic sites of disease. In selecting patients with oligometastatic NSCLC for definitive therapy, proper staging through radiographic studies, including PET and brain MRI, and the pathologic staging of the mediastinal lymph nodes and potential sites of metastatic disease, are critical. With that in mind, the available literature suggests that in highly selected patients with solitary metastases to the brain, adrenals and other organs, long term survival may be achieved with combined definitive therapy of both the primary lung tumor and the solitary metastatic site.

RENAL MALIGNANT NEOPLASMS: RENAL CELL CARCINOMA

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Elisangela Giachini

2017-06-01

Full Text Available The aim of this study is to evaluate the incidence and prevalence of malignant kidney tumors, to contribute to identifying factors which the diagnosis of renal cell carcinomas. Through this study, we understand that kidney disease over the years had higher incidence rates, especially in adults in the sixth decade of life. The renal cell carcinoma (RCC is the third most common malignancy of the genitourinary tract, affecting 2% to 3% of the population. There are numerous ways of diagnosis; however, the most important are ultrasonography, magnetic resonance imaging and computed tomography. In general most of the patients affected by the CCR, have a good prognosis when diagnosed early and subjected to an effective treatment. This study conducted a literature review about the CCR, through this it was possible to understand the development needs of the imaging methods used for precise diagnosis and classification of RCC through the TNM system.

Safety and Efficacy of Stereotactic Ablative Radiation Therapy for Renal Cell Carcinoma Extracranial Metastases

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Wang, Chiachien Jake; Christie, Alana; Lin, Mu-Han; Jung, Matthew; Weix, Derek; Huelsmann, Lorel; Kuhn, Kristin; Meyer, Jeffrey; Desai, Neil; Kim, D. W. Nathan; Pedrosa, Ivan; Margulis, Vitaly; Cadeddu, Jeffrey; Sagalowsky, Arthur; Gahan, Jeffrey; Laine, Aaron; Xie, Xian-Jin; Choy, Hak; Brugarolas, James; Timmerman, Robert

2017-01-01

Purpose: Renal cell carcinoma is refractory to conventional radiation therapy but responds to higher doses per fraction. However, the dosimetric data and clinical factors affecting local control (LC) are largely unknown. We aimed to evaluate the safety and efficacy of stereotactic ablative radiation therapy (SAbR) for extracranial renal cell carcinoma metastases. Methods and Materials: We reviewed 175 metastatic lesions from 84 patients treated with SAbR between 2005 and 2015. LC and toxicity after SAbR were assessed with Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 and Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Predictors of local failure were analyzed with χ 2 , Kaplan-Meier, and log-rank tests. Results: In most cases (74%), SAbR was delivered with total doses of 40 to 60 Gy, 30 to 54 Gy, and 20 to 40 Gy in 5 fractions, 3 fractions, and a single fraction, respectively. The median biologically effective dose (BED) using the universal survival model was 134.5 Gy. The 1-year LC rate after SAbR was 91.2% (95% confidence interval, 84.9%-95.0%; median follow-up, 16.7 months). Local failures were associated with prior radiation therapy (hazard ratio [HR], 10.49; P<.0001), palliative-intent radiation therapy (HR, 4.63; P=.0189), spinal location (HR, 5.36; P=.0041), previous systemic therapy status (0-1 vs >1; HR, 3.52; P=.0217), and BED <115 Gy (HR, 3.45; P=.0254). Dose received by 99% of the target volume was the strongest dosimetric predictor for LC. Upon multivariate analysis, dose received by 99% of the target volume greater than BED of 98.7 Gy and systemic therapy status remained significant (HR, 0.12 and 3.64, with P=.0014 and P=.0472, respectively). Acute and late grade 3 toxicities attributed to SAbR were observed in 3 patients (1.7%) and 5 patients (2.9%), respectively. Conclusions: SAbR demonstrated excellent LC of metastatic renal cell carcinoma with a favorable safety profile when an adequate dose and

Safety and Efficacy of Stereotactic Ablative Radiation Therapy for Renal Cell Carcinoma Extracranial Metastases

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Wang, Chiachien Jake [Kidney Cancer Program, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas (United States); Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, Texas (United States); Christie, Alana [Kidney Cancer Program, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas (United States); Lin, Mu-Han; Jung, Matthew; Weix, Derek; Huelsmann, Lorel; Kuhn, Kristin; Meyer, Jeffrey; Desai, Neil; Kim, D. W. Nathan [Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, Texas (United States); Pedrosa, Ivan [Department of Radiology, Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, Texas (United States); Margulis, Vitaly; Cadeddu, Jeffrey; Sagalowsky, Arthur; Gahan, Jeffrey [Department of Urology, University of Texas Southwestern Medical Center, Dallas, Texas (United States); Laine, Aaron [Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, Texas (United States); Xie, Xian-Jin [Kidney Cancer Program, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas (United States); Choy, Hak [Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, Texas (United States); Brugarolas, James [Kidney Cancer Program, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas (United States); Division of Hematology/Oncology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas (United States); Timmerman, Robert [Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, Texas (United States); and others

2017-05-01

Purpose: Renal cell carcinoma is refractory to conventional radiation therapy but responds to higher doses per fraction. However, the dosimetric data and clinical factors affecting local control (LC) are largely unknown. We aimed to evaluate the safety and efficacy of stereotactic ablative radiation therapy (SAbR) for extracranial renal cell carcinoma metastases. Methods and Materials: We reviewed 175 metastatic lesions from 84 patients treated with SAbR between 2005 and 2015. LC and toxicity after SAbR were assessed with Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 and Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Predictors of local failure were analyzed with χ{sup 2}, Kaplan-Meier, and log-rank tests. Results: In most cases (74%), SAbR was delivered with total doses of 40 to 60 Gy, 30 to 54 Gy, and 20 to 40 Gy in 5 fractions, 3 fractions, and a single fraction, respectively. The median biologically effective dose (BED) using the universal survival model was 134.5 Gy. The 1-year LC rate after SAbR was 91.2% (95% confidence interval, 84.9%-95.0%; median follow-up, 16.7 months). Local failures were associated with prior radiation therapy (hazard ratio [HR], 10.49; P<.0001), palliative-intent radiation therapy (HR, 4.63; P=.0189), spinal location (HR, 5.36; P=.0041), previous systemic therapy status (0-1 vs >1; HR, 3.52; P=.0217), and BED <115 Gy (HR, 3.45; P=.0254). Dose received by 99% of the target volume was the strongest dosimetric predictor for LC. Upon multivariate analysis, dose received by 99% of the target volume greater than BED of 98.7 Gy and systemic therapy status remained significant (HR, 0.12 and 3.64, with P=.0014 and P=.0472, respectively). Acute and late grade 3 toxicities attributed to SAbR were observed in 3 patients (1.7%) and 5 patients (2.9%), respectively. Conclusions: SAbR demonstrated excellent LC of metastatic renal cell carcinoma with a favorable safety profile when an adequate dose

Engineering kidney cells: reprogramming and directed differentiation to renal tissues.

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Kaminski, Michael M; Tosic, Jelena; Pichler, Roman; Arnold, Sebastian J; Lienkamp, Soeren S

2017-07-01

Growing knowledge of how cell identity is determined at the molecular level has enabled the generation of diverse tissue types, including renal cells from pluripotent or somatic cells. Recently, several in vitro protocols involving either directed differentiation or transcription-factor-based reprogramming to kidney cells have been established. Embryonic stem cells or induced pluripotent stem cells can be guided towards a kidney fate by exposing them to combinations of growth factors or small molecules. Here, renal development is recapitulated in vitro resulting in kidney cells or organoids that show striking similarities to mammalian embryonic nephrons. In addition, culture conditions are also defined that allow the expansion of renal progenitor cells in vitro. Another route towards the generation of kidney cells is direct reprogramming. Key transcription factors are used to directly impose renal cell identity on somatic cells, thus circumventing the pluripotent stage. This complementary approach to stem-cell-based differentiation has been demonstrated to generate renal tubule cells and nephron progenitors. In-vitro-generated renal cells offer new opportunities for modelling inherited and acquired renal diseases on a patient-specific genetic background. These cells represent a potential source for developing novel models for kidney diseases, drug screening and nephrotoxicity testing and might represent the first steps towards kidney cell replacement therapies. In this review, we summarize current approaches for the generation of renal cells in vitro and discuss the advantages of each approach and their potential applications.

Reacquisition of E-cadherin expression in metastatic deposits of signet-ring cell carcinoma of the upper gastrointestinal system: a potential anchor for metastatic deposition.

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Ma, Yihong R; Siegal, Gene P; Wei, Shi

2017-06-01

To examine the expression of E-cadherin in paired primary and metastatic signet-ring cell carcinomas (SRCC) of various organ systems in order to explore the potential role of the molecule in metastatic dissemination of this unique tumour type. Thirty-seven consecutive cases of SRCC from various organs with paired primary and metastatic tumorous tissue available were retrieved. The intensity of membranous E-cadherin expression was semiquantitatively scored on a scale of 0-3+. Reduced E-cadherin expression was a distinct feature of primary SRCC and was observed in 78% of primary tumours. Interestingly, the E-cadherin reduction was less frequently seen in metastatic SRCC when compared with their primary counterparts, and was only found in 57% of tumours in lymph node metastases or at distant sites of relapse. Furthermore, the mean score of E-cadherin expression of primary SRCC was significantly lower than that of their metastatic counterparts (2.3 vs 1.8; p=0.008). When divided by organ systems, the reacquisition of E-cadherin expression in the metastatic deposits was most remarkable in the SRCC of upper gastrointestinal tract origin (2.3 vs 1.4; p=0.003), whereas no significant difference was observed in other organ systems. While the reduction of E-cadherin in primary SRCC supports its pivotal role in epithelial-mesenchymal transition, a process crucial in tumour progression and metastatic dissemination, the re-expression of this molecule in metastatic SRCC cells implies a reversal to their epithelial phenotype (thus mesenchymal-epithelial transition) which, in turn, theoretically helps tumour cells to anchor and form cohesive metastatic deposits. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

Donor-Derived Regulatory Dendritic Cell Infusion Maintains Donor-Reactive CD4+CTLA4hi T Cells in Non-Human Primate Renal Allograft Recipients Treated with CD28 Co-Stimulation Blockade

OpenAIRE

Mohamed B. Ezzelarab; Lien Lu; William F. Shufesky; Adrian E. Morelli; Adrian E. Morelli; Angus W. Thomson; Angus W. Thomson

2018-01-01

Donor-derived regulatory dendritic cell (DCreg) infusion before transplantation, significantly prolongs renal allograft survival in non-human primates. This is associated with enhanced expression of the immunoregulatory molecules cytotoxic T-lymphocyte-associated antigen (Ag) 4 (CTLA4) and programmed cell death protein 1 (PD1) by host donor-reactive T cells. In rodents and humans, CD28 co-stimulatory pathway blockade with the fusion protein CTLA4:Ig (CTLA4Ig) is associated with reduced differ...

Phase II trial of interleukin 2, interferon alpha, and 5-fluorouracil in metastatic renal cell cancer: a cytokine working group study.

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Dutcher, J P; Logan, T; Gordon, M; Sosman, J; Weiss, G; Margolin, K; Plasse, T; Mier, J; Lotze, M; Clark, J; Atkins, M

2000-09-01

The purpose of this study was to evaluate the potential efficacy of alternating two outpatient regimens for the treatment of metastatic renal cell cancer. These regimens consisted of 4 weeks of recombinant interleukin 2 (rIL-2) plus IFN-alpha2B followed by 4 weeks of 5-fluorouracil plus IFN-alpha2B. Fifty patients meeting eligibility criteria of previous Cytokine Working Group studies were treated on an outpatient basis. Patients received s.c. rIL-2 (Proleukin; Chiron, Emeryville, CA) during weeks 1-4 of the 8-week regimen. During weeks 1 and 4, the dosage for rIL-2 was 10 MIU/m2 twice daily on days 3-5, and the dosage for IFN-alpha2B (Intron; Schering Plough, Kenilworth, NJ) was 6 MIU/m2 on day 1. During weeks 2 and 3, the dosage for rIL-2 was 5 MIU/m2 on days 1, 3, and 5, and the dosage for IFN-alpha2B was 6 MIU/m2 on days 1, 3, 5. During weeks 5-8, 5-fluorouracil (750 mg/m2) was administered once weekly by i.v. infusion, and IFN-alpha2B (9 MIU/mZ) was administered as a s.c. injection three times weekly. Throughout the treatment, an assessment of quality of life was made and a symptom-distress scale was evaluated. There were two patients with complete responses (CRs) and seven with partial responses (PRs) for an objective response rate of 18% (95% confidence interval, 10-25). The median response duration was 8 months (range, 3-51+ months). The CRs lasted 5 months and 51+ months and the PRs ranged from 3+ to 18 months. After completing at least one course of treatment, eight patients (three with PR, one with minor response, four with stable disease) became CRs after surgery for remaining metastatic disease. Six remain alive at 43+ to 53+ months, and 5 remain disease-free since surgery. The median survival of the study group is 17.5 months, with a maximal follow-up of 53+ months. The range in survival is 1-53+ months. Toxicity was primarily constitutional. and treatment modifications were designed to maintain toxicity at grade 2/3. The most common toxicities during

Aqueous Extract of Paeonia suffruticosa Inhibits Migration and Metastasis of Renal Cell Carcinoma Cells via Suppressing VEGFR-3 Pathway

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Shih-Chin Wang

2012-01-01

Full Text Available Renal cell carcinoma (RCC cells are characterized by strong drug resistance and high metastatic incidence. In this study, the effects of ten kinds of Chinese herbs on RCC cell migration and proliferation were examined. Aqueous extract of Paeonia suffruticosa (PS-A exerted strong inhibitory effects on cancer cell migration, mobility, and invasion. The results of mouse xenograft experiments showed that the treatment of PS-A significantly suppressed tumor growth and pulmonary metastasis. We further found that PS-A markedly decreased expression of VEGF receptor-3 (VEGFR-3 and phosphorylation of FAK in RCC cells. Moreover, the activation of Rac-1, a modulator of cytoskeletal dynamics, was remarkably reduced by PS-A. Additionally, PS-A suppressed polymerization of actin filament as demonstrated by confocal microscopy analysis and decreased the ratio of F-actin to G-actin in RCC cells, suggesting that PS-A inhibits RCC cell migration through modulating VEGFR-3/FAK/Rac-1 pathway to disrupt actin filament polymerization. In conclusion, this research elucidates the effects and molecular mechanism for antimigration of PS-A on RCC cells and suggests PS-A to be a therapeutic or adjuvant strategy for the patients with aggressive RCC.

Metastatic clear-cell hidradenocarcinoma of the vulva.

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Messing, M J; Richardson, M S; Smith, M T; King, L; Gallup, D G

1993-02-01

Clear-cell hidradenocarcinoma is a malignant tumor of sweat gland origin. It is most often found on the trunk, head, and extremities. This case report describes a rare occurrence of this tumor on the vulva of a young woman. The discovery of metastatic disease reflects the potentially aggressive nature of this tumor.

[Plasma cell dyscrasias and renal damage].

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Pasquali, Sonia; Iannuzzella, Francesco; Somenzi, Danio; Mattei, Silvia; Bovino, Achiropita; Corradini, Mattia

2012-01-01

Kidney damage caused by immunoglobulin free light chains in the setting of plasma cell dyscrasias is common and may involve all renal compartments, from the glomerulus to the tubulointerstitium, in a wide variety of histomorphological and clinical patterns. The knowledge of how free light chains can promote kidney injury is growing: they can cause functional changes, be processed and deposited, mediate inflammation, apoptosis and fibrosis, and obstruct nephrons. Each clone of the free light chain is unique and its primary structure and post-translation modification can determine the type of renal disease. Measurement of serum free light chain concentrations and calculation of the serum kappa/lambda ratio, together with renal biopsy, represent essential diagnostic tools. An early and correct diagnosis of renal lesions due to plasma cell dyscrasias will allow early initiation of disease-specific treatment strategies. The treatment of free light chain nephropathies is evolving and knowledge of the pathways that promote renal damage should lead to further therapeutic developments.

A generic RNA-pulsed dendritic cell vaccine strategy for renal cell carcinoma

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Geiger, Christiane; Regn, Sybille; Weinzierl, Andreas; Noessner, Elfriede; Schendel, Dolores J

2005-01-01

We present a generic dendritic cell (DC) vaccine strategy for patients with renal cell carcinoma (RCC) based on the use of RNA as a source of multiplex tumor-associated antigens (TAAs). Instead of preparing RNA from tumor tissue of each individual RCC patient, we propose to substitute RNA prepared from a well characterized highly immunogenic RCC cell line (RCC-26 tumor cells) as a generic source of TAAs for loading of DCs. We demonstrate here that efficient RNA transfer can be achieved using lipofection of immature DCs, which are subsequently matured with a cytokine cocktail to express high levels of MHC and costimulatory molecules as well as the chemokine receptor CCR7. Neither RNA itself nor the lipid component impacted on the phenotype or the cytokine secretion of mature DCs. Following RNA loading, DCs derived from HLA-A2-positive donors were able to activate effector-memory cytotoxic T lymphocytes (CTLs) specific for a TAA ligand expressed by the RCC-26 cell line. CTL responses to RNA-loaded DCs reached levels comparable to those stimulated directly by the RCC-26 tumor cells. Furthermore, DCs expressing tumor cell RNA primed naïve T cells, yielding T cell lines with cytotoxicity and cytokine secretion after contact with RCC tumor cells. RCC-26 cell lines are available as good manufacturing practice (GMP)-certified reagents enabling this source of RNA to be easily standardized and adapted for clinical testing. In addition, well defined immune monitoring tools, including the use of RNA expressing B cell lines, are available. Thus, this DC vaccine strategy can be directly compared with an ongoing gene therapy trial using genetically-engineered variants of the RCC-26 cell line as vaccines for RCC patients with metastatic disease. PMID:16045799

A generic RNA-pulsed dendritic cell vaccine strategy for renal cell carcinoma

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Noessner Elfriede

2005-07-01

Full Text Available Abstract We present a generic dendritic cell (DC vaccine strategy for patients with renal cell carcinoma (RCC based on the use of RNA as a source of multiplex tumor-associated antigens (TAAs. Instead of preparing RNA from tumor tissue of each individual RCC patient, we propose to substitute RNA prepared from a well characterized highly immunogenic RCC cell line (RCC-26 tumor cells as a generic source of TAAs for loading of DCs. We demonstrate here that efficient RNA transfer can be achieved using lipofection of immature DCs, which are subsequently matured with a cytokine cocktail to express high levels of MHC and costimulatory molecules as well as the chemokine receptor CCR7. Neither RNA itself nor the lipid component impacted on the phenotype or the cytokine secretion of mature DCs. Following RNA loading, DCs derived from HLA-A2-positive donors were able to activate effector-memory cytotoxic T lymphocytes (CTLs specific for a TAA ligand expressed by the RCC-26 cell line. CTL responses to RNA-loaded DCs reached levels comparable to those stimulated directly by the RCC-26 tumor cells. Furthermore, DCs expressing tumor cell RNA primed naïve T cells, yielding T cell lines with cytotoxicity and cytokine secretion after contact with RCC tumor cells. RCC-26 cell lines are available as good manufacturing practice (GMP-certified reagents enabling this source of RNA to be easily standardized and adapted for clinical testing. In addition, well defined immune monitoring tools, including the use of RNA expressing B cell lines, are available. Thus, this DC vaccine strategy can be directly compared with an ongoing gene therapy trial using genetically-engineered variants of the RCC-26 cell line as vaccines for RCC patients with metastatic disease.

Radiation induced esophageal adenocarcinoma in a woman previously treated for breast cancer and renal cell carcinoma

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Raissouni Soundouss

2012-08-01

Full Text Available Abstract Background Secondary radiation-induced cancers are rare but well-documented as long-term side effects of radiation in large populations of breast cancer survivors. Multiple neoplasms are rare. We report a case of esophageal adenocarcinoma in a patient treated previously for breast cancer and clear cell carcinoma of the kidney. Case presentation A 56 year-old non smoking woman, with no alcohol intake and no familial history of cancer; followed in the National Institute of Oncology of Rabat Morocco since 1999 for breast carcinoma, presented on consultation on January 2011 with dysphagia. Breast cancer was treated with modified radical mastectomy, 6 courses of chemotherapy based on CMF regimen and radiotherapy to breast, inner mammary chain and to pelvis as castration. Less than a year later, a renal right mass was discovered incidentally. Enlarged nephrectomy realized and showed renal cell carcinoma. A local and metastatic breast cancer recurrence occurred in 2007. Patient had 2 lines of chemotherapy and 2 lines of hormonotherapy with Letrozole and Tamoxifen assuring a stable disease. On January 2011, the patient presented dysphagia. Oesogastric endoscopy showed middle esophagus stenosing mass. Biopsy revealed adenocarcinoma. No evidence of metastasis was noticed on computed tomography and breast disease was controlled. Palliative brachytherapy to esophagus was delivered. Patient presented dysphagia due to progressive disease 4 months later. Jejunostomy was proposed but the patient refused any treatment. She died on July 2011. Conclusion We present here a multiple neoplasm in a patient with no known family history of cancers. Esophageal carcinoma is most likely induced by radiation. However the presence of a third malignancy suggests the presence of genetic disorders.

Radiation induced esophageal adenocarcinoma in a woman previously treated for breast cancer and renal cell carcinoma.

Science.gov (United States)

Raissouni, Soundouss; Raissouni, Ferdaous; Rais, Ghizlane; Aitelhaj, Meryem; Lkhoyaali, Siham; Latib, Rachida; Mohtaram, Amina; Rais, Fadoua; Mrabti, Hind; Kabbaj, Nawal; Amrani, Naima; Errihani, Hassan

2012-08-09

Secondary radiation-induced cancers are rare but well-documented as long-term side effects of radiation in large populations of breast cancer survivors. Multiple neoplasms are rare. We report a case of esophageal adenocarcinoma in a patient treated previously for breast cancer and clear cell carcinoma of the kidney. A 56 year-old non smoking woman, with no alcohol intake and no familial history of cancer; followed in the National Institute of Oncology of Rabat Morocco since 1999 for breast carcinoma, presented on consultation on January 2011 with dysphagia. Breast cancer was treated with modified radical mastectomy, 6 courses of chemotherapy based on CMF regimen and radiotherapy to breast, inner mammary chain and to pelvis as castration. Less than a year later, a renal right mass was discovered incidentally. Enlarged nephrectomy realized and showed renal cell carcinoma. A local and metastatic breast cancer recurrence occurred in 2007. Patient had 2 lines of chemotherapy and 2 lines of hormonotherapy with Letrozole and Tamoxifen assuring a stable disease. On January 2011, the patient presented dysphagia. Oesogastric endoscopy showed middle esophagus stenosing mass. Biopsy revealed adenocarcinoma. No evidence of metastasis was noticed on computed tomography and breast disease was controlled. Palliative brachytherapy to esophagus was delivered. Patient presented dysphagia due to progressive disease 4 months later. Jejunostomy was proposed but the patient refused any treatment. She died on July 2011. We present here a multiple neoplasm in a patient with no known family history of cancers. Esophageal carcinoma is most likely induced by radiation. However the presence of a third malignancy suggests the presence of genetic disorders.

Evaluation of Anti-Metastatic Potential of the Combination of Fisetin with Paclitaxel on A549 Non-Small Cell Lung Cancer Cells.

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Klimaszewska-Wiśniewska, Anna; Hałas-Wiśniewska, Marta; Grzanka, Alina; Grzanka, Dariusz

2018-02-27

The identification and development of new agents with a therapeutic potential as well as novel drug combinations are gaining the attention of scientists and clinicians as a plausible approach to improve therapeutic regimens for chemoresistant tumors. We have recently reported that the flavonoid fisetin (FIS), at physiologically attainable concentrations, acts synergistically with clinically achievable doses of paclitaxel (PTX) to produce growth inhibitory and pro-death effects on A549 human non-small cell lung cancer (NSCLC) cells. To further investigate a potential therapeutic efficacy of the combination of fisetin with paclitaxel, we decided to assess its impact on metastatic capability of A549 cells as well as its toxicity toward normal human lung fibroblast. Cell viability, cell migration, and invasion were measured by thiazolyl blue tetrazolium bromide (MTT) assay, wound healing assay, and Transwell chamber assay, respectively. The expression of metastasis-related genes was assessed with quantitative reverse transcriptase real-time polymerase chain reaction (qRT-PCR). Actin and vimentin filaments were examined under the fluorescence microscope. The combination of FIS and PTX significantly reduced cancer cell migration and invasion, at least partially, through a marked rearrangement of actin and vimentin cytoskeleton and the modulation of metastasis-related genes. Most of these effects of the combination treatment were significantly greater than those of individual agents. Paclitaxel alone was even more toxic to normal cells than the combination of this drug with the flavonoid, suggesting that FIS may provide some protection against PTX-mediated cytotoxicity. The combination of FIS and PTX is expected to have a synergistic anticancer efficacy and a significant potential for the treatment of NSCLC, however, further in vitro and in vivo studies are required to confirm this preliminary evidence.

Evaluation of Anti-Metastatic Potential of the Combination of Fisetin with Paclitaxel on A549 Non-Small Cell Lung Cancer Cells

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Anna Klimaszewska-Wiśniewska

2018-02-01

Full Text Available The identification and development of new agents with a therapeutic potential as well as novel drug combinations are gaining the attention of scientists and clinicians as a plausible approach to improve therapeutic regimens for chemoresistant tumors. We have recently reported that the flavonoid fisetin (FIS, at physiologically attainable concentrations, acts synergistically with clinically achievable doses of paclitaxel (PTX to produce growth inhibitory and pro-death effects on A549 human non-small cell lung cancer (NSCLC cells. To further investigate a potential therapeutic efficacy of the combination of fisetin with paclitaxel, we decided to assess its impact on metastatic capability of A549 cells as well as its toxicity toward normal human lung fibroblast. Cell viability, cell migration, and invasion were measured by thiazolyl blue tetrazolium bromide (MTT assay, wound healing assay, and Transwell chamber assay, respectively. The expression of metastasis-related genes was assessed with quantitative reverse transcriptase real-time polymerase chain reaction (qRT-PCR. Actin and vimentin filaments were examined under the fluorescence microscope. The combination of FIS and PTX significantly reduced cancer cell migration and invasion, at least partially, through a marked rearrangement of actin and vimentin cytoskeleton and the modulation of metastasis-related genes. Most of these effects of the combination treatment were significantly greater than those of individual agents. Paclitaxel alone was even more toxic to normal cells than the combination of this drug with the flavonoid, suggesting that FIS may provide some protection against PTX-mediated cytotoxicity. The combination of FIS and PTX is expected to have a synergistic anticancer efficacy and a significant potential for the treatment of NSCLC, however, further in vitro and in vivo studies are required to confirm this preliminary evidence.

The effect of neighboring cells on the stiffness of cancerous and non-cancerous human mammary epithelial cells

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Guo, Xinyi; Bonin, Keith; Scarpinato, Karin; Guthold, Martin

2014-10-01

Using an Atomic Force Microscope (AFM) with a 5.3 μm diameter spherical probe, we determined mechanical properties of individual human mammary epithelial cells. The cells were derived from a pair of cell lines that mimic cell progression through four phases of neoplastic transformation: normal (non-transformed), immortal, tumorigenic, and metastatic. Measurements on cells in all four phases were taken over both the cytoplasmic and nuclear regions. Moreover, the measurements were made for cells in different microenvironments as related to cell-cell contacts: isolated cells; cells residing on the periphery of a contiguous cell monolayer; and cells on the inside of a contiguous cell monolayer. By fitting the AFM force versus indentation curves to a Hertz model, we determined the pseudo-elastic Young’s modulus, E. Combining all data for the cellular subregions (over nucleus and cytoplasm) and the different cell microenvironments, we obtained stiffness values for normal, immortal, tumorigenic, and metastatic cells of 870 Pa, 870 Pa, 490 Pa, and 580 Pa, respectively. That is, cells become softer as they advance to the tumorigenic phase and then stiffen somewhat in the final step to metastatic cells. We also found a distinct contrast in the influence of a cell’s microenvironment on cell stiffness. Normal mammary epithelial cells inside a monolayer are stiffer than peripheral cells, which are stiffer than isolated cells. However, the microenvironment had a slight, opposite effect on tumorigenic and little effect on immortal and metastatic cell stiffness. Thus, the stiffness of cancer cells is less sensitive to the microenvironment than normal cells. Our results show that the mechanical properties of a cell can depend on cancer progression and microenvironment (cell-cell interactions).

Epidemiologic characteristics and risk factors for renal cell cancer

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Loren Lipworth

2009-04-01

Full Text Available Loren Lipworth1,2, Robert E Tarone1,2, Lars Lund2,3, Joseph K McLaughlin1,21International Epidemiology Institute, Rockville, MD, USA; 2Department of Medicine (JKM, RET and Preventive Medicine (LL, Vanderbilt University Medical Center and Vanderbilt-Ingram Cancer Center, Nashville, TN, USA; 3Department of Urology, Viborg Hospital, Viborg, DenmarkAbstract: Incidence rates of renal cell cancer, which accounts for 85% of kidney cancers, have been rising in the United States and in most European countries for several decades. Family history is associated with a two- to four-fold increase in risk, but the major forms of inherited predisposition together account for less than 4% of renal cell cancers. Cigarette smoking, obesity, and hypertension are the most consistently established risk factors. Analgesics have not been convincingly linked with renal cell cancer risk. A reduced risk of renal cell cancer among statin users has been hypothesized but has not been adequately studied. A possible protective effect of fruit and vegetable consumption is the only moderately consistently reported dietary finding, and, with the exception of a positive association with parity, evidence for a role of hormonal or reproductive factors in the etiology of renal cell cancer in humans is limited. A recent hypothesis that moderate levels of alcohol consumption may be protective for renal cell cancer is not strongly supported by epidemiologic results, which are inconsistent with respect to the categories of alcohol consumption and the amount of alcohol intake reportedly associated with decreased risk. For occupational factors, the weight of the evidence does not provide consistent support for the hypotheses that renal cell cancer may be caused by asbestos, gasoline, or trichloroethylene exposure. The established determinants of renal cell cancer, cigarette smoking, obesity, and hypertension, account for less than half of these cancers. Novel epidemiologic approaches

Culture and Characterization of Circulating Endothelial Progenitor Cells in Patients with Renal Cell Carcinoma.

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Gu, Wenyu; Sun, Wei; Guo, Changcheng; Yan, Yang; Liu, Min; Yao, Xudong; Yang, Bin; Zheng, Junhua

2015-07-01

Although emerging evidence demonstrates increased circulating endothelial progenitor cells in patients with solid tumors, to our knowledge it is still unknown whether such cells can be cultured from patients with highly angiogenic renal cell carcinoma. We cultured and characterized circulating endothelial progenitor cells from patients with renal cell carcinoma. The circulating endothelial progenitor cell level (percent of CD45(-)CD34(+) VEGF-R2(+) cells in total peripheral blood mononuclear cells) was quantified in 47 patients with renal cell carcinoma and 40 healthy controls. Peripheral blood mononuclear cells were then isolated from 33 patients with renal cell carcinoma and 30 healthy controls to culture and characterize circulating endothelial progenitor cells. The circulating endothelial progenitor cell level was significantly higher in patients with renal cell carcinoma than in healthy controls (0.276% vs 0.086%, p cells first emerged significantly earlier in patient than in control preparations (6.72 vs 14.67 days, p culture success rate (87.8% vs 40.0% of participants) and the number of colonies (10.06 vs 1.83) were significantly greater for patients than for controls (each p cell level correlated positively with the number of patient colonies (r = 0.762, p Cells cultured from patients and controls showed a similar growth pattern, immunophenotype, ability to uptake Ac-LDL and bind lectin, and form capillary tubes in vitro. However, significantly more VEGF-R2(+) circulating endothelial progenitor cells were found in preparations from patients with renal cell carcinoma than from healthy controls (21.1% vs 13.4%, p cell colonies, a higher cell culture success rate and more colonies were found for patients with renal cell carcinoma than for healthy controls. Results indicate the important significance of VEGF-R2(+) circulating endothelial progenitors in patients with renal cell carcinoma. Copyright © 2015 American Urological Association Education and Research