Management Of Renal Cell Carcinoma Research Articles

The Role of DNA Methylation in Renal Cell Carcinoma.

Renal cell carcinoma (RCC) is the most common kidney cancer and includes several molecular and histological subtypes with different clinical characteristics. While survival rates are high if RCC is diagnosed when still confined to the kidney and treated definitively, there are no specific diagnostic screening tests available and symptoms are rare in early stages of the disease. Management of advanced RCC has changed significantly with the advent of targeted therapies, yet survival is usually increased by months due to acquired resistance to these therapies. DNA methylation, the covalent addition of a methyl group to a cytosine, is essential for normal development and transcriptional regulation, but becomes altered commonly in cancer. These alterations result in broad transcriptional changes, including in tumor suppressor genes. Because DNA methylation is one of the earliest molecular changes in cancer and is both widespread and stable, its role in cancer biology, including RCC, has been extensively studied. In this review, we examine the role of DNA methylation in RCC disease etiology and progression, the preclinical use of DNA methylation alterations as diagnostic, prognostic and predictive biomarkers, and the potential for DNA methylation-directed therapies.

Time trends in service provision and survival outcomes for patients with renal cancer treated by nephrectomy in England 2000-2010.

ObjectiveTo describe the temporal trends in nephrectomy practice and outcomes for English patients with renal cell carcinoma (RCC).Patients and MethodsAdult RCC nephrectomy patients treated between 2000 and 2010 were identified in the National Cancer Data Repository and Hospital Episode Statistics, and followed‐up until date of death or 31 December 2015 (n = 30 763). We estimated the annual frequency for each nephrectomy type, the hospital and surgeon numbers and their case volumes. We analysed short‐term surgical outcomes, as well as 1‐ and 5‐year relative survivals.ResultsAnnual RCC nephrectomy number increased by 66% during the study period. Hospital number decreased by 24%, whilst the median annual hospital volume increased from 10 to 23 (P < 0.01). Surgeon number increased by 27% (P < 0.01), doubling the median consultant number per hospital. The proportion of minimally invasive surgery (MIS) nephrectomies rose from 1% to 46%, whilst the proportion of nephron‐sparing surgeries (NSS) increased from 5% to 16%, with 29% of all T1 disease treated with partial nephrectomy in 2010 (P < 0.01). The 30‐day mortality rate halved from 2.4% to 1.1% and 90‐day mortality decreased from 4.9% to 2.6% (P < 0.01). The 1‐year relative survival rate increased from 86.9% to 93.4%, whilst the 5‐year relative survival rate rose from 68.2% to 81.2% (P < 0.01). Improvements were most notable in patients aged ≥65 years and those with T3 and T4 disease.ConclusionsSurgical RCC management has changed considerably with nephrectomy centralisation and increased NSS and MIS. In parallel, we observed significant improvements in short‐ and long‐term survival particularly for elderly patients and those with locally advanced disease.

Imaging and Management of Intrathoracic Renal Cell Carcinoma Metastases.

Renal cell carcinoma (RCC) has a propensity to metastasize to the chest, with the lungs being the most common distant metastatic site. The histologic subtype of RCC has implications for prognosis. Significant advances have been made in the management of metastatic RCC, both in systemic and locoregional therapies. The aim of this article is to review appearances of intrathoracic metastases from RCC and to discuss treatment considerations.

EZH2 enhances the invasive capability of renal cell carcinoma cells via activation of STAT3.

The enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2) gene has been recognized to be a proto-oncogene and to be linked to human malignancies. However, the additional functions of EZH2 in renal cell carcinoma (RCC) are not completely understood. In the present study, a possible role of EZH2 in RCC was identified. EZH2 was demonstrated to promote the cell proliferation and invasion potential of 769-P cells, and inhibition of EZH2 was demonstrated to prevent these two processes in 786-O cells. Mechanically, EZH2 was demonstrated to increase the phosphorylation of signal transducer and activator of transcription 3 (STAT3) and upregulate 72 kDa type IV collagenase (MMP-2) expression. When cells were treated with small interfering RNA targeting STAT3 or Stattic, a specific inhibitor of STAT3, the invasive ability of the cells was decreased and downregulation of MMP-2 was observed. Based on these results, in the present study it was hypothesized that EZH2 may serve a critical role in the progression of RCC. Its ability to facilitate invasion makes EZH2 a promising target for the management of advanced RCC.

Perioperative Morbidity of Lymph Node Dissection for Renal Cell Carcinoma: A Propensity Score–based Analysis

BackgroundThere are little data regarding the morbidity of lymph node dissection (LND) for renal cell carcinoma (RCC) to assess its risk–benefit ratio. ObjectiveTo evaluate the association of LND with 30-d complications among patients undergoing radical nephrectomy (RN) for RCC. Design, setting, and participantsA total of 2066 patients underwent RN for M0 or M1 RCC between 1990 and 2010, of whom 774 (37%) underwent LND. InterventionRN with or without LND. Outcome measurements and statistical analysisAssociations of LND with 30-d complications were examined using logistic regression with several propensity score techniques. Extended LND, defined as removal of ≥13 lymph nodes, was examined in a sensitivity analysis. Results and limitationsA total of 184 (9%) patients were pN1 and 302 (15%) were M1. Thirty-day complications occurred in 194 (9%) patients, including Clavien grade ≥3 complications in 81 (4%) patients. Clinicopathologic features were well balanced after propensity score adjustment. In the overall cohort, LND was not statistically significantly associated with Clavien grade ≥3 complications, although there was an approximately 40% increased risk of any Clavien grade complication that did not reach statistical significance. Likewise, LND was not significantly associated with any Clavien grade or Clavien grade ≥3 complications when separately evaluated among M0 or M1 patients. Extended LND was not significantly associated with any Clavien grade or Clavien grade ≥3 complications. LND was not associated with length of stay or estimated blood loss. Limitations include a retrospective design. ConclusionsLND is not significantly associated with an increased risk of Clavien grade ≥3 complications, although it may be associated with a modestly increased risk of minor complications. In the absence of increased morbidity, LND may be justified in a predominantly staging role in the management of RCC. Patient summaryLymph node dissection for renal cell carcinoma is not associated with increased rates of major complications.

Nivolumab in renal cancer

Renal cell carcinoma (RCC) is a chemoresistant tumor, characterized by a poor response and lack of survival benefit with conventional cytotoxic agents. Furthermore, the complexity and heterogeneity of RCC limit the biologic targets for novel agents to manage RCC. Expression of the multiple drug resistance (MDR) protein (ATP-binding cassette P-glycoprotein) is increased in RCC, while the Von Hippel Lindau protein is mutated or silenced in approximately half of sporadic RCC, resulting in high levels of hypoxia inhibiting factor (HIF) and the activation of several genes codifying growth factors and growth factors receptors, such as vascular endothelial growth factor (VEGF), platelet-derived growth factor B (PDGF-B), and transforming growth factor alpha (TGFα). Consequently, immunodrugs targeting pathways related to these proteins have been evaluated for the management of metastatic RCC (mRCC). This review provides an overview of drugs that have been evaluated or are under investigation for the treatment of mRCC, including the multi-tyrosine kinase inhibitors (TKIs) sunitinib, pazopanib, axitinib, the mammalian target of rapamycin (mTOR) inhibitors everolimus and temsirolimus, and nivolumab, which targets the programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) pathway. Promising results have been obtained with nivolumab, alone or in combination with TKIs such as sunitinib and pazopanib, and with ipilimumab, an immune checkpoint inhibitor which acts on the CTLA-4 pathway. Although much progress has been made, research with these and other agents is ongoing, and there is a need to identify makers of response to “tailor” the most suitable therapy, or sequence of therapies, to the individual patient, with the aim of improving outcomes and reducing unneeded toxicity.

Radiofrequency Ablation for Renal Cancer in Von Hippel-Lindau Syndrome Patients: A Prospective Cohort Analysis.

Management of renal-cell carcinoma (RCC) in patients with Von Hippel-Lindau syndrome (VHL) represents a clinical dilemma: the oncologic outcomes must be weighed against preservation of renal function. Radiofrequency ablation (RFA) is currently used in selected cases for treatment of small-size RCC. The aim of this study was to evaluate the safety, complications, and functional and oncologic outcomes of RFA in the treatment of RCC in VHL patients. RCCs were treated with ultrasound-guided RFA or with laparoscopic RFA. Clinical and radiologic response, disease recurrence, and survival outcomes were evaluated during follow-up. Early and late complications were recorded and graded. Nine RCC patients underwent RFA. The median number of RCCs per patient was 3 (interquartile range, 2-4). Among these 9 patients, a total of 20 RCCs were treated by RFA (19ultrasound-guided RFA and 1 laparoscopic procedure). Median RCC size was 2.5 cm (interquartile range, 2.0-3.0). RFA did not impair renal function (P= .35). In 2 cases disease persisted, and in 1 case disease recurred after 18 months. These patients were retreated with ultrasound-guided RFA with complete response and no renal function impairment. RFA treatment was overall well tolerated and safe. No complications were recorded. Postoperative stay was no longer than 1 day. RCC occurred in about two-thirds of VHL patients, who had young age at presentation; it was frequently multifocal and recurrent. The use of RFA, with extended indications, could represent a tailored treatment for VHL patients, reducing the risk of renal failure and resulting in satisfying oncologic results.

Advanced Renal Cell Carcinoma: Role of the Radiologist in the Era of Precision Medicine.

For the past decade, advanced renal cell carcinoma (RCC) has been at the forefront of oncologic innovation. Our rapidly evolving understanding of the molecular and genetic basis of RCC has revolutionized the management of advanced RCC; 10 novel molecular targeted agents and immune checkpoint inhibitor have received U.S. Food and Drug Administration approval for treatment of advanced RCC in a little over a decade. Amid this progress, imaging has assumed a central role in metastatic surveillance and follow-up of advanced RCC. State-of-the-art knowledge of the molecular basis of RCC and its treatment and imaging will help ensure that the radiology community remains relevant and central in the care of patients with advanced RCC. This article will review developments in management of advanced RCC from a radiologist's perspective to highlight our clinical role. It will describe how the underlying molecular mechanisms of RCC provide specific targets for novel anticancer agents. The relationship between the mechanisms of action of these novel anticancer agents and the imaging appearance of tumor response will be discussed, along with the available tumor response criteria and their strengths and weaknesses, thus assisting radiologists in response assessment in the setting of clinical trials or routine practice. The class- and drug-specific toxicities and complications associated with the novel anticancer agents will be summarized, since these are frequently missed or misinterpreted and require the radiologist's input in prompt detection and management. The potential role of radiogenomics and texture analysis in the management of advanced RCC will also be discussed. © RSNA, 2017.

Renal Cell Carcinoma: Insights into Risk Factors, Diagnosis and Management

In the last decade, there is an increasing incidence of renal cell carcinoma (RCC) worldwide. Most patients with RCC are diagnosed late with advanced stages of the disease which are often refractory to treatment and associated with poor prognosis. Management of RCC has changed greatly over the past years. Progress in the surgical management of the primary tumor and increased understanding of the molecular biology of the disease have led to the development of new therapeutic lines. This mini-review sheds light on the risk factors, the clinical presentation, methods of diagnosis and the up-to-date lines of management of RCC.

Maslinic Acid Inhibits Proliferation of Renal Cell Carcinoma Cell Lines and Suppresses Angiogenesis of Endothelial Cells.

Despite the introduction of many novel therapeutics in clinical practice, metastatic renal cell carcinoma (RCC) remains a treatment-resistant 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.

Tumor genomic analysis for 128 renal cell carcinoma (RCC) patients receiving first-line everolimus: Correlation between outcome and mutations status in MTOR, TSC1, and TSC2.

484 Background: MTOR inhibitors are standard agents in the management of advanced RCC. Case series have suggested somatic mutations in MTOR, TSC1, and TSC2 may sensitize tumors to everolimus (EVE) [Voss et al., CCR 2014; Kwiatkowski et al., CCR 2016]. We sought to test this hypothesis through next generation sequencing (NGS) of tumors from a large cohort of patients (pts) treated with everolimus (EVE) on the randomized RECORD3 trial of first-line EVE vs. sunitinib. Methods: Somatic mutations were investigated using a custom exon-targeted NGS platform with deep sequence coverage. This analysis focused on mutations in TSC1, TSC2, PTEN, PIK3CA, and MTOR. Association between genotypes and progression free survival (PFS) was assessed by Cox PH models and log-rank tests. Mutations in other pathways and non-genetic covariates were investigated. Functional investigation of individual mutations in MTOR, TSC1, and TSC2 were undertaken. Results: 238 pts received 1st line EVE with median PFS of 7.85 mo (95% CI 5.6-8.2). Tumor sampleswere analyzed for 128 pts. Median depth of coverage was ~540X. There was no correlation between PFS and mutation status of mTOR, TSC1, or TSC2 (15 pts [12%]; HR 0.99 [95% CI 0.47-2.07]; p=0.4697); the objective response rate (ORR) in this group was 0%. Individual PFS for all 15 pts clustered outside the 95% CI for the population of 128 everolimus-treated pts (8 pts PFS&lt;2.8mo; 7pts PFS&gt;8.3mo). 3 of 8 pts with PFS&lt;2.8mo had &gt;1 mutation in MTOR, TSC1, or TSC2, while none among the 7 pts with PFS &gt;8.3mo. When including pts with mutations in PTEN, PIK3Ca, MTOR, or TSC1 (30pts [23%]), we found no association between mutation status and PFS (HR 1.02 [95% CI 0.61-1.71]; p=0.3025). Functional investigations suggest varying biologic effects of individual mutations. Conclusions: "One-dimensional" mutation status for core components of the MTOR signaling pathway did not correlate with PFS in this dataset. Grouping based on more detailed characterization incorporating copy number status and functional annotation may provide better insights and should be considered for future biomarker development. Clinical trial information: NCT00903175.

The current management of renal cell carcinoma.

Although the broad use of ultrasound and computed tomography (CT) has led to an early diagnosis of the disease, renal cell carcinoma (RCC) remains one of the most lethal urological cancers. The present review is based on the latest data published on RCC management. A literature search was carried out searching recent publications from PubMed, MEDLINE, Embase up to December 2016 as well as European Association of Urology (EAU) and European Society of Medical Oncology (ESMO) guidelines. A narrative synthesis based on recent publications was undertaken. Current evidence regarding treatment strategies and guidelines is based on prospective randomized controlled trials and retrospective studies although the level of evidence for surgical management is generally lower than for systemic therapy. This narrative review depicts a summary of the evidence base for treatment of RCC. Management of RCC is a rapidly evolving and changing field. As a consequence guidelines need regular updating and patients may benefit from centralization of care and multidisciplinary approach.

Sunitinib: Ten Years of Successful Clinical Use and Study in Advanced Renal Cell Carcinoma.

2017;22:41-52 IMPLICATIONS FOR PRACTICE: Approved globally, sunitinib is established as a standard of care for first-line advanced renal cell carcinoma (RCC) therapy and, along with other targeted agents, has significantly altered the treatment landscape in RCC. Research with sunitinib that has sought to refine its role via patient selection and prognostic markers, improve dosing and adverse event management, and identify predictive efficacy biomarkers has contributed to the overall understanding and management of RCC. Key learnings regarding study design and data interpretation from the sunitinib studies and the sunitinib development program, in general, can be a model for the successful development of other agents.

Multidetector computed tomography scan for renal cell carcinoma: A review

Renal cell carcinoma (RCC) is the most common renal malignant tumour. Owing to its retroperitoneal location, RCC remains asymptomatic and non-palpable until advanced disease develops. Most cases are identified during radiological examination for other reasons. The management of RCC depends substantially on the effective use of imaging. This is true in all the stages of the RCC, from initial diagnosis to follow-up. This article sets to review the current knowledge about multidetector computed tomography (MDCT) scan and how it characterises the RCC. A search of PubMed database was made to locate the original and review articles in English that address the MDCT scan or RCC, without limit to publication date. Relevant articles and textbook chapters were reviewed, analysed and summarised. MDCT reveals the renal tumour, its extent, venous involvement, status of loco-regional lymph nodes as well as adrenal and liver extension. It is available and relatively affordable presently in some centres across the subregion. MDCT is an essential tool that has aided not only the early diagnosis of RCC, but also the staging and characterisation of the RCC.

Recent advances in the management of renal cell carcinoma-a radiation oncology perspective.

Renal cell carcinoma (RCC) is a rare cancer in developing countries like Nigeria. However, with an increasing understanding of its epidemiology, the increasing availability of trained personnel, improvement in diagnostic facilities, and greater awareness in the populace, an increase in its incidence as was witnessed in developed nations in the last few decades could be safely predicted. This narrative review highlights the international best practices in the multidisciplinary approach to the management of RCC, its diagnosis and treatment, with emphasis on recent advances and radiation treatment. The National Comprehensive Cancer Network (NCCN) guideline (version 3.2015) served as a guide to select relevant articles through a PubMed and Google scholar query.

Combination therapy of three-dimensional (3D) visualisation operative treatment planning system and US-guided percutaneous microwave ablation in larger renal cell carcinomas (D ≥ 4 cm): preliminary results

Purpose: To analyse the clinical outcomes of combination therapy of three-dimensional (3D) visualisation operative treatment planning system and US-guided percutaneous microwave ablation (PMWA) in larger renal cell carcinomas (RCCs) (D ≥ 4 cm).Materials and methods: The results from 20 patients with 20 larger RCCs treated with a 3D visualisation operative treatment planning system and US-guided PMWA were reviewed retrospectively. The patients were followed up by contrast-enhanced images at 1, 3, and 6 months and every 6 months thereafter. The outcomes of overall survival and local tumour progression rate were statistically analysed.Results: The median follow-up period was 26 months. The mean time of ablation for one tumour was 1.1 ± 0.3 sessions. The average number of ablation points of one tumour was 4.5 ± 0.9. The mean output power of ablation was 50.50 ± 2.2 W. The mean time of ablation for one tumour was 1374.4 ± 391.1 s. Artificial ascites was used in 12 (60%) tumours adjacent to the intestinal tract, and thermal monitoring system was used in all tumours (100%). Technical effectiveness and metastasis-free status were achieved in all tumours. The 1- and 2-year local tumour progression rates were both 5%. The cancer-specific survival rate and 2-year overall survival rates were both 100%. No severe major complications occurred. There was no significant difference in creatinine or urea nitrogen before or 3 days after ablation.Conclusions: Combination therapy of 3D visualisation operative treatment planning system and US-guided PMWA appeared to be a safe and effective technique for the management of larger RCCs, which could improve clinical efficacy.

Oncology Gold Standard™ practical consensus recommendations 2016 for treatment of advanced clear cell renal cell carcinoma.

The Oncology Gold Standard (OGS) Expert Group on renal cell carcinoma (RCC) developed the consensus statement to provide community oncologists practical guidelines on the management of advanced clear cell (cc) RCC using published evidence, practical experience of experts in real life management, and results of a nationwide survey involving 144 health-care professionals. Six broad question categories containing 33 unique questions cover major situations in the routine management of RCC. This document serves as a ready guide for the standard of care to optimize outcome. The table of “Take Home Messages” at the end is a convenient tool for busy practitioners.

The Place of FDG PET/CT in Renal Cell Carcinoma: Value and Limitations.

Unlike for most other malignancies, application of FDG PET/CT is limited for renal cell carcinoma (RCC), mainly due to physiological excretion of 18F-fluoro-2-deoxy-2-d-glucose (FDG) from the kidneys, which decreases contrast between renal lesions and normal tissue, and may obscure or mask the lesions of the kidneys. Published clinical observations were discordant regarding the role of FDG PET/CT in diagnosing and staging RCC, and FDG PET/CT is not recommended for this purpose based on current national and international guidelines. However, quantitative FDG PET/CT imaging may facilitate the prediction of the degree of tumor differentiation and allows for prognosis of the disease. FDG PET/CT has potency as an imaging biomarker to provide useful information about patient’s survival. FDG PET/CT can be effectively used for postoperative surveillance and restaging with high sensitivity, specificity, and accuracy, as early diagnosis of recurrent/metastatic disease can drastically affect therapeutic decision and alter outcome of patients. FDG uptake is helpful for differentiating benign or bland emboli from tumor thrombosis in RCC patients. FDG PET/CT also has higher sensitivity and accuracy when compared with bone scan to detect RCC metastasis to the bone. FDG PET/CT can play a strong clinical role in the management of recurrent and metastatic RCC. In monitoring the efficacy of new target therapy such as tyrosine kinase inhibitors (TKIs) treatment for advanced RCC, FDG PET/CT has been increasingly used to assess the therapeutic efficacy, and change in FDG uptake is a strong indicator of biological response to TKI.

Medical treatment of renal cancer: new horizons.

Renal cell carcinoma (RCC) makes up 2–3% of adult cancers. The introduction of tyrosine kinase inhibitors (TKIs) and mammalian target of rapamycin inhibitors in the mid-2000s radically changed the management of RCC. These targeted treatments superseded immunotherapy with interleukin-2 and interferon. The pendulum now appears to be shifting back towards immunotherapy, with the evidence of prolonged overall survival of patients with metastatic RCC on treatment with the anti-programmed cell death 1 ligand monoclonal antibody, nivolumab. Clinical prognostic criteria aid prediction of relapse risk for resected localised disease. Unfortunately, for patients at high risk of relapse, no adjuvant treatment has yet shown benefit, although further trials are yet to report. Clinical prognostic models also have a role in the management of advanced disease; now there is a pressing need for predictive biomarkers to direct therapy. Treatment selection for metastatic disease is currently based on histology, prognostic group and patient preference based on side effect profile. In this article, we review the current medical and surgical management of localised, oligometastatic and advanced RCC, including side effect management and the evidence base for management of poor-risk and non-clear cell disease. We discuss recent results from clinical trials and how these are likely to shape future practice and a renaissance of immunotherapy for renal cell cancer.

Insulin-like growth factor-1 signaling in renal cell carcinoma.

Renal cell carcinoma (RCC) incidence is highest in highly developed countries and it is the seventh most common neoplasm diagnosed. RCC management include nephrectomy and targeted therapies. Type 1 insulin-like growth factor (IGF-1) pathway plays an important role in cell proliferation and apoptosis resistance. IGF-1 and insulin share overlapping downstream signaling pathways in normal and cancer cells. IGF-1 receptor (IGF1R) stimulation may promote malignant transformation promoting cell proliferation, dedifferentiation and inhibiting apoptosis. Clear cell renal cell carcinoma (ccRCC) patients with IGF1R overexpression have 70 % increased risk of death compared to patients who had tumors without IGF1R expression. IGF1R signaling deregulation may results in p53, WT, BRCA1, VHL loss of function. RCC cells with high expression of IGF1R are more resistant to chemotherapy than cells with low expression. Silencing of IGF1R increase the chemosensitivity of ccRCC cells and the effect is greater in VHL mutated cells. Understanding the role of IGF-1 signaling pathway in RCC may result in development of new targeted therapeutic interventions. First preclinical attempts with anti-IGF-1R monoclonal antibodies or fragment antigen-binding (Fab) fragments alone or in combination with an mTOR inhibitor were shown to inhibit in vitro growth and reduced the number of colonies formed by of RCC cells.