Search

PURPOSE: A challenge in the diagnosis of renal cell carcinoma (RCC) is to distinguish chromophobe RCC (chRCC) from benign renal oncocytoma, because these tumor types are histologically and morphologically similar, yet they require different clinical management. Molecular biomarkers could provide a way of distinguishing oncocytoma from chRCC, which could prevent unnecessary treatment of oncocytoma. Such biomarkers could also be applied to preoperative biopsy specimens such as needle core biopsy specimens, to avoid unnecessary surgery of oncocytoma. METHODS: We profiled DNA methylation in fresh-frozen oncocytoma and chRCC tumors and adjacent normal tissue and used machine learning to identify a signature of differentially methylated cytosine-phosphate-guanine sites (CpGs) that robustly distinguish oncocytoma from chRCC. RESULTS: Unsupervised clustering of Stanford and preexisting RCC data from The Cancer Genome Atlas (TCGA) revealed that of all RCC subtypes, oncocytoma is most similar to chRCC. Unexpectedly, however, oncocytoma features more extensive, overall abnormal methylation than does chRCC. We identified 79 CpGs with large methylation differences between oncocytoma and chRCC. A diagnostic model trained on 30 CpGs could distinguish oncocytoma from chRCC in 10-fold cross-validation (area under the receiver operating curve [AUC], 0.96 (95% CI, 0.88 to 1.00)) and could distinguish TCGA chRCCs from an independent set of oncocytomas from a previous study (AUC, 0.87). This signature also separated oncocytoma from other RCC subtypes and normal tissue, revealing it as a standalone diagnostic biomarker for oncocytoma. CONCLUSION: This CpG signature could be developed as a clinical biomarker to support differential diagnosis of oncocytoma and chRCC in surgical samples. With improved biopsy techniques, this signature could be applied to preoperative biopsy specimens. [ABSTRACT FROM AUTHOR]

Loss of the von Hippel-Lindau (VHL) tumor suppressor is a hallmark feature of renal clear cell carcinoma. VHL inactivation results in the constitutive activation of the hypoxia-inducible factors (HIFs) HIF-1 and HIF-2 and their downstream targets, including the proangiogenic factors VEGF and PDGF. However, antiangiogenic agents and HIF-2 inhibitors have limited efficacy in cancer therapy due to the development of resistance. Here we employed an innovative computational platform, Mining of Synthetic Lethals (MiSL), to identify synthetic lethal interactions with the loss of VHL through analysis of primary tumor genomic and transcriptomic data. Using this approach, we identified a synthetic lethal interaction between VHL and the m6A RNA demethylase FTO in renal cell carcinoma. MiSL identified FTO as a synthetic lethal partner of VHL because deletions of FTO are mutually exclusive with VHL loss in pan cancer datasets. Moreover, FTO expression is increased in VHLdeficient ccRCC tumors compared to normal adjacent tissue. Genetic inactivation of FTO using multiple orthogonal approaches revealed that FTO inhibition selectively reduces the growth and survival of VHL-deficient cells in vitro and in vivo. Notably, FTO inhibition reduced the survival of both HIF wild type and HIFdeficient tumors, identifying FTO as an HIF-independent vulnerability of VHL-deficient cancers. Integrated analysis of transcriptome-wide m6A-seq and mRNA-seq analysis identified the glutamine transporter SLC1A5 as an FTO target that promotes metabolic reprogramming and survival of VHL-deficient ccRCC cells. These findings identify FTO as a potential HIF-independent therapeutic target for the treatment of VHL-deficient renal cell carcinoma. [ABSTRACT FROM AUTHOR]

Objective: To assess whether patient factors, such as age and preoperative kidney function, were associated with receipt of partial nephrectomy in a national integrated healthcare system.Materials and Methods: We identified patients treated with a radical or partial nephrectomy from 2002 to 2014 in the Veterans Health Administration. We examined associations among patient age, sex, race or ethnicity, multimorbidity, baseline kidney function, tumor characteristics, and receipt of partial nephrectomy. We estimated the odds of receiving a partial nephrectomy and assessed interactions between covariates and the year of surgery to explore whether patient factors associated with partial nephrectomy changed over time.Results: In our cohort of 14,186 patients, 4508 (31.2%) received a partial nephrectomy. Use of partial nephrectomy increased from 17% in 2002 to 32% in 2008 and to 38% in 2014. Patient race or ethnicity, age, tumor stage, and year of surgery were independently associated with receipt of partial nephrectomy. Black veterans had significantly increased odds of receipt of partial nephrectomy, whereas older patients had significantly reduced odds. Partial nephrectomy utilization increased for all groups over time, but older patients and patients with worse baseline kidney function showed the least increase in odds of partial nephrectomy.Conclusion: Although the utilization of partial nephrectomy increased for all groups, the greatest increase occurred in the youngest patients and those with the highest baseline kidney function. These trends warrant further investigation to ensure that patients at the highest risk of impaired kidney function are considered for partial nephrectomy whenever possible. [ABSTRACT FROM AUTHOR]

Androgen receptor (AR) is expressed in normal murine and human kidneys of both genders, but its physiologic role is uncertain. Several studies showed loss of AR in renal cell carcinoma (RCC) in conjunction with increasing clinical stage and pathological grade, but others found that higher AR expression correlated with worse outcomes. Limited functional studies with renal cell lines suggested tumor-promoting activity of AR. In this study, we queried transcriptomic, proteomic, epigenetic and survival data from The Cancer Genome Atlas (TCGA) to evaluate AR expression and its association with overall survival in three subtypes of RCC (clear cell [ccRCC], papillary [pRCC], and chromophobe [chRCC]). We found that although there was no significant difference in AR mRNA expression in ccRCC of males vs. females, AR protein expression in ccRCC was significantly higher in male compared to female patients. More importantly, higher expression of AR at both transcript and protein levels was associated with improved overall survival in both genders with ccRCC, but did not predict survival of either gender with pRCC or chRCC. Genes whose transcript levels were associated with AR mRNA levels significantly overlapped between ccRCC and pRCC, but not with chRCC, suggesting a similar transcriptional program mediated by AR in ccRCC and pRCC. Ingenuity pathway analysis also identified overlapping pathways and upstream regulators enriched in AR-associated genes in ccRCC and pRCC. Hypermethylation of CpG sites located in the promoter and first exon of AR was associated with loss of AR expression and poor overall survival. Our findings support a tumor suppressor role for AR in both genders that might be exploited to decrease the incidence or progression of ccRCC. [ABSTRACT FROM AUTHOR]

Objective: To examine the patient, tumor, and temporal factors associated with receipt of renal mass biopsy (RMB) in a contemporary nationally representative sample. Methods: We queried the Surveillance, Epidemiology, and End Results-Medicare data set for incident cases of renal cell carcinoma diagnosed between 1992 and 2007. We tested for associations among receipt of RMB and patient and tumor characteristics, type of therapy, and procedure type. Temporal trends in receipt of RMB were characterized over the study period. Results: Approximately 1 in 5 (20.7%) patients diagnosed with renal cell carcinoma (n = 24,702) underwent RMB before instituting therapy. There was a steady and modest increase in RMB utilization, with the highest utilization (30%) occurring in the final study year. Of patients who underwent radical (n = 15,666) or partial (n = 2211) nephrectomy, 17% and 20%, respectively, underwent RMB in advance of surgery. Sixty-five percent of patients who underwent ablation (n = 314) underwent RMB before or in conjunction with the procedure. Roughly half of patients (50.4%) treated with systemic therapy alone underwent RMB. Factors independently associated with use of RMB included younger age, black race, Hispanic ethnicity, tumor size <7 cm, and metastatic disease at presentation. Conclusion: At present, most patients who eventually undergo radical or partial nephrectomy do not undergo RMB, whereas most patients who eventually undergo ablation or systemic therapy do. The optimal use of RMB in the evaluation of kidney tumors has yet to be determined. [Copyright &y& Elsevier]

Study Type – Diagnostic (exploratory cohort) Level of Evidence 2b OBJECTIVE To prospectively determine the accuracy of 14-, 18- and 20-G core needle biopsies to render the appropriate histological diagnosis of solid, enhancing renal masses, using a controlled, ex-vivo biopsy technique. PATIENTS AND METHODS From March 2007 to September 2007, 31 patients undergoing partial or radical nephrectomy were randomly selected for biopsy. After extirpative surgery, three ex-vivo biopsies were taken from each lesion with 14-, 18- and 20-G biopsy needles. One experienced genitourinary pathologist, unaware of patient identifiers and final pathology results, determined the biopsy histology and tumour grade, based on standard haematoxylin and eosin (H&E) techniques and immunohistochemistry. RESULTS The final pathological evaluation classified 21 masses (68%) as clear cell renal cell carcinoma (RCC), three (10%) as papillary RCC, three (10%) as chromophobe RCC, three (10%) as oncocytoma and one (3%) as a benign lymphoid infiltrate. The biopsy histology correlated with the final pathology in 29/31 cases (94%) with the 14-G, 30/31 cases (97%) with the 18-G and 25/31 cases (81%) with the 20-G needles. In two cases chromophobe RCC was misdiagnosed with oncocytoma, and vice versa. CONCLUSION In this study a minimum of an 18-G biopsy needle was the most accurate in determining the histological diagnosis. Clear cell and papillary RCCs were accurately diagnosed on biopsy using an 18-G, whereas oncocytoma and chromophobe RCC were difficult to differentiate using standard H&E techniques and immunohistochemistry. [ABSTRACT FROM AUTHOR]

Background: The mammalian target of rapamycin (mTOR) pathway is up-regulated in many human cancers, and agents targeting the mTOR pathway are in various stages of clinical development. The goal of the study was to evaluate the potential and limitations of targeting the mTOR pathway in renal cell carcinoma (RCC).Methods: Immunohistochemical analysis using antibodies against pAkt, PTEN, p27, and pS6 was performed on a tissue microarray constructed from paraffin-embedded specimens from 375 patients treated by nephrectomy for RCC. The expression was associated with pathological parameters and survival.Results: The mTOR pathway was more significantly altered in clear-cell RCC, high-grade tumors, and tumors with poor prognostic features. PS6 and PTEN showed the strongest associations with pathological parameters. Survival tree analysis regarding expression of cytoplasmic pAkt, nuclear pAkt, PTEN, cytoplasmic p27, and pS6 identified staining percentages of 40%, 10%, 75%, 7%, and 70%, respectively, as ideal cutoff values for stratification, with corresponding P-values of .03, .001, .02, .005, and <.0001, respectively. Interestingly, high nuclear pAkt expression was associated with a favorable prognosis, whereas high cytoplasmic pAkt expression was associated with a poor prognosis. In multivariate Cox regression analysis, ECOG PS, T classification, N classification, M classification, cytoplasmic Akt, nuclear pAkt, PTEN, and pS6 were independent prognostic factors of DSS.Conclusions: Components of the mTOR pathway are significantly associated with pathological features and survival. Not all RCC tumor types seem to be equally amenable to mTOR targeted therapy. PTEN, pAkt, p27, and pS6 may serve as surrogate parameters for patient selection and predicting prognosis. Patients with a highly activated mTOR pathway should benefit most from this therapy. External validation of our results is recommended. [ABSTRACT FROM AUTHOR]

The article presents medical research into the role of human molecular gene/protein expression markers in the staging and prognosis of renal cell carcinoma (RCC). An example of a molecular marker is carbonic anhydrase IX (CAIX). Future directions in molecular staging include predicting the response to targeted treatments and predicting the response to immunotherapy.

OBJECTIVE To define the prognostic relevance of capsular involvement (invasion with no penetration) and collecting-system invasion in patients with stage I (pT1N0M0) and stage II (pT2N0M0) renal cell carcinoma (RCC), by evaluating the outcome of patients treated with nephrectomy. PATIENTS AND METHODS In all, 519 patients from a kidney cancer database treated with nephrectomy for stage I and II RCC between 1985 and 2005 were assessed retrospectively. The primary endpoint was recurrence-free survival time. The prognostic relevance of capsular involvement and collecting-system invasion were examined using univariate and multivariate survival analysis. RESULTS Capsular involvement and collecting-system invasion were evident in 112 (21.6%) and 39 (7.5%) patients, respectively. Capsular involvement was associated with higher Fuhrman grades and larger tumours. The incidence of collecting-system invasion was higher in patients with microvascular invasion. The median follow-up was 49 months. In univariate analysis, patients with capsular involvement and collecting-system invasion had a worse prognosis than patients without ( P = 0.007 and <0.001, respectively). In multivariate analysis, capsular involvement (hazard ratio 1.84, P = 0.036) and collecting-system invasion (3.78, P < 0.001) were independent prognostic factors of recurrence-free survival. Interestingly, there was no survival difference between patients with capsular involvement in stage I/II and patients with invasion of perinephric tissue (pT3aN0M0). CONCLUSIONS These findings suggest that capsular involvement and collecting-system invasion are poor prognostic findings in stage I and II RCC. They should both be considered when planning the follow-up. A revised pT3a stage including patients with capsular involvement could improve its prognostic validity. [ABSTRACT FROM AUTHOR]

Reports on the open surgical management of renal cell carcinoma in the era of minimally invasive kidney surgery. Evidence showing that nephron-sparing surgery (NSS) for patients with small tumors is equivalent to total radical nephroctomy in terms of long-term survival; Safety and efficacy of NSS; Clinical factors determining prognosis and survival in the management of the disease.

Abstract: Recent advances in the understanding of the pathogenesis, behavior, and molecular biology of renal cell carcinoma (RCC) have paved the way for developments that may enhance early diagnosis, better predict prognosis, and improve survival. Reliable predictive factors are essential for the stratification of patients into clinically meaningful categories that can be used to provide patients with counseling regarding prognosis, select treatment modalities, and determine eligibility for clinical trials. The TNM (tumor, nodes, metastasis) staging system is currently the most extensively used staging system for RCC, but it has undergone systematic revisions as a result of emerging data. Comprehensive integrated staging systems that combine important clinical and pathological variables have been created in an attempt to improve prognostication. Although staging has improved with the development of integrated systems, the incorporation of molecular tumor markers are expected to revolutionize the staging of RCC. This article reviews the important molecular markers in RCC to date and discusses their role in the diagnosis, prognostication, and therapy of patients with RCC. [Copyright &y& Elsevier]

Reports on the adjuvant therapy of renal cell carcinoma in patient selection and therapeutic options. Renal cell carcinoma, survival and prognostic factors; Postoperative surveillance protocol for patients with localized and locally advanced renal cell carcinoma; Risk group assessment and clinical outcome algorithm to predict the natural history of patients with surgically resected renal cell carcinoma; Correlations with tumor oxygen measurements and prognostic in locally advanced carcinoma of the cervix.

The use of carbonic anhydrase IX as a promising molecular marker in RCC is described by authors from Los Angeles, who discuss the promise that molecular markers hold to improve diagnosis, staging, treatment surveillance and survival of patients with RCC. There is a whole range of new treatments being introduced in the management of metastatic renal cancer. The use of VEOF-targeted therapy has particular importance, especially as it has a strong genetically linked rationale for its potential success in this area. Authors from the USA show that substantial clinical activity has been reported in initial clinical trials. In prostate cancer, drugs targeting microtubules, such as taxanes, have already been introduced clinically, and their success has received widespread attention. A new group of drugs, the epothilones, have similar but not identical binding properties to microtubules, and authors from the USA describe how they have shown activity in hormone-refractory prostate cancer, and are moving to phase III testing. [ABSTRACT FROM AUTHOR]

Renal cell carcinoma (RCC) is the most lethal of the common urologic malignancies, with approximately 40% of patients eventually dying of cancer progression. Approximately one third of patients present with metastatic disease, and up to 40% treated for localized disease have a recurrence. Recent advances in the understanding of the pathogenesis, behavior, and molecular biology of RCC have paved the way for developments that may enhance early diagnosis, better predict tumor prognosis, and improve survival for RCC patients. The recent discovery of molecular tumor markers is expected to revolutionize the staging of RCC in the future and lead to the development of new therapies based on molecular targeting. Cytokine-based immunotherapy can be considered standard therapy in the treatment of metastatic RCC today. However, new therapies such as tumor vaccines, anti-angiogenesis agents, and small molecule inhibitors are being developed to improve efficacy and treat those patients who are unable to tolerate or are resistant to systemic immunotherapy. The aim of this review is to provide an update on current therapeutic approaches and targeted molecular therapy for metastatic RCC. [ABSTRACT FROM AUTHOR]

The authors discusses the use of partial nephrectomy in the health care system of the U.S. Department of Veterans Affairs (VA). Guidelines issued by the American Urological Association describe nephron sparing surgery (NSS) as the preferred treatment modality for renal cell carcinoma (RCC). An overview of the Veteran's Affairs Central Cancer Registry (VACCR) data repository is provided. The authors conclude that current partial nephrectomy rates in the VA health care system are comparable to those in the SEER-Medicare tumor registry studies.

The article discusses issues related to the emergence of targeted molecular therapies as mainstays of treating advanced renal cell carcinoma (RCC). According to the article, the discovery of specific genes, gene products and aberrant molecular pathways associated with RCC has fueled the development of targeted therapies and clinical trials examining their efficacy. The article also discusses the rationale and evidence for targeted therapy strategies.

Background: Prognostic models for patients with metastatic renal cell carcinoma (mRCC) include select laboratory values. These models have important limitations, including reliance on a limited array of laboratory tests, and use of dichotomous ("high-low") cutoffs. We applied a Laboratory-Wide Association Study (LWAS) framework to systematically evaluate common clinical laboratory results associated with survival for patients diagnosed with mRCC.Methods: We used laboratory data for 3,385 patients diagnosed with mRCC from 2002 to 2017. We developed a LWAS framework, to examine the association with 53 common clinical laboratory tests results (641,712 measurements) and overall survival. We employed false-discovery rate to test the association of multiple laboratory tests with survival, and validated these results using 3 separate cohorts to generate a standardized hazard ratio (sHR), reported for a 1 standard deviation unit change in each laboratory test.Results: The LWAS approach confirmed the association of laboratory values currently used in prognostic models with survival, including calcium (HR 1.35, 95%CI 1.24-1.48), leukocyte count (HR 1.40, 95%CI 1.30-1.51), platelet count (HR 1.36, 95%CI 1.27-1.51), and hemoglobin (HR 0.79, 95%CI 0.72-0.86). Use of these tests as continuous variables improved model performance. LWAS also identified acute phase reactants associated with survival not typically included in prognostic models, including serum albumin (HR 0.66, 95%CI 0.61-0.72), ferritin (HR 1.25, 95%CI 1.08-1.45), alkaline phosphatase (HR 1.31, 95%CI 1.23-1.40), and C-reactive protein (HR 1.70, 95%CI 1.14-2.53).Conclusions: Routinely measured laboratory tests can refine current prognostic models, facilitate comparisons across clinical trial cohorts, and match patients with specific systemic therapies. [ABSTRACT FROM AUTHOR]

OBJECTIVE To determine the extent to which the year of diagnosis, year of birth, and age at diagnosis influence the incidence trends of kidney cancer in the United States. METHODS Cancer registry data from the National Cancer Institute's Surveillance, Epidemiology, and End- Results (SEER) program were obtained for 64,041 patients with kidney cancer diagnosed between 1973 and 2008. Overall and age-specific incidence rates were calculated and adjustments were made for birth cohort and period effects. Results were stratified by race and sex. Age-period-cohort analysis was used to examine the effects of age, year of diagnosis (period), and year of birth (cohort) on incidence trends. RESULTS The overall age-standardized annual incidence per 100,000 increased during the study period (1973 to 2008) by race, from 6.75 (95% confidence interval, 6.18-7.36) to 19.56 (18.85-20.20) among whites, from 5.31 (3.50-7.71) to 25.38 (23.00-27.92) among blacks, and from 5.61 (3.50-8.50) to 13.98 (12.41-15.71) among other races; and by sex, from 9.44 (8.49-10.47) to 26.48 (25.39-27.60) among men and from 4.21 (3.65-4.84) to 13.38 (12.64-14.11) among women. Age-period-cohort analysis revealed a strong influence from period and cohort effects. The 1983 birth cohort, for example, had a 2-fold increase in kidney cancer (incidence rate ratio, 1.93 [1.63-2.25]) compared with the referent 1948 cohort. CONCLUSION From 1973 to 2008, the incidence rate of kidney cancer increased for each sex and race across all age groups. Age-period-cohort models revealed that period-related factors, although significant, cannot alone account for these unfavorable temporal trends. [ABSTRACT FROM AUTHOR]

Abstract: Background: While it is well known that clear cell renal cell carcinoma (ccRCC) that presents with lymphatic spread is associated with an extremely poor prognosis, its molecular and genetic biology is poorly understood. Objective: Define the clinicopathologic, molecular, and genetic biological characteristics of these tumors in comparison to nonmetastatic (N0M0) renal cell carcinomas. Design, setting, and participants: A retrospective study defined clinicopathologic features, expression of 28 molecular markers, and occurrence of chromosomal aberrations for their correlation with lymphatic spread in three cohorts of 502, 196, and 272 patients, respectively. Measurements: Fisher exact test or the χ2 test were used to compare categorical variables; continuous variables were compared with the Mann-Whitney U test or student t test. Cut-off values were calculated based on receiver operating characteristic curves and the Youden Index. Uni- and multivariate regression analyses were used to investigate the correlation with lymphatic spread. Results and limitations: In clinical analyses, a predictive model consisting of smoking history (p =0.040), T stage (p <0.0001), Fuhrman grade (p <0.0001), Eastern Cooperative Oncology Group performance status (p <0.0001), and microvascular invasion (p <0.0001) was independently associated with lymphatic spread. After adjustment with these clinical variables, low carbonic anhydrase IX (CAIX) (p =0.043) and high epithelial vascular endothelial growth factor receptor 2 (p =0.033) protein expression were associated with a higher risk of lymphatic spread, and loss of chromosome 3p (p <0.0001) with a lower risk. The current study is limited by its retrospective design, small sample size, and single-center experience. Conclusions: The low rates of CAIX expression and loss of chromosome 3p suggest that lymphatic spread in ccRCC occurs independently of von Hippel-Lindau tumor suppressor inactivation. [Copyright &y& Elsevier]

Objectives: Carbonic anhydrase-IX (CA-IX) is a cell surface tumor-associated antigen expressed by most clear cell renal cell carcinomas (RCCs). The specificity and the prognostic value of CA-IX provide impetus to create a mouse model of CA-IX-expressing RCC for testing CA-IX-targeted therapies against RCC. Methods: A retrovirus encoding the human CA-IX gene was used to transduce the murine RCC line, RENCA. In vivo growth kinetics and CA-IX expression were compared between RENCA and RENCA/CA-IX using heterotopic, metastatic, and orthotopic models. Results: Transduction of RENCA created the RENCA/CA-IX line with nearly 100% CA-IX surface expression. In the heterotopic model, subcutaneous injection of 500,000 and 50,000 cells led to tumor formation at 2 to 2.5 weeks after injection, with similar growth kinetics between the two cell lines at either cell number. In the pulmonary metastatic model, a similar number of metastases was noted after inoculation of RENCA and RENCA/CA-IX. In the orthotopic model, autopsy revealed a CA-IX-expressing renal tumor, as well as CA-IX-expressing metastases to the lungs, liver, contralateral kidney, intestines, and lymph nodes. In all the above models, the RENCA/CA-IX tumors retained expression of CA-IX, as demonstrated by immunohistochemistry staining. Conclusions: RENCA/CA-IX is the first tumor model that manifests in immunocompetent Balb/c mice and stably expresses a defined kidney cancer-associated antigen. It maintains antigen expression, forms metastases, and produces reliable tumor growth kinetics equivalent to that of its parental cell line. [ABSTRACT FROM AUTHOR]