Primary Nephrectomy Research Articles

Comparison of primary versus metastatic tumor tissue sources when designing panels for whole genome–based tumor-informed ctDNA assays in clear cell renal cell carcinoma.

3039 Background: Due to low shedding and low tumor-mutation burden, metastatic clear cell renal cell carcinoma (ccRCC) is poorly modeled by current cell-free circulating tumor DNA (ctDNA) assays. Second generation tumor-informed ctDNA approaches may demonstrate improved sensitivity in ccRCC, where somatic variants identified by whole-genome sequencing (WGS) of tumor tissue are tracked in probe panels to monitor molecular residual disease (MRD) in patient plasma. However, intertumoral genomic heterogeneity of input tissue may hinder optimal panel design. Here we evaluated the concordance of ctDNA results using panels designed from primary nephrectomy or metastatic tumors in ccRCC. Methods: In five patients with oligometastatic ccRCC (≤5 lesions of metastatic disease; median of 1, range 1-4), 13 primary tumor, 24 metastatic lesion subsites and matched buffy coat samples were collected. Baseline plasma was collected prior to radiotherapy. Samples were tested with Myriad Genetics High-Definition MRD assay. Briefly, tumor and normal DNA were whole-genome sequenced (median coverage 30x). A sub-panel with up to 1000 somatic variants was designed for each lesion subsite; variants could be common across sub-panels. Sites were enriched using hybridization capture from patient plasma-derived cfDNA and sequenced to high depth. A statistical model of variant allele counts was used to assess the presence or absence of ctDNA (MRD status) and infer quantitative tumor fraction. Results: Median time from nephrectomy or most recent metastasis sample collection to baseline plasma collection was 146 months (71-169) and 32 months (7-48), respectively. Median panel probe count per patient was 4,311 (3,400-5,000) and per tumor sample was 1,545 (102-2,158). Confident calls were emitted for tumor fractions ranging from 0.0004% to 0.027%. Baseline MRD status was fully concordant across sub-panels derived from primary tumor lesion subsites and metastases in three of five patients (3/5; 60%). Of the patients with discordant calls, a single metastasis-derived sub-panel (comprising 20%-25% of metastatic sub-panels) called MRD discordantly in each. Of the three patients MRD positive at baseline, only one was alive at last follow up. All patients MRD negative at baseline are still alive. Conclusions: A tumor-informed, WGS MRD assay for ccRCC showed comparable performance between probe capture panels designed from primary tumor and metastatic lesion subsites despite differences in anatomical location and time from plasma collection. This result suggests that intertumoral genomic heterogeneity may not be consequential in MRD assays that leverage large panels to detect ctDNA variants, obviating the need for repeat biopsies of metastatic sites. Work is underway to validate this MRD assay in a larger cohort of patients with ccRCC before and after treatment.

Characteristics and clinical outcomes of children with Wilms’ tumour: A 15-year experience in a single centre in Nigeria

BackgroundWilms' tumor (WT) is the most common paediatric renal tumor and is one of the most treatment-responsive solid tumours. Survival from Wilms tumour (WT) in sub-Saharan Africa remains dismal as a result of late presentation, treatment abandonment and infrastructure deficit. The purpose of this study was to analyze the clinical outcome of children with Wilms tumour managed in a Nigerian referral centre over a 15-year period. MethodsThis is a retrospective study of children with WT (nephroblastoma) who were treated at our institution between January 2006 and December 2020. Clinical characteristics, treatments, and outcomes were analyzed. ResultsThirty-five patients were identified. The median age at diagnosis was 36 months including 22(62.9%) females. Twenty-six (74.3%) had advanced (stage III & IV) disease. Confirmatory histology was available for 16 patients ((45.7%) among which 10(62.5%) were mixed type. The right kidney was affected in 18 patients (51.4%), left in 15(42.9%) and 2 were not documented. Preoperative chemotherapy was given in 22(62.9%) patients and 13(37.1) patients had primary nephrectomy. Eight (22.9%) patients died during treatment (from disease or treatment related causes), and one abandoned treatment. A total of 26 patients completed treatment. Out of these, 8(30.8%) were lost to follow up, four patients died and 14 (53.8%) patients survived at a median follow-up period of 18months. The survival decreased with advancing stages of the disease, p=0.002. ConclusionsMajority of children with Wilms tumour in our practice presented with advanced disease. Death during treatment, treatment abandonment and lost to follow up were common. Level of EvidenceLevel II Retrospective Study.

Abstract A005: Regulation of HHLA2 expression in renal cell carcinoma and myeloid cells

Abstract The immune checkpoint HERV-H LTR-associating 2 (HHLA2) is expressed in many tumors, including clear cell renal cell carcinoma (ccRCC). Multiple therapeutics directed against HHLA2 or its inhibitory receptor KIR3DL3 are about to enter clinical trials in metastatic RCC; however, little is known about the regulation of HHLA2 expression. Better understanding the regulation of HHLA2 in tumor cells and within the tumor microenvironment will facilitate translation of these therapeutic agents into the clinic by assisting in patient selection and development of rational drug combinations. Using flow cytometry, immunohistochemistry (IHC), and RNA analysis, HHLA2 expression was examined in monocytes, primary nephrectomy specimens and the established ccRCC cell lines, A498 and 786-0. A panel of cytokines was screened for the induction of HHLA2 in vitro. In vivo expression of HHLA2 in A498 and 786-0 human kidney cancer xenograft mouse models was examined. Tumor cells obtained from these xenograft models (either freshly isolated or cultured ex vivo) were characterized by RNASeq and flow cytometry. Analysis of HHLA2 expression in monocytes shows that among a wide range of cytokines tested, only IL-10 and BMP4, and to a lesser extent, IL-1b and IL-6, modestly enhanced HHLA2 mRNA and protein expression. These combinations of cytokines failed to induce HHLA2 in both A498 and 786-0. HHLA2 was frequently expressed in primary ccRCC tumors by IHC. Interestingly, analysis of HHLA2 by flow cytometry in primary RCC tumors showed that HHLA2 is progressively lost over 4 weeks when cells are cultured ex vivo. Hypoxia alone did not change HHLA2 expression. While HHLA2 was not expressed on either A498 or 786O cells in vitro, both A498 and 786-0 cells expressed HHLA2 when grown as subcutaneous xenografts in NSG immunodeficient mice. A498 xenografts express significantly more HHLA2 than 786-0 xenografts. HHLA2 expression is differentially regulated in monocytes and kidney cancer epithelial cells. High concentrations of cytokines, particularly IL10, that induce HHLA2 expression in monocytes fail to upregulate HHLA2 expression in ccRCC; however, the tumor microenvironment in NSG mice significantly induced HHLA2 expression in both A498 and 786-0 xenografts. Complementary whole genome CRISPR knock out and gain-of-function screens are underway to assess by an unbiased means both nonimmune and immunologic regulators or repressors that may be responsible for inducing HHLA2 in kidney cancer in vivo. Furthermore, the A498 xenograft mouse model is an excellent humanized HHLA2 model for testing regulation of HHLA2 and HHLA2-directed therapeutics. Citation Format: Tomonari Shigemura, Nahuel Perrot, Zimo Huang, Aseman Bagheri Sheshdeh, Nourhan El Ahmar, David McDermott, Sabina Signoretti, Gordon Freeman, Kathleen Mahoney. Regulation of HHLA2 expression in renal cell carcinoma and myeloid cells [abstract]. In: Proceedings of the AACR Special Conference: Advances in Kidney Cancer Research; 2023 Jun 24-27; Austin, Texas. Philadelphia (PA): AACR; Cancer Res 2023;83(16 Suppl):Abstract nr A005.

How we approach paediatric renal tumour core needle biopsy in the setting of preoperative chemotherapy: A Review from the SIOP Renal Tumour Study Group.

The International Society of Paediatric Oncology Renal Tumour Study Group (SIOP-RTSG) advocate treating children with Wilms tumour (WT) with preoperative chemotherapy, whereas the Renal Tumor Committee of the Children's Oncology Group (COG) advocates primary nephrectomy (without biopsy) when feasible. Successive SIOP-RTSG trial protocols recommended pretreatment biopsy of children with unilateral tumours only where there were features to suggest an increased probability of a non-WT requiring a change in management. The UK experience in the SIOP WT 2001 trial showed that an alternate approach of performing biopsies on all children with renal tumour masses to determine histology at diagnosis rarely changes management, and can result in misdiagnosis (particularly patients in the age range typical for WT). Although a more selective approach to biopsy has been routine practice in all other countries participating in SIOP-RTSG trials, there was variation between national groups. To address this variation and provide evidence-based recommendations for the indications and recommended approach to renal tumour biopsy within the SIOP paradigm, an international, multidisciplinary working group of SIOP-RTSG members was convened. We describe the resulting recommendations of this group, which are to be incorporated in the ongoing SIOP-RTSG UMBRELLA study.

A risk stratification model based on four novel biomarkers predicts prognosis for patients with renal cell carcinoma

BackgroundAccurate prediction of the prognosis of RCC using a single biomarker is challenging due to the genetic heterogeneity of the disease. However, it is essential to develop an accurate system to allow better patient selection for optimal treatment strategies. ARL4C, ECT2, SOD2, and STEAP3 are novel molecular biomarkers identified in earlier studies as survival-related genes by comprehensive analyses of 43 primary RCC tissues and RCC cell lines.MethodsTo develop a prognostic model based on these multiple biomarkers, the expression of four biomarkers ARL4C, ECT2, SOD2, and STEAP3 in primary RCC tissue were semi-quantitatively investigated by immunohistochemical analysis in an independent cohort of 97 patients who underwent nephrectomy, and the clinical significance of these biomarkers were analyzed by survival analysis using Kaplan-Meier curves. The prognostic model was constructed by calculation of the contribution score to prognosis of each biomarker on Cox regression analysis, and its prognostic performance was validated.ResultsPatients whose tumors had high expression of the individual biomarkers had shorter cancer-specific survival (CSS) from the time of primary nephrectomy. The prognostic model based on four biomarkers segregated the patients into a high- and low-risk scored group according to defined cut-off value. This approach was more robust in predicting CSS compared to each single biomarker alone in the total of 97 patients with RCC. Especially in the 36 metastatic RCC patients, our prognostic model could more accurately predict early events within 2 years of diagnosis of metastasis. In addition, high risk-scored patients with particular strong SOD2 expression had a much worse prognosis in 25 patients with metastatic RCC who were treated with molecular targeting agents.ConclusionsOur findings indicate that a prognostic model based on four novel biomarkers provides valuable data for prediction of clinical prognosis and useful information for considering the follow-up conditions and therapeutic strategies for patients with primary and metastatic RCC.

Commentary Re: Lymph node sampling in Wilms tumor—Getting risk based therapy right

Risk-based therapy for Wilms tumor (WT) is based on clinical, histological, and biological factors [1]. In particular, the presence or absence of disease in hilar and regional lymph nodes is critical to accurately stage a child with WT. This is true whether or not the child undergoes a primary nephrectomy or after induction chemotherapy. Several studies have documented the presence or absence of lymph node disease as the most important stage III prognostic factor for EFS or OS [2,3]. Even in children with stage IV disease, local staging is vital because it will determine the need for local radiation therapy.

Application of the pathological classification of "CCCG-WT-2016" (2019 revision) for treatment of Wilms tumors

Objective: To describe our experiences in application of the 2019 revision of "CCCG-WT-2016" for the diagnosis of Wilms tumors. Methods: Ninety-one cases of Wilms tumor diagnosed at Shanghai Children's Medical Center from January 2015 to December 2018 were collected. All cases were reviewed by two senior pathologists, including one from China and the other from Singapore, according to the 2019 revision of "CCCG-WT-2016." Results: The specimens were obtained by core biopsy (n=21), primary nephrectomy (n=41), post-chemotherapy nephrectomy/resection (n=18), or biopsy/resection of metastatic/relapse/post-chemotherapy metastatic lesion(s) (n=11). The specimens of core biopsy and primary nephrectomy (n=62) all had favorable histology.Twelve post-chemotherapy nephrectomy cases were subdivided into three risk groups: low risk (n=0), intermediate risk (n=10) and high risk (n=2). Six post-chemotherapy resection cases were subdivided into 3 risk groups:low risk (n=0), intermediate risk (n=5) and high risk (n=1). The remaining 11 cases were comprised of metastatic, relapse, and post-chemotherapy metastatic lesions. The concordance rate of the two senior pathologists was 100%(91/91). Conclusions: The 2019 revision of "CCCG-WT-2016" is clearly written and easy to use. It can serve as the basis of accurate classification for clinical treatment.

MiRNA profiling in renal carcinoma suggest the existence of a group of pro-angionenic tumors in localized clear cell renal carcinoma.

Renal cell carcinoma comprises a variety of entities, the most common being the clear-cell, papillary and chromophobe subtypes. These subtypes are related to different clinical evolution; however, most therapies have been developed for clear-cell carcinoma and there is not a specific treatment based on different subtypes. In this study, one hundred and sixty-four paraffin samples from primary nephrectomies for localized tumors were analyzed. MiRNAs were isolated and measured by microRNA arrays. Significance Analysis of Microarrays and Consensus Cluster algorithm were used to characterize different renal subtypes. The analyses showed that chromophobe renal tumors are a homogeneous group characterized by an overexpression of miR 1229, miR 10a, miR 182, miR 1208, miR 222, miR 221, miR 891b, miR 629-5p and miR 221-5p. On the other hand, clear cell renal carcinomas presented two different groups inside this histological subtype, with differences in miRNAs that regulate focal adhesion, transcription, apoptosis and angiogenesis processes. Specifically, one of the defined groups had an overexpression of proangiogenic microRNAs miR185, miR126 and miR130a. In conclusion, differences in miRNA expression profiles between histological renal subtypes were established. In addition, clear cell renal carcinomas had different expression of proangiogenic miRNAs. With the emergence of antiangiogenic drugs, these differences could be used as therapeutic targets in the future or as a selection method for tailoring personalized treatments.

Management of Wilms' tumour

Abstract Wilms' tumour (WT) is the commonest renal tumour of childhood and its treatment is regarded as one of the success stories of paediatric oncology with over 90% cure rate. Most patients present with localized unilateral tumours. Histology and stage are important prognostic factors, and children with stage IV and diffuse anaplasia have poorer outcomes. Whilst there are differences in the treatment approaches around the world, outcomes are excellent for most subgroups of Wilms' tumour. The European Societe Internationale d'Oncologie Pediatrique (SIOP) recommends pre-operative chemotherapy to children over 6 months whilst the North American Children's Oncology Group offers primary nephrectomy and uses biomarkers for treatment stratification. Overall, 15% patients experience a relapse and their management depends on the initial treatment they had received. The focus of research is to decrease long term side effects, reduce treatment for selected subgroups, and improve our understanding of prognostic biomarkers to help tailor treatments. This article provides an overview for paediatricians giving an update on the important recent advances.

Factors responsible for stage III disease in patients with Wilms tumor enrolled in the JWiTS-2 study.

Treatment is more intensive for stage III Wilms tumor (WT) than for stages I and II non-metastatic WTs. Various factors including tumor spillage, unresectability, and lymph node metastasis are responsible for stage III disease. The present study aimed to not identify clinical factors associated with the features of stage III WT to establish new treatment strategies. Of 166 patients with non-metastatic WT enrolled in the Japan Wilms Tumor Study (JWiTS)-2, 51 patients had stage III disease. The treatment protocol for JWiTS-2 was essentially the same as that in the National Wilms Tumor study (NWTS)-5. Local hospitals were surveyed to collect details of clinical findings related to stage III disease, and data regarding 45 (88%) patients were obtained. Nine patients with massive tumors underwent preoperative chemotherapy. Biopsy was performed in 6. Reduction in the tumor size was achieved in 8 of the 9 cases. Nephrectomy was finally performed in all of them. Thirty-six patients underwent primary nephrectomy. The reason for the stage III disease was lymph node metastasis (n = 9, 25%), tumor spillage (n = 20, 56%), and tumor extension/incomplete resection (n = 17, 47%). Some patients had more than one of these factors. Most patients were treated with the DD-4A regimen, and 43 (95.6%) of the 45 patients received abdominal radiation therapy. Tumors recurred in three patients (local, 1; metastasis, 2), and two patients died. Overall and relapse-free survival rates were 95.2% and 90.8%, respectively. The prognosis of stage III WT was good. In the next stage, the doses of chemotherapy and radiotherapy should be reduced to avoid late effects. The high rate of tumor spillage after primary resection suggests that preoperative chemotherapy should be started instead of aggressive tumor resection in the large tumor cases with surgical risks.

Tumor de Wilms: experiencia de 12 años en dos hospitales de alto nivel en Medellín, Colombia

Objetivo: describir la epidemiología y los resultados en el manejo de los niños menores de 15 años con el diagnóstico de tumor de Wilms (TW) en dos hospitales de alto nivel de complejidad en un período de 12 años.Métodos: estudio de seguimiento a una cohorte retrospectiva. Se revisaron las historias clínicas de pacientes con diagnóstico de TW entre enero de 2005 y mayo de 2017, buscando información centrada en edad, forma de presentación, confirmación histopatológica y estratificación del tumor, tipo de tratamiento ofrecido y desenlaces en el seguimiento relacionados con recaída y supervivencia.Resultados: en total se encontraron 84 pacientes con el diagnóstico de TW, con un promedio de edad de presentación de 3 años. Predominó el estadio III al momento del diagnóstico y la principal presentación fue masa abdominal. El 8,3 % de los pacientes tuvieron histología desfavorable. El tiempo promedio de supervivencia libre de recaída fue 97 meses. A los 108 meses después del diagnóstico, la supervivencia fue del 71 %. En nuestros hospitales se realiza nefrectomía inicial (protocolo COG/NWTS). El 39 % de los pacientes fueron sometidos a quimioterapia prequirúrgica, la cual se rigió en el 72,7 % con el protocolo SIOP y 27,3 % con el COG/NWTS.Conclusiones:en los dos hospitales analizados, el manejo del TW se rige por el protocolo del COG/NWTS con nefrectomía inicial y posterior quimioterapia. Un grupo de pacientes son llevados a quimioterapia prequirúrgica con las mismas indicaciones descritas en el protocolo americano. El diagnóstico de nuestros pacientes es con mayor frecuencia en estadios avanzados. La supervivencia en esta serie, 71 %, es menor que la reportada en la literatura mundial, 93 %.

Pro-angiogenic gene expression is associated with better outcome on sunitinib in metastatic clear-cell renal cell carcinoma

Objectives: Clear-cell renal cell carcinomas (ccRCC) are characterized by hyper-vascularization and can respond to vascular endothelial growth factor receptor (VEGFR) inhibitors such as sunitinib. We aimed to study the predictive value of the expression of genes in the hypoxia induced factor (HIF) – vascular endothelial growth factor (VEGF) - VEGFR-pro-angiogenic pathway in metastatic ccRCC (m-ccRCC) patients treated with sunitinib and the correlation between the expression of these genes and the molecular ccrcc-classification, the expression of genes involved in the immune-suppressive microenvironment and Von Hippel-Lindau (VHL) - and Polybromo-1 (PBRM1) - mutational status.Material and methods: m-ccRCC patients treated with sunitinib as first-line targeted therapy were included. Gene expression was studied in the primary nephrectomy sample by qRT-PCR, VHL- and PBRM1-mutational status by sequencing. Response rate by RECIST, progression-free survival (PFS) and overall survival (OS) were study endpoints.Results: One hundred and four patients were included. On multivariate-analysis, HIF2A-, platelet derived growth factor receptor beta (PDGFRB)-, VEGFC-, VEGFR1- and VEGFR2-expression were correlated with PFS and HIF1A-, HIF2A-, VEGFR1- and VEGFR2-expression with OS. VEGFR2-expression showed the strongest association with outcome, being significantly correlated with all outcome parameters. HIF2A, VEGFA, VEGFR1, VEGFR2 and VEGFR3 were highly expressed in the transcriptomic ccrcc2-subtype of tumors, known to be highly sensitive to sunitinib. In the total tumor series, there was no correlation nor inverse correlation between the expression of genes involved in angiogenesis and in the immune-suppressive microenvironment. In tumors with a bi-allelic PBRM1-inactivation, HIF2A-, VEGFA-, VEGFR1- and VEGFR2-expression were higher, compared to tumors with one or two functional PBRM1-alleles.Conclusions: Intratumoral expression of genes involved in the HIF-VEGF-VEGFR-pro-angiogenic pathway, especially VEGFR2, is associated with favorable outcome on sunitinib in m-ccRCCs. Several genes involved in this pathway are upregulated in the molecular ccrcc2-subgroup, which usually responds well to sunitinib.

Surgical resection of locally recurrent renal cell carcinoma after nephrectomy: Oncological outcome and predictors of survival

ObjectiveTo describe the course of disease of patients surgically treated for locally recurrent renal cell carcinoma (LRRCC) after nephrectomy and to identify potential predictive factors for long-term survival. Patients and methodsWe, retrospectively, identified 54 patients who underwent surgical resection of LRRCC after open nephrectomy for localized kidney cancer. The median age at time of surgery for LRRCC was 65 years. Survival rates were determined with the Kaplan-Meier method. Mantel-Haenszel hazard ratios were calculated. Comparisons were made with the log-rank test. Cox proportional hazard models were used to analyze combined effects of variables. ResultsMedian time to local recurrence after nephrectomy was 36 months (5–242 months). Median follow-up after surgery for LRRCC was 39 months. At time of analysis 18 patients (33%) were alive without any evidence of disease, 8 patients (15%) were alive with disease, 20 patients (37%) died of renal cell carcinoma, and 8 patients (15%) died of other causes. A 5-year overall survival (OS) was 60% (95% CI: 0.44–0.73) and 10-year OS was 32% (95% CI: 0.15–0.51). The median survival after surgery for LRRCC was 79 months. In univariate analysis OS differed significantly by the time period between primary surgery and occurrence of LRRCC (<2 years vs. ≥2 years: 10-year OS rate 31% (95% CI: 10.2–55.0) vs. 45% (95% CI: 21.5–65.8; hazard ratio = 0.26; P = 0.0034). In multivariate analysis sarcomatoid features in the primary nephrectomy specimen, positive surgical margins of the LRRCC specimen and a Charlson score of ≥2 were associated with a significantly worse prognosis in this cohort. ConclusionIn patients with a disease-free interval of more than 2 years after surgery for the primary tumor, surgical removal of LRRCC may achieve long-term survival in most patients. In those with a shorter disease-free interval, long-term survival is unlikely.

Genomic Biomarkers of a Randomized Trial Comparing First-line Everolimus and Sunitinib in Patients with Metastatic Renal Cell Carcinoma

BackgroundMetastatic renal cell carcinoma (RCC) patients are commonly treated with vascular endothelial growth factor (VEGF) inhibitors or mammalian target of rapamycin inhibitors. Correlations between somatic mutations and first-line targeted therapy outcomes have not been reported on a randomized trial. ObjectiveTo evaluate the relationship between tumor mutations and treatment outcomes in RECORD-3, a randomized trial comparing first-line everolimus (mTOR inhibitor) followed by sunitinib (VEGF inhibitor) at progression with the opposite sequence in 471 metastatic RCC patients. Design, setting, and participantsTargeted sequencing of 341 cancer genes at ∼540× coverage was performed on available tumor samples from 258 patients; 220 with clear cell histology (ccRCC). Outcome measurements and statistical analysisAssociations between somatic mutations and median first-line progression free survival (PFS1L) and overall survival were determined in metastatic ccRCC using Cox proportional hazards models and log-rank tests. Results and limitationsPrevalent mutations (≥ 10%) were VHL (75%), PBRM1 (46%), SETD2 (30%), BAP1 (19%), KDM5C (15%), and PTEN (12%). With first-line everolimus, PBRM1 and BAP1 mutations were associated with longer (median [95% confidence interval {CI}] 12.8 [8.1, 18.4] vs 5.5 [3.1, 8.4] mo) and shorter (median [95% CI] 4.9 [2.9, 8.1] vs 10.5 [7.3, 12.9] mo) PFS1L, respectively. With first-line sunitinib, KDM5C mutations were associated with longer PFS1L (median [95% CI] of 20.6 [12.4, 27.3] vs 8.3 [7.8, 11.0] mo). Molecular subgroups of metastatic ccRCC based on PBRM1, BAP1, and KDM5C mutations could have predictive values for patients treated with VEGF or mTOR inhibitors. Most tumor DNA was obtained from primary nephrectomy samples (94%), which could impact correlation statistics. ConclusionsPBRM1, BAP1, and KDM5C mutations impact outcomes of targeted therapies in metastatic ccRCC patients. Patient summaryLarge-scale genomic kidney cancer studies reported novel mutations and heterogeneous features among individual tumors, which could contribute to varied clinical outcomes. We demonstrated correlations between somatic mutations and treatment outcomes in clear cell renal cell carcinoma, supporting the value of genomic classification in prospective studies.

Concordance of Pathologic Features Between Metastatic Sites and the Primary Tumor in Surgically Resected Metastatic Renal Cell Carcinoma

To evaluate the concordance of pathologic features in metastatic renal cell carcinoma (RCC) between the primary nephrectomy and metastasectomy specimens. Primary nephrectomy (n = 454) and matched metastasectomy specimens (n = 680) from patients treated between 1970 and 2009 for RCC were re-reviewed by 1 urologic pathologist in a blinded fashion. RCC histologic subtype, grade, coagulative necrosis, and the presence of sarcomatoid differentiation were compared between the primary and the metastatic tumor with kappa statistics. Concordance with the primary tumor was observed for subtype in 647 (95%, kappa = 0.71) of the metastases, for grade in 411 (60%, kappa = 0.35), necrosis in 460 (68%, kappa = 0.32), and sarcomatoid differentiation in 643 (95%, kappa = 0.60). Upgrading was observed in 100%, 63%, and 13% of patients with grades 1, 2, and 3 primary tumors, respectively (no patient had a grade 1 metastatic lesion). Metastatic tumors treated with metastasectomy within 30 days of nephrectomy (n = 145) had similar rates of concordant subtype, necrosis, and sarcomatoid differentiation to those undergoing metastasectomy beyond 30 days from nephrectomy (P >.05 for all), but had higher rates of concordant grade (71% vs 58%, P = .003). Pre-metastasectomy exposure to systemic targeted or immunotherapy was not associated with a change in concordance of histopathologic features. Among 454 surgically managed metastatic RCC patients, we observed a high degree of concordance for histologic subtype and sarcomatoid differentiation, and varying degrees of discordance for grade and coagulative tumor necrosis, between primary and metastatic tumors. Further investigation is warranted to understand the biologic and therapeutic implications of these observations.

Implications of TCGA Network Data on 2nd Generation Immunotherapy Concepts Based on PD-L1 and PD-1 Target Structures

The era of cytokines, given to patients with metastatic renal cell carcinoma (mRCC) as part of an unspecific immunomodulatory treatment concept, seems to have ended with the introduction of targeted therapies. However, preliminary data from studies on treatment with checkpoint inhibitors (e. g. anti-PD-1 and anti-PD-L1) may point the way to second-generation immunotherapy. The rationale of such immunomodulatory treatment is to stop or interrupt the tumour from "escaping" the body's immune defence. Thompson et al. report that increased protein expression of PD-L1 (CD274/ B7-H1) in tumour cells and tumour-infiltrating immune cells (TILs; lymphocytes and histiocytes) is associated with unfavourable clinical pathological parameters as well as poor survival. In small pilot groups of mRCC patients it was found that increased PD-L1 protein expression in tumours and TILs may be correlated with the objective response to anti-PD-1 treatment. Sometimes, however, a very wide variety of response rates was observed, which raises the question if this can be explained by individual expression levels of PD-L1 (CD 274) or PD-1 (PDCD1).Recently published data from the Cancer Genome Atlas (TCGA) Kidney Renal Clear Cell Carcinoma (KIRC) Network now provide a genome-wide data base that allows us to review or validate the molecular results obtained in clear cell renal cell carcinomas (ccRCC) to date.In this study, we analysed the TCGA KIRC mRNA expression data for PD-L1 and PD-1 for a possible association with clinical pathological parameters and the survival of 417 ccRCC patients.The mRNA expression of PD-L1 in primary nephrectomy specimens revealed no significant association with unfavourable clinical parameters. Interestingly, though, a positive correlation with patient survival was found (HR=0,59, p=0,006).These results, which partly contradict the concept applied to date, point out the necessity to ascertain the characteristics of PD-L1 and PD-1 expression at mRNA and protein level in an appropriately sized patient population and evaluate the clinical significance.

The role of surgery in renal cell carcinoma with pancreatic metastasis.

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.

Sarcomatoid Dedifferentiation in Metastatic Clear Cell Renal Cell Carcinoma and Outcome on Treatment With Anti–Vascular Endothelial Growth Factor Receptor Tyrosine Kinase Inhibitors: A Retrospective Analysis

IntroductionThis study aimed to assess the efficacy of anti–vascular endothelial growth factor receptor tyrosine kinase inhibitors (anti-VEGFR-TKIs) in patients with metastatic clear cell renal cell carcinoma (m-ccRCC) with sarcomatoid dedifferentiation. Patients and MethodsThe files of all patients with m-ccRCC consecutively treated with first-line anti-VEGFR-TKIs at the authors' institution were retrospectively reviewed. Pathology slides from nephrectomy and metastasectomy were assessed for the presence and extent of sarcomatoid dedifferentiation. ResultsA total of 124 patients were included; nephrectomy and metastasectomy specimens were available in 117 and 35 patients, respectively. Thirty percent of the primary nephrectomy specimens had sarcomatoid features, and the median involvement of the sarcomatoid component was 21% (range, 1%-95%). Patients with an important sarcomatoid component, defined as ≥ 25% involvement of the tumor, had a very poor outcome: progression-free survival (PFS) and overall survival (OS) were 3 and 6 months, respectively, and no partial responses (PR) were observed. Patients without sarcomatoid dedifferentiation or with sarcomatoid involvement < 25% had a PFS of 12 months (P < .0001; hazard ratio [HR], 51; 95% CI, 12.58-207.3), an OS of 22 months (P < .0001, HR, 10.72; 95% CI, 3.56-32.25), and a PR rate of 50% (P = .0015). Patients with a sarcomatoid component ≥ 25% in the metastasectomy also had a poorer PFS and OS on anti-VEGFR-TKIs compared with patients with < 25% of sarcomatoid features at these sites. ConclusionPatients with m-ccRCC whose tumors contain a component of sarcomatoid dedifferentiation of ≥ 25% of the total tumor volume have a very poor outcome when treated with anti-VEGFR-TKIs. Analysis of the extent of sarcomatoid features in resected metastases can provide additional prognostic information.

MP9-17 UROLOGICAL TRAUMA IN A EUROPEAN LEVEL 1 TRAUMA CENTRE: AN UPDATE

You have accessJournal of UrologyTrauma/Reconstruction: Trauma & Reconstructive Surgery III1 Apr 2014MP9-17 UROLOGICAL TRAUMA IN A EUROPEAN LEVEL 1 TRAUMA CENTRE: AN UPDATE Jonathan Makanjuola, Taylor Claire, Philippe Grange, Gordon Muir, Johan Poulsen, Christian Brown, Peter Thompson, Devendra Sharma, and Gordon Kooiman Jonathan MakanjuolaJonathan Makanjuola More articles by this author , Taylor ClaireTaylor Claire More articles by this author , Philippe GrangePhilippe Grange More articles by this author , Gordon MuirGordon Muir More articles by this author , Johan PoulsenJohan Poulsen More articles by this author , Christian BrownChristian Brown More articles by this author , Peter ThompsonPeter Thompson More articles by this author , Devendra SharmaDevendra Sharma More articles by this author , and Gordon KooimanGordon Kooiman More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2014.02.505AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES King’s Collage Hospital in London UK has been a Level 1 Trauma Centre since October 2008. We present an update of the King’s experience, including lessons learnt from ultraconservative management of renal trauma. METHODS In our prospectively collected urological database we have identified 72 cases of renal trauma since October 2008. We have 3 month follow up data that has been analysed. RESULTS There were 72 cases of renal trauma between October 2008 to July 2013. The mean age 30.2. 19 patients sustained an isolated renal trauma, 53 were part of polytrauma. Grade 1 7 cases, Grade II8, Grade III 22, Grade IV 31 and Grade V 4. 33 patients (45.8%) had penetrating trauma. Non-surgical management in 69 cases (95.8%), of this 61 (88.4%) were managed conservatively with bed rest and 8 patients required (12.5%) angioembolisation. 3 patients (4.2%) had a primary nephrectomy as unstable. 2 patients has a delayed nephrectomy following failed embolisation(s). 44 patients (61.1%) attended the scheduled follow-up at three months. 18 (25%) were lost to follow up. All patients that attended follow up appointments with a preserved kidney had a DMSA scan. From these patients, all had preserved their renal function at 3 months. CONCLUSIONS Our series has one of the largest number of published penetrating trauma from a European centre. We confirm and reinforce the idea that ultraconservative approach should be first line management when possible in renal trauma, even in the high grade, as it is a feasible, safe approach. © 2014FiguresReferencesRelatedDetails Volume 191Issue 4SApril 2014Page: e128 Advertisement Copyright & Permissions© 2014MetricsAuthor Information Jonathan Makanjuola More articles by this author Taylor Claire More articles by this author Philippe Grange More articles by this author Gordon Muir More articles by this author Johan Poulsen More articles by this author Christian Brown More articles by this author Peter Thompson More articles by this author Devendra Sharma More articles by this author Gordon Kooiman More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Nephroblastoma – 30-Years Period of its Treatment in the University Hospital Motol, Prague

Nephroblastoma (Wilms tumor - WT) is the most common solid tumor of kidney in children. We present treatment development of WT at the Department of Pediatric Hematology and Oncology, Charles University in Prague, 2nd Faculty of Medicine and University Hospital Motol (KDHO) in the Czech Republic over 30 years. Patients that were treated prior to access to the International Society of Pediatric Oncology (SIOP) protocols are considered to be the historical group, then we have patients treated according to SIOP 9, SIOP 93-01 and SIOP 2001 protocols as full participants of SIOP studies. Between January 1980 and April 2009, we treated 330 patients with WT at KDHO: 91 patients in historical group (1980-1988), 94 pts in SIOP 9 (1988-1993), 80 pts in SIOP 93-01 (1994-2001) and 65 pts in SIOP 2001 (2002-2009). Overall survival (OS) and event-free survival (EFS) were analyzed by Kaplan-Meier test. The overall ten-year EFS was 81.2% and OS 87.6%. Fifty-eight patients from the 330 (17.6%) had metastases at diagnosis, EFS without metastatic process was 84.6% compared to 65.4% with metastasis presented at diagnosis (p = 0.0003), OS was 70.7% compared to 91.2% (p < 0.0001). One hundred and seventy patients (51.5%) were treated with preoperative chemotherapy and/or radiotherapy, whereas 158 patients (47.5%) underwent primary nephrectomy; EFS and OS did not differ: neoadjuvant vs primary nephrectomy EFS was 81.2% vs 80.9% (p = 0.85), OS 89.4% vs 85.4% (p = 0.38). Sixty (18%) patients experienced disease recurrence; OS after relapse was 33%. In the historical group, EFS and OS were 85.7% and 91.2%. In patients treated according to the SIOP 9 protocol, EFS and OS were 68.1% and 74.5%, resp. In patients treated according to SIOP 93-01, it was 83.6% and 93.7%, resp. and in patients treated according to 87 SIOP 2001, it was 7% and 95.4% (p = 0.001 and p = 0.0008), resp. WT is a well treatable disease. The aim for the future is to maintain the current very good survival while minimizing the treatment intensity.