Study Of Renal Cell Carcinoma Research Articles

Prevalence of Germline Pathogenic Variants in Renal Cancer Predisposition Genes in a Population-Based Study of Renal Cell Carcinoma.

Renal cell carcinoma (RCC) has been associated with germline pathogenic or likely pathogenic (PLP) variants in recognised cancer susceptibility genes. Studies of RCC using gene panel sequencing have been highly variable in terms of study design, genes included, and reported prevalence of PLP variant carriers (4-26%). Studies that restricted their analysis to established RCC predisposition genes identified variants in 1-6% of cases. This work assessed the prevalence of clinically actionable PLP variants in renal cancer predisposition genes in an Australian population-based sample of RCC cases. Germline DNA from 1029 individuals diagnosed with RCC who were recruited through the Victoria and Queensland cancer registries were screened using a custom amplicon-based panel of 21 genes. Mean age at cancer diagnosis was 60 ± 10 years, and two-thirds (690, 67%) of the participants were men. Eighteen participants (1.7%) were found to carry a PLP variant. Genes with PLP variants included BAP1, FH, FLCN, MITF, MSH6, SDHB, TSC1, and VHL. Most carriers of PLP variants did not report a family history of the disease. Further exploration of the clinical utility of gene panel susceptibility testing for all RCCs is warranted.

Prevention, incidence, and risk factors of chyle leak after radical nephrectomy and thrombectomy.

To define the incidence and risk factors of chyle leak (CL) after radical nephrectomy and thrombectomy and to determine the impact of chyle leak on oncological outcomes. A total of 445 patients who underwent radical nephrectomy and thrombectomy between January 2014 and January 2023 were included. CL is defined as the drainage of chyle with a triglyceride level greater than 110 mg/dL after oral intake or enteral nutrition. Multivariate logistic regression analysis was performed to identify the risk factors of postoperative (CL). The Kaplan-Meier curves were used to compare overall survival and cancer-specific survival. 44 patients (9.9%) were diagnosed as (CL). All patients developed CL within 6 days after the operation with a median time of 3 days. In multivariate logistic regression analysis, Mayo grade and side were independent patient-related risk factors. In addition, operation approach, operation time, and number of lymph nodes harvested were independent surgery-related risk factors. Between the CL group and the non-CL group, neither overall survival nor cancer-specific survival showed statistical differences. Based on this retrospective study of renal cell carcinoma and tumor thrombus patients in our center, we found that the risk factors were Mayo grade, side, operation approach,operation time, and number of lymph nodes harvested, and the occurrence of CL significantly prolonged hospital stay, but had no effect on long-term oncological outcomes.

Identification of miR-20a-5p as Robust Normalizer for Urine microRNA Studies in Renal Cell Carcinoma and a Profile of Dysregulated microRNAs.

Renal cell carcinoma (RCC) is the third most frequent urinary malignancy and one of the most lethal. Current diagnostic and follow-up techniques are harmful and unspecific in low-grade tumors. Novel minimally invasive markers such as urine microRNAs (miRNAs) are under study. However, discrepancies arise among studies in part due to lack of consent regarding normalization. We aimed to identify the best miRNA normalizer for RCC studies performed in urine samples together with a miRNA profile with diagnostic value and another for follow-up. We evaluated the performance of 120 candidate miRNAs in the urine of 16 RCC patients and 16 healthy controls by RT-qPCR followed by a stability analysis with RefFinder. In this screening stage, miR-20a-5p arose as the most stably expressed miRNA in RCC and controls, with a good expression level. Its stability was validated in an independent cohort of 51 RCC patients and 32 controls. Using miR-20a-5p as normalizer, we adjusted and validated a diagnostic model for RCC with three miRNAs (miR-200a-3p, miR-34a-5p and miR-365a-3p) (AUC = 0.65; Confidence Interval 95% [0.51, 0.79], p = 0.043). let-7d-5p and miR-205-5p were also upregulated in patients compared to controls. Comparing RCC samples before surgery and fourteen weeks after, we identified let-7d-5p, miR-152-3p, miR-30c-5p, miR-362-3p and miR-30e-3p as potential follow-up profile for RCC. We identified validated targets of most miRNAs in the renal cell carcinoma pathway. This is the first study that identifies a robust normalizer for urine RCC miRNA studies, miR-20a-5p, which may allow the comparison of future studies among laboratories. Once confirmed in a larger independent cohort, the miRNAs profiles identified may improve the non-invasive diagnosis and follow-up of RCC.

A histopathological study of renal cell carcinoma at a tertiary care hospital

Background: Renal cell carcinoma (RCC) accounts for 80-85% of malignant kidney tumors. However incidence of RCC is less in Asian Countries including India and data available from Indian studies is scarce. Outcome of RCC depends on the morphological type and hence accurate classification is essential. Aims and Objectives: The objective of the present study was to assess the profile of patients of RCC in respect to age distribution, Sex distribution, laterality of the tumor, location within the kidney and Pathological tumor stage and compare our results with available literature from India and other countries. Material and Methods: The study is a retrospective study, which was conducted over a three and half year period from January 2016 to June 2019 at Goa Medical College, Bambolim Goa. A total of 60 cases of RCC diagnosed over this period were included in the study. Patient details were obtained from the Histopathology requisition forms from the records of Pathology department. The data was collected, analysed and compared with other similar studies. Histopathological examination of the specimens was conducted using standard processing technique and taking 5 micron sections and staining by Hematoxylin and Eosin technique. Results: A total of 60 cases of RCC were diagnosed over 3and 12 year period with Clear Cell Carcinoma 38(63.3%) cases being the commonest histopathological type. The tumor was more commonly seen in males with a M:F ratio of 3.6:1. The age ranged from 25 to 78 years with a median of 56.5 years which is decade earlier as compared to Western data. The tumor size(Pathological stage pT) in this study was lower with 24 cases(40%) being diagnosed in pTa stage and 22cases(36.7%) treated with nephron sparing surgery which is a much higher figure as compared to other Indian studies. Keywords: Renal cell carcinoma, Clear cell, Chromophobe, Multilocular cystic, Papillary.

MK-6482 as a potential treatment for von Hippel-Lindau disease-associated clear cell renal cell carcinoma

ABSTRACT Introduction Von Hippel-Lindau (VHL) disease is an inherited autosomal dominant syndrome caused by a germline mutation and/or deletion of the VHL gene. Inappropriate hypoxia-inducible factor (HIF)-mediated transcription of proangiogenic and metabolic genes leads to the development of tumors and cysts in multiple organs. Surgery is a standard treatment for localized tumors with a risk of metastasis or organ dysfunction. Repeated surgeries cause substantial morbidity and have a major impact on quality of life. There is an urgent need to develop effective and safe systemic treatments for VHL disease manifestations. The small-molecule HIF 2 alpha inhibitor MK-6482 (belzutifan) has demonstrated significant efficacy in VHL disease related renal cell carcinomas, hemangioblastomas, and pancreatic neuroendocrine tumors while demonstrating an acceptable safety profile. Areas covered This paper reviews the development of the HIF-2 alpha inhibitor, MK-6482, and discusses preliminary results of ongoing phase I/II studies in renal cell carcinoma (RCC) and VHL disease. An examination of ongoing clinical development of MK-6482 and perspectives on potential future developments and challenges are offered. Expert opinion Because of its favorable safety profile, its clear efficacy in VHL disease, promising findings in sporadic, advanced RCC, and convenient oral formulation, MK-6482 is expected to become a leading treatment for VHL disease. Among other currently available oral agents, we believe that MK-6482 will be a preferred treatment for VHL-associated RCC.

Metabolomic Analysis to Elucidate Mechanisms of Sunitinib Resistance in Renal Cell Carcinoma.

Metabolomics analysis possibly identifies new therapeutic targets in treatment resistance by measuring changes in metabolites accompanying cancer progression. We previously conducted a global metabolomics (G-Met) study of renal cell carcinoma (RCC) and identified metabolites that may be involved in sunitinib resistance in RCC. Here, we aimed to elucidate possible mechanisms of sunitinib resistance in RCC through intracellular metabolites. We established sunitinib-resistant and control RCC cell lines from tumor tissues of RCC cell (786-O)-injected mice. We also quantified characteristic metabolites identified in our G-Met study to compare intracellular metabolism between the two cell lines using liquid chromatography-mass spectrometry. The established sunitinib-resistant RCC cell line demonstrated significantly desuppressed protein kinase B (Akt) and mesenchymal-to-epithelial transition (MET) phosphorylation compared with the control RCC cell line under sunitinib exposure. Among identified metabolites, glutamine, glutamic acid, and α-KG (involved in glutamine uptake into the tricarboxylic acid (TCA) cycle for energy metabolism); fructose 6-phosphate, D-sedoheptulose 7-phosphate, and glucose 1-phosphate (involved in increased glycolysis and its intermediate metabolites); and glutathione and myoinositol (antioxidant effects) were significantly increased in the sunitinib-resistant RCC cell line. Particularly, glutamine transporter (SLC1A5) expression was significantly increased in sunitinib-resistant RCC cells compared with control cells. In this study, we demonstrated energy metabolism with glutamine uptake and glycolysis upregulation, as well as antioxidant activity, was also associated with sunitinib resistance in RCC cells.

Abstract C059: Clinical and molecular profile of renal cell carcinoma in Hispanic Americans, Native Americans, and European Americans

Abstract Background: Racial/ethnic minority groups, including Hispanic Americans (HAs) and Native Americans (NAs), have a heavier burden of kidney cancer with a higher incidence and mortality than European Americans (EAs). However, HAs and NAs are under-represented in clinical and molecular genomic studies of renal cell carcinoma (RCC), the most common type of kidney cancer, and clinical and molecular characteristics of RCC among them are also unknown. We investigated variations in clinical and molecular characteristics of RCC patients. Methods: A total of 284 patients, including 90 HAs (31.6%) and 22 NAs (7.7%), who were diagnosed with RCC and without prior diagnosis of cancer were included to understand the patients' clinical characteristics. A subset of 51 samples were selected to screen for somatic mutations on the VHL gene, and 33 samples were selected for whole-transcriptome sequencing analysis. Results: Compared to EAs, HA and NA patients were diagnosed with RCC at younger ages (P<0.001). HA had about 5 years younger average age at diagnosis than EAs (55.2 vs. 60.6) and an over 2-fold increased odds of diagnosis before age 60 years (OR 2.50, 95% C.I.: 1.36-4.60). Mean age of diagnosis among NAs was 48.9, and NAs had more than 4-fold higher odds of diagnosis at a younger age (OR 4.12, 95% C.I.: 1.31-12.95). NA patients had higher body mass index than EA patients with 77.3% of NA obese patients. Diabetes was more common in HA (45.6%) and NA (50.0%) patients compared to EA (19.6%) patients. An RCC histologic subtype, clear cell RCC (ccRCC), was more common in HAs and NAs than EAs. Over 90% of HA patients had ccRCC, while only 77.6% of EA patients had ccRCC. HAs had increased odds of diagnosis with ccRCC compared to EAs (OR 2.39, 95% C.I.: 1.01-5.67). Among HAs, older patients were more likely to have advanced-stage RCC diagnosis (OR 7.06, 95% C.I.: 1.46-34.11). HAs who used Spanish as their primary language were more likely to have radical nephrectomy rather than partial nephrectomy (OR 5.13, 95% C.I.: 1.23-21.33). We detected pathogenic somatic mutations on the VHL gene, which is known to cause von Hippel-Lindau syndrome, in 4 patients, and these patients were younger than the patients without these mutations (45.5 vs. 57.1). We were able to assign 32 out of 33 patients into molecular subtypes (ccA and ccB). Molecular subtype could not be assigned to one HA patient with high-grade and advanced-stage ccRCC. Molecular subtype, ccA, was more common in HAs than EAs (64.3% vs. 41.2%), but this difference was not statistically significant. One gene, HABP2, showed evidence of differential expression between HA and EA tumors (PADJ<0.05) and was downregulated in HA tumors with log2 fold change <-2.0. Conclusion: HA and NA RCC patients had different clinical and molecular characteristics from EA patients. Impact: As we move toward a precision medicine approach for RCC care, it is necessary to better understand the clinical and molecular characteristics of these underserved HA and NA populations with high kidney cancer burden. Citation Format: Ken Batai, Alfredo Harb de la Rosa, Francine Gachupin, Elliot Imlaer, Erika R. Bracamonte, Bruce Seligmann, Benjamin R. Lee. Clinical and molecular profile of renal cell carcinoma in Hispanic Americans, Native Americans, and European Americans [abstract]. In: Proceedings of the Eleventh AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2018 Nov 2-5; New Orleans, LA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl):Abstract nr C059.

Magnetic resonance spectroscopy of rat kidney in vivo at 9.4 T

Glutamate (Glu), glutamine (Gln), myo-insotol (Ins), taurine (Tau), choline (Cho), and betaine (Bet) are kidney metabolites whose levels are relevant to the study of Renal Cell Carcinoma (RCC). The presented work investigates the quantification of Glx (Glu + Gln), Ins, and Tau, relative to Cho + Bet with magnetic resonance spectroscopy (MRS) in rat kidney at 9.4 T. The Point-Resolved Spectroscopy (PRESS) pulse sequence was employed for non-invasive MRS acquisition in vivo from the right kidney of four rats. LCModel was utilized for peak fitting and spectral analysis of the in-vivo spectra. Relative metabolite concentrations and LCModel Cramér-Rao Lower Bounds (CRLBs) are reported. Relative metabolite concentrations are reported because the absolute concentration of any metabolite is unknown. The concentrations of Glx, Ins, and Tau, relative to Cho + Bet, the largest peak, were found to be, on average, 2.16, 1.40, and 2.17, with average CRLB values of 12.5%, 12.8%, and 16.8%, respectively. The average CRLB of Cho + Bet was 4.8%. To our knowledge, this is the first non-invasive MRS study of rat kidney.

TranscriptAchilles: a genome-wide platform to predict isoform biomarkers of gene essentiality in cancer.

BackgroundAberrant alternative splicing plays a key role in cancer development. In recent years, alternative splicing has been used as a prognosis biomarker, a therapy response biomarker, and even as a therapeutic target. Next-generation RNA sequencing has an unprecedented potential to measure the transcriptome. However, due to the complexity of dealing with isoforms, the scientific community has not sufficiently exploited this valuable resource in precision medicine.FindingsWe present TranscriptAchilles, the first large-scale tool to predict transcript biomarkers associated with gene essentiality in cancer. This application integrates 412 loss-of-function RNA interference screens of >17,000 genes, together with their corresponding whole-transcriptome expression profiling. Using this tool, we have studied which are the cancer subtypes for which alternative splicing plays a significant role to state gene essentiality. In addition, we include a case study of renal cell carcinoma that shows the biological soundness of the results. The databases, the source code, and a guide to build the platform within a Docker container are available at GitLab. The application is also available online.ConclusionsTranscriptAchilles provides a user-friendly web interface to identify transcript or gene biomarkers of gene essentiality, which could be used as a starting point for a drug development project. This approach opens a wide range of translational applications in cancer.

Structure-Based Virtual Screening for the Identification of High Affinity Compounds as Potent VEGFR2 Inhibitors for the Treatment of Renal Cell Carcinoma.

Renal Cell Carcinoma is a common type of renal cancer-causing deaths worldwide which is characterized by sustained angiogenesis. VEGF and its receptors play a major role in physiologic and pathologic angiogenesis, which is marked in tumour progression and metastasis development. Induction of VEGF genes occur due to hypoxic condition induced by tumour growth after a critical size in cancerous cell. Signal transduction networks originated by VEGFA/VEGFR2, (a notable ligand-receptor complex in the VEGF system) leads to major angiogenesis events ranging from endothelial cell proliferation, to new vessel formation, Furthermore, differential expression of VEGF-VEGFR mRNA also found in different types of RCC. The aim of present study is to inhibit the VEGFR2 protein by the action of certain inhibitors and then to search an efficient inhibitor. A total of 23 potential inhibitors were searched and used to target the protein using the concept of molecular docking. Among 23 inhibitors, CHEMBL346631 shows best affinity with the target protein and was used for high throughput virtual screening to find similar compounds. The compound obtained from virtual screeningSCHEMBL469307, shows much more better affinity with VEGFR2 than CHEMBL346631. Relative study for both the compounds showed a minor difference in relevant properties. The compound SCHEMBL469307 have a high potential to inhibit the VGFR2 protein and can be backed for future studies in Renal Cell Carcinoma.

C-MET Oncogene in Renal Cell Carcinomas

c-Met plays a significant role in multiple cellular processes. Being encoded by a proto-oncogene, tyrosine kinase supports aggressive tumour behaviour such as tumour invasiveness and formation of metastases. For some subtypes of renal cell carcinoma studies have shown a association between c-Met expression and clinical outcome or prognosis. Therefore, c-Met represents a prognostic marker in renal cell carcinoma.Furthermore, c-MET will play a decisive role as a possible target for targeted therapies in the era of personalised medicine. Especially for RCC, the dual inhibition of VEGF and c-MET tyrosine kinase in cases of metastatic, treatment-resistant tumours is gaining clinical relevance. The role of c-Met has not been fully elucidated for all subtypes of renal cell carcinomas. The relevance of c-Met for the remaining subtypes of renal tumours has yet to be clarified.

Abstract LB-086: Combination therapy of immune checkpoint and nuclear exporter inhibitors in a renal cell carcinoma mouse model

Abstract Selective inhibitor of nuclear export (SINE) compounds represent a novel class of drugs that have shown therapeutic equivalence to multiple kinase inhibitors in pre-clinical studies of renal cell carcinoma (RCC) and are currently in phase I/II clinical trials for patients with advanced malignancies including RCC. Immune checkpoint blockade using antibodies against PD-1 or PD-L1 has also shown promising results in phase I/II/III clinical trials for RCC, with objective tumor responses of around 20% that rise to 40-50% with the combination of antibodies against CTLA-4. Here, we tested the hypothesis that the oral SINE compound, selinexor (KPT-330), would induce rapid death of RCC tumor cells and prime the tumor microenvironment for a response to checkpoint inhibition with antibodies against PD-1 or CTLA-4. Groups of 10, six-week old, male, syngeneic (Balb/c) mice were injected heterotopically (subcutaneous) with 500,000 RENCA cells. After visible tumors appeared seven days later, mice were treated every three days with vehicle (controls), selinexor, anti-PD-1, or anti-CTLA4 alone, or with selinexor in combination with either antibody. Mice were euthanized 10 days after the initiation of treatment when the control groups reached the tumor endpoint. Tumor volume, tumor size, and tumor growth rate were determined by physical measurements; the composition of the tumor immune environment was determined by multi-parameter flow cytometry. As expected, selinexor significantly reduced the overall tumor burden (P<0.05) and the checkpoint inhibitors had only modest effects on tumor growth in this acute 10-day treatment setting, both when used alone alone or in combination with selinexor. Consistent with the hypothesis, selinexor altered the local immune environment, increasing the relative number of T cells and NKT cells with a concomitant reduction in Gr1+ and CD11b+ myeloid cells, and Foxp3+ regulatory T cells (Tregs). Anti-CTLA4 and anti-PD-1 alone led to comparable increases in the relative number of T cells and NKT cells, but with an additional increase in the proportion of effector and activated T cells. The combination of selinexor with either checkpoint blockade antibody resulted in similar reorganization of the tumor immune landscape, with increases in the total number of T cells, effector and activated T cells, and NKT cells and reductions in myeloid cells and Tregs. The data suggest that treatment with selinexor promotes a rapid reduction in tumor burden, while priming the inflammatory and immune environment to potentially maximize the therapeutic effects of checkpoint inhibition. Additional pre-clinical assessments of dose and schedule for this combination can and will be feasibly done in the RENCA model of RCC. Citation Format: Josephine Trott, Katie Anderson, Jeffrey Kim, Ashley Graef, Sharon Shacham, Yosef Landesman, Aaron Sarver, Jaime Modiano, Robert H. Weiss. Combination therapy of immune checkpoint and nuclear exporter inhibitors in a renal cell carcinoma mouse model. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-086.

Abstract 4216: Experimental imaging in orthotopic xenograft models of renal cell carcinoma: comparative evaluation of high-resolution ultrasonography, in vivo micro-CT, and 9.4T MRI

Abstract Introductory Sentence Orthotopic xenografts are increasingly used as preclinical in-vivo models for the study of renal cell carcinoma (RCC). However, monitoring of these tumors requires sophisticated imaging techniques. In this study, we comparatively evaluated modern small animal imaging tools like high-resolution 3D-ultrasonography (3D-US), contrast-enhanced in-vivo micro-CT (CE-CT) and 9,4T MRI (MRI) to non-invasively monitor tumor growth and progression in an orthotopic RCC xenograft model. Material and Methods 106 CAKI-1 cells were injected under the renal capsule of 18 Balb/c-nude mice. Every 14 days from week 4 imaging was performed by CE-CT and 3D-US. 10 weeks after tumor cell inoculation, all animals additionally underwent multiparametric MRI (T1, T2, T2*, DWI). At autopsy, tumor volumes were determined using a caliper and compared to in-vivo imaging results. CE-CT, MRI and 3D-US were evaluated regarding tumor detection, analysis of tumor volume, radiographic imaging properties and examination time. Finally, similar experiments were performed with the RCC cell lines KTCTL30 (n = 2) and 786-0 (n = 1) to test their applicability for the orthotopic xenograft model. Results Tumors were detected in 16/18 animals (89%) 4 weeks after orthotopic inoculation. All methods enabled to adequately visualize orthotopic tumors and to display their growth over time. While the tumors had a homogenously radiolucent signal in CT scans, sonography and MRI were better able to visualized intratumoral structures (e.g. solid areas or intratumoral bleedings) and surrounding soft tissue. CT had the best spatial resolution, followed by 3D-US and MRI. The median examination time was 4.8min per 3D-US, 12.5min per CT and 37.9min per MRI, respectively. Of interest, tumor volumes determined by KM-CT and ultrasonography showed strong correlation with each other (n = 85, R = 0.985) as well as with caliper measurements at autopsy (CT: n = 16. R = 0.922; sonography: n = 16, R = 0.934). Similarly, tumor volumes measured with T2-weighted MRI correlated well with those determined by CT, sonography and caliper. No side effects due to radiation exposure were observed. Mice inoculated with KTCTL30 cells developed partly cystic, partly solid tumors. 786-O cells yielded purely solid, exponentially growing tumors. Conclusion All three imaging modalities are feasible tools for the non-invasive monitoring of orthotopic tumor growth and show excellent correlation with each other. While sonography allows for a fast analysis of tumor volume with excellent resolution and no radiation exposure, MRI provides the best visualization of soft tissue and can give information about tumor biology when acquiring additional sequences. CT has the best spatial resolution of all methods and enables simultaneous screening for bone and lung metastases but relies on the use of contrast agent and ionizing radiation. Citation Format: Johannes Linxweiler, Christina Körbel, Andreas Müller, Volker Jung, Eva Jüngel, Stefan Siemer, Michael Stöckle, Kerstin Junker, Michael D. Menger, Matthias Saar. Experimental imaging in orthotopic xenograft models of renal cell carcinoma: comparative evaluation of high-resolution ultrasonography, in vivo micro-CT, and 9.4T MRI. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4216.

MP92-20 DIFFERENTIATION BETWEEN NORMAL AND CANCEROUS RENAL TISSUES USING ELECTRICAL IMPEDANCE SPECTROSCOPY NEEDLE.

INTRODUCTION AND OBJECTIVES: Orthotopic xenografts are increasingly used preclinical in-vivo models for the study of renal cell carcinoma (RCC). However, monitoring of these tumors requires sophisticated imaging techniques. Herein we comparatively evaluated modern small animal imaging tools like high-resolution 3D-ultrasonography (3D-US), contrast-enhanced in-vivo micro-CT (CE-CT) and 9,4T MRI (MRI) to monitor tumor growth in an orthotopic RCC xenograft model. METHODS: 10 CAKI-1 cells were injected under the renal capsule of 18 Balb/c-nude mice. Every 14 days from week 4 imaging was performed by CE-CT and 3D-US. 10 weeks after cell inoculation, all animals additionally underwent MRI. At autopsy, tumor volumes were determined with a caliper and compared to in-vivo imaging results. CE-CT, MRI and 3D-US were evaluated regarding tumor detection, tumor volume analysis, radiographic imaging properties and examination time. Finally, RCC cell lines KTCTL30 (n1⁄42) and 786-0 (n1⁄41) were used to test their applicability for the orthotopic xenograft model. RESULTS: In 16/18 animals (take rate 89%) all methods enabled to adequately visualize orthotopic tumors and to display their growth over time. While the tumors had a homogenously radiolucent signal in CE-CT, 3D-US and MRI could better visualize intratumoral structures and surrounding soft tissue. CT had the best spatial resolution, followed by 3D-US and MRI. Median examination time was 4.8min per 3D-US, 12.5min per CT and 37.9min per MRI, respectively. Of interest, tumor volumes determined by CE-CT and 3D-US showed strong correlation with each other (n1⁄485, R1⁄40.985) as well as with caliper measurements at autopsy (CT: n1⁄416. R1⁄40.922; 3D-US: n1⁄416, R1⁄40.934). Similarly, tumor volumes measured with T2w MRI correlated well with those determined by CT, 3D-US and caliper. No side effects due to radiation exposure were seen. Mice inoculated with KTCTL30 cells developed partly cystic, partly solid tumors. 786-O cells yielded purely solid, fast growing tumors. CONCLUSIONS: All three imaging modalities are feasible tools for a non-invasive monitoring of orthotopic tumor growth and show excellent correlation with each other. While 3D-US allows for a fast analysis of tumor volume with excellent resolution, MRI provides the best soft tissue contrast and can give additional information about tumor biology (e.g. diffusion, perfusion). CT has the best spatial resolution and enables simultaneous screening for bone and lung metastases but relies on the use of contrast agent and ionizing radiation.

Abstract A24: Neuropilin 1 (NRP1) as a potential biomarker for tivozanib + mFOLFOX6 versus bevacizumab + mFOLFOX6 in metastatic colorectal cancer (mCRC): Post-hoc biomarker analysis of BATON-CRC phase 2 trial

Abstract Purpose: Tivozanib (T), is a potent oral selective inhibitor of VEGF receptors 1, 2, and 3. Bevacizumab (B) is an antibody targeting VEGF A mediated signaling. The randomized, open label phase 2 BATON-CRC (Biomarker Assessment of Tivozanib in ONcology), trial compared the progression free survival (PFS) and safety of T + mFOLFOX6 vs. B + mFOLFOX6 in mCRC patients. Data from the pre-specified interim analysis demonstrated futility for superiority; however the addition of T to mFOLFOX6 resulted in comparable PFS (9.4 vs 10.7 months, p=0.706), overall response rate (45.2% vs 43.2%, p=0.718), and safety to B + mFOLFOX6 and resulted in discontinuation of the study. At the time of the interim analysis (September, 2013) 62 patients out of 163 progressed to generate a PFS event and none of the pre-specified biomarkers demonstrated statistically significant association with PFS (ESMO 2014). At the close of the study (February, 2014), there were 91 PFS events out of 164 patients with baseline serum samples. The final analysis included the updated events which led to the observation that serum NRP1 may be a predictive biomarker for T. Serum NRP1, a pre-specified biomarker in BATON CRC, is associated with improved PFS and overall survival (OS) in multiple T studies in renal cell carcinoma (RCC). This strong association and clinical benefit in RCC prompted a post-hoc analysis of the final BATON-CRC PFS data to examine the differential association between base line serum NRP1 levels and outcomes in the two arms. Methods: Similar to the RCC trials, baseline serum from patients in BATON-CRC had NRP1 quantified using the Myriad RBM ELISA assay. The median NRP1 level from this dataset was used to define the cut off for NRP1 high and NRP1 low. A Cox proportional hazard model was used to assess the association between serum NRP1 levels and PFS. Results: In BATON-CRC, 265 patients were enrolled and randomized 2:1 to T + mFOLFOX6 (n = 177) or B + mFOLFOX6 (n = 88). A total of 164 baseline serum samples (T, n = 109 and B, n = 55) were available for NRP1 analysis. In both the T and B arms, patients with NRP1 low showed an improved PFS vs patients with NRP1 high; for T HR (95% CI): 0.224 [0.120, 0.42], p=3.56e-7 and for B HR [95% CI]: 0.487 [0.237, 1.00], p=0.046) supporting the value of NRP1 as a potential prognostic marker for angiogenesis inhibitors. T treated NRP1 low patients demonstrated a statistically significantly improvement in PFS vs B, PFS =17.9 vs 11.2 mos (multivariate analysis stratified for cancer origin, metastatic sites, LDH levels HR [95% CI]: 0.325 [0.147, 0.717], p=0.005). In NRP1 high patients, there was no difference in PFS between the two arms (HR (95% CI): 0.889 [0.639, 1.980], p=0.683). The interaction p-value is 0.027. Conclusions: The data suggest that NRP1 might be a predictive biomarker of T PFS benefit over B in combination with mFOLFOX 6 in advanced CRC. This finding needs to be further validated in another prospective trial. The differential activity observed with T vs B, in NRP1 low patients is potentially due to the broader VEGF pathway inhibitory activity of T. Citation Format: Al Benson, III, Andrew K. Krivoshik, Chip Van Sant, Jeno Gyuris, Bin Feng. Neuropilin 1 (NRP1) as a potential biomarker for tivozanib + mFOLFOX6 versus bevacizumab + mFOLFOX6 in metastatic colorectal cancer (mCRC): Post-hoc biomarker analysis of BATON-CRC phase 2 trial. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Angiogenesis and Vascular Normalization: Bench to Bedside to Biomarkers; Mar 5-8, 2015; Orlando, FL. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl):Abstract nr A24.

PD10-03 IN-VIVO MULTIPARAMETRIC MAGNETIC RESONANCE STUDIES IN RENAL CELL CARCINOMA AND CORRELATION WITH HISTOPATHOLOGY

You have accessJournal of UrologyKidney Cancer: Evaluation/Staging I1 Apr 2014PD10-03 IN-VIVO MULTIPARAMETRIC MAGNETIC RESONANCE STUDIES IN RENAL CELL CARCINOMA AND CORRELATION WITH HISTOPATHOLOGY Girdhar Bora, Rajeev Kumar, Durgesh Dwivedi, Naranamangalam Jagannathan, and Prabhjot Singh Girdhar BoraGirdhar Bora More articles by this author , Rajeev KumarRajeev Kumar More articles by this author , Durgesh DwivediDurgesh Dwivedi More articles by this author , Naranamangalam JagannathanNaranamangalam Jagannathan More articles by this author , and Prabhjot SinghPrabhjot Singh More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2014.02.479AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Over 20% of incidentally detected renal lesions are benign. However, current imaging modalities are often unable to definitively rule out malignancy. Functional magnetic resonance (MR) methods have been used to identify malignancy in various organs. As a first step in evaluating their role in kidney cancer, we evaluated their ability to differentiate renal cell carcinoma from normal kidney parenchyma. METHODS In an IRB approved protocol, 32 patients with suspected renal cell carcinoma (RCC) on computerized tomography were enrolled for pre-surgery multiparametric MR studies. Using a 1.5T whole body MR scanner, single voxel spectroscopy (MRS) and diffusion weighted imaging (DWI) was carried out with tumor identification based on conventional MR images. The MR data obtained from the malignant lesion was compared with normal kidney parenchyma and the final histology of the nephrectomy specimen. RESULTS Mobile lipid resonances at 0.9, 1.3, 2.2 and 5.4 ppm were seen in both cancers and healthy tissue. Metabolite resonance at 0.9ppm (L0.9) was due to the terminal methyl group of fatty acids,at 1.3-1.35 ppm (L1.3) due to methylene of fatty acid originating from lipids,at 2.2ppm (T2.2) due to methylene of unsaturated fatty acids in triglycerides and 5.4ppm (C5.4) due to unsaturated lipid (cholesterol). Resonance at 3.2ppm (C3.2) was attributed to choline containing compounds. On ratio analysis, there was an increase in mobile lipids in RCC and the C5.4/L1.3 ratio and C3.2/L1.3 ratio was significantly higher in RCC (Table 1). These mobile lipids also correlated with the aggressiveness of the RCC (Table 2). On DWI, there was significant restriction of diffusion in RCC (1.51±0.61x10-3 mm2/s) compared to the normal parenchyma(2.25±0.29x10-3 mm2/s) (p=0.00). CONCLUSIONS In vivo MR visible mobile lipids could reliably differentiate malignant tissue from normal kidney parenchyma. These may form the basis for differentiating malignant small renal masses in future studies. Table 1. MRS data from malignant and normal parenchyma Signal to noise ratio RCC (n=26) Normal (n=22) P value C5.4/L1.3 1.61±2.92 0.18±0.25 0.029 T2.2/L1.3 0.32±0.44 0.09±0.09 0.240 L0.9/L1.3 0.21±0.24 0.18±0.16 0.983 C3.2/L1.3 1.51±2.54(n=20) 0.11±0.17(n=16) 0.009 L0.9: Lipid at 0.9ppm; L1.3: Lipid at 1.3ppm; T2.2: Triglycerides at 2.2ppm; C3.2: Choline at 3.2ppm; C5.4: Cholesterol at 5.4ppm Table 2. MRS ratios varying by tumor grade Signal to noise ratio Low grade RCC High grade RCC P value C5.4/L1.3 0.41±0.88 4.94±3.63 0.001 T2.2/L1.3 0.14±0.19 0.61±0.18 0.003 L0.9/L1.3 0.24±0.26 0.49±0.47 0.566 L0.9: Lipid at 0.9ppm; L1.3: Lipid at 1.3ppm; T2.2: Triglycerides at 2.2ppm; C3.2: Choline at 3.2ppm; C5.4: Cholesterol at 5.4ppm © 2014FiguresReferencesRelatedDetails Volume 191Issue 4SApril 2014Page: e282-e283 Advertisement Copyright & Permissions© 2014MetricsAuthor Information Girdhar Bora More articles by this author Rajeev Kumar More articles by this author Durgesh Dwivedi More articles by this author Naranamangalam Jagannathan More articles by this author Prabhjot Singh More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Systematically Extracting Metal- and Solvent-Related Occupational Information from Free-Text Responses to Lifetime Occupational History Questionnaires

Lifetime occupational history (OH) questionnaires often use open-ended questions to capture detailed information about study participants' jobs. Exposure assessors use this information, along with responses to job- and industry-specific questionnaires, to assign exposure estimates on a job-by-job basis. An alternative approach is to use information from the OH responses and the job- and industry-specific questionnaires to develop programmable decision rules for assigning exposures. As a first step in this process, we developed a systematic approach to extract the free-text OH responses and convert them into standardized variables that represented exposure scenarios. Our study population comprised 2408 subjects, reporting 11991 jobs, from a case-control study of renal cell carcinoma. Each subject completed a lifetime OH questionnaire that included verbatim responses, for each job, to open-ended questions including job title, main tasks and activities (task), tools and equipment used (tools), and chemicals and materials handled (chemicals). Based on a review of the literature, we identified exposure scenarios (occupations, industries, tasks/tools/chemicals) expected to involve possible exposure to chlorinated solvents, trichloroethylene (TCE) in particular, lead, and cadmium. We then used a SAS macro to review the information reported by study participants to identify jobs associated with each exposure scenario; this was done using previously coded standardized occupation and industry classification codes, and a priori lists of associated key words and phrases related to possibly exposed tasks, tools, and chemicals. Exposure variables representing the occupation, industry, and task/tool/chemicals exposure scenarios were added to the work history records of the study respondents. Our identification of possibly TCE-exposed scenarios in the OH responses was compared to an expert's independently assigned probability ratings to evaluate whether we missed identifying possibly exposed jobs. Our process added exposure variables for 52 occupation groups, 43 industry groups, and 46 task/tool/chemical scenarios to the data set of OH responses. Across all four agents, we identified possibly exposed task/tool/chemical exposure scenarios in 44-51% of the jobs in possibly exposed occupations. Possibly exposed task/tool/chemical exposure scenarios were found in a nontrivial 9-14% of the jobs not in possibly exposed occupations, suggesting that our process identified important information that would not be captured using occupation alone. Our extraction process was sensitive: for jobs where our extraction of OH responses identified no exposure scenarios and for which the sole source of information was the OH responses, only 0.1% were assessed as possibly exposed to TCE by the expert. Our systematic extraction of OH information found useful information in the task/chemicals/tools responses that was relatively easy to extract and that was not available from the occupational or industry information. The extracted variables can be used as inputs in the development of decision rules, especially for jobs where no additional information, such as job- and industry-specific questionnaires, is available.

A Genome-Wide Association Study of Renal Cell Carcinoma among African Americans

Genome-wide association studies (GWAS) of renal cell carcinoma (RCC) in populations of European ancestry have identified four susceptibility loci. No GWAS has been conducted among African Americans (AA), who experience a higher incidence of RCC. We conducted a GWAS in which we analyzed 1,136,723 common single-nucleotide polymorphisms (SNP) among 255 cases and 375 controls of African ancestry, and further investigated 16 SNPs in a replication set (140 cases and 543 controls). The 12p11.23 variant rs10771279, located 77 kb from the European-ancestry RCC marker rs718314, was associated with RCC risk in the GWAS (P = 1.2 × 10(-7)) but did not replicate (P = 0.99). Consistent with European-ancestry findings, the A allele of rs7105934 on 11q13.3 was associated with decreased risk [OR, 0.76, 95% confidence interval (CI), 0.64-0.91; P = 0.0022]. The frequency of this allele was higher than that observed in the European-ancestry GWAS (0.56 and 0.07, respectively, among controls). The rs7105934 association was stronger for clear cell RCC (ccRCC: OR, 0.56; P = 7.4 × 10(-7)) and absent for cases of other or unknown histology (OR, 1.02; P = 0.86). Analyses of rs7105934 by subtype among European-ancestry participants from these studies yielded similar findings (ORs 0.69 and 0.92, respectively). This study provides, to our knowledge, the first evidence that rs7105934 is an RCC susceptibility locus among AAs. Our finding that the association with this SNP may be specific to clear-cell RCC is novel and requires additional investigation. Additional investigation of rs10771279 and other suggestive GWAS findings is also needed.

Transition of Organizational Category on Renal Cancer

The incidence of kidney cancer is gradually increasing, with a rate of 2-3% per decade. The kidney develops various kinds of neoplasms, some of which are associated with familial cancer syndromes. Such cases have provided clues to identify the cancer-responsible genes. In 2004, the World Health Organization published a new classification system of renal neoplasms, incorporating recent knowledge obtained in the cytogenetic and molecular biological fields, i.e. genes responsible for each histologic subtype (von Hippel-Lindau for clear cell renal cell carcinoma, c-met for papillary renal cell carcinoma type 1, etc.). Subsequently, the Japanese classification system in 'the General Rule for Clinicopathological Study of Renal Cell Carcinoma' has been revised as the 4th edition, according to the World Health Organization system. Several novel subtypes have been introduced, i.e. mucinous tubular and spindle cell carcinoma, and Xp11.2/TFE3 translocation-associated renal cell carcinoma. Even after the publication of the classification, other novel subtypes have emerged, i.e. acquired cystic disease-associated renal cell carcinoma and tubulocystic renal cell carcinoma. Additionally, some of the subtypes seem to form families based on morphological transition, immunohistochemical features and gene expression profile. In future, the classification of renal cell carcinoma should be reorganized on the basis of molecular biological characteristics to establish personalized therapeutic strategies.

Absence of loss of heterozygosity of BRCA1 in a renal tumor from a BRCA1 germline mutation carrier

BRCA1 functions as a tumor suppressor gene and germline and somatic mutations in this gene have been shown to be associated with many types of cancer. We report the first tumor study of renal cell carcinoma in a carrier of the deleterious BRCA1 mutation-c.68_69delAG.