Browsing by Subject "renal cell carcinoma"
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Item Ambient ionization mass spectrometric analysis of human surgical specimens to distinguish renal cell carcinoma from healthy renal tissue(Springer, 2016-08) Alfaro, Clint M.; Jarmusch, Alan K.; Pirro, Valentina; Kerian, Kevin S.; Masterson, Timothy A.; Cheng, Liang; Cooks, R. Graham; Urology, School of MedicineTouch spray - mass spectrometry (TS-MS) is an ambient ionization technique (ionization of unprocessed samples in the open air) that may find intraoperative applications in quickly identifying the disease state of cancerous tissues and in defining surgical margins. In this study, TS-MS was performed on fresh kidney tissue (~1–5 cm3), within one hour of resection, from 21 human subjects afflicted by renal cell carcinoma (RCC). The preliminary diagnostic value of TS-MS data taken from freshly resected tissue was evaluated. Principal component analysis (PCA) of the negative ion mode (m/z 700–1000) data provided separation between RCC (16 samples) and healthy renal tissue (13 samples). Linear discriminant analysis (LDA) on the PCA compressed data estimated sensitivity (true positive rate) and specificity (true negative rate) of 98% and 95%, respectively, based on histopathological evaluation. The results indicate that TS-MS might provide rapid diagnostic information in spite of the complexity of unprocessed kidney tissue and the presence of interferences such as urine and blood. Desorption electrospray ionization imaging (DESI-MSI) in the negative ionization mode was performed on the tissue specimens after TS-MS analysis as a reference method. The DESI imaging experiments provided phospholipid profiles (m/z 700–1000) that also separated RCC and healthy tissue in the PCA space, with PCA-LDA sensitivity and specificity of 100% and 89%, respectively. The TS and DESI loading plots indicated that different ions contributed most to the separation of RCC from healthy renal tissue (m/z 794 [PC 34:1+Cl]− and 844 [PC 38:4+Cl]− for TS vs. m/z 788 [PS 36:1-H]− and 810 [PS 38:4-H]− for DESI), while m/z 885 ([PI 38:4-H]−) was important in both TS and DESI. The prospect, remaining hurdles, and future work required for translating TS-MS into a method of intraoperative tissue diagnosis is discussed.,Item The Combination of Low Skeletal Muscle Mass and High Tumor Interleukin-6 Associates with Decreased Survival in Clear Cell Renal Cell Carcinoma(MDPI, 2020-06-17) Kays, Joshua K.; Koniaris, Leonidas G.; Cooper, Caleb A.; Pili, Roberto; Jiang, Guanglong; Liu, Yunlong; Zimmers, Teresa A.; Medical and Molecular Genetics, School of MedicineClear cell renal carcinoma (ccRCC) is frequently associated with cachexia which is itself associated with decreased survival and quality of life. We examined relationships among body phenotype, tumor gene expression, and survival. Demographic, clinical, computed tomography (CT) scans and tumor RNASeq for 217 ccRCC patients were acquired from the Cancer Imaging Archive and The Cancer Genome Atlas (TCGA). Skeletal muscle and fat masses measured from CT scans and tumor cytokine gene expression were compared with survival by univariate and multivariate analysis. Patients in the lowest skeletal muscle mass (SKM) quartile had significantly shorter overall survival versus the top three SKM quartiles. Patients who fell into the lowest quartiles for visceral adipose mass (VAT) and subcutaneous adipose mass (SCAT) also demonstrated significantly shorter overall survival. Multiple tumor cytokines correlated with mortality, most strongly interleukin-6 (IL-6); high IL-6 expression was associated with significantly decreased survival. The combination of low SKM/high IL-6 was associated with significantly lower overall survival compared to high SKM/low IL-6 expression (26.1 months vs. not reached; p < 0.001) and an increased risk of mortality (HR = 5.95; 95% CI = 2.86–12.38). In conclusion, tumor cytokine expression, body composition, and survival are closely related, with low SKM/high IL-6 expression portending worse prognosis in ccRCC.Item Complexity of the genomic landscape of renal cell carcinoma: Implications for targeted therapy and precision immuno-oncology(Elsevier, 2017-11) Sanfrancesco, Joseph M.; Cheng, Liang; Pathology and Laboratory Medicine, School of MedicineThe topic of tumoral heterogeneity at the genetic level has become relevant in various solid origin tumors, particularly in an age of targeted treatment. Renal cell carcinoma is known for a sizable subset of tumors presenting at advanced clinical stage, further highlighting the importance and timeliness of this topic and its potential impact on adjuvant therapy. Recent studies have shown that molecular aberrations in renal cell carcinoma go beyond known truncal mutations and that downstream, subclonal aberrations are spatially heterogenous. Intratumoral heterogeneity as well as the differences in the molecular landscape between primary and metastatic lesions remains underappreciated, often due to inadequate sampling of tumors. The overall effect of these factors on the efficacy of current treatment options in renal cell carcinoma remains unknown; however, several recent studies have attempted to elucidate the extent and impact genetic heterogeneity in renal cell neoplasia may have on patient treatment and prognosis.Item Endoscopic ultrasound-guided fine needle aspiration cytology of metastatic renal cell carcinoma to the pancreas: A multi-center experience(Medknow Publications, 2016-10-03) Pannala, Rahul; Hallberg-Wallace, Karyn M.; Smith, Amber L.; Nassar, Aziza; Zhang, Jun; Zarka, Matthew; Reynolds, Jordan P.; Chen, LongwenIntroduction: The increasing use of endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) cytology to examine pancreatic neoplasms has led to an increase in the diagnosis of metastases to the pancreas. Renal cell carcinoma (RCC) is the most common metastasis to the pancreas. Our study examines 33 cases of metastatic RCC to the pancreas sampled by EUS-FNA from four large tertiary care hospitals. Materials and Methods: We searched the cytopathology database for RCC metastatic to the pancreas diagnosed by EUS-FNA from January 2005 to January 2015. Patient age, history of RCC, nephrectomy history, follow-up postnephrectomy, radiological impression, and EUS-FNA cytologic diagnosis were reviewed. Results: Thirty-three patients were identified. The average age was 67.5 years (range, 49–84 years). Thirty-two patients had a previous documented history of RCC. One patient had the diagnosis of pancreatic metastasis at the same time of the kidney biopsy. Thirty-one patients had been treated with nephrectomy. Twenty-seven patients were being monitored annually by computed tomography or magnetic resonance imaging. Twenty-five patients had multiple masses by imaging, but 8 patients had a single mass in the pancreas at the time of EUS-FNA. EUS-FNA of 20 cases showed classic morphology of RCC. Thirteen cases had either “atypical” clinical-radiologic features or morphologic overlaps with primary pancreatic neoplasms or other neoplasms. Cell blocks were made on all 13 cases and immunochemical stains confirmed the diagnosis. Conclusions: EUS-FNA cytology is useful for the diagnosis of metastatic RCC to the pancreas. Cytomorphology can be aided with patient history, imaging analyses, cell blocks, and immunochemical stains.Item EZH2 modifies sunitinib resistance in renal cell carcinoma by kinome reprogramming(Cancer Research, 2017-12-01) Adelaiye-Ogala, Remi; Budka, Justin; Damayanti, Nur P.; Arrington, Justine; Ferris, Mary; Hsu, Chuan-Chih; Chintala, Sreenivasulu; Orillion, Ashley; Miles, Kiersten Marie; Shen, Li; Elbanna, May; Ciamporcero, Eric; Arisa, Sreevani; Pettazzoni, Piergiorgio; Draetta, Giulio F.; Seshadri, Mukund; Hancock, Bradley; Radovich, Milan; Kota, Janaiah; Buck, Michael; Keilhack, Heike; McCarthy, Brian P.; Persohn, Scott A.; Territo, Paul R.; Zang, Yong; Irudayaraj, Joseph; Tao, W. Andy; Hollenhorst, Peter; Pili, RobertoAcquired and intrinsic resistance to receptor tyrosine kinase inhibitors (RTKi) represent a major hurdle in improving the management of clear cell renal cell carcinoma (ccRCC). Recent reports suggest that drug resistance is driven by tumor adaptation via epigenetic mechanisms that activate alternative survival pathways. The histone methyl transferase EZH2 is frequently altered in many cancers including ccRCC. To evaluate its role in ccRCC resistance to RTKi, we established and characterized a spontaneously metastatic, patient-derived xenograft (PDX) model that is intrinsically resistant to the RTKI sunitinib but not to the VEGF therapeutic antibody bevacizumab. Sunitinib maintained its anti-angiogenic and anti-metastatic activity but lost its direct anti-tumor effects due to kinome reprogramming, which resulted in suppression of pro- apoptotic and cell cycle regulatory target genes. Modulating EZH2 expression or activity suppressed phosphorylation of certain RTK, restoring the anti-tumor effects of sunitnib in models of acquired or intrinsically resistant ccRCC. Overall, our results highlight EZH2 as a rational target for therapeutic intervention in sunitinib-resistant ccRCC as well as a predictive marker for RTKi response in this disease.Item Long non-coding RNAs in renal cell carcinoma: A systematic review and clinical implications(Impact Journals, 2017-04-12) Li, Ming; Wang, Ying; Cheng, Liang; Niu, Wanting; Zhao, Guoan; Raju, Jithin K.; Huo, Jun; Wu, Bin; Yin, Bo; Song, Yongsheng; Bu, Renge; Pathology and Laboratory Medicine, School of MedicineRenal cell carcinoma is one of the most common malignancy in adults, its prognosis is poor in an advanced stage and early detection is difficult due to the lack of molecular biomarkers. The identification of novel biomarkers for RCC is an urgent and meaningful project. Long non-coding RNA (lncRNA) is transcribed from genomic regions with a minimum length of 200 bases and limited protein-coding potential. Recently, lncRNAs have been greatly studied in a variety of cancer types. They participate in a wide variety of biological processes including cancer biology. In this review, we provide a new insight of the profiling of lncRNAs in RCC and their roles in renal carcinogenesis, with an emphasize on their potential in diagnosis, prognosis and potential roles in RCC therapy.Item Merlin immunohistochemistry is useful in diagnosis of tumours within the spectrum of biphasic hyalinizing psammomatous renal cell carcinoma(Wiley, 2022-11) Collins, Katrina; Hwang, Michael; Antic, Tatjana; Paintal, Ajit; Argani, Pedram; Matoso, Andres; Gopinath, Arun; Baskovich, Brett; Mehra, Rohit; Williamson, Sean R.; Idrees, Muhammad T.; Barletta, Justine A.; Anderson, William J.; Hirsch, Michelle S.; Hornick , Jason L.; Acosta, Andres M.; Pathology and Laboratory Medicine, School of MedicineAims: Biphasic hyalinizing psammomatous (BHP) renal cell carcinoma (RCC) is a newly described emerging entity within the spectrum of papillary RCC in the WHO 2022 classification. Molecular analyses have discovered that BHP RCC consistently harbour somatic mutations in the neurofibromin 2 (NF2) gene. The NF2 gene product, merlin, is known to primarily function as a tumour suppressor. Merlin protein loss correlates closely with the presence of NF2 mutations in benign and malignant tumours arising in different sites. In the present study we explored the role of merlin immunohistochemistry (IHC) in tumours within the spectrum of BHP RCC to determine the diagnostic utility of this marker. Materials and methods: We performed merlin IHC in 13 BHP RCC, 18 papillary RCC, 10 TFE3-translocation RCC, 15 TFEB-altered RCC (including 13 TFEB-rearranged and 2 TFEB-amplified), and 10 mucinous tubular and spindle cell carcinomas of unknown mutational status. Results: Unequivocal loss of merlin expression in >90% of the tumour cells was observed in 12/13 BHP-RCC (92%), with the remaining tumour demonstrating weak focal cytoplasmic expression in ~10% of the tumour. In contrast, merlin was diffusely or multifocally expressed in all papillary RCC, TFE3-translocation RCC, and TFEB-altered RCC, as well as in 70% of mucinous tubular and spindle carcinomas. Conclusions: In this study, merlin IHC was ~92% sensitive and ~94% specific for BHP RCC. These data suggest that merlin IHC is a reliable surrogate marker for the presence of underlying NF2 gene inactivation, being diagnostically useful to identify BHP RCC.Item A novel preoperative model to predict 90-day surgical mortality in patients considered for renal cell carcinoma surgery(Elsevier, 2018-10) Calaway, Adam C.; Monn, M. Francesca; Bahler, Clinton D.; Cary, Clint; Boris, Ronald S.; Urology, School of MedicineIntroduction Surgical benefits for renal cell carcinoma must be weighed against competing causes of mortality, especially in the elderly patient population. We used a large cancer registry to evaluate the impact of patient and cancer-specific factors on 90-day mortality (90DM). A nomogram to predict the odds of short-term mortality was created. Materials and Methods The National Cancer Database was queried to identify all patients with clinically localized, nonmetastatic disease treated with partial or radical nephrectomy. Using a random sample of 60%, multiple logistic regression with 90DM outcomes were performed to identify preoperative variables associated with mortality. Variables included age, sex, race, co-morbidity score, tumor size, and presence of a thrombus. A nomogram was created and tested on the remaining 40% of patients to predict 90DM. Results 183,407 patients met inclusion criteria. Overall 90DM for the cohort was 1.9%. All preoperative variables significantly influenced the risk of 90DM. Patient age was by far the strongest predictor. Nomogram scores ranged from 0 to 12. Compared to patients with 0 to 1 points, those with 2 to 3 (odds ratio [OR] 2.89, 2.42–3.46; P < 0.001), 4 to 5 (OR 6.25, 5.26–7.43; P < 0.001), and >6 (OR 12.86, 10.83–15.27; P < 0.001) were at incrementally significantly higher odds of 90DM. Being >80 years of age alone placed patients into the highest risk of surgical mortality. Conclusions Management of localized kidney cancer must consider competing causes of mortality, especially in elderly patients with multiple co-morbidities. We present a preoperative tool to calculate risk of surgical short-term mortality to aid surgeon–patient counseling.Item Renal Cell Carcinoma with Angioleiomyoma-Like Stroma and Clear Cell Papillary Renal Cell Carcinoma: Exploring SDHB Protein Immunohistochemistry and the Relationship to Tuberous Sclerosis Complex(Elsevier, 2017) Williamson, Sean R.; Hornick, Jason L.; Eble, John N.; Gupta, Nilesh S.; Rogers, Craig G.; True, Lawrence; Grignon, David J.; Cheng, Liang; Pathology and Laboratory Medicine, School of MedicineRenal cell carcinoma (RCC) with angioleiomyoma-like stroma appears to be molecularly distinct from clear cell RCC; however, its relationship to clear cell papillary RCC remains debated. Recent studies have found that similar tumors sometimes occur in patients with tuberous sclerosis complex (TSC), of which one study found unexpectedly negative succinate dehydrogenase (SDH) B immunostaining. We evaluated immunohistochemistry for SDHB in 12 apparently sporadic RCCs with angioleiomyoma-like stroma and correlated with clinical information for stigmata of TSC. Tumors were compared to a group of 16 clear cell papillary RCCs and 6 unclassified tumors with prominent stroma. With exception of 1 unclassified tumor, all exhibited at least focal cytoplasmic staining for SDHB protein, often requiring high magnification and better appreciated with increased antibody concentration. Detailed history information was available for 9/12 patients with smooth muscle-rich tumors, revealing no stigmata of undiagnosed TSC. Electron microscopy performed on 1 of these tumors revealed mitochondria to be very sparse, potentially accounting for the weak immunohistochemical labeling for SDHB protein. Weak SDHB immunostaining may represent another shared feature of RCC with angioleiomyoma-like stroma and clear cell papillary RCC, likely due to sparse mitochondria, strengthening the possible relationship of these entities. Although smooth muscle-rich tumors have been recently reported in patients with TSC, absence of staining in tumors with this pattern may not be specific for TSC. In tumors with pale or clear cytoplasm, immunohistochemical staining for SDHB should be interpreted with caution as evidence of abnormality in the SDH pathway.Item Renal Volume Loss During Partial Nephrectomy Due to Resected Healthy Parenchyma: A Tool for Quick Estimation(Liebert, 2020) Plattner, Haley S.; Sundaram, Chandru P.; Cheng, Liang; Bahler, Clinton D.; Urology, School of MedicinePurpose: Our objective is to evaluate a technique for estimating the amount of healthy margin resected during partial nephrectomy (PN). Materials and Methods: The resected healthy margin volume was determined by planimetry (gold standard), which was performed in a prospective manner on 30 freshly resected renal masses by cross-sectional slicing every ∼5 mm. A single cross-sectional slice containing the largest tumor diameter (bivalved tumor) was chosen to build a model for estimating the amount of healthy kidney removed. This single-slice technique was then applied to a second series of patients (n = 39) status post PN. Three-dimensional models were created using pre- and postoperative CT scans to determine the overall volume loss following PN. Results: The median (range) for tumor diameter and tumor volume was 3.2 cm (1–6.1) and 10.7 cm3 (0.5–101.9), respectively, for the 30 PN specimens used to build the single-slice estimation equation. The median (range) healthy margin volume calculated by planimetry and single slice technique was 9.0 cm3 (1.0–22.1) and 7.8 cm3 (1.0–31.0), respectively (p = 0.37). The Pearson correlation was 0.84, and the median (range) percent difference between the planimetry and single slice techniques was −0.5% (−39% to 57%). For the 39 PN patients, the median (range) total renal volume loss, 25.8 cm3 (3–79), was significantly greater than the volume of healthy margin removed during resection, 5.7 cm3 (1–22), p < 0.001. Conclusions: The healthy margin resected during PN differs widely and can be estimated from a single cross-section. The healthy margin resected accounted for <50% of the total volume loss seen during PN.