Essential Peer-Reviewed Reading in Kidney Cancer The peer-reviewed articles summarized in this section were selected by the Editor-in-Chief, Robert A. Figlin, MD, for their timeliness, importance, relevance, and potential impact on clinical practice or translational research. Chromosome instability drives phenotypic switching to metastasis. Gao C, Su Y, Koeman J, et al. Proc Natl Acad Sci USA. 2016 Dec 5; pii:201618215 Summary: Chromosome instability (CIN) is the most striking feature of human cancers. However, how CIN drives tumor progression to metastasis remains elusive. Here we studied the role of chromosome content changes in generating the phenotypic dynamics that are required for metastasis. We isolated epithelial and mesenchymal clones from human carcinoma cell lines and showed that the epithelial clones were able to generate mesenchymal variants, which had the potential to further produce epithelial revertants autonomously. The successive acquisition of invasive mesenchymal and then epithelial phenotypes recapitulated the steps in tumor progression to metastasis. Importantly, the generation of mesenchymal variants from clonal epithelial populations was associated with subtle changes in chromosome content, which altered the chromosome transcriptome and influenced the expression of genes encoding intercellular junction (IJ) proteins, whereas the loss of chromosome 10p, which harbors the ZEB1 gene, was frequently detected in epithelial variants generated from mesenchymal clones. Knocking down these IJ genes in epithelial cells induced a mesenchymal phenotype, whereas knocking down the ZEB1 gene in mesenchymal cells induced an epithelial phenotype, demonstrating a causal role of chromosome content changes in phenotypic determination. Conclusion: This analysis suggests a paradigm of tumor metastasis: primary epithelial carcinoma cells that lose chromosomes harboring IJ genes acquire an invasive mesenchymal phenotype, and subsequent chromosome content changes such as loss of 10p in disseminated mesenchymal cells generate epithelial variants, which can be selected for to generate epithelial tumors during metastatic colonization. Alternating Treatment with Pazopanib and Everolimus vs Continuous Pazopanib to Delay Disease Progression in Patients with Metastatic Clear Cell Renal Cell Cancer: The ROPETAR Randomized Clinical Trial. Cirkel GA, Hamberg P, Sleijfer S, et al. JAMA Oncol. 2016 Dec 1. doi:10.1001/jamaoncol.2016.5202. Summary: A total of 52 patients were randomized to the rotating arm (median range age, 65 44-87 years) and 49 patients to the control arm (median range age, 67 38-82 years). Memorial Sloan Kettering Cancer Center risk category was favorable in 26% of patients, intermediate in 58%, and poor in 15%. Baseline characteristics and risk 128 Kidney Cancer Journal categories were well balanced between arms. One-year PFS1 for rotating treatment was 45% (95% CI, 33-60) and 32% (95% CI, 21-49) for pazopanib (control). Median time until first progression or death for rotating treatment was 7.4 months (95% CI, 5.6-18.4) and 9.4 months (95% CI, 6.6-11.9) for pazopanib (control) (P= .37). Mucositis, anorexia, and dizziness were more prevalent in the rotating arm during first-line treatment. No difference in quality of life was observed. Conclusion: Rotating treatment did not result in prolonged progression-free-survival, fewer toxic effects, or improved quality of life. First-line treatment with a vascular endothelial growth factor inhibitor remains the optimal approach in metastatic clear cell renal cell carcinoma. Renal Cell Carcinoma Associated with Xp11.2 Translocation/TFE3 Gene Fusions: Clinical Features, Treatments and Prognosis. Liu N, Wang Z, Gan W, et al. PLoS One. 2016 Nov 28; 11(11): e0166897. doi:10.1371/ journal.pone.0166897. Summary: To investigate the clinical characteristics, treatments and prognosis of renal cell carcinoma associated with Xp11.2 translocation/TFE3 gene fusions (Xp11.2 tRCC), the epidemiological features and treatment results of 34 cases of Xp11.2 tRCC, which were diagnosed by immunohistochemistry staining of TFE3 and fluorescence in situ hybridization at our center, were retrospectively reviewed. The 34 patients included 21 females and 13 males aged 3 to 64 years (median age: 27 years). Four patients were children or adolescents (<18 years of age), and 26 patients were young or middle-aged adults (18-45 years). Radical nephrectomy was performed on 25 patients. Laparoscopic nephron-sparing surgery was performed on 9 patients who presented with an isolated mass with a small diameter (<7 cm) and well-defined boundary on computed tomography imaging. Postoperative staging showed that 25 cases (73.53%) were at stage I/II, while 9 cases (26.47%) were at stage III/IV. All stage I/II patients received a favorable prognosis with a three-year overall survival rate of 100%, including the patients who underwent laparoscopic nephron-sparing surgery. With the exception of 2 children, the other 7 stage III/IV patients died or developed recurrence with a median follow-up of 29 months. On univariate analysis, maximum diameter, adjuvant treatment, TNM stage, lymph node metastasis, inferior vena cava tumor thrombosis and tumor boundary were identified as statistically significant factors impacting survival (P<0.05). Multivariate analysis indicated that TNM stage and inferior J O U R N A L C L U B (continued on page 140)
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