Publications by authors named "Thai H Ho"

65 Publications

Differential impact of tumor suppressor gene (TP53, PTEN, RB1) alterations and treatment outcomes in metastatic, hormone-sensitive prostate cancer.

Prostate Cancer Prostatic Dis 2021 Jul 22. Epub 2021 Jul 22.

Division of Hematology and Medical Oncology, Phoenix, AZ, USA.

Background: Altered tumor suppressor genes (TSG-alt) in prostate cancer are associated with worse outcomes. The prognostic value of TSG-alt in metastatic, hormone-sensitive prostate cancer (M1-HSPC) is unknown. We evaluated the effects of TSG-alt on outcomes in M1-HSPC and their prognostic impact by first-line treatment.

Methods: We retrospectively identified patients with M1-HSPC at our institution treated with first-line androgen deprivation therapy plus docetaxel (ADT + D) or abiraterone acetate (ADT + A). TSG-alt was defined as any alteration in one or more TSG. The main outcomes were Kaplan-Meier-estimated progression-free survival (PFS) and overall survival, analyzed with the log-rank test. Clinical characteristics were compared with the χ test and Kruskal-Wallis rank sum test. Cox regression was used for univariate and multivariable analyses.

Results: We identified 97 patients with M1-HSPC: 48 (49%) with ADT + A and 49 (51%) with ADT + D. Of 96 patients with data available, 33 (34%) had 1 TSG-alt, 16 (17%) had 2 TSG-alt, and 2 (2%) had 3 TSG-alt. The most common alterations were in TP53 (36%) and PTEN (31%); 6% had RB1 alterations. Median PFS was 13.1 (95% CI, 10.3-26.0) months for patients with normal TSGs (TSG-normal) vs. 7.8 (95% CI, 5.8-10.5) months for TSG-alt (P = 0.005). Median PFS was lower for patients with TSG-alt vs TSG-normal for those with ADT + A (TSG-alt: 8.0 [95% CI, 5.8-13.8] months vs. TSG-normal: 23.2 [95% CI, 13.1-not estimated] months), but not with ADT + D (TSG-alt: 7.8 [95% CI, 5.7-12.9] months vs. TSG-normal: 9.5 [95% CI, 4.8-24.7] months). On multivariable analysis, only TSG-alt predicted worse PFS (hazard ratio, 2.37; 95% CI, 1.42-3.96; P < 0.001).

Conclusions: The presence of TSG-alt outperforms clinical criteria for predicting early progression during first-line treatment of M1-HSPC. ADT + A was less effective in patients with than without TSG-alt. Confirmation of these findings may establish the need for inclusion of molecular stratification in treatment algorithms.
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http://dx.doi.org/10.1038/s41391-021-00430-4DOI Listing
July 2021

Clinical Results and Biomarker Analyses of Axitinib and TRC105 versus Axitinib Alone in Patients with Advanced or Metastatic Renal Cell Carcinoma (TRAXAR).

Oncologist 2021 07 29;26(7):560-e1103. Epub 2021 Apr 29.

Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah, USA.

Lessons Learned: The combination of carotuximab with axitinib did not provide a benefit over axitinib monotherapy in patients with metastatic clear cell renal cell carcinoma who had previously progressed on one or more vascular endothelial growth factor (VEGF)-targeted therapies. Exploratory evaluation of pretreatment circulating biomarkers suggested the combination might benefit patients who have low baseline VEGF levels.

Background: Endoglin is an angiogenic receptor expressed on proliferating tumor vessels and renal cell carcinoma (RCC) stem cells that is implicated as a mechanism of resistance to vascular endothelial growth factor receptor (VEGFR) inhibitors. This study evaluated an antiendoglin monoclonal antibody (carotuximab, TRC105) combined with axitinib in patients with advanced or metastatic clear cell renal cell carcinoma (mccRCC) who had progressed following one or more prior VEGF inhibitors.

Methods: TRAXAR was a multicenter, international randomized 1:1 (stratified by ECOG, 0 vs. 1), phase II study of carotuximab combined with axitinib versus axitinib alone in mccRCC patients who had progressed following one or more prior VEGF inhibitors. The primary endpoint was progression-free survival (PFS) assessed by independent central review (ICR) per RECIST 1.1 RESULTS: A total of 150 patients were randomized. The combination therapy resulted in shorter median PFS by RECIST 1.1 than axitinib monotherapy (6.7 vs. 11.4 months). The combination was tolerated similarly to axitinib monotherapy, and there were no treatment related deaths. Exploratory evaluation of pretreatment circulating biomarkers suggested the combination might benefit patients who have low baseline VEGF levels.

Conclusion: The combination of carotuximab with axitinib did not demonstrate additional efficacy over single agent axitinib in patients with mccRCC who progressed following one or more prior VEGF inhibitor treatment.
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http://dx.doi.org/10.1002/onco.13777DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8265348PMC
July 2021

A Living, Interactive Systematic Review and Network Meta-analysis of First-line Treatment of Metastatic Renal Cell Carcinoma.

Eur Urol 2021 Apr 3. Epub 2021 Apr 3.

Mayo Clinic, Rochester, MN, USA.

Context: Identifying the most effective first-line treatment for metastatic renal cell carcinoma (mRCC) is challenging as rapidly evolving data quickly outdate the existing body of evidence, and current approaches to presenting the evidence in user-friendly formats are fraught with limitations.

Objective: To maintain living evidence for contemporary first-line treatment for previously untreated mRCC.

Evidence Acquisition: We have created a living, interactive systematic review (LISR) and network meta-analysis for first-line treatment of mRCC using data from randomized controlled trials comparing contemporary treatment options with single-agent tyrosine kinase inhibitors. We applied an advanced programming and artificial intelligence-assisted framework for evidence synthesis to create a living search strategy, facilitate screening and data extraction using a graphical user interface, automate the frequentist network meta-analysis, and display results in an interactive manner.

Evidence Synthesis: As of October 22, 2020, the LISR includes data from 14 clinical trials. Baseline characteristics are summarized in an interactive table. The cabozantinib + nivolumab combination (CaboNivo) is ranked the highest for the overall response rate, progression-free survival, and overall survival, whereas ipilimumab + nivolumab (NivoIpi) is ranked the highest for achieving a complete response (CR). NivoIpi, and atezolizumab + bevacizumab (AteBev) were ranked highest (lowest toxicity) and CaboNivo ranked lowest for treatment-related adverse events (AEs). Network meta-analysis results are summarized as interactive tables and plots, GRADE summary-of-findings tables, and evidence maps.

Conclusions: This innovative living and interactive review provides the best current evidence on the comparative effectiveness of multiple treatment options for patients with untreated mRCC. Trial-level comparisons suggest that CaboNivo is likely to cause more AEs but is ranked best for all efficacy outcomes, except NivoIpi offers the best chance of CR. Pembrolizumab + axitinib and NivoIpi are acceptable alternatives, except NivoIpi may not be preferred for patients with favorable risk. Although network meta-analysis provides rankings with statistical adjustments, there are inherent biases in cross-trial comparisons with sparse direct evidence that does not replace randomized comparisons.

Patient Summary: It is challenging to decide the best option among the several treatment combinations of immunotherapy and targeted treatments for newly diagnosed metastatic kidney cancer. We have created interactive evidence summaries of multiple treatment options that present the benefits and harms and evidence certainty for patient-important outcomes. This evidence is updated as soon as new studies are published.
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http://dx.doi.org/10.1016/j.eururo.2021.03.016DOI Listing
April 2021

ZMYND8 preferentially binds phosphorylated EZH2 to promote a PRC2-dependent to -independent function switch in hypoxia-inducible factor-activated cancer.

Proc Natl Acad Sci U S A 2021 02;118(8)

Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine and Science, Rochester, MN 55905;

Both gene repressor (Polycomb-dependent) and activator (Polycomb-independent) functions of the Polycomb protein enhancer of zeste homolog 2 (EZH2) are implicated in cancer progression. EZH2 protein can be phosphorylated at various residues, such as threonine 487 (T487), by CDK1 kinase, and such phosphorylation acts as a Polycomb repressive complex 2 (PRC2) suppression "code" to mediate the gene repressor-to-activator switch of EZH2 functions. Here we demonstrate that the histone reader protein ZMYND8 is overexpressed in human clear cell renal cell carcinoma (ccRCC). ZMYND8 binds to EZH2, and their interaction is largely enhanced by CDK1 phosphorylation of EZH2 at T487. ZMYND8 depletion not only enhances Polycomb-dependent function of EZH2 in hypoxia-exposed breast cancer cells or von Hippel-Lindau (VHL)-deficient ccRCC cells, but also suppresses the FOXM1 transcription program. We further show that ZMYND8 is required for EZH2-FOXM1 interaction and is important for FOXM1-dependent matrix metalloproteinase () gene expression and EZH2-mediated migration and invasion of VHL-deficient ccRCC cells. Our results identify a previously uncharacterized role of the chromatin reader ZMYND8 in recognizing the PRC2-inhibitory phosphorylation "code" essential for the Polycomb-dependent to -independent switch of EZH2 functions. They also reveal an oncogenic pathway driving cell migration and invasion in hypoxia-inducible factor-activated (hypoxia or VHL-deficient) cancer.
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http://dx.doi.org/10.1073/pnas.2019052118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7923384PMC
February 2021

Integrative molecular characterization of sarcomatoid and rhabdoid renal cell carcinoma.

Nat Commun 2021 02 5;12(1):808. Epub 2021 Feb 5.

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.

Sarcomatoid and rhabdoid (S/R) renal cell carcinoma (RCC) are highly aggressive tumors with limited molecular and clinical characterization. Emerging evidence suggests immune checkpoint inhibitors (ICI) are particularly effective for these tumors, although the biological basis for this property is largely unknown. Here, we evaluate multiple clinical trial and real-world cohorts of S/R RCC to characterize their molecular features, clinical outcomes, and immunologic characteristics. We find that S/R RCC tumors harbor distinctive molecular features that may account for their aggressive behavior, including BAP1 mutations, CDKN2A deletions, and increased expression of MYC transcriptional programs. We show that these tumors are highly responsive to ICI and that they exhibit an immune-inflamed phenotype characterized by immune activation, increased cytotoxic immune infiltration, upregulation of antigen presentation machinery genes, and PD-L1 expression. Our findings build on prior work and shed light on the molecular drivers of aggressivity and responsiveness to ICI of S/R RCC.
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http://dx.doi.org/10.1038/s41467-021-21068-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7865061PMC
February 2021

Identification of DNA methylation signatures associated with poor outcome in lower-risk Stage, Size, Grade and Necrosis (SSIGN) score clear cell renal cell cancer.

Clin Epigenetics 2021 01 18;13(1):12. Epub 2021 Jan 18.

Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA.

Background: Despite using prognostic algorithms and standard surveillance guidelines, 17% of patients initially diagnosed with low risk clear cell renal cell carcinoma (ccRCC) ultimately relapse and die of recurrent disease, indicating additional molecular parameters are needed for improved prognosis.

Results: To address the gap in ccRCC prognostication in the lower risk population, we performed a genome-wide analysis for methylation signatures capable of distinguishing recurrent and non-recurrent ccRCCs within the subgroup classified as 'low risk' by the Mayo Clinic Stage, Size, Grade, and Necrosis score (SSIGN 0-3). This approach revealed that recurrent patients have globally hypermethylated tumors and differ in methylation significantly at 5929 CpGs. Differentially methylated CpGs (DMCpGs) were enriched in regulatory regions and genes modulating cell growth and invasion. A subset of DMCpGs stratified low SSIGN groups into high and low risk of recurrence in independent data sets, indicating that DNA methylation enhances the prognostic power of the SSIGN score.

Conclusions: This study reports a global DNA hypermethylation in tumors of recurrent ccRCC patients. Furthermore, DMCpGs were capable of discriminating between aggressive and less aggressive tumors, in addition to SSIGN score. Therefore, DNA methylation presents itself as a potentially strong biomarker to further improve prognostic power in patients with low risk SSIGN score (0-3).
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http://dx.doi.org/10.1186/s13148-020-00998-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7814746PMC
January 2021

8q24 clear cell renal cell carcinoma germline variant is associated with VHL mutation status and clinical aggressiveness.

BMC Urol 2020 Oct 29;20(1):173. Epub 2020 Oct 29.

Department of Health Sciences Research, Mayo Clinic, Jacksonville, FL, USA.

Background: The four most commonly-mutated genes in clear cell renal cell carcinoma (ccRCC) tumors are BAP1, PBRM1, SETD2 and VHL. And, there are currently 14 known RCC germline variants that have been reproducibly shown to be associated with RCC risk. However, the association of germline genetics with tumor genetics and clinical aggressiveness are unknown.

Methods: We analyzed 420 ccRCC patients from The Cancer Genome Atlas. Molecular subtype was determined based on acquired mutations in BAP1, PBRM1, SETD2 and VHL. Aggressive subtype was defined clinically using Mayo SSIGN score and molecularly using the ccA/ccB gene expression subtype. Publically-available Hi-C data were used to link germline risk variants with candidate target genes.

Results: The 8q24 variant rs35252396 was significantly associated with VHL mutation status (OR = 1.6, p = 0.0037) and SSIGN score (OR = 1.9, p = 0.00094), after adjusting for multiple comparisons. We observed that, while some germline variants have interactions with nearby genes, some variants demonstrate long-range interactions with target genes.

Conclusions: These data further demonstrate the link between rs35252396, HIF pathway and ccRCC clinical aggressiveness, providing a more comprehensive picture of how germline genetics and tumor genetics interact with respect to tumor development and progression.
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http://dx.doi.org/10.1186/s12894-020-00745-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7597051PMC
October 2020

Macrophage HIF-1α Is an Independent Prognostic Indicator in Kidney Cancer.

Clin Cancer Res 2020 09 25;26(18):4970-4982. Epub 2020 Jun 25.

University of Utah, Salt Lake City, Utah.

Purpose: Clear cell renal cell carcinoma (ccRCC) is frequently associated with inactivation of the von Hippel-Lindau tumor suppressor, resulting in activation of HIF-1α and HIF-2α. The current paradigm, established using mechanistic cell-based studies, supports a tumor promoting role for HIF-2α, and a tumor suppressor role for HIF-1α. However, few studies have comprehensively examined the clinical relevance of this paradigm. Furthermore, the hypoxia-associated factor (HAF), which regulates the HIFs, has not been comprehensively evaluated in ccRCC.

Experimental Design: To assess the involvement of HAF/HIFs in ccRCC, we analyzed their relationship to tumor grade/stage/outcome using tissue from 380 patients, and validated these associations using tissue from 72 additional patients and a further 57 patients treated with antiangiogenic therapy for associations with response. Further characterization was performed using single-cell mRNA sequencing (scRNA-seq), RNA- hybridization (RNA-ISH), and IHC.

Results: HIF-1α was primarily expressed in tumor-associated macrophages (TAMs), whereas HIF-2α and HAF were expressed primarily in tumor cells. TAM-associated HIF-1α was significantly associated with high tumor grade and increased metastasis and was independently associated with decreased overall survival. Furthermore, elevated TAM HIF-1α was significantly associated with resistance to antiangiogenic therapy. In contrast, high HAF or HIF-2α were associated with low grade, decreased metastasis, and increased overall survival. scRNA-seq, RNA-ISH, and Western blotting confirmed the expression of HIF-1α in M2-polarized CD163-expressing TAMs.

Conclusions: These findings highlight a potential role of TAM HIF-1α in ccRCC progression and support the reevaluation of HIF-1α as a therapeutic target and marker of disease progression.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-3890DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7968518PMC
September 2020

Lgr5-positive endothelial progenitor cells occupy a tumor and injury prone niche in the kidney vasa recta.

Stem Cell Res 2020 07 20;46:101849. Epub 2020 May 20.

Department of Obstetrics, Gynecology and Reproductive Biology, College of Human Medicine, Michigan State University, Grand Rapids, MI 49503, USA; Center for Epigenetics, Van Andel Research Institute, Grand Rapids, MI 49503, USA; Department of Women's Health, Spectrum Health System, Grand Rapids, MI 49341, USA. Electronic address:

The Wnt pathway co-receptor, Leucine Rich Repeat Containing G Protein-Coupled Receptor 5 (LGR5), labels tumor-prone stem cell populations in certain types of tissue. In this study, we show that ARID1A and PIK3CA mutations in LGR5 cells result in renal angiosarcomas in adult mice. The tumors originate in the renal medulla. We further show that LGR5 labels SOX17/CD31/CD34/CD133/AQP1/CD146 endothelial progenitor cells within the descending vasa recta or straight arterioles of the kidney, which are specialized capillaries that maintain medullary osmotic gradients necessary for water reabsorption and the production of concentrated urine. LGR5 endothelial progenitor cells are tightly associated with contractile pericytes within the descending vasa recta. Long-term in vivo lineage tracing revealed that LGR5 cells give rise to renal medullary vasculature. We further show that LGR5 cells are activated in response to ischemic kidney injury. Our findings uncover a physiologically relevant endothelial progenitor cell population within the kidney vasa recta.
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http://dx.doi.org/10.1016/j.scr.2020.101849DOI Listing
July 2020

Molecular characterization of sarcomatoid clear cell renal cell carcinoma unveils new candidate oncogenic drivers.

Sci Rep 2020 01 20;10(1):701. Epub 2020 Jan 20.

Department of Urology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Sarcomatoid clear-cell renal cell carcinomas (sRCC) are associated with dismal prognosis. Genomic alterations associated with sarcomatoid dedifferentiation are poorly characterized. We sought to define the genomic landscape of sRCC and uncover potentially actionable therapeutic targets. We assessed the genomic landscape of sRCC using targeted panel sequencing including patients with microdissected sarcomatoid and epithelial components. Along with common genomic alterations associated with clear-cell histology, we found that Hippo was one of the most frequently altered pathways in these tumours. Hippo alterations were differentially enriched in sRCC compared to non-sRCC. Functional analysis showed that Hippo members mutations were associated with higher nuclear accumulation of YAP/TAZ, core effectors of the Hippo pathway. In a NF2-mutant sRCC model, YAP1 knockdown and NF2 reconstitution suppressed cell proliferation, tumour growth and invasion, both in vitro and in vivo. Overall, we show that Hippo pathway alterations are a feature of sRCC, and enable the exploration of the Hippo pathway as a novel potential therapeutic target.
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http://dx.doi.org/10.1038/s41598-020-57534-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6971072PMC
January 2020

Concordance of PD-1 and PD-L1 (B7-H1) in paired primary and metastatic clear cell renal cell carcinoma.

Cancer Med 2020 02 12;9(3):1152-1160. Epub 2019 Dec 12.

Department of Health Sciences Research, Mayo Clinic, Jacksonville, FL, USA.

Objectives: Previous studies noted discordance of programmed death-1 (PD-1) and one of its ligands (PD-L1) across patient-matched primary and metastatic clear cell renal cell carcinoma (ccRCC). There are inconsistencies if the primary or metastatic tumor has higher expression, and whether metastatic tumor expression is associated with patient outcome. Thus, we examined PD-1 and PD-L1 in patient-matched tumors using a large number of ccRCC patients with long follow-up.

Materials And Methods: We analyzed PD-1 and PD-L1 using immunohistochemistry in patient-matched primary and metastatic tumors from 110 ccRCC patients. Concordance was assessed among longitudinal metastatic tumors, as well as across patient-matched primary and metastatic tumors. Cox proportional hazards regression was used to evaluate the associations of metastatic tumor expression with cancer-specific survival.

Results: We observed inter-metastatic tumor heterogeneity of PD-1 in 25 (69%) of the 36 patients and of PD-L1 in seven (19%) patients. Concordance between patient-matched primary and metastatic tumors was 73% (Kappa = 0.16, 95% CI: -0.003-0.32). Similarly, concordance of PD-L1 between metastatic and patient-matched primary tumors was 78% (Kappa = 0.27, 95% CI: 0.09-0.46). Both markers demonstrated higher expression in primary vs metastatic tumors. Metastatic tumor expression of PD-1 was significantly associated with metastatic location (P < .0001) and ccRCC-specific survival (HR = 2.15, 95% CI: 1.06-4.36, P = .035).

Conclusions: The expression of PD-1 and PD-L1 is discordant across patient-matched ccRCC tumors, with higher expression in primary tumors. Higher PD-1 expression was associated with metastatic location and lower cancer-specific survival. If validated, these results highlight the importance of evaluating these biomarkers in metastatic tissue specifically.
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http://dx.doi.org/10.1002/cam4.2769DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6997072PMC
February 2020

Molecular Inhibitor of QSOX1 Suppresses Tumor Growth .

Mol Cancer Ther 2020 01 1;19(1):112-122. Epub 2019 Oct 1.

School of Life Sciences, Arizona State University, Tempe, Arizona.

Quiescin sulfhydryl oxidase 1 (QSOX1) is an enzyme overexpressed by many different tumor types. QSOX1 catalyzes the formation of disulfide bonds in proteins. Because short hairpin knockdowns (KD) of QSOX1 have been shown to suppress tumor growth and invasion and , we hypothesized that chemical compounds inhibiting QSOX1 enzymatic activity would also suppress tumor growth, invasion, and metastasis. High throughput screening using a QSOX1-based enzymatic assay revealed multiple potential QSOX1 inhibitors. One of the inhibitors, known as "SBI-183," suppresses tumor cell growth in a Matrigel-based spheroid assay and inhibits invasion in a modified Boyden chamber, but does not affect viability of nonmalignant cells. Oral administration of SBI-183 inhibits tumor growth in 2 independent human xenograft mouse models of renal cell carcinoma. We conclude that SBI-183 warrants further exploration as a useful tool for understanding QSOX1 biology and as a potential novel anticancer agent in tumors that overexpress QSOX1.
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http://dx.doi.org/10.1158/1535-7163.MCT-19-0233DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6946859PMC
January 2020

In silico DNA methylation analysis identifies potential prognostic biomarkers in type 2 papillary renal cell carcinoma.

Cancer Med 2019 09 30;8(12):5760-5768. Epub 2019 Jul 30.

Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota.

There are currently no effective treatments for advanced-stage papillary renal cell carcinoma (PRCC). The goal of this study is to define potential DNA methylation-based markers and treatment targets for advanced-stage type 2 PRCC. Progressive DNA methylation changes and copy number variation (CNV) from localized to advanced-stage type 2 PRCC are analyzed by using methylation data generated by TCGA's kidney renal papillary cell carcinoma (TCGA-KIRP, 450k array) project. Survival analyses are performed for the identified biomarkers and genes with CNV. In addition, expression of the corresponding genes is investigated by RNA-seq analysis. Progressive methylation changes in several CpGs from localized to advanced-stage type 2 PRCC are observed. Four CpGs (cg00489401, cg27649239, cg20555674, and cg07196505) in particular are identified as markers for differentiating between localized and advanced-stage type 2 PRCC. Copy number analysis reveals that copy gain of PTK7 mostly occurs in advanced-stage type 2 PRCC. Both the four CpG methylation changes and PTK7 copy number gain are associated with patient survival. RNA-seq analysis demonstrates that PTK7 copy gain leads to higher PTK7 expression relative to tumors without copy number gain. Moreover, PTK7 is significantly upregulated from localized to advanced-stage type 2 PRCC and is linked to cancer cell invasion. In conclusion, DNA methylation markers that differentiate between localized and advanced-stage type 2 PRCC may serve as useful markers for disease staging or outcome, while PTK7 copy gain represents a potential treatment target for advanced-stage type 2 PRCC. Stepwise methylation changes and copy number gain also associate with disease stage in PRCC patients.
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http://dx.doi.org/10.1002/cam4.2402DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6745825PMC
September 2019

Role of robot-assisted retroperitoneal lymph node dissection in malignant mesothelioma of the tunica vaginalis: case series and review of the literature.

Can J Urol 2019 06;26(3):9752-9757

Department of Urology, Mayo Clinic Hospital, Phoenix, Arizona, USA.

Introduction: The management of malignant mesothelioma of the tunica vaginalis (MMTVT) is not clearly defined. Retroperitoneal lymph node dissection has been reported as a potential management option. Herein we present our experience with robot-assisted retroperitoneal lymph node dissection (RARPLND) in our series of patients with MMTVT.

Materials And Methods: The Mayo Clinic cancer registry was queried from 1972-present for all patients who had a diagnosis of MMTVT. Six patients were identified, five of whom were treated with RPLND, where four underwent RARPLND.

Results: In five patients who underwent RPLND, the median age was 50 years (IQR 34-51). Four patients originally presented with right sided symptomatic hydroceles, while one presented with right sided chronic epididymitis. Orchiectomy (one simple, two inguinal radical) was performed in three patients prior to presentation. Preoperative cross-sectional imaging, including PET-CT scan in three patients, was negative for lymphadenopathy or metastasis. RARPLND was performed in 4/5 (80%) cases and concomitant hemiscrotectomy in 4/5 (80%) cases. Full bilateral template was performed in three patients and right modified template was performed in the remaining two. Median lymph node yield was 29 (IQR 22-32) and median blood loss was 275 cc (IQR 200-300). Positive retroperitoneal lymph nodes were found in 3/5 (60%) cases. All patients who underwent RARPLND were discharged home on postoperative day one. Mean follow up was 27 months (range 3-47). No patients recurred.

Conclusions: Regardless of the approach, RPLND may provide a diagnostic benefit in patients who present with MMTVT, with the robotic approach affording a potentially expedited recovery.
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June 2019

Germ Cell Tumors with Malignant Somatic Transformation: A Mayo Clinic Experience.

Oncol Res Treat 2019 27;42(3):95-100. Epub 2019 Feb 27.

Background: Germ cell tumors (GCTs) with malignant somatic transformation (MST) represent an uncommon variant of what is typically a curable malignancy. There is a paucity of data on time of somatic transformation, response to conventional therapy, and survival outcomes of different somatic subtypes.

Methods: After obtaining institutional review board (IRB) approval, we searched our institutional database from 1982 to 2017 and identified patients with GCTs with MST. Patient characteristics, pathologic description, treatment, and clinical outcomes were extracted from the medical records.

Results: We identified 24 cases of GCTs with MST; the MST was adenocarcinoma in 50% and sarcoma in 50%. Median age at diagnosis was 27. Alpha-fetoprotein and beta-human chorionic gonadotropin were undetectable in 44%, both were elevated in 54%. The majority were advanced stage (71% stage III), and International Germ Cell Cancer Collaborative Group (IGCCCG) risk was classified as 'good' in 60%. Median follow-up was 41 months (range 10-346 months). Median progression-free survival was 84 months (95% confidence interval (CI) 56-232), and median overall survival was 219 months (95% CI 165-not reported).

Conclusion: Patients with GCTs with an MST appear to have poor responses to cisplatin-based chemotherapy, suggesting that somatic component-driven therapies should be considered. Furthermore, resection of residual disease when feasible is an essential component of management.
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http://dx.doi.org/10.1159/000495802DOI Listing
August 2019

Loss of SETD2 Induces a Metabolic Switch in Renal Cell Carcinoma Cell Lines toward Enhanced Oxidative Phosphorylation.

J Proteome Res 2019 01 27;18(1):331-340. Epub 2018 Nov 27.

Division of Hematology/Oncology , Mayo Clinic Arizona , Phoenix , Arizona 85054 , United States.

SETD2, a histone H3 lysine trimethyltransferase, is frequently inactivated and associated with recurrence of clear cell renal cell carcinoma (ccRCC). However, the impact of SETD2 loss on metabolic alterations in ccRCC is still unclear. In this study, SETD2 null isogenic 38E/38F clones derived from 786-O cells were generated by zinc finger nucleases, and subsequent metabolic, genomic, and cellular phenotypic changes were analyzed by targeted metabolomics, RNA sequencing, and biological methods, respectively. Our results showed that compared with parental 786-O cells, 38E/38F cells had elevated levels of MTT/Alamar blue levels, ATP, glycolytic/mitochondrial respiratory capacity, citrate synthase (CS) activity, and TCA metabolites such as aspartate, malate, succinate, fumarate, and α-ketoglutarate. The 38E/38F cells also utilized alternative sources beyond pyruvate to generate acetyl-CoA for the TCA cycle. Moreover, 38E/38F cells showed disturbed gene networks mainly related to mitochondrial metabolism and the oxidation of fatty acids and glucose, which was associated with increased PGC1α, mitochondrial mass, and cellular size/complexity. Our results indicate that SETD2 deficiency induces a metabolic switch toward enhanced oxidative phosphorylation in ccRCC, which can be related to PGC1α-mediated metabolic networks. Therefore, this current study lays the foundation for the further development of a global metabolic analysis of cancer cells in individual patients, which ultimately will have significant potential for the discovery of novel therapeutics and precision medicine in SETD2-inactivated ccRCC.
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http://dx.doi.org/10.1021/acs.jproteome.8b00628DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6465098PMC
January 2019

Trends in Renal-Cell Carcinoma Incidence and Mortality in the United States in the Last 2 Decades: A SEER-Based Study.

Clin Genitourin Cancer 2019 Feb 11;17(1):46-57.e5. Epub 2018 Oct 11.

Mayo Clinic Cancer Center, Phoenix, AZ. Electronic address:

Background: Renal-cell carcinoma (RCC) is one of the common malignancies in the United States. RCC incidence and mortality have been changing for many reasons. We performed a thorough investigation of incidence and mortality trends of RCC in the United States using the cell Surveillance, Epidemiology, and End Results (SEER) database.

Patients And Methods: The 13 SEER registries were accessed for RCC cases diagnosed between 1992 and 2015. Incidence and mortality were calculated by demographic and tumor characteristics. We calculated annual percentage changes of these rates. Rates were expressed as 100,000 person-years.

Results: A total of 104,584 RCC cases were reviewed, with 47,561 deaths. The overall incidence was 11.281 per 100,000 person-years. Incidence increased by 2.421% per year (95% confidence interval, 2.096, 2.747; P < .001) but later became stable since 2008. However, the incidence of clear-cell subtype continued to increase (1.449%; 95% confidence interval, 0.216, 2.697; P = .024). RCC overall mortality rates have been declining since 2001. However, mortality associated with distant RCC only started to decrease in 2012, with an annual percentage change of 18.270% (95% confidence interval, -28.775, -6.215; P = .006).

Conclusion: Despite an overall increase in the incidence of RCC, there has been a recent plateau in RCC incidence rates with a significant decrease in mortality.
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http://dx.doi.org/10.1016/j.clgc.2018.10.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6348014PMC
February 2019

Adjuvant Antiangiogenic Agents in Post-nephrectomy Renal Cell Carcinoma: A Systematic Review and Meta-analysis.

Eur Urol Oncol 2018 Jun 15;1(2):101-108. Epub 2018 Mar 15.

Mayo Clinic Cancer Center, Mayo Clinic, Phoenix. AZ, USA.

Context: The role of antiangiogenic agents in advanced renal cell carcinoma (RCC) is well established. However, it is still not clear whether this benefit can be extrapolated to the adjuvant setting.

Objective: To determine the efficacy and safety of antiangiogenic agents in patients with RCC and a high risk of relapse after nephrectomy.

Evidence Acquisition: We searched PubMed, Embase, and the Cochrane Central Register of Controlled Trials for randomized controlled trials (RCTs) evaluating the use of any oral antiangiogenic agent compared to placebo in post-nephrectomy RCC patients. Prespecified data elements were extracted from each trial. Outcomes of interest included overall survival (OS) and disease-free survival (DFS). The overall effect was pooled using the DerSimonian and Laird random-effects models.

Evidence Synthesis: Three RCTs comparing antiangiogenics to placebo among 3693 patients met our inclusion criteria and were used in meta-analyses. Overall, antiangiogenics did not improve DFS (hazard ratio [HR] 0.92, 95% confidence interval [CI] 0.78-1.07) or OS (HR 0.99, 95% CI 0.79-1.25). These results persisted when restricting the analysis to patients with clear cell carcinoma and patients with highest risk of relapse. Similarly, sunitinib did not show any improvement in the entire cohort for either DFS (HR 0.89, 95% CI 0.67-1.19) or OS (HR 1.11, 95% CI 0.90-1.37).

Conclusions: In this meta-analysis, antiangiogenics did not improve OS and DFS over placebo in high-risk RCC after nephrectomy. Further studies are needed to identify the patient population that might derive a benefit from antiangiogenics in the adjuvant setting.

Patient Summary: In this article, we found that there is currently insufficient evidence to support the use of oral antiangiogenics in nonmetastatic renal cell carcinoma after nephrectomy. In addition, the use of oral antiangiogenics was associated with a 2.7-fold higher rate of significant side effects compared to placebo.
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http://dx.doi.org/10.1016/j.euo.2018.03.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6192050PMC
June 2018

Behavior of blood plasma glycan features in bladder cancer.

PLoS One 2018 24;13(7):e0201208. Epub 2018 Jul 24.

School of Molecular Sciences, Arizona State University, Tempe, AZ, United States of America.

Despite systemic therapy and cystectomy, bladder cancer is characterized by a high recurrence rate. Serum glycomics represents a promising source of prognostic markers for monitoring patients. Our approach, which we refer to as "glycan node analysis", constitutes the first example of molecularly "bottom-up" glycomics. It is based on a global glycan methylation analysis procedure that is applied to whole blood plasma/serum. The approach detects and quantifies partially methylated alditol acetates arising from unique glycan features such as α2-6 sialylation, β1-4 branching, and core fucosylation that have been pooled together from across all intact glycans within a sample into a single GC-MS chromatographic peak. We applied this method to 122 plasma samples from former and current bladder cancer patients (n = 72 former cancer patients with currently no evidence of disease (NED); n = 38 non-muscle invasive bladder cancer (NMIBC) patients; and n = 12 muscle invasive bladder cancer (MIBC) patients) along with plasma from 30 certifiably healthy living kidney donors. Markers for α2-6 sialylation, β1-4 branching, β1-6 branching, and outer-arm fucosylation were able to separate current and former (NED) cases from certifiably healthy controls (ROC curve c-statistics ~ 0.80); but NED, NMIBC, and MIBC were not distinguished from one another. Based on the unexpectedly high levels of these glycan nodes in the NED patients, we hypothesized that recurrence of this disease could be predicted by some of the elevated glycan features. Indeed, α2-6 sialylation and β1-6 branching were able to predict recurrence from the NED state using a Cox proportional hazards regression model adjusted for age, gender, and time from cancer. The levels of these two glycan features were correlated to C-reactive protein concentration, an inflammation marker and known prognostic indicator for bladder cancer, further strengthening the link between inflammation and abnormal plasma protein glycosylation.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0201208PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6057681PMC
January 2019

Quantitative Spatial Profiling of PD-1/PD-L1 Interaction and HLA-DR/IDO-1 Predicts Improved Outcomes of Anti-PD-1 Therapies in Metastatic Melanoma.

Clin Cancer Res 2018 11 18;24(21):5250-5260. Epub 2018 Jul 18.

Navigate BioPharma Services, Inc., a Novartis Subsidiary, Carlsbad, California.

PD-1/L1 axis-directed therapies produce clinical responses in a subset of patients; therefore, biomarkers of response are needed. We hypothesized that quantifying key immunosuppression mechanisms within the tumor microenvironment by multiparameter algorithms would identify strong predictors of anti-PD-1 response. Pretreatment tumor biopsies from 166 patients treated with anti-PD-1 across 10 academic cancer centers were fluorescently stained with multiple markers in discovery ( = 24) and validation ( = 142) cohorts. Biomarker-positive cells and their colocalization were spatially profiled in pathologist-selected tumor regions using novel Automated Quantitative Analysis algorithms. Selected biomarker signatures, PD-1/PD-L1 interaction score, and IDO-1/HLA-DR coexpression were evaluated for anti-PD-1 treatment outcomes. In the discovery cohort, PD-1/PD-L1 interaction score and/or IDO-1/HLA-DR coexpression was strongly associated with anti-PD-1 response ( = 0.0005). In contrast, individual biomarkers (PD-1, PD-L1, IDO-1, HLA-DR) were not associated with response or survival. This finding was replicated in an independent validation cohort: patients with high PD-1/PD-L1 and/or IDO-1/HLA-DR were more likely to respond ( = 0.0096). These patients also experienced significantly improved progression-free survival (HR = 0.36; = 0.0004) and overall survival (HR = 0.39; = 0.0011). In the combined cohort, 80% of patients exhibiting higher levels of PD-1/PD-L1 interaction scores and IDO-1/HLA-DR responded to PD-1 blockers ( = 0.000004). In contrast, PD-L1 expression was not predictive of survival. Quantitative spatial profiling of key tumor-immune suppression pathways by novel digital pathology algorithms could help more reliably select melanoma patients for PD-1 monotherapy. .
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http://dx.doi.org/10.1158/1078-0432.CCR-18-0309DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6214750PMC
November 2018

The Impact of Pazopanib on the Cardiovascular System.

J Cardiovasc Pharmacol Ther 2018 09 29;23(5):387-398. Epub 2018 Apr 29.

1 Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH, USA.

Pazopanib is an approved treatment for renal cell carcinoma and a second-line treatment for nonadipocytic soft-tissue sarcoma. However, its clinical efficacy is limited by its cardiovascular side effects. Pazopanib and other vascular endothelial growth factor receptor tyrosine kinase inhibitors have been associated with the development of hypertension, QT interval prolongation, and other cardiovascular events; however, these mechanisms are largely unknown. Gaining a deeper understanding of these mechanisms is essential for the development of appropriate surveillance strategies and possible diagnostic biomarkers to allow us to monitor patients and modulate therapy prior to significant cardiac insult. This approach will be vital in keeping patients on these life-saving therapies and may be applicable to other tyrosine kinase inhibitors as well. In this review, we provide a comprehensive overview of the preclinical and clinical side effects of pazopanib with a focus on the mechanisms responsible for its toxicity to the cardiovascular system.
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http://dx.doi.org/10.1177/1074248418769612DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6257996PMC
September 2018

The Cancer Genome Atlas Comprehensive Molecular Characterization of Renal Cell Carcinoma.

Cell Rep 2018 04;23(1):313-326.e5

Leukemia Therapeutics LLC., Hull, MA 02045, USA.

Renal cell carcinoma (RCC) is not a single disease, but several histologically defined cancers with different genetic drivers, clinical courses, and therapeutic responses. The current study evaluated 843 RCC from the three major histologic subtypes, including 488 clear cell RCC, 274 papillary RCC, and 81 chromophobe RCC. Comprehensive genomic and phenotypic analysis of the RCC subtypes reveals distinctive features of each subtype that provide the foundation for the development of subtype-specific therapeutic and management strategies for patients affected with these cancers. Somatic alteration of BAP1, PBRM1, and PTEN and altered metabolic pathways correlated with subtype-specific decreased survival, while CDKN2A alteration, increased DNA hypermethylation, and increases in the immune-related Th2 gene expression signature correlated with decreased survival within all major histologic subtypes. CIMP-RCC demonstrated an increased immune signature, and a uniform and distinct metabolic expression pattern identified a subset of metabolically divergent (MD) ChRCC that associated with extremely poor survival.
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http://dx.doi.org/10.1016/j.celrep.2018.03.075DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6075733PMC
April 2018

Inhibition of intracellular lipolysis promotes human cancer cell adaptation to hypoxia.

Elife 2017 12 19;6. Epub 2017 Dec 19.

Department of Biochemistry and Molecular Biology, Mayo Clinic in Arizona, Scottsdale, United States.

Tumor tissues are chronically exposed to hypoxia owing to aberrant vascularity. Lipid droplet (LD) accumulation is a hallmark of hypoxic cancer cells, yet how LDs form and function during hypoxia remains poorly understood. Herein, we report that in various cancer cells upon oxygen deprivation, HIF-1 activation down-modulates LD catabolism mediated by adipose triglyceride lipase (ATGL), the key enzyme for intracellular lipolysis. Proteomics and functional analyses identified hypoxia-inducible gene 2 (HIG2), a HIF-1 target, as a new inhibitor of ATGL. Knockout of HIG2 enhanced LD breakdown and fatty acid (FA) oxidation, leading to increased ROS production and apoptosis in hypoxic cancer cells as well as impaired growth of tumor xenografts. All of these effects were reversed by co-ablation of ATGL. Thus, by inhibiting ATGL, HIG2 acts downstream of HIF-1 to sequester FAs in LDs away from the mitochondrial pathways for oxidation and ROS generation, thereby sustaining cancer cell survival in hypoxia.
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http://dx.doi.org/10.7554/eLife.31132DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5739538PMC
December 2017

Pazopanib for renal cell carcinoma leads to elevated mean arterial pressures in a murine model.

Clin Exp Hypertens 2018 27;40(6):524-533. Epub 2017 Nov 27.

a Department of Internal Medicine (Division of Cardiology) , The Ohio State University College of Medicine , Columbus , OH , USA.

Background: In the setting of metastatic RCC (mRCC), pazopanib is approved as first line therapy. Unfortunately treatment may lead to cardiotoxicity such as hypertension, heart failure, and myocardial ischemia.

Objective: Define the in vivo role of pazopanib in the development of cardiotoxicity.

Methods: Wild type mice were dosed for 42 days via oral gavage, and separated into control and treatment (pazopanib) groups. Baseline ECG's, echocardiograms, and blood pressures were recorded. At the conclusion of the study functional parameters were again recorded, and animals were used for pathological, histological, and protein analysis.

Results: After 2 weeks of dosing with pazopanib, the treatment group exhibited a statistically significant increase in mean arterial pressure compared to control mice (119 ± 11.7 mmHg versus 108 ± 8.2 mmHg, p = 0.049). Treatment with pazopanib led to a significant reduction in the cardiac output of mice.

Conclusion: Our findings in mice clearly demonstrate that treatment with pazopanib leads to a significant elevation in blood pressure after 2 weeks of dosing and this persists for the duration of dosing. The continued development of the cardio-oncology field will be paramount in providing optimal oncologic care while simultaneously improving cardiac outcomes through further investigation into the mechanisms of CV toxicity.
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http://dx.doi.org/10.1080/10641963.2017.1403623DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6203326PMC
October 2018

Stage Dependence, Cell-Origin Independence, and Prognostic Capacity of Serum Glycan Fucosylation, β1-4 Branching, β1-6 Branching, and α2-6 Sialylation in Cancer.

J Proteome Res 2018 01 21;17(1):543-558. Epub 2017 Nov 21.

School of Molecular Sciences, Arizona State University , Tempe, Arizona 85287, United States.

Glycans represent a promising but only marginally accessed source of cancer markers. We previously reported the development of a molecularly bottom-up approach to plasma and serum (P/S) glycomics based on glycan linkage analysis that captures features such as α2-6 sialylation, β1-6 branching, and core fucosylation as single analytical signals. Based on the behavior of P/S glycans established to date, we hypothesized that the alteration of P/S glycans observed in cancer would be independent of the tissue in which the tumor originated yet exhibit stage dependence that varied little between cancers classified on the basis of tumor origin. Herein, the diagnostic utility of this bottom-up approach as applied to lung cancer patients (n = 127 stage I; n = 20 stage II; n = 81 stage III; and n = 90 stage IV) as well as prostate (n = 40 stage II), serous ovarian (n = 59 stage III), and pancreatic cancer patients (n = 15 rapid autopsy) compared to certifiably healthy individuals (n = 30), nominally healthy individuals (n = 166), and risk-matched controls (n = 300) is reported. Diagnostic performance in lung cancer was stage-dependent, with markers for terminal (total) fucosylation, α2-6 sialylation, β1-4 branching, β1-6 branching, and outer-arm fucosylation most able to differentiate cases from controls. These markers behaved in a similar stage-dependent manner in other types of cancer as well. Notable differences between certifiably healthy individuals and case-matched controls were observed. These markers were not significantly elevated in liver fibrosis. Using a Cox proportional hazards regression model, the marker for α2-6 sialylation was found to predict both progression and survival in lung cancer patients after adjusting for age, gender, smoking status, and stage. The potential mechanistic role of aberrant P/S glycans in cancer progression is discussed.
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http://dx.doi.org/10.1021/acs.jproteome.7b00672DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5978412PMC
January 2018

Correlation Between Molecular Subclassifications of Clear Cell Renal Cell Carcinoma and Targeted Therapy Response.

Eur Urol Focus 2016 Jun 9;2(2):204-209. Epub 2015 Dec 9.

Department of Medical Oncology and Experimental Therapeutics, City of Hope Comprehensive Cancer Center, Duarte, CA, USA. Electronic address:

Background: Vascular endothelial growth factor (VEGF) and mammalian target of rapamycin (mTOR)-directed therapies are the standard of care in metastatic clear cell renal cell carcinoma (mccRCC) but are not used based on molecular subclassifications of ccRCC.

Objective: To determine if an association exists between genomic alterations (GAs) detected by comprehensive genomic profiling (CGP) in the course of clinical care and the response to anti-VEGF receptor (VEGFR) and anti-MTOR pathway targeted therapies in a cohort of patients with treated mccRCC.

Design, Setting, And Participants: CGP, using a Clinical Laboratory Improvement Amendments-certified platform, was performed on 31 formalin-fixed, paraffin-embedded tissue specimens (84% from cytoreductive nephrectomies) obtained from patients with metastatic renal cell carcinoma who had received VEGFR and/or mTOR inhibitors. Duration of treatment (DOT) and extent and duration of clinical response were obtained from review of medical records.

Outcome Measurements And Statistical Analysis: All classes of GAs-base substitutions, short insertions, deletions, gene fusions, rearrangements, and copy number-were assessed via hybrid capture-based CGP. Descriptive statistics were used to determine the frequency of GAs in groups segregated by the DOT with VEGF-directed agents.

Results And Limitations: The most common GAs detected in this series were in VHL (70%), PBRM1 (48%), SETD2 (32%), TSC1 (29%), MLL (19%), TERT (16%), ARID1B (16%), and KDM5C (16%). Across 61 administrations of VEGF-directed therapy in 27 patients, exceptional responses (DOT >21 mo) were more frequent among patients with GAs in KDM5C, PBRM1, and VHL. Conversely, these patients also featured a lower frequency of GA associated with response to mTOR-directed therapy, such as TSC1.

Conclusions: Molecular subclassifications may affect response to VEGF-directed therapy. The predictive and prognostic nature of these molecular subclassifications in the metastatic setting should be explored in an extended series.

Patient Summary: Comprehensive genomic profiling in the course of clinical care in the community oncology setting can delineate subgroups of patients with advanced kidney cancer who stand to benefit more from specific molecular-targeted agents.
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http://dx.doi.org/10.1016/j.euf.2015.11.007DOI Listing
June 2016

Validation of Gene Expression Signatures to Identify Low-risk Clear-cell Renal Cell Carcinoma Patients at Higher Risk for Disease-related Death.

Eur Urol Focus 2016 Dec 2;2(6):608-615. Epub 2016 Apr 2.

Division of Hematology and Oncology and Cancer Center and Breast Clinic, Mayo Clinic, Jacksonville, FL, USA. Electronic address:

Background: Approximately 5-10% of patients with "low-risk" clear cell renal cell carcinoma (ccRCC), as stratified by externally validated clinicopathologic prognostic algorithms, eventually have disease relapse and die. Improving prognostic algorithms for these low-risk patients could help to provide improved individualized surveillance recommendations.

Objective: To identify genes that are differentially expressed in patients with low-risk ccRCC who did and did not die of their disease.

Design, Setting, And Participants: Using the Mayo Clinic Renal Registry, we identified formalin-fixed paraffin-embedded samples from patients with low-risk ccRCC, as defined by Mayo Clinic stage, size, grade, and necrosis score of 0-3. We conducted a nested case-control study between patients who did (cases) and did not (controls) have ccRCC relapse and death, using two independent sets (discovery and validation). We performed RNA sequencing of all samples in the discovery set to identify differentially expressed genes. In the independent validation set, we assessed the top 50 expressed genes using the nCounter Analysis System (NanoString Technologies, Seattle, WA, USA).

Results And Limitations: In the discovery set of 24 cases and 24 controls, 92 genes were differentially expressed with p<0.001. The top 50 genes were validated in an independent set of 22 cases and 22 controls using linear mixed models. In the validation set, 10 genes remained differentially expressed between the groups.

Conclusions: RNA signatures from formalin-fixed paraffin-embedded blocks can identify patients with low-risk ccRCC who die of their disease. This finding provides an opportunity to help guide improved surveillance in patients with low-risk ccRCC.

Patient Summary: In the current study we identified RNA signatures from low-risk clear cell renal cell carcinoma patients who died from this disease. Improving prognostic algorithms for these low-risk patients could help to provide improved individualized surveillance recommendations.
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http://dx.doi.org/10.1016/j.euf.2016.03.008DOI Listing
December 2016

Factors Associated With Survival Following Radium-223 Treatment for Metastatic Castration-resistant Prostate Cancer.

Clin Genitourin Cancer 2017 12 26;15(6):e969-e975. Epub 2017 Apr 26.

Department of Radiation Oncology, Mayo Clinic Arizona, Phoenix, AZ.

Background: Radium-223 (Ra) improves survival in patients with metastatic castration-resistant prostate cancer (mCRPC). This retrospective analysis was performed to better understand its efficacy in routine clinical practice and identify factors associated with survival.

Materials And Methods: Sixty-four patients with mCRPC who received Ra between 2013 and 2015 were the basis of this retrospective study. Clinical outcomes and patient characteristics were obtained. Potential prognostic factors for survival were evaluated by univariate analysis using the log-rank test and multivariate analysis using the Cox proportional hazard method.

Results: The median survival was 12.9 months. Twenty-one patients (33%) developed a skeletal event, and the median time to the first skeletal event was 4.4 months. In univariate analysis, factors significantly associated with survival included: no prior chemotherapy, ≤ 5 bone metastases, baseline prostate-specific antigen (PSA) ≤ 36 ng/mL, baseline alkaline phosphatase (ALP) < 115 U/L, baseline hemoglobin > 12 g/dL, ALP response after Ra treatment, PSA decrease during Ra treatment, and absence of > 25% PSA increase during Ra treatment. In multivariate analysis, 4 factors remained significant: no prior chemotherapy, ≤ 5 bone metastases, baseline ALP < 115 U/L, and ALP response after Ra treatment.

Conclusion: When Ra is administered in routine clinical practice, clinical outcomes can be more variable than those reported in the randomized study owing to patient heterogeneity. Four factors were identified to be significantly associated with survival after Ra treatment. These pretreatment factors may be used as stratification factors in future studies to investigate whether Ra would be more effective for patients with newly diagnosed metastatic disease that is sensitive to androgen deprivation therapy.
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http://dx.doi.org/10.1016/j.clgc.2017.04.016DOI Listing
December 2017
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