Publications by authors named "James Brugarolas"

106 Publications

Neoadjuvant SABR for Renal Cell Carcinoma Inferior Vena Cava Tumor Thrombus-Safety Lead-in Results of a Phase 2 Trial.

Int J Radiat Oncol Biol Phys 2021 Feb 5. Epub 2021 Feb 5.

Kidney Cancer Program, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas; Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, Texas. Electronic address:

Purpose: To evaluate the feasibility, safety, oncologic outcomes, and immune effect of neoadjuvant stereotactic radiation (Neo-SAbR) followed by radical nephrectomy and thrombectomy (RN-IVCT).

Methods And Materials: These are results from the safety lead-in portion of a single-arm phase 1 and 2 trial. Patients with kidney cancer (renal cell carcinoma [RCC]) and inferior vena cava (IVC) tumor thrombus (TT) underwent Neo-SAbR (40 Gy in 5 fractions) to the IVC-TT followed by open RN-IVCT. Absence of grade 4 to 5 adverse events (AEs) within 90 days of RN-IVCT was the primary endpoint. Exploratory studies included pathologic and immunologic alterations attributable to SAbR.

Results: Six patients were included in the final analysis. No grade 4 to 5 AEs were observed. A total of 81 AEs were reported within 90 days of surgery: 73% (59/81) were grade 1, 23% (19/81) were grade 2, and 4% (3/81) were grade 3. After a median follow-up of 24 months, all patients are alive. One patient developed de novo metastatic disease. Of 3 patients with metastasis at diagnosis, 1 had a complete and another had a partial abscopal response without the concurrent use of systemic therapy. Neo-SABR led to decreased Ki-67 and increased PD-L1 expression in the IVC-TT. Inflammatory cytokines and autoantibody titers reflecting better host immune status were observed in patients with nonprogressive disease.

Conclusions: Neo-SAbR followed by RN-IVCT for RCC IVC-TT is feasible and safe. Favorable host immune environment correlated with abscopal response to SABR and RCC relapse-free survival, though direct causal relation to SABR has yet to be established.
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http://dx.doi.org/10.1016/j.ijrobp.2021.01.054DOI Listing
February 2021

Summary from the Kidney Cancer Association's Inaugural Think Thank: Coalition for a Cure.

Clin Genitourin Cancer 2020 Nov 14. Epub 2020 Nov 14.

Urologic Oncology Branch, Center for Cancer Research, Mayo Clinic, Rochester, MN.

Close to 74,000 cases of renal cell carcinoma (RCC) are diagnosed each year in the United States. The past 2 decades have shown great developments in surgical techniques, targeted therapy and immunotherapy agents, and longer complete response rates. However, without a global cure, there is still room for further advancement in improving patient care in this space. To address some of the gaps restricting this progress, the Kidney Cancer Association brought together a group of 27 specialists across the areas of clinical care, research, industry, and advocacy at the inaugural "Think Tank: Coalition for a Cure" session. Topics addressed included screening, imaging, rarer RCC subtypes, combination drug therapy options, and patient response. This commentary summarizes the discussion of these topics and their respective clinical challenges, along with a proposal of projects for collaboration in overcoming those needs and making a greater impact on care for patients with RCC moving forward.
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http://dx.doi.org/10.1016/j.clgc.2020.10.005DOI Listing
November 2020

Complement as Prognostic Biomarker and Potential Therapeutic Target in Renal Cell Carcinoma.

J Immunol 2020 12 6;205(11):3218-3229. Epub 2020 Nov 6.

Department of Immunotherapeutics and Biotechnology, School of Pharmacy, Texas Tech University Health Sciences Center, Abilene, TX 79601;

Preclinical studies demonstrated that complement promotes tumor growth. Therefore, we sought to determine the best target for complement-based therapy among common human malignancies. High expression of 11 complement genes was linked to unfavorable prognosis in renal cell carcinoma. Complement protein expression or deposition was observed mainly in stroma, leukocytes, and tumor vasculature, corresponding to a role of complement in regulating the tumor microenvironment. Complement abundance in tumors correlated with a high nuclear grade. Complement genes clustered within an aggressive inflammatory subtype of renal cancer characterized by poor prognosis, markers of T cell dysfunction, and alternatively activated macrophages. Plasma levels of complement proteins correlated with response to immune checkpoint inhibitors. Corroborating human data, complement deficiencies and blockade reduced tumor growth by enhancing antitumor immunity and seemingly reducing angiogenesis in a mouse model of kidney cancer resistant to PD-1 blockade. Overall, this study implicates complement in the immune landscape of renal cell carcinoma, and notwithstanding cohort size and preclinical model limitations, the data suggest that tumors resistant to immune checkpoint inhibitors might be suitable targets for complement-based therapy.
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http://dx.doi.org/10.4049/jimmunol.2000511DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7703597PMC
December 2020

The Evolution of Angiogenic and Inflamed Tumors: The Renal Cancer Paradigm.

Cancer Cell 2020 Dec 5;38(6):771-773. Epub 2020 Nov 5.

Kidney Cancer Program, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address:

Gene expression analyses have identified subtypes of conventional renal cell carcinoma broadly distributed into angiogenic and proliferative/ immunogenic clades. Integration with genomic and functional experiments in animal models yields an evolutionary model. Evolutionary trajectories illustrate remarkable plasticity, particularly for a tumor that typically begins with inactivation of a single gene.
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http://dx.doi.org/10.1016/j.ccell.2020.10.021DOI Listing
December 2020

Acute interstitial nephritis, a potential predictor of response to immune checkpoint inhibitors in renal cell carcinoma.

J Immunother Cancer 2020 10;8(2)

Department of Internal Medicine, University of Texas Southwestern, Dallas, Texas, USA

Immune checkpoint inhibitors (ICIs) such as nivolumab and ipilimumab have improved outcomes in metastatic renal cell carcinoma (mRCC) patients, but they are also associated with immune-related adverse events (irAEs). As observed in melanoma, we hypothesized that patients experiencing an autoimmune reaction directed against the tissue of origin may be more likely to benefit from ICI. Specifically, we asked whether patients with immune-related acute interstitial nephritis (irAIN) exhibited improved outcomes. Using Kidney Cancer Explorer (KCE), a data portal and i2b2-based central database for clinical, pathological and experimental genetic data, we systematically identified all patients with mRCC at UT Southwestern Medical Center (UTSW) from 2014-2018 who received at least one dose of ICI. More recent cases were identified through a provider query. We extracted creatinine (Cr) values at baseline and over the entirety of each patient ICI treatment course using KCE. Patients with ≥ 1.5-fold Cr increase over baseline were investigated. The likelihood of irAIN was determined based on the work-up (biopsy, if available), or by clinical criteria (timing of kidney injury, exclusion of other etiologies, treatment with immunosuppressants and response). We identified 177 mRCC patients who received at least one dose of ICI, 36 of whom had ≥ 1.5-fold increase in Cr over baseline while on treatment. Of those, two had biopsy-proven irAIN and one was clinically diagnosed, resulting in an incidence of 1.7%. One additional biopsy-proven case past 2018 was identified through a provider query, for a total of four patients. Two received combination nivolumab and ipilimumab in the first line, whereas the remaining received nivolumab after first line therapy. irAIN onset ranged from 1.5 to 12 months. All four patients stopped ICI with recovery of renal function, at least partially, three after receiving systemic steroids. Notably, all four patients had a deep response. In conclusion, irAIN is a rare event, but it may portend a higher likelihood of response. One possible explanation is antigenic overlap between normal renal tubular cells and tumor cells.
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http://dx.doi.org/10.1136/jitc-2020-001198DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7607606PMC
October 2020

Checking the Hippo in Sarcomatoid Renal Cell Carcinoma with Immunotherapy.

Clin Cancer Res 2021 Jan 26;27(1):5-7. Epub 2020 Oct 26.

Department of Medicine, Duke University, Durham, North Carolina.

Subset analysis of patients with sarcomatoid renal cell carcinoma (sRCC) included in the CheckMate 214 trial of ipilimumab-nivolumab versus sunitinib showed improved outcomes in sRCC with ipilimumab-nivolumab. The use of checkpoint inhibitor-based regimens in sRCC, for which therapeutic options were once limited, is further supported by additional clinical trials..
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http://dx.doi.org/10.1158/1078-0432.CCR-20-3506DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7785667PMC
January 2021

The von Hippel-Lindau Tumor Suppressor Gene: Implications and Therapeutic Opportunities.

Cancer J 2020 Sep/Oct;26(5):390-398

From the Kidney Cancer Program, Simmons Comprehensive Cancer Center.

The discovery of the von Hippel-Lindau (VHL) gene marked a milestone in our understanding of clear cell renal cell carcinoma (ccRCC) pathogenesis. VHL inactivation is not only a defining feature of ccRCC, but also the initiating event. Herein, we discuss canonical and noncanonical pVHL functions, as well as breakthroughs shaping our understanding of ccRCC evolution and evolutionary subtypes. We conclude by presenting evolving strategies to therapeutically exploit effector mechanisms downstream of pVHL.
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http://dx.doi.org/10.1097/PPO.0000000000000480DOI Listing
September 2020

De novo prediction of cancer-associated T cell receptors for noninvasive cancer detection.

Sci Transl Med 2020 08;12(557)

Lyda Hill Department of Bioinformatics, UT Southwestern Medical Center, Dallas, TX 75390, USA.

The adaptive immune system recognizes tumor antigens at an early stage to eradicate cancer cells. This process is accompanied by systemic proliferation of the tumor antigen-specific T lymphocytes. While detection of asymptomatic early-stage cancers is challenging due to small tumor size and limited somatic alterations, tracking peripheral T cell repertoire changes may provide an attractive solution to cancer diagnosis. Here, we developed a deep learning method called DeepCAT to enable de novo prediction of cancer-associated T cell receptors (TCRs). We validated DeepCAT using cancer-specific or non-cancer TCRs obtained from multiple major histocompatibility complex I (MHC-I) multimer-sorting experiments and demonstrated its prediction power for TCRs specific to cancer antigens. We blindly applied DeepCAT to distinguish over 250 patients with cancer from over 600 healthy individuals using blood TCR sequences and observed high prediction accuracy, with area under the curve (AUC) ≥ 0.95 for multiple early-stage cancers. This work sets the stage for using the peripheral blood TCR repertoire for noninvasive cancer detection.
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http://dx.doi.org/10.1126/scitranslmed.aaz3738DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7887928PMC
August 2020

Biological Mechanisms and Clinical Significance of Mutations in Human Cancer.

Cancer Discov 2020 Aug 20;10(8):1103-1120. Epub 2020 Jul 20.

University of Hawai'i Cancer Center, Honolulu, Hawai'i.

Among more than 200 -mutant families affected by the "BAP1 cancer syndrome," nearly all individuals inheriting a mutant allele developed one or more malignancies during their lifetime, mostly uveal and cutaneous melanoma, mesothelioma, and clear-cell renal cell carcinoma. These cancer types are also those that, when they occur sporadically, are more likely to carry somatic biallelic mutations. Mechanistic studies revealed that the tumor suppressor function of BAP1 is linked to its dual activity in the nucleus, where it is implicated in a variety of processes including DNA repair and transcription, and in the cytoplasm, where it regulates cell death and mitochondrial metabolism. BAP1 activity in tumor suppression is cell type- and context-dependent. BAP1 has emerged as a critical tumor suppressor across multiple cancer types, predisposing to tumor development when mutated in the germline as well as somatically. Moreover, has emerged as a key regulator of gene-environment interaction..
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http://dx.doi.org/10.1158/2159-8290.CD-19-1220DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8006752PMC
August 2020

Magnetic Resonance Imaging Radiomics Analyses for Prediction of High-Grade Histology and Necrosis in Clear Cell Renal Cell Carcinoma: Preliminary Experience.

Clin Genitourin Cancer 2021 Feb 23;19(1):12-21.e1. Epub 2020 May 23.

Department of Radiology, UT Southwestern Medical Center, Dallas, TX; Department of Urology, UT Southwestern Medical Center, Dallas, TX; Kidney Cancer Program, UT Southwestern Medical Center, Dallas, TX; Advanced Imaging Research Center, UT Southwestern Medical Center, Dallas, TX. Electronic address:

Introduction: Percutaneous renal mass biopsy results can accurately diagnose clear cell renal cell carcinoma (ccRCC); however, their reliability to determine nuclear grade in larger, heterogeneous tumors is limited. We assessed the ability of radiomics analyses of magnetic resonance imaging (MRI) to predict high-grade (HG) histology in ccRCC.

Patients And Methods: Seventy patients with a renal mass underwent 3 T MRI before surgery between August 2012 and August 2017. Tumor length, first-order statistics, and Haralick texture features were calculated on T2-weighted and dynamic contrast-enhanced (DCE) MRI after manual tumor segmentation. After a variable clustering algorithm was applied, tumor length, washout, and all cluster features were evaluated univariably by receiver operating characteristic curves. Three logistic regression models were constructed to assess the predictability of HG ccRCC and then cross-validated.

Results: At univariate analysis, area under the curve values of length, and DCE texture cluster 1 and cluster 3 for diagnosis of HG ccRCC were 0.7 (95% confidence interval [CI], 0.58-0.82, false discovery rate P = .008), 0.72 (95% CI, 0.59-0.84, false discovery rate P = .004), and 0.75 (95% CI, 0.63-0.87, false discovery rate P = .0009), respectively. At multivariable analysis, area under the curve for model 1 (tumor length only), model 2 (length + DCE clusters 3 and 4), and model 3 (DCE cluster 1 and 3) for diagnosis of HG ccRCC were 0.67 (95% CI, 0.54-0.79), 0.82 (95% CI, 0.71-0.92), and 0.81 (95% CI, 0.70-0.91), respectively.

Conclusion: Radiomics analysis of MRI images was superior to tumor size for the prediction of HG histology in ccRCC in our cohort.
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http://dx.doi.org/10.1016/j.clgc.2020.05.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7680717PMC
February 2021

Corrigendum to ''Ontological analyses reveal clinically-significant clear cell renal cell carcinoma subtypes with convergent evolutionary trajectories into an aggressive type'' [EBioMedicine 51 (2020) 102526].

EBioMedicine 2020 05 24;55:102707. Epub 2020 Apr 24.

Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390, United States; Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX 75390, United States; Kidney Cancer Program, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, United States. Electronic address:

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http://dx.doi.org/10.1016/j.ebiom.2020.102707DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7184150PMC
May 2020

Pancreatic tropism of metastatic renal cell carcinoma.

JCI Insight 2020 04 9;5(7). Epub 2020 Apr 9.

Kidney Cancer Program, Simmons Comprehensive Cancer Center.

Renal cell carcinoma (RCC) is characterized by a particularly broad metastatic swath, and, enigmatically, when the pancreas is a destination, the disease is associated with improved survival. Intrigued by this observation, we sought to characterize the clinical behavior, therapeutic implications, and underlying biology. While pancreatic metastases (PM) are infrequent, we identified 31 patients across 2 institutional cohorts and show that improved survival is independent of established prognostic variables, that these tumors are exquisitely sensitive to antiangiogenic agents and resistant to immune checkpoint inhibitors (ICIs), and that they are characterized by a distinctive biology. Primary tumors of patients with PM exhibited frequent PBRM1 mutations, 3p loss, and 5q amplification, along with a lower frequency of aggressive features such as BAP1 mutations and loss of 9p, 14q, and 4q. Gene expression analyses revealed constrained evolution with remarkable uniformity, reduced effector T cell gene signatures, and increased angiogenesis. Similar findings were observed histopathologically. Thus, RCC metastatic to the pancreas is characterized by indolent biology, heightened angiogenesis, and an uninflamed stroma, likely underlying its good prognosis, sensitivity to antiangiogenic therapies, and refractoriness to ICI. These data suggest that metastatic organotropism may be an indicator of a particular biology with prognostic and treatment implications for patients.
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http://dx.doi.org/10.1172/jci.insight.134564DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7205259PMC
April 2020

Tumor neoantigenicity assessment with CSiN score incorporates clonality and immunogenicity to predict immunotherapy outcomes.

Sci Immunol 2020 02;5(44)

Quantitative Biomedical Research Center, Department of Population and Data Sciences, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.

Lack of responsiveness to checkpoint inhibitors is a central problem in the modern era of cancer immunotherapy. Tumor neoantigens are critical targets of the host antitumor immune response, and their presence correlates with the efficacy of immunotherapy treatment. Many studies involving assessment of tumor neoantigens principally focus on total neoantigen load, which simplistically treats all neoantigens equally. Neoantigen load has been linked with treatment response and prognosis in some studies but not others. We developed a Cauchy-Schwarz index of Neoantigens (CSiN) score to better account for the degree of concentration of immunogenic neoantigens in truncal mutations. Unlike total neoantigen load determinations, CSiN incorporates the effect of both clonality and MHC binding affinity of neoantigens when characterizing tumor neoantigen profiles. By analyzing the clinical responses in 501 treated patients with cancer (with most receiving checkpoint inhibitors) and the overall survival of 1978 patients with cancer at baseline, we showed that CSiN scores predict treatment response to checkpoint inhibitors and prognosis in patients with melanoma, lung cancer, and kidney cancer. CSiN score substantially outperformed prior genetics-based prediction methods of responsiveness and fills an important gap in research involving assessment of tumor neoantigen burden.
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http://dx.doi.org/10.1126/sciimmunol.aaz3199DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7239327PMC
February 2020

Ontological analyses reveal clinically-significant clear cell renal cell carcinoma subtypes with convergent evolutionary trajectories into an aggressive type.

EBioMedicine 2020 01 16;51:102526. Epub 2019 Dec 16.

Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390, United States; Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX 75390, United States; Kidney Cancer Program, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, United States. Electronic address:

Background: Clear cell renal cell carcinoma (ccRCC) is a particularly challenging tumor type because of its extensive phenotypic variability as well as intra-tumoral heterogeneity (ITH). Clinically, this complexity has been reduced to a handful of pathological variables such as stage, grade and necrosis, but these variables fail to capture the breadth of the disease. How different phenotypes affect patient prognosis and influence therapeutic response is poorly understood. Extensive ITH illustrates remarkable plasticity, providing a framework to study tumor evolution. While multiregional genomic analyses have shown evolution from an ancient clone that acquires metastatic competency over time, these studies have been conducted agnostic to morphological cues and phenotypic plasticity.

Methods: We established a systematic ontology of ccRCC phenotypic variability by developing a multi-scale framework along three fundamental axes: tumor architecture, cytology and the microenvironment. We defined 33 parameters, which we comprehensively evaluated in 549 consecutive ccRCCs retrospectively. We systematically evaluated the impact of each parameter on patient outcomes, and assessed their contribution through multivariate analyses. We measured therapeutic impact in the context of anti-angiogenic therapies. We applied dimensionality reduction by t-distributed stochastic neighbor embedding (t-SNE) algorithms to tumor architectures for the study of tumor evolution superimposing tumor size and grade vectors. Evolutionary models were refined through empirical analyses of directed evolution of tumor intravascular extensions, and metastatic competency (as determined by tumor reconstitution in a heterologous host).

Findings: We discovered several novel ccRCC phenotypes, developed an integrated taxonomy, and identified features that improve current prognostic models. We identified a subset of ccRCCs refractory to anti-angiogenic therapies. We developed a model of tumor evolution, which revealed converging evolutionary trajectories into an aggressive type.

Interpretation: This work serves as a paradigm for deconvoluting tumor complexity and illustrates how morphological analyses can improve our understanding of ccRCC pleiotropy. We identified several subtypes associated with aggressive biology, and differential response to targeted therapies. By analyzing patterns of spatial and temporal co-occurrence, intravascular tumor extensions and metastatic competency, we were able to identify distinct trajectories of convergent phenotypic evolution.
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http://dx.doi.org/10.1016/j.ebiom.2019.10.052DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7000318PMC
January 2020

HIF-2 Complex Dissociation, Target Inhibition, and Acquired Resistance with PT2385, a First-in-Class HIF-2 Inhibitor, in Patients with Clear Cell Renal Cell Carcinoma.

Clin Cancer Res 2020 02 14;26(4):793-803. Epub 2019 Nov 14.

Hematology-Oncology Division, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas.

Purpose: The heterodimeric transcription factor HIF-2 is arguably the most important driver of clear cell renal cell carcinoma (ccRCC). Although considered undruggable, structural analyses at the University of Texas Southwestern Medical Center (UTSW, Dallas, TX) identified a vulnerability in the α subunit, which heterodimerizes with HIF1β, ultimately leading to the development of PT2385, a first-in-class inhibitor. PT2385 was safe and active in a first-in-human phase I clinical trial of patients with extensively pretreated ccRCC at UTSW and elsewhere. There were no dose-limiting toxicities, and disease control ≥4 months was achieved in 42% of patients.

Patients And Methods: We conducted a prospective companion substudy involving a subset of patients enrolled in the phase I clinical trial at UTSW ( = 10), who were treated at the phase II dose or above, involving multiparametric MRI, blood draws, and serial biopsies for biochemical, whole exome, and RNA-sequencing studies.

Results: PT2385 inhibited HIF-2 in nontumor tissues, as determined by a reduction in erythropoietin levels (a pharmacodynamic marker), in all but one patient, who had the lowest drug concentrations. PT2385 dissociated HIF-2 complexes in ccRCC metastases, and inhibited HIF-2 target gene expression. In contrast, HIF-1 complexes were unaffected. Prolonged PT2385 treatment resulted in the acquisition of resistance, and we identified a gatekeeper mutation (G323E) in HIF2α, which interferes with drug binding and precluded HIF-2 complex dissociation. In addition, we identified an acquired mutation elsewhere, suggesting a possible alternate mechanism of resistance.

Conclusions: These findings demonstrate a core dependency on HIF-2 in metastatic ccRCC and establish PT2385 as a highly specific HIF-2 inhibitor in humans. New approaches will be required to target mutant HIF-2 beyond PT2385 or the closely related PT2977 (MK-6482).
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http://dx.doi.org/10.1158/1078-0432.CCR-19-1459DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7024660PMC
February 2020

Pathologic response and surgical outcomes in patients undergoing nephrectomy following receipt of immune checkpoint inhibitors for renal cell carcinoma.

Urol Oncol 2019 12 12;37(12):924-931. Epub 2019 Sep 12.

Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX. Electronic address:

Objective: To evaluate the pathologic response, safety, and feasibility of nephrectomy following receipt of immune checkpoint inhibition (ICI) for renal cell carcinoma (RCC).

Methods: Patients who underwent nephrectomy for RCC after exposure to nivolumab monotherapy or combination ipilimumab/nivolumab were reviewed. Primary surgical outcomes included operative time (OT), estimated blood loss (EBL), length of stay (LOS), readmission rates, and complication rates. Pathologic response in the primary and metastatic sites constituted secondary outcomes.

Results: Eleven nephrectomies (10 radical, 1 partial) were performed in 10 patients after ICI with median postoperative follow-up 180 days. Six patients received 1 to 4 cycles of ipilimumab/nivolumab, while 5 received 2 to 12 infusions of nivolumab preoperatively. Five surgeries were performed laparoscopically, and 4 patients underwent concomitant thrombectomy. One patient exhibited complete response (pT0) to ICI, and 3/4 patients who underwent metastasectomy for hepatic, pulmonary, or adrenal lesions exhibited no detectable malignancy in any of the metastases resected. No patients experienced any major intraoperative complications, and all surgical margins were negative. Median OT, EBL, and LOS were 180 minutes, 100 ml, and 4 days, respectively. Four patients experienced a complication, including 3 that were addressed with interventional radiology procedures. One patient died of progressive disease >3 months after surgery, and 1 patient succumbed to pulmonary embolism complicated by sepsis. No complications or readmissions were noted in 6 patients.

Conclusion: Nephrectomy following ICI for RCC is safe and technically feasible with favorable surgical outcomes and pathologic response. Timing of the nephrectomy relative to checkpoint dosing did not seem to impact outcome. Biopsies of lesions responding radiographically to ICI may warrant attention prior to surgical excision.
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http://dx.doi.org/10.1016/j.urolonc.2019.08.012DOI Listing
December 2019

Stereotactic Ablative Radiation Therapy (SAbR) Used to Defer Systemic Therapy in Oligometastatic Renal Cell Cancer.

Int J Radiat Oncol Biol Phys 2019 10 1;105(2):367-375. Epub 2019 Aug 1.

Department of Radiation Oncology; Kidney Cancer Program, Simmons Comprehensive Cancer Center. Electronic address:

Purpose: Stereotactic ablative radiotherapy (SAbR) is a promising alternative for selected patients with renal cell carcinoma (RCC) with oligometastasis. The objective of this study was to evaluate the potential of SAbR for longitudinal control in patients with persistently oligometastatic RCC. We report the impact of SAbR on tumor control rates as well as its tolerability in systemic therapy-naïve patients with oligometastatic disease (without brain metastases) and assess the effect of SAbR on subsequent first line systemic therapy by comparison to historical controls.

Methods And Materials: We reviewed patients with metastatic RCC treated with front-line SAbR with a curative intent from 2007 to 2017 at UT Southwestern Kidney Cancer Program. We analyzed local control rates (LCR), toxicity, freedom from systemic therapy (FST), type and duration of first-line systemic therapy, and overall survival (OS). Cox regression and Kaplan-Meier analyses were used.

Results: We identified 47 patients with oligometastatic RCC treated with SAbR to 88 metastases; 11 patients had more than 1 SAbR course. The local control rate was 91.5% at 2 years with no reported grade ≥3 toxicity. With a median follow-up of 30 months (interquartile range, 13.7-40.9), median FST from first SAbR was 15.2 months (95% confidence interval [CI], 8.8-40.1). The most common systemic therapies initiated after SAbR were pazopanib (60.7%) and sunitinib (14.3%). The duration of first line systemic therapy appeared unaffected by SAbR. Improved FST was observed in patients with metachronous disease (hazard ratio, 2.67; P = .02), solitary metastasis (HR, 2.26; P = .05), and non-bone metastasis (HR, 2.21; P = .04). One-year and 2-year OS after SAbR were 93.1% (95% CI, 80.1-97.7) and 84.8% (95% CI, 69.1-92.9), respectively. Median OS was not reached.

Conclusions: SAbR is an effective and safe treatment for selected patients with oligometastatic RCC, can provide longitudinal disease control without systemic therapy for over a year, and does not appear to adversely affect the effectiveness of first-line systemic therapy once initiated. Prospective validation of these findings is being sought through a phase 2 trial.
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http://dx.doi.org/10.1016/j.ijrobp.2019.07.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7647381PMC
October 2019

SCINA: A Semi-Supervised Subtyping Algorithm of Single Cells and Bulk Samples.

Genes (Basel) 2019 07 12;10(7). Epub 2019 Jul 12.

Quantitative Biomedical Research Center, Department of Population and Data Sciences, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.

Advances in single-cell RNA sequencing (scRNA-Seq) have allowed for comprehensive analyses of single cell data. However, current analyses of scRNA-Seq data usually start from unsupervised clustering or visualization. These methods ignore prior knowledge of transcriptomes and the probable structures of the data. Moreover, cell identification heavily relies on subjective and possibly inaccurate human inspection afterwards. To address these analytical challenges, we developed SCINA (Semi-supervised Category Identification and Assignment), a semi-supervised model that exploits previously established gene signatures using an expectation-maximization (EM) algorithm. SCINA is applicable to scRNA-Seq and flow cytometry/CyTOF data, as well as other data of similar format. We applied SCINA to a wide range of datasets, and showed its accuracy, stability and efficiency, which exceeded most popular unsupervised approaches. SCINA discovered an intermediate stage of oligodendrocytes from mouse brain scRNA-Seq data. SCINA also detected immune cell population changes in cytometry data in a genetically-engineered mouse model. Furthermore, SCINA performed well with bulk gene expression data. Specifically, we identified a new kidney tumor clade with similarity to FH-deficient tumors (FHD), which we refer to as FHD-like tumors (FHDL). Overall, SCINA provides both methodological advances and biological insights from perspectives different from traditional analytical methods.
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http://dx.doi.org/10.3390/genes10070531DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6678337PMC
July 2019

Familial Kidney Cancer: Implications of New Syndromes and Molecular Insights.

Eur Urol 2019 12 18;76(6):754-764. Epub 2019 Jul 18.

Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Context: Hereditary cases account for about 5% of all cases of renal cell carcinoma (RCC). With advances in next-generation sequencing, several new hereditary syndromes have been described in the last few years.

Objective: To review and summarise the recent preclinical and clinical literature in hereditary renal cancer.

Evidence Acquisition: A systematic review of the literature was performed in November 2018 using PubMed and OMIM databases, with an emphasis on kidney cancer, genetics and genomics, clinical criteria, and management.

Evidence Synthesis: Several autosomal dominant hereditary RCC syndromes have been described, including those related to germline pathogenic variants in VHL, MET, FH, TSC1/TSC2, FLCN, SDHA/B/C/D, BAP1, CDC73, and MITF. Clinical spectrum of SDH, BAP1, and MITF is still being defined, although these appear to be associated with a lower incidence of RCC. FH and likely BAP1 RCC are associated with more aggressive disease. Preclinical and clinical studies show that using systemic therapy that exploits specific genetic pathways is a promising strategy.

Conclusions: There are several well-described hereditary RCC syndromes, as well as recently identified ones, for which the full clinical spectrum is yet to be defined. In the new era of precision medicine, identification of these syndromes may play an important role in management and systemic treatment selection.

Patient Summary: This review covers updates in the diagnosis and management of familial kidney cancer syndromes. We describe updates in testing and management of the most common syndromes such as von Hippel-Lindau, and hereditary leiomyomatosis and renal cell carcinoma. We also provide insights into recently described familial kidney cancer syndromes.
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http://dx.doi.org/10.1016/j.eururo.2019.06.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7673107PMC
December 2019

Inflammatory Reaction Secondary to Immune Checkpoint Inhibitor Therapy Mimicking a Post-Operative Brain Abscess.

World Neurosurg 2019 Sep 14;129:354-358. Epub 2019 Jun 14.

Department of Neurological Surgery, University of Texas Southwestern Medical Center, Dallas, Texas, USA. Electronic address:

Background: Immune checkpoint inhibitors have revolutionized the treatment of many cancers, including melanoma, non-small cell lung cancer, and renal cell carcinoma. These therapeutics increase the activity of T cells against neoplastic cells, although the immune response generated also has the potential to target normal cells, resulting in immune related adverse events (irAEs). Most irAEs occur outside of the nervous system, but cases of limbic encephalitis, hypophysitis, optic neuritis, and pseudoprogression have been reported.

Case Description: Here, we present a case of an intracranial irAE after neoadjuvant stereotactic radiosurgery and craniotomy for resection of a left parietal lobe metastasis. The patient presented with headache, right-sided apraxia, and a pronator drift 2 weeks after surgery. Imaging findings were suggestive of an intracranial abscess. The lack of fever, normal white blood cell count, and benign clinical appearance in the setting of combination nivolumab and ipilimumab therapy argued in favor of an irAE, however. After initiation of dexamethasone, the neurologic deficits resolved and the magnetic resonance imaging of the brain normalized over 7 weeks.

Conclusions: This is the first report of an acute surgical-site irAE after stereotactic radiosurgery and craniotomy in a patient receiving nivolumab and ipilimumab. These immune-mediated responses can be treated with corticosteroids and close observation.
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http://dx.doi.org/10.1016/j.wneu.2019.06.024DOI Listing
September 2019

Current Challenges in Diagnosis and Assessment of the Response of Locally Advanced and Metastatic Renal Cell Carcinoma.

Radiographics 2019 Jul-Aug;39(4):998-1016. Epub 2019 Jun 14.

From the Department of Radiology (A.D.d.L., A.P., D.N.C., I.P.), Advanced Imaging Research Center (D.N.C., I.P.), Department of Pathology (P.K.), Department of Urology (P.K.), Kidney Cancer Program-Simmons Comprehensive Cancer Center (P.K., H.H., J.B., I.P.), and Department of Internal Medicine (H.H., J.B.), UT Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390.

Locally advanced and metastatic renal cell carcinoma (RCC) present a specific set of challenges to the radiologist. The detection of metastatic disease is confounded by the ability of RCC to metastasize to virtually any part of the human body long after surgical resection of the primary tumor. This includes sites not commonly included in routine surveillance, which come to light after the patient becomes symptomatic. In the assessment of treatment response, the phenomenon of tumor heterogeneity, where clone selection through systemic therapy drives the growth of potentially more aggressive phenotypes, can result in oligoprogression despite overall disease control. Finally, advances in therapy have resulted in the development of immuno-oncologic agents that may result in changes that are not adequately evaluated with conventional size-based response criteria and may even be misinterpreted as progression. This article reviews the common challenges a radiologist may encounter in the evaluation of patients with locally advanced and metastatic RCC. RSNA, 2019.
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http://dx.doi.org/10.1148/rg.2019180178DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6677287PMC
May 2020

PD-L1 detection using Zr-atezolizumab immuno-PET in renal cell carcinoma tumorgrafts from a patient with favorable nivolumab response.

J Immunother Cancer 2019 06 3;7(1):144. Epub 2019 Jun 3.

Kidney Cancer Program, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA.

Background: Programmed death-ligand 1 (PD-L1) expression in metastatic renal cell carcinoma (RCC) correlates with a worse prognosis, but whether it also predicts responsiveness to anti-PD-1/PD-L1 therapy remains unclear. Most studies of PD-L1 are limited by evaluation in primary rather than metastatic sites, and in biopsy samples, which may not be representative. These limitations may be overcome with immuno-positron emission tomography (iPET), an emerging tool allowing the detection of cell surface proteins with radiolabeled antibodies. Here, we report iPET studies of PD-L1 in a preclinical tumorgraft model of clear cell RCC (ccRCC) from a patient who had a favorable response to anti-PD-1 therapy.

Case Presentation: A 49-year-old man underwent a cytoreductive nephrectomy in 2017 of a right kidney tumor invading into the adrenal gland that was metastatic to the lungs and a rib. Histological analyses revealed a ccRCC of ISUP grade 4 with extensive sarcomatoid features. IMDC risk group was poor. Within two hours of surgery, a tumor sample was implanted orthotopically into NOD/SCID mice. Consistent with an aggressive tumor, a renal mass was detected 18 days post-implantation. Histologically, the tumorgraft showed sarcomatoid differentiation and high levels of PD-L1, similar to the patient's tumor. PD-L1 was evaluated in subsequently transplanted mice using iPET and the results were compared to control mice implanted with a PD-L1-negative tumor. We labeled atezolizumab, an anti-PD-L1 antibody with a mutant Fc, with zirconium-89. iPET revealed significantly higher Zr-atezolizumab uptake in index than control tumorgrafts. The patient was treated with high-dose IL2 initially, and subsequently with pazopanib, with rapidly progressive disease, but had a durable response with nivolumab.

Conclusions: To our knowledge, this is the first report of non-invasive detection of PD-L1 in renal cancer using molecular imaging. This study supports clinical evaluation of iPET to identify RCC patients with tumors deploying the PD-L1 checkpoint pathway who may be most likely to benefit from PD-1/PD-L1 disrupting drugs.
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http://dx.doi.org/10.1186/s40425-019-0607-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6545669PMC
June 2019

Downregulation of Human DAB2IP Gene Expression in Renal Cell Carcinoma Results in Resistance to Ionizing Radiation.

Clin Cancer Res 2019 07 18;25(14):4542-4551. Epub 2019 Apr 18.

Department of Urology, University of Texas Southwestern Medical Center, Dallas, Texas.

Purpose: Renal cell carcinoma (RCC) is known to be highly radioresistant but the mechanisms associated with radioresistance have remained elusive. We found DOC-2/DAB2 interactive protein (DAB2IP) frequently downregulated in RCC, is associated with radioresistance. In this study, we investigated the underlying mechanism regulating radioresistance by DAB2IP and developed appropriate treatment.

Experimental Design: Several RCC lines with or without DAB2IP expression were irradiated with ionizing radiation (IR) for determining their radiosensitivities based on colony formation assay. To investigate the underlying regulatory mechanism of DAB2IP, immunoprecipitation-mass spectrometry was performed to identify DAB2IP-interactive proteins. PARP-1 expression and enzymatic activity were determined using qRT-PCR, Western blot analysis, and ELISA. ubiquitination assay was used to test PARP-1 degradation. Furthermore, mice xenograft model and patient-derived xenograft (PDX) model were used to determine the effect of combination therapy to sensitizing tumors to IR.

Results: We notice that DAB2IP-deficient RCC cells acquire IR-resistance. Mechanistically, DAB2IP can form a complex with PARP-1 and E3 ligases that is responsible for degrading PARP-1. Indeed, elevated PARP-1 levels are associated with the IR resistance in RCC cells. Furthermore, PARP-1 inhibitor can enhance the IR response of either RCC xenograft model or PDX model.

Conclusions: In this study, we unveil that loss of DAB2IP resulted in elevated PARP-1 protein is associated with IR-resistance in RCC. These results provide a new targeting strategy to improve the efficacy of radiotherapy of RCC.
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http://dx.doi.org/10.1158/1078-0432.CCR-18-3004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6635020PMC
July 2019

DEFOR: depth- and frequency-based somatic copy number alteration detector.

Bioinformatics 2019 10;35(19):3824-3825

Department of Clinical Sciences, University of Texas Southwestern Medical Center, Dallas, TX, USA.

Motivation: Detection of somatic copy number alterations (SCNAs) using high-throughput sequencing has become popular because of rapid developments in sequencing technology. Existing methods do not perform well in calling SCNAs for the unstable tumor genomes.

Results: We developed a new method, DEFOR, to detect SCNAs in tumor samples from exome-sequencing data. The evaluation showed that DEFOR has a higher accuracy for SCNA detection from exome sequencing compared with the five existing tools. This advantage is especially apparent in unstable tumor genomes with a large proportion of SCNAs.

Availability And Implementation: DEFOR is available at https://github.com/drzh/defor.

Supplementary Information: Supplementary data are available at Bioinformatics online.
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http://dx.doi.org/10.1093/bioinformatics/btz170DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6761943PMC
October 2019

Stereotactic Radiosurgery for Multiple Brain Metastases From Renal-Cell Carcinoma.

Clin Genitourin Cancer 2019 04 22;17(2):e273-e280. Epub 2018 Nov 22.

Kidney Cancer Program, Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, TX; Department of Radiation Oncology, UT Southwestern Medical Center, Dallas, TX.

Background: Brain metastases (BM) pose a significant problem in patients with metastatic renal-cell carcinoma (mRCC). Local and systemic therapies including stereotactic radiosurgery (SRS) are rapidly evolving, necessitating reassessments of outcomes for modern patient management.

Patients And Methods: The mRCC patients with BM treated with SRS were reviewed. Patient demographics, clinical history, and SRS treatment parameters were identified.

Results: Among 268 patients with mRCC treated between 2006 and 2015, 38 patients were identified with BM. A total of 243 BM were treated with SRS with 1 to 26 BMs treated per SRS session (median, 2 BMs). The median (range) BM size was 0.6 (0.2-3.1) cm and median (range) SRS treatment dose was 18 (12-24) Gy. Treated BM local control rates at 1 and 2 years were 91.8% (95% confidence interval, 85.7-95.4) and 86.1% (95% confidence interval, 77.1-91.7), respectively. BM control declined for larger tumors. Survival after 1-year was 57.5% (95% CI 40.2-71.4) for all patients. Survival was not statistically different between patients with < 5 BM versus ≥ 5 BM. Survival was prognostic based on International Metastatic Renal Cell Carcinoma Database (IMDC) risk groups in patients with < 5 BM. Two patients experienced grade 3 radiation necrosis requiring surgical intervention.

Conclusion: SRS is effective in controlling BM in patients with mRCC. Over half of treated patients survive past a year, and no differences in survival were noted in patients with > 5 metastases. Prognostic risk categories based on systemic disease (IMDC) are predictive of survival in this BM population, with limited rates of symptomatic radiation necrosis.
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http://dx.doi.org/10.1016/j.clgc.2018.11.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6563340PMC
April 2019

Next Generation Sequencing in Renal Cell Carcinoma: Towards Precision Medicine.

Kidney Cancer J 2019 ;17(4):94-104

Department of Internal Medicine, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas TX, 75390.

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7089604PMC
January 2019

Improved Survival Outcomes for Kidney Cancer Patients With Brain Metastases.

Clin Genitourin Cancer 2019 04 5;17(2):e263-e272. Epub 2018 Dec 5.

Kidney Cancer Program, Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, TX; Division of Hematology and Oncology, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX. Electronic address:

Background: Brain metastases (BM) occur frequently in patients with metastatic kidney cancer and are a significant source of morbidity and mortality. Although historically associated with a poor prognosis, survival outcomes for patients in the modern era are incompletely characterized. In particular, outcomes after adjusting for systemic therapy administration and International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk factors are not well-known.

Patients And Methods: A retrospective database of patients with metastatic renal cell carcinoma (RCC) treated at University of Texas Southwestern Medical Center between 2006 and 2015 was created. Data relevant to their diagnosis, treatment course, and outcomes were systematically collected. Survival was analyzed by the Kaplan-Meier method. Patients with BM were compared with patients without BM after adjusting for the timing of BM diagnosis, either prior to or during first-line systemic therapy. The impact of stratification according to IMDC risk group was assessed.

Results: A total of 56 (28.4%) of 268 patients with metastatic RCC were diagnosed with BM prior to or during first-line systemic therapy. Median overall survival (OS) for systemic therapy-naive patients with BM compared with matched patients without BM was 19.5 versus 28.7 months (P = .0117). When analyzed according to IMDC risk group, the median OS for patients with BM was similar for favorable- and intermediate-risk patients (not reached vs. not reached; and 29.0 vs. 36.7 months; P = .5254), and inferior for poor-risk patients (3.5 vs. 9.4 months; P = .0462). For patients developing BM while on first-line systemic therapy, survival from the time of progression did not significantly differ by presence or absence of BM (11.8 vs. 17.8 months; P = .6658).

Conclusions: Survival rates for patients with BM are significantly better than historical reports. After adjusting for systemic therapy, the survival rates of patients with BM in favorable- and intermediate-risk groups were remarkably better than expected and not statistically different from patients without BM, though this represents a single institution experience, and numbers are modest.
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http://dx.doi.org/10.1016/j.clgc.2018.11.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6534272PMC
April 2019

Consensus report of the 8 and 9th Weinman Symposia on Gene x Environment Interaction in carcinogenesis: novel opportunities for precision medicine.

Cell Death Differ 2018 11 15;25(11):1885-1904. Epub 2018 Oct 15.

MRC Toxicology Unit, Leicester, UK.

The relative contribution of intrinsic genetic factors and extrinsic environmental ones to cancer aetiology and natural history is a lengthy and debated issue. Gene-environment interactions (G x E) arise when the combined presence of both a germline genetic variant and a known environmental factor modulates the risk of disease more than either one alone. A panel of experts discussed our current understanding of cancer aetiology, known examples of G × E interactions in cancer, and the expanded concept of G × E interactions to include somatic cancer mutations and iatrogenic environmental factors such as anti-cancer treatment. Specific genetic polymorphisms and genetic mutations increase susceptibility to certain carcinogens and may be targeted in the near future for prevention and treatment of cancer patients with novel molecularly based therapies. There was general consensus that a better understanding of the complexity and numerosity of G × E interactions, supported by adequate technological, epidemiological, modelling and statistical resources, will further promote our understanding of cancer and lead to novel preventive and therapeutic approaches.
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http://dx.doi.org/10.1038/s41418-018-0213-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6219489PMC
November 2018

Reliable gene mutation prediction in clear cell renal cell carcinoma through multi-classifier multi-objective radiogenomics model.

Phys Med Biol 2018 10 24;63(21):215008. Epub 2018 Oct 24.

School of Electronic and Information Engineering, Xi'an Jiaotong University, Xi'an, Shaanxi 710049, People's Repubic of China.

Genetic studies have identified associations between gene mutations and clear cell renal cell carcinoma (ccRCC). Since the complete gene mutational landscape cannot be characterized through biopsy and sequencing assays for each patient, non-invasive tools are needed to determine the mutation status for tumors. Radiogenomics may be an attractive alternative tool to identify disease genomics by analyzing amounts of features extracted from medical images. Most current radiogenomics predictive models are built based on a single classifier and trained through a single objective. However, since many classifiers are available, selecting an optimal model is challenging. On the other hand, a single objective may not be a good measure to guide model training. We proposed a new multi-classifier multi-objective (MCMO) radiogenomics predictive model. To obtain more reliable prediction results, similarity-based sensitivity and specificity were defined and considered as the two objective functions simultaneously during training. To take advantage of different classifiers, the evidential reasoning (ER) approach was used for fusing the output of each classifier. Additionally, a new similarity-based multi-objective optimization algorithm (SMO) was developed for training the MCMO to predict ccRCC related gene mutations (VHL, PBRM1 and BAP1) using quantitative CT features. Using the proposed MCMO model, we achieved a predictive area under the receiver operating characteristic curve (AUC) over 0.85 for VHL, PBRM1 and BAP1 genes with balanced sensitivity and specificity. Furthermore, MCMO outperformed all the individual classifiers, and yielded more reliable results than other optimization algorithms and commonly used fusion strategies.
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http://dx.doi.org/10.1088/1361-6560/aae5cdDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6240911PMC
October 2018

Personalized Management of Advanced Kidney Cancer.

Am Soc Clin Oncol Educ Book 2018 May;38:330-341

From the Tom Baker Cancer Centre, University of Calgary, Calgary, Alberta, Canada; Kidney Cancer Program, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX; Karmanos Cancer Institute, Wayne State University, Detroit, MI.

The treatment of renal cell carcinoma represents one of the great success stories in translational cancer research, with the development of novel therapies targeting key oncogenic pathways. These include drugs that target the VEGF and mTOR pathways, as well as novel immuno-oncology agents. Despite the therapeutic advancements, there is a paucity of well-validated prognostic and predictive biomarkers in advanced kidney cancer. With a number of highly effective therapies available across multiple lines, it will become increasingly important to develop a more tailored approach to treatment selection. Prognostic clinical models, such the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) model, are routinely used for prognostication in clinical practice. The IMDC model has demonstrated a predictive capability in the context of these treatments including immune checkpoint inhibition. A number of promising molecular markers and gene expression signatures are being explored as prognostic and predictive biomarkers, but none are ready to be widely used for treatment selection. In this review, we will explore the current landscape of personalized care in metastatic renal cell carcinoma. This will include a focus on both prognostic and predictive factors as well as clinical applications of biology in kidney cancer.
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http://dx.doi.org/10.1200/EDBK_201215DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6865066PMC
May 2018