42 results on '"Maria J. Merino"'
Search Results
2. Evaluating Diagnostic Accuracy and Inter-reader Agreement of the Prostate Imaging After Focal Ablation Scoring System
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David G. Gelikman, Alexander P. Kenigsberg, Yan Mee Law, Enis C. Yilmaz, Stephanie A. Harmon, Sahil H. Parikh, Jason A. Hyman, Hannah Huth, Christopher R. Koller, Daniel Nethala, Charles Hesswani, Maria J. Merino, Sandeep Gurram, Peter L. Choyke, Bradford J. Wood, Peter A. Pinto, and Baris Turkbey
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Focal therapy ,Magnetic resonance imaging ,Post-treatment surveillance ,Prostate ablation ,Prostatic neoplasms ,Diseases of the genitourinary system. Urology ,RC870-923 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Background and objective: Focal therapy (FT) is increasingly recognized as a promising approach for managing localized prostate cancer (PCa), notably reducing treatment-related morbidities. However, post-treatment anatomical changes present significant challenges for surveillance using current imaging techniques. This study aimed to evaluate the inter-reader agreement and efficacy of the Prostate Imaging after Focal Ablation (PI-FAB) scoring system in detecting clinically significant prostate cancer (csPCa) on post-FT multiparametric magnetic resonance imaging (mpMRI). Methods: A retrospective cohort study was conducted involving patients who underwent primary FT for localized csPCa between 2013 and 2023, followed by post-FT mpMRI and a prostate biopsy. Two expert genitourinary radiologists retrospectively evaluated post-FT mpMRI using PI-FAB. The key measures included inter-reader agreement of PI-FAB scores, assessed by quadratic weighted Cohen’s kappa (κ), and the system’s efficacy in predicting in-field recurrence of csPCa, with a PI-FAB score cutoff of 3. Additional diagnostic metrics including sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and overall accuracy were also evaluated. Key findings and limitations: Scans from 38 patients were analyzed, revealing a moderate level of agreement in PI-FAB scoring (κ = 0.56). Both radiologists achieved sensitivity of 93% in detecting csPCa, although specificity, PPVs, NPVs, and accuracy varied. Conclusions and clinical implications: The PI-FAB scoring system exhibited high sensitivity with moderate inter-reader agreement in detecting in-field recurrence of csPCa. Despite promising results, its low specificity and PPV necessitate further refinement. These findings underscore the need for larger studies to validate the clinical utility of PI-FAB, potentially aiding in standardizing post-treatment surveillance. Patient summary: Focal therapy has emerged as a promising approach for managing localized prostate cancer, but limitations in current imaging techniques present significant challenges for post-treatment surveillance. The Prostate Imaging after Focal Ablation (PI-FAB) scoring system showed high sensitivity for detecting in-field recurrence of clinically significant prostate cancer. However, its low specificity and positive predictive value necessitate further refinement. Larger, more comprehensive studies are needed to fully validate its clinical utility.
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- 2024
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3. The Cancer Genome Atlas Comprehensive Molecular Characterization of Renal Cell Carcinoma
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Christopher J. Ricketts, Aguirre A. De Cubas, Huihui Fan, Christof C. Smith, Martin Lang, Ed Reznik, Reanne Bowlby, Ewan A. Gibb, Rehan Akbani, Rameen Beroukhim, Donald P. Bottaro, Toni K. Choueiri, Richard A. Gibbs, Andrew K. Godwin, Scott Haake, A. Ari Hakimi, Elizabeth P. Henske, James J. Hsieh, Thai H. Ho, Rupa S. Kanchi, Bhavani Krishnan, David J. Kwiatkowski, Wenbin Liu, Maria J. Merino, Gordon B. Mills, Jerome Myers, Michael L. Nickerson, Victor E. Reuter, Laura S. Schmidt, C. Simon Shelley, Hui Shen, Brian Shuch, Sabina Signoretti, Ramaprasad Srinivasan, Pheroze Tamboli, George Thomas, Benjamin G. Vincent, Cathy D. Vocke, David A. Wheeler, Lixing Yang, William Y. Kim, A. Gordon Robertson, Paul T. Spellman, W. Kimryn Rathmell, and W. Marston Linehan
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Biology (General) ,QH301-705.5 - Published
- 2024
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4. High-throughput and targeted drug screens identify pharmacological candidates against MiT-translocation renal cell carcinoma
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Martin Lang, Laura S. Schmidt, Kelli M. Wilson, Christopher J. Ricketts, Carole Sourbier, Cathy D. Vocke, Darmood Wei, Daniel R. Crooks, Youfeng Yang, Benjamin K. Gibbs, Xiaohu Zhang, Carleen Klumpp-Thomas, Lu Chen, Rajarshi Guha, Marc Ferrer, Crystal McKnight, Zina Itkin, Darawalee Wangsa, Danny Wangsa, Amy James, Simone Difilippantonio, Baktir Karim, Francisco Morís, Thomas Ried, Maria J. Merino, Ramaprasad Srinivasan, Craig J. Thomas, and W. Marston Linehan
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MiT family translocation RCC ,TFE3-RCC ,TFE3-fusion ,GPNMB ,RCC therapy ,NVP-BGT226 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Background MiT-Renal Cell Carcinoma (RCC) is characterized by genomic translocations involving microphthalmia-associated transcription factor (MiT) family members TFE3, TFEB, or MITF. MiT-RCC represents a specific subtype of sporadic RCC that is predominantly seen in young patients and can present with heterogeneous histological features making diagnosis challenging. Moreover, the disease biology of this aggressive cancer is poorly understood and there is no accepted standard of care therapy for patients with advanced disease. Tumor-derived cell lines have been established from human TFE3-RCC providing useful models for preclinical studies. Methods TFE3-RCC tumor derived cell lines and their tissues of origin were characterized by IHC and gene expression analyses. An unbiased high-throughput drug screen was performed to identify novel therapeutic agents for treatment of MiT-RCC. Potential therapeutic candidates were validated in in vitro and in vivo preclinical studies. Mechanistic assays were conducted to confirm the on-target effects of drugs. Results The results of a high-throughput small molecule drug screen utilizing three TFE3-RCC tumor-derived cell lines identified five classes of agents with potential pharmacological efficacy, including inhibitors of phosphoinositide-3-kinase (PI3K) and mechanistic target of rapamycin (mTOR), and several additional agents, including the transcription inhibitor Mithramycin A. Upregulation of the cell surface marker GPNMB, a specific MiT transcriptional target, was confirmed in TFE3-RCC and evaluated as a therapeutic target using the GPNMB-targeted antibody-drug conjugate CDX-011. In vitro and in vivo preclinical studies demonstrated efficacy of the PI3K/mTOR inhibitor NVP-BGT226, Mithramycin A, and CDX-011 as potential therapeutic options for treating advanced MiT-RCC as single agents or in combination. Conclusions The results of the high-throughput drug screen and validation studies in TFE3-RCC tumor-derived cell lines have provided in vitro and in vivo preclinical data supporting the efficacy of the PI3K/mTOR inhibitor NVP-BGT226, the transcription inhibitor Mithramycin A, and GPNMB-targeted antibody-drug conjugate CDX-011 as potential therapeutic options for treating advanced MiT-RCC. The findings presented here should provide the basis for designing future clinical trials for patients with MiT-driven RCC.
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- 2023
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5. TFEB and TFE3 drive kidney cystogenesis and tumorigenesis
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Chiara Di Malta, Angela Zampelli, Letizia Granieri, Claudia Vilardo, Rossella De Cegli, Laura Cinque, Edoardo Nusco, Salvatore Pece, Daniela Tosoni, Francesca Sanguedolce, Nicolina Cristina Sorrentino, Maria J Merino, Deborah Nielsen, Ramaprasad Srinivasan, Mark W Ball, Christopher J Ricketts, Cathy D Vocke, Martin Lang, Baktiar Karim, Luisa Lanfrancone, Laura S Schmidt, W Marston Linehan, and Andrea Ballabio
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BHD ,cysts ,kidney cancer ,TFE3 ,TFEB ,Medicine (General) ,R5-920 ,Genetics ,QH426-470 - Abstract
Abstract Birt‐Hogg‐Dubé (BHD) syndrome is an inherited familial cancer syndrome characterized by the development of cutaneous lesions, pulmonary cysts, renal tumors and cysts and caused by loss‐of‐function pathogenic variants in the gene encoding the tumor‐suppressor protein folliculin (FLCN). FLCN acts as a negative regulator of TFEB and TFE3 transcription factors, master controllers of lysosomal biogenesis and autophagy, by enabling their phosphorylation by the mechanistic Target Of Rapamycin Complex 1 (mTORC1). We have previously shown that deletion of Tfeb rescued the renal cystic phenotype of kidney‐specific Flcn KO mice. Using Flcn/Tfeb/Tfe3 double and triple KO mice, we now show that both Tfeb and Tfe3 contribute, in a differential and cooperative manner, to kidney cystogenesis. Remarkably, the analysis of BHD patient‐derived tumor samples revealed increased activation of TFEB/TFE3‐mediated transcriptional program and silencing either of the two genes rescued tumorigenesis in human BHD renal tumor cell line‐derived xenografts (CDXs). Our findings demonstrate in disease‐relevant models that both TFEB and TFE3 are key drivers of renal tumorigenesis and suggest novel therapeutic strategies based on the inhibition of these transcription factors.
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- 2023
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6. Kidney tumors associated with germline mutations of FH and SDHB show a CpG island methylator phenotype (CIMP).
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Christopher J Ricketts, J Keith Killian, Cathy D Vocke, Yonghong Wang, Maria J Merino, Paul S Meltzer, and W Marston Linehan
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Medicine ,Science - Abstract
Germline mutations within the Krebs cycle enzyme genes fumarate hydratase (FH) or succinate dehydrogenase (SDHB, SDHC, SDHD) are associated with an increased risk of aggressive and early metastasizing variants of renal cell carcinoma (RCC). These RCCs express significantly increased levels of intracellular fumarate or succinate that inhibit 2-oxoglutarate-dependent dioxygenases, such as the TET enzymes that regulate DNA methylation. This study evaluated the genome-wide methylation profiles of 34 RCCs from patients with RCC susceptibility syndromes and 11 associated normal samples using the Illumina HumanMethylation450 BeadChip. All the HLRCC (FH mutated) and SDHB-RCC (SDHB mutated) tumors demonstrated a distinct CpG island methylator phenotype (CIMP). HLRCC tumors demonstrated an extensive and relatively uniform level of hypermethylation that showed some correlation with tumor size. SDHB-RCC demonstrated a lesser and more varied pattern of hypermethylation that overlapped in part with the HLRCC hypermethylation. Combined methylation and mRNA expression analysis of the HLRCC tumors demonstrated hypermethylation and transcription downregulation of genes associated with the HIF pathway, HIF3A and CITED4, the WNT pathway, SFRP1, and epithelial-to-mesenchymal transition and MYC expression, OVOL1. These observations were confirmed in the TCGA CIMP-RCC tumors. A selected panel of probes could identify the CIMP tumors and differentiate between HLRCC and SDHB-RCC tumors. This panel accurately detected all CIMP-RCC tumors within the TCGA RCC cohort, identifying them as HLRCC -like, and could potentially be used to create a liquid biopsy-based screening tool. The CIMP signature in these aggressive tumors could provide both a useful biomarker for diagnosis and a target for novel therapies.
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- 2022
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7. KLF3 and PAX6 are candidate driver genes in late-stage, MSI-hypermutated endometrioid endometrial carcinomas
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Meghan L. Rudd, Nancy F. Hansen, Xiaolu Zhang, Mary Ellen Urick, Suiyuan Zhang, Maria J. Merino, National Institutes of Health Intramural Sequencing Center Comparative Sequencing Program, James C. Mullikin, Lawrence C. Brody, and Daphne W. Bell
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Medicine ,Science - Abstract
Endometrioid endometrial carcinomas (EECs) are the most common histological subtype of uterine cancer. Late-stage disease is an adverse prognosticator for EEC. The purpose of this study was to analyze EEC exome mutation data to identify late-stage-specific statistically significantly mutated genes (SMGs), which represent candidate driver genes potentially associated with disease progression. We exome sequenced 15 late-stage (stage III or IV) non-ultramutated EECs and paired non-tumor DNAs; somatic variants were called using Strelka, Shimmer, SomaticSniper and MuTect. Additionally, somatic mutation calls were extracted from The Cancer Genome Atlas (TCGA) data for 66 late-stage and 270 early-stage (stage I or II) non-ultramutated EECs. MutSigCV (v1.4) was used to annotate SMGs in the two late-stage cohorts and to derive p-values for all mutated genes in the early-stage cohort. To test whether late-stage SMGs are statistically significantly mutated in early-stage tumors, q-values for late-stage SMGs were re-calculated from the MutSigCV (v1.4) early-stage p-values, adjusting for the number of late-stage SMGs tested. We identified 14 SMGs in the combined late-stage EEC cohorts. When the 14 late-stage SMGs were examined in the TCGA early-stage data, only Krüppel-like factor 3 (KLF3) and Paired box 6 (PAX6) failed to reach significance as early-stage SMGs, despite the inclusion of enough early-stage cases to ensure adequate statistical power. Within TCGA, nonsynonymous mutations in KLF3 and PAX6 were, respectively, exclusive or nearly exclusive to the microsatellite instability (MSI)-hypermutated molecular subgroup and were dominated by insertions-deletions at homopolymer tracts. In conclusion, our findings are hypothesis-generating and suggest that KLF3 and PAX6, which encode transcription factors, are MSI target genes and late-stage-specific SMGs in EEC.
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- 2022
8. A Cascaded Deep Learning–Based Artificial Intelligence Algorithm for Automated Lesion Detection and Classification on Biparametric Prostate Magnetic Resonance Imaging
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Peter A. Pinto, Stephanie Harmon, Samira Masoudi, Dong Yang, Holger R. Roth, Deepak Kesani, Baris Turkbey, Daguang Xu, Thomas Sanford, Sherif Mehralivand, Bradford J. Wood, Maria J. Merino, Nathan Lay, Peter L. Choyke, and Ziyue Xu
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Male ,Lesion ,Prostate cancer ,Deep Learning ,Artificial Intelligence ,Prostate ,medicine ,Humans ,Radiology, Nuclear Medicine and imaging ,Segmentation ,Aged ,Retrospective Studies ,medicine.diagnostic_test ,Lesion detection ,business.industry ,Deep learning ,Prostatic Neoplasms ,Cancer ,Magnetic resonance imaging ,medicine.disease ,Magnetic Resonance Imaging ,medicine.anatomical_structure ,Artificial intelligence ,medicine.symptom ,business ,Algorithm ,Algorithms - Abstract
Rationale and objectives Prostate MRI improves detection of clinically significant prostate cancer; however, its diagnostic performance has wide variation. Artificial intelligence (AI) has the potential to assist radiologists in the detection and classification of prostatic lesions. Herein, we aimed to develop and test a cascaded deep learning detection and classification system trained on biparametric prostate MRI using PI-RADS for assisting radiologists during prostate MRI read out. Materials and Methods T2-weighted, diffusion-weighted (ADC maps, high b value DWI) MRI scans obtained at 3 Tesla from two institutions (n = 1043 in-house and n = 347 Prostate-X, respectively) acquired between 2015 to 2019 were used for model training, validation, testing. All scans were retrospectively reevaluated by one radiologist. Suspicious lesions were contoured and assigned a PI-RADS category. A 3D U-Net-based deep neural network was used to train an algorithm for automated detection and segmentation of prostate MRI lesions. Two 3D residual neural network were used for a 4-class classification task to predict PI-RADS categories 2 to 5 and BPH. Training and validation used 89% (n = 1290 scans) of the data using 5 fold cross-validation, the remaining 11% (n = 150 scans) were used for independent testing. Algorithm performance at lesion level was assessed using sensitivities, positive predictive values (PPV), false discovery rates (FDR), classification accuracy, Dice similarity coefficient (DSC). Additional analysis was conducted to compare AI algorithm's lesion detection performance with targeted biopsy results. Results Median age was 66 years (IQR = 60-71), PSA 6.7 ng/ml (IQR = 4.7-9.9) from in-house cohort. In the independent test set, algorithm correctly detected 111 of 198 lesions leading to 56.1% (49.3%-62.6%) sensitivity. PPV was 62.7% (95% CI 54.7%-70.7%) with FDR of 37.3% (95% CI 29.3%-45.3%). Of 79 true positive lesions, 82.3% were tumor positive at targeted biopsy, whereas of 57 false negative lesions, 50.9% were benign at targeted biopsy. Median DSC for lesion segmentation was 0.359. Overall PI-RADS classification accuracy was 30.8% (95% CI 24.6%-37.8%). Conclusion Our cascaded U-Net, residual network architecture can detect, classify cancer suspicious lesions at prostate MRI with good detection, reasonable classification performance metrics.
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- 2022
9. Prospective Evaluation of PI-RADS Version 2.1 for Prostate Cancer Detection and Investigation of Multiparametric MRI–derived Markers
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Enis C. Yilmaz, Joanna H. Shih, Mason J. Belue, Stephanie A. Harmon, Tim E. Phelps, Charisse Garcia, Lindsey A. Hazen, Antoun Toubaji, Maria J. Merino, Sandeep Gurram, Peter L. Choyke, Bradford J. Wood, Peter A. Pinto, and Baris Turkbey
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Radiology, Nuclear Medicine and imaging - Published
- 2023
10. An MRI-based radiomics model to predict clear cell renal cell carcinoma growth rate classes in patients with von Hippel-Lindau syndrome
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Pouria Yazdian Anari, Nathan Lay, Nikhil Gopal, Aditi Chaurasia, Safa Samimi, Stephanie Harmon, Fatemeh Dehghani Firouzabadi, Maria J. Merino, Paul Wakim, Evrim Turkbey, Elizabeth C. Jones, Mark W. Ball, Baris Turkbey, W. Marston Linehan, and Ashkan A. Malayeri
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Adult ,Machine Learning ,von Hippel-Lindau Disease ,Radiological and Ultrasound Technology ,Urology ,Gastroenterology ,Humans ,Radiology, Nuclear Medicine and imaging ,Middle Aged ,Carcinoma, Renal Cell ,Magnetic Resonance Imaging ,Kidney Neoplasms ,Retrospective Studies - Abstract
Upfront knowledge of tumor growth rates of clear cell renal cell carcinoma in von Hippel-Lindau syndrome (VHL) patients can allow for a more personalized approach to either surveillance imaging frequency or surgical planning. In this study, we implement a machine learning algorithm utilizing radiomic features of renal tumors identified on baseline magnetic resonance imaging (MRI) in VHL patients to predict the volumetric growth rate category of these tumors.A total of 73 VHL patients with 173 pathologically confirmed Clear Cell Renal Cell Carcinoma (ccRCCs) underwent MRI at least at two different time points between 2015 and 2021. Each tumor was manually segmented in excretory phase contrast T1 weighed MRI and co-registered on pre-contrast, corticomedullary and nephrographic phases. Radiomic features and volumetric data from each tumor were extracted using the PyRadiomics library in Python (4544 total features). Tumor doubling time (DT) was calculated and patients were divided into two groups: DT = 1 year and DT 1 year. Random forest classifier (RFC) was used to predict the DT category. To measure prediction performance, the cohort was randomly divided into 100 training and test sets (80% and 20%). Model performance was evaluated using area under curve of receiver operating characteristic curve (AUC-ROC), as well as accuracy, F1, precision and recall, reported as percentages with 95% confidence intervals (CIs).The average age of patients was 47.2 ± 10.3 years. Mean interval between MRIs for each patient was 1.3 years. Tumors included in this study were categorized into 155 Grade 2; 16 Grade 3; and 2 Grade 4. Mean accuracy of RFC model was 79.0% [67.4-90.6] and mean AUC-ROC of 0.795 [0.608-0.988]. The accuracy for predicting DT classes was not different among the MRI sequences (P-value = 0.56).Here we demonstrate the utility of machine learning in accurately predicting the renal tumor growth rate category of VHL patients based on radiomic features extracted from different T1-weighted pre- and post-contrast MRI sequences.
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- 2022
11. Differential VHL Mutation Patterns in Bilateral Clear Cell RCC Distinguishes Between Independent Primary Tumors and Contralateral Metastatic Disease
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Cathy D. Vocke, Christopher J. Ricketts, Adam R. Metwalli, Peter A. Pinto, Rabindra Gautam, Mark Raffeld, Maria J. Merino, Mark W. Ball, and W. Marston Linehan
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Von Hippel-Lindau Tumor Suppressor Protein ,Urology ,Mutation ,Humans ,DNA Methylation ,Carcinoma, Renal Cell ,Article ,Kidney Neoplasms - Abstract
OBJECTIVE: To evaluate whether bilateral, multifocal clear cell renal cell carcinoma (ccRCC) patients can be differentiated by VHL mutation analysis into cases that represent either multiple independently arising primary tumors, or a single primary tumor which has spread ipsilaterally as well as to the contralateral kidney. The nature of kidney cancer multifocality outside of known hereditary syndromes is as yet poorly understood. MATERIALS AND METHODS: DNA from multiple tumors per patient were evaluated for somatic VHL gene mutation and hypermethylation. A subset of tumors with shared VHL mutations were analyzed with targeted, next-generation sequencing assays. RESULTS: This cohort contained 5 patients with multiple tumors that demonstrated a shared somatic VHL mutation consistent with metastatic spread including to the contralateral kidney. In several cases this was substantiated by additional shared somatic mutations in ccRCC-associated genes. In contrast, the remaining 14 patients with multiple tumors demonstrated unique, unshared VHL alterations in every analyzed tumor, consistent with independently arising kidney tumors. None of these latter patients showed any evidence of local spread or distant metastasis. CONCLUSION: The spectrum of VHL alterations within evaluated bilateral, multifocal ccRCC tumors from a single patient can distinguish between multiple independent tumor growth and metastasis. This can be performed using currently available clinical genetic tests and will improve the accuracy of patient diagnosis and prognosis, as well as informing appropriate management.
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- 2022
12. Supplementary Figure 2 from A Novel Germline Mutation in BAP1 Predisposes to Familial Clear-Cell Renal Cell Carcinoma
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James Brugarolas, W. Marston Linehan, Charis Eng, Patricia L.M. Dahia, Xian-Jin Xie, Chao Xing, Adam R. Metwalli, Maria J. Merino, Nick Grishin, Lisa Kinch, Lindsay Middelton, James Peterson, Christopher J. Ricketts, Cathy D. Vocke, Alana Christie, Andrea Pavia-Jimenez, Samuel Peña-Llopis, Jessica L. Mester, Laura S. Schmidt, and Megan N. Farley
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PDF file - 233K, VHL mutation status in some but not all tumors from Family NCI-1326.
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- 2023
13. Supplementary Figure Legend from A Novel Germline Mutation in BAP1 Predisposes to Familial Clear-Cell Renal Cell Carcinoma
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James Brugarolas, W. Marston Linehan, Charis Eng, Patricia L.M. Dahia, Xian-Jin Xie, Chao Xing, Adam R. Metwalli, Maria J. Merino, Nick Grishin, Lisa Kinch, Lindsay Middelton, James Peterson, Christopher J. Ricketts, Cathy D. Vocke, Alana Christie, Andrea Pavia-Jimenez, Samuel Peña-Llopis, Jessica L. Mester, Laura S. Schmidt, and Megan N. Farley
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PDF file - 104K
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- 2023
14. Supplementary Figure Legends from Outcomes of Children and Adolescents with Advanced Hereditary Medullary Thyroid Carcinoma Treated with Vandetanib
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Brigitte C. Widemann, Jack F. Shern, John W. Glod, Paul S. Meltzer, Maria J. Merino, Frank M. Balis, Elizabeth Fox, Oxana Kapustina, Steven G. Waguespack, Maya Lodish, Seth M. Steinberg, Eva Dombi, Claudia Derse-Anthony, Haiyan Lei, Yuelin Zhu, Srivandana Akshintala, and Ira L. Kraft
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Legends for all included Supplementary Figures
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- 2023
15. Supplementary Figure 5 from Outcomes of Children and Adolescents with Advanced Hereditary Medullary Thyroid Carcinoma Treated with Vandetanib
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Brigitte C. Widemann, Jack F. Shern, John W. Glod, Paul S. Meltzer, Maria J. Merino, Frank M. Balis, Elizabeth Fox, Oxana Kapustina, Steven G. Waguespack, Maya Lodish, Seth M. Steinberg, Eva Dombi, Claudia Derse-Anthony, Haiyan Lei, Yuelin Zhu, Srivandana Akshintala, and Ira L. Kraft
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Heat map of cell cycle gene expression. Gene expression was normalized and compared between the primary MTC, metastasis one, and metastasis two lesions from the whole transcriptome RNA-seq data. Purple indicates lower and yellow indicates higher expression. Values to generate colors are z-scores across each genes' relative transcript levels [log2(FPKM)].
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- 2023
16. Data from A Unique Spectrum of Somatic PIK3CA (p110α) Mutations Within Primary Endometrial Carcinomas
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Daphne W. Bell, Maria J. Merino, Dennis C. Sgroi, Andrew K. Godwin, Sarah Fogoros, Jessica C. Price, and Meghan L. Rudd
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Purpose: The goal of this study was to comprehensively define the incidence of mutations in all exons of PIK3CA in both endometrioid endometrial cancer (EEC) and nonendometrioid endometrial cancer (NEEC).Experimental Design: We resequenced all coding exons of PIK3CA and PTEN, and exons 1 and 2 of KRAS, from 108 primary endometrial tumors. Somatic mutations were confirmed by sequencing matched normal DNAs. The biochemical properties of a subset of novel PIK3CA mutations were determined by exogenously expressing wild type and mutant constructs in U2OS cells and measuring levels of AKTSer473 phosphorylation.Results: Somatic PIK3CA mutations were detected in 52.4% of 42 EECs and 33.3% of 66 NEECs. Half (29 of 58) of all nonsynonymous PIK3CA mutations were in exons 1–7 and half were in exons 9 and 20. The exons 1–7 mutations localized to the ABD, ABD-RBD linker and C2 domains of p110α. Within these regions, Arg88, Arg93, Gly106, Lys111, Glu365, and Glu453, were recurrently mutated; Arg88, Arg93, and Lys111 formed mutation hotspots. The p110α-R93W, -G106R, -G106V, -K111E, -delP449-L455, and -E453K mutants led to increased levels of phospho-AKTSer473 compared to wild-type p110α. Overall, 62% of exons 1–7 PIK3CA mutants and 64% of exons 9–20 PIK3CA mutants were activating; 72% of exon 1–7 mutations have not previously been reported in endometrial cancer.Conclusions: Our study identified a new subgroup of endometrial cancer patients with activating mutations in the amino-terminal domains of p110α; these patients might be appropriate for consideration in clinical trials of targeted therapies directed against the PI3K pathway. Clin Cancer Res; 17(6); 1331–40. ©2011 AACR.
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- 2023
17. Supplementary Figure 4 from Outcomes of Children and Adolescents with Advanced Hereditary Medullary Thyroid Carcinoma Treated with Vandetanib
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Brigitte C. Widemann, Jack F. Shern, John W. Glod, Paul S. Meltzer, Maria J. Merino, Frank M. Balis, Elizabeth Fox, Oxana Kapustina, Steven G. Waguespack, Maya Lodish, Seth M. Steinberg, Eva Dombi, Claudia Derse-Anthony, Haiyan Lei, Yuelin Zhu, Srivandana Akshintala, and Ira L. Kraft
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Weight-for-age and height-for-age growth curves. Male patient weights (A), heights (B) and female patient weights (C), and heights (D) were monitored during the follow up period. Patient weight-for-age and height-for-age values were compared to U.S. Center for Disease Control reference growth curves.
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- 2023
18. Supplementary Figure 3 from Outcomes of Children and Adolescents with Advanced Hereditary Medullary Thyroid Carcinoma Treated with Vandetanib
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Brigitte C. Widemann, Jack F. Shern, John W. Glod, Paul S. Meltzer, Maria J. Merino, Frank M. Balis, Elizabeth Fox, Oxana Kapustina, Steven G. Waguespack, Maya Lodish, Seth M. Steinberg, Eva Dombi, Claudia Derse-Anthony, Haiyan Lei, Yuelin Zhu, Srivandana Akshintala, and Ira L. Kraft
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Doubling time of calcitonin and CEA for patient #12 was suggestive of progressive disease. Patient #12 experienced best response 434 days after starting vandetanib, with stable lesions in the thyroid bed (showed on T2-weighted MRI of the neck, A) and the mediastinum (showed on CT of the chest, B). In August 2016, the sum of longest diameter (per RECIST) of target lesions was consistent with SD (C,D) (note that not all target lesions are shown). Biomarker response in the two years prior (E) showed CEA doubling time 1.2 years (F) and calcitonin doubling time 1.67 years (G). Patient #12 was confirmed to have PD via RECIST February 2017.
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- 2023
19. Data from Sequential Prostate Magnetic Resonance Imaging in Newly Diagnosed High-risk Prostate Cancer Treated with Neoadjuvant Enzalutamide is Predictive of Therapeutic Response
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William L. Dahut, Peter A. Pinto, Baris Turkbey, Adam G. Sowalsky, James L. Gulley, Peter L. Choyke, Huihui Ye, Rosina T. Lis, Monique N. Williams, Amy Hankin, Anna Couvillon, Marijo Bilusic, Guinevere Chun, Nicolas T. Terrigino, John R. Bright, Nicole V. Carrabba, Lisa M. Cordes, David J. VanderWeele, Stephanie A. Harmon, Maria J. Merino, Joanna H. Shih, Ravi A. Madan, Scott Wilkinson, Stephanie M. Walker, and Fatima Karzai
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Purpose:For high-risk prostate cancer, standard treatment options include radical prostatectomy (RP) or radiotherapy plus androgen deprivation therapy (ADT). Despite definitive therapy, many patients will have disease recurrence. Imaging has the potential to better define characteristics of response and resistance. In this study, we evaluated prostate multiparametric MRI (mpMRI) before and after neoadjuvant enzalutamide plus ADT.Patients and Methods:Men with localized intermediate- or high-risk prostate cancer underwent a baseline mpMRI and mpMRI-targeted biopsy followed by a second mpMRI after 6 months of enzalutamide and ADT prior to RP. Specimens were sectioned in the same plane as mpMRI using patient-specific 3D-printed molds to permit mpMRI-targeted biopsies to be compared with the same lesion from the RP. Specimens were analyzed for imaging and histologic correlates of response.Results:Of 39 patients enrolled, 36 completed imaging and RP. Most patients (92%) had high-risk disease. Fifty-eight lesions were detected on baseline mpMRI, of which 40 (69%) remained measurable at 6-month follow-up imaging. Fifty-five of 59 lesions (93%) demonstrated >50% volume reduction on posttreatment mpMRI. Three of 59 lesions (5%) demonstrated growth in size at follow-up imaging, with two lesions increasing more than 3-fold in volume. On whole-mount pathology, 15 patients demonstrated minimal residual disease (MRD) of Conclusions:Low relative lesion volume at baseline mpMRI was predictive of pathologic response. A subset of patients had limited response. Selection of patients based on these metrics may improve outcomes in high-risk disease.
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- 2023
20. Data from Outcomes of Children and Adolescents with Advanced Hereditary Medullary Thyroid Carcinoma Treated with Vandetanib
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Brigitte C. Widemann, Jack F. Shern, John W. Glod, Paul S. Meltzer, Maria J. Merino, Frank M. Balis, Elizabeth Fox, Oxana Kapustina, Steven G. Waguespack, Maya Lodish, Seth M. Steinberg, Eva Dombi, Claudia Derse-Anthony, Haiyan Lei, Yuelin Zhu, Srivandana Akshintala, and Ira L. Kraft
- Abstract
Purpose: Vandetanib is well-tolerated in patients with advanced medullary thyroid carcinoma (MTC). Long-term outcomes and mechanisms of MTC progression have not been reported previously.Experimental Design: We monitored toxicities and disease status in patients taking vandetanib for hereditary, advanced MTC. Tumor samples were analyzed for molecular mechanisms of disease progression.Results: Seventeen patients [8 male, age 13 (9–17)* years] enrolled; 16 had a RET p.Met918Thr germline mutation. The duration of vandetanib therapy was 6.1 (0.1–9.7+)* years with treatment ongoing in 9 patients. Best response was partial response in 10, stable disease in 6, and progressive disease in one patient. Duration of response was 7.4 (0.6–8.7+)* and 4.9 (0.6–7.8+)* years in patients with PR and SD, respectively. Six patients died 2.0 (0.4–5.7)* years after progression. Median progression-free survival (PFS) was 6.7 years [95% confidence interval (CI): 2.3 years–undefined] and 5-year overall survival (OS) was 88.2% (95% CI: 60.6%–96.9%). Of 16 patients with a RET p.Met918Thr mutation, progression-free survival was 6.7 years (95% CI: 3.1–undefined) and 5-year overall survival was 93.8% (95% CI: 63.2%–99.1%). No patients terminated treatment because of toxicity. DNA sequencing of tissue samples (n = 11) identified an increase in copy number alterations across the genome as a potential mechanism of drug resistance [*median (range)].Conclusions: This study demonstrates that vandetanib is safe and results in sustained responses in children and adolescents with hereditary MTC. Our preliminary molecular data suggest that an increase in copy number abnormalities may be associated with tumor progression in hereditary MTC patients treated with vandetanib. Clin Cancer Res; 24(4); 753–65. ©2017 AACR.
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- 2023
21. Data from Vandetanib in Children and Adolescents with Multiple Endocrine Neoplasia Type 2B Associated Medullary Thyroid Carcinoma
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Frank M. Balis, Samuel A. Wells, Seth M. Steinberg, Eva Dombi, Maya Lodish, Maria J. Merino, Patricia O. Whitcomb, Alberta Aikin, Leigh Marcus, Meredith K. Chuk, Brigitte C. Widemann, and Elizabeth Fox
- Abstract
Purpose: Medullary thyroid carcinoma (MTC) is a manifestation of multiple endocrine neoplasia type 2 (MEN2) syndromes caused by germline, activating mutations in the RET (REarranged during Transfection) proto-oncogene. Vandetanib, a VEGF and EGF receptor inhibitor, blocks RET tyrosine kinase activity and is active in adults with hereditary MTC.Experimental Design: We conducted a phase I/II trial of vandetanib for children (5–12 years) and adolescents (13–18 years) with MTC to define a recommended dose and assess antitumor activity. The starting dose was 100 mg/m2 administered orally, once daily, continuously for 28-day treatment cycles. The dose could be escalated to 150 mg/m2/d after two cycles. Radiographic response to vandetanib was quantified using RECIST (v1.0), biomarker response was measured by comparing posttreatment serum calcitonin and carcinoembryonic antigen (CEA) levels to baseline, and a patient-reported outcome was used to assess clinical benefit.Results: Sixteen patients with locally advanced or metastatic MTC received vandetanib for a median (range) 27 (2–52) cycles. Eleven patients remain on protocol therapy. Diarrhea was the primary dose-limiting toxicity. In subjects with M918T RET germline mutations (n = 15) the confirmed objective partial response rate was 47% (exact 95% confidence intervals, 21%–75%). Biomarker partial response was confirmed for calcitonin in 12 subjects and for CEA in 8 subjects.Conclusion: Using an innovative trial design and selecting patients based on target gene expression, we conclude that vandetanib 100 mg/m2/d is a well-tolerated and highly active new treatment for children and adolescents with MEN2B and locally advanced or metastatic MTC. Clin Cancer Res; 19(15); 4239–48. ©2013 AACR.
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- 2023
22. Supplementary Data from A Unique Spectrum of Somatic PIK3CA (p110α) Mutations Within Primary Endometrial Carcinomas
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Daphne W. Bell, Maria J. Merino, Dennis C. Sgroi, Andrew K. Godwin, Sarah Fogoros, Jessica C. Price, and Meghan L. Rudd
- Abstract
Supplementary Figure S1; Supplementary Tables S1-S5.
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- 2023
23. Supplementary Figure Legend from Vandetanib in Children and Adolescents with Multiple Endocrine Neoplasia Type 2B Associated Medullary Thyroid Carcinoma
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Frank M. Balis, Samuel A. Wells, Seth M. Steinberg, Eva Dombi, Maya Lodish, Maria J. Merino, Patricia O. Whitcomb, Alberta Aikin, Leigh Marcus, Meredith K. Chuk, Brigitte C. Widemann, and Elizabeth Fox
- Abstract
PDF file - 67K
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- 2023
24. Supplementary Data from Sequential Prostate Magnetic Resonance Imaging in Newly Diagnosed High-risk Prostate Cancer Treated with Neoadjuvant Enzalutamide is Predictive of Therapeutic Response
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William L. Dahut, Peter A. Pinto, Baris Turkbey, Adam G. Sowalsky, James L. Gulley, Peter L. Choyke, Huihui Ye, Rosina T. Lis, Monique N. Williams, Amy Hankin, Anna Couvillon, Marijo Bilusic, Guinevere Chun, Nicolas T. Terrigino, John R. Bright, Nicole V. Carrabba, Lisa M. Cordes, David J. VanderWeele, Stephanie A. Harmon, Maria J. Merino, Joanna H. Shih, Ravi A. Madan, Scott Wilkinson, Stephanie M. Walker, and Fatima Karzai
- Abstract
Contains supplementary methods and 3 supplementary tables.
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- 2023
25. Supplementary Figure 2 from Outcomes of Children and Adolescents with Advanced Hereditary Medullary Thyroid Carcinoma Treated with Vandetanib
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Brigitte C. Widemann, Jack F. Shern, John W. Glod, Paul S. Meltzer, Maria J. Merino, Frank M. Balis, Elizabeth Fox, Oxana Kapustina, Steven G. Waguespack, Maya Lodish, Seth M. Steinberg, Eva Dombi, Claudia Derse-Anthony, Haiyan Lei, Yuelin Zhu, Srivandana Akshintala, and Ira L. Kraft
- Abstract
Doubling time of calcitonin and CEA during vandetanib therapy. Calcitonin and CEA slopes and doubling times were calculated from the change during the initial four months of vandetanib (A,B), from values the year before experiencing PD or the data cutoff (C,D) and in patients that experienced progressive disease (E).
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- 2023
26. Supplementary Figure 1b from Outcomes of Children and Adolescents with Advanced Hereditary Medullary Thyroid Carcinoma Treated with Vandetanib
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Brigitte C. Widemann, Jack F. Shern, John W. Glod, Paul S. Meltzer, Maria J. Merino, Frank M. Balis, Elizabeth Fox, Oxana Kapustina, Steven G. Waguespack, Maya Lodish, Seth M. Steinberg, Eva Dombi, Claudia Derse-Anthony, Haiyan Lei, Yuelin Zhu, Srivandana Akshintala, and Ira L. Kraft
- Abstract
Patients #2, #5, #10, #11, #13, #15, and #16 experienced durable SD or PR during the follow up period. Calcitonin and CEA are shown as percent change from baseline at the start of vandetanib therapy (left y-axis). Tumor size is the sum of longest diameter of lesions per RECISTv1.0 (right y-axis).
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- 2023
27. Data from Nm23-H1 Suppresses Metastasis by Inhibiting Expression of the Lysophosphatidic Acid Receptor EDG2
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Patricia S. Steeg, Chand Khanna, Seth M. Steinberg, Maria J. Merino, Emily Hua, William G. McDermott, Cari Graff-Cherry, Mary Albaugh, Eleazar Vega-Valle, Arnulfo Mendoza, and Christine E. Horak
- Abstract
Nm23-H1 transcriptionally down-regulates expression of the lysophosphatidic acid receptor EDG2 and this down-regulation is critical for Nm23-H1–mediated motility suppression in vitro. We investigated the effect of altered EDG2 expression on Nm23-H1–mediated metastasis suppression in vivo. Clonal MDA-MB-435–derived tumor cell lines transfected with Nm23-H1 together with either a vector control or EDG2 had similar anchorage-dependent and anchorage-independent growth rates in vitro. However, a 45- and 300-fold inhibition of motility and invasion (P < 0.0001), respectively, was observed in Nm23-H1/vector lines, whereas coexpression of EDG2 restored activity to levels observed in the parental line. Using fluorescently labeled cells and ex vivo microscopy, the capacity of these cells to adhere, arrest, extravasate, and survive in the murine lung over a 24-h time course was measured. Only 5% of Nm23-H1/vector–transfected cells were retained in the murine lung 6 h following tail vein injection; coexpression of EDG2 enhanced retention 8- to 13-fold (P < 0.01). In a spontaneous metastasis assay, the primary tumor size of Nm23-H1/vector and Nm23-H1/EDG2 clones was not significantly different. However, restoration of EDG2 expression augmented the incidence of pulmonary metastasis from 51.9% to 90.4% (P = 2.4 × 10−5), comparable with parental MDA-MB-435 cells. To determine the relevance of this model system to human breast cancer, a cohort of breast carcinomas was stained for Nm23-H1 and EDG2 and a statistically significant inverse correlation between these two proteins was revealed (r = −0.73; P = 0.004). The data indicate that Nm23-H1 down-regulation of EDG2 is functionally important to suppression of tumor metastasis. [Cancer Res 2007;67(24):11751–9]
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- 2023
28. Supplementary Table 1, Figure Legend from Nm23-H1 Suppresses Metastasis by Inhibiting Expression of the Lysophosphatidic Acid Receptor EDG2
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Patricia S. Steeg, Chand Khanna, Seth M. Steinberg, Maria J. Merino, Emily Hua, William G. McDermott, Cari Graff-Cherry, Mary Albaugh, Eleazar Vega-Valle, Arnulfo Mendoza, and Christine E. Horak
- Abstract
Supplementary Table 1, Figure Legend from Nm23-H1 Suppresses Metastasis by Inhibiting Expression of the Lysophosphatidic Acid Receptor EDG2
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- 2023
29. Supplementary Figure 1 from Nm23-H1 Suppresses Metastasis by Inhibiting Expression of the Lysophosphatidic Acid Receptor EDG2
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Patricia S. Steeg, Chand Khanna, Seth M. Steinberg, Maria J. Merino, Emily Hua, William G. McDermott, Cari Graff-Cherry, Mary Albaugh, Eleazar Vega-Valle, Arnulfo Mendoza, and Christine E. Horak
- Abstract
Supplementary Figure 1 from Nm23-H1 Suppresses Metastasis by Inhibiting Expression of the Lysophosphatidic Acid Receptor EDG2
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- 2023
30. Deep learning‐based decision forest for hereditary clear cell renal cell carcinoma segmentation on MRI
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Nathan Lay, Pouria Yazdian Anari, Aditi Chaurasia, Fatemeh Dehghani Firouzabadi, Stephanie Harmon, Evrim Turkbey, Rabindra Gautam, Safa Samimi, Maria J. Merino, Mark W. Ball, William Marston Linehan, Baris Turkbey, and Ashkan A. Malayeri
- Subjects
General Medicine - Published
- 2023
31. Why Does Magnetic Resonance Imaging-Targeted Biopsy Miss Clinically Significant Cancer?
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Nabila Khondakar, Christian Hague, Nitin Yerram, Michael Ahdoot, Peter A. Pinto, Baris Turkbey, Howard L. Parnes, Joanna Shih, Sherif Mehralivand, Michael Daneshvar, Maria J. Merino, Patrick T. Gomella, Andrew R Wilbur, Bradford J. Wood, Cheyenne Williams, Paul F. Pinsky, Sandeep Gurram, and Minhaj Siddiqui
- Subjects
Image-Guided Biopsy ,Male ,medicine.medical_specialty ,medicine.diagnostic_test ,Missed Diagnosis ,business.industry ,Urology ,Prostate ,Cancer ,Prostatic Neoplasms ,Magnetic resonance imaging ,Middle Aged ,medicine.disease ,Targeted biopsy ,Magnetic Resonance Imaging ,Article ,Biopsy ,medicine ,Humans ,Radiology ,business ,Systematic biopsy ,Aged ,Retrospective Studies - Abstract
PURPOSE: Multiple studies demonstrate MRI-targeted biopsy detects more clinically significant cancer than systematic biopsy, however some clinically significant cancers are detected by systematic biopsy only. While these events are rare, we sought to perform a retrospective analysis of these cases to ascertain the reasons that MRI-targeted biopsy missed clinically significant cancer, which was subsequently detected on systematic prostate biopsy. METHODS: Patients were enrolled in a prospective study comparing cancer detection rates by transrectal MRI-targeted fusion biopsy and systematic 12-core biopsy. Patients with an elevated PSA, abnormal digital rectal exam, or imaging findings concerning for prostate cancer underwent prostate MRI and subsequent MRI-targeted and systematic biopsy in the same setting. The subset of patients with grade group (GG) ≥3 cancer found on systematic biopsy and GG≤2 cancer (or no cancer) on MRI-targeted biopsy were classified as MRI-targeted biopsy misses. A retrospective analysis of the MRI and MRI-targeted biopsy real-time screen captures determined the cause of MRI-targeted biopsy miss. Multivariable logistic regression analysis compared baseline characteristics of patients with MRI-targeted biopsy misses to GG-matched patients whose clinically significant cancer was detected by MRI-targeted biopsy. RESULTS: Over the study period of 2007 to 2019, 2103 patients met study inclusion criteria and underwent combined MRI-targeted and systematic prostate biopsies. 41 (1.9%) men were classified as MRI-targeted biopsy misses. Most MRI-targeted biopsy misses were due to errors in lesion targeting (n=21, 51.2%), followed by MRI-invisible lesions (n=17, 40.5%), and MRI lesions missed by the radiologist (n=3, 7.1%). On logistic regression analysis, lower PI-RADS score was associated with having clinically significant cancer missed on MRI-targeted biopsy. CONCLUSION: While uncommon, most MRI-targeted biopsy misses are due to errors in lesions targeting, which highlights the importance of accurate co-registration and targeting when using software-based fusion platforms. Additionally, some patients will harbor MRI-invisible lesions which are un-targetable by MRI-targeted platforms. The presence of a low PI-RADS score despite a high PSA is suggestive of harboring an MRI-invisible lesion.
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- 2023
32. Ipsilateral hemigland prostate biopsy may underestimate cancer burden in patients with unilateral mpMRI-visible lesions
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Tim E. Phelps, Enis C. Yilmaz, Stephanie A. Harmon, Mason J. Belue, Joanna H. Shih, Charisse Garcia, Lindsey A. Hazen, Antoun Toubaji, Maria J. Merino, Sandeep Gurram, Peter L. Choyke, Bradford J. Wood, Peter A. Pinto, and Baris Turkbey
- Subjects
Radiological and Ultrasound Technology ,Urology ,Gastroenterology ,Radiology, Nuclear Medicine and imaging - Published
- 2022
33. A diagnosis of Birt–Hogg–Dubé syndrome in individuals with Smith–Magenis syndrome: Recommendation for cancer screening
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Cathy D. Vocke, Leah R. Fleming, Anna M. Piskorski, Ali Amin, Chanika Phornphutkul, Suzanne de la Monte, Thierry Vilboux, Folami Duncan, Joan Pellegrino, Bonnie Braddock, Lindsay A. Middelton, Laura S. Schmidt, Maria J. Merino, Edward W. Cowen, Wendy J. Introne, W. Marston Linehan, and Ann C. M. Smith
- Subjects
Genetics ,Genetics (clinical) ,Article - Abstract
We report a series of four unrelated adults with Smith-Magenis syndrome (SMS) and concomitant features of Birt-Hogg-Dubé (BHD) syndrome based upon haploinsufficiency for FLCN and characteristic renal cell carcinomas and/or evidence of cutaneous fibrofolliculomas. Three of the cases constitute the first known association of histopathologically verified characteristic BHD-associated renal tumors in adults with SMS; the fourth was identified to have histologically confirmed skin fibrofolliculomas. Molecular analysis documented second-hit FLCN mutations in two of the three cases with confirmed BHD renal pathology. These cases suggest the need to expand management recommendations for SMS to include kidney cancer surveillance starting at 20 years of age, as per the screening recommendations for BHD syndrome.
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- 2022
34. MRI Guided Fresh Tissue Procurement in Radical Prostatectomy Specimens: An Evolutionary Paradigm
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Raiza Z Freidlin, Marcial A Garmendia, Jonathan Krynitsky, Cody Bastian, Connor Schultz, Julian Custer, Sarah Young, Sherif Mehralivand, Maria J Merino, Vladimir A Valera, Peter Pinto, Baris Turkbey, Choyke L Peter, and Thomas J Pohida
- Abstract
PurposeThe aim of this work is to assess the feasibility of novel targeted methods for fresh tissue procurement that facilitate accurate identification of lesion location and tissue sample extraction in an excised prostate gland, while minimizing the tissue deformation or damage.Methods and ResultsProposed fresh tissue procurement methods are based on utilizing a custom 3D printed patient-specific prostate mold. In the semi-freehand method, the access cut is guided by a set of markers on the bottom of the mold that define the boundary of a lesion in two orthogonal directions. The procurement site is identified by palpation. In the guided cut with-locator card method the procurement sites are identified by a cutout in the locator cards inserted into the access cuts. The two approaches were utilized to procure >50 samples. In the biopsy needle method guiding channels were designed into the prostate mold to procure fresh tissue. This method was used 4 times. Finally, a mixed-reality biopsy needle method was developed for phantom testing.ConclusionsPreliminary results of fresh tissue procurement utilizing novel methods showed improve precision of obtaining cancerous fresh tissue for molecular and genomic cancer research compared to current methods which rely on surgical estimation of lesion location.
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- 2022
35. Abstract 1518: Benign oncocytic tumors in the setting of HLRCC syndrome
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Dilara Akbulut, Mark Ball, Mark Raffeld, Marston Linehan, and Maria J. Merino
- Subjects
Cancer Research ,Oncology - Abstract
Background: Renal cell carcinomas developing in patients with HLRCC syndrome are known to be aggressive single tumors of variable sizes, with a well-established morphology. Other morphological tumor types occurring in association with classic HLRCC tumors as independent neoplasias in this syndrome, have not been clearly recognized and described. We describe four patients with known HLRCC syndrome with confirmed germ line mutation who developed benign oncocytic renal tumors. Since HLRCC can also be oncocytic in many instances, it is important to be aware of the possible benign oncocytic tumors in this patient group. Design: Four patients with known positive germ line FH mutation and known HLRCC syndrome developed associated or new oncocytic tumors. All tumors were morphologically evaluated, IHC staining was done for FH, 2SC, CKIT, CK7, PAX8 and molecular studies were performed with TSO-500 for the evaluation of other genes. Clinicopathological correlation was done in all cases. Results: The tumors had been identified radiologically and were suspicious for malignancy. Age range was 37-73 years, and all the patients were female. Two patients had coexistent HLRCC cancers while two only had the oncocytomas. Localization was left kidney for all the masses, which were brown in color and well circumscribed and varied in size from 0.7 to 4 cm. In one patient, four separate masses were identified with different locations and sizes, but with the same morphology. This specific patient presented with two additional masses in the opposite kidney later. Tumors were composed of large oncocytic cells with prominent granular eosinophilic cytoplasm and dark pyknotic nuclei. No evidence of atypia, mitosis or necrosis was found. FH was positive, 2SC and CK7 were negative on IHC stains, whereas CKIT showed diffuse membranous positivity. Tumors were diagnosed as oncocytomas. All patients were positive for FH germ line mutation and the mutation was also identified in the tissues. Other molecular studies on the patient with multiple tumors showed additional pathogenic ERCC2 inactivating mutation, suggesting germline, which is rarely encountered in kidney tumors. All the patients are alive and free of disease up to 10 years after diagnosis. Conclusion: HLRCC cancers can have a variety of morphologic patterns and frequently have oncocytic features. Clinical information, genetic testing and special techniques are helpful in the diagnosis of these high-grade tumors. Recognizing that other benign indolent tumors with oncocytic features can occur in this syndrome is important to avoid errors in diagnosis and treatment. Citation Format: Dilara Akbulut, Mark Ball, Mark Raffeld, Marston Linehan, Maria J. Merino. Benign oncocytic tumors in the setting of HLRCC syndrome [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1518.
- Published
- 2023
36. Inherited risk for prostate cancer (PCa): Following the natural history of men with high-risk genetics using multiparametric MRI (mpMRI)
- Author
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Anna Couvillon, Baris Turkbey, Peter L. Choyke, Katherine Lee-Wisdom, Yolanda McKinney, Robert Sidlow, Michael P. Mullane, Veda N. Giri, Todd Matthew Morgan, Heather H. Cheng, Maria J. Merino, William Douglas Figg, Peter A. Pinto, William L. Dahut, and Fatima Karzai
- Subjects
Cancer Research ,Oncology - Abstract
390 Background: PCa has inherited risk factors including high genetic risk variants such as BRCA1/2, HOXB13, and DNA mismatch repair genes. mpMRI has been shown to be effective for detection and staging of localized PCa. This study follows participants (prts), born biologically male, without a diagnosis of PCa with known germline pathogenic or likely pathogenic variants (PV) in BRCA1/2, MLH1, MSH2, MSH6, PMS2, EPCAM, HOXB13, ATM, NBN, TP53, CHEK2, PALB2, RAD51C/D, BRIP1, or FANCA-FANCM (NCT03805919). Methods: Up to 500 eligible prts 30-75 years old (yo) with a documented germline PV will enroll. Prts undergo biennial clinical exam and mpMRI, and annual PSA monitoring and are followed at 12-month intervals to determine PSA, prostate cancer diagnosis, and/or disease/survival status until death. Indication for prostate biopsy includes clinical or imaging findings. Biopsy specimens undergo molecular analyses. Results: To date, 175 prts have been enrolled: 169 (97%) White, 3 Hispanic (2%), 1 African American (1%), 1 Asian (1%), and 1 biethnic (1%). Median age is 47 yo. The most common monoallelic PV are: 48.6% BRCA2, 25.1% BRCA1, 6.3% CHEK2 and 5.7% MSH2. PVs in ATM, PALB2, HOXB13, PMS2, MLH1, MSH6, BRIP1, EPCAM and RAD51D are ≤4%. One subject carries three distinct PVs ( BRCA2, CHEK2, BRIP1). Indication for biopsy was found in 26.3% of prts with 22/46 (47.8%) with a PIRADS 4 lesion, 6/46 (13.0%) PIRADS 3 lesion, 12/46 (26.1%) elevated PSA (median=2.8 ng/mL) or 6/46 (13.0%) due to clinical discretion. Adenocarcinoma was diagnosed on 13/39 (33.3%) biopsies with median age at diagnosis=59 yo. 9/13 (69%) prts had a PSA
- Published
- 2023
37. Contributors
- Author
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Sylvia Asa, Elizaveta Belyaeva, Pincas Bitterman, Dustin E. Bosch, Elizabeth J. Cochran, Kumarasen Cooper, Byron Crawford, Kossivi Dantey, Virginia E. Duncan, Adel K. El-Naggar, Mark F. Evans, Huma Fatima, Sandra E. Fischer, Julia T. Geyer, Richard J. Grostern, Ralph H. Hruban, Aliya N. Husain, Alexandra N. Kalof, Nikolaj P. Lagwinski, Cristina Magi-Galluzzi, Meera Mahalingam, Maria J. Merino, Ira Miller, Attilio Orazi, Hreem N. Patel, Sunny B. Patel, Robert E. Petras, Michael R. Pins, Sonam Prakash, Vijaya B. Reddy, E. Rene Rodriguez, John J. Schmieg, Jefree Schulte, David Suster, Saul Suster, Paul E. Swanson, Carmela D. Tan, Elizabeth Thompson, Michelle D. Williams, Lei Yan, Matthew M. Yeh, and Ming Zhou
- Published
- 2022
38. Breast
- Author
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Maria J. Merino
- Published
- 2022
39. Magnetic Resonance Imaging-Guided Biopsy in Active Surveillance of Prostate Cancer
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Elizabeth Tran, S. Raman, Nitin Yerram, Vidit Sharma, Peter L. Choyke, Wayne Brisbane, Michael Ahdoot, Rajiv Jayadevan, Maria J. Merino, Ryan Chuang, Alan Priester, Danielle Barsa, Anthony Sisk, Merdie Delfin, Peter A. Pinto, Michael Daneshvar, Leonard S. Marks, Ely Felker, Bradford J. Wood, Lorna Kwan, Baris Turkbey, Luke P. O'Connor, Robert E. Reiter, and Adam Kinnaird
- Subjects
Image-Guided Biopsy ,Male ,medicine.medical_specialty ,Urology ,Active surveillance of prostate cancer ,Disease ,MRI guided biopsy ,Prostate cancer ,Risk Factors ,medicine ,Humans ,Prospective Studies ,Watchful Waiting ,Aged ,Prostatectomy ,business.industry ,fungi ,food and beverages ,Prostatic Neoplasms ,Middle Aged ,medicine.disease ,Magnetic Resonance Imaging ,Radiology ,Neoplasm Grading ,business ,Follow-Up Studies - Abstract
The underlying premise of prostate cancer active surveillance (AS) is that cancers likely to metastasize will be recognized and eliminated before cancer-related disease can ensue. Our study was designed to determine the prostate cancer upgrading rate when biopsy guided by magnetic resonance imaging (MRGBx) is used before entry and during AS.The cohort included 519 men with low- or intermediate-risk prostate cancer who enrolled in prospective studies (NCT00949819 and NCT00102544) between February 2008 and February 2020. Subjects were preliminarily diagnosed with Gleason Grade Group (GG) 1 cancer; AS began when subsequent MRGBx confirmed GG1 or GG2. Participants underwent confirmatory MRGBx (targeted and systematic) followed by surveillance MRGBx approximately every 12 to 24 months. The primary outcome was tumor upgrading to ≥GG3.Upgrading to ≥GG3 was found in 92 men after a median followup of 4.8 years (IQR 3.1-6.5) after confirmatory MRGBx. Upgrade-free probability after 5 years was 0.85 (95% CI 0.81-0.88). Cancer detected in a magnetic resonance imaging lesion at confirmatory MRGBx increased risk of subsequent upgrading during AS (HR 2.8; 95% CI 1.3-6.0), as did presence of GG2 (HR 2.9; 95% CI 1.1-8.2) In men who upgraded ≥GG3 during AS, upgrading was detected by targeted cores only in 27%, systematic cores only in 25% and both in 47%. In 63 men undergoing prostatectomy, upgrading from MRGBx was found in only 5 (8%).When AS begins and follows with MRGBx (targeted and systematic), upgrading rate (≥GG3) is greater when tumor is initially present within a magnetic resonance imaging lesion or when pathology is GG2 than when these features are absent.
- Published
- 2021
40. Abstract 5831: Urinary exosome analysis as a marker of treatment response in bladder cancer patients
- Author
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Vladimir Valera, Beatriz Walter, and Maria J. Merino
- Subjects
Cancer Research ,Oncology - Abstract
Introduction: Intravesical Bacillus Calmette-Guerin (BCG) is an effective immunotherapy for non-muscle invasive bladder cancer (NMIBC). However, BCG treatment failure will lead to recurrence and tumor progression. In this study, urinary exosomes content (miRNA profile) was evaluated as a possible marker of BCG treatment response in NMIBC patients. Methods: Urine samples from patients with bladder cancer were collected at the time of surgery and during patient follow up to 1 year. Urine from healthy volunteers were also included. Clinical and pathological information such as tumor grade (High Grade (HG), Low Grade (LG)), depth of invasion (Ta, T1, CIS), and response to BCG treatment was also obtained. Exosome Isolation and total RNA extraction including microRNAs from cell-free urine after centrifugation were obtained. Library preparation for miRNA expression was done (QIAseq® miRNA Library) for Next-Generation Sequencing (NGS) analysis in a NextSeq 2000 single read platform, 75 bp with 15-20 million reads per sample. Reads were then queried against miRDeep2 software for identification. Only miRNAs having at least 20 counts considering all samples were included. After normalization, significantly and deferentially expressed microRNAs (>2-Fold) were selected for analysis. Bioinformatic analysis including sequence alignment was performed under the STAR-based approach. Identified microRNAs were then used to classify/predict the response to treatment and its relationship with other clinicopathologic variables. Results: A total of 56 urine samples from 13 patients were available/used for analysis including 10 High Grade Ta and 3 High Grade T1 patients. Urine from normal healthy donors (N=3) was also included. Clinicopathological features were patients with HGTa=10, HGT1=3 and 3 control samples. Regarding treatment response 9 patients were BCG responders and 4 BCG unresponsive. When compared to BCG unresponsive patients, BCG responders showed 45 differentially expressed miRNAs. Statistically significant differentially expressed miRNAs (Fold-change >2, p value Conclusion: Our study supports the value of urinary exosomal microRNAs as non-invasive biomarkers to predict BCG treatment response in nonmuscle-invasive bladder cancer. Citation Format: Vladimir Valera, Beatriz Walter, Maria J. Merino. Urinary exosome analysis as a marker of treatment response in bladder cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5831.
- Published
- 2022
41. MPAPASS software enables stitched multiplex, multidimensional EV repertoire analysis and a standard framework for reporting bead-based assays
- Author
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Joshua A. Welsh, Bryce Killingsworth, Julia Kepley, Tim Traynor, Sean Cook, Jason Savage, Jenn Marte, Min-Jung Lee, Hoyoung M. Maeng, Michelle L. Pleet, Setty Magana, André Gorgens, Cecile L. Maire, Katrin Lamszus, Franz L. Ricklefs, Maria J. Merino, W. Marston Linehan, Tim Greten, Tomer Cooks, Curtis C. Harris, Andrea Apolo, Asim Abdel-Mageed, Alexander R. Ivanov, Jane B. Trepel, Matthew Roth, Mercedes Tkach, Aleksandar Milosavljevic, Clotilde Théry, Amy LeBlanc, Jay A. Berzofsky, Eytan Ruppin, Kenneth Aldape, Kevin Camphausen, James L. Gulley, Ionita Ghiran, Steve Jacobson, and Jennifer C. Jones
- Subjects
Cultural Studies ,History ,Literature and Literary Theory - Published
- 2022
42. Risk of adverse pathology at prostatectomy in the era of MRI and targeted biopsies; rethinking active surveillance for intermediate risk prostate cancer patients
- Author
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Baris Turkbey, Peter L. Choyke, Michael Ahdoot, Howard L. Parnes, Graham R. Hale, Amir H. Lebastchi, Bradford J. Wood, Maria J. Merino, Thomas Sanford, Samuel Gold, Jonathan Bloom, Peter A. Pinto, Michael Daneshvar, Vladimir Valera, and Sherif Mehralivand
- Subjects
Image-Guided Biopsy ,Male ,Pathology ,medicine.medical_specialty ,Urology ,medicine.medical_treatment ,030232 urology & nephrology ,Disease ,Gleason grade ,Logistic regression ,03 medical and health sciences ,Prostate cancer ,0302 clinical medicine ,Biopsy ,medicine ,Humans ,Retrospective Studies ,Prostatectomy ,medicine.diagnostic_test ,business.industry ,Prostate ,Prostatic Neoplasms ,Cancer ,Middle Aged ,medicine.disease ,Magnetic Resonance Imaging ,Oncology ,030220 oncology & carcinogenesis ,business ,Intermediate risk - Abstract
Purpose Men with intermediate risk (IR) prostate cancer (CaP) are often excluded from active surveillance (AS) due to higher rates of adverse pathology (AP). We determined our rate of AP in men who underwent multiparametric MRI (MpMRI) with combined biopsy (CB) consisting of targeted biopsy (TB) and systematic biopsy (SB) prior to radical prostatectomy (RP). Methods A retrospective review was conducted of men with Gleason Grade Group (GG) 2 disease who underwent RP after SB alone or after preoperative MRI with CB. AP was defined as either pathologic stage T3a (AP ≥ T3a) or pathologic stage T3b (AP ≥ T3b) and/or GG upgrading. Rates of AP were determined for both groups and those who fit the National Comprehensive Cancer Network (NCCN) definition of favorable IR (FIR) or the low volume IR (LVIR) criteria. Multivariable logistic regression was used to determine predictive factors. Results The overall rate of AP ≥ T3b was 21.2% in the SB group vs. 8.6% in the MRI with CB group, P = 0.006. This rate was lowered to 6.8% and 5.6% when men met the definition of NCCN FIR or LVIR, respectively. Suspicion for extraprostatic extension (EPE) (OR 7.65, 95% CI 1.77−33.09, P = 0.006) and positive cores of GG 2 on SB (OR 1.43, 95% CI 1.05−1.96, P = 0.023) were significant for predicting AP ≥ T3b. Conclusions Rates of AP at RP after MRI with CB are lower than studies prior to the adoption of this technology, suggesting that more men with IR disease may be considered for AS. However, increasing cores positive on SB and MRI findings suggestive of EPE remain unsafe.
- Published
- 2021
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