Publications by authors named "Chantal Pauli"

41 Publications

Targeted Therapies and Checkpoint Inhibitors in Sarcoma.

QJM 2021 Jan 24. Epub 2021 Jan 24.

Department of Plastic Surgery and Hand Surgery, University Hospital Zurich, Zurich, Switzerland.

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http://dx.doi.org/10.1093/qjmed/hcab014DOI Listing
January 2021

Site of Recurrence and Survival after Surgery for Colorectal Peritoneal Metastasis.

J Natl Cancer Inst 2021 Jan 23. Epub 2021 Jan 23.

Surgical Oncology Research Laboratory, Department of Surgery & Transplantation, University Hospital of Zurich, Zurich, Switzerland.

Background: Multimodal treatment, including systemic treatment and surgery, improved the prognosis of peritoneal metastasis (PM). Despite all efforts, recurrence rates remain high, and only little data is available about clinical behavior or molecular patterns of PM in comparison to hematogenous metastasis. Here, we aimed to analyze recurrence patterns after multimodal treatment for PM from colorectal cancer.

Methods: Patients with colorectal PM undergoing multimodal treatment including systemic chemotherapy and cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) between 2005-2017 at four centers were analyzed retrospectively.

Results: A total of 505 patients undergoing CRS/HIPEC were analyzed. 82.1% of patients received preoperative chemotherapy. Median peritoneal cancer index (PCI) was 6 (IQR = 3-11). Median disease-free and overall survival was 12 months (95% confidence interval [CI] = 11 to 14 months) and 51 months (95% CI = 43 to 62 months) respectively. Disease recurred in 361 (71.5%) patients, presenting as isolated peritoneal recurrence in 24.6%, isolated hematogenous recurrence in 28.3%, and mixed recurrence in 13.9% of patients. Recurrence to the peritoneum was associated with an impaired time from recurrence to death of 21 months (95% CI = 18 to 31 months) for isolated peritoneal, and 22 months (95% CI = 16 to 30 months) for mixed recurrence, compared to 43 months (95% CI = 31 to > 121 months) for hematogenous recurrence (hazard ratio [HR] = 1.79, 95% CI = 1.27 to 2.53, p = .001 and HR = 2.44, 95% CI = 1.61 to 3.79, p < .001). On multiple logistic regression analysis, RAS mutational status (OR = 2.42, 95% CI = 1.11 to 5.47, p = .03) and positive nodal stage of the primary (OR = 3.88, 95% CI = 1.40 to 11.86, p = .01) were identified as predictive factors for peritoneal recurrence.

Conclusions: This study highlights the heterogeneity of peritoneal metastasis in patients with colorectal cancer. Recurrent peritoneal metastasis after radical treatment represents a more aggressive subset of metastatic colorectal cancer.
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http://dx.doi.org/10.1093/jnci/djab001DOI Listing
January 2021

Metastasis and immune evasion from extracellular cGAMP hydrolysis.

Cancer Discov 2020 Dec 28. Epub 2020 Dec 28.

HOPP and Radiation Oncology, Memorial Sloan Kettering Cancer Center

Cytosolic DNA is characteristic of chromosomally unstable metastatic cancer cells, resulting in constitutive activation of the cGAS-STING innate immune pathway. How tumors co-opt inflammatory signaling while evading immune surveillance remains unknown. Here we show that the ectonucleotidase ENPP1 promotes metastasis by selectively degrading extracellular cGAMP, an immune stimulatory metabolite whose breakdown products include the immune suppressor, adenosine. ENPP1 loss suppresses metastasis, restores tumor immune infiltration, and potentiates response to immune checkpoint blockade in a manner dependent on tumor cGAS and host STING. Conversely, overexpression of wildtype ENPP1, but not an enzymatically weakened mutant, promotes migration and metastasis, in part, through the generation of extracellular adenosine, and renders otherwise sensitive tumors completely resistant to immunotherapy. In human cancers, ENPP1 expression correlates with reduced immune cell infiltration, increased metastasis, and resistance to anti-PD1/PD-L1 treatment. Thus, cGAMP hydrolysis by ENPP1 enables chromosomally unstable tumors to transmute cGAS activation into an immune suppressive pathway.
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http://dx.doi.org/10.1158/2159-8290.CD-20-0387DOI Listing
December 2020

Cancer Sample Biobanking at the Next Level: Combining Tissue With Living Cell Repositories to Promote Precision Medicine.

Front Cell Dev Biol 2019 22;7:246. Epub 2019 Oct 22.

Department of Pathology and Molecular Pathology, University Hospital of Zürich, Zurich, Switzerland.

Biorespositories of formalin-fixed and paraffin-embedded (FFPE) or fresh frozen human tissues from malignant diseases generated as integral part of the diagnostic workup in many pathology departments have been pivotal resources for translational cancer studies. However, such tissue biobanks have traditionally contained only non-viable specimens and thus cannot enable functional assays for the discovery and validation of therapeutic targets or the assessment of drug responses and resistance to treatment. To overcome these limitations, we have developed a next-generation comprehensive biobanking platform that includes the generation of patient-derived cell models from colorectal, pancreatic and kidney cancers among others. As such patient-derived cell (PDC) models retain important features of the original human tumors, they have emerged as relevant tools for more dynamic clinical and experimental analyses of cancer. Here, we describe details of the complex processes of acquisition and processing of patient-derived samples, propagation, annotation, characterization and distribution of resulting cell models and emphasize the requirements of quality assurance, organizational considerations and investment into resources. Taken together, we show how clinical tissue collections can be taken to the next level thus promising major new opportunities for understanding and treating cancer in the context of precision medicine.
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http://dx.doi.org/10.3389/fcell.2019.00246DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6817465PMC
October 2019

Integrative Molecular Analysis of Patients With Advanced and Metastatic Cancer.

JCO Precis Oncol 2019 20;3. Epub 2019 Sep 20.

Weill Cornell Medicine, New York, NY.

Purpose: We developed a precision medicine program for patients with advanced cancer using integrative whole-exome sequencing and transcriptome analysis.

Patients And Methods: Five hundred fifteen patients with locally advanced/metastatic solid tumors were prospectively enrolled, and paired tumor/normal sequencing was performed. Seven hundred fifty-nine tumors from 515 patients were evaluated.

Results: Most frequent tumor types were prostate (19.4%), brain (16.5%), bladder (15.4%), and kidney cancer (9.2%). Most frequently altered genes were (33%), (11%), (10%), (8%), (8%), and (8%). Pathogenic germline alterations were present in 10.7% of patients, most frequently (1.9%), (1.5%), (1.5%), and (1.4%). Novel gene fusions were identified, including a fusion in a metastatic prostate cancer sample. The rate of clinically relevant alterations was 39% by whole-exome sequencing, which was improved by 16% by adding RNA sequencing. In patients with more than one sequenced tumor sample (n = 146), 84.62% of actionable mutations were concordant.

Conclusion: Integrative analysis may uncover informative alterations for an advanced pan-cancer patient population. These alterations are consistent in spatially and temporally heterogeneous samples.
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http://dx.doi.org/10.1200/PO.19.00047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6778956PMC
September 2019

Tracing Clonal Dynamics Reveals that Two- and Three-dimensional Patient-derived Cell Models Capture Tumor Heterogeneity of Clear Cell Renal Cell Carcinoma.

Eur Urol Focus 2019 Jun 29. Epub 2019 Jun 29.

Department of Pathology and Molecular Pathology, University Hospital and University of Zurich, Zurich, Switzerland.

Background: Extensive DNA sequencing has led to an unprecedented view of the diversity of individual genomes and their evolution among patients with clear cell renal cell carcinoma (ccRCC).

Objective: To understand subclonal architecture and dynamics of patient-derived two-dimensional (2D) and three-dimensional (3D) ccRCC models in vitro, in order to determine whether they mirror ccRCC inter- and intratumor heterogeneity.

Design, Setting, And Participants: We have established a comprehensive platform of living renal cancer cell models from ccRCC surgical specimens.

Outcome Measurements And Statistical Analysis: We confirmed the concordance of 2D and 3D patient-derived cell (PDC) models with the original tumor tissue in terms of histology, biomarker expression, cancer driver mutations, and copy number alterations. We addressed inter- and intrapatient heterogeneity by analyzing clonal dynamics during serial passaging.

Results And Limitations: In-depth genetic characterization verified the presence of heterogeneous cell populations, and revealed a high degree of similarity between subclonal compositions of monolayer and organoid cell cultures and the corresponding parental ccRCCs. Clonal dynamics were evident during serial passaging of cells in vitro, suggesting that PDC cultures can offer insights into evolutionary potential and treatment susceptibility of ccRCC subclones in vivo. Proof-of-concept drug profiling using selected ccRCC-targeted therapy agents highlighted patient-specific vulnerabilities in PDC models that could not be anticipated by interrogating commercially available cell lines.

Conclusions: We demonstrate that PDC models mirror inter- and intratumor heterogeneity of ccRCC in vitro. Based on our findings, we envision that the use of these models will advance our understanding of the trajectories that cause genetic diversity and their consequences for treatment on an individual level.

Patient Summary: In this study, we developed two- and three-dimensional patient-derived models from clear cell renal cell carcinoma (ccRCC) as "mini-tumors in a dish." We show that these cell models retain important features of the human ccRCCs such as the profound tumor heterogeneity, thus highlighting their importance for cancer research and precision medicine.
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http://dx.doi.org/10.1016/j.euf.2019.06.009DOI Listing
June 2019

High-fructose corn syrup enhances intestinal tumor growth in mice.

Science 2019 03;363(6433):1345-1349

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.

Excessive consumption of beverages sweetened with high-fructose corn syrup (HFCS) is associated with obesity and with an increased risk of colorectal cancer. Whether HFCS contributes directly to tumorigenesis is unclear. We investigated the effects of daily oral administration of HFCS in adenomatous polyposis coli (APC) mutant mice, which are predisposed to develop intestinal tumors. The HFCS-treated mice showed a substantial increase in tumor size and tumor grade in the absence of obesity and metabolic syndrome. HFCS increased the concentrations of fructose and glucose in the intestinal lumen and serum, respectively, and the tumors transported both sugars. Within the tumors, fructose was converted to fructose-1-phosphate, leading to activation of glycolysis and increased synthesis of fatty acids that support tumor growth. These mouse studies support the hypothesis that the combination of dietary glucose and fructose, even at a moderate dose, can enhance tumorigenesis.
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http://dx.doi.org/10.1126/science.aat8515DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6487857PMC
March 2019

Suppression of insulin feedback enhances the efficacy of PI3K inhibitors.

Nature 2018 08 4;560(7719):499-503. Epub 2018 Jul 4.

Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA.

Mutations in PIK3CA, which encodes the p110α subunit of the insulin-activated phosphatidylinositol-3 kinase (PI3K), and loss of function mutations in PTEN, which encodes a phosphatase that degrades the phosphoinositide lipids generated by PI3K, are among the most frequent events in human cancers. However, pharmacological inhibition of PI3K has resulted in variable clinical responses, raising the possibility of an inherent mechanism of resistance to treatment. As p110α mediates virtually all cellular responses to insulin, targeted inhibition of this enzyme disrupts glucose metabolism in multiple tissues. For example, blocking insulin signalling promotes glycogen breakdown in the liver and prevents glucose uptake in the skeletal muscle and adipose tissue, resulting in transient hyperglycaemia within a few hours of PI3K inhibition. The effect is usually transient because compensatory insulin release from the pancreas (insulin feedback) restores normal glucose homeostasis. However, the hyperglycaemia may be exacerbated or prolonged in patients with any degree of insulin resistance and, in these cases, necessitates discontinuation of therapy. We hypothesized that insulin feedback induced by PI3K inhibitors may reactivate the PI3K-mTOR signalling axis in tumours, thereby compromising treatment effectiveness. Here we show, in several model tumours in mice, that systemic glucose-insulin feedback caused by targeted inhibition of this pathway is sufficient to activate PI3K signalling, even in the presence of PI3K inhibitors. This insulin feedback can be prevented using dietary or pharmaceutical approaches, which greatly enhance the efficacy/toxicity ratios of PI3K inhibitors. These findings have direct clinical implications for the multiple p110α inhibitors that are in clinical trials and provide a way to increase treatment efficacy for patients with many types of tumour.
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http://dx.doi.org/10.1038/s41586-018-0343-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6197057PMC
August 2018

Patient derived organoids to model rare prostate cancer phenotypes.

Nat Commun 2018 06 19;9(1):2404. Epub 2018 Jun 19.

Department of Medicine, Division of Hematology and Medical Oncology, Weill Cornell Medicine, New York, NY, 10021, USA.

A major hurdle in the study of rare tumors is a lack of existing preclinical models. Neuroendocrine prostate cancer is an uncommon and aggressive histologic variant of prostate cancer that may arise de novo or as a mechanism of treatment resistance in patients with pre-existing castration-resistant prostate cancer. There are few available models to study neuroendocrine prostate cancer. Here, we report the generation and characterization of tumor organoids derived from needle biopsies of metastatic lesions from four patients. We demonstrate genomic, transcriptomic, and epigenomic concordance between organoids and their corresponding patient tumors. We utilize these organoids to understand the biologic role of the epigenetic modifier EZH2 in driving molecular programs associated with neuroendocrine prostate cancer progression. High-throughput organoid drug screening nominated single agents and drug combinations suggesting repurposing opportunities. This proof of principle study represents a strategy for the study of rare cancer phenotypes.
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http://dx.doi.org/10.1038/s41467-018-04495-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6008438PMC
June 2018

Phosphatidylinositol-5-Phosphate 4-Kinases Regulate Cellular Lipid Metabolism By Facilitating Autophagy.

Mol Cell 2018 05;70(3):531-544.e9

Sanford Burnham Prebys Medical Discovery Institute, Cancer Metabolism and Signaling Networks Program, La Jolla, CA 92037, USA. Electronic address:

While the majority of phosphatidylinositol-4, 5-bisphosphate (PI-4, 5-P) in mammalian cells is generated by the conversion of phosphatidylinositol-4-phosphate (PI-4-P) to PI-4, 5-P, a small fraction can be made by phosphorylating phosphatidylinositol-5-phosphate (PI-5-P). The physiological relevance of this second pathway is not clear. Here, we show that deletion of the genes encoding the two most active enzymes in this pathway, Pip4k2a and Pip4k2b, in the liver of mice causes a large enrichment in lipid droplets and in autophagic vesicles during fasting. These changes are due to a defect in the clearance of autophagosomes that halts autophagy and reduces the supply of nutrients salvaged through this pathway. Similar defects in autophagy are seen in nutrient-starved Pip4k2aPip4k2b mouse embryonic fibroblasts and in C. elegans lacking the PI5P4K ortholog. These results suggest that this alternative pathway for PI-4, 5-P synthesis evolved, in part, to enhance the ability of multicellular organisms to survive starvation.
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http://dx.doi.org/10.1016/j.molcel.2018.03.037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5991623PMC
May 2018

Gene expression profiles of the meniscus avascular phenotype: A guide for meniscus tissue engineering.

J Orthop Res 2018 07 14;36(7):1947-1958. Epub 2018 Mar 14.

Shiley Center for Orthopaedic Research and Education at Scripps Clinic, La Jolla, California.

Avascular (Avas) meniscus regeneration remains a challenge, which is partly a consequence of our limited knowledge of the cells that maintain this tissue region. In this study, we utilized microarrays to characterize gene expression profiles of intact human Avas meniscus tissue and of cells following culture expansion. Using these data, we examined various 3D culture conditions to redifferentiate Avas cells toward the tissue phenotype. RNA was isolated from either the tissue directly or following cell isolation and 2 weeks in monolayer culture. RNA was hybridized on human genome arrays. Differentially expressed (DE) genes were identified by ranking analysis. DAVID pathway analysis was performed and visualized using STRING analysis. Quantitative PCR (qPCR) on additional donor menisci (tissues and cells) were used to validate array data. Avas cells cultured in 3D were subjected to qPCR to compare with the array-generated data. A total of 387 genes were DE based on differentiation state (>3-fold change; p < 0.01). In Avas-cultured cells, the upregulated pathways included focal adhesion, ECM-receptor interaction, regulation of actin cytoskeleton, and PDGF Signaling. In 3D-cultured Avas cells, TGFβ1 or combinations of TGFβ1 and BMP6 were most effective to promote an Avas tissue phenotype. THBS2 and THBS4 expression levels were identified as a means to denote meniscus cell phenotype status. We identified the key gene expression profiles, new markers and pathways involved in characterizing the Avas meniscus phenotype in the native state and during in vitro dedifferentiation and redifferentiation. These data served to screen 3D conditions to generate meniscus-like neotissues. © 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1947-1958, 2018.
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http://dx.doi.org/10.1002/jor.23864DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6326361PMC
July 2018

Exploratory Radiomics in Computed Tomography Perfusion of Prostate Cancer.

Anticancer Res 2018 02;38(2):685-690

Department of Radiation Oncology, University Hospital Zurich, University of Zurich, Zurich, Switzerland.

Background/aim: An evaluation if radiomic features of CT perfusion (CTP) can predict tumor grade and aggressiveness in prostate cancer was performed.

Materials And Methods: Forty-seven patients had biopsy-confirmed prostate cancer, and received a CTP. Blood volume (BV), blood flow (BF) and mean transit time (MTT) maps were derived and 1,701 radiomic features were determined per patient. Regression models were built to estimate post-surgical Gleason score (GS), microvessel density (MVD) and distinguish between the different risk groups.

Results: Six out of the 47 patients had to be excluded from further analysis. A weak relationship between postsurgical GS and one radiomic parameter was found (R=0.21, p=0.01). The same parameter combined with MTT inter-quartile range was prognostic for the risk group categorisation (AUC=0.81). Two different radiomic parameters were able to distinguish between low-intermediate risk and high-intermediate risk (AUC=0.77). Four parameters correlated with MVD (R2=0.53, p<0.02).

Conclusion: This exploratory study shows the potential of radiomics to classify prostate cancer.
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http://dx.doi.org/10.21873/anticanres.12273DOI Listing
February 2018

Chromosomal instability drives metastasis through a cytosolic DNA response.

Nature 2018 01 17;553(7689):467-472. Epub 2018 Jan 17.

Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, New York 10065, USA.

Chromosomal instability is a hallmark of cancer that results from ongoing errors in chromosome segregation during mitosis. Although chromosomal instability is a major driver of tumour evolution, its role in metastasis has not been established. Here we show that chromosomal instability promotes metastasis by sustaining a tumour cell-autonomous response to cytosolic DNA. Errors in chromosome segregation create a preponderance of micronuclei whose rupture spills genomic DNA into the cytosol. This leads to the activation of the cGAS-STING (cyclic GMP-AMP synthase-stimulator of interferon genes) cytosolic DNA-sensing pathway and downstream noncanonical NF-κB signalling. Genetic suppression of chromosomal instability markedly delays metastasis even in highly aneuploid tumour models, whereas continuous chromosome segregation errors promote cellular invasion and metastasis in a STING-dependent manner. By subverting lethal epithelial responses to cytosolic DNA, chromosomally unstable tumour cells co-opt chronic activation of innate immune pathways to spread to distant organs.
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http://dx.doi.org/10.1038/nature25432DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5785464PMC
January 2018

Next-Generation Rapid Autopsies Enable Tumor Evolution Tracking and Generation of Preclinical Models.

JCO Precis Oncol 2017 14;2017. Epub 2017 Jun 14.

Weill Cornell Medicine. The Caryl and Israel Englander Institute for Precision Medicine, Weill Cornell Medicine and NewYork-Presbyterian Hospital.

Purpose: Patients with cancer who graciously consent for autopsy represent an invaluable resource for the study of cancer biology. To advance the study of tumor evolution, metastases, and resistance to treatment, we developed a next-generation rapid autopsy program integrated within a broader precision medicine clinical trial that interrogates pre- and postmortem tissue samples for patients of all ages and cancer types.

Materials And Methods: One hundred twenty-three (22%) of 554 patients who consented to the clinical trial also consented for rapid autopsy. This report comprises the first 15 autopsies, including patients with metastatic carcinoma (n = 10), melanoma (n = 1), and glioma (n = 4). Whole-exome sequencing (WES) was performed on frozen autopsy tumor samples from multiple anatomic sites and on non-neoplastic tissue. RNA sequencing (RNA-Seq) was performed on a subset of frozen samples. Tissue was also used for the development of preclinical models, including tumor organoids and patient-derived xenografts.

Results: Three hundred forty-six frozen samples were procured in total. WES was performed on 113 samples and RNA-Seq on 72 samples. Successful cell strain, tumor organoid, and/or patient-derived xenograft development was achieved in four samples, including an inoperable pediatric glioma. WES data were used to assess clonal evolution and molecular heterogeneity of tumors in individual patients. Mutational profiles of primary tumors and metastases yielded candidate mediators of metastatic spread and organotropism including and in metastatic ependymoma and in metastatic melanoma to the lung. RNA-Seq data identified novel gene fusion candidates.

Conclusion: A next-generation sequencing-based autopsy program in conjunction with a pre-mortem precision medicine pipeline for diverse tumors affords a valuable window into clonal evolution, metastasis, and alterations underlying treatment. Moreover, such an autopsy program yields robust preclinical models of disease.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5761727PMC
http://dx.doi.org/10.1200/PO.16.00038DOI Listing
June 2017

Fenofibrate prevents skeletal muscle loss in mice with lung cancer.

Proc Natl Acad Sci U S A 2018 01 8;115(4):E743-E752. Epub 2018 Jan 8.

Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10021;

The cancer anorexia cachexia syndrome is a systemic metabolic disorder characterized by the catabolism of stored nutrients in skeletal muscle and adipose tissue that is particularly prevalent in nonsmall cell lung cancer (NSCLC). Loss of skeletal muscle results in functional impairments and increased mortality. The aim of the present study was to characterize the changes in systemic metabolism in a genetically engineered mouse model of NSCLC. We show that a portion of these animals develop loss of skeletal muscle, loss of adipose tissue, and increased inflammatory markers mirroring the human cachexia syndrome. Using noncachexic and fasted animals as controls, we report a unique cachexia metabolite phenotype that includes the loss of peroxisome proliferator-activated receptor-α (PPARα) -dependent ketone production by the liver. In this setting, glucocorticoid levels rise and correlate with skeletal muscle degradation and hepatic markers of gluconeogenesis. Restoring ketone production using the PPARα agonist, fenofibrate, prevents the loss of skeletal muscle mass and body weight. These results demonstrate how targeting hepatic metabolism can prevent muscle wasting in lung cancer, and provide evidence for a therapeutic strategy.
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http://dx.doi.org/10.1073/pnas.1714703115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5789923PMC
January 2018

Bone biopsy protocol for advanced prostate cancer in the era of precision medicine.

Cancer 2018 03 19;124(5):1008-1015. Epub 2017 Dec 19.

Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, New York.

Background: Metastatic biopsies are increasingly being performed in patients with advanced prostate cancer to search for actionable targets and/or to identify emerging resistance mechanisms. Due to a predominance of bone metastases and their sclerotic nature, obtaining sufficient tissue for clinical and genomic studies is challenging.

Methods: Patients with prostate cancer bone metastases were enrolled between February 2013 and March 2017 on an institutional review board-approved protocol for prospective image-guided bone biopsy. Bone biopsies and blood clots were collected fresh. Compact bone was subjected to formalin with a decalcifying agent for diagnosis; bone marrow and blood clots were frozen in optimum cutting temperature formulation for next-generation sequencing. Frozen slides were cut from optimum cutting temperature cryomolds and evaluated for tumor histology and purity. Tissue was macrodissected for DNA and RNA extraction, and whole-exome sequencing and RNA sequencing were performed.

Results: Seventy bone biopsies from 64 patients were performed. Diagnostic material confirming prostate cancer was successful in 60 of 70 cases (85.7%). The median DNA/RNA yield was 25.5 ng/μL and 16.2 ng/μL, respectively. Whole-exome sequencing was performed successfully in 49 of 60 cases (81.7%), with additional RNA sequencing performed in 20 of 60 cases (33.3%). Recurrent alterations were as expected, including those involving the AR, PTEN, TP53, BRCA2, and SPOP genes.

Conclusions: This prostate cancer bone biopsy protocol ensures a valuable source for high-quality DNA and RNA for tumor sequencing and may be used to detect actionable alterations and resistance mechanisms in patients with bone metastases. Cancer 2018;124:1008-15. © 2017 American Cancer Society.
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http://dx.doi.org/10.1002/cncr.31173DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5821525PMC
March 2018

Assessment of prostate cancer with integrated CT-perfusion using a sector-wise approach.

Turk J Urol 2017 Jun 3;43(2):152-157. Epub 2017 May 3.

Department of Urology, Lucerne Cantonal Hospital, Switzerland.

Objective: The role of computed tomography perfusion (CTP) in characterizing primary prostate cancer (PCa) is not definitely known. The aim of the present study was to investigate the relationship between CTP parameters and histopathological features of PCa tissue, using a sector-wise approach.

Material And Methods: Fifty-one patients with biopsy-proven PCa underwent prospectively a CTP scan prior to radical prostatectomy. Blood flow (BF), mean blood volume (BV) and mean transit time (MTT) were calculated, with the prostate being divided into eight sectors. Corresponding sector-wise histopathological analysis of whole-mount prostatectomy specimens was performed to determine tumoral area (mm), mean microvessel density (MVD), Gleason patterns (primary, secondary) and total Gleason score. Spearman's rank correlation coefficient was used to analyze the association between CTP and histopathological parameters.

Results: BF correlated weakly with tumoral area [ρs coefficient (p-value): 0.25 (0.00)] and MVD [ρs coefficient (p-value): 0.23 (0.00)]. No valuable correlation was found between CTP parameters and primary and secondary Gleason patterns, whereas total Gleason score was weakly correlated with BV [ρs coefficient (p-value): 0.22 (0.00)] and MTT [ρs coefficient (p-value): 0.25 (0.00)].

Conclusion: BF correlates weakly with size and vascularity of PCa. There is a need for further studies to elucidate the association between CTP parameters and other histopathological parameters.
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http://dx.doi.org/10.5152/tud.2017.11455DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5503433PMC
June 2017

Transplantation of engineered organoids enables rapid generation of metastatic mouse models of colorectal cancer.

Nat Biotechnol 2017 06 1;35(6):577-582. Epub 2017 May 1.

Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

Colorectal cancer (CRC) is a leading cause of death in the developed world, yet facile preclinical models that mimic the natural stages of CRC progression are lacking. Through the orthotopic engraftment of colon organoids we describe a broadly usable immunocompetent CRC model that recapitulates the entire adenoma-adenocarcinoma-metastasis axis in vivo. The engraftment procedure takes less than 5 minutes, shows efficient tumor engraftment in two-thirds of mice, and can be achieved using organoids derived from genetically engineered mouse models (GEMMs), wild-type organoids engineered ex vivo, or from patient-derived human CRC organoids. In this model, we describe the genotype and time-dependent progression of CRCs from adenocarcinoma (6 weeks), to local disseminated disease (11-12 weeks), and spontaneous metastasis (>20 weeks). Further, we use the system to show that loss of dysregulated Wnt signaling is critical for the progression of disseminated CRCs. Thus, our approach provides a fast and flexible means to produce tailored CRC mouse models for genetic studies and pre-clinical investigation.
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http://dx.doi.org/10.1038/nbt.3837DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5462850PMC
June 2017

On-site Cytology for Development of Patient-Derived Three-dimensional Organoid Cultures - A Pilot Study.

Anticancer Res 2017 04;37(4):1569-1573

Weill Cornell Medicine and New York Presbyterian, Department of Pathology and Laboratory Medicine, New York, NY, U.S.A.

Background/aim: Development of patient-derived three-dimensional (3D) organoid cultures is an emerging technique in the field of precision oncology. We aimed to integrate on-site adequacy evaluation using cytology into the tumor organoid development workflow to ensure precise characterization and growth of these cultures.

Patients And Methods: Cancer patients were consented to a Precision Medicine trial. Fresh tissue was procured for genomic analyses as well as organoid development. Fresh tissue destined for organoid development was evaluated by preparing on-site cytology smears to ensure that only lesional tissue would be submitted for further cell culture work.

Results: Cytology preparations were made from 64 different tumor samples and evaluated prior to tissue submission for organoid development. In 53 (82.2%) of those tumor samples, the cytology preparation was diagnostic, thus providing adequate material for organoid development.

Conclusion: Characterizing the tissue prior to submission for organoid development ensures submission of lesional tissue only. Furthermore, it is a cost-effective method that can help document patient diagnosis. This can be of importance in biopsies, since the tissue submitted for organoid development cannot be retrieved for clinical diagnosis afterwards. Our findings in this pilot study led to the implementation of on-site cytological evaluation in the tumor organoid development workflow at the Englander Institute for Precision Medicine, NY, USA.
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http://dx.doi.org/10.21873/anticanres.11486DOI Listing
April 2017

Personalized and Cancer Models to Guide Precision Medicine.

Cancer Discov 2017 05 22;7(5):462-477. Epub 2017 Mar 22.

Englander Institute for Precision Medicine, Weill Cornell Medicine-New York Presbyterian Hospital, New York, New York.

Precision medicine is an approach that takes into account the influence of individuals' genes, environment, and lifestyle exposures to tailor interventions. Here, we describe the development of a robust precision cancer care platform that integrates whole-exome sequencing with a living biobank that enables high-throughput drug screens on patient-derived tumor organoids. To date, 56 tumor-derived organoid cultures and 19 patient-derived xenograft (PDX) models have been established from the 769 patients enrolled in an Institutional Review Board-approved clinical trial. Because genomics alone was insufficient to identify therapeutic options for the majority of patients with advanced disease, we used high-throughput drug screening to discover effective treatment strategies. Analysis of tumor-derived cells from four cases, two uterine malignancies and two colon cancers, identified effective drugs and drug combinations that were subsequently validated using 3-D cultures and PDX models. This platform thereby promotes the discovery of novel therapeutic approaches that can be assessed in clinical trials and provides personalized therapeutic options for individual patients where standard clinical options have been exhausted. Integration of genomic data with drug screening from personalized and cancer models guides precision cancer care and fuels next-generation research. .
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http://dx.doi.org/10.1158/2159-8290.CD-16-1154DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5413423PMC
May 2017

Relevance of meniscal cell regional phenotype to tissue engineering.

Connect Tissue Res 2017 May - Jul;58(3-4):259-270. Epub 2016 Dec 7.

a Shiley Center for Orthopaedic Research and Education at Scripps Clinic , La Jolla , CA , USA.

Purpose: Meniscus contains heterogeneous populations of cells that have not been fully characterized. Cell phenotype is often lost during culture; however, culture expansion is typically required for tissue engineering. We examined and compared cell-surface molecule expression levels on human meniscus cells from the vascular and avascular regions and articular chondrocytes while documenting changes during culture-induced dedifferentiation.

Materials And Methods: Expressions of 16 different surface molecules were examined by flow cytometry after monolayer culture for 24 h, 1 week, and 2 weeks. Menisci were also immunostained to document the spatial distributions of selected surface molecules.

Results: Meniscus cells and chondrocytes exhibited several similarities in surface molecule profiles with dynamic changes during culture. A greater percentage of meniscal cells were positive for CD14, CD26, CD49c, and CD49f compared to articular chondrocytes. Initially, more meniscal cells from the vascular region were positive for CD90 compared to cells from the avascular region or chondrocytes. Cells from the vascular region also expressed higher levels of CD166 and CD271 compared to cells from the avascular region. CD90, CD166, and CD271-positive cells were predominately perivascular in location. However, CD166-positive cells were also located in the superficial layer and in the adjacent synovial and adipose tissue.

Conclusions: These surface marker profiles provide a target phenotype for differentiation of progenitors in tissue engineering. The spatial location of progenitor cells in meniscus is consistent with higher regenerative capacity of the vascular region, while the surface progenitor subpopulations have potential to be utilized in tears created in the avascular region.
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http://dx.doi.org/10.1080/03008207.2016.1268604DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5433889PMC
March 2018

An emerging role for cytopathology in precision oncology.

Cancer Cytopathol 2016 Mar 7;124(3):167-73. Epub 2015 Dec 7.

Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, New York.

Precision medicine is an emerging field in medicine for disease prevention and treatment that takes into account the individual variability in genes, environment, and lifestyle for each individual patient. The authors have developed a special program as part of the Englander Institute for Precision Medicine to grow patient-derived, 3-dimensional tumor organoids for tumor-specific drug testing, tailoring treatment strategies, and as models for studying drug resistance. Routine cytology preparations represent a cost-effective and powerful tool to aid in performing molecular testing in the age of personalized medicine. In this commentary, the platforms used for the characterization and validation of patient-derived, 3-dimensional tumor organoids are outlined and discussed, and the role of cytology as a cost-effective and powerful quality-control measure is illustrated.
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http://dx.doi.org/10.1002/cncy.21647DOI Listing
March 2016

Quantitative bi-component T2* analysis of histologically normal Achilles tendons.

Muscles Ligaments Tendons J 2015 Apr-Jun;5(2):58-62. Epub 2015 Jul 3.

Radiology Service, VA San Diego Healthcare System, USA ; Department of Radiology, University of California, San Diego Medical Center, Usa.

Introduction: the aim of this pilot study was to implement ultrashort echo time (UTE) MRI with bi-component analysis on grossly normal Achilles tendons with histologic correlation.

Materials And Methods: six tendon samples which were grossly normal on visual inspection and palpation were harvested. A 2D UTE pulse sequence was implemented on a 3T MR scanner and bi-component and single-component T2* analysis was performed. Tendon samples were histologically processed and evaluated.

Results: mean short T2* fraction was 79.2% (95% confidence interval [CI], 70.1 - 88.3%), mean short T2* was 1.8 ms (95% CI, 1.3 - 2.3 ms), mean long T2* fraction was 20.8% (95% CI, 11.7 - 29.9%), mean long T2* was 9.2 ms (95% CI, 5.1 - 13.3 ms), and mean single-component T2* was 2.5 ms (95% CI, 1.8 - 3.1 ms).

Discussion: 2D UTE MRI with bi-component and single-component T2* analysis was successfully implemented. Inter-individual variation can be demonstrated in grossly and histologically normal Achilles tendons.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4496019PMC
August 2015

Whole-Exome Sequencing of Metastatic Cancer and Biomarkers of Treatment Response.

JAMA Oncol 2015 Jul;1(4):466-74

Institute for Precision Medicine, New York Presbyterian Hospital-Weill Cornell Medical College, New York, New York5Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, New York.

Importance: Understanding molecular mechanisms of response and resistance to anticancer therapies requires prospective patient follow-up and clinical and functional validation of both common and low-frequency mutations. We describe a whole-exome sequencing (WES) precision medicine trial focused on patients with advanced cancer.

Objective: To understand how WES data affect therapeutic decision making in patients with advanced cancer and to identify novel biomarkers of response.

Design, Setting, And Patients: Patients with metastatic and treatment-resistant cancer were prospectively enrolled at a single academic center for paired metastatic tumor and normal tissue WES during a 19-month period (February 2013 through September 2014). A comprehensive computational pipeline was used to detect point mutations, indels, and copy number alterations. Mutations were categorized as category 1, 2, or 3 on the basis of actionability; clinical reports were generated and discussed in precision tumor board. Patients were observed for 7 to 25 months for correlation of molecular information with clinical response.

Main Outcomes And Measures: Feasibility, use of WES for decision making, and identification of novel biomarkers.

Results: A total of 154 tumor-normal pairs from 97 patients with a range of metastatic cancers were sequenced, with a mean coverage of 95X and 16 somatic alterations detected per patient. In total, 16 mutations were category 1 (targeted therapy available), 98 were category 2 (biologically relevant), and 1474 were category 3 (unknown significance). Overall, WES provided informative results in 91 cases (94%), including alterations for which there is an approved drug, there are therapies in clinical or preclinical development, or they are considered drivers and potentially actionable (category 1-2); however, treatment was guided in only 5 patients (5%) on the basis of these recommendations because of access to clinical trials and/or off-label use of drugs. Among unexpected findings, a patient with prostate cancer with exceptional response to treatment was identified who harbored a somatic hemizygous deletion of the DNA repair gene FANCA and putative partial loss of function of the second allele through germline missense variant. Follow-up experiments established that loss of FANCA function was associated with platinum hypersensitivity both in vitro and in patient-derived xenografts, thus providing biologic rationale and functional evidence for his extreme clinical response.

Conclusions And Relevance: The majority of advanced, treatment-resistant tumors across tumor types harbor biologically informative alterations. The establishment of a clinical trial for WES of metastatic tumors with prospective follow-up of patients can help identify candidate predictive biomarkers of response.
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http://dx.doi.org/10.1001/jamaoncol.2015.1313DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4505739PMC
July 2015

Prognostic value of tumor suppressors in osteosarcoma before and after neoadjuvant chemotherapy.

BMC Cancer 2015 May 9;15:379. Epub 2015 May 9.

Laboratory for Orthopedic Research, Department of Orthopedics, Balgrist University Hospital, Forchstrasse 340, 8008, Zurich, Switzerland.

Background: Primary bone cancers are among the deadliest cancer types in adolescents, with osteosarcomas being the most prevalent form. Osteosarcomas are commonly treated with multi-drug neoadjuvant chemotherapy and therapy success as well as patient survival is affected by the presence of tumor suppressors. In order to assess the prognostic value of tumor-suppressive biomarkers, primary osteosarcoma tissues were analyzed prior to and after neoadjuvant chemotherapy.

Methods: We constructed a tissue microarray from high grade osteosarcoma samples, consisting of 48 chemotherapy naïve biopsies (BXs) and 47 tumor resections (RXs) after neoadjuvant chemotherapy. We performed immunohistochemical stainings of P53, P16, maspin, PTEN, BMI1 and Ki67, characterized the subcellular localization and related staining outcome with chemotherapy response and overall survival. Binary logistic regression analysis was used to analyze chemotherapy response and Kaplan-Meier-analysis as well as the Cox proportional hazards model was applied for analysis of patient survival.

Results: No significant associations between biomarker expression in BXs and patient survival or chemotherapy response were detected. In univariate analysis, positive immunohistochemistry of P53 (P = 0.008) and P16 (P16; P = 0.033) in RXs was significantly associated with poor survival prognosis. In addition, presence of P16 in RXs was associated with poor survival in multivariate regression analysis (P = 0.003; HR = 0.067) while absence of P16 was associated with good chemotherapy response (P = 0.004; OR = 74.076). Presence of PTEN on tumor RXs was significantly associated with an improved survival prognosis (P = 0.022).

Conclusions: Positive immunohistochemistry (IHC) of P16 and P53 in RXs was indicative for poor overall patient survival whereas positive IHC of PTEN was prognostic for good overall patient survival. In addition, we found that P16 might be a marker of osteosarcoma chemotherapy resistance. Therefore, our study supports the use of tumor RXs to assess the prognostic value of biomarkers.
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http://dx.doi.org/10.1186/s12885-015-1397-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4435808PMC
May 2015

MAGI3-AKT3 fusion in breast cancer amended.

Nature 2015 Apr;520(7547):E11-2

Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, New York 10065, USA.

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http://dx.doi.org/10.1038/nature14265DOI Listing
April 2015

Off-resonance saturation ratio obtained with ultrashort echo time-magnetization transfer techniques is sensitive to changes in static tensile loading of tendons and degeneration.

J Magn Reson Imaging 2015 Oct 23;42(4):1064-71. Epub 2015 Mar 23.

Radiology Service, VA San Diego Healthcare System, San Diego, California, USA.

Background: To determine if off-saturation ratio (OSR) measured with the ultrashort echo time magnetization transfer (UTE-MT) sequence could differentiate between tendons under different states of tensile load and to compare these changes between normal versus degenerated tendons.

Methods: Fourteen tendons were imaged at 3 Tesla before and during the application of 0.5-1 kg tension. A two-dimensional (2D) -UTE-MT sequence with 1.5, 3, and 5 kHz frequency offsets was used on nine tendons and a 3D-UTE-MT sequence with 1.5 kHz frequency offset was used on five tendons. OSR was calculated and compared for each condition. Histologic correlation was performed using light microscopy.

Results: In general, OSR increased after the application of tension. Mean increase of 2D OSR was 0.035 (95% confidence interval [CI], 0.013-0.056) at 1.5 kHz offset (P < 0.01), 0.031 (95% CI, 0.023-0.040) at 3 kHz offset (P < 0.01), and 0.013 (95% CI, -0.013-0.027) at 5 kHz offset (P = 0.07) from pre- to posttension states. Mean increase of 3D OSR was 0.026 (95% CI, 0.008-0.044) at a 1.5 kHz offset (P = 0.02) from pre- to posttension states. Mean decrease of 2D OSR at 1.5 kHz offset was 0.074-0.087 when comparing normal versus degenerated tendons (P < 0.01).

Conclusion: OSR as measured with 2D or 3D UTE-MT sequences can detect the changes in hydration seen when tendons are placed under two different states of tensile load, but these changes are smaller than those encountered when comparing between normal versus pathologic tendons. Lower off-resonance saturation frequencies (3 kHz or less) are more sensitive to these changes than higher off-resonance saturation frequencies.
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http://dx.doi.org/10.1002/jmri.24881DOI Listing
October 2015

Integrated CT-perfusion shows no meaningful correlation with PSA and presurgical Gleason score in patients with early prostate cancer.

Clin Imaging 2014 Nov-Dec;38(6):850-7. Epub 2014 Aug 2.

Department of Radiology and Nuclear Medicine, Lucerne Cantonal Hospital, Spitalstrasse 1, 6004 Lucerne, Switzerland. Electronic address:

Objectives: To analyze the correlation of computed tomography (CT) perfusion parameters blood flow (BF), blood volume (BV), and mean transit time (MTT) with presurgical prostate cancer data.

Methods: Ninety-eight patients with biopsy-proven prostate cancer underwent a CT-perfusion scan of the prostate. MTT, BF, and BV were determined and correlated with prostate-specific antigen (PSA) level, tumor load and Gleason score of transrectal ultrasonography-guided biopsy specimens.

Results: Mean BF was 41.3 ml/100 ml*min(-1), BV 5.2 ml/100 ml, MTT 8.7 s. Moderate correlations were observed between Gleason score and BF (0.35) and between PSA and BF (0.33) and BV (0.30).

Conclusions: CT-perfusion shows no valuable correlation with presurgical prostate cancer data.
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http://dx.doi.org/10.1016/j.clinimag.2014.07.011DOI Listing
June 2015

Assessment of prostate cancer with dynamic contrast-enhanced computed tomography using an en bloc approach.

Invest Radiol 2014 Sep;49(9):571-8

From the *Department of Radiology and Nuclear Medicine, †Institute of Pathology, and ‡Department of Urology, Lucerne Cantonal Hospital, Switzerland.

Objectives: The aim of this study was to assess the performance of dynamic contrast-enhanced computed tomography of the prostate in patients with biopsy-proven prostate cancer.

Material And Methods: A total of 46 male patients (median age, 65 years; range, 49-73 years) with biopsy-proven prostate cancer underwent an en bloc computed tomography perfusion (CTP) scan of the prostate before surgery. The perfusion parameters mean transit time (MTT), blood flow (BF), and blood volume (BV), as well as the microvessel density (MVD) of surgical specimens were determined. Differences in CTP parameters and MVD among postsurgical Gleason score (sGS) and postsurgical combined Gleason grade (sGG) groups were analyzed. Spearman correlation coefficients were determined between CTP parameters and presurgical biopsy-derived Gleason score (bGS), presurgical biopsy-derived combined Gleason grade (bGG), sGS, sGG, MVD, and pathological tumor stage. A linear regression analysis was carried out for exogenous variables BF, BV, MTT, bGS, and presurgical biopsy-derived combined Gleason grade and endogenous variables sGS, sGG, MVD, and T stage. A receiver operating characteristics analysis was performed to analyze the discriminating performance of CTP parameters and bGS between intermediate- and high-grade tumors.

Results: The mean perfusion parameters within the prostate tissue were as follows: BF, 39.1 ± 13.4 mL/100 mL min; BV, 4.9 ± 2.4 mL/100 mL; and MTT, 8.9 ± 3.7 seconds. The mean MVD of the tumor tissue was 144.3 ± 55.6/mm. Computed tomography perfusion parameters and MVD were significantly higher in patients with high-grade tumors compared with those with intermediate-grade tumors (P < 0.01 for BF, BV, and MVD). Only BV and MVD were significantly different among sGS and sGG groups. Moderate correlations were found between BF and sGS (0.38) and between BV and sGS (0.43). Linear relations of BV to sGS and to sGG were found. Blood volume (area under the curve, 0.86) was superior to bGS (area under the curve, 0.75) in discriminating high-grade from intermediate-grade tumors.

Conclusion: Computed tomography perfusion parameters derived by en bloc perfusion of the prostate are higher in high-grade tumors compared with intermediate-grade tumors. Blood flow and BV correlate with the definitive Gleason score. Blood volume predicts high-grade tumors better than does the Gleason score of biopsy specimens. Further studies are needed to determine a potential role for CTP in prostate cancer patients.
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http://dx.doi.org/10.1097/RLI.0000000000000055DOI Listing
September 2014