Publications by authors named "Anne Y Warren"

87 Publications

Multiparametric MRI for assessment of early response to neoadjuvant sunitinib in renal cell carcinoma.

PLoS One 2021 26;16(10):e0258988. Epub 2021 Oct 26.

University of Cambridge, Cambridge, United Kingdom.

Purpose: To detect early response to sunitinib treatment in metastatic clear cell renal cancer (mRCC) using multiparametric MRI.

Method: Participants with mRCC undergoing pre-surgical sunitinib therapy in the prospective NeoSun clinical trial (EudraCtNo: 2005-004502-82) were imaged before starting treatment, and after 12 days of sunitinib therapy using morphological MRI sequences, advanced diffusion-weighted imaging, measurements of R2* (related to hypoxia) and dynamic contrast-enhanced imaging. Following nephrectomy, participants continued treatment and were followed-up with contrast-enhanced CT. Changes in imaging parameters before and after sunitinib were assessed with the non-parametric Wilcoxon signed-rank test and the log-rank test was used to assess effects on survival.

Results: 12 participants fulfilled the inclusion criteria. After 12 days, the solid and necrotic tumor volumes decreased by 28% and 17%, respectively (p = 0.04). However, tumor-volume reduction did not correlate with progression-free or overall survival (PFS/OS). Sunitinib therapy resulted in a reduction in median solid tumor diffusivity D from 1298x10-6 to 1200x10-6mm2/s (p = 0.03); a larger decrease was associated with a better RECIST response (p = 0.02) and longer PFS (p = 0.03) on the log-rank test. An increase in R2* from 19 to 28s-1 (p = 0.001) was observed, paralleled by a decrease in Ktrans from 0.415 to 0.305min-1 (p = 0.01) and a decrease in perfusion fraction from 0.34 to 0.19 (p<0.001).

Conclusions: Physiological imaging confirmed efficacy of the anti-angiogenic agent 12 days after initiating therapy and demonstrated response to treatment. The change in diffusivity shortly after starting pre-surgical sunitinib correlated to PFS in mRCC undergoing nephrectomy, however, no parameter predicted OS.

Trial Registration: EudraCtNo: 2005-004502-82.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0258988PLOS
October 2021

The mutational landscape of human somatic and germline cells.

Nature 2021 09 25;597(7876):381-386. Epub 2021 Aug 25.

Cancer, Ageing and Somatic Mutation (CASM), Wellcome Sanger Institute, Hinxton, UK.

Over the course of an individual's lifetime, normal human cells accumulate mutations. Here we compare the mutational landscape in 29 cell types from the soma and germline using multiple samples from the same individuals. Two ubiquitous mutational signatures, SBS1 and SBS5/40, accounted for the majority of acquired mutations in most cell types, but their absolute and relative contributions varied substantially. SBS18, which potentially reflects oxidative damage, and several additional signatures attributed to exogenous and endogenous exposures contributed mutations to subsets of cell types. The rate of mutation was lowest in spermatogonia, the stem cells from which sperm are generated and from which most genetic variation in the human population is thought to originate. This was due to low rates of ubiquitous mutational processes and may be partially attributable to a low rate of cell division in basal spermatogonia. These results highlight similarities and differences in the maintenance of the germline and soma.
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http://dx.doi.org/10.1038/s41586-021-03822-7DOI Listing
September 2021

Comparison of biparametric versus multiparametric prostate MRI for the detection of extracapsular extension and seminal vesicle invasion in biopsy naïve patients.

Eur J Radiol 2021 Aug 27;141:109804. Epub 2021 May 27.

CamPARI Prostate Cancer Group, Addenbrooke's Hospital and University of Cambridge, Cambridge, UK; Department of Radiology, Addenbrooke's Hospital and University of Cambridge, Cambridge, UK. Electronic address:

Purpose: To compare biparametric MRI (bpMRI) with multiparametric MRI (mpMRI) staging accuracy in assessing extracapsular extension (ECE) and seminal vesicle invasion (SVI).

Method: Biopsy-naïve patients undergoing 3 T-MRI before radical prostatectomy for clinically significant prostate cancer were included in this single-centre retrospective study. Two uroradiologists separately evaluated bpMRI and mpMRI for presence of ECE and SVI using a 5-point Likert scale (1: ECE/SVI highly unlikely, 5: ECE/SVI highly likely).

Results: 110 men of median age 63 years and PSA 8.5 ng/mL were included. ECE and SVI was confirmed histologically in 71/110 (64.5 %) and 18/110 (16.4 %) patients, respectively. Sensitivity and specificity of bpMRI versus mpMRI for predicting ECE was 59.1 % and 87.2 % versus 66.2 % and 84.6 %, respectively. For SVI detection, the sensitivity and specificity for bpMRI versus mpMRI was 66.7 % and 92.4 % versus 83.3 % and 97.8 %, respectively. At an optimal cut-off Likert score ≥3 for ECE prediction, mpMRI area under the receiver operating curve (AUC) was 0.80 (95 % confidence interval (CI) 0.72-0.87) versus 0.78 (95 % CI 0.69-0.86) for bpMRI (p = 0.52) and for SVI, mpMRI AUC was 0.91 (95 % CI 0.84-0.96) versus 0.86 (95 % CI 0.78-0.92) for bpMRI (p = 0.02), respectively. Inter-reader agreement for both ECE and SVI prediction was substantial, with a marginally higher k-value for mpMRI (k range, 0.67-0.75) than bpMRI (k range, 0.65-0.69).

Conclusions: Diagnostic performance of bpMRI and mpMRI was comparable for detection of ECE, however, mpMRI with contrast was superior for SVI detection and improved the inter-reader agreement.
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http://dx.doi.org/10.1016/j.ejrad.2021.109804DOI Listing
August 2021

Morphological findings in frozen non-neoplastic kidney tissues of patients with kidney cancer from large-scale multicentric studies on renal cancer.

Virchows Arch 2021 Jun 5;478(6):1099-1107. Epub 2021 Jan 5.

International Agency for Research on Cancer, World Health Organization, 150 Cours Albert Thomas, 69372, Lyon Cedex 8, France.

There are unexplained geographical variations in the incidence of kidney cancer with the high rates reported in Baltic countries, as well as eastern and central Europe. Having access to a large and well-annotated collection of "tumor/non-tumor" pairs of kidney cancer patients from the Czech Republic, Romania, Serbia, UK, and Russia, we aimed to analyze the morphology of non-neoplastic renal tissue in nephrectomy specimens. By applying digital pathology, we performed a microscopic examination of 1012 frozen non-neoplastic kidney tissues from patients with renal cell carcinoma. Four components of renal parenchyma were evaluated and scored for the intensity of interstitial inflammation and fibrosis, tubular atrophy, glomerulosclerosis, and arterial wall thickening, globally called chronic renal parenchymal changes. Moderate or severe changes were observed in 54 (5.3%) of patients with predominance of occurrence in Romania (OR = 2.67, CI 1.07-6.67) and Serbia (OR = 4.37, CI 1.20-15.96) in reference to those from Russia. Further adjustment for comorbidities, tumor characteristics, and stage did not change risk estimates. In multinomial regression model, relative probability of non-glomerular changes was 5.22 times higher for Romania and Serbia compared to Russia. Our findings show that the frequency of chronic renal parenchymal changes, with the predominance of chronic interstitial nephritis pattern, in kidney cancer patients varies by country, significantly more frequent in countries located in central and southeastern Europe where the incidence of kidney cancer has been reported to be moderate to high. The observed association between these pathological features and living in certain geographic areas requires a larger population-based study to confirm this association on a large scale.
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http://dx.doi.org/10.1007/s00428-020-02986-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8203524PMC
June 2021

MRI-derived PRECISE scores for predicting pathologically-confirmed radiological progression in prostate cancer patients on active surveillance.

Eur Radiol 2021 May 16;31(5):2696-2705. Epub 2020 Nov 16.

CamPARI Prostate Cancer Group, Addenbrooke's Hospital and University of Cambridge, Cambridge, UK.

Objectives: To assess the predictive value and correlation to pathological progression of the Prostate Cancer Radiological Estimation of Change in Sequential Evaluation (PRECISE) scoring system in the follow-up of prostate cancer (PCa) patients on active surveillance (AS).

Methods: A total of 295 men enrolled on an AS programme between 2011 and 2018 were included. Baseline multiparametric magnetic resonance imaging (mpMRI) was performed at AS entry to guide biopsy. The follow-up mpMRI studies were prospectively reported by two sub-specialist uroradiologists with 10 years and 13 years of experience. PRECISE scores were dichotomized at the cut-off value of 4, and the sensitivity, specificity, positive predictive value and negative predictive value were calculated. Diagnostic performance was further quantified by using area under the receiver operating curve (AUC) which was based on the results of targeted MRI-US fusion biopsy. Univariate analysis using Cox regression was performed to assess which baseline clinical and mpMRI parameters were related to disease progression on AS.

Results: Progression rate of the cohort was 13.9% (41/295) over a median follow-up of 52 months. With a cut-off value of category ≥ 4, the PRECISE scoring system showed sensitivity, specificity, PPV and NPV for predicting progression on AS of 0.76, 0.89, 0.52 and 0.96, respectively. The AUC was 0.82 (95% CI = 0.74-0.90). Prostate-specific antigen density (PSA-D), Likert lesion score and index lesion size were the only significant baseline predictors of progression (each p < 0.05).

Conclusion: The PRECISE scoring system showed good overall performance, and the high NPV may help limit the number of follow-up biopsies required in patients on AS.

Key Points: • PRECISE scores 1-3 have high NPV which could reduce the need for re-biopsy during active surveillance. • PRECISE scores 4-5 have moderate PPV and should trigger either close monitoring or re-biopsy. • Three baseline predictors (PSA density, lesion size and Likert score) have a significant impact on the progression-free survival (PFS) time.
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http://dx.doi.org/10.1007/s00330-020-07336-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8043947PMC
May 2021

Extensive heterogeneity in somatic mutation and selection in the human bladder.

Science 2020 10;370(6512):75-82

Cancer, Ageing and Somatic Mutation Programme, Wellcome Sanger Institute, Hinxton CB10 1SA, UK.

The extent of somatic mutation and clonal selection in the human bladder remains unknown. We sequenced 2097 bladder microbiopsies from 20 individuals using targeted ( = 1914 microbiopsies), whole-exome ( = 655), and whole-genome ( = 88) sequencing. We found widespread positive selection in 17 genes. Chromatin remodeling genes were frequently mutated, whereas mutations were absent in several major bladder cancer genes. There was extensive interindividual variation in selection, with different driver genes dominating the clonal landscape across individuals. Mutational signatures were heterogeneous across clones and individuals, which suggests differential exposure to mutagens in the urine. Evidence of APOBEC mutagenesis was found in 22% of the microbiopsies. Sequencing multiple microbiopsies from five patients with bladder cancer enabled comparisons with cancer-free individuals and across histological features. This study reveals a rich landscape of mutational processes and selection in normal urothelium with large heterogeneity across clones and individuals.
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http://dx.doi.org/10.1126/science.aba8347DOI Listing
October 2020

Pathogenic germline variants in patients with features of hereditary renal cell carcinoma: Evidence for further locus heterogeneity.

Genes Chromosomes Cancer 2021 01 19;60(1):5-16. Epub 2020 Sep 19.

Department of Medical Genetics, University of Cambridge and NIHR Cambridge Biomedical Research Centre, and Cancer Research UK Cambridge Centre, Cambridge Biomedical Campus, Cambridge, UK.

Inherited renal cell carcinoma (RCC) is associated with multiple familial cancer syndromes but most individuals with features of non-syndromic inherited RCC do not harbor variants in the most commonly tested renal cancer predisposition genes (CPGs). We investigated whether undiagnosed cases might harbor mutations in CPGs that are not routinely tested for by testing 118 individuals with features suggestive of inherited RCC (family history of RCC, two or more primary RCC aged <60 years, or early onset RCC ≤46 years) for the presence of pathogenic variants in a large panel of CPGs. All individuals had been prescreened for pathogenic variants in the major RCC genes. We detected pathogenic or likely pathogenic (P/LP) variants of potential clinical relevance in 16.1% (19/118) of individuals, including P/LP variants in BRIP1 (n = 4), CHEK2 (n = 3), MITF (n = 1), and BRCA1 (n = 1). Though the power to detect rare variants was limited by sample size the frequency of truncating variants in BRIP1, 4/118, was significantly higher than in controls (P = 5.92E-03). These findings suggest that the application of genetic testing for larger inherited cancer gene panels in patients with indicators of a potential inherited RCC can increase the diagnostic yield for P/LP variants. However, the clinical utility of such a diagnostic strategy requires validation and further evaluation and in particular, confirmation of rarer RCC genotype-phenotype associations is required.
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http://dx.doi.org/10.1002/gcc.22893DOI Listing
January 2021

Three-Dimensional Printed Molds for Image-Guided Surgical Biopsies: An Open Source Computational Platform.

JCO Clin Cancer Inform 2020 08;4:736-748

Cancer Research UK, Cambridge Institute, University of Cambridge, Cambridge, United Kingdom.

Purpose: Spatial heterogeneity of tumors is a major challenge in precision oncology. The relationship between molecular and imaging heterogeneity is still poorly understood because it relies on the accurate coregistration of medical images and tissue biopsies. Tumor molds can guide the localization of biopsies, but their creation is time consuming, technologically challenging, and difficult to interface with routine clinical practice. These hurdles have so far hindered the progress in the area of multiscale integration of tumor heterogeneity data.

Methods: We have developed an open-source computational framework to automatically produce patient-specific 3-dimensional-printed molds that can be used in the clinical setting. Our approach achieves accurate coregistration of sampling location between tissue and imaging, and integrates seamlessly with clinical, imaging, and pathology workflows.

Results: We applied our framework to patients with renal cancer undergoing radical nephrectomy. We created personalized molds for 6 patients, obtaining Dice similarity coefficients between imaging and tissue sections ranging from 0.86 to 0.96 for tumor regions and between 0.70 and 0.76 for healthy kidneys. The framework required minimal manual intervention, producing the final mold design in just minutes, while automatically taking into account clinical considerations such as a preference for specific cutting planes.

Conclusion: Our work provides a robust and automated interface between imaging and tissue samples, enabling the development of clinical studies to probe tumor heterogeneity on multiple spatial scales.
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http://dx.doi.org/10.1200/CCI.20.00026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7469624PMC
August 2020

Multicenter Multireader Evaluation of an Artificial Intelligence-Based Attention Mapping System for the Detection of Prostate Cancer With Multiparametric MRI.

AJR Am J Roentgenol 2020 10 5;215(4):903-912. Epub 2020 Aug 5.

Department of Radiology and Imaging Sciences, Clinical Center, National Institutes of Health, Bethesda, MD.

The purpose of this study was to evaluate in a multicenter dataset the performance of an artificial intelligence (AI) detection system with attention mapping compared with multiparametric MRI (mpMRI) interpretation in the detection of prostate cancer. MRI examinations from five institutions were included in this study and were evaluated by nine readers. In the first round, readers evaluated mpMRI studies using the Prostate Imaging Reporting and Data System version 2. After 4 weeks, images were again presented to readers along with the AI-based detection system output. Readers accepted or rejected lesions within four AI-generated attention map boxes. Additional lesions outside of boxes were excluded from detection and categorization. The performances of readers using the mpMRI-only and AI-assisted approaches were compared. The study population included 152 case patients and 84 control patients with 274 pathologically proven cancer lesions. The lesion-based AUC was 74.9% for MRI and 77.5% for AI with no significant difference ( = 0.095). The sensitivity for overall detection of cancer lesions was higher for AI than for mpMRI but did not reach statistical significance (57.4% vs 53.6%, = 0.073). However, for transition zone lesions, sensitivity was higher for AI than for MRI (61.8% vs 50.8%, = 0.001). Reading time was longer for AI than for MRI (4.66 vs 4.03 minutes, < 0.001). There was moderate interreader agreement for AI and MRI with no significant difference (58.7% vs 58.5%, = 0.966). Overall sensitivity was only minimally improved by use of the AI system. Significant improvement was achieved, however, in the detection of transition zone lesions with use of the AI system at the cost of a mean of 40 seconds of additional reading time.
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http://dx.doi.org/10.2214/AJR.19.22573DOI Listing
October 2020

Comparison of Likert and PI-RADS version 2 MRI scoring systems for the detection of clinically significant prostate cancer.

Br J Radiol 2020 Aug 11;93(1112):20200298. Epub 2020 Jun 11.

Department of Radiology, Addenbrooke's Hospital and University of Cambridge, Cambridge, UK.

Objective: To compare the performance of Likert and Prostate Imaging-Reporting and Data System (PI-RADS) multiparametric (mp) MRI scoring systems for detecting clinically significant prostate cancer (csPCa).

Methods: 199 biopsy-naïve males undergoing prostate mpMRI were prospectively scored with Likert and PI-RADS systems by four experienced radiologists. A binary cut-off (threshold score ≥3) was used to analyze histological results by three groups: negative, insignificant disease (Gleason 3 + 3; iPCa), and csPCa (Gleason ≥3 +4). Lesion-level results and prostate zonal location were also compared.

Results: 129/199 (64.8%) males underwent biopsy, 96 with Likert or PI-RADS score ≥3, and 21 with negative MRI. A further 12 patients were biopsied during follow-up (mean 507 days). Prostate cancer was diagnosed in 87/199 (43.7%) patients, 65 with (33.6%) csPCa. 30/92 (32.6%) patients with negative MRI were biopsied, with an NPV of 83.3% for cancer and 86.7% for csPCa. Likert and PI-RADS score differences were observed in 92 patients (46.2%), but only for 16 patients (8%) at threshold score ≥3. Likert scoring had higher specificity than PI-RADS (0.77 0.66), higher area under the curve (0.92 0.87, = 0.002) and higher PPV (0.66 0.58); NPV and sensitivity were the same. Likert had more five score results (58%) compared to PI-RADS (36%), but with similar csCPa detection (81.0 and 80.6% respectively). Likert demonstrated lower proportion of false positive in the predominately AFMS-involving lesions.

Conclusion: Likert and PI-RADS systems both demonstrate high cancer detection rates. Likert scoring had a higher AUC with moderately higher specificity and lower positive call rate and could potentially help to reduce the number of unnecessary biopsies performed.

Advances In Knowledge: This paper illustrates that the Likert scoring system has potential to help urologists reduce the number of prostate biopsies performed.
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http://dx.doi.org/10.1259/bjr.20200298DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7446003PMC
August 2020

The 2019 International Society of Urological Pathology (ISUP) Consensus Conference on Grading of Prostatic Carcinoma.

Am J Surg Pathol 2020 08;44(8):e87-e99

Department of Pathology, Medical College of Wisconsin, Milwaukee, WI.

Five years after the last prostatic carcinoma grading consensus conference of the International Society of Urological Pathology (ISUP), accrual of new data and modification of clinical practice require an update of current pathologic grading guidelines. This manuscript summarizes the proceedings of the ISUP consensus meeting for grading of prostatic carcinoma held in September 2019, in Nice, France. Topics brought to consensus included the following: (1) approaches to reporting of Gleason patterns 4 and 5 quantities, and minor/tertiary patterns, (2) an agreement to report the presence of invasive cribriform carcinoma, (3) an agreement to incorporate intraductal carcinoma into grading, and (4) individual versus aggregate grading of systematic and multiparametric magnetic resonance imaging-targeted biopsies. Finally, developments in the field of artificial intelligence in the grading of prostatic carcinoma and future research perspectives were discussed.
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http://dx.doi.org/10.1097/PAS.0000000000001497DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7382533PMC
August 2020

Independence of HIF1a and androgen signaling pathways in prostate cancer.

BMC Cancer 2020 May 25;20(1):469. Epub 2020 May 25.

Nuffield Department of Surgical Sciences, University of Oxford, Oxford, OX3 9DU, UK.

Background: Therapeutic targeting of the androgen signaling pathway is a mainstay treatment for prostate cancer. Although initially effective, resistance to androgen targeted therapies develops followed by disease progression to castrate-resistant prostate cancer (CRPC). Hypoxia and HIF1a have been implicated in the development of resistance to androgen targeted therapies and progression to CRCP. The interplay between the androgen and hypoxia/HIF1a signaling axes was investigated.

Methods: In vitro stable expression of HIF1a was established in the LNCaP cell line by physiological induction or retroviral transduction. Tumor xenografts with stable expression of HIF1a were established in castrated and non-castrated mouse models. Gene expression analysis identified transcriptional changes in response to androgen treatment, hypoxia and HIF1a. The binding sites of the AR and HIF transcription factors were identified using ChIP-seq.

Results: Androgen and HIF1a signaling promoted proliferation in vitro and enhanced tumor growth in vivo. The stable expression of HIF1a in vivo restored tumor growth in the absence of endogenous androgens. Hypoxia reduced AR binding sites whereas HIF binding sites were increased with androgen treatment under hypoxia. Gene expression analysis identified seven genes that were upregulated both by AR and HIF1a, of which six were prognostic.

Conclusions: The oncogenic AR, hypoxia and HIF1a pathways support prostate cancer development through independent signaling pathways and transcriptomic profiles. AR and hypoxia/HIF1a signaling pathways independently promote prostate cancer progression and therapeutic targeting of both pathways simultaneously is warranted.
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http://dx.doi.org/10.1186/s12885-020-06890-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7249645PMC
May 2020

The Efficacy of Sunitinib Treatment of Renal Cancer Cells Is Associated with the Protein PHAX In Vitro.

Biology (Basel) 2020 Apr 7;9(4). Epub 2020 Apr 7.

Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, UK.

Anti-angiogenic agents, such as the multi-tyrosine kinase inhibitor sunitinib, are key first line therapies for metastatic clear cell renal cell carcinoma (ccRCC), but their mechanism of action is not fully understood. Here, we take steps towards validating a computational prediction based on differential transcriptome network analysis that phosphorylated adapter RNA export protein (PHAX) is associated with sunitinib drug treatment. The regulatory impact factor differential network algorithm run on patient tissue samples suggests PHAX is likely an important regulator through changes in genome-wide network connectivity. Immunofluorescence staining of patient tumours showed strong localisation of PHAX to the microvasculature consistent with the anti-angiogenic effect of sunitinib. In normal kidney tissue, PHAX protein abundance was low but increased with tumour grade (G1 vs. G3/4; < 0.01), consistent with a possible role in cancer progression. In organ culture, ccRCC cells had higher levels of PHAX protein expression than normal kidney cells, and sunitinib increased PHAX protein expression in a dose dependent manner (untreated vs. 100 µM; < 0.05). PHAX knockdown in a ccRCC organ culture model impacted the ability of sunitinib to cause cancer cell death ( < 0.0001 untreated vs. treated), suggesting a role for PHAX in mediating the efficacy of sunitinib.
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http://dx.doi.org/10.3390/biology9040074DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7236799PMC
April 2020

Diagnostic accuracy of biparametric versus multiparametric prostate MRI: assessment of contrast benefit in clinical practice.

Eur Radiol 2020 Jul 12;30(7):4039-4049. Epub 2020 Mar 12.

Department of Radiology, Addenbrooke's Hospital and University of Cambridge, Cambridge, UK.

Purpose: To assess the added value of dynamic contrast-enhanced (DCE) in prostate MR in clinical practice.

Methods: Two hundred sixty-four patients underwent prostate MRI, with T2 and DWI sequences initially interpreted, prior to full multiparametric magnetic resonance imaging (mpMRI) interpretation using a Likert 1-5 scale. A prospective opinion was given on likely benefit of contrast prior to review of the DCE sequence, and retrospectively following full mpMRI review. The final histology result following targeted and/or systematic biopsy of the prostate was used for outcome purposes.

Results: Biparametric magnetic resonance imaging (bpMRI) and mpMRI were assigned the same score in 86% of cases; when dichotomising to a negative or positive MRI (Likert score ≥ 3), concordance increased to 92.8%. At Likert score ≥ 3 bpMRI detected 89.9% of all cancers and 93.5% clinically significant prostate cancers (csPCa) and mpMRI 90.7% and 94.6%, respectively. mpMRI had fewer false positives than bpMRI (11.4% vs 18.9%) and a lower Likert 3 rate (8.3% vs 17%), conferring higher specificity (74% vs 67%), but similar sensitivity (95% versus 94%) and ROC-AUC (90% vs 89%). At a positive MRI threshold of Likert ≥ 4, mpMRI had a higher sensitivity than bpMRI (89% versus 80%) and detected more csPCa (89.2% versus 79.6%). DCE was prospectively considered of potential benefit in 27.3%, but readers would only recall 11% of patients for DCE sequences, mainly to assess score 3 peripheral zone lesions. Following full mpMRI review, DCE was considered helpful in 28.4% of cases; in 23/75 (30.6%) of these cases this only became apparent after reviewing the sequence, reasons included increased confidence, presence of "safety-net" lesions or inflammatory lesions.

Conclusion: BpMRI has equivalent cancer detection rates to mpMRI; however, mpMRI had fewer Likert 3 call rates and increased specificity and was subjectively considered of benefit by readers in 28.4% of cases.

Key Points: • bpMRI has similar cancer detection rates to the full mpMRI protocol at a positive MRI threshold of Likert 3. • mpMRI had fewer intermediate category 3 calls (8.3%) than bpMRI (17%) and fewer false positives than bpMRI (11.4% vs 18.9%), conferring higher specificity (74% vs 67%). • Readers considered DCE beneficial in 28.4% of cases, but in a relatively high number (30.6%) this only became apparent after reviewing the sequence.
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http://dx.doi.org/10.1007/s00330-020-06782-0DOI Listing
July 2020

Tumor necrosis factor receptor-2 signaling pathways promote survival of cancer stem-like CD133 cells in clear cell renal carcinoma.

FASEB Bioadv 2020 Feb 3;2(2):126-144. Epub 2020 Jan 3.

Department of Medicine NIHR Cambridge Biomedical Research Centre University of Cambridge Cambridge UK.

Clear cell renal cell carcinoma (ccRCC) contains cancer stem-like cells (CSCs) that express CD133 (ccRCC-CD133). CSCs are rarely in cell cycle and, as nonproliferating cells, resist most chemotherapeutic agents. Previously, we reported that tumor necrosis factor receptor-2 (TNFR2) signaling promotes the cell cycle entry of ccRCC-CD133CSCs, rendering them susceptible to cell-cycle-dependent chemotherapeutics. Here, we describe a TNFR2-activated signaling pathway in ccRCC-CSCs that is required for cell survival. Wild-type (wt)TNF or R2TNF but not R1TNF (TNF muteins that selectively bind to TNFR2 and TNFR1) induces phosphorylation of signal transducer and activator of transcription 3 (STAT3) on serine but not tyrosine, resulting in pSTAT3 translocation to and colocalization with TNFR2 in mitochondria. R2TNF signaling activates a kinase cascade involving the phosphorylation of VEGFR2, PI-3K, Akt, and mTORC. Inhibition of any of the kinases or siRNA knockdown of TNFR2 or STAT3 promotes cell death associated with mitochondrial morphological changes, cytochrome c release, generation of reactive oxygen species, and TUNELcells expressing phosphorylated mixed lineage kinase-like (MLKL). Pretreatment with necrostatin-1 is more protective than z-VAD.fmk, suggesting that most death is necroptotic and TNFR2 signaling promotes cell survival by preventing mitochondrial-mediated necroptosis. These data suggest that a TNFR2 selective agonist may offer a potential therapeutic strategy for ccRCC.
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http://dx.doi.org/10.1096/fba.2019-00071DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7003657PMC
February 2020

Comprehensive characterization of cell-free tumor DNA in plasma and urine of patients with renal tumors.

Genome Med 2020 02 28;12(1):23. Epub 2020 Feb 28.

Hutchison/MRC Research Centre, University of Cambridge, Cambridge, CB2 0QQ, UK.

Background: Cell-free tumor-derived DNA (ctDNA) allows non-invasive monitoring of cancers, but its utility in renal cell cancer (RCC) has not been established.

Methods: Here, a combination of untargeted and targeted sequencing methods, applied to two independent cohorts of patients (n = 91) with various renal tumor subtypes, were used to determine ctDNA content in plasma and urine.

Results: Our data revealed lower plasma ctDNA levels in RCC relative to other cancers of similar size and stage, with untargeted detection in 27.5% of patients from both cohorts. A sensitive personalized approach, applied to plasma and urine from select patients (n = 22) improved detection to ~ 50%, including in patients with early-stage disease and even benign lesions. Detection in plasma, but not urine, was more frequent amongst patients with larger tumors and in those patients with venous tumor thrombus. With data from one extensively characterized patient, we observed that plasma and, for the first time, urine ctDNA may better represent tumor heterogeneity than a single tissue biopsy. Furthermore, in a subset of patients (n = 16), longitudinal sampling revealed that ctDNA can track disease course and may pre-empt radiological identification of minimal residual disease or disease progression on systemic therapy. Additional datasets will be required to validate these findings.

Conclusions: These data highlight RCC as a ctDNA-low malignancy. The biological reasons for this are yet to be determined. Nonetheless, our findings indicate potential clinical utility in the management of patients with renal tumors, provided improvement in isolation and detection approaches.
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http://dx.doi.org/10.1186/s13073-020-00723-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7048087PMC
February 2020

Characterization of renal cell carcinoma-associated constitutional chromosome abnormalities by genome sequencing.

Genes Chromosomes Cancer 2020 06 5;59(6):333-347. Epub 2020 Feb 5.

Department of Medical Genetics, University of Cambridge and NIHR Cambridge Biomedical Research Centre, Cancer Research UK Cambridge Centre, Cambridge Biomedical Campus, Cambridge, UK.

Constitutional translocations, typically involving chromosome 3, have been recognized as a rare cause of inherited predisposition to renal cell carcinoma (RCC) for four decades. However, knowledge of the molecular basis of this association is limited. We have characterized the breakpoints by genome sequencing (GS) of constitutional chromosome abnormalities in five individuals who presented with RCC. In one individual with constitutional t(10;17)(q11.21;p11.2), the translocation breakpoint disrupted two genes: the known renal tumor suppressor gene (TSG) FLCN (and clinical features of Birt-Hogg-Dubé syndrome were detected) and RASGEF1A. In four cases, the rearrangement breakpoints did not disrupt known inherited RCC genes. In the second case without chromosome 3 involvement, the translocation breakpoint in an individual with a constitutional t(2;17)(q21.1;q11.2) mapped 12 Kb upstream of NLK. Interestingly, NLK has been reported to interact indirectly with FBXW7 and a previously reported RCC-associated translocation breakpoint disrupted FBXW7. In two cases of constitutional chromosome 3 translocations, no candidate TSGs were identified in the vicinity of the breakpoints. However, in an individual with a constitutional chromosome 3 inversion, the 3p breakpoint disrupted the FHIT TSG (which has been reported previously to be disrupted in two apparently unrelated families with an RCC-associated t(3;8)(p14.2;q24.1). These findings (a) expand the range of constitutional chromosome rearrangements that may be associated with predisposition to RCC, (b) confirm that chromosome rearrangements not involving chromosome 3 can predispose to RCC, (c) suggest that a variety of molecular mechanisms are involved the pathogenesis of translocation-associated RCC, and (d) demonstrate the utility of GS for investigating such cases.
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http://dx.doi.org/10.1002/gcc.22833DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7187337PMC
June 2020

The ProtecT trial: analysis of the patient cohort, baseline risk stratification and disease progression.

BJU Int 2020 04 12;125(4):506-514. Epub 2020 Feb 12.

Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK.

Objective: To test the hypothesis that the baseline clinico-pathological features of the men with localized prostate cancer (PCa) included in the ProtecT (Prostate Testing for Cancer and Treatment) trial who progressed (n = 198) at a 10-year median follow-up were different from those of men with stable disease (n = 1409).

Patients And Methods: We stratified the study participants at baseline according to risk of progression using clinical disease stage, pathological grade and PSA level, using Cox proportional hazard models.

Results: The findings showed that 34% of participants (n = 505) had intermediate- or high-risk PCa, and 66% (n = 973) had low-risk PCa. Of 198 participants who progressed, 101 (51%) had baseline International Society of Urological Pathology Grade Group 1, 59 (30%) Grade Group 2, and 38 (19%) Grade Group 3 PCa, compared with 79%, 17% and 5%, respectively, for 1409 participants without progression (P < 0.001). In participants with progression, 38% and 62% had baseline low- and intermediate-/high-risk disease, compared with 69% and 31% of participants with stable disease (P < 0.001). Treatment received, age (65-69 vs 50-64 years), PSA level, Grade Group, clinical stage, risk group, number of positive cores, tumour length and perineural invasion were associated with time to progression (P ≤ 0.005). Men progressing after surgery (n = 19) were more likely to have a higher Grade Group and pathological stage at surgery, larger tumours, lymph node involvement and positive margins.

Conclusions: We demonstrate that one-third of the ProtecT cohort consists of people with intermediate-/high-risk disease, and the outcomes data at an average of 10 years' follow-up are generalizable beyond men with low-risk PCa.
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http://dx.doi.org/10.1111/bju.14987DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7187290PMC
April 2020

Embryonal precursors of Wilms tumor.

Science 2019 12;366(6470):1247-1251

Great Ormond Street Hospital for Children NHS Foundation Trust, London WC1N 3JH, UK.

Adult cancers often arise from premalignant clonal expansions. Whether the same is true of childhood tumors has been unclear. To investigate whether Wilms tumor (nephroblastoma; a childhood kidney cancer) develops from a premalignant background, we examined the phylogenetic relationship between tumors and corresponding normal tissues. In 14 of 23 cases studied (61%), we found premalignant clonal expansions in morphologically normal kidney tissues that preceded tumor development. These clonal expansions were defined by somatic mutations shared between tumor and normal tissues but absent from blood cells. We also found hypermethylation of the locus, a known driver of Wilms tumor development, in 58% of the expansions. Phylogenetic analyses of bilateral tumors indicated that clonal expansions can evolve before the divergence of left and right kidney primordia. These findings reveal embryonal precursors from which unilateral and multifocal cancers develop.
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http://dx.doi.org/10.1126/science.aax1323DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6914378PMC
December 2019

Fumarate Metabolic Signature for the Detection of Reed Syndrome in Humans.

Clin Cancer Res 2020 01 21;26(2):391-396. Epub 2019 Oct 21.

Department of Medical Genetics, University of Cambridge and NIHR Cambridge Biomedical Research Centre and Cancer Research UK Cambridge Centre, Cambridge, United Kingdom.

Purpose: Inherited pathogenic variants in genes encoding the metabolic enzymes succinate dehydrogenase (SDH) and fumarate hydratase predispose to tumor development through accumulation of oncometabolites (succinate and fumarate, respectively; ref. 1). Noninvasive detection of tumor succinate by proton magnetic resonance spectroscopy (H-MRS) has been reported in SDH-deficient tumors, but the potential utility of this approach in the management of patients with hereditary leiomyomatosis and renal cell cancer syndrome or Reed syndrome is unknown.

Experimental Design: Magnetic resonance spectroscopy (H-MRS) was performed on three cases and correlated with germline genetic results and tumor IHC when available.

Results: Here, we have demonstrated a proof of principle that H-MRS can provide a noninvasive diagnosis of hereditary leiomyomatosis and renal cell cancer syndrome or Reed syndrome through detection of fumarate accumulation .

Conclusions: This study demonstrates that detection of fumarate could be employed as a functional biomarker.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-1729DOI Listing
January 2020

Spatiotemporal immune zonation of the human kidney.

Science 2019 09;365(6460):1461-1466

Cambridge University Hospitals NHS Foundation Trust and NIHR Cambridge Biomedical Research Centre, Cambridge CB2 0QQ, UK.

Tissue-resident immune cells are important for organ homeostasis and defense. The epithelium may contribute to these functions directly or by cross-talk with immune cells. We used single-cell RNA sequencing to resolve the spatiotemporal immune topology of the human kidney. We reveal anatomically defined expression patterns of immune genes within the epithelial compartment, with antimicrobial peptide transcripts evident in pelvic epithelium in the mature, but not fetal, kidney. A network of tissue-resident myeloid and lymphoid immune cells was evident in both fetal and mature kidney, with postnatal acquisition of transcriptional programs that promote infection-defense capabilities. Epithelial-immune cross-talk orchestrated localization of antibacterial macrophages and neutrophils to the regions of the kidney most susceptible to infection. Overall, our study provides a global overview of how the immune landscape of the human kidney is zonated to counter the dominant immunological challenge.
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http://dx.doi.org/10.1126/science.aat5031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7343525PMC
September 2019

Molecular imaging of the prostate: Comparing total sodium concentration quantification in prostate cancer and normal tissue using dedicated C and Na endorectal coils.

J Magn Reson Imaging 2020 01 13;51(1):90-97. Epub 2019 May 13.

Department of Radiology, University of Cambridge, Cambridge, UK.

Background: There has been recent interest in nonproton MRI including hyperpolarized carbon-13 ( C) imaging. Prostate cancer has been shown to have a higher tissue sodium concentration (TSC) than normal tissue. Sodium ( Na) and C nuclei have a frequency difference of only 1.66 MHz at 3T, potentially enabling Na imaging with a C-tuned coil and maximizing the metabolic information obtained from a single study.

Purpose: To compare TSC measurements from a C-tuned endorectal coil to those quantified with a dedicated Na-tuned coil.

Study Type: Prospective.

Population: Eight patients with biopsy-proven, intermediate/high risk prostate cancer imaged prior to prostatectomy.

Sequence: 3T MRI with separate dual-tuned H/ Na and H/ C endorectal receive coils to quantify TSC.

Assessment: Regions-of-interest for TSC quantification were defined for normal peripheral zone (PZ), normal transition zone (TZ), and tumor, with reference to histopathology maps.

Statistical Tests: Two-sided Wilcoxon rank sum with additional measures of correlation, coefficient of variation, and Bland-Altman plots to assess for between-test differences.

Results: Mean TSC for normal PZ and TZ were 39.2 and 33.9 mM, respectively, with the Na coil and 40.1 and 36.3 mM, respectively, with the C coil (P = 0.22 and P = 0.11 for the intercoil comparison, respectively). For tumor tissue, there was no statistical difference between the overall mean tumor TSC measured with the Na coil (41.8 mM) and with the C coil (46.6 mM; P = 0.38). Bland-Altman plots showed good repeatability for tumor TSC measurements between coils, with a reproducibility coefficient of 9 mM; the coefficient of variation between the coils was 12%. The Pearson correlation coefficient for TSC between coils for all measurements was r = 0.71 (r = 0.51), indicating a strong positive linear relationship. The mean TSC within PZ tumors was significantly higher compared with normal PZ for both the Na coil (45.4 mM; P = 0.02) and the C coil (49.4 mM; P = 0.002).

Data Conclusion: We demonstrated the feasibility of using a carbon-tuned coil to quantify TSC, enabling dual metabolic information from a single coil. This approach could make the acquisition of both Na-MRI and C-MRI feasible in a single clinical imaging session.

Level Of Evidence: 2 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2020;51:90-97.
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http://dx.doi.org/10.1002/jmri.26788DOI Listing
January 2020

Defining the incremental value of 3D T2-weighted imaging in the assessment of prostate cancer extracapsular extension.

Eur Radiol 2019 Oct 18;29(10):5488-5497. Epub 2019 Mar 18.

Department of Radiology, Addenbrooke's Hospital and University of Cambridge, Cambridge, UK.

Objectives: To assess the added value of 3D T2-weighted imaging (T2WI) over conventional 2D T2WI in diagnosing extracapsular extension (ECE).

Methods: Seventy-five patients undergoing 3-T MRI before radical prostatectomy were included. PI-RADS ≥ 4 lesions were assessed for ECE on 2D T2W images using a 5-point Likert scale (1 = no ECE, 5 = definite ECE) and the length of tumour prostatic capsular contact. A second read using 3D T2W images and reformats evaluated ECE and the maximal 3D capsular contact length and surface.

Results: One hundred six lesions were identified at MRI. ECE was confirmed by histology in 54% (57/106) of lesions and 64% (48/75) of patients. Sensitivity and specificity for 3D T2 reads were 75.4% versus 64.9% (p = 0.058), respectively, and 83.7% versus 85.7% (p = 0.705) for 2D T2 reads, respectively. 3D T2W reads showed significantly higher mean subjective Likert scores of 3.7 ± 1.4 versus 3.3 ± 1.4 (p = 0.001) in ECE-positive lesions and lower mean Likert score of 1.5 ± 1 versus 1.6 ± 0.9 (p = 0.27) in ECE-negative lesions compared with 2D T2W reads. 3D contact significantly increased sensitivity from 59.6 to 73.7% (p = 0.03), whilst maintaining the same specificity of 87.8% (p = 1). High-grade group tumours (≥ Gleason 4 + 3) showed significantly higher ECE prevalence than low-grade tumours (88% versus 44%, p < 0.001) and a positive predictive value (PPV) for ECE of 90.9% with ≥ 5 mm of contact versus PPV of 90.4% at ≥ 12.5 mm for lower grade tumours.

Conclusions: 3D T2WI significantly increases sensitivity and confidence in calling ECE. The capsular contact length threshold differed between low- and high-grade cancers.

Key Points: • 3D capsular contact length and 3D surface contact significantly increased sensitivity in diagnosing ECE. • 3D T2W reads significantly increased reader confidence in calling ECE. • Thresholds for capsular contact length differed between low-grade and high-grade cancers.
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http://dx.doi.org/10.1007/s00330-019-06070-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6719333PMC
October 2019

A KLF6-driven transcriptional network links lipid homeostasis and tumour growth in renal carcinoma.

Nat Commun 2019 03 11;10(1):1152. Epub 2019 Mar 11.

MRC Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre, Box 197, Cambridge Biomedical Campus, Cambridge, CB2 0XZ, UK.

Transcriptional networks are critical for the establishment of tissue-specific cellular states in health and disease, including cancer. Yet, the transcriptional circuits that control carcinogenesis remain poorly understood. Here we report that Kruppel like factor 6 (KLF6), a transcription factor of the zinc finger family, regulates lipid homeostasis in clear cell renal cell carcinoma (ccRCC). We show that KLF6 supports the expression of lipid metabolism genes and promotes the expression of PDGFB, which activates mTOR signalling and the downstream lipid metabolism regulators SREBF1 and SREBF2. KLF6 expression is driven by a robust super enhancer that integrates signals from multiple pathways, including the ccRCC-initiating VHL-HIF2A pathway. These results suggest an underlying mechanism for high mTOR activity in ccRCC cells. More generally, the link between super enhancer-driven transcriptional networks and essential metabolic pathways may provide clues to the mechanisms that maintain the stability of cell identity-defining transcriptional programmes in cancer.
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http://dx.doi.org/10.1038/s41467-019-09116-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6411998PMC
March 2019

Rare Abdominal Cutaneous Presentation of Clear Cell Renal Cell Carcinoma: A Case Report.

Urology 2019 May 8;127:e8-e9. Epub 2019 Feb 8.

Department of Histopathology, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge, United Kingdom.

Cutaneous metastasis from renal cell carcinoma is rare, typically involves the head and neck, and occurs inlatestage disease, usually in the context of previously diagnosed and treated primary tumour, and after lymphaticspread. This patients' initial presentation of clear cell renal cell carcinoma was a cutaneous lesion to the ipsilateral abdominal wall. The primary renal tumour was subsequently demonstrated on CT; this also showed no apparent lymph nodeinvolvement despite cutaneous metastatic disease. The patient underwent radical laparoscopic nephrectomy and biological therapy, but disease progression continued, and he passed away within 6 months of diagnosis.
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http://dx.doi.org/10.1016/j.urology.2019.01.028DOI Listing
May 2019

Repeatability of diffusion-weighted MRI of the prostate using whole lesion ADC values, skew and histogram analysis.

Eur J Radiol 2019 Jan 17;110:22-29. Epub 2018 Nov 17.

Department of Radiology, University of Cambridge, Cambridge, UK; Department of Radiology, Addenbrooke's Hospital, Cambridge, UK.

Purpose: To investigate the repeatability of diffusion-weighted imaging parameter including ADC-derived histogram values in prostate cancer.

Methods: 10 patients with prostate cancer were prospectively recruited to a retest cohort. 3 T diffusion-weighted MRI of the prostate was acquired consecutively with patient getting off the scanner between studies. Prostatectomy-histopathology defined tumour regions-of-interest were outlined on ADC maps and diffusion-weighted metrics including histograms were calculated. The coefficient of reproducibility (CoR) and Bland-Altman plots were used to assess repeatability.

Results: 10 centile, 90 centile, and median ADC showed good repeatability with mean difference ranging from -0.005 to -0.025 × 10 mms, and CoR ranging from 0.271-0.294 × 10 mms of scan 1 mean). Two measures of heterogeneity and simplified texture, IQR and mean local range, had only moderate repeatability. IQR had a mean difference of -0.032 × 10 mms between scans with CoR 0.181 × 10 mms (56% of scan 1 mean). Mean local range had a mean difference -0.008 × 10 mms between scans (37% of scan 1 mean). Bland-Altman plots showed good repeatability for test and re-test analysis for median, percentile and mean range values. All ADC values had good reliability regardless of whether the tumour border was included in quantitative analysis. ADC histogram skew had poor repeatability, CoR 0.78 × 10 mms (373% of scan 1 mean).

Conclusion: 10 and 90 centile ADC demonstrated sufficient repeatability for clinical use. However, more advanced measures of heterogeneity such as histogram skew, IQR, or mean local range may be limited by their repeatability.
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http://dx.doi.org/10.1016/j.ejrad.2018.11.014DOI Listing
January 2019

Can computer-aided diagnosis assist in the identification of prostate cancer on prostate MRI? a multi-center, multi-reader investigation.

Oncotarget 2018 Sep 18;9(73):33804-33817. Epub 2018 Sep 18.

Molecular Imaging Program, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.

For prostate cancer detection on prostate multiparametric MRI (mpMRI), the Prostate Imaging-Reporting and Data System version 2 (PI-RADSv2) and computer-aided diagnosis (CAD) systems aim to widely improve standardization across radiologists and centers. Our goal was to evaluate CAD assistance in prostate cancer detection compared with conventional mpMRI interpretation in a diverse dataset acquired from five institutions tested by nine readers of varying experience levels, in total representing 14 globally spread institutions. Index lesion sensitivities of mpMRI-alone were 79% (whole prostate (WP)), 84% (peripheral zone (PZ)), 71% (transition zone (TZ)), similar to CAD at 76% (WP, p=0.39), 77% (PZ, p=0.07), 79% (TZ, p=0.15). Greatest CAD benefit was in TZ for moderately-experienced readers at PI-RADSv2 <3 (84% vs mpMRI-alone 67%, p=0.055). Detection agreement was unchanged but CAD-assisted read times improved (4.6 vs 3.4 minutes, p<0.001). At PI-RADSv2 ≥ 3, CAD improved patient-level specificity (72%) compared to mpMRI-alone (45%, p<0.001). PI-RADSv2 and CAD-assisted mpMRI interpretations have similar sensitivities across multiple sites and readers while CAD has potential to improve specificity and moderately-experienced radiologists' detection of more difficult tumors in the center of the gland. The multi-institutional evidence provided is essential to future prostate MRI and CAD development.
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http://dx.doi.org/10.18632/oncotarget.26100DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6173466PMC
September 2018

A reciprocal feedback between the PDZ binding kinase and androgen receptor drives prostate cancer.

Oncogene 2019 02 20;38(7):1136-1150. Epub 2018 Sep 20.

Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK.

Elucidation of mechanisms underlying the increased androgen receptor (AR) activity and subsequent development of aggressive prostate cancer (PrCa) is pivotal in developing new therapies. Using a systems biology approach, we interrogated the AR-regulated proteome and identified PDZ binding kinase (PBK) as a novel AR-regulated protein that regulates full-length AR and AR variants (ARVs) activity in PrCa. PBK overexpression in aggressive PrCa is associated with early biochemical relapse and poor clinical outcome. In addition to its carboxy terminus ligand-binding domain, PBK directly interacts with the amino terminus transactivation domain of the AR to stabilise it thereby leading to increased AR protein expression observed in PrCa. Transcriptome sequencing revealed that PBK is a mediator of global AR signalling with key roles in regulating tumour invasion and metastasis. PBK inhibition decreased growth of PrCa cell lines and clinical specimen cultured ex vivo. We uncovered a novel interplay between AR and PBK that results in increased AR and ARVs expression that executes AR-mediated growth and progression of PrCa, with implications for the development of PBK inhibitors for the treatment of aggressive PrCa.
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http://dx.doi.org/10.1038/s41388-018-0501-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6514849PMC
February 2019

WHO/ISUP classification, grading and pathological staging of renal cell carcinoma: standards and controversies.

World J Urol 2018 Dec 19;36(12):1913-1926. Epub 2018 Aug 19.

School of Medicine, University of St Andrews, St Andrews, KY16 9TF, UK.

Purpose: Pathological parameters assessed on biopsies and resection specimens have a pivotal role in the diagnosis, prognosis and management of patients with renal cell carcinoma (RCC).

Methods: A non-systematic literature search was performed, updated to January 2018, to identify key standards and controversies in the pathological classification, grading and staging of RCC.

Results: Although most RCCs exhibit characteristic morphology that enables easy categorisation, RCCs show considerable morphological heterogeneity and it is not uncommon for there to be difficulty in assigning a tumour type, especially with rarer tumour subtypes. The differentiation between benign and malignant oncocytic tumours remains a particular challenge. The development of additional immunohistochemical and molecular tests is needed to facilitate tumour typing, because of the prognostic and therapeutic implications, and to enable more reliable identification of poorly differentiated metastatic tumours as being of renal origin. Any new tests need to be applicable to small biopsy samples, to overcome the heterogeneity of renal tumours. There is also a need to facilitate identification of tumour types that have genetic implications, to allow referral and management at specialist centres. Digital pathology has a potential role in such referral practice.

Conclusion: Much has been done to standardise pathological assessment of renal cell carcinomas in recent years, but there still remain areas of difficulty in classification and grading of these heterogeneous tumours.
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http://dx.doi.org/10.1007/s00345-018-2447-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6280811PMC
December 2018

Single-cell transcriptomes from human kidneys reveal the cellular identity of renal tumors.

Science 2018 08;361(6402):594-599

Human Developmental Biology Resource, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK.

Messenger RNA encodes cellular function and phenotype. In the context of human cancer, it defines the identities of malignant cells and the diversity of tumor tissue. We studied 72,501 single-cell transcriptomes of human renal tumors and normal tissue from fetal, pediatric, and adult kidneys. We matched childhood Wilms tumor with specific fetal cell types, thus providing evidence for the hypothesis that Wilms tumor cells are aberrant fetal cells. In adult renal cell carcinoma, we identified a canonical cancer transcriptome that matched a little-known subtype of proximal convoluted tubular cell. Analyses of the tumor composition defined cancer-associated normal cells and delineated a complex vascular endothelial growth factor (VEGF) signaling circuit. Our findings reveal the precise cellular identities and compositions of human kidney tumors.
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http://dx.doi.org/10.1126/science.aat1699DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6104812PMC
August 2018
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