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Embryogenesis is a vulnerable time. Mutations in developmental cells can result in the wide dissemination of cells predisposed to disease within mature organs. We characterised the evolutionary history of four synchronous renal tumours from a 14-year-old girl using whole genome sequencing alongside single cell and bulk transcriptomic sequencing. Phylogenetic reconstruction timed the origin of all tumours to a multipotent embryonic cell committed to the right kidney, around 4 weeks post-conception. Biochemical and structural analysis of their shared MTOR mutation, absent from normal tissues, demonstrates enhanced protein flexibility, enabling a FAT domain hinge to dramatically increase activity of mTORC1 and mTORC2. Developmental mutations, not usually detected in traditional genetic screening, have vital clinical importance in guiding prognosis, targeted treatment, and family screening decisions for paediatric tumours., (© 2024. The Author(s).)

Hyperpolarised magnetic resonance imaging (HP- 13 C-MRI) has shown promise as a clinical tool for detecting and characterising prostate cancer. Here we use a range of spatially resolved histological techniques to identify the biological mechanisms underpinning differential [1- 13 C]lactate labelling between benign and malignant prostate, as well as in tumours containing cribriform and non-cribriform Gleason pattern 4 disease. Here we show that elevated hyperpolarised [1- 13 C]lactate signal in prostate cancer compared to the benign prostate is primarily driven by increased tumour epithelial cell density and vascularity, rather than differences in epithelial lactate concentration between tumour and normal. We also demonstrate that some tumours of the cribriform subtype may lack [1- 13 C]lactate labelling, which is explained by lower epithelial lactate dehydrogenase expression, higher mitochondrial pyruvate carrier density, and increased lipid abundance compared to lactate-rich non-cribriform lesions. These findings highlight the potential of combining spatial metabolic imaging tools across scales to identify clinically significant metabolic phenotypes in prostate cancer., (© 2024. The Author(s).)

Background: Clinical imaging tools to probe aggressiveness of renal masses are lacking, and T2-weighted imaging as an integral part of magnetic resonance imaging protocol only provides qualitative information. We developed high-resolution and accelerated T2 mapping methods based on echo merging and using k-t undersampling and reduced flip angles (TEMPURA) and tested their potential to quantify differences between renal tumour subtypes and grades., Methods: Twenty-four patients with treatment-naïve renal tumours were imaged: seven renal oncocytomas (RO); one eosinophilic/oncocytic renal cell carcinoma; two chromophobe RCCs (chRCC); three papillary RCCs (pRCC); and twelve clear cell RCCs (ccRCC). Median, kurtosis, and skewness of T2 were quantified in tumours and in the normal-adjacent kidney cortex and were compared across renal tumour subtypes and between ccRCC grades., Results: High-resolution TEMPURA depicted the tumour structure at improved resolution compared to conventional T2-weighted imaging. The lowest median T2 values were present in pRCC (high-resolution, 51 ms; accelerated, 45 ms), which was significantly lower than RO (high-resolution; accelerated, p = 0.012) and ccRCC (high-resolution, p = 0.019; accelerated, p = 0.008). ROs showed the lowest kurtosis (high-resolution, 3.4; accelerated, 4.0), suggestive of low intratumoural heterogeneity. Lower T2 values were observed in higher compared to lower grade ccRCCs (grades 2, 3 and 4 on high-resolution, 209 ms, 151 ms, and 106 ms; on accelerated, 172 ms, 160 ms, and 102 ms, respectively), with accelerated TEMPURA showing statistical significance in comparison (p = 0.037)., Conclusions: Both high-resolution and accelerated TEMPURA showed marked potential to quantify differences across renal tumour subtypes and between ccRCC grades., Trial Registration: ClinicalTrials.gov, NCT03741426 . Registered on 13 November 2018., Relevance Statement: The newly developed T 2 mapping methods have improved resolution, shorter acquisition times, and promising quantifiable readouts to characterise incidental renal masses., (© 2024. The Author(s).)

Background: Seminal vesicle involvement (SVI) in patients with newly diagnosed prostate cancer is associated with high rates of treatment failure and tumor recurrence; correct identification of SVI allows for effective management decisions and surgical planning., Methods: This single-center retrospective study analyzed MR images of the seminal vesicles from patients undergoing radical prostatectomy with confirmed T3b disease, comparing them to a control group without SVI matched for age and Gleason grade with a final stage of T2 or T3a. Seminal vesicles were segmented by an experienced uroradiologist, "raw" and bladder-normalized T2 signal intensity, as well as SV volume, were obtained., Results: Among the 82 patients with SVI, 34 (41.6%) had unilateral invasion, and 48 (58.4%) had bilateral disease. There was no statistically significant difference in the degree of distension between normal and involved seminal vesicles (P = 0.08). Similarly, no statistically significant difference was identified in the raw SV T2 signal intensity (P = 0.09) between the groups. In the 159 patients analyzed, SVI was prospectively suspected in 10 of 82 patients (specificity, 100%; sensitivity, 12.2%). In all these cases, lesions macroscopically invaded the seminal vesicle, and the raw T2 signal intensity was significantly lower than that in the SVI and control groups (P = 0.02 and 0.01)., Conclusion: While signal intensity measurements in T2-weighted images may provide insight into T3b disease, our findings suggest that this data alone is insufficient to reliably predict SVI, indicating the need for further investigation and complementary diagnostic approaches., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The development of cancer is an evolutionary process involving the sequential acquisition of genetic alterations that disrupt normal biological processes, enabling tumor cells to rapidly proliferate and eventually invade and metastasize to other tissues. We investigated the genomic evolution of prostate cancer through the application of three separate classification methods, each designed to investigate a different aspect of tumor evolution. Integrating the results revealed the existence of two distinct types of prostate cancer that arise from divergent evolutionary trajectories, designated as the Canonical and Alternative evolutionary disease types. We therefore propose the evotype model for prostate cancer evolution wherein Alternative-evotype tumors diverge from those of the Canonical-evotype through the stochastic accumulation of genetic alterations associated with disruptions to androgen receptor DNA binding. Our model unifies many previous molecular observations, providing a powerful new framework to investigate prostate cancer disease progression., Competing Interests: Declaration of interests An international patent related to this work has been published under international publication no. WO 2023/047140 A1. R.A.E. has the following conflicts of interest to declare: she has received honoraria from GU-ASCO, Janssen, The University of Chicago, and Dana-Farber Cancer Institute USA as a speaker and educational honorarium from Bayer and Ipsen and is a member of the external expert committee to Astra Zeneca UK. She undertakes private practice as a sole trader at The Royal Marsden NHS Foundation Trust and 90 Sloane Street SW1X 9PQ and 280 Kings Road SW3 4NX, London, UK., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

While radical prostatectomy remains the mainstay of prostate cancer (PCa) treatment, 20 to 40% of patients develop postsurgical biochemical recurrence (BCR). A particularly challenging clinical cohort includes patients with intermediate-risk disease whose risk stratification would benefit from advanced approaches that complement standard-of-care diagnostic tools. Here, we show that imaging tumor lactate using hyperpolarized 13 C MRI and spatial metabolomics identifies BCR-positive patients in two prospective intermediate-risk surgical cohorts. Supported by spatially resolved tissue analysis of established glycolytic biomarkers, this study provides the rationale for multicenter trials of tumor metabolic imaging as an auxiliary tool to support PCa treatment decision-making., Competing Interests: Competing interests statement:G.H., J.R., S.T.B., and R.J.A.G. are AstraZeneca employees.

Lineage switching can induce therapy resistance in cancer. Yet, how lineage fidelity is maintained and how it can be lost remain poorly understood. Here, we have used CRISPR-Cas9-based genetic screening to demonstrate that loss of SMARCB1, a member of the SWI/SNF chromatin remodeling complex, can confer an advantage to clear cell renal cell carcinoma (ccRCC) cells upon inhibition of the renal lineage factor PAX8. Lineage factor inhibition-resistant ccRCC cells formed tumors with morphological features, but not molecular markers, of neuroendocrine differentiation. SMARCB1 inactivation led to large-scale loss of kidney-specific epigenetic programs and restoration of proliferative capacity through the adoption of new dependencies on factors that represent rare essential genes across different cancers. We further developed an analytical approach to systematically characterize lineage fidelity using large-scale CRISPR-Cas9 data. An understanding of the rules that govern lineage switching could aid the development of more durable lineage factor-targeted and other cancer therapies., Competing Interests: The authors declare no competing interests., (© 2023 The Author(s).)

Serial MRI is an essential assessment tool in prostate cancer (PCa) patients enrolled on active surveillance (AS). However, it has only moderate sensitivity for predicting histopathological tumour progression at follow-up, which is in part due to the subjective nature of its clinical reporting and variation among centres and readers. In this study, we used a long short-term memory (LSTM) recurrent neural network (RNN) to develop a time series radiomics (TSR) predictive model that analysed longitudinal changes in tumour-derived radiomic features across 297 scans from 76 AS patients, 28 with histopathological PCa progression and 48 with stable disease. Using leave-one-out cross-validation (LOOCV), we found that an LSTM-based model combining TSR and serial PSA density (AUC 0.86 [95% CI: 0.78-0.94]) significantly outperformed a model combining conventional delta-radiomics and delta-PSA density (0.75 [0.64-0.87]; p = 0.048) and achieved comparable performance to expert-performed serial MRI analysis using the Prostate Cancer Radiologic Estimation of Change in Sequential Evaluation (PRECISE) scoring system (0.84 [0.76-0.93]; p = 0.710). The proposed TSR framework, therefore, offers a feasible quantitative tool for standardising serial MRI assessment in PCa AS. It also presents a novel methodological approach to serial image analysis that can be used to support clinical decision-making in multiple scenarios, from continuous disease monitoring to treatment response evaluation. KEY POINTS: •LSTM RNN can be used to predict the outcome of PCa AS using time series changes in tumour-derived radiomic features and PSA density. •Using all available TSR features and serial PSA density yields a significantly better predictive performance compared to using just two time points within the delta-radiomics framework. •The concept of TSR can be applied to other clinical scenarios involving serial imaging, setting out a new field in AI-driven radiology research., (© 2023. The Author(s).)

Purpose: Patients with resected localized clear-cell renal cell carcinoma (ccRCC) remain at variable risk of recurrence. Incorporation of biomarkers may refine risk prediction and inform adjuvant treatment decisions. We explored the role of tumor genomics in this setting, leveraging the largest cohort to date of localized ccRCC tissues subjected to targeted gene sequencing., Experimental Design: The somatic mutation status of 12 genes was determined in 943 ccRCC cases from a multinational cohort of patients, and associations to outcomes were examined in a Discovery (n = 469) and Validation (n = 474) framework., Results: Tumors containing a von-Hippel Lindau (VHL) mutation alone were associated with significantly improved outcomes in comparison with tumors containing a VHL plus additional mutations. Within the Discovery cohort, those with VHL+0, VHL+1, VHL+2, and VHL+≥3 tumors had disease-free survival (DFS) rates of 90.8%, 80.1%, 68.2%, and 50.7% respectively, at 5 years. This trend was replicated in the Validation cohort. Notably, these genomically defined groups were independent of tumor mutational burden. Amongst patients eligible for adjuvant therapy, those with a VHL+0 tumor (29%) had a 5-year DFS rate of 79.3% and could, therefore, potentially be spared further treatment. Conversely, patients with VHL+2 and VHL+≥3 tumors (32%) had equivalent DFS rates of 45.6% and 35.3%, respectively, and should be prioritized for adjuvant therapy., Conclusions: Genomic characterization of ccRCC identified biologically distinct groups of patients with divergent relapse rates. These groups account for the ∼80% of cases with VHL mutations and could be used to personalize adjuvant treatment discussions with patients as well as inform future adjuvant trial design., (©2023 The Authors; Published by the American Association for Cancer Research.)

Metabolic reprogramming is critical for tumor initiation and progression. However, the exact impact of specific metabolic changes on cancer progression is poorly understood. Here, we integrate multimodal analyses of primary and metastatic clonally-related clear cell renal cancer cells (ccRCC) grown in physiological media to identify key stage-specific metabolic vulnerabilities. We show that a VHL loss-dependent reprogramming of branched-chain amino acid catabolism sustains the de novo biosynthesis of aspartate and arginine enabling tumor cells with the flexibility of partitioning the nitrogen of the amino acids depending on their needs. Importantly, we identify the epigenetic reactivation of argininosuccinate synthase (ASS1), a urea cycle enzyme suppressed in primary ccRCC, as a crucial event for metastatic renal cancer cells to acquire the capability to generate arginine, invade in vitro and metastasize in vivo. Overall, our study uncovers a mechanism of metabolic flexibility occurring during ccRCC progression, paving the way for the development of novel stage-specific therapies., (© 2022. The Author(s).)

Tumor behavior is intricately dependent on the oncogenic properties of cancer cells and their multi-cellular interactions. To understand these dependencies within the wider microenvironment, we studied over 270,000 single-cell transcriptomes and 100 microdissected whole exomes from 12 patients with kidney tumors, prior to validation using spatial transcriptomics. Tissues were sampled from multiple regions of the tumor core, the tumor-normal interface, normal surrounding tissues, and peripheral blood. We find that the tissue-type location of CD8 + T cell clonotypes largely defines their exhaustion state with intra-tumoral spatial heterogeneity that is not well explained by somatic heterogeneity. De novo mutation calling from single-cell RNA-sequencing data allows us to broadly infer the clonality of stromal cells and lineage-trace myeloid cell development. We report six conserved meta-programs that distinguish tumor cell function, and find an epithelial-mesenchymal transition meta-program highly enriched at the tumor-normal interface that co-localizes with IL1B-expressing macrophages, offering a potential therapeutic target., Competing Interests: Declaration of interests In the past 3 years, S.A.T. has consulted for Roche and Genentech and is a Scientific Advisory Board member of Qiagen, Foresite labs, Biogen, and GSK, as well as a consultant and equity holder as co-founder of Transition Bio., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

An updated European Network of Cancer registries (ENCR) Recommendations on Recording and Reporting of Urothelial Tumours of the Urinary Tract had been published in 2022. After the publication by the ENCR of the "Recommendations for coding bladder cancers" in 1995, knowledge about the biology and pathology of urinary tract tumors and their classification has varied and increased substantially. On the other hand, several studies have shown that cancer registries use different definitions, criteria for inclusion and coding of urothelial tumors. This great variability among registries affects not only the criteria for recording (registration, coding and classification) but also the criteria of reporting (counting in the statistics of incidence and survival) urinary tract tumors. This causes difficulties in the data comparability from different registries. Recording and reporting of urothelial tumors requires the application of standard criteria that must take into account the combination of the multiple aspects as the primary topography, the histological type, the grade, the extent of invasion, the multi-centricity, the progressions and the time interval between tumors. This led to the creation of a Working Group of the ENCR that developed these recommendations on the recording and reporting of urothelial tumors of the urinary tract. This article reports these recommendations and the rationale for each., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Galceran, Parada, Eden, Tumino, Warren, Martos, Neamtiu, Visser and Daubisse-Marliac.)

Hyperpolarised [1- 13 C]pyruvate MRI (HP- 13 C-MRI) is an emerging metabolic imaging technique that has shown promise for evaluating prostate cancer (PCa) aggressiveness. Accurate tumour delineation on HP- 13 C-MRI is vital for quantitative assessment of the underlying tissue metabolism. However, there is no consensus on the optimum method for segmenting HP- 13 C-MRI, and whole-mount pathology (WMP) as the histopathological gold-standard is only available for surgical patients. Although proton MRI can be used for tumour delineation, this approach significantly underestimates tumour volume, and metabolic tumour segmentation based on HP- 13 C-MRI could provide an important functional metric of tumour volume. In this study, we quantified metabolism using HP- 13 C-MRI and segmentation approaches based on WMP maps, 1 H-MRI-derived T 2 -weighted imaging (T2WI), and HP- 13 C-MRI-derived total carbon signal-to-noise ratio maps (TC-SNR) with an SNR threshold of 5.0. 13 C-labelled pyruvate SNR, lactate SNR, TC-SNR, and the pyruvate-to-lactate exchange rate constant (k PL ) were significantly higher when measured using the TC-SNR-guided approach, which also corresponded to a significantly higher tumour epithelial expression on RNAscope imaging of the enzyme catalysing pyruvate-to-lactate metabolism (lactate dehydrogenase (LDH)). However, linear regression and Bland-Altman analyses demonstrated a strong linear relationship between all three segmentation approaches, which correlated significantly with RNA-scope-derived epithelial LDH expression. These results suggest that standard-of-care T2WI and TC-SNR maps could be used as clinical reference tools for segmenting localised PCa on HP- 13 C-MRI in the absence of the WMP gold standard. The TC-SNR-guided approach could be used clinically to target biopsies towards highly glycolytic tumour areas and therefore to sample aggressive disease with higher precision. KEY POINTS: • T2WI- and TC-SNR-guided segmentations can be used in all PCa patients and do not explicitly require WMP maps. • Agreement between the three segmentation approaches is biologically validated by their strong relationship with epithelial LDH mRNA expression. • The TC-SNR-guided approach can potentially be used to identify occult disease on 1 H-MRI and target the most glycolytically active regions., (© 2022. The Author(s).)

Background: Surgery for renal cell carcinoma (RCC) with venous tumour thrombus (VTT) extension into the renal vein (RV) and/or inferior vena cava (IVC) has high peri-surgical morbidity/mortality. NAXIVA assessed the response of VTT to axitinib, a potent tyrosine kinase inhibitor., Methods: NAXIVA was a single-arm, multi-centre, Phase 2 study. In total, 20 patients with resectable clear cell RCC and VTT received upto 8 weeks of pre-surgical axitinib. The primary endpoint was percentage of evaluable patients with VTT improvement by Mayo level on MRI. Secondary endpoints were percentage change in surgical approach and VTT length, response rate (RECISTv1.1) and surgical morbidity., Results: In all, 35% (7/20) patients with VTT had a reduction in Mayo level with axitinib: 37.5% (6/16) with IVC VTT and 25% (1/4) with RV-only VTT. No patients had an increase in Mayo level. In total, 75% (15/20) of patients had a reduction in VTT length. Overall, 41.2% (7/17) of patients who underwent surgery had less invasive surgery than originally planned. Non-responders exhibited lower baseline microvessel density (CD31), higher Ki67 and exhausted or regulatory T-cell phenotype., Conclusions: NAXIVA provides the first Level II evidence that axitinib downstages VTT in a significant proportion of patients leading to reduction in the extent of surgery., Clinical Trial Registration: NCT03494816., (© 2022. The Author(s).)

Current gold standard diagnostic strategies are unable to accurately differentiate malignant from benign small renal masses preoperatively; consequently, 20% of patients undergo unnecessary surgery. Devising a more confident presurgical diagnosis is key to improving treatment decision-making. We therefore developed MethylBoostER, a machine learning model leveraging DNA methylation data from 1228 tissue samples, to classify pathological subtypes of renal tumors (benign oncocytoma, clear cell, papillary, and chromophobe RCC) and normal kidney. The prediction accuracy in the testing set was 0.960, with class-wise ROC AUCs >0.988 for all classes. External validation was performed on >500 samples from four independent datasets, achieving AUCs >0.89 for all classes and average accuracies of 0.824, 0.703, 0.875, and 0.894 for the four datasets. Furthermore, consistent classification of multiregion samples ( N = 185) from the same patient demonstrates that methylation heterogeneity does not limit model applicability. Following further clinical studies, MethylBoostER could facilitate a more confident presurgical diagnosis to guide treatment decision-making in the future.

Background: Up to 80% of cases of prostate cancer present with multifocal independent tumour lesions leading to the concept of a field effect present in the normal prostate predisposing to cancer development. In the present study we applied Whole Genome DNA Sequencing (WGS) to a group of morphologically normal tissue (n = 51), including benign prostatic hyperplasia (BPH) and non-BPH samples, from men with and men without prostate cancer. We assess whether the observed genetic changes in morphologically normal tissue are linked to the development of cancer in the prostate., Results: Single nucleotide variants (P = 7.0 × 10 -03 , Wilcoxon rank sum test) and small insertions and deletions (indels, P = 8.7 × 10 -06 ) were significantly higher in morphologically normal samples, including BPH, from men with prostate cancer compared to those without. The presence of subclonal expansions under selective pressure, supported by a high level of mutations, were significantly associated with samples from men with prostate cancer (P = 0.035, Fisher exact test). The clonal cell fraction of normal clones was always higher than the proportion of the prostate estimated as epithelial (P = 5.94 × 10 -05 , paired Wilcoxon signed rank test) which, along with analysis of primary fibroblasts prepared from BPH specimens, suggests a stromal origin. Constructed phylogenies revealed lineages associated with benign tissue that were completely distinct from adjacent tumour clones, but a common lineage between BPH and non-BPH morphologically normal tissues was often observed. Compared to tumours, normal samples have significantly less single nucleotide variants (P = 3.72 × 10 -09 , paired Wilcoxon signed rank test), have very few rearrangements and a complete lack of copy number alterations., Conclusions: Cells within regions of morphologically normal tissue (both BPH and non-BPH) can expand under selective pressure by mechanisms that are distinct from those occurring in adjacent cancer, but that are allied to the presence of cancer. Expansions, which are probably stromal in origin, are characterised by lack of recurrent driver mutations, by almost complete absence of structural variants/copy number alterations, and mutational processes similar to malignant tissue. Our findings have implications for treatment (focal therapy) and early detection approaches., (© 2022. The Author(s).)

Around 95% of patients with clinical features that meet the diagnostic criteria for von Hippel-Lindau disease (VHL) have a detectable inactivating germline variant in VHL. The VHL protein (pVHL) functions as part of the E3 ubiquitin ligase complex comprising pVHL, elongin C, elongin B, cullin 2 and ring box 1 (VCB-CR complex), which plays a key role in oxygen sensing and degradation of hypoxia-inducible factors. To date, only variants in VHL have been shown to cause VHL disease. We undertook trio analysis by whole-exome sequencing in a proband with VHL disease but without a detectable VHL mutation. Molecular studies were also performed on paired DNA extracted from the proband's kidney tumour and blood and bioinformatics analysis of sporadic renal cell carcinoma (RCC) dataset was undertaken. A de novo pathogenic variant in ELOC NM_005648.4(ELOC):c.236A>G (p.Tyr79Cys) gene was identified in the proband. ELOC encodes elongin C, a key component [C] of the VCB-CR complex. The p.Tyr79Cys substitution is a mutational hotspot in sporadic VHL-competent RCC and has previously been shown to mimic the effects of pVHL deficiency on hypoxic signalling. Analysis of an RCC from the proband showed similar findings to that in somatically ELOC-mutated RCC (expression of hypoxia-responsive proteins, no somatic VHL variants and chromosome 8 loss). These findings are consistent with pathogenic ELOC variants being a novel cause for VHL disease and suggest that genetic testing for ELOC variants should be performed in individuals with suspected VHL disease with no detectable VHL variant., (© The Author(s) 2022. Published by Oxford University Press.)

Germ cell tumours (GCTs) are a collection of benign and malignant neoplasms derived from primordial germ cells. They are uniquely able to recapitulate embryonic and extraembryonic tissues, which carries prognostic and therapeutic significance. The developmental pathways underpinning GCT initiation and histogenesis are incompletely understood. Here, we study the relationship of histogenesis and clonal diversification in GCTs by analysing the genomes and transcriptomes of 547 microdissected histological units. We find no correlation between genomic and histological heterogeneity. However, we identify unifying features including the retention of fetal developmental transcripts across tissues, expression changes on chromosome 12p, and a conserved somatic evolutionary sequence of whole genome duplication followed by clonal diversification. While this pattern is preserved across all GCTs, the developmental timing of the duplication varies between prepubertal and postpubertal cases. In addition, tumours of younger children exhibit distinct substitution signatures which may lend themselves as potential biomarkers for risk stratification. Our findings portray the extensive diversification of GCT tissues and genetic subclones as randomly distributed, while identifying overarching transcriptional and genomic features., (© 2022. Crown.)

Purpose: To assess the added value of histological information for local staging of prostate cancer (PCa) by comparing the accuracy of multiparametric MRI alone (mpMRI) and mpMRI with biopsy Gleason grade (mpMRI+Bx)., Methods: 133 consecutive patients who underwent preoperative 3T-MRI and subsequent radical prostatectomy for PCa were included in this single-centre retrospective study. mpMRI imaging was reviewed independently by two uroradiologists for the presence of extracapsular extension (ECE) and seminal vesicle invasion (SVI) on a 5-point Likert scale. For second reads, the radiologists received results of targeted fused MR/US biopsy (mpMRI+Bx) prior to re-staging., Results: The median patient age was 63 years (interquartile range (IQR) 58-67 years) and median PSA was 6.5 ng/mL (IQR 5.0-10.0 ng/mL). Extracapsular extension was present in 85/133 (63.9%) patients and SVI was present in 22/133 (16.5%) patients. For ECE prediction, mpMRI showed sensitivity and specificity of 63.5% and 81.3%, respectively, compared to 77.7% and 81.3% achieved by mpMRI+Bx. At an optimal cut-off value of Likert score ≥ 3, areas under the curves (AUCs) was .85 for mpMRI+Bx and .78 for mpMRI, P < .01. For SVI prediction, AUC was .95 for mpMRI+Bx compared to .92 for mpMRI; P = .20. Inter-reader agreement for ECE and SVI prediction was substantial for mpMRI (k range, .78-.79) and mpMRI+Bx (k range, .74-.79)., Conclusions: MpMRI+Bx showed superior diagnostic performance with an increased sensitivity for ECE prediction but no significant difference for SVI prediction. Inter-reader agreement was substantial for both protocols. Integration of biopsy information adds value when staging prostate mpMRI.

Large-scale human genetic data 1-3 have shown that cancer mutations display strong tissue-selectivity, but how this selectivity arises remains unclear. Here, using experimental models, functional genomics and analyses of patient samples, we demonstrate that the lineage transcription factor paired box 8 (PAX8) is required for oncogenic signalling by two common genetic alterations that cause clear cell renal cell carcinoma (ccRCC) in humans: the germline variant rs7948643 at 11q13.3 and somatic inactivation of the von Hippel-Lindau tumour suppressor (VHL) 4-6 . VHL loss, which is observed in about 90% of ccRCCs, can lead to hypoxia-inducible factor 2α (HIF2A) stabilization 6,7 . We show that HIF2A is preferentially recruited to PAX8-bound transcriptional enhancers, including a pro-tumorigenic cyclin D1 (CCND1) enhancer that is controlled by PAX8 and HIF2A. The ccRCC-protective allele C at rs7948643 inhibits PAX8 binding at this enhancer and downstream activation of CCND1 expression. Co-option of a PAX8-dependent physiological programme that supports the proliferation of normal renal epithelial cells is also required for MYC expression from the ccRCC metastasis-associated amplicons at 8q21.3-q24.3 (ref. 8 ). These results demonstrate that transcriptional lineage factors are essential for oncogenic signalling and that they mediate tissue-specific cancer risk associated with somatic and inherited genetic variants., (© 2022. The Author(s).)

Purpose: To retrospectively determine the prevalence and diagnostic performance of the capsular enhancement sign (CES) on multiparametric (mp) MRI for the detection of prostate cancer (PCa) extracapsular extension (ECE)., Methods: This retrospective study included patients who underwent mpMRI prior to radical prostatectomy. CES was defined as an area of asymmetrical early hyperenhancement on DCE-MRI adjacent to a peripheral zone tumour, matched or exceeded the tumour circumferential diameter, and with persistent enhancement. Two uro-radiologists evaluated the presence of CES on mpMRI, independently and in consensus, with interobserver agreement calculated using bias and prevalence-adjusted kappa (PABAK). CES performance for predicting ECE was assessed using sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV)., Results: The study included 146 patients, with 91/146 (62%) having ECE on surgical pathology. Following initial review, Reader 1 identified 12/146 (8%) CES-positive cases, while Reader 2 reported 14/146 (10%) CES-positive cases, with 15/146 (10%) lesions determined as demonstrating the CES sign on consensus reading. PABAK for CES between the two readers was high at 0.90. All consensus determined CES-positive lesions represented pathological stage ≥ T3a disease, with the overall prevalence of CES among tumours with confirmed ECE being 15/91 (17%). The sign showed high specificity (100%) and PPV (100%) for ECE detection, but with low sensitivity, NPV, and accuracy at 16.5%, 41.3%, and 47.4%, respectively., Conclusions: CES was demonstrated to be a rare but highly specific ECE predictor on mpMRI that may improve local staging in the patients in whom it is demonstrated., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Hyperpolarised magnetic resonance imaging (HP  13 C-MRI) is an emerging clinical technique to detect [1- 13 C]lactate production in prostate cancer (PCa) following intravenous injection of hyperpolarised [1- 13 C]pyruvate. Here we differentiate clinically significant PCa from indolent disease in a low/intermediate-risk population by correlating [1- 13 C]lactate labelling on MRI with the percentage of Gleason pattern 4 (%GP4) disease. Using immunohistochemistry and spatial transcriptomics, we show that HP  13 C-MRI predominantly measures metabolism in the epithelial compartment of the tumour, rather than the stroma. MRI-derived tumour [1- 13 C]lactate labelling correlated with epithelial mRNA expression of the enzyme lactate dehydrogenase (LDHA and LDHB combined), and the ratio of lactate transporter expression between the epithelial and stromal compartments (epithelium-to-stroma MCT4). We observe similar changes in MCT4, LDHA, and LDHB between tumours with primary Gleason patterns 3 and 4 in an independent TCGA cohort. Therefore, HP  13 C-MRI can metabolically phenotype clinically significant disease based on underlying metabolic differences in the epithelial and stromal tumour compartments., (© 2022. The Author(s).)