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Purpose To evaluate the performance of an artificial intelligence (AI) model in detecting overall and clinically significant prostate cancer (csPCa)-positive lesions on paired external and in-house biparametric MRI (bpMRI) scans and assess performance differences between each dataset. Materials and Methods This single-center retrospective study included patients who underwent prostate MRI at an external institution and were rescanned at the authors' institution between May 2015 and May 2022. A genitourinary radiologist performed prospective readouts on in-house MRI scans following the Prostate Imaging Reporting and Data System (PI-RADS) version 2.0 or 2.1 and retrospective image quality assessments for all scans. A subgroup of patients underwent an MRI/US fusion-guided biopsy. A bpMRI-based lesion detection AI model previously developed using a completely separate dataset was tested on both MRI datasets. Detection rates were compared between external and in-house datasets with use of the paired comparison permutation tests. Factors associated with AI detection performance were assessed using multivariable generalized mixed-effects models, incorporating features selected through forward stepwise regression based on the Akaike information criterion. Results The study included 201 male patients (median age, 66 years [IQR, 62-70 years]; prostate-specific antigen density, 0.14 ng/mL 2 [IQR, 0.10-0.22 ng/mL 2 ]) with a median interval between external and in-house MRI scans of 182 days (IQR, 97-383 days). For intraprostatic lesions, AI detected 39.7% (149 of 375) on external and 56.0% (210 of 375) on in-house MRI scans ( P < .001). For csPCa-positive lesions, AI detected 61% (54 of 89) on external and 79% (70 of 89) on in-house MRI scans ( P < .001). On external MRI scans, better overall lesion detection was associated with a higher PI-RADS score (odds ratio [OR] = 1.57; P = .005), larger lesion diameter (OR = 3.96; P < .001), better diffusion-weighted MRI quality (OR = 1.53; P = .02), and fewer lesions at MRI (OR = 0.78; P = .045). Better csPCa detection was associated with a shorter MRI interval between external and in-house scans (OR = 0.58; P = .03) and larger lesion size (OR = 10.19; P < .001). Conclusion The AI model exhibited modest performance in identifying both overall and csPCa-positive lesions on external bpMRI scans. Keywords: MR Imaging, Urinary, Prostate Supplemental material is available for this article. © RSNA, 2024.

von Hippel-Lindau (VHL) is an autosomal-dominant hereditary tumour susceptibility disease associated with pathogenic germline variants in the VHL tumour suppressor gene. VHL patients are at increased risk of developing multiple benign and malignant tumours. Current CLIA-based genetic tests demonstrate a very high detection rate of germline VHL variants in patients with clinical manifestations of VHL. In this report, we describe a large family with canonical VHL manifestations, for which no germline alteration had been detected by conventional germline testing. We identified a novel 291 kb chromosomal inversion involving chromosome 3p in affected family members. This inversion disrupts the VHL gene between exon 2 and exon 3 and is thereby responsible for the disease observed in this family., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Rationale and Objectives: The increasing use of focal therapy (FT) in localized prostate cancer (PCa) management requires a standardized MRI interpretation system to detect recurrent clinically significant PCa (csPCa). This pilot study evaluates the novel Transatlantic Recommendations for Prostate Gland Evaluation with MRI after Focal Therapy (TARGET) and compares its performance to that of the Prostate Imaging after Focal Ablation (PI-FAB) system., Materials and Methods: This retrospective study included 38 patients who underwent primary FT for localized PCa, with follow-up multiparametric MRI (mpMRI) and biopsy. Two radiologists assessed the mpMRIs using both PI-FAB and TARGET independently. Diagnostic performance metrics and area under the receiver operating characteristic curve (AUC) were calculated. Inter-reader and intrareader agreement were assessed using Cohen's κ and Kendall's τ., Results: 14 patients had recurrent csPCa. PI-FAB showed high sensitivity (92.9% for both readers) and NPV (reader 1: 93.8%, reader 2: 92.9%) but moderate specificity (reader 1: 62.5%, reader 2: 54.2%). TARGET demonstrated lower sensitivity for one reader (reader 1: 78.6%, reader 2: 92.9%) but higher specificity (reader 1: 79.2%, reader 2: 62.5%) for both readers. Both systems displayed moderate inter-reader agreement (κ = 0.56 for PI-FAB, 0.57 for TARGET)., Conclusion: PI-FAB and TARGET exhibit similar performances in post-FT MRI. While PI-FAB had consistently high sensitivity, TARGET offered higher specificity for one reader. Moderate agreement levels demonstrate the viability of these systems in clinical settings and a promise for improvement., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: B. J. Wood receives support as part of a cooperative research and development agreement (CRADA) between NIH and Philips Healthcare, receives royalties from NIH related to a licensing agreement with Philips Healthcare, and is party to patents or potential patents related to this work. P. L. Choyke receives royalties for MRI/ultrasound fusion biopsy patents licensed to Philips Medical. P. A. Pinto receives royalties from NIH related to a Philips licensing agreement and support as part of a CRADA between NIH and Philips Healthcare. B. Turkbey receives support as part of a CRADA between NIH and NVDIA and between NIH and Philips Healthcare, receives royalties from NIH, and is party to patents or potential patents related to this work. The remaining authors declare that there are no other disclosures relevant to the subject matter of this article. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government., (Published by Elsevier Inc.)

Rationale and Objectives: Extraprostatic extension (EPE) is well established as a significant predictor of prostate cancer aggression and recurrence. Accurate EPE assessment prior to radical prostatectomy can impact surgical approach. We aimed to utilize a deep learning-based AI workflow for automated EPE grading from prostate T2W MRI, ADC map, and High B DWI., Material and Methods: An expert genitourinary radiologist conducted prospective clinical assessments of MRI scans for 634 patients and assigned risk for EPE using a grading technique. The training set and held-out independent test set consisted of 507 patients and 127 patients, respectively. Existing deep-learning AI models for prostate organ and lesion segmentation were leveraged to extract area and distance features for random forest classification models. Model performance was evaluated using balanced accuracy, ROC AUCs for each EPE grade, as well as sensitivity, specificity, and accuracy compared to EPE on histopathology., Results: A balanced accuracy score of .390 ± 0.078 was achieved using a lesion detection probability threshold of 0.45 and distance features. Using the test set, ROC AUCs for AI-assigned EPE grades 0-3 were 0.70, 0.65, 0.68, and 0.55 respectively. When using EPE≥ 1 as the threshold for positive EPE, the model achieved a sensitivity of 0.67, specificity of 0.73, and accuracy of 0.72 compared to radiologist sensitivity of 0.81, specificity of 0.62, and accuracy of 0.66 using histopathology as the ground truth., Conclusion: Our AI workflow for assigning imaging-based EPE grades achieves an accuracy for predicting histologic EPE approaching that of physicians. This automated workflow has the potential to enhance physician decision-making for assessing the risk of EPE in patients undergoing treatment for prostate cancer due to its consistency and automation., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: B. J. Wood receives support as part of a cooperative research and development agreement (CRADA) between NIH and Philips Healthcare, receives royalties from NIH related to a licensing agreement with Philips Healthcare, and is party to patents or potential patents related to this work. P. L. Choyke receives royalties for MRI/ultrasound fusion biopsy patents licensed to Philips Medical. P. A. Pinto receives royalties from NIH related to a Philips licensing agreement and support as part of a CRADA between NIH and Philips Healthcare. B. Turkbey receives support as part of a CRADA between NIH and NVDIA and between NIH and Philips Healthcare, receives royalties from NIH, and is party to patents or potential patents related to this work. Jesse Tetreault: employee of NVIDIA Corporation. The remaining authors declare that there are no other disclosures relevant to the subject matter of this article. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government., (Published by Elsevier Inc.)

Drug repurposing aims to find new therapeutic applications for existing drugs in the pharmaceutical market, leading to significant savings in time and cost. The use of artificial intelligence and knowledge graphs to propose repurposing candidates facilitates the process, as large amounts of data can be processed. However, it is important to pay attention to the explainability needed to validate the predictions. We propose a general architecture to understand several explainable methods for graph completion based on knowledge graphs and design our own architecture for drug repurposing. We present XG4Repo (eXplainable Graphs for Repurposing), a framework that takes advantage of the connectivity of any biomedical knowledge graph to link compounds to the diseases they can treat. Our method allows methapaths of different types and lengths, which are automatically generated and optimised based on data. XG4Repo focuses on providing meaningful explanations to the predictions, which are based on paths from compounds to diseases. These paths include nodes such as genes, pathways, side effects, or anatomies, so they provide information about the targets and other characteristics of the biomedical mechanism that link compounds and diseases. Paths make predictions interpretable for experts who can validate them and use them in further research on drug repurposing. We also describe three use cases where we analyse new uses for Epirubicin, Paclitaxel, and Predinisone and present the paths that support the predictions., (© 2024. The Author(s).)

Introduction: Renal cell carcinoma is one of the ten more common malignant tumors worldwide, with a high incidence and mortality rate. Kidney cancer frequently presents at an advanced stage, and it is almost invariably fatal. Much progress has been made in identifying molecular targets for therapy in the hope of improving survival rates, but still, we have no good markers for early detection or progression of the disease. Von Hippel Lindau syndrome (VHL) is an autosomal dominant cancer hereditary syndrome in which affected individuals are at risk of developing bilateral and multifocal renal cell carcinomas (RCC) as well as other tumors. These patients provide an ideal platform to investigate the potential of urinary exosomal miRNA biomarkers in the early development of ccRCC, as these patients are regularly imaged and tumors are actively monitored until the tumor reaches 3 cm before surgical excision. This allows for pre- and post-surgical urine collection and comparison to excised tumor tissues. Studying different biomarkers in urine can provide comprehensive molecular profiling available to patients and physicians and can be a great source of additional tumor genetic information., Methods: Pre- and postoperative urine samples were obtained from a cohort of VHL patients undergoing surveillance and surgical excision of ccRCCs, and exosomes were extracted. MicroRNA-Seq analysis was performed on miRNA extracted from both urine-derived exosomes and FFPE material from excised ccRCCs., Results: MicroRNA-Seq analysis highlighted a significant difference in the urinary exosome-derived miRNA expression profiles between VHL patients and normal control individuals. This included decreased expression of the miR-320 family, such as miR-320a, known to be decreased in sporadic ccRCC and suppressed by the HIF1α transcription factor activated by the loss of the VHL gene. MiR-542-5p represented a potential marker of VHL-associated ccRCC that was lowly expressed in normal control urinary exosomes, significantly increased in the preoperative urinary exosomes of tumor-bearing VHL patients, and subsequently reduced to normal levels of expression after tumor excision. In concordance with this, the expression of miR-542-5p was increased in the VHL-associated ccRCC in comparison to the normal kidney., Conclusions: This study shows the potential for miRNA profiling of exosomes from readily available biofluids to both distinguish VHL patient urine from normal control urine microRNAs and to provide biomarkers for the presence of VHL syndrome-associated ccRCC. Further validation studies are necessary to demonstrate the utility of urinary exosome-derived miRNAs as biomarkers in kidney cancer.

Competing Interests: The authors declare no conflict of interest.

Introduction: Nosocomial infectious ventriculitis caused by multidrug-resistant (MDR) Gram-negative bacilli associated with external ventricular drainage (EVD) placement poses a significant mortality burden and hospital costs., Objectives: This study aims to analyze the characteristics, ventriculitis evolution, treatment, and outcomes of patients with ventriculitis due to MDR Gram-negative bacilli associated with EVD placement., Methods: A retrospective cohort study focusing on patients with nosocomial infection caused by MDR Gram-negative bacilli while on EVD was conducted from 2019 to 2022. Medical, laboratory, and microbiological records were collected. The antibiotic resistance of the Gram-negative bacilli isolated in the cerebrospinal fluid (CSF) of patients was analyzed. The risk factors were identified using univariate risk models and were analyzed using survival curves (Cox regression). An adjusted Cox proportional hazards model was also constructed., Results: Among 530 patients with suspected EVD-associated ventriculitis, 64 patients with isolation of Gram-negative bacilli in CSF were included. The estimated mortality was 78.12%. Hemorrhages (intracranial, subarachnoid, and intraventricular) were observed in 69.8% of patients. Acinetobacter baumannii, Klebsiella pneumoniae , and Pseudomonas aeruginosa were the most frequently isolated bacilli. In the univariate analysis, significant risk factors for mortality included arterial hypertension, a Glasgow Coma Scale (GCS) score of ≤ 8, invasive mechanical ventilation (IMV) upon hospital admission and during hospitalization, septic shock, and ineffective treatment. The adjusted Cox proportional hazards model revealed that septic shock (HR = 3.3, 95% CI = 1.5-7.2; p = 0.003) and ineffective treatment (HR = 3.2, 1.6-6.5, 0.001) were significant predictors. A high resistance to carbapenems was found for A. baumannii (91.3%) and P. aeruginosa (80.0%). Low resistance to colistin was found for A. baumannii (4.8%) and P. aeruginosa (12.5%)., Conclusion: Ineffective treatment was an independent hazard factor for death in patients with ventriculitis caused by MDR Gram-negative bacilli associated with EVD., 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 © 2024 Corona-Nakamura, Arias-Merino, Ávila-Esparza, Tolentino-Corona, Cañedo-Castañeda, Flores-Salinas, Corona-Macías and Vázquez-Arias.)

Background and Objective: Focal therapy (FT) is increasingly recognized as a promising approach for managing localized prostate cancer (PCa), notably reducing treatment-related morbidities. However, post-treatment anatomical changes present significant challenges for surveillance using current imaging techniques. This study aimed to evaluate the inter-reader agreement and efficacy of the Prostate Imaging after Focal Ablation (PI-FAB) scoring system in detecting clinically significant prostate cancer (csPCa) on post-FT multiparametric magnetic resonance imaging (mpMRI)., Methods: A retrospective cohort study was conducted involving patients who underwent primary FT for localized csPCa between 2013 and 2023, followed by post-FT mpMRI and a prostate biopsy. Two expert genitourinary radiologists retrospectively evaluated post-FT mpMRI using PI-FAB. The key measures included inter-reader agreement of PI-FAB scores, assessed by quadratic weighted Cohen's kappa ( κ ), and the system's efficacy in predicting in-field recurrence of csPCa, with a PI-FAB score cutoff of 3. Additional diagnostic metrics including sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and overall accuracy were also evaluated., Key Findings and Limitations: Scans from 38 patients were analyzed, revealing a moderate level of agreement in PI-FAB scoring ( κ  = 0.56). Both radiologists achieved sensitivity of 93% in detecting csPCa, although specificity, PPVs, NPVs, and accuracy varied., Conclusions and Clinical Implications: The PI-FAB scoring system exhibited high sensitivity with moderate inter-reader agreement in detecting in-field recurrence of csPCa. Despite promising results, its low specificity and PPV necessitate further refinement. These findings underscore the need for larger studies to validate the clinical utility of PI-FAB, potentially aiding in standardizing post-treatment surveillance., Patient Summary: Focal therapy has emerged as a promising approach for managing localized prostate cancer, but limitations in current imaging techniques present significant challenges for post-treatment surveillance. The Prostate Imaging after Focal Ablation (PI-FAB) scoring system showed high sensitivity for detecting in-field recurrence of clinically significant prostate cancer. However, its low specificity and positive predictive value necessitate further refinement. Larger, more comprehensive studies are needed to fully validate its clinical utility.

Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is an autosomal dominant condition characterized by the development of cutaneous and uterine leiomyomas and risk for development of an aggressive form of papillary renal cell cancer. HLRCC is caused by germline inactivating pathogenic variants in the fumarate hydratase (FH) gene, which encodes the enzyme that catalyzes the interconversion of fumarate and L-malate. We utilized enzyme and protein mobility assays to evaluate the FH enzyme in a cohort of patients who showed clinical manifestations of HLRCC but were negative for known pathogenic FH gene variants. FH enzyme activity and protein levels were decreased by 50% or greater in three family members, despite normal FH mRNA expression levels as measured by quantitative PCR. Direct Nanopore RNA sequencing demonstrated 57 base pairs of retained intron sequence between exons 9 and 10 of polyadenylated FH mRNA in these patients, resulting in a truncated FH protein. Genomic sequencing revealed a heterozygous intronic alteration of the FH gene (chr1: 241498239 T/C) resulting in formation of a splice acceptor site near a polypyrimidine tract, and a uterine fibroid obtained from a patient showed loss of heterozygosity at this site. The same intronic FH variant was identified in an unrelated patient who also showed a clinical phenotype of HLRCC. These data demonstrate that careful clinical assessment as well as biochemical characterization of FH enzyme activity, protein expression, direct RNA sequencing, and genomic DNA sequencing of patient-derived cells can identify pathogenic variants outside of the protein coding regions of the FH gene., (Published by Oxford University Press 2023.)

Neurotuberculosis (neuroTB) is a devastating disease, and is difficult to diagnose. The aim of this study was to analyze the clinical and imaging characteristics, and outcomes of a retrospective cohort (2000-2022) of hospitalized patients diagnosed with intraspinal and intracranial neuroTB. This work was designed through clinical, laboratory and imaging findings. Variables included: demographic data, history of tuberculosis, neurological complications, comorbidities and outcomes. Morbi-mortality risk factors were identified by univariate analysis. The cohort included: 103 patients with intraspinal and 82 with intracranial neuroTB. During the study period, in-hospital mortality of 3% for intraspinal and 29.6% for intracranial neuroTB was estimated. Motor deficit was found in all patients with intraspinal neuroTB. Risk factors for the unfavorable outcome of patients with intraspinal neuroTB were: age ≥ 40 years, diabetes mellitus (DM), diagnostic delay, kyphosis and spondylodiscitis ≥ 3 levels of involvement. Among the patients with intracranial neuroTB, 79/82 (96.3%) had meningitis and 22 patients had HIV infection (10 of them died). Risk factors for mortality from intracranial neuroTB were: HIV infection, hydrocephalus, stroke, lymphopenia and disseminated and gastrointestinal TB. Patients with intraspinal neuroTB had a significant number of destroyed vertebrae that determined their neurological deficit status. The mortality burden in intracranial neuroTB was conditioned by HIV infection and renal transplantation patients.

The aim of this study was to analyze the risk factors and predictors of mortality in a retrospective cohort of patients with coronavirus disease (COVID-19) who presented central nervous system (CNS) manifestations and complications when admitted to hospital. Patients hospitalized from 2020 to 2022 were selected. Demographic variables; history of neurological, cardiological and pulmonary manifestations; comorbidities; prognostic severity scales; and laboratory tests were included. Univariate and adjusted analyses were performed to determine risk factors and predictors of mortality. A forest plot diagram was used to show the strength of the associated risk factors. The cohort included 991 patients; at admission, 463 patients presented CNS damage and of these, 96 hospitalized patients presented de novo CNS manifestations and complications. We estimate a general mortality of 43.7% (433/991) and 77.1% (74/96), for hospitalized patients with de novo CNS manifestations and complications, respectively. The following were identified as risks for the development of hospital CNS manifestations and complications when in hospital: an age of ≥64 years, a history of neurological disease, de novo deep vein thrombosis, D-dimer ≥ 1000 ng/dL, a SOFA ≥ 5, and a CORADS 6. In a multivariable analysis, the mortality predictors were an age of ≥64 years, a SOFA ≥ 5, D-dimer ≥ 1000 ng/mL and hospital CNS manifestations and complications when admitted to hospital. Old age, being hospitalized in critical condition, and having CNS manifestations and complications in hospital are predictors of mortality in hospitalized patients with COVID-19.

Birt-Hogg-Dubé (BHD) syndrome is an inherited familial cancer syndrome characterized by the development of cutaneous lesions, pulmonary cysts, renal tumors and cysts and caused by loss-of-function pathogenic variants in the gene encoding the tumor-suppressor protein folliculin (FLCN). FLCN acts as a negative regulator of TFEB and TFE3 transcription factors, master controllers of lysosomal biogenesis and autophagy, by enabling their phosphorylation by the mechanistic Target Of Rapamycin Complex 1 (mTORC1). We have previously shown that deletion of Tfeb rescued the renal cystic phenotype of kidney-specific Flcn KO mice. Using Flcn/Tfeb/Tfe3 double and triple KO mice, we now show that both Tfeb and Tfe3 contribute, in a differential and cooperative manner, to kidney cystogenesis. Remarkably, the analysis of BHD patient-derived tumor samples revealed increased activation of TFEB/TFE3-mediated transcriptional program and silencing either of the two genes rescued tumorigenesis in human BHD renal tumor cell line-derived xenografts (CDXs). Our findings demonstrate in disease-relevant models that both TFEB and TFE3 are key drivers of renal tumorigenesis and suggest novel therapeutic strategies based on the inhibition of these transcription factors., (© 2023 The Authors. Published under the terms of the CC BY 4.0 license.)

Background Data regarding the prospective performance of Prostate Imaging Reporting and Data System (PI-RADS) version 2.1 alone and in combination with quantitative MRI features for prostate cancer detection is limited. Purpose To assess lesion-based clinically significant prostate cancer (csPCa) rates in different PI-RADS version 2.1 categories and to identify MRI features that could improve csPCa detection. Materials and Methods This single-center prospective study included men with suspected or known prostate cancer who underwent multiparametric MRI and MRI/US-guided biopsy from April 2019 to December 2021. MRI scans were prospectively evaluated using PI-RADS version 2.1. Atypical transition zone (TZ) nodules were upgraded to category 3 if marked diffusion restriction was present. Lesions with an International Society of Urological Pathology (ISUP) grade of 2 or higher (range, 1-5) were considered csPCa. MRI features, including three-dimensional diameter, relative lesion volume (lesion volume divided by prostate volume), sphericity, and surface to volume ratio (SVR), were obtained from lesion contours delineated by the radiologist. Univariable and multivariable analyses were conducted at the lesion and participant levels to determine features associated with csPCa. Results In total, 454 men (median age, 67 years [IQR, 62-73 years]) with 838 lesions were included. The csPCa rates for lesions categorized as PI-RADS 1 ( n = 3), 2 ( n = 170), 3 ( n = 197), 4 ( n = 319), and 5 ( n = 149) were 0%, 9%, 14%, 37%, and 77%, respectively. csPCa rates of PI-RADS 4 lesions were lower than PI-RADS 5 lesions ( P < .001) but higher than PI-RADS 3 lesions ( P < .001). Upgraded PI-RADS 3 TZ lesions were less likely to harbor csPCa compared with their nonupgraded counterparts (4% [one of 26] vs 20% [20 of 99], P = .02). Predictors of csPCa included relative lesion volume (odds ratio [OR], 1.6; P < .001), SVR (OR, 6.2; P = .02), and extraprostatic extension (EPE) scores of 2 (OR, 9.3; P < .001) and 3 (OR, 4.1; P = .02). Conclusion The rates of csPCa differed between consecutive PI-RADS categories of 3 and higher. MRI features, including lesion volume, shape, and EPE scores of 2 and 3, predicted csPCa. Upgrading of PI-RADS category 3 TZ lesions may result in unnecessary biopsies. ClinicalTrials.gov registration no. NCT03354416 © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Goh in this issue.

Background: MiT-Renal Cell Carcinoma (RCC) is characterized by genomic translocations involving microphthalmia-associated transcription factor (MiT) family members TFE3, TFEB, or MITF. MiT-RCC represents a specific subtype of sporadic RCC that is predominantly seen in young patients and can present with heterogeneous histological features making diagnosis challenging. Moreover, the disease biology of this aggressive cancer is poorly understood and there is no accepted standard of care therapy for patients with advanced disease. Tumor-derived cell lines have been established from human TFE3-RCC providing useful models for preclinical studies., Methods: TFE3-RCC tumor derived cell lines and their tissues of origin were characterized by IHC and gene expression analyses. An unbiased high-throughput drug screen was performed to identify novel therapeutic agents for treatment of MiT-RCC. Potential therapeutic candidates were validated in in vitro and in vivo preclinical studies. Mechanistic assays were conducted to confirm the on-target effects of drugs., Results: The results of a high-throughput small molecule drug screen utilizing three TFE3-RCC tumor-derived cell lines identified five classes of agents with potential pharmacological efficacy, including inhibitors of phosphoinositide-3-kinase (PI3K) and mechanistic target of rapamycin (mTOR), and several additional agents, including the transcription inhibitor Mithramycin A. Upregulation of the cell surface marker GPNMB, a specific MiT transcriptional target, was confirmed in TFE3-RCC and evaluated as a therapeutic target using the GPNMB-targeted antibody-drug conjugate CDX-011. In vitro and in vivo preclinical studies demonstrated efficacy of the PI3K/mTOR inhibitor NVP-BGT226, Mithramycin A, and CDX-011 as potential therapeutic options for treating advanced MiT-RCC as single agents or in combination., Conclusions: The results of the high-throughput drug screen and validation studies in TFE3-RCC tumor-derived cell lines have provided in vitro and in vivo preclinical data supporting the efficacy of the PI3K/mTOR inhibitor NVP-BGT226, the transcription inhibitor Mithramycin A, and GPNMB-targeted antibody-drug conjugate CDX-011 as potential therapeutic options for treating advanced MiT-RCC. The findings presented here should provide the basis for designing future clinical trials for patients with MiT-driven RCC., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Germline mutations within the Krebs cycle enzyme genes fumarate hydratase (FH) or succinate dehydrogenase (SDHB, SDHC, SDHD) are associated with an increased risk of aggressive and early metastasizing variants of renal cell carcinoma (RCC). These RCCs express significantly increased levels of intracellular fumarate or succinate that inhibit 2-oxoglutarate-dependent dioxygenases, such as the TET enzymes that regulate DNA methylation. This study evaluated the genome-wide methylation profiles of 34 RCCs from patients with RCC susceptibility syndromes and 11 associated normal samples using the Illumina HumanMethylation450 BeadChip. All the HLRCC (FH mutated) and SDHB-RCC (SDHB mutated) tumors demonstrated a distinct CpG island methylator phenotype (CIMP). HLRCC tumors demonstrated an extensive and relatively uniform level of hypermethylation that showed some correlation with tumor size. SDHB-RCC demonstrated a lesser and more varied pattern of hypermethylation that overlapped in part with the HLRCC hypermethylation. Combined methylation and mRNA expression analysis of the HLRCC tumors demonstrated hypermethylation and transcription downregulation of genes associated with the HIF pathway, HIF3A and CITED4, the WNT pathway, SFRP1, and epithelial-to-mesenchymal transition and MYC expression, OVOL1. These observations were confirmed in the TCGA CIMP-RCC tumors. A selected panel of probes could identify the CIMP tumors and differentiate between HLRCC and SDHB-RCC tumors. This panel accurately detected all CIMP-RCC tumors within the TCGA RCC cohort, identifying them as HLRCC -like, and could potentially be used to create a liquid biopsy-based screening tool. The CIMP signature in these aggressive tumors could provide both a useful biomarker for diagnosis and a target for novel therapies., Competing Interests: Authors C.J.R., C.D.V., Y.W., M.J.M., P.S.M., and W.M.L. have declared that no competing interests exist. Subsequent to working on this project, author J.K.K. changed employment to work for Foundation Medicine, Inc., a commercial company that is involved in the development of diagnostic tests for cancer related therapies. All the author’s involvement with this study pre-date employment by Foundation Medicine, Inc. and so this does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.)

Rationale and Objectives: Prostate MRI improves detection of clinically significant prostate cancer; however, its diagnostic performance has wide variation. Artificial intelligence (AI) has the potential to assist radiologists in the detection and classification of prostatic lesions. Herein, we aimed to develop and test a cascaded deep learning detection and classification system trained on biparametric prostate MRI using PI-RADS for assisting radiologists during prostate MRI read out., Materials and Methods: T2-weighted, diffusion-weighted (ADC maps, high b value DWI) MRI scans obtained at 3 Tesla from two institutions (n = 1043 in-house and n = 347 Prostate-X, respectively) acquired between 2015 to 2019 were used for model training, validation, testing. All scans were retrospectively reevaluated by one radiologist. Suspicious lesions were contoured and assigned a PI-RADS category. A 3D U-Net-based deep neural network was used to train an algorithm for automated detection and segmentation of prostate MRI lesions. Two 3D residual neural network were used for a 4-class classification task to predict PI-RADS categories 2 to 5 and BPH. Training and validation used 89% (n = 1290 scans) of the data using 5 fold cross-validation, the remaining 11% (n = 150 scans) were used for independent testing. Algorithm performance at lesion level was assessed using sensitivities, positive predictive values (PPV), false discovery rates (FDR), classification accuracy, Dice similarity coefficient (DSC). Additional analysis was conducted to compare AI algorithm's lesion detection performance with targeted biopsy results., Results: Median age was 66 years (IQR = 60-71), PSA 6.7 ng/ml (IQR = 4.7-9.9) from in-house cohort. In the independent test set, algorithm correctly detected 111 of 198 lesions leading to 56.1% (49.3%-62.6%) sensitivity. PPV was 62.7% (95% CI 54.7%-70.7%) with FDR of 37.3% (95% CI 29.3%-45.3%). Of 79 true positive lesions, 82.3% were tumor positive at targeted biopsy, whereas of 57 false negative lesions, 50.9% were benign at targeted biopsy. Median DSC for lesion segmentation was 0.359. Overall PI-RADS classification accuracy was 30.8% (95% CI 24.6%-37.8%)., Conclusion: Our cascaded U-Net, residual network architecture can detect, classify cancer suspicious lesions at prostate MRI with good detection, reasonable classification performance metrics., (Published by Elsevier Inc.)

Background: Sotrovimab is a neutralizing monoclonal antibody (mAb) that seems to remain active against recent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants. The evidence on its use in kidney transplant (KT) recipients, however, is limited., Methods: We performed a multicenter, retrospective cohort study of 82 KT patients with SARS-CoV-2 infection {coronavirus disease 2019 [COVID-19]} treated with sotrovimab., Results: Median age was 63 years. Diabetes was present in 43.9% of patients, and obesity in 32.9% of patients; 48.8% of patients had an estimated glomerular filtration rate under 30 mL/minute/1.73 m 2 . Additional anti-COVID-19 therapies were administered to 56 patients, especially intravenous steroids (65.9%). Sotrovimab was administered early (<5 days from the onset of the symptoms) in 46 patients (56%). Early-treated patients showed less likely progression to severe COVID-19 than those treated later, represented as a lower need for ventilator support (2.2% vs 36.1%; P  < .001) or intensive care admission (2.2% vs 25%; P  = .002) and COVID-19-related mortality (2.2% vs 16.7%; P  = .020). In the multivariable analysis, controlling for baseline risk factors to severe COVID-19 in KT recipients, early use of sotrovimab remained as a protective factor for a composite outcome, including need for ventilator support, intensive care, and COVID-19-related mortality. No anaphylactic reactions, acute rejection episodes, impaired kidney function events, or non-kidney side effects related to sotrovimab were observed., Conclusions: Sotrovimab had an excellent safety profile, even in high-comorbidity patients and advanced chronic kidney disease stages. Earlier administration could prevent progression to severe disease, while clinical outcomes were poor in patients treated later. Larger controlled studies enrolling KT recipients are warranted to elucidate the true efficacy of monoclonal antibody therapies., (© The Author(s) 2022. Published by Oxford University Press on behalf of the ERA.)

Background: Gleason score grading is a cornerstone of risk stratification and management of patients with prostate cancer (PCa). In this work, we derive and validate a nomogram that uses prostate multiparametric magnetic resonance imaging (MP-MRI) and clinical patient characteristics to predict biopsy Gleason scores (bGS)., Materials and Methods: A predictive nomogram was derived from 143 men who underwent MP-MRI prior to any prostate biopsy and then validated on an independent cohort of 235 men from a different institution who underwent MP-MRI for PCa workup. Screen positive lesions were defined as lesions positive on T2W and DWI sequences on MP-MRI. Prostate specific antigen (PSA) density, number of screen positive lesions, and MRI suspicion were associated with PCa Gleason score on biopsy and were used to generate a predictive nomogram. The independent cohort was tested on the nomogram and the most likely bGS was noted., Results: The mean PSA in the validation cohort was 9.25ng/mL versus 6.8ng/mL in the original cohort ( p = 0.001). The distribution of Gleason scores between the 2 cohorts were not significantly different ( p = 0.7). In the original cohort of men, the most probable nomogram generated Gleason score agreed with actual pathologic bGS findings in 61% of the men. In the validation cohort, the most likely nomogram predicted bGS agreed with actual pathologic bGS 51% of the time. The nomogram correctly identified any PCa versus non-PCa 63% of the time and clinically significant (Gleason score ≥ 7) PCa 69% of the time. The negative predictive value for clinically significant PCa using this prebiopsy nomogram was 74% in the validation group., Conclusions: A preintervention nomogram based on PSA and MRI findings can help narrow down the likely pathologic finding on biopsy. Validation of the nomogram demonstrated a significant ability to correctly identify the most likely bGS. This feasibility study demonstrates the potential of a prebiopsy prediction of bGS and based on the high negative predictive value, identification of men who may not need biopsies, which could impact future risk stratification for PCa., Competing Interests: The authors report no conflicts of interest., (Copyright © 2022 The Authors. Published by Wolters Kluwer Health, Inc.)

Endometrioid endometrial carcinomas (EECs) are the most common histological subtype of uterine cancer. Late-stage disease is an adverse prognosticator for EEC. The purpose of this study was to analyze EEC exome mutation data to identify late-stage-specific statistically significantly mutated genes (SMGs), which represent candidate driver genes potentially associated with disease progression. We exome sequenced 15 late-stage (stage III or IV) non-ultramutated EECs and paired non-tumor DNAs; somatic variants were called using Strelka, Shimmer, SomaticSniper and MuTect. Additionally, somatic mutation calls were extracted from The Cancer Genome Atlas (TCGA) data for 66 late-stage and 270 early-stage (stage I or II) non-ultramutated EECs. MutSigCV (v1.4) was used to annotate SMGs in the two late-stage cohorts and to derive p-values for all mutated genes in the early-stage cohort. To test whether late-stage SMGs are statistically significantly mutated in early-stage tumors, q-values for late-stage SMGs were re-calculated from the MutSigCV (v1.4) early-stage p-values, adjusting for the number of late-stage SMGs tested. We identified 14 SMGs in the combined late-stage EEC cohorts. When the 14 late-stage SMGs were examined in the TCGA early-stage data, only Krüppel-like factor 3 (KLF3) and Paired box 6 (PAX6) failed to reach significance as early-stage SMGs, despite the inclusion of enough early-stage cases to ensure adequate statistical power. Within TCGA, nonsynonymous mutations in KLF3 and PAX6 were, respectively, exclusive or nearly exclusive to the microsatellite instability (MSI)-hypermutated molecular subgroup and were dominated by insertions-deletions at homopolymer tracts. In conclusion, our findings are hypothesis-generating and suggest that KLF3 and PAX6, which encode transcription factors, are MSI target genes and late-stage-specific SMGs in EEC., Competing Interests: The authors have declared that no competing interests exist.

Extracellular vesicles (EVs) of various types are released or shed from all cells. EVs carry proteins and contain additional protein and nucleic acid cargo that relates to their biogenesis and cell of origin. EV cargo in liquid biopsies is of widespread interest owing to its ability to provide a retrospective snapshot of cell state at the time of EV release. For the purposes of EV cargo analysis and repertoire profiling, multiplex assays are an essential tool in multiparametric analyte studies but are still being developed for high-parameter EV protein detection. Although bead-based EV multiplex analyses offer EV profiling capabilities with conventional flow cytometers, the utilization of EV multiplex assays has been limited by the lack of software analysis tools for such assays. To facilitate robust EV repertoire studies, we developed multiplex analysis post-acquisition analysis (MPA PASS ) open-source software for stitched multiplex analysis, EV database-compatible reporting, and visualization of EV repertoires., Competing Interests: A.G. has an affiliation with Evox Therapeutics, Ltd. All other authors declare no competing interests., (© 2022.)

Intratumoral heterogeneity (IH) has been recently described as an important contributor to tumor growth through a branched rather than a linear pattern of tumor evolution for renal cell carcinoma. As to whether the miRNA profiling of the different and heterogeneous areas is the same or not, it is not known. This study analyzed the differences and similarities of the miRNA profiles in histologically distinct regions within several RCC tumors. The observed differences may have great implications for the development of predictive biomarkers and the identification of druggable targets with improvement of combinatorial therapeutic approaches for the effective treatment of kidney cancer, as well as for the identification of circulating malignant cells that can be useful to detect tumor recurrences., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Genetic resource banks (GRB) preserve the genetic material of endangered, valuable individuals or genetically relevant breeds. Semen cryopreservation is a crucial technique to reach these goals. Thus, we aimed to assess the sperm parameters of semen doses from the native pig breed Gochu Asturcelta stored at the GRB of Principado de Asturias (GRB-PA, Gijón, Spain), focusing on intrinsic and extrinsic (boar, season) factors. Two straws per boar ( n = 18, 8-71 months of age) were thawed, pooled, and assessed after 30 and 150 min at 37 °C by CASA (computer-assisted sperm analysis system; motility and kinematic parameters) and flow cytometry (viability, acrosomal status, mitochondrial activity, apoptosis, reactive oxygen species, and chromatin status). The effects of age, incubation, and season on post-thawing quality were determined using linear mixed-effects models. Parameters were on the range for commercial boar breeds, with chromatin status (SCSA: fragmentation and immaturity) being excellent. Incubation decreased sperm quality and functionality. The boar age did not have a significant effect ( p > 0.05), but the between-boar variability was significant ( p < 0.001). The season significantly affected many parameters (motility, kinematics, viability, acrosomal status, mitochondrial activity), especially after 150 min of incubation. In general, samples collected in spring and summer showed higher quality post-thawing, the lowest in winter. In conclusion, the sperm doses from the Gochu Asturcelta breed stored at the GRB-PA showed excellent chromatin status and acceptable characteristics after thawing. Therefore, boar and seasonal variability in this autochthonous breed could be relevant for cryobank management.

Background Although prostate MRI is routinely used for the detection and staging of localized prostate cancer, imaging-based assessment and targeted molecular sampling for risk stratification are an active area of research. Purpose To evaluate features of preoperative MRI and MRI-guided biopsy immunohistochemistry (IHC) findings associated with biochemical recurrence (BCR) of prostate cancer after surgery. Materials and Methods In this retrospective case-control study, patients underwent multiparametric MRI before MRI-guided biopsy followed by radical prostatectomy between 2008 and 2016. Lesions were retrospectively scored with the Prostate Imaging Reporting and Data System (PI-RADS) (version 2) by radiologists who were blinded to the clinical-pathologic results. The IHC staining, including stains for the ETS-related gene, phosphatase and tensin homolog, androgen receptor, prostate specific antigen, and p53, was performed with targeted biopsy specimens of the index lesion (highest suspicion at MRI and pathologic grade) and scored by pathologists who were blinded to clinical-pathologic outcomes. Cox proportional hazards regression analysis was used to evaluate associations with recurrence-free survival (RFS). Results The median RFS was 31.7 months (range, 1-101 months) for 39 patients (median age, 62 years; age range, 47-76 years) without BCR and 14.6 months (range, 1-61 months) for 40 patients (median age, 59 years; age range, 47-73 years) with BCR. MRI features that showed a significant relationship with the RFS interval included an index lesion with a PI-RADS score of 5 (hazard ratio [HR], 2.10; 95% CI: 1.05, 4.21; P = .04); index lesion burden, defined as ratio of index lesion volume to prostate volume (HR, 1.55; 95% CI: 1.2, 2.1; P = .003); and suspicion of extraprostatic extension (EPE) (HR, 2.18; 95% CI: 1.1, 4.2; P = .02). Presurgical multivariable analysis indicated that suspicion of EPE at MRI (adjusted HR, 2.19; 95% CI: 1.1, 4.3; P = .02) and p53 stain intensity (adjusted HR, 2.22; 95% CI: 1.0, 4.7; P = .04) were significantly associated with RFS. Conclusion MRI features, including Prostate Imaging Reporting and Data System score, index lesion burden, extraprostatic extension, and preoperative guided biopsy p53 immunohistochemistry stain intensity are associated with biochemical relapse of prostate cancer after surgery. © RSNA, 2021 Online supplemental material is available for this article . See also the editorial by Costa in this issue.

Purpose: We aimed to assess post-interventional and 36-month follow-up results of a single-center, single-arm, in-bore phase I trial of focal laser ablation (FLA) guided by multiparametric magnetic resonance imaging (mpMRI)., Methods: FLA procedures were done in-bore MRI using a transperineal approach. Primary endpoints were feasibility and safety expressed as lack of grade 3 complications. Secondary endpoints were changes in international prostate symptom score (IPSS), sexual health inventory for men (SHIM), quality of life (QoL) scores, and serum prostate specific antigen (PSA) levels. Treatment outcomes were assessed by combined mpMRI-ultrasound fusion-guided and extended sextant systematic biopsy after 12, 24, and optionally after 36 months., Results: Fifteen participants were included. Seven patients (46.67%) had Gleason 3+3 and 8 patients (53.33%) had Gleason 3+4 cancer. All patients tolerated the procedure well, and no grade 3/4 complications occurred. All grade 1 and 2 complications were transient and resolved completely. There was no significant change in mean IPSS from baseline (-1, p = 0.460) and QoL (0, p = 0.441) scores following FLA but there was a significant drop in mean SHIM scores (-2, p = 0.010) compared to pretreatment baselines. Mean PSA significantly decreased after FLA (-2.5, p < 0.001). Seven out of 15 patients (46.67%) had residual cancer in, adjacent, or in close proximity to the treatment area (1 × 4+3=7, 1 × 3+4=7, and 5 × 3+3=6). Four out of 15 patients (26.67%) underwent salvage therapy (2 repeat FLA, 2 radical prostatectomy)., Conclusion: After 3 years of follow-up we conclude focal laser ablation is safe and feasible without significant complications.

Part 2 of this series on granulomatous diseases focuses on skin biopsy findings. Whereas the first part treated noninfectious conditions (metabolic disorders and tumors, among other conditions), this part mainly deals with various types of infectious disease along with other conditions seen fairly often by clinical dermatologists., (Copyright © 2021 AEDV. Publicado por Elsevier España, S.L.U. All rights reserved.)

This series of 2 articles on dermatopathologic diagnoses reviews conditions in which granulomas form. Part 1 clarifies concepts, discusses the presentation of different types of granulomas and giant cells, and considers a large variety of noninfectious diseases. Some granulomatous diseases have a metabolic origin, as in necrobiosis lipoidica. Others, such as granulomatous mycosis fungoides, are related to lymphomas. Still others, such as rosacea, are so common that dermatologists see them nearly daily in clinical practice., (Copyright © 2021 AEDV. Publicado por Elsevier España, S.L.U. All rights reserved.)

Paragangliomas and pheochromocytomas (PPGLs) are chromaffin tumors associated with severe catecholamine-induced morbidities. Surgical removal is often curative. However, complete resection may not be an option for patients with succinate dehydrogenase subunit A-D ( SDHx ) mutations. SDHx mutations are associated with a high risk for multiple recurrent, and metastatic PPGLs. Treatment options in these cases are limited and prognosis is dismal once metastases are present. Identification of new therapeutic targets and candidate drugs is thus urgently needed. Previously, we showed elevated expression of succinate receptor 1 ( SUCNR1 ) in SDHB PPGLs and SDHD head and neck paragangliomas. Its ligand succinate has been reported to accumulate due to SDHx mutations. We thus hypothesize that autocrine stimulation of SUCNR1 plays a role in the pathogenesis of SDHx mutation-derived PPGLs. We confirmed elevated SUCNR1 expression in SDHx PPGLs and after SDHB knockout in progenitor cells derived from a human pheochromocytoma (hPheo1). Succinate significantly increased viability of SUCNR1 -transfected PC12 and ERK pathway signaling compared to control cells. Candidate SUCNR1 inhibitors successfully reversed proliferative effects of succinate. Our data reveal an unrecognized oncometabolic function of succinate in SDHx PPGLs, providing a growth advantage via SUCNR1 ., 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 © 2021 Matlac, Hadrava Vanova, Bechmann, Richter, Folberth, Ghayee, Ge, Abunimer, Wesley, Aherrahrou, Dona, Martínez-Montes, Calsina, Merino, Schwaninger, Deen, Zhuang, Neuzil, Pacak, Lehnert and Fliedner.)

Purpose: For high-risk prostate cancer, standard treatment options include radical prostatectomy (RP) or radiotherapy plus androgen deprivation therapy (ADT). Despite definitive therapy, many patients will have disease recurrence. Imaging has the potential to better define characteristics of response and resistance. In this study, we evaluated prostate multiparametric MRI (mpMRI) before and after neoadjuvant enzalutamide plus ADT., Patients and Methods: Men with localized intermediate- or high-risk prostate cancer underwent a baseline mpMRI and mpMRI-targeted biopsy followed by a second mpMRI after 6 months of enzalutamide and ADT prior to RP. Specimens were sectioned in the same plane as mpMRI using patient-specific 3D-printed molds to permit mpMRI-targeted biopsies to be compared with the same lesion from the RP. Specimens were analyzed for imaging and histologic correlates of response., Results: Of 39 patients enrolled, 36 completed imaging and RP. Most patients (92%) had high-risk disease. Fifty-eight lesions were detected on baseline mpMRI, of which 40 (69%) remained measurable at 6-month follow-up imaging. Fifty-five of 59 lesions (93%) demonstrated >50% volume reduction on posttreatment mpMRI. Three of 59 lesions (5%) demonstrated growth in size at follow-up imaging, with two lesions increasing more than 3-fold in volume. On whole-mount pathology, 15 patients demonstrated minimal residual disease (MRD) of <0.05 cc or pathologic complete response. Low initial mpMRI relative tumor burden was most predictive of MRD on final pathology., Conclusions: Low relative lesion volume at baseline mpMRI was predictive of pathologic response. A subset of patients had limited response. Selection of patients based on these metrics may improve outcomes in high-risk disease., (©2020 American Association for Cancer Research.)

This research analyses the emotional and behavioural problems, as well as the problems in the executive functions, of children in residential care under protective measures, between 8 and 12 years of age. We analyse the relationship between the problems with their executive functions and their emotional and behavioural problems, as well as the predictive value of the executive functions for the said emotional and behavioural problems. The instruments used were as follows: five digits test (FDT), behavioural assessment of the dysexecutive syndrome in children (BADS-C) and the system of evaluation for children and adolescents (SENA). The results indicate that the children have difficulties in their executive functions, with such problems as in attention control and regulation, impulsiveness, mental rigidity, behavioural organisation and planning and resolving problems. They also have internalising and externalising problems, as well as difficulties in controlling their emotional reactions and understanding the emotions of others. It becomes evident that the difficulties in their executive functions are related to and predict their emotional and behavioural problems. The research demonstrates the need to intervene in the problems detected through the design of therapeutic programmes and interventions in the residential context.

MicroRNAs (miRNAs) are small, non-coding RNA molecules with multiple roles in many biological processes. Few studies have shown the molecular characteristics in younger prostate cancer (PCa) patients. In this study, we performed miRNA profiling in young PCa (EO-PCa) cases compared with PCa arising in older men (LO-PCa). Experimental Design : Formalin-fixed, paraffin embedded tissue was used. miRNA was extracted for PCR array and NanoString methods. Relative miRNAs expression levels were obtained by comparing young vs older men, and young PCa tumor samples vs normal epithelium. Results : miRNA profiling showed a different expression pattern in PCa arising in younger men, and young PCa tumoral and its normal counterpart. Nine miRNAs (hsa-miR-140-5p, hsa-miR-146a, hsa-miR-29b, hsa-miR-9, hsa-miR-124-3p, hsa-let-7f-5p, hsa-miR-184, hsa-miR-373, hsa-miR-146b-5p) showed differences in the expression compared to LO-PCa. Fourteen miRNAs were significantly up-regulated (miR-1973, miR-663a, miR-575, miR-93-5p, miR-630, miR-600, miR-494, miR-150-5p, miR-137, miR-25-3p, miR-375, miR-489, miR-888-5p, miR-142-3p), while 9 were found down-regulated (miR-21-5p, miR-363-3p, miR-205-5p, miR-548ai, miR-3195, 145-5p, miR-143-3p, miR-222-3p, miR-221-3p) comparing young PCa tumoral tissue compared to normal counterpart. The higher expression of miR-600 and miR-137 were associated with high Gleason score, extraprostatic extension and lymphatic invasion. Conclusion : These results suggest that PCa in younger patients has a different expression profile compared to normal tissue and PCa arising in older man. Differentially expressed miRNAs provide insights of molecular mechanisms involve in this PCa subtype., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Immunotherapy is reportedly an effective form of therapy for some advanced cancers such as lung adenocarcinoma, malignant melanoma and colorectal adenocarcinoma. In renal cell carcinoma (RCC), the role of immunotherapy is under investigation. Programmed Death-Ligand 1 (PD-L1) is a molecule expressed on the surface of certain tumor cells and binds to the Programmed cell death protein 1 (PD-1) on cytotoxic T-cells, an interaction that inhibits the antitumor immune response. The aim of this study is to evaluate PD-L1 expression in the morphologic spectrum of RCC. A total of 172 cases of RCC comprising all types were studied and the PD-L1 was correlated with immune response for CD4 and CD8. Positive membranous staining for PD-L1 was seen in 59 (34%) of the 172 samples. The positive cases were HLRCC (31/53), Type 1 Papillary RCC (10/31), Chromophobe (7/20), Hybrid (3/9), TFE-3 related cancer (3/8), Undifferentiated (3/5), and TFEB tumors (2/2). Clear cell carcinomas, Oncocytomas and SDHB deficient-RCC didn't show any expression of PD-L1; (0/34;0/7;0/3). Our results demonstrated that aggressive forms of RCC such as HLRCC have high expression of PD-L1, in contrast to clear cell renal carcinomas. Our findings support a possible role of anti-PD-L1/PD-1 immunotherapies in the treatment of PD-L1-positive RCC., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Localized prostate cancers are genetically variable and frequently multifocal, comprising spatially distinct regions with multiple independently-evolving clones. To date there is no understanding of whether this variability can influence management decisions for patients with prostate tumors. Here, we present a single case from a clinical trial of neoadjuvant intense androgen deprivation therapy. A patient was diagnosed with a large semi-contiguous tumor by imaging, histologically composed of a large Gleason score 9 tumor with an adjacent Gleason score 7 nodule. DNA sequencing demonstrates these are two independent tumors, as only the Gleason 9 tumor harbors single-copy losses of PTEN and TP53. The PTEN/TP53-deficient tumor demonstrates treatment resistance, selecting for subclones with mutations to the remaining copies of PTEN and TP53, while the Gleason 7 PTEN-intact tumor is almost entirely ablated. These findings indicate that spatiogenetic variability is a major confounder for personalized treatment of patients with prostate cancer.

Background: To assess the influence of specific histopathologic patterns on MRI diffusion characteristics by performing rigorous whole-mount/imaging registration and correlating histologic architectures observed in prostate cancer with diffusion characteristics in prostate MRIs., Methods: Fifty-two whole-mount pathology blocks from 15 patients who underwent multiparametric MRI (mpMRI) at a single institution prior to radical prostatectomy were retrospectively analyzed. Regions containing individual morphologic patterns (N=21 patterns, including variations of cribriforming, expansile sheets, single cells, patterns of early intraluminal complexity, and mucin rupture patterns) were digitally annotated by an expert genitourinary pathologist. Distinct tumor foci on each slide were also assigned a Gleason grade and scored as having any high-risk histologic pattern. Digital sections were aligned to MRI using a patient-specific mold and registered using local mean weighted piecewise transformation based on anatomic control points. Density and presence of morphological patterns was correlated to apparent diffusion coefficient (ADC) signal intensity using mixed effects model accounting for nested intra-foci, intra-patient correlation. Influence of intra-tumoral heterogeneity was assessed by affinity propagation clustering (APC) of morphology features and correlated to foci- and cluster-level ADC metrics., Results: One hundred eleven distinct tumor foci were evaluated. Beta diversity, reflecting average morphology representation across inter- and intra-foci areas, demonstrated higher intra-tumor diversity within high-risk foci (P<0.05). ADC signal demonstrated an inverse correlation with foci-level Gleason grade (P>0.05), which was strengthened in cluster-level analysis for intra-foci regions containing high-risk morphologies (P=0.017). In voxel-based analysis, dense regions demonstrate lower ADC, but the presence and density for each morphology influenced ADC independently (ANOVA P<0.001)., Conclusions: Architectural features influence ADC characteristics of MRI, with more complex tumors having lower ADC values regulated by presence and density of specific morphologies., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare., (2020 Quantitative Imaging in Medicine and Surgery. All rights reserved.)

Summary: Adrenocortical carcinoma (ACC) is an aggressive cancer that originates in the cortex of the adrenal gland and generally has a poor prognosis. ACC is rare but can be more commonly seen in those with cancer predisposition syndromes (e.g. Li-Fraumeni and Lynch Syndrome). The diagnosis of ACC is sometimes uncertain and it requires the use of precise molecular pathology; the differential diagnosis includes pheochromocytoma, adrenal adenoma, renal carcinoma, or hepatocellular carcinoma. We describe a case of a 57-year-old woman with Lynch Syndrome and metastatic ACC who was initially diagnosed as having pheochromocytoma. The tumor was first identified at 51 years of age by ultrasound followed by a CT scan. She underwent a left adrenalectomy, and the histopathology identified pheochromocytoma. Two years later, she had tumor recurrence with imaging studies showing multiple lung nodules. Following a wedge resection by video-assisted thoracoscopic surgery (VATS), histopathology was read as metastatic pheochromocytoma at one institution and metastatic ACC at another institution. She later presented to the National Institutes of Health (NIH) where the diagnosis of ACC was confirmed. Following her ACC diagnosis, she was treated with mitotane and pembrolizumab which were stopped due to side effects and progression of disease. She is currently receiving etoposide, doxorubicin, and cisplatin (EDP). This case highlights the importance of using a multi-disciplinary approach in patient care. Thorough evaluation of the tumor's pathology and analysis of the patient's genetic profile are necessary to obtain the correct diagnosis for the patient and can significantly influence the course of treatment., Learning Points: Making the diagnosis of ACC can be difficult as the differential diagnosis includes pheochromocytoma, adrenal adenoma, renal carcinoma, or hepatocellular carcinoma. Patients with Lynch Syndrome should undergo surveillance for ACC as there is evidence of an association between Lynch Syndrome and ACC. Conducting a complete tumor immunoprofile and obtaining a second opinion is very important in cases of suspected ACC in order to confirm the proper diagnosis. A multi-disciplinary approach including genetic testing and a thorough evaluation of the tumor's pathology is imperative to ensuring that the patient receives an accurate diagnosis and the appropriate treatment.