Histological Phenotype Research Articles

Prognostic Relevance of Metabolic Dysfunction-associated Steatohepatitis for Patients with Chronic Hepatitis B.

Metabolic dysfunction-associated fatty liver disease (MAFLD) is prevalent in patients with chronic hepatitis B (CHB). The effect of the histologic MAFLD phenotype on long-term CHB outcomes is unknown. We performed a longitudinal study to determine the prognostic relevance of biopsy-proven hepatic steatosis and steatohepatitis for CHB patients. Clinical and laboratory data were obtained from CHB patients who underwent liver biopsy during 2002-2008 and were treated with antiviral drugs. A hepatopathologist reviewed the biopsy specimens. Cox proportional hazards regression was used to estimate the adjusted hazard ratio (aHR) of outcomes, including all-cause mortality, liver transplantation, and liver-related events. In accordance with Brunt's classification, 408 patients had steatohepatitis (n=34), "steatosis but not steatohepatitis" (n=118), or "non-steatosis" (n=256). All steatohepatitis patients had features of metabolic dysfunction. Over a mean follow-up of 13.8±3.1 years, 18 patients died or underwent liver transplantation. In multivariate-adjusted analysis, steatohepatitis (aHR, 6.37; 95% confidence interval [CI]: 1.59-25.5) compared with non-steatosis and advanced fibrosis (aHR, 11.3; 95% CI: 1.32-96.3) compared with no fibrosis were associated with overall mortality/liver transplantation. Thirty-five patients developed 43 liver-related events, among which 32 were hepatocellular carcinoma. These events were associated with steatohepatitis (aHR, 5.55; 95% CI: 2.01-15.3) compared with non-steatosis and advanced fibrosis (aHR, 6.23; 95% CI: 1.75-22.2) compared with no fibrosis. The steatosis but not steatohepatitis group had a non-significantly higher risk of overall mortality and liver-related events. Metabolic dysfunction-associated steatohepatitis increased the risk of long-term mortality/transplantation and liver-related events in CHB patients.

A systematic study on phenotypical characteristics of invasive breast carcinoma and surrounding ductal carcinoma in situ in multifocal breast cancers

Multifocal breast cancers are heterogeneous in terms of histologic characteristics and molecular types. In this study, we annotated multiple foci of invasive lesions and ductal carcinoma in situ lesions of 17 cases of multifocal breast cancer and investigated their immunohistochemical phenotypes (estrogen receptor [ER], progesterone receptor [PR], human epidermal growth factor 2 [HER2], and Ki-67 proliferative index). Tumor histologic grade, proliferative index, and phenotypes were varied within each patient. We observed that there were some cases in which the treatment consideration could be changed due to different phenotypes of lesions. The proliferative index tended to be higher in areas where the histologic grade was higher. The triple-negative (TN) type had the highest Ki-67 index, followed by luminal B/HER2-, HER2, luminal B/HER2+, and luminal A types sequentially. As the luminal B lesions comprised a considerable portion of multifocal cancer, we subcategorized them according to several criteria. The proliferation index of the luminal B group was significantly (P<.001) higher in the low hormone receptor (HR) group than in the HR group. When compared by the phenotypes of the surrounding lesions, the proliferative index of luminal B lesions were intimately related to the coexisting phenotypes. In conclusion, the immunohistochemical phenotypes of multifocal breast cancer are heterogeneous, and luminal B type is the commonest of the heterogeneous phenotypes.

Automated fibrosis phenotyping of liver tissue from non-tumor lesions of patients with and without hepatocellular carcinoma after liver transplantation for non-alcoholic fatty liver disease.

Fibrosis is the most important pathological feature in predicting development of Hepatocellular carcinoma (HCC). However, the incidence rate of HCC in patients with non-alcoholic fatty liver disease (NAFLD) is relatively low. We evaluated phenotypic histological features to differentiate HCC from non-HCC in patients with non-tumor lesions of cirrhotic livers. Seventeen patients with NAFLD who underwent liver transplantation were enrolled. FibroNest was used to quantify histological phenotypes of non-tumor fibrosis lesions. Quantification included collagen content and structure traits, fiber morphometric traits, and fibrosis architecture traits. Each trait was described by up to seven quantitative fibrosis traits (qFTs). Among the qFTs measured in each specimen, those that described most of the variability between consecutive groups were automatically detected and combined into a normalized Phenotypic Composite Fibrosis Score (Ph-CFS). We trained FibroNest to identify the principal traits that differentiate HCC from non-HCC. HCC was found in 8 cases and non-HCC in 9 cases. The Ph-CFS significantly differentiated HCC from non-HCC (4.6 vs. 5.9, p < 0.05). Individual qFTs for morphometric features including collagen fiber length, width, perimeter, and area denoted significant differences between HCC and non-HCC. The Ph-CFS could be used to distinguish HCC (Ph-FCS < 5.0) from non-HCC (Ph-FCS ≥ 5.0) with 75% sensitivity and 100% specificity. In patients who underwent liver transplantation, fibrotic histological phenotypes in non-tumor lesions appeared to be different between HCC and non-HCC. Phenotypic analysis of collagen in non-tumor lesions might be an effective and automated method to distinguish HCC from non-HCC on histopathology imaging.

Radiomics on Gadoxetate Disodium-enhanced MRI: Non-invasively Identifying Glypican 3-Positive Hepatocellular Carcinoma and Postoperative Recurrence

To investigate the impact of preoperative gadoxetate disodium (EOB) MRI-based radiomics on predicting glypican 3 (GPC3)-positive expression and the relevant recurrence-free survival (RFS) of HCC ≤ 5 cm. Between January 2014 and October 2018, 259 patients with solitary HCC ≤ 5 cm who underwent hepatectomy and preoperative EOB-MRI were retrieved. Multivariate logistic regression was implemented to identify independent predictors for GPC3. By combining five feature selection strategies and three classifiers, 15 GPC3-oriented radiomics models could be constructed, the best of which with independent clinicoradiologic predictors was integrated into the comprehensive nomogram. GPC3 was an independent risk factor of postoperative recrudescence for HCC. Alpha-fetoprotein >20 ng/mL, homogenous T2 signal and hypointensity on hepatobiliary phase were independently related to GPC3-positive expression in the clinicoradiologic model. With 10 features selected by support vector machines-recursive feature elimination, logistic regression-based classifier achieved the best performance among 15 radiomics models. After five-fold cross-validation, our comprehensive nomogram acquired better average area under receiver operating characteristic curves (training and validation cohorts: 0.931 vs. 0.943) than the clinicoradiologic algorithm (0.738 vs. 0.739) and the optimal radiomics model (0.943 vs. 0.931). Net reclassification indexes further demonstrated the superiority of GPC3 nomogram over clinicoradiologic and radiomics algorithms (46.54%, p < 0.001; 7.84%, p=0.207). Meanwhile, higher radiomics score significantly shortened the median RFS (from >77.9 to 48.2 months, p=0.044), which was analogue to that of the histological GPC3-positive phenotype (from >73.9 to 43.2 months, p < 0.001). Preoperative EOB-MRI radiomics-based nomogram satisfactorily distinguished GPC3 status and outcomes of solitary HCC ≤ 5 cm.

Heterogeneous genetic landscape of congenital neutropenia in Korean patients revealed by whole exome sequencing: genetic, phenotypic and histologic correlations

Congenital neutropenia (CN) is a hematological disease heterogeneous in its genetic, phenotypic and histologic aspects. We aimed to identify the genetic etiology of Korean CN patients in the context of bone marrow (BM) histology and clinical phenotype. Whole-exome sequencing (WES) or targeted sequencing was performed on the BM or peripheral blood specimens of 16 patients diagnosed with CN based on BM exam from 2009 to 2018. Absolute count of myeloperoxidase (MPO)-positive cells was calculated using ImageJ software. Semi-quantitation of MPO-positive cells in BM sections was performed by MPO grading (grades 0–3). Comprehensive retrospective review on real-world data of 345 pediatric patients with neutropenia including 16 patients in this study during the same period was performed. Seven disease-causing variants were identified in ELANE, G6PC3 and CXCR4 in 7 patients. A novel homozygous G6PC3 variant (K72fs) of which the mechanism was copy-neutral loss of heterozygosity was detected in two brothers. A low myeloid-to-erythroid ratio (0.5–1.5) was consistently observed in patients with ELANE mutations, while MPO-positive cells (40%–50%) with MPO grade 1 or 2 were detected in myelokathexis caused by G6PC3 and CXCR4 mutations. Meanwhile, disease-causing variants were detected in ELANE, TAZ and SLC37A4 in 5 patients by retrospective review of medical records. Our results suggest that following the immunological study and BM exam, WES or an expanded next generation sequencing panel that covers genes related to immunodeficiency and other inherited bone marrow failures as well as CN is recommended for neutropenia patient diagnosis.

Impact of Type 2 Diabetes Mellitus on Endometrial Cancer Survival: A Prospective Database Analysis

PurposeType 2 diabetes mellitus (T2DM) is an established risk factor for endometrial cancer but its impact on endometrial cancer survival outcomes is unclear. The aim of this study was to investigate whether pre-existing T2DM impacts survival outcomes in endometrial cancer.Patients and MethodsWomen diagnosed with endometrial cancer were recruited to a single centre prospective cohort study. Relevant sociodemographic and clinico-pathological data were recorded at baseline. T2DM status was based on clinical and biochemical assessment, verified by general practitioner records and analysed in relation to overall, cancer-specific and recurrence-free survival using Kaplan-Meier estimation and multivariable Cox-regression.ResultsIn total, 533 women with median age and BMI of 66 years (Interquartile range (IQR), 56, 73) and 32kg/m2 (IQR 26, 39) respectively, were included in the analysis. The majority had low-grade (67.3%), early-stage (85.1% stage I/II), endometrial cancer of endometrioid histological phenotype (74.7%). A total of 107 (20.1%) had pre-existing T2DM. Women with T2DM had a two-fold increase in overall mortality (adjusted HR 2.07, 95%CI 1.21-3.55, p=0.008), cancer-specific mortality (adjusted HR 2.15, 95% CI 1.05-4.39, p=0.035) and recurrence rates (adjusted HR 2.22, 95% CI 1.08-4.56, p=0.030), compared to those without, in multivariable analyses.ConclusionT2DM confers an increased risk of death in endometrial cancer patients. Well-designed longitudinal studies with large sample sizes are now needed to confirm these findings.

MO042: Biallelic variants in TTC21B as a rare cause of early-onset arterial hypertension and tubuloglomerular kidney disease

Abstract BACKGROUND Massively parallel sequencing (MPS) has propelled precision medicine into the next generation. With genetic data more accessible than ever, the focus has now shifted from obtaining data to converting the acquired data into applicable clinical information. A major obstacle to such task arises when there is limited knowledge of the phenotypic spectrum of a genetic entity, limiting the application of virtual panels and prioritization of genetic candidates. METHOD We performed in-depth clinical, imaging and histological phenotyping of an index family presenting with extremely early-onset hypertension and kidney disease. We then performed genetic investigations on the proband, starting with a limited MPS panel testing for monogenic causes of arterial hypertension. This was followed by Genomics England 100 000 Genomes Project whole genome sequencing (WGS) and application of a 26-gene virtual panel for ‘extreme early-onset hypertension’. Subsequently, we reviewed the 100 000 Genomes Project rare disease data for patients recruited with extreme early-onset hypertension. We also conducted a literature review to identify any existing studies correlating TTC21B mutations and systemic hypertension. RESULTS The proband (Table 1, II.1) was a 3.5-year-old girl presenting with severe hypertension, proteinuria, kidney failure, left ventricular hypertrophy, liver function test abnormalities and growth retardation. A kidney ultrasound scan showed bilateral small kidneys with loss of corticomedullary differentiation. Kidney biopsy showed sclerosed glomeruli, severe tubular atrophy with tubulointerstitial fibrosis in addition to arteriolar changes in secondary to systemic hypertension. Her sibling (Table 1, II.2) equally presented with early-onset hypertension and progressive kidney disease. MPS panel testing and WGS virtual panel for early-onset hypertension both failed to identify pathogenic variants. Manual curation of WGS data then revealed a heterozygous nonsense variant p.(Gln834Ter) in conjunction with a heterozygous missense variant p.(Pro209Leu) in TTC21B, both of which were predicted to be pathogenic according to ACMG criteria. This was missed as the gene did not form part of the hypertension virtual panel. TTC21B mutations have been previously associated with typical ciliopathies such as nephronophthisis (NPHP) and Jeune asphyxiating thoracic dystrophy, but only recently implicated in glomerular kidney disease such as focal segmental glomerulosclerosis (FSGS). Literature review suggests roles for TTC21B (IFT139) both in the primary cilium and in podocyte cytoskeleton, revealing a striking association between TTC21B missense variants and early-onset hypertension. Searching the 100 000 Genomes Project revealed one additional case of arterial hypertension and mild proteinuria explained by biallelic mutations in TTC21B. CONCLUSION In conclusion, biallelic mutations in TTC21B produce a spectrum of phenotypes from typical ciliopathies to kidney-limited phenotypes. The latter are mostly encountered in patients carrying two missense, often hypomorphic, variants, and are characterized by lesions of the glomerular as well as the tubulointerstitial compartment, resembling both FSGS and NPHP. Increased clinical recognition of this mixed glomerular and tubulointerstitial disease with often mild or absent features of a typical ciliopathy as well as inclusion of TTC21B on gene panels for early-onset arterial hypertension may shorten the diagnostic odyssey for patients affected by this rare tubuloglomerular kidney disease.

PD39-01 PSA DENSITY IS CORRELATED WITH BPH CELLULAR COMPOSITION

You have accessJournal of UrologyCME1 May 2022PD39-01 PSA DENSITY IS CORRELATED WITH BPH CELLULAR COMPOSITION Liwei Jia, Douglas Strand, Claus Roehrborn, and Ryan Mauck Liwei JiaLiwei Jia More articles by this author , Douglas StrandDouglas Strand More articles by this author , Claus RoehrbornClaus Roehrborn More articles by this author , and Ryan MauckRyan Mauck More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002597.01AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Current AUA guidelines suggest treatment with 5ARI for men with BPH and PSA >1.5 ng/ml. Phenotypic heterogeneity in benign prostatic hyperplasia (BPH) has been hypothesized to underlie variable response to medical therapy, but non-invasive clinical predictors of BPH cellular composition are lacking. In this study, we evaluated the stromo-glandular composition of BPH specimens for correlation with PSA density. METHODS: H&E stained sections from 132 untreated and 78 5ARI-treated BPH patients undergoing TURP or simple prostatectomy from 11/2015 to 11/2020 were scored for glandular content (Figure 1). Patients with missing PSA or prostate volume (PV) data were excluded. Univariate analysis was conducted to determine correlation of glandular content with PSA and PSA density. All analyses were performed using GraphPad Prism (v. 9.2.0). RESULTS: Prostate volume was positively correlated with PSA (P=0.0002) and the percentage of glandular content was positively correlated with PSA (P=0.0018) and PSA density (P=0.0027) in 5ARI-naive men, but not in 5ARI-treated men. CONCLUSIONS: There is strong correlation between histologic phenotype and PSA. In addition, PSA density may improve selection of patients for 5ARI medical therapy over PSA alone. Source of Funding: DK115477 (DWS) © 2022 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 207Issue Supplement 5May 2022Page: e652 Advertisement Copyright & Permissions© 2022 by American Urological Association Education and Research, Inc.MetricsAuthor Information Liwei Jia More articles by this author Douglas Strand More articles by this author Claus Roehrborn More articles by this author Ryan Mauck More articles by this author Expand All Advertisement PDF DownloadLoading ...

Volumetric apparent diffusion coefficient histogram analysis of the testes in nonobstructive azoospermia: a noninvasive fingerprint of impaired spermatogenesis?

To explore the association between testicular volumetric apparent diffusion coefficient (ADC) histogram analysis metrics and histologic categories in nonobstructive azoospermia (NOA). The role of ADC histogram analysis in predicting the presence of spermatozoa, prior to testicular sperm extraction (TESE), was also investigated. Forty-one NOA men and 17 age-matched controls underwent scrotal MRI with diffusion-weighted imaging. Histogram analysis of ADC data of the whole testis was performed. Metrics including mean, standard deviation, median, mode, 25th percentile, 75th percentile, skewness, kurtosis, and entropy of volumetric ADC histograms were calculated. Nonparametric statistical tests were used to assess differences in ADC histogram parameters between NOA histologic categories (hypospermatogenesis, severe hypospermatogenesis, early maturation arrest, and Sertoli cell-only syndrome) and normal testes and, between NOA with positive and negative sperm retrieval. Normal testes had a lower mean, median, mode, 25th percentile (p < 0.001), and 75th percentile of ADC (p = 0.001), compared to NOA histologic phenotypes. NOA with hypospermatogenesis had a lower 25th percentile of ADC compared to NOA with severe hypospermatogenesis. Regression analysis revealed that the 25th percentile of ADC had a moderately negative correlation with NOA histologic phenotype. The median ADC proved the most significant metric (p = 0.007) to predict the presence of sperm. Testicular volumetric ADC histogram parameters may contribute in the identification of the subpopulation of NOA men with a specific type of spermatogenic arrest. • Volumetric ADC histogram analysis metrics may be used as noninvasive markers of impaired spermatogenesis in nonobstructive azoospermia. • The 25th percentile of ADC proved useful in discriminating between NOA testes with hypospermatogenesis and severe hypospermatogenesis. • The median ADC proved the most significant parameter to predict the presence of viable spermatozoa prior to TESE.

Erythematous, telangiectatic nodule within the melomental fold

Erythematous, telangiectatic nodule within the melomental fold

Ferret Lung Transplantation Models Differential Lymphoid Aggregate Morphology Between Restrictive and Obstructive Forms of Chronic Lung Allograft Dysfunction.

Long-term survival after lung transplantation remains limited by chronic lung allograft dysfunction (CLAD). CLAD has 2 histologic phenotypes, namely obliterative bronchiolitis (OB) and restrictive alveolar fibroelastosis (AFE), which have distinct clinical presentations, pathologies, and outcomes. Understanding of OB versus AFE pathogenesis would improve with better animal models. We utilized a ferret orthotopic single-lung transplantation model to characterize allograft fibrosis as a histologic measure of CLAD. Native lobes and "No CLAD" allografts lacking aberrant histology were used as controls. We used morphometric analysis to evaluate the size and abundance of B-cell aggregates and tertiary lymphoid organs (TLOs) and their cell composition. Quantitative RNA expression of 47 target genes was performed simultaneously using a custom QuantiGene Plex Assay. Ferret lung allografts develop the full spectrum of human CLAD histology including OB and AFE subtypes. While both OB and AFE allografts developed TLOs, TLO size and number were greater with AFE histology. More activated germinal center cells marked by B-cell lymphoma 6 Transcription Repressor, (B-cell lymphoma 6) expression and fewer cells expressing forkhead box P3 correlated with AFE, congruent with greater diffuse immunoglobulin, plasma cell abundance, and complement 4d staining. Furthermore, forkhead box P3 RNA induction was significant in OB allografts specifically. RNA expression changes were seen in native lobes of animals with AFE but not OB when compared with No CLAD native lobes. The orthotopic ferret single-lung transplant model provides unique opportunities to better understand factors that dispose allografts to OB versus AFE. This will help develop potential immunomodulatory therapies and antifibrotic approaches for lung transplant patients.

Prognostic significance of histologic phenotype in periampullary adenocarcinomas

Prognostic significance of histologic phenotype in periampullary adenocarcinomas

Fetal Tissue-Derived Mast Cells (MC) as Experimental Surrogate for In Vivo Connective Tissue MC.

Bone-marrow-derived mast cells are matured from bone marrow cells in medium containing 20% fetal calf serum (FCS), interleukin (IL)-3 and stem-cell factor (SCF) and are used as in vitro models to study mast cells (MC) and their role in health and disease. In vivo, however, BM-derived hematopoietic stem cells account for only a fraction of MC; the majority of MC in vivo are and remain tissue resident. In this study we established a side-by-side culture with BMMC, fetal skin MC (FSMC) or fetal liver MC (FLMC) for comparative studies to identify the best surrogates for mature connective tissue MC (CTMC). All three MC types showed comparable morphology by histology and MC phenotype by flow cytometry. Heterogeneity was detected in the transcriptome with the most differentially expressed genes in FSMC compared to BMMC being Hdc and Tpsb2. Expression of ST2 was highly expressed in BMMC and FSMC and reduced in FLMC, diminishing their secretion of type 2 cytokines. Higher granule content, stronger response to FcεRI activation and significantly higher release of histamine from FSMC compared to FLMC and BMMC indicated differences in MC development in vitro dependent on the tissue of origin. Thus, tissues of origin imprint MC precursor cells to acquire distinct phenotypes and signatures despite identical culture conditions. Fetal-derived MC resemble mature CTMC, with FSMC being the most developed.

The Pathological and Clinical Diversity of Acute Vascular Rejection in Kidney Transplantation.

Vascular rejection (VR) is characterized by arteritis, steroid resistance, and increased graft loss but is poorly described using modern diagnostics. We screened 3715 consecutive biopsies and retrospectively evaluated clinical and histological phenotypes of VR (n = 100) against rejection without arteritis (v0REJ, n = 540) and normal controls (n = 1108). Biopsy sample size affected the likelihood of arterial sampling, VR diagnosis, and final Banff v scores ( P < 0.001). Local v and cv scores were greatest in larger arteries (n = 258). VR comprised 15.6% of all rejection episodes, presented earlier (median 1.0 mo, interquartile range, 0.4-8 mo) with higher serum creatinine levels and inferior graft survival, versus v0REJ ( P < 0.001). Early VR (≤1 mo) was common (54%) and predicted by sensitization, delayed function, and prior corticosteroid use, with associated acute dysfunction and optimal therapeutic response, independent of Banff v score. Late VR followed under-immunosuppression in 71.4% (noncompliance 38.8%, iatrogenic 32.6%), and was associated with chronic interstitial fibrosis, incomplete renal functional recovery and persistent inflammation using sequential histopathology. The etiology was "pure" antibody-mediated VR (n = 21), mixed VR (n = 36), and "pure" T cell-mediated VR (n = 43). Isolated VR (n = 34, Banff i < 1 without tubulitis) comprised 24 T cell-mediated VR and 10 antibody-mediated VR, presenting with mild renal dysfunction, minimal Banff acute scores, and better graft survival compared with inflamed VR. Interstitial inflammation influenced acute renal dysfunction and early treatment response, whereas chronic tubulointerstitial damage determined long-term graft loss. VR is a heterogenous entity influenced by time-of-onset, pathophysiology, accompanying interstitial inflammation and fibrosis. Adequate histological sampling is essential for its accurate diagnostic classification and treatment.

459 Total polyunsaturated fatty acids level in abdominal adipose tissue is as an independent predictive factor predictor of recurrence-free survival in women with epithelial ovarian cancer

Background: Prognostic factors for epithelial ovarian cancers (EOCs) are in particular clinical factors such as pathology staging at diagnosis (FIGO stages), genetic mutation or histological phenotypes. In the present study, we explored whether fatty acid composition of adipose tissue, reflecting the qualitative intake in lipids, may be associated with progression-free survival in EOC. Methods: Forty-eight women with epithelial ovarian cancers and 6 with borderline ovarian tumors were included between March 2017 and January 2020 in this prospective study in Tours university teaching hospital (central France).

Changes in the clinical phenotype and behavior of pediatric luminal Crohn's disease at diagnosis in the last decade.

The aims of this study were to describe the trends in the behavior of pediatric CD during the last decade and to describe the seasonal variation of disease presentation. Patients under 18 years old and diagnosed between 2009 and 2019 were included. The clinical, endoscopic, histological, and laboratory data were collected from the medical records. We analyzed the trends of these parameters according to the year and season of diagnosis. 654 patients were included in the study. The number of incident CD cases increased yearly. Patients diagnosed between 2015 and 2019 were younger at diagnosis (OR 2.53, p=0.02), had more perianal diseases (OR: 2.30, p<0.0001) and more granulomas (OR: 1.61, p=0.003), but fewer eosinophils (OR: 0.35, p<0.0001) and less chronic lymphoplasmacytic infiltrate (OR: 0.56, p=0.008) as compared to the 2009-2014 cohort. There was fewer CD diagnosis during winter. Patients diagnosed in the fall had lower PCDAIs, less failure to thrive and less extensive digestive involvement. Colonic disease was significantly more frequent during summer and fall. The clinical and histological phenotype of CD has changed over time and there are important seasonal trends in the frequency and severity on disease behavior suggesting possible disease triggers.

MRI Features Associated with Histology of Benign Prostatic Hyperplasia Nodules: Generation of a Predictive Model.

Background: Histologic phenotypic variation of benign prostatic hyperplasia (BPH) has been hypothesized to underlie response to medical therapy. We evaluate preoperative MRI of robot-assisted simple prostatectomy (RASP) specimens and determine imaging features associated with histologic phenotype. Materials and Methods: All patients undergoing RASP from November 2015 to November 2019 with a multiparametric MRI ≤1 year before RASP were included. Patients without identifiable BPH nodules on histologic specimens were excluded. Histology slides were obtained from whole mount adenoma specimens and corresponding MRI were reviewed and graded independently by a blinded expert in BPH histopathology (D.W.S.) and an experienced radiologist specializing in prostate imaging (D.N.C.), respectively. Each nodule was assigned a phenotypic score on a 5-point Likert scale (1 = predominantly glandular; 5 = predominantly stromal) by each reviewer. Scores were compared using the sign test and univariate analysis. Signal intensity relative to background transition zone and nodule texture were noted on T2, diffusion-weighted imaging (DWI), and dynamic contrast-enhanced (DCE) imaging sequences. Univariate and multivariate stepwise linear regression analysis were conducted to identify MRI features associated with histology score. All analyses were performed using Statistical Analysis System (version 9.4). Results: A total of 99 prostate nodules in 29 patients were included. Median phenotypic scores by histology and MRI were comparable (2, interquartile range [IQR] 2-3 vs 2, IQR 2-4, respectively; p = 0.63). Histology scores were positively correlated with MRI scores (Pearson's correlation 0.84, p < 0.0001). Multivariate stepwise linear regression analysis showed that low apparent diffusion coefficient (ADC) signal intensity (p < 0.001) and DCE wash-in (p = 0.03) were positively associated with more stromal histology, whereas ADC standard deviation (p = 0.03), DCE wash-out (p = 0.001), and heterogeneous T2 texture (p = 0.003) were associated with more glandular histology. Conclusion: There is a strong correlation between MRI features and the histologic phenotype of BPH nodules. MRI may provide a noninvasive method to determine underlying BPH nodule histology.

Predicting Mutational Status of Driver and Suppressor Genes Directly from Histopathology With Deep Learning: A Systematic Study Across 23 Solid Tumor Types.

In the last four years, advances in Deep Learning technology have enabled the inference of selected mutational alterations directly from routine histopathology slides. In particular, recent studies have shown that genetic changes in clinically relevant driver genes are reflected in the histological phenotype of solid tumors and can be inferred by analysing routine Haematoxylin and Eosin (H&E) stained tissue sections with Deep Learning. However, these studies mostly focused on selected individual genes in selected tumor types. In addition, genetic changes in solid tumors primarily act by changing signaling pathways that regulate cell behaviour. In this study, we hypothesized that Deep Learning networks can be trained to directly predict alterations of genes and pathways across a spectrum of solid tumors. We manually outlined tumor tissue in H&E-stained tissue sections from 7,829 patients with 23 different tumor types from The Cancer Genome Atlas. We then trained convolutional neural networks in an end-to-end way to detect alterations in the most clinically relevant pathways or genes, directly from histology images. Using this automatic approach, we found that alterations in 12 out of 14 clinically relevant pathways and numerous single gene alterations appear to be detectable in tissue sections, many of which have not been reported before. Interestingly, we show that the prediction performance for single gene alterations is better than that for pathway alterations. Collectively, these data demonstrate the predictability of genetic alterations directly from routine cancer histology images and show that individual genes leave a stronger morphological signature than genetic pathways.

Proof of concept of peptide-linked blockmiR-induced MBNL functional rescue in myotonic dystrophy type 1 mouse model

Myotonic dystrophy type 1 is a debilitating neuromuscular disease causing muscle weakness, myotonia, and cardiac dysfunction. The phenotypes are caused by muscleblind-like (MBNL) protein sequestration by toxic RNA in the DM1 protein kinase (DMPK) gene. DM1 patients exhibit a pathogenic number of repetitions in DMPK, which leads to downstream symptoms. Another disease characteristic is altered microRNA (miRNA) expression. It was previously shown that miR-23b regulates the translation of MBNL1 into protein. Antisense oligonucleotide (AON) treatment targeting this miRNA can improve disease symptoms. Here, we present a refinement of this strategy targeting a miR-23b binding site on the MBNL1 3ʹ UTR in DM1 model cells and mice by using AONs called blockmiRs. BlockmiRs linked to novel cell-penetrating peptide chemistry showed an increase in MBNL1 protein in DM1 model cells and HSALR mice. They also showed an increase in muscle strength and significant rescue of downstream splicing and histological phenotypes in mice without disturbing the endogenous levels of other miR-23b target transcripts.

Distinct histologic and genetic characteristics of round cell sarcoma with CIC-DUX4 fusion and comparison with ewing sarcoma

CIC-DUX4 fusion gene associated sarcoma is a new emerging subgroup of round cell sarcoma with Ewing sarcoma-like morphology. Distinguishing these tumors from Ewing sarcoma family tumors (ESFT) is critical because of the clinical impact but is still challenging due to the overlapped histological and immunohistochemical phenotypes of each subtype. The present study investigated small round cell sarcoma to identify CIC-DUX4 fusion positive sarcoma, examined clinical, histopathologic and immunohistochemical characteristics of CIC-DUX4 sarcoma, and evaluated parameters to differentiate Ewing sarcoma family tumors. Seventy patients with undifferentiated round cell sarcoma or Ewing–like sarcoma were retrieved. Molecular tests including EWSR1, CIC break apart FISH, and RT-PCR for CIC-DUX4 gene fusion were performed and immunohistochemistry was performed. Six cases (8.6%) of CIC-DUX4 sarcomas were detected. Histologically, CIC-DUX4 sarcomas composed of heterogeneous round, plasmacytoid, and spindle cells and more commonly showed cytologic pleomorphism with bizarre nuclei and multinucleated cells and myxoid stoma unlike ESFT. CIC-DUX4 sarcomas didn’t show overall survival differences (p = 0.325) compared to ESFT but they demonstrated short disease-free survival (p = 0.034) and poor response to treatment (p = 0.007). Therefore, molecular analysis to detect the distinctive genetic alteration is mandatory in tumors with atypical histologic, immunohistochemical and/or clinical presentation for accurate diagnosis and treatment.