Accurate detection of copy number aberrations in FFPE samples using the mFAST-SeqS approach.

BACKGROUND: Shallow whole genome sequencing (Shallow-seq) is used to determine the copy number aberrations (CNA) in tissue samples and circulating tumor DNA. However, costs of NGS and challenges of small biopsies ask for an alternative to the untargeted NGS approaches. The mFAST-SeqS approach, relying on LINE-1 repeat amplification, showed a good correlation with Shallow-seq to detect CNA in blood samples. In the present study, we evaluated whether mFAST-SeqS is suitable to assess CNA in small formalin-fixed paraffin-embedded (FFPE) tissue specimens, using vulva and anal HPV-related lesions. METHODS: Seventy-two FFPE samples, including 36 control samples (19 vulva;17 anal) for threshold setting and 36 samples (24 vulva; 12 anal) for clinical evaluation, were analyzed by mFAST-SeqS. CNA in vulva and anal lesions were determined by calculating genome-wide and chromosome arm-specific z-scores in comparison with the respective control samples. Sixteen samples were also analyzed with the conventional Shallow-seq approach. RESULTS: Genome-wide z-scores increased with the severity of disease, with highest values being found in cancers. In vulva samples median and inter quartile ranges [IQR] were 1[0-2] in normal tissues (n = 4), 3[1-7] in premalignant lesions (n = 9) and 21[13-48] in cancers (n = 10). In anal samples, median [IQR] were 0[0-1] in normal tissues (n = 4), 14[6-38] in premalignant lesions (n = 4) and 18[9-31] in cancers (n = 4). At threshold 4, all controls were CNA negative, while 8/13 premalignant lesions and 12/14 cancers were CNA positive. CNA captured by mFAST-SeqS were mostly also found by Shallow-seq. CONCLUSION: mFAST-SeqS is easy to perform, requires less DNA and less sequencing reads reducing costs, thereby providing a good alternative for Shallow-seq to determine CNA in small FFPE samples.

Estrogen receptor 1 chromatin profiling in human breast tumors reveals high inter-patient heterogeneity with enrichment of risk SNPs and enhancer activity at most-conserved regions.

Estrogen Receptor 1 (ESR1; also known as ERα, encoded by ESR1 gene) is the main driver and prime drug target in luminal breast cancer. ESR1 chromatin binding is extensively studied in cell lines and a limited number of human tumors, using consensi of peaks shared among samples. However, little is known about inter-tumor heterogeneity of ESR1 chromatin action, along with its biological implications. Here, we use a large set of ESR1 ChIP-seq data from 70 ESR1+ breast cancers to explore inter-patient heterogeneity in ESR1 DNA binding to reveal a striking inter-tumor heterogeneity of ESR1 action. Of note, commonly shared ESR1 sites show the highest estrogen-driven enhancer activity and are most engaged in long-range chromatin interactions. In addition, the most commonly shared ESR1-occupied enhancers are enriched for breast cancer risk SNP loci. We experimentally confirm SNVs to impact chromatin binding potential for ESR1 and its pioneer factor FOXA1. Finally, in the TCGA breast cancer cohort, we can confirm these variations to associate with differences in expression for the target gene. Cumulatively, we reveal a natural hierarchy of ESR1-chromatin interactions in breast cancers within a highly heterogeneous inter-tumor ESR1 landscape, with the most common shared regions being most active and affected by germline functional risk SNPs for breast cancer development.

Validation of Diagnostic Thresholds for Compensated Advanced Chronic Liver Disease Using Supersonic Shear Imaging.

Background The Society of Radiologists in Ultrasound (SRU) has proposed thresholds for acoustic radiation force impulse techniques to diagnose compensated advanced chronic liver disease (cACLD). However, the diagnostic performance of these thresholds has not been extensively validated. Purpose To validate the SRU thresholds in patients with chronic liver disease who underwent supersonic shear imaging and, if suboptimal diagnostic performance is observed, to identify optimal values for diagnosing cACLD. Materials and Methods This retrospective single-center study included high-risk patients with chronic liver disease who had liver stiffness (LS) measurements and had undergone endoscopy or liver biopsy between January 2018 and December 2021. Patients were randomly allocated to test and validation sets. cACLD was defined as varices at endoscopy and/or severe fibrosis or cirrhosis at liver biopsy. The diagnostic performance of the SRU guidelines was evaluated, and optimal threshold values were identified using receiver operating characteristic (ROC) curve analysis. Results A total of 1180 patients (median age, 57 years [IQR, 50-64 years]; 761 men), of whom 544 (46%) had cACLD, were included. With the SRU recommended thresholds of less than 9 kPa and greater than 13 kPa in the test set (n = 786), the sensitivity and specificity for ruling out and ruling in cACLD were 81% (303 of 374 patients; 95% CI: 77, 85) and 92% (380 of 412 patients; 95% CI: 89, 94), respectively. In ROC curve analysis, the identified optimal threshold values were less than 7 kPa and greater than 12 kPa, showing 91% sensitivity (340 of 374 patients; 95% CI: 88, 93) for ruling out cACLD and 91% specificity (373 of 412 patients; 95% CI: 87, 93) for ruling in cACLD, respectively. In the validation set (n = 394), the optimal thresholds showed 91% sensitivity (155 of 170 patients; 95% CI: 86, 95) and 92% specificity (206 of 224 patients; 95% CI: 88, 95). Conclusion Compared with the SRU guidelines, the dual LS threshold values of less than 7 kPa and greater than 12 kPa were better for diagnosing cACLD. © RSNA, 2024 Supplemental material is available for this article. See also the editorial by Barr in this issue.

Breast cancer risk SNPs converge on estrogen receptor binding sites commonly shared between breast tumors to locally alter estrogen signalling output.

Estrogen Receptor alpha (ERα) is the main driver and prime drug target in luminal breast. ERα chromatin binding is extensively studied in cell lines and a limited number of human tumors, using consensi of peaks shared among samples. However, little is known about inter-tumor heterogeneity of ERα chromatin action, along with its biological implications. Here, we use a large set of ERα ChIP-seq data from 70 ERα+ breast cancers to explore inter-patient heterogeneity in ERα DNA binding, to reveal a striking inter-tumor heterogeneity of ERα action. Interestingly, commonly-shared ERα sites showed the highest estrogen-driven enhancer activity and were most-engaged in long-range chromatin interactions. In addition, the most-commonly shared ERα-occupied enhancers were enriched for breast cancer risk SNP loci. We experimentally confirm SNVs to impact chromatin binding potential for ERα and its pioneer factor FOXA1. Finally, in the TCGA breast cancer cohort, we could confirm these variations to associate with differences in expression for the target gene. Cumulatively, we reveal a natural hierarchy of ERα-chromatin interactions in breast cancers within a highly heterogeneous inter-tumor ERα landscape, with the most-common shared regions being most active and affected by germline functional risk SNPs for breast cancer development.

Multi-scale spatial modeling of immune cell distributions enables survival prediction in primary central nervous system lymphoma.

To understand the clinical significance of the tumor microenvironment (TME), it is essential to study the interactions between malignant and non-malignant cells in clinical specimens. Here, we established a computational framework for a multiplex imaging system to comprehensively characterize spatial contexts of the TME at multiple scales, including close and long-distance spatial interactions between cell type pairs. We applied this framework to a total of 1,393 multiplex imaging data newly generated from 88 primary central nervous system lymphomas with complete follow-up data and identified significant prognostic subgroups mainly shaped by the spatial context. A supervised analysis confirmed a significant contribution of spatial context in predicting patient survival. In particular, we found an opposite prognostic value of macrophage infiltration depending on its proximity to specific cell types. Altogether, we provide a comprehensive framework to analyze spatial cellular interaction that can be broadly applied to other technologies and tumor contexts.

Prognostic Value of T-Cell Density in the Tumor Center and Outer Margins in Gastric Cancer.

Tumor-infiltrating lymphocytes are associated with the survival of gastric cancer patients. T-cell densities in the tumor and its periphery were previously identified as prognostic T-cell markers for resectable gastric cancer. Immunohistochemistry for 5 T-cell markers, CD3, CD45RO, CD8, FOXP3, and granzyme B was performed on serial sections of N = 251 surgical resection specimens of patients treated with surgery only in the D1/D2 trial. Positive T cells were digitally quantified into tiles of 0.25 mm2 across 3 regions: the tumor center (TC), the inner invasive margin, and the outer invasive margin (OIM). A classification and regression tree model was employed to identify the optimal combination of median T-cell densities per region with cancer-specific survival (CSS) as the outcome. All statistical tests were 2-sided. CD8OIM was identified as the most dominant prognostic factor, followed by FOXP3TC, resulting in a decision tree containing 3 prognostically distinct subgroups with high (Hi) or low (Lo) density of the markers: CD8OIMHi, CD8OIMLo/FOXP3TCHi, and CD8OIMLo/FOXP3TCLo. In a multivariable Cox regression analysis, which included pathological T and N stages, Lauren histologic types, EBV status, microsatellite instability, and type of surgery, the immune subgroups were independent predictors for CSS. CSS was lower for CD8OIMLo/FOXP3TCHi (HR: 5.02; 95% CI: 2.03-12.42) and for CD8OIMLo/FOXP3TCLo (HR: 7.99; 95% CI: 3.22-19.86), compared with CD8OIMHi (P < .0001). The location and density of both CD8+ and FOXP3+ T cells in resectable gastric cancer are independently associated with survival. The combination of CD8OIM and FOXP3TC T-cell densities is a promising stratification factor that should be validated in independent studies.

A Comprehensive Overview of RNA Deconvolution Methods and Their Application.

Tumors are surrounded by a variety of tumor microenvironmental cells. Profiling individual cells within the tumor tissues is crucial to characterize the tumor microenvironment and its therapeutic implications. Since single-cell technologies are still not cost-effective, scientists have developed many statistical deconvolution methods to delineate cellular characteristics from bulk transcriptome data. Here, we present an overview of 20 deconvolution techniques, including cutting-edge techniques recently established. We categorized deconvolution techniques by three primary criteria: characteristics of methodology, use of prior knowledge of cell types and outcome of the methods. We highlighted the advantage of the recent deconvolution tools that are based on probabilistic models. Moreover, we illustrated two scenarios of the common application of deconvolution methods to study tumor microenvironments. This comprehensive review will serve as a guideline for the researchers to select the appropriate method for their application of deconvolution.

Enhancer profiling identifies epigenetic markers of endocrine resistance and reveals therapeutic options for metastatic castration-resistant prostate cancer patients.

Androgen Receptor (AR) signaling inhibitors, including enzalutamide, are treatment options for patients with metastatic castration-resistant prostate cancer (mCRPC), but resistance inevitably develops. Using metastatic samples from a prospective phase II clinical trial, we epigenetically profiled enhancer/promoter activities with H3K27ac chromatin immunoprecipitation followed by sequencing, before and after AR-targeted therapy. We identified a distinct subset of H3K27ac-differentially marked regions that associated with treatment responsiveness. These data were successfully validated in mCRPC patient-derived xenograft models (PDX). In silico analyses revealed HDAC3 as a critical factor that can drive resistance to hormonal interventions, which we validated in vitro . Using cell lines and mCRPC PDX tumors in vitro , we identified drug-drug synergy between enzalutamide and the pan-HDAC inhibitor vorinostat, providing therapeutic proof-of-concept. These findings demonstrate rationale for new therapeutic strategies using a combination of AR and HDAC inhibitors to improve patient outcome in advanced stages of mCRPC.

A Bounding-Box Regression Model for Colorectal Tumor Detection in CT Images Via Two Contrary Networks.

The field of medical image analysis has been attracted to deep learning. Various deep learning-based techniques have been introduced to aid diagnosis in the CT image of the patient. The auxiliary model for diagnosis that we proposed is to detect colorectal tumors in the CT image. The model is combined with two contrary networks of 'Detection Transformer" and 'Hourglass". Furthermore., to improve the performance of the model., we propose an efficient connection method for two contrary models by using intermediate prediction information. A total of 3.,509 patients (193.,567 CT images) were applied to the experiment and our model outperforms the conventional models in colorectal tumor detection. Clinical Relevance - The proposed model in this paper automatically detects colorectal tumors and provides the bounding box in the CT images. Colorectal tumor is one of the common diseases. In addition, the mortality rate is so high that in-time treatment is required. The model we present here has a sensitivity (or recall) of 84.73 % for tumor detection and a precision of 88.25 % in the patient CT data. The in-slice performance of the tumor detection shows an IoU of 0.56, a sensitivity of 0.67, and a precision of 0.68.

Urine creatinine concentration influences the prognostic value of proteinuria for MACE prediction from the findings of the KNOW-CKD study.

Proteinuria is typically quantified according to the spot urine protein-creatinine ratio (UPCR) and an association with cardiovascular events has not been thoroughly investigated in chronic kidney disease (CKD) patients. We investigated whether the severity of proteinuria assessed by spot UPCR is associated with an increased risk for cardiovascular outcomes in the CKD population, and whether the relationship is influenced by urine creatinine concentration. We analyzed 1746 patients enrolled as part of The KoreaN cohort study for Outcome in patients With Chronic Kidney Disease (KNOW-CKD). Multivariable Cox proportional hazard analysis was performed to evaluate models with proteinuria as a predictor of renal events and extended major adverse cardiovascular events (eMACEs). Risk for renal events was significantly associated with proteinuria across all eGFR and UPCR categories. By contrast, risk for eMACEs increased significantly with UPCR in patients with eGFR ≥ 60 mL/min/1.73 m2 (hazard ratio [HR] 2.109; 95% confidence interval [CI] 1.375-3.235; P = 0.001), but not in patients with eGFR < 60 mL/min/1.73 m2 (HR 1.086; 95% CI 0.910-1.296; P = 0.358). However, in those with the lower eGFR, risk for eMACEs increased significantly with UPCR in participants with urine creatinine concentration ≥ 95 mg/dL (HR 1.503; 95% CI 1.047-2.159; P = 0.027). In non-dialysis CKD patients, the prognostic value of UPCR for eMACEs is weakened in patients with reduced eGFR levels, for whom it has prognostic significance only in patients with high urine creatinine concentration.

Impact of classical and basal-like molecular subtypes on overall survival in resected pancreatic cancer in the SPACIOUS-2 multicentre study.

BACKGROUND: The recently identified classical and basal-like molecular subtypes of pancreatic cancer impact on overall survival (OS). However, the added value of routine subtyping in both clinical practice and randomized trials is still unclear, as most studies do not consider clinicopathological parameters. This study examined the clinical prognostic value of molecular subtyping in patients with resected pancreatic cancer. METHODS: Subtypes were determined on fresh-frozen resected pancreatic cancer samples from three Dutch centres using the Purity Independent Subtyping of Tumours classification. Patient, treatment, and histopathological variables were compared between subtypes. The prognostic value of subtyping in (simulated) pre- and postoperative settings was assessed using Kaplan-Meier and Cox regression analyses. RESULTS: Of 199 patients with resected pancreatic cancer, 164 (82.4 per cent) were classified as the classical and 35 (17.6 per cent) as the basal-like subtype. Patients with a basal-like subtype had worse OS (11 versus 16 months (HR 1.49, 95 per cent c.i. 1.03 to 2.15; P = 0.035)) than patients with a classical subtype. In multivariable Cox regression analysis, including only clinical variables, the basal-like subtype was a statistically significant predictor for poor OS (HR 1.61, 95 per cent c.i. 1.11 to 2.34; P = 0.013). When histopathological variables were added to this model, the prognostic value of subtyping decreased (HR 1.49, 95 per cent c.i. 1.01 to 2.19; P = 0.045). CONCLUSION: The basal-like subtype was associated with worse OS in patients with resected pancreatic cancer. Adding molecular classification to inform on tumor biology may be used in patient stratification.

Drug-Induced Epigenomic Plasticity Reprograms Circadian Rhythm Regulation to Drive Prostate Cancer toward Androgen Independence.

In prostate cancer, androgen receptor (AR)-targeting agents are very effective in various disease stages. However, therapy resistance inevitably occurs, and little is known about how tumor cells adapt to bypass AR suppression. Here, we performed integrative multiomics analyses on tissues isolated before and after 3 months of AR-targeting enzalutamide monotherapy from patients with high-risk prostate cancer enrolled in a neoadjuvant clinical trial. Transcriptomic analyses demonstrated that AR inhibition drove tumors toward a neuroendocrine-like disease state. Additionally, epigenomic profiling revealed massive enzalutamide-induced reprogramming of pioneer factor FOXA1 from inactive chromatin sites toward active cis-regulatory elements that dictate prosurvival signals. Notably, treatment-induced FOXA1 sites were enriched for the circadian clock component ARNTL. Posttreatment ARNTL levels were associated with patients' clinical outcomes, and ARNTL knockout strongly decreased prostate cancer cell growth. Our data highlight a remarkable cistromic plasticity of FOXA1 following AR-targeted therapy and revealed an acquired dependency on the circadian regulator ARNTL, a novel candidate therapeutic target. SIGNIFICANCE: Understanding how prostate cancers adapt to AR-targeted interventions is critical for identifying novel drug targets to improve the clinical management of treatment-resistant disease. Our study revealed an enzalutamide-induced epigenomic plasticity toward prosurvival signaling and uncovered the circadian regulator ARNTL as an acquired vulnerability after AR inhibition, presenting a novel lead for therapeutic development. See related commentary by Zhang et al., p. 2017. This article is highlighted in the In This Issue feature, p. 2007.

Bayesian log-normal deconvolution for enhanced in silico microdissection of bulk gene expression data.

Deconvolution of bulk gene expression profiles into the cellular components is pivotal to portraying tissue's complex cellular make-up, such as the tumor microenvironment. However, the inherently variable nature of gene expression requires a comprehensive statistical model and reliable prior knowledge of individual cell types that can be obtained from single-cell RNA sequencing. We introduce BLADE (Bayesian Log-normAl Deconvolution), a unified Bayesian framework to estimate both cellular composition and gene expression profiles for each cell type. Unlike previous comprehensive statistical approaches, BLADE can handle > 20 types of cells due to the efficient variational inference. Throughout an intensive evaluation with > 700 simulated and real datasets, BLADE demonstrated enhanced robustness against gene expression variability and better completeness than conventional methods, in particular, to reconstruct gene expression profiles of each cell type. In summary, BLADE is a powerful tool to unravel heterogeneous cellular activity in complex biological systems from standard bulk gene expression data.

Smoking Cessation and Coronary Artery Calcification in CKD.

BACKGROUND AND OBJECTIVES: Smoking is associated with vascular calcification and a higher risk of cardiovascular disease. In this study, we investigated the association of smoking dose and cessation with coronary artery calcification (CAC) in patients with CKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: From a nationwide, prospective cohort of Korean patients with CKD, 1914 participants were included. Prevalent CAC was defined as an Agatston score >0, using computed tomography. CAC progression was defined as ≥30%/yr increase in Agatston score at the 4-year follow-up examination in patients with baseline CAC. RESULTS: Prevalent CAC was observed in 952 (50%) patients. Compared with never smokers, former smokers had a similar prevalence ratio for CAC, but current smokers had a 1.25-fold higher prevalence ratio (95% confidence interval [95% CI], 1.10 to 1.42). Among former smokers, a lower smoking load of <10 pack-years (prevalence ratio, 0.77; 95% CI, 0.65 to 0.90) and longer duration of smoking cessation (prevalence ratio for 10 to <20 years, 0.85; 95% CI, 0.73 to 0.98: prevalence ratio for ≥20 years, 0.83; 95% CI, 0.73 to 0.96) were associated with lower risk of prevalent CAC compared with current smoking. The prevalence ratios did not differ between never smoking and long-term cessation. However, short-term cessation with heavy smoking load was associated with a higher risk of prevalent CAC (prevalence ratio, 1.21; 95% CI, 1.03 to 1.40) compared with never smoking. CAC progression was observed in 111 (33%) patients with baseline CAC. Compared with never smokers, former smokers showed a similar risk of CAC progression, but current smokers had a higher risk (relative risk, 1.92; 95% CI, 1.30 to 2.86). CONCLUSIONS: In CKD, former smoking with a lower smoking load and long-term cessation were associated with a lower risk of prevalent CAC than current smoking. CAC progression was more pronounced in current smokers.

Association between the transtubular potassium gradient and progression of chronic kidney disease: results from KNOW-CKD.

BACKGROUND: The transtubular potassium gradient which reflects potassium secretion by the kidney through the cortical collecting duct, has not yet been tested as a surrogate marker of kidney function decline. Here, we investigate the relationship between the transtubular potassium gradient and chronic kidney disease (CKD) progression. METHODS: We studied 1672 patients from the KoreaN Cohort Study for Outcome in Patients With Chronic Kidney Disease (KNOW-CKD) cohort. The transtubular potassium gradient was calculated using a standard equation. The study endpoint was CKD progression, defined as a composite of a ≥ 50% decrease in estimated glomerular filtration rate (eGFR) from baseline values or end-stage kidney disease. RESULTS: During a median follow-up of 4.1 years (7149 person-years), 441 participants reached the endpoint. In cause-specific competing risk analysis, the highest tertile was associated with a significantly lower risk of an adverse kidney outcome compared with the lowest tertile [hazard ratio (HR), 0.73; 95% confidence interval (CI), 0.55-0.97]. When the transtubular potassium gradient was treated as a continuous variable, an increase of 1 in the transtubular potassium gradient was associated with a 6% lower risk of CKD progression (95% CI, 0.90-0.99). This association was particularly evident in patients with an eGFR ≥ 45 mL/min/1.73 m2. A time-updated transtubular potassium gradient model showed similar results. The predictive performance of the transtubular potassium gradient was significantly less than that of the eGFR, but similar to that of proteinuria, serum bicarbonate, and urine osmolality. CONCLUSIONS: A higher transtubular potassium gradient is associated with a significantly lower risk of CKD progression, suggesting that it may offer insights into the prognosis of CKD.

Mortality prediction of serum neutrophil gelatinase-associated lipocalin in patients requiring continuous renal replacement therapy.

BACKGROUND/AIMS: We investigated whether serum neutrophil gelatinase-associated lipocalin (NGAL) can predict mortality in patients with acute kidney injury (AKI) requiring continuous renal replacement therapy (CRRT). METHODS: This study enrolled 169 patients who underwent serum NGAL testing at CRRT initiation from June 2017 to January 2019. The predictive power of serum NGAL level for 28-day mortality was compared to the Acute Physiology and Chronic Health Evaluation-II (APACHE-II) score and Sequential Organ Failure Assessment (SOFA) score via area under the receiver operating characteristic curve (AuROC) value. RESULTS: There were 55 survivors and 114 non-survivors at 28 days post-CRRT initiation. Median serum NGAL level was significantly higher in the non-survivor group than in the survivor group (743.0 ng/mL vs. 504.0 ng/mL, p = 0.003). The AuROC value of serum NGAL level was 0.640, which was lower than APACHEII score and SOFA score values (0.767 and 0.715, respectively). However, in the low APACHE-II score group (< 27.5), AuROC value of serum NGAL was significantly increased (0.698), and it was an independent risk factor for 28 day-mortality (hazard ratio, 2.405; 95% confidence interval, 1.209 to 4.783; p = 0.012). CONCLUSION: In patients with AKI requiring CRRT, serum NGAL levels may be useful for predicting short-term mortality in those with low APACHE-II scores.

Discrepant glomerular filtration rate trends from creatinine and cystatin C in patients with chronic kidney disease: results from the KNOW-CKD cohort.

BACKGROUND: Serum creatinine (Cr) and cystatin C (CysC) can both be used to estimate glomerular filtration rate (eGFRCr and eGFRCysC). However, certain conditions may cause discrepancies between eGFR trends from Cr and CysC, and these remain undetermined in patients with chronic kidney disease (CKD). METHODS: A total of 1069 patients from the Korean CKD cohort (KNOW-CKD), which enrolls pre-dialytic CKD patients, whose Cr and CysC had been followed for more than 4 years were included in the sample. We performed trajectory analysis using latent class mixed modeling and identified members of the discrepancy group when patient trends between eGFRCr and eGFRCysC differed. Multivariate logistic analyses with Firth's penalized likelihood regression models were performed to identify conditions related to the discrepancy. RESULTS: Trajectory patterns of eGFRCr were classified into three groups: two groups with stable eGFRCr (stable with high eGFRCr and stable with low eGFRCr) and one group with decreasing eGFRCr. Trajectory analysis of eGFRCysC also showed similar patterns, comprising two groups with stable eGFRCysC and one group with decreasing eGFRCysC. Patients in the discrepancy group (decreasing eGFRCr but stable & low eGFRCysC; n = 55) were younger and had greater proteinuria values than the agreement group (stable & low eGFRCr and eGFRCysC; n = 706), differences that remained consistent irrespective of the measurement period (4 or 5 years). CONCLUSIONS: In the present study, we identify conditions related to discrepant trends of eGFRCr and eGFRCysC. Clinicians should remain aware of such potential discrepancies when tracing both Cr and CysC.

Acute kidney injury with extreme hyperuricemia after antithymocyte globulin treatment in a kidney transplant recipient with underlying aplastic anemia: a case report.

BACKGROUND: The occurrences of hyperuricemia and acute kidney injury after antithymocyte globulin treatment are unusual in kidney transplant recipients. Here, we report a unique case of acute kidney injury with extreme hyperuricemia after antithymocyte globulin treatment in a kidney transplant recipient with underlying aplastic anemia. CASE PRESENTATION: A 40-year-old woman with aplastic anemia who received a kidney transplant 5 years 6 months before presented to our emergency department with complaints of oliguria, generalized edema, and general weakness 6 days after receiving antithymocyte globulin treatment for acute T-cell-mediated rejection. Urinalysis revealed 100 uric acid crystal particles. The blood chemistry test results showed rapid increases in serum creatinine (from 2.86 mg/dL to 5.58 mg/dL) and uric acid levels (from 10.2 mg/dL to 32.7 mg/dL), which suggested acute uric acid nephropathy. Tumor lysis syndrome was suspected to be the cause of the acute uric acid nephropathy; hence, the patient was reevaluated for aplastic anemia. Human leukocyte antigen-DR15 was positive, and flow cytometry revealed a low percentage of glycophosphatidyl inositol-deficient granulocytes (2.9%), which suggested paroxysmal nocturnal hemoglobinuria clones. These findings indicate that the previously diagnosed aplastic anemia had either originally been hypocellular myelodysplastic syndrome (MDS) or later transformed into hypocellular MDS, which is a type of bone marrow failure syndrome. CONCLUSIONS: Clinicians should consider unexpected tumor lysis syndrome to be the cause of complications after antithymocyte globulin treatment in kidney transplant recipients with underlying bone marrow failure syndrome.

Ultrasonographic morphological diagnosis of chronic liver disease: 2-dimensional shear wave elastography as an add-on test.

PURPOSE: This study investigated the impact of liver stiffness measurements (LSM) made using 2-dimensional (2D) shear wave elastography (SWE) on the diagnosis and grading of hepatic fibrosis and liver cirrhosis (LC) using grayscale ultrasonography (US). METHODS: This retrospective study included 46 patients who underwent liver biopsy for chronic liver disease and 33 non-biopsied subjects with no or mild fibrosis (an aspartate aminotransferase-to-platelet ratio index <0.50 and a Forns score <4.21). Two abdominal radiologists reviewed randomized grayscale hepatic sonogram sets with and without LSM, separated by a 4-week interval. They graded the features of echogenicity, echotexture, surface nodularity, and edge blunting and classified patients by fibrosis grade. Interobserver agreement and correlations with the fibrosis grades were compared before and after the reviewers were informed regarding LSM, and the impact of LSM on diagnostic performance was evaluated. RESULTS: The standard diagnoses were no or mild fibrosis (F0-1, n=39), moderate to advanced fibrosis (F2-3, n=23), or LC (n=17). The correlations between US and the diagnostic reference standard increased significantly with LSM incorporation (0.499 and 0.312 to 0.782 and 0.804, P<0.01 for both reviewers), as did interobserver agreement (0.318 to 0.753, P<0.01). The areas under the receiver operating characteristic curve (AUCs) for the diagnosis of significant fibrosis increased when LSM was included (0.682 and 0.591 to 0.855 and 0.907, P<0.01 for both reviewers), while the AUCs for the diagnosis of LC did not change significantly (0.891 and 0.783 to 0.904 and 0.900, P=0.849 and P=0.166). CONCLUSION: Incorporating LSM values obtained by 2D-SWE improved the diagnostic accuracy and interobserver agreement of grayscale US for hepatic fibrosis.