Comparación entre las calculadoras de riesgo del European Randomized Study for Screening of Prostate Cancer (ERSPC) y Prostate Biopsy Collaborative Group (PBCG): predicción del riesgo de cáncer de próstata clínicamente significativo en una cohorte de pacientes de Argentina / Comparison between the European Randomized Study for Screening of Prostate Cancer (ERSPC) and Prostate Biopsy Collaborative Group (PBCG) risk calculators: Prediction of clinically significant prostate cancer risk in a cohort of patients from Argentina

Objetivo Comparar el desempeño de las calculadoras de riesgo del European Randomised Study for Screening of Prostate Cancer (ERSPC-RC) y el Prostate Biopsy Collaborative Group (PBCG-RC) en predecir el riesgo de presentar cáncer de próstata clínicamente significativo. Material y métodos Retrospectivamente, se identificó a los pacientes que fueron sometidos a biopsia prostática en el Sanatorio Allende Cerro, Ciudad de Córdoba, Argentina, desde enero de 2018 a diciembre de 2021. Se calculó la probabilidad de tener cáncer de próstata con las dos calculadoras por separado y luego se compararon los resultados para establecer cuál de las dos tuvo mejor desempeño. Para esto, se analizaron áreas bajo la curva (ABC). Resultados Se incluyeron 250 pacientes, 140 (56%) presentaron cáncer de próstata, de los cuales 92 (36,8%) tuvieron cáncer de próstata clínicamente significativo (Score de Gleason ≥7). Los pacientes que presentaron cáncer tenían mayor edad, mayor valor de antígeno prostático específico (PSA) y menor tamaño prostático. El ABC para predecir la probabilidad de tener cáncer de próstata clínicamente significativo fue de 0,79 y 0,73 para PBCG-RC y ERSPC-RC, respectivamente (p=0,0084). Conclusión En esta cohorte de pacientes, ambas calculadoras de riesgo de cáncer de próstata mostraron un buen desempeño para predecir el riesgo de cáncer de próstata clínicamente significativo, si bien el PBCG-RC mostró mejor exactitud. (AU)

Objective To compare the performance of the risk calculators of the European Randomized Study for Screening of Prostate Cancer (ERSPC) and the Prostate Biopsy Collaborative Group (PBCG) in predicting the risk of presenting clinically significant prostate cancer. Material and methods Retrospectively, patients who underwent prostate biopsy at Sanatorio Allende Cerro, Ciudad de Córdoba, Argentina, were identified from January 2018 to December 2021. The probability of having prostate cancer was calculated with the two calculators separately and then the results were compared to establish which of the two performed better. For this, areas under the curve (AUC) were analyzed. Results 250 patients were included, 140 (56%) presented prostate cancer, of which 92 (65.71%) had clinically significant prostate cancer (Gleason score ≥7). The patients who presented cancer were older, had a higher prostate-specific antigen (PSA) value, and had a smaller prostate size. The AUC to predict the probability of having clinically significant prostate cancer was 0.79 and 0.73 for PBCG-RC and ERSPC-RC respectively (p=0.0084). Conclusion In this cohort of patients, both prostate cancer risk calculators performed well in predicting clinically significant prostate cancer risk, although the PBCG-RC showed better accuracy. (AU)

Análise de biópsias renais de um centro de atendimento terciário: correlação clínico-histológica / Analysis of renal biopsies from a tertiary care center: clinical-histological radiography

A biópsia renal é um procedimento de vasta importância no ambiente hospitalar, realizado principalmente nos grandes centros com equipe de radiologia ou nefrologia intervencionista. Sua frequência varia de acordo com o orçamento financeiro disponível no local, porém, seus resultados alteram o desfecho do seguimento do paciente em até 60% dos casos. As grandes indicações para a biópsia renal são: síndrome nefrítica, síndrome nefrótica e lesão renal aguda inexplicada, cujo resultado pode fornecer diagnóstico etiológico e orientar o manejo terapêutico. Objetivo: serão levantados e comparados os resultados frente as biópsias renais e as hipóteses diagnósticas elencadas pela equipe médica de residentes e assistentes da Nefrologia. Metodologia: trata-se de um estudo observacional, longitudinal, retrospectivo, de abordagem quantitativa, no qual os resultados serão comparados com os dados do Registro Paulista de Glomerulopatias visando a avaliação da população de um único centro de atendimento terciário da cidade de São Paulo. Resultados: O estudo analisou 68 biópsias renais de 2016 a 2022, identificando predomínio de mulheres (54%), idade entre 46-65 anos (49.2%), com hipertensão (61.9%) e diabetes (38.1%) como principais comorbidades. As principais indicações de biópsia incluíram síndrome nefrótica (36.5%), disfunção renal aguda (28.6%), e proteinúria isolada (23.8%). Os resultados indicaram prevalência de glomeruloesclerose focal e segmentar (20.6%), glomerulonefrite lúpica (15.9%), e nefropatia diabética (15.9%). Associações relevantes incluíram síndrome nefrótica e nefropatia diabética (p=0.029), disfunção renal aguda e nefrite intersticial aguda (p=0.001), além de lúpus/reumatologia e glomerulonefrite lúpica (p<0.001). A presença de dislipidemia correlacionou-se a outros diagnósticos (p=0.017). Conclusão: O estudo destaca dados relevantes para abordagem de patologias renais, perfil de pacientes em 6 anos, associações com referências e a importância de integrar propedêutica, literatura e tecnologia para indicar biópsia renal, impactando a qualidade de vida dos pacientes. Palavras-chave: Biópsia. Nefrologia. Rim.

Stage-dependent expression of fibrogenic markers in alcohol-related liver disease.

Alcohol-related liver disease (ALD) is the primary cause of liver-related mortality and morbidity. Liver fibrosis remains the best validated surrogate marker for patient prognosis and is usually assessed in liver biopsies using histochemical stains detecting collagen as the major extracellular matrix (ECM) component in ALD. Distinction of collagen subtypes is of clinical interest, as they, including their cleavage products, have different functions. Changes in production, distribution, and composition of specific collagen subtypes and other extracellular matrix (ECM) components as well as markers for their main cellular source (activated hepatic stellate cells (aHSCs) and myofibroblasts (MFBs)) have not been fully elucidated in ALD. Our aims were to investigate the stage-dependent expression of collagen subtypes and markers for aHSCs and MFBs in ALD. We included liver biopsies from 49 ALD patients with fibrosis stages F0-F4. Biopsies were classified according to the semi-quantitative non-alcoholic fatty liver disease (NAFLD) activity score (NAS-CRN). Slides were stained with H&E, Sirius Red, and immunohistochemically with antibodies against collagen types I, III, IV and VI, and aHSC/MFB markers α-SMA, osteonectin, and CD271. Expression was examined using automated digital imaging analysis (DIA), by calculating the positive area relative to the total liver biopsy area (proportionate area). Likewise, collagen-proportionate area (CPA) was assessed using DIA of Sirius Red stained slides. CPA correlated highly with fibrosis stage (rs = 0.88, P = 5.9E-17) and moderately with activity score (rs = 0.58, P = 0.00001). Collagen type I proportionate area increased from 0.3% (± 0.1) at F1 to 10.2% (± 1.6) at F4 (P < 0.001). Collagen type III proportionate area increased from 0.6% (± 0.2) at F0 to 11.9% (± 1.7) at F4 (P < 0.001). Collagen type IV proportionate area increased from 17.0% (± 2.5) at F0 to 27.0% (± 3.9) at F4 (P = 0.079). Collagen type VI proportionate area increased from 14.8% (± 1.4) at F0 to 31.4% (± 2.4) at F4 (P < 0.001). Proportionate areas for α-SMA and CD271 increased from 10.7% (± 1.6) and 6.5% (± 1.0) at F0 to 29.5% (± 3.4) and 22.1% (± 2.2) at F4 (P < 0.001). Proportionate area for osteonectin increased from 1.4-1.8% at F0-F2 to 3.1% (± 0.5) at F3 and 3.2% (± 0.6) at F4 (P < 0.05). In conclusion, our data indicate that collagen types I, III and VI and the aHSC/MFB markers α-SMA and CD271 show a stage-dependent increase in ALD. In early ALD, collagen types IV and VI are important components of the perisinusoidal and pericellular fibrosis. Immunohistochemistry is a valuable additional tool to characterize the ECM changes in ALD. Further research is needed to explore the functional role of CD271 and the stage-dependent expression of other collagen subtypes in ALD.

Distinct contributions of metabolic dysfunction and genetic risk factors in the pathogenesis of non-alcoholic fatty liver disease.

BACKGROUND & AIMS: There is substantial inter-individual variability in the risk of non-alcoholic fatty liver disease (NAFLD). Part of which is explained by insulin resistance (IR) ('MetComp') and part by common modifiers of genetic risk ('GenComp'). We examined how IR on the one hand and genetic risk on the other contribute to the pathogenesis of NAFLD. METHODS: We studied 846 individuals: 492 were obese patients with liver histology and 354 were individuals who underwent intrahepatic triglyceride measurement by proton magnetic resonance spectroscopy. A genetic risk score was calculated using the number of risk alleles in PNPLA3, TM6SF2, MBOAT7, HSD17B13 and MARC1. Substrate concentrations were assessed by serum NMR metabolomics. In subsets of participants, non-esterified fatty acids (NEFAs) and their flux were assessed by D5-glycerol and hyperinsulinemic-euglycemic clamp (n = 41), and hepatic de novo lipogenesis (DNL) was measured by D2O (n = 61). RESULTS: We found that substrate surplus (increased concentrations of 28 serum metabolites including glucose, glycolytic intermediates, and amino acids; increased NEFAs and their flux; increased DNL) characterized the 'MetComp'. In contrast, the 'GenComp' was not accompanied by any substrate excess but was characterized by an increased hepatic mitochondrial redox state, as determined by serum ß-hydroxybutyrate/acetoacetate ratio, and inhibition of hepatic pathways dependent on tricarboxylic acid cycle activity, such as DNL. Serum ß-hydroxybutyrate/acetoacetate ratio correlated strongly with all histological features of NAFLD. IR and hepatic mitochondrial redox state conferred additive increases in histological features of NAFLD. CONCLUSIONS: These data show that the mechanisms underlying 'Metabolic' and 'Genetic' components of NAFLD are fundamentally different. These findings may have implications with respect to the diagnosis and treatment of NAFLD. LAY SUMMARY: The pathogenesis of non-alcoholic fatty liver disease can be explained in part by a metabolic component, including obesity, and in part by a genetic component. Herein, we demonstrate that the mechanisms underlying these components are fundamentally different: the metabolic component is characterized by hepatic oversupply of substrates, such as sugars, lipids and amino acids. In contrast, the genetic component is characterized by impaired hepatic mitochondrial function, making the liver less able to metabolize these substrates.

Role of the IgG4-related cholangitis autoantigen annexin A11 in cholangiocyte protection.

BACKGROUND & AIMS: Annexin A11 was identified as autoantigen in IgG4-related cholangitis (IRC), a B-cell driven disease. Annexin A11 modulates calcium-dependent exocytosis, a crucial mechanism for insertion of proteins into their target membranes. Human cholangiocytes form an apical 'biliary bicarbonate umbrella' regarded as defense against harmful hydrophobic bile acid influx. The bicarbonate secretory machinery comprises the chloride/bicarbonate exchanger AE2 and the chloride channel ANO1. We aimed to investigate the expression and function of annexin A11 in human cholangiocytes and a potential role of IgG1/IgG4-mediated autoreactivity against annexin A11 in the pathogenesis of IRC. METHODS: Expression of annexin A11 in human liver was studied by immunohistochemistry and immunofluorescence. In human control and ANXA11 knockdown H69 cholangiocytes, intracellular pH, AE2 and ANO1 surface expression, and bile acid influx were examined using ratio microspectrofluorometry, cell surface biotinylation, and 22,23-3H-glycochenodeoxycholic acid permeation, respectively. The localization of annexin A11-mEmerald and ANO1-mCherry was investigated by live-cell microscopy in H69 cholangiocytes after incubation with IRC patient serum containing anti-annexin A11 IgG1/IgG4-autoantibodies or disease control serum. RESULTS: Annexin A11 was strongly expressed in human cholangiocytes, but not hepatocytes. Knockdown of ANXA11 led to reduced plasma membrane expression of ANO1, but not AE2, alkalization of intracellular pH and uncontrolled bile acid influx. High intracellular calcium conditions led to annexin A11 membrane shift and colocalization with ANO1. Incubation with IRC patient serum inhibited annexin A11 membrane shift and reduced ANO1 surface expression. CONCLUSION: Cholangiocellular annexin A11 mediates apical membrane abundance of the chloride channel ANO1, thereby supporting biliary bicarbonate secretion. Insertion is inhibited by IRC patient serum containing anti-annexin A11 IgG1/IgG4-autoantibodies. Anti-annexin A11 autoantibodies may contribute to the pathogenesis of IRC by weakening the 'biliary bicarbonate umbrella'. LAY SUMMARY: We previously identified annexin A11 as a specific autoantigen in immunoglobulin G4-related cholangitis (IRC), a B-cell driven disease affecting the bile ducts. Human cholangiocytes are protected against harmful hydrophobic bile acid influx by a defense mechanism referred to as the 'biliary bicarbonate umbrella'. We found that annexin A11 is required for the formation of a robust bicarbonate umbrella. Binding of patient-derived annexin A11 autoantibodies inhibits annexin A11 function, possibly contributing to bile duct damage by weakening the biliary bicarbonate umbrella in patients with IRC.

Effects of the 2012 and 2018 US preventive services task force prostate cancer screening guidelines on pathologic outcomes after prostatectomy.

BACKGROUND: In May 2018, the US Preventive Services Task Force (USPSTF) recommended prostate cancer (PCa) screening for ages 55-69 be an individual decision. This changed from the USPSTF's May 2012 recommendation against screening for all ages. The effects of the 2012 and 2018 updates on pathologic outcomes after prostatectomy are unclear. METHODS: This study included 647 patients with PCa who underwent prostatectomy at our institution from 2005 to 2018. Patient groups were those diagnosed before the 2012 update (n = 179), between 2012 and 2018 updates (n = 417), and after the 2018 update (n = 51). We analyzed changes in the age of diagnosis, pathologic Gleason grade group (pGS), pathologic stage, lymphovascular invasion (LVI), and favorable/unfavorable pathology. Multivariable logistic regression adjusting for pre-biopsy covariables (age, prostate-specific antigen [PSA], African American race, family history) assessed impacts of 2012 and 2018 updates on pGS and pathologic stage. A p  < 0.05 was statistically significant. RESULTS: Median age increased from 60 to 63 (p = 0.001) between 2012 and 2018 updates and to 64 after the 2018 update. A significant decrease in pGS1, pGS2, pT2, and favorable pathology (p < 0.001), and a significant increase in pGS3, pGS4, pGS5, pT3a, and unfavorable pathology (p < 0.001) was detected between 2012 and 2018 updates. There was no significant change in pT3b or LVI between 2012 and 2018 updates. On multivariable regression, diagnosis between 2012 and 2018 updates was significantly associated with pGS4 or pGS5 and pT3a (p < 0.001). Diagnosis after the 2018 update was significantly associated with pT3a (p = 0.005). Odds of pGS4 or pGS5 were 3.2× higher (p < 0.001) if diagnosed between 2012 and 2018 updates, and 2.3× higher (p = 0.051) if after the 2018 update. Odds of pT3a were 2.4× higher (p < 0.001) if diagnosed between 2012 and 2018 updates and 2.9× higher (p = 0.005) if after the 2018 update. CONCLUSIONS: The 2012 USPSTF guidelines negatively impacted pathologic outcomes after prostatectomy. Patients diagnosed between 2012 and 2018 updates had increased frequency of higher-risk PCa and lower frequency of favorable disease. In addition, data after the 2018 update demonstrate a continued negative impact on postprostatectomy pathology. Thus, further investigation of the long-term effects of the 2018 USPSTF update is warranted.

The cost of diagnosing endometrial cancer: Quantifying the healthcare cost of an abnormal uterine bleeding workup.

OBJECTIVE: The evaluation of women with perimenopausal abnormal uterine bleeding (AUB) and postmenopausal bleeding (PMB) to detect endometrial cancer (EC) and its precursors is not standardized and can vary widely. Consequently, costs associated with the workup and management undoubtedly vary. This study aimed to quantify costs of AUB/PMB evaluation to understand the healthcare burden associated with securing a pathologic diagnosis. METHODS: Women ≥45 years of age presenting to a single institution gynecology clinic with AUB/PMB for diagnostic workup were prospectively enrolled February 2013-October 2017 for a lower genital tract biospecimen research study. Clinical workup of AUB/PMB was determined by individual provider discretion. Costs of care were collected from administrative billing systems from enrollment to 90 days post enrollment. Costs were standardized and inflation-adjusted to 2017 US Dollars (USD). RESULTS: In total, there were 1017 women enrolled with 5.6% diagnosed with atypical hyperplasia or endometrial cancer (EC). Within the full cohort, 90-day median cost for AUB/PMB workup and management was $2279 (IQR $512-4828). Among patients with a diagnostic biopsy, median 90-day costs ranged from $2203 (IQR $499-3604) for benign or disordered proliferative endometrium (DPE) diagnosis to $21,039 (IQR $19,084-24,536) for a diagnosis of EC. CONCLUSIONS: The costs for diagnostic evaluation of perimenopausal AUB and PMB vary greatly according to ultimate tissue-based diagnosis. Even reassuring benign findings that do not require further intervention-the most common in this study's cohort-yield substantial costs. The development of sensitive, specific, and more cost-effective diagnostic strategies is warranted.

Epidemiological, clinical, pathological and genetic characteristics of epidermolysis bullosa in New Zealand.

OBJECTIVE: To establish the epidemiological, clinical, pathological and genetic characteristics of epidermolysis bullosa (EB) in New Zealand (NZ). METHODS: Participants were recruited through the Dystrophic Epidermolysis Bullosa Research Association of New Zealand (DEBRA NZ). Dedicated EB nurse medical records, Genetic Health Service NZ (GHSNZ) records and, where available, public hospital records were manually reviewed for relevant clinical data. RESULTS: Ninety-two participants took part in the study (56% participation rate). Forty-nine (53%) participants had EB simplex (EBS), 40 (43%) had dystrophic EB (DEB), and 3 (3%) had junctional EB (JEB). Point prevalence for EB of all types was 19.5 per million, and 10.4, 8.6 and 0.9 per million for EBS, DEB and JEB, respectively. Thirty-four participants had intermediate or severe EB. There were 29 paediatric cases and almost even numbers of males and females. Compared to NZ European and Maori, prevalence rates were lower for Pacific and Asian people and higher in the Middle Eastern/Latin American/African population. Eight out of 14 skin biopsy results were informative, and 14 of 15 genetic test results were informative. CONCLUSION: New Zealand has similar prevalence rates of EB compared with other national cohorts. This is likely to be an underestimate due to methodological limitations. Recent advancements in genomic testing have resulted in an improved diagnostic rate in our population. Further research into ethnic differences in prevalence, and exploring the characteristics of lethal forms of EB, is warranted. A dynamic registry may be helpful for the EB community in NZ.

Influence of Histologic Types and Subtypes on Survival Outcomes of Intermediate-High and High-Risk Renal Cell Carcinoma Following Nephrectomy: Findings From the SEER Database.

OBJECTIVE: To understand the influence of histologic subtypes on the survival outcomes of intermediate-high and high-risk renal cell carcinoma (RCC) following nephrectomy. METHODS: This study employed data files from the SEER Program to identify patients diagnosed with intermediate-high or high risk RCC and treated with nephrectomy. Unadjusted Kaplan Meier curves, and multivariable Cox regression analyses were applied to estimate the hazards of histologic types for overall survival (OS) and cancer-specific survival (CSS). RESULTS: OS was higher for chromophobe (HR=0.58, 95% CI 0.47-0.70; P<.0001), similar for papillary (HR=0.90, 95% CI 0.80-1.02; P=.11) and worse for sarcomatoid (HR=3.17, 95% CI 2.70-3.72; P<.0001) subtypes relative to the clear cell subtype. OS was lower in the high-risk disease (HR=2.35, 95% CI 2.01-2.74; P <.0001) versus intermediate-high risk disease. CSS was higher for chromophobe (HR=0.47, 95% CI 0.35-0.63; P<.0001), similar for papillary (HR=0.91, 95% CI 0.77-1.08; P=.28) and worse for sarcomatoid (HR=4.19, 95% CI 3.50-5.02; P<.0001) subtypes relative to the clear cell subtype. CSS was lower for the high-risk disease (HR=2.86, 95%CI 2.39-3.43; P <.0001) relative to intermediate-high risk disease.

ADAMTSL2 protein and a soluble biomarker signature identify at-risk non-alcoholic steatohepatitis and fibrosis in adults with NAFLD.

BACKGROUND & AIMS: Identifying fibrosis in non-alcoholic fatty liver disease (NAFLD) is essential to predict liver-related outcomes and guide treatment decisions. A protein-based signature of fibrosis could serve as a valuable, non-invasive diagnostic tool. This study sought to identify circulating proteins associated with fibrosis in NAFLD. METHODS: We used aptamer-based proteomics to measure 4,783 proteins in 2 cohorts (Cohort A and B). Targeted, quantitative assays coupling aptamer-based protein pull down and mass spectrometry (SPMS) validated the profiling results in a bariatric and NAFLD cohort (Cohort C and D, respectively). Generalized linear modeling-logistic regression assessed the ability of candidate proteins to classify fibrosis. RESULTS: From the multiplex profiling, 16 proteins differed significantly by fibrosis in cohorts A (n = 62) and B (n = 98). Quantitative and robust SPMS assays were developed for 8 proteins and validated in Cohorts C (n = 71) and D (n = 84). The A disintegrin and metalloproteinase with thrombospondin motifs like 2 (ADAMTSL2) protein accurately distinguished non-alcoholic fatty liver (NAFL)/non-alcoholic steatohepatitis (NASH) with fibrosis stage 0-1 (F0-1) from at-risk NASH with fibrosis stage 2-4, with AUROCs of 0.83 and 0.86 in Cohorts C and D, respectively, and from NASH with significant fibrosis (F2-3), with AUROCs of 0.80 and 0.83 in Cohorts C and D, respectively. An 8-protein panel distinguished NAFL/NASH F0-1 from at-risk NASH (AUROCs 0.90 and 0.87 in Cohort C and D, respectively) and NASH F2-3 (AUROCs 0.89 and 0.83 in Cohorts C and D, respectively). The 8-protein panel and ADAMTSL2 protein had superior performance to the NAFLD fibrosis score and fibrosis-4 score. CONCLUSION: The ADAMTSL2 protein and an 8-protein soluble biomarker panel are highly associated with at-risk NASH and significant fibrosis; they exhibited superior diagnostic performance compared to standard of care fibrosis scores. LAY SUMMARY: Non-alcoholic fatty liver disease (NAFLD) is one of the most common causes of liver disease worldwide. Diagnosing NAFLD and identifying fibrosis (scarring of the liver) currently requires a liver biopsy. Our study identified novel proteins found in the blood which may identify fibrosis without the need for a liver biopsy.

Gene expression signature as a surrogate marker of microvascular invasion on routine hepatocellular carcinoma biopsies.

BACKGROUND & AIMS: Microvascular invasion (MVI), a major risk factor for tumor recurrence after surgery in hepatocellular carcinoma (HCC), is only detectable by microscopic examination of the surgical specimen. We aimed to define a transcriptomic signature associated with MVI in HCC than can be applied to formalin-fixed paraffin-embedded (FFPE) biopsies for use in clinical practice. METHODS: To identify a gene expression signature related to MVI by using NanoString technology, we selected a set of 200 genes according to the literature and RNA-sequencing data obtained from a cohort of 150 frozen HCC samples previously published. We used 178 FFPE-archived HCC samples, including 109 surgical samples for the training set and 69 paired pre-operative biopsies for the validation set. In 14 cases of the training set, a paired biopsy was available and was also analyzed. RESULTS: We identified a 6-gene signature (ROS1, UGT2B7, FAS, ANGPTL7, GMNN, MKI67) strongly associated with MVI in the training set of FFPE surgical HCC samples, with 82% accuracy (sensitivity 82%, specificity 81%, AUC 0.82). The NanoString gene expression was highly correlated in 14 paired surgical/biopsy HCC samples (mean R: 0.97). In the validation set of 69 FFPE HCC biopsies, the 6-gene NanoString signature predicted MVI with 74% accuracy (sensitivity 73%, specificity 76%, AUC 0.74). Moreover, on multivariate analysis, the MVI signature was associated with overall survival in both sets (hazard ratio 2.29; 95% CI 1.03-5.07; p = 0.041). CONCLUSION: We defined a 6-gene signature that can accurately predict MVI in FFPE HCC biopsy samples, which is also associated with overall survival, although its survival impact must be confirmed by extensive study with further clinical data. LAY SUMMARY: Microvascular invasion, a major risk factor for tumor recurrence after surgery in hepatocellular carcinoma, is only detectable by microscopic examination of a surgical specimen. In this study, we defined a relevant surrogate signature of microvascular invasion in hepatocellular carcinoma that may be applied in clinical practice with routine tumor biopsy and integrated into the therapeutic strategy.

Hepatocyte glutathione S-transferase mu 2 prevents non-alcoholic steatohepatitis by suppressing ASK1 signaling.

BACKGROUND & AIMS: Non-alcoholic fatty liver disease (NAFLD) has become the most common chronic liver disease worldwide. The advanced stage of NAFLD, non-alcoholic steatohepatitis (NASH), has been recognized as a leading cause of end-stage liver injury for which there are no FDA-approved therapeutic options. Glutathione S-transferase Mu 2 (GSTM2) is a phase II detoxification enzyme. However, the roles of GSTM2 in NASH have not been elucidated. METHODS: Multiple RNA-seq analyses were used to identify hepatic GSTM2 expression in NASH. In vitro and in vivo gain- or loss-of-function approaches were used to investigate the role and molecular mechanism of GSTM2 in NASH. RESULTS: We identified GSTM2 as a sensitive responder and effective suppressor of NASH progression. GSTM2 was significantly downregulated during NASH progression. Hepatocyte GSTM2 deficiency markedly aggravated insulin resistance, hepatic steatosis, inflammation and fibrosis induced by a high-fat diet and a high-fat/high-cholesterol diet. Mechanistically, GSTM2 sustained MAPK pathway signaling by directly interacting with apoptosis signal-regulating kinase 1 (ASK1). GSTM2 directly bound to the N-terminal region of ASK1 and inhibited ASK1 N-terminal dimerization to subsequently repress ASK1 phosphorylation and the activation of its downstream JNK/p38 signaling pathway under conditions of metabolic dysfunction. CONCLUSIONS: These data demonstrated that hepatocyte GSTM2 is an endogenous suppressor that protects against NASH progression by blocking ASK1 N-terminal dimerization and phosphorylation. Activating GSTM2 holds promise as a therapeutic strategy for NASH. CLINICAL TRIAL NUMBER: IIT-2021-277. LAY SUMMARY: New therapeutic strategies for non-alcoholic steatohepatitis are urgently needed. We identified that the protein GSTM2 exerts a protective effect in response to metabolic stress. Therapies that aim to increase the activity of GSTM2 could hold promise for the treatment of non-alcoholic steatohepatitis.

Stereotactic Biopsy for Brainstem Lesions: A Meta-analysis with Noncomparative Binary Data.

OBJECTIVES: To evaluate the diagnostic yield and safety of brainstem stereotactic biopsy for brainstem lesions. METHODS: We performed a meta-analysis of English articles retrieved from the PubMed, Web of Science, Cochrane Library, and APA psycInfo databases up to May 12, 2021. A binary fixed-effect model, the inverse variance method, or a binary random-effect model, the Dersimonian Laird method, were utilized for pooling the data. This meta-analysis was registered with INPLASY, INPLASY202190034. FINDINGS: A total of 41 eligible studies with 2792 participants were included. The weighted average diagnostic yield was 97.0% (95% confidential interval [CI], 96.0-97.9%). The weighted average proportions of temporary complications, permanent deficits, and deaths were 6.2% (95% CI, 4.5-7.9%), .5% (95% CI, .2-.8%), and .3% (95% CI, .1-.5%), respectively. The subgroup analysis indicated a nearly identical weighted average diagnostic yield between MRI-guided stereotactic biopsy and CT-guided stereotactic biopsy (95.9% vs 95.8%) but slightly increased proportions of temporary complications (7.9% vs 6.0%), permanent deficits (1.9% vs .2%), and deaths (1.1% vs .4%) in the former compared to the latter. Moreover, a greater weighted average diagnostic yield (99.2% vs 97.6%) and lower proportions of temporary complications (5.1% vs 6.8%) and deaths (.7% vs 1.5%) were shown in the pediatric patient population than in the adult patient population. CONCLUSIONS: Brainstem stereotactic biopsy demonstrates striking accuracy plus satisfying safety in the diagnosis of brainstem lesions. The diagnostic yield, morbidity, and mortality mildly vary based on the diversity of assistant techniques and subject populations.

Surgical Interventions During End-of-Life Hospitalizations in Children's Hospitals.

OBJECTIVES: To characterize patterns of surgery among pediatric patients during terminal hospitalizations in children's hospitals. METHODS: We reviewed patients ≤20 years of age who died among 4 424 886 hospitalizations from January 2013-December 2019 within 49 US children's hospitals in the Pediatric Health Information System database. Surgical procedures, identified by International Classification of Diseases procedure codes, were classified by type and purpose. Descriptive statistics characterized procedures, and hypothesis testing determined if undergoing surgery varied by patient age, race and ethnicity, or the presence of chronic complex conditions (CCCs). RESULTS: Among 33 693 terminal hospitalizations, the majority (n = 30 440, 90.3%) of children were admitted for nontraumatic causes. Of these children, 15 142 (49.7%) underwent surgery during the hospitalization, with the percentage declining over time (P < .001). When surgical procedures were classified according to likely purpose, the most common were to insert or address hardware or catheters (31%), explore or aid in diagnosis (14%), attempt to rescue patient from mortality (13%), or obtain a biopsy (13%). Specific CCC types were associated with undergoing surgery. Surgery during terminal hospitalization was less likely among Hispanic children (47.8%; P < .001), increasingly less likely as patient age increased, and more so for Black, Asian American, and Hispanic patients compared with white patients (P < .001). CONCLUSIONS: Nearly half of children undergo surgery during their terminal hospitalization, and accordingly, pediatric surgical care is an important aspect of end-of-life care in hospital settings. Differences observed across race and ethnicity categories of patients may reflect different preferences for and access to nonhospital-based palliative, hospice, and end-of-life care.

Can addition of frozen section analysis to preoperative endometrial biopsy and MRI improve identification of high-risk endometrial cancer patients?

BACKGROUND: Surgeons sometimes have difficulty determining which result to favor when preoperative results (MRI + preoperative endometrial biopsy [pre-op EB]) differ from intraoperative frozen section histology (FS) results. Investigation of how FS can complement ordinary preoperative examinations like MRI and pre-op EB in identification of patients at high risk of lymph node metastasis (high-risk patients) could provide clarity on this issue. Therefore, the aim of this study is to assess the utility of pre-op EB, MRI and FS results and determine how to combine these results in identification of high-risk patients. METHODS: The subjects were 172 patients with endometrial cancer. Patients with a histological high-grade tumor (HGT), namely, grade 3 endometrioid cancer, clear cell carcinoma or serous cell carcinoma, or with any type of cancer invading at least half of the uterine myometrium were considered high-risk. Tumors invading at least half of the uterine myometrium were classified as high-stage tumors (HST). We compared (a) detection of HGT using pre-op EB versus FS, (b) detection of HST using MRI versus FS, and (c) identification of high-risk patients using MRI + pre-op EB versus FS. Lastly, we determined to what degree addition of FS results improves identification of high-risk patients by routine MRI + pre-op EB. RESULTS: (a) Sensitivity, specificity, and accuracy for detecting HGT were 59.6, 98.4 and 87.8% for pre-op EB versus 55.3, 99.2 and 87.2% for FS (P = 0.44). (b) These figures for detecting HST were 74.4, 83.0 and 80.8% for MRI versus 46.5, 99.2 and 86.0% for FS (P < 0.001). (c) These figures for identifying high-risk patients were 78.3, 85.4 and 82.6% for MRI + pre-op EB versus 55.1, 99.0 and 81.2% for FS (P < 0.001). The high specificity of FS improved the sensitivity of MRI + pre-op EB from 78.3 to 81.2%, but this difference was not statistically significant (P < 0.16). CONCLUSION: Frozen section enables identification of high-risk patients with nearly 100% specificity. This advantage can be used to improve sensitivity for identification of high-risk patients by routine MRI + pre-op EB, although this improvement is not statistically significant.

Incidence of Clinically Relevant Thyroid Cancers Remains Stable for Almost a Century: A Population-Based Study.

OBJECTIVE: To examine the trends in incidence of clinically relevant thyroid cancers within the overall rising incidence of thyroid cancers. PATIENTS AND METHODS: This is a population-based cohort study conducted using the Rochester Epidemiology Project database to identify all new cases of thyroid cancer in Olmsted County, Minnesota, between January 1, 1935, and December 31, 2018. We extracted information about demographics and tumor pathologic type, size, and invasiveness. Clinically relevant cancers included aggressive histology or presence of metastatic disease, size larger than 4 cm, and gross extrathyroidal tumor invasion. RESULTS: Between 1935 and 2018, 596 thyroid cancer cases were diagnosed (mean age, 46.4 years; 72% female; 87% papillary cancers; and median tumor size, 1.5 cm). The sex- and age-adjusted incidence of thyroid cancer increased from 1.3 per 100,000 person-years (p-y) from 1935-1949 to 12.0 per 100,000 p-y in 2010-2018, corresponding to an absolute change per decade of 1.4 (95% CI, 0.7 to 2.2). There was a nonsignificant period absolute change for patients with tumor greater than 4 cm (0.03; 95% CI, -0.2 to 0.3), with evidence of tumor invasion (0.1; 95% CI, -0.1 to 0.4), and with aggressive histology or presence of metastatic disease (0.2; 95% CI, -0.1 to 0.6). Thyroid cancer mortality was unchanged over the observation period. CONCLUSION: Incidence rates of clinically relevant thyroid cancers, as defined by histology, size, and invasiveness, have not changed significantly in 80 years. The rising thyroid cancer incidence is driven by indolent thyroid cancers.

Clinical Presentation of Celiac Disease and Diagnosis Accuracy in a Single-Center European Pediatric Cohort over 10 Years.

(1) Background: Changes in the clinical presentation of celiac disease (CD) in children have been reported. The guidelines of the European Society of Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) allow esophagogastroduodenoscopy (EGD) with biopsies to be avoided under specific circumstances. We aimed to assess the clinical picture of pediatric CD patients at diagnosis and to validate ESPGHAN non-biopsy criteria. (2) Methods: Patients with suspected CD or undergoing screening from 2004 to 2014 at the University Hospital in Modena, Italy were enrolled. The accuracy of ESPGHAN non-biopsy criteria and modified versions were assessed. (3) Results: In total, 410 patients were enrolled, of whom 403 were considered for analysis. Of the patients considered, 45 were asymptomatic and diagnosed with CD (11.2%) while 358 patients (88.2%) were symptomatic, of whom 295 were diagnosed with CD. Among symptomatic CD patients, 57 (19.3%) had gastrointestinal symptoms, 98 (33%) had atypical symptoms and 140 (47.4%) had both. No difference was found for the presence of gastrointestinal symptoms at different ages. The non-biopsy ESPGHAN criteria yielded an accuracy of 59.4% with a positive predictive value (PPV) of 100%; 173 out of 308 EGD (56.2%) could have been avoided. The modified 7× and 5× upper limit of normal cut-offs for IgA anti tissue-transglutaminase reached 60.7% and 64.3% of EGD avoided, respectively. (4) Conclusions: Over 10 years, late age at diagnosis and increased rates of atypical CD presentation were found. ESPGHAN non-biopsy criteria are accurate for CD diagnosis and allow half of unneeded EGD to be avoided. Modified versions allowed sparing a greater number of EGD.