Rim enhancement of pancreatic ductal adenocarcinoma: investigating the relationship with DCE-MRI-based radiomics and next-generation sequencing.

Purpose: To identify the clinical and genetic variables associated with rim enhancement of pancreatic ductal adenocarcinoma (PDAC) and to develop a dynamic contrast-enhanced (DCE) MRI-based radiomics model for predicting the genetic status from next-generation sequencing (NGS). Materials and methods: Patients with PDAC, who underwent pretreatment pancreatic DCE-MRI between November 2019 and July 2021, were eligible in this prospective study. Two radiologists evaluated presence of rim enhancement in PDAC, a known radiological prognostic indicator, on DCE MRI. NGS was conducted for the tissue from the lesion. The Mann-Whitney U and Chi-square tests were employed to identify clinical and genetic variables associated with rim enhancement in PDAC. For continuous variables predicting rim enhancement, the cutoff value was set based on the Youden's index from the receiver operating characteristic (ROC) curve. Radiomics features were extracted from a volume-of-interest of PDAC on four DCE maps (Ktrans, Kep, Ve, and iAUC). A random forest (RF) model was constructed using 10 selected radiomics features from a pool of 392 original features. This model aimed to predict the status of significant NGS variables associated with rim enhancement. The performance of the model was validated using test set. Results: A total of 55 patients (32 men; median age 71 years) were randomly assigned to the training (n = 41) and test (n = 14) sets. In the training set, KRAS, TP53, CDKN2A, and SMAD4 mutation rates were 92.3%, 61.8%, 14.5%, and 9.1%, respectively. Tumor size and KRAS variant allele frequency (VAF) differed between rim-enhancing (n = 12) and nonrim-enhancing (n = 29) PDACs with a cutoff of 17.22%. The RF model's average AUC from 10-fold cross-validation for predicting KRAS VAF status was 0.698. In the test set comprising 6 tumors with low KRAS VAF and 8 with high KRAS VAF, the RF model's AUC reached 1.000, achieving a sensitivity of 75.0%, specificity of 100% and accuracy of 87.5%. Conclusion: Rim enhancement of PDAC is associated with KRAS VAF derived from NGS-based genetic information. For predicting the KRAS VAF status in PDAC, a radiomics model based on DCE maps showed promising results.

High Expression of NRF2 and Low Expression of KEAP1 Predict Worse Survival in Patients With Operable Triple-Negative Breast Cancer.

PURPOSE: Triple-negative breast cancer (TNBC) is an aggressive type of breast cancer. Currently, no effective treatment options for this condition exist. Nuclear factor erythroid 2-related factor 2 (NRF2), encoded by nuclear factor erythroid-derived 2-like 2 (NFE2L2) gene and its endogenous inhibitor, Kelch-like ECH-associated protein 1 (KEAP1), both participate in cellular defense mechanisms against oxidative stress and contribute to chemoresistance and tumor progression in numerous types of cancers. This study aimed to evaluate the expression patterns of NRF2 and KEAP1 and their prognostic value in operable TNBC. METHODS: Tissue microarrays were prepared using tumor tissues collected from 203 patients with TNBC who underwent surgery. Immunohistochemical staining analyses of NRF2 and KEAP1 were performed. The expression of each immunomarker was categorized into two groups (low or high) based on the median H-score. We analyzed the association between the expression of each immunomarker and clinicopathological information to predict survival. A total of 225 TNBC samples from the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) dataset were used to validate our results. RESULTS: NRF2 immunoreactivity was detected in the nucleus and was associated with histologic grade and Ki-67 index, whereas KEAP1 immunoreactivity was detected in the cytoplasm and was associated with the Ki-67 index. Survival analyses showed that NRF2 and KEAP1 expressions were independent prognostic factors for overall survival (OS) (hazard ratio [HR], 2.45 and 0.30; p = 0.015 and 0.016, respectively) and disease-free survival (HR, 2.27 and 0.42; p = 0.019 and 0.022, respectively). NFE2L2 mRNA expression was an independent prognostic factor for OS (HR, 0.59; p = 0.009) in the METABRIC dataset. CONCLUSION: High NRF2 and low KEAP1 expressions independently predicted poor survival in patients with operable TNBC. Further investigations are warranted to examine the possible therapeutic benefits of targeting the KEAP1-NRF2 pathway for TNBC treatment.

Intrahepatic infiltration of activated CD8+ T cells and mononuclear phagocyte is associated with idiosyncratic drug-induced liver injury.

Background: Idiosyncratic drug-induced liver injury (DILI) is caused by the interplay among drugs, their metabolites, and the host immune response. The characterization of infiltrated immune cells in the liver may improve the understanding of the pathogenesis of idiosyncratic DILI. This study investigated the phenotypes and clinical implications of liver-infiltrating immune cells in idiosyncratic DILI. Methods: From January 2017 to June 2021, 53 patients with idiosyncratic DILI who underwent liver biopsy were prospectively enrolled in this study. Immunohistochemical staining and flow cytometry analyses were performed on the biopsy specimens. Serum levels of CXC chemokine ligand 10 (CXCL10) and soluble CD163 were measured. A multivariate cox proportional hazards model was used to evaluate predictors of DILI resolution within 30 days. Results: The numbers of intrahepatic T cells and mononuclear phagocytes were positively correlated with serum levels of total bilirubin, alanine aminotransferase (ALT), and the model of end-stage liver disease score. The frequency of activated CD8+ T cells among liver-infiltrating CD8+ T cells in DILI livers was higher than that in healthy livers. Notably, the percentages of activated intrahepatic CD8+ T cells and mononuclear phagocytes in DILI livers showed a positive correlation with ALT. Additionally, serum CXCL10 level was positively correlated with intrahepatic T cell infiltration and ALT, and soluble CD163 level was positively correlated with intrahepatic mononuclear phagocyte infiltration and ALT. Thirty-six patients (70.6%) were treated with steroids. In multivariate analysis, total bilirubin and steroid use independently influenced DILI resolution within 30 days. Conclusions: Activated CD8+ T cells and mononuclear phagocyte are associated with liver injury caused by drugs. Therefore, we suggest that steroids are a potential treatment option for idiosyncratic DILI.

An Immunological Perspective on the Mechanism of Drug Induced Liver Injury: Focused on Drugs for Treatment of Hepatocellular Carcinoma and Liver Transplantation.

The liver is frequently exposed to potentially toxic materials, and it is the primary site of clearance of foreign agents, along with many innate and adaptive immune cells. Subsequently, drug induced liver injury (DILI), which is caused by medications, herbs, and dietary supplements, often occurs and has become an important issue in liver diseases. Reactive metabolites or drug-protein complexes induce DILI via the activation of various innate and adaptive immune cells. There has been a revolutionary development of treatment drugs for hepatocellular carcinoma (HCC) and liver transplantation (LT), including immune checkpoint inhibitors (ICIs), that show high efficacy in patients with advanced HCC. Along with the high efficacy of novel drugs, DILI has become a pivotal issue in the use of new drugs, including ICIs. This review demonstrates the immunological mechanism of DILI, including the innate and adaptive immune systems. Moreover, it aims to provide drug treatment targets, describe the mechanisms of DILI, and detail the management of DILI caused by drugs for HCC and LT.

Granulomatous gastritis induced by chronic peanut ingestion.

Granulomatous gastritis (GG) is a rare condition, with incidence between 0.08 and 0.35% in gastric biopsies. Various infectious and non-infectious aetiologies can be considered to cause granulomatous gastritis. Foreign bodies are a rare aetiology of GG and may result from foods, suture materials, or medications. We report a 59-year-old woman who had eaten large amounts of peanuts for more than 10 years and presented with epigastric discomfort. Esophagogastroduodenoscopy revealed multiple nodular lesions with ulcer scars at the stomach, which was diagnosed as GG probably caused by chronic peanut ingestion on endoscopic mucosal resection.

Association between the early high level of serum tacrolimus and recurrence of hepatocellular carcinoma in ABO-incompatible liver transplantation.

BACKGROUND: Clinical factors predicting graft survival (GS) after ABO-incompatible (ABOi) liver transplantation (LT), and differences between recipients with and without hepatocellular carcinoma (HCC) are unclear. AIM: To analyze the impact of serial serum tacrolimus trough concentration in recipients with or without HCC) in ABOi living-donor liver transplantation (LDLT). METHODS: We analyzed a historical cohort of 89 recipients who underwent ABOi LDLT, including 47 patients with HCC. RESULTS: The 1-, 3-, 5-, and 10-year GS rates were 85.9%, 73.3%, 71.4%, and 71.4%, respectively, and there were no significant differences between HCC and non-HCC recipients. In multivariate Cox-regression analyses, tacrolimus trough concentrations below 5.4 ng/mL at 24 wk post-LT, in addition to the antibody-mediated rejection (AMR) were associated with poor-graft outcomes. In HCC patients, AMR [hazard ratio (HR) = 63.20, P < 0.01] and HCC recurrence (HR = 20.72, P = 0.01) were significantly associated with poor graft outcomes. HCCs outside Milan criteria, and tacrolimus concentrations at 4 wk post-LT > 7.3 ng/mL were significant predictive factors for HCC recurrence. After propensity score matching, patients with high tacrolimus concentrations at 4 wk had significantly poor recurrence-free survival. CONCLUSION: Elevated tacrolimus levels at 4 wk after ABOi LDLT have been found to correlate with HCC recurrence. Therefore, careful monitoring and control of tacrolimus levels are imperative in ABOi LT recipients with HCC.

Combined high NEDD9 expression and E-cadherin loss correlate with poor clinical outcome in gastric cancer.

BACKGROUND AND AIM: Neural precursor cell expressed developmentally downregulated 9 (NEDD9) is a member of the Cas family. Previous studies have revealed that NEDD9 coordinates the focal adhesion kinase and Src signaling cascades that are involved in integrin-dependent adhesion and migration, invasion, cell apoptosis and life cycle, and survival, which may play a role in epithelial-mesenchymal transformation. The aim of this study was to analyze the expression of NEDD9 and E-cadherin in gastric cancer (GC) and evaluate their clinical significance. METHODS: NEDD9 and E-cadherin expression was analyzed with immunohistochemistry using tissue microarray technique in 435 GC patients who underwent gastrectomy. The NEDD9 expression level was defined by the combination score, which was determined by multiplying the staining intensity score and the proportion score (≥5; NEDD9-high, <5; NEDD9-low). E-cadherin loss was defined as a total loss of staining. The clinicopathologic parameters, overall survival, and disease-free survival rates were analyzed according to the NEDD9 and E-cadherin expression status. RESULTS: The combined NEDD9 and E-cadherin expression status correlated with lymphatic invasion (P = 0.001), vascular invasion (P = 0.020), and T stage (P = 0.001). Combined high NEDD9 expression and loss of E-cadherin expression status had a worse overall survival rate (P < 0.001) and served as a poor prognostic factor (Hazard ratio 2.49, 95% CI 1.25-5, P = 0.01). CONCLUSIONS: Immunohistochemical staining for NEDD9 and E-cadherin may function as a candidate prognostic marker for gastric cancer in everyday practice, especially when applied in combination.

Prognostic Implications of Portal Venous Circulating Tumor Cells in Resectable Pancreatic Cancer.

Circulating tumor cells (CTCs) are a promising prognostic biomarker for cancers. However, the paucity of CTCs in peripheral blood in early-stage cancer is a major challenge. Our study aimed to investigate whether portal venous CTCs can be a biomarker for early recurrence and poor prognosis in pancreatic cancer. Patients who underwent upfront curative surgery for resectable pancreatic cancer were consecutively enrolled in this prospective study. Intraoperatively, 7.5 mL of portal and peripheral blood was collected, and CTC detection and identification were performed using immunofluorescence staining. Peripheral blood CTC sampling was performed in 33 patients, of which portal vein CTC sampling was performed in 28. The median portal venous CTCs (2.5, interquartile ranges (IQR) 1−7.75) were significantly higher than the median peripheral venous CTCs (1, IQR 0−2, p < 0.001). Higher stage and regional lymph node metastasis were related with a larger number of CTCs (≥3) in portal venous blood. Patients with low portal venous CTCs (≤2) showed better overall (p = 0.002) and recurrence-free (p = 0.007) survival than those with high portal venous CTCs (≥3). If validated, portal CTCs can be used as a prognostic biomarker in patients with resectable pancreatic cancer.

Intrahepatic inflammatory IgA+PD-L1high monocytes in hepatocellular carcinoma development and immunotherapy.

BACKGROUND: IgA neutralizes pathogens to prevent infection at mucosal sites. However, emerging evidence shows that IgA contributes to aggravating inflammation or dismantling antitumor immunity in human diseased liver. The aim of this study was to elucidate the roles of inflammation-induced intrahepatic inflammatory IgA+ monocytes in the development of hepatocellular carcinoma (HCC). METHODS: Patient cohorts including steatohepatitis cohort (n=61) and HCC cohort (n=271) were established. Patients' surgical and biopsy specimens were analyzed using immunohistochemistry. Multicolor flow cytometry was performed with a subset of patient samples. Single-cell RNA-Seq analysis was performed using Gene Expression Omnibus (GEO) datasets. Additionally, we performed in vitro differentiation of macrophages, stimulation with coated IgA, and RNA sequencing. Hepa1-6 cells and C57BL/6N mice were used to obtain HCC syngeneic mouse models. RESULTS: Serum IgA levels were associated (p<0.001) with fibrosis progression and HCC development in patients with chronic liver diseases. Additionally, immunohistochemical staining of inflamed livers or HCC revealed IgA positivity in monocytes, with a correlation between IgA+ cell frequency and IgA serum levels. Compared with IgA- monocytes, intrahepatic IgA+ monocytes expressed higher levels of programmed death-ligand 1 (PD-L1) in inflamed livers and in HCC tumor microenvironment. Single-cell RNA sequencing using NCBI GEO database indicated an upregulation in inflammation-associated genes in the monocytes of patients whose plasma cell IGHA1 expression was greater than or equal to the median value. Bulk RNA sequencing demonstrated that in vitro stimulation of M2-polarized macrophages using coated IgA complex induced PD-L1 upregulation via YAP-mediated signaling. In vivo blockade of IgA signaling decreased the number of tumor-infiltrating IgA+PD-L1high macrophages and increased the number of CD69+CD8+ T cells to enhance antitumor effects in HCC mice models. CONCLUSIONS: Overall, the findings of this study showed that serum IgA levels was correlated with intrahepatic and intratumoral infiltration of inflammatory IgA+PD-L1high monocytes in chronic liver diseases and HCC, providing potential therapeutic targets.

Metastatic breast cancer from a hepatocellular carcinoma: a case report.

Breast metastases from extramammary malignancies are rare. Here, we report a case of breast metastasis from hepatocellular carcinoma (HCC) after breast mass excision in a 63-year-old woman. A new breast nodule was noticed after transarterial chemoembolization, transarterial radioembolization, and stereotactic body radiation therapy for HCC. Breast ultrasound and core needle biopsy were performed to differentiate between the breast tumors. The biopsy result was invasive breast carcinoma, and wide excision of the breast was performed. The final pathological diagnosis was HCC breast metastasis based on histological findings and immunohistochemical staining results. After 9 months of follow-up, HCC and breast metastasis recurred. Despite palliative treatment, the patient died due to complications and general health deterioration. Although breast metastasis due to HCC is very rare, HCC breast metastasis should be considered when a new breast mass is discovered in a patient with a history of HCC for effective treatment and management.

Preferential Expression of Programmed Death Ligand 1 Protein in Tumor-Associated Macrophages and Its Potential Role in Immunotherapy for Hepatocellular Carcinoma.

A predictive biomarker of immune checkpoint inhibitor (ICI)-based treatments in hepatocellular carcinoma (HCC) has not been clearly demonstrated. In this study, we focused on the infiltration and programmed death ligand 1 (PD-L1) expression of tumor-associated macrophages (TAMs) in the tumor microenvironment of HCC. Immunohistochemistry demonstrated that PD-L1 was preferentially expressed on CD68+ macrophages in the tumor microenvironment of HCC, suggestive of its expression in TAMs rather than in T cells or tumor cells (P < 0.05). A co-culture experiment using activated T cells and M2 macrophages confirmed a significant increase in T cell functionality after the pretreatment of M2 macrophages with anti-PD-L1. Syngeneic mouse model experiments demonstrated that TAMs expressed PD-L1 and tumors treated with anti-PD-L1 showed smaller diameters than those treated with IgG. In these mice, anti-PD-L1 treatment increased activation markers in intratumoral CD8+ T cells and reduced the size of the TAM population. Regarding nivolumab-treated patients, three of eight patients responded to the anti-PD-1 treatment. The percentage of Ki-67-positive CD4+ and CD8+ T cells was higher in responders than non-responders after nivolumab. Overall, PD-L1 expression on TAMs may be targeted by immune-based HCC treatment, and ICI treatment results in the reinvigoration of exhausted CD8+ T cells in HCC.

Tumor Microenvironmental Prognostic Risk in Primary Operable Small Intestinal Adenocarcinoma.

The tumor microenvironment (TME) has become an important area of investigation with respect to improving prognosis in malignancies. Here we evaluated TME prognostic risk in small intestinal adenocarcinomas based on histologic assessment of tumor budding at the peritumoral-invasive front (pTB) and stromal tumor-infiltrating lymphocytes (sTILs). pTB and sTILs were analyzed in 230 surgically resected small intestinal adenocarcinomas, as recommended by the International Tumor Budding Consensus Conference (ITBCC) and the International TILs Working Group (ITWG). On the basis of high levels of pTB count (≥10) and sTIL density (≥20%), we combined pTB and sTIL to produce a collective TME-based prognostic risk index: low-risk (pTBLow/sTILHigh; n=39, 17.0%), intermediate-risk (pTBLow/sTILLow or pTBHigh/sTILHigh; n=99, 43.0%), and high-risk groups (pTBHigh/sTILLow; n=92, 40.0%). TME risk index provided better prognostic stratification than the individual pTB and sTIL (14.9 vs. 6.7 vs. 10.3). Tumors with higher TME prognostic risk were associated with an infiltrative growth pattern and nonintestinal immunophenotype (both P=0.001), pancreatic invasion (P=0.010), lymphovascular (P<0.001) or perineural invasion (P=0.006), higher T-category (P<0.001), N-category (P=0.004), and stage grouping (P=0.002), and KRAS mutation (P=0.008). In multivariate analysis, higher TME prognostic risk index (P<0.001), distal tumor location and nonintestinal immunophenotype (both P=0.001), higher N-category (P<0.001), and microsatellite stable (P=0.015) were worse-independent prognosticators. TME prognostic risk index consistently stratified patient survival regardless of tumor location (P<0.001 in proximal; P=0.002 in distal), stages (P<0.001 in lower stages I to II; P=0.028 in stage III), and DNA mismatch repair gene status (P<0.001 in microsatellite stable; P=0.001 in microsatellite instability). TME risk index is a powerful prognostic predictor for risk stratification of patients with small intestinal adenocarcinoma.

Hot snare polypectomy versus endoscopic mucosal resection for small colorectal polyps: a randomized controlled trial.

BACKGROUND AND AIMS: This study was performed to compare endoscopic mucosal resection (EMR) with hot snare polypectomy (HSP) in terms of the complete resection rate and the incidence of adverse events for resecting small (5-10 mm) colorectal polyps. METHODS: Small colorectal polyps (5-10 mm) with neoplastic features were randomly allocated to either the HSP or EMR group. A submucosal injection was performed prior to hot snaring in the EMR group only. Complete resection was defined as the absence of neoplastic tissue from two additional biopsies of the polypectomy site. R0 resection was defined as the absence of neoplastic tissue at the margin of the resected specimen. RESULTS: A total of 362 colon polyps from 272 patients were included, and 167 polyps in the HSP group and 155 polyps in the EMR group were analyzed. Between the polypectomy techniques, there was no significant difference in the complete resection rates, which were 96.4% (161/167) in the HSP group and 95.5% (148/155) in the EMR group (P = 0.67). The R0 resection rate in the HSP and EMR groups was significantly different, with 49.7% (83/167) and 74.8% (116/155), respectively (P < 0.001). There was no significant difference in the incidence of adverse events between the two groups. CONCLUSIONS: The complete resection rates for small (5-10 mm) polyps were not different between HSP and EMR. TRIAL REGISTRY: ClincialTrials.gov number NCT02239536.

Benefits of the multiplanar and volumetric analyses of pancreatic cancer using computed tomography.

Although pancreatic cancer tumors are irregularly shaped in terms of their three-dimensional (3D) structure, when T staging by imaging results, generally only the axial plane is used to measure the largest tumor diameter. We investigated the size of pancreatic cancer tumors using multi-plane and 3D reconstructed computed tomography (CT) images and investigated their clinical usefulness. Patients who underwent surgery for pancreatic adenocarcinoma were included. We measured the largest diameter of each pancreatic tumor in the axial, coronal, and sagittal planes of CT images. In addition, maximal diameter and cancer volume were measured from 3D images that were constructed using a semi-automated software system. Final data were compared with pathologic examination and the effect of each value on prognosis was analyzed. A total of 183 patients were analyzed. The maximal diameters measured on the axial, coronal, and sagittal planes were 2.9 ± 1.1, 3.2 ± 0.9, and 3.2 ± 1.0 cm, respectively, which were significantly smaller than pathologic results (3.4 ± 1.4 cm, all p<0.05 by paired t-test). The longest diameter among them (3.4 ± 1.1 cm) was nearly similar to the pathologic diameter. Cancer volume measured on 3D images demonstrated a higher area under the receptor operating characteristic curve [0.714, (95% confidence interval: 0.640-0.788)] for predicting early death compared to any unidimensional CT diameters measured. The longest pancreatic tumor diameter measured on multiplanar CT images was most accurate when compared to its corresponding pathologic diameter. Tumor volume had a stronger correlation with overall survival than tumor diameter.

Nilotinib-Induced Immune-Mediated Liver Injury: Corticosteroid as a Possible Therapeutic Option.

Introduction: Nilotinib is a BCR-ABL tyrosine kinase inhibitor approved for chronic myeloid leukemia. We present a case of severe immune-mediated liver injury by nilotinib treatment. Case report: A 59-year-old woman was referred to the liver clinic because of elevated liver enzyme levels. One year prior, she was diagnosed as having chronic myeloid leukemia and treated with nilotinib therapy. The level of aspartate aminotransferase and alanine aminotransferase were 578 IU/L and 499 IU/L, respectively. Percutaneous needle liver biopsy showed extensive centrilobular infiltration of immune cells and destruction of the lobular architecture with minimal inflammation in the portal triad. Immunohistochemical staining showed that many CD8+ T cells and CD56+ cells infiltrated the site of inflammation. Multicolor fluorescence-activated cell-sorting analysis revealed that a considerable number of intrahepatic CD8+ T cells showed an activated phenotype compared with the healthy control. She was diagnosed with nilotinib-induced, immune-mediated liver injury. Prednisolone treatment (30 mg daily) was started and caused rapid normalization of liver enzyme levels. Conclusion: Nilotinib can cause immune-mediated liver injury. The use of corticosteroid can be treatment option in immune-mediated liver injury.

Tumor Budding and Poorly Differentiated Clusters in Small Intestinal Adenocarcinoma.

The clinicopathologic and prognostic significances of tumor budding (TB) and poorly-differentiated clusters (PDC) have not been investigated in small intestinal adenocarcinomas (SIACs). In 236 surgically-resected SIACs, we counted TB (single cells or clusters ≤4 tumor cells) and PDC (clusters ≥5 tumor cells) at the peritumoral-invasive front (p) and in the intratumoral area (i) independently to classify as grade-1 (≤4), grade-2 (5-9), or grade-3 (≥10). Consequently, grades-2 and -3 were considered high-grade. High-pTB, -iTB, -pPDC, and -iPDC were observed in 174 (73.7%), 129 (54.7%), 118 (50.0%), and 85 (36.0%) cases, respectively. High-TB/PDCs were more frequently observed in tumors with high-grade, higher T- and N-categories and stage grouping, and perineural or lymphovascular invasion. Patients with high-TB/PDC had a shorter survival than those with low-TB/PDC. In a multivariate analysis, high-pTB, nonintestinal type, high N-category, retroperitoneal seeding, and microsatellite-stable were worse independent-prognostic predictors. Subgroup analysis demonstrated that patients with high-pTB showed worse survival (median: 42.5 months) than those with low-pTB (133.7 months; p = 0.007) in the lower stage (stages I-II) group. High-TB/PDC, both in peritumoral and intratumoral localizations, were associated with aggressive behaviors in SIACs. High-pTB can be used as an adverse prognostic indicator in SIAC patients, especially when patients are in early disease stages.

Radiologic-Pathologic Correlation of Hepatobiliary Phase Hypointense Nodules without Arterial Phase Hyperenhancement at Gadoxetic Acid-enhanced MRI: A Multicenter Study.

Background Hepatobiliary phase (HBP) hypointense nodules without arterial phase hyperenhancement (APHE) at gadoxetic acid-enhanced MRI may indicate hepatocellular carcinoma (HCC) or nonmalignant cirrhosis-associated nodules. Purpose To assess the distribution of pathologic diagnoses of HBP hypointense nodules without APHE at gadoxetic acid-enhanced MRI and to evaluate clinical and imaging features in differentiating their histologic grades. Materials and Methods This retrospective multicenter study included pathologic analysis-confirmed HBP hypointense nodules without APHE (≤30 mm) in patients with chronic liver disease or cirrhosis screened between January 2008 and June 2016. Central pathologic review by 10 pathologists determined final histologic grades as progressed HCC, early HCC, high-grade dysplastic nodule (DN), and low-grade DN or regenerative nodule. Gadoxetic acid-enhanced MRI features were analyzed by three radiologists. Multivariable logistic regression analyses with elastic net regularization were performed to identify clinical and imaging features for differentiating histologic grades. Results There were 298 patients (mean age, 59 years ± 10; 226 men) with 334 nodules evaluated, and progressed HCCs were diagnosed in 44.0% (147 of 334), early HCCs in 20.4% (68 of 334), high-grade DNs in 27.5% (92 of 334), and low-grade DNs or regenerative nodules in 8.1% (27 of 334). Serum α-fetoprotein level 100 ng/mL or greater (odds ratio, 2.7; P = .01) and MRI features including well-defined margin (odds ratio, 5.5; P = .003), hypointensity at precontrast T1-weighted imaging (odds ratio, 3.2; P < .001), intermediate hyperintensity at T2-weighted imaging (odds ratio, 3.4; P < .001), and restricted diffusion (odds ratio, 1.9; P = .04) were independent predictors for progressed HCC at multivariable analysis. Conclusion In patients at high risk for hepatocellular carcinoma (HCC), hepatobiliary phase hypointense nodules without arterial phase hyperenhancement at gadoxetic acid-enhanced MRI corresponded mainly to progressed HCCs, early HCCs, and high-grade dysplastic nodules. High α-fetoprotein level and some imaging features at MRI helped to differentiate progressed HCC from lower grade nodules. © RSNA, 2020 Online supplemental material is available for this article. See also the editorial by Motosugi in this issue.

A scoring system for the diagnosis of non-alcoholic steatohepatitis from liver biopsy.

BACKGROUND: Liver biopsy is the essential method to diagnose non-alcoholic steatohepatitis (NASH), but histological features of NASH are too subjective to achieve reproducible diagnoses in early stages of disease. We aimed to identify the key histological features of NASH and devise a scoring model for diagnosis. METHODS: Thirteen pathologists blindly assessed 12 histological factors and final histological diagnoses ('not-NASH,' 'borderline,' and 'NASH') of 31 liver biopsies that were diagnosed as non-alcoholic fatty liver disease (NAFLD) or NASH before and after consensus. The main histological parameters to diagnose NASH were selected based on histological diagnoses and the diagnostic accuracy and agreement of 12 scoring models were compared for final diagnosis and the NAFLD Activity Score (NAS) system. RESULTS: Inter-observer agreement of final diagnosis was fair (κ = 0.25) before consensus and slightly improved after consensus (κ = 0.33). Steatosis at more than 5% was the essential parameter for diagnosis. Major diagnostic factors for diagnosis were fibrosis except 1C grade and presence of ballooned cells. Minor diagnostic factors were lobular inflammation ( ≥ 2 foci/ × 200 field), microgranuloma, and glycogenated nuclei. All 12 models showed higher inter-observer agreement rates than NAS and post-consensus diagnosis (κ = 0.52-0.69 vs. 0.33). Considering the reproducibility of factors and practicability of the model, summation of the scores of major (× 2) and minor factors may be used for the practical diagnosis of NASH. CONCLUSIONS: A scoring system for the diagnosis of NAFLD would be helpful as guidelines for pathologists and clinicians by improving the reproducibility of histological diagnosis of NAFLD.

EpCAM-high liver cancer stem cells resist natural killer cell-mediated cytotoxicity by upregulating CEACAM1.

BACKGROUND: Natural killer (NK) cells can recognize and kill cancer cells directly, but their activity can be attenuated by various inhibitory molecules expressed on the surface. The expression of epithelial cell adhesion molecule (EpCAM), a potential marker for cancer stem cells (CSCs), is known to be strongly associated with poor clinical outcomes in hepatocellular carcinoma (HCC). NK cells targeting CSCs may be a promising strategy for anti-tumor therapy, but little is known about how they respond to EpCAMhigh CSCs in HCC. METHODS: EpCAM expression was assessed by immunohistochemistry in 280 human HCC tissues obtained from curative surgery. To investigate the functional activity of NK cells against liver CSCs, EpCAMhigh and EpCAMlow Huh-7 cells were sorted by flow cytometry. The functional role of carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1), which is related to NK cells, was determined by in vitro co-culture of NK cells and hepatoma cells using Hepa1-6 mouse hepatoma cells, as well as in vivo experiments using C57/BL6 mice. RESULTS: The frequency of recurrence after curative surgery was higher in patients with positive EpCAM expression than in those with negative EpCAM expression. In subsequent analysis based on the anatomical location of EpCAM expression, patients with peritumoral EpCAM expression showed worse prognosis than those with pantumoral EpCAM expression. Co-culture experiments demonstrated that CEACAM1 was upregulated on the surface of EpCAMhigh HCC cells, resulting in resistance to NK cell-mediated cytotoxicity. Inversely, silencing CEACAM1 restored cytotoxicity of NK cells against EpCAMhigh Huh-7 cells. Moreover, neutralizing CEACAM1 on the NK cell surface enhanced killing of Huh-7 cells, suggesting that homophilic interaction of CEACAM1 is responsible for attenuated NK cell-mediated killing of CEACAM1high cells. In mouse experiments with Hepa1-6 cells, EpCAMhigh Hepa1-6 cells formed larger tumors and showed higher CEACAM1 expression after NK cell depletion. NK-mediated cytotoxicity was enhanced after blocking CEACAM1 expression using the anti-CEACAM1 antibody, thereby facilitating tumor regression. Moreover, CEACAM1 expression positively correlated with EpCAM expression in human HCC tissues, and serum CEACAM1 levels were also significantly higher in patients with EpCAM+ HCC. CONCLUSION: Our data demonstrated that EpCAMhigh liver CSCs resist NK cell-mediated cytotoxicity by upregulation of CEACAM1 expression.

Regional Lymph Node Dissection as an Additional Treatment Option to Endoscopic Resection for Expanded Indications in Gastric Cancer: a Prospective Cohort Study.

PURPOSE: Expanded indications for endoscopic submucosal dissection (ESD) in early gastric cancer (EGC) remain controversial due to the potential risk of undertreatment after adequate lymph node dissection (LND). Regional LND (RLND) is a novel technique used for limited lymphadenectomy to avoid gastrectomy. This study established the safety and effectiveness of RNLD as an additional treatment option after ESD for expanded indications. MATERIALS AND METHODS: A total of 69 patients who met the expanded indications for ESD were prospectively enrolled from 2014 to 2017. The tumors were localized using intraoperative esophagogastroduodenoscopy (EGD) before RLND. All patients underwent RLND first, followed by conventional radical gastrectomy with LND. The locations of the preoperative and intraoperative EGD were compared. Pathologic findings of the primary lesion and the RLND status were analyzed. RESULTS: The concordance rates of tumor location between the preoperative and intraoperative EGD were 79.7%, 76.8%, and 63.8% according to the longitudinal, circumferential, and regional locations, respectively. Of the 4 patients (5.7%) with metastatic LNs, 3 were pathologically classified as beyond the expanded indication for ESD and 1 had a single LN metastasis in the regional lymph node. CONCLUSIONS: RLND is a safe additional option for the treatment of EGC in patients meeting expanded indications after ESD.