Discovery of non-genomic drivers of YAP signaling modulating the cell plasticity in CRC tumor lines.

In normal intestines, a fetal/regenerative/revival cell state can be induced upon inflammation. This plasticity in cell fate is also one of the current topics in human colorectal cancer (CRC). To dissect the underlying mechanisms, we generated human CRC organoids with naturally selected genetic mutation profiles and exposed them to two different conditions by modulating the extracellular matrix (ECM). Among tested mutation profiles, a fetal/regenerative/revival state was induced following YAP activation via a collagen type I-enriched microenvironment. Mechanistically, YAP transcription was promoted by activating AP-1 and TEAD-dependent transcription and suppressing intestinal lineage-determining transcription via mechanotransduction. The phenotypic conversion was also involved in chemoresistance, which could be potentially resolved by targeting the underlying YAP regulatory elements, a potential target of CRC treatment.

Granulomatous hepatitis with Crohn's disease: a case report.

A 45-year-old man who was regularly followed up for Crohn's disease (CD) and maintained clinical remission with vedolizumab (VDZ). At 37 years old, he was diagnosed CD from longitudinal ulcers in the distal ileum by balloon-assisted enteroscopy (BAE). During the follow-up, liver enzyme elevation, splenomegaly and thrombocytopenia were in progress. Esophagogastric varices suggested chronic liver disease and portal hypertension. Magnetic resonance elastography (MRE) showed liver stiffness of 3.4 kPa and proton density fat fraction (PDFF) of 1.86%. He was diagnosed with granulomatous hepatitis based on a liver biopsy. The hepatic venous pressure gradient (HVPG) was mildly elevated at 7 mmHg, consistent with the pre-sinusoidal portal hypertension due to granulomatous hepatitis. We report a rare case with granulomatous hepatitis diagnosed from liver injury and portal hypertension, despite the stable intestinal symptoms of CD.

Impact of immune-related adverse events in patients with hepatocellular carcinoma treated with atezolizumab plus bevacizumab.

BACKGROUND AND AIM: Immune checkpoint inhibitors pose the risk of immune-related adverse events (irAEs). Recent data suggest that irAEs may be associated with a favorable prognosis. This study aimed to investigate and analyze the association between these adverse events and the clinical benefits in patients with unresectable hepatocellular carcinoma. METHODS: The study enrolled 130 patients with advanced hepatocellular carcinoma treated with atezolizumab plus bevacizumab between November 2020 and January 2023 at a single center. The relationship between irAEs and both response rate and post-treatment outcomes was investigated. RESULTS: Out of the 130 patients, irAEs developed in 36 (27.7%) patients. The irAE group exhibited a significantly longer progression-free survival (PFS) than the non-irAE group, with a median PFS of 8.9 compared with 4.6 months (P < 0.01). No difference was found in the overall survival between the irAE and non-irAE groups. The irAE group demonstrated significantly higher disease control rate (DCR) than the non-irAE group (97.0% vs 65.5%, P < 0.01). The analysis by irAE severity revealed that the grade 1/2 group exhibited significantly longer PFS (7.9 vs 4.6 months, P = 0.007) and higher DCR (100% vs 65.5%, P < 0.01) than the non-irAE group. Furthermore, hypothyroidism correlated with a favorable PFS (8.9 vs 5.4 months, P = 0.02), DCR (100% vs 71.3%, P = 0.03), and overall response rate (58.3% vs 18.5%, P = 0.005). CONCLUSION: The presence of irAEs is associated with prolonged PFS and higher DCR. Specifically, mild irAEs (grade 1/2) and hypothyroidism displayed prolonged PFS and higher DCR.

Analysis of prognosis and background liver disease in non-advanced hepatocellular carcinoma in two decades.

BACKGROUND/AIM: Antiviral hepatitis and systemic therapies for hepatocellular carcinoma (HCC) remarkably progressed in the recent 10 years. This study aimed to reveal the actual transition and changes in the prognosis and background liver disease in non-advanced HCC in the past 20 years. METHODS: This retrospectively recruited 566 patients who were diagnosed with non-advanced HCC from February 2002 to February 2022. The prognosis was analyzed by subdividing according to the diagnosis date (period I: February 2002-April 2009 and period Ⅱ: May 2009-February 2022). RESULTS: Patients in period II (n = 351) were significantly older, with lower albumin-bilirubin (ALBI) scores and alpha-fetoprotein (AFP) and more anti-viral therapy, systemic therapy, and hepatic arterial infusion chemotherapy as compared with those in period I (n = 215). The etiology ratio of the background liver disease revealed decreased hepatitis C virus from 70.6% to 49.0% and increased non-B, non-C from 17.7% to 39.9% from periods I to Ⅱ. The multivariate analysis revealed older age and higher ALBI score in Barcelona Clinic Liver Cancer (BCLC) 0/A stage, AFP of >20 ng/mL, and higher ALBI score in BCLC B stage as independent prognosis factors. Fine-Gray competing risk model analysis revealed that liver-related deaths significantly decreased in period II as compared to period I, especially for BCLC stage 0/A (HR: 0.656; 95%CI: 0.442-0.972, P = 0.036). CONCLUSION: The characteristics of patients with non-advanced HCC have changed over time. Appropriate background liver management led to better liver-related prognoses in BCLC 0/A.

Single cell analysis revealed that two distinct, unique CD4+ T cell subsets were increased in the small intestinal intraepithelial lymphocytes of aged mice.

Recent advances in research suggest that aging has a controllable chronic inflammatory disease aspect. Aging systemic T cells, which secrete pro-inflammatory factors, affect surrounding somatic cells, and accelerate the aging process through chronic inflammation, have attracted attention as potential therapeutic targets in aging. On the other hand, there are few reports on the aging of the intestinal immune system, which differs from the systemic immune system in many ways. In the current study, we investigated the age-related changes in the intestinal immune system, particularly in T cells. The most significant changes were observed in the CD4+ T cells in the small intestinal IEL, with a marked increase in this fraction in old mice and reduced expression of CD27 and CD28, which are characteristic of aging systemic T cells. The proliferative capacity of aging IEL CD4+ T cells was significantly more reduced than that of aging systemic T cells. Transcriptome analysis showed that the expression of inflammatory cytokines was not upregulated, whereas Cd8α, NK receptors, and Granzymes were upregulated in aging IEL CD4+ T cells. Functional analysis showed that aging IEL T cells had a higher cytotoxic function against intestinal tumor organoids in vitro than young IEL T cells. scRNAseq revealed that splenic T cells show a transition from naïve to memory T cells, whereas intestinal T cells show the emergence of a CD8αα+CD4+ T cell fraction in aged mice, which is rarely seen in young cells. Further analysis of the aging IEL CD4+ T cells showed that two unique subsets are increased that are distinct from the systemic CD4+ T cells. Subset 1 has a pro-inflammatory component, with expression of IFNγ and upregulation of NFkB signaling pathways. Subset 2 does not express IFNγ, but upregulates inhibitory molecules and nIEL markers. Expression of granzymes and Cd8a was common to both. These fractions were in opposite positions in the clustering by UMAP and had different TCR repertoires. They may be involved in the suppression of intestinal aging and longevity through anti-tumor immunity, elimination of senescent cells and stressed cells in the aging environment. This finding could be a breakthrough in aging research.

Combination of leucine-rich alpha-2 glycoprotein and fecal markers detect Crohn's disease activity confirmed by balloon-assisted enteroscopy.

BACKGROUND/AIMS: Endoscopic activity confirmed by enteroscopy is associated with poor clinical outcome in Crohn's disease (CD). We investigated which of the existing biomarkers best reflects endoscopic activity in CD patients including the small bowel, and whether their combined use can improve accuracy. METHODS: One hundred and four consecutive patients with ileal and ileocolonic type CD who underwent balloon-assisted enteroscopy (BAE) from October 2021 to August 2022 were enrolled, with clinical and laboratory data prospectively collected and analyzed. RESULTS: Hemoglobin, platelet count, C-reactive protein, leucine-rich alpha-2 glycoprotein (LRG), fecal calprotectin, and fecal hemoglobin all showed significant difference in those with ulcers found on BAE. LRG and fecal calprotectin showed the highest areas under the curve (0.841 and 0.853) for detecting ulcers. LRG showed a sensitivity of 78% and specificity of 80% at a cutoff value of 13 µg/mL, whereas fecal calprotectin showed a sensitivity of 91% and specificity of 67% at a cutoff value of 151 µg/g. Dual positivity for LRG and fecal calprotectin, as well as LRG and fecal hemoglobin, both predicted ulcers with an improved specificity of 92% and 100%. A positive LRG or fecal calprotectin/hemoglobin showed an improved sensitivity of 96% and 91%. Positivity for LRG and either of the fecal biomarkers was associated with increased risk of hospitalization, surgery, and relapse. CONCLUSIONS: The biomarkers LRG, fecal calprotectin, and fecal hemoglobin can serve as noninvasive and accurate tools for assessing activity in CD patients confirmed by BAE, especially when used in combination.

Clinical Response of Primary Malignant Pericardial Mesothelioma with Peritoneal Dissemination to Nivolumab.

Malignant pericardial mesothelioma (MPM) is extremely rare, and peritoneal dissemination has not yet been reported. There is no consensus regarding appropriate pharmacological treatment for MPM, including immune checkpoint inhibitors (ICIs). We herein report a 36-year-old man with MPM diagnosed by peritoneal dissemination and treated with an ICI. Cytology of the ascites revealed malignant peritonitis, and a re-evaluation of a pericardial biopsy performed at the previous hospital led to a diagnosis of MPM. The patient was treated with nivolumab and showed a clinical response despite several complications, such as renal dysfunction and performance status deterioration. This case report provides suggestive information for the diagnosis and ICI therapy of a rare type of mesothelioma.

Exploring extracellular matrix and prostaglandin pathway alterations across varying resection margin distances of right-sided colonic adenocarcinoma.

BACKGROUND: Surgical resection followed by indicated adjuvant therapy offers potential curative treatment in colonic adenocarcinoma. Beyond the well-established seed and soil theory of colon cancer progression, the 'normal-appearing' tissues near the tumor are not genuinely normal and remain as remnants in patients following surgery. Our objective was to elucidate the alteration of gene expression and pathways across various distances of resection margins in right-sided colonic adenocarcinoma. METHODS: Twenty-seven fresh samples of primary cancer and 56 matched non-tumor tissues adjacent to the tumor (NAT) were collected from patients with resectable right-sided colon cancer. NAT were systematically obtained at varying distances (1, 5, and 10 cm) on both proximal and distal sides. Comprehensive gene expression analysis was performed using 770-gene PanCancer Progression Panel, delineating distinctive pathways and functional predictions for each region. RESULTS: Distinctive gene signatures and pathways exhibited by normal-appearing tissues were discovered at varying distances from cancer. Notably, SFRP2, PTGDS, COL1A1, IL1B, THBS2, PTGIS, COL1A2, NPR1, and BGN were upregulated, while ENPEP, MMP1, and NRCAM were downregulated significantly in 1-cm tissue compared to farther distances. Substantial alterations in the extracellular matrix (ECM) and prostaglandin/thromboxane synthesis were significantly evident at the 1-cm distance. Functional analysis indicated enhanced cell viability and survival, alongside reduced cellular death and apoptosis. CONCLUSIONS: Different distances exerted a significant impact on gene alteration within the normal-looking mucosa surrounding primary cancer, influenced by various mechanisms. These findings may highlight potential therapeutic targets related to the ECM and prostaglandin/thromboxane pathways for treatment strategies.

Prognostic significance of C-reactive protein in unresectable hepatocellular carcinoma treated with atezolizumab and bevacizumab.

AIM: C-reactive protein (CRP) is both an inflammatory and prognostic marker in various cancers. This study aimed to elucidate the characteristics of CRP and the prognostic factors in patients who were administered with atezolizumab plus bevacizumab (ATZ + BEV) for unresectable hepatocellular carcinoma (HCC). METHODS: A total of 213 patients who received ATZ + BEV for HCC from November 2020 to March 2023 at 15 hospitals were enrolled in this retrospective study. The prognosis was analyzed by subdividing the patients based on baseline characteristics, radiologic response, and treatment lines. Accuracy of survival prediction was assessed using CRP, alpha fetoprotein (AFP), C-reactive protein and alpha fetoprotein in immunotherapy (CRAFITY), and Glasgow Prognostic Score. RESULTS: Compared with patients with baseline CRP <1 mg/dL, those with baseline CRP ≥1 mg/dL (n = 45) had a significantly higher baseline albumin-bilirubin score and AFP levels, significantly lower disease control rate (62.2%), and significantly shorter median overall survival (hazards ratios 2.292; 95% confidence interval 1.313-5.107; log-rank test, p < 0.001). Multivariate analysis identified CRP ≥1 mg/dL, AFP ≥100 ng/mL, and modified albumin-bilirubin grade as the significant prognostic factors. The baseline CRP, AFP, CRAFITY, and Glasgow Prognostic Score demonstrated higher discrimination for 1-year survival prediction after first-line ATZ + BEV administration, compared with beyond second line, with area under the receiver operating characteristic curves of 0.759, 0.761, 0.805, and 0.717, respectively. CONCLUSIONS: CRP was a significant biomarker in patients treated with ATZ + BEV for HCC. Elevated CRP levels may indicate aggressive cancer progression and potential resistance to ATZ + BEV therapy.

Detecting advanced liver fibrosis using ultrasound shear wave velocity measurement in the general population.

Background: Advanced fibrosis detection in the general population is an unmet need. Additionally, screening method for advanced fibrosis in the general population is not established. Thus, this study aimed to examine the use of shear wave measurement (SWM), which measures liver stiffness by ultrasound elastography as a screening tool for advanced fibrosis in health checkups that represents the general population. Methods: SWM was performed in all subjects. Magnetic resonance elastography (MRE) was performed in those with SWM shear wave velocity (Vs) ≥1.3 m/s to determinate advanced fibrosis. The diagnostic accuracy of SWM Vs for advanced fibrosis (determined by MRE of ≥3.62 kPa) was examined. This prospective study was registered with the University Hospital Medical Information Network clinical trial registry (UMIN000041609). Results: A total of 2,233 subjects were included. SWM Vs of 1.64 m/s was selected as the best threshold for advanced fibrosis. Using the threshold of SWM Vs at ≥1.64 m/s, subjects were narrowed down to 1.7%, and sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) for advanced fibrosis were 53.3%, 92.4%, 47.1%, and 94.0%, respectively, among these subjects. The multivariable analysis, after adjusting the age, sex, body mass index (BMI), hypertension, diabetes mellitus (DM), dyslipidemia, and alcohol use, revealed an SWM Vs of ≥1.64 m/s as the significant factor for advanced fibrosis with an odds ratio (95% confidence interval) of 14.5 (3.4-62; P<0.001). Conclusions: SWM has high diagnostic accuracy for advanced fibrosis (PPV 47.1%) and may be used as a screening tool for liver fibrosis in the general population.

The gut microbiota-induced kynurenic acid recruits GPR35-positive macrophages to promote experimental encephalitis.

The intricate interplay between gut microbes and the onset of experimental autoimmune encephalomyelitis (EAE) remains poorly understood. Here, we uncover remarkable similarities between CD4+ T cells in the spinal cord and their counterparts in the small intestine. Furthermore, we unveil a synergistic relationship between the microbiota, particularly enriched with the tryptophan metabolism gene EC:1.13.11.11, and intestinal cells. This symbiotic collaboration results in the biosynthesis of kynurenic acid (KYNA), which modulates the recruitment and aggregation of GPR35-positive macrophages. Subsequently, a robust T helper 17 (Th17) immune response is activated, ultimately triggering the onset of EAE. Conversely, modulating the KYNA-mediated GPR35 signaling in Cx3cr1+ macrophages leads to a remarkable amelioration of EAE. These findings shed light on the crucial role of microbial-derived tryptophan metabolites in regulating immune responses within extraintestinal tissues.

Diagnosis and Clinical Features of Perianal Lesions in Newly Diagnosed Crohn's Disease: Subgroup Analysis from Inception Cohort Registry Study of Patients with Crohn's Disease (iCREST-CD).

BACKGROUND AND AIMS: Perianal lesion is a refractory phenotype of Crohn's disease [CD] with significantly diminished quality of life. We evaluated the clinical characteristics of perianal lesions in newly diagnosed CD patients and the impact of perianal lesions on the quality of life in Japanese patients with CD. METHODS: Patients newly diagnosed with CD after June 2016 were included between December 2018 and June 2020 from the Inception Cohort Registry Study of Patients with CD [iCREST-CD]. RESULTS: Perianal lesions were present in 324 [48.2%] of 672 patients with newly diagnosed CD; 71.9% [233/324] were male. The prevalence of perianal lesions was higher in patients aged <40 years vs ≥40 years, and it decreased with age. Perianal fistula [59.9%] and abscess [30.6%] were the most common perianal lesions. In multivariate analyses, male sex, age <40 years and ileocolonic disease location were significantly associated with a high prevalence of perianal lesions, whereas stricturing behaviour and alcohol intake were associated with low prevalence. Fatigue was more frequent [33.3% vs 21.6%] while work productivity and activity impairment-work time missed [36.3% vs 29.5%] and activity impairment [51.9% vs 41.1%] were numerically higher in patients with than those without perianal lesions. CONCLUSIONS: At the time of CD diagnosis, approximately half of the patients had perianal lesions; perianal abscesses and perianal fistulas were the most common. Young age, male sex, disease location and behaviour were significantly associated with the presence of perianal lesions. The presence of perianal lesion was associated with fatigue and impairment of daily activities. CLINICAL TRIALS REGISTRY: University Hospital Medical Information Network Clinical Trials Registry System [UMIN-CTR, UMIN000032237].

Clinical Utility of Comprehensive Genomic Profiling in Patients with Unresectable Hepatocellular Carcinoma.

The molecular mechanism of hepatocellular carcinoma (HCC) is partially demonstrated. Moreover, in the patients receiving multiple molecular-targeted therapies, the gene alternations are still unknown. Six molecular-targeted therapies of unresectable HCC (uHCC) and comprehensive genomic profiling (CGP) have been approved in clinical practice. Hence, the utility of CGP in patients with uHCC treated with multiple molecular-targeted agents is investigated. The data of the patients with uHCC who received CGP tests were collected, retrospectively, between February 2021 and May 2022. Gene alterations detected by foundation testing, excluding variants of unknown significance, were reported in all nine patients. The samples for CGP were derived from liver tumor biopsy (n = 2), surgical specimens of bone metastases (n = 2), and blood (n = 5). The median number of systemic therapies was four. Seven patients were candidates eligible for clinical trials. One patient with a high tumor mutation burden (TMB) could receive pembrolizumab after CGP. This study presented genomic alternations after receiving multiple molecular-targeted therapies. However, further investigation needs to be conducted to develop personalized therapies and invent newer agents for treating HCC.

Effect of fatty liver and fibrosis on hepatocellular carcinoma development in patients with chronic hepatitis B who received nucleic acid analog therapy.

The number of patients with fatty liver has been increasing worldwide; however, the significance of fatty liver in patients with chronic hepatitis B who are receiving nucleic acid analog (NA) therapy remains unclear. Thus, we aimed to determine whether fatty liver affects the development of hepatocellular carcinoma (HCC) in patients receiving NA therapy. This study included 445 patients who received NA therapy, and the development of HCC was investigated. The primary outcome was the association between fatty liver and HCC development. During a mean follow-up period of 7.4 years, 46 patients (10.3%) developed HCC. No significant difference in the cumulative incidence of HCC was observed between patients with fatty liver and those without (p = 0.17). Multivariable analysis for age, gender, platelet count, alanine aminotransferase level at 1 year following NA therapy, and fatty liver revealed that the presence of fatty liver was not a significant factor for HCC development (hazard ratio [HR]: 0.96, 95% confidence interval [CI]: 0.5-1.9). In another multivariable analysis for advanced fibrosis, gender, and fatty liver, advanced fibrosis was found to be a significant factor for HCC development (HR: 9.50, 95% CI: 5.1-18) but not fatty liver (HR: 0.90, 95% CI: 0.5-1.7). In conclusion, in patients with chronic hepatitis B who received NA therapy, advanced fibrosis was found to be an important risk factor for HCC development but not fatty liver, suggesting the importance of providing treatment before the progression of liver fibrosis regardless of the presence of fatty liver.

Factors associated with liver injury and prognosis in advanced cancer patients treated with immune checkpoint inhibitors.

AIM: The use of immune checkpoint inhibitors (ICIs) has increased remarkably, and immune-related adverse events (irAEs) have also increased. This study aimed to identify factors associated with immune-related liver injury (irLI), and the relationship between the grades of irLI and overall survival (OS) in patients treated with ICIs. METHODS: A total of 571 patients who had been treated for advanced malignancies with ICIs between January 2015 and March 2022 were retrospectively recruited. The presence of liver injury was determined by the aspartate aminotransferase and alanine aminotransferase elevation. The irLI grading was based on Common Terminology Criteria for Adverse Events version 5.0. RESULTS: A total of 50 (8.8%) patients had grade ≥2 irLI and 24 (4.2%) had grade ≥3 irLI. Treatment with anti-cytotoxic T-lymphocyte-associated protein-4 agents and baseline grade 1 aspartate aminotransferase/alanine aminotransferase elevation were independent predictive factors of grade ≥2 irLI. Treatment with anti-cytotoxic T-lymphocyte-associated protein-4 was the only independent predictive factor of grade ≥3 irLI. The median OS for patients who experienced any irAEs was significantly longer than of those without irAEs (hazard ratio 0.503, 95% CI 0.398-0.636, p < 0.001). The median OS in patients with grade ≥2 irLI was significantly longer (HR 0.570, 95% CI 0.387-0.838, p = 0.022). There was no significant difference between the median OS in patients with grade ≥3 irLI and the others (p = 0.11). CONCLUSION: The incidence of irLI was significantly higher in patients treated with anti-cytotoxic T-lymphocyte-associated protein-4 agents. Even in patients with pre-existing grade 1 aspartate aminotransferase/alanine aminotransferase elevation, appropriate follow-up and control of the irLI can improve the prognosis.

Transmural Remission Characterized by High Biologic Concentrations Demonstrates Better Prognosis in Crohn's Disease.

BACKGROUND: The importance and pathophysiology of transmural healing in patients with Crohn's disease [CD] remains to be verified. We aimed to examine the association between serum concentrations of biologics and transmural remission evaluated via magnetic resonance enterography [MRE]. METHODS: We enrolled patients with CD who received maintenance biologics 1 year after induction and prospectively followed up for at least 1 year after baseline laboratory, endoscopic and MRE examination. We evaluated the relationship between baseline factors including the presence of transmural remission and patient prognosis, as well as between serum concentrations and transmural remission. RESULTS: We included 134 patients, of whom 65, 31, 27 and 11 received infliximab, adalimumab, ustekinumab and vedolizumab, respectively. Those who achieved transmural remission showed a lower risk of hospitalization and surgery than those who did not achieve remission [p < 0.01]. Adjusted hazard ratios of transmural remission for predicting hospitalization and surgery were 0.11 and 0.02, respectively, which were lower than those of clinical remission, biochemical remission and endoscopic remission. Regarding serum concentrations, the median concentration was higher in patients with transmural remission than in patients with transmural activity for all agents [p < 0.01 for infliximab, p = 0.04 for adalimumab, p < 0.01 for ustekinumab, p = 0.08 for vedolizumab]. CONCLUSIONS: Transmural remission was the best predictor for prognosis in CD patients who received maintenance biologic therapy. High drug concentration levels were associated with transmural remission confirmed via MRE.

Serum Leucine-Rich α2 Glycoprotein: A Novel Biomarker for Transmural Inflammation in Crohn's Disease.

INTRODUCTION: Leucine-rich alpha-2 glycoprotein (LRG) is a newly studied biomarker for inflammatory diseases. This study aimed to investigate whether LRG can be used for evaluating transmural activity in patients with Crohn's disease (CD). METHODS: We performed magnetic resonance enterography (MRE) in 227 consecutive patients with CD from June 2020 to August 2021. We prospectively compared MRE findings with clinical and laboratory data including LRG. MRE was evaluated using 2 validated scoring systems, and transmural inflammation was defined as having a maximum simplified magnetic resonance index of activity (sMaRIA) score of ≥4 and a 5-point classification score of ≥9, respectively. RESULTS: The correlation between LRG and the total MRE score showed a positive correlation ( r = 0.576 for the sMaRIA score, P < 0.01, and r = 0.633 for the 5-point score, P < 0.01). Serum concentrations of LRG significantly increased as MRE scores increased ( P < 0.01). The area under the curve of LRG for a sMaRIA score of ≥4 and a 5-point score of ≥9 was 0.845 and 0.869, respectively, which was significantly higher than that of CDAI ( P < 0.01) or C-reactive protein ( P < 0.01). LRG levels of ≥14 µg/mL had a 67% sensitivity and 90% specificity for a sMaRIA score of ≥4 and a 73% sensitivity and 89% specificity for a 5-point score of ≥9. Patients with high LRG levels were also strongly associated with CD-related hospitalization, surgery, and clinical relapse compared with those with low LRG levels ( P < 0.01 for all). DISCUSSION: LRG is a highly accurate serum biomarker for detecting transmural activity in patients with CD. Results need to be validated in further multicenter studies.

Impact of eradication of hepatitis C virus on liver-related and -unrelated diseases: morbidity and mortality of chronic hepatitis C after SVR.

Hepatitis C virus infection is characterized by chronic liver inflammation and fibrogenesis, leading to end-stage liver failure and hepatocellular carcinoma over the course of 20 to 30 years. It seems not only the chronicity of hepatitis C but also the presence of the virus in non-hepatic tissues creates a favorable environment for the potential development of pathogenic impacts on extrahepatic systems and organs. Numerous extra-hepatic manifestations have been reported in association with HCV infection, all of which can substantially affect morbidity, mortality, and quality of life. With the recent development of DAAs, antiviral treatment can cure almost all patients with HCV infection, even those intolerant of or unresponsive to IFN treatment, and several large multicenter studies have confirmed the association of DAA-induced SVR with reductions in liver-related and liver-unrelated complications, such as cardiovascular events, end stage renal disease, and so on. Because, in addition to liver-related diseases, extrahepatic lesions are threatening for patients, it is important to eradicate the virus before these progress and affect life prognosis; in other words, patients should be treated before reaching the point of no return. Tailored surveillance with biomarkers such as M2BPGi and Ang-2, which can be used to identify patients with an elevated risk of EHM, and early prevention or treatment for these patients could improve the morbidity, mortality and QOL. Advancement of both basic and clinical research in this field including the development of more precise biomarkers is highly anticipated.

Development and Application of Regenerative Medicine in Inflammatory Bowel Disease.

BACKGROUND: Inflammatory bowel disease (IBD) is characterized by idiopathic and chronic inflammation arising elsewhere within the gastrointestinal tract. Consequently, the mucosal tissue is destroyed during the active phase of the disease, and therefore, spontaneous repair of damaged tissue is required to restore the function and long-term homeostasis of the intestinal mucosa. Also, in patients with refractory Crohn's disease, loss of massive intestinal function can lead to short bowel syndrome or may lead to fatal intestinal failure. SUMMARY: The concept of mucosal healing shares the idea that both regulation of mucosal inflammation and repair of the damaged mucosa are critical to achieve the ideal clinical outcome in patients with IBD. However, current treatments lack the option of those targeted to mucosal repair, and therefore, patients must achieve mucosal healing depending on their intrinsic system. To counteract inflammation-induced mucosal damage, various biologics or cell-based treatments are currently being developed. In the early developmental phase, various growth factors have been tested for their ability to promote mucosal repair. However, most of these factors did not show clinical benefit, except the recombinant glucagon-like peptide-2 (GLP-2). On the contrary, cell-based treatments are rapidly emerging, using both somatic stem cells and pluripotent stem cells. KEY MESSAGES: In this review, we focus on the current state of factor-based or cell-based regenerative medicine in the treatment of IBD. Additionally, we would like to introduce current examples of tissue engineering technologies and provide future prospects for the application of regenerative medicine in IBD.

Alanine aminotransferase levels as therapeutic targets after nucleotide/nucleoside analog therapy in patient with chronic hepatitis B.

AIM: Alanine aminotransferase (ALT) is a criterion for the introduction of nucleotide/nucleoside analog (NA), and ALT levels are decreased by NA treatment. However, the association between post-treatment ALT levels and hepatocellular carcinoma (HCC) risk remains unclear. To fill this gap, we aimed to establish a target value of ALT level during NA treatment. METHODS: In total, 413 patients with chronic hepatitis B who received entecavir, tenofovir alafenamide, or tenofovir disoproxil fumarate were enrolled. The subsequent development of HCC was examined and a target value of ALT level during NA treatment as a risk marker for HCC was evaluated. RESULTS: The median follow-up duration was 5.1 years, during which time 27 patients (8.6%) developed HCC. ALT level at the start of treatment was not associated with HCC development (p = 0.08). When stratified by ALT at 1 year after NA initiation, the cumulative 3- and 5-year rates of HCC for patients with ALT ≥21 IU/L were 11.5% and 18.1%, and those with ALT <21 IU/L was 2.3% and 6.5%, respectively. Patients with ALT <21 IU/L had a significantly lower risk of HCC development compared with patients with ALT ≥21 IU/L (p = 0.002). In multivariable analysis adjusting age, sex, and platelet counts, ALT ≥21 IU/L was an independent risk factor of HCC development with hazard ratio of 4.5 (95% confidence interval: 1.01-20.4). CONCLUSIONS: ALT <21 IU/L at 1 year after NA initiation has a lower risk of HCC and could be used as a target value for NA treatment.