Role of Epiregulin on Lipopolysaccharide-Induced Hepatocarcinogenesis as a Mediator via EGFR Signaling in the Cancer Microenvironment.

Lipopolysaccharides (LPSs) have been reported to be important factors in promoting the progression of hepatocellular carcinoma (HCC), but the corresponding molecular mechanisms remain to be elucidated. We hypothesize that epiregulin (EREG), an epidermal growth factor (EGF) family member derived from hepatic stellate cells (HSCs) and activated by LPS stimulation, is a crucial mediator of HCC progression with epidermal growth factor receptor (EGFR) expression in the tumor microenvironment. We used a mouse xenograft model of Huh7 cells mixed with half the number of LX-2 cells, with/without intraperitoneal LPS injection, to elucidate the role of EREG in LPS-induced HCC. In the mouse model, LPS administration significantly enlarged the size of xenografted tumors and elevated the expression of EREG in tumor tissues compared with those in negative controls. Moreover, CD34 immunostaining and the gene expressions of angiogenic markers by a reverse transcription polymerase chain reaction revealed higher vascularization, with increased interleukin-8 (IL-8) expression in the tumors of the mice group treated with LPS compared to those without LPS. Our data collectively suggested that EREG plays an important role in the cancer microenvironment under the influence of LPS to increase not only the tumor cell growth and migration/invasion of EGFR-positive HCC cells but also tumor neovascularization via IL-8 signaling.

ADAMTS-13: A Prognostic Biomarker for Portal Vein Thrombosis in Japanese Patients with Liver Cirrhosis.

Portal vein thrombosis (PVT), one of the most prevalent hepatic vascular conditions in patients with liver cirrhosis (LC), is associated with high mortality rates. An imbalance between a disintegrin-like metalloproteinase with thrombospondin type-1 motifs 13 (ADAMTS-13) enzyme and von Willebrand factor (VWF) is responsible for hypercoagulability, including spontaneous thrombus formation in blood vessels. Herein, we aimed to identify potential prognostic and diagnostic biomarkers in Japanese patients with LC and PVT. In total, 345 patients were divided into two groups: 40 patients who developed PVT (PVT group) and 305 who did not develop PVT (NPVT group). Among the 345 patients with LC, 81% (279/345) were deemed ineligible due to the presence of preventive comorbidities, active or recent malignancies, and organ dysfunction. The remaining 66 patients were divided into two groups: the PVT group (n = 33) and the NPVT group (n = 33). Plasma ADAMTS-13 activity (ADAMTS-13:AC) and the vWF antigen (VWF:Ag) were measured using enzyme-linked immunosorbent assays. Contrast-enhanced, three-dimensional helical computed tomography (CT) was used to detect and characterize PVT. ADAMTS-13:AC was significantly lower in the PVT group than in the NPVT group. No significant differences in plasma vWF:Ag or liver stiffness were observed between the two groups. ADAMTS-13:AC of <18.8 was an independent risk factor for PVT on multivariate analyses (odds ratio: 1.67, 95% confidence interval: 1.21-3.00, p < 0.002). The receiver operating characteristic analysis of ADAMTS-13:AC revealed an area under the curve of 0.913 in PVT detection. Patients with PVT having ADAMTS-13:AC ≥18.8 (n = 17) had higher albumin levels and better prognoses than those with ADAMTS-13:AC <18.8 (n = 16). No significant correlations of ADAMTS-13:AC levels with either fibrin degradation product or D-dimer levels were observed. ADAMTS-13:AC levels could be potential diagnostic and prognostic biomarkers for PVT in Japanese patients with LC.

Improvement of liver histology in hepatic sarcoidosis due to treatment with corticosteroids and ursodeoxycholic acid: a case report.

We report the case of a 48-year-old male with a history of pulmonary and ocular sarcoidosis. Non-caseating granulomas, identified histologically, are the most characteristic manifestation of sarcoidosis. Hepatic sarcoidosis is difficult to diagnose using radiological imaging. In the patient reported in this study, ultrasound and contrast-enhanced computed tomography scans identified multiple intra-abdominal lymphadenopathies, with evidence of liver and splenic infiltrations. The first liver biopsy revealed non-caseating granulomatous hepatitis consistent with hepatic sarcoidosis. The patient was treated with ursodeoxycholic acid (UDCA), but his laboratory parameters did not improve. Prednisone was initiated at a dose of 30 mg daily and slowly tapered. At a dose of 12.5 mg daily, marked improvements in the fibrotic and sarcoid-like lesions were noted at the second biopsy. A third biopsy was performed, with the patient on a prednisone taper of 5 mg/day showed mild fibrous expansion in the portal tracts and mild parenchymal necro-inflammatory lesions. However, overall, fibrosis marker levels remained stable over the course of treatment. A fourth biopsy was performed after a 5-year course of 5 mg/day prednisone. This revealed minimal lobular inflammation without fibrosis. Thus, treatment of this patient with corticosteroids and UDCA resulted in marked improvements in his biochemical and histological parameters.

VWF/ADAMTS13 Ratio as a Potential Predictive Biomarker for Acute Kidney Injury Onset in Cirrhosis.

AIM: We investigated the von Willebrand factor to ADAMTS13 ratio (von Willebrand factor [VWF]:Ag/ADAMTS13:AC) as a potential biomarker for the outcomes of acute kidney injury (AKI) in liver cirrhosis (LC). METHODS: This retrospective cross-sectional study included patients with LC who developed AKI (AKI group: n = 91) and patients with LC who did not develop AKI [non-AKI (NAKI) group, n = 91] as a control group. Plasma levels of the von Willebrand factor antigen (Ag) and ADAMTS13 activity (AC) were measured in patients with AKI or NAKI. Moreover, risk factors for onset of AKI, AKI-associated 90-day mortality, and poor AKI treatment response were identified. RESULTS: The AKI group had a significantly higher VWF:Ag/ADAMTS13:AC than the NAKI group. Values of VWF:Ag/ADAMTS13:AC ≥ 5.7 were identified as risk factors for AKI onset in patients with LC (odds ratio [OR] 2.56; 95% CI 1.26-4.99; p < 0.001). Among patients with AKI, values of VWF:Ag/ADAMTS13:AC ≥ 9.0 were identified as risk factors for 90-day mortality (OR 6.83; 95% CI 2.32-20.10; p < 0.001). Cumulative survival was significantly lower in those with high (≥ 9.0) than in those with low (< 9.0) VWF:Ag/ADAMTS13:AC. Furthermore, values of VWF:Ag/ADAMTS13:AC ≥ 7.4 were identified as risk factors for poor treatment response (OR 4.2; 95% CI 1.39-12.70; p < 0.001). The treatment response rates were significantly higher in those with low (< 7.4) VWF:Ag/ADAMTS13:AC than in those with high (≥ 7.4) VWF:Ag/ADAMTS13:AC. CONCLUSION: VWF:Ag/ADAMTS13:AC potentially predicts the onset, prognosis, and treatment response of AKI in patients with LC.

Zinc Supplementation and an Improved Quality of Life in Patients with Autoimmune Hepatitis.

Objecive Patients with autoimmune hepatitis (AIH) reportedly have an impaired quality of life (QOL), mainly due to depression, even during remission. In addition, hypozincaemia has been demonstrated in patients with chronic liver disease, including AIH, and is known to be related to depression. Corticosteroids are known to cause mental instability. We therefore investigated the longitudinal association between zinc supplementation and changes in the mental status among AIH patients treated with corticosteroids. Materials This study enrolled 26 patients with serological remission of AIH routinely treated at our facility after excluding 15 patients who either discontinued polaprezinc (150 mg/day) within 24 months or interrupted treatment. Two questionnaires, the Chronic Liver Disease Questionnaire (CLDQ) and SF-36, were adopted to evaluate the QOL before and after zinc supplementation. Results Serum zinc levels were significantly elevated after zinc supplementation (p<0.0001). The CLDQ worry subscale significantly improved after zinc supplementation (p=0.017), but none of the SF-36 subscales was affected. Multivariate analyses demonstrated that daily prednisolone dosing was inversely related to both the CLDQ worry domain score (p=0.036) and the SF-36 mental health component (p=0.031). There was a significant negative correlation between the changes in the daily steroid dose and the CLDQ worry domain scores before and after zinc supplementation (p=0.006). No serious adverse events occurred during the observation period. Conclusion Zinc supplementation safely and efficiently improved mental impairment, possibly caused by continuous treatment with corticosteroids, in patients with AIH.

Concurrent Ulcerative Colitis in a Pregnant Patient with Rheumatoid Arthritis.

We herein report a rare concurrent case of ulcerative colitis (UC) in a pregnant woman with rheumatoid arthritis (RA), which was well managed by biologics. When a 32-year-old woman with seropositive RA became pregnant, she began experiencing hematochezia; colonoscopy revealed diffuse inflammation with multiple ulcers. Based on clinical examinations and pathological assessments, she was diagnosed with severe UC. Although prednisolone had no curative effect and infliximab caused an infusion reaction, golimumab successfully induced remission with normal delivery. This case report describes the successful treatment of a pregnant woman with UC and RA through biologics administration.

Effects of entecavir and tenofovir alafenamide fumarate treatment on renal function in Japanese elderly patients with chronic hepatitis B.

AIM: Entecavir (ETV) and tenofovir alafenamide fumarate (TAF) are considered safe nucleoside/nucleotide analogs (NA) for the kidney. This study aimed to investigate the long-term effects of ETV or TAF on renal function in elderly patients with chronic hepatitis B (CHB) in Japan. METHODS: The study included 246 CHB patients treated with ETV (184 patients) or TAF (62 patients) for at least 2 years. These patients were divided into two groups: those <65 years of age (130 patients) and those ≥65 years of age (116 patients). The effects of the NAs on renal functions were examined by comparing the estimated glomerular filtration rates (eGFR) from baseline to 2 years between the two groups. RESULTS: The change in eGFR from baseline to 1 or 2 years after treatment was significantly decreased in both groups. However, the amount of change at 1 and 2 years was significantly greater in the group aged ≥65 years than in the group aged <65 years. The amount of change in eGFR from baseline to 1 and 2 years after treatment was significantly greater in the group aged ≥65 years than in the group aged <65 years, regardless of the type of NA, the prior treatment history, cirrhosis/chronic hepatitis, hypertension, dyslipidemia, and diabetes. Additionally, logistic regression analysis showed that age ≥65 years was independently associated with a decreased eGFR after 2 years of NA treatment. CONCLUSIONS: Long-term administration of NA to CHB patients over 65 years of age should be carefully monitored for renal impairment.

Vitamin D deficiency exacerbates alcohol-related liver injury via gut barrier disruption and hepatic overload of endotoxin.

Endogenous lipopolysaccharide (LPS) that translocates via the disrupted intestinal barrier plays an essential role in the progression of alcohol-related liver disease (ALD). Vitamin D deficiency is observed in ALD, and it participates in regulating gut barrier function. The current study aimed to examine the association between vitamin D deficiency and endotoxemia in patients with ALD-related cirrhosis. Moreover, the effect of vitamin D deficiency on ethanol (EtOH)- and carbon tetrachloride (CCl4)-induced liver injury relevant to gut barrier disruption in mice was investigated. Patients with ALD-related cirrhosis (Child-Pugh Class A/B/C; n=56/15/7) had lower 25(OH)D levels and higher endotoxin activities than non-drinking healthy controls (n=19). The serum 25(OH)D levels were found to be negatively correlated with endotoxin activity (R=-0.481, P<.0001). The EtOH/CCl4-treated mice developed hepatic inflammation and fibrosis, which were significantly enhanced by vitamin D-deficient diet. Vitamin D deficiency enhanced gut hyperpermeability by inhibiting the intestinal expressions of tight junction proteins including ZO-1, occludin, and claudin-2/5/12/15 in the EtOH/CCl4-treated mice. Consequently, it promoted the accumulation of lipid peroxidases, increased the expression of NADPH oxidases, and induced Kupffer cell infiltration and LPS/toll-like receptor 4 signaling-mediated proinflammatory response. Based on the in vitro assay, vitamin D-mediated vitamin D receptor activation inhibited EtOH-stimulated paracellular permeability and the downregulation of tight junction proteins via the upregulation of caudal-type homeobox 1 in Caco-2 cells. Hence, vitamin D deficiency exacerbates the pathogenesis of ALD via gut barrier disruption and hepatic overload of LPS.

Hemoglobin and Endotoxin Levels Predict Sarcopenia Occurrence in Patients with Alcoholic Cirrhosis.

Alcohol is a major risk factor of liver cirrhosis (LC). This study aimed to elucidate a surrogate marker of sarcopenia in patients with LC of different etiology. Out of 775 patients with LC, 451 were assessed for handgrip strength and skeletal muscle mass (by computed tomography). They were then divided into two groups: alcoholic cirrhosis (AC; n = 149) and nonalcoholic cirrhosis (NAC; n = 302). Endotoxin activity (EA) levels were measured with an EA assay. Group AC showed significantly higher platelet counts (p = 0.027) and lower blood urea nitrogen levels and fibrosis-4 index than group NAC (p = 0.0020 and p = 0.038, respectively). The risk factors of sarcopenia were age ≥ 65 years, female sex, CP-C LC, Hb levels < 12 g/dL, and EA level > 0.4 in all patients with LC; hemoglobin (Hb) levels < 12 g/dL and EA level > 0.4 in group AC; and age ≥ 65 years, CP-C LC, and Hb levels < 12 g/dL in group NAC. The prediction accuracy of Hb for sarcopenia in group AC, group NAC, and all patients was 83.6%, 75.9%, and 78.1% (sensitivity: 92.0%, 69.0%, and 80.2%; specificity: 66.4%, 71.0%, and 64.0%), respectively. Although not significant, the predictive performance was better when using the combination of Hb and EA measurements than when using Hb alone in group AC but was comparable in all patients. Hb levels can predict sarcopenia in patients with LC, but in those with AC, the combination of Hb and EA improves the prediction performance.

Efficacy of Serum Ferritin-Zinc Ratio for Predicting Advanced Liver Fibrosis in Patients with Autoimmune Hepatitis.

Background/Aims: The search for noninvasive biomarkers that can efficiently estimate the extent of liver fibrosis progression is ongoing. Although Fibrosis-4 (FIB-4), the aspartate transaminase-to-platelet ratio index (APRI), and the Forns index have been reported as useful biomarkers, their investigation in autoimmune hepatitis (AIH) is limited. This study aimed to examine the usefulness of these serological indices and a newly developed index in predicting liver fibrosis progression in AIH. Methods: The study analyzed data from 190 patients diagnosed with AIH at our institution between 1990 and 2015. Their histological liver fibrosis progression and clinical long-term prognosis were evaluated retrospectively (cohort 1). In 90 patients, receiver operating characteristic (ROC) curves were compared to choose severe fibrosis cases with respect to existing indices (FIB-4, APRI, and Forns index) and the ferritin-zinc ratio (cohort 2). Results: In cohort 1, liver-related death and hepatocellular carcinoma rates were significantly higher in the severe (n = 27) than in the mild (n = 63) fibrosis group (p = 0.0001 and 0.0191, respectively). In cohort 2, liver-related death in the severe fibrosis group was significantly frequent (p = 0.0071), and their ferritin-zinc ratio was higher (median 2.41 vs. 0.62, p = 0.0011). ROC analyses were performed to compare the ability of the ferritin-zinc ratio, FIB-4, APRI, and the Forns index to predict severe and mild fibrosis. Accordingly, areas under the ROC were 0.732, 0.740, 0.721, and 0.729, respectively. Conclusions: The serum ferritin-zinc ratio can noninvasively predict liver fibrosis progression in AIH and be applied to predict long-term prognosis.

Aspartate aminotransferase to platelet ratio index has utility as a biomarker of COVID-19 severity in patients with nonalcoholic fatty liver disease.

AIM: Patients with nonalcoholic fatty liver disease (NAFLD) are reported to have greater coronavirus disease 2019 (COVID-19) severity compared with patients without NAFLD. Previous studies have reported that noninvasive liver fibrosis scores, including the Fibrosis-4 index, NAFLD fibrosis score, and aspartate aminotransferase to platelet ratio index (APRI), have utility in predicting COVID-19 mortality and disease severity in patients without NAFLD. However, the utility of liver fibrosis scores in predicting COVID-19 mortality and disease severity among patients with NAFLD infected with SARS-CoV-2 has yet to be evaluated. METHODS: This retrospective observational study comprised 126 patients with NAFLD and active SARS-CoV-2 infection. Patients were classified into low COVID-19 severity (mild or moderate I disease) and high COVID-19 severity (moderate II or severe disease) groups based on the therapeutic guideline implemented by the Ministry of Health, Labor, and Welfare of Japan. RESULTS: Of the 126 patients, only one had been diagnosed with NAFLD before admission. Age; levels of serum aspartate aminotransferase, γ-glutamyl transpeptidase, lactate dehydrogenase, blood urea nitrogen, and serum C-reactive protein; Fibrosis-4 index; NAFLD fibrosis score; and APRI levels on admission were higher in the high COVID-19 severity group compared with the low COVID-19 severity group. Serum albumin levels, platelet counts, and lymphocyte counts on admission were lower in the high COVID-19 severity group compared with the low COVID-19 severity group. Univariate and multivariate analysis revealed that APRI values were significantly associated with COVID-19 severity and hospitalization duration for COVID-19. CONCLUSIONS: APRI was independently associated with COVID-19 severity and hospitalization duration for COVID-19 in patients with NAFLD.

Severe superior mesenteric vein thrombosis after COVID-19 mRNA vaccination.

Venous thrombosis is a rare occurrence following the administration of the COVID-19 mRNA vaccine. The occurrence of superior mesenteric vein (SMV) is even more rare. SMV thrombosis should be considered as a differential diagnosis in patients who develop abdominal pain after COVID-19 mRNA vaccination.

Hemoglobin levels as a surrogate marker of sarcopenia in patients with liver cirrhosis.

AIM: This study aimed to elucidate a surrogate marker of sarcopenia in patients with liver cirrhosis (LC). METHODS: A total of 424 patients were assessed for handgrip strength (HGS) and skeletal muscle index (SMI). They were divided into two groups: sarcopenia (Group S; n = 80) and nonsarcopenia (Group NS; n = 344). RESULTS: Group S showed significantly lower HGS, SMI, and hemoglobin (Hb) levels in males and female patients, and lower serum levels of albumin, cholinesterase, and zinc (all p < 0.001), along with significantly higher serum levels of procollagen type III-N-peptide and type IV collagen 7S-domain (p < 0.001 and p < 0.0017) than Group NS. The risk factors for sarcopenia were age 65 years or older, female gender, Child-Pugh class C, and Hb levels <10.9 g/dL in women and <12.4 g/dL in men (p = 0.012, p < 0.001, p = 0.031, and p < 0.001, respectively). Significant positive correlations were found between the Hb level and the SMI and HGS (r = 0.4, p < 0.001 and r = 0.4, p < 0.001, respectively). Sarcopenia, low HGS, and low SMI were significantly associated with overall survival in patients with LC (all p < 0.001). The predictive accuracy of Hb levels for predicting sarcopenia was significantly higher than for predicting SMI and tended to be higher than for predicting HGS (p = 0.014 and p = 0.059, respectively). CONCLUSION: Hemoglobin levels are predictive of sarcopenia in patients with LC and warrants further investigation as a biomarker for sarcopenia in LC.

Changes in Coagulation and Fibrinolytic Factors in Patients With Cirrhotic Refractory Ascites Undergoing Cell-free and Concentrated Ascites Reinfusion Therapy: A Retrospective Observational Study in Japan.

BACKGROUND/AIM: The management of refractory ascites is critical for the treatment of patients with decompensated cirrhosis. This study aimed to evaluate the feasibility and safety of cell-free and concentrated ascites reinfusion therapy (CART) in patients with cirrhosis and refractory ascites, with a focus on changes in coagulation and fibrinolytic factors in ascitic fluid following CART. PATIENTS AND METHODS: This was a retrospective cohort study including 23 patients with refractory ascites undergoing CART. Serum endotoxin activity (EA) before and after CART and the levels of coagulation and fibrinolytic factors and proinflammatory cytokines in original and processed ascitic fluid were measured. The Ascites Symptom Inventory-7 (ASI-7) scale was used for subjective symptom assessment before and after CART. RESULTS: Body weight and waist circumference significantly decreased after CART, whereas serum EA did not significantly change after CART. Similar to the previous reports, ascitic fluid concentrations of total protein, albumin, high-density lipoprotein cholesterol, γ-globulin, and immunoglobulin G levels were significantly increased after CART; mild elevations in body temperature and interleukin 6 and tumor necrosis factor-alpha levels in ascitic fluid were also observed. Importantly, the levels of antithrombin-III, factor VII, and X, which are useful for patients with decompensated cirrhosis, were markedly increased in the reinfused fluid during CART. Finally, the total ASI-7 score was significantly lower following CART, compared with the pre-CART score. CONCLUSION: CART is an effective and safe approach for the treatment of refractory ascites that allows the intravenous reinfusion of coagulation and fibrinolytic factors in the filtered and concentrated ascites.

The Ratio of von Willebrand Factor Antigen to ADAMTS13 Activity: Usefulness as a Prognostic Biomarker in Acute-on-Chronic Liver Failure.

Acute-on-chronic liver failure (ACLF) has a high risk of short-term mortality. A disintegrin-like and metalloproteinase with thrombospondin type-1 motifs 13 (ADAMTS13) is a metalloproteinase that specifically cleaves multimeric von Willebrand factor (VWF). Imbalance between ADAMTS13 and VWF is associated with portal hypertension, which induces ACLF development. A previous study reported that ADAMTS13 activity (ADAMTS13:AC) and VWF antigen (VWF:Ag) are predictive biomarkers of ACLF development in patients with cirrhosis. This study investigated the changes in ADAMTS13:AC and VWF:Ag levels from before to after the development of ACLF to determine their usefulness as a prognostic biomarker in patients with ACLF. In total, 101 patients with cirrhosis were enrolled in this study. The level of ADAMTS13:AC and VWF:Ag was determined by an enzyme-linked immunosorbent assay. Cox proportional hazard regression analysis was conducted to determine independent prognostic factors for patients with liver cirrhosis in the post-ACLF group. ADAMTS13:AC levels gradually decreased in the order of non-ACLF group, pre-ACLF group, and finally post-ACLF group. VWF:Ag and the ratio of VWF:Ag to ADAMTS13:AC (VWF:Ag/ADAMTS13:AC) levels gradually increased in the order of non-ACLF group, pre-ACLF group, followed by post-ACLF group. VWF:Ag/ADAMTS13:AC and CLIF-C ACLF scores were associated with prognosis in the post-ACLF group in multivariate analysis. The cumulative survival of the post-ACLF group was significantly lower for patients with high VWF:Ag/ADAMTS13:AC (>9) compared with those with low VWF:Ag/ADAMTS13:AC (≤9) (HR: 10.72, 95% confidence interval: 1.39-82.78, p < 0.05). The VWF:Ag/ADAMTS13:AC increased according to the progression of ACLF in patients with cirrhosis and predicted prognosis in patients with cirrhosis with ACLF.

Cell-free and concentrated ascites reinfusion therapy versus large-volume paracentesis for the treatment of cirrhotic patients with refractory ascites: A multicenter prospective observational study.

AIM: Cell-free and concentrated ascites reinfusion therapy (CART) and large-volume paracentesis (LVP) with albumin infusion are useful for managing refractory ascites (RA). However, it remains unclear which therapy is more effective in patients with cirrhosis with RA. METHODS: From June 2018 to March 2022, 25 patients with RA treated with CART or LVP with albumin infusion were enrolled in this multicenter prospective observational study to investigate the number of abdominal paracenteses, albumin preparations used, and drainage volume during an 8-week observation period. RESULTS: Among all patients at entry (median age, 63 years; 52% men; 60% Child-Pugh B and 40% Child-Pugh C), 92% were treated with furosemide (median, 20 mg/day), 92% with spironolactone (25 mg/day), and all with tolvaptan (7.5 mg/day). Patients with RA had a poor health-related quality of life (HRQOL) and prominent ascites-related symptoms. Four of the 20 eligible patients were treated with CART, 11 with LVP with albumin infusion, and five with their combination. The median number of paracenteses, total drainage volume, and albumin infusions were 1.5, 7.4 L, and 0, respectively, in the CART group; 5.0, 22.0 L, and 5.0, respectively, in the LVP group; and 5.0, 30.0 L, and 5.0, respectively in their combination group. The treatment effects did not differ significantly among the three groups regarding weight loss, liver function, renal function, electrolytes, and HRQOL. However, patients treated with CART had fewer paracenteses and albumin infusions than those treated with LVP. CONCLUSIONS: CART and LVP have comparable therapeutic efficacy for RA in patients with cirrhosis.

Diagnostic yield of liquid-based cytology in serial pancreatic juice aspiration cytological examination.

Objectives: Serial pancreatic juice aspiration cytological examination (SPACE) via endoscopic retrograde cholangiopancreatography is a useful diagnostic method for early-stage pancreatic cancer, such as carcinoma in situ that are difficult to diagnose by endoscopic ultrasound-guided fine needle aspiration (EUS-FNA). However, the diagnostic accuracy of SPACE is low, which is attributed to problems regarding specimen treatment. Hence, we evaluated the diagnostic efficacy of liquid-based cytology (LBC) in pancreatic juice cytology for pancreatic cancer. Methods: We retrospectively analyzed 24 patients with suspected pancreatic cancer that was difficult to diagnose by endoscopic ultrasound-guided fine needle aspiration who underwent SPACE using LBC between April 2017 and April 2021. Results: The most common reason for performing SPACE was localized stenosis of the main pancreatic duct without a mass. Eleven patients were diagnosed with malignancy after surgical resection, nine of whom had pancreatic ductal adenocarcinoma. Ten patients were diagnosed as benign after a follow-up of more than 1 year. The nine cases of malignancy were diagnosed before surgical resection by SPACE using LBC, with a sensitivity of 81.8% and specificity of 100%. The overall diagnostic accuracy was 91.7%. A total of 152 LBC examinations were performed via SPACE, with an adequate sample collection rate of 88.9%. No adverse events, including acute pancreatitis, occurred after endoscopic retrograde cholangiopancreatography. Conclusion: SPACE with LBC offers good diagnostic efficacy in patients with pancreatic cancer that is difficult to diagnose by endoscopic ultrasound-guided fine needle aspiration.

Leaky Gut and Severe Adverse Events in Advanced Hepatocellular Carcinoma Treated With Lenvatinib.

BACKGROUND/AIM: To identify predictors of severe adverse events (≥grade 3) in patients with advanced hepatocellular carcinoma treated with lenvatinib. PATIENTS AND METHODS: Of 41 patients, 25 and 16 were stratified into the severe and non-severe adverse events groups, respectively. Of these, 19 formed a lactulose-mannitol test subgroup, which was divided into severe adverse events (n=11) and non-severe adverse events (n=8) groups. Severe adverse events were assessed by liver disease etiology and modified albumin-bilirubin grade. Intestinal permeability by lactulose-mannitol test and serum soluble CD163, soluble mannose receptor, and zonulin levels. RESULTS: Severe adverse event incidence rates were higher in patients with advanced hepatocellular carcinoma related to alcoholic liver disease and nonalcoholic fatty-liver disease than in those with advanced hepatocellular carcinoma of other etiologies (p=0.014). The rates were higher for modified albumin-bilirubin grades 2a and 2b compared to modified albumin-bilirubin grade 1 (p=0.0104). Zonulin levels were higher in the severe adverse event group (p=0.0331) and were independently associated with severe adverse events (odds ratio=140, 95% confidence interval=1.66-11800; p=0.029). Patients with high zonulin levels (≥0.518 ng/ml) experienced more severe adverse events than those with low levels (<0.518 ng/ml) (p=0.0137). In the lactulose-mannitol test subgroup, the urine lactulose:mannitol ratio was higher in the severe vs. non-severe adverse event group (p=0.0164). Moreover, it was higher in patients with alcoholic liver disease and nonalcoholic fatty-liver disease-related advanced hepatocellular carcinoma compared to those with other advanced hepatocellular carcinoma etiologies (p=0.0108). CONCLUSION: Serum zonulin levels predict severe adverse events in patients with advanced hepatocellular carcinoma treated with lenvatinib.

Initial Experience With Atezolizumab Plus Bevacizumab for Unresectable Hepatocellular Carcinoma: A Real-world Retrospective Study.

BACKGROUND/AIM: The current study evaluated the efficacy and toxicity of atezolizumab plus bevacizumab in patients with advanced-stage hepatocellular carcinoma in a real-world setting. PATIENTS AND METHODS: This retrospective study enrolled 23 patients. The primary endpoint was progression-free survival (PFS). Antitumor responses 6 weeks after initiation of atezolizumab plus bevacizumab were assessed using the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 and the modified RECIST (mRECIST). The Common Terminology Criteria for Adverse Events version 5.0 was used to evaluate the severity of adverse events. Relative changes in hepatic function and nutritional status were investigated. RESULTS: The median PFS was 119 days. The objective response rate (ORR) and disease control rate (DCR) at 6 weeks based on RECIST were 21.7% and 60.9%, respectively. The ORR and DCR based on mRECIST were 26.1% and 69.6%, respectively. The group with hepatitis B/C-related HCC had a higher ORR based on mRECIST than the non-hepatitis B and C-related group. Patients with Barcelona Clinic Liver Cancer (BCLC) stage A and B disease had a higher DCR based on RECIST than those with BCLC stage C disease. The incidence rates of any grade and grade ≥3 adverse events were 65.2% and 21.7%, respectively. The albumin-bilirubin and Child-Pugh scores, neutrophil-to-lymphocyte ratio and skeletal muscle index did not significantly worsen within 6 weeks after treatment initiation. CONCLUSION: Atezolizumab plus bevacizumab is effective and safe and can help achieve complete remission in patients with advanced-stage hepatocellular carcinoma in a real-world setting. Nevertheless, large-scale studies must be conducted to validate its outcomes in this patient group.

Macrophage Activation Markers Predict Liver-Related Complications in Primary Biliary Cholangitis.

Primary biliary cholangitis (PBC) has a wide variation in clinical presentation and course. There is no significant correlation between these symptoms and the disease stage, although patients with more advanced stages generally have more symptoms. It is important to develop biomarkers in order to identify patients with an increased risk of complications and end-stage liver disease. This study investigated surrogate markers for risk estimation of PBC-related complications, including a study population of 77 patients with PBC who underwent liver biopsy and were measured for serum levels of macrophage activation markers, soluble CD163 (sCD163), soluble mannose receptor (sMR), and zonulin. Patients with PBC were divided into symptomatic (Group S, n = 20) and asymptomatic (Group A, n = 57) groups. The correlations of histological stages based on both Scheuer and Nakanuma classifications with the three serum markers were investigated. The Nakanuma classification involves grading for liver fibrosis and bile duct loss. The three biomarkers were assessed for their diagnostic ability to identify patients with PBC having high risk of developing complications. The predictive factors of these complications were examined as well. Group S had significantly higher serum sMR (p = 0.011) and sCD163 (p = 0.048) levels versus Group A. A composite index of sMR and sCD163 measurements had significantly better prediction performance than sCD163 alone (p = 0.012), although not when compared to sMR alone (p = 0.129). Serum sMR was an independent factor for developing complications on both univariate (Odds ratio (OR) = 30.20, 95% confidence interval (95% CI): 3.410−267.0, p = 0.00220), and multivariate (OR = 33.70, 95% CI: 3.6600−311.0, p = 0.0019) analyses. Patients with PBC having sMR of ≥56.6 had a higher incidence of clinical complications versus those with a sMR of <56.6. Serum sMR predicts the development of complications in patients with PBC. sMR plus sCD163 showed better predictive power than either marker alone, although the addition of sCD163 did not improve the predictive power of sMR. Future prospective studies are required in order to validate the findings of the present study.