Poorly Differentiated Hepatocellular Carcinoma Cells Avoid Apoptosis by Interacting with T Cells via CD40-CD40 Ligand Linkage.

Hepatocellular carcinoma (HCC) is associated with increased soluble CD40 levels. This study aimed to investigate CD40's role in liver tumor progression. CD40 levels were examined in HCC patient tissues and various HCC cell lines, and their interaction with CD4+T cells was studied. RNA sequencing analysis was performed to explore the mechanisms of CD40 induction. Poorly differentiated HCC tumor tissues exhibited high membrane-bound CD40 expression, in contrast to nontumor areas. Poorly differentiated HCC cell lines showed high expression of membrane-bound CD40 with low CD40 promoter methylation, which was the opposite of that observed in the well-differentiated HCC cell lines. Solely modulating CD40 expression in HCC cells exerted no direct consequences on cell growth or appearance. Interestingly, the human hepatoma cell line HLF co-cultured with activated (CD40 ligand+) CD4+ T cells had increased CD40 levels and a modest 3.2% dead cells. The percentage of dead cells increased to 10.9% and underwent preneutralizing CD40 condition, whereas preblocking both CD40 and integrin α5ß1 concomitantly caused only 1.9% cell death. RNA sequencing of co-cultured HLFs with activated CD4+ T cells revealed the up-regulation of interferon and immune-response pathways. Increased interferon-γ levels in the activated T-cell media stimulated the Janus kinase/signal transducer and activator of transcription 3 pathway, resulting in increased CD40 expression in HLF. Collectively, CD40 expression in poorly differentiated HCC cells prevented cell death by interacting with CD40 ligand in activated T cells. Targeting CD40 may represent a promising anticancer therapy.

Hepatitis B surface antigen glycan isomer is a predictor of the development of hepatocellular carcinoma during nucleoside/nucleotide analog therapy.

AIM: A recombinant monoclonal antibody against the hepatitis B surface antigen glycan isomer (HBsAgGi) was newly developed using the O-glycosylated PreS2 peptide in M-HBsAg of hepatitis B virus (HBV) genotype C. However, the association between HBsAgGi and the development of hepatocellular carcinoma (HCC) during nucleoside/nucleotide analog (NA) therapy remains unknown. METHODS: A total of 112 HBV genotype C-infected patients who were treated with NA were included in this study. We assessed the association between HBV markers, including HBsAgGi and other conventional markers, and the development of HCC during NA therapy. RESULTS: Ten patients developed HCC during the follow-up period. Of the HBV markers, HBsAg (≤3.53 log IU/mL; p = 0.047), HBsAgGi/HBsAg ratio (≥1.10; p = 0.035), and HBV DNA (≤6.3 log copies/mL; p = 0.012) at baseline and HBsAg (≤3.19 log IU/mL; p = 0.033) and HBsAgGi/HBsAg ratio (≥1.09; p = 0.003) at 48 weeks after NA therapy were significantly associated with the development of HCC according to the log rank test. In contrast, no significant association was observed between HBsAgGi and the development of HCC. Multivariate analysis revealed that a platelet count at baseline ≤88 × 103/mm3 (p = 0.026; hazard ratio [HR], 10.577) and an HBsAgGi/HBsAg ratio at 48 weeks after NA therapy ≥1.09 (p = 0.040; HR, 10.099) were independently and significantly associated with the development of HCC. CONCLUSIONS: Our findings suggest that a combination of on-treatment HBsAgGi and HBsAg predicts the development of HCC during NA therapy.

Impact of frailty on long-term outcomes after liver resection for hepatocellular carcinoma in elderly patients: A prospective study.

BACKGROUND: sFrailty affects short-term outcomes after liver resection in elderly patients. However, frailty's effects on long-term outcomes after liver resection in elderly patients with hepatocellular carcinoma (HCC) are unknown. METHODS: This prospective, single-center study included 81 independently living patients aged ≥65 years scheduled to undergo liver resection for initial HCC. Frailty was evaluated according to the Kihon Checklist, a phenotypic frailty index." We investigated and compared postoperative long-term outcomes after liver resection between patients with and without frailty. RESULTS: Of the 81 patients, 25 (30.9%) were frail. The proportion of patients with cirrhosis, high serum alpha-fetoprotein level (≥200 ng/mL), and poorly differentiated HCC was higher in the frail group than in the nonfrail group (n = 56). Among the patients with postoperative recurrence, the incidence of extrahepatic recurrence was higher in the frail group than in the nonfrail group (30.8% vs. 3.6%, P = 0.028). Moreover, the proportion of patients who underwent repeat liver resection and ablation for recurrence who met the Milan criteria tended to be lower in the frail group than in the nonfrail group. Although there was no difference in disease-free survival between the two groups, the overall survival rate in the frail group was significantly worse than that in the nonfrail group (5-year overall survival: 42.7% vs. 77.2%, P = 0.005). Results of the multivariate analysis indicated that frailty and blood loss were independent prognostic factors for postoperative survival. CONCLUSION: Frailty is associated with unfavorable long-term outcomes after liver resection in elderly patients with HCC.

Transcatheter Arterial Chemoembolization for Treatment-Naive Hepatocellular Carcinoma Has Different Treatment Effects Depending on Central or Peripheral Tumor Location.

Introduction: The purpose of this study was to evaluate the treatment efficacy of transcatheter arterial chemoembolization (TACE) for treatment-naive hepatocellular carcinoma (HCC) according to tumor location and burden. Methods: Between 2010 and 2019, consecutive patients who underwent TACE as the first treatment were enrolled. Tumors were classified into two categories based on their location, as central or peripheral tumors. Tumors in the central zone, which is within 1 cm of the main trunk or the first branch of the portal vein, were classified as central tumors, while those located in the peripheral zone were classified as peripheral tumors. Patients were grouped according to the HCC location and up-to-7 criteria. Patients with central tumors were classified into the central arm and those with only peripheral tumors were classified into the peripheral arm. Patients within and beyond the up-to-7 criteria were classified into the up-to-7 in and up-to-7 out-groups, respectively. Local recurrence-free survival (LRFS) and progression-free survival (PFS) were compared per nodule (central tumor vs. peripheral tumor) and per patient (central arm vs. peripheral arm), respectively. The prognostic factors of LRFS and PFS were analyzed by univariate and multivariate analyses. Results: A total of 174 treatment-naive patients with 352 HCCs were retrospectively enrolled. Ninety-six patients and 130 lesions were selected by propensity score matching. Median LRFS was longer for peripheral tumors than central tumors (not reached vs. 3.3 months, p < 0.001). Median PFS was 17.1 months (8.3-24.9) in the peripheral arm and up-to-7 in, 7.0 months (3.3-12.7) in the peripheral arm and up-to-7 out, 8.4 months (4.0-12.6) in the central arm and up-to-7 in, and 3.0 months (1.2-4.9) in the central arm and up-to-7 out-groups. The peripheral arm and up-to-7 in-groups had significantly longer PFS than the other three groups (p = 0.013, p = 0.015, p < 0.001, respectively). Multivariate analysis confirmed that the central zone and central arm were associated with high adjusted hazard ratios for tumor recurrence or death (2.87, p < 0.001; 2.89, p < 0.001, respectively). Conclusion: Treatment-naive HCCs in the peripheral zone had a longer LRFS and PFS following TACE compared to those in the central zone.

Severity of Liver Fibrosis Is Associated with the Japanese Diet Pattern and Skeletal Muscle Mass in Patients with Nonalcoholic Fatty Liver Disease.

It is not fully clear as to which dietary patterns are associated with the pathogenesis of nonalcoholic fatty liver disease (NAFLD) in Asia. We conducted a cross-sectional study of 136 consecutively recruited patients with NAFLD (49% female, median age 60 years). Severity of liver fibrosis was assessed using the Agile 3+ score, a recently proposed system based on vibration-controlled transient elastography. Dietary status was assessed using the 12-component modified Japanese diet pattern index (mJDI12). Skeletal muscle mass was assessed by bioelectrical impedance. Factors associated with intermediate-high-risk Agile 3+ scores and skeletal muscle mass (75th percentile or higher) were analyzed by multivariable logistic regression. After adjustment for confounders, such as age and sex, the mJDI12 (OR: 0.77; 95% CI: 0.61, 0.99) and skeletal muscle mass (75th percentile or higher) (OR: 0.23; 95% CI: 0.07, 0.77) were significantly associated with intermediate-high-risk Agile 3+ scores. Soybeans and soybean foods were significantly associated with skeletal muscle mass (75th percentile or higher) (OR: 1.02; 95% CI: 1.00, 1.04). In conclusion, the Japanese diet pattern was associated with the severity of liver fibrosis in Japanese patients with NAFLD. Skeletal muscle mass was also associated with the severity of liver fibrosis, and intake of soybeans and soybean foods.

A case of hepatocellular carcinoma with "pseudoprogression" followed by complete response to atezolizumab plus bevacizumab.

Atezolizumab plus bevacizumab (Atezo + Bev) is the first immunotherapy for hepatocellular carcinoma (HCC), and in the current guidelines, it is positioned as the first-line chemotherapy for unresectable cases. Herein, we report a case of HCC with pseudoprogression followed by a complete response to Atezo + Bev. A 56 year-old man was diagnosed with intermediate-stage HCC, as defined by the Barcelona Clinic Liver Cancer system stage B. Computed tomography (CT) revealed multiple lesions in the liver without any extrahepatic lesions. First, he was treated with transcatheter arterial chemoembolization (TACE); however, multiple residual lesions were observed on CT scan 2 months after TACE. Therefore, treatment with Atezo + Bev was initiated 4 months after TACE. After the third administration of Atezo + Bev, a CT scan showed progressive disease in intrahepatic lesions, along with increased serum levels of tumor markers. Although TACE was planned again, Atezo + Bev was continued while the patient was waiting for hospitalization. After the fifth administration of Atezo + Bev, serum levels of tumor markers decreased to the normal range. Magnetic resonance imaging showed prominently reduced tumor size. Therefore, Atezo + Bev was continued, and after the eighth administration, the CT scan showed the disappearance of all the liver lesions, indicating a complete response. In immunotherapy, the therapeutic response can sometimes be obtained in an atypical pattern due to either an increase in tumor burden or the appearance of new lesions, called "pseudoprogression," which is rare in HCC.

Short-term hepatocyte function and portal hypertension outcomes of sofosbuvir/velpatasvir for decompensated hepatitis C-related cirrhosis.

BACKGROUND: It is unclear whether hepatocyte function and/or portal hypertension improves if a sustained virologic response (SVR) is achieved with direct-acting antivirals in patients with decompensated hepatitis C-related cirrhosis. METHODS: We examined the safety and efficacy of a 12-week course of sofosbuvir/velpatasvir (SOF/VEL) in 20 patients with decompensated hepatitis C-related cirrhosis. We also investigated changes in the hepatocyte receptor index (LHL15) and blood clearance index (HH15) by Tc-99 m-galactosyl human serum albumin scintigraphy, liver stiffness measurement (LSM) by transient elastography, and hepatic venous pressure gradient (HVPG) in patients who achieved an SVR at 24 weeks after treatment (SVR24). RESULTS: One patient discontinued treatment because of rectal variceal hemorrhage, and 19 patients completed treatment. SVR24 was achieved in 17 patients (89%). Median LHL15 increased from 0.72 pre-treatment to 0.82 after SVR24 (p = 0.012), and median HH15 decreased from 0.82 pre-treatment to 0.76 after SVR24 (p = 0.010). The percentage of patients with LSM ≥ 20 kPa was 90% before treatment and remained at 90% after SVR24. However, the percentage with severe portal hypertension (defined as HVPG ≥ 12 mmHg) decreased from 92% pre-treatment to 58% after SVR24 (p = 0.046). Patients with a decreased HVPG from pre-treatment to after SVR24 had a smaller pre-treatment spleen volume than those with an increased HVPG (median, 252 vs. 537 mL, p = 0.028). CONCLUSION: Achieving SVR24 with SOF/VEL treatment in patients with decompensated hepatitis C-related cirrhosis can be expected to improve hepatocyte function and portal hypertension on short-term follow-up.

Risk factors for liver-related and non-liver-related mortality following a sustained virological response after direct-acting antiviral treatment for hepatitis C virus infection in a real-world cohort.

A direct-acting antiviral (DAA)-induced sustained virological response (SVR) reduces the risk of mortality. However, the risk factors associated with liver-related and non-liver-related mortality following a SVR after DAA treatment are unclear. We assessed the incidence and risk factors of liver-related and non-liver-related mortality in 1180 patients who achieved a SVR after DAA treatment. During the follow-up period after DAA treatment (median duration, 1099 [range: 84-2345] days), 53 (4.5%) patients died: 15 due to liver-related mortality, 25 due to non-liver-related mortality and 13 due to unknown causes. The all-cause, liver-related and non-liver-related mortality rates were 14.9, 4.2 and 7.0/1000 person-years, respectively. In a multivariate analysis, the development of hepatocellular carcinoma (HCC) after DAA treatment (p = .009; hazard ratio [HR], 31.484), an estimated glomerular filtration rate (eGFR) at baseline ≤61.68 ml/min/1.73 m2 (p = .015; HR, 6.607), and an α-fetoprotein level post-treatment ≥7.6 ng/ml (p = .041; HR, 18.490) were significantly associated with liver-related mortality. Furthermore, eGFR ≤67.94 ml/min/1.73 m2 at baseline (p = .012; HR, 3.407) and albumin-bilirubin (ALBI) grade ≥ 2 at SVR (p = .024; HR, 3.449) were significantly associated with non-liver-related mortality. Early diagnosis and therapeutic interventions for HCC development after DAA treatment are important to reduce liver-related mortality. The ALBI grade, which reflects the hepatic functional reserve, is a useful predictor of non-liver-related mortality after a SVR induced by DAA treatment. Furthermore, the renal dysfunction caused by metabolic syndrome may affect prognosis even after eliminating hepatitis C virus.

Prognostic Nutrition Index as an Indicator of Therapeutic Response to Lenvatinib Therapy in Hepatocellular Carcinoma.

BACKGROUND/AIM: Lenvatinib (LEN) has been approved as an oral tyrosine kinase inhibitor for advanced hepatocellular carcinoma (HCC). However, in some patients, LEN does not provide adequate therapeutic benefits. In this study, we examined the factors that affect the therapeutic response to LEN. PATIENTS AND METHODS: This retrospective cohort study involved patients with HCC who received LEN therapy at Osaka Metropolitan University Hospital. We used the delivered dose intensity to body surface area ratio for 60 days (2M-DBR) as an index of the therapeutic response. RESULTS: This study included 83 patients divided into two groups, the high 2M-DBR group (47 patients, 56.7%) and low 2M-DBR group (36 patients, 43.4%). Univariate analysis showed that Child-Pugh class, C-reactive protein, and prognostic nutrition index (PNI) were significant factors for high 2M-DBR. Furthermore, multivariate logistic regression analysis revealed that a PNI>39.15 was significantly associated with high 2M-DBR. CONCLUSION: A PNI cut-off value of less than 39.15 may indicate a poor response to LEN therapy. PNI, an easy, simple, and inexpensive tool, may be useful in identifying patients in need of early intervention.

Efficacy of rechallenge transcatheter arterial chemoembolization after lenvatinib treatment for advanced hepatocellular carcinoma.

Background and Aim: We evaluated the efficacy of rechallenge transcatheter arterial chemoembolization (TACE) after lenvatinib (LEN) treatment in patients with previous TACE failure/refractoriness. Methods: We enrolled 63 consecutive patients with a history of TACE failure/refractoriness prior to LEN treatment as a first-line systemic therapy. We reviewed the clinical backgrounds and courses of the patients. Results: In total, 25 patients underwent rechallenge TACE after LEN due to LEN-refractoriness (17 cases) or intolerance (8 cases). A complete or partial response was obtained for 13 (65.0%) of the 20 patients whose therapeutic effects were determined. The survival rate of patients who underwent rechallenge TACE was significantly higher than that of patients who did not undergo rechallenge TACE (median survival time, not reached vs 403 days, P = 0.015). Rechallenge TACE significantly reduced the risk of death in univariate (hazard ratio [HR] 0.24, 95% confidence interval [CI] 0.08-0.69, P = 0.008) and multivariate analyses (HR 0.26, 95% CI 0.08-0.80, P = 0.019). If complete or partial response was obtained by rechallenge TACE, the median survival time of these patients was significantly longer than those of the progressive disease (PD) group (P = 0.05), and the median survival time of the PD group after rechallenge TACE was not different from that of the group who did not undergo rechallenge TACE (P = 0.36). We did not observe a decrease in the ALBI score after TACE. Conclusion: Rechallenge TACE after LEN is an effective treatment that may result in a favorable prognosis.

Suppression of intrahepatic cholangiocarcinoma cell growth by SKI via upregulation of the CDK inhibitor p21.

Cholangiocarcinoma (CC) has a poor prognosis and different driver genes depending on the site of onset. Intrahepatic CC is the second-most common liver cancer after hepatocellular carcinoma, and novel therapeutic targets are urgently needed. The present study was conducted to identify novel therapeutic targets by exploring differentially regulated genes in human CC. MicroRNA (miRNA) and mRNA microarrays were performed using tissue and serum samples obtained from 24 surgically resected hepatobiliary tumor cases, including 10 CC cases. We conducted principal component analysis to identify differentially expressed miRNA, leading to the identification of miRNA-3648 as a differentially expressed miRNA. We used an in silico screening approach to identify its target mRNA, the tumor suppressor Sloan Kettering Institute (SKI). SKI protein expression was decreased in human CC cells overexpressing miRNA-3648, endogenous SKI protein expression was decreased in human CC tumor tissues, and endogenous SKI mRNA expression was suppressed in human CC cells characterized by rapid growth. SKI-overexpressing OZ cells (human intrahepatic CC cells) showed upregulation of cyclin-dependent kinase inhibitor p21 mRNA and protein expression and suppressed cell proliferation. Nuclear expression of CDT1 (chromatin licensing and DNA replication factor 1), which is required for the G1/S transition, was suppressed in SKI-overexpressing OZ cells. SKI knockdown resulted in the opposite effects. Transgenic p21-luciferase was activated in SKI-overexpressing OZ cells. These data indicate SKI involvement in p21 transcription and that SKI-p21 signaling causes cell cycle arrest in G1, suppressing intrahepatic CC cell growth. Therefore, SKI may be a potential therapeutic target for intrahepatic CC.

Soluble Immune Checkpoint Protein CD27 Is a Novel Prognostic Biomarker of Hepatocellular Carcinoma Development in Hepatitis C Virus-Sustained Virological Response Patients.

Factors affecting the probability of hepatocellular carcinoma (HCC) development even after sustained virological response (SVR) following anti-hepatitis C virus (HCV) therapy remain unelucidated. This study characterized the role of 16 soluble (s) immune checkpoint proteins in 168 HCV-SVR patients, with 47 developing HCC at the study end point. At baseline, high concentrations of 10 immune checkpoint proteins were found in the sera of the HCC group. At the study end point, levels of sCD27, sCD28, sCD40, and sCD86 in the HCC group, which were depleted following SVR, returned to higher levels than those in the non-HCC group. More importantly, patients with baseline levels of sCD27 ≥ 4104 pg/mL, sCD28 ≥ 1530 pg/mL, and sCD40 ≥ 688 pg/mL predicted a significantly greater HCC cumulative rate. Although sCD27 was elevated in patient sera, its membrane-bound form, mCD27, accumulated in the tumor and peritumor area, mainly localized in T cells. Interestingly, T-cell activation time dependently induced sCD27. Furthermore, CD70, the ligand of CD27, was robustly expressed in HCC area in which CD70 promoter methylation analysis indicated the hypomethylation compared with the nontumor pairs. Recombinant human CD27 treatment induced the proliferation of CD70-bearing HepG2 cells via the mitogen-activated protein kinase (MEK)-extracellular signal-regulated kinase pathway, but not NF-κB or p38 pathway. In conclusion, these data indicate that baseline sCD27, sCD28, and sCD40 levels could be used as HCC prognostic markers in HCV-SVR patients. sCD27 likely promotes HepG2 cell growth via the CD27-CD70 axis.

Selenium Associates With Response to Erythropoiesis-Stimulating Agents in Hemodialysis Patients.

Introduction: Impaired response to erythropoiesis-stimulating agents (ESAs) is associated with increased mortality in patients with end-stage kidney disease. However, the underlying mechanisms are not fully elucidated. Accumulating data reveal that selenium (Se), a trace element, plays a key role in stress erythropoiesis and erythrocyte homeostasis. We evaluated the relationship between serum Se levels and the response to ESAs in hemodialysis patients. Methods: In this cross-sectional study, we determined serum Se levels in 173 hemodialysis patients. We analyzed the association of serum Se with ESA responsiveness, as defined by ESA resistance index. Results: Of the study participants, 50% had lower Se levels than the population-based reference values. We found that serum Se levels were significantly and inversely correlated with erythropoiesis resistance index (ERI) but not transferrin saturation (TSAT) or ferritin levels. Multiple regression analyses confirmed the association between Se levels and ESA hyporesponsiveness, independently of other known factors, such as iron status, being female, and dialysis vintage (ß = -0.11, P < 0.001). When patients were divided according to Se levels and iron status, both low serum Se (<10.5 µg/dl) and iron deficiency significantly affected the response to ESA. Conversely, serum Se levels were significantly different among groups when patients were divided according to ERI quartiles. The association of low serum Se with ESA hyporesponsiveness persisted after adjustment of confounding variables. Conclusion: Serum Se levels are associated with the response to ESAs and can predict ESA resistance independently of iron status in Japanese hemodialysis patients. These data open the possibility to test whether Se supplementation reduces ESA demand.

Cytoglobin attenuates pancreatic cancer growth via scavenging reactive oxygen species.

Pancreatic cancer is a highly challenging malignancy with extremely poor prognosis. Cytoglobin (CYGB), a hemeprotein involved in liver fibrosis and cancer development, is expressed in pericytes of all organs. Here, we examined the role of CYGB in the development of pancreatic cancer. CYGB expression appeared predominately in the area surrounding adenocarcinoma and negatively correlated with tumor size in patients with pancreatic cancer. Directly injecting 7, 12-dimethylbenz[a]anthracene into the pancreatic tail in wild-type mice resulted in time-dependent induction of severe pancreatitis, fibrosis, and oxidative damage, which was rescued by Cygb overexpression in transgenic mice. Pancreatic cancer incidence was 93% in wild-type mice but only 55% in transgenic mice. Enhanced CYGB expression in human pancreatic stellate cells in vitro reduced cellular collagen synthesis, inhibited cell activation, increased expression of antioxidant-related genes, and increased CYGB secretion into the medium. Cygb-overexpressing or recombinant human CYGB (rhCYGB) -treated MIA PaCa-2 cancer cells exhibited dose-dependent cell cycle arrest at the G1 phase, diminished cell migration, and reduction in colony formation. RNA sequencing in rhCYGB-treated MIA PaCa-2 cells revealed downregulation of cell cycle and oxidative phosphorylation pathways. An increase in MIA PaCa-2 cell proliferation and reactive oxygen species production by H2O2 challenge was blocked by rhCYGB treatment or Cygb overexpression. PANC-1, OCUP-A2, and BxPC-3 cancer cells showed similar responses to rhCYGB. Known antioxidants N-acetyl cysteine and glutathione also inhibited cancer cell growth. These results demonstrate that CYGB suppresses pancreatic stellate cell activation, pancreatic fibrosis, and tumor growth, suggesting its potential therapeutic application against pancreatic cancer.

Emergence of proteinase 3-antineutrophil cytoplasmic antibody-associated glomerulonephritis with mesangial immune deposition during the clinical course of IgG λ monoclonal gammopathy of uncertain significance.

Patients with monoclonal gammopathy of uncertain significance (MGUS) is sometimes associated with renal diseases, usually due to the deposition of secreted monoclonal immunoglobulin or a fragment thereof, a condition which is defined as monoclonal gammopathy of renal significance. Patients with MGUS appear to be at increased risk for various autoimmune conditions. We report the case of a 68-year-old man developed nephritic syndrome and mild renal insufficiency during the course of IgG λ MGUS. Laboratory findings showed hypocomplementemia, cryoglobulinemia, proteinase 3-antineutrophil cytoplasmic antibody (PR3-ANCA) positivity and monoclonal proteins (λ light chain and λ-Bence-Jones protein) in the urine. A kidney biopsy revealed crescentic glomerulonephritis with mesangial immune deposits without paraproteins. Treatment with prednisolone for ANCA-associated glomerulonephritis, normalized urinalysis and decreased PR3-ANCA but MGUS persisted. This is a rare case of PR3-ANCA-associated glomerulonephritis with comorbid IgG λ MGUS with various pathological paraproteins. We highlight it as a clinical example with diagnostic and therapeutic implications.

Soluble programmed cell death-1 predicts hepatocellular carcinoma development during nucleoside analogue treatment.

Soluble immune checkpoint molecules are emerging novel mediators of immune regulation. However, it is unclear whether soluble immune checkpoint proteins affect the development of hepatocellular carcinoma (HCC) during nucleos(t)ide analogue (NA) treatment in patients with chronic hepatitis B virus infection. This study included 122 NA-naïve patients who received NA therapy. We assessed the associations of clinical factors, including soluble immune checkpoint proteins, with HCC development during NA treatment. The baseline serum concentrations of 16 soluble immune checkpoint proteins were measured using multiplexed fluorescent bead-based immunoassay. In total, 13 patients developed HCC during the follow-up period (median duration, 4.3 years). Of the 16 proteins, soluble inducible T-cell co-stimulator (≥ 164.71 pg/mL; p = 0.014), soluble programmed cell death-1 (sPD-1) (≤ 447.27 pg/mL; p = 0.031), soluble CD40 (≤ 493.68 pg/mL; p = 0.032), and soluble herpes virus entry mediator (≤ 2470.83 pg/mL; p = 0.038) were significantly associated with HCC development (log-rank test). In multivariate analysis, an sPD-1 level ≤ 447.27 pg/mL (p = 0.014; hazard ratio [HR], 4.537) and α-fetoprotein level ≥ 6.4 ng/mL (p = 0.040; HR, 5.524) were independently and significantly associated with HCC development. Pre-treatment sPD-1 is a novel predictive biomarker for HCC development during NA treatment.

Direct-acting antivirals reduce the risk of tumour progression of hepatocellular carcinoma after curative treatment.

Hepatocellular carcinoma (HCC) has high recurrence rates. HCC sometimes progresses from early-stage HCC (Barcelona Clinic Liver Cancer [BCLC] stage 0/A) to advanced-stage HCC after repeated recurrences and treatments. HCC progression deteriorates quality of life and prognosis. However, the effect of direct-acting antiviral (DAA)-induced sustained virologic response (SVR) on HCC progression remains uninvestigated. We conducted a retrospective cohort study of patients with hepatitis C virus-related HCC with BCLC stage 0/A diagnosed for the first time and treated by curative resection or ablation. Using a time-varying method, we estimated the risk of tumour progression (defined as progression to BCLC stage B-D) and liver-related death and the characteristics of repeated recurrence. Overall, 165 patients were enrolled. Following curative HCC treatment, 72 patients received DAA therapy (DAA-treated group), whereas 93 did not (untreated group). Approximately 75% of the recurrences were at an early stage and expected to be disease-free by retreatment. We recorded 56 tumour progressions, of which 60.7% were observed after second recurrence. Multivariate adjusted time-varying Cox regression analysis showed that the DAA-induced SVR significantly reduced the risk of tumour progression (hazard ratio [HR] 0.28; p = .001) and liver-related death (HR 0.12; p < .001). The annual incidence of HCC treatment until tumour progression was 82.8% and 23.9% in the untreated and DAA-treated groups, respectively (HR 0.30; p < .001). DAA-induced SVR significantly reduced the risk for tumour progression and liver-related death and the frequency of HCC treatment following curative treatment for HCC at BCLC stage 0/A.

The Albumin-bilirubin Score Detects Changes in the Liver Function during Treatment for Budd-Chiari Syndrome: A Retrospective Observational Study.

Objective Mapping the long-term prognosis of Budd-Chiari syndrome (BCS) is difficult, as the prognosis is associated with changes in the liver function. The present study evaluated the time course changes in the liver function in a treatment group with percutaneous old balloon angioplasty (POBA) and a non-treatment group using the albumin-bilirubin score (ALBI) and Child-Pugh score during long-term follow-up. Methods In this retrospective study, 13 consecutive patients diagnosed with BCS at our hospital between 2007 and 2020 were categorized into a treatment group (n=8), which received POBA, and a non-treatment group (n=5). Differences in the liver function in the ALBI and Child-Pugh scores between the initial visit and one- and three-year follow-up were calculated and statistically evaluated. We investigated the changes in the liver function during the long-term follow-up, including events such as re-stenosis and re-treatment. Results While the Child-Pugh scores in the treatment group did not differ significantly between the initial visit and 1- or 3-year follow-up, the ALBI scores in this group improved significantly between the initial visit and the 1- or 3-year follow-up visit (p=0.0078 and 0.0156, respectively). The liver function according to the ALBI score in the treatment group showed gradual improvement from the initial value but gradual worsening in the non-treatment group. The ALBI scores also revealed that the liver function varies according to re-stenosis and re-POBA in BCS patients. Conclusion Unlike the Child-Pugh score, the ALBI score was able to capture changes in the liver function of BCS patients during the long-term course of BCS.

Influence of a biliary stent in patients with advanced pancreatic cancer treated with modified FOLFIRINOX.

Endoscopic biliary drainage is the recommended 1st-line treatment for malignant biliary obstruction. Although a high incidence of febrile neutropenia has been reported in patients treated with FOLFIRINOX and a biliary stent, it remains unknown whether the biliary stent contributes to patient survival. Thus, we aimed to elucidate the effects of biliary stents on the survival of patients with advanced pancreatic cancer treated with modified FOLFIRINOX (mFFX). We retrospectively reviewed medical charts of patients with advanced pancreatic cancer treated with mFFX between January 2014 and April 2020. We compared the overall survival (OS) of patients with and without biliary stent during mFFX treatment and examined the independent effect on mortality using propensity score matching. Overall, we included 89 patients (stent group, n = 24; non-stent group, n = 65). The proportion of patients with pancreatic head cancer was significantly higher in the stent group than in the non-stent group (P < .01). Stratification analysis in patients with pancreatic head cancer revealed that OS was significantly shorter in the stent group than in the non-stent group (P = .03). After propensity score matching, 19 pairs of patients in each group were analyzed. The stent group revealed a significantly shorter survival than the non-stent group (median OS, 10.3 vs 24.9 months; P < .01). The incidences of febrile neutropenia (P = .01) and biliary tract-related events that required biliary stenting or stent replacement (P < .01) were significantly higher in the stent group than in the non-stent group. Stent insertion was an independent risk factor for overall mortality. Biliary stents may reduce survival in patients with advanced pancreatic cancer. The rate of febrile neutropenia was higher in the stent group than in the non-stent group. There is a need to assess the patient's condition with discretion and develop a treatment strategy with short prognosis in mind after stent insertion.