Progression pattern and post-progression survival following atezolizumab and bevacizumab treatment in advanced hepatocellular carcinoma.

BACKGROUND: Although the combination of atezolizumab and bevacizumab (ATZ + BEV) is a standard treatment for advanced hepatocellular carcinoma (HCC), strategies for addressing treatment failure and prognostic factors of post-progression survival (PPS) remain unestablished. METHODS: We conducted a multicentre retrospective study to evaluate PPS following ATZ + BEV treatment in patients with advanced HCC. We classified the patients into three groups: BCLC stage B and BCLC stage C without or with new extrahepatic lesions (BCLCp-C1 and BCLCp-C2, respectively) at the time of progression. RESULTS: Of the 204 patients who started ATZ + BEV treatment between October 2020 and September 2022, 110 showed disease progression, with 33, 55 and 22 showing the BCLCp-B, BCLCp-C1 and BCLCp-C2 stages of the disease, respectively. Specifically, patients with the BCLCp-B stage of the disease showed better overall survival than those with the BCLCp-C1 and BCLCp-C2 stages (hazard ratios: 1.93 [95% confidence interval, CI, 1.06-3.51] and 2.64 [95% CI, 1.32-5.30] for HCC stages BCLCp-C1 and BCLCp-C2, respectively). Via multivariable analysis, we identified the BCLCp-C1 and BCLCp-C2 stages, as well as performance status, Child-Pugh class and alpha-fetoprotein as poor prognostic factors for PPS. CONCLUSIONS: BCLCp-B1 stage was identified as a better prognostic factor for PPS following ATZ + BEV treatment compared with BCLCp-C1 and BCLCp-C2 stages. This may help in making decisions regarding subsequent treatment after ATZ + BEV.

Association Between Immune-Related Adverse Events and Survival in Patients with Hepatocellular Carcinoma Treated With Atezolizumab Plus Bevacizumab.

BACKGROUND: Immune checkpoint inhibitors (ICIs) are effective for advanced hepatocellular carcinoma (HCC). However, there are few reports on the correlation between the clinical efficacy of ICIs and the development of immune-related adverse events (irAEs) in patients with HCC. The aim of this study was to investigate the association between irAE development and survival in patients with HCC treated with atezolizumab plus bevacizumab. PATIENTS AND METHODS: We enrolled 150 patients with advanced HCC treated with atezolizumab plus bevacizumab between October 2020 and October 2021 at 5 territorial institutions. We compared the efficacy of atezolizumab plus bevacizumab between patients who experienced irAEs (irAE group) and those who did not (non-irAE group). RESULTS: Thirty-two patients (21.3%) developed irAEs of any grade. Grade 3/4 irAEs were observed in 9 patients (6.0%). The median progression-free survivals (PFS) in the irAE and non-irAE groups were 273 and 189 days, respectively (P = .055). The median overall survivals (OS) in the irAE and non-irAE groups were not reached and 458 days, respectively (P = .036). Grade 1/2 irAEs significantly prolonged PFS (P = .014) and OS (P = .003). Grade 1/2 irAEs were significantly associated with PFS (hazard ratio [HR], 0.339; 95% confidence interval [CI], 0.166-0.691; P = .003) and OS (HR, 0.086; 95% CI, 0.012-0.641; P = .017) on multivariate analysis. CONCLUSION: The development of irAEs was associated with increased survival in a real-world population of patients with advanced HCC treated with atezolizumab plus bevacizumab. Grade 1/2 irAEs were strongly correlated with PFS and OS.

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.

Clinical outcomes of antithrombin III-based therapy for patients with portal vein thrombosis: A retrospective, multicenter study.

AIM: The association between thrombolytic therapy and the outcome in patients with portal vein thrombosis (PVT) remains controversial. This study aimed to evaluate the outcome in patients with PVT who received antithrombin III-based therapy. METHODS: This study was a retrospective, multicenter study to investigate the liver-related events and the survival rates in 240 patients with PVT who received the therapy. RESULTS: The patients comprised 151 men and 89 women, with a median age of 69 years. The rate of favorable response, defined as maximum area of PVT changed to ≤75%, was 67.5% (162/240). The cumulative rates of liver-related events at 1, 2, and 3 years were 38.2%, 53.9%, and 68.5%, respectively. The multivariate analysis showed that viable hepatocellular carcinoma, absence of maintenance therapy, non-responder, and PVT progression were significantly associated with liver-related events. The PVT progression was observed in 23.3% (56/240). The multivariate analysis identified older age, absence of maintenance therapy, and non-responder as independent factors associated with PVT progression. The multivariate analysis revealed that younger age, no hepatocellular carcinoma, presence of maintenance therapy, and lower Model for End-stage Liver Disease-Sodium score significantly contributed to 3-year survival. Of the 240 patients, 13 (8.9%) prematurely discontinued treatment due to any adverse events. CONCLUSIONS: This study suggests that maintenance therapy, favorable response, and absence of PVT progression may suppress or control liver-related events in antithrombin III-based therapy for patients with PVT. Specifically, maintenance therapy could suppress not only liver-related events, but also PVT progression and improve the prognosis.

The Risk of Cirrhosis and Its Complications Based on PNPLA3 rs738409 G Allele Frequency.

BACKGROUND: Data regarding the influence of patatin-like phospholipase domain-containing 3 (PNPLA3) polymorphism for patients with liver cirrhosis (LC) are scarce. OBJECTIVE: This study assesses the role of the PNPLA3 polymorphism for the development of LC and its complications by the findings of genetic examinations. METHODS: Patients with LC caused by virus (n = 157), alcohol (n = 104), nonalcoholic fatty liver disease (NAFLD) (n = 106), or autoimmune disease (n = 33) and without LC (n = 128) were enrolled. LC was composed of the presence and absence of complications, such as variceal bleeding, hepatic ascites, and hepatic encephalopathy. To assess the role of the PNPLA3 polymorphism, odds ratio (OR) for the rs738409 variant was calculated for the patients between (i) with LC and without LC in the entire cohort and (ii) the presence and absence of complications in the patients with LC. RESULTS: There was a significant difference among the patients without LC and those with alcohol, NAFLD-related LC in the frequency of G alleles (p < 0.001, both). According to complications of LC, the OR for NAFLD-related cirrhosis significantly increased in the presence of the two mutated alleles (OR = 3.165; p = 0.046) when the wild type was used as the reference. However, there were no significant risks for the complications in the virus and alcohol-related cirrhosis unless there was a presence of G alleles. CONCLUSION: The PNPLA3 polymorphism was associated with the risk of NAFLD-related LC and its complications.

Safety and efficacy of atezolizumab plus bevacizumab in patients with unresectable hepatocellular carcinoma in early clinical practice: A multicenter analysis.

PURPOSE: To assess the impact of clinical factors on the safety and efficacy of atezolizumab plus bevacizumab (ATZ + BV) treatment in patients with unresectable hepatocellular carcinoma (u-HCC). METHOD: Ninety-four u-HCC patients who were treated with ATZ + BV at multiple centers were enrolled. We defined Child-Pugh (CP)-A patients who received ATZ + BV treatment as a first line therapy as the 'meets the broad sense of the IMbrave150 criteria' group (B-IMbrave150-in, n = 46), and patients who received ATZ + BV treatment as a later line therapy or CP-B patients (regardless of whether ATZ + BV was a first line or later line therapy) as the B-IMbrave150-out group (n = 48). Patients were retrospectively analyzed for adverse events (AEs) and treatment outcomes according to their clinical characteristics, including neutrophil lymphocyte ratio (NLR) at baseline. RESULTS: The overall incidence of AEs was 87.2% (82/94 patients). The frequency of interruption of ATZ + BV treatment due to fatigue was higher in CP-B than CP-A patients (p = 0.030). Objective response (OR) rates of the B-IMbrave150-in group (28.3%, 39.1%) were significantly higher than those of the B-IMbrave150-out group (8.3%, 18.8%; p = 0.0157, 0.0401) using Response Evaluation Criteria in Solid Tumors (RECIST) and modified RECIST, respectively. In multivariate analysis, NLR (hazard ratio (HR), 4.591; p = 0.0160) and B-IMbrave150 criteria (HR, 4.108; p = 0.0261) were independent factors associated with the OR of ATZ + BV treatment using RECIST. CONCLUSION: In real-world practice, ATZ + BV treatment might offer significant benefits in patients who meet B-IMbrave150 criteria or have low NLR.

Clinicopathological Features of Autoimmune Hepatitis with IgG4-Positive Plasma Cell Infiltration.

BACKGROUND: We aimed to elucidate the characteristics and prognosis of autoimmune hepatitis (AIH) patients with immunoglobulin (Ig) G4-positive plasma cell infiltration. METHODS: We enrolled 84 AIH patients. The number of IgG- and IgG4-positive plasma cells was immunohistochemically counted per high-power field in the portal area. Patients with 3 or more IgG4-positive plasma cells on average and a ratio of IgG4 to IgG-positive plasma cells ≥5% were defined as IgG4-associated AIH (IgG4-AIH), and their clinicopathological characteristics and prognosis were compared to those of the remaining classical-AIH patients. RESULTS: Ten (11.9%) and 74 patients (88.1%) were categorized as IgG4-AIH and classical-AIH patients, respectively. The median age of the IgG4-AIH patients was 67 years, the majority was female (80.0%), and the distribution was similar to that of the classical-AIH patients. The IgG4-AIH patients exhibited significantly more severe phenotypes in portal inflammation, interface hepatitis, fibrosis, and rosette formation. All clinical laboratory data were similar except for serum IgG4 levels, which were higher in IgG4-AIH patients (168.5 vs. 22.9 mg/dL, p = 0.014). During a median follow-up period of 139 months, the relapse rate was significantly lower in the IgG4-AIH group than in the classical-AIH group (11.1 vs. 49.2%; p = 0.048). Twelve (16.2%) and 6 (8.1%) classical-AIH patients underwent liver-related events and liver-related deaths, respectively. In contrast, none of the IgG4-AIH patients progressed to severe liver disease. CONCLUSIONS: The IgG4-AIH patients had more severe inflammation and advanced fibrosis in the liver. However, their prognosis was not poor compared to that of classical-AIH patients. IgG4-AIH may have a phenotype distinct from classical-AIH.

Impact of Anti-GPIIb/IIIa Antibody-Producing B Cells as a Predictor of the Response to Lusutrombopag in Thrombocytopenic Patients with Liver Disease.

BACKGROUND: To make an accurate estimate of the response to thrombopoietin (TPO) receptor agonists for thrombocytopenia associated with chronic liver disease, we evaluated the influence of antiplatelet autoantibodies on the response to lusutrombopag in thrombocytopenic patients with liver disease. METHODS: A prospective study was conducted at 2 hospitals. Thrombocytopenic patients with liver disease received oral lusutrombopag 3.0 mg once daily for up to 7 days. We analyzed changes in platelet counts from baseline to the maximum platelet count on days 9-14. The definition of clinical response was a platelet count of ≥5 × 104/µL with an increased platelet count of ≥2 × 104/µL from baseline. We assessed the correlation between the response to treatment drug and antiplatelet autoantibodies measured by anti-GPIIb/IIIa antibody-producing B cells. RESULTS: Thirty patients received the trial drug. There were 25 responders and 5 nonresponders. The median change in platelet counts was 3.9 × 104/µL (95% CI 2.8-4.6, p < 0.0001). The correlation between change in platelet counts and the frequency of the anti-glycoprotein IIb/IIIa antibody-producing B cells was moderate (r = 0.414, 95% CI 0.064-0.674, p = 0.023). In multivariate analysis of factors affecting the change in platelet counts, the anti-GPIIb/IIIa antibody-producing B cells were identified as an independent factor (regression coefficient [B] = 0.089; CI 0.021-0.157, p = 0.013). CONCLUSION: Anti-GPIIb/IIIa antibody-producing B cells may be a predictor for TPO receptor agonists in patients with chronic liver disease.

Case of hepatitis B virus reactivation after ibrutinib therapy in which the patient remained negative for hepatitis B surface antigens throughout the clinical course.

A 71-year-old man was diagnosed with B-cell chronic lymphocytic leukemia. He was negative for hepatitis B surface antigen (HBsAg), positive for antibodies against the hepatitis B surface and core, and negative for hepatitis B virus (HBV)-DNA before starting chemotherapy. A total of 13 months after the initiation of ibrutinib (a Bruton's tyrosine kinase inhibitor), the patient's alanine aminotransferase levels suddenly increased to 427 U/L. As the level of serum HBV-DNA increased to 5.2 logIU/mL, a diagnosis of HBV reactivation was made, whereas the patient remained negative for HBsAg. The patient's serum alanine aminotransferase levels normalized after the initiation of entecavir at a dose of 1 mg/day. However, it took >1 year to achieve an undetectable level of HBV-DNA, even with an add-on therapy of tenofovir disoproxil fumarate. Interestingly, the patient remained negative for HBsAg throughout the clinical course owing to triple HBsAg escape mutations: Q101K, M133L, and G145A.

Longitudinal alterations in health-related quality of life and its impact on the clinical course of patients with advanced hepatocellular carcinoma receiving sorafenib treatment.

BACKGROUND: This study aimed to identify the health-related quality of life (HRQOL) domains associated with prognosis by assessing longitudinal alterations in HRQOL in patients with advanced hepatocellular carcinoma receiving sorafenib. METHODS: We prospectively assessed HRQOL by administering the SF-36 questionnaire 3-monthly to consecutive patients with advanced hepatocellular carcinoma receiving sorafenib. We evaluated the impact of HRQOL on their overall survival and duration of treatment with sorafenib using Cox's proportional hazards model. RESULTS: There were 54 participants: 42 (78 %) were male, the median age was 71 years, 24 (44 %) had hepatitis C virus infection, 33 (61 %) had Child-Pugh scores of 5, and 30 (56 %) had TNM stage IV hepatocellular carcinoma. The median overall survival and treatment duration were 9 and 5 months, respectively, and 40 patients (74 %) died. Thirteen patients receiving sorafenib over a 1-year period maintained all domain scores >40, without a significant decline during the treatment period. In contrast, physical functioning, physical role, and vitality scores declined continuously and significantly in the year before death (in the 40 patients who died). Previous curative treatment and physical functioning scores ≥40 at baseline were significantly associated with longer overall survival by multivariate analysis. Social functioning scores ≥40, absence of vascular invasion, and lower DCP value were significant predictors of longer treatment duration. CONCLUSIONS: HRQOL was not significantly impaired in those patients who were able to complete a 1-year course of sorafenib treatment. Baseline physical functioning scores ≥40 and social functioning scores ≥40 were significantly associated with longer overall survival and longer treatment duration, respectively. Thus, HRQOL could be a valuable marker to predict the clinical course of patients with advanced hepatocellular carcinoma receiving sorafenib.

Off-treatment durability of antiviral response to nucleoside analogues in patients with chronic hepatitis B.

BACKGROUND: Off-treatment durability of nucleoside analogue (NA) therapy in patients with chronic hepatitis B has not been well investigated. In this study we monitored antiviral effect of NA therapy and evaluated off-treatment durability after NA cessation in patients with chronic hepatitis B. PATIENTS AND METHODS: A total of 94 consecutive patients (39 HBeAg-negative and 55 HBeAg-positive patients) who received NA therapy were followed up for approximately 9 years. We discontinued NA according to the following criteria; undetectable serum HBV-DNA by polymerase chain reaction (PCR) on three separate occasions at least 6 months apart in HBeAg-negative patients (APASL stopping recommendation), and seroconversion from HBeAg-positive to HBeAb-positive and undetectable serum HBV-DNA by PCR for at least 12 months in HBeAg-positive patients. RESULTS: The cumulative rate of relapse after NA cessation was 48 % and 40 % in HBeAg-negative and -positive patients, respectively. Higher baseline serum alanine aminotransferase level was the only significant predictor for maintaining remission. No patients experienced decompensation after relapse. HBsAg loss occurred at an annual rate of 1.4 % and 0.4 % in HBeAg-negative and -positive patients, respectively. Hepatocellular carcinoma developed at an annual rate of 0.6 % in both HBeAg-negative and -positive patients. CONCLUSIONS: Almost half of the patients did not relapse after cessation of NA therapy in both HBeAg-negative and -positive patients. Therefore, NA therapy could be discontinued with close monitoring if the APASL stopping recommendation is satisfied even in HBeAg-negative patients.

Recessive inheritance of population-specific intronic LINE-1 insertion causes a rotor syndrome phenotype.

Sequences of long-interspersed elements (LINE-1, L1) make up ∼17% of the human genome. De novo insertions of retrotransposition-active L1s can result in genetic diseases. It has been recently shown that the homozygous inactivation of two adjacent genes SLCO1B1 and SLCO1B3 encoding organic anion transporting polypeptides OATP1B1 and OATP1B3 causes a benign recessive disease presenting with conjugated hyperbilirubinemia, Rotor syndrome. Here, we examined SLCO1B1 and SLCO1B3 genes in six Japanese diagnosed with Rotor syndrome on the basis of laboratory data and laparoscopy. All six Japanese patients were homozygous for the c.1738C>T nonsense mutation in SLCO1B1 and homozygous for the insertion of a ∼6.1-kbp L1 retrotransposon in intron 5 of SLCO1B3, which altogether make up a Japanese-specific haplotype. RNA analysis revealed that the L1 insertion induced deleterious splicing resulting in SLCO1B3 transcripts lacking exon 5 or exons 5-7 and containing premature stop codons. The expression of OATP1B1 and OATP1B3 proteins was not detected in liver tissues. This is the first documented case of a population-specific polymorphic intronic L1 transposon insertion contributing to molecular etiology of recessive genetic disease. Since L1 activity in human genomes is currently seen as a major source of individual genetic variation, further investigations are warranted to determine whether this phenomenon results in other autosomal-recessive diseases.

No contribution of the ABCB11 p.444A polymorphism in Japanese patients with drug-induced cholestasis.

European studies have revealed that the ABCB11 c.1331T>C (V444A) polymorphism (rs2287622) C-allele frequency is higher among patients with drug-induced cholestasis. Given the low incidence of this disease, however, this association has not been sufficiently elucidated. We aimed to investigate the significance of this polymorphism in Japanese patients. We determined ABCB11 V444A polymorphism frequencies and HLA genotypes in two independent drug-induced cholestasis cohorts. Expression and taurocholate transport activity of proteins from 444A variants were analyzed using Madin-Darby canine kidney II cells. In cohort 1 (n = 40), the V444A polymorphism C-allele frequency (66%) was lower than that in controls (n = 190, 78%), but this difference was not significant (P = 0.09). In cohort 2 (n = 119), comprising patients with cholestatic (n = 19), hepatocellular (n = 74), and mixed (n = 26) liver injuries, the C-allele frequency was lower among patients with cholestatic liver injury (68%) than among those with hepatocellular (75%) or mixed liver injury (83%), although this difference was not significant. In cohort 1, HLA-A*0201 was observed more frequently in patients (22%) than in controls [11%; P = 0.003; odds ratio, 2.4 (95% confidence interval, 1.4-4.0)]. Taurocholate transport activity of 444A-encoded protein was significantly lower than that of 444V-encoded protein (81% of 444V, P < 0.05) because of the reduced protein stability. In conclusion, ABCB11 444A had slightly reduced transport activity, but it did not contribute to the occurrence of drug-induced cholestasis in Japanese patients. Therefore, genetic susceptibility to acquired cholestasis may differ considerably by ethnicity.

Effects of ethanol and acetaldehyde load on erythrocyte deformability in healthy subjects and patients with liver cirrhosis.

Alcohol intake leads to the distribution of alcohol and its metabolite, acetaldehyde throughout the blood and organs. Hepatic cirrhosis is associated with abnormal red blood cell morphology and function, particularly impaired red blood cell deformability. To investigate the effect of drinking on red blood cells in patients with hepatic cirrhosis, erythrocyte deformability was evaluated in response to alcohol and acetaldehyde tolerance. Erythrocyte deformability in 10 healthy and 15 cirrhotic subjects was examined by filterability of the red blood cells. Erythrocyte deformability decreased markedly in the cirrhosis group compared with the healthy group (p < 0.05). No significant change in erythrocyte deformability was observed in healthy or cirrhotic subjects due to ethanol 100 mM tolerance. Acetaldehyde tolerance elicited a significant decrease in erythrocyte deformability at 2 mM in the cirrhosis group (p < 0.05). Alcohol consumption in cirrhotic patients was suggested to worsen erythrocyte deformability and red blood cell function. Decreased erythrocyte deformability worsens microcirculation in the liver, resulting in more severe hepatic dysfunction.

Ectopic Adrenocorticotropic Hormone Syndrome due to Pancreatic Neuroendocrine Carcinoma: A Case Report.

A 55-year-old woman presented to her primary care physician with facial and lower leg edema. After being referred to our hospital because of hypothyroidism and hypokalemia on blood tests, she also had elevated adrenocorticotropic hormone (ACTH) and cortisol levels, but a dexamethasone suppression test showed no cortisol suppression. Ectopic ACTH syndrome due to pancreatic neuroendocrine carcinoma (PNEC) was suspected. endoscopic ultrasound-guided fine-needle aspiration was performed, and a histopathological examination of the obtained specimen revealed multiple liver metastases of the PNEC. Imaging after etoposide and cisplatin therapy showed cystic changes in the primary lesions and shrinkage of the liver metastases, and the ACTH levels were within the normal range.

Low-grade Appendiceal Mucinous Neoplasm with Appendiceal Reduction and Re-expansion Over a Two-year Period.

A 71-year-old woman was found to have submucosal tumor-like lesion on colonoscopy (CS) before gastric surgery, and computed tomography (CT) showed a 12-mm structure at the base of the appendix. The lesion could not be clearly detected on CT nine months later, but it had enlarged again on CT one year later; therefore, CS and endoscopic ultrasound (EUS) were performed. The lesion was determined to be cystic with viscous contents, and laparoscopic appendicectomy was performed. This is the first report of low-grade appendiceal mucinous neoplasm (LAMN) diagnosed by a histopathologic examination of a resected specimen showing shrinkage and re-expansion of the appendix.

Helicobacter pylori Eradication Therapy for Colorectal Mucosa-associated Lymphoid Tissue Lymphoma: Report of Two Cases.

Two cases of colorectal mucosa-associated lymphoid tissue lymphoma (cMALT) are presented and discussed with the reports from 1997 to the present. Helicobacter pylori (HP)-negative cases showed tumor resolution 2 months after eradication therapy. HP-positive cases were successfully eradicated and tumor resolution was confirmed 16 months later. Analysis of the data reported to date shows that cMALT resolution rates were 68.4% (13/19) in the HP-negative group and 33.3% (7/21) in the HP-positive group. HP eradication should be considered the primary treatment for cMALT regardless of HP infection, especially in untreated patients under follow-up.