Multiomics identifies the link between intratumor steatosis and the exhausted tumor immune microenvironment in hepatocellular carcinoma.

BACKGROUND AND AIMS: Immunotherapy has become the standard-of-care treatment for hepatocellular carcinoma (HCC), but its efficacy remains limited. To identify immunotherapy-susceptible HCC, we profiled the molecular abnormalities and tumor immune microenvironment (TIME) of rapidly increasing nonviral HCC. APPROACHES AND RESULTS: We performed RNA-seq of tumor tissues in 113 patients with nonviral HCC and cancer genome sequencing of 69 genes with recurrent genetic alterations reported in HCC. Unsupervised hierarchical clustering classified nonviral HCCs into three molecular classes (Class I, II, III), which stratified patient prognosis. Class I, with the poorest prognosis, was associated with TP53 mutations, whereas class III, with the best prognosis, was associated with cadherin-associated protein beta 1 (CTNNB1) mutations. Thirty-eight percent of nonviral HCC was defined as an immune class characterized by a high frequency of intratumoral steatosis and a low frequency of CTNNB1 mutations. Steatotic HCC, which accounts for 23% of nonviral HCC cases, presented an immune-enriched but immune-exhausted TIME characterized by T cell exhaustion, M2 macrophage and cancer-associated fibroblast (CAF) infiltration, high PD-L1 expression, and TGF-ß signaling activation. Spatial transcriptome analysis suggested that M2 macrophages and CAFs may be in close proximity to exhausted CD8+ T cells in steatotic HCC. An in vitro study showed that palmitic acid-induced lipid accumulation in HCC cells upregulated PD-L1 expression and promoted immunosuppressive phenotypes of cocultured macrophages and fibroblasts. Patients with steatotic HCC, confirmed by chemical-shift MR imaging, had significantly longer PFS with combined immunotherapy using anti-PD-L1 and anti-VEGF antibodies. CONCLUSIONS: Multiomics stratified nonviral HCCs according to prognosis or TIME. We identified the link between intratumoral steatosis and immune-exhausted immunotherapy-susceptible TIME.

Effect of sofosbuvir and velpatasvir therapy on clinical outcome in hepatitis C virus patients with decompensated cirrhosis.

AIM: To determine the impact of direct-acting antiviral therapy on the long-term prognosis of decompensated cirrhotic patients. METHODS: A total of 37 patients with hepatitis C virus-induced decompensated cirrhosis treated with sofosbuvir and velpatasvir (SOF/VEL group) were prospectively enrolled. For historical control, 65 hepatitis C virus-positive decompensated cirrhotic patients who did not receive direct-acting antiviral therapy were included (control group). The incidence rates of hepatocellular carcinoma (HCC), decompensated events with hospitalization, and overall survival were compared between both groups. RESULTS: A total of 41 patients experienced decompensated events during 15.0 months in the control group, and six patients during 21.6 months in the SOF/VEL group. The cumulative incidence rates of decompensated events after 2 years were significantly higher in the control group (53.1%) than in the SOF/VEL group (14.5%; p < 0.001). A total of 27 patients died within 22.0 months in the control group, and three patients died within 25.6 months in the SOF/VEL group. The overall survival rates after 2 years were significantly lower in the control group (67.6%) than in the SOF/VEL group (91.3%; p = 0.010). A total of 13 patients in the control group developed HCC during 15.8 months, and 10 patients during 17.3 months in the SOF/VEL group. The HCC incidence rates after 2 years were 20.3% and 29.6% in the control and SOF/VEL groups, respectively, with no significant difference (p = 0.327). CONCLUSIONS: SOF/VEL therapy may suppress the development of decompensated events and improve the prognosis in decompensated cirrhotic patients; however, the incidence of HCC remains prevalent in these patients irrespective of SOF/VEL therapy.

Improved Liver Function After Sustained Virologic Response Enhanced Prognosis in Hepatitis C with Compensated Advanced Liver Fibrosis.

BACKGROUND AND AIM: Liver function can be improved in patients with chronic hepatitis C virus (HCV) infection who achieved sustained virologic response (SVR) with direct-acting antiviral (DAA) treatment. However, to our knowledge, the impact of liver function improvement after SVR on prognosis has not been investigated. METHODS: A total of 716 patients with chronic HCV infection and compensated advanced liver fibrosis who began receiving DAA treatment between September 2014 and August 2018 in 25 Japanese hospitals and achieved SVR were enrolled. RESULTS: The median age was 73 years, and 336 (47%) and 380 (53%) patients had albumin-bilirubin (ALBI) grade 1 and grade 2, respectively. Improvement to ALBI grade 1 at 1 year after the end of treatment (EOT) was observed in 76% of the patients with baseline ALBI grade 2. Among 380 patients with baseline ALBI grade 2, alanine aminotransferase (ALT) levels ≥ 40 U/L (p < 0.001) and modified ALBI (mALBI) grade 2a (p < 0.001) were significantly associated with improvement to ALBI grade 1 at 1 year after EOT in multivariate analysis. During the median observation period of 51.8 months, 4 and 10 patients with baseline ALBI grade 1 and 2, respectively, died. In patients with baseline ALBI grade 2, only the absence of improvement to ALBI grade 1 at 1 year after EOT was significantly associated with all-cause mortality in univariate analysis. CONCLUSIONS: Baseline ALT levels and mALBI grade were significantly associated with improvement in liver function after SVR. Patients whose liver function improved after SVR could have better prognosis.

Comparison of atezolizumab plus bevacizumab and lenvatinib in terms of efficacy and safety as primary systemic chemotherapy for hepatocellular carcinoma.

AIM: Atezolizumab plus bevacizumab and lenvatinib have each shown efficacy as primary systemic chemotherapies for hepatocellular carcinoma (HCC) in clinical trials. However, comparative trials of these two treatments have not been conducted. This study aimed to compare the therapeutic outcomes of these two treatments. METHODS: This prospectively registered multicenter study analyzed 272 patients with HCC who received atezolizumab plus bevacizumab (the Atezo + Beva group; n = 90) or lenvatinib (the Len group; n = 182) as primary systemic chemotherapy. After propensity score matching (PSM), 66 patients were assigned to each group. RESULTS: After PSM, the median progression-free survival (PFS) was significantly longer in the Atezo + Beva group than in the Len group (8.8 vs. 5.2 months; p = 0.012). No significant differences were noted between the two groups in terms of median overall survival (not reached vs. 20.6 months; p = 0.577), objective response rates (43.8% vs. 52.4%; p = 0.330), and disease control rates (76.6% vs. 82.5%; p = 0.404). The percentage of patients with modified albumin-bilirubin grades of one or 2a was maintained during treatment in the Atezo + Beva group but decreased over time in the Len group. The rate of discontinuation due to adverse events (AEs) was lower in the Atezo + Beva group than in the Len group (12.1% vs. 28.8%; p = 0.018). CONCLUSIONS: Atezolizumab plus bevacizumab showed prolonged PFS, maintained hepatic reserve, and had lower rates of severe AEs compared with that on using lenvatinib as primary systemic chemotherapy for HCC.

Hyperprogressive disease in patients with unresectable hepatocellular carcinoma receiving atezolizumab plus bevacizumab therapy.

BACKGROUND: Atezolizumab plus bevacizumab was approved for hepatocellular carcinoma (HCC) patients in 2020, but treatment outcomes of atezolizumab plus bevacizumab in real-world settings remain unclear. Hyperprogressive disease (HPD), an acceleration of tumor growth occurring in some types of malignancies treated with immune checkpoint inhibitors, was assessed in HCC patients receiving atezolizumab plus bevacizumab. METHODS: Tumor growth kinetics (TGK) and tumor growth rate (TGR) were calculated at pre- and post-treatment in 88 Japanese patients with HCC receiving atezolizumab plus bevacizumab. Hyperprogressive disease was defined as progressive disease (PD) with ≥ two-fold increase in TGK and TGR. The association of baseline characteristics with HPD was analyzed. RESULTS: The best objective responses were partial response, stable disease, and PD in 12 (13.6%), 51 (58.0%), and 25 (28.4%) patients, respectively. The median progression-free survival was 5.0 months. Eleven (12.5%) and 9 (10.2%) patients had a TGK ratio and a TGR ratio of ≥2, respectively. Hyperprogressive disease was observed in nine patients (10.2%) and they showed significantly shorter overall survival than patients without HPD (median, 4.3 months vs. not reached; p < 0.001). Patients with HPD had larger and more intrahepatic tumors, higher levels of α-fetoprotein and lactate dehydrogenase, and higher neutrophil-to-lymphocyte ratio (NLR) at baseline than patients without HPD. NLR of ≥3 at baseline was identified as the only independent factor associated with HPD in multivariate analysis. CONCLUSIONS: Hyperprogressive disease was observed in 10.2% of HCC patients receiving atezolizumab plus bevacizumab, and an elevated NLR at baseline had an increased risk of HPD.

Risk of hepatocellular carcinoma after sustained virologic response in hepatitis C virus patients without advanced liver fibrosis.

AIM: Hepatocellular carcinoma (HCC) after sustained virologic response (SVR) has been observed even in hepatitis C virus (HCV) patients without advanced liver fibrosis. Identifying predictors for HCC incidence in patients without advanced liver fibrosis will enable efficient post-SVR HCC surveillance. This study aimed to develop a scoring system to predict the incidence of HCC after SVR in HCV patients without advanced liver fibrosis. METHODS: A total of 1682 HCV patients without advanced liver fibrosis (defined as Fibrosis-4 index <3.25) with no history of HCC who initiated direct-acting antiviral treatment between September 2014 and October 2020 at 26 institutions, and achieved SVR24, were included. We divided 1682 patients into training (1122) and validation (560) cohorts. RESULTS: In the multivariate analysis, baseline age ≥ 65 years (p = 0.030), alanine aminotransferase (ALT) levels at SVR24 ≥ 30 U/l (p = 0.001), and α-fetoprotein (AFP) levels at SVR24 ≥ 5.0 ng/ml (p = 0.001) were independent predictors for HCC incidence in the training cohort. We developed a scoring system to predict HCC incidence after SVR24 using these three factors (1 point was added for each factor). The cumulative HCC incidence rates at 5 years were 7.1% in patients who scored 2 or 3, and no patients developed HCC in those who scored 0 in the validation cohort. CONCLUSIONS: Our scoring system using the three factors of baseline age, ALT levels at SVR, and AFP levels at SVR is useful for post-SVR HCC surveillance of patients without advanced liver fibrosis.

Development of Ferromagnetic Fluctuations in Heavily Overdoped (Bi,Pb)_{2}Sr_{2}CuO_{6+δ} Copper Oxides.

We demonstrate the presence of ferromagnetic (FM) fluctuations in the superconducting and nonsuperconducting heavily overdoped regimes of high-temperature superconducting copper oxides, using (Bi,Pb)_{2}Sr_{2}CuO_{6+δ} (Bi-2201) single crystals. Magnetization curves exhibit a tendency to be saturated in high magnetic fields at low temperatures in the heavily overdoped crystals, which is probably a precursor phenomenon of a FM transition at a lower temperature. Muon spin relaxation detects the enhancement of spin fluctuations at high temperatures below 200 K. Correspondingly, the ab-plane resistivity follows a 4/3 power law in a wide temperature range, which is characteristic of metals with two-dimensional FM fluctuations due to itinerant electrons. As the Wilson ratio evidences the enhancement of spin fluctuations with hole doping in the heavily overdoped regime, it is concluded that two-dimensional FM fluctuations reside in the heavily overdoped Bi-2201 cuprates, which is probably related to the decrease in the superconducting transition temperature in the heavily overdoped cuprates.

Quick and stable parallel puncture of hepatic tumors using a double-barreled needle direction system for ultrasound-guided bipolar radiofrequency ablation.

AIM: In bipolar radiofrequency ablation (RFA) therapy, insertion of multiple needles at appropriate points on a target is difficult. The aim of our study was to evaluate a simplified method for multi-electrode insertion using a newly developed double-barreled needle guidance system for percutaneous RFA of hepatic tumors. METHODS: RFA using two bipolar electrodes was performed in 15 consecutive patients (nine men, six women; mean age, 72.0 ± 8.2 years) with a solitary small (≤3 cm) hepatic tumor. The first five nodules were treated using the conventional puncture method with the standard attachment, then 10 nodules were ablated using the parallel puncture method with the double-barreled attachment. The times required for double-needle placement and the shapes of the ablated areas were compared between the two puncture methods. RESULTS: The parallel puncture method required a shorter time for double-needle placement than the conventional method (12 s [range, 8-24] vs 96 s [range, 50-240]; P = 0.0003), and allowed continuous observation of the tip of all needles and the size of the ablated area as it increased until completion of the ablation. The method also provided a stable ellipsoidal ablated area. The median height, width and thickness were 30 mm (range, 22-34), 30 mm (range, 21-33) and 20 mm (range, 7-25), respectively, using 20-mm electrodes, and 34 mm (range, 32-41), 36 mm (range, 35-38) and 24 mm (range, 23-24), respectively, using 30-mm electrodes. CONCLUSION: The parallel puncture method may be a feasible procedure for multi-needle RFA therapy.

Periostin promotes the generation of fibrous membranes in proliferative vitreoretinopathy.

Proliferative vitreoretinopathy (PVR) is a severe, vision-threatening disorder characterized by the fibrous membrane formation that leads to tractional retinal detachment. There has been no effective therapeutic approach other than vitreoretinal surgery. In this study, DNA microarray analysis of the fibrous membranes revealed significant up-regulation of periostin. We also found increased periostin expression in the vitreous and retinal pigment epithelial (RPE) cells from fibrous membranes of PVR patients. In vitro, periostin increased proliferation, adhesion, migration, and collagen production in RPE cells through integrin αV-mediated FAK and AKT phosphorylation. Periostin blockade suppressed migration and adhesion induced by TGFß2 and PVR vitreous. In vivo, periostin inhibition had the inhibitory effect on progression of experimental PVR in rabbit eyes without affecting the viability of retinal cells. These results identified periostin as a pivotal molecule for fibrous membrane formation as well as a promising therapeutic target for PVR.

Post-treatment levels of α-fetoprotein predict incidence of hepatocellular carcinoma after interferon therapy.

BACKGROUND & AIMS: In patients with chronic hepatitis C virus (HCV) infection, lack of sustained virologic response (SVR) 24 weeks after the end of interferon therapy is a significant risk factor for hepatocellular carcinoma (HCC). Although many pretreatment factors are known to affect HCC incidence, less is known about post-treatment factors-many change during the course of interferon therapy. METHODS: We performed a prospective study, collecting data from 2659 patients with chronic hepatitis C without a history of HCC who had been treated with pegylated interferon (Peg-IFN) plus ribavirin from 2002 through 2008 at hospitals in Japan. Biopsy specimens were collected before treatment; all patients received Peg-IFN plus ribavirin for 48 to 72 weeks (HCV genotype 1) or 24 weeks (HCV genotype 2). Hematologic, biochemical, and virologic data were collected every 4 weeks during treatment and every 6 months after treatment. HCC was diagnosed based on angiography, computed tomography, and/or magnetic resonance imaging findings. RESULTS: HCC developed in 104 patients during a mean observation period of 40 months. Older age, male sex, lower platelet counts and higher levels of α-fetoprotein at baseline, and lack of an SVR were significant risk factors for HCC. The cumulative incidence of HCC was significantly lower in patients without SVRs who relapsed than those with no response to treatment. Levels of α-fetoprotein 24 weeks after the end of treatment (AFP24) were significantly lower than levels of α-fetoprotein at baseline in patients with SVRs and those who relapsed, but not in nonresponders. Post-treatment risk factors for HCC among patients with SVRs included higher AFP24 level and older age; among those without SVRs, risk factors included higher AFP24 level, integrated level of alanine aminotransferase, older age, and male sex. AFP24 (≥10 ng/mL, 10-5 ng/mL, and then <5 ng/mL) was a better predictor of HCC incidence than pretreatment level of AFP among patients with and without SVRs. CONCLUSIONS: In patients with chronic HCV infection, levels of α-fetoprotein decrease during interferon therapy. High post-treatment levels of α-fetoprotein predict HCC, regardless of whether patients achieve an SVR. University Hospital Medical Information Network Clinical Trials Registry: C000000196, C000000197.

Significance of liver stiffness measurement by acoustic radiation force impulse (ARFI) among hepatitis C patients.

The degree of liver fibrosis is strongly associated with the antiviral effect of interferon on chronic hepatitis C patients. In this study, the accuracy of acoustic radiation force impulse (ARFI) in assessing liver fibrosis and the association between liver stiffness using ARFI and antiviral effects were investigated. The 124 patients with chronic hepatitis C enrolled in this study included 94 with HCV genotype 1 and 40 (30%) with moderate fibrosis (METAVIR fibrosis score ≥ F2). Sixty-one patients received pegylated interferon (peg-IFN) plus ribavirin combination therapy and the treatment responses were assessed. The shear wave velocity (Vs value) by ARFI had a strong correlation with the histological fibrosis stage (P < 0.001). The AUROC of the Vs value, aspartate aminotransferase platelet ratio index and FIB4 for the diagnoses of moderate fibrosis (≥F2) were 0.890, 0.779, and 0.737, respectively. HCV genotype 1 patients with the TT allele of IL28B and with a low Vs value (<1.40 m/sec) who were treated with peg-IFN plus ribavirin therapy achieved a sustained virologic response at a rate of 79% (15/19), while all patients with the TG/GG allele of IL28B and a high Vs value (≥1.40 m/sec) experienced a non-virologic response (6/6). The Vs value measured by ARFI could not predict the treatment response for patients with HCV genotype 2. It is concluded that the combination of ARFI at cut off of 1.4 m/sec and IL28B may be useful for patients with chronic hepatitis C with genotype 1 treated with peg-IFN/ribavirin combination therapy.

TIE2-expressing monocytes as a diagnostic marker for hepatocellular carcinoma correlates with angiogenesis.

UNLABELLED: Angiogenesis is a critical step in the development and progression of hepatocellular carcinoma (HCC). Myeloid lineage cells, such as macrophages and monocytes, have been reported to regulate angiogenesis in mouse tumor models. TIE2, a receptor of angiopoietins, conveys pro-angiogenic signals and identifies a monocyte/macrophage subset with pro-angiogenic activity. Here, we analyzed the occurrence and kinetics of TIE2-expressing monocytes/macrophages (TEMs) in HCC patients. This study enrolled 168 HCV-infected patients including 89 with HCC. We examined the frequency of TEMs, as defined as CD14+CD16+TIE2+ cells, in the peripheral blood and liver. The localization of TEMs in the liver was determined by immunofluorescence staining. Micro-vessel density in the liver was measured by counting CD34+ vascular structures. We found that the frequency of circulating TEMs was significantly higher in HCC than non-HCC patients, while being higher in the liver than in the blood. In patients who underwent local radio-ablation or resection of HCC, the frequency of TEMs dynamically changed in the blood in parallel with HCC recurrence. Most TEMs were identified in the perivascular areas of tumor tissue. A significant positive correlation was observed between micro-vessel density in HCC and frequency of TEMs in the blood or tumors, suggesting that TEMs are involved in HCC angiogenesis. Receiver operating characteristic analyses revealed the superiority of TEM frequency to AFP, PIVKA-II and ANG-2 serum levels as diagnostic marker for HCC. CONCLUSION: TEMs increase in patients with HCC and their frequency changes with the therapeutic response or recurrence. We thus suggest that TEM frequency can be used as a diagnostic marker for HCC, potentially reflecting angiogenesis in the liver.

Computed tomography during hepatic arteriography pattern may predict hepatocellular carcinoma recurrence following transarterial chemoembolization.

AIM: This study aimed to determine the role of morphological patterns seen on imaging in predicting hepatocellular carcinoma recurrence following transarterial chemoembolization therapy. METHODS: Forty-seven patients from a single center who underwent transarterial chemoembolization to treat unresectable hepatocellular carcinomas between January 2011 and June 2012 were included in this study. We investigated whether the two pretreatment findings on computed tomography during hepatic arteriography (pattern 1, the single nodule pattern; pattern 2, at least one nodule showing the contiguous multinodular pattern) and other factors (age, sex, etiology, serum total bilirubin, serum albumin, prothrombin time, platelet count, serum level of protein induced by vitamin K absence/antagonist-II, serum α-fetoprotein, number of previous treatments for hepatocellular carcinoma, tumor number and maximum tumor size, presence of hypovascular lesions) could predict post-treatment recurrence. RESULTS: In a univariate analysis using Cox's proportional hazards model, serum total bilirubin, the serum level of protein induced by vitamin K absence/antagonist-II (≤100 vs ≥101 mAU/mL), tumor morphology (pattern 1 vs 2) and tumor number (≤3 vs ≥4) showed statistical significance (≤0.05). In a multivariate analysis of these factors, morphology and tumor number showed significance. According to Kaplan-Meier estimation, the cumulative disease-free survival rates were significantly lower in patients with four or more lesions than in those with three or less lesions and in patients showing pattern 2 than in those showing pattern 1. CONCLUSION: Patients with pattern 2 hepatocellular carcinoma and/or four or more lesions may have a relatively high recurrence rate after transarterial chemoembolization.

Clinical factors associated with the therapeutic efficacy of atezolizumab plus bevacizumab in patients with unresectable hepatocellular carcinoma: A multicenter prospective observational study.

The treatment efficiency and predictors of atezolizumab plus bevacizumab therapy for unresectable hepatocellular carcinoma in real-world practice have not been established. This study aimed to assess the efficacy and safety of atezolizumab plus bevacizumab and to investigate predictors of progression-free survival and overall survival. Patients with unresectable hepatocellular carcinoma treated with atezolizumab plus bevacizumab therapy in 19 hospitals were enrolled before treatment and observed prospectively. The outcomes of 222 patients in this cohort were analyzed. The objective response rate and disease control rate were 22.0% and 70.6%, respectively, whereas the median progression-free survival was 5.7 months. Independent risk factors for shortened progression-free survival were younger age (<75 years; 3.9 months vs. 8.6 months), higher number of intrahepatic tumors (≥5; 4.0 months vs. 7.9 months), macrovascular invasion (2.3 months vs. 6.7 months), and higher neutrophil-to-lymphocyte ratio (≥3.03; 3.0 months vs. 7.8 months). The median overall survival was not reached; however, independent risk factors for shortened overall survival were absence of hyperlipidemia, higher number of intrahepatic tumors (≥5), macrovascular invasion, higher α-fetoprotein level (≥400 ng/mL), worse Child-Pugh score (≥6), and higher neutrophil-to-lymphocyte ratio (≥3.03). Severe adverse events (grade ≥3) were observed in 96 patients (36.0%), with proteinuria being the most frequent. In conclusion, patients with older age, lower number of intrahepatic tumors, absent macrovascular invasion, and lower neutrophil-to-lymphocyte ratio are expected to have better progression-free survival with atezolizumab plus bevacizumab therapy for unresectable hepatocellular carcinoma.

Managing hepatitis B virus carriers with systemic chemotherapy or biologic therapy in the outpatient clinic.

AIM: The number of outpatients receiving systemic chemotherapy in Japan has recently increased. We retrospectively examined whether hepatitis B virus (HBV) carriers were safely treated and managed with systemic chemotherapy or biologic agents as outpatients at our oncology center. METHODS: A total of 40 115 consecutive infusion chemotherapy or biologic therapies were administrated to 2754 outpatients in the Chemotherapy and Oncology Center at Osaka University Hospital from December 2003 to March 2011. We first studied the prevalence of outpatients with hepatitis B surface antigen (HBsAg), and then retrospectively evaluated a database to determine the frequencies of testing for other HBV-related markers and the incidence of developing hepatitis or HBV reactivation in patients positive for HBsAg. As a control for comparison, we also examined these same factors in patients with hepatitis C virus antibody (anti-HCV). RESULTS: The majority of physicians at our hospital screened for HBsAg (95%) and anti-HCV (94%) prior to administrating chemotherapy. Of the 2754 outpatients, 46 (1.7%) were positive for HBsAg and 90 (3.3%) were positive for anti-HCV. Fifteen patients that were HBsAg positive were treated with lamivudine or entecavir prior to chemotherapy. None of the patients with HBsAg taking a prophylactic antiviral developed hepatitis, and only one breast cancer patient without prophylactic antiviral treatment (1/31 [3.2%]) developed hepatitis due to HBV reactivation. CONCLUSION: HBV reactivation occurred in outpatients without prophylactic antiviral treatment, but the incidence was relatively low.

Altered vascular microenvironment by bevacizumab in diabetic fibrovascular membrane.

PURPOSE: The purpose of this study was to evaluate the impact of intravitreal bevacizumab (IVB) on three cellular components (vascular endothelial cells, pericytes, and myofibroblasts) of the vascular microenvironment in fibrovascular membranes (FVMs) of patients with proliferative diabetic retinopathy. METHODS: Immunohistological studies with antibodies of CD34, αSMA, and transforming growth factor-ß were performed on 20 surgical specimens obtained during a pars plana vitrectomy from 8 IVB-treated eyes, whereas 12 remained untreated. Four different indexes of vascular phenotype (vascular area, vascular major axis, CD34 endothelial area, and blood vessel density) and αSMA expression in vascular and stromal components were quantitatively analyzed. RESULTS: The intraluminal area of blood vessels, CD34 endothelial area, and the blood vessel density in IVB-treated FVMs were significantly less than in untreated FVMs. The number of CD34 blood vessels in IVB-treated FVMs was similar to that in untreated FVMs. Intravitreal bevacizumab could not affect vascular and stromal αSMA area significantly. However, the ratio of vascular αSMA area/CD34 area was significantly higher in IVB-treated FVMs than in untreated FVMs. Transforming growth factor-ß expression could be observed in the IVB-treated FVM. CONCLUSION: Intravitreal bevacizumab might primarily affect blood vessels, and the effects on pericytes and myofibroblasts might be secondary. Intravitreal bevacizumab treatment regulates vascular microenvironment by the contraction of blood vessels, the increasing pericyte ratio, and transforming growth factor-ß expression in FVMs of patients with proliferative diabetic retinopathy.

[Hemobilia into a metallic biliary stent due to pseudoaneurysm: a case report].

A 48-year-old man with locally advanced pancreatic cancer underwent combined treatment with gemcitabine and proton radiation therapy. Because of subsequent obstruction of the common bile duct, a metallic biliary stent was placed and he received further gemcitabine chemotherapy. During chemotherapy, he developed an acute abdomen with a sudden-onset of tarry stool and jaundice. Gastroduodenoscopy revealed hemobilia from the biliary metallic stent. Contrast-enhanced abdominal computed tomography revealed the presence of a pseudoaneurysm arising from the right hepatic artery adjacent to the top of the stent. Hemostasis of the right hepatic artery pseudoaneurysm was achieved via transcatheter arterial embolization using cyanoacrylate.

Pretreatment with antibiotics is associated with reduced therapeutic response to atezolizumab plus bevacizumab in patients with hepatocellular carcinoma.

AIM: Alterations in microbial composition of gut microbiota due to antibiotics (ATB) may lead to resistance to immune checkpoint inhibitors (ICIs). This study aimed to assess the impact of ATB use on therapeutic response in patients with hepatocellular carcinoma (HCC) receiving atezolizumab plus bevacizumab. METHODS: This study retrospectively analyzed 105 patients with HCC treated with atezolizumab plus bevacizumab as a primary systemic therapy from prospectively-registered, multicenter, cohorts. Nineteen patients who received prior ATB were included in the ATB (+) group; 86 patients who did not receive prior ATB were included in the ATB (-) group. The therapeutic outcomes were compared between the two groups. RESULTS: Most of the patients' baseline characteristics were not significantly different between the two groups. The objective response rates according to the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) (30.1% vs. 11.1%; p = 0.143) and modified RECIST (mRECIST) (44.6% vs. 27.8%; p = 0.190) were not significantly different between the ATB (-) and ATB (+) groups. The disease control rates were higher in the ATB (-) group than in the ATB (+) group according to RECIST v1.1 (74.7% vs. 44.4%; p = 0.012) and mRECIST (78.3% vs. 50.0%; p = 0.020). Prior ATB use was found to be independently associated with radiological progressive disease of the first therapeutic assessment. The median progression-free survival according to RECIST v1.1 (9.1 months vs. 3.0 months; p = 0.049) and mRECIST (9.1 months vs. 3.0 months; p = 0.036), and overall survival (not reached vs. 11.4 months; p = 0.015) were longer in the ATB (-) group than in the ATB (+) group. CONCLUSIONS: Prior ATB use was associated with reduced therapeutic responses in patients with HCC receiving atezolizumab plus bevacizumab.

A follow-up questionnaire survey 2022 on radiation protection among 464 medical staff from 34 endoscopy-fluoroscopy departments in Japan.

Objectives: We surveyed and reported low protective equipment usage and insufficient knowledge among endoscopy-fluoroscopy departments in Japan in 2020. Two years later, we conducted a follow-up survey of doctors, nurses, and technologists in Japan. Methods: We conducted a questionnaire survey on radiation protection from May to June 2022. The participants were medical staff, including doctors, nurses, and radiological and endoscopy technicians in endoscopy-fluoroscopy departments. The questionnaire included 17 multiple-choice questions divided into three parts: background, equipment, and knowledge. Results: We surveyed 464 subjects from 34 institutions. There were 267 doctors (58%), 153 nurses (33%), and 44 technologists (9%). The rate of wearing a lead apron was 98% in this study. The rates of wearing a thyroid collar, lead glasses, and radiation dosimeter were 27%, 35%, and 74%, respectively. The trend of the protective equipment rate was similar to that of our previous study; however, radiation dosimetry among doctors was still low at 58%. The percentage of subjects who knew the radiation exposure (REX) dose of each procedure was low at 18%. Seventy-six percent of the subjects attended lectures on radiation protection, and 73% knew about the three principles of radiation protection; however, the concept of diagnostic reference levels was not well known (18%). Approximately 60% of the subjects knew about the exposure dose increasing cancer mortality (63%) and the 5-year lens REX limit (56%). Conclusions: There was some improvement in radiation protection equipment or education, but relatively little compared to the 2020 survey of endoscopy departments.

Posttreatment liver function, but not baseline liver function stratifies patient survival after direct-acting antiviral treatment in decompensated cirrhosis with hepatitis C virus.

BACKGROUND: The prognosis of cirrhosis is clearly stratified by liver function. Although direct-acting antiviral (DAA) has recently been used to eliminate hepatitis C virus (HCV), it is not clear whether liver function stratifies the prognosis of decompensated cirrhotic patients treated with DAA. METHODS: A total of 206 HCV-associated decompensated cirrhotic patients who started DAA from February 2019 to December 2021 at 31 Japanese hospitals were prospectively registered. RESULTS: The median age was 68, and the proportions of patients with Child-Pugh class A (CP-A), CP-B and CP-C were 10% (20/206), 76% (156/206) and 15% (30/206), respectively. Twenty-six patients died, and two patients underwent liver transplantation (LT); the 2- and 3-year LT-free survival rates were 90.0% and 83.2%, respectively. We examined factors associated with LT-free survival using 2 models including either CP class (Model 1) or MELD score (Model 2). In multivariate Cox proportional hazard analysis, CP class at 12 weeks after the end of treatment (EOT) in Model 1 and MELD score at 12 weeks after the EOT in Model 2 were significant factors, while baseline CP class or MELD score was not. Two-year LT-free survival rates were 100%, 91.6% and 60.4% for patients with CP-A, CP-B and CP-C at 12 weeks after the EOT and 95.2% and 69.6% for patients with MELD < 15 and MELD ≥ 15 at 12 weeks after the EOT, respectively. CONCLUSIONS: The prognosis of decompensated cirrhotic patients receiving DAA was stratified by liver function at 12 weeks after the EOT, not by baseline liver function.