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In Asia–Pacific region, hepatocellular carcinoma is a serious health threat attributing to over 600,000 deaths each year and account for over 70% of global cases. Clinically, the major unmet needs are recurrence after curative-intent surgery, liver transplantation or local ablation and disease progression in those with hepatocellular carcinoma not eligible for resection or failed locoregional therapy. In the recent few years, new targeted therapy and immune-checkpoint inhibitors have been registered as systemic therapy to address these issues. Notably, new forms of systemic therapy, either as first-line or second-line therapy for unresectable hepatocellular or those not eligible for locoregional therapy, are now available. New data is also emerging with the use of systemic therapy to prevent hepatocellular carcinoma recurrence after curative-intent resection or local ablation therapy and to retard disease progression after locoregional therapy. In the future, further implementation of immune-checkpoint inhibitors and other forms of immunotherapy are expected to bring a new paradigm to the management of hepatocellular carcinoma. New insight related to immune-related adverse events with the use of immunotherapy has allso enabled optimization of the therapeutic approach to patients with hepatocellular carcinoma. The purpose of this clinical practice guideline is to provide an up-to-date recommendation based on clinical evidence and experience from expert Asia–Pacific key opinion leaders in the field of hepatocellular carcinoma. Three key questions will be addressed, namely: (1) Which patients with hepatocellular carcinoma should be considered for systemic therapy? (2) Which systemic therapy should be used? (3) How should a patient planned for immune checkpoint-based systemic therapy be managed and monitored? [ABSTRACT FROM AUTHOR]

Dental microwear analysis is a well-established technique that provides valuable information about the diets of extant and extinct taxa. It has been used effectively in most major groups of vertebrates. However, in chondrichthyans, these methods have been implemented only recently in the form of dental microwear texture analysis, with conflicting results. Causes intrinsic to chondrichthyan biology, such as limited food-to-tooth contact, low diversity in terms of trophic categories or fast tooth replacement, have been suggested to reduce diet-related wear on individual teeth, hindering the use of this approach for reliable dietary reconstruction. Here, we explored the relationship between diet and dental microwear in chondrichthyans by using 2D analysis, which can provide finer-scale identification and accurate definition of scratch morphology from tooth surfaces a priori. Scratches were counted and measured on the teeth of 34 extant elasmobranchs grouped into three categories (piscivorous, durophagous and generalist) according to dietary preferences. Our results revealed specific patterns of tooth microwear as a function of dietary abrasiveness, enabling the discrimination of trophic groups and thus establishing a useful comparative framework for inferring aspects of trophic ecology in fossils. We then used this information to study dental microwear in six fossil species from the same locality and stratigraphic levels. First, analyses of the enameloid surfaces of the fossil show that post-mortem alterations are distinguishable, allowing reliable quantification of diet-related ante-mortem microwear signatures. Discriminant analysis allowed the recognition of microwear patterns comparable to those of living sharks and linked them to specific trophic groups with high probability levels (> 90%). Thus, microwear features developing on chondrichthyan teeth during feeding are intense enough to retain information regarding diet preferences. 2D microwear analysis can track this information, proving to be a useful tool for providing significant information not only about diet but also about oral processing mechanisms in extinct chondrichthyans. [ABSTRACT FROM AUTHOR]

The presence of neuronal amyloid β (Aβ) plaques and neurofibrillary tangles are the main indicators of Alzheimer's disease (AD) and Parkinson's disease (PD), which are the most common neurological diseases of old age. It is obvious that the existing and developed treatments are not able to change the conditions and cure these diseases, so the development of preventive therapeutic interventions without complications seems necessary. Clinical findings indicate that oxidative stress and neurotoxicity caused by amyloid β (Aβ) play a fundamental role in the pathogenesis of Alzheimer's disease (AD). Among a wide range of medicinal compounds studied for the treatment and prevention of neurological diseases, Nobiletin (NOB)has been the focus of researchers. NOB is a bioflavonoid isolated from citrus peel that has anti-inflammatory, antioxidant and anti-dementia properties and the ability to improve intracellular and extracellular antibodies. In this study, the neuroprotective effects of NOB against Aβ-induced neurotoxicity discovered in the last decade were discussed. The molecular mechanisms involved have also been considered. [ABSTRACT FROM AUTHOR]

Objectives: The recognition of arterial phase hyperenhancement (APHE) and washout during the late phase is key for correct diagnosis of hepatocellular carcinoma (HCC) with contrast-enhanced ultrasound (CEUS). This meta-analysis was conducted to compare SonoVue®-enhanced and Sonazoid®-enhanced ultrasound in the assessment of HCC enhancement and diagnosis. Methods: Studies were included in the analysis if they reported data for HCC enhancement in the arterial phase and late phase for SonoVue® or in the arterial phase and Kupffer phase (KP) for Sonazoid®. Forty-two studies (7502 patients) with use of SonoVue® and 30 studies (2391 patients) with use of Sonazoid® were identified. In a pooled analysis, the comparison between SonoVue® and Sonazoid® CEUS was performed using chi-square test. An inverse variance weighted random-effect model was used to estimate proportion, sensitivity, and specificity along with 95% confidence interval (CI). Results: In the meta-analysis, the proportion of HCC showing APHE with SonoVue®, 93% (95% CI 91–95%), was significantly higher than the proportion of HCC showing APHE with Sonazoid®, 77% (71–83%) (p < 0.0001); similarly, the proportion of HCC showing washout at late phase/KP was significantly higher with SonoVue®, 86% (83–89%), than with Sonazoid®, 76% (70–82%) (p < 0.0001). The sensitivity and specificity for the detection of APHE plus late-phase/KP washout detection in HCC were also higher with SonoVue® than with Sonazoid® (sensitivity 80% vs 52%; specificity 80% vs 73% in studies within unselected patient populations). Conclusion: APHE and late washout in HCC are more frequently observed with SonoVue® than with Sonazoid®. This may affect the diagnostic performance of CEUS in the diagnosis of HCCs. Clinical relevance statement: Meta-analysis data show the presence of key enhancement features for diagnosis of hepatocellular carcinoma is different between ultrasound contrast agents, and arterial hyperenhancement and late washout are more frequently observed at contrast-enhanced ultrasound with SonoVue® than with Sonazoid®. Key Points: • Dynamic enhancement features are key for imaging-based diagnosis of HCC. • Arterial hyperenhancement and late washout are more often observed in HCCs using SonoVue®-enhanced US than with Sonazoid®. • The existing evidence for contrast-enhanced US may need to be considered being specific to the individual contrast agent. [ABSTRACT FROM AUTHOR]

Purpose of Review: Portal vein thromboses occur in patients with cirrhosis, including those awaiting liver transplant, and uncertainty exists regarding its prognosis, workup, and optimal management. Recent Findings: The prevalence of PVT is higher in those with more severe liver disease (24% vs 14% for Child-Pugh B/C vs A, respectively). PVT, especially those with complete occlusion, is associated with mortality and graft loss in liver transplant recipients. Increasing data on direct oral anticoagulant (DOAC) use in cirrhosis and specifically for use in patients with PVT provides physicians and patients with more appealing anticoagulation options. In addition to observation and anticoagulation, there is an emerging role of transjugular intrahepatic porto-systemic (TIPS) shunt for recanalization of the portal vein in certain patients, with prospective single-center study demonstrating 98–100% efficacy in those with complete occlusion compared to a lower rate of patency with medical therapy alone (13%). Summary: Due to the complexities involved in assessing and managing PVTs in cirrhosis based on individual patient factors, a multidisciplinary approach with hepatologists, hematologists, interventional radiologists, and transplant surgeons is strongly recommended for patients who are transplant candidates, have recurrent thromboses or complex anatomy, and may be considered in any patient with cirrhosis. [ABSTRACT FROM AUTHOR]

A meta-analysis was performed to assess the benefits and safety profile of approved immune checkpoint inhibitors in hepatocellular carcinoma patients. Eligible studies were searched from Cochrane, Embase, and PubMed databases based on a well-established strategy. Following the exclusion of ineligible studies, 12 studies were included in this meta-analysis. Compared with control group, immune checkpoint inhibitors were associated with improved ORR (OR 3.03, 95% CI 2.26–4.05, P < 0.00001), SD (OR 0.77, 95% CI 0.62–0.95, P = 0.02), OS (HR 0.75, 95% CI 0.68–0.83, P < 0.00001), and PFS (HR 0.74, 95% CI 0.63–0.87, P < 0.0003). However, no significant differences were observed in DCR (OR 1.33, 95% CI 0.97–1.81, P = 0.07), PD (OR 0.90, 95% CI 0.67–1.21, P = 0.48), and all caused any-grade adverse events (OR 1.22, 95% CI 0.62–2.39, P = 0. 57), all caused ≥ grade 3 adverse events (OR 1.10, 95% CI 0.97–1.25, P = 0.14), treatment-related any-grade adverse events (OR 1.13, 95% CI 0.55–2.32, P = 0.73), and treatment-related ≥ grade 3 events (OR 0.82, 95% CI 0.34–1.97, P = 0.65) between the two groups. After subgroup analysis conducted, patients in the immune checkpoint inhibitor group compared with targeted drug group showed significant improvements in OS (HR 0.74, 95% CI 0.66–0.84, P < 0.00001) and PFS (HR 0.75, 95% CI 0.61–0.91, P = 0.004). Immune checkpoint inhibitors have demonstrated peculiar benefits in the treatment of HCC with an acceptable safety profile. Compared to targeted drugs, immune checkpoint inhibitors still offer advantages in the treatment of hepatocellular carcinoma. However, there is still considerable room for further improvement. [ABSTRACT FROM AUTHOR]

CD58 plays roles in cell adhesion and co-stimulation with antigen presentation from major histocompatibility complex class II on antigen-presenting cells to T-cell antigen receptors on naïve T cells. CD58 reportedly contributes to the development of various human autoimmune diseases. Recently, genome-wide association studies (GWASs) identified CD58 as a susceptibility locus for autoimmune diseases such as systemic lupus erythematosus (SLE), multiple sclerosis (MS), and primary biliary cholangitis (PBC). However, the primary functional variant and molecular mechanisms of susceptibility to autoimmune diseases in the CD58 locus were not clarified. Here, rs10924104, located in the ZNF35-binding motif within the gene expression regulatory motif, was identified as the primary functional variant for SLE, MS, and PBC among genetic variants showing stronger linkage disequilibrium (LD) with GWAS-lead variants in the CD58 locus. Expression-quantitative trait locus (e-QTL) data for each distinct blood cell type and in vitro functional analysis using the CRISPR/Cas9 system corroborated the functional role of rs10924104 in the upregulation of CD58 transcription by the disease-risk allele. Additionally, the strength of disease susceptibility observed in the CD58 locus could be accounted for by the strength of LD between rs10924104 and each GWAS-lead variant. In conclusion, the present study demonstrated for the first time the existence of a shared autoimmune disease-related primary functional variant (i.e., rs10924104) that regulates the expression of CD58. Clarifying the molecular mechanism of disease susceptibility derived from such a shared genetic background is important for understanding human autoimmune diseases and human immunology. [ABSTRACT FROM AUTHOR]

The African bichir (Polypterus senegalus) is a living representative of Polypteriformes. P. senegalus possesses teeth composed of dentin covered by an enameloid cap and a layer of collar enamel on the tooth shaft, as in lepisosteids. A thin layer of enamel matrix can also be found covering the cap enameloid after its maturation and during the collar enamel formation. Teleosts fish do not possess enamel; teeth are protected by cap and collar enameloid, and inversely in sarcopterygians, where teeth are only covered by enamel, with the exception of the cap enameloid in teeth of larval urodeles. The presence of enameloid and enamel in the teeth of the same organism is an opportunity to solve the evolutionary history of the presence of enamel/enameloid in basal actinopterygians. In silico analyses of the jaw transcriptome of a juvenile bichir provided twenty SCPP transcripts. They included enamel, dentin, and bone-specific SCPPs known in sarcopterygians and several actinopterygian-specific SCPPs. The expression of these 20 genes was investigated by in situ hybridizations on jaw sections during tooth and dentary bone formation. A spatiotemporal expression patterns were established and compared with previous studies of SCPP gene expression during enamel/enameloid and bone formation. Similarities and differences were highlighted, and several SCPP transcripts were found specifically expressed during tooth or bone formation suggesting either conserved or new functions of these SCPPs. [ABSTRACT FROM AUTHOR]

Hepatic sinusoidal obstruction syndrome (SOS) is a severe and life-threatening complication after allogeneic hematopoietic stem cell transplantation (HSCT). We conducted a multi-center retrospective study to evaluate the utility of our ultrasonographic scoring system for the diagnosis of SOS (HokUS-10) in predicting SOS-related mortality (SOS-RM). We analyzed a total of 42 patients who developed SOS after HSCT. The cumulative incidences of SOS-RM, non-relapse mortality (NRM), and overall survival at day 180 after the diagnosis of SOS were 26.4%, 28.8% and 54.5%, respectively. The area under the receiver operating characteristic curve analysis showed that the optimal cut-off value of HokUS-10 total score to predict SOS-RM was 8 points after the treatment of SOS. In the individual HokUS-10 score, ascites and portal vein flow-related scores (PV mean velocity and PV flow direction) after the treatment of SOS were shown as significant risk factors for SOS-RM. Our study suggested that US findings after the treatment can predict the treatment outcomes for SOS. [ABSTRACT FROM AUTHOR]

Background and aim: Baveno VII workshop recommends management of acute variceal bleeding (AVB) in cirrhotic patients with nonmalignant portal vein thrombosis (PVT) should be performed according to the guidelines for patients without PVT. Nevertheless, whether PVT affects the outcome of patients with cirrhosis and AVB remains unclear. The aim of this study was to assess the clinical impact of PVT on the outcomes in the pre-emptive TIPSS eligible patients with cirrhosis and AVB. Methods: From December 2010 to June 2016, 1219 consecutive cirrhotic patients admitted due to AVB with (n = 151; 12.4%) or without PVT (n = 1068; 87.6%), who received drug plus endoscopic treatment (a combination of vasoactive drugs, antibiotics, and endoscopic ligation for AVB, followed by beta-blockers plus variceal ligation for prevention of rebleeding) were retrospectively included. Fine and Gray competing risk regression models were taken to evaluate the impact of PVT on clinical outcomes after adjusting for potential confounders. Results: During follow-up, 211 patients (17.3%) died, 490 (40.2%) experienced further bleeding, and 78 (6.4%) experienced new or worsening ascites within 1 year. Compared with those without PVT, patients with PVT had a similar risk of mortality (PVT vs no-PVT: 19.9% vs 16.7% at 1 year; adjusted HR 0.88, 95%CI 0.51–1.52, p = 0.653), further bleeding (47.0% vs 39.2% at 1 year, adjusted HR 1.19, 95% CI 0.92–1.53, p = 183), and new or worsening ascites (7.9% vs 9.6%, adjusted HR 0.70, 95% CI 0.39–1.28, p = 0.253) after adjusting for confounders in multivariable models. These findings were consistent across different relevant subgroups and confirmed by propensity score matching analysis. Conclusions: Our study showed no evidence that the PVT was associated with an improved or worsened outcome among cirrhotic patients with AVB who received standard treatment. [ABSTRACT FROM AUTHOR]

Purpose: To prospectively evaluate the potential of four-dimensional (4D) flow magnetic resonance imaging (MRI) in predicting treatment responses after transcatheter arterial chemoembolization (TACE) in cirrhotic patients with hepatocellular carcinoma (HCC). Methods: A total of 195 patients were classified into four groups (A–D): A, cirrhotic patients without HCC (n = 30); B, cirrhotic patients with HCC before TACE (n = 75); C, cirrhotic patients with HCC showing an incomplete response following TACE (n = 56); and D, cirrhotic patients with HCC achieving a complete response (CR) following TACE (n = 34). The patients were subjected to routine laboratory tests and 4D flow MRI using a 3-T MRI system to measure the quantitative parameters of blood flow in the portal vein (PV), splenic vein (SV), and superior mesenteric vein. The data collected by 4D flow MRI were compared among the groups using one-way analysis of variance. A multivariate analysis was performed to verify the association of clinical characteristics and 4D flow parameters with CR after TACE treatment. Results: The average through-plane velocity, peak velocity magnitude, average net flow, peak flow, and net forward volume in the PV and SV were significantly lower in groups B and C (P < 0.05) compared to those in group A. Moreover, average through-plane velocity and peak velocity magnitude in the PV in groups B and C were significantly lower than those in group D (P < 0.05). The multivariate analysis demonstrated that the average through-plane velocity and peak velocity magnitude in the PV were independently associated with CR in HCC patients after TACE (P < 0.05). Conclusion: The quantitative flow data obtained by 4D flow MRI may be useful for predicting CR after TACE in cirrhotic patients with HCC. [ABSTRACT FROM AUTHOR]

Post-resective liver failure is a frequent complication of liver surgery and it is due to portal hyperperfusion of the remnant liver and to arterial vasoconstriction, as buffer response of the hepatic artery. In this context, splenectomy allows a reduction of portal flow and increases the survival chance in preclinical models. SerpinB3 is over-expressed in the liver in oxidative stress conditions, as a mechanism of cell defense to provide survival by apoptosis inhibition and cell proliferation. In this study, the expression of SerpinB3 was assessed as predictor of liver damage in in vivo models of major hepatic resection with or without splenectomy. Wistar male rats were divided into 4 groups: group A received 30% hepatic resection, group B > 60% resection, group C > 60% resection with splenectomy and group D sham-operated. Before and after surgery liver function tests, echo Doppler ultrasound and gene expression were assessed. Transaminase values and ammonium were significantly higher in groups that underwent major hepatic resection. Echo Doppler ultrasound showed the highest portal flow and resistance of the hepatic artery in the group with > 60% hepatectomy without splenectomy, while the association of splenectomy determined no increase in portal flow and hepatic artery resistance. Only the group of rats without splenectomy showed higher shear-stress conditions, reflected by higher levels of HO-1, Nox1 and of Serpinb3, the latter associated with an increase of IL-6. In conclusion, splenectomy controls inflammation and oxidative damage, preventing the expression of Serpinb3. Therefore, SerpinB3 can be considered as a marker of post-resective shear stress. [ABSTRACT FROM AUTHOR]

Methods for the synthesis of crinane alkaloids of isoquinoline series of Amaryllidaceae that possess various biological activities are reviewed. [ABSTRACT FROM AUTHOR]

Intracranial aneurysms are reported to affect 2–5% of the population. Despite advances in the surgical management of this disease, diagnostic technologies have marginally improved and still rely on expensive or invasive imaging procedures. Currently, there is no blood-based test to detect cerebral aneurysm formation or quantify the risk of rupture. The aim of this review is to summarize current literature on the mechanism of aneurysm formation, specifically studies relating to inflammation, and provide a rationale and commentary on a hypothetical future blood-based test. Efforts should be focused on clinical-translational approaches to create an assay to screen for cerebral aneurysm presence and risk-stratify patients to allow for superior treatment timing and management. Cerebral Aneurysm Blood Test Considerations: There are multiple caveats to development of a putative blood test to detect cerebral aneurysm presence. [ABSTRACT FROM AUTHOR]

Background and Aims: Cavernous transformation of the portal vein can occur after portal vein thrombosis (PVT). In this study, we investigated clinical complications associated with cavernous transformation in the context of cirrhosis and PVT. Methods: In this retrospective cohort analysis, 204 patients with cirrhosis and PVT with or without cavernous transformation were identified using MUSC's Clinical Data Warehouse between January 1, 2013, through December 31, 2019. Complete demographic data, clinical history, and laboratory tests were abstracted from the electronic medical record. Results: Of 204 patients, 41 (20%) had cavernous transformation. MELD, Child–Pugh, and Charlson Comorbidity Index scores were similar among groups. There were no significant differences in the prevalence of esophageal varices (with or without bleeding), splenomegaly, or hepatic encephalopathy in patients with and without cavernous transformation, although ascites tended to be lower in patients with cavernous transformation (31/41 (76%) vs 142/163 (87%), p = 0.06). Patients with cavernous transformation were significantly less likely to have hepatocellular carcinoma (HCC) (13/41 (32%) vs 81/163 (50%), p < 0.05) and had significantly lower APRI (1.4 vs 2.0, p < 0.05) and Fib-4 (4.7 vs 6.5, p < 0.05). Patients with cavernous transformation had lower 5-year mortality (12/41 (29%) vs 81/163 (49%) died, p = 0.06). The 10-year mortality of patients with cavernous transformation without HCC was significantly lower than in those without cavernous transformation (8/28 (29%) vs 46/82 (56%), respectively, p < 0.05). Conclusions: Patients with cavernous transformation appeared to have better outcomes than those without cavernous transformation. [ABSTRACT FROM AUTHOR]

Introduction: Immune checkpoint inhibitor (ICI)-based regimens are transforming the landscape of hepatocellular carcinoma (HCC) treatment. We describe the effect of combined ipilimumab and nivolumab in patients with advanced HCC after the failure of prior ICI-based combination treatments. Methods: The clinical course of patients with advanced HCC who received combined ipilimumab and nivolumab after prior ICI-based combination therapies was assessed. Progression-free survival (PFS), overall response rate (ORR) and disease control rate (DCR) per RECIST v1.1 and mRECIST, overall survival (OS), and safety were analyzed. Results: Of 109 patients treated with atezolizumab and bevacizumab or other ICI-based combination treatments, ten patients received subsequent therapy with ipilimumab and nivolumab. The majority of patients had Barcelona Clinic Liver Cancer (BCLC) Stage C (80%) HCC and a preserved liver function as defined by Child–Pugh A (80%). At a median follow-up of 15.3 months, ORR for ipilimumab and nivolumab was 30% with a DCR of 40%. Median PFS was 2.9 months and the median OS was 7.4 months. Conclusion: This retrospective study demonstrates that combined ipilimumab and nivolumab can be effective and tolerable after prior ICI-based combination therapies and provides a rationale for the prospective clinical evaluation of this treatment sequencing. [ABSTRACT FROM AUTHOR]

The Notch pathway is an ancient, evolutionary conserved intercellular signaling mechanism that is involved in cell fate specification and proper embryonic development. The Jagged2 gene, which encodes a ligand for the Notch family of receptors, is expressed from the earliest stages of odontogenesis in epithelial cells that will later generate the enamel-producing ameloblasts. Homozygous Jagged2 mutant mice exhibit abnormal tooth morphology and impaired enamel deposition. Enamel composition and structure in mammals are tightly linked to the enamel organ that represents an evolutionary unit formed by distinct dental epithelial cell types. The physical cooperativity between Notch ligands and receptors suggests that Jagged2 deletion could alter the expression profile of Notch receptors, thus modifying the whole Notch signaling cascade in cells within the enamel organ. Indeed, both Notch1 and Notch2 expression are severely disturbed in the enamel organ of Jagged2 mutant teeth. It appears that the deregulation of the Notch signaling cascade reverts the evolutionary path generating dental structures more reminiscent of the enameloid of fishes rather than of mammalian enamel. Loss of interactions between Notch and Jagged proteins may initiate the suppression of complementary dental epithelial cell fates acquired during evolution. We propose that the increased number of Notch homologues in metazoa enabled incipient sister cell types to form and maintain distinctive cell fates within organs and tissues along evolution. [ABSTRACT FROM AUTHOR]

Spontaneous portosystemic shunts (SPSS) are an often neglected cause of hepatic encephalopathy associated with cirrhosis. Nowadays, SPSS are considered as radiological biomarkers of clinically significant portal hypertension rather than the previous dogmatic perceived decompressive vessels. SPSS are not rare as they can be diagnosed in over 60% of the patients with cirrhosis by mere contrast-enhanced CT. Moreover, they are clinically relevant since they impact on all portal hypertensive related complications, in particular medically refractory HE, and represent an independent predictor of decompensation and mortality in cirrhosis, irrespective of the type of SPSS. Taken together, these elements warrant strategies to target these shunts directly which is currently is achieved via interventional radiology embolization. In this review, we discuss why it makes sense to tackle SPSS, how to do it and what it takes to do it right based on aggregated literature. [ABSTRACT FROM AUTHOR]

Objective: This study prospectively observed the incidence of all malignancies and the prognosis of all patients in a population of patients who achieved Sustained Virological Response (SVR) with a 100% capture rate. Design: A prospective study of 651 SVR cases was conducted from July 2013 to December 2021. The primary endpoint was the occurrence of all malignancies, and the secondary endpoint was overall survival. The cancer incidence during the follow-up period was calculated using the man-year method, and risk factors were analyzed. In addition, sex- and age-matched standardized mortality ratio (SMR) was used to compare the general population with the study population. Results: The overall median follow-up was 5.44 years. 107 malignancies occurred in 99 patients during the follow-up. The incidence of all malignancies was 3.94/100 person-years. The cumulative incidence was 3.6% at 1 year, 11.1% at 3 years, and 17.9% at 5 years, and continued to increase almost linearly. The incidence of liver cancer and non-liver cancer was 1.94/100 patient-years vs. 1.81%/100 patient-years. The 1-year, 3-year, and 5-year survival rates were 99.3%, 96.5%, and 94.4%, respectively. This life expectancy was compared to the standardized mortality ratio of the Japanese population, which proved non-inferior. Conclusion: It was found that malignancies of other organs occur as frequently as hepatocellular carcinoma (HCC). Therefore, follow-up of patients who have achieved SVR should focus not only on HCC but also on malignant tumors of other organs, and lifelong follow could contribute prolonged life expectancy for the previously short-lived. [ABSTRACT FROM AUTHOR]

Purpose: To analyze the benefits of laparoscopic common bile duct exploration and laparoscopic cholecystectomy (LCBDE + LC) versus endoscopic retrograde cholangiopancreatography and/or endoscopic sphincterotomy following laparoscopic cholecystectomy (ERCP/EST + LC) for difficult common bile duct stones combined with gallstones. Methods: A retrospective analysis of consecutive patients with difficult common bile duct stones combined with gallstones in three hospitals from January 2016 to January 2021 was performed. Results: ERCP/EST + LC contributed to reducing postoperative drainage time. However, LCBDE + LC showed a higher rate of complete clearance, along with lower postoperative hospital stays, expenses and incidence of postoperative hyperamylasemia, pancreatitis, re-operation and recurrence. In addition, LCBDE + LC showed safe and feasible performance in the elderly and patients with previous upper abdominal surgery. Conclusion: It is an effective and safe method for LCBDE + LC for difficult common bile duct stones combined with gallstones. [ABSTRACT FROM AUTHOR]

Objectives: To evaluate the diagnostic accuracy of perfluorobutane contrast-enhanced ultrasonography (CEUS) for hepatocellular carcinoma (HCC) and to explore how accuracy can be improved compared to conventional diagnostic criteria in at-risk patients. Methods: A total of 123 hepatic nodules (≥ 1 cm) from 123 at-risk patients who underwent perfluorobutane CEUS between 2013 and 2020 at three institutions were retrospectively analyzed. Ninety-three percent of subjects had pathological results, except benign lesions stable in follow-up images. We evaluated presence of arterial phase hyperenhancement (APHE), washout time and degree, and Kupffer phase (KP) defects. KP defects are defined as hypoenhancing lesions relative to the liver in KP. HCC was diagnosed in two ways: (1) Liver Imaging Reporting and Data System (LI-RADS) criteria defined as APHE and late (≥ 60 s)/mild washout, and (2) APHE and Kupffer (AK) criteria defined as APHE and KP defect. We explored grayscale features that cause misdiagnosis of HCC and reflected in the adjustment. Diagnostic performance was compared using McNemar's test. Results: There were 77 HCCs, 15 non-HCC malignancies, and 31 benign lesions. An ill-defined margin without hypoechoic halo on grayscale applied as a finding that did not suggest HCC. Regarding diagnosis of HCC, sensitivity of AK criteria (83.1%; 95% confidence interval [CI]: 72.9–90.7%) was higher than that of LI-RADS criteria (75.3%; 95% CI: 64.2–84.4%; p = 0.041). Specificity was 91.3% (95% CI: 79.2–97.6%) in both groups. Conclusion: On perfluorobutane CEUS, diagnostic criteria for HCC using KP defect with adjustment by grayscale findings had higher diagnostic performance than conventional criteria without losing specificity. Key Points: • Applying Kupffer phase defect instead of late/mild washout and adjusting with grayscale findings can improve the diagnostic performance of perfluorobutane-enhanced US for HCC. • Adjustment with ill-defined margins without a hypoechoic halo for features unlikely to be HCC decreases false positives for HCC diagnosis using the perfluorobutane-enhanced US. • After adjustment with grayscale findings, the sensitivity and accuracy of the APHE and Kupffer criteria were higher than those of the LI-RADS criteria; specificity was 91.3% for both. [ABSTRACT FROM AUTHOR]

Background: Portal vein thrombus (PVT) in cirrhotic patients is associated with worsening portal hypertension, leads to increased complexity of necessary interventions such as transjugular liver portosystemic shunt or liver transplantation, and is associated with worse outcomes after liver transplantation. Additionally, there are no established consensus guidelines for management of bland PVT in cirrhotic patients, which currently exists on a spectrum and is patient and provider dependent. Purpose: The aim of this study was to determine whether there are associations between key clinical and imaging variables and bland PVT burden over time. Material and Methods: This exploratory, retrospective, single-center study included patients who underwent two or more multiphase CT or MRI examinations between 1/1/2013 and 12/31/2019 and had a diagnosis of PVT. Three readers independently evaluated all index and follow-up examinations for PVT burden using a proposed 8-point scale and the established Yerdel score. Key clinical factors were collected from the electronic medical record. The PVT burden over time and the association of this burden with key clinical and imaging variables were assessed using logistic regression models. Results: 138 patients with cirrhosis and bland PVT were included in the analyses. Median age was 60 years (interquartile range 55–67; 90 men) and median follow-up time was 19.6 months. At baseline, the mean score was 2.31 (± 1.44) and at the final follow-up examination, the mean score was 2.52 (± 1.99). Baseline occlusion level was the only statistically significant association with worsening PVT burden in all four vascular territories (p-value < 0.0001). Anticoagulation status did not have a statistically significant association with change in thrombus burden in any vascular territory or cumulative thrombus burden across all territories (p-value 0.11–0.43). Conclusion: In conclusion, our study shows that in cirrhotic patients with bland PVT, the thrombus burden did not change significantly over time and baseline thrombus burden is the only clinical factor significantly associated with increasing burden over time. [ABSTRACT FROM AUTHOR]

Background: Lenvatinib combined with pembrolizumab showed a promising result in an early phase study for hepatocellular carcinoma (HCC). The efficacy and safety of lenvatinib plus pembrolizumab for patients with unresectable HCC (uHCC) beyond the first-line setting were unclear. Methods: Seventy-one consecutive patients who received lenvatinib plus pembrolizumab for uHCC were prospectively enrolled. Effect of lenvatinib combinations on Albumin-Bilirubin (ALBI) score and factors associated with progression-free survival (PFS) and overall survival (OS) were analyzed. Results: Of the 71 cases, 58 (81.7%) were in BCLC C. There were 44 (62%) for the first-line systemic treatment, and 27 (38%) had experienced targeted therapy or nivolumab treatment. The objective response rate and disease control rate (DCR) were 34.1% and 84.1% for the first-line setting, and 18.5% and 70.4% for systemic therapy-experienced cases (Response Evaluation Criteria in Solid Tumors version 1.1, RECIST v1.1), respectively. The mean ALBI score was stable during the treatment course. After a median of 9.3 months of follow-up, the median PFS was 9.3 months versus 4.4 months, and the median OS was not estimable yet versus 12 months for Child–Pugh A versus B patients, respectively. Prior nivolumab failure was the only significant factor associated with poorer PFS (HR = 3.253, p = 0.004). Child–Pugh class B (HR = 2.646, p = 0.039) and prior nivolumab failure (HR = 3.340, p = 0.014) were independent factors for poorer OS in multivariate analysis. Conclusions: A high DCR was observed by lenvatinib/pembrolizumab combination without adverse effect on ALBI score for systemic therapy-naïve and -experienced uHCC. Suboptimal response to prior nivolumab-failed patients requires further exploration. [ABSTRACT FROM AUTHOR]

Selective internal radiation therapy represents an endovascular treatment option for patients with primary liver malignancies, in different clinical stages. Potential applications of this treatment are in early-stage hepatocellular carcinoma, as a curative option, or in combination with systemic treatments in intermediate and advanced-stages. This review, based on existing literature and ongoing trials, will focus on the future of this treatment in patients with hepatocellular carcinoma, in combination with systemic treatments, or with the use of new devices and technological developments; it will also describe new potential future indications and structural and organizational perspectives. [ABSTRACT FROM AUTHOR]

Opinion statement: Sarcomas are a rare group of tumors with many subtypes, conventionally classified into soft-tissue sarcomas and bone sarcomas. Chemotherapeutic regimens form the mainstay of systemic therapy but are not well defined beyond the first-line setting and clinical outcomes are variable. Tyrosine kinase inhibitors (TKIs), with a broad inhibition profile which have been shown to target tumor angiogenesis, have an established role in the treatment of sarcomas without characteristic driver alterations. One such TKI, regorafenib, has been evaluated in sarcomas and clinical data are discussed in this review. An overview of regorafenib data from five phase 2 and one phase 1b clinical trials in over 10 sarcoma subtypes (both soft-tissue and bone) in adult and pediatric patients is reviewed. Regorafenib demonstrated clinical benefit in patients with non-adipocytic soft-tissue sarcomas, osteosarcoma and Ewing sarcoma who had progressed on prior therapy. Patients with otherwise limited treatment options may therefore benefit from regorafenib therapy. Plain language summary: Sarcomas are a type of cancer that start from the bones or soft tissues (such as muscle, blood vessel, or fat tissue) anywhere in the body. Sarcomas are rare – only about 1% of all cancers are sarcomas, and there are many different types. Sarcomas occur more often in children than in adults. People with sarcomas which cannot be removed by surgery are usually treated with chemotherapy first, but chemotherapy may only help some people and can cause a lot of side effects. Only a few chemotherapies work in sarcomas, and if they do not work or stop working the patient does not have many other treatment options. A different type of therapy known as "tyrosine kinase inhibitors" may work in these patients. These medicines, usually swallowed as a pill, target the way that sarcoma cells grow and may help patients in whom chemotherapy has not worked. Medical doctors and scientists tested "regorafenib", a type of tyrosine kinase inhibitor, in clinical trials. This publication summarizes the results from six clinical trials that tested regorafenib in over 500 adults, teenagers, and children with sarcomas. People included in these trials had more than ten different types of sarcomas in total, and usually had already received a treatment that had not stopped the sarcoma from growing. Regorafenib treatment helped people with certain types of sarcomas that developed from bones or soft tissues, but not fat tissue. Doctors also managed the side effects of regorafenib well for patients in these trials. [ABSTRACT FROM AUTHOR]

We describe here 11 consecutive patients with recurrence of high-grade glioma treated with regorafenib at our university medical center. The majority of patients had MGMT promoter methylation (9/11 cases). Regorafenib was given as 2nd line systemic treatment in 6/11 patients and 3rd or higher line treatment in 5/11 patients. The median number of applied cycles was 2 with dosage reductions in 5/11. Response to treatment was observed in 4/11 (PR in 1/11, and SD in 3/11). Median overall survival for the cohort was 16.1 months, median progression-free survival 9.0 months, and median time to treatment failure 3.3 months. Side effects of any CTCAE grade were noted in all patients, hereby 6/11 with CTCAE °III-IV reactions. High-grade side effects were of dermatologic, cardiovascular, and hematologic nature. A mean treatment delay of 57.5 days (range 23–119) was noted between tumor board recommendation and treatment initiation due to the application process for off-label use in this indication. In conclusion, treatment with regorafenib in relapsed high-grade glioma is a feasible treatment option but has to be considered carefully due to the significant side effect profile. [ABSTRACT FROM AUTHOR]

Low molecular weight proteins (LMWPs) in the bloodstream participate in various biological processes and are closely associated with disease status, whereas identification of serous LMWPs remains a great technical challenge due to the wide dynamic range of protein components. In this study, we constructed an integrated LMWP library by combining the LMWPs obtained by three enrichment methods (50% ACN, 20% ACN + 20 mM ABC, and 30 kDa) and their fractions identified by the data-dependent acquisition method. With this newly constructed library, we comprehensively profiled LMWPs in serum using data-independent acquisition and reliably achieved quantitative results for 75% serous LMWPs. When applying this strategy to quantify LMWPs in human serum samples, we could identify 405 proteins on average per sample, of which 136 proteins were with a MW less than 30 kDa and 293 proteins were with a MW less than 65 kDa. Of note, pre- and post-operative gastric carcinoma (GC) patients showed differentially expressed serous LWMPs, which was also different from the pattern of LWMP expression in healthy controls. In conclusion, our results showed that LMWPs could efficiently distinguish GC patients from healthy controls as well as between pre- and post-operative statuses, and more importantly, our newly developed LMWP profiling platform could be used to discover candidate LMWP biomarkers for disease diagnosis and status monitoring. [ABSTRACT FROM AUTHOR]

Background: The phase 2 REGOMA trial suggested an encouraging overall survival benefit in glioblastoma patients at first relapse treated with the multikinase inhibitor regorafenib. Here, we evaluated the efficacy and side effects of regorafenib in a real-life setting. Methods: From 2018 to 2021, 30 patients with progressive WHO CNS grade 3 or 4 gliomas treated with regorafenib (160 mg/day; first 3 weeks of each 4-week cycle) with individual dose adjustment depending on toxicity were retrospectively identified. Side effects were evaluated according to the Common Terminology Criteria for Adverse Events (version 5.0). MRI was obtained at baseline and after every second cycle. Tumor progression was assessed according to RANO criteria. After regorafenib initiation, the median PFS and OS were calculated. Results: The median number of treatment lines before regorafenib was 2 (range 1–4). Most patients (73%) had two or more pretreatment lines. At first relapse, 27% of patients received regorafenib. A total of 94 regorafenib cycles were administered (median 2 cycles; range 1–9 cycles). Grade 3 and 4 side effects were observed in 47% and 7% of patients, respectively, and were not significantly increased in patients with two or more pretreatments (P > 0.05). The most frequent grade 3 or 4 side effects were laboratory abnormalities (62%). PFS was 2.6 months (range 0.8–8.2 months), and the OS was 6.2 months (range 0.9–24 months). Conclusions: In patients with progressive WHO grade 3 or 4 gliomas, predominantly with two pretreatment lines or more, regorafenib seems to be effective despite considerable grade 3 or 4 side effects. [ABSTRACT FROM AUTHOR]

Purpose: Gadoxetic acid uptake on hepatobiliary phase MRI has been shown to correlate with ß-catenin mutation in patients with HCC, which is associated with resistance to certain therapies. This study aimed to evaluate the prognostic value of gadoxetic acid uptake on hepatobiliary phase MRI in patients with advanced HCC receiving sorafenib. Methods: 312 patients with available baseline hepatobiliary phase MRI images received sorafenib alone or following selective internal radiation therapy (SIRT) within SORAMIC trial. The signal intensity of index tumor and normal liver parenchyma were measured on the native and hepatobiliary phase MRI images, and relative tumor enhancement higher than relative liver enhancement were accepted as high gadoxetic acid uptake, and its prognostic value was assessed using univariate and multivariate Cox proportional hazard models. Results: The median OS of the study population was 13.4 (11.8–14.5) months. High gadoxetic acid uptake was seen in 51 (16.3%) patients, and none of the baseline characteristics was associated with high uptake. In univariate analysis, high gadoxetic acid uptake was significantly associated with shorter overall survival (10.7 vs. 14.0 months, p = 0.005). Multivariate analysis confirmed independent prognostic value of high gadoxetic acid uptake (HR, 1.7 [1.21–2.3], p = 0.002), as well as Child–Pugh class (p = 0.033), tumor diameter (p = 0.002), and ALBI grade (p = 0.015). Conclusion: In advanced HCC patients receiving sorafenib (alone or combined with SIRT), high gadoxetic acid uptake of the tumor on pretreatment MRI, a surrogate of ß-catenin mutation, correlates with shorter survival. Gadoxetic acid uptake status might serve in treatment decision-making process. [ABSTRACT FROM AUTHOR]

The present study aimed to determine antiproliferative, antimicrobial, antioxidant activities and also phytochemical composition of different nine Adonis L. species from Turkey. Leaves extracts of the plant samples were used to evaluate antimicrobial activity against 7 bacteria and 2 yeast strains using MICs and disc-diffusion methods. The antioxidant activity of plant samples was determined by using DPPH radical scavenging activity method. MTT assay was used for evaluation antiproliferative activities of the extracts against HL-60, HCA-7 and HUVEC human cells. Chemical composition of plant extracts were determined by Gas Chromatography/Mass Spectrometry. The antimicrobial analyses results showed Gram-negative bacteria more sensitive than Gram-positive against the extracts, and the values were varied from 3.1 to 13.4 μg/mL. The leaf extract of different Adonis species exhibited remarkable antiproliferative activities towards tested human cancer cells in a dose and time dependently, and they were found to possess more antiproliferative activity against HL-60 cells than that of the HCA-7 cells. As for the chemical composition of Adonis species, they were found to contain many components with antimicrobial and beneficial effects, such as ethyl palmitate, ethyl linoleate. Overall, it was concluded that leaves extracts of Adonis species could have a great potential for use in medicinal drug sources. [ABSTRACT FROM AUTHOR]

Lenvatinib, a multi-tyrosine kinase inhibitor that inhibits vascular endothelial growth factor and fibroblast growth factor receptors pathway, activated the immune response in tumor microenvironment. However, the combination of lenvatinib and anti-PD-1 has been reported in early phase studies. Hence, this study aims to explore the efficacy and toxicity of lenvatinib combined with nivolumab in the real-world setting. Advanced HCC patients who underwent lenvatinib combined with nivolumab (L + N group) treatment at Taipei Veterans General Hospital (Taipei, Taiwan) were reviewed between January 2016 and December 2020. Treatment response and outcomes were collected and analyzed. A control group with lenvatinib (L group) was also included for comparison. Forty patients were included in L + N group and 47 in L group. The L + N group demonstrated a higher objective response rate than L group (45.0% vs. 23.4%, p = 0.03). The L + N group also achieved longer PFS (7.5 vs. 4.8 months, p = 0.05) and OS (22.9 vs. 10.3 months, p = 0.01) than L group. Patients with HBV infection and REFLECT criteria fit demonstrated a trend of better prognosis. The PFS for those with PR, SD and PD groups were 11.2, 6.4, and 2.2 months and OS were non-reached, 14.6 and 4.7 months, respectively. Portal vein thrombosis (HR 4.3, 95% C.I. 1.5–12.8) and AFP > 400 ng/mL (HR 3.3, 95% C.I. 1.1–9.3) were poor prognostic factors and nivolumab used remained a protective factor (HR 0.2, 95% C.I. 0.1–0.7). Dermatitis (35.0%), pruritis (27.5%), and hypothyroidism (27.5%) were the common toxicities. Few patients developed grade 3/4 toxicities, including dermatitis (15%), gastrointestinal bleeding (7.5%), hypertension (5.0%), pneumonitis (2.5%) and stomatitis (2.5%). This is the first real-world data reporting the promising efficacy and tolerable toxicities of lenvatinib combined with nivolumab in advanced HCC. Further randomized trials are prompted. [ABSTRACT FROM AUTHOR]

With advances in technologic approaches in patients with cirrhosis, including the improvement of management, a simple, one-step approach for advanced fibrotic state of the liver is clinically useful. Although refining the diagnosis of cirrhosis to reflect disease heterogeneity is essential, current diagnostic tests have not kept pace with the progression of this new paradigm. There are unmet needs in primary care centers with respect to patients with cirrhosis. Liver biopsy and measurement of hepatic venous pressure gradient in patients with cirrhosis are the gold standards for the estimation of hepatic fibrosis, and they have diagnostic and prognostic value. However, both approaches are invasive and cannot be used repeatedly in clinical practice. Ultrasonography (US) is safe, easy to perform, inexpensive, and yields numerical and accurate results. Conventionally, the size of the liver and spleen, bluntness of the liver edge, nodularity of the liver surface, and coarseness of the liver parenchyma have been known as useful parameters for hepatic fibrosis or portal hypertension (PHT) in chronic liver disease. Additionally, some functional US indices including Doppler and CEUS-based examination have been suggested as promising markers for diagnosing cirrhosis and PHT. Identification of the reproducibility and long-term prognostic value through further investigations can demonstrate the clinical usefulness of functional US indices, which are characterized as quantitative parameters for hepatic fibrosis and PHT. [ABSTRACT FROM AUTHOR]

Purpose: Sorafenib is an oral multikinase inhibitor with regulatory approval in advanced renal cell carcinoma (RCC), hepatocellular carcinoma (HCC) and refractory differentiated thyroid carcinoma (DTC). Vascular endothelial growth factor receptor (VEGFR) inhibitors like sorafenib may cause proteinuria. This study aimed to analyze the effectiveness and safety of sorafenib in RCC, HCC and DTC patients with chronic kidney disease (CKD). Methods: This retrospective study analyzed integrated data from prospective post-marketing surveillance studies for advanced RCC, HCC and DTC. Background factors considered to affect patients' prognosis were balanced by propensity score matching using eGFR cut-off values of 60 mL/min/1.73 m2. Results: In the combined matched population (N = 2430), sorafenib was equally effective in patients with lower and higher eGFR values. Sorafenib had an overall response rate (ORR: complete + partial responses) of 18.9% and a disease control rate (DCR: complete + partial responses + stable disease) of 67.0%. There were no significant differences between lower and higher eGFR groups for response rates. Renal function was maintained throughout the 12-month study period in the combined population and in each indication. Adverse events (AEs) and serious AEs were reported in 91.6% and 58.2% of propensity score-matched patients, and with no significant differences between lower and higher eGFR groups. Conclusion: The effectiveness and safety of sorafenib were similar in patients with eGFR < 60 and ≥ 60 mL/min/1.73 m2 during the 12-month observation period, and without impairing renal function. [ABSTRACT FROM AUTHOR]

Background: Peroral cholangioscopy (POCS) has been used to overcome the difficulty in diagnosing indeterminate biliary stricture or tumor spread. However, the value of adding POCS to computed tomography (CT) remains unclear. Our aim was to evaluate the diagnostic value of adding POCS to CT for indeterminate biliary stricture and tumor spread by interpretation of images focusing on the high diagnostic accuracy of visual findings in POCS. Methods: We retrospectively identified 52 patients with biliary stricture who underwent endoscopic retrograde cholangiography (ERC) at our institution between January 2013 and December 2018. Two teams, each composed of an expert endoscopist and surgeon, performed the interpretation independently, referring to the CT findings of the radiologist. The CT + ERC + POCS images (POCS group) were evaluated 4 weeks after the evaluation of CT + ERC images (CT group). A 5-point scale (1: definitely benign to 5: definitely malignant) was used to determine the confident diagnosis rate, which was defined as an evaluation value of 1 or 5. Tumor spread was also evaluated. Results: In the evaluation of 45 malignant diagnoses, the score was significantly closer to 5 in the POCS group than in the CT group in both teams (P < 0.001). The confident diagnosis rate was significantly higher for the POCS group (92% and 73%) than for the CT group (25% and 12%) in teams 1 and 2, respectively (P < 0.001). We found no significant difference in diagnostic accuracy for tumor spread between the groups. Conclusion: Visual POCS findings confirmed the diagnosis of biliary strictures. POCS was useful in cases of indefinite diagnosis of biliary strictures by CT. [ABSTRACT FROM AUTHOR]

Despite advances in noninvasive techniques for imaging the pancreaticobiliary system, several disease processes including indeterminate biliary strictures as well as neuroendocrine tumors, inflammatory pseudotumors, and complex cysts of the pancreas remain difficult to characterize. New endoscopic imaging technologies have emerged to address these challenges. Cholangioscopy and intraductal ultrasound (IDUS) are powerful tools to characterize subtle biliary concretions and strictures. Confocal Laser Endomicroscopy (CLE) and Optical Coherence Tomography (OCT) are emerging approaches for the most difficult biliary lesions. Contrast harmonic endoscopic ultrasound (CH-EUS), elastography, and 3D-EUS are improving the approach to subtle pancreatic lesions, particularly in the context of indeterminate tissue sampling. Pancreatoscopy, pancreatic IDUS, and intracystic CLE hold promise to further improve the assessment of pancreatic cysts. We aim to comprehensively review the emerging clinical evidence for these innovative endoscopic imaging techniques. [ABSTRACT FROM AUTHOR]

Cymbal transducers have been discovered as a viable design for piezoelectric energy harvesting under heavy impact loads. However, low-output voltage remains a source of concern; therefore, many promising approaches for enhancing performance efficiency are crucial in the field of piezoelectricity. This study presents a viable angular poling approach for flex tensional based cymbal structures solely for energy harvesting applications. Elementary and Euler angular poling are two types of angular poling introduced for cymbal piezoelectric transducers. Using the energy method, theoretical modelling is performed on a cymbal structure exposed to a 1000 N impact force. Pb(Mg1/3Nb2/3)O3-PbTiO3 (PMN-0.33 PT) is utilised as a piezoelectric material because of its strong piezoelectric properties in both tetragonal and rhombohedral symmetry. The findings show that Euler angular poling outperforms elementary angular poling due to its reliance on two angles. When elementary angular poling is used, the voltage and energy reach 108.9 V and 380.1 μJ, respectively, resulting in a 198.02% and 2800% enhancement over the original PMN-0.33PT material. Similarly, in Euler angular poling, voltage and energy reached 123.59 V and 450 μJ, respectively, resulting in increase of 238.1% and 3340%. Finally, potential applications include powering light-emitting diodes and charging small portable electronic devices such as digital cameras and cell phones. A large-scale system can be built using cymbal piezoelectric tiles, making it suitable for use in industrial applications such as ultrasonic welding, diesel fuel injectors, and robotic systems. [ABSTRACT FROM AUTHOR]

Syringopicroside is a kind of iridoid monomer compound isolated from Syringa oblata exhibiting a potent effect against hepatitis B virus (HBV). The therapeutic effect and safety of syringopicroside-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles (SYR-NP) were studied on the model of HBV-infected ducklings and on cultured HepG2.2.15 cells. HBV DNA in ducklings was assessed by fluorescence quantitative PCR. In HepG2.2.15 cells, the content of HBsAg and HBeAg were assayed. Acute toxicity of SYR-NP was studied in ICR mice in 12 h and 7 days after SYR-NP administration. The serum levels of HBV DNA in ducklings treated with SYR-NP in a high dose was significantly lower than in the control. In HepG2.2.15 cells treated with different doses of SYR-NP, the concentrations of HBsAg and HBeAg were significantly below the control. Acute toxicity test showed high safety of SYR-NP. Thus, SYR-NP can inhibit replication of HBV DNA and protect the liver tissue. [ABSTRACT FROM AUTHOR]

Background: Total hepatic vascular exclusion (THVE) is an essential technique to control hemorrhage during surgical treatment of advanced liver tumors or injury. However, surgeons often have difficulty securing the intrapericardial inferior vena cava (IVC) because few reports have described the anatomy around the supra-diaphragmatic IVC or the techniques and surgical outcomes for this procedure. This study presents our safe and feasible intrapericardial IVC approach, which is based on anatomical landmarks, and reports the surgical outcomes of this procedure. Methods: We performed THVE using our technique for hepatectomy, accompanied by resection of the hepatic vein confluence or tumor thrombectomy of the supra-hepatic IVC, in five patients between August 2011 and March 2018. Results: The mean operative time was 568 min (range: 240–820 min). The mean THVE time was 10 min (range: 5–15 min), with a mean blood loss of 1882 mL (range: 1010–3100 mL). Postoperatively, one patient was classified as Clavien-Dindo grade II due to medication for tachycardia, and two patients were classified as grade IIIa due to drainage of bile and pleural effusion, including one patient with tachycardia. The mean postoperative hospital stay was 26 days (range: 18–34 days). No patient exhibited decreased cardiac function during surgery or postoperatively, and no patient experienced thoracotomy or phrenic nerve paralysis. Conclusions: Anatomical landmarks are important to ensure a safe approach to the intrapericardial IVC. Incising the pericardium does not lead to serious problems. The transmediastinal, intrapericardial IVC approach for THVE is a feasible method to secure the supra-diaphragmatic intrapericardial IVC. [ABSTRACT FROM AUTHOR]

Purpose: To explore the potential correlation between baseline interleukin (IL) values and overall survival or objective response in patients with hepatocellular carcinoma (HCC) receiving sorafenib. Methods: A subset of patients with HCC undergoing sorafenib monotherapy within a prospective multicenter phase II trial (SORAMIC, sorafenib treatment alone vs. combined with Y90 radioembolization) underwent baseline IL-6 and IL-8 assessment before treatment initiation. In this exploratory post hoc analysis, the best cut-off points for baseline IL-6 and IL-8 values predicting overall survival (OS) were evaluated, as well as correlation with the objective response. Results: Forty-seven patients (43 male) with a median OS of 13.8 months were analyzed. Cut-off values of 8.58 and 57.9 pg/mL most effectively predicted overall survival for IL-6 and IL-8, respectively. Patients with high IL-6 (HR, 4.1 [1.9–8.9], p < 0.001) and IL-8 (HR, 2.4 [1.2–4.7], p = 0.009) had significantly shorter overall survival than patients with low IL values. Multivariate analysis confirmed IL-6 (HR, 2.99 [1.22–7.3], p = 0.017) and IL-8 (HR, 2.19 [1.02–4.7], p = 0.044) as independent predictors of OS. Baseline IL-6 and IL-8 with respective cut-off values predicted objective response rates according to mRECIST in a subset of 42 patients with follow-up imaging available (IL-6, 46.6% vs. 19.2%, p = 0.007; IL-8, 50.0% vs. 17.4%, p = 0.011). Conclusion: IL-6 and IL-8 baseline values predicted outcomes of sorafenib-treated patients in this well-characterized prospective cohort of the SORAMIC trial. We suggest that the respective cut-off values might serve for validation in larger cohorts, potentially offering guidance for improved patient selection. [ABSTRACT FROM AUTHOR]

This study aimed to evaluate the virucidal effect and potential use as a disinfectant of undiluted and diluted slightly acidic electrolyzed water (SAEW) on human noroviruses (HuNoVs) using the in vitro suspension test and in food test. The oxidization reduction potential of SAEW gradually decreased with the increase in distilled water volume. Moreover, as the volume of distilled water and the dilution ratio increased, the available chlorine concentration of the samples significantly decreased from 31.2 ± 0.63 (SAEW) to 1.3 ± 0.21 (1:10 dilution of SAEW solution) (p < 0.05). Undiluted SAEW presented the lowest pH (5.56 ± 0.02) and as SAEW was diluted in distilled water, the pH of the sample increased. Considering the standard reduction values of pathogenic virus (> 4.00 log reduction), the reduction value of HuNoVs in cabbage samples was 4.65 (GI.6) and 4.28 (GII.4) log. These results suggest the potential application of SAEW for inactivating HuNoVs in the food industry. [ABSTRACT FROM AUTHOR]

Although direct-acting antiviral (DAA)-based anti-hepatitis C virus (HCV) therapies are very effective for patients with genotypes 1 and 2, evidence of the efficacy of DAA-based therapy for the special population of patients with genotypes 3–6 is insufficient due to the relatively small number of these subjects in Japan. Human immunodeficiency virus (HIV)/HCV-co-infected patients are recommended to be treated as HCV-mono-infected patients by the latest version of the Japan Society of Hepatology guidelines. However, evidence of efficacy in patients with HIV/HCV genotype 3–6 co-infection is insufficient. Currently, HCV genotypes 3–6 can be treated with two DAA-based therapies, including glecaprevir (GLE)/pibrentasvir (PIB) therapy in Japan. We experienced a relatively rare case of a Japanese hemophilia patient co-infected with HIV/HCV genotype 4a. We evaluated resistance-associated substitutions (RASs) against GLE and PIB before GLE/PIB therapy and found that he had no RASs. He was treated with 12 weeks of GLE/PIB therapy and achieved a sustained virologic response at post-treatment weeks 24. Although the treatment was well tolerated, the patient developed hyper-low-density lipoproteinemia that was probably associated with HCV elimination during the therapy. Additional studies are needed to confirm the efficacy and safety of GLE/PIB therapy for this special population in Japan. [ABSTRACT FROM AUTHOR]

Purpose: To date, the optimal treatment for portal vein thrombosis (PVT) in cirrhotic patients has not been established in guidelines or consensus. We conducted a systematic review and meta-analysis to evaluate the effect of anticoagulation therapy in patients with cirrhosis and PVT. Methods: PubMed, Embase, the Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov were searched (until 31st October 2020) for studies evaluating the effect of anticoagulation therapy on treating PVT in patients with cirrhosis. Odds ratios (ORs) and their 95% confidence intervals (CIs) were pooled using the Mantel–Haenszel method. Results: A total of 13 studies were included in the analysis, comprising 6005 patients. Of these, three were prospective cohort studies, nine were retrospective cohort studies and one was case–control study. Compared to no treatment, anticoagulation therapy was associated with higher rates of PVT recanalization (OR 4.29; 95% CI 3.01–6.13). Anticoagulation therapy demonstrated a significant 74% reduction in PVT extension compared to no treatment (OR 0.26; 95% CI 0.14–0.49). Anticoagulation therapy was associated with a nonsignificantly lower risk of death (OR 0.53; 95% CI 0.20–1.40). However, anticoagulation therapy was associated with slightly higher risk of bleeding compared to no treatment (OR 1.16; 95% CI 1.02–1.32). Conclusions: In cirrhotic patients with PVT, anticoagulation therapy helps increase rate of PVT recanalization and improve survival, but may also carry higher risks of bleeding compared to no treatment. Our findings support the use of anticoagulation in cirrhotic patients with PVT. [ABSTRACT FROM AUTHOR]

Background: Recently, three published phase III trials highlighted the superiority of investigational drugs compared to placebo, thus leading to their approval in the second-line setting. We report here a MAIC of second-line MKI options for patients with HCC previously treated with sorafenib using individual real-world data of regorafenib and aggregate data of second-line cabozantinib from the CELESTIAL trial. Methods: Data from 278 patients who received regorafenib as second-line therapy after sorafenib failure for unresectable HCC were used as IPD. Data inclusion were adapted to those reported in the CELESTIAL trial in the subset of patients who received sorafenib as the only prior therapy. Survival medians and rates were obtained from Kaplan–Meier curves, and differences between regorafenib and cabozantinib groups were explored through Cox regression adjusted for weights originating from MAIC. Results: The median OS of the weighted regorafenib group was 11.1 months (IQR: 5.6–16.4) and 11.3 (IQR: 6.7–22.4) for cabozantinib; HR 0.83 (95%CI 0.62–1.09). The median PFS of the weighted regorafenib group was 3.0 months (IQR: 1.9–4.8) and 5.5 (IQR: 2.3–9.3) for cabozantinib; HR 0.50 (95%CI 0.41–0.62). In the subgroup who received prior sorafenib for < 3 months, the median OS of the regorafenib group was 6.5 months (IQR: 4.7–10.9) and 9.5 months (IQR: 5.9–18.2) for cabozantinib; HR 0.68 (95%CI 0.39–1.16). In the subgroup receiving prior sorafenib for 3 to < 6 months, the median OS of the regorafenib group was 8.0 months (IQR: 4.2–15.2) and 11.5 (IQR: 6.5–23.9) for cabozantinib; HR 0.66 (95%CI 0.42–1.02). In the subgroup receiving prior sorafenib for ≥ 6 months, the median OS of the regorafenib group was 13.4 (IQR: 8.1–46.5) and 12.3 (IQR: 6.6–22.9) for cabozantinib; HR 0.89 (95%CI 0.52–1.51). Conclusion: Our results confirmed no differences between regorafenib and cabozantinib in terms of OS. However, in earlier progressors on prior sorafenib a larger benefit might be expected from cabozantinib treatment. [ABSTRACT FROM AUTHOR]

Purpose: Long-term effects on patient health-related quality of life (HRQoL) after direct-acting antiviral (DAA) treatment for hepatitis C virus (HCV) are unknown. We assessed the impact of DAA-mediated HCV clearance on HRQoL from DAA initiation to 1 year after confirmed sustained virological response at 24 weeks post-treatment (SVR24). Methods: HRQoL was evaluated using the eight-item Short Form Health Survey (SF-8). Chronic HCV-infected patients were treated for 12 weeks with sofosbuvir-based DAAs. SF-8 was administered at baseline, treatment cessation, SVR24, and 1-year post-SVR24. Results: A total of 109 chronic HCV-infected patients were enrolled. The average SF-8 scores were higher than the Japanese national standard values for bodily pain (BP) and mental health at baseline and for general health at 1-year post-SVR24. None of the SF-8 scores differed significantly between baseline and 1-year post-SVR24. Regarding age, sex, liver status, and treatment regimen, the SF-8 scores at 1-year post-SVR24 were affected by only age; individuals aged < 65 years had significantly higher physical component score (PCS), physical functioning, role physical, and BP scores than older individuals. In the multivariable analysis, only age of ≥ 65 years was significantly associated with influencing PCS at 1-year post-SVR24. However, no significant factors were identified for mental component score. Conclusion: Upon long-term assessment, although more factors trended higher than national standard values at 1-year post-SVR24 than at baseline, there were no significant changes within factors. As PCS tended to be associated with age, patients aged ≥ 65 years should be carefully monitored for PCS. [ABSTRACT FROM AUTHOR]

Background: To evaluate the lateral extent of extrahepatic cholangiocarcinoma, the value of cholangioscopy-guided mapping biopsy (CMB) compared with that of fluoroscopy-guided mapping biopsy (FMB) remains unknown. The aim of this study was to compare these two techniques. Methods: In this prospective, randomized, crossover study, both CMB and FMB techniques were performed for all patients in a randomized order. Target sites for the mapping biopsy were determined based on resection lines of possible surgical procedures. At least two biopsy strokes were attempted at each target site. The primary outcome was the rate of site-based successful biopsies, which was defined as acquisition of epithelium-containing material appropriate for diagnosing benignancy/malignancy from each site, regardless of amount of materials obtained from the same site. Results: Between September 2016 and October 2018, 28 patients (16 distal bile duct cancer and 12 perihilar bile duct cancer) were enrolled and divided into two groups of 14 patients: CMB first and FMB first. Although all 118 target sites could be approached using CMB, FMB forceps reached only 71% of them with significantly poor accessibility to the B2/3 confluence. Since several materials were too small and did not contain epithelium, the overall rates of site-based successful biopsies were 78% (92/118) using CMB and 64% (76/118) using FMB (P = 0.031). Conclusions: The rate of site-based successful biopsies using CMB was significantly higher than that using FMB when evaluated using specimens obtained from several biopsy strokes. [ABSTRACT FROM AUTHOR]

Purpose: Early detection of pancreatic ductal adenocarcinoma (PDAC) may improve the prognosis. We evaluated novel imaging findings that may contribute to early detection. Methods: This single-center, retrospective study enrolled 37 patients with a localized main pancreatic duct (MPD) stricture and no obvious pancreatic mass. All patients underwent endoscopic retrograde cholangiopancreatography and brush sampling with cytology and serial pancreatic juice aspiration cytologic examination via endoscopic naso-pancreatic drainage. Patients with cytology-confirmed malignancy underwent surgical resection. The remaining patients were followed by contrast-enhanced computed tomography (CECT), magnetic resonance imaging (MRI), and endoscopic retrograde cholangiopancreatography. Results: Twenty patients had confirmed malignancy (cancer group) and 17 did not (non-cancer group). Age, MPD stricture location, and PDAC risk factors were similar, but the sex predominance and symptom rate differed between the two groups. In the cancer group, 17 patients were diagnosed by cytology and three by clinical symptoms. CECT, MRI, and endoscopic ultrasonography (EUS) revealed no solid tumors in either group. CECT revealed no significant differences between groups. Diffusion-weighted MRI revealed significant differences in the signal intensity between groups. EUS detected indistinct and small hypoechoic areas in 70% and 41.2% of patients in the cancer and non-cancer groups, respectively. In the cancer group, 11 were diagnosed with cancer at the first indication, and nine were diagnosed at follow-up; the prognosis did not differ between these two subgroups.ss Conclusions: High signal intensity in diffusion-weighted MRI may be useful for detecting early-stage PDAC and may be an indication for surgical resection even without pathologic confirmation. Clinical trial registration: The study was a registered at the University Hospital Medical Information Network (UMIN000039623). [ABSTRACT FROM AUTHOR]

Summary: Purpose Despite the established activity of regorafenib in metastatic colorectal cancer (CRC), gastrointestinal stromal tumor (GIST), and hepatocellular carcinoma (HCC), its toxicity profile has limited clinical use. We aimed to evaluate the pharmacokinetics of regorafenib and its active metabolites M-2/M-5, and to clarify the relationships between total drug-related exposure and clinical outcomes in real-world practice. Methods Blood samples at steady state were obtained during Cycle 1 from patients treated with regorafenib. Plasma concentrations of regorafenib and its metabolites were measured by liquid chromatography–tandem mass spectrometry. The efficacy and safety endpoints were progression-free survival (PFS) and dose-limiting toxicities (DLTs), respectively. The exposure–response relationships were assessed. Results Thirty-four Japanese patients with advanced cancers were enrolled (CRC, n = 26; GIST and HCC, each n = 4). Nine patients started regorafenib treatment at the recommended dose of 160 mg once daily (3 weeks on / 1 week off), while the other patients received a reduced starting dose to minimize toxicities. The median PFS was significantly longer in patients achieving total trough concentrations (Ctrough) of regorafenib and M-2/M-5 ≥2.9 µg/mL than those who did not (112 vs. 57 days; p = 0.044). Furthermore, the cumulative incidence of DLTs during the first 2 cycles was significantly higher in patients with summed Ctrough levels ≥4.3 µg/mL than in others (p = 0.0003). Conclusions Dose titration of regorafenib to achieve drug-related Ctrough levels between 2.9 and 4.3 µg/mL in Cycle 1 may improve efficacy and safety, warranting further investigation in a larger patient population. Clinical trial registry: Not applicable. [ABSTRACT FROM AUTHOR]

The present study proposes a 3-dimensional approach for enhancing the effective piezoelectric properties by poling orientation. The governing parameters for actuation and sensing applications are d 31 and d 31 / ε 33 , respectively. The effective magnitudes of these parameters, i.e., d 31 eff and d 31 eff / ε 33 eff , change with poling angles (roll and pitch angles). The combination of poling angles corresponding to the maximum magnitude of d 31 eff and d 31 eff / ε 33 eff is called the optimum poling angle for piezoelectric materials. BaTiO3 and KNN piezoelectric materials with tetragonal symmetry show an enhancement in d 31 eff / ε 33 eff and d 31 eff at an optimized poling angle (roll angle). The piezoelectric material, 0.67Pb(Mg1/3Nb2/3)O3-0.33PbTiO3 (PMN-0.33PT) with rhombohedral symmetry, shows a maximum improvement of 575% in d 31 eff / ε 33 eff at an optimum roll angle of 29° and a pitch angle of 60°. On the other hand, PMN-0.33PT shows an enhancement of 2034.44% in the d 31 eff coefficient at optimum roll and pitch angles of 50° and 60°. The effect of poling orientation on different piezoelectric materials with tetragonal and rhombohedral symmetry has been studied for actuation and sensing applications. The experimental approach to achieve inclination of dipoles through the placement of electrodes for different piezoelectric materials is also discussed. [ABSTRACT FROM AUTHOR]

Background: The role of anticoagulation (AC) in the management of cirrhotic patients with portal vein thrombosis (PVT) remains unclear. Aims: We conducted a retrospective study of cirrhotic patients diagnosed with PVT from 1/1/2000 through 2/1/2019, comparing those who received AC to those who did not. Methods: Outcomes included rate of complete radiographic resolution (CRR) of PVT, recanalization of occlusive PVT (RCO), PVT extension, major bleeding, and overall survival (OS). The log-rank test was used to compare Kaplan–Meier distributions of time-to-event outcomes. Multivariable Cox-proportional-hazards modeling was used to estimate adjusted hazard ratios (HRs) with 95% confidence intervals. Results: A total of 214 patients were followed for a median 27 months (IQR 12–48). Eighty-six patients (39%) received AC. AC was associated with significantly greater CRR (48% vs. 27%, p = 0.0007), (multivariable HR for CRR with AC; 2.49 (1.54–4.04, p = 0.0002)). AC was also associated with significantly greater RCO (69% vs. 28%, p = 0.0013), (multivariable HR for RCO with AC; 4.86 (1.91–12.37, p = 0.0009)). Rates of major bleeding were similar with and without AC (20% vs. 17%, p = 0.5207), multivariable HR for major bleeding with AC; 1.29 (0.68–2.46, p = 0.4423)). OS rates in the AC and no-AC groups were 83% and 70%, respectively (p = 0.1362), (HR for death with AC; 0.69 (0.38–1.28, p = 0.2441)). Among 75 patients who had CRR, 10 (13%) experienced recurrent PVT during follow-up (none were receiving AC at the time of recurrence). Conclusions: AC appears safe and effective for the treatment of cirrhotic PVT; however, prospective studies to confirm these findings and evaluate additional outcomes are needed. [ABSTRACT FROM AUTHOR]

Bismuth layer-structured ferroelectric (BLSF) ceramics exhibit linearity in resistivity with respect to temperature changes, and therefore find application as high-temperature sensor materials. In this study, calcium bismuth titanate (CBT), a BLSF material, was synthesized by calcining combined oxide precursors at 850°C for 2 h, and its particle size distribution, phase analysis, grain size distribution and morphology were characterized. Circular discs were prepared by sintering in the temperature range of 1000 to 1200°C. The sintered discs were characterized for dielectric constant (K), P-E hysteresis loop and DC electrical resistivity (ρ) from 100 to 900°C. The highest density (> 95% Th.) was obtained for samples sintered at 1175°C. DC resistivity decreased linearly from 1014 to 105 Ω cm with the rise in temperature from 100 to 900°C, therefore confirming CBT as a prospective high-temperature sensor material. [ABSTRACT FROM AUTHOR]