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Background/Aims Chronic hepatitis C (CHC) patients who failed antiviral therapy are at increased risk for hepatocellular carcinoma (HCC). This study assessed the potential role of metformin and statins, medications for diabetes mellitus (DM) and hyperlipidemia (HLP), in reducing HCC risk among these patients. Methods We included CHC patients from the T-COACH study who failed antiviral therapy. We tracked the onset of HCC 1.5 years post-therapy by linking to Taiwan’s cancer registry data from 2003 to 2019. We accounted for death and liver transplantation as competing risks and employed Gray’s cumulative incidence and Cox subdistribution hazards models to analyze HCC development. Results Out of 2,779 patients, 480 (17.3%) developed HCC post-therapy. DM patients not using metformin had a 51% increased risk of HCC compared to non-DM patients, while HLP patients on statins had a 50% reduced risk compared to those without HLP. The 5-year HCC incidence was significantly higher for metformin non-users (16.5%) versus non-DM patients (11.3%; adjusted sub-distribution hazard ratio [aSHR]=1.51; P=0.007) and metformin users (3.1%; aSHR=1.59; P=0.022). Statin use in HLP patients correlated with a lower HCC risk (3.8%) compared to non-HLP patients (12.5%; aSHR=0.50; P

Abstract Favorable prognostic factors and therapeutic strategies are important for patients with single large hepatocellular carcinoma (HCC). This retrospective study aimed to investigate the prognostic factors in patients with single large (≥5 cm) HCC with Child‐Pugh (CP) class A patients and to recommend therapeutic strategies. Overall, 298 HCC patients with single and large (≥5 cm) tumors with CP class A, but without distant metastasis and macrovascular invasion were included, and their clinicopathological data, overall survival (OS), and progression‐free survival (PFS) were recorded. OS and PFS was analyzed by the Kaplan–Meier method and Cox regression analysis. Propensity score matching (PSM) analysis was performed. The 298 HCC patients were 79.2% male and median age of 64 years. For the initial treatment, surgical resection (SR) and transarterial chemoembolization (TACE) was 50.8% and 49.2%, respectively. The OS and PFS were significantly higher in patients receiving SR than those receiving TACE before and after PSM. Furthermore, in multivariate analysis, cirrhosis (Hazard ratio [HR]: 2.04; 95% confidence interval [CI]: 1.35–3.03, p

Abstract Hepatocellular carcinoma (HCC) is a highly invasive malignancy. Recently, GATOR1 (Gap Activity TOward Rags 1) complexes have been shown to play an important role in regulating tumor growth. NPRL2 is a critical component of the GATOR1 complex. Therefore, this study used NPRL2 knockdown to investigate how GATORC1 regulates the prognosis and development of HCC via the mammalian target of rapamycin (mTOR) and autophagy signaling pathways. We established HepG2 cells with NPRL2 knockdown using small interfering RNA (siRNA) and short hairpin RNA (shRNA) systems. The siRNA‐mediated and shRNA‐mediated NPRL2 down‐regulation significantly reduced the expression of NPRL2 and two other GATPOR1 complex components, NPRL3 and DEPDC5, in HepG2 cells; furthermore, the efficient down‐regulation of NPRL2 protein expression by both the shRNA and siRNA systems enhanced the proliferation, migration, and colony formation in vitro. Additionally, the NPRL2 down‐regulation significantly increased HCC growth in the subcutaneous and orthotopic xenograft mouse models. The NPRL2 down‐regulation increased the Rag GTPases and mTOR activation and inhibited autophagy in vitro and in vivo. Moreover, the NPRL2 level in the tumors was significantly associated with mortality, recurrence, the serum alpha fetoprotein level, the tumor size, the American Joint Committee on Cancer stage, and the Barcelona Clinic Liver Cancer stage. Low NPRL2, NPRL3, DEPDC5, and LC3, and high p62 and mTOR protein expression in the tumors was significantly associated with disease‐free survival and overall survival in 300 patients with HCC after surgical resection. Conclusion: The efficient down‐regulation of NPRL2 significantly increased HCC proliferation, migration, and colony formation in vitro, and increased HCC growth in vivo. Low NPRL2 protein expression in the tumors was closely correlated with poorer clinical outcomes in patients with HCC. These results provide a mechanistic understanding of HCC and aid the development of treatments for HCC.

Background/purpose: The Taiwan Association for the Study of the Liver (TASL) HCV Registry (TACR) is a nationwide registry of chronic hepatitis C patients in Taiwan. This study evaluated antiviral effectiveness of ledipasvir (LDV)/sofosbuvir (SOF) in patients in the TACR. Methods: Patients enrolled in TACR from 2017–2020 treated with LDV/SOF were eligible. The primary outcome was the proportion of patients with sustained virologic response 12 weeks after end of treatment (SVR12). Results: 5644 LDV/SOF ± ribavirin-treated patients were included (mean age: 61.4 years; 54.4% female). Dominant viral genotypes were GT1 (50.8%) and GT2 (39.3%). 1529 (27.1%) patients had liver cirrhosis, including 201 (3.6%) with liver decompensation; 686 (12.2%) had chronic kidney disease. SVR12 was achieved in 98.6% of the overall population and in 98.2% and 98.7% of patients with and without cirrhosis, respectively. SVR12 rates in patients with compensated cirrhosis treated with LDV/SOF without RBV were >98%, regardless of prior treatment experience. SVR12 was 98.6%, 98.4%, 100%, 100%, and 98.7% among those with GT1, GT2, GT4, GT5, and GT6 infections, respectively. Although patient numbers were relatively small, SVR12 rates of 100% were reported in patients infected with HCV GT2, GT5, and GT6 with decompensated cirrhosis and 98% in patients with severely compromised renal function. LDV/SOF adherence ≤60% (P

Abstract In cell culture environment, some cells adhere firmly to the culture plates and may be vulnerable to cell detachment during passage. Therefore, it is important to harvest cells with a proper detaching method to maintain the viability of cells after detachment. Trypsinization is frequently used for cellular dissociation and detachment. However, most surface proteins and the extracellular matrix are degraded by enzymatic digestion. A mild cell detachment buffer, accutase, is recommended for the replacement of trypsin to dissociate adherent cells and thereby avoid cellular damage. In this study, we demonstrated that use of accutase for cellular detachment may compromise some surface proteins. Compared with ethylenediaminetetraacetic acid (EDTA)-based nonenzymatic cell dissociation buffers, accutase was associated with significant decreases in the surface Fas ligands and Fas receptors. Moreover, we found that accutase may be able to cleave surface Fas ligands into pieces. Our results also illustrated that surface proteins required 20 h to recover after accutase treatment. We demonstrated that using accutase to dissociate adherent cells compromised the expression of Fas ligands and Fas receptors on the cell surface. These findings indicate that it is important to choose suitable cell detachment buffers and allow cells to recover after detachment before experiments.

Precise detection and localization of the Endotracheal tube (ETT) is essential for patients receiving chest radiographs. A robust deep learning model based on U-Net++ architecture is presented for accurate segmentation and localization of the ETT. Different types of loss functions related to distribution and region-based loss functions are evaluated in this paper. Then, various integrations of distribution and region-based loss functions (compound loss function) have been applied to obtain the best intersection over union (IOU) for ETT segmentation. The main purpose of the presented study is to maximize IOU for ETT segmentation, and also minimize the error range that needs to be considered during calculation of distance between the real and predicted ETT by obtaining the best integration of the distribution and region loss functions (compound loss function) for training the U-Net++ model. We analyzed the performance of our model using chest radiograph from the Dalin Tzu Chi Hospital in Taiwan. The results of applying the integration of distribution-based and region-based loss functions on the Dalin Tzu Chi Hospital dataset show enhanced segmentation performance compared to other single loss functions. Moreover, according to the obtained results, the combination of Matthews Correlation Coefficient (MCC) and Tversky loss functions, which is a hybrid loss function, has shown the best performance on ETT segmentation based on its ground truth with an IOU value of 0.8683.

Chest X-ray is a radiological clinical assessment tool that has been commonly used to detect different types of lung diseases, such as lung tumors. In this paper, we use the Segmentation-based Deep Fusion Networks and Squeeze and Excitation blocks for model training. The proposed approach uses both wholes and cropped lung X-ray images and adds an attention mechanism to address the problems encountered during lesion identification, such as image misalignments, possible false positives from irrelevant objects, and the loss of small objects after image resizing. Two CNNs are used for feature extraction, and the extracted features are stitched together to form the final output, which is used to determine the presence of lung tumors in the image. Unlike previous methods which identify lesion heatmaps from X-ray images, we use the Semantic Segmentation via Gradient-Weighted Class Activation Mapping (Seg-Grad-CAM) to add semantic data for improved lung tumor localization. Experimental results show that our method achieves 98.51% accuracy and 99.01% sensitivity for classifying chest X-ray images with and without lung tumors. Furthermore, we combine the Seg-Grad-CAM and semantic segmentation for feature visualization. Experimental results show that the proposed approach achieves better results than previous methods that use weakly supervised learning for localization. The method proposed in this paper reduces the errors caused by subjective differences among radiologists, improves the efficiency of image interpretation and facilitates the making of correct treatment decisions.

Abstract Background The detection rate of Barcelona Clinic Liver Cancer (BCLC) very-early-stage hepatocellular carcinoma (HCC) is increasing because of advances in surveillance and improved imaging technologies for high-risk populations. Surgical resection (SR) and radiofrequency ablation (RFA) are both first‐line treatments for very-early-stage HCC, but the differences in clinical outcomes between patients treated with SR and RFA remain unclear. This study investigated the prognosis of SR and RFA for very-early‐stage HCC patients with long‐term follow‐up. Methods This study was retrospectively collected data on the clinicopathological characteristics, overall survival (OS), and disease-free survival (DFS) of 188 very-early-stage HCC patients (≤ 2 cm single HCC). OS and DFS were analyzed using the Kaplan–Meier method and Cox regression analysis. Propensity score matching (PSM) analysis was performed. Results Of the 188 HCC patients, 103 received SR and 85 received RFA. The median follow‐up time was 56 months. The SR group had significantly higher OS than the RFA group (10-year cumulative OS: 55.2% and 31.3% in the SR and RFA groups, respectively). No statistically significant difference was observed in DFS between the SR and RFA groups (10-year cumulative DFS: 45.9% and 32.6% in the SR and RFA groups, respectively). After PSM, the OS in the SR group remained significantly higher than that in the RFA group (10-year cumulative OS: 54.7% and 42.2% in the SR and RFA groups, respectively). No significant difference was observed in DFS between the SR and RFA groups (10-year cumulative DFS: 43.0% and 35.4% in the SR and RFA groups, respectively). Furthermore, in the multivariate Cox regression analysis, treatment type (hazard ratio (HR): 0.54, 95% confidence interval (CI): 0.31–0.95; P = 0.032) and total bilirubin (HR: 1.92; 95% CI: 1.09–3.41; P = 0.025) were highly associated with OS. In addition, age (HR: 2.14, 95% CI: 1.36–3.36; P = 0.001) and cirrhosis (HR: 1.79; 95% CI: 1.11–2.89; P = 0.018) were strongly associated with DFS. Conclusion For patients with very-early-stage HCC, SR was associated with significantly higher OS rates than RFA. However, no significant difference was observed in DFS between the SR and RFA groups.

Abstract Background Autophagy-related proteins may predict postresection overall survival (OS) and disease-free survival (DFS) in patients with combined hepatocellular carcinoma and cholangiocarcinoma (cHCC-CC). Methods We prospectively investigated how these proteins affect clinical prognosis in 40 patients who underwent hepatectomy for cHCC-CC from 2011 to 2019 at a Taiwanese hospital. Levels of autophagy-related proteins, namely LC3, Beclin-1, and p62, were immunohistochemically assessed in patient tumor and non-tumor tissues. Results We noted that LC3 expression was significantly correlated with mild clinicopathological characteristics, including macrovascular invasion, lymph node metastasis, American Joint Committee on Cancer and Barcelona Clinic Liver Cancer stages, recurrence, and mortality. Ten patient showed tumor recurrence, and 15 patients died. Postresection 5-year OS and DFS rates were 43.7 and 57.4%, respectively. Cox regression analysis showed that high intratumoral LC3 expression was significantly associated with improved OS [hazard ratio (HR; 95% confidence interval (CI)): (1.68–26.9), p = 0.007], but multiple tumors and microvascular invasion was significantly correlated with poor OS [HR (95% CI): 0.03 (0.01–0.34), p = 0.004, and 0.07 (0.01–0.46), p = 0.006, respectively]. Furthermore, high LC3 expression and cirrhosis had improved DFS [HR (95% CI): 51.3 (2.85–922), p = 0.008, and 17.9 (1.05–306), p = 0.046, respectively]. The 5-year OS and DFS rates were respectively 61.2 and 74.6% in high LC3 expression patients and 0 and 0% in those with low LC3 expression. Conclusion High LC3 expression in tumors is significantly associated with mild clinicopathological characteristics and favorable clinical prognosis in patients with cHCC-CC after resection.

Abstract Background The benefits of surgical resection (SR) for various Barcelona Clinic Liver Cancer (BCLC) stages of hepatocellular carcinoma (HCC) remain unclear. We investigated the risk factors of overall survival (OS) and survival benefits of SR over nonsurgical treatments in patients with HCC of various BCLC stages. Methods Overall, 2316 HCC patients were included, and their clinicopathological data and OS were recorded. OS was analyzed by the Kaplan-Meier method and Cox regression analysis. Propensity score matching (PSM) analysis was performed. Results In total, 66 (2.8%), 865 (37.4%), 575 (24.8%) and 870 (35.0%) patients had BCLC stage 0, A, B, and C disease, respectively. Furthermore, 1302 (56.2%) of all patients, and 37 (56.9%), 472 (54.6%), 313 (54.4%) and 480 (59.3%) of patients with BCLC stage 0, A, B, and C disease, respectively, died. The median follow-up duration time was 20 (range 0–96) months for the total cohort and was subdivided into 52 (8–96), 32 (1–96), 19 (0–84), and 12 (0–79) months for BCLC stages 0, A, B, and C cohorts, respectively. The risk factors for OS were (1) SR and cirrhosis; (2) SR, cirrhosis, and Child–Pugh (C–P) class; (3) SR, hepatitis B virus (HBV) infection, and C–P class; and (4) SR, HBV infection, and C–P class for the BCLC stage 0, A, B, and C cohorts, respectively. Compared to non-SR treatment, SR resulted in significantly higher survival rates in all cohorts. The 5-year OS rates for SR vs. non-SR were 44.0% versus 28.7%, 72.2% versus 42.6%, 42.6% versus 36.2, 44.6% versus 23.5%, and 41.4% versus 15.3% (all P values

Abstract Background Combined hepatocellular carcinoma and cholangiocarcinoma (cHCC-CC) is an infrequent type of primary liver cancer that comprises hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC). This study investigated the clinicopathological features and prognosis among cHCC-CC, HCC, and CC groups. Methods We prospectively collected the data of 608 patients who underwent surgical resection for liver cancer between 2011 and 2018 at E-Da Hospital, I-Shou University, Kaohsiung, Taiwan. Overall, 505 patients with cHCC-CC, HCC, and CC were included, and their clinicopathological features, overall survival (OS), and recurrence were recorded. OS and recurrence rates were analyzed using the Kaplan–Meier analysis. Results In the entire cohort, the median age was 61 years and 80% were men. Thirty-five (7.0%) had cHCC-CC, 419 (82.9%) had HCC, and 51 (10.1%) had CC. The clinicopathological features of the cHCC-CC group were more identical to those of the HCC group than the CC group. OS was significantly lower in the cHCC-CC group than in the HCC group but was not significantly higher in the cHCC-CC group than in the CC group. The median OS of cHCC-CC, HCC, and CC groups was 50.1 months [95% confidence interval (CI): 38.7–61.2], 62.3 months (CI: 42.1–72.9), and 36.2 months (CI: 15.4–56.5), respectively. Cumulative OS rates at 1, 3, and 5 years in cHCC-CC, HCC, and CC groups were 88.5%, 62.2%, and 44.0%; 91.2%, 76.1%, and 68.0%; and 72.0%, 48.1%, and 34.5%, respectively. After propensity score matching (PSM), OS in the cHCC-CC group was not significantly different from that in the HCC or CC group. However, OS was significantly higher in the HCC group than in the CC group before and after PSM. Furthermore, the disease-free survival was not significantly different among cHCC-CC, HCC, and CC groups before and after PSM. Conclusion The clinicopathological features of the cHCC-CC group were more identical to those of the HCC group than the CC group. The OS rate was significantly lower in the cHCC-CC group than the HCC group. However, after PSM, OS and disease-free survival in the cHCC-CC group were not significantly different from those in the HCC or CC group.

Abstract Background Patients with Barcelona Clinic Liver Cancer (BCLC) stage B hepatocellular carcinoma (HCC) are recommended to undergo transcatheter arterial chemoembolization (TACE). However, TACE in combination with radiofrequency ablation (RFA) is not inferior to surgical resection (SR), and the benefits of surgical resection (SR) for BCLC stage B HCC remain unclear. Hence, this study aims to compare the impact of SR, TACE+RFA, and TACE on analyzing overall survival (OS) in BCLC stage B HCC. Methods Overall, 428 HCC patients were included in BCLC stage B, and their clinical data and OS were recorded. OS was analyzed by the Kaplan-Meier method and Cox regression analysis. Results One hundred forty (32.7%) patients received SR, 57 (13.3%) received TACE+RFA, and 231 (53.9%) received TACE. The OS was significantly higher in the SR group than that in the TACE+RFA group [hazard ratio (HR): 1.78; 95% confidence incidence (CI): 1.15–2.75, p = 0.009]. The OS was significantly higher in the SR group than that in the TACE group (HR: 3.17; 95% CI: 2.31–4.36, p

Background: We aimed to study the safety of cold snare polypectomy (CSP) for colorectal polyps in patients administered periprocedural antithrombotic agents. Methods: We searched the PubMed, Embase, and Cochrane Library databases through June 2021. The primary outcomes were the rates of delayed and immediate bleeding (requiring endoscopic hemostasis). Secondary outcomes included thromboembolic events. Meta-analysis using odds ratios (ORs) and corresponding 95% confidence intervals (CIs) was performed to compare the outcomes. Results: Seventeen studies, including five randomized trials, were included. Over 96% of polyps were ⩽1 cm. The pooled rates of delayed and immediate bleeding for patients receiving CSP and periprocedural antithrombotic agents were 1.6% and 10.5%, respectively. Both the delayed (OR = 4.02, 95% CI = 1.98–8.17) and immediate bleeding (OR = 5.85, 95% CI = 3.84–8.89) rates were significantly higher in patients using periprocedural antithrombotic agents than in non-users. Although both antiplatelet agents and anticoagulants increased the risk of delayed bleeding, the risks associated with the use of direct oral anticoagulants (DOACs; 2.5%) or multiple agents (3.9%) were particularly high. Compared to their counterparts, diminutive polyps and uncomplicated lesions not requiring hemoclipping were associated with lower risks of delayed bleeding (pooled estimates of 0.4% and 0.18%, respectively). Thromboembolic risk was similar among patients using and not using periprocedural antithrombotic agents. Conclusions: CSP with periprocedural antiplatelet agents and warfarin may be feasible, especially for diminutive polyps. However, drug discontinuation should be considered with the use of DOACs or multiple agents which entail higher bleeding risk even with hemoclipping.

Abstract Background The role of Axl and LC3 as predictors of tumor recurrence and overall survival (OS) after hepatocellular carcinoma (HCC) resection remains unclear. Methods We retrospectively included 535 HCC patients who underwent hepatectomy from 2010 to 2014 in this study. Axl and the autophagy‐related marker LC3 were immunohistochemically assessed in tumors. Results Axl expression was significantly associated with advanced clinicopathological features, including cirrhosis, microvascular invasion, macrovascular invasion, tumor size, BCLC stage, recurrence, and mortality. HCC recurrence occurred in 245 patients, and 219 patients died. The 5‐year cumulative incidences of HCC recurrence and OS rate after HCC resection were 53.3% and 58.8%, respectively. In the Cox proportional analyses, high Axl expression and high LC3 expression were significantly associated with HCC recurrence (hazard ratio [HR]: 3.85, 95% confidence interval [CI]: 2.95‐5.02, P

Ciphertext-policy attribute-based encryption (CP-ABE) is an access control mechanism where a data provider encrypts a secret message and then sends the ciphertext to the receivers according to the access policy which she/he decides. If the attributes of the receivers match the access policy, then they can decrypt the ciphertext. This paper shows a relation between CP-ABE and identity-based encryption (IBE), and presents a bi-directional conversion between an access structure and identities. By the proposed conversion, the CP-ABE scheme constructed from an IBE scheme will inherit the features, such as constant-size ciphertexts and anonymity, from the IBE scheme, and vice versa. It turns out that the proposed conversion also gives the first CP-ABE achieving access structures with wildcard and constant-size ciphertexts/private keys. Finally, we prove the CCA security for confidentiality and anonymity.

Abstract Background Hepatocellular carcinoma (HCC) accounts for 75–85% of primary liver cancers and is prevalent in the Asia-Pacific region. Till now, trans-arterial chemoembolization (TACE) is still one of common modalities in managing unresectable intermediate-stage HCC. However, post-TACE residual viable HCC is not uncommon, resulting in unsatisfied overall survival after TACE alone. Recently, stereotactic ablative radiotherapy (SABR) has been suggested to manage HCC curatively. However, evidence from phase-III trials is largely lacking. Hence, the present phase III randomized trial is designed to compare clinical outcomes between SABR and re-TACE for unresectable HCC patients who had incomplete response after initial TACE. Methods The present study is an open-label, parallel, randomized controlled trial. A total of 120 patients will be included into two study groups, i.e., SABR and re-TACE, with a 1:1 allocation rate. A 3-year allocating period is planned. Patients with incomplete response after initial TACE will be enrolled and randomized. The primary endpoint is 1-year freedom-form-local-progression rate. Secondary endpoints are disease-progression-free survival, overall survival, local control, response rate, toxicity, and duration of response of the treated tumor. Discussion SABR has been reported as an effective modality in managing intermediate-stage HCC patients, but evidence from phase-III randomized trials is largely lacking. As a result, conducting randomized trials to demarcate the role of SABR in these patients is warranted, especially in the Asia-Pacific region, where HBV- and HCV-related HCCs are prevalent. Trial registration Before enrolling participants, the present study was registered prospectively on ClinicalTrials.gov (trial identifier, NCT02921139) on Sep. 29, 2016. This study is ongoing.

Aim: The aim of this study was to investigate the long-term outcomes of endoscopic submucosal dissection (ESD) for superficial esophageal squamous cancer. Methods: A literature search was conducted using PubMed, ProQuest and Cochrane Library databases. Primary outcomes were overall survival, disease-specific survival and recurrence-free survival at 5 years. Secondary outcomes included adverse events, recurrence and metastasis. Hazard ratios were calculated based on time to events for survival analysis, and odds radios were used to compare discrete variables. Results: A total of 3796 patients in 21 retrospective studies, including 5 comparative studies for ESD and esophagectomy were enrolled. The invasion depth was 52.0% for M1–M2, 43.2% for M3–SM1 and 4.7% for SM2 or deeper. The 5-year survival rate was: overall survival 87.3%, disease-specific survival 97.7%, and recurrence-free survival 85.1%, respectively. Pooled local recurrence of ESD was 1.8% and metastasis was 3.3%. In terms of the comparison between ESD and esophagectomy, there was no difference in the overall survival (86.4% versus 81.8%, hazard ratio = 0.66, 95% CI = 0.39–1.11) as well as disease-specific and recurrence-free survival. In addition, ESD was associated with fewer adverse events (19.8 % versus 44.0%, odds ratio = 0.3, 95% CI = 0.23–0.39). Conclusions: For superficial esophageal squamous cancer, ESD may be considered as the primary treatment of for mucosal lesions, and additional treatment should be available for submucosal invasive cancers.

Introduction and aim. In chronic hepatitis B (CHB) patients with equivocal indication for antiviral therapy, therapeutic decision currently depends on histopathology of the liver. We aimed to evaluate if acoustic radiation force impulse (ARFI) in conjunction with aspartate transaminase to platelet ratio index (APRI) and fibrosis-4 (FIB-4) score could replace liver biopsy to indicate treatment for CHB.Material and methods. We prospectively enrolled 101 clinically non-cirrhotic patients whose serum alanine aminotransferase was mildly elevated (1-2 folds above the upper normal limit) despite a high viral load (HBV DNA > 2,000 IU/mL). All participants underwent liver biopsy, and measurement of ARFI, APRI and FIB-4. The ability of the markers to distinguish fibrosis ≥ METAVIR F2 was evaluated.Results. According to histopathology, liver fibrosis was METAVIR F0 in 2 (2.0%), F1 in 43 (42.6%), F2 in 34 (33.7%), F3 in 16 (15.8%), and F4 in 6 (5.9%) patients, and was correlated with ARFI (p = 0.0001), APRI (p = 0.012), and FIB-4 (p = 0.004). The six patients with cirrhosis were included for analysis, and received antiviral therapy. The C statistics of ARFI, APRI, and FIB-4 for fibrosis ≥ F2 were 0.70 (95% confidence interval [CI], 0.59-0.80), 0.62 (95% CI, 0.51-0.73), and 0.64 (0.53-0.75), respectively. The cut-off values for 95% sensitivity and 95% specificity to identify significant fibrosis were 0.97 m/sec and 1.36 m/sec for ARFI, 0.36 and 1.0 for APRI, 0.63 and 2.22 for FIB-4, respectively. Using a combination of these 3 indices, 44 patients (43.6%) could be spared a liver biopsy procedure.Conclusions. A combination of ARFI, APRI, and FIB-4 may spare some CHB patients with equivocal indication for antiviral treatment a liver biopsy.

To clarify the predictive factors of significant platelet count improvement in thrombocytopenic chronic hepatitis C (CHC) patients. CHC patients with baseline platelet counts of 3/μL receiving direct-acting antiviral (DAA) therapy with at least 12-weeks post-treatment follow-up (PTW12) were enrolled. Significant platelet count improvement was defined as a ≥10% increase in platelet counts at PTW12 from baseline. Platelet count evolution at treatment week 4, end-of-treatment, PTW12, and PTW48 was evaluated. This study included 4922 patients. Sustained virologic response after 12 weeks post-treatment was achieved in 98.7% of patients. Platelet counts from baseline, treatment week 4, and end-of-treatment to PTW12 were 108.8 ± 30.2, 121.9 ± 41.1, 123.1 ± 43.0, and 121.1 ± 40.8 × 103/μL, respectively. Overall, 2230 patients (45.3%) showed significant platelet count improvement. Multivariable analysis revealed that age (odds ratio (OR) = 0.99, 95% confidence interval (CI): 0.99–1.00, p = 0.01), diabetes mellitus (DM) (OR = 1.20, 95% CI: 1.06–1.38, p = 0.007), cirrhosis (OR = 0.66, 95% CI: 0.58–0.75, p < 0.0001), baseline platelet counts (OR = 0.99, 95% CI: 0.98–0.99, p < 0.0001), and baseline total bilirubin level (OR = 0.80, 95% CI: 0.71–0.91, p = 0.0003) were independent predictive factors of significant platelet count improvement. Subgroup analyses showed that patients with significant platelet count improvement and sustained virologic responses, regardless of advanced fibrosis, had a significant increase in platelet counts from baseline to treatment week 4, end-of-treatment, PTW12, and PTW48. Young age, presence of DM, absence of cirrhosis, reduced baseline platelet counts, and reduced baseline total bilirubin levels were associated with significant platelet count improvement after DAA therapy in thrombocytopenic CHC patients.

Abstract Background The serum gradient of hepatitis B surface antigen (HBsAg) varies over time after cessation of nucleos(t)ide analog (NA) treatment in patients with chronic hepatitis B (CHB). The association between the time-varying HBsAg serum gradient and risk of relapse has not been elucidated. Methods This multicenter cohort study prospectively enrolled CHB patients who discontinued 3 year-NA treatment. Eligible patients were serologically negative for HBeAg and viral DNA at NA cessation. The participants (n = 140) were followed every 3 months through HBsAg quantification. Virological and clinical relapses were defined as viral DNA levels >2000 IU/mL and alanine aminotransferase (ALT) levels >80 U/mL, respectively. The association of time-varying HBsAg levels with relapses was assessed through a time-dependent Cox analysis. Results During a median follow-up of 19.9 (interquartile range [IQR], 10.6–25.3) months, virological and clinical relapses occurred in 94 and 49 patients, with a 2-year cumulative incidence of 79.2% (95% confidence interval [CI], 70.9%–86.4%) and 42.9% (95% CI, 34.1%–52.8%), respectively. The serum level of HBsAg was associated with virological (P

Targeted therapy is currently limited for patients with hepatocellular carcinoma (HCC) due to the lack of suitable targets. Kinases play pivotal roles in many cellular biological processes, whereas dysregulation of kinases may lead to various diseases, particularly cancer. However, the role of kinases in HCC malignancy remains unclear. In this study, we employed a kinome small interfering RNA (siRNA) library, comprising 710 kinase-related genes, to screen whether any kinases were essential for cell proliferation in various HCC cell lines. Through a kinome siRNA library screening, we found that MAP3K7 was a crucial gene for HCC cell proliferation. Pharmacological or genetic ablation of MAP3K7 diminished the growth, migration, and invasion of HCC cells, including primary HCC cells. Stable knockdown of MAP3K7 attenuated tumor formation in a spheroid cell culture model and tumor xenograft mouse model. In addition, silencing MAP3K7 reduced the phosphorylation and expression of mammalian target of rapamycin (mTOR) in HCC cells. MAP3K7 expression was positively correlated with mTOR expression in tumors of patients with HCC. Higher co-expression of MAP3K7 and mTOR was significantly associated with poor prognosis of HCC. Taken together, our results revealed that the MAP3K7-mTOR axis might promote tumorigenesis and malignancy, which provides a potential marker or therapeutic target for HCC patients.

The lysosomal degradation pathway, or autophagy, plays a fundamental role in cellular, tissue, and organismal homeostasis. A correlation between dysregulated autophagy and liver fibrosis (including end-stage disease, cirrhosis) is well-established. However, both the up and downregulation of autophagy have been implicated in fibrogenesis. For example, the inhibition of autophagy in hepatocytes and macrophages can enhance liver fibrosis, whereas autophagic activity in hepatic stellate cells and reactive ductular cells is permissive towards fibrogenesis. In this review, the contributions of specific cell types to liver fibrosis as well as the mechanisms underlying the effects of autophagy are summarized. In view of the functional effects of multiple cell types on the complex process of hepatic fibrogenesis, integrated approaches that consider the role of autophagy in each liver cell type should be a focus of future research.

BACKGROUND:The predictive factors of overall survival after hepatectomy for HCC remain controversial and need to be investigated. METHODS:In total, 535 consecutive HCC patients undergoing resection were included and their clinicopathological data and overall survival were recorded. Both the tumor and adjacent non-tumor (ANT) tissues were subjected to immunohistochemistry analysis for the expression of autophagy-related markers. RESULTS:Death was observed for 219 patients, and the cumulative overall survival rates at 1, 3, 5 and 7 years were 91.0%, 72.3%, 58.8%, and 27.7%, respectively. In the multivariate analysis, mortality was significantly associated with the following: diminished LC3 expression in both the tumor and ANT tissues, in the HCC tissues alone and in the ANT tissues alone (hazard ratio/95% confidence interval: 6.74/2.052-22.19, 6.70/1.321-33.98 and 2.58/1.499-4.915, respectively); recurrent HCC (5.11/3.136-8.342); HBV infection (2.75/1.574-4.784); cirrhosis (1.78/1.059-2.974); and antiviral therapy (0.42/0.250-0.697). The 5-year overall survival rates were 70.2%, 57.3%, 49.6% and 10.7% for patients with positive LC3 expression in both tissue types, in the HCC tissues alone, in the ANT tissues alone, and in neither tissue type, respectively. The 5-year overall survival rates were 56.7%, 47.3%, 51.2% and 38.7% for patients with HBV-related HCC, cirrhosis, no antiviral therapy, and recurrent HCC, respectively, and these rates were significantly lower than those in their counterparts. CONCLUSIONS:Patients with recurrent HCC, HBV-related HCC, cirrhosis, and the absence of antiviral therapy showed significantly lower overall survival rates. Furthermore, LC3 expression in both the tumor and liver microenvironments were significantly predictive of overall survival after resection for HCC.

Helicobacter pylori infection and drugs are the two major risk factors for peptic ulcer bleeding. The role of these two factors may change with changes in the prevalence of H pylori and use of NSAIDs. This study aimed to determine the cause, endoscopic features, and outcome of peptic ulcer bleeding in a community hospital in southern Taiwan. Methods: Patients who received esophagogastroduodenoscopy on arrival at the emergency department and were found to have actively bleeding ulcers or ulcers with stigmata of recent hemorrhage were included. H pylori infection was documented by the rapid urease test, histology, and/or C-13 urease breath test. Medication history, comorbidities, requirement for endoscopic therapy, blood transfusion, hospitalization days, and rebleeding rates were analyzed. Results: A total of 204 patients were enrolled with a mean age of 64.8 ± 15.2 years, with 58.3% of the subjects being female. There were 62 patients (30.4%) with H pylori infection only, 40 patients (19.6%) with drug use only, 67 patients (32.8%) with H pylori infection and drug use, and 37 patients (17.2%) without H pylori or drug use. A total of 107 patients (52.5%) were found to have had drug exposure. Drug exposure had an odds ratio (OR) of 2.34 [95% Confidence Interval (CI) = 1.30-4.20] for gastric ulcer bleeding and H pylori had an OR of 2.64 (95% CI = 1.17-5.97) for combined gastric and duodenal ulcer bleeding. The mean hospitalization period was 5.7 ± 4.0 days and the overall re-bleeding rate was 4.0%. The H pylori negative and drug negative subjects needed more endoscopic therapy (p < 0.05). Conclusion: Drug use, especially NSAIDs, aspirin, and clopidogrel has become an important cause of peptic ulcer bleeding in southern Taiwan.

Although the role of autophagy in sepsis has been characterized in several organs, its role in the adaptive immune system remains to be ascertained. This study aimed to investigate the role of autophagy in sepsis-induced T cell apoptosis and immunosuppression, using knockout mice with T cell specific deletion of autophagy essential gene Atg7.Sepsis was induced in a cecal ligation and puncture (CLP) model, with T-cell-specific Atg7-knockout mice compared to control mice. Autophagic vacuoles examined by electron microscopy were decreased in the spleen after CLP. Autophagy proteins LC3-II and ATG7, and autophagosomes and autolysosomes stained by Cyto-ID Green and acridine orange were decreased in CD4+ and CD8+ splenocytes at 18 h and 24 h after CLP. This decrease in autophagy was associated with increased apoptosis of CD4+ and CD8+ after CLP. Moreover, mice lacking Atg7 in T lymphocytes showed an increase in sepsis-induced mortality, T cell apoptosis and loss of CD4+ and CD8+ T cells, in comparison to control mice. This was accompanied by suppressed cytokine production of Th1/Th2/Th17 by CD4+ T cells, reduced phagocytosis in macrophages and decreased bacterial clearance in the spleen after sepsis.These results indicated that sepsis led to down-regulation of autophagy in T lymphocytes, which may result in enhanced apoptosis induction and decreased survival in sepsis. Autophagy may therefore play a protective role against sepsis-induced T lymphocyte apoptosis and immunosuppression.