Salvage Surgery for Initially Unresectable HCC With PVTT Converted by Locoregional Treatment Plus Tyrosine Kinase Inhibitor and Anti-PD-1 Antibody.

BACKGROUND: This study aimed to compare the survival outcomes of patients with initially unresectable hepatocellular carcinoma (HCC) and portal vein tumor thrombus (PVTT) who underwent or did not undergo salvage surgery followed by a triple combination conversion treatment consisted of locoregional treatment (LRT), tyrosine kinase inhibitors (TKIs), and anti-PD-1 antibodies. METHODS: The data from 93 consecutive patients with initially unresectable HCC and PVTT across 4 medical centers were retrospectively reviewed. They were converted successfully by the triple combination treatment and underwent or did not undergo salvage resection. The baseline characteristics, conversion schemes, conversion treatment-related adverse events (CTRAEs), overall survival (OS), and progression-free survival (PFS) of the salvage surgery and non-surgery groups were compared. Multivariate Cox regression analysis was performed to identify independent risk factors for OS and PFS. Additionally, subgroup survival analysis was conducted by stratification of degree of tumor response and type of PVTT. RESULTS: Of the 93 patients, 44 underwent salvage surgery, and 49 did not undergo salvage surgery. The OS and PFS of the salvage surgery and non-surgery groups were not significantly different (P = .370 and .334, respectively). The incidence and severity of CTRAEs of the 2 groups were also comparable. Subgroup analyses revealed that for patients with complete response (CR) or types III-IV PVTT, there was a trend toward better survival in patients who did not undergo salvage surgery. Multivariate analysis showed that baseline α-fetoprotein and best tumor response per mRECIST criteria were independent prognostic factors for OS and PFS. CONCLUSIONS: For patients with initially unresectable HCC and PVTT who were successfully converted by the triple combination therapy, salvage liver resection may not be necessary, especially for the patients with CR or types III-IV PVTT.

Outcomes of Salvage Surgery Versus Non-Salvage Surgery for Initially Unresectable Hepatocellular Carcinoma After Conversion Therapy with Transcatheter Arterial Chemoembolization Combined with Lenvatinib Plus Anti-PD-1 Antibody: A Multicenter Retrospective Study.

BACKGROUND: Combination treatment with transcatheter arterial chemoembolization (TACE), lenvatinib, and anti-programmed death-1 (anti-PD-1) antibodies (triple therapy) has a high rate of tumor response and converted resection for initially unresectable hepatocellular carcinoma (uHCC) patients. This study aimed to assess the outcomes of salvage surgery in uHCC patients after conversion therapy with triple therapy. METHODS: uHCC patients who met the criteria for hepatectomy after receiving triple therapy as first-line treatment were eligible for inclusion in this study. The overall survival (OS) and progression-free survival (PFS) rates in patients who received salvage surgery (SR group) and those who did not (non-SR group) were compared. RESULTS: Of the 144 patients assessed, 91 patients underwent salvage surgery and 53 did not. The OS rates in the SR group were significantly better than those in the non-SR group. The 1- and 2-year OS rates in the SR group were 92.0% and 79.9%, respectively, whereas those in the non-SR group were 85.5% and 39.6 %, respectively (p = 0.007); however, there was no significant difference in the PFS rates. Upon further stratification, OS and PFS were significantly better in the SR group than in the non-SR group in patients who were assessed as partial responses (PR), while there was no significant difference in patients who were assessed as complete response (CR). CONCLUSIONS: Salvage surgery is recommended and is associated with a favorable prognosis for uHCC patients who were assessed as PR after conversion therapy, however it may not be necessary for uHCC if CR was achieved.

Crenobacter oryzisoli sp. nov., a novel phosphate-solubilizing bacterium isolated from the paddy soil.

Two Gram-staining-negative, facultative anaerobic, rod-shaped and phosphate-solubilizing strains designated SG2303T and SG2305, were isolated from paddy soil in China. Phylogenetic analysis based on 16 S rRNA gene sequences indicated that SG2303T and SG2305 represented a member of the genus Crenobacter within the family Neisseriaceae of the phylum Pseudomonadota. Strain SG2303T displayed higher 16 S rRNA gene sequence similarities with members of the genus Crenobacter ranging from 93.5 to 94.0%. Strains C. luteus YIM 78141T and C. cavernae K1W11S-77T were closest related to the isolated strains and were considered as type strains. Growth of strain SG2303T occurred at 10-55 °C (optimum 37 °C), pH 5.0-9.0 (optimum pH 6.0-7.0) and 0-1% (w/v) NaCl (optimum 0%). The average nucleotide identity (ANI) and digital DNA-DNA hybridization (dDDH) values between strain SG2303T and its closely related taxa were 76.1-78.2% and 20.5-22.1%, respectively. The genomic DNA G + C content was 62.2%. The quinone of strain SG2303T was Q-8. The major fatty acids (> 10%) of strain SG2303T were C16:0 (30.6%), summed feature 3 (C16:1ω7c and/or C16:1ω6c) (26.0%) and C12:0 3OH (12.1%). The polar lipids were phosphatidylglycerol (PG), diphosphatidylglycerol (DPG), phosphatidylethanolamine (PE), phospholipids (PL), glycolipid (GL) and unidentified lipids (UL). Based on the results of the phylogenetic, physiological, biochemical, and morphological analysis, strain SG2303T is recognized as a novel species of the genus Crenobacter, for which the name Crenobacter oryzisoli sp. nov. is proposed. The type strain is SG2303T (= GDMCC 1.3970T = JCM 36468T). In addition, SG2303T was also able of phosphorus solubilization and promoting the growth of rice seeds. Strain SG2303T exhibited a relatively high dissolvable phosphorus content of 2.52 µg·mL- 1.

Computational Insights into SARS-CoV-2 Main Protease Mutations and Nirmatrelvir Efficacy: The Effects of P132H and P132H-A173V.

Nirmatrelvir, a pivotal component of the oral antiviral Paxlovid for COVID-19, targets the SARS-CoV-2 main protease (Mpro) as a covalent inhibitor. Here, we employed combined computational methods to explore how the prevalent Omicron variant mutation P132H, alone and in combination with A173V (P132H-A173V), affects nirmatrelvir's efficacy. Our findings suggest that P132H enhances the noncovalent binding affinity of Mpro for nirmatrelvir, whereas P132H-A173V diminishes it. Although both mutants catalyze the rate-limiting step more efficiently than the wild-type (WT) Mpro, P132H slows the overall rate of covalent bond formation, whereas P132H-A173V accelerates it. Comprehensive analysis of noncovalent and covalent contributions to the overall binding free energy of the covalent complex suggests that P132H likely enhances Mpro sensitivity to nirmatrelvir, while P132H-A173V may confer resistance. Per-residue decompositions of the binding and activation free energies pinpoint key residues that significantly affect the binding affinity and reaction rates, revealing how the mutations modulate these effects. The mutation-induced conformational perturbations alter drug-protein local contact intensities and the electrostatic preorganization of the protein, affecting noncovalent binding affinity and the stability of key reaction states, respectively. Our findings inform the mechanisms of nirmatrelvir resistance and sensitivity, facilitating improved drug design and the detection of resistant strains.

Exploring the impact of women-specific reproductive factors on phenotypic aging and the role of life's essential 8.

BACKGROUND: Aging is an inevitable biological process. Accelerated aging renders adults more susceptible to chronic diseases and increases their mortality rates. Previous studies have reported the relationship between lifestyle factors and phenotypic aging. However, the relationship between intrinsic factors, such as reproductive factors, and phenotypic aging remains unclear. METHODS: This study utilized data from the National Health and Nutrition Examination Survey (NHANES), spanning from 1999 to 2010 and 2015-2018, with 14,736 adult women. Random forest imputation was used to handle missing covariate values in the final cohort. Weighted linear regression was utilized to analyze the relationship between women-specific reproductive factors and PhenoAgeAccel. Considering the potential impact of menopausal status on the results, additional analyses were conducted on premenopausal and postmenopausal participants. Additionally, the Life's Essential 8 (LE8) was used to investigate the impact of healthy lifestyle and other factors on the relationship between women-specific reproductive factors and PhenoAgeAccel. Stratified analyses were conducted based on significant interaction p-values. RESULTS: In the fully adjusted models, delayed menarche and gynecological surgery were associated with increased PhenoAgeAccel, whereas pregnancy history were associated with a decrease. Additionally, early or late ages of menopause, first live birth, and last live birth can all negatively impact PhenoAgeAccel. The relationship between women-specific reproductive factors and PhenoAgeAccel differs between premenopausal and postmenopausal women. High LE8 scores positively impacted the relationship between certain reproductive factors (age at menarche, age at menopause, age at first live birth, and age at last live birth) and phenotypic age acceleration. Stratified analysis showed significant interactions for the following variables: BMI with age at menarche, pregnancy history, and age at menopause; ethnicity with age at menopause, age at first live birth, and parity; smoking status with use of contraceptive pills and gynecologic surgery; hypertension with use of contraceptive pills, pregnancy history, and age at menopause. CONCLUSION: Delayed menarche, gynecological surgery, and early or late ages of menopause, first live birth, and last live birth are associated with accelerated phenotypic aging. High LE8 score may alleviate the adverse effects of reproductive factors on phenotypic aging.

An inferior vena cava-priority approach in laparoscopic isolated hepatic caudate lobectomy.

PURPOSE: Laparoscopic isolated caudate lobectomy is still a challenging operation for surgeons. The access route of the operation plays a vital role during laparoscopic caudate lobectomy. There are few references regarding this technique. Here, we introduce a preferred inferior vena cava (IVC) approach in laparoscopic caudate lobectomy. METHODS: Twenty-one consecutive patients with caudate hepatic tumours between June 2016 and December 2021 were included in this study. All of them received laparoscopic caudate lobectomy involving an IVC priority approach. The IVC priority approach refers to prioritizing the dissection of the IVC from the liver parenchyma before proceeding with the conventional left or right approach. It emphasizes the importance of the IVC dissection during process. Clinical data, intraoperative parameters and postoperative results were evaluated. Sixteen patients were performed pure IVC priority approach, while 5 patients underwent a combined approach. We subsequently compared the intraoperative and postoperative between the two groups. RESULTS: All 21 patients were treated with laparoscopic technology. The operative time was 190.95 ± 92.65 min. The average estimated blood loss was 251.43 ± 247.45 ml, and four patients needed blood transfusions during the perioperative period. The average duration of hospital stay was 8.43 ± 2.64 (range from 6.0 to 16.0) days. Patients who underwent the pure inferior vena cava (IVC) approach required a shorter hepatic pedicle clamping time (26 vs. 55 min, respectively; P < 0.001) and operation time (150 vs. 380 min, respectively; P = 0.002) than those who underwent the combined approach. Hospitalization (7.0 vs. 9.0 days, respectively; P = 0.006) was shorter in the pure IVC group than in the combined group. CONCLUSIONS: Laparoscopic caudate lobectomy with an IVC priority approach is safe and feasible for patients with caudate hepatic tumours.

A new scoring system for predicting the outcome of hepatocellular carcinoma patients without microvascular invasion-a large-scale multicentre study.

BACKGROUND: The prognosis of HCC patients without MVI (so called M0) is highly heterogeneous and the need for adjuvant therapy is still controversial. METHODS: Patients with HCC with M0 who underwent liver resection (LR) or liver transplantation (LT) as an initial therapy were included. The Eastern Hepatobiliary Surgery Hospital (EHBH)-M0 score was developed from a retrospective cohort to form the training cohort. The classification which was developed using multivariate cox regression analysis was externally validated. RESULTS: The score was developed using the following factors: α-fetoprotein level, tumour diameter, liver cirrhosis, total bilirubin, albumin and aspartate aminotransferase. The score differentiated two groups of M0 patients (≤3, >3 points) with distinct long-term prognoses outcomes (median overall survival (OS), 98.0 vs. 46.0 months; p < 0.001). The predictive accuracy of the score was greater than the other commonly used staging systems for HCC. And for M0 patients with a higher score underwent LR. Adjuvant transcatheter arterial chemoembolization (TACE) was effective to prolong OS. CONCLUSIONS: The EHBH M0 scoring system was more accurate in predicting the prognosis of HCC patients with M0 after LR or LT. Adjuvant therapy is recommended for HCC patients who have a higher score.

Combination of alpha-fetoprotein and neutrophil-to-lymphocyte ratio to predict treatment response and survival outcomes of patients with unresectable hepatocellular carcinoma treated with immune checkpoint inhibitors.

BACKGROUND: Immune-checkpoint inhibitors (ICIs) have revolutionized the treatment of hepatocellular carcinoma (HCC). However, long-term survival outcomes and treatment response of HCC patients undergoing immunotherapy is unpredictable. The study aimed to evaluate the role of alpha-fetoprotein (AFP) combined with neutrophil-to-lymphocyte ratio (NLR) to predict the prognosis and treatment response of HCC patients receiving ICIs. METHODS: Patients with unresectable HCC who received ICI treatment were included. The HCC immunotherapy score was developed from a retrospective cohort at the Eastern Hepatobiliary Surgery Hospital to form the training cohort. The clinical variables independently associated with overall survival (OS) were identified using univariate and multivariate Cox regression analysis. Based on multivariate analysis of OS, a predictive score based on AFP and NLR was constructed, and patients were stratified into three risk groups according to this score. The clinical utility of this score to predict progression-free survival (PFS) and differentiate objective response rate (ORR) and disease control rate (DCR) was also performed. This score was validated in an independent external validation cohort at the First Affiliated Hospital of Wenzhou Medical University. RESULTS: Baseline AFP ≤ 400 ng/ml (hazard ratio [HR] 0.48; 95% CI, 0.24-0.97; P = 0.039) and NLR ≤ 2.77 (HR 0.11; 95% CI, 0.03-0.37; P<0.001) were found to be independent risk factors of OS. The two labolatory values were used to develop the score to predict survival outcomes and treatment response in HCC patients receiving immunotherapy, which assigned 1 point for AFP > 400 ng/ml and 3 points for NLR > 2.77. Patients with 0 point were classified as the low-risk group. Patients with 1-3 points were categorized as the intermediate-risk group. Patients with 4 points were classified as the high-risk group. In the training cohort, the median OS of the low-risk group was not reached. The median OS of the intermediate-risk group and high-risk group were 29.0 (95% CI 20.8-37.3) months and 16.0 (95% CI 10.8-21.2) months, respectively (P < 0.001). The median PFS of the low-risk group was not reached. The median PFS of the intermediate-risk group and high-risk group were 14.6 (95% CI 11.3-17.8) months and 7.6 (95% CI 3.6-11.7) months, respectively (P < 0.001). The ORR and DCR were highest in the low-risk group, followed by the intermediate-risk group and the high-risk group (P < 0.001, P = 0.007, respectively). This score also had good predictive power using the validation cohort. CONCLUSION: The HCC immunotherapy score based on AFP and NLR can predict survival outcomes and treatment response in patients receiving ICI treatments, suggesting that this score could serve as a useful tool for identification of HCC patients likely to benefit from immunotherapy.

Overall survival of patients with hepatocellular carcinoma treated with sintilimab and disease outcome after treatment discontinuation.

BACKGROUND: The use of Anti-PD-1 therapy has yielded promising outcomes in hepatocellular carcinoma (HCC). However, limited research has been conducted on the overall survival (OS) of patients with varying tumor responses and treatment duration. METHODS: This retrospective study analyzed HCC patients who received sintilimab between January 2019 and December 2020 at four centers in China. The evaluation of tumor progression was based on Response Evaluation Criteria in Solid Tumors version 1.1. The study investigated the correlation between tumor response and OS, and the impact of drug use on OS following progressive disease (PD). RESULTS: Out of 441 treated patients, 159 patients satisfied the inclusion criteria. Among them, 77 patients with disease control exhibited a significantly longer OS compared to the 82 patients with PD (median OS 26.0 vs. 11.3 months, P < 0.001). Additionally, the OS of patients with objective response (OR) was better than that of patients with stable disease (P = 0.002). Among the 47 patients with PD who continued taking sintilimab, the OS was better than the 35 patients who discontinued treatment (median OS 11.4 vs. 6.9 months, P = 0.042). CONCLUSIONS: In conclusion, the tumor response in HCC patients who received sintilimab affects OS, and patients with PD may benefit from continued use of sintilimab.

Gemcitabine and cisplatin or oxaliplatin chemotherapy combined with atezolizumab plus bevacizumab for advanced biliary tract cancers: a single-arm trial.

Advanced biliary tract cancer (BTC) has a poor prognosis, even after combined chemotherapy of gemcitabine and oxaliplatin (GEMOX). To investigate the efficacy and safety of GEMOX chemotherapy combining atezolizumab and bevacizumab in advanced BTC, the authors designed an open-label, single-arm, phase II clinical trial and will enroll patients with stage IV BTC. The participants will receive GEMOX chemotherapy combined with atezolizumab plus bevacizumab. The primary end point is objective response rate; the secondary end points are overall survival, disease control rate, progression-free survival, time to progression, duration of response and safety. The results of this trial are expected to provide novel, safe and effective treatment options for patients with advanced BTC, which could further improve their prognosis. Clinical Trial Registration: ChiCTR2100049830 (ChiCTR.org).

Chromatin remodeling factor ARID2 suppresses hepatocellular carcinoma metastasis via DNMT1-Snail axis.

Recurrence and metastasis remain the major obstacles to successful treatment of hepatocellular carcinoma (HCC). Chromatin remodeling factor ARID2 is commonly mutated in HCC, indicating its important role in cancer development. However, its role in HCC metastasis is largely elusive. In this study, we find that ARID2 expression is significantly decreased in metastatic HCC tissues, showing negative correlation with pathological grade, organ metastasis and positive association with survival of HCC patients. ARID2 inhibits migration and invasion of HCC cells in vitro and metastasis in vivo. Moreover, ARID2 knockout promotes pulmonary metastasis in different HCC mouse models. Mechanistic study reveals that ARID2 represses epithelial-mesenchymal transition (EMT) of HCC cells by recruiting DNMT1 to Snail promoter, which increases promoter methylation and inhibits Snail transcription. In addition, we discover that ARID2 mutants with disrupted C2H2 domain lose the metastasis suppressor function, exhibiting a positive association with HCC metastasis and poor prognosis. In conclusion, our study reveals the metastasis suppressor role as well as the underlying mechanism of ARID2 in HCC and provides a potential therapeutic target for ARID2-deficient HCC.

Identification of and Mechanistic Insights into SARS-CoV-2 Main Protease Non-Covalent Inhibitors: An In-Silico Study.

The indispensable role of the SARS-CoV-2 main protease (Mpro) in the viral replication cycle and its dissimilarity to human proteases make Mpro a promising drug target. In order to identify the non-covalent Mpro inhibitors, we performed a comprehensive study using a combined computational strategy. We first screened the ZINC purchasable compound database using the pharmacophore model generated from the reference crystal structure of Mpro complexed with the inhibitor ML188. The hit compounds were then filtered by molecular docking and predicted parameters of drug-likeness and pharmacokinetics. The final molecular dynamics (MD) simulations identified three effective candidate inhibitors (ECIs) capable of maintaining binding within the substrate-binding cavity of Mpro. We further performed comparative analyses of the reference and effective complexes in terms of dynamics, thermodynamics, binding free energy (BFE), and interaction energies and modes. The results reveal that, when compared to the inter-molecular electrostatic forces/interactions, the inter-molecular van der Waals (vdW) forces/interactions are far more important in maintaining the association and determining the high affinity. Given the un-favorable effects of the inter-molecular electrostatic interactions-association destabilization by the competitive hydrogen bond (HB) interactions and the reduced binding affinity arising from the un-compensable increase in the electrostatic desolvation penalty-we suggest that enhancing the inter-molecular vdW interactions while avoiding introducing the deeply buried HBs may be a promising strategy in future inhibitor optimization.

DCAF13 promotes breast cancer cell proliferation by ubiquitin inhibiting PERP expression.

Evolutionarily conserved DDB1-and CUL4-associated factor 13 (DCAF13) is a recently discovered substrate receptor for the cullin RING-finger ubiquitin ligase 4 (CRL4) E3 ubiquitin ligase that regulates cell cycle progression. DCAF13 is overexpressed in many cancers, although its role in breast cancer is currently elusive. In this study we demonstrate that DCAF13 is overexpressed in human breast cancer and that its overexpression closely correlates with poor prognosis, suggesting that DCAF13 may serve as a diagnostic marker and therapeutic target. We knocked down DCAF13 in breast cancer cell lines using CRISPR/Cas9 and found that DCAF13 deletion markedly reduced breast cancer cell proliferation, clone formation, and migration both in vitro and in vivo. In addition, DCAF13 deletion promoted breast cancer cell apoptosis and senescence, and induced cell cycle arrest in the G1/S phase. Genome-wide RNAseq analysis and western blotting revealed that loss of DCAF13 resulted in both mRNA and protein accumulation of p53 apoptosis effector related to PMP22 (PERP). Knockdown of PERP partially reversed the hampered cell proliferation induced by DCAF13 knockdown. Co-immunoprecipitation assays revealed that DCAF13 and DNA damage-binding protein 1 (DDB1) directly interact with PERP. Overexpression of DDB1 significantly increased PERP polyubiquitination, suggesting that CRL4DCAF13 E3 ligase targets PERP for ubiquitination and proteasomal degradation. In conclusion, DCAF13 and the downstream effector PERP occupy key roles in breast cancer proliferation and potentially serve as prognostics and therapeutic targets.

Impact of Bile Duct Tumor Thrombus on the Long-Term Surgical Outcomes of Hepatocellular Carcinoma Patients: A Propensity Score Matching Analysis.

BACKGROUND: Hepatectomy with tumor thrombectomy is the preferred treatment option for hepatocellular carcinoma (HCC) patients with bile duct tumor thrombus (BDTT); however, the impact of BDTT on their prognosis is unclear. OBJECTIVE: We aimed to investigate the long-term surgical outcomes of HCC patients with BDTT. METHODS: The data of HCC patients with and without BDTT who underwent hepatectomy were retrospectively reviewed and the long-term outcomes were compared. For propensity score matching (PSM) analysis, patients were matched in a 1:1 ratio. Subgroup analysis was conducted according to the American Joint Committee on Cancer (AJCC) staging system. RESULTS: Before PSM, HCC patients with BDTT had more advanced tumor stages and adverse clinicopathological features. Recurrence-free survival (RFS) and overall survival (OS) were significantly higher in the non-BDTT group before PSM (RFS, p < 0.001; OS, p < 0.001), while after PSM, the BDTT group had significantly poorer RFS (p = 0.025). There was no difference in OS between the groups (p = 0.588). Subgroup analysis showed that RFS and OS in AJCC stage I-II patients were significantly poorer in the BDTT group; no differences were found in the AJCC stage III group before or after PSM. When the presence of BDTT was recommended to increase the AJCC staging system by one stage in AJCC stage I-II patients, the predictive ability for RFS and OS was higher. CONCLUSIONS: BDTT was associated with significantly poorer long-term surgical outcomes in AJCC stage I-II patients. A modified AJCC staging system including BDTT status in stage I-II might have a better prognostic ability.

Amitosis as a strategy of cell division-Insight from the proliferation of Tetrahymena thermophila macronuclei.

Cell division is a necessity of life which can be either mitotic or amitotic. While both are fundamental, amitosis is sometimes considered a relic of little importance in biology. Nevertheless, eukaryotes often have polyploid cells, including cancer cells, which may divide amitotically. To understand how amitosis ensures the completion of cell division, we turn to the macronuclei of ciliates. The grand scheme governing the proliferation of the macronuclei of ciliate cells, which involves chromosomal replication and amitosis, is currently unknown, which is crucial for developing population genetics model of ciliate populations. Using a novel model that encompasses a wide range of mechanisms together with experimental data of the composition of mating types at different stages derived from a single karyonide of Tetrahymena thermophila, we show that the chromosomal replication of the macronucleus has a strong head-start effect, with only about five copies of chromosomes replicated at a time and persistent reuse of the chromosomes involved in the early replication. Furthermore the fission of a fully grown macronucleus is non-random with regard to chromosome composition, with a strong tendency to push chromosomes and their replications to the same daughter cell.

Targeted modification of the Per2 clock gene alters circadian function in mPer2luciferase (mPer2Luc) mice.

Modification of the Per2 clock gene in mPer2Luc reporter mice significantly alters circadian function. Behavioral period in constant dark is lengthened, and dissociates into two distinct components in constant light. Rhythms exhibit increased bimodality, enhanced phase resetting to light pulses, and altered entrainment to scheduled feeding. Mechanistic mathematical modelling predicts that enhanced protein interactions with the modified mPER2 C-terminus, combined with differential clock regulation among SCN subregions, can account for effects on circadian behavior via increased Per2 transcript and protein stability. PER2::LUC produces greater suppression of CLOCK:BMAL1 E-box activity than PER2. mPer2Luc carries a 72 bp deletion in exon 23 of Per2, and retains a neomycin resistance cassette that affects rhythm amplitude but not period. The results show that mPer2Luc acts as a circadian clock mutation illustrating a need for detailed assessment of potential impacts of c-terminal tags in genetically modified animal models.

Hazard rate for postoperative recurrence in patients with hepatocellular carcinoma at Barcelona Clinic Liver Cancer stage 0 or A1: A multicenter observational study.

AIM: Surgical treatment is the first-line treatment for patients with Barcelona Clinic Liver Cancer (BCLC) stage 0 or A1 hepatocellular carcinoma (HCC), and postoperative monitoring improves long-term survival. We aimed to establish a reasonable short-interval follow-up duration for patients with HCC. METHODS: The cohort for this retrospective study included 1396 HCC patients with BCLC stage 0 or A1 disease who underwent curative resection from 2013 to 2016 at five centers in China. Hazard rates for recurrence were calculated using the hazard function. RESULTS: The recurrence rates in patients with BCLC stage 0 and A1 HCC were 46.4% and 58.0%, respectively. The hazard curve for stage 0 patients was relatively flat, and the hazard rate was consistently low (peak hazard rate 0.0163). The hazard rate curve for recurrence was initially high (peak hazard rate 0.0441) in patients with BCLC stage A1 disease and showed a rapid decreasing trend within 1 year, followed by a slow decreasing trend, reaching a low level (<0.0163) at approximately 36 months. The time to low risk was 47, 41, and 51 months in patients with cirrhosis, hepatitis B virus (HBV) infection, and satellite lesions, respectively. CONCLUSIONS: A short-interval follow-up of 1 year is sufficient for HCC patients with BCLC stage 0 disease, whereas a short-interval follow-up time of 3 years should be considered for patients with stage A1 disease. The follow-up period should be appropriately prolonged for patients with cirrhosis, HBV infection, and satellite lesions.

Transarterial chemoembolization plus a PD-1 inhibitor with or without lenvatinib for intermediate-stage hepatocellular carcinoma.

AIM: Transarterial chemoembolization (TACE) combined with a PD-1 inhibitor and TACE combined with a PD-1 inhibitor and lenvatinib have recently been reported as promising treatments to improve the prognosis of hepatocellular carcinoma (HCC) patients. This study aims to compare the efficacy of these two treatments. METHODS: A retrospective study was conducted, and patients were recruited from two centers in China. Progression-free survival (PFS) and overall survival (OS) were compared, and the objective response rate (ORR) and disease control rate (DCR) were evaluated according to the modified Response Evaluation Criteria in Solid Tumors (mRECIST). Treatment-related adverse events (AEs) were analyzed to assess safety. RESULTS: The median follow-up for the entire cohort was 11.4 months. Of the 103 patients included in this study, 56 received triple therapy, and 47 received doublet therapy. PFS was significantly higher in the triple therapy group than in the doublet therapy group (mPFS 22.5 vs. 14.0 months, P < 0.001). Similar results were obtained in terms of OS (P = 0.001). The ORR and DCR were also better in the triple therapy group (64.3% vs. 38.3%, P = 0.010; 85.7% vs. 57.4%, P = 0.002). The most common AEs in the triple therapy group were decreased albumin (55.3%), decreased platelet count (51.8%) and hypertension (44.6%). CONCLUSIONS: The combination of TACE with a PD-1 inhibitor and lenvatinib in patients with BCLC stage B HCC might result in significantly improved clinical outcomes with a manageable safety profile compared with TACE with a PD-1 inhibitor.

Developmental artificial neural network model to evaluate the preoperative safe limit of future liver remnant volume for HCC combined with clinically significant portal hypertension.

Background & aims: Finding a way to comprehensively integrate the presence and grade of clinically significant portal hypertension, amount of preserved liver function and extent of hepatectomy into the guidelines for choosing appropriate candidates to hepatectomy remained challenging. This study sheds light on these issues to facilitate precise surgical decisions for clinicians. Methods: Independent risk factors associated with grade B/C post-hepatectomy liver failure were identified by stochastic forest algorithm and logistic regression in hepatitis B virus-related hepatocellular carcinoma patients. Results: The artificial neural network model was generated by integrating preoperative pre-ALB, prothrombin time, total bilirubin, AST, indocyanine green retention rate at 15 min, standard future liver remnant volume and clinically significant portal hypertension grade. In addition, stratification of patients into three risk groups emphasized significant distinctions in the risk of grade B/C post-hepatectomy liver failure. Conclusion: The authors' artificial neural network model could provide a reasonable therapeutic option for clinicians to select optimal candidates with clinically significant portal hypertension for hepatectomy and supplement the hepatocellular carcinoma surgical treatment algorithm.

Hepatectomy involves removing the tumor from the liver and is considered the most effective treatment for hepatocellular carcinoma (HCC). Clinically significant portal hypertension is characterized by the presence of gastric and/or esophageal varices and a platelet count <100 × 10⁹/l with the presence of splenomegaly, which would aggravate the risk of post-hepatectomy liver failure, and is therefore regarded as a contraindication to hepatectomy. Over the past few decades, with improvement in surgical techniques and perioperative care, the morbidity of postoperative complications and mortality have decreased greatly. Current HCC guidelines recommend the expansion of hepatectomy to HCC patients with clinically significant portal hypertension. However, determining how to select optimal candidates for hepatectomy remains challenging. The authors' artificial neural network is a mathematical tool developed by simulating the properties of neurons with large-scale information distribution and parallel structure. Here the authors retrospectively enrolled 871 hepatitis B virus-related HCC patients and developed an artificial neural network model to predict the risk of post-hepatectomy liver failure, which could provide a reasonable therapeutic option and facilitate precise surgical decisions for clinicians.

Transcatheter arterial chemoembolization plus atezolizumab and bevacizumab for unresectable hepatocellular carcinoma: a single-arm, phase II trial.

The therapeutic effect of transcatheter arterial chemoembolization (TACE) is limited for patients with hepatocellular carcinoma (HCC). Herein, we designed an open-label, single-arm phase II clinical trial to investigate the efficacy and safety of TACE combined with atezolizumab plus bevacizumab for patients with Barcelona Clinic Liver Cancer (BCLC) stage-B HCC. Patients will initially receive TACE. Atezolizumab and bevacizumab will be initiated 2-14 days after the first TACE session. TACE will be repeated on demand. The primary endpoint is the objective response rate. The secondary end points include overall survival, disease control rate, progression-free survival, time-to-progression and safety. The study results will provide evidence for establishing a novel therapeutic regimen for patients with unresectable HCC. Clinical Trial Registration: ChiCTR2100049829 (ChiCTR.org).