Balance of Gata3 and Ramp2 in hepatocytes regulates hepatic vascular reconstitution in postoperative liver regeneration.

BACKGROUND & AIMS: Post-hepatectomy liver failure (PHLF) leads to poor prognosis in patients undergoing hepatectomy, with hepatic vascular reconstitution playing a critical role. However, the regulators of hepatic vascular reconstitution remain unclear. In this study, we aimed to investigate the regulatory mechanisms of hepatic vascular reconstitution and identify biomarkers predicting PHLF in patients undergoing hepatectomy. METHODS: Candidate genes that were associated with hepatic vascular reconstitution were screened using adeno-associated virus vectors in Alb-Cre-CRISPR/Cas9 mice subjected to partial hepatectomy. The biological activities of candidate genes were estimated using endothelial precursor transfusion and associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) models. The level of candidates was detected in biopsies from patients undergoing ALPPS. Risk factors for PHLF were also screened using retrospective data. RESULTS: Downregulation of Gata3 and upregulation of Ramp2 in hepatocytes promoted the proliferation of liver sinusoidal endothelial cells and hepatic revascularization. Pigment epithelium-derived factor (PEDF) and vascular endothelial growth factor A (VEGFA) played opposite roles in regulating the migration of endothelial precursors from bone marrow and the formation of new sinusoids after hepatectomy. Gata3 restricted endothelial cell function in patient-derived hepatic organoids, which was abrogated by a Gata3 inhibitor. Moreover, overexpression of Gata3 led to higher mortality in ALPPS mice, which was improved by a PEDF-neutralizing antibody. The expression of Gata3/RAMP and PEDF/VEGFA tended to have a negative correlation in patients undergoing ALPPS. A nomogram incorporating multiple factors, such as serum PEDF/VEGF index, was constructed and could efficiently predict the risk of PHLF. CONCLUSIONS: The balance of Gata3 and Ramp2 in hepatocytes regulates the proliferation of liver sinusoidal endothelial cells and hepatic revascularization via changes in the expression of PEDF and VEGFA, revealing potential targets for the prevention and treatment of PHLF. IMPACT AND IMPLICATIONS: In this study, we show that the balance of Gata3 and Ramp2 in hepatocytes regulates hepatic vascular reconstitution by promoting a shift from pigment epithelium-derived factor (PEDF) to vascular endothelial growth factor A (VEGFA) expression during hepatectomy- or ALLPS (associating liver partition and portal vein ligation for staged hepatectomy)-induced liver regeneration. We also identified serum PEDF/VEGFA index as a potential predictor of post-hepatectomy liver failure in patients who underwent hepatectomy. This study improves our understanding of how hepatocytes contribute to liver regeneration and provides new targets for the prevention and treatment of post-hepatectomy liver failure.

A Prognostic Model To Predict Survival After Recurrence Among Patients With Recurrent Hepatocellular Carcinoma.

OBJECTIVE: We sought to develop and validate a preoperative model to predict survival after recurrence (SAR) in hepatocellular carcinoma (HCC). BACKGROUND: Although HCC is characterized by recurrence as high as 60%, models to predict outcomes after recurrence remain relatively unexplored. METHODS: Patients who developed recurrent HCC between 2000 and 2020 were identified from an international multi-institutional database. Clinicopathologic data on primary disease and laboratory and radiologic imaging data on recurrent disease were collected. Multivariable Cox regression analysis and internal bootstrap validation (5000 repetitions) were used to develop and validate the SARScore. Optimal Survival Tree analysis was used to characterize SAR among patients treated with various treatment modalities. RESULTS: Among 497 patients who developed recurrent HCC, median SAR was 41.2 months (95% CI 38.1-52.0). The presence of cirrhosis, number of primary tumors, primary macrovascular invasion, primary R1 resection margin, AFP>400 ng/mL on the diagnosis of recurrent disease, radiologic extrahepatic recurrence, radiologic size and number of recurrent lesions, radiologic recurrent bilobar disease, and early recurrence (≤24 months) were included in the model. The SARScore successfully stratified 1-, 3- and 5-year SAR and demonstrated strong discriminatory ability (3-year AUC: 0.75, 95% CI 0.70-0.79). While a subset of patients benefitted from resection/ablation, Optimal Survival Tree analysis revealed that patients with high SARScore disease had the worst outcomes (5-year AUC; training: 0.79 vs. testing: 0.71). The SARScore model was made available online for ease of use and clinical applicability ( https://yutaka-endo.shinyapps.io/SARScore/ ). CONCLUSION: The SARScore demonstrated strong discriminatory ability and may be a clinically useful tool to help stratify risk and guide treatment for patients with recurrent HCC.

Prognostic significance of postoperative serological incomplete conversion of AFP and PIVKA-II after hepatic resection for hepatocellular carcinoma: a multicenter analysis of 1755 patients.

BACKGROUND: The value of serum biomarkers, particularly alpha-fetoprotein (AFP) and protein induced by vitamin K absence or antagonist-II (PIVKA-II), gains increasing attention in prognostic evaluation and recurrence monitoring for patients with hepatocellular carcinoma (HCC). This study investigated the implications of serological incomplete conversion (SIC) of these 2 biomarkers as prognostic indicators for long-term outcomes after HCC resection. METHODS: A multicenter observational study was conducted on a cohort of HCC patients presenting with AFP (>20 ng/mL) or PIVKA-II (>40 mAU/mL) positivity who underwent curative-intent resection. Based on their postoperative AFP and PIVKA-II levels at first postoperative follow-up (4~8 weeks after surgery), these patients were stratified into the serological incomplete conversion (SIC) and serological complete conversion (SCC) groups. The study endpoints were recurrence and overall survival (OS). RESULTS: Among 1755 patients, 379 and 1376 were categorized as having SIC and SCC, respectively. The SIC group exhibited 1- and 5-year OS rates of 67.5% and 26.3%, with the corresponding recurrence rates of 53.2% and 79.0%, respectively; while the SCC group displayed 1- and 5-year OS rates of 95.8% and 62.5%, with the corresponding recurrence rates of 16.8% and 48.8%, respectively (both P < .001). Multivariate Cox regression analysis demonstrated that postoperative SIC was an independent risk factor for both increased recurrence (HR: 2.40, 95% CI, 2.04-2.81, P < .001) and decreased OS (HR: 2.69, 95% CI, 2.24-3.24, P < .001). CONCLUSION: The results emphasize that postoperative incomplete conversion of either AFP or PIVKA-II is a significant prognostic marker, indicating a higher risk for adverse oncologic outcomes following HCC resection. This revelation has crucial implications for refining postoperative adjuvant therapy and surveillance strategies for HCC patients.

Ultrasensitive Proteomics of Trace Cardiac Tissues with Anchor-Nanoparticles.

Pathological cardiac hypertrophy is a complex process that often leads to heart failure. Label-free proteomics has emerged as an important platform to reveal protein variations and to elucidate the mechanisms of cardiac hypertrophy. Endomyocardial biopsy is a minimally invasive technique for sampling cardiac tissue, but it yields only limited amounts of an ethically permissible specimen. After regular pathological examination, the remaining trace samples pose significant challenges for effective protein extraction and mass spectrometry analysis. Herein, we developed trace cardiac tissue proteomics based on the anchor-nanoparticles (TCPA) method. We identified an average of 6666 protein groups using ∼50 µg of myocardial interventricular septum samples by TCPA. We then applied TCPA to acquire proteomics from patients' cardiac samples both diagnosed as hypertrophic hearts and myocarditis controls and identified significant alterations in pathways such as regulation of actin cytoskeleton, oxidative phosphorylation, and cGMP-PKG signaling pathway. Moreover, we found multiple lipid metabolic pathways to be dysregulated in transthyretin cardiac amyloidosis compared to other types of cardiac hypertrophy. TCPA offers a new technique for studying pathological cardiac hypertrophy and can serve as a platform toolbox for proteomic research in other cardiac diseases.

YBX1 promotes stemness and cisplatin insensitivity in intrahepatic cholangiocarcinoma via the AKT/ß-catenin axis.

BACKGROUND: Intrahepatic cholangiocarcinoma (ICC) is a highly aggressive malignancy characterized by a poor prognosis and closely linked to tumor stemness. However, the key molecules that regulate ICC stemness remain elusive. Although Y-box binding protein 1 (YBX1) negatively affects prognosis in various cancers by enhancing stemness and chemoresistance, its effect on stemness and cisplatin sensitivity in ICC remains unclear. METHODS: Three bulk and single-cell RNA-seq datasets were analyzed to investigate YBX1 expression in ICC and its association with stemness. Clinical samples and colony/sphere formation assays validated the role of YBX1 in stemness and sensitivity to cisplatin. AZD5363 and KYA1979K explored the interaction of YBX1 with the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PKB/AKT) and WNT/ß-catenin pathways. RESULTS: YBX1 was significantly upregulated in ICC, correlated with worse overall survival and shorter postoperative recurrence time, and was higher in chemotherapy-non-responsive ICC tissues. The YBX1-high group exhibited significantly elevated stemness scores, and genes linked to YBX1 upregulation were enriched in multiple stemness-related pathways. Moreover, YBX1 expression is significantly correlated with several stemness-related genes (SOX9, OCT4, CD133, CD44 and EPCAM). Additionally, YBX1 overexpression significantly enhanced the colony- and spheroid-forming abilities of ICC cells, accelerated tumor growth in vivo and reduced their sensitivity to cisplatin. Conversely, the downregulation of YBX1 exerted the opposite effect. The transcriptomic analysis highlighted the link between YBX1 and the PI3K/AKT and WNT/ß-catenin pathways. Further, AZD5363 and KYA1979K were used to clarify that YBX1 promoted ICC stemness through the regulation of the AKT/ß-catenin axis. CONCLUSIONS: YBX1 is upregulated in ICC and promotes stemness and cisplatin insensitivity via the AKT/ß-catenin axis. Our study describes a novel potential therapeutic target for improving ICC prognosis.

Tailoring the Hydrophobic Interface of Core-Shell HKUST-1@Cu2O Nanocomposites for Efficiently Selective CO2 Electroreduction.

The electrochemical reduction of carbon dioxide (CO2) to ethylene creates a carbon-neutral approach to converting carbon dioxide into intermittent renewable electricity. Exploring efficient electrocatalysts with potentially high ethylene selectivity is extremely desirable, but still challenging. In this report, a laboratory-designed catalyst HKUST-1@Cu2O/PTFE-1 is prepared, in which the high specific surface area of the composites with improved CO2 adsorption and the abundance of active sites contribute to the increased electrocatalytic activity. Furthermore, the hydrophobic interface constructed by the hydrophobic material polytetrafluoroethylene (PTFE) effectively inhibits the occurrence of hydrogen evolution reactions, providing a significant improvement in the efficiency of CO2 electroreduction. The distinctive structures result in the remarkable hydrocarbon fuels generation with high Faraday efficiency (FE) of 67.41%, particularly for ethylene with FE of 46.08% (-1.0 V vs RHE). The superior performance of the catalyst is verified by DFT calculation with lower Gibbs free energy of the intermediate interactions with improved proton migration and selectivity to emerge the polycarbon（C2+） product. In this work, a promising and effective strategy is presented to configure MOF-based materials with tailored hydrophobic interface, high adsorption selectivity and more exposed active sites for enhancing the efficiency of the electroreduction of CO2 to C2+ products with high added value.

Targeting hepatic serine-arginine protein kinase 2 ameliorates alcohol-associated liver disease by alternative splicing control of lipogenesis.

BACKGROUND AND AIMS: Lipid accumulation induced by alcohol consumption is not only an early pathophysiological response but also a prerequisite for the progression of alcohol-associated liver disease (ALD). Alternative splicing regulates gene expression and protein diversity; dysregulation of this process is implicated in human liver diseases. However, how the alternative splicing regulation of lipid metabolism contributes to the pathogenesis of ALD remains undefined. APPROACH AND RESULTS: Serine-arginine-rich protein kinase 2 (SRPK2), a key kinase controlling alternative splicing, is activated in hepatocytes in response to alcohol, in mice with chronic-plus-binge alcohol feeding, and in patients with ALD. Such induction activates sterol regulatory element-binding protein 1 and promotes lipogenesis in ALD. Overexpression of FGF21 in transgenic mice abolishes alcohol-mediated induction of SRPK2 and its associated steatosis, lipotoxicity, and inflammation; these alcohol-induced pathologies are exacerbated in FGF21 knockout mice. Mechanistically, SRPK2 is required for alcohol-mediated impairment of serine-arginine splicing factor 10, which generates exon 7 inclusion in lipin 1 and triggers concurrent induction of lipogenic regulators-lipin 1ß and sterol regulatory element-binding protein 1. FGF21 suppresses alcohol-induced SRPK2 accumulation through mammalian target of rapamycin complex 1 inhibition-dependent degradation of SRPK2. Silencing SRPK2 rescues alcohol-induced splicing dysregulation and liver injury in FGF21 knockout mice. CONCLUSIONS: These studies reveal that (1) the regulation of alternative splicing by SRPK2 is implicated in lipogenesis in humans with ALD; (2) FGF21 is a key hepatokine that ameliorates ALD pathologies largely by inhibiting SRPK2; and (3) targeting SRPK2 signaling by FGF21 may offer potential therapeutic approaches to combat ALD.

Noninvasive assessment of liver disease severity in patients with nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes.

BACKGROUND AND AIMS: We evaluated the diagnostic accuracy of simple, noninvasive tests (NITs) in NAFLD patients with type 2 diabetes (T2D). METHODS AND RESULTS: This was an individual patient data meta-analysis of 1780 patients with biopsy-proven NAFLD and T2D. The index tests of interest were FIB-4, NAFLD Fibrosis Score (NFS), aspartate aminotransferase-to-platelet ratio index, liver stiffness measurement (LSM) by vibration-controlled transient elastography, and AGILE 3+. The target conditions were advanced fibrosis, NASH, and fibrotic NASH(NASH plus F2-F4 fibrosis). The diagnostic performance of noninvasive tests. individually or in sequential combination, was assessed by area under the receiver operating characteristic curve and by decision curve analysis. Comparison with 2278 NAFLD patients without T2D was also made. In NAFLD with T2D LSM and AGILE 3+ outperformed, both NFS and FIB-4 for advanced fibrosis (area under the receiver operating characteristic curve:LSM 0.82, AGILE 3+ 0.82, NFS 0.72, FIB-4 0.75, aspartate aminotransferase-to-platelet ratio index 0.68; p < 0.001 of LSM-based versus simple serum tests), with an uncertainty area of 12%-20%. The combination of serum-based with LSM-based tests for advanced fibrosis led to a reduction of 40%-60% in necessary LSM tests. Decision curve analysis showed that all scores had a modest net benefit for ruling out advanced fibrosis at the risk threshold of 5%-10% of missing advanced fibrosis. LSM and AGILE 3+ outperformed both NFS and FIB-4 for fibrotic NASH (area under the receiver operating characteristic curve:LSM 0.79, AGILE 3+ 0.77, NFS 0.71, FIB-4 0.71; p < 0.001 of LSM-based versus simple serum tests). All noninvasive scores were suboptimal for diagnosing NASH. CONCLUSIONS: LSM and AGILE 3+ individually or in low availability settings in sequential combination after FIB-4 or NFS have a similar good diagnostic accuracy for advanced fibrosis and an acceptable diagnostic accuracy for fibrotic NASH in NAFLD patients with T2D.

Classification of Intrahepatic Cholangiocarcinoma into Perihilar Versus Peripheral Subtype.

BACKGROUND: Intrahepatic cholangiocarcinoma (ICC) constitutes a group of heterogeneous malignancies within the liver. We sought to subtype ICC based on anatomical origin of tumors, as well as propose modifications of the current classification system. METHODS: Patients undergoing curative-intent resection for ICC, hilar cholangiocarcinoma (CCA), or hepatocellular carcinoma (HCC) were identified from three international multi-institutional consortia of databases. Clinicopathological characteristics and survival outcomes were assessed. RESULTS: Among 1264 patients with ICC, 1066 (84.3%) were classified as ICC-peripheral subtype, whereas 198 (15.7%) were categorized as ICC-perihilar subtype. Compared with ICC-peripheral subtype, ICC-perihilar subtype was more often associated with aggressive tumor characteristics, including a higher incidence of nodal metastasis, macro- and microvascular invasion, perineural invasion, as well as worse overall survival (OS) (median: ICC-perihilar 19.8 vs. ICC-peripheral 37.1 months; p < 0.001) and disease-free survival (DFS) (median: ICC-perihilar 12.8 vs. ICC-peripheral 15.2 months; p = 0.019). ICC-perihilar subtype and hilar CCA had comparable OS (19.8 vs. 21.4 months; p = 0.581) and DFS (12.8 vs. 16.8 months; p = 0.140). ICC-peripheral subtype tumors were associated with more advanced tumor features, as well as worse survival outcomes versus HCC (OS, median: ICC-peripheral 37.1 vs. HCC 74.3 months; p < 0.001; DFS, median: ICC-peripheral 15.2 vs. HCC 45.5 months; p < 0.001). CONCLUSIONS: ICC should be classified as ICC-perihilar and ICC-peripheral subtype based on distinct clinicopathological features and survival outcomes. ICC-perihilar subtype behaved more like carcinoma of the bile duct (i.e., hilar CCA), whereas ICC-peripheral subtype had features and a prognosis more akin to a primary liver malignancy.

Prognostic Value of Serum α-Fetoprotein Level as an Important Characteristic of Tumor Biology for Patients Undergoing Liver Resection of Early-Stage Hepatocellular Carcinoma (BCLC Stage 0/A): A Large Multicenter Analysis.

BACKGROUND AND OBJECTIVE: According to the Barcelona Clinic Liver Cancer (BCLC) algorithm, tumor burden and liver function, but not tumor biology, are the key factors in determining tumor staging and treatment modality, and evaluating treatment prognosis. The serum α-fetoprotein (AFP) level is an important characteristic of hepatocellular carcinoma (HCC) biology, and we aimed to evaluate its prognostic value for patients undergoing liver resection of early-stage HCC. METHODS: Patients who underwent curative liver resection for early-stage HCC were identified from a multi-institutional database. Patients were divided into three groups according to preoperative AFP levels: low (< 400 ng/mL), high (400-999 ng/mL), and extremely-high (≥ 1000 ng/mL) AFP groups. Overall survival (OS) and recurrence rates were compared among these three groups. RESULTS: Among 1284 patients, 720 (56.1%), 262 (20.4%), and 302 (23.5%) patients had preoperative low, high, and extremely-high AFP levels, respectively. The cumulative 5-year OS and recurrence rates were 71.3 and 38.9% among patients in the low AFP group, 66.3 and 48.5% in the high AFP group, and 45.7 and 67.2% in the extremely-high AFP group, respectively (both p < 0.001). Multivariate Cox regression analysis identified both high and extremely-high AFP levels to be independent risk factors of OS (hazard ratio [HR] 1.275 and 1.978, 95% confidence interval [CI] 1.004-1.620 and 1.588-2.464, respectively; p = 0.047 and p < 0.001, respectively) and recurrence (HR 1.290 and 2.050, 95% CI 1.047-1.588 and 1.692-2.484, respectively; p = 0.017 and p < 0.001, respectively). CONCLUSIONS: This study demonstrated the important prognostic value of preoperative AFP levels among patients undergoing resection for early-stage HCC. Incorporating AFP to prognostic estimation of the BCLC algorithm can help guide individualized risk stratification and identify neoadjuvant/adjuvant treatment necessity.

Impact of Hepatic Pedicle Clamping on Long-Term Survival Following Hepatectomy for Hepatocellular Carcinoma: Stratified Analysis Based on Intraoperative Blood Transfusion Status.

BACKGROUND: Hepatic pedicle clamping (HPC) is frequently utilized during hepatectomy to reduce intraoperative bleeding and diminish the need for intraoperative blood transfusion (IBT). The long-term prognostic implications of HPC following hepatectomy for hepatocellular carcinoma (HCC) remain under debate. This study aims to elucidate the association between HPC and oncologic outcomes after HCC resection, stratified by whether IBT was administered. PATIENTS AND METHODS: Prospectively collected data on patients with HCC who underwent curative resection from a multicenter database was studied. Patients were stratified into two cohorts on the basis of whether IBT was administered. The impact of HPC on long-term overall survival (OS) and recurrence-free survival (RFS) between the two cohorts was assessed by univariable and multivariable Cox regression analyses. RESULTS: Of 3362 patients, 535 received IBT. In the IBT cohort, using or not using HPC showed no significant difference in OS and RFS outcomes (5-year OS and RFS rates 27.9% vs. 24.6% and 13.8% vs. 12.0%, P = 0.810 and 0.530). However, in the non-IBT cohort of 2827 patients, the HPC subgroup demonstrated significantly decreased OS (5-year 45.9% vs. 56.5%, P < 0.001) and RFS (5-year 24.7% vs. 33.3%, P < 0.001) when compared with the subgroup without HPC. Multivariable Cox regression analysis identified HPC as an independent risk factor of OS and RFS [hazard ratios (HR) 1.16 and 1.12, P = 0.024 and 0.044, respectively] among patients who did not receive IBT. CONCLUSIONS: The impact of HPC on the oncological outcomes following hepatectomy for patients with HCC differed significantly whether IBT was administered, and HPC adversely impacted on long-term survival for patients without receiving IBT during hepatectomy.

Benchmarks in Liver Resection for Intrahepatic Cholangiocarcinoma.

INTRODUCTION: Benchmarking in surgery has been proposed as a means to compare results across institutions to establish best practices. We sought to define benchmark values for hepatectomy for intrahepatic cholangiocarcinoma (ICC) across an international population. METHODS: Patients who underwent liver resection for ICC between 1990 and 2020 were identified from an international database, including 14 Eastern and Western institutions. Patients operated on at high-volume centers who had no preoperative jaundice, ASA class <3, body mass index <35 km/m2, without need for bile duct or vascular resection were chosen as the benchmark group. RESULTS: Among 1193 patients who underwent curative-intent hepatectomy for ICC, 600 (50.3%) were included in the benchmark group. Among benchmark patients, median age was 58.0 years (interquartile range [IQR] 49.0-67.0), only 28 (4.7%) patients received neoadjuvant therapy, and most patients had a minor resection (n = 499, 83.2%). Benchmark values included ≥3 lymph nodes retrieved when lymphadenectomy was performed, blood loss ≤600 mL, perioperative blood transfusion rate ≤42.9%, and operative time ≤339 min. The postoperative benchmark values included TOO achievement ≥59.3%, positive resection margin ≤27.5%, 30-day readmission ≤3.6%, Clavien-Dindo III or more complications ≤14.3%, and 90-day mortality ≤4.8%, as well as hospital stay ≤14 days. CONCLUSIONS: Benchmark cutoffs targeting short-term perioperative outcomes can help to facilitate comparisons across hospitals performing liver resection for ICC, assess inter-institutional variation, and identify the highest-performing centers to improve surgical and oncologic outcomes.

Recurrent Intrahepatic Cholangiocarcinoma: A 10-Point Score to Predict Post-Recurrence Survival and Guide Treatment of Recurrence.

INTRODUCTION: Although up to 50-70% of patients with intrahepatic cholangiocarcinoma (ICC) recur following resection, data to predict post-recurrence survival (PRS) and guide treatment of recurrence are limited. METHODS: Patients who underwent resection of ICC between 2000 and 2020 were identified from an international, multi-institutional database. Data on primary disease as well as laboratory and radiologic data on recurrent disease were collected. Factors associated with PRS were examined and a novel scoring system to predict PRS (PRS score) was developed and internally validated. RESULTS: Among 986 individuals who underwent resection for ICC, 588 (59.6%) patients developed recurrence at a median follow up of 20.3 months. Among patients who experienced a recurrence, 97 (16.5%) underwent re-resection/ablation for recurrent ICC; 88 (15.0%) and 403 (68.5%) patients received intra-arterial treatment or systemic chemotherapy/supportive therapy, respectively. Patient American Society of Anesthesiologists (ASA) class > 2 (1 point), primary tumor N1/Nx status (1 point), primary R1 resection margin (1 point), primary tumor G3/G4 grade (1 point), carbohydrate antigen (CA) 19-9 > 37 UI/mL (2 points) at recurrence and carcinoembryonic antigen (CEA) > 5 ng/mL (2 points) at recurrence, as well as recurrent bilateral disease (1 point) and early recurrence (1 point) were included in the PRS score. The PRS score successfully stratified patients relative to PRS and demonstrated strong discriminatory ability (C-index 0.70, 95% confidence interval 0.68-0.72). While a PRS score of 0-3 was associated with a 3-year PRS of 62.5% following resection/ablation for recurrent ICC, a PRS score > 3 was associated with a low 3-year PRS of 35.5% (p = 0.03). CONCLUSIONS: The PRS score demonstrated strong discriminatory ability to predict PRS among patients who had developed recurrence following initial resection of ICC. The PRS score may be a useful tool to guide treatment among patients with recurrent ICC.

Early Onset Intrahepatic Cholangiocarcinoma: Clinical Characteristics, Oncological Outcomes, and Genomic/Transcriptomic Features.

INTRODUCTION: Data on clinical characteristics and disease-specific prognosis among patients with early onset intrahepatic cholangiocarcinoma (ICC) are currently limited. METHODS: Patients undergoing hepatectomy for ICC between 2000 and 2020 were identified by using a multi-institutional database. The association of early (≤50 years) versus typical onset (>50 years) ICC with recurrence-free (RFS) and disease-specific survival (DSS) was assessed in the multi-institutional database and validated in an external cohort. The genomic and transcriptomic profiles of early versus late onset ICC were analyzed by using the Total Cancer Genome Atlas (TCGA) and Memorial Sloan Kettering Cancer Center databases. RESULTS: Among 971 patients undergoing resection for ICC, 22.7% (n = 220) had early-onset ICC. Patients with early-onset ICC had worse 5-year RFS (24.1% vs. 29.7%, p < 0.05) and DSS (36.5% vs. 48.9%, p = 0.03) compared with patients with typical onset ICC despite having earlier T-stage tumors and lower rates of microvascular invasion. In the validation cohort, patients with early-onset ICC had worse 5-year RFS (7.4% vs. 20.5%, p = 0.002) compared with individuals with typical onset ICC. Using the TCGA cohort, 652 and 266 genes were found to be upregulated (including ATP8A2) and downregulated (including UTY and KDM5D) in early versus typical onset ICC, respectively. Genes frequently implicated as oncogenic drivers, including CDKN2A, IDH1, BRAF, and FGFR2 were infrequently mutated in the early-onset ICC patients. CONCLUSIONS: Early-onset ICC has distinct clinical and genomic/transcriptomic features. Morphologic and clinicopathologic characteristics were unable to fully explain differences in outcomes among early versus typical onset ICC patients. The current study offers a preliminary landscape of the molecular features of early-onset ICC.

Perioperative Lymphopenia is Associated with Increased Risk of Recurrence and Worse Survival Following Hepatectomy for Hepatocellular Carcinoma.

INTRODUCTION: Immune dysregulation may be associated with cancer progression. We sought to investigate the prognostic value of perioperative lymphopenia on short- and long-term outcomes among patients undergoing resection of hepatocellular carcinoma (HCC). METHODS: Patients undergoing resection of HCC between 2000 and 2020 were identified using an international database. The incidence and impact of perioperative lymphopenia [preoperative, postoperative day (POD) 1/3/5], defined as absolute lymphocyte count (ALC) <1000/µL, on short- and long-term outcomes was assessed. RESULTS: Among 1448 patients, median preoperative ALC was 1593/µL [interquartile range (IQR) 1208-2006]. The incidence of preoperative lymphopenia was 14.0%, and 50.2%, 45.1% and 35.6% on POD1, POD3 and POD5, respectively. Preoperative lymphopenia predicted 5-year overall survival (OS) [lymphopenia vs. no lymphopenia: 49.1% vs. 66.1%] and 5-year disease-free survival (DFS) [25.0% vs. 41.5%] (both p < 0.05). Lymphopenia on POD1 (5-year OS: 57.1% vs. 71.2%; 5-year DFS: 30.0% vs. 41.1%), POD3 (5-year OS: 57.3% vs. 68.9%; 5-year DFS: 35.4% vs. 42.7%), and POD5 (5-year OS: 53.1% vs. 66.1%; 5-year DFS: 32.8% vs. 42.3%) was associated with worse long-term outcomes (all p < 0.05). Patients with severe lymphopenia (ALC <500/µL) on POD5 had worse 5-year OS and DFS (5-year OS: 44.7% vs. 54.3% vs. 66.1%; 5-year DFS: 27.8% vs. 33.3% vs. 42.3%) [both p < 0.05], as well as higher incidence of overall (45.5% vs. 25.3% vs. 30.9%; p = 0.013) and major complications (18.2% vs. 3.4% vs. 4.5%; p < 0.001) versus individuals with moderate (ALC 500-1000/µL) or no lymphopenia following hepatectomy for HCC. After adjusting for competing risk factors, prolonged lymphopenia was independently associated with higher hazards of death [hazard ratio (HR) 1.38, 95% CI 1.11-1.72] and recurrence (HR 1.22, 95% CI 1.02-1.45). CONCLUSION: Perioperative lymphopenia had short- and long-term prognostic implications among individuals undergoing hepatectomy for HCC.

RUNX1 targeting AKT3 promotes alveolar hypercoagulation and fibrinolytic inhibition in LPS induced ARDS.

BACKGROUND: Alveolar hypercoagulation and fibrinolytic inhibition are mainly responsible for massive alveolar fibrin deposition, which are closely related with refractory hypoxemia in acute respiratory distress syndrome (ARDS). Our previous study testified runt-related transcription factor (RUNX1) participated in the regulation of this pathophysiology in this syndrome, but the mechanism is unknown. We speculate that screening the downstream genes associated with RUNX1 will presumably help uncover the mechanism of RUNX1. METHODS: Genes associated with RUNX1 were screened by CHIP-seq, among which the target gene was verified by Dual Luciferase experiment. Then the efficacy of the target gene on alveolar hypercoagulation and fibrinolytic inhibition in LPS-induced ARDS was explored in vivo as well as in vitro. Finally, whether the regulatory effects of RUNX1 on alveolar hypercoagulation and fibrinolytic in ARDS would be related with the screened target gene was also sufficiently explored. RESULTS: Among these screened genes, AKT3 was verified to be the direct target gene of RUNX1. Results showed that AKT3 was highly expressed either in lung tissues of LPS-induced rat ARDS or in LPS-treated alveolar epithelia cell type II (AECII). Tissue factor (TF) and plasminogen activator inhibitor 1 (PAI-1) were increasingly expressed both in lung tissues of ARDS and in LPS-induced AECII, which were all significantly attenuated by down-regulation of AKT3. Inhibition of AKT3 gene obviously ameliorated the LPS-induced lung injury as well as the collagen I expression in ARDS. RUNX1 overexpression not only promoted the expressions of TF, PAI-1, but also boosted AKT3 expression in vitro. More importantly, the efficacy of RUNX1 on TF, PAI-1 were all effectively reversed by down-regulation of AKT3 gene. CONCLUSION: AKT3 is an important target gene of RUNX1, through which RUNX1 exerted its regulatory role on alveolar hypercoagulation and fibrinolytic inhibition in LPS-induced ARDS. RUNX1/ATK3 signaling axis is expected to be a new target for the exploration of ARDS genesis and treatment.

Long-term survivors after curative-intent resection for intrahepatic cholangiocarcinoma.

OBJECTIVES: The objective of the current study was to characterize prognostic factors related to long-term recurrence-free survival after curative-intent resection of intrahepatic cholangiocarcinoma (ICC). METHODS: Data on patients who underwent curative-intent resection for ICC between 2000 and 2020 were collected from an international multi-institutional database. Prognostic factors were investigated among patients who recurred within 5 years versus long-term survivors who survived more than 5 years with no recurrence. RESULTS: Among 635 patients who underwent curative-intent resection for ICC, 104 (16.4%) patients were long-term survivors with no recurrence beyond 5 years after surgery. Patients who survived for more than 5 years with no recurrence were more likely to have less aggressive tumor features, as well as have undergone an R0 resection versus patients who recurred within 5 years after resection. On multivariable analysis, tumor size (>5 cm) (HR: 1.535, 95% CI: 1.254-1.879), satellite lesions (HR: 1.253, 95% CI: 1.003-1.564), and lymph node metastasis (HR: 1.733, 95% CI: 1.349-2.227) were independently associated with recurrence within 5 years. Patients who recurred beyond 5 years (n = 23), 2-5 years (n = 60), and within 2 years (n = 471) had an incrementally worse post-recurrence survival (PRS, 28.0 vs. 20.0 vs. 12.0 months, p = 0.032). Among patients with N0 status, tumor size (>5 cm) (HR: 1.612, 95% CI: 1.087-2.390) and perineural invasion (PNI) (HR: 1.562,95% CI: 1.081-2.255) were risk factors associated with recurrence. Among patients with N1 disease, only a minority (5/128, 3.9%) of patients survived with no recurrence to 5 years. CONCLUSION: Roughly 1 in 6 patients survived for more than 5 years with no recurrence following curative-intent resection of ICC. Among N0 patients, tumor recurrence was associated with tumor size and PNI. Only a small subset of N1 patients experienced long-term survival.

A prognostic model based on tumor microenvironment and immune cell in colorectal cancer.

BACKGROUND: Colorectal cancer (CRC) is the second leading cause of cancer-related death. Immunotherapy is one of the new options for cancer treatment. This study aimed to develop an immune-related signature associated with CRC. METHODS: We performed differential analysis to screen out the differentially expressed genes (DEGs) of The Cancer Genome Atlas-Colorectal Cancer (TCGA-CRC) datasets. Weighted gene co-expression network analysis (WGCNA) was performed to obtain the key module genes associated with differential immune cells. The candidate genes were obtained through overlapping key DEGs and key module genes. The univariate and multivariate Cox regression analyses were adopted to build a CRC prognostic signature. We further conducted immune feature estimation and chemotherapy analysis between two risk subgroups. Finally, we verified the expression of immune-related prognostic genes at the transcriptional level. RESULTS: A total of 61 candidate genes were obtained by overlapping key DEGs and key module genes associated with differential immune cells. Then, an immune-related prognostic signature was built based on the three prognostic genes (HAMP, ADAM8, and CD1B). The independent prognostic analysis suggested that age, stage, and RiskScore could be used as independent prognostic factors. Further, we found significantly higher expression of three prognostic genes in the CRC group compared with the normal group. Finally, real-time polymerase chain reaction verified the expression of three genes in patients with CRC. CONCLUSION: The prognostic signature comprising HAMP, ADAM8, and CD1B based on immune cells was established, providing a theoretical basis and reference value for the research of CRC.

Study on the predictive value of pretreatment peripheral blood inflammatory markers regarding immunotherapy in patients with inoperable advanced or locally advanced oesophageal squamous cell carcinoma.

OBJECTIVE: To explore the effects of pretreatment peripheral blood panimmune-inflammation value (PIV), systemic immune-inflammation index (SII), neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR) on the efficacy and prognostic value of immunotherapy in patients with inoperable advanced or locally advanced oesophageal squamous cell carcinoma (ESCC). METHODS: Clinical data of 107 inoperable advanced or locally advanced ESCC patients were retrospectively analysed between May 2019 and August 2023, the receiver operating characteristic curves (ROCs) of PIV, SII, NLR, and PLR in patients prior to immunotherapy were plotted, and their optimal cutoff values were determined. The risk factors were determined by univariate and multivariate analyses in groups based on the optimal cut-off values. RESULTS: Peripheral blood PIV, SII and PLR before immunotherapy had predictive value for the optimal efficacy of immunotherapy in patients with inoperable advanced or locally advanced ESCC; patients with PIV ≥415.885, SII ≥834.295 and NLR ≥3.740 had a low objective response rate (ORR), disease control rate (DCR), a short progression-free survival (PFS) and overall survival (OS) after immunotherapy (p < 0.05). Patient tumour stage, distant lymph node metastasis, lung metastasis, liver metastasis, PIV, SII, and NLR were risk factors affecting PFS and OS (p < 0.05). Tumour stage and SII were independent risk factors affecting PFS and OS (p < 0.05). CONCLUSION: In patients with inoperable advanced or locally advanced ESCC, peripheral blood PIV, SII, and NLR have predictive value for immunotherapy outcome, SII is an independent risk factor affecting the survival prognosis, and SII ≥834.295 suggests a poor prognosis from immunotherapy.

An Improved A-Star Path Planning Algorithm Based on Mobile Robots in Medical Testing Laboratories.

In the blood sample management pipeline environment, we have innovatively improved the traditional A-star algorithm to enhance the efficiency of mobile robots. This study employs a grid environmental modeling approach to accurately simulate medical testing laboratories. On the grid map, we utilize an 8-neighbor search method for path planning to accommodate the complex structure within the laboratory. By introducing an improved evaluation function and a bidirectional search strategy, we have successfully reduced the number of search nodes and significantly improved path search efficiency. Additionally, we eliminate redundant nodes in the path, smooth the path using cubic uniform B-spline curves, remove unnecessary inflection points, and further optimize the motion trajectory of the robot. The experimental results of the path planning simulation under different scenarios and specifications show that the improved A-star algorithm has higher search efficiency and traverses fewer nodes compared to the traditional A-star algorithm and the bidirectional A-star algorithm. Overall, the simulation experiments verify the feasibility of the improved A-star algorithm, which can better meet the needs of actual mobile robots in real medical testing laboratories.