Spatial proteomic landscape of primary and relapsed hepatocellular carcinoma reveals immune escape characteristics in early relapse.

BACKGROUND AND AIMS: Surgical resection serves as the principal curative strategy for HCC, yet the incidence of postoperative recurrence remains alarmingly high. However, the spatial molecular structural alterations contributing to postoperative recurrence in HCC are still poorly understood. APPROACH AND RESULTS: We employed imaging mass cytometry to profile the in situ expression of 33 proteins within 358,729 single cells of 92 clinically annotated surgical specimens from 46 patients who were treated with surgical resections for primary and relapsed tumors. We revealed the recurrence progression of HCC was governed by the dynamic spatial distribution and functional interplay of diverse cell types across adjacent normal, tumor margin, and intratumor regions. Our exhaustive analyses revealed an aggressive, immunosuppression-related spatial ecosystem in relapsed HCC. Additionally, we illustrated the prominent implications of the tumor microenvironment of tumor margins in association with relapse HCC. Moreover, we identified a novel subpopulation of dendritic cells (PDL1 + CD103 + DCs) enriched in the peritumoral area that correlated with early postoperative recurrence, which was further validated in an external cohort. Through the analysis of single-cell RNA sequencing data, we found the interaction of PDL1 + CD103 + DCs with regulatory T cells and exhausted T cells enhanced immunosuppression and immune escape through multiple ligand-receptor pathways. CONCLUSIONS: We comprehensively depicted the spatial landscape of single-cell dynamics and multicellular architecture within primary and relapsed HCC. Our findings highlight spatial organization as a prominent determinant of HCC recurrence and provide valuable insight into the immune evasion mechanisms driving recurrence.

Clinical Effectiveness of Drug-Eluting Microsphere Transcatheter Arterial Chemoembolization Combined with First-Line Chemotherapy as the Initial Treatment for Patients with Unresectable Intrahepatic Cholangiocarcinoma.

PURPOSE: To evaluate the safety and effectiveness of the combination of drug-eluting microsphere (DEM) transcatheter arterial chemoembolization (TACE) with those of chemotherapy in treating unresectable intrahepatic cholangiocarcinoma (ICC). MATERIALS AND METHODS: Seventy patients diagnosed with unresectable ICC between January 2016 and December 2020 were retrospectively included in this study. Of these, 39 patients received DEM-TACE and first-line chemotherapy (TACE+Chemo group) and 31 received chemotherapy alone (Chemo group). Propensity score matching was performed to reduce selection bias between the TACE+Chemo and the Chemo groups. Differences in tumor response, progression-free survival (PFS), overall survival (OS), and treatment-related adverse events (TRAEs) were compared between 2 two groups. RESULTS: The patients in the TACE+Chemo group had better median OS (18.6 vs 11.9 months; P = .018), median PFS (11.9 vs 6.9 months, P = .033), and objective response rates (56.8% vs 13.3%; P < .001) than those in the Chemo group. TRAEs showed a higher incidence of transient elevation of transaminase and abdominal pain in the TACE+Chemo group than in the Chemo group (P < .001). CONCLUSIONS: Compared with chemotherapy alone, DEM-TACE combined with first-line chemotherapy may be a viable and safe treatment option for unresectable ICC.

Association between white matter hyperintensities and altered cerebral blood flow in maintenance hemodialysis patients: a longitudinal study.

OBJECTIVES: To explore changes in cerebral blood flow (CBF) and white matter in hemodialysis patients. METHODS: Thirty-three hemodialysis patients who underwent two brain MRI at an interval of three years and 33 age- and sex-matched healthy controls (HC) underwent structural and arterial spin-labeling MRI examinations. Intergroup differences in CBF in the gray matter, white matter, and whole matter, and regional white matter hyperintensities (WMH) were analyzed. Based on the changes in CBF between the baseline and follow-up groups, the hemodialysis patients were divided into two subgroups: an increased CBF group and a decreased CBF group. Differences in CBF and WMH between the subgroups and HC were analyzed. RESULTS: Patients undergoing hemodialysis exhibited increased cerebral watershed (CW) WMH, deep WMH, and periventricular WMH (P < 0.01). The CBF of patients with decreased CBF was higher than that of HC at baseline (,P < 0.01) and lower than that of HC at follow-up (P < 0.01). Compared with the increased CBF group, obvious development of deep WMH was found in the decreased CBF group for the gray matter, white matter, and whole matter (P < 0.01). CONCLUSIONS: WMH in hemodialysis patients were distributed in the deep white matter, periventricular white matter and CW, and progressed with the extension of hemodialysis duration. CBF in hemodialysis patients could manifest as both increased and decreased, and WMH in patients with decreased CBF developed severely with prolongation of hemodialysis duration. ADVANCES IN KNOWLEDGE: These findings provide a basis for exploring neuropathological changes of hemodialysis patients.

Dysfunctional Coupling of Cerebral Blood Flow and Susceptibility Value in the Bilateral Hippocampus is Associated with Cognitive Decline in Nondialysis Patients with CKD.

SIGNIFICANCE STATEMENT: Patients with end stage CKD often develop cognitive decline, but whether this is related to the underlying disease or to hemodialysis remains unclear. We performed three-dimensional pseudocontinuous arterial spin labeling and quantitative susceptibility mapping prospectively in 40 patients with stage 1-4 CKD, 47 nondialysis patients with stage 5 CKD, and 44 healthy controls. Our magnetic resonance imaging data demonstrate that changes in cerebral blood flow-susceptibility coupling might underlie this cognitive decline, perhaps in the hippocampus and thalamus. These results suggest that magnetic resonance imaging parameters are potential biomarkers of cognitive decline in patients with CKD. Moreover, our findings may lead to discovery of novel therapeutic targets to prevent cognitive decline in patients with CKD. BACKGROUND: Cerebral blood flow (CBF) and susceptibility values reflect vascular and iron metabolism, providing mechanistic insights into conditions of health and disease. Nondialysis patients with CKD show a cognitive decline, but the pathophysiological mechanisms underlying this remain unclear. METHODS: Three-dimensional pseudocontinuous arterial spin labeling and quantitative susceptibility mapping were prospectively performed in 40 patients with stage 1-4 CKD (CKD 1-4), 47 nondialysis patients with stage 5 CKD (CKD 5ND), and 44 healthy controls (HCs). Voxel-based global and regional analyses of CBF, susceptibility values, and vascular-susceptibility coupling were performed. Furthermore, the association between clinical performance and cerebral perfusion and iron deposition was analyzed. RESULTS: For CBF, patients with CKD 5ND had higher normalized CBF in the hippocampus and thalamus than HCs. Patients with CKD 5ND had higher normalized CBF in the hippocampus and thalamus than those with CKD 1-4. The susceptibility values in the hippocampus and thalamus were lower in patients with CKD 5ND than in HCs. Patients with CKD 5ND had higher susceptibility value in the caudate nucleus than those with CKD 1-4. More importantly, patients with CKD 5ND had lower CBF-susceptibility coupling than HCs. In addition, CBF and susceptibility values were significantly associated with clinical performance. CONCLUSIONS: Our findings demonstrate a new neuropathological mechanism in patients with CKD, which leads to regional changes in CBF-susceptibility coupling. These changes are related to cognitive decline, providing potential imaging markers for assessing clinical disability and cognitive decline in these patients.

Preimplantation genetic testing in the current era, a review.

BACKGROUND: Preimplantation genetic testing (PGT), also referred to as preimplantation genetic diagnosis (PGD), is an advanced reproductive technology used during in vitro fertilization (IVF) cycles to identify genetic abnormalities in embryos prior to their implantation. PGT is used to screen embryos for chromosomal abnormalities, monogenic disorders, and structural rearrangements. DEVELOPMENT OF PGT: Over the past few decades, PGT has undergone tremendous development, resulting in three primary forms: PGT-A, PGT-M, and PGT-SR. PGT-A is utilized for screening embryos for aneuploidies, PGT-M is used to detect disorders caused by a single gene, and PGT-SR is used to detect chromosomal abnormalities caused by structural rearrangements in the genome. PURPOSE OF REVIEW: In this review, we thoroughly summarized and reviewed PGT and discussed its pros and cons down to the minutest aspects. Additionally, recent studies that highlight the advancements of PGT in the current era, including their future perspectives, were reviewed. CONCLUSIONS: This comprehensive review aims to provide new insights into the understanding of techniques used in PGT, thereby contributing to the field of reproductive genetics.

Idarubicin versus epirubicin in drug-eluting beads-transarterial chemoembolization for treating hepatocellular carcinoma: A real-world retrospective study.

The purpose of this study was to compare the efficacy and safety of idarubicin-loaded drug-eluting beads-transarterial chemoembolization (IDA-TACE) and epirubicin-loaded drug-eluting beads-TACE (EPI-TACE) in treating hepatocellular carcinoma (HCC). All patients with HCC treated with TACE in our hospital between June 2020 and January 2022 were screened. The included patients were divided into the IDA-TACE group and EPI-TACE group to compare overall survival (OS), time to progression (TTP), objective response rate (ORR), and adverse events. There were 55 patients each in the IDA-TACE and EPI-TACE groups. Compared with the EPI-TACE group, the median TTP in the IDA-TACE group was not significantly different (10.50 vs. 9.23 months; HR 0.68; 95% CI 0.40-1.16; P = 0.154), whereas the survival status in the IDA-TACE group tended to be better (neither achieved; HR 0.47; 95% CI 0.22-1.02; P = 0.055). Based on the Barcelona Clinic Liver Cancer staging system for subgroup analysis, considering stage C patients, the IDA-TACE group performed significantly better in terms of ORR (77.1% vs. 54.3%, P = 0.044), median TTP (10.93 vs. 5.20 months; HR 0.46; 95% CI 0.24-0.89; P = 0.021), and median OS (not achieved vs. 17.80 months; HR 0.41; 95% CI 0.18-0.93; P = 0.033). Considering stage B patients, there were no significant differences between the IDA-TACE and EPI-TACE groups in terms of ORR (80.0% vs. 80.0%, P = 1.000), median TTP (10.20 vs. 11.2 months; HR 1.41; 95% CI 0.54-3.65; P = 0.483), or median OS (neither achieved, HR 0.47; 95% CI 0.04-5.24; P = 0.543). Notably, leukopenia was more common in the IDA-TACE group (20.0%, P = 0.052), and fever was more common in the EPI-TACE group (49.1%, P = 0.010). IDA-TACE was more effective than EPI-TACE in treating advanced-stage HCC and comparable in treating intermediate-stage HCC.

6-mm shunt transjugular intrahepatic portosystemic shunt in patients with severe liver atrophy and variceal bleeding.

OBJECTIVES: We proposed a strategy for the creation of a 6-mm transjugular intrahepatic portosystemic shunt (TIPS) and to assess its effectiveness compared to a conventional 8-mm shunt for TIPS-induced hepatic encephalopathy (HE). METHODS: Patients were reviewed retrospectively using propensity score matching (1:1) and divided into 6-mm and 8-mm shunt groups based on shunt diameter. The stent patency, HE incidence, and rebleeding rate between the two groups were then compared. RESULTS: From January 2018 to June 2021, both 6-mm shunt group and 8-mm shunt group included 58 patients. The 6-mm shunt group had significantly smaller liver volumes (879.3 ± 237.1 vs. 1008.8 ± 293.0; p = 0.010), and the median stent patency times were 30.7 and 33.8 months in the 6-mm and 8-mm groups, respectively (p = 0.124). No statistically significant difference was found between the two groups in the 1-year (8.6% vs. 3.4%; p = 0.242) and 2-year (17.2% vs. 12.1%; p = 0.242) rebleeding rates. The 1-year cumulative incidences of overt HE were 12.1% and 27.6% in the 6-mm and 8-mm groups, respectively (p = 0.040), and the 2-year cumulative overt HE incidences in these groups were 19.0% and 36.2%, respectively (p = 0.038). Notably, patients with a 6-mm shunt also experienced less hepatic impairment. CONCLUSIONS: For patients with variceal bleeding and a small liver volume, the 6-mm shunt significantly reduced the incidence of overt HE, protected perioperative liver function, and did not affect stent patency or rebleeding rate. CLINICAL RELEVANCE STATEMENT: For patients with variceal bleeding with small liver volume, the 6-mm transjugular intrahepatic portosystemic shunt (TIPS) significantly reduced the incidence of overt hepatic encephalopathy after TIPS, protected perioperative liver function, and did not affect stent patency and rebleeding rate. KEY POINTS: • A strategy for the creation of a 6-mm transjugular intrahepatic portosystemic shunt for patients with variceal bleeding and a small liver volume was proposed. • The 6-mm transjugular intrahepatic portosystemic shunt significantly reduced the incidence of overt hepatic encephalopathy. • The 6-mm transjugular intrahepatic portosystemic shunt did not affect stent patency or rebleeding rate.

DNA N6-methyladenine involvement and regulation of hepatocellular carcinoma development.

DNA N6-methyladenine (6 mA) is a new type of DNA methylation identified in various eukaryotic cells. However, its alteration and genomic distribution features in hepatocellular carcinoma (HCC) remain elusive. In this study, we found that N6AMT1 overexpression increased HCC cell viability, suppressed apoptosis, and enhanced migration and invasion, whereas ALKBH1 overexpression induced the opposite effects. Further, 23,779 gain-of-6 mA regions and 11,240 loss-of-6 mA regions were differentially identified in HCC tissues. The differential gain and loss of 6 mA regions were considerably enriched in intergenic regions. Moreover, 7% of the differential 6 mA modifications were associated with tumors, with 60 associated with oncogenes and 57 with tumor suppressor genes (TSGs), and 17 were common to oncogenes and TSGs. The candidate genes affected by 6 mA were filtered by gene ontology (GO) and RNA-seq. Using quantitative polymerase chain reaction (qPCR), BCL2 and PARTICL were found to be correlated with DNA 6 mA in certain HCC processes.

DEM-TACE as the initial treatment could improve the clinical efficacy of the hepatocellular carcinoma with portal vein tumor thrombus: a retrospective controlled study.

BACKGROUND: Conventional-transarterial chemoembolization (C-TACE) was proven to improve overall survival (OS) in hepatocellular carcinoma (HCC) patients with portal vein tumor thrombus (PVTT), drug-eluting microsphere-TACE (DEM-TACE) was supposed to provide more benefit than C-TACE in this respect. PURPOSE: To compare the safety and efficacy between DEM-TACE and C-TACE as the initial treatment in HCC patients with PVTT and to identify prognostic factors of OS. METHODS: The medical records of advanced HCC patients with PVTT who underwent DEM-TACE or C-TACE as the initial thearpy from September 2015 with mean follow-up time 14.9 ± 1.2 (95% CI 12.6-17.2) months were retrospectively evaluated. A total of 97 patients were included, 49 patients in the DEM-TACE group and 48 in the C-TACE group. Adverse events (AEs) related to TACE were compared. Tumor and PVTT radiologic response, time to tumor progression (TTP) and OS were calculated and compared in both groups. RESULTS: Patients in DEM-TACE group had a better radiologic response (Tumr response: 89.8% vs. 75.0%; PVTT response: 85.7% vs. 70.8%; overall response: 79.6% vs. 58.3%, P = 0.024) and longer TTP (7.0 months vs. 4.0 months, P = 0.040) than patients in C-TACE group. A lower incidence of abdominal pain was found in the DEM-TACE group than in C-TACE group (21 vs. 31, P = 0.032), but there were no significant differences between DEM-TACE and C-TACE patients in any other AEs reported. When compared to C-TACE, DEM-TACE also showed significant OS benefits (12.0 months vs. 9.0 months, P = 0.027). DEM-TACE treatment, the absence of arterioportal shunt (APS), lower AFP value and better PVTT radiologic response were the independent prognostic factors for OS in univariate/multivariate analyses, which provided us with a guide for better patient selection. CONCLUSIONS: Based on our retrospective study, DEM-TACE can be performed safely and might be superior to C-TACE as the initial treatment for HCC patients with PVTT. TRIAL REGISTRATION: Retrospectively registered.

Identification of circRNAs involved in the development of hepatocellular carcinoma after insufficient radiofrequency ablation.

Previous studies have reported that circular RNAs (circRNAs) play a key role in the pathogenesis and progression of various diseases. In the present study, we aimed to identify potential circRNAs associated with the progression of hepatocellular carcinoma (HCC) after insufficient radiofrequency ablation (IRFA). A xenograft mouse IRFA model was initially established, and immunohistochemical staining (IHC) and polymerase chain reaction (PCR) were performed to confirm the expression of programmed cell death-ligand 1 (PD-L1) and vascular endothelial growth factor receptor-1 (VEGFR-1). CircRNA expression alterations were screened by next-generation sequencing (RNA-seq). Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were conducted to predict the function of genes coding differentially expressed circRNAs. The selected circRNAs were validated utilizing PCR and Sanger sequencing. The relationships between circRNAs, microRNAs, PD-L1, and VEGFR-1 were predicted by bioinformatics. Overall, a total of 612 circRNAs were differentially expressed in IRFA-treated subcutaneous tumorigenesis tissue. Among them, 435 circRNAs were significantly upregulated and 177 circRNAs were downregulated. GO and KEGG analyses were employed to predict the functions of these circRNAs. Thereafter, quantitative reverse transcription PCR (qRT-PCR) assays determined that these seven circRNAs were overexpressed in the IRFA group, which was consistent with the RNA-seq results. Based on the bioinformatic analysis, seven circRNAs confirmed by Sanger sequencing were predicted to likely regulate PD-L1 and VEGFR-1 expression levels by functioning as sponges for microRNAs (miRNAs) and forming a circRNA-miRNA-PD-L1/VEGFR-1 regulatory network. Finally, IHC and qRT-PCR of PD-L1 and VEGFR-1 confirmed the activation of this pathway. Taken together, we report that differentially expressed circRNAs might simultaneously regulate PD-L1 and VEGFR-1 in the IRFA tissues, which provides a novel view of circRNAs in HCC progression after the IRFA procedure.