IMPORTANCE Late recurrence (more than 2 years) after liver resection for hepatocellular carcinoma (HCC) is generally considered as a multicentric tumor or a de novo cancer. OBJECTIVE To investigate the risk factors, patterns, and outcomes of late recurrence after curative liver resection for HCC. DESIGN, SETTING, AND PARTICIPANTS This study was a multicenter retrospective analysis of patients who underwent curative liver resection for HCC at 6 hospitals in China from January 2001 to December 2015. Among 734 patients who were alive and free of recurrence at 2 years after resection, 303 patients developed late recurrence. Data were analyzed from June 2017 to February 2018. INTERVENTIONS Liver resection for HCC. MAIN OUTCOMES AND MEASURES Risk factors of late recurrence as well as patterns, treatments, and long-term outcomes of patients with late recurrence. Univariate and multivariate Cox regression analyses were performed to identify independent risk factors of late recurrence. RESULTS Of the included 734 patients, 652 (88.8%) were male, and the mean (SD) age was 51.0 (10.3) years. At a median (interquartile range) follow-up of 78.0 (52.8-112.5) months, 303 patients (41.3%) developed late recurrence. Multivariate analysis revealed that male sex, cirrhosis, multiple tumors, satellite nodules, tumor size greater than 5 cm, and macroscopic and microscopic vascular invasion were independent risk factors of late recurrence. Of the 303 patients with late recurrence, 273 (90.1%) had only intrahepatic recurrence, 30 (9.9%) had both intrahepatic and extrahepatic recurrence, and none had only extrahepatic recurrence. Potentially curative treatments were given to 165 of 303 patients (54.5%) with late recurrence, which included reresection, transplant, and local ablation. Multivariate Cox regression analysis showed that regular surveillance for postoperative recurrence (hazard ratio [HR], 0.470; 95% CI, 0.310-0.713;

Hepatocellular carcinoma (HCC) is one of the most common and deadly gastrointestinal malignancies. Given its insensitivity to traditional systematic chemotherapy, new therapeutic strategies for efficient HCCs treatment are urgently needed. Here, the development of a novel 2D MXene-based composite nanoplatform for highly efficient and synergistic chemotherapy and photothermal hyperthermia against HCC is reported. A surface-nanopore engineering strategy is developed for the MXenes' surface functionalization, which achieves the uniform coating of a thin mesoporous-silica layer onto the surface of 2D Ti C MXene (Ti C @mMSNs). This strategy endows MXenes with well-defined mesopores for on-demand drug release/delivery, enhanced hydrophilicity/dispersity, and abundant surface chemistry for targeting engineering. Systematic in vitro and in vivo evaluations have demonstrated the high active-targeting capability of arginine-glycine-aspartic acid (RGD)-targeting Ti C @mMSNs into tumor, and the synergistic chemotherapy (contributed by the mesoporous shell) and photothermal hyperthermia (contributed by the Ti C MXene core) completely eradicate the tumor without obvious reoccurrence. This work not only provides a novel strategy for efficiently combating HCC by developing MXene-based composite nanoplatforms, but also paves a new way for extending the biomedical applications of MXenes by surface-nanopore engineering.

Hepatocellular carcinoma (HCC) is one of the deadliest malignancies worldwide featured with the poor prognosis and high mortality in affected patients. Given its insensitivity to conventional systemic chemotherapy, the development of novel modalities for HCC management is highly urgent. Sonodynamic therapy (SDT) has gained considerable momentum in cancer therapy. Especially, through synergistic SDT/chemotherapy, SDT would enhance the chemotherapeutic process on inhibiting tumor growth, which holds great potential on combating HCC. In this work, we report on the design/fabrication of targeted biodegradable nanosonosensitizers based on hollow mesoporous organosilica nanoparticles (HMONs), followed by pore-engineering including covalent anchoring of protoporphyrin (PpIX, HMONs-PpIX) and conjugation of arginine-glycine-aspartic acid in order to specifically targeting HCC cells. Such nanosonosensitizers provide efficient loading and controllable stimuli-responsive release of chemotherapeutic agents for HCC-targeting chemotherapy, thus promoting an enhancing chemotherapeutic process via the unique sonotoxicity under ultrasound irradiation. The HMONs matrix with biologically active organic groups in the framework (disulfide bond) are endowed with intrinsic tumor microenvironment-responsive biodegradability and improved biocompatibility/ biosafety. In particular, a synergistic inhibition effect of drug-loaded HMONs-PpIX-arginine-glycine-aspartic acid on HCC growth has been systematically demonstrated both in vitro and in vivo (84.7% inhibition rate), which brings insights and meets the versatile therapeutic requirements for HCC management. Scheme 1. Schematic illustration of the synthetic process of HMONs-PpIX-RGD and synergistic chemo-SDT against HCC tumor xenograft on nude mice. a) Schematic diagram of synthesizing HMONs and further pore engineering with PpIX. b) Schematic process of surface PEG modification, RGD conjugation, and DOX loading on as-synthesized HMONs. c) Schematic illustration of multitherapeutic functions of HMONs-PpIX-RGD, including free transport within blood vessel after intravenous injection, specific recognition between RGD and ligands expressed on HCC cell membranes, GSH/ US-responsive drug release, and enhanced/synergistic chemo-SDT process.www.afm-journal.de www.advancedsciencenews.com 1800145 (3 of 16)

Purpose: Circulating tumor DNA (ctDNA) provides a novel approach for detecting tumor burden and predicting clinical outcomes of hepatocellular carcinoma (HCC). Here, we performed a thorough evaluation of HCC circulating genetic features and further fully integrated them to build a robust strategy for HCC monitoring and prognostic outcome assessment. Experimental Design: We performed target sequencing and low-coverage whole-genome sequencing on plasma samples collected from 34 long-term follow-up patients with HCC to capture tumor somatic SNVs and CNVs, respectively. Clinical information was also obtained to evaluate the prognostic performance of ctDNA comparing with clinically applied protein biomarkers. Results: All plasma samples before surgery showed somatic genetic variations resembling corresponding tumor tissues. During follow-up, SNVs and CNVs dynamically changed correlating to patients' tumor burden. We integrated the comprehensive ctDNA mutation profiles to provide a robust strategy to accurately assess patients' tumor burden with high consistence comparing with imaging results. This strategy could discover tumor occurrence in advance of imaging for an average of 4.6 months, and showed superior performance than serum biomarkers AFP, AFP-L3%, and Des-Gamma-Carboxy Prothrombin (DCP). Furthermore, our strategy could precisely detect minimal residual disease (MRD) in advance and predict patients' prognostic outcomes for both relapsefree survival (P ¼ 0.001) and overall survival (P ¼ 0.001); further combining ctDNA with DCP could increase the sensitivity for MRD detection. Conclusions: We demonstrated that plasma CNV and SNV levels dynamically correlated with patients' tumor burden in HCC. Our strategy of comprehensive mutation profile integration could accurately and better evaluate patients' prognostic risk and detect tumor occurrence in advance than traditional strategies.

Circular RNA (circRNA) can participate in various biological processes, including tumorigenesis, through their microRNA response elements. Alterations in circRNA profiles during hepatocellular carcinoma (HCC) progression and their clinical significance remain unclear. Here, we present extensive analysis of circRNA profiles in tumor and matched peritumor tissues collected from 10 HCC patients, conducted to identify circRNA related to HCC progression. A total of 42 dysregulated circRNA (38 down‐regulated and 4 up‐regulated) were identified in HCC tumor tissues compared with matched peritumor tissues, revealing the heterogeneity of circRNA profiles in HCC. CircADAMTS13, derived from Exon 13–14 of the ADAMTS13 gene, was significantly downregulated in HCC tumor tissues. Furthermore, clinicopathological analysis revealed that up‐regulation of circADAMTS13 was negatively associated with tumor size but positively associated with prognosis. In addition, overexpression of circADAMTS13 could markedly inhibit HCC cell proliferation in vitro. Bioinformatic analysis and luciferase reporter assays further revealed that circADAMTS13 directly interacts with microRNA (miR)‐484. Rescue experiments showed that miR‐484 mimics can reverse the tumor‐suppressing roles of circADAMTS13 in HCC. Therefore, our results demonstrated that circADAMTS13 can serve as a tumor suppressor during HCC progression via the functional pathway of sponging miR‐484.

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Background: The resection margin (RM) status and microscopic vascular invasion (MVI) are known prognostic factors for hepatocellular carcinoma (HCC). An enhanced understanding of their impact on long-term prognosis is required to improve oncological outcomes. Methods: Using multi-institutional data, the different impact of the RM status (narrow, <1 cm, or wide, 1 cm) and MVI (positive or negative) on overall survival (OS) and recurrence-free survival (RFS) after curative liver resection of solitary HCC without macrovascular invasion was analyzed. Results: In 801 patients, 306 (38%) had a narrow RM and 352 (44%) had positive MVI. The median OS and RFS were 109.8 and 74.8 months in patients with wide RM & negative MVI, 93.5 and 53.1 months with wide RM & positive MVI, 79.2 and 41.6 months with narrow RM & negative MVI, and 69.2 and 37.5 months with narrow RM & positive MVI (both P < 0.01). On multivariable analyses, narrow RM & positive MVI had the highest hazard ratio with reduced OS and RFS (HR 2.96, 95% CI 2.11-4.17, and HR 3.15, 95% CI, 2.09-4.67, respectively). Conclusions: Concomitant having narrow RM and positive MVI increases the risks of postoperative death and recurrence by about 2-fold in patients with solitary HCC.

SummaryThe endometrial layer comprises luminal and glandular epithelia that both develop from the same simple layer of fetal uterine epithelium. Mechanisms of uterine epithelial progenitor self-renewal and differentiation are unclear. This study aims to systematically analyze the molecular and cellular mechanisms of uterine epithelial development by single-cell analysis. An integrated set of single-cell transcriptomic data of uterine epithelial progenitors and their differentiated progenies is provided. Additionally the unique molecular signatures of these cells, characterized by sequential upregulation of specific epigenetic and metabolic activities, and activation of unique signaling pathways and transcription factors, were also investigated. Finally a unique subpopulation of early progenitor, as well as differentiated luminal and glandular lineages, were identified. A complex cellular hierarchy of uterine epithelial development was thus delineated. Our study therefore systematically decoded molecular markers and a cellular program of uterine epithelial development that sheds light on uterine developmental biology.