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Background Hepatectomy combined with intraoperative radiofrequency ablation (IORFA) is a strategy to eliminate all tumors in patients with multiple colorectal liver metastases (CRLM). This study aimed to evaluate the surgical and oncological outcomes of hepatectomy + IORFA for multiple unresectable CRLM. Methods We included patients who underwent combined hepatectomy and IORFA for multiple unresectable CRLM (n = 67) or hepatectomy alone (n = 268) for CRLM. Patients were matched in a 1:1 propensity score analysis to compare the short- and long-term outcomes between groups. Results Patients in hepatectomy + IORFA group had a median number of 10 liver lesions. Postoperative morbidity and the rate of major complications was similar between groups (P = 0.362, P = 1.000). The median overall survival (OS), progression free survival (PFS) and hepatic recurrence free survival (HRFS) was similar between groups (3-year OS: 54.2% versus 60.9%, P = 0.389; 3-year PFS: 7.9% versus 19.6%, P = 0.148; 3-year HRFS: 16.7% versus 31.5%, P = 0.202). Re-hepatectomy or radiofrequency ablation was used to treat 47.5% of hepatic recurrences, and the median OS was significantly higher than for patients treated with systemic treatment alone (P Conclusions Combining hepatectomy and IORFA could provide comparable survival rates for patients with multiple unresectable CRLM compared to those with resectable CRLM treated with hepatectomy alone.

This prospective non-randomized, multicenter clinical trial was performed to investigate efficacy and safety of 131I-labeled metuximab in adjuvant treatment of unresectable hepatocellular carcinoma. Methods: Patients were assigned to treatment with transcatheter arterial chemoembolization (TACE) combined with 131I-metuximab or TACE alone. The primary outcome was overall tumor recurrence. The secondary outcomes were safety and overall survival. Results: The median time to tumor recurrence was 6 months in the TACE+131I-metuximab group (n = 160) and 3 months in the TACE group (n = 160) (hazard ratio, 0.55; 95% confidence interval, 0.43 to 0.70; P < 0.001). The median overall survival was 28 months in the TACE+131I-metuximab group and 19 months in the TACE group (hazard ratio, 0.62; 95% confidence interval, 0.47 to 0.82; P = 0.001). Conclusion: TACE+131I-metuximab showed a greater anti-recurrence benefit, significantly improved the 5-year survival of patients with advanced hepatocellular carcinoma, and was well tolerated by patients.

Background The exploration of genomic alterations in Chinese colorectal liver metastasis (CRLM) is limited, and corresponding genetic biomarkers for patient’s perioperative management are still lacking. This study aims to understand genome diversification and complexity that developed in CRLM. Methods A custom-designed IDT capture panel including 620 genes was performed in the Chinese CRLM cohort, which included 396 tumor samples from metastatic liver lesions together with 133 available paired primary tumors. Results In this Chinese CRLM cohort, the top-ranked recurrent mutated genes were TP53 (324/396, 82%), APC (302/396, 76%), KRAS (166/396, 42%), SMAD4 (54/396, 14%), FLG (52/396, 13%) and FBXW7 (43/396, 11%). A comparison of CRLM samples derived from left- and right-sided primary lesions confirmed that the difference in survival for patients with different primary tumor sites could be driven by variations in the transforming growth factor β (TGF-β), phosphatidylinositol 3-kinase (PI3K) and RAS signaling pathways. Certain genes had a higher variant rate in samples with metachronous CRLM than in samples with simultaneous metastasis. Overall, the metastasis and primary tumor samples displayed highly consistent genomic alterations, but there were some differences between individually paired metastases and primary tumors, which were mainly caused by copy number variations. Conclusion We provide a comprehensive depiction of the genomic alterations in Chinese patients with CRLM, providing a fundamental basis for further personalized therapy applications.

Summary Background China has a high burden of hepatocellular carcinoma, and hepatitis B virus (HBV) infection is the main causative factor. Patients with hepatocellular carcinoma have a poor prognosis and a substantial unmet clinical need. The phase 2–3 ORIENT-32 study aimed to assess sintilimab (a PD-1 inhibitor) plus IBI305, a bevacizumab biosimilar, versus sorafenib as a first-line treatment for unresectable HBV-associated hepatocellular carcinoma. Methods This randomised, open-label, phase 2–3 study was done at 50 clinical sites in China. Patients aged 18 years or older with histologically or cytologically diagnosed or clinically confirmed unresectable or metastatic hepatocellular carcinoma, no previous systemic treatment, and a baseline Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 were eligible for inclusion. In the phase 2 part of the study, patients received intravenous sintilimab (200 mg every 3 weeks) plus intravenous IBI305 (15 mg/kg every 3 weeks). In the phase 3 part, patients were randomly assigned (2:1) to receive either sintilimab plus IBI305 (sintilimab–bevacizumab biosimilar group) or sorafenib (400 mg orally twice daily; sorafenib group), until disease progression or unacceptable toxicity. Randomisation was done using permuted block randomisation, with a block size of six, via an interactive web response system, and stratified by macrovascular invasion or extrahepatic metastasis, baseline α-fetoprotein, and ECOG performance status. The primary endpoint of the phase 2 part of the study was safety, assessed in all patients who received at least one dose of study drug. The co-primary endpoints of the phase 3 part of the study were overall survival and independent radiological review committee (IRRC)-assessed progression-free survival according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 in the intention-to-treat population. The study is registered with ClinicalTrials.gov , NCT03794440 . The study is closed to new participants and follow-up is ongoing for long-term outcomes. Findings Between Feb 11, 2019 and Jan 15, 2020, we enrolled 595 patients: 24 were enrolled directly into the phase 2 safety run-in and 571 were randomly assigned to sintilimab–bevacizumab biosimilar (n=380) or sorafenib (n=191). In the phase 2 part of the trial, 24 patients received at least one dose of the study drug, with an objective response rate of 25·0% (95% CI 9·8–46·7). Based on the preliminary safety and activity data of the phase 2 part, in which grade 3 or worse treatment-related adverse events occurred in seven (29%) of 24 patients, the randomised phase 3 part was started. At data cutoff (Aug 15, 2020), the median follow-up was 10·0 months (IQR 8·5–11·7) in the sintilimab–bevacizumab biosimilar group and 10·0 months (8·4–11·7) in the sorafenib group. Patients in the sintilimab–bevacizumab biosimilar group had a significantly longer IRRC-assessed median progression-free survival (4·6 months [95% CI 4·1–5·7]) than did patients in the sorafenib group (2·8 months [2·7–3·2]; stratified hazard ratio [HR] 0·56, 95% CI 0·46–0·70; p Interpretation Sintilimab plus IBI305 showed a significant overall survival and progression-free survival benefit versus sorafenib in the first-line setting for Chinese patients with unresectable, HBV-associated hepatocellular carcinoma, with an acceptable safety profile. This combination regimen could provide a novel treatment option for such patients. Funding Innovent Biologics. Translation For the Chinese translation of the abstract see Supplementary Materials section.

Background Surgical margin status remains a controversial factor in predicting the outcome of colorectal liver metastases (CRLM) resection. Our study aims to evaluate the effects of surgical margins on oncologic outcomes with regard to the genetic and morphological evaluation (GAME) score. Methods R1 resection was defined as having a less than 1 mm margin width. Patients who underwent surgery for CRLM from January 2005 to December 2018 were recruited. The patients were divided into two risk subgroups, namely, the low or medium risk (GAME 0-3) and high-risk (GAME score 4 or more) groups. The effects of margin status on overall survival (OS) and recurrence-free survival rate (RFS) were examined. Results In total, 661 patients were recruited, among which 159 (24.1%) had R1 resection. Before hepatectomy, 514 patients showed a low or medium risk (R1 resection: n = 124), while 147 patients demonstrated a high risk (R1 resection: n = 35). In the whole cohort, multivariable analysis did show that R1 resection was associated with worse RFS and OS. While further research only found that in the low or medium risk group, R1 resection was related to poor OS and RFS. Meanwhile, in the high risk group, no significant difference was found in the median OS and RFS among patients with R0 or R1 resection. Conclusion The prognostic role of margin status varied according to the GAME score. Margin clearance only improved survival rates in patients with low or medium GAME score. In contrast, R1 resection demonstrated similar oncologic outcomes with R0 resection in patients with high GAME score.

Background En bloc right hemicolectomy with pancreatoduodenectomy (RHCPD) is the optimum treatment to achieve the adequate margin of resection (R0) for locally advanced right-sided colon cancer with duodenal invasion. Information regarding the indications and outcomes of this procedure is limited. Method In this retrospective study, 2269 patients with right colon cancer underwent radical right colectomy between October 2010 and May 2019, in which 19 patients underwent RHCPD for LARCC were identified. The overall survival (OS), disease-free survival (DFS), operative mortality, postsurgical complications, gene mutational analysis, and prognostic factors were evaluated. Survival was estimated using Kaplan–Meir method. Results Of these 19 patients who underwent LARCC, the OS was 88%, 66%, and 58% at 1, 3, and 5 years. The DFS was 72%, 56%, and 56% at 1, 3, and 5 years. The median operative time was 320 min (range: 222–410 min), and the median operative blood loss was 268 mL (range: 100–600 mL). The OS was significantly better among patients with well-differentiated tumor, N0 stage, and high microsatellite instability (MSI) and in patients who received adjuvant chemotherapy. The major postoperative complications occurred in 8 patients (42%), with pancreatic fistula (PF) being the most common. On the basis of the univariate analysis, poorly differentiated tumor, regional lymph node dissemination, MSI status, and no perioperative chemotherapy were the significant predictors of poor survival (P Conclusions This study suggests that RHCPD is feasible and can achieve complete tumor clearance with favorable outcome, particularly in patients with lymph node-negative status.

Background Cancer stem cell (CSC)-related chemoresistance leads to poor outcome of the patients with colorectal cancer (CRC). In this study, we identified the chemoresistance-relevant molecules and decipher the involved mechanisms to provide potential therapeutic target for CRC. We focused on Sec62, a novel target with significantly increased expression in chemoresistant CRC tissues, and further investigated its role in the progression of CRC. Methods Through analyzing the differentially-expressed genes between chemoresistant and chemosensitive CRCs, we selected Sec62 as a novel chemoresistance-related target in CRC. The expression and clinical significance of Sec62 were determined by immunoblotting and immunohistochemistry in tissues and cell lines of CRC. The roles of Sec62 in drug resistance, stemness and tumorigenesis were evaluated in vitro and in vivo using functional experiments. GST pull-down, western blot, coimmunoprecipitation and Me-RIP assays were performed to further explore the downstream molecular mechanisms. Results Sec62 upregulation was associated with the chemoresistance of CRC and poor outcome of CRC patients. Depletion of Sec62 sensitized CRC cells to chemotherapeutic drugs. Sec62 promoted the stemness of CRC cells through activating Wnt/β-catenin signaling. Mechanistically, Sec62 bound to β-catenin and inhibited the degradation of β-catenin. Sec62 competitively disrupted the interaction between β-catenin and APC to inhibit the β-catenin destruction complex assembly. Moreover, Sec62 expression was upregulated by the m6A-mediated stabilization of Sec62 mRNA. Conclusions Sec62 upregulated by the METTL3-mediated m6A modification promotes the stemness and chemoresistance of CRC by binding to β-catenin and enhancing Wnt signalling. Thus, m6A modification-Sec62-β-catenin molecular axis might act as therapeutic targets in improving treatment of CRC.

RNA binding proteins (RBPs) are aberrantly expressed in a tissue-specific manner across many tumors. These proteins, which play a vital role in post-transcriptional gene regulation, are involved in RNA splicing, maturation, transport, stability, degradation, and translation. We set out to establish an accurate risk score model based on RBPs to estimate prognosis in hepatocellular carcinoma (HCC). RNA-sequencing data, proteomic data and corresponding clinical information were acquired from the Cancer Genome Atlas database and the Clinical Proteomic Tumor Analysis Consortium database respectively. We identified 406 differentially expressed RBPs between HCC tumor and normal tissues at the transcriptional and protein level. Overall, 11 RBPs (BRIX1, DYNC1H1, GTPBP4, PRKDC, RAN, RBM19, SF3B4, SMG5, SPATS2, TAF9, and THOC5) were selected to establish a risk score model. We divided HCC patients into low-risk and high-risk groups based on the median of risk score values. The survival analysis indicated that patients in the high-risk group had poorer overall survival compared to patients in the low-risk group. Our study demonstrated that 11 RBPs were associated with the overall survival of HCC patients. These RBPs may represent potential drug targets and can help optimize future clinical treatment.

Objective To develop a nomogram to estimate the risk of SPLD (International Study Group of Liver Surgery definition grade B or C) and long-term survival in patients with HCC before hepatectomy. Background SPLD is the leading cause of post-hepatectomy mortality. The decision to refer an HCC patient for hepatectomy is mainly based on the survival benefit and SPLD risk. Prediction of SPLD risk before hepatectomy is of great significance. Methods A total of 2071 consecutive patients undergoing hepatectomy for HCC were recruited and randomly divided into the development cohort (n = 1036) and internal validation cohort (n = 1035). Five hundred ninety patients from another center were enrolled as the external validation cohort. A nomogram was developed based on independent preoperative predictors of SPLD determined in multivariable logistic regression analysis. Results The SPLD incidences in the development, internal, and external validation cohorts were 10.1%, 9.5%, and 8.6%, respectively. Multivariable analysis identified total bilirubin, albumin, gamma-glutamyl transpeptidase, prothrombin time, clinically significant portal hypertension, and major resection as independent predictors for SPLD. Incorporating these variables, the nomogram showed good concordance statistics of 0.883, 0.851, and 0.856, respectively in predicting SPLD in the 3 cohorts. Its predictive performance in SPLD, 90-day mortality, and overall survival (OS) outperformed Child-Pugh, model for end-stage liver disease, albumin-bilirubin, and European Association for the Study of the Liver recommended algorithm. With a nomogram score of 137, patients were stratified into low and high risk of SPLD. High-risk patients also had decreased OS. Conclusions The nomogram showed good performance in predicting both SPLD and OS. It could help surgeons select suitable HCC patients for hepatectomy.

Liver metastasis is one of the major causes of cancer-related death in patients with colorectal cancer (CRC). The purpose of this study was to identify specific molecules which are involved in colorectal liver metastasis (CRLM). In this study, we employed TMT (tandem mass tags)-labeling combined with liquid chromatography–mass spectrometry technology to do comparative analyses of proteomics between the primary tumor specimens derived from colorectal cancer patients with or without liver metastasis. Pathway enrichment analyses were performed using DAVID database. The crucial molecules were identified through protein–protein interaction network. Immunohistochemistry (IHC) was employed to analyze the expression of THBS1 (thrombospondin-1) in CRC tissues. Finally, transwell cell migration and invasion assays were performed to explore the roles of THBS1 in CRC cell migration and invasion. We found that the expression of 311 proteins was dysregulated in CRLM using quantitative proteomics. Among these proteins, we identified FN1, TIMP1, THBS1, POSTN and VCAN as five crucial proteins in CRLM by analysis in silico. IHC assay revealed that increased THBS1 expression was significantly correlated with liver metastasis as well as poor prognosis of CRC patients. GEO data analysis also suggests that upregulated mRNA level of THBS1 is also associated with shorter overall survival of CRC patients. Moreover, THBS1 depletion inhibited migration and invasion of CRC cells through attenuating epithelial–mesenchymal transition. Co-expression analyses with TCGA data indicated that THBS1 is co-expressed with mesenchymal markers, including Vimentin, N-cadherin, Snail1 and Twist1 in CRC tissues. By collecting the omics data with functional studies, the present results reveal that THBS1 facilitates colorectal liver metastasis through promoting epithelial–mesenchymal transition. This understanding of molecular roles of THBS1 in CRLM may be promising to develop targeted therapies to prolong survival in CRC patients.

Uncovering the functionally essential variations related to tumorigenesis and tumor progression from cancer genomics data is still challenging due to the genetic diversity among patients, and extensive inter- and intra-tumoral heterogeneity at different levels of gene expression regulation, including but not limited to the genomic, epigenomic, and transcriptional levels. To minimize the impact of germline genetic heterogeneities, in this study, we establish multiple primary cultures from the primary and recurrent tumors of a single patient with hepatocellular carcinoma (HCC). Multi-omics sequencing was performed for these cultures that encompass the diversity of tumor cells from the same patient. Variations in the genome sequence, epigenetic modification, and gene expression are used to infer the phylogenetic relationships of these cell cultures. We find the discrepancy among the relationships revealed by single nucleotide variations (SNVs) and transcriptional/epigenomic profiles from the cell cultures. We fail to find overlap between sample-specific mutated genes and differentially expressed genes (DEGs), suggesting that most of the heterogeneous SNVs among tumor stages or lineages of the patient are functionally insignificant. Moreover, copy number alterations (CNAs) and DNA methylation variation within gene bodies, rather than promoters, are significantly correlated with gene expression variability among these cell cultures. Pathway analysis of CNA/DNA methylation-related genes indicates that a single cell clone from the recurrent tumor exhibits distinct cellular characteristics and tumorigenicity, and such an observation is further confirmed by cellular experiments both in vitro and in vivo. Our systematic analysis reveals that CNAs and epigenomic changes, rather than SNVs, are more likely to contribute to the phenotypic diversity among subpopulations in the tumor. These findings suggest that new therapeutic strategies targeting gene dosage and epigenetic modification should be considered in personalized cancer medicine. This culture model may be applied to the further identification of plausible determinants of cancer metastasis and relapse.

Recent cancer studies have found that the thrombospondin (THBS) family, including THBS1, THBS2, THBS3, THBS4, and THBS5, play vital roles in the development and progression of human cancers. However, their relationships with tumor stage, prognosis, and tumor immunity in pan-cancer have not been systematically reported. In the present study, we employed versatile public databases to assess the expression and mutations of different THBSs in pan-cancer and performed functional experiments to analyze the roles of THBS2 in gastrointestinal cancer metastasis. Our findings indicate that THBS genes are frequently mutated in various cancers and the dysregulation of THBS family members is associated with the progression of some cancers such as gastric cancer, colon cancer, and lung cancer. Further analyses indicate that THBS genes are associated with cancer hallmarks such as cell cycle and epithelial-mesenchymal transition (EMT). Importantly, thrombospondins, especially THBS1 and THBS2, are correlated with the immune cell infiltration level in gastrointestinal cancers. Our experiments further verified that THBS2 participates in tumor metastasis by enhancing EMT. Therefore, the overall analyses reveal that THBSs might offer us potential chances for tumor diagnosis and therapy.

Simple Summary Exosomal miRNAs are associated with colorectal cancer liver metastasis (CRLM)-related biological behavior and prognosis. However, an exosomal miRNA signature predicting postoperative survival and the value of adjuvant chemotherapy for CRLM remains elusive. Using miRNA sequencing and the LASSO model, we constructed an miRNA signature comprising four exosomes. The signature showed a good predictive performance for patient outcome and the advantage of adjuvant chemotherapy after hepatectomy in two institutions’ training and validation cohorts. In addition, we found that the four miRNAs could target signaling molecules playing crucial roles in colorectal cancer metastasis, vesicle-related processing, and T cell activation. Furthermore, the exosomal miRNA score also increased with the decreasing Immunoscore. We believe that our signature can predict the prognosis and guide adjuvant chemotherapy decisions after liver metastasectomy in CRLM patients, further improving the predictive performance of the current CRLM predictive model system. Abstract Background: The clinical risk score (CRS) for prediction and treatment decision in colorectal liver metastasis (CRLM) is important, but imprecise. Exosomal miRNAs play critical roles in CRLM-related biological behavior. However, an exosomal miRNA score system for predicting posthepatectomy survival and the adjuvant chemotherapy benefit of CRLM remains elusive. Methods: miRNA sequencing was used to identify differentially expressed miRNAs, and the LASSO model was used to select miRNAs to construct the intent model. The predictive performance of the model was evaluated by the area under the ROC curve (AUC) in the training, internal validation, and external validation cohorts. Results: Sixteen differentially expressed exosomal miRNAs were identified, and four miRNAs were selected for model construction. Our model performed well in predicting prognosis with five-year AUCs of 0.70 (95% CI: 0.59–0.81), 0.70 (0.61–0.81), and 0.72 (057–0.86) in the training, internal, and external validation cohorts, respectively. miRNA classifier high-risk patients had better survival benefit from adjuvant chemotherapy regardless of CRS. All four miRNAs target signaling molecules play crucial roles in colorectal cancer metastasis, vesicle-related processing, and T cell activation. It also negatively correlated with the liver metastasis Immunoscore. Conclusion: We developed a circulating exosomal miRNA signature that can predict the prognosis and guide adjuvant chemotherapy decisions after hepatectomy in CRLM.

Colorectal cancer is the third most common cancer worldwide, and its incidence continues to grow. Approximately one-third of patients with colorectal cancer develop liver metastases during the natural course of disease. Complete surgical resection is associated with very low mortality in colorectal liver metastasis patients, but only a small fraction of colorectal liver metastasis patients fulfill the selection criteria for surgical treatment. We herein describe a high-risk stage-IV rectal carcinoma patient who was initially unresectable according to the National Comprehensive Cancer Network guidelines with a clinical risk score of 4 but received conversion surgery combined with systemic chemotherapy and achieved a favorable long-term clinical outcome (pathologic complete response) of approximately 28 months. Furthermore, serial circulating tumor DNA monitoring using next-generation sequencing provided a comprehensive view of the patient’s clinical and pathologic status for better clinical decision support over the course of the disease. The absence of circulating tumor DNA/cells after conversion surgery was correlated with pathologic complete response. This case study not only demonstrated that a curative oncosurgical approach could be considered for high-risk colorectal liver metastasis patients under specific circumstances but also highlighted the role of circulating tumor DNA monitoring to gain further insight into the evolution of a patient’s response over time.

Background The definition of R1 resection in colorectal cancer liver metastases (CRLM) remains debatable. This retrospective study was conducted to clarify the impact of R1 margin on patient survival after liver resection for CRLM, taking into consideration tumor biology, including RAS status and chemotherapy response. Methods We retrospectively analysed the clinical and survival data of 214 CRLM patients with initially resectable liver metastases who underwent liver resection after receiving neoadjuvant chemotherapy between January 2006 and December 2016. Results R1 resection significantly impacted patients’ overall survival (OS) and disease-free survival (DFS) in the overall patient cohort (5-year OS: 53.2% for R0 vs 38.2% for R1, P = 0.001; 5-year DFS: 26.5% for R0 vs 10.5% for R1, P = 0.002). In the RAS wild-type subgroup and respond to chemotherapy (RC) subgroup, R1 reached a similar OS to those who underwent R0 resection (RAS wild-type, P = 0.223; RC, P = 0.088). For the RAS mutated subgroup and no response to chemotherapy (NRC) subgroup, OS was significantly worse underwent R1 resection (RAS mutant, P = 0.002; NRC, P = 0.022). When considering tumor biology combining RAS and chemotherapy response status, R1 resection was only acceptable in patients with both RAS wild-type and RC (5-year OS: 66.4% for R0 vs 65.2% for R1, p = 0.884), but was significantly worse in those with either RAS mutation or NRC. Conclusions Tumor biology plays an important role in deciding the appropriate resection margin in patients with CRLM undergoing radical surgery. R1 resection margin is only acceptable in RAS wild-type patients who respond to chemotherapy.

Systemic inflammation response is involved in the development and progression of cancers. This study aimed to evaluate the prognostic value of a preoperative Fibrinogen–Albumin Ratio Index (FARI) in patients undergoing hepatectomy for colorectal liver metastases (CRLM) and compare it with established systemic inflammation markers, including the neutrophil–lymphocyte ratio, lymphocyte–monocyte ratio, platelet–lymphocyte ratio, and systemic immune–inflammation index. Patients who underwent hepatectomy for CRLM between November 2002 and December 2016 were considered for inclusion. Time-dependent receiver operating characteristic (ROC) curve analysis was conducted to evaluate the ability of markers in predicting survival. Multivariable Cox regression analysis was used to identify independent predictors for overall survival (OS) or disease-free survival (DFS). A total of 452 consecutive patients were enrolled. The areas under the ROC curve of the FARI in predicting OS and DFS were superior to other inflammatory markers and carcinoembryonic antigen (CEA). The optimal cut-off value of the FARI was 7.6%. Patients with a high FARI (> 7.6%) showed significantly decreased OS and DFS (all p

Background: Human N-acetyltransferase 10 (NAT10) plays pivotal roles in cellular biological processes, such as senescence, autophagy and cytokinesis. The expression of NAT10 is dysregulated in colorectal cancer (CRC) and is associated with the prognosis of patients. However, it remains unclear how NAT10 is regulated in CRC. Methods: The microRNA(miRNA) regulating NAT10 was predicted by bioinformatics analysis and further validated by real-time quantitative PCR(RT-qPCR),Western blot and dual luciferase reporter assays. The expression of the miRNA regulating NAT10 in CRC tissues was examined using RT-qPCR. Cell proliferation, cell apoptosis, cell migration and cell invasion assays were performed after transfection with miRNA mimic and inhibitor. Results: Here, we report that miR-6716-5p inhibits the expression of NAT10 in CRC. The NAT10 protein level was downregulated by the miR-6716-5p mimic, and was upregulated by the miR-6716-5p inhibitor in CRC cell lines. In addition, miR-6716-5p bound to the 3'-untranslated region of NAT10 mRNA and decreased NAT10 mRNA levels. Significantly, the miR-6716-5p level was higher in the tumor tissues of the CRC patients with liver metastasis than that in the non-metastatic CRC patients. In addition, the miR-6716-5p level was correlated with poor overall survival of CRC patients with liver metastasis. The miR-6716-5p inhibitor inhibited CRC cell migration and invasion. Consistently, the miR-6716-5p mimic significantly promoted cell migration and invasion, and this effect is dependent on NAT10. However, miR-6716-5p had no effect on CRC cell proliferation and apoptosis. We found that miR-6716-5p negatively regulated E-cadherin protein levels. In addition, E-cadherin was upregulated by NAT10 in CRC cells, confirming that miR-6716-5p downregulated E-cadherin levels by inhibiting NAT10 expression. Conclusion: We demonstrated that miR-6716-5p acts as a crucial regulator of NAT10 to promote cell migration and invasion in CRC by inhibiting NAT10 expression. Our data suggest that miR-6716-5p/NAT10 might act as a potential therapeutic target for CRC treatment.

The human UTP14a (hUTP14a) promotes degradation of p53 and RB. Moreover, hUTP14a stabilizes c-Myc and is associated with the metastasis of human colorectal cancer (CRC). Angiogenesis plays a key role in tumor growth and metastasis. However, how hUTP14a regulates angiogenesis is unknown. Here, we show that nucleolar expression of hUTP14a is positively associated with higher microvascular density (MVD) in the CRC tumor tissues. The conditioned medium (CM) from CRC cells HCT116 and LoVo with hUTP14a knockdown impairs tube formation and migration of human umbilical vein endothelial cells (HUVECs). RNA-seq analysis indicates that hUTP14a might regulate expression of angiogenic factors in tumor cells. We further demonstrate that hUTP14a upregulates transcription and secretion of platelet-derived growth factor subunit A (PDGFA) in CRC cells. The CRC-CM derived from hUTP14a-depleted cells inhibits the PDGFA-mediated signaling pathway and induces apoptosis in HUVECs. In contrast, the CRC-CM derived from cells expressing Flag-hUTP14a activates the PDGFA-mediated signaling pathway in HUVECs. Importantly, the CRC-CM derived from Flag-hUTP14a-expressing cells promotes angiogenesis in HUVECs, which is counteracted by PDGFR inhibitor imatinib. We thus demonstrate that hUTP14a promotes angiogenesis by upregulating expression and secretion of PDGFA. The in vivo Matrigel plug assay shows that depletion of hUTP14a dramatically decreased MVD in mice xenografts. Collectively, we demonstrate that hUTP14a promotes angiogenesis in CRC and indicate that targeting hUTP14a might improve the prognosis of the hUTP14a-expressing CRC patients.

Microvascular invasion (MVI) is a powerful predictor of recurrence in patients who undergo liver resection for hepatocellular carcinoma (HCC). This study aimed to evaluate the efficacy of postoperative adjuvant transarterial chemoembolization (PA-TACE) in HCC patients with MVI, and further select potential patients benefitting from PA-TACE.Patients who had HCC with MVI and underwent liver resection between September 2004 and December 2015 were identified for further analysis. Overall survival (OS) and disease-free survival (DFS) were compared between patients treated with and without PA-TACE. Propensity score matching analysis was used to minimize inter-group differences.A total of 176 patients with HCC and MVI were included. In both the entire and propensity-matched cohorts, OS and DFS were higher in PA-TACE group than non-TACE group (all P 0.05). In subgroup analyses, PA-TACE showed efficacy in improving OS and DFS in HCC patients at early stage beyond Milan criteria and intermediate stage, but not in patients within Milan criteria. Multivariable analysis identified PA-TACE as a significantly favorable factor of OS and DFS for patients beyond Milan criteria, but not for those within Milan criteria.PA-TACE could be beneficial for patients who have HCC with MVI beyond Milan criteria, but not for those within Milan criteria.

Hepatocellular carcinoma is the third leading cause of deaths from cancer worldwide. Infection with the hepatitis B virus is one of the leading risk factors for developing hepatocellular carcinoma, particularly in East Asia1. Although surgical treatment may be effective in the early stages, the five-year overall rate of survival after developing this cancer is only 50–70%2. Here, using proteomic and phospho-proteomic profiling, we characterize 110 paired tumour and non-tumour tissues of clinical early-stage hepatocellular carcinoma related to hepatitis B virus infection. Our quantitative proteomic data highlight heterogeneity in early-stage hepatocellular carcinoma: we used this to stratify the cohort into the subtypes S-I, S-II and S-III, each of which has a different clinical outcome. S-III, which is characterized by disrupted cholesterol homeostasis, is associated with the lowest overall rate of survival and the greatest risk of a poor prognosis after first-line surgery. The knockdown of sterol O-acyltransferase 1 (SOAT1)—high expression of which is a signature specific to the S-III subtype—alters the distribution of cellular cholesterol, and effectively suppresses the proliferation and migration of hepatocellular carcinoma. Finally, on the basis of a patient-derived tumour xenograft mouse model of hepatocellular carcinoma, we found that treatment with avasimibe, an inhibitor of SOAT1, markedly reduced the size of tumours that had high levels of SOAT1 expression. The proteomic stratification of early-stage hepatocellular carcinoma presented in this study provides insight into the tumour biology of this cancer, and suggests opportunities for personalized therapies that target it. A subtype of early-stage hepatocellular carcinoma characterized by disrupted cholesterol homeostasis and associated with a poor prognosis responds to treatment with the SOAT1 inhibitor avasimibe in a patient-derived xenograft mouse model.

The lungs are the second most common site of metastasis for colorectal cancer (CRC) after the liver. Rectal cancer is associated with a higher incidence of lung metastases compared to colon cancer. In China, the proportion of rectal cancer cases is around 50%, much higher than that in Western countries (nearly 30%). However, there is no available consensus or guideline focusing on CRC with lung metastases. We conducted an extensive discussion and reached a consensus of management for lung metastases in CRC based on current research reports and the experts’ clinical experiences and knowledge. This consensus provided detailed approaches of diagnosis and differential diagnosis and provided general guidelines for multidisciplinary therapy (MDT) of lung metastases. We also focused on recommendations of MDT management of synchronous lung metastases and initial metachronous lung metastases. This consensus might improve clinical practice of CRC with lung metastases in China and will encourage oncologists to conduct more clinical trials to obtain high-level evidences about managing lung metastases. Electronic supplementary material The online version of this article (10.1186/s13045-019-0702-0) contains supplementary material, which is available to authorized users.

Background The Barcelona Clinic Liver Cancer (BCLC) staging system is the most widely used staging system for hepatocellular carcinoma (HCC). However, the classifications of early (BCLC-A) and intermediate (BCLC-B) stage HCC remain controversial. Aim To refine the staging of BCLC-A and -B. Methods A total of 986 patients with HCC undergoing liver resection from two institutions formed the training cohort, and 694 from another institution were the validation cohort. Time-dependent receiver operating characteristic (ROC) curve analysis was performed to evaluate the performance of tumour size in predicting overall survival (OS), and determined the optimised cut-off. Discriminatory performance was evaluated using Harrell's concordance index (C-index). Results Patients with multiple tumours exceeding Milan criteria but within up-to-seven criteria had similar OS and disease-free survival (DFS) to those with multiple tumours meeting Milan criteria, and were assigned to the modified BCLC-A stage. The area under the ROC curve of tumour size for predicting OS was 0.778, and the diameter of 7 cm was the optimal cut-off to identify patients with single tumours who had higher OS than BCLC-B stage patients. Due to the similar OS, patients with single HCCs >7 cm were assigned to the modified BCLC-B stage. The C-indexes of the modified BCLC classification for OS and DFS were higher compared to the original version. The findings were supported by the validation cohort. Conclusions The modified staging of BCLC-A and -B, based on single tumour >7 cm and multiple tumours beyond up-to-seven criteria, could be more accurate to predict the prognosis of HCC patients. Liver resection could benefit patients with resectable multifocal HCCs beyond the Milan criteria.

Deficiency of the DNA damage repair (DDR) signaling pathways is potentially responsible for genetic instability and oncogenesis in tumors, including colorectal cancer. However, the correlations of mutated DDR signaling pathways to the prognosis of colorectal cancer liver metastasis (CRLM) after resection and other clinical applications have not been fully investigated. Here, to test the potential correlation of mutated DDR pathways with survival and pre-operative chemotherapy responses, tumor tissues from 146 patients with CRLM were collected for next-generation sequencing with a 620-gene panel, including 68 genes in 7 DDR pathways, and clinical data were collected accordingly. The analyses revealed that 137 of 146 (93.8%) patients had at least one mutation in the DDR pathways. Mutations in BER, FA, HRR and MMR pathways were significantly correlated with worse overall survival than the wild-types (P < 0.05), and co-mutated DDR pathways showed even more significant correlations (P < 0.01). The number of mutated DDR pathways was also proved an independent stratifying factor of overall survival by Cox multivariable analysis with other clinical factors and biomarkers (hazard ratio = 9.14; 95% confidence interval, 1.21–68.9; P = 0.032). Additionally, mutated FA and MMR pathways were positively and negatively correlated with the response of oxaliplatin-based pre-operative chemotherapy (P = 0.0095 and 0.048, respectively). Mutated DDR signaling pathways can predict pre-operative chemotherapy response and post-operative survival in CRLM patients.

Background It is assumed that the impact of primary tumor stage (PTS) on prognosis gradually weakens with increasing disease-free interval (DFI) from colorectal cancer resection to liver metastases. Methods Data from 733 patients undergoing hepatectomy in the Hepato-pancreato-biliary Surgery Department I of Peking University Cancer Hospital were retrospectively analyzed. Early and late metastases were defined as DFI ≤ and >12 months, respectively. Results In early metastases group, patients with T4 stage had a significantly worse recurrence-free survival (RFS) and overall survival (OS) than those with T1-3 stage (P = 0.002 and P Discussion The impact of PTS on prognosis is diminished with increasing DFI and limited only to patients with early metastases.

Background. Preoperative chemotherapy has widely been used in colorectal cancer liver metastasis (CRLM). Pathological response to chemotherapy is very important in evaluating tumor biology. However, there is still a lack of a non-invasive and accurate method to evaluate pathological response before surgery.Methods. We retrospectively analyzed the clinicopathologic data of patients with CRLM who underwent liver resection after preoperative chemotherapy between January 2006 and December 2018. Pathological responses were defined as minor when there are ≥50% remnant viable cells and as major when 0-49% remnant viable cells exist.Results: A total of 482 patients were included and randomly divided into training (n = 241) and validation (n = 241) cohorts. The proportion of major pathologic response was similar between the two groups (51.5% and 48.5%). Multivariate analysis determined the disease-free interval, tumor size, tumor number, and RAS status as independent predictors of major pathologic response to preoperative chemotherapy. The nomogram incorporating these variables showed good concordance statistics in the training cohort (0.746, 95% CI: 0.685-0.807) and validation cohort (0.764, 95% CI: 0.704-0.823). In addition, the nomogram showed good applicability in patients with different characteristics.Conclusions. The established nomogram model performed well in predicting pathological response in patients with CRLM.

The role of preoperative carbohydrate antigen 19-9 (CA19-9) in colorectal cancer liver metastases (CRLM) patients is still unclear. The present study aimed to explore the prognostic significance of preoperative CA19-9 in those patients. A total of 691 CRLM patients were included in this study. X-tile analyses were performed to determine the optimal cut-off values of CA19-9 and carcinoembryonic antigen (CEA). Prognostic predictors were identified by multivariate analyses. The optimal cut-off values of CA19-9 and CEA for 5-year recurrence-free survival (RFS) were 35.24 U/ml and 20.4 ng/ml, respectively. Patients with high-level CA19-9 had significantly worse RFS and overall survival (OS) than those with low-level CA19-9 (P = 0.001 and P = 0.002, respectively). In addition, patients with high-level CA19-9 had poor RFS and OS (P = 0.028 and P = 0.011, respectively) at low-level CEA. Multivariate analyses confirmed that preoperative CA19-9 was an independent predictor for RFS (hazard ratio [HR] 1.295; 95% confidence interval [CI] 1.043–1.607; P = 0.019) but not for OS (HR 1.213; 95% CI 0.902–1.631; P = 0.201). CA19-9 is a promising predictor of recurrence for CRLM patients undergoing hepatectomy, and an effective supplement for patients with low-level CEA.

Background Local treatment remains the best option for recurrent colorectal liver metastasis (CRLM). The current study aimed to investigate predictive factors of survival outcomes and select candidates for local treatment for CRLM at first recurrence. Methods Data were collected retrospectively from CRLM patients who underwent hepatic resection and developed first recurrence between 2000 and 2019 at our institution. A nomogram predicting overall survival was established based on a multivariable Cox model of clinicopathologic factors. The predictive accuracy and discriminative ability of the nomogram were determined by the concordance index and calibration curve. Results Among 867 patients who underwent curative hepatic resection, 549 patients developed recurrence. Three hundred patients were evaluated and had resectable and liver-limited disease. Among them, repeat liver resection and percutaneous radiofrequency ablation were performed in 88 and 85 patients, respectively. The other 127 patients received only systemic chemotherapy. Multivariable analysis identified primary lymph node positivity, tumor size > 3 cm, early recurrence, RAS gene mutation and no local treatment as independent risk factors for survival outcomes. Integrating these five variables, the nomogram presented a good concordance index of 0.707. Compared with patients who received only systemic chemotherapy, radical local treatment did not significantly improve survival outcomes (median OS: 21 vs. 15 months, p = 0.126) in the high-risk group (total score ≥ 13). Conclusion Radical local treatment improved the survival of recurrent CRLM patients. The proposed model facilitates personalized assessments of prognosis for patients who develop first recurrence in the liver.

Background: Primary liver cancer, around 90% are hepatocellular carcinoma in China, is the fourth most common malignancy and the second leading cause of tumor-related death, thereby posing a significant threat to the life and health of the Chinese people. Summary: Since the publication of Guidelines for Diagnosis and Treatment of Primary Liver Cancer (2017 Edition) in 2018, additional high-quality evidence has emerged with relevance to the diagnosis, staging, and treatment of liver cancer in and outside China that requires the guidelines to be updated. The new edition (2019 Edition) was written by more than 70 experts in the field of liver cancer in China. They reflect the real-world situation in China regarding diagnosing and treating liver cancer in recent years. Key Messages: Most importantly, the new guidelines were endorsed and promulgated by the Bureau of Medical Administration of the National Health Commission of the People’s Republic of China in December 2019.

Background Few studies have focused on the role of hepatectomy for colorectal liver-limited metastases in elderly patients compared to matched younger patients. Methods From January 2000 to December 2018, 724 patients underwent hepatectomy for colorectal liver-limited metastases. Based on a 1:2 propensity score matching (PSM) model, 64 elderly patients (≥ 70 years of age) were matched to 128 younger patients ( Results There were 73 elderly and 651 younger patients in the unmatched cohort. Compared with the younger group (YG), the elderly group (EG) had significantly higher proportion of American Society of Anesthesiologists score III and comorbidities and lower proportion of more than 3 liver metastases and postoperative chemotherapy (p p = 0.046), a shorter median postoperative hospital stay (8 days vs. 11 days, p = 0.020), and a higher readmission rate (4.7% vs.0%, p = 0.036). The EG also had longer disease-free survival (DFS), overall survival (OS), and cancer-specific survival (CSS) compared to the YG, but these findings were not statistically significant (p > 0.05). Old age was not an independent factor for DFS, OS, and CSS by Cox multivariate regression analysis (p > 0.05). Conclusions Hepatectomy is safe for colorectal liver-limited metastases in elderly patients, and these patients may subsequently benefit from prolonged DFS, OS, and CSS.

An individualized treatment decision is based on the accurate evaluation of clinical risk factors and prognosis for resectable colorectal liver metastases. The current study aimed to develop an effective nomogram to predict progression-free survival (PFS) and to design a treatment schedule preoperatively. The study enrolled a primary cohort of 532 patients with resectable colorectal liver metastases (CRLM) who underwent hepatic resection at two institutions and a validation cohort of 237 patients at two additional institutions with resectable CRLM between 1 January 2008 and 31 December 2018. A nomogram was created based on the independent predictors in the multivariable analysis of progression-free survival in the primary cohort. The predictive accuracy and discriminative ability of the nomogram were determined by the concordance index (C-index) and the calibration curve. The score was compared with the current standard Fong score and validated with an external cohort. The independent risk factors for CRLM patients identified in the multivariable analysis were tumor larger than 5 cm, more than one tumor, RAS mutation, primary lymph node metastasis, and primary tumor located on the right side. All five factors were considered in the nomogram. The C-index of the nomogram for predicting survival was 0.696. With external validation, the C-index of the nomogram for the prediction of the PFS was 0.682, which demonstrated that this model has a good level of discriminative ability. For high-risk patients (score > 16), neoadjuvant chemotherapy improved PFS and overall survival (OS) after hepatic resection. The current nomogram demonstrated an accurate performance in predicting PFS for resectable CRLM patients with liver-limited disease. Based on the current nomogram, high-risk patients (nomogram score > 16) might benefit from neoadjuvant chemotherapy.

Background The mortality following pancreaticoduodenectomy has markedly decreased but remains an important challenge for the complexity of operation and technical skills involved. The present study aimed to clarify the impact of individualized pancreaticoenteric anastomosis and management to postoperative pancreatic fistula. Methods Data from 529 consecutive pancreaticoduodenectomies were retrospectively analysed from the Hepatobiliary and Pancreatic Surgery Unit I, Peking Cancer Hospital. The pancreaticoenteric anastomosis was determined based on the pancreatic texture and diameter of the main pancreatic duct. The amylase value of the drainage fluid was dynamically monitored postoperatively on days 3, 5 and 7. A low speed intermittent irrigation was performed in selected patients. Intraoperative and postoperative results were collected and compared between the pancreaticogastrostomy (PG) group and pancreaticojejunostomy (PJ) group. Results From 2010 to 2019, 529 consecutive patients underwent pancreaticoduodenectomy. Pancreaticogastrostomy was performed in 364 patients; pancreaticojejunostomy was performed in 150 patients respectively. The clinically relevant pancreatic fistula (CR-POPF) was 9.8% and mortality was zero. The soft pancreas, diameter of main pancreatic duct≤3 mm, BMI ≥ 25, operation time > 330 min and pancreaticogastrostomy was correlated with postoperative pancreatic fistula significantly. The CR-POPF of PJ was significantly higher than that of PG in soft pancreas patients; the operation time of PJ was shorter than that of PG significantly in hard pancreas patients. Intraoperative blood loss and operation time of PG was less than that of PJ significantly in normal pancreatic duct patients (p Conclusions Individualized pancreaticoenteric anastomosis should be determined based on the pancreatic texture and pancreatic duct diameter. The appropriate anastomosis and postoperative management could prevent mortality.

Li-Jun Wang, Xiao-Luan Yan, Juan Li, Kun Wang, Bao-Cai Xing Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Hepatopancreatobiliary Surgery Unit I, Peking University Cancer Hospital & Institute, Beijing 100142, People’s Republic of ChinaCorrespondence: Bao-Cai XingKey Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Hepatopancreatobiliary Surgery Unit I, Peking University Cancer Hospital & Institute, 52 Fucheng Road, Haidian, Beijing 100142, People’s Republic of ChinaEmail xingbaocai88@sina.comPurpose: The aim of the present study was to determine the value of the indocyanine green (ICG) clearance test in the preoperative assessment of chemotherapy-related hepatic injury in patients with liver metastasis from colorectal cancer.Methods: A total of 218 patients who underwent hepatic dissection due to colorectal cancer liver metastasis at the Peking University Cancer Hospital between January 2016 and December 2017 were retrospectively evaluated; 179 patients who received chemotherapy prior to hepatic resection were further examined. Patient- and chemotherapy-related factors were analyzed in both groups with normal and abnormal ICG retention rate at 15 min (ICG-R15), and their intraoperative and postoperative outcomes were compared.Results: The chemotherapy group had a higher mean ICG-R15 value and a higher number of patients who exhibited abnormal ICG-R15, compared with the no-chemotherapy group. Under the guidance of ICG test, no patients experienced severe complications in the abnormal ICG-R15 group compared with the normal ICG-R15 group, and the overall morbidity was also not significantly different between the two groups. However, the incidence of severe complications was higher in patients who underwent major resection with a normal ICG-R15 value compared with patients with an abnormal ICG-R15 value who underwent minor resection (P< 0.05). Multivariable logistic regression analyses revealed that body mass index (BMI) ≥ 28 and oxaliplatin use were independent predictors of abnormal ICG-R15. The ICG-R15 value was significantly higher in the two-risk factors group compared with the no-risk factor group (P=0.012), but not statistically different compared with the one risk factor group.Conclusion: Screening of patients with chemotherapy-associated liver injury using the IGC test may help in performing safe hepatectomy by avoiding major resection. BMI ≥ 28 and oxaliplatin use were independent preoperative predictors of abnormal ICG-R15.Keywords: indocyanine green, resection, liver metastasis, colorectal cancer, morbidity

Primary tumour location has long been debated as a prognostic factor in colorectal cancer patients with liver metastases (CRLM) undergoing liver resection. This retrospective study was conducted to clarify the prognostic value of tumour location after radical hepatectomy for CRLM and its underlying causes.We retrospectively analysed clinical data from 420 patients with CRLM whom underwent liver resection between January 2002 and December 2015. Right-sided (RS) tumours include tumours located in the cecum, ascending colon, and transverse colon, and left-sided (LS) tumours include those located in the splenic flexure, descending colon, sigmoid colon, and rectum.Both overall survival (OS) and disease-free survival (DFS) were similar between patients with RS and LS primary tumours (5-year OS: 46.5% vs 38.3%, P = 0.699; 5-year DFS: 29.1% vs 22.4%, P = 0.536). Specifically, RAS mutation rate was significantly higher in patients with RS tumours (P = 0.007). Subgroup analysis showed that the RAS mutation on the LS and RS tumours have different prognostic impact for CRLM patients on long-term survival after hepatic resection (RS, OS: P = 0.437, DFS: P = 0.471; LS, OS: P 0.001, DFS: P = 0.002). The multivariable analysis showed that RAS mutant is an independent factor influencing OS in patients with LS primary tumour only.The site of the primary tumour has no significant impact on the long-term survival in patients with CRLM undergoing radical surgery. However, prognostic value of RAS status differs depending on the site of the primary tumour.

Background: Hepatocellular carcinoma (HCC) is a primary malignancy of the liver. New serum biomarkers for HCC screening are needed, especially for alpha-fetoprotein (AFP) negative patients. As a proximal fluid between body fluids and intracellular fluid, tissue interstitial fluid (TIF) is a suitable source for serum biomarker discovery. Methods: Sixteen paired TIF samples from HCC tumour and adjacent non-tumour tissues were analysed by isobaric tags for relative and absolute quantitation (iTRAQ) method. Two proteins were selected for ELISA validation in serum samples. Results: Totally, 3629 proteins were identified and 3357 proteins were quantified in TIF samples. Among them, 232 proteins were significantly upregulated in HCC-TIF and 257 proteins down-regulated. Two overexpressed extracellular matrix proteins, SPARC and thrombospondin-2 (THBS2) were selected for further validation. ELISA result showed that the serum levels of SPARC and THBS2 in HCC patients were both significantly higher than those in healthy controls. The combination of serum SPARC and THBS2 could distinguish HCC (AUC=0.97, sensitivity=86%, specificity=100%) or AFP-negative HCC (AUC=0.95, sensitivity=91%, specificity=93%) from healthy controls. And the combination of serum SPARC and THBS2 could also distinguish HCC patients from benign liver disease patients (AUC=0.93, sensitivity=80%, specificity=94%). In addition, serum THBS2 was found to be a novel independent indicator for poor prognosis of HCC. Conclusions: Novel HCC candidate serum markers were found through in-depth proteomic analysis of TIF, which demonstrated the successful utility of TIF in cancer serum biomarker discovery.

// Kun Wang 1, * , Wei Liu 1, * , Xiao-Luan Yan 1 , Juan Li 1 and Bao-Cai Xing 1 1 Hepatopancreatobiliary Surgery Department I, Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, Peking University School of Oncology, Beijing Cancer Hospital and Institute, Beijing, PR China * These authors contributed equally to this work Correspondence to: Bao-Cai Xing, email: xingbaocai88@sina.com Keywords: colorectal cancer, KRAS mutation, colorectal liver metastasis, chemotherapy, survival Received: May 24, 2017 Accepted: August 05, 2017 Published: August 18, 2017 ABSTRACT Numerous factors affect the prognosis of colorectal liver metastasis (CRLM) patients after hepatic resection. We investigated several factors related to overall survival in patients with CRLM to identify those most likely to benefit from hepatic resection, and produced a rational tumor biology score system. Three hundred CRLM patients treated with preoperative chemotherapy followed by hepatic resection between 2006 and 2016 were enrolled in our study. Clinicopathologic and long-term survival data were collected and assessed. Patient 1-, 3-, and 5-year overall survival rates were 92.7%, 58.3%, and 45.8%, respectively, while 1-, 3-, and 5-year disease-free survival rates were 44.7%, 28.6%, and 24.2%, respectively. Multivariate Cox regression analysis revealed poor preoperative chemotherapy response, Fong clinical risk score > 2, and KRAS mutation to be independent prognostic indicators in CRLM patients. As part of a preoperative staging system in which one point was assigned for each factor, a total score (out of 3) was predictive of long-term survival following surgery. These factors facilitate personalized prognostic assessments in CRLM patients planning for resection.

Purpose To evaluate the efficacy and safety of hepatic arterial infusion (HAI) of oxaliplatin and 5-fluorouracil for advanced perihilar cholangiocarcinoma (PCC) in this prospective phase II study. Materials and Methods The protocol was approved by the local ethics committee, and all patients gave informed consent. Patients with nonresectable PCC were included in a prospective, open phase II study investigating HAI through interventionally implanted port catheters. HAI consisted of infusions of oxaliplatin 40 mg/m2 for 2 hours, followed by 5-fluorouracil 800 mg/m2 for 22 hours on days 1-3 every 3-4 weeks. A maximum of six cycles of HAI were applied for tumor control patients followed by maintenance with oral capecitabine until tumor progression. The primary end points were tumor response and progression-free survival (PFS). The secondary end points were local PFS, overall survival, and adverse events. Kaplan-Meier methodology and Cox regression analysis were used to evaluate the risk factors for survival. Results Between 2012 and 2015, 37 patients were enrolled. The overall response rate was 67.6% (25 of 37), and the disease control rate was 89.2% (33 of 37). Median PFS, local PFS, and overall survival were 12.2, 25.0, and 20.5 months, respectively. All three survival lengths in patients with periductal infiltrating pattern were found to be significantly longer than those in patients with mass-forming pattern (P < .001, hazard ratio < 0.2). Macroscopic growth patterns (P = .018) and number of HAI cycles (P < .001) were independent risk factors of survival. The most frequent adverse events were grades 1 and 2 gastrointestinal side effects and sensory neuropathy in 31 (83.8%) and 28 (75.7%) patients, respectively. Conclusion HAI with oxaliplatin and 5-fluorouracil may be an encouraging treatment choice for advanced PCC due to its high tumor control, survival benefit, and low toxicity, especially in patients with periductal infiltrating pattern. © RSNA, 2016.

Background: Human U three protein 14a (hUTP14a) promotes p53 degradation. Moreover, hUTP14a expression is upregulated in several types of tumors. However, the expression pattern of hUTP14a in hepatocellular carcinoma (HCC) remains unknown. The aim of this study was to investigate hUTP14a expression and its prognostic value in HCC. Methods: The hUTP14a expression was evaluated using immunohistochemistry (IHC) in HCC tissue specimens. The correlations between hUTP14a expression and clinicopathological variables were analyzed. The Kaplan-Meier method was used to analyze the association between hUTP14a expression and survival. Independent prognostic factors associated with overall survival (OS) and disease-free survival (DFS) were analyzed using the Cox proportional-hazards regression model. Results: The IHC data revealed that the hUTP14a positivity rate in HCC tissue specimens was significantly higher than that in nontumorous tissue specimens (89.9% vs. 72.7%, P < 0.05). The hUTP14a expression was detected in both the nucleolus and the cytoplasm. The positivity rate of nucleolar hUTP14a expression in HCC tissue specimens was higher than that in the nontumorous tissue specimens (29.3% vs. 10.1%, P < 0.05). No significant difference was found between HCC and nontumorous tissue specimens of cytoplasmic hUTP14a expression (60.6% vs. 62.6%, P > 0.05). In addition, no significant correlation was found between nucleolar hUTP14a expression and other clinicopathological variables. The 5-year OS and DFS rates in patients with positive nucleolar hUTP14a expression were significantly lower than those in patients with negative hUTP14a expression (P = 0.004 for OS, P = 0.003 for DFS). Multivariate analysis showed that nucleolar hUTP14a expression was an independent prognostic factor for OS (P = 0.004) and DFS (P < 0.001). Conclusions: The positivity rate of hUTP14a expression was significantly higher in HCC specimens. Positive expression of nucleolar hUTP14a might act as a novel prognostic predictor for patients with HCC.

To compare the efficacy and safety of hepatic arterial infusion chemotherapy (HAIC) to transarterial chemoembolization/embolization (TACE/TAE) for the treatment of advanced hepatocellular carcinoma (HCC) with major portal vein tumor thrombosis (PVTT). Forty-six patients with advanced HCC with major PVTT who underwent HAIC or TACE/TAE between April 2013 and April 2017 were included. In the HAIC group (n = 22), oxaliplatin (35–40 mg/m2 for 2 h) and 5-fluorouracil (600–800 mg/m2 for 22 h) on days 1–3 every 4 weeks were administered for a maximum of six serial courses. In the TACE/TAE group (n = 24), an emulsion of epirubicin (40–60 mg) and lipiodol was administered followed by particles (cTACE), or particles alone embolization (TAE). Overall survival (OS), tumor response according to mRECIST, progression-free survival (PFS), and adverse events were investigated. Median OS was 20.8 months in the HAIC group versus 4.0 months in the TACE/TAE group (P

This Article contains an error in Figure 3. In panel g, images representing miR-222-TuD and miR-424-TuD were both taken from the miR-222-TuD image. The correct version of Figure 3 is shown in the accompanying Author Correction.

Background: Liver is the most common metastatic site in advanced colorectal cancer. Most patients with colorectal cancer liver metastasis (CRLM) do not benefit from current treatment. Patient-derived xenografts (PDXs) with defined molecular signatures are attractive models for preclinical studies. Methods: Successfully established PDXs were evaluated to elucidate their fidelity of patients' biologic characteristics (pathologic, genetic and protein properties, together with chemosensitivity). The genomic variations of PDXs were analyzed by next-generation sequencing to explore the underlying molecular mechanism of metastasis and potential therapeutic targets. Results: CRLM (N=73) showed a significantly higher successful PDX establishment rate than primary specimens (N=26; 76.7% vs. 57.7%). CRLM PDXs recapitulated the pathologic, genetic and protein properties of parental tumors, as well as chemosensitivity. Frequent altered genes in PDXs showed high consistency compared to patients' genomic alterations and were enriched in MAPK, ErbB, cell cycle, focal adhesion pathways for CRLM PDXs, whereas primary tumor-derived PDXs only exhibited genomic variations involving ErbB and cell cycle. The genetic alterations showed high concordance between paired PDXs from primary and metastatic tissues, except for recurrent gene mutations (ARID1A, CDK8, ETV1, STAT5B and WNK3) and common copy number gains in chromosomes 20q (e.g., SRC/AURKA). Several potential drug targets such as KRAS, HER2, and FGFR2 were validated using corresponding inhibitors. Additionally, PDX models could also be used in screening efficient regimens for patients with no druggable alterations. Conclusion: This study has successfully established and validated a large panel of molecularly annotated platforms from patients with CRLM for preclinical studies.

Objective Location of the primary tumor side has become an increasingly prognostic factor for colorectal liver metastasis. The present study was to perform a meta-analysis to investigate if primary right-sided tumor impacted on long-term survival outcome of colorectal liver metastases following local treatment. Method Eligible trials were identified from the Embase, PubMed, Web of Science and the Cochrane database that were published before October in 2018. English language trials that compared long-term survival outcome of primary left-sided tumor with right-sided tumor colorectal liver metastases following local treatment were included. Hepatic resection for colorectal liver metastases was investigated. The main study outcomes included overall survival and disease free survival of primary right-sided colorectal liver metastases following local treatment. The risk factors of largest tumor size, primary node metastases, multiple tumor and RAS mutation were also analyzed. A systematic review and meta-analysis was done using a fixed-effects model. Hazard ratio with a 95% confidence interval was used to measure the pooled effect. Results A total of twelve studies with 6387 patients were included. For primary right-sided colorectal liver metastases patients following hepatic resection, the overall pooled HR for 5-year overall survival rate was 1.354 (95% CI: 1.238–1.482; p = 0.000; I2 = 33.7%, p = 0.138). The pooled HR for 5-year disease free survival rate of primary right-sided CRLM in the included studies calculated using the fix-effects model was 1.104 (95% CI: 0.987–1.235; p = 0.084; I2 = 0%, p = 0.477). Conclusion It demonstrated that primary right-sided for colorectal liver metastases location was a significantly worse prognostic factor in terms of overall survival.

Tumor-infiltrating myeloid cells (TIMs) are key regulators in tumor progression, but the similarity and distinction of their fundamental properties across different tumors remain elusive. Here, by performing a pan-cancer analysis of single myeloid cells from 210 patients across 15 human cancer types, we identified distinct features of TIMs across cancer types. Mast cells in nasopharyngeal cancer were found to be associated with better prognosis and exhibited an anti-tumor phenotype with a high ratio of TNF+/VEGFA+ cells. Systematic comparison between cDC1- and cDC2-derived LAMP3+ cDCs revealed their differences in transcription factors and external stimulus. Additionally, pro-angiogenic tumor-associated macrophages (TAMs) were characterized with diverse markers across different cancer types, and the composition of TIMs appeared to be associated with certain features of somatic mutations and gene expressions. Our results provide a systematic view of the highly heterogeneous TIMs and suggest future avenues for rational, targeted immunotherapies.

NIR, a novel INHAT, negatively regulates the transcription activity of tumor repressor p53. However, if NIR functions in the tumorigenesis dependent on the regulation of p53 remains unknown. Here, we report that NIR promotes progression of colorectal cancer (CRC) through regulating RB function. Firstly, we found that NIR expression is upregulated in the human CRC tissues and significantly associated with the poor outcome of the patients. Sequence alignment shows that NIR contains an RB-binding motif LxCxE in its INHAT-2 domain. We demonstrate that NIR interacts with RB via INHAT-2 in CRC cells and promotes RB degradation through proteasome-mediated pathway. Further, either full-length GFP-NIR or GFP-NIR-INHAT2 facilitates poly-ubiquitination of RB. In addition, NIR inhibits RB acetylation by INHAT-2, suggesting NIR might promote RB degradation through inhibiting RB acetylation. Importantly, endogenous NIR is downregulated upon DNA damage, which is consistent with the upregulation of total level and acetylation of RB. We further show that Flag-NIR inhibits DNA damage-induced RB acetylation. Thus, downregulation of NIR might contribute to maintain the cellular homeostasis under DNA damage. Consequently, depletion of NIR inhibits cell proliferation and tumor growth in mouse xenografts. Taken together, we demonstrate that NIR promotes CRC progression partially through inhibiting RB acetylation and promoting RB degradation. Targeting NIR may provide a potential therapeutic strategy for NIR-upregulated CRC patients.

Neoadjuvant chemotherapy is being increasingly accepted as an effective treatment of resectable colorectal liver metastases (CRLM), but it may also damage the hepatic parenchyma. We performed a meta-analysis to compare the outcomes of patients who received neoadjuvant chemotherapy (NEO) prior to hepatic resection with hepatic resection without neoadjuvant chemotherapy (SG). Eligible trials were identified from Embase, PubMed, the Web of Science and the Cochrane library. Hazard ratios (HRs) with a 95% confidence intervals (CIs) were used to measure the pooled effect using a random-effects model. Statistical heterogeneity was detected by I2 test. Sensitivity analyses and publication bias were also assessed. The study outcomes included 3-year, 5-year disease-free and overall survival rate, respectively. Eighteen studies involving 6,254 patients were included. The pooled HRs for 5-year DFS and 5-year OS for NEO in the included studies calculated using the random-effects model were 1.38 (95 % CI; 1.26-1.51, p=0.00; I2=9.6%, p=0.36) and 1.19 (95% CI: 1.02-1.38; p=0.03; I2=49.2%, p=0.03), respectively. For CRLM patients with factors indicating a high risk of recurrence, the pooled HR for 5-year OS of NEO in the included studies calculated using the random-effects model was 0.69 (95% CI: 0.55-0.87; p=0.00; I2=0.0%, p=0.48). These results suggest neoadjuvant chemotherapy improved survival of patients with initially resectable CRLM and a high risk of disease recurrence.

Hepatocellular carcinoma (HCC) ranks fourth in cancer mortality worldwide, and third in China. Hepatitis B virus (HBV) infection is a main risk factor for HCC in China, and the early diagnosis of HCC in high-risk population is very important. However, the commonly used diagnostic biomarker alpha-fetoprotein has limitations in clinical practice. In order to identify reliable and noninvasive HCC urinary biomarkers, a high-throughput proteomics streamline was applied in the analysis of urine samples from 74 HCC and 82 high-risk patients with chronic HBV infected liver diseases. Candidate diagnostic markers were screened by feature selection algorithm, and were combined with random forest or simple voting algorithms in the training dataset. Then the multiple feature models were validated in an independent test dataset. The selected features were further verified by Multiple Reaction Monitoring (MRM) in another independent dataset. By integrating 7 features screened in the discovery phase, random forest model achieved AUC of 0.92 and 0.87 in training and test datasets, respectively, while voting model performed better with AUC of 0.94 and 0.90, respectively. In the MRM dataset, the 7 features were targeted quantified, and voting model integrating the 7 features achieved AUC of 0.95. Our work highlights the potential of noninvasive urinary protein biomarkers in HCC diagnosis with high-risk population, which will be beneficial to HCC auxiliary diagnosis and HCC surveillance. SIGNIFICANCE: A high throughput urinary proteome analysis platform was committed into the discovery of noninvasive HCC biomarkers in high-risk patients with chronic HBV infected liver diseases. The combination of 7 urinary features achieved good performance in distinguishing HCC from high-risk population. The expression of the 7 features was validated by targeted MRM, and the integration of the features also worked well in the MRM dataset. This is the first time that urinary proteomic strategy was applied in discovering HCC biomarkers from high-risk population. This result will be helpful for HCC auxiliary diagnosis and surveillance in a noninvasive way.

e16004 Background: Patients of colorectal cancer with liver metastatic (CRLM) show various in recurrence and prognosis. Previous researches have revealed that the disfunction of DNA damage repair (DDR) signaling pathways was correlative with oncogenesis and poor prognosis. Here we aimed to determine the impact of DDR gene mutations on survival in patients undergoing CRLM resection. Methods: Tumor tissues from 164 patients with CRLM were collected for next generation sequencing (NGS). Single nucleotide variants, indels, and copy number variations were obtained from a 620-gene panel, including 68 genes in 7 DDR signaling pathways. Correlations of mutations in DDR genes with overall survival (OS) and recurrence-free survival (RFS) were determined by using Kaplan-Meier analysis. Results: 152/164 of patients carried at least one of DDR gene alternations. The most frequently mutated gene was TP53 (132/164), followed by CHEK2 (21/164), BRCA2 (10/164), ATM (9/164), PRKDC (8/164), FANCM (8/164), ATR (7/164), POLE (5/164), BRCA1 (4/164), POLD (3/164). Survival analysis indicated that TP53 mutations were not correlated with OS and RFS (P = 0.38 and 0.21). Further analysis in the TP53mut subgroup showed that the patients with other DDR gene mutations (64/132, 48.48%) exhibited a significantly worse OS than the wild type ones (P = 0.04). Especially, gene alternations involving in the Fanconi anemia (FA) pathway were significantly associated with worse OS and RFS (P = 0.0014 and 0.006). Interestingly, besides the TP53 mutation, patients carrying more than 2 other DDR gene mutations (10/64, 15.63%) also showed worse OS and RFS than patients with single mutation and wild type in DDR genes. (OS: 19 vs 35 months, P = 0.053; RFS: 3 vs 11 months, P = 0.084). Conclusions: Mutations in DDR signaling pathways predicted worse survival in TP53-mutated CRLM patients after surgery. These findings may be useful for clinical decision making in patients with tumor characteristics associated with poor prognosis and for risk stratification of patients in future clinical studies.

Background Liver resection is the first-line treatment for patients with resectable colorectal liver metastasis (CRLM), while radiofrequency ablation (RFA) can be used for small unresectable CRLM because of disease extent, poor anatomical location, or comorbidities. However, the long-term outcomes are unclear for RFA treatment in resectable CRLM. This study aimed to compare the recurrence rates and prognosis between resectable CRLM patients receiving either liver resection or RFA. Methods Consecutive patients who underwent RFA or hepatic resection from November 2010 to December 2015 were assigned in this retrospective study. Propensity score analysis was used to eliminate baseline differences between groups. Survival and recurrence rates were compared between patients receiving liver resection and RFA. Results With 1:2 ratio of propensity scoring, 46 patients in the RFA group and 92 in the resection group were successfully matched. Overall survival was similar between the two groups, but the resection group had a higher disease-free survival (median, 22 months vs. 14 months). Whereas among patients with a tumor size of ≤ 3 cm, disease-free survival was similar in the two groups (median, 24 months vs. 21 months). Compared to the resection group, the RFA group had a higher rate of intrahepatic recurrence (34.8% vs. 12.0%) and a shorter recurrence free period. The local and systemic recurrence rate and recurrence-free period for the same were insignificant in the two groups. Poor disease-free survival was associated with RFA, T4, tumor diameter > 3 cm, and lymph node positivity. Conclusion Among patients with technically resectable CRLM, resection provided greater disease-free survival, although both treatment modalities provided similar overall survival.

The aim of the present study was to evaluate the role of hepatectomy plus adjuvant transcatheter arterial chemoembolization (TACE) in patients with multicentric occurrence (MO) or intrahepatic metastases (IM) of hepatocellular carcinoma (HCC). Patients with multifocal HCC who underwent hepatic resection only (HR) or HR plus adjuvant TACE (HRT) between January 2005 and December 2015 were divided into MO or IM groups. The patient characteristics and outcomes were retrospectively analyzed. A total of 103 patients (59 and 44 in the MO and IM groups, respectively) were included in the analysis. The 1-, 3- and 5-year overall survival (OS) rates were 92.7, 76.8 and 56.8% for the MO group, and 93.1, 41.6 and 18.5% for the IM group, respectively (OS, P=0.001), and the 1-, 3- and 5-year disease-free survival (DFS) rates were 84.1, 44.6 and 40.5% for the MO group and 51.7, 22.5 and 15.0% for the IM group, respectively (DFS, P

NAT10, a nucleolar acetyltransferase, participates in a variety of cellular processes including ribosome biogenesis and DNA damage response. Immunohistochemistry staining showed that cytoplasmic and membranous NAT10 is related to the clinical pathologic characteristics in human cancer tissues. However, the mechanism about how NAT10 translocates from the nucleolus to cytoplasm and membrane is unclear. Here, we obtain a NAT10 deletion mutant localizing in cytoplasm and membrane. Bioinformatics analysis showed that residues 68-75 and 989-1018 are two potential nuclear localization signals (NLS) of NAT10. GFP-NAT10 deletion mutant (Δ989-1018) predominantly translocates into cytoplasm with faint signal retained in the nucleolus, while GFP-NAT10(Δ68-75) still remains in the nucleolus and nucleoplasm, indicating residues 989-1018 is the main nucleolar localization signal (NuLS). GFP-NAT10-D3, with both fragments (residues 68-75 and 989-1018) deleted, completely excludes from the nucleolus and translocates to cytoplasm and membrane. Therefore, complete NuLSs of NAT10 should include residues 68-75 and 989-1018. The cytoplasmic and membranous NAT10 mutant (Flag-NAT10-D3) colocalizes with α-tubulin in cytoplasm and with integrin on cell membrane. Importantly, Flag-NAT10-D3 promotes α-tubulin acetylation and stabilizes microtubules. Consequently, Flag-NAT10-D3 promotes migration and invasion in hepatocellular carcinoma (HCC) cells. Statistical analysis of immunohistochemistry staining of NAT10 in HCC tissues demonstrates that the cytoplasmic NAT10 is correlated with poorer prognosis compared with nuclear NAT10, while the membranous NAT10 predicts the poorest clinical outcome of the patients. We thus provide the evidence for the function of cytoplasmic and membranous NAT10 in the metastasis and prognosis of HCC patients.