Imaging-based surrogate classification for risk stratification of hepatocellular carcinoma with microvascular invasion to adjuvant hepatic arterial infusion chemotherapy: a multicenter retrospective study.

BACKGROUND: Patients with microvascular invasion (MVI)-positive hepatocellular carcinoma (HCC) have shown promising results with adjuvant hepatic arterial infusion chemotherapy (HAIC) with FOLFOX after curative resection. We aim to develop an imaging-derived biomarker to depict MVI-positive HCC patients more precisely and promote individualized treatment strategies of adjuvant HAIC. MATERIALS AND METHODS: Patients with MVI-positive HCC were identified from five academic centers and utilized for model development (n=470). Validation cohorts were pooled from a previously reported prospective clinical study conducted (control cohort (n=145), adjuvant HAIC cohort (n=143)) (NCT03192618). The primary endpoint was recurrence-free survival (RFS). Imaging features were thoroughly reviewed, and multivariable logistic regression analysis was employed for model development. Transcriptomic sequencing was conducted to identify the associated biological processes. RESULTS: Arterial phase peritumoral enhancement, boundary of the tumor enhancement, tumor necrosis stratification, and boundary of the necrotic area were selected and incorporated into the nomogram for RFS. The imaging-based model successfully stratified patients into two distinct prognostic subgroups in both the training, control, and adjuvant HAIC cohorts (median RFS, 6.00 vs. 66.00 mo, 4.86 vs. 24.30 mo, 11.46 vs. 39.40 mo, all P<0.01). Furthermore, no significant statistical difference was observed between patients at high-risk of adjuvant HAIC and those in the control group (P=0.61). The area under the receiver operating characteristic curve at two years was found to be 0.83, 0.84, and 0.73 for the training, control, and adjuvant HAIC cohorts respectively. Transcriptomic sequencing analyses revealed associations between the radiological features and immune-regulating signal transduction pathways. CONCLUSION: The utilization of this imaging-based model could help to better characterize MVI-positive HCC patients and facilitate the precise subtyping of patients who genuinely benefit from adjuvant HAIC treatment.

Smad4 Deficiency Promotes Pancreatic Cancer Immunogenicity by Activating the Cancer-Autonomous DNA-Sensing Signaling Axis.

Smad4, a key mediator of the transforming growth factor-ß signaling, is mutated or deleted in 20% of pancreatic ductal adenocarcinoma (PDAC) cancers and significantly affects cancer development. However, the effect of Smad4 loss on the immunogenicity and tumor immune microenvironment of PDAC is still unclear. Here, a surprising function of Smad4 in suppressing mouse PDAC tumor immunogenicity is identified. Although Smad4 deletion in tumor cells enhances proliferation in vitro, the in vivo growth of Smad4-deficient PDAC tumor is significantly inhibited on immunocompetent C57BL/6 (B6) mice, but not on immunodeficient mice or CD8+ cell-depleted B6 mice. Mechanistically, Smad4 deficiency significantly increases tumor cell immunogenicity by promoting spontaneous DNA damage and stimulating STING-mediated type I interferon signaling,which contributes to the activation of type 1 conventional dendritic cells (cDC1) and subsequent CD8+ T cells for tumor control. Furthermore, retarded tumor growth of Smad4-deficient PDAC cells on B6 mice is largely reversed when Sting is codeleted, or when the cells are implanted into interferon-alpha receptor-deficientmice or cDC1-deficientmice. Accordingly, Smad4 deficiency promotes PDAC immunogenicity by inducing tumor-intrinsic DNA damage-elicited type I interferon signaling.

Development and Validation of a Model Including Distinct Vascular Patterns to Estimate Survival in Hepatocellular Carcinoma.

Importance: Because of tumor heterogeneity, traditional clinical variables remain insufficient to predict recurrence, which impairs long-term survival among patients undergoing radical hepatectomy for hepatocellular carcinoma (HCC). Vessels encapsulating tumor clusters (VETC) constitute a novel vascular pattern distinct from microvascular invasion (MVI), representing biological aggressiveness of HCC. Objective: To establish a model to estimate individualized recurrence-free survival (RFS) in HCC by integrating VETC and MVI. Design, Setting, and Participants: This prognostic study included 498 patients undergoing radical hepatectomy for HCC from 5 academic centers in China from January 1, 2013, to December 31, 2016, and consisted of 3 cohorts: training (243 [48.8%]), internal validation (122 [24.5%]), and external validation (133 [26.7%]). Follow-up was completed on March 30, 2020, and the data were analyzed from December 1 to 31, 2020. Exposures: VETC, MVI, tumor number, and maximum tumor size. Main Outcomes and Measures: The primary end point was RFS. The risk score for relative recurrence and nomogram for absolute RFS probability were derived from the final model, which contained variables recommended by multivariate least absolute shrinkage and selection operator Cox proportional hazards regression analysis. Their performance was quantified using the Harrell concordance index (C index), the time-dependent area under the receiver operating characteristic curve, and calibration curves and was compared with 6 prognostic systems. Recurrence-free survival was estimated by the Kaplan-Meier method, and RFS curves were compared using a log-rank test. Results: Among the 498 patients, 432 (86.7%) were men; the mean (SD) age at diagnosis was 51.4 (11.3) years. Independent predictors for RFS identified included VETC, MVI, tumor number, and maximum tumor size, which were incorporated into the multivariate model (VMNS model). The C index (0.702; 95% CI, 0.653-0.752) for the VMNS score of the training cohort was significantly higher than those of 6 conventional systems (0.587 [95% CI, 0.535-0.638] to 0.657 [95% CI, 0.606-0.708]). Different recurrence risk groups defined by the VMNS score showed significantly different 2-year RFS (low-risk group, 81.4% [SE, 0.036]; medium-risk group, 62.1% [SE, 0.054]; high-risk group, 30.1% [SE, 0.079]; P < .001). Calibration curves of the VMNS nomogram showed good agreement between the nomogram-predicted RFS probability and actual RFS proportion. The internal and external validation cohorts confirmed the results. Conclusions and Relevance: The VMNS model enabled individualized prognostication of RFS in patients with HCC undergoing curative resection.

Immune-related adverse events predict responses to PD-1 blockade immunotherapy in hepatocellular carcinoma.

Immune checkpoint blockade has demonstrated remarkable efficacy in hepatocellular carcinoma (HCC) but is also commonly accompanied by immune-related adverse events (irAEs). However, the association between irAEs and antitumor efficacy in HCC patients remains unknown. All patients with HCC treated with anti-PD-1 antibodies from July 2018 to November 2019 were analyzed and divided into different groups according to their irAEs' status. In total, 101 HCC patients, including 21 (20.8%) patients who presented with irAEs (irAEs+ ), were enrolled. Among the adverse events, rash (n = 9, 8.9%) was the most frequent irAE, followed by mucositis (n = 3, 3.0%) and thyroiditis (n = 3, 3.0%). Patients in the irAEs+ group showed a higher tumor response rate than those in the irAEs- group (overall response rate: 28.6% vs 6.3%, P = .011; disease control rate: 85.7% vs 60.0%, P = .028). The median progression-free survival (PFS) times were 14.8 months in the irAEs+ group and 4.1 months in the irAEs- group (P < .001). Further analysis based on the presence or absence of rash showed that the PFS of the patients in the irAEs+ /rash+ group was better than that of those in the irAEs+ /rash- or irAEs- group (all P < .05). Multivariate analysis showed that irAEs were an independent prognostic factor for PFS (hazard ratio [HR]: 0.22, P = .002). Thus, the occurrence of irAEs, especially rash, was associated with markedly improved PFS. Awareness of irAEs may help classify the subtype of HCC patients with an unprecedented survival benefit from anti-PD-1 antibodies.

SYPL1 Inhibits Apoptosis in Pancreatic Ductal Adenocarcinoma via Suppression of ROS-Induced ERK Activation.

Synaptophysin-like 1 (SYPL1) is a neuroendocrine-related protein. The role of SYPL1 in pancreatic ductal adenocarcinoma (PDAC) and the underlying molecular mechanism remain unclarified. Here, after analyzing five datasets (GSE15471, GSE16515, GSE28735, TCGA, and PACA-AU) and 78 PDAC patients from Sun Yat-sen University Cancer Center, we demonstrated that SYPL1 was upregulated in PDAC and that a high level of SYPL1 indicated poor prognosis. Bioinformatics analysis implied that SYPL1 was related to cell proliferation and cell death. To validate these findings, gain-of-function and loss-of-function experiments were carried out, and we found that SYPL1 promoted cell proliferation in vitro and in vivo and that it protected cells from apoptosis. Mechanistic studies revealed that sustained extracellular-regulated protein kinase (ERK) activation was responsible for the cell death resulting from knockdown of SYPL1. In addition, bioinformatics analysis showed that the expression of SYPL1 positively correlated with antioxidant activity. Reactive oxygen species (ROS) were upregulated in cells with SYPL1 knockdown and vice versa. Upregulated ROS led to ERK activation and cell death. These results suggest that SYPL1 plays a vital role in PDAC and promotes cancer cell survival by suppressing ROS-induced ERK activation.

A Novel Prognostic Nomogram for Patients With Recurrence of Intrahepatic Cholangiocarcinoma After Initial Surgery.

Background: The prognosis of patients with post-operative recurrent intrahepatic cholangiocarcinoma (ICC) is at great variance. We aimed to propose a novel efficient prognostic nomogram in facilitating the risk stratification for post-operative recurrent ICC patients. Methods: From 2000 to 2016, a total of 237 post-operative recurrent ICC patients were enrolled in this study, and randomly divided into training (n = 178) and validation cohorts (n = 59) at a ratio of 3:1. The performance of this nomogram was assessed by discrimination, calibration, and clinical usefulness, and the results were compared with four other currently used ICC staging systems. Results: On multivariate analysis of the training cohort, serum CA 19-9, albumin-bilirubin grade at recurrence, time from primary resection to recurrence, tumor number at recurrence, and treatment for recurrence were selected for the model. The concordance index (C-index) of our model was 0.791 [95% confidence interval (CI), 0.736-0.846], which was statistically higher than the values of the following systems: American Joint Committee on Cancer (AJCC) 8th edition (0.610), Liver Cancer Study Group of Japan (0.613), Nathan (0.582), and Okabayashi (0.600; P < 0.001 for all). The nomogram performed well in terms of calibration when compared with actual observation. The findings were supported by the validation cohort. Conclusions: Compared with four currently used staging systems for ICC, our nomogram showed more promising clinical utility in improving individualized predictions of survival for post-operative recurrent ICC patients.

Induced CD10 expression during monocyte-to-macrophage differentiation identifies a unique subset of macrophages in pancreatic ductal adenocarcinoma.

OBJECTIVE: Tumor associated macrophages (TAMs) promoted pancreatic ductal adenocarcinoma (PDAC) initiation and progression. In this study we aimed to evaluate CD10 expression by monocytes/macrophages and its clinical significance in PDAC. METHODS: Human CD14+ peripheral blood monocytes were isolated and cultured for 6-7 days to differentiate into macrophages in vitro. Monocytic THP-1 cells were cultured and treated with 100 ng/ml phorbol 12-myristate 13-acetate (PMA) for 72 h to induce macrophage differentiation. Reverse transcription-quantitative PCR, immunohistochemistry, immunofluorescence, multiplex immunohistochemical staining and flow cytometry were performed to detect CD10 expression. In addition, the correlations between CD10 expression and immune cells infiltration were investigated through TIMER or GEPIA. Finally, Kaplan-Meier plotter and GEPIA databases were adopted to evaluate the influence of CD10 on clinical prognosis. RESULTS: Our results indicated that CD10 was expressed by a subset of human monocytes and many more cells expressed CD10 after differentiation into macrophages in vitro (13.19% vs. 41.39%; P < 0.0001). As for PDAC tissues, CD10 was correlated with immune cells infiltration and was expressed by a subset of TAMs. For THP-1 cells, PMA could induce CD10 expression through the MAPK pathway. The Kaplan-Meier plotter results suggested that CD10 expression had an impact on the prognosis of PDAC. CONCLUSIONS: In this study we demonstrated that CD10 was expressed by human primary monocytes, human monocyte-derived macrophages and TAMs, and was correlated with poor prognosis in PDAC, suggesting CD10 to be a potential therapeutic target in PDAC.

Preoperative CEA levels are supplementary to CA19-9 levels in predicting prognosis in patients with resectable intrahepatic cholangiocarcinoma.

Background: There are few diagnostic tools that can be used to determine which patient with intrahepatic cholangiocarcinoma (ICC) can benefit from surgery actually, highlighting that the need for new preoperative stratification strategies. The aim of this study was to investigate the predictive values of preoperative biomarkers in survival analyses for patients with ICC after surgical resection. Methods: A total of 285 patients with ICC were retrospectively reviewed. Receiver operating charateristics (ROC) curves were used to evaluate the predictive effects of preoperative carbohydrate antigen 19-9 (CA19-9) with different cutoff values and carcinoembryonic antigen (CEA) in patients with ICC. Results: Preoperative CA19-9 with a cutoff value of 200 U/ml performed better in predicting overall survival (OS) and progression free survival (PFS) in ICC patients. Patients with preoperative CA19-9 value > 200 U/ml generally had a poor surgical response. However, surgical resection could also benefit patients whose CA19-9 levels decreased postoperatively or preoperative CEA levels were negative. Conclusions: With the cutoff value of 200U/ml, CA19-9 was a better preoperative biomarker for predicting survival for ICC patients after surgical resection. Combination of preoperative CA19-9 and CEA showed the strongest predictive power in survival analyses in these patients and should be recognized in daily clinical care.