Mengchao Wu

PURPOSE: This study aimed to establish an effective prognostic nomogram for intrahepatic cholangiocarcinoma (ICC) after partial hepatectomy. PATIENTS AND METHODS: The nomogram was based on a retrospectively study on 367 patients who underwent partial hepatectomy for ICC at the Eastern Hepatobiliary Surgery Hospital from 2002 to 2007. The predictive accuracy and discriminative ability of the nomogram were determined by concordance index (C-index) and calibration curve and compared with five currently used staging systems on ICC. The results were validated using bootstrap resampling and a prospective study on 82 patients operated on from 2007 to 2008 at the same institution. RESULTS: On multivariate analysis of the primary cohort, independent factors for survival were serum carcinoembryonic antigen, CA 19-9, tumor diameter and number, vascular invasion, lymph node metastasis, direct invasion, and local extrahepatic metastasis, which were all selected into the nomogram. The calibration curve for probability of survival showed good agreement between prediction by nomogram and actual observation. The C-index of the nomogram for predicting survival was 0.74 (95% CI, 0.71 to 0.77), which was statistically higher than the C-index values of the following systems: American Joint Committee on Cancer (AJCC) seventh edition (0.65), AJCC sixth edition (0.65), Nathan (0.64), Liver Cancer Study Group of Japan (0.64), and Okabayashi (0.67; P < .001 for all). It was also higher (0.74) in predicting survival for the mass-forming type of ICC (P < .001). In the validation cohort, the nomogram discrimination was superior to the five other staging systems (C-index: 0.75 v 0.60 to 0.63; P < .001 for all). CONCLUSION: The proposed nomogram resulted in more-accurate prognostic prediction for patients with ICC after partial hepatectomy.

The communication between tumor-derived elements and stroma in the metastatic niche has a critical role in facilitating cancer metastasis. Yet, the mechanisms tumor cells use to control metastatic niche formation are not fully understood. Here we report that in the lung metastatic niche, high-metastatic hepatocellular carcinoma (HCC) cells exhibit a greater capacity to convert normal fibroblasts to cancer-associated fibroblasts (CAFs) than low-metastatic HCC cells. We show high-metastatic HCC cells secrete exosomal miR-1247-3p that directly targets B4GALT3, leading to activation of β1-integrin-NF-κB signaling in fibroblasts. Activated CAFs further promote cancer progression by secreting pro-inflammatory cytokines, including IL-6 and IL-8. Clinical data show high serum exosomal miR-1247-3p levels correlate with lung metastasis in HCC patients. These results demonstrate intercellular crosstalk between tumor cells and fibroblasts is mediated by tumor-derived exosomes that control lung metastasis of HCC, providing potential targets for prevention and treatment of cancer metastasis.

<h3>Importance</h3> The presence of microvascular invasion (MVI) decreases surgical outcomes of hepatocellular carcinoma (HCC). An accurate preoperative prediction of MVI can help surgeons to better choose surgical procedures, but accuracy is still difficult to achieve. <h3>Objective</h3> To develop a nomogram to predict MVI presence before liver resection for hepatitis B virus (HBV)–related HCC within the Milan criteria (solitary nodule ≤5 cm; ≤3 nodules, none &gt;3 cm; and no macrovascular invasion). <h3>Design, Setting, and Participants</h3> Data on 1004 consecutive patients who underwent liver resection for HBV-related HCC within the Milan criteria at the Eastern Hepatobiliary Surgery Hospital between April 6, 2004, and February 22, 2011, were prospectively collected. Of these, patients who underwent surgery in an earlier period formed the training cohort (n = 707) for nomogram development, and those who underwent surgery thereafter formed the validation cohort (n = 297) to confirm the model’s performance. Data analysis was conducted from August 1 to November 11, 2014. <h3>Exposures</h3> Liver resection for HCC. <h3>Main Outcomes and Measures</h3> Overall survival and time to recurrence after liver resection were measured. Multivariate logistic regression was used to identify the independent risk factors associated with MVI that then were incorporated into the nomogram. <h3>Results</h3> Histopathologically identified MVI was found in 211 of 707 patients (29.8%) and 89 of 297 patients (30.0%) in the training and validation cohorts, respectively. In the training cohort, the 5-year recurrence and overall survival rates were 78.5% and 46.9%, respectively, in patients with MVI and 58.4%, and 70.9%, respectively, in patients without MVI (both<i>P</i> &lt; .001). The preoperative factors associated with MVI were large tumor diameter, multiple nodules, incomplete capsule, α-fetoprotein level greater than 20 ng/mL, platelet count less than 100 × 10³/µL, hepatitis B virus DNA load greater than 10⁴IU/mL, and a typical dynamic pattern of tumors on contrast-enhanced magnetic resonance imaging. Incorporating these 7 factors, the nomogram achieved good concordance indexes of 0.81 (95% CI, 0.78-0.85) and 0.80 (95% CI, 0.75-0.86) in predicting MVI in the training and validation cohorts, respectively, and had well-fitted calibration curves. The positive and negative predictive values (95% CIs) of the nomogram were calculated, resulting in positive predictive values of 57.2% (52.0%-64.9%) and 57.9% (49.2%-68.5%) and negative predictive values of 87.2% (83.2%-89.4%) and 83.2% (76.0%-87.7%) for the training and validation cohorts, respectively. Patients who had a nomogram score of less than 200 or 200 or greater were considered to have low or high risks of MVI presence, respectively. <h3>Conclusions and Relevance</h3> The nomogram achieved an optimal preoperative prediction of MVI in HBV-related HCC within the Milan criteria. Using the model, the risk for an individual patient to harbor MVI can be determined, which can lead to a rational therapeutic choice.

Importance: Late recurrence (more than 2 years) after liver resection for hepatocellular carcinoma (HCC) is generally considered as a multicentric tumor or a de novo cancer. Objective: To investigate the risk factors, patterns, and outcomes of late recurrence after curative liver resection for HCC. Design, Setting, and Participants: This study was a multicenter retrospective analysis of patients who underwent curative liver resection for HCC at 6 hospitals in China from January 2001 to December 2015. Among 734 patients who were alive and free of recurrence at 2 years after resection, 303 patients developed late recurrence. Data were analyzed from June 2017 to February 2018. Interventions: Liver resection for HCC. Main Outcomes and Measures: Risk factors of late recurrence as well as patterns, treatments, and long-term outcomes of patients with late recurrence. Univariate and multivariate Cox regression analyses were performed to identify independent risk factors of late recurrence. Results: Of the included 734 patients, 652 (88.8%) were male, and the mean (SD) age was 51.0 (10.3) years. At a median (interquartile range) follow-up of 78.0 (52.8-112.5) months, 303 patients (41.3%) developed late recurrence. Multivariate analysis revealed that male sex, cirrhosis, multiple tumors, satellite nodules, tumor size greater than 5 cm, and macroscopic and microscopic vascular invasion were independent risk factors of late recurrence. Of the 303 patients with late recurrence, 273 (90.1%) had only intrahepatic recurrence, 30 (9.9%) had both intrahepatic and extrahepatic recurrence, and none had only extrahepatic recurrence. Potentially curative treatments were given to 165 of 303 patients (54.5%) with late recurrence, which included reresection, transplant, and local ablation. Multivariate Cox regression analysis showed that regular surveillance for postoperative recurrence (hazard ratio [HR], 0.470; 95% CI, 0.310-0.713; P = .001), cirrhosis (HR, 1.381; 95% CI, 1.049-1.854; P = .02), portal hypertension (HR, 2.424; 95% CI, 1.644-3.574; P < .001), Child-Pugh grade of B or C (HR, 1.376; 95% CI, 1.153-1.674; P < .001), Barcelona Clinic Liver Cancer stage B (HR, 1.304; 95% CI, 1.007-1.708; P = .04) and stage C (HR, 2.037; 95% CI, 1.583-2.842; P < .001), and potentially curative treatment (HR, 0.443; 95% CI, 0.297-0.661; P < .001) were independent predictors of overall survival for patients with late recurrence. Conclusions and Relevance: Late recurrence after HCC resection was associated with sex, cirrhosis, and several aggressive tumor characteristics of the initial HCC. The patterns of late recurrence suggested surveillance for recurrence after 2 years of surgery should be targeted to the liver. Postoperative surveillance improved the chance of potentially curative treatments, with improved survival outcomes in patients with late recurrence.

Adult hepatic progenitor (oval) cells are facultative stem cells in liver, which participate in a range of human liver diseases, including hepatocellular carcinoma (HCC). However, the molecular pathways regulating the expansion and differentiation of these cells are poorly understood. We show that active Wnt/beta-catenin signaling occurs preferentially within the oval cell population, and forced expression of constitutively active beta-catenin mutant promotes expansion of the oval cell population in the regenerated liver. More importantly, we identify a subpopulation of less differentiated progenitor-like cells in HCC cell lines and primary HCC tissues, which are defined by expression of the hepatic progenitor marker OV6 and endowed with endogenously active Wnt/beta-catenin signaling. These OV6(+) HCC cells possess a greater ability to form tumor in vivo and show a substantial resistance to standard chemotherapy compared with OV6(-) tumor cells. The fraction of tumor cells expressing OV6 is enriched after Wnt pathway activation, whereas inhibition of beta-catenin signaling leads to a decrease in the proportion of OV6(+) cells. In addition, the chemoresistance of OV6(+) HCC progenitor-like cells can be reversed by lentivirus-delivered stable expression of microRNA targeting beta-catenin. These results highlight the importance of the Wnt/beta-catenin pathway in activation and expansion of oval cells in normal rodent models and human HCCs. OV6(+) tumor cells may represent the cellular population that confers HCC chemoresistance, and therapies targeted to the Wnt/beta-catenin signaling may provide a specific method to disrupt this resistance mechanism to improve overall tumor control with chemotherapy.