ONECUT2 facilitates hepatocellular carcinoma metastasis by transcriptionally upregulating FGF2 and ACLY

Metastasis is the predominant reason for high mortality of hepatocellular carcinoma (HCC) patients. It is critical to explore the molecular mechanism underlying HCC metastasis. Here, we reported that transcription factor One Cut homeobox 2 (ONECUT2) functioned as an oncogene to facilitate HCC metastasis. Elevated ONECUT2 expression was positively correlated with increased tumor number, tumor encapsulation loss, microvascular invasion, poor tumor differentiation, and advanced TNM stage. Mechanistically, ONECUT2 directly bound to the promoters of fibroblast growth factor 2 (FGF2) and ATP citrate lyase (ACLY) and transcriptionally upregulated their expression. Knockdown of FGF2 and ACLY inhibited ONECUT2-mediated HCC metastasis, whereas upregulation of FGF2 and ACLY rescued ONECUT2 knockdown-induced suppression of HCC metastasis. ONECUT2 expression was positively correlated with FGF2 and ACLY expression in human HCC tissues. HCC patients with positive coexpression of ONECUT2/FGF2 or ONECUT2/ACLY exhibited the worst prognosis. In addition, FGF2 upregulated ONECUT2 expression through the FGFR1/ERK/ELK1 pathway, which formed an FGF2-FGFR1-ONECUT2 positive feedback loop. Knockdown of ONECUT2 inhibited FGF2-induced HCC metastasis. Furthermore, the combination of FGFR1 inhibitor PD173074 with ACLY inhibitor ETC-1002 markedly suppressed ONECUT2-mediated HCC metastasis. In summary, ONECUT2 was a potential prognostic biomarker in HCC and targeting this oncogenic signaling pathway may provide an efficient therapeutic strategy against HCC metastasis.

Disease recurrence after colorectal cancer surgery in the modern era: a population-based study

Purpose This population-based study determined the cumulative incidence (CI) of local, regional, and distant recurrences, examined metastatic patterns, and identified risk factors for recurrence after curative treatment for CRC. Methods All patients undergoing resection for pathological stage I–III CRC between January 2015 and July 2015 and registered in the Netherlands Cancer Registry were selected (N = 5412). Additional patient record review and data collection on recurrences was conducted by trained administrators in 2019. Three-year CI of recurrence was calculated according to sublocation (right-sided: RCC, left-sided: LCC and rectal cancer: RC) and stage. Cox competing risk regression analyses were used to identify risk factors for recurrence. Results The 3-year CI of recurrence for stage I, II, and III RCC and LCC was 0.03 vs. 0.03, 0.12 vs. 0.16, and 0.31 vs. 0.24, respectively. The 3-year CI of recurrence for stage I, II, and III RC was 0.08, 0.24, and 0.38. Distant metastases were found in 14, 12, and 16% of patients with RCC, LCC, and RC. Multiple site metastases were found often in patients with RCC, LCC, and RC (42 vs. 32 vs. 28%). Risk factors for recurrence in stage I–II CRC were age 65–74 years, pT4 tumor size, and poor tumor differentiation whereas in stage III CRC, these were ASA III, pT4 tumor size, N2, and poor tumor differentiation. Conclusions Recurrence rates in recently treated patients with CRC were lower than reported in the literature and the metastatic pattern and recurrence risks varied between anatomical sublocations.

Programmed Death Ligand-1 (PD-L1) Is an Independent Negative Prognosticator in Western-World Gallbladder Cancer

Inhibition of the programmed cell death protein-1/ligand-1 (PD-1/PD-L1) axis has opened a new era in the treatment of solid cancers. However, there is no data on the expression and relevance of PD-L1 in Western gallbladder cancer (GBC). We assessed PD-L1 immunohistochemically in 131 GBC patients as Tumor Proportion Score (TPS), Immune Cell Score (IC) and Combined Positivity Score (CPS). Tumor cells expressed PD-L1 in a subset of 14.7% GBC patients at a TPS cut-off of 1%. Higher PD-L1 levels above 10% and 25% TPS were reached in 4.7% and 3.1% of GBC cases, respectively. At a 10% cut-off, TPS was associated with distinct histomorphological subtypes and correlated with poor tumor differentiation. Survival analysis revealed a TPS above 10% to be a highly significant and independent negative prognosticator in GBC. PD-L1 expression was associated with increased CD4+, CD8+ and PD-1+ immune cell densities. In 14.8% of the cases, scattered immune cells expressed T-cell immunoreceptor with Ig and ITIM domains (TIGIT), which was correlated to tumoral expression of its ligand CD155. We here show that a high PD-L1 expression confers a negative prognostic value in Western-world GBC and highlight the TIGIT/CD155 immune checkpoint as a potential new target for GBC immunotherapy.

Significance of Cytoplasmic Expression of Telomerase Reverse Transcriptase in Patients with Hepatocellular Carcinoma Undergoing Liver Resection

Telomerase reverse transcriptase (TERT) is reportedly expressed in various types of cancer. However, the significance of TERT expression in hepatocellular carcinoma (HCC) has not been fully evaluated. Herein, we evaluated TERT expression in resected HCC tumor tissues using immunohistochemistry. TERT expression was assessed in both the cytoplasm and the nucleus of HCC cells. The relationships between TERT expression and clinical characteristics were investigated. Among the 135 HCCs, TERT expression was positive only in the cytoplasm in 86 tumors (63.7%), was positive only in the nucleus in 3 tumors (2.2%), was positive in both the cytoplasm and the nucleus in 5 tumors (3.7%) and was negative in 41 tumors (30.4%). Cytoplasmic TERT expression was significantly associated with HBs antigen, poor tumor differentiation, and DNA-dependent protein kinase catalytic unit (DNA-PKcs) expression. However, TERT expression in the cytoplasm or in the nucleus was not significantly correlated with the overall or the recurrence-free survival periods. In conclusion, TERT was mainly expressed in the cytoplasm of HCC tissues. Cytoplasmic TERT expression is closely associated with HBV-related HCC and DNA-PKcs expression. The overexpression of TERT and DNA-PKcs arise from cccDNA and may be related to liver carcinogenesis in the presence of HBV infection.

Eyelid sebaceous gland carcinoma: An assessment of the T classification of the American Joint Committee of Cancer TNM staging system 8th versus 7th edition

Purpose: To assess the prognostic values of the T classification of the 8th edition of the American Joint Committee of Cancer staging system and compare it to the 7th edition. Methods: Multicenter retrospective study of patients with eyelid sebaceous gland carcinoma. The primary outcome measure was the differences between outcomes when tumors were staged with either 7th or 8th edition. The measures evaluated included presenting features, management, histopathology, metastasis, recurrence, and mortality. Results: Of the 60 patients (median age 73 years), 31 (51.7%) were females. A change in T staging occurred in 39 patients (65%) when the 8th edition was applied. Advanced categories (T3/T4) were significantly associated with nodal metastasis ( p = 0.037) using the 8th edition criteria but not with the 7th edition ( p = 0.066). The 8th edition T categorization significantly correlated with eye survival ( p = 0.022) while the 7th edition did not ( p = 0.058). Applying the 8th edition, category T4 at presentation was associated with a higher risk of nodal metastasis ( p = 0.037) but not associated with local recurrence, distant metastasis, or tumor-related death ( p = 0.281, p = 0.737, p = 0.319, respectively). T3/T4 category tumors were significantly associated with poor tumor differentiation ( p = 0.001), and papillary histologic pattern ( p = 0.024) but not with pagetoid spread ( p = 0.056). Conclusion: The application of the 8th edition AJCC staging system for eyelid SGC may accurately predict nodal metastasis. Local recurrence and distant metastasis were not significantly associated with T classification, using either edition. Poor tumor differentiation and papillary pattern were associated with T3/T4 categories suggesting that pathological features may assist in determining prognosis.

Prognostic value of programmed cell death ligand 1 (PD-L1) for hepatocellular carcinoma: a meta-analysis

The prognostic role of programmed death ligand-1 (PD-L1) expression in hepatocellular carcinoma (HCC) has been widely studied but the results are controversial. In this comprehensive meta-analysis, we elucidated the clinical value of PD-L1 in HCC. Relevant studies were systematically searched in the Cochrane Library, EMBASE, and PubMed until June 27, 2019. Eligible studies were validated for the prognostic effect of PD-L1 on the overall survival (OS), disease-free survival (DFS), and relapse-free survival (RFS) in HCC using a hazard ratio (HR) and its 95% confidence interval (95% CI). Twenty-three studies with 3529 patients were involved in this meta-analysis. The pooled results revealed that high membrane-bound PD-L1 (mPD-L1) expression was associated with poor OS (HR: 1.42; 95% CI: 1.12–1.80; P = 0.004) and had no significant correlation with RFS (HR: 1.14; 95% CI: 0.85–1.54; P = 0.39), and DFS (HR: 1.36; 95% CI: 0.81–2.28; P = 0.25). The results also indicated that high soluble PD-L1 (sPD-L1) levels were associated with worse OS (HR: 2.93; 95% CI: 2.20–3.91; P < 0.00001). In addition, high mPD-L1 expression was associated with high alpha-fetoprotein levels (AFP; OR = 1.46; 95% CI: 1.16–1.84; P = 0.001), hepatitis (OR = 0.72; 95% CI: 0.54–0.98; P = 0.03), poor tumor differentiation (OR = 0.68; 95% CI: 0.55–0.84; P = 0.03), and tumor-infiltrating lymphocytes (OR = 3.39; 95% CI: 1.06–10.91; P = 0.04). The mPD-L1 expression had no significant correlation with age, number of tumors, gender, tumor size, liver cirrhosis, vascular invasion, tumor encapsulation, or TNM stage. The study revealed that high mPD-L1 expression in the tumor tissue and high sPD-L1 levels were associated with shorter OS in HCC. Moreover, overexpression of mPD-L1 was significantly associated with poor tumor differentiation, hepatitis, AFP elevation, and tumor-infiltrating lymphocytes.

P107 PREDICTION OF A POSITIVE CIRCUMFERENTIAL RESECTION MARGIN IN ADENOCARCINOMA OF THE ESOPHAGUS

Aim To determine if a positive circumferential resection margin (CRM) can be predicted in patients with esophageal adenocarcinoma undergoing neo-adjuvant chemotherapy prior to surgery Methods 223 patients were included in this study. Multivariable analyses of clinico-pathological and computed tomography (CT) imaging predictors were performed to evaluate the likelihood of a positive CRM at initial staging and following neoadjuvant chemotherapy, with prediction models constructed. Area under curve (AUC) with 95% confidence interval (CI) from 1000 bootstrapping was assessed. Results Advanced clinical T-stage (T3-4) (odds ratio, OR 2.93 95%CI 1.03-9.48) and poor tumor differentiation (OR 2.84, 95%CI 1.39-6.01) were independently associated with an increased risk of a positive CRM. Non response to chemotherapy as estimated by CT independently corresponded with an increased risk of CRM positivity (OR 3.38 95% CI 1.43-8.50). Additional CT evidence of local invasion/pleural thickening and higher CT tumor volume (14cm3) improved the performance of a prediction model, including all above parameters; with AUC (c-index) of 0.76 (0.68-0.83). Conclusion Combining advanced clinical T-stage, poor tumor differentiation, CT non-response to chemotherapy, higher CT tumor volume and local invasion may be helpful in selecting patients for intensification of neo-adjuvant treatment prior to resection.

A Surgeon’s Role in the Management of Early Esophageal, EGJ and Gastric Lesions

Background: Endoscopic mucosal resection and submucosal dissection (ESD) are indicated in a majority of mucosal esophageal, esophagogastric junction and gastric cancers (GC), and selected cases of submucosal cancers as well. Summary: The presence of lymph node metastases in early esophageal cancer (EC) has been proven in up to 50% of ­patients with sm3 cancers treated with surgical resection, and up to 18.5 and 30.5% in sm1 and sm2 cancer respectively. The presence of lymphovascular invasion (LVI), tumor depth >500 μm and poor tumor differentiation seem to be a common predictor of worse outcomes in literature reports. In case of early esophagogastric junction cancer (EGJC) these predictors include LVI, tumor size >3 cm, Barrett’s origin of the tumor and ulcerative tumor appearance. Extended indications for ESD in early GC are already adopted in high volume centers with high success rates (up to 98%). Jet, positive resection margins after ESD, LVI and poor tumor differentiation carry high metastatic potential, therefore advocating surgery. Limited resections and cooperative laparoscopic endoscopic approach may be implemented in cases of early EGJC and GC. Key Messages: The presence of LVI, depth of submucosal invasion, and poor tumor differentiation in cases of early EC, EGJC, and GC favor surgical treatment despite improvements in endoscopic techniques.