Extrahepatic Invasion Research Articles

Upfront or delayed surgery in resectable hepatoblastoma: analysis from the children’s hepatic tumors international collaboration database

In the treatment of resectable hepatoblastoma (HB), it has not been established whether upfront surgery (UF) at diagnosis or neoadjuvant chemotherapy and delayed surgery (DL) is preferred. We compared patients with localized HB who underwent either UF, or DL after neoadjuvant chemotherapy in the Children's Hepatic tumors International Collaboration (CHIC) database of 1605 cases enrolled in eight multicenter hepatoblastoma trials between 1988 and2010. Among the 512 resectable HB patients who had PRETEXT (PRETreament EXTent of disease) I or II unruptured tumors at diagnosis without extrahepatic invasion, distant metastases, or massive vascular invasion, 172 underwent UF and 340 underwent DL. The primary outcomes were event-free and overall survivals after start of treatment in these two groups. Survival analysis was performed using the Kaplan-Maier analysis with long-rank tests and multivariable Cox regression models. Complete resection rates were comparable (93.6% in UF and 89.7% in DL). The total cycles of chemotherapy of DL (median:6) were significantly more than those of UF (median:4) (P<0.01). The 5-year event-free survival (EFS) was 90.6% and 86.6% (P=0.89) in the UF and DL cohorts, respectively. The surgical complications, recurrence rates, and late complications were not significantly different between the cohorts but the EFS rates of DL patients with a low alpha-fetoprotein (AFP) level (100-999ng/mL) or older age at diagnosis (≥3 years old) were significantly worse than others. The outcomes, surgical resectability, and complications were not significantly different between the UF and DL groups. Eligible patients with a low AFP level (<1000ng/mL) or older age (≥3 years old) showed better outcomes in the UF group and might be considered for initial resection. European Network for Cancer Research in Children and Adolescents, funded through the Framework Program 7 of the European Commission; Children's Oncology Group Cure Search grant contributed by the Hepatoblastoma Foundation; Practical Research for Innovative Cancer Control and Project Promoting Clinical Trials for Development of New Drugs and Medical Devices, Japan Agency for Medical Research and Development; Japan Society for the Promotion of Science; and Swiss Cancer Research grant.

The effect of CXCL12 on survival outcomes of patients with viral hepatitis-associated hepatocellular carcinoma after hepatectomy

BackgroundThe CXCL12-CXCR4/CXCR7 axis is garnering growing attention. But the comprehension of its function in the progression of HCC remains controversial. The purpose of this study was to investigate the effects of CXCL12 and its receptor on the prognosis of patients with viral hepatitis-associated HCC after hepatectomy. MethodsA total of 86 patients had been enrolled who had undergone hepatectomy for HCC and followed up to July 31, 2019, and their clinicopathological and follow-up data were recorded. Tumor and peritumoral tissues were obtained to detect the expression of CXCL12, CXCR4, and CXCR7 using immunohistochemistry. Real-time polymerase chain reaction was utilized to detect hepatitis B or C virus loads, while survival analysis was performed using the Kaplan–Meier method. Furthermore, the Cox proportional hazards regression model was employed to analyze the factors affecting the prognosis. ResultsThe results revealed that the CXCL12, CXCR4, and CXCR7 expression in tumor tissues was lower than in the corresponding non-tumor tissues in 20.93 %, 22.09 %, and 23.26 % of the patients, respectively, and that only CXCL12 was found to be related to the extrahepatic invasion of HCC. The survival analysis and Cox regression showed that only CXCL12 was associated with the postoperative survival of patients with HCC, and that it was an independent prognostic risk factor in the CXCL12-CXCR4/CXCR7 axis. The CXCL12low group represented shorter progression-free survival and lower overall survival rates. However, the subgroup analysis displayed that the survival difference associated with CXCL12 was only manifested in patients with higher expression of CXCR4 or CXCR7 in HCC, as compared to the surrounding tissues. ConclusionsOur findings suggest that, when assessing the prognostic significance of CXCL12 in HCC, it is essential to consider the expression level of its receptor. Nevertheless, CXCL12 can potentially serve as a promising prognostic marker for HCC.

Efficacy of S-1 Adjuvant Chemotherapy for Resected Biliary Tract Cancer: A Retrospective Propensity-Matched Analysis.

Surgical resection is considered an effective cure for biliary tract cancer (BTC); however, the prognosis is unsatisfactory despite improved surgical techniques and perioperative management. The recurrence rate remains high even after curative resection. The efficacy of adjuvant chemotherapy in pancreatic and gastric cancers has been previously reported, and the feasibility of adjuvant therapy with S-1 has recently been reported in patients with resected BTC. We aimed to retrospectively investigate the effects of adjuvant chemotherapy with S-1 on resected advanced BTC. We included data from 438 BTC patients who underwent resection between 2001 and 2020. After excluding patients with pTis-pT1 (n = 112) and other exclusion criteria, 266 patients were included in the analysis. After propensity score matching, 48 patients received S-1 adjuvant chemotherapy (S-1 group), and 48 patients received non-S1 adjuvant chemotherapy or underwent surgery alone (Non-S-1 group). The patients in the S-1 group had significantly better overall survival (OS) than those in the non-S-1 group (MST 51 vs 37 months, hazard ratio [HR]:.54, 95% confidence interval [CI]:.30-.98, P = .04). The S-1 group had a significantly better recurrence-free survival (RFS) than the non-S-1 group (94 vs 21 months, HR: .57, 95% CI: .33-.97, P = .03). Subgroup analyses for OS and RFS exhibited the benefits of S-1 in patients aged <75 years and in patients with primary sites of extrahepatic and perineural invasion and curability of R0. S-1 adjuvant therapy is promising for improving the postoperative survival of patients with resected advanced BTC, positive nerve invasion, and R0 resection.

Impact of Trinal Histological Glandular Differentiation Grade on the Prognosis of Patients with Intrahepatic Cholangiocarcinoma: a Multicenter Retrospective Study

IntroductionIt is unclear whether the histological glandular differentiation (HGD) score that evaluates the tumor grade of two dominant components is prognostic for survival in patients with intrahepatic cholangiocarcinoma (ICC). MethodWe retrospectively analyzed the clinical and histopathologic data of 235 consecutive patients with histologically confirmed ICC following hepatectomy at 5 university hospitals in the Kansai region of Japan. ResultsSurvival was statistically significantly stratified by trinal HGD grade (p < 0.05). Median disease-free survival (DFS) of patients with high HGD grade was significantly shorter compared with moderate HGD grade (13.0 vs 31.2 months, respectively; p = 0.004). By Cox proportional hazards regression analysis, HGD grade had the fifth-highest hazard ratio (HR = 1.77, p = 0.002) for DFS after vascular and/or biliary invasion, extrahepatic invasion, lymph node metastasis and multiple tumors. Multivariate logistic regression analysis revealed four predictors of early recurrence after hepatectomy (lymph node metastasis: odds ratio [OR] = 3.74, p = 0.001; tumor size > 50 mm: OR = 2.80, p = 0.002; HGD grade, high: OR = 2.11, p = 0.012; and vascular or biliary tract invasion: OR = 2.11, p = 0.048). ConclusionTrinal HGD grade had a significant prognostic impact on the survival of patients with ICC after radical hepatectomy.

Loco-regional therapies competing with radiofrequency ablation in potential indications for hepatocellular carcinoma: a network meta-analysis.

There is no clear consensus on the relative ranking of interventional and radiation techniques with indications similar to those of radiofrequency ablation (RFA) for the treatment of early hepatocellular carcinoma (HCC). We used a network meta-analysis to compare the efficacy of non-surgical treatments for early HCC. We searched databases for randomized trials assessing the efficacy of loco-regional treatments for HCCs ≤5 cm with no extrahepatic spread or portal invasion. The primary outcome was the pooled hazard ratio (HR) for overall survival (OS), and secondary outcomes included overall and local progression-free survival (PFS). A frequentist network meta-analysis was performed, and the relative ranking of therapies was assessed with P-scores. Nineteen studies comparing 11 different strategies in 2,793 patients were included. Chemoembolization plus RFA improved OS better than RFA alone (HR 0.52, 95% confidence interval [CI] 0.33-0.82; P-score=0.951). Cryoablation, microwave ablation, laser ablation, and proton beam therapy had similar effects on OS compared with RFA. For overall PFS, but not local PFS, only chemoembolization plus RFA performed significantly better than RFA (HR 0.61, 95% CI 0.42-0.88; P-score=0.964). Injection of percutaneous ethanol or acetic acid was significantly less effective than RFA for all measured outcomes, while no differences in progression outcomes were identified for other therapies included in the network. Our results suggest that chemoembolization combined with RFA is the best option for local treatment of early HCC. Cases with potential contraindications for RFA may benefit from a tailored approach using thermal or radiation modalities.

Transmembrane serine protease 2 cleaves nidogen 1 and inhibits extrahepatic liver cancer cell migration and invasion.

We aimed to confirm whether transmembrane serine protease 2 (TMPRSS2) regulates nidogen 1 (NID1) expression in extracellular vesicles (EVs) and metastatic hepatocellular carcinoma (HCC) cells. HCC cells, HUVEC cells, MRC-5 cells, HLE cells, MHCCLM3 cells, MHCC97L cells, H2P cells, H2M cells, as well as LO2 cells were cultured according to providers' instruction and EV models were established by using BALB/cAnN-nu mice to facilitate the verifications. We found that TMPRSS2 expression was inversely correlated with the metastatic potential of HCC cell lines. The expression of TMPRSS2 decreased in a time-dependent manner in tumor-bearing model mice implanted with MHCCLM3 cells compared with uninoculated mice. TMPRSS2 overexpression in MHCCLM3 and MHCC97L cells led to the significant downregulation of NID1 expression in total cell lysates and isolated EVs. In contrast, TMPRSS2 silencing resulted in the elevation of NID1 expression in cells and EVs. Administration of EVs from MHCCLM3 and MHCC97L cells with overexpressed or silenced TMPRSS2 inhibited or strengthened, respectively, the invasion, proliferation, and migration of LO2 tumor cells. EVs derived from MHCCLM3 and MHCC97L cells with overexpressed or depleted TMPRSS2 also deactivated or activated fibroblasts, respectively. These EVs secrete inflammatory cytokines and phosphorylated p65, facilitate the colonization of fibroblasts, and augment fibroblast growth and motility. These findings provide evidence for a new candidate drug targeting tumorigenic EV-NID1 to treat HCC.

PD-7 Cabozantinib plus atezolizumab in previously untreated advanced hepatocellular carcinoma (aHCC) and previously treated gastric cancer (GC) and gastroesophageal junction adenocarcinoma (GEJ): Results of the COSMIC-021 study

Cabozantinib may enhance response to immune checkpoint inhibitors by promoting an immune-permissive microenvironment. COSMIC-021 (NCT03170960), a multinational phase 1b study, is evaluating cabozantinib plus atezolizumab in various solid tumors. Efficacy and safety results in previously untreated aHCC (cohort 14) and previously treated GEJ/GC (cohort 15) are presented. Patients had measurable disease and ECOG PS of 0 or 1. Patients with aHCC, Child-Pugh A status, and no prior systemic anticancer therapy were eligible for cohort 14. Patients with GC, GEJ, or lower one-third esophageal adenocarcinoma who radiographically progressed during or following platinum- or fluoropyrimidine-containing chemotherapy and had ≤2 prior lines of therapy were eligible for cohort 15. Patients received cabozantinib 40 mg PO QD and atezolizumab 1200 mg IV Q3W. CT/MRI scans were performed Q6W for 52W and Q12W thereafter. The primary endpoint was ORR by investigator per RECIST 1.1. Other endpoints included safety, PFS, and OS. As of the data cutoff of 21 Dec 2021, 30 patients with aHCC and 31 with GEJ/GC (22 with GEJ, 8 with GC, and 1 other) were enrolled with a median (range) follow-up of 31.2 mo (23.0, 34.2) and 30.4 mo (19.5, 33.6), respectively. For aHCC, median age was 71 y, 12 (40%) had ECOG PS 0; disease etiology was 6 (20%) HBV, 11 (37%) HCV, and 13 (43%) non-viral. Extrahepatic invasion was present/absent in 13 (43%)/16 (53%), macrovascular invasion in 2 (7%)/20 (67%), and portal vein invasion in 10 (33%)/13 (43%). For GEJ/GC, median age was 61 y, 11 (35%) had ECOG PS 0, and 16 (52%), 14 (45%), and 1 (3%) received 1, 2, or 3 prior lines of systemic therapy. ORR per RECIST 1.1 was 13% (all confirmed PRs) for aHCC and 0 for GEJ/GC. Median DOR was 22.1 mo for aHCC. DCR (CR + PR + SD) was 83% for aHCC and 48% for GEJ/GC. Median PFS per RECIST 1.1 was 5.7 mo in aHCC and 2.4 mo in for GEJ/GC; median OS was 19.0 mo and 6.4 mo, respectively. Frequent treatment-related adverse events (TRAEs) for aHCC and GEJ/GC were PPE (47% and 13%), diarrhea (37% and 26%), AST increased (33% and 13%), and fatigue (23% both). Grade 3/4 TRAEs occurred in 40% for aHCC and 35% for GEJ/GC. No grade 5 TRAEs occurred in either cohort. Cabozantinib plus atezolizumab had clinical activity with a manageable safety profile in previously untreated aHCC, consistent with the recently presented phase 3 results in this indication (NCT03755791). Clinical activity of cabozantinib plus atezolizumab was minimal in previously treated GEJ/GC.

Single center real-world treatment and outcomes in patients with hepatocellular carcinoma receiving immunotherapy.

e16134 Background: Immune checkpoint inhibitor (ICI) based therapy has emerged as a therapeutic option in hepatocellular carcinoma (HCC), both in combination (IC-C) and as single agent (IC-SA). Approvals were based on clinical trials with strict eligibility criteria limiting generalizability to the entire spectrum of clinical practice. Survival outcomes have not been evaluated in a real-world population and there is no established post ICI treatment standard. Methods: Patients (pts) with advanced HCC treated with ICI across lines of therapy were included in this retrospective study. Data regarding demographics, comorbidities, HCC etiology, liver function (Child Pugh Score [CPS] and ALBI Grade [G]), tumor burden, AFP, treatments, reason for discontinuation (dc) and outcomes were collected. Descriptive statistics and survival analysis were performed using Stata with cox regression analysis. Results: The cohort consisted of 138 pts: median age 63 years (24,95); 83% male; 38% Hispanic/Latino, 27% Asian, 17% Non-Hispanic White, 4% Black and 14% other/unknown. Etiology of cirrhosis: 16% Hepatitis B, 38% Hepatitis C, 12% alcohol liver disease, 9% NAFLD and 24 % mixed/other; Baseline CPS were 74% CPA, 23% CPB, and 2% CPC; ALBI Scores were G1 in 35%, G2 in 53%, and G3 in 12% pts; 62% had extrahepatic disease and/or portal invasion; AFP was ≥ 400ng/mL in 30% of pts. 88% of pts had prior local therapy. For the entire cohort, first line systemic therapy consisted of 52% ICI (18% IC-C and 34% IC-SA) and 48% TKI. mOS was 12 months (mo) (0,74) for first line ICI group and 19.5 mo (3,78) in those with first line TKI. In CPA pts, first line therapy was 51% ICI (24% IC-C and 27% IC-SA) and 39% TKI. 79% of CPA patients received ≥ 2 lines of therapy with second line consisting of 65% ICI and 20% TKI. First line therapy for pts with CPB cirrhosis was 58% ICI (2% IC-C and 55% IC-SA) and 42% TKI. 55% of CPB patients received ≥ 2 lines of therapy and second line therapy for CPB pts included 71% ICI and 18% TKI. mOS was 18 mo in CPA pts and 10 mo in CPB pts. Cirrhosis related complications resulted in treatment discontinuation in 2% of CPA pts vs. 14% of CPB pts. On multivariable analysis, Asian ethnicity (HR 0.41 p = 0.006), CPS (HR 1.64 p = 0.027), and number of treatment lines (HR 0.74 p = 0.005) were associated with OS. Conclusions: This single institution real-world cohort highlights the reality of sequential therapy in pts with advanced HCC. Survival outcomes in our CPA cohort are comparable to data from recent phase 3 trials. The survival in our CPB cohort in a tertiary care setting compares favorably with available data from clinical trials and suggests the feasibility of sequential and effective anti-cancer therapy in this population. Liver function, Asian ethnicity, and number of treatment lines are independent predictors of OS in this cohort of HCC patients receiving ICI. Prospective studies related to optimal treatment sequence and to CPB pts are needed.

Single-center real-world treatment and outcomes in patients with hepatocellular carcinoma receiving immunotherapy.

401 Background: Immune checkpoint inhibitor (ICI) based therapy has emerged as a therapeutic option in hepatocellular carcinoma (HCC). Approvals were based on clinical trials with strict eligibility criteria limiting generalizability to clinical practice. Further, there is no established post ICI treatment standard. Methods: Patients (pts) with advanced HCC treated with ICI as single agent (ICI-SA) or in combination (ICI-C) across lines of therapy were included in this retrospective study. Results: The cohort consisted of 118 pts: median age 63 years (24, 88); 84% male; 35% Hispanic/Latino, 26% Asian, 19% Non-Hispanic White, 5% Black and 15% unknown. Etiology of cirrhosis: 13% Hepatitis B, 45% Hepatitis C, 16 % alcohol liver disease, 10% NAFLD and 16 % mixed/other; 73% had baseline Child Pugh (CP) A, 25% had CP-B, and 2% had CP-C; ALBI Scores were ≤ -2.60 in 32%, 2.60 &lt; and ≤-1.39 in 48%, and ≥-1.39 in 19% pts; 62% had extrahepatic disease and/or portal invasion; AFP was ≥ 400 ng/mL in 25% of pts. 81% of pts had prior local therapy. First line systemic therapies were: TKIs in 52 pts (44%), ICI-SA in 42 (36%), ICI-C in 15 (13%), clinical trial agent (CTA) in 8 (7%) and chemotherapy in 1 (1%), with a median duration (dur) of 4 months (95% CI 2.3 to 4). Ninety one (77%) and 61 pts (52%) received ≥ 2 or 3 lines of therapy, respectively. Fifty seven pts had ICI-SA and 14 ICI-C in second line or beyond. Median dur of ICI therapy was 4 months (95% CI 3-5) for all lines. Post-ICI therapies included 11% ICI, 30% CTA and 59% TKIs. TKIs included sorafenib (46%), cabozantinib (27%), lenvatinib (15%), and regorafenib (27%). For the 118 pt cohort, mOS was 14 months (95% CI 12-19). For pts treated with ICI in first line, mOS was 11 months (0, 74); post-ICI mOS was 6 months (95% CI 3-9) and mPFS was 3 months (95% CI 2-3). Thirty one pts received a TKI post ICI; mOS for this subset was 19 months (15, 22); mOS from start of TKI post ICI was 6.5 months (4, 12). On multivariable regression analysis, ALBI score was associated with OS (HR 1.63, p=0.02, CI: 1.08-2.27). Conclusions: Pts with advanced HCC and CP-A or B cirrhosis are able to receive sequential systemic therapy including ICI. Survival outcomes in this cohort are impacted by the inclusion of patients with more compromised liver function and less restrictive pt selection compared to clinical trials. Usage of TKIs post ICI is feasible with suggestion of clinical activity but this is an area in need of prospective studies.

Hepatectomy Versus Sorafenib in Advanced Nonmetastatic Hepatocellular Carcinoma: A Real-life Multicentric Weighted Comparison.

The aim of the study was to compare SURG vs SOR regarding the OS and progression-free survival (PFS) in a real-world clinical scenario. The treatment for advanced nonmetastatic HCC belonging to the Barcelona Clinic Liver Cancer stage C (BCLC C) is still controversial. BCLC C patients without extrahepatic spread and tumoral invasion of the main portal trunk were considered. Surgical patients were obtained from the HE.RC.O.LE.S. Register, whereas sorafenib patients were obtained from the ITA.LI.CA register The inverse probability weighting (IPW) method was adopted to balance the confounders between the 2 groups. Between 2008 and 2019, 478 patients were enrolled: 303 in SURG and 175 in SOR group. Eastern Cooperative Oncological Group Performance Status (ECOG-PS), presence of cirrhosis, steatosis, Child-Pugh grade, hepatitis B virus and hepatitis C virus, alcohol intake, collateral veins, bilobar disease, localization of the tumor thrombus, number of nodules, alpha-fetoprotein, age, and Charlson Comorbidity index were weighted by IPW to create two balanced pseudo-populations: SURG = 374 and SOR = 263. After IPW, 1-3-5 years OS was 83.6%, 68.1%, 55.9% for SURG, and 42.3%, 17.8%, 12.8% for SOR (P < 0.001). Similar trends were observed after subgrouping patients by ECOG-PS = 0 and ECOG-PS >0, and by the intrahepatic location of portal vein invasion. At Cox regression, sorafenib treatment (hazard ratio 4.436; 95% confidence interval 3.19-6.15; P < 0.001) and Charlson Index (hazard ratio 1.162; 95% confidence interval 1.06-1.27; P = 0.010) were the only independent predictors of mortality. PFS at 1-3-5 years were 65.9%, 40.3%, 24.3% for SURG and 21.6%, 3.5%, 2.9% for SOR (P = 0.007). In BCLC C patients without extrahepatic spread but with intrahepatic portal invasion, liver resection, if feasible, was followed by better OS and PFS compared with sorafenib.

The Application Value of ceMDCT in the Diagnosis of Gastric Cancer Extramural Vascular Invasion and Its Influencing Factors.

Objective To investigate the value of enhanced multislice spiral CT (ceMDCT) in the diagnosis of extramural vascular invasion of gastric cancer and the influencing factors of extramural vascular invasion. There are different methods used in this paper. Method 131 patients with primary gastric cancer treated in our hospital from January 2017 to May 2019 were selected. All patients underwent surgical resection and ceMDCT examination before operation. Result There were 40 cases with extramural vascular invasion of gastric cancer by surgical pathological diagnosis. The kappa value of ceMDCT in diagnosing extramural vascular invasion of gastric cancer was 0.947, and the consistency was excellent. The diagnostic sensitivity, specificity, positive predictive value, and negative predictive value were 100.00%, 96.70%, 93.02%, and 100.00%, respectively. The proportions of T3-T4, tumour diameter ≥5.0 cm, and growth pattern of proximal nodular + diffuse type in patients with gastric cancer extramural vascular invasion were 92.50%, 85.00%, and 65.00%, respectively, which were significantly higher than those in patients without extramural vascular invasion (P < 0.05). The logistic regression analysis results showed that T3-T4, tumour diameter ≥5.0 cm, proximal nodular + diffuse growth pattern were the risk factors for extrahepatic vascular invasion in gastric cancer (OR = 3.751, 2.901, and 3.367, P < 0.05). Conclusion ceMDCT has good application value in diagnosing gastric cancer extramural vascular invasion. The occurrence of gastric cancer extramural vascular invasion is affected by T staging, tumour diameter, and tumour growth pattern.

Morbidity, Prognostic Factors, and Competing Risk Nomogram for Combined Hepatocellular-Cholangiocarcinoma.

Background Combined hepatocellular-cholangiocarcinoma (CHC) is a rare and heterogeneous histological subtype of primary liver cancer, which is still poorly understood. This study aimed to describe the epidemiological and clinical features, investigate the prognostic indicators, and develop a competing risk nomogram for CHC. Methods The study cohort was taken from the Surveillance, Epidemiology, and End Results database. The annual percent change (APC) in incidence was calculated using the joinpoint regression. The nomogram was developed based on multivariate competing risk survival analyses and validated by calibration curves. Akaike information criterion, Bayesian information criterion, Harrell's C-index, and area under the receiver operating characteristic curves were obtained to compare prognostic performance. Decision curve analysis was introduced to examine the clinical value of the models. Results The overall incidence of CHC was 0.062 per 100,000 individuals in 2004 and 0.081 per 100,000 individuals in 2018, with an APC of 1.0% (P > 0.05). CHC displayed intermediate clinicopathological features of hepatocellular carcinoma and intrahepatic cholangiocarcinoma. Race, tumor size, vascular invasion, extrahepatic invasion, distant metastasis, grade, surgery, and Metavir stage were confirmed as the independent predictors of cancer-specific survival. The constructed nomogram was well calibrated, which showed better discrimination power and higher net benefits than the current American Joint Committee on Cancer staging system. Patients with liver transplantation had better survival than those with hepatectomy, especially patients within the Milan Criteria (P=0.022 and P=0.015). There was no survival difference between liver transplantation and hepatectomy in patients beyond the Milan Criteria (P=0.340). Conclusion The morbidity of CHC remained stable between 2004 and 2018. The constructed nomogram could predict the prognosis with good performance, which was meaningful to individual treatment strategies optimization. CHC patients should also be considered as potential liver transplantation recipients, especially those within the Milan Criteria, but the finding still needs more evidence to be further confirmed.

Clinical features and prognostic analysis of hepatoblastoma in children under six years old

Objective: To summarize and analyze the clinical features, treatment effects and related factors affecting the prognosis of hepatoblastoma (HB) in children under six years old. Methods: Clinical data of 382 children with HB under six years old who were pathologically diagnosed at the Pediatric Single Center of Beijing Tongren Hospital from May 2005 to May 2019 were analyzed retrospectively. The factors affecting the treatment effect and survival rate of HB were analyzed. The independent risk factors affecting the prognosis of HB were studied by Cox regression model. The χ(2) test was used to compare the enumeration data between groups. Kaplan-Meier method was used for survival analysis. Log-rank test was used to compare the survival rates among subgroups. Results: Children enrolled were with median age of 1.75 (0.08 ~ 5.92) years old and a male to female ratio of 1.5. Alpha-fetoprotein (AFP) median level was 197 406.5 μg/L at initial diagnosis, and the pathological tissue type was mainly epithelial (55.8%). Preoperative PRETEXT stage was mostly stage III (58.6%). 86 cases (22.5%) had portal vein or hepatic vein, and vena cava invasion. 73 cases (19.1%) had extrahepatic adjacent tissues and organs invasion. Twenty-four cases (6.3%) had tumor rupture and bleeding. 171 cases (44.8%) had distant metastases, and 96 cases (25.1%) had multiple intrahepatic lesions. Patients were followed-up to May 2020 (median follow-up time was 56 months). After comprehensive treatment, 218 cases were completely relieved, and 69 cases were partially relieved, and the treatment efficiency was 75.1%. Kaplan-Meier survival analysis showed that the 1, 3, and 5-years overall survival rates (OS) were 93.7%, 84.0%, and 73.9%, respectively, and the event-free survival rates were 90.5%, 79.2%, and 67.5%, respectively. Comparison of the clinical factors of 5-year OS showed that AFP < 100 μg/L (HR = 3.341, P = 0.005), PRETEXT stage IV (HR = 4.026, P = 0.001), vascular invasion (HR = 2.178, P = 0.019) and distant metastasis (HR = 2.634, P = 0.010) were independent risk factors in each subgroup affecting the prognosis of children with HB, and the difference was statistically significant. Conclusion: HB prognosis is related to AFP level, PRETEXT stage, presence or absence of vascular invasion and distant metastasis. Therefore, its survival and prognosis will be different in the presence of different risk factors.

Combined Stereotactic Body Radiotherapy and Immunotherapy (SBRT-IO) vs. TACE in Locally Advanced Hepatocellular Carcinoma (HCC): Propensity Score Matching Analysis

<h3>Purpose/Objective(s)</h3> We reported the first study of combined stereotactic body radiotherapy and immunotherapy (SBRT-IO) in unresectable hepatocellular carcinoma (uHCC) and found this combination was synergistic and safe. Based on these results, we conducted a propensity score matching analysis to compare the clinical outcome of this combination versus TACE alone. <h3>Materials/Methods</h3> This was a retrospective study conducted in a tertiary center of Hong Kong. Eligible patients were HCC patients, who were unsuitable or refractory to curative surgical interventions. Patients with extra-hepatic vascular invasion or metastasis were excluded. 16 and 202 patients received SBRT-IO and TACE alone respectively. Propensity score matching was used to adjust for the differences in patients' demographics and tumor characteristics. The primary outcome was progression-free survival (PFS); the secondary outcomes included overall survival (OS), objective response rate (ORR) per modified response evaluation criteria in solid tumors (mRECIST version 1.1) and toxicities. <h3>Results</h3> After matching, 16 patients were in the SBRT-IO group and 48 patients in the TACE group with similar baseline characteristics. Median 2 sessions of TACE (range: 1-16) were given in TACE group; for SBRT-IO arm, median dose of 35Gy in 5 fractions (range: 27.5-37.5Gy) was prescribed and median 10 cycles of nivolumab (range: 1-20 doses) were given. The median size of tumor was 10cm (range: 3.4-19.6cm) and 20.3% had portal vein invasion. The 12-month and 24-month PFS were better in SBRT-IO group (93.3% vs. 41.7% and 77.8% vs. 2.1%, <i>P</i> < 0.001); the 12-month and 24-month OS were also better in combination arm (93.8% vs. 54.2% and 80.4% vs. 8.3%, <i>P</i> < 0.001). The ORR was 87.5% (CR: 50%, PR: 37.5%) in patients receiving SBRT-IO compared to 11.9% (CR: 2.4%, PR: 9.5%) in those receiving TACE alone (<i>P</i> < 0.001). There were fewer ≥ grade 3 adverse events (AE) and treatment discontinuation due to AE in SBRT-IO arm (60.4% vs. 18.8%, <i>P</i> = 0.004; 25% vs. 12.5%, <i>P</i> = 0.295). No classical RILD and treatment-related death was reported in SBRT-IO arm. In multivariate analysis, SBRT-IO was an independent good prognostic factor for OS and PFS (HR of OS = 0.14 [0.30-0.96], <i>P</i> = 0.036; HR of PFS = 0.1 [range 0.03-0.33], <i>P</i> < 0.001) <h3>Conclusion</h3> SBRT-IO resulted in better survival than TACE alone in unresectable HCC. Our results provided strong rationale for studying this combination in prospective trial.

Hepatocellular Carcinoma in Non-cirrhotic Liver Arises with a More Advanced Tumoral Appearance: A Single-Center Cohort Study.

A small proportion of all hepatocellular carcinomas (HCCs) arise in a non-cirrhotic liver (NCL). However, our knowledge about the HCCs developing in a NCL is scarce. This study was undertaken to investigate the characteristics and survival course of this patient group. We retrospectively analyzed the database of patients with HCC at a tertiary center during a 10-year period (2009-2019). All demographic, clinical, laboratory, and tumoral features with survival outcomes were compared between the HCC-CL and HCC-NCL groups. Out of 384 HCC cases, 11.2% (n = 43) had no cirrhosis. The dominant etiology in the HCC-NCL group was hepatitis B virus (n = 26, 60.5%), followed by non-alcoholic fatty liver disease (n = 10, 23.2%), and hepatitis C virus (n = 7, 16.3%). The maximum tumor diameter was approximately 2 times larger in the HCC-NCL group (HCC-NCL: 90 mm vs. HCC-CL: 46.5 mm, P < .001). The proportion of patients with vascular (HCC-NCL: 27.9% vs. HCC-CL: 8.6%, P < .001) and extrahepatic invasion (HCC-NCL: 14% vs. HCC-CL: 3%, P = .001) were prominently higher in the HCC-NCL group. Patients with HCC-NCL were less often detected in early-curable stages (BCLC 0-A) than those in the HCC-CL group (HCC-NCL: 16.3% vs. HCC-CL: 34.9%, P = .004). The overall survival was not different between the 2 groups (HCC-NCL: 19.4 ± 9.8 months vs. HCC-CL: 17.5 ± 2.3 months, P = .581). HCC in NCL is diagnosed at more advanced tumoral stages with larger tumor size and more often with vascular and extrahepatic spread. Despite the preserved liver functions, the overall survival is not prolonged in HCCs without cirrhosis, due to the late recognition.

Preoperative prediction of postsurgical outcomes in mass-forming intrahepatic cholangiocarcinoma based on clinical, radiologic, and radiomics features.

Current prognostic systems for intrahepatic cholangiocarcinoma (IHCC) rely on surgical pathology data and are not applicable to a preoperative setting. We aimed to develop and validate preoperative models to predict postsurgical outcomes in mass-forming IHCC patients based on clinical, radiologic, and radiomics features. This multicenter retrospective cohort study included patients who underwent curative-intent resection for mass-forming IHCC. In the development cohort (single institution data), three preoperative multivariable Cox models for predicting recurrence-free survival (RFS) were constructed, including the clinical-radiologic, radiomics, and clinical-radiologic-radiomics (CRR) models based on clinical and CT findings, CT-radiomics features, and a combination of both, respectively. Model performance was evaluated in the test cohort (data from five institutions) using Harrell's C-index and compared with postoperative prognostic systems. A total of 345 patients (233, development cohort; 112, test cohort) were evaluated. The clinical-radiologic model included five independent CT predictors (infiltrative contour, multiplicity, periductal infiltration, extrahepatic organ invasion, and suspicious metastatic lymph node) and showed similar performance in predicting RFS to the radiomics model (C-index, 0.65 vs. 0.68; p = 0.43 in the test cohort). The CRR model showed significantly improved performance (C-index, 0.71; p = 0.01) than the clinical-radiologic model and demonstrated similar performance to the postoperative prognostic systems in predicting RFS (C-index, 0.71-0.73 vs. 0.70-0.73; p ≥ 0.40) and overall survival (C-index, 0.68-0.71 vs. 0.64-0.74; p ≥ 0.27) in the test cohort. A model integrating clinical, CT, and radiomics information may be useful for the preoperative assessment of postsurgical outcomes in patients with mass-forming IHCC. • The radiomics analysis had incremental value in predicting recurrence-free survival of patients with intrahepatic mass-forming cholangiocarcinoma. • The clinical-radiologic-radiomics model demonstrated similar performance to the postoperatively available prognostic systems (including 8th AJCC system) in predicting recurrence-free survival and overall survival. • The clinical-radiologic-radiomics model may be useful for the preoperative assessment of postsurgical outcomes in patients with mass-forming intrahepatic cholangiocarcinoma.

Trends of clinical outcomes with sorafenib in randomized controlled trials for patients with treatment-naïve advanced hepatocellular carcinoma.

327 Background: Sorafenib was first approved by the US FDA to treat patients with advanced hepatocellular carcinoma (HCC) after two landmark trials (SHARP and Asia-Pacific) showed improved overall survival (OS). Since those two landmark trials, median OS has increased in the sorafenib arms in several recent phase III trials in HCC. We analyzed trends in OS, progression-free survival (PFS), and objective response rates (ORR) in published randomized clinical trials of sorafenib in HCC to better understand factors underlying the improvements. Methods: We searched PubMed for all published trials of sorafenib in advanced HCC. Trials were included if the patients were naïve to systemic therapy and had a comparison arm that was active systemic therapy or placebo. We extracted demographic and trial-level outcome data to correlate outcomes such as OS, PFS, ORR, and duration of therapy. T-tests were used to compare outcomes and linear regression was used to identify temporal trends with significance set at p£0.05. Results: The PubMed search returned 100 studies. A total of 15 studies met inclusion criteria with a total of 3755 patients treated with sorafenib (9 phase III and 6 phase II). Included trials enrolled patients from 2005-2019. The median OS in all trials was 10.0 mos (range: 6.5-14.8 mos). OS has significantly improved since the first trial began accruing (p = 0.04). A total of 12 studies provided data on PFS using RECIST 1.1, with a median PFS of 4.0 months (range: 2.7-6.6 mos). PFS has not changed over time (p = 0.99). However, ORR assessed by RECIST 1.1 have trended toward improvement over time (p = 0.08). Median duration of therapy with sorafenib has decreased by 53% since the enrollment of the first clinical trial in 2005, from 23.1 weeks to 12.2 weeks (p = 0.02). Despite this, no significant correlations were observed with the interaction of duration of therapy and OS (p = 0.92). Further, there was no significant change in the age of patients included, proportion of patients with Childs-Pugh A, Barcelona Clinic Liver Cancer (BCLC) B, BCLC C, ECOG performance status 0, HBV or HCV, proportion of patients with extrahepatic spread or vascular invasion at time of enrollment, or proportion of patients who have undergone prior locoregional therapies to explain the OS findings. Conclusions: The OS of patients with advanced HCC on the sorafenib arm in published trials has been increasing, however the reasons for this increase are not apparent from data available in the published literature. At the same time, the median duration of treatment with sorafenib has been decreasing over time and PFS is unchanged, suggesting improvements in sorafenib delivery may not be the primary factor. It is possible these trends represent heretofore unquantified changes in patient selection for systemic therapy, improvements in supportive care, or post-progression treatment for patients on HCC clinical trials.

Long-term outcome and prognostic factors of combined hepatocellular carcinoma and cholangiocarcinoma after curative resection.

BackgroundCombined hepatocellular carcinoma and cholangiocarcinoma (cHCC-CC) is a rare subtype of primary liver cancers. Its prognostic factors remain unclear. The study aimed to evaluate its long-term outcome and prognostic factors by retrospectively reviewing the series of cHCC-CC after curative resection from our institute.MethodsA total of 55 pathologically confirmed cHCC-CC patients undergoing curative resections between January 2003 and January 2018 at the First Affiliated Hospital of Sun Yat-sen University (Guangzhou, China) were included. The clinicopathological and follow-up data were retrieved. Overall survival (OS) and recurrence-free survivals (RFS) were analysed by Kaplan–Meier curve. The independent prognostic factors were determined by using univariate and multivariate Cox analyses.ResultsThere were 41 males and 14 females, with a median age of 51.0 (interquartile range, 44.0–60.0) years. The 1-, 3-, and 5-year OS and RFS rates in cHCC-CC were 80.0%, 25.5%, and 16.4%, respectively, and 52.7%, 21.8%, and 10.9%, respectively. The median OS and RFS were 24.9 and 14.5 months, respectively. Univariate and multivariate analyses revealed that elevated alpha-fetal protein (AFP) and/or CA19-9, vascular invasion, local extra-hepatic invasion, and lymph-node metastasis (LNM) were independent unfavorable prognostic factors for OS and RFS (all P < 0.005). Furthermore, elevated AFP and/or CA19-9 were independent unfavorable prognostic factors in various subgroups of cHCC-CC, including patients aged <60 years, positive hepatitis B surface antigen, cirrhosis, single tumor, tumor size ≥5 cm, no vascular invasion, no LNM, and no local extra-hepatic invasion (all P < 0.05).ConclusionsElevated AFP and/or CA19-9, vascular invasion, local extra-hepatic invasion, and LNM were independent unfavorable prognostic factors for long-term survival of cHCC-CC undergoing curative resections. Patients with normal levels of AFP and CA19-9 had better prognosis.

Effect of surgical delay on survival outcomes in patients undergoing curative resection for primary hepatocellular carcinoma

Background: There is currently conflicting evidence regarding the effect of delays from time of diagnosis to time of surgery on survival outcomes in patients with hepatocellular carcinoma (HCC). We sought to investigate the impact of time-to-surgery (TTS) on overall survival (OS) for patients who underwent curative resection for primary HCC. Conclusions: We performed a retrospective review of all patients who underwent liver resection for HCC between 2000 and 2015. We investigated the TTS on survival outcomes in the overall cohort by iteratively dichotomizing the TTS at each integer value, and computing hazard ratios at each cutoff value using a user-written STATA implementation of a previously-published R package. Optimal windows for surgery were proposed by inspecting and evaluating the time points whereby either upper or lower 95% confidence limit of hazard ratios crossed the line of no difference (ie. HR=1). Results: A total of 863 consecutive patients underwent curative liver resection for primary HCC in our institution during the study period. Median TTS was 27 days (IQR 14-42 days). In the overall patient cohort, TTS was not observed to have a significant bearing on OS. We subsequently proceeded to investigate the extent to which TTS modifies the relative hazard of death by modelling the interactions between TTS and other prognostic factors [Table 1]. For elderly patients (>70 years), patients with Child-Pugh B liver disease, ASA status 2/3, tumour size >5cm, tumour size >10cm, presence of microvascular invasion, extrahepatic invasion and satellite nodules, it was observed that the HR decreased and OS improved as TTS increased. However for patients with liver cirrhosis, multifocal tumours or portal hypertension, an increasing TTS was found to portend higher risks of death. Conclusion: Modest delays in time to surgery appear to be associated with improved survival in certain subsets of patients undergoing surgery for HCC.

Effect of surgical delay on survival outcomes in patients undergoing curative resection for primary hepatocellular carcinoma: Inverse probability of treatment weighting using propensity scores and propensity score adjustment

BackgroundThe evidence is conflicting regarding the effect of delays from the time of diagnosis to surgery on the survival in patients with hepatocellular carcinoma. We sought to investigate the impact of time to surgery on overall survival for patients who underwent curative resection for primary hepatocellular carcinoma. MethodsWe performed a retrospective review of all patients who underwent liver resection for primary hepatocellular carcinoma between the years 2000 and 2015. Using 30-, 60-, and 90-day cutoffs, we investigated the effect of time to surgery on survival outcomes by dichotomizing the patients and using inverse probability of treatment weighting to ensure comparability. We also investigated time to surgery in prognostic subgroups by modeling the statistical interaction between time to surgery and the relevant prognostic variable in multivariable Cox models. ResultsA total of 863 patients underwent liver resection for primary hepatocellular carcinoma during the study period. Using 30-, 60-, and 90-day cutoffs, time to surgery did not have a significant bearing on overall survival. For elderly patients (>70 years), patients with Child-Pugh B liver disease, American Society of Anesthesiologists status 2/3, tumor size >5cm, tumor size ≥10cm and presence of extrahepatic invasion, hazard ratio decreased and overall survival improved as time to surgery increased. However, for patients with liver cirrhosis or portal hypertension, increasing time to surgery was found to portend higher risks of death. ConclusionTime to surgery does not have a significant bearing on overall survival, and modest delays even appear to be associated with improved survival in specific subsets of patients. The importance of these findings is that patients with hepatocellular carcinoma should be fully optimized before and not rushed to surgery because of concerns of tumor progression and a diminished survival.