Portal Invasion Research Articles

Clinical Significance of Biliary Invasion at Diagnosis in Barcelona Clinic Liver Cancer Stage B–C Hepatocellular Carcinoma: A Nationwide Cohort Analysis in South Korea

Introduction: Evidence of biliary invasion as a prognostic factor in patients with hepatocellular carcinoma (HCC) is unclear. We aimed to verify the significance of clinically diagnosed biliary involvement in patients with Barcelona Clinic Liver Cancer stage B–C (BCLC B–C) HCC. Methods: The Korean Liver Cancer Study Group randomly extracted data of patients with HCC enrolled in the Korean Central Cancer Registry between 2011 and 2016 from approximately 50 hospitals nationwide. After excluding records without information regarding serum bilirubin level, alpha-fetoprotein (AFP) level, and Child-Pugh class, a pre-propensity score matching cohort comprising 4,077 patients was included. Considering age, sex, body mass index, viral cause, serum bilirubin level, AFP, Child-Pugh class, tumor size, multiplicity, portal invasion, and extrahepatic metastasis, patients with and without bile duct invasion at initial imaging diagnosis were matched at a ratio of 1:2 from the pre-propensity score matching cohort to form a matched cohort (propensity score matching cohort). Results: The pre-propensity score matching cohort included 4,077 patients with BCLC B–C and 165 (4.0%) with biliary invasion at diagnosis. Regarding biliary invasion at diagnosis, 1- and 2-year overall survival (OS) rates were 41.2% and 29.1% (with invasion) and 54% and 40.9% (without invasion), respectively (p < 0.0001). Corresponding cancer-specific survival (CSS) rates at 1 and 2 years were 43.4% and 30.7% (with invasion) and 56.6% and 44% (without invasion), respectively (p < 0.0001). Although biliary invasion was a significant factor affecting overall and CSS rates in a univariate analysis, it was not statistically significant in multivariate analyses for overall (p = 0.153) and cancer-specific (p = 0.198) survival rates. The propensity score matching cohort included 165 patients with biliary invasion at diagnosis and 330 without biliary invasion. In the propensity score matching cohort, biliary invasion at diagnosis was not a significant factor affecting overall (p = 0.603) or cancer-specific (p = 0.960) survival rates in the univariate analyses. One- and 2-year OS were 41.2% and 29.1% (with invasion) and 36.1% and 28.2% (without invasion), respectively. The corresponding CSS at one and 2 years were 43.4% and 30.7% (with invasion) and 39.8% and 31.4% (without invasion), respectively. Multivariate analyses revealed that AFP levels, Child-Pugh class, tumor singularity, tumor size, portal invasion, lymph node metastases, and distant metastases significantly affected both overall and CSS rates. Conclusion: Biliary invasion at diagnosis in patients with BCLC B–C does not affect overall or CSS rates; however, other prognostic factors associated with biliary invasion could have a greater impact.

Postoperative adjuvant immunotherapy and molecular targeted therapy for patients of hepatocellular carcinoma with portal vein tumor thrombus after hepatectomy: a propensity score matching study.

Portal vein tumor thrombus (PVTT) is a major risk factor of recurrence of hepatocellular carcinoma (HCC) after hepatectomy. Whether postoperative adjuvant immunotherapy and molecular targeted therapy (I-O and MTT) is effective in reducing the risk of recurrence of HCC with minimal portal invasion after hepatectomy and improving prognosis is unknown. We collected the data of HCC with Vp1 or Vp2 PVTT patients who underwent hepatectomy at our center between January 2019 and June 2022 from the hospital database. We utilized propensity score matching (PSM) to establish a 1:1 match between the postoperative group treated with I-O and MTT and the postoperative group without I-O and MTT. To compare the recurrence-free survival (RFS) and overall survival (OS) between the two groups, we employed the Kaplan-Meier method. Additionally, we conducted Cox regression analysis to identify the prognostic factors that influence patient prognosis. To account for different high-risk factors, subgroup analyses were carried out. Among the 189 patients included in the study, 42 patients received postoperative adjuvant I-O and MTT. After PSM, the 1, 2-years RFS were 59.2%, 21.3% respectively in the I-O and MTT group and 40.8%, 9.6% respectively in the non-I-O and MTT group. The median RFS was 13.2 months for the I-O and MTT group better than 7.0 months for the non-I-O and MTT group (P = 0.028). 1, 2-years OS were 89.8%, 65.8% respectively in the I-O and MTT group and 42.4%, 27.7% respectively in the non-I-O and MTT group. The median OS was 23.5 months for the I-O and MTT group better than 17.2 months for the non-I-O and MTT group (P = 0.027). Multivariate analysis showed that postoperative adjuvant I-O and MTT was a prognostic protective factor associated with OS and RFS. The most frequent AE observed in this study was pruritus, and rare AEs included decreased platelet, hypothyroidism, proteinuria, myocarditis and hypoadrenocorticism. The incidence of GRADE ≥3 AE with no deaths recorded. The study suggested that postoperative adjuvant I-O and MTT strategy was beneficial to improve the prognosis of HCC patients with PVTT patients, while the therapy was safe and reliable.

Apatinib and camrelizumab plus Intravenous FOLFOX or hepatic arterial infusion chemotherapy with FOLFOX for advanced HCC: A multicenter, prospective, randomized phase III trial.

TPS4193 Background: The combination of anti-angiogenesis and immune checkpoint blockade showed promising outcomes for advanced hepatocellular carcinoma (HCC). Hepatic artery infusion chemotherapy (HAIC) combined with apatinib and camrelizumab could augment treatment efficacy in preliminary study. But HAIC has disadvantages such as technical limitations, expensive cost, impaired liver function and poor patient comfort. Results from our previous phase II trial (NCT05412589) demonstrate that the triplet treatment of Venous Infusional FOLFOX plus camrelizumab and apatinib showed inspiring antitumor activity and acceptable safety for CNLC stage Ⅲ HCC, especially in those with main portal trunk invasion (Vp4). These results encourage us to further compare the efficacy and safety of intravenous FOLFOX with apatinib and camrelizumab versus HAIC-FOLFOX with apatinib and camrelizumab as first-line treatment in advanced HCC. Methods: This multicenter, randomized, open-label, non-inferiority phase 3 study (NCT06172205) will enroll 192 patients. Essential criteria for patient inclusion encompassed: age between 18 and 75 years; a clinical diagnosis conforms to primary hepatocellular carcinoma (HCC); classification with in BCLC stage C; no prior anti-tumor treatment exposure; presence of at least one measurable tumor as per RECIST v1.1; ECOG performance status score of either 0 or 1; and a Child-Pugh A or B. Eligible patients were randomized (1:1) into two groups. Randomization is stratified by the presence of macrovascular invasion or extrahepatic metastasis (yes vs no), and baseline alpha-fetoprotein concentration (&lt;400 ng/mL vs ≥400 ng/mL). There are 2 arms in the study: (1) Arm A: FOLFOX (oxaliplatin 85 mg/m2, leucovorin 200 mg/m2,5-fluorouracil bolus 400 mg/m2 on day 1, and 5-fluorouracil infusion 2400 mg/m2 for 46 hours; q3w; up to 6 cycles) intravenously in combination with apatinib (250 mg po qd) and camrelizumab (200 mg iv q3w). (2) Arm B: hepatic arterial infusion FOLFOX (oxaliplatin, leucovorin and 5-fluorouracil q3w; up to 6 cycles), combined with apatinib (250 mg po qd) and camrelizumab (200 mg iv q3w). The primary endpoint is 6-month progression-free survival (PFS) rate according to RECIST v1.1. Secondary outcomes encompass the Objective response rate, Disease control rate, Duration of response, PFS, Overall survival (OS), along with 12-month PFS rate, 6-month and 12-month OS rates. The additional secondary endpoints include assessment of treatment-related adverse events. With the assumption of a median 6-month PFS rate of 85% in the Arm B and 71% in the Arm A (noninferiority margin, 14%), a total of 162 patients were required under a two-sided 5% significance level and 80% power. Allowing a dropout rate of 15%, we aimed to enroll 192 patients. The trial is currently screening eligible patients. Clinical trial information: NCT06172205 .

Proton Beam Therapy for Treating Patients with Hepatocellular Carcinoma with Major Portal Vein Tumor Invasion: A Single Center Retrospective Study.

Hepatocellular carcinoma (HCC) with portal vein tumor thrombosis (PVTT) has a poor prognosis and is generally not indicated for surgery. Proton beam therapy (PBT) may offer an alternative treatment. In this study, long-term outcomes were examined in 116 patients (median age 66 years, 100 males) with HCC with advanced PVTT (Vp3 or Vp4) who received PBT from April 2008 to March 2018. Of these patients, 63 received PBT as definitive treatment and 53 as palliative treatment. The representative dose was 72.6 Gy (RBE) in 22 fractions. Eight patients died in follow-up, including 72 due to tumor progression. The 5-year overall survival (OS) rate was 18.0% (95% CI 9.8-26.2%) and the 5-year local control (LC) rate was 86.1% (74.9-97.3%). In multivariate analyses, performance status and treatment strategy were significantly associated with OS. The median follow-up period for survivors with definitive treatment was 33.5 (2-129) months, and the 5-year OS rate was 25.1% (12.9-37.3%) in these cases. The median survival time after definitive irradiation was >20 months. The 5-year OS rate was 9.1% (0-19.7%) for palliative irradiation. These results compare favorably with those of other therapies and suggest that PBT is a useful option for cases of HCC with advanced PVTT that cannot undergo surgery, with an expected survival benefit and good local control. Determining the optimal indication for this treatment is a future challenge.

Beyond histology: A tissue algorithm predictive of post-surgical recurrence in hepatocellular carcinomas, including TERT promoter mutation.

Surgical resection for hepatocellular carcinoma (HCC) is burdened with a high recurrence rate and a lack of reliable prognostic factors. The aim of this study was to integrate the HCC pathological features with gene mutations to improve the prognostic role of pathological analysis.This is a monocentric prospective study, including 67 patients resected for HCC. All clinical data and histological features were collected, including tumor grade, architecture, margins, microvascular invasion, and microscopic portal vascular invasion (MPVI). Next-generation sequencing (NGS) was performed using a laboratory-developed multi-gene panel, allowing to amplify 330 amplicons (21.77kb), covering the relevant targets for solid tumor analysis. The most represented mutations were TERT promoter (n = 41, 61.2%), TP53 (n = 18, 26.9%) and CTNNB1 (n = 17, 25.4%). At follow-up, 13 (19.4%) patients experienced HCC recurrence: at multivariate analysis, tumor dimensions (p = 0.040), MPVI (p = 0.010), and TERT mutation (p = 0.034) correlated with recurrence. Dimensions ≥ 4.5cm (very close to AJCC stage pT3; 9 recurrences, p = 0.041, odd-ratio = 3.7), MPVI (9 recurrences, p = 0.062, OR = 3.3), and TERT (11 recurrences, p = 0.049, OR = 4.4) correlated with disease-free survival also at univariate analysis. The concomitant occurrence of these three variables was present in 7 cases, among which 5 recurred (p = 0.002, OR = 15.94).In conclusion, NGS analysis in resected HCC could not only be used for future therapies but should be integrated with histopathology to predict the risk of tumor recurrence after surgical resection: TERT mutation is among the strongest predictors of tumor recurrence, together with tumor stage (dimensions) and the occurrence of MPVI, which should always be reported separately from the classic MVI.

Undifferentiated sarcomatoid carcinoma of the pancreas-a single-institution experience with 23 cases

BackgroundThe clinical course and surgical outcomes of undifferentiated sarcomatoid carcinoma of the pancreas (USCP) remain poorly characterized owing to its rarity. This study aimed to describe the histology, clinicopathologic features, perioperative outcomes, and overall survival (OS) of 23 resected USCP patients.MethodsWe retrospectively described the histology, clinicopathologic features, perioperative outcomes and OS of patients who underwent pancreatectomy with a final diagnosis of USCP in a single institution.ResultsA total of 23 patients were included in this study. Twelve patients were male, the median age at diagnosis was 61.5 ± 13.0 years (range: 35–89). Patients with USCP had no specific symptoms and characteristic imaging findings. The R0 resection was achieved in 21 cases. The En bloc resection and reconstruction of mesenteric–portal axis was undertaken in 9 patients. There were no deaths attributed to perioperative complications in this study. The intraoperative tumor-draining lymph nodes (TDLNs) dissection was undergone in 14 patients. The 1-, 3- and 5-year survival rates were 43.5%, 4.8% and 4.8% in the whole study, the median survival was 9.0 months. Only 1 patient had survived more than 5 years and was still alive at last follow-up. The presence of distant metastasis (p = 0.004) and the presence of pathologically confirmed mesenteric–portal axis invasion (p = 0.007) was independently associated with poor OS.ConclusionsUSCP was a rare subgroup of pancreatic malignancies with a bleak prognosis. To make a diagnose of USCP by imaging was quite difficult because of the absence of specific manifestations. Accurate diagnosis depended on pathological biopsy, and the IHC profile of USCP was mainly characterized by co-expression of epithelial and mesenchymal markers. A large proportion of patients have an early demise, especially for patients with distant metastasis and pathologically confirmed mesenteric–portal axis invasion. Long-term survival after radical resection of USCPs remains rare.

MiR-199a/b-3p inhibits HCC cell proliferation and invasion through a novel compensatory signaling pathway DJ-1\\Ras\\PI3K/AKT

Several studies have reported the effects of DJ-1 gene and miR-199a/b-3p on HCC development. However, whether miR-199a/b-3p regulates HCC progression through a novel compensatory signaling pathway involving DJ-1, Ras, and PI3K/AKT remains unknown. We used (TCGA, HPA, miRWalk and Target scan) databases, cancer and para-tissue HCC patients, dual-luciferase reporter gene analysis, proteomic imprinting, qPCR, cell proliferation, scratch, transport, and flow cytometry to detect the molecular mechanism of DJ-1 and miR-199a/b-3p co-expression in HCC cell lines. Bioinformatics analysis showed that DJ-1 was highly expressed in HCC ((P < 0.001) were closely associated with tumor stage (T), portal vein vascular invasion, OS, DSS, and PFI (P < 0.05); miR-199a/b-3p was lowly expressed in HCC (P < 0.001), which was the upstream regulator of DJ-1. Spearman coefficient r = −0.113, P = 0.031; Dual luciferase gene report verified the negative targeting relationship between them P< 0.001; Western blotting demonstrated that miR-199a/b-3p could inhibit the protein expression of DJ-1, Ras and AKT(P < 0.05); The results of CCK8, cell scratch, Transwell migration and flow cytometry showed that OE + DJ-1 increased the proliferation, migration and invasion ability of HepG2 cells, and decreased the apoptosis process, and the differences were statistically significant (P < 0.05), while miR-199a/b-3p had the opposite effect (P < 0.05).

Serum AKR1B10 as an indicator of unfavorable survival of hepatocellular carcinoma.

A large-scale multicenter study validated aldo-keto reductase 1B10 (AKR1B10) as a new serum marker of hepatocellular carcinoma (HCC). This study aimed to evaluate the prognostic value of serum AKR1B10 in HCC. 273 naïve HCC patients enrolled for serum AKR1B10 tests were followed up for 2years. Survival and clinical data were collected. Kaplan-Meier survival analysis and log-rank tests were used to estimate correlation of patient survival with serum AKR1B10. Univariate and multivariate COX regression analyses were used to evaluate the prognostic value of serum AKR1B10 level independently or in combination with other clinicopathological factors. α-fetoprotein (AFP) was analyzed in parallel for comparison. Serum AKR1B10 associated with tumor stage (p = 0.012), size (p = 0.004), primary tumor number (p = 0.019), and Child-Pugh classification (p = 0.003). HCC patients with a high level of serum AKR1B10 (≥ 267.9pg/ml) had median survival (MS) of 25months (95% confidence interval [CI] 20.788-29.212) vs. MS of 34months (CI 28.911-39.089) in patients with normal serum AKR1B10 (p < 0.001). Univariate and multivariate COX regression analyses showed that serum AKR1B10 level was an unfavorable prognostic marker of HCC independently (HR 1.830, 95% CI 1.312-2.552; p < 0.001) or in combination with other clinical factors (HR 1.883, 95% CI 1.264-2.806; p = 0.002), such as TNM stage, tumor size and portal invasion. In the same cohort of HCC patients, AFP exhibited prognostic value at a cut-off of 400ng/ml, but not at 20ng/ml and 200ng/ml. Serum AKR1B10 is a new prognostic marker of HCC, better than AFP.

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.

Efficacy and safety of first-line treatments for patients with advanced hepatocellular carcinoma: A systematic review and network meta-analysis.

4094 Background: In recent years, the first-line treatment options for advanced HCC has been increasingly abundant, including transarterial therapies, combination of the immune checkpoint inhibitors (ICIs) and the anti-vascular endothelial growth factor (VEGF) inhibitor, ICIs combined with ICIs, and tyrosine kinase inhibitors. However, it remains to be confusing which treatment pattern would benefit people most, especially for different subgroups. Methods: A systematic literature search was conducted on PubMed, Embase, Cochrane Central Register of Controlled Trials, and American Society of Clinical Oncology and European Society of Medical Oncology meeting proceedings for III phase randomized clinical trials (RCTs) investigating first-line treatments for HCC compared with sorafenib. The survival outcomes and toxic effects of RCTs should be reported, including overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and adverse events (AEs) of grade 3 or higher. This systematic review was performed in line with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Guidelines. The random-effects model was used to calculate the summary hazard ratios (HRs) of OS and PFS. The likelihood of ORR, and AEs of grade 3 or higher was performed by odds ratios (ORs) using a random-effects model. Results: A total of 13 phase III RCTs involving 8505 patients were included in this study. Hepatic arterial infusion of oxaliplatin combined with fluorouracil (FOHAIC-1) showed OS, PFS, and ORR benefit over all other first-line therapies, except for the regimen of sorafenib plus HAIC of FOLFOX (OS: HR, 0.88; 95% CI, 0.37-2.09; ORR: OR, 1.53; 95% CI, 0.29-8.13). More importantly, we found that sorafenib combined with FOLFOX was superior to other regimens in patients with HBV infection regarding OS except FOHAIC-1 (HR, 0.57; 95%CI, 0.21-1.52) and tremelimumab-durvalumab (HR, 0.42; 95%CI, 0.16-1.11). While in HCV-infected subgroup, ICIs combined with anti-VEGF inhibitor improved OS benefit compared with tremelimumab-durvalumab (HR, 0.31; 95% CI, 0.11-0.84) and sorafenib (HR, 0.38; 95% CI, 0.16-0.88). HAIC-FO also showed significant OS benefits to other therapies in patients with portal invasion or extrahepatic metastasis. The probability of adverse events of grade 3 or higher was significantly lower with HAIC-FO than with others except for nivolumab (RR, 0.96; 95%CI, 0.51-1.82) and tislelizumab (RR, 0.57; 95%CI, 0.30-1.08). Conclusions: This network meta-analysis supports arterial infusion as the first-line treatment for patients with HCC. In portal invasion and extrahepatic metastasis subgroups, HAIC-FO may be a preferred option, with sorafenib combined with FOLFOX as an additional option in those with HBV infection. Besides, novel combination therapy should be focused on in patients with certain subgroups.

Venous infusion chemotherapy (VIC) combined with apatinib and camrelizumab for hepatocellular carcinoma (HCC) in CNLC stage III: A prospective, single-arm, phase II trial.

e16166 Background: The combination of anti-angiogenesis and immune checkpoint blockade showed promising outcomes for advanced HCC. Hepatic artery infusion chemotherapy (HAIC) combined with apatinib and camrelizumab could augment treatment efficacy in preliminary study. But HAIC had disadvantages such as technical limitations, expensive cost and poor patient comfort. In the present study, we aimed to investigate the efficacy and safety profile of VIC with apatinib and camrelizumab for CNLC stage Ⅲ HCC. Methods: This single-arm, phase II study enrolled treatment-naive adult (18 years) patients(pts) with CNLC stage Ⅲ and Child-Pugh score small or equal to 7 points (NCT05412589). Eligible pts received VIC (oxaliplatin 85 mg/ m2, leucovorin 200 mg/m2, 5-fluorouracil bolus 400 mg/m2 on day 1, and 5-fluorouracil infusion 2400 mg/m2 for 46 hours; q3w; 6 cycles), combined with apatinib (250 mg qd) and camrelizumab (200 mg q3w). The primary endpoint was objective response rate (ORR) per RECIST 1.1. Following an optimal Simon 2-stage design, 15 eligible pts needed to be included in the 1st stage, of whom at least 9 pts had to achieve objective responses to warrant further investigation in the second stage. Secondary endpoints were progression-free survival (PFS) rate at 6 months, PFS, overall survival (OS) per RECIST v1.1 or mRECIST, and safety. Results: At the data cut-off date (Jan. 31,2023), 17 pts were enrolled from Apr. 25, 2021, to Oct. 30, 2022 (1 woman and 16 men; median age, 48 years; 16 had HBV infection). The median tumor size was 87 mm. 11 (64.7%) pts had more than 3 tumors. 8 (47%) pts had main portal trunk invasion (Vp4). 7 (41.2%) pts had distant metastasis. The median follow-up was 8.17 months and all pts had at least one post-baseline tumor assessment. The confirmed ORR was 58.8% with 10 partial responses (PR) per RECIST v1.1, which met the threshold for expanding enrollment, while 70.6% per mRECIST. Among them, 11 (64.7%) pts received operation successfully and 5 (29.4%) pts reached pathological complete response (pCR). Notably, four pCR pts had Vp4 before the trial. The disease control rate was 94.11% whether per RECIST v1.1 or mRECIST. The median time to response was 2.27 months (interquartile range (IQR), 1.29-2.56) per RECIST v1.1 or 1.57 months (IQR, 1.17-2.32) per mRECIST. The estimated 6-month PFS rate was 76.4% per RECIST v1.1. The 6-month OS rate were 100%. Grade 3-4 treatment-related adverse events (AEs) occurred in 56.2% of pts, of which the most common were decreased neutrophils (38.5%), diarrhea (23.9%), thrombocytopenia (25.9%), and hypertension (11.1%). All AEs were expected and manageable, and no treatment-related deaths were reported. Conclusions: The triplet treatment of VIC plus camrelizumab and apatinib showed promising antitumor activity and acceptable safety for CNLC stage Ⅲ HCC, especially in those with main portal trunk invasion. Clinical trial information: NCT05412589 .

Population Sensitive to Lenvatinib Plus Anti-PD-1 for Unresectable Hepatocellular Carcinoma Infected with Hepatitis B Virus.

We explore the dose-efficacy relationship of lenvatinib plus anti-PD-1 in patients with unresectable hepatocellular carcinoma (u-HCC) infected with hepatitis B virus (HBV) in real-world practice. Furthermore, we identify the population sensitive to lenvatinib plus anti-PD-1 treatments. This retrospective study included 70 patients treated with lenvatinib plus at least 3 cycles of anti-PD-1 and 140 with lenvatinib alone. Stabilized inverse probability of treatment weighting (SIPTW) was used to balance clinical features between the two groups. The overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and adverse events (AEs) were analyzed. Subpopulation treatment effect pattern plot (STEPP) estimated treatment-effect differences between the two groups. The median age was 54 years, and 189 (90%) cases were male. A total of 180 (85%) patients were infected with HBV. A slowly increasing 12-month survival rate was with the cycles of anti-PD-1, and 5 cycles and more of anti-PD-1 appeared the most beneficial and stable survival rate. The lenvatinib plus at least 3 cycles anti-PD-1 group had better OS (21.4 vs 14 months, p = 0.041), PFS (8.0 vs 6.3 months, p = 0.015) than the lenvatinib alone group in unadjusted cohorts, and the SIPTW adjusted cohorts had confirmed it. For patients with portal vein trunk invasion (PVTI) or extrahepatic spread (EHS) combined with Child-Pugh class B (CPB), lenvatinib plus anti-PD-1 made the 12-month survival rate increase by 38%, while, in the other population, it did only 18%. The two groups had similar AEs (p ≥ 0.05). The lenvatinib combined with at least 3 cycles of anti-PD-1 was efficacy and safe for u-HCC patients infected with HBV. Especially, patients with PVTI or EHS combined with CPB may benefit most from the combination therapy.

Bile detection of squamous cell carcinoma antigen (SCCA) in extrahepatic cholangiocarcinoma.

Cholangiocarcinoma (CCA) is a rare biliary tract tumor with poor prognosis that often is challenging to diagnose and the majority of patients present with advanced stage. Squamous cell carcinoma antigen 1 (SCCA1) overexpression has been found in different tumors associated with poor prognosis and chemoresistance. To assess the presence and possible prognostic role of SCCA1/2 isoforms in bile and serum of patients with CCA. Forty seven surgical patients (36 with CCA and 11 with benign diseases) were prospectively included in the study. Serum and bile specimens were collected at the time of surgery and free and IgM-complexed SCCA was quantified by ELISA (Xeptagen, srl). Free or IgM linked SCCA was rarely found in serum, while SCCA was detectable in bile samples of patients with CCA, especially in those with extrahepatic form (43% vs 17%, p=0.008), but not in controls. Despite similar tumor stage, these positive patients presented a trend toward a higher percentage of portal invasion (27% vs 15%) and of tumor recurrence than negative cases (62% vs 40%), although the difference was not statistically significant. These preliminary results indicate that bile testing for SCCA is a specific marker of extrahepatic CCA, with potential prognostic value.

A Comprehensive Overview of In-patients Treated for Hepatocellular Carcinoma at a Tertiary Care Facility in Tanzania

Hepatocellular carcinoma (HCC) is one of the commonest causes of cancer-related morbidity and mortality worldwide. However, only a limited number of studies on HCC have been conducted in Tanzania. We therefore conducted a cross-sectional study among in-patients treated for HCC in a tertiary referral hospital located in Dar es Salaam, Tanzania, in order to provide a concise description of the clinical characteristics and treatment options offered in the study setting. We identified 36 in-patients treated for HCC over a 6-month data collection period. Seventy-seven percent (n = 28) of the participants were males and about two-thirds (61.2%) were aged between 40 and 60 years. Majority (44.4% [n = 16]) of the patients had Child-Pugh class B and an Eastern Cooperative Oncology Group (ECOG) performance status of 2 (33.3% [n = 12]). Patients with tumors &gt;6.5 cm and multinodular tumors (&gt;3 nodules) accounted for 69.4% (n = 25) and 55.6% (n = 20), respectively. Portal vascular invasion and extrahepatic metastasis were respectively present in 27.8% (n = 10) and 25% (n = 9) of the patients. Of the study participants, only two had early-stage disease as per the Barcelona Clinic Liver Cancer (BCLC) staging system, corresponding to the observed tumor resection rate of 5.6%. The most frequently reported inoperable factor among the study participants was an ECOG performance status &gt; 0 (n = 30 [83.3%]). Findings thus reveal a high proportion of late-stage diseases among participants that could have resulted in the observed low tumor resection rate. Initiatives to facilitate identification of the disease at an early stage are therefore paramount in optimizing care.

Abstract No. 268 Modified Radiation Lobectomy as Bridge to Liver Resection: A Single-Center Experience

To investigate outcomes of patients who received modified radiation lobectomy for hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). Institutional review board approved this retrospective study of patients who underwent modified radiation lobectomy with yttrium-90 (90Y) glass microspheres for HCC or ICC with intent to grow the future liver remanent (FLR) between 2019-2022. Outcome measures included tumor response according to modified Response Evaluation Criteria in Solid Tumors (mRECIST), FLR kinetics, tumor progression, and surgical resection or liver transplantation. Adverse events were assessed according to the Society of Interventional Radiology classification. Descriptive statistics were used to assess data. Fifteen patients (7 women, 8 men; mean age 66 ± 11 years) with HCC (n = 7) and ICC (n = 8) underwent modified radiation lobectomy of left (n = 1) or right (n = 14) sided tumors. Mean index tumor size was 7.8 ± 3.7 cm (range, 2.4-16.2). HCC patients were intermediate stage BCLC B (n = 6), or advanced stage BCLC C (n = 1) due to portal vein tumor invasion. Six patients had cirrhosis. Neoadjuvant chemotherapy was concurrently given to 4/8 (50%) of the ICC patients. The average lobar dose was 198 ± 58 Gy and the average segmental boost dose was 186 ± 81 Gy, with an average of 1.6 segmental doses per patient. No severe adverse event from 90Y treatment occurred. Mean bilirubin was unchanged at 30-days. All patients had objective response at 30 days, including 6/15 (40%) with complete response and 9/15 (60%) with partial response. FLR increased by an average of 16.8% ± 14.6% at 30 days (n = 15), and 42.1% ± 22.8% at 90 days (n = 9). A total of 12/15 (80%) were eligible for surgical resection after treatment. One patient refused surgery and another developed concurrent breast cancer, thus 10/15 (67%) went on to hepatectomy (n = 9) or transplant (n = 1) with negative margins at a mean 122 ± 77 days post-treatment. Surgical resection included right (n = 4), extended right (n = 4), or extended left (n = 1) hepatectomies. The remaining 3 patients were ineligible for resection due to new disease progression in the contralateral liver lobe (n = 2) or to lungs (n = 1) at 1-, 2- and 3-months post-treatment. This study demonstrates that modified radiation lobectomy is safe and effective for treatment of HCC and ICC, with a high number of patients going on to definitive surgical management. This is an effective method to attain liver remnant hypertrophy while maintaining control over tumor progression.

Two cases of hepatocellular carcinoma successfully treated by carbon ion radiotherapy after atezolizumab plus bevacizumab treatment.

We herein report two cases of huge hepatocellular carcinoma (HCC) that were successfully treated by carbon ion radiotherapy after atezolizumab plus bevacizumab treatment. Case 1, an 84-year-old man, was diagnosed with HCC (maximum diameter: 11cm) with portal invasion and presented HCC rupture. After obtaining hemostasis with transcatheter embolization, three cycles of atezolizumab-bevacizumab therapy were administered, and marked shrinkage of the HCC was confirmed. However, he developed jaundice, liver damage and cerebral subcortical hemorrhage. Thus, atezolizumab-bevacizumab therapy was discontinued. Total bilirubin, transaminase levels, and physical activity improved well with prednisolone, an antihypertensive agent, and rehabilitation. Thus, treatment with carbon ion radiotherapy (CIRT) was added, and the treatment effect at 4months after CIRT was judged as a complete response (CR) according to the modified response evaluation criteria in solid tumors (mRECIST). Case 2, a 68-year-old man, was diagnosed with HCC (maximum diameter: 14cm). Hepatic resection was difficult because the residual liver volume after treatment would be insufficient. Five cycles of atezolizumab-bevacizumab therapy were performed, and marked shrinkage of the HCC to a maximum diameter of 9cm was confirmed. The treatment was converted to CIRT, and atezolizumab-bevacizumab therapy resumed one month after CIRT. The treatment effect at 3months after CIRT was judged as CR according to mRECIST. Although conversion therapy after atezolizumab-bevacizumab therapy, including surgery and radiofrequency ablation, have been reported, CIRT may be a promising new tool for conversion therapy for HCC.

PNI-Based Nomograms to Predict Tumor Progression and Survival for Patients with Unresectable Hepatocellular Carcinoma Undergoing Transcatheter Arterial Chemoembolization.

The relationship between the prognostic nutritional index (PNI) and the prognosis of malignancy has been increasingly mentioned in recent research. This study aimed to construct nomograms based on the PNI to predict tumor progression and survival in patients with unresectable hepatocellular carcinoma (HCC) undergoing transcatheter arterial chemoembolization (TACE). The development set included 785 patients who underwent their first TACE between 2012 and 2016, and the validation set included 336 patients who underwent their first TACE between 2017 and 2018. The clinical outcomes included the time to progression (TTP) and overall survival (OS). Cox regression was applied to screen for independent risk factors of TTP and OS in the development set, and PNI-based nomograms were constructed for TTP and OS. The predictive performance of nomograms was conducted through the C-index, calibration curves, and decision analysis curves in the development set and validation set. After multivariate analysis, the prognostic predictors of both TTP and OS included portal vessel invasion, extrahepatic metastasis, tumor number, alpha-fetoprotein (AFP) level, longest tumor diameter, and PNI. Furthermore, the Child-Pugh classification and platelets (PLTs) were independent risk factors for OS only. Nomograms for predicting TTP and OS were constructed using TTP and OS prognostic factors. In the development set and the validation set, the C-index of the TTP nomograms was 0.699 (95% confidence interval (CI): 0.680-0.718) and 0.670 (95%CI: 0.638-0.702), and the C-index of the OS nomograms was 0.730 (95%CI: 0.712-0.748) and 0.700 (95%CI: 0.665-0.723), respectively. Nomograms based on the PNI can effectively predict tumor progression and survival in patients with unresectable HCC undergoing TACE.

Liver resection for hepatocellular carcinoma beyond the BCLC: are multinodular disease, portal hypertension, and portal system invasion real contraindications?

Barcelona Clinic Liver Cancer (BCLC) is a recognized guideline to standardize treatment allocation for hepatocellular carcinoma (HCC); however, many centers criticize its restrictive liver resection recommendations and have published good results after more liberal hepatectomy indications. The objective is to evaluate the results of HCC resection in a single center, with a more liberal indication for resection than proposed by the BCLC guideline. It was performed a retrospective cohort study including all patients who underwent liver resection for HCC in a single center between April 2008 and November 2018. The results of 150 patients who underwent hepatectomy were evaluated and compared facing both 2010 and 2018 BCLC guidelines. Overall and disease-free survival after resection in patients with none, one, two, or three of the risk factors, as proposed by the BCLC, as contraindications to resection (portal hypertension, portal invasion, and more than one nodule) were analyzed. Nodule size and presence of portal invasion alone did not affect prognosis. If the BCLC 2010 and 2018 guidelines were followed, 46.7% and 26.7% of the patients, respectively, would not have received potentially curative treatment. The median overall and disease-free survival for patients with one BCLC contraindication factor were 43.3 and 15.1 months, respectively. The presence of two risk factors had a negative impact on overall survival (OS) and disease-free survival (DFS), although some patients had long-term survival. The only patient with the three risk factors had a poor outcome. Selected patients with one BCLC contraindication factor may undergo resection with good results, whereas those with two factors should be allocated for hepatectomy only in favorable scenarios. Patients with the three risk factors do not appear to benefit from resection.

Prognostic significance of intrahepatic lymphatic invasion in colorectal liver metastases

BackgroundIntrahepatic lymphatic invasion is an adverse prognostic factor after hepatectomy for colorectal liver metastases (CLMs). However, most patients in previous reports had liver resection before the era of FOLFOX/FIRI-based chemotherapy. MethodsForty-six patients who underwent hepatectomy for CLMs from 2004 to 2020 were evaluated. We histologically evaluated portal invasion, intrahepatic lymphatic invasion, and biliary invasion on hematoxylin-eosin slides. We also collected the following clinicopathologic factors: gender, age, timing, the number and maximum size of CLMs, preoperative tumor markers, neutrophil/lymphocyte ratio, location, and lymph node metastases of primary cancer, and chemotherapy after hepatectomy. A multivariate Cox proportional hazard model was used to define the relationship between overall (OS) or disease-free survival (DFS) and clinicopathologic factors. ResultsHistological invasions were portal invasion in 8 (17.4 %), intrahepatic lymphatic invasion in 6 (13.0 %), and biliary invasion in 5 (10.9 %). Chemotherapy for recurrence after hepatectomy (n = 29) was performed in 22 and 14 of those who received FOLFOX/FIRI-based chemotherapy. By multivariate analysis, the number of CLMs (p < 0. 01) and presence of intrahepatic lymphatic invasion (p = 0.02) were independent predictors of recurrence. The number of CLMs (p = 0.02) and prehepatectomy carcinoembryonic antigen level (p = 0.02), but not intrahepatic lymphatic invasion (p = 0.18), were independent predictors of survival using multivariate analysis. ConclusionsThe presence of intrahepatic lymphatic invasion adversely affected patient's DFS, but not OS in patients with CLMs in the era of FOLFOX/FIRI chemotherapy. FOLFOX/FIRI-based chemotherapy might improve OS, even in patients with positive intrahepatic lymphatic invasion.

Comparison of Arterial Infusion Chemotherapy and Chemoembolization for Locally Advanced Hepatocellular Carcinoma: a Multicenter Retrospective Study

BackgroundUnresectable hepatocellular carcinoma (HCC) has a poor prognosis. We aimed to evaluate the efficacy and safety of hepatic arterial infusion chemotherapy (HAIC) for locally advanced HCC compared to transcatheter arterial chemoembolization (TACE). MethodsA propensity score–matched cohort study was performed in patients with locally advanced HCC with ≥ 4 tumors or portal vein tumor thrombosis (PVTT) who underwent either HAIC using oxaliplatin plus raltitrexed or TACE at three institutions between June 2015 and December 2021. Overall survival (OS), progression-free survival (PFS), objective response rates (ORR), and adverse events (AEs) were compared between the groups. ResultsAfter propensity score matching, 62 pairs of patients were evaluated. The HAIC group had longer OS (15.0 [95% CI: 12.1–17.9] vs. 9.0 [95% CI: 5.1–12.9] months; P = 0.034), better PFS (6.7 [95% CI: 5.1–8.3] vs. 4.0 [95% CI: 2.6–5.4] months; P = 0.020), and a higher ORR (RECIST 1.1: 54.8% vs. 11.3%; P < 0.001) than the TACE group in the intention-to-treat population. Compared with the TACE group, Grade 1–2 nausea and vomiting occurred significantly more frequently in the HAIC group. ConclusionCompared to TACE, HAIC significantly increased the ORR of locally advanced HCC with multiple tumors or portal invasion and prolonged survival without causing a significant increase in severe AEs.