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Hepatocellular carcinoma (HCC) is often diagnosed at an unresectable stage without opportunities for curative therapy. Future liver remnant (FLR) insufficiency limits the range of patients who can undergo radical resection. Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) can ultimately achieve short-term hypertrophy of the FLR in patients with viral hepatitis-related fibrosis/cirrhosis and R0 resection. However, the influence of immune checkpoint inhibitors (ICIs) on liver regeneration remains unknown. We report two patients diagnosed with Barcelona Clinic Liver Cancer (BCLC)-B stage hepatitis B virus (HBV)-related HCC who underwent pioneering ALPPS after immunotherapy without posthepatectomy liver failure (PHLF). ALPPS has been shown to be safe and feasible in patients with HCC who underwent immunotherapy previously for the first time and might provide an alternative salvage option for future conversion therapy of HCC.

BackgroundToripalimab shows antitumor efficacy in cholangiocarcinoma. Radiotherapy (RT) may enhance systemic responses of PD-1 inhibitors and lenvatinib. This study was designed to assess the safety and feasibility of toripalimab plus lenvatinib with or without RT in advanced BTC.MethodsThis study involved 88 patients with advanced BTC receiving toripalimab plus lenvatinib with or without RT from the clinical trials (NCT03892577). Propensity score matching (PSM) (1:1) analysis was used to balance potential bias. The overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and adverse events (AEs) were evaluated.ResultsAfter PSM, the final analysis included 40 patients: 20 receiving toripalimab plus lenvatinib without RT (NRT); 20 receiving toripalimab plus lenvatinib with RT. The AEs were more frequent in the RT group than in the NRT group without treatment-associated mortality. The addition of RT did not cause specific AEs. The median PFS was significantly longer with RT (10.8 versus 4.6 months, p

BackgroundLenvatinib combined with anti-PD-1 antibodies and systemic chemotherapy has demonstrated a relatively high antitumor activity for intrahepatic cholangiocarcinoma in phase 2 clinical trials. However, its efficacy and safety in advanced biliary tract cancer (BTC) has not been reported in a real-world study.MethodsPatients with advanced BTC who received lenvatinib combined with PD-1/PD-L1 inhibitors plus oxaliplatin and gemcitabine (Gemox) chemotherapy were retrospectively screened. The overall survival, progression-free survival, objective response rate, disease control rate, clinical benefit rate, and safety were evaluated.ResultsFifty-seven patients with advanced BTC were included in the study. The median follow-up time was 15.1 (95% CI: 13.6–19.7) months. The median overall survival and progression-free survival were 13.4 (95% CI: 10.0–NA), and 9.27 (95% CI: 7.1–11.6) months, respectively. The objective response rate, disease control rate and clinical benefit rate were 43.9% (95% CI: 31.8%–56.7%), 91.2% (95% CI: 81.1%–96.2%), and 73.7% (95% CI: 61.0%–83.4%), respectively. Subgroup analysis revealed that the first-line treatment group had a longer median progression-free survival (12.13 vs. 6.77 months, P

BackgroundLenvatinib is a standard first-line systemic therapy in advanced hepatocellular carcinoma (aHCC) and is widely used in all lines. However, the efficacy and safety of immune checkpoint inhibitors (ICIs) plus molecular targeted agents (MTAs) after the progression of lenvatinib treatment are unclear.ObjectiveThe aim of this study was to evaluate the anticancer effects of ICI plus MTA in patients with aHCC who progressed after lenvatinib.MethodsWe retrospectively included aHCC patients treated with ICI plus MTA after the progression of lenvatinib from two medical centers. Participants who continued lenvatinib treatment were classified into the “ICI+Lenva” group, while the “ICI+Others” group included patients receiving other MTAs. The efficacy endpoints were progression-free survival (PFS), post-progression survival (PPS), overall survival (OS), and tumor response following RECIST v1.1. Safety was evaluated according to Common Terminology Criteria for Adverse Events v5.0.ResultsIn this study, 85 eligible aHCC patients were enrolled, including 58 in the ICI+Lenva group and 27 in the ICI+Others group. At a median follow-up time of 22.8 months, the median PPS and PFS were 14.0 (95% CI: 9.0-18.2) and 4.5 months (95% CI: 3.5-8.3), respectively. The objective response and disease control rates were 10.6% and 52.9%, respectively. No significant differences were observed in any of the efficacy endpoints between the two groups. Prolonged PPS was associated with Child–Pugh grade A, AFP < 400 IU/ml, and concomitant locoregional treatment. All patients experienced adverse events (AEs), but no fatal AEs were observed.ConclusionICI plus MTA in aHCC patients after the progression of lenvatinib presented high antitumor activity and safety. Patients could continue lenvatinib treatment and receive ICIs as well as locoregional treatment to achieve better OS.

The tumor immune microenvironment significantly affects tumor progression, metastasis, and clinical therapy. Its basic cell components include tumor-associated endothelial cells, fibroblasts, and macrophages, all of which constitute the tumor stroma and microvascular network. However, the functions of tumor stromal cells have not yet been fully elucidated. The three-dimensional (3D) model created by 3D bioprinting is an efficient way to illustrate cellular interactions in vitro. However, 3D bioprinted model has not been used to explore the effects of stromal cells on cholangiocarcinoma cells. In this study, we fabricated 3D bioprinted models with tumor cells and stromal cells. Compared with cells cultured in two-dimensional (2D) environment, cells in 3D bioprinted models exhibited better proliferation, higher expression of tumor-related genes, and drug resistance. The existence of stromal cells promoted tumor cell activity in 3D models. Our study shows that 3D bioprinting of an immune microenvironment is an effective way to study the effects of stromal cells on cholangiocarcinoma cells.

BackgroundHepatocellular carcinoma (HCC) has a high risk of recurrence after surgical resection, particularly among patients with multifocal HCC. Genomic heterogeneity contributes to the early recurrence. Few studies focus on targeted next-generation sequencing (tNGS) to depict mutational footprints of heterogeneous multifocal HCC.MethodsWe conducted tNGS with an ultra-deep depth on 31 spatially distinct regions from 11 resected multifocal HCC samples. Matched preoperative peripheral circulating-free DNA (cfDNA) were simultaneously collected. Genomic alterations were identified and compared to depict the heterogeneity of multifocal HCC.ResultsWidespread intertumoral heterogeneity of driver mutations was observed in different subfoci of multifocal HCC. The identified somatic mutations were defined as truncal drivers or branchy drivers according to the phylogenetic reconstruction. TP53 and TERT were the most commonly altered truncal drivers in multifocal HCC, while the most frequently mutated branchy driver was TSC2. HCC patients with a higher level of intertumoral heterogeneity, defined by the ratio of truncal drivers less than 50%, had a shorter RFS after surgical resection (HR=0.17, p=0.028). Genome profiling of cfDNA could effectively capture tumor-derived driver mutations, suggesting cfDNA was a non-invasive strategy to gain insights of genomic alterations in patients with resected multifocal HCC.ConclusionsTruncal mutations and the level of genomic heterogeneity could be identified by tNGS panel in patients with resected multifocal HCC. cfDNA could serve as a non-invasive and real-time auxiliary method to decipher the intertumoral heterogeneity and identify oncodrivers of multifocal HCC.