Long-Bin Jeng

BACKGROUND Immune checkpoint inhibitors (ICIs) are widely used as first-line combination therapies for many cancers. However, ICIs are associated with an increased risk of graft rejection in patients requiring liver transplants, and the tumor response rate has yet to be determined. MATERIAL AND METHODS This retrospective study included liver transplant recipients who received ICIs for recurrent hepatocellular carcinoma. During ICI therapy, baseline immunosuppressant doses were maintained, with low-dose steroid treatments added when clinically indicated. RESULTS A total of 25 patients were included, with 12 receiving ICIs as first-line therapy, and 13 as second-line therapy. The median progression-free survival (PFS) was 4.93 months (95% CI, 2.33-28.63) and 7.20 months (3.80-32.47), respectively. One patient (4.0%) developed grade 2 hepatitis, and 2 (8%) experienced grade 3 gastrointestinal bleeding. Concurrent steroid use was associated with fewer immune-related adverse events (0% vs 30%, P=0.052) but showed a trend toward shorter PFS (HR=2.30, P=0.071). Two patients (8%) achieved complete remission, and 4 (16%) maintained disease control for more than 1 year. In multivariable analysis, recurrence within 1 year after transplantation was the only significant prognostic factor for PFS (HR=2.98, P=0.043). CONCLUSIONS Our findings suggest that ICIs can be administered after liver transplantation without reducing baseline immunosuppressant doses, potentially minimizing the risk of fatal allograft rejection while still allowing antitumor activity. These results should be interpreted cautiously, and larger studies are needed to define the safe and appropriate use of ICIs in this population.

Early allograft failure (EAF) after living donor liver transplantation (LDLT) remains a clinical challenge. Existing prediction models developed for deceased donor transplantation poorly apply to LDLT due to distinct surgical and physiological factors. This study identifies clinical determinants of EAF and develops an LDLT-specific prediction model. We conducted a multicenter retrospective cohort study from 17 high-volume LDLT centers (January 2016–December 2020) with external validation at a tertiary center in Saudi Arabia (January 2015–December 2022). The primary outcome was EAF (graft loss or patient death ≤90 d). Multivariable mixed-effects logistic regression identified preoperative/intraoperative risk factors. The EAGLE-LDLT model was constructed using postoperative laboratory values. Performance was compared against established models (EAD, MEAF, A2ALL) using ROC analysis and decision curve analysis. The development cohort included 2944 adult LDLT recipients (67.7% male; median age 55 y; median MELD 14) with a 5.5% EAF rate. External validation included 1020 recipients (median MELD 21, 6.7% EAF). Independent risk factors for EAF were MELD (OR 1.06, 95% CI 1.04–1.08), donor BMI (OR 1.05, 95% CI 1.00–1.10), portal vein thrombosis (OR 1.73, 95% CI 1.13–2.63), and hepaticojejunostomy (OR 1.58, 95% CI 1.06–2.36). The EAGLE-LDLT model incorporating peak ALT (>468 U/L), peak INR (>1.9), and bilirubin (>3.5 mg/dL) and INR (>1.3) at POD7, demonstrated superior discrimination (AUC=0.81) compared with MEAF (AUC=0.77, p =0.004), EAD (AUC=0.67, p p <0.001). EAGLE-LDLT achieved balanced sensitivity (75.0%) and specificity (73.7%), effectively stratifying patients into high-risk (15% of patients; 40.4% EAF incidence) and low-risk groups. Preoperative and intraoperative clinical factors predict EAF in LDLT. The EAGLE-LDLT model accurately identifies LDLT recipients at the highest risk for EAF postoperatively.

Chemoresistance remains an obstacle to effective cancer therapy across multiple tumor types. Damaged DNA-binding protein 2 (DDB2), a key component of the nucleotide excision repair (NER) pathway, contributes to chemoresistance by enhancing DNA repair and inhibiting apoptosis. Although the role of DDB2 in tumor progression is context-dependent, its upregulation has been associated with poor prognosis in various malignancies. In this study, elevated DDB2 levels found in breast, liver, cholangiocarcinoma, and lung cancers correlated with reduced patient survival. DDB2 confers resistance to chemotherapeutic agents. Through structure-based virtual screening and molecular dynamics simulations, lapatinib, an FDA-approved EGFR/HER2 inhibitor, was identified as a compound capable of disrupting the DDB2/DNA complex, which was confirmed by the cellular thermal shift assay and chromatin fractionation. Mechanistically, lapatinib binds to the DNA-binding region of DDB2, thereby reducing its chromatin association and promoting proteasomal degradation. Co-treatment with lapatinib and doxorubicin exhibited synergistic cytotoxicity in both cancer cell lines and patient-derived organoids. These findings reveal a previously unrecognized role for lapatinib in targeting DNA repair machinery, supporting its repurposing as a chemosensitizing agent. Our study highlights DDB2 as a critical mediator of chemoresistance and proposes disruption of DDB2-dependent DNA repair as a novel strategy for chemosensitization.

Background: Patients with metastatic colorectal cancer (mCRC) who are refractory to two or more lines of systemic chemotherapy have limited therapeutic options. The aim of this study was to evaluate the effect of autologous dendritic cell cytokine-induced killer (DC-CIK) transfer on the survival of patients with mCRC who are refractory or intolerant to at least two lines of systemic chemotherapies.Methods: A matched case–control comparative study was conducted with patients who received DC-CIK immunotherapy in addition to standard chemotherapy (cases) and those with standard chemotherapy alone (controls). The primary objective was to compare the duration of oncologic survival, including overall survival (OS) and progression-free survival (PFS), between the two groups.Results: A total of 27 cases and 27 controls were included. The median OS in the DC-CIK case group was 18.73 ± 5.48 months, which was significantly longer than that in the control group (14.23 ± 1.90 months, p = 0.045). However, there was no significant difference in PFS between the two groups (p = 0.086). Subgroup analysis showed that in patients with liver or extra-regional lymph node metastasis, DC-CIK cases had longer OS than controls (17.0 vs. 11.87 months, p = 0.019; not match vs. 6.93 months, p = 0.002, respectively). In patients with Eastern Cooperative Oncology Group (ECOG) scale 0 or wild RAS/BRAF, DC-CIK cases showed a significant increase in OS duration compared to controls (28.03 vs. 14.53 months, p = 0.038; 18.73 vs. 11.87 months, p = 0.013, respectively).Conclusions: The addition of autologous DC-CIK to standard chemotherapy had a positive effect on OS of patients with refractory mCRC, especially those with liver or extra-regional lymph node metastasis, ECOG = 0, and wild RAS/BRAF status.

This study explores the synergistic impact of Programmed Death Ligand 1 (PD-L1) and Protein Kinase B (Akt) overexpression in adipose-derived mesenchymal stem cells (AdMSCs) for ameliorating cardiac dysfunction after myocardial infarction (MI). Post-MI adult Wistar rats were allocated into four groups: sham, MI, ADMSC treatment, and ADMSCs overexpressed with PD-L1 and Akt (AdMSC-PDL1-Akt) treatment. MI was induced via left anterior descending coronary artery ligation, followed by intramyocardial AdMSC injections. Over four weeks, cardiac functionality and structural integrity were assessed using pressure–volume analysis, infarct size measurement, and immunohistochemistry. AdMSC-PDL1-Akt exhibited enhanced resistance to reactive oxygen species (ROS) in vitro and ameliorated MI-induced contractile dysfunction in vivo by improving the end-systolic pressure–volume relationship and preload-recruitable stroke work, together with attenuating infarct size. Molecular analyses revealed substantial mitigation in caspase3 and nuclear factor-κB upregulation in MI hearts within the AdMSC-PDL1-Akt group. Mechanistically, AdMSC-PDL1-Akt fostered the differentiation of normal T cells into CD25⁺ regulatory T cells in vitro, aligning with in vivo upregulation of CD25 in AdMSC-PDL1-Akt-treated rats. Collectively, PD-L1 and Akt overexpression in AdMSCs bolsters resistance to ROS-mediated apoptosis in vitro and enhances myocardial protective efficacy against MI-induced dysfunction, potentially via T-cell modulation, underscoring a promising therapeutic strategy for myocardial ischemic injuries.

Background: Comprehensive and integrative analysis of hepatocellular carcinoma (HCC) is important. In this study, we explored Taiwanese HCCs using multi-omics analyses. Methods: We analyzed 254 HCCs by whole genome sequencing and total RNA sequencing, and then used bioinformatic tools to analyze genomic and transcriptomic alterations in coding and non-coding sequences to explore the clinical importance of each sequence. Results: The frequencies of the five most commonly mutated cancer-related genes were TERT, TP53, CTNNB1, RB1, and ARID1A. Genetic alteration frequencies influenced the etiology of HCC; some alterations were also correlated with clinicopathological conditions. Many cancer-related genes had copy number alterations (CNAs) and structure variants (SVs) that changed according to etiology and exhibited potential associations with survival. We also identified several alterations in histone-related genes, HCC-related long non-coding RNAs, and non-coding driver genes that may contribute to the onset and progression of HCC. Transcriptomic analysis revealed that 229 differentially expressed and 148 novel alternative splicing (AS) genes, as well as the presence of fusion genes, were associated with patient survival. Moreover, somatic mutations, CNAs, and SVs were associated with immune checkpoint gene expression and tumor microenvironment. Finally, we identified relationships among AS, immune checkpoint gene expression and tumor microenvironment. Conclusions: This study shows that genomic alterations are associated with survival, including DNA-based and RNA-based data. Moreover, genomic alterations and their associations with immune checkpoint genes and the tumor microenvironment may provide novel insights for the diagnosis and treatment of HCC.

Background: Despite resection surgery as a curative therapy for hepatocellular carcinoma (HCC), the high rate of postoperative HCC recurrence remains a big challenge for patient survival. Chronic hepatitis B virus (HBV) infection is the most important risk factor for HCC. Deletion mutation in the HBV pre‐S2 gene leads to expression of an essential viral oncoprotein called pre‐S2 mutant and represents an independent prognostic biomarker for HCC recurrence after curative surgical resection. Additionally, cytokines are multifunctional secreted proteins and implicated in all stages of HBV‐related HCC tumorigenesis.Methods: This study aimed to identify the cytokines whose plasma levels were associated with pre‐S2 gene deletion mutation and HCC recurrence and evaluate their potential to be combined with pre‐S2 gene deletion mutation in predicting HCC recurrence.Results: Among a panel of 27 cytokines examined, plasma levels of monocyte chemoattractant protein‐1 (MCP‐1) were significantly upregulated in patients with pre‐S2 gene deletion mutation or HCC recurrence. MCP‐1 was validated as an independent prognostic biomarker for HCC recurrence. Moreover, patients with both the presence of pre‐S2 gene deletion mutation and high levels of MCP‐1 displayed a higher risk of HCC recurrence than patients with either one or none of these two biomarkers. The combination of pre‐S2 gene deletion mutation and MCP‐1 levels exhibited a better prognostic performance for HCC recurrence than each biomarker alone.Conclusions: This study discovered that MCP‐1 levels had a significance to be as a combination biomarker with pre‐S2 gene deletion mutation providing an improved performance in predicting HCC recurrence after curative surgical resection.