Background Schisandrin A (Sch A), a major bioactive lignan isolated from Schisandra chinensis, exhibits hepatoprotective and metabolic regulatory activities. However, whether its metabolic effects involve context-dependent regulation of intestinal farnesoid X receptor (FXR) signaling under distinct bile acid environments remains unknown. Objective To investigate how Sch A regulates intestinal FXR to ameliorate obesity and MAFLD. Methods DIO and MAFLD mouse models were established separately with Fexaramine (Fex) as a positive control. Therapeutic effects were evaluated through histopathology, biochemistry, metabolic phenotyping, and targeted bile acid metabolomics. Mechanisms were explored using microbiota depletion, fecal microbiota transplantation, intestine-specific Fxr knockout mice, intestinal Camk2d knockdown mice, and target-binding assays. Results Sch A reduced body weight, improved glucose and lipid metabolism, alleviated hepatic steatosis, and enhanced energy expenditure in both obesity and MAFLD models, with broader effects on selected metabolic endpoints, particularly in DIO mice, compared with Fex. In DIO mice, Sch A reduced bile salt hydrolase-producing Lactobacillus, increased conjugated bile acids, inhibited intestinal FXR signaling to enhance bile acid synthesis and boost energy expenditure. In MAFLD mice, Sch A restored FXR activity in association with FXR engagement, CAMK2D-dependent phosphorylation, and nuclear translocation. Conclusion Sch A ameliorates obesity and MAFLD through bile acid context-dependent regulation of intestinal FXR, supporting further preclinical evaluation of Sch A in metabolic disease models.

Background: Surgical resection remains an important curative therapy for hepatocellular carcinoma (HCC); however, the 5-year recurrence rate still exceeds 70%. The majority of recurrences manifest within the initial 2 years post-surgery, in accordance with the early recurrence criteria. Nonalcoholic fatty liver disease (NAFLD) has been reported to promote early recurrence of HCC. Objective of this study was to investigate the role of NAFLD in shaping an immunosuppressive tumor microenvironment after surgical resection, thereby promoting the early recurrence of HCC. Methods: Models of early recurrence were established with luciferase-expressing Hepa1-6 cells in C57BL/6J mice. A randomized, controlled animal experiment was conducted. Single-cell RNA sequencing (scRNA-seq) was performed to examine the immune microenvironment in the liver in the context of NAFLD. Multiplex immunofluorescence staining and flow cytometry were used to validate immune cell population dynamics. Lipidomics was used to delineate the metabolic landscape of NAFLD. Results: We discovered that the NAFLD microenvironment promoted the expansion of CD11b+Gr1+ myeloid-derived suppressor cells (MDSCs), which concurrently promoted the exhaustion of tumor-specific CD8+ T cells. This expansion was positively correlated with the early recurrence of HCC. Furthermore, lipidomic analysis of tumor tissues from NAFLD mice revealed 22 upregulated metabolites. Pathway enrichment analysis revealed a predominant association between these metabolites and glycerophospholipid metabolism. Infiltrating MDSCs enhanced choline metabolism through the significant upregulation of the key rate-limiting enzyme choline kinase alpha (CHKA), consequently activating the PI3K-AKT-mTOR axis. Interrupting the CHKA-PI3K-AKT-mTOR axis with CHKA inhibitor MN58b or AKT inhibitor capivasertib significantly mitigated tumor progression induced by NAFLD and restored CD8+ T cell function. Intercellular interaction analysis suggested that MDSCs reciprocally communicate with T/NK cells to remodel unfavorable conditions via the CEACAM1-CD8a, CD86-CTLA4/CD28, and IL34-CSF1R tumor-promoting signaling pathways. Conclusions: NAFLD drives early HCC recurrence by remodeling the immunosuppressive niche via the CHKA-PI3K-AKT-mTOR axis. Targeting this pathway represents a novel therapeutic strategy against NAFLD-related HCC recurrence.

AmisChemotherapy-induced hepatotoxicity (CIH) is a significant concern in colorectal cancer (CRC) patients treated with the CAPEOX (capecitabine and oxaliplatin) regimen. Identifying predictive factors for CIH is crucial for clinical management.Patients and MethodsThis study analyzed colorectal tissue (CRT), plasma, and urine samples from CRC patients. Differentially expressed metabolites (DEMs) across these tissues were integrated for multi-omics analysis, and predictive models for CIH susceptibility were developed. An independent set of 75 plasma samples was used for validation.ResultsA total of 492 differentially expressed compounds were identified in samples from 63 CRC patients, including 105, 149, and 238 DEMs in CRT, plasma, and urine, respectively. Lipids and lipid-like molecules were predominant in all samples. Among these, urine samples exhibited the highest variability and provided the strongest predictive power for CIH susceptibility. Principal component analysis (PCA) effectively differentiated normal patients from those with CIH. The study revealed steatosis as the primary pathological feature of CIH, with disrupted lipid metabolism emerging as a key characteristic. Predictive models constructed from multi-tissue metabolites profile exhibited high accuracy, with the plasma model achieving an AUC of 0.933 in external validation set. Our study underscores the importance of individual metabolic variations in CIH susceptibility, reflecting the complex interplay of genetic, environmental, and lifestyle factors.ConclusionThis study emphasizes the critical role of alterations in lipid, polyamine, and purine metabolism, as well as impaired tissue repair mechanisms, were identified as key endogenous factors underlying CIH susceptibility. The developed predictive models demonstrate potential for clinical application in assessing CIH risk in CRC patients undergoing CAPEOX chemotherapy.

AIMS:This study aims to assess whether pre-chemotherapy endogenous plasma metabolome can offer improved predictive values for Capecitabine chemotherapy-related adverse events (CRAEs). RESEARCH DESIGN AND METHODS:Plasma samples were collected from 25 colorectal cancer patients at different time points: 0 hours (before), and 1, 2.5, 4 hours after oral Capecitabine administration, to assess individual variations in exposure levels. Additionally, the endogenous metabolome profile was analyzed using UHPLC/Q-TOF-MS. RESULTS:Capecitabine and its metabolites can predict two CRAEs, with 5-FU, 5'-DFCR, and FUH2 exposures being associated with diarrhea and thrombocytopenia, respectively. In contrast, identified plasma endogenous biomarker metabolites can predict all seven observed CRAEs. These CRAE-related endogenous plasma metabolites are involved in various physiological functions, including cell proliferation, maintenance, and inflammation. Pre-chemotherapy endogenous plasma metabolites established superior predictive performance for CRAEs (AUROC values ranging from 0.718 to 0.998) compared to conventional drug exposure (AUROC values ranging from 0.737 to 0.773). Additionally, the endogenous plasma metabolome demonstrated a strong correlation with drug exposures. CONCLUSIONS:Our study demonstrates that pre-chemotherapy endogenous plasma metabolome serve as superior biomarkers for predicting CRAEs, outperforming drug exposure levels. However, the limited sample size may impact the generalizability of these findings, and validation in larger patient cohorts is warranted.Trial Registration: NCT03030508 (registered at www.clinicaltrials.gov).

BACKGROUND AND PURPOSE:The CAPEOX (combination of oxaliplatin and capecitabine) chemotherapy protocol is widely used for colorectal cancer treatment, but it can lead to chemotherapy-induced adverse effects (CRAEs). EXPERIMENTAL APPROACH:To uncover the mechanisms and potential biomarkers for CRAE susceptibility, we performed whole-genome sequencing on normal colorectal tissue (CRT) before adjuvant chemotherapy. This is followed by in vivo and in vitro verifications for selected gene and CRAE pair. KEY RESULTS:Our analysis revealed specific germline mutations linked to Grade 2 (or higher) chemotherapy-induced thrombocytopenia (CIT) and nausea/vomiting (CINV). Notably, both CRAEs were associated with mutations in the DLG5 gene. We found that DLG5 mutations related to CIT were associated with increased gene expression, while those associated with CINV were linked to suppressed gene expression, as indicated by the Genotype-Tissue Expression (GTEX) database. In megakaryocytes, overexpression of human DLG5 suppressed the hippo signalling pathway and induced YAP expression. In zebrafish, overexpression of human DLG5 not only reduced platelet production but also inhibited thrombus formation. Subsequent qPCR analysis revealed that DLG5 overexpression affected genes involved in cytoskeleton formation and alpha-granule formation, which could impact the normal generation of proplatelets. CONCLUSION AND IMPLICATIONS:We identified a series of germline mutations associated with susceptibility to CIT and CINV. Of particular interest, we demonstrated that induced and suppressed DLG5 expression is respectively related to CIT and CINV. These findings shed light on the involvement of the hippo signalling pathway and DLG5 in the development of CRAEs, providing valuable insights into potential targets for therapeutic interventions.

BACKGROUND:Gut microorganisms are involved in the occurrence and progression of various types of cancer, including colorectal cancer. Previous studies have shown that the disruption of commensal homeostasis can promote tumor metastasis. The present study aimed to investigate the effects of gut commensal dysbiosis on the risk of colorectal cancer liver metastasis (CRLM) and its mechanisms. MATERIALS AND METHODS:A mouse model of CRLM with the commensal dysbiosis background was established. This model was used to investigate the impact of commensal dysbiosis on CRLM. RESULTS:Commensal dysbiosis promoted CRLM development via the C-C chemokine ligand 6 ( CCL6 ) and C-C chemokine receptor 1 ( CCR1 ) axis. Moreover, it altered the liver tumor microenvironment (TME) by recruiting tumor-associated macrophages (TAMs), notably M2-like TAMs, and promoted liver metastasis growth. Liver metastasis was promoted via the upregulation of CCL6 expression levels, which resulted in CCR1 +TAM infiltration into the TME. Notably, inhibiting CCR1 expression could reduce CRLM. CONCLUSION:Commensal dysbiosis could promote CRLM development via CCL6/CCR1 signaling. Targeting this signaling axis could be an effective method to inhibit CRLM by regulating the TME.

Purpose: Gut microorganisms are involved in the occurrence and progression of various cancer types, including colorectal cancer. Several studies have indicated that the destruction of commensal homeostasis can promote tumor metastasis. The purpose of our study was to clarify the effect of gut commensal dysbiosis on the risk of liver metastasis of colorectal cancer (CRLM) and its mechanisms. Methods: We established a mouse model of CRLM with a background of commensal dysbiosis. Using this model, we studied the impact of commensal dysbiosis on CRLM. Results: Commensal dysbiosis promotes the development of CRLM via the C-C chemokine ligand 6 (CCL6) and the C-C chemokine receptor 1 (CCR1) axis. It was found that commensal dysbiosis altered the tumor microenvironment (TME) of the liver by recruiting tumor-associated macrophages (TAMs), notably M-2-like TAMs and promoted the growth of liver metastasis. The effect of promoting liver metastasis was achieved by upregulating the expression levels of CCL6 to drive CCR1+TAMs infiltration into the TME. It is important to note that inhibition of CCR1 expression can reduce CRLM. Conclusion: Commensal dysbiosis could promotes the development of CRLM via CCL6/CCR1 signaling and represent an approach to prevent CRLM. The results of the current research study suggested that targeting this axis could be an effective method to inhibit the CRLM by regulating the TME.

Background: Polygonum capitatum Buch.-Ham. ex D. Don (P. capitatum), a traditional herb used in Miao medicine, is renowned for its heart-clearing properties. Davidiin, the primary bioactive component (approximately 1%), has been used to treat various conditions, including diabetes. Given its wide range of effects and the diverse biomolecular pathways involved in diabetes, there is a crucial need to study how davidiin interacts with these pathways to better understand its anti-diabetic properties. Materials and Methods: Diabetic rats were induced using a high-fat diet and streptozotocin (STZ) administered intraperitoneally at 35 mg/kg. Out of these, 24 rats with blood glucose levels >= 11.1 mmol/L and fasting blood glucose levels >= 7.0 mmol/L were selected for three experimental groups. These groups were then treated with either metformin (gavage, 140 mg/kg) or davidiin (gavage, 90 mg/kg) for four weeks. After the treatment period, we measured body weight, blood glucose levels, and conducted untargeted metabolic profiling using UPLC-QTOF-MS. Results: Davidiin has been shown to effectively treat diabetes by reducing blood glucose levels from 30.2 +/- 2.6 mmol/L to 25.1 +/- 2.4 mmol/L (P < 0.05). This effect appears stronger than that of metformin, which lowered glucose levels to 26.5 +/- 2.6 mmol/L. The primary outcomes of serum metabolomics are significant changes in lipid and lipid-like molecular profiles. Firstly, davidiin may affect phosphatide metabolism by increasing levels of phosphatidylinositol and sphingosine-1-phosphate. Secondly, davidiin could influence cholesterol metabolism by reducing levels of glycocholic acid and glycochenodeoxycholic acid. Lastly, davidiin might impact steroid hormone metabolism by increasing hepoxilin B3 levels and decreasing prostaglandins. Conclusion: Our study demonstrates that davidiin modulates various lipid-related metabolic pathways to exert its anti-diabetic effects. These findings offer the first detailed metabolic profile of davidiin's action mechanism, contributing valuable insights to the field of Traditional Chinese Medicine in the context of diabetes treatment.

AIM:The purpose of this study was to interpret real-world clinical data to analyze the surgical safety and survival outcomes of patients with initial unresectable hepatocellular carcinoma (uHCC) after conversion therapy. METHODS:A retrospective analysis was performed on 2984 hepatocellular carcinoma (HCC) patients hospitalized in Shandong Cancer Hospital Affiliated to Shandong First Medical University from June 1st, 2019 to June 1st, 2023. Clinicopathological features, response to systemic and/or loco-regional treatments, surgical resection rate after conversion therapy, surgical safety, and postoperative recurrence were analyzed. RESULTS:A total of 38 patients were successfully converted to obtain surgical resection. 35 patients underwent radical resection. A high objective response rate (ORR) (52.6% under RECIST v1.1 and 78.9% under mRECIST criteria) was observed in patients under conversion therapy, and the disease control rate (DCR) was 100%. Pathologic complete response (pCR) was 42.9%. Treatment-related adverse events (TRAEs) of any grade were observed in 37 patients (97.4%). Safety of conversion or direct surgery continues to improve. The median follow-up time was 19.3 months. The 1-year Disease-free survival (DFS) rate of patients with direct surgery and patients with conversion surgery were 91.4% and 86.8%, respectively. CONCLUSIONS:With conversion therapy, a small percentage (1.81%) of uHCC patients are likely to be converted to radical resection. Local combined systemic therapy is a relatively safe and effective conversion therapy, and the safety of surgery is gradually improved after successful conversion. Preliminary follow-up data showed satisfactory survival benefits for patients undergoing conversion surgery. TRIAL REGISTRATION:This was a retrospective study and it did not interfere with treatment decisions.

Introduction: Diarrhea is the primary dose-limiting side effect of capecitabine(Cap) hindering its clinical application, but the mechanism is unclear. Clarifying this mechanism may enhance the patient compliance and improve the treatment outcome. Objectives: To assess if the endogenous metabolic profile could prodict the diarrhea induced by Cap and explore and validate underlying mechanisms. Methods: Untargeted and targeted bile acids(BAs) metabolomics were performed to analyzed the metabolic profile of baseline samples from colorectal cancer(CRC) patients and the association with the diarrhea induced by Cap was assessed. The toxicity of BAs and Cap and its metabolites alone or their combinations to the human normal intestinal epithelial cell(HIEC) was assessed, and the key genes that mediated the BAs-enhanced toxicity of Cap were discovered by RNA-seq and then validated. A mouse model with high exposure levels of BAs was constructed and then treated with Cap to verify the Cap-induced diarrhea enhanced by BAs. Results: The baseline endogenous metabolic profile showed obviously difference between diarrhea and non-diarrhea CRC patients, and the differential metabolites mainly enriched in BAs metabolism; the deoxycholic acid(DCA) and lithocholic acid(LCA) were selected to be the key BAs that enhanced the toxicity of Cap metabolite 5-FU to the HIEC cell; the DCA and LCA could inhibit the Wnt/β-catenin signaling pathway, which then suppressed the P-glycoprotein and increased the exposure level of 5-FU in the HIEC cell. The results of animal experiment verified that the excessive DCA and LCA could aggravate the Cap-induced diarrhea through inhibiting Wnt/β-catenin-P-glycoprotein pathway. Conclusions: The disordered BAs metabolic profile showed close relationship with diarrhea induced by Cap, and excessive DCA and LCA were proved to be the key BAs, which could aggravate the Cap-induced diarrhea through inhibiting Wnt/β-catenin-P-glycoprotein pathway.

Background: Adverse effects resulting from Capecitabine-based chemotherapy pose a significant concern in clinical practice. While the pharmacokinetics (PK) approach has been commonly used to investigate the toxicity of Capecitabine, its predictive ability remains limited. This study aims to assess whether pre-chemotherapy endogenous plasma metabolome can offer improved predictive values for Capecitabine chemotherapy-related adverse events (CRAEs). Methods: Plasma samples were collected from colorectal cancer patients at different time points: 0 hours (before), and 1, 2.5, 4 hours after oral Capecitabine administration, to assess individual variations in exposure levels of Capecitabine and its metabolites. Additionally, the endogenous metabolome profile was analyzed using UHPLC-MS/MS and UHPLC/Q-TOF-MS. Results: Capecitabine and its metabolites can predict two CRAEs, with 5-FU, 5’-DFCR, and FUH2 exposures being associated with diarrhea and thrombocytopenia, respectively. In contrast, identified plasma engougenous biomarker metabolites can predict all seven observed CRAEs. These CRAE-related endogenous plasma metabolites are involved in various physiological functions, including cell proliferation, maintenance, and inflammation. Pre-chemotherapy endogenous plasma metabolites established superior predictive performance for CRAEs (AUROC values ranging from 0.834 to 0.984) compared to conventional drug exposure (AUROC values ranging from 0.737 to 0.773). Additionally, the endogenous plasma metabolome demonstrated a strong correlation with Capecitabine and its metabolite exposures. Conclusions: Our study demonstrates that pre-chemotherapy endogenous plasma metabolome serve as superior biomarkers for predicting Capecitabine-related adverse effects, surpassing the value of exposures to Capecitabine and its metabolites. This finding holds significant potential in guiding personalized medicine approaches.

AbstractNotable-HCC (NCT05185531) is a phase 1b trial, aiming to evaluate the safety and preliminary effectiveness of neoadjuvant PD-1 blockade plus stereotactic body radiotherapy (SBRT) in early-stage resectable hepatocellular carcinoma (HCC). Twenty patients with HCC of BCLC stage 0-A received 3$$\times $$ × Gy SBRT and two cycles of tislelizumab, an anti-PD-1 monoclonal antibody before the curative HCC resection. Primary endpoints were the surgery delay, radiographic and pathological tumor response after the neoadjuvant therapy, safety and tolerability. During the neoadjuvant therapy, treatment-related adverse events (TRAEs) of grade 1-2 occurred in all 20 patients (100%), eight patients (40%) had grade 3 TRAEs, no grade 4 to 5 TRAE occurred, and all resolved without corticosteroids treatment. Per mRECIST, the objective response rate was 63.2% (12/19), with 3 complete response; the disease control rate was 100%. Two (10.5%) patients achieved complete pathological response. No surgery delay occurred. The neoadjuvant therapy did not increase the surgical difficulty or the incidence of complications. Secondary endpoints of disease-free survival and overall survival were not mature at the time of the analysis. Our pilot trial shows that neoadjuvant therapy with anti-PD-1 + SBRT is safe and promotes tumor responses in early-stage resectable HCC.

The aerial parts of Mosla chinensis Maxim. and Mosla chinensis cv. ‘Jiangxiangru’ (MCJ) are widely utilized in traditional Chinese medicine (TCM), known collectively as Xiang-ru. However, due to clinical effectiveness concerns and frequent misidentification, the original plants have increasingly been substituted by various species within the genera Elsholtzia and Mosla. The challenge in distinguishing between these genera arises from their similar morphological and metabolic profiles. To address this issue, our study introduced a rapid method for metabolic characterization, employing high-resolution mass spectrometry-based metabolomics. Through detailed biosynthetic and chemometric analyses, we pinpointed five phenolic compounds—salviaflaside, cynaroside, scutellarein-7-O-D-glucoside, rutin, and vicenin-2—among 203 identified compounds, as reliable chemical markers for distinguishing Xiang-ru from closely related Elsholtzia species. This methodology holds promise for broad application in the analysis of plant aerial parts, especially in verifying the authenticity of aromatic traditional medicinal plants. Our findings underscore the importance of non-volatile compounds as dependable chemical markers in the authentication process of aromatic traditional medicinal plants.

Purpose:The aim of this study was to verify the effectiveness and explore the mechanism of Chaihu-Guizhi-Ganjiang decoction (CGGD) in the treatment of chronic non-atrophic gastritis (CNAG) with gallbladder heat and spleen cold syndrome (GHSC) by metabolomics based on UHPLC-Q-TOF/MS.Patients and Methods:An observational controlled before-after study was conducted to verify the effectiveness of CGGD in the treatment of CNAG with GHSC from January to June 2023, enrolling 27 patients, who took CGGD for 28 days. 30 healthy volunteers were enrolled as the controls. The efficacy was evaluated by comparing the traditional Chinese medicine (TCM) syndrome and CNAG scores, and clinical parameters before and after treatment. The plasma levels of hormones related to gastrointestinal function were collected by ELISA. The mechanisms of CGGD in the treatment of CNAG with GHSC were explored using a metabolomic approach based on UHPLC-Q-TOF/MS.Results:Patients treated with CGGD experienced a statistically significant improvement in TCM syndrome and CNAG scores (p < 0.01). CGGD treatment evoked the concentration alteration of 15 biomarkers, which were enriched in the glycerophospholipid metabolism, and branched-chain amino acids biosynthesis pathways. Moreover, CGGD treatment attenuated the abnormalities of the gastrointestinal hormone levels and significantly increased the pepsinogen level.Conclusion:It was the first time that this clinical trial presented detailed data on the clinical parameters that demonstrated the effectiveness of CGGD in the treatment of CNAG with GHSC patients. This study also provided supportive evidence that CNAG with GHSC patients were associated with disturbed branched-chain amino acid metabolism and glycerophospholipid levels, suggesting that CNAG treatment based on TCM syndrome scores was reasonable and also provided a potential pharmacological mechanism of action of CGGD.

Abstract Background Hepatocellular carcinoma (HCC) is highly invasive, even for early stage HCC, the 1-year post-operative recurrence rates were over a quarter; so far no standard neoadjuvant therapy (NAT) is recommended by major guidelines. NAT with immune checkpoint inhibitors (ICIs) has been tried in varying solid tumors including HCC; radiotherapy showed immuno-modulating effect in the treatment of some malignancies. So we aimed to evaluate the safety, tolerability and preliminary effectiveness of neoadjuvant anti-programmed cell death protein-1(PD-1) monoclonal antibody plus stereotactic body radiotherapy (SBRT) in early stage resectable HCC. Methods/Procedures Notable-HCC (NCT05185531) is a single-center phase Ib trial; in this pilot study, patients with resectable HCC of Barcelona Clinic Liver Cancer (BCLC) stage 0 to A planned to receive three fractions of 8 Gy SBRT on day 1, 3 and 5, and two cycles of tislelizumab, an anti-PD-1 monoclonal antibody, 3 weeks apart at a dose of 200mg. Curative liver resection of HCC was scheduled on day 50. Adjuvant therapy was tislelizumab every 3 weeks for up to 1 year. The primary endpoints were the surgery delay over 6 weeks, objective response rate (ORR) after the neoadjuvant therapy, pathological response rates, and the safety and tolerability of the combination neoadjuvant therapy as well as the adjuvant therapy. Secondary endpoints were 1-, 3- and 5-year disease-free survival (DFS) and over survival (OS) rates assessed every 3 or 6 months after hepatic resection. Exploratory endpoints included patients’ immune response, incidence of surgical complications, and mortality rate. Results Between Mar 22, 2022, and Jul 17, 2023, 22 patients were screened and 20 were enrolled. During the neoadjuvant therapy period, treatment-related adverse events (TRAEs) of any grade occurred in all 20 patients (100%), eight patients (40%) had grade 3 TRAEs, the most common grade 3 TRAEs were decreased lymphocyte count (n = 3, 15.0%) and decreased neutrophil count (n = 3, 15.0%); no grade 4 to 5 TRAE occurred. All adverse events resolved spontaneously without the need for corticosteroids treatment. Per RECIST v1.1, ORR was 42.1% (8/19), all were partial response (PR) and no patients achieved complete response (CR), and other 11 (57.9%) patients were stable disease (SD), so the disease control rate (DCR) was 100%. While per mRECIST, the ORR was 63.2% (12/19), with 3 CR and 9 PR, the DCR was also 100%. All patients had radiographic tumor regression in varying degree. Two (10.5%) patients achieved complete pathological response (pCR), and 6 (31.6%) reached major pathological response (MPR). No patient had surgery delay over 6 weeks due to any reason. One patient had radiofrequency ablation, other 19 patients achieved curative R0 resection. The neoadjuvant therapy did not increase the difficulty of surgical resection, nor did it increase the incidence of post-operative complications. TRAEs of any grade occurred in all 17 patients who received adjuvant tislelizumab after the R0 HCC resection, with the vast majority were grade 1 to 2. The three most common types TRAEs were decreased lymphocyte count (n = 13, 76.5%), decreased platelet count (n = 12, 70.6%) and decreased white blood cell (n = 7, 41.2%). Three patients experienced grade 3 TRAEs, which were decrease lymphocyte count (n = 3, 17.6%) and decreased platelet count (n = 1, 5.9%), all TRAEs during the adjuvant therapy were asymptomatic and no corticosteroids treatment was needed, no grade 4 or 5 TRAE occurred. Median time from enrollment to data cutoff (Dec 1, 2023) for the preliminary analysis was 6.1months (IQR 5-12.5). The median cycle of adjuvant tislelizumab in 15 patients who received regular adjuvant treatment was 4 (range, 2–16). With a median follow-up of 4.0 months since the resection (range, 2.2–18.8), disease recurrence developed in only 1 out of 19 patients (5.3%). The neoadjuvant therapy of tislelizumab plus SBRT effectively activated the immune system, indicated by the increases of both adaptive and innate immune-related cell populations, upregulation of T cell activation-related gene expression, the gene signatures of tumor-reactive T cells and cytotoxic cells, enhanced expression of HLA class I and II genes, as well as a larger proportion of newly generated TCR clonotypes after the neoadjuvant therapy, and the immuno-enhancing effects were more significant in patients with better radiographic tumor responses. Conclusion In patients with early stage resectable HCC, the combination neoadjuvant therapy with anti-PD-1 monoclonal antibody (tislelizumab) and SBRT appears to be safe and well-tolerated, and achieves significant tumor responses as well as anti-tumor immunity. Our pilot results warrant further studies of neoadjuvant therapy with ICI plus radiotherapy in resectable HCC.

Abstract Aim To understand the proportion of uHCC (unresectable hepatocellular carcinoma) patients who achieve successful conversion resection in a high-volume setting with state of the art treatment options. Methods We retrospectively reviewed all HCC patients hospitalized to our center from June 1st, 2019 to June 1st, 2022. Conversion rate, clinicopathological features, response to systemic and/or loco-regional therapy and surgical outcomes were analyzed. Results A total of 1,904 HCC patients were identified, with 1672 patients receiving anti-HCC treatment. 328 patients were considered up-front resectable. Of the remaining 1344 uHCC patients, 311 received loco-regional treatment, 224 received systemic treatment, and the remainder (809) received combination systemic plus loco-regional treatment. Following treatment, one patient from the systemic group and 25 patients from the combination group were considered to have resectable disease. A high objective response rate (ORR) was observed in these converted patients (42.3% under RECIST v1.1 and 76.9% under mRECIST criteria). The disease control rate (DCR) reached 100%. 23 patients underwent curative hepatectomy. Major post-operative morbidity was equivalent in the both groups (P=0.76). Pathologic complete response (pCR) was 39.1%. During conversion treatment, grade 3 or higher treatment-related adverse events (TRAEs) were observed in 50% of patients. The median follow-up time was 12.9 months (range, 3.9~40.6) from index diagnosis and 11.4 months (range, 0.9~26.9) from resection. Three patients experienced disease recurrence following conversion surgery. Conclusions By intensive treatment, a small sub-group of uHCC patients (2%) may potentially be converted to curative resection. Loco-regional combined with systemic modality was relative safe and effective in the conversion therapy. Short-term outcomes are encouraging, but long-term follow-up in a larger patient population are required to fully understand the utility of this approach.

Background Apatinib (YN968D1) is the first small-molecule-targeting drug with anti-tumor activity created in China for the treatment of advanced gastric cancer (GC) and hepatocellular carcinoma (HCC). It showed significant variation in the efficacy for treating cancers, including advanced non-squamous non-small-cell lung cancer (NSCLC). Whether its efficacy could be optimized by subgrouping patients with certain genetic variation remains elusive. Methods Here, we firstly used kinase screening to identify any possible target of apatinib against 138 kinases. The effects of apatinib on proliferation rates, cell cycle, cell apoptosis, and cell migration on cancer cell lines were analyzed; the in vitro potential pathways of apatinib on cancer cell lines were screened. The effect of apatinib on mouse cancer models in vivo was also analyzed. Results Based on HCC364 cells with BRAF V600E mutation, we have shown that apatinib could inhibit their growth, migration, cell cycle, and induce their apoptosis. Based on mice with transplanted HCC364 cells, we have also shown that apatinib could inhibit the tumor growth. Based on immunohistochemistry, we have demonstrated that apatinib could suppress the phosphorylation of mitogen-activated protein kinase/extracellular signal-regulated kinase and extracellular regulated protein kinases. This may account at least part of the apatinib’s inhibitory effect on HCC364 cancer cells. Conclusions BRAF V600E protein kinase is a target of apatinib by kinase screening. We have demonstrated that apatinib can effectively inhibit tumor cells with BRAF V600E mutation by in vitro and in vivo experiments. Our results have demonstrated that targeting BRAF V600E mutation, apatinib appears to be effective and safe for treating NSCLC and possibly other cancers with the same mutation.

Tacrolimus is widely used in organ transplantation to prevent rejection. However, the narrow therapeutic window and the large inter-and intra-individual variability in the pharmacokinetics (PK) of tacrolimus make it difficult for individualization of dosing. This study aimed at developing a population pharmacokinetic model for estimating the oral clearance of tacrolimus in Chinese liver transplant patients, and identifying factors that contribute to the PK variability of tacrolimus. Data of 151 liver transplant patients who received tacrolimus were analyzed in this study. The population PK model was analyzed and the covariates including population demographic and biochemical characteristics, drug combination, and genetic polymorphism were explored using non-linear mixed-effects modeling approach. A single-compartment population PK model was developed, and the final model was CL/F = (14.6-2.38 × cytochrome P450 (CYP) 3A5-3.72 × WZC+1.04 × (POD/9)+2.48 × COR) × Exp(ηi ), where CYP3A5 was 1 for CYP3A5*3/*3, Wuzhi Capsule (WZC) was 1 when patients took tacrolimus combined with WZC, otherwise it was 0, corticosteroids (COR) was 1 when patients take tacrolimus combined with COR, otherwise, it was 0, POD was the post-operative day. Visual inspection and bootstrap indicated that the final model was stable and robust. In this study, we developed the first tacrolimus population PK model in Chinese adult liver transplant patients. We first determined the influence of WZC on tacrolimus in these people, which could provide useful PK information for the drug combination of tacrolimus and WZC. We also revealed the influence of genetic polymorphism of CYP3A5, POD, and a combination of COR on tacrolimus PK. Therefore, these significant factors should be taken into consideration in optimizing dosage regimens.