Hepatocellular carcinoma (HCC) was characterized by a highly complex genome, with structural variations (SVs) playing a significant role in its development. In this study, we employed Oxford Nanopore Technology long-read sequencing in paired tumor and adjacent normal liver tissues from 74 Chinese HCC patients to thoroughly characterize the landscape of somatic SVs. Our analysis revealed that somatic SVs were more prevalent in hepatitis B virus (HBV)-related HCC, with chromosome 1 emerging as a major hotspot, and several members of the chromosome 1 open reading frame (C1orf) family genes expression level exhibited significant age-related difference. Notably, HBV-related HCC cases exhibited a higher frequency of deletions, particularly among younger ones (≤ 35 years old). In addition, we observed an increased burden of HBV integration events in younger ones. Remarkably, the divergent-paired related homeobox ( DPRX ) loci was identified as a novel gene for HBV integration in younger patients. Together, these findings delineated the somatic SV landscape in HCC and underscored age-associated HBV-related genomic alterations as key pathological features of hepatocarcinogenesis.

BACKGROUND:The management and outcomes of liver cancer in China have not been well studied. This study aimed to evaluate the management and prognosis of patients with liver cancer in China through a comprehensive multicenter analysis and to compare these findings with data from the United States (US). METHODS:We conducted a retrospective cohort study using data from 13 hospitals across 10 provinces in China, covering patients diagnosed with primary liver cancer between January 2016 and December 2017. We collected data on sociodemographic characteristics, lifestyle factors, stage at diagnosis, and first-line treatment. Patients' survival outcomes were tracked using active and passive follow-up methods until December 2023. Multivariable Cox regression was used to identify prognostic factors. We further compared treatment patterns and prognoses of liver cancer patients between 13 hospitals in China and the Surveillance, Epidemiology, and End Results (SEER) cohort in the US. RESULTS:A total of 4951 patients with liver cancer from China and 18,365 from the Surveillance, Epidemiology, and End Results cohort were analyzed. In the Chinese cohort, commonly used treatments, ranked from highest to lowest, were surgery (37.3%, 1821/4879), interventional therapy (32.1%, 1570/4898), chemotherapy (17.4%, 850/4877), radiofrequency ablation (6.9%, 337/4872), radiotherapy (3.7%, 182/4890), and targeted therapy (2.6%, 127/4875). Surgery rates for patients with liver cancer in stages I to IV were 59.2% (309/522), 58.8% (443/753), 39.0% (328/841), and 18.6% (141/760), respectively. According to the stage at diagnosis, 5-year survival rates for patients in stages I to IV were 48.1% (95% confidence interval [CI]: 44.0-52.6%), 37.8% (95% CI: 34.5-41.4%), 24.0% (95% CI: 21.3-27.0%), and 8.0% (95% CI: 6.2-10.1%), respectively. Compared with the US, China had higher surgery rates and stage-specific survival for patients with liver cancer across all stages. Data from both countries indicated a poor prognosis for liver cancer, with the stage at diagnosis and surgical intervention being key prognostic factors in both China and the US. CONCLUSION:The present findings underscore the urgent need for early diagnosis and curative treatment interventions such as surgery to enhance survival outcomes for patients with liver cancer.

2542 Background: KRAS G12V is a prevalent oncogenic driver in solid tumors, particularly pancreatic cancer (PC), occurring in approximately 20-30% of patients (pts). Advanced solid tumors harboring this mutation carry a poor prognosis and limited treatment options following standard chemotherapy. This phase 1 study evaluates a novel TCR-engineered T cell (TCR-T) therapy derived from a naturally occurring, KRAS G12V/HLA-A*11:01–restricted T cell receptor (TCR) isolated from patient tumor-infiltrating lymphocytes. Methods: This open-label, single-arm, dose-escalation phase 1 trial assessed the safety, tolerability, and preliminary efficacy of autologous TCR-T cells in pts with advanced solid tumors. Eligible pts had confirmed KRAS G12V mutation and HLA-A*11:01 positivity. Using a standard 3+3 design, autologous T cells were transduced with a lentiviral vector encoding the TCR and a CD8 co-receptor. Pts received lymphodepletion with cyclophosphamide and fludarabine, followed by a single infusion of TCR-T cells at either 5×10⁹ (DL1) or 1×10¹⁰ (DL2) cells, with adjunctive interleukin-2. Results: As of January 2026, 8 pts were enrolled; of whom 6 (median age 69.5 years, ECOG PS 1) received the planned infusion, including pts with colorectal cancer (n = 2), pancreatic cancer (n = 3), and endometrial cancer (n = 1). All pts had liver or lung metastases and > 2 metastatic sites. No dose-limiting toxicities (DLTs) or grade ≥3 treatment-related adverse events (TRAEs) were observed. The treatment was generally well-tolerated; the most common (≥50%) treatment-emergent adverse events (TEAEs) were pyrexia, cytokine release syndrome (CRS), neutropenia, anemia, and thrombocytopenia. Grade 1-2 CRS occurred in 4/6 pts and resolved without sequelae. No immune effector cell–associated neurotoxicity syndrome (ICANS) was observed. TCR-T cells peaked in peripheral blood at a median of day 4 (range, 1–10), with a median peak expansion of 61,863 copies/µg DNA (range, 40,394–80,824). The objective response rate (ORR) was 50.0% (3/6), with a disease control rate (DCR) of 83.3% (5/6). In the pancreatic cancer subset, the ORR was 66.7% (2/3) and the DCR was 100%. Conclusions: This KRAS G12V/HLA-A*11:01–restricted TCR-T therapy demonstrated a favorable safety profile and encouraging preliminary antitumor activity in advanced solid tumors. Notably, a high response rate was observed in heavily pretreated pancreatic cancer patients, supporting further clinical development of this novel cellular therapy. Clinical trial information: NCT06767046 .

Background:Intrahepatic cholangiocarcinoma (ICC) is a highly aggressive primary liver malignancy, with poor long-term outcomes even after curative-intent resection. Postoperative adjuvant chemotherapy (pAC) is increasingly used, but its benefit is not uniform across all patients. The systemic immune-inflammation index (SII) has emerged as a potential prognostic marker in several cancers, but its role in ICC remains unclear. Methods:We retrospectively analyzed 445 ICC patients who underwent R0 hepatic resection at a single tertiary center between 2000 and 2023. Preoperative SII was calculated, and patients were stratified into high- and low-SII groups. The impact of SII on overall survival (OS) and recurrence-free survival (RFS) was evaluated, along with its interaction with pAC. Multivariate Cox regression models and maximally selected rank statistics were used for analysis. Results:The median follow-up was 34.3 months. High SII independently predicted worse OS and RFS (p < 0.001), outperforming conventional inflammatory and nodal indices. Lymph node ratio (LNR) also independently predicted survival but did not modify the effect of pAC. Interaction analysis revealed that pAC significantly improved OS in high-SII patients (5-year OS: 33% with pAC vs. 23% without; HR 0.62, 95% CI 0.42-0.94, p = 0.022) but conferred no significant benefit in low-SII patients (5-year OS: 49% with pAC vs. 55% without; HR 0.71, 95% CI 0.48-1.05, p = 0.089). Conclusions:SII is a robust prognostic biomarker in ICC and can guide individualized postoperative therapy. High-SII patients derive substantial survival benefit from adjuvant chemotherapy, whereas low-SII patients may be spared unnecessary treatment. Integrating SII into postoperative risk stratification may optimize outcomes and reduce overtreatment in ICC.

Tumor fibrosis is recognized as a malignant hallmark in various solid tumors; however, the clinical importance and associated molecular characteristics of tumor fibrosis in liver metastases (LM) from colorectal cancer (CRLM) remain poorly understood. Here we show that patients with CRLM whose liver metastases (LM) exhibited tumor fibrosis (Fibrosis+ LM) had significantly worse progression-free survival (P = 0.025) and overall survival (P = 0.008). Single-cell RNA sequencing revealed that the tumor microenvironment of the Fibrosis+ LM was characterized by T cells with an exhausted phenotype, macrophages displaying a profibrotic and suppressive phenotype and fibrosis-promoting fibroblasts. Further investigation highlighted the pivotal role of VCAN_eCAF in remodeling the tumor fibrosis in the tumor microenvironment of Fibrosis+ LM, emphasizing potential targetable interactions such as FGF23 or FGF3-FGFR1. Validation through multiplex immunohistochemistry/immunofluorescence and spatial transcriptomics supported these findings. Here we present a comprehensive single-cell atlas of tumor fibrosis in LM, revealing the intricate multicellular environment and molecular features associated with it. These insights deepen our understanding of tumor fibrosis mechanisms and inform improved clinical diagnosis and treatment strategies.

OBJECTIVES:MicroRNA-192-5p, a liver-enriched miRNA downregulated in hepatocellular carcinoma (HCC), is a promising biomarker, but its clinical use is limited by technical challenges in detecting low-abundance plasma miRNAs. This study innovatively uses droplet digital PCR (ddPCR) with locked nucleic acid (LNA)-modified probes to develop an ultrasensitive and standardized method for miRNA quantification in liquid biopsies. METHODS:Following Minimum Information for Publication of Quantitative Real-Time PCR Experiments guidelines, seven primer-probe combinations were screened by qPCR, and one with the lowest Ct variability (Ct <35) was selected. LNA-modified Probe P-2 was designed to enhance target hybridization. Reaction conditions were optimized to 1 μM primers, 300 nM probes, and 55 cycles. Analytical validation included trueness, precision, sensitivity, linear range, and interference testing. Plasma from 87 HCC patients and 57 controls was analyzed, and a logistic model combining miR-192-5p, AFP, and AFU was evaluated. RESULTS:The LNA probe improved positive droplet counts by 32 %. The dPCR showed excellent precision (intra-batch CV 2.31-21.63 %, inter-batch 17.54 %) and trueness (R=0.92 vs. RT-qPCR). Sensitivity thresholds were LoB=1.75, LoD=3.33, LoQ=13.45 copies/μL, with linear range 13.45-129,693 copies/μL (R2=0.9965). It tolerated low hemoglobin and triglycerides but was affected by bilirubin. HCC patients had lower miR-192-5p (444.2 vs. 753.5 copies/μL, p<0.001), with AUC=0.70. The multi-marker model had AUC=0.88. CONCLUSIONS:This LNA-optimized ddPCR assay resolves miRNA liquid biopsy barriers. The combinatorial model outperforms single biomarkers, offering a clinical tool for the precise quantification of HCC-specific miRNAs. Standardized workflows ensure reproducibility, and multicenter studies are needed for validation.

BackgroundThe prognosis of metastatic or recurrent hepatocellular carcinoma (HCC) remains poor, and new treatment strategies are warranted. Despite promising preclinical results demonstrating that radiation primes the immune system and produces a synergistic antitumor response for long-term disease control, limited clinical data are available. Therefore, in this study, we investigated the efficacy and safety of combining radiotherapy with immune checkpoint inhibitors (ICIs) for patients with metastatic and recurrent HCC in a real-world setting.Materials and methodsPatients with stage IV or recurrent HCC who received sequential or concurrent radiotherapy and ICIs in our institution were enrolled in this study. Data regarding clinicopathological characteristics, treatment protocols, response rates, toxicities, and survival were collected.ResultsFrom January 2018 to December 2021, 108 patients were included. Extra-hepatic metastasis and portal vein tumor thrombosis were recorded in 58 (53.7%) and 69 patients (63.9%), respectively. A median radiation dose of 55 Gy was administered, and ICIs were administered for 3 weeks until disease progression or limiting toxicities occurred. After treatment, the overall response rate was 75.0%, and the median follow-up duration was 18.8 months. Median overall survival and progression-free survival were 17.0 and 12.6 months, respectively. Only one patient experienced in-field recurrence. Grade ≥3 adverse events were observed in 30.6% of patients. Dermatitis was the most common toxicity-related event and thrombocytopenia was the most common grade ≥3 adverse event, occurring overall in 17.6% of patients.ConclusionThe ICI and radiotherapy combination was effective and well-tolerated in real-world patients, achieving more favorable results compared with historical ones and providing a new multimodality therapy for patients with recurrent and metastatic HCC.

To explore the value of laboratory serum markers and magnetic resonance imaging(MRI) features in the preoperative differential diagnosis of pancreatic ductal adenocarcinoma (PDAC) in periampullary carcinoma (PAC). A retrospective analysis of clinical data from 105 PAC patients who underwent pancreaticoduodenectomy was conducted, including 33 cases of PDAC (observation group) and 72 cases of non-PDAC (control group), with 25 cases of ampullary carcinoma, 38 cases of distal bile duct carcinoma, and 9 cases of periampullary duodenal carcinoma. Laboratory serum markers, MRI features, and pathological diagnosis data were compared between the two groups to analyze the value of laboratory serum markers and MRI features for differential diagnosis of PDAC within PAC. Compared to the control group, the observation group had higher proportions in total bilirubin, direct bilirubin, carcinoembryonic antigen(CEA), carbohydrate antigen 19 − 9 (CA19-9), quadruple duct sign, pancreatobiliary junction angle, main pancreatic duct diameter, pancreatic head side branch duct dilation, and hypovascular mass in pancreatic head, consistency of imaging and pathology diagnosis, perineural invasion (p < 0.05).The common bile duct diameter was smaller in the observation group (p < 0.05). The sensitivities of CA19-9, main pancreatic duct diameter, pancreatic head side branch duct dilation, and hypovascular mass in pancreatic head in PDAC within PAC are 53.8

Colorectal neuroendocrine tumors with liver metastases (CRNELM) are associated with a poorer prognosis compared to their nonmetastatic counterparts. A comprehensive understanding of the tumor microenvironment (TME) heterogeneity between primary lesions (PL) and liver metastases (LM) could provide crucial insights for enhancing clinical management strategies for these patients. We utilized single-cell RNA sequencing to analyze fresh tissue samples from CRNELM patients, aiming to elucidate the variations in TME between PL and LM. Complementary multidimensional validation was achieved through spatial transcriptomics, bulk RNA sequencing, and multiplex immunohistochemistry/immunofluorescence. Our single-cell RNA sequencing analysis revealed that LM harboured a higher proportion of CD8 + T cells, CD4 + T cells, NK cells, NKT cells, and B cells exhibiting a stress-like phenotype compared to PL. RGS5 + pericytes may play a role in the stress-like phenotype observed in immune cells within LM. MCs in PL (PL_MCs) and LM (LM_MCs) exhibit distinct activation of tumor-associated signaling pathways. Notably, COLEC11 + matrix cancer-associated fibroblasts (COLEC11_mCAFs) were found to be significantly associated with LM_MCs. Cell communication analysis unveiled potential targetable receptor-ligand interactions between COLEC11_mCAFs and LM_MCs. Multidimensional validation confirmed the prominence of the characteristic stress-like phenotypes, including HSPA6_CD8_Tstr, HSPA6_NK, and COLEC11_mCAFs in LM. Moreover, a higher abundance of COLEC11_mCAFs correlated with poorer survival rates in the neuroendocrine tumor patient cohort. Overall, our study provides the first single-cell analysis of the cellular and molecular differences between PL and LM in CRNELM patients. We identified distinct cell subsets and receptor-ligand interactions that may drive TME discrepancies and support metastatic tumor growth. These insights highlight potential therapeutic targets and inform strategies for better managing CRNELM patients.

Hepatocellular carcinoma (HCC) is a common malignancy in China, with high recurrence rate and low resection rate among patients first diagnosed. Preoperative treatments including neoadjuvant and conversion therapy have the potential to overcome these challenges. In December 2021, Chinese expert consensus on neoadjuvant and conversion therapies for hepatocellular carcinoma was published. With the emersion of new evidence regarding the neoadjuvant and conversion therapies for HCC, the cooperative group brought together multidisciplinary researchers and scholars with experience in related fields to update the new edition (2023 Edition) for reference in China, including principle of the treatment strategies, the potential populations selection, treatment methods, multi-disciplinary team (MDT) and future research for preoperative treatments. The new consensus aims to provide guidance for clinical application. Through the use of neoadjuvant therapy and conversion therapy, we can enhance the resection rate and reduce the recurrence of intermediate-to-advanced HCC patients, thereby improving survival outcomes.

BACKGROUND:The objective of this study was to determine the role and regulatory mechanism of miR-380 in cholangiocarcinoma.METHODS:The TargetScan database and a dual-luciferase reporter assay system were used to determine if LIS1 was a target gene of miR-380. The Cell Counting Kit 8 assay, flow cytometry, and Transwell assay were used to detect the effects of miR-380 and LIS1 on the proliferation, S-phase ratio, and invasiveness of HCCC-9810/HuCCT1/QBC939 cells. Western blotting was used to determine the effect of miR-380 on MMP-2/p-AKT. Immunohistochemistry detected the regulatory effect of miR-380 on the expression of MMP-2/p-AKT/LIS1.RESULTS:Expression of miR-380 in cholangiocarcinoma was decreased but expression of LIS1 was increased. LIS1 was confirmed to be a target gene of miR-380. Transfection with miR-380 mimics inhibited the proliferation, S-phase arrest, and invasion of HCCC-9810/HuCCT1/QBC939 cells, and LIS1 reversed these inhibitory effects. miR-380 inhibitor promoted proliferation, S-phase ratio, and invasiveness of HCCC-9810/HuCCT1/QBC939 cells. si-LIS1 salvaged the promotive effect of miR-380 inhibitor. Overexpression of miR-380 inhibited expression of MMP-2/p-AKT/LIS1, but miR-380 inhibitor promoted their expression.CONCLUSION:An imbalance of miR-380 expression is closely related to cholangiocarcinoma, and overexpression of miR-380 inhibits the expression of MMP-2/p-AKT by directly targeting LIS1.

BackgroundEpithelioid hemangioendothelioma (EHE), is an uncommon, intermediate-grade malignant vascular tumor that can manifest in diverse organs, including the liver, lungs, and bones. Given its unique malignancy profile and rarity, there lacks a consensus on a standardized treatment protocol for EHE, particularly for hepatic epithelioid hemangioendothelioma (HEHE). This study aims to elucidate factors influencing the clinical prognosis of EHE by analyzing data from the SEER database, complemented with insights from a departmental cohort of 9 HEHE cases. Through this, we hope to shed light on potential clinical outcomes and therapeutic strategies for HEHE.MethodsUsing SEER data from 22 registries, we analyzed 313 liver cancer patients with ICD-O-3 9130 and 9133 histology. Twelve variables were examined using Cox regression and mlr3 machine learning. Significant variables were identified and compared. Clinical data, imaging characteristics, and treatment methods of nine patients from our cohort were also presented.ResultIn univariate and multivariate Cox regression analyses, Age, Sex, Year of diagnosis, Surgery of primary site, Chemotherapy, and Median household income were closely related to survival outcomes. Among the ten survival-related machine learning models, CoxPH, Flexible, Mboost, and Gamboost stood out based on Area Under the Curve(AUC), Decision Curve Analysis(DCA), and Calibration Curve Metrics. In the feature importance analysis of these four selected models, Age and Surgery of primary site were consistently identified as the most critical factors influencing prognosis. Additionally, the clinical data of nine patients from our cohort not only demonstrated unique imaging characteristics of HEHE but also underscored the importance of surgical intervention.ConclusionFor patients with resectable HEHE, surgical treatment is currently a highly important therapeutic approach.

OBJECTIVE:Hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC), mostly characterised by HBV integrations, is prevalent worldwide. Previous HBV studies mainly focused on a few hotspot integrations. However, the oncogenic role of the other HBV integrations remains unclear. This study aimed to elucidate HBV integration-induced tumourigenesis further. DESIGN:Here, we illuminated the genomic structures encompassing HBV integrations in 124 HCCs across ages using whole genome sequencing and Nanopore long reads. We classified a repertoire of integration patterns featured by complex genomic rearrangement. We also conducted a clustered regularly interspaced short palindromic repeat (CRISPR)-based gain-of-function genetic screen in mouse hepatocytes. We individually activated each candidate gene in the mouse model to uncover HBV integration-mediated oncogenic aberration that elicits tumourigenesis in mice. RESULTS:These HBV-mediated rearrangements are significantly enriched in a bridge-fusion-bridge pattern and interchromosomal translocations, and frequently led to a wide range of aberrations including driver copy number variations in chr 4q, 5p (TERT), 6q, 8p, 16q, 9p (CDKN2A/B), 17p (TP53) and 13q (RB1), and particularly, ultra-early amplifications in chr8q. Integrated HBV frequently contains complex structures correlated with the translocation distance. Paired breakpoints within each integration event usually exhibit different microhomology, likely mediated by different DNA repair mechanisms. HBV-mediated rearrangements significantly correlated with young age, higher HBV DNA level and TP53 mutations but were less prevalent in the patients subjected to prior antiviral therapies. Finally, we recapitulated the TONSL and TMEM65 amplification in chr8q led by HBV integration using CRISPR/Cas9 editing and demonstrated their tumourigenic potentials. CONCLUSION:HBV integrations extensively reshape genomic structures and promote hepatocarcinogenesis (graphical abstract), which may occur early in a patient's life.

Purpose: To explore the value of laboratory serum markers and magnetic resonance imaging（MRI）features in the preoperative differential diagnosis of pancreatic ductal adenocarcinoma (PDAC) in periampullary carcinoma (PAC). Methods: A retrospective analysis of clinical data from 105 PAC patients who underwent pancreaticoduodenectomy, including 33 cases of PDAC (observation group) and 72 cases of non-PDAC (control group),with 25 cases of ampullary cancer, 38 cases of distal bile duct cancer, and 9 cases of periampullary duodenal cancer, was conducted. Laboratory serum markers, MRI features, and pathological diagnosis data were compared between the two groups to analyze the value of laboratory serum markers and MRI features for differential diagnosis of PDAC within PAC. Results: Compared to the control group, the observation group had higher proportions in total bilirubin, direct bilirubin, carcinoembryonic antigen（CEA）, carbohydrate antigen 199（CA199), quadruple duct sign, biliopancreatic junction angle, main pancreatic duct diameter, pancreatic head side branch duct dilatation, and hypovascular mass in pancreatic head, consistency of imaging and pathology diagnosis, nerve invasion (p<0.05). But the common bile duct diameter is smaller in the observation group (p<0.05). The sensitivities of CA199, main pancreatic duct diameter, dilatation of the accessory pancreatic duct in the head, and focal hypovascular mass in PDAC within PAC are 53.8%, 51%, 84.6%, and 81.1%, respectively; the specificities are 81.8%, 87%, 86.1%, and 95.6%, respectively; and the areas under the ROC curve are 0.74, 0.749, 0.806, and 0.906, respectively. Conclusion: In the preoperative diagnosis of PAC, CA199, main pancreatic duct diameter, focal hypovascular mass in the pancreatic head, and dilatation of the accessory pancreatic duct are effective indicators for distinguishing PDAC.

This study aimed to investigate the prognostic value of the preoperative alkaline phosphatase-to-albumin ratio (APAR) in patients with hepatocellular carcinoma (HCC) who underwent radical hepatectomy. The clinicopathological data from 330 patients was retrospectively analyzed. Receiver operating characteristic curves of APAR for diagnostic tumor recurrence were plotted with a cut-off value of 1.74. A high preoperative APAR value was significantly associated with hepatitis B surface antigen level, tumor diameter, and tumor-node-metastasis stage. The disease-free survival (DFS) and overall survival (OS) of patients with a high preoperative APAR were shorter than those with a low APAR. The independent risk factors for DFS were an APAR ≥1.74, and macrovascular invasion or tumor thrombus. The independent risk factors for OS were an APAR ≥1.74, existing clinical symptoms, α-fetoprotein level ≥20 ng/ml, macrovascular invasion or tumor thrombus, and family history of cancer. In conclusion, a preoperative APAR (≥1.74) is an independent risk factor influencing the poor prognosis of patients with HCC after curative hepatectomy, and patients with such a result should be closely monitored.

目的:评估帕博利珠单抗对于经治亚洲晚期肝细胞癌(hepatocellular carcinoma,HCC)患者的疗效和安全性.方法:本研究为一项双盲、Ⅲ期临床研究,纳入了453例既往接受索拉非尼或以奥沙利铂为基础的化学药物治疗期间或治疗后出现疾病进展及对治疗不耐受的晚期HCC患者,按2:1随机分配,分别给予帕博利珠单抗(200mg)或安慰剂治疗,每3周1次,最多持续35个周期,并同步给予最佳支持治疗.主要终点是总生存期[单侧显著性阈值P=0.0193(最终分析)].次要终点包括无进展生存期和客观缓解率[单侧显著性阈值P分别为0.0134和0.0091(第二次中期分析);由盲态独立中心审查委员会根据实体瘤疗效评价标准(response evaluation criteria in solid tumors,RECIST)v1.1评定].结果:帕博利珠单抗组中位总生存期较安慰剂组显著延长[14.6个月比13.0个月;死亡风险比0.79[95％置信区间(confidence interval,CI):0.63～0.99;P=0.0180],中位无进展生存期也显著延长[2.6个月比2.3个月;疾病进展或死亡风险比0.74(95％CI:0.60～0.92);P=0.0032].帕博利珠单抗组客观缓解率[12.7％(95％CI:9.1～17.0)]显著高于安慰剂组[1.3％(95％CI:0.2～4.6);P<0.0001].帕博利珠单抗组和安慰剂组分别有66.9％(3级,12.0％;4级,1.3％;5级,1.0％)和49.7％(3级,5.9％;4级,0;5级,0)的患者发生了与治疗相关的不良反应.结论:对于经治的亚洲晚期HCC患者,帕博利珠单抗较安慰剂显著延长了患者的总生存期和无进展生存期,且客观缓解率较安慰剂组显著提高.

Background To explore the clinical prognostic utility of the preoperative cholesterol-to-lymphocyte ratio (CLR) in outcomes for colorectal cancer liver metastasis (CRLM) patients receiving simultaneous resection of the primary lesion and liver metastases. Methods A total of 444 CRLM patients receiving simultaneous resections were enrolled. The optimal cut-off value for CLR was determined using the highest Youden’s index. Patients were divided into the CLR < 3.06 group and the CLR≥3.06 group. Propensity score matching analysis (PSM) and the inverse probability of treatment weighting (IPTW) method were conducted to eliminate bias between the two groups. The outcomes included short-term outcomes and long-term outcomes. Kaplan–Meier curves and log-rank tests were used to analyse progression-free survival (PFS) and overall survival (OS). Results In the short-term outcome analysis, after 1:1 PSM, 137 patients were distributed to the CLR < 3.06 group and CLR≥3.06 group. No significant difference was noted between the two groups ( P > 0.1). Compared with patients with CLR < 3.06, patients with CLR≥3.06 had comparable operation times (320.0 [272.5–421.0] vs. 360.0 [292.5-434.5], P = 0.088), blood loss (200.0 [100.0-400.0] vs. 200.0 [150.0-450.0], P = 0.831), postoperative complication rates (50.4% vs. 46.7%, P = 0.546) and postoperative ICU rates (5.8% vs. 11.7%, P = 0.087). In the long-term outcome analysis, Kaplan–Meier analysis showed that compared with patients with CLR < 3.06, patients with CLR≥3.06 had worse PFS ( P = 0.005, median: 10.2 months vs. 13.0 months) and OS ( P = 0.002, median: 41.0 months vs. 70.9 months). IPTW-adjusted Kaplan–Meier analysis showed that the CLR≥3.06 group had worse PFS ( P = 0.027) and OS ( P = 0.010) than the CLR < 3.06 group. In the IPTW-adjusted Cox proportional hazards regression analysis, CLR≥3.06 was an independent factor for PFS (HR = 1.376, 95% CI 1.097–1.726, P = 0.006) and OS (HR = 1.723, 95% CI 1.218–2.439, P = 0.002). IPTW-adjusted Cox proportional hazards regression analysis including postoperative complications, operation time, intraoperative blood loss, intraoperative blood transfusion and postoperative chemotherapy revealed that CLR≥3.06 was an independent factor for PFS (HR = 1.617, 95% CI 1.252–2.090, P < 0.001) and OS (HR = 1.823, 95% CI 1.258–2.643, P = 0.002). Conclusions The preoperative CLR level predicts unfavourable outcomes in CRLM patients receiving simultaneous resection of the primary lesion and liver metastases and should be taken into consideration when developing treatment and monitoring strategies.

Background: This case report presents two clinical cases of metastatic refractory gastrointestinal stromal tumor (GIST) with treatment history of 6–14 years. The follow-up treatment of both cases comprised ripretinib dose escalation and its combination with other tyrosine kinase inhibitors (TKIs). To the best of our knowledge, this is the first report that explored ripretinib combination therapy in the late-line treatment of GISTs.Case description: Case-1 represents a 57-year-old female patient who underwent surgical resection for retroperitoneal GIST in 2008. After tumor recurrence in 2009, imatinib was started with complete response for 8 years. Imatinib was followed by sunitinib and regorafenib treatment. In March 2021, due to progressive disease (PD), the patient started ripretinib (150 mg QD) and achieved partial response (PR). Six months later, the patient showed PD. Subsequently, ripretinib dose was increased (150 mg BID) followed by ripretinib (100 mg QD) and imatinib (200 mg QD) combination. CT performed in February 2022 revealed stable lesions with internal visible necrosis. Combination therapy achieved stable disease (SD) for 7 months. On further follow-up in July 2022, the patient showed PD and died in September 2022.Case-2: represents a 73-year-old female patient diagnosed with unresectable duodenal GIST with liver, lung, and lymph node metastases in 2016. After treatment with imatinib, followed by sunitinib, regorafenib, and imatinib rechallenge, ripretinib (150 mg QD) was administered in May 2021, and SD was achieved. Ripretinib dose was increased (200 mg QD) due to PD in December 2021. The tumor showed heterogeneous manifestations, with overall size increase and regression in right posterior lobe. In February 2022, ripretinib (150 mg) plus sunitinib (25 mg) QD was commenced. On follow-up in April 2022, the patient showed slightly improved symptoms with stable hematologic parameters. Combination therapy achieved SD for 5 months and the patient showed PD in July 2022 and discontinued the treatment later. The patient was in poor general condition and was receiving nutritional therapy until last follow-up in October 2022.Conclusion: This case report provides evidence that combination therapy of ripretinib with other TKIs could be an effective late-line treatment option for refractory GIST patients.

Background:Although immunotherapy combined with targeted therapy can be effective for hepatocellular carcinoma (HCC), not all HCC patients respond to this treatment. Models for predicting tumour response in HCC patients receiving immunotherapy combined with targeted therapy are lacking.Methods:A total of 221 HCC patients from two independent prospective cohorts were retrospectively reviewed. The patients were randomly divided into training and validation cohorts at a ratio of 7:3. Standard clinical data were collected from each patient, including age, sex, hepatitis B infection status, laboratory tests, and immune target-related adverse events (itrAEs). Tumour responses were evaluated using the Response Evaluation Criteria in Solid Tumours (RECIST) v1.1 guidelines. ItrAEs were assessed based on the Common Terminology Criteria for Adverse Events version 4.0. The nomogram for tumour response prediction was constructed based on the results of the multivariate logistic regression analysis, areas under the receiver operating characteristic curves (AUROCs) were used to determine the sensitivity and specificity of the model, and calibration plots and Hosmer-Lemeshow chi-square tests were performed to assess the calibration of the model.Results:In the multivariate logistic regression analysis, a solitary tumour (P=0.006), neutropenia (P=0.003) and hypertension (P=0.042) independently predicted objective response (OR). A nomogram for OR was established with AUROCs of 0.734, 0.675, 0.730, and 0.707 in the training, validation, first-line and second-line treatment sets, respectively. Tumour sizes less than 5 cm (P=0.005), a solitary tumour (P=0.037), prognostic nutritional indices greater than or equal to 54.3 (P=0.037), neutropenia (P=0.004) and fatigue (P=0.041) independently predicted disease control (DC). A nomogram for DC was established with AUROCs of 0.804, 0.667, and 0.768 in the training, first-line and second-line treatment sets, respectively. All the Hosmer-Lemeshow tests and calibration curves showed acceptable calibration.Conclusions:The current provides clinicians with new insights into selecting patients for immunotherapy combined with targeted therapy and contributes to the development of immunotherapy for HCC. It is necessary to expand the scale of our research and perform prospective studies to verify our findings.