Immune checkpoint inhibitors and anti-vascular endothelial growth factor antibody/tyrosine kinase inhibitors with or without transarterial chemoembolization as first-line treatment for advanced hepatocellular carcinoma (CHANCE2201): a target trial emulation study.

Background: The role of transarterial chemoembolization (TACE) in the treatment of advanced hepatocellular carcinoma (HCC) is unconfirmed. This study aimed to assess the efficacy and safety of immune checkpoint inhibitors (ICIs) plus anti-vascular endothelial growth factor (anti-VEGF) antibody/tyrosine kinase inhibitors (TKIs) with or without TACE as first-line treatment for advanced HCC. Methods: This nationwide, multicenter, retrospective cohort study included advanced HCC patients receiving either TACE with ICIs plus anti-VEGF antibody/TKIs (TACE-ICI-VEGF) or only ICIs plus anti-VEGF antibody/TKIs (ICI-VEGF) from January 2018 to December 2022. The study design followed the target trial emulation framework with stabilized inverse probability of treatment weighting (sIPTW) to minimize biases. The primary outcome was overall survival (OS). Secondary outcomes included progression-free survival (PFS), objective response rate (ORR), and safety. The study is registered with ClinicalTrials.gov, NCT05332821. Findings: Among 1244 patients included in the analysis, 802 (64.5%) patients received TACE-ICI-VEGF treatment, and 442 (35.5%) patients received ICI-VEGF treatment. The median follow-up time was 21.1 months and 20.6 months, respectively. Post-application of sIPTW, baseline characteristics were well-balanced between the two groups. TACE-ICI-VEGF group exhibited a significantly improved median OS (22.6 months [95% CI: 21.2-23.9] vs 15.9 months [14.9-17.8]; P < 0.0001; adjusted hazard ratio [aHR] 0.63 [95% CI: 0.53-0.75]). Median PFS was also longer in TACE-ICI-VEGF group (9.9 months [9.1-10.6] vs 7.4 months [6.7-8.5]; P < 0.0001; aHR 0.74 [0.65-0.85]) per Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1. A higher ORR was observed in TACE-ICI-VEGF group, by either RECIST v1.1 or modified RECIST (41.2% vs 22.9%, P < 0.0001; 47.3% vs 29.7%, P < 0.0001). Grade ≥3 adverse events occurred in 178 patients (22.2%) in TACE-ICI-VEGF group and 80 patients (18.1%) in ICI-VEGF group. Interpretation: This multicenter study supports the use of TACE combined with ICIs and anti-VEGF antibody/TKIs as first-line treatment for advanced HCC, demonstrating an acceptable safety profile. Funding: National Natural Science Foundation of China, National Key Research and Development Program of China, Jiangsu Provincial Medical Innovation Center, Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, and Nanjing Life Health Science and Technology Project.

Locoregional therapies for hepatocellular carcinoma: The current status and future perspectives.

Hepatocellular carcinoma (HCC) is one of the most common cancers and a leading cause of cancer-related mortality. Locoregional therapies (LRTs) play a crucial role in HCC management and are selectively adopted in real-world practice across various stages. Choosing the best form of LRTs depends on technical aspects, patient clinical status and tumour characteristics. Previous studies have consistently highlighted the efficacy of combining LRTs with molecular targeted agents in HCC treatment. Recent studies propose that integrating LRTs with immune checkpoint inhibitors and molecular targeted agents could provide substantial therapeutic benefits, a notion underpinned by both basic and clinical evidence. This review summarised the current landscape of LRTs in HCC and discussed the anticipated outcomes of combinations with immunotherapy regimens.

New First-line Immunotherapy-based Therapies for Unresectable Hepatocellular Carcinoma: A Living Network Meta-analysis.

Background and Aims: Several first-line immune checkpoint inhibitor (ICI)-based combination therapies have been identified for unresectable hepatocellular carcinoma (uHCC). This network meta-analysis (NMA) aimed to provide the most updated evidence about the preferred first-line ICI-based regimens for uHCC. Methods: A comprehensive literature search was performed in various databases from database inception to May 2022. The phase 3 trials evaluating first-line single-agent ICIs, molecular-target agents (MTAs), or their combinations in uHCC were included. The main endpoints were overall survival (OS) and progression-free survival (PFS). Pooled effect estimates were calculated using a random effects model within the frequentist framework. Subgroup analyses based on etiology were also conducted. Results: Twelve trials at low risk of bias with 8,275 patients comparing 13 treatments were included. OS with atezolizumab plus bevacizumab was comparable to sintilimab plus IBI305 [hazard ratio (HR): 1.16; 95% confidence interval (CI): 0.80-1.68] and camrelizumab plus apatinib (HR: 1.06; 95% CI: 0.75-1.51). The combination therapies, apart from atezolizumab plus cabozantinib in OS and durvalumab plus tremelimumab in PFS, had higher P-score than single-agent MTAs or ICIs. The survival benefits were associated with a high risk of adverse events leading to treatment discontinuation. The proportion of patients with hepatitis B virus-related HCC receiving ICIs combinations might positively correlate with survival advantages (R2=0.8039, p=0.0155). Conclusion: This NMA demonstrated that atezolizumab plus bevacizumab remains the stand of care and confers comparable survival benefits to sintilimab plus IBI305 and camrelizumab plus apatinib in first-line therapy for uHCC. The optimal treatment algorithms should consider efficacy, safety, and etiology.

Real-world efficacy and safety of TACE plus camrelizumab and apatinib in patients with HCC (CHANCE2211): a propensity score matching study.

OBJECTIVES: This study aimed to investigate the efficacy and safety of transarterial chemoembolization (TACE) plus camrelizumab, a monoclonal antibody targeting programmed death-1, and apatinib for patients with intermediate and advanced hepatocellular carcinoma (HCC) in a real-world setting. METHODS: A total of 586 HCC patients treated with either TACE plus camrelizumab and apatinib (combination group, n = 107) or TACE monotherapy (monotherapy group, n = 479) were included retrospectively. Propensity score matching analysis was used to match patients. The overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and safety in the combination group were described in comparison to monotherapy. RESULTS: After propensity score matching (1:2), 84 patients in the combination group were matched to 147 patients in the monotherapy group. The median age was 57 years and 71/84 (84.5%) patients were male in the combination group, while the median age was 57 years with 127/147 (86.4%) male in the monotherapy group. The median OS, PFS, and ORR in the combination group were significantly higher than those in the monotherapy group (median OS, 24.1 vs. 15.7 months, p = 0.008; median PFS, 13.5 vs. 7.7 months, p = 0.003; ORR, 59.5% [50/84] vs. 37.4% [55/147], p = 0.002). On multivariable Cox regression, combination therapy was associated with significantly better OS (adjusted hazard ratio [HR], 0.41; 95% confidence interval [CI], 0.26-0.64; p < 0.001) and PFS (adjusted HR, 0.52; 95% CI, 0.37-0.74; p < 0.001). Grade 3 or 4 adverse events occurred in 14/84 (16.7%) and 12/147 (8.2%) in the combination and monotherapy groups, respectively. CONCLUSIONS: TACE plus camrelizumab and apatinib showed significantly better OS, PFS, and ORR versus TACE monotherapy for predominantly advanced HCC. CLINICAL RELEVANCE STATEMENT: Compared with TACE monotherapy, TACE plus immunotherapy and molecular targeted therapy showed better clinical efficacy for predominantly advanced HCC patients, with a higher incidence of adverse events. KEY POINTS: • This propensity score-matched study demonstrates that TACE plus immunotherapy and molecular targeted therapy have a longer OS, PFS, and ORR compared with TACE monotherapy in HCC. • Grade 3 or 4 adverse events occurred in 14/84 (16.7%) patients treated with TACE plus immunotherapy and molecular targeted therapy compared with 12/147 (8.2%) patients in the monotherapy group, while no grade 5 adverse events were observed in all cohorts.

A Novel Neutrophil-to-Lymphocyte Ratio and Sarcopenia Based TACE-Predict Model of Hepatocellular Carcinoma Patients.

Purpose: Transarterial chemoembolization (TACE) was commonly applied in hepatocellular carcinoma (HCC) patients across BCLC A-C stages with heterogeneous outcomes in real-world practice. We aimed to develop a neutrophil-to-lymphocyte ratio (NLR) and sarcopenia-based prognostic nomogram to estimate the prognosis of HCC patients after TACE treatment. Patients and Methods: Between June 2013 and December 2019, a total of 364 HCC patients who underwent TACE were included and randomly assigned to the training (n=255) and the validation cohort (n=109). Sarcopenia was diagnosed based on the third lumbar vertebra skeletal muscle mass index (L3-SMI). The multivariate Cox proportional risk model was used to generate a nomogram. Results: NLR ≥4.0, sarcopenia, alpha-fetoprotein (AFP) ≥200 ng/mL, albumin-bilirubin (ALBI) grade 2 or 3, number of lesions (≥2), and maximum size of the lesion (≥5 cm) were independent predictors for overall survival (OS) (P < 0.05). The calibration curve shows that the predicted results agree well with the observed results. The time-dependent areas under the receiver-operating characteristic curves for OS at 1, 2, and 3 years predicted by the nomogram were 0.818/0.827, 0.742/0.823, and 0.748/0.836 in both training and validation cohorts. Nomogram can divide patients into low-, medium- and high-risk groups based on predictor factors. The C-indexes of the nomogram for OS were 0.782/0.728 in the training and validation cohorts, outperforming other currently available models. Conclusion: A novel nomogram based on NLR and sarcopenia may be useful to predict the prognosis of HCC patients who underwent TACE across BCLC A-C stage patients.

Transarterial chemoembolization with PD-(L)1 inhibitors plus molecular targeted therapies for hepatocellular carcinoma (CHANCE001).

There is considerable potential for integrating transarterial chemoembolization (TACE), programmed death-(ligand)1 (PD-[L]1) inhibitors, and molecular targeted treatments (MTT) in hepatocellular carcinoma (HCC). It is necessary to investigate the therapeutic efficacy and safety of TACE combined with PD-(L)1 inhibitors and MTT in real-world situations. In this nationwide, retrospective, cohort study, 826 HCC patients receiving either TACE plus PD-(L)1 blockades and MTT (combination group, n = 376) or TACE monotherapy (monotherapy group, n = 450) were included from January 2018 to May 2021. The primary endpoint was progression-free survival (PFS) according to modified RECIST. The secondary outcomes included overall survival (OS), objective response rate (ORR), and safety. We performed propensity score matching approaches to reduce bias between two groups. After matching, 228 pairs were included with a predominantly advanced disease population. Median PFS in combination group was 9.5 months (95% confidence interval [CI], 8.4-11.0) versus 8.0 months (95% CI, 6.6-9.5) (adjusted hazard ratio [HR], 0.70, P = 0.002). OS and ORR were also significantly higher in combination group (median OS, 19.2 [16.1-27.3] vs. 15.7 months [13.0-20.2]; adjusted HR, 0.63, P = 0.001; ORR, 60.1% vs. 32.0%; P < 0.001). Grade 3/4 adverse events were observed at a rate of 15.8% and 7.5% in combination and monotherapy groups, respectively. Our results suggest that TACE plus PD-(L)1 blockades and MTT could significantly improve PFS, OS, and ORR versus TACE monotherapy for Chinese patients with predominantly advanced HCC in real-world practice, with an acceptable safety profile.

Role of Transarterial Chemoembolization in the Treatment of Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. According to the Barcelona Clinic Liver Cancer (BCLC) staging system, transarterial chemoembolization (TACE) is the first-line recommendation for intermediate-stage HCC. In real-world clinical practice, TACE also plays an important role in early- and advanced-stage HCC. This review article by the experts from Chinese Liver Cancer Clinical Study Alliance (CHANCE) summarizes the available clinical evidence pertaining to the current application of TACE in patients with early-, intermediate-, and advanced-stage HCC. In addition, combination of TACE with other treatment modalities, especially immunotherapy, is reviewed.

Efficacy and Safety of Radioactive 125I Seed Implantation for Patients with Oligo-Recurrence Soft Tissue Sarcomas.

PURPOSE: To evaluate the efficacy and safety of computed tomography-guided radioactive iodine-125 (125I) seed implantation for oligo-recurrence soft tissue sarcomas following surgical resection. MATERIALS AND METHODS: Patients with oligo-recurrence soft tissue sarcomas after curative surgical resection between June 2013 and December 2020 were included. The primary outcome measure was objective response rate according to the Response Evaluation Criteria in Solid Tumors (RECIST 1.1). The secondary outcomes included progression-free survival, overall survival, and safety profiles. RESULTS: Twenty-nine patients receiving computed tomography-guided 125I seed implantation were included in the study. The objective response rates at 2-, 6- and 12-month follow-up were 48.3%, 65.5% and 40.9%, respectively. The median progression-free survival was 11.3 months. The median overall survival was 25.1 months, with a 1- and 2-year overall survival rate of 81.5% and 50.0%, respectively. No severe treatment-related adverse effects occured. CONCLUSION: 125I seed implantation has the potential to be an effective and safe treatment for oligo-recurrence soft tissue sarcomas after surgical resection.

Impact of COVID-19 Pandemic on Intervals and Outcomes of Repeated Transarterial Chemoembolization in Patients With Hepatocellular Carcinoma.

PURPOSE: Given that the novel coronavirus disease (COVID-19) pandemic has disrupted operations globally, an institution's ability to repeat transarterial chemoembolization (TACE) for patients with hepatocellular carcinoma (HCC) has also been affected. The aim of this study was to evaluate the impact of the COVID-19 on the intervals and outcomes of TACE in HCC patients. MATERIALS AND METHODS: This retrospective study included 154 HCC patients who underwent follow-up after TACE treatment from January 2020 to March 2020 (n = 71, study group) and January 2019 to March 2019 (n = 83, control group) at two institutions in China. The endpoints included the follow-up interval and overall response rate (ORR). Multivariate logistic regression analyses were performed to identify independent risk factors for a worse ORR. The cut-off point was determined to divide follow-up durations into long- and short-intervals. RESULTS: The median follow-up interval was 82.0 days (IQR, 61-109) in the study group, which was significantly longer than 66.0 days (IQR, 51-94) in the control group (P = 0.004). The ORR was 23.9 and 39.8% in the study and control group, respectively (P = 0.037). The cut-off value was 95 days. The grouping (OR, 2.402; 95% CI, 1.040-5.546; P = 0.040), long interval (OR, 2.573; 95% CI, 1.022-6.478; P = 0.045), and China liver cancer staging system (OR, 2.500; 95% CI, 1.797-3.480; P <0.001) were independent predictors for the efficacy of TACE treatment. CONCLUSIONS: The COVID-19 pandemic causes a longer follow-up interval in general, which may further lead to a lower ORR in HCC patients. Those with a follow-up interval of >95 days tend to have a worse prognosis.

Development of TACE Refractoriness Scores in Hepatocellular Carcinoma.

Purpose: To identify the independent risk factors for transarterial embolization (TACE) refractoriness and to develop a novel TACE refractoriness score and nomogram for predicting TACE refractoriness in patients with hepatocellular carcinoma (HCC). Methods: Between March 2006 and March 2016, HCC patients who underwent TACE monotherapy as initial treatment at two hospitals formed the study cohort and validation cohort. The criteria of TACE refractoriness followed the Japan Society of Hepatology 2014 version of TACE refractoriness. In the study cohort, the independent risk factors for TACE refractoriness were identified, and TACE refractoriness score and nomogram were then developed. The accuracy of the systems was validated externally in the validation cohort. Results: In total, 113 patients from hospital A formed the study cohort and 122 patients from hospital B formed the validation cohort. In the study cohort, 82.3% of the patients (n = 93) developed TACE refractoriness with a median overall survival (OS) of 540 days (95% CI, 400.8-679.1), and the remaining 20 patients in the TACE-non-refractory group had a median OS of 1,257 days (95% CI, 338.8-2,175.2) (p = 0.019). The median time for developing TACE refractoriness was 207 days (95% CI, 134.8-279.2), and a median number of two TACE procedures were performed after refractoriness developed. The independent risk factors for TACE refractoriness were the number of tumors and bilobular invasion of HCC. TACE refractoriness scores <3.5 indicated a lower incidence of TACE refractoriness, whereas scores >3.5 points indicated a higher incidence (p < 0.001). In the validation cohort, 77.9% of the patients (n = 95) developed TACE refractoriness with a median OS of 568 days (95% CI, 416.3-719.7), and a median OS of 1,324 days was observed in the TACE-non-refractory group (n = 27; 95% CI, 183.5-2,464.5). Conclusions: TACE refractoriness impairs the OS of HCC patients. The number of tumors and bilobular invasion status were independent risk factors for TACE refractoriness. The TACE refractoriness score can be an effective tool and easy approach to predict the risk of TACE refractoriness status.

Radiomics Facilitates Candidate Selection for Irradiation Stents Among Patients With Unresectable Pancreatic Cancer.

Purpose: To develop a model to select appropriate candidates for irradiation stent placement among patients with unresectable pancreatic cancer with malignant biliary obstruction (UPC-MBO). Methods: This retrospective study included 106 patients treated with an irradiation stent for UPC-MBO. These patients were randomly divided into a training group (74 patients) and a validation group (32 patients). A clinical model for predicting restenosis-free survival (RFS) was developed with clinical predictors selected by univariate and multivariate analyses. After integrating the radiomics signature, a combined model was constructed to predict RFS. The predictive performance was evaluated with the concordance index (C-index) in both the training and validation groups. The median risk score of progression in the training group was used to divide patients into high- and low-risk subgroups. Results: Radiomics features were integrated with clinical predictors to develop a combined model. The predictive performance was better in the combined model (C-index, 0.791 and 0.779 in the training and validation groups, respectively) than in the clinical model (C-index, 0.673 and 0.667 in the training and validation groups, respectively). According to the median risk score of 1.264, the RFS was significantly different between the high- and low-risk groups (p < 0.001 for the training group, and p = 0.016 for the validation group). Conclusions: The radiomics-based model had good performance for RFS prediction in patients with UPC-MBO who received an irradiation stent. Patients with slow progression should consider undergoing irradiation stent placement for a longer RFS.

Proteomic Analysis of the Peritrophic Matrix from the Midgut of Third Instar Larvae, Musca domestica / 生物医学与环境科学（英文）

<p><b>OBJECTIVE</b>To better comprehend the molecular structure and physiological function of the housefly larval peritrophic matrix (PM), a mass spectrometry approach was used to investigate the PM protein composition.</p><p><b>METHODS</b>The PM was dissected from the midgut of the third instar larvae, and protein extracted from the PM was evaluated using SDS-PAGE. A 1D-PAGE lane containing all protein bands was cut from top to bottom, the proteins in-gel trypsinised and analysed via shotgun liquid chromatography- tandem mass spectrometry (LC-MS/MS).</p><p><b>RESULTS</b>In total, 374 proteins, with molecular weights varying from 8.225 kD to 996.065 kD and isoelectric points ranging from 3.83 to 11.24 were successfully identified, most identified proteins were mainly related to immunity, digestion, nutrient metabolism and PM structure. Furthermore, many of these proteins were functionally associated with pattern binding, polysaccharide binding, structural constituent of peritrophic membrane and chitin binding, according to Gene Ontology annotation.</p><p><b>CONCLUSION</b>The PM protein composition, which provides a basis for further functional investigations of the identified proteins, will be useful for understanding the housefly larval gut immune system and may help to identify potential targets and exploit new bioinsecticides.</p>