The Influence of Visceral Adiposity on Overall Survival: Exploring "Obesity Paradox" Among Hepatocellular Carcinoma Patients Who Receiving Immunotherapy.

Purpose: The impact of visceral adiposity on overall survival (OS) in hepatocellular carcinoma (HCC) receiving immunotherapy was unclear. We aimed to determine how visceral adiposity affected OS and explore the interrelationships between visceral adiposity, body mass index (BMI), and other body compositions. Patients and Methods: Data from three centers were retrospectively analyzed. Skeletal muscle index (SMI), skeletal muscle density (SMD), visceral adipose tissue index (VATI), and subcutaneous adipose tissue index (SATI) were used to define each body composition. The BMI subgroups included the underweight, the normal weight, and the obesity. The Log rank test compared survival curves calculated by the Kaplan-Meier method. The relationships between body compositions and BMI with OS were examined using Cox proportional risk regression models. Results: A total of 305 patients who met the criteria were included. Patients with low VATI had significantly worse OS (P = 0.001). The protections of VATI (P = 0.011) on OS were independent of covariates. However, after additional adjustment of SMI, the effect of VATI on OS disappeared (P = 0.146), but the effect of SMD on OS did not (P = 0.021). BMI has a significant U-shaped relationship with OS, and the effect of BMI on OS equally disappeared after additional adjustment by SMI. Conclusion: This study first demonstrated that high VATI and mid-level BMI were protective for the survival of patients with HCC receiving immunotherapy. Skeletal muscle status (including SMI and SMD) may be the better predictor for outcomes of patients with HCC receiving immunotherapy.

Long-term prognosis of patients with gallbladder carcinoma after curative-intent resection based on changes in the ratio of carbohydrate antigen 19-9 to total bilirubin (CA19-9/TB): a multicenter retrospective cohort study.

BACKGROUND: The prognostic value of carbohydrate antigen 19-9 (CA19-9) is known to be affected by elevated bilirubin levels in patients with gallbladder carcinoma (GBC). The clinical significance of changes in the ratio of CA19-9 levels to total bilirubin (TB) levels in patients with GBC after curative-intent resection remains unknown. The aim of this study was to determine the prognostic value of changes in preoperative and postoperative CA19-9/TB ratio in these patients. METHODS: Prospectively collected data on consecutive patients who underwent curative-intent resection for GBC between January 2015 and December 2020 stored in a multicenter database from 10 hospitals were analyzed in this retrospective cohort study. Based on the adjusted CA19-9 defined as the ratio of CA19-9 to TB, and using 2×10 3  U/µmol as the upper normal value, patients were divided into a normal group (with normal preoperative and postoperative adjusted CA19-9), a normalization group (with abnormal preoperative but normal postoperative adjusted CA19-9), and a non-normalization group (with abnormal postoperative adjusted CA19-9). The primary outcomes were overall survival (OS) and recurrence-free survival (RFS). The log-rank test was used to compare OS and RFS among the groups. The Cox regression model was used to determine factors independently associated with OS and RFS. RESULTS: The normal group ( n =179 patients) and the normalization group ( n =73 patients) had better OS and RFS than the non-normalization group ( n =65 patients) (the 3-year OS rates 72.0%, 58.4% and 24.2%, respectively; the RFS rates 54.5%, 25.5% and 11.8%, respectively; both P <0.001). There were no significant differences between the normal and the normalization groups in OS and RFS (OS, P =0.255; RFS, P =0.130). Cox regression analysis confirmed that the non-normalization group was independently associated with worse OS and RFS. Subgroup analysis revealed that the non-normalization group of patients who received adjuvant therapy had significantly improved OS and RFS as compared to those who did not receive adjuvant therapy (OS, P =0.025; RFS, P =0.003). CONCLUSIONS: Patients with GBC who underwent curative-intent surgical resection with postoperative abnormal levels of adjusted CA19-9 (the CA19-9/TB ratio) were associated with poorer long-term survival outcomes. Adjuvant therapy after surgery improved the long-term outcomes of these patients.

Laparoscopic liver resection versus radiofrequency ablation for caudate lobe solitary hepatocellular carcinoma: A propensity score matching study.

OBJECTIVE: This study aimed to compare the clinical efficacy of laparoscopic liver resection (LLR) and radiofrequency ablation (RFA) in treating solitary hepatocellular carcinoma (HCC) of the hepatic caudate lobe. METHODS: Patients with hepatic caudate lobe HCC who underwent LLR or RFA at three hospitals in China between February 2015 and February 2021 were included. In total, 112 patients met the inclusion criteria, of whom 52 underwent RFA and 60 underwent LLR. The outcomes of the two groups were compared and analyzed using propensity score matching (PSM) method. RESULTS: There were no significant differences between the two groups in terms of sex, HBV/HCV positivity, AFP positivity (>100 ng/mL), tumor position, Child-Pugh score, or preoperative liver function tests (ALT, AST, TBIL, ALB, and PT) (p > 0.05). Compared to the LLR group, the RFA group had a shorter operation time, less intraoperative bleeding, and shorter postoperative hospital stay (p < 0.05). There was no statistically significant difference in overall postoperative complications between the two groups (p > 0.05). Despite the larger tumor size, the LLR group had better postoperative recurrence-free survival (RFS) (p = 0.00027) and overall survival (OS) (p = 0.0023) than the RFA group. After one-to-one PSM, 31 LLR patients and 31 RFA patients were selected for further analyses. The advantages of LLR over RFA were observed in terms of RFS (p < 0.0001) and OS (p = 0.00029). CONCLUSION: LLR should probably be recommended as the preferred method for solitary caudate lobe HCC.

Tyrosine phosphatase PTPN11/SHP2 in solid tumors - bull's eye for targeted therapy?

Encoded by PTPN11, the Src-homology 2 domain-containing phosphatase 2 (SHP2) integrates signals from various membrane-bound receptors such as receptor tyrosine kinases (RTKs), cytokine and integrin receptors and thereby promotes cell survival and proliferation. Activating mutations in the PTPN11 gene may trigger signaling pathways leading to the development of hematological malignancies, but are rarely found in solid tumors. Yet, aberrant SHP2 expression or activation has implications in the development, progression and metastasis of many solid tumor entities. SHP2 is involved in multiple signaling cascades, including the RAS-RAF-MEK-ERK-, PI3K-AKT-, JAK-STAT- and PD-L1/PD-1- pathways. Although not mutated, activation or functional requirement of SHP2 appears to play a relevant and context-dependent dichotomous role. This mostly tumor-promoting and infrequently tumor-suppressive role exists in many cancers such as gastrointestinal tumors, pancreatic, liver and lung cancer, gynecological entities, head and neck cancers, prostate cancer, glioblastoma and melanoma. Recent studies have identified SHP2 as a potential biomarker for the prognosis of some solid tumors. Based on promising preclinical work and the advent of orally available allosteric SHP2-inhibitors early clinical trials are currently investigating SHP2-directed approaches in various solid tumors, either as a single agent or in combination regimes. We here provide a brief overview of the molecular functions of SHP2 and collate current knowledge with regard to the significance of SHP2 expression and function in different solid tumor entities, including cells in their microenvironment, immune escape and therapy resistance. In the context of the present landscape of clinical trials with allosteric SHP2-inhibitors we discuss the multitude of opportunities but also limitations of a strategy targeting this non-receptor protein tyrosine phosphatase for treatment of solid tumors.

Induction of MTHFD2 in Macrophages Inhibits Reactive Oxygen Species-mediated NF-κB Activation and Protects against Inflammatory Responses.

The one-carbon metabolism enzyme methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) is critical for cancer cell proliferation and immune cell phenotypes, but whether it can contribute to macrophage inflammatory responses remains unclear. In this study, we show that MTHFD2 was upregulated by LPS in murine macrophages upon activation of the TLR4-MyD88-IKKα/ß-NF-κB signaling pathway. MTHFD2 significantly attenuated LPS-induced macrophage proinflammatory cytokine production through its enzymatic activity. Notably, ablation of myeloid MTHFD2 rendered mice more sensitive to septic shock and CCl4-induced acute hepatitis. Mechanistically, MTHFD2 restrained IKKα/ß-NF-κB activation and macrophage inflammatory phenotype by scavenging reactive oxygen species through the generation of NADPH. Our study reveals MTHFD2 as a "self-control" mechanism in macrophage-mediated inflammatory responses.

Genomic characterization and immunotherapy for microsatellite instability-high in cholangiocarcinoma.

BACKGROUND: Microsatellite instability-high (MSI-H) is a unique genomic status in many cancers. However, its role in the genomic features and immunotherapy in cholangiocarcinoma (CCA) is unclear. This study aimed to systematically investigate the genomic characterization and immunotherapy efficacy of MSI-H patients with CCA. METHODS: We enrolled 887 patients with CCA in this study. Tumor samples were collected for next-generation sequencing. Differences in genomic alterations between the MSI-H and microsatellite stability (MSS) groups were analyzed. We also investigated the survival of PD-1 inhibitor-based immunotherapy between two groups of 139 patients with advanced CCA. RESULTS: Differential genetic alterations between the MSI-H and MSS groups included mutations in ARID1A, ACVR2A, TGFBR2, KMT2D, RNF43, and PBRM1 which were enriched in MSI-H groups. Patients with an MSI-H status have a significantly higher tumor mutation burden (TMB) (median 41.7 vs. 3.1 muts/Mb, P < 0.001) and more positive programmed death ligand 1 (PD-L1) expression (37.5% vs. 11.9%, P < 0.001) than those with an MSS status. Among patients receiving PD-1 inhibitor-based therapy, those with MSI-H had a longer median overall survival (OS, hazard ratio (HR) = 0.17, P = 0.001) and progression-free survival (PFS, HR = 0.14, P < 0.001) than patients with MSS. Integrating MSI-H and PD-L1 expression status (combined positive score ≥ 5) could distinguish the efficacy of immunotherapy. CONCLUSIONS: MSI-H status was associated with a higher TMB value and more positive PD-L1 expression in CCA tumors. Moreover, in patients with advanced CCA who received PD-1 inhibitor-based immunotherapy, MSI-H and positive PD-L1 expression were associated with improved both OS and PFS. TRIAL REGISTRATION: This study was registered on ClinicalTrials.gov on 07/01/2017 (NCT03892577).

The GRAPHS-CRAFITY score: a novel efficacy predictive tool for unresectable hepatocellular carcinoma treated with immunotherapy.

OBJECTIVES: To investigate MR features associated with prognosis of unresectable HCC receiving immunotherapy and establish a MR feature-based scoring system to predict efficacy of immunotherapy. METHODS: This retrospective study included patients with unresectable HCC who received immunotherapy at 2 hospitals between August 2018 and February 2022. The last follow-up was October 2022. Clinical variables and MR features were assessed using univariate and multivariate Cox regression analyses. A new scoring system was constructed based on independent risk factors and the CRAFITY score consisting of AFP (≥ 100 ng/ml) and CRP (≥ 1 mg/dl). And the predictive performance of CRAFITY core and new score were compared by receiver-operating-characteristics curves (ROCs), area under ROCs (AUCs), and calibration curves. RESULTS: A total of 166 patients (55.6 ± 10.4 years) were included in training cohort and 77 patients (55.4 ± 10.7 years) were included in validation cohort. There were significant differences in BCLC stage, max size, macrovascular invasion, intratumoral artery, and enhancing capsule between the 2 groups. Based on independent risk factors (gross GRowtH type, intratumoral fAt, enhancing tumor caPsule, Sex and CRAFITY score), a novel efficacy predictive tool named the GRAPHS-CRAFITY score was developed to predict OS. The OS was significantly different among the 3 groups according to GRAPHS-CRAFITY score (p value < 0.001). The GRAPHS-CRAFITY score could predict tumor response and disease control (p value < 0.001, p value < 0.001). CONCLUSIONS: The GRAPHS-CRAFITY score is a reliable and easily applicable tool to predict the efficacy of unresectable HCC receiving immunotherapy.

Reclassification of therapeutic response of unresectable hepatocellular carcinoma to anti-angiogenic therapy and immunotherapy using alpha RECIST.

OBJECTIVES: To assess the therapeutic response of HCC to antiangiogenic therapy plus immunotherapy by integrating RECIST 1.1 and alpha-fetoprotein (AFP) response at the 6th week to predict overall survival (OS). METHODS: This retrospective study included 150 and 214 patients with HCC who received combination therapy in training and validation cohorts. The medical images and AFP levels obtained at baseline and 6th week were collected. AFP response stratification: partial response (PR): AFP% ≥ 75% decline; stable disease (SD): AFP% < 75% decline and ≤ 10% elevation; progressive disease (PD): AFP% > 10% elevation. The alpha-RECIST was: PR: RECIST 1.1-PR or AFP-PR; PD: AFP-PD or RECIST 1.1-PD and does not satisfy AFP-PR; SD: neither PR nor PD. OS was compared using Kaplan-Meier curves. The predictive ability of various criteria was evaluated using the concordance index and time-dependent area under the receiver-operating characteristic curve. RESULTS: RECIST 1.1 achieved significant OS stratification (p = 0.020) for AFP < 20 ng/mL. For AFP ≥ 20 ng/mL, alpha-RECIST showed better performance than RECIST 1.1, mRECIST, and AFP response according to C-index (0.73 vs 0.66 vs 0.68 vs 0.69). The National Cancer Center (NCC) strategy utilized RECIST 1.1 for AFP < 20 ng/mL and alpha-RECIST for AFP ≥ 20 ng/mL and showed better performance than RECIST 1.1, mRECIST and AFP response according to C-index (0.73 vs 0.67 vs 0.69 vs 0.64). The performances of alpha-RECIST and NCC Strategy were confirmed in the validation cohort (C-index = 0.77 and 0.74). CONCLUSIONS: The alpha-RECIST and NCC Strategy achieved better survival stratification in patients with HCC under combination therapy in the AFP ≥ 20 ng/mL group and the whole cohort compared to the RECIST 1.1, mRECIST, and AFP response. CLINICAL TRANSLATIONAL RELEVANCE: The alpha-RECIST and National Cancer Center strategy are optimal methods for determining therapeutic response to a combination of anti-angiogenic therapy plus immunotherapy and facilitating accurate prognostic stratification for HCC in the AFP ≥ 20 ng/mL group and the whole cohort, which may help oncologists for early identification of responders and progression at 6 weeks and clinical decision-making. KEY POINTS: • RECIST 1.1 is indicated for patients with baseline alpha-fetoprotein (AFP) < 20 ng/mL. • For patients with baseline AFP ≥ 20 ng/mL, integrating RECIST 1.1 and AFP response (alpha-RECIST) may aid in the early identification of survival benefits and progression definition prior to the administration of additional efficacious drugs. • The National Cancer Center strategy is an optimal stratified strategy for determining therapeutic response to a combination of anti-angiogenic therapy and immunotherapy for HCC based on baseline AFP levels.

Comparative efficacy and safety of systemic therapy for advanced hepatocellular carcinoma: a systematic review and network meta-analysis.

Background: In recent years, there has been rapid development in systemic therapeutic agents for advanced hepatocellular carcinoma. However, most treatment modalities lack head-to-head comparisons, and the distinctions in their efficacy and safety have yet to be elucidated. Consequently, the accurate selection of a treatment regimen poses a significant challenge for clinicians. Methods: This study incorporated twenty-three randomized controlled trials, encompassing fifteen first-line and eight second-line treatments, and involving a total of 14,703 patients with advanced hepatocellular carcinoma. Results: In the context of first-line treatment, it was observed that the combination of a PD-1 inhibitor with bevacizumab (1/15) significantly extended overall survival in patients with advanced HCC. Furthermore, PD-1 inhibitors combined with TKIs (1/15) and PD-1 inhibitors combined with bevacizumab (2/15) exhibited enhanced efficacy in reducing the risk of progression-free survival events. In second-line therapy, the network meta-analysis revealed that all investigational agents prolonged progression-free survival in patients with advanced hepatocellular carcinoma when compared to placebo. Cabozantinib ranked first (1/7) in this regard. However, this translated into an overall survival benefit only for cabozantinib, regorafenib, ramucirumab, and pembrolizumab, with regorafenib achieving the highest ranking (1/7). Conclusion: In the treatment of advanced HCC, the immune checkpoint inhibitor combined with bevacizumab regimen and the immune checkpoint inhibitor combined with TKI regimen stand out as the two most effective first-line treatment options. It is noteworthy that, for patients with absolute contraindications to VEGF inhibitors, dual immunotherapy is the preferred choice. For second-line treatment, regorafenib and cabozantinib are identified as the two most effective options. Systematic review registration: https://www.crd.york.ac.uk/prospero, identifier CRD42023440173.

Association Between MRI Radiomics and Intratumoral Tertiary Lymphoid Structures in Intrahepatic Cholangiocarcinoma and Its Prognostic Significance.

BACKGROUND: Tertiary lymphoid structures (TLSs) have prognostic value in intrahepatic cholangiocarcinoma (ICC) patients. Noninvasive tool to preoperatively evaluate TLSs is still lacking. PURPOSE: To explore the association between TLSs status of ICC and preoperative MRI radiomics analysis. STUDY TYPE: Retrospective. SUBJECTS: One hundred and ninety-two patients with ICC, divided into training (T = 105), internal validation groups (V1 = 46), and external validation group (V2 = 41). SEQUENCE: Coronal and axial single-shot fast spin-echo T2-weighted, diffusion-weighted imaging, T1-weighted, and T1WI fat-suppressed spoiled gradient-recall echo LAVA sequence at 3.0 T. ASSESSMENT: The VOIs were drawn manually within the visible borders of the tumors using ITK-SNAP version 3.8.0 software in the axial T2WI, DWI, and portal vein phase sequences. Radiomics features were subjected to least absolute shrinkage and selection operator regression to select the associated features of TLSs and construct the radiomics model. Univariate and multivariate analyses were used to identify the clinical radiological variables associated with TLSs. The performances were evaluated by the area under the receiver operator characteristic curve (AUC). STATISTICAL TESTS: Logistic regression analysis, ROC and AUC, Hosmer-Lemeshow test, Kaplan-Meier method with the log-rank test, calibration curves, and decision curve analysis. P < 0.05 was considered statistically significant. RESULTS: The AUCs of arterial phase diffuse hyperenhancement were 0.59 (95% confidence interval [CI], 0.50-0.67), 0.52 (95% CI, 0.43-0.61), and 0.66 (95% CI, 0.52-0.80) in the T, V1, and V2 cohorts. The AUCs of Rad-score were 0.85 (95% CI, 0.77-0.92), 0.81 (95% CI, 0.67-0.94), and 0.84 (95% CI, 0.71-0.96) in the T, V1, and V2 cohorts, respectively. In cohort T, low-risk group showed significantly better median recurrence-free survival (RFS) than that of the high-risk group, which was also confirmed in cohort V1 and V2. DATA CONCLUSION: A preoperative MRI radiomics signature is associated with the intratumoral TLSs status of ICC patients and correlate significantly with RFS. LEVEL OF EVIDENCE: 3 TECHNICAL EFFICACY: Stage 2.

Using immunovascular characteristics to predict very early recurrence and prognosis of resectable intrahepatic cholangiocarcinoma.

OBJECTIVE: To predict the very early recurrence (VER) of patients with intrahepatic cholangiocarcinoma (ICC) based on TLSs and MVI status, and further perform prognosis stratifications. METHODS: A total of 160, 51 ICC patients from two institutions between May 2012 and July 2022 were retrospectively included as training, external validation cohort. Clinical, radiological and pathological variables were evaluated and collected. Univariate and multivariate analysis were applied to select the significant factors related to VER of ICC. The factors selected were combined to perform stratification of overall survival (OS) using the Kaplan-Meier method with the log-rank test. RESULTS: Overall, 39 patients (24.4%) had VER, whereas 121 (75.6%) did not (non-VER group). In the training cohort, the median OS was 40.5 months (95% CIs: 33.2-47.7 months). The VER group showed significantly worse OS than the non-VER group (median OS: 14.8, 95% CI:11.6-18.0 months vs. 53.4, 34.3-72.6 months; p<0.001), and it was confirmed in the validation cohort (median OS: 22.1, 95% CI: 8.8-35.4 months vs. 40.1, 21.2-59.0 months; p = 0.003). According to the univariate analysis, four variables were significantly different between the VER group and non-VER group (TLSs status, p = 0.028; differentiation, p = 0.023; MVI status, p = 0.012; diameter, p = 0.028). According to the multivariate analysis, MVI-positive status was independently associated with a higher probability of VER (odds ratio [OR], 2.5; 95% CIs,1.16-5.18; p = 0.018), whereas intra-tumoral TLSs-positive status was associated with lower odds of VER (OR, 0.43; 95% CIs, 0.19-0.97; p = 0.041). Based on the TLSs and MVI status, patients of ICC were categorized into four groups: TLSs-positive and MVI-negative (TP/MN); TLSs-negative and MVI-negative (TN/MN); TLSs-positive and MVI-positive (TP/MP), TLSs-negative and MVI-positive groups (TN/MP). In the training cohort, the four groups could be correlated with OS significantly (p<0.001), and it was confirmed in the validation cohort (p<0.001). CONCLUSION: Intra-tumoral TLSs and MVI status are independent predictive factors of VER after surgery, based on which immunovascular stratifications are constructed and associated with OS significantly of resectable intrahepatic cholangiocarcinoma.

A CT-based radiomics approach to predict intra-tumoral tertiary lymphoid structures and recurrence of intrahepatic cholangiocarcinoma.

PURPOSE: To predict the tertiary lymphoid structures (TLSs) status and recurrence-free survival (RFS) of intrahepatic cholangiocarcinoma (ICC) patients using preoperative CT radiomics. PATIENTS AND METHODS: A total of 116 ICC patients were included (training: 86; external validation: 30). The enhanced CT images were performed for the radiomics model. The logistic regression analysis was applied for the clinical model. The combined model was based on the clinical and radiomics models. RESULTS: A total of 107 radiomics features were extracted, and after being eliminated and selected, six features were combined to establish a radiomics model for TLSs prediction. Arterial phase diffuse hyperenhancement and AJCC 8th stage were combined to construct a clinical model. The combined (radiomics nomogram) model outperformed both the independent radiomics model and clinical model in the training cohort (AUC, 0.85 vs. 0.82 and 0.75, respectively) and was validated in the external validation cohort (AUC, 0.88 vs. 0.86 and 0.71, respectively). Patients in the rad-score no less than -0.76 (low-risk) group showed significantly better RFS than those in the less than -0.76 (high-risk) group (p < 0.001, C-index = 0.678). Patients in the nomogram score no less than -1.16 (low-risk) group showed significantly better RFS than those of the less than -1.16 (high-risk) group (p < 0.001, C-index = 0.723). CONCLUSIONS: CT radiomics nomogram could serve as a preoperative biomarker of intra-tumoral TLSs status, better than independent radiomics or clinical models; preoperative CT radiomics nomogram achieved accurate stratification for RFS of ICC patients, better than the postoperative pathologic TLSs status. CRITICAL RELEVANCE STATEMENT: The radiomics nomogram showed better performance in predicting TLSs than independent radiomics or clinical models and better prognosis stratification than postoperative pathologic TLSs status in ICC patients, which may facilitate identifying patients benefiting most from surgery and subsequent immunotherapy. KEY POINTS: • The combined (radiomics nomogram) model consisted of the radiomics model and clinical model (arterial phase diffuse hyperenhancement and AJCC 8th stage). • The radiomics nomogram showed better performance in predicting TLSs than independent radiomics or clinical models in ICC patients. • Preoperative CT radiomics nomogram achieved more accurate stratification for RFS of ICC patients than the postoperative pathologic TLSs status.

The MAPS-CRAFITY score: a novel efficacy predictive tool for unresectable hepatocellular carcinoma treated with targeted therapy plus immunotherapy.

BACKGROUND: Body composition parameters (BCPs) are associated with mortality in patients with hepatocellular carcinoma (HCC). Our purpose was to develop a practical scoring model by BCP and the CRAFITY score to predict the overall survival (OS) and tumor response of patients with HCC who received targeted therapy plus immunotherapy. METHODS: This retrospective study included 265 patients with HCC who received targeted therapy plus immunotherapy at 2 centers in China from August 2018 to February 2022. Univariate and multivariate Cox regression analyses were applied to analyze clinical factors and BCP. A scoring model based on independent risk factors was developed to predict OS and tumor response. Moreover, the model's prediction was further validated by an external cohort. RESULTS: A total of 150 patients (55.5 ± 10.8 years) and 115 patients (55.0 ± 8.9 years) treated with lenvatinib or bevacizumab biosimilar plus anti-programmed death-1 (PD-1) antibody were included in training and validation cohorts, respectively. In the training cohort, independent predictive factors for OS included macrovascular invasion (p = 0.016), Child‒Pugh class (A vs. B, p = 0.001; A vs. C, p < 0.001), sarcopenia (p = 0.034), and the CRAFITY score (p = 0.011). Based on independent risk factors (MAcrovascular invasion, Child‒Pugh class, Sarcopenia, and the CRAFITY score) identified by multivariate analysis, a novel efficacy predictive tool named the MAPS-CRAFITY score was developed to predict OS. In all the training and validation cohorts, the OS differed significantly across the three groups based on the MAPS-CRAFITY score (< 2.1, 2.1-2.3, ≥ 2.4; p < 0.001). Moreover, the C-index of the MAPS-CRAFITY score was 0.720 and 0.761 in the training and validation cohorts, respectively. In both the validation and training cohorts, the MAPS-CRAFITY score was predictive of tumor response and disease control (p < 0.001). The AUCs of the MAPS-CRAFITY score for predicting disease control were 0.752 in the training cohort and 0.836 in the validation cohort. CONCLUSIONS: The MAPS-CRAFITY score based on sarcopenia and the CRAFITY score is a reliable and practical tool for predicting the efficacy of targeted therapy plus immunotherapy in patients with unresectable HCC, and may help hepatologists and oncologists in clinical decision-making.

Adjuvant Lenvatinib Plus PD-1 Antibody for Hepatocellular Carcinoma with High Recurrence Risks After Hepatectomy: A Retrospective Landmark Analysis.

Purpose: To evaluate the efficacy and safety of lenvatinib plus programmed death-1 (PD-1) antibody as postoperative adjuvant therapy in patients with hepatocellular carcinoma (HCC) at high risks of recurrence. Patients and Methods: A series of 137 patients with HCC at high risks of recurrence who underwent hepatectomy at our hospital between October 2019 and January 2022 were retrospectively analyzed. Recurrence-free survival (RFS), overall survival (OS), and treatment-related adverse events (TRAEs) were assessed. Landmark analysis was used to compare short- and long-term RFS. Univariable and multivariable analyses were used to identify prognostic factors, and subgroup analyses were performed according to high risks of recurrence. Results: A total of 85 patients underwent hepatectomy alone and 52 patients received postoperative adjuvant therapy. Compared with the hepatectomy group (HG), RFS was significantly improved in the adjuvant therapy group (ATG) (P < 0.001), but OS was not (P = 0.098). Landmark analysis revealed that RFS within 6 months of the HG was significantly different from that of the ATG (P < 0.001) but not after 6 months (P = 0.486). Multivariable analysis showed that without adjuvant therapy, high Child-Pugh classification, high alpha-fetoprotein levels, microvascular invasion, and satellite lesions were independent risk factors for recurrence within 6 months after hepatectomy. Subgroup analysis revealed that patients with MVI significantly benefited from adjuvant therapy in RFS. But for OS, adjuvant therapy was only significantly effective in patients with single tumor. The most common treatment-related adverse events during adjuvant therapy were hypertension (36.5%), rash or itching (28.8%), diarrhea (23.1%), and fatigue (21.2%). Conclusion: Postoperative adjuvant lenvatinib plus PD-1 antibody significantly improved RFS in patients with HCC at high risks of recurrence with acceptable safeties.

MRI-Based Radiomics Nomogram for Preoperatively Differentiating Intrahepatic Mass-Forming Cholangiocarcinoma From Resectable Colorectal Liver Metastases.

RATIONALE AND OBJECTIVES: To establish a radiomics nomogram based on multiparameter magnetic resonance (MR) images for preoperatively differentiating intrahepatic mass-forming cholangiocarcinoma (IMCC) from colorectal cancer liver metastasis (CRLM). MATERIALS AND METHODS: A total of 133 patients in training cohort (64 IMCC and 69 CRLM), 57 patients in internal validation cohort (29 IMCC and 28 CRLM), and 51 patients (23 IMCC and 28 CRLM) in external validation cohort were included. Radiomics features were extracted from the multiparameter MR images and selected by the least absolute shrinkage and selection operator algorithm to establish the radiomics model. Clinical variables and magnetic resonance imaging (MRI) findings were selected by univariate and multivariate analyses to construct a clinical model. The radiomics nomogram was combined with radiomics model and clinical model. RESULTS: Six features were selected to construct the radiomics model. The radiomics signature showed better discrimination than the clinical model in the training cohort (Area Under the Curve (AUC), 0.92; 95% confidence interval (CI), 0.87-0.96 vs. AUC, 0.74; 95% CI, 0.66-0.83) and the external validation cohort (AUC, 0.90; 95% CI, 0.82-0.98 vs. AUC, 0.81; 95% CI, 0.69-0.93). The radiomics nomogram showed the best discrimination performance with favorable calibration in the training cohort (AUC, 0.94; 95% CI, 0.90-0.97) and the external validation cohort (AUC, 0.92; 95% CI, 0.84-1.00). CONCLUSION: The radiomics nomogram combining radiomics signatures based on multiparameter MRI with clinical factors (serum carcinoembryonic antigen level and tumor diameter) may provide a reliable and noninvasive tool to discriminate IMCC from CRLM, which could help guide treatment strategies and prognosis preoperatively prediction.

Textbook outcomes in liver surgery for gallbladder cancer patients treated with curative-intent resection: a multicenter observational study.

BACKGROUND: Cholecystectomy, hepatectomy, and lymphadenectomy are recommended as the curative treatment for resectable gallbladder cancer (GBC). Textbook outcomes in liver surgery (TOLS) is a novel composite measure that has been defined by expert consensus to represent the optimal postoperative course after hepatectomy. This study aimed to determine the incidence of TOLS and the independent predictors associated with TOLS after curative-intent resection in GBC patients. METHODS: All consecutive GBC patients who underwent curative-intent resection between 2014 and 2020 were enrolled from a multicenter database from 11 hospitals as the training and the internal testing cohorts, and Southwest Hospital as the external testing cohort. TOLS was defined as no intraoperative grade greater than or equal to 2 incidents, no grade B/C postoperative bile leaks, no postoperative grade B/C liver failure, no 90-day postoperative major morbidity, no 90-day readmission, no 90-day mortality after hospital discharge, and R0 resection. Independent predictors of TOLS were identified using logistic regression and were used to construct the nomogram. The predictive performance was assessed using the area under the curve and calibration curves. RESULTS: TOLS was achieved in 168 patients (54.4%) and 74 patients (57.8%) from the training and internal testing cohorts, and the external testing cohort, respectively. On multivariate analyses, age less than or equal to 70 years, absence of preoperative jaundice (total bilirubin≤3 mg/dl), T1 stage, N0 stage, wedge hepatectomy, and no neoadjuvant therapy were independently associated with TOLS. The nomogram that incorporated these predictors demonstrated excellent calibration and good performance in both the training and external testing cohorts (area under the curve: 0.741 and 0.726). CONCLUSIONS: TOLS was only achieved in approximately half of GBC patients treated with curative-intent resection, and the constructed nomogram predicted TOLS accurately.

Predictive Factors of Treatment Outcomes After Percutaneous Radiofrequency Ablation of Hepatocellular Carcinoma in the Hepatocaval Confluence: A Propensity Score Matching Analysis.

RATIONALE AND OBJECTIVES: To compare the efficacy and complications of ultrasound-guided percutaneous radiofrequency ablation of hepatocellular carcinoma (HCC) in the hepatocaval confluence with those of HCC in the non-hepatocaval confluence and to explore the risk factors that lead to radiofrequency ablation failure and patient local tumor progression (LTP). MATERIALS AND METHODS: From January 2017 to January 2022, 86 patients with HCC in the hepatocaval confluence who had radiofrequency ablation were included. A 1:1 propensity-matched group of patients with HCC in the non-hepatocaval confluence with comparable clinical baseline traits, such as tumor diameter and tumor number, served as the control group. The two groups' complications, primary efficacy rate (PER), technical success rate (TSR), and prognosis were estimated. RESULTS: After PSM, no significant difference of TSR (91.7% vs 95.8%, p = 0.491) and PER (95.8% vs 97.2%, p = 1.000) and 1-, 3-, and 5-year LTP rate (12.5% vs 9.9%, 28.2% vs 27.7%, 40.8% vs 43.8%, p = 0.959) and 1-, 3-, and 5-year DFS rate (87.5% vs 87.5%, 62.3% vs 54.2%, 18.1% vs 22.6%, p = 0.437) and 1-, 3-, and 5-year OS rate (94.3% vs 95.7%, 72.7% vs 69.6%, 20.9% vs 33.6%, p = 0.904) was detected between the two groups. The tumor-to-IVC distance was an independent risk factor for radiofrequency ablation failure in HCC patients in the hepatocaval confluence (OR = 0.611, p = 0.022). Besides, tumor diameter was an independent risk factor for predicting LTP in patients with HCC in the hepatocaval confluence (HR = 2.209, p = 0.046). CONCLUSION: HCC in the hepatocaval confluence can be effectively treated with radiofrequency ablation. To maximize treatment efficacy, the tumor-to-IVC distance and tumor diameter should be assessed before the operation begins.