Tough, aorta-inspired soft composites.

Spatial variations in fiber alignment (and, therefore, in mechanical anisotropy) play a central role in the excellent toughness and fatigue characteristics of many biological materials. In this work, we examine the effect of fiber alignment in soft composites, including both "in-plane" and "out-of-plane" fiber arrangements. We take inspiration from the spatial variations of fiber alignment found in the aorta to three-dimensionally (3D) print soft, tough silicone composites with an excellent combination of stiffness, toughness, and fatigue threshold, regardless of the direction of loading. These aorta-inspired composites exhibit mechanical properties comparable to skin, with excellent combinations of stiffness and toughness not previously observed in synthetic soft materials.

3D fusion is superior to 2D point-to-point contrast-enhanced US to evaluate the ablative margin after RFA for hepatocellular carcinoma.

PURPOSE: To compare the efficiency of three-dimensional (3D) and two-dimensional (2D) contrast-enhanced ultrasound (CEUS)-derived techniques in evaluating the ablative margin (AM) after radiofrequency ablation (RFA) for hepatocellular carcinoma (HCC). METHODS: In total, 98 patients with 98 HCCs were enrolled. The 2D CEUS point-to-point imaging (2D CEUS-PI) was conducted by comparing the pre- and post-RFA 2D CEUS images manually, and the 3D CEUS fusion imaging (3D CEUS-FI) was conducted by fusing the pre- and post-RFA 3D CEUS images automatically. These two techniques were compared in distinguishing an adequate AM ≥ 5 mm. Risk factors for local tumor progression (LTP) after RFA were analyzed by the Kaplan-Meier method with log-rank test. RESULTS: The mean registration time of 3D CEUS-FI and 2D CEUS-PI was 5.0 and 9.3 min, respectively (p < 0.0001). The kappa coefficient was 0.680 for agreement between 2D CEUS-PI and 3D CEUS-FI in the evaluation of AM (p < 0.0001). Tumors with AM < 5 mm by 2D CEUS-PI were all identified as AM < 5 mm by 3D CEUS-FI. Nonetheless, 16 (26%) tumors identified as AM ≥ 5 mm by 2D CEUS-PI were re-classified as AM < 5 mm by 3D CEUS-FI. During a median follow-up time of 31.2 months (range, 3.2-66.0 months), LTP was identified in 8 tumors. The estimated 1-/2-/3-year cumulative incidence of LTP was 4.4%, 8.1%, and 10.3%, respectively. Higher estimated cumulative incidence of LTP was identified in tumors with AM < 5 mm by 2D CEUS-PI (at 3-year, 27.2% vs 0%; p < 0.001), and by 3D CEUS-FI (at 3-year, 20.7% vs 0%; p = 0.004). CONCLUSION: 3D CEUS-FI excelled in the evaluation of AM when compared with 2D CEUS-PI. With equivalent efficacy in the prediction of LTP, 3D CEUS-FI was superior to 2D CEUS-PI for its automatic and time-saving procedure. CLINICAL RELEVANCE STATEMENT: 3D CEUS fusion imaging may serve as an effective tool in evaluating ablative margin and predicting local tumor progression after RFA in HCC. KEY POINTS: • Both 2D and 3D CEUS-derived techniques could evaluate ablative margin (AM) after RFA for hepatocellular carcinoma. • 3D CEUS fusion imaging was more precise in the evaluation of AM compared to 2D CEUS point-to-point imaging, with advantages of its automatic and time-saving procedure. • An inadequate AM < 5 mm evaluated by CEUS-derived techniques was the only risk factor of LTP after RFA for hepatocellular carcinoma (p < 0.001 for 2D CEUS point-to-point imaging, and p = 0.004 for 3D CEUS fusion imaging).

Predicting symptomatic post-hepatectomy liver failure in patients with hepatocellular carcinoma: development and validation of a preoperative nomogram.

OBJECTIVE: To develop and validate a nomogram based on liver stiffness (LS) for predicting symptomatic post-hepatectomy (PHLF) in patients with hepatocellular carcinoma (HCC). METHODS: A total of 266 patients with HCC were enrolled prospectively from three tertiary referral hospitals from August 2018 to April 2021. All patients underwent preoperative laboratory examination to obtain parameters of liver function. Two-dimensional shear wave elastography (2D-SWE) was performed to measure LS. Three-dimensional virtual resection obtained the different volumes including future liver remnant (FLR). A nomogram was developed by using logistic regression and determined by receiver operating characteristic (ROC) curve analysis and calibration curve analysis, which was validated internally and externally. RESULTS: A nomogram was constructed with the following variables: FLR ratio (FLR of total liver volume), LS greater than 9.5 kPa, Child-Pugh grade, and the presence of clinically significant portal hypertension (CSPH). This nomogram enabled differentiation of symptomatic PHLF in the derivation cohort (area under curve [AUC], 0.915), internal fivefold cross-validation (mean AUC, 0.918), internal validation cohort (AUC, 0.876) and external validation cohort (AUC, 0.845). The nomogram also showed good calibration in the derivation, internal validation, and external validation cohorts (Hosmer-Lemeshow goodness-of-fit test, p = 0.641, p = 0.06, and p = 0.127, respectively). Accordingly, the safe limit of the FLR ratio was stratified using the nomogram. CONCLUSION: An elevated level of LS was associated with the occurrence of symptomatic PHLF in HCC. A preoperative nomogram integrating LS, clinical and volumetric features was useful in predicting postoperative outcomes in patients with HCC, which might help surgeons in the management of HCC resection. CLINICAL RELEVANCE STATEMENT: A serial of the safe limit of the future liver remnant was proposed by a preoperative nomogram for hepatocellular carcinoma, which might help surgeons in 'how much remnant is enough in liver resection'. KEY POINTS: • An elevated liver stiffness with the best cutoff value of 9.5 kPa was associated with the occurrence of symptomatic post-hepatectomy liver failure in hepatocellular carcinoma. • A nomogram based on both quality (Child-Pugh grade, liver stiffness, and portal hypertension) and quantity of future liver remnant was developed to predict symptomatic post-hepatectomy liver failure for HCC, which enabled good discrimination and calibration in both derivation and validation cohorts. • The safe limit of future liver remnant volume was stratified using the proposed nomogram, which might help surgeons in the management of HCC resection.

Treatment outcomes after radiofrequency ablation in patients with non-B non-C hepatocellular carcinoma within Milan criteria: comparison with HBV-related hepatocellular carcinoma.

PURPOSE: This study aims to evaluate the treatment outcomes of radiofrequency ablation (RFA) for patients with non-B non-C hepatocellular carcinoma (HCC) (NBNC-HCC) within Milan criteria, as well as to compare them with those of patients with hepatitis B virus (HBV)-related HCC (HBV-HCC). METHODS: From January 2007 to February 2020, 303 patients with primary HCC who underwent RFA were retrospectively reviewed, including 259 patients with HBV-HCC (HBV-HCC group) and 44 patients with NBNC-HCC (NBNC-HCC group). The clinical characteristics and treatment survivals were evaluated and compared. Moreover, the propensity score matching was used to reduce selection bias. RESULTS: A significantly lower proportion of cirrhosis was observed in the NBNC-HCC group (p = .048). Before propensity score matching, local tumor progression, disease-free survival, and overall survival after RFA showed no significant differences between the two groups (all p > .05). After matching, the overall survival rates in the NBNC-HCC group were significantly better than those in the HBV-HCC group (p = .042). Moreover, for patients with NBNC-HCC, tumor size (hazard ratio = 8.749, 95% confidence interval, 1.599-47.849; p = .012) was the only independent predictor of local tumor progression. CONCLUSIONS: Patients with NBNC-HCC within the Milan criteria after RFA had better long-term survival than patients with HBV-HCC, although larger, prospective and multicenter trials are required to validate these results.

Radiofrequency ablation for pediatric recurrent hepatocellular carcinoma: a single-center experience.

PURPOSE: To summarize our single-center experience with percutaneous ultrasound (US)-guided radiofrequency ablation (RFA) for pediatric recurrent hepatocellular carcinoma (RHCC). METHODS: From September 2007 to September 2021, patients under 18 who underwent percutaneous US-guided RFA for RHCC were retrospectively enrolled in this study. Local effectiveness, complications, local tumor progression (LTP), progression free survival (PFS), and overall survival (OS) were evaluated. RESULTS: A total of 10 patients (9 male and 1 female; mean age, 11.7 ± 4 years ; age range, 6-17 years) with 15 intrahepatic RHCC lesions were enrolled in this study. Complete ablation (CA) was achieved in 14 out of 15 lesions (93.3%) after the first RFA. During the follow-up (mean, 63.1 ± 18 months; range, 5.3-123.3 months), LTP did not occur. Five patients died including three with tumor progression and one with liver failure. The accumulative one- and three-year PFS rates were 30% and 10%, respectively. The accumulative one- and three-year OS rates were 77.8% and 44.4%, respectively. CONCLUSIONS: Our single-center experience suggests the safety and feasibility of percutaneous US-guided RFA for pediatric RHCC.

Liver Stiffness Measured by Two-Dimensional Shear Wave Elastography for Predicting Symptomatic Post-hepatectomy Liver Failure in Patients with Hepatocellular Carcinoma.

OBJECTIVES: To evaluate the ability of liver stiffness (LS) measured by two-dimensional shear wave elastography (2D SWE) to predict symptomatic post-hepatectomy liver failure (SPHLF) in patients with hepatocellular carcinoma (HCC). METHODS: A total of 119 patients who underwent hepatectomy for HCC between August 2018 and July 2019 were enrolled. Preoperative assessments for LS and other clinicopathological tests were performed in all patients. Univariate and multivariate analyses were conducted for the risk factors of SPHLF. Further subgroup analysis was performed according to multivariate analysis results. RESULTS: SPHLF occurred in 38 patients (31.9%). The best cutoff value of LS for predicting SPHLF was 9.5 kPa. Multivariate analysis identified LS ≥ 9.5 kPa, greater Child-Turcotte-Pugh (CTP) grade, and major hepatectomy as independent predictors of SPHLF. Based on the extent of hepatectomy, CTP grade could stratify the risk of SPHLF in the minor hepatectomy group (12.2% vs. 100.0%, p = 0.001), whereas LS was superior in predicting SPHLF in the major hepatectomy group (18.9% vs. 72.4%, p < 0.001). In patients with CTP grade A, LS could further stratify the risks of SPHLF in both the minor and major hepatectomy groups (3.7% vs. 22.7%, p = 0.043; 17.6% vs. 70.4%, p < 0.001, respectively). CONCLUSIONS: LS measured using 2D SWE could predict SPHLF using the best cutoff value of 9.5 kPa. CTP grade was a stronger indicator of SPHLF in minor hepatectomy, whereas LS was more effective in selecting candidates for major hepatectomy. LS could further stratify the risk of SPHLF in CTP grade A patients, regardless of the extent of hepatectomy.

Percutaneous ethanol injection enhanced the efficacy of radiofrequency ablation in the treatment of HCC: an insight into the mechanism of ethanol action.

PURPOSE: To discuss the possible reasons why percutaneous intratumoral ethanol injection (PEI) combined with radiofrequency ablation (RFA) to treat hepatocellular carcinoma (HCC) reduced the recurrence and metastasis compared with RFA alone. MATERIALS AND METHODS: Forty VX2 tumor-bearing rabbits were randomly divided into four groups (n = 10): the PEI, RFA, PEI-RFA, and control groups. Five rabbits from each group were sacrificed on the 3rd and 7th days after ablation. The number of metastatic tumors in the lung was counted. The ablation volume was measured, and residual tumor specimens were prepared for hematoxylin and eosin staining and caspase-3, Ki-67, and VEGF immunohistochemical staining. RESULTS: The volume of ablation in the PEI-RFA group was significantly larger than that in the RFA and PEI groups (p < 0.05). However, no significant differences in the number of lung metastases after ablation were observed among the groups (p > 0.05). The number of microthrombi in the PEI-RFA group was greater than that in the control and RFA groups (p < 0.001 and p < 0.05). The Ki-67 labeling index (LI) and H-score of VEGF in the PEI-RFA group were lower than those in the RFA group, while the H-score of caspase-3 was higher than that in the RFA group on the 7th day after ablation (p < 0.05). CONCLUSION: PEI occluded blood vessels by inducing microthrombi formation, and thereby reducing heat dissipation and increasing the effect of RFA. More importantly, in comparison with an incomplete RFA, PEI-RFA inhibited the increase in the Ki-67 and VEGF expression levels and the decrease in the caspase-3 expression level to happen at some extent and therefore improved the prognosis.

Predictive factors of treatment outcomes after percutaneous ablation of hepatocellular carcinoma in the caudate lobe: a retrospective study.

BACKGROUND: Hepatocellular carcinomas (HCC) arising in the caudate lobe is rare and the treatment is difficult. The aim of this study is to summarize the experience of ultrasound-guided percutaneous ablation therapy for HCC located in the caudate lobe and to investigate the predictive factors of the treatment outcomes. METHODS: From August 2006 to June 2017, 73 patients (63 males and 10 females; mean age, 54.9 ± 11.6 years; age range, 25-79 years) with 73 caudate lobe HCCs (mean size, 2.6 ± 1.1 cm; size range, 1.0-5.0 cm) were treated with percutaneous ablation, including 33 patients with radiofrequency ablation (RFA), 23 patients with ethanol ablation (EA), and 17 patients with combination of RFA and EA. The treatment outcome and survival after ablation for caudate lobe HCC were assessed and the predictive factors were calculated by univariate and multivariate analyses. RESULTS: A total of 72 patients achieved complete ablation after the first or second session of ablation. The treatment effectiveness was 98.6% (72/73). During the follow-up, 16 tumors developed local tumor progression (LTP) and a total of 61 patients (61/73, 83.6%) were detected distant recurrence (DR). According to univariate and multivariate analyses, tumor size > 2 cm (hazard ratio[HR] = 3.667; 95% confidence interval[CI], 1.043-12.889; P = 0.043) was a significant prognostic factor of LTP after ablation for HCC in the caudate lobe, while tumor number (HR = 2.245; 95%CI, 1.168-4.317; P = 0.015) was a significant prognostic factor of DR. The mean overall survival time after ablation was 28.7 ± 2.8 months, without independent predictive factors detected. Four patients (4/73, 5.5%) were detected treatment-related major complications, without independent predictive factor detected. CONCLUSION: Ultrasound-guided percutaneous ablation is a feasible treatment for a selected case with HCC in the caudate lobe. Tumor size > 2 cm increases the risk of LTP and intrahepatic tumor number is associated with DR after ablation.

Transarterial Chemoembolization Followed by Radiofrequency Ablation for Hepatocellular Carcinoma: Impact of the Time Interval between the Two Treatments on Outcome.

PURPOSE: To compare the efficacy of radiofrequency (RF) ablation after transarterial chemoembolization within or beyond 30 days for medium-large or multiple recurrent hepatocellular carcinomas (HCCs). MATERIALS AND METHODS: In this single-center retrospective study conducted from 2007 through 2015, 135 patients with a single recurrent HCC (>3 cm) or multiple (2-5 tumors) recurrent HCCs underwent transarterial chemoembolization plus RF ablation. A total of 62 patients underwent RF ablation after transarterial chemoembolization within 30 days (sequential group) and 73 patients underwent RF ablation after transarterial chemoembolization beyond 30 days (delayed group). Outcomes of interests included overall survival (OS), progression-free survival (PFS), and complete response (CR) rate. RESULTS: The median OS and PFS were 49.8 and 38.0 months for sequential group, and 31.0 and 11.6 months for the delayed group. The sequential group experienced significantly better OS (hazard ratio [HR]: 0.517; P = .002) and PFS (HR, 0.621; P = .021). Among patients with multiple tumors or a single tumor >5 cm, the sequential group still had significantly longer OS (P = .022; P = .018, respectively) and PFS (P = 0.042; P = .036, respectively) than the delayed group, although no significant differences were observed among patients with solitary 3- to 5-cm tumors (P = .138; P = .803, respectively). The sequential group had a significantly better CR rate than the delayed group (85.4% vs. 68.5%, respectively; P = .035). Significant predictors of OS and PFS included maximum tumor size, number of tumors, and time interval between transarterial chemoembolization and RF ablation. CONCLUSIONS: Transarterial chemoembolization plus sequential RF ablation within 30 days was more effective for recurrent HCCs than transarterial chemoembolization plus delayed RF ablation. The time interval within 30 days is required for treating large or multiple HCCs but may not be necessary for solitary medium-sized HCC.

Feasibility and Measurement Value of Pancreatic 2-D Shear Wave Elastography in Healthy Adults: Evaluation, Influencing Factors, Reference Range, Measurement Stability and Reproducibility.

OBJECTIVE: The present study was aimed at assessing the success rate and measurement value, determining the influencing factors and reference range and examining the intra-operator stability and inter-operator reproducibility of pancreatic 2-D shear wave elastography (SWE) measurement in healthy adults. METHODS: In 2022, 387 healthy adults were prospectively recruited. Logistic regression and linear regression analyses were used to explore the factors influencing the success rate and the measurement value of pancreatic 2-D SWE measurement, respectively. A two-sided 95% reference range was estimated accordingly. The intraclass correlation coefficient was calculated to evaluate the intra-operator stability and inter-operator reproducibility of the pancreatic 2-D SWE measurement. RESULTS: The pancreatic body (89.6%) bore the highest while the tail (72.8%) bore the lowest success rate of pancreatic 2-D SWE measurement. Sex and body mass index (BMI) were the independent factors influencing measurement success rate in all three parts of the pancreas. Mean measurement values (Emean) were not the same in the three parts of the pancreas of the same participant. BMI and image depth were the independent factors influencing Emean in the pancreatic body, while region of interest depth and BMI were the only independent factors influencing Emean in the pancreatic head and tail, respectively. The intra-operator stability of pancreatic 2-D SWE measurement was found to be excellent, whereas its inter-operator reproducibility was poor to good. CONCLUSION: Pancreatic 2-D SWE is a reliable technique for evaluating pancreatic stiffness in healthy adults, but its success rate and measurement value are influenced by multiple factors.

Liver stiffness in hepatocellular carcinoma and chronic hepatitis patients: Hepatitis B virus infection and transaminases should be considered.

BACKGROUND: Liver condition is a crucial prognostic factor for patients with hepatocellular carcinoma (HCC), but a convenient and comprehensive method to assess liver condition is lacking. Liver stiffness (LS) measured by two-dimensional shear wave elastography may help in assessing liver fibrosis and liver condition. Chronic hepatitis B (CHB) is an important risk factor for HCC progression, but LS was found to be less reliable in assessing liver fibrosis following hepatitis viral eradication. We hypothesize that the status of hepatitis virus infection would affect the accuracy of LS in assessing the liver condition. AIM: To test the feasibility and impact factors of using LS to assess liver condition in patients with HCC and CHB. METHODS: A total of 284 patients were retrospectively recruited and classified into two groups on the basis of serum CHB virus hepatitis B virus (HBV)-DNA levels [HBV-DNA ≥ 100.00 IU/mL as Pos group (n = 200) and < 100.00 IU/mL as Neg group (n = 84)]. Correlation analyses and receiver operating characteristic analyses were conducted to evaluate the relationship between LS and liver condition. RESULTS: A significant correlation was found between LS and most of the parameters considered to have the ability to evaluate liver condition (P < 0.05). When alanine aminotransferase (ALT) concentrations were normal (≤ 40 U/L), LS was correlated with liver condition indices (P < 0.05), but the optimal cutoff of LS to identify a Child-Pugh score of 5 was higher in the Neg group (9.30 kPa) than the Pos group (7.40 kPa). When ALT levels were elevated (> 40 U/L), the correlations between LS and liver condition indices were not significant (P > 0.05). CONCLUSION: LS was significantly correlated with most liver condition indices in patients with CHB and HCC. However, these correlations varied according to differences in HBV-DNA and transaminase concentrations.

Ablative strategies for recurrent hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the most common primary liver cancer and is the fifth leading cause of cancer death worldwide and the third leading cause of all diseases worldwide. Liver transplantation, surgical resection and ablation are the three main curative treatments for HCC. Liver transplantation is the optimal treatment option for HCC, but its usage is limited by the shortage of liver sources. Surgical resection is considered the first choice for early-stage HCC, but it does not apply to patients with poor liver function. Therefore, more and more doctors choose ablation for HCC. However, intrahepatic recurrence occurs in up to 70% patients within 5 years after initial treatment. For patients with oligo recurrence after primary treatment, repeated resection and local ablation are both alternative. Only 20% patients with recurrent HCC (rHCC) indicate repeated surgical resection because of limitations in liver function, tumor location and intraperitoneal adhesions. Local ablation has become an option for the waiting period when liver transplantation is unavailable. For patients with intrahepatic recurrence after liver transplantation, local ablation can reduce the tumor burden and prepare them for liver transplantation. This review systematically describes the various ablation treatments for rHCC, including radiofrequency ablation, microwave ablation, laser ablation, high-intensity focused ultrasound ablation, cryablation, irreversible electroporation, percutaneous ethanol injection, and the combination of ablation and other treatment modalities.

Predicting Post-hepatectomy Liver Failure Preoperatively for Child-Pugh A5 Hepatocellular Carcinoma Patients by Liver Stiffness.

BACKGROUND: Post-hepatectomy liver failure (PHLF) represents the major source of mortality after liver resection (LR) in hepatocellular carcinoma (HCC) patients. Child-Pugh (CP) score 5 is always considered to indicate a normal liver function but represents a heterogeneous population with a considerable number suffering from PHLF. The present study aimed to access the ability of liver stiffness (LS) measured by two-dimensional shear wave elastography (2D-SWE) to predict PHLF in HCC patients with a CP score of 5. METHODS: From August 2018 to May 2021, 146 HCC patients with a CP score of 5 who underwent LR were reviewed. The patients were randomly divided into training (n = 97) and validation (n = 49) groups. Logistic analyses were conducted for the risk factors and a linear model was built to predict the development of PHLF. The discrimination and calibration were assessed in the training and validation cohorts by the areas under the receiver operating characteristic curve (AUC). RESULTS: Analyses revealed that the minimum of LS (Emin) higher than 8.05 (p = 0.006, OR = 4.59) and future liver remnant / estimated total liver volume (FLR/eTLV) (p < 0.001, OR < 0.01) were independent predictors of PHLF in HCC patients with CP score 5, and the AUC calculated by the model based on them for differentiation of PHLF in the training and validation group was 0.78 and 0.76, respectively. CONCLUSION: LS was associated with the development of PHLF. A model combining Emin and FLR/eTLV showed proper ability in predicting PHLF in HCC patients with a CP score of 5.

Stiffness on shear wave elastography as a potential microenvironment biomarker for predicting tumor recurrence in HBV-related hepatocellular carcinoma.

BACKGROUND: To explore the pathologic basis and prognostic value of tumor and liver stiffness measured pre-operatively by two-dimensional shear wave elastography (2D-SWE) in hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) patients who undergo hepatic resection. METHODS: A total of 191 HBV-infected patients with solitary resectable HCC were prospectively enrolled. The stiffness of intratumoral tissue, peritumoral tissue, adjacent liver tissue, and distant liver tissue was evaluated by 2D-SWE. The correlations between stiffness and pathological characteristics were analyzed in 114 patients. The predictive value of stiffness for recurrence-free survival (RFS) was evaluated, and Cutoff Finder was used for determining optimal cut-off stiffness values. Cox proportional hazards analysis was used to identify independent predictors of RFS. RESULTS: Pathologically, intratumoral stiffness was associated with stroma proportion and microvascular invasion (MVI) while peritumoral stiffness was associated with tumor size, capsule, and MVI. Adjacent liver stiffness was correlated with capsule and liver fibrosis stage while distant liver stiffness was correlated with liver fibrosis stage. Peritumoral stiffness, adjacent liver stiffness, and distant liver stiffness were all correlated to RFS (all p < 0.05). Higher peritumoral stiffness (> 49.4 kPa) (HR = 1.822, p = 0.023) and higher adjacent liver stiffness (> 24.1 kPa) (HR = 1.792, p = 0.048) were significant independent predictors of worse RFS, along with tumor size and MVI. The nomogram based on these variables showed a C-index of 0.77 for RFS prediction. CONCLUSIONS: Stiffness measured by 2D-SWE could be a tumor microenvironment and tumor invasiveness biomarker. Peritumoral stiffness and adjacent liver stiffness showed important values in predicting tumor recurrence after curative resection in HBV-related HCC. CLINICAL RELEVANCE STATEMENT: Tumor and liver stiffness measured by two-dimensional shear wave elastography serve as imaging biomarkers for predicting hepatocellular carcinoma recurrence, reflecting biological behavior and tumor microenvironment. KEY POINTS: • Stiffness measured by two-dimensional shear wave elastography is a useful biomarker of tumor microenvironment and invasiveness. • Higher stiffness indicated more aggressive behavior of hepatocellular carcinoma. • The study showed the prognostic value of peritumoral stiffness and adjacent liver stiffness for recurrence-free survival. • The nomogram integrating peritumoral stiffness, adjacent liver stiffness, tumor size, and microvascular invasion showed a C-index of 0.77.

An Interpretable Radiomics Model Based on Two-Dimensional Shear Wave Elastography for Predicting Symptomatic Post-Hepatectomy Liver Failure in Patients with Hepatocellular Carcinoma.

OBJECTIVE: The aim of this study was to develop and validate an interpretable radiomics model based on two-dimensional shear wave elastography (2D-SWE) for symptomatic post-hepatectomy liver failure (PHLF) prediction in patients undergoing liver resection for hepatocellular carcinoma (HCC). METHODS: A total of 345 consecutive patients were enrolled. A five-fold cross-validation was performed during training, and the models were evaluated in the independent test cohort. A multi-patch radiomics model was established based on the 2D-SWE images for predicting symptomatic PHLF. Clinical features were incorporated into the models to train the clinical-radiomics model. The radiomics model and the clinical-radiomics model were compared with the clinical model comprising clinical variables and other clinical predictive indices, including the model for end-stage liver disease (MELD) score and albumin-bilirubin (ALBI) score. Shapley Additive exPlanations (SHAP) was used for post hoc interpretability of the radiomics model. RESULTS: The clinical-radiomics model achieved an AUC of 0.867 (95% CI 0.787-0.947) in the five-fold cross-validation, and this score was higher than that of the clinical model (AUC: 0.809; 95% CI: 0.715-0.902) and the radiomics model (AUC: 0.746; 95% CI: 0.681-0.811). The clinical-radiomics model showed an AUC of 0.822 in the test cohort, higher than that of the clinical model (AUC: 0.684, p = 0.007), radiomics model (AUC: 0.784, p = 0.415), MELD score (AUC: 0.529, p < 0.001), and ALBI score (AUC: 0.644, p = 0.016). The SHAP analysis showed that the first-order radiomics features, including first-order maximum 64 × 64, first-order 90th percentile 64 × 64, and first-order 10th percentile 32 × 32, were the most important features for PHLF prediction. CONCLUSION: An interpretable clinical-radiomics model based on 2D-SWE and clinical variables can help in predicting symptomatic PHLF in HCC.

Perfluorocarbon nanodrug induced oxygen self-enriching sonodynamic therapy improves cancer immunotherapy after insufficient radiofrequency ablation.

Residual lesions and undetectable metastasis after insufficient radiofrequency ablation (iRFA) are associated with earlier new metastases and poor survival in cancer patients, for induced aggressive tumor phenotype and immunosuppression. Programmed cell death protein 1(PD-1) blockade has been reported to enhance the radiofrequency ablation-elicited antitumor immunity, but its ability to eliminate incompletely ablated residual lesions has been questioned. Here, we report a combined treatment modality post iRFA based on integrating an oxygen self-enriching nanodrug PFH-Ce6 liposome@O2 nanodroplets (PCL@O2)-augmented noninvasive sonodynamic therapy (SDT) with PD-1 blockade. PCL@O2 containing Ce6 as the sonosensitizer and PFH as O2 reservoir, was synthesized as an augmented SDT nanoplatform and showed increased ROS generation to raise effective apoptosis of tumor cells, which also exposed more calreticulin to induce stronger immunogenic cell death (ICD). Combining with PD-1 blockade post iRFA, this optimized SDT induced a better anti-tumor response in MC38 tumor bearing mouse model, which not only arrested residual primary tumor progression, but also inhibited the growth of distant tumor, therefore prolonging the survival. Profiling of immune populations within the tumor draining lymph nodes and tumors further revealed that combination therapy effectively induced ICD, and promoted the maturation of dendritic cells, tumor infiltration of T cells, as well as activation of cytotoxic T lymphocytes. While iRFA alone could result in an increase of regulatory T cells (Tregs) in the residual tumors, SDT plus PD-1 blockade post iRFA reduced the number of Tregs in both primary and distant tumors. Moreover, the combined treatment could significantly initiate long-term immune memory, manifesting as elevated levels of CD8+ and CD4+ central memory cells. Therefore, this study establishes the preclinical proof of concept to apply oxygen self-enriching SDT to augment cancer immunotherapy after iRFA.

The "stiff rim" sign of hepatocellular carcinoma on shear wave elastography: correlation with pathological features and potential prognostic value.

PURPOSE: To explore the pathologic basis, the influencing factors and potential prognostic value of the stiff rim sign in two-dimensional shear wave elastography (2D-SWE) of hepatocellular carcinoma (HCC). METHODS: HCC patients who underwent tumor 2D-SWE examination before resection were prospectively enrolled. The stiff rim sign was defined as increased stiffness in the peritumoral region. Interobserver and intraobserver variability of the stiff rim sign was assessed. The correlation between the stiff rim sign and pathological characteristics was analyzed. Multivariate analysis was performed to examine clinical and radiological factors influencing the appearance of stiff rim sign. The Kaplan-Meier method was used to analyze the relationship between recurrence-free survival (RFS) and the stiff rim sign. RESULTS: The stiff rim sign on 2D-SWE was present in 44.7% of HCC lesions. Interobserver agreement and intraobserver agreement for the stiff rim sign were substantial (κ = 0.772) and almost perfect (κ = 0.895), respectively. Pathologically, the stiff rim sign was associated with capsule status, capsule integrity, capsule thickness, proportion of peritumoral fibrous tissue, and peritumoral fibrous arrangement. Multivariate analysis showed that tumor size was an independent clinical predictor for the appearance of stiff rim sign (OR 1.201, p = 0.008). Kaplan-Meier analysis showed RFS was significantly poorer in the stiff rim sign (+) group than the stiff rim sign (-) group in solitary tumors smaller than 5 cm (p = 0.007) and solitary tumors with intratumoral stiffness less than 33.7 kPa (p = 0.007). CONCLUSION: The stiff rim sign on 2D-SWE was mainly correlated with peritumoral fibrous tissue status and was a poor prognostic indicator for HCC.

Prognostic Role of Albumin-Bilirubin Grade in Hepatocellular Carcinoma After Ultrasound-guided Percutaneous Radiofrequency Ablation: A Single-center Experience Over a Decade.

BACKGROUND: The albumin-bilirubin (ALBI) grade has been proposed to evaluate liver function and predict prognosis in patients with hepatocellular carcinoma (HCC). Data are scarce in terms of the clinical application of ALBI score in patients with HCC undergoing radiofrequency ablation (RFA). The current study sought to assess the prognostic efficacy of ALBI grade in early-stage HCC after RFA. METHODS: We retrospectively reviewed 344 treatment-naive patients, whereby the overall survival (OS), recurrence-free survival (RFS), local tumor progression, and intrahepatic distant recurrence were assessed using Kaplan-Meier analysis. Predictors determining OS and RFS after RFA were analyzed using Cox proportional hazards analysis. RESULTS: During a median follow-up time of 48.0 months (range: 2 to 158 mo), 48 patients had died because of tumor progression or liver failure. Patients with ALBI grade 2 had poorer OS (P=0.033) and RFS (P=0.002), and higher intrahepatic distant recurrence rate (P<0.001) than those with ALBI grade 1. Local tumor progression rates were comparable between the 2 groups (P=0.801). Multivariate analyses showed that ABLI grade 2 was the only independent risk factor for poor OS (hazard ratio=1.850, 95% confidence interval: 1.041-3.286, P=0.036) and poor RFS (hazard ratio=1.467, 95% confidence interval: 1.094-1.968, P=0.011) after RFA. For Child-Pugh grade A group, patients divided by ALBI grade 1 versus grade 2 showed significant differences in both OS and RFS (P=0.039 and 0.002). CONCLUSION: The ALBI grade can be used to discriminate long-term prognosis in patients with HCC following RFA and to further stratify prognosis in those with Child-Pugh grade A.

Feasibility of liver stiffness measured using two-dimensional shear wave elastography in assessing preoperative liver function for patients with hepatocellular carcinoma.

OBJECTIVES: To evaluate the feasibility of liver stiffness (LS) measured using two-dimensional shear wave elastography (2D SWE) in assessing preoperative liver function for patients with hepatocellular carcinoma (HCC). MATERIALS AND METHODS: A total of 143 patients who underwent surgical resection for HCC between August 2018 and December 2019 were enrolled prospectively. LS measurement, liver function tests including serum biochemical indicators, and indocyanine green (ICG) clearance test were performed preoperatively. Child-Pugh (CP) score, Albumin-bilirubin (ALBI) score and Model for End-Stage Liver Disease score were calculated. ICG retention rate at 15 min (ICG R15) and ICG elimination rate constant (ICG K) were determined automatically. Fibrosis stage was determined based on pathological findings. The association between LS and serum biochemical indicators, liver function scores, and the ICG results were analyzed. RESULTS: Weak to moderate correlations were identified between LS and biochemical indicators of liver function (all p < 0.01). Weak correlation was identified between LS and CP score, and between LS and ALBI score (all p < 0.001). Moderate correlation was identified between LS and ICG R15 (Pearson r = 0.62, p < 0.001), and between LS and ICG K value (Pearson r = - 0.49, p < 0.001). The best cutoff of LS to discriminate a normal ICG R15 was 10.6 kPa, with area under the curve (AUC), sensitivity, specificity of 0.874, 0.900 and 0.724, respectively. CONCLUSIONS: LS determined using 2D SWE could be a potential tool for the preoperative evaluation of liver function in patients with HCC.