Background: This study aimed to evaluate the longitudinal progression of residual lung abnormalities (ground-glass opacities, reticulation and fibrotic-like changes) and pulmonary function at 3 years following coronavirus disease 2019 (COVID-19).Methods: This prospective, longitudinal cohort study enrolled COVID-19 survivors who exhibited residual lung abnormalities upon discharge from two hospitals. Follow-up assessments were conducted at 6 months, 12 months, 2 years and 3 years post-discharge, and included pulmonary function tests, 6-min walk distance (6MWD), chest computed tomography (CT) scans and symptom questionnaires. Non-COVID-19 controls were retrospectively recruited for comparative analysis.Results: 728 COVID-19 survivors and 792 controls were included. From 6 months to 3 years, there was a gradual improvement in reduced diffusing capacity of the lung for carbon monoxide (D_LCO<80% predicted: 49%versus38%; p=0.001), 6MWD (496versus510 m; p=0.002) and residual lung abnormalities (46%versus36%; p<0.001), regardless of disease severity. Patients with residual lung abnormalities at 3 years more commonly had respiratory symptoms (32%versus16%; p<0.001), lower 6MWD (494versus510 m; p=0.003) and abnormalD_LCO(57%versus27%; p<0.001) compared with those with complete resolution. Compared with controls, the proportions ofD_LCOimpairment (38%versus17%; p<0.001) and respiratory symptoms (23%versus2.2%; p<0.001) were significantly higher in the matched COVID-19 survivors at the 3-year follow-up.Conclusions: Most patients exhibited improvement in radiological abnormalities and pulmonary function over time following COVID-19. However, more than a third continued to have persistent lung abnormalities at the 3-year mark, which were associated with respiratory symptoms and reduced diffusion capacity.

Objective: To evaluate the efficacy and safety of transarterial chemoembolization (TACE) combined with tyrosine kinase inhibitors (TKIs: sorafenib, lenvatinib, and apatinib) plus camrelizumab (TACE-TKIs-C) vs TACE combined with TKIs (TACE-TKIs) for advanced hepatocellular carcinoma (HCC). Methods: In this two-center retrospective study, patients with advanced HCC treated with TACE-TKIs-C or TACE-TKIs were enrolled between January 1, 2018, to October 1, 2020. A total of 260 eligible patients received TACE-TKIs-C (N=70) or TACE-TKIs (N=190). The differences in overall survival (OS), progression-free survival (PFS) and tumor response were compared between two groups. Propensity score matching (PSM) analysis was applied to reduce patient selection bias. The risk factors affecting OS or PFS were analyzed. Results: Fifty-three pairs of patients were matched after PSM analysis. Before PSM analysis, the median OS and PFS of TACE-TKIs-C were significantly longer than those of the TACE-TKIs (OS: not reached vs 12.0 months, P< 0.0001; PFS: 10.0 months vs 6.0 months, P< 0.0001). After PSM analysis, the median OS and PFS of TACE-TKIs-C were significantly longer than those of the TACE-TKIs (OS: Not reached vs 13.0 months, P< 0.0001; PFS: 9.0 months vs 6.0 months, P< 0.0001); the uni- and multivariate analysis revealed that TACE-TKIs-C treatment was a protective factor of OS and PFS. Grade 3 or 4 hypertension occurred in 14.3% of patients in the TACE-TKIs-C group and other high-grade toxic effects were infrequent. Conclusion: In patients with advanced HCC, TACE-TKIs-C may improve overall and progression-free survival outcomes over TACE-TKIs with manageable safety profile.

Time-dependent diffusion MRI can be used to effectively evaluate liver fibrosis grading, potentially enabling noninvasive assessment of treatment efficacy and facilitating personalized clinical treatment.

Background: Diabetes is prevalent among patients with hepatocellular carcinoma (HCC) and is associated with a poor prognosis. Although the hypoglycemic drug metformin has shown antitumor effects, its potential positive effect on patients with HCC and diabetes undergoing transarterial chemoembolization (TACE) remains unclear. Therefore, this study aimed to investigate the efficacy and safety of metformin in patients with HCC and type II diabetes who are receiving TACE. Materials and methods: This retrospective study involved 372 consecutive patients with HCC and type II diabetes across three medical centers between January 2014 and June 2021. All patients underwent TACE. Propensity score matching (PSM) was used to reduce selection bias. Cox proportional hazards regression was employed to compare all-cause death between the metformin and nonmetformin groups while competing risk regression was performed to assess cancer-specific death. Results: Among 372 patients included in the study, 208 patients (177 male patients and 31 female patients) with a mean age of 59.6 (10.3) years received metformin, and 164 patients (139 male patients and 25 female patients) with a mean age of 60.3 (10.0) years did not. Before PSM, patients with metformin had significantly longer median overall survival (mOS) and median progression-free survival (mPFS) than those without metformin (mOS: 34 months, 95% CI: 25.6–42.4 vs. 20 months, 95% CI: 15.3–24.7; P <0.001; mPFS: 11 months, 95% CI: 9.3–12.7 vs. 8 months, 95% CI: 5.9–10.1; P <0.001). Similar results were observed after PSM. Multivariate regression analysis indicated that metformin was associated with a reduced risk of all-cause mortality (HR: 0.589, 95% CI: 0.454–0.763; P <0.001) and tumor progression (HR: 0.667, 95% CI: 0.526–0.845; P =0.001) before PSM. After excluding deaths related to other factors, metformin continued to demonstrate a reduction in cancer-specific mortality risk among the patients. Subgroup analysis further revealed that patients using metformin had lower all-cause mortality risk and tumor progression risk than those without metformin in most subgroups. Adverse event evaluation suggested that metformin could lead to elevated nausea incidence. Conclusion: Metformin may confer survival benefits to patients with HCC and type II diabetes undergoing TACE. Metformin may simultaneously address multiple aspects of treatment in these patients.

Purpose: Type II diabetes mellitus (T2DM) has been found to increase the mortality of patients with hepatocellular carcinoma (HCC). Therefore, this study aimed to establish and validate a machine learning-based explainable prediction model of prognosis in patients with HCC and T2DM undergoing transarterial chemoembolization (TACE). Patients and Methods: The prediction model was developed using data from the derivation cohort comprising patients from three medical centers, followed by external validation utilizing patient data extracted from another center. Further, five predictive models were employed to establish prognosis models for 1-, 2-, and 3-year survival, respectively. Prediction performance was assessed by the receiver operating characteristic (ROC), calibration, and decision curve analysis curves. Lastly, the SHapley Additive exPlanations (SHAP) method was used to interpret the final ML model. Results: A total of 636 patients were included. Thirteen variables were selected for the model development. The final random survival forest (RSF) model exhibited excellent performance in the internal validation cohort, with areas under the ROC curve (AUCs) of 0.824, 0.853, and 0.810 in the 1-, 2-, and 3-year survival groups, respectively. This model also demonstrated remarkable discrimination in the external validation cohort, achieving AUCs of 0.862, 0.815, and 0.798 in the 1-, 2-, and 3-year survival groups, respectively. SHAP summary plots were also created to interpret the RSF model. Conclusion: An RSF model with good predictive performance was developed by incorporating simple parameters. This prognostic prediction model may assist physicians in early clinical intervention and improve prognosis outcomes in patients with HCC and comorbid T2DM after TACE.

Tirapazamine (TPZ) is a promising hypoxia-selective cytotoxic agent that may exert synergistic tumor-killing activity with transcatheter arterial embolization (TAE) for liver cancer. To investigated whether TPZ-loaded microspheres enhance the synergy between TPZ and TAE in liver cancer, we prepared TPZ-loaded CalliSpheres microspheres (CSMTPZs) and characterized their properties as a chemoembolization agent in vitro. Tumor hypoxia after TAE was detected in the rabbit VX2 model of liver cancer using a modified Clark-type microelectrode research system. CSMTPZ therapy was performed in the animal model. The plasma and tumor concentrations of TPZ and its metabolites were measured, and the efficacy and safety of CSMTPZ therapy were evaluated and compared with those of the conventional combination of intraarterial TPZ injection and embolization. The results showed that CSMTPZs displayed favorable in vitro properties including drug loading and release and microsphere size, shape, and surface profiles. TAE induced acute tumor hypoxia, but residual tumor cells responded to hypoxia through hypoxia-inducible factor 1α. CSMTPZ therapy improved TPZ delivery into tumor tissue with minimal systemic exposure. Accordingly, CSMTPZ therapy exhibited advantages in terms of hypoxia-selected cytotoxicity, tumor apoptosis and necrosis, animal survival, and safety over the conventional combination of TPZ and TAE. We revealed the improved synergistic anti-tumor effects of CSMTPZ therapy in the rabbit VX2 liver cancer model. Our data support the clinical evaluation of CSMTPZs in the treatment of hepatocellular carcinoma, and CSMTPZ administration might serve as a successful therapeutic strategy for this malignancy.