Programmable DNA Hydrogel Assisting Microcrystal Formulations for Sustained Locoregional Drug Delivery in Surgical Residual Tumor Lesions and Lymph Node Metastasis.

Surgical residual tumor lesions (R1 resection of surgical procedures (e.g., liver cancer infiltrating the diaphragm, surgical residual breast cancer, postoperative residual ovarian cancer) or boundary residual after ablation) and lymph node metastasis that cannot be surgically resected (retroperitoneal lymph nodes) significantly affect postoperative survival of tumor patients. This clinical conundrum poses three challenges for local drug delivery systems: stable and continuous delivery, good biocompatibility, and the ability to package new targeted drugs that can synergize with other treatments. Here, a drug-laden hydrogel generated from pure DNA strands and highly programmable in adjusting its mesh size is reported. Meanwhile, the DNA hydrogel can assist the microcrystallization of novel radiosensitizing drugs, ataxia telangiectasia and rad3-related protein (ATR) inhibitor (Elimusertib), further facilitating its long-term release. When applied to the tumor site, the hydrogel system demonstrates significant antitumor activity, minimized systemic toxicity, and has a modulatory effect on the tumor-immune cell interface. This drug-loaded DNA-hydrogel platform represents a novel modality for adjuvant therapy in patients with surgical residual tumor lesions and lymph node metastasis.

Two-Dimensional Shear Wave Elastography Evaluation of Post-transplantation Complications in Pediatric Receipt: A Retrospective Cohort.

Background: The 20-year survival rate in pediatric patients after liver transplantation (LT) was no more than 70%. Hepatic fibrosis is one of the principal factors affecting the long-term prognosis. Imaging evaluation was the first-line examination for pediatric liver graft assessment. However, the sensitivity and specificity were insufficient. Thus, two-dimensional shear wave elastography (2D-SWE) was performed to evaluate liver graft stiffness and complication in post-transplant pediatric receipt. Materials and Methods: In this retrospective cohort, 343 pediatric recipients who underwent liver graft biopsy in our tertiary LT center were recruited between June 2018 and December 2020. The 2D-SWE evaluation, laboratory examination, routine post-transplant biopsy, and hepatic pathological assessment were performed. Results: Ninety-eight of the 343 pediatric patients were included according to the protocol. The Liver Stiffness Measurements (LSM) value of 2D-SWE was significantly elevated in post-transplant fibrosis (p < 0.0001). The LSM value of patients with post-transplant biliary complications (p < 0.0001) and biopsy-proven rejection (BPR, p = 0.0016) also rose compared to regular recovery patients. Concerning the sensitivity and specificity of 2D-SWE in diagnosing liver graft fibrosis, the area under the ROC curve (AUC) was 88%, and the optimal cutoff value was 10.3 kPa. Conclusion: Pediatric LSM by 2D-SWE was efficient. Routine 2D-SWE evaluation could be optimal to predict significant liver graft fibrosis.

Transplantation for EASL-CLIF and APASL acute-on-chronic liver failure (ACLF) patients: The TEA cohort to evaluate long-term post-Transplant outcomes.

Background: The forecast accuracy of the European Association for the Study of the Liver-Chronic Liver Failure (EASL-CLIF) and Asian Pacific Association for the Study of the Liver (APASL) acute-on-chronic liver failure (ACLF) criteria in assessing long-term outcomes after liver transplantation (LT) is still unclear, especially when the staging of the two standards is inconsistent. Methods: A retrospective cohort (NCT05036031) including 565 patients from January 2015 to June 2021 was conducted. The 28 and 90 days, 1- and 3-years overall survival (OS) after LT were compared between different grades. Findings: Total of 162 (28.7%) and 230 (40.7%) patients met the ACLF standards. In the EASL-CLIF criteria, the 3-year OS rates were 83·0%, 80·3%, and 69·8% for ACLF1-3, respectively. In the APASL criteria, the 3-year OS rates were 85·7% for APASL ACLF Research Consortium (AARC)-1, similar to ACLF-1. The 3-year OS rates were 84·5% for AARC-2, which were slightly better than ACLF-2. Regarding AARC-3, the 3-year OS rate was 5·8% higher than ACLF-3. For patients who met neither set of criteria for ACLF, the 3-year OS rates were 89·8%. The multivariate analysis showed that alanine aminotransferase >100 U/L, respiration failure, and cerebral failure were independent risk factors for post-LT death. Interpretation: This study provides the first large-scale long-term follow-up data in Asia. Both criteria showed favorable distinguishing ability for post-LT survival. Patients with ACLF had a higher post-LT mortality risk, and ACLF-3 and AARC-3 correlated with significantly greater mortality. Funding: National Natural Science Foundation of China and Science and Technology Commission of Shanghai Municipality.

Aggregation-Induced Emission (AIE) and Magnetic Resonance Imaging Characteristics for Targeted and Image-Guided siRNA Therapy of Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is the most common form of primary liver cancer and remains a global health challenge. Small interfering RNA (siRNA) is a promising therapeutic modality that blocks multiple disease-causing genes without impairing cell structures. However, siRNA therapeutics still have off-target proportion and lack effective quantitative analysis method in vivo. Thus, a novel theragnostic nanoparticle with dual-mode imaging is synthesized for targeted and image-guided siRNA therapy of HCC. Survivin siRNA is carried by Poly-ethylenimine (PEI) and interacted with T7-AIE/Gd NPs, which are self-assembled of DSPE-PEG-DTPA(Gd), DSPE-PEG-Mal, DSPE-PEG-PEI, and TPE. The resulting theragnostic nanoparticles exhibit lower toxicity and high therapeutic effect, and excellent T1-weighted magnetic resonance imaging (MRI) and aggregation-induced emission (AIE) imaging performance. Moreover, in vivo MRI and AIE imaging indicate that this kind of theragnostic nanoparticles rapidly accumulates in the tumor due to active targeting and enhanced permeability and retention (EPR) effects. Sur@T7-AIE-Gd suppresses HCC tumor growth by inducing autophagy and destabilizes DNA integrity in tumor cells. The results suggest that T7-AIE-Gd nanoparticles carrying Survivin siRNA with dual-mode imaging characteristics are promising for targeted and image-guided siRNA therapy of hepatocellular carcinoma.

Neoadjuvant Programmed Cell Death 1 (PD-1) Inhibitor Treatment in Patients With Hepatocellular Carcinoma Before Liver Transplant: A Cohort Study and Literature Review.

Programmed cell death 1 (PD-1) blockade is considered contraindicated in liver transplant (LT) recipients due to potentially lethal consequences of graft rejection and loss. Though post-transplant PD-1 blockade had already been reported, pre-transplant use of PD-1 blockade has not been thoroughly investigated. This study explores the safety and efficacy of neoadjuvant PD-1 blockade in patients with hepatocellular carcinoma (HCC) after registration on the waiting list. Seven transplant recipients who underwent neoadjuvant PD-1 blockade combined with lenvatinib and subsequent LT were evaluated. The objective response rate (ORR) and disease control rate (DCR) was 71% and 85% according to the mRECIST criteria. Additionally, a literature review contained 29 patients were conducted to summarize the PD-1 blockade in LT for HCC. Twenty-two LT recipients used PD-1 inhibitors for recurrent HCC. 9.1% (2/22) and 4.5% (1/22) recipients achieved complete remission (CR) and partial remission (PR), respectively; 40.9% (9/22) recipients had progressive disease (PD). Allograft rejection occurred in 45% of patients. In total, seven patients from our center and three from the literature used pretransplant anti-PD-1 antibodies, eight patients (80%) had a PR, and the disease control rate was 100%. Biopsy-proven acute rejection (BPAR) incidence was 30% (3 in 10 patients), two patients died because of BPAR. This indicated that neoadjuvant PD-1-targeted immunotherapy plus tyrosine kinase inhibitors (TKI) exhibited promising efficacy with tolerable mortality in transplant recipients under close clinical monitoring.