Safety and efficacy of interventional embolization in cirrhotic patients with refractory hepatic encephalopathy associated with spontaneous portosystemic shunts.

This study aimed to assess the safety and efficacy of interventional embolization in cirrhotic patients with refractory hepatic encephalopathy (HE) associated with large spontaneous portosystemic shunts (SPSS). Inverse probability of treatment weighting (IPTW) was employed to minimize potential bias. A total of 123 patients were included in this study (34 in the embolization group and 89 in the control group). In the unadjusted cohort, the embolization group demonstrated significantly better liver function, a larger total area of SPSS, and a higher percentage of patients with serum ammonia levels > 60 µmol/L and the presence of hepatocellular carcinoma (HCC) (all P < 0.05). In the IPTW cohort, baseline characteristics were comparable between the two groups (all P > 0.05). Patients in the embolization group exhibited significantly longer HE-free survival compared to the control group in both the unadjusted and IPTW cohorts (both P < 0.05). Subsequent subgroup analyses indicated that patients with serum ammonia level > 60 µmol/L, hepatopetal flow within the portal trunk, the presence of solitary SPSS, a baseline HE grade of II, and the absence of HCC at baseline showed statistically significant benefit from embolization treatment (all P < 0.05). No early procedural complications were observed in the embolization group. The incidence of long-term postoperative complications was comparable to that in the control group (all P > 0.05). Hence, interventional embolization appears to be a safe and effective treatment modality for cirrhotic patients with refractory HE associated with large SPSS. However, the benefits of embolization were discernible only in a specific subset of patients.

Proteomic Analysis Identifies GSN as a Noninvasive Circulating Serum Biomarker for Predicting Early Recurrence of Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is susceptible to early recurrence, but it lacks effective predictive biomarkers. In this study, we retrospectively selected 179 individuals as a discovery cohort (126 HCC patients and 53 liver cirrhosis (LC) patients) for screening candidate serum biomarkers of early recurrence based on data independent acquisition-mass spectrometry strategy. And then, the candidate biomarkers were validated in an additional independent cohort with 192 individuals (142 HCC patients and 50 LC patients) using parallel reaction monitoring targeted quantitative techniques (PXD047852). Eventually, we validated that gelsolin (GSN) concentrations were significantly lower in HCC than in LC (p < 0.0001), patients with low GSN concentrations had a poor prognosis (p < 0.0001), and GSN concentrations were significantly lower in early recurrence HCC than in late recurrence HCC (p < 0.0001). These trends were also observed in alpha-fetoprotein (AFP)-negative HCC patients. The area under the curve of machine-learning-based predictive model (GSN and microvascular invasion) for predicting early recurrence risk reached 0.803 (95% confidence interval (CI): 0.786-0.820) and maintained the same efficacy in AFP-negative patients. In conclusion, GSN is a novel serum biomarker for early recurrence of HCC. The model could provide timely warning to HCC patients at high risk of recurrence.

Integrated omics landscape of hepatocellular carcinoma suggests proteomic subtypes for precision therapy.

Patients with hepatocellular carcinoma (HCC) at the same clinical stage can have extremely different prognoses, and molecular subtyping provides an opportunity for individualized precision treatment. In this study, genomic, transcriptomic, proteomic, and phosphoproteomic profiling of primary tumor tissues and paired para-tumor tissues from HCC patients (N = 160) are integrated. Proteomic profiling identifies three HCC subtypes with different clinical prognosis, which are validated in three publicly available external validation sets. A simplified panel of nine proteins associated with metabolic reprogramming is further identified as a potential subtype-specific biomarker for clinical application. Multi-omics analysis further reveals that three proteomic subtypes have significant differences in genetic alterations, microenvironment dysregulation, kinase-substrate regulatory networks, and therapeutic responses. Patient-derived cell-based drug tests (N = 26) show personalized responses for sorafenib in three proteomic subtypes, which can be predicted by a machine-learning response prediction model. Overall, this study provides a valuable resource for better understanding of HCC subtypes for precision clinical therapy.

Proteomics-driven noninvasive screening of circulating serum protein panels for the early diagnosis of hepatocellular carcinoma.

Early diagnosis of hepatocellular carcinoma (HCC) lacks highly sensitive and specific protein biomarkers. Here, we describe a staged mass spectrometry (MS)-based discovery-verification-validation proteomics workflow to explore serum proteomic biomarkers for HCC early diagnosis in 1002 individuals. Machine learning model determined as P4 panel (HABP2, CD163, AFP and PIVKA-II) clearly distinguish HCC from liver cirrhosis (LC, AUC 0.979, sensitivity 0.925, specificity 0.915) and healthy individuals (HC, AUC 0.992, sensitivity 0.975, specificity 1.000) in an independent validation cohort, outperforming existing clinical prediction strategies. Furthermore, the P4 panel can accurately predict LC to HCC conversion (AUC 0.890, sensitivity 0.909, specificity 0.877) with predicting HCC at a median of 11.4 months prior to imaging in prospective external validation cohorts (No.: Keshen 2018_005_02 and NCT03588442). These results suggest that proteomics-driven serum biomarker discovery provides a valuable reference for the liquid biopsy, and has great potential to improve early diagnosis of HCC.

Personalized neoantigen vaccine combined with PD-1 blockade increases CD8+ tissue-resident memory T-cell infiltration in preclinical hepatocellular carcinoma models.

BACKGROUND: Personalized neoantigen vaccine could induce a robust antitumor immune response in multiple cancers, whose efficacy could be further enhanced by combining with programmed cell death 1 blockade (α-PD-1). However, the corresponding immune response and synergistic mechanisms remain largely unclear. Here, we aimed to develop clinically available combinational therapeutic strategy and further explore its potential antitumor mechanisms in hepatocellular carcinoma (HCC). METHODS: Neoantigen peptide vaccine (NeoVAC) for murine HCC cell line Hepa1-6 was developed and optimized by neoantigen screening and adjuvant optimization. Then the synergistic efficacy and related molecular mechanisms of NeoVAC combined with α-PD-1 in HCC were evaluated by orthotopic HCC mouse model, single-cell RNA sequencing, tetramer flow cytometry, immunofluorescence, etc. The tumor-killing capacity of CD8+ tissue-resident memory T cells (CD8+ TRMs) was assessed by orthotopic HCC mouse model, and autologous patient-derived cells. RESULTS: NeoVAC, which consisted of seven high immunogenic neoantigen peptides and clinical-grade Poly(I:C), could generate a strong antitumor immune response in HCC mouse models. Significantly, its efficacy could be further improved by combining with α-PD-1, with 80% of durable tumor regression and long-term immune memory in orthotopic HCC models. Moreover, in-depth analysis of the tumor immune microenvironment showed that the percentage of CD8+ TRMs was remarkedly increased in NeoVAC plus α-PD-1 treatment group, and positively associated with the antitumor efficacy. In vitro and in vivo T-cell cytotoxicity assay further confirmed the strong tumor-killing capacity of CD8+ TRMs sorting from orthotopic mouse HCC or patient's HCC tissue. CONCLUSIONS: This study showed that NeoVAC plus α-PD-1 could induce a strong antitumor response and long-term tumor-specific immune memory in HCC by increasing CD8+ TRMs infiltration, which might serve as a potential immune-therapeutic target for HCC.

Localized NIR-II photo-immunotherapy through the combination of photothermal ablation and in situ generated interleukin-12 cytokine for efficiently eliminating primary and abscopal tumors.

Recently, photothermal therapy (PTT) in the second near-infrared (NIR-II) biowindow has emerged as a promising treatment modality; however, its therapeutic outcomes are still limited by heterogeneous heat distribution and insufficient control of metastatic lesions. Tremendous efforts have been made to overcome the PTT's shortcomings by combining PTT with immunotherapy, but unfortunately current strategies still suffer from low response rates, primary/acquired resistance or severe immune-related adverse events. Herein, a novel photothermal agent and gene co-delivery nanoparticle (CSP), with CuS inside the SiO2 pore channels and PDMAEMA polycation on the outside of SiO2 surface, is explored for tumor localized NIR-II PTT and in situ immunotherapy through local generation of IL-12 cytokine. The resulting CSP integrated with the plasmid encoding IL-12 gene (CSP@IL-12) exhibited good gene transfection efficiency, outstanding NIR-II PTT effect and excellent therapeutic outcomes both in vitro and in vivo. Meanwhile, such an in situ joint therapy modality could significantly induce systemic immune responses including promoting DC maturation, CD8+ T cell proliferation and infiltration to efficiently eliminate possible metastatic lesions through abscopal effects. Hence, this creative combinational strategy of NIR-II PTT and IL-12 cytokine therapy might provide a more efficient, controllable and safer alternative strategy for future photo-immunotherapy.

Clinical evaluation of the rapid recovery of patients who underwent video-assisted thoracoscopic lung surgery under non-intubated anesthesia.

BACKGROUND: Non-intubated anesthesia thoracoscopic surgery is an evolving form of minimally invasive thoracic surgery. It has had encouraging results in the treatment of lung cancer, and the current concept of enhanced recovery after surgery has become indispensable to surgical treatment. Our center retrospectively evaluated the clinical effect of rapid postoperative rehabilitation in patients who underwent thoracoscopic lung surgery under non-intubated anesthesia. METHODS: The clinical data of 192 patients undergoing video-assisted thoracoscopic surgery (VATS) at the Department of Thoracic Surgery of The First People's Hospital of Yunnan Province were retrospectively analyzed. Among them, 75 received double-lumen endotracheal intubation anesthesia, and 117 received a laryngeal mask instead of endotracheal intubated anesthesia. Comparing the intra-and post-operative indicators difference of these 2 groups. RESULTS: There were no significant differences in the postoperative complications, length of hospital stay, hemoglobin counts and platelet count 24 h after surgery between the non-intubated anesthesia and intubated anesthesia groups (P>0.05). In terms of the postoperative rehabilitation indicators of the VATS patients, the non-intubated anesthesia group had an earlier recovery in terms of water (food) intake, out-of-bed activity, and defecation (exhaust) times (P<0.001), less postoperative complications and adverse throat reactions (P<0.05), and higher levels of satisfaction (P<0.05) than the intubated anesthesia group. Compared to the intubated anesthesia group, the non-intubated anesthesia group had fewer changes of white blood cell counts, neutrophil percentages and lymphocytes percentages 24 h postoperatively (9.25×109 vs. 7.67×109, P=0.045; 7.06 vs. 5.53, P=0.039; 1.45 vs. 1.27, P=0.017), significant reduction pleural drainage after restoring oral intake in postoperative 24 and 48 h (198.43 vs. 131.07 and 114.04 vs. 57.47 mL, P<0.001), shorter postoperative thoracic tube drainage times (3.73 vs. 3.13 d, P<0.001). Notably, there was no difference between the smoking history and previous medical history of the patients in the 2 groups. CONCLUSIONS: Compared to intubation by general anesthesia, non-intubated thoracoscopic anesthesia is a safe and effective option. Patients who undergo non-intubated thoracoscopic lung surgery have a rapid recovery after surgery. Thus, it is worthy of promotion in clinical surgery settings.