Purpose: The purpose of this study was to investigate the triple-combination therapy of lenvatinib plus sintilimab plus arterially-directed therapy as a conversion therapy for initially unresectable hepatocellular carcinoma (HCC). Patients and Methods: We retrospectively analyzed data from all HCC patients who underwent lenvatinib plus sintilimab plus arterially-directed therapy at Tianjin Medical University Cancer Hospital between December 2018 and October 2020. Of 98 enrolled patients, 37 patients were classified as potentially resectable. We compared the potentially resectable population (PRP) with the non-potentially resectable population (NPRP). The primary study endpoint was conversion rate, and secondary endpoints included progression-free survival (PFS), overall survival (OS), objective response rate (ORR), disease control rate (DCR), and safety. Results: The baseline characteristics were comparable between populations except for a higher proportion of patients with extrahepatic metastases in the NPRP versus PRP (23/61 [37.7%] vs 3/37 [8.1%], respectively; p=0.003). For PRP, the ORR was 67.6% based on RECIST v1.1 (75.7% based on mRECIST), conversion rate was 40.5% (15/37). Of the 15 patients who underwent surgical resection, three achieved complete pathological remission. The median follow-up for all patients was 28 months (range: 2– 47). For NPRP, the ORR was 22.9% based on RECIST v1.1 (31.1% based on mRECIST), The median PFS for PRP was significantly longer than that of NPRP (25 vs 13 months, p = 0.0025). The median OS for PRP was significantly longer than that of NPRP (not reached VS 21 months, p=0.014). Hypertension was the most common grade ≥ 3 adverse reaction in both PRP and NPRP. No new safety signals were observed for any of the treatments. Conclusion: The triple-combination therapy of lenvatinib plus sintilimab plus arterially-directed therapy can convert potentially unresectable HCC into resectable disease and improve long-term survival.

Background. Endometrial regenerative cells (ERCs) have been identified to ameliorate colitis in mice; however, whether exosomes derived from ERCs (ERC-exos) own similar effects on colitis remains unclear. Ferroptosis, an iron-dependent cell programmed death form, has been reported to promote inflammation in UC. Thus, in this study, whether ERC-exos can treat colitis and regulate intestine ferroptosis will be explored. Methods. In this study, iron, malondialdehyde (MDA) production, glutathione (GSH) synthesis, and acyl-CoA synthetase long-chain family member (ACSL) 4 and glutathione peroxidase 4 (GPX4) expressions were measured in colon samples from healthy people and UC patients to explore the effects of ferroptosis. In vitro, ERC-exos were cocultured with ferroptosis inducer erastin-treated NCM460 human intestinal epithelial cell line, and ferroptotic parameters were measured. In vivo, colitis was induced by 3 dextran sulfate sodium (DSS) in BALB/c mice, and animals were randomly assigned to normal, untreated, and ERC-exos-treated groups. The Disease Activity Index (DAI) score, histological features, tissue iron, MDA, GSH, ACSL4, and GPX4 were measured to verify the role of ERC-exos in attenuating UC. Results. Compared with healthy people, UC samples exhibited higher levels of iron, MDA, and ACSL4, while less levels of GSH and GPX4. In vitro, the CCK-8 assay showed that ERC-exos rescued erastin-induced cell death, and ERC-exos treatment significantly increased the levels of GSH and expression of GPX4, while markedly decreasing the levels of iron, MDA, and expression of ACSL4. In vivo, ERC-exos treatment effectively reduced DAI score, ameliorated colon pathological damage, and improved disease symptoms. Moreover, ERC-exos treatment further enhanced the levels of GSH and the expression of GPX4 but reduced the levels of iron, MDA, and expression of ACSL4 in the colon of colitis mice. Conclusions. Ferroptosis was involved in the pathogenesis of UC, and ERC-exos attenuated DSS-induced colitis through downregulating intestine ferroptosis. This study may provide a novel insight into treating UC in the future.

Purpose: This study aimed to explore the relationship between the tumor marker score (TMS) and the postoperative recurrence of single small hepatocellular carcinoma (HCC). Patients and Methods: A total of 409 patients with one resectable HCC with a diameter of 3 cm or less who visited Tianjin Medical University Cancer Institute & Hospital from January 2010 to December 2014 were included in this study. Their alpha-fetoprotein (AFP), carcinoembryonic antigen (CEA), and carbohydrate antigen 19-9 (CA19-9) levels were classified into low and high groups using X-tile software. Each patients’ TMS was calculated as the sum of each tumor marker (low = 0; high = 1). Results: A total of 142 patients were classified as TMS0, 171 as TMS1, and 96 as TMS2. Kaplan–Meier analysis illustrated that TMS could divide the patients into groups with remarkably different prognoses, and the patients with high TMS had worse recurrence-free survival (RFS) than those with low TMS. Multivariate analysis showed that TMS, age, and HBeAg positive were the independent predictors of RFS rate. Subgroup analysis revealed that high TMS was a stable risk factor relative to TMS0. Receiver operating curves showed that the 1-, 3-, and 5-year area under curve (AUC) values of TMS were 0.698, 0.662, and 0.673, respectively. The AUC of TMS was higher than that of other common prognostic models in time-dependent receiver operating curve. Conclusion: TMS was an independent prognostic factor for the postoperative recurrence of a single small HCC and can provide a well-discriminated risk stratification, thus contributing to prognostic prediction and adjuvant therapeutic development.

Background: Endometrial regenerative cells (ERCs) play an important role in attenuation of acute allograft rejection, while their effects are limited. IL-37, a newly discovered immunoregulatory cytokine of the IL-1 family, can regulate both innate and adaptive immunity. Whether IL-37 overexpression can enhance the therapeutic effects of ERCs in inhibition of acute cardiac allograft rejection remains unknown and will be explored in this study. Methods: C57BL/6 mice recipients receiving BALB/c mouse heterotopic heart allografts were randomly divided into the phosphate-buffered saline (untreated), ERC treated, negative lentiviral control ERC (NC-ERC) treated, and IL-37 overexpressing ERC (IL-37-ERC) treated groups. Graft pathological changes were assessed by H&E staining. The intra-graft cell infiltration and splenic immune cell populations were analyzed by immunohistochemistry and flow cytometry, respectively. The stimulatory property of recipient DCs was tested by an MLR assay. Furthermore, serum cytokine profiles of recipients were measured by ELISA assay. Results: Mice treated with IL-37-ERCs achieved significantly prolonged allograft survival compared with the ERC-treated group. Compared with all the other control groups, IL-37-ERC-treated group showed mitigated inflammatory response, a significant increase in tolerogenic dendritic cells (Tol-DCs), regulatory T cells (Tregs) in the grafts and spleens, while a reduction of Th1 and Th17 cell population. Additionally, there was a significant upregulation of immunoregulatory IL-10, while a reduction of IFN-γ, IL-17A, IL-12 was detected in the sera of IL-37-ERC-treated recipients. Conclusion: IL-37 overexpression can promote the therapeutic effects of ERCs to inhibit acute allograft rejection and further prolong graft survival. This study suggests that gene-modified ERCs overexpressing IL-37 may pave the way for novel therapeutic options in the field of transplantation.

Background: The prognostic value of m6A-related genes in hepatocellular carcinoma (HCC) and its correlation with the immune microenvironment still requires further investigation. Methods: Consensus clustering by m6A related genes was used to classify 374 patients with HCC from The Cancer Genome Atlas (TCGA) database. Then we performed the least absolute shrinkage and selection operator (LASSO) to construct the m6A related genes model. The International Cancer Genome Consortium (ICGC) and Gene Expression Omnibus (GEO) datasets were used to verify and evaluate the model. ESTIMATE, CIBERSORTx, the expression levels of immune checkpoint genes, and TIDE were used to investigate the tumor microenvironment (TME) and the response to immunotherapy. Gene set enrichment analyses (GSEA), tumor-associated macrophages (TAMs), and gene-drug sensitivity were also analyzed. Results: By expression value and regression coefficient of five m6A related genes, we constructed the risk score of each patient. The patients with a higher risk score had a considerably poorer prognosis in the primary and validated cohort. For further discussing TME and the response to immunotherapy, we divided the entire set into two groups based on the risk score. Our findings implied that the tumor-infiltrating lymphocytes (TILs) were proportional to the risk scores, which seemed to contradict that patients with higher scores had a poor prognosis. Further, we found that the high-risk group had higher expression of PD-L1, CTLA-4, and PDCD1, indicating immune dysfunction, which may be a fundamental reason for poor prognosis. This was further reinforced by the fact that the low-risk group responded better than the high-risk group to monotherapy and combination therapy. Conclusion: The m6A related risk score is a new independent prognostic factor that correlates with immunotherapy response. It can provide a new therapeutic strategy for improving individual immunotherapy in HCC.