Interleukin-17A educated hepatic stellate cells promote hepatocellular carcinoma occurrence through fibroblast activation protein expression.

BACKGROUND: Liver cancer is typified by a complex inflammatory tumor microenvironment, where an array of cytokines and stromal cells orchestrate a milieu that significantly influences tumorigenesis. Interleukin-17A (IL-17A), a pivotal pro-inflammatory cytokine predominantly secreted by Th17 cells, is known to play a substantial role in the etiology and progression of liver cancer. However, the precise mechanism by which IL-17A engages with hepatic stellate cells (HSCs) to facilitate the development of hepatocellular carcinoma (HCC) remains to be fully elucidated. This investigation seeks to unravel the interplay between IL-17A and HSCs in the context of HCC. METHODS: An HCC model was established in male Sprague-Dawley rats using diethylnitrosamine to explore the roles of IL-17A and HSCs in HCC pathogenesis. In vivo overexpression of Il17a was achieved using adeno-associated virus. A suite of molecular techniques, including RT-qPCR, enzyme-linked immunosorbent assays, Western blotting, cell counting kit-8 assays and colony formation assays, was employed for in vitro analyses. RESULTS: The study findings indicate that IL-17A is a key mediator in HCC promotion, primarily through the activation of hepatic progenitor cells (HPCs). This pro-tumorigenic influence appears to be mediated by HSCs, rather than through a direct effect on HPCs. Notably, IL-17A-induced expression of fibroblast activation protein (FAP) in HSCs emerged as a critical factor in HCC progression. Silencing Fap in IL-17A-stimulated HSCs was observed to reverse the HCC-promoting effects of HSCs. CONCLUSIONS: The collective evidence from this study implicates the IL-17A/FAP signaling axis within HSCs as a contributor to HCC development by enhancing HPC activation. These findings bolster the potential of IL-17A as a diagnostic and preventative target for HCC, offering new avenues for therapeutic intervention.

Hippocampal volume and resting-state functional connectivity on magnetic resonance imaging in patients with Parkinson and depression.

Background: Recent structural and functional imaging studies of depression in Parkinson disease (DPD) have failed to reveal the relevant mechanism, and relatively few studies have been conducted on limbic systems such as the hippocampus. This study thus aimed to gain new insights into the pathogenesis of DPD by detecting the changes in the hippocampal structure and the resting-state functional connectivity (FC) of patients with DPD. Methods: This study included 30 patients with DPD (DPD group), 30 patients with nondepressed Parkinson disease (NDPD; NDPD group), and 30 normal controls (NCs; NC group) with no significant age or gender differences with the DPD group. The Hamilton Depression Rating Scale (HAMD) and three-dimensional T1-weighted imaging and blood oxygen level-dependent imaging data of all patients were collected. The hippocampal volumes were measured using MATLAB software (MathWorks). The correlation between hippocampal volume and the HAMD score in the DPD group was analyzed with Pearson correlation coefficient. The bilateral hippocampi were used as the regions of interest and as the seed points for FC. FC analysis was performed between the preprocessed functional data of the whole brain and the two seed points with Data Processing Assistant for Resting-State and Statistical Parametric Mapping 8 software, respectively. The correlation between FC and HAMD scores in the patients with DPD was determined using partial correlation analysis. Results: Compared with those in the NC group and the NDPD group, the bilateral hippocampal volumes in the DPD group were significantly decreased (P<0.05). There was a negative correlation between the bilateral hippocampal volume and the HAMD score in the DPD group (P<0.05). Compared with that of the NDPD group, the FC of the right hippocampus with the right occipital lobe and left precuneus was reduced in the DPD group. In the DPD group, the FC values of the right hippocampus, right occipital lobe, and left anterior cuneiform lobe were negatively correlated with HAMD scores. Conclusions: The volume of bilateral hippocampi in patients with DPD is significantly decreased and negatively correlated with the severity of depressive disorder. The weakened FC of the right hippocampus to the right occipital lobe and the left precuneus may play an important role in the neurological basis of DPD.

Transarterial Chemoembolization for Patients with Unresectable Hepatocellular Carcinoma with Child-Pugh B7.

Background and Objectives: This study aimed to evaluate the efficacy and safety of transarterial chemoembolization (TACE) in patients with unresectable early or intermediate hepatocellular carcinoma (HCC) and Child-Pugh (CP)-B liver dysfunction. Methods: This multicenter retrospective study enrolled patients with treatment-naïve HCC treated with TACE monotherapy between January 2012 and December 2020 at six Chinese hospitals. The primary outcome was overall survival (OS), and the secondary outcomes included the objective response rate (ORR) according to the modified RECIST and adverse events (AEs). Propensity score matching (PSM) was performed to reduce bias between the CP-B and CP-A groups. Results: A total of 847 patients were included in the study. CP-A patients had significantly longer OS (median, 22.0 vs 19.3 months, P = 0.032) than CP-B (score of 7-9) patients, but a non-significant trend compared with CP-B (score of 7) patients (median, 22.0 vs 20.5 months, P = 0.254). After PSM, the median OS was 22.7 months for CP-A patients, while it was 19.3 months for CP-B (score of 7-9) patients (p = 0.026) and 20.5 months for CP-B (score of 7) patients (p = 0.155). CP-A patients achieved a significantly better ORR (53.0% vs 35.8%, P < 0.05) compared to CP-B (score of 7-9) patients, but a non-significant trend was observed in CP-B (score of 7) patients (53.0% vs 51.1%, P > 0.05). The post-embolization syndrome rates in the CP-A and CP-B (score of 7) cohorts were 52.1% and 53.3%, respectively. No new safety concerns were observed. Conclusion: Patients with HCC with a CP score of 7 receiving TACE showed a similar prognosis and safety profile to CP-A patients.

Prognostic Performance of the China Liver Cancer Staging System in Hepatocellular Carcinoma Following Transarterial Chemoembolization.

Background and Aims: To validate prognostic performance of the China liver cancer (CNLC) staging system as well as to compare these parameters with those of the Barcelona Clinic Liver Cancer (BCLC) staging system for Chinese hepatocellular carcinoma (HCC) treated with transarterial chemoembolization (TACE). Methods: This multicenter retrospective study included 1,124 patients with HCC between January 2012 and December 2020 from six Chinese hospitals. Based on overall survival (OS), the prognostic performance outcomes for the CNLC and BCLC staging systems were compared by model discrimination [C statistic and Akaike information criterion (AIC)], monotonicity of the gradient (linear trend chi-square test), homogeneity (likelihood ratio chi-square test), and calibration (calibration plots). A prospective cohort of 44 patients receiving TACE-based therapy included between January 2021 and December 2022 was used to prospectively validate the outcomes. Results: Median OS was 19.1 (18.2-20.0) months, with significant differences in OS between stages defined by the CNLC and BCLC observed (p<0.001). The CNLC performed better than the BCLC regarding model discrimination (C-index: 0.661 vs. 0.644; AIC: 10,583.28 vs. 10,583.72), model monotonicity of the gradient (linear trend chi-square test: 66.107 vs. 57.418; p<0.001), model homogeneity (159.2 vs. 158.7; p<0.001). Both staging systems had good model calibration. Similar results were observed in the prospective cohort. Conclusions: Combining model discrimination, gradient monotonicity, homogeneity, and calibration, the CNLC performed better than the BCLC for Chinese HCC patients receiving TACE.

Real-world efficacy and safety of TACE plus camrelizumab and apatinib in patients with HCC (CHANCE2211): a propensity score matching study.

OBJECTIVES: This study aimed to investigate the efficacy and safety of transarterial chemoembolization (TACE) plus camrelizumab, a monoclonal antibody targeting programmed death-1, and apatinib for patients with intermediate and advanced hepatocellular carcinoma (HCC) in a real-world setting. METHODS: A total of 586 HCC patients treated with either TACE plus camrelizumab and apatinib (combination group, n = 107) or TACE monotherapy (monotherapy group, n = 479) were included retrospectively. Propensity score matching analysis was used to match patients. The overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and safety in the combination group were described in comparison to monotherapy. RESULTS: After propensity score matching (1:2), 84 patients in the combination group were matched to 147 patients in the monotherapy group. The median age was 57 years and 71/84 (84.5%) patients were male in the combination group, while the median age was 57 years with 127/147 (86.4%) male in the monotherapy group. The median OS, PFS, and ORR in the combination group were significantly higher than those in the monotherapy group (median OS, 24.1 vs. 15.7 months, p = 0.008; median PFS, 13.5 vs. 7.7 months, p = 0.003; ORR, 59.5% [50/84] vs. 37.4% [55/147], p = 0.002). On multivariable Cox regression, combination therapy was associated with significantly better OS (adjusted hazard ratio [HR], 0.41; 95% confidence interval [CI], 0.26-0.64; p < 0.001) and PFS (adjusted HR, 0.52; 95% CI, 0.37-0.74; p < 0.001). Grade 3 or 4 adverse events occurred in 14/84 (16.7%) and 12/147 (8.2%) in the combination and monotherapy groups, respectively. CONCLUSIONS: TACE plus camrelizumab and apatinib showed significantly better OS, PFS, and ORR versus TACE monotherapy for predominantly advanced HCC. CLINICAL RELEVANCE STATEMENT: Compared with TACE monotherapy, TACE plus immunotherapy and molecular targeted therapy showed better clinical efficacy for predominantly advanced HCC patients, with a higher incidence of adverse events. KEY POINTS: • This propensity score-matched study demonstrates that TACE plus immunotherapy and molecular targeted therapy have a longer OS, PFS, and ORR compared with TACE monotherapy in HCC. • Grade 3 or 4 adverse events occurred in 14/84 (16.7%) patients treated with TACE plus immunotherapy and molecular targeted therapy compared with 12/147 (8.2%) patients in the monotherapy group, while no grade 5 adverse events were observed in all cohorts.

Perioperative and long-term survival outcomes of laparoscopic versus open hepatectomy for BCLC stage A large hepatocellular carcinoma patients in difficult segments: A two-centre, propensity score matching analysis.

Background: The differences in short- and long-term outcome between laparoscopic liver resection (LLR) and open liver resection (OLR) for BCLC stage A large hepatocellular carcinoma (HCC) in difficult segments (I, IVa, VII, VIII) remain unclear. This PSM two-centre study aimed to compare perioperative and long-term survival outcomes of LLR with OLR for this HCC. Methods: HCC patients with BCLC stage A who underwent OLR or LLR in two medical centres were enrolled in the study. PSM analysis was performed to match patients between the LLR cohort and OLR cohort. Survival was analysed based on the Kaplan-Meier method. Independent risk factors were identified by Cox regression. Results: After PSM, 35 patients remained in the LLR cohort, and 84 remained in the OLR cohort. Patients in the LLR cohort had more intraoperative blood loss (p=0.036) and shorter hospital stays after surgery (p<0.001). The LLR cohort and OLR cohort had no difference in intraoperative blood transfusion, surgical margin or postoperative short-term outcomes. The OS and RFS were not significantly different between the two cohorts. The OS and RFS of these two cohorts were not different in the subgroup analysis. Surgical margin was identified as an independent risk factor for tumour recurrence. Conclusion: For BCLC stage A large HCC patients with lesions in difficult segments, LLR was feasible and had shorter hospital stay than OLR. In addition, a surgical margin ≥1 cm could significantly decrease the recurrence probability for large HCC located in different segments without compromising short-term outcomes.

Transarterial chemoembolization with PD-(L)1 inhibitors plus molecular targeted therapies for hepatocellular carcinoma (CHANCE001).

There is considerable potential for integrating transarterial chemoembolization (TACE), programmed death-(ligand)1 (PD-[L]1) inhibitors, and molecular targeted treatments (MTT) in hepatocellular carcinoma (HCC). It is necessary to investigate the therapeutic efficacy and safety of TACE combined with PD-(L)1 inhibitors and MTT in real-world situations. In this nationwide, retrospective, cohort study, 826 HCC patients receiving either TACE plus PD-(L)1 blockades and MTT (combination group, n = 376) or TACE monotherapy (monotherapy group, n = 450) were included from January 2018 to May 2021. The primary endpoint was progression-free survival (PFS) according to modified RECIST. The secondary outcomes included overall survival (OS), objective response rate (ORR), and safety. We performed propensity score matching approaches to reduce bias between two groups. After matching, 228 pairs were included with a predominantly advanced disease population. Median PFS in combination group was 9.5 months (95% confidence interval [CI], 8.4-11.0) versus 8.0 months (95% CI, 6.6-9.5) (adjusted hazard ratio [HR], 0.70, P = 0.002). OS and ORR were also significantly higher in combination group (median OS, 19.2 [16.1-27.3] vs. 15.7 months [13.0-20.2]; adjusted HR, 0.63, P = 0.001; ORR, 60.1% vs. 32.0%; P < 0.001). Grade 3/4 adverse events were observed at a rate of 15.8% and 7.5% in combination and monotherapy groups, respectively. Our results suggest that TACE plus PD-(L)1 blockades and MTT could significantly improve PFS, OS, and ORR versus TACE monotherapy for Chinese patients with predominantly advanced HCC in real-world practice, with an acceptable safety profile.

Development of preoperative prognostic models including radiological features for survival of singular nodular HCC patients.

BACKGROUND: Early singular nodular hepatocellular carcinoma (HCC) is an ideal surgical indication in clinical practice. However, almost half of the patients have tumor recurrence, and there is no reliable prognostic prediction tool. Besides, it is unclear whether preoperative neoadjuvant therapy is necessary for patients with early singular nodular HCC and which patient needs it. It is critical to identify the patients with high risk of recurrence and to treat these patients preoperatively with neoadjuvant therapy and thus, to improve the outcomes of these patients. The present study aimed to develop two prognostic models to preoperatively predict the recurrence-free survival (RFS) and overall survival (OS) in patients with singular nodular HCC by integrating the clinical data and radiological features. METHODS: We retrospective recruited 211 patients with singular nodular HCC from December 2009 to January 2019 at Eastern Hepatobiliary Surgery Hospital (EHBH). They all met the surgical indications and underwent radical resection. We randomly divided the patients into the training cohort (n =132) and the validation cohort (n = 79). We established and validated multivariate Cox proportional hazard models by the preoperative clinicopathologic factors and radiological features for association with RFS and OS. By analyzing the receiver operating characteristic (ROC) curve, the discrimination accuracy of the models was compared with that of the traditional predictive models. RESULTS: Our RFS model was based on HBV-DNA score, cirrhosis, tumor diameter and tumor capsule in imaging. RFS nomogram had fine calibration and discrimination capabilities, with a C-index of 0.74 (95% CI: 0.68-0.80). The OS nomogram, based on cirrhosis, tumor diameter and tumor capsule in imaging, had fine calibration and discrimination capabilities, with a C-index of 0.81 (95% CI: 0.74-0.87). The area under the receiver operating characteristic curve (AUC) of our model was larger than that of traditional liver cancer staging system, Korea model and Nomograms in Hepatectomy Patients with Hepatitis B Virus-Related Hepatocellular Carcinoma, indicating better discrimination capability. According to the models, we fitted the linear prediction equations. These results were validated in the validation cohort. CONCLUSIONS: Compared with previous radiography model, the new-developed predictive model was concise and applicable to predict the postoperative survival of patients with singular nodular HCC. Our models may preoperatively identify patients with high risk of recurrence. These patients may benefit from neoadjuvant therapy which may improve the patients' outcomes.

Serum thrombospondin-1 serves as a novel biomarker and agonist of gemcitabine-based chemotherapy in intrahepatic cholangiocarcinoma.

BACKGROUND: At present, the first-line treatment for advanced intrahepatic cholangiocarcinoma (ICC) is gemcitabine combined with cisplatin, but a considerable portion of ICC patients exhibit resistance to gemcitabine. Therefore, finding sensitisers for gemcitabine chemotherapy in ICC patients and predicting molecular markers for chemotherapy efficacy have become urgent needs. METHODS: In this study, PDX models were established to conduct gemcitabine susceptibility tests. The selected PDX tissues of the chemotherapy-sensitive group and drug-resistant group were subjected to transcriptome sequencing and protein chip technology to identify the key genes. Sixty-one ICC patients treated with gemcitabine chemotherapy were recruited for clinical follow-up validation. RESULTS: We found that thrombospondin-1 (TSP1) can predict gemcitabine chemosensitivity in ICC patients. The expression level of TSP1 could reflect the sensitivity of ICC patients to gemcitabine chemotherapy. Functional experiments further confirmed that TSP1 can increase the efficacy of gemcitabine chemotherapy for ICC. A mechanism study showed that TSP1 may affect the intake of oleic acid by binding to the CD36 receptor. CONCLUSIONS: In summary, we found a key molecule-TSP1-that can predict and improve the sensitivity of ICC patients to gemcitabine chemotherapy, which is of great significance for the treatment of advanced cholangiocarcinoma.

HBV/Pregenomic RNA Increases the Stemness and Promotes the Development of HBV-Related HCC Through Reciprocal Regulation With Insulin-Like Growth Factor 2 mRNA-Binding Protein 3.

BACKGROUND AND AIMS: HBV-pgRNA (pregenomic RNA) has been proposed for predicting the response of nucleos(t)ide analogue (NA) treatment, guiding discontinuation of NA therapy and monitoring the emergence of viral mutations. However, the contributions of HBV-pgRNA to HCC remain open for study. APPROACH AND RESULTS: Double-center cohorts of serum samples with undetectable serum HBV-DNA (below the lower limit of detection) were obtained from long-term NA-treated (≥48 weeks) HBV-related HCC patients. The correlation between serum pgRNA concentration and the prognosis of HCC were analyzed. The role pgRNA played in HCC development was assessed both in vitro and in vivo. Our findings revealed that for patients who underwent long-term NA therapy with undetectable serum HBV-DNA, patients with high serum pgRNA expression had a poorer overall survival rate and higher cumulative recurrence rate after hepatectomy. Experiments demonstrated that pgRNA promotes proliferation, stemness, and tumorigenicity of HCC cells. Mechanistically, we found that pgRNA could up-regulate the expression of insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3), a well-proven oncoprotein, at the posttranscriptional level. Furthermore, interferon (IFN)-α-2a could degrade the stability of pgRNA through increasing its N6-methyladenosine (m6A) RNA modification. Collectively, our findings uncover that serum pgRNA could serve as a potential biomarker for predicting the prognosis and recurrence of HCC in patients who received long-term NA therapy with undetectable serum HBV-DNA; and the pgRNA-IGF2BP3 axis plays an important role in the development of HBV-related HCC. Moreover, IFN-α-2a could reduce the stability of pgRNA by increasing its m6A RNA modification level, thereby suppressing the development of HBV-related HCC. CONCLUSIONS: In conclusion, our studies reveal a significance and mechanism of HBV-pgRNA in increasing stemness features and offer a potential prognostic marker and a therapeutic target for HBV-related HCC.

A new less invasive surgical technique in the management of acute Achilles tendon rupture through limited-open procedure combined with a single-anchor and "circuit" suture technique.

BACKGROUND: Traditional incision repair and minimally invasive repair for acute Achilles tendon repair have limitations. This study aimed to present our series of 23 patients with acute Achilles tendon rupture that was repaired using two small incisions to assist the anchor repair of the tear and a new "circuit" suture technique. METHODS: This was a retrospective study of 23 patients with acute Achilles tendon rupture treated with the new technique at Changhai Hospital between January 2015 and December 2016 and followed up for 14-33 months. Clinical outcome was assessed using the AOFAS, Leppilahti, and Arner-Lindholm scores. Complications, range of motion (ROM), and time to return to work and light sport activity were assessed. RESULTS: The AOFAS score was 85-96 at 3 months and 92-100 at 12 months. The 3-month ROM was 27°-37°, and the 12-month ROM was 36°-48°. The Leppilahti score was 85-95 at 3 months and 90-100 at 12 months. The recovery time of the patients was 10-18 weeks. The postoperative recovery time to exercise was 16-24 weeks. There was only one case of deep venous thrombosis. According to the Arner-Lindholm assessment criteria, patient outcomes were rated as excellent in 20 (87.0%) cases, good in three (13.0%) cases, and poor in 0 cases. The excellent-to-good rate was 100%. CONCLUSION: The limited-open procedure combined with a single-anchor and "circuit" suture technique could be used to repair torn Achilles sites, with a low occurrence of complications. This new and minimally invasive technique could be an alternative in the management of acute Achilles tendon rupture.

miR-422a inhibits osteosarcoma proliferation by targeting BCL2L2 and KRAS.

Osteosarcoma is the most common primary malignant bone tumor in children and adolescents. However, the underlying mechanism of osteosarcoma carcinogenesis and progression remains unknown. In the present study, we evaluated the expression profile of miRNAs in osteosarcoma tissues and the adjacent normal tissues. We found that the expression of miR-422a was down-regulated in osteosarcoma tissues and cell lines. In addition, we observed significantly elevated levels of repressive H3K9me3 and H3K27me3 and decreased active H3K4me3 on the promote region of miR-422a in osteosarcoma cells and clinical samples. Furthermore, up-regulation of miR-422a exhibited both in vitro and in vivo anti-tumor effects by inhibiting osteosarcoma cell growth and inducing apoptosis and cell cycle arrest. We also found that miR-422a targeted BCL2L2 and KRAS and negatively regulated their protein expression. Furthermore, restoration of miR-422a and knockdown of BCL2L2 and KRAS promoted apoptosis and induce cell cycle arrest in osteosarcoma cells. Taken together, the present study demonstrates that miR-422a may serve as a tumor suppressor in osteosarcoma via inhibiting BCL2L2 and KRAS translation both in vitro and in vivo Therefore, miR-422a could be developed as a novel therapeutic target in osteosarcoma.

Autophagy contributes to the enrichment and survival of colorectal cancer stem cells under oxaliplatin treatment.

Currently, chemoresistance is an important cause of treatment failure in colorectal cancer. Cancer stem cells, which are a population of multi-potent cells with the capacity to self-renew and differentiate, have been found to participate in chemoresistance. In the present study, the chemotherapeutic drug oxaliplatin induced autophagy in colorectal cancer cell lines, which in turn protected cancer cells from apoptosis. Further results showed that oxaliplatin-induced autophagy enriched the population of colorectal CSCs and participated in maintaining the stemness of colorectal CSCs, thus making the cells more resistant to chemotherapy. Taken together, the results indicate that autophagy might enhance the chemoresistance of colorectal cancer cells by protecting the stemness and chemoresistance of colorectal CSCs. Our study demonstrates that autophagy plays a pro-survival role in colorectal CSCs subjected to oxaliplatin. Therefore, targeting autophagy may be considered as a potential therapeutic strategy to address chemoresistance in the treatment of colorectal cancer.