Exosome-derived circUPF2 enhances resistance to targeted therapy by redeploying ferroptosis sensitivity in hepatocellular carcinoma.

BACKGROUND: Advanced hepatocellular carcinoma (HCC) can be treated with sorafenib, which is the primary choice for targeted therapy. Nevertheless, the effectiveness of sorafenib is greatly restricted due to resistance. Research has shown that exosomes and circular RNAs play a vital role in the cancer's malignant advancement. However, the significance of exosomal circular RNAs in the development of resistance to sorafenib in HCC remains uncertain. METHODS: Ultracentrifugation was utilized to isolate exosomes (Exo-SR) from the sorafenib-resistant HCC cells' culture medium. Transcriptome sequencing and differential expression gene analysis were used to identify the targets of Exo-SR action in HCC cells. To identify the targets of Exo-SR action in HCC cells, transcriptome sequencing and analysis of differential expression genes were employed. To evaluate the impact of exosomal circUPF2 on resistance to sorafenib in HCC, experiments involving gain-of-function and loss-of-function were conducted. RNA pull-down assays and mass spectrometry analysis were performed to identify the RNA-binding proteins interacting with circUPF2. RNA immunoprecipitation (RIP), RNA pull-down, electrophoretic mobility shift assay (EMSA), immunofluorescence (IF) -fluorescence in situ hybridization (FISH), and rescue assays were used to validate the interactions among circUPF2, IGF2BP2 and SLC7A11. Finally, a tumor xenograft assay was used to examine the biological functions and underlying mechanisms of Exo-SR and circUPF2 in vivo. RESULTS: A novel exosomal circRNA, circUPF2, was identified and revealed to be significantly enriched in Exo-SR. Exosomes with enriched circUPF2 enhanced sorafenib resistance by promoting SLC7A11 expression and suppressing ferroptosis in HCC cells. Mechanistically, circUPF2 acts as a framework to enhance the creation of the circUPF2-IGF2BP2-SLC7A11 ternary complex contributing to the stabilization of SLC7A11 mRNA. Consequently, exosomal circUPF2 promotes SLC7A11 expression and enhances the function of system Xc- in HCC cells, leading to decreased sensitivity to ferroptosis and resistance to sorafenib. CONCLUSIONS: The resistance to sorafenib in HCC is facilitated by the exosomal circUPF2, which promotes the formation of the circUPF2-IGF2BP2-SLC7A11 ternary complex and increases the stability of SLC7A11 mRNA. Focusing on exosomal circUPF2 could potentially be an innovative approach for HCC treatment.

Outcomes of Robotic Versus Laparoscopic Pancreatoduodenectomy Following Learning Curves of Surgeons: A Multicenter Study on 2255 Patients.

OBJECTIVE: This study aimed to compare robotic pancreatoduodenectomy (RPD) with laparoscopic pancreatoduodenectomy (LPD) in operative and oncologic outcomes. BACKGROUND: Previous studies comparing RPD with LPD have only been carried out in small, single-center studies with variable quality. METHODS: Consecutive patients from nine centers in China who underwent RPD or LPD between 2015 and 2022 were included. A 1:1 propensity score matching (PSM) was used to minimize bias. RESULTS: Of the 2,255 patients, 1158 underwent RPD and 1097 underwent LPD. Following PSM, 1006 patients were enrolled in each group. The RPD group had significantly shorter operative time (270.0 vs. 305.0 minutes, P<0.001), lower intraoperative blood transfusion rate (5.9% vs. 12.0%, P<0.001), lower conversion rate (3.8% vs. 6.7%, P=0.004), and higher vascular reconstruction rate (7.9% vs. 5.6%, P=0.040) than the LPD group. There were no significant differences in estimated blood loss, postoperative length of stay, perioperative complications, and 90-day mortality. Patients who underwent vascular reconstruction had similar outcomes between the two groups, although they had significantly lower estimated blood loss (300.0 vs. 360.0 mL; P=0.021) in the RPD group. Subgroup analysis on pancreatic ductal adenocarcinoma (PDAC) found no significant differences between the two groups in median recurrence-free survival (14.3 vs. 15.3 mo, P=0.573) and overall survival (24.1 vs. 23.7 mo, P=0.710). CONCLUSIONS: In experienced hands, both RPD and LPD are safe and feasible procedures with similar surgical outcomes. RPD had the perioperative advantage over LPD especially in vascular reconstruction. For PDAC patients, RPD resulted in similar oncological and survival outcomes as LPD.

Surgical method choice and coincidence rate of pathological diagnoses in transduodenal ampullectomy: A retrospective case series study and review of the literature.

BACKGROUND: Transduodenal ampullectomy (TDA) is not in wide clinical use due to its low radical effect and a high recurrence rate of tumors. However, TDA is still an effective treatment method; it has great clinical value in cases of duodenal benign tumors, precancerous lesions, and benign and malignant borderline tumors, and can avoid the risks associated with pancreaticoduodenectomy with larger resection range and greater thoroughness than endoscopic papillectomy. AIM: To investigate the surgical method choice and the coincidence rate of pathological diagnoses in TDA for ampullary neoplasms. METHODS: Ten patients with ampullary neoplasms underwent TDA based on the fact that their endoscopic biopsy results suggested benign lesions, and the endoscopic ultrasound (EUS)-assessed tumors were resectable. All cases underwent duodenal ampullary lesion endoscopic biopsy, intraoperative frozen-section pathological examination, and postoperative pathological examination. RESULTS: This study included seven patients with benign tumors and three with malignant tumors (1 pTis, 2 pT1), according to the postoperative pathology results. The coincidence rate of the postoperative pathology results with the intraoperative frozen-section biopsy results was 100% (10/10), and the coincidence rate with the endoscopic biopsy results was 70% (7/10) based on pathological characteristics. The endoscopic biopsy false-negative rate was 30% (3/10). All patients were followed for 6 to 70 mo without tumor recurrence or metastasis. CONCLUSION: The coincidence rate of postoperative pathology results, intraoperative frozen-section pathology results, and endoscopic biopsy results is the restraining factor of TDA clinical application. Endoscopic biopsy results and EUS have importance relevance to surgical planning. Intraoperative frozen-section pathology results have a significant influence on the choice of surgical procedure.

Unicentric Castleman disease presenting as a retroperitoneal peripancreatic mass: A report of two cases and review of literature.

Castleman disease (CD) is a rare disorder of lymph nodes and related tissues. CD generally occurs in the mediastinum, as well as in cervical, retroperitoneal and axillary regions. The disease is classified into two major types: unicentric CD (UCD) and multicentric CD. The occurrence of UCD in the retroperitoneal peripancreatic region is quite rare. We encountered two cases of retroperitoneal peripancreatic UCD in our hospital during the past three years. Following a series of medical examinations, including magnetic resonance imaging, computed tomography, ultrasonography and postoperative histopathological examination, these two patients were diagnosed with UCD, which presented as a retroperitoneal peripancreatic mass. The mass in each patient was completely excised, and no postoperative radiochemotherapy was administered. Both patients recovered well without recurrence during a follow-up period of 30 mo and 8 mo.

Integrin αvß3 is required for cathepsin B-induced hepatocellular carcinoma progression.

The cysteine protease cathepsin B (Cat B) is important in the progression of tumor cells, however, the function and molecular mechanisms of Cat B in hepatocellular carcinoma (HCC) remain to be elucidated. Our previous study demonstrated that integrin αvß3 regulated the biological behavior of HCC. The present study demonstrated that Cat B was also important in cell proliferation and apoptosis in HCC. Notably, Cat B was observed to activate the phosphoinositide 3­kinase (PI3K)/Akt signaling pathway to promote HCC proliferation. Furthermore, inhibition of integrin αvß3 significantly prevented Cat B­induced activation of PI3K/Akt and the progression of HCC. Thus, the results of the present study suggested the presence of a Cat B/integrin αvß3/PI3K/Akt axis in the regulation of the progression of HCC.