The efficacy and feasibility of neoadjuvant immunotherapy plus chemotherapy followed by McKeown minimally invasive oesophagectomy for locally advanced oesophageal squamous cell carcinoma.

Introduction: In immunotherapy, antibodies are activated to block immune checkpoints, resist tumour immunosuppression, shrink tumours and prevent a recurrence. As the science behind tumour immunotherapy continuously develops and improves, neoadjuvant immunotherapy bears more prominent advantages: antigen exposure not only enhances the degree of tumour-specific T-cell response but also prolongs the duration of actions. In this study, we evaluated the efficacy and safety of McKeown minimally invasive oesophagectomy (McKeown MIO) following neoadjuvant immunotherapy combined with chemotherapy (NICT) in patients with locally advanced oesophageal cancer (OC). Patients and Methods: In this retrospective study, 94 patients underwent either NICT or neoadjuvant chemotherapy (NCT) followed by MIO at our institution from January 2020 to October 2022. We assessed the therapy-related adverse events and perioperative outcomes and compared them between the two groups. Results: After completing at least two cycles of neoadjuvant therapy, all patients underwent McKeown MIO with negative margins within 4-7 weeks. Demographic data of the two cohorts were similar. Regarding perioperative characteristics, the median intraoperative blood loss was 50 ml in the NICT group, lower than that of the NCT group (100 ml, P < 0.05). In addition, the NICT group had significantly more harvested lymph nodes than the NCT group (P < 0.05). No significant differences were found in post-operative complications. The rate of objective response rate in the NICT group was higher than that in the NCT group (88.3% vs. 58.8%). Regarding tumour regression, the number of patients with TRG Grades 1-3 in the NICT group was more than that in the NCT. Adverse events experienced by the two groups included anaemia and elevated transaminase. We found no difference in the adverse events between the two groups. Conclusions: This study showed the efficacy and feasibility of NICT followed by McKeown MIO in treating locally advanced OC.

A comparison of two methods of lymph node dissection along the left recurrent laryngeal nerve in McKeown minimally invasive esophagectomy.

Background: Lymph nodes dissection in esophagectomy is an essential procedure for radical resection, which can not only provide more accurate staging but may also improve survival, while it is technically challenging and may lead to recurrent laryngeal nerve (RLN) paralysis. Numerous efforts have been directed to achieve the dissection of more LNs around the RLN and to lower the incidence of RLN palsy, including Bascule method and modified Bascule method. On this basis, we modified and applied a novel method which involves the en bloc dissection of lymph nodes dissection along the left RLN in McKeown minimally invasive esophagectomy (MIE). Methods: A total of 244 consecutive cases of lymphadenectomy along the left RLN during McKeown MIE at our institution between January 2018 and August 2021 were retrospectively analyzed. The cases were divided into two groups based on the methods of lymphadenectomy along the left RLN: 77 cases received the conventional method (CM group) and 167 cases received the novel method (NM group). The surgical outcomes, especially the impact of surgical proficiency on the outcomes of lymphadenectomy along the left RLN, were assessed and compared between the two groups. Results: Demographic data of the two cohorts were similar. The number of harvested lymph nodes (LNs) (total/abdomen/left RLN) in the NM group was markedly higher than that in the CM group (32 vs. 27, P=0.006; 11 vs. 9, P=0.038; 3 vs. 2, P=0.044). However, the number of harvested LNs from the chest or right RLN was not significantly different in the two groups. The hoarseness rate was 1.8% in the NM group, which was slightly but not notably lower than that of the CM group (1.8% vs. 2.6%, P=0.681). The incidence of LN metastasis along the left RLN was 13.9%, 15.6%, and 13.2% in the whole cohort, CM group, and NM group, respectively. Conclusions: Our novel method not only increased the number of LN dissections along left RLN but also slightly reduced the incidence of hoarseness. Therefore, this novel method of lymphadenectomy along the left RLN during McKeown MIE is safe and reliable.

A tumor-suppressive circular RNA mediates uncanonical integrin degradation by the proteasome in liver cancer.

Circular RNAs (circRNAs) have emerged as important regulators of various cellular processes and have been implicated in cancer. Previously, we reported the discovery of several dysregulated circRNAs including circPABPC1 (polyadenylate-binding protein 1) in human hepatocellular carcinoma (HCC), although their roles in HCC development remained unclear. Here, we show that circPABPC1 is preferentially lost in tumor cells from clinical samples and inhibits both intrahepatic and distant metastases in a mouse xenograft model. This tumor-suppressive function of circPABPC1 can be attributed to its inhibition of cell adhesion and migration through down-regulating a key member of the integrin family, ITGB1 (ß1 integrin). Mass spectrometry and biochemical evidence demonstrate that circPABPC1 directly links ITGB1 to the 26S proteasome for degradation in a ubiquitination-independent manner. Our data have revealed an uncanonical route for integrin turnover and a previously unidentified mode of action for circRNAs in HCC that can be harnessed for anticancer treatment.

Hydrogenation of Toluene to Methyl Cyclohexane over PtRh Bimetallic Nanoparticle-Encaged Hollow Mesoporous Silica Catalytic Nanoreactors.

PtRh bimetallic nanoparticle (NP)-encaged hollow mesoporous silica nanoreactors (PtRh@HMSNs) are prepared by employing metal-ion-containing charge-driven polymer micelles as templates. These nanoreactors feature ∼1-2 nm PtRh NPs in ∼11 nm hollow cavities of HMSNs. Among various Pt x Rh y @HMSNs, Pt0.77Rh1@HMSNs show the best catalytic performance for toluene hydrogenation. Under 30 °C, atmospheric H2 pressure, and a toluene/(Pt+Rh) molar ratio of 200/1, Pt0.77Rh1@HMSNs reach 100.0% of methyl cyclohexane yield and demonstrate a much better catalytic performance than monometallic Pt@HMSNs and Rh@HMSNs and their physical mixtures. Moreover, Pt0.77Rh1@HMSNs exhibit a good catalytic stability during recycling experiments. The enhanced performance of Pt0.77Rh1@HMSNs is ascribed to the interaction between Pt and Rh, the beneficial effect of the relatively large mesoporous channels for mass transfer, as well as the confinement effect of functional NPs inside hollow cavities.

Androgen receptor affects the response to immune checkpoint therapy by suppressing PD-L1 in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a heterogeneous malignancy with gender-related differences in onset and course. Androgen receptor (AR), a male hormone receptor, is critical in the initiation and progression of HCC. The role of AR in HCC has been mechanistically characterized and anti-AR therapies have been developed, showing limited efficacy. Immunotherapy targeting immune checkpoint proteins may substantially improve the clinical management of HCC. The mechanism by which AR influences HCC immune state remains unclear. In this study, we demonstrated that AR negatively regulated PD-L1, by acting as a transcriptional repressor of PD-L1. Notably, AR over-expression in HCC cells enhanced CD8+T function in vitro. We then verified the AR/PD-L1 correlation in patients. In animal experiment we found that lower AR expressed tumor achieved better response to PD-L1 inhibitor. Thus, AR suppressed PD-L1 expression, possibly contributing to gender disparity in HCC. Better understanding of the roles of AR during HCC initiation and progression will provide a novel angle to develop potential HCC immunotherapies.

Ferric Hydroxide-Modified Upconversion Nanoparticles for 808 nm NIR-Triggered Synergetic Tumor Therapy with Hypoxia Modulation.

The efficacy of dynamic therapy for solid tumors suffers daunting challenges induced by tumor hypoxia. Herein, we report a biocompatible nanosystem containing Fe(OH)3-modified upconversion nanoparticles (UCNPs) for promoting synergetic chemo- and photodynamic therapy with the modulation of tumor hypoxia. In this system, UCNPs convert 808 nm near-infrared excitation to visible photon energy, which stimulates chlorin-e6 photosensitizers to generate toxic reactive oxygen species (ROS) by consumption of dissolved oxygen in cancer cells. Importantly, we employ Fe(OH)3 compounds to enable continuous oxygen generation in cancer cells and, meanwhile, induce extra ROS formation through the Fenton-like reaction. The system consequently improves the tumor treatment efficacy in vitro and in vivo. This study puts forward a novel combinatorial therapeutic platform for tumor microenvironment modulation and enhanced cancer therapy.

Gold nanorod-assembled ZnGa2O4:Cr nanofibers for LED-amplified gene silencing in cancer cells.

Nanoparticles are now commonly used as non-viral gene vectors for RNA interference (RNAi) in cancer therapy but suffer from low targeting efficiency in situ. Meanwhile, localized drug delivery systems do not offer the effective capability for intracellular gene transportation. We describe here the design and synthesis of a localized therapeutic system, consisting of gold nanorods (Au NRs) loaded with hTERT siRNA assembled on the surface of ZnGa2O4:Cr (ZGOC) nanofibers. This composite system offers the potential for a LED-induced mild photothermal effect which enhances the phagocytosis of Au NRs carrying siRNA and the subsequent release of siRNA in the cytoplasm. Both phenomena amplify the gene silencing effect and consequently offer the potential for a superior therapeutic outcome.

The Safety and Efficacy of Laparoscopic Common Bile Duct Exploration Combined with Cholecystectomy for the Management of Cholecysto-choledocholithiasis: An Up-to-date Meta-analysis.

OBJECTIVE: The aim of this study was to compare the efficacy and safety of the laparoscopic common bile duct exploration (LCBDE) and laparoscopic cholecystectomy (LC) with preoperative endoscopic sphincterotomy (pre-EST) and LC for concomitant gallstones and common bile duct (CBD) stones. BACKGROUND: It remains controversial whether LCBDE+LC is better than pre-EST+LC for gallstones and CBD stones. METHODS: A specific search of online databases was performed from January 2006 to October 2017. Relative outcomes of perioperative safety and postoperative efficacy were synthesized. Single-arm meta-analysis and cumulative meta-analysis were also conducted. RESULTS: A total of 13 studies involving 1757 (872 vs 885) patients were included for analysis in our study. The CBD stones clearance rate [94.1% vs 90.1%; odds ratio (OR) 1.56, P = 0.012] was significantly higher in patients who underwent LCBDE+LC than pre-EST+LC, while perioperative complications (7.6% vs 12.0%; OR 0.67, P = 0.015), conversion to other procedure (4.1% vs 7.1%; OR 0.64, P = 0.025), retained stones rate (1.2% vs 7.9%; OR 0.34, P = 0.004), lithiasis recurrence rate (1.8% vs 5.6%, OR 0.32, P = 0.005), operative time [112.28 vs 132.03 minutes; weighted mean difference (WMD) -18.08, P = 0.002], length of hospital stay (4.94 vs 6.62 days; WMD -1.63, P = 0.023), and total charges [standardized mean difference (SMD) -2.76, P = 0.002] were significantly lower in LCBDE+LC. The mortality (0.6% vs 1.1%; OR 0.32, P = 0.117) was similar between the 2 groups. The cumulative meta-analyses indicated the effect sizes of CBD stones clearance rate, perioperative complications, and conversion to other procedure have already stabilized between 2 groups. CONCLUSION: The updated meta-analysis first confirms that LCBDE+LC is superior to pre-EST+LC both in perioperative safety and short- and long-term postoperative efficacy, which should be considered as optimal treatment choice for cholecysto-choledocholithiasis.

Circular RNA expression is suppressed by androgen receptor (AR)-regulated adenosine deaminase that acts on RNA (ADAR1) in human hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a heterogeneous malignancy as a result of complex genetic and epigenetic alterations. HCC is characterized by a clear gender disparity for which there is lack of a clear mechanistic understanding. Androgen receptor (AR) is thought to be critical for such bias. Meanwhile, the potential function of circular RNA (circRNA), regulated by RNA editing enzyme, remained largely unknown in malignancy till now. By utilizing circRNA microarray survey coupled with in vitro analysis, we analyzed the influence of AR on circRNA expression in HCC. Our results indicated that AR could suppress circRNA expression by upregulating ADAR1 p110. Such effect is because AR served as a transcriptional activator of ADAR1 promoter. More significantly, data collected from our center strongly suggest that ADAR1 expression can effectively predict HCC patients' prognosis and an abnormal overexpression of ADAR1 is positively correlated with AR in HCC. In addition, we found CircARSP91 (hsa_circ_0085154), one of the circRNAs downregulated by AR in an ADAR1-dependent manner, could inhibit HCC tumor growth both in vitro and in vivo. These findings highlight the fact that AR as a contributing factor for gender disparity in HCC can cause complex consequences though regulation of circRNA expression. Better understanding of the roles of circRNA during HCC initiation and progression will provide a novel angle to develop potential HCC therapies.

BCLB, methylated in hepatocellular carcinoma, is a starvation stress sensor that induces apoptosis and autophagy through the AMPK-mTOR signaling cascade.

Epigenetic disruption of tumor suppressor genes (TSGs), particularly DNA methylation, plays a key role in hepatocellular carcinoma (HCC) pathogenesis. Through methylome study, we identified BCLB as a methylated gene in HCC. BCLB was methylated in all tumor cell lines with silenced or reduced expression. BCLB was further found to be silenced in 55.2% (58/105) of HCC samples, while 91.4% (96/105) of paired non-tumor tissues showed high BCLB expression. BCLB protein expression was significantly correlated with HBV status (p = 0.036), AFP (p = 0.048), tumor size (p = 0.006), and TNM stage (p = 0.022). The overall survival and disease-free survival rate of HCC patients with positive BCLB expression were both significantly higher than those with negative BCLB expression (p = 0.032 and 0.027, respectively). Ectopic expression of BCLB in HCC cells inhibited cell growth in vitro and in vivo. Mechanistic study showed that BCLB expression was a starvation stress sensor inducing apoptosis and autophagy simultaneously in HCC cells through the adenosine monophosphate-activated protein kinase AMPK-mTOR signaling cascade. Thus, epigenetic suppression of BCLB expression is involved in HCC development, which might have therapeutic implications for HCC patients.

Covered Stents versus Uncovered Stents for Unresectable Malignant Biliary Strictures: A Meta-Analysis.

AIM: To summarize the covered or uncovered SEMS for treatment of unresectable malignant distal biliary obstruction, comparing the stent patency, patient survival, and incidence of adverse events between the two SEMSs. METHODS: The meta-analysis search was performed independently by two of the authors, using MEDLINE, EMBASE, OVID, and Cochrane databases on all studies between 2010 and 2015. Pooled effect was calculated using either the fixed or the random effects model. RESULTS: Statistics shows that there is no difference between SEMSs in the hazard ratio for patient survival (HR 1.04; 95% CI, 0.92-1.17; P = 0.55) and stent patency (HR 0.87, 95% CI: 0.58 to 1.30, P = 0.5). However, incidence of adverse events (OR: 0.74, 95% CI: 0.57 to 0.97, P = 0.03) showed significant different results in the covered SEMS, with dysfunctions events (OR: 0.75, 95% CI: 0.56 to 1.00, P = 0.05) playing a more important role than complications (OR: 0.87, 95% CI: 0.58 to 1.30, P = 0.50). CONCLUSIONS: Covered SEMS group had lower incidence of adverse events. There is no significant difference in dysfunctions, but covered SEMS trends to be better, with no difference in stent patency, patient survival, and complications.