Hai-Bin Shi

Purpose To investigate the utility of combining clinical and contrasted-enhanced tomography (CECT) parameters for the preoperative evaluation of perineural invasion (PNI) in gallbladder carcinoma (GBC). Methods A total of 134 patients with GBC (male/female, 52/82; age, 64.4 ± 9.7 years) were divided into PNI-positive (n = 63) and PNI-negative groups (n = 71). Clinical characteristics (demographic information, liver function indicators and tumor markers) and CECT parameters (tumor type, tumor size, gallbladder stone, invasion of gallbladder neck/cystic duct, clinical T stage and N stage) were collected and compared between two groups. Binary logistic regression analysis, receiver operating characteristic curves analyses and Delong test were used in further statistical analyses in clinical T3-4 stage (cT3-4) GBC patients. Overall survival (OS) rates after surgery were compared between PNI-negative group and PNI-positive group of cT3-4 GBC patients. Results The majority of GBC patients with PNI were classified as cT3-4 (61/63, 96.8%), while only 3.2% (2/63) of PNI-positive cases were identified at cT1-2. Among cT3-4 GBC, OS was significantly lower in the PNI-positive group than the PNI-negative group after surgery (HR,1.661; 95% CI, 1.044–2.643; P = 0.032). Gender and gallbladder neck/cystic duct invasion were independent predictive factors for cT3-4 GBC patients with PNI. A combination of gender and gallbladder neck/cystic duct invasion showed the best diagnostic performance than that of individual parameters (all P < 0.05). Conclusions Preoperative T staging using CECT enables the initial assessment of PNI status in GBC patients. A combination of gender and gallbladder neck/cystic duct invasion may effectively predict PNI in GBC, particularly in cT3-4 GBC.

Glioma is the most common malignant tumor of the brain and enhancing the efficacy of chemotherapy in glioma is critical for improving patients’ prognosis. In this study, a glioma-targeting drug delivery system is constructed using biodegradable periodic mesoporous organosilica nanoparticles (PMO) that are modified with lactoferrin (Lf) ligands. The obtained PMO is doped with thioether groups and can be degraded in the high concentration of glutathione in tumor cells. The surface area and pore volume of PMO are 772 cm²/g and 0.98 cm³/g, respectively and the loading capacity of doxorubicin (Dox) is as high as 20%. The results of the confocal laser scanning microscope show that the uptake of PMO-Lf@Dox by C6 cells is higher than PMO@Dox. The quantitative analysis of the flow cytometer further demonstrates that more PMO-Lf@Dox enter C6 cells, indicating that the modification of lactoferrin can significantly increase the uptake of C6 cells. Finally, the therapeutic efficacy results show that Lf-modified PMO enhances the inhibitory effect of Dox on C6 cells when incubated for 24 h and 72 h. In summary, this lactoferrin receptor-mediated PMO drug carrier with biodegradability in glutathione in tumor cells can be used to enhance drug delivery into glioma without long-term accumulation in vivo. Graphical

Purpose: To compare the efficacy and safety of transcatheter arterial chemoembolization combined with microwave ablation (TACE–MWA) versus TACE alone for the treatment of recurrent small hepatocellular carcinoma (sHCC) after resection. Materials and methods: From June 2015 to January 2020, a total of 45 patients with recurrent sHCC (size ≤ 3 cm) treated by TACE–MWA or TACE were included in this study. The radiological response at 1-, 3-, 6-month after initial treatment [modified Response Evaluation Criteria in Solid Tumors (mRECIST)], progression-free survival (PFS), overall survival (OS), and complications were evaluated. Results: The TACE–MWA group showed better 1-, 3-, 6-month tumor response rates than TACE group. The corresponding 1-, 3-, and 5-year PFS rates were 76.5%, 70.6%, and 70.6% for the TACE–MWA group, and 56.1%, 15.0%, and 15.0% for the TACE group (P = 0.003). The 1-, 3-, and 5-year OS rates were 100.0%, 82.1%, and 61.5% for the TACE–MWA group, and 89.0%, 58.1%, and 50.8% for the TACE group (P = 0.389), respectively. Moreover, no major complications related to treatment were observed in either of the groups. Compared with the TACE group, the TACE–MWA group had a significantly lower number of re-TACE sessions (P = 0.003). Conclusions: Although TACE alone provides equivalent effectiveness for recurrent sHCC in terms of OS rates, TACE–MWA had better 1-, 3-, 6-month tumor response rates and may prolong tumor PFS time.

Blockade of programmed cell death 1 ligand (PD-L1) has been used to treat triple-negative breast cancer (TNBC), and various strategies are under investigation to improve the treatment response rate. Inhibition of glutamine metabolism can reduce the massive consumption of glutamine by tumor cells and meet the demand for glutamine by lymphocytes in tumors, thereby improving the anti-tumor effect on the PD-L1 blockade therapy. Here, molybdenum disulfide (MoS₂) was employed to simultaneously deliver anti-PDL1 antibody (aPDL1) and V9302 to boost the anti-tumor immune response in TNBC cells. The characterization results show that MoS₂ has a dispersed lamellar structure with a size of about 181 nm and a size of 232 nm after poly (l-lysine) (PLL) modification, with high stability and biocompatibility. The loading capacity of aPDL1 and V9302 are 3.84% and 24.76%, respectively. V9302 loaded MoS₂ (MoS₂-V9302) can effectively kill 4T1 cells and significantly reduce glutamine uptake of tumor cells. It slightly increases CD8⁺ cells in the tumor and promotes CD8⁺ cells from the tumor edge into the tumor core. In vivo studies demonstrate that the combination of aPDL1 and V9302 (MoS₂-aPDL1-V9302) can strongly inhibit the growth of TNBC 4T1 tumors. Interestingly, after the treatment of MoS₂-aPDL1-V9302, glutamine levels in tumor interstitial fluid increased. Subsequently, subtypes of cytotoxic T cells (CD8⁺) in the tumors were analyzed according to two markers of T cell activation, CD69, and CD25, and the results reveal a marked increase in the proportion of activated T cells. The levels of cytokines in the corresponding tumor interstitial fluid are also significantly increased. Additionally, during the treatment, the body weights of the mice remain stable, the main indicators of liver and kidney function in the blood do not increase significantly, and there are no obvious lesions in the main organs, indicating low systemic toxicity. In conclusion, our study provides new insights into glutamine metabolism in the tumor microenvironment affects immune checkpoint blockade therapy in TNBC, and highlights the potential clinical implications of combining glutamine metabolism inhibition with immune checkpoint blockade in the treatment of TNBC. Graphical Abstract

Objective This study aims to evaluate the effectiveness and safety of hepatic arterial infusion chemotherapy (HAIC) following the simultaneous placement of self-expandable metallic stent (SEMS) and iodine-125 (¹²⁵I) seed strands for the management of advanced cholangiocarcinoma (CCA) patients presenting with malignant obstructive jaundice (MOJ). Methods Data from 74 patients with MOJ caused by advanced CCA treated with stent placement with ¹²⁵I seed strands with or without HAIC between November 2015 and October 2020 were analysed retrospectively. Eighteen patients received 5 sessions of HAIC after SEMS placement with ¹²⁵I seed strands (HAIC group), and 56 patients only underwent SEMS placement with ¹²⁵I seed strands and served as controls (control group). HAIC consisted of infusions of gemcitabine (600–1000 mg/m² given over 30 min) followed by oxaliplatin (60–100 mg/m² given over 2 h), with an interval of 4 weeks. Propensity score matching (PSM) analysis was used to adjust for differences in the baseline characteristics of the groups (including age, total bilirubin, and serum alanine aminotransferase level). Overall survival (OS), stent patency, and adverse events were compared between the two groups. Results OS and stent patency were significantly better in patients in the HAIC group than in those in the control group (median survival time: before PSM, 362 vs. 185 days, p = 0.005; after PSM, 357 vs. 183 days, p = 0.012; median duration of stent patency: before PSM, 294 vs. 156 days, p = 0.001; after PSM, 287 vs. 183 days, p = 0.039). All adverse reactions were controllable by temporary symptomatic treatment. Serious complications and treatment-related deaths were not observed. Conclusion Our preliminary study showed that HAIC following SEMS placement with ¹²⁵I seed strands is effective and safe for the management of advanced CCA patients presenting with MOJ and could improve stent patency and patient survival.

A new prognostic model, the “six-and-twelve” (SAT) score, was suggested to be effective in selecting ideal transarterial chemoembolization (TACE) candidates from treatment naïve hepatocellular carcinoma (HCC) patients. However, whether the SAT score could also be applied in recurrent HCC patients with prior curative-intent treatments remains unknown. We aimed to validate and compare SAT focussing on these patients. From January 2014 to May 2019, 121 unresectable HCC patients with recurrence in Barcelona Clinic Liver Cancer (BCLC) A/B receiving TACE were enrolled. Survival distribution was evaluated by the Kaplan–Meier method compared by the log-rank test. Discriminatory ability was compared with the concordance index (C-index) to rank six prognostic systems (SAT, Four-and-seven, HAP, mHAP, mHAP2, mHAP3). The area under the curve (AUC) was performed to assess the mortality prediction at 1, 2, and 3 years. In recurrent HCC patients receiving TACE, SAT had better performances in survival distribution. Due to the highest C-index, SAT was deemed the first ranking prognostic score. In terms of mortality prediction at 1, 2 and 3 years, SAT had the best mortality prediction at 2 and 3 years and mHAP3 had the best mortality prediction at 1 year. Among the six prognostic systems analysed in ideal TACE patients with recurrences after curative-intent treatments, SAT was proven to be superior to other systems, suggesting that it could also be used in these patients.

Non-small cell lung cancer (NSCLC) is the leading cause of cancer-associated death worldwide. MicroRNA (miRNA)-32-5p is as an important cancer-associated miRNA in different types cancer. To date, the role of miR-32-5p in the migration and invasion of NSCLC remains unknown. In the present study, a Transwell assay was performed to investigate the role of miR-32-5p in lung adenocarcinoma. miR-32-5p expression level was determined via reverse transcription-quantitative PCR in 24 pairs of NSCLC and adjacent normal tissues. SMAD family member 3 (SMAD3) was considered as a novel target gene by luciferase reporter assay and western blot in NSCLC. The present study demonstrated that miR-32-5p is frequently downregulated in NSCLC tissues. The overexpression of miR-32-5p resulted in the inhibition of migratory and invasive abilities in NSCLC cells. Thus, SMAD3 was identified as a target of miR-32-5p, and its expression was negatively correlated with miR-32-5p expression in clinical NSCLC tissues. Overall, these findings indicate that miR-32-5p serves as a tumor suppressor by targeting SMAD3. Thus, miR-32-5p may be a potential therapeutic target for the treatment of lung adenocarcinoma.

The interleukin-11 (IL-11) and the IL-11 receptor alpha-subunit (IL-11R alpha) have been demonstrated to regulate the invasion and proliferation of tumor cells. Our study intends to evaluate a noninvasive imaging of IL-11R alpha expression in breast tumors using near-infrared (NIR) fluorescent dye Cy7-labeled IL-11 mimic peptide CGRRAGGSC. This work evaluated the IL-11R alpha expression of breast tumor cells and the binding status of this peptide to IL-11R alpha in vitro and in vivo by using Western blotting, immunofluorescence staining and near-infrared fluorescence imaging. Our biochemical study showed that IL-11R alpha was overexpressed in breast tumor cells (MCF-7). The cell-binding assay demonstrated specific binding of peptide CGRRAGGSC to MCF-7 cells in vitro. In vivo imaging results showed that NIR fluorescent signals of Cy7-CGRRAGGSC were selectively accumulated in tumor and metabolic organs. While in the blocking experiment, free CGRRAGGSC obviously blocked the concentration of the Cy7-CGRRAGGSC in the tumors. These results suggested that IL-11R alpha may be used as a potential target for noninvasive imaging in IL-11R alpha overexpressed tumors. Furthermore, the imaging agent of near-infrared fluorescent dye Cy7-labeled CGRRAGGSC is suitable for IL-11R alpha expression imaging study in vivo.

Purpose To evaluate the effectiveness and safety of simultaneous placement of a self-expandable metallic stents (SEMS) and iodine-125 seed strand in the management of malignant obstructive jaundice (MOJ). Materials and Methods This study included 132 patients with MOJ treated from November 2015 to October 2017. Forty-five patients underwent insertion of SEMS with iodine-125 seed strands (Seeds group); the remaining 87 patients underwent SEMS placement alone (Control group). Technical success was defined as accurate, successful deployment of SEMS with or without iodine-125 seed strand; clinical success was defined as 20% reduction in serum bilirubin within 1 week after the procedure, compared with baseline. Complications, duration of primary stent patency, and overall survival were evaluated. Results Technical success was achieved in all patients in both groups. In the Seeds group, an average of 14 seeds (range 8–22) were implanted in the bile duct as a strand. Clinical success rates were similar between the groups (Seeds group, 93.3%; Control group, 95.4%). Major complications occurred in only one patient, in the Control group. The median period of primary stent patency was significantly longer in the Seeds group (194 days) than in the Control group (86 days; P = 0.049). The median overall survival was also significantly longer in the Seeds group (194 days) than in the Control group (96 days; P = 0.031). Conclusion SEMS combined with iodine-125 seed strands is effective and safe in the management of MOJ and can improve stent patency and patient survival.