Risk factors of missed early gastric cancer in endoscopic resected population: a retrospective, case-control study.

BACKGROUND: Missed early gastric cancer (MEGC) is prevalent during esophagogastroduodenoscopy (EGD), which is the first-line recommended strategy for detecting early gastric cancer (EGC). Hence, we explored the risk factors for MEGC and different types of MEGC, based on the endoscopic resected population. METHODS: This retrospective, case-control study was conducted at Nanjing Drum Tower Hospital (NJDTH). We included patients who were diagnosed with EGC during screening EGD, underwent endoscopic resection, and were confirmed by postoperative pathology at the NJDTH from January 2014 to December 2021, and classified them into different types according to the different root causes of misses. Univariable, multivariable, subgroup and propensity score analyses were used to explore the risk factors for MEGC and different types of MEGC. RESULTS: A total of 447 patients, comprising 345 with initially detected early gastric cancer (IDEGC) and 102 with MEGC, were included in this study. Larger size (≥ 1 cm) (OR 0.45, 95% CI 0.27-0.74, P = 0.002) and invasion depth of submucosa (OR 0.26, 95% CI 0.10-0.69, P = 0.007) were negatively associated with MEGC. Use of sedation (OR 0.32, 95% CI 0.20-0.52, P < 0.001) and longer observation time (OR 0.60, 95% CI 0.37-0.96, P = 0.034) exhibited protective effect on MEGC. CONCLUSIONS: Smaller and more superficial EGC lesions are more susceptible to misdiagnosis. The use of sedation and prolonged observation time during EGD could help reduce the occurrence of MEGC.

HHLA2 deficiency inhibits pancreatic cancer progression and THP-1 macrophage M2 polarization via EGFR/MAPK/ERK and mTOR/AKT pathway.

BACKGROUND: Human endogenous retrovirus subfamily H long terminal repeat associating protein 2, (HHLA2), a member of B7 family, exhibits heightened expression in various malignant tumors. However, the exact functions of HHLA2 in pancreatic cancer (PC) remain incompletely elucidated. METHODS: We initially conducted an analysis of the B7 family members' expression pattern in pancreatic tumor samples and adjacent normal tissues using The Cancer Genome Atlas (TCGA) database. Subsequently, immunohistochemistry, RT-qPCR and western blot methods were used to assess HHLA2 expression levels in PC tissues and cell lines. Furthermore, after silencing HHLA2 in PC cell lines, cell migration and proliferation of PC cells were detected by wound healing and CCK-8 assays, and cell invasion of PC cells was detected by transwell assays. We also investigated the regulation of epithelial-mesenchymal transition (EMT) markers and levels of EGFR, MEK, ERK1/2, mTOR and AKT via western blot analysis. Finally, the correlation between HHLA2 expression and immune infiltration was further explored. RESULTS: Silencing of HHLA2 resulted in the inhibition of PC cell proliferation, migration and invasion, potentially through the suppression of the EGFR/MAPK/ERK and mTOR/AKT signaling pathway. Additionally, silencing HHLA2 led to the inhibition of M2-type polarization of tumor associated macrophages (TAMs). CONCLUSION: The knockdown of HHLA2 was observed to inhibit the migration and invasion of PC cells through the regulation of the EMT process and EGFR/MAPK/ERK and mTOR/AKT pathway. Furthermore, silencing HHLA2 was found to modulate M2 polarization of TAMs. These finding suggest that HHLA2 could be a promising therapeutic target for Pancreatic cancer.

High-throughput enrichment of portal venous circulating tumor cells for highly sensitive diagnosis of CA19-9-negative pancreatic cancer patients using inertial microfluidics.

The carbohydrate antigen 19-9 (CA19-9) is commonly used as a representative biomarker for pancreatic cancer (PC); however, it lacks sensitivity and specificity for early-stage PC diagnosis. Furthermore, some patients with PC are negative for CA19-9 (<37 U/mL), which introduces additional limitations to their accurate diagnosis and treatment. Hence, improved methods to accurately detect PC stages in CA19-9-negative patients are warranted. In this study, tumor-proximal liquid biopsy and inertial microfluidics were coupled to enable high-throughput enrichment of portal venous circulating tumor cells (CTCs) and support the effective diagnosis of patients with early-stage PC. The proposed inertial microfluidic system was shown to provide size-based enrichment of CTCs using inertial focusing and Dean flow effects in slanted spiral channels. Notably, portal venous blood samples were found to have twice the yield of CTCs (21.4 cells per 5 mL) compared with peripheral blood (10.9 CTCs per 5 mL). A combination of peripheral and portal CTC data along with CA19-9 results showed to greatly improve the average accuracy of CA19-9-negative PC patients from 47.1% with regular CA19-9 tests up to 87.1%. Hence, portal venous CTC-based microfluidic biopsy can be used with high sensitivity and specificity for the diagnosis of early-stage PC, particularly in CA19-9-negative patients.

Lipid Metabolism-Related Gene Signature Predicts Prognosis and Indicates Immune Microenvironment Infiltration in Advanced Gastric Cancer.

Objective: Abnormal lipid metabolism is known to influence the malignant behavior of gastric cancer. However, the underlying mechanism remains elusive. In this study, we comprehensively analyzed the biological significance of genes involved in lipid metabolism in advanced gastric cancer (AGC). Methods: We obtained gene expression profiles from The Cancer Genome Atlas (TCGA) database for early and advanced gastric cancer samples and performed differential expression analysis to identify specific lipid metabolism-related genes in AGC. We then used consensus cluster analysis to classify AGC patients into molecular subtypes based on lipid metabolism and constructed a diagnostic model using least absolute shrinkage and selection operator- (LASSO-) Cox regression analysis and Gene Set Enrichment Analysis (GSEA). We evaluated the discriminative ability and clinical significance of the model using the Kaplan-Meier (KM) curve, ROC curve, DCA curve, and nomogram. We also estimated immune levels based on immune microenvironment expression, immune checkpoints, and immune cell infiltration and obtained hub genes by weighted gene co-expression network analysis (WGCNA) of differential genes from the two molecular subtypes. Results: We identified 6 lipid metabolism genes that were associated with the prognosis of AGC and used consistent clustering to classify AGC patients into two subgroups with significantly different overall survival and immune microenvironment. Our risk model successfully classified patients in the training and validation sets into high-risk and low-risk groups. The high-risk score predicted poor prognosis and indicated low degree of immune infiltration. Subgroup analysis showed that the risk model was an independent predictor of prognosis in AGC. Furthermore, our results indicated that most chemotherapeutic agents are more effective for AGC patients in the low-risk group than in the high-risk group, and risk scores for AGC are strongly correlated with drug sensitivity. Finally, we performed qRT-PCR experiments to verify the relevant results. Conclusion: Our findings suggest that lipid metabolism-related genes play an important role in predicting the prognosis of AGC and regulating immune invasion. These results have important implications for the development of targeted therapies for AGC patients.

DDX3X interacts with SIRT7 to promote PD-L1 expression to facilitate PDAC progression.

Pancreatic ductal adenocarcinoma (PDAC) is recognized as the most aggressive and fatal malignancy. A previous study reported that PDAC patients who exhibit elevated levels of DDX3X have a poor prognosis and low overall survival rate. However, the underlying molecular mechanism remains unclear. This study aimed to investigate the specific roles of DDX3X in PDAC. Multiple bioinformatics analyses were used to evaluate DDX3X expression and its potential role in PDAC. In vitro and in vivo studies were performed to assess the effects of DDX3X on PDAC cell growth. Furthermore, Western blotting, quantitative PCR, immunohistochemistry, immunofluorescence, mass spectrometry, coimmunoprecipitation and multiplexed immunohistochemical staining were conducted to identify the specific regulatory mechanism in PDAC. The results verified that DDX3X expression is notably upregulated in the tumor tissue vs. normal tissue of PDAC patients. DDX3X knockdown markedly suppressed the proliferation, invasion and migration of PDAC cells in vitro and inhibited tumor growth in vivo. Conversely, overexpression of DDX3X induced the opposite effect. Further studies supported that the DDX3X protein can associate with sirtuin 7 (SIRT7) to stimulate PDAC carcinogenesis and progression. Furthermore, SIRT7 inhibition significantly impeded DDX3X-mediated tumor growth both ex vivo and in vivo. The results also revealed that programmed death ligand 1 (PD-L1) expression is positively correlated with DDX3X expression. These results reveal significant involvement of the DDX3X-SIRT7 axis in the initiation and advancement of PDAC and offer previously undiscovered therapeutic options for PDAC management.

Ileitis promotes MASLD progression via bile acid modulation and enhanced TGR5 signaling in ileal CD8+ T cells.

BACKGROUND & AIMS: Clinical evidence substantiates a link between inflammatory bowel disease, particularly Crohn's disease (CD), and metabolic dysfunction-associated steatotic liver disease (MASLD). This study aims to explore the underlying molecular mechanisms responsible for this association. METHODS: MASLD was induced by administering high-fat and western diets, while inflammatory bowel disease was induced using DSS (dextran sulfate sodium) and the Il10 knockout (KO) mouse model. The investigation into the role of secondary bile acids (SBAs) in ileitis involved employing metagenomic sequencing, conducting metabolomics detection, performing fecal microbiota transplantation, and constructing CD8+ T cell-specific gene knockout mice. RESULTS: In MASLD+DSS and Il10 KO MASLD mice, we observed ileitis characterized by T-cell infiltration and activation in the terminal ileum. This condition resulted in decreased bile acid levels in the portal vein and liver, inhibited hepatic farnesoid X receptor (FXR) activation, and exacerbated MASLD. Metagenomic and metabolomic analysis of ileal contents revealed increased Clostridium proliferation and elevated SBA levels in MASLD-associated ileitis. Experiments using germ-free mice and fecal microbiota transplantation suggested an association between SBA and MASLD-related ileitis. In vitro, SBAs promoted CD8+ T-cell activation via the TGR5, mTOR, and oxidative phosphorylation pathways. In vivo, TGR5 KO in CD8+ T cells effectively alleviated ileitis and reversed the MASLD phenotype. Clinical data further supported these findings, demonstrating a positive correlation between ileitis and MASLD. CONCLUSION: MASLD-induced changes in intestinal flora result in elevated levels of SBAs in the ileum. In the presence of a compromised intestinal barrier, this leads to severe CD8+ T cell-mediated ileitis through the TGR5/mTOR/oxidative phosphorylation signaling pathway. Ileitis-induced tissue damage impairs enterohepatic circulation, inhibits hepatic FXR activation, and exacerbates the MASLD phenotype. IMPACT AND IMPLICATIONS: Our study provides a comprehensive investigation of the interplay and underlying mechanisms connecting ileitis and metabolic dysfunction-associated steatotic liver disease (MASLD). Secondary bile acids produced by intestinal bacteria act as the critical link between MASLD and ileitis. Secondary bile acids exert their influence by disrupting liver lipid metabolism through the promotion of CD8+ T cell-mediated ileitis. In future endeavors to prevent and treat MASLD, it is essential to thoroughly account for the impact of the intestinal tract, especially the ileum, on liver function via the enterohepatic circulation.

An oncolytic system produces oxygen selectively in pancreatic tumor cells to alleviate hypoxia and improve immune activation.

INTRODUCTION: Hypoxia is one of the important reasons for the poor therapeutic efficacy of current pancreatic cancer treatment, and the dense stroma of pancreatic cancer restricts the diffusion of oxygen within the tumor. METHODS: A responsive oxygen-self-supplying adv-miRT-CAT-KR (adv-MCK) cascade reaction system to improve hypoxia in pancreatic cancer is constructed. We utilized various experiments at multiple levels (cells, organoids, in vivo) to investigate its effect on pancreatic cancer and analyzed the role of immune microenvironment changes in it through high-throughput sequencing. RESULTS: The adv-MCK system is an oncolytic adenovirus system expressing three special components of genes. The microRNA (miRNA) targets (miRTs) enable adv-MCK to selectively replicate in pancreatic cancer cells. Catalase catalyzes the overexpressed hydrogen peroxide in pancreatic cancer cells to generate endogenous oxygen, which is catalyzed by killerRed to generate singlet oxygen (1O2) and further to enhance the oncolytic effect. Meanwhile, the adv-MCK system can specifically improve hypoxia in pancreatic cancer, exert antitumor effects in combination with photodynamic therapy, and activate antitumor immunity, especially by increasing the level of γδ T cells in the tumor microenvironment. CONCLUSION: The responsive oxygen-self-supplying adv-MCK cascade reaction system combined with photodynamic therapy can improve the hypoxic microenvironment of pancreatic cancer and enhance antitumor immunity, which provides a promising alternative treatment strategy for pancreatic cancer.

CAFs Homologous Biomimetic Liposome Bearing BET Inhibitor and Pirfenidone Synergistically Promoting Antitumor Efficacy in Pancreatic Ductal Adenocarcinoma.

BRD4 is a member of the BET protein family involved in chromatin remodeling and transcriptional regulation. Several BET inhibitors (BETi) have entered clinical trials, demonstrating potential in inducing cancer cell apoptosis and tumor regression. However, resistance to BETi is common in solid tumors. In pancreatic cancer, it is found that cancer-associated fibroblasts (CAFs) in the tumor microenvironment reduce the BET inhibitor JQ1 sensitivity by inducing BRD4 expression. Moreover, CAFs play a crucial role in the formation of a dense stromal barrier. Therefore, targeting CAFs in the tumor microenvironment of pancreatic cancer not only enhances cancer cells sensitivity to JQ1 but also increases drug perfusion and improves oxygen supply, thus reducing glycolysis and limiting energy supply. To address this challenge, a homologous targeting mechanism utilizing activated fibroblast membrane-coated liposomes is proposed for specific drug precise target to CAFs-rich pancreatic cancer. Additionally, TAT peptides enable liposomes penetration, delivering PFD for targeted anti-fibrotic therapy, reducing extracellular matrix generation and glycolysis, and enhancing JQ1 delivery and sensitivity. In conclusion, the findings indicate the tremendous potential of this CAFs-targeting liposomal delivery system in pancreatic cancer.

Erratum: Targeting sphingosine kinase 2 suppresses cell growth and synergizes with BCL2/BCL-XL inhibitors through NOXA-mediated MCL1 degradation in cholangiocarcinoma.

[This corrects the article on p. 546 in vol. 9, PMID: 30949409.].

Feasibility of gallbladder lesion visualization using a novel ultrafine peroral cholangioscopy: A preliminary investigation.

BACKGROUND: Endoscopic visualization of gallbladder lesions by the traditional peroral cholangioscopy (POCS) during the endoscopic retrograde cholangiopancreatography process is challenging. In the present study, we evaluated the feasibility of a newly designed POCS with an ultrafine outer diameter that facilitates gallbladder visualization. METHODS: The novel POCS was designed and manufactured with an outer diameter of 7 French and achieved extremely high performance. The feasibility of this novel POCS for gallbladder observation was assessed in our center between April 2022 and January 2023. The primary outcome was technical success. RESULTS: A total of 16 patients (64.6 ± 18.1 years, 9 males) who underwent novel ultrafine POCS inspection for gallbladder visualization were included. Technical success was achieved in 14 of 16 cases (87.5%); the main reasons for the two unsuccessful inspections were the presence of cystic duct strictures. A total of 1 adverse event occurred, for an overall rate of 6.3%, and there were no serious adverse events during the follow-up. CONCLUSIONS: The results suggest that endoscopic visualization of the gallbladder using the novel ultrafine POCS is feasible. The device is expected to provide a new direction for the management of gallbladder disorders in the future.

Lithium chloride induces apoptosis by activating endoplasmic reticulum stress in pancreatic cancer.

Lithium compounds, a classic class of metal complex medicine that target GSK 3ß and are widely known as mood-stabilizer, have recently been reported as potential anti-tumor drugs. The objective of this investigation was to explore the anticancer potential of lithium chloride (LiCl) and elucidate its mode of action in pancreatic cancer cells. The MTT, colony formation, and Edu assay were used to evaluate the impact of LiCl on pancreatic cancer cell proliferation. Various methods were employed to investigate the anti-tumor activity of LiCl and its underlying mechanisms. Cell cycle analysis and apoptosis detection assays were utilized for in vitro experiments, while the orthotopic pancreatic cancer mouse model was employed to evaluate the effectiveness of LiCl treatment in vivo. Furthermore, the impact of LiCl on the proliferation of patient-derived organoids was also studied. The results demonstrated that LiCl inhibited the proliferation of pancreatic cancer (PC) cells, induced G2/M phase arrest, and activated apoptosis. Notably, the triggering of endoplasmic reticulum (ER) stress by LiCl was observed, leading to the activation of the PERK/CHOP/GADD34 pathway, which subsequently promoted apoptosis in PC cells. In the future, Lithium compounds could become an essential adjunct in the treatment of human pancreatic cancer.

ABBV-744 induces autophagy in gastric cancer cells by regulating PI3K/AKT/mTOR/p70S6k and MAPK signaling pathways.

The mortality rates of gastric cancer remain high due to limited therapeutic strategies. As a highly selective inhibitor of the BD2 domain of BET family proteins, ABBV-744 has potent chemotherapeutic activity against various human solid tumors. However, whether ABBV-744 has potential anti-tumor effects in gastric cancer remain largely unknown. In this study, we evaluated the effect of ABBV-744 on gastric cancer cells and explored the possible underlying mechanisms. We found that ABBV-744 inhibited the growth of gastric cancer cells and patient-derived tumor organoids in a dose-dependent manner. Cellular experiments revealed that ABBV-744 induced mitochondria damage, reactive oxygen species accumulation, cell cycle arrest and apoptotic cell death in gastric cancer cells. Transcriptomic analysis using RNA-sequencing data identified autophagy as a crucial pathway involved in the cell death caused by ABBV-744. Mechanically, further studies showed that ABBV-744 induced autophagy flux in gastric cancer cells by inactivating PI3K/AKT/mTOR/p70S6k and activating the MAPK signaling pathways. In vivo mouse xenograft studies demonstrated that ABBV-744 significantly suppressed the growth of gastric cancer cells via inducing autophagy. Taken together, our results suggest that ABBV-744 is a novel drug candidate for gastric cancer.

Single cell transcriptomic analyses implicate an immunosuppressive tumor microenvironment in pancreatic cancer liver metastasis.

Pancreatic ductal adenocarcinoma (PDAC) is a highly metastatic disease refractory to all targeted and immune therapies. However, our understanding of PDAC microenvironment especially the metastatic microenvironment is very limited partly due to the inaccessibility to metastatic tumor tissues. Here, we present the single-cell transcriptomic landscape of synchronously resected PDAC primary tumors and matched liver metastases. We perform comparative analysis on both cellular composition and functional phenotype between primary and metastatic tumors. Tumor cells exhibit distinct transcriptomic profile in liver metastasis with clearly defined evolutionary routes from cancer cells in primary tumor. We also identify specific subtypes of stromal and immune cells critical to the formation of the pro-tumor microenvironment in metastatic lesions, including RGS5+ cancer-associated fibroblasts, CCL18+ lipid-associated macrophages, S100A8+ neutrophils and FOXP3+ regulatory T cells. Cellular interactome analysis further reveals that the lack of tumor-immune cell interaction in metastatic tissues contributes to the formation of the immunosuppressive microenvironment. Our study provides a comprehensive characterization of the transcriptional landscape of PDAC liver metastasis.

C-C motif chemokine CCL11 is a novel regulator and a potential therapeutic target in non-alcoholic fatty liver disease.

Background & Aims: Non-alcoholic fatty liver disease (NAFLD) is characterised by accelerated lipid deposition, aberrant inflammation, and excessive extracellular matrix production in the liver. Short of effective intervention, NAFLD can progress to cirrhosis and hepatocellular carcinoma. In the present study we investigated the involvement of the C-C motif ligand 11 (CCL11) in NAFLD pathogenesis. Methods: NAFLD was induced by feeding mice with a high-fat high-carbohydrate diet. CCL11 targeting was achieved by genetic deletion or pharmaceutical inhibition. The transcriptome was analysed using RNA-seq. Results: We report that CCL11 expression was activated at the transcription level by free fatty acids (palmitate) in hepatocytes. CCL11 knockdown attenuated whereas CCL11 treatment directly promoted production of pro-inflammatory/pro-lipogenic mediators in hepatocytes. Compared with wild-type littermates, CCL11 knockout mice displayed an ameliorated phenotype of NAFLD when fed a high-fat high-carbohydrate diet as evidenced by decelerated body weight gain, improved insulin sensitivity, dampened lipid accumulation, reduced immune cell infiltration, and weakened liver fibrosis. RNA-seq revealed that interferon regulatory factor 1 as a mediator of CCL11 induced changes in hepatocytes. Importantly, CCL11 neutralisation or antagonism mitigated NAFLD pathogenesis in mice. Finally, a positive correlation between CCL11 expression and NAFLD parameters was identified in human patients. Conclusions: Our data suggest that CCL11 is a novel regulator of NAFLD and can be effectively targeted for NAFLD intervention. Impact and implications: Non-alcoholic fatty liver disease (NAFLD) precedes cirrhosis and hepatocellular carcinoma. In this paper we describe the regulatory role of CCL11, a C-C motif ligand chemokine, in NAFLD pathogenesis. Our data provide novel insights and translational potential for NAFLD intervention.

The ATR inhibitor VE-821 increases the sensitivity of gastric cancer cells to cisplatin.

BACKGROUND: Chemoresistance is a common event after cancer chemotherapy, including gastric cancer (GC). Cisplatin has been reported to induce the DNA damage response (DDR), thus leading to chemoresistance. VE-821, a specific inhibitor of ATR, has been proven to suppress a variety of solid malignancies effectively. Our study aimed to explore the effect of VE-821 on enhancing the chemical sensitivity to cisplatin and clarify the potential molecular mechanisms. METHODS: Cell viability and apoptosis of MKN-45 and AGS were measured by CCK8 and flow cytometry assay respectively. Western blotting was used to detect the expression of target proteins. TCGA database was used to analyze the correlation between the ATR expression with the prognosis of GC patients. The viability of GC organoids was detected by Cell Titer Glo (CTG) through luminescence. RESULTS: Cisplatin inhibited the proliferation and induced apoptosis of GC cells with a relatively high IC50 value, and increased the phosphorylation levels of ATR-CHK1 and H2AX. VE-821 achieved the same effects but by downregulating the phosphorylation levels of the ATR-CHK1 pathway. Besides, higher ATR expression in GC tissues was positively correlated with higher pathological stage in GC patients. Interestingly, ATR inhibition reversed cisplatin-induced STAT3 activation and enhanced H2AX levels. Moreover, VE-821 significantly sensitized GC cells to cisplatin, and these two drugs had synergistic effects in GC cell lines, organoids, and in vivo. CONCLUSION: Our results suggested VE-821 sensitized GC cells to cisplatin via reversing DDR activation. And VE-821 treatment may be a promising therapeutic strategy for GC patients with cisplatin resistance.

Human-Like Artificial Intelligent System for Predicting Invasion Depth of Esophageal Squamous Cell Carcinoma Using Magnifying Narrow-Band Imaging Endoscopy: A Retrospective Multicenter Study.

INTRODUCTION: Endoscopic evaluation is crucial for predicting the invasion depth of esophagus squamous cell carcinoma (ESCC) and selecting appropriate treatment strategies. Our study aimed to develop and validate an interpretable artificial intelligence-based invasion depth prediction system (AI-IDPS) for ESCC. METHODS: We reviewed the PubMed for eligible studies and collected potential visual feature indices associated with invasion depth. Multicenter data comprising 5,119 narrow-band imaging magnifying endoscopy images from 581 patients with ESCC were collected from 4 hospitals between April 2016 and November 2021. Thirteen models for feature extraction and 1 model for feature fitting were developed for AI-IDPS. The efficiency of AI-IDPS was evaluated on 196 images and 33 consecutively collected videos and compared with a pure deep learning model and performance of endoscopists. A crossover study and a questionnaire survey were conducted to investigate the system's impact on endoscopists' understanding of the AI predictions. RESULTS: AI-IDPS demonstrated the sensitivity, specificity, and accuracy of 85.7%, 86.3%, and 86.2% in image validation and 87.5%, 84%, and 84.9% in consecutively collected videos, respectively, for differentiating SM2-3 lesions. The pure deep learning model showed significantly lower sensitivity, specificity, and accuracy (83.7%, 52.1% and 60.0%, respectively). The endoscopists had significantly improved accuracy (from 79.7% to 84.9% on average, P = 0.03) and comparable sensitivity (from 37.5% to 55.4% on average, P = 0.27) and specificity (from 93.1% to 94.3% on average, P = 0.75) after AI-IDPS assistance. DISCUSSION: Based on domain knowledge, we developed an interpretable system for predicting ESCC invasion depth. The anthropopathic approach demonstrates the potential to outperform deep learning architecture in practice.

Three-in-One Oncolytic Adenovirus System Initiates a Synergetic Photodynamic Immunotherapy in Immune-Suppressive Cholangiocarcinoma.

Although photodynamic immunotherapy has been promoted in the clinical practice of cholangiocarcinoma, the insensitivity to photodynamic immunotherapy remains to be a great problem. This can be largely attributed to an immune-suppressive tumor microenvironment (TME) manifested as immature myeloid cells and exhausted cytotoxic T lymphocytes. Here, a three-in-one oncolytic adenovirus system PEG-PEI-Adv-Catalase-KillerRed (p-Adv-CAT-KR) has been constructed to multiply, initiate, and enhance immune responses in photodynamic immunotherapy, using genetically-engineered KillerRed as photosensitizer, catalase as in situ oxygen-supplying mediator, and adenovirus as immunostimulatory bio-reproducible carrier. Meanwhile, PEG-PEI is applied to protect adenovirus from circulating immune attack. The administration of p-Adv-CAT-KR induces increased antigen presenting cells, elevated T cell infiltrations, and reduced tumor burden. Further investigation into underlying mechanism indicates that hypoxia inducible factor 1 subunit alpha (Hif-1α) and its downstream PD-1/PD-L1 pathway contribute to the transformation of immune-suppressive TME in cholangiocarcinoma. Collectively, the combination of KillerRed, catalase, and adenovirus brings about multi-amplified antitumor photo-immunity and has the potential to be an effective immunotherapeutic strategy for cholangiocarcinoma.

Protein tyrosine phosphatase nonreceptor type 2 exerts antimetastatic functions in pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is a highly invasive tumor with a dismal prognosis. Recent studies have demonstrated PTPN2 (protein tyrosine phosphatase nonreceptor type 2) as a potential target for cancer therapy. However, the functions of PTPN2 in PDAC progression remain poorly understood. In this study, we found PTPN2 expression was downregulated in PDAC tissues, and decreased PTPN2 expression was associated with unfavorable prognosis. Functional studies indicated that PTPN2 knockdown promoted the migration and invasion abilities of PDAC cells in vitro, and the liver metastasis in vivo through epithelial-mesenchymal transition process. Mechanistically, MMP-1 was identified as a downstream target of PTPN2 via RNA-seq data and was responsible for the enhanced metastasis of PDAC cells upon PTPN2 knockdown. Moreover, according to chromatin immunoprecipitation and electrophoretic mobility shift assay, PTPN2 depletion transcriptionally activated MMP-1 via regulating the interaction of p-STAT3 with its distal promoter. This study, for the first time, demonstrated that PTPN2 inhibited PDAC metastasis, and presented a novel PTPN2/p-STAT3/MMP-1 axis in PDAC progression.

A Chinese prospective multicenter cohort study evaluating EUS-guided drainage of pancreatic fluid collections using the Hot AXIOS system.

Background and Objectives: The Hot AXIOS system, which features a cautery-enhanced lumen-apposing metal stent, facilitates EUS-guided transmural drainage of pancreatic fluid collection (PFC). We aimed to evaluate the safety and efficacy of stents in a multicenter Chinese cohort. Patients and Methods: Thirty patients from nine centers with a single pancreatic pseudocyst (PP) or walled-off necrosis (WON) who underwent EUS-guided transgastric or transduodenal drainage with the novel stent were prospectively enrolled. Results: We included 15 (50%) patients with PPs and 15 (50%) with WONs. The mean diameter of the PFCs was 11.06 ± 3.56 cm. Stent placement was technically successful in all patients (100%), whereas clinical success was achieved in 93.3% of patients (28/30). Clinical success was defined as the alleviation of clinical symptoms combined with at least a 50% reduction in PFC diameter within 60 days after surgery. 73.3% (22/30) of AXIOS stents were removed after reaching clinical success in the 1st month of follow-up. A total of 14 (46.7%) PFC-associated infections occurred (4 pre- and 10 postoperation), which recovered within 1 week after treatment. Other complications included three (10%) partially or fully blocked stents and two (6.7%) stent migrations. Regarding the fully opened stent without blocking, complete remission of PFCs within 1 month was independently predicted by a previous pancreatitis attack > 6 months prior (adjusted odds ratio: 11.143; 95% confidence interval: 1.108-112.012; P = 0.041). Conclusion: EUS-guided drainage of PFCs using the Hot AXIOS system is safe and efficient. Regarding completely patent stents, a previous pancreatitis attack > 6 months prior predicts a greater chance of achieving 100% remission of PFCs within 1 month of AXIOS treatment.

Comparison of Modified Cap-Assisted Endoscopic Mucosal Resection and Endoscopic Submucosal Dissection in Treating Intraluminal Gastric Gastrointestinal Stromal Tumor (≤20 mm).

INTRODUCTION: A modified cap-assisted endoscopic mucosal resection (mEMR-C), introduced in this study, was a novel variation of the standard EMR. We aimed to compare the outcomes of mEMR-C and endoscopic submucosal dissection (ESD) for the treatment of small (≤20 mm) intraluminal gastric gastrointestinal stromal tumors (gGISTs). METHODS: This retrospective study included 43 patients who underwent mEMR-C and 156 patients who received ESD at Nanjing Drum Tower Hospital. Baseline characteristics, adverse events, and clinical outcomes were compared between the 2 groups. Univariate and multivariable analyses were conducted to adjust for confounders. After propensity score matching using sex, year, location, and tumor size, outcomes were compared with 41 patients in each group. RESULTS: A total of 199 patients underwent endoscopic resection and the en bloc resection rate was 100%. The complete resection rate was comparable in both groups ( P = 1.000). Approximately 9.5% of all patients had a positive margin. There was no significant difference in positive margin for patients undergoing mEMR-C or ESD (9.3% vs 9.6%, P = 1.000). No difference in adverse events in both groups ( P = 0.724). The mEMR-C was associated with shorter operation time and lower cost than the ESD. Recurrence was reported in 2 patients at 1 and 5 years after ESD during a median follow-up of 62 months. No metastasis and disease-related death were identified in both groups. Propensity score matching analysis revealed similar results. DISCUSSION: The mEMR-C was found to be the preferable technique for small (≤20 mm) intraluminal gGISTs with shorter operation time and lower cost as compared with ESD.