Tumor-infiltrating T lymphocytes: A promising immunotherapeutic target for preventing immune escape in cholangiocarcinoma.

Cholangiocarcinoma (CCA) is becoming more common and deadly worldwide. Tumor-infiltrating T cell subtypes make distinct contributions to the immune system; collectively, they constitute a significant portion of the tumor microenvironment (TME) in CCA. By secreting cytokines and other chemicals, regulatory T cells (Tregs) decrease activated T cell responses, acting as immunosuppressors. Reduced CD8+ T cell activation results in stimulating programmed death-1 (PD-1), which undermines the immunological homeostasis of T lymphocytes. On the other hand, cancer cells are eliminated by activated cytotoxic T lymphocyte (CTL) through the perforin-granzyme or Fas-FasL pathways. Th1 and CTL immune cell infiltration into the malignant tumor is also facilitated by γδ T cells. A higher prognosis is typically implied by CD8+ T cell infiltration, and survival is inversely associated with Treg cell density. Immune checkpoint inhibitors, either singly or in combination, provide novel therapeutic strategies for CCA immunotherapy. Furthermore, it is anticipated that immunotherapeutic strategies-such as the identification of new immune targets, combination treatments involving several immune checkpoint inhibitors, and chimeric antigen receptor-T therapies (CAR-T)-will optimize the effectiveness of anti-CCA treatments while reducing adverse effects.

Comprehensive analysis of the expression, prognostic, and immune infiltration for COL4s in stomach adenocarcinoma.

BACKGROUND: Collagen (COL) genes, play a key role in tumor invasion and metastasis, are involved in tumor extracellular matrix (ECM)-receptor interactions and focal adhesion pathways. However, studies focusing on the diagnostic value of the COL4 family in stomach adenocarcinoma (STAD) are currently lacking. METHODS: The TCGA database was employed to retrieve the clinical features and RNA sequencing expression profiles of patients with STAD. We conducted an investigation to examine the expression disparities between STAD and adjacent normal tissues. Kaplan-Meier survival analysis was utilized to assess their prognostic significance, while Spearman correlation analysis was employed to determine their association with immune checkpoint genes and immunomodulatory molecules. Furthermore, GO and KEGG analyses were performed on the COL4s-related genes, revealing potential biological pathways through gene set enrichment analysis (GSEA). Subsequently, we explored the extent of immune infiltration of the COL4 family in STAD using the TIMER database. Lastly, the expression levels of the COL4 family in STAD were further validated through quantitative PCR (qPCR) and western blot techniques. RESULTS: The expression levels of COL4A1/2 were significantly upregulated, while COL4A5/6 were conspicuously downregulated in STAD. The survival analysis revealed that the upregulated COL4s indicated poorer overall survival, first progression and post-progression survival outcomes. Additionally, our findings demonstrated a positive correlation between the expressions of COL4A1/2/3/4 and the infiltration of immune cells, including CD8 + T cells, dendritic cells, macrophages, neutrophils and CD4 + T cells. Further correlation analysis uncovered a favorable association between the expression of COL4A1/2/3/4 and various crucial immunomodulatory molecules, immunological checkpoint molecules, and chemokines. Quantitative PCR analysis confirmed that the expression patterns of COL4A1/3/4/6 genes aligned with the finding from the TCGA database. However, gastric cancer cells exhibited downregulation of COL4A2. Consistently, the protein level of COL4A1 was elevated, whereas the protein level of COL4A2 was reduced in the gastric cancer cell lines. CONCLUSION: COL4s could potentially serve as biomarkers for diagnosing and predicting the prognosis of STAD.

LC3-dependent extracellular vesicles promote M-MDSC accumulation and immunosuppression in colorectal cancer.

For a long time, myeloid-derived suppressor cells (MDSCs) dilated in circulation system of colorectal cancer (CRC) patients have been puzzling clinicians. Various evidence shows that MDSCs constitute the bulk of immunosuppression in CRC, which is related to tumor growth, adhesion, invasion, metastasis, and immune escape. However, the mechanisms underlying these cells formation remain incompletely understood. In this study, we reported that CRC cell-derived LC3-dependent extracellular vesicles (LDEVs)-mediated M-MDSCs formation via TLR2-MYD88 pathway. Furthermore Hsp60 was the LDEVs surface ligand that triggered these MDSCs induction. In clinical studies, we reported that accumulation of circulating M-MDSCs as well as IL-10 and arginase1 secretion were reliant upon the levels of tumor cell-derived LDEVs in CRC patients. These findings indicated how local tumor cell-derived extracellular vesicles influence distal hematopoiesis and provided novel justification for therapeutic targeting of LDEVs in patients with CRC.

Ferroptosis exacerbates hyperlipidemic acute pancreatitis by enhancing lipid peroxidation and modulating the immune microenvironment.

Abnormal activation of ferroptosis worsens the severity of acute pancreatitis and intensifies the inflammatory response and organ damage, but the detailed underlying mechanisms are unknown. Compared with other types of pancreatitis, hyperlipidemic acute pancreatitis (HLAP) is more likely to progress to necrotizing pancreatitis, possibly due to peripancreatic lipolysis and the production of unsaturated fatty acids. Moreover, high levels of unsaturated fatty acids undergo lipid peroxidation and trigger ferroptosis to further exacerbate inflammation and worsen HLAP. This paper focuses on the malignant development of hyperlipidemic pancreatitis with severe disease combined with the core features of ferroptosis to explore and describe the mechanism of this phenomenon and shows that the activation of lipid peroxidation and the aberrant intracellular release of many inflammatory mediators during ferroptosis are the key processes that regulate the degree of disease development in patients with HLAP. Inhibiting the activation of ferroptosis effectively reduces the intensity of the inflammatory response, thus reducing organ damage in patients and preventing the risk of HLAP exacerbation. Additionally, this paper summarizes the key targets and potential therapeutic agents of ferroptosis associated with HLAP deterioration to provide new ideas for future clinical applications.

Hyperthermia improves gemcitabine sensitivity of pancreatic cancer cells by suppressing the EFNA4/ß-catenin axis and activating dCK.

Background: Previously, our investigations have underscored the potential of hyperthermia to improve the therapeutic efficacy of gemcitabine (GEM) in pancreatic cancer (PC). Nonetheless, the precise underlying mechanisms remain elusive. Methods: We engineered two GEM-resistant PC cell lines (BxPC-3/GEM and PANC-1/GEM) and treated them with GEM alongside hyperthermia. The impact of hyperthermia on the therapeutic potency of GEM was ascertained through MTT assay, assessment of the concentration of its active metabolite dFdCTP, and evaluation of deoxycytidine kinase (dCK) activity. Lentivirus-mediated dCK silencing was further employed to validate its involvement in mediating the GEM-sensitizing effect of hyperthermia. The mechanism underlying hyperthermia-mediated dCK activation was explored using bioinformatics analyses. The interplay between hyperthermia and the ephrin A4 (EFNA4)/ß-catenin/dCK axis was investigated, and their roles in GEM resistance was further explored via the establishment of xenograft tumor models in nude mice. Results: Hyperthermia restored dCK expression in GEM-resistant cell lines, concurrently enhancing GEM sensitivity and fostering DNA damage and cell death. These observed effects were negated by dCK silencing. Regarding the mechanism, hyperthermia activated dCK by downregulating EFNA4 expression and mitigating ß-catenin activation. Overexpression of EFNA4 activated the ß-catenin while suppressing dCK, thus diminishing cellular GEM sensitivity-a phenomenon remediated by the ß-catenin antagonist MSAB. Consistently, in vivo, hyperthermia augmented the therapeutic efficacy of GEM on xenograft tumors through modulation of the ephrin A4/ß-catenin/dCK axis. Conclusion: This study delineates the role of hyperthermia in enhancing GEM sensitivity of PC cells, primarily mediated through the suppression of the EFNA4/ß-catenin axis and activation of dCK.

Endoscopic treatment for early duodenal papillary carcinoma: long-term outcomes.

BACKGROUND AND AIM: This study aims to determine whether endoscopic papillectomy (EP) is a safe and effective treatment for early duodenal papillary carcinoma with long-term follow-up. METHODS: From June 2012 to September 2022, 48 patients with early duodenal papilloma carcinoma who received endoscopic treatment were included. The histological types, percentage of complete resections, postoperative residuals, adverse events, and recurrences were evaluated. RESULTS: EP was successful in all patients; 46 were lumped, and two were fragmented, with a 95.8% intact removal rate (46/48). The preoperative biopsy pathological positive rate was 70.8% (34/48). The incidence of early postoperative adverse events (within 1 month after EP) were 16.7% (8/48), including four cases of acute pancreatitis, three cases of delayed bleeding, and one case of acute cholangitis. In addition, 4.2% (2/48) of the late adverse events were bile duct stenosis. After 6 months, the postoperative residual rate was 0%. The median time to recurrence was 17.5 months, and the postoperative recurrence rate was 16.7% (8/48) in patients treated with radiofrequency ablation. The median progression-free survival was 18.6 months (95% CI, 12.1-25.1), and the median overall survival was 121.5 months (95% CI, 105.6-120.9). CONCLUSIONS: EP is a safe and efficient alternative therapy for early duodenal papillary carcinoma. Endoscopic follow-up and treatment are essential because of the potential for recurrence.

HtrA3: a promising prognostic biomarker and therapeutic target for head and neck squamous cell carcinoma.

Objective: The dysregulation of the human high-temperature requirement A (HtrA) family of serine proteases is associated with many malignancies. However, there are few reports on HtrAs in head and neck squamous cell carcinoma (HNSCC). The aim of this study was to investigate the expression, prognostic value, and biological functions of HtrAs in HNSCC. Methods: The RNA-sequencing data and clinical data of HNSCC were downloaded from The Cancer Genome Atlas (TCGA) database. The GSE30784 and GSE31056 datasets from the Gene Expression Omnibus (GEO) database were used for further verification. This study explored the differential expression of HtrAs and assessed their potential impact on the prognosis of HNSCC patients using a survival module. Correlations between clinical characteristics and HtrA expression levels were then explored using a Wilcoxon rank sum test. A Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Set Enrichment Analysis (GSEA) were performed using "clusterProfile" in the R software. A Pearson/Spearman correlation test was applied to analyze the relationship between HtrAs and immune infiltration level/checkpoint genes. Validation of HtrA expression levels were carried out by RT-PCR and western blot in human squamous carcinoma cell lines (Fadu and Cal-27) and human non-tumorigenic bronchial epithelium cells (BEAS-2B). Finally, through cell transfection, CCK-8, Ki-67 immunofluorescence, and flow cytometry assays, the effect of HtrA3 knockdown on the malignant biological behavior of HNSCC cells was explored. Results: The gene expression levels of HtrAs were significantly upregulated and associated with patient age, TNM stage, clinical stage, and TP53 mutation status in the TCGA-HNSCC cohort. High expressions of HtrA1/3 were associated with shorter overall survival, shorter progress-free interval, and lower disease-specific survival in HNSCC. A nomogram for HtrAs was constructed and validated. HtrA-related genes were significantly enriched in the immune response and cell apoptosis pathway. In addition, the expression of HtrAs showed significant correlations with B cells, M cells, DC cell infiltration, and immune infiltration checkpoint (CD276, TNFRSF14). Validation of HtrA expression was carried out by RT-PCR and western blot. Results of in vitro experiments indicated that HtrA3 gene knockdown inhibits the proliferation of FaDu and Cal-27 cells while concurrently promoting apoptosis. Conclusions: HtrA3 shows significant potential as both a prognostic marker and a promising therapeutic target for HNSCC, highlighting its relevance and importance in future research and potential clinical applications.

Primary choledocholithiasis occurrence and recurrence is synergetcally modulated by the bile microbiome and metabolome alternations.

AIMS: Primary choledocholithiasis is a common digestive disease with high morbidity and relapse. However, the compositions and functions of the bile microbial ecosystem and the pathogenesis of microfloral regulation of host metabolism resulting in stone formation are poorly understood. MAIN METHODS: Biliary samples collected from patients with acute cholangitis induced by benign biliary stricture (nonlithiasis group, n = 17) and primary choledocholithiasis (lithiasis group, n = 33) were subjected to multiomics analyses. Furthermore, clinicopathological features collected over a 24-month follow-up period were examined to evaluate the predictive value of candidate microbes. KEY FINDINGS: Five alpha diversity indices of the bile microbiome were significantly decreased in the lithiasis group. Furthermore, we identified 49 differential bile flora between the two groups, and the relative abundances of 6 bacteria, Actinobacteria, Actinobacteriota, Staphylococcales, Micrococcales, Altererythrobacter and Carnobacteriaceae, were associated with primary choledocholithiasis relapse conditions. Multiomics analyses showed that specific changes in disease-related bacterial taxa were closely related to metabolite variation (low-molecular weight carboxylic acids, sterol liquid and acylcarnitine), which might reflect disease prognosis. According to microbiomic and metabolomic pathway analyses, we revealed that bacterial infections, microbiota-derived amino acid metabolites and secondary bile acid-related pathways were significantly enriched in the stone-formation group, suggesting a novel host-microbial metabolic mechanism of primary choledocholithiasis. SIGNIFICANCE: Our study first indicates bile host-microbial dysbiosis modulates the abnormal accumulation of metabolites might further disrupt calcium homeostasis and generate insoluble saponification. Additionally, we determined the predictive value of Actinomycetes phylum reduction for recurrence in primary common bile duct stone patients.

Risk Factors for Carbapenem Resistant Gram Negative Bacteria (CR-GNB) Carriage Upon Admission to the Gastroenterology Department in a Tertiary First Class Hospital of China: Development and Assessment of a New Predictive Nomogram.

Background: With the increasing number of critically ill patients in the gastroenterology department (GED), infections associated with Carbapenem resistant gram-negative bacteria (CR-GNB) are of great concern in GED. As the turn-around time (TAT) for a positive screening culture result is slow, contact precaution and pre-emptive isolation, cohorting methods should be undertaken immediately on admission for high-risk patients. Accurate prediction tools for CR-GNB colonization in GED can help determine target populations upon admission. And thus, clinicians and nurses can implement preventive measures more timely and effectively. Objective: The purpose of the current study was to develop and internally validate a CR-GNB carrier risk predictive nomogram for a Chinese population in GED. Methods: Based on a training dataset of 400 GED patients collected between January 2020 and December 2021, we developed a model to predict CR-GNB carrier risk. A rectal swab was used to evaluate the patients' CR-GNB colonization status microbiologically. We optimized features selection using the least absolute shrinkage and selection operator regression model (LASSO). In order to develop a predicting model, multivariable logistic regression analysis was then undertaken. Various aspects of the predicting model were evaluated, including discrimination, calibration, and clinical utility. We assessed internal validation using bootstrapping. Results: The prediction nomogram includes the following predictors: Transfer from another hospital (Odds ratio [OR] 3.48), High Eastern Cooperative Oncology Group (ECOG) performance status (OR 2.61), Longterm in healthcare facility (OR 10.94), ICU admission history (OR 9.03), Blood stream infection history (OR 3.31), Liver cirrhosis (OR 4.05) and Carbapenem usage history within 3 month (OR 2.71). The model demonstrated good discrimination and good calibration. Conclusion: With an estimate of individual risk using the nomogram developed in this study, clinicians and nurses can take more timely infection preventive measures on isolation, cohorting and medical interventions.

The Diagnostic Value of Serum Gastrin-17 and Pepsinogen for Gastric Cancer Screening in Eastern China.

OBJECTIVE: To evaluate the diagnostic value of gastrin-17 (G-17) and pepsinogen (PG) in gastric cancer (GC) screening in China, especially eastern China, and to determine the best diagnostic combination and threshold (cutoff values) to screen out patients who need gastroscopy. METHODS: The serum concentrations of G-17 and pepsinogen I and II (PGI and PGII) in 834 patients were analyzed, and the PGI/PGII ratio (PGR) was calculated. According to pathological results, patients can be divided into chronic nonatrophic gastritis (NAG)/chronic atrophic gastritis (CAG)/intraepithelial neoplasia (IN)/GC groups. The differences in G-17, PG, and PGR in each group were analyzed, and their values in GC diagnosis were evaluated separately and in combination. RESULTS: There were differences in serum G-17, PGII, and PGR among the four groups (NAG/CAG/IN/GC) (P ≤ 0.001). In total, 54 GC cases were diagnosed, of which 50% were early GC. There was no significant difference in the PGI levels among the four groups (P = 0.377). NAG and CAG composed the chronic gastritis (CG) group. The G-17 and PGII levels in the IN and GC groups were higher than those in the CG group (both P ≤ oth C), while the PGR levels were lower (P ≤ lower). When distinguishing NAG from CAG, the best cutoff value for G-17 was 9.25 pmol/L, PGII was 7.06 µg/L, and PGR was 12.07. When distinguishing CG from IN, the best cutoff value for G-17 was 3.86 pmol/L, PGII was 11.92 µg/L, and PGR was 8.26. When distinguishing CG from GC, the best cutoff value for G-17 was 3.89 pmol/L, PGII was 9.16 µg/L, and PGR was 14.14. The sensitivity, specificity, accuracy, and positive and negative predictive values of G-17/PGII/PGR for GC diagnosis were 83.3%/70.4%/79.6%, 51.8%/56.3%/47.8%, 53.8%/57.2%/49.9%, 10.7%/10.9%/9.6%, and 97.8%/96.5%/97.1%, respectively. The sensitivity, specificity, accuracy, and positive predictive and negative predictive values of PGII/G-17 vs. PGR/G-17 vs. PGR/PGII in the diagnosis of GC were 63.0% vs. 70.4% vs. 64.8%, 70.5% vs. 70.1% vs. 60.4%, 70.0% vs. 70.1% vs. 60.7%, 12.9% vs. 14.0% vs. 10.2%, and 96.5% vs. 97.2% vs. 96.1%, respectively. CONCLUSION: The PGII and G-17 levels in patients with gastric IN and GC were significantly increased, while the serum PGR level was significantly decreased. Serological detection is effective for screening GC. The combination of different markers can improve the diagnostic efficiency. The highest diagnostic accuracy was G-17 combined with PGR, and the best cutoff values were G - 17 > 3.89 pmol/L and PGR < 14.14.

Endoscopic radiofrequency ablation plus plastic stent placement versus stent placement alone for unresectable extrahepatic biliary cancer: a multicenter randomized controlled trial.

BACKGROUND AND AIMS: We sought to compare the efficacy and safety between endoscopic radiofrequency ablation (RFA) and stent placement alone in patients with unresectable extrahepatic biliary cancer (EBC). METHODS: In this randomized controlled trial, patients with locally advanced or metastatic cholangiocarcinoma (CCA) or ampullary cancer who were unsuitable for surgery were recruited from 3 tertiary centers. Eligible patients were randomly assigned to RFA plus plastic stent placement (RFA group) or plastic stent placement alone (stent placement alone group) in a 1:1 ratio. Both groups underwent 2 scheduled interventions with an interval of approximately 3 months. The primary outcome was overall survival (OS). RESULTS: Altogether, 174 participants completed the 2 index endoscopic interventions. No significant differences in baseline characteristics were noted between the 2 groups. The median OS was significantly higher in the RFA group (14.3 vs 9.2 months; hazard ratio, .488; 95% confidence interval, .351-.678; P < .001). A survival benefit was also shown in patients with CCA (13.3 vs 9.2 months; hazard ratio, .546; 95% confidence interval, .386-.771; P < .001). However, no significant between-group differences were found in jaundice control or stent patency duration. The postprocedural Karnofsky performance scores were significantly higher in the RFA group until 9 months (all P < .001). Adverse events were comparable between the 2 groups (27.6% vs 19.5%, P = .211), except for acute cholecystitis, which was more frequently observed in the RFA group (9 vs 0, P = .003). CONCLUSIONS: Compared with stent placement alone, additional RFA may improve OS and quality of life of patients with inoperable primary EBC who do not undergo systemic treatments. (Clinical trial registration number: NCT01844245.).

Linked Color Imaging Can Improve Detection Rate of Early Gastric Cancer in a High-Risk Population: A Multi-Center Randomized Controlled Clinical Trial.

BACKGROUND: Early diagnosis of gastric cancer is difficult in China due to the lack of a valid method for endoscopic screening. Early gastric cancer, especially flat gastric cancer, lacks specific endoscopic features. Many cases appear to be similar to ordinary gastritis cases under normal white light endoscopy, which can lead to misdiagnosis. AIMS: In order to find a new method to improve detection rate of early gastric cancer in China, we designed a trial to validate linked color imaging (LCI) for screening of early gastric cancer in a high-risk population, as compared to white light imaging (WLI). METHOD: Subjects were randomly allocated to either the LCI + WLI or WLI group and then subjected to gastroscopy and all endoscopies were made after special preparation. All endoscopists had knowledge of this experiment. The main indicator was the rate of detection of gastric neoplastic lesions. The difference in the detection rate between the two groups is reported. RESULTS: The detection rate was 4.31% in the WLI group and 8.01% in the LCI + WLI group. This is a difference of 3.70% with a P value < 0.001 and an OR (95% CI) of 1.934 (1.362, 2.746). The lower limit of the 95% CI was greater than 0, and the superiority margin was 1%. CONCLUSION: The detection rate of gastric neoplastic lesions was higher in the LCI + WLI group than in the WLI group, LCI might be an effective method for screening early gastric cancer.

Endoscopic radiofrequency ablation plus a novel oral 5-fluorouracil compound versus radiofrequency ablation alone for unresectable extrahepatic cholangiocarcinoma.

BACKGROUND AND AIMS: Endoscopic radiofrequency ablation (RFA) is a new ablative treatment for unresectable extrahepatic cholangiocarcinoma (EHCC). A novel 5-fluorouracil compound, S-1 (Taiho Pharmaceutical Co, Ltd, Tokushima Plant. Japan), has been widely used as a key drug with first-line or second-line chemotherapy for the treatment of advanced cholangiocarcinoma. The aim of this study was to evaluate the clinical efficacy and safety of endoscopic RFA combined with S-1 for the treatment of unresectable locally advanced EHCC. METHODS: Patients with unresectable EHCC were prospectively randomized to 1 of 2 groups: the RFA + S-1 group and the RFA group. Median overall survival (OS), stent patency time, Karnofsky performance status (KPS) score, and adverse events rate were analyzed. RESULTS: The median OS was longer in the RFA + S-1 group (n = 37) than that in the RFA group (n = 38) (16.0 months [95% confidence interval, 13.1-19.0] vs 11.0 months [95% confidence interval, 9.7-12.3]; P < .001). Stent patency time was significantly longer in the RFA + S-1 group than that in the RFA group (6.6 ± 1.5 vs 5.6 ± .1 months, P = .014). KPS scores at postoperative month 9 (51.6 ± 17.0 vs 40.4 ± 16.4, P = .012) and month 12 (35.2 ± 18.3 vs 23.9 ± 11.4, P = .014) were all higher in the RFA + S-1 group than those in the RFA group (P < .05). The incidence of ERCP-related adverse events was not significantly different between RFA+S-1 and RFA groups (8.1% vs 10.5%, P > .05). CONCLUSIONS: For the treatment of locally advanced EHCC, endoscopic RFA combined with S-1 is associated with longer survival and stent patency and improved functional status than RFA alone. (Clinical trial registration number: NCT02592538.).

Biliary Microbial Structure of Gallstone Patients With a History of Endoscopic Sphincterotomy Surgery.

The biliary microbiota is related to the pathogenesis of human bile duct stones. However, the extent to which a history of invasive endoscopic sphincterotomy (EST) affects the biliary bacterial community remains largely unknown. We collected bile samples from the common bile duct of 100 choledocholithiasis patients. We performed 16S rRNA sequencing to investigate and compare the biliary microbial community. The patients without antibiotic treatment (AT) were grouped into three clusters based on their biliary microbial compositions. The patients with a history of EST were significantly enriched in one cluster mainly consisting of gastrointestinal bacteria compared with the other two clusters consisting of oral and environmental bacteria. The ß-diversities of patients with and without EST were also significantly different, whereas the α-diversities were comparable. The only significantly enriched bacterial genus associated with a history of EST was Pyramidobacter, while eight other genera were significantly decreased. For patients with AT, seven of these genera maintained their association with EST, including Pyramidobacter. However, after AT, the difference in ß-diversities was diminished. EST induced a marked shift in the biliary microbial composition. A cluster of biliary bacteria was associated with a history of EST, and Pyramidobacter was specific to EST.

Endoscopic ultrasound-guided versus endoscopic retrograde cholangiopancreatography-guided biliary drainage for primary treatment of distal malignant biliary obstruction: A systematic review and meta-analysis.

OBJECTIVES: Current evidence supporting the utility of endoscopic ultrasound-guided biliary drainage (EUS-BD) as primary treatment for distal malignant biliary obstruction (MBO) is limited. We conducted a meta-analysis to compare the performance of EUS-BD and endoscopic retrograde cholangiopancreatography-guided biliary drainage (ERCP-BD) as primary palliation of distal MBO. METHODS: We searched several databases for comparative studies evaluating EUS-BD vs. ERCP-BD in primary drainage of distal MBO up to 28 February 2019. Primary outcomes were technical success and clinical success. Secondary outcomes included adverse events, stent patency, stent dysfunction, tumor in/overgrowth, reinterventions, procedure duration, and overall survival. RESULTS: Four studies involving 302 patients were qualified for the final analysis. There was no difference in technical success (risk ratio [RR] 1.00; 95% confidence interval [95% CI] 0.93-1.08), clinical success (RR 1.00; 95% CI 0.94-1.06) and total adverse events (RR 0.68; 95% CI: 0.31-1.48) between the two procedures. EUS-BD was associated with lower rates of post-procedure pancreatitis (RR 0.12; 95% CI 0.02-0.62), stent dysfunction (RR 0.54; 95% CI 0.32-0.91), and tumor in/overgrowth (RR 0.22; 95% CI 0.07-0.76). No differences were noted in reinterventions (RR 0.59; 95% CI 0.21-1.69), procedure duration (weighted mean difference -2.11; 95% CI -9.51 to 5.29), stent patency (hazard ratio [HR] 0.61; 95% CI 0.34-1.11), and overall survival (HR 1.00; 95% CI 0.66-1.51). CONCLUSIONS: With adequate endoscopy expertise, EUS-BD could show similar efficacy and safety when compared with ERCP-BD for primary palliation of distal MBO and exhibits several clinical advantages.

Hyperthermia enhances the sensitivity of pancreatic cancer SW1990 cells to gemcitabine through ROS/JNK signaling.

Pancreatic cancer (PC) is a highly aggressive type of cancer. Gemcitabine (GEM) is a standard chemotherapeutic treatment of advanced PC; however, it requires improvement, and more effective therapeutic methods must be further explored. In the present study, hyperthermia combined with GEM was used on the PC cell line SW1990. The results revealed that mild hyperthermia (at 42°C) effectively increased the inhibitory effect of GEM on cell viability, as determined using an MTT assay, and increased the effect of GEM-induced apoptosis, as determined using an Annexin V-fluorescein isothiocyanate/propidium iodide assay, in PC SW1990 cells. Additionally, it resulted in increased S-phase arrest, downregulated the expression of the anti-apoptosis protein B-cell lymphoma 2 and upregulated the expression of the pro-apoptosis protein Bcl-2-associated X protein, cleaved caspase-3 and cleaved caspase-9, as determined using a reverse transcription-quantitative polymerase chain reaction and western blot analysis. Furthermore, it was revealed that hyperthermia resulted in the rapid generation of reactive oxygen species (ROS) and substantial activation of c-Jun-N-terminal kinase (JNK). The introduction of ROS and JNK inhibitors suppressed hyperthermia-induced apoptosis in GEM-treated cells, suggesting that hyperthermia increased GEM cytotoxicity in PC SW1990 cells by inducing apoptosis via the ROS/JNK signaling pathway.

Hyperthermia inhibits the motility of gemcitabine-resistant pancreatic cancer PANC-1 cells through the inhibition of epithelial-mesenchymal transition.

Pancreatic cancer (PC) is one of the most common types of malignant tumor and the leading cause of cancer­associated mortality worldwide. The chemotherapeutic drug gemcitabine (GEM) is used as a first­line chemotherapeutic agent for advanced PC. However, the acquisition of drug resistance is a major limitation of the clinical effect of GEM and commonly leads to increased metastasis. The occurrence of epithelial­mesenchymal transition (EMT) has been demonstrated to be the underlying mechanism of acquired resistance. It has been reported that heat treatment is able to inhibit EMT in pancreatic adenocarcinoma cells. In the present study the effect of hyperthermia on the sensitivity of GEM­resistant PC cells was investigated. First a GEM­resistant PC cell line PANC­1 (PAN/GEM) was developed and it was demonstrated that drug resistant PAN/GEM cells exhibited significantly increased migratory and invasive abilities compared with control PANC­1 cells using a Transwell assay. EMT was induced in resistant PAN/GEM cells, followed by reduced epithelial marker epithelial (E)­cadherin expression and increased mesenchymal marker Vimentin expression compared with control PANC­1 cells. Next, the Transwell assay demonstrated that the hyperthermia at 42˚C for 1 h combined with GEM significantly attenuated migration and invasion in drug resistant PAN/GEM cells, while GEM alone treatment did not significantly affect the migration and invasion. Additionally, EMT in PAN/GEM cells was reversed by hyperthermia, as demonstrated by the restoration of E­cadherin and downregulation of mesenchymal markers Vimentin, matrix metalloproteinase (MMP)2 and MMP9. Furthermore, an MMP2 inhibitor tissue inhibitor of metalloproteinases (TIMP)2 and MMP9 inhibitor TIMP1 were used to treat PAN/GEM cells and it was demonstrated that both inhibitors increased the inhibition of hyperthermia treatment combined with GEM on cell invasion, suggesting an association between cell invasion and MMP2, and MMP9. Additionally, proliferation of PAN/GEM cells following hyperthermia was assessed using an MTT assay. The results demonstrated that proliferation in PAN/GEM cells treated with hyperthermia was significantly inhibited by GEM compared with GEM alone treated cells, indicating that hyperthermia enhanced the inhibition of GEM on cell growth and resensitized the drug­resistant cells to GEM. Overall, the results of the present study suggested that hyperthermia is able to resensitize GEM­resistant PANC­1 cells to GEM by reversing EMT via the regulation of EMT­associated factors, therefore inhibiting cell migration and invasion.

Efficacy and safety of endoscopic radiofrequency ablation for unresectable extrahepatic cholangiocarcinoma: a randomized trial.

BACKGROUND: Endoscopic placement of biliary stents to relieve jaundice is the main palliative treatment for unresectable extrahepatic cholangiocarcinoma. Endoscopic biliary radiofrequency ablation (RFA) has been reported to prolong stent patency, which may be beneficial in improving patient survival. However, available evidence is still insufficient, as most reported studies are retrospective case series. The aim of this study was to explore the clinical effect and safety of RFA in patients with unresectable extrahepatic cholangiocarcinoma. METHODS: 65 patients with unresectable extrahepatic cholangiocarcinoma, except Bismuth type III and IV hilar cholangiocarcinoma, were enrolled and randomly underwent either RFA combined with biliary stenting (RFA + stent group; n = 32) or biliary stent only (stent-only group; n = 33). Overall survival time, stent patency period, and postoperative adverse events were recorded. RESULTS: In the 21-month follow-up period, the overall mean survival time was significantly longer in the RFA + stent group than in the stent-only group (13.2 ±â€Š0.6 vs. 8.3 ±â€Š0.5 months; P < 0.001). The mean stent patency period of the RFA + stent group was also significantly longer than that of the stent-only group (6.8 vs. 3.4 months; P = 0.02). There was no significant difference in the incidence of postoperative adverse events between the two groups (6.3 % [2/32] vs. 9.1 % [3/33]; P = 0.67). CONCLUSION: Endoscopic RFA combined with stenting can significantly prolong survival and the stent patency period without increasing the incidence of adverse events in patients with extrahepatic cholangiocarcinoma patient, except Bismuth type III and IV hilar cholangiocarcinoma. This approach can be considered as a safe and effective palliative treatment for these patients.

Endoscopic ultrasound-guided pancreaticogastrostomy for symptomatic pancreatic duct obstruction caused by migrated pancreatic stent.

Endoscopic pancreatic stenting has been widely used in various pancreatic conditions. With the increasing use of pancreatic stents, many complications have been recognized. Especially, proximal stent migration presents a serious condition because of subsequent pancreatic duct obstruction, impaired drainage, ductal dilation, and pancreatic pain. Although endoscopic retrieval is the preferred treatment for proximally migrated pancreatic stents, it is not always successful, resulting in conversion to surgery. To date, endoscopic ultrasound-guided pancreatic duct drainage (EUS-PD) has never been reported for treatment of pancreatic duct obstruction caused by proximally migrated pancreatic stent. We herein describe a case of pancreatic duct rupture and obstruction caused by proximally migrated pancreatic stent that was successfully treated by EUS-guided pancreaticogastrostomy while keeping the former stent in situ after failed endoscopic retrograde cholangiopancreatography. We believe that this report adds to the increasing evidence of symptomatic pancreatic duct obstruction being successfully treated by EUS-PD.

Interventional endoscopic ultrasound for a symptomatic pseudocyst secondary to gastric heterotopic pancreas.

Heterotopic pancreas (HP) is a relatively uncommon entity that is defined as pancreatic tissue without a true anatomical or vascular connection to the pancreas. HP does not cause symptoms in most cases but can occasionally produce various manifestations, including nausea, vomiting, abdominal pain, and even heterotopic pancreatitis. Here, we report an unusual case in which heterotopic pancreatitis complicated by the formation of a pseudocyst that caused gastric outlet obstruction was diagnosed based on serum hyperamylasemia and findings from endoscopic ultrasonography (EUS)-guided fine needle aspiration (EUS-FNA) cytology. EUS-guided single pigtail stent insertion was successfully performed for recurrent gastric outlet obstruction. The patient has remained healthy and symptom-free during 4 years of surveillance. In the context of the relevant literature, the described case is a rare case of HP complicated by a pseudocyst treated via EUS-FNA and stent insertion.