The Effect of Perioperative Dexamethasone on Postoperative Complications after Pancreaticoduodenectomy: A Multicenter Randomized Controlled Trial.

OBJECTIVE: This study aimed to evaluate the effect of perioperative dexamethasone on postoperative complications after pancreaticoduodenectomy. BACKGROUND: The glucocorticoid dexamethasone has been shown to improve postoperative outcomes in surgical patients, but its effects on postoperative complications after pancreaticoduodenectomy are unclear. METHODS: This multicenter, double-blind, randomized controlled trial was conducted in four Chinese high-volume pancreatic centers. Adults undergoing elective pancreaticoduodenectomy were randomized to receive either 0.2 mg/kg dexamethasone or a saline placebo as an intravenous bolus within 5 minutes after anesthesia induction. The primary outcome was the Comprehensive Complication Index (CCI) score within 30 days after the operation, analyzed using the modified intention-to-treat principle. RESULTS: Among 428 patients for eligibility, 300 participants were randomized and 265 were included in the modified intention-to-treat analyses. 134 patients received dexamethasone and 131 patients received a placebo. The mean (SD) CCI score was 14.0 (17.5) in the dexamethasone group and 17.9 (20.3) in the placebo group (mean difference, -3.8; 95% CI, -8.4 to 0.7; P=0.100). The incidence of major complications (Clavien-Dindo grade ≥III) (12.7% vs. 16.0%, risk ratio 0.79; 95% CI, 0.44 to 1.43; P=0.439) and postoperative pancreatic fistula (25.4% vs. 31.3%, risk ratio 0.81; 95% CI, 0.55 to 1.19; P=0.286) were not significantly different between the two groups. In the stratum of participants with a main pancreatic duct ≤3 mm (n=202), the CCI score was significantly lower in the dexamethasone group (mean difference, -6.4; 95% CI, -11.2 to -1.6; P=0.009). CONCLUSION: Perioperative dexamethasone did not significantly reduce postoperative complications within 30 days after pancreaticoduodenectomy.

Short-term and Long-term Outcomes of Robotic Enucleation of Tumors Located in the Pancreatic Head and Uncinate Process.

OBJECTIVE: To assess short-term and long-term outcomes following robotic enucleation (REn) of tumors in the proximal pancreas. BACKGROUND: Despite the advantages of preserving function via pancreatic enucleation, controversies persist, since this can be associated with severe complications, such as clinically relevant postoperative pancreatic fistula, especially when performed near the main pancreatic duct. The safety and efficacy of REn in this context remain largely unknown. METHODS: A retrospective analysis was performed of all patients who underwent REn for benign and low-grade malignant neoplasms in the pancreatic head and uncinate process between January 2005 and December 2021. Clinicopathologic, perioperative, and long-term outcomes were compared with a similar open enucleation (OEn) group. RESULTS: Of 146 patients, 92 underwent REn with a zero conversion-to-open rate. REn was superior to OEn in terms of shorter operative time (90.0 minutes vs 120.0 minutes, P<0.001), decreased blood loss (20.0 mL vs 100.0 min, P=0.001), and lower clinically relevant postoperative pancreatic fistula rate (43.5% vs 61.1%, P=0.040). Bile leakage rate, major morbidity, 90-day mortality, and length of hospital stay were comparable between groups. No post-REn grade C POPF or grade IV/V complication was identified. Subgroup analyses for uncinate process tumors and proximity to the main pancreatic duct did not demonstrate inferior postoperative outcomes. In a median follow-up period of 50 months, REn outcomes were comparable to OEn regarding recurrence rate and pancreatic endocrine or exocrine function. CONCLUSIONS: REn for pancreatic head and uncinate process tumors improved clinically relevant outcomes without increased major complications compared to OEn, while demonstrating comparable long-term oncological and functional outcomes.

Robotic versus open pancreatoduodenectomy in patients with pancreatic duct adenocarcinoma after the learning curve: a propensity score-matched analysis.

BACKGROUND: Studies have demonstrated that the learning curve plays an important role in robotic pancreatoduodenectomy (RPD). Although improved short-term outcomes of RPD after the learning curve have been reported compared to open pancreatoduodenectomy (OPD), there is a lack of long-term survival analyses. METHODS: Patients who underwent curative intended RPD and OPD for pancreatic duct adenocarcinoma (PDAC) between January 2017 and June 2020 were retrospectively reviewed. A 1:2 propensity score matching (PSM) analysis was performed to balance the baseline characteristics between the RPD and OPD groups. RESULTS: Of the 548 patients (108 RPD and 440 OPD), 103 RPD patients were matched with 206 OPD patients after PSM. There were 194 (62.8%) men and 115 (37.2%) women, with a median age of 64 (58-69) years. The median overall survival (OS) in the RPD group was 33.2 months compared with 25.7 months in the OPD group (p = 0.058, log-rank). The median disease-free survival (DFS) following RPD was longer than the OPD (18.5 vs. 14.0 months, p = 0.011, log-rank). The RPD group has a lower incidence of local recurrence compared the OPD group (36.9% vs. 51.2%, p = 0.071). Multivariate Cox analysis demonstrated that RPD was independently associated with improved OS (HR 0.70, 95% CI 0.52-0.94, p = 0.019) and DFS (HR 0.66, 95% CI 0.50-0.88, p = 0.005). CONCLUSION: After the learning curve, RPD had improved oncologic outcomes in PDAC patients compared to OPD. Future prospective randomized clinical trials will be required to validate these findings.

BHLHE40 Inhibits Ferroptosis in Pancreatic Cancer Cells via Upregulating SREBF1.

Pancreatic cancer (PCa) is one of the most fatal human malignancies. The enhanced infiltration of stromal tissue into the PCa tumor microenvironment limits the identification of key tumor-specific transcription factors and epigenomic abnormalities in malignant epithelial cells. Integrated transcriptome and epigenetic multiomics analyses of the paired PCa organoids indicate that the basic helix-loop-helix transcription factor 40 (BHLHE40) is significantly upregulated in tumor samples. Increased chromatin accessibility at the promoter region and enhanced mTOR pathway activity contribute to the elevated expression of BHLHE40. Integrated analysis of chromatin immunoprecipitation-seq, RNA-seq, and high-throughput chromosome conformation capture data, together with chromosome conformation capture assays, indicate that BHLHE40 not only regulates sterol regulatory element-binding factor 1 (SREBF1) transcription as a classic transcription factor but also links the enhancer and promoter regions of SREBF1. It is found that the BHLHE40-SREBF1-stearoyl-CoA desaturase axis protects PCa cells from ferroptosis, resulting in the reduced accumulation of lipid peroxidation. Moreover, fatostatin, an SREBF1 inhibitor, significantly suppresses the growth of PCa tumors with high expressions of BHLHE40. This study highlights the important roles of BHLHE40-mediated lipid peroxidation in inducing ferroptosis in PCa cells and provides a novel mechanism underlying SREBF1 overexpression in PCa.

Schwann cells regulate tumor cells and cancer-associated fibroblasts in the pancreatic ductal adenocarcinoma microenvironment.

Neuropathy is a feature more frequently observed in pancreatic ductal adenocarcinoma (PDAC) than other tumors. Schwann cells, the most prevalent cell type in peripheral nerves, migrate toward tumor cells and associate with poor prognosis in PDAC. To unveil the effects of Schwann cells on the neuro-stroma niche, here we perform single-cell RNA-sequencing and microarray-based spatial transcriptome analysis of PDAC tissues. Results suggest that Schwann cells may drive tumor cells and cancer-associated fibroblasts (CAFs) to more malignant subtypes: basal-like and inflammatory CAFs (iCAFs), respectively. Moreover, in vitro and in vivo assays demonstrate that Schwann cells enhance the proliferation and migration of PDAC cells via Midkine signaling and promote the switch of CAFs to iCAFs via interleukin-1α. Culture of tumor cells and CAFs with Schwann cells conditioned medium accelerates PDAC progression. Thus, we reveal that Schwann cells induce malignant subtypes of tumor cells and CAFs in the PDAC milieu.

Targeting KRASG12V mutations with HLA class II-restricted TCR for the immunotherapy in solid tumors.

KRAS mutation is a significant driving factor of tumor, and KRASG12V mutation has the highest incidence in solid tumors such as pancreatic cancer and colorectal cancer. Thus, KRASG12V neoantigen-specific TCR-engineered T cells could be a promising cancer treatment approach for pancreatic cancer. Previous studies had reported that KRASG12V-reactive TCRs originated from patients' TILs could recognized KRASG12V neoantigen presented by specific HLA subtypes and remove tumor persistently in vitro and in vivo. However, TCR drugs are different from antibody drugs in that they are HLA-restricted. The different ethnic distribution of HLA greatly limits the applicability of TCR drugs in Chinese population. In this study, we have identified a KRASG12V-specific TCR which recognized classII MHC from a colorectal cancer patient. Interestingly, we observed that KRASG12V-specific TCR-engineered CD4+ T cells, not CD8+ T cells, demonstrated significant efficacy in vitro and in xenograft mouse model, exhibiting stable expression and targeting specificity of TCR when co-cultured with APCs presenting KRASG12V peptides. TCR-engineered CD4+ T cells were co-cultured with APCs loaded with neoantigen, and then HLA subtypes were identified by the secretion of IFN-γ. Collectively, our data suggest that TCR-engineered CD4+ T cells can be used to target KRASG12V mutation presented by HLA-DPB1*03:01 and DPB1*14:01, which provide a high population coverage and are more suitable for the clinical transformation for Chinese, and mediate tumor killing effect like CD8+ T cells. This TCR hold promise for precision therapy in immunotherapy of solid tumors as an attractive candidate.

Comprehensive machine learning-generated classifier identifies pro-metastatic characteristics and predicts individual treatment in pancreatic cancer: A multicenter cohort study based on super-enhancer profiling.

Rationale: Accumulating evidence illustrated that the reprogramming of the super-enhancers (SEs) landscape could promote the acquisition of metastatic features in pancreatic cancer (PC). Given the anatomy-based TNM staging is limited by the heterogeneous clinical outcomes in treatment, it is of great clinical significance to tailor individual stratification and to develop alternative therapeutic strategies for metastatic PC patients based on SEs. Methods: In our study, ChIP-Seq analysis for H3K27ac was performed in primary pancreatic tumors (PTs) and hepatic metastases (HMs). Bootstrapping and univariate Cox analysis were implemented to screen prognostic HM-acquired, SE-associated genes (HM-SE genes). Then, based on 1705 PC patients from 14 multicenter cohorts, 188 machine-learning (ML) algorithm integrations were utilized to develop a comprehensive super-enhancer-related metastatic (SEMet) classifier. Results: We established a novel SEMet classifier based on 38 prognostic HM-SE genes. Compared to other clinical traits and 33 published signatures, the SEMet classifier possessed robust and powerful performance in predicting prognosis. In addition, patients in the SEMetlow subgroup owned dismal survival rates, more frequent genomic alterations, and more activated cancer immunity cycle as well as better benefits in immunotherapy. Remarkably, there existed a tight correlation between the SEMetlow subgroup and metastatic phenotypes of PC. Among 18 SEMet genes, we demonstrated that E2F7 may promote PC metastasis through the upregulation of TGM2 and DKK1. Finally, after in silico screening of potential compounds targeted SEMet classifier, results revealed that flumethasone could enhance the sensitivity of metastatic PC to routine gemcitabine chemotherapy. Conclusion: Overall, our study provided new insights into personalized treatment approaches in the clinical management of metastatic PC patients.

Short-term outcomes between robot-assisted and open pancreaticoduodenectomy in patients with high body mass index: A propensity score matched study.

BACKGROUND: High body mass index was considered as a risk factor for minimally invasive surgery. The short-term outcomes of robot-assisted pancreaticoduodenectomy (RPD) remain controversial. This study aims to investigate the feasibility and advantage of RPD in patients with high body mass index compared to open pancreaticoduodenectomy (OPD). METHODS: Clinical data of 304 patients who underwent pancreaticoduodenectomy from January 2016 to December 2019 in Ruijin Hospital, Shanghai Jiao Tong University School of Medicine was collected. Patients with BMI >25 kg/m2 were included and divided into RPD and OPD group. After PSM at a 1:1 ratio, 75 patients of OPD and 75 patients of RPD were recorded and analyzed. RESULTS: The RPD group showed advantages in the estimated blood loss (EBL) (323.3 mL vs. 480.7 mL, p = 0.010), the postoperative abdominal infection rate (24% vs. 44%, p = 0.010), the incidence of Clavien-Dindo III-V complications (14.7% vs. 28.0%, p = 0.042) over OPD group. CONCLUSION: RPD shows advantages in less EBL, lower incidence rate of Clavien-Dindo III-V complications over OPD in overweight and obese patients. RPD was confirmed as a safe and feasible surgical approach for overweight or obsess patients.

Specific human leukocyte antigen class I genotypes predict prognosis in resected pancreatic adenocarcinoma: a retrospective cohort study.

BACKGROUND: Patients with resected pancreatic adenocarcinoma (PAAD) often experience short-term relapse and dismal survival, suggesting an urgent need to develop predictive and/or prognostic biomarkers for these populations. Given the potential associations of the human leukocyte antigen class I ( HLA -I) genotype with oncogenic mutational profile and immunotherapy efficacy, we aimed to assess whether differential HLA -I genotype could predict the postoperative outcomes in resected PAAD patients. MATERIALS AND METHODS: HLA -I ( A , B , and C ) genotyping and somatic variants of 608 Chinese PAAD patients were determined by targeted next-generation sequencing of matched blood cells and tumor tissues. HLA - A / B alleles were classified with the available definition of 12 supertypes. The Kaplan-Meier curves of disease-free survival (DFS) and multivariable Cox proportional-hazards regression analyses were performed to determine the survival difference in 226 selected patients with radical resection. Early-stage (I-II) patients constituted the majority (82%, 185/226) and some stage I-II individuals with high-quality tumor samples were analyzed by RNA-sequencing to examine immunophenotypes. RESULTS: Patients with HLA-A02 + B62 + B44 - had significantly shorter DFS (median, 239 vs. 410 days; hazard ratio=1.65, P =0.0189) than patients without this genotype. Notably, stage I-II patients carrying HLA-A02 + B62 + B44 - had sharply shorter DFS than those without HLA-A02 + B62 + B44 - (median, 237 vs. 427 days; hazard ratio=1.85, P =0.007). Multivariate analysis revealed that HLA-A02 + B62 + B44 - was associated with significantly inferior DFS ( P =0.014) in stage I-II patients but not in stage III patients. Mechanistically, HLA-A02 + B62 + B44 - patients were associated with a high rate of KRAS G12D and TP53 mutations, lower HLA-A expression, and less inflamed T-cell infiltration. CONCLUSION: The current results suggest that a specific combination of germline HLA-A02/B62/B44 supertype, HLA-A02 + B62 + B44 - , was a potential predictor for DFS in early-stage PAAD patients after surgery.

Silencing of KNTC1 inhibits hepatocellular carcinoma cells progression via suppressing PI3K/Akt pathway.

Kinetochore associated 1 (KNTC1) encodes a kinetochore component in Rod-Zwilch-ZW10 (RZZ) complex which is essential for the segregation of sister chromatids during mitosis and participates in the spindle checkpoint. Recent research demonstrated that kinetochore proteins may be potential biomarkers and may contribute to the development of human malignancies. Our immunohistochemistry experiment showed that KNTC1 was highly expressed in hepatocellular carcinoma (HCC) tissues and correlated with terrible prognosis, indicating that KNTC1 acts a pivotal role in HCC development. Furthermore, lentivirus delivered short hairpin RNA (shRNA) KNTC1 (Lv-shKNTC1) was applied to infect BEL-7404 and SK-HEP-1 to identify roles of KNTC1 on HCC. Lv-shKNTC1 cells showed reduced proliferation ability, increased apoptosis and decreased migration ability. In vivo experiments suggested that xenografts grow significantly slower upon the silencing of KNTC1. Mechanistically, the protein levels of PIK3CA, p-Akt, CCND1, CDK6 are all down-regulated in Lv-KNTC1 cells and the Lv-shKNTC1 tumor tissues of nude mice. Therefore, KNTC1 may affect the biological activity of HCC cells through PI3K/Akt signaling pathway. Further studies revealed that ZW10 is a pivotal protein that participates in KNTC1-induced regulation of PI3K/Akt signaling pathway. In summary, the key finding of this report highlighted the significance of KNTC1 in tumor regression of HCC, demonstrating KNTC1 as an innovative target for adjuvant treatment of HCC.

The Impact of Additional Para-aortic Dissection During Pancreaticoduodenectomy for Resectable Pancreatic Cancer.

BACKGROUND: The short-term outcome and long-term survival of pancreaticoduodenectomy with additional para-aortic dissection (PAD) for patients with resectable pancreatic cancer remain obscure. PATIENTS AND METHODS: Consecutive patients who underwent radical pancreaticoduodenectomy for resectable pancreatic cancer in a single high-volume center during a 7-year period were included retrospectively. Both short- and long-term effects of PAD were compared between the PAD group and the no PAD group. Then, the PAD group was divided into the non-metastatic para-aortic lymph node (PALN-) group and the metastatic PALN (PALN+) group to further analyze the prognosis of PALN+. RESULTS: Of the 909 included patients, 280 (30.8%) underwent PAD during pancreaticoduodenectomy. The PAD group had a higher rate of intra-abdominal infection compared with the no PAD group (28.6% vs. 20.7%, P = 0.009) but no differences were found in the incidence of other complications. The overall survival (OS) and recurrence-free survival (RFS) were also comparable between the two groups. Subgroup analysis showed that patients with PALN+ had a worse OS than patients in the PALN- group (median of 14 vs. 20 months, P = 0.048). Multivariate Cox regression analysis further revealed that PALN+ was an independent adverse predictor of OS (hazard ratio: 1.70, P = 0.007). CONCLUSIONS: This study suggests that the addition of PAD during pancreaticoduodenectomy does not improve the prognosis of patients with resectable pancreatic cancer and may lead to an increased risk of infection. However, the accurate preoperative assessment and appropriate treatment strategy for patients with PALN+ need further investigation due to the poor prognosis.

Single-cell RNA-seq analysis reveals BHLHE40-driven pro-tumour neutrophils with hyperactivated glycolysis in pancreatic tumour microenvironment.

OBJECTIVE: Innate immunity plays important roles in pancreatic ductal adenocarcinoma (PDAC), as non-T-cell-enriched tumour. Neutrophils are major players in innate immune system. Here, we aimed to explore the heterogeneity and pro-tumour mechanisms of neutrophils in PDAC. DESIGN: We analysed single-cell transcriptomes of peripheral blood polymorphonuclear leucocytes (PMNs) and tumour-infiltrating immune cells from five patients with PDAC, and performed immunofluorescence/immunohistochemistry staining, multi-omics analysis and in vitro experiments to validate the discoveries of bioinformatics analysis. RESULTS: Exploration of the heterogeneity of tumour-associated neutrophils (TANs) revealed a terminally differentiated pro-tumour subpopulation (TAN-1) associated with poor prognosis, an inflammatory subpopulation (TAN-2), a population of transitional stage that have just migrated to tumour microenvironment (TAN-3) and a subpopulation preferentially expressing interferon-stimulated genes (TAN-4). Glycolysis signature was upregulated along neutrophil transition trajectory, and TAN-1 was featured with hyperactivated glycolytic activity. The glycolytic switch of TANs was validated by integrative multi-omics approach of transcriptomics, proteomics and metabolomics analysis. Activation of glycolytic activity by LDHA overexpression induced immunosuppression and pro-tumour functions in neutrophil-like differentiated HL-60 (dHL-60) cells. Mechanistic studies revealed BHLHE40, downstream to hypoxia and endoplasmic reticulum stress, was a key regulator in polarisation of neutrophils towards TAN-1 phenotype, and direct transcriptional regulation of BHLHE40 on TAN-1 marker genes was demonstrated by chromatin immunoprecipitation assay. Pro-tumour and immunosuppression functions were observed in dHL-60 cells overexpressing BHLHE40. Importantly, immunohistochemistry analysis of PDAC tissues revealed the unfavourable prognostic value of BHLHE40+ neutrophils. CONCLUSION: The dynamic properties of TANs revealed by this study will be helpful in advancing PDAC therapy targeting innate immunity.

Long-term outcomes of standard versus extended lymphadenectomy in pancreatoduodenectomy for pancreatic ductal adenocarcinoma: A Chinese multi-center prospective randomized controlled trial.

INTRODUCTION: The value of extended lymphadenectomy in pancreatoduodenectomy (PD) has been discussed by five randomized controlled studies. However, the limitations in the studies made their conclusions not sufficiently reliable. OBJECTIVES: This multi-center randomized controlled study was designed to clarify the efficacy of extended lymphadenectomy in PD for pancreatic ductal adenocarcinoma (PDAC). METHODS: From December 2016 to October 2018, 170 consecutive patients undergoing PD were enrolled and randomized to standard or extended lymphadenectomy for the treatment of PDAC from three high-volume institutions in China. Demographic, pathological characteristics and survival data of these patients were collected and analyzed. No neoadjuvant treatment was performed. The primary endpoint was the 3-year overall survival. RESULTS: For all patients, the 3-year survival rate was 25.88 %. There was no between-group difference in 3-year survival rate (27.16 % vs 24.72 % p = 0.717). The median survival time for the standard group was 18 months, while for the extended group it was 15 months. The demographic and pathological characteristics were similar between groups. More positive lymph nodes could be found in the extended group (2.34 ± 3.46 vs 1.41 ± 2.12, p = 0.035), which led to nodule stage migration. All patients received chemotherapy. But patients in extended group were more likely to fail in completion of all-cycles chemotherapy before recurrence (31.46 % vs 17.28 %, p = 0.032). Incomplete chemotherapy before recurrence, higher N status and abnormal CA125 were independent risk factors for 1-year survival (p < 0.001, 95 % CI 0.076-0.368; p = 0.017, 95 % CI 1.113-3.021; p = 0.021, 95 % CI 1.136-4.960, respectively), which was higher in the standard group (75.31 % vs 58.43 %, p = 0.020). CONCLUSION: The extended lymphadenectomy in PD did not improve the long-term survival in patients with PDAC. Patients with extended lymphadenectomy had a worse 1-year overall survival. However, the nodule stage migration facilitated by the extended lymphadenectomy contributed to the precise tumor staging.

Hypoxia-induced exosomal circPDK1 promotes pancreatic cancer glycolysis via c-myc activation by modulating miR-628-3p/BPTF axis and degrading BIN1.

BACKGROUND: circRNA has been established to play a pivotal role in tumorigenesis development in a variety of cancers; nevertheless, the biological functions and molecular mechanisms of hypoxia-induced exosomal circRNAs in pancreatic cancer remain largely unknown. METHODS: Differentially expressed circRNAs in exosomes between hypoxic exosomes and normoxic exosomes in PC cells were verified by RNA sequencing. The expression of circPDK1 in PC tumors and PC patients was evaluated by qRT-PCR and ISH, and the biological functions of circPDK1 in PC were verified through a series of in vitro and in vivo experiments. Using Western blotting, Co-IP, RNA pull-down, ChIP, RIP, dual-luciferase assays, and rescue experiments, the underlying mechanism of circPDK1 was verified. RESULTS: CircPDK1 was highly abundant in PC tumor tissues and serum exosomes and was associated with poor survival. Exosomal circPDK1 significantly promoted PC cell proliferation, migration, and glycolysis both in vitro and in vivo. Mechanistically, circPDK1 could be activated by HIF1A at the transcriptional level and sponges miR-628-3p to activate the BPTF/c-myc axis. In addition, circPDK1 serves as a scaffold that enhances the interaction between UBE2O and BIN1, inducing the UBE2O-mediated degradation of BIN1. CONCLUSIONS: We found that circPDK1 was activated by HIF1A at the transcriptional level by modulating the miR-628-3p/BPTF axis and degrading BIN1. Exosomal circPDK1 is a promising biomarker for PC diagnosis and prognosis and represents a potential therapeutic target for PC.

The LINC00623/NAT10 signaling axis promotes pancreatic cancer progression by remodeling ac4C modification of mRNA.

BACKGROUND: Although a substantial increase in the survival of patients with other cancers has been observed in recent decades, pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest diseases. No effective screening approach exists. METHODS: Differential exosomal long noncoding RNAs (lncRNAs) isolated from the serum of patients with PDAC and healthy individuals were profiled to screen for potential markers in liquid biopsies. The functions of LINC00623 in PDAC cell proliferation, migration and invasion were confirmed through in vivo and in vitro assays. RNA pulldown, RNA immunoprecipitation (RIP) and coimmunoprecipitation (Co-IP) assays and rescue experiments were performed to explore the molecular mechanisms of the LINC00623/NAT10 signaling axis in PDAC progression. RESULTS: A novel lncRNA, LINC00623, was identified, and its diagnostic value was confirmed, as it could discriminate patients with PDAC from patients with benign pancreatic neoplasms and healthy individuals. Moreover, LINC00623 was shown to promote the tumorigenicity and migratory capacity of PDAC cells in vitro and in vivo. Mechanistically, LINC00623 bound to N-acetyltransferase 10 (NAT10) and blocked its ubiquitination-dependent degradation by recruiting the deubiquitinase USP39. As a key regulator of N4-acetylcytidine (ac4C) modification of mRNA, NAT10 was demonstrated to maintain the stability of oncogenic mRNAs and promote their translation efficiency through ac4C modification. CONCLUSIONS: Our data revealed the role of LINC00623/NAT10 signaling axis in PDAC progression, showing that it is a potential biomarker and therapeutic target for PDAC.

Oncological outcomes of robotic pancreatectomy in patients with pancreatic cancer who receive adjuvant chemotherapy: A propensity score-matched retrospective cohort study.

BACKGROUND: Limited data are available regarding long-term oncological outcomes in patients with pancreatic ductal adenocarcinoma (PDAC) who undergo robotic pancreatectomy (RP). METHOD: All patients who underwent RP and open pancreatectomy (OP) for resectable PDAC between January 2011 and December 2019 were included. The RP group was matched 1:1 with OP group by propensity score matching (PSM). The oncological outcomes were collected and analyzed. RESULTS: Overall, 1606 patients were included in this study. After PSM, a well-balanced cohort of 335 patients in each group was selected for further analysis. The RP group had shorter operative time (210 min vs. 240 min, P < 0.001), lower estimated blood loss (200 ml vs. 300 ml, P = 0.011), lower wound infection rates (4.5% vs. 10.1%, P = 0.005) and shorter length of postoperative hospital stay (15 days vs. 17 days, P = 0.001) compared to the OP group, with no significant differences in other perioperative outcomes. OS was comparable between the two groups (31 months vs. 28 months, P = 0.077); however, RFS was improved in the RP group (17 months vs. 14 months, P = 0.015). Subgroup analysis showed that patients who received adjuvant chemotherapy (AC) in the RP group had better RFS than the similar patient cohort in the OP group (17 months vs. 14 months, P = 0.024). CONCLUSION: Robotic pancreatectomy is safe and oncologically effective for resectable PDAC. OS was comparable between RP and OP, and RFS was improved in the RP group, especially in patients who receive AC.

Machine learning algorithms as early diagnostic tools for pancreatic fistula following pancreaticoduodenectomy and guide drain removal: A retrospective cohort study.

OBJECTIVE: Clinically relevant postoperative pancreatic fistula (CR-POPF) remains the major cause of morbidity following pancreaticoduodenectomy (PD). Several model score systems such as the Fistula Risk Score (FRS) have been developed to predict CR-POPF using preoperative and intraoperative data. Machine learning (ML) algorithms are increasingly applied in the medical field and they could be used to assess the risk of CR-POPF, identify clinically meaningful data and guide drain removal. METHODS: Data from consecutive patients who underwent PD between January 1, 2010 and March 31, 2021 at a single high-volume center was collected retrospectively in this study. Demographics, clinical features, intraoperative parameters, and laboratory values were used to conduct the ML model. Four different ML algorithms (CatBoost, lightGBM, XGBoost and Random Forest) were used to train this model with cross-validation. RESULTS: A total of 2421 patients with 62 clinical parameters were enrolled in this ML model. The majority of patients (76.3%) underwent open PD while others underwent robot-assisted PD. CR-POPF occurred in 424 (17.5%) patients. The CatBoost algorithm outperformed other algorithms with a mean area under the receiver operating characteristic curve (AUC) of 0.81 (95% confidence interval: 0.80-0.82) from the 5-fold cross-validation procedure. In the test dataset, the CatBoost algorithm also achieved the best mean-AUC of 0.83. The most important value was mean drain fluid amylase (DFA) in the first seven postoperative days (POD). The performance of models that used only preoperative data and intraoperative data was marginally lower than that of models that used combined data. CONCLUSION: Our ML algorithms could be applied as early diagnostic tools for CR-POPF in patients who underwent PD. Such real-time clinical decision support tools can identify patients with a high risk of CR-POPF, help in developing the perioperative management plan and guide the optimal timing of drain removal.

The CTCF/LncRNA-PACERR complex recruits E1A binding protein p300 to induce pro-tumour macrophages in pancreatic ductal adenocarcinoma via directly regulating PTGS2 expression.

BACKGROUND: Tumour-associated macrophages (TAMs) play an important role in promoting the progression of pancreatic ductal adenocarcinoma (PDAC). Here, we aimed to study the epigenetic mechanisms in regulating pro-tumour M2-polarised TAMs in the PDAC tumour microenvironment. METHODS: This study was conducted based on ex vivo TAMs isolated from PDAC tissues and in vitro THP1-derived TAM model. RNA-sequencing (RNA-seq), assay for transposase-accessible chromatin with sequencing and chromatin immunoprecipitation sequencing were performed to investigate gene expression, chromatin accessibility, transcription factor binding sites and histone modifications. Gene knockdown in THP1-derived TAMs was performed with lentivirus, and the impact of THP1-derived TAMs on invasion and metastasis ability of PDAC cells were investigated with in vitro and in vivo functional assays. RNA-chromatin interaction was analysed by chromatin isolation through RNA purification with sequencing. RNA-protein interaction was studied by RNA immunoprecipitation and RNA pull-down. RESULTS: Our data showed that the transcription factor CTCF (CCCTC-binding factor) was highly expressed in TAMs and predicted to be significantly enriched in hyper-accessible chromatin regions when compared to monocytes. High infiltration of CTCF+ TAMs was significantly associated with poor prognosis in PDAC patients. Knockdown of CTCF in THP1-derived TAMs led to the down-regulation of specific markers for M2-polarised TAMs, including CD206 and CD163. When THP1-derived TAMs with CTCF knockdown, they showed a decreased ability of invasion and metastasis. Further integrative analysis of multi-omics data revealed that prostaglandin-endoperoxide synthase 2 (PTGS2) and PTGS2 antisense NF-κB1 complex-mediated expression regulator RNA (PACERR) were critical downstream targets of CTCF and positively correlated with each other, which are closely situated on a chromosome. Knockdown of PACERR exhibited a similar phenotype as observed in CTCF knockdown THP1-derived TAMs. Moreover, PACERR could directly bind to CTCF and recruit histone acetyltransferase E1A binding protein p300 to the promoter regions of PACERR and PTGS2, thereby enhancing histone acetylation and gene transcription, promoting the M2 polarization of TAMs in PDAC. CONCLUSIONS: Our study demonstrated a novel epigenetic regulation mechanism of promoting pro-tumour M2-polarised TAMs in the PDAC tumour microenvironment.