Notch signaling regulates macrophage-mediated inflammation in metabolic dysfunction-associated steatotic liver disease.

The liver macrophage population comprises resident Kupffer cells (KCs) and monocyte-derived macrophages with distinct pro- or anti-inflammatory properties that affect the severity and course of liver diseases. The mechanisms underlying macrophage differentiation and functions in metabolic dysfunction-associated steatotic liver disease and/or steatohepatitis (MASLD/MASH) remain mostly unknown. Using single-cell RNA sequencing (scRNA-seq) and fate mapping of hepatic macrophage subpopulations, we unraveled the temporal and spatial dynamics of distinct monocyte and monocyte-derived macrophage subsets in MASH. We revealed a crucial role for the Notch-Recombination signal binding protein for immunoglobulin kappa J region (RBPJ) signaling pathway in controlling the monocyte-to-macrophage transition, with Rbpj deficiency blunting inflammatory macrophages and monocyte-derived KC differentiation and conversely promoting the emergence of protective Ly6Clo monocytes. Mechanistically, Rbpj deficiency promoted lipid uptake driven by elevated CD36 expression in Ly6Clo monocytes, enhancing their protective interactions with endothelial cells. Our findings uncover the crucial role of Notch-RBPJ signaling in monocyte-to-macrophage transition and will aid in the design of therapeutic strategies for MASH treatment.

Characterization of Pancreatic Fistula after Post-pancreatectomy Acute Pancreatitis.

OBJECTIVE: This study aimed to investigate the clinical significance and risk factors of postoperative pancreatic fistula (POPF) after post-pancreatectomy acute pancreatitis (PPAP) in patients who underwent pancreaticoduodenectomy (PD). SUMMARY BACKGROUND DATA: PPAP has been recognized as a critical factor in the pathophysiology of POPF after PD. METHODS: A total of 817 consecutive patients who underwent elective PD between January 2020 and June 2022 were included. PPAP and POPF were defined in accordance with the International Study Group for Pancreatic Surgery (ISGPS) definitions. Multivariate logistic analyses were performed to investigate the risk factors for POPF. Comparisons between PPAP-associated POPF and non-PPAP-associated POPF were made to further characterize this intriguing complication. RESULTS: Overall, 159 (19.5%) patients developed POPF after PD, of which 73 (45.9%) occurred following PPAP, and the remaining 86 (54.1%) had non-PPAP-associated POPF. Patients with PPAP-associated POPF experienced significantly higher morbidity than patients without POPF. Multivariate analyses revealed distinct risk factors for each POPF type. For PPAP-associated POPF, independent risk factors included estimated blood loss >200 mL (OR 1.93), MPD ≤3 cm (OR 2.88), and soft pancreatic texture (OR 2.01), largely overlapping with FRS (Fistula Risk Score) elements. On the other hand, non-PPAP-associated POPF was associated with age >65 years (OR 1.95), male (OR 2.10), and MPD ≤3 cm (OR 2.57). Notably, among patients with PPAP, the incidence of POPF consistently hovered around 50% regardless of the FRS stratification. CONCLUSIONS: PPAP-associated POPF presents as a distinct pathophysiology in the development of POPF after PD, potentially opening doors for future prevention strategies targeting the early postoperative period.

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.

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

OBJECTIVE: 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. One hundred thirty-four 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). CONCLUSIONS: Perioperative dexamethasone did not significantly reduce postoperative complications within 30 days after pancreaticoduodenectomy.

Immunogram defines four cancer-immunity cycle phenotypes with distinct clonal selection patterns across solid tumors.

BACKGROUND: The cancer-immunity cycle (CI cycle) provides a theoretical framework to illustrate the process of the anticancer immune response. Recently, the update of the CI cycle theory emphasizes the importance of tumor's immunological phenotype. However, there is lack of immunological phenotype of pan-cancer based on CI cycle theory. METHODS: Here, we applied a visualizing method termed 'cancer immunogram' to visualize the state of CI cycle of 8460 solid tumors from TCGA cohort. Unsupervised clustering of the cancer immunogram was performed using the nonnegative matrix factorization (NMF) analysis. We applied an evolutionary genomics approach (dN/dS ratio) to evaluate the clonal selection patterns of tumors with distinct immunogram subtypes. RESULTS: We defined four major CI cycle patterns across 32 cancer types using a cancer immunogram approach. Immunogram-I was characterized by 'hot' and 'exhausted' features, indicating a favorable prognosis. Strikingly, immunogram-II, immunogram-III, and immunogram-IV represented distinct immunosuppressive patterns of 'cold' tumor. Immunogram-II was characterized by 'cold' and 'radical' features, which represented increased expression of immune inhibitor molecules and high levels of positive selection, indicating the worst prognosis. Immunogram-III was characterized by 'cold' and 'recognizable' features and upregulated expression of MHC I molecules. Immunogram-IV was characterized by 'cold' and 'inert' features, which represented overall immunosuppression, lower levels of immunoediting and positive selection, and accumulation of more tumor neoantigens. In particular, favorable overall survival was observed in metastatic urothelial cancer patients with immunogram-I and immunogram-IV after immune checkpoint inhibitor (ICI) therapy. Meanwhile, a higher response rate to ICI therapy was observed in metastatic gastric cancer patients with immunogram-I phenotype. CONCLUSIONS: Our findings provide new insight into the interaction between immunity and cancer evolution, which may contribute to optimizing immunotherapy strategies.

Comprehensive analysis of KLF family reveals KLF6 as a promising prognostic and immune biomarker in pancreatic ductal adenocarcinoma.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest tumors worldwide, with extremely aggressive and complicated biology. Krüppel-like factors (KLFs) encode a series of transcriptional regulatory proteins and play crucial roles in a variety of processes, including tumor cell differentiation and proliferation. However, the potential biological functions and possible pathways of KLFs in the progression of PDAC remain elusive. METHODS: We systematically evaluated the transcriptional variations and expression patterns of KLFs in pancreatic cancer from the UCSC Xena. Based on difference analysis, the non-negative matrix factorization (NMF) algorithm was utilized to identify the immune characteristics and clinical significance of two different subtypes. The multivariate Cox regression was used to construct the risk model and then explore the differences in tumor immune microenvironment (TIME) and drug sensitivity between high and low groups. Through single-cell RNA sequencing (scRNA-seq) analysis, we screened KLF6 and further investigated its biological functions in pancreatic cancer and pan-cancer. RESULTS: The KLFs exhibited differential expression and mutations in the transcriptomic profile of PDAC. According to the expression of KLFs, patients were classified into two distinct subtypes, each exhibiting significant differences in prognosis and TIME. Moreover, the KLF signature was developed using univariate Cox and Lasso regression, which proved to be a reliable and effective prognostic model. Furthermore, the KLF_Score was closely associated with immune infiltration, response to immunotherapy, and drug sensitivity and we screened small molecule compounds targeting prognostic genes separately. Through scRNA-seq analysis, KLF6 was selected to further demonstrate its role in the malignance of PC in vitro. Finally, pan-cancer analysis emphasized the biological significance of KLF6 in multiple types of tumors and its clinical utility in assessing cancer prognosis. CONCLUSION: This study elucidated the pivotal role of KLF family genes in the malignant development of PC through comprehensive analysis and revealed that KLF6 would be a novel diagnostic biomolecule marker and potential therapeutic target for PDAC.

Enhancement pattern of the pancreatic parenchyma predicts postpancreatectomy acute pancreatitis after pancreaticoduodenectomy.

OBJECTIVES: To assess the association between the enhancement pattern of the pancreatic parenchyma on preoperative multiphasic contrast-enhanced computed tomography (CECT) and the occurrence of postpancreatectomy acute pancreatitis (PPAP) after pancreaticoduodenectomy (PD). METHODS: A total of 513 patients who underwent PD were retrospective enrolled. The CT attenuation values of the nonenhanced (N), arterial (A), portal venous (P), and late (L) phases in the pancreatic parenchyma were measured on preoperative multiphasic CECT. The enhancement pattern was quantized by the CT attenuation value ratios in each phase. Receiver operating characteristic (ROC) curve analyses were computed to evaluate predictive performance. Regression analyses were used to identify independent risk factors for PPAP. RESULTS: PPAP developed in 102 patients (19.9%) and was associated with increased morbidity and a worse postoperative course. The A/P ratio, P/L ratio, and A/L ratio were significantly higher in the PPAP group. On the ROC analysis, the A/L ratio and A/P ratio both performed well in predicting PPAP (A/L: AUC = 0.7579; A/P: AUC = 0.7497). On multivariate analyses, the A/L ratio > 1.29 (OR 4.30 95% CI: 2.62-7.06, p < 0.001) and A/P ratio > 1.13 (OR 5.02 95% CI: 2.98-8.45, p < 0.001) were both independent risk factors of PPAP in each model. CONCLUSIONS: The enhancement pattern of the pancreatic parenchyma on multiphasic preoperative CECT is a good predictor of the occurrence of PPAP after PD, which could help clinicians identify high-risk patients or enable selective enhance recovery protocols. CLINICAL RELEVANCE STATEMENT: Preoperative identification of patients at high risk for postpancreatectomy acute pancreatitis by enhancement patterns of the pancreatic parenchyma allows surgeons to tailor their perioperative management and take precautions. KEY POINTS: PPAP is associated with increased risk of postoperative complications and a worse postoperative course. A rapid-decrease enhancement pattern of the pancreatic parenchyma is related to the occurrence of PPAP. The A/L and A/P ratios were both independent risk factors of PPAP in each multivariate model.

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.

Impact of patient age on outcome of minimally invasive versus open pancreatoduodenectomy: a propensity score matched study.

BACKGROUND: Pancreatoduodenectomy in elderly patients may be associated with increased postoperative mortality, but studies in minimally invasive pancreatoduodenectomy (MIPD) are scarce. METHODS: International multicenter retrospective study including patients aged >60 years undergoing MIPD (robot-assisted and laparoscopic) and open pancreatoduodenectomy (OPD), were categorized by age: 60-69, 70-79, and 80+ years. In each category, propensity score matching (PSM) was performed (1:1 ratio) between MIPD and OPD. Primary outcome was 30-day/in-hospital mortality. RESULTS: Among 3820 patients, we matched 1468 patients aged 60-69, 1154 patients aged 70-79, and 196 patients aged 80+ years. In patients aged 60-69 and 70-79 years, MIPD was associated with longer operative time, less blood loss and a longer length of stay. Major morbidity was higher after MIPD with similar 30-day/in-hospital mortality. The R0 resection rate was higher after MIPD. In patients aged 80+ years, besides a longer operative time in MIPD, outcomes were comparable between both groups. CONCLUSION: This study found no evidence that increasing age worsens mortality of MIPD. MIPD was associated with longer operative time, higher rate of major morbidity, prolonged length of stay versus less blood loss and a higher R0 resection in patients aged 60-69 and 70-79 years. These differences continue in patients aged 80+ years, but became less evident.

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.

Postpancreatectomy Acute Pancreatitis After Pancreaticoduodenectomy: A Distinct Clinical Entity.

OBJECTIVE: This study aimed to characterize postpancreatectomy acute pancreatitis (PPAP) after pancreaticoduodenectomy (PD) in a high-volume center. BACKGROUND: The International Study Group for Pancreatic Surgery (ISGPS) has recently proposed a new definition and grading scale of PPAP, but specific studies are lacking. METHODS: Patients who underwent PD from 2020 to 2021 were retrospectively reviewed. PPAP was defined based on the International Study Group for Pancreatic Surgery definition: sustained elevation of serum amylase levels for least the first 48 hours postoperatively and radiologic alterations consistent with PPAP. RESULTS: Among a total of 716 patients who were finally analyzed, PPAP occurred in 152 (21.2%) patients. Patients with PPAP were associated with significantly higher incidences of postoperative pancreatic fistula (POPF) (40.8% vs 11.7%, P <0.001), major complications (13.8% vs 6.6%, P =0.004), and biliary leak (11.8% vs 4.6%, P =0.001). Among them, 8 patients developed grade C PPAP leading to organ failure, reoperation, or death. Patients developing PPAP alone also demonstrated a statistically significantly increased rate of major complications than those without PPAP or POPF. In contrast, no differences were found in postoperative outcomes in patients with POPF in terms of whether they were associated with PPAP. CONCLUSION: PPAP is a distinct complication after PD with distinctive clinical outcomes. A part of PPAP presents as an inflammatory process in the early postoperative period but sometimes could lead to necrotizing pancreatitis or other severe clinical scenarios, and another part of PPAP would lead to anastomotic failure that accounts for a great proportion of POPF occurrence.

Identification of a novel immune checkpoint molecule V-set immunoglobulin domain-containing 4 that leads to impaired immunity infiltration in pancreatic ductal adenocarcinoma.

BACKGROUND: Checkpoint-based immunotherapy has failed to elicit responses in the majority of patients with pancreatic cancer. In our study, we aimed to identify the role of a novel immune checkpoint molecule V-set Ig domain-containing 4 (VSIG4) in pancreatic ductal adenocarcinoma (PDAC). METHODS: Online datasets and tissue microarray (TMA) were utilized to analyze the expression level of VSIG4 and its correlation with clinical parameters in PDAC. CCK8, transwell assay and wound healing assay were applied to explore the function of VSIG4 in vitro. Subcutaneous, orthotopic xenograft and liver metastasis model was established to explore the function of VSIG4 in vivo. TMA analysis and chemotaxis assay were conducted to uncover the effect of VSIG4 on immune infiltration. Histone acetyltransferase (HAT) inhibitors and si-RNA were applied to investigate factors that regulate the expression of VSIG4. RESULTS: Both mRNA and protein levels of VSIG4 were higher in PDAC than normal pancreas in TCGA, GEO, HPA datasets and our TMA. VSIG4 showed positive correlations with tumor size, T classification and liver metastasis. Patients with higher VSIG4 expression were related to poorer prognosis. VSIG4 knockdown impaired the proliferation and migration ability of pancreatic cancer cells both in vitro and in vivo. Bioinformatics study showed positive correlation between VSIG4 and infiltration of neutrophil and tumor-associated macrophages (TAMs) in PDAC, and it inhibited the secretion of cytokines. According to our TMA panel, high expression of VSIG4 was correlated with fewer infiltration of CD8+ T cells. Chemotaxis assay also showed knockdown of VSIG4 increased the recruitment of total T cells and CD8+ T cells. HAT inhibitors and knockdown of STAT1 led to decreased expression of VSIG4. CONCLUSIONS: Our data indicate that VSIG4 contributes to cell proliferation, migration and resistance to immune attack, thus identified as a promising target for PDAC treatment with good prognostic value.

TP53 missense mutation reveals gain-of-function properties in small-sized KRAS transformed pancreatic ductal adenocarcinoma.

BACKGROUND: Although the molecular features of pancreatic ductal adenocarcinoma (PDAC) have been well described, the impact of detailed gene mutation subtypes on disease progression remained unclear. This study aimed to evaluate the impact of different TP53 mutation subtypes on clinical characteristics and outcomes of patients with PDAC. METHODS: We included 639 patients treated with PDAC in Ruijin Hospital affiliated to Shanghai Jiaotong University School of Medicine between Jan 2019 and Jun 2021. The genomic alterations of PDAC were analyzed, and the association of TP53 mutation subtypes and other core gene pathway alterations with patients' clinical characteristics were evaluated by Chi-squared test, Kaplan-Meier method and Cox regression model. RESULTS: TP53 missense mutation was significantly associated with poor differentiation in KRASmut PDAC (50.7% vs. 36.1%, P = 0.001). In small-sized (≤ 2 cm) KRASmut tumors, significantly higher LNs involvement (54.8% vs. 23.5%, P = 0.010) and distal metastic rate (20.5% vs. 2.9%, P = 0.030) were observed in those with TP53 missense mutation instead of truncating mutation. Compared with TP53 truncating mutation, missense mutation was significantly associated with reduced DFS (6.6 [5.6-7.6] vs. 9.2 [5.2-13.3] months, HR 0.368 [0.200-0.677], P = 0.005) and OS (9.6 [8.0-11.1] vs. 18.3 [6.7-30.0] months, HR 0.457 [0.248-0.842], P = 0.012) in patients who failed to receive chemotherapy, while higher OS (24.2 [20.8-27.7] vs. 23.8 [19.0-28.5] months, HR 1.461 [1.005-2.124], P = 0.047) was observed in TP53missense cases after chemotherapy. CONCLUSIONS: TP53 missense mutation was associated with poor tumor differentiation, and revealed gain-of-function properties in small-sized KRAS transformed PDAC. Nonetheless, it was not associated with insensitivity to chemotherapy, highlighting the neoadjuvant therapy before surgery as the potential optimized strategy for the treatment of a subset of patients.

LIPH contributes to glycolytic phenotype in pancreatic ductal adenocarcinoma by activating LPA/LPAR axis and maintaining ALDOA stability.

BACKGROUND: LIPH, a membrane-associated phosphatidic acid-selective phospholipase A1a, can produce LPA (Lysophosphatidic acid) from PA (Phosphatidic acid) on the outer leaflet of the plasma membrane. It is well known that LIPH dysfunction contributes to lipid metabolism disorder. Previous study shows that LIPH was found to be a potential gene related to poor prognosis with pancreatic ductal adenocarcinoma (PDAC). However, the biological functions of LIPH in PDAC remain unclear. METHODS: Cell viability assays were used to evaluate whether LIPH affected cell proliferation. RNA sequencing and immunoprecipitation showed that LIPH participates in tumor glycolysis by stimulating LPA/LPAR axis and maintaining aldolase A (ALDOA) stability in the cytosol. Subcutaneous, orthotopic xenograft models and patient-derived xenograft PDAC model were used to evaluate a newly developed Gemcitabine-based therapy. RESULTS: LIPH was significantly upregulated in PDAC and was related to later pathological stage and poor prognosis. LIPH downregulation in PDAC cells inhibited colony formation and proliferation. Mechanistically, LIPH triggered PI3K/AKT/HIF1A signaling via LPA/LPAR axis. LIPH also promoted glycolysis and de novo synthesis of glycerolipids by maintaining ALDOA stability in the cytosol. Xenograft models show that PDAC with high LIPH expression levels was sensitive to gemcitabine/ki16425/aldometanib therapy without causing discernible side effects. CONCLUSION: LIPH directly bridges PDAC cells and tumor microenvironment to facilitate aberrant aerobic glycolysis via activating LPA/LPAR axis and maintaining ALDOA stability, which provides an actionable gemcitabine-based combination therapy with limited side effects.

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.

Drain fluid volume combined with amylase level predicts clinically relevant postoperative pancreatic fistula after pancreaticoduodenectomy: A retrospective clinical study.

BACKGROUND AND AIM: Several indicators are recognized in the development of clinically relevant postoperative pancreatic fistula (CR-POPF) after pancreaticoduodenectomy (PD). However, drain fluid volume (DFV) remains poorly studied. We aimed to discover the predictive effects of DFV and guide clinical management. METHODS: We retrospectively reviewed the clinical data of patients that received PD between January 2015 and December 2019 in a high-volume center. DFV was analyzed as a potential risk factor and postoperative short-term outcomes as well as drain removal time were compared stratified by different DFV levels. Receiver operating characteristic curves and area under curves (AUC) were compared for DFV alone and DFV combined with drain fluid amylase (DFA). Subgroup analysis of DFV stratified by DFA evaluated the predictability of CR-POPF. RESULTS: CR-POPF occurred in 19.7% of 841 patients. Hypertension, postoperative day 3 (POD3) DFA ≥ 300 U/L, and POD3 DFV ≥ 30 mL were independent risk factors, while pancreatic main duct diameter ≥ 3 mm was a protective factor. POD3 DFV ≥ 30 mL increased the overall occurrences of CR-POPF and major complications (P = 0.017; P = 0.029). POD3 DFV alone presented a low predictive value (AUC 0.602), while POD3 DFV combined with DFA had a high predictive value (AUC 0.759) for CR-POPF. Subgroup analysis showed that the combination of POD3 DFV ≥ 30 mL and DFA ≥ 300 U/L led to higher incidences of CR-POPF (P = 0.003). CONCLUSION: CR-POPF is common after PD, and high DFV combined with DFA may predict its occurrence and facilitate appropriate management.

Impact of the transection plan on postoperative pancreatic fistulas occurring after robot-assisted distal pancreatectomy for nonmalignant pancreatic neoplasms.

OBJECTIVES: Postoperative pancreatic fistula (POPF) is the main complication of distal pancreatectomy (DP) and affects the prognosis of patients. The impact of several clinical factors mentioned in recent studies on POPF remains controversial. This study aimed to investigate the impact of a remnant pancreas and other perioperative factors on POPFs occurring after robot-assisted distal pancreatectomy (RDP) for nonmalignant pancreatic neoplasms. METHODS: A total of 197 patients who received robot-assisted distal pancreatectomy (RDP) for nonmalignant pancreatic neoplasms at the Pancreatic Disease Center, Ruijin Hospital Shanghai Jiaotong University School of Medicine from January 2018 to December 2020 were included in this retrospective study. According to the intraoperative transection plan, patients were divided into an RDP body group and an RDP tail group. Clinical and pathological features and perioperative factors affecting POPF were analyzed and compared between the two groups. RESULTS: The results showed that a transection plan involving the tail of the pancreas (OR = 2.133, 95% CI 1.109-4.103, p = 0.023) and spleen preservation (OR = 2.588, 95% CI 1.435-4.665, p = 0.001) independently increased the incidence of POPF in patients with nonmalignant pancreatic neoplasms treated by RDP. A transection plan involving the tail of the pancreas was also an independent risk factor (OR = 3.464, 95% CI 1.270-9.450, p = 0.015) for grade B/C POPF. Length of remnant pancreas > 6.23 cm was an independent risk factor for POPF (OR = 3.116, 95% CI 1.364-7.121, p = 0.007). Length of remnant pancreas > 9.82 cm was an independent risk factor for grade B/C POPF (OR = 3.340, 95% CI 1.386-8.051, p = 0.007). CONCLUSION: This retrospective study suggests that a transection plan involving the tail of the pancreas is an independent risk factor for POPF in patients with nonmalignant neoplasms treated by RDP. We also propose that the postoperative length of the remnant pancreas evaluated by computed tomography scans can be used to identify patients with a high risk of POPF in order to optimize the individualized strategy.

A Novel Criterion for Lymph Nodes Dissection in Distal Pancreatectomy for Ductal Adenocarcinoma: A Population Study of the US SEER Database.

OBJECTIVE: The aim of this study was to clarify the minimum number of examined lymph nodes (MNELNs) required to ensure the quality of lymph node detection and its impact on long-term survival in distal pancreatectomy for pancreatic ductal adenocarcinoma. METHODS: Clinicopathological characteristics and survival data of patients with resectable pancreatic cancer who underwent distal pancreatectomy between 2004 and 2017 were collected from the Surveillance, Epidemiology, and End Results database. The associations between the number of examined lymph nodes (ELNs) and number of positive lymph nodes (PLNs), stage migration, and overall survival were investigated through adjusted multivariate models with locally weighted scatterplot smoothing smoothing fitting curves and estimation of the structural breakpoints. Kaplan-Meier survival analysis and X-tile software were used to identify the ideal cut-off value for ELNs. RESULTS: In total, 2610 consecutive patients who underwent distal pancreatectomy between 2004 and 2017 were included in this study. The optimal ELN count according to the associations between the number of ELNs and number of PLNs, odds ratio for stage migration, or hazard ratio for overall survival were 19, 17, and 19, respectively. Furthermore, the optimal division of ELN count for maximum overall survival was divided into three populations (ELN ≤ 8, ELN 9-18, ELN ≥ 19) based on X-tile software. CONCLUSION: A minimal count of 19 lymph nodes was demanded to guarantee the quality of lymph node examination in patients with distal pancreatectomy. Long-term survival could be delimited by MNELNs. A sufficient number of ELNs could improve the accuracy of cancer staging and reflect a better overall survival.

Postoperative hyperprogression disease of pancreatic ductal adenocarcinoma after curative resection: a retrospective cohort study.

BACKGROUND: Prognosis for patients recurred rapidly after resection of pancreatic ductal adenocarcinoma (PDAC) was extremely poor. We proposed the concept of postoperative hyper-progression disease (PO-HPD) to define recurrence within 2 months after surgery, explored the role of surgery for postoperative HPD patients and determined the predictive preoperative risk factors and genomic features of PO-HPD. METHODS: 976 patients undergoing curative resection of PDAC were enrolled. Survival data of 1733 stage IV patients from the US Surveillance, Epidemiology and End Results database was also collected. Patients relapsed were grouped into 3 groups regarding of the recurrence time (within 2 months were PO-HPD, within 2 to 12 months were early recurrence (ER) and within > 12 months were late recurrence (LR)). Risk factors for PO-HPD were explored with logistic regression models. Genomic features of 113 patients were investigated using next-generation sequencing-based gene panel testing. RESULTS: 718 of 976 cases relapsed, 101were PO-HPD, 418 were ER and 199 were LR. Total survival of PO-HPD was 12.5 months, shorter than that of ER (16.7 months) and LR (35.1 months), and verged on that of stage IV patients (10.6 months). Preoperative risk factors for PO-HPD included red blood cell count < 3.94*10^12/L, CA19-9 ≥ 288.6 U/mL, CA125 ≥ 22.3 U/mL and tumor size≥3.45 cm. Mutations of CEBPA, ATR and JAK1 were only identified in PO-HPD and they owned lower level of CN gain compared to others. CONCLUSIONS: Prognosis of PO-HPD was extremely poor and the role of surgery for PO-HPD should be prudently assessed.

Serum lipase on postoperative day one is a strong predictor of clinically relevant pancreatic fistula after pancreaticoduodenectomy: A retrospective cohort.

BACKGROUND: Increased postoperative serum amylase has been recently reported to be associated with increased postoperative morbidity, but studies on postoperative serum lipase are limited. The aim of this study was to evaluate the value of postoperative serum lipase in predicting clinically relevant postoperative pancreatic fistula (CR-POPF) after pancreaticoduodenectomy (PD). METHOD: A retrospective analysis was performed on 212 patients who underwent PD from September 2018 and March 2021, focusing on the association between postoperative day (POD) 1 serum lipase and CR-POPF. RESULTS: Overall, 108 (50.9%) patients had elevated serum lipase levels (>68 U/L) on POD 1. Patients with elevated serum lipase exhibited a significantly higher incidence of CR-POPF (37.0% vs. 6.7%, p < 0.001). Receiver operating characteristic (ROC) analyses showed improved diagnostic accuracy for POD 1 serum lipase compared with POD 1 serum amylase in predicting CR-POPF (AUC: 0.801 vs. 0.745, p = 0.029). Elevated serum lipase on POD 1 and elevated serum CRP on POD 3 were identified as independent predictors of CR-POPF. A simple early postoperative model, consisting of POD 1 serum lipase levels and POD 3 serum CRP levels, showed good discrimination (AUC 0.76, 95% CI 0.69-0.83) to identify the onset of CR-POPF. CONCLUSION: Serum lipase on POD 1 outperformed serum amylase on POD 1 in predicting CR-POPF after PD. The combination of POD 1 serum lipase and POD 3 serum CRP provides a reliable predicting model for CR-POPF.