In vivo CRISPR screens identify Mga as an immunotherapy target in triple-negative breast cancer.

Immune evasion is not only critical for tumor initiation and progression, but also determines the efficacy of immunotherapies. Through iterative in vivo CRISPR screens with seven syngeneic tumor models, we identified core and context-dependent immune evasion pathways across cancer types. This valuable high-confidence dataset is available for the further understanding of tumor intrinsic immunomodulators, which may lead to the discovery of effective anticancer therapeutic targets. With a focus on triple-negative breast cancer (TNBC), we found that Mga knock-out significantly enhances antitumor immunity and inhibits tumor growth. Transcriptomics and single-cell RNA sequencing analyses revealed that Mga influences various immune-related pathways in the tumor microenvironment. Our findings suggest that Mga may play a role in modulating the tumor immune landscape, though the precise mechanisms require further investigation. Interestingly, we observed that low MGA expression in breast cancer patients correlates with a favorable prognosis, particularly in those with active interferon-γ signaling. These observations provide insights into tumor immune escape mechanisms and suggest that further exploration of MGA's function could potentially lead to effective therapeutic strategies in TNBC.

Role of a novel circRNA-CGNL1 in regulating pancreatic cancer progression via NUDT4-HDAC4-RUNX2-GAMT-mediated apoptosis.

BACKGROUND: Pancreatic cancer (PC) is an extremely malignant tumor with low survival rate. Effective biomarkers and therapeutic targets for PC are lacking. The roles of circular RNAs (circRNAs) in cancers have been explored in various studies, however more work is needed to understand the functional roles of specific circRNAs. In this study, we explore the specific role and mechanism of circ_0035435 (termed circCGNL1) in PC. METHODS: qRT-PCR analysis was performed to detect circCGNL1 expression, indicating circCGNL1 had low expression in PC cells and tissues. The function of circCGNL1 in PC progression was examined both in vitro and in vivo. circCGNL1-interacting proteins were identified by performing RNA pulldown, co-immunoprecipitation, GST-pulldown, and dual-luciferase reporter assays. RESULTS: Overexpressing circCGNL1 inhibited PC proliferation via promoting apoptosis. CircCGNL1 interacted with phosphatase nudix hydrolase 4 (NUDT4) to promote histone deacetylase 4 (HDAC4) dephosphorylation and subsequent HDAC4 nuclear translocation. Intranuclear HDAC4 mediated RUNX Family Transcription Factor 2 (RUNX2) deacetylation and thereby accelerating RUNX2 degradation. The transcription factor, RUNX2, inhibited guanidinoacetate N-methyltransferase (GAMT) expression. GAMT was further verified to induce PC cell apoptosis via AMPK-AKT-Bad signaling pathway. CONCLUSIONS: We discovered that circCGNL1 can interact with NUDT4 to enhance NUDT4-dependent HDAC4 dephosphorylation, subsequently activating HDAC4-RUNX2-GAMT-mediated apoptosis to suppress PC cell growth. These findings suggest new therapeutic targets for PC.

High pyroptosis activity in pancreatic adenocarcinoma: poor prognosis and oxaliplatin resistance.

BACKGROUND: Pyroptosis, as a type of inflammatory programmed cell death, has been studied in inflammatory diseases and numerous cancers but its role in pancreatic ductal adenocarcinoma (PDAC) remains further exploration. METHODS: A TCGA-PDAC cohort was enrolled for bioinformatics analysis to investigate the effect of pyroptosis on the prognosis and drug sensitivity of patients. PA-TU-8988T and CFPAC-1 cells were selected for investigating the role of GSDMC in PDAC. RESULTS: A distinct classification pattern of PDAC mediated by 21 pyroptosis-related genes (PRGs) was identified. It was suggested that higher pyroptosis activity was associated with poor prognosis of patients and higher tumor proliferation rates. We further established a prognostic model based on three PRGs (GSDMC, CASP4 and NLRP1) and the TCGA-PDAC cohort was classified into low and high-risk subgroups. It is noteworthy that the high-risk group showed significantly higher tumor proliferation rates and was proved to be highly correlated with oxaliplatin resistance. Further experiments suggested that overexpression of GSDMC promoted the proliferation and oxaliplatin resistance of PA-TU-8988T cells in vitro and vivo, while downregulation of GSDMC showed opposite effects in CFPAC-1 cells. Finally, we found that the activation of pentose phosphate pathway (PPP) was the mechanism by which GSDMC overexpression promoted the proliferation and oxaliplatin resistance of pancreatic cancer cells. CONCLUSIONS: In this study, we found that higher pyroptosis activity is associated with worse prognosis and oxaliplatin resistance of PDAC patients. In addition, as a core effector of pyroptosis, GSDMC promoted proliferation and oxaliplatin resistance of pancreatic cancer cells, which will provide new therapeutic target for PDAC patients.

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.

Interobserver Variability in the International Study Group for Pancreas Surgery (ISGPS)-Defined Complications After Pancreatoduodenectomy: An International Cross-Sectional Multicenter Study.

OBJECTIVE: To determine the interobserver variability for complications of pancreatoduodenectomy as defined by the International Study Group for Pancreatic Surgery (ISGPS) and others. SUMMARY BACKGROUND DATA: Good interobserver variability for the definitions of surgical complications is of major importance in comparing surgical outcomes between and within centers. However, data on interobserver variability for pancreatoduodenectomy-specific complications are lacking. METHODS: International cross-sectional multicenter study including 52 raters from 13 high-volume pancreatic centers in 8 countries on 3 continents. Per center, 4 experienced raters scored 30 randomly selected patients after pancreatoduodenectomy. In addition, all raters scored six standardized case vignettes. This variability and the 'within centers' variability were calculated for twofold scoring (no complication/grade A vs grade B/C) and threefold scoring (no complication/grade A vs grade B vs grade C) of postoperative pancreatic fistula (POPF), post-pancreatoduodenectomy hemorrhage (PPH), chyle leak (CL), bile leak (BL), and delayed gastric emptying (DGE). Interobserver variability is presented with Gwet's AC-1 measure for agreement. RESULTS: Overall, 390 patients after pancreatoduodenectomy were included. The overall agreement rate for the standardized cases vignettes for twofold scoring was 68% (95%-CI: 55%-81%, AC1 score: moderate agreement) and for threefold scoring 55% (49%-62%, AC1 score: fair agreement). The mean 'within centers' agreement for twofold scoring was 84% (80%-87%, AC1 score; substantial agreement). CONCLUSION: The interobserver variability for the ISGPS defined complications of pancreatoduodenectomy was too high even though the 'within centers' agreement was acceptable. Since these findings will decrease the quality and validity of clinical studies, ISGPS has started efforts aimed at reducing the interobserver variability.

Clinical and Financial Validation of the International Study Group for Pancreatic Surgery (ISGPS) Definition of Post-Pancreatectomy Acute Pancreatitis (PPAP): International Multicenter Prospective Study.

OBJECTIVE: To validate the ISGPS definition and grading system of PPAP after pancreatoduodenectomy (PD). SUMMARY BACKGROUND DATA: In 2022, the International Study Group for Pancreatic Surgery (ISGPS) defined post-pancreatectomy acute pancreatitis (PPAP) and recommended a prospective validation of its diagnostic criteria and grading system. METHODS: This was a prospective, international, multicenter study including patients undergoing PD at 17 referral pancreatic centers across Europe, Asia, Oceania, and the United States. PPAP diagnosis required the following three parameters: (1) postoperative serum hyperamylasemia /hyperlipasemia (POH) persisting on postoperative days 1 and 2, (2) radiologic alterations consistent with PPAP, and (3) a clinically relevant deterioration in the patient's condition. To validate the grading system, clinical and economic parameters were analyzed across all grades. RESULTS: Among 2902 patients undergoing PD, 7.5% (n=218) developed PPAP (6.3% grade B and 1.2% grade C). POH occurred in 24.1% of patients. Hospital stay was associated with PPAP grades (No POH/PPAP 10 days (IQR 7-17) days, grade B 22 days (IQR 15-34) days, and grade C 43 days (IQR 27-54) days; P<0.001), as well as intensive care unit admission (No POH/PPAP 5.4%, grade B 12.6%, grade C 82.9%; P<0.010), and hospital readmission rates (No POH/PPAP 7.3%, grade B 16.1%, grade C 18.5%; P<0.05). Costs of grade B and C PPAP were 2 and 11 times greater than uncomplicated clinical course, resp. (P<0.001). CONCLUSIONS: This first prospective, international validation study of the ISGPS definition and grading system for PPAP highlighted the relevant clinical and financial implications of this condition. These results stress the importance of routine screening for PPAP in patients undergoing PD.

Peptidase inhibitor 16 promotes proliferation of pancreatic ductal adenocarcinoma cells through OASL signaling.

Pancreatic ductal adenocarcinoma (PDAC) is a highly invasive cancer with a poor prognosis and a 5-year survival rate of less than 11%. As a member of the CAP superfamily of proteins, the role of peptidase inhibitor 16 (Pi16) in tumor progression is still unclear. Immunohistochemistry and quantitative RT-PCR methods were used to detect the expression levels of Pi16 protein and mRNA in PDAC patients. CRISPR/Cas9 technology was used to knock out the expression of Pi16 in PDAC cell lines. In vivo and in vitro experiments were used to verify the effect of Pi16 on PDAC proliferation ability. By RNA sequencing, we found that oligoadenylate synthetase L (OASL) can serve as a potential downstream target of Pi16. The expression of Pi16 was higher in PDAC tissues than in matched adjacent tissues. High expression of Pi16 was associated with PDAC progression and poor prognosis. Overexpression of Pi16 could promote the proliferation of PDAC cells in vitro and in vivo. Bioinformatics analysis and coimmunoprecipitation assays showed that Pi16 could bind to OASL. Moreover, the functional recovery test confirmed that Pi16 could promote the proliferation of PDAC via OASL. Our present study demonstrates that Pi16 might participate in the occurrence and development of PDAC by regulating cell proliferation by binding to OASL, indicating that Pi16 might be a promising novel therapeutic target for PDAC.

Efficiency evaluation of dual-energy CT to predict the postoperative early recurrence of pancreatic ductal adenocarcinoma.

OBJECTIVES: To evaluate the efficacy of quantitative parameters from dual-energy CT (DECT) and basic CT features in predicting the postoperative early recurrence (ER) of pancreatic ductal adenocarcinoma (PDAC). METHODS: In this study, patients with PDAC who underwent radical resection and DECT from 2018 to 2022 were enrolled and categorised into ER and non-ER groups. The clinical data, basic CT features and DECT parameters of all patients were analyzed. Independent predictors of ER were identified with Logistic regression analyses. Three models (model A: basic CT features; model B: DECT parameters; model C: basic CT features + DECT parameters) were established. Receiver operating characteristic curve analysis was utilized to evaluate predictive performance. RESULTS: A total of 150 patients were enrolled (ER group: n = 63; non-ER group: n = 87). Rim enhancement (odds ratio [OR], 3.32), peripancreatic strands appearance (OR, 2.68), electron density in the pancreatic parenchymal phase (P-Rho; OR, 0.90), arterial enhancement fraction (AEF; OR, 0.05) and pancreatic parenchyma fat fraction in the delayed phase (OR, 1.25) were identified as independent predictors of ER. Model C showed the highest area under the curve of 0.898. In addition, the corresponding ER risk factors were identified separately for resectable and borderline resectable PDAC subgroups. CONCLUSIONS: DECT quantitative parameters allow for the noninvasive prediction of postoperative ER in patients with PDAC, and the combination of DECT parameters and basic CT features shows a high prediction efficiency. Our model can help to identify patients with high-risk factors to guide preoperative decision making.

Extracellular volume fraction derived from dual-energy CT: a potential predictor for acute pancreatitis after pancreatoduodenectomy.

OBJECTIVES: To investigate the value of extracellular volume (ECV) fraction and fat fraction (FF) derived from dual- energy CT (DECT) for predicting postpancreatectomy acute pancreatitis (PPAP) after pancreatoduodenectomy (PD). METHODS: This retrospective study included patients who underwent DECT and PD between April 2022 and September 2022. PPAP was determined according to the International Study Group for Pancreatic Surgery (ISGPS) definition. Iodine concentration (IC) and FF of the pancreatic parenchyma were measured on preoperative DECT. The ECV fraction was calculated from iodine map images of the equilibrium phase. The independent predictors for PPAP were assessed by univariate and multivariable logistic regression analysis and receiver operating characteristic (ROC) curve analysis. RESULTS: Sixty-nine patients were retrospectively enrolled (median age, 60 years; interquartile range, 55-70 years; 47 men). Of these, nine patients (13.0%) developed PPAP. These patients had lower portal venous phase IC, equilibrium phase IC, FF, and ECV fraction, and higher pancreatic parenchymal-to-portal venous phase IC ratio and pancreatic parenchymal-to-equilibrium phase IC ratio, compared with patients without PPAP. After multivariable analysis, ECV fraction was independently associated with PPAP (odd ratio [OR], 0.87; 95% confidence interval [CI]: 0.79, 0.96; p < 0.001), with an area under the curve (AUC) of 0.839 (sensitivity 100.0%, specificity 58.3%). CONCLUSIONS: A lower ECV fraction is independently associated with the occurrence of PPAP after PD. ECV fraction may serve as a potential predictor for PPAP after PD. CLINICAL RELEVANCE STATEMENT: DECT-derived ECV fraction of pancreatic parenchyma is a promising biomarker for surgeons to preoperatively identify patients with higher risk for postpancreatectomy acute pancreatitis after PD and offer selective perioperative management. KEY POINTS: PPAP is a complication of pancreatic surgery, early identification of higher-risk patients allows for risk mitigation. Lower DECT-derived ECV fraction was independently associated with the occurrence of PPAP after PD. DECT aids in preoperative PAPP risk stratification, allowing for appropriate treatment to minimize complications.

Comprehensive prognostic and immune analysis of a glycosylation related risk model in pancreatic cancer.

BACKGROUND: Pancreatic cancer (PC) is a malignant tumor with extremely poor prognosis, exhibiting resistance to chemotherapy and immunotherapy. Nowadays, it is ranked as the third leading cause of cancer-related mortality. Glycation is a common epigenetic modification that occurs during the tumor transformation. Many studies have demonstrated a strong correlation between glycation modification and tumor progression. However, the expression status of glycosylation-related genes (GRGs) in PC and their potential roles in PC microenvironment have not been extensively investigated. METHOD: We systematically integrated RNA sequencing data and clinicopathological parameters of PC patients from TCGA and GTEx databases. A GRGs risk model based on glycosylation related genes was constructed and validated in 60 patients from Pancreatic biobank via RT-PCR. R packages were used to analyze the relationships between GRGs risk scores and overall survival (OS), tumor microenvironment, immune checkpoint, chemotherapy drug sensitivity and tumor mutational load in PC patients. Panoramic analysis was performed on PC tissues. The function of B3GNT8 in PC was detected via in vitro experiments. RESULTS: In this study, we found close correlations between GRGs risk model and PC patients' overall survival and tumor microenvironment. Multifaceted predictions demonstrated the low-risk cohort exhibits superior OS compared to high-risk counterparts. Meanwhile, the low-risk group was characterized by high immune infiltration and may be more sensitive to immunotherapy or chemotherapy. Panoramic analysis was further confirmed a significant relationship between the GRGs risk score and both the distribution of PC tumor cells as well as CD8 + T cell infiltration. In addition, we also identified a unique glycosylation gene B3GNT8, which could suppress PC progression in vitro and in vivo. CONCLUSION: We established a GRGs risk model, which could predict prognosis and immune infiltration in PC patients. This risk model may provide a new tool for PC precision treatment.

Management and Outcome of Blunt Pancreatic Trauma: A Retrospective Cohort Study.

BACKGROUND: Pancreatic injury is rare, but it has a high mortality rate and its optimal treatment remains controversial. This study aimed to evaluate the clinical characteristics, management strategies, and outcomes of patients with blunt pancreatic injury. METHODS: This retrospective cohort study was performed on patients with a confirmed blunt pancreatic injury who were admitted to our hospital from March 2008 to December 2020. The clinical characteristics and outcomes of patients receiving different management strategies were compared. The risk factors for in-hospital mortality were evaluated by performing a multivariate regression analysis. RESULTS: A total of 98 patients diagnosed with blunt pancreatic injury were identified, with 40 patients having undergone nonoperative treatment (NOT) and 58 patients having undergone surgical treatment (ST). The overall in-hospital deaths were 6 (6.1%), including 2 (5.0%) and 4 (6.9%) in the NOT and ST groups, respectively. Pancreatic pseudocysts occurred in 15 (37.5%) and 3 (5.2%) of the NOT and ST groups, respectively, showing a significant difference between the two groups (P < 0.001). In the multivariate regression analysis, concomitant duodenal injury (OR = 14.42, 95% CI 1.27-163.52; P = 0.031) and sepsis (OR = 43.47, 95% CI, 4.15-455.75; P = 0.002) were independently associated with in-hospital mortality. CONCLUSIONS: Except for the higher incidence of pancreatic pseudocysts in the NOT group than in the ST group, there were no significant differences in the other clinical outcomes between the two groups. Concomitant duodenal injury and sepsis were the risk factors for in-hospital mortality.

Perioperative safety and prognosis following parenchyma-preserving surgery for solid pseudopapillary neoplasm of the pancreas.

BACKGROUND/OBJECTIVES: To evaluate perioperative safety and outcome of parenchyma-preserving pancreatectomy and risk factors of metastasis and recurrence for patients with solid pseudopapillary neoplasm (SPN). METHODS: Demographic data, operative and pathological parameter, follow-up data of patients with SPN undergoing their first operation were collected in our single center from May 2016 to October 2021 and compared between regular pancreatectomy group and parenchyma-preserving surgery group. Risk factors for metastasis and recurrence were investigated. RESULTS: A total of 194 patients were included, 154 of whom were female and the average age of all patients was 33 years old. Most patients were asymptomatic, with the most common complaint being abdominal pain or discomfort. Of them, 62 patients underwent parenchyma-preserving pancreatectomy including middle segment pancreatectomy and enucleation, and 132 patients underwent regular pancreatectomy including pancreaticoduodenectomy, distal pancreatectomy and total pancreatectomy. Patients in the parenchyma-preserving surgery group had a shorter duration of operation, less intraoperative bleeding, and decreased risk of combined organ removal and blood transfusion, with no statistical significance yet. The two groups exhibited a similar incidence of postoperative complications including grade B and C pancreatic fistula, delayed gastric emptying, postoperative pancreatic hemorrhage, and other complications, as well as radiological intervention, relaparotomy and the length of postoperative hospital stay. There were no perioperative deaths. All the patients, except 18 of those who discontinued follow-up, were alive with a median follow-up time of 31 months. Three patients in the regular pancreatectomy group were observed to have liver metastasis, and no metastasis was observed in the parenchyma-preserving surgery group. Significant risk factors for tumor metastasis and recurrence were tumor size, angioinvasion, and nerve infiltration. CONCLUSIONS: Parenchyma-preserving surgery did not significantly increase the frequency of perioperative complications or recurrence and might be preferable if comprehensive conditions allow.

CircSTX6 promotes pancreatic ductal adenocarcinoma progression by sponging miR-449b-5p and interacting with CUL2.

BACKGROUND: circular RNAs (circRNAs) have been reported to play crucial roles in the biology of different cancers. However, little is known about the function of circSTX6 (hsa_circ_0007905) in pancreatic ductal adenocarcinoma (PDAC). METHODS: circSTX6, a circRNA containing exons 4, 5, 6 and 7 of the STX6 gene, was identified by RNA sequencing and detected by quantitative reverse transcription PCR (qRT-PCR). The biological function of circSTX6 was assessed in vitro and in vivo. The relationship between circSTX6 and miR-449b-5p was confirmed by biotin-coupled circRNA capture, fluorescence in situ hybridization (FISH) and luciferase reporter assays. The interaction of circSTX6 with Cullin 2 (CUL2) was verified by RNA-protein RNA pull-down, RNA immunoprecipitation (RIP) and western blotting assays. RESULTS: circSTX6 was frequently upregulated in PDAC tissues, and circSTX6 overexpression promoted tumor proliferation and metastasis both in vitro and in vivo. Furthermore, circSTX6 expression was associated with tumor differentiation and N stage. Mechanistically, circSTX6 regulated the expression of non-muscle myosin heavy chain 9 (MYH9) by sponging miR-449b-5p. Moreover, circSTX6 was confirmed to participate in the ubiquitin-dependent degradation of hypoxia-inducible factor 1-alpha (HIF1A) by interacting with CUL2 and subsequently accelerating the transcription of MYH9. CONCLUSIONS: Our findings indicate that circSTX6 facilitates proliferation and metastasis of PDAC cells by regulating the expression of MYH9 through the circSTX6/miR-449b-5p axis and circSTX6/CUL2/HIF1A signaling pathway. Therefore, circSTX6 could serve as a potential therapeutic target for the treatment of PDAC.

Dual-Energy CT Iodine Concentration to Evaluate Postoperative Pancreatic Fistula after Pancreatoduodenectomy.

Background Pancreatic fibrosis and fatty infiltration are associated with postoperative pancreatic fistula (POPF), but accurate preoperative assessment remains a challenge. Iodine concentration (IC) and fat fraction derived from dual-energy CT (DECT) may reflect the amount of fibrosis and steatosis, potentially enabling the preoperative prediction of POPF. Purpose To identify multiphasic DECT-derived IC and fat fraction that improve the prediction of POPF risks compared with contrast-enhanced CT attenuation values and to evaluate the underlying histopathologic changes. Materials and Methods This retrospective study included patients who underwent pancreatoduodenectomy and DECT (including pancreatic parenchymal, portal venous, and delayed phase scanning) between January 2020 and December 2020. The relationships of the quantitative DECT-derived IC and fat fraction, along with CT attenuation values from enhanced images with POPF risk, were analyzed with logistic regression analysis. The predictive performance of the IC was compared with that of the CT values. The histopathologic underpinnings of IC were evaluated with multivariable linear regression analysis. Results A total of 107 patients (median age, 65 years; interquartile range, 57-70 years; 56 men) were included. Of these, 23 (21%) had POPF. The pancreatic parenchymal-to-portal venous phase IC ratio (adjusted odds ratio [OR], 13; 95% CI: 2, 162; P < .001) was an independent predictor of POPF occurrence. The accuracy of the pancreatic parenchymal-to-portal venous phase IC ratio in predicting POPF was higher than that of the CT value ratio in the same phases (78% vs 65%, P < .001). The pancreatic parenchymal-to-portal venous phase IC ratio was independently associated with pancreatic fibrosis (ß = -1.04; 95% CI: -0.44, -1.64; P = .001). Conclusion A higher pancreatic parenchymal-to-portal venous phase IC ratio was associated with less histologic fibrosis and greater risk of POPF. © RSNA, 2022 Online supplemental material is available for this article. See also the editorial by Lee and Yoon in this issue.

The short-term outcomes of distal pancreatectomy with portal vein/superior mesenteric vein resection.

BACKGROUND: Portal vein/superior mesenteric vein (PV/SMV) resection during distal pancreatectomy (DP) is often associated with technical difficulties due to the close anatomic relationship between pancreatic head and PV/SMV. In this paper, we present our operative technique and short-term outcomes of DP combined with venous resection (DP-VR) for left-sided pancreatic cancer (PC). METHODS: We reviewed 368 consecutive cases of DP for PC from January 2013 to December 2018 in our institution, and identified 41 patients (11.1%) who had undergone DP-VR. The remaining 327 DP patients (88.9%) were matched to DP-VR using propensity scores in the proportion of 1:2. Demographics, intraoperative details, postoperative complications and the pathological results were compared between the two groups. RESULTS: Out of the 41 DP-VR cases, in 14 (34.1%) venous resection with primary closure was performed, while the remaining 27 (65.9%) underwent end-to-end anastomosis without graft. A propensity-score-matched analysis revealed that DP-VR caused an increased risk of postoperative bleeding (17.1% vs. 3.7%, P = 0.016) and delayed gastric emptying (9.8% vs. 1.2%, P = 0.042) compared to standard DP. Overall morbidity (46.3% vs. 36.6%, P = 0.332), postoperative pancreatic fistula (31.7% vs. 26.8%, P = 0.672), R0 resection (58.5% vs. 67.1%, P = 0.223), 30-day reoperation (2.4% vs. 3.7%, P = 0.719), and 90-day mortality (0% vs. 2.5%, P = 0.550) were comparable between the two groups. In postoperative computed tomographic scans of 34 patients (82.9%) at a 90-day follow-up, PV/SMV stenosis was suggested in two patients (5.9%). CONCLUSION: Despite the higher rates of postoperative bleeding, DP-VR was found to be a feasible and safe surgery with acceptable postoperative morbidity and mortality compared to standard DP for left-sided pancreatic cancer.

Single-layer continuous duct-to-mucosa pancreaticojejunostomy: "how we do it".

PURPOSE: Pancreatic anastomosis reconstruction is one of the most technically demanding and complicated procedures in general surgery. No single technique has been demonstrated to be superior to the others in the prevention of postoperative pancreatic fistula (POPF), and the accumulation of surgical experience is closely related to the quality of this anastomosis. The aim of the current study was to evaluate the feasibility of our simplified technique, single-layer continuous duct-to-mucosa pancreaticojejunostomy. METHODS: A single-center prospective single-arm trial was performed. The first 20 patients who underwent Whipple's procedure with the new technique performed by a single surgeon in our center were recruited. General information, preoperative treatments, risk factors for POPF, and postoperative morbidity of the patients were prospectively recorded and reported. RESULTS: From January to February 2020, 13 male and 7 female patients were included. Ten cases were classified as intermediate/high risk according to validated fistula prediction models. The median operation time was 260 min, including a median pancreaticojejunostomy time of 7.7 min. There were 2 cases (10%) of grade B POPF, and no grade C POPF occurred. The overall morbidity rate was 30%, including 2 cases with severe complications (Clavien-Dindo grade ≥ 3). No patients underwent reoperation, and no patient died within 90 days after surgery. The median length of hospitalization was 11 days. CONCLUSION: Single-layer continuous duct-to-mucosa pancreaticojejunostomy is a simplified and feasible method for pancreatic anastomosis. Further studies are warranted to evaluate the indications or contraindications and efficacy of preventing POPF with our new technique.

A histopathological study of artery wall involvement in pancreatic cancer surgery.

PURPOSE: This study aims to study the depth of artery wall tumour invasion in patients undergoing surgery for pancreatic ductal adenocarcinoma. METHODS: Specimens from 47 pancreatic cancer patients with major arterial (splenic, SA; celiac, CA; common hepatic, CHA) invasion were examined: 45 left (distal) pancreatectomies, including 11 celiac artery resections, and two total pancreatectomies. Dissection of tumour-invaded arteries in 25 fresh specimens was attempted ex vivo using the sub-adventitial dissection technique (SDT). Tumour invasion of 66 arteries was graded using the tumour-free distance (TFD) from the external elastic lamina (EEL): 0 = no arterial invasion; I = TFD ≥ 1 mm; II = TFD < 1 mm; and grade III = EEL invasion. RESULTS: AJCC TNM staging was IA = 1 (2%), IB = 4 (9%), IIA = 5 (11%), IIB = 17(36%) and III = 20 (43%). Grade III tumour invasion was found in 17/47(36%) SAs, in 5/11 (45%) CAs and in 1/8 (13%) CHAs (p = 0.318). Attempted ex vivo SDT undertaken in 33 arteries from 25 specimens was complete in 16 and incomplete in 17 arteries. The median (IQR) TFD was 0.97 (0.11-2.54) mm in dissected and 0.14 (0.10, 0.14) mm in non-dissected SAs (p = 0.034). EEL tumour invasion occurred in 0/12 (0%) dissected compared to 7/13 (54%) non-dissected SAs (p = 0.005). Grades 0, I, II and III invasion were found in four (33%), two (17%) and six (50%), respectively, of 12 dissected SAs and grades II and III in six 6 (46%) and seven (54%), respectively, of 13 non-dissected SAs (p = 0.002). CONCLUSIONS: The grading system described may form the basis for classification to further develop arterial dissection techniques for pancreatic cancer.

Effects of body mass index and serum albumin on overall survival in patients with cancer undergoing pancreaticoduodenectomy: a single-center retrospective cohort study.

OBJECTIVES: We aimed to explore whether body mass index (BMI) and albumin were associated with overall survival (OS) in individuals who underwent pancreaticoduodenectomy (PD) for cancer. METHODS: Three-hundred twenty-nine consecutive patients who underwent PD for cancer were enrolled from January 2020 to December 2020. All clinicopathological information was extracted based on medical records. The survival follow-ups were regularly performed and ended on June 30, 2021. The Kaplan-Meier survival analysis and univariate and multivariate Cox proportional-hazards models were used to assess the association of BMI and albumin with OS. RESULTS: Of the 329 patients, 186 (56.5%) were male, and median age at admission was 65.0 (56.0-71.0) years. There were 258 patients (78.4%) with BMI < 25.0 kg/m2 and 89 patients (27.05%) with albumin < 35.0 g/L respectively. In overall cohort, BMI < 25.0 kg/m2 was associated with OS (adjusted HR = 3.516, 95% CI = 1.076-11.492, P = 0.037). In contrast, albumin < 35.0 g/L did not affect OS. Subgroup analysis showed, in patients with pancreas lesion, BMI < 25.0 kg/m2 had a higher risk for OS compared to BMI ≥ 25.0 kg/m2 (adjusted HR = 3.209, 95% CI = 0.985-10.451, P = 0.048), while albumin < 35.0 g/L was not linked to OS. In patients with lesion in ampulla of Vater, duodenum, or common bile duct, there was no significant association of BMI and albumin with OS. CONCLUSIONS: BMI, rather than serum albumin, was associated with OS in patients who underwent PD for cancer.

Surgical revision for pancreatojejunostomy stricture: a case series of 14 patients.

BACKGROUND: Pancreatojejunostomy stricture (PJS) is a rare long-term complication of pancreaticojejunal anastomosis. This study aimed to investigate the role of surgery in the management of pancreatojejunostomy strictures. METHODS: The database of the Pancreas Center of Nanjing Medical University was retrospectively screened for patients who underwent a surgical revision for PJS between June 2012 and August 2019, and their clinical characteristics and management modalities were reviewed. RESULTS: Fourteen consecutive cases were retrieved, the median age at index operation was 41.1 years (19-71). The average time between the two operations was 70.6 months (8-270 months). Index procedures included pancreaticoduodenectomy (PD) (7/14, 50%), pylorus-preserving PD (4/14, 28.6%), Berger procedure (2/14, 14.3%), and middle pancreatectomy (1/14, 7.1%). The diameter of the main pancreatic duct was < 4 mm in all 14 cases, and nine underwent pancreaticojejunostomy (PJ) stenting during the index operation. The most frequent complaints were abdominal pain (6/14, 42.9%), recurrent acute pancreatitis (6/14, 42.9%), pancreatic fistula (1/14, 7.1%), and abdominal distention (1/14, 7.1%). The diagnosis of PJ stricture was confirmed by computed tomography or magnetic resonance imaging in all cases. All patients had a main duct diameter > 5 mm before surgical revision. All patients underwent wedge excision with interrupted one-layer suturing with absorbable sutures and without stent placement. In this series, only one patient required reoperation. Upon follow-up, 11 of 12 patients had complete resolution of the PJ stricture. CONCLUSION: PJS is a long-term complication of pancreatojejunostomy. Surgical revision of the anastomosis is a safe and effective treatment modality.

CircNEIL3 regulatory loop promotes pancreatic ductal adenocarcinoma progression via miRNA sponging and A-to-I RNA-editing.

BACKGROUND: A growing number of studies have focused on investigating circRNAs as crucial regulators in the progression of multiple cancer types. Nevertheless, the biological effects and underlying mechanisms of circRNAs in pancreatic ductal adenocarcinoma (PDAC) remain unclear. METHODS: Differentially expressed circRNAs between cancerous tissue and adjacent normal tissues were identified by RNA sequencing in PDAC. Subsequently, in vitro and in vivo functional experiments were performed to investigate the functional roles of circNEIL3 in PDAC tumour growth and metastasis. Furthermore, RNA pull-down, dual-luciferase reporter assays, RNA immunoprecipitation (RIP) assays, fluorescent in situ hybridization (FISH) and Sanger sequencing assays were performed to examine the circular interaction among circNEIL3, miR-432-5p and adenosine deaminases acting on RNA 1 (ADAR1). RESULTS: CircNEIL3 was upregulated in PDAC and promoted the progression of PDAC cells both in vitro and in vivo. Mechanistically, circNEIL3 was shown to regulate the expression of ADAR1 by sponging miR-432-5p to induce RNA editing of glioma-associated oncogene 1 (GLI1), ultimately influencing cell cycle progression and promoting epithelial-to-mesenchymal transition (EMT) in PDAC cells. Moreover, we discovered that the circNEIL3/miR-432-5p/ADAR1 axis was correlated with the PDAC clinical stage and overall survival of PDAC patients, while ADAR1 may reduce the biogenesis of circNEIL3. CONCLUSIONS: Our findings reveal that circNEIL3 facilitates the proliferation and metastasis of PDAC through the circNEIL3/miR-432-5p/ADAR1/GLI1/cell cycle and EMT axis and that its expression is regulated by ADAR1 through a negative feedback loop. Therefore, circNEIL3 may serve as a prognostic marker and a therapeutic target for PDAC.