Prognostic significance of systemic immune-inflammation index in patients with nonfunction pancreatic neuroendocrine tumor undergoing surgical resection.

PURPOSE: The purpose of our study was to investigate the clinical significance and prognostic role of the systemic immune-inflammation index (SII) in patients who underwent surgical resection for nonfunctioning pancreatic neuroendocrine tumors (pNETs). METHODS: We conducted a retrospective analysis of 364 patients with nonfunctioning pNETs. The association between the SII level and clinical parameters was investigated. The receiver operating characteristic (ROC) curve was used to calculate the optimal SII value. Cox proportional hazard analysis was performed to evaluate the prognostic factors. RESULTS: Our study included 364 patients with nonfunctioning pNETs who underwent surgery. The median age was 51.0 (43.0, 59.3), and 164 (45.1%) were male. The optimal threshold of SII determined by ROC analysis was 523.95. Higher SII levels were significantly associated with older age (p = 0.001), sex (p = 0.011), tumor size (p = 0.032), and tumor grade (p = 0.002). Recurrence was observed in 70 (19.2%) patients following a median follow-up of 98 months. Univariate analysis showed that higher SII (p < 0.0001), tumor size >4 cm (p = 0.015), and G2/G3 grade (p = 0.002) were significantly associated with disease-free survival (DFS). Multivariate analysis revealed that higher SII (HR: 7.35; 95% CI: 3.44, 15.70; p < 0.0001) and G2/G3 grade (HR: 3.11; 95% CI: 1.42, 6.82; p = 0.005) remained significantly associated with tumor recurrence. Furthermore, 46 (12.6%) patients died during the follow-up. Higher SII (HR: 8.43; 95% CI: 3.19, 22.72; p < 0.0001) and G2/G3 grade (HR: 3.16; 95% CI: 1.01, 9.86; p = 0.048) were independent predictors of overall survival (OS) by multivariate analysis. CONCLUSION: In conclusion, our study revealed that a higher SII level was associated with tumor-related features (larger tumor size and advanced grade) and subsequent shorter DFS and OS in patients with nonfunctioning pNETs. These results indicated that the SII could serve as an efficient prognostic biomarker for nonfunctioning pNETs.

Pedicled ligament flaps during pancreatoduodenectomy are associated with reduced hemorrhage from hepatic artery and gastroduodenal artery stump during pancreatoduodenectomy: a systematic review, meta-analysis and trial sequential analysis.

BACKGROUND: The aim of this study was to investigate whether pedicled ligament flaps (PLF) covering around the hepatic and gastroduodenal artery stump can provide better clinical outcomes in pancreatoduodenectomy (PD). METHODS: We conducted a comprehensive search of databases (inception to January 2023) to identify studies comparing PD with or without PLF covering the skeletonized arteries. The perioperative and postoperative outcomes were compared. Pooled odds ratios (ORs) with 95 % confidence intervals (CIs) were calculated using fixed-effects models. RESULTS: Ten studies were included in the qualitative synthesis. Six studies with 3538 patients met the inclusion criteria for the meta-analysis. Patients in the PLF group had a significantly lower rate of PPH from the hepatic artery or gastroduodenal artery stump (H/G PPH) (OR: 0.41; 95 % CI, 0.22-0.75; P < 0.01) and overall PPH (OR: 0.65; 95 % CI, 0.46-0.93; P = 0.02). There were no significant differences between the two groups in terms of morbidity, grade B/C postoperative pancreatic fistula (B/C POPF), delayed gastric emptying (DGE), reoperation, or mortality. CONCLUSION: Prophylactic pedicled ligament flaps covering around the skeletonized arteries significantly reduced overall PPH and H/G PPH, and it seemed to have no obvious influence on other complications.

A nomogram to preoperatively predict the aggressiveness of non-functional pancreatic neuroendocrine tumors based on CT features.

OBJECTIVES: To develop a nomogram to predict the aggressiveness of non-functional pancreatic neuroendocrine tumors (NF-pNETs) based on preoperative computed tomography (CT) features. METHODS: This study included 176 patients undergoing radical resection for NF-pNETs. These patients were randomly divided into the training (n = 123) and validation sets (n = 53). A nomogram was developed based on preoperative predictors of aggressiveness of the NF-pNETs which were identified by univariable and multivariable logistic regression analysis. The aggressiveness of NF-pNETs was defined as a composite measure including G3 grading, N+, distant metastases, and/ or disease recurrence. RESULTS: Altogether, the number of patients with highly aggressive NF-pNETs was 37 (30.08 %) and 15 (28.30 %) in the training and validation sets, respectively. Multivariable logistic regression analysis identified that tumor size, biliopancreatic duct dilatation, lymphadenopathy, and enhancement pattern were preoperative predictors of aggressiveness. Those variables were used to develop a nomogram with good concordance statistics of 0.89 and 0.86 for predicting aggressiveness in the training and validation sets, respectively. With a nomogram score of 59, patients with NF-pNETs were divided into low-aggressive and high-aggressive groups. The high-aggressive group had decreased overall survival (OS) and disease-free survival (DFS). Moreover, the nomogram showed good performance in predicting OS and DFS at 3, 5, and 10 years. CONCLUSION: The nomogram integrating CT features helped preoperatively predict the aggressiveness of NF-pNETs and could potentially facilitate clinical decision-making.

Clusterin is upregulated by erastin, a ferroptosis inducer and exerts cytoprotective effects in pancreatic adenocarcinoma cells.

Ferroptosis is a novel form of cell death, which is distinguished from apoptosis and necrosis, and characterized by accumulation of lipid-based reactive oxygen species (ROS) in an iron-dependent manner. Erastin, a small molecule, was widely reported to trigger ferroptosis in various kinds of cancer cells, including pancreatic cancer cells by inducing ROS accumulation. However, how erastin treatment exerts cytotoxicity is not still fully understood. In this study, the effects of erastin in causing pancreatic cancer cell death via inducing ferroptosis and apoptosis are investigated. As expected, erastin treatment caused ROS accumulation, increase in iron concentration and non-apoptotic cell death, which is different from that of induced by apoptosis inducer, staurosporine. Interestingly, erastin treatment caused the upregulation of clusterin, which contributes to the regulation of malignant behaviors of pancreatic cancer, including preventing apoptosis and inducing chemoresistance. Without erastin treatment, overexpressed clusterin significantly promoted cell proliferation, which is consistent with its cytoprotective roles. After erastin treatment, overexpressed clusterin decreased erastin-induced ROS accumulation and cell death. By measuring iron concentration, reduced glutathione (GSH) and glutathione peroxidase 4 (GPX4), it is revealed that clusterin caused resistance to erastin-induced ferroptosis potentially via maintaining the enzymatic activity of GPX4, without disturbing GSH amount. Thus, ferroptosis inducer, erastin, may crosstalk with apoptotic cell death via regulating clusterin, indicating a more complex regulatory network between ferroptosis and apoptosis.

Dinaciclib exerts a tumor-suppressing effect via ß-catenin/YAP axis in pancreatic ductal adenocarcinoma.

Dinaciclib, a cyclin-dependent kinase-5 (CDK5) inhibitor, has significant anti-tumor properties. However, the precise mechanism of dinaciclib requires further investigation. Herein, we investigated the anti-tumor functions and molecular basis of dinaciclib in pancreatic ductal adenocarcinoma (PDAC). PDAC and matched para-carcinoma specimens were collected from the patients who underwent radical resection. Immunohistochemistry was performed to assess CDK5 expression. Cell proliferation ability, migration, and invasion were measured using Cell Counting Kit-8, wound healing, and transwell assay, respectively. The cell cycle and apoptosis were assessed using flow cytometry. Gene expression was examined using RNA-seq and quantitative real-time PCR. Protein expression of proteins was measured by western blot analysis and immunofluorescence microscopy. Tumor-bearing mice were intraperitoneally injected with dinaciclib. CDK5 is highly expressed in PDAC. The expression level of CDK5 was significantly related to tumor size, T stage, and the American Joint Committee on Cancer stage. High CDK5 expression can predict poor survival in PDAC patients. In addition, the expression level of CDK5 might be an independent prognostic factor for PDAC patients. Dinaciclib inhibits the growth and motility of PDAC cells and induces apoptosis and cell cycle arrest in the G2/M phase. Mechanistically, dinaciclib down-regulated yes-associated protein (YAP) mRNA and protein expression by reducing ß-catenin expression. Moreover, dinaciclib significantly inhibited PDAC cell growth in vivo . Our findings reveal a novel anti-tumor mechanism of dinaciclib in which it decreases YAP expression by down-regulating ß-catenin at the transcriptional level rather than by activating Hippo pathway-mediated phosphorylation-dependent degradation.

Regional differences in islet amyloid deposition in the residual pancreas with new-onset diabetes secondary to pancreatic ductal adenocarcinoma.

BACKGROUND: Islet amyloid deposition and reduced ß-cell mass are pathological hallmarks in type 2 diabetes mellitus subjects. To date, the pathological features of the islets in diabetes secondary to pancreatic ductal adenocarcinoma (PDAC) have not been specifically addressed. AIM: To provide further insight into the relationship between islet amyloid deposition of the residual pancreas in PDAC patients and to explore whether regional differences (proximal vs distal residual pancreas) are associated with islet amyloid deposition. METHODS: We retrospectively collected clinical information and pancreatic tissue removed from tumors of 45 PDAC patients, including 14 patients with normal glucose tolerance (NGT), 16 patients with prediabetes and 15 new-onset diabetes (NOD) patients diagnosed before surgery by an oral glucose tolerance test at West China Hospital from July 2017 to June 2020. Pancreatic volume was calculated by multiplying the estimated area of pancreatic tissue on each image slice by the interval between slices based on abdominal computer tomography scans. Several sections of paraffin-embedded pancreas specimens from both the proximal and/or distal regions remote from the tumor were stained as follows: (1) Hematoxylin and eosin for general histological appearance; (2) hematoxylin and insulin for the determination of fractional ß-cell area (immunohistochemistry); and (3) quadruple insulin, glucagon, thioflavin T and DAPI staining for the determination of ß-cell area, α-cell area and amyloid deposits. RESULTS: Screening for pancreatic histologic features revealed that duct obstruction with islet amyloid deposition, fibrosis and marked acinar atrophy were robust in the distal pancreatic regions but much less robust in the proximal regions, especially in the prediabetes and NOD groups. Consistent with this finding, the remnant pancreatic volume was markedly decreased in the NOD group by nearly one-half compared with that in the NGT group (37.35 ± 12.16 cm3 vs 69.79 ± 18.17 cm3, P < 0.001). As expected, islets that stained positive for amyloid (islet amyloid density) were found in the majority of PDAC cases. The proportion of amyloid/islet area (severity of amyloid deposition) was significantly higher in both prediabetes and NOD patients than in NGT patients (P = 0.002; P < 0.0001, respectively). We further examined the regional differences in islet amyloid deposits. Islet amyloid deposit density was robustly increased by approximately 8-fold in the distal regions compared with that in the proximal regions in the prediabetes and NOD groups (3.98% ± 3.39% vs 0.50% ± 0.72%, P = 0.01; 12.03% vs 1.51%, P = 0.001, respectively). CONCLUSION: In conclusion, these findings suggest that robust alterations of the distal pancreas due to tumors can disturb islet function and structure with islet amyloid formation, which may be associated with the pathogenesis of NOD secondary to PDAC.

A double-cannula pancreatic gastrostomy method for pancreatic duct stenosis due to disconnected pancreatic duct syndrome: A surgical case report.

INTRODUCTION AND IMPORTANCE: Disconnected Pancreatic Duct Syndrome (DPDS) without peripancreatic fluid collections are relatively difficult for endoscopists to manage and usually treated with distal pancreatectomy or pancreaticojejunostomy. However, these procedures are risky for patients with severe edema of pancreatic tissue. We report an original one-stage surgical approach for these patients, namely, the "double-cannula pancreatic gastrostomy method". CASE PRESENTATION: A 38-year-old man was admitted with recurrent acute pancreatitis. ct images suggest pancreatic duct discontinuity syndrome. Intraoperative exploration revealed that pancreas inflammation was severe and distal pancreatectomy or pancreaticojejunostomy were risky. Therefore, we decided to perform a double-cannula pancreatic gastrostomy. A 16F type catheter penetrated the front and back walls of the stomach for gastrostomy, and a 6F catheter was inserted into the pancreatic duct for drainage. We placed the drainage tube of pancreatic duct into the gastrostomy tube to ensure the drainage tube of pancreatic duct could reach the gastric cavity. The gastrostomy tube is led out of the body through the abdominal wall. CLINICAL DISCUSSION: Both endoscopic and surgical approaches have been reported in treating DPDS patients. Internal drainage and excision are common surgical methods. CONCLUSIONS: The double-cannula pancreatic gastrostomy was a safe and effective method in this patient. CORE TIP: In this case, the patient suffered recurrent acute pancreatitis due to disconnected pancreatic duct syndrome. This patient without peripancreatic fluid collections was relatively difficult for endoscopists to manage. However, intraoperative exploration revealed a high risk of distal pancreatectomy or pancreaticojejunostomy. Therefore, we used A double-cannula pancreatic gastrostomy method and successfully treated the complications of pancreatic duct stenosis.

Optimal glycated hemoglobin A1c value for prediabetes and diabetes in patients with pancreatic diseases.

Background: Some articles suggest that using HbA1c alone for diabetes diagnosis is inappropriate. It requires considerable researches to explore the efficacy of HbA1c for diagnosing hyperglycemia in patients with pancreatic disease. Methods: This study analyzed 732 patients, comprising of 331 without pancreatic disease and 401 patients diagnosed with pancreatic diseases. All participants underwent the HbA1c assay and oral glucose tolerance test. Kappa coefficients were calculated to assess agreement between the HbA1c and glucose criteria. The receiver operating characteristic curve (ROC) was used to calculate the optimal HbA1c value. DeLong test was analyzed to compared the aera under curves (AUCs). Results: There were 203 (61.3%) patients with NGT, 78 (23.6%) with prediabetes, and 50 (15.1%) with diabetes in patients without pancreatic diseases. In patients with pancreatic disease, 106 participants were diagnosed with NGT (36.4%), 125 with prediabetes (31.2%), and 130 with diabetes (32.4%). Patients with pancreatic disease exhibited elevated levels of bilirubin, transaminase enzymes, aspartate transaminase, high density lipoprotein cholesterol and total bile acid. The sensitivity and specificity of the HbA1c (6.5%) for diagnosing pancreatic diabetes were 60.8% (95% CI 52.3, 69.3) and 92.6% (95% CI 89.5, 95.7). In prediabetes, the sensitivity and specificity of HbA1c (5.7%) is 53.2% (44.3, 62.0) and 59.6 (51.5, 67.6). The optimal HbA1c value for diagnosing diabetes was 6.0% (AUC = 0.876, 95% CI 0.839, 0.906), with the sensitivity of 83.8% and the specificity of 76.8%. The optimal HbA1c value for the diagnosis of prediabetes was 5.8% (AUC = 0.617, 95% CI: 0.556, 0.675), with the corresponding sensitivity and specificity of 48.0% and 72.6% respectively. The combined tests (HbA1c, 6.0% or FPG, 7.0mmol/L) presented the sensitivity of 85.7% (95% CI 79.1, 91.3)and the specificity of 92.6% (95% CI 87.6, 97.3) in pancreatic diabetes. Conclusion: From our results, the recommended HbA1c by ADA criterion may not be sufficiently sensitive to diagnose hyperglycemia in pancreatic disease. The optimal value of 5.8% and 6.0% improved the accuracy for diagnosing prediabetes and diabetes and should be considered to be applied. Besides, we advocate the combination of HbA1c and FPG test for the diagnosis of diabetes in patients with pancreatic diseases.

The differential effects of sarcopenia and cachexia on overall survival for pancreatic ductal adenocarcinoma patients following pancreatectomy: A retrospective study based on a large population.

OBJECTIVES: Both cachexia and sarcopenia have been considered adverse predictors for prognosis in patients with pancreatic cancer; although sarcopenia and cachexia share some similarities, they are still defined as distinct nutritional conditions. We aimed to explore the differential impacts of sarcopenia and cachexia on prognosis for pancreatic ductal adenocarcinoma (PDAC) patients following radical excision. METHODS: From January 2015 to May 2022, 614 patients undergoing surgery for PDAC were retrospectively included. Sarcopenia was defined as the L3 total skeletal muscle index below 52.4 cm2 /m2 (men) and 38.5 cm2 /m2 (women). Cachexia was classified according to the following criteria: involuntary weight loss >5% over the past 6 months, or weight loss >2% and BMI <20 kg/m2 , or weight loss >2% and sarcopenia. RESULTS: Of the 614 patients included in the analysis, 62% and 48% were diagnosed with sarcopenia and cachexia, respectively. Kaplan-Meier analysis showed that sarcopenia and/or cachexia were significantly associated with worse overall survival (OS) rather than worse recurrence-free survival (RFS). Moreover, Cox regression analysis revealed that cachexia rather than sarcopenia was an adverse factor for OS in all PDAC patients. For poorly differentiated PDAC, both cachexia and sarcopenia were significantly associated with shorter OS. However, for moderately/well-differentiated PADC, cachexia was an independent factor for adverse OS, but not sarcopenia. CONCLUSIONS: Sarcopenia and cachexia have different effects on OS for PDAC patients undergoing radical excision. This difference may provide some important information for preoperative management.

Elevated Bile Acid Is Associated with Worsened Impaired Glucose Homeostasis in Pancreatic Ductal Adenocarcinoma Patients with Extrahepatic Cholestasis through Increased Hepatic Insulin Clearance.

BACKGROUND: Patients after pancreaticoduodenectomy (PD) showed improved glucose tolerance. Evidence for the effect of extrahepatic cholestasis on impaired glucose homeostasis secondary to ductal adenocarcinoma of the pancreatic head is limited. METHODS: In this prospective cross-sectional study, 50 patients with ductal adenocarcinoma of the pancreatic head were included to assess the effect of extrahepatic cholestasis on glucose tolerance status based on the oral glucose tolerance test (OGTT) before pancreatic surgery. RESULTS: Patients with extrahepatic cholestasis more frequently suffered from worsened impaired glucose homeostasis (prediabetes and new-onset diabetes, 95.2% vs. 58.6%, p = 0.004). Elevated bile acid level was recognized as an independent risk factor for impaired glucose homeostasis (p = 0.024, OR = 6.85). Hepatic insulin clearance (HIC) was significantly higher in patients with elevated bile acid levels (p = 0.001). A strong positive correlation was found between bile acid levels and HIC (r = 0.45, p = 0.001). CONCLUSIONS: This study suggested a connection between elevated bile acid levels and worsened impaired glucose homeostasis through increased insulin clearance function in ductal adenocarcinoma of pancreatic head patients.

Associations between Systemic Immune-Inflammation Index and Diabetes Mellitus Secondary to Pancreatic Ductal Adenocarcinoma.

BACKGROUND: There is a high prevalence of diabetes mellitus (DM) in patients with pancreatic ductal adenocarcinoma (PDAC). An inflammatory response is considered as a potential mechanism involved in the process. The systemic immune-inflammation (SII) index is an integrated and novel inflammatory indicator developed in recent years. The purpose of this study was to determine the relationship between the SII and DM secondary to PDAC. METHOD: Patients with a confirmed diagnosis of PDAC were analyzed in this cross-sectional study. Anthropometric measures, glucose-related data (including fasting glucose, 2 h OGTT, glycated hemoglobin, fasting insulin, and fasting c-peptide), tumor characteristics (tumor volumes, location and stages), and the periphery blood inflammatory index (white blood cell count, neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, and SII) were recorded. The inflammation index was analyzed for its association with glucose-related parameters. Multivariable logistic regression analysis was used to analyze the association between SII levels and DM secondary to PDAC. RESULTS: Blood cell results showed that the white blood cell count, neutrophils, lymphocytes, monocytes, platelets, the neutrophil-to-lymphocyte ratio, and platelet-to-lymphocyte ratio were higher in patients with diabetes. It was worth noting that SII significantly increased in patients with diabetes secondary to PDAC (4.41 vs. 3.19, p < 0.0001). Multivariable logistic regression analysis showed that SII (OR: 2.024, 95%CI: 1.297, 3.157, p = 0.002) and age (OR: 1.043, 95%CI: 1.01, 1.077, p = 0.011) were the risk factors for DM secondary to PDAC after adjusting for covariates. According to Spearmen correlation analysis, SII was positively correlated with fasting glucose (r = 0.345, p < 0.0001), 2 h OGTT (r = 0.383, p < 0.0001), HbA1c (r = 0.211, p = 0.005), fasting insulin (r = 0.435, p < 0.0001), fasting C-peptide (r = 0.420, p < 0.0001), and HOMA2-IR (r = 0.491, p < 0.0001). CONCLUSIONS: In conclusion, SII is significantly increased among patients with DM secondary to PDAC and is associated with the DM in patients with PDAC (OR: 2.382, 95% CI: 1.157, 4.903, p = 0.019). Additionally, SII is significantly correlated with insulin resistance. We are the first to investigate the relationship between SII and diabetes secondary to PDAC and further confirm the role of an inflammatory response in this process. More studies need to be designed to clarify how inflammatory responses participate.

Beyond successful hemostasis: CT findings and organ failure predict postoperative death in patients suffering from post-pancreatoduodenectomy hemorrhage.

BACKGROUND: To predict postoperative death even after successful hemostasis in patients with post pancreatoduodenectomy pancreatic fistula-associated hemorrhage (PPFH). METHODS: Patients who underwent pancreatoduodenectomy (PD) between September 2011 and August 2020 were identified. PPFH patients were enrolled in this retrospective case-control study and divided into the Cured and Death groups. Perioperative variables were analyzed, especially the characteristics of PPFH and CT image findings. RESULTS: Among the 2732 consecutive pancreaticoduodenectomies, 63 patients (2.3%) were confirmed to have PPFH. The mortality rate of patients following PPFH was 50.8% (32/63). After univariate and multivariate analysis, organ failure 24 h before initial hemorrhage (P = 0.039, OR = 11.53, 95% CI: 1.14-117.00), CT imaging findings of the operative area bubble sign (P = 0.021, OR = 5.15, 95% CI: 1.28-20.79) and PJ dehiscence (P = 0.016, OR = 8.95, 95% CI: 1.50-53.38) were remained as significant predictive factors of postoperative death for PPFH patients. CONCLUSIONS: Patients following PPFH showed a high mortality rate. Organ failure and CT evidence of pancreaticojejunostomy (PJ) dehiscence and operative area bubble signs before initial hemorrhage may allow early prediction of postoperative death in PPFH patients.

Clinicopathological features and long-term prognosis of purely cystic pancreatic neuroendocrine tumors: A single-center experience.

BACKGROUND: Pancreatic neuroendocrine tumors (pNETs) are heterogenous neoplasms, of which the prognosis varies widely. Purely cystic pancreatic neuroendocrine tumors (C-pNETs) are a small subset of pNETs in which data are extremely rare. This study aimed to compare clinicopathological and long-term survival differences between C-pNETs and solid pNETs (S-pNETs). METHODS: A retrospective review of 242 patients with pNETs underwent resection in our institution from 2009 to 2019 was conducted. Demography characteristics, clinicopathological features and long-term outcomes of them were analyzed. RESULTS: Sixteen out of 242 patients (6.6%) were identified as C-pNETs. Compared with S-pNETs, C-pNETs were more frequently non-functional (75% vs 45%, P = 0.02), and the median tumor diameter of C-pNETs was smaller (36 mm vs. 47 mm, P = 0.001). And the accuracy of preoperative diagnosis of C-pNETs was significantly lower (31% vs 78%, P = 0.001). Of note, the majority of C-pNETs were well-differentiated with G1 (81% vs 35%, P = 0.001). And there were no G3 (0 vs 7%, P = 0.001) in C-pNETs. No T4 stage or R1/R2 surgical margin detected in C-pNETs. And only one C-pNETs (6%) had regional lymph node metastasis (N) or synchronous distant metastasis (M). Additionally, only one patient with C-pNETs (6%) suffered tumor recurrence, compared with 24 (13%) for S-pNETs. And survival analysis showed the patients with C-pNETs seemed to be with better disease-free survival (P = 0.26). CONCLUSION: C-pNETs are rare subtype with possibly less aggressive behavior comparing with their solid counterparts. Recurrence and tumor-related death still occurs in patients with resected C-pNETs, although they tend to be with more favorable prognosis.

Prevention and Treatment of Grade C Postoperative Pancreatic Fistula.

Postoperative pancreatic fistula (POPF) is a troublesome complication after pancreatic surgeries, and grade C POPF is the most serious situation among pancreatic fistulas. At present, the incidence of grade C POPF varies from less than 1% to greater than 9%, with an extremely high postoperative mortality rate of 25.7%. The patients with grade C POPF finally undergo surgery with a poor prognosis after various failed conservative treatments. Although various surgical and perioperative attempts have been made to reduce the incidence of grade C POPF, the rates of this costly complication have not been significantly diminished. Hearteningly, several related studies have found that intra-abdominal infection from intestinal flora could promote the development of grade C POPF, which would help physicians to better prevent this complication. In this review, we briefly introduced the definition and relevant risk factors for grade C POPF. Moreover, this review discusses the two main pathways, direct intestinal juice spillover and bacterial translocation, by which intestinal microbes enter the abdominal cavity. Based on the abovementioned theory, we summarize the operation techniques and perioperative management of grade C POPF and discuss novel methods and surgical treatments to reverse this dilemma.

Neoadjuvant therapy in resectable pancreatic cancer: A promising curative method to improve prognosis.

Currently, 15 randomized controlled trials (RCTs) have been designed to investigate whether neoadjuvant therapy (NAT) benefits patients with resectable pancreatic adenocarcinoma (R-PA) compared to surgery alone. Five of them have acquired results so far; however, corresponding conclusions have not been obtained. We speculated that the reason for this phenomenon could be that some prognostic factors had proven to be adverse through upfront surgery curative patterns, but some of them were not regarded as independent baseline characteristics, which is important to obtaining comparability between the NAT and upfront surgery groups. This fact could cause bias and lead to the difference in the outcomes of RCTs. In this review, we collate data about risk factors (such as tumor size, resection margin, and lymph node status) influencing the prognoses of patients with R-PA from five RCTs and discuss the possible reasons for the varying outcomes.

Prospects and applications of enucleation in solid pseudopapillary neoplasms of the pancreas.

Solid pseudopapillary neoplasms (SPNs) of the pancreas are rare, low-grade, malignant neoplasms that are mostly seen in young women in the second and third decades of life and are quite uncommon in children. Standard resection for benign and borderline neoplasms of the pancreas is associated with a substantial risk of postoperative morbidity and long-term functional impairment, whereas enucleation leads to less morbidity and preserves healthy parenchyma as well as exocrine and endocrine function. Enucleation of SPNs has been increasingly reported to be feasible and safe for preserving the normal physiological function of the pancreas, especially in teenagers and children. This review summarizes findings published in recent years on the enucleation of SPNs as well as potential future developments and directions. Enucleation has undoubtedly come to stay as an alternative surgical procedure for SPNs. However, many questions remain unresolved, and future directions toward the best surgical indication, the prevention and intervention of complications, especially pancreatic fistula, intraoperative resection margin safety assessment, and long-term oncology prognosis remain to be evaluated and should be explored in future clinical trials.

Analysis of invasiveness and tumor-associated macrophages infiltration in solid pseudopapillary tumors of pancreas.

BACKGROUND: Solid pseudopapillary tumor (SPT) is a rare pancreatic tumor. Considering its malignant behaviors, SPT has been classified as a low-grade malignant tumor. Indeed, only 9.2% of all SPT patients are initially diagnosed as malignant with invasion or metastasis. Thus, one of the challenges in managing SPT patients is predicting malignant behavior. AIM: To investigate the malignant behavior and tumor-associated macrophage (TAM) infiltration between different histopathologic features of SPT patients. METHODS: Twenty-five formalin-fixed paraffin-embedded tissue samples from 22 patients pathologically diagnosed with an SPT between 2009 and 2019 at West China Hospital were included in this retrospective study. Integrity of the capsule and growth pattern of the tumor cells was assessed microscopically in hematoxylin-eosin (HE)-stained sections. Based on the histopathological features, the SPT patients were divided into two groups: capsule or invasion. Clinical features, malignant behavior, and TAM infiltration were compared between the two groups. RESULTS: Among the 22 SPT patients, 11 were identified for each group, having either a capsule or invasion histopathologic feature. Malignant behavior was more frequent in the invasion group, including 2 patients who had peripheral organ invasion, 3 with liver metastasis, and 1 with both lymph node and spleen metastases (P= 0.045). Ki-67 index of more than 3% was also more frequent in the invasion group (P = 0.045). Immunohistochemical analysis showed that the invasion group had a significant increase of CD68-positive TAMs in intratumor and peritumor sites in comparison with the capsule group (all P < 0.0001). Similarly, CD163-positive M2-like macrophages were also markedly increased in the intratumor and peritumor sites in the invasion group (all P < 0.0001). At the liver metastasis site, both intratumor and peritumor tissues showed relatively high-level CD68-positive TAMs and CD163-positive M2-like macrophages infiltration. However, the differences between the intratumor, peritumor and normal hepatic tissues did not reach statistical significance (all P > 0.05). CONCLUSION: SPT patients with invasion evident under microscope were more likely to exhibit malignant behavior and TAM infiltration, especially M2-like macrophages. This finding can help in future investigations of the underlying mechanism of TAM-mediated SPT malignant behavior.

Association Between the Neutrophil-To-Lymphocyte Ratio and Diabetes Secondary to Exocrine Pancreatic Disorders.

Background: Diabetes mellitus among patients with exocrine pancreatic disorders is commonly known to be associated with chronic inflammation, including chronic pancreatitis and pancreatic ductal adenocarcinoma (PDAC). The neutrophil-to-lymphocyte ratio (NLR) is a novel marker that indicates the presence of various chronic inflammatory diseases, including type 2 diabetes (T2DM). However, no studies have examined the relationship between the NLR value and diabetes secondary to exocrine pancreatic disorders. Aim: To determine whether the NLR value is associated with diabetes secondary to exocrine pancreatic disorders. Methods: The medical data of subjects with confirmed pancreatic disease who were admitted to the Department of Pancreatic Surgery of our institution from August 2017 to October 2021 were obtained from the database and retrospectively analyzed. Anthropometric measures, laboratory data, including HbA1c, fasting insulin, and fasting C-peptide levels and the inflammatory index (white blood cell count, NLR, platelet-to-lymphocyte ration, monocyte-to-lymphocyte ratio) were recorded. The NLR is the ratio of neutrophils to lymphocytes. A homeostasis model (HOMA-B and HOMA-IR) was used to measure beta-cell dysfunction and insulin resistance. Results: The NLR values of the diabetes secondary to exocrine pancreatic disorders group were significantly higher than those of the nondiabetic group (P=0.001). In multivariate logistic regression, after adjusting for covariates, high NLR values were found to be an independent risk factor for diabetes secondary to exocrine pancreatic disorders (OR: 1.37, 95% CI: 1.138-1.649, P=0.001). According to Spearman correlation analysis, the NLR was significantly correlated with fasting plasma glucose levels (P<0.0001) and HOMA2-IR values (P=0.02). Conclusion: The NLR inflammation marker was significantly higher in subjects with diabetes secondary to exocrine pancreatic disorders and was associated with insulin resistance. NLR values may be reliable predictive markers for diabetes among patients with exocrine pancreatic disorders.

Dapagliflozin partially restores reproductive function in MC4R KO obese female mice.

Obese women often have certain degree of reproductive dysfunction with infertility. Although the clinical impact of obesity on female infertility has been extensively studied, the effective and targeted treatment is still lacking. Melanocortin-4-receptor knock-out (MC4R KO) mouse is an over-eating obese model with hyperphagia, hyperinsulinemia, reduced growth hormone (GH), and insulin resistance. Dapagliflozin improved the metabolic and hormonal parameters in MC4R KO mice. MC4R KO female mice were treated with dapagliflozin for 14 weeks from 14-week age. Age-matched WT littermates and non-treated MC4R KO mice were used as control groups. Food intake was measured daily. Body weight was measured twice a week. Estrous cycles, GH, and luteinizing hormone (LH) profiles were measured. Selected tissues were collected at the end of experiments for gene expression profiles and hematoxylin-eosin staining. Regularity and mode of hormonal profiles were restored by the dapagliflozin treatment. Estrous cycle was partially normalized, number of CL was significantly increased, and the expression of Kiss1 and Gnrh1 in the hypothalamus and LH in the pituitary was markedly increased by the dapagliflozin treatment. It is conclsuded that dapagliflozin may recover LH and GH profiles partially through modification of relevant gene expression in the hypothalamus and pituitary, and result in an improved ovulation rate in obese mouse model. Dapagliflozin may therefore improve fertility in obese patients.

Prognostic value of preoperative diabetes mellitus in patients with non-functional pancreatic neuroendocrine neoplasms.

BACKGROUND: The main aim of this study was to investigate the prevalence and prognostic value of preoperative diabetes mellitus (DM) in patients with non-functional pancreatic neuroendocrine neoplasms (NF-PNENs). METHODS: Data were retrospectively collected from 190 patients with NF-PNENs from January 2009 to December 2019 in a single center. RESULTS: The prevalence of longstanding DM, new-onset DM and impaired fasting glucose (IFG) was 11.6% (22/190), 8.4% (16/190), and 25.8% (49/190), respectively. Regression analysis showed that tumor size, tumor grade and lymph node metastasis were risk factors for new-onset DM and IFG. Multivariate survival analysis demonstrated preoperative new-onset DM (hazard ratio [HR], 4.33; P = 0.009) and IFG (HR, 4.53; P = 0.027) as independent predictors of poor recurrence-free survival (RFS) in patients with NF-PNENs. CONCLUSION: Preoperative new-onset DM and IFG are associated with aggressive tumor behavior and poor RFS in patients with NF-PNENs.