Metabolic responses to the occurrence and chemotherapy of pancreatic cancer: biomarker identification and prognosis prediction.

As the most malignant tumor, the prognosis of pancreatic cancer is not ideal even in the small number of patients who can undergo radical surgery. As a highly heterogeneous tumor, chemotherapy resistance is a major factor leading to decreased efficacy and postoperative recurrence of pancreatic cancer. In this study, nuclear magnetic resonance (NMR)-based metabolomics was applied to identify serum metabolic characteristics of pancreatic ductal adenocarcinoma (PDAC) and screen the potential biomarkers for its diagnosis. Metabolic changes of patients with different CA19-9 levels during postoperative chemotherapy were also monitored and compared to identify the differential metabolites that may affect the efficacy of chemotherapy. Finally, 19 potential serum biomarkers were screened to serve the diagnosis of PDAC, and significant metabolic differences between the two CA19-9 stratifications of PDAC were involved in energy metabolism, lipid metabolism, amino acid metabolism, and citric acid metabolism. Enrichment analysis of metabolic pathways revealed six shared pathways by PDAC and chemotherapy such as alanine, aspartate and glutamate metabolism, arginine biosynthesis, glutamine and glutamate metabolism, citrate cycle, pyruvate metabolism, and glycogolysis/gluconeogeneis. The similarity between the metabolic characteristics of PDAC and the metabolic responses to chemotherapy provided a reference for clinical prediction of benefits of postoperative chemotherapy in PDAC patients.

Effects of intraoperative fixation of residual hernia sac on postoperative seroma in laparoscopic transabdominal preperitoneal inguinal hernia repair: a prospective randomized controlled trial.

The study was aimed to evaluate a prospective randomized controlled trial (RCT) In laparoscopic transabdominal preperitoneal inguinal hernia repair (TAPP), whether fixation of the residual sac after transecting the hernia sac can reduce the severity of postoperative seroma. A total of 252 male patients with a primary unilateral indirect inguinal hernia who underwent TAPP from September 2018 to November 2022 were recruited. Patients were randomized to the control group (CG)and the experimental group (EG). In the experimental group, after the hernia sac was transected, the residual sac was fixed to the lower edge of the rectus abdominis, while it was left in the preperitoneal space in the control group. Close follow-up was arranged to observe the incidence of seroma and other postoperative complications. All 214 patients were discharged successfully. 106 patients were randomly assigned to the control group, and 108 patients were assigned to the experimental group. There was no significant difference in the incidence of postoperative fluid extraction between the experimental group and the control group (11.1% VS.10.4%, p = 0.862), but the patients with seroma after the operation had fewer repeated extraction (0% VS. 45.5%, P = 0.033). The incidences of other postoperative complications were comparable in the two groups. In the treatment of indirect inguinal hernia with TAPP, after transecting the hernia sac, suturing and fixing the residual sac to the inferior edge of the rectus abdominis can reduce the incidence of repeated aspiration.

Metabolomic analyses redefine the biological classification of pancreatic cancer and correlate with clinical outcomes.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by high heterogeneity, and the postoperative prognosis of different patients often varies greatly. Therefore, the classification of pancreatic cancer patients and precise treatment becomes particularly important. In our study, 1 H NMR spectroscopy was used to analyze the 76 PDAC serum samples and identify the potential metabolic subtypes. The metabolic characteristics of each metabolic subtype were screened out and the relationship between metabolic subtype and the long-term prognosis was further identified. The clinical stages of PDAC did not show the metabolic differences at the serum metabolomic level. And three metabolic subtypes, basic, choline-like and amino acid-enriched types, were defined by the hierarchical cluster analysis of the serum metabolites and the disturbed metabolic pathways. The characteristic metabolites of each PDAC subtype were identified, and the metabolite model was established to distinguish the PDAC patients in the different subtypes. Among the three metabolic subtypes, choline-like type displayed better long-term prognosis compared to the other two types of patients. Metabolic subtypes are of clinical importance and are closer to expressing the heterogeneity in the actual life activities of pancreatic cancer than molecular typing. The excavation of metabolic subtypes based on this will be more in line with clinical reality and more promising to guide clinical precision individualization treatment.

Radiopaque Chitosan Ducts Fabricated by Extrusion-Based 3D Printing to Promote Healing After Pancreaticoenterostomy.

Long-term placement of non-degradable silicone rubber pancreatic duct stents in the body is likely to cause inflammation and injury. Therefore, it is necessary to develop degradable and biocompatible stents to replace silicone rubber tubes as pancreatic duct stents. The purpose of our research was to verify the feasibility and biological safety of extrusion-based 3D printed radiopaque chitosan (CS) ducts for pancreaticojejunostomy. Chitosan-barium sulfate (CS-Ba) ducts with different molecular weights (low-, medium-, and high-molecular weight CS-Ba: LCS-Ba, MCS-Ba, and HCS-Ba, respectively) were soaked in vitro in simulated pancreatic juice (SPJ) (pH 8.0) with or without pancreatin for 16 weeks. Changes in their weight, water absorption rate and mechanical properties were tested regularly. The biocompatibility, degradation and radiopaque performance were verified by in vivo and in vitro experiments. The results showed that CS-Ba ducts prepared by this method had regular compact structures and good molding effects. In addition, the lower the molecular weight of the CS-Ba ducts was, the faster the degradation rate was. Extrusion-based 3D-printed CS-Ba ducts have mechanical properties that match those of soft tissue, good biocompatibility and radioopacity. In vitro studies have also shown that CS-Ba ducts can promote the growth of fibroblasts. These stents have great potential for use in pancreatic duct stent applications in the future.

Development and validation of a simple-to-use nomogram to predict liver metastasis in patients with pancreatic neuroendocrine neoplasms: a large cohort study.

BACKGROUND: Liver metastasis is an important prognostic factor for pancreatic neuroendocrine neoplasms (pNENs), but the relationship between the clinical features of patients with pNEN and liver metastasis remains undetermined. The aim of this study was to establish and validate an easy-to-use nomogram to predict liver-metastasis in patients with pNEN. METHODS: We obtained the clinicopathologic data of 2960 patients with pancreatic neuroendocrine neoplasms from the Surveillance, Epidemiology and End Results (SEER) database between 2010 and 2016. Univariate and multivariate logistic regression were done to screen out independent influencing factors to establish the nomogram. The calibration plots and the area under the receiver operating characteristic curve (AUC) were used to evaluate the performance of nomogram. Decision curve analysis (DCA) was applied to compare the novel model with the conventional predictive methods. RESULTS: A total of 2960 patients with pancreatic neuroendocrine neoplasms were included in the study. Among these, 1974 patients were assigned to the training group and 986 patients to the validation group. Multivariate logistic regression identified, tumor size, grade, other site metastasis, T stage and N stage as independent risk factors. The calibration plot showed good discriminative ability in the training and validation groups, with C-indexes of 0.850 for the training cohort and 0.846 for the validation cohort. The AUC values were 0.850 (95% CI 0.830-0.869) and 0.839 (95% CI 0.812-0.866), respectively. The nomogram total points (NTP) had the potential to stratify patients into low risk, medium risk and high risk (P < 0.001). Finally, comparing the nomogram with traditional prediction methods, the DCA curve showed that the nomogram had better net benefit. CONCLUSIONS: Our nomogram has a good ability to predict liver metastasis of pancreatic neuroendocrine neoplasms, and it can guide clinicians to provide suitable prevention and treatment measures for patients with medium- and high-risk liver metastasis.

Chemotherapeutic efficacy of cucurmosin for pancreatic cancer as an alternative of gemcitabine: a comparative metabolomic study.

BACKGROUND: As the preferred drug for single chemotherapeutic application in pancreatic cancer, gemcitabine often demonstrated low sensitivity and strong chemotherapy resistance in patients. Therefore, the search for other drugs with high efficiency and low side effects has become of high importance. The aim of this study was to assess the therapeutic effects of cucurmosin on pancreatic cancer as an alternative of gemcitabine and explore its underlying biochemical mechanism. METHODS: The subcutaneous xenograft mice with pancreatic cancer were treated by high- and low-dose cucurmosin and gemcitabine, respectively. A comparative metabolomic analysis was performed on the serum samples from the different groups by 1H nuclear magnetic resonance (NMR) techniques and then subjected to univariate and multivariate statistical analysis. RESULTS: Cucurmosin demonstrated a dose-dependent inhibition to the pancreatic tumors. High-dose cucurmosin provided similar chemotherapeutic efficacy with gemcitabine by positively regulating pyruvate metabolism, glycolysis or gluconeogenesis, and cysteine and methionine metabolism. Inactivating GFR signaling pathway and further inducing apoptosis of tumor cells are the important mechanism of anti-tumor function of cucurmosin. CONCLUSIONS: Cucurmosin is a promising chemotherapeutic drug for pancreatic cancer. However, the dose selection and surface modification should be optimized according to the stage of pancreatic cancer, and an expanded study in both laboratory and clinical regimes needs to be performed.

Photothermal augment stromal disrupting effects for enhanced Abraxane synergy chemotherapy in pancreatic cancer PDX mode.

Cancer-associated fibroblasts (CAFs) are crucial for forming the desmoplastic stroma that is associated with chemoresistance in pancreatic ductal adenocarcinoma (PDAC). In the clinic, depleting dense stroma in PDAC tumor tissue is a promising chemotherapeutic strategy. In this study, we report that the local hyperthermia can reduce the number of CAFs in the PDAC PDX mouse mode, which further augments chemotherapeutic efficiency in the PDAC therapy. To achieve this goal, a photothermal-chemotherapeutic agent termed as Abraxane@MoSe2 as a vehicle-saving theranostic probe is prepared by simply mixing an FDA-approved Abraxane and hydrophobic MoSe2 nanosheets via electrostatic and hydrophobic interactions. After labeling with indocyanine green (ICG) dye on the Abraxane@MoSe2, a relatively high fluorescence signal (near infrared second (NIR II)) in PDX tumors can be obtained, which can be precisely imaging-guide local photothermal-chemotherapy upon the 808 nm laser irradiation in vivo. Importantly, the synergy therapeutic efficiency in PDAC is enhanced by the photothermal effect reduction of the number of CAFs, which is confirmed viaα-SMA and vimentin immunofluorescence analysis. This combined therapeutic strategy may provide a new sight for PDAC therapy.

Sublay repair for primary superior lumbar hernia with the Kugel patch.

BACKGROUND: A superior lumbar hernia is a posterior ventral hernia that is rarely encountered in the clinical setting. However, no standard operative strategy exists for superior lumbar hernia repair at present. METHODS: Twelve patients with primary superior lumbar hernia who underwent sublay repair via the retroperitoneal space with the Kugel patch between December 2008 and June 2019 were included in this study. The demographic, peri-operative and post-operative data of the patients were collected to analyse the effectiveness of this technique. RESULTS: All patients underwent an uneventful operation. The median operative time was 60 min, and the median blood loss was 35 mL. The median hernia defect area was 16 cm2 . Five medium-sized Kugel patches (11 cm × 14 cm) and seven large-sized Kugel patches (14 cm × 17 cm) were used for the repairs. The median visual analogue scale score on post-operative day 1 was 3. The median time to removal of drainage was 3 days. The median duration of the hospital stay was 3 days. No serious post-operative complications, including seroma, haematoma, incision or mesh infection, recurrence and chronic pain, occurred during the follow-up period. CONCLUSION: Sublay repair for primary superior lumbar hernia with the Kugel patch shows benefits including a reliable repair, minimal invasiveness and few post-operative complications.

Correction to: Mesenchymal stem cells decrease blood-brain barrier permeability in rats with severe acute pancreatitis.

[This corrects the article DOI: 10.1186/s11658-019-0167-8.].

Mesenchymal stem cells decrease blood-brain barrier permeability in rats with severe acute pancreatitis.

BACKGROUND: Impairment of the blood-brain barrier (BBB) could result in secondary cerebral edema and life-threatening pancreatic encephalopathy in patients with severe acute pancreatitis (SAP). Mesenchymal stem cells (MSCs) have been widely adopted in clinical research because of their pleiotropic functions. The aim of this study was to investigate the impact of MSCs on BBB permeability in SAP and the potential mechanisms driving these effects. METHODS: Sprague-Dawley rats were randomly assigned to the control, SAP and SAP+MSCs groups. Pancreatic impairment was assessed. The serum levels of amylase, TNF-α and IL-10, expression levels of claudin-5, Bax, Bcl-2 and MMP-9, and the BBB permeability were measured. Endothelial cell apoptosis was evaluated. RESULTS: SAP rats showed BBB impairment with increased permeability and secondary cerebral edema, which was confirmed using the Evans blue assay and the calculation of the brain dry/wet ratio. Treatment with MSCs decreased the serum levels of amylase and TNF-α, increased the serum levels of IL-10, attenuated the apoptosis of brain microvascular endothelial cells, upregulated claudin-5 expression and downregulated MMP-9 expression. This treatment attenuated the increased BBB permeability in SAP rats. CONCLUSIONS: MSCs attenuated the impairment of the BBB and decreased its permeability, producing protective effects in SAP rats.

Interleukin-10 attenuates impairment of the blood-brain barrier in a severe acute pancreatitis rat model.

BACKGROUND: Impairment of the blood-brain barrier (BBB) in severe acute pancreatitis (SAP) could result in life-threatening pancreatic encephalopathy. Interleukin-10 (IL-10) is a classical cytokine that is well-known for its strong immunoregulatory and anti-inflammatory abilities. However, whether and how IL-10 protects the BBB in SAP are still unclear. METHODS: This study includes in vivo experiments using a SAP rat model and in vitro experiments using an in vitro BBB model consisting of a monolayer of brain microvascular endothelial cells (BMECs). The study groups are divided into the control, SAP (in vivo)/TNF-α (in vitro), IL-10 treatment, IL-10 + signal transducer and activator of transcription 3 (STAT3) inhibitor S3I-201 treatment groups. Pancreatic pathological scores, serum amylase, serum TNF-α levels and BBB permeability by Evan's blue assay in SAP rat models were evaluated. BMEC apoptosis in SAP rats or induced by TNF-αin vitro was detected by terminal-deoxynucleotidyl transferase-mediated nick end labeling (TUNEL) and flow cytometry, separately. Expression levels of claudin-5 and proteins involved in the STAT3 signaling pathway were measured by Western blotting. Location and changes of junctional structure of claudin-5 on BMECs were assessed by immunohistochemistry and immunofluorescence. RESULTS: In vivo, IL-10 alleviated the severity of inflammation, attenuated the increased BBB permeability in SAP rat models by reducing BMEC apoptosis via the STAT3 pathway and ameliorated the down-regulation of claudin-5 expression in BMECs; in vitro, IL-10 improved BBB integrity against TNF-α by attenuating BMEC apoptosis via the STAT3 pathway, the impairment of tight junction structure and the down-regulation of claudin-5 expression in BMECs. CONCLUSIONS: IL-10 improves BBB properties in SAP by attenuating the down-regulation of claudin-5 expression and the impairment of tight junctions and by STAT3 pathway-mediated anti-apoptotic effects on BMECs.