-
BJS Open May 2024Postoperative pancreatic fistulas remain a driver of major complications after partial pancreatectomy. It is unclear whether coverage of the anastomosis or pancreatic... (Meta-Analysis)
Meta-Analysis
Effect of artificial or autologous coverage of the pancreatic remnant or anastomosis on postoperative pancreatic fistulas after partial pancreatectomy: meta-analysis of randomized clinical trials.
BACKGROUND
Postoperative pancreatic fistulas remain a driver of major complications after partial pancreatectomy. It is unclear whether coverage of the anastomosis or pancreatic remnant can reduce the incidence of postoperative pancreatic fistulas. The aim of this study was to evaluate the effect of autologous or artificial coverage of the pancreatic remnant or anastomosis on outcomes after partial pancreatectomy.
METHODS
A systematic literature search was performed using MEDLINE and the Cochrane Central Register of Controlled Trials (CENTRAL) up to March 2024. All RCTs analysing a coverage method in patients undergoing partial pancreatoduodenectomy or distal pancreatectomy were included. The primary outcome was postoperative pancreatic fistula development. Subgroup analyses for pancreatoduodenectomy or distal pancreatectomy and artificial or autologous coverage were conducted.
RESULTS
A total of 18 RCTs with 2326 patients were included. In the overall analysis, coverage decreased the incidence of postoperative pancreatic fistulas by 29% (OR 0.71, 95% c.i. 0.54 to 0.93, P < 0.01). This decrease was also seen in the 12 RCTs covering the remnant after distal pancreatectomy (OR 0.69, 95% c.i. 0.51 to 0.94, P < 0.02) and the 4 RCTs applying autologous coverage after pancreatoduodenectomy and distal pancreatectomy (OR 0.53, 95% c.i. 0.29 to 0.96, P < 0.04). Other subgroup analyses (artificial coverage or pancreatoduodenectomy) showed no statistically significant differences. The secondary endpoints of mortality, reoperations, and re-interventions were each affected positively by the use of coverage techniques. The certainty of evidence was very low to moderate.
CONCLUSION
The implementation of coverage, whether artificial or autologous, is beneficial after partial pancreatectomy, especially in patients undergoing distal pancreatectomy with autologous coverage.
Topics: Humans; Pancreatic Fistula; Pancreatectomy; Randomized Controlled Trials as Topic; Postoperative Complications; Anastomosis, Surgical; Pancreaticoduodenectomy; Pancreas
PubMed: 38814751
DOI: 10.1093/bjsopen/zrae059 -
Turkish Journal of Medical Sciences 2023Type 1 diabetes mellitus (T1DM) is caused by the autoimmune-mediated destruction of insulin-producing cells (IPCs) and still has no effective cure. Better understanding...
BACKGROUND/AIM
Type 1 diabetes mellitus (T1DM) is caused by the autoimmune-mediated destruction of insulin-producing cells (IPCs) and still has no effective cure. Better understanding of the molecular mechanisms involved in the differentiation of embryonic stem cells (ESCs) into IPCs may help us improve the therapeutic strategies for treating T1DM. 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatases (Pfkfb1-4) are key regulators of glucose metabolism. Although Pfkfb3 has been shown to be required for the growth of early differentiated mouse ESCs (mESCs), more studies are needed to further assess the roles of Pfkfb isoenzymes in embryonic development and differentiation, particularly into specific cell types. In this study, we aimed to elucidate the changes in the expression of Pfkfb isoenzymes on the differentiation of mESCs into IPCs.
MATERIALS AND METHODS
A 3-step protocol was used to differentiate R1 and J1 mESCs into IPCs. The changes in the gene expression of MafA, MafB, Ins2, and Nkx6.1 (IPC specific markers) and Pfkfb1-4 were analyzed using real-time quantitative polymerase chain reaction (qPCR). Insulin expression and secretion were determined by immunofluorescence (IF) staining and the enzyme linked immunosorbent assay (ELISA), respectively.
RESULTS
Upon differentiation, the IPC specific markers in differentiated cells were upregulated. Continued differentiation was confirmed by the development of insulin-positive islet-like clusters that secreted insulin in response to glucose uptake. Expressions of the Pfkfb2 and Pfkfb3 isoenzymes were markedly increased in various stages of differentiation.
CONCLUSION
These findings suggest that Pfkfb2 and Pfkfb3 may impact the differentiation of mESCs into IPCs and the regulation of the insulin response to glucose levels. This study also lays a foundation for researchers to further probe the roles of Pfkfb isoenzymes on the differentiation of mESCs into IPCs and may open new avenues for regenerative medicine.
Topics: Animals; Phosphofructokinase-2; Cell Differentiation; Mice; Mouse Embryonic Stem Cells; Isoenzymes; Insulin-Secreting Cells; Insulin
PubMed: 38813509
DOI: 10.55730/1300-0144.5725 -
Turkish Journal of Medical Sciences 2023Long noncoding RNAs (lncRNAs) are noncoding RNA molecules with a heterogeneous structure consisting of 200 or more nucleotides. Because these noncoding RNAs are... (Review)
Review
Long noncoding RNAs (lncRNAs) are noncoding RNA molecules with a heterogeneous structure consisting of 200 or more nucleotides. Because these noncoding RNAs are transcribed by RNA polymerase II, they have properties similar to messenger RNA (mRNA). Contrary to popular belief, the term "ncRNA" originated before the discovery of microRNAs. LncRNA genes are more numerous than protein-coding genes. They are the focus of current molecular research because of their pivotal roles in cancer-related processes such as cell proliferation, differentiation, and migration. The incidence of pancreatic cancer (PC) is increasing around the world and research on the molecular aspects of PC are growing. In this review, it is aimed to provide critical information about lncRNAs in PC, including the biological and oncological behaviors of lncRNAs in PC and their potential application in therapeutic strategies and as diagnostic tumor markers.
Topics: Humans; RNA, Long Noncoding; Pancreatic Neoplasms; Biomarkers, Tumor; Gene Expression Regulation, Neoplastic
PubMed: 38813489
DOI: 10.55730/1300-0144.5724 -
World Journal of Gastroenterology May 2024Contrast-enhanced endoscopic ultrasound (CH-EUS) can overcome the limitations of endoscopic ultrasound-guided acquisition by identifying microvessels inside... (Review)
Review
Contrast-enhanced endoscopic ultrasound (CH-EUS) can overcome the limitations of endoscopic ultrasound-guided acquisition by identifying microvessels inside inhomogeneous tumours and improving the characterization of these tumours. Despite the initial enthusiasm that oriented needle sampling under CH-EUS guidance could provide better diagnostic yield in pancreatic solid lesions, further studies did not confirm the supplementary values in cases of tissue acquisition guided by CH-EUS. This review details the knowledge based on the available data on contrast-guided procedures. The indications for CH-EUS tissue acquisition include isoechoic EUS lesions with poor visible delineation where CH-EUS can differentiate the lesion vascularisation from the surrounding parenchyma and also the mural nodules within biliopancreatic cystic lesions, which occur in select cases. Additionally, the roles of CH-EUS-guided therapy in patients whose pancreatic fluid collections or bile ducts that have an echogenic content have indications for drainage, and patients who have nonvisualized vessels that need to be highlighted Doppler EUS are presented. Another indication is represented if there is a need for an immediate assessment of the post-radiofrequency ablation of pancreatic neuroendocrine tumours, in which case CH-EUS can be used to reveal the incomplete tumour destruction.
Topics: Humans; Contrast Media; Pancreatic Neoplasms; Endosonography; Pancreas; Endoscopic Ultrasound-Guided Fine Needle Aspiration; Ultrasonography, Interventional; Drainage; Pancreatic Diseases
PubMed: 38813054
DOI: 10.3748/wjg.v30.i17.2311 -
Turkish Journal of Medical Sciences 2023Early identification of patients at risk for developing postoperative pancreatic fistula (POPF) after pancreaticoduodenectomy (PD) may facilitate drain management. In...
BACKGROUND/AIM
Early identification of patients at risk for developing postoperative pancreatic fistula (POPF) after pancreaticoduodenectomy (PD) may facilitate drain management. In this context, it was aimed to examine the efficiency of the serum amylase (SA) value on postoperative day (PoD) 1 in predicting the occurrence of POPF.
MATERIALS AND METHODS
A total of 132 patients who underwent PD were studied. Occurrences of POPF were classified according to the International Study Group on Pancreatic Fistula classification as a biochemical leak (BL) or clinically relevant grade b/c POPF (CR-POPF). Receiver operating characteristic analysis identified a threshold value of SA on PoD 1 associated with POPF formation.
RESULTS
Overall, 66 (50%) patients had POPF, including 51 (38.7%) with BL and 15 with CR-POPF (11.3%). The threshold value of SA associated with the development of POPF was 120 IU/L (odds ratio [OR]: 3.20; p = 0.002). In the multivariate analysis, independent POPF risk factors were SA ≥120 IU/L, soft pancreatic texture, and high-risk pathology (i.e., duodenal, biliary, ampullary, islet cell, and benign tumors); SA ≥120 IU/L outperformed soft pancreatic texture and high-risk pathology in predicting POPF, respectively (OR: 2.22; p = 0.004 vs. OR: 1.37; p = 0.012 vs. OR: 1.35; p = 0.018). In a subset analysis according to gland texture (soft vs. hard), patients with soft pancreatic texture exhibited a significantly higher incidence of POPF (63.4% vs. 34.4%) and SA ≥120 IU/L (52.1% vs. 27.9%); SA <120 IU/L had a negative predictive value of 82.5% for developing POPF in patients with hard pancreatic texture (OR: 4.28, p = 0.028).
CONCLUSION
A SA value ≥120 IU/L on the day after PD, which is the strongest predictor for POPF, can be used as a biomarker of the occurrence of POPF. The advantage of SA measurement is that it can contribute to identifying suitable patients for early drain removal.
Topics: Humans; Pancreatic Fistula; Pancreaticoduodenectomy; Amylases; Male; Female; Retrospective Studies; Middle Aged; Aged; Postoperative Complications; Risk Factors; Predictive Value of Tests; Adult; Biomarkers; ROC Curve; Postoperative Period
PubMed: 38813023
DOI: 10.55730/1300-0144.5693 -
Radiation Oncology (London, England) May 2024Local treatment options for locally recurrent pancreatic adenocarcinoma (LR-PAC) are limited, with median survival time (MST) of 9-13 months (mos) following recurrence....
BACKGROUND
Local treatment options for locally recurrent pancreatic adenocarcinoma (LR-PAC) are limited, with median survival time (MST) of 9-13 months (mos) following recurrence. MRI-guided stereotactic body radiation therapy (MRgSBRT) provides the ability to dose escalate while sparing normal tissue. Here we report on the early outcomes of MRgSBRT for LR-PAC.
METHODS
Patients with prior resection of pancreatic adenocarcinoma with local recurrence treated with MRgSBRT at a single tertiary referral center from 5-2021 to 2-2023 were identified from our prospective database. MRgSBRT was delivered to 40-50 Gy in 4-5 fractions with target and OAR delineation per institutional standards. Endpoints included local control per RECIST v1.1, distant failure, overall survival (OS), and acute and chronic toxicities per Common Terminology Criteria for Adverse Events, v5.
RESULTS
Fifteen patients with LR-PAC were identified with median follow-up of 10.6 mos (2.8-26.5 mos) from MRgSBRT. There were 8 females and 7 males, with a median age of 69 years (50-83). One patient underwent neoadjuvant radiation for 50.4 Gy in 28 fractions followed by resection, and one underwent adjuvant radiation for 45 Gy in 25 fractions prior to recurrence. MRgSBRT was delivered a median of 18.8 mos (3.5-52.8 mos) following resection. OS following recurrence at 6 and 12 mos were 87% and 51%, respectively, with a median survival time of 14.1 mos (3.2-27.4 mos). Three patients experienced local failure at 5.9, 7.8, and 16.6 months from MgSBRT with local control of 92.3% and 83.9% at 6 and 12 months. 10 patients experienced distant failure at a median of 2.9 mos (0.3-6.7 mos). Grade 1-2 acute GI toxicity was noted in 47% of patients, and chronic GI toxicity in 31% of patients. No grade > 3 toxicities were noted.
CONCLUSIONS
This is the first report on toxicity and outcomes of MRgSBRT for LR-PAC in the literature. MRgSBRT is a safe, feasible treatment modality with the potential for improved local control in this vulnerable population. Future research is necessary to better identify which patients yield the most benefit from MRgSBRT, which should continue to be used with systemic therapy as tolerated.
TRIAL REGISTRATION
Jefferson IRB#20976, approved 2/17/21.
Topics: Humans; Male; Pancreatic Neoplasms; Female; Aged; Radiosurgery; Middle Aged; Adenocarcinoma; Neoplasm Recurrence, Local; Aged, 80 and over; Magnetic Resonance Imaging; Radiotherapy, Image-Guided; Survival Rate; Prospective Studies; Retrospective Studies
PubMed: 38812040
DOI: 10.1186/s13014-024-02457-y -
Scientific Reports May 2024Evaluating the quality of isolated human islets before transplantation is crucial for predicting the success in treating Type 1 diabetes. The current gold standard...
Evaluating the quality of isolated human islets before transplantation is crucial for predicting the success in treating Type 1 diabetes. The current gold standard involves time-intensive in vivo transplantation into diabetic immunodeficient mice. Given the susceptibility of isolated islets to hypoxia, we hypothesized that hypoxia present in islets before transplantation could indicate compromised islet quality, potentially leading to unfavorable outcomes. To test this hypothesis, we analyzed expression of 39 hypoxia-related genes in human islets from 85 deceased donors. We correlated gene expression profiles with transplantation outcomes in 327 diabetic mice, each receiving 1200 islet equivalents grafted into the kidney capsule. Transplantation outcome was post-transplant glycemic control based on area under the curve of blood glucose over 4 weeks. In linear regression analysis, DDIT4 (R = 0.4971, P < 0.0001), SLC2A8 (R = 0.3531, P = 0.0009) and HK1 (R = 0.3444, P = 0.0012) had the highest correlation with transplantation outcome. A multiple regression model of 11 genes increased the correlation (R = 0.6117, P < 0.0001). We conclude that assessing pre-transplant hypoxia in human islets via gene expression analysis is a rapid, viable alternative to conventional in vivo assessments. This approach also underscores the importance of mitigating pre-transplant hypoxia in isolated islets to improve the success rate of islet transplantation.
Topics: Humans; Animals; Islets of Langerhans Transplantation; Mice; Islets of Langerhans; Diabetes Mellitus, Experimental; Male; Diabetes Mellitus, Type 1; Hypoxia; Female; Cell Hypoxia; Middle Aged; Blood Glucose
PubMed: 38811610
DOI: 10.1038/s41598-024-61604-3 -
Nature Communications May 2024The IL-22RA1 receptor is highly expressed in the pancreas, and exogenous IL-22 has been shown to reduce endoplasmic reticulum and oxidative stress in human pancreatic...
The IL-22RA1 receptor is highly expressed in the pancreas, and exogenous IL-22 has been shown to reduce endoplasmic reticulum and oxidative stress in human pancreatic islets and promote secretion of high-quality insulin from beta-cells. However, the endogenous role of IL-22RA1 signaling on these cells remains unclear. Here, we show that antibody neutralisation of IL-22RA1 in cultured human islets leads to impaired insulin quality and increased cellular stress. Through the generation of mice lacking IL-22ra1 specifically on pancreatic alpha- or beta-cells, we demonstrate that ablation of murine beta-cell IL-22ra1 leads to similar decreases in insulin secretion, quality and islet regeneration, whilst increasing islet cellular stress, inflammation and MHC II expression. These changes in insulin secretion led to impaired glucose tolerance, a finding more pronounced in female animals compared to males. Our findings attribute a regulatory role for endogenous pancreatic beta-cell IL-22ra1 in insulin secretion, islet regeneration, inflammation/cellular stress and appropriate systemic metabolic regulation.
Topics: Animals; Insulin-Secreting Cells; Receptors, Interleukin; Female; Humans; Male; Insulin; Mice; Homeostasis; Glucose; Mice, Knockout; Insulin Secretion; Mice, Inbred C57BL; Interleukin-22; Glucose Intolerance; Interleukins; Aging
PubMed: 38811550
DOI: 10.1038/s41467-024-48320-2 -
Cell Death & Disease May 2024High workload-induced cellular stress can cause pancreatic islet β cell death and dysfunction, or β cell failure, a hallmark of type 2 diabetes mellitus. Thus,...
High workload-induced cellular stress can cause pancreatic islet β cell death and dysfunction, or β cell failure, a hallmark of type 2 diabetes mellitus. Thus, activation of molecular chaperones and other stress-response genes prevents β cell failure. To this end, we have shown that deletion of the glucose-regulated protein 94 (GRP94) in Pdx1 pancreatic progenitor cells led to pancreas hypoplasia and reduced β cell mass during pancreas development in mice. Here, we show that GRP94 was involved in β cell adaption and compensation (or failure) in islets from leptin receptor-deficient (db/db) mice in an age-dependent manner. GRP94-deficient cells were more susceptible to cell death induced by various diabetogenic stress conditions. We also identified a new client of GRP94, insulin-like growth factor-1 receptor (IGF-1R), a critical factor for β cell survival and function that may mediate the effect of GRP94 in the pathogenesis of diabetes. This study has identified essential functions of GRP94 in β cell failure related to diabetes.
Topics: Animals; Insulin-Secreting Cells; Mice; Receptor, IGF Type 1; Diabetes Mellitus, Type 2; Cell Death; Receptors, Leptin; Membrane Glycoproteins; Mice, Inbred C57BL; Mice, Knockout
PubMed: 38811543
DOI: 10.1038/s41419-024-06754-y -
Nature Communications May 2024Metabolic dysfunction-associated steatohepatitis (MASH) is the most prevalent cause of liver disease worldwide, with a single approved therapeutic. Previous research has...
Metabolic dysfunction-associated steatohepatitis (MASH) is the most prevalent cause of liver disease worldwide, with a single approved therapeutic. Previous research has shown that interleukin-22 (IL-22) can suppress β-cell stress, reduce local islet inflammation, restore appropriate insulin production, reverse hyperglycemia, and ameliorate insulin resistance in preclinical models of diabetes. In clinical trials long-acting forms of IL-22 have led to increased proliferation in the skin and intestine, where the IL-22RA1 receptor is highly expressed. To maximise beneficial effects whilst reducing the risk of epithelial proliferation and cancer, we designed short-acting IL-22-bispecific biologic drugs that successfully targeted the liver and pancreas. Here we show 10-fold lower doses of these bispecific biologics exceed the beneficial effects of native IL-22 in multiple preclinical models of MASH, without off-target effects. Treatment restores glycemic control, markedly reduces hepatic steatosis, inflammation, and fibrogenesis. These short-acting IL-22-bispecific targeted biologics are a promising new therapeutic approach for MASH.
Topics: Interleukin-22; Interleukins; Animals; Liver; Pancreas; Humans; Mice; Fatty Liver; Male; Mice, Inbred C57BL; Disease Models, Animal; Insulin Resistance; Receptors, Interleukin
PubMed: 38811532
DOI: 10.1038/s41467-024-48317-x