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Endoscopy International Open Sep 2023Recently studies have compared early (<4 weeks) vs. late or standard (>4 weeks) endoscopic treatment of pancreatic necrotic collections (PNC) and have reported... (Review)
Review
Recently studies have compared early (<4 weeks) vs. late or standard (>4 weeks) endoscopic treatment of pancreatic necrotic collections (PNC) and have reported favorable results for early treatment. In this meta-analysis, we compared the efficacy and safety of early vs. late endoscopic treatment of PNC. We reviewed several databases from inception to September 30, 2021 to identify studies that compared early with late endoscopic treatment of PNC. Our outcomes of interest were adverse events (AEs), resolution of PNC, performance of direct endoscopic necrosectomy, need for further interventions, and mean number of endoscopic necrosectomy sessions. We calculated pooled risk ratios (RRs) with 95% confidence intervals (CIs) for categorical variables and mean differences (MDs) with 95% CIs for continuous variables. Data were analyzed by random effect model. Heterogeneity was assessed by I statistic. We included four studies with 427 patients. We found no significant difference in rates of AEs, RR (95% CI) 1.70 (range, 0.56-5.20), resolution of necrotic or fluid collections, RR (95% CI) 0.89 (range, 0.71-1.11), need for further interventions, RR (95% CI) 1.47 (range, 0.70-3.08), direct necrosectomy, RR (95% CI) 1.39 (range, 0.22-8.80), mortality, RR (95% CI) 2.37 (range, 0.26-21.72) and mean number of endoscopic necrosectomy sessions, MD (95% CI) 1.58 (range,-0.20-3.36) between groups. Early endoscopic treatment of PNC can be considered for indications such as infected necrosis or sterile necrosis with symptoms or complications; however, future large multicenter studies are required to further evaluate its safety.
PubMed: 37671081
DOI: 10.1055/a-2100-9076 -
Frontiers in Immunology 2024Human allogeneic pancreatic islet transplantation is a life-changing treatment for patients with severe Type 1 Diabetes (T1D) who suffer from hypoglycemia unawareness... (Review)
Review
Human allogeneic pancreatic islet transplantation is a life-changing treatment for patients with severe Type 1 Diabetes (T1D) who suffer from hypoglycemia unawareness and high risk of severe hypoglycemia. However, intensive immunosuppression is required to prevent immune rejection of the graft, that may in turn lead to undesirable side effects such as toxicity to the islet cells, kidney toxicity, occurrence of opportunistic infections, and malignancies. The shortage of cadaveric human islet donors further limits islet transplantation as a treatment option for widespread adoption. Alternatively, porcine islets have been considered as another source of insulin-secreting cells for transplantation in T1D patients, though xeno-transplants raise concerns over the risk of endogenous retrovirus transmission and immunological incompatibility. As a result, technological advancements have been made to protect transplanted islets from immune rejection and inflammation, ideally in the absence of chronic immunosuppression, to improve the outcomes and accessibility of allogeneic islet cell replacement therapies. These include the use of microencapsulation or macroencapsulation devices designed to provide an immunoprotective environment using a cell-impermeable layer, preventing immune cell attack of the transplanted cells. Other up and coming advancements are based on the use of stem cells as the starting source material for generating islet cells 'on-demand'. These starting stem cell sources include human induced pluripotent stem cells (hiPSCs) that have been genetically engineered to avoid the host immune response, curated HLA-selected donor hiPSCs that can be matched with recipients within a given population, and multipotent stem cells with natural immune privilege properties. These strategies are developed to provide an immune-evasive cell resource for allogeneic cell therapy. This review will summarize the immunological challenges facing islet transplantation and highlight recent bio-engineering and cell-based approaches aimed at avoiding immune rejection, to improve the accessibility of islet cell therapy and enhance treatment outcomes. Better understanding of the different approaches and their limitations can guide future research endeavors towards developing more comprehensive and targeted strategies for creating a more tolerogenic microenvironment, and improve the effectiveness and sustainability of islet transplantation to benefit more patients.
Topics: Islets of Langerhans Transplantation; Humans; Animals; Diabetes Mellitus, Type 1; Graft Rejection; Biomedical Engineering; Islets of Langerhans
PubMed: 38650946
DOI: 10.3389/fimmu.2024.1375177 -
Frontiers in Pharmacology 2023Oncolytic viruses (OVs) represent a novel therapeutic strategy in oncology due to their capability to selectively infect and replicate in cancer cells, triggering a...
Oncolytic viruses (OVs) represent a novel therapeutic strategy in oncology due to their capability to selectively infect and replicate in cancer cells, triggering a direct and/or immune-induced tumor lysis. However, the mechanisms governing OV pharmacokinetics are still poorly understood. This work aims to develop a physiologically based pharmacokinetic model of the novel OV, V937, in non-tumor-bearing mice to get a quantitative understanding of its elimination and tissue uptake processes. Model development was performed using data obtained from 60 mice. Viral levels were quantified from eight tissues after a single intravenous V937 dose. An external dataset was used for model validation. This test set included multiple-dose experiments with different routes of administration. V937 distribution in each organ was described using a physiological structure based on mouse-specific organ blood flows and volumes. Analyses were performed using the non-linear mixed-effects approach with NONMEM 7.4. Viral levels showed a drop from 10 to 10 copies/µg RNA at day 1 in blood, reflected in a high estimate of total clearance (18.2 mL/h). A well-stirred model provided an adequate description for all organs except the muscle and heart, where a saturable uptake process improved data description. The highest numbers of viral copies were observed in the brain, lymph node, kidney, liver, lung, and spleen on the first day after injection. On the other hand, the maximum amount of viral copies in the heart, muscle, and pancreas occurred 3 days after administration. To the best of our knowledge, this is the first physiologically based pharmacokinetic model developed to characterize OV biodistribution, representing a relevant source of quantitative knowledge regarding the behavior of OVs. This model can be further expanded by adding a tumor compartment, where OVs could replicate.
PubMed: 37771727
DOI: 10.3389/fphar.2023.1211452 -
Stem Cell Research & Therapy Jun 2024Diabetes mellitus, a significant global public health challenge, severely impacts human health worldwide. The organoid, an innovative in vitro three-dimensional (3D)... (Review)
Review
Diabetes mellitus, a significant global public health challenge, severely impacts human health worldwide. The organoid, an innovative in vitro three-dimensional (3D) culture model, closely mimics tissues or organs in vivo. Insulin-secreting islet organoid, derived from stem cells induced in vitro with 3D structures, has emerged as a potential alternative for islet transplantation and as a possible disease model that mirrors the human body's in vivo environment, eliminating species difference. This technology has gained considerable attention for its potential in diabetes treatment. Despite advances, the process of stem cell differentiation into islet organoid and its cultivation demonstrates deficiencies, prompting ongoing efforts to develop more efficient differentiation protocols and 3D biomimetic materials. At present, the constructed islet organoid exhibit limitations in their composition, structure, and functionality when compared to natural islets. Consequently, further research is imperative to achieve a multi-tissue system composition and improved insulin secretion functionality in islet organoid, while addressing transplantation-related safety concerns, such as tumorigenicity, immune rejection, infection, and thrombosis. This review delves into the methodologies and strategies for constructing the islet organoid, its application in diabetes treatment, and the pivotal scientific challenges within organoid research, offering fresh perspectives for a deeper understanding of diabetes pathogenesis and the development of therapeutic interventions.
Topics: Humans; Organoids; Islets of Langerhans; Animals; Islets of Langerhans Transplantation; Diabetes Mellitus; Cell Differentiation
PubMed: 38937834
DOI: 10.1186/s13287-024-03780-7 -
Determining the Risk Factors of Complications Due to Endoscopic Retrograde Cholangiopancreatography.Cureus Jan 2024Background and objective The effective use of endoscopic retrograde cholangiopancreatography (ERCP) has been on the rise in diagnosing and treating benign and malignant...
Background and objective The effective use of endoscopic retrograde cholangiopancreatography (ERCP) has been on the rise in diagnosing and treating benign and malignant pathologies of the common bile duct and pancreas. ERCP, a complex procedure requiring high knowledge, skills, and practice, differs from other endoscopic applications as it involves the use of different techniques and equipment and the occurrence of more complications. The most commonly observed complications of ERCP are pancreatitis, bleeding, perforation, and infections. In this study, we aimed to assess the incidence of post-ERCP complications to identify the associated risk factors and indications. Methodology In this study, 181 ERCP procedures performed on 122 consecutive patients in the endoscopy unit of Istanbul Training Hospital were prospectively evaluated by using an observational method to determine the frequency of and risk factors for post-ERCP complications. The patients were followed up in the course of the ERCP procedure and for 30 days after the procedure; the complications and clinical developments were recorded. Results The mean age of the cohort was 59.7 ± 17.7 (19-97) years; 40.9% were female and 59.1% were male. The cannulation success was achieved in 77.3% of the ERCP procedure performed. Among the ERCP procedures applied, 89% were performed for therapeutic purposes, and choledocholithiasis (60.2%) was the most common indication for ERCP. Major complications were detected in 25.4% of the patients after ERCP. The most common major complication was cholangitis (9.9%), followed by pancreatitis (7.2%), cholecystitis (5.5%), bleeding (3.9%), and perforation (1.1%). It was observed that sphincterotomy was associated with an increase in all complications. The incidence of cholangitis decreased in the presence of dilated bile ducts unrelated to obstruction. The increased incidence of pancreatitis was associated with the female gender, the use of sphincterotomy and basket, inexperienced endoscopists, and inpatient admissions. The incidence of cholecystitis, on the other hand, was found to be linked with sphincterotomy and inexperienced endoscopists. Conclusions ERCP is a complex endoscopic procedure that requires high technical knowledge and skill and can cause serious complications. For endoscopists to perform clinically effective and accurate ERCP, it is important that they correctly determine the indications for the procedure, know its potential complications, and refrain from practices that will create complications and are unnecessary as much as possible.
PubMed: 38313949
DOI: 10.7759/cureus.51666 -
European Radiology Oct 2023This multicenter study assessed the extent of pancreatic fatty replacement and its correlation with demographics, iron overload, glucose metabolism, and cardiac...
OBJECTIVES
This multicenter study assessed the extent of pancreatic fatty replacement and its correlation with demographics, iron overload, glucose metabolism, and cardiac complications in a cohort of well-treated patients with thalassemia major (TM).
METHODS
We considered 308 TM patients (median age: 39.79 years; 182 females) consecutively enrolled in the Extension-Myocardial Iron Overload in Thalassemia Network. Magnetic resonance imaging was used to quantify iron overload (IO) and pancreatic fat fraction (FF) by T2* technique, cardiac function by cine images, and to detect replacement myocardial fibrosis by late gadolinium enhancement technique. The glucose metabolism was assessed by the oral glucose tolerance test.
RESULTS
Pancreatic FF was associated with age, body mass index, and history of hepatitis C virus infection. Patients with normal glucose metabolism showed a significantly lower pancreatic FF than patients with impaired fasting glucose (p = 0.030), impaired glucose tolerance (p < 0.0001), and diabetes (p < 0.0001). A normal pancreatic FF (< 6.6%) showed a negative predictive value of 100% for abnormal glucose metabolism. A pancreatic FF > 15.33% predicted the presence of abnormal glucose metabolism. Pancreas FF was inversely correlated with global pancreas and heart T2* values. A normal pancreatic FF showed a negative predictive value of 100% for cardiac iron. Pancreatic FF was significantly higher in patients with myocardial fibrosis (p = 0.002). All patients with cardiac complications had fatty replacement, and they showed a significantly higher pancreatic FF than complications-free patients (p = 0.002).
CONCLUSION
Pancreatic FF is a risk marker not only for alterations of glucose metabolism, but also for cardiac iron and complications, further supporting the close link between pancreatic and cardiac disease.
KEY POINTS
• In thalassemia major, pancreatic fatty replacement by MRI is a frequent clinical entity, predicted by a pancreas T2* < 20.81 ms and associated with a higher risk of alterations in glucose metabolism. • In thalassemia major, pancreatic fatty replacement is a strong risk marker for cardiac iron, replacement fibrosis, and complications, highlighting a deep connection between pancreatic and cardiac impairment.
Topics: Female; Humans; Adult; Iron; beta-Thalassemia; Contrast Media; Liver; Gadolinium; Iron Overload; Magnetic Resonance Imaging; Myocardium; Cardiomyopathies; Glucose; Heart Diseases; Fibrosis; Pancreatic Diseases
PubMed: 37115218
DOI: 10.1007/s00330-023-09630-z -
The British Journal of Surgery Jan 2024Although robotic pancreatoduodenectomy has shown promising outcomes in experienced high-volume centres, it is unclear whether implementation on a nationwide scale is...
BACKGROUND
Although robotic pancreatoduodenectomy has shown promising outcomes in experienced high-volume centres, it is unclear whether implementation on a nationwide scale is safe and beneficial. The aim of this study was to compare the outcomes of the early experience with robotic pancreatoduodenectomy versus open pancreatoduodenectomy in the Netherlands.
METHODS
This was a nationwide retrospective cohort study of all consecutive patients who underwent robotic pancreatoduodenectomy or open pancreatoduodenectomy who were registered in the mandatory Dutch Pancreatic Cancer Audit (18 centres, 2014-2021), starting from the first robotic pancreatoduodenectomy procedure per centre. The main endpoints were major complications (Clavien-Dindo grade greater than or equal to III) and in-hospital/30-day mortality. Propensity-score matching (1 : 1) was used to minimize selection bias.
RESULTS
Overall, 701 patients who underwent robotic pancreatoduodenectomy and 4447 patients who underwent open pancreatoduodenectomy were included. Among the eight centres that performed robotic pancreatoduodenectomy, the median robotic pancreatoduodenectomy experience was 86 (range 48-149), with a 7.3% conversion rate. After matching (698 robotic pancreatoduodenectomy patients versus 698 open pancreatoduodenectomy control patients), no significant differences were found in major complications (40.3% versus 36.2% respectively; P = 0.186), in-hospital/30-day mortality (4.0% versus 3.1% respectively; P = 0.326), and postoperative pancreatic fistula grade B/C (24.9% versus 23.5% respectively; P = 0.578). Robotic pancreatoduodenectomy was associated with a longer operating time (359 min versus 301 min; P < 0.001), less intraoperative blood loss (200 ml versus 500 ml; P < 0.001), fewer wound infections (7.4% versus 12.2%; P = 0.008), and a shorter hospital stay (11 days versus 12 days; P < 0.001). Centres performing greater than or equal to 20 robotic pancreatoduodenectomies annually had a lower mortality rate (2.9% versus 7.3%; P = 0.009) and a lower conversion rate (6.3% versus 11.2%; P = 0.032).
CONCLUSION
This study indicates that robotic pancreatoduodenectomy was safely implemented nationwide, without significant differences in major morbidity and mortality compared with matched open pancreatoduodenectomy patients. Randomized trials should be carried out to verify these findings and confirm the observed benefits of robotic pancreatoduodenectomy versus open pancreatoduodenectomy.
Topics: Humans; Pancreaticoduodenectomy; Retrospective Studies; Robotic Surgical Procedures; Pancreas; Blood Loss, Surgical; Postoperative Complications
PubMed: 38415878
DOI: 10.1093/bjs/znae043 -
Open Forum Infectious Diseases Mar 2024Geographically endemic fungi can cause significant disease among solid organ transplant (SOT) recipients. We provide an update on the epidemiology, clinical... (Review)
Review
BACKGROUND
Geographically endemic fungi can cause significant disease among solid organ transplant (SOT) recipients. We provide an update on the epidemiology, clinical presentation, and outcomes of 5 endemic mycoses in SOT recipients.
METHODS
Multiple databases were reviewed from inception through May 2023 using key words for endemic fungi (eg, coccidioidomycosis or histoplasmosis or etc). We included adult SOT recipients and publications in English or with English translation.
RESULTS
Among 16 cohort studies that reported on blastomycosis (n = 3), coccidioidomycosis (n = 5), histoplasmosis (n = 4), and various endemic mycoses (n = 4), the incidence rates varied, as follows: coccidioidomycosis, 1.2%-5.8%; blastomycosis, 0.14%-0.99%; and histoplasmosis, 0.4%-1.1%. There were 204 reports describing 268 unique cases of endemic mycoses, including 172 histoplasmosis, 31 blastomycosis, 34 coccidioidomycosis, 6 paracoccidioidomycosis, and 25 talaromycosis cases. The majority of patients were male (176 of 261 [67.4%]). Transplanted allografts were mostly kidney (192 of 268 [71.6%]), followed by liver (n = 39 [14.6%]), heart (n = 18 [6.7%]), lung (n = 13 [4.9%]), and combined kidney-liver and kidney-pancreas (n = 6 [2.7%]). In all 5 endemic mycoses, most patients presented with fever (162 of 232 [69.8%]) and disseminated disease (179 of 268 [66.8%]). Cytopenias were frequently reported for histoplasmosis (71 of 91 [78.0%]), coccidioidomycosis (8 of 11 [72.7%]) and talaromycosis (7 of 8 [87.5%]). Graft loss was reported in 12 of 136 patients (8.8%). Death from all-causes was reported in 71 of 267 (26.6%); half of the deaths (n = 34 [50%]) were related to the underlying mycoses.
CONCLUSIONS
Endemic mycoses commonly present with fever, cytopenias and disseminated disease in SOT recipients. There is a relatively high all-cause mortality rate, including many deaths that were attributed to endemic mycoses.
PubMed: 38444820
DOI: 10.1093/ofid/ofae036 -
Frontiers in Surgery 2023Pancreatic necrosis is one of the most severe acute abdominal conditions, accounting for 15%-20% of all patients with acute pancreatitis and characterized by significant...
INTRODUCTION
Pancreatic necrosis is one of the most severe acute abdominal conditions, accounting for 15%-20% of all patients with acute pancreatitis and characterized by significant rates of postoperative complications and mortality. Patients with pancreatic necrosis, in which pathological changes are localized in the proximal pancreas and retroperitoneal space, deserve special attention. This form of the disease includes patients with disconnected main pancreatic duct (MPD) syndrome who have a difficult prognosis.
AIM
The aim of the study was an improvement of treatment results in patients with necrotizing pancreatitis and signs of the dissociation of the pancreas duct system using the endoscopic transpapillary stent placement method.
MATERIAL AND METHODS
This study was a retrospective cohort study. There were 32 patients with acute necrotizing pancreatitis who were managed using the endoscopic transpapillary stent placement method between 2019 and 2021. Disconnected MPD syndrome was diagnosed in all 32 patients. In total, 26 patients were admitted to hospital in the first 72 h, while 6 patients were admitted after 72 h. We diagnosed the necrotizing process located in the proximal and central areas of the pancreas and peripancreatic space in all these patients ("model III").
RESULTS
Positive results related to transpapillary stent placement were noted in 24 (75%) patients (first cohort). A total of 20 patients from this group were admitted to hospital in the first 48 h, and 4 patients were admitted later than 72 h from the onset of disease. Moreover, 8 patients (25%; second cohort) failed to succeed in transpapillary stent placement. Complications in the first cohort occurred in 3 (12.5%) patients: dislocation of the stent into the duodenum occurred in 1 patient, and bleeding after papillosphincterotomy took place in 2 patients. Meanwhile, infected necrotized pancreatitis developed in 5 patients, and 1 patient (5%) died. Complications among the second cohort occurred in 2 (25%) patients: erosive bleeding (after debridement). Infected necrotized pancreatitis developed in 4 patients, and 2 patients (25%) died.
CONCLUSIONS
Endoscopic transpapillary stent placement is an effective minimally invasive approach in the management of patients with necrotizing pancreatitis.
PubMed: 38148749
DOI: 10.3389/fsurg.2023.1328304 -
Cancer Cell International Mar 2024Resistance to targeted therapies represents a significant hurdle to successfully treating hepatocellular carcinoma (HCC). While epigenetic abnormalities are critical...
BACKGROUND
Resistance to targeted therapies represents a significant hurdle to successfully treating hepatocellular carcinoma (HCC). While epigenetic abnormalities are critical determinants of HCC relapse and therapeutic resistance, the underlying mechanisms are poorly understood. We aimed to address whether and how dysregulated epigenetic regulators have regulatory and functional communications in establishing and maintaining drug resistance.
METHODS
HCC-resistant cells were characterized by CCK-8, IncuCyte Live-Cell analysis, flow cytometry and wound-healing assays. Target expression was assessed by qPCR and Western blotting. Global and promoter DNA methylation was measured by dotblotting, methylated-DNA immunoprecipitation and enzymatic digestion. Protein interaction and promoter binding of DNMT3a-TET2 were investigated by co-immunoprecipitation, ChIP-qPCR. The regulatory and functional roles of DNMT3a and TET2 were studied by lentivirus infection and puromycin selection. The association of DNMT and TET expression with drug response and survival of HCC patients was assessed by public datasets, spearman correlation coefficients and online tools.
RESULTS
We identified the coordination of DNMT3a and TET2 as an actionable mechanism of drug resistance in HCC. The faster growth and migration of resistant HCC cells were attributed to DNMT3a and TET2 upregulation followed by increased 5mC and 5hmC production. HCC patients with higher DNMT3a and TET2 had a shorter survival time with a less favorable response to sorafenib therapy than those with lower expression. Cancer stem cell-like cells (CSCs) displayed DNMT3a and TET2 overexpression, which were insensitive to sorafenib. Either genetic or pharmacological suppression of DNMT3a or/and TET2 impaired resistant cell growth and oncosphere formation, and restored sorafenib sensitivity. Mechanistically, DNMT3a did not establish a regulatory circuit with TET2, but formed a complex with TET2 and HDAC2. This complex bound the promoters of oncogenes (i.e., CDK1, CCNA2, RASEF), and upregulated them without involving promoter DNA methylation. In contrast, DNMT3a-TET2 crosstalk silences tumor suppressors (i.e., P15, SOCS2) through a corepressor complex with HDAC2 along with increased promoter DNA methylation.
CONCLUSIONS
We demonstrate that DNMT3a and TET2 act coordinately to regulate HCC cell fate in DNA methylation-dependent and -independent manners, representing strong predictors for drug resistance and poor prognosis, and thus are promising therapeutic targets for refractory HCC.
PubMed: 38528605
DOI: 10.1186/s12935-024-03288-3