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BMC Gastroenterology Jun 2024About 20% of patients with acute pancreatitis develop a necrotising form with a worse prognosis due to frequent appearance of organ failure(s) and/or infection of... (Observational Study)
Observational Study
BACKGROUND
About 20% of patients with acute pancreatitis develop a necrotising form with a worse prognosis due to frequent appearance of organ failure(s) and/or infection of necrosis. Aims of the present study was to evaluate the "step up" approach treatment of infected necrosis in terms of: feasibility, success in resolving infection, morbidity of procedures, risk factors associated with death and long-term sequels.
METHODS
In this observational retrospective monocentric study in the real life, necrotizing acute pancreatitis at the stage of infected walled-off necrosis were treated as follow: first step with drainage (radiologic and/or endoscopic-ultrasound-guided with lumen apposing metal stent); in case of failure, minimally invasive necrosectomy sessions(s) by endoscopy through the stent and/or via retroperitoneal surgery (step 2); If necessary open surgery as a third step. Efficacy was assessed upon to a composite clinical-biological criterion: resolution of organ failure(s), decrease of at least two of clinico-biological criteria among fever, CRP serum level, and leucocytes count).
RESULTS
Forty-one consecutive patients were treated. The step-up strategy: (i) was feasible in 100% of cases; (ii) allowed the infection to be resolved in 33 patients (80.5%); (iii) Morbidity was mild and rapidly resolutive; (iv) the mortality rate at 6 months was of 19.5% (significant factors: SIRS and one or more organ failure(s) at admission, fungal infection, size of the largest collection ≥ 16 cm). During the follow-up (median 72 months): 27% of patients developed an exocrine pancreatic insufficiency, 45% developed or worsened a previous diabetes, 24% had pancreatic fistula and one parietal hernia.
CONCLUSIONS
Beside a very good feasibility, the step-up approach for treatment of infected necrotizing pancreatitis in the real life displays a clinico-biological efficacy in 80% of cases with acceptable morbidity, mortality and long-term sequels regarding the severity of the disease.
Topics: Humans; Pancreatitis, Acute Necrotizing; Retrospective Studies; Male; Female; Drainage; Middle Aged; Aged; Follow-Up Studies; Adult; Feasibility Studies; Stents; Treatment Outcome; Risk Factors
PubMed: 38943052
DOI: 10.1186/s12876-024-03289-6 -
Scientific Reports Jun 2024Telocytes are closely associated with the regulation of tissue smooth muscle dynamics in digestive system disorders. They are widely distributed in the biliary system...
Telocytes are closely associated with the regulation of tissue smooth muscle dynamics in digestive system disorders. They are widely distributed in the biliary system and exert their influence on biliary motility through mechanisms such as the regulation of CCK and their electrophysiological effects on smooth muscle cells. To investigate the relationship between telocytes and benign biliary diseases,such as gallbladder stone disease and biliary dilation syndrome, we conducted histopathological analysis on tissues affected by these conditions. Additionally, we performed immunohistochemistry and immunofluorescence double staining experiments for telocytes. The results indicate that the quantity of telocytes in the gallbladder and bile duct is significantly lower in pathological conditions compared to the control group. This reveals a close association between the decrease in telocyte quantity and impaired gallbladder motility and biliary fibrosis. Furthermore, further investigations have shown a correlation between telocytes in cholesterol gallstones and cholecystokinin-A receptor (CCK-AR), suggesting that elevated cholesterol levels may impair telocytes, leading to a reduction in the quantity of CCK-AR and ultimately resulting in impaired gallbladder motility.Therefore, we hypothesize that telocytes may play a crucial role in maintaining biliary homeostasis, and their deficiency may be associated with the development of benign biliary diseases, including gallstone disease and biliary dilation.
Topics: Telocytes; Cholelithiasis; Humans; Gallbladder; Female; Male; Bile Ducts; Middle Aged; Aged; Dilatation, Pathologic
PubMed: 38942924
DOI: 10.1038/s41598-024-65776-w -
Korean Journal of Radiology Jul 2024To develop and validate a preoperative risk score incorporating carbohydrate antigen (CA) 19-9, CT, and fluorine-18-fluorodeoxyglucose (F-FDG) PET/CT variables to...
Predicting Recurrence-Free Survival After Upfront Surgery in Resectable Pancreatic Ductal Adenocarcinoma: A Preoperative Risk Score Based on CA 19-9, CT, and F-FDG PET/CT.
OBJECTIVE
To develop and validate a preoperative risk score incorporating carbohydrate antigen (CA) 19-9, CT, and fluorine-18-fluorodeoxyglucose (F-FDG) PET/CT variables to predict recurrence-free survival (RFS) after upfront surgery in patients with resectable pancreatic ductal adenocarcinoma (PDAC).
MATERIALS AND METHODS
Patients with resectable PDAC who underwent upfront surgery between 2014 and 2017 (development set) or between 2018 and 2019 (test set) were retrospectively evaluated. In the development set, a risk-scoring system was developed using the multivariable Cox proportional hazards model, including variables associated with RFS. In the test set, the performance of the risk score was evaluated using the Harrell C-index and compared with that of the postoperative pathological tumor stage.
RESULTS
A total of 529 patients, including 335 (198 male; mean age ± standard deviation, 64 ± 9 years) and 194 (103 male; mean age, 66 ± 9 years) patients in the development and test sets, respectively, were evaluated. The risk score included five variables predicting RFS: tumor size (hazard ratio [HR], 1.29 per 1 cm increment; < 0.001), maximal standardized uptake values of tumor ≥ 5.2 (HR, 1.29; = 0.06), suspicious regional lymph nodes (HR, 1.43; = 0.02), possible distant metastasis on F-FDG PET/CT (HR, 2.32; = 0.03), and CA 19-9 (HR, 1.02 per 100 U/mL increment; = 0.002). In the test set, the risk score showed good performance in predicting RFS (C-index, 0.61), similar to that of the pathologic tumor stage (C-index, 0.64; = 0.17).
CONCLUSION
The proposed risk score based on preoperative CA 19-9, CT, and F-FDG PET/CT variables may have clinical utility in selecting high-risk patients with resectable PDAC.
Topics: Humans; Male; Fluorodeoxyglucose F18; Female; Positron Emission Tomography Computed Tomography; Middle Aged; Carcinoma, Pancreatic Ductal; Aged; Pancreatic Neoplasms; Retrospective Studies; Radiopharmaceuticals; CA-19-9 Antigen; Tomography, X-Ray Computed; Neoplasm Recurrence, Local; Risk Assessment; Disease-Free Survival; Predictive Value of Tests
PubMed: 38942458
DOI: 10.3348/kjr.2023.1235 -
Critical Reviews in Oncology/hematology Jun 2024Pancreatic cancer remains one of the deadliest malignancies with an overall 5-year survival rate of 13%. This dismal fact can be partly attributed to currently limited... (Review)
Review
Pancreatic cancer remains one of the deadliest malignancies with an overall 5-year survival rate of 13%. This dismal fact can be partly attributed to currently limited understanding of tumor heterogeneity and immune microenvironment. Traditional bulk-sequencing techniques overlook the diversity of tumor cells, while single-cell sequencing disorganizes the position localizing of cells in tumor microenvironment. The advent of spatial transcriptomics (ST) presents a novel solution by integrating location and whole transcript expression information. This technology allows for detailed observation of spatio-temporal changes across various cell subtypes within the pancreatic tumor microenvironment, providing insights into their potential functions. This review offers an overview of recent studies implementing ST in pancreatic cancer research, highlighting its instrumental role in investigating the heterogeneity and functions of tumor cells, stromal cells, and immune cells. On the basis, we also prospected and summarized the clinical application scenarios, technical limitations and challenges of ST technology in pancreatic cancer.
PubMed: 38942220
DOI: 10.1016/j.critrevonc.2024.104430 -
Stem Cell Reports Jun 2024Genetic differences between pluripotent stem cell lines cause variable activity of extracellular signaling pathways, limiting reproducibility of directed differentiation...
Genetic differences between pluripotent stem cell lines cause variable activity of extracellular signaling pathways, limiting reproducibility of directed differentiation protocols. Here we used human embryonic stem cells (hESCs) to interrogate how exogenous factors modulate endogenous signaling events during specification of foregut endoderm lineages. We find that transforming growth factor β1 (TGF-β1) activates a putative human OTX2/LHX1 gene regulatory network which promotes anterior fate by antagonizing endogenous Wnt signaling. In contrast to Porcupine inhibition, TGF-β1 effects cannot be reversed by exogenous Wnt ligands, suggesting that induction of SHISA proteins and intracellular accumulation of Fzd receptors render TGF-β1-treated cells refractory to Wnt signaling. Subsequently, TGF-β1-mediated inhibition of BMP and Wnt signaling suppresses liver fate and promotes pancreas fate. Furthermore, combined TGF-β1 treatment and Wnt inhibition during pancreatic specification reproducibly and robustly enhance INSULIN cell yield across hESC lines. This modification of widely used differentiation protocols will enhance pancreatic β cell yield for cell-based therapeutic applications.
PubMed: 38942030
DOI: 10.1016/j.stemcr.2024.05.010 -
EBioMedicine Jun 2024Pancreatic ductal adenocarcinoma (PDAC) is a tumour entity with unmet medical need. To assess the therapeutic potential of oncolytic virotherapy (OVT) against PDAC,...
BACKGROUND
Pancreatic ductal adenocarcinoma (PDAC) is a tumour entity with unmet medical need. To assess the therapeutic potential of oncolytic virotherapy (OVT) against PDAC, different oncolytic viruses (OVs) are currently investigated in clinical trials. However, systematic comparisons of these different OVs in terms of efficacy against PDAC and biomarkers predicting therapeutic response are lacking.
METHODS
We screened fourteen patient-derived PDAC cultures which reflect the intra- and intertumoural heterogeneity of PDAC for their sensitivity to five clinically relevant OVs, namely serotype 5 adenovirus Ad5-hTERT, herpes virus T-VEC, measles vaccine strain MV-NIS, reovirus jin-3, and protoparvovirus H-1PV. Live cell analysis, quantification of viral genome/gene expression, cell viability as well as cytotoxicity assays and titration of viral progeny were conducted. Transcriptome profiling was employed to identify potential predictive biomarkers for response to OV treatment.
FINDINGS
Patient-derived PDAC cultures showed individual response patterns to OV treatment. Twelve of fourteen cultures were responsive to at least one OV, with no single OV proving superior or inferior across all cultures. Known host factors for distinct viruses were retrieved as potential biomarkers. Compared to the classical molecular subtype, the quasi-mesenchymal or basal-like subtype of PDAC was found to be more sensitive to H-1PV, jin-3, and T-VEC. Generally, expression of viral entry receptors did not correlate with sensitivity to OV treatment, with one exception: Expression of Galectin-1 (LGALS1), a factor involved in H-1PV entry, positively correlated with H-1PV induced cell killing. Rather, cellular pathways controlling immunological, metabolic and proliferative signaling appeared to determine outcome. For instance, high baseline expression of interferon-stimulated genes (ISGs) correlated with relative resistance to oncolytic measles virus, whereas low cyclic GMP-AMP synthase (cGAS) expression was associated with exceptional response. Combination treatment of MV-NIS with a cGAS inhibitor improved tumour cell killing in several PDAC cultures and cells overexpressing cGAS were found to be less sensitive to MV oncolysis.
INTERPRETATION
Considering the heterogeneity of PDAC and the complexity of biological therapies such as OVs, no single biomarker can explain the spectrum of response patterns. For selection of a particular OV, PDAC molecular subtype, ISG expression as well as activation of distinct signaling and metabolic pathways should be considered. Combination therapies can overcome resistance in specific constellations. Overall, oncolytic virotherapy is a viable treatment option for PDAC, which warrants further development. This study highlights the need for personalised treatment in OVT. By providing all primary data, this study provides a rich source and guidance for ongoing developments.
FUNDING
German National Science Foundation (Deutsche Forschungsgemeinschaft, DFG), German Cancer Aid (Deutsche Krebshilfe), German National Academic Scholarship Foundation (Studienstiftung des deutschen Volkes), Survival with Pancreatic Cancer Foundation.
PubMed: 38941955
DOI: 10.1016/j.ebiom.2024.105219 -
Tuberculosis (Edinburgh, Scotland) Jun 2024Isoniazid-induced pancreatitis is a potentially serious adverse drug reaction, however, the frequency of its occurrence is unknown. We conducted a systematic review to... (Review)
Review
BACKGROUND
Isoniazid-induced pancreatitis is a potentially serious adverse drug reaction, however, the frequency of its occurrence is unknown. We conducted a systematic review to explore this adverse drug reaction comprehensively.
METHODS
We performed an advanced search in PubMed, Web of Science, Scopus, Ovid, and Embase for studies that reported isoniazid-induced pancreatitis. From the extracted data of eligible cases, we performed a descriptive analysis and a methodological risk of bias assessment using a standardized tool.
RESULTS
We included 16 case reports from eight countries comprising 16 patients in our systematic review. Most of the isoniazid-induced pancreatitis cases were extrapulmonary tuberculosis cases. We found the mean age across all case reports was 36.7 years. In all the cases, discontinuation of isoniazid resulted in the resolution of pancreatitis.
CONCLUSIONS
We found the latency period for isoniazid-induced pancreatitis to be ranged from 12 to 45 days after initiation of isoniazid therapy. A low threshold for screening of pancreatitis by measuring pancreatic enzymes in patients on isoniazid presenting with acute abdominal pain is recommended. This would facilitate an early diagnosis and discontinuation of isoniazid, thus reducing the severity of pancreatitis and preventing the complications of pancreatitis.
PubMed: 38941909
DOI: 10.1016/j.tube.2024.102535 -
Biophysical Chemistry Jun 2024Human islet amyloid polypeptide (hIAPP) forms amyloid deposits that contribute to β-cell death in pancreatic islets and are considered a hallmark of Type II diabetes...
Human islet amyloid polypeptide (hIAPP) forms amyloid deposits that contribute to β-cell death in pancreatic islets and are considered a hallmark of Type II diabetes Mellitus (T2DM). Evidence suggests that the early oligomers of hIAPP formed during the aggregation process are the primary pathological agent in islet amyloid induced β-cell death. The self-assembly mechanism of hIAPP, however, remains elusive, largely due to limitations in conventional biophysical techniques for probing the distribution or capturing detailed structures of the early, structurally dynamic oligomers. The advent of Ion-mobility Mass Spectrometry (IM-MS) has enabled the characterisation of hIAPP early oligomers in the gas phase, paving the way towards a deeper understanding of the oligomerisation mechanism and the correlation of structural information with the cytotoxicity of the oligomers. The sensitivity and the rapid structural characterisation provided by IM-MS also show promise in screening hIAPP inhibitors, categorising their modes of inhibition through "spectral fingerprints". This review delves into the application of IM-MS to the dissection of the complex steps of hIAPP oligomerisation, examining the inhibitory influence of metal ions, and exploring the characterisation of hetero-oligomerisation with different hIAPP variants. We highlight the potential of IM-MS as a tool for the high-throughput screening of hIAPP inhibitors, and for providing insights into their modes of action. Finally, we discuss advances afforded by recent advancements in tandem IM-MS and the combination of gas phase spectroscopy with IM-MS, which promise to deliver a more sensitive and higher-resolution structural portrait of hIAPP oligomers. Such information may help facilitate a new era of targeted therapeutic strategies for islet amyloidosis in T2DM.
PubMed: 38941872
DOI: 10.1016/j.bpc.2024.107285 -
Medicine Jun 2024Acute pancreatitis (AP) is a common emergency condition with high morbidity, mortality, and socio-economic impact. Soluble urokinase plasminogen activator receptor...
BACKGROUND
Acute pancreatitis (AP) is a common emergency condition with high morbidity, mortality, and socio-economic impact. Soluble urokinase plasminogen activator receptor (suPAR) is a potential biomarker for AP prognosis. This study systematically reviews the literature on suPAR's prognostic roles in assessing AP severity, organ failure, mortality, and other pathological markers.
METHODS
A comprehensive search of 5 databases up to March 19, 2023, was conducted, selecting cohort studies that examined suPAR's relationship with AP outcomes. Outcome variables included AP severity, organ failure, mortality, hospital stay length, and suPAR's association with other inflammatory markers. Our paper has been registered on Prospero (ID: CRD42023410628).
RESULTS
Nine prospective observational studies with 1033 AP patients were included. Seven of eight studies found suPAR significantly elevated in severe acute pancreatitis (P < .05). Four studies showed suPAR effectively predicted organ failure risk, and 4 studies concluded suPAR significantly predicted mortality (P < .05). The review had no high-risk studies, enhancing credibility.
CONCLUSION
suPAR is a valuable prognostic marker in AP, significantly predicting severity, organ failure, hospital stay length, and mortality. Further large-scale studies are needed to explore suPAR's role in other clinical outcomes related to AP disease course, to establish it as a mainstay of AP prognosis.
Topics: Humans; Pancreatitis; Receptors, Urokinase Plasminogen Activator; Prognosis; Biomarkers; Systematic Reviews as Topic; Severity of Illness Index; Length of Stay; Acute Disease
PubMed: 38941433
DOI: 10.1097/MD.0000000000037064 -
JAMA Network Open Jun 2024While most patients with acute pancreatitis (AP) fulfill diagnostic criteria with characteristic abdominal pain and serum lipase levels of at least 3 times the upper...
IMPORTANCE
While most patients with acute pancreatitis (AP) fulfill diagnostic criteria with characteristic abdominal pain and serum lipase levels of at least 3 times the upper limit of normal (reference range) at presentation, early imaging is often used for confirmation. A prior prediction model and corresponding point-based score were developed using nonimaging parameters to diagnose AP in patients presenting to the emergency department (ED).
OBJECTIVE
To evaluate the performance of the prediction model to diagnose AP in a prospective patient cohort.
DESIGN, SETTING, AND PARTICIPANTS
This prospective diagnostic study included consecutive adult patients presenting to the ED between January 1, 2020, and March 9, 2021, at 2 large academic medical centers in the northeastern US with serum lipase levels at least 3 times the upper limit of normal. Patients transferred from outside institutions or with malignant disease and established intra-abdominal metastases, acute trauma, or altered mentation were excluded. Data were analyzed from October 15 to October 23, 2023.
EXPOSURES
Participants were assigned scores for initial serum lipase level, number of prior AP episodes, prior cholelithiasis, abdominal surgery within 2 months, presence of epigastric pain, pain of worsening severity, duration from pain onset to presentation, and pain level at ED presentation.
MAIN OUTCOME AND MEASURES
A final diagnosis of AP, established by expert review of hospitalization records.
RESULTS
Prospective scores in 349 participants (mean [SD] age, 53.0 [18.8] years; 184 women [52.7%]; 66 Black [18.9%]; 199 White [57.0%]) demonstrated an area under the receiver operating characteristics curve of 0.91. A score of at least 6 points achieved highest accuracy (F score, 82.0), corresponding to a sensitivity of 81.5%, specificity of 85.9%, positive predictive value of 82.6%, and negative predictive value of 85.1% for AP diagnosis. Early computed tomography or magnetic resonance imaging was performed more often in participants predicted to have AP (116 of 155 [74.8%] with a score ≥6 vs 111 of 194 [57.2%] with a score <6; P < .001). Early imaging revealed an alternative diagnosis in 8 of 116 participants (6.9%) with scores of at least 6 points, 1 of 93 (1.1%) with scores of at least 7 points, and 1 of 73 (1.4%) with scores of at least 8 points.
CONCLUSIONS AND RELEVANCE
In this multicenter diagnostic study, the prediction model demonstrated excellent AP diagnostic accuracy. Its application may be used to avoid unnecessary confirmatory imaging.
Topics: Humans; Pancreatitis; Female; Male; Prospective Studies; Middle Aged; Adult; Lipase; Emergency Service, Hospital; Aged; Predictive Value of Tests; Acute Disease; Abdominal Pain
PubMed: 38941094
DOI: 10.1001/jamanetworkopen.2024.19014