Impact of therapeutic plasmapheresis on the duration of organ failure in patients with hypertriglyceridemia-associated acute pancreatitis.

BACKGROUND: Plasmapheresis is widely used for severe hypertriglyceridemia-associated acute pancreatitis (HTG-AP) to remove excessive triglycerides from plasma. This study aimed to evaluate whether plasmapheresis could improve the duration of organ failure in HTG-AP patients. METHODS: We analyzed a cohort of patients from a multicenter, prospective, long-running registry (the PERFORM) collecting HTG-AP patients admitted to the study sites within 72 h from the onset of symptoms. This study was based on data collected from November 2020 to March 2023. Patients who had organ failure at enrollment were involved in the analyses. The primary outcome was time to organ failure resolution within 14 days. Multivariable Cox regression model was used to evaluate the association between plasmapheresis and time to organ failure resolution. Directed acyclic graph (DAG) was used to identify potential confounders. RESULTS: A total of 122 HTG-AP patients were included (median [IQR] sequential organ failure assessment (SOFA) score at enrollment, 3.00 [2.00-4.00]). Among the study patients, 46 underwent plasmapheresis, and 76 received medical treatment. The DAG revealed that baseline serum triglyceride, APACHE II score, respiratory failure, cardiovascular failure, and renal failure were potential confounders. After adjusting for the selected confounders, there was no significant difference in time to organ failure resolution between patients undergoing plasmapheresis and those receiving exclusive medical treatment (HR = 1.07; 95%CI 0.68-1.68; P = 0.777). Moreover, the use of plasmapheresis was associated with higher ICU requirements (97.8% [45/46] vs. 65.8% [50/76]; OR, 19.33; 95%CI 2.20 to 169.81; P = 0.008). CONCLUSIONS: In HTG-AP patients with early organ failure, plasmapheresis was not associated with accelerated organ failure resolution compared to medical treatment but may be associated with more ICU admissions. TRIAL REGISTRATION: The PERFORM study was registered in the Chinese Clinical Trial Registry (ChiCTR2000039541). Registered 30 October 2020.

Recurrence of hypertriglyceridemia-associated acute pancreatitis: A multicenter, prospective cohort study.

OBJECTIVES: There are scarce prospective data on recurrent hypertriglyceridemia-associated acute pancreatitis (HTG-AP). This study aimed to investigate the incidence, potential prognostic factors, and clinical relevance of recurrent HTG-AP. METHODS: This study is a multicenter, prospective cohort study. Adult patients with the first HTG-AP attack enrolled in the PERFORM registry between November 2020 and December 2021 were involved. All the study patients were followed up for more than two years with a two-round schedule. The Cox proportional-hazards model was applied to analyze the potential factors. Quality of life was evaluated using the EuroQol five-dimensional five-level health scale (EQ-5D-5L). RESULTS: A total of 184 patients from 25 sites were included in the study, and 161 patients completed the two-round follow-up. Among them, the mean follow-up time for the study patients was 31±4 months, and the incidence rate of recurrent HTG-AP attack was 23 % (37/161). All patients with recurrent episodes required readmission to the hospital. The EQ visual analog scale (VAS) score was significantly lower in patients with recurrent episodes compared to those without (76±10 vs. 82±12; P = 0.02) at the latest follow-up. Age <40 years old (hazard ratio [HR], 3.6; 95 % confidence interval [CI], 1.5-8.7; P = 0.004) and a history of diabetes (HR, 2.6; 95 %CI, 1.3-5.1; P = 0.005) were identified as potential predictor factors for recurrence. CONCLUSIONS: Recurrence of HTG-AP is common, especially for younger patients with diabetes. Recurrence necessitated additional hospital readmissions and was associated with compromised quality of life.

Recurrence rates and risk factors for recurrence after first episode of acute pancreatitis: A systematic review and meta-analysis.

BACKGROUND: There are a certain number of acute pancreatitis (AP) patients who may suffer from multiple episodes and develop recurrent acute pancreatitis (RAP), but recurrence rates and associated risk factors for RAP vary significantly in the published literature. METHODS: We searched PubMed, Web of Science, Scopus, and Embase databases to identify all publications reporting AP recurrence until October 20th, 2022. Meta-analysis and meta-regression were performed to calculate the pooled estimates using the random-effects model. RESULTS: A total of 36 studies met the inclusion criteria and all were used in pooled analyses. The overall rate of recurrence after first-time AP was 21% (95% CI, 18%- 24%), and pooled rates in biliary, alcoholic, idiopathic, and hypertriglyceridemia etiology patients were 12%, 30%, 25%, and 30%, respectively. After managing underlying causes post-discharge, the recurrence rate decreased (14% versus 4% for biliary, 30% versus 6% for alcoholic, and 30% versus 22% for hypertriglyceridemia AP). An increased risk of recurrence was reported in patients with a smoking history (odds ratio [OR] = 1.99), alcoholic etiology (OR = 1.72), male sex (hazard ratio [HR] = 1.63), and local complications (HR = 3.40), while biliary etiology was associated with lower recurrence rates (OR = 0.38). CONCLUSION: More than one-fifth of AP patients experienced recurrence after discharge, with the highest recurrence rate in alcoholic and hypertriglyceridemia etiologies, and managing underlying causes post-discharge was related to decreased incidence. In addition, smoking history, alcoholic etiology, male gender, and presence of local complications were independent risks for the recurrence.

Early Plasmapheresis Among Patients With Hypertriglyceridemia-Associated Acute Pancreatitis.

Importance: The incidence of hypertriglyceridemia-associated acute pancreatitis (HTG-AP) is increasing. Plasmapheresis is theoretically effective in removing triglyceride from plasma, but whether it confers clinical benefits is unclear. Objective: To assess the association between plasmapheresis and the incidence and duration of organ failure among patients with HTG-AP. Design, Setting, and Participants: This is an a priori analysis of data from a multicenter, prospective cohort study with patients enrolled from 28 sites across China. Patients with HTG-AP were admitted within 72 hours from the disease onset. The first patient was enrolled on November 7th, 2020, and the last on November 30th, 2021. The follow-up of the 300th patient was completed on January 30th, 2022. Data were analyzed from April to May 2022. Exposures: Receiving plasmapheresis. The choice of triglyceride-lowering therapies was at the discretion of the treating physicians. Main Outcomes and Measures: The primary outcome was organ failure-free days to 14 days of enrollment. Secondary outcomes included other measures for organ failure, intensive care unit (ICU) admission, duration of ICU and hospital stays, incidence of infected pancreatic necrosis, and 60-day mortality. Propensity score matching (PSM) and inverse probability of treatment weighting (IPTW) analyses were used to control potential confounders. Results: Overall, 267 patients with HTG-AP were enrolled (185 [69.3%] were male; median [IQR] age, 37 [31-43] years), among whom 211 underwent conventional medical treatment and 56 underwent plasmapheresis. PSM created 47 pairs of patients with balanced baseline characteristics. In the matched cohort, no difference was detected concerning organ failure-free days between patients undergoing plasmapheresis or not (median [IQR], 12.0 [8.0-14.0] vs 13.0 [8.0-14.0]; P = .94). Moreover, more patients in the plasmapheresis group required ICU admission (44 [93.6%] vs 24 [51.1%]; P < .001). The IPTW results conformed to the results from the PSM analysis. Conclusions and Relevance: In this large multicenter cohort study of patients with HTG-AP, plasmapheresis was commonly used to lower plasma triglyceride. However, after adjusting for confounders, plasmapheresis was not associated with the incidence and duration of organ failure, but with increased ICU requirements.

Nomogram development and validation for predicting minimally invasive step-up approach failure in infected necrotizing pancreatitis patients: a retrospective cohort study.

BACKGROUND: Previous studies have shown that minimally invasive treatment for infected necrotizing pancreatitis (INP) may be safer and more effective than open necrosectomy (ON), but ON is still irreplaceable in a portion of INP patients. Furthermore, there is a lack of tools to identify INP patients at risk of minimally invasive step-up approach failure (eventually received ON or died), which may enable appropriate treatment for them. Our study aims to identify risk factors that can predict minimally invasive step-up approach failure in INP patients and to develop a nomogram for early prediction. METHODS: Multivariate logistic regression was performed to evaluate the association between minimally invasive step-up approach failure and factors regarding demographics, disease severity, laboratory index, and the location of extrapancreatic necrotic collections. A novel nomogram was developed, and its performance was validated both internally and externally by its discrimination, calibration, and clinical usefulness. RESULTS: There were 267, 89, and 107 patients in the training, internal, and external validation cohorts, respectively. Multivariate logistic regression demonstrated that the computed tomography severity index (CTSI) greater than 8 points, Acute Physiology and Chronic Health Evaluation II (APACHE II) score of 16 points or more, early spontaneous bleeding, fungi infection, granulocyte and platelet decrease within 30 days of acute pancreatitis onset, and extrapancreatic necrosis collection located in small bowel mesentery were independent risk factors for minimally invasive step-up approach failure. The area under the curve and coefficient of determination ( R2 ) of the nomogram constructed from the above factors were 0.920 and 0.644, respectively. The Hosmer-Lemeshow test showed that the model had good fitness ( P =0.206). In addition, the nomogram performed well in both the internal and external validation cohorts. CONCLUSIONS: The nomogram had a good performance in predicting minimally invasive step-up approach failure, which may help clinicians distinguish INP patients at risk of minimally invasive step-up approach failure early.

Distinct differences between calvarial and long bone osteocytes in cell morphologies, gene expression and aging responses.

Osteocytes are the terminally differentiated bone cells resulted from bone formation. Although there are two distinct processes of bone formation, intramembranous and endochondral ossifications contributing to the formation of calvarial and long bones, it is not clear whether the distinct pathways determine the differences between calvaria and femoral cortical bone derived osteocytes. In the present study, we employed confocal structured illumination microscopy and mRNA-sequencing analysis to characterize the morphologic and transcriptomic expression of osteocytes from murine calvaria and mid-shaft femoral cortical bone. Structured illumination microscopy and geometric modelling showed round shaped and irregularly scattered calvarial osteocytes compared to spindle shaped and orderly arrayed cortical osteocytes. mRNA-sequencing analysis indicated different transcriptomic profiles between calvarial and cortical osteocytes and provided evidence that mechanical response of osteocytes may contribute to geometrical differences. Furthermore, transcriptomic analysis showed that these two groups of osteocytes come from distinct pathways with 121 ossification-related genes differentially expressed. Analysis of correlation between ossification and osteocyte geometries via a Venn diagram showed that several genes related to ossification, cytoskeleton organization and dendrite development were differentially expressed between calvarial and cortical osteocytes. Finally, we demonstrated that aging disrupted the organization of dendrites and cortical osteocytes but had no significant effects on calvarial osteocytes. Together, we conclude that calvarial and cortical osteocytes are different in various aspects, which is probably the consequence of their distinct pathways of ossification.

Therapeutic plasma exchange in patients with sepsis: Secondary analysis of a cluster-randomized controlled trial.

INTRODUCTION: Sepsis is life-threatening organ dysfunction caused by infection-related inflammatory response. Therapeutic plasma exchange (TPE) can remove inflammatory mediators and benefit patients in different disease settings. However, no solid evidence showed the efficacy and safety of TPE in sepsis. METHODS: This study was a secondary analysis of a randomized controlled trial. Critically ill patients with sepsis were divided into two groups according to whether treated with TPE. The primary outcome was the delta Sequential Organ Failure Assessment (SOFA) score from days 1 to 7. Secondary outcomes included new-onset organ failure, intensive care unit (ICU)-free and alive days to day 28, and 28-day mortality. Propensity score-matched (PSM) analysis was applied to control confounders. Analysis of covariance (ANCOVA) and logistic regression were used to assess the association between TPE and selected outcomes. RESULTS: Among the 2772 critically ill patients enrolled in the trial, 742 patients with sepsis were selected and 22 patients received TPE were matched with 22 control patients. No significant difference was found in the delta SOFA score and 28-day mortality between TPE group and control group. The ICU-free and alive days in the TPE group were significantly shorter than the control group. CONCLUSIONS: TPE may be not associated with improvement of organ failure and mortality in critically ill patients with sepsis and may be associated with a prolonged ICU stay.

The Effect of Plasma Triglyceride-Lowering Therapy on the Evolution of Organ Function in Early Hypertriglyceridemia-Induced Acute Pancreatitis Patients With Worrisome Features (PERFORM Study): Rationale and Design of a Multicenter, Prospective, Observational, Cohort Study.

Background: Acute pancreatitis (AP) is a potentially life-threatening inflammatory disease with multiple etiologies. The prevalence of hypertriglyceridemia-induced acute pancreatitis (HTG-AP) has been increasing in recent years. It is reported that early triglyceride (TG) levels were associated with the severity of the disease, and TG- lowering therapies, including medical treatment and blood purification, may impact the clinical outcomes. However, there is no consensus regarding the optimal TG-lowering therapy, and clinical practice varies greatly among different centers. Our objective is to evaluate the TG-lowering effects of different therapies and their impact on clinical outcomes in HTG-AP patients with worrisome features. Methods: This is a multicenter, observational, prospective cohort study. A total of approximately 300 patients with HTG-AP with worrisome features are planned to be enrolled. The primary objective of the study is to evaluate the relationship between TG decline and the evolution of organ failure, and patients will be dichotomized depending on the rate of TG decline. The primary outcome is organ failure (OF) free days to 14 days after enrollment. Secondary outcomes include new-onset organ failure, new-onset multiple-organ failure (MOF), new-onset persistent organ failure (POF), new receipt of organ support, requirement of ICU admission, ICU free days to day 14, hospital free days to day 14, 60-day mortality, AP severity grade (Based on the Revised Atlanta Classification), and incidence of systemic and local complications. Generalized linear model (GLM), Fine and Gray competing risk regression, and propensity score matching will be used for statistical analysis. Discussion: Results of this study will reveal the current practice of TG-lowering therapy in HTG-AP and provide necessary data for future trials.

Clinical characteristics and management of gastric outlet obstruction in acute pancreatitis.

OBJECTIVE: The aim of this study was to describe the clinical characteristics and management of gastric outlet obstruction following acute pancreatitis(AP). BACKGROUND: Gastric outlet obstruction (GOO) is not uncommon in acute pancreatitis (AP) and can occur throughout the course. However, the clinical features and related treatment of GOO is rarely reported. METHODS: A retrospective review of AP patients with a diagnosis of GOO from March 2017 to June 2020 was performed. The diagnosis and management of GOO, as well as the demographic characteristics and clinical outcomes of the study patients, were collected and analyzed. RESULTS: Over the three years, there were 60 AP patients developed GOO, constituting an incidence of 5.7%. Thirty-three patients (55.0%, 33/60) developed GOO in the first 4 weeks and 27 patients (45.0%, 27/60) after 4 weeks from onset. Pancreatic necrosis compression (60.6%; 20/33), gastric outlet gastrointestinal edema (27.3%, 9/33) are the main causes of early-onset GOO (≤4 weeks), while wall-off necrosis (92.6%, 25/27) is the leading cause in the late phase (>4 weeks). The management of GOO incorporates both supportive and specific treatment like gastric decompression, gastric juice reinfusion, percutaneous catheter drainage, etc. The mortality of AP patients with GOO (≤4 weeks) was 21.2% and none patients who developed GOO (>4 weeks) died. CONCLUSIONS: GOO, as a gastrointestinal complication developed in AP patients, has two peak incidences in the duration of AP and needs to be paid more attention to.

Machine Learning Models of Acute Kidney Injury Prediction in Acute Pancreatitis Patients.

Background. Acute kidney injury (AKI) has long been recognized as a common and important complication of acute pancreatitis (AP). In the study, machine learning (ML) techniques were used to establish predictive models for AKI in AP patients during hospitalization. This is a retrospective review of prospectively collected data of AP patients admitted within one week after the onset of abdominal pain to our department from January 2014 to January 2019. Eighty patients developed AKI after admission (AKI group) and 254 patients did not (non-AKI group) in the hospital. With the provision of additional information such as demographic characteristics or laboratory data, support vector machine (SVM), random forest (RF), classification and regression tree (CART), and extreme gradient boosting (XGBoost) were used to build models of AKI prediction and compared to the predictive performance of the classic model using logistic regression (LR). XGBoost performed best in predicting AKI with an AUC of 91.93% among the machine learning models. The AUC of logistic regression analysis was 87.28%. Present findings suggest that compared to the classical logistic regression model, machine learning models using features that can be easily obtained at admission had a better performance in predicting AKI in the AP patients.

Early on-demand drainage versus standard management among acute necrotizing pancreatitis patients complicated by persistent organ failure: The protocol for an open-label multi-center randomized controlled trial.

INTRODUCTION/AIM: Pancreatic necrosis occurs in a quarter of patients with acute pancreatitis, many of whom form an acute necrotic collection (ANC). The current standard treatment is to defer percutaneous catheter drainage (PCD) until the latter becomes "walled off," which takes approximately four weeks. The majority of patients that develop persistent organ failure (POF), the primary determinant of mortality, do so within four weeks. To defer PCD until after four weeks may result in a worse outcome because of a missed opportunity to treat early infection and thereby reduce the severity and/or duration of POF. This study is aimed to compare the clinical outcome of the current standard approach with early on-demand PCD in acute necrotizing pancreatitis (ANP) patients with ANC and POF. METHODS/DESIGN: This is an open-label, multi-center, parallel, randomized, controlled trial. All patients with ANP who develop POF during the first week of onset will be screened for eligibility. In total, 120 study subjects will be randomized to either early on-demand PCD or standard care. Patients assigned to the former will receive PCD when they show signs of decompensation like new-onset OF, aggravation of pre-existent OF, and persistent OF for more than a week. The primary composite endpoint is major complication and/or death. Patients will be followed until discharge or death with an additional follow-up 90 days after randomization. DISCUSSION: This study challenges the standard 4-week delay before PCD and will answer the question whether early on-demand PCD is associated with a lower incidence of major complications and/or death.

Ecliptasaponin A induces apoptosis through the activation of ASK1/JNK pathway and autophagy in human lung cancer cells.

BACKGROUND: Non-small cell lung cancer (NSCLC) is one of the causes of carcinomas mortality worldwide. Ecliptasaponin A (ES), a natural product extracted from the plant known as Eclipta prostrata, has been reported as an anti-cancer drug against various cancer cell lines. However, the exact mechanisms of ES have not yet been fully characterized. METHODS: Numerous studies have been done to support that ES has a powerful inhibiting effect on the growth of cancers via the activation of apoptosis and autophagy. To explore the underlying mechanisms of anti-cancer and investigate the relationships of the apoptosis and autophagy, we used apoptosis signal-regulating kinase 1 (ASK1) inhibitor (GS-4997), c-Jun N-terminal kinase (JNK) inhibitor (SP600125), and autophagy inhibitor [chloroquine (CQ) and 3-methyladenine (3-MA)]. RESULTS: ES could potently suppress cell viability and induces apoptotic cell death of human lung cancer cells H460 and H1975. ES activated apoptosis via ASK1/JNK pathway, GS-4997 and SP600125 can attenuated these effects. Furthermore, ES could triggered autophagy in lung cancer cell lines, and the autophagy inhibitor 3-MA and CQ reversed ES-induced apoptosis in H460 and H1975 cells. Furthermore, SP600125 can inhibit autophagy. CONCLUSIONS: This study showed that ES induces apoptosis in human lung cancer cells by triggering enhanced autophagy and ASK1/JNK pathway, which may thus be a promising agent against lung cancer.

Downregulation of HSPA2 inhibits proliferation via ERK1/2 pathway and endoplasmic reticular stress in lung adenocarcinoma.

BACKGROUND: To explore the mechanisms of HSPA2 downregulation in inhibiting the proliferation of lung adenocarcinoma. METHODS: We obtained 85 specimens of human lung adenocarcinoma and specimens of adjacent nontumor tissues from the First Affiliated Hospital, School of Medicine, Zhejiang University. We then analyzed the expression of HSPA2 in these tissues and in lung adenocarcinoma and normal lung cell lines. Human lung adenocarcinoma cell lines were transfected with siRNA silencing HSPA2 and subjected to colony forming, Thiazolyl blue tetrazolium bromide (MTT), propidium iodide flow cytometry, immunofluorescence assay and western blotting to explore the causes of the reduction in the proliferation of lung adenocarcinoma cells and the endoplasmic reticulum stress induced by HSPA2 downregulation. Finally, we confirmed these mechanisms via rescue assay. RESULTS: Greater HSPA2 expression was found in the lung adenocarcinoma specimens than in the specimens of adjacent nontumor tissues, and greater expression was found in lung adenocarcinoma cell lines than in normal cell lines. HSPA2 knockdown via siRNA reduced proliferation and led to G1/S phase cell cycle arrest in the lung adenocarcinoma cell lines. G1/S phase cell cycle arrest triggered by HSPA2 downregulation could be attributed, at least in part, to phosphorylation and activation of the Erk1/2 pathway and probably to activation of IRE1α/PERK-mediated endoplasmic reticulum stress. CONCLUSIONS: HSPA2 plays an important role in the origin and development of lung adenocarcinoma. It is thus deserving of further study as a promising clinical therapeutic target.

Clinical, cellular, and bioinformatic analyses reveal involvement of WRAP53 overexpression in carcinogenesis of lung adenocarcinoma.

Lung cancer, of which non-small cell lung cancer accounts for 80%, remains a leading cause of cancer-related mortality and morbidity worldwide. Our study revealed that the expression of WD repeat containing antisense to P53 (WRAP53) is higher in lung-adenocarcinoma specimens than in specimens from adjacent non-tumor tissues. The prevalence of WRAP53 overexpression was significantly higher in patients with tumor larger than 3.0 cm than in patients with tumor smaller than 3.0 cm. The depletion of WRAP53 inhibits the proliferation of lung-adenocarcinoma A549 and SPC-A-1 cells via G1/S cell-cycle arrest. Several proteins interacting with WRAP53 were identified through co-immunoprecipitation and liquid chromatography/mass spectrometry. These key proteins indicated previously undiscovered functions of WRAP53. These observations strongly suggested that WRAP53 should be considered a promising target in the prevention or treatment of lung adenocarcinoma.