The Diabetes-Pancreatic Ductal Adenocarcinoma Working Group (DM-PDAC WG) was formed within the Consortium for Study of Chronic Pancreatitis Diabetes and Pancreatic Cancer (CPDPC) to study the link between new-onset diabetes and pancreatic cancer. Its goals were to i) estimate the risk of PDAC in a prospectively assembled cohort of individuals with NOD identified at its glycemic onset (GNOD), ii) Establish a biobank of clinically annotated bio-specimens from GNOD subjects with pre-symptomatic PDAC and control new-onset type 2 DM, iii) Conduct Phase 3 validation studies of promising biomarkers for identification of occult PDAC in GNOD; iv) Provide a platform for development of a future interventional screening protocol for early detection of PDAC in NOD patients that incorporates imaging studies and clinical algorithms. The study identified >20,000 subjects with GNOD and assembled a biobank of serial blood samples in 2270 GNOD subjects. The risk of PDAC in GNOD and the distribution of lead time from GNOD to PDAC clinical diagnosis have been definitively defined in a cohort of 18,838 GNOD subjects identified during the course of the study. Ongoing biomarker and metabolomics studies will not only provide data on performance of tested biomarkers, but also an unprecedented repository of data on a large number of type 2 DM subjects. There are also ongoing studies on the "science of NOD" to understand its pathogenesis. Overall, the DM-PDAC Working Group has been successful in its mission to further our understanding of the link between diabetes pancreatic cancer.
This article provides an overview of 10 years of accomplishments of the National Institute of Diabetes and Digestive and Kidney Diseases-supported Consortium for the Study of Chronic Pancreatitis, Diabetes, and Pancreatic Cancer (CPDPC) and outlines strategies for the next 5 years as the Chronic Pancreatitis Clinical Research Consortium (CPCRC). The overriding objectives of the CPDPC have been to provide an enhanced understanding of the natural history of recurrent acute and chronic pancreatitis in children and adults; to investigate the interrelationships between diabetes on both the progressive forms of pancreatitis and pancreatic cancer; and to develop methods for diagnosis, treatment, and clinical management of these pancreatic disorders. This article also serves as an introduction for 2 papers in this issue of Pancreas describing the progress and direction for 2 of the 4 working groups of CPDPC-the Pediatric and the Adult Recurrent Acute and Chronic Pancreatitis Groups. These 2 working groups have made great progress in studies of the natural history, mechanisms, etiology, complications, and treatment of pancreatitis in adults and children. The working groups investigating diabetes due to pancreatitis or pancreatic cancer (Diabetes Mellitus and Pancreatic Cancer Working Group and the Type 3c Diabetes Working Group) have also made great progress in studies focused on the interrelationships between the endocrine and exocrine pancreas, and these are published in the journal Pancreatology .
Aggressive fluid expansion has been an undisputed aspect of navigating the early stages of acute pancreatitis. Evidence produced by the WATERFALL trial supports a more conservative approach to fluid resuscitation as patients face higher odds of fluid overload while experiencing no benefit of their underlying condition. This retrospective monocentric observational study seeks to identify fluid-related complications in patients with acute pancreatitis of any grade of severity. One hundred twenty-nine patients with acute pancreatitis including moderately severe and severe courses were divided into groups based on their cumulative fluid administration within the first 24 hours (restrictive: <3 L; moderate: 3-6 L; aggressive: >6 L). Vital signs and laboratory values were reported at defined time points. Most patients were allocated to the group of moderate fluid resuscitation. At baseline, patients did not differ in systemic disease severity indicated by critical illness scores. A higher proportion of patients with moderately severe or severe pancreatitis associated with an acute peripancreatic fluid collection had previously been administered >6 L fluids. C-reactive protein levels were significantly higher in patients with >6 L, whereas albumin levels were decreased.Patients receiving >6 L fluids were more likely to show radiologic features of pulmonary fluid overload and be transferred to intensive care unit. In addition, oxygenation markedly deteriorated in aggressively hydrated patients versus restrictive and moderate fluid regimes. The extent of fluid resuscitation was found to be strongly associated with the prevalence of clinical and radiologic signs of pulmonary fluid overload. Furthermore, moderately severe and severe courses of pancreatitis were more frequently observed in excessively hydrated patients.
Acute pancreatitis (AP) may develop in patients with cirrhosis of the liver due to higher prevalence of etiological factors such as alcoholism and gallstones in them. However, the data are limited regarding the clinical outcomes in patients with AP and underlying cirrhosis. National Inpatient Sample (2016-2020) was reviewed to identify adult inpatients with AP. They were divided into three groups based on presence of cirrhosis. STATA was used to compare clinical outcomes and resource utilization using multivariate and propensity score-matched analyses. 1.38 million patients were admitted with AP, with 2.2 % and 2.1 % having compensated and decompensated cirrhosis respectively. Compared to non-cirrhotics, patients with decompensated cirrhosis had higher odds of mortality (OR 4.27,95 %C.I.:3.53-5.17,p = 0.001), length of stay (LOS) (1.9 days,95 %C.I.:1.69-2.10,p = 0.001) and total hospitalization charges (THC) (9544$,95 %C.I.:16,484-22,603,p = 0.001); worse secondary outcomes including AP-related: sepsis (OR 2.59,95 %C.I.:2.23-3.00,p-0.001), acute kidney injury (AKI) (OR 1.64,95 %C.I.:1.53-1.77,p = 0.001), shock (OR 2.8,95 %C.I.:2.23-3.51,p = 0.001), acute respiratory failure (OR 1.76,95 %C.I.:1.56-1.99,p = 0.001); and cirrhosis-related: gastrointestinal bleeding (OR 5.08,95 %C.I.:4.62-5.59,p = 0.001) and portal vein thrombosis (OR 9.22,95 %C.I.:8.22-10.36,p = 0.001). Patients with compensated cirrhosis had similar odds of mortality, lower LOS (-0.23 days,95 %C.I.: 0.34 to -0.12,p = 0.001) and THC (-2727$,95 %C.I.: 4091 to -1362,p = 0.001) but higher odds of gastrointestinal bleeding (OR 1.92,95 %C.I.:1.50-2.45,p = 0.001), blood transfusion requirements (OR 1.52,95 %C.I.:1.16-2.00,p = 0.002) and portal vein thrombosis (OR 1.93,95 %C.I.:1.53-2.44,p = 0.001). Patients with decompensated cirrhosis had higher odds of mortality, higher healthcare resource utilization, and worse clinical outcomes compared to those without cirrhosis. Patients with compensated cirrhosis had higher odds of portal vein thrombosis, GI bleeding, and blood transfusion. Complications of portal hypertension are likely the primary drivers behind increased odds of mortality in cirrhotic patients with AP. Patients with decompensated cirrhosis also seem to be at a higher risk of complications due to AP.
Early-onset pancreatic adenocarcinoma (EOPA), defined as the diagnosis of pancreatic adenocarcinoma before the age of 50, is increasingly reported and may differ molecularly from average-onset pancreatic adenocarcinoma (AOPA). Understanding these differences is essential for precision medicine in this poor-prognosis malignancy. A systematic review and meta-analysis were conducted following PRISMA guidelines. Studies published between 2015 and 2025 reporting molecular data on EOPA and/or AOPA were identified. Comparative studies stratified by age group for molecular alterations were included in the meta-analysis. Quality assessment was performed using the JBI checklist. This study aimed at systematically review and meta-analyse existing data comparing the molecular landscape of EOPA and AOPA, and evaluate whether EOPA constitutes a distinct molecular subgroup of pancreatic adenocarcinoma. Thirty-nine articles were included in the systematic review, of which eight met criteria for meta-analysis. KRAS mutations were significantly less frequent in EOPA than in AOPA (OR = 0.61; 95%CI [0.43-0.86], p = 0.005). No significant differences were observed for TP53, CDKN2A, SMAD4, or BRCA1/2 alterations. Sensitivity analyses confirmed the robustness of the KRAS finding. Study heterogeneity was moderate (I2 = 40%). Quality assessment revealed substantial variability in design, molecular methods, and reporting standards. EOPA is enriched in KRAS wild-type tumours. This profile may offer alternative therapeutic opportunities, including RNA-based fusion detection, inclusion in targeted therapy trials, and suggest alternative oncogenic pathways for a proportion of this subpopulation. Standardised definitions, consistent molecular reporting, and exploration of age-specific risk factors are critical to improve understanding and management of EOPA.
The aim of our study was to evaluate if the histopathological changes occurring in the pancreas post neoadjuvant-therapy (PNAT) for pancreatic ductal adenocarcinoma (PDAC) may negatively affect the assessment of intra-operative frozen section (FS) analysis of pancreatic resection margins (PRMs). The clinicopathological data of patients who underwent pancreatoduodenectomy for PDAC between 2015 and 2022 were analyzed. Comparison of the accuracy of the FS analysis in treatment naïve (TN) and PNAT patients for all pancreatic margins was performed. We identified 81 patients with PDAC (40 female, 41 male) of which 47 (58.0 %) were TN and 34 (42.0 %) PNAT. Including FSs performed for re-excisions of initially positive PRMs, we identified 2/103 discrepancies for the pancreatic neck margin, one in a TN patient and one in a PNAT patient; one discrepancy for the common bile duct margin (1/47) in a TN patient; and 2/14 discrepancies for the uncinate margin, both in TN patients. In summary, accuracy of FS analysis was similar in the PNAT and TN groups (98.8 % vs. 96.7 %). The histopathological changes occurring in the pancreas PNAT for PDAC do not affect the histopathological interpretation of FS analysis of PRMs, and the accuracy of FS analysis is similar in the PNAT and TN patients.
Early detection is critical in pancreatic ductal adenocarcinoma (PDAC)-one of the most lethal malignancies due to its typically late diagnosis. In this study, we aimed to validate an epidemiological risk score (ERS) designed to identify individuals at increased risk of developing PDAC prior to the use of imaging or other diagnostic procedures. The ERS was constructed through a meta-analysis of 24 well-established epidemiological risk factors. We applied this score to a prospective cohort of 178 high-risk individuals with a family history of PDAC within the IMAGene project (ClinicalTrials.gov registration code: NCT06334458). To evaluate the predictive value of the ERS, all participants underwent whole-body or abdominal magnetic resonance imaging (MRI) and the findings were classified according to the Oncologically Relevant Findings Reporting and Data System criteria to identify and categorize lesions based on their malignant potential. External validation was conducted by using a subset of the UK Biobank (UKB) cohort (≈300 000 individuals), among whom 1648 were diagnosed with PDAC. Higher ERS values were associated with the presence of potentially malignant lesions on MRI. Both pancreatic and extra-pancreatic malignant lesions were more frequent among individuals with higher ERS scores (P = .01 and P = .02 respectively) compared with controls. External validation in PDAC cases within the UKB cohort confirmed these associations. Our findings support the integration of the ERS as a feasible, low-cost tool for PDAC risk stratification, with the potential to facilitate earlier detection and improve clinical outcomes.
Acute pancreatitis (AP) varies in severity, and traditional severity stratifications often fail to predict its early course. In people living with HIV (PLWH), chronic immune dysregulation leads to aberrant cytokine responses which influence biomarker performance. We hypothesize that in regions with high prevalence of HIV infection, HIV status will influence the immune biomarker performance in the prediction of severity of AP. In this prospective case-control study conducted in KwaZulu-Natal, 144 adult patients with AP (29 % PLWH) were enrolled. Blood samples were collected within 24 h of admission, and plasma was isolated and cryopreserved before cytokine levels were quantified using a multiplex electrochemiluminescence assay. Clinical severity was assessed using revised Atlanta classification. Receiver operating characteristic analyses were performed to derive optimal biomarker thresholds based on Youden's index, with significance set at p < 0.01. In people without HIV, IL-6, TNF-α, IL-15, IL-17, and MCP-1 were significantly upregulated in severe AP, with IL-15 demonstrating the highest discriminative performance (AUC 0.917; optimal cut-off 3.79 pg/mL; sensitivity 94.1 %, specificity 72.9 %). In PLWH patients, TNF-α was the only cytokine significantly associated with AP severity (AUC 0.974; optimal cut-off 9.42 pg/mL; sensitivity 100 %, specificity 97.4 %), while IL-17 did not predict severity in PLWH. Across the combined cohort, cytokine thresholds were higher in PLWH. Distinct immune signatures correlate with AP severity and are significantly influenced by HIV status. IL-15 outperformed IL-6, TNF-α, IL-17, and MCP-1 in people without HIV, whereas TNF-α was the only predictor of severity in PLWH. Higher thresholds for prediction of severity in PLWH underscore the need for HIV-specific biomarker thresholds and further research into tailored severity stratification, and development of immunomodulating therapies in AP.
Early identification of severe acute pancreatitis (SAP) within 24 h of admission remains challenging and specific biomarkers reflecting the underlying mechanisms, particularly pancreatic necrosis, are lacking. We have previously identified a crucial role of AXL and MERTK in regulating pancreatic necrosis. Their ligands, Growth Arrest-Specific 6 (GAS6) and Protein S (PROS1) can be detected in serum. Therefore, this study aims to evaluate the value of serum GAS6 and PROS1 levels within 24 h of admission for identifying SAP. Serum GAS6 and PROS1 were initially assessed in a retrospective discovery cohort and subsequently validated in a prospective cohort using ELISA. A subset of patients provided serial serum samples over 4 weeks to analyze temporal dynamics and correlations with disease severity. A total of 869 AP patients were enrolled. Serum GAS6 levels were significantly elevated and PROS1 levels reduced compared with healthy controls, with greater changes in moderately severe and severe cases. As a single marker, GAS6 showed robust performance for predicting SAP (AUC = 0.722, 95%CI: 0.620-0.832), outperforming CRP (AUC = 0.595) and BUN (AUC = 0.681), and comparable to SIRS (AUC = 0.659), BISAP (AUC = 0.755), and APACHE-II (AUC = 0.797). The GAS6+BISAP combination yielded an AUC of 0.818, significantly superior to GAS6 alone (p = 0.001), SIRS (p = 0.013), CRP (p = 0.002), and BUN (p = 0.015), and numerically higher than APACHE-II (0.818 vs. 0.797). The temporal dynamic changes of both further correlated with disease severity. Serum levels of GAS6 measured within 24 h provide a valuable, rapid approach for identifying SAP, and when combined with established scoring systems, can further improve performance.
Fibrosis is considered the criterion standard for diagnosing chronic pancreatitis (CP) but adequate tissue specimens are difficult to obtain, carry risk and are often obtained at the time of surgery in advanced stages of CP. Noninvasive biomarkers that correlate with fibrosis across the continuum of pancreatitis are needed. Our aim was to determine which clinical variables are associated with fibrosis in patients with recurrent acute pancreatitis (RAP) or CP undergoing total pancreatectomy with islet autotransplantation (TPIAT). The demographic, clinical and radiologic data for patients undergoing TPIAT for RAP or CP between 2011 and 2023 were reviewed. Excisional biopsies from the proximal and distal pancreas were each scored from 0 to 6 for both perilobular and intralobular fibrosis, and the score of each biopsy was the sum of perilobular and intralobular fibrosis (0-12). The fibrosis score (FS), ranging from 0 to 12, was the mean FS from the proximal and distal pancreas. There were 88 patients with a mean age 38 ± 14 years and 46 (52.3 %) were female. There were 35 (39.8 %) and 53 (60.2 %) with RAP and CP, respectively. Genetic (52.3 %) and idiopathic (37.5 %) were the most common etiologies. The mean FS was 6.52 ± 3.53. Large duct CP (β = 3, p = 0.001), exocrine pancreatic insufficiency (EPI) (β = 1.5, p = 0.037) and a genetic etiology (β = 1.6, p = 0.03) were significant predictors of fibrosis after adjusting for age, BMI, disease duration and use of oral hypoglycemic drugs and/or insulin. Large duct CP, genetic etiology and EPI are all independent predictors of pancreatic fibrosis in a cohort of patients undergoing TPIAT. Computed tomography (CT) imaging and fecal elastase-1 (FE-1) concentration may be sufficient to estimate fibrosis without acquisition of a tissue specimen.
Nonalcoholic fatty liver disease (NAFLD) has been identified as an emerging risk factor for hepatocellular carcinoma (HCC). Identifying non-cirrhotic NAFLD patients at risk for HCC is crucial. We aimed to investigate the utility of noninvasive tests (NITs) as predictors for HCC and to determine optimal and cost-effective NIT cutoffs for HCC surveillance in non-cirrhotic NAFLD patients. Medline, EMBASE, and Scopus databases were searched for studies evaluating the relationship between NITs and HCC in this population. Random-effects models were used to estimate hazard ratios or risk ratios and 95% confidence interval (95% CI). Cutoffs of NITs for identifying high-risk patients for HCC were determined. This systematic review comprised 20 studies. A meta-analysis of 379 194 patients was conducted using six studies with individual patient data and five studies with aggregate data. Among NITs studied, fibrosis-4 index (FIB-4), aspartate aminotransferase to platelet ratio index (APRI), and NAFLD fibrosis score (NFS) were significantly associated with HCC, with pooled risk ratio (95% CI) of 9.21 (5.79-14.64), pooled hazard ratio of 12.53 (6.57-23.90), and 13.32 (6.48-27.37), respectively. FIB-4, APRI, and NFS of more than 2.06, 0.65, and 0.51 resulted in the highest area under the receiver operating characteristics of 0.83, 0.80, and 0.85, respectively. Surveillance in patients with FIB-4 ≥ 5.91 and NFS ≥ 2.85 would be cost-effective with an annual HCC incidence of ≥15 per 1000 patient-years. FIB-4, APRI, and NFS are associated with HCC development in non-cirrhotic NAFLD patients. Different NIT cutoffs may be used to enroll high-risk NAFLD patients for HCC surveillance, according to resource availability in different settings.
Alcohol-related liver disease (ALD) is associated with dysbiosis and translocation of gut microbial components, stimulating the innate immunity. The potential role of adaptive immune responses to gut microbiota has been less studied. We hypothesized that microbiota-specific antibody responses could be associated with ALD severity and outcomes. Two hundred and seven patients with ALD were recruited at a single site and classified as steato-fibrosis, compensated cirrhosis Child-Pugh A, decompensated cirrhosis Child-Pugh B or C without (CP B/C) and with severe alcohol-related hepatitis (sAH). Biophysical and functional characteristics of antibodies specific for 11 classes of microbiota antigens were determined. High-dimensional analyses were used to compare levels and characteristics of antibodies between groups and explore their association with clinical outcomes.ALD severity was associated with increased levels of microbiota-specific antibodies and binding to Fc-gamma-receptors (FcgR), with the strongest relationships observed for levels of Staphylococcus aureus IgA and Candida albicans IgG and for binding of Escherichia coli IgG to FcgRIIb. Additional associations were observed between ALD severity and microbiota-specific antibody effector functions, suggesting regulation of their functional potential. Among patients with CP B/C and sAH, microbiota-specific antibody profiles predicted the occurrence of septic shock and mortality at 90 days, independently of the MELD score. The antibody response to microbiota is associated with ALD severity and predicts the risk of severe outcomes. These results suggest a role for immune complexes in ALD pathogenesis and that antibody profiling has potential as a biomarker for clinical management of ALD patients.
Chronic pancreatitis (CP) and acute recurrent pancreatitis (ARP) cause significant morbidity in pediatric patients and may be candidates for total pancreatectomy with islet auto-transplantation (TPIAT). We examined opioid use and pain outcomes in a large cohort of pediatric patients post-TPIAT at a single institution. Prospective data was collected from 105 pediatric patients from 2015 to 2023 with at least 12 months post-operative data available, up to 5 years. Number of patients at each time point dependent on time from surgery, with median time point 36 months post-TPIAT (70.5 % of patients). Opioid use significantly decreased from 55 % of patients pre-TPIAT (58/105) to 4 % at 12 months post-TPIAT (4/103, p < 0.001), sustained over time with no patients requiring opioids at 60 months (0/23). 60 % of patients with abdominal pain pre-TPIAT (93/105) reported complete resolution of pain at 3 months (48/102, p < 0.001), with downtrend over time, sustained through 60 months (4/25, 16 %). SF-36 physical component summary and SF-10 physical health and psychosocial summaries showed significant improvement over time post-TPIAT (p < 0.0001). Univariable analysis showed no significant association between post-TPIAT opioid use at 12 months and age at TPIAT, gender, duration from first pancreatitis attack to TPIAT, number of endoscopic retrograde cholangiopancreatographies pre-TPIAT, or diagnosis of CP. PRSS1 mutation more likely to have resolution of abdominal pain at 12 months (p = 0.005). Utilizing a standardized multidisciplinary approach to TPIAT in pediatric patients with pancreatitis showed significant decreases in opioid use and abdominal pain, regardless of severity of disease, pain, or opioid use pre-TPIAT.
As cancer survival rates are increasing, alternative treatments to improve quality of life, such as cannabinoids, are gaining attention. Although cannabinoids are widely used to manage cancer-related symptoms, clear guidelines are lacking. This systematic review and meta-analysis assessed the safety and efficacy of cannabinoids in the management of symptoms among cancer patients. The study protocol was registered on PROSPERO (CRD42023479375). A systematic search was conducted using three main databases (PubMed, Embase, and CENTRAL) on 4 November 2023. We included interventional and observational studies that evaluated cannabinoids for symptom management in cancer patients compared to standard care, placebo, or baseline values. Pooled mean differences (MD), proportions and odds ratios (OR), and the 95% confidence intervals (CI) were calculated with a random-effects model. Overall, 98 articles were eligible. Cannabinoids reduced pain (MRAW: -1.22, CI: -1.92; -0.52) and anxiety (MRAW: -1.30, CI: -2.22; -0.39) as compared to baseline values. Appetite (MRAW: -1.88, CI: -6.23; 2.46), chemotherapy-induced nausea and vomiting (OR: 2.18, CI: 0.79; 6.00), as well as insomnia (MD: -1.08, CI: -2.48; 0.33) presented with a tendency toward improvement. Cannabinoids do not influence constipation, depression, fatigue, mobility or overall quality of life. In terms of safety issues, THC-predominant formulations increase the risks of psychiatric (OR: 10.62, CI: 1.35; 83.57), neurological (OR:2.24, CI: 1.15; 4.35), and gastrointestinal (OR:2.69, CI:0.73;9.90) side effects. The risk of bias of articles included varied from some concerns to high. Cannabinoids may be beneficial for the treatment of cancer-related pain and anxiety; however, their use carries a significant risk of adverse effects, particularly psychiatric complications. Careful patient selection is essential when considering cannabinoid-based treatments.
Elevated serum carbohydrate antigen 19-9 was incorporated as a worrisome feature in the International Association of Pancreatology 2017 Fukuoka guidelines and is associated with an increased risk of invasive carcinoma. We compared the independent predictive value of carbohydrate antigen 19-9 >100 U/mL with other worrisome feature and high-risk stigmata to better delineate its utility and importance. We conducted a retrospective analysis of all patients who underwent pancreatic resection for intraductal papillary mucinous neoplasms at a high-volume tertiary center in the United States. Clinicopathologic and radiologic variables were compared by the final pathologic status. Multivariable logistic regression was used to adjust for worrisome feature and high-risk stigmata. Of 645 patients who underwent pancreatectomy, 49% had low-grade dysplasia, 23% had high-grade dysplasia, and 28% had invasive carcinoma. A greater proportion of patients with invasive carcinoma had serum carbohydrate antigen 19-9 levels >100 U/mL (30% vs 5% vs 4%, P < .001). Multivariable analysis revealed that serum carbohydrate antigen 19-9 >100 U/mL (odds ratio, 7.24, P < .001), jaundice (odds ratio, 6.04, P < .001), main pancreatic duct diameter >10 mm (odds ratio, 4.05, P < .001), and mural nodules >5 mm (odds ratio, 3.12, P < .001) were significant predictors of invasive carcinoma. Serum carbohydrate antigen 19-9 was not predictive of high-grade dysplasia. Serum carbohydrate antigen 19-9 >100 U/mL performed more similarly to other high-risk stigmata and appeared to be the strongest predictor of invasive carcinoma. Serum carbohydrate antigen 19-9 >100 U/mL is a concerning finding that warrants consideration of surgical resection.
Metabolic dysfunction-associated steatohepatitis (MASH) cirrhosis is rapidly growing as an indication for liver transplantation (LT). However, the impact of Model for End-stage Liver Disease (MELD) 3.0 on waitlist outcomes in this population is not established. This study assessed the impact of MELD 3.0 on waitlist outcomes of patients with MASH cirrhosis using the Scientific Registry of Transplant Recipients database. This was a retrospective analysis of the Scientific Registry of Transplant Recipients/United Network for Organ Sharing database including LT waitlist registrants from January 1, 2016, to December 31, 2022. Primary outcomes were 90-day waitlist mortality and transplantation probability in patients with MASH vs non-MASH cirrhosis. Among 44,037 waitlist registrants, 12,790 had MASH cirrhosis and 31,247 had non-MASH cirrhosis. The median follow-up was 2.63 months. In MASH cirrhosis, 65.4% were up-categorized and 11.2% were down-categorized when transitioning from MELD-Na to MELD 3.0. Up-categorization was associated with higher 90-day waitlist mortality (hazard ratio, 1.14; 95% confidence interval, 1.05-1.24; P = .002) but not higher transplantation probability (hazard ratio, 1.04; 95% confidence interval, 0.98-1.09; P = .18). Among female patients with MASH cirrhosis, up-categorization similarly did not translate into improved transplant probability. Although MELD 3.0 reclassifies a substantial proportion of patients with MASH-particularly women-it does not appear to increase transplant access despite higher predicted mortality risk. These findings highlight residual gaps in how MELD 3.0 captures clinical risk in MASH cirrhosis and underscore the need for prospective data following its implementation.
To systematically review the literature on quality of life (QOL) after islet transplantation following total pancreatectomy in chronic pancreatitis (CP). Total pancreatectomy and islet auto-transplantation (TPIAT) aims to relieve pain while preserving β-cell function in CP patients. A systematic search of Medline, PubMed, EMBASE was performed according to PRISMA framework to identify studies reporting on QOL after TPIAT for CP. Random effects meta-analyses were performed to pool results on change in physical component summary (PCS) and mental component summary (MCS) QOL scores. Twenty-nine studies performed between 2011 and 2025 with a total of 4075 patients were included of which 24.8% were paediatric patients. 19 studies used the RAND SF36 QOL instrument, the most used instrument. The QOL surveys were performed from 1 month to more than 10 years post-TPIAT. Response rates varied from 14% to 100%. PCS scores were significantly higher at 1-year post-TPIAT (pooled estimate 10.36, 95% CI 7.33 to 13.4, p = <0.001) and at longest follow up (pooled estimate 16.07, 95% CI 5.80 to 26.34, p = 0.002). MCS scores were also significantly higher at 1-year post-TPIAT (pooled estimate 5.54, 95% CI 3.30 to 7.78, p = <0.001) and at longest follow up (pooled estimate 13.26, 95% CI 3.67 to 22.85, p = 0.007). Improvements in QOL appear to persist beyond 10 years. TPIAT offers both short-term and long-term improvements in physical and mental components of QOL. However, development of TPIAT specific QOL instrument is warranted to capture TPIAT specific outcomes which determine QOL.
Increasing evidence has linked the Hippo pathway with the fibroinflammatory diseases. However, the detailed roles of key hippo components in pancreatic inflammatory diseases still remain unclear. A series of genetic knockout mice were generated targeting the key components of Hippo pathway to examine the individual effects of YAP1 and TAZ on pancreatic inflammation. Hematoxylin and eosin (H&E) staining, immunohistochemistry, and immunofluorescence staining were performed to evaluate the pancreas tissue from mice with various genotypes. The therapeutic potential of a recently developed YAP1/TAZ inhibitor VT-104 was also evaluated in our mouse model. Mice with acinar-specific knockout of YAP1/TAZ did not exhibit any histological abnormalities in the pancreas. LATS1/2 deficiency induced acinar to ductal metaplasia, immune cell infiltration, and fibroblast activation, which were rescued by the homozygous knockout YAP1, but not TAZ. Additionally, treatment with VT-104 also decreased pathological alterations induced by deletions of LATS1 and LATS2 in acinar cells. Our findings highlight the critical role of YAP1 in modulating pancreatic inflammation and demonstrate that VT-104 holds therapeutic potential to mitigate pancreatitis-associated pathological manifestations. Further exploration is necessary to unravel the underlying mechanisms and translate these insights into clinical applications.
Abdominal pain is the cardinal symptom of acute pancreatitis (AP), often requiring opioid therapy. This study aimed to investigate the dose-dependent relationship between opioid therapy and moderately severe or severe AP. This was a post-hoc analysis of the prospective PAINAP database, which recruited patients with first-time AP from 118 centres across 27 countries between April-June 30, 2022. Baseline demographic details, opioid treatment dose, and AP outcome characteristics were extracted. The intravenous morphine-equivalent doses (MEDs) of each opioid administered were calculated based on daily doses and duration. They were subsequently summarised into cumulative MEDs. Furthermore, mean daily intravenous MEDs were registered. Using multivariable regression analysis, associations between opioid doses and the severity of AP were explored. The final cohort consisted of 1,043 patients receiving various doses of opioids (51 % male; median age 54 years). Most (79 %) patients had mild, 14 % moderately severe, and 7 % severe AP. Median cumulative MED was 20 mg (IQR, 8-48), whereas median daily MED was 6 (IQR, 3-11), and median duration was 3 days (IQR, 2-5). There was a significant association between moderately severe or severe AP and cumulative intravenous MEDs per 10 mg (OR 1.02 (IQR 1.00-1.03), P = 0.01). When considering daily intravenous MEDs, this association was non-significant (P = 0.15). The association between opioid doses and AP severity was dose-dependent with cumulative opioid doses but not with daily doses. In the absence of adequate evidence and potential reverse causation bias, future studies are warranted to assess the safety of opioids in AP.
It's been suggested that non-steroidal anti-inflammatory drugs (NSAIDs) may reduce the inflammatory response and severity of acute pancreatitis (AP). In this systematic review and meta-analysis, we aimed to explore the impact of selective COX-2 and non-selective NSAIDs compared to non-NSAID options on the severity of AP. We searched MEDLINE, EMBASE, and Cochrane Central, from database inception through September 2023. We included RCTs and observational studies comparing NSAIDs with non-NSAID controls. The primary outcome was the development of severe acute pancreatitis (SAP) characterized by persistent organ failure lasting >48 h. Secondary outcomes included mortality, pancreatic necrosis, length of stay (LOS), pain relief, and requirement for rescue analgesia. Meta-analysis was conducted separately for selective COX-2 inhibitors and non-selective NSAIDs. Eleven studies met eligibility criteria including 1830 patients with AP. Of 3 studies that used selective NSAIDs (1 RCT and 2 observational), COX-2 inhibitors significantly reduced SAP (OR = 0.38; 95 %CI 0.27-0.52; p < 0.001; I2 = 0 %), pancreatic necrosis (OR = 0.48; 95 %CI 0.29-0.78; p = 0.003; I2 = 0 %), LOS by 5.51 days (95 %CI -10.80 to -0.22; p = 0.04; I2 = 97 %), and rescue opioids (OR = 0.32; 95 %CI 0.24-0.45; p < 0.001; I2 = 0 %). However, the certainty of the evidence was graded as low to very low using GRADE methodology. There was no significant effect of COX-2 inhibitors on mortality. Of 8 studies (all RCTs) that compared non-selective NSAIDs and non-NSAIDs, there was no difference in clinical outcomes, pain relief, and need for rescue analgesia. Selective COX-2 inhibitors potentially mitigate disease severity and shorten hospitalization in patients with AP, while non-selective NSAIDs lack this benefit. Confirmatory large-scale RCTs are warranted to validate these findings.