Chronic Pancreatitis Patients Research Articles

Identification of Chronic Pancreatitis Associated microRNAs and Genes for the Diagnosis of Pancreatic Cancer.

The timely identification of both malignant and nonmalignant pancreatic lesions has the potential to significantly enhance prognosis and implement risk management strategies across various levels. microRNAs (miRs) and their corresponding targets play a crucial role in the development of pancreatic lesions and can serve as valuable diagnostic and therapeutic targets. The objective of our study was to investigate potential diagnostic markers that can effectively differentiate between malignant and nonmalignant pancreatic lesions. Gene Expression Omnibus (GEO) database with GSE24279 dataset was utilized to screen differentially expressed miRNAs (DEMs). We utilized the TargetScanHuman database to predict the target genes associated with hsa-miR-150-3p, hsa-miR-150-5p, and hsa-miR-214-3p. Furthermore, a cohort comprising healthy individuals (n = 52), chronic pancreatitis (CP; n = 34), and pancreatic adenocarcinoma (PAAD; n = 53) patients was recruited to ascertain the levels of plasma markers. We identified 3 miRNAs (hsa-miR-150-3p, hsa-miR-150-5p, and hsa-miR-214-3p) and 2 proteins (PCDH1 and AMN) as potential diagnostic markers for distinguishing between CP and PAAD. The area under the curve (AUC) values for all markers exceeded .800. Notably, a combination of plasma PCDH1 and AMN demonstrated excellent diagnostic performance (AUC = .921; 95% CI: .866-.977; sensitivity = .792; specificity = .941) in discriminating between CP and PAAD. In addition, the model of hsa-miR-150-3p, hsa-miR-150-5p, and hsa-miR-214-3p yielded an AUC of .928, sensitivity of .830, and specificity of .912, respectively. Plasma levels of miRNAs (hsa-miR-150-3p, hsa-miR-150-5p, and hsa-miR-214-3p) and their corresponding targets (PCDH1 and AMN) hold promise as potential biomarkers for predicting PAAD in patients with CP.

Impact of Ethno-racial Factors on Clinical Outcomes and Health Care Utilization in Chronic Pancreatitis.

Healthcare disparities adversely affect clinical outcomes in racial and ethnic minorities. Chronic pancreatitis (CP) is a complex disorder, and pressures for time and cost-containment may amplify the disparity for minorities in this condition. This study aimed to assess ethno-racial differences in the clinical outcomes of CP patients cared for at our institution. This is a study of CP patients with available ethno-racial information followed at our pancreas center. We reviewed their demographics, comorbidities, clinical outcomes, and resource utilization: pain, frequent flares (≥ 2/year), local complications, psychosocial variables, exocrine, and endocrine insufficiency, imaging, endoscopic procedures, and surgeries. The outcomes underwent logistic regression to ascertain association(s) with covariates and were expressed as odds ratio (95% confidence intervals). Of the 445 CP patients, there were 23 Hispanics, 330 Non-Hispanic Whites, 47 Non-Hispanic Blacks, 16 Asian Americans, and 29 patients from Other/mixed races. Over a median follow-up of 7years, no significant differences in the pain profile (p = 0.36), neuromodulator use (p = 0.94), and opioid use for intermittent (p = 0.34) and daily pain (p = 0.80) were observed. Frequent flares were associated with Hispanic ethnicity [2.98(1.20-7.36); p = 0.02], despite adjustment for smoking [2.21(1.11-4.41); p = 0.02)] and alcohol [1.88(1.06-3.35); p = 0.03]. Local complications (pseudocysts, mesenteric thrombosis, and biliary obstruction), exocrine and endocrine dysfunction, and healthcare resource utilization (cross-sectional imaging, endoscopic procedures, celiac blocks, or surgeries) were comparable across all ethno-racial groups. Although no significant differences in clinical outcomes, and health resource utilization were noted across ethno-racial groups, Hispanic ethnicity had significant association with CP flares. This study calls for further investigation of an understudied minority population with CP.

Plasma metabolite profiling identifies non-diabetic CP patients with metabolic alterations progressing to prediabetes prior to HbA1c.

Diabetes (T3cDM) secondary to chronic pancreatitis (CP) arises due to endocrine dysfunction and metabolic dysregulations. Currently, diagnostic tests are not available to identify patients who may progress from normoglycemia to hyperglycemia in CP. We conducted plasma metabolomic profiling to diagnose glycemic alterations early in the course of disease. Liquid chromatography-tandem mass spectrometry was employed to generate untargeted, targeted plasma metabolomic profiles in CP patients, controls (n=445) following TRIPOD guidelines. Patients were stratified based on glucose tolerance tests following ADA guidelines. Multivariate analysis was performed using PLS-DA to assess discriminatory ability of metabolites among stratified groups. COMBIROC, logistic regression were employed to derive biomarker signatures. AI-ML tool(Rapidminer) was employed to verify these preliminary results. Ceramide, lysophosphatidylethanolamine, phosphatidylcholine, lysophosphatidic acid, phosphatidylethanolamine, carnitine and lysophosphatidylcholine discriminated T3cDM CP patients from healthy controls with AUC 93%(95%CI 0.81-0.98, p<0.0001), integration with pancreatic morphology improved AUC to 100%(95%CI 0.93-1.00, p<0.0001). Lysophosphatidic acid, phosphatidylinositol and ceramide discriminated non-diabetic CP with glycemic alterations (pre-diabetic CP);AUC 66% (95% CI 0.55-0.76, p=0.1),integration enhanced AUC to 74%,(95% CI 0.55-0.88,p=0.86). T3cDM was distinguished from pre-diabetic by lysophosphatidic acid, phosphatidylinositol and sphinganine(AUC 70%; 95%CI 0.54-0.83,p=0.08), integration improved AUC to 83% (95%CI 0.68-0.93,p=0.05). CombiROC cutoff identified 75% and 78% prediabetes in validation 1 and 2 cohorts. Random forest algorithm assessed performance of integrated panel demonstrating AUC of 72% in predicting glycemic alterations. We report for the first time that a panel of metabolites integrated with pancreatic morphology detects glycemia progression prior to HbA1c in CP patients.

Chronic Pancreatitis-Associated Metabolic Bone Diseases: Epidemiology, Mechanisms, and Clinical Advances.

Chronic pancreatitis (CP) is a progressive inflammatory disease with an increasing global prevalence. In recent years, a strong association between CP and metabolic bone diseases (MBDs), especially osteoporosis, has been identified, attracting significant attentions in the research field. Epidemiological data suggest a rising trend in the incidence of MBDs among CP patients. Notably, recent studies have highlighted a profound interplay between CP and altered nutritional and immune profiles, offering insights into its linkage with MBDs.At molecular level, CP introduces a series of biochemical disturbances that compromise bone homeostasis. One critical observation is the disrupted metabolism of vitamin D and vitamin K, both essential micronutrients for maintaining bone integrity, in CP patients. In this review, we provide physio-pathological perspectives on the development and mechanisms of CP-related MBDs. We also outline some of the latest therapeutic strategies for treating patients with CP-associated MBDs, including stem cell transplantation, monoclonal antibodies, and probiotic therapy. In summary, CP-associated MBDs represent a rising medical challenge, involving multiple tissues and organs, complex disease mechanisms, and diverse treatment approaches. More in-depth studies are required for understanding the complex interplay between CP and MBDs to facilitate the development of more specific and effective therapeutic approaches.

Exploring the Associations of Inflammatory and Oxidative Stress Biomarkers with Pancreatic Diseases: An Observational and Mendelian Randomisation Study.

Identifying biomarkers linked to pancreatic ductal adenocarcinoma (PDAC) and chronic pancreatitis (CP) is crucial for early detection, treatment, and prevention. Methods: Association analyses of 10 serological biomarkers involved in cell signalling (IFN-γ, IL-6, IL-8, IL-10), oxidative stress (superoxide dismutase (SOD) and glutathione peroxidase (GPx) enzyme activities, total glutathione (GSH), malondialdehyde (MDA) levels), and intestinal permeability proteins (zonulin, I-FABP2) were conducted across PDAC (n = 12), CP (n = 21) and control subjects (n = 23). A Mendelian randomisation (MR) approach was used to assess causality of the identified significant associations in two large genetic cohorts (FinnGen and UK Biobank). Results: Observational results showed a downregulation of SOD and GPx antioxidant enzyme activities in PDAC and CP patients, respectively, and higher MDA levels in CP patients. Logistic regression models revealed significant associations between CP and SOD activity (OR = 0.21, 95% CI [0.05, 0.89], per SD), GPx activity (OR = 0.28, 95% CI [0.10, 0.79], per SD), and MDA levels (OR = 2.05, 95% CI [1.36, 3.08], per SD). MR analyses, however, did not support causality. Conclusions: These findings would not support oxidative stress-related biomarkers as potential targets for pancreatic diseases prevention. Yet, further research is encouraged to assess their viability as non-invasive tools for early diagnosis, particularly in pre-diagnostic CP populations.

Serum trace elements during treatment in pancreatic cancer patients and their associations with cancer prognosis

Background & AimsIn this study, we assessed serum trace element concentrations in patients with pancreatic cancer and compared the results to those of healthy controls and patients with chronic pancreatitis. We evaluated the association between trace element concentrations during cancer treatment and the risk of cancer progression and mortality in pancreatic cancer patients. MethodsA retrospective cohort study was conducted at a tertiary center in Korea. Serum trace element concentrations of cobalt (Co), copper (Cu), selenium (Se), and zinc (Zn) were measured at diagnosis using an inductively coupled plasma-mass spectrometry in 124 pancreatic cancer patients, 50 chronic pancreatitis patients, and 120 healthy controls. Trace elements were measured after a median of 282.5 (95% confidence interval [CI], 224.0–326.5) days from treatment initiation to assess changes in trace element concentrations during treatment. ResultsSerum Co and Cu concentrations were significantly higher in patients with chronic pancreatitis and pancreatic cancer than in healthy controls, while serum Se and Zn concentrations were significantly lower. During treatment, serum concentrations of Cu, Se, and Zn were significantly decreased in patients with pancreatic cancer.During the follow-up (median 152.5; 95% CI, 142.8–160.0 months), 85.5% of patients experienced progression or relapse, and 84.7% of patients died. Patients with decreased Se and Zn concentrations during treatment had a higher mortality (hazard ratio [HR], 2.10; 95% CI, 1.31–3.38; P = 0.0020 for Se; HR, 1.72; 95% CI, 1.06–2.79; P = 0.0269 for Zn) compared to those with unchanged or increased trace element concentrations during treatment. Patients with a greater reduction in Zn concentrations during treatment had a higher mortality than those with a smaller reduction (HR, 1.59; 95% CI, 1.01–2.52; P = 0.0483). Patients whose Zn status changed to deficient after treatment had an increased mortality (HR, 1.76; 95% CI, 1.16–2.67, P = 0.0084). Patients with multiple (≥ 2) trace element deficiencies after treatment had poorer outcomes than those with no or single trace element deficiency. ConclusionsThis study revealed that decreases in Se and Zn concentrations during cancer treatment were associated with adverse outcomes in terms of cancer progression and mortality in patients with pancreatic cancer. Further prospective investigations are recommended.

Genetic Factors Associated With Adverse Pregnancy Outcomes in Chronic Pancreatitis.

The effects of genetic factors on pregnancy outcomes in chronic pancreatitis (CP) patients remain unclear. We evaluated the impacts of clinical features and mutations in main CP-susceptibility genes ( SPINK1 , PRSS1 , CTRC , and CFTR ) on pregnancy outcomes in Chinese CP patients. This was a prospective cohort study with 14-year follow-up. The sample comprised female CP patients with documented pregnancy and known genetic backgrounds. Adverse pregnancy outcomes were compared between patients with and without gene mutations. Univariate and multivariate analyses were performed to determine the impact factors for adverse pregnancy outcomes. Totally, 160 female CP patients with a pregnancy history were enrolled; 59.4% of patients carried pathogenic mutations in CP-susceptibility genes. Adverse pregnancy outcomes occurred in 38 patients (23.8%); the prevalence of adverse outcomes was significantly higher in those harboring gene mutations than those without (30.5% vs 13.8%, P = 0.015). Notably, the rates of preterm delivery (12.6% vs 3.1%, P = 0.036) and abortion (17.9% vs 4.6%, P = 0.013) were remarkably higher in patients with gene mutations (especially SPINK1 mutations) than those without. In multivariate analyses, both CP-susceptibility gene mutations (odds ratio, 2.52; P = 0.033) and SPINK1 mutations (odds ratio, 2.60; P = 0.037) significantly increased the risk of adverse pregnancy outcomes. Acute pain attack during pregnancy was another risk factor for adverse pregnancy outcomes. Pathogenic mutations in CP-susceptibility genes, especially SPINK1 , were independently related to adverse pregnancy outcomes in CP patients. Significant attention should be paid to pregnant females harboring CP-susceptibility gene mutations (ClinicalTrials.gov: NCT06055595).

Evaluating the Efficacy of Antioxidant Therapy in Enhancing the Quality of Life of Chronic Pancreatitis Patients: A Systematic Review.

Chronic pancreatitis (CP), an inflammatory disease characterized by irreversible pancreatic changes and progressive fibrosis, significantly impairs patients' quality of life. This systematic review aims to assess the efficacy of antioxidant therapy in enhancing the quality of life of CP patients. Focusing on the role of oxidative stress in CP pathogenesis, we explored several databases for studies evaluating the impact of antioxidant supplementation. The review included randomized controlled trials and cohort studies reporting pain frequency, intensity, and overall quality of life measures. Findings from these studies present a mixed view of the efficacy of antioxidants in CP, with some suggesting benefits in symptom management, while others show inconsistency in improving patient outcomes. The review concludes that while antioxidant therapy holds potential, especially in symptom alleviation, there is a need for more rigorous, larger-scale studies to confirm its effectiveness in CP management and to establish standardized treatment protocols. The incorporation of antioxidants into CP treatment plans should be approached with personalized care, considering the varied responses observed in different patient populations.

Chronic pancreatitis: Pain and computed tomography/magnetic resonance imaging findings

Chronic pancreatitis (CP) is a fibroinflammatory disease characterized by irreversible destruction of pancreatic tissue. With the development of the disease, it may lead to exocrine and/or endocrine insufficiency. CP is one of the common diseases that cause abdominal pain, which will not get permanent spontaneous relief as the disease evolves. The American College of Gastroenterology clinical guidelines recommend computed tomography or magnetic resonance imaging as the first-line examination for the diagnosis of CP. CP common imaging findings include pancreatic atrophy, irregular dilatation of the pancreatic duct, calcification of pancreatic parenchyma, pancreatic duct stones, etc. In clinical practice, whether any correlations between CP-induced abdominal pain patterns (no pain/constant/intermittent pain) and corresponding imaging findings present are not well known. Therefore, this review aims to comprehensively sort out and analyze the relevant information by collecting lots of literature on this field, so as to construct a cross-bridge between the clinical manifestations and imaging manifestations of CP patients. Also, it provides an imaging basis and foundation for the classification and diagnosis of abdominal pain types in clinical CP patients.

COMP promotes pancreatic fibrosis by activating pancreatic stellate cells through CD36-ERK/AKT signaling pathways

BackgroundPancreatic fibrosis is one of the most important pathological features of chronic pancreatitis (CP) and pancreatic stellate cells (PSCs) are the key cells of fibrosis. As an extracellular matrix (ECM) glycoprotein, cartilage oligomeric matrix protein (COMP) is critical for collagen assembly and ECM stability and recent studies showed that COMP exert promoting fibrosis effect in the skin, lungs and liver. However, the role of COMP in activation of PSCs and pancreatic fibrosis remain unclear. We aimed to investigate the role and specific mechanisms of COMP in regulating the profibrotic phenotype of PSCs and pancreatic fibrosis. MethodsELISA method was used to determine serum COMP in patients with CP. Mice model of CP was established by repeated intraperitoneal injection of cerulein and pancreatic fibrosis was evaluated by Hematoxylin-Eosin staining (H&E) and Sirius red staining. Immunohistochemical staining was used to detect the expression changes of COMP and fibrosis marker such as α-SMA and Fibronectin in pancreatic tissue of mice. Cell Counting Kit-8, Wound Healing and Transwell assessed the proliferation and migration of human pancreatic stellate cells (HPSCs). Western blotting, qRT-PCR and immunofluorescence staining were performed to detect the expression of fibrosis marker, AKT and MAPK family proteins in HPSCs. RNA-seq omics analysis as well as small interfering RNA of COMP, recombinant human COMP (rCOMP), MEK inhibitors and PI3K inhibitors were used to study the effect and mechanism of COMP on activation of HPSCs. ResultsELISA showed that the expression of COMP significantly increased in the serum of CP patients. H&E and Sirius red staining analysis showed that there was a large amount of collagen deposition in the mice in the CP model group and high expression of COMP, α-SMA, Fibronectin and Vimentin were observed in fibrotic tissues. TGF-β1 stimulates the activation of HPSCs and increases the expression of COMP. Knockdown of COMP inhibited proliferation and migration of HPSCs. Further, RNA-seq omics analysis and validation experiments in vitro showed that rCOMP could significantly promote the proliferation and activation of HPSCs, which may be due to promoting the phosphorylation of ERK and AKT through membrane protein receptor CD36. rCOMP simultaneously increased the expression of α-SMA, Fibronectin and Collagen I in HPSCs. ConclusionIn conclusion, this study showed that COMP was up-regulated in CP fibrotic tissues and COMP induced the activation, proliferation and migration of PSCs through the CD36-ERK/AKT signaling pathway. COMP may be a potential therapeutic candidate for the treatment of CP. Interfering with the expression of COMP or the communication between COMP and CD36 on PSCs may be the next direction for therapeutic research.

Exploring the enigmatic association between PNLIP variants and risk of chronic pancreatitis in a large Chinese cohort

Background & AimsProtease-sensitive PNLIP variants were recently associated with chronic pancreatitis (CP) in European populations. The pathological mechanism yet remains elusive. Herein, we performed a comprehensive genetic and functional analysis of PNLIP variants found in a large Chinese cohort, aiming to further unravel the enigmatic association of PNLIP variants with CP. MethodsAll coding and flanking intronic regions of the PNLIP gene were analyzed for rare variants by targeted next-generation sequencing in 1082 Chinese CP patients and 1196 controls. All novel missense variants were subject to analysis of secretion, lipase activity, and proteolytic degradation. One variant was further analyzed for its potential to misfold and induce endoplasmic reticulum (ER) stress. p.F300L, the most common PNLIP variant associated with CP, was used as a control. ResultsWe identified 12 rare heterozygous PNLIP variants, with 10 being novel. The variant carrier frequency did not differ between the groups. Of them, only the variant p.A433T found in a single patient was considered pathologically relevant. p.A433T exhibited increased susceptibility to proteolytic degradation, which was much milder than p.F300L. Interestingly, both variants exhibited an increased tendency to misfold, leading to intracellular retention as insoluble aggregates, reduced secretion, and elevated ER stress. ConclusionsOur genetic and functional analysis of PNLIP variants identified in a Chinese CP cohort suggests that the p.A433T variant and the previously identified p.F300L variant are not only protease-sensitive but also may be potentially proteotoxic. Mouse studies of the PNLIP p.F300L and p.A433T variants are needed to clarify their role in CP.

Circulating immune signatures in chronic pancreatitis with and without preceding acute pancreatitis: A pilot study

ObjectiveTo investigate profiles of circulating immune signatures in healthy controls and chronic pancreatitis patients (CP) with and without a preceding history of acute pancreatitis (AP). MethodsWe performed a phase 1, cross-sectional analysis of prospectively collected serum samples from the PROspective Evaluation of Chronic Pancreatitis for EpidEmiologic and Translation StuDies (PROCEED) study. All samples were collected during a clinically quiescent phase. CP subjects were categorized into two subgroups based on preceding episode(s) of AP. Healthy controls were included for comparison. Blinded samples were analyzed using an 80-plex Luminex assay of cytokines, chemokines, and adhesion molecules. Group and pairwise comparisons of analytes were performed between the subgroups. ResultsIn total, 133 patients with CP (111 with AP and 22 without AP) and 50 healthy controls were included. Among the 80 analytes studied, CP patients with a history of AP had significantly higher serum levels of pro-inflammatory cytokines (interleukin (IL)-6, IL-8, IL-1 receptor antagonist, IL-15) and chemokines (Cutaneous T-Cell Attracting Chemokine (CTACK), Monokine induced Gamma Interferon (MIG), Macrophage-derived Chemokine (MDC), Monocyte Chemoattractant Protein-1 (MCP-1)) compared to CP without preceding AP and controls. In contrast, CP patients without AP had immune profiles characterized by low systemic inflammation and downregulation of anti-inflammatory mediators, including IL-10. ConclusionCP patients with a preceding history of AP have signs of systemic inflammatory activity even during a clinically quiescent phase. In contrast, CP patients without a history of AP have low systemic inflammatory activity. These findings suggest the presence of two immunologically diverse subtypes of CP.

Nutritional status in patients with chronic pancreatitis and liver cirrhosis is related to disease conditions and not dietary habits

Malnutrition is a common complication of chronic pancreatitis (CP) and liver cirrhosis (LC). Inadequate food intake is considered a relevant driver of malnutrition in both entities. However, the contribution of habitual diet to impaired nutritional status is unclear. In a prospective, multicenter cross-sectional study, we recruited patients with confirmed CP or LC and healthy volunteers as a control group. Malnutrition was diagnosed according to the Global Leadership Initiative on Malnutrition criteria. We comprehensively investigated habitual dietary intake on nutrient, food group, and dietary pattern level applying two validated food frequency questionnaires. We included 144 patients (CP: n = 66; LC: n = 78) and 94 control subjects. Malnutrition was prevalent in 64% and 62% of patients with CP or LC, respectively. In both CP and LC, despite slightly altered food group consumption in malnourished and non-malnourished patients there were no differences in energy or nutrient intake as well as dietary quality. Compared to controls patients showed distinct dietary food group habits. Patients consumed less alcohol but also lower quantities of fruits and vegetables as well as whole grain products (p < 0.001, respectively). Nevertheless, overall dietary quality was comparable between patients and healthy controls. Nutritional status in CP and LC patients is rather related to disease than habitual dietary intake supporting the relevance of other etiologic factors for malnutrition such as malassimilation or chronic inflammation. Despite distinct disease-related differences, overall dietary quality in patients with CP or LC was comparable to healthy subjects, which suggests susceptibility to dietary counselling and the benefits of nutrition therapy in these entities.

Features of the clinical course of chronic pancreatitis in patients with chronic obstructive pulmonary disease

Aim. The purpose of the study is to determine the intensity of the manifestation of clinical syndromes in the comorbid course of chronic pancreatitis (CP) in patients with chronic obstructive pulmonary disease (COPD) in comparison with the isolated course of CP and to assess the intensity of the mutual burden syndrome. Material and methods. A prospective cohort study was conducted, analyzing the medical records of 212 inpatients. The first group comprised 96 individuals with an isolated course of chronic pancreatitis (CP), while the second group included 116 patients with CP and comorbid chronic obstructive pulmonary disease (COPD), categorized as Group E. The study focused on subjective manifestations of pain syndrome in CP, the extent of exocrine pancreatic insufficiency, clinical blood analysis, biochemical research regarding the content of markers indicating pancreatic enzyme deviation in the blood, and the level of elastase-1 in feces. Additionally, ultrasonographic examination of the organs in the abdominal cavity was performed. Results. Patients in group 2 exhibited manifestations of abdominal pain syndrome 1.2 times more frequently than those in group 1 (p &lt; 0.05). The frequency of pain in the pancreas radiating to the right subcostal region was 1.9 times higher in group 2 compared to group 1 (p &lt; 0.05), along with a 2.1 times increase in the symptom of girdled pain radiating to the back (p &lt; 0.05). Although the frequency of dyspeptic syndrome was slightly higher in group 2 (1.3 times, p &gt; 0.05), astheno-vegetative syndrome was significantly more pronounced, exceeding the frequency in group 1 by 1.7 times (p &lt; 0.05). Ultrasonography parameters of the pancreas in both groups revealed characteristic signs of chronic pancreatitis (CP). The analysis of pancreatic functional state indicators during exacerbation indicated hyperenzymemia syndrome, with α-amylase activity significantly higher in patients of both groups compared to the control group – by 1.8 and 2.6 times, respectively (p &lt; 0.05). Conclusions. CP with chronic obstructive pulmonary disease (COPD) is characterized by a significantly lower frequency of paroxysmal abdominal pain syndrome but a higher frequency of constant aching pain in the pancreas area. Additionally, it is associated with the maximum intensity of inflammation, hyperfermentemia, a decrease in the activity of elastase-1 in feces, and a higher intensity of astheno-vegetative, painful, dyspepsia, intoxication syndromes. Moreover, there is a more pronounced exocrine dysfunction of the pancreas and more significant changes in the sonographic structure of the pancreas compared to cases with the isolated course of CP.

MicroRNA Signatures for Pancreatic Cancer and Chronic Pancreatitis: Expression Profiling by NGS.

Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease due to the lack of early detection. Because chronic pancreatitis (CP) patients are a high-risk group for pancreatic cancer, this study aimed to assess the differential miRNA profile in pancreatic tissue of patients with CP and pancreatic cancer. MiRNAs were isolated from formalin-fixed paraffin-embedded pancreatic tissue of 22 PDAC patients, 18 CP patients, and 10 normal pancreatic tissues from autopsy (C) cases and processed for next-generation sequencing. Known and novel miRNAs were identified and analyzed for differential miRNA expression, target prediction, and pathway enrichment between groups. Among the miRNAs identified, 166 known and 17 novel miRNAs were found exclusively in PDAC tissues, while 106 known and 10 novel miRNAs were found specifically in CP tissues. The pathways targeted by PDAC-specific miRNAs and differentially expressed miRNAs between PDAC versus CP tissues and PDAC versus control tissues were the proteoglycans pathway, Hippo signaling pathway, adherens junction, and transforming growth factor-β signaling pathway. This study resulted in a set of exclusive and differentially expressed miRNAs in PDAC and CP can be assessed for their diagnostic value. In addition, studying the role of miRNA-target gene interactions in carcinogenesis may open new therapeutic avenues.

Inhibition of the Alternative Complement Pathway May Cause Secretion of Factor B, Enabling an Early Detection of Pancreatic Cancer.

This study aims to elucidate the cellular mechanisms behind the secretion of complement factor B (CFB), known for its dual roles as an early biomarker for pancreatic ductal adenocarcinoma (PDAC) and as the initial substrate for the alternative complement pathway (ACP). Using parallel reaction monitoring analysis, we confirmed a consistent ∼2-fold increase in CFB expression in PDAC patients compared with that in both healthy donors (HD) and chronic pancreatitis (CP) patients. Elevated ACP activity was observed in CP and other benign conditions compared with that in HD and PDAC patients, suggesting a functional link between ACP and PDAC. Protein-protein interaction analyses involving key complement proteins and their regulatory factors were conducted using blood samples from PDAC patients and cultured cell lines. Our findings revealed a complex control system governing the ACP and its regulatory factors, including Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation, adrenomedullin (AM), and complement factor H (CFH). Particularly, AM emerged as a crucial player in CFB secretion, activating CFH and promoting its predominant binding to C3b over CFB. Mechanistically, our data suggest that the KRAS mutation stimulates AM expression, enhancing CFH activity in the fluid phase through binding. This heightened AM-CFH interaction conferred greater affinity for C3b over CFB, potentially suppressing the ACP cascade. This sequence of events likely culminated in the preferential release of ductal CFB into plasma during the early stages of PDAC. (Data set ID PXD047043.).

A novel early cancer detection approach for pancreatic cancer.

613 Background: Pancreatic adenocarcinoma (PDAC) is commonly diagnosed at advanced stages, leading to high mortality rates. Earlier detection of PDAC is associated with improved long-term survival, but effective population-level screening is not available. There is therefore an urgent need to improve early detection of PDAC. Wholomics has developed a PDAC-specific proprietary early detection test, using cancer-specific molecular signatures in peripheral blood. Methods: We conducted a retrospective analysis of serum samples from the Amsterdam UMC Liquid Biopsy Center. Three cohorts were included in this study: 1) A cohort of healthy control subjects, 2) patients with a histopathologically confirmed diagnosis of PDAC spanning stages I through IV, and 3) patients with a confirmed diagnosis of chronic pancreatitis. Peripheral blood samples of cancer patients were taken before treatment or surgery. Wholomics used its proprietary technology to quantitatively analyse all serum specimens. Disease-specific molecular signatures were identified and used to develop computational biomarkers specific to both pancreatic pathologies (chronic pancreatitis and pancreatic cancer) and to pancreatic cancer individually. A comparative analysis was conducted employing multiple machine learning algorithms, which were subjected to a 10-fold cross-validation procedure. The accuracy, specificity and sensitivity of the best-performing algorithm is reported. Results: This retrospective study included 50 healthy controls, 12 patients with chronic pancreatitis, and 42 patients with pancreatic cancer (12 stage I, 15 stage II, 9 stage III, 6 stage IV). Applying Wholomics´ technology, an accuracy of 99.1% in differentiating the chronic pancreatitis and pancreatic cancer patients from the healthy controls was achieved. A specificity of 98.0% and a sensitivity of 100.0% were reached. Furthermore, pancreatic cancer patients and chronic pancreatitis patients were differentiated with 95.2% accuracy. Wholomics was also capable of differentiating between early stage (stages I and II) and late-stage (stages III and IV) pancreatic cancer with an accuracy of 100%. Conclusions: Taken together, this study demonstrates that disease-specific molecular signatures in peripheral blood can distinguish patients with PDAC from healthy individuals and patients with pancreatitis with very high accuracy. If validated in additional cohorts, this method could be evaluated as a screening test for PDAC to allow for early detection and improve patient outcomes.

Predictive Factors Correlated with Successful Early Endoscopic Removal of Pancreaticolithiasis in Chronic Pancreatitis after Extracorporeal Shock Wave Lithotripsy.

The treatment of chronic pancreatitis (CP) and symptomatic pancreatic duct (PD) calculi often involves techniques like endoscopic retrograde cholangiopancreatography (ERCP), extracorporeal shock wave lithotripsy (ESWL), or a combination of both. However, identifying predictive factors for the successful removal of these calculi remains variable. This study aimed to determine the factors predicting successful ESWL and endoscopic removal in CP and PD calculi patients. We examined data from CP patients who underwent complete PD calculi removal via ESWL combined with ERCP between July 2012 and 2022, and assessed baseline characteristics, imaging findings, and treatment details. Patients were categorized into early- and late-endoscopic complete removal groups (EER and LER groups, respectively). Of the 27 patients analyzed, 74.1% were male with an average age of 44 ± 9.6 years. EER was achieved in 74% of the patients. Patients in the EER group exhibited smaller PD calculi diameter (8.5 vs. 19 mm, p = 0.012) and lower calculus density (964.6 vs. 1313.3 HU, p = 0.041) compared to the LER group. Notably, PD stricture and the rate of PD stent insertion were not different between the groups. A calculus density threshold of 1300 HU on non-contrast CT demonstrated 71% sensitivity and 80% specificity in predicting EER. Smaller and low-density PD calculi may serve as predictors for successful EER, potentially aiding in the management of CP patients with PD calculi.

Alpha-1 Antitrypsin Augmentation Therapy in Chronic Pancreatitis Patients Undergoing Total Pancreatectomy and Islet Autotransplantation: A Randomized, Controlled Study.

Stress-induced islet graft loss during the peri-transplantation period reduces the efficacy of islet transplantation. In this prospective, randomized, double-blind clinical trial, we evaluated the safety and efficacy of 60 mg/kg human alpha-1 antitrypsin (AAT) or placebo infusion weekly for four doses beginning before surgery in chronic pancreatitis (CP) patients undergoing total pancreatectomy and islet autotransplantation (TP-IAT). Subjects were followed for 12 months post-TP-IAT. The dose of AAT was safe, as there was no difference in the types and severity of adverse events in participants from both groups. There were some biochemical signals of treatment effect with a higher oxygen consumption rate in AAT islets before transplantation and a lower serum C-peptide (an indicator of islet death) in the AAT group at 15 min after islet infusion. Findings per the statistical analysis plan using a modified intention to treat analysis showed no difference in the C-peptide area under the curve (AUC) following a mixed meal tolerance test at 12 months post-TP-IAT. There was no difference in the secondary and exploratory outcomes. Although AAT therapy did not show improvement in C-peptide AUC in this study, AAT therapy is safe in CP patients and there are experiences gained on optimal clinical trial design in this challenging disease.

EVALUATING LACTOFERRIN AND CALPROTECTIN AS MARKERS OF INTESTINAL INFLAMMATION INCHRONIC PANCREATITIS.

The treatment of chronic pancreatitis does not consistently solve intestinal abnormalities, and despite the implementation of various therapeutic measures, patients often continue to experience persistent diarrhea. Therefore, it is imperative to recognize that diarrhea may stem from factors beyond pancreatic insufficiency, and intestinal inflammation emerges as a potential contributing factor. The aim of this study was to assess fecal lactoferrin and calprotectin levels as indicators of intestinal inflammation in patients with chronic pancreatitis experiencing persistent diarrhea. In this study, 23 male patients with chronic pancreatitis primarily attributed to alcohol consumption and presenting with diarrhea (classified as Bristol stool scale type 6 or 7), underwent a comprehensive evaluation of their clinical and nutritional status. Fecal lactoferrin and calprotectin levels were mea-sured utilizing immunoassay techniques. The average age of the participants was 54.8 years, 43.5% had diabetes, and 73.9% were smokers. Despite receiving enzyme replacement therapy and refraining from alcohol for over 4 years, all participants exhibited persistent diarrhea, accompanied by elevated calprotectin and lactoferrin levels indicative of ongoing intestinal inflammation. The findings of this study underscore that intestinal inflammation, as evidenced by elevated fecal biomarkers calprotectin and lactoferrin, may contribute to explaining the persistence of diarrhea in patients with chronic pancreatitis. • Exploration of intestinal inflammation in chronic pancreatitis patients with altered bowel habits. • Assessment of 23 patients using lactoferrin and calprotectin as intestinal inflammation biomarkers. • Intestinal inflammation was detected in all patients; positive correlation between both biomarkers. • Established connection between altered bowel habits and intestinal inflammation in chronic pancreatitis.