Chronic Pancreatitis Group Research Articles

Exosomes Derived from Bone Marrow Dendritic Cells Exhibit Protective and Therapeutic Potential Against Chemically Induced Chronic Pancreatitis in Rats.

Chronic pancreatitis (CP) is a specific clinical disorder that develops from pancreatic fibrosis and immune cell dysregulation. It has been proposed that bone marrow dendritic cells (BMDCs) exosomes have significant effects on immune regulation. Thus, the current study acquainted the prophylactic and therapeutic effects of exosomes derived from BMDCs on a rat model of CP. BMDCs were prepared and identified, and then the exosomes were isolated by differential ultracentrifugation. Prophylactic and therapeutic effects of exosomes were investigated on L-arginine induced CP model. Administration of two tail vein injections of exosomes (200μg/kg/dose suspended in 0.2ml PBS) markedly improved the pancreatic function and histology compared to CP group. Moreover, exosomes prominently mitigated the increase in amylase, lipase, tumor necrosis factor-α (TNF-α), transforming growth factor-β (TGF-β) and elevated antioxidant enzymes; catalase, superoxide dismutase (SOD) and glutathione peroxidase (GPx). BMDCs exosomes can be considered as a promising candidate, with a high efficacy and stability compared with its parent cell, for management of CP and similar inflammatory diseases.

The Prospect of Improving Pancreatic Cancer Diagnostic Capabilities by Implementing Blood Biomarkers: A Study of Evaluating Properties of a Single IL-8 and in Conjunction with CA19-9, CEA, and CEACAM6.

Background/Objectives: This study aims to evaluate the possible clinical application of interleukin 8 (IL-8) as a single biomarker and its capabilities in combination with carbohydrate antigen (CA19-9), carcinoembryonic antigen (CEA), and carcinoembryonic antigen cell adhesion molecule 6 (CEACAM6) as diagnostic and prognostic tools for pancreatic ductal adenocarcinoma (PDAC). Methods: A total of 170 serum samples from patients with PDAC (n = 100), chronic pancreatitis (CP) (n = 39), and healthy individuals (n = 31) were analysed. IL-8 and CEACAM6 were measured by an enzyme-linked immunosorbent assay (ELISA). CA19-9 and CEA were determined by chemiluminescent microparticle immunoassay, and bilirubin was quantified using a diazonium salt reaction. Receiver operating characteristic curve analysis, logistic regression, and Kaplan-Meier analyses were performed to evaluate the properties of a single IL-8 and in combination with other biomarkers. Results: The concentrations of IL-8 were statistically significantly higher in the PDAC group compared to the CP and control groups. Heterogeneous levels of IL-8 correlated with PDAC stages (p = 0.007). IL-8 had good and satisfactory diagnostic efficacy in differentiating PDAC from controls (0.858; p < 0.001) and patients with CP (0.696; p < 0.001), respectively. High and low expressions of IL-8 were not significantly associated with overall survival (OS) or disease-free survival (DFS). A combination of IL-8, CEACAM6, and CA19-9 reached the highest AUC values for differentiating PDAC from the control group. The best classification score between PDAC and the control group with CP patients was obtained by merging IL-8 and CA19-9 (0.894; p < 0.001). Conclusions: These results provide compelling evidence of IL-8 as a promising diagnostic biomarker. Nonetheless, due to the high complexity of PDAC, only the conjunction of IL-8, CA19-9, and CEACAM6 integrates sufficient diagnostic capabilities.

Unraveling Proto-Oncogene (ErbB2) Expression in Patients With Carcinoma Head of Pancreas and Chronic Pancreatitis Patients: A Case-Control Study.

Background The pre-malignant tendency of the normal, non-affected portion of the pancreas is not as well explored as the multicentricity documented in pancreatic cancer cases. In order to ascertain the expression of inflammatory markers and Erythroblastic Oncogene B (ErbB2) in the non-affected pancreas in patients with pancreatic cancer, a case-control study was carried out. Materials and methods In patients who underwent pancreatoduodenectomy for pancreatic cancer (PC), pro-inflammatory genes and a tumor marker, erythroblastic oncogene 2 (ErbB2) in the epidermal growth factor receptor family were analyzed in the pancreatic tissue at the cut surface of the normal pancreas using qRT-PCR. Twenty patients diagnosed with Chronic pancreatitis (CP) after Frey's surgical procedure were selected, and their pancreatic tissues were analyzed as controls. The HPLC-purified primers were designed using National Center for Biotechnology Information (NCBI) software. The primer's specificity was verified for gene expression analysis using the Basic Local Alignment Search Tool (BLAST). The genes under study were normalized using β-actin as the housekeeping gene, and the 2-ddct method was used to compute the fold change compared to the control sample. Results Patients with margin-positive were not included. Pro-inflammatory genes (TNF-α, NF-kβ,andCOX-2) had significantly lower foldchange in PC patients compared to the CP group. The CP control group had higher levels ofIL-6gene expression than the PC group. Patients with pancreatic cancer had a considerably higher expression of theErbB2gene than patients with CP. Conclusion The upregulatedErbB2gene in the unaffected pancreatic tissue of pancreatic cancer patients, when compared to controls, indicates that the remaining pancreas may have the capacity to cause cancer. Proto-oncogene may play a role in the pathophysiologic process in patients with pancreatic cancer.

Association of pancreatitis with risk of diabetes: analysis of real-world data.

Diabetes is a major cause of disease burden with considerable public health significance. While the pancreas plays a significant role in glucose homeostasis, the association between pancreatitis and new onset diabetes is not well understood. The purpose of this study was to examine that association using large real-world data. Utilizing the IBM® MarketScan® commercial claims database from 2016 to 2019, pancreatitis and diabetes regardless of diagnostic category, were identified using International Classification of Diseases, Tenth Revision [ICD-10] codes. We then performed descriptive analyses characterizing non-pancreatitis (NP), acute pancreatitis (AP), and chronic pancreatitis (CP) cohort subjects. Stratified Cox proportional hazards regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CI) of diabetes across the three clinical categories. In total, 310,962 individuals were included in the analysis. During 503,274 person-years of follow-up, we identified 15,951 incident diabetes cases. While men and women had higher incidence rates of CP and AP-related diabetes, the rates were significantly greater in men and highest among individuals with CP (91.6 per 1000 persons-years (PY)) followed by AP (75.9 per 1000-PY) as compared to those with NP (27.8 per 1000-PY). After adjustment for diabetes risk factors, relative to the NP group, the HR for future diabetes was 2.59 (95% CI: 2.45-2.74) (P<0.001) for the CP group, and 2.39 (95% CI: 2.30-2.48) (P<0.001) for the AP group. Pancreatitis was associated with a high risk of diabetes independent of demographic, lifestyle, and comorbid conditions.

Metabolic Risk Factors and Their Impact on Quality of Life in Patients with Pancreatic Cancer, Acute or Exacerbated Chronic Pancreatitis

Аim: to evaluate metabolic risk factors and their impact on quality of life in patients with pancreatic cancer (PC) and in patients with acute or exacerbated chronic pancreatitis.Materials and methods. Forty-five patients with PC (group 1) and 141 patients with acute pancreatitis or exacerbated chronic pancreatitis (group 2) in an observational multicenter clinical cross-sectional uncontrolled study were examined. Clinical, laboratory and instrumental examination of patients and assessment of risk factors (lipid profile, blood plasma glucose, obesity, arterial hypertension) were carried out in accordance with clinical recommendations. Patients completed the SF-36 questionnaire once to assess quality of life at hospital admission before treatment.Results. In group 1, indicators of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) in blood serum (3.7 ± 0.2; 2.2 ± 0.2 and 0.8 ± 0.1 mmol/L) were lower than in group 2 (5.1 ± 0.1; 3.1 ± 0.1 and 1.2 ± 0.1 mmol/L; p &lt; 0.05). Arterial hypertension was more common in group 1 (55.6 %) than in group 2 (34.8 %; p = 0.013). The presence of arterial hypertension increases the chance of having PC by 2.7 times (p &lt; 0.05). Body mass index parameters, including obesity, as well as parameters of triglycerides, and fasting plasma glucose, did not differ between the groups. Logistic regression analysis revealed a direct relationship with PC HDL hypocholesterolemia (Exp B = 4.976; p &lt; 0.001) and arterial hypertension (Exp B = 2.742; p = 0.027) and an inverse relationship — with hypercholesterolemia (Exp B = 0.204; p = 0.002). The chance of having PC was not associated with age, fasting plasma glucose ³ 7.0 mmol/L, obesity. Quality of life indicators were higher in group 1 than in group 2 on four SF-36 scales: bodily pain (68.1 ± 5.1 and 36.8 ± 2.0; p &lt; 0.001), general health (51.1 ± 2.5 and 38.0 ± 1.7 points; p &lt; 0.001), social functioning (74.7 ± 3.0 and 64.5 ± 2.2 points; p = 0.007), role emotional functioning (28.2 ± 5.2 and 12.5 ± 3.1 points; p = 0.007) and in the general domain “physical component of health” (40.2 ± 1.0 and 33.6 ± 0.8 points; p &lt; 0.001). In group 1 with HDL hypocholesterolemia compared with its absence, the indicators of role emotional functioning (22.2 ± 5.1 and 51.9 ± 13.7 points; p = 0.020) were lower, with arterial hypertension compared with its absence — role physical functioning (5.0 ± 4.0 and 25.5 ± 7.5 points; p = 0.036) and role emotional functioning (16.0 ± 5.1 and 43.3 ± 8.8 points; p = 0.007) were lower.Conclusions. In patients with PC arterial hypertension was more common and the levels of total cholesterol, LDL-C and HDL-C were lower than in patients with acute or exacerbated chronic pancreatitis. The chance of having PC is directly associated with HDL hypocholesterolemia, with arterial hypertension, inversely — with hypercholesterolemia, and is not associated with age, fasting plasma glucose ³ 7 mmol/L, or obesity. In patients with PC, quality of life indicators were higher on four SF-36 scales and on the general domain “physical component of health” than in the group with acute or exacerbated chronic pancreatitis. In patients with PC metabolic factors significantly worsened self-assessment of quality of life in terms of role functioning; in patients with acute or exacerbated chronic pancreatitis there was no such association.

The diagnostic accuracy of endoscopic ultrasound-shear wave elastography in multiple pancreatic regions for chronic pancreatitis based on the Rosemont criteria.

Although endoscopic ultrasound (EUS) has been widely used for diagnosing chronic pancreatitis (CP), the assessment of fibrosis using the Rosemont criteria (RC) is generally subjective. Shear wave elastography using EUS (EUS-SWE) has been advocated as an objective approach to evaluating pancreatic fibrosis; however, it is unknown which pancreatic region should be selected for measurement. This study aims to compare the diagnostic accuracy in diagnosing CP by measurement site. Fifty patients with CP or suspected CP who underwent EUS-SWE were retrospectively analyzed. As per the RC, they were classified into two groups: CP and non-CP. Pancreatic stiffness was evaluated by measuring the velocities of the shear wave (Vs) in addition to determining the relevant cutoff value of Vs for diagnosing CP. The correlation between Vs and RC, and the RC factors affecting pancreatic stiffness were evaluated. In the CP group, the Vs were notably higher in all regions (P < 0.001). The Vs for diagnostic accuracy of CP were highest in the body [area under the curve (AUC): 0.87]. A significant correlation was seen between the number of RC and Vs in all regions, with the correlation coefficient being highest in the pancreatic body (rs = 0.55). Multivariate analysis revealed that lobularity with honeycombing was an independent factor for pancreatic stiffness (P = 0.02). The pancreatic body is a suitable region for assessing pancreatic stiffness using EUS-SWE. Additionally, quantifying Vs is a valuable objective indicator for diagnosing CP.

Intra-pancreatic fat deposition across the pancreatitis spectrum and the influence of gut hormones.

Acute pancreatitis (AP) and chronic pancreatitis (CP) often represent parts of the spectrum of disease. While growing evidence indicates that intra-pancreatic fat deposition (IPFD) plays an important role in the pathogenesis of pancreatitis, no study of living individuals has investigated IPFD in both AP and CP. Further, the associations between IPFD and gut hormones remain to be elucidated. The aims were to investigate the associations of IPFD with AP, CP, and health; and to study whether gut hormones affect these associations. Magnetic resonance imaging on the same 3.0 Tesla scanner was used to determine IPFD in 201 study participants. These participants were arranged into the health, AP, and CP groups. Gut hormones (ghrelin, glucagon-like peptide-1, gastric inhibitory peptide, peptide YY, and oxyntomodulin) were measured in blood, both after an 8-hour overnight fasting and after ingestion of a standardised mixed meal. A series of linear regression analyses was run, accounting for age, sex, ethnicity, body mass index, glycated haemoglobin, and triglycerides. Both the AP group and CP group had significantly higher IPFD in comparison with the health group, consistently across all models (p for trend 0.027 in the most adjusted model). Ghrelin in the fasted state had a significant positive association with IPFD in the AP group (but not the CP or health group), consistently across all models (p=0.019 in the most adjusted model). None of the studied gut hormones in the postprandial state was significantly associated with IPFD. Fat deposition in the pancreas is similarly high in individuals with AP and those with CP. The gut-brain axis, and more specifically overexpression of ghrelin, may contribute to increased IPFD in individuals with AP.

Pediatric Drug-Associated Pancreatitis Reveals Concomitant Risk Factors and Poor Reliability of Causality Scoring: Report From INSPPIRE.

Drug-associated acute pancreatitis (DAP) studies typically focus on single acute pancreatitis (AP) cases. We aimed to analyze the (1) characteristics, (2) co-risk factors, and (3) reliability of the Naranjo scoring system for DAP using INSPPIRE-2 (the INternational Study group of Pediatric Pancreatitis: In search for a cuRE-2) cohort study of acute recurrent pancreatitis (ARP) and chronic pancreatitis (CP) in children. Data were obtained from ARP group with ≥1 episode of DAP and CP group with medication exposure ± DAP. Physicians could report multiple risk factors. Pancreatitis associated with Medication (Med) (ARP+CP) was compared to Non-Medication cases, and ARP-Med vs CP-Med groups. Naranjo score was calculated for each DAP episode. Of 726 children, 392 had ARP and 334 had CP; 51 children (39 ARP and 12 CP) had ≥1 AP associated with a medication; 61% had ≥1 AP without concurrent medication exposure. The Med group had other risk factors present (where tested): 10 of 35 (28.6%) genetic, 1 of 48 (2.1%) autoimmune pancreatitis, 13 of 51 (25.5%) immune-mediated conditions, 11 of 50 (22.0%) obstructive/anatomic, and 28 of 51 (54.9%) systemic risk factors. In Med group, 24 of 51 (47%) had involvement of >1 medication, simultaneously or over different AP episodes. There were 20 ARP and 4 CP cases in "probable" category and 19 ARP and 7 CP in "possible" category by Naranjo scores. Medications were involved in 51 of 726 (7%) of ARP or CP patients in INSPPIRE-2 cohort; other pancreatitis risk factors were present in most, suggesting a potential additive role of different risks. The Naranjo scoring system failed to identify any cases as "definitive," raising questions about its reliability for DAP.

Assessment of morphological changes in the gastroduodenal area of patients with chronic pancreatitis in comorbidity with chronic viral hepatitis C

Background. Viral hepatitis C (HCV) is not only as a liver disease but also as a systemic (generalized) infection that affects ot­her organs, in particular, the pancreas and gastroduodenal zone. The state of the gastrointestinal mucosa in combined course of chronic pancreatitis (CP) and chronic HCV is little studied, but extremely relevant, as it is important for the clinical course, the quality of life of patients, as well as for assessing the safety of the performed (etiotropic, etc.) and planned restorative comprehensive treatment of such patients. The purpose is to evaluate the morphological changes of the gastroduodenal mucosa of patients with chronic pancreatitis associated with chronic viral hepatitis C who were treated etiotropically. Materials and methods. Thirty patients with CP and 65 patients with CP in comorbidity with chronic HCV after etiotropic treatment of HCV were examined. Regardless of the HCV genotype, they received a course of treatment with sofosbuvir at a dose of 400 mg and velpatasvir 100 mg in the morning after meals for 3 months (some patients took daclatasvir at a dose of 60 mg also in the morning after meals for 3 months instead of velpatasvir). The period after diagnosed and treated HCV before the examination was on average (2.35 ± 0.61) years. All patients underwent a morphological study of gastric and duodenal biopsy samples obtained by esophagogastroscopy. The prepared samples were evaluated according to the international OLGA and OLGIM systems based on the evaluation of 5 gastric biopsies (1 from the corner of the stomach, 2 from the body, and 2 from the antrum) with a description of the main pathomorphological changes evaluated on a visual analog scale. Alcian yellow and toluidine blue were used to detect H.pylori. An own system for assessing the morphological state of the gastroduodenal mucosa was also proposed. Results. The detected structural changes indicate the presence of chronic atrophic gastritis with moderate dysplasia of the glandular epithelium. Stage of chronic gastritis according to the OLGA system was III. Stage of chronic gastritis according to the OLGIM system was III. Thus, the practically asymptomatic course of quite significant gastroduodenal changes in CP combined with chronic HCV requires additional therapeutic influence, as well as an assessment of comprehensive treatment based on the effect on the gastroduodenal mucosa. In case of changes in gastroduodenal mucosa in CP on the background of chronic HCV, in contrast to those with isolated CP, a significantly higher level of inflammatory infiltrate density (moderate (2+) vs. mild (1+)) is determined, which is accompanied by moderate neutrophilic infiltration (2+) vs. mild (1+) and mild lymphohistiocytic infiltration (1+) versus no such infiltration (0), the appearance of intestinal metaplasia (2+) and moderate non-metaplastic glandular atrophy (2+) versus the absence of metaplasia (0) and mild non-metaplastic glandular atrophy (1+), as well as zones of metaplastic atrophy (1+), which was manifested by the appearance of Paneth cells and goblet cells. In CP with chronic HCV, mucosa has atrophic changes. Metaplasia is manifested by a change in cellular phenotype: complete intestinal metaplasia type I–II is manifested by the appearance of Paneth cells and goblet cells; incomplete — by the presence of columnar epithelium and goblet cells; colonic metaplasia — by enlargement of the glands and the absence of Paneth cells. Conclusions. It was proved that the state of the gastric and duodenal mucosa in the group of patients with CP and chronic HCV was significantly severe than that in isolated CP: lymphohistiocytic infiltration of the mucous membrane was detected 2.68 times more often, non-metaplastic infiltration glandular atrophy (there was practically no glandular atrophy in the group of isolated CP) — 12.65 times more often, metaplastic atrophy (it was not detected in the group of CP) — 10.64 times more often, acute leukocyte infiltration — 2.31 times more often, dysplasia of the mucosal epithelium (with isolated CP, mild dysplasia was detected) — 7.30 times more often, erosion of the mucosal epithelium — 3.07 times more often, focal hyperplasia of the glands — 3.88 times more often, intestinal metaplasia — 12.89 times more often, which was practically absent in CP. In general, the total number of pathological signs of the mucous membrane in the group of CP with comorbid chronic HCV was found to be 2.76 times higher than that in isolated CP.

Relationship between pancreatic cancer and Maresin 1

Aims: Pancreatic cancer is the 4th most common cause of death from cancer. In addition, pancreatic cancer is the most common primary malignant tumor of the pancreas. There are many risk factors for pancreatic cancer, including age, certain genetic syndromes, smoking, diabetes, alcohol abuse and obesity. In our study, we aimed to evaluate the role of Maresin 1 (MaR1), which is responsible for the resolution of inflammation, in the pathogenesis of pancreatic cancer and its differential power between chronic pancreatitis and pancreatic cancer. Methods: The study included 47 patients diagnosed with pancreatic cancer, 32 patients diagnosed with chronic pancreatitis, and 30 volunteers without any additional disease who applied to the internal medicine polyclinic for routine control, who applied to our clinic since October 2021 and accepted to participate in the study. MaR1 levels were measured using the ELISA technique from blood samples obtained from these volunteers. Results: In our study, MaR1 level was 374.42 (97.27-74.129) pg/ml in the pancreatic cancer group, 491.39 (252.66-949.28) pg/ml in the chronic pancreatitis group and 558.53 (286.94) in the healthy control group. -886,68) pg/ml was measured. There was a significant difference between the pancreatic cancer patients group and the chronic pancreatitis patients and healthy control group. In the pancreatic cancer patient group, MaR1 level was found to be lower than the chronic pancreatitis group (p=0.01). In our ROC analysis, the discriminative performance of MaR1 (AUC=0.651; [95%CI: 0.535-0.754]; p=0.0169 values) was found to be high in predicting patients with pancreatic cancer according to the patient group with chronic pancreatitis. For MaR1 ?315.52 cut-off point sensitivity was 36.17% and selectivity was 90.62%. Conclusion: Proinflammatory cytokines, which have a role in the pathogenesis of pancreatic cancer, increase as a result of the decrease in lipid mediators involved in resolution pathways. Reduction of MaR1 may trigger chronic inflammation and pancreatic carcinogenesis. MaR1 may make an important diagnostic contribution in clinical practice in predicting the progression of patients with chronic pancreatitis to pancreatic cancer.

O148 Risk of osteoporotic fractures in patients with chronic pancreatitis: a systematic review and meta-analysis

Abstract Introduction Chronic pancreatitis is a progressive fibroinflammatory disease and can lead to irreversible loss of pancreatic function and malnutrition. These, alongside excess alcohol intake, increase the risk of low bone density. Osteoporosis can be debilitating, reduces quality of life, increases fracture risk, and poses significant costs to healthcare. There remains, however, a paucity in current literature evaluating the prevalence of osteoporosis in this population. This meta-analysis evaluates the prevalence of osteoporosis and fractures in chronic pancreatitis. Methods A systematic search of Medline, Embase, CENTRAL, and ClinicalTrials.gov databases was undertaken to identify studies between January 2000 and May 2022. The primary outcome of osteoporosis prevalence and secondary outcomes of osteopenia prevalence and fragility fractures were extracted from the included studies. Where available, a subgroup analysis was performed to compare the likelihood of developing osteoporosis in chronic pancreatitis compared with control. Results Nineteen studies evaluating 2,027,767 participants were included in the analysis (20,463 and 2,007,304 were in the chronic pancreatitis and control groups respectively). The pooled prevalence of osteoporosis was 19% (95% CI 13-26%; I2=94%). Patients with chronic pancreatitis were more likely to have osteoporosis when compared with controls (OR 2.80, 95% CI 1.86-4.21). The prevalence of osteopenia and overall fractures were 37% (95% CI 31-44%; I2=81%) and 14% (95% CI 7-22%; I2= 99%) respectively. Conclusion The prevalence of osteoporosis and osteopenia are considerable in chronic pancreatitis and can also result in fractures. Further population-based studies are required to evaluate the disease burden of osteoporotic fractures and associated mortality in chronic pancreatitis.

Significantly Lower Physical Activity Participation in Individuals with Chronic Pancreatitis Compared to Controls: An Exploratory Study of Objectively Assessed Physical Activity Levels

Introduction: The beneficial effects of exercise and physical activity (PA) have been demonstrated in many chronic inflammatory diseases. Knowledge on PA levels is unknown in the chronic pancreatitis population, and there are currently no specific PA recommendations for this condition. Methods: PA was measured objectively over a 7-day period in 17 individuals with chronic pancreatitis using an accelerometer (ActiGraph) and in 15 controls, matched for age, sex, and body mass index. Results: Participants with chronic pancreatitis spent a significantly lower amount of time in moderate, light, and moderate/vigorous activity compared to the healthy control group. Mean time in light activity in the chronic pancreatitis group was 825.4 ± 972 (standard deviation [SD]) compared to 1,500 ± 958 (SD) in the healthy control group. Moderate activity mean minutes were 61.6 ± 85 in the chronic pancreatitis group compared to 161.4 ± 131.2 in the healthy control group. Moderate/vigorous mean minutes were 62.1 ± 86 (SD) in the chronic pancreatitis group compared to 164.3 ± 132 (SD) in the healthy control group. There was no significant difference found between the groups for either vigorous activity or time spent sedentary. Conclusion: This exploratory study offers early objective evidence that activity levels in the chronic pancreatic group are not meeting current international recommendations. Further investigation of this chronic illness population is strongly recommended.

Functional state of the autonomic nervous system in patients with chronic pancreatitis combined with chronic bronchitis

60 patients with chronic pancreatitis (acute exacerbation) combined with chronic bronchitis (mild exacerbation) were examined. 33 almost healthy patients (the control group) were also examined.&#x0D; The functional state of the autonomic nervous system was assessed using an analysis of heart rate variability.&#x0D; The study was carried out in two stages. The electrocardiogram was recorded in standard lead II at rest and in active orthostasis for 100 cardiocycles. The obtained data were processed using the Korveg computer program. Based on the data obtained, the following indices were calculated: the regulatory system stress index (SI), which reflects the total activity of the central regulatory mechanisms, allows us to assess the degree of shift of the autonomic balance towards sympathetic regulation, characterizes the stress of compensatory mechanisms, and the level of functioning of the central circuit of heart rate regulation; vegetative balance index (VBI), which reflects the ratio of the activity of the sympathetic and parasympathetic divisions of the autonomic nervous system; an indicator of the adequacy of regulation processes (IARP), which reflects the adequacy of the activity of the sympathetic division of the autonomic nervous system; vegetative rhythm index (VRI), which reflects the vegetative balance in terms of assessing the activity of the autonomic regulation circuit; orthoprobe ratio (OR), which is the ratio of the 30th R–R interval to the 15th R–R interval after standing up, this coefficient reflects the state of the parasympathetic division of the autonomic nervous system.&#x0D; SI was statistically significantly higher in the group of chronic pancreatitis combined with bronchitis at rest than in controls, indicating a shift in the autonomic balance towards the sympathetic system.&#x0D; VBI in patients with chronic pancreatitis combined with bronchitis was significantly higher in the lying position, but significantly lower in the standing position than in the control group.&#x0D; IARP was statistically significantly lower in the group of patients in the standing position, which indicates some excessive centralization of heart rate control in comorbidities.&#x0D; VRI did not differ statistically significantly in the control group and in the group of chronic pancreatitis combined with bronchitis, which indicates the normalization of parasympathetics in the group of patients during exercise.&#x0D; OR was significantly lower in chronic pancreatitis combined with bronchitis, which indicates an increase in the effect of the parasympathetic nervous system.&#x0D; Thus, there is an imbalance in the sympathetic and parasympathetic divisions of the autonomic nervous system in patients with chronic pancreatitis combined with chronic bronchitis, which depends on the position of the patient (lying or standing).&#x0D;

Alterations of commensal microbiota are associated with pancreatic cancer.

Dysbiosis commonly occurs in pancreatic cancer, but its specific characteristics and interactions with pancreatic cancer remain obscure. The 16S rRNA sequencing method was used to analyze multisite (oral and gut) microbiota characteristics of pancreatic cancer, chronic pancreatitis, and healthy controls. Differential analysis was used to identify the pancreatic cancer-associated genera and pathways. A random forest algorithm was adopted to establish the diagnostic models for pancreatic cancer. The chronic pancreatitis group exhibited the lowest microbial diversity, while no significant difference was found between the pancreatic cancer group and healthy controls group. Diagnostic models based on the characteristics of the oral (area under the curve (AUC) 0.916, 95% confidence interval (CI) 0.832-1) or gut (AUC 0.856; 95% CI 0.74, 0.972) microbiota effectively discriminate the pancreatic cancer samples in this study, suggesting saliva as a superior sample type in terms of detection efficiency and clinical compliance. Oral pathogenic genera (Granulicatella, Peptostreptococcus, Alloprevotella, Veillonella, etc.) and gut opportunistic genera (Prevotella, Bifidobacterium, Escherichia/Shigella, Peptostreptococcus, Actinomyces, etc.), were significantly enriched in pancreatic cancer. The 16S function prediction analysis revealed that inflammation, immune suppression, and barrier damage pathways were involved in the course of pancreatic cancer. This study comprehensively described the microbiota characteristics of pancreatic cancer and suggested potential microbial markers as non-invasive tools for pancreatic cancer diagnosis.

Comparative analysis of the intestinal microbiota in patients with exocrine pancreatic insufficiency of various severity

Exocrine pancreatic insufficiency (EPI) is a critical host factor in determining the composition of the gut microbiota. Diseases that cause exocrine insufficiency can affect the gut microbiome, which can potentiate disease progression and complications. To date, the relationship of exocrine insufficiency in various pancreatic (PA) pathologies, in chronic pancreatitis (CP), with dysbiotic changes in the intestinal microbiota (IM) has not been reliably studied. The available data are heterogeneous and contradictory, which determines the need for further research. To conduct a comparative analysis of the taxonomic composition of the intestinal microbiota in patients with CP of various etiologies, without or with the presence of EPI of varying severity, as well as patients with severe EPI with a history of surgical intervention (SI) on the pancreas. A total of 85 patients were included in the study. Patients were divided into groups according to the severity of EPI: Group 1 (n=16) - patients with CP without EPI; Group 2 (n=11) - patients with CP and mild EPI; Group 3 (n=17) - patients with severe CP and EPI; Group 4 (n=41) - severe EPI in persons with a history of SI on the pancreas. Verification of CP was carried out according to clinical, anamnestic and instrumental data. The degree of EPI was determined by the level of pancreatic elastase-1 (PE-1) feces. Informed consent for the study was obtained for each patient, an anamnesis was collected, physical and laboratory examinations were performed, and a stool sample was obtained. DNA was extracted from each stool sample, the taxonomic composition of BM was determined by sequencing the bacterial 16S rRNA genes, followed by bioinformatic analysis. We followed the changes in the gut microbiota from a group of patients with CP without EPI to a group with severe EPI, in those who underwent SI. At the level of the phylum, the IM of all groups showed the dominance of Firmicutes, with the lowest representation in the severe EPI group, both with SI and CP, and the growth of the Actinobacteria, Verrucomicrobiota and Fusobacteria types. The differential representation of childbirth varied: in patients with severe EPI and CP, compared with mild, statistically significant genera - Akkermansia, Ruminococcus gauvreauii group and Holdemanella; compared with CP without exocrine insufficiency, Prevotella, Ruminococcus gauvreauii group, Peptostreptococcus and Blautia dominated. The CP group with mild EPI was dominated by the following genera: Lachnospiraceae_ND 2004 group, Faecalitalea, Fusobacterium, Catenibacterium, Roseburia, Atopobium, Cloacibacillus, Clostridium innococum group, Ruminococcus torques group. All groups showed a low diversity of taxa with a predominance of opportunistic flora, including participants in oncogenesis. The results of the study show that patients with CP of various etiologies and patients with severe EPI who underwent specific intervention on the pancreas have intestinal microbiota dysbiosis, the severity of which is significantly influenced by the degree of EPI.

Cross-sectional evaluation of gut microbial-host co-metabolites in patients with chronic pancreatitis.

Gut bacteria facilitate nutrient metabolism and generate small molecules that form part of the broader "metabolome." It is unclear whether these metabolites are disturbed during chronic pancreatitis. This study aimed to evaluate the gut microbial-host co-metabolites and the relationship between them in patients with chronic pancreatitis. We collected fecal samples from 40 patients with chronic pancreatitis and 38 healthy family members with each sample undergoing 16S rRNA gene profiling and gas chromatography time-of-flight mass spectrometry , to estimate the relative abundance of specific bacterial taxa between the two groups and to profile any changes in the metabolome, respectively. Correlation analysis was used to evaluate differences in metabolites and bacteria between the two groups. The abundance of Actinobacteria was lower at the phylum level, and that of Bifidobacterium was lower at the genus level in the chronic pancreatitis group metabolites had a significantly different. Oxoadipic acid and citric acid levels were positively correlated with Bifidobacterium abundance (Spearman's r = 0.306, and r = 0.33, respectively, p < 0.05),and the 3-methylindole concentration was negatively correlated with Bifidobacterium abundance (r = -0.252, p = 0.026). Gut microbiome and host microbiome metabolic products might be altered in patients with chronic pancreatitis. Evaluating gastrointestinal tract metabolite levels in this regard may further enhance our understanding of the pathogenesis and/or progression of chronic pancreatitis.

Acute Pancreatitis Recurrences Augment Long-Term Pancreatic Cancer Risk.

In animal models, inflammation caused by experimental acute pancreatitis (AP) promotes pancreatic carcinogenesis that is preventable by suppressing inflammation. Recent studies noted higher long-term risk of pancreatic ductal adenocarcinoma (PDAC) after AP. In this study, we evaluated whether the long-term PDAC risk after AP was influenced by the etiology of AP, number of recurrences, and if it was because of progression to chronic pancreatitis (CP). This retrospective study used nationwide Veterans Administration database spanning 1999-2015. A 2-year washout period was applied to exclude patients with preexisting AP and PDAC. PDAC risk was estimated in patients with AP without (AP group) and with underlying CP (APCP group) and those with CP alone (CP group) and compared with PDAC risk in patients in a control group, respectively, using cause-specific hazards model. The final cohort comprised 7,147,859 subjects (AP-35,550 and PDAC-16,475). The cumulative PDAC risk 3-10 years after AP was higher than in controls (0.61% vs 0.18%), adjusted hazard ratio (1.7 [1.4-2.0], P < 0.001). Adjusted hazard ratio was 1.5 in AP group, 2.4 in the CP group, and 3.3 in APCP group. PDAC risk increased with the number of AP episodes. Elevated PDAC risk after AP was not influenced by the etiology of AP (gallstones, smoking, or alcohol). There is a higher PDAC risk 3-10 years after AP irrespective of the etiology of AP, increases with the number of episodes of AP and is additive to higher PDAC risk because of CP.

Evaluation of Ultrasound Based Point Shear Wave Elastography for Diagnosis of Inflammatory Pancreatic Diseases

Introduction: A variety of imaging techniques exists for the diagnosis of pancreatic disorders. None of the broadly accepted diagnostic methods, uses elasticity as an indicator of tissue damage. A well-known fact is that pathological changes influence tissue stiffness and elasticity. US elastography in its different modalities has been widely used for evaluation and characterization of multiple abdominal structures. Point Shear Wave Elastography (pSWE) particularly has been reported to be highly effective in various clinical diagnostic applications. However, data on the role of pSWE in a deep-seated organ like pancreas is scarce. Objective: To prospectively assess the diagnostic value of abdominal US elastography in the form of point shear wave elastography (pSWE) in characterizing and differentiating between normal pancreatic parenchyma and chronic pancreatitis. To establish a cut off value for the diagnosis of chronic pancreatitis. To investigate the influence of certain independent variables and the severity of pancreatitis on the acquired results. Patients Twenty five patients diagnosed with chronic pancreatitis who visited the Department of Gastroenterology in University Hospital Kaspela, between December 2020 and August 2021, for diagnosis and/or treatment and twenty eight individuals with no evidence of pancreatic disorder, admitted at the hospital during the same period of time, were included in the study. Based on the clinical symptomatic criteria, diagnostic imaging and histological findings, patients were divided into chronic pancreatitis (CP) and healthy pancreatic parenchyma group. Methods: The ultrasound based point Shear Wave Elastography (pSWE) imaging techniques were applied. A total of five measurements was obtained in each segment of the gland. The depth of region of interest (ROI) was also recorded. Design Prospective single-center study. Results: The mean shear wave speed (SWS) values of the entire pancreatic parenchyma were 1.71m/s, 1.15m/s for the chronic pancreatitis and the normal pancreatic parenchyma respectively. With a cut off value of 1.43m/s, sensitivity (Se), specificity (Sp), positive predictive value (PPV), negative predictive value (NPV) and accuracy (Ac) of 89.7%, 95.2%, 94.59%, 90.91% and 92.59% respectively were calculated for the diagnosis of chronic pancreatitis. Neither the independent variables researched, nor the severity of disease, defined according to the Cambridge score, proved to have statistically significant reflection on the SWS in patients with CP. Conclusion: pSWE established considerably higher SWS in patients with chronic pancreatitis, therefore it may be successfully adopted as a diagnostic modality in patients with chronic inflammatory pancreatic disorders. External factors have minor effect on the results obtained, suggesting that the technique is highly objective. High SWS were obtained both in patients with discrete structural abnormalities (Cambridge 2) and advanced forms of pancreatitis (Cambridge 4), which points that pSWE may be utilized as differential diagnostic method in cases in which other imaging techniques provide equivocal and inconclusive results.

XCHT alleviates the pancreatic fibrosis via VDR/NLRP3 signaling pathway in a mouse model of CP

Ethnopharmacological relevanceXiao Chai Hu Tang (XCHT) derived from the classic medical book Shang Han Lun (Treatise on Febrile Diseases) in the Eastern Han Dynasty, which has been widely used in China and other Asian countries for the treatment of inflammation and fibrosis of chronic pancreatitis (CP), but the therapeutic mechanism of XCHT in pancreatic fibrosis remains unclear. Aim of the studyThis study aimed to evaluate the intervention effects and explore pharmacological mechanism of XCHT on inflammation and fibrosis in cerulein-induced CP model. Materials and methodsFifty male C57BL/6 mice were randomly divided into five main groups, 10 animals in each: Control, CP model (50 μg/kg cerulein), high dose XCHT-treated CP group (60 g/kg XCHT), medium dose XCHT-treated CP group (30 g/kg XCHT) and low dose XCHT-treated CP group (15 g/kg XCHT). Different doses of XCHT were given to mice by gavage twice a day for 2 weeks after the CP model induction. Pancreatic tissues were harvested and the pancreatic inflammation and fibrosis were evaluated by histological score, Sirius red staining, and alpha-smooth muscle actin (α-SMA) immunohistochemical staining. ELISA, IHC and RT-qPCR were performed to detect the expression of Vitamin D3 (VD3) and Vitamin D receptor (VDR) in serum and pancreatic tissues, respectively. The expressions of NLRP3 inflammasome related genes and molecules were assayed by WB, IHC and RT-qPCR. ResultsThe pathohistological results demonstrated that XCHT markedly inhibited the fibrosis and chronic inflammation of cerulein-induced CP, indicated by reduction of collagen I, collagen III, α-SMA, and NLRP3 expressions. XCHT significantly increased VD3 and VDR expression while reduced the pancreatic NLRP3 expression. Correspondingly, XCHT decreased the levels of NLRP3 downstream targets IL-1β, TNF-α and IL-6. ConclusionsThese results revealed that XCHT suppressed the pancreatic fibrosis and chronic inflammation in cerulein-induced CP model by enhancing the VD3/VDR expression and inhibiting the secretion of NLRP3-assoicated inflammatory factors.

Quantitative MRI of chronic pancreatitis: results from a multi-institutional prospective study, magnetic resonance imaging as a non-invasive method for assessment of pancreatic fibrosis (MINIMAP).

PurposeTo determine if quantitative MRI techniques can be helpful to evaluate chronic pancreatitis (CP) in a setting of multi-institutional study.MethodsThis study included a subgroup of participants (n = 101) enrolled in the Prospective Evaluation of Chronic Pancreatitis for Epidemiologic and Translational Studies (PROCEED) study (NCT03099850) from February 2019 to May 2021. MRI was performed on 1.5 T using Siemens and GE scanners at seven clinical centers across the USA. Quantitative MRI parameters of the pancreas included T1 relaxation time, extracellular volume (ECV) fraction, apparent diffusion coefficient (ADC), and fat signal fraction. We report the diagnostic performance and mean values within the control (n = 50) and CP (n = 51) groups. The T1, ECV and fat signal fraction were combined to generate the quantitative MRI score (Q-MRI).ResultsThere was significantly higher T1 relaxation time; mean 669 ms (± 171) vs. 593 ms (± 82) (p = 0.006), ECV fraction; 40.2% (± 14.7) vs. 30.3% (± 11.9) (p < 0.001), and pancreatic fat signal fraction; 12.2% (± 5.5) vs. 8.2% (± 4.4) (p < 0.001) in the CP group compared to controls. The ADC was similar between groups (p = 0.45). The AUCs for the T1, ECV, and pancreatic fat signal fraction were 0.62, 0.72, and 0.73, respectively. The composite Q-MRI score improved the diagnostic performance (cross-validated AUC: 0.76).ConclusionQuantitative MR parameters evaluating the pancreatic parenchyma (T1, ECV fraction, and fat signal fraction) are helpful in the diagnosis of CP. A Q-MRI score that combines these three MR parameters improves diagnostic performance. Further studies are warranted with larger study populations including patients with acute and recurrent acute pancreatitis and longitudinal follow-ups.Graphical abstract Supplementary InformationThe online version contains supplementary material available at 10.1007/s00261-022-03654-7.