Pancreatic Fibrosis Research Articles

Histopathologic correlation of pancreatic fibrosis with pancreatic magnetic resonance imaging quantitative metrics and Cambridge classification

To determine the correlation of the T1-weighted signal intensity ratio (T1 SIR, or T1 Score) and arterial-to-delayed venous enhancement ratio (ADV ratio) of the pancreas with pancreatic fibrosis on histopathology. Sixty consecutive adult CP patients who had an MRI/MRCP study prior to pancreatic surgery were analyzed. Three blinded observers measured T1 SIR of pancreas to spleen (T1 SIR p/s), pancreas-to-paraspinal muscle (T1 SIR p/m), ADV ratio, and Cambridge grade. Histopathologic grades were given by a gastrointestinal pathologist using Ammann's fibrosis score. Statistical analysis included Spearman's correlation coefficient of the T1 SIR, ADV ratio, Cambridge grade with the fibrosis score, and weighted kappa for interobserver agreement. The study population included 31 female and 29 male patients, with an average age of 52.1 (26-78years). Correlations between fibrosis score and T1 SIR p/s, T1 SIR p/m, and ADV ratio were ρ = - 0.54 (p = 0.0001), ρ = - 0.19 (p = 0.19), and ρ = - 0.39 (p = 0.003), respectively. The correlation of Cambridge grade with fibrosis score was ρ = 0.26 (p = 0.07). There was substantial interobserver agreement (weighted kappa) for T1 SIR p/s (0.78), T1 SIR p/m (0.71), and ADV ratio (0.64). T1 SIR p/s of ≤ 1.20 provided a sensitivity of 74% and specificity of 50% (AUC: 0.74), while ADV ratio of ≤ 1.10 provided a sensitivity of 75% and specificity of 55% (AUC: 0.68) to detect a fibrosis score of ≥ 6. There is a moderate negative correlation between the T1 Score (SIR p/s) and ADV ratio with pancreatic fibrosis and a substantial interobserver agreement. These parenchymal metrics show a higher correlation than the Cambridge grade.

Pancreatogenic Diabetes in Children With Recurrent Acute and Chronic Pancreatitis: Risks, Screening, and Treatment (Mini-Review).

Up to 9% of children with acute recurrent pancreatitis (ARP) or chronic pancreatitis have pancreatogenic diabetes mellitus (DM), and this risk likely increases as they age into adulthood. Risk factors for pancreatogenic DM in children vary depending on the clinical cohort but may include pancreatic atrophy, exocrine insufficiency, pancreatic calcifications, obesity/metabolic syndrome features, or autoimmune diseases. Knowledge regarding disease pathology is extrapolated nearly entirely from studies in adults. Insulin deficiency is the primary defect, resulting from islet loss associated with pancreatic fibrosis and cytokine-mediated β-cell dysfunction. Beta cell autoimmunity (type 1 diabetes) should also be considered as markers for this have been identified in a small subset of children with pancreatogenic DM. Hepatic insulin resistance, a deficient pancreatic polypeptide state, and dysfunctional incretin hormone response to a meal are all potential contributors in adults with pancreatogenic DM but their significance in pediatrics is yet unknown. Current guidelines recommend yearly screening for diabetes with fasting glucose and hemoglobin A1c (HbA1c). Insulin in the first-line pharmacologic therapy for treatment of pancreatogenic DM in children. Involvement of a multidisciplinary team including a pediatric endocrinologist, gastroenterologist, and dietitian are important, and nutritional health and exocrine insufficiency must also be addressed for optimal DM management.

The impact of postoperative exocrine index on non-alcoholic fatty liver disease following pancreaticoduodenectomy.

BackgroundTo study exocrine function of the remnant pancreas after pancreatoduodenectomy (PD), we propose the use of an exocrine index (PEI) that combines the volume of the remnant pancreas and the intraoperative amylase activity of the pancreatic juice. Here, we aimed to determine whether the PEI can predict non‐alcoholic fatty liver disease (NAFLD) following PD.MethodsFifty‐seven patients for whom pancreatic juice amylase activity was measured during PD were enrolled. NAFLD was defined as a liver‐to‐spleen attenuation ratio of <0.9 on plain CT 1 year following surgery. We retrospectively evaluated clinical parameters, including the PEI, to identify predictors of NAFLD.ResultsFifty‐four patients (95%) were regularly administered 1200 mg of pancreatic lipase. NAFLD was diagnosed in 13 participants (23%) 1 year following surgery. NAFLD was associated with pancreatic ductal adenocarcinoma (P = .006), soft pancreas (P = .001), small main pancreatic duct (P = 0008), low remnant pancreatic volume (P < .001), low intraoperative amylase activity in the pancreatic juice (P = .001), high pancreatic fibrosis (P = .032), and large body weight loss (P = .015). The PEI was significantly lower in the participants with NAFLD than in those without (P < .001). The participants were then classified into tertiles of PEI: <5 × 106, 5‐25 × 106, and >25 × 106. The prevalence of NAFLD in these groups was 53% (10/19), 11% (2/19), and 5% (1/19), respectively. In multivariable analyses, there was a significant association between NAFLD and the PEI (P value for trend = .042).ConclusionThe PEI, calculated using the remnant pancreatic volume and the intraoperative pancreatic juice amylase activity, predicts NAFLD development following PD.

Piezo1-mediated stellate cell activation causes pressure-induced pancreatic fibrosis in mice.

Pancreatic fibrosis is a complication of chronic pancreatitis and is a prominent feature of pancreatic cancer. Pancreatic fibrosis is commonly observed in patients with prolonged pancreatic duct obstruction, which elevates intrapancreatic pressure. We show here that increased pancreatic duct pressure causes fibrosis and describes the mechanism by which pressure increases deposition of extracellular matrix proteins and fibrosis. We found that pancreatic stellate cells (PSCs), the source of the extracellular matrix proteins in fibrosis, express the mechanically activated ion channel Piezo1. By increasing intracellular calcium, mechanical stress or the Piezo1 agonist Yoda1-activated PSCs manifest by loss of perinuclear fat droplets and increased TGF-β1, fibronectin, and type I collagen expression. These effects were blocked by the Piezo1 inhibitor GsMTx4 and absent in PSCs from mice with conditional genetic deletion of Piezo1 in stellate cells, as was pancreatic duct ligation–induced fibrosis. Although TRPV4 has been proposed to have direct mechanosensing properties, we discovered that PSCs from Trpv4-KO mice were protected against Yoda1-triggered activation. Moreover, mice devoid of TRPV4 were protected from pancreatic duct ligation–induced fibrosis. Thus, high pressure within the pancreas stimulates Piezo1 channel opening, and subsequent activation of TRPV4 leads to stellate cell activation and pressure-induced chronic pancreatitis and fibrosis.

Challenges and Opportunities Associated With Platelets in Pancreatic Cancer.

Pancreatic cancer is one of the most common malignant tumors in the digestive system with a poor prognosis. Accordingly, better understanding of the molecular mechanisms and innovative therapies are warranted to improve the prognosis of this patient population. In addition to playing a crucial role in coagulation, platelets reportedly contribute to the growth, invasion and metastasis of various tumors, including pancreatic cancer. This narrative review brings together currently available evidence on the impact of platelets on pancreatic cancer, including the platelet-related molecular mechanisms of cancer promotion, pancreatic cancer fibrosis, immune evasion, drug resistance mechanisms, thrombosis, targeted platelet therapy, combined radiotherapy and chemotherapy treatment, platelet combined with nanotechnology treatment and potential applications of pancreatic cancer organoids. A refined understanding of the role of platelets in pancreatic cancer provides the foothold for identifying new therapeutic targets.

Murine Chronic Pancreatitis Model Induced by Partial Ligation of the Pancreatic Duct Encapsulates the Profile of Macrophage in Human Chronic Pancreatitis.

Immune responses are an integral part of the pathogenesis of pancreatitis. Studies applying the mouse model of pancreatitis induced by partial ligation of the pancreatic duct to explore the pancreatic immune microenvironment are still lacking. The aim of the present study is to explore the macrophage profile and associated regulatory mechanisms in mouse pancreatitis, as well as the correlation with human chronic pancreatitis (CP). In the present study, the mouse model of pancreatitis was induced by partial ligation of the pancreatic duct. Mice in the acute phase were sacrificed at 0, 4, 8, 16, 32, 72 h after ligation, while mice in the chronic phase were sacrificed at 7, 14, 21, 28 days after ligation. We found that the pancreatic pathological score, expression of TNF-α and IL-6 were elevated over time and peaked at 72h in the acute phase, while in the chronic phase, the degree of pancreatic fibrosis peaked at day 21 after ligation. Pancreatic M1 macrophages and pyroptotic macrophages showed a decreasing trend over time, whereas M2 macrophages gradually rose and peaked at day 21. IL-4 is involved in the development of CP and is mainly derived from pancreatic stellate cells (PSCs). The murine pancreatitis model constructed by partial ligation of the pancreatic duct, especially the CP model, can ideally simulate human CP caused by obstructive etiologies in terms of morphological alterations and immune microenvironment characteristics.

IL11 Activates Pancreatic Stellate Cells and Causes Pancreatic Inflammation, Fibrosis and Atrophy in a Mouse Model of Pancreatitis.

Interleukin-11 (IL11) is important for fibrosis and inflammation, but its role in the pancreas is unclear. In pancreatitis, fibrosis, inflammation and organ dysfunction are associated with pancreatic stellate cell (PSC)-to-myofibroblast transformation. Here, we show that IL11 stimulation of PSCs, which specifically express IL11RA in the pancreas, results in transient STAT3 phosphorylation, sustained ERK activation and PSC activation. In contrast, IL6 stimulation of PSCs caused sustained STAT3 phosphorylation but did not result in ERK activation or PSC transformation. Pancreatitis factors, including TGFβ, CTGF and PDGF, induced IL11 secretion from PSCs and a neutralising IL11RA antibody prevented PSC activation by these stimuli. This revealed an important ERK-dependent role for autocrine IL11 activity in PSCs. In mice, IL11 was increased in the pancreas after pancreatic duct ligation, and in humans, IL11 and IL11RA levels were elevated in chronic pancreatitis. Following pancreatic duct ligation, administration of anti-IL11RA to mice reduced pathologic (ERK, STAT, NF-κB) signalling, pancreatic atrophy, fibrosis and pro-inflammatory cytokine (TNFα, IL6 and IL1β) levels. This is the first description of IL11-mediated activation of PSCs, and the data suggest IL11 as a stromal therapeutic target in pancreatitis.

Dual-Energy CT Iodine Concentration to Evaluate Postoperative Pancreatic Fistula after Pancreatoduodenectomy.

Background Pancreatic fibrosis and fatty infiltration are associated with postoperative pancreatic fistula (POPF), but accurate preoperative assessment remains a challenge. Iodine concentration (IC) and fat fraction derived from dual-energy CT (DECT) may reflect the amount of fibrosis and steatosis, potentially enabling the preoperative prediction of POPF. Purpose To identify multiphasic DECT-derived IC and fat fraction that improve the prediction of POPF risks compared with contrast-enhanced CT attenuation values and to evaluate the underlying histopathologic changes. Materials and Methods This retrospective study included patients who underwent pancreatoduodenectomy and DECT (including pancreatic parenchymal, portal venous, and delayed phase scanning) between January 2020 and December 2020. The relationships of the quantitative DECT-derived IC and fat fraction, along with CT attenuation values from enhanced images with POPF risk, were analyzed with logistic regression analysis. The predictive performance of the IC was compared with that of the CT values. The histopathologic underpinnings of IC were evaluated with multivariable linear regression analysis. Results A total of 107 patients (median age, 65 years; interquartile range, 57-70 years; 56 men) were included. Of these, 23 (21%) had POPF. The pancreatic parenchymal-to-portal venous phase IC ratio (adjusted odds ratio [OR], 13; 95% CI: 2, 162; P < .001) was an independent predictor of POPF occurrence. The accuracy of the pancreatic parenchymal-to-portal venous phase IC ratio in predicting POPF was higher than that of the CT value ratio in the same phases (78% vs 65%, P < .001). The pancreatic parenchymal-to-portal venous phase IC ratio was independently associated with pancreatic fibrosis (β = -1.04; 95% CI: -0.44, -1.64; P = .001). Conclusion A higher pancreatic parenchymal-to-portal venous phase IC ratio was associated with less histologic fibrosis and greater risk of POPF. © RSNA, 2022 Online supplemental material is available for this article. See also the editorial by Lee and Yoon in this issue.

Pancreatic Stellate Cells and Metabolic Alteration: Physiology and Pathophysiology.

Pancreatic stellate cells play a pivotal role in the development of pancreatic fibrosis. A wide variety of external stimuli can cause PSC activation accompanied by metabolic changes, which alters the tissue microenvironment by producing extracellular matrix proteins, cytokines, growth factors, and other mediators. Several metabolites aggravate fibrosis and inflammation by acting as key activating factors for PSCs. In other words, PSCs sense systemic metabolic changes. The detrimental effects of PSC activation on normal pancreatic cells, especially islet cells, further complicate metabolic imbalance through the dysregulation of glucose metabolism. PSC activation promotes cancer by altering the metabolism in pancreatic cancer cells, which collaborate with PSCs to efficiently adapt to environmental changes, promoting their growth and survival. This collaboration also contributes to the acquisition of chemoresistance. PSCs sequester chemotherapeutic agents and produce competing molecules as additional resistance mechanisms. The application of these metabolic targets for novel therapeutic strategies is currently being explored. This mini-review summarizes the role of PSCs in metabolic regulation of normal and cancerous cells.

High serum CA19–9 preoperatively reduces POPF risk after pancreatoduodenectomy in PDAC

Recent groundbreaking work revealed CA19–9 is not only a tumor marker for PDAC. It also induces severe pancreatitis and promotes pancreatic fibrosis. The aim of this study was evaluation if due fibrosis CA19–9 may stratify for reduced postoperative pancreatic fistula (POPF) risk. Retrospective analysis of our institutional database of 954 consecutive patients having undergone PD between 2001 and 2018. Potential risk factors for POPF were evaluated. 436 (46%) patients with pancreatic ductal adenocarcinoma (PDAC) were analysed separately. POPF rate, degree of pancreatic fibrosis, inflammation and acinar cell area at the cut edge of pancreas (CEP) were investigated in correlation of CA19–9. The median age was 67 (range 9–89) years. 533 (56%) were male, 22% of patients developed clinically relevant POPF (CR-POPF). Overall postoperative mortality was 3.4%. Elevated preoperative CA19–9, elevated bilirubin and postoperative low serum amylase were significantly ( p <0.01) associated with a reduced POPF rate in patients with PDAC. In addition, elevated CA19–9 was significantly associated with more pancreatic fibrosis ( p <0.02), inflammation ( p <0.01) and acinar atrophy ( p <0.01). In our experience, increased CA19–9 correlates with pancreatic fibrosis and reduced CR-POPF. CA19–9 could be complementary for preoperative POPF-scores.

Autoimmune pancreatitis and its relevance

Autoimmune pancreatitis (AIP) is a rare form of chronic pancreatitis characterized by an autoimmune inflammatory process; there is a lymphocytic infiltrate associated with pancreatic fibrosis, causing organic dysfunction. The first descriptions began in the 1990s, and the disease is often underdiagnosed.

Analysis of Intraoperative Frozen Pancreatic Resection Margin and Prediction of Postoperative Pancreatic Fistula Risk During Pancreatoduodenectomy.

Pancreatic duct diameter and pancreatic texture are important predictive factors for a postoperative pancreatic fistula (POPF) and are assessed intraoperatively by the surgeon. However, surgical evaluation is arbitrary and difficult to objectify, especially in minimally invasive approaches in pancreatic surgery. We conducted a retrospective analysis of 275 patients that underwent pancreatoduodenectomy from 2012 to 2019 at our institution. Pancreatic duct diameter and pancreatic fibrosis were assessed by histopathologic examination of the pancreatic resection margin using intraoperative frozen sections and correlated with the occurrence of POPF and clinically relevant POPF (CR-POPF). The POPF and CR-POPF rates were 27% and 19%, respectively. Univariate analysis indicated that the indication for surgery, the surgically determined pancreatic duct diameter, and pancreatic texture, as well as the histopathologically determined pancreatic duct diameter and pancreatic fibrosis were significant predictive factors for POPF and CR-POPF. A multivariate analysis revealed histopathologically determined pancreatic duct diameter and pancreatic fibrosis as independent risk factors for POPF (OR [odds ratio] 2.3 [1.1 to 4.5], p = 0.022 and OR 2.4 [1.1 to 5.1], p = 0.023, respectively) and CR-POPF (OR 2.2 [1.1 to 4.8], p = 0.037 and OR 2.6 [1.1 to 6.1], p = 0.036). Histopathologically determined pancreatic duct diameter and pancreatic fibrosis are quantitatively measurable independent risk factors for POPF and CR-POPF. An intraoperative objective histopathologic evaluation of these parameters using frozen sections could support the surgical assessment of the pancreatic duct diameter and the pancreatic texture.

Activated Pancreatic Stellate Cells Promote Acinar Duct Metaplasia by Disrupting Mitochondrial Respiration and Releasing Reactive Oxygen Species

Background: Chronic Pancreatitis (CP) is a long-term risk factor for pancreatic ductal adenocarcinoma (PDAC), and both diseases share a common etiology. The activation of Pancreatic stellate cells (PaSCs) caused by inflammation of the chronic pancreas plays a pivotal role in the pathology of pancreatic fibrosis and the malignant phenotype of PDAC. However, the central role of activated PaSCs in Acinar-to-Ductal Metaplasia (ADM) remains unknown. Objective: In the present study, we investigated the link between pancreatic fibrosis and ADM and the possible underlying mechanism. Methods: A caerulein-treated mouse CP model was established, and Masson trichrome histochemical stain and Transmission Electron Microscope (TEM) were used to observe stromal fibrosis and cell ultrastructure, respectively. The expression of amylase and cytokeratin 19 (CK19), mitochondria respiration, and reactive oxygen species (ROS) were detected in vitro in the co-culture model of primary pancreatic acinar cells and PaSCs. Results: The activation of PaSCs and pancreatic fibrosis were accompanied by ADM in pancreatic parenchyma in caerulein-treated mice, which was verified by the co-cultivation experiment in vitro. Furthermore, we showed that activated PaSCs promote ADM by disrupting mitochondrial respiration and releasing ROS. The expression of inflammation-and ADM-related genes, including S100A8, S100A9, and CK19, was observed to be up-regulated in pancreatic acinar cells in the presence of activated PaSCs. The expression of S100A9 and CK19 proteins was also up-regulated in acinar cells co-cultured with activated PaSCs. Conclusion: The manipulation of mitochondrial respiration and ROS release is a promising preventive and/or therapeutic strategy for PDAC, and S100A9 is expected to be a therapeutic target to block the ADM process induced by the activation of PaSCs.

Stem bark of Fraxinus rhynchophylla ameliorates the severity of pancreatic fibrosis by regulating the TGF-β/Smad signaling pathway

Chronic pancreatitis (CP) is a pathological fibroinflammatory syndrome of the pancreas. Currently, there are no therapeutic agents available for treating CP-associated pancreatic fibrosis. Fraxinus rhynchophylla (FR) reportedly exhibits anti-inflammatory, antioxidative...

Inflammatory-miR-301a circuitry drives mTOR and Stat3-dependent PSC activation in chronic pancreatitis and PanIN

Activated pancreatic stellate cells (PSCs) are the main cells involved in chronic pancreatitis and pancreatic intraepithelial neoplasia lesion (PanIN). Fine-tuning the precise molecular targets in PSC activation might help the development of PSC-specific therapeutic strategies to tackle progression of pancreatic cancer-related fibrosis. miR-301a is a pro-inflammatory microRNA known to be activated by multiple inflammatory factors in the tumor stroma. Here, we show that miR-301a is highly expressed in activated PSCs in mice, sustained tissue fibrosis in caerulein-induced chronic pancreatitis, and accelerated PanIN formation. Genetic ablation of miR-301a reduced pancreatic fibrosis in mouse models with chronic pancreatitis and PanIN. Cell proliferation and activation of PSCs was inhibited by downregulation of miR-301a via two of its targets, Tsc1 and Gadd45g. Moreover, aberrant PSC expression of miR-301a and Gadd45g restricted the interplay between PSCs and pancreatic cancer cells in tumorigenesis. Our findings suggest that miR-301a activates two major cell proliferation pathways, Tsc1/mTOR and Gadd45g/Stat3, in vivo, to facilitate development of inflammatory-induced PanIN and maintenance of PSC activation and desmoplasia in pancreatic cancer.

Pancreatic fibrosis, acinar atrophy and chronic inflammation in surgical specimens associated with survival in patients with resectable pancreatic ductal adenocarcinoma

BackgroundPancreatic ductal adenocarcinoma (PDAC), one of the most lethal malignancies, is increasing in incidence. However, the stromal reaction pathophysiology and its role in PDAC development remain unknown. We, therefore, investigated the potential role of histological chronic pancreatitis findings and chronic inflammation on surgical PDAC specimens and disease-specific survival (DSS).MethodsBetween 2000 and 2016, we retrospectively enrolled 236 PDAC patients treated with curative-intent pancreatic surgery at Helsinki University Hospital. All pancreatic transection margin slides were re-reviewed and histological findings were evaluated applying international guidelines.ResultsDSS among patients with no fibrosis, acinar atrophy or chronic inflammation identified on pathology slides was significantly better than DSS among patients with fibrosis, acinar atrophy and chronic inflammation [median survival: 41.8 months, 95% confidence interval (CI) 26.0–57.6 vs. 20.6 months, 95% CI 10.3–30.9; log-rank test p = 0.001]. Multivariate analysis revealed that Ca 19–9 > 37 kU/l [hazard ratio (HR) 1.48, 95% CI 1.02–2.16], lymph node metastases N1–2 (HR 1.71, 95% CI 1.16–2.52), tumor size > 30 mm (HR 1.47, 95% CI 1.04–2.08), the combined effect of fibrosis and acinar atrophy (HR 1.91, 95% CI 1.27–2.88) and the combined effect of fibrosis, acinar atrophy and chronic inflammation (HR 1.63, 95% CI 1.03–2.58) independently served as unfavorable prognostic factors for DSS. However, we observed no significant associations between tumor size (> 30 mm) and the degree of perilobular fibrosis (p = 0.655), intralobular fibrosis (p = 0.587), acinar atrophy (p = 0.584) or chronic inflammation (p = 0.453).ConclusionsOur results indicate that the pancreatic stroma is associated with PDAC patients’ DSS. Additionally, the more severe the fibrosis, acinar atrophy and chronic inflammation, the worse the impact on DSS, thereby warranting further studies investigating stroma-targeted therapies.

The relationship between the morphofunctional state of pancreatic insular apparatus and islet fibrosis in old rats under alloxan-induced diabetes and alpha-lipoic acid correction

The scientific data on age-related changes in the insular apparatus of the pancreas are contradictory, including age-related insular fibrosis. There are some questions about the relationship between different pathomorphological changes in the insular apparatus and the possibility of their pharmacological correction with antioxidants, for example, alpha-lipoic acid, proved for treatment of diabetic cardiomyopathy and polyneuropathy. The aim of this study is to identify the relationship between the morphofunctional state of pancreatic insular apparatus and islet fibrosis in old rats with alloxan-induced diabetes and its correction using alpha-lipoic acid. Materials and methods. The experiment was conducted on 40 white male Wistar rats, which were divided into 4 groups: 1st — young intact animals 6 months old (n=10), 2nd — control group, old intact animals 18 months old (n=10), 3rd — old animals 18 months old with experimental diabetes (n=10), 4th — old animals 18 months old with experimental diabetes mellitus and administration of alpha-lipoic acid (n=10). Diabetes mellitus was designed with 3-times intraperitoneal injections of alloxan solution at a total dose of 170 µg/kg of animal weight. Alpha-lipoic acid was administered intramuscularly at a dose of 4 mg/100g of animal weight for 30 days. A morphological investigation of the pancreas was conducted, followed by immunohistochemical staining for insulin, as well as an assessment of the histotopographic localization of collagen. The obtained data were processed by mathematical statistics. Results. Decrease in the functionality of the pancreatic insular apparatus is due to a decrease in the number of beta-cells and an increase in fibrotic changes in it as a result of physiological aging, which was confirmed by an increase in the level of glucose in the blood plasma and a decrease in insulin expression in the islets. Alloxan diabetes exacerbated these changes. Administration of alpha-lipoic acid to aged animals with experimental diabetes contributed to an increase in the number of islets, their cellularity, the content of islet beta cells and their insulin-producing activity, a decrease in blood glucose levels and the severity of fibrotic changes in the islets. Conclusion. In this study, it was shown for the first time that the administration of alpha-lipoic acid, which has an antioxidant capacity, caused a decrease in islet fibrosis in old animals with diabetes due to an increase in insulinocytes in the islet and a decrease in glucose concentration. Thus, alpha-lipoic acid has not only antidiabetic, but also geroprotective and antifibrogenic effects in old rats with alloxan-induced diabetes.

Pancreatic Fibrosis, Acinar Atrophy and Chronic Inflammation in Surgical Specimens Associated with Survival in Patients with Resectable Pancreatic Ductal Adenocarcinoma

Introduction: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies. However, the stromal reaction pathophysiology and its role in PDAC development remain unknown. We aimed to investigate the potential role of histological chronic pancreatitis findings and chronic inflammation on surgical PDAC specimens and disease-specific survival (DSS). Method: Between 2000–2016, we retrospectively enrolled 236 PDAC patients treated with curative-intent pancreatic surgery at Helsinki University Hospital. All pancreatic transection margin slides were re-reviewed. Results: DSS among patients with no fibrosis, acinar atrophy or chronic inflammation identified on pathology slides was significantly better than DSS among patients with fibrosis, acinar atrophy and chronic inflammation [median survival: 41.8 months, 95% confidence interval (CI)26.0–57.6 vs. 20.6 months, 95% CI10.3–30.9; log-rank test p = 0.001]. Multivariate analysis revealed that Ca 19-9 >37 kU/l [hazard ratio (HR)1.48, 95% CI1.02–2.16], lymph node metastases N1–2 (HR1.71, 95% CI1.16–2.52), tumor size >30 mm (HR1.47, 95% CI1.04–2.08), the combined effect of fibrosis and acinar atrophy (HR1.91, 95% CI1.27–2.88) and the combined effect of fibrosis, acinar atrophy and chronic inflammation (HR1.63, 95% CI1.03–2.58) independently served as unfavorable prognostic factors for DSS. However, we observed no significant associations between tumor size (> 30 mm) and the degree of perilobular or (p=0.655) intralobular fibrosis (p=0.587) or acinar atrophy (p=0.584). Conclusions: Our results indicate that the pancreatic stroma is associated with PDAC patients’ DSS. Additionally, the more severe the fibrosis, acinar atrophy and chronic inflammation, the worse the impact on DSS, thereby warranting further studies investigating stroma-targeted therapies.

Histomorphological Changes in Pancreas and Liver among Chronic AlcoholicsAn Autopsy Study

Introduction: The clinical and pathological association between pancreatitis and alcohol abuse is well recognised, however the concurrence of prevalence of alcoholic related pancreatitis and liver disease is less well studied. Aim: To evaluate frequency of histomorphological changes in pancreas and liver among patients with history of alcohol abuse and observe the prevalence of coexistence between chronic pancreatitis and liver cirrhosis. Materials and Methods: This was observational cross-sectional study conducted in Department of Pathology at Lokmanya Tilak Municipal Medical College, Mumbai, Maharashtra, India, from July 2013 to July 2018. The study included 1917 autopsies and 107 cases with a documented history of chronic alcohol abuse. Haematoxylin and Eosin (H&amp;E) staining was done on all sections and special stain like Masson’s trichrome was performed as per indication. Gross and microscopy were studied under variable defined parameters. Data was entered in Microsoft Excel sheets. Results: Histomorphologically, 12 cases (11.21%) were diagnosed as pancreatitis; 10 cases (9.34%) were of acute pancreatitis and two cases (1.86%) were of chronic pancreatitis. Total 21 cases were diagnosed as liver cirrhosis. The most dominant pattern of fibrosis seen in pancreatitis was perilobular and interlobular periductal fibrosis. The frequency of pancreatitis (14.28%) and pancreatic fibrosis (38.09%) was found to be more in cirrhotics. Chronic pancreatitis was commonly seen in cirrhotics than in non cirrhotics. Similarly, liver cirrhosis was more commonly observed in cases of chronic pancreatitis. Conclusion: The frequency of histomorphological changes seen in pancreas and liver was observed considerably among patients giving history of alcohol abuse. The prevalence of co-existence of chronic pancreatitis and liver cirrhosis was 50%.

Hypoglycemic effect of Zingiber striolatum bud extract in db/db mice

To evaluate the effectiveness of regulating insulin sensitivity via the insulin receptor substrate-1 of Zingiber striolatum bud extract in C57BL/KsJ-db/db mice. The C57BL mice were randomly divided into 5 groups (n=10), including normal control group, model group, metformin group, ZS-l (ZS low dose) group, and ZS-h (ZS high dose) group. The body weight and blood glucose were determined weekly. The oral glucose tolerance test, plasma insulin and biochemical parameters, pancreas histopathology, and the expression of insulin receptor substrate-1 were assayed at the end of experimental point. The results showed that Z. striolatum bud extract can significantly decrease the fasting blood glucose and glycated hemoglobin levels and insulin resistance (HOMA-IR) in C57BL mice. Western blot analysis demonstrated Z. striolatum bud extract could regulate the insulin sensitivity by upregulating the express of phospho-insulin receptor substrate-1. In conclusion, Z. striolatum bud extract could prevent the progression of diabetes and pancreatic fibrosis in C57BL mice.