Predictive Insights Into Exocrine Pancreatic Insufficiency in Chronic Pancreatitis and Autoimmune Pancreatitis: A Decision Tree Approach.

OBJECTIVE: Exocrine pancreatic insufficiency (EPI) is a common manifestation of chronic pancreatitis (CP) and autoimmune pancreatitis (AIP). This study aimed to estimate the presence of EPI in patients with CP or AIP using alternative clinical markers. MATERIALS AND METHODS: A machine learning analysis employing a decision tree model was conducted on a retrospective training cohort comprising 57 patients with CP or AIP to identify EPI, defined as fecal elastase-1 levels less than 200 µg/g. The outcomes were then confirmed in a validation cohort of 26 patients. RESULTS: Thirty-nine patients (68%) exhibited EPI in the training cohort. The decision tree algorithm revealed body mass index (≤21.378 kg/m 2 ) and total protein level (≤7.15 g/dL) as key variables for identifying EPI. The algorithm's performance was assessed using 5-fold cross-validation, yielding area under the receiver operating characteristic curve values of 0.890, 0.875, 0.750, 0.625, and 0.771, respectively. The results from the validation cohort closely replicated those in the training cohort. CONCLUSIONS: Decision tree analysis revealed that EPI in patients with CP or AIP can be identified based on body mass index and total protein. These findings may help guide the implementation of appropriate treatments for EPI.

Citrullinated fibrinogen-SAAs complex causes vascular metastagenesis.

Primary tumor cells metastasize to a distant preferred organ. However, the most decisive host factors that determine the precise locations of metastases in cancer patients remain unknown. We have demonstrated that post-translational citrullination of fibrinogen creates a metastatic niche in the vulnerable spots. Pulmonary endothelial cells mediate the citrullination of fibrinogen, changing its conformation, surface charge, and binding properties with serum amyloid A proteins (SAAs), to make it a host tissue-derived metastatic pathogen. The human-specific SAAs-citrullinated fibrinogen (CitFbg) complex recruits cancer cells to form a protein-metastatic cell aggregation in humanized SAA cluster mice. Furthermore, a CitFbg peptide works as a competitive inhibitor to block the homing of metastatic cells into the SAAs-CitFbg sites. The potential metastatic sites in the lungs of patients are clearly visualized by our specific antibody for CitFbg. Thus, CitFbg deposition displays metastatic risks for cancer patients, and the citrullinated peptide is a new type of metastasis inhibitor.

The levels of IL-1ß and soluble IL-1 receptors in patients with IgG4-related periaortitis/periarteritis.

PURPOSE: IgG4-related disease (IgG4-RD) is a chronic fibrotic inflammatory and an immune-mediated disease characterized by high serum IgG4 concentration and IgG4-bearing plasma cell infiltration in affected organs. IgG4-related periaortitis/periarteritis is a recently identified disease entity in IgG4-RD that affects the cardiovascular system, and its pathogenesis and characteristics remain unclear. The inflammatory cytokine IL-1ß is involved in a variety of cellular activities including inflammation, fibrosis, and angiogenesis. The present study compared the levels of the inflammatory cytokine IL-1ß and two soluble IL-1 receptors, IL-1R1 and IL-1R2, between IgG4-RD patients with and without IgG4-related periaortitis/periarteritis. METHODS: The patients with IgG4-related periaortitis/periarteritis (n â€‹= â€‹38), those without (n â€‹= â€‹66) and healthy (n â€‹= â€‹33) were recruited to measure cytokines of IL-1ß and soluble receptors (sIL-1R1 and sIL-1R2) in sera by ELISA assay. RESULTS: Serum IgG4 was significantly higher in patients with periaortitis/periarteritis compared to non-periaortitis/periarteritis (p â€‹= â€‹0.0074), while serum IL-1ß was significantly lower in patients with periaortitis/periarteritis (p â€‹= â€‹0.00037). The three groups did not show significant difference in sIL1-R1, while sIL-1R2 in the periaortitis/periarteritis and healthy group was higher than in the group without periaortitis/periarteritis (p â€‹= â€‹0.00001). CONCLUSIONS: The characteristic changes in IL-1ß, sIL-1R1, and sIL-1R2 levels in IgG4-RD patients with and without IgG4-related periaortitis/periarteritis may indicate an active phase of the inflammatory process in these diseases.

IL1R1 gene variants associate with disease susceptibility to IgG4-related periaortitis/periarteritis in IgG4-related disease.

BACKGROUND: IgG4-related disease (IgG4-RD) is an immune-mediated disorder characterized by high serum IgG4 concentration and IgG4-bearing plasma cell infiltration in affected organs. IgG4-related periaortitis/periarteritis is a recently identified disease entity in IgG4-RD that affects the cardiovascular system. Since the genetic factors related to disease onset are unclear, we examined the genetic associations with IgG4-related periaortitis/periarteritis susceptibility. METHODS: A small scale of genome-wide association analysis identified that interleukin 1 receptor type 1 (IL1R1) gene variants were correlated with the development of IgG4-related periaortitis/periarteritis in 75 patients with IgG4-RD. Accordingly, 8 single nucleotide polymorphisms (SNPs) in the IL1R1 gene were selected and genotyped in 124 patients with IgG4-RD (43 with periaortitis/periarteritis and 81 without periaortitis/periarteritis) and 344 healthy subjects. RESULTS: The minor allele frequencies of 6 SNPs (rs2287049, rs3917273, rs2160227, rs951192, rs3917318, rs7582198) were significantly increased in IgG4-related periaortitis/periarteritis patients compared with those without periaortitis/periarteritis (corrected P < 0.05). In addition, the frequency of the AGAAA haplotype, comprised of 5 SNPs (rs3917273, rs2160227, rs951192, rs3917318, rs7582198), was significantly higher in patients with periaortitis/periarteritis (OR = 2.41, 95% CI:1.42-4.10). CONCLUSION: Our findings indicated that IL1R1 genetic polymorphisms contributed to IgG4-related periaortitis/periarteritis and the possibility of certain genetic factors influencing the risk of specific IgG4-RD manifestations.

[Pancreatic adenocarcinoma:a case containing a cyst enclosing a dilated tubular gland duct].

This case report describes a 73-year-old woman with pancreatic adenocarcinoma who had undergone a colectomy for colorectal cancer in 1995 and a right mastectomy and axillary dissection for breast cancer in 2013. In January 2019, a tumor, approximately 20mm in diameter, was detected in the pancreatic body. It contained a cyst noted to have delayed perfusion towards the center on abdominal computed tomography. On T1-weighted magnetic resonance imaging (MRI), almost the entire tumor exhibited low intensity. On T2-weighted MRI, however, the tumor center displayed high intensity, the tumor wall displayed low intensity, and the outermost layer displayed high intensity. On endoscopic ultrasound, the tumor center displayed low echo density, the tumor wall had a slightly elevated echo density, and the outermost layer had a low echo density. A distal pancreatectomy was performed for a suspected metastatic pancreatic cancer, pancreatic neuroendocrine neoplasm, or invasive ductal carcinoma without tubular adenocarcinoma. Histopathological examination revealed that the tumor cells had formed atypical tubular gland ducts with a fibrous stroma in the background. The lesion differed from the histopathological findings of her previous colorectal and breast cancers, and it was ultimately diagnosed as a pancreatic ductal adenocarcinoma. The lumen of the cyst was covered with tumor cells identical to those of the atypical tubular gland ducts in the tumor parenchyma, suggesting that the cyst was a dilated tubular gland duct.

Corticosteroids prevent the progression of autoimmune pancreatitis to chronic pancreatitis.

BACKGROUND/OBJECTIVES: Patients with autoimmune pancreatitis (AIP) sometimes progress to chronic pancreatitis (CP). We evaluated the ability of corticosteroids to prevent the progression to CP. METHODS: We defined patients with definitive findings of CP (stones in the main pancreatic duct [MPD] or multiple pancreatic calcifications) as having severe calcification (SC). A total of 145 AIP patients were enrolled. We measured the duration between AIP diagnosis and SC development and retrospectively compared the time to SC development between patients with and without steroids. Multivariate analysis for factors associated with SC were performed. RESULTS: Nineteen (13%) patients progressed to SC. Since 95 patients had pancreatic head swelling and SC was found in these patients only, our analysis focused mainly on these at-risk populations. In Kaplan-Meier analysis limited to patients with pancreatic head swelling, the incidence of SC was significantly lower in patients with steroids than in those without (hazard ratio [HR] 0.18, 95% confidence interval [CI] 0.07-0.52; p < 0.001). Multivariate testing of patients with pancreatic head swelling confirmed that steroid therapy was significantly associated with a lower incidence of SC (HR 0.11, 95% CI 0.03-0.34; p < 0.001), while MPD dilation at AIP diagnosis was related to a higher incidence of SC (HR 4.02, 95% CI 1.43-11.7; p = 0.009). CONCLUSIONS: Corticosteroids appeared to prevent progression to CP in AIP patients, especially in those with pancreatic head swelling. Patients with both pancreatic head swelling and MPD dilation at diagnosis have a higher incidence of progression to CP. Steroid therapy is suggested for these high-risk cases.

Polymorphism at rs9264942 is associated with HLA-C expression and inflammatory bowel disease in the Japanese.

An expression quantitative trait locus (eQTL) single-nucleotide polymorphism (SNP) at rs9264942 was earlier associated with human leukocyte antigen (HLA)-C expression in Europeans. HLA-C has also been related to inflammatory bowel disease (IBD) risk in the Japanese. This study examined whether an eQTL SNP at rs9264942 could regulate HLA-C expression and whether four SNP haplotypes, including the eQTL SNP at rs9264942 and three SNPs at rs2270191, rs3132550, and rs6915986 of IBD risk carried in the HLA-C*12:02~B*52:01~DRB1*15:02 allele, were associated with IBD in the Japanese. HLA-C expression on CD3e+CD8a+ lymphocytes was significantly higher for the CC or CT genotype than for the TT genotype of rs9264942. The TACC haplotype of the four SNPs was associated with a strong susceptibility to ulcerative colitis (UC) but protection against Crohn's disease (CD) as well as with disease clinical outcome. While UC protectivity was significant but CD susceptibility was not for the CGTT haplotype, the significance of UC protectivity disappeared but CD susceptibility reached significance for the CGCT haplotype. In conclusion, our findings support that the eQTL SNP at rs9264942 regulates HLA-C expression in the Japanese and suggest that the four SNPs, which are in strong linkage disequilibrium, may be surrogate marker candidates of a particular HLA haplotype, HLA-C*12:02~B*52:01~DRB1*15:02, related to IBD susceptibility and disease outcome.

Correlation of Pancreatic T1 Values Using Modified Look-Locker Inversion Recovery Sequence (MOLLI) with Pancreatic Exocrine and Endocrine Function.

Quantifying myocardial T1 values has been useful for detecting and characterizing fibrotic appearance in myocardial infarction, focal scars, and non-ischemic cardiomyopathies. Since pancreatic exocrine function decreases with chronic pancreatic fibrosis advancement, this study examined the correlation between pancreatic T1 values and pancreatic exocrine and endocrine insufficiency. METHODS: Thirty-two patients underwent abdominal contrast-enhanced MRI in our department between October 2017 and February 2019. We evaluated the T1 values of the pancreas using a modified Look-Locker inversion recovery sequence (MOLLI), pancreatic exocrine insufficiency (PEI) by fecal elastase 1 (FE1) values, and pancreatic endocrine insufficiency using fasting insulin and blood glucose levels to calculate the HOMA-ß. This trial is registered in the UMIN Clinical Trials Registry as UMIN 000030067. RESULTS: The median cohort (9 males and 23 females) age was 71 (range: 49-84) years. Eighteen patients had pancreatic cysts, three had alcohol-induced chronic pancreatitis, three had pancreatic cancer, and eight possessed other pancreatic features (two patients each with autoimmune pancreatitis, acute pancreatitis, or a bile duct tumor, one with idiopathic chronic pancreatitis, and one healthy control with negative findings). The median pancreatic T1 value measured by the MOLLI was 857.5 ms (597-2569). A significant negative correlation was found between the T1 mapping and FE1 values (r = 0.69, p < 0.01), with none for the T1 with HOMA-ß or serum albumin, triglycerides, or body mass index. CONCLUSIONS: the pancreatic T1 values correlated significantly with pancreatic exocrine function and might be useful in PEI diagnosis.

Validity and safety of endoscopic biliary stenting for biliary stricture associated with IgG4-related pancreatobiliary disease during steroid therapy.

Background Patients with IgG4-related sclerosing cholangitis and autoimmune pancreatitis frequently develop obstructive jaundice, which requires endoscopic biliary stenting (EBS) during steroid therapy to prevent bile duct infection from cholestasis and adverse steroid effects. However, it is controversial whether EBS during steroid therapy is advisable, because the procedure itself carries a risk of cholangitis and procedure-related adverse events. This study aimed to clarify the validity and safety of EBS for patients with biliary stricture associated with IgG4-related pancreatobiliary disease (IgG4-PBD) during steroid therapy. Methods We enrolled 59 patients who presented with biliary stricture exhibiting jaundice or liver dysfunction and who were treated with EBS. The incidences of recurrent biliary obstruction and acute cholangitis were compared for EBS cases with and without steroid administration. Results EBS was present in 55 periods with steroid administration and 110 periods without. The incidence of recurrent biliary obstruction was significantly lower in cases with steroids than in those without (1-month no obstruction rate: 100 % vs. 82 %; log-rank test P  = 0.0015). The incidence of acute cholangitis related to stenting was significantly lower in cases with steroids than in those without (1-month no acute cholangitis rate: 100 % vs. 90 %; log-rank test P  = 0.0278). Biliary stents could be removed without acute cholangitis, liver dysfunction, or stent replacement in 96 % of patients who underwent endoscopic retrograde cholangiopancreatography 1 month after commencing steroid administration. Conclusions EBS during steroid administration was both valid and safe in patients with biliary stricture associated with IgG4-PBD. Stents could be safely removed 1 month after steroid initiation.

Effectiveness of steroid therapy for pancreatic cysts complicating autoimmune pancreatitis and management strategy for cyst-related complications.

Objectives: Autoimmune pancreatitis (AIP) sometimes becomes complicated with pancreatic cysts, although their detailed characteristics and management strategy have not been fully determined. We aimed to clarify the efficiency of steroid therapy and the risk factors for cyst formation and cyst-related complications. Methods: One hundred sixty-three AIP patients were retrospectively analyzed for relevant factors of cyst formation. We compared subjects with and without steroids to evaluate drug effectiveness on cyst size change and investigated the factors associated with cyst-related complications. Results: Thirty-two patients (19.6%) had complicating pancreatic cyst formation, and 40 cystic lesions of ≥10 mm in size were detected. Multivariate analysis revealed a drinking habit, abdominal/back pain, and elevated serum amylase to be significantly associated with cyst formation. Steroid-treated cysts became significantly reduced in size in the short-term and disappeared significantly more frequently within 1-year as compared with non-treated ones, which was confirmed by multivariate analysis. Six of 40 cysts exhibited cyst-related complications significantly associated with multilocular morphology and larger size. Conclusions: Steroid therapy is an effective choice for cysts developing in AIP to promote the release of pancreatic juice stasis. Larger lesions with multilocular morphology should be monitored closely for cyst-related complications and be considered strong candidates for steroid therapy.

Denosumab is Effective for Controlling Serum Calcium Levels in Patients with Humoral Hypercalcemia of Malignancy Syndrome: A Case Report on Parathyroid Hormone-related Protein-producing Cholangiocarcinoma.

Hypercalcemia resulting in the elevation of serum parathyroid hormone-related protein (PTHrP) and suppression of serum PTH was observed in a patient with advanced cholangiocarcinoma (CCC) and multiple lymph node metastases. We confirmed humoral hypercalcemia of malignancy based on PTHrP-producing CCC. Chemotherapy with gemcitabine and cisplatin could not control the patient's serum PTHrP levels and the patient was affected with bisphosphonate-refractory hypercalcemia. We administered a single dose of denosumab, an anti-receptor activator of nuclear factor-kappaB ligand monoclonal antibody, and the patient's serum calcium levels remained close to the normal range for approximately 3 weeks without additional treatment.