The relationship between observation interval and prognosis in pancreatic cancer concomitant with intraductal papillary mucinous neoplasia.

BACKGROUND: Intraductal papillary mucinous neoplasia (IPMN) is a risk factor for pancreatic cancer (PC). PC concomitant with IPMN shows rapid progression similar to de novo PC, therefore, the appropriate observation interval (OI) is not yet clear. PATIENTS AND METHOD: This was a multicenter retrospective observational study, and patients with PC concomitant with IPMN were analyzed. OI was defined as the interval between the date of imaging at PC diagnosis and just before the diagnosis. Clinical factors of PC and prognosis were assessed according to OI. RESULTS: From January 2010 to December 2018, 73 patients from 11 institutions were enrolled. The images performed just before PC diagnosis were contrast-enhanced CT/magnetic resonance imaging/endoscopic ultrasonography in 44/27/2 patients, respectively. The median cyst size was 14.0 mm, and the median main pancreatic duct diameter was 3.0 mm. The median OI was 6.8 months. In OI 6 months or less (OI ≤ 6 M)/OI more than 6 months (OI > 6 M), the mean tumor size, the frequencies of metastatic PC, resectable PC and early-stage PC were 20.1/21.5 mm (P = 0.91), 12.1 %/32.5 % (P = 0.05), 72.7 %/52.5 % (P = 0.09) and 27.3 %/25.0 % (P = 1.00), respectively. The median overall survival was 35.5 months in OI ≤ 6 M and 16.2 months in OI > 6 M (P = 0.05). CONCLUSION: In OI 6 months or less, the rate of resectable PC was high, however, the rate of early PC was almost the same as that of OI more than 6 months. Approximately 10 % of cases found in the advanced stage with metastasis even if OI 6 months or less.

Adverse events of self-expandable metal stent placement for malignant distal biliary obstruction: a large multicenter study.

BACKGROUND AND AIMS: Endoscopic placement of self-expandable metal stents (SEMSs) for malignant distal biliary obstruction (MDBO) may be accompanied by several types of adverse events. The present study analyzed the adverse events occurring after SEMS placement for MDBO. METHODS: The present study retrospectively investigated the incidence and types of adverse events in patients who underwent SEMS placement for MDBO between April 2018 and March 2021 at 26 hospitals. Risk factors for acute pancreatitis, cholecystitis, and recurrent biliary obstruction (RBO) were evaluated by univariate and multivariate analyses. RESULTS: Of the 1425 patients implanted with SEMSs for MDBO, 228 (16.0%) and 393 (27.6%) experienced early adverse events and RBO, respectively. Pancreatic duct without tumor involvement (P = .023), intact papilla (P = .025), and SEMS placement across the papilla (P = .037) were independent risk factors for acute pancreatitis. Tumor involvement in the orifice of the cystic duct was an independent risk factor for cholecystitis (P < .001). Use of fully and partially covered SEMSs was an independent risk factor for food impaction and/or sludge. Use of fully covered SEMSs was an independent risk factor for stent migration. Use of uncovered SEMSs and laser-cut SEMSs was an independent risk factor for tumor ingrowth. CONCLUSIONS: Pancreatic duct without tumor involvement, intact papilla, and SEMS placement across the papilla were independent risk factors for acute pancreatitis, and tumor involvement in the orifice of the cystic duct was an independent risk factor for cholecystitis. The risk factors for food impaction and/or sludge, stent migration, and tumor ingrowth differed among types of SEMSs.

Pentraxin 3 is an adipose tissue-related serum marker for pancreatic cancer cachexia predicting subsequent muscle mass and visceral fat loss.

Cancer cachexia, a paraneoplastic syndrome characterized by ongoing skeletal muscle mass loss, is accompanied by adipose tissue loss and strongly affects chemotherapy endurance. Our aim was to detect a serum marker reflecting pancreatic cancer cachexia and predicting subsequent loss of muscle mass and adipose tissue, focusing on adipose tissue-secreted proteins. Murine-derived pancreatic cancer cells were orthotopically injected into the mouse pancreatic tail. After 3 weeks, RNA sequencing of perigonadal fat and orthotopic tumors was carried out. We analyzed stocked sera and clinical data of metastatic pancreatic cancer patients who received chemotherapy. Perigonadal fat weight/body weight decreased in mice with orthotopic tumors compared to those without tumors. By RNA sequencing and real-time PCR validation, pentraxin 3 (PTX3) was identified as a secreted protein-encoded gene whose expression was significantly higher in the perigonadal fat of mice with orthotopic tumors than in that of mice without orthotopic tumors and was least expressed in orthotopic tumors. Serum PTX3 levels correlated with PTX3 mRNA levels in perigonadal fat and were higher in mice with orthotopic tumors than in those without tumors. In 84 patients diagnosed with metastatic pancreatic cancer, patients with high serum PTX3 levels showed a greater visceral fat loss/month and skeletal muscle mass index (SMI) decrease/month than those with low serum PTX3 levels. High serum PTX3 was an independent risk factor for visceral fat loss, decreased SMI, and poor prognosis. High serum PTX3 in pancreatic cancer patients predicts visceral fat and muscle mass loss and major clinical outcomes of cancer cachexia.

Hepatic Stellate Cells in Hepatocellular Carcinoma Promote Tumor Growth Via Growth Differentiation Factor 15 Production.

BACKGROUND & AIMS: Although the tumor microenvironment plays an important role in tumor growth, it is not fully understood what role hepatic stellate cells (HSCs) play in the hepatocellular carcinoma (HCC) microenvironment. METHODS: A high-fat diet after streptozotocin was administered to HSC-specific Atg7-deficient (GFAP-Atg7 knockout [KO]) or growth differentiation factor 15 (GDF15)-deficient (GFAP-GDF15KO) mice. LX-2 cells, a human HSC cell line, were cultured with human hepatoma cells. RESULTS: In the steatohepatitis-based tumorigenesis model, GFAP-Atg7KO mice formed fewer and smaller liver tumors than their wild-type littermates. Mixed culture of LX-2 cells and hepatoma cells promoted LX-2 cell autophagy and hepatoma cell proliferation, which were attenuated by Atg7 KO in LX-2 cells. Hepatoma cell xenograft tumors grew rapidly in the presence of LX-2 cells, but Atg7 KO in LX-2 cells abolished this growth. RNA-sequencing revealed that LX-2 cells cultured with HepG2 cells highly expressed GDF15, which was abolished by Atg7 KO in LX-2 cells. GDF15 KO LX-2 cells did not show a growth-promoting effect on hepatoma cells either in vitro or in the xenograft model. GDF15 deficiency in HSCs reduced liver tumor size caused by the steatohepatitis-based tumorigenesis model. GDF15 was highly expressed and GDF15-positive nonparenchymal cells were more abundant in human HCC compared with noncancerous parts. Single-cell RNA sequencing showed that GDF15-positive rates in HSCs were higher in HCC than in background liver. Serum GDF15 levels were high in HCC patients and increased with tumor progression. CONCLUSIONS: In the HCC microenvironment, an increase of HSCs that produces GDF15 in an autophagy-dependent manner may be involved in tumor progression.

Pancreatic CT density is an optimal imaging biomarker for earlier detection of malignancy in the pancreas with intraductal papillary mucinous neoplasm.

BACKGROUND: Intraductal papillary mucinous neoplasms (IPMNs) are typically detected as incidental findings by computed tomography (CT); however, the conventional surveillance is not valid for the early detection of concomitant pancreatic cancer. The pancreas of IPMN is often accompanied by fatty infiltration in the parenchyma, and pancreatic fatty infiltration could be evaluated by pancreatic CT density (pancreatic index, PI). We aimed to investigate whether PI could be an imaging biomarker for the early prediction of malignancies in the pancreas with IPMN. METHODS: Two different cohorts were investigated. (Investigation cohort): A total of 1137 patients with initially low-risk IPMN were compensated by initial IPMN findings, and 2 groups (malignancy/possible benign, 50 cases each) were investigated for yearly changes in PI and for the cutoff value of PI indicating the development of malignancies. (Validation cohort): To validate the cutoff value, 256 patients radiologically suspected of having IPMNs were investigated. RESULTS: (Investigation-cohort): The malignancy group showed a gradual decrease in PI every year, and PI significantly differed among the 2 groups 1 year prior to the last investigation. The cutoff value of PI was set at 0.65. (Validation-cohort): A total of 55% of the patients with a PI below the cutoff value had malignancy in the pancreas, including concomitant pancreatic cancer, and the cutoff value was the most significant risk factors for the development of malignancies in the pancreas compared to the conventional risk factors for IPMN. CONCLUSIONS: Decreasing PI would be an optimal imaging biomarker for earlier detection of malignancies in the pancreas with IPMN.

Needle tract seeding after endoscopic ultrasound-guided tissue acquisition of pancreatic tumors: A nationwide survey in Japan.

OBJECTIVES: Endoscopic ultrasound-guided tissue acquisition (EUS-TA) plays a crucial role in the diagnosis of pancreatic tumors. The present study aimed to investigate the current status of needle tract seeding (NTS) after EUS-TA of pancreatic tumors based on a nationwide survey in Japan. METHODS: Patients who underwent surgical resection of primary pancreatic tumors after EUS-TA performed between April 2010 and March 2018 were surveyed. The incidence rates of NTS were determined, and compared in patients with pancreatic ductal adenocarcinomas (PDACs) and other tumors, and in patients who underwent transgastric and transduodenal EUS-TA of PDACs. The detailed features and prognosis of patients with NTS were also assessed. RESULTS: A total of 12,109 patients underwent surgical resection of primary pancreatic tumors after EUS-TA. The overall incidence rate of NTS was 0.330%, and the NTS rate was significantly higher in patients with PDAC than in those with other tumors (0.409% vs. 0.071%, P=0.004). NTS was observed in 0.857% of patients who underwent transgastric EUS-TA, but in none of those who underwent transduodenal EUS-TA. Of the patients with NTS of PDACs, the median time from EUS-TA to occurrence of NTS and median patient survival were 19.3 and 44.7 months, respectively, with 97.4% of NTS located in the gastric wall and 65.8% of NTS resected. The patient survival was significantly longer in patients who underwent NTS resection than in those without NTS resection (P=0.037). CONCLUSIONS: NTS appeared only after transgastric not after transduodenal EUS-TA. Careful follow-up provides an opportunity to remove localized NTS lesions by gastrectomy.

Endoscopic biliary stenting as the risk factor for cholangitis after endoscopic ultrasound in patients with biliary strictures.

BACKGROUND AND AIM: Endoscopic ultrasound (EUS) and EUS-guided fine needle aspiration (FNA) are established as efficient and safe diagnostic modalities. However, the risk of cholangitis after EUS/EUS-FNA (post-EUS cholangitis) in patients who have biliary strictures has not been fully examined. METHODS: We retrospectively reviewed 136 consecutive inpatients with biliary strictures who received EUS/EUS-FNA at our hospital from April 2012 to September 2017 and evaluated complications that occurred by the next day after EUS/EUS-FNA. Patients with percutaneous biliary drainage, those in whom it was difficult to reach the duodenum, and those receiving concurrent endoscopic retrograde cholangiopancreatography were excluded. RESULTS: We included 121 patients (147 cases); 90 patients were malignant. Endoscopic biliary stenting (EBS) with plastic stents had already been performed in 86 cases. Post-EUS cholangitis was observed in 4.1% (6/147). No other EUS-related complications were observed. The incidence of cholangitis with EBS was significantly higher than that in the cases without EBS (7.0% [6/86] vs 0% [0/61], P = 0.042). Biliary enzyme elevation was also identified as a risk factor of cholangitis. CONCLUSION: Endoscopic biliary stenting was identified as a risk factor associated with post-EUS cholangitis in patients with biliary strictures. Endoscopists should pay attention to post-EUS cholangitis, especially in cases with EBS and biliary enzyme elevation.

Histological diagnosis and grading of pancreatic neuroendocrine tumor by endoscopic ultrasound-guided fine needle biopsy using a 25-gauge needle with a core trap: A multicenter prospective trial.

OBJECTIVES: Preoperative grading of pancreatic neuroendocrine tumors (PanNET) is challenging. The aim of this study was to prospectively evaluate the use of a 25-gauge needle with a core trap for diagnosis and grading of PanNET. METHODS: This multicenter prospective trial was registered with the University Hospital Medical Information Network (UMIN000021409). Consecutive patients with suspected PanNET between June 2016 and November 2017 were enrolled. All patients underwent endoscopic ultrasound-guided fine needle biopsy (EUS-FNB) using a 25-gauge needle with a core trap. Samples obtained after the first needle pass were used for central pathological review. EUS-FNB was evaluated in terms of (i) technical success rate, (ii) adequacy for histological evaluation, (iii) complication rate during the procedure, and (iv) concordance between PanNET grading on EUS-FNB and that after analysis of the resected tumor. RESULTS: Fifty-two patients were enrolled. Of the 36/52 patients who underwent surgical resection, 31 were finally diagnosed with PanNET and were eligible for analysis. The technical success rate of EUS-FNB was 100%. The rate of adequacy for histological evaluation was 90.3%. There were no complications related to EUS-FNB. The concordance rate between PanNET grading on EUS-FNB and that after analysis of the resected tumor was 82.6% (95% confidence interval = 61.22-95.05, P = 0.579). CONCLUSIONS: EUS-FNB using a 25-gauge needle with a core trap is feasible, providing histological samples are of sufficient quality for diagnosis and grading of PanNET.

Comparison of a 22-gauge Franseen-tip needle with a 20-gauge forward-bevel needle for the diagnosis of type 1 autoimmune pancreatitis: a prospective, randomized, controlled, multicenter study (COMPAS study).

BACKGROUND AND AIMS: Histologic diagnosis of autoimmune pancreatitis (AIP) using EUS-guided FNA (EUS-FNA) is difficult. To address this issue, new fine-needle biopsy (FNB) needles were recently developed. Here, we prospectively evaluated 2 newly designed EUS-FNB needles for histologic evaluation in patients with type 1 AIP. METHODS: This was a prospective, randomized, multicenter trial comparing biopsy specimens obtained with a 22-gauge Franseen needle or a 20-gauge forward-bevel needle in patients with suspected type 1 AIP. AIP was diagnosed according to international consensus diagnostic criteria. The primary endpoint was the sensitivity of EUS-FNB needles, and secondary endpoints were the amount of specimen obtained, histology of the pancreas based on evaluation of lymphoplasmacytic sclerosing pancreatitis (LPSP), and contribution of histologic findings to the diagnosis of AIP. RESULTS: One hundred ten patients were randomly assigned to the Franseen group (22-gauge Franseen needle) or the forward-bevel group (20-gauge forward-bevel needle). EUS-FNB sampling was successful in all patients. Nine patients were excluded because of diagnoses other than AIP. Compared with the forward-bevel needle, the Franseen needle obtained a significantly greater number of high-power fields. Of 101 patients, 39 patients (78%) in the Franseen group and 23 patients (45%) in the Forward-bevel group were diagnosed with level 1 or 2 LPSP (P = .001). Thirty-six patients could not be diagnosed with type 1 AIP without EUS-FNB specimen results. CONCLUSIONS: The 22-gauge Franseen needle should be routinely used for histologic diagnosis of type 1 AIP. (Clinical trial registration number: UMIN 000027668.).

Hypovascular hepatic nodules as a predictive factor for transcatheter arterial chemoembolization refractoriness in hepatocellular carcinoma.

AIM: Intermediate-stage hepatocellular carcinoma (HCC) targeted for transcatheter arterial chemoembolization (TACE) corresponds to a highly heterogeneous population for whom the factors predicting TACE efficacy have not been established. This study aimed to evaluate the impact of hypovascular hepatic nodules coexisting with intermediate-stage HCC as a significant predictive factor for TACE refractoriness. METHODS: A total of 66 patients with intermediate-stage HCC who received initial TACE were retrospectively analyzed. Hypovascular hepatic nodules were detected by dynamic computed tomography or magnetic resonance imaging, as well as angiography, before all initial TACE. The time to TACE refractoriness (TTTR) was defined as the period from initial TACE until the diagnosis of TACE refractoriness. RESULTS: Hypovascular hepatic nodules were detected in 36 patients (54.5%), 15 (41.7%) of whom had a single nodule, whereas 21 (58.3%) had multiple nodules, and the median size of the maximum nodule was 10 mm (range 5-80 mm). The median TTTR was 17.4 months for all patients, and 7.3 and 33.1 months for patients with and without hypovascular hepatic nodules, respectively. The TTTR was significantly shorter for patients with hypovascular hepatic nodules than that for the other patients. In the multivariate analysis, the presence of hypovascular hepatic nodules (HR 7.016, 95% CI 3.534-13.930; P < 0.001) and being out of the up-to-seven criteria (HR 2.861, 95% CI 1.493-5.486; P = 0.002) were independent risk factors for a short TTTR. CONCLUSIONS: The presence of hypovascular hepatic nodules with intermediate-stage HCC represents a significant predictive risk factor for TACE refractoriness.

Soluble UL16-binding protein 2 is associated with a poor prognosis in pancreatic cancer patients.

The immune system plays important roles in pancreatic cancer. MHC class I-chain-related proteins A and B (MICA/B) and UL16-binding proteins (ULBPs) are known natural killer group 2D (NKG2D) ligands. Soluble NKG2D ligands can inhibit the activation of Natural killer (NK) cells. In pancreatic cancer, soluble ULBPs are relatively unstudied in contrast to soluble MICA/B. We examined the significance of soluble ULBPs, especially ULBP2, in pancreatic cancer. Soluble ULBP2 but neither soluble ULBP1 nor soluble ULBP3, was etected in the supernatants of pancreatic cancer cells. Soluble ULBP2 derived from pancreatic cancer cells could reduce the cytotoxicity of NK cells. Multivariate analysis demonstrated that serum soluble ULBP2 was a significant independent factor associated with poor overall survival (OS) in all pancreatic cancer patients, specifically in stage IV patients. In conclusion, pancreatic cancer-derived soluble ULBP2 might affect the prognosis in pancreatic cancer.

Cotreatment with lenvatinib and warfarin potassium caused prothrombin time prolongation.

Lenvatinib is approved as a standard systemic therapy for unresectable hepatocellular carcinoma (HCC) patients; however, experience with lenvatinib in clinical practice is insufficient. We present the case of a patient with advanced HCC whose prothrombin time - international normalized ratio (PT-INR) was elevated after cotreatment with lenvatinib and warfarin potassium. The patient was a 26-year-old man with congenital abnormalities who had to take warfarin potassium because he had a mechanical heart valve. He was diagnosed with unresectable HCC at 24 years old and was treated by transcatheter arterial chemoembolization and transcatheter arterial infusion. After some interventional radiology treatments, lenvatinib was started. After 4 days of treatment with lenvatinib and warfarin potassium, his PT-INR increased to 4.13, and the treatment had to be stopped. No changes were observed in other Child-Pugh score factors. The elevation in the PT-INR after cotreatment with lenvatinib and warfarin potassium was thought to be caused by pharmacological effects of concurrent use or pharmacological sensitivity to warfarin potassium in this patient with liver dysfunction. The PT-INR must be monitored when lenvatinib is given to advanced HCC patients taking warfarin potassium.

Autophagy impairment in pancreatic acinar cells causes zymogen granule accumulation and pancreatitis.

Basal autophagy degrades many kinds of proteins and organelles to maintain quality and plays important roles in cellular homeostasis. However, the impact of basal autophagy on zymogen granules in pancreatic acinar cells is unknown. In the present study, we examined the influence of autophagy impairment in acinar cells on zymogen granules and homeostasis of the pancreas, using mice with pancreas-specific autophagy impairment (Pdx1-Cre+/-Atg7fl/fl mice). The number of zymogen granules in acinar cells from these mice did not differ from that in acinar cells from their wild-type littermates at 3 weeks of age. However, the number of zymogen granules in acinar cells drastically increased at 4 weeks of age in mice with pancreas-specific autophagy impairment. In addition to the increased number of zymogen granules, serum lipase was elevated, and the pancreas became oedematous at 4 weeks of age, suggesting pancreatitis. After 5 weeks of age, acinar cell death was accelerated, and several histological features of chronic pancreatitis were observed, including glandular atrophy and pseudotubular complexes with fibrotic changes. In conclusion, the impairment of pancreas-specific basal autophagy caused spontaneous zymogen granule accumulation in acinar cells and pancreatitis, which eventually led to chronic pancreatitis.

Immunological responses against hepatitis B virus in human peripheral blood mononuclear cell-engrafted mice.

It is well known that immune-mediated virus elimination is necessary for the treatment of HBV infection. Reconstitution of human immune cells in liver chimeric mice is warranted to understand the immunopathogenesis of HBV infection. Here, we report a new immunologically humanized mouse model with a human immune system via reconstitution of immunodeficient NOG-Iaß/ß2 m double KO mice, which are NOG mice that are deficient in both MHC class I and II (DKO-NOG mice), with human HLA-A2-positive peripheral blood mononuclear cells (PBMCs). After injection of PBMCs, the xenogeneic graft-versus-host disease observed in PBMC-engrafted NOG mice was prevented in PBMC-engrafted DKO-NOG mice. Liver damage was reduced, and the survival time was prolonged in human PBMC-engrafted DKO-NOG mice compared to those in the NOG mice. The expression levels of PD-1 and Tim-3 on human T cells from PBMC-engrafted DKO-NOG mice were lower than those from NOG mice. By induction of HBV-specific T cell responses, such as vaccination with HBc-derived, peptide-pulsed DCs, hydrodynamic injection of HBV vector and intrasplenic injection of HepG2.2.15, the number of HBc-derived, peptide-specific CTLs increased in PBMC-engrafted DKO-NOG mice. Moreover, the recombinant HBV vaccine resulted in the production of hepatitis B surface antibody in 50% of the vaccinated mice. The induction of HBV-specific immune responses could be established in the immunologically humanized mice.

CD14+ monocyte-derived galectin-9 induces natural killer cell cytotoxicity in chronic hepatitis C.

Natural killer (NK) cell activation is associated with both liver injury and persistent infection in chronic hepatitis C (CHC); however, the detailed mechanism of this activation has not yet been fully elucidated. Because galectin-9 (Gal-9) has been reported to be increased in the serum and liver tissue of CHC patients, we investigated the function of Gal-9 in NK cell activation in CHC. First, we evaluated the function of Gal-9 on NK cytotoxicity in vitro. Gal-9 treatment resulted in increased cytotoxicity of naïve NK cells, and the Gal-9-activated NK cells demonstrated cytotoxicity toward hepatoma cells and T cells. Additionally, coculturing peripheral blood mononuclear cells (PBMCs) with JFH-1/Huh7.5.1 cells increased both Gal-9 production and NK cell cytotoxicity. Next, we investigated the source of Gal-9 and the mechanism of Gal-9 production. Deletion of CD14+ monocytes from PBMCs resulted in reduced Gal-9 production in the coculture with JFH-1/Huh7.5.1 cells. Gal-9 production was driven by coculturing of PBMCs with apoptotic hepatocytes. Blocking integrin αv ß3 , a receptor for phosphatidylserine expressed on apoptotic cells, also resulted in decreased Gal-9 production. Finally, we found that serum Gal-9 levels were significantly higher in CHC patients than in healthy donors and patients who achieved sustained virologic response. Among CHC patients, serum Gal-9 levels were significantly higher in patients with elevated alanine aminotransferase (ALT) than in those with normal ALT. CONCLUSION: These results demonstrate that CD14+ monocyte-derived Gal-9 increases NK cell cytotoxicity in HCV infection, which might be associated with liver injury and persistent infection. (Hepatology 2017;65:18-31).

S100A8 Production in CXCR2-Expressing CD11b+Gr-1high Cells Aggravates Hepatitis in Mice Fed a High-Fat and High-Cholesterol Diet.

Nonalcoholic fatty liver disease (NAFLD) is a common chronic liver disease with a spectrum of presentations. S100A8 has been suggested to play a pivotal role as an endogenous immune-activator in inflammatory diseases. In this study, we investigated the involvement of S100A8 in the development of NAFLD. We used a diet model of NAFLD, in which mice were fed either a high-fat and high-cholesterol diet (HFHCD) or a normal diet (ND) as a control. We also assessed liver tissues from patients with NAFLD, including patients with nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH). HFHCD-fed mice, but not ND-fed mice, developed steatohepatitis. S100A8 expression was significantly elevated in the livers of HFHCD-fed mice compared with the controls. S100A8 was exclusively expressed in CXCR2-expressing CD11b(+)Gr-1(high) cells, which significantly increased in the livers of HFHCD-fed mice. These cells were F4/80 negative and did not possess a suppressor function. TNF-α expression was enhanced by S100A8 in primary liver leukocytes or a hepatocyte cell line and significantly elevated in the livers of HFHCD-fed mice. TNF-α was primarily produced from CD11b(+)F4/80(+) cells in liver leukocytes in response to S100A8. TNF-α deficiency attenuated hepatitis in HFHCD-fed mice. S100A8 was significantly more expressed in the liver tissues of patients with NASH than in those of patients with NAFL. In conclusion, these results suggest that S100A8 is primarily produced from CXCR2-expressing CD11b(+)Gr-1(high) cells, and it upregulates TNF-α production in CD11b(+)F4/80(+) cells through cellular cross-talk, which is an important mechanism in the development of NAFLD.

The safety and benefit of pancreatic juice cytology under ERCP in IPMN patients.

BACKGROUND: International consensus guidelines 2012 for intraductal papillary mucinous neoplasia (IPMN), defined two characteristics: high-risk stigmata (HRS) and worrisome features (WF). Patients with WF require detailed examination including cytology. However, routine endoscopic retrograde cholangiopancreatography (ERCP) for cytology is not recommended in the guidelines due to risk of post-ERCP pancreatitis (PEP). Our aim was to clarify what types of IPMN were susceptible for PEP and gain benefit of ERCP. PATIENTS/METHODS: We examined 138 consecutive IPMN patients who underwent ERCP in our hospital, retrospectively. Patients were classified into HRS, WF and the others (N) based on imaging findings before ERCP. We assessed pancreatic juice cytology, PEP frequency and rate of malignant IPMN at 12 months after ERCP. RESULTS: The rates of cytological malignancy were 0% (N), 4.8% (WF) and 19.5% (HRS). The PEP frequency was 14.5%, and these risk factors were branch duct (BD)-IPMN, body/tail cysts and brush cytology by multivariate logistic analysis. The rates of malignant IPMN were 0% (N), 16.4% (WF) and 48.8% (HRS). Furthermore, we examined patients with WF in detail. The PEP frequency/rate of malignancy were 3.6%/23.1% in patients with main pancreatic duct (MPD) dilatation (5-9 mm), and the sensitivity of cytology was 33.3%. On the other hand, the PEP frequency/rate of malignancy were 17.2%/0% in patients with BD-IPMN fulfilling only cyst size over 30 mm. CONCLUSIONS: Routine ERCP for IPMN, especially for BD-IPMN, is not recommended. ERCP may be beneficial for WF patients with MPD dilatation based on a balance between PEP risk and presence of malignancy.

The Bcl-2 homology domain 3 (BH3)-only proteins Bim and bid are functionally active and restrained by anti-apoptotic Bcl-2 family proteins in healthy liver.

An intrinsic pathway of apoptosis is regulated by the B-cell lymphoma-2 (Bcl-2) family proteins. We previously reported that a fine rheostatic balance between the anti- and pro-apoptotic multidomain Bcl-2 family proteins controls hepatocyte apoptosis in the healthy liver. The Bcl-2 homology domain 3 (BH3)-only proteins set this rheostatic balance toward apoptosis upon activation in the diseased liver. However, their involvement in healthy Bcl-2 rheostasis remains unknown. In the present study, we focused on two BH3-only proteins, Bim and Bid, and we clarified the Bcl-2 network that governs hepatocyte life and death in the healthy liver. We generated hepatocyte-specific Bcl-xL- or Mcl-1-knock-out mice, with or without disrupting Bim and/or Bid, and we examined hepatocyte apoptosis under physiological conditions. We also examined the effect of both Bid and Bim disruption on the hepatocyte apoptosis caused by the inhibition of Bcl-xL and Mcl-1. Spontaneous hepatocyte apoptosis in Bcl-xL- or Mcl-1-knock-out mice was significantly ameliorated by Bim deletion. The disruption of both Bim and Bid completely prevented hepatocyte apoptosis in Bcl-xL-knock-out mice and weakened massive hepatocyte apoptosis via the additional in vivo knockdown of mcl-1 in these mice. Finally, the hepatocyte apoptosis caused by ABT-737, which is a Bcl-xL/Bcl-2/Bcl-w inhibitor, was completely prevented in Bim/Bid double knock-out mice. The BH3-only proteins Bim and Bid are functionally active but are restrained by the anti-apoptotic Bcl-2 family proteins under physiological conditions. Hepatocyte integrity is maintained by the dynamic and well orchestrated Bcl-2 network in the healthy liver.

The serum tenascin C level is a marker of metabolic disorder-related inflammation affecting pancreatic cancer prognosis.

Obesity is a risk factor for pancreatic cancer development, partly due to the tissue environment of metabolic disorder-related inflammation. We aimed to detect a tissue environment marker triggered by obesity-related metabolic disorders related to pancreatic cancer progression. In murine experiments, Bl6/j mice fed a normal diet (ND) or a high-fat diet (HFD) were orthotopically injected with mPKC1, a murine-derived pancreatic cancer cell line. We used stocked sera from 140 pancreatic cancer patients for analysis and 14 colon polyp patients as a disease control. Compared with ND-fed mice, HFD-fed mice exhibited obesity, larger tumors, and worse prognoses. RNA sequencing of tumors identified tenascin C (TNC) as a candidate obesity-related serum tissue environment marker with elevated expression in tumors of HFD-fed mice. Serum TNC levels were greater in HFD-fed mice than in ND-fed mice. In pancreatic cancer patients, serum TNC levels were greater than those in controls. The TNC-high group had more metabolic disorders and greater CA19-9 levels than did the TNC-low group. There was no relationship between serum TNC levels and disease stage. Among 77 metastatic patients treated with chemotherapy, a high serum TNC concentration was an independent poor prognostic factor. Pancreatic cancer patients with high serum TNC levels experienced progression more rapidly.