A case of ulcerative colitis with a variety of autoimmune diseases including ankylosing spondylitis, type 2 autoimmune pancreatitis, and primary sclerosing cholangitis.

Ankylosing spondylitis (AS), primary sclerosing cholangitis (PSC), and autoimmune pancreatitis (AIP) are known as extraintestinal manifestations (EIMs) of ulcerative colitis (UC). A 74-year-old Japanese man visited our hospital because of white stool. He had been diagnosed with AS when he was 30 years old, and he was HLA-B27-positive. Based on various examination results, it was suspected that AIP had caused bile duct stricture. During the clinical course, he was diagnosed with UC and PSC. Then, AIP was diagnosed because he had localized pancreatic enlargement, irregular stenosis of the main pancreatic duct, PSC, and no tumor cells of pancreas. A patient with all four of these diseases, AS, AIP, PSC, and UC, is very rare. Therefore, we report a quite rare case with three EIMs (AS, PSC, and AIP) of UC.

Complement complex 1 subunit q-mediated hepatic stellate cell activation with connective tissue growth factor elevation is a prognostic factor for survival in rat and human chronic liver diseases.

Complement complex 1 subunit q (C1q) has multiple functions, including cell migration, in addition to its traditional complement-activating effect. Research shows C1q is a ligand for frizzled receptors (FZDs). FZD-induced yes-associated protein (YAP)/transcriptional co-activator with PDZ-binding motif (TAZ) alternate Wnt signaling activation induces connective tissue growth factor (CTGF) production and hepatic stellate cell (HSC) activation. However, no study exists in which C1q directly induces CTGF in HSCs. Here, we investigated the role of C1q in HSC activation. Human HSCs (LX2) were incubated with C1q to assess HSC activation. C1q and fibrotic markers were assessed using immunohistochemistry, immunoblotting, and quantitative reverse-transcription polymerase chain reaction in cirrhotic rats administered CCl4 for 21 weeks. Serum C1q, liver function, and fibrosis score were measured in 91 patients with chronic liver disease. The correlations between serum C1q and liver function, fibrosis score, and survival prognosis were examined. C1q-activated LX2s showed morphologic changes, up-regulation of CTGF, tissue inhibitors of metalloproteinases (TIMP-1), and alternate Wnt signal genes FZD2, TAZ, and cysteine-rich angiogenic inducer 61 (Cyr61). Cirrhotic rat liver C1q expression correlated with the Azan-positive area and expression of CTGF, TIMP-1, hyaluronan synthase (HAS)1, HAS3, and CD44. Expression of C1q protein and C1q, CTGF, and TIMP-1 genes were higher in deceased cirrhotic rat livers compared to surviving rats. Human serum C1q levels increased in liver cirrhosis compared to chronic hepatitis and correlated with liver fibrosis and functional markers. Ten patients suffered liver-related death over a 66-month observation period. The C1q cut-off value (11 mg/dl) showed patients with serum values < 11 mg/dl had longer rates of survival compared to C1q ≥ 11 mg/dl. Conclusion: C1q-mediated HSC activation in liver fibrosis is associated with CTGF elevation. Additionally, serum C1q may be diagnostic for survival in human chronic liver diseases.

miR-3940-5p/miR-8069 ratio in urine exosomes is a novel diagnostic biomarker for pancreatic ductal adenocarcinoma.

Despite the development of several therapeutic options, the prognosis of pancreatic cancer remains poor. One reason for this is the difficulty of diagnosing the disease at an early stage. For example, carbohydrate antigen (CA) 19-9, which is the most widely used biomarker for pancreatic cancer, cannot be used to detect the disease at early stages. Some studies have attempted to find novel biomarkers for pancreatic cancer. The aim of the present study was to find a novel diagnostic biomarker for pancreatic ductal adenocarcinoma (PDAC) in urine exosomes. Exosomes were isolated from urine and serum samples of patients with PDAC and control subjects, or culture media of cancer cell lines. MicroRNAs (miRNAs) were purified from exosomes. Novel biomarker candidates for PDCA were identisfied from urine exosome miRNA using expression profiling, and validated in a larger number of samples using 3D digital PCR. The results of a preliminary analysis of nine PDAC and seven control subjects revealed that the miR-3940-5p/miR-8069 ratio in urine exosomes was elevated in the patients with PDAC. Experiments using cultured cancer cell lines revealed that the elevation of the miR-3940-5p/miR-8069 ratio was specific for PDAC. Furthermore, the elevation of the miR-3940-5p/miR-8069 ratio in exosomes tended to be higher in the urine than in the serum of patients with PDAC. Validation experiments on 43 PDAC, 12 chronic pancreatitis and 25 control subjects demonstrated that the miR-3940-5p/miR-8069 ratio in urine exosomes was elevated in PDAC at a relatively early stage of the disease. When this ratio was used in combination with CA19-9 for the diagnosis of PDAC, the sensitivity and positive predictive value improved to 93.0 and 78.4%, respectively, when either of them was positive. Additionally, the positive predictive value reached 100% when both were positive. The negative predictive value also improved to 89.7% when both were negative. The miR-3940-5p/miR-8069 ratio in urine exosomes may be useful as a tool for the diagnosis of PDAC, particularly when used in combination with CA19-9.

Ratio between estimated glomerular filtration rates of creatinine and cystatin C predicts overall survival in patients with hepatocellular carcinoma.

AIM: Hepatocellular carcinoma (HCC) patients with sarcopenia have a poor survival, but there are no predictive markers for survival relating to muscle mass and liver function. Therefore, we investigated whether the ratio between estimated glomerular filtration rates of serum creatinine (Scre) and serum cystatin C (Scys) (eGFRcre/eGFRcys) can be used as a predictive marker of survival in HCC patients. METHODS: First, the correlation between Scre/Scys ratio and muscle mass was examined in 50 patients with chronic liver disease. Second, a change in Scre/Scys ratio relating to liver function was investigated in cirrhotic rats. Finally, the relationship between the eGFRcre/eGFRcys ratio and survival was assessed in 86 HCC patients. RESULTS: The Scre/Scys ratio was correlated with skeletal muscle mass index (r = 0.331, P = 0.019) and psoas muscle area index (r = 0.397, P = 0.004) in chronic liver disease patients. In cirrhotic rats, Scre and Scre/Scys ratio were decreased corresponding with liver function. Thirty-five of 86 HCC patients died within the average follow-up period of 35 months. The patients with an eGFRcre/eGFRcys ratio <1.26 had significantly longer rates of survival compared to patients with an eGFRcre/eGFRcys ratio ≥1.26 (28.8 vs. 18.5 months, P = 0.001). Using multivariate Cox regression analyses, the patient-related eGFRcre/eGFRcys ratio (hazard ratio [HR], 4.178; P = 0.007), as well as the tumor-related factors α-fetoprotein (HR, 1.000; P < 0.001) and Barcelona Clinic Liver Cancer stage (HR, 2.589; P < 0.001), were independent predictors of survival. CONCLUSION: The Scre/Scys ratio is associated with muscle mass and liver function. Furthermore, the eGFRcre/eGFRcys ratio could serve as a useful predictive marker for survival of HCC.

Comparison of endoscopic ultrasound-guided fine-needle aspiration and biopsy with 22-gauge and 25-gauge needles for the "precision medicine" of pancreatic cancer: A retrospective study.

We compared the sample volume of endoscopic ultrasound-guided fine-needle aspiration and biopsy (EUS-FNAB) specimens obtained by 22-gauge (22G) and 25-gauge (25G) needles, and the accuracy rate.This was a retrospective study in a single tertiary referral center. We investigated 153 patients with pancreatic ductal adenocarcinoma (PDAC) who underwent diagnostic EUS-FNAB before neoadjuvant gemcitabine-based chemoradiotherapy between October 2006 and November 2015. We performed immunohistochemical (IHC) analysis of human equilibrative nucleoside transporter 1 using the remnant cell blocks following pathological PDAC diagnosis. We compared the sampling rate, accuracy rate, and success rate of IHC analysis between 22G and 25G.There were 70 patients in the 22G group and 83 patients in the 25G group. The overall sampling rates on cytology and histology were 100% and 98.0%, respectively. The sampling rate did not differ between the 22G and 25G groups. The overall diagnostic accuracy rates on cytology and histology were 94.8% and 79.7%, respectively. The accuracy rates of 22G and 25G groups on cytology were 94.3% and 95.2%, respectively, whereas those on histology were 80.0% and 79.5%, respectively. The diagnostic accuracy on cytology and histology did not differ significantly between the 22G and 25G groups. Of 153 histology specimens, 69.3% of those with PDAC provided sufficient samples for IHC analysis. The success rate of IHC analysis did not differ significantly between the 22G (67.1%) and 25G (71.1%) groups (P = .60).Both 22G and 25G provided a high diagnostic yield with equivalent accuracy rates on histology. EUS-FNAB specimens obtained using 22G or 25G can be equally adequate for IHC analysis and may be suitable for diagnostic examination. Further investigations such as EUS-FNAB needle design and novel cell block preparation are needed to obtain adequate samples for use in "precision medicine."

Pancreatic Adenocarcinoma Producing Parathyroid Hormone-Related Protein.

A 48-year-old woman presented to our hospital with a 1-year history of a continuous high fever. She was diagnosed with metastatic pancreatic adenocarcinoma accompanied by leukocytosis without infection. Her serum concentration of granulocyte colony-stimulating factor was highly elevated. Forty-five days after initiating chemotherapy, she was readmitted because of a neuropsychiatric disturbance and hypercalcemia. Her serum concentration of parathyroid hormone-related protein (PTH-rP) was elevated. A pretreatment biopsy specimen showed strong cytoplasmic immunoreactivity to anti-PTH-rP antibody, suggesting that overproduction of PTH-rP accounted for the hypercalcemia. Although the patient regained consciousness after treatment, she died of progressive disease 60 days after chemotherapy.

Genetic analyses of isolated high-grade pancreatic intraepithelial neoplasia (HG-PanIN) reveal paucity of alterations in TP53 and SMAD4.

High-grade pancreatic intraepithelial neoplasia (HG-PanIN) is the major precursor of pancreatic ductal adenocarcinoma (PDAC) and is an ideal target for early detection. To characterize pure HG-PanIN, we analysed 23 isolated HG-PanIN lesions occurring in the absence of PDAC. Whole-exome sequencing of five of these HG-PanIN lesions revealed a median of 33 somatic mutations per lesion, with a total of 318 mutated genes. Targeted next-generation sequencing of 17 HG-PanIN lesions identified KRAS mutations in 94% of the lesions. CDKN2A alterations occurred in six HG-PanIN lesions, and RNF43 alterations in five. Mutations in TP53, GNAS, ARID1A, PIK3CA, and TGFBR2 were limited to one or two HG-PanINs. No non-synonymous mutations in SMAD4 were detected. Immunohistochemistry for p53 and SMAD4 proteins in 18 HG-PanINs confirmed the paucity of alterations in these genes, with aberrant p53 labelling noted only in three lesions, two of which were found to be wild type in sequencing analyses. Sixteen adjacent LG-PanIN lesions from ten patients were also sequenced using targeted sequencing. LG-PanIN harboured KRAS mutations in 94% of the lesions; mutations in CDKN2A, TP53, and SMAD4 were not identified. These results suggest that inactivation of TP53 and SMAD4 are late genetic alterations, predominantly occurring in invasive PDAC. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Neutrophil gelatinase-associated lipocalin level is a prognostic factor for survival in rat and human chronic liver diseases.

Chronic liver disease patients often have complications, such as hepatocellular carcinoma (HCC) and acute bacterial infection. Model for end-stage liver disease and Child-Pugh scores are useful prognostic factors for chronic liver diseases but not for all chronic conditions, such as HCC. Our investigative aim targeted the prognostic abilities of neutrophil gelatinase-associated lipocalin (NGAL) in rat and human chronic liver diseases. Blood NGAL levels were measured by enzyme-linked immunosorbent assay in rats with cirrhosis and 96 patients with chronic liver disease and HCC. We examined the correlation between blood NGAL levels and liver functions as well as survival. In our rat model, liver NGAL expression was assessed by immunostaining, real-time quantitative polymerase chain reaction, and immunoblot. In rats with cirrhosis, blood NGAL levels were continuously and significantly elevated in the deceased group and were significantly correlated with liver functions. Liver NGAL, toll-like receptor 4, and interleukin-6 levels were increased in the deceased group compared to the survival group. Blood NGAL levels were significantly correlated with liver NGAL levels, indicating blood NGAL was derived from the liver. In patients with chronic liver disease, blood NGAL levels were associated with liver function and renal function. Blood NGAL levels were significantly increased in patients with chronic liver disease with HCC compared to without HCC. For the survival group, 38 out of 96 patients were dead in the average follow-up period of 9.9 months. The patients with blood NGAL ≤119 ng/mL had significantly longer rates of survival compared to patients with blood NGAL >119 ng/mL. Conclusion: Blood NGAL predicts the survival rate in rat and human chronic liver diseases. Our findings suggest blood NGAL may be prognostic of survival in chronic liver diseases complicated by HCC. (Hepatology Communications 2017;1:946-956).

A case report of adenosquamous cell carcinoma of the duodenal papilla.

Adenosquamous carcinoma of the duodenal papilla is rare. A 73-year-old man was referred to the Saiseikai-Matsusaka General Hospital with upper abdominal pain and liver dysfunction. Computed tomography (CT) revealed dilatation of the common bile duct (CBD) and intrahepatic bile duct along with a tumor in the distal CBD. The tumor showed enhancement in the arterial phase on contrast-enhanced CT. We performed endoscopic retrograde cholangiopancreatography and noted a red, erosive, bleeding mass in the duodenal papilla with obstruction of the distal CBD, and dilatation of the CBD. Histopathological inspection of a biopsy of the duodenal papilla showed a mixture of adenocarcinoma and squamous cell carcinoma, suggesting the presence of adenosquamous cell carcinoma in the duodenal papilla. Abdominal examinations including positron emission tomography/CT showed no metastasis or lymph node swelling. The clinical stage was determined to be cT2N0M0 Stage IB. We performed subtotal stomach-preserving pancreaticoduodenectomy. Histopathological inspection of the specimen showed a mixture of adenocarcinoma and squamous cell carcinoma, and squamous cell carcinoma accounted for 40% of the tumor. The tumor was defined as pathological Stage IIA, AcbBd, mixed type, med, pT3b, sci, INFb, ly2, v1, ne2, pN1, HM0, PM0, EM0, PV0, A0, R0, pT3N0M0. We suggested adjuvant chemotherapy, but the patient declined adjuvant chemotherapy and wished to be discharged. Abdominal ultrasonography revealed multiple liver metastases 3 months postoperatively. The patient opted for best supportive care and died 9 months postoperatively. Examination of 23 reports of adenosquamous cell carcinoma of the duodenal papilla in Japan suggested that adenosquamous cell carcinoma of the duodenal papilla has a poorer prognosis compared with adenocarcinoma of the duodenal papilla. Some reports have stated that the growth rate is faster for squamous cell carcinoma than for adenocarcinoma. In our case, the tumor was enhanced in the arterial phase and this represents a feature of adenosquamous cell carcinoma of the duodenal papilla. Chemotherapy has not been established for adenosquamous cell carcinoma of the duodenal papilla. We are confident that we can establish effective chemotherapies in the future.

Peripancreatic Tuberculous Lymphadenitis with Biliary Obstruction Diagnosed by Endoscopic Ultrasound-guided Fine-needle Aspiration Biopsy.

A 57-year-old man with a history of tuberculosis (TB) was found to have a pancreatic head mass, accompanied by stenosis of the common bile duct. Due to the inherent difficulty in differentiating pancreatic carcinoma from an inflammatory mass, endoscopic ultrasound-guided fine-needle aspiration biopsy (EUS-FNAB) was thus performed. The pathological findings confirmed granuloma with caseous necrosis, and the results of the QuantiFERON TB2G test were positive. Accordingly, the patient was diagnosed with peripancreatic TB and thereafter was successfully treated with anti-TB therapy. Based on the findings of this case, we conclude that EUS-FNAB is a useful modality for the diagnosis of pancreatic TB.

A patient with a pancreatic neuroendocrine tumor who developed everolimus-induced interstitial pneumonia: a case report.

A patient in her 60s was referred to our hospital with pancreatic enlargement. Laboratory data and endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) revealed a nonfunctioning pancreatic neuroendocrine tumor (WHO classification 2010 G2). Resection was contraindicated because of portal vein invasion and extensive collateral vascularization. Everolimus (10 mg/day) was started after seven months of treatment with S-1 (an oral formulation of tegafur with the modulators gimeracil and oteracil) following its insurance approval in Japan. Four months later, the patient developed cough and fever, and there was radiological and clinical evidence of Grade 2 everolimus-associated interstitial pneumonia (according to the Everolimus Proper-Usage Guide). Everolimus was replaced with steroid therapy (30 mg/day), resulting in immediate symptomatic improvement. After conclusion of steroid therapy, everolimus was restarted. The patient has since remained on a dosage of 10 mg/day of everolimus, with the tumor in a state of partial response.

Sarcomatous hepatocellular carcinoma with remittent fever.

We herein report a rare case of hepatocellular carcinoma (HCC) with sarcomatous changes. A 66-year-old man was admitted to our hospital with a high fever and upper abdominal pain. Initially, he was diagnosed as having a liver abscess; however, antibiotic treatment and drainage were ineffective. Further imaging studies revealed the typical appearance of HCC: the tumor had invaded the hepatic and portal veins. Surgical resection of the tumor was performed. A pathological examination demonstrated the presence of a sarcomatous hepatocellular carcinoma. Sarcomatous hepatocellular carcinoma with remittent fever is a rare disease entity.