Hiromasa Ohira

Primary biliary cirrhosis – Autoimmune hepatitis overlap syndrome: A rationale for corticosteroids use based on a nation‐wide retrospective study in Japan

Aims:u2002 Primary biliary cirrhosis (PBC) and autoimmune hepatitis (AIH) may simultaneously coexist in some patients, designated as PBC‐AIH overlap syndrome. Previous studies suggest that combination therapy of ursodeoxycholic acid (UDCA) and corticosteroids may be effective. In the current study, we aimed to describe clinical features of these cases and to propose a rationale for combination treatment in PBC‐AIH overlap.

Replicated association of 17q12-21 with susceptibility of primary biliary cirrhosis in a Japanese cohort

To examine the genetics of susceptibility to primary biliary cirrhosis (PBC), genome-wide association studies GWAS have been performed in patients of European ancestry and have shown the significant associations of IL12-related pathways, SPIB, IRF5-TNPO3, and 17q12-21. We tested whether these findings could be extended to a Japanese cohort, 303 Japanese PBC and 298 controls. We failed to detect significant associations at IL12A (rs574808, rs1075498) and IL12RB2 (rs3790567). There was no genetic variance at IRF5-TNPO3 (rs10488631) in Japanese. A single nucleotide polymorphism (SNP) at SPIB (rs3745516) reached nominal significance, but the corrected P value did not reach significance. For the 17q12-21 region, two SNPs had nominally significant associations [GSDMB (rs2305480, P = 0.022) and ZPBP2 (rs11557467, P = 0.021)] and we noted a significant P value at a SNP in IKZF3 (rs939327, P = 0.0024, P(c) = 0.017) after correction for multiple comparisons. Thus, these results indicate a haplotype on 17q12-21 with a similar association in Japanese and European PBC.

Phase I trial of preoperative intratumoral injection of immature dendritic cells and OK-432 for resectable pancreatic cancer patients

PurposeTo determine the feasibility, safety and histological change of preoperative endoscopic ultrasound-guided fine-needle injection (PEU-FNI) of immature DCs (iDCs) with OK-432 in pancreatic cancer patients.MethodsNine patients enrolled in the trial (DC group) and were compared with 15 patients operated on without iDC injection (non-DC group). Adverse events of PEU-FNI and postoperative complications were evaluated according to CTC-AE ver.3.0 and the Clavien–Dindo classification/ISGPF definition, respectively. Histological changes within the tumor and lymph nodes were evaluated by immunohistochemical examination of infiltrating inflammatory cells (CD4+, CD8+, Foxp3+ and CD83+).ResultsThere were no severe toxicities following PEU-FNI, except for one transient grade 3 fever, and there were no significant differences in the incidence of postoperative complications between the two groups. Colliquative necrosis and diffusely scattered TUNEL-positive cells were observed at the injection sites. CD83+ cells significantly accumulated in the regional lymph nodes of the DC group as well as Foxp3+ cells in the regional and distant lymph nodes. The two DC group patients, one of which was stage IV with distant lymph node metastasis, survived more than 5 years without requiring adjuvant theraphy.ConclusionPEU-FNI was feasible and safe, and further study needs to confirm and enhance antitumor responses.

Cathepsin L is highly expressed in gastrointestinal stromal tumors

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract that are diagnosed by c-kit staining in most cases. A lysosomal cysteine proteinase termed cathepsin L has been commonly associated with malignancy in several cancer types, but this finding has not been reported for GISTs. We analyzed the cathepsin L mRNA and protein expression in GISTs. Real-time reverse transcription polymerase chain reaction (RT-PCR) analysis revealed that cathepsin L levels were higher in GISTs than those in gastric or colorectal tumors; this finding was supported by results of the Western blot analysis. Immunohistochemistry revealed that cathepsin L was localized to the cytoplasm of GIST cells as an intense granular signal, which was not observed in the cells of leiomyoma, a mesenchymal tumor that was analyzed as a control specimen. Double immunofluorescence microscopy revealed that a portion of the granular signal colocalized with lysosome-associated membrane protein-1 (LAMP-1), which is a lysosomal marker. Moreover, immunohistochemical analysis of 43 tumor specimens revealed that 86.0% (n=37) were cathepsin-L positive, and this positivity was significantly correlated with c-kit positivity but not with other clinicopathological factors, including gender, age, region, size, mitosis and risk of recurrence. From these results, we conclude that cathepsin L is highly expressed in GISTs compared to its expression in other cancerous lesions; this identifies cathepsin-L as a new diagnostic marker for GISTs.

Genetic association of Fc receptor-like 3 polymorphisms with susceptibility to primary biliary cirrhosis: ethnic comparative study in Japanese and Italian patients

A functional variant in the Fc receptor-like 3 (FCRL3) gene is associated with the susceptibility to several autoimmune diseases. In this study, we examined whether the FCRL3 is associated with susceptibility to primary biliary cirrhosis (PBC) by comparing the two different ethnic groups, Japanese and Italians. We enrolled 232 patients with PBC and 230 controls in Japanese, and 216 PBC and 180 controls in Italians. Minor allele frequency of fcrl3_3 (-169 T>C) in the patients with PBC and controls was 0.20 and 0.09 in Japanese and 0.24 and 0.21 in Italians, respectively. We found a significant association of fcrl3_3 with PBC only in Japanese (P = 9.64 × 10(-7) ). These findings support the presence of common FCRL3-related pathological pathways in several autoimmune diseases, especially in Asians.

Risk factors associated with relapse of type 1 autoimmune hepatitis in Japan.

Aim:u2002 Patients receiving corticosteroid therapy on a tapered schedule occasionally suffer autoimmune hepatitis (AIH) relapses. The aim of this study was to assess the frequency and features of relapses, explore risk factors associated with relapses, and evaluate the effectiveness of azathioprine (AZP) therapy against relapses in Japanese patients with type 1 AIH.

ATP assay-guided chemosensitivity testing for gemcitabine with biopsy specimens obtained from unresectable pancreatic cancer using endoscopic ultrasonography-guided fine-needle aspiration

ObjectivesThis study evaluates the feasibility of chemosensitivity testing by use of endoscopic ultrasonography-guided fine-needle aspiration (EUS-FNA) samples and determines the optimum cut-off value for gemcitabine.MethodsThirty-four consecutive patients with unresectable pancreatic cancer were enrolled. Chemosensitivity (treated/control ratio: T/C ratio) was calculated as the quantity of adenosine triphosphate for a tumor treated with gemcitabine as a percentage of that for the control. To identify the cut-off value sufficient to predict 180xa0days of progression-free survival (PFS), the receiver operating characteristic curve and the corresponding area under the curve (AUC) were calculated.ResultsThe success of this assay was 88.2% (30/34); therefore, 30 patients were assessable and included in the population of analyzable patients.. The response was 6.7%. Median PFS was 96xa0days and median overall survival was 241xa0days, respectively. The cut-off value was determined as 74% (AUC, 0.745; pxa0=xa00.053; 95% CI 0.485–1.005). According to this cut-off value, we predicted 180xa0days PFS with a sensitivity and specificity of 71.4 and 91.3%, respectively. When patients were divided into two groups at T/C ratio 74%, a significant difference was found in PFS (median 77 vs. 205xa0days, pxa0=xa00.0036). Moreover, T/C ratioxa0<xa074% and decrease of CA19-9 were significant and independent prognostic factors by multivariate analysis.ConclusionChemosensitivity testing by use of EUS-FNA samples in patients with unresectable pancreatic cancer is feasible. This definition emphasizes the possibility of selecting patients for whom favorable results from gemcitabine treatment can be expected.

Autoimmune Neutropenia Associated with Autoimmune Pancreatitis

CONTEXTnWe report a rare case of autoimmune neutropenia associated with autoimmune pancreatitis.nnnCASE REPORTnA 61-year-old man was referred to our hospital with slight epigastralgia. He had been admitted to another hospital with exacerbation of diabetes and jaundice. Blood tests showed low white blood cell and neutrophil counts (1,800 µL-1 and 3%, respectively), and elevated transaminase, biliary enzyme, amylase and lipase levels. Serum IgG and IgG4 levels were elevated to 2,693 mg/dL and 454 mg/dL, respectively. Abdominal CT showed diffuse pancreatic swelling, and MRCP revealed diffuse narrowing of the main pancreatic duct and dilation of the common bile duct. An additional EUS-FNA was performed in our hospital. Laboratory data, imaging and histopathological findings confirmed the diagnosis of autoimmune pancreatitis. However, the low white blood cell count continued. For additional investigation, a bone marrow examination was performed, indicating a granulocyte maturation disorder. Moreover, anti-neutrophil antibodies were positive. Therefore, a diagnosis of autoimmune neutropenia associated with autoimmune pancreatitis was made. After steroid therapy, the anti-neutrophil antibodies disappeared and the white blood cell count was within the reference limit. No recurrence of disease has been observed since then.nnnCONCLUSIONnAutoimmune neutropenia, which is positive for anti-neutrophil antibodies, can be associated with autoimmune pancreatitis.