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Inflammatory bowel diseases (IBDs), including ulcerative colitis (UC) and Crohn’s disease (CD), are chronic intestinal diseases of unknown etiology that present with variable disease extents and outcomes. The use of biomarkers for the diagnosis and management of IBDs is considered beneficial. Palmitoleic acid (PO) is an adipose tissue-derived mono-unsaturated free fatty acid that potentially serves as a lipokine in metabolic and inflammatory diseases. The aim of this study was to investigate the significance of PO levels in the serum of patients with UC and CD. The study included patients with UC (n = 22), patients with CD (n = 35), and controls (n = 22). The levels of serum PO were analyzed using gas chromatography. The association of serum PO levels with the clinical features and disease outcomes in IBD was examined. Serum PO levels were significantly higher in patients with CD than in controls, whereas no difference in these levels was observed between patients with UC and controls. Serum PO levels were significantly associated with the CD activity index. Additionally, high serum PO levels were associated with an increased risk of surgical intervention requirement during follow-up. In a pilot study with a few patients, high PO levels were observed in the mesenteric tissue in the active disease site of patients with CD (n = 7) compared with those with colon cancer (n = 6). Elevated serum PO levels might serve as a marker for local inflammation and prognosis in patients with CD., Scientific Reports, 11, art. no. 16260; 2021

Gastroesophageal reflux disease (GERD) in systemic sclerosis (SSc) can significantly reduce a patient's quality of life. GERD in SSc is occasionally resistant to conventional anti-acid treatment. Vonoprazan is an H+/K+-ATPase blocker that is approved in Japan for treatment of GERD. The aim of the present study was to evaluate the efficacy of vonoprazan in SSc-related GERD. The frequency scale for symptoms of GERD (FSSG) scores were collected before and after vono-prazan treatment in 15 SSc patients with GERD. Additionally, endoscopic esophagogastroduodenoscopy was performed in select patients. Conventional proton pump inhibitors or hista-mine-2 receptor antagonists had been previously administered in 93% (14/15) of the patients. Although the baseline esophago-gastroduodenoscopy examination did not show severe erosion in the majority of patients,the mean total FSSG score before vonoprazan treatment was notably high (25.2±10.7) compared to a normal score of <8. After vonoprazan treatment, the FSSG score decreased to 9.6±7.0. The mean improvement rate of the total FSSG, acid reflux and dysmotility scores were 60.8±21.2% (P=0.0004), 67.3±24.8% (P<0.0001) and 55.4±26.0% (P=0.0022), respectively.These results suggest that vonoprazan may be a potentially effective treatment for GERD in patients with SSc., Biomedical Reports, 14(2), pp.1-8; 2020

While retrospective studies have compared the efficacy of anti?tumour necrosis factor (TNF) agents and tacrolimus (TAC) in ulcerative colitis (UC), information regarding first-time use of these agents is limited. The aim of our study was to investigate the short- and long-term efficacy of anti-TNF agents [adalimumab (ADA) and infliximab (IFX)] and TAC in anti-TNF agent- and TAC-naive steroid-refractory UC patients. We evaluated 150 steroid-refractory UC patients receiving anti-TNF agents (IFX: n = 30, ADA: n = 41) or TAC (n = 79) at eight institutions in Japan. Clinical response rates at 8 weeks were 73.2% and 75.9% while remission rates were 30.1% and 25.3% in the anti-TNF and TAC groups, respectively. Logistic regression analysis showed the male sex and higher C-reactive protein to be independent factors for response to anti-TNF agents and TAC, respectively. Use of TAC was an independent factor for relapse. No differences in response to the treatment or relapse were observed between IFX and ADA. In conclusion, TAC and anti-TNF agents promoted similar short-term effects, but anti-TNF agents ensured better long-term outcomes at first-time treatment of steroid-refractory UC patients., Scientific Reports, 10(1), art.no.12546; 2020

Copy number alterations and loss of heterozygosity are associated with increasing tumor grade and bladder cancer stage. Our previous study suggested that co-expression of Ki-67 and p53-binding protein 1 (53BP1) could provide an indicator of an abnormal DNA damage response (DDR) pathway. The present study investigated 53BP1 expression as a novel molecular marker in urothelial carcinoma (UC) using bladder tissues with in total of 40 cases including a normal urothelium, urothelial papilloma, low-grade UC, or high-grade UC. Double-label immunofluorescence was used to analyze 53BP1 and Ki-67 expression. This was compared with the level of chromosomal instability and with the expression of other DDR molecules catalytic subunit. This study identified clear differences in the 53BP1 expression patterns in urothelial carcinogenesis, and their close association with genomic instability. 53BP1 abnormal immunoreactivity, particularly with co-localization of Ki-67, was restricted to malignant tissues. Our analyses indicated that a cut-off of >4% of nuclei with 53BP1 abnormal expression plus Ki-67 immunoreactivity distinguished high-grade UC from low-grade UC with 80.0% sensitivity and 100% specificity. We therefore propose that double immunofluorescent analysis of 53BP1 and Ki-67 expression could provide a useful tool to estimate the chromosomal instability and malignant potential of urothelial tumors., Scientific Reports, 8(1), art. no.15477; 2018

Programmed cell death ligand-1 (PD-L1) expression may predict the response to both programmed cell death-1 and PD-L1 inhibitors in lung cancer. However, the extent of intratumoral heterogeneity of PD-L1 expression, which may cause false negative results, is largely unexplored. We aimed to assess the intratumoral heterogeneity of PD-L1 expression in surgically resected lung cancer specimens by applying a novel method of tissue microarray, namely Spiral Arrays, which enables us to observe the heterogeneity in spiral-shaped tissue cores. Adenocarcinoma and squamous cell carcinoma specimens were obtained from consecutive patients with lung cancer who had undergone surgical resection at Nagasaki University Hospital (Nagasaki, Japan) since 2009. Small cell lung cancer and large cell carcinoma specimens were selected from patients in the same archive who had undergone resection since 1998. Spiral Arrays were constructed of spiral-shaped cores, prepared from representative blocks of each case, which were subjected to immunohistochemistry using an anti-PD-L1 antibody. Each core was divided into 8 segments and each segment was classified as either PD-L1-positive or PD-L1-negative using thresholds of 1.0%, 5.0%, 10.0%, and 50.0%, respectively. In total, 138 specimens were selected, including 60 adenocarcinomas, 59 squamous cell carcinomas, 12 small cell lung cancers, and 7 large cell carcinomas. The majority of specimens with PD-L1-positive segments exhibited heterogeneous expression (i.e., had a mixture of PD-L1-positive and PD-L1-negative segments within a core) irrespective of the threshold (1.0%, 66.7%; 5.0%, 74.4%; 10.0%, 75.8%; and 50.0%, 85.7%]. Large variations in the ratios of PD-L1-positive segments were observed. At least 50.0% of the segments within a core were negative in no fewer than 50.0% (range, 50.0?76.0%) of cases with heterogeneous PD-L1 expression. In conclusion, intratumoral heterogeneity of PD-L1 expression was frequently observed in cases of lung cancer, PLOS ONE, 12(10), e0186192; 2017

Mohammed Tag-Adeen,1,2 Ahlam Mohamed Sabra,1 Yuko Akazawa,2 Ken Ohnita,2 Kazuhiko Nakao2 1Department of Internal Medicine, Qena School of Medicine, South Valley University, Qena, Egypt; 2Department of Gastroenterology and Hepatology, Nagasaki School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan Background: Liver fibrosis is the most important prognostic factor in chronic hepatitis C virus (HCV) patients, and Egypt shows the highest worldwide HCV prevalence with genotype-4 predominance. The aim of this study was to investigate the degree of liver stiffness measurement (LSM) improvement after successful HCV eradication.Patients and methods: The study included 84 chronic HCV Egyptian patients, and was conducted at Qena University Hospital from November 1, 2015 till October 31, 2016. LSM was obtained by FibroScan® before starting direct acting antiviral (DAA) treatment and after achieving sustained virologic response-24 (SVR-24). Based on baseline LSM, patients were stratified into F0–F1, F2, F3 and F4 groups (METAVIR). LSM and laboratory data after achieving SVR-24 was compared with that before starting therapy in each fibrosis group (F0-F4), p-value <0.05 was statistically significant.Results: Following DAA treatment, 80 patients achieved SVR-24; of these, 50 were males (62.5%), mean age: 54.2±7.6 years, and mean body mass index: 28.6±2.2 kg/m2. Mean baseline LSM dropped from 15.6±10.8 to 12.1±8.7 kPa post-SVR; the maximum change of −5.8 occurred in F4 versus −2.79, −1.28 and +0.08 in F3, F2 and F0–F1 respectively (p<0.0001). At baseline, 41 patients were in the F4 group; only 16 (39%) regressed to non-cirrhotic range (<12.5 kPa), while 25 (61%) were still cirrhotic despite achieving SVR-24 (p<0.0001). Patients who achieved LSM improvement (n=64) have had significantly higher baseline aspartate transferase (AST) and

Background: Mitotically active cellular fibroma (MACF) of the ovary, characterized by relatively high mitotic activity without severe atypia, represents a relatively new disease entity. MACF is categorized as a benign ovarian tumor. However, due to a limited number of case reports, its clinical and pathological features and optimum management remains largely undetermined. Herein, we report on a rare case of MACF that grew rapidly in size and was diagnosed on detailed pathological examination. Case presentation: A 44-year-old Japanese woman, who detected a myoma-like lesion 1-year earlier, was referred to our hospital when the follow-up examination demonstrated that the mass had increased in size. Magnetic resonance imaging revealed a T1 isointense and T2 hyperintense tumor (11 cm in diameter) in the right pelvic cavity. Laparoscopy confirmed the presence of a right ovarian tumor and laparoscopic right adnexectomy was performed. The tumor cells consisted of dense cellular proliferations of spindle fibroblast-like cells without significant cytological atypia. The mitotic activity index was estimated at >15 mitotic figures per 10 high-power fields. Reticulin staining and FOXL2 mutation analysis excluded the possibility of an adult granulosa cell tumor, and the patient was diagnosed with a MACF of the ovary. Conclusions: To the best of our knowledge, we are the first to report on a case of rapid growth of a MACF of the ovary during follow-up. When an increase in the size of a solid ovarian mass is detected, a MACF should be considered as a differential diagnosis., Diagnostic Pathology, 11, 101; 2016

Background: There are few reports of the efficacy of adalimumab (ADA) for clinical remission and preventing postoperative recurrence in Crohn's disease (CD) in Asian real practice settings. We conducted a Japanese multicenter retrospective observational study. Methods: We evaluated patients with CD who were treated with ADA at 11 medical institutions in Japan to investigate the clinical efficacy of remission up to 52 weeks and the associated factors to achieve remission with a CD Activity Index (CDAI) < 150. The effects of preventing postoperative recurrence were also evaluated. Results: In 62 patients, the remission rates were 33.9, 74.2, 75.8, 77.4, and 66.1 % at 0, 4, 12, 26, and 52 weeks, respectively. Although 10 patients discontinued treatment due to primary nonresponse, secondary nonresponse, or adverse events, the ongoing treatment rate at 52 weeks was 83.9 %. Comparison of remission and non-remission on univariate analysis identified colonic type and baseline CDAI value as significant associated factors (P < 0.05). In 16 patients who received ADA to prevent postoperative recurrence, the clinical remission maintenance rate was 93.8 % and the mucosal healing rate was 64.3 % during a mean postoperative follow-up period of 32.3 months. Conclusions: ADA effectively induced remission and prevented postoperative recurrence in patients with CD in a real practice setting., BMC Gastroenterology, 16, 82; 2016

A 77-year-old man with a history of non-steroidal anti-inflammatory drugs (NSAID) use was admitted to our hospital due to anemia and hypoalbuminemia. Radioisotope scintigraphy indicated protein loss from the small intestine. The patient underwent capsule endoscopy, which was later found to be retained in the ileum. Double-balloon endoscopy showed multiple strictures with ulcers in the small intestine. The capsule was found in proximal to one of the stenosis, and was removed by doubleballoon enteroscopy. Based on endoscopic findings, NSAID-induced enteritis was diagnosed. Although anemia and hypoalbuminemia improved after discontinuing NSAID, the patient developed ileus and underwent partial resection of the ileum. Multiple diaphragm-like strictures were present in the resected intestine. The current case highlights the importance of screening for intestinal strictures when NSAID ulcer is suspected., Acta medica Nagasakiensia, 58(4), pp.135-138; 2014

Endoscopic submucosal dissection (ESD) enables the curative resection of early gastric cancer (EGC); however, little information is available on the long-term outcomes of ESD. This study was conducted to clarify the clinical outcomes of a large number of patients with EGC who underwent ESD. The early outcomes were assessed in 1,209 patients and the long-term outcomes were assessed in 300 patients at a follow-up >5 years after the ESD procedure. The overall survival rates were compared between indication and expanded-indication groups, and between the patients who did or did not undergo additional surgery in an out-of-indication group. Overall survival rates were also compared among different age groups. In total, 617 lesions were classed as the indication group, 507 as the expanded-indication group and 208 as the out-of-indication group. Curative resection rates were 96.6% and 91.5% in the indication and expanded-indication groups, respectively. In terms of the long-term outcomes, 20 of the 146 patients in the indication group, 15 of the 105 patients in the expanded-indication group and one of the 23 patients who underwent additional surgery in the out-of-indication group succumbed due to causes other than gastric cancer. Among the 26 patients who did not undergo additional surgery in the out-of-indication group, 10 mortalities occurred, including one due to gastric cancer. The five-year survival rates were not significantly different between the indication and expanded-indication groups. In the out-of-indication group, the five-year survival rate for the patients who did not undergo additional surgery (65.0%) was significantly lower than that for those who did undergo additional surgery (100%) (P<0.01). The five-year survival rate of patients aged >80 years (67.1%) was significantly lower than that of the younger patients (<60 years, 91.6%; sixties, 93.0%; seventies, 84.5%) (P<0.0001). In conclusion, although expanded-indication of ESD for EGC is appropriate, comor, Experimental and Therapeutic Medicine, 7(3), pp.594-598; 2014

Background: High-dose (4.0 g/day) mesalazine is typically used for induction therapy, but its efficacy as maintenance therapy remains to be determined. We conducted a multicenter retrospective study to investigate the efficacy of continuous treatment with 4.0 g/day of mesalazine. Material/Methods: Japanese ulcerative colitis (UC) patients receiving acute induction therapy with 4.0 g/day mesalazine were enrolled and followed. Those who clinically improved or who achieved clinical remission were categorized into 2 sub-groups according to the median duration of treatment with 4.0 g/day of mesalazine. The clinical relapse frequency and the time to relapse were analyzed. Results: We enrolled 180 patients with active UC, and then 115 patients who clinically improved or who achieved clinical remission after treatment with 4.0 g/day mesalazine were categorized into 2 sub-groups according to the median of treatment duration: a short-term treatment group (?105 days, n=58) and a long-term treatment group (>105 days, n=57). Overall, 45 (39.1%) patients relapsed: 28 (48.3%) in the short-term treatment group and 17 (29.8%) in the long-term treatment group. This difference was statistically significant (p<0.05). The relapse- free rate in the long-term treatment group was significantly higher than that in the short-term treatment group (p<0.05). The mean time to relapse in the long-term treatment group was significantly longer than that in the short-term treatment group (425.6±243.8 days vs. 277.4±224.5 days; p<0.05). Conclusions: Long-term continuous treatment with high-dose mesalazine (4.0 g/day) may be more effective than short-term treatment for maintenance of remission in UC patients., Medical Science Monitor, 20, pp.1314-1318; 2014

Background: Adipocytokines are associated with energy homeostasis and mediate various immune responses and inflammatory processes. Vaspin is a novel adipocytokine that is thought to exhibit anti-inflammatory effects. Aim: We aimed to evaluate serum vaspin levels in inflammatory bowel disease (IBD) and determine its possible associations with the course and to clarify its intestinal localization. Methods: Serum samples were obtained from patients with Crohn's disease (CD; n = 30) and ulcerative colitis (UC; n = 33) and from healthy volunteers (controls; n = 26). Enzyme-linked immunosorbent assays were performed for all patients. Vaspin immunohistochemical staining was performed for intestines affected with IBD. Results: Serum vaspin concentrations were significantly higher in patients with UC than in patients with CD and controls (422.9 ± 361.9 vs. 163.4 ± 116.2 vs. 147.5 ± 89.4 pg/mL, respectively; P < 0.01). There was no difference in the serum vaspin concentrations between the patients with CD and controls. There was also no difference in the serum vaspin concentrations between the patients with active IBD and those with inactive IBD. However, the serum vaspin concentrations of most patients with UC increased after remission induction. Vaspin was expressed in the adipocytes of the mesenteric adipose tissues but not in the epithelial or inflammatory cells of large intestines of the patients with IBD. Conclusions: Serum vaspin concentrations are elevated in patients with UC and increase further after remission induction, suggesting that vaspin may aid the auxiliary diagnosis of UC and may be useful for assessing disease activity in patients., Digestive Diseases and Sciences, 59(2), pp.315-321; 2014

Vacuolating cytotoxin A (VacA) is one of the important virulence factors produced by H. pylori. VacA induces apoptotic cell death, which is potentiated by ammonia. VacA also causes cell death by mitochondrial damage, via signaling pathways that are not fully defined. Our aim was to determine whether endoplasmic reticulum (ER) stress is associated with VacA-induced mitochondrial dysfunction and apoptosis. We found that C/EBP homologous protein (CHOP), a key signaling protein of ER stress-induced apoptosis, was transcriptionally up-regulated following incubation of gastric epithelial cells with VacA. The effect of VacA on CHOP induction was significantly enhanced by co-incubation with ammonium chloride. Phosphorylation of eukaryotic initiation factor 2 (eIF2)-alpha, which is known to occur downstream of the ER stress sensor PKR-like ERlocalized eIF2-alpha kinase (PERK) and to regulate CHOP expression, was also observed following incubation with VacA in the presence of ammonium chloride. Knockdown of CHOP by siRNA resulted in inhibition of VacA-induced apoptosis. Further studies showed that silencing of the PERK gene with siRNA attenuated VacA-mediated phosphorylation of eIF2-alpha, CHOP induction, expression of BH3-only protein Bim and Bax activation, and cell death induced by VacA with ammonium chloride, indicating that ER stress may lead to mitochondrial dysfunction during VacA-induced toxicity. Activation of ER stress and up-regulation of BH3-only proteins were also observed in human H. pylori-infected gastric mucosa. Collectively, this study reveals a possible association between VacA-induced apoptosis in gastric epithelial cells, and activation of ER stress in H. pylori-positive gastric mucosa., PLoS ONE, 8(12), e82322; 2013

Background: Per oral endoscopic myotomy (POEM) has been reported to be a new therapeutic option for esophageal achalasia. The possibility that POEM could reduce the risk of developing esophageal squamous cell carcinoma was evaluated.Methods: This was a single-centre, retrospective study. Fifteen consecutive patients with esophageal achalasia who underwent POEM in our institution between August 2010 and January 2012 were enrolled. Ultra-high magnification with endocytoscopy was performed, and both histopathological and immunohistochemical evaluations for Ki-67 and p53 were assessed before and 3 months after POEM.Results: POEM was successfully performed and effectively released the dysphagia symptom in all patients without severe complications. Subjective symptoms (mean Ekcardt score, before 7.4 vs. after 0.5, p<0.05) and manometric pressure studies (mean lower esophageal sphincter pressure), before 82.7 vs. after 22.9 mmHg, p<0.05) showed substantial improvement following POEM. The average numbers of esophageal epithelial nuclei before and after POEM on endocytoscopic images were 128.0 and 78.0, respectively (p<0.05). The mean Ki-67-positive ratio was 26.0 (median 25.4, range, 10.3-33.2) before and 20.7 (median 20.0, 13.1-29.9; p=0.07) after POEM, and the mean p53-positive ratio was 2.35 (median 2.61, 0.32-4.23) before and 0.97 (median 1.49, 0.32-1.56; p<0.05) after POEM. A significant positive correlation was seen between the number of nuclei and the Ki-67-positive ratio (p<0.05).Conclusions: POEM appears to be an effective and less invasive treatment of choice against achalasia and may reduce the risk of esophageal carcinogenesis. Endocytoscopy can be useful for the assessment of esophageal cellular proliferation., BMC Gastroenterology, 13(1), 22; 2013

A 37-year-old woman was evaluated at our hospital for a treatment-resistant proctosigmoiditis. Fifteen years previously, ulcerative colitis was suspected and she was cured by steroid therapy. Colonoscopy revealed multiple sessile polyps covered with white exudate from the rectum to the sigmoid colon. Histopathological examination revealed a mucosal surface cover of granulation tissue. Based on these findings, cap polyposis was diagnosed. She underwent Helicobacter pylori eradication therapy, and at 1 month after therapy, her symptoms had improved. We present a case of cap polyposis relapsing 15 years after remission with steroid therapy, and that was improved by H. pylori eradication therapy., Internal Medicine, 51(4), pp.435-439; 2012

Endoscopy, 43(2), pp.E26-E27; 2011

Endoscopy, 42(S2), pp.E320-E321; 2010