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Abstract Background Patients with chronic liver disease (CLD) frequently suffer from malnutrition and bone diseases, both of which heighten the risk of poor clinical outcomes. This study investigated the relationship between geriatric nutritional risk index (GNRI) and osteoporosis or fracture risk using the fracture risk assessment tool (FRAX) in patients with CLD. Methods This cross-sectional study included 209 consecutive patients with CLD. The participants were divided into two groups: the all-risk group (GNRI ≤ 98.0) with nutrition-related risk and the no-risk group (GNRI > 98.0) without nutrition-related risk. Osteoporosis was diagnosed according to the World Health Organization criteria. The FRAX was used to estimate the 10-year probabilities of hip fracture (FRAX-HF) and major osteoporotic fracture (FRAX-MOF). Results Of the 209 patients, 72 (34.4%) had osteoporosis. The all-risk group had a significantly higher prevalence of osteoporosis than the no-risk group (p

Background We aimed to develop a chemoimmunotherapy regimen consisting of a novel Wilms’ tumor 1 (WT1) peptide-pulsed dendritic cell (WT1-DC) vaccine and multiagent chemotherapy and to investigate the safety, clinical outcomes, and WT1-specific immune responses of patients with unresectable advanced pancreatic ductal adenocarcinoma (UR-PDAC) who received this treatment.Methods Patients with UR-PDAC with stage III disease (locally advanced (LA-PDAC; n=6)), stage IV disease (metastatic (M-PDAC; n=3)), or recurrent disease after surgery (n=1) were enrolled in this phase I study. The patients received one cycle of nab-paclitaxel plus gemcitabine alone followed by 15 doses of the WT1-DC vaccine independent of chemotherapy. The novel WT1 peptide cocktail was composed of a multifunctional helper peptide specific for major histocompatibility complex class II, human leukocyte antigen (HLA)-A*02:01, or HLA-A*02:06 and a killer peptide specific for HLA-A*24:02.Results The chemoimmunotherapy regimen was well tolerated. In the nine patients for whom a prognostic analysis was feasible, the clinical outcomes of long-term WT1 peptide-specific delayed-type hypersensitivity (WT1-DTH)-positive patients (n=4) were significantly superior to those of short-term WT1-DTH-positive patients (n=5). During chemoimmunotherapy, eight patients were deemed eligible for conversion surgery and underwent R0 resection (four patients with LA-PDAC, one patient with M-PDAC, and one recurrence) or R1 resection (one patient with M-PDAC), and one patient with LA-PDAC was determined to be unresectable. Long-term WT1-DTH positivity was observed in three of the four patients with R0-resected LA-PDAC. These three patients exhibited notable infiltration of T cells and programmed cell death protein-1+ cells within the pancreatic tumor microenvironment (TME). All patients with long-term WT1-DTH positivity were alive for at least 4.5 years after starting therapy. In patients with long-term WT1-DTH positivity, the percentage of WT1-specific circulating CD4+ or CD8+ T cells that produced IFN-γ or TNF-α was significantly greater than that in patients with short-term WT1-DTH positivity after two vaccinations. Moreover, after 12 vaccinations, the percentages of both circulating regulatory T cells and myeloid-derived suppressor cells were significantly lower in patients with long-term WT1-DTH-positive PDAC than in short-term WT1-DTH-positive patients.Conclusions Potent activation of WT1-specific immune responses through a combination chemoimmunotherapy regimen including the WT1-DC vaccine in patients with UR-PDAC may modulate the TME and enable conversion surgery, resulting in clinical benefits (Online supplemental file 1).Trial registration number jRCTc030190195.

Abstract Increasing number of patients with ulcerative colitis (UC) have received biologic treatment during the last decade. The association between endoscopic healing (EH) and biologic treatment failure remains understudied. Medical information of UC patients who started biologic treatment was retrospectively collected. EH was defined as Mayo endoscopic subscore of 0 or 1. Loss of response (LOR)-free drug continuation rate was compared between patients who achieved EH and those who did not using Kaplan–Meier estimator. Fifty-two patients received 53 biologic treatments and underwent follow-up colonoscopies within 2 years. Thirty-three patients achieved EH, all of which remained on the same treatment without LOR during the observational period. Twenty patients did not achieve EH, 8 of which ultimately discontinued the treatment due to LOR to biologic agents. Kaplan–Meier estimator found a significantly lower drug continuation rate in patients without EH (p

Abstract Liver cancer, particularly hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC), is more common in Asians than in Caucasians. This is due, at least in part, to regional differences in the prevalence of exogenous factors such as HBV; however, endogenous factors specific to Asia might also play a role. Such endogenous factors include HLA (human leukocyte antigen) genes, which are considered candidates due to their high racial diversity. Here, we performed a pancancer association analysis of 147 alleles of HLA-class I/II genes (HLA-A, B, and C/DRB1, DQA1, DQB1, DPA1, and DPB1) in 31,727 cases of 12 cancer types, including 1684 liver cancer cases and 107,103 controls. HLA alleles comprising a haplotype prevalent in Asia were significantly associated with pancancer risk (e.g., odds ratio [OR] for a DRB1*15:02 allele = 1.12, P = 2.7 × 10–15), and the associations were particularly strong in HBV-related HCC (OR 1.95, P = 2.8 × 10–5). In silico prediction suggested that the DRB1*15:02 molecule encoded by the haplotype does not bind efficiently to HBV-derived peptides. RNA sequencing indicated that HBV-related HCC in carriers of the haplotype shows low infiltration by NK cells. These results indicate that the Asian-prevalent HLA haplotype increases the risk of HBV-related liver cancer risk by attenuating immune activity against HBV infection, and by reducing NK cell infiltration into the tumor.

Abstract Background Thiopurines continue to play an important role in the treatment of inflammatory bowel disease (IBD). It is well known that thiopurines can cause several adverse reactions. Especially, hematopoietic toxicity may lead to severe agranulocytosis. In a previous prospective study, we investigated the relationship between inosine triphosphate pyrophosphatase (ITPA) c.94c > a polymorphism, 6-thioguanine nucleotide (6-TGN) concentration and toxicity. Methods To clarify the cause of thiopurine toxicity, we analysed nucleoside disphosphate-linked moiety X-type motif 15 (NUDT15) gene polymorphisms, i.e., R139C, V18I, and V19_V19insGV, and measured 6-mercaptopurines and 6-methylmercaptopurines (6-MMP) using the archived blood samples collected from 49 IBD patients for our previous study. Results The ITPA c.94c > a polymorphism was detected in 19 patients (38.7%, all heterozygous). The R139C polymorphism was found in 10 patients (20.4%, 1 homozygous, 9 heterozygous), V18_V19insGV in 7 patients (14.3%, all heterozygous), and V18I in 2 patients (4.08%, all heterozygous). Although R139C was more strongly associated with leukopenia than c.94c > a, there were no significant correlations with 6-TGN and 6-MMP levels, as for c.94c > a. The leukopenia incidence rates for each gene polymorphism were 0% in those with all wild-type genes, 21.4% for c.94c > a only, 42.9% for NUDT15 polymorphism (s) only, and 80.0% for both polymorphisms. Conclusions All cases of leukopenia were associated with ITPA c.94c > a and/or polymorphism of NUDT15 and the risk of developing leukopenia was synergistically increased by ITPA and NUDT15 gene polymorphism. However, there was no association between the level of azathioprine metabolites and these polymorphisms.

Abstract Prostaglandin E-major urinary metabolite (PGE-MUM) is a urinary biomarker reflecting ulcerative colitis (UC) activity. This prospective observational study aimed to evaluate the usefulness of PGE-MUM via rapid chemiluminescent enzyme immunoassay in detecting endoscopic remission (ER) and histologic remission (HR) in pediatric UC (6–16 years) in comparison with fecal calprotectin (FCP). ER and HR were defined as Mayo endoscopic score (MES) of 0 and Matts’ histological grades (Matts) of 1 or 2, respectively. A total of 104 UC and 39 functional gastrointestinal disorder (FGID) were analyzed. PGE-MUM levels were significantly higher in the UC group than in the FGID group (P

Abstract Background Osteosarcopenia, defined as the coexistence of sarcopenia and osteoporosis, is associated with adverse clinical outcomes. The present study investigated the prognostic significance of osteosarcopenia in patients with cirrhosis. Methods This retrospective study evaluated 126 patients with cirrhosis. Participants were classified into three groups based on the presence or absence of (1) sarcopenia and/or osteoporosis; and (2) Child–Pugh (CP) class B/C cirrhosis and/or osteosarcopenia, and the cumulative survival rates were compared between the groups. Cox proportional hazards model was used to identify independent factors associated with mortality. Sarcopenia and osteoporosis were diagnosed according to the Japan Society of Hepatology and the World Health Organization criteria, respectively. Results Among the 126 patients, 24 (19.0%) had osteosarcopenia. Multivariate analysis identified osteosarcopenia as a significant and independent prognostic factor. The cumulative survival rates were significantly lower in patients with osteosarcopenia than in those without (1/3/5-year survival rates = 95.8%/73.7%/68.0% vs. 100%/93.6%/86.5%, respectively; p = 0.020). Patients with osteosarcopenia, but not sarcopenia or osteoporosis alone, had significantly lower cumulative survival rates than those without both conditions (p = 0.019). Furthermore, patients with both CP class B/C and osteosarcopenia had significantly lower cumulative survival rates than those without both (p

Abstract Background and Aim Sarcopenia and severe vitamin D deficiency are associated with malnutrition and poor prognosis. We investigated the impact of the comorbidity of Child–Pugh (CP) class B/C cirrhosis and the aforementioned complications on the prognosis of patients with cirrhosis. Methods We retrospectively evaluated 104 patients with cirrhosis. The cumulative survival rates were compared between patients with and without both or either of these disease conditions: CP class B/C and complications (sarcopenia or severe vitamin D deficiency). Sarcopenia was diagnosed according to the Japan Society of Hepatology criteria. Severe vitamin D deficiency was defined as levels of 25‐hydroxyvitamin D

Abstract Patients with cirrhosis are at high risk for sarcopenia and malnutrition, which are associated with reduced quality of life and increased mortality. We investigated the relationship between the Geriatric Nutritional Risk Index (GNRI) and sarcopenia/gait speed and assessed the usefulness of the GNRI for predicting sarcopenia in patients with cirrhosis. We evaluated 202 patients with cirrhosis and divided them into three groups based on baseline GNRI values: low (L)-GNRI ( 109.5, n = 50). Sarcopenia was diagnosed according to the criteria of the Japan Society of Hepatology. The prevalence of sarcopenia and slow gait speed was the lowest in the H-GNRI group (8.0% and 26.0%, respectively) and the highest in the L-GNRI group (49.0% and 44.9%, respectively). They increased stepwise with a decline in the GNRI group (p

AimMalnutrition, which increases the risk of liver disease-related events and mortality, is a serious complication in cirrhosis. This study aimed to investigate whether the geriatric nutritional risk index (GNRI) could predict the long-term prognosis in patients with cirrhosis.MethodsWe retrospectively evaluated 266 patients with cirrhosis and classified them into two groups based on baseline GNRI scores: risk (≤98, n = 104) and no-risk groups (>98, n = 162). The cumulative survival rates were compared between the two groups in patients with compensated and decompensated cirrhosis, respectively. Cox proportional hazards regression analysis was used to identify significant and independent factors associated with mortality.ResultsThe median observation period was 54.9 (33.6–61.7) months and 65 (24.4%) liver disease-related deaths occurred during the follow-up period. The GNRI scores significantly and inversely correlated with Child-Pugh score (r = −0.579), model for end-stage liver disease score (r = −0.286), and Mac-2 binding protein glycosylation isomer (r = −0.494). Multivariate analysis identified low GNRI as a significant and independent factor associated with mortality [overall cohort: hazard ratio (HR), 0.926; p

Background and Aims: Japan has experienced 8 waves of the coronavirus disease 2019 (COVID-19) outbreak over the past 3 years, resulting in an increasing number of deaths and incidence of severe infections. This study aimed to analyze the data from the Japanese inflammatory bowel disease (IBD) patients with COVID-19 registry (J-COSMOS) up to the eighth wave to investigate the clinical course of IBD patients with COVID-19 and factors contributing to disease severity. Methods: In this multicenter, observational, cohort study, we analyzed a cohort of 1308 IBD patients diagnosed with COVID-19, enrolled across 77 participating facilities in the J-COSMOS registry from June 2020 to December 2022. Data on age, sex, IBD (classification, treatment, and activity), and COVID-19 (symptoms, severity, and treatment) were analyzed. Results: The majority of patients (76%) were in clinical remission. According to the World Health Organization classification of COVID-19 severity, 98.4% of IBD patients had nonsevere disease, while 1.6% of patients had severe or critical disease. COVID-19 did not affect disease activity in most IBD patients. Stepwise logistic regression analysis revealed that high body mass index, and cerebrovascular disease were risk factors for severe COVID-19. Corticosteroids could affect COVID-19 severity, whereas anti-tumor necrosis factor α antibodies and thiopurines were associated with a reduced risk of severe COVID-19. No deaths were observed among IBD patients with COVID-19 registered in this cohort. Conclusion: The impact of COVID-19 on IBD disease activity and factors associated with COVID-19 severity were consistent with findings of previous reports. No deaths in Japanese patients with IBD were observed.

Background/Aims The safety and efficacy of filgotinib, a once-daily oral Janus kinase 1 preferential inhibitor, were evaluated in Japanese patients with ulcerative colitis (UC) in the phase 2b/3 SELECTION trial. Methods SELECTION (NCT02914522) was a randomized, placebo-controlled trial comprising 2 induction studies and a maintenance study. Adults with moderately to severely active UC were randomized in induction study A (biologic-naïve) or B (biologic-experienced) to receive filgotinib 200 mg, 100 mg, or placebo once daily for 11 weeks. Patients in clinical remission or Mayo Clinic score response at week 10 entered the 47-week maintenance study. Efficacy and safety outcomes were assessed in Japanese patients enrolled in Japan. Results Overall, 37 and 72 Japanese patients were enrolled in Japan in induction studies A and B, respectively, and 54 entered the maintenance study. Numerically higher proportions of filgotinib 200 mg-treated than placebo-treated patients achieved clinical remission in induction study A (4/15 [26.7%] vs. 0/6 [0%]) and the maintenance study (5/20 [25.0%] vs. 0/9 [0%]), but not induction study B (1/29 [3.4%] vs. 1/14 [7.1%]). Both doses were well tolerated, and no new safety signals were noted. Herpes zoster was reported in 1 filgotinib 200 mg-treated patient in each of induction study A (2.3%, 1/44) and the maintenance study (5.0%, 1/20). Conclusions These data, alongside those of the overall SELECTION population, suggest the potential of filgotinib 200 mg as a viable treatment option for Japanese patients with UC. Owing to small patient numbers, data should be interpreted cautiously.

Backgrounds and Aims: Hepatocellular carcinoma (HCC) is the most common cancer with a poor prognosis. Identification of an alternative biomarker that can detect early-stage and conventional tumor marker-negative HCC is urgently needed. We found that protein kinase C delta (PKCδ) is specifically secreted from HCC cell lines into extracellular space and contributes to tumor development and that its serum levels were elevated in HCC patients. This study aimed to assess the practical usefulness of serum PKCδ for detecting HCC in chronic liver disease (CLD) patients. Methods: Serum PKCδ levels in 313 CLD patients with and without HCC (n = 187 and 126, respectively) were measured using a sandwich enzyme-linked immunosorbent assay. The diagnostic performance of PKCδ for HCC was evaluated using the receiver operating characteristic curve analysis and was compared with that of conventional markers, α-fetoprotein (AFP), and des-γ-carboxy prothrombin (DCP). Results: Serum PKCδ levels in HCC patients were significantly higher than those in CLD patients without HCC. PKCδ distinguished HCC patients from CLD patients without HCC, with high sensitivity and specificity. Subgroup analyses revealed that the diagnostic performance of PKCδ for HCC was comparable to that of AFP and DCP, and that approximately 40% of AFP/DCP double-negative HCC patients were positive for PKCδ. PKCδ yielded better diagnostic performance for detecting solitary small-sized (ie, very early stage) HCC than AFP and DCP. There was no significant correlation between serum PKCδ and AFP/DCP levels. Conclusion: Serum PKCδ is a novel HCC biomarker, which is independent of and complementary to conventional markers. Specifically, PKCδ may be useful for detecting very early-stage or AFP/DCP double-negative HCC.

Abstract Background and Aim Patients with gastroesophageal reflux disease (GERD) frequently also have functional dyspepsia (FD) symptoms, which impair their quality of life. However, the magnitude and characteristics of the effects of each symptom on daily life have been unclarified. Using multiple regression analysis, we aimed to clarify these questions. Methods We enrolled 290 patients from 29 institutions across Japan, in this prospective, observational study. Patients responded to three questionnaires (Gastroesophageal Reflux and Dyspepsia Therapeutic Efficacy and Satisfaction Test [GERD‐TEST], Hospital Anxiety and Depression Scale [HADS], and 8‐item Short‐Form Health Survey [SF‐8]) before and after 4 weeks of proton pump inhibitor treatment. Pearson correlation and multiple regression analyses were conducted between symptoms such as typical GERD, epigastric pain syndrome (EPS) and postprandial distress syndrome (PDS) of FD, and aspects of daily life, namely, level of satisfaction with the daily life of GERD‐TEST, anxiety and depression score of HADS, and physical and mental component summary of SF‐8. Results Pearson correlation analysis showed a significant correlation in all combinations between GERD/FD‐EPS/FD‐PDS symptoms and the nine aspects of daily life. However, multiple regression analysis results deviated from these results, with the most significant effects seen in the PDS‐symptom subscale (SS) on the five aspects of daily life, that is, dissatisfaction with eating, daily life‐SS, anxiety, depression, and mental component summary (MCS) whereas the significant effects in GERD‐SS on five aspects of daily life, that is, dissatisfaction for eating, anxiety, depression, physical component summary, and MCS, disappeared. Conclusion Dealing with co‐existing FD symptoms without overlooking them may be important in the management of GERD.

Background/Aims Endoscopic submucosal dissection (ESD) for residual or recurrent colorectal lesions after incomplete resection is challenging because of severe fibrosis. This study aimed to compare the efficacy of the pocket-creation method (PCM) with a traction device (TD) with that of conventional ESD for residual or recurrent colorectal lesions. Methods We retrospectively studied 72 patients with residual or recurrent colorectal lesions resected using ESD. Overall, 31 and 41 lesions were resected using PCM with TD and conventional ESD methods, respectively. We compared patient background and treatment outcomes between the PCM with TD and conventional ESD groups, respectively. The primary endpoints were en bloc resection and R0 resection rates. The secondary endpoints were the dissection speed and incidence of adverse events. Results En bloc resection was feasible in all cases with PCM with TD, but failed in 22% of cases of conventional ESD. The R0 resection rates for PCM with TD and conventional ESD were 97% and 66%, respectively. Dissection was significantly faster in the PCM with TD group (13.0 vs. 7.9 mm2/min). Perforation and postoperative bleeding were observed in one patient in each group. Conclusions PCM with TD is an effective method for treating residual or recurrent colorectal lesions after incomplete resection.

AimInsulin-like growth factor 1 (IGF-1), which is primarily produced in hepatocytes and is associated with liver functional reserve, plays a crucial role in the pathological condition of cirrhosis. This study aimed to investigate the usefulness of serum IGF-1 levels for predicting the long-term prognosis and decompensation development in patients with cirrhosis.MethodsWe retrospectively evaluated 148 patients with cirrhosis and divided them into three groups according to baseline IGF-1 levels: low (L)-, intermediate (I)-, and high (H)-IGF-1 groups. The cumulative survival rates were compared among these groups in compensated and decompensated cirrhosis, respectively. Significant and independent factors associated with mortality and decompensation development were identified using Cox proportional hazards regression analysis.ResultsThe median observation period was 57.1 (41.7–63.2) months. Thirty (20.3%) patients died of liver disease-related events and 21 (22.3%) patients with compensated cirrhosis developed decompensation. Multivariate analysis identified low serum IGF-1 levels as a significant and independent factor associated with mortality (all patients: hazard ratio [HR], 0.967; p = 0.004; patients with compensated cirrhosis: HR, 0.927; p = 0.002). The cumulative survival rates were significantly lower in the L-IGF-1 group than in the H-IGF-1 and I-IGF-1 groups (all patients: p

Background & Aims: Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide, and has a poor prognosis. However, the molecular mechanisms underlying hepatocarcinogenesis and progression remain unknown. In vitro gain- and loss-of-function analyses in cell lines and xenografts revealed that dual-specificity tyrosine-regulated kinase 2 (DYRK2) influences tumour growth in HCC. Methods: To investigate the role of Dyrk2 during hepatocarcinogenesis, we developed liver-specific Dyrk2 conditional knockout mice and an in vivo gene delivery system with a hydrodynamic tail vein injection and the Sleeping Beauty transposon. The antitumour effects of Dyrk2 gene transfer were investigated in a murine autologous carcinogenesis model. Results: Dyrk2 expression was reduced in tumours, and that its downregulation was induced before hepatocarcinogenesis. Dyrk2 gene transfer significantly suppressed carcinogenesis. It also suppresses Myc-induced de-differentiation and metabolic reprogramming, which favours proliferative, and malignant potential by altering gene profiles. Dyrk2 overexpression caused Myc and Hras degradation at the protein level rather than at the mRNA level, and this degradation mechanism was regulated by the proteasome. Immunohistochemical analyses revealed a negative correlation between DYRK2 expression and MYC and longer survival in patients with HCC with high-DYRK2 and low-MYC expressions. Conclusions: Dyrk2 protects the liver from carcinogenesis by promoting Myc and Hras degradation. Our findings would pave the way for a novel therapeutic approach using DYRK2 gene transfer. Impact and Implications: Hepatocellular carcinoma (HCC) is one of the most common cancers, with a poor prognosis. Hence, identifying molecules that can become promising targets for therapies is essential to improve mortality. No studies have clarified the association between DYRK2 and carcinogenesis, although DYRK2 is involved in tumour growth in various cancer cells. This is the first study to show that Dyrk2 expression decreases during hepatocarcinogenesis and that Dyrk2 gene transfer is an attractive approach with tumour suppressive activity against HCC by suppressing Myc-mediated de-differentiation and metabolic reprogramming that favours proliferative and malignant potential via Myc and Hras degradation.

Abstract Background and Aim Radiofrequency ablation (RFA) therapy is frequently used as first‐line treatment for small hepatocellular carcinoma (HCC). RFA is often associated with pain; however, no definitive solution has been established for its relief. We retrospectively analyzed the safety and efficacy of the combination of pentazocine and midazolam to relieve pain experienced by HCC patients undergoing RFA. Methods We studied 77 patients with 98 HCCs treated with RFA between January 2015 and August 2019. Patients were divided into two groups: the sedative‐free group, which included those who received pentazocine alone, and the pentazocine–midazolam group, which included those who received a combination of pentazocine and midazolam. The degrees of analgesia and sedation were evaluated using the numerical rating scale (NRS) and the Richmond Agitation‐Sedation Scale (RASS), respectively. Other parameters such as treatment time, awakening time, midazolam dosage, vital signs, local recurrence rate, and time to recurrence were also examined. Results The median NRS score and RASS score were significantly lower in the pentazocine–midazolam group. Ninety‐five percent of patients in the pentazocine–midazolam group had no memory of the RFA session. The treatment time and awakening time were prolonged for the pentazocine–midazolam group. No significant differences in oxygen saturation, recurrence rates, and time to local recurrence were observed between groups. Conclusion A combination of pentazocine and midazolam is safe and effective for pain and anxiety relief experienced by patients undergoing RFA for local treatment of HCC.

Abstract Introduction Patients with ulcerative colitis (UC) are known to have a significantly poor quality of life due to bowel frequency (night) and urgent defecation. Budesonide foam is a topical medication that was approved in Japan in 2017 for the treatment of UC. However, its efficacy in the treatment of bowel frequency (night) or urgent defecation is unknown. This study aimed to explore the efficacy of budesonide foam for the alleviation of these symptoms. Methods UC patients who received budesonide foam between December 2017 and January 2020 at the Jikei University School of Medicine in Tokyo were enrolled. The simple clinical colitis activity index (SCCAI) was evaluated at the start of budesonide foam treatment and 2 and 6 weeks later in patients who initially scored ≥ 1 for bowel frequency (night) and urgent defecation, respectively. We also studied the effect of budesonide foam on remaining symptoms in patients who had used 5-aminosalicylic acid (5-ASA) topical treatment, those with SCCAI ≥ 3, and those in remission with residual symptoms (SCCAI 1 or 2). Results Of the 233 enrolled patients, 102 were eligible for the study. In 36 patients with bowel frequency (night) treated with budesonide foam were significantly effective, score in SCCAI decreased from 1.17 ± 0.45 at baseline to 0.53 ± 0.61 at week 2 (p

Abstract Fusobacteria have been suspected to be pathobionts of colon cancer and inflammatory bowel disease. However, the immunomodulatory properties that affect these inflammatory reactions in dendritic cells (DCs) under anaerobic and aerobic conditions have not yet been characterized. We directly assessed the stimulatory effects of anaerobic commensal bacteria, including fusobacteria, on a human DC line through coculture under aerobic or anaerobic conditions. Under aerobic or anaerobic conditions, stimulation of the DC line with all live commensal bacteria examined, except the probiotic Lactobacillus delbrueckii subsp. bulgaricus (L. bulgaricus), significantly increased the geometric mean fluorescent intensity (MFI) of marker proteins (HLA-ABC, HLA-DR, CD80, CD86, CD83, or CCR7) on the DC surface. In particular, both Fusobacterium nucleatum (F. nucleatum) and Escherichia coli (E. coli) significantly increased the expression of DC-associated molecules, except for CD83 under both aerobic and anaerobic conditions. The DC line stimulated with Fusobacterium varium (F. varium) significantly increased only CD80, HLA-ABC, and HLA-DR expression under anaerobic conditions. Moreover, differences in the levels of proinflammatory cytokines, such as IL-6, IL-8, and TNF-α, were detected in the DC line stimulated by all live commensal bacteria under either aerobic or anaerobic conditions. Under aerobic conditions, the DC line stimulated with E. coli produced significantly more IL-6, IL-8, and TNF-α than did the cells stimulated with any of the bacteria examined. When E. coli were used to stimulate the DC line under anaerobic conditions, TNF-α was predominantly produced compared to stimulation with any other bacteria. Compared to the DC line stimulated with any other bacteria, the cells stimulated with F. nucleatum showed significantly increased production of IL-6, IL-8 and TNF-α only under anaerobic conditions. In particular, E. coli, F. nucleatum, and F. varium strongly stimulated the DC line, resulting in significantly increased expression of surface molecules associated with DCs and production of inflammatory cytokines.

Abstract Objectives Selection criteria for self‐expandable metal stents (SEMSs) with or without cover during palliative treatment of distal malignant biliary obstruction (DMBO) remain unclear. We evaluated factors associated with time to recurrent biliary obstruction (TRBO) in fully covered SEMSs (FCSEMSs) and uncovered SEMSs (UCSEMSs). Methods We retrospectively analyzed consecutive patients with DMBO who received a SEMS. TRBO was determined using the Kaplan–Meier analysis, and complications were compared between the FCSEMS and UCSEMS groups. After TRBO‐associated factors were extracted using multivariate competing‐risks regression (CRR), propensity score‐adjusted CRRs were performed to verify their robustness. Results There were 180 patients (66 FCSEMSs and 114 UCSEMSs) enrolled in this study. There was no significant difference between median TRBO in the FCSEMS and UCSEMS groups (275 vs. 255 days, p = 0.67). Complications were more frequent in the FCSEMS than UCSEMS group (21.2% vs. 8.8%; p = 0.023). Multivariate CRR for TRBO‐associated factors revealed that “pancreatic ductal carcinoma (PDAC) treated with UCSEMS” was the only independent predictor of TRBO (p = 0.03). Similarly, the propensity score‐adjusted CRRs showed no significant difference in TRBO in “FCSEMS” vs “UCSEMS” (p = 0.96); however, there was a significant difference in “PDAC using UCSEMS” vs “other” (p = 0.043). In the palliative care group including any DMBO without chemotherapy, the first quartile of the TRBO of UCSEMS was 100 days. Conclusions UCSEMSs are a possible option for both patients with DMBO arising from PDAC and for patients with any DMBO receiving palliative care who should avoid SEMS‐related complications.

Neuroendocrine neoplasms are rare epithelial neoplasms with neuroendocrine differentiation. Few cases of primary testicular poorly differentiated neuroendocrine carcinomas (PD-NECs) have been reported, and secondary testicular neoplasms are rare. A 61-year-old man with a chief complaint of left testicular swelling was referred to our hospital. An orchiectomy was performed in order to determine the pathological diagnosis. Pathological examination showed diffuse sheets of highly atypical cells that were positive for neuroendocrine markers and a Ki-67 proliferation index of 80%. The patient was diagnosed with poorly differentiated small-cell NEC. Contrast-enhanced computed tomography revealed multiple metastases to the pancreas, adrenal glands, and lymph nodes. Esophagogastroduodenoscopy showed multiple gastric metastases, and biopsy revealed the same histological findings as observed for the testicular tumor. Contrast-enhanced magnetic resonance imaging of the head also revealed multiple brain metastases. The confirmed diagnosis was PD-NEC of unknown primary with metastases to the testis, stomach, pancreas, adrenal glands, brain, and lymph nodes. We started the first-line chemotherapy with etoposide and cisplatin. Stereotactic radiotherapy for the brain metastases was administered between the first and second cycles. After five cycles, a partial response was observed; however, disease progression was observed after seven cycles with recurrence of the brain metastases and enlargement of all tumors. To our knowledge, this is the first report of an unknown primary PD-NEC with metastasis to the testis.

Abstract Background Taking advantage of the current advances in diagnostic imaging modalities, including endoscopic ultrasonography (EUS), and due to the increased attention to ectopic fat accumulation in the pancreas following the rising trend of metabolic syndrome, we qualitatively assessed the clinical implication of pancreatic steatosis by EUS in this study. Methods The study included 243 patients that were divided into four groups. The correlation between the average echogenicity of the pancreas and that of the control organs and the key clinical data of all study patients were collectively analyzed. The cut‐off point of the pancreas‐control (PC) ratio in EUS and liver‐control (LC) ratio on abdominal ultrasound were determined from the population distribution and the obtained median values. Results With the cut‐off point of 1.30 for the PC ratio and 1.20 for the LC ratio, sex, the Brinkman index, habitual alcohol drinkers, and fatty pancreas were significant factors. The associations between each relevant factor in fatty pancreas, metabolic syndrome in the fatty liver group, and age in the pancreatic cancer group were all significant in the analysis. In addition, we investigated whether the PC ratio differed according to age and staging in pancreatic cancer patients. Interestingly, the PC ratio was lower in the advanced stage group than in the early‐stage group. Conclusion Our results suggest that, irrespective of the degree, ectopic fat infiltration in the pancreas could be a specific clinical phenotype of serious pancreatic diseases, including pancreatic cancer, especially in high‐risk patients.

Ulcerative colitis (UC) is an intractable disorder characterized by a chronic inflammation of the colon. Studies have identified UC as a multifactorial disorder affected by both genetic and environmental factors; however, the precise mechanism remains unclear. Recent advances in the field of microRNA (miRNA) research have identified an association between this small non-coding RNA in the pathophysiology of UC and altered miRNA expression profiles in patients with UC. Nevertheless, the roles of individual miRNAs are uncertain due to heterogeneity in both research samples and clinical backgrounds. In this review, we focus on miRNA expression in colonic mucosa where inflammation occurs in UC and discuss the potential roles of individual miRNAs in disease development, outlining the pathophysiology of UC.

Abstract Background Both activated tumor-infiltrating lymphocytes (TILs) and immune-suppressive cells, such as regulatory T cells (Tregs), in the tumor microenvironment (TME) play an important role in the prognosis of patients with pancreatic ductal adenocarcinoma (PDAC). Methods The densities of TILs, programmed death receptor 1 (PD-1) + T cells, and forkhead box P3 (Foxp3) + T cells were analyzed by immunohistochemical staining. The associations of the immunological status of the PDAC microenvironment with overall survival (OS) time and disease-free survival (DFS) time were evaluated. Results PDAC patients with a high density of TILs in the TME or PD-1-positive T cells in tertiary lymphoid aggregates (TLAs) demonstrated a significantly better prognosis than those with a low density of TILs or PD-1-negativity, respectively. Moreover, PDAC patients with high levels of Foxp3-expressing T cells showed a worse prognosis than those with low levels of Foxp3-expressing T cells. Importantly, even with a high density of the TILs in TME or PD-1-positive T cells in TLAs, PDAC patients with high levels of Foxp3-expressing T cells showed a worse prognosis than patients with low levels of Foxp3-expressing T cells. A PDAC TME with a high density of TILs/high PD-1 positivity/low Foxp3 expression was an independent predictive marker associated with superior prognosis. Conclusion Combined assessment of TILs, PD-1+ cells, and Foxp3+ T cells in the TME may predict the prognosis of PDAC patients following surgical resection.

Abstract Background and Aim Fine‐needle biopsy (FNB) needles obtain more core samples and support the shift from cytologic to histologic evaluation; however, recent studies have proposed a superior diagnostic potential for liquid‐based cytology (LBC). This study compared the diagnostic ability of endoscopic ultrasound (EUS)‐guided FNB histology with a 22‐gauge Franseen needle (22G‐FNB‐H) and fine‐needle aspiration (FNA) LBC with a conventional 25‐gauge needle (25G‐FNA‐LBC). Methods We analyzed 46 patients who underwent both 22G‐FNB‐H and 25G‐FNA‐LBC in the same lesion during the same endoscopic procedure. This study evaluated the diagnostic ability of each needle, diagnostic concordance between needles, and incremental diagnostic effect of both needles compared to using each needle alone. Results The agreement rate for malignancy between both techniques was 93.5% (kappa value = 0.82). There was no significant difference in the diagnostic ability of both methods. 22G‐FNB‐H and 25G‐FNA‐LBC provided an incremental diagnostic accuracy in two (4.3%) cases and one (2.2%) case, respectively. Conclusion Our study demonstrated that the diagnostic accuracy of 25G‐FNA‐LBC and 22G‐FNA‐H for solid pancreatic lesions were comparable. A conventional 25‐gauge needle that punctures lesions with ease can be used in difficult cases and according to the skill of the endoscopist.

Abstract Background and Aim Sarcopenia frequently develops in patient with liver cirrhosis (LC). Ethanol reduces muscle protein synthesis and accelerates proteolysis. However, the relationship between heavy alcohol consumption and sarcopenia remains controversial. This study aimed to investigate the characteristics and prevalence of sarcopenia among patients with alcoholic LC (ALC) in real‐world clinical settings. Methods This cross‐sectional study included 181 patients with LC. Heavy alcohol consumption was defined as >60 g/day. Sarcopenia was diagnosed according to the Japan Society of Hepatology criteria. Results Among the 181 patients, 64 (35.4%) were diagnosed with ALC. Patients with ALC were younger (median, 61.5 vs 72.0 years; P

Objective MicroRNAs (miRNAs) are implicated in the pathogenesis of autoimmune diseases and could be biomarkers of disease activity. This study aimed to identify highly expressed circulating miRNAs in patients with autoimmune hepatitis (AIH) and to evaluate their association with clinical characteristics.Methods Microarray analyses were performed, and miRNA expression profiling for AIH, primary biliary cholangitis (PBC) and overlap syndrome (OS) using the serum of patients and healthy individuals was done. Samples were divided into discovery and test sets to identify candidate miRNAs that could discriminate AIH from PBC; the former included 21 AIH and 23 PBC samples, while the latter included five AIH and eight PBC samples.Results Among 11 candidate miRNAs extracted in the discovery set, 4 (miR-3196, miR-6125, miR-4725–3 p and miR-4634) were specifically and highly expressed in patients with AIH in the test set. These four miRNAs discriminated AIH from PBC with high sensitivity (0.80–1.00) and specificity (0.88–1.00). In situ hybridisation analysis revealed that these miRNAs were expressed in the cytoplasm of hepatocytes in patients with AIH. Their expression levels were highest in untreated patients with AIH, followed by those in untreated patients with OS. They drastically or moderately decreased after prednisolone treatment. Histological analysis demonstrated that the expression levels of miR-3196, miR-6125 and miR-4634 in patients with AIH and OS were correlated with severe hepatic necroinflammatory activity.Conclusion These circulating miRNAs are suggested to reflect hepatic necroinflammatory activity and serve as AIH-related and treatment-responsive biomarkers. These miRNAs could be beneficial in developing new therapeutic strategies for AIH.

Abstract Introduction Pericardial effusion is a rare complication of pancreatic cancer. We report a case of cardiac tamponade secondary to pancreatic cancer. Case presentation A 68-year-old Japanese man was diagnosed as having pancreatic cancer during surgery and received chemotherapy for 28 months after the diagnosis. He was admitted to the emergency room with severe dyspnea. Echocardiography revealed pericardial effusion with severe hypofunction. Emergency pericardial drainage was performed to maintain hemodynamics, which resulted in the elimination of 450 mL of blood and the maintenance of circulatory dynamics. Cytological examination of the pericardial fluid revealed atypical cells and tumor cells suggesting adenocarcinoma. Conclusions To our knowledge, pancreatic cancer complicated with cancerous pericarditis has not been previously documented. This case highlights the extreme severity of pericardial effusion, a sign of progressive disease, secondary to pancreatic cancer. In the case of neoplastic pericardial effusion, an extremely poor prognosis must be considered.

Background/Aims PF-00547659 is a monoclonal antibody against human mucosal addressin cell adhesion molecule-1 (MAdCAM-1) that prevents the binding of α4β7+ lymphocytes to MAdCAM-expressing sites in the gastrointestinal tract with high affinity and selectivity, and is being developed for the treatment of Crohn’s disease (CD). Methods OPERA is a randomized, multicenter, double-blind, placebo-controlled study to investigate the efficacy, safety, and pharmacokinetics of PF-00547659 following subcutaneous administration in subjects with active CD, a history of failure or intolerance to anti-tumor necrosis factor and/or immunosuppressants, high-sensitivity C-reactive protein > 3.0 mg/L, and ulcers on colonoscopy. The primary endpoint was Crohn’s Disease Activity Index-70 response at week 8 or 12. Subpopulation analyses for Asian subjects were performed as some differences are observed in genetics and clinical phenotypes in Asian CD patients compared with Western patients. Results In this study, 265 CD subjects were randomized, with a subpopulation of 21 subjects (8 Japanese and 13 Korean) defined as the Asian population. In the overall and Asian populations; PF-00547659 was pharmacologically active as evidenced by soluble MAdCAM and circulating β7+ central memory CD4+ T-lymphocytes, although no clear evidence of efficacy was observed in any clinical endpoints; pharmacokinetics of PF-00547659 in the Asian subpopulation was generally comparable to the overall population; and the safety profile of PF-00547659 appeared acceptable up to 12 weeks of treatment. Conclusions In the overall and Asian populations, efficacy of PF-00547659 could not be demonstrated using any clinical endpoints compared with placebo. Pharmacokinetics and safety of PF-00547659 were generally comparable. Further studies with larger numbers of patients are required to confirm our results. (Trial Registration Number: NCT01276509)

Abstract Background Sarcopenia and osteoporosis reduce life quality and worsen prognosis in patients with liver cirrhosis (LC). When these two complications coexist, a diagnosis of osteosarcopenia is made. We aimed to investigate the actual situations of sarcopenia, osteoporosis, osteosarcopenia, and vertebral fracture, and to clarify the relationship among these events in patients with LC. Methods We describe a cross-sectional study of 142 patients with LC. Sarcopenia was defined according to the Japan Society of Hepatology (JSH) criteria, Asian Working Group for Sarcopenia (AWGS) criteria, and European Working Group on Sarcopenia in Older People (EWGSOP2) criteria. The skeletal muscle mass index (SMI) and handgrip strength were assessed using bioelectrical impedance analysis and a digital grip strength dynamometer, respectively. Bone mineral density (BMD) was measured using dual energy X-ray absorptiometry, and vertebral fracture was evaluated using spinal lateral X-rays. The severity of LC was assessed using the Child-Pugh classification. Results Among the 142 patients, the prevalence of sarcopenia was 33.8% (48/142) according to the JSH and AWGS criteria and 28.2% (40/142) according to the EWGSOP2 criteria. The number of patients with osteoporosis, osteosarcopenia, and vertebral fracture was 49 (34.5%), 31 (21.8%), and 41 (28.9%), respectively. Multivariate analysis revealed a close association between sarcopenia and osteoporosis. Osteoporosis was independently associated with sarcopenia [odds ratio (OR) = 3.923, P = 0.010]. Conversely, sarcopenia was independently associated with osteoporosis (OR = 5.722, P

Abstract Photoimmunotherapy (PIT) is a new type of tumor‐specific treatment utilizing monoclonal antibody (mAb)‐photosensitizer conjugates and near‐infrared (NIR) light irradiation. One potential PIT target, the type I transmembrane protein TROP2, is expressed at high levels in many cancers, including pancreatic carcinoma (PC) and cholangiocarcinoma (CC), in which its expression is correlated with poor prognosis and tumor aggressiveness. In this study, we assessed the efficacy of PIT utilizing newly developed humanized anti‐TROP2 mAb conjugated to the photosensitizer IR700 (TROP2‐IR700) for PC and CC. Immunohistochemistry on PC and CC tissue microarrays confirmed that TROP2 is overexpressed in about half of PC and CC specimens. Using cultured PC and CC cells, TROP2‐IR700 localized TROP2‐specific and target‐specific cell killing was observed after NIR light irradiation. In addition, TROP2‐IR700 was localized to mouse xenograft tumors expressing TROP2 after intravenous injection. PC and CC xenograft tumor growth was significantly inhibited by TROP2‐targeted PIT relative to controls. The efficacy of TROP2‐targeted PIT in vitro and against xenografted tumors in vivo suggests promise as a therapy for human PC and CC, both of which currently have dismal prognoses and limited therapeutic options.

Cystic artery pseudoaneurysm (CAP) is a rare disease, with small number of previous reports related to CAP. Besides, it is frequently prone to critical condition due to arterial bleeding. Here, we presented a case of ruptured CAP with acute calculus cholecystitis and its subsequent successful management with temporary endoscopic biliary drainage for obstructive jaundice and embolization for the culprit artery without cholecystectomy. Since CAP is at high risk of bleeding, intravascular treatment, which is only one currently available therapeutic option, is urgently required in the clinical sites.

Insulin-like growth factor 1 (IGF-1) plays an important role in bone growth and maintenance, and its decreased levels are associated with bone disorders. This study aimed to evaluate the association of serum IGF-1 levels with osteoporosis, prevalent fractures and fracture risk based on the Fracture Risk Assessment Tool (FRAX) in patients with primary biliary cholangitis (PBC). This study included 127 consecutive patients with PBC. Based on the baseline serum IGF-1 levels, the participants were classified into the low (L)-, intermediate (I)- and high (H)-IGF-1 groups. According to the FRAX score, high fracture risk was defined as a 10-year major osteoporotic fracture probability (FRAX-MOF) ≥ 20% or a 10-year hip fracture probability (FRAX-HF) ≥ 3%. The serum IGF-1 levels were positively correlated with bone mineral density, and were negatively correlated with the FRAX-MOF/FRAX-HF. The L-IGF-1 group had the highest prevalence of osteoporosis (58.1%), prevalent fracture (48.4%) and high fracture risk (71.0%). Meanwhile, the H-IGF-1 group had the lowest prevalence of osteoporosis (9.7%), prevalent fracture (12.9%) and high fracture risk (9.7%). The prevalence of these events increased stepwise with decreasing serum IGF-1 levels. The cutoff values of IGF-1 for predicting osteoporosis, prevalent fracture and high fracture risk were 61.5 ng/mL (sensitivity/specificity, 0.545/0.894), 69.5 ng/mL (0.633/0.784) and 61.5 ng/mL (0.512/0.929), respectively. Serum IGF-1 levels were associated with bone disorders and the FRAX-derived fracture risk, and may be a useful indicator for initiating therapeutic intervention to prevent the incidence of fracture in patients with PBC.

AimOsteoporotic fractures negatively impact health-related quality of life and prognosis. Advanced glycation end products (AGEs) impair bone quality and reduce bone strength. The aim of this study was to determine the relationship between plasma levels of pentosidine, a surrogate marker for AGEs, and prevalent fractures in patients with chronic liver disease (CLD).MethodsThis cross-sectional study included 324 patients with CLD. Vertebral fractures were evaluated using lateral thoracolumbar spine radiographs. Information on prevalent fractures was obtained through a medical interview, medical records, and/or radiography. The patients were classified into low (L), intermediate (I), and high (H) pentosidine (Pen) groups based on baseline plasma pentosidine levels.ResultsOf the 324 patients, 105 (32.4%) had prevalent fractures. The prevalence of liver cirrhosis (LC) and prevalent fractures significantly increased stepwise with elevated pentosidine levels. The H-Pen group had the highest prevalence of LC (88.6%, p < 0.001) and prevalent fractures (44.3%, p = 0.007), whereas the L-Pen group had the lowest prevalence of LC (32.1%, p < 0.001) and prevalent fractures (21.0%, p = 0.007). Multiple logistic regression analysis identified pentosidine as a significant independent factor related to prevalent fractures (odds ratio = 1.069, p < 0.001). Pentosidine levels increased stepwise and correlated with liver disease severity. They were markedly high in patients with decompensated LC. In multiple regression analysis, liver functional reserve factors (total bilirubin, albumin, and prothrombin time-international normalized ratio) significantly and independently correlated with pentosidine levels.ConclusionsPlasma pentosidine was significantly associated with prevalent fractures and liver functional reserve in patients with CLD. Pentosidine may be useful in predicting fracture risk and should be closely followed in CLD patients with advanced disease.

BackgroundIn clinical practice, the same chemotherapeutic agents are occasionally reused (re-challenge) after failure of all available standard chemotherapy options for metastatic colorectal cancer (mCRC). However, the benefits of re-challenge chemotherapy (Re-Cx) are unclear. This retrospective study evaluated the efficacy of Re-Cx, focusing on the tumor growth rate (TGR).MethodsThe study included mCRC patients with measurable lesions who received Re-Cx from November 2011 to October 2018 at National Cancer Center Hospital. Re-Cx was defined as re-administration of agents which had been used in prior lines of chemotherapy and discontinued due to disease progression. We compared the TGR immediately after initiating Re-Cx regimens with that observed at the time of disease progression during prior chemotherapy (Prior-Cx) immediately before Re-Cx.ResultsOf the 25 patients who received Re-Cx, five patients received two Re-Cx regimens. Therefore, a total of 30 cases of Re-Cx were analyzed in this study. The regimens of Re-Cx were oxaliplatin based (19 cases), irinotecan based (8 cases), and others (3 cases). Although the objective response rate to Re-Cx was 0%, the disease control rate was 60% (18 cases), and 40% (12 cases) showed some tumor shrinkage. We compared the effects of Re-Cx and Prior-Cx by the TGR and found that the TGR of Re-Cx was slower than that recorded in Prior-Cx in 26 of 30 cases (87%). In particular, the ratio of% TGR ConclusionWe found that Re-Cx may have some anti-tumor efficacy as salvage treatment for mCRC and these results also suggested the clinical benefits of Re-Cx.

Introduction: Inflammatory bowel disease (IBD) is characterized by chronic inflammation of the intestinal tract. Known types are Crohn’s disease (CD) and ulcerative colitis (UC), but their cause remains unclear and there is no convenient biomarker for IBD. The present study aimed to demonstrate an association between the onset of CD and activating transcription factor 3 (ATF3); as a new biomarker, measurement of blood ATF3 mRNA would be useful for distinguishing between CD and UC. Methods: First, in a mouse model of IBD in which damage to the intestinal mucosa was chemically induced with dextran sulfate sodium (DSS), intestinal ATF3 mRNA was evaluated. Next, in human subjects, CD and UC patients, blood ATF3 mRNA and intestinal ATF3 protein production were evaluated. Results: In the mouse model of IBD, intestinal ATF3 mRNA was elevated compared with the control ( P

The incidence of metabolic syndrome with fatty liver is spreading on a worldwide scale. Correspondingly, the number of patients with the hepatic phenotype of metabolic syndrome, non-alcoholic fatty liver disease (NAFLD), and in its advanced states, non-alcoholic steatohepatitis (NASH), and the subsequent hepatocellular carcinoma (HCC) derived from NASH (NASH-HCC) is increasing remarkably. A large-scale epidemiological study revealed that obesity can be a risk factor of such cancers as HCC. Moreover, despite the ongoing trends of declining cancer incidence and mortality for most cancer types, HCC has experienced a markedly increased rate of both. Considering the differences in liver-related mortality among NAFLD patients, NASH, and NASH-HCC should be included in the objectives of initiatives to manage NAFLD patients and their progression to the advanced stages. Unfortunately, research has yet to make a crucial drug discovery for the effective treatment of NASH and NASH-HCC, although it is urgently needed. The latest widespread concept of the “multiple parallel hits hypothesis,” whereby multiple factors contribute concurrently to disease pathogenesis has led to advances in the elucidation of hepatic and systemic molecular mechanisms driving NASH and the subsequent NASH-HCC progression; the results are not only extensive but promising for therapeutics. Here, we have summarized the myriad landmark discoveries of recent research into the pathogenic processes underlying NASH-HCC development and with the greatest possibility for a new generation of pharmaceutical products for interference and treatment.

Background and study aims Colorectal endoscopic submucosal dissection (ESD) is technically challenging owing to submucosal fibrosis and difficult endoscope manipulation. Therefore, various traction methods have been reported. We often use a simple looped nylon thread attached to a clip to assist with dissection. We assessed the feasibility of mentor-guided colorectal ESD using this traction device (TD). Patients and methods From December 2017 to March 2018, we retrospectively reviewed outcomes of 101 colorectal ESDs performed by two groups of endoscopists (A, 5 endoscopists with colorectal ESD experience of 300 cases). Group A was further divided into two subgroups that performed ESD with or without TD. Results No significant difference was observed in ESD completion rates (86.1 % [62/72] vs. 96.6 % [28/29]; odds ratio [OR], 0.22; 95 % confidence interval [CI], 0.005 – 1.71; P = 0.17) or procedure times (52.0 min vs. 40.0 min; P = 0.27) and adverse event rates between groups A and B. The rate of TD use was significantly higher in group A than in group B (44.4 % [32/72] vs. 20.7 % [6/29]; OR, 3.03; CI, 1.04 – 10.23; P = 0.03). The completion rate was not different between the two subgroups of group A (with vs. without TD) (81.2 % [26/32] vs. 90.0 % [36/40]; OR, 0.49; CI, 0.09 – 2.29; P = 0.32); however, the proportion of fibrosis cases was significantly higher in the TD-use group (46.8 % [15/32] vs. 22.5 % [9/40]; OR, 2.99; CI, 0.98 – 9.59; P = 0.03). Conclusion Mentor-guided colorectal ESD using TD was performed efficiently, safely, and in a manner comparable to that of experts.

Transforming growth factor-β (TGF-β) is a key driver for liver fibrogenesis. TGF-β must be activated in order to function. Plasma kallikrein (PLK) is a TGF-β activator that cleaves the latency-associated protein (LAP) between arginine58 and lysine59 residues and releases active TGF-β from the latent TGF-β-LAP complex. Thus, the generation of two LAP degradation products, ending at arginine58 (R58/LAP-DPs) and beginning from lysine59 (L59/LAP-DPs), reflects PLK-dependent TGF-β activation. However, the significance and details of TGF-β activation in patients with chronic liver disease (CLD) remain uncertain. We herein examined the PLK-dependent TGF-β activation in patients by detecting R58 and L59/LAP-DPs. A total of 234 patients with CLD were included in this study. Liver biopsy specimens were used for immunostaining to detect R58/LAP-DPs, while plasma samples were subjected to an enzyme-linked immunosorbent assay to measure the L59/LAP-DP concentration. R58/LAP-DP was robustly expressed in and around the sinusoidal cells before the development of the fibrous regions. The R58/LAP-DP expression at fibrosis stage 1 was higher than at any other stages, and the relationship between the plasma L59/LAP-DP level and the stage of fibrosis also showed a similar trend. The abundance of plasma L59/LAP-DP showed no correlation with the levels of direct serum biomarkers of liver fibrosis; however, its changes during interferon-based therapy for chronic hepatitis C were significantly associated with virological responses. Our results suggest that PLK-dependent TGF-β activation occurs in the early stages of fibrosis and that its unique surrogate markers, R58 and L59/LAP-DPs, are useful for monitoring the clinical course of CLD.

Recent studies have suggested an association between certain members of the Fusobacterium genus, especially F. nucleatum, and the progression of advanced colorectal carcinoma (CRC). We assessed such an association of the gut microbiota in Japanese patients with colorectal adenoma (CRA) or intramucosal CRC using colonoscopy aspirates. We analyzed samples from 81 Japanese patients, including 47 CRA and 24 intramucosal CRC patients, and 10 healthy subjects. Metagenomic analysis of the V3-V4 region of the 16S ribosomal RNA gene was performed. The linear discriminant analysis (LDA) effect size (LEfSe) method was used to examine microbial dysbiosis, revealing significant differences in bacterial abundances between the healthy controls and CRA or intramucosal CRC patients. In particular, F. varium was statistically more abundant in patients with CRA and intramucosal CRC than in healthy subjects. Here, we present the metagenomic profile of CRA and intramucosal CRC and demonstrate that F. varium is at least partially involved in the pathogenesis of CRA and intramucosal CRC.

Background: Recent advances in endoscopic devices such as small bowel capsule endoscopy and balloon-assisted endoscopy have improved the level of medical care for small bowel bleeding. However, treating small bowel angioectasia remains challenging because repeated intermittent bleeding can occur from the multiple minute lesions (about 1 mm in size) that develop in a synchronous and metachronous manner. Here, we report a case of small bowel angioectasia in which capsule endoscopy performed early in a bleeding episode contributed to treatment. Case Summary: A 66-year-old man with suspected small bowel bleeding underwent small bowel capsule endoscopy and balloon-assisted endoscopy with argon plasma coagulation hemostasis for a small intestinal angioectasia. Because small bowel bleeding recurred intermittently after the treatment, small bowel capsule endoscopy and balloon-assisted endoscopy were repeated when there was no bleeding, but no abnormalities were found. Subsequent small bowel capsule endoscopy during a bleeding episode revealed bloody intestinal fluid in the proximal small intestine. Peroral balloon-assisted endoscopy was performed 2 days after SBCE for detailed observation of the small intestinal mucosa at the suspected bleeding site, and there a 1-mm Dieulafoy’s lesion with no active bleeding was identified. We performed argon plasma coagulation, and no bleeding was observed thereafter. Conclusions: Small bowel capsule endoscopy immediately after bleeding onset can identify the bleeding source of multiple minute lesions in small bowel angioectasia.

Low vitamin D status is related to frailty and/or sarcopenia in elderly individuals. However, these relationships are unclear in patients with chronic liver disease (CLD). This study aimed at exploring the relationship between serum 25-hydroxyvitamin D [25(OH)D] levels and frailty or sarcopenia in 231 patients with CLD. Frailty was determined based on five factors (weight loss, low physical activity, weakness, slowness, and exhaustion). Sarcopenia was diagnosed by applying the Japan Society of Hepatology criteria. The patients were classified into three groups according to baseline 25(OH)D levels: low (L), intermediate (I), and high (H) vitamin D (VD) groups. Of the 231 patients, 70 (30.3%) and 66 (28.6%) had frailty and sarcopenia, respectively. The prevalence rate of frailty and sarcopenia significantly increased stepwise with a decline in the vitamin D status. The L-VD group showed the highest prevalence rates of frailty and sarcopenia (49.1% (28/57), p < 0.001 for both), whereas the H-VD group showed the lowest prevalence rates of frailty (15.3% (9/59)) and sarcopenia (18.6% (11/59)) (p < 0.001 for both). Multivariate analysis identified serum 25(OH)D levels as a significant independent factor related to frailty and sarcopenia. Serum 25(OH)D levels significantly correlated with handgrip strength, skeletal muscle mass index, and gait speed. In conclusion, low serum vitamin D level, especially severe vitamin D deficient status, is closely related to frailty and sarcopenia in patients with CLD.

A 76-year-old man presented to our hospital with abdominal distention and loss of appetite. The 10% of weight lost relative to this patient in 1 month. Abdominal computed tomography and magnetic resonance imaging revealed a giant mass, with a major axis of 23 cm, containing solid components, not involving the upper abdominal organs. Esophagogastroduodenoscopy showed extramural compression from the middle gastric body to the antrum, as well as a normal mucosal surface. These findings were suggestive of a gastrointestinal stromal tumor attached to the anterior wall of the stomach without metastasis or invasion. Partial gastrectomy was performed for tumor resection, and the patient was subsequently treated with adjuvant imatinib. We report a rare case of a large extramural gastrointestinal stromal tumor of the stomach that was larger than 20 cm in diameter and present a pertinent literature review.

OBJECTIVE:Epithelial tumors less commonly occur in the duodenum than in the stomach or large intestine. The clinicopathological characteristics of duodenal epithelial tumors remain a matter of debate. We therefore studied resected specimens to investigate the clinicopathological characteristics of duodenal epithelial tumors. MATERIALS AND METHODS:Among duodenal epithelial tumors resected endoscopically or surgically in our hospital, we studied the clinicopathological characteristics of 110 adenomas or intramucosal carcinomas. The grade of atypia of all tumors was classified into 3 groups according to the World Health Organization (WHO) 2010 classification. The tumors were immunohistochemically evaluated to determine the frequency of differentiation toward fundic glands. RESULTS:As for patient characteristics, there were 76 men (75.2%) and 25 women (24.8%), with a median age of 65 years (range, 34 to 84). The tumors most commonly arose in the first to second part of the duodenum. Many lesions were flat, and the median tumor diameter was 8.0 mm. The lesions were classified into 2 types according to mucin phenotype: intestinal-type tumors (98 lesions, 89.1%) and gastric-type tumors (12 lesions, 10.9%). Intestinal-type tumors were subdivided into 2 groups: tubular-type tumors (91 lesions, 82.7%) and tubulovillous-type tumors (7 lesions, 6.4%). Gastric-type tumors were classified into 2 types: foveolar type (3 lesions, 2.7%) and pyloric gland-type (PG) tumors (9 lesions, 8.2%). The grade of atypia was significantly higher in gastric-type tumors (p

Although many diagnostic and therapeutic modalities for pancreatic cancer have been proposed, an urgent need for improved therapeutic strategies remains. Oligonucleotide therapeutics, such as those based on antisense RNAs, small interfering RNA (siRNA), microRNA (miRNA), aptamers, and decoys, are promising agents against pancreatic cancer, because they can identify a specific mRNA fragment of a given sequence or protein, and interfere with gene expression as molecular-targeted agents. Within the past 25 years, the diversity and feasibility of these drugs as diagnostic or therapeutic tools have dramatically increased. Several clinical and preclinical studies of oligonucleotides have been conducted for patients with pancreatic cancer. To support the discovery of effective diagnostic or therapeutic options using oligonucleotide-based strategies, in the absence of satisfactory therapies for long-term survival and the increasing trend of diseases, we summarize the current clinical trials of oligonucleotide therapeutics for pancreatic cancer patients, with underlying preclinical and scientific data, and focus on the possibility of oligonucleotides for targeting pancreatic cancer in clinical implications.

We experienced a case of mass-forming intrahepatic cholangiocarcinoma which could not been diagnosed accurately without pathologic findings. A 78-year-old Japanese woman with no particular symptoms was admitted for changes in liver function tests. Ultrasonography revealed a solid liver tumor. When there are no typical imaging features, no pathognomonic clinical findings and no obvious risk factors for any specific hepatic tumor, it may be difficult to make an accurate diagnosis before surgical resection. The lesion was resected on the basis of a high degree of suspicion for malignancy and submitted for pathologic evaluation. Microscopically, the neoplasm was a moderately differentiated adenocarcinoma with abundant fibrous stroma, consistent with a mass-forming cholangiocarcinoma. This case exemplifies the importance of considering the various tumorous and non-tumorous diseases in the differential diagnosis of a liver mass with atypical features, especially when malignancy cannot be excluded.

Activated granulocytes, monocytes, and platelets appear to be closely involved in active Crohn’s disease (CD). Adsorptive granulocyte apheresis (GCAP) is a new treatment for inflammatory bowel disease. GCAP was used to treat a 23-year-old female patient with CD resistant to both infliximab (IFX) and azathioprine (AZA). At 16 years of age, the patient underwent a partial ileal resection for peritonitis caused by perforative ileitis. On pathological examination of the resected specimen, the diagnosis was CD. Mesalazine was started, but the patient did not comply with therapy. She was admitted to our hospital again in 2007 due to an acute exacerbation. IFX induction therapy was started. The combination of both AZA daily and IFX every 8 weeks was continued as maintenance therapy. However, she developed severe abdominal pain in September 2009. Computed tomography revealed ileitis and ascending colitis, and blood tests showed high inflammatory response marker levels. She was considered to have IFX- and AZA-resistant CD. Initial intravenous steroid therapy did not result in any improvement. Therefore, weekly GCAP therapy was given for 5 weeks, which immediately improved the inflammatory response markers. GCAP combined with prednisolone could be effective for IFX- and AZA-refractory CD.