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Autoantibodies (aAbs) to type I interferons (IFNs) have been found in less than 1% of individuals under the age of 60 in the general population, with the prevalence increasing among those over 65. Neutralizing autoantibodies (naAbs) to type I IFNs have been found in at least 15% of patients with life-threatening COVID-19 pneumonia in several cohorts of primarily European descent. We aimed to evaluate the prevalence of aAbs and naAbs to IFN-α2 or IFN-ω in Japanese patients who suffered from COVID-19 as well as in the general population.Patients who suffered from COVID-19 (n = 622, aged 0-104) and an uninfected healthy control population (n = 3,456, aged 20-91) were enrolled in this study. The severities of the COVID-19 patients were as follows: critical (n = 170), severe (n = 235), moderate (n = 112), and mild (n = 105). ELISA and ISRE reporter assays were used to detect aAbs and naAbs to IFN-α2 and IFN-ω using E. coli-produced IFNs.In an uninfected general Japanese population aged 20-91, aAbs to IFNs were detected in 0.087% of individuals. By contrast, naAbs to type I IFNs (IFN-α2 and/or IFN-ω, 100 pg/mL) were detected in 10.6% of patients with critical infections, 2.6% of patients with severe infections, and 1% of patients with mild infections. The presence of naAbs to IFNs was significantly associated with critical disease (P = 0.0012), age over 50 (P = 0.0002), and male sex (P = 0.137). A significant but not strong correlation between aAbs and naAbs to IFN-α2 existed (r = - 0.307, p value 0.0001) reinforced the importance of measuring naAbs in COVID-19 patients, including those of Japanese ancestry.In this study, we revealed that patients with pre-existing naAbs have a much higher risk of life-threatening COVID-19 pneumonia in Japanese population.

Sarcopenia is well recognized as a prognostic factor of chronic liver diseases. However, its impact on the clinical course of primary sclerosing cholangitis (PSC) is unclear. This study aimed to clarify the importance of trunk muscles evaluated by computed tomography (CT) in the pathophysiology of patients with PSC.22 PSC patients (12 men, mean age 42.8 years) were enrolled in this study. Patients who died of hepatic failure or had to receive liver transplantation were defined as event group. 44 age- and gender-matched individuals without hepatic disorder were served as controls. At the level of third lumbar vertebrae, the area of psoas muscle and trunk muscle as well as the CT values of multifidus muscle and subcutaneous fat were evaluated. Based on these, skeletal muscle index (SMI), psoas muscle mass index (PMI) and intramuscular adipose tissue content (IMAC) were calculated. Then we analyzed the relationship between these parameters and laboratory data, Fibrosis-4 index, MELD score and Mayo risk score.At baseline evaluation, SMI and PMI were statistically lower in male PSC patients compared with those in controls (P 0.05). In male PSC, regarding the laboratory data, PMI was associated with total bilirubin, ALT, ALP, and platelet count (P 0.05). We found close relationship between PMI and MELD score (RSkeletal muscle mass evaluated by CT scan can be suitable for evaluating clinical and prognostic marker in male PSC.

Background The clinical characteristics of IgG4-related sclerosing cholangitis (IgG4-SC) especially without autoimmune pancreatitis (AIP) have not been investigated in a large cohort. Aims To clarify the clinical characteristics of IgG4-SC and IgG4-SC without AIP. Methods We retrospectively reviewed imaging, serology, other organ involvement (OOI) and histology of 872 patients with IgG4-SC who participated in a Japanese nationwide survey in 2019, and compared these items between IgG4-SC with and without AIP. Results AIP was present in 83.7% (730/872) of IgG4-SC. In IgG4-SC, bile duct wall thickening was observed on ultrasound (528/650; 81.2%), computed tomography (375/525; 71.4%) and magnetic resonance imaging or cholangiopancreatography (290/440; 65.9%). An elevated serum IgG4 level (≥ 135 mg/dL) was found in 88.0% (322/366). IgG4-related OOI other than AIP was observed in 25.2% (211/836). The proportion of females was significantly higher in IgG4-SC without AIP (28.9% vs. 20.1%; p = 0.025). Hilar stricture was the most common cholangiographic type in IgG4-SC without AIP (39/107; 36.4%).There were no significant differences between IgG4-SC with and without AIP in the rates of bile duct wall thickening, elevated serum IgG4 level, or IgG4-related OOI. Conclusions The clinical characteristics of IgG4-SC was similar between IgG4-SC with and without AIP in a large cohort.

It is expected that a low-toxicity natural compound like Kampo formulas would exhibit a preventive effect on COVID-19, in a global outbreak of coronavirus disease 2019 (COVID-19). Although the biological properties and safety of the representative Kampo, Hochuekkito (HET), and Kakkonto (KKT) have been confirmed in various animal model experiments and clinical studies, and in a few human studies to induce biological effects on various infectious diseases without significant toxicity, it is unclear whether HET and KKT are safe and effective for COVID-19 prevention. We summarized the clinical characteristics of HCWs and the preventive effects of HET and KKT. We performed a retrospective, single-center, cohort study that included 175 HCWs (aged 21-77 years) from a total number of 217 in a hospital with a history of COVID-19 cluster infection. In total, 175 HCWs were tested for severe acute respiratory coronavirus virus 2 (SARS-CoV-2) antibodies. We identified 27 patients (median age: 49 ± 10.7 years) who were diagnosed with COVID-19. The patients in the group that had a body mass index ≥ 25 had a high COVID-19 infection risk, while those in the group with a Kampo formula adherence rate ≥ 40% had a low COVID-19 risk. Patients in the group with an adherence rate ≥ 40%, as well as those in the current alcohol consumption group, were at a low risk of developing severe COVID-19. In conclusion, HET and KKT may have prevented the onset or worsening of COVID-19, which could be clinically used. Obesity might have increased the patients' susceptibility to COVID-19 and the disease severity.

Background Gastric cancer remains a severe public health problem worldwide, particularly in Japan. Recent studies have demonstrated that serum markers are beneficial for risk stratification in gastric cancer development. We aimed to evaluate the usefulness of serum markers either alone or in combination (serum markers plus endoscopy) for effective risk stratification of gastric cancer development. Methods We enrolled 22,736 patients aged 20–95 years who underwent blood sampling and endoscopic examination at Hiroshima University Hospital in Japan between 1990 and 2014. The serum pepsinogen (PG) levels and anti-Helicobacter pylori antibody (Hp-Ab) titers were evaluated in each patient. The enrolled patients were matched with the database of the Hiroshima Prefecture Regional Cancer Registry. We processed the medical records and excluded patients with possible confounding factors for PG levels, such as proton pump inhibitor use, prior successful eradication therapy, post-gastrectomy, severe hepatorenal dysfunction, Zollinger–Ellison syndrome, and autoimmune gastritis. Among the remaining 5131 patients, we reviewed records of endoscopic examinations and selected 1507 patients (mean age, 62.5 years; 985 men and 522 women) who underwent endoscopic examination more than three months after blood sampling. First, based on the ABC method, patients were classified as follows: High PG levels and negative Hp-Ab, group A, high PG levels and positive Hp-Ab, group B, low PG levels and positive Hp-Ab, group C, and low PG levels and negative Hp-Ab, group D. Group A was further classified into two subgroups using endoscopic findings: true A without atrophic gastritis and pseudo A with atrophic gastritis. All patients underwent annual endoscopy follow-up. Results Among the 1,507 patients (mean age, 62.5 years; 985 men), 24 were diagnosed with newly developed gastric cancer. No significant difference in cancer development was found between group A (PG negative and Hp-Ab negative) and the other groups. Remarkably, no true A group subjects developed gastric cancer. Conclusions The combination of serum markers and endoscopic findings is essential for the risk evaluation of gastric cancer.

We herein report a case of aortitis induced by granulocyte colony-stimulating factor (G-CSF) that coincided with lung injury, splenomegaly, and cutaneous manifestations during treatment for recurrent extraosseous mucinous chondrosarcoma. Computed tomography revealed large-vessel vasculitis, splenomegaly, and pulmonary interstitial changes. Treatment with prednisolone was successful. Because sarcoma is a rare disease, this case is valuable for showing clinicians that G-CSF preparations could cause aortitis regardless of the patient's underlying diseases or therapeutic pharmacological backgrounds.

The Japanese Society of Gastroenterology (JSGE) revised the third edition of evidence-based clinical practice guidelines for peptic ulcer disease in 2020 and created an English version. The revised guidelines consist of nine items: epidemiology, hemorrhagic gastric and duodenal ulcers, Helicobacter pylori (H. pylori) eradication therapy, non-eradication therapy, drug-induced ulcers, non-H. pylori, and nonsteroidal anti-inflammatory drug (NSAID) ulcers, remnant gastric ulcers, surgical treatment, and conservative therapy for perforation and stenosis. Therapeutic algorithms for the treatment of peptic ulcers differ based on ulcer complications. In patients with NSAID-induced ulcers, NSAIDs are discontinued and anti-ulcer therapy is administered. If NSAIDs cannot be discontinued, the ulcer is treated with proton pump inhibitors (PPIs). Vonoprazan (VPZ) with antibiotics is recommended as the first-line treatment for H. pylori eradication, and PPIs or VPZ with antibiotics is recommended as a second-line therapy. Patients who do not use NSAIDs and are H. pylori negative are considered to have idiopathic peptic ulcers. Algorithms for the prevention of NSAID- and low-dose aspirin (LDA)-related ulcers are presented in this guideline. These algorithms differ based on the concomitant use of LDA or NSAIDs and ulcer history or hemorrhagic ulcer history. In patients with a history of ulcers receiving NSAID therapy, PPIs with or without celecoxib are recommended and the administration of VPZ is suggested for the prevention of ulcer recurrence. In patients with a history of ulcers receiving LDA therapy, PPIs or VPZ are recommended and the administration of a histamine 2-receptor antagonist is suggested for the prevention of ulcer recurrence.

Aim To investigate the clinical factors and factors that affect the decisions regarding storage of cryopreserved embryos obtained using assisted reproductive technology. Methods Clinical characteristics affecting the decisions regarding cryopreserved embryos were analyzed in 5724 Japanese couples who underwent in vitro fertilization (IVF) or intra-cytoplasmic sperm insemination (ICSI) and embryo transfer over 4 years since April 2015 at our clinic. Statistical analysis was carried out using JMP software. Results The number of oocytes retrievals and embryos stored, outcomes and number of children, and age of the female patients and male partners were related to the decision-making regarding cryopreserved embryos. Childbearing and no wish for another child were the major reasons for discontinuing embryo storage. The number of oocytes retrievals and embryos in storage, age of the female patients, and sex of the child were independently associated with this decision-making in 2682 patients with a single child. Women with male children were more likely to choose discontinuation of embryo storage than those with female children. Conclusion Already having a child and not wishing for further treatment due to age along with the presence of a male child affect the decision to continue or discontinue embryo storage in Japanese patients with infertility.

Various motion correction (MC) algorithms for positron emission tomography (PET) have been proposed to accelerate the diagnostic performance and research in brain activity and neurology. We have incorporated MC system-based optical motion tracking into the brain-dedicated time-of-flight PET scanner. In this study, we evaluate the performance characteristics of the developed PET scanner when performing MC in accordance with the standards and guidelines for the brain PET scanner.We evaluate the spatial resolution, scatter fraction, count rate characteristics, sensitivity, and image quality of PET images. The MC evaluation is measured in terms of the spatial resolution and image quality that affect movement.In the basic performance evaluation, the average spatial resolution by iterative reconstruction was 2.2 mm at 10 mm offset position. The measured peak noise equivalent count rate was 38.0 kcps at 16.7 kBq/mL. The scatter fraction and system sensitivity were 43.9% and 22.4 cps/(Bq/mL), respectively. The image contrast recovery was between 43.2% (10 mm sphere) and 72.0% (37 mm sphere). In the MC performance evaluation, the average spatial resolution was 2.7 mm at 10 mm offset position, when the phantom stage with the point source translates to ± 15 mm along the y-axis. The image contrast recovery was between 34.2 % (10 mm sphere) and 66.8 % (37 mm sphere).The reconstructed images using MC were restored to their nearly identical state as those at rest. Therefore, it is concluded that this scanner can observe more natural brain activity.

Background Solitary death is an emerging public health problem in developed countries. Alcohol abuse is associated with social isolation and excess mortality. However, data on the association between alcohol abuse and solitary death are limited. Our purposes were to assess whether alcohol abuse is associated with a long interval from death to discovery among people living alone. Methods This is a cross-sectional study using the data on subjects from the largest forensic database in Kyoto, Japan, from February 2012 to December 2015. Solitary death was defined as a phenomenon of dying alone at home and remaining undiscovered for more than 1 week. All the subjects who lived alone and aged over 18 at the time of death were included in the study. The presence of alcohol abuse was identified via an investigation during home visits. Proportional ratios were calculated using a fitted logit model to evaluate the association of alcohol abuse on solitary death after adjusting for possible confounders. Results A total of 235 subjects were included in the analysis. The mean age (standard deviation) of subjects at the time of death was 63.4 (15.1) years, and approximately 61.8% and 38.9% of subjects in the alcohol and non-alcohol abuse groups, respectively, experienced solitary death. Multivariable analyses revealed that alcohol abuse was associated with solitary death (adjusted proportion ratio: 1.50; 95% confidence interval: 1.12–2.00). Conclusions The findings of this study could help identify individuals at higher risk of solitary death. Moreover, calling the attention of people with alcohol abuse may be beneficial to prevent solitary death.

Delirium is a common adverse event observed in patients admitted to the intensive care unit (ICU). However, the prognostic value of delirium and its determinants have not been thoroughly investigated in patients with acute heart failure (AHF).We investigated 408 consecutive patients with AHF admitted to the ICU. Delirium was diagnosed by means of the Confusion Assessment Method for ICU tool and evaluated every 8 hours during the patients' ICU stays.Delirium occurred in 109 patients (26.7%), and the in-hospital mortality rate was significantly higher in patients with delirium (13.8% vs 2.3%; P0.001). Multivariate logistic regression analysis showed that delirium independently predicted in-hospital mortality (odds ratio [OR] 4.33, confidence interval [CI] 1.62-11.52; P = 0.003). Kaplan-Meier analysis showed that the 12-month mortality rate was significantly higher in patients with delirium compared with those without (log-rank test: P0.001), and Cox proportional hazards analysis showed that delirium remained an independent predictor of 12-month mortality (hazard ratio 2.19, 95% CI 1.49-3.25; P0.001). The incidence of delirium correlated with severity of heart failure as assessed by means of the Get With The Guidelines-Heart Failure risk score (chi-square test: P = 0.003). Age (OR 1.05, 95% CI 1.02-1.09; P = 0.003), nursing home residential status (OR 3.32, 95% CI 1.59-6.94; P = 0.001), and dementia (OR 5.32, 95% CI 2.83-10.00; P0.001) were independently associated with the development of delirium.Development of delirium during ICU stay is associated with short- and long-term mortality and is predicted by the severity of heart failure, nursing home residential, and dementia status.

We herein report on two male patients (age, 22 and 44 years) who were referred to our department with swelling of the upper right arm after attending other hospitals. Right subclavian vein thrombosis was demonstrated by ultrasonography and they were then further evaluated by contrast-enhanced computed tomography (CT). Successful treatment involved venous thrombectomy in one patient and anticoagulant therapy in the other. Paget-Schhroetter syndrome was confirmed using standard vascular ultrasonography. Despite the accuracy of this method for diagnosing Paget-Schroetter syndrome, some cases are difficult to confirm. We reviewed 29 previously published case reports of Paget-Schroetter syndrome and analyzed the patient baseline characteristics, time to diagnosis, and the diagnostic methods used.

BACKGROUND AND AIM: In Japan, the prevalence of autoimmune gastritis (AIG) is assumed to be very low. With the recent rapid decrease in Helicobacter pylori (Hp) prevalence, reports on AIG are increasing. This multicenter registry study aimed to clarify the characteristics of AIG, especially its endoscopic appearance. METHODS: A total of 245 patients with AIG from 11 institutions in Japan from January 2010 to October 2016 were included, and their clinical and endoscopic findings were evaluated. RESULTS: Mean age was 67.2±11.4years, and 63.7% of the participants were women. The most common approach to diagnose AIG was endoscopic examination. Repeated incorrect treatment for Hp infection, due to a false-positive result in 13 C-urea breath test, ranked third among the basis for diagnosis of AIG. Associated gastric lesions were type 1 neuroendocrine tumor (11.4%), adenocarcinoma (9.8%), and hyperplastic polyps (21.1%). Corpus pan-atrophy was the most common appearance (90.1%); however, remnant oxyntic mucosa was found in 31.5% of the patients (flat, localized type, 48.6%). Sticky adherent dense mucus and scattered minute whitish protrusions were also observed in approximately 30% of the patients. Despite the prevailing presumption of the antral mucosa remaining normal, 42.3% of the patients presented with various extents of atrophy, and patchy redness and circular wrinkle-like patterns were both observed in approximately 20% of the patients. CONCLUSIONS: The present study showed some prominent clinical characteristics and endoscopic findings of AIG. We believe that our study will facilitate the diagnosis of potential AIG., 著者最終稿（査読済み）, © 2019 Japan Gastroenterological Endoscopy Society.

The current status of Helicobacter pylori infection in Japan has not been investigated. We evaluated the status of H. pylori infection in a Japanese general population using large-scale resident-register-based sampling.All 6069 adults in a rural town and 6000 adults in two urban cities (3000 each), selected by register-based random sampling, were enrolled in our health check-up program. Antibody titers against Helicobacter pylori (cut-off value was 3 U/mL by Eiken E-plate) were evaluated, and subjects with a positive result were encouraged to undergo further examinations.A total of 1586 subjects participated in serum sampling. The overall prevalence of H. pylori infection was 40.0% (634/1586), and it increased with age both in rural and urban areas. Although the overall positive rate was higher in the rural area (49.4%) than in the urban areas (35.6 and 32.3%), there was no difference in H. pylori status of younger subjects between the two areas. Among 634 patients with a positive titer, 374 (59.0%) underwent further examinations including endoscopic examination, and 180/634 (28.4%) patients received eradication therapy. Gastric neoplasms (three adenocarcinomas and one adenoma) were found in our screening program.We clarified population-based random sampling data of H. pylori infection in a Japanese general population. In younger subjects, a decrease in the prevalence of H. pylori infection was confirmed both in rural and urban areas. This provides basic information for establishing a strategy to reduce gastric cancer deaths.

Objective The Chicago classification using high-resolution manometry (HRM) has been proposed for the diagnosis of esophageal motility disorders. However, HRM is expensive, and few patients are likely to benefit from this method. We established a method using a raised infusion catheter called "esophageal manometry using a trans-nasal endoscope". In this study, we examined the clinical utility of this new method for the assessment of patients with dysphagia. Methods We enrolled 124 consecutive patients who complained of dysphagia and were suspected of having esophageal motility disorders. Patients underwent manometry using a trans-nasal endoscope at Hiroshima University Hospital from September 2008 to December 2018. An esophageal biopsy was performed during the procedure from the thoracic esophagus to detect eosinophilic esophagitis. In addition, we examined the clinical courses of patients diagnosed with achalasia. Results The diagnostic ability of manometry using a trans-nasal endoscope was 98%, and no major complications associated with the procedure were recorded. About 30% of patients were diagnosed with achalasia, and most (77%) were well controlled by medications or balloon dilation. One patient was diagnosed with eosinophilic esophagitis. Conclusion Manometry using a trans-nasal endoscope is beneficial and can be used for the clinical management of patients with dysphagia.

New treatment methods, such as REGN-CoV2, have been approved for patients with coronavirus disease (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, the effect of the drug on the duration of infectious viral shedding and viral mutations is unknown. In this study, we investigated the clinical efficacy of REGN-CoV2 treatment in patients with mild to moderate disease and compared its antiviral effects against different strains of SARS-CoV-2.Viral culture and PCR testing were performed on the pharyngeal swabs collected from 28 patients with COVID-19 who were admitted and treated at Hiroshima University Hospital during the study period. Of these, 23 patients were treated with REGN-CoV2. The patients were classified into the REGN-CoV2(+) and REGN-CoV2(-) groups, and the clinical course was compared between the groups. The 50% inhibitory concentrations (ICAfter treatment with REGN-CoV2, the virus culture positivity rate was greatly reduced. The time to negative viral culture was significantly shorter in the REGN-CoV2(+) group than in the REGN-CoV2(-) group. In vitro evaluation of REGN-CoV2 against isolated virus strains also showed efficacy.REGN-CoV2 treatment was effective in patients with mild COVID-19 and could shorten the period of infectious viral shedding. This may be an important factor in preventing the spread of infection. It may be possible to revise the isolation period for patients with mild disease treated with REGN-CoV2.

Background Gastric cancer may develop after successful eradication of Helicobacter pylori, although the incidence is lower than in non-eradicated individuals. We previously reported the appearance of characteristic epithelium with low-grade atypia (ELA) on the surface of gastric cancer after H. pylori eradication. However, whether ELA originates from cancer after re-differentiation or from the non-cancerous surrounding mucosa is unknown. Methods We isolated ELA regions from 10 early gastric cancer patients and analyzed the nucleotide sequences for 90 oncogenes and 35 fusion oncogenes, comparing them with counterpart cancer tissue, normal gastric mucosa, and blood cell-derived DNA. Somatic mutations in each tissue were identified by comparing them with the sequences from whole blood-derived DNA. Result Gene alterations were observed in nine of the ten patients, and up to 42 and 70 somatic mutations were seen in cancer and ELA samples, respectively. Common mutations shared between cancer and ELA tissues were found in eight of these nine patients. In contrast, common mutations between non-cancer mucosa and ELA were only detected in one patient, who also had common mutation between cancer and ELA. ELA-specific nucleotide substitutions were seen in seven patients. In contrast, cancer-specific substitutions were only found in two patients. 18 out of 19 amino acid substitutions present in cancer tissue were also identified in ELA. These results suggest that ELA originated from cancer tissue and accumulated further nucleotide substitutions. Conclusions Differential diagnosis of ELA and normal mucosa should be carefully performed to prevent misdiagnosis of ELA as normal mucosa with atypia., This study was supported by grants from the Japan Society for the Promotion of Science (JSPS KAKENHI GrantNumber: 16K19379; https://www.jsps.go.jp/j-grantsinaid/).

BACKGROUND AND AIM The typical histology of Helicobacter pylori-uninfected gastric cancer is signet ring cell carcinoma (SRCC) localized in the mucosal layer, but the potential of these SRCCs to invade the submucosal layer is unclear. This study aimed to investigate the clinicopathological characteristics of SRCC in H. pylori-uninfected patient and its prevalence in diffuse-type gastric cancer (DGC) within Japan. METHODS We enrolled consecutive pure DGC patients diagnosed with the disease either localized in the mucosal layer or with submucosal invasion. H. pylori infection was investigated, and the patients were divided into three groups according to histological types: pure SRCC, SRCC with poorly differentiated adenocarcinoma (PDA), and pure PDA. RESULTS Of the 345 pure DGC patients, 132 (38%), 127 (37%), and 86 (25%) had pure SRCC, SRCC with PDA, and pure PDA histologies, respectively. The prevalence of H. pylori infection and the SM ratio were significantly lower in the pure SRCC group than other groups (P

Background: Practical criteria for the use of serum pepsinogen (PG) values in diagnosing Helicobacter pylori infection have not yet been determined. Methods: The results of gastric endoscopies, H. pylori infection tests, and PG values were retrospectively reviewed. Subjects were assigned to groups, including never-infected (with neither infection nor gastric mucosal atrophy), infected (with atrophy or findings indicating infection in endoscopy and positive infection tests except for antibody tests), and ex-infected (with gastric mucosal atrophy and negative infection tests, except for antibody tests). The optimal criteria with combined use of the PG II concentrations and the PG I/PG II ratio were investigated separately for PG measurements obtained with the chemiluminescent magnetic particle immunoassay (CLIA) and latex agglutination (LA) methods, such that the specificity was greater than 70% and the sensitivity was no less than 95% among the never-infected and infected subjects. Similar analyses were performed by combining the data from ex-infected and infected subjects. Results: For the CLIA (LA) method, the optimal criterion among 349 (397) never-infected and 748 (863) infected subjects was a PG II value of at least 10 (12) ng/mL or a PG I/PG II ratio no more than 5.0 (4.0), which produced 96.3% (95.1%) sensitivity and 82.8% (72.8%) specificity. When 172 (236) ex-infected subjects were included, the optimal criterion was the same, and the sensitivity was 89.1% (86.9%). Conclusions: The above criteria may be practical for clinical use, and PG tests using these criteria might prevent unnecessary endoscopic examinations for never-infected subjects.

AimsSecreted factors produced by adipose tissue are involved in the pathogenesis of cardiovascular disease. We previously identified adipolin, also known as C1q/TNF-related protein 12, as an insulin-sensitizing adipokine. However, the role of adipolin in vascular disease remains unknown. Here, we investigated whether adipolin modulates pathological vascular remodelling.Methods and resultsAdipolin-knockout (APL-KO) and wild-type (WT) mice were subjected to wire-induced injury of the femoral artery. APL-KO mice showed increased neointimal thickening after vascular injury compared with WT mice, which was accompanied by an enhanced inflammatory response and vascular cell proliferation in injured arteries. Adipolin deficiency also led to a reduction in transforming growth factor-β (TGF-β) 1 protein levels in injured arteries. Treatment of cultured macrophages with adipolin protein led to a reduction in lipopolysaccharide-stimulated expression of inflammatory mediators, including tumour necrosis factor (TNF)-α, interleukin (IL) 6, and monocyte chemotactic protein (MCP)-1. These effects were reversed by inhibition of TGF-β receptor II (TGF-βRII)/Smad2 signalling. Adipolin also reduced platelet-derived growth factor (PDGF)-BB-stimulated proliferation of vascular smooth muscle cells (VSMCs) through a TGF-βRII/Smad2-dependent pathway. Furthermore, adipolin treatment significantly increased TGF-β1 concentration in media from cultured VSMCs and macrophages.ConclusionThese data indicate that adipolin protects against the development of pathological vascular remodelling by attenuating macrophage inflammatory responses and VSMC proliferation.

Objective Rectal lymphoid follicular aphthous (LFA) lesions are related to ulcerative colitis (UC) and can be initial lesions of UC. We investigated the clinical course and prognosis of rectal LFA lesions. Methods This is a retrospective analysis of the clinical records at a single center. Patients Thirteen consecutive cases with LFA lesions treated at Hiroshima University Hospital between 1998 and 2015 were evaluated. Another 49 consecutive cases with ulcerative proctitis treated in the same period were enrolled as the control group. The clinical course and prognosis of both groups were evaluated. Results The group with LFA lesions included 9 women and 4 men with a median age of 39.9 years (range, 21-70 years). A total of 11 cases progressed to typical UC at 5-51 months. Proximal extension of these typical UC lesions was observed in 7 (53.8%) cases, which was significantly higher than in the control group (10 cases, 20.8%). Three cases (5-year accumulation incidence rate, 27.3%) progressed to steroid-intractable UC, a significantly higher incidence than that of the control group (3 cases; 5-year accumulation incidence rate, 6.9%). Conclusion Rectal LFA lesions frequently progress to typical UC with proximal extension, some of which become intractable to corticosteroid treatment.

Background Gastric adenocarcinoma of fundic-gland type (GA-FG) is a rare variant of gastric neoplasia. However, the etiology, classification, and clinicopathological features of gastric epithelial neoplasm of fundic-gland mucosa lineage (GEN-FGML; generic term of GA-FG related neoplasm) are not fully elucidated. We performed a large, multicenter, retrospective study to establish a new classification and clarify the clinicopathological features of GEN-FGML. Methods One hundred GEN-FGML lesions in 94 patients were collected from 35 institutions between 2008 and 2019. We designed a new histopathological classification of GEN-FGML using immunohistochemical analysis and analyzed via clinicopathological, immunohistochemical, and genetic evaluation. Results GEN-FGML was classified into 3 major types; oxyntic gland adenoma (OGA), GA-FG, and gastric adenocarcinoma of fundic-gland mucosa type (GA-FGM). In addition, GA-FGM was classified into 3 subtypes; Type 1 (organized with exposure type), Type 2 (disorganized with exposure type), and Type 3 (disorganized with non-exposure type). OGA and GA-FG demonstrated low-grade epithelial neoplasm, and GA-FGM should be categorized as an aggressive variant of GEN-FGML that demonstrated high-grade epithelial neoplasm (Type 2 > 1, 3). The frequent presence of GNAS mutation was a characteristic genetic feature of GEN-FGML (7/34, 20.6%; OGA 1/3, 33.3%; GA-FG 3/24, 12.5%; GA-FGM 3/7, 42.9%) in mutation analysis using next-generation sequencing. Conclusions We have established a new histopathological classification of GEN-FGML and propose a new lineage of gastric epithelial neoplasm that harbors recurrent GNAS mutation. This classification will be useful to estimate the malignant potential of GEN-FGML and establish an appropriate standard therapeutic approach.

To minimize motion-related distortion of reconstructed images, conventional positron emission tomography (PET) measurements of the brain inevitably require a firm and tight head restraint. While such a restraint is now a routine procedure in brain imaging, the physiological and psychological consequences resulting from the restraint have not been elucidated. To address this problem, we developed a restraint-free brain PET system and conducted PET scans under both restrained and non-restrained conditions. We examined whether head restraint during PET scans could alter brain activities such as regional cerebral blood flow (rCBF) and dopamine release along with psychological stress related to head restraint. Under both conditions, 20 healthy male participants underwent [15O]H2O and [11C]Raclopride PET scans during working memory tasks with the same PET system. Before, during, and after each PET scan, we measured physiological and psychological stress responses, including the State-Trait Anxiety Inventory (STAI) scores. Analysis of the [15O]H2O-PET data revealed higher rCBF in regions such as the parahippocampus in the restrained condition. We found the binding potential (BPND) of [11C]Raclopride in the putamen was significantly reduced in the restrained condition, which reflects an increase in dopamine release. Moreover, the restraint-induced change in BPND was correlated with a shift in the state anxiety score of the STAI, indicating that less anxiety accompanied smaller dopamine release. These results suggest that the stress from head restraint could cause unsolicited responses in brain physiology and emotional states. The restraint-free imaging system may thus be a key enabling technology for the natural depiction of the mind.

Deoxycholic acid (DCA), a secondary bile acid, is reportedly increased in the serum of patients with nonalcoholic steatohepatitis and animals with experimentally induced hepatocellular carcinoma (HCC), but its contribution to malignant behaviors of HCC has not been precisely clarified. This study aimed to examine the effect of DCA on hepatic stellate cells (HSCs), a major component of nonparenchymal cells in the liver, and its subsequent indirect effect on HCC cells.LX2 cells, a human HSC line, were treated with DCA in vitro. Then, HuH7 cells, a human hepatoma cell line, were incubated in conditioned media of DCA-treated LX2 to investigate the subsequent effect focusing on malignant behaviors.DCA resulted in cellular senescence in LX2 with the decreased cell proliferation via cell cycle arrest at G0/1 phase, together with the induction of senescence-associated secretory phenotype (SASP) factors. To investigate the influence of SASP factors secreted by HSCs in response to DCA, HCC cells were treated with conditioned media that promoted cell migration and invasion via induction of epithelial mesenchymal transition. These changes were attenuated in the presence of neutralizing antibody against IL8 or TGFβ. Pathological analysis of surgical specimens from HCC patients revealed that senescent HSCs were detected in the stroma surrounding HCC.Our data suggest an important role of HSC senescence caused by DCA for the malignant biological behaviors of HCC via induction of SASP factors, particularly IL8 and TGFβ.

Background Gastric cancer develops even in Helicobacter pylori(H. pylori)-uninfected patients and its typical histological feature is signet ring cell carcinoma (SRCC) within the mucosal layer. However, the biological characteristics of SRCC remain unclear. We aimed to clarify the pathological and genetic features of SRCC in H. pylori-uninfected patients. Methods Seventeen H. pylori-uninfected patients with mucosal SRCCs were enrolled and their clinicopathological characteristics were compared with those of H. pylori-infected patients with mucosal SRCCs. Seven SRCCs without H. pylori-infected, including two invasive SRCCs, and seven H. pylori-infected SRCCs were subjected to a genetic analysis using next-generation sequencing. Results H. pylori-uninfected patients with mucosal SRCCs revealed male dominancy and a significantly higher prevalence of smokers among them as compared with the H. pylori-infected patients with SRCC. A CDH1 mutation (frame shift indel) was detected in one H. pylori-uninfected cancer not only in the mucosal SRCC but also in the invasive portion. A TP53 mutation was detected in one SRCC without H. pylori-infected. In the control group, ARID1A and TP53 mutations were detected in one SRCC each. The C to A mutation, which is a characteristic smoking-induced mutation, was not found in any of the samples. Conclusions Some SRCCs in H. pylori-uninfected patients may have a malignant potential similar to that of SRCCs in H. pylori-infected patients. Smoking may not be the main carcinogenic factor for the development of SRCCs among the H. pylori-uninfected patients.

Background and aim Non-alcoholic steatohepatitis (NASH) is characterized by hepatic steatosis, inflammation, and hepatocellular injury with varying degrees of fibrosis. There are currently no established treatment approaches for NASH other than lifestyle interventions. Periostin, a matricellular protein required for tissue remodeling and fibrosis, plays an important role in hepatic steatosis and fibrosis and could be a potential target for NASH treatment. Advances in molecular biology and biochemical engineering have led to the development of antisense oligonucleotides (ASOs) that can inhibit target genes with no significant toxic effects. Herein, we investigated the therapeutic effects of periostin-targeting ASO (PNASO) in NASH. Methods C57BL/6J mice were fed a choline-deficient, l-amino acid-defined, high-fat diet (CDAHFD) to induce NASH with or without intraperitoneal injection of mouse PNASO. To explore the role of periostin in hepatocellular steatosis, Hc3716 cells, an immortalized human hepatocyte line, were treated with recombinant periostin in vitro. Results The induced periostin expression in the liver of CDAHFD-fed mice was significantly suppressed by PNASO. The deletion of hepatic periostin by PNASO significantly ameliorated hepatic steatosis while restoring the expression levels of peroxisome proliferator-activated receptor-alpha (PPAR-α) and its target genes. PNASO also inhibited hepatic fibrosis, reflected by the reduction of alpha-smooth muscle actin, collagen type I, and other fibrotic markers. In vitro experiments demonstrated that treatment with recombinant periostin increased cellular lipid accumulation in Hc3716 cells accompanied with the downregulation of PPAR-α. Conclusions Periostin-targeting ASO is a potential therapeutic approach for the efficient treatment of hepatic steatosis and fibrosis in NASH.

The prevalence of gastric cancer after eradication (GCAE) is increasing dramatically in Japan. GCAE has characteristic features, and we must understand these features in endoscopic examinations. Differentiated cancer types were frequently found after eradication and included characteristic endoscopic features such as reddish depression (RD). However, benign RD can be difficult to distinguish from gastric cancer because of histological alterations in the surface structures (nonneoplastic epithelium or epithelium with low-grade atypia [ELA]) as well as multiple appearances of RD. Recently, we clarified similar alterations in genetic mutations between ELA and gastric cancer, suggesting that ELA is derived from gastric cancer. Clinically, submucosal invasive cancer was frequently found in patients after eradication therapy even if they received annual endoscopic surveillance. We can improve the diagnostic ability using image-enhanced endoscopy with magnified observation. (Gut Liver 2021;15:-345)

Many studies have evaluated surgical treatments for spinal deformities in patients with neuromuscular disease. However, few reports have described patients with Fukuyama congenital muscular dystrophy (FCMD). A 13-year-old boy with FCMD was unable to sit for long periods or sleep in the supine position because of progressive scoliosis. His Cobb angle worsened from 27° to 41° in 5months. He underwent standard posterior spinal fusion and pedicle-screw-alone fixation from T5 to S1. Postoperatively, his Cobb angle improved from 41° to 25° without exacerbation for 2years. After the surgery, he was able to sit for longer periods without pain, and he and his family were satisfied with the efficacy of the spinal fusion. Some patients with mild FCMD can sit at the age of puberty, but progression to scoliosis is possible. Therefore, spinal fusion for progressive scoliosis in patients with FCMD should be considered.

It is clinically important to diagnose drug-induced gastric lesions correctly. Recently, the use of proton pump inhibitors (PPI) has increased worldwide. The histological features induced by PPI have been reported; however, few reports have described endoscopic findings induced by PPI. Therefore, we aimed to clarify the characteristic endoscopic features in PPI users and associated pathogenic factors.We prospectively registered 1007 consecutive participants (70 PPI users and 937 nonusers) who underwent endoscopic examination for cancer screening in three hospitals/clinics. Clinical data and endoscopic findings were recorded in the registration forms. We compared the endoscopic features between the two groups and evaluated contributing factors via univariate and multivariate analyses.Multiple white elevated lesions (MWEL) and cobblestone-like mucosa (CLM) were more commonly observed in PPI users compared with nonusers (p .01). Foveolar hyperplastic polyps were also frequently observed in PPI users but were not statistically significantly different (p = .06). MWEL and CLM were more frequently observed in older patients than in younger patients. MWEL was more frequently observed in female patients than in male patients; however, CLM was predominantly observed in male patients.MWEL and CLM are characteristic endoscopic features in PPI users. A gender-associated difference was noted in terms of the frequency of these lesions.

Background and aims Obesity contributes to the progression of vascular disorders. C1q/TNF-related protein (CTRP) 1 is a circulating adipokine, which is upregulated in obese complications including coronary artery disease. Here, we investigated the role of CTRP1 in regulation of vascular remodeling after mechanical injury and evaluated its potential mechanism. Methods Mice were subjected to wire-induced injury of left femoral arteries. An adenoviral vector encoding CTRP1 (Ad-CTRP1) or β-galactosidase as a control was injected into the jugular vein of mice 3 days prior to surgery. Results Systemic administration of Ad-CTRP1 to wild-type mice led to reduction of the neointimal thickening after wire-induced arterial injury and the number of bromodeoxyuridine-positive cells in injured vessels as compared with treatment with control vectors. Treatment of vascular smooth muscle cells (VSMCs) with CTRP1 protein attenuated proliferative activity and ERK phosphorylation in response to PDGF-BB. CTRP1 treatment increased cyclic AMP (cAMP) levels in VSMCs, and inhibition of adenylyl cyclase reversed the inhibitory effect of CTRP1 on VSMC growth and ERK phosphorylation. Antagonization of sphingosine-1-phosphaterote (S1P) receptor 2 blocked the effects of CTRP1 on cAMP production and VSMC growth. Furthermore, CTRP1-knockout mice had enhanced neointimal thickening following injury and increased numbers of proliferating cells in neointima compared to control WT mice. Conclusions These findings indicate that CTRP1 functions to prevent the development of pathological vascular remodeling by reducing VSMC growth through the cAMP-dependent pathway.

Objective The aim of the present study is to assess the difference in the detection rates of small-bowel lesions in chronic abdominal pain (CAP) patients with irritable bowel syndrome (IBS) and non-IBS. Patients Ninety-nine CAP patients who were scheduled to undergo capsule endoscopy (CE) to investigate their abdominal symptoms were included in this study. Among the subjects, 34 patients fulfilled the Rome III criteria for IBS (IBS group); the remaining 65 patients were categorized as the non-IBS group. CE was performed in both groups and the total enteroscopy achievement rate, small-bowel lesion detection rate, and the presence of small-bowel lesions were evaluated. We also evaluated the patients' blood test results and the rate at which abdominal symptoms improved following internal medication. Results Total enteroscopy was achieved in 62% (21/34) and 86% (56/65) of the IBS and non-IBS patients, respectively. The total enteroscopy achievement rate was significantly higher in non-IBS patients. The small-bowel lesion detection rates were 3% (1/34) and 19% (12/65), respectively, and the detection rate was significantly higher in the non-IBS patients. In the non-IBS patients, mean C-reactive protein (CRP) was significantly higher in the patients with small-bowel lesions. The abdominal symptoms of 12 (92%) of the CAP patients with small-bowel lesions were improved by internal medication. Conclusion CE may be considered for non-IBS CAP patients with high levels of CRP.

The serological risk prediction system combines the pepsinogen test and anti-Helicobacter pylori (H. pylori) antibody determination. In this system, chronic atrophic gastritis (CAG) is diagnosed using the pepsinogen test. Patients who are H. pylori negative and pepsinogen negative are classified into group A, are assumed to be H. pylori uninfected, and are at an extremely low risk for gastric cancer. However, gastric cancers are detected in this group. The aim of this study is to clarify the clinicopathological status of group A patients with gastric cancer. A total of 109 gastric cancer patients classified as group A were enrolled in a multicenter study. Group A patients were divided into two subgroups: group AN (H. pylori uninfected) and group AP (H. pylori infected). They were compared to 183 H. pylori-infected gastric cancer patients who were not in group A. Of the 109 patients, only 7 were classified as group AN; the other 102 were classified as group AP. The clinicopathological features of group AP included older age, predominantly differentiated type cancer, endoscopically visualized CAG, and pepsinogen (PG) I/II ratio lower than that of group AN. In group AN, the depressed type was dominant, and the PG I/II ratio was higher than in those gastric cancer patients who were infected with H. pylori. Patients in group AP had CAG, and their gastric cancers were similar to those of H. pylori-eradicated patients. Concerning the recent ABC classification system, advanced decision criteria should be proposed to decrease the false-negative evaluation of gastric cancer risk.

A 57-year-old woman sustained gradually progressive sensorimotor disturbance in the left upper extremity for one year. Neurological examination found a diminished sensation below the left C7 dermatome and reduced strength in the left interosseous muscles. Computed tomography of the cervical spine revealed a high density mass at C7, in the left dorsal part of the spinal canal. Magnetic resonance imaging found an enhancing, en-plaque tumor at C6-T1, involving a non-enhancing part, and considerable compression of the spinal cord. The patient underwent tumor resection through hemilaminectomy of C5-C7. The tumor was located epidurally, highly fibrous including bony-hard parts, and severely adhered to the dura mater that necessitated drilling for debulking. A subtotal resection was achieved and histological diagnosis was a fibrous meningioma with metaplastic ossification. Ossification may be a pathognomonic appearance of spinal extradural meningiomas that makes resection maneuvers difficult.

The Japanese Respiratory Society 2017 guidelines strongly recommend switching from intravenous (IV) to oral antibiotics in patients with community-acquired pneumonia (CAP), following improvement in clinical symptoms and laboratory findings. Here, we retrospectively investigated the real-world, nationwide treatment and switching patterns for hospitalized patients with CAP in Japan using administrative data from 372 Japanese Diagnosis Procedure Combination hospitals from April 2010 to December 2018. Hospitalizations for CAP (patient age ≥20 years) with an A-DROP classification for CAP severity and IV antibiotics initiated on the admission date were included. Overall, 210,314 hospitalizations (moderate CAP: 61.7%) in 183,607 patients were analyzed. The median (interquartile range [IQR]) age at admission was 79 (70–86) years. Penicillin (51.9%) and cephalosporin (38.9%) were the most common IV antibiotic classes used and the median (IQR) duration of IV use was 8 (6–11) days. Switching to oral antibiotics during a hospitalization occurred in 30.1% (n = 63,311) of patients after a median (IQR) of 7 (5–10) days of IV treatment. The most frequently used oral antibiotic classes after a switch were fluoroquinolone (45.9%) and penicillin (24.8%). The switch rate was higher among hospitalizations with milder CAP, in respiratory medicine ward and in larger hospitals. The overall switch rates did not change over the study period. The findings from this analysis suggest that early switch from IV to oral antibiotics was not widely implemented during the 8 years of the study period. Further observation will be needed to see the potential impact of the guidelines update in 2017 in Japan.

The incidence of gastric cancer occurring after successful Helicobacter pylori eradication has been increasing. We aimed to clarify the influence of eradication therapy on the ability to diagnose early gastric cancer after successful H. pylori eradication in patients who underwent annual endoscopic screening.A total of 220 patients (179 men; mean age 71.0 years) had differentiated-type early gastric cancer that was discovered through annual endoscopic screening. Patients were categorized into 2 groups: the H. pylori-eradicated group (n = 81) and the non-eradicated control group (n = 139). After matching patients by propensity scores, we retrospectively analyzed the clinicopathological characteristics of 162 patients (81 patients in each group). Furthermore, we compared the characteristics of gastric cancer with submucosal invasion between the 2 groups.The prevalence of early gastric cancer with submucosal invasion was significantly higher in the eradicated group than in the control group, both before propensity score matching (16.0 vs. 7.2%, respectively; p = 0.038) and after propensity score matching of 81 pairs (16.0 vs. 4.9%, respectively; p = 0.021). In the comparative analysis of gastric cancer with submucosal invasion, there was no difference between the 2 groups with respect to factors influencing the ability to diagnose its presence endoscopically.H. pylori eradication therapy increased the prevalence of differentiated-type gastric cancer with submucosal invasion despite patients' completion of annual endoscopic screening after eradication.

Summary Background Mucormycosis is an uncommon invasive fungal disease with high mortality and few treatment options. Isavuconazole is a triazole active in vitro and in animal models against moulds of the order Mucorales. We assessed the efficacy and safety of isavuconazole for treatment of mucormycosis and compared its efficacy with amphotericin B in a matched case-control analysis. Methods In a single-arm open-label trial (VITAL study), adult patients (≥18 years) with invasive fungal disease caused by rare fungi, including mucormycosis, were recruited from 34 centres worldwide. Patients were given isavuconazole 200 mg (as its intravenous or oral water-soluble prodrug, isavuconazonium sulfate) three times daily for six doses, followed by 200 mg/day until invasive fungal disease resolution, failure, or for 180 days or more. The primary endpoint was independent data review committee-determined overall response—ie, complete or partial response (treatment success) or stable or progressive disease (treatment failure)—according to prespecified criteria. Mucormycosis cases treated with isavuconazole as primary treatment were matched with controls from the FungiScope Registry, recruited from 17 centres worldwide, who received primary amphotericin B-based treatment, and were analysed for day-42 all-cause mortality. VITAL is registered with ClinicalTrials.gov, number NCT00634049. FungiScope is registered with ClinicalTrials.gov, number NCT01731353. Findings Within the VITAL study, from April 22, 2008, to June 21, 2013, 37 patients with mucormycosis received isavuconazole for a median of 84 days (IQR 19–179, range 2–882). By day 42, four patients (11%) had a partial response, 16 (43%) had stable invasive fungal disease, one (3%) had invasive fungal disease progression, three (8%) had missing assessments, and 13 (35%) had died. 35 patients (95%) had adverse events (28 [76%] serious). Day-42 crude all-cause mortality in seven (33%) of 21 primary-treatment isavuconazole cases was similar to 13 (39%) of 33 amphotericin B-treated matched controls (weighted all-cause mortality: 33% vs 41%; p=0·595). Interpretation Isavuconazole showed activity against mucormycosis with efficacy similar to amphotericin B. Isavuconazole can be used for treatment of mucormycosis and is well tolerated. Funding Astellas Pharma Global Development, Basilea Pharmaceutica International.

The findings from previously published studies have suggested that radiation exposure is associated with increased mortality and incidence of gastric cancer. However, few cohort studies have incorporated risk factors such as Helicobacter pylori (H. pylori) infection or chronic atrophic gastritis (CAG). The current study is aimed at evaluating the modifying effect of CAG on radiation risk of noncardia gastric cancer by histological type, by reanalyzing data from a nested case-control study conducted within the longitudinal clinical cohort of atomic bomb survivors. The analysis was restricted to 297 intestinal- or diffuse-type noncardia cases and 873 controls rematched to the cases on gender, age, city, and time and type of serum storage, and countermatched on radiation dose. Multivariable-adjusted relative risks [95% confidence interval (CI)] of noncardia gastric cancer were 3.9 (2.1-7.2) for H. pylori IgG seropositivity with cytotoxin-associated gene A (CagA) IgG low titer, 2.6 (1.9-3.6) for CAG, 1.9 (1.3-2.8) for current smoking, and 1.4 (1.1-1.9) for 1 Gy irradiation. Among subjects without CAG, the relative risk (95% CI) of noncardia gastric cancer at 1 Gy was 2.3 (1.4-3.7), whereas relative risk (95% CI) at 1 Gy was 1.1 (0.8-1.5) among subjects with CAG (for the overall interaction, P = 0.012). By histological type, the risk at 1 Gy was high for diffuse type without CAG, with adjusted relative risk (95% CI) of 3.8 (2.0-7.6), but was not high for diffuse type with CAG or for intestinal-type irrespective of CAG status. The results indicate that radiation exposure is associated with increased risk of diffuse-type noncardia gastric cancer without CAG, and this association exists despite adjustment for H. pylori infection and smoking habit.

Primary malignant melanoma of the esophagus (PMME) is rare but aggressive. PMME accounts for approximately 0. 1% of all malignant esophageal neoplasms occurring worldwide, and is usually diagnosed during the advanced stage. A 67-year-old man underwent an esophagogastroduodenoscopy (EGD) at our hospital and confirmed 20 mm of black pigmentation in the lower esophagus in the chest area. Pathological biopsy findings of the black-pigmented epithelial tissue revealed the presence of tumor cells with brown granules, leading to the diagnosis of malignant melanoma. Owing to difficulty in accurately diagnosing the range in this PMME case, we performed thoracoscopic esophagectomy. Pathological organisation test results were pT1a-LPM, INFb, pN0, and pM0, which were diagnosed at pStage I. The lesion expanded extensively, measuring > 10 cm in diameter. The tumor cells, which were centrally located in the black-pigmented area, were observed to have proliferated beyond the surrounding brownish area into the mucosa, but no findings were found in the endoscopic examination. As in this case, because PMME may diffusely spread along the basal layer outside the range of pigmentation, endoscopic diagnosis of the extent of disease spread may be impossible; hence, it is important to keep this phenomenon in mind while performing resection to treat PMME.

The aim of this study was to quantitatively evaluate the function of the cranial diploic and spinal epidural veins as cerebrospinal fluid (CSF) drainage pathways by measuring lipocalin-type prostaglandin D synthase (PGDS) and cystatin C (CysC) dissolved in the blood of these veins. This was a prospective study involving 51 consecutive patients, 31 males and 20 females, who underwent 41 cranial and 10 spinal surgeries. Intraoperatively, peripheral venous blood and diploic venous blood, or peripheral venous blood and spinal epidural venous blood samples were simultaneously collected and immediately centrifuged. For all samples, dissolved albumin (for reference), PGDS and CysC were measured using an enzyme-linked immunosorbent assay. The diploic vein/peripheral vein ratios in five cranial locations and epidural vein/peripheral vein ratios were calculated and statistically evaluated for the three biomarkers. For PGDS, the diploic vein/peripheral vein ratio was significantly increased in the frontal (P = 0.011), temporal (P = 0.028), parietal (P = 0.046) and skull base (P = 0.039), while it did not reach statistical significance for CysC. For patients older than 45 years, the diploic vein/peripheral vein ratio for PGDS was significantly decreased in the frontal region (P = 0.028), and the epidural vein/peripheral vein ratio for CysC was significantly decreased (P = 0.014). These results show that the diploic veins constitute CSF drainage pathways with heterogeneous functional intensity at different cranial locations. Compared with the diploic veins, spinal epidural veins seem to drain less CSF. The cranial diploic and spinal epidural veins may jointly function as an alternative, age-related trans-dural CSF drainage system.

Background Helicobacter pylori infection produces progressive mucosal damage that may eventually result in gastric cancer. We studied the changes that occurred in the presence and severity of atrophic gastritis and the prevalence of H. pylori infection that occurred coincident with improvements in economic and hygienic conditions in Japan since World War II. Materials and Methods The prevalence of H. pylori infection and histologic grades of gastric damage were retrospectively evaluated using gastric biopsy specimens obtained over a 40-year period. Gastric atrophy and intestinal metaplasia were scored using the updated Sydney classification system. Results The prevalence of H. pylori and severity of atrophy were examined in 1381 patients including 289 patients examined in the 1970s (158 men; mean age, 44.9 years), 787 in the 1990s (430 men; 44.2 years), and 305 in the 2010s (163 men; 53.2 years). Overall, the prevalence of H. pylori infection decreased significantly from 74.7% (1970s) to 53% (1990s) and 35.1% (2010s) (p

Background and Aim. Although many epidemiologic studies have shown thatHelicobacter pylorieradication has prophylactic effects on gastric cancer, it does not completely eliminate the risk of gastric cancer. We aimed to investigate the changes in histological gastritis in patients receiving rebamipide treatment afterH. pylorieradication.Methods. 206 patients who had undergoneH. pylorieradication were evaluated. Of these, 169 patients who achieved successful eradication were randomly allocated to 2 groups: the rebamipide group (n= 82) and the untreated group (n= 87). The primary endpoints were histopathological findings according to the updated Sydney system at the start of the study and after 1 year.Results. Final assessment for histological gastritis was possible in 50 cases from the rebamipide group and 53 cases from the untreated group. The activity and atrophy improved in both the rebamipide and untreated groups, and no significant intergroup differences were observed. Chronic inflammation affecting the lesser curvature of the corpus was significantly improved in the rebamipide group compared to in the untreated group (1.12±0.08versus1.35±0.08;P= 0.043).Conclusions. Rebamipide treatment afterH. pylorieradication alleviated chronic inflammation in the lesser curvature of the corpus compared to that in the untreated group. This trial is registered withUMIN000002369.

Reddish depressed lesions (RDLs) frequently observed in patients following Helicobacter pylori eradication are indistinguishable from gastric cancer. We examined the clinical and histological feature of RDLs and its relevant endoscopic diagnosis including magnifying narrow-band imaging (M-NBI).We enrolled 301 consecutive patients with H. pylori eradication who underwent endoscopy using white light imaging (WLI). We examined the prevalence and host factors contributing to the presence of RDLs. Next, we used M-NBI in 90 patients (104 RDLs), and compared the diagnostic efficacy between M-NBI and WLI groups using propensity-score matching analysis.In 301 patients after eradication, 117 (39%) showed RDLs. Male, open-type atrophy, and gastric cancer history were risk factors for RDLs. A gastric biopsy was needed in 83 (71%) during WLI observation and only 2 were diagnosed with adenocarcinoma. In M-NBI group, a biopsy was performed in 21 (20%), and 9 were diagnosed with adenocarcinoma. A biopsy was required in fewer patients, and the positive predictive value of a biopsy was statistically higher in M-NBI than in the WLI group (p0.01).RDLs are frequently observed in high-risk patients for gastric cancer after eradication. M-NBI demonstrated significantly superior diagnostic efficacy with respect to RDL.

Despite extensive investigations, the process of development of chronic subdural hematoma (CSDH) is not known. The present study aims to investigate CSDH by measuring biomarkers in it, gas analysis, and immunohistochemical examination. A total of 42 patients with symptomatic CSDH who underwent burr-hole drainage were enrolled. Intraoperatively, hematoma fluid and peripheral venous blood (PVCSDH) were simultaneously collected. As controls, peripheral venous blood (PVControl) and intracranial cerebrospinal fluid (CSF) were collected from other subjects during other surgeries. CatK, lipocalin-type prostaglandin D synthase (PGDS), and cystatin C (CysC) present in these specimens were measured using enzyme-linked immunosorbent assay. Data obtained were statistically analyzed after age correction. In 15 patients, gas analysis was performed for CSDH and PVCSDH. Furthermore, immunohistochemical examination for the outer membrane was performed for four patients. CatK, PGDS, and CysC levels were markedly elevated in the CSF and CSDH. CatK levels in PVCSDH were significantly higher than in PVControl (P

Chondroid chordoma (CC) is a rare but commonest subtype of chordoma with little reported clinical information. The present study summarizes and updates present knowledge of CC. Literature search for demographic data and clinical appearance of cranial CCs except for those entirely confined to the sinonasal region. A total of 48 English language papers published from 1968–2013 were retrieved describing 132 CCs as skull base tumors. The male-to-female ratio was 1:1. The mean age at diagnosis was 43 years, predisposing to the third to fifth decades of life. The clival (34 %) and spheno-occipital (29 %) regions were the most frequent sites of origin followed by the sellar (12 %) and sphenoid (5 %) regions. Intratumoral calcification and bony erosion were identified as the characteristic neuroimaging findings. Surgical resection by the transcranial, transsphenoidal, transnasal, transpharyngeal, or transpalatal route with or without adjuvant radiotherapy was the main treatment option. The initial treatment outcome was satisfactory in 82 % of cases with considerably better prognosis compared with typical chordomas. CC is a distinct entity to be discriminated from the typical type of chordoma. There are no distinguishing features on magnetic resonance imaging between CC and typical chordoma. Intratumoral calcification and concurrent bony erosion on neuroimaging should suggest the possibility of CC. Extensive surgical resection and adjuvant radiotherapy can achieve satisfactory outcome.

BACKGROUND AND PURPOSE: Studies have suggested that arachnoid villi or granulations found in the walls of the cranial dural sinuses, olfactory mucosa, and cranial nerve sheaths function as outlets for intracranial CSF. However, their role as CSF outlets has not yet been verified. Here we show that arachnoid protrusions and contiguous diploic veins provide an alternative drainage route for intracranial CSF. MATERIALS AND METHODS: Four hundred patients with intact skull, dura mater, and dural sinuses underwent MR imaging to explore arachnoids protruding into the skull and diploic veins. Patients with symptoms of increased intracranial pressure or intracranial hypotension were excluded. For 15 patients undergoing craniotomy, both peripheral and diploic venous blood was collected. Albumin and the CSF-specific biomarkers were measured by enzyme-linked immunosorbent assay. RESULTS: With MR imaging, arachnoid protrusions into the skull and contiguous diploic veins were consistently identified throughout the cranium with their characteristic appearance depending on the cranial region. In addition, elevated amounts of prostaglandin D synthase and cystatin C were confirmed in diploic veins compared with peripheral venous blood. CONCLUSIONS: Diploic veins are distributed ubiquitously throughout the cranium. A portion of the intracranial CSF may be drained through arachnoid protrusions and contiguous diploic veins.

Background The incidence of gastric cancer after successful Helicobacter pylori eradication has been increasing. We previously reported that epithelium with low-grade atypia (ELA) appeared on the surface of gastric cancer after H. pylori eradication. Here, we investigate the clinical and biological characteristics of such ELA. Methods We studied 27 cases of gastric cancer detected after successful H. pylori eradication therapy. We examined the prevalence of ELA among these cases and its significance for endoscopic discovery after H. pylori eradication. We additionally investigated the mucus, p53 and Ki67 expressions in ELA. Results Epithelium with low-grade atypia that continuous with the gastric tumor was detected in 22 of 27 cases (81%), a significantly greater percentage than that for controls (p

The serological risk-prediction system combined the pepsinogen (PG) test, and anti-Helicobacter pylori antibody is available for evaluation of gastric cancer risk. In this system, chronic atrophic gastritis (CAG) or H. pylori infection is diagnosed. Subjects with H. pylori negative and PG test negative (group A) are supposed to be those who have never been infected with H. pylori and are at extremely low risk for gastric cancer. However, a certain proportion of patients with CAG has been identified as the extremely low-risk group (group A). Here we examined endoscopic atrophy and investigated its relationship with the ABC classification system.We examined 540 patients. All patients underwent an endoscopic examination for evaluating corpus atrophy. Fasting sera were collected and serum PGs and anti-H. pylori antibody (Hp-Ab) titer (E-plate Eiken) were evaluated.Of the 540 patients, 306 were classified into group A. However, 136 of them showed signs of endoscopic atrophy (group A with CAG). Group A with CAG frequently comprised the elderly. A new titer cut-off (3 U/mL) of the Hp-Ab improved the discrimination of group A with CAG by 8%.The prevalence of group A with CAG patients is a critical problem, especially in elderly subjects.

Background and Aim Type I gastric carcinoids (TIGC) are associated with chronic atrophic gastritis (CAG) with hypergastrinemia and hyperplasia of enterochromaffin-like cells. Several treatment options are currently available for these tumors including total gastrectomy, partial resection, antrectomy, endoscopic resection and endoscopic surveillance. The present study evaluated different treatment approaches and clinical outcomes of patients with TIGC in Japan. Methods Between 1991 and 2011, 82 patients with TIGC were identified at multicenter institutions in Japan. Patient demographics, tumor size, depth of invasion, vessel involvement, treatment approach, Helicobacter pylori infection, serum gastrin level, recurrence-free survival (RFS) and disease-specific survival (DSS) were analyzed. Results Median age of all patients at the time of diagnosis was 56 years (range, 24−79 years). There were 44 males and 38females. Patients underwent endoscopic surveillance (n = 25), endoscopic resection (n = 41) or surgical resection (n = 16). Intramucosal invasion was found in 19 patients, submucosal invasion in 44 patients and muscularis propria invasion in one patient. Tumor diameter was ≤10 mm in 71 patients, 11–20 mm in five patients and ≥21 mm in five patients. None of the patients showed rapidly growing tumors, local recurrence or metastasis. The median (range) follow-up period was 7 (0–20) years. RFS was 97.6% and DSS was 100% in all the patients. Conclusion The prognosis of TIGC patients treated by different modalities in Japan is favorable regardless of the generational change of management for TIGC.

Primary spinal extradural Ewing’s sarcoma (PSEES) or primitive neuroectodermal tumor (PNET) is uncommon. The present study summarizes the magnetic resonance (MR) imaging appearance of PSEES. Literature search from 1994 to 2012 with our representative case presentation. Twenty-one patients, 12 males and 9 females, aged 3 weeks to 44 years, were identified. The thoracic spine was most frequently affected, followed by the cervical, cervicothoracic, and thoracolumbar spine. Superior–inferior extension of lesions was three vertebral levels in 7, two in 7, five in 4, four in 1, one in 1 and unknown in 1. PSEESs appeared isointense in 9 cases, hypointense in 2, hyperintense in 1, and no description in 9 on T1-weighted imaging, while hyperintense in 6, hypointense in 3, heterogeneous in 1, and no description in 11 on T2-weighted imaging. Varying enhancement was noted in 13 cases (62 %), with no description of contrast study in the other 8 cases. Dumbbell-shaped configuration of PSEES was found in 5 cases, foraminal widening in 4, and erosions or scalloping of the adjacent vertebral bodies in 4. The MR imaging appearance of PSEESs is indistinguishable from other tumors. PSEES should be assumed as the differential diagnosis of spinal extradural tumors in pediatric, adolescent, and young adult patients, and prompt surgical exploration should be performed.