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Eradication of Helicobacter pylori has contributed to the treatment of peptic ulcers and mucosa-associated lymphoid tissue lymphoma. Moreover, it has possibly decreased the prevalence of gastric cancer. However, eradication therapy is associated with various adverse effects, of which diarrhea is the most common. The incidence of diarrhea after eradication treatment varies from 8% to 48%. In particular, the incidence is higher in patients who receive first-line standard triple therapy compared with those who receive second-line therapy. Both antibiotics and proton pump inhibitors, components of eradication therapy, have short-term and long-term impacts on gut microbiota. The alterations of gut microbiota may not recover until 1 year after eradication therapy. Most cases of diarrhea that occur after eradication therapy are antibiotic-associated diarrhea caused by the destruction of the normal gut microbiota. In some cases, Clostridioides difficile-associated diarrhea occurs after eradication therapy. If bloody diarrhea occurs after eradication therapy and the Clostridioides difficile toxin is not detected, antibiotic-associated hemorrhagic colitis associated with Klebsiella oxytoca infection should be suspected. It is crucial to explain the possibility of diarrhea before initiating eradication therapy to increase compliance. Furthermore, probiotics may be administered to reduce diarrhea. If severe diarrhea or symptoms other than the usual antibiotic-associated diarrhea occur during or after eradication therapy, antibiotics should be discontinued. In addition, appropriate tests to determine the cause of diarrhea should be performed. This review summarizes the alteration of the gut microbiota, the causes of diarrhea after Helicobacter pylori eradication therapy, and its management.

Background/Aims: Studies in healthy humans have reported that the addition of mosapride to acid suppressants resulted in higher intragastric pH than acid suppressant administration alone. We investigated the effect of the addition of mosapride to famotidine on the intragastric pH and gastric emptying rate (GER) in rats.Materials and Methods: Sixty male Wistar rats were used in this study. Experimental groups were divided into control, famotidine-only, mosapride-only, and famotidine with mosapride (combination). The first experiment was performed in non-stressed rats. Mosapride was administered by oral gavage 1 hour before the meal, and famotidine was administered just before the meal. The rats were provided with food for 30 minutes. The intragastric pH was measured under isoflurane anesthesia, and the GER was measured after harvesting the stomach. In the stress experiment, rats were exposed to 1-hour restraint stress immediately after mosapride administration and subjected to the same process as in the experiment with the non-stressed rats.Results: The famotidine-only and combination groups showed significantly higher gastric pH levels than the control group in non-stressed (P

Background/aim We evaluated the predictive value of candidate serum biomarkers for recurrence in stage II and III colorectal cancer (CRC) after curative surgery. Patients and methods A total of 33 and 120 patients with CRC with or without recurrence at 5 years after curative surgery were included in the training set and the validation set, respectively. Possible serum biomarkers were examined for associations with CRC recurrence using receiver operating characteristics (ROC) curve analysis. Results In the training set, the expression levels of the 14 biomarkers were compared according to recurrence. Among them, five biomarkers that had significantly different expression levels were validated in 60 patients with recurrence at 5 years after curative surgery and 60 patients without. Multivariate analysis showed that natural log-transformed values of carcinoembryonic antigen (CEA), cyclin-dependent kinase regulatory subunit 2 (CKS2), 2'-5'-oligoadenylate synthetase 2 (OAS2), and autophagy-related gene 5 (ATG5) in preoperative serum were significantly related to recurrence. ROC analysis showed that these biomarkers were able to discriminate patients with recurrence from those without (area under the curve=0.828, 95% confidence interval=0.755-0.990). Conclusion Preoperative serum levels of CEA, CKS2, OAS2 and ATG5 were independent risk factors for recurrence. A combination of serum CEA, CKS2, OAS2 and ATG5 predicted tumor recurrence well in patients with stage II and III CRC.

IntroductionThe proximal femur is a common site for primary sarcomas and metastatic lesions. Although the early results of tumor prostheses are promising, the long-term results of reconstruction are unknown. The purpose of this study is to evaluate the prognostic factors affecting prosthesis survival and complications after proximal femoral resection and reconstruction.MethodsWe reviewed the results of 68 patients who underwent proximal femoral resection and reconstruction with a modular bipolar-type tumor prosthesis between 2005 and 2017. The mean follow-up was 55.6 months (range 6–172 months). There were 50 male and 18 female patients with a mean age of 41.5 years (range 11–80 years). Cumulative survival analysis was performed to analyze the risk factors of prosthesis survival. We also evaluated the complications after operation.ResultsFourteen (21%) patients required further surgery at a mean 37 months post-operatively (range 5–125 months). There were three cases of infection (4%), six of local recurrence (9%), three of acetabular erosion (4%) and two of stem loosening (3%). The implant survival rates were 83.9% at 5 years and 59.8% at 10 years. Prosthesis survivals did not differ based on fixation method (P = 0.085), age (P = 0.329) or resection length (P = 0.61). Acetabular chondrolysis was identified in 18 (26%) patients and longer resection length (≥20 cm) showed a trend for risk of acetabular wear (P = 0.132).ConclusionThe results of proximal femoral resection and reconstruction with a modular bipolar-type prosthesis were found to be acceptable with infection and local recurrence as short-term complications and loosening and acetabular erosion as long-term complications.

Background/Aims Gastroparesis is identified as a subject that is understudied in Asia. The scientific committee of the Asian Neurogastroenterology and Motility Association performed a Knowledge, Attitude, and Practices survey on gastroparesis among doctors in Asia. Methods The questionnaire was created and developed through a literature review of current gastroparesis works of literature by the scientific committee of Asian Neurogastroenterology and Motility Association. Results A total of 490 doctors from across Asia (including Bangladesh, China, Hong Kong, Indonesia, Japan, Malaysia, Myanmar, the Philippines, Singapore, South Korea, Taiwan, Thailand, and Vietnam) participated in the survey. Gastroparesis is a significant gastrointestinal condition. However, a substantial proportion of respondents was unable to give the correct definition and accurate diagnostic test. The main reason for lack of interest in diagnosing gastroparesis was “the lack of reliable diagnostic tests” (46.8%) or “a lack of effective treatment” (41.5%). Only 41.7% of respondents had access to gastric emptying scintigraphy. Most doctors had never diagnosed gastroparesis at all (25.2%) or diagnosed fewer than 5 patients a year (52.1%). Conclusions Gastroparesis can be challenging to diagnose due to the lack of instrument, standardized method, and paucity of research data on normative value, risk factors, and treatment studies in Asian patients. Future strategies should concentrate on how to disseminate the latest knowledge of gastroparesis in Asia. In particular, there is an urgent need to estimate the magnitude of the problems in high risk and idiopathic patients as well as a standardized diagnostic procedure in Asia. (J Neurogastroenterol Motil 2021;27:46-54)

Background/Aims The gut microbiota regulates intestinal immune homeostasis through host-microbiota interactions. Multiple factors affect the gut microbiota, including age, sex, diet, and use of drugs. In addition, information on gut microbiota differs depending on the samples. The aim of this study is to investigate whether changes in cecal microbiota depend on aging. Methods Gut microbiota in cecal contents of 6-, 31-, and 74-week-old and 2-year-old male Fischer-344 rats (corresponding to 5-, 30-, 60-, and 80-year-old humans in terms of age) were analyzed using 16S ribosomal RNA metagenome sequencing and phylogenetic investigation of communities by reconstruction of unobserved states (PICRUSt) based on the Kyoto Encyclopedia of Genes and Genomes orthology. Moreover, short-chain fatty acid (SCFA) level in cecum and inflammation related factors were measured using real-time quantitative polymerase chain reaction and enzyme linked immunosorbent assay. Results Alpha and beta diversity did not change significantly with age. At the family level, Lachnospiraceae and Ruminococcaceae, which produce SCFAs, showed significant change in 31-week-old rats: Lachnospiraceae significantly increased at 31 weeks of age, compared to other age groups, while Ruminococcaceae decreased. Butyrate levels in cecum were significantly increased in 31-week-old rats, and the expression of inflammation related genes was increased followed aging. Especially, EU622775_s and EU622773_s, which were highly abundance species in 31-week-old rats, showed significant relationship with butyrate concentration. Enzymes required for producing butyrate―acetyl-CoA transferase, butyryl-CoA dehydrogenase, and butyrate kinase―were not predicted by PICRUSt. Conclusions Major bacterial taxa in the cecal lumen, such as Lachnospiraceae, well-known SCFAs-producing family, changed in 31-week-old rats. Moreover, unknown species EU622775_s and EU622773_s showed strong association with cecal butyrate level at 31 weeks of age. (J Neurogastroenterol Motil 2021;27:134-146)

Background/Aims: The incidence of peptic ulcer disease has decreased in past decades; however, the trends in peptic ulcer bleeding (PUB) are inconsistent among regions. This study aimed to investigate the trends in PUB incidence and the effect of risk factors on PUB in Korea. Methods: The records of patients hospitalized with PUB from 2006 to 2015 were retrieved from the Korean National Health Insurance Service Database. Standardized incidences of PUB were calculated, and the clinical characteristics such as age, sex, Helicobacter pylori infection, drug exposure, comorbidities, and mortality were obtained. Results: In total, 151,507 hospitalizations with PUB were identified. The overall annual hospitalization rate was 34.98 per 100,000 person-years. The incidence of PUB showed no significant change from 2006 to 2008 and decreased from 2008 to 2015, with an annual change of -2.7% (p

As few genotype–phenotype correlations are available for nonsyndromic hereditary colorectal cancer (CRC), we implemented genomic analysis on the basis of the revised Bethesda guideline (RBG) and extended (12 items) to verify possible subtypes. Patients with sporadic CRC (n = 249) were enrolled, stratified according to the revised Bethesda guidelines (RBG+ and RBG− groups) plus additional criteria. Exome/transcriptome analyses (n = 98) and cell-based functional assays were conducted. We detected 469 somatic and 830 germline gene mutations differing significantly between the positive and negative groups, associated with 12 RBG items/additional criteria. Twenty-one genes had significantly higher mutation rates in left, relative to right, colon cancer, while USP40, HCFC1, and HSPG2 mutation rates were higher in rectal than colon cancer. FAT4 mutation rates were lower in early-onset CRC, in contrast to increased rates in microsatellite instability (MSI)-positive tumors, potentially defining an early-onset microsatellite-stable subtype. The mutation rates of COL6A5 and MGAM2 were significantly and SETD5 was assumably, associated CRC pedigree with concurrent gastric cancer (GC). The predicted deleterious/damaging germline variants, SH2D4A rs35647122, was associated with synchronous/metachronous CRC with related tumors, while NUP160 rs381660 and KRTAP27-1 rs2244485 were potentially associated with a GC pedigree and less strictly defined hereditary CRC, respectively. SH2D4A and NUP160 acted as oncogenic facilitators. Our limited genomic analysis for RBG and additional items suggested that specific somatic alterations in the respective items may enlighten relevant pathogenesis along with the knowledge of germline mutations. Further validation is needed to indicate appropriate surveillance in suspected individuals.

Background/Aims Effect of proton pump inhibitor (PPI) use on the risk of hip fracture is controversial. This study aimed to clarify the association between PPI use and hip fracture risk using a large cohort. Methods This study recruited participants from the nationwide cohort (n = 1,025,340). After exclusion of participants who had hip fractures or were aged less than 40 years during the baseline period (2002 to 2004), 371,806 participants were followed to 2013. Participants prescribed PPIs for more than 90 days during baseline period were defined as users. Fracture cases were defined when participants were hospitalized with claims of a hip fracture. Results During 4,159,343 person-years of follow-up, fractures developed more often in PPI users than in nonusers (relative risk [RR], 1.787; 95% confidence interval [CI], 1.260 to 2.534; p = 0.002). The results persisted after adjusting for age, sex, and many drugs relevant to osteoporosis or influential in bone health. Furthermore, fracture risk associated with PPI use increased with duration of use (p trend < 0.001). The fully adjusted RRs of hip fracture development were 1.350 (95% CI, 1.203 to 1.515) for 1- to 90-day users, 1.487 (95% CI, 0.957 to 2.311) for 91- to 180-day users, and 1.771 (95% CI, 0.931 to 3.368) for > 180-day users. The positive association between PPI use and fracture was also confirmed in a subgroup with health screening data where further adjustment for body mass index, smoking status, alcohol consumption, and physical activity was available (adjusted RR, 2.025; 95% CI, 1.151 to 3.564, p = 0.014). Conclusions PPI use is associated with hip fracture development.

Background Spontaneous disease stabilization of desmoid-type fibromatosis (DF) has been demonstrated in many reports, and the watchful waiting approach without any frontline treatment is becoming popular as an initial management strategy. In this study, we aimed to assess the disease stabilization rate and identify predictive factors for disease stabilization of DF in patients with conservative treatment. Methods We reviewed 76 patients with sporadic extra-abdominal DF who were managed with frontline conservative treatment in our institute. The minimum follow-up was 12 months. Stabilization was defined as radiological evidence of no change or continuous decrease in size of the tumor for six months or more. The primary endpoint was stabilization of DF. Possible patient-, disease-, and treatment-related factors predictive of disease stabilization were analyzed with multivariate analysis. Results At final follow-up, 54 of the 76 tumors (71%) were stable, and mean time to stabilization was 30.4 months (range, 7 to 112 months). On Kaplan-Meier survival analysis, the spontaneous stabilization rate was 25.4% at one year, 52.7% at two years, and 70.9% at three years. The mean time to spontaneous stabilization was longer in patients with ≤ 40 years of age (p = 0.022) or recurrence (p = 0.041). On multivariate analysis with the Cox proportional hazard method, recurrence (hazard ratio [HR], 1.79; p = 0.041) and younger age (HR, 2.04; p = 0.022) were identified as independent prognostic factors for longer time to disease stabilization. Conclusions Frontline conservative treatment seems to be the optimal treatment for most patients with DF. Younger patients or those with recurrence may require longer time to spontaneous disease stabilization.

Approximately half of colorectal cancer (CRC) patients experience disease recurrence and metastasis, and these individuals frequently fail to respond to treatment due to their clinical and biological diversity. Here, we aimed to identify a prognostic signature consisting of a small gene group for precisely predicting CRC heterogeneity. We performed transcriptomic profiling using RNA-seq data generated from the primary tissue samples of 130 CRC patients. A prognostic index (PI) based on recurrence-associated genes was developed and validated in two larger independent CRC patient cohorts (n = 795). The association between the PI and prognosis of CRC patients was evaluated using Kaplan–Meier plots, log-rank tests, a Cox regression analysis and a RT-PCR analysis. Transcriptomic profiling in 130 CRC patients identified two distinct subtypes associated with systemic recurrence. Pathway enrichment and RT-PCR analyses revealed an eleven gene signature incorporated into the PI system, which was a significant prognostic indicator of CRC. Multivariate and subset analyses showed that PI was an independent risk factor (HR = 1.812, 95% CI = 1.342–2.448, P, Colorectal cancer: a tool to identify risk of recurrence A prognostic tool that searches for eleven genes associated with colorectal cancer recurrence shows promise in initial trials. The complexity of colorectal cancer (CRC) makes it challenging to treat. A significant number of patients relapse or experience metastasis even after surgical intervention, and fail to respond to post-surgical chemotherapy. Yong Sung Kim at the Korea Research Institute of Bioscience and Biotechnology, Daejeon, and Jin Cheon Kim from the University of Ulsan, Seoul, South Korea, and co-workers, conducted RNA-sequencing analysis on samples from 130 patients with CRC, 58 of whom had suffered relapse. They pinpointed eleven genes strongly associated with recurrence-free survival. They used these to develop a prognostic tool to identify high-risk patients and those more likely to respond poorly to chemotherapy. The tool was validated on a further 795 patients with CRC.

Clear cell chondrosarcoma (CCC) is a rare subtype of chondrosarcoma with a relatively low malignant potential, mainly diagnosed by its characteristic location in the epiphysis of long bones. We report the case of a 33-year-old gentleman who presented with pain, difficulty in walking and restricted range of motion of the right hip joint, with a lesion located in the proximal femoral metaphysis and completely sparing the epiphysis. Needle biopsy was consistent with CCC, which was extremely unusual considering the location of the tumour. The patient was treated by “en bloc” resection of the tumour along with femoral head and reconstruction with hemiarthroplasty. The final histopathology report confirmed the diagnosis with clear surgical margins. The aim of this case report and literature review was to highlight the unusual location of this rare tumour, as such an isolated case of CCC completely sparing the epiphysis has never been reported.

Dietary control plays an important role in the treatment of irritable bowel syndrome (IBS). However, few studies have examined the relationship between dietary intake and symptoms of IBS in Koreans. The current cross-sectional study aimed to examine the diet in food consumption and nutrient intake in Korean adults aged 20 to 40 with IBS. The data collected were completed by 857 subjects using a community-based web survey. The questionnaire covered functional bowel disorders based on Rome III, the semi-quantitative Food Frequency Questionnaire (SQ-FFQ), and the food items causing symptoms. In total, 186 of 857 subjects (21.7%) were diagnosed with IBS. The non-IBS group had a fat intake of 76.9 ± 47.9 g/day, while the IBS group had a fat intake of 86.6 ± 55.1 g/day (p = 0.014). The non-IBS group had a total fermentable oligosaccharide, disaccharide, monosaccharide, and polyol (FODMAP) intake of 12.6 ± 9.7 g/day, whereas the IBS group had a total FODMAP intake of 13.9 ± 9.9 g/day (p = 0.030). Foods that contributed to the onset of symptoms in the IBS group were instant noodles (70.8%), Chinese noodles with vegetables and seafood (68.7%), pizza (67.2%), and black bean sauce noodles (66.3%) which are mostly classified as high fat and high gluten foods. The dietary intake of IBS patients differs from that of non-IBS subjects. Increased intake of gluten-containing or high-fat foods due to the westernized diet caused more IBS symptoms than high FODMAPs and dairy products in Korean adults in their 20 s to 40 s.

Simple Summary Thyroid nodules are frequently detected, but the majority of these nodules are benign. Molecular markers have become useful for diagnosing the minority of thyroid cancer. We performed high-throughput small RNA sequencing in a discovery cohort and identified three miRNAs (miR-136, miR-21, and miR-127) as potential biomarkers for thyroid cancer. We validated the diagnostic and prognostic utilities of three miRNAs in patients with thyroid cancer in an independent cohort. High expression of the three miRNAs could be used to differentiate thyroid cancers from benign tumors and tumors with extremely low malignant potential. In patients with thyroid cancers, a high expression of three miRNAs was associated with poor clinicopathological features and recurrent or persistent disease following surgery. Therefore, testing for high expression levels of these three miRNAs in thyroid nodules may be useful for diagnosing and assessing the recurrence of the thyroid cancer’s risk stratification. Abstract The challenge in managing thyroid nodules is to accurately diagnose the minority of those with malignancy. We aimed to identify diagnostic and prognostic miRNA markers for thyroid nodules. In a discovery cohort, we identified 20 candidate miRNAs to differentiate between noninvasive follicular thyroid neoplasms with papillary-like nuclear features (NIFTP) and papillary thyroid carcinomas (PTC) by using the high-throughput small RNA sequencing method. We then selected three miRNAs (miR-136, miR-21, and miR-127) that were differentially expressed between the PTC follicular variant and other variants in The Cancer Genome Atlas data. High expression of three miRNAs differentiated thyroid cancer from nonmalignant tumors, with an area under curve (AUC) of 0.76–0.81 in an independent cohort. In patients with differentiated thyroid cancer, the high-level expression of the three miRNAs was an independent indicator for both distant metastases and recurrent or persistent disease. In patients with PTC, a high expression of miRNAs was associated with an aggressive histologic variant, extrathyroidal extension, distant metastasis, or recurrent or persistent disease. Three miRNAs may be used as diagnostic markers for differentiating thyroid cancers from benign tumors and tumors with extremely low malignant potential (NIFTP), as well as prognostic markers for predicting the risk of recurrent/persistent disease for differentiated thyroid cancer.

Objectives We aimed to evaluate the sex-specific effect of apolipoprotein E (APOE) alleles and methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism on the biochemical, anatomical, and cognitive profiles of Alzheimer's disease (AD) patients. Methods The patient (followed-up for at least 2 years) medical records, which comprised of data on plasma homocysteine and folate levels, lipid profile, HbA1c, MTHFR C677T genotype, APOE allele type, mini-mental state examination (MMSE) and clinical dementia rating (CDR) scores, and brain scans, were retrospectively analyzed. Two trained neurologists scored the white matter lesions (Fazekas scale), medial temporal lobe atrophy (MTA), and microbleeds using brain magnetic resonance imaging scans. Results This study included 574 patients clinically diagnosed with probable AD (average age, 73.2 years; mean MMSE score, 10.05). The effect of sex on all parameters was evaluated. The triglyceride (TG) and homocysteine levels and the MTA and Fazekas scores were higher in female APOE-e4/e4 carriers than in women without APOE-e4. The TG and homocysteine levels were lower in men with the MTHFR CC allele than in those with the MTHFR TT allele. In contrast, MTHFR polymorphism and APOE-e4 alleles were not significantly correlated with anatomical lesions and rate of decline in the MMSE and CDR scores. Conclusions We demonstrated the sex-specific effect of the APOE allele and MTHFR polymorphism on the serological and anatomical biomarkers in AD patients. The APOE allele and MTHFR mutations did not directly affect cognitive progression, but differentially affected other biochemical factors, between the sexes. These findings will aid in devising novel preventive and therapeutic strategies.

The pathophysiology of functional gastrointestinal disorders (FGIDs) is still unclear and various complex mechanisms have been suggested to be involved. In many cases, improvement of symptoms and quality of life (QoL) in patients with FGIDs is difficult to achieve with the single-targeted treatments alone and clinical application of these treatments can be challenging owing to the side effects. Herbal preparations as complementary and alternative medicine can control multiple treatment targets of FGIDs simultaneously and relatively safely. To date, many herbal ingredients and combination preparations have been proposed across different countries and together with a variety of traditional medicine. Among the herbal therapies that are comparatively considered to have an evidence base are iberogast (STW-5) and peppermint oil, which have been mainly studied and used in Europe, and rikkunshito and motilitone (DA-9701), which are extracted from natural substances in traditional medicine, are the focus of this review. These herbal medications have multi-target pharmacology similar to the etiology of FGIDs, such as altered intestinal sensory and motor function, inflammation, neurohormonal abnormality, and have displayed comparable efficacy and safety in controlled trials. To achieve the treatment goal of refractory FGIDs, extensive and high quality studies on the pharmacological mechanisms and clinical effects of these herbal medications as well as efforts to develop new promising herbal compounds are required.

Quality of life (QoL) has become an important issue after early gastric cancer (EGC) treatment. We aimed to compare the QoL of EGC survivors after ESD (n = 241) or laparoscopic subtotal gastrectomy (n = 241) without recurrence and to evaluate the QoL over the 5-year period after adjusting for various confounding factors related to QoL. QoL related to the gastric cancer subscale (GCS) was significantly higher in the ESD group than surgery group (p p = 0.983). Therefore, we concluded that EGC survivors who undergo ESD have significantly better QoL related to GCS over a 5-year period after treatment than those who undergo surgery. This may be a useful consideration when selecting treatment modalities for patients with EGC.

Background/aims The different clinical manifestations of gastroesophageal reflux disease (GERD) may be influenced by associated psychological factors. We evaluated the psychological status (anxiety and depression) according to each subtype of GERD. Methods Subjects who underwent esophagogastroduodenoscopy and completed a symptom questionnaire between January 2008 and December 2011 were analyzed. The subjects were classified into the following groups: erosive reflux disease (ERD), non-erosive reflux disease (NERD), asymptomatic erosive esophagitis (AEE), and controls. Anxiety and depression were assessed using the State-Trait Anxiety Inventory and Beck Depression Inventory, respectively. Results We analyzed 19 099 subjects: 16 157 (84.6%), 176 (0.9%), 1398 (7.3%), and 1368 (7.2%) in the control, ERD, NERD, and AEE groups, respectively. Multiple multinomial logistic regression revealed a significant association of increased state (adjusted OR, 1.89; 95% CI, 1.53-2.33) and trait anxiety (adjusted OR, 1.78; 95% CI, 1.34-2.35) and depression (adjusted OR, 2.21; 95% CI, 1.75-2.80) with NERD. ERD group showed a significant association only with state anxiety (adjusted OR, 2.20; 95% CI, 1.27-3.81) and depression (adjusted OR, 2.23; 95% CI, 1.18-4.22). The AEE group, however, did not show any significant association with psychological factors. Conclusion This cross-sectional study revealed that anxiety and depression levels were significantly higher in subjects with GERD (notably in the NERD) than in controls.

Background Cerebellum has an important role in sensorimotor control including speech. Multiple system atrophy (MSA) is a sporadic and rapidly progressive neurodegenerative disorder that presents with autonomic failure in combination with Parkinsonism or cerebellar ataxia. Case Report We report a case of MSA-cerebellum subtype associated with emergence of irreversible explosive speech following olanzapine therapy. Conclusions Further investigation into speech problems in MSA according to subtype and disease severity is needed, and side effects of olanzapine therapy should also be considered.

Importance Knowledge and attitude influence compliance and individuals’ practices. The risk and protective factors associated with high compliance to these preventive measures are critical to enhancing pandemic preparedness. Objective This survey aims to assess differences in mental health, knowledge, attitudes, and practices (KAP) of preventive measures for COVID-19 amongst healthcare professionals (HCP) and non-healthcare professionals. Design Multi-national cross-sectional study was carried out using electronic surveys between May-June 2020. Setting Multi-national survey was distributed across 36 countries through social media, word-of-mouth, and electronic mail. Participants Participants ≥21 years working in healthcare and non-healthcare related professions. Main outcome Risk factors determining the difference in KAP towards personal hygiene and social distancing measures during COVID-19 amongst HCP and non-HCP. Results HCP were significantly more knowledgeable on personal hygiene (AdjOR 1.45, 95% CI -1.14 to 1.83) and social distancing (AdjOR 1.31, 95% CI -1.06 to 1.61) compared to non-HCP. They were more likely to have a positive attitude towards personal hygiene and 1.5 times more willing to participate in the contact tracing app. There was high compliance towards personal hygiene and social distancing measures amongst HCP. HCP with high compliance were 1.8 times more likely to flourish and more likely to have a high sense of emotional (AdjOR 1.94, 95% CI (1.44 to 2.61), social (AdjOR 2.07, 95% CI -1.55 to 2.78), and psychological (AdjOR 2.13, 95% CI (1.59–2.85) well-being. Conclusion and relevance While healthcare professionals were more knowledgeable, had more positive attitudes, their higher sense of total well-being was seen to be more critical to enhance compliance. Therefore, focusing on the well-being of the general population would help to enhance their compliance towards the preventive measures for COVID-19.

Background/Aims In spite of increased concerns about the overlaps among the various functional gastrointestinal disorders (FGIDs), studies for the overlap between constipation and other common FGIDs are rare. Therefore, we investigated the patterns of overlaps between constipation and other common FGIDs. Methods This study was designed as a prospective nationwide multi-center questionnaire study using Rome III questionnaires for functional dyspepsia (FD), irritable bowel syndrome (IBS), and functional constipation (FC), as well as various questionnaires about patients' information, degree of symptoms, and quality of life. For the evaluation of gastroesophageal reflux disease (GERD), GERD-Q was used. Results From 19 centers, 759 patients with constipation were enrolled. The proportions of FC and IBS subtypes of constipation (IBS-C) were 59.4% and 40.6%, respectively. Among them, 492 (64.8%) showed no overlap. One hundred and thirty-six patients (17.9%) presented overlapping GERD, and 80 patients (10.5%) presented overlapping FD. Fifty one (6.7%) of patients were overlapped by both GERD and FD. Coincidental herniated nucleus pulposus (HNP) (P = 0.026) or pulmonary diseases (P = 0.034), reduced fiber intake (P = 0.013), and laxative use (P < 0.001) independently affected the rate of overlaps. These overlapping conditions negatively affected the constipation-associated quality of life, general quality of life, and degree of constipation. Conclusions The overlap of GERD or FD was common in patients with constipation. Coincidental HNP or pulmonary diseases, reduced fiber intake, and laxatives use were found to be independent associated factors for overlapping common FGIDs in Korean patients with constipation.

Background/Aims Neuronal degeneration and changes in interstitial cells of Cajal (ICCs) are important mechanisms of age-related constipation. This study aims to compare the distribution of ICCs and neuronal nitric oxide synthase (nNOS) with regard to age-related changes between the ascending colon (AC) and descending colon (DC) in 6-, 31-, and 74-week old and 2-year old male Fischer-344 rats. Methods The amount of fecal pellet and the bead expulsion times were measured. Fat proportion in the muscle layer of the colon was analyzed by hematoxylin and eosin staining. Proto-oncogene receptor tyrosine kinase (KIT) and neuronal nitric oxide synthase (nNOS) expression were analyzed with Western blotting and immunohistochemistry. Isovolumetric contractile measurements and electrical field stimulation were used to assess smooth muscle contractility. Results Colon transit and bead expulsion slowed with senescence. Fat in the muscle layer accumulated with age in the AC, but not in the DC. The proportion of KIT-immunoreactive ICCs in the submucosal and myenteric plexus was higher in the DC than in the AC, and it declined with age, especially in the AC. In contrast, the proportion of NOS-immunoreactive neurons in the myenteric plexus was higher in the AC than in the DC, and both decreased in older rats. Nitric oxide levels declined with age in the DC. Muscle strip experiments showed that the inhibitory response mediated by nitric oxide in the circular direction of the DC was reduced in 2-year old rats. Conclusion The AC and DC differ in their distribution of ICCs and nNOS, and age-related loss of nitrergic neurons more severely affects the DC than the AC.

Background and Aim Coexistent gastrointestinal symptom profiles and prevalence or associated factors for the overlap between each functional dyspepsia (FD) and irritable bowel syndrome (IBS) group remain unclear. Thus, the aim of the present study was to evaluate the clinicodemographic features of FD, IBS, and IBS-FD overlap and assess the risk factors thereof, including subtype and genetic polymorphisms for IBS-FD. Methods Consecutive patients were enrolled from the outpatient Gastroenterology clinics of Bundang Seoul National University Hospitals in Korea. All gastrointestinal symptoms occurring at least once per week in the previous 3 months were recorded. Diagnostic criteria of functional gastrointestinal disorders were based on the Rome III criteria. Risk factors including genetic polymorphisms of 5-HTTLPR and ADRA2A 1291 G alleles and CCK-1R intron 779T>C were assessed using a multivariate logistic regression model. Results A total of 632 subjects (278 control subjects, 308 FD, 156 IBS, and 110 who met the criteria for both FD and IBS) were included in this study. Patients with IBS-FD overlap had more severe symptoms (such as bloating, nausea, vomiting, hard or lumpy stools, defecation straining, and a feeling of incomplete bowel movement) and higher depression scores compared with non-overlap patients. Single/divorced or widowed marital status, nausea, bloating, and a feeling of incomplete emptying after bowel movements were independent risk factors for IBS-FD overlap among IBS patients. In contrast, young age, depression, bloating, and postprandial distress syndrome were positively associated with IBS-FD overlap among FD patients. 5-HTTLPR L/L was a risk factor for the co-occurrence of IBS-C among FD patients (OR: 12.47; 95% CI: 2.00–77.75; P = 0.007). Conclusions Bloating was a risk factor for IBS-FD overlap. Patients with postprandial distress syndrome have a higher risk of coexisting IBS, particularly constipation-dominant IBS.

Background Studies on gut microbiota regarding colorectal carcinogenesis, including sessile serrated adenoma (SSA), have been scarce. The aim of this study is to investigate the role of mucosa-associated gut microbiota in the colorectal carcinogenesis. Methods We collected biopsy samples of normal rectal mucosa during colonoscopy from healthy control and patients with conventional adenoma, SSA, and colorectal cancer (CRC), respectively (n = 6). Pyrosequencing for 16S rRNA gene of bacteria was performed to compare gut microbiota. Results The most abundant phylum in total samples was Proteobacteria (55.6%), followed by Firmicutes (27.4%) and Bacteroidetes (11.6%). There was no significant difference in relative abundance of the phylum level among the four groups. Fusobacterium nucleatum, known to be frequently detected during colorectal carcinogenesis, was found in only one sample of patient with SSA. The rarefaction curves showed that the diversity of mucosal communities of patients with CRC is the lowest among the four groups and the diversity of mucosal communities of patients with SSA is higher than that of healthy control. Among the four groups, Shannon's and Simpson's index for diversity was the lowest and the highest in the patients with CRC, respectively; it did not reach statistical significance. The proportion of genus Pseudomonas was very high in the samples of patients with stage II-IV CRC compared with those with stage I CRC (59.3% vs. 0.3%, P = 0.064). Conclusions Our study suggests no significant role of mucosa-associated gut microbiota in the colorectal carcinogenesis. Further study for many samples or using fecal material could be helpful.

Background: Camurati-Engelmann disease (CED) is a rare genetic skeletal disorder characterized by limb pain, muscle emaciation and weakness, and cortical thickening of the diaphysis of long bones. It is caused by mutations in the transforming growth factor beta 1 (TGFB1) (type I) or other unknown gene(s) (type II). We present 8 consecutive patients with type I CED. Methods: We retrospectively reviewed medical records and radiographs of type I CED patients with special reference to the mode of presentation, process of diagnostic work-up, and disease course. They were 4 sporadic patients, and two pairs of mother and son. Results: We categorized the mode of presentation into three groups. Group I had 4 patients who mainly presented with motor disturbances in young age. They drew medical attention for waddling gait, awkward ambulation or running, difficulty in going upstairs, or a positive Gower's sign at age 4 to 6 years. Subsequent development of limb pain and radiographic abnormality led to the diagnosis of CED at age 6 to 29 years. Group II had 3 patients who mainly presented with limb pain at age 15, 20, and 54 years, respectively. Radiographic evaluation and molecular genetic test led to the diagnosis of CED. The remaining 1 patient (group III) was asymptomatic until age 9 years when bony lesions at the tibiae were found incidentally. For the last 10 years, he intermittently complained of leg pain in the morning or after sports activities, which did not interfere with daily life. All the patients in group I showed a body mass index in the underweight range (< 18.4 kg/m(2)). At the latest follow-up, 4 patients in groups I and II required medication for the limb pain. Conclusions: CED presents with a wide range of severity. Awareness of this rare disease entity may be the key to timely correct diagnosis. This disease entity should be considered in the differential diagnosis of limb pain or motor disturbance in children to avoid unnecessary diagnostic work-up.

Microsatellite stable (MSS) BRAF p.V600E mutation colorectal cancer (BRAF-CRC) has a poor prognosis, whereas microsatellite instability (MSI) in BRAF-CRC is associated with a favorable prognosis. Although usually considered a single clinical entity, the MSI BRAF-CRC subtype shows some distinct characteristics in comparison with the MSS BRAF-CRC subtype.We conducted a meta-analysis to investigate the influence of clinicopathological features on MSI status in BRAF-CRC. We searched publications up to March 2019 from PubMed, Embase, and the Cochrane Library. The effect of MSI status on outcome parameters was assessed using odds ratios (ORs) with 95% confidence intervals (CIs) and fixed- or random-effects models according to the heterogeneity.After reviewing 2839 reports, 16 eligible studies including 1381 patients with BRAF-CRC met the criteria. The MSI BRAF-CRC subtype was associated with older age, female sex (OR = 1.70; 95% CI = 1.35-2.14; P0.00001), proximal tumor location (OR = 5.10; 95% CI = 3.70-7.03; P0.00001), early TNM stage (OR = 5.28; 95% CI = 3.93-7.09; P0.00001), and poor differentiation (OR = 2.29; 95% CI = 1.60-3.28; P0.00001).MSI was significantly correlated with distinct favorable clinicopathological characteristics in BRAF-CRC. These results suggest that MSI status should be considered as a stratification factor for better management of the BRAF-CRC.

Background/aim Colorectal cancer (CRC) is the leading cause of cancer mortality worldwide. Its poor prognosis can be ascribed primarily to high recurrence rates. Accordingly, the aim of this study was to identify novel prognostic biomarkers and therapeutic targets for management of CRC. Materials and methods To develop prognostic biomarkers, we performed RNA-seq analysis and real-time RT-PCR in primary cancer tissues with or without systemic recurrence. To characterize the molecular functions of the encoded proteins, CRC cells underexpressing or overexpressing the candidate genes were established and appropriate cell-based assays were applied. Results ITGB1 and RHOC mRNA levels were up-regulated in the recurrence group of CRC patients. Overexpression of ITGB1 or RHOC stimulated CRC cell proliferation, invasion and migration, whereas the opposite effects were observed in cells underexpressing either protein. Five-year recurrence-free survival rates were significantly higher in the ITGB1- and RHOC-underexpression groups than those in the overexpression. Conclusion ITGB1 and RHOC are potential predictors of recurrence and therapeutic targets for CRC, possibly predicting a high-risk group of stage II patients.

Background/objectives The International Agency for Research on Cancer defined alcohol beverages and acetaldehyde derived from alcoholic beverages as a Group 1 carcinogen to humans. However, the association between alcohol consumption and gastric cancer risk has been controversial in Korean. We assessed the relationship between alcohol consumption and gastric cancer risk in Korea through a case-control study. Subjects/methods From 2 hospitals, a total of 316 cases with gastric cancer (208 men, 108 women) were selected and matched to 316 controls by sex and age (± 5 years) during the same duration. The current status, frequency, and amount of alcohol consumption for a year three years ago were assessed by trained interviewers. Results Alcohol consumption status and frequency did not show any significant association with gastric cancer risk. However, high alcohol consumption (≥ 20 g/day for women or ≥ 40 g/day for men) significantly increased the risk of gastric cancer (odds ratio (OR) 1.73; 95% confidence interval (CI) 1.05-2.85). Gastric cancer risk was strongly positively associated with alcohol consumption of ≥ 20 g/day, especially in women (OR 5.62; 95% CI 1.32-23.81). Conclusion The results from this study suggest that excessive alcohol consumption rather than the current status or frequency of alcohol consumption contributes to the increased risk of gastric cancer, especially in women.

Background/Aims: To evaluate changes in gut microbiota composition following long-term proton pump inhibitor (PPI) treatment. Methods: Twenty-four-week-old F344 rats were fed diets with (n=6) or without (n=5) lansoprazole for 50 weeks. Profiles of luminal microbiota in the terminal ileum were then analyzed. Pyrosequencing of the 16S rRNA gene was performed using an FLX genome sequencer (454 Life Sciences/Roche). Results: Rats treated with lansoprazole showed significantly reduced body weights compared to controls (lansoprazole-treated rats and controls, 322.3±15.3 g vs 403.2±5.2 g, respectively, p

Bevacizumab improves survival in patients with metastatic colorectal cancer (mCRC) under chemotherapy, but few predictive markers have been identified. To investigate chemosensitive single nucleotide polymorphisms (SNPs) of mCRC, we performed exome sequencing and RNA sequencing in 19 patients. A clinical association analysis was performed with the other 116 patients who had received chemotherapy to bevacizumab regimens. In vivo biodistribution studies and [18F]FDG-PET imaging were performed on mice bearing human colorectal cancer (HCT116 and SW480) xenografts after injection of bevacizumab with 5-FU, leucovorin, and irinotecan (FOLFIRI). PPP1R15A rs557806 showed the most significant association with FRB-driven tumor IR in exome sequencing and the highest correlation (r = 0.74) with drug responses in RNA sequencing. Patients homozygous for the reference alleles (GG) of PPP1R15A rs557806 exhibited greater disease control rate and a tendency toward greater objective response rate (ORR) than those with homozygous or heterozygous substitution alleles (GC and CC; P = 0.027 and 0.073, respectively). In xenografted mice, HCT116 clones transfected with the G allele at PPP1R15A rs557806 were more sensitive to bevacizumab regimens than those with the C allele. Tumor volume of xenografts with the G allele was significantly lower than that of xenografts with the C allele (P = 0.004, day 13). [18F]FDG uptake decreased to 75 % in HCT116 xenograft-bearing mice with the G allele, whereas [18F]FDG uptake was 42 % in mice xenografts with the C allele (P = 0.032). ANXA11 rs1049550, a predictive biomarker of SNP described in our previous study, was validated using the xenograft model. Tumor volume and [18F]FDG uptake analyses showed that tumors in the SW480 xenografts expressing the substitution allele (T) at ANXA11 rs1049550 were more susceptible to FOLFIRI plus bevacizumab-induced suppression than those expressing the reference allele (C) (P = 0.001 and 0.026, respectively). ANXA11 rs1049550 and PPP1R15A rs557806 may improve the identification of mCRC patients sensitive to bevacizumab regimens, and further validation is required in large cohorts.

Although it has been established that diabetes increases susceptibility to infections, the role of insulin (INS) in the immune response is unknown. Here, we investigated the immunological function of INS. Proinsulin dimer (pINSd) was a potent immune stimulus that induced inflammatory cytokines, but mature INS was unable to induce an immune response. An affinity-purified rabbit polyclonal antibody raised against mature IL-1α recognized IL-1α and pINS but failed to detect mature INS and IL-1β. Analysis of the pINS sequence revealed the existence of an INS/IL-1α motif in the C-peptide of pINS. Surprisingly, the INS/IL-1α motif was recognized by monoclonal antibody raised against IL-1α. Deleting the INS/IL-1α motif in pINSd and IL-1α changed their activities. To investigate the pINSd receptor, the reconstitution of IL-1 receptor 1 (IL-1R1) in Wish cells restored pINSd activity that was reversed by an IL-1R antagonist. These data suggested that pINSd needs IL-1R1 for inflammatory cytokine induction. Mouse embryo fibroblast cells of IL-1R1-deficient mice further confirmed that pINSd promotes immune responses through IL-1R1.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) represents an effective agent for the treatment of many cancers, though the majority of thyroid cancers are found to be resistant. Therefore it would be necessary to identify agents capable of increasing the sensitivity of these cancers to TRAIL-mediated cell death. Here, we examined the therapeutic effect and its underlying mechanism of combination treatment of TRAIL and histone deacetylase inhibitor, Valproic acid (VPA) in vitro using human papillary thyroid cancer (PTC) cells and in vivo using an orthotopic mouse model of PTC. TRAIL-VPA combination therapy synergistically induced apoptotic cell death in TRAIL-resistant PTC through caspase activation. In addition, downregulation of antioxidant transcription factor, Nrf2 by co-treatment of TRAIL-VPA induces cell death via suppression of Bcl-xL in vitro and in vivo; these effects were further enhanced following siRNA inhibition of these proteins in combination with TRAIL or TRAIL-VPA. Taken together, VPA sensitized TRAIL-resistant PTC cells to apoptotic cell death through involvement of Nrf2 and Bcl-xL. Thus, the combination of VPA and TRAIL may be a promising therapy for TRAIL-resistant PTC.

Using data from the real world to solve clinical questions that cannot be answered using data from clinical trials is attracting more attention. Clinical outcomes for patients with esophageal cancer in a real-world setting might be different from data in randomized controlled trials. This study aimed to provide real world data on treatment and prognosis in Korean patients with esophageal cancer. This retrospective cancer cohort included newly diagnosed cases of esophageal cancer at 19 tertiary hospitals between January 1, 2005 and December 31, 2017. Cancer staging was defined according to the 7th edition of the American Joint Committee on Cancer criteria. We identified 6,354 patients with newly diagnosed esophageal cancer (mean age: 64.9 ± 9.0 years, 96.9% squamous cell carcinoma). The proportion of early esophageal cancer increased from 24.7% in 2005 to 37.2% in 2015 (p

BACKGROUND Genomic profiling of tumors has contributed to the understanding of colorectal cancer (CRC), facilitating diagnosis, prognosis and selection of treatments, including targeted regimens. A report suggested that a 19-gene-based risk classifier (TCA19) was a prognostic tool for patients with stage III CRC. The survival outcomes in patients with stage IV CRC are still poor and appropriate selection of targeted therapies and immunotherapies is challenging. AIM To assess clinical implication of TCA19 in patients with stage IV CRC, and to identify TCA19 with involvement in immune-oncology. METHODS A retrospective review of the medical records of 60 patients with stage IV CRC was conducted, assessing clinicopathological variables and progression-free survival (PFS). TCA19 gene expression was determined by quantitative polymerase chain reaction (qPCR) in matched normal and tumor tissues taken from the study cohort. Expression of potential immune-oncology regulatory proteins and targets was examined by immunohistochemistry (IHC), western blot, immunofluorescence staining in tissues from a validation cohort of 10 patients, and in CRC cell lines co-cultured with monocyte in vitro. RESULTS In the patients with TCA19 score higher than the median, the PFS rates of eight patients who received the targeted regimens were significantly higher than the PFS rates of four patients who received 5-fluorouracil-based regimen (P = 0.041). In multivariate analysis, expression of signaling lymphocytic activation molecule family, member 7 (SLAMF7) and triggering receptor expressed on myeloid cells 1 (TREM1) was associated with PFS in the 60-patient cohort. After checking another 10 validate set, the expression of the IHC, the level of real-time qPCR, and the level of western blot were lower for SLAMF7 and higher for TREM7 in primary and metastatic tumors than in normal tissues. In CRC cells expressing SLAMF7 that were co-cultured with a monocytic cell line, levels of CD 68 and CD 73 were significantly lower at day 5 of co-culture than at day 0. CONCLUSION The TCA19 score might be prognostic for target-regimen-specific PFS in stage IV CRC. Down-regulation of SLAMF7 and up-regulation of TREM1 occur in primary and metastatic tumor tissues.

Background/Aims: Behavioral factors, such as smoking and heavy alcohol consumption, increase the risk of gastric cancer (GC), but their effects on survival are not clear. We examined associations between prediagnostic smoking and alcohol drinking behavior and GC death by long-term follow-up. Methods: The participants were 508 GC patients enrolled at Chungnam University Hospital and Hanyang University Guri Hospital from 2001 to 2006. Information on clinicopathologic and behavioral risk factors was collected, and patient survival was prospectively followed until 2016 by medical chart review and telephone survey. Results: During above 10 years follow-up period, overall death was 46.2% (n=226) and GC deaths was 38.2% (n=187) among the 489 GC patients included in the analysis. No significant association was found between smoking habits and overall or GC survival. However, after stratification by histological type, the hazard ratio (HR) of GC death for current smokers tended to be higher for the diffuse type (HR 1.61, 95% CI 0.57-4.59 for current vs. never) rather than for the intestinal type (HR 0.78, 95% CI 0.28-2.19 for current vs. never). Light alcohol consumption was found to be associated with a significantly lower risk of GC death (HR 0.52, 95% CI 0.36-0.75 for

Background/Aims: This study was performed to evaluate the relationship between family history of gastrointestinal (GI) cancers and incidence of any GI cancer in the Korean population. Methods : : Between January 2015 and July 2016, 711 GI cancer patients and 849 controls in 16 hospitals in Korea were enrolled. Personal medical histories, life styles, and family history of GI cancers were collected via questionnaire. Results: There was a significant difference in the incidence of family history of GI cancer between GI cancer patients and controls (p=0.002). Patients with family history of GI cancer tended to be diagnosed as GI cancer at younger age than those without family history (p=0.016). The family members of GI cancer patients who were diagnosed before 50 years of age were more frequently diagnosed as GI cancer before the age of 50 years (p=0.017). After adjusting for major confounding factors, age (adjusted odds ratio [AOR] 1.065, 95% confidence interval [CI]; 1.053-1.076), male gender (AOR 2.270, 95% CI; 1.618-3.184), smoking (AOR 1.570, 95% CI; 1.130-2.182), and sibling’s history of GI cancer (AOR 1.973, 95% CI; 1.246-3.126) remained independently associated with GI cancers. Conclusions: GI cancer patients tended to have a first relative with a history of concordant GI cancer. Personal factors (old age and male) and lifestyle (smoking) contribute to the development of GI cancer, independently. Individuals with high risk for GI cancers may be advised to undergo screening at an earlier age.

Morgagni hernia (MH) is a very rare congenital defect found in the anterior aspect of the diaphragm between the costal and sternal portions of the muscle. The most common defect is congenital diaphragmatic hernia, 90% of which are Bochdalek type. MHs account for approximately 3% of all diaphragmatic hernias. Most MHs are found and repaired in children, but 5% are found in adults. Here, we present the case of an incarcerated and strangulated MH with synchronous prolapse of the liver and transverse colon in a 77-year-old man who was admitted to our hospital for abdominal pain and symptoms of intestinal obstruction.

In recent decades, we have regarded irritable bowel syndrome (IBS) as a functional disorder which means symptoms of IBS are not explained by identifiable structural or biochemical abnormalities.1 Under the premise that the symptom of IBS originated from disturbance of function, multi-factorial etiologies have been suggested, including abnormal motility, visceral hypersensitivity, genetic predisposition, and psycho-social influences. Of these, the role of the central nervous system in terms of brain-gut interaction has been considered as an important factor for abnormal motility and visceral hypersensitivity, and has been intensively studied. For example, the corticotrophin-releasing factor, a key modulator of stress response in the brain, has been extensively investigated and the present role in the gastrointestinal tract such as decreasing gastric emptying, increasing colonic motility, and inducing visceral hypersensitivity are established.2–4 Psychological comorbidities such as depression and anxiety are also more prevalent in patients with IBS compared to healthy controls and is thought to play an important role in IBS.1 However, latest medical and scientific developments have led to further investigation of organic changes in patients with IBS such as inflammatory cell infiltration, increased permeability, and changes in neuroendocrine system in the gut.5,6 The enteric nervous system (ENS) is one of the candidates for a possible organic cause of underlying IBS pathophysiology. The ENS regulates muscular, neuro-hormonal, and secretory systems of the gastrointestinal tract to generate functionally effective patterns of various digestive states.7 The ENS can be divided into 2 major regions, the submucosal plexus (SMP) and the myenteric plexus (MP). The SMP controls absorptive and secretory functions of the mucosal epithelium, intramural blood flow, and neuroimmune interactions, while the MP regulates intestinal motility for specific digestive states.7 In this issue of the Journal of Neurogastroenterology and Motility, Li et al8 nicely and diligently described changes in the ENS using a diarrhea dominant IBS (IBS-D) rat model induced by heterotypic chronic and acute stress (CAS). Rats exposed to CAS exhibited accelerated intestinal transit, increased number of secreto-motor neurons such as choline acetyltransferase (ChAT), vasoactive intestinal peptide (VIP)—immunoreactive neurons in SMP, and decreased inhibitory musculomotor neurons such as nitric oxide synthase (NOS)-immunoreactive neurons in MP. The previous study from the authors on the CAS rats had shown that changes secreto- and musculomotor neurons were not limited to the small intestine but to the colon as well.9 Altogether, the increase of ChAT and VIP neurons in the intestinal SMP of rats could promote intestinal secretion leading to secretory diarrhea in the IBS-D rat model. Nitric oxide is an inhibitory transmitter released by enteric inhibitory musculomotor neurons.10 In rats exposed to CAS in this study, NOS positive neurons in the MP were decreased while the number of cholinergic neurons was unchanged. In other words, attenuated inhibitory capacity in musculomotor neurons may be responsible for the enhanced propulsive motility found in CAS model of IBS-D. This study suggested some possibility of structural change in the ENS as an underlying pathophysiology in stress related IBS-D symptoms. However, we have to be cautious before translating this finding into human IBS. First, because it is difficult to obtain full-thickness biopsy specimens, scientifically reliable evidence of the changes in ENS in human IBS patient has been hard to come by these days. Early in this century, a study with laparoscopic full-thickness jejunal biopsies from 10 IBS patients reported low grade peri- and intra-ganglionic lymphocyte infiltration and neuronal degeneration in the MP, while the SMP was rarely affected.11 However, patients in this study were recruited from a tertiary referral center and had very severe symptoms. In addition, mast cells infiltration, which is a well known pathophysiology of IBS, was not found in these patients. Therefore, these findings could not be representative for all IBS patients. Some authors suggest that the presence of anti-enteric neuronal antibodies in IBS patients indicate some form of an autoimmune degenerative neuropathy in the ENS.12 However, a relatively high percentage of anti-enteric neuronal antibodies in the normal population also suggests that it may be a consequence of complex intestinal pathophysiology, rather than the cause of it. Second, we should consider the difference between human and animal models because the evidence regarding ENS abnormalities in IBS usually came from animal studies. Although the authors did not state the exact age of the rats in this study, the weight 160–180 g is roughly equivalent to 6–7 weeks old. In rats, young adulthood begins from postnatal 70 days.13 So the rats used in this study were in the relatively adolescent period, and 10.5 days of rat age in this stage is equivalent to 1 human year. If we roughly translate the experimental condition of this study to human life, it would be a teenager who has been exposed to severe, unpredictable and chronic stress (such as water and food deprivation, experience of physical pain, exposure to hot weather, swimming in cold water, and inversion of day and night) for several years until early adulthood. Therefore, the experimental condition in this study represents only very specific situation of human life, and the results of this study cannot be considered for all patients with IBS. However, few human and several animal studies undoubtedly points to the possibility of disturbance of ENS in some portion of patients with IBS, so efforts to explore the changes in the ENS in patients with IBS should be continued. As a practical matter, it would be helpful to see if CAS rats could recover from neuronal alterations caused by stress after a certain period of “relaxing” time, since we would like to believe that ENS, like other complex nervous systems, could have restoring or adaptive plasticity over outside stimuli and stress. In conclusion, we should strongly deliberate if we can really expand these findings to human IBS intestinal physiology and pathophysiology for the reasons mentioned above. Does increase or decrease in immune reactive secretomotor neurons or musculo-motor neurons can really account for actual alterations in intestinal secretions or muscular contractions? And if so, are they reversible or redeemable with specific target drugs in which we hope to use for the treatment of IBS? The question still remains to be answered desperately, while we struggle to manage IBS patients in our daily practice.

Keloids are mysterious soft‐tissue tumors that are characterized by excessive reparative processes composed of collagen‐forming fibroblasts and inflammatory cells. Generally, complete tumor excision regardless of sufficient margin is considered as a first‐line treatment because they are considered reactive rather than a neoplastic condition. Recently, a specific part of the keloids is being highlighted as an important microstructure for local recurrence, but there has been very little evidence. We conducted a prospective study to evaluate the relationship of recurrence and several clinicopathological parameters with specific focus on surgical resection margin. A total 87 cases of auricular keloids from 71 patients were included. The resection margins were carefully evaluated by an exhaustive grossing method and thorough microstructural assessment. During up to 48.8 months of the follow‐up period, local recurrence has been monitored and documented. The clinicopathological data including symptoms, bilaterality, size, location, prior treatment and operation history, gross type and etiology were collected and analyzed. Positive margin status was significantly related to tumor recurrence (P < 0.0001). Complete excision warrants a lower recurrence of auricular keloids in an Asian population. The most reasonable explanation for this seems to be remnant “proliferating core”, which may serve a key role in local recurrence.

The colonic response to stress is greater in female rats than in male rats. The aim of this study was to evaluate the effect of probiotics in the repeated water avoidance stress (rWAS)-induced colonic microinflammation model of Wistar rats in a sex-specific manner. The three groups (no-stress, WAS, and WAS with probiotics) were exposed to r-WAS for 1 h daily for 10 days, and Lactobacillus farciminis was administered by oral gavage for 10 days to animals in the probiotics group. The visceromotor response (VMR) to colorectal distension (CRD) was assessed using a barostat and noninvasive manometry before and after WAS exposure. Immunohistochemistry for mast cells and real-time polymerase chain reaction (RT-PCR) for detection of mucosal cytokines were performed using distal colon tissue after the animals were sacrificed. Significant reduction of VMR to CRD (visceral analgesia) was observed at 60 mmHg in the female WAS group (P = 0.045), but not in males. In addition, the female WAS with probiotics group showed a significantly lower colonic mucosal mast cell count in comparison to the female WAS group (P = 0.013), but this phenomenon was not observed in the male group. The colonic mucosal mRNA levels of interferon-γ (IFNR), tumor necrosis factor-α (TNFA), interleukin (IL) 6, and IL17 were higher in the female WAS group than in the male WAS group. The mRNA levels of IFNR, TNFA, and IL6 were significantly decreased in WAS females who received probiotics (all P < 0.050). In conclusion, rWAS is induced in a sex-specific manner. A 10-day-long treatment with L. farciminis is an effective therapy for rWAS-induced colonic microinflammation in female rates, but not in male rats.

The gastric accommodation reflex is an important mechanism in gastric physiology. However, the aging-associated structural and functional changes in gastric relaxation have not yet been established. Thus, we evaluated the molecular changes of interstitial cell of Cajal (ICC) and neuronal nitric oxide synthase (nNOS) and the function changes in the corpus of F344 rats at different ages (6-, 31-, 74-wk and 2-yr). The proportion of the c-Kit-positive area in the submucosal border (SMB) and myenteric plexus (MP) layer was significantly lower in the older rats, as indicated by immunohistochemistry. The density of the nNOS-positive immunoreactive area also decreased with age in the SMB, circular muscle (CM), and MP. Similarly, the percent of nNOS-positive neuronal cells per total neuronal cells and the proportion of nNOS immunoreactive area of MP also decreased in aged rats. In addition, the mRNA and protein expression of c-Kit and nNOS significantly decreased with age. Expression of stem cell factor (SCF) and the pan-neuronal marker PGP 9.5 mRNA was significantly lower in the older rats than in the younger rats. Barostat studies showed no difference depending on age. Instead, the change of volume was significantly decreased by L-NG63-nitroarginine methyl ester in the 2-yr-old rats compared with the 6-wk-old rats (P = 0.003). Taken together, the quantitative and molecular nNOS changes in the stomach might play a role in the decrease of gastric accommodation with age.

Bone fusion surgery is required for the surgical treatment of degenerative spinal diseases, bone fractures, and tumors. To date, autogenous bone has been considered the most ideal bone graft for bone fusion. However, due to its quantitative limits and donor site morbidity,1) the usage of autogenous bone is gradually decreasing, and various bone graft substitutes have been developed. Bioactive ceramics such as hydroxyapatite, tricalcium phosphate, and calcium pyrophosphate are representative bone graft substitutes which are clinically applied to areas such as spine fusion.2,3,4,5,6) While bioactive ceramics have appealing advantages such as mass production and low risk of inflammation and virus infection, they are osteoconductive materials with a negligible level of osteoinductivity, and thus need to be mixed with autogenous bone for application. To complement this limitation, bone morphogenetic proteins (BMPs) with high osteoinductivity have been developed and applied in various areas, including spinal fusion and tibial non-union.7,8) BMPs are gradually replacing autogenous bone grafts, since they are known to facilitate bone healing and improve fusion rate. However, their many advantages are also accompanied by some disadvantages. They are costly, and are known to cause side effects including ectopic bone formation, formation of seroma,9) neuropathy by neuritis, osteolysis, and soft tissue swelling.10) Moreover, the risk of retrograde ejaculation,11) male infertility and malignancy were also recently reported. Thus, the risk of possible side effects is now advised, rather than their usefulness. Due to its osteoinductivity, demineralized bone matrix (DBM) was frequently applied clinically, before BMP was actively used. However, the usage of DBM is also decreasing, since it has significantly lower osteoinductivity than BMP and mainly functions through osteoconductivity. Thus, it cannot be applied for bone fusion by itself.12) Despite the limitations, use of DBM is still advantageous to reduce autogenous bone graft without using BMP, as DBM rarely develops side effects. DBM is provided in a powder form, which is hard to pattern and fix to the right position. Thus, it requires various types of carriers such as calcium sulfate, hydroxyapatite, tricalcium phosphate, carboxymethylcellulose, glycerol, hyaluronic acid, and bovine gelatin. Poloxamer 407 is a tri-block copolymer consisting of a central hydrophobic polypropylene oxide block flanked by two hydrophilic ethylene oxide blocks.13,14) Poloxamer 407 shows thermoreversible properties, forming a gel-like composite at room temperature to facilitate the solubilization of poorly water-soluble drugs, and forming a gel state at body temperature. Poloxamer 407 has been used in the pharmaceutical field because of the properties such as solubilization promotion, stabilization and bio-adhesiveness.14,15) The putty type of DBM with a carrier improves handling during surgery, but effects on osteoinductivity or osteogenesis have not yet been well examined. This study evaluates the effect on osteogenesis of using poloxamer 407-based hydrogel as a carrier, through various in vitro and in vivo experiments.

Colorectal cancer (CRC) patients frequently experience disease recurrence and distant metastasis. This study aimed to identify prognostic indicators, including individual responses to chemotherapy, in CRC patients. RNA-seq data was generated using 54 samples (normal colon, primary CRC, and liver metastases) from 18 CRC patients and genes associated with CRC aggressiveness were identified. A risk score based on these genes was developed and validated in four independent CRC patient cohorts (n = 1063). Diverse statistical methods were applied to validate the risk scoring system, including a generalized linear model likelihood ratio test, Kaplan–Meier curves, a log-rank test, and the Cox model. TREM1 and CTGF were identified as two activated regulators associated with CRC aggressiveness. A risk score based on 19 genes regulated by TREM1 or CTGF activation (TCA19) was a significant prognostic indicator. In multivariate and subset analyses based on pathological staging, TCA19 was an independent risk factor (HR = 1.894, 95% CI = 1.227–2.809, P = 0.002). Subset stratification in stage III patients revealed that TCA19 had prognostic potential and identified patients who would benefit from adjuvant chemotherapy, regardless of age. The TCA19 predictor represents a novel diagnostic tool for identifying high-risk CRC patients and possibly predicting the response to adjuvant chemotherapy.