BMC Gastroenterology

Synchronous colorectal cancer (SCRC) is featured by the presence of multiple primary tumor lesions in a single patient at initial diagnosis. It is less common with the prevalence of approximately 3.5% among colorectal cancer (CRC). Some studies of SCRC have been performed in patients with two tumor lesions. However, SCRC cases with three or more tumor lesions were rare and remained to be investigated. In this case report, we presented a 56-year-old male SCRC case with quadruple tumor lesions which is rarely seen in clinical practice. After laparoscopic radical resection of sigmoid carcinoma and partial rectum resection, the four tumor samples were subjected to pathological evaluation and next-generation sequencing (NGS) based genetic profiling. The four tumor lesions included two adenocarcinomas with moderate differentiation at sigmoid colon and rectum respectively, a grade 1 neuroendocrine tumor (NET) at rectum and a high-grade intraepithelial neoplasia at ascending colon. Each tumor exhibited distinct histology types and mutation profiles. After surgical resection, the patient remained disease-free after four cycles of chemotherapy with oxaliplatin and capecitabine (XELOX). The tumor lesions in this case showed different pathological and genetic features which indicats the heterogeneity of SCRC. The genomic profilling might provide novel insights to understand SCRC at molecular level.

Proper histomorphological interpretation of intestinal acute graft versus host disease (A-GVHD) associated with allogeneic bone marrow transplantation (BMT) is critical for clinical managaement. However, studies methodically evaluating different histomorphological features of A-GVHD are rare. Colonic biopsies from 44 allogeneic BMT patients having biopsy-proven cutaneous A-GVHD were compared with colon biopsies from 48 negative controls. A-GVHD showed intra-cryptal apoptosis in 91% and pericryptal apoptosis in adjacent lamina propria in 70% (p < 0.002). Nonspecific apoptosis along the surface epithelium was observed in all groups with comparable frequency. The number of apoptotic cells in mucosa were approximately four times (5.3 per 10 HPF) the negative controls (p < 0.002) in A-GVHD group. 48% of cases with A-GVHD showed decreased number of lymphocytes in lamina propria. Some features, including intraepithelial lymphocytes in surface or crypt epithelium; and neutrophils, eosinophils, and edema in lamina propria, did not demonstrate significant difference in A-GVHD and negative controls. Pericryptal apoptosis, dilated crypts, irregular distribution of crypts, decreased lymphocytes, increased microvessel network, focal fibrosis, presence of muciphages, reactive changes in surface epithelium with mucin depletion, mucosal ulceration, and/or reduced mucosal thickness showed higher association with A-GVHD group. Intracyptal apoptosis is a reliable indicator of A-GVHD. Its diagnostic significance was improved if intracyptal apoptosis was associated with features which were observed more frequently in A-GVHD group as mentioned above.

What kind of patients with hypertriglyceridemic acute pancreatitis (HLAP) might benefit from plasmapheresis (PP) remains unknown. The objective of this study is to determine the predict function of total cholesterol (TC) on the Triglyceride (TG)-lowing effect in patients on either non-PP or PP therapy. Patients were categorized into high total cholesterol (HTC)/low total cholesterol (LTC) groups based on TC level of 12.4 mmol/L. The primary outcome was TG reduction to below 500 mg/dL within 48 h. Linear mixed-effect model and logistic regression analyses were used to assess the association of TC level and TG-lowing efficacy in different therapy groups. Compared with LTC group, patients with HTC showed more severe imaging manifestations (p < 0.001) and higher APACH II scores (p = 0.036). Deaths occurred only in HTC groups. Significant interaction of time sequence with the 2 TGs-lowing therapy groups on TG level was only found in HTC group (p < 0.001). In patients with elevated TC level, primary outcome occurred in 66.67% of patients in the PP group, and 27.91% in the non-PP group. After adjustment for age, gender, CT grade and APACH II score, the odd ratio remain significant (OR 5.47, 95% confidence interval [CI] 1.84–16.25, p = 0.002). Furthermore, in patients with lower TC level, no significant difference was found in primary outcome between PP group and non-PP group (81.25% versus 62.30%, adjusted OR 2.05; 95% CI 0.45–9.40; p = 0.353). TC could be a potential biomarker to predict the effects of TG-lowing therapy in patients with HLAP.

Oxidative stress, an increase in oxidants and/or a decrease in antioxidant capacity, is one of the potential biochemical mechanisms involved in the pathogenesis of nonalcoholic steatohepatitis. We aimed to investigate the total antioxidant response using a novel automated method in nonalcoholic steatohepatitis subjects. As a reciprocal measure, we also aimed to determine total peroxide level in the same plasma samples. Twenty-two subjects with biopsy proven nonalcoholic steatohepatitis and 22 healthy controls were enrolled. Total antioxidant response and total peroxide level measurements were done in all participants. The ratio percentage of total peroxide level to total antioxidant response was regarded as oxidative stress index. Total antioxidant response of subjects with nonalcoholic steatohepatitis was significantly lower than controls (p < 0.05), while mean total peroxide level and mean oxidative stress index were higher (all p < 0.05). In subjects with nonalcoholic steatohepatitis, fibrosis score was significantly correlated with total peroxide level, total antioxidant response and oxidative stress index (p < 0.05, r = 0.607; p < 0.05, r = -0.506; p < 0.05, r = 0.728, respectively). However, no correlation was observed between necroimflamatory grade and those oxidative status parameters (all p > 0.05). Nonalcoholic steatohepatitis is associated with increased oxidant capacity, especially in the presence of liver fibrosis. The novel automated assay is a reliable and easily applicable method for total plasma antioxidant response measurement in nonalcoholic steatohepatitis.

Mini-Mental State Examination (MMSE) is one of the most commonly used methods in the assessment of cognitive mental status. MMSE has been used in hepatology but its usefulness in the evaluation of hepatic encephalopathy (HE) has never been properly assessed. The aim of the study was to investigate the value of MMSE in detection of HE in patients with cirrhosis. One hundred and one consecutive patients with liver cirrhosis underwent neurological examination, MMSE and electroencephalography (EEG). Spectral analysis of EEG was done with calculation of mean dominant frequency (MDF) and relative power of delta, theta, alpha and beta rhythms. Minimal HE was diagnosed in patients with normal neurological status and alterations in spectral EEG. Statistical analysis included Fisher’s exact and Anova analysis. Categorical data were compared using Levene’s test for equality of variances. Correlation-coefficient analysis was performed by the Pearson’s r or Z-test, as needed. Tests performance was assessed by the calculating the area under the ROC curve (AUC) and evaluating its difference from reference area (AUC=0.5). A p value <0.05 was considered statistically significant. Overt HE was identified in 49 (48.5%) and minimal HE in 22 (21.8%) patients. Although there were significant correlations between both severity of liver disease (Child-Pugh classification), overt HE (West-Haven criteria) and various MMSE items, MDF showed no correlation with any of MMSE items as well as MMSE summary score. MMSE (score and items) did not discriminate patients without HE and minimal HE. The only significant differences between patients without HE and with overt HE were seen in respect of MMSE score (p<0.02), orientation to place (p<0.003), repetition (p<0.01) and complex commands-understanding (p<0.02). Test performance analysis has shown that MMSE has no value as a prediction method in determining minimal HE and in respect of overt HE has a sensitivity of 63% and specificity of 52% by a cut-off level at 27.5 points to diagnose overt HE. In conclusion, although MMSE score and single items are altered in patients with overt HE, MMSE has no value in the assessment of minimal HE. Because MMSE could be impaired in several cognitive dysfunctions, more specific test should be used for measuring HE.

Limited data are available for advanced colorectal neoplasm in asymptomatic individuals aged 40–49 years. We aimed to identify risk factors and develop a simple prediction model for advanced colorectal neoplasm in these persons. Clinical data were collected on 2781 asymptomatic subjects aged 40–49 years who underwent colonoscopy for routine health examination. Subjects were randomly allocated to a development or validation set. Logistic regression analysis was used to determine predictors of advanced colorectal neoplasm. The prevalence of overall and advanced colorectal neoplasm was 20.2 and 2.5% respectively. Older age (45–49 years), male sex, positive serology of Helicobacter pylori, and high triglyceride and low high-density lipoprotein (HDL) levels were independently associated with an increased risk of advanced colorectal neoplasm. BMI (body mass index) was not significant in multivariable analysis. We developed a simple scoring model for advanced colorectal neoplasm (range 0–9). A cutoff of ≥4 defined 43% of subjects as high risk for advanced colorectal neoplasm (sensitivity, 79%; specificity, 58%; area under the receiver operating curve = 0.72) in the validation datasets. Older age (45–49 years), male sex, positive serology of H. pylori, high triglyceride level, and low HDL level were identified as independent risk factors for advanced colorectal neoplasm.

Activated hepatic stellate cell (HSC) is the main fibrogenic cell type in the injured liver. miRNA plays an important role in activation and proliferation of HSC. Our previous study examined the expression profiles of microRNAs in quiescent and activated HSC. Real-time PCR and western blot were used to detect the expression of Collagen type I (Col 1) and Alpha-Smooth Muscle Actin (α-SMA). CCK-8 and Edu assay was used to measure the proliferation rate of HSC. Luciferase reporter gene assay was used to tested the binding between miR-338-3p and Cyclin-dependent kinase 4 (CDK4). We found overexpression of miR-338-3p could inhibit Col 1 and α-SMA, two major HSC activation markers, whereas miR-338-3p inhibitor could promote them. Besides, miR-338-3p overexpression could suppress the growth rate of HSC. Further, we found that CDK4, a pleiotropic signaling protein, was a direct target gene of miR-338-3p. Moreover, we found that overexpression of CDK4 could block the effects of miR-338-3p. We found miR-338-3p is an anti-fibrotic miRNA which inhibits cell activation and proliferation. Our findings suggest that miR-338-3p/CDK4 signaling pathway participates in the regulation of HSC activation and growth and may act as a novel target for further anti-fibrotic therapy.

Cirrhosis is a long-term consequence of chronic hepatic injury with fibrosis. No effective therapy is currently available for decompensated cirrhosis except liver transplantation. Hence, we investigated the effect of bone marrow-derived mesenchymal stem cells (BM-MSCs) on hepatic fibrosis in a thioacetamide (TAA)-induced cirrhotic rat model. The BM-MSCs were injected directly into the right liver lobe twice, at 6 and 8 weeks during the 12-week TAA administration, in thioacetamide (TAA)-induced cirrhotic rats model, and hepatic fibrosis was evaluated. At 12 weeks, the effect of BM-MSCs on hepatic fibrosis was analyzed histomorphologically using the Laennec fibrosis scoring system, and the collagen proportionate area was quantified. Cirrhosis-related factors, such as transforming growth factor β1 (TGF-β1), type 1 collagen (collagen-1), α-smooth muscle actin (α-SMA), and P-Smad3/Smad3 expression levels, were evaluated using real-time polymerase chain reaction and western blot assays. According to the Laennec fibrosis scoring system, histological improvement was observed in hepatic fibrosis after BM-MSC treatment (P <0.01). The percentage of the collagen proportionate area decreased from 16.72 ± 5.51 to 5.06 ± 1.27 after BM-MSC treatment (P <0.01). The content of hepatic hydroxyproline was significantly lower in the BM-MSC treated group (46.25 ± 13.19) compared to the untreated cirrhotic group (85.81 ± 17.62; P <0.01). BM-MSC administration significantly decreased TGF-β1, collagen-1, and α-SMA expression in TAA-induced cirrhotic rats (P <0.01). We also confirmed P-Smad3/Smad3, downstream effectors of the TGF-β1 signaling pathway, and found that MSC transplantation inhibited Smad3 phosphorylation. BM-MSC treatment attenuated hepatic fibrosis in rats with TAA-induced cirrhosis, raising the possibility of the clinical use of BM-MSCs in the treatment of cirrhosis.

Primary malignant melanoma of esophagus (PMME) is an extremely rare disease with poor prognosis. We aimed to determine the clinical characteristics and treatment outcomes of patients with PMME. We retrospectively reviewed 17 patients diagnosed with PMME in Samsung Medical Center between 2000 and 2020 with median 34 months of follow-up. Survival outcomes were analyzed with Kaplan–Meier method. 15 patients (88.2%) were male and the most common presenting symptom was dysphagia (9/17, 52.9%). On endoscopy, tumors were mass-forming in 15 patients (88.2%) and diffusely infiltrative in two patients (11.8%). Lesions were melanotic in 13 patients (76.5%) and amelanotic in four patients (23.5%). The most common tumor location was lower esophagus (11/17, 64.7%). The disease was metastatic at the time of diagnosis in four patients (23.5%). As for treatment, 10 patients (58.8%) underwent surgery. In all 17 patients, the median overall survival was 10 months. In surgically treated patients, all patients experienced recurrence and the median disease-free survival was 4 months. There was no statistical difference in overall survival between patients with or without surgery. Patients with diffusely infiltrative tumor morphology had better overall survival compared to those with mass-forming tumor morphology (P = 0.048). Two patients who received immunotherapy as the first-line treatment without surgery showed overall survival of 34 and 18 months, respectively. As radical resection for patients with PMME does not guarantee favorable treatment outcomes, novel treatment strategy is required. Further large-scale studies are warranted to determine the efficacy of immunotherapy for patients with PMME.

Chronic active Epstein–Barr virus infection (CAEBV) is defined as Epstein–Barr virus (EBV)-positive T/NK cell-related neoplasia, and its major clinical symptom is systemic inflammation presenting as infectious mononucleocytosis, whereas enteritis and diarrhea are minor clinical symptoms. The complex mixture of tumorigenic processes of EBV-positive cells and physical symptoms of systemic inflammatory disease constitutes the varied phenotypes of CAEBV. Herein, we describe a case of CAEBV that was initially diagnosed as Crohn’s disease (CD) based on ileal ulcers and clinical symptoms of enteritis. A 19-year-old woman complained of abdominal pain and fever. Blood examination showed normal blood cell counts without atypical lymphocyte but detected modest inflammation, hypoalbuminemia, slight liver dysfunction, and evidence of past EBV infection. The esophagogastroduodenoscopic findings were normal. However, colonoscopy revealed a few small ulcers in the terminal ileum. The jejunum and ileum also exhibited various forms of ulcers, exhibiting a cobblestone appearance, on capsule endoscopy. Based on these clinical findings, she was strongly suspected with CD. In the course of treatment by steroid and biologics for refractory enteritis, skin ulcers appeared about 50 months after her initial hospital visit. Immunohistology of her skin biopsy revealed proliferation of EBV-encoded small RNA (EBER)-positive atypical lymphocytes. We retrospectively assessed her previous ileal ulcer biopsy before treatment and found many EBER-positive lymphocytes. Blood EBV DNA was also positive. Therefore, she was diagnosed with extranodal NK/T-cell lymphoma with CAEBV-related enteritis rather than CD. She was treated with cyclosporine and prednisolone combination therapy for CAEBV-related systemic inflammation and chemotherapy for malignant lymphoma. Unfortunately, her disease continued to progress, leading to multiple organ failure and death at the age of 23 years. Clinicians need to remember the possibility of CAEBV as a differential diagnosis of refractory enteritis. Enteritis with intestinal ulcer is a rare symptom of CAEBV, and it is impossible to acquire a definitive diagnosis by ulcer morphology only. In cases where the possibility of CAEBV remains, tissue EBVR expression should be checked by in situ hybridization and blood EBV DNA.