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Background: Fungal organisms are frequently observed in surgical pathological diagnosis. In order to more accurately identify fungi in formalin-fixed and paraffin-embedded (FFPE) tissues, it is necessary to use genomic information. The purpose of our pilot study is to identify the factors to be considered for the identification of pathogenic fungi using mycobiome analysis in FFPE tissues. Methods: We selected 49 cases in five hospitals. In each case, FFPE tissue was cut into 50 µm and DNA was extracted. Multiplex PCR with four primers (ITS1, ITS2, ITS3 and ITS4) was performed. Multiplex sequencing was performed using a MinION device according to the manufacturer’s protocol. Sequences of each case were searched using BLASTN with an ITS database from NCBI RefSeq Targeted Loci Project with default parameters. Results: A total of 2,526 DNA sequences were sequenced. We were able to identify 342 fungal sequences in 24 (49.0%, 24/49) cases. The median number of detected fungal sequences per case was 3 (1Q: 1 and 3Q: 14.25). Of the fungal DNA sequences, 215 (62.87%) contained the entire region of ITS1 or ITS2. The remaining 127 fungal DNA sequences were identified as fungi using a partial sequence of ITS1, ITS2, 5.8S, LSU or SSU. Conclusion: In conclusion, we have identified the possibility of finding pathogenic fungi through mycobiome analysis in fungal infected FFPE tissues using nanopore sequencing. However, we have also found several limitations to be solved for further studies. If we develop a method to characterize pathogenic fungi in FFPE tissues in a follow-up study, we think it will help patients to use appropriate antifungal agents.

Background: Periodontitis (PT) is a multifactorial, chronic inflammatory disease that can have heterogeneous clinical presentations. The oral microbiome and its metabolites have been implicated as the causes and regulators of PT pathogenesis. In this study, we assessed the oral microbiome and its metabolome in PT patients to clarify the interactions between the microbiome and its metabolites.Methods: A total of 112 subjects were recruited. Buccal and supragingival samples were collected for microbiome analysis. Saliva samples were collected for metabolomic analyses. Microbiome and metabolome data were analyzed and further integrated for combined analysis using various bioinformatics approaches.Results: Oral metabolomic analysis identified 28 metabolites distinguishing the healthy (H) and PT groups. PT group were further clustered into two subgroups (PT_G1 and PT_G2) depending on metabolite profiles. Oral microbiome analysis revealed discriminatory bacterial species in the H, PT_G1, and PT_G2 microbiota. Interestingly, PT_G2 had significantly higher concentration of short chain fatty acids and higher abundance of pathogenic bacteria. Integrated analysis of the microbiome and metabolome showed close association.Conclusion: Our results provide evidence of a close interplay between the oral microbiome and metabolome. Multi-omics approach including microbiome and microbe-associated metabolites may serve as diagnostic biomarkers and enhance treatment prediction in periodontal disease.

Background: High cathepsin D has been associated with poor prognosis in breast cancer; however, the results of many studies are controversial. Here, we assessed the association between high cathepsin D levels and worse breast cancer prognosis by conducting a meta-analysis. Methods: A comprehensive search strategy was used to search relevant literature in PUBMED and EMBASE by September 2018. The meta-analysis was performed in Review Manager 5.3 using hazard ratios (HRs) with 95% confidence intervals (CIs). Results: A total of 15,355 breast cancer patients from 26 eligible studies were included in this meta-analysis. Significant associations between elevated high cathepsin D and poor overall survival (OS) (HR = 1.61, 95% CI: 1.35–1.92, p

Background The up-regulation of the lipogenic pathway has been reported in many types of malignant tumors. However, its pathogenic role or clinical significance is not fully understood. The objective of this study was to examine the expression levels of adipophilin and related hypoxic signaling proteins and to determine their prognostic impacts and associations with the pathologic characteristics of lung adenocarcinoma. Methods Expression levels of adipophilin, heat shock protein 27 (HSP27), carbonic anhydrase IX, and hypoxia-inducible factor 1α were examined by immunohistochemical staining using tissue microarray blocks. Correlations between protein expression levels and various clinicopathologic features were analyzed. Results A total of 230 cases of primary adenocarcinoma of the lung were enrolled in this study. Adipophilin expression was more frequent in males and with the solid histologic type. It was correlated with HSP27 expression. Patients with adipophilin-positive adenocarcinoma showed a shorter progression-free survival (PFS) (median PFS, 17.2 months vs 18.4 months) in a univariable survival analysis, whereas HSP27 positivity correlated with favorable overall survival (OS) and PFS. In a multivariable analysis, adipophilin and HSP27 were independent prognostic markers of both OS and PFS. Conclusions Activated lipid metabolism and the hypoxic signaling pathway might play a major role in the progression of lung adenocarcinoma, especially in the solid histologic type.

Background/Aims Intestinal barrier dysfunction is a hallmark of inflammatory bowel diseases (IBDs) such as ulcerative colitis. This dysfunction is caused by increased permeability and the loss of tight junctions in intestinal epithelial cells. The aim of this study was to investigate whether estradiol treatment reduces colonic permeability, tight junction disruption, and inflammation in an azoxymethane (AOM)/dextran sodium sulfate (DSS) colon cancer mouse model. Methods : The effects of 17β-estradiol (E2) were evaluated in ICR male mice 4 weeks after AOM/DSS treatment. Histological damage was scored by hematoxylin and eosin staining and the levels of the colonic mucosal cytokine myeloperoxidase (MPO) were assessed by enzyme-linked immunosorbent assay (ELISA). To evaluate the effects of E2 on intestinal permeability, tight junctions, and inflammation, we performed quantitative real-time polymerase chain reaction and Western blot analysis. Furthermore, the expression levels of mucin 2 (MUC2) and mucin 4 (MUC4) were measured as target genes for intestinal permeability, whereas zonula occludens 1 (ZO-1), occludin (OCLN), and claudin 4 (CLDN4) served as target genes for the tight junctions. Results : The colitis-mediated induced damage score and MPO activity were reduced by E2 treatment (p

Background/Aims: We aimed to compare the outcomes of Helicobacter pylori eradication in patients receiving sequential therapy (ST) depending on the use of ecabet sodium (ES). Materials and Methods : Between January to December 2015, 176 patients randomly received either ST alone (n=72) or 10-day ES therapy combined with ST (n=104). After applying the exclusion criteria, 56 patients were finally assigned to the ST-only group and 84 to the ST with ES group. We retrospectively reviewed and analyzed the H. pylori eradication rate and adverse events between the two groups. Results : Among the 140 patients, 121 (86.4%) achieved successful H. pylori eradication and 24 (17.1%) had adverse events. Eradication was achieved in 50 patients (89.3%) in the ST-only group and in 71 patients (84.5%) in the ST with ES group (P=0.420). No significant difference in the incidence of adverse events was found between the ST-only and ST with ES groups (12.5% vs. 20.2%, respectively; P=0.234). However, the ST with ES group tended to have a higher prevalence of nausea or vomiting than the ST-only group (11.9% vs. 1.8%; P=0.050). Conclusions : ST showed a good H. pylori eradication rate without deteriorating the adverse events regardless of adding ES.

Abstract Background Percutaneous endoscopic gastrostomy (PEG) is a relatively safe procedure; however, acute and chronic complications of PEG have been reported. We aimed to determine risk factors associated with complications and 30-day mortality after PEG, based on 11 years of experience at a single tertiary hospital. Methods In total, 401 patients who underwent first PEG insertion at the Asan Medical Center, Seoul, Korea, between January 2005 and December 2015 were eligible. Medical records were retrospectively reviewed to determine clinical characteristics and outcomes of 139 and 262 patients who underwent pull-type and introducer-type PEG, respectively. Results The median age of the overall population was 68 years, and the median body mass index was 19.5 kg/m2. Acute and chronic complications developed in 96 (23.9%) and 105 (26.2%) patients. Acute ileus and chronic tube obstruction were significantly more frequent in the introducer-type PEG group (p = 0.033 and 0.001, respectively). The 30-day mortality rate was 5.0% (median survival: 10.5 days). Multivariate analysis revealed that underlying malignancy was a predictor of acute complications; age ≥ 70 years and diabetes mellitus were predictors of chronic complications. The median follow-up was 354 days. Neurologic disease and malignancy were the most common indications for PEG. Neurologic diseases were classified into two groups: stroke and the other neurologic disease group (including dementia, Parkinson’s disease, neuromuscular disease, and hypoxic brain damage). Multivariate analysis showed that 30-day mortality was significantly lower in the other neurologic disease group and higher in patients with platelet count

Background/AimsWe aimed to investigate whether the current indications for curative endoscopic resection (ER) of gastric cancer (GC) can be applied to GC caused by adenoma. Additionally, we attempted to identify factors predictive of lesions subsequently found in addition to the expanded indications for ER.Methods : We retrospectively analyzed 342 patients diagnosed with GC caused by adenoma who underwent ER at a single tertiary center between February 2011 and December 2014. The gross whole tumor size was measured using the endoscopically resected specimen. The microscopic whole tumor size was measured using mapping paper. The estimated cancer size was calculated using the microscopic whole tumor size and the square root of the carcinoma component.Results : A gross whole tumor size ≥3 cm, carcinoma component ≥35%, and gross ulceration were predictive of lesions other than the expanded indications for ER. The overall rate of lymph node metastasis was 0.3% (1/327), which only occurred in one patient with a lesion other than the expanded indications (4.5%, 1/22).Conclusion : sThe current indications for curative ER in GC can be applied to GC caused by adenoma. In cases suspected of having lesions other than the expanded indications, patients should be cautiously selected for ER to reduce the risk of an inappropriate procedure.

The C‐type lectin‐like domain of CLEC14a (CLEC14a‐C‐type lectin‐like domain [CTLD]) is a key domain that mediates endothelial cell–cell contacts in angiogenesis. However, the role of CLEC14a‐CTLD in pathological angiogenesis has not yet been clearly elucidated. In this study, through complementarity‐determining region grafting, consecutive deglycosylation, and functional isolation, we generated a novel anti‐angiogenic human monoclonal antibody that specifically targets CLEC14a‐CTLD and that shows improved stability and homogeneity relative to the parental antibody. We found that this antibody directly inhibits CLEC14a‐CTLD‐mediated endothelial cell–cell contact and simultaneously downregulates expression of CLEC14a on the surface of endothelial cells. Using various in vitro and in vivo functional assays, we demonstrated that this antibody effectively suppresses vascular endothelial growth factor (VEGF)‐dependent angiogenesis and tumor angiogenesis of SNU182 human hepatocellular carcinoma, CFPAC‐1 human pancreatic cancer, and U87 human glioma cells. Furthermore, we also found that this antibody significantly inhibits tumor angiogenesis of HCT116 and bevacizumab‐adapted HCT116 human colorectal cancer cells. These findings suggest that antibody targeting of CLEC14a‐CTLD has the potential to suppress VEGF‐dependent angiogenesis and tumor angiogenesis and that CLEC14a‐CTLD may be a novel anti‐angiogenic target for VEGF‐dependent angiogenesis and tumor angiogenesis.

Background/Aims: We aimed to compare the outcomes and timing of Helicobacter pylori eradication in patients with iatrogenic and peptic ulcers. Materials and Methods: This was a retrospective study of 183 patients treated between 2012 and 2015 with 7-day standard triple therapy after endoscopic resection (ER). The patients were enrolled as the iatrogenic ulcer group and assigned to an early treatment group (n=139, H. pylori eradication initiated 2 days after ER) and a late treatment group (n=44, 8 weeks after ER). During the same period, 152 patients with peptic ulcer were assigned to the peptic ulcer group. Results: Successful H. pylori eradication was achieved in 141 patients (77.0%) in the iatrogenic ulcer group and 114 (75.0%) in the peptic ulcer group (P=0.661). Among the ER patients, the eradication rate was 79.9% (n=111) in the early treatment group and 68.2% (n=30) in the late treatment group (P=0.109). The adverse event rate was significantly higher in the peptic ulcer group than in the iatrogenic ulcer group (13.8% vs. 4.9%, P=0.005). Compliance and adverse events did not significantly differ between the early and late treatment groups. Conclusions: In iatrogenic ulcer, H. pylori eradication can be performed with a relatively lower adverse event rate, regardless of treatment timing, than that in peptic ulcer.

A gastrocolocutaneous fistula is a rare complication of percutaneous endoscopic gastrostomy (PEG). We report a case of a gastrocolocutaneous fistula presenting with intractable diarrhea and gastrostomy tube malfunction. A 62-year-old woman with a history of multiple system atrophy was referred to us because of PEG tube malfunction. Twenty days prior to presentation, the patient started developing sudden diarrhea within minutes after starting PEG feeding. Fluoroscopy revealed that the balloon of the PEG tube was located in the lumen of the transverse colon with the contrast material filling the colon. Subsequently, the PEG tube was removed and the opening of the gastric site was endoscopically closed using hemoclips. Clinicians should be aware of gastrocolocutaneous fistula as one of the complications of PEG insertion. Sudden onset of diarrhea, immediately after PEG feedings, might suggest this complication, which can be effectively treated with endoscopic closure.

Background/AimsWe used three-dimensional (3D) printing technology to create a new biopsy simulator for the stomach and investigated its efficacy and realism in endoscopic biopsy training.Methods : A novel stomach biopsy simulator, with 10 biopsy sites, was produced using a 3D printer. We enrolled 26 participants, including 10 residents, six first-year fellows, five second-year fellows, and five faculty members. We recorded and reviewed five training sessions and evaluated the simulator with questionnaires using a 7-point Likert scale.Results : The mean completion time (seconds) was 244.8±11.5 for the residents, 107.9±33.4 for the first-year fellows, 106.8±20.1 for the second-year fellows, and 103.8±19.2 for the faculty members. The completion time became shorter with repetition and was significantly lower for residents by the fifth trial (first trial, 347.0±159.5; fifth trial, 169.6±57.7; p=0.007). The faculty members strongly agreed that the simulator realistically reflected endoscopic handling and was reasonable for endoscopic training (scores of 6.2±0.8 and 6.4±0.9, respectively). Importantly, experienced endoscopists reported that the difficulty levels of the 10 biopsy sites in the simulator were a realistic match for the actual stomach.Conclusion : sThis endoscopic biopsy simulator created using a 3D printer is a realistic and useful method to improve the biopsy skills of trainee endoscopists.

(1) Background: Accurate preoperative identification of medullary thyroid carcinoma (MTC) is challenging due to a spectrum of cytomorphologic features. However, there is a scarcity of studies describing the cytomorphologic features as seen on fine-needle aspiration (FNA) smears prepared using different staining methods. (2) Methods: We performed a retrospective study on MTC cases with available FNA slides from 13 hospitals distributed across 8 Asia-Pacific countries. The differences in the constitutive cytomorphologic features of MTC with each cytopreparatory method were recorded. A comparative analysis of cytologic characteristics was carried out with appropriate statistical tests. (3) Results: Of a total of 167 MTC samples retrospectively recruited, 148 (88.6%) were interpreted as MTC/suspicious for MTC (S-MTC). The staining methods used were Papanicolaou, hematoxylin-eosin, and Romanowsky stains. Seven out of the eleven cytologic criteria can be readily recognized by all three cytopreparatory methods: high cellularity, cellular pleomorphism, plasmacytoid cells, round cells, dyshesive cells, salt-and-pepper chromatin, and binucleation or multinucleation. An accurate diagnosis was achieved in 125 (84.5%) of the 148 samples whose FNAs exhibited five or more atypical features. Conclusions: The present work is the first study on MTC to compare the morphological differences among the cytologic staining techniques. We investigated the constitutive features and the reliability of diagnostic parameters. A feasible scoring system based upon cytomorphologic data alone is proposed to achieve a high degree of diagnostic accuracy.

Background/Aims The detection of multifocal lesions is important for the successful management of gastric neoplasms. We investigated the characteristics of missed simultaneous lesions and the reason for the missed diagnoses. Methods A total of 140 patients who underwent repeat endoscopy before endoscopic resection between June 2013 and June 2014 were retrospectively reviewed. We classified simultaneous lesions into three groups based on a review of earlier images: group 1, no images of the location of simultaneous lesions were taken; group 2, no corresponding lesion was evident in the previous images; and group 3, simultaneous lesions were visible in the earlier images but a biopsy was not performed. Results Simultaneous lesions were found in 12 patients (8.6%) with 13 lesions, comprising 10 dysplasia (76.9%) and three adenocarcinoma (23.1%). Regarding the reasons for missed diagnoses, seven lesions (53.8%) were classified as group 3, five (38.5%) as group 1, and the remaining lesion (7.7%) as group 2. There were no significant differences in the characteristics of the patients with and without simultaneous lesions. Conclusions Lesions disregarded or unnoticed during endoscopic examination were the main reason for missed diagnosis of simultaneous lesions. Endoscopists should consider the possibility of simultaneous lesions and attempt to meticulously evaluate the entire gastric mucosa.

Mucinous cystadenoma of the testis is a very rare tumor. Herein, we report a case of mucinous cystadenoma arising in the testis of a 61-year-old man, along with a literature review. Computed tomography showed a 2.5-cm-sized poorly enhancing cystic mass. Grossly, the tumor was a unilocular cystic mass filled with mucinous material and confined to the testicular parenchyma. Histologically, the cyst had a fibrotic wall lined by mucinous columnar epithelium without atypia. Immunohistochemical staining was positive for cytokeratin 20 and CDX2, as well as focally positive for cytokeratin 7. The pathologic diagnosis was mucinous cystadenoma.

Cytologic diagnosis of thyroid follicular adenoma and carcinoma, and Hurthle cell adenoma and carcinoma (FACHAC) is challenging due to cytomorphologic features that overlap with other follicular-patterned lesions. This study was designed to analyze diagnostic categories (DCs) of preoperative fine needle aspiration cytology (FNAC) of histologically proven thyroid FACHACs to evaluate under- or misdiagnoses in FNAC and elucidate potential causes for such phenomena. A total of 104 thyroid nodules with preoperative FNAC which were diagnosed as FACHAC in resection specimens were included in this study. Of these, 66 cases had also undergone thyroid core needle biopsy (CNB); FNAC and CNB DCs were compared in these cases. Various cytologic and histologic parameters were compared between the nodules with different FNAC DCs. After a review of FNAC slides, DCs were re-assigned in 20 (19.2%) out of the 104 cases. Of the 66 cases with CNB diagnoses which were mostly classified as lower DCs in FNAC, 31 (47.0%) were diagnosed as suspicious for a follicular neoplasm in CNB. Cases which were underdiagnosed in FNACs were associated with lower cellularity, predominant macrofollicular pattern, absence of microfollicles arranged in trabecular pattern, and absence of transgressing vessels in cytology smears. High cellularity, microfollicles arranged in trabecular pattern, nucleolar prominence, and large cell dysplasia were more frequently found in malignancy than in benign neoplasm. In conclusion, thyroid FACHACs seem to be under- and misdiagnosed in preoperative FNAC. Innate characteristics of the nodules were associated with under-diagnosis as well as the quality of the FNAC specimens. Certain cytomorphologic features can be helpful in differentiating malignancy among FACHACs.

Background: Checking Helicobacter pylori susceptibility tests in the clinical setting before first-line treatment is considered difficult. We compared susceptibility-guided therapy (SGT) with empirical therapy (ET) as a first-line treatment containing clarithromycin and investigated the eradication rate using antimicrobial susceptibility testing (AST). Methods: 257 patients with H. pylori infection, with AST, performed before the eradication of clarithromycin-containing regimens were enrolled and divided into two groups: the SGT and ET groups. Results: Eradication rates in the SGT and ET groups were 85.4% and 58.4% (P < 0.01), respectively. In triple therapy (TT), eradication rates of the SGT and ET groups were 85.1% and 56.6% (P < 0.01), respectively. In sequential therapy (SET), eradication rates of the SGT and ET groups were 86.2% and 65.6% (P = 0.06), respectively. According to AST, TT had an eradication rate of 84.6% with strains susceptible to clarithromycin and amoxicillin and 11.1% with strains resistant to both. SET had an eradication rate of 89.5% with strains susceptible to clarithromycin, amoxicillin, and metronidazole, whereas it was 0% with strains resistant to clarithromycin and metronidazole. Conclusions: SGT as first-line treatment improved eradication rates of TT and SET by 28.5 (P < 0.01) and 20.6 (P = 0.06) percent points, respectively, compared with ET.

Background/AimsWe developed a new endoscopic biopsy training simulator and determined its efficacy for improving the endoscopic biopsy skills of beginners.Methods : This biopsy simulator, which presents seven biopsy sites, was constructed using readily available materials. We enrolled 40 participants: 14 residents, 11 first-year clinical fellows, 10 second-year clinical fellows, and five staff members. We recorded the simulation completion time for all participants, and then simulator performance was assessed via a questionnaire using the 7-point Likert scale.Results : The mean times for completing the five trials were 417.7±138.8, 145.2±31.5, 112.7±21.9, and 90.5±20.0 seconds for the residents, first-year clinical fellows, second-year clinical fellows, and staff members, respectively. Endoscopists with less experience reported that they found this simulator more useful for improving their biopsy technique (6.8±0.4 in the resident group and 5.7±1.0 in the first-year clinical fellow group). The realism score of the simulator for endoscopic handling was 6.4±0.5 in the staff group.Conclusion : sThis new, easy-to-manufacture endoscopic biopsy simulator is useful for biopsy training for beginner endoscopists and shows good efficacy and realism.

Background/AimsWe investigated the effectiveness of Helicobacter pylori eradication therapy for gastric mucosa-associated lymphoid tissue (MALT) lymphoma regardless of the H. pylori infection status or disease stage.Methods : From November 1995 to September 2014, 345 subjects who were diagnosed with gastric MALT lymphoma and had received eradication therapy as their first-line treatment were eligible for inclusion in this study. A retrospective review was performed using the medical records.Results : Of the 345 patients, H. pylori infection was detected in 317 patients (91.9%). The complete remission (CR) rate after eradication therapy was 82.3%, which was higher in H. pylori-positive patients than in H. pylori-negative patients (84.5% vs 57.1%, p=0.001). CR rates after eradication did not present significant differences between stages, and the CR rate was 83.3% for stage IE1 and 74.4% for stage IE2 or above (p=0.167). The overall CR rate was 87.2% after additional treatment, and neither H. pylori infection status nor stage showed differences according to the treatment response.Conclusion : sEradication therapy led to CR in 57.1% of H. pylori-negative patients and in 74.4% of patients with stage IE2 or above. Eradication therapy is worthwhile as an initial treatment for gastric MALT lymphoma regardless of the H. pylori infection status and stage.

Aberrant expression of CD5 has been reported in 5-10% of diffuse large B-cell lymphomas (DLBCLs). CD5+ DLBCL had been recognized as an aggressive immunophenotypic subgroup of DLBCL in the 2008 WHO classification of haematolymphoid neoplasm; however, it was eliminated from the list of subgroups of DLBCLs in the revised 2016 classification. Nevertheless, there is much controversy regarding the clinical significance of CD5 expression, and many researchers still assert that this subgroup exhibits an extremely unfavorable prognosis with frequent treatment failure. We retrospectively investigated 405 DLBCLs recruited from three university hospitals in Korea from 1997 to 2013. The clinical profile, immunophenotype, and chromosomal structural alterations of the BCL2 and MYC genes were compared according to CD5 expression. A total of 29 cases of de novo CD5+ DLBCL were identified out of 405 in our series (7.4%). Clinicopathologic correlation was performed in all 29 CD5+ DLBCLs and 166 CD5- DLBCLs which were eligible for full clinical review and further pathologic examination. Compared with CD5- counterparts, CD5+ DLBCLs showed female preponderance, frequent bone marrow involvement, higher lactate dehydrogenase level, advanced Ann Arbor stages and poorer prognosis (all p