Association between Endoscopist Volume and Interval Cancers after Colonoscopy: Results from the National Colorectal Cancer Screening Program in Korea.

Purpose: The rate of interval colorectal cancer (iCRC) is now accepted as a key performance indicator of organized colorectal cancer (CRC) screening programs. We aimed to examine the association between endoscopist volumes and the rate of iCRC among individuals with a positive fecal immunochemical test (FIT) within a nationwide population-based CRC screening program. Materials and Methods: Individuals aged ≥50 years who underwent colonoscopy after a positive FIT from January 1, 2019 until December 31, 2020 in the Korean National Cancer Screening Program (KNCSP) were enrolled. We converted the data into per-endoscopist screening results, calculated the iCRC rates per endoscopist, and compared them to the previous year's annual volume that was divided into five groups (V1, 1-9; V2, 10-29; V3, 30-59; V4, 60-119; V5, ≥120). Results: A total of 10,412 endoscopists performed 216,907 colonoscopies. Overall, the average rate of iCRC per endoscopist was 8.46 per 1,000 examinations. Compared with the group with the highest volume (V5 group), the rate of iCRC was 2.21 times higher in the V1 group. Similar trends were observed in the other groups (V2: Relative risks [RR], 2.15; 95% Confidence Interval [CI], 1.57-2.94; V3: RR, 1.56, 95% CI, 1.15-2.13; V4: RR, 1.18; 95% CI, 0.83-1.67). Conclusion: The findings emphasize that endoscopists with lower procedure volumes have higher risks of interval cancer being missed or undetected. To maximize the preventative impact of colonoscopy for colorectal cancer, this issue should be addressed by monitoring endoscopist volumes and variations in performances.

Tumour-associated myeloid cells expressing IL-10R2/IL-22R1 as a potential biomarker for diagnosis and recurrence of pancreatic ductal adenocarcinoma.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with a poor survival rate, largely due to the lack of early diagnosis. Although myeloid cells are crucial in the tumour microenvironment, whether their specific subset can be a biomarker of PDAC progression is unclear. METHODS: We analysed IL-22 receptor expression in PDAC and peripheral blood. Additionally, we analysed gene expression profiles of IL-10R2+/IL-22R1+ myeloid cells and the presence of these cells using single-cell RNA sequencing and murine orthotropic PDAC models, respectively, followed by examining the immunosuppressive function of IL-10R2+/IL-22R1+ myeloid cells. Finally, the correlation between IL-10R2 expression and PDAC progression was evaluated. RESULTS: IL-10R2+/IL-22R1+ myeloid cells were present in PDAC and peripheral blood. Blood IL-10R2+ myeloid cells displayed a gene expression signature associated with tumour-educated circulating monocytes. IL-10R2+/IL-22R1+ myeloid cells from human myeloid cell culture inhibited T cell proliferation. By mouse models for PDAC, we found a positive correlation between pancreatic tumour growth and increased blood IL-10R2+/IL-22R1+ myeloid cells. IL-10R2+/IL-22R1+ myeloid cells from an early phase of the PDAC model suppressed T cell proliferation and cytotoxicity. IL-10R2+ myeloid cells indicated tumour recurrence 130 days sooner than CA19-9 in post-pancreatectomy patients. CONCLUSIONS: IL-10R2+/IL-22R1+ myeloid cells in the peripheral blood might be an early marker of PDAC prognosis.

Clinicopathologic and Endosonographic Characteristics of Colon Subepithelial Tumors Discovered Incidentally.

BACKGROUND/AIMS: Colonoscopy is commonly used for colorectal cancer screening; therefore, the detection of colon subepithelial tumors (SETs) has also increased. Several research studies have been undertaken to diagnose and treat stomach and rectal SETs. The purpose of this study was to determine a diagnostic point for colon SETs by comparing histological findings with the endoscopic characteristics of colon SETs discovered by chance. METHODS: A total 194 patients underwent an endoscopic ultrasound (EUS) for suspicious colon SETs during a colonoscopy from May 2014 to December 2021. A total of 105 colon SETs, which were histologically diagnosed, were finally included. Fisher's exact test was used to determine the factors associated with malignant SETs. RESULTS: Colon SETs were predominantly present in the right colon (n = 73, 69.5%), particularly in the transverse colon (n = 32, 30.5%). The majority were smaller than 10 mm (n = 88, 83.8%), and they had hard consistencies (n = 84, 80%) and exhibited no surface changes (n = 96, 91.4%). Most of them were found in the submucosal layers (n = 54, 51.4%) and had a hypoechoic pattern (n = 56, 53.3%) in the EUS. Of the histologically confirmed cases, only three (3/105, 2.9%) were malignant. Most benign lesions were lipomas, suspected parasitic infections, or lesions caused by various inflammatory reactions, including fibrous/fibrocalcific lesions and necrotic nodules. All soft lesions were benign. Two of the three malignant lesions were adenocarcinomas, and the other was lymphoma. For the malignant SETs, there was a statistically significant alteration in the surface of the tumors (p < 0.001), and they were located where the muscularis mucosa layer was included (p = 0.008). The potential malignant SETs, granular cell tumors, and neuroendocrine tumors (NETs) had similar features, such as yellowish hypoechoic masses. Colon NETs were only found in the rectosigmoid junction. Parasitic infections and lesions, resulting in various inflammatory reactions, were observed as pale and hard SETs and mostly revealed as mixed echogenic masses located in the muscularis mucosa, submucosa, or multi-layers in the EUS. CONCLUSION: This study showed that small colon SETs were mostly benign lesions. Despite its rarity, pathological confirmation is crucial in cases where the SET has surface changes and has been located in a position where the muscularis mucosa layer was included on the EUS, due to the risk of malignancy.

Autotaxin inhibition attenuates the aortic valve calcification by suppressing inflammation-driven fibro-calcific remodeling of valvular interstitial cells.

BACKGROUND: Patients with fibro-calcific aortic valve disease (FCAVD) have lipid depositions in their aortic valve that engender a proinflammatory impetus toward fibrosis and calcification and ultimately valve leaflet stenosis. Although the lipoprotein(a)-autotaxin (ATX)-lysophosphatidic acid axis has been suggested as a potential therapeutic target to prevent the development of FCAVD, supportive evidence using ATX inhibitors is lacking. We here evaluated the therapeutic potency of an ATX inhibitor to attenuate valvular calcification in the FCAVD animal models. METHODS: ATX level and activity in healthy participants and patients with FCAVD were analyzed using a bioinformatics approach using the Gene Expression Omnibus datasets, enzyme-linked immunosorbent assay (ELISA), immunohistochemistry, and western blotting. To evaluate the efficacy of ATX inhibitor, interleukin-1 receptor antagonist-deficient (Il1rn-/-) mice and cholesterol-enriched diet-induced rabbits were used as the FCAVD models, and primary human valvular interstitial cells (VICs) from patients with calcification were employed. RESULTS: The global gene expression profiles of the aortic valve tissue of patients with severe FCAVD demonstrated that ATX gene expression was significantly upregulated and correlated with lipid retention (r = 0.96) or fibro-calcific remodeling-related genes (r = 0.77) in comparison to age-matched non-FCAVD controls. Orally available ATX inhibitor, BBT-877, markedly ameliorated the osteogenic differentiation and further mineralization of primary human VICs in vitro. Additionally, ATX inhibition significantly attenuated fibrosis-related factors' production, with a detectable reduction of osteogenesis-related factors, in human VICs. Mechanistically, ATX inhibitor prohibited fibrotic changes in human VICs via both canonical and non-canonical TGF-ß signaling, and subsequent induction of CTGF, a key factor in tissue fibrosis. In the in vivo FCAVD model system, ATX inhibitor exposure markedly reduced calcific lesion formation in interleukin-1 receptor antagonist-deficient mice (Il1rn-/-, P = 0.0210). This inhibition ameliorated the rate of change in the aortic valve area (P = 0.0287) and mean pressure gradient (P = 0.0249) in the FCAVD rabbit model. Moreover, transaortic maximal velocity (Vmax) was diminished with ATX inhibitor administration (mean Vmax = 1.082) compared to vehicle control (mean Vmax = 1.508, P = 0.0221). Importantly, ATX inhibitor administration suppressed the effects of a high-cholesterol diet and vitamin D2-driven fibrosis, in association with a reduction in macrophage infiltration and calcific deposition, in the aortic valves of this rabbit model. CONCLUSIONS: ATX inhibition attenuates the development of FCAVD while protecting against fibrosis and calcification in VICs, suggesting the potential of using ATX inhibitors to treat FCAVD.

Risk factors and management of iatrogenic colorectal perforation in diagnostic colonoscopy: a single-center cohort study.

BACKGROUND AND AIMS: Diagnostic colonoscopy plays a central role in colorectal cancer screening programs. We analyzed the risk factors for perforation during diagnostic colonoscopy and discussed the treatment outcomes. METHODS: We performed a retrospective analysis of risk factors and treatment outcomes of perforation during 74,426 diagnostic colonoscopies between 2013 and 2018 in a tertiary hospital. RESULTS: A total of 19 perforations were identified after 74,426 diagnostic colonoscopies or sigmoidoscopies, resulting in a standardized incidence rate of 0.025% or 2.5 per 10,000 colonoscopies. The majority (15 out of 19, 79%) were found at the sigmoid colon and recto-sigmoid junction. Perforation occurred mostly in less than 1000 cases of colonoscopy (16 out of 19, 84%). In particular, the incidence of perforation was higher in more than 200 cases undergoing slightly advanced colonoscopy rather than beginners who had just learned colonoscopy. Old age (≥ 70 years), inpatient setting, low body mass index (BMI), and sedation status were significantly associated with increased risk of perforation. Nine (47%) of the patients underwent operative treatment and ten (53%) were managed non-operatively. Patients who underwent surgery were often diagnosed with delayed or concomitant abdominal pain. Perforations of rectum tended to be successfully treated with endoscopic clipping. CONCLUSIONS: Additional precautions are required to prevent perforation in elderly patients, hospital settings, low BMI, sedated patients, or by a doctor with slight familiarity with endoscopies (but still insufficient experience). Endoscopic treatment should be actively considered if diagnosis is prompt, abdominal pain absent, and especially the rectal perforation is present.

Forecasting the future prevalence of inflammatory bowel disease in Korea through 2048: an epidemiologic study employing autoregressive integrated moving average models.

BACKGROUND AND AIM: The global inflammatory bowel disease (IBD) escalation has precipitated an increased disease burden and economic impact, particularly in Asia. This study primarily aimed to predict the future prevalence of IBD in Korea and elucidate its evolution pattern. METHODS: Using a validated diagnostic algorithm, we analyzed data from the Korean National Health Insurance Service between 2004 and 2017 to identify patients with IBD. We predicted the number and prevalence of patients with IBD from 2018 to 2048 with the autoregressive integrated moving average method. A generalized linear model (GLM) was also employed to identify factors contributing to the observed trend in IBD prevalence. RESULTS: Our prediction model validation demonstrated an acceptable error range for IBD prevalence, with a 2.45% error rate and a mean absolute difference of 2.61. We foresee a sustained average annual increase of 4.51 IBD cases per 100 000, culminating in a prevalence of 239.73 per 100 000 by 2048. The forecasted average annual percent change was 6.17% for males and 2.75% for females over the next 30 years. The GLM analysis revealed that age, gender and time significantly impact the prevalence of IBD, with notable disparities observed between genders in specific age groups for both Crohn's disease and ulcerative colitis (all interaction P < 0.05). CONCLUSIONS: Our study forecasts a notable increase in Korean IBD prevalence by 2048, particularly among males and the 20-39 age group, highlighting the need to focus on these high-risk groups to mitigate the future disease burden.

Prolonged Supplementation of Ozonated Sunflower Oil Bestows an Antiaging Effect, Improves Blood Lipid Profile and Spinal Deformities, and Protects Vital Organs of Zebrafish (Danio rerio) against Age-Related Degeneration: Two-Years Consumption Study.

Ozonated sunflower oil (OSO) is renowned for its diverse therapeutic benefits. Nonetheless, the consequences of extended dietary intake of OSO have yet to be thoroughly investigated. Herein, the effect of 2-year dietary supplementation of OSO was examined on the survivability, obesity, skeletal deformities, swimming behavior, and liver, kidney, ovary, and testis function of zebrafish. Results showed that the zebrafish feed supplemented with 20% (wt/wt) OSO for 2 years emerged with higher survivability and body weight management compared to sunflower oil (SO) and normal diet (ND)-supplemented zebrafish. Radio imaging (X-ray)-based analysis revealed 2.6° and 15.2° lower spinal curvature in the OSO-supplemented groups than in the SO and ND-supplemented groups; consistently, OSO-supplemented zebrafish showed better swimming behavior. The histology analysis of the liver revealed the least fatty liver change and interleukin (IL)-6 generation in the OSO-supplemented group. Additionally, a significantly lower level of reactive oxygen species (ROS), apoptotic, and senescent cells were observed in the liver of the OSO-supplemented zebrafish. Also, no adverse effect on the kidney, testis, and ovary morphology was detected during 2 years of OSO consumption. Moreover, lower senescence with diminished ROS and apoptosis was noticed in the kidney and ovary in response to OSO consumption. The OSO supplementation was found to be effective in countering age-associated dyslipidemia by alleviating total cholesterol (TC), triglycerides (TG), low-density lipoproteins (LDL-C) and elevating high-density lipoproteins (HDL-C)/TC levels. Conclusively, prolonged OSO consumption showed no adverse effect on the morphology and functionality of vital organs; in fact, OSO supplementation displayed a protective effect against age-associated detrimental effects on spinal deformities, vital organ functionality, cell senescence, and the survivability of zebrafish.

FLI-1 is expressed in a wide variety of hematolymphoid neoplasms: a special concern in the differential diagnosis.

Friend Leukemia Virus Integration 1 (FLI-1) is a member of E26 transformation-specific family of transcription factors that participates in hematopoietic and vascular endothelial cell development. Immunohistochemical detection of FLI-1 has been widely used to diagnose vascular tumors or, more evidently, Ewing's sarcoma. However, the expression pattern of FLI-1 in hematolymphoid neoplasms remains unclear. Therefore, in this study, we aimed to investigate the expression of FLI-1 in these tumors, focusing on high-grade lesions, which presents a diagnostic challenge by mimicking Ewing's sarcoma. We evaluated the expression FLI-1 in various types of lymphoid and plasmacytic tumors, including 27 plasmablastic lymphomas, 229 diffuse large B-cell lymphomas, 22 precursor T- or B-lymphoblastic lymphomas, 24 angioimmunoblastic-type nodal T-follicular helper cell lymphomas, 52 peripheral T-cell lymphomas, NOS, 18 Burkitt lymphomas, 18 non-gastric lymphomas of mucosa-associated lymphoid tissue, 38 chronic lymphocytic leukemia/small lymphocytic lymphomas, 15 mantle cell lymphomas, 23 gastric MALT lymphomas, 50 plasma cell myelomas, and 38 follicular lymphomas. We calculated the H-scores of FLI-1 immunostaining, ranging from 0 to 200, and used the scores to analyze the clinicopathological significance of FLI-1 statistically. FLI-1 was expressed to varying degrees in all types of hematological tumors. FLI-1 expression was detected in 84.1% of patients (466/554). FLI-1 was highly expressed in precursor T- or B-lymphoblastic lymphomas. Follicular lymphomas exhibited low FLI-1 expression. In plasmablastic lymphoma, 85.2% of the patients were focally positive for FLI-1. FLI-1 expression did not correlate with clinicopathological variables, such as demographic data or disease stage, in patients with plasmablastic lymphoma and diffuse large B-cell lymphoma. However, FLI-1 overexpression was associated with poorer overall survival in patients with plasmablastic lymphoma. This study demonstrates that FLI-1 is expressed in various hematolymphoid neoplasms. FLI-1 expression can lead to diagnostic confusion, especially in small blue round cell tumors, such as lymphoblastic lymphoma, plasmablastic lymphoma, and plasma cell myeloma, when distinguishing tumors positive for CD99 and CD56 without CD3, CD20, or CD45. Our findings also suggested the possibility of FLI-1 as a potential prognostic biomarker for plasmablastic lymphoma.

Comparison of an Endoscopic Scoring System and the Simplified Magnetic Resonance Index of Activity in Patients with Small Bowel Crohn's Disease.

Background/Aims: The newly derived simplified magnetic resonance index of activity (MARIAs) has not been verified in comparison to balloon-assisted enteroscopy (BAE) for patients with small bowel Crohn's disease (CD). We studied the correlation of MARIAs with simple endoscopic scores for CD (SES-CD) of the ileum based on magnetic resonance enterography (MRE) and BAE in patients with small bowel CD. Methods: Fifty patients with small bowel CD who underwent BAE and MRE concurrently within 3 months from September 2020 to June 2021 were enrolled in the study. The primary outcome was the correlation between the active score of ileal SES-CD (ileal SES-CDa)/ileal SES-CD and MARIAs based on BAE and MRE. The cutoff value for MARIAs identifying endoscopically active/severe disease, defined as ileal SES-CDa/ileal SES-CD of 5/7 or more, was analyzed. Results: Ileal SES-CDa/ileal SES-CD and MARIAs showed strong associations (R=0.76, p<0.001; R=0.78, p<0.001). The area under the receiver operating characteristic curve of MARIAs for ileal SES-CDa ≥5 and ileal SES-CD ≥7 was 0.92 (95% confidence interval, 0.88 to 0.97) and 0.92 (95% confidence interval, 0.87 to 0.97). The cutoff value of MARIAs for detecting active/severe disease was 3. A MARIAs index value of ≥3 identified ileal SES-CDa ≥5 with a sensitivity of 85% and specificity of 87% and detected ileal SES-CD ≥7 with a sensitivity of 87% and specificity of 86%. Conclusions: This study validated the applicability of MARIAs compared to BAE-based ileal SES-CDa/SES-CD.

Personalized Biomarker-Based Umbrella Trial for Patients With Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma: KCSG HN 15-16 TRIUMPH Trial.

PURPOSE: A precise oncologic approach for head and neck squamous cell carcinoma (HNSCC) is necessary. We performed a genomic profile-based umbrella trial for the patients with platinum-refractory recurrent and/or metastatic HNSCC. METHODS: In this multicenter, open-label, single-arm phase II trial, we performed targeted next-generation sequencing (NGS). Patients were assigned to each treatment arm on the basis of their matching genomic profiles: arm 1, alpelisib, a PIK3CA inhibitor; arm 2, poziotinib, an epidermal growth factor receptor/HER2 inhibitor; arm 3, nintedanib, an fibroblast growth factor receptor inhibitor; and arm 4, abemaciclib, a CDK4/6 inhibitor. If there was no matching target, patients were allocated to arm 5, duvalumab ± tremelimumab, anti-PD-L1/cytotoxic T-cell lymphocyte-4 inhibitor. When progressive disease (PD) occurred in arms 1-4, cross over to arm 5 was allowed. The primary end point was disease control rate (DCR) in arm 1 and overall response rate (ORR) in arms 2-5 by investigator assessment. RESULTS: Between October 2017 and August 2020, 203 patients were enrolled, including crossover. In arm 1, the ORR was 21.2% and DCR was 65.6%. The ORR was 0% for arm 2, 42.9% for arm 3, 0% for arm 4, and 15.6% for arm 5. In the case of PD with durvalumab, tremelimumab was added, and the ORR for durvalumab + tremelimumab was 2.2%. The median progression-free survival was 3.4, 3.2, 5.6, 1.6, and 1.7 months for each arm, respectively. The median overall survival was 12.4, 6.1, 11.1, 9.1, and 12.7 months, respectively. Overall, the toxicity profiles were manageable, and there were no treatment-related deaths. CONCLUSION: To our knowledge, this study is the first biomarker-driven umbrella trial for platinum-refractory HNSCC using matched molecular targeted agents. We found that NGS-based genomic phenotyping was methodologically feasible and applicable.

Long-term findings of rectal endoscopy and rectal bleeding after moderately hypofractionated, intensity-modulated radiotherapy for prostate cancer.

To present rectal endoscopic findings and toxicity after definitive moderately hypofractionated, intensity-modulated radiotherapy (IMRT) for prostate cancer. We retrospectively reviewed patients who underwent IMRT for prostate cancer and underwent post-radiotherapy endoscopies between 2008 and 2018. Endoscopic findings were reviewed and graded using Vienna Rectoscopy Score (VRS). We have analyzed the association between endoscopic findings and rectal bleeding, and investigated risk factors for rectal bleeding. Total 162 patients met the inclusion criteria of this study. There was a trend of VRS worsening during the initial 3 years after radiotherapy followed by recovery. Rectal bleeding was highest at 1 year after radiotherapy and improved thereafter. The 5-year cumulative incidence of grade ≥ 2 rectal bleeding was 14.8%. In the multivariable Cox regression analysis, cardiovascular disease (hazard ratio [HR] 2.732, P = 0.037), rectal wall V65 (HR 1.158, P = 0.027), and VRS ≥ 3 in first post-radiotherapy endoscopy (HR 2.573, P = 0.031) were significant risk factors for rectal bleeding. After IMRT for prostate cancer, VRS and rectal bleeding worsened over 1-3 years after radiotherapy and recovered. Cardiovascular disease, rectal wall V65, and VRS ≥ 3 in first post-radiotherapy endoscopy were significant risk factors for rectal bleeding.

Weight loss from diagnosis of Crohn's disease to one year post-diagnosis results in earlier surgery.

Malnutrition might play a key role in the prognosis of patients with Crohn's disease (CD). The aim of this study was to explore the impact of weight loss from diagnosis of CD to one-year post-diagnosis on disease prognosis in terms of surgery. Patients who were diagnosed with CD at Samsung Medical Center between 1995 to 2020 were included in this study. The study defined the "group with weight loss" as patients with weight loss in one year after diagnosis and the "group without body weight loss" as patients without weight loss in one year after diagnosis. Their data such as demographics, laboratory findings, and medical interventions were collected retrospectively. The primary outcome was confirmation of the difference in the incidence of surgery associated with CD between the group with weight loss and the group without body weight loss. We further analyzed factors associated with surgery outcomes. A total of 165 patients were analyzed in this study. Forty-one patients (24.8%) had body weight loss whereas 124 patients (75.2%) had no body weight loss. Body change at one year showed no significant association with direct surgical incidence. However, the patients with weight loss tended to undergo surgery earlier than patients without body weight loss. Among factors associated with outcomes of Crohn's surgery, the albumin was the only significant factor. Patients with weight loss had no statistically significant increase in the risk of surgery than patients without weight loss, although they tended to undergo surgery earlier than patients without body weight loss. A prospective study is needed to determine serial body weight changes during follow-up for patients with CD.

Chemosensitivity to doxorubicin in primary cells derived from tumor of FVB/N-Trp53tm1Hw1 with TALEN-mediated Trp53 mutant gene.

BACKGROUND: To evaluate the chemosensitivity to doxorubicin (DOX) in two primary cells derived from a tumor of FVB/N-Trp53tm1Hw1 knockout (KO) mice with TALEN-mediated Trp53 mutant gene, we evaluated the cell survivability, cell cycle distribution, apoptotic cell numbers and apoptotic protein expression in solid tumor cells and ascetic tumor cells treated with DOX. RESULTS: The primary tumor cells showed a significant (P < 0.05) defect for UV-induced upregulation of the Trp53 protein, and consisted of different ratios of leukocytes, fibroblasts, epithelial cells and mesenchymal cells. The IC50 level to DOX was lower in both primary cells (IC50 = 0.12 µM and 0.20 µM) as compared to the CT26 cells (IC50 = 0.32 µM), although the solid tumor was more sensitive. Also, the number of cells arrested at the G0/G1 stage was significantly decreased (24.7-23.1% in primary tumor cells treated with DOX, P < 0.05) while arrest at the G2 stage was enhanced to 296.8-254.3% in DOX-treated primary tumor cells compared with DOX-treated CT26 cells. Furthermore, apoptotic cells of early and late stage were greatly increased in the two primary cell-lines treated with DOX when compared to same conditions for CT26 cells. However, the Bax/Bcl-2 expression level was maintained constant in the primary tumor and CT26 cells. CONCLUSIONS: To the best of our knowledge, these results are the first to successfully detect an alteration in chemosensitivity to DOX in solid tumor cells and ascetic tumor cells derived from tumor of FVB/N-Trp53tm1Hw1 mice TALEN-mediated Trp53 mutant gene.

Can balloon-assisted enteroscopy predict disease outcomes in patients with small-bowel Crohn's disease?

There are limited studies on the endoscopic assessment of disease activity using balloon-assisted enteroscopy (BAE) and its predictive role for long-term outcomes of patients with small bowel Crohn's disease (CD). We sought to investigate the value of BAE as a predictor of long-term outcomes in patients with small-bowel CD. A total of 111 patients with small-bowel CD whose endoscopic disease activity was assessed using BAE based on the small-bowel simple endoscopic score for Crohn's disease (small-bowel SES-CD) at Samsung Medical Center were retrospectively selected from January 2014 to August 2020. The outcome was an evaluation of the risk of surgery according to a small-bowel SES-CD of 0-6 vs. ≥ 7 and endoscopic findings (presence of any ulcer and degree of stricture) using the Cox proportional hazards model. The risk of surgery was significantly increased in patients with a small-bowel SES-CD of ≥ 7 compared to a small-bowel SES-CD of 0-6 [hazard ratio (HR) 6.31; 95% confidence interval (CI) 1.48-26.91; p = 0.013]. In addition, the risk of surgery was significantly increased in patients with stenosis with "cannot be passed" compared to the cases without stenosis (HR 12.34; 95% CI 1.66-91.92; p = 0.014), whereas there was no significance in any ulcer. The present study demonstrated the role of BAE in the endoscopic assessment of disease activity and its predictive value for the risk of surgery in small-bowel CD patients. Further optimization of BAE utilization for the assessment of disease activity is warranted in clinical practice.

Prevalence of human papillomavirus in eyelid carcinoma among Koreans: a clinicopathological study.

BACKGROUND: Human papillomavirus (HPV) has been detected in eyelid sebaceous gland carcinoma (SGC) and squamous cell carcinoma (SCC), and detection rates greatly varied across studies. This study aimed to investigate the presence of HPV in eyelid SGC and SCC among Koreans and its correlation with clinicopathological characteristics. METHODS: Surgically resected eyelid samples diagnosed as SGC or SCC from January 1999 to June 2011 were identified from the pathology database of three referral centres in Korea. Clinicopathological information including origin (skin vs. tarsal conjunctiva) and treatment outcomes were retrospectively reviewed. Immunohistochemistry (IHC) for p16, HPV DNA in situ hybridisation (ISH), and polymerase chain reaction-based DNA microarray were performed in paraffin-embedded tissue sections. RESULTS: Our cohort included 34 SGC and 12 SCC cases with Asian ethnicity. HPV was detected in 4 SGC and 6 SCC by DNA microarray, while 2 SCC (16.7%) showed positivity in ISH. SCC of tarsal conjunctival origin was significantly more common in HPV-positive SCC than in HPV-negative SCC (5 of 6 vs. 0 of 6, P = 0.015, Fisher's exact test). Among samples showing positive staining in p16 IHC, HPV positivity rates were 0.0% (0/19) in SGC and 100% (3/3) in SCC. There was no significant difference in overall and local recurrence rate in eyelid SGC and SCC according to the HPV status (P > 0.99). CONCLUSIONS: HPV was found in a subset of eyelid SGC and SCC among Koreans and might be aetiologically related to SCC of tarsal conjunctival origin. Overexpression of p16 is considered to be inappropriate as an indicator of HPV infection in eyelid SGC. Further investigation is required to elucidate the transmission route and pathogenic roles of HPV.

Comparison of Policosanols via Incorporation into Reconstituted High-Density Lipoproteins: Cuban Policosanol (Raydel®) Exerts the Highest Antioxidant, Anti-Glycation, and Anti-Inflammatory Activity.

Reconstituted high-density lipoproteins (rHDL) containing each policosanol from Cuba (Raydel®), China (Shaanxi Pioneer), and the United States (Lesstanol®) were synthesized to compare the physiological properties of policosanol depending on sources and origin countries. After synthesis with apolipoproteinA-I (apoA-I) into rHDL, all policosanols bound well with phospholipid and apoA-I to form discoidal rHDL. An rHDL containing Cuban policosanol (rHDL-1) showed the largest rHDL particle size of around 83 ± 3 nm, while rHDL containing Chinese policosanol (rHDL-2) or American policosanol (rHDL-3) showed smaller particles around 63 ± 3 nm and 60 ± 2 nm in diameter, respectively. The rHDL-1 showed the strongest anti-glycation activity to protect the apoA-I degradation of HDL from fructose-mediated glycation: approximately 2.7-times higher ability to suppress glycation and 1.4-times higher protection ability of apoA-I than that of rHDL-2 and rHDL-3. The rHDL-1 showed the highest antioxidant ability to inhibit cupric ion-mediated LDL oxidation in electromobility and the quantification of oxidized species. A microinjection of each rHDL into a zebrafish embryo in the presence of carboxymethyllysine (CML) showed that rHDL-1 displayed the strongest anti-oxidant activity with the highest embryo survivability, whereas rHDL-2 and rHDL-3 showed much weaker protection ability, similar to rHDL alone (rHDL-0). An intraperitoneal injection of CML (250 µg) into adult zebrafish caused acute death and hyperinflammation with an elevation of infiltration of neutrophils and IL-6 production in the liver. On the other hand, a co-injection of rHDL-1 resulted in the highest survivability and the strongest anti-inflammatory ability to suppress IL-6 production with an improvement of the blood lipid profile, such as elevation of HDL-C and lowering of the total cholesterol, LDL-cholesterol, and triglyceride. In conclusion, Cuban policosanol exhibited the most desirable properties for the in vitro synthesis of rHDL with the stabilization of apoA-I, the largest particle size, anti-glycation against fructation, and antioxidant activities to prevent LDL oxidation. Cuban policosanol in rHDL also exhibited the strongest in vivo antioxidant and anti-inflammatory activities with the highest survivability in zebrafish embryos and adults via the prevention of hyperinflammation in the presence of CML.

Development of an SNP marker set for marker-assisted backcrossing using genotyping-by-sequencing in tetraploid perilla.

High-quality molecular markers are essential for marker-assisted selection to accelerate breeding progress. Compared with diploid species, recently diverged polyploid crop species tend to have highly similar homeologous subgenomes, which is expected to limit the development of broadly applicable locus-specific single-nucleotide polymorphism (SNP) assays. Furthermore, it is particularly challenging to make genome-wide marker sets for species that lack a reference genome. Here, we report the development of a genome-wide set of kompetitive allele specific PCR (KASP) markers for marker-assisted recurrent selection (MARS) in the tetraploid minor crop perilla. To find locus-specific SNP markers across the perilla genome, we used genotyping-by-sequencing (GBS) to construct linkage maps of two F2 populations. The two resulting high-resolution linkage maps comprised 2326 and 2454 SNP markers that spanned a total genetic distance of 2133 cM across 16 linkage groups and 2169 cM across 21 linkage groups, respectively. We then obtained a final genetic map consisting of 22 linkage groups with 1123 common markers from the two genetic maps. We selected 96 genome-wide markers for MARS and confirmed the accuracy of markers in the two F2 populations using a high-throughput Fluidigm system. We confirmed that 91.8% of the SNP genotyping results from the Fluidigm assay were the same as the results obtained through GBS. These results provide a foundation for marker-assisted backcrossing and the development of new varieties of perilla.

A designer peptide against the EAG2-Kvß2 potassium channel targets the interaction of cancer cells and neurons to treat glioblastoma.

Glioblastoma (GBM) is an incurable brain cancer that lacks effective therapies. Here we show that EAG2 and Kvß2, which are predominantly expressed by GBM cells at the tumor-brain interface, physically interact to form a potassium channel complex due to a GBM-enriched Kvß2 isoform. In GBM cells, EAG2 localizes at neuron-contacting regions in a Kvß2-dependent manner. Genetic knockdown of the EAG2-Kvß2 complex decreases calcium transients of GBM cells, suppresses tumor growth and invasion and extends the survival of tumor-bearing mice. We engineered a designer peptide to disrupt EAG2-Kvß2 interaction, thereby mitigating tumor growth in patient-derived xenograft and syngeneic mouse models across GBM subtypes without overt toxicity. Neurons upregulate chemoresistant genes in GBM cells in an EAG2-Kvß2-dependent manner. The designer peptide targets neuron-associated GBM cells and possesses robust efficacy in treating temozolomide-resistant GBM. Our findings may lead to the next-generation therapeutic agent to benefit patients with GBM.

Establishment and characterization of BMC-PDC-019: a novel patient-derived cell line of EGFR-mutant pulmonary adenocarcinoma transformed into small-cell lung cancer.

Transformed small-cell lung cancer (tSCLC) from EGFR-mutant adenocarcinoma is a rare and aggressive form of lung cancer that can occur when the tumor develops resistance to EGFR targeted therapy and the cancer cells acquire additional genomic alterations that cause them to transform into SCLC. Treatment for tSCLC has not been established yet, and chemotherapy regimens for de novo SCLC are mostly recommended. However, these treatments showed disappointing outcome, and novel anti-cancer agents and immunological approaches are currently being developed. The patient-derived cell line is a critical tool for pre-clinical and translational research, but cell line models for tSCLC are not publicly available from cell banks. The aim of this study was to establish and characterize a novel cell line for tSCLC. Using a lymph-node biopsy tissue from a 58-year-old female patient, whose tumor was EGFR-mutant lung adenocarcinoma progressed on afatinib, we successfully established a cell line, named BMC-PDC-019. The tumor sample and cell line showed a typical expression of SCLC markers, such as CD56 and synaptophysin. The population doubling-time of BMC-PDC-019 cells was 48 h. We examined a range of proliferation-inhibiting effects of anti-cancer drugs currently used for de novo SCLC, using BMC-PDC-019 cells. We concluded that BMC-PDC-019 would be a useful tool for pre-clinical and translational research.