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PurposeThe clinical significance of body mass index (BMI) on long-term outcomes has not been extensively investigated in Asian patients with colorectal cancer (CRC). This study aims to describe the association between BMI and survival, plus providing BMI cut-off value for predicting prognosis in CRC patients.Materials and MethodsA total of 1,182 patients who had undergone surgery for stage I-III CRC from June 2004 to February 2014 were included. BMI was categorized into four groups based on the recommendation for Asian ethnicity. The optimal BMI cut-off value was determined to maximize overall survival (OS) difference. ResultsIn multivariable analysis, underweight BMI was significantly associated with poor OS (hazard ratio [HR], 2.38; 95% confidence interval [CI], 1.55 to 3.71; p < 0.001) and obese BMI was associated with better OS (HR, 0.72; 95% CI, 0.53 to 0.97; p=0.036) compared with the normal BMI. Overweight and obese BMI were associated with better recurrence-free survival (HR, 0.64; 95% CI, 0.42 to 0.99; p=0.046 and HR, 0.58; 95% CI, 0.38 to 0.89; p=0.014, respectively) compared with the normal BMI group. BMI cutoff value was 20.44 kg/m2. Adding the BMI cutoff value to cancer staging could increase discriminatory performance in terms of integrated area under the curve and Harrell’s concordance index. ConclusionCompared to normal BMI, underweight BMI was associated with poor survival whereas obese BMI was associated with better survival. BMI cut-off value of 20.44 kg/m2 is a useful discriminator in Asian patients with CRC.

Periodontitis and osteoarthritis are major public health concerns that result in decreased quality of life among middle-aged and older adults. We sought to examine whether the severity of periodontitis is related to osteoarthritis according to the presence of type 2 diabetes mellitus.This study included 3,527 participants age ≥50 years from the Korean National Health and Nutrition Examination Survey. Periodontitis was assessed using the Community Periodontal Index; severe periodontitis was defined as periodontal tissue forming deep periodontal pockets ≥6-mm depth. Osteoarthritis was defined as Kellgren/Lawrence grade ≥2 on radiographic images of the knee or hip area with joint pain. The odds ratios (ORs) and 95% confidence intervals (95% CIs) for osteoarthritis according to the severity of periodontitis, stratified by type 2 diabetes mellitus, were calculated using multiple logistic regression analyses.Participants with type 2 diabetes mellitus were more likely to have osteoarthritis as the severity of periodontitis increased (nonsevere periodontitis OR 1.23 [95% CI 0.67-2.32]; severe periodontitis OR 3.01 [95% CI 1.51-5.84]) after adjusting for age, sex, body mass index, smoking status, alcohol consumption, regular exercise, education level, household income, hypertension, and frequent tooth-brushing. However, this positive association was not found in individuals without type 2 diabetes mellitus after adjusting for the same covariables.Severe periodontitis was positively and significantly associated with osteoarthritis in middle-aged and older individuals with type 2 diabetes mellitus. Our findings suggest that the oral inflammation manifesting in periodontitis may be at least partly involved in the pathogenesis of osteoarthritis, particularly in patients with type 2 diabetes mellitus.

Background & Aims One of the features of ulcerative colitis (UC) is a defect in the protective mucus layer. This has been attributed to a reduced number of goblet cells (GCs). However, it is not known whether abnormal GC mucus secretion also contributes to the reduced mucus layer. Our aims were to investigate whether GC secretion was abnormal in UC and exists as a long-term effect of chronic inflammation. Methods Colonoids were established from intestinal stem cells of healthy subjects (HS) and patients with UC. Colonoids were maintained as undifferentiated (UD) or induced to differentiate (DF) and studied as three-dimensional or monolayers on Transwell filters. Total RNA was extracted for quantitative real-time polymerase chain reaction analysis. Carbachol and prostaglandin E2 mediated mucin stimulation was examined by MUC2 IF/confocal microscopy and transmission electron microscopy. Results Colonoids from UC patients can be propagated over many passages; however, they exhibit a reduced rate of growth and transepithelial electrical resistance compared with HS. Differentiated UC colonoid monolayers form a thin and non-continuous mucus layer. UC colonoids have increased expression of secretory lineage markers ATOH1 and SPDEF, along with MUC2 positive GCs, but failed to secrete mucin in response to the cholinergic agonist carbachol and prostaglandin E2, which caused increased secretion in HS. Exposure to tumor necrosis factor α (5 days) reduced the number of GCs, with a greater percentage decrease in UC colonoids compared with HS. Conclusions Chronic inflammation in UC causes long-term changes in GCs, leading to abnormal mucus secretion. This continued defect in GC mucus secretion may contribute to the recurrence in UC., Graphical abstract

Background Sarcopenia and osteoporosis frequently co‐occur in the elderly and have common pathophysiological determinants. Slit guidance ligand 3 (SLIT3) has been recently discovered as a novel therapeutic factor against osteoporosis, and a SLIT3 fragment containing the second leucine‐rich repeat domain (LRRD2) had a therapeutic efficacy against osteoporosis. However, a role of SLIT3 in the skeletal muscle is unknown. Methods Skeletal muscle mass, strength, and/or physical activity were evaluated in Slit3 −/−, ovariectomized, and aged mice, based on the measurements of muscle weight and grip strength, Kondziella's inverted hanging test, and/or wheel‐running test. Skeletal muscles were also histologically evaluated by haematoxylin and eosin staining and/or immunofluorescence. The ovariectomized and aged mice were intravenously injected with recombinant SLIT3 LRRD2 for 4 weeks. C2C12 cells were used to know cellular effects of SLIT3, such as in vitro myogenesis, fusion, cell viability, and proliferation, and also used to evaluate its molecular mechanisms by immunocytochemistry, immunoprecipitation, western blotting, real‐time PCR, siRNA transfection, and receptor‐ligand binding ELISA. Results Slit3‐deficient mice exhibited decreased skeletal muscle mass, muscle strength, and physical activity. The relative masses of gastrocnemius and soleus were lower in the Slit3 −/− mice (0.580 ± 0.039% and 0.033 ± 0.003%, respectively) than those in the WT littermates (0.622 ± 0.043% and 0.038 ± 0.003%, respectively) (all, P

Background: We evaluated the risk of developing primary open-angle glaucoma (POAG) according to androgen deprivation therapy (ADT) status in patients with prostate cancer. Materials and methods: From the nationwide claims database in South Korea, 218,203 men with prostate cancer were identified between 2008 and 2017. After applying the inclusion and exclusion criteria, a total of 170,701 patients (42,877 in the ADT and non-ADT groups and 127,824 in the non-ADT group) were included in the analysis. To adjust for comorbidities between cohorts, exact matching was performed. Cox proportional hazard regression models were used to estimate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) of POAG associated with ADT after controlling for potential confounding factors. Results: In the matched cohort, the ADT group had a lower proportion of newly developed POAG than the non-ADT group (2.10% vs. 2.88%, respectively; P

Background Although levodopa-induced dyskinesia-relevant white matter change has been evaluated, it is uncertain whether these changes may reflect the underlying predisposing conditions leading to the development of levodopa-induced dyskinesia. Objective To elucidate the role of white matter connectivity networks in the development of levodopa-induced dyskinesia in drug-naive Parkinson's disease. Methods We recruited 30 patients who developed levodopa-induced dyskinesia within 5 years from MRI acquisition (vulnerable-group), 47 patients who had not developed levodopa-induced dyskinesia within 5 years (resistant-group), and 28 controls. We performed comparative analyses of whole-brain white matter integrity and connectivity using tract-based spatial and network- and degree-based statistics. We evaluated the predictability of levodopa-induced dyskinesia development and relationship with its latency, using the average connectivity strength as a predictor in Cox- and linear-regression, respectively. Results Mean-diffusivity was lower mainly at the left frontal region in the vulnerable-group compared to the resistant-group. Network-based statistics identified a subnetwork consisting of the bilateral fronto-striato-pallido-thalamic and lateral parietal regions (subnetwork A) and degree-based statistics identified four subnetworks (hub-subnetwork) consisting of edges centered on the left superior frontal gyrus, left putamen, left insular, or left precentral gyrus, where the vulnerable-group had stronger connectivity compared to the resistant-group. Stronger connectivity within the subnetwork A and hub-subnetwork centered on the left superior frontal gyrus was a predictor of levodopa-induced dyskinesia development independent of known risk factors and had an inverse relationship with its latency. Conclusions Our data suggest that white matter connectivity subnetworks within corticostriatal regions play a pivotal role in the development of levodopa-induced dyskinesia.

Purpose: Kidney, Ureter, and Bladder radiography (KUB) has frequently been used in suspected urolithiasis, but its performance is known to be lower than that of Computed Tomography (CT). This study aimed to investigate the diagnostic performance of digitally KUB in the detection of ureteral stones. Materials And Methods: Thirty patients who underwent digital KUB and CT were included in this retrospective study. The original digital KUB underwent post-processing that involved noise estimation, reduction, and whitening in improving the visibility of ureteral stones. Thus, 60 digital original or post-processed KUB images were obtained and ordered randomly for blinded review. After a period, a second review was performed after unblinding stone laterality. The detection rates were evaluated at both initial and second reviews, using CT as a reference standard. The objective (size) and subjective (visibility) parameters of ureteral stones were analyzed. Fisher’s exact test was used to compare the detection sensitivity between the original and post-processed KUB data set. Visibility analysis was assessed with a paired t-test. The correlation of stone size between CT and digital KUB data sets was assessed with the Pearson’s correlation test. Results: The detection rate was higher for most reviewers once stone laterality was provided and was non-significantly better for the post-processed KUB images (p > 0.05). There was no significant difference in stone size among CT and digital KUB data sets. In all reviews, visibility grade was higher in the post-processed KUB images, irrespective of whether stone laterality was provided. Conclusion: Digital post-processing of KUB yielded higher visibility of ureteral stones and could improve stone detection, especially when stone laterality was available. Thus, digitally post-processed KUB can be an excellent modality for detecting ureteral stones and measuring their exact size.

Abstract. Background/Aims: Trials on the effects of cholecalciferol supplementation in type 2 diabetes with chronic kidney disease patients were underexplored. Therefore, the aim of this study was to investigate the effects of two different doses of vitamin D supplementation on serum 25-hydroxyvitamin D [25(OH)D] concentrations and metabolic parameters in vitamin D-deficient Korean diabetes patients with chronic kidney disease. Methods: 92 patients completed this study: the placebo group (A, n = 33), the oral cholecalciferol 1,000 IU/day group (B, n = 34), or the single 200,000 IU injection group (C, n = 25, equivalent to 2,000 IU/day). 52% of the patients had less than 60 mL/min/1.73m2 of glomerular filtration rates. Laboratory test and pulse wave velocity were performed before and after supplementation. Results: After 12 weeks, serum 25(OH)D concentrations of the patients who received vitamin D supplementation were significantly increased (A, -2.4 ± 1.2 ng/mL vs. B, 10.7 ± 1.2 ng/mL vs. C, 14.6 ± 1.7 ng/mL; p

To compare the diagnostic performances of physicians and a deep convolutional neural network (CNN) predicting malignancy with ultrasonography images of thyroid nodules with atypia of undetermined significance (AUS)/follicular lesion of undetermined significance (FLUS) results on fine-needle aspiration (FNA). This study included 202 patients with 202 nodules ≥ 1 cm AUS/FLUS on FNA, and underwent surgery in one of 3 different institutions. Diagnostic performances were compared between 8 physicians (4 radiologists, 4 endocrinologists) with varying experience levels and CNN, and AUS/FLUS subgroups were analyzed. Interobserver variability was assessed among the 8 physicians. Of the 202 nodules, 158 were AUS, and 44 were FLUS; 86 were benign, and 116 were malignant. The area under the curves (AUCs) of the 8 physicians and CNN were 0.680–0.722 and 0.666, without significant differences (P > 0.05). In the subgroup analysis, the AUCs for the 8 physicians and CNN were 0.657–0.768 and 0.652 for AUS, 0.469–0.674 and 0.622 for FLUS. Interobserver agreements were moderate (k = 0.543), substantial (k = 0.652), and moderate (k = 0.455) among the 8 physicians, 4 radiologists, and 4 endocrinologists. For thyroid nodules with AUS/FLUS cytology, the diagnostic performance of CNN to differentiate malignancy with US images was comparable to that of physicians with variable experience levels.

Immune checkpoint inhibitors (ICI) have demonstrated efficacy in the treatment of solid cancers. However, there is no unified predictive biomarker available for ICIs. We aimed to compare the prognostic impact of using three PD-L1 antibodies (SP142, SP263, and 22C3) for immunohistochemical (IHC) analysis. We retrospectively investigated tumor tissues derived from 316 breast cancer cases, by constructing tissue microarrays and by performing IHC staining. The immune-cell expression rate (for SP142 and SP263) and combined proportional score (for 22C3) were evaluated, and survival outcomes were analyzed. Prediction models were developed, and values of Harrel’s c-index and areas under curves were calculated to compare the discriminatory power. Negative PD-L1 expression based on the 22C3-IHC assay was determined to be an independent prognostic marker for recurrence-free survival (RFS, P = 0.0337) and distant metastasis-free survival (DMFS, P = 0.0131). However, PD-L1 expression based on SP142- and SP263-IHC assays did not reveal a prognostic impact. Among the three antibodies, adding PD-L1 expression data obtained via 22C3-IHC assay to the null model led to a significant improvement in the discriminatory power of RFS and DMFS. We suggest that PD-L1 expression based on the 22C3-IHC assay is a superior prognostic marker than that based on SP142- and SP263-IHC assays.

To investigate whether women with a short cervical length (CL), but delivered at term in the first pregnancy might have increased risks of having short cervix and spontaneous preterm birth (sPTB) in the subsequent pregnancies.This is a retrospective cohort study including singleton gestations who were delivered between Jan 2011 and Dec 2018, who had had one childbirth experience and who had transvaginal sonographic CL assessment performed at mid-trimester (18 ~ 30 weeks) in both pregnancy. The women were divided into four group according to the history of preterm birth and a short cervix ( 25 mm before 30 weeks of gestation): (1) the Preterm-short cervix group, (2) the Preterm-no shortening group, (3) the Term-short cervix group, and (4) the Term-no shortening group. We compared the risk of having short cervix and sPTB during the second pregnancy of women. Secondary outcomes were threatened preterm labor, need for tocolytics, and cerclage placement.A total of 804 women met our inclusion criteria. The rate of having short cervix ( 25 mm before 28 weeks of gestation) during the second pregnancy in women in the Term-short cervix group (43.2%) was significantly higher than those in women in the Term-no shortening group (6.6%), and in the Preterm-no shortening group (8.8%) (all p 0.001 with Bonferroni correction), but not higher than those in women with the Preterm-short cervix group (30.8%, p 0.05 with Bonferroni correction). When compared with women in the Preterm-no shortening group, women in the Term-short cervix group were also at an increased risk of need for need of tocolytics (60.2% vs. 26.5%) and cerclage placement (15.9% vs. 6.1%, all p 0.001). Women in the Term-short cervix group had an increased risk of sPTB ( 37 weeks) during the second pregnancy, as compared to those in the Term-no shortening group (adjusted odds ratio 5.098, 95% CI 2.107-11.874).Women with a history of short cervix in their first pregnancy, but who delivered at term, were at increased risk of having a short cervix and sPTB in their second pregnancy, as compared to women with a history of term delivery without cervical shortening. Thus, short cervix of the previous pregnancy might be a predictive factors for preterm birth in the subsequent pregnancy.

Growth and differentiation factor 15 (GDF-15) is associated with muscle, fat, and bone metabolism; however, this association has not been well characterized. Plasma GDF-15, appendicular skeletal muscle mass (ASM), fat mass (FM), and bone mineral density (BMD) were measured in 146 postmenopausal women. GDF-15 levels were higher in subjects with low Body Mass Index (BMI)-adjusted ASM than in those without (median [interquartile range] 831.3 [635.4-1011.4] vs. 583.8 [455.8-771.1] pg/mL, p = 0.018). The GDF-15 level was inversely correlated with BMI-adjusted ASM (r = - 0.377, p 0.001) and BMD at femur neck (FN-BMD; r = - 0.201, p = 0.015), and positively correlated with percent FM (pFM; r = 0.328, p 0.001). After adjusting for confounders, the GDF-15 level was inversely associated with BMI-adjusted ASM (β = -0.250, p = 0.006) and positively associated with pFM (β = 0.272, p = 0.004), and tended to be inversely associated with FN-BMD (β = - 0.176, p = 0.076). The area under the receiver-operating characteristic curve of GDF-15 level 618.4 pg/mL for sarcopenia was 0.706 (95% confidence interval (CI) 0.625-0.779) with a sensitivity of 83.3% and a specificity of 54.5%. Using a GDF-15 level of 618.4 pg/mL as a cut-off, the GDF-15 level was associated with a significantly greater likelihood of sarcopenia (odds ratio [OR] 2.35; 95% CI 1.00-5.51; p = 0.049), obesity (OR 3.28; 95% CI 1.48-7.27; p = 0.001), osteopenic obesity (OR 3.10; 95% CI 1.31-7.30; p = 0.010), and sarcopenic or osteosarcopenic obesity (OR 4.84; 95% CI 0.88-26.69; p = 0.070). These findings support the potential of GDF-15 as a biomarker for age-related changes in muscle, fat, and bone.

Objective: This study aimed to analyze the prediction rate of the modified Global Alignment and Proportion (GAP) scoring system with body mass index and bone mineral density (GAPB) in each GAP of the 3 categories.Methods: Between January 2009 and December 2016, 203 consecutive patients with adult spinal deformity (ASD) underwent corrective fusion of more than 4 levels and were followedup for more than 2 years. As a validation of the GAPB, the GAPB was divided into tertiles (Q1, Q2, Q3) for each section of the GAP score. Each patient’s GAP score and GAPB system complication rate were examined.Results: Of the 203 patients, 89 patients (44%) developed mechanical complications after ASD surgery. A GAP score analysis of the patients found that 42 patients were proportioned, 85 patients were moderately disproportioned, and 76 patients were severely disproportioned. Mechanical complications occurred with increasing GAPB in the proportioned group, but were not statistically significant (p = 0.0534). However, mechanical complications occurred in a statistically significant manner in the moderately disproportioned and severely disproportioned groups as GAPB increased (p < 0.001).Conclusion: The GAPB system showed improved predictability for mechanical complications after surgery for ASD in each category of the GAP score.

Objective Neuroscience research using laboratory animals has increased over the years for a number of reasons. Some of these studies require the use of anesthetics for surgical procedures. However, the use of anesthetics promotes several physiological changes that may interfere with experimental results. Although the anesthetics and methods of delivery used to vary, one of the most common is ketamine associated with another compound such as xylazine. We aimed to evaluate the effect of ketamine and xylazine (KX) on corticosterone levels and on the degree of phosphorylation of p44/42 (ERK1/2), Src kinases and calcium/calmodulin-dependent kinase II (CAMKII). We also compared the effects of KX on sleep deprivation, which is known to affect the hormonal profile including corticosterone. Results We found that the use of KX can increase corticosterone levels and alter the degree of phosphorylation of signaling proteins.

Introduction: Pheochromocytoma are tumors arising from the chromaffin tissue located in the adrenal medulla, associated with typical symptoms and signs. Case Presentation: Occasionally, metastasis, defined as the presence of tumor cells at sites other than the original site, secondary to pheochromocytoma have been reported. Pelvic metastatic malignant pheochromocytoma has rarely been reported in English literature. Conclusion: Here, we have reported a very rare case of pelvic metastatic malignant pheochromocytoma, with a particular focus on sonoelastographic features.

Jung Hyun Kim,1 Jae-Hoon Lee,2 Hye Sun Lee,3 Su-Jin Shin,4 Eun Jung Park,1 Eun-Suk Cho,5 Seung Hyuk Baik,1 Kang Young Lee,6 Jeonghyun Kang1 1Department of Surgery, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea; 2Department of Nuclear Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea; 3Biostatistics Collaboration Unit, Yonsei University College of Medicine, Seoul, Republic of Korea; 4Department of Pathology, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea; 5Department of Radiology, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea; 6Department of Surgery, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of KoreaCorrespondence: Jeonghyun KangDepartment of Surgery, Gangnam Severance Hospital, Yonsei University College of Medicine, 211 Eonju-ro, Gangnam-gu, Seoul, 06273, Republic of KoreaTel +82-2-2019-3372Fax +82-2-3462-5994Email ravic@naver.comBackground: Recent data suggest that alterations in the neutrophil-to-lymphocyte ratio (NLR) in the perioperative periods can serve as prognostic factors. However, research on the clinical impact has been limited and even discordant in patients with colorectal cancer (CRC).Patients and Methods: The optimal cut-off value of preoperative NLR (NLR-pre), postoperative NLR (NLR-post), and its change (NLR-delta) were determined to maximize differences in overall survival (OS) between groups. Patients were categorized into four groups (NLR-trend) as follows: G1, low NLR-pre and NLR-post; G2, low NLR-pre and high NLR-post; G3, high NLR-pre and low NLR-post; and G4, high NLR-pre and NLR-post. Discriminatory performance was compared using integrated AUC (iAUC) between all indicators.Results: A total of 576 patients diagnosed with stage I–IV CRC were included. The cut-off points were determined as 2.33 for NLR-pre, 2.06 for NLR-post, and − 1.08 for NLR-delta. Subgroup dichotomization using NLR-pre, NLR-post, NLR-delta and NLR-trend were all identified as significant prognostic factors by univariate analysis. However, NLR-trend was only remained as an independent prognostic factor in the multivariate analysis. The iAUC of the NLR-trend was superior to that of NLR-pre (bootstrap iAUC mean difference=0.036; 95% CI 0.013– 0.073), NLR-post (bootstrap iAUC mean difference=0.045; 95% CI 0.019– 0.081) and NLR-delta (bootstrap iAUC mean difference=0.061; 95% CI 0.025– 0.104).Conclusion: Risk stratification and combining of preoperative and postoperative NLR (NLR-trend) can improve prognostic discrimination compared with single measurements or simple changes in NLR in patients with CRC.Keywords: NLR, colorectal cancer, survival, iAUC

Statins are more widely used not only for the primary and secondary prevention of cardiovascular disease by blocking cholesterol biosynthesis but also for the potential neuroprotective agents during neurological disorders due to their pleiotropic effects. In this study, we investigate whether the previous use of statins affect baseline nigrostriatal dopamine loss at the time of diagnosis and longitudinal motor and cognitive outcomes in patients with Parkinson’s disease. Five hundred drug-naïve patients with Parkinson’s disease who underwent dopamine transporter imaging were classified into two groups according to the prior use of statins: patients with and without statin use. Multivariate linear regression was used to determine intergroup differences in dopamine transporter availability. We evaluated the longitudinal changes in levodopa-equivalent dose and dementia conversion between the groups using a linear mixed model and survival analysis, respectively. In addition, mediation analysis was applied to examine the effect of total cholesterol. Patients with Parkinson’s disease treated with statins had a lower baseline dopamine transporter availability in the anterior (2.13 ± 0.55 versus 2.37 ± 0.67; P = 0.002), posterior (1.31 ± 0.43 versus 1.49 ± 0.54; P = 0.003) and ventral putamina (1.40 ± 0.39 versus 1.56 ± 0.47; P = 0.002) than that in matched patients with Parkinson’s disease without statins. After adjusting for age at symptom onset, sex, disease duration and vascular risk factors, linear regression models showed that a previous treatment with statins remained significantly and independently associated with more severely decreased dopamine transporter availability in the anterior putamen (Beta = −0.140, P = 0.004), posterior putamen (Beta = −0.162, P = 0.001) and ventral putamen (Beta = −0.140, P = 0.004). A linear mixed model revealed that patients with Parkinson’s disease being treated with statins had a faster longitudinal increase in levodopa-equivalent dose than those without. A survival analysis showed that the rate of dementia conversion was significantly higher in patients with Parkinson’s disease with statins (hazard ratio, 2.019; 95% confidence interval, 1.108–3.678; P = 0.022) than those without. Mediation analyses revealed that the effect of statin treatment on baseline dopamine transporter availability and longitudinal outcome was not mediated by total cholesterol levels. This study suggests that statin use may have a detrimental effect on baseline nigrostriatal dopamine degeneration and long-term outcomes in patients with Parkinson’s disease.

Background Primary ovarian high-grade endometrial stromal sarcoma is a very rare disease. Even though it has poor prognosis, the gold standard treatment has not been established owing to its rarity. This report aimed to present therapeutic options for primary ovarian high-grade endometrial stromal sarcoma. Case presentation A 49-year-old Asian woman presented with disseminated intravascular coagulation due to ruptured primary high-grade ovarian endometrial stromal sarcoma with multiple intraperitoneal metastases. After the initial surgery, the patient underwent adjuvant chemotherapy with three courses of Adriamycin (75 mg/m2). We performed the secondary debulking operation including total hysterectomy, metastasectomy, omentectomy, peritonectomy, appendectomy, and hyperthermic intraperitoneal chemotherapy (paclitaxel 175 mg/m2). Currently she has been alive for 28 months under a new chemotherapy regimen. Conclusion We suggest cytoreductive surgery with hyperthermic intraperitoneal chemotherapy could be a therapeutic option for primary high-grade ovarian endometrial stromal sarcoma with peritoneal dissemination.

BACKGROUND Diagnostic accuracy of various tumor markers and their combinations for hepatocellular carcinoma (HCC) was not fully investigated. AIM To evaluate the diagnostic accuracy of alpha-fetoprotein (AFP), the Lens culinaris agglutinin-reactive fraction of AFP (AFP-L3), and protein induced by vitamin K absence or antagonist-II (PIVKA-II) and their combination for HCC diagnosis. METHODS Patients with newly detected liver mass or elevated serum AFP levels were considered eligible. Serum AFP level, AFP-L3 fraction, and PIVKA-II level were measured at the first visit. RESULTS In total, 622 patients were included; 355 patients (57.1%) had chronic liver disease, and 208 (33.4%) had liver cirrhosis. HCC was diagnosed in 160 patients (25.7%). The area under the receiver operating characteristics curves (AUROCs) of the serum AFP, AFP-L3 fraction, AFP-L3, and PIVKA-II levels for the diagnosis of HCC were 0.775, 0.792, 0.814, and 0.834, respectively. A novel diagnostic model was developed by classifying patients in a 1:1 ratio into training and validation sets. Using the binary regression analysis of the training cohort, the AFP, AFP-L3 fraction, and PIVKA-II (ALPs) score was calculated as follows: ALPs score = 3.8 × [serum AFP level (ng/mL) × AFP-L3 fraction (%) × 0.01] + 0.2 × PIVKA-II level (mAU/mL). The AUROC of the ALPs score for diagnosis of HCC was 0.878, significantly higher than that of serum AFP level (P < 0.001), AFP-L3 fraction (P < 0.001), PIVKA-II level (P = 0.036), and AFP-L3 level (P = 0.006). The optimal ALPs score cut-off was 5.3 (sensitivity, 85.0%, specificity 80.1%). The validation cohort showed similar results. CONCLUSION The ALPs score calculated using serum AFP level, AFP-L3 fraction, and PIVKA-II level showed improved accuracy in HCC diagnosis.

Background/Aims Most prognostic prediction models for patients with liver cirrhosis include serum total bilirubin (TB) level as a component. This study investigated prognostic performance of serum direct bilirubin (DB) and developed new DB level-based prediction models for cirrhosis. Methods A total of 983 hospitalized patients with liver cirrhosis were included. DB-Model for End-Stage Liver Disease (MELD) score was calculated using MELD score formula, with serum DB level replacing TB level. Results Mean age of study population was 56.1 years. Alcoholic liver disease was the most frequent underlying condition (471 patients, 47.9%). Within 6 months, 144 patients (14.6%) died or received liver transplantation due to severe liver dysfunction. The area under the receiver operating characteristic curve (AUROC) for prediction of 6-month mortality with DB level was significantly higher than that with TB level (p

Despite the potential roles of sphingosine 1-phosphate (S1P) as a biomarker of osteoporotic fracture (OF), independent of bone mineral density (BMD) and clinical risk factors (CRFs), its association with bone microarchitecture, a key determinant of bone quality, have not been studied yet. We here investigated the association of S1P with the trabecular bone score (TBS), an index of the bone microarchitecture. The plasma S1P concentrations, TBS, and BMD were measured in the 339 postmenopausal women. The S1P level was inversely correlated with the TBS (γ=-0.096, p=0.049) and BMD at the femur neck (FN-BMD: γ=-0.122, p=0.025) and tended to be inversely correlated the BMD at the total hip (TH-BMD: γ=-0.096, p=0.079), but not at the lumbar spine (LS-BMD). After adjusting for fracture risk assessment tool probabilities of major OF from CRFs, the S1P level was inversely associated with the TBS (β=-0.096, p=0.049) and FN-BMD (β=-0.118, p=0.025) and tended to be inversely associated with the TH-BMD (β=-0.092, p=0.083). Compared with subjects in the lowest S1P tertile, those in the highest S1P tertile had a significantly lower TBS (p=0.032) and BMD at femur (p=0.004-0.036). These findings indicated that a high S1P level in postmenopausal women was inversely associated with the both bone mass and microarchitecture, reflecting the compromised bone strength.

The effect of deer antler extract on muscle differentiation and muscle atrophy were evaluated to minimize muscle loss following aging. Various deer antler extracts (HWE, hot water extract of deer antler; FE, HWE of fermented deer antler; ET, enzyme-assisted extract of deer antler; UE, extract prepared by ultrasonication of deer antler) were evaluated for their effect on muscle differentiation and inhibition of 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR)-induced muscle atrophy in C2C12 cells. Morphological changes according to the effect of antler extracts on muscle differentiation were confirmed by Jenner-Giemsa staining. In addition, the expression levels of genes related to muscle differentiation and atrophy were confirmed through qRT-PCR. In the presence of antler extracts, the length and thickness of myotubes and myogenin differentiation 1 (MyoD1) and myogenic factor 5 (Myf5) gene expression were increased compared to those in the control group (CON). Gene expression of AMP-activated protein kinase (AMPK), MyoD1, and myogenin, along with the muscle atrophy factors muscle RING finger-1 (MuRF-1) and forkhead box O3a (FoxO3a) upon addition of deer antler extracts to muscle-atrophied C2C12 cells was determined by qRT-PCR after treatment with AICAR. The expression of MuRF-1 and FoxO3a decreased in the groups treated with antler extracts compared to that in the group treated with AICAR alone. In addition, gene expression of MyoD1 and myogenin in the muscle atrophy cell model was significantly increased compared that into the CON. Therefore, our findings indicate that antler extract can increase the expression of MyoD1, Myf5 and myogenin, inhibit muscle atrophy, and promote muscle differentiation.

Nonalcoholic steatohepatitis (NASH) is considered as a progressive form of nonalcoholic fatty liver disease (NAFLD). To distinguish NASH from nonalcoholic fatty liver (NAFL), we evaluated the diagnostic value of circulating miRNAs. Small RNA sequencing was performed on 12 NAFL patients and 12 NASH patients, and the miRNA expression was compared. After selecting miRNAs for the diagnosis of NASH, we analyzed the diagnostic accuracy of each miRNA and the combination of miRNAs. External validation was performed using quantitative reverse transcription PCR. Among the 2,588 miRNAs, 26 miRNAs significantly increased in the NASH group than in the NAFL group. Among the 26 elevated miRNAs in the NASH group, 8 miRNAs were selected, and in silico analysis was performed. Only four miRNAs (miR-21-5p, miR-151a-3p, miR-192-5p, and miR-4449) showed significant area under the receiver operating characteristic curve (AUC) values for NASH diagnosis. The combination of the four miRNAs showed satisfactory diagnostic accuracy for NASH (AUC 0.875; 95% CI 0.676–0.973). External validation revealed similar diagnostic accuracy for NASH (AUC 0.874; 95% CI 0.724–0.960). NASH represents significantly distinct miRNA expression profile compared with NAFL. The combination of serum circulating miRNAs can be used as a novel biomarker for the NASH diagnosis in NAFLD.

Low-density-lipoprotein cholesterol (LDL-C) is the main target in atherosclerotic cardiovascular disease (ASCVD). We aimed to validate and compare a new LDL-C estimation equation with other well-known equations. 177,111 samples were analysed from two contemporary population-based cohorts comprising asymptomatic Korean adults who underwent medical examinations. Performances of the Friedewald (FLDL), Martin (MLDL), and Sampson (SLDL) equations in estimating direct LDL-C by homogenous assay were assessed by measures of concordance (R2, RMSE, and mean absolute difference). Analyses were performed according to various triglyceride (TG) and/or LDL-C strata. Secondary analyses were conducted within dyslipidaemia populations of each database. MLDL was superior or at least similar to other equations regardless of TG/LDL-C, in both the general and dyslipidaemia populations (RMSE = 11.45/9.20 mg/dL; R2 = 0.88/0.91; vs FLDL: RMSE = 13.66/10.42 mg/dL; R2 = 0.82/0.89; vs SLDL: RMSE = 12.36/9.39 mg/dL; R2 = 0.85/0.91, per Gangnam Severance Hospital Check-up/Korea Initiatives on Coronary Artery Calcification data). MLDL had a slight advantage over SLDL with the lowest MADs across the full spectrum of TG levels, whether divided into severe hyper/non-hyper to moderate hypertriglyceridaemia samples or stratified by 100-mg/dL TG intervals, even up to TG values of 500–600 mg/dL. MLDL may be a readily adoptable and cost-effective alternative to direct LDL-C measurement, irrespective of dyslipidaemia status. In populations with relatively high prevalence of mild-to-moderate hypertriglyceridaemia, Martin’s equation may be optimal for LDL-C and ASCVD risk estimation.

Somatics refers to body work and movement study that emphasize internal perception and experience. Recently, a new perspective has emerged that views somatics-based techniques as a kind of mindful movement. Somatic techniques as contemplative movement can improve emotional regulation ability through improvement of body awareness or interoception. Based on this background, the present study attempts to develop a somatics based program suitable for a group of clinical patients suffering from emotional dysregulation. This study plans to collect quantitative and qualitative data in order to clarify how interoception and the related emotional regulation ability change after the program. These findings will help to explore whether the somatics technique has potential as an emotion regulation program in the future. In addition, the results are expected to contribute to finding an alternative treatment modality for patients who have not achieved a sufficient effect with conventional psychotherapy.

Background and Purpose: Patients with acute stroke are often accompanied by comorbidities, such as active cancer. However, adequate treatment guidelines are not available for these patients. The purpose of this study was to evaluate the association between cancer and the outcomes of reperfusion therapy in patients with stroke. Methods: We compared treatment outcomes in patients who underwent reperfusion therapy, using a nationwide reperfusion therapy registry. We divided the patients into 3 groups according to cancer activity: active cancer, nonactive cancer, and without a history of cancer. We investigated reperfusion processes, 24-hour neurological improvement, adverse events, 3-month functional outcome, and 6-month survival and related factors after reperfusion therapy. Results: Among 1338 patients who underwent reperfusion therapy, 62 patients (4.6%) had active cancer, 78 patients (5.8%) had nonactive cancer, and 1198 patients (89.5%) had no history of cancer. Of the enrolled patients, 969 patients received intravenous thrombolysis and 685 patients underwent endovascular treatment (316 patients received combined therapy). Patients with active cancer had more comorbidities and experienced more severe strokes; however, they showed similar 24-hour neurological improvement and adverse events, including cerebral hemorrhage, compared with the other groups. Although the functional outcome at 3 months was poorer than the other groups, 36.4% of patients with active cancer showed functional independence. Additionally, 52.9% of the patients with determined stroke etiology showed functional independence despite active cancer. During the 6-month follow-up, 46.6% of patients with active cancer died, and active cancer was independently associated with poor survival (hazard ratio, 3.973 [95% CI, 2.528–6.245]). Conclusions: In patients with active cancer, reperfusion therapy showed similar adverse events and short-term outcomes to that of other groups. While long-term prognosis was worse in the active cancer group than the nonactive cancer groups, not negligible number of patients had good functional outcomes, especially those with determined stroke mechanisms.

Background and Purpose We aimed to develop a model predicting early recanalization after intravenous tissue plasminogen activator (t-PA) treatment in large-vessel occlusion.Methods Using data from two different multicenter prospective cohorts, we determined the factors associated with early recanalization immediately after t-PA in stroke patients with large-vessel occlusion, and developed and validated a prediction model for early recanalization. Clot volume was semiautomatically measured on thin-section computed tomography using software, and the degree of collaterals was determined using the Tan score. Follow-up angiographic studies were performed immediately after t-PA treatment to assess early recanalization.Results Early recanalization, assessed 61.0±44.7 minutes after t-PA bolus, was achieved in 15.5% (15/97) in the derivation cohort and in 10.5% (8/76) in the validation cohort. Clot volume (odds ratio [OR], 0.979; 95% confidence interval [CI], 0.961 to 0.997; P=0.020) and good collaterals (OR, 6.129; 95% CI, 1.592 to 23.594; P=0.008) were significant factors associated with early recanalization. The area under the curve (AUC) of the model including clot volume was 0.819 (95% CI, 0.720 to 0.917) and 0.842 (95% CI, 0.746 to 0.938) in the derivation and validation cohorts, respectively. The AUC improved when good collaterals were added (derivation cohort: AUC, 0.876; 95% CI, 0.802 to 0.950; P=0.164; validation cohort: AUC, 0.949; 95% CI, 0.886 to 1.000; P=0.036). The integrated discrimination improvement also showed significantly improved prediction (0.097; 95% CI, 0.009 to 0.185; P=0.032).Conclusions The model using clot volume and collaterals predicted early recanalization after intravenous t-PA and had a high performance. This model may aid in determining the recanalization treatment strategy in stroke patients with large-vessel occlusion.

To investigate the association between cognitive function at baseline and the progression of motor disability in Parkinson’s disease (PD). We consecutively enrolled 257 drug-naive patients with early-stage PD (follow-up > 2 years) who underwent a detailed neuropsychological test at initial assessment. Factor analysis was conducted to yield four cognitive function factors and composite scores thereof: Factor 1 (visual memory/visuospatial), Factor 2 (verbal memory), Factor 3 (frontal/executive), and Factor 4 (attention/working memory/language). The global cognitive composite score of each patient was calculated based on these factors. Subsequently, we assessed the effect of baseline cognitive function on long-term motor outcomes, namely levodopa-induced dyskinesia (LID), wearing-off, freezing of gait (FOG), and rate of longitudinal increases in levodopa-equivalent dose (LED). Cox regression analysis demonstrated that higher Factor 3 (frontal/executive) composite scores (i.e., better cognitive performance) were associated with early development of LID [hazard ratio (HR), 1.507; p = 0.003], whereas higher Factor 1 (visual memory/visuospatial) composite scores (i.e., better cognitive performance) were associated with a lower risk for FOG (HR 0.683; p = 0.017). We noted that higher global cognitive composite scores were associated with a lower risk for developing FOG (HR 0.455; p = 0.045). The linear mixed model demonstrated that higher global cognitive composite scores and better cognitive performance in visual memory/visuospatial function were associated with slower longitudinal increases in LED. These findings suggest that baseline cognitive profiles have prognostic implications on several motor aspects in patients with PD.

This study aimed to compare the patterns of β-amyloid deposition between patients with early-stage Alzheimer's disease (AD) with mild parkinsonism and those without parkinsonism. Sixty-one patients with early-stage AD (Clinical Dementia Rating [CDR], 0.5 or 1) who underwent 18F-florbetaben (18F-FBB) PET scans were enrolled. We performed comparative analyses of regional FBB uptake in the frontal, parietal, lateral temporal, medial temporal, occipital, anterior cingulate, and posterior cingulate cortices and in the precuneus, striatum, and thalamus between AD patients with mild parkinsonism (AD-p+; n = 23) and those without parkinsonism (AD-p−; n = 38). There was no significant difference in age, sex, years of education, Mini-Mental State Examination score, and white matter hyperintensity severity between groups. The AD-p+ group had lower composite scores in frontal/executive function domain than the AD-p− group. The AD-p+ group had a higher FBB uptake in the occipital cortex, but not in other cortical regions, than the AD-p− group. Our findings suggest that additional β-amyloid deposition in the occipital region is associated with mild parkinsonism in early-stage AD.

We evaluated the risk of osteoporosis and fractures associated with androgen deprivation therapy (ADT) use and duration in men with prostate cancer. From the nationwide claims database in South Korea, a total of 218,203 men with prostate cancer were identified between 2008 and 2017. After applying the inclusion and exclusion criteria, a total of 144,670 patients were included in the analysis. To adjust for comorbidities between cohorts, 1:1 propensity score matching was used. Cox proportional hazard regression models were used to estimate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) of events associated with ADT, after controlling for potential confounding factors. In the matched cohort, there were differences in the incidence of newly developed osteoporosis (8.79% in the ADT group vs. 7.08% in the non-ADT group, p

PURPOSE:This study aimed to examine the effects of resistance and balance training on physical function and postural control in individuals with Down syndrome (DS).METHODS:Ten adults with DS constituted the experimental group (EX) and attended an 8-week resistance and balance training program. The results were compared with those of the control group (CON), which consisted of 10 patients who did not undergo any physical training. Body composition, postural stability, and physical fitness were measured before and after the training program. Resistance and balance training were performed for 60 minutes, three times a week for 8 weeks.RESULTS: Body weight, body mass index, body fat percentage, and waist circumference decreased significantly in the EX group after completing the 8-week resistance and balance training program. The center of pressure and the difference between standing foot pressure on the left and right were significantly improved in the EX group. Physical fitness including sit-to-stand repetitions and 10 m shuttle duration significantly improved in the EX and CON groups.CONCLUSIONS:These results suggest that resistance and balance training to improve musculoskeletal problems is an effective strategy to prevent injury, fatigue, and falls during exercise and to improve general health in individuals with DS.

Purpose Decision-making for treatment of newly diagnosed prostate cancer (PCa) is complex due to the multiple initial treatment modalities available. We aimed to externally validate the SCaP (Severance Study Group of Prostate Cancer) Survival Calculator that incorporates a long short-term memory artificial neural network (ANN) model to estimate survival outcomes of PCa according to initial treatment modality. Materials and Methods The validation cohort consisted of clinicopathological data of 4,415 patients diagnosed with biopsy-proven PCa between April 2005 and November 2018 at three institutions. Area under the curves (AUCs) and time-to-event calibration plots were utilized to determine the predictive accuracies of the SCaP Survival Calculator in terms of progression to castration-resistant PCa (CRPC)–free survival, cancer-specific survival (CSS), and overall survival (OS). Results Excellent discrimination was observed for CRPC-free survival, CSS, and OS outcomes, with AUCs of 0.962, 0.944, and 0.884 for 5-year outcomes and 0.959, 0.928, and 0.854 for 10-year outcomes, respectively. The AUC values were higher for all survival endpoints compared to those of the development cohort. Calibration plots showed that predicted probabilities of 5-year survival endpoints had concordance comparable to those of the observed frequencies. However, calibration performances declined for 10-year predictions with an overall underestimation. Conclusion The SCaP Survival Calculator is a reliable and useful tool for determining the optimal initial treatment modality and for guiding survival predictions for patients with newly diagnosed PCa. Further modifications in the ANN model incorporating cases with more extended follow-up periods are warranted to improve the ANN model for long-term predictions.

Jae-Min Park,1,2 Hye Sun Lee,3 Ju-Young Park,4 Dong-Hyuk Jung,5 Ji-Won Lee1 1Department of Family Medicine, Yonsei University College of Medicine, Gangnam Severance Hospital, Seoul, Republic of Korea; 2Department of Medicine, Graduate School of Medicine, Yonsei University, Seoul, Republic of Korea; 3Biostatistics Collaboration Unit, Yonsei University College of Medicine, Seoul, Republic of Korea; 4Department of Statistics and Data Science, Yonsei University, Seoul, Republic of Korea; 5Department of Family Medicine, Yonsei University College of Medicine, Yongin Severance Hospital, Gyeonggi-do, Republic of KoreaCorrespondence: Ji-Won LeeDepartment of Family Medicine, Yonsei University College of Medicine, Gangnam Severance Hospital, 211 Eonju-ro, Gangnam-gu, Seoul, 06273, Republic of KoreaTel +82 2 2019 3482Fax +82 2 3462 8209Email indi5645@yuhs.acPurpose: Limited evidence is available on whether the white blood cell (WBC) count is a predictor of type 2 diabetes mellitus (T2DM) in non-obese individuals. This study aimed to determine whether WBC count could be used as an indicator for the prediction of incident T2DM among non-obese individuals using a large, community-based Korean cohort that was observed over 10 years.Patients and methods: A total of 4211 non-obese adults without diabetes aged 40– 69 years were selected from the Korean Genome and Epidemiology Study. The participants were divided into four groups according to WBC count quartiles. We prospectively assessed the hazard ratios (HRs) with 95% confidence intervals (CIs) for incident T2DM, based on the American Diabetes Association criteria, using multivariate Cox proportional hazards regression models over 10 years after the baseline survey.Results: During the follow-up period, 592 (14.1%) participants had newly developed T2DM. The higher quartile of WBC count groups showed significantly higher cumulative T2DM incidence over 10 years after the baseline survey (log-rank test, P < 0.001). Compared with the HRs for individuals in the referent lowest quartile, the HR (95% CI) for incident T2DM in individuals in the highest quartile was 1.55 (1.10– 2.18) after adjusting for confounding variables.Conclusion: A higher WBC count predicts future incident T2DM among community-dwelling non-obese Korean adults. This study suggests that WBC count could facilitate the prediction of non-obese individuals susceptible to T2DM.Keywords: white blood cell count, type 2 diabetes mellitus, chronic low-grade inflammation, non-obese adults

No single effective method has yet been established for the primary prophylaxis of bleeding from gastric varices (GV). We retrospectively analyzed liver cirrhosis patients with GV who had undergone either endoscopic variceal obturation (EVO) or balloon-occluded retrograde transvenous obliteration (BRTO) as prophylactic treatments, comparing them with those who were observed without any procedural intervention. The endpoints were GV bleeding rate and complete eradication rate. 72 patients in EVO, 41 patients in BRTO, and 97 patients in the clinical observation groups were enrolled. No difference was observed in baseline characteristics. As the primary endpoint, 14 (19.4%) patients in the EVO group and 3 (7.3%) in the BRTO group bled from GV after prophylactic treatment, and 34 (35.1%) patients bled in the observation group during the median follow-up of 35 months (p = 0.001). Patients who received EVO or BRTO developed less bleeding from GV than those who received observation only, with no difference between EVO and BRTO (EVO vs. observation, p = 0.038; BRTO vs. observation, p = 0.001; EVO vs. BRTO, p = 0.089). As secondary endpoints, GV disappeared completely in 33 patients (45.8%) in the EVO group and 31 patients (75.6%) in the BRTO group (p = 0.003). By multivariate analysis, complete eradication of GV was the sole determinant for predicting GV bleeding. EVO and BRTO are effective and safe primary prophylactic treatments for preventing bleeding from GV. In particular, BRTO is better than EVO in complete eradication of GV.

Yu-Jin Kwon,1– 3 Hyangkyu Lee,4 Chung Mo Nam,5 Hyuk-Jae Chang,6 Young-Ran Yoon,7 Hye Sun Lee,8 Ji-Won Lee1 1Department of Family Medicine, Yonsei University College of Medicine, Severance Hospital, Seoul, Republic of Korea; 2Department of Medicine, Graduate School of Yonsei University College of Medicine, Seoul, Republic of Korea; 3Department of Family Medicine, Yongin Severance Hospital, Yonsei University College of Medicine, Yongin, Republic of Korea; 4 Yonsei University College of Nursing, Mo-Im Kim Nursing Research Institute, Seoul, Republic of Korea; 5Department of Preventive Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea; 6Department of Internal Medicine, Division of Cardiology, Severance Cardiovascular Hosp, Yonsei University College of Medicine, Seoul, Republic of Korea; 7Department of Molecular Medicine, School of Medicine, Kyungpook National University, Daegu, Republic of Korea; 8Biostatistics Collaboration Unit, Department of Research Affairs, Yonsei University College of Medicine, Seoul, Republic of KoreaCorrespondence: Ji-Won LeeDepartment of Family Medicine, Yonsei University College of Medicine, Gangnam Severance Hospital, 211 Eonju‐ro, Gangnam‐gu, 06273, Seoul, 135-720, Republic of KoreaTel +82 2 2019 3480Fax +82 3462 8209Email indi5645@yuhs.acBackground: In clinical practice, concomitant treatment of orlistat with phentermine is commonly used off-label. However, clinical trials have not been performed to evaluate whether their combination improves metabolic parameters and cardiovascular risk factors other than weight loss. Therefore, we aimed to compare the efficacy of concomitant administration of orlistat and phentermine versus phentermine alone on the endothelial cell function in overweight and obese adults with back pain.Methods: We conducted a 12-week, double-blinded, placebo-controlled clinical trial involving 114 patients with a body mass index of ≥ 30 (obese) or ≥ 27 (overweight) with weight-related comorbidities. We randomly assigned patients in a 1:1 ratio to receive orlistat (120mg) three times daily and phentermine (37.5mg) once daily, or a placebo three times daily and phentermine (37.5mg) once daily. Primary endpoint was changes in endothelium-dependent vasodilatation measured using ultrasound assessment of flow-mediated dilatation (FMD). Differences within groups after intervention were compared using the paired t-test or Wilcoxon signed-rank test. Differences in changes between the groups were calculated using an analysis of covariance after adjusting for each baseline value.Results: Mean weight loss during the 12-week study period was 6.1kg in the orlistat/phentermine group and in the placebo/phentermine group. Adjusted mean changes in total and non-high-density lipoprotein cholesterol were significantly greater in the orlistat/phentermine group than in the placebo/phentermine group. Adjusted mean changes in endothelium-dependent FMD were significantly greater in the orlistat/phentermine group than in the placebo/phentermine group (4.97± 0.98% vs 2.05± 0.99%, respectively; p=0.038). Changes in endothelium-independent nitroglycerin-mediated dilatation were not significantly different between the groups.Conclusion: Orlistat/phentermine significantly improved the vascular endothelial cell function compared with phentermine alone. Orlistat might have beneficial effects on the decrease of the risk of cardiovascular disease, especially in overweight and obese patients with comorbidities.Trial Registration: ClinicalTrails.gov number, NCT03675191.Keywords: obesity, orlistat, phentermine, endothelial cell function

Background Several studies have suggested that adverse neurodevelopment could be induced by systemic inflammation in preterm infants. We aimed to investigate whether preterm infants with systemic inflammation would have impaired neurodevelopment and which biomarkers and neurophysiologic studies during inflammation are associated with poor neurodevelopment. Methods This prospective cohort study enrolled infants born before 30 weeks of gestation or with birth weight n = 49), I (systemic inflammation, n = 45). Blood and cerebrospinal fluid samples for markers of brain injury and inflammation were collected and amplitude-integrated electroencephalography (aEEG) was performed within 4 h of septic workup. We evaluated aEEG at 35 weeks postmenstrual age (PMA), head circumference at 36 weeks PMA, and brain MRI at discharge. The Bayley Scales of Infant and Toddler Development III (Bayley-III) was performed at a corrected age (CA) of 18 months. Results The I group had more white matter injuries (2 vs. 26.7%, Control vs. I, respectively) at the time of discharge, lower brain functional maturation (9.5 vs. 8), and smaller head size (z-score − 1.45 vs. -2.12) at near-term age and poorer neurodevelopment at a CA of 18 months than the control (p p Conclusions Systemic inflammation induced by clinical infection and NEC are associated with neurodevelopmental impairment in preterm infants. The seizure spike on aEEG, elevated I/T ratio, CRP, and plasma TNF-alpha during inflammatory episodes are associated with poor neurodevelopment.

Background: Neratinib is a potent small molecule tyrosine kinase inhibitor (TKI) of human epidermal growth factor receptors (HER1,2,4). One of the major side effects of neratinib is diarrhea. The human gut contains a dense microbiome ecosystem that is essential in maintaining a healthy host physiology, and its disruption may lead to increased risk of toxicities from cancer therapy. In this study, we aimed to develop a machine learning model based on analysis of gut microbiota data to predict neratinib-induced diarrhea. Methods: Patients were enrolled in a phase II trial evaluating safety and tolerability of neratinib in older adults with HER2+ breast cancer (NCT02673398). Neratinib was administered as single agent, 240 mg oral daily in a 28-day cycle. Stool samples were collected at baseline and during treatment for 16S rRNA gene sequencing. Using microbial relative abundance data, we developed gradient-boosted tree models with two nested loops of cross validations to classify whether diarrhea would occur or not after treatment onset. For the inner validation loop, we used ten-fold cross validation to determine the optimal model from hyper-parameters including regularization. For the outer validation loop, we utilized a leave-one-patient-out cross validation to test this model on the hold-out patient’s baseline data and the predictions were used for model assessment. Results: A total of 11 patients and 50 longitudinal stool samples were collected. The median age was 66 years. 73% developed grade ≥ 1 diarrhea attributed to neratinib. Shannon diversity index of gut microbiome was not associated with diarrhea. For predictive modeling, the outer validation loop Area Under the Receiver Operating Characteristic Curve (AUROC) and Area Under the Precision Recall Curve (AUPRC) were 0.92 and 0.97, respectively. The two most important taxa predictive of protection from diarrhea were Ruminiclostridium 9, and Bacteroides sp. HPS0048. We found that patients with a larger relative abundance of Ruminiclostridium 9 and Bacteroides sp. HPS0048 have reduced risk of neratinib-related diarrhea. Conclusions: The machine learning model can identify breast cancer patients at risk of diarrhea prior to neratinib use. Future studies are required to validate this finding. Citation Format: Chi Wah Wong, Susan E. Yost, Jin Sun Lee, John D. Gillece, Megan Folkerts, Lauren Reining, Sarah K. Highlander, Zahra Eftekhari, Joanne Mortimer, Yuan Yuan. Machine learning model of gut microbiota predicts neratinib induced diarrhea in patients with breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS5-41.

Background: Even though almost half of women have dense breasts (DB), the density of breasts has been an obstacle to detect breast cancer (BC) correctly by the gold standard of screening, mammography. It is strongly recommended to take consideration of breast density in analyzing mammogram. We have reported the possibility of serum level of thioredoxin 1 (Trx1) as a novel means to assess the risk of BC regardless of various conditions of breasts. In present study, we have evaluated how serum level of Trx1 can mitigate the difficulty to detect BC from dense breast by mammography. Methods: We have generated monoclonal antibodies against Trx1 and developed an ELISA kit that quantitates Trx1 in serum. The level of Trx1 was determined in each serum from BC patients (n=106) who had been confirmed as BC by various examinations including mammography as well as surgery. Each Trx1 level was analyzed with corresponding patient’s mammography results such as patterns, asymmetry, shapes, margin, and density. The analyzed results were compared with those from other biomarker tests including CA15-5 and CEA to evaluate the clinical validity of Trx1 in this study. Each test was duplicated two times, and test results were analyzed by ROC analysis, one-way ANOVA tests, and unpaired t-tests.Results: Most of BC patients (82.6%, n=86) was classified as mammography pattern 3 and 4, and BI-RADS score higher than 4 (74.0%, n=77). More than half of patients’ breast density was in high density group (54.8%, n=57), whereas 5.8% of iso density (n=6) and 39.4% of not determined (n=41). The blood Trx1 levels of patients were higher than the cut-off value of 14 U/ml indicating BC regardless of characteristics of breasts. Although other breast cancer biomarker tests such as CA15-3 and CEA could not identify BC, Trx1 level could correctly detect BC even in the cases that mammography could not show the mass clearly. The sensitivity/specificity of mammography and Trx1 test were 75.2%/74.0% and 96.2%/99.0%, respectively. When mammography and Trx1 test were combined, the whole sensitivity/specificity was 99.3%/100.0%. Conclusion: Even though it is obvious that larger size of further study necessary, the serum Trx1 level showed that it could identify BC in dense breasts easily. These results indicated that serum Trx1 level could efficiently mitigate the difficulty to detect BC from dense breasts by mammography. Keywords: Thioredoxin 1, Breast cancer, Dense breast, Diagnostics, Sensitivity, Specificity, Blood Citation Format: Kyoung Hoon Suh, Bo Bae Choi, Youn Ju Lee, Je Ryoong Kim, Jin Sun Lee, Young Kim. Quantitation of serum thioredoxin 1 could mitigate difficulty to detect breast cancer from dense breasts by mammography [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS3-25.

The rate of undiagnosed type 2 diabetes tends to increase in lean Koreans, while the triglyceride glucose (TyG) index has been proposed as a surrogate marker of peripheral insulin resistance. We investigated the longitudinal relationship between TyG and incident type 2 diabetes among apparently healthy Korean adults. We assessed 4285 lean adults without diabetes aged 40-69 years from the Korean Genome and Epidemiology Study. Participants were divided into 4 groups according to quartiles of TyG index, calculated as ln [fasting triglycerides (mg/dL) × fasting plasma glucose (mg/dL)/2]. We prospectively assessed the hazard ratios (HRs) with 95% confidence intervals (CIs) for incident type 2 diabetes, based on the American Diabetes Association criteria, using multivariate Cox proportional hazards regression models, over 12 years after the baseline survey. During the follow-up period, 631 (14.7%) participants had newly developed type 2 diabetes. The HRs of incident type 2 diabetes in each TyG index quartile were 1.00, 1.63 (95%CI, 1.18-2.24), 2.30 (95%CI, 1.68-3.14), and 3.67 (95%CI, 2.71-4.98), respectively, after adjusting for age, sex, body mass index, waist circumference, smoking status, alcohol intake, and physical activity. Higher TyG index precedes and significantly predicts type 2 diabetes among community-dwelling middle aged and elderly lean Koreans.

Chronic stress can cause psychological diseases and affect male fertility and the reproductive system. Maillard reaction of milk proteins improves their functional and nutritional properties through modification of proteins. Previously, we determined that Maillard reaction product (MRP) from milk casein and MRP fermented (FMRP) with Lactobacillus rhamnosus 4B15 (4B15) had anti-anxiolytic effects in mice under chronic stress. Therefore, we aimed to investigate the effects of MRP and FMRP on chronic stress-induced testicular dysfunction in mice through quantitative real-time PCR (qRT-PCR) and in situ hybridization analysis. Mice were pretreated with MRP and FMRP for 10 wk; simultaneously, from the third week of the experimental period, they were exposed to unpredictable chronic mild stress (UCMS) for 7 wk. The expression levels of the luteinizing hormone subunit β (Lhb) and follicle-stimulating hormone subunit β (Fshb) were remarkably reduced after exposure to UCMS. However, treatment with MRP and FMRP inhibited the UCMS-induced reduction, with FMRP showing especially significant inhibition. Moreover, the expression of steroidogenesis-related genes [luteinizing hormone receptor (Lhr), follicle-stimulating hormone (Fshr), 3-β hydroxysteroid dehydrogenase 2 (Hsd3b2), and steroidogenic acute regulatory protein (StAR)] were significantly reduced in response to UCMS. In contrast, the transcript levels of these genes were highest in the MRP-treated mice. Mice pretreated with FMRP also exhibited higher levels of gene expression compared with the nonstressed mice. Moreover, UCMS significantly downregulated the expression of genes associated with testicular function [i.e., a disintegrin and metallopeptidase domain 5 (Adam5), Adam29, bone morphogenetic protein 2 (Bmp2), tektin 3 (Tekt3), and sperm adhesion molecule 1 (Spam1)]. However, the administration of MRP and FMRP prevented the UCMS-induced reduction in the expressions of above genes. The localization of Lhr, Srd5a2, Adam29, and Spam1 was confirmed by in situ hybridization analysis and the results were consistent with those of qRT-PCR. Consequently, these results indicated that MRP and FMRP, manufactured by the heat treatment of milk casein and fermentation with probiotic 4B15, have the potential to prevent chronic stress-induced testicular dysfunction.

Background/Aims: Useful biomarkers for metabolic syndrome have been insufficient. We investigated the performance of serum milk fat globule-EGF factor-8 (MFG-E8), the key mediator of inflammatory pathway, in diagnosis of metabolic syndrome. Methods: Subjects aged between 30 and 64 years were prospectively enrolled in the Seoul Metabolic Syndrome cohort. Serum MFG-E8 levels were measured at baseline. Results: A total of 556 subjects were included, comprising 279 women (50.2%) and 277 men (49.8%). Metabolic syndrome was diagnosed in 236 subjects (42.4%), and the mean MFG-E8 level of subjects with metabolic syndrome was significantly higher than that of subjects without metabolic syndrome (P

Background White matter hyperintensities, prevalent in patients with Parkinson's disease (PD), significantly affect parkinsonian motor symptoms. The objective of this study was to investigate the relationship between white matter hyperintensities and nigrostriatal dopamine depletion and their interaction or mediating effects on motor symptoms in patients with drug-naive early-stage PD. Methods This cross-sectional study enrolled 501 patients with de novo PD who initially underwent [18 F] N-(3-fluoropropyl)-2β-carbonethoxy-3β-(4-iodophenyl) nortropane positron emission tomography and brain magnetic resonance imaging scans between April 2009 and September 2015 in a tertiary-care university hospital. We quantified dopamine transporter availability in each striatal subregion and assessed the severity of periventricular and lobar white matter hyperintensities using the Scheltens scale. The relationship between white matter hyperintensities, dopamine transporter availability in the posterior putamen, and Unified Parkinson's Disease Rating Scale (UPDRS) motor scores was assessed using multivariate linear regression and mediation analyses. Results Periventricular and frontal white matter hyperintensities were generally associated with dopamine transporter availability in striatal subregions after adjusting for age at symptom onset, sex, disease duration, and vascular risk factors. There was an interaction effect between periventricular white matter hyperintensities and dopamine transporter availability in the posterior putamen for the axial motor score. The effect of white matter hyperintensities on UPDRS total score and bradykinesia subscore was indirectly mediated by dopamine transporter availability in the posterior putamen, whereas the axial sub-score was directly affected by white matter hyperintensities. Conclusions This study suggests that the detrimental effect of white matter hyperintensities on parkinsonian motor symptoms is more relevant and independent for axial motor impairments in the status of mildly decreased striatal dopamine transporter availability. © 2021 International Parkinson and Movement Disorder Society.

Liver injuries after blunt abdominal trauma vary from mild contusions to life-threatening damage, indicating that initial risk stratification of liver injuries is critical to improve clinical outcomes, especially in a medical resource-constrained area. This study analyzed 148 patients who underwent abdominal and chest computed tomography with elevated transaminases, with suspected liver injury after blunt abdominal trauma, between January 2008 and December 2017. The mean age was 49.6 (standard deviation 17.2) years; most patients were men (69.6%). The most common cause of trauma was motor vehicle accidents (55.4%), followed by falls (27.7%) and assault (11.5%). Patients with no liver injury (n = 63, 42.6%) and those with American Association for the Surgery of Trauma (AAST) grades I (n = 11, 7.4%) and II (n = 15, 10.1%) were treated with non-operative management. However, 2.8% of patients with AAST III (n = 36, 24.3%), 29.4% with AAST IV (n = 17, 11.5%), and 50.0% with AAST V (n = 6, 4.1%) required trans-arterial embolization, and patients with AAST IV and V had 11.8% and 33.3% mortality rates, respectively. Predictors for major liver injury (AAST IV and V) were aspartate aminotransferase ≥ 450 IU/L (p < 0.0005) and international normalized ratio ≥ 1.2 (p = 0.028). In conclusion, these laboratory values enable an initial risk stratification of liver injuries after blunt abdominal trauma that early appropriate treatment and, if not possible, a prompt transfer to a capable facility would be considered in patients who had the predictors of major liver injury.

Both transient elastography (TE) and 2D shear wave elastography (SWE) are accurate methods to evaluate liver fibrosis. We aimed to evaluate the diagnostic performance of 2D-SWE in predicting post-hepatectomy complication and to compare it with TE. We prospectively enrolled 125 patients with liver tumors. Liver stiffness (LS) (kilopascal [kPa]) was measured using both TE and 2D-SWE before surgery. All post-operative complication was evaluated using the comprehensive complication index (CCI), and CCI ≥ 26.2 was defined as severe complication. Logistic regression analysis was performed to identify predictive factors for severe complication. Receiver operating characteristic analysis was used to evaluate the diagnostic performance of TE/2D-SWE in detecting liver fibrosis and severe complication. Severe complication developed in 18 patients. The median LS in patients with severe complication was significantly higher for both 2D-SWE (11.4 kPa vs. 7.0 kPa, p

To investigate the diagnostic performances and unnecessary fine-needle aspiration (FNA) rates of two point-scale based TIRADS and compare them with a modified version using the ACR TIRADS’ size thresholds. Our Institutional Review Board approved this retrospective study and waived the requirement for informed consent. A total of 2106 thyroid nodules 10 mm or larger in size in 2084 patients with definitive cytopathologic findings were included. Ultrasonography categories were assigned according to each guideline. We applied the ACR TIRADS’ size thresholds for FNA to the Kwak TIRADS and defined it as the modified Kwak TIRADS (mKwak TIRADS). Diagnostic performances and unnecessary FNA rates were evaluated for both the original and modified guidelines. Of the original guidelines, the ACR TIRADS had higher specificity, accuracy, and area under the receiver operating characteristic curve (AUC) (63.1%, 68.9%, and 0.748, respectively). When the size threshold of the ACR TIRADS was applied to the Kwak TIRADS, the resultant mKwak TIRADS had higher specificity, accuracy, and AUC (64.7%, 70.3%, and 0.765, respectively) than the ACR TIRADS. The mKwak TIRADS also had a lower unnecessary FNA rate than the ACR TIRADS (54.8% and 56.4%, respectively). The false-negative rate of the Kwak TIRADS was the lowest (1.9%) among all TIRADS. The modified Kwak TIRADS incorporating the size thresholds of the ACR TIRADS showed higher diagnostic performance and a lower unnecessary FNA rate than the original point-scale based TIRADS. • Of the original guidelines, the ACR TIRADS had the highest specificity, accuracy, and area under the receiver operating characteristic curve (AUC) (63.1%, 68.9%, and 0.748, respectively). • When the size threshold of the ACR TIRADS was applied to the Kwak TIRADS, the resultant modified version of Kwak TIRADS had higher specificity, accuracy, and AUC (64.7%, 70.3%, and 0.765, respectively) than the ACR TIRADS. • The false-negative rate of the Kwak TIRADS was the lowest (1.9%) among all TIRADS.

The prognosis of patients with node-negative T1b tumors according to human epidermal growth factor receptor 2 (HER2) status is not known. This group of patients has not been studied in the available randomized trials. The objective of this study was to evaluate the survival of patients in a monoethnic group diagnosed with T1b lymph node-negative breast cancer depending on HER2 status. We analyzed 3110 patients with T1bN0M0 breast cancer whose data were deposited into the Korean Breast Cancer Society Registry database between 2000 and 2009. Overall survival (OS) and breast cancer-specific survival (BCSS) were compared according to HER2 status. Among all patients, 494 (15.9%) had HER2-positive breast cancer. At a mean follow-up of 93 months, 108 deaths and 86 breast cancer-specific deaths were noted among all patients. There was no significant difference in OS between the HER2-negative and HER2-positive groups (p = 0.103). The same result was observed for BCSS. However, in the subgroup of estrogen receptor (ER)-positive women, HER2-negative patients had a better BCSS prognosis than HER2-positive patients (p = 0.025). Multivariate analysis also indicated a significant difference in BCSS in the ER-positive subgroup (HR 2.60; 95% CI 1.15–5.87; p = 0.021). This study analyzed a large nationwide and monoethnic cohort and found a significant difference only in BCSS in the ER-positive subgroup according to HER2 status. Anti-HER2 therapy may be considered in HER2-positive and ER-positive patients with small, node-negative breast cancer.