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Impacted mandibular third molars (M3M) are associated with the occurrence of distal caries on the adjacent mandibular second molars (DCM2M). In this study, we aimed to develop and validate five machine learning (ML) models designed to predict the occurrence of DCM2Ms due to the proximity with M3Ms and determine the relative importance of predictive variables for DCM2Ms that are important for clinical decision making. A total of 2642 mandibular second molars adjacent to M3Ms were analyzed and DCM2Ms were identified in 322 cases (12.2%). The models were trained using logistic regression, random forest, support vector machine, artificial neural network, and extreme gradient boosting ML methods and were subsequently validated using testing datasets. The performance of the ML models was significantly superior to that of single predictors. The area under the receiver operating characteristic curve of the machine learning models ranged from 0.88 to 0.89. Six features (sex, age, contact point at the cementoenamel junction, angulation of M3Ms, Winter's classification, and Pell and Gregory classification) were identified as relevant predictors. These prediction models could be used to detect patients at a high risk of developing DCM2M and ultimately contribute to caries prevention and treatment decision-making for impacted M3Ms.

This study aimed to demonstrate pharmacokinetic (PK) equivalence of a single dose of the proposed adalimumab biosimilar CT‐P17 to United States‐licensed adalimumab (US‐adalimumab) and European Union‐approved adalimumab (EU‐adalimumab). This double‐blind, parallel‐group, phase I trial (clinicaltrials.gov NCT03970824) was conducted at 10 hospitals (Republic of Korea), in which healthy subjects (1:1:1) were randomized to receive a single 40 mg (100 mg/ml) subcutaneous injection of CT‐P17, US‐adalimumab, or EU‐adalimumab. Primary end points were PK equivalence in terms of: area under the concentration–time curve from time zero to infinity (AUC0–inf); AUC from time zero to the last quantifiable concentration (AUC0–last); and maximum serum concentration (Cmax). PK equivalence was concluded if 90% confidence intervals (CIs) for percent ratios of geometric least squares means (GLSMs) for pairwise comparisons were within the equivalence margin of 80–125%. Additional PK end points, safety, and immunogenicity were evaluated. Of the 312 subjects who were randomized (103 CT‐P17; 103 US‐adalimumab; 106 EU‐adalimumab), 308 subjects received study drug. AUC0–inf, AUC0–last, and Cmax were equivalent among CT‐P17, US‐adalimumab, and EU‐adalimumab, because 90% CIs for the ratios of GLSMs were within the 80–125% equivalence margin for each pairwise comparison. Secondary PK end points, safety, and immunogenicity were similar between treatment groups. In conclusion, PK equivalence for single‐dose administration of CT‐P17, EU‐adalimumab, and US‐adalimumab was demonstrated in healthy adults. Safety and immunogenicity profiles were comparable between treatment groups and consistent with previous reports for adalimumab biosimilars.

Objectives To design and evaluate 3D‐printed nasal swabs for collection of samples for SARS‐CoV‐2 testing. Design An iterative design process was employed. Laboratory evaluation included in vitro assessment of mock nasopharyngeal samples spiked with two different concentrations of gamma‐irradiated SARS‐CoV‐2. A prospective clinical study compared SARS‐CoV‐2 and human cellular material recovery by 3D‐printed swabs and standard nasopharyngeal swabs. Setting, participants Royal Melbourne Hospital, May 2020. Participants in the clinical evaluation were 50 hospital staff members attending a COVID‐19 screening clinic and two inpatients with laboratory‐confirmed COVID‐19. Intervention In the clinical evaluation, a flocked nasopharyngeal swab sample was collected with the Copan ESwab and a mid‐nasal sample from the other nostril was collected with the 3D‐printed swab. Results In the laboratory evaluation, qualitative agreement with regard to SARS‐CoV‐2 detection in mock samples collected with 3D‐printed swabs and two standard swabs was complete. In the clinical evaluation, qualitative agreement with regard to RNase P detection (a surrogate measure of adequate collection of human cellular material) in samples collected from 50 hospital staff members with standard and 3D‐printed swabs was complete. Qualitative agreement with regard to SARS‐CoV‐2 detection in three pairs of 3D‐printed mid‐nasal and standard swab samples from two inpatients with laboratory‐confirmed SARS‐CoV‐2 was also complete. Conclusions Using 3D‐printed swabs to collect nasal samples for SARS‐CoV‐2 testing is feasible, acceptable to patients and health carers, and convenient.

Background Poly (ADP-ribose) polymerase-1 (PARP-1) inhibitor has therapeutic potential for acute ischemic stroke by suppressing microglial activation and facilitating neuroprotection. In this first-in-human study, we investigate the safety, tolerability and pharmacokinetics (PK) of JPI-289 in healthy male volunteers. Subjects and methods In single ascending dose (SAD) study, 35, 75, 150, 300, 600 mg JPI-289 or placebo was infused intravenously over 30 minutes to 40 subjects. In multiple ascending dose (MAD) study, 150, 300, 450 mg JPI-289 or placebo was infused over 1 hour every 12 hours to each of 24 subjects for 3.5 days (7 times). The plasma and urine concentrations of JPI-289 and its metabolites were determined. Results In the SAD study, AUClast and Cmax tended to increase supra-proportionally especially at higher doses in SAD study. However, Cmax showed dose-proportionality in the range of 75-600mg. JPI-289 reached a mean Tmax within 0.50 hour after dosing and a mean elimination half-life (t1/2) was 2.18 to 3.21 hours. In the MAD study, observed accumulation index ranged from 1.52 to 1.76. The effective half-life of JPI-289 was 1.88 to 3.05 hours, indicating that the plasma JPI-289 concentration rapidly reaches steady state. % recovered of JPI-289 measured in urine was 1.59-9.05%. In both studies, concentration of metabolites was less than 10% of JPI-289. Adverse events reported in the study were all mild in intensity and resolved without any sequelae. Conclusion The tolerable dose ranges and pharmacokinetic characteristics of JPI-289 evaluated in these studies will be useful in further clinical development of JPI-289.

Refereed/Peer-reviewed Importance: More than 1 billion adults have hypertension globally, of whom 70% cannot achieve their hypertension control goal with monotherapy alone. Data are lacking on clinical use patterns of dual combination therapies prescribed to patients who escalate from monotherapy. Objective: To investigate the most common dual combinations prescribed for treatment escalation in different countries and how treatment use varies by age, sex, and history of cardiovascular disease. Design, Setting, and Participants: This cohort study used data from 11 electronic health record databases that cover 118 million patients across 8 countries and regions between January 2000 and December 2019. Included participants were adult patients (ages ≥18 years) who newly initiated antihypertensive dual combination therapy after escalating from monotherapy. There were 2 databases included for 3 countries: the Iqvia Longitudinal Patient Database (LPD) Australia and Electronic Practice-based Research Network 2019 linked data set from South Western Sydney Local Health District (ePBRN SWSLHD) from Australia, Ajou University School of Medicine (AUSOM) and Kyung Hee University Hospital (KHMC) databases from South Korea, and Khoo Teck Puat Hospital (KTPH) and National University Hospital (NUH) databases from Singapore. Data were analyzed from June 2020 through August 2021. Exposures: Treatment with dual combinations of the 4 most commonly used antihypertensive drug classes (angiotensin-converting enzyme inhibitor [ACEI] or angiotensin receptor blocker [ARB]; calcium channel blocker [CCB]; β-blocker; and thiazide or thiazide-like diuretic). Main Outcomes and Measures: The proportion of patients receiving each dual combination regimen, overall and by country and demographic subgroup. Results: Among 970 335 patients with hypertension who newly initiated dual combination therapy included in the final analysis, there were 11 494 patients from Australia (including 9291 patients in Australia LPD and 2203 patients in ePBRN SWSLHD), 6980 patients from South Korea (including 6029 patients in Ajou University and 951 patients in KHMC), 2096 patients from Singapore (including 842 patients in KTPH and 1254 patients in NUH), 7008 patients from China, 8544 patients from Taiwan, 103 994 patients from France, 76 082 patients from Italy, and 754 137 patients from the US. The mean (SD) age ranged from 57.6 (14.8) years in China to 67.7 (15.9) years in the Singapore KTPH database, and the proportion of patients by sex ranged from 24 358 (36.9%) women in Italy to 408 964 (54.3%) women in the US. Among 12 dual combinations of antihypertensive drug classes commonly used, there were significant variations in use across country and patient subgroup. For example starting an ACEI or ARB monotherapy followed by a CCB (ie, ACEI or ARB + CCB) was the most commonly prescribed combination in Australia (698 patients in ePBRN SWSLHD [31.7%] and 3842 patients in Australia LPD [41.4%]) and Singapore (216 patients in KTPH [25.7%] and 439 patients in NUH [35.0%]), while in South Korea, CCB + ACEI or ARB (191 patients in KHMC [20.1%] and 1487 patients in Ajou University [24.7%]), CCB + β-blocker (814 patients in Ajou University [13.5%] and 217 patients in KHMC [22.8%]), and ACEI or ARB + CCB (147 patients in KHMC [15.5%] and 1216 patients in Ajou University [20.2%]) were the 3 most commonly prescribed combinations. The distribution of 12 dual combination therapies were significantly different by age and sex in almost all databases. For example, use of ACEI or ARB + CCB varied from 873 of 3737 patients ages 18 to 64 years (23.4%) to 343 of 2292 patients ages 65 years or older (15.0%) in South Korea’s Ajou University database (P for database distribution by age

Delpazolid, an oxazolidinone, has been studied in non-clinical studies of efficacy and toxicity and Phase 1 clinical studies. Delpazolid has in vitro activity against Gram-positive bacteria, including Mycobacterium tuberculosis .

Please see the Editorial Comment by Tyler J. Fraum discussing this article. Background: Long acquisition times for breath-hold contrast-enhanced T1-weighted (CE-T1W) imaging in MR enterography (MRE) protocols result in reduced image quality. Objective: To compare CE-T1W imaging performed using sensitivity encoding (SENSE) and compressed-sensing SENSE (CS-SENSE) in terms of image quality and diagnostic performance for active inflammation in Crohn disease (CD). Methods: This retrospective study included 41 patients (31 men, 10 women; mean age, 34±12 years) who underwent MRE for known or suspected CD between June 2020 and September 2020. MRE was performed in one of two scanning rooms based on scheduling availability. Per institutional protocol, in one room, the enteric phase was acquired using SENSE (acceleration factor 3), and the portal phase was acquired using CS-SENSE (acceleration factor 5); this order was reversed in the other room. Two radiologists independently assessed sequences for subjective image quality measures at the patient level and for active inflammation at the bowel-segment level. Mean image quality scores between readers were computed. Diagnostic performance for active inflammation was compared using generalized estimating equations; a separate experienced radiologist reviewed the full MRE protocol to establish the reference standard. Results: The mean acquisition time of CE-T1W imaging was 17.2 ± 1.1 seconds for SENSE versus 11.5 ± 0.8 seconds for CS-SENSE (P .05). For reader 1, CS-SENSE, compared with SENSE, demonstrated sensitivity of 86% versus 81% (P=.09), specificity of 88% versus 83% (P=.08), and accuracy of 87% versus 82% (P=.56). For reader 2, CS-SENSE, compared with SENSE, demonstrated sensitivity of 92% versus 80% (P=.006), specificity of 91% versus 98% (P=.16), and accuracy of 91% versus 86% (P=.002). Conclusion: Use of CS-SENSE for CE-T1W imaging in MRE protocols results in reduced scan times with reduced artifact and improved image quality. Clinical impact: The benefits of CS-SENSE in MRE protocols may improve the diagnostic performance for active inflammation in CD.

We investigated head-up tilt test (HUTT) results across age-groups in syncope/presyncope patients to establish pediatric postural orthostatic tachycardia syndrome (POTS) characteristics. We retrospectively reviewed syncope patients' medical records. Adolescents were defined as 10 to 19 years old, adults as 20 to 59 years old, and older individuals as ≥60 years old. From HUTT results, we determined POTS prevalence and differences among the age-groups. We included 147 adolescents, 269 adults, and 123 older patients. Seventy (13.0%) patients (61.4% females; median age: 20 [17-25] years) were diagnosed with POTS. The syndrome was more prevalent among adolescents (33 [22.4%]) than adults (37 [13.8%]), and was absent among older individuals. Affected adolescents had significantly lower resting diastolic blood pressure (DBP) and heart rate (HR), and converted to maximum HR more rapidly than adolescents without the syndrome during the passive phase. Adolescents with POTS demonstrated several unique characteristics compared to adults with and adolescents without this syndrome. POTS may be underrecognized among syncope and presyncope patients, among which 22.4% of adolescents were diagnosed with the syndrome. POTS should be considered when evaluating syncope patients.

Background and purpose To evaluate the safety and efficacy of preoperative chemotherapy (CTx) followed by chemoradiotherapy (CCRT) for high-risk gastric cancer (GC). Methods and materials The inclusion criteria were as follows: (1) Borrmann type 4; (2) large Borrmann type 3 (≥8 cm); (3) single bulky (≥3 cm × 1) or multiple lymph nodes (≥1.5 cm × 3). Patients received two 21-day courses of induction CTx of TS-1 (35 mg/m2, p.o, twice daily on days 1–14), docetaxel (30 mg/m2, i.v., days 1 and 8), and cisplatin (30 mg/m2, i.v., days 1 and 8) followed by CCRT (two courses of TS-1 and cisplatin in combination with 45 Gy radiation). Results Forty-two patients were enrolled between March 2014 and February 2016, and 39 of these completed sequential CTx and CCRT. Among the 33 patients who underwent R0 resection, the pathologic response rate was 39.4% [no residual carcinoma (n = 5, 15.2%), with 1–10% residual carcinoma (n = 8, 24.2%)]. Overall, 4 patients (12.1%) were pathologic stage 0, 7 (21.2%) were stage I, 10 (30.3%) were stage II, and 12 (36.4%) were stage III. The overall survival rate at 3 years was 77.9% for stages 0 and I, 66.8% for stages II–III, and 33.3% for unresectable cases (P = 0.001). Toxicity was mild to moderate with grade 4 neutropenia (n = 1) and neutropenic fever (n = 1) as the most prominent side-effects. Conclusions Sequential CTx and CCRT prior to surgery are feasible and effective for high-risk GC. Trial registration number: NCT02495493.

Objective. Patients with diabetes have higher mortality rate than patients without diabetes after ST-segment elevated myocardial infarction (STEMI). Prognosis of patients with new onset diabetes (N...

Background Tegoprazan (CJ-12420) is a potassium-competitive acid blocker (P-CAB) with therapeutic potential for gastro-oesophageal reflux disease (GERD) by reversibly suppressing gastric H+ /K+ -ATPase. Aims To investigate the safety, tolerability, pharmacokinetics and pharmacodynamics of tegoprazan METHODS: A phase I, randomised, double-blind and placebo-controlled clinical trial was conducted in 56 healthy male subjects without Helicobacter pylori infection. In the single ascending dose study, 50, 100, 200 and 400 mg tegoprazan were administered to 32 subjects. In the multiple ascending dose study, 100 and 200 mg tegoprazan were administered every 24 hours to each of the eight subjects for 7 days. In the comparative pharmacodynamics study, 40 mg esomeprazole was administered to eight subjects every 24 hours for 7 days. The assessment included safety, tolerability, pharmacodynamics through monitoring of 24-hour gastric pH and pharmacokinetics of tegoprazan in plasma and urine. Results Tegoprazan was generally well tolerated. Most adverse events reported in the study were mild in intensity and resolved without any sequelae. Exposure to tegoprazan increased in a dose-proportional manner. Multiple dosing with tegoprazan showed no accumulation in plasma on day 7. The pharmacodynamic analysis revealed that tegoprazan showed rapid, dose-dependent gastric acid suppression. Conclusions Tegoprazan was well tolerated and showed rapid and potent gastric acid suppression. This supports the further development of tegoprazan as a treatment for acid-related disorders.

Cilostazol is a selective inhibitor of phosphodiesterase III (PDE III), which is prescribed for patients with peripheral arterial disease, especially intermittent claudication. The purpose of the study was to investigate the pharmacokinetic (PK) of cilostazol and its metabolites on the immediate (IR) formulation of cilostazol in healthy Korean male volunteers by population PK modeling analysis implemented using NONMEM software.A 2 × 2 crossover study comparing multiple oral doses of IR and SR formulations of cilostazol were conducted. Serial plasma concentrations of cilostazol and its active metabolites were used in this analysis.The PK was best depicted by one-compartment model, with absorption kinetics of cilostazol having mixed first- and zero-order kinetics with a time delay at the beginning of absorption. The introduction of interoccasion variabilities into zero-order (D1), first-order (Ka), and relative bioavailability (F1) significantly improved the model fit, and total body water (TBW) was identified as a significant covariate positively affecting the clearance of cilostazol. The model validation suggested that the model constructed in this study predicted the plasma concentration of cilostazol and its two active metabolites reasonably well.The PK model we developed explored the PK characteristics of cilostazol in Korean male subjects, and may be useful for identifying optimal individual dosing regimens of cilostazol.

MINI: A risk-scoring system for predicting extragastric recurrence after surgical resection of early gastric cancer was developed. The low-risk group showed an extremely rare extragastirc recurrence and higher extragastric recurrence-free survival than the high-risk group. Postsurgical computed tomography surveillance may be unnecessary in the low-risk group after curative resection of early gastric cancer. OBJECTIVE To stratify the postsurgical computed tomography (CT) surveillance based on a risk-scoring system for predicting extragastric recurrence after surgical resection of early gastric cancer (EGC). SUMMARY OF BACKGROUND DATA Postsurgical CT surveillance should not be routinely performed in all patients because of the low incidence of extragastric recurrence and potential risk of radiation exposure. METHODS Data from 3162 patients who underwent surgical resection for EGC were reviewed to develop a risk-scoring system to predict extragastric recurrence. Risk scores were based on the predictive factors for extragastric recurrence, which were determined using Cox proportional hazard regression model. The risk-scoring system was validated by Uno censoring adjusted C-index. External validation was performed using an independent dataset (n = 430). RESULTS The overall incidence of extragastric recurrence was 1.4% (44/3162). Five risk factors (lymph node metastasis, indications for endoscopic resection, male sex, positive lymphovascular invasion, and elevated macroscopic type), which were significantly associated with extragastric recurrence, were incorporated into the risk-scoring system, and the patients were categorized into 2 risk groups. The 10-year extragastric recurrence-free survival differed significantly between low- and high-risk groups (99.7% vs 96.5%; P < 0.001). The predictive accuracy of the risk-scoring system in the development cohort was 0.870 [Uno C-index; 95% confidence interval (95% CI), 0.800-0.939]. Discrimination was good after internal (0.859) and external validation (0.782, 0.549-1.000). CONCLUSION This risk-scoring system might be useful to predict extragastric recurrence of EGC after curative surgical resection. We suggest that postsurgical CT surveillance to detect extragastric recurrence should be avoided in the low-risk group.

Disability in patients with acute stroke varies over time, with the prediction of outcomes being critical for proper management. This study aimed to develop a model to predict the cumulative probability of each modified Rankin Scale (mRS) score over time with inclusion of significant covariates. Longitudinal data obtained from 193 patients, 1–24 months after onset of acute ischemic stroke, were included for a modeling analysis using nonlinear mixed‐effect modeling (NONMEM). After selecting a model that best described the time course of the probability of different mRS scores, potential covariates were tested. Visual predicted check plots, parameter estimates, and decreases in minimum objective function values were used for model evaluation. The inclusion of disease progression (DP) in the baseline proportional odds cumulative logit model significantly improved the model compared to the baseline model without DP. An inhibitory maximum effect (Emax) model was determined to be the best DP model for describing the probability of specific mRS scores over time. In the final model, DP was multiplied with the baseline cumulative logit probability with a baseline adjustment. In addition to differences in lesion volume (DLV), the final model included comorbid diabetes mellitus (DM) and baseline National Institutes of Health Stroke Scale (NIHSS) scores on Emax as statistically significant covariates. This study developed a model including DLV, NIHSS score, and comorbid DM for predicting the disability time course in patients with acute ischemic stroke. This model may help to predict disease outcomes and to develop more appropriate management plans for patients with acute stroke.

Introduction The combination of an anti-angiogenic agent with cytotoxic chemotherapy is a standard treatment strategy for metastatic colorectal cancer. CKD-516 is an oral vascular disrupting agent that was preliminarily shown to be safe and efficacious as a monotherapy in refractory solid cancers. We evaluated the recommended phase 2 dose, safety, and preliminary efficacy of CKD-516 in combination with irinotecan in treatment-refractory metastatic colorectal cancer. Methods This phase 1 dose-escalation and dose-expansion study included patients with treatment-refractory metastatic colorectal cancer. CKD-516 tablets were administered for five consecutive days followed by two days off in combination with intravenous irinotecan (120 mg/m2) administered on day one of each treatment cycle every two weeks. A traditional 3 + 3 dose-escalation design was used. Results In total, 16 and 23 patients were enrolled in the dose-escalation and dose-expansion cohorts, respectively. The most common adverse events included diarrhea (79%), nausea (74%), vomiting (67%), and neutropenia (62%). No dose-limiting toxicity occurred, and the recommended phase 2 dose was determined at CKD-516/irinotecan doses of 11/120 mg/m2. No cases of cardiac ischemia, cardiac dysfunction, or thromboembolism were reported. Among the 34 patients with available tumor response assessments, one patient achieved partial response (3%) and 26 patients achieved stable disease (76%). The median progression-free survival and overall survival were 4.1 and 11.6 months, respectively. Conclusion This phase 1 study showed that the combination of oral CKD-516 and irinotecan is safe and tolerable in metastatic, treatment-refractory colorectal patients and showed favorable efficacy outcomes. Further studies to confirm these preliminary findings are warranted. Trial registration number NCT03076957 (Registered at March 10, 2017).

Although both angiotensin receptor blockers (ARBs) and dihydropyridine calcium channel blockers (CCBs) are all suitable for the initiation of antihypertensive treatment, studies investigating efficacy and safety between ARBs and CCBs are limited, and there is no previous study comparing their clinical outcomes during long-term follow-up periods in real world setting. We compared cardiovascular (CV) events between ARBs and CCBs in 464,948 hypertensive adults using the Korean National Health Insurance Service database during a 3-year follow-up. The patients with hypertension without heart failure, ischemic heart disease, cerebrovascular disease, or peripheral artery disease were enrolled. The CV events between only single prescription of CCBs and ARBs were finally compared. The primary endpoint for this study was the first occurrence of a major adverse CV events, defined as the composite of all-cause death, cardiac death, nonfatal myocardial infarction, or nonfatal stroke. ARB was significantly more administered in male and patients with higher income, diabetes mellitus, chronic kidney diseases, and higher Charlson comorbidity index. The primary endpoints occurred in 10,526 patients (5.2%) in the ARB group and in 19,363 patients (7.3%) in the CCB group (p

Objective To evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of TU2670, a novel orally active, nonpeptide gonadotropin-releasing hormone (GnRH) antagonist administered to healthy female participants. Methods This was a first-in-human, multicenter, phase 1, randomized, double-blind, placebo-controlled, single-dose ascending trial that took place in multiple medical centers. A total of 16 healthy premenopausal women (23 to 45 years of age) were randomized and received 20, 40, 80, and 160 mg TU2670 (GnRH antagonist) or placebo 7 days (±1 day) after the onset of menstrual bleeding. We performed a noncompartmental analysis for pharmacokinetic parameters and calculated relative minimum concentration values (Cmin, % Baseline) of serum pharmacodynamic (PD) markers (luteinizing hormone [LH], follicle-stimulating hormone [FSH], and estradiol). Results There were no significant differences among treatments with respect to vital signs, electrocardiography, adverse events, ovulation test results, and ultrasonography. The median Tmax of TU2670 occurred 0.75 to 1.00 hours after dosing, and concentrations then declined, with a mean apparent half-life (t1/2) of 3.0 to 5.9 hours. AUClast (17.7-417.9 ng·h/mL) and Cmax (8.1-95.4 ng/mL) increased in a dose-dependent manner. The PD analysis after a single administration of TU2670 revealed dose-dependent suppression of LH, FSH, and estradiol. Maximal suppression of the pre-dose baseline (%) was 58% to 82% at 6 to 8 hours for LH, 28% to 39% at 6 to 12 hours for FSH, and 34% to 82% at 12 to 24 hours for estradiol. Conclusion The single administration of TU2670 in healthy premenopausal women was well tolerated and resulted in the dose-dependent suppression of LH, FSH, and estradiol, suggesting rapid and significant inhibition of pituitary and ovarian hormones.

OBJECTIVE To compare the performance of the deep learning-based lesion detection algorithm (DLLD) in detecting liver metastasis with that of radiologists. MATERIALS AND METHODS This clinical retrospective study used 4386-slice computed tomography (CT) images and labels from a training cohort (502 patients with colorectal cancer [CRC] from November 2005 to December 2010) to train the DLLD for detecting liver metastasis, and used CT images of a validation cohort (40 patients with 99 liver metastatic lesions and 45 patients without liver metastasis from January 2011 to December 2011) for comparing the performance of the DLLD with that of readers (three abdominal radiologists and three radiology residents). For per-lesion binary classification, the sensitivity and false positives per patient were measured. RESULTS A total of 85 patients with CRC were included in the validation cohort. In the comparison based on per-lesion binary classification, the sensitivity of DLLD (81.82%, [81/99]) was comparable to that of abdominal radiologists (80.81%, p = 0.80) and radiology residents (79.46%, p = 0.57). However, the false positives per patient with DLLD (1.330) was higher than that of abdominal radiologists (0.357, p < 0.001) and radiology residents (0.667, p < 0.001). CONCLUSION DLLD showed a sensitivity comparable to that of radiologists when detecting liver metastasis in patients initially diagnosed with CRC. However, the false positives of DLLD were higher than those of radiologists. Therefore, DLLD could serve as an assistant tool for detecting liver metastasis instead of a standalone diagnostic tool.

Drug-induced QT prolongation is one of the most common side effects of drug use and can cause fatal outcomes such as sudden cardiac arrest. This study adopts the data-driven approach to assess the QT prolongation risk of all the frequently used drugs in a tertiary teaching hospital using both standard 12-lead ECGs and intensive care unit (ICU) continuous ECGs. We used the standard 12-lead ECG results (n = 1,040,752) measured in the hospital during 1994–2019 and the continuous ECG results (n = 4,835) extracted from the ICU’s patient-monitoring devices during 2016–2019. Based on the drug prescription frequency, 167 drugs were analyzed using 12-lead ECG data under the case-control study design and 60 using continuous ECG data under the retrospective cohort study design. Whereas the case-control study yielded the odds ratio, the cohort study generated the hazard ratio for each candidate drug. Further, we observed the possibility of inducing QT prolongation in 38 drugs in the 12-lead ECG analysis and 7 drugs in the continuous ECG analysis. The seven drugs (vasopressin, vecuronium, midazolam, levetiracetam, ipratropium bromide, nifedipine, and chlorpheniramine) that showed a significantly higher risk of QT prolongation in the continuous ECG analysis were also identified in the 12-lead ECG data analysis. The use of two different ECG sources enabled us to confidently assess drug-induced QT prolongation risk in clinical practice. In this study, seven drugs showed QT prolongation risk in both study designs.

Background With advances in gastric cancer chemotherapy, conversion surgery has drawn attention as a new strategy to improve the outcome of stage IV disease. We investigated the efficacy of conversion surgery following chemotherapy for patients with stage IV gastric cancer. Methods We retrospectively reviewed clinico-pathologic variables and oncologic outcomes for 101 patients with stage IV gastric cancer who were treated with systemic chemotherapy followed by gastrectomy with intension of curative resection from January 2005 to December 2012. Results In terms of the best response from palliative chemotherapy, complete or partial response were observed in 65 patients (64.4%) in overall. Complete response of metastatic site were observed in 72 (71.3%) and 66 (65.3%) patients as best and pre-operative response, respectively. The overall complete macroscopic resection, rate was 56.4%. Eleven patients (10.9%) received combined metastasectomy. There was no postoperative surgery-related mortality for 1 month. The median overall survival time was 26.0 months. Multivariable analysis identified complete macroscopic resection, chemotherapy response (complete response/partial response) of metastatic sites, and change in CEA level as independent prognostic factors contributing to overall survival. Conclusions Patients with stage IV gastric cancer who exhibit a good clinical response to chemotherapy might obtain greater survival benefit from gastrectomy following chemotherapy compared with patients who exhibit a poor response to chemotherapy. Prospective, randomized trials are required to determine the best strategy for combining initial chemotherapy with subsequent gastrectomy. Electronic supplementary material The online version of this article (10.1186/s12885-018-4998-x) contains supplementary material, which is available to authorized users.

To evaluate the diagnostic value of signal intensity (SI)-selected volumetry findings in T2-weighted magnetic resonance imaging (MRI) as a potential biomarker for predicting pathological complete response (pCR) to preoperative chemoradiotherapy (CRT) in patients with rectal cancer. Forty consecutive patients with pCR after preoperative CRT were compared with 80 age- and sex-matched non-pCR patients in a case-control study. SI-selected tumor volume was measured on post-CRT T2-weighted MRI, which included voxels of the treated tumor exceeding the SI (obturator internus muscle SI + [ischiorectal fossa fat SI – obturator internus muscle SI] × 0.2). Three blinded readers independently rated five-point pCR confidence scores and compared the diagnostic outcome with SI-selected volumetry findings. The SI-selected volumetry protocol was validated in 30 additional rectal cancer patients. The area under the receiver-operating characteristic curve (AUC) of SI-selected volumetry for pCR prediction was 0.831, with an optimal cutoff value of 649.6 mm3 (sensitivity 0.850, specificity 0.725). The AUC of the SI-selected tumor volume was significantly greater than the pooled AUC of readers (0.707, p < 0.001). At this cutoff, the validation trial yielded an accuracy of 0.87. SI-selected volumetry in post-CRT T2-weighted MRI can help predict pCR after preoperative CRT in patients with rectal cancer. • Fibrosis and viable tumor MRI signal intensities (SIs) are difficult to distinguish. • T2 SI-selected volumetry yields high diagnostic performance for assessing pathological complete response. • T2 SI-selected volumetry is significantly more accurate than readers and non-SI-selected volumetry. • Post-chemoradiation therapy T2-weighted MRI SI-selected volumetry facilitates prediction of pathological complete response.

Udenafil is a phosphodiesterase-5 inhibitor used to treat erectile dysfunction. Although udenafil is not predominantly eliminated by the kidney, renal impairment can alter its secretion/transport pathways. Drug pharmacokinetics and safety must therefore be assessed in subjects with a renal impairment. We investigated the effects of impaired renal function on the pharmacokinetics and safety of a single 100-mg oral dose of udenafil in a single-dose, open-label, parallel-group study of 31 subjects. Cockcroft-Gault creatinine clearance was used to stratify these subjects into healthy controls (>80 mL·min-1 ) and individuals with mild (50 to ≤80 mL·min-1 ), moderate (30 to ≤50 mL·min-1 ), and severe (

Highlights • The present study analyzed the diagnosis pattern of childhood malignant diseases using public health data and viral surveillance data in Korea. • The number of newly diagnosis showed the highest monthly average in January, and the lowest in September. • Seasonal trends were apparent in acute myeloid leukemia, Non-Hodgkin’s lymphoma, acute lymphoblastic leukemia and germ cell tumors. • In winter, significantly more patients were diagnosed with acute lymphoblastic leukemia, acute myeloid leukemia, neuroblastoma, and Hodgkin’s lymphoma than in other seasons. • There was a temporal correlation with the diagnostic trends of several diseases and the prevalence of recent human parainfluenza virus., Background Several studies have reported a seasonal trend in the diagnosis of childhood cancer suggesting seasonal factors such as infection. The present study aimed to analyze the diagnosis pattern of childhood malignant diseases using public health data, and to compare this pattern with seasonal viral infection trends. Method Using the open data source of the Health Insurance Review and Assessment Service, we extracted data regarding all patients under 21 years of age and who had any cancer, aplastic anemia or myelodysplastic syndrome between September 2009 and December 2013. The positive detection rates of 11 viruses was collected from the surveillance data of Korea Centers for Disease Control and Prevention, and seasonality analysis were conducted with both data. Results In total, 9085 patients were diagnosed with malignant disease during the study period; there were about 175 new cases per month on average. Monthly stacked time series by year showed an apparent seasonal variation with the highest monthly average in January as 236, and the lowest in September as 120. In winter, significantly more patients were diagnosed with acute lymphoblastic leukemia, acute myeloid leukemia, neuroblastoma, and Hodgkin’s lymphoma than in other seasons. There was a temporal correlation with the diagnostic trends of several diseases and the prevalence of recent human parainfluenza virus. Conclusion This study tentatively suggests that the diagnosis of childhood malignancy follows a seasonal trend in Korea, and has a possible correlation with viral prevalence in several diseases. Further long-term analysis of epidemiological data is needed to explore possible causality.

Chronic diseases pose a major challenge to population health worldwide. Diabetes is a major chronic disease that is managed overwhelmingly in primary care. There is an increasing recognition of the role that primary care physicians play to achieve high-quality care for patients with diabetes. By analyzing 2013 Korean Health Panel data, the authors aimed to determine the current status of having a regular doctor (RD) for adults (aged 18 years or older) with diabetes. In addition, the association of having a RD with the experience of emergency department (ED) visits was determined in this study. Among adults with diabetes, those with RD accounted for 41.0%. The older the age group and the higher the Charlson comorbidity index score, the higher the percentage of adults with diabetes had RD. Even for those with RD, coordination of care was very poor (positive answer: 27.1%). After adjustment for confounding variables, those having (vs. not having) a RD (odds ratio [OR], 0.57; 95% confidence interval [CI], 0.35–0.94), especially those whose RDs delivered good comprehensiveness of care (OR, 0.47; 95% CI, 0.26–0.84) or worked at a primary care clinic (OR, 0.43; 95% CI, 0.22–0.81), and those whose longitudinal relationship with a RD was 5 years or less (OR, 0.45; 95% CI, 0.22–0.91) were less likely to have ED visits within the last year. In conclusion, health care policies that promote having a RD who delivers high-quality primary care could decrease unnecessary ED visits by diabetic adults. This can partly reduce ED overcrowding in Korea., Graphical Abstract

To investigate the optimal magnetic resonance (MR) imaging protocol in pregnant women suspected of having acute appendicitis. One hundred and forty-six pregnant women with suspected appendicitis were included. MR images were reviewed by two radiologists in three separate sessions. In session 1, only axial single-shot turbo spin echo (SSH-TSE) T2-weighted images (WI) were included with other routine sequences. In sessions 2 and 3, coronal and sagittal T2WI were sequentially added. The visibility of the appendix and diagnostic confidence of appendicitis were evaluated in each session using a 5-point grading scale. If diseases other than appendicitis were suspected, specific diagnosis with a 5-point confidence scale was recorded. Diagnostic performance for appendicitis and other diseases were evaluated. Twenty-five patients (17.1%) were diagnosed with appendicitis. Among the patients with normal appendix, 28 were diagnosed with other disease. Diagnostic performance including sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and area under the curve values for diagnosing appendicitis and other diseases showed no significant difference among sets for both reviewers (p>0.05). Diagnostic performance of MR in pregnant patients with suspected appendicitis can be preserved with omission of sagittal or both coronal and sagittal SSH-T2WI. • Diagnostic performance of appendicitis is preserved with omission of sagittal/coronal T2WIs. • Diagnosis of other disease may be sufficient with axial T2WIs only. • Careful serial omission of sagittal and coronal T2WIs can be considered.

// Choong-Kun Lee 1 , Seung-Seob Kim 2 , Saemi Park 3 , Chan Kim 1 , Su Jin Heo 1 , Joon Seok Lim 2 , Hyunki Kim 4 , Hyo Song Kim 1 , Sun Young Rha 1 , Hyun Cheol Chung 1 , Sohee Park 3 , Minkyu Jung 1 1 Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University, College of Medicine, Seoul, Korea 2 Department of Radiology, Yonsei University College of Medicine, Seoul, Korea 3 Department of Biostatistics, Graduate School of Public Health, Yonsei University, Seoul, Korea 4 Department of Pathology, Yonsei University College of Medicine, Seoul, Korea Correspondence to: Sohee Park, email: soheepark@yuhs.ac Minkyu Jung, email: minkjung@yuhs.ac Keywords: gastric cancer, trastuzumab, depth of response, early tumor shrinkage, survival Received: December 14, 2016 Accepted: March 01, 2017 Published: March 10, 2017 ABSTRACT Purpose: We aimed to determine and compare the predictive values of depth of response (DpR) and early tumor shrinkage (ETS) on long-term outcomes in gastric cancer patients treated with trastuzumab. Results: From a total of 368 computed tomography examinations, DpR and ETS were evaluated. DpR was a significant tumor-size metric in predicting PFS and OS, and showed better discriminatory ability (higher Cτ indices, 0.6957 for PFS; 0.7191 for OS) than ETS. DpR ≥ 45% (vs. < 45%) was the optimal cutoff value, as it was best able to identify patients with longer PFS (median 9.0 vs. 6.3 months, hazard ratio [HR] = 0.608; 95% confidence interval [CI]: 0.335 to 1.104; P = 0.102) and OS (median 23.5 vs. 13.1 months, HR = 0.441; 95% CI: 0.203 to 0.955; P = 0.038). Materials and Methods: Sixty-one gastric cancer patients who received first-line trastuzumab-based chemotherapy were assessed for DpR and ETS. We employed Kaplan-Meier estimates, log-rank tests, Cox proportional hazards regression models, time-dependent receiver operating characteristics, and Youden’s J index to evaluate and determine cutoff values of DpR and ETS as predictors of progression-free survival (PFS) and overall survival (OS). Conclusions: DpR and ETS were significant predictors of long-term outcomes in gastric cancer patients treated with first-line trastuzumab. Validation in prospective trials with larger patient populations is needed.

The aim of this study was to report the clinical results of reduced pelvic field radiotherapy (RT), excluding the anastomotic site, after total mesorectal excision in selected patients with rectal cancer. Between 2011 and 2014, 99 patients underwent upfront surgery for clinically less-advanced tumors but were finally diagnosed as pT3/N+. Among them, 50 patients with mid–upper rectal cancer who received postoperative RT with a reduced pelvic field were included in this retrospective review. This group was composed of patients with high seated tumors, complete resection with a clear circumferential resection margin, and no complication during surgery. We investigated treatment outcomes, toxicity and the effect of RT-field reduction on organs-at risk in 5 randomly selected patients. During the median follow-up period of 42 months (range: 15−59 months), tumors recurred in 9 patients (18%). The 3-year overall and disease-free survival were 98% and 81%, respectively. Distant metastasis was the dominant failure pattern (n = 8, 16%), while no recurrences occurred at or near anastomotic sites. No anastomotic complications were found on pelvic examination, images and/or colonoscopy. Reported acute and late RT-related toxicities were mostly mild to moderate, with only small numbers of Grade 3 toxicities. None of the patients developed Grade 4−5 acute or late toxicity. With a caudally reduced field, 64% reduction in absolute anastomotic exposure at the maximum dose was achieved compared with the traditional whole-pelvic field (P = 0.008). The reduced pelvic field RT was able to minimize late anastomotic complication without increasing its recurrence in selected patients with mid–upper rectal cancer in the postoperative setting.

To evaluate the diagnostic value of the T1 bright appendix sign for the diagnosis of acute appendicitis in pregnant women. This retrospective study included 125 pregnant women with suspected appendicitis who underwent magnetic resonance (MR) imaging. The T1 bright appendix sign was defined as a high intensity signal filling more than half length of the appendix on T1-weighted imaging. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of the T1 bright appendix sign for normal appendix identification were calculated in all patients and in those with borderline-sized appendices (6-7 mm). The T1 bright appendix sign was seen in 51% of patients with normal appendices, but only in 4.5% of patients with acute appendicitis. The overall sensitivity, specificity, PPV, and NPV of the T1 bright appendix sign for normal appendix diagnosis were 44.9%, 95.5%, 97.6%, and 30.0%, respectively. All four patients with borderline sized appendix with appendicitis showed negative T1 bright appendix sign. The T1 bright appendix sign is a specific finding for the diagnosis of a normal appendix in pregnant women with suspected acute appendicitis. • Magnetic resonance imaging is increasingly used in emergency settings. • Acute appendicitis is the most common cause of acute abdomen. • Magnetic resonance imaging is widely used in pregnant population. • T1 bright appendix sign can be a specific sign representing normal appendix.

Lead poisoning is an uncommon and challenging diagnosis to make. In 2018, The Victorian Department of Health issued a health warning following four cases of lead poisoning associated with illicit opium use in Melbourne, Australia. We present these cases to highlight clinical features and the relevant investigations leading to diagnosis. All cases occurred in recent immigrants to Australia, who had access to non-traditional sources of opioids. Health care professionals should consider lead poisoning in patients with appropriate symptoms and a history of illicit opium use.

CTB-001, a recently developed generic version of bivalirudin, an FDA-approved anticoagulant used for prophylaxis and treatment of cardiovascular diseases, has shown good efficacy and safety in clinical trials. We characterized the pharmacokinetics (PK) and pharmacodynamics (PD) of CTB-001 by modeling and simulation analysis. PK/PD data were collected from a randomized, double-blind, placebo-controlled, single-dose, dose-escalation phase 1 study conducted in 24 healthy Korean male subjects. PK/PD analysis was conducted sequentially by nonlinear mixed-effects modeling implemented in NONMEM®. Monte-Carlo simulations were conducted for PK, activated partial thromboplastin time (aPTT), prothrombin time (PT), and thrombin time (TT). The CTB-101 PK was best described by a three-compartment linear model with a saturable binding peripheral compartment. All PD endpoints showed dose-response relationship, and their changes over time paralleled those of CTB-101 concentrations. A simple maximum effect model best described the aPTT, PT in INR, PT in seconds, and TT, whereas an inhibitory simple maximum effect model best described PT in percentages. The maximum duration of effect of CTB-001 on aPTT prolongation was 52.1 s. The modeling and simulation analysis well-characterized the PK and PD of CTB-001 in healthy Koreans, which will be valuable for identifying optimal dosing regimens of CBT-001.

This study evaluated the 5-year clinical outcomes of the Genoss DES, the first Korean-made sirolimus-eluting coronary stent with abluminal biodegradable polymer. We previously conducted the first-in-patient prospective, multicenter, randomized trial with a 1:1 ratio of patients using the Genoss DES and Promus Element stents; the angiographic and clinical outcomes of the Genoss DES stent were comparable to those of the Promus Element stent. The primary endpoint was major adverse cardiac events (MACE), which was a composite of death, myocardial infarction (MI), and target lesion revascularization (TLR) at 5 years. We enrolled 38 patients in the Genoss DES group and 39 in the Promus Element group. Thirty-eight patients (100%) from the Genoss DES group and 38 (97.4%) from the Promus Element group were followed up at 5 years. The rates of MACE (5.3% vs 12.8%, P = .431), death (5.3% vs 10.3%, P = .675), TLR (2.6% vs 2.6%, P = 1.000), and target vessel revascularization (TVR) (7.9% vs 2.6%, P = .358) at 5 years did not differ significantly between the groups. No TLR or target vessel revascularization was reported from years 1 to 5 after the index procedure, and no MI or stent thrombosis occurred in either group during 5 years. The biodegradable polymer Genoss DES and durable polymer Promus Element stents showed comparable low rates of MACE at the 5-year clinical follow-up.

Background/Aims: Because of the limited geographic distribution, there have been insufficient data regarding hepatitis C virus (HCV) genotype 6 in Korea. This study aimed to investigate the clinical characteristics and available treat-ment outcomes of patients with genotype 6 HCV in Korea. Methods: From 2004 to 2014, data were collected from Korean patients infected with genotype 6 HCV in eight hos-pitals. Results: Thirty-two patients had genotype 6 HCV. The median age was 44 years, and 6c was the most common subtype. The baseline median alanine transaminase level was 88 (21 to 1,019) IU/mL, and the HCV RNA level was 1,405,000 (96,500 to 28,844,529) IU/mL. Twenty-five pa-tients were treated with peginterferon (PEG-IFN) and ribavirin. Three follow-up losses occurred. Additionally, 13 patients attained a sustained virologic response (SVR), seven patients relapsed, and two patients exhibited a null response. The SVR rates were 40% and 75% for the 24- and more than 48- week treatments, respectively, and five of the six patients who achieved a rapid virologic response (RVR) attained a SVR. Conclusions: Korean patients infected with genotype 6 HCV are relatively young, and 6c is the most common sub-type. When treated with PEG-IFN and ribavirin, the SVR rate was 52%. Similar to other genotypes, a longer duration of treatment and attainment of RVR are important for SVR. (Gut Liver 2017;11:270-275)

GCC-4401C, an orally active direct factor Xa inhibitor that is similar to rivaroxaban, is currently under development for venous thromboembolic disease (VTE). The purpose of this study was to characterize the pharmacokinetics (PKs) and pharmacodynamics (PDs) of GCC-4401C by population modeling analysis and to predict proper dosage regimens compared to rivaroxaban using data from two phase I clinical studies. Plasma GCC-4401C concentrations over time were best described by a two-compartment linear model and body weight was associated with central volume of distribution. Relevant PD markers generally changed in a dose-dependent manner and were described well with sigmoid, simple maximum effect, or linear models. GCC-4401C was absorbed more rapidly than rivaroxaban. Comparisons based on simulations of PD marker changes over time suggest that 20 mg and 40 mg of GCC-4401C administered under fasted status are comparable to 10 mg and 20 mg of rivaroxaban under fed status.

// Hyo Song Kim 1 , Su-Jin Shin 2 , Seung-Hoon Beom 1 , Minkyu Jung 1 , Yoon Young Choi 3 , Taeil Son 3 , Hyoung-Il Kim 3 , Jae-Ho Cheong 3 , Woo Jin Hyung 3 , Sung Hoon Noh 3 , Hyunsoo Chung 4 , Jun Chul Park 4 , Sung Kwan Shin 4 , Sang Kil Lee 4 , Yong Chan Lee 4 , Woong Sub Koom 5 , Joon Seok Lim 6 , Hyun Cheol Chung 1 , Sun Young Rha 1 , Hyunki Kim 2 1 Division of Medical Oncology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea 2 Department of Pathology, Yonsei University College of Medicine, Seoul, Republic of Korea 3 Department of Surgery, Yonsei University College of Medicine, Seoul, Republic of Korea 4 Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea 5 Department of Radiation Oncology, Yonsei University College of Medicine, Seoul, Republic of Korea 6 Department of Radiology, Yonsei University College of Medicine, Seoul, Republic of Korea Correspondence to: Hyunki Kim, email: kimhyunki@yuhs.ac Sun Young Rha, email: rha7655@yuhs.ac Keywords: gastric cancer, molecular subtypes, immunohistochemistry, in-situ hybridization Received: April 04, 2016 Accepted: May 29, 2016 Published: June 16, 2016 ABSTRACT Gastric cancer (GC) is a leading cause of death. We aim to establish a clinically relevant assay that encompasses recent molecular classifications and provides useful clinical information in a large cohort of GC patients. A consecutive series of 438 GC patients that underwent palliative chemotherapy between 2014 and 2015 were assessed using 10 GC panels: EBER in-situ hybridization, immunohistochemistry for mismatch repair (MMR) proteins (MLH1, PMS2, MSH2, and MSH6), receptor tyrosine kinases (RTKs; HER2, EGFR, and MET), PTEN, and p53 protein. With a median of one aberration, 3.3 % of samples analyzed were Epstein-Barr virus (EBV)-positive; 4.8%, MMR-deficient. RTKs were overexpressed in 218 patients; EGFR was most commonly overexpressed (39.9%), followed by HER2 (13.5%) and MET (12.1%). Furthermore, 2.5 % and 10.7 % of cases had simultaneous overexpression of three and two RTKs, respectively. p53 overexpression/null tumors were identified in 259 patients (59.1%), and PTEN loss was identified in 89 patients (20.3%). EBV-positivity was mutually exclusive with MMR-deficiency, predominantly identified in male patients, and these tumors were undifferentiated with proximal location. p53 mutant type was significantly found predominantly in the EBV-negative (60.6% vs 14.3%, P=0.001) and HER2-positive (78.0% vs 56.2%, P=0.002) groups. We described a molecular spectrum of distinct GC subtypes using clinically applicable assay. This assay will provide a convenient screening tool and facilitate the development of targeted agents in clinical trials.

// Minsu Lee 1, 2 , Song-Ee Baek 1, 2 , Jieun Moon 3 , Yun Ho Roh 3 , Joon Seok Lim 1, 2 , Mi-Suk Park 1, 2 , Myeong-Jin Kim 1, 2 , Honsoul Kim 1, 2 1 Department of Radiology, Yonsei University College of Medicine, Seoul, Republic of Korea 2 Research Institute of Radiological Science, Yonsei University College of Medicine, Seoul, Republic of Korea 3 Biostatistics Collaboration Unit, Yonsei University College of Medicine, Seoul, Republic of Korea Correspondence to: Honsoul Kim, email: pine0205@yuhs.ac Keywords: treatment response, melanoma liver metastasis, magnetic resonance imaging, subtraction technique, mRECIST Received: January 18, 2016 Accepted: May 08, 2016 Published: May 24, 2016 ABSTRACT Purpose: To determine whether contrast-enhanced MRI including subtraction sequences can predict the treatment response of melanoma liver metastasis. Results: High precontrast T1 signal intensity (SI) of melanoma lesions obscured detection of enhancement after contrast injection. It was impossible to determine whether or not enhancement occurred in the majority of lesions (85.4%, n = 35/41) without including the subtraction technique. Positive enhancement was identified in 14.6% ( n = 6/41) of patients without subtraction images, but increased to 68.3% ( n = 28/41) by including subtraction images. Follow-up studies determined lesion progression in 34.1% ( n = 14/41) of patients. Positive enhancement on the subtraction image (odds ratio = 12.1, P = 0.048) and intermediate high T2 SI (odds ratio = 8.16, P = 0.040) were significantly associated with higher risk of lesion progression. Materials and Methods: Patients who underwent MRI for melanoma liver metastases between January 2007 and February 2015 were enrolled. The study analyzed 41 liver metastases in 15 patients [11 male and four female; median age 56 years (range 21–81)] for size, lesion enhancement with and without subtraction images, and T2 SI. Follow-up imaging studies were used to determine treatment response. Data were analyzed with generalized estimating equations. Conclusions: MRI including the subtraction technique is useful for determining the treatment response of melanoma liver metastases. Lesion contrast enhancement and intermediate high T2 SI increased the risk of lesion progression.

Lipoprotein(a) [Lp(a)] has mainly been considered to be a predictor of the incidence of cardiovascular disease. In addition, previous studies have shown potential linkage between Lp(a) and diabetic microvascular complications.We investigated the incidence and risk factors for the development of diabetic retinopathy (DR) in patients with type 2 diabetes.A total of 787 patients with type 2 diabetes without DR were consecutively enrolled and followed up prospectively. Retinopathy evaluation was annually performed by ophthalmologists. The main outcome was new onset of DR.The median follow-up time was 11.1 years. Patients in the DR group had a longer duration of diabetes (P.001), higher baseline HbA1c (P.001), higher albuminuria level (P = .033), and higher level of Lp(a) (P = .005). After adjusting for sex, age, diabetes duration, presence of hypertension, renal function, LDL cholesterol, mean HbA1c, and medications, the development of DR was significantly associated with the serum Lp(a) level (HR 1.57, 95% confidence interval [1.11-2.24]; P = .012, comparing the 4th vs 1st quartile of Lp(a)). The patient group with the highest quartile range of Lp(a) and mean HbA1c levels ≥7.0% had an HR of 5.09 (95% confidence interval [2.63-9.84]; P.001) for developing DR compared with patients with lower levels of both factors.In this prospective cohort study, we demonstrated that the DR was independently associated with the serum Lp(a) level in patients with type 2 diabetes.

Recently, anti-vascular endothelial growth factor (anti-VEGF) agents have been described in the literature as a valid treatment option for symptomatic liver hemangiomas, but only limited evidence supports this notion. The purpose of this study was to elucidate whether or not the administration of anti-VEGF agents can reliably achieve a size reduction in liver hemangiomas. We examined patients with incidental hemangiomas who received anti-angiogenic agents for the treatment of other malignancies. Our study population consisted of 17 colorectal cancer patients and one lung cancer patient carrying 21 hemangiomas who received bevacizumab, and seven renal cell carcinoma patients carrying nine hepatic hemangiomas who received sunitinib. We have measured the liver hemangioma volume on both the pre-treatment and post-treatment computed tomography images and then calculated the volume alteration rates. No statistically significant difference (P = 0.365) in the volume of the liver hemangiomas was observed before (1.1-168.8 cm(3); mean ± SD 19.8 ± 39.7 cm(3)) or after (1.2-163.6 cm(3); 19.3 ± 38.0 cm(3)) bevacizumab treatment. The volume reduction rate ranged from -35.0 to 11.2 % (mean ± SD -1.3 ± 10.8 %). The sunitinib treatment group also showed no statistically significant difference (P = 0.889) in hemangioma volume before (1.2-6.5 cm(3); 3.0 ± 1.8 cm(3)) or after (1.2-6.0 cm(3); 3.0-1.7 cm(3)) treatment. The volume reduction rate ranged from -13.3 to 7.7 % (median: mean ± SD -2.5 ± 6.6 %). We did not observe liver hemangioma shrinkage after bevacizumab or sunitinib treatment. Our data do not support the application of anti-VEGF agents for the treatment of hepatic hemangiomas.

OBJECTIVE To identify patients who are at a higher risk of pathologic circumferential resection margin involvement using preoperative magnetic resonance imaging. METHODS Between October 2008 and November 2012, 165 patients with locally advanced rectal cancer (cT4 or cT3 with

To evaluate the ability of magnetic resonance imaging (MRI) to predict pathologic complete response (pCR) after neoadjuvant chemoradiation therapy (CRT) in patients with clinical T1/T2 rectal cancer to indicate candidates for organ-saving strategies. Between 2012 and 2016, 38 patients with clinical T1/T2 rectal cancer received neoadjuvant CRT. Radiologic complete response (rCR) was assigned when dense fibrotic tissue without tumor signal intensity was observed on post-CRT MRI. Surgical pathologic assessment was used to evaluate tumor regression. The association between rCR and the mural extent of the primary tumor, pCR, and pathologic T stage were analyzed. In rCR patients, the pCR rate was higher; the odds of achieving pCR were 8.00 times higher than for non-rCR patients (P = .02). rCR patients were also more likely to have early-stage cancer than non-rCR patients (P = 0.01). Patients with partial extent of the primary tumor on post-CRT MRI were more likely to be diagnosed with early-stage cancer than those with transmural extent (P = .01). rCR indicated by post-CRT MRI can be used as a supportive factor to predict pCR after neoadjuvant CRT in patients with clinical T1/T2 rectal cancer and can guide management decisions around organ-saving treatments.

BackgroundFew studies report the effects of tamoxifen intake and the occurrence of de novo fatty liver and the deterioration of existing fatty liver. The aim of this study was to investigate the effects of tamoxifen on fatty change of liver over time and also the impact of fatty liver on the prognosis of patients with breast cancer.MethodsThis was a single-center, retrospective study of patients who were diagnosed with primary breast cancer from January 2007 to July 2017. 911 consecutive patients were classified into three groups according to treatment method: tamoxifen group, aromatase inhibitor (AI) group, and control group.ResultsMedian treatment duration was 49 months (interquartile range, IQR; 32-58) and median observational period was 85 months (IQR; 50-118). Long-term use of tamoxifen significantly aggravated fatty liver status compared to AI or control groups [hazard ratio (HR): 1.598, 95% confidence interval (CI): 1.173-2.177, P = 0.003] after adjusting other factors. When analyzed separately depending on pre-existing fatty liver at baseline, tamoxifen was involved in the development of de novo fatty liver [HR: 1.519, 95% CI: 1.100-2.098, P = 0.011) and had greater effect on fatty liver worsening (HR: 2.103, 95% CI: 1.156-3.826, P = 0.015). However, the progression of fatty liver did not significantly affect the mortality of breast cancer patients.ConclusionsTamoxifen had a significant effect on the fatty liver status compared to other treatment modalities in breast cancer patients. Although fatty liver did not affect the prognosis of breast cancer, meticulous attention to cardiovascular disease or other metabolic disease should be paid when used for a long time.

Prediction of survival endpoints, e.g., overall survival (OS) and progression-free survival (PFS), based on early observations, i.e., tumor size, may facilitate early decision making in oncology drug development. In this paper, using data from six randomized trials for first- or second-line advanced breast cancer (ABC) treatments with various mechanisms of action, tumor size change from baseline at different observation time points was evaluated as a predictor for survival endpoints using different modeling approaches. The aim is to establish a predictive model where tumor size change from baseline can be used as a treatment independent predictive marker for PFS and OS in first- and second-line ABC. The results showed that tumor size change at single time point (TSP) or up to certain time points as a time-varying covariate (TSTVC) were significant predictors for OS and PFS in the survival models along with other covariates identified for each line of treatment. TSP and TSTVC models performed similarly for first-line treatments; TSTVC performed significantly better for second-line treatments. Eight weeks was selected as the recommended early evaluation time of tumor size change to predict OS and PFS in both first- and second-line treatment, while better prediction can be achieved for first-line OS by using 16 weeks tumor size change. The result of this study is treatment independent and can be used to predict the outcome of the clinical trials using early readout of tumor size change for the classes of drugs that have been evaluated in this study.

Amitriptyline is a tricyclic antidepressant that is metabolized mainly by CYP2C19 and CYP2D6 enzymes. Higher plasma levels of amitriptyline and its active metabolite, nortriptyline, are associated with an increased risk of adverse events including anticholinergic effects. The aim of this study was to evaluate the effects of CYP2C19 and CYP2D6 genetic polymorphisms on amitriptyline and nortriptyline pharmacokinetics. Twenty-four Korean healthy adult male volunteers were enrolled in the study after stratification by their CYP2C19 and CYP2D6 genotypes. Serial blood draws for pharmacokinetic analysis were made after a single oral 25-mg dose of amitriptyline was administered. Plasma amitriptyline and nortriptyline concentrations were measured by a validated liquid chromatography with tandem mass spectrometry. Population pharmacokinetic modeling analysis was conducted using NONMEM, which evaluated the effects of CYP2C19 and CYP2D6 genotypes on amitriptyline and nortriptyline pharmacokinetics. The biotransformation of amitriptyline into nortriptyline was significantly different between subjects with the CYP2C19*2/*2, *2/*3, and *3/*3 genotypes and those with the other genotypes, with an estimated metabolic clearance of 17 and 61.5 L/h, respectively. Clearance of amitriptyline through pathways other than biotransformation into nortriptyline was estimated as 18.8 and 30.6 L/h for subjects with the CYP2D6*10/*10 and *10/*5 genotypes and those with the other genotypes, respectively. This study demonstrated a quantitative effect of the CYP2C19 and CYP2D6 genotypes on amitriptyline and nortriptyline pharmacokinetics. Production of nortriptyline from amitriptyline was associated with CYP2C19 genotypes, and clearance of amitriptyline through pathways other than biotransformation into nortriptyline was associated with CYP2D6 genotypes. These observations may be useful in developing individualized, optimal therapy with amitriptyline.

Background Preoperative therapy has gained wide interest in advanced gastric cancer patients due to its potential advantages of improved disease control. Selection of high risk patients based on preoperative staging is crucial to choose the candidates for neoadjuvant therapy. Methods Our institutional review board approved this retrospective study and waived the requirement for patient consent. We searched 394 advanced gastric cancer patients (pT2-4) who underwent curative resection in 2010 without neoadjuvant therapies. Two abdominal radiologists independently reviewed the preoperative CT including tumor depth on CT (CT-tumor depth), which was categorized as follows: intramural, minimal extramural(

Background Autism spectrum disorder involves neurodevelopmental dysregulations that lead to visible symptoms at early stages of life. Many autism spectrum disorder–related mechanisms suggested by animal studies are supported by demonstrated improvement in autistic-like phenotypes in adult animals following experimental reversal of dysregulated mechanisms. However, whether such mechanisms also act at earlier stages to cause autistic-like phenotypes is unclear. Methods We used Shank2−/− mice carrying a mutation identified in human autism spectrum disorder (exons 6 and 7 deletion) and combined electrophysiological and behavioral analyses to see whether early pathophysiology at pup stages is different from late pathophysiology at juvenile and adult stages and whether correcting early pathophysiology can normalize late pathophysiology and abnormal behaviors in juvenile and adult mice. Results Early correction of a dysregulated mechanism in young mice prevents manifestation of autistic-like social behaviors in adult mice. Shank2−/− mice, known to display N-methyl-D-aspartate receptor (NMDAR) hypofunction and autistic-like behaviors at postweaning stages after postnatal day 21 (P21), show the opposite synaptic phenotype—NMDAR hyperfunction—at an earlier preweaning stage (∼P14). Moreover, this NMDAR hyperfunction at P14 rapidly shifts to NMDAR hypofunction after weaning (∼P24). Chronic suppression of the early NMDAR hyperfunction by the NMDAR antagonist memantine (P7–P21) prevents NMDAR hypofunction and autistic-like social behaviors from manifesting at later stages (∼P28 and P56). Conclusions Early NMDAR hyperfunction leads to late NMDAR hypofunction and autistic-like social behaviors in Shank2−/− mice, and early correction of NMDAR dysfunction has the long-lasting effect of preventing autistic-like social behaviors from developing at later stages.

LCB01-0371 is a novel oxazolidinone with broad-spectrum activity against Gram-positive pathogens in both in vitro studies and animal infection models. The objectives of this study were to evaluate its safety, tolerability, pharmacokinetics, and pharmacodynamics following single ascending doses. Single oral doses of 600 mg linezolid, a placebo, or LCB01-0371 of between 50 mg and 3,200 mg were tested in 69 healthy male subjects. Blood and urine were sampled, LCB01-0371 concentrations were measured, and the serum inhibitory and bactericidal titers of LCB01-0371 and linezolid were determined. LCB01-0371 was well tolerated up to 2,400 mg. The most common drug-related clinical and laboratory adverse events were nausea with or without vomiting, decreased neutrophil counts, and increased total bilirubin levels. The frequency of adverse events and drug-related adverse events was similar among the treatment groups. The systemic exposure was approximately dose proportional over the range of 50 mg to 800 mg, which includes the anticipated clinical dose. The mean clearance, renal clearance, and volume of distribution were significantly decreased at higher doses (above 800 mg). LCB01-0371 exhibited early bacteriostatic activity against all tested strains except for Streptococcus pneumoniae strains, and the potency of LCB01-0371 at 800 mg was similar to that of linezolid at the therapeutic dose (600 mg). However, LCB01-0371 had less bactericidal activity than linezolid. Taken together, LCB01-0371 was well tolerated, exhibited approximate dose proportionality within the anticipated clinically relevant dose range, and showed bacteriostatic and bactericidal activity comparable to that of linezolid. These results support the further clinical development of LCB01-0371. (This study has been registered at ClinicalTrials.gov under registration no. NCT01554995.)

Purpose LCB01-0371 is a novel broad-spectrum oxazolidinone antibacterial agent under investigation for the treatment of infection by gram-positive pathogens, including methicillin-resistant Staphylococcus aureus. This study evaluated the safety, tolerability, and pharmacokinetics of LCB01-0371 after a single intravenous (IV) infusion and determined its absolute oral bioavailability at a therapeutic dose of 800 mg. Methods : This study was conducted in 2 parts. The first part was a single-blind, placebo-controlled, escalating single IV dose study (200, 400, 800, and 1200 mg) of LCB01-0371 via 2 different infusion regimens (250 mL over 60 min or 150 mL over 30 min) in 36 healthy male volunteers. The second part was an open-label, 2-way crossover design study in which 8 subjects were randomly assigned to 1 of 2 sequences of a single oral (800 mg) or IV (400 mg) administration of LCB01-0371. Safety assessments were conducted at regular intervals. Blood and urine were serially sampled, and drug concentrations were measured for up to 24 h to calculate pharmacokinetic parameters. Findings LCB01-0371 after IV administration was generally safe and well tolerated up to 800 mg regardless of the infusion regimen. Adverse events were mild, excluding nausea at the highest dose, and resolved spontaneously. After a single IV administration, LCB01-0371 exhibited linear pharmacokinetic properties over the range of 200–800 mg. The elimination t1/2, volume of distribution, and clearance ranged from 1.48 to 1.68 h, 57.74–76.72 L, and 33.17–43.31 L/h, respectively, and they remained unchanged over the corresponding dose range. Cmax, AUC0–last, and AUC0–∞ increased in a dose-dependent manner. The dose-normalized total exposure after single PO and IV dosing were equivalent, with 90% CIs of the geometric least squares mean ratio of 86.6%–110% for AUC0–last and 86.6%–111% for AUC0–∞. The dose-normalized Cmax was not equivalent between oral and IV dosing, with a 90% CI of the geometric least squares mean ratio of 50.0%–105%. The absolute oral bioavailability of LCB01-0371 after a single 800-mg dose was 99.75%. Implications After a single IV administration, LCB01-0371 was well tolerated in healthy volunteers at doses up to 800 mg, and it exhibited linear pharmacokinetic properties. The comparable total systemic exposure between IV and oral administration supports the ability to switch administration routes without a need for dose adjustment. ClinicalTrials.gov identifier: NCT02882789 .

Purpose LCB01-0371 is a novel oxazolidinone broad-spectrum antibacterial that is more potent than linezolid against systemic infections in animals. The goal of this investigation was to evaluate the pharmacokinetics, pharmacodynamics, safety, and tolerability of multiple-dose LCB01-0371 as well as the pharmacokinetic characteristics of a new 400-mg tablet formulation. Methods : Thirty-two healthy male subjects received BID 400–1600 mg multiple oral dosing of LCB01-0371 (200-mg tablet or 400-mg tablet) for 7 days, and 6 subjects received an 800-mg single oral dose of LCB01-0371 (400-mg tablet). Safety assessments were undertaken at regular intervals. Blood and urine were sampled, and drug concentration and inhibitory and bactericidal titers were measured. Findings LCB01-0371 was generally safe and well tolerated up to 1200 mg BID for 7 days. Adverse events were mild, except for headache, nausea, and dizziness at the dose of 1600 mg, and resolved spontaneously. LCB01-0371 was absorbed rapidly within 2 h after administration, and its accumulation observed on day 7 ranged between 1.10- and 1.46-fold. The elimination t1/2 was 1.64–1.94 h, which remained unchanged across all doses. AUC0–12 and Cmax were not dose proportional across the dose range from 400 to 1200 mg after both single and multiple dosing, indicating a nonlinear pharmacokinetic profile. The percentage of the dose excreted via the urine ranged from 7.84% to 8.95%. The new (400-mg tablet) formulation exhibited less interindividual variability with pharmacokinetic characteristics similar to the original formulation (200-mg tablet). LCB01-0371 exhibited both early serum inhibitory and bactericidal activities against the 4 strains tested in the ex vivo pharmacodynamics study. Implications BID doses of LCB01-0371 up to 1200 mg for 7 days were well tolerated and exhibited rapid serum inhibitory and bactericidal activities against common gram-positive pathogens. The results warrant further clinical investigation of the antibacterial effect of BID LCB01-0371 administration. ClinicalTrial.gov identifier: NCT01842516 .

Background In type 2 diabetes mellitus therapy, fixed-dose combination (FDC) can offer not only benefits in glucose control via the combined use of agents, but also increase patient compliance. The aim of this study was to assess the pharmacokinetic equivalence of the high dose of the FDC tablet (gemigliptin/metformin sustained release [SR] 50/1,000 mg) and a corresponding co-administered dose of individual tablets. Methods This study was randomized, open-label, single dose, two treatments, two-period, crossover study, which included 24 healthy subjects. Subjects received the FDC or individual tablets of gemigliptin (50 mg) and metformin XR (1,000 mg) in each period. Geometric mean ratios (GMRs) and 90% confidence intervals (CIs) of maximum plasma concentration (Cmax) and area under the plasma concentration-time curve from time zero to the time of the last quantifiable concentration (AUClast) of the FDC tablet and co-administration of individual tablet for both gemigliptin and metformin were calculated. Results The GMRs (FDC tablets/co-administration; 90% CIs) for Cmax and AUClast of gemigliptin were 1.079 (0.986–1.180) and 1.047 (1.014–1.080), respectively. For metformin, the GMRs for Cmax, and AUClast were 1.038 (0.995–1.083) and 1.041 (0.997–1.088), respectively. The 90% CIs for GMRs of Cmax and AUClast for gemigliptin and metformin fell entirely within bounds of 0.800–1.250. Both administration of FDC tablet and co-administration of individual tablets were well tolerated. Conclusion FDC tablet exhibited pharmacokinetic equivalence and comparable safety and tolerability to co-administration of corresponding doses of gemigliptin and metformin XR as individual tablets. Trial registry at ClinicalTrials.gov, NCT02056600., Graphical Abstract

Objective The effects of various polymorphisms in cytochrome P450 (CYP) enzyme and transporter genes on the pharmacokinetics (PK) of simvastatin were evaluated in healthy Korean men. Methods Plasma concentration data for simvastatin and simvastatin acid were pooled from four phase I studies comprising 133 participants. The polymorphisms CYP2D6*4, CYP2D6*5, CYP2D6*14, CYP2D6*41, CYP3A5*3, CYP2C19*2, CYP2C19*3, CYP2A6*7, and CYP2A6*9; SLCO1B1 rs4149056, rs2306283, and rs4149015; ABCB1 rs1128503, rs2032582, and rs1045642; and ABCG2 rs2231142 were evaluated in each participant. Noncompartmental PK results were compared by genotype. Results CYP2D6*5 and CYP2D6*14 were found to be associated with a higher area under the curve (AUC) for simvastatin, whereas the AUC of simvastatin acid was significantly increased in patients with the SLCO1B1 rs4149056, ABCG2 rs2231142, and CYP2D6*41 allele variants. Patients with the CYP2D6*41 variant showed a higher peak serum concentration (Cmax) of both simvastatin and simvastatin acid. The SLCO1B1 rs4149056 and rs4149015 polymorphisms were associated with an increased AUC ratio (i.e. ratio of simvastatin acid to simvastatin), whereas the SLCO1B1 rs4149056 and CYP2D6*5 variants were related to a higher Cmax ratio. Conclusion The CYP2D6*5, CYP2D6*14, CYP2D6*41, CYP3A5*3, SLCO1B1 rs4149056 and rs4149015, and ABCG2 rs2231142 genetic polymorphisms are associated with the PK of both simvastatin and simvastatin acid. This could potentially be used as a basis for individualized simvastatin therapy by predicting the clinical outcomes of this treatment.

Purpose The purpose of this study was to evaluate the rate of pathologic complete response (pCR) in patients with locally advanced rectal cancer (LARC) treated with neoadjuvant chemoradiation therapy (CRT) with leucovorin (FL) versus irinotecan/S-1 (IS). Methods and Materials Patients with resectable LARC (clinical stage T3/4, lymph node positive, or both) were randomly assigned to receive preoperative radiation (45-50.4 Gy in 25 to 28 daily fractions) and concomitant chemotherapy either with a bolus injection of FL (400 mg/m 2 /day 5-fluorouracil and 20 mg/m 2 /day leucovorin) for 3 consecutive days every 4 weeks for 2 cycles (FL group) or with 40 mg/m 2 irinotecan on days 1, 8, 15, 22, and 29, and 35 mg/m 2 S-1 twice on the day of irradiation (IS group). Curative surgery was performed approximately 4 to 8 weeks after the completion of CRT. The postoperative chemotherapy regimen was FL with a primary endpoint of a pCR rate evaluation. Results One hundred forty-two eligible patients were randomly assigned, and the median follow-up duration was 43.8 months (95% confidence interval, 40.8-46.8 months). One hundred thirty-three patients (93.7%) of 142 underwent total mesorectal excision; pCR was achieved in 11 (16.7%) of 66 patients in the FL group and 17 (25.8%) of 67 patients in the IS group ( P =.246). When good responders were defined as patients with Mandard grades 1 and 2, the rate of good responders was significantly higher in the IS group than in the FL group (54.6% vs 36.4%, respectively, P =.036). The preoperative rates of grade 3 and 4 toxicities were higher in the IS group (7.0%) than in the FL group (1.4%, P =.095). The 3-year disease-free survival was not significantly different between the 2 groups (79.7% vs 76.6%, respectively, P =.896). Conclusions IS-based preoperative CRT did not increase pCR rate, but it did increase acute toxicities compared with standard 5-FU treatment. Therefore, further investigation is needed.