Histologic features and predicting prognosis in ulcerative colitis patients with mild endoscopic activity.

BACKGROUND/AIMS: We aimed to evaluate the histologic features predictive of prognosis and correlate them with endoscopic findings in patients with ulcerative colitis (UC) having complete or partial mucosal healing (MH). METHODS: We prospectively collected and reviewed data from patients with UC who underwent colonoscopy or sigmoidoscopy with biopsy. Complete and partial MH were defined as Mayo endoscopic subscores (MESs) of 0 and 1, respectively. Histologic variables, including the Nancy index (NI), predicting disease progression (defined as the need for medication upgrade or hospitalization/surgery), were evaluated and correlated with endoscopic findings. RESULTS: Overall, 441 biopsy specimens were collected from 194 patients. The average follow-up duration was 14.7 ± 7.4 months. There were 49 (25.3%) and 68 (35.1%) patients with MESs of 0 and 1, respectively. Disease progression occurred only in patients with an MES of 1. NI ≥ 3 was significantly correlated with disease progression during follow-up. Mucosal friability on endoscopy was significantly correlated with NI ≥ 3 (61.1% in NI < 3 vs. 88.0% in NI ≥ 3; p = 0.013). CONCLUSION: Histological activity can help predict the prognosis of patients with UC with mild endoscopic activity. Mucosal friability observed on endoscopy may reflect a more severe histological status, which can be a risk factor for disease progression.

Effects of prior endoscopic resection on recurrence in patients with T1 colorectal cancer who underwent radical surgery.

PURPOSE: Endoscopic resection (ER) is a reliable treatment for early colorectal cancer without lymph node metastasis. We aimed to examine the effects of ER performed prior to T1 colorectal cancer (T1 CRC) surgery by comparing long-term survival after radical surgery with prior ER to that after radical surgery alone. METHODS: This retrospective study included patients who underwent surgical resection of T1 CRC at the National Cancer Center, Korea, between 2003 and 2017. All eligible patients (n = 543) were divided into primary and secondary surgery groups. To ensure similar characteristics between the groups, 1:1 propensity score matching was used. Baseline characteristics, gross and histological features, along with postoperative recurrence-free survival (RFS) between the two groups were compared. Cox proportional hazard model was used to identify the risk factors affecting recurrence after surgery. Cost analysis was performed to examine the cost-effectiveness of ER and radical surgeries. RESULTS: No significant differences were observed in 5-year RFS between the two groups in matched data (96.9% vs. 95.5%, p = 0.596) and in the unadjusted model (97.2% vs. 96.8%, p = 0.930). This difference was also similar in subgroup analyses based on node status and high-risk histologic features. ER before surgery did not increase the medical costs of radical surgery. CONCLUSION: ER prior to radical surgery did not affect the long-term oncologic outcomes of T1 CRC or significantly increased the medical costs. Attempting ER first for suspected T1 CRC would be a good strategy to avoid unnecessary surgery without concerns of worsening cancer-related prognosis.

Sex-specific differences in colorectal cancer: A multicenter retrospective cohort study.

BACKGROUND: Due to sex-specific differences in the incidence and clinical and histopathological characteristics of colorectal cancer (CRC), understanding the impact of sex on CRC may suggest sex-targeted strategies for screening, treatment, and prevention, leading to improved prognosis of CRC. However, there have been few studies investigating the sex-specific differences in CRC in the Republic of Korea. We aimed to assess sex differences in CRC in the Republic of Korea. METHODS: This was a retrospective, multicenter, cohort study of patients diagnosed with CRC between January 2012 and December 2013 at nine hospitals. Patients who had an uncertain CRC stage, were diagnosed with other cancers within 5 years, had carcinoma in situ, non-epithelial cancer, or primary cancer other than CRC, were excluded. Factors associated with overall survival or progression-free survival were investigated using Cox regression analysis. Cumulative probability of metachronous lesions was compared using the Kaplan-Meier estimator survival analysis and we compared the survival curves of each group using a log-rank test. Outcomes were compared using the chi-square, Fisher's exact, or Student's t-test, as appropriate. RESULTS: Three thousand one hundred and forteen patients (1999 men, 1315 women) were included. There was no significant difference in the age at onset between men and women. The proportion of patients diagnosed through regular health check-ups, and asymptomatic at time of diagnosis, was higher in men (48.9% men vs. 42.0% women, p < .001). Rectal cancers were more common in men (38.8% men vs. 31.8% women, p < .001). Right colon cancers were more common in women (31.4% women vs. 22.7% men, p < .001). KRAS mutations were found in 109/317 (34.4%) women and 112/480 (23.3%) men. Overall CRC survival and progression-free survival were similar in both sexes. CONCLUSION: Sex differences in CRC may be due to the biological and social-behavioral differences between the sexes. They should be considered during screening, diagnosis, and treatment of CRC for better outcomes.

Capecitabine and temozolomide for metastatic intermediate to high-grade pancreatic neuroendocrine neoplasm: a single center experience.

BACKGROUND/AIMS: The combination of capecitabine and temozolomide (CAPTEM) is one of the treatment options for metastatic pancreatic neuroendocrine neoplasms (pNENs). This study aims to evaluate the efficacy of CAPTEM in patients with metastatic intermediate to high-grade pancreatic neuroendocrine tumor (pNET) or carcinoma (pNEC). METHODS: This study was conducted retrospectively in a single center. Patients were treated for intermediate to high-grade tumor with 750 mg/m² of capecitabine twice daily from day 1 to 14 and 200 mg/m² of temozolomide once daily from day 10 to 14, repeating twice in a cycle of 28 days. The primary outcomes were durations of overall survival (OS) and progression-free survival (PFS). The secondary outcomes consisted of objective response rate and disease control rate. RESULTS: A total of 12 patients (grade 2 NET in six, grade 3 NET in three, NEC in three patients) who received CAPTEM were included in this study. Patients received a median of five cycles (range, 2 to 46) of CAPTEM. The median dose combined 1,150 mg of capecitabine and 300 mg of temozolomide. The median OS and PFS were 41.2 months (range, 3.2 to 167) and 39.7 months (range, 2.1 to 100), respectively. Patients with NET had longer OS and PFS compared to those of patients with NEC (p = 0.002 and p = 0.028). High Ki-67 proliferative index (> 50%) was significantly associated with poor survival outcomes. CONCLUSION: CAPTEM showed favorable survival outcomes in patients with metastatic intermediate to high-grade pNENs. Our study supports that CAPTEM may be an effective treatment option for metastatic pNENs.

Tele-consent using mixed reality glasses (NREAL) in pediatric inguinal herniorrhaphy: a preliminary study.

There is an increasing demand and need for patients and caregivers to actively participate in the treatment process. However, when there are unexpected findings during pediatrics surgery, access restrictions in the operating room may lead to a lack of understanding of the medical condition, as the caregivers are forced to indirectly hear about it. To overcome this, we designed a tele-consent system that operates through a specially constructed mixed reality (MR) environment during surgery. We enrolled 11 patients with unilateral inguinal hernia and their caregivers among the patients undergoing laparoscopic inguinal herniorrhaphy between January through February 2021. The caregivers were informed of the intraoperative findings in real-time through MR glasses outside the operating room. After surgery, we conducted questionnaire surveys to evaluate the satisfaction and usefulness of tele-consent. We identified contralateral patent processus vaginalis in seven out of 11 patients, and then additionally performed surgery on the contralateral side with tele-consent from their caregivers. Most caregivers and surgeons answered positively about the satisfaction and usefulness of tele-consent. This study found that tele-consent with caregivers using MR glasses not only increased the satisfaction of caregivers and surgeons, but also helped to accommodate real-time findings by adapting surgical plan through the tele-consent.

Augmented Reality-Based Visual Cue for Guiding Central Catheter Insertion in Pediatric Oncologic Patients.

BACKGROUND: Pediatric hemato-oncologic patients require central catheters for chemotherapy, and the junction of the superior vena cava and right atrium is considered the ideal location for catheter tips. Skin landmarks or fluoroscopic supports have been applied to identify the cavoatrial junction; however, none has been recognized as the gold standard. Therefore, we aim to develop a safe and accurate technique using augmented reality technology for the location of the cavoatrial junction in pediatric hemato-oncologic patients. METHODS: Fifteen oncology patients who underwent chest computed tomography were enrolled for Hickman catheter or chemoport insertion. With the aid of augmented reality technology, three-dimensional models of the internal jugular veins, external jugular veins, subclavian veins, superior vena cava, and right atrium were constructed. On inserting the central vein catheters, the cavoatrial junction identified using the three-dimensional models were marked on the body surface, the tip was positioned at the corresponding location, and the actual insertion location was confirmed using a portable x-ray machine. The proposed method was evaluated by comparing the distance from the cavoatrial junction to the augmented reality location with that to the conventional location on x-ray. RESULTS: The mean distance between the cavoatrial junction and augmented reality location on x-ray was 1.2 cm, which was significantly shorter than that between the cavoatrial junction and conventional location (1.9 cm; P = 0.027). CONCLUSIONS: Central catheter insertion using augmented reality technology is more safe and accurate than that using conventional methods and can be performed at no additional cost in oncology patients.

A Liquid Chromatography - Tandem Mass Spectrometry Approach for the Identification of Mebendazole Residue in Pork, Chicken, and Horse.

A confirmatory and quantitative method of liquid chromatography-tandem mass spectrometry (LC-MS/MS) for the determination of mebendazole and its hydrolyzed and reduced metabolites in pork, chicken, and horse muscles was developed and validated in this study. Anthelmintic compounds were extracted with ethyl acetate after sample mixture was made alkaline followed by liquid chromatographic separation using a reversed phase C18 column. Gradient elution was performed with a mobile phase consisting of water containing 10 mM ammonium formate and methanol. This confirmatory method was validated according to EU requirements. Evaluated validation parameters included specificity, accuracy, precision (repeatability and within-laboratory reproducibility), analytical limits (decision limit and detection limit), and applicability. Most parameters were proved to be conforming to the EU requirements. The decision limit (CCα) and detection capability (CCß) for all analytes ranged from 15.84 to 17.96 µgkg-1. The limit of detection (LOD) and the limit of quantification (LOQ) for all analytes were 0.07 µgkg-1 and 0.2 µgkg-1, respectively. The developed method was successfully applied to monitoring samples collected from the markets in major cities and proven great potential to be used as a regulatory tool to determine mebendazole residues in animal based foods.

Effects of the ABCG2 and ABCB1 drug transporter polymorphisms on the pharmacokinetics of bicalutamide in humans.

BACKGROUNDS: Bicalutamide is an oral non-steroidal anti-androgen used in the treatment of prostate cancer. Drug transporters P-glycoprotein encoded by ABCB1 and breast cancer resistance protein (BCRP) encoded by ABCG2 are involved in the transportation of bicalutamide and its treatment failure. We evaluated the roles of ABCB1 and ABCG2 genetic polymorphisms in the pharmacokinetics of bicalutamide in humans. METHODS: After a single oral dose of 150mg bicalutamide was administered, plasma concentrations of bicalutamide were measured, and pharmacokinetic analyses were performed in 27 healthy subjects according to ABCB1 (c.1236C>T, c.2677G>T/A, and c.3435C>T) and ABCG2 (c.34G>A and c.421C>A). RESULTS: ABCB1 polymorphisms did not affect the plasma levels of bicalutamide and the pharmacokinetic parameters did not differ among ABCB1 genotype groups. However, the ABCG2 c.421C>A polymorphism significantly influenced the plasma levels and pharmacokinetics of bicalutamide gene dose-dependently. CONCLUSIONS: The ABCB1 genetic polymorphisms did not influence the pharmacokinetics of bicalutamide. However, ABCG2 c.421C>A significantly and gene dose-dependently influenced its pharmacokinetics, but c.34G>A did not.

Multiplex pyrosequencing method to determine CYP2C9*3, VKORC1*2, and CYP4F2*3 polymorphisms simultaneously: its application to a Korean population and comparisons with other ethnic groups.

Warfarin is an anticoagulant that is difficult to administer because of the wide variation in dose requirements to achieve a therapeutic effect. CYP2C9, VKROC1, and CYP4F2 play important roles in warfarin metabolism, and their genetic polymorphisms are related to the variability in dose determination. In this study we describe a new multiplex pyrosequencing method to identify CYP2C9*3 (rs1057910), VKORC1*2 (rs9923231), and CYP4F2*3 (rs2108661) simultaneously. A multiplex pyrosequencing method to simultaneously detect CYP2C9*3, VKORC1*2, and CYP4F2*3 alleles was designed. We assessed the allele frequencies of the polymorphisms in 250 Korean subjects using the multiplex pyrosequencing method. The results showed 100 % concordance between single and multiplex pyrosequencing methods, and the polymorphisms identified by pyrosequencing were also validated with the direct sequencing method. The allele frequencies of these polymorphisms in this population were as follows: 0.040 for CYP2C9*3, 0.918 for VKORC1*2, and 0.416 for CYP4F2*3. Although the allele frequencies of the CYP2C9*3 and VKROC1*2 were comparable to those in Japanese and Chinese populations, their frequencies in this Korean population differed from those in other ethnic groups; the CYP4F2*3 frequency was the highest among other ethnic populations including Chinese and Japanese populations. The pyrosequencing methods developed were rapid and reliable for detecting CYP2C9*3, VKORC1*2, and CYP4F2*3. Large ethnic differences in the frequency of these genetic polymorphisms were noted among ethnic groups. CYP4F2*3 exhibited its highest allele frequency among other ethnic populations compared to that in a Korean population.

Influence of ABCB1 and CYP3A5 genetic polymorphisms on the pharmacokinetics of quetiapine in healthy volunteers.

BACKGROUND AND OBJECTIVES: Quetiapine is an atypical antipsychotic drug used to treat schizophrenia and acute episodes of mania. Quetiapine is metabolized by CYP3A enzymes including CYP3A5 and is a substrate of P-glycoprotein, an efflux drug transporter encoded by the ABCB1 gene. We assessed the effects of ABCB1 [c.1236C>T (rs1128503), c.2677G>T/A (rs2032582), c.3435C>T (rs1045642)] and CYP3A5*3 (6986A>G) (rs776746) polymorphisms on the pharmacokinetics of quetiapine in humans. MATERIALS AND METHODS: Forty healthy male individuals were enrolled, and their ABCB1 and CYP3A5 polymorphisms were assessed. After a single dose of 100 mg quetiapine was administered, plasma concentrations of quetiapine were measured for 24 h and pharmacokinetic analysis was carried out. RESULTS: The ABCB1 polymorphisms including c.1236C>T, c.2677G>T/A, and c.3435C>>T did not affect plasma levels of quetiapine, and its pharmacokinetic parameters did not differ among ABCB1 genotype groups. However, the CYP3A5*3 polymorphism significantly affected the plasma level of quetiapine and its pharmacokinetics. The peak plasma concentration of quetiapine was 208.39 ng/ml for CYP3A5*1/*1, 243.46 ng/ml for CYP3A5*1/*3, and 332.94 ng/ml for CYP3A5*3/*3 (P=0.0118). The mean AUC(inf) (area under the time vs. concentration curve from 0 to infinity) value was 627.3, 712.77, and 1045.29 ng h/ml, respectively (P=0.0017). CONCLUSION: The results indicated that the genetic polymorphism of CYP3A5*3 but not ABCB1 significantly influences the plasma level of quetiapine and its pharmacokinetics. These findings suggest that the CYP3A5 genetic polymorphism affects the disposition of quetiapine and provide a plausible explanation for interindividual variation in the disposition of this drug.

Effects of polymorphisms of the SLCO2B1 transporter gene on the pharmacokinetics of montelukast in humans.

Montelukast, a leukotriene receptor antagonist, is a substrate of organic anion transporting OATP2B1 encoded by the SLCO2B1. We evaluated the effects of six non-synonymous (c.1175C>T, c.1457C>T, c.43C>T, c.935G>A, c.601G>A, and c.644A>T) polymorphisms and one promoter (g.-282G>A) polymorphism on the pharmacokinetics of montelukast. A single dose of 10 mg montelukast was administered in 24 healthy subjects. Its levels were measured up to 24 hours and a pharmacokinetic analysis was performed based on the SLCO2B1 polymorphisms. We did not encounter subjects with c.1175C>T, c.43C>T, or c.644A>T polymorphisms. The remaining SLCO2B1 polymorphisms did not affect plasma levels of montelukast, and pharmacokinetic parameters of montelukast did not differ among genotype groups. Oral clearance results were as follows: (1) 3.3 L/h for c.935GG, 3.0 L/h for c.935GA, and 3.5 L/h for c.935AA; (2) 3.4 L/h for c.1457CC, 2.9 L/h for c.1457CT, and 3.2 L/h for c.1457TT; (3) 3.2 L/h for c.601GG, 3.4 L/h for c.601GA, and 3.4 L/h for c.601AA; (4) 3.2 L/h for g.-282GG, 3.4 L/h for g.-282GA, and 3.2 L/h for g.-282AA. The findings suggest that SLCO2B1 polymorphisms do not affect the pharmacokinetics of montelukast and that SLCO2B1 polymorphisms appear to be a minor determinant of inter-individual variability of montelukast.

Effect of P2Y1 and P2Y12 genetic polymorphisms on the ADP-induced platelet aggregation in a Korean population.

BACKGROUND: P2Y1 and P2Y12 receptors are expressed in platelet membranes and are involved in ADP-induced platelet aggregation. Genetic polymorphisms of P2Y1 and P2Y12 play a major role in the variation of ADP-induced platelet aggregation and in response in antiplatelet therapy. OBJECTIVE: To evaluate the allele frequencies of P2Y1 and P2Y12 genetic polymorphisms in a Korean population and to assess their role in ADP (5 µmol/L)-induced maximal platelet aggregation. METHODS: P2Y1 (c.1622A>G) and P2Y12 (i-139C>T, i-744T>C, i-ins801, c.52G>T, c.34C>T) polymorphisms were analyzed in 158 Korean healthy participants using pyrosequencing methods. Their ADP-induced maximal platelet aggregation was assessed by the turbidometric method. RESULTS: The observed allele frequencies of P2Y1 and P2Y12 were as follows: 0.3101 for P2Y1 c.1622A>G; 0.1804 for P2Y12 i-139C>T, 0.1804 for i-744T>C, 0.1804 for i-801insA, 0.1266 for P2Y12 c.52G>T, and 0.2658 for P2Y12 c.34C>T. ADP-induced maximal platelet aggregation was not influenced by the P2Y1 c.1622A>G polymorphism and was also not affected by three intronic P2Y12 polymorphisms and the P2Y12 c.34C>T polymorphism. However, the P2Y12 c.52G>T polymorphism caused a substantial difference in ADP-induced maximal platelet aggregation (62.75% for c.52GG, 66.27% for c.52GT, and 80.60% for c.52TT; P=0.0092). CONCLUSIONS: The P2Y1 and P2Y12 genes were very polymorphic in a Korean population. Three intronic P2Y12 polymorphisms (i-139C>T, i-744T>C, i-801insA) were in complete linkage disequilibrium but not with the c.52C>T polymorphism in this population. Maximal platelet aggregation in response to ADP is associated with the c.52C>T polymorphism but not with the three intronic polymorphisms or the P2Y1 c.1622A>T polymorphism.

SLCO2B1 genetic polymorphisms in a Korean population: pyrosequencing analyses and comprehensive comparison with other populations.

SLCO2B1, also known as OATP2B1 (Organic Anion Transporter) or OATP-B or SLC21A9, is an organic anion uptake transporter that is encoded by the SLCO2B1 gene. In this study we assessed the frequencies of SLCO2B1 polymorphisms in a Korean population using newly developed pyrosequencing methods and compared their frequencies with those in other ethnic groups. We developed pyrosequencing methods to identify the following six SLCO2B1 non-synonymous polymorphisms: c.1175C > T (rs1621378), c.1457C > T (rs2306168), c.43C > T (rs56837383), c.935G > A (rs12422149), c.601G > A (rs35199625) and c.644A > T (rs72559740). The allele frequencies of these polymorphisms were analyzed in 227 Korean subjects. The allele frequencies of SLCO2B1 polymorphisms in the population tested were as follows: 0.0 for c.1175C > T, c.43C > T and c.644A > T; 0.2687 for c.1457C > T; 0.4273 for c.935G > A; and 0.0727 for c. 601G > A. Even though the allele frequencies of the c.1175C > T and c.1457C > T polymorphisms were comparable to those in Japanese subjects, the frequencies in this Korean population differed from those in other ethnic groups. The developed pyrosequencing methods are rapid and reliable for detecting non-synonymous SLCO2B1 polymorphisms. Large ethnic differences in the frequency of SLCO2B1 genetic polymorphisms were noted among ethnic groups. The SLCO2B1 polymorphisms at c.1175C > T, c.43C > T and c.644A > T were not found in the Korean population while c.1457C > T, c.935G > A and c.601G > A exhibited mostly higher frequencies in Koreans compared with Finnish, Caucasian and African-American populations.

Influence of orthodontic adhesives and clean-up procedures on the stain susceptibility of enamel after debonding.

OBJECTIVE: To determine the influence of the type of orthodontic adhesive system, such as conventional acid-etching (CE) and self-etching primers (SEPs), on the stain susceptibility of enamel surface after debonding. Effects of clean-up procedures on the enamel surface were also determined. MATERIALS AND METHODS: Two types and four brands of adhesive systems were investigated using 135 human premolars. Unbonded teeth were used as controls. Three-dimensional scanning of the enamel surface was performed before bracket bonding, after debonding, and after clean-up procedures. The color of each tooth was measured before bracket bonding and again after debonding and clean-up procedures. This was followed by methylene blue staining. The stain susceptibility of the enamel surface was measured after finishing only (F-condition) and after finishing/polishing (FP-condition). RESULTS: After debonding, the amount of residual adhesive resins in CE materials was greater than that in SEP materials. For the F-condition, staining color change in SEP materials was significantly higher than that in CE materials. For the FP-condition, staining color change in both CE and SEP materials was not different from those of the control. CONCLUSIONS: The SEP system would show less stain susceptibility if the thin residual adhesive resin layer after debonding is removed by polishing.

Effect of ABCG2 genotypes on the pharmacokinetics of A771726, an active metabolite of prodrug leflunomide, and association of A771726 exposure with serum uric acid level.

OBJECTIVE: It has been reported that leflunomide and its active metabolite, A771726, are substrates of the ABCG2 (BCRP) transporter in vitro. Recent genome-wide association studies have shown that ABCG2 transporter modulates serum uric acid (UA) levels. We explored the role of ABCG2 genotypes in the pharmacokinetics of A771726 and the relationship between serum UA levels and pharmacokinetics of A771726 in healthy participants. METHODS: Twenty-four healthy individuals were recruited and genotyped for ABCG2. After administration of a single dose of 20 mg leflunomide, plasma concentrations of A771726 were measured. Serum UA levels were measured just before medication, and ABCG2 c.421C>A and c.34G> A polymorphism were genotyped. RESULTS: ABCG2 c.421C>A but not c.34G>A substantially influenced the pharmacokinetics of A771726. A771726 C(max) was 30% higher, area under the concentration-time curve (AUC) 83% larger, and oral clearance (CL/F) 41% lower in c.421C>A carriers than in noncarriers. Serum UA levels were also higher in carriers than in noncarriers and exhibited a strong and positive correlation with A771726 AUC (Spearman r = 0.6746, P = 0.0003), but a negative correlation was observed with A771726 CL/F (Spearman r = -0.6616, P = 0.0004). CONCLUSION: ABCG2 c.421C>A but not c.34G>A polymorphism appears to be a major determinant of interindividual variability in A771726 disposition. Additionally, serum UA levels exhibited a strong correlation with exposure to A771726.