Non-alcoholic Fatty Liver Disease (NAFLD) and its association with kidney and cardiovascular outcomes in moderate to advanced chronic kidney disease.

Introduction Non-alcoholic fatty liver disease (NAFLD) has emerged as a potential indicator for cardio-metabolic risk. However, clinical implications of NAFLD in patients with chronic kidney disease (CKD) are still elusive. We investigated to explore the association between NAFLD and adverse clinical outcomes among patients with CKD. Methods In this national population-based retrospective cohort study, we analyzed 816,857 individuals who underwent National Health Insurance Service health examinations and had an eGFR of 15-59 mL/min/1.73 m2. The main predictor was the fatty liver index (FLI), a surrogate marker for NAFLD. The primary outcome was a composite cardiovascular or kidney events, which were examined combined or separately. Results During a median follow-up of 7.7 (IQR, 6.4-9.6) years, the composite outcome events occurred in 74,266 (9.1%) individuals. Among these, there were 55,525 (6.8%) cardiovascular events and 22,961 (2.8%) kidney events, respectively. Compared to FLI of <30, the HRs (95% CIs) for the composite outcome were 1.16 (1.14-1.18) and 1.30 (1.26-1.33) for the FLIs of 30-59 and ≥60, respectively. The corresponding HRs for cardiovascular events were 1.21 (95% CI, 1.18-1.23) and 1.36 (95% CI, 1.31-1.40), respectively. Furthermore, FLIs of 30-59 and ≥60 were associated with an 11% (HR, 1.11; 95% CI, 1.07-1.15) and 24% (HR, 1.24; 95% CI, 1.17-1.30) increased risk of kidney events, respectively. Conclusions NAFLD was associated with higher risk of adverse clinical outcomes in individuals with CKD. These findings suggest that NAFLD, as assessed by the FLI, can serve as a predictor of cardiovascular and kidney events in CKD population.

Safety and feasibility of reduced-port robotic distal gastrectomy for gastric cancer: a phase I/II clinical trial.

INTRODUCTION: Theoretically, reducing the number of ports required in minimally invasive surgery for gastric cancer would further minimize trauma associated therewith. Advances in single-site surgery have afforded surgeons the ability to perform reduced-port distal gastrectomy via a robotic approach using the Single-Site™ system, eliminating restrictions on the movement of surgical instruments. METHODS: This phase I/II study was designed as a single-arm prospective trial of reduced-port robotic distal gastrectomy (RRDG) by a single surgeon (NCT02347956). From January to October 2015, 40 individuals scheduled to undergo robotic surgery for early gastric cancer were asked to participate in the trial. Nineteen were enrolled and underwent RRDG. The primary endpoints were 30-day morbidity and mortality. RESULTS: No intraoperative event requiring conversion to laparoscopic or open surgery occurred, and no major complication was observed following RRDG (0.0% [80% CI (0.0-11.4%)]). Medians of operation time, blood loss, the number of retrieved lymph nodes, days until gas passing, and hospital stay were 190 min, 20 mL, 48, 3, and 5 days, respectively. CONCLUSIONS: Deemed safe and feasible through the present trial, RRDG could be a valid alternative to conventional robot distal gastrectomy for managing early gastric cancer. Our reduced-port robotic surgery using the Single-Site system and a third robotic arm could potentially be applicable as a highly advanced, minimally invasive surgery for other solid organ diseases.

Multicenter Prospective Comparative Study of Robotic Versus Laparoscopic Gastrectomy for Gastric Adenocarcinoma.

OBJECTIVE: To compare short-term surgical outcomes including financial cost of robotic and laparoscopic gastrectomy. BACKGROUND: Despite a lack of supporting evidence, robotic surgery has been increasingly adopted as a minimally invasive modality for the treatment of gastric cancer because of its assumed technical superiority over conventional laparoscopy. METHODS: A prospective, multicenter comparative study was conducted. Patients were matched according to the surgeon, extent of gastric resection, and sex. The primary endpoint was morbidity and mortality. Outcomes were analyzed on an intention-to-treat and per-protocol basis. RESULTS: A total of 434 patients were enrolled for treatment with either robotic (n = 223) or laparoscopic (n = 211) gastrectomy for intention-to-treat analysis, and a total of 370 patients (n = 185 per treatment) were compared in per-protocol analysis. Results were similar between both analyses. In per-protocol analysis, both groups showed similar overall complication rates (robotic = 11.9% vs laparoscopic = 10.3%) and major complication rates (robotic = 1.1% vs laparoscopic = 1.1%) with no operative mortality in either group. Patients treated with robotic surgery showed significantly longer operative time (robotic = 221 minutes vs laparoscopic = 178 minutes; P < 0.001) and significantly higher total costs (robotic = US$13,432 vs laparoscopic = US$8090; P < 0.001), compared with those who underwent laparoscopic gastrectomy. No significant differences between groups were noted in estimated blood loss, rates of open conversion, diet build-up, or length of hospital stay. CONCLUSIONS: The use of robotic systems is assumed to provide a technically superior operative environment for minimally invasive surgery. However, our analysis of perioperative surgical outcomes indicated that robotic gastrectomy is not superior to laparoscopic gastrectomy. Clinical trials identification: NCT01309256.

Bone alkaline phosphatase as a surrogate marker of bone metastasis in gastric cancer patients.

BACKGROUND: Bone metastasis is relatively uncommon in gastric cancer patients, but its incidence has been rising. Early detection of bone metastasis is important in preventing complications related to bone metastasis such as pain, fracture and the compromise of chemotherapy. In this pilot study, we investigated the feasibility of bone turnover markers as surrogate markers of bone metastasis in gastric cancer patients. METHODS: Fifty-eight patients with gastric cancer were included in this study. Serum levels of bone alkaline phosphatase (ALP), parathyroid hormone (PTH), 25(OH) D, osteocalcin (OC) and C terminal telopeptide were measured and compared between patients with bone metastasis and those without. Student's t-test and Mann-Whitney U test were used in comparing two groups, and Spearman's rank order correlation coefficient was calculated to quantify the strength of the associations. RESULTS: Fifty eight age- and sex-matched patients were evaluated for bone turnover markers, among whom 29 patients had bone metastasis and 29 patients with no bone metastasis. The median age was 62 and there were 20 (68.9 %) males and 9 (31.1 %) females in each group. Bone ALP was significantly higher in the patient group (57.32 ± 46.83 vs. 34.57 ± 21.57, P = 0.037) than control group. Bone ALP was positively associated with ALP, osteocalcin, CA19-9, CA 72-4 and negatively associated with 25(OH) D. According to ROC-curve analysis, at the threshold value of 29.60 µg/L, the sensitivity of bone ALP was 76.7 % and the specificity was 59.4 %. CONCLUSION: Bone ALP may be a surrogate marker of bone metastasis in gastric cancer patients. More prospective studies are warranted to determine the optimal bone turnover markers in the evaluation of bone metastasis.

Comparison of perioperative surgical outcomes between a bipolar device and an ultrasonic device during laparoscopic gastrectomy for gastric cancer.

BACKGROUND: The use of energy devices during laparoscopic gastrectomy for gastric cancer has increased as the frequency of laparoscopic surgery has increased. Our aim was to compare the perioperative surgical outcomes between using a bipolar device and an ultrasonic device during laparoscopic gastrectomy. METHODS: Retrospective review of a prospectively maintained database identified 186 patients who underwent laparoscopic gastrectomy performed by a single surgeon between November 2010 and August 2013. A bipolar device was used for 116 patients, and an ultrasonic device was used for 70 patients. Patient characteristics and perioperative surgical outcomes were compared between groups. RESULTS: Clinicopathologic characteristics were similar for both groups. The bipolar group had a significantly shorter operation time (154.9 vs. 167.8 min, p = 0.028) and higher rate of D2 lymph node dissection (29.3 vs. 15.7 %, p = 0.012). The bipolar device group experienced significantly less pain at 12 h [visual analog scale (VAS) pain score: 3.9 vs. 4.7, p = 0.027) and 18 h (VAS pain score: 3.5 vs. 4.1, p = 0.036) postoperatively. The bipolar group had earlier abdominal drain removal (p = 0.001) and a shorter hospital stay (p = 0.024). No significant differences in laboratory value changes, morbidity, or mortality were observed between the groups. CONCLUSION: Compared with the ultrasonic device, the bipolar device provided advantages in operation time, degree of postoperative pain, time of drain removal, and length of hospital stay. The bipolar device may be a useful and efficient energy device for laparoscopic gastrectomy. However, larger studies to confirm the safety of bipolar device during laparoscopic gastrectomy are warranted.

Standardization of D2 lymphadenectomy and surgical quality control (KLASS-02-QC): a prospective, observational, multicenter study [NCT01283893].

BACKGROUND: Extended systemic lymphadenectomy (D2) is standard procedure for surgical treatment of advanced gastric cancer (AGC) although less extensive lymphadenectomy (D1) can be applied to early gastric cancer. Complete D2 lymphadenectomy is the mandatory procedure for studies that evaluate surgical treatment results of AGC. However, the actual extent of D2 lymphadenectomy varies among surgeons because of a lacking consensus on the anatomical definition of each lymph node station. This study is aimed to develop a consensus for D2 lymphadenectomy and also to qualify surgeons that can perform both laparoscopic and open D2 gastrectomy. METHODS/DESIGN: This (KLASS-02-QC) is a prospective, observational, multicenter study to qualify the surgeons that will participate in the KLASS-02-RCT, which is a prospective, randomized, clinical trial comparing laparoscopic and open gastrectomy for AGC. Surgeons and reviewers participating in the study will be required to complete a questionnaire detailing their professional experience and specific gastrectomy surgical background/training, and the gastrectomy metrics of their primary hospitals. All surgeons must submit three laparoscopic and three open D2 gastrectomy videos, respectively. Each video will be allocated to five peer reviewers; thus each surgeon's operations will be assessed by a total of 30 reviews. Based on blinded assessment of unedited videos by experts' review, a separate review evaluation committee will decide whether or not the evaluated surgeon will participate in the KLASS-02-RCT. The primary outcome measure is each surgeon's proficiency, as assessed by the reviewers based on evaluation criteria for completeness of D2 lymphadenectomy. DISCUSSION: We believe that our study for standardization of D2 lymphadenectomy and surgical quality control (KLASS-02-QC) will guarantee successful implementation of the subsequent KLASS-02-RCT study. After making consensus on D2 lymphadenectomy, we developed evaluation criteria for completeness of D2 lymphadenectomy. We also developed a unique surgical standardization and quality control system that consists of recording unedited surgical videos, and expert review according to evaluation criteria for completeness of D2 lymphadenectomy. We hope our systematic approach will set a milestone in surgical standardization that is essential for surgical clinical trials. Additionally, our methods will serve as a novel system for educating surgeons and assessing surgical proficiency. TRIAL REGISTRATION: NCT01283893.

Association of systolic blood pressure with incident chronic kidney disease estimated by marginal structural model: a nationwide population-based study.

Background: We aimed to investigate the association between systolic blood pressure (SBP) and risk of incident chronic kidney disease (CKD) using marginal structural model (MSM) to reflect mutual effects of exposure and confounders on the outcome. Methods: A total of 195,970 adults with an estimated glomerular filtration rate (eGFR) of >60 mL/min/1.73 m2 and no proteinuria were included from a nationally representative sample cohort of Korean population. SBPs were measured through national health examinations. Primary outcome was incident CKD, defined as a composite of events of a decrease in eGFR to <60 mL/min/1.73 m2 or a newly developed proteinuria for at least two consecutive measurements. The association between SBP and risk of CKD was examined using Cox model, time-dependent Cox model, and MSM. Results: During a follow-up of 5 years, CKD occurred in 3,355 participants (1.7%). With SBP treated as a continuous variable, each 10-mmHg increment was associated with higher risk for incident CKD, regardless of analytical models used. Compared to SBP group of 120-129 mmHg, hazard ratios (95% confidence intervals) for incident CKD for SBP groups of <110, 110-119, 130-139, and ≥140 mmHg in MSM were 0.70 (0.62-0.80), 0.85 (0.77-0.95), 1.16 (1.05-1.27), and 1.63 (1.47-1.80), respectively. Conclusion: In this nationwide study, we found a significant relationship between higher SBP and higher risk of incident CKD. Further studies are warranted to verify the potential significance of high SBP as a preventable risk factor for the development of CKD in those with preserved renal function.

Safety and feasibility of reduced-port robotic distal gastrectomy for gastric cancer: a phase I/II clinical trial using the da Vinci Single Port(SP) robotic system.

Minimally invasive surgery reduces surgical trauma and the size and number of incisions. The da Vinci SP robotic surgical system was designed to overcome the technical demands of single-incision laparoscopic surgery. This study aimed to demonstrate the safety and feasibility of single-port (SP) robotic distal gastrectomy (SPRDG) for patients with gastric cancer using the da Vinci SP system (Intuitive Surgical Inc., Sunnyvale, CA, USA). This study was designed as a single-arm prospective phase I/II clinical trial of SPRDG (first posted date: 21/09/2021, NCT05051670; clinicaltrials.gov). SPRDG using the da Vinci SP system was performed on 19 patients with gastric cancer between December 2021 and October 2022. The primary outcome was the safety of SPRDG as measured by major postoperative complications. The secondary outcomes were operation time, bleeding amount, bowel motility recovery, and length of hospital stay. SPRDG was performed in all 19 patients without unexpected events, such as use of additional trocars or conversion to laparoscopic or open surgery. No major complications occurred postoperatively (0/19, 0.0%). The mean operation time was 218 min (range 164-286 min). The mean hospital stay duration was 3.2 days (range 2-4 days). This phase I/II clinical trial, performed by a single expert surgeon, demonstrated the safety and feasibility of SPRDG with the da Vinci SP system in selected patients with gastric cancer. SPRDG could be a reasonable alternative to conventional or reduced-port minimally invasive gastrectomy, as it has cosmetic advantages, early recovery, and safe discharge.

Fluorescence-guided Two-port Robotic Gastrectomy Versus Conventional Laparoscopic Gastrectomy: A Nonrandomized Controlled Trial.

Objective: To compare the number of retrieved lymph nodes between conventional laparoscopic gastrectomy (CLG) and robotic gastrectomy integrated with fluorescence guidance and a two-port system (integrated robotic gastrectomy, IRG). Background: The benefits of robotic surgery over laparoscopic surgery for gastric cancer have not yet been established. Using built-in features of robotic system, further benefit can be provided to the patients with effective lymphadenectomy and enhanced recovery. Methods: A nonrandomized controlled trial was performed by a single surgeon at single-center, tertiary referral hospital between January 2018 and October 2021. Overall, 140 patients scheduled to undergo minimally invasive subtotal gastrectomy for early gastric cancer were enrolled. The primary endpoint was the number of retrieved lymph nodes. Secondary endpoints were complications, hospital stay, pain score, body image, and operative cost. Results: This study analyzed 124 patients in the per-protocol group (IRG, 64; CLG, 60). The number of retrieved lymph nodes was higher in the IRG group than those in the CLG group (IRG vs CLG; 42.1 ± 17.9 vs 35.1 ± 14.6, P = 0.019). Moreover, other surgical parameters, such as hospital stay (4.1 ± 1.0 vs 5.2 ± 1.8, P < 0.001) and body image scale (better in 4 of the 10 questions), were significantly better in the IRG than in the CLG. Conclusions: Robotic surgical procedures integrated with fluorescence guidance and a reduced-port system yielded more retrieved lymph nodes. In addition, the IRG group showed better perioperative surgical outcomes, particularly regarding the length of hospital stay and postoperative body image. Trial registration: NCT03396354.

Cost-effective mammography screening in Korea: high incidence of breast cancer in young women.

The epidemiological characteristics of breast cancer in Korean women are different from the characteristics reported in Western women. The highest incidence rate occurs in Korean women in their 40s. The purpose of this study was to determine the most cost-effective screening interval and target age range for Korean women from the perspective of the national healthcare system. A stochastic model was used to simulate breast cancer screenings by varying both the screening intervals and the age ranges. The effectiveness of mammography screening was defined as the probability of detecting breast cancer in the preclinical state and the cost was based on the direct cost of mammography screening and the confirmative tests. The age-specific mean sojourn times and the sensitivity of the mammography were applied in the stochastic model. An optimal cost-effectiveness was determined by the incremental cost-effectiveness ratio and lifetime schedule sensitivity. Sensitivity analyses were undertaken to assess parameter uncertainty. The selected cost-effective strategies were: (1) the current biennial mammography screenings for women who are at least 40 years old; (2) biennial screening for women between the ages of 35 and 75 years; and (3) a combination strategy consisting of biennial screening for women aged between 45 and 54 years, and 3-year interval screening for women aged between 40 and 44 years and 55 and 65 years. Further studies should follow to investigate the effectiveness of mammography screening in women younger than 40 years in Asia as well as in Korea.

Soy food consumption and risk of prostate cancer: a meta-analysis of observational studies.

Soybean products have been suggested to have a chemo preventive effect against prostate cancer. The aim of this study was to provide a comprehensive meta-analysis on the extent of the possible association between soy-based food consumption and the risk of prostate cancer. Five cohort studies and 8 case-control studies were identified using MEDLINE, EMBASE, CINAHL, Korea Medical Database, KoreaMed, Korean studies Information Service System, Japana Centra Revuo Medicina, China National Knowledge Infrastructure, and a manual search. Summary odds ratios (ORs) comparing high versus low categories of soybean consumptions were calculated on the basis of the random effect model. We analyzed the associations based on the different types of soybean consumptions. The summary ORs (95% CI) for total soy foods were 0.69 (CI = 0.57-0.84) and 0.75 (CI = 0.62-0.89) for nonfermented soy foods. Among individual soy foods, only tofu yielded a significant value of 0.73 (CI = 0.57-0.92). Consumption of soybean milk, miso, or natto did not significantly reduce the risk of prostate cancer. Genistein and daidzein were associated with a lower risk of prostate cancer. This systematic review suggests that soy food consumption could lower the risk of prostate cancer. This conclusion, however, should be interpreted with caution because various biases can affect the results of a meta-analysis.

Effects of Gelidium elegans on Weight and Fat Mass Reduction and Obesity Biomarkers in Overweight or Obese Adults: A Randomized Double-Blinded Study.

The edible seaweed Gelidium elegans (GEE) is known to inhibit adipocyte differentiation. However, there has been no report on its effects in humans. In this study, we investigated whether GEE reduces body weight or fat mass in obese or overweight individuals. A total of 78 participants were randomly assigned to the test (GEE extract 1000 mg/day) and placebo groups at a 1:1 ratio, and treated for 12 weeks. At six or 12 weeks after randomization, they were evaluated for anthropometric parameters, biomarkers, and body composition. Changes in body weight and fat mass between the two groups was significantly different, as determined using ANCOVA adjusted for baseline, calorie intake, and physical activity. Body weight and fat mass were significantly decreased by GEE after 12 weeks but increased in the placebo group. Moreover, although not significant, triglyceride levels tended to decrease after GEE intake. There was no significant difference in other laboratory biomarkers between the two groups. Taken together, these results suggested that GEE significantly reduced body weight, especially fat mass, in overweight or obese individuals.

Estimating age group-dependent sensitivity and mean sojourn time in colorectal cancer screening.

OBJECTIVE: In evaluating the efficacy of cancer screening programmes, sojourn time (duration of the preclinical detectable phase) and sensitivity of the screening test are the two key parameters. Studies suggest that in breast cancer screening, both parameters may vary depending on age at the time of screening, but few studies have examined other cancers. We expanded an existing probability model for periodic screening by performing simultaneous estimation of age group-dependent and sensitivity at preclinical onset time, and tested the expanded model using data from the Korean National Colorectal Cancer Screening Programme. METHODS: Simulation studies were conducted to assess the performance of the proposed probability model. The method was then applied to the analysis of 376,542 participants aged 50 or over who underwent fecal occult blood testing (FOBT) as part of the National Colorectal Cancer Screening Programme between 2004 and 2007. Age group-dependent mean sojourn time and screening sensitivity of FOBT for colorectal cancer were derived using maximum likelihood estimation. RESULTS: The method performed well in terms of bias, standard deviation, and coverage probability. National Colorectal Cancer Screening Programme data results indicated that the sensitivity of FOBT to detect colorectal cancer increases with age, while mean sojourn time decreases with age (approximately 4.3 years for participants aged 50-54, 3.9 years at age 55-59, 3.4 years at age 60-64, and 3.6 years at age 65-69, with corresponding sensitivity estimates around 41%, 47%, 45%, and 51%, respectively). CONCLUSION: Simulation studies showed that the proposed stochastic model considering both mean sojourn time and sensitivity yields highly accurate results.

Early detection of colorectal cancer based on presence of methylated syndecan-2 (SDC2) in stool DNA.

BACKGROUND: Colorectal cancer (CRC) screening can effectively reduce disease-related mortality by detecting CRC at earlier stages. We have previously demonstrated that the presence of SDC2 methylation in stool DNA is significantly associated with the occurrence of CRC regardless of clinical stage. The aim of this study was to evaluate the clinical performance of stool DNA-based SDC2 methylation test for CRC. METHODS: Aberrant SDC2 methylation in stool-derived DNA was measured by linear target enrichment (LTE)-quantitative methylation-specific real-time PCR (qMSP). Duplicate reactions of meSDC2 LTE-qMSP test were performed for stool samples obtained from CRC patients representing all stages (0-IV) and asymptomatic individuals who were subsequently underwent colonoscopy examination. To determine the diagnostic value of test in CRC and control groups, sensitivity and specificity were evaluated by receiver operating characteristic curve analysis. RESULTS: Of 585 subjects who could be evaluated, 245 had CRC, 44 had various sizes of adenomatous polyps, and 245 had negative colonoscopy results. Stool DNA-based meSDC2 LTE-qMSP showed an overall sensitivity of 90.2% with AUC of 0.902 in detecting CRC (0-IV) not associated with tumor stage, location, sex, or age (P > 0.05), with a specificity of 90.2%. Sensitivity for detecting early stages (0-II) was 89.1% (114/128). This test also detected 66.7% (2/3) and 24.4% (10/41) of advanced and non-advanced adenomas, respectively. CONCLUSIONS: Results of this study validated the capability of stool DNA based-SDC2 methylation test by LTE-qMSP for early detection of CRC patient with high specificity. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03146520 , Registered 10 May 2017, Retrospectively registered; however, control arm was prospectively registered.

Feasibility and Effects of a Postoperative Recovery Exercise Program Developed Specifically for Gastric Cancer Patients (PREP-GC) Undergoing Minimally Invasive Gastrectomy.

PURPOSE: Exercise intervention after surgery has been found to improve physical fitness and quality of life (QOL). The purpose of this study was to investigate the feasibility and effects of a postoperative recovery exercise program developed specifically for gastric cancer patients (PREP-GC) undergoing minimally invasive gastrectomy. MATERIALS AND METHODS: Twenty-four patients treated surgically for early gastric cancer were enrolled in the PREP-GC. The exercise program comprised sessions of In-hospital Exercise (1 week), Home Exercise (1 week), and Fitness Improvement Exercise (8 weeks). Adherence and compliance to PREP-GC were evaluated. In addition, body composition, physical fitness, and QOL were assessed during the preoperative period, after the postoperative recovery (2 weeks after surgery), and upon completing the PREP-GC (10 weeks after surgery). RESULTS: Of the 24 enrolled patients, 20 completed the study without any adverse events related to the PREP-GC. Adherence and compliance rates to the Fitness Improvement Exercise were 79.4% and 99.4%, respectively. Upon completing the PREP-GC, patients also exhibited restored cardiopulmonary function and muscular strength, with improved muscular endurance and flexibility (P<0.05). Compared to those in the preoperative period, no differences were found in symptom scale scores measured using the European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life Questionnaire (QLQ-C30) and Quality of Life Questionnaire-Stomach Cancer-Specific Module (QLQ-STO22); however, higher scores for global health status and emotional functioning were observed after completing the PREP-GC (P<0.05). CONCLUSIONS: In gastric cancer patients undergoing minimally invasive gastrectomy, PREP-GC was found to be feasible and safe, with high adherence and compliance. Although randomized studies evaluating the benefits of exercise intervention during postoperative recovery are needed, surgeons should encourage patients to participate in systematic exercise intervention programs in the early postoperative period (Registered at the ClinicalTrials.gov NCT01751880).

Unblinded, randomized multicenter trial comparing lamotrigine and valproate combination with controlled-release carbamazepine monotherapy as initial drug regimen in untreated epilepsy.

PURPOSE: To compare controlled-release carbamazepine monotherapy (CBZ-CR) with lamotrigine and valproate combination therapy (LTG + VPA) in equivalent total drug load, as initial drug regimen in untreated patients with partial and/or generalized tonic-clonic seizures (GTCS). METHODS: This unblinded, randomized, 60-week superiority trial recruited patients having two or more unprovoked seizures with at least one seizure during previous three months. After randomization into CBZ-CR or LTG + VPA, patients entered into eight-week titration phase (TP), followed by 52-week maintenance phase (MP). Median doses of CBZ-CR and LTG + VPA were 600 mg/day and 75 mg/day + 500 mg/day, respectively. Primary outcome measure was completion rate (CR), a proportion of patients who have completed the 60-week study as planned. Secondary efficacy measures included seizure-free rate (SFR) for 52-week of MP and time to first seizure (TTFS) during MP. RESULTS: Among 207 randomized patients, 202 underwent outcome analysis (104 in CBZ-CR, 98 in LTG + VPA). CR was 62.5% in CBZ-CR and 65.3% in LTG + VPA (p = 0.678). SFR during MP was higher in LTG + VPA (64.1%) than CBZ-CR (47.8%) (P = 0.034). TTFS was shorter with CBZ-CR (p = 0.041). Incidence of adverse effects (AEs) were 57.7% in CBZ-CR and 60.2% in LTG + VPA and premature drug withdrawal rates due to AEs were 12.5% and 7.1%, respectively, which were not significantly different. CONCLUSION: CR was comparable between LTG + VPA and CBZ-CR, however, both SFR for 52-week MP and TTFS during MP were in favor of LTG + VPA than CBZ-CR. The study suggested that LTG + VPA can be an option as initial drug regimen for untreated patients with partial seizures and/or GTCS except for women of reproductive age.

Effects of Triflusal and Clopidogrel on the Secondary Prevention of Stroke Based on Cytochrome P450 2C19 Genotyping.

BACKGROUND AND PURPOSE: To compare the efficacy and safety of antiplatelet agents for the secondary prevention of ischemic stroke based on cytochrome P450 2C19 (CYP2C19) polymorphisms. METHODS: This study was a prospective, multicenter, randomized, parallel-group, open-label, blind genotype trial. First time non-cardiogenic ischemic stroke patients were enrolled and screened within 30 days. Participants were randomized to receive either triflusal or clopidogrel for secondary stroke prevention. The primary outcome was the time from randomization to first recurrent ischemic stroke or hemorrhagic stroke. RESULTS: The required sample size was 1,080 but only 784 (73%) participants were recruited. In patients with a poor CYP2C19 genotype for clopidogrel metabolism (n=484), the risk of recurrent stroke among those who received triflusal treatment was 2.9% per year, which was not significantly different from those who received clopidogrel treatment (2.2% per year; hazard ratio [HR], 1.23; 95% confidence interval [CI], 0.60-2.53). In the clopidogrel treatment group (n=393), 38% had good genotypes and 62% poor genotypes for clopidogrel metabolism. The risk of recurrent stroke in patients with a good CYP2C19 genotype was 1.6% per year, which was not significantly different from those with a poor genotype (2.2% per year; HR, 0.69; 95% CI, 0.26-1.79). CONCLUSIONS: Whilst there were no significant differences between the treatment groups in the rates of stroke recurrence, major vascular events, or coronary revascularization, the efficacy of antiplatelet agents for the secondary prevention of stroke according to CYP2C19 genotype status remains unclear.

Protocol for the comparison of triflusal and clopidogrel in secondary prevention of stroke based on cytochrome P450 2C19 genotyping (MASETRO study): A multicenter, randomized, open-label, parallel-group trial.

RATIONALE AND AIM: The antiplatelet effect of clopidogrel is reportedly influenced by cytochrome P450 2C19 (CYP2C19) polymorphisms. However, there is no data concerning the relationship between stroke recurrence and CYP2C19 polymorphisms in patients treated with clopidogrel for secondary prevention of ischemic stroke. Triflusal may be an alternative therapy for clopidogrel in patients with poor genotype. The Comparison of Triflusal and Clopidogrel Effects in Secondary Prevention of Stroke Based on Cytochrome P450 2C19 Genotyping (MAESTRO) study will investigate the effect of antiplatelet agents based on CYP2C19 polymorphisms in secondary prevention of ischemic stroke. SAMPLE SIZE AND DESIGN: Assuming that 55% of patients belong to the poor genotype group, the required sample size is 1080 patients with at least 24 months of follow-up. This study is designed as a prospective, multicenter, randomized, parallel-group, open-label, and blind genotype trial. Patients who experience their first non-cardiogenic ischemic stroke within 30 days prior to screening are eligible. Patients received 300 mg triflusal twice a day or 75 mg clopidogrel once daily during the trial. The study is registered with ClinicalTrials.gov (NCT01174693). STUDY OUTCOME: The primary outcome is recurrent ischemic stroke or hemorrhagic stroke. Secondary outcomes consist of composite major vascular events including stroke, myocardial infarction, coronary revascularization, or vascular death. DISCUSSION: Personalized medicine may be essential for patients according to individual drug metabolism abilities. MAESTRO is the first prospective study designed to evaluate the effect of CYP2C19 polymorphism in secondary stroke prevention and will resolve several questions regarding preventive antiplatelet agents for recurrent stroke.

Effect and Safety of Rosuvastatin in Acute Ischemic Stroke.

BACKGROUND AND PURPOSE: The benefit of statins in acute stroke remains uncertain. Statins may prevent stroke recurrence during the acute stage of stroke via pleiotropic effects. However, statins may increase the risk of intracerebral hemorrhage. We investigated the effect and safety of rosuvastatin in acute stroke patients. METHODS: This randomized, double-blind, multi-center trial compared rosuvastatin 20 mg and placebo in statin-naïve stroke patients who underwent diffusion-weighted imaging (DWI) within 48 hours after symptom onset. The primary outcome was occurrence of new ischemic lesions on DWI at 5 or 14 days. RESULTS: This trial was stopped early after randomization of 316 patients due to slow enrollment. Among 289 patients with at least one follow-up imaging, the frequency of new ischemic lesions on DWI was not different between groups (rosuvastatin: 27/137, 19.7% vs. placebo: 36/152, 23.6%) (relative risk 0.83, 95% confidence interval 0.53-1.30). Infarct volume growth at 5 days (log-transformed volume change, rosuvastatin: 0.2±1.0 mm(3) vs. placebo: 0.3±1.3 mm(3); P=0.784) was not different, either. However, hemorrhagic infarction or parenchymal/subarachnoid hemorrhage on gradient-recalled echo magnetic resonance imaging occurred less frequently in the rosuvastatin group (6/137, 4.4%) than the placebo group (22/152, 14.5%, P=0.007). Among 314 patients with at least one dose of study medication, progression or clinical recurrence of stroke tended to occur less frequently in the rosuvastatin group (1/155, 0.6% vs. 7/159, 4.4%, P=0.067). Adverse events did not differ between groups. CONCLUSIONS: The efficacy of rosuvastatin in reducing recurrence in acute stroke was inconclusive. However, statin use was safe and reduced hemorrhagic transformation.

Effect of ketoconazole on lobeglitazone pharmacokinetics in Korean volunteers.

PURPOSE: Lobeglitazone, a peroxisome proliferator-activated receptor-γ agonist, is metabolized primarily by the cytochrome P450 (CYP) 3A4 isoenzyme. Individuals concomitantly taking lobeglitazone and a CYP3A4 inhibitor may experience some adverse effects secondary to increased systemic exposure to lobeglitazone. To address such potential concern, we evaluated the effects of ketoconazole, a prototypic CYP3A4 inhibitor, on the pharmacokinetic (PK) properties and associated adverse effects of lobeglitazone. METHODS: A PK drug-drug interaction study was conducted in healthy individuals between 20 and 45 years old in a randomized, open-label, 2-way crossover design. Even though the PK study was performed on a single dose of lobeglitazone, multiple ketoconazole doses were given to ensure that the full extent of inhibition of CYP3A4 was maintained during the PK sampling. All study participants received a single oral dose of lobeglitazone 0.5 mg with or without 9 oral 200-mg doses of ketoconazole pretreatment twice daily. The primary PK parameter end points (AUC and Cmax) were estimated using noncompartmental analysis, and the 90% CIs for the geometric mean ratios (ratio of lobeglitazone and ketoconazole to lobeglitazone alone) were investigated. Tolerability (adverse events, vital signs, ECG, and laboratory tests) was also assessed. FINDINGS: A total of 24 Korean men (mean age, 26 years; age range, 20-32 years; mean weight, 68 kg; weight range, 59-81 kg) completed the study and were evaluable for lobeglitazone PK properties and tolerability. The mean (SD) Cmax values of lobeglitazone with and without ketoconazole were 49 (7) ng/mL and 48 (6) ng/mL at 1.5 and 1.0 hours after dosing, respectively. The mean (SD) AUC∞ values were 532 (117) ng·h/mL and 405 (110) ng·h/mL, respectively. Although the Cmax was not significantly affected, the geometric mean ratio for AUC∞ was increased by a point estimate of 1.33 (90% CI, 1.23-1.44). A single oral administration of lobeglitazone 0.5 mg with or without ketoconazole pretreatment did not produce any clinically significant adverse effects on vital signs, 12-lead ECG profiles, or laboratory tests. IMPLICATIONS: The administration of lobeglitazone, 0.5 mg alone or in combination with multiple doses of ketoconazole, was generally well tolerated. The systemic exposure of lobeglitazone was increased to a modest extent by pretreatment with 9 twice-daily doses of ketoconazole. Clinicaltrials.gov identifier: NCT01330563.