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Tumor immune-gene expression profiles and peripheral immune phenotypes associated with clinical outcomes of locally advanced pancreatic cancer following FOLFIRINOX.
Hyung, J, Lee, H, Jin, H, Lee, S, Lee, HJ, Gong, G, Song, TJ, Lee, SS, Hwang, DW, Kim, SC, et al
ESMO open. 2022;(3):100484
Abstract
BACKGROUND A comprehensive analysis of peripheral immune cell phenotypes and tumor immune-gene expression profiles in locally advanced pancreatic cancer patients treated with neoadjuvant chemotherapy in a phase II clinical trial was carried out. METHODS Patients were treated with neoadjuvant modified folinic acid, fluorouracil, irinotecan hydrochloride, oxaliplatin (mFOLFIRINOX) followed by surgery and adjuvant gemcitabine at the Asan Medical Center. Correlations between survival outcomes and baseline peripheral immune cells and their changes during preoperative chemotherapy were analyzed. Patients who had surgery were divided into two groups according to achievement of disease-free survival >10 months (achieved versus failed). Differential expression and pathway analysis of immune-related genes were carried out using the Nanostring platform, and immune cells within the tumor microenvironment were compared by immunohistochemistry. RESULTS Forty-four patients were treated in the phase II clinical trial. Higher baseline CD14+CD11c+HLA-DR+ monocytes (P = 0.044) and lower Foxp3+CD4+ T cells (P = 0.02) were associated with poor progression-free survival of neoadjuvant mFOLFIRINOX. During the preoperative chemotherapy, PD-1 T cells significantly decreased (P = 0.0110). Differential expression and pathway analysis of immune-genes from the resected tumor after neoadjuvant treatment revealed transforming growth factor-β pathway enrichment and higher expression of MARCO (adjusted P < 0.05) associated with early recurrence. Enrichment of the Th1 pathway and higher peritumoral CD8+ T cells (P = 0.0103) were associated with durable disease-free survival from surgery (>10 months) following neoadjuvant mFOLFIRINOX. CONCLUSIONS Our results identify potential immune biomarkers for locally advanced pancreatic cancer and provide insights into pancreatic cancer immunity.
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The effect of comprehensive oral care program on oral health and quality of life in patients undergoing radiotherapy for head and neck cancer: A quasi-experimental case-control study.
Lee, HJ, Han, DH, Kim, JH, Wu, HG
Medicine. 2021;(16):e25540
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OBJECTIVES The purpose of this study is to investigate the effect of the comprehensive oral care program on oral health status and symptoms in head and neck cancer (HNC) patients undergoing radiotherapy. METHODS This was a quasi-experimental study using a non-equivalent control group in non-synchronized design. All participants including control and experimental group were asked for the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire H&N35 (EORTC QLQ-H&N35) and given an oral health education 4 times at baseline, immediate postradiotherapy, 3 months after radiotherapy, and 6 months after radiotherapy. In each visit except for final, the experimental group was given fluoride varnish application and fluoride mouth rinsing solution for daily use. Oral health examination for dental caries, plaque score (PS), bleeding on probing (BOP), and salivary flow rate was performed in baseline and 6 months after radiotherapy. Statistical analyses were done by paired t-tests and mixed ANCOVA repeated-measures analysis. RESULTS From November 1, 2013 to October 31, 2015, a total 61 patients undergoing radiotherapy for HNC cancer were enrolled (30 in control and 31 in experimental groups). Decrease in salivary flow rate was comparable between 2 groups. Dental caries increased in control group (P = .006); PS and BOP were decreased in experimental group (P < .001 and .004, respectively). Experimental group showed lower swallowing, speech problems, and less sexuality scores in EORTC QLQ-H&N35 than control group. CONCLUSION We found improvement in oral health and the quality of life in HNC patients with comprehensive oral care intervention by dental professionals. Communicating and cooperating between the healthcare and dental professionals is needed to raise the quality of health care services for HNC patients receiving radiotherapy.
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Effects of circuit training or a nutritional intervention on body mass index and other cardiometabolic outcomes in children and adolescents with overweight or obesity.
Seo, YG, Lim, H, Kim, Y, Ju, YS, Choi, YJ, Lee, HJ, Jang, HB, Park, SI, Park, KH
PloS one. 2021;(1):e0245875
Abstract
OBJECTIVE We aimed to assess the effectiveness of the first 6 months of a 24 month multidisciplinary intervention program including circuit training and a balanced diet in children and adolescents with obesity. METHODS A quasi-experimental intervention trial included 242 participants (age [mean±standard deviation]: 11.3±2.06 years, 97 girls) of at least 85th percentile of age- and sex-specific body mass index (BMI). Participants were grouped into three to receive usual care (usual care group), exercise intervention with circuit training (exercise group), or intensive nutritional and feedback intervention with a balanced diet (nutritional group). Primary outcome was BMI z-score, while secondary outcomes included body composition, cardiometabolic risk markers, nutrition, and physical fitness. RESULTS Among the participants, 80.6% had a BMI ≥ the 97th percentile for age and sex. The BMI z-score of the overall completers decreased by about 0.080 after 6 months of intervention (p < 0.001). After the intervention, both exercise and nutritional groups had significantly lower BMI z-scores than the baseline data by about 0.14 and 0.075, respectively (p < 0.05). Significant group by time interaction effects were observed between exercise versus usual care group in BMI z-score (β, -0.11; 95% confidence interval (CI), -0.20 to -0.023) and adiponectin (β, 1.31; 95% CI, 1.08 to 1.58); and between nutritional versus usual care group in waist circumference (β, -3.47; 95% CI, -6.06 to -0.89). No statistically significant differences were observed in any of the other secondary outcomes assessed. CONCLUSION Multidisciplinary intervention including circuit training and a balanced diet for children and adolescents with obesity reduced the BMI z-score and improved cardiometabolic risk markers such as adiponectin and waist circumference.
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Effect of Intravenous Ferric Carboxymaltose on Hemoglobin Response Among Patients With Acute Isovolemic Anemia Following Gastrectomy: The FAIRY Randomized Clinical Trial.
Kim, YW, Bae, JM, Park, YK, Yang, HK, Yu, W, Yook, JH, Noh, SH, Han, M, Ryu, KW, Sohn, TS, et al
JAMA. 2017;(20):2097-2104
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IMPORTANCE Acute isovolemic anemia occurs when blood loss is replaced with fluid. It is often observed after surgery and negatively influences short-term and long-term outcomes. OBJECTIVE To evaluate the efficacy and safety of ferric carboxymaltose to treat acute isovolemic anemia following gastrectomy. DESIGN, SETTING, AND PARTICIPANTS The FAIRY trial was a patient-blinded, randomized, phase 3, placebo-controlled, 12-week study conducted between February 4, 2013, and December 15, 2015, in 7 centers across the Republic of Korea. Patients with a serum hemoglobin level of 7 g/dL to less than 10 g/dL at 5 to 7 days following radical gastrectomy were included. INTERVENTIONS Patients were randomized to receive a 1-time or 2-time injection of 500 mg or 1000 mg of ferric carboxymaltose according to body weight (ferric carboxymaltose group, 228 patients) or normal saline (placebo group, 226 patients). MAIN OUTCOMES AND MEASURES The primary end point was the number of hemoglobin responders, defined as a hemoglobin increase of 2 g/dL or more from baseline, a hemoglobin level of 11 g/dL or more, or both at week 12. Secondary end points included changes in hemoglobin, ferritin, and transferrin saturation levels over time, percentage of patients requiring alternative anemia management (oral iron, transfusion, or both), and quality of life at weeks 3 and 12. RESULTS Among 454 patients who were randomized (mean age, 61.1 years; women, 54.8%; mean baseline hemoglobin level, 9.1 g/dL), 96.3% completed the trial. At week 12, the number of hemoglobin responders was significantly greater for ferric carboxymaltose vs placebo (92.2% [200 patients] for the ferric carboxymaltose group vs 54.0% [115 patients] for the placebo group; absolute difference, 38.2% [95% CI, 33.6%-42.8%]; P = .001). Compared with the placebo group, patients in the ferric carboxymaltose group experienced significantly greater improvements in serum ferritin level (week 12: 233.3 ng/mL for the ferric carboxymaltose group vs 53.4 ng/mL for the placebo group; absolute difference, 179.9 ng/mL [95% CI, 150.2-209.5]; P = .001) and transferrin saturation level (week 12: 35.0% for the ferric carboxymaltose group vs 19.3% for the placebo group; absolute difference, 15.7% [95% CI, 13.1%-18.3%]; P = .001); but there were no significant differences in quality of life. Patients in the ferric carboxymaltose group required less alternative anemia management than patients in the placebo group (1.4% for the ferric carboxymaltose group vs 6.9% for the placebo group; absolute difference, 5.5% [95% CI, 3.3%-7.6%]; P = .006). The total rate of adverse events was higher in the ferric carboxymaltose group (15 patients [6.8%], including injection site reactions [5 patients] and urticaria [5 patients]) than the placebo group (1 patient [0.4%]), but no severe adverse events were reported in either group. CONCLUSION AND RELEVANCE Among adults with isovolemic anemia following radical gastrectomy, the use of ferric carboxymaltose compared with placebo was more likely to result in improved hemoglobin response at 12 weeks. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01725789.
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Bone Mineral Density According to Dual Energy X-ray Absorptiometry is Associated with Serial Serum Alkaline Phosphatase Level in Extremely Low Birth Weight Infants at Discharge.
Lee, J, Park, HK, Kim, JH, Choi, YY, Lee, HJ
Pediatrics and neonatology. 2017;(3):251-257
Abstract
BACKGROUND To examine bone mineral density in extremely low birth weight infants at discharge and investigate whether serial measurements of serum alkaline phosphatase (ALP) and phosphate can predict bone mineralization. METHODS The individuals were 70 preterm infants. Serum calcium, phosphate, and ALP were measured at weekly intervals during admission in extremely low birth weight infants (mean gestational age, 25.3±2.1 weeks; birth weight, 812.8±141.1 g). Bone mineral apparent density (BMAD) of the lumbar spine was prospectively evaluated by dual energy X-ray absorptiometry at discharge (n=70). RESULTS BMAD was classified as poor (< 25th percentile) at < 0.014 g/cm3, fair (25th-75th percentile) at < 0.014-0.021 g/cm3, and good (> 75th percentile) at > 0.021 g/cm3, based on the distribution of BMAD values in infants with noncomplicated courses of prematurity (n=43). In a further multivariate analysis, the number of total parenteral nutrition days, phosphate at 2 postnatal weeks and 3 postnatal weeks, and ALP at 4 postnatal weeks and 5 postnatal weeks had an impact on bone mineral density at the lumbar spine, independent of gestational age and body weight. Peak ALP activities exceeding 650 IU/L revealed low bone mineral density with 80% sensitivity and 64% specificity (AUC, 0.70; p=0.005). CONCLUSION Serial measurements of serum ALP and phosphate are associated with decreased bone mineralization by dual energy X-ray absorptiometry at discharge in extremely low birth weight infants.
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Efficacy and safety of paricalcitol in children with stages 3 to 5 chronic kidney disease.
Webb, NJA, Lerner, G, Warady, BA, Dell, KM, Greenbaum, LA, Ariceta, G, Hoppe, B, Linde, P, Lee, HJ, Eldred, A, et al
Pediatric nephrology (Berlin, Germany). 2017;(7):1221-1232
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BACKGROUND Elevated intact parathyroid hormone (iPTH) levels can contribute to morbidity and mortality in children with chronic kidney disease (CKD). We evaluated the pharmacokinetics, efficacy, and safety of oral paricalcitol in reducing iPTH levels in children with stages 3-5 CKD. METHODS Children aged 10-16 years with stages 3-5 CKD were enrolled in two phase 3 studies. The stage 3/4 CKD study characterized paricalcitol pharmacokinetics and compared the efficacy and safety of paricalcitol with placebo followed by an open-label period. The stage 5 CKD study evaluated the efficacy and safety of paricalcitol (no comparator) in children with stage 5 CKD undergoing dialysis. RESULTS In the stage 3/4 CKD study, mean peak plasma concentration and area under the time curve from zero to infinity were 0.13 ng/mL and 2.87 ng•h/((or ng×h/))mL, respectively, for 12 children who received 3 μg paricalcitol. Thirty-six children were randomized to paricalcitol or placebo; 27.8% of the paricalcitol group achieved two consecutive iPTH reductions of ≥30% from baseline versus none of the placebo group (P = 0.045). Adverse events were higher in children who received placebo than in those administered paricalcitol during the double-blind treatment (88.9 vs. 38.9%; P = 0.005). In the stage 5 CKD study, eight children (61.5%) had two consecutive iPTH reductions of ≥30% from baseline, and five (38.5%) had two consecutive iPTH values of between 150 and 300 pg/mL. Clinically meaningful hypercalcemia occurred in 21% of children. CONCLUSIONS Oral paricalcitol in children aged 10-16 years with stages 3-5 CKD reduced iPTH levels and the treatment was well tolerated. Results support an initiating dose of 1 μg paricalcitol 3 times weekly in children aged 10-16 years.
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Phase II trial of neoadjuvant letrozole and lapatinib in Asian postmenopausal women with estrogen receptor (ER) and human epidermal growth factor receptor 2 (HER2)-positive breast cancer [Neo-ALL-IN]: Highlighting the TILs, ER expressional change after neoadjuvant treatment, and FES-PET as potential significant biomarkers.
Park, JH, Kang, MJ, Ahn, JH, Kim, JE, Jung, KH, Gong, G, Lee, HJ, Son, BH, Ahn, SH, Kim, HH, et al
Cancer chemotherapy and pharmacology. 2016;(4):685-95
Abstract
PURPOSE Neo-ALL-IN (NCT 01275859) is a single-center, phase II study aimed to evaluate the efficacy and safety profiles of neoadjuvant letrozole plus lapatinib, as well as potential biomarkers, in postmenopausal women with ER- and HER2-positive (ER+HER2+) breast cancer. METHODS Postmenopausal ER+HER2+ breast cancer of stages II-III was eligible. Daily 2.5 mg letrozole plus 1500 mg lapatinib were administered for 18-21 weeks before surgery. Clinical responses were assessed by palpation with caliper, breast ultrasonography, mammogram, and/or MRI. Biologic samples were collected for biomarker analyses at three time points (baseline, day 14, and before surgery). Baseline fluorine-18 fluorodeoxyglucose and fluorine-18 fluoroestradiol PET-CT scans were performed. RESULTS Among 24 patients enrolled, 17 (70.8 %) completed planned neoadjuvant treatment, whereas 7 prematurely terminated the treatment and proceeded to surgery because of toxicity or progression; 2 patients showed definite progression, and 2 showed clinical regrowth by palpation regardless of minimal response. All patients eventually underwent breast cancer surgery. Toxicities were generally mild mostly within grades 1-2 except prolonged or recurrent grade 3 liver toxicities in 3 patients (13.6 %) regardless of sequential dose reduction, which finally led to discontinuation of treatment. The overall clinical response rates were 62.5 % (n = 15) including 1 CR in breast. However, no pathologic CR (ypT0-is N0) was achieved. SUVmax lower than 5.5 in baseline FES PET-CT (p = 0.007), baseline TILs over 20 % (p = 0.026), and decreased IHC ER Allred score after neoadjuvant treatment (p = 0.021) were significantly associated with adverse clinical response. CONCLUSIONS When this chemo-free, combination neoadjuvant therapy with letrozole and lapatinib is given for Asian postmenopausal ER+HER2+ breast cancer, TILs, change of ER expression following neoadjuvant treatment, and SUVmax in baseline FES-PET are to be considered potential biomarkers in these patients.
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Multicenter Prospective Comparative Study of Robotic Versus Laparoscopic Gastrectomy for Gastric Adenocarcinoma.
Kim, HI, Han, SU, Yang, HK, Kim, YW, Lee, HJ, Ryu, KW, Park, JM, An, JY, Kim, MC, Park, S, et al
Annals of surgery. 2016;(1):103-9
Abstract
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.
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Analysis of the prevalence and associated risk factors of tinnitus in adults.
Kim, HJ, Lee, HJ, An, SY, Sim, S, Park, B, Kim, SW, Lee, JS, Hong, SK, Choi, HG
PloS one. 2015;(5):e0127578
Abstract
BACKGROUND Tinnitus is a common condition in adults; however, the pathophysiology of tinnitus remains unclear, and no large population-based study has assessed the associated risk factors. The aim of this study was to analyze the prevalence and associated risk factors of tinnitus. METHODS We conducted a cross-sectional study using data from the Korea National Health and Nutrition Examination Survey, with 19,290 participants ranging in age from 20 to 98 years old, between 2009 and 2012. We investigated the prevalence of tinnitus using a questionnaire and analyzed various possible factors associated with tinnitus using simple and multiple logistic regression analysis with complex sampling. RESULTS The prevalence of tinnitus was 20.7%, and the rates of tinnitus associated with no discomfort, moderate annoyance, and severe annoyance were 69.2%, 27.9%, and 3.0%, respectively. The prevalence of tinnitus and the rates of annoying tinnitus increased with age. The adjusted odds ratio (AOR) of tinnitus was higher for females, those with a smoking history, those reporting less sleep (≤ 6 h), those with more stress, those in smaller households, those with a history of hyperlipidemia osteoarthritis, rheumatoid arthritis, asthma, depression, thyroid disease, an abnormal tympanic membrane, unilateral hearing loss, bilateral hearing loss, noise exposure from earphones, noise exposure at the workplace, noise exposure outside the workplace, and brief noise exposure. Additionally, unemployed individuals and soldiers had higher AORs for tinnitus. The AOR of annoying tinnitus increased with age, stress, history of hyperlipidemia, unilateral hearing loss, and bilateral hearing loss. CONCLUSIONS Tinnitus is very common in the general population and is associated with gender, smoking, stress, sleep, hearing loss, hyperlipidemia, osteoarthritis, rheumatoid arthritis, asthma, depression, and thyroid disease history.
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A randomized, double-blind, placebo-controlled, phase II clinical trial to investigate the efficacy and safety of oral DA-1229 in patients with type 2 diabetes mellitus who have inadequate glycaemic control with diet and exercise.
Jung, CH, Park, CY, Ahn, KJ, Kim, NH, Jang, HC, Lee, MK, Park, JY, Chung, CH, Min, KW, Sung, YA, et al
Diabetes/metabolism research and reviews. 2015;(3):295-306
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BACKGROUND DA-1229 is a novel, potent and selective dipeptidyl peptidase-4 (DPP-IV) inhibitor that is orally bioavailable. We aimed to evaluate the optimal dose, efficacy and safety of DA-1229, in Korean subjects with type 2 diabetes mellitus suboptimally controlled with diet and exercise. METHODS We enrolled 158 patients (mean age, 53 years and a mean BMI, 25.6 kg/m(2) ). The mean baseline fasting plasma glucose level, HbA1c and duration of diabetes were 8.28 mmol/L, 7.6% (60 mmol/mol) and 3.9 years, respectively. After 2 or 6 weeks of an exercise and diet program followed by 2 weeks of a placebo period, the subjects were randomized into one of four groups for a 12-week active treatment period: placebo, 2.5, 5 or 10 mg of DA-1229. RESULTS All three doses of DA-1229 significantly reduced HbA1c from baseline compared to the placebo group (-0.09 in the placebo group vs. -0.56, -0.66 and -0.61% in 2.5, 5 and 10-mg groups, respectively) but without any significant differences between the doses. Insulin secretory function, as assessed by homeostasis model assessment β-cell, the insulinogenic index, 2-h oral glucose tolerance test (OGTT) C-peptide and post-OGTT C-peptide area under the curve (AUC)0-2h, significantly improved with DA-1229 treatment. The incidence of adverse events was similar between the treatment groups and DA-1229 did not affect body weight or induce hypoglycaemic events. CONCLUSIONS DA-1229 monotherapy (5 mg for 12 weeks) improved HbA1c, fasting plasma glucose level, OGTT results and β-cell function. This drug was well tolerated in Korean subjects with type 2 diabetes mellitus.