You Jin Kim

Impact of body mass index on luteinizing hormone secretion in gonadotropin-releasing hormone stimulation tests of boys experiencing precocious puberty.

Objective: Excess adiposity may influence various aspects of pubertal development, including the timing of pubertal initiation and hormonal parameters during puberty. The aim of the study was to evaluate the impact of body mass index (BMI) on luteinizing hormone (LH) secretion to gonadotropin-releasing hormone (GnRH) stimulation test in boys with precocious puberty. Methods: Boys with precocious puberty, who were normal weight, overweight, and obese underwent GnRH stimulation tests between 2003 and 2010. Subjects were classified as normal weight (BMI ≥5th percentile and BMI <85th percentile), overweight (BMI ≥85th percentile and BMI <95th percentile), and obese (BMI ≥95th percentile). Results: Of 56 children whose data were included in the final analysis, mean age at diagnosis was 8.7 ± 1.0 years. The majority of boys were of normal weight (n = 28, 50%), while 15 children (26%) were overweight, and 13 (23%) obese. Peak LH levels after GnRH stimulation were 19.8 ± 8.8, 9.0 ± 3.5, and 8.1 ± 4.0 mIU/ml among normal weight, overweight, and obese subjects, respectively (p < 0.001 for all comparisons). By multivariate analysis, there was a significant negative association of BMI with peak-stimulated LH level. Conclusions: The higher BMI is associated with lower LH response to the GnRH stimulation test in boys experiencing precocious puberty. In boys with precocious puberty, BMI should be considered when interpreting GnRH stimulation test.

Associations between serum vitamin D levels and precocious puberty in girls

Purpose Vitamin D deficiency has been linked to chronic diseases, such as diabetes mellitus, obesity and autoimmune disease. However, data on the vitamin D status and its association with precocious puberty in girls are limited. We aimed to investigate the association between serum 25-hydroxyvitamin D (25OHD) and precocious puberty in girls. Methods A total of 60 girls with central precocious puberty (CPP) and 30 control girls were enrolled. Anthropometric measurement and serum level of 25OHD were estimated for all subjects. Results There was a significant difference in the mean serum 25OHD concentration between the precocious puberty group and the control group (17.1±4.5 ng/mL vs. 21.2±5.0 ng/mL, P<0.05). Forty-two of the 60 girls with CPP (70%) had vitamin D deficiency (defined as serum 25OHD<20 ng/mL) and 18 (30%) had vitamin D insufficiency. Of the 30 girls in the control group, vitamin D deficiency was seen in 13 subjects (43.3%), 15 subjects (50%) had vitamin D insufficiency, and 2 subjects (6.7%) had sufficient serum vitamin D (defined as serum 25OHD>30 ng/mL). Vitamin D deficient girls had a significantly higher odds ratio (OR, 3.05; 95% CI, 1.22-7.57, P=0.021). Conclusion These results showed that vitamin D levels may be associated with precocious puberty. Further studies are required to establish the potential effect of vitamin D status on puberty.

Multicenter clinical trial of leuprolide acetate depot (Luphere depot 3.75 mg) for efficacy and safety in girls with central precocious puberty

Purpose We evaluated the efficacy, safety and psychological aspect of monthly administrations of the gonadotropin-releasing hormone agonists (GnRHa), leuprolide acetate depot (Luphere depot 3.75 mg), in patients with precocious puberty. Methods A total of 54 girls with central precocious puberty were administered with leuprolide acetate (Luphere depot 3.75 mg) every four weeks over 24 weeks. We evaluated the percentage of children exhibiting a suppressed luteinizing hormone (LH) response to GnRH (LH peak≤3 IU/L), peak LH/follicle stimulating hormone (FSH) ratio of GnRH stimulation test less than 1, change in bone age/chronologic age ratio, change in the Tanner stage and change in eating habit and psychological aspect. Results (1) The percentage of children exhibiting a suppressed LH response to GnRH, defined as an LH peak≤3 IU/L at 24 weeks was 96.3 % (52/54). (2) The percentage of children exhibiting peak LH/FSH ratio<1 at 24 weeks of the study was 94.4 % (51/54). (3) The ratio of bone age and chronological age significantly declined from 1.27±0.07 to 1.24±0.01 after the 6 months of the study. (4) The mean Tanner stage manifested a significant change 2.3±0.48 at baseline, down to 1.70±0.61 at 24 weeks. (5) Based on the questionnaires, the score for eating habits showed a significant change from the baseline 34.0±6.8 to 31.3±6.8. (6) The psychological assessment did not exhibit a significant difference except with scores for sociability, problem behavior total score and other problems. Conclusion The leuprolide 3.75 mg (Luphere depot) is useful and safety for treating children with central precocious puberty.

Estrogen receptor α gene analysis in girls with central precocious puberty.

Abstract Objective: Estrogen is the final key factor that triggers the onset of puberty. The raised sensitivity of estrogen receptor, which may be caused by an estrogen receptor α (ERα) gene mutation or polymorphism, has been implicated in the etiology of precocious puberty. The aim of this study is to identify ERα gene mutations or polymorphisms in girls with central precocious puberty (CPP). Methods: A total of 204 Korean girls with CPP were included in this study along with 102 healthy Korean female adults as controls. All coding exons and exon-intron boundaries of the ERα gene were sequenced. The relationship between identified sequence variations and CPP were evaluated via comparison of allele frequencies between the two groups. Results: Eight polymorphisms were identified in the ERα gene. Among the eight polymorphisms in this study, five have been previously reported, whereas the other three were novel polymorphisms. Two of the three novel polymorphisms, p.G145S in exon 1 and p.R555H in exon 8 were only identified in the patient group. The subgroup with p.G145S showed a significantly higher level of peak luteinizing hormone than the subgroup without p.G145S in girls with CPP. Conclusion: The scanning and typing of ERα polymorphism has uncovered several potentially meaningful polymorphisms. However, no solid conclusion can be made from this study and further studies are necessary to validate the function of these polymorphisms.

MerTK inhibition by RXDX-106 in MerTK activated gastric cancer cell lines

RXDX-106 is a potent and selective type II pseudo-irreversible (slow off-rate) inhibitor of TYRO3, AXL, MER and c-MET. MER tyrosine kinase (MerTK) is expressed in a variety of malignancies, including gastric cancer (GC). The oncogenic potential of MerTK is supported by various lines of evidence. First, we surveyed 10 GC cell lines for MerTK protein overexpression and MerTk phosphorylation. We next evaluated the change of downstream signaling molecules including (p)-ERK and (p)-AKT, following RXDX-106 treatment. We also investigated the effect of RXDX-106 in patient-derived cell lines to mimic the in vivo condition. The prevalence of MerTK protein overexpression was evaluated in 229 cancer tissue specimens. We have found that MerTK inhibitor treatment resulted in considerable inhibition of cell growth and downstream signaling. In addition, MerTK phosphorylation, not total MerTK expression, is likely more predictive of therapeutic success. p-MerTK protein overexpression by IHC was found in 18% (17/87) of GC patients. Lastly, RXDX-106 inhibited cell proliferation in MerTK activated gastric cancer cell line. These findings provide further evidence of oncogenic roles for MerTK in GC, and demonstrate the importance of kinase activity for MerTK tumorigeneicity and validate RXDX-106, a novel MerTK inhibitor, as a potential therapeutic agent for treatment of GC.

Efficacy and Safety of Afatinib for EGFR -mutant Non-small Cell Lung Cancer, Compared with Gefitinib or Erlotinib

Purpose We tried to evaluate whether there are any specific features in treatment outcomes of firstline afatinib in patients with epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC), compared with gefitinib or erlotinib. Materials and Methods We analyzed patients treated with first-line afatinib, gefitinib, or erlotinib for advanced EGFR-mutant NSCLC at Samsung Medical Center between 2014 and 2016. Results In total, 467 patients received first-line afatinib (n=165), gefitinib (n=230), or erlotinib (n=72). Afatinib was used more often in patients with tumors harboring deletion in exon 19 (Del19), whereas the gefitinib group had more elderly, females, and never smokers. The median progression-free survival (PFS) time for afatinib, gefitinib, and erlotinib was 19.1 months, 13.7 months, and 14.0 months, respectively (p=0.001). The superior PFS of afatinib was more remarkable in subgroups of Del19 or uncommon EGFR mutations. Overall toxicity profiles of the three drugs were comparable, though more grade 3 or 4 toxicities were detected in afatinib (7.3%) compared with gefitinib (2.6%) or erlotinib (1.8%). The common grade 3 or 4 toxicities of afatinib included diarrhea (3.0%), paronychia (2.4%), and skin rash (1.8%). Dose modification was more frequently required in patients treated with afatinib (112/165, 68%), compared with gefitinib (5/230, 2%) and erlotinib (4/72, 6%). Interestingly, however, dose reduction in the afatinib group did not impair its efficacy in terms of PFS (dose reduction vs. no reduction group, 23.5 months vs. 12.4 months). Conclusion First-line afatinib showed satisfactory efficacy data and manageable toxicity profiles.

Discordance of the PAM50 Intrinsic Subtypes Compared with IHC-Based Surrogate in Breast Cancer Patients: Potential Implication of Genomic Alterations of Discordance

Purpose We aimed to analyze the discordance between immunohistochemistry (IHC)-based surrogate subtyping and PAM50 intrinsic subtypes and to assess overall survival (OS) according to discordance. Materials and Methods A total of 607 patients were analyzed. Hormone receptor (HR) expression was evaluated by IHC, and human epidermal growth factor receptor 2 (HER2) expression was analyzed by IHC and/or fluorescence in situ hybridization. PAM50 intrinsic subtypes were determined according to 50 cancer genes using the NanoString nCounter Analysis System. We matched concordant tumor as luminal A and HR+/HER2–, luminal B and HR+/HER2+, HR–/HER2+ and HER2–enriched, and triple-negative breast cancer (TNBC) and normal- or basal-like. We used Ion Ampliseq Cancer Panel v2 was used to identify the genomic alteration related with discordance. The Kaplan-Meier method was used to estimate OS. Results In total, 233 patients (38.4%) were discordant between IHC-based subtype and PAM50 intrinsic subtype. Using targeted sequencing, we detected somatic mutation–related discordant breast cancer including the VHL gene in the HR+/HER2– group (31% in concordant group, 0% in discordant group, p=0.03) and the IDH and RET genes (7% vs. 12%, p=0.02 and 0% vs. 25%, p=0.02, respectively) in the TNBC group. Among the luminal A/B patients with a discordant result had significantly worse OS (median OS, 73.6 months vs. not reached; p < 0.001), and among the patients with HR positivity, the basal-like group as determined by PAM50 showed significantly inferior OS compared to other intrinsic subtypes (5-year OS rate, 92.2% vs. 75.6%; p=0.01). Conclusion A substantial portion of patients showed discrepancy between IHC subtype and PAM50 intrinsic subtype in our study. The survival analysis demonstrated that current IHC-based classification could mislead the treatment and result in poor outcome. Current guidelines for IHC might be updated accordingly.

EGFR Mutation is Associated with Short Progression Free Survival in Patients with Stage III Non-Squamous Cell Lung Cancer Treated with Concurrent Chemoradiotherapy

Purpose This study was conducted to evaluate the relationship between epidermal growth factor receptor (EGFR) mutation and clinical outcomes in patients with stage III non-squamous cell lung cancer treated with definitive concurrent chemoradiotherapy (CCRT). Materials and Methods From January 2008 to December 2013, the medical records of 197 patients with stage III non- squamous non-small cell lung cancer treated with definitive CCRT were analyzed to determine progression-free survival (PFS) and overall survival (OS) according to EGFR mutation status. Results Among 197 eligible patients, 81 patients were EGFR wild type, 36 patients had an EGFR mutation (exon 19 Del, n=18; L858R, n=9, uncommon [G719X, L868, T790M], n=9), and 80 patients had unknown EGFR status. The median age was 59 years (range, 28 to 80 years) and 136 patients (69.0%) were male. The median follow-up duration was 66.5 months (range, 1.9 to 114.5 months). One hundred sixty-four patients (83.2%) experienced disease progression. Median PFS was 8.9 months for the EGFR mutation group, 11.8 months for EGFR wild type, and 10.5 months for the unknown EGFR group (p=0.013 and p=0.042, respectively). The most common site of metastasis in the EGFR mutant group was the brain. However, there was no significant difference in OS among the three groups (34.6 months for EGFR mutant group vs. 31.9 months for EGFR wild type vs. 22.6 months for EGFR unknown group; p=0.792 and p=0.284). A total of 29 patients (80.6%) with EGFR mutation were treated with EGFR tyrosine kinase inhibitor (gefitinib, n=24; erlotinib, n=3; afatinib, n=2) upon progression. Conclusion EGFR mutation is associatedwith short PFS and the brain is the most common site of distant metastasis in patients with stage III non- squamous cell lung cancer treated with CCRT.

Clinical Outcomes of EGFR Exon 20 Insertion Mutations in Advanced Non-small Cell Lung Cancer in Korea

Purpose Epidermal growth factor receptor (EGFR) exon 20 insertion mutations account for approximately 4% of all EGFR mutations. Given the rarity of this mutation, its clinical outcomes are not fully established. Materials and Methods Between 2009 and 2017, non-small cell lung cancer (NSCLC) patients who showed an exon 20 insertion were retrospectively reviewed for clinical characteristics and outcomes, including responses to chemotherapy (CTx) or targeted therapy. Results Of 3,539 NSCLC patients who harbored an activating EGFR mutation, 56 (1.6%) had an exon 20 insertion. Of the advanced NSCLC patients, 27 of 1,479 (1.8%) had an exon 20 insertion. The median overall survival was 29.4 months (95% confidence interval 9.3 to 49.6) for 27 advancedNSCLC patients. The 22 patientswho received systemic CTx achieved a 50.0% response rate and a 77.2% disease control rate, with 4.2 months of progressionfree survival. Six patients received EGFR tyrosine kinase inhibitors (TKIs). Three of the four patients that had only an exon 20 insertion showed progressive disease, while one showed stable disease. The othertwo patients had an exon 20 insertion and another EGFR mutation and achieved a partial response. Conclusion The incidence of an exon 20 insertion mutation is rare in Korea and occasionally accompanied by other common EGFR mutations. Although the response to systemic CTx. in these patients is comparable to that of patients with other mutations, the response rate to firstor second-generation EGFR TKIs is quite low. Therefore, the development of a more efficient agent is urgently needed.

Clinical characteristics and laboratory findings of children and adolescents who were newly diagnosed with diabetes mellitus

Results Children diagnosed with type 1 DM were 110 out of 145 (75.9%) and 35 out of 145 (24.1%) were type 2 diabetes. Mean age of onset was 10.6 ± 0.9 years and there was no seasonal variation of incidence. 36.4% of children with type 1 DM presented initially with diabetic ketoacidosis. Mean body mass index (BMI) was 16.9 ± 3.8 kg/m, mean blood glucose level was 482.7 ± 214.4 mg/dL and mean glycated hemoglobin (HbA1c) level was 12.1 ± 2.28%. Positive result was revealed in 70% of the subjects with type 1 DM for antibodies to glutamic acid decarboxylase (GAD), 1.8% for islet-cell antibodies (ICA), 20.9% for insulin autoantibodies (IAA) and 75.4% showed positive results for at least one of these autoantibodies. 35 patients (24.1%) were diagnosed with type 2 diabetes. Mean age of onset of type 2 diabetes was 12.2 ± 3.4 years. 22 out of 35 (63%) subjects were diagnosed with type 2 DM in the process of evaluating the cause of obesity without any other presenting symptoms. Mean BMI was 27.1 ± 7.9 kg/m, mean blood glucose level was 229.0 ± 108.8 mg/dL and mean HbA1c concentration was 9.3 ± 2.9%. 63% of the subjects diagnosed with type 2 DM had a family history of DM and 75% were either overweight or obese. Fatty liver were diagnosed in 20% patients.