Purpose: The aim of this study is to evaluate the safety and efficacy of ex vivo activated and expanded natural killer (NK) cell therapy (SNK01) plus pembrolizumab in a randomized phase I/IIa clinical trial. Materials and Methods: Overall, 18 patients with advanced non–small cell lung cancer (NSCLC) and a programmed death ligand 1 tumor proportion score of 1% or greater who had a history of failed frontline platinum-based therapy were randomized (2:1) to receive pembrolizumab every 3 weeks +/– 6 weekly infusions of SNK01 at either 2×109 or 4×109 cells per infusion (pembrolizumab monotherapy vs. SNK01 combination). The primary endpoint was safety, whereas the secondary endpoints were the objective response rate (ORR), progression-free survival (PFS), overall survival, and quality of life. Results: Since no dose-limiting toxicity was observed, the maximum tolerated dose was determined as SNK01 4×109 cells/dose. The safety data did not show any new safety signals when SNK01 was combined with pembrolizumab. The ORR and the 1-year survival rate in the NK combination group were higher than those in patients who underwent pembrolizumab monotherapy (ORR, 41.7% vs. 0%; 1-year survival rate, 66.7% vs. 50.0%). Furthermore, the median PFS was higher in the SNK01 combination group (6.2 months vs. 1.6 months, p=0.001). Conclusion Based on the findings of this study, the NK cell combination therapy may consider as a safe treatment method for stage IV NSCLC patients who had a history of failed platinum-based therapy without an increase in adverse events.

Purpose: The clinical implications of tumor-infiltrating T cell subsets and their spatial distribution in biliary tract cancer (BTC) patients treated with gemcitabine plus cisplatin were investigated. Materials and Methods: A total of 52 BTC patients treated with palliative gemcitabine plus cisplatin were included. Multiplexed immunohistochemistry was performed on tumor tissues, and immune infiltrates were separately analyzed for the stroma, tumor margin, and tumor core. Results: The density of CD8+ T cells, FoxP3- CD4+ helper T cells, and FoxP3+ CD4+ regulatory T cells was significantly higher in the tumor margin than in the stroma and tumor core. The density of LAG3- or TIM3-expressing CD8+ T cell and FoxP3- CD4+ helper T cell infiltrates was also higher in the tumor margin. In extrahepatic cholangiocarcinoma, there was a higher density of T cell subsets in the tumor core and regulatory T cells in all regions. A high density of FoxP3- CD4+ helper T cells in the tumor margin showed a trend toward better progression-free survival (PFS) (p=0.092) and significantly better overall survival (OS) (p=0.012). In multivariate analyses, a high density of FoxP3- CD4+ helper T cells in the tumor margin was independently associated with favorable PFS and OS. Conclusion The tumor margin is the major site for the active infiltration of T cell subsets with higher levels of LAG3 and TIM3 expression in BTC. The density of tumor margin-infiltrating FoxP3- CD4+ helper T cells may be associated with clinical outcomes in BTC patients treated with gemcitabine plus cisplatin.

The Korean Endocrine Society (KES) published clinical practice guidelines for the treatment of acromegaly in 2011. Since then, the number of acromegaly cases, publications on studies addressing medical treatment of acromegaly, and demands for improvements in insurance coverage have been dramatically increasing. In 2017, the KES Committee of Health Insurance decided to publish a position statement regarding the use of somatostatin analogues in acromegaly. Accordingly, consensus opinions for the position statement were collected after intensive review of the relevant literature and discussions among experts affiliated with the KES, and the Korean Neuroendocrine Study Group. This position statement includes the characteristics, indications, dose, interval (including extended dose interval in case of lanreotide autogel), switching and preoperative use of somatostatin analogues in medical treatment of acromegaly. The recommended approach is based on the expert opinions in case of insufficient clinical evidence, and where discrepancies among the expert opinions were found, the experts voted to determine the recommended approach.
Acromegaly ; Consensus ; Expert Testimony ; Insurance Coverage ; Insurance, Health ; Octreotide ; Somatostatin

PURPOSE: The study analyzed the prevalence of peri-implantitis and factors which may have affected the disease. MATERIALS AND METHODS: This study based on medical records and radiographs of 422 patients (853 implant cases) who visited Ewha Womans University Mokdong Hospital Dental Center from January 1, 2012 to December 31, 2016. Generalized estimation equations (GEE) was utilized to determine the statistical relationship between peri-implantitis and each element, and the cumulative prevalence of peri-implantitis during the observation period was obtained by using the Kaplan Meier Method. RESULTS: The prevalence rate of peri-implantitis at the patient level resulted in 7.3% (31 patients out of a total of 422 patients), and at the implant level 5.5% (47 implants out of a total of 853 implants). Sex, GBR, guided bone regeneration (GBR) and functional loading periods had statistical significance with the occurrence of peri-implantitis. Upon analysis of the cumulative prevalence of peri-implantitis in terms of implant follow-up period, the first case of peri-implantitis occurred at 9 months after the placement of an implant, and the prevalence of peri-implantitis showed a non-linear rise over time without a hint of a critical point. CONCLUSION: The prevalence of peri-implantitis at the patient level and the implant were 7.3% and 5.5%, respectively. Male, implant installed with GBR and longer Functional Loading Periods were related with the risk of peri-implantitis.
Bone Regeneration ; Female ; Follow-Up Studies ; Humans ; Male ; Medical Records ; Methods ; Peri-Implantitis* ; Prevalence* ; Retrospective Studies* ; Risk Factors*

Acromegaly is a chronic disorder caused by excessive growth hormone (GH) secretion. In most cases, the excess GH originates from GH-producing pituitary adenomas. Surgery is the preferred first-line treatment for patients with acromegaly, but medical management is considered when the disease persists after surgery or in cases where patients refuse surgery or are poor candidates for surgery. Somatostatin analogues are commonly used to treat acromegaly. The Korean Endocrine Society and the Korean Neuroendocrine Study Group have developed a position statement for the use of somatostatin analogues in the medical treatment of acromegaly. This position statement is based on evidence from the current literature and expert opinions. In the case of discrepancies among expert opinions, the experts voted to determine the recommended approach.

PURPOSE: The purpose of this study was to evaluate the prognostic effect of patient compliance with supportive periodontal treatment (PC-SPT). Chronic periodontitis patients were classified based on their compliance level, and factors affecting PC-SPT and the prognosis of PC-SPT were investigated. METHODS: This study selected 206 patients who started SPT after receiving periodontal treatment between 2010 and 2012. Patients who continued SPT through February 2016 were included. The patients were classified according to whether they exhibited complete compliance (100% of visits), excellent compliance (≥70% of visits), incomplete compliance (<70% of visits), or non-compliance (only 2 visits). Patient characteristics that could affect PC-SPT, such as age, sex, distance of the clinic from their residence, implantation, and periodontal treatment, were investigated. The number of newly decayed and extracted teeth, alveolar bone level changes around the teeth and implants, and implant removal were examined to evaluate the prognosis of PC-SPT. RESULTS: Sex and the presence of an implant significantly affected PC-SPT. Additionally, the number of newly decayed and extracted teeth and changes in alveolar bone levels around the teeth and implants were significant prognostic factors related to PC-SPT. CONCLUSIONS: PC-SPT in chronic periodontitis patients will help maintain periodontal health and prevent further periodontal disease.
Chronic Periodontitis ; Compliance ; Humans ; Patient Compliance ; Periodontal Diseases ; Prognosis ; Retrospective Studies ; Tooth

Acromegaly is a chronic disorder caused by excessive growth hormone (GH) secretion. In most cases, the excess GH originates from GH-producing pituitary adenomas. Surgery is the preferred first-line treatment for patients with acromegaly, but medical management is considered when the disease persists after surgery or in cases where patients refuse surgery or are poor candidates for surgery. Somatostatin analogues are commonly used to treat acromegaly. The Korean Endocrine Society and the Korean Neuroendocrine Study Group have developed a position statement for the use of somatostatin analogues in the medical treatment of acromegaly. This position statement is based on evidence from the current literature and expert opinions. In the case of discrepancies among expert opinions, the experts voted to determine the recommended approach.
Acromegaly ; Expert Testimony ; Growth Hormone ; Humans ; Octreotide ; Pituitary Neoplasms ; Somatostatin

BackgroundUntil now, various types of combined therapy with nucleotide analogs and pegylated interferon (Peg-INF) in patients with hepatitis B patients have been tried. However, studies regarding the benefits of de novo combination, late-add on, and sequential treatment are very limited. The objective of the current study was to identify the efficacy of sequential treatment of Peg-INF after short-term antiviral treatment.

MethodsBetween June 2010 and June 2015, hepatitis B e antigen (HBeAg)-positive patients (n = 162) received Peg-IFN for 48 weeks (mono-treatment group, n = 81) and entecavir (ETV) for 12 weeks with a 48-week course of Peg-IFN starting at week 5 of ETV therapy (sequential treatment group, n = 81). The primary endpoint was HBeAg seroconversion at the end of follow-up period after the 24-week treatment. The primary endpoint was analyzed using Chi-square test, Fisher's exact test, and regression analysis.

ResultsHBeAg seroconversion rate (18.2% vs. 18.2%, t = 0.03, P = 1.000) and seroclearance rate (19.7% vs. 19.7%, t = 0.03, P = 1.000) were same in both mono-treatment and sequential treatment groups. The rate of alanine aminotransferase (ALT) normalization (45.5% vs. 54.5%, t = 1.12, P = 0.296) and serum hepatitis B virus (HBV)-DNA <2000 U/L (28.8% vs. 28.8%, t = 0.10, P = 1.000) was not different in sequential and mono-treatment groups at 24 weeks of Peg-INF. Viral response rate (HBeAg seroconversion and serum HBV-DNA <2000 U/L) was not different in the two groups (12.1% vs. 16.7%, t = 1.83, P = 0.457). Baseline HBV-DNA level (7 logU/ml vs. 7.5 logU/ml, t = 1.70, P = 0.019) and hepatitis B surface antigen titer (3.6 logU/ml vs. 4.0 logU/ml, t = 2.19, P = 0.020) were lower and predictors of responder in mono-treatment and sequential treatment groups, respectively.

ConclusionsThe current study shows no differences in HBeAg seroconversion rate, ALT normalization, and HBV-DNA levels between mono-therapy and sequential therapy regimens.

Trial RegistrationClinicalTrials.gov, NCT01220596; https://clinicaltrials.gov/ct2/show/NCT01220596?term=NCT01220596&rank=1.

PURPOSE: The present study investigated the dynamics and prognostic role of messenger RNA (mRNA) expression responsible for 18F-fluorodeoxyglucose (FDG) uptake in FDG positron emission tomography (PET) and radioactive iodine (131I) uptake in whole-body radioactive iodine scans (WBS) in papillary thyroid cancer (PTC) patients. MATERIALS AND METHODS: The primary and processed data were downloaded from the Genomic Data Commons Data Portal. Expression data for sodium/iodide symporter (solute carrier family 5 member 5, SLC5A5), hexokinase (HK1–3), glucose-6-phosphate dehydrogenase (G6PD), and glucose transporter (solute carrier family 2, SLC2A1–4) mRNA were collected. RESULTS: Expression of SLC5A5 mRNA were negatively correlated with SLC2A1 mRNA and positively correlated with SLC2A4 mRNA. In PTC with BRAF mutations, expressions of SLC2A1, SLC2A3, HK2, and HK3 mRNA were higher than those in PTC without BRAF mutations. Expression of SLC5A5, SLC2A4, HK1, and G6PD mRNA was lower in PTC without BRAF mutation. PTCs with higher expression of SLC5A5 mRNA had more favorable disease-free survival, but no association with overall survival. CONCLUSION: Expression of SLC5A5 mRNA was negatively correlated with SLC2A1 mRNA. This finding provides a molecular basis for the management of PTC with negative WBS using 18F-FDG PET scans. In addition, higher expression of SLC5A5 mRNA was associated with less PTC recurrence, but not with deaths.
Disease-Free Survival ; Fluorodeoxyglucose F18 ; Genome* ; Glucose Transport Proteins, Facilitative ; Glucosephosphate Dehydrogenase ; Hexokinase ; Humans ; Iodine ; Ion Transport ; Positron-Emission Tomography ; Recurrence ; RNA, Messenger* ; Thyroid Gland* ; Thyroid Neoplasms*

Interferon-γ (IFN-γ) is an important cytokine produced by natural killer (NK) cells and T cells in response to various stimuli. The levels of IFN-γ secreted after stimulation of NK cells using a recombinant cytokine is represented as one of functions of NK cells. Recently, a method for evaluating NK cell activity in whole blood samples was developed. The levels of IFN-γ secreted after NK cell stimulation with PROMOCA™ (ATGen, Korea) and T cell stimulation with phytohemagglutinin (PHA) were compared using two different commercial kits: NK Vue Gold (ATGen, Korea) and QuantiFERON-TB Gold In-Tube (Cellestis, Australia). Participants included 43 healthy individuals. Whole blood samples were incubated with either PROMOCA, a recombinant cytokine that specifically activates NK cells, or with PHA. IFN-γ levels in the supernatants were measured by ELISA. The level of IFN-γ by PROMOCA stimulation (PROMOCA IFN-γ) was more varied than that by stimulation with PHA (PHA IFN-γ) (median 1,544.4 pg/mL [ range 193.7–2,530.9] vs. median 2,470.1 pg/mL [ 2,250.1–2,874.4] P=0.0001). The median of PHA IFN-γ/PROMOCA IFN-γ ratio was 1.9 (1.1–12.4). There was a significant difference in levels of IFN-γ secreted after stimulation with PROMOCA or PHA in the healthy population.
Enzyme-Linked Immunosorbent Assay ; Healthy Volunteers ; Interferon-gamma ; Killer Cells, Natural ; Methods ; T-Lymphocytes