GNUV201, a novel human/mouse cross-reactive and low pH-selective anti-PD-1 monoclonal antibody for cancer immunotherapy.

BACKGROUND: Several PD-1 antibodies approved as anti-cancer therapies work by blocking the interaction of PD-1 with its ligand PD-L1, thus restoring anti-cancer T cell activities. These PD-1 antibodies lack inter-species cross-reactivity, necessitating surrogate antibodies for preclinical studies, which may limit the predictability and translatability of the studies. RESULTS: To overcome this limitation, we have developed an inter-species cross-reactive PD-1 antibody, GNUV201, by utilizing an enhanced diversity mouse platform (SHINE MOUSE™). GNUV201 equally binds to human PD-1 and mouse PD-1, equally inhibits the binding of human PD-1/PD-L1 and mouse PD-1/PD-L1, and effectively suppresses tumor growth in syngeneic mouse models. The epitope of GNUV201 mapped to the "FG loop" of hPD-1, distinct from those of Keytruda® ("C'D loop") and Opdivo® (N-term). Notably, the structural feature where the protruding epitope loop fits into GNUV201's binding pocket supports the enhanced binding affinity due to slower dissociation (8.7 times slower than Keytruda®). Furthermore, GNUV201 shows a stronger binding affinity at pH 6.0 (5.6 times strong than at pH 7.4), which mimics the hypoxic and acidic tumor microenvironment (TME). This phenomenon is not observed with marketed antibodies (Keytruda®, Opdivo®), implying that GNUV201 achieves more selective binding to and better occupancy on PD-1 in the TME. CONCLUSIONS: In summary, GNUV201 exhibited enhanced affinity for PD-1 with slow dissociation and preferential binding in TME-mimicking low pH. Human/monkey/mouse inter-species cross-reactivity of GNUV201 could enable more predictable and translatable efficacy and toxicity preclinical studies. These results suggest that GNUV201 could be an ideal antibody candidate for anti-cancer drug development.

Cancer Risk in Graves Disease with Radioactive 131I Treatment: A Nationwide Cohort Study.

Radioactive 131I (RAI) therapy has potential effects for the treatment of Graves disease (GD). However, whether RAI therapy for GD increases cancer risk remains controversial in medicine and public health. We aimed to investigate whether the risk of cancer increases in patients with GD receiving RAI therapy compared with those who did not. Methods: We used the Korean National Health Insurance Service's National Health Information Database from 2004 to 2020 and defined GD as prescribing antithyroid drugs, RAI, or thyroidectomy as a treatment for GD (International Classification of Diseases, 10th revision, E05 group). We investigated the hazard ratios (HRs) of overall and site-specific cancers associated with RAI in patients with GD. Subsequent cancer was defined as a primary malignancy treated at least 1 y after RAI therapy. Results: In total, 10,737 patients with GD who received RAI therapy (7,193 women, 67.0%; mean age, 43.7 ± 13.4 y) were matched to 53,003 patients with GD who had never received RAI treatment (35,471 women, 66.9%; mean age, 43.8 ± 13.2 y) in a 1:4-5 ratio by age, sex, and health checkup data. The median follow-up duration was 8.7 y (interquartile range, 5.2-12.1 y), and the median cumulative RAI dose was 555 MBq (interquartile range, 370-630 MBq) in the RAI therapy group. During 2004-2020, the overall subsequent cancer rates were 5.66 and 5.84 per 1,000 person-years in the RAI and non-RAI groups, respectively, with an unadjusted HR of 0.97 (95% CI, 0.88-1.06); this remained at 0.96 (95% CI, 0.83-1.10) after adjustment for multiple clinical confounding factors. For cancer subtypes, the risk of leukemia was significantly increased, with an HR of 2.39 (95% CI, 1.17-4.91). However, a loss of statistical significance was observed after adjusting for confounding factors, which may be attributed to the limited number of absolute events. Moreover, cancer-specific mortality was not different between the RAI and the non-RAI groups, with an adjusted HR of 0.99 (95% CI, 0.66-1.47). Conclusion: This study identified that the overall cancer risk in patients with GD who received RAI therapy compared with those who did not was not significant in Korea. Further long-term studies are needed to determine the risks and advantages of RAI therapy in patients with GD.

Elevated morbidity and mortality in patients with chronic idiopathic hypophosphatemia: a nationwide cohort study.

Background: Chronic idiopathic hypophosphatemia (CIH) induced by X-linked hypophosphatemic rickets or tumor-induced osteomalacia is a rare inherited or acquired disorder. However, due to its rarity, little is known about the epidemiology and natural course of CIH. Therefore, we aimed to identify the prevalence and long-term health outcomes of CIH patients. Methods: Using the Korean Health Insurance Review and Assessment claims database, we evaluated the incidence of hypophosphatemia initially diagnosed from 2003 to 2018. After excluding secondary conditions that could change serum phosphorus levels, we identified 154 patients (76 men and 78 women) with non-secondary and non-renal hypophosphatemia. These hypophosphatemic patients were compared at a ratio of 1:10 with age-, sex-, and index-year-matched controls (n = 1,540). Results: In the distribution of age at diagnosis, a large peak was observed in patients aged 1-4 years and small peaks were observed in ages from 40-70 years. The age-standardized incidence rate showed non-statistically significant trend from 0.24 per 1,000,000 persons in 2003 to 0.30 in 2018. Hypophosphatemic patients had a higher risk of any complication (adjusted hazard ratio [aHR], 2.17; 95% confidence interval [CI], 1.67-2.69) including cardiovascular outcomes, chronic kidney disease, hyperparathyroidism, osteoporotic fractures, periodontitis, and depression. Hypophosphatemic patients also had higher risks of mortality and hospitalization than the controls (aHR, 3.26; 95% CI, 1.83-5.81; and aHR, 2.49; 95% CI, 1.97-3.16, respectively). Conclusion: This first nationwide study of CIH in South Korea found a bimodal age distribution and no sex differences among patients. Hypophosphatemic patients had higher risks of complications, mortality, and hospitalization compared to age- and sex-matched controls.

Weight-adjusted waist as an integrated index for fat, muscle and bone health in adults.

BACKGROUND: Unhealthy body composition, including high fat mass, low muscle mass and low bone mass, is a critical health issue in adults. The weight-adjusted waist index (WWI) estimates fat and muscle mass and may have implications for bone health. We examined its association with body composition outcomes in a large Korean adult cohort. METHODS: This study used data from the Korean National Health and Nutrition Examination Survey (2008-2011). WWI was calculated as waist circumference (cm) divided by the square root of body weight (kg). Dual-energy X-ray absorptiometry was used to measure bone mineral density (BMD), appendicular lean mass (ALM) and total body fat percentage. Unhealthy body composition was defined as combined presence of high fat mass, low bone mass and low muscle mass. RESULTS: A total of 5983 individuals (3034 men [50.7%] and 2949 women [49.3%]; mean age: 63.5 ± 8.7 years) were included. WWI was positively correlated with total body fat percentage (r = 0.478, P < 0.001) and inversely with ALM/weight (r = -0.485, P < 0.001) and BMD at the lumbar spine (r = -0.187, P < 0.001), femoral neck (r = -0.269, P < 0.001) and total hip (r = -0.255, P < 0.001). Higher WWI quartiles correlated with lower BMD, T-scores and ALM/weight, along with increased total body fat, evident in both genders and more pronounced in women, even after adjusting for confounders. This trend remained statistically significant across WWI quartiles for all analyses (P < 0.001). Higher WWI quartiles were also significantly associated with higher odds of unhealthy body composition, with adjusted odds ratio in the highest WWI group of 18.08 (95% CI, 4.32-75.61) in men and 6.36 (95% CI, 3.65-11.07) in women. The optimal cutoff values of WWI for unhealthy body composition were 10.4 cm/√kg in men and 10.5 cm/√kg in women. CONCLUSIONS: In community-dwelling adults, high WWI values are associated with unfavourable body composition outcomes, indicating high fat mass, low muscle mass and low bone mass. WWI can potentially serve as an integrated index of body composition, underscoring the need for further research to validate its use in clinical settings.

All-cause and cause-specific mortality risks associated with calcium supplementation with or without vitamin D: A nationwide population-based study.

BACKGROUND: Current evidence regarding the mortality outcomes associated with calcium supplementation with or without low-dose vitamin D is conflicting. OBJECTIVES: To investigate the effects of calcium supplementation with or without vitamin D on all-cause and cause-specific mortalities in a large-scale cohort. METHODS: This study used data from the Korean National Health Insurance System database and National Death Registry. A total of 27,846 participants aged >55 years who had taken calcium supplements with or without vitamin D for at least 90 days (calcium supplementation only [CaO], n = 6256; calcium supplementation in combination with vitamin D [CaD], n = 21,590) were matched in a 1:1 ratio to those who did not take calcium or vitamin D supplements (control group) using propensity scores. RESULTS: No difference in all-cause mortality risk was found between the CaO and control groups: (adjusted hazard ratio [HR] = 1.00; 95% confidence interval [CI]: 0.92-1.10). However, all-cause mortality was lower in the CaD group (HR = 0.85; 95% CI: 0.80-0.89) compared with that in the control group. Mortality risk associated with cardiovascular disease (CVD) was decreased in the CaD group when the daily vitamin D dose received was less than 1000 IU (HR = 0.72; 95% CI: 0.64-0.81). Subgroup analysis showed significant effect of vitamin D with calcium in individuals who were female, aged ≥65 years or had previous history of cancer or CVD. CONCLUSION: In combination with calcium, vitamin D supplementation provides better outcomes for all-cause mortality, particularly CVD-associated mortality, in a duration-dependent manner.

Linear association between radioactive iodine dose and second primary malignancy risk in thyroid cancer.

BACKGROUND: We aimed to investigate whether the risk of second primary malignancy (SPM) in patients with thyroid cancer (TC) receiving radioactive iodine (RAI) therapy rises in a cumulative, dose-dependent manner compared with those not undergoing RAI. METHODS: Using the Korean National Health Insurance Service National Health Information Database (2002-2019), we investigated hazard ratios of SPM associated with RAI in TC. SPM was defined as a second primary malignancy diagnosed at least 1 year after TC diagnosis. RESULTS: Of 217 777 patients with TC (177 385 women and 40 392 men; mean [SD] age, 47.2 [11.6] years), 100 448 (46.1%) received RAI therapy. The median (IQR) follow-up duration was 7.7 (5.5-10.3) years, and the median (IQR) cumulative RAI dose was 3.7 (1.9-5.6) GBq. From 2004 to 2019, SPM incidence rates were 7.30 and 6.56 per 1000 person-years in the RAI and non-RAI groups, respectively, with an unadjusted hazard ratio of 1.09 (95% confidence interval = 1.05 to 1.13); this rate remained at 1.08 (95% confidence interval = 1.04 to 1.13) after adjustment for multiple clinical confounding factors. Notably, SPM risk increased significantly, from 3.7 GBq with full adjustments, and a strong linear association between cumulative RAI dose and SPM was observed in the restricted cubic spline analysis. Regarding cancer subtypes, myeloid leukemia and salivary gland, trachea, lung and bronchus, uterus, and prostate cancers were the most significantly elevated risks in patients who underwent RAI therapy. CONCLUSIONS: This study identified that SPM risk increased linearly in a dose-dependent manner in patients with TC undergoing RAI therapy compared with those not undergoing RAI therapy.

Biomarkers for Locally Advanced Hepatocellular Carcinoma Patients Treated with Liver-Directed Combined Radiotherapy.

Introduction: In the era of biomarker-driven cancer therapy, robust biomarkers for hepatocellular carcinoma (HCC) have not been well-defined. In this hypothesis-generating study, we investigated biomarkers that can be incorporated to predict treatment outcomes in patients with locally advanced HCC who are administered liver-directed combined radiotherapy (LDCRT). Methods: Ninety-nine patients with HCC who were treated with conventional fractionation LDCRT between July 2016 and October 2018 were enrolled in this prospective single-arm study. Clinical outcomes and possible serum biomarkers, including soluble programmed cell death ligand-1 (sPD-L1), interleukin (IL)-10, IL-6, cell-free DNA (cfDNA), inter-alpha inhibitor H4, and interferon-gamma, were analyzed. The primary endpoint was disease progression, and additional endpoints were local failure-free rate, intrahepatic failure-free rate, and lung metastasis-free rate. Results: The median follow-up period was 18.7 months. The 1-year progression-free rate was 38.2%. Increasing baseline sPD-L1 per pg/mL, previous treatment history, protein induced by vitamin K absence-II >1,629 mAU/mL, and multiple tumors were the adverse factors for progression based on multivariate analysis. Survival tree analysis revealed three prognostic groups for progression, in which patients with multiple lesions and baseline sPD-L1 ≥41.07 pg/mL showed the worst outcomes. For dynamic changes in biomarker levels, sPD-L1 fold change and cfDNA fold-change values were unfavorable factors for progression. Conclusion: Baseline sPD-L1, sPD-L1 fold change, and cfDNA fold-change values showed the highest potential as biomarkers for predicting post-treatment progression after LDCRT in HCC patients. By incorporating clinical factors, these biomarkers may be useful for devising a biomarker-driven treatment paradigm in locally advanced HCC.

Diagnosis for Pheochromocytoma and Paraganglioma: A Joint Position Statement of the Korean Pheochromocytoma and Paraganglioma Task Force.

Pheochromocytoma and paraganglioma (PPGLs) are rare catecholamine-secreting neuroendocrine tumors but can be life-threatening. Although most PPGLs are benign, approximately 10% have metastatic potential. Approximately 40% cases are reported as harboring germline mutations. Therefore, timely and accurate diagnosis of PPGLs is crucial. For more than 130 years, clinical, molecular, biochemical, radiological, and pathological investigations have been rapidly advanced in the field of PPGLs. However, performing diagnostic studies to localize lesions and detect metastatic potential can be still challenging and complicated. Furthermore, great progress on genetics has shifted the paradigm of genetic testing of PPGLs. The Korean PPGL task force team consisting of the Korean Endocrine Society, the Korean Surgical Society, the Korean Society of Nuclear Medicine, the Korean Society of Pathologists, and the Korean Society of Laboratory Medicine has developed this position statement focusing on the comprehensive and updated diagnosis for PPGLs.

Role of Interleukin-7 in the Development of and Recovery from Radiation-Induced Lymphopenia: A Post-hoc Analysis of a Prospective Cohort.

PURPOSE: Radiation-induced lymphopenia is associated with worse outcomes in solid tumors. We assessed the impact of interleukin-7 (IL-7), a key cytokine in lymphocyte homeostasis, on radiation-induced lymphopenia. MATERIALS AND METHODS: A post-hoc analysis was performed in a prospective cohort of 98 patients with hepatocellular carcinoma who were treated with radiotherapy in 2016-2018. Blood IL-7 levels were assayed before and at the end of radiotherapy. Acute severe lymphopenia (ASL) was defined as a total lymphocyte count of < 200/µL during radiotherapy. Cox and logistic regression analyses were performed to identify predictors of survival and ASL development, respectively. RESULTS: Patients with ASL (n=41) had significantly poorer overall survival than those without (12.0 months vs. 25.3 months, p=0.001). Patients with lymphocyte recovery showed significantly longer overall survival than those without (21.8 months vs. 10.3 months, p=0.042). ASL was an independent predictor of poor survival (hazard ratio, 2.07; p=0.015). Patients with ASL had significantly lower pre-radiotherapy IL-7 levels (2.07 pg/mL vs. 3.01 pg/mL, p=0.010). A high pre-radiotherapy IL-7 level was an independent predictor of a reduced risk of ASL development (hazard ratio, 0.40; p=0.004). IL-7 levels reflected a feedback response to ASL, with a higher ΔIL-7 in patients with ASL and a lower ΔIL-7 in those without ASL (0.48 pg/mL vs. -0.66 pg/mL, p < 0.001). Post-radiotherapy IL-7 levels were significantly positively correlated with the total lymphocyte counts at 2 months. CONCLUSION: IL-7 is associated with the development of and recovery from ASL, which may impact survival. To overcome radiation-induced lymphopenia, a novel strategy using IL-7 may be considered.

Effect of Interleukin-7 on Radiation-Induced Lymphopenia and Its Antitumor Effects in a Mouse Model.

PURPOSE: Local ionizing radiation (IR) can lead to systemic lymphocyte depletion, which is associated with poor survival outcomes in patients with cancer. Interleukin-7 (IL-7) plays an important role in lymphocyte homeostasis; however, its role in alleviating radiation-induced lymphopenia remains unclear. Hence, we established a radiation-induced lymphopenia animal model and evaluated the effect of exogenous IL-7 administration. METHODS: C3H/HeN mice underwent x-ray irradiation of 30 Gy in 10 fractions at the right hind limbs. Next, 10 mg/kg of IL-7 was injected subcutaneously, and the lymphocyte count in blood was measured. Murine hepatocellular carcinoma (HCa-1) cells were inoculated subcutaneously into the right thighs of tumor model mice, which underwent the same treatment. RESULTS: In the naïve mouse model, the decreased CD45+ cell count after irradiation gradually recovered to the initial level over 3 weeks in the IR group, whereas it markedly increased to 373% of the initial level in 1 week in the IR+IL-7 group. Similar trends were observed for the CD3+, CD8+, CD4+, regulatory T cells, and CD19+ B cell counts. Similar findings were observed in the tumor mouse model. CD8+ and CD4+ T cell infiltration in tumor specimens was higher in the IL-7 and IR+IL-7 groups than in the nontreated and IR groups. Tumor growth was significantly more suppressed in the IR+IL-7 group than in the IR group. The median survival time was significantly longer in the IR+IL-7 group (not reached) than in the IR (56 days; P = .0382), IL-7 (36 days; P = .0004), or nontreated groups (36 days; P < .0001). CONCLUSIONS: Administration of exogenous IL-7 after IR not only restored lymphocyte counts but also enhanced the antitumor effect. Exogenous IL-7 can be beneficial in overcoming radiation-induced lymphopenia and in enhancing the treatment outcome in combination with radiation therapy, which needs validation through future clinical studies.

Combination therapy with anti-T-cell immunoglobulin and mucin-domain containing molecule 3 and radiation improves antitumor efficacy in murine hepatocellular carcinoma.

BACKGROUND AND AIM: T-cell immunoglobulin and mucin-domain containing molecule 3 (TIM3) has emerged as a promising immune checkpoint inhibitor target; however, immune checkpoint inhibitor monotherapy does not benefit a substantial percentage of patients. Therefore, this study investigated the antitumor effect of anti-TIM3 therapy combined with radiation in a murine hepatocellular carcinoma (HCC) model. METHODS: The effect of radiation on TIM3 expression was determined in murine and human HCC cells using western blotting, immunohistochemistry, and flow cytometry. Tumor growth and survival rate were measured to evaluate the antitumor effect of this combination therapy. Tumor immunological parameters were assessed using flow cytometry and histology. RESULTS: TIM3 was upregulated in tumor-infiltrating CD8+ and CD4+ T cells in radiation-treated HCa-1-implanted mice. Combination treatment significantly delayed tumor growth compared with monotherapy (P < 0.01). Overall survival was improved in the combination group compared with that in the anti-TIM3 or radiation monotherapy groups (median survival time: 52 days vs 26 or 38 days, respectively, P < 0.001). The antitumor effect of the combination treatment was associated with increased apoptosis and decreased proliferation of tumor cells and reinvigorated CD8+ T-cell activation. CD8+ T-cell depletion reversed the antitumor efficacy of the combination treatment. These findings suggest that CD8+ T cells play key roles in the therapeutic effect of the combination treatment. CONCLUSION: Anti-TIM3 and radiation combination therapy significantly improved the antitumor effect in a murine HCC model, as evidenced by inhibited tumor growth and increased overall survival. This approach could be a novel combined immune-radiotherapy strategy for HCC.

A Simple-to-Use Score for Identifying Individuals at High Risk of Denosumab-Associated Hypocalcemia in Postmenopausal Osteoporosis: A Real-World Cohort Study.

Since denosumab-associated hypocalcemia occurs infrequently, data on its incidence and risk factors are limited. We aimed to evaluate risk factors and develop a useful score for identifying individuals at risk of denosumab-associated hypocalcemia. In this retrospective cohort, 790 consecutive female patients who received 60 mg denosumab at least once between 2016 and 2017 were analyzed. Based on biochemical records from a large-scale single-center, mild and moderate hypocalcemia were defined as albumin-corrected calcium (cCa) levels < 8.5 and < 8.0 mg/dL (< 2.12 and < 2.0 mmol/L), respectively. Mild and moderate hypocalcemia were observed in 8.2% and 1.0% patients, respectively. Patients who developed mild hypocalcemia had lower baseline cCa (8.9 vs. 9.3 mg/dL and 2.22 vs. 2.32mmo/L) and estimated glomerular filtration rate (75.0 vs. 83.2 mL/min/1.73 m2) and more frequent loop diuretic use (10.8% vs. 4.4%; all p < 0.05). In multivariate analysis, low baseline cCa (OR 1.29; 95% CI 1.20-1.40) and chronic kidney disease (CKD) stages 3b-5 were associated with elevated mild hypocalcemia risk (OR 2.92; 95% CI 1.38-6.20). Loop diuretics use was associated with mild hypocalcemia (OR 2.61; 95% CI 1.11-6.18) by univariate analysis, independent of baseline cCa and CKD stage. A scoring approach identified two risk groups: (1) patients without CKD (eGFR ≥ 45) and cCa < 8.5 mg/dL (2.12 mmol/L) and (2) patients with CKD (eGFR < 45) and cCa < 9.5 mg/dL (2.37 mmol/L).

Smoking, alcohol intake, and frailty in older Korean adult men: cross-sectional study with nationwide data.

PURPOSE: Smoking and alcohol intake are major causes of negative health outcomes and may be co-inherited traits. However, little is known about the association of frailty with smoking and alcohol intake in older adults. METHODS: Community-dwelling older men (N = 1426) aged 70-84 years were divided into four groups: 1) non-smoking (< 100 cigarettes in life-time) and non-alcohol intake (< one time/month); 2) smoking (≥ 100 cigarettes) and alcohol intake (≥ one time/month); 3) non-smoking with alcohol intake; and 4) smoking and no alcohol intake. Frailty was assessed with a modified version of the Cardiovascular Health Study (CHS) frailty index, the Korean version of the Fatigue, Resistance, Ambulation, Illness, and Loss of Weight (KFRAIL) index, the Korean Frailty Index (KFI), and the Study of Osteoporotic Fracture (SOF) frailty index. Frailty risks were estimated with multiple logistic regression models after adjusting for age, income, education, residence, marital status, hospitalization, physical activity, comorbidities, and levels of vitamin B12, aspartate aminotransferase, and gamma-glutamyl transferase. RESULTS: Frailty differed according to smoking and alcohol status. Frailty in the smoking and non-alcohol-intake group was significantly higher according to the CHS frailty index (Odds ratio = 1.592; 95% confidence interval [CI] 1.032-2.455), KFRAIL (CI 1.613, 1.037-2.509), and KFI (CI 1.869, 1.115-3.131) compared with the non-smoking and alcohol-intake group. However, there was no increased frailty risk in the other study groups. CONCLUSION: Frailty prevalence differed depending on smoking status and alcohol intake in older Korean men. Therefore, we should adopt a comprehensive approach to understanding frailty in older adults that considers both smoking and alcohol intake.

Genetic Analysis and Clinical Characteristics of Hereditary Pheochromocytoma and Paraganglioma Syndrome in Korean Population.

BACKGROUND: Pheochromocytoma and paragangliomas (PPGL) are hereditary in approximately 30% to 40% cases. With the advancement of genetic analysis techniques, including next-generation sequencing (NGS), there were attempts to classify PPGL into molecular clusters. With NGS being applied to clinical settings recently, we aimed to review the results of genetic analysis, including NGS, and investigate the association with clinical characteristics in Korean PPGL patients. METHODS: We reviewed the medical records of PPGL patients who visited Severance hospital from 2006 to 2019. We documented the clinical phenotype of those who underwent targeted NGS or had known germline mutations of related genes. RESULTS: Among 57 PPGL patients, we found 28 pathogenic germline mutations of susceptibility genes. Before the targeted NGS was implemented, only obvious syndromic feature lead to the Sanger sequencing for the specific genes. Therefore, for the exact prevalence, only patients after the year 2017, when targeted NGS was added, were included (n=43). The positive germline mutations were found in 14 patients; thus, the incidence rate is 32.6%. Patients with germline mutations had a higher likelihood of family history. There were significant differences in the type of PPGLs, percentage of family history, metastasis rate, presence of other tumors, and biochemical profile among three molecular clusters: pseudohypoxic tricarboxylic acid cycle-related, pseudohypoxic von Hippel-Lindau (VHL)/endothelial PAS domain-containing protein 1-related, and kinase-signaling group. Germline mutations were identified in seven PPGL-related genes (SDHB, RET, VHL, NF1, MAX, SDHA, and SDHD). CONCLUSION: We report the expected prevalence of germline mutations in Korean PPGL patients. NGS is a useful and accessible tool for genetic analysis in patients with PPGLs, and further research on molecular classification is needed for precise management.

Actual causes of death in thyroid cancer patients in Korea: A Nationwide Case Control Cohort Study.

OBJECTIVE: Thyroid cancer (TC) incidence has increased robustly in Korea. However, the actual cause of death, overall mortality risk, and cause-specific mortality risk in TC patients have not been clearly elucidated. DESIGN: Retrospective cohort study. METHODS: We analyzed 4082 TC patients from the Korean National Health Insurance Service-National Health Screening Cohort (NHIS-HEALS, 2002-2013) with a median of 48-month follow-up. We compared these patients with 12 246 controls matched for age, sex, and histories of major cardiovascular disease (CVD) to investigate the cause of death and risks of overall and cause-specific mortality. RESULTS: Overall, 61 deaths (1.5%) occurred in the TC group. The most common cause of death was TC-specific mortality (32.8%), followed by other malignancy-related mortality (31.1%) and CVD mortality (13.1%). The overall mortality risk was comparable between the TC and control groups (unadjusted hazard ratio (HR): 1.17; 95% confidence interval (CI): 0.87-1.58); the adjusted HR remained at 1.25 (95% CI: 0.90-1.74) after multivariate adjustment for body mass index (BMI), socioeconomic status (SES), smoking, alcohol consumption, and histories of hypertension, diabetes mellitus, and dyslipidemia. In addition, there was not enough evidence against the surmise that the CVD mortality risk was similar between the TC and control groups, with an HR of 0.50 (95% CI: 0.22-1.16) after adjustment for CVD risk factors. CONCLUSIONS: Excellent overall survival was observed in TC patients. The most common cause of death was TC-specific mortality, suggesting the importance of thyroid cancer treatment. The overall and cause-specific mortality risks, particularly CVD mortality risk, did not differ between TC patients and the general population.

Association of Geriatric Syndromes with Urinary Incontinence according to Sex and Urinary-Incontinence-Related Quality of Life in Older Inpatients: A Cross-Sectional Study of an Acute Care Hospital.

BACKGROUND: Geriatric syndromes are associated with morbidity and poor quality of life (QOL). Urinary incontinence (UI) is one of the most prevalent geriatric syndromes. However, there is little research on the association of UI and UI-related QOL with other geriatric syndromes. We investigated the relationship between geriatric syndromes and UI according to gender and UI-related QOL among older inpatients. METHODS: This study was conducted among 444 older inpatients (aged 65 years and older) between October 2016 and July 2017. We examined geriatric syndromes and related factors involving cognitive impairment, delirium, depression, mobility decline, polypharmacy, undernutrition, pain, and fecal incontinence. UI-related QOL was assessed using the International Consultation on Incontinence Questionnaire-Short Form. Multiple logistic regression analysis was used to evaluate these associations. RESULTS: Geriatric syndromes and related factors were associated with UI. Mobility decline (odds ratio [OR], 4.16; 95% confidence interval [CI], 2.29-7.56), polypharmacy (OR, 3.35; 95% CI, 1.89-5.92), and pain (OR, 6.80; 95% CI, 3.53-13.09) were related to UI in both genders. Especially, delirium (OR, 7.55; 95% CI, 1.61-35.44) and fecal incontinence (OR, 10.15; 95% CI, 2.50-41.17) were associated with UI in men, while cognitive impairment (OR, 4.19; 95% CI, 1.14-15.44) was significantly associated with UI in women. Patients with depression were more likely to have poor UI-related QOL (OR, 8.54; 95% CI, 1.43-51.15). CONCLUSION: UI was associated with different geriatric syndromes and related factors according to gender. Care for patients with depression, related to poor UI-related QOL, should be considered in primary care to improve the UI-related QOL of these individuals.

Cancer Risk from Exposure to Particulate Matter and Ozone According to Obesity and Health-Related Behaviors: A Nationwide Population-Based Cross-Sectional Study.

BACKGROUND: There is little evidence of an association between cancer risk and long-term exposure to ambient particulate matter <10 µm (PM10) and ozone (O3), according to obesity and health-related behaviors. METHODS: In the 2012 Korean Community Health Survey, survey data on socioeconomic characteristics, health-related behaviors, and previous cancer history were collected from 100,867 participants. Daily average concentrations of PM10 and O3 (2003-2012) were obtained from the Korean Air Pollutants Emission Service. The cancer risks for interquartile increases in PM10 and O3 were evaluated using multiple logistic regression and were stratified by age, sex, obesity, and health-related behaviors. RESULTS: Increased cancer risk was found among obese subjects aged ≥50 years after adjusting for confounding factors [PM10: ≥60 years: OR 1.34, 95% confidence interval (CI) 1.03-1.74; 50-60 years: OR 1.40, CI 1.01-1.96; O3: ≥60 years: OR 1.12, CI 1.04-1.20; 50-60 years: OR 1.20, CI 1.08-1.33]. However, we did not observe similar trends in the nonobese subjects. Among obese subjects aged ≥50 who had been exposed to PM10, men, ever smokers, and inactive subjects were at increased cancer risk. Regarding O3, the cancer risk was significantly higher among obese adults >50 years old, regardless of sex or health-related behaviors. CONCLUSIONS: Long-term exposure to PM10 and O3 was found to increase cancer risk. In particular, the risk differed according to obesity status, age, sex, and health-related behaviors. IMPACT: The effect of air pollution on cancer risk was compounded by obesity, smoking, and physical inactivity among subjects over 50 years old.

Clinical significance of soluble programmed cell death ligand-1 (sPD-L1) in hepatocellular carcinoma patients treated with radiotherapy.

PURPOSE: To investigate the clinical implications of the soluble programmed cell death-ligand 1 (sPD-L1) level in hepatocellular carcinoma (HCC) patients treated with radiotherapy (RT). MATERIALS/METHODS: HCC patients treated with RT between June 2011 and March 2015 were prospectively recruited and sPD-L1 levels were measured using an enzyme-linked immunosorbent assay. Blood samples were obtained at the RT start, RT end, and 1-month follow-up. The associations of the sPD-L1 level with the clinical features and outcomes were analyzed. RESULTS: Fifty-three patients with HCC were included. Thirty-four patients received conventional fractionated RT with hepatic arterial infusional chemotherapy, while 19 patients received stereotactic body radiotherapy (SBRT). The initial sPD-L1 level was significantly associated with stage, tumor size, portal vein tumor thrombosis, and venous invasion. The overall-survival was significantly poorer in patients with a higher level of initial sPD-L1 (≥1.315 pg/mL). A higher level of sPD-L1 at 1 month (≥12.9 pg/mL) was significantly related to early lung metastasis. The sPD-L1 level was significantly increased after RT and the change pattern of sPD-L1 was different between two RT schemes. CONCLUSIONS: The level of sPD-L1 was associated with tumor aggressiveness and outcomes, suggesting its role as a possible predictive biomarker. The increases in sPD-L1 after RT suggests that combined treatment with RT and immune checkpoint inhibitors may be a promising therapeutic strategy in HCC.

Inter-alpha Inhibitor H4 as a Potential Biomarker Predicting the Treatment Outcomes in Patients with Hepatocellular Carcinoma.

PURPOSE: Early prediction of treatment outcomes represents an essential step towards increased treatment efficacy and survival in patients with hepatocellular carcinoma (HCC). In this study, we performed two-dimensional electrophoresis (2-DE) followed by protein profiling to identify biomarkers predictive of therapeutic outcomes in patients with HCC who received liver-directed therapy (LDTx) involving local radiotherapy (RT), and studied the underlying mechanisms of the identified proteins. MATERIALS AND METHODS: 2-DE analysis was conducted by pooling sera from patients with a good or poor prognosis; serum proteomic profiles of the two groups were compared and analyzed using matrixassisted laser desorption/ionization time-of-flight mass spectrometry. Identified proteins were confirmed via enzyme-linked immunosorbent assay. An invasion assay was performed after overexpression and knockdown of target protein in Huh7 cells. RESULTS: Levels of inter-alpha inhibitor H4 (ITIH4), fibrinogen gamma chain, keratin 9/1 complex, carbonic anhydrase I, and carbonmonoxyhemoglobin S were changed by more than 4-fold in response to LDTx. In particular, pre-LDTx ITIH4 expression was more than 5-fold higher in patients with a good prognosis, compared to patients with a poor prognosis. The migration ability of Huh7 cells was significantly suppressed and enhanced by ITIH4 overexpression and knockdown, respectively. The tumors of patients with HCC and a good prognosis expressed high levels of ITIH4, compared to those of patients with a poor prognosis. CONCLUSION: Taken together, ITIH4 may be a potential therapeutic target that could inhibit cancer metastasis, as well as a prognostic marker for patients with HCC who are receiving LDTx.

A Case of Pulmonary Carcinoid Tumor with a Superimposed Aspergilloma Presenting As a Covert Ectopic Adrenocorticotropic Hormone Syndrome.

Ectopic adrenocorticotropic hormone (ACTH) syndrome is a challenging diagnosis only responsible for approximately 10% of Cushing syndrome cases. It has been associated with a variety of benign and malignant tumors including a carcinoid tumor accompanied by aspergilloma in our case that was significantly difficult to be detected. We report a patient over 70 years old with uncontrolled hypertension and hypokalemia presenting with generalized edema. Laboratory results revealed ACTH-dependent Cushing syndrome, but imaging studies did not show any discrete lesions secreting ACTH. The petrosal to peripheral ACTH gradient resulted in no evidence of pituitary adenoma. As the only lesion suspicious for ectopic ACTH secretion was a right lower round cystic lesion that did not appear to be a carcinoid tumor on computed tomography scan of the chest, the patient underwent video-assisted thoracic surgical resection to provide a definitive diagnosis. The final diagnosis was a small ectopic ACTH-secreting carcinoid tumor with unusual superimposed aspergilloma in the periphery of the lung. Postoperatively, the abnormal endocrine levels were normalized, and all of the clinical symptoms and signs were ameliorated. This is an informative case of ectopic ACTH syndrome (EAS) that was the cause of hypokalemia, hypertension, metabolic alkalosis, and hypercortisolism despite its poorly specific cushingoid morphology and uncommon imaging findings. Therefore, we recommend that clinicians investigate any possible lesion as a potential source of EAS.