A Proposal for Standardization of Early Outcomes Following Robot-Assisted Radical Cystectomy (RARC): RARC Tetrafecta.

BACKGROUND: Currently, there is no dedicated tool to record the early outcomes of robot-assisted radical cystectomy (RARC), and existing criteria for longer-term outcomes require a minimum of 3 months for assessment. However, early evaluation is essential to prevent future morbidity and mortality, especially in surgeries with a high risk of complications in the short term. We propose a comprehensive approach to report early RARC outcomes and investigate the influence of surgeon experience on these results. PATIENTS AND METHODS: We retrospectively analyzed the outcomes of patients who underwent RARC for bladder cancer between April 2009 and April 2020. The cohort was divided chronologically into three groups: patients 1-60 in group 1, 61-120 in group 2, and 121-192 in group 3. Patients with yields of ≥ 16 lymph nodes (LN), negative soft tissue surgical margins, absence of transfusion, and absence of major complications at 30 days were regarded as attaining the RARC tetrafecta. RESULTS: Of the 192 included patients, 93 (48.4%) achieved RARC tetrafecta, with the proportion increasing with surgical experience from 41.7% in group 1 to 55.6% in group 3. Age [odds ratio (OR) 0.947; 95% confidence interval (CI) 0.924-0.970; P = 0.021], LN yield (OR 1.432; 95% CI 1.139-1.867; P = 0.001), and greater surgical experience with RARC (> 120 patients; OR 2.740; 95% CI 1.231-6.100; P = 0.014) were significantly associated with the achievement of RARC tetrafecta. CONCLUSIONS: RARC tetrafecta could be a comprehensive method for reporting early outcomes in patients undergoing RARC, with improvements aligned with the surgeon's experience.

Sextant Systematic Biopsy Versus Extended 12-Core Systematic Biopsy in Combined Biopsy for Prostate Cancer.

BACKGROUND: This study assessed the comparative effectiveness of sextant and extended 12-core systematic biopsy within combined biopsy for the detection of prostate cancer. METHODS: Patients who underwent combined biopsy targeting lesions with a Prostate Imaging Reporting and Data System (PI-RADS) score of 3-5 were assessed. Two specialists performed all combined cognitive biopsies. Both specialists performed target biopsies with five or more cores. One performed sextant systematic biopsies, and the other performed extended 12-core systematic biopsies. A total of 550 patients were analyzed. RESULTS: Cases requiring systematic biopsy in combined biopsy exhibited a significant association with age ≥ 65 years (odds ratio [OR], 2.32; 95% confidence interval [CI], 1.25-4.32; P = 0.008), PI-RADS score (OR, 2.32; 95% CI, 1.25-4.32; P = 0.008), and the number of systematic biopsy cores (OR, 3.69; 95% CI, 2.11-6.44; P < 0.001). In patients with an index lesion of PI-RADS 4, an extended 12-core systematic biopsy was required (target-negative/systematic-positive or a greater Gleason score in the systematic biopsy than in the targeted biopsy) (P < 0.001). CONCLUSION: During combined biopsy for prostate cancer in patients with PI-RADS 3 or 5, sextant systematic biopsy should be recommended over extended 12-core systematic biopsy when an effective targeted biopsy is performed.

Selection Criteria for Completion Thyroidectomy in Follicular Thyroid Carcinoma Using Primary Tumor Size and TERT Promoter Mutational Status.

BACKGROUND: A stepwise surgical approach with hemithyroidectomy and completion thyroidectomy was used to achieve definite characterization of follicular thyroid carcinoma (FTC). Choosing appropriate candidates for completion thyroidectomy has been controversial. OBJECTIVE: The aim of this study was to clarify the selection criteria for completion thyroidectomy using telomerase reverse transcriptase (TERT) promoter mutation. METHODS: A total of 87 FTC patients who had information about TERT promoter mutation from August 1995 to November 2020 were investigated. The cumulative risk of initial distant metastasis, disease recurrence, and cancer-specific death according to primary tumor size in each of the World Health Organization (WHO) 2017 classifications were calculated. RESULTS: Of the 87 patients, 8 (9.2%) had initial distant metastasis and 15 (17.2%) had persistent disease or developed structural recurrence. The threshold diameter for initial distant metastasis, disease recurrence, and cancer-specific death was 2 cm in minimally invasive FTC (MI-FTC) with mutant TERT (M-TERT) and in encapsulated angioinvasive FTC (EA-FTC) with M-TERT, while that in MI-FTC with wild-type TERT (WT-TERT) and EA-FTC with WT-TERT was 4 cm. The cumulative risk of initial distant metastasis, disease recurrence, and cancer-specific death according to primary tumor size in each WHO 2017 classification was significantly different only in patients with WT-TERT (p = 0.001, p = 0.019, and p = 0.005, respectively). CONCLUSIONS: The data suggest 2 cm as a critical threshold diameter for performance of completion thyroidectomy in MI-FTC with M-TERT and EA-FTC with M-TERT. TERT promoter mutational status can help select candidates for completion thyroidectomy.

Fat Loss in Patients with Metastatic Clear Cell Renal Cell Carcinoma Treated with Immune Checkpoint Inhibitors.

The purpose of this study was to determine the prognostic impact of fat loss after immune checkpoint inhibitor (ICI) treatment in patients with metastatic clear cell renal cell carcinoma (ccRCC). Data from 60 patients treated with ICI therapy for metastatic ccRCC were retrospectively analyzed. Changes in cross-sectional areas of subcutaneous fat (SF) between the pre-treatment and post-treatment abdominal computed tomography (CT) images were expressed as percentages and were divided by the interval between the CT scans to calculate ΔSF (%/month). SF loss was defined as ΔSF < -5%/month. Survival analyses for overall survival (OS) and progression-free survival (PFS) were performed. Patients with SF loss had shorter OS (median, 9.5 months vs. not reached; p < 0.001) and PFS (median, 2.6 months vs. 33.5 months; p < 0.001) than patients without SF loss. ΔSF was independently associated with OS (adjusted hazard ratio (HR), 1.49; 95% confidence interval (CI), 1.07-2.07; p = 0.020) and PFS (adjusted HR, 1.57; 95% CI, 1.17-2.12; p = 0.003), with a 5%/month decrease in SF increasing the risk of death and progression by 49% and 57%, respectively. In conclusion, Loss of SF after treatment initiation is a significant and independent poor prognostic factor for OS and PFS in patients with metastatic ccRCC who receive ICI therapy.

Molecular classification of follicular thyroid carcinoma based on TERT promoter mutations.

Follicular thyroid carcinoma (FTC) has different clinicopathological characteristics than papillary thyroid carcinoma. However, there are no independent systems to predict cancer-specific survival (CSS) in FTC. Telomerase reverse transcriptase (TERT) promoter mutations are associated with tumor aggressiveness. Thus, it could be a potential prognostic marker. The aim of this study was to refine the CSS risk prediction using TERT promoter mutations in combination with the fourth edition of World Health Organization (WHO 2017) morphological classification. We investigated 77 FTC patients between August 1995 and November 2020. Cox regression was used to calculate hazard ratios to derive alternative groups. Disease-free survival (DFS) and CSS predictability were compared using Proportion of variation explained (PVE) and C-index. CSS was significantly different in encapsulated angioinvasive (EA)-FTC patients stratified by TERT promoter mutations [wild-type (WT-TERT) vs. mutant (M-TERT); P < 0.001] but not in minimally invasive (MI)-FTC and widely invasive (WI)-FTC patients (P = 0.691 and 0.176, respectively). We defined alternative groups as follows: Group 1 (MI-FTC with WT-TERT and M-TERT; EA-FTC with WT-TERT), Group 2 (WI-FTC with WT-TERT), and Group 3 (EA-FTC with M-TERT; WI-FTC with M-TERT). Both PVE (22.44 vs. 9.63, respectively) and C-index (0.831 vs. 0.731, respectively) for CSS were higher in the alternative groups than in the WHO 2017 groups. Likewise, both PVE (27.1 vs. 14.9, respectively) and C-index (0.846 vs. 0.794, respectively) for DFS were also higher in the alternative groups than in the WHO 2017 groups. Alternative group harmonizing of the WHO 2017 classification and TERT promoter mutations is effective in predicting CSS in FTC patients, thereby improving DFS predictability.

Bone-density testing interval and transition to osteoporosis in differentiated thyroid carcinoma patients on TSH suppression therapy.

OBJECTIVE: Thyrotropin (TSH) suppression therapy is a standard treatment after surgery for differentiated thyroid carcinoma (DTC). It may be associated with osteoporosis in postmenopausal women. However, there are no guidelines for bone mineral density (BMD) testing intervals to screen for osteoporosis in these patients. Therefore, we evaluated the timing of repeated BMD testing in DTC patients with TSH suppression according to baseline T-scores. DESIGN, PATIENTS, AND MEASUREMENT: We retrospectively evaluated 658 DTC patients who underwent BMD testing more than twice between January 2007 and January 2020. A 1:3 propensity score matching was conducted to compare the timing of repeated BMD tests between the DTC and non-DTC groups. We stratified the participants into four groups based on their baseline T-scores: normal (-1.00 or higher), mild osteopenia (-1.01 to -1.49), moderate osteopenia (-1.50 to -1.99), and severe osteopenia (-2.00 to -2.49). Additionally, the 10% of patients in each group that transitioned to osteoporosis were analysed. RESULTS: The estimated BMD testing interval for 10% of patients who developed osteoporosis was 85 months for patients with initially mild osteopenia, 65 months for those with moderate osteopenia, and 15 months for those with severe osteopenia in the DTC group. In the non-DTC group, the testing intervals for mild, moderate, and severe osteopenia were 98, 57, and 13 months, respectively. On multivariate analysis, baseline T-score (mild osteopenia: hazard ratio [HR] 5.91, p = .105; moderate osteopenia: HR, 25.27, p = .02; and severe osteopenia: HR, 134.82, p < .001) and duration of TSH suppression (tertile 2: HR, 2.25, p = .005; Tertile 3: 1.78, p = .033) were independent risk factors for osteoporosis in the DTC group. CONCLUSION: This study provides guidance for the timing of repeated BMD tests in women over 50 years of age with TSH suppression. The rescreening interval for BMD testing can be modified based on the baseline T-score. The appropriate BMD testing intervals in female DTC patients were similar to those in non-DTC females.

The longitudinal effect of oxcarbazepine on thyroid function in children and adolescents with epilepsy.

OBJECTIVE: Thyroid hormone abnormalities have been linked to antiseizure medications (ASMs). Oxcarbazepine is considered safer than carbamazepine because it induces the hepatic cytochrome P450 metabolic enzymes less than the carbamazepine does. However, limited data exist for the influence of oxcarbazepine on thyroid function in children and adolescents. The objective of this study was to determine the effect of oxcarbazepine on thyroid function in these patients. METHODS: A total of 162 pediatric patients with epilepsy who started oxcarbazepine for the first time between April 2003 and May 2020 were enrolled. The longitudinal effects of oxcarbazepine for thyroid functions were confirmed using general estimating equations. RESULTS: Serum triiodothyronine (T3), thyroxine (T4), and free thyroxine (fT4) levels decreased significantly during 5 years of follow-up (all p's < .001). In particular, T3 and fT4 levels were reduced steeply in the first 2 years of oxcarbazepine treatment. There was no significant change in thyroid-stimulating hormone during oxcarbazepine treatment. SIGNIFICANCE: Serum T3, T4, and fT4 levels decreased significantly during oxcarbazepine use, and this change was maintained during the treatment period. In patients receiving oxcarbazepine, it is recommended that periodic thyroid function testing should be performed, especially within the first 2 years after starting this ASM. Our results indicate that oxcarbazepine-induced hypothyroidism does not appear to be accompanied by a significant increase in TSH, and consequently might be missed if TSH alone is monitored as a measure of thyroid dysfunction.

Inner surface modification of ureteral stent polyurethane tubes based by plasma-enhanced chemical vapor deposition to reduce encrustation and biofilm formation.

Encrustation and/or biofilm formation in ureteral stents are major causes of obstruction and reduce the lifetime of a ureteral stent. In this study, the inner surfaces of polyurethane (PU) tubes (inner and outer diameters of 1.2 and 2.0 mm, respectively) were reformed with Ar, O2, and C2H2 gases using specialized plasma-enhanced chemical vapor deposition techniques for the first time. Then, the modified PU tubes were immersed in urine for 15 days, and the characteristics of the inner surfaces were analyzed. Depending on the modification procedure, the corresponding inner surface exhibited different chemical properties and different rates of encrustation and biofilm formation. For a hydrophilic surface treated with Ar and O2, encrustation and biofilm formation increased, while for the C2H2 coating, the development of encrustation and biofilm reduced by more than five times compared with the untreated bare PU tube. This study demonstrated that inner plasma surface modification of ureteral stents greatly enhances resistance to encrustation and biofilm formation.

Transrectal ultrasound features and biopsy outcomes of transition PI-RADS 5.

BACKGROUND: Transition Prostate Imaging and Reporting and Data System (PI-RADS) 5 is easily detected owing to typical magnetic resonance imaging features. However, it is unclear as to how transition PI-RADS 5 appears on transrectal ultrasound (TRUS). PURPOSE: To assess TRUS features of transition PI-RADS 5 and outcomes of TRUS-guided target biopsy. MATERIAL AND METHODS: Between March 2014 and November 2018, 186 male patients underwent TRUS-guided biopsy of PI-RADS 5. Of them, 82 and 104were transition and peripheral PI-RADS 5, respectively. Transition and peripheral PI-RADS 5 were compared according to echogenicity (hyperechoic or hypoechoic) and hypoechoic rim (present or absent). Each tumor was targeted with TRUS based on TRUS features. Significant (Gleason score ≥7) and insignificant (Gleason score 6) cancer detection rates (CDRs) were compared between transition and peripheral PI-RADS 5. Standard reference was biopsy examination. Fisher's exact test was used for statistical analysis. RESULTS: Transition PI-RADS 5 was hyperechoic in 89.0% (73/82) and had a hypoechoic rim in 97.6% (80/82), whereas peripheral PI-RADS 5 was hypoechoic in 99.0% (103/104) and had a hypoechoic rim in 26.9% (28/104) (both, P<0.0001). The significant CDRs of transition and peripheral PI-RADS 5 were 56.1% (46/82) and 65.4% (68/104), respectively (P=0.2263). However, the insignificant CDRs of these categories were 22.0% (18/82) and 8.7% (9/104), respectively (P=0.0123). CONCLUSION: Transition PI-RADS 5 tends to have hyperechoic echogenicity and a hypoechoic rim. These findings help to target the transition PI-RADS 5 using TRUS. However, transition PI-RADS 5 is confirmed more frequently as insignificant cancer than peripheral PI-RADS 5.

Impact of etiology on force and kinetics of left ventricular end-stage failing human myocardium.

BACKGROUND: Heart failure (HF) is associated with highly significant morbidity, mortality, and health care costs. Despite the significant advances in therapies and prevention, HF remains associated with poor clinical outcomes. Understanding the contractile force and kinetic changes at the level of cardiac muscle during end-stage HF in consideration of underlying etiology would be beneficial in developing targeted therapies that can help improve cardiac performance. OBJECTIVE: Investigate the impact of the primary etiology of HF (ischemic or non-ischemic) on left ventricular (LV) human myocardium force and kinetics of contraction and relaxation under near-physiological conditions. METHODS AND RESULTS: Contractile and kinetic parameters were assessed in LV intact trabeculae isolated from control non-failing (NF; n = 58) and end-stage failing ischemic (FI; n = 16) and non-ischemic (FNI; n = 38) human myocardium under baseline conditions, length-dependent activation, frequency-dependent activation, and response to the ß-adrenergic stimulation. At baseline, there were no significant differences in contractile force between the three groups; however, kinetics were impaired in failing myocardium with significant slowing down of relaxation kinetics in FNI compared to NF myocardium. Length-dependent activation was preserved and virtually identical in all groups. Frequency-dependent activation was clearly seen in NF myocardium (positive force frequency relationship [FFR]), while significantly impaired in both FI and FNI myocardium (negative FFR). Likewise, ß-adrenergic regulation of contraction was significantly impaired in both HF groups. CONCLUSIONS: End-stage failing myocardium exhibited impaired kinetics under baseline conditions as well as with the three contractile regulatory mechanisms. The pattern of these kinetic impairments in relation to NF myocardium was mainly impacted by etiology with a marked slowing down of kinetics in FNI myocardium. These findings suggest that not only force development, but also kinetics should be considered as a therapeutic target for improving cardiac performance and thus treatment of HF.

Surgeon Volume and Long-Term Oncologic Outcomes in Patients with Medullary Thyroid Carcinoma.

BACKGROUND: Surgery is the most important curative treatment for medullary thyroid carcinoma (MTC). The relationship between surgeon volume (the number of surgeries performed) and short-term surgical outcomes, such as increased postoperative complication or costs, is well established. This study evaluated whether surgeon volume influenced long-term oncologic outcomes. METHODS: We retrospectively reviewed 246 patients diagnosed with MTC after initial thyroid surgery from 1995 to 2019. After exclusion, 194 patients were eligible for inclusion in the study. Surgeons were categorized as low/intermediate volume (fewer than 100 operations per year) or high volume (at least 100 operations per year). RESULTS: Of the 194 included patients, 60 (30.9%) developed disease recurrence, and 9 (4.6%) died of MTC during the median follow-up of 92.5 months. Having a low/intermediate-volume surgeon was associated with high disease recurrence (log-rank test, p < 0.001). After adjustment for age, sex, tumor type (sporadic versus hereditary), primary tumor size, presence of central lymph node metastasis (LNM), presence of lateral LNM, extrathyroidal extension, and positive resection margin, surgeon volume was a significant factor for disease recurrence (hazard ratio 2.28, p = 0.004); however, cancer-specific survival was not affected by surgeon volume (hazard ratio 4.16, p = 0.115). CONCLUSIONS: Surgeon volume is associated with long-term oncologic outcome. MTC patients will be able to make the best decisions for their treatment based on the results of this study.

Ultrasound-guided fine-needle aspiration or core needle biopsy for diagnosing follicular thyroid carcinoma?

OBJECTIVE: We evaluated the preoperative diagnostic values of ultrasound (US), fine-needle aspiration (FNA) and core needle biopsy (CNB) leading to surgery in patients with FTC. METHODS: From October 1994 to July 2016, 298 patients with FTC who had preoperative US images and underwent US-guided FNA or CNB and surgery were included in this study. We evaluated the results of preoperative FNA or CNB based on the Bethesda system and the US findings according to the Korean thyroid imaging reporting and data system (K-TIRADS). RESULTS: Predominant US features of FTC showed solid, hypo- or iso-echogenicity, oval smooth margin and halo with no calcification. Based on K-TIRADS, 140 (47.0%) patients with FTC were categorized as low suspicion, 133 (44.63%) as intermediate suspicion and 25 (8.4%) as high suspicion at US. Considering only FNA cytology (n = 230), 6.9% were revealed as Bethesda class I, 16.1% as class II, 37.0% as class III, 29.1% as class IV and 10.9% as class V. Considering the 68 cases with CNB results, 2.9% were revealed as class I, 4.4% as class II, 20.6% as class III and 72.1% as class IV. Despite multiple FNAs, 16.7% of the 84 patients with FTC still obtained Bethesda class I or class II. CNB results in patients with FTC had a significantly higher rate of Bethesda class IV compared to the FNA results (P < .001). FTCs with distant metastasis exhibited a significantly higher rate of Bethesda classes IV and V compared to those without distant metastasis (P = .004). CONCLUSION: Surgery for FTC is deferred only with preoperative US and FNA. CNB in patients with FTC can lead to surgery better than FNA. Therefore, if the US feature is characteristic and a serially growing large nodule is suspected, the first attempt of CNB may be helpful in selecting a surgical candidate.

Effects of poloxamer-based thermo-sensitive sol-gel agent on urethral stricture after transurethral resection of the prostate for benign prostatic hyperplasia: a multicentre, single-blinded, randomised controlled trial.

OBJECTIVE: To evaluate the effectiveness of poloxamer-based thermo-sensitive sol-gel instillation, after transurethral resection of the prostate (TURP), for preventing urethral stricture. PATIENTS AND METHODS: In all, 198 patients underwent TURP for benign prostatic hyperplasia. Recruited patients were randomly divided into two groups: groups A and B. Patients in Group A (100 patients, experimental group) received poloxamer-based thermo-sensitive sol-gel instillation and patients in the Group B (98 patients, control group) received lubricant instillation after TURP. Each patient was evaluated at 4 (V1), 12 (V2), and 24 weeks (V3) after TURP. The effectiveness of poloxamer-based thermo-sensitive sol-gel instillation was evaluated based on the International Prostate Symptom Score (IPSS), IPSS-Quality of Life (QoL), Overactive bladder questionnaire (OAB-q), maximum urinary flow rate (Qmax ), post-void residual urine volume (PVR), and cystoscopy. RESULTS: Amongst the initial 198 participants, 80 patients in Group A and 83 in Group B completed the study. There were no significant differences in IPSS-QoL and OAB-q between the groups. However, Qmax was significantly different between groups A and B, at a mean (SD) of 18.92 (9.98) vs 15.58 (9.24) mL/s (P = 0.028) at 24 weeks after TURP. On cystoscopic examination, urethral stricture after TURP was found in two of the 80 patients in Group A and 10 of 83 in Group B (P = 0.023). CONCLUSIONS: Poloxamer-based thermo-sensitive sol-gel instillation after TURP lowered the incidence of urethral stricture.

BRAF and TERT promoter mutations: clinical application in thyroid cancer.

Given the long-term survival of most patients with thyroid cancer, it is very important to distinguish patients who need aggressive treatment from those who do not. Conventional clinicopathological prognostic parameters could not completely predict the final outcome of each patient. Recently, molecular marker-based risk stratification of thyroid cancer has been proposed to better estimate the cancer risk. Although BRAF mutation has drawn much attention based on its high prevalence, its association with recurrence or mortality is not clear. Recently, telomerase reverse transcriptase (TERT) promoter mutation has been identified in thyroid cancer. It increases telomerase activity, which allows cancer cells to immortalize. It was found in 10 to 20% of differentiated thyroid carcinoma and 40% of dedifferentiated thyroid carcinoma. It is highly prevalent in old age, large tumor, aggressive histology, advanced stages, and distant metastasis. It is associated with increased recurrence and mortality. Concomitant BRAF and TERT promoter mutations worsen the survival rate. Inclusion of TERT promoter mutation analysis with conventional clinicopathological evaluation can lead to better prognostication and management for individual patients.

Strategy for Prostate Cancer Patients with Low Prostate Specific Antigen Level (2.5 to 4.0 ng/mL).

BACKGROUND: To evaluate the strategy for detection of prostate cancer (PCa) with low prostate specific antigen (PSA) level (2.5-4.0 ng/mL), prostate biopsy patients with low PSA were assessed. We evaluated the risk of low PSA PCa and the strategy for screening low-PSA patients. METHODS: We retrospectively analyzed the patients who underwent prostate biopsy with low PSA level. Baseline characteristics, PSA level before prostate biopsy, prostate volume, prostate specific antigen density (PSAD), and pathological data were assessed. RESULTS: Among the 1986 patients, 24.97% were diagnosed with PCa. The PSAD was 0.12 ± 0.04 ng/mL² in the PCa-diagnosed group and 0.10 ± 0.04 ng/mL² in non-cancer-diagnosed group (P < 0.001). Of the 496 patients diagnosed with PCa, 302 (60.89%) were in the intermediate- or high-risk group. PSAD was 0.13 ± 0.04 ng/mL² in the intermediate- or high-risk group and 0.11 ± 0.03 ng/mL² in the very low- and low-risk group (P < 0.001). Of 330 patients who underwent radical prostatectomy, 85.15% were diagnosed as having significant cancer. There was significant correlation between PSAD and PCa (r = 0.294, P < 0.001). PSAD with a specificity of 80.00% of a clinically significant cancer diagnosis was assessed at 0.1226 ng/mL². CONCLUSION: The PCa detection rate in the low-PSA group was not lower than that of previous studies of patients with PSA from 4.0 to 10.0 ng/mL. Further, it may be helpful to define a strategy for PCa detection using PSAD in the low-PSA group.

Highly Sensitive and Specific Molecular Test for Mutations in the Diagnosis of Thyroid Nodules: A Prospective Study of BRAF-Prevalent Population.

Molecular testing offers more objective information in the diagnosis and personalized decision making for thyroid nodules. In Korea, as the BRAF V600E mutation is detected in 70-80% of thyroid cancer specimens, its testing in fine-needle aspiration (FNA) cytology specimens alone has been used for the differential diagnosis of thyroid nodules until now. Thus, we aimed to develop a mutation panel to detect not only BRAF V600E, but also other common genetic alterations in thyroid cancer and to evaluate the diagnostic accuracy of the mutation panel for thyroid nodules in Korea. For this prospective study, FNA specimens of 430 nodules were obtained from patients who underwent thyroid surgery for thyroid nodules. A molecular test was devised using real-time PCR to detect common genetic alterations in thyroid cancer, including BRAF, N-, H-, and K-RAS mutations and rearrangements of RET/PTC and PAX8/PPARr. Positive results for the mutation panel were confirmed by sequencing. Among the 430 FNA specimens, genetic alterations were detected in 293 cases (68%). BRAF V600E (240 of 347 cases, 69%) was the most prevalent mutation in thyroid cancer. The RAS mutation was most prevalently detected for indeterminate cytology. Among the 293 mutation-positive cases, 287 (98%) were diagnosed as cancer. The combination of molecular testing and cytology improved sensitivity from 72% (cytology alone) to 89% (combination), with a specificity of 93%. We verified the excellent diagnostic performance of the mutation panel applicable for clinical practice in Korea. A plan has been devised to validate its performance using independent FNA specimens.

Impact of heart rate on cross-bridge cycling kinetics in failing and nonfailing human myocardium.

The force-frequency relationship (FFR) is an important regulatory mechanism that increases the force-generating capacity as well as the contraction and relaxation kinetics in human cardiac muscle as the heart rate increases. In human heart failure, the normally positive FFR often becomes flat, or even negative. The rate of cross-bridge cycling, which has been reported to affect cardiac output, could be potentially dysregulated and contribute to blunted or negative FFR in heart failure. We recently developed and herein use a novel method for measuring the rate of tension redevelopment. This method allows us to obtain an index of the rate of cross-bridge cycling in intact contracting cardiac trabeculae at physiological temperature and assess physiological properties of cardiac muscles while preserving posttranslational modifications representative of those that occur in vivo. We observed that trabeculae from failing human hearts indeed exhibit an impaired FFR and a reduced speed of relaxation kinetics. However, stimulation frequencies in the lower spectrum did not majorly affect cross-bridge cycling kinetics in nonfailing and failing trabeculae when assessed at maximal activation. Trabeculae from failing human hearts had slightly slower cross-bridge kinetics at 3 Hz as well as reduced capacity to generate force upon K+ contracture at this frequency. We conclude that cross-bridge kinetics at maximal activation in the prevailing in vivo heart rates are not majorly impacted by frequency and are not majorly impacted by disease.NEW & NOTEWORTHY In this study, we confirm that cardiac relaxation kinetics are impaired in filing human myocardium and that cross-bridge cycling rate at resting heart rates does not contribute to this impaired relaxation. At high heart rates, failing myocardium cross-bridge rates are slower than in nonfailing myocardium.

Urinary iodine concentration and thyroid hormones: Korea National Health and Nutrition Examination Survey 2013-2015.

PURPOSE: An epidemiologic study that evaluated population's iodine nutrition status and its relationship with thyroid hormones is lacking in iodine-sufficient area. This nationwide study aimed to evaluate the iodine nutrition status in Korea and relationship between urine iodine concentration (UIC) and thyroid hormones. METHODS: A total of 8318 subjects of the Korea National Health and Nutrition Examination Survey VI (2013-2015) with UIC and thyroid hormone evaluation were included. Median UIC level and estimated 24-h iodine intake were calculated. The prevalence of iodine deficiency or excess was obtained using estimated average requirement or above the tolerable upper intake level cut-point method by estimated iodine intake. We analyzed UIC with regard to age, sex, social economic status, and geographic characteristics. RESULTS: The median UIC in general population and estimated iodine intake in adult population were 293.9 µg/L (above requirement according to World Health Organization classification) and 249.3µg/day, respectively. The prevalence of iodine deficiency and excess was 14.0 and 13.4%. The median UIC was higher among SAC [511 (299.9-948.5)] and lower among seventies [251.2 (98.9-761.6)] compared to other age groups. The median UIC increased with household income level (p for trend < 0.001). The subjects living in rural and inland region had lowest UIC among the enrolled subjects. The subgroups with higher median UIC were associated with higher mean TSH levels. CONCLUSIONS: This first nationwide study in Korea demonstrated that the median of UIC and estimated iodine intake lie at nearly 300 µg/L and 250 µg/day, respectively, which shows an overall excellent iodine nutrition.

Non-immune-related hypothyroidism and its relationship with excess iodine.

PURPOSE: In iodine-sufficient areas, autoimmune hypothyroidism has been regarded as the major subtype of hypothyroidism. Non-immune-related hypothyroidism has received little attention because it is considered to be rare. The aim of this study was to evaluate the prevalence of non-immune-related hypothyroidism in Korea and to identify its associating factors. METHODS: A total of 6434 participants in the Korea National Health and Nutrition Examination Survey VI (2013-2015) without known thyroid disease who were examined for thyroid stimulating hormone, free thyroxine, TPO Ab, and urine iodine concentration (UIC) were enrolled. The weighted proportions, demographic variables, and severity of immune-related and non-immune-related hypothyroidism were compared. To assess the effect of iodine on hypothyroidism in TPO Ab positive or negative populations, the weighted prevalence of hypothyroidism was assessed in each population according to UIC or estimated iodine intake subgroups. RESULTS: The prevalence of undetected hypothyroidism in Korea was 3.8% (n = 233). Of these 233 cases, 171 (71.8%) were non-immune-related. In the TPO Ab negative population, the prevalence of hypothyroidism was increased significantly in the subgroup with UIC between 250 and 749 µg/L (HR 2.12 [1.17, 3.83]) and ≥ 750 µg/L (HR 3.42 [1.93, 6.04]) or the subgroups with estimated iodine intake ≥ 750 µg/day (HR 2.81 [1.64, 4.80]). CONCLUSIONS: This nationwide study demonstrated that most cases of hypothyroidism in iodine-sufficient areas are non-immune-related and are associated with excess iodine above a certain level. More attention to this unrecognized but widespread potential health risk is needed.

Antithyroid Drugs and Congenital Malformations: A Nationwide Korean Cohort Study.

Background: Untreated or insufficiently treated Graves disease in pregnancy may pose risks to both mother and fetus. Antithyroid drugs (ATDs) are the treatment mainstay, but the potential teratogenic effect of these drugs has prompted clinicians to question the safe management of this vulnerable population. Objective: To examine the association between maternal prescriptions for ATDs and congenital malformations in live births. Design: Nationwide cohort study. Setting: Korean National Health Insurance database. Participants: A cohort of 2 886 970 completed pregnancies linked to live-born infants in 2 210 253 women between 2008 and 2014. Intervention: Maternal prescriptions for ATDs in the first trimester. Measurements: The risk for overall and organ-specific congenital malformations in offspring, with logistic regression models used to control for potential confounders. Results: 12 891 pregnancies (0.45%) were exposed to ATDs during the first trimester. The prevalence of malformations in exposed offspring was 7.27%, compared with 5.94% in offspring of women who were not prescribed ATDs during pregnancy (P < 0.001) (adjusted odds ratio, 1.19 [95% CI, 1.12 to 1.28]). Absolute increases in the prevalence of congenital malformations per 1000 live births were 8.81 cases (CI, 3.92 to 13.70 cases) for propylthiouracil alone, 17.05 cases (CI, 1.94 to 32.15 cases) for methimazole (MMI) alone, and 16.53 cases (CI, 4.73 to 28.32 cases) for propylthiouracil and MMI, compared with pregnancies without ATD prescriptions. In the MMI group, a high cumulative dose (>495 mg) during the first trimester was associated with an increased risk for malformations compared with a low dose (1 to 126 mg) (adjusted odds ratio, 1.87 [CI, 1.06 to 3.30]). Limitation: The study used a prescription claims database to assess ATD exposure. Conclusion: Exposure to ATDs during the first trimester was associated with increased risk for congenital malformations, particularly for pregnancies in which women received prescriptions for MMI or both ATDs. Primary Funding Source: None.