Shortened telomere length in peripheral blood leukocytes is associated with cumulative radioactive iodine doses in patients with differentiated thyroid carcinoma.

BACKGROUND: Telomere length is associated with cancer risk and cancer aggressiveness. Radioactive iodine (RAI) therapy for thyroid cancer has raised concerns for second primary malignancy (SPM) in patients with high cumulative doses. The association between RAI dose and peripheral blood leukocyte telomere length was examined. METHODS: A total of 425 patients were included who underwent total thyroidectomy and were followed up for at least 1 year with or without RAI treatment. The relative telomere length (RTL) of the patients was assessed via a quantitative polymerase chain reaction amplification method. RAI doses were divided into five groups on the basis of cumulative dose, and a comparison was made among these groups. RESULTS: The number of patients with RAI treatment was 287 (67.5%), and the cumulative RAI dose was 3.33 GBq (range, 1.11-131.35 GBq). The mean RTL was significantly shorter in the highest RAI group (>22.2 GBq) compared to both the no-RAI and lower dose groups. The association between RAI dose and RTL was positive in the lower RAI group (1.1-3.7 GBq) and negative in the highest RAI group in both univariate and multivariate analyses. We observed 59 (13.9%) SPMs and 20 (4.7%) mortalities, and RTL did not show a significant risk effect for all-cause, thyroid cancer-specific, or SPM-specific mortality. CONCLUSIONS: In patients with thyroid cancer who underwent total thyroidectomy, peripheral blood leukocyte telomere length exhibited a significant association with cumulative RAI dose higher than 22.2 GBq. These results suggest the possibility of telomere length shortening in patients who undergo high-dose RAI treatment.

Distribution of urinary trace element exposure and dietary sources in women over 50 in an agricultural region- A community-based KoGES cohort study.

BACKGROUND: There is a noticeable lack of information on the levels of both non-essential and essential trace elements in women aged over 50. The main objective of this study is to investigate trace element concentrations and explore the influence of sociodemographic factors and dietary sources of exposure in this demographic. METHODS: We analyzed 19 trace elements, including manganese, cobalt, copper, zinc, molybdenum, chromium, nickel, arsenic, strontium, cadmium, tin, antimony, cesium, barium, tungsten, mercury, thallium, lead, and uranium, using ICP-MS and mercury analyzer. Urine samples were obtained from a cohort of 851 women aged over 50 who participated in the 8th KoGES-Ansung study (2017-2018). Multiple linear models were employed to explore associations between urinary trace element concentrations and sociodemographic factors and dietary sources of exposure. We used K-means clustering to discern patterns of exposure to trace elements and identify contributing factors and sources. RESULTS: Our findings indicate higher concentrations of molybdenum (Mo), arsenic (As), cadmium (Cd), and lead (Pb) in our study population compared to women in previous studies. The study population were clustered into two distinct groups, characterized by lower or higher urinary concentrations. Significant correlations between age and urinary concentrations were observed in Ni. Smoking exhibited positive associations with urinary Cd and As. Associations with dietary sources of trace elements were more distinct in women in the high-exposure group. Urinary antimony (Sb) was positively linked to mushroom and egg intake, As to mushroom and fish, and Hg to egg, dairy products, fish, seaweed, and shellfish. CONCLUSIONS: Our study underscores the significant gap in understanding urinary concentrations of trace elements in women aged over 50. With higher concentrations of certain elements compared to previous studies and significant correlations between age, smoking, and specific food sources, it is imperative to address this gap through targeted dietary source-specific risk management.

Surgical Outcomes in Patients With Low-risk Papillary Thyroid Microcarcinoma From MAeSTro Study: Immediate Operation Versus Delayed Operation After Active SurveillanceA Multicenter Prospective Cohort Study.

OBJECTIVE: To investigate surgical, and clinical outcomes in patients with low-risk papillary thyroid microcarcinoma (PTMC) according to treatment options [immediate operation (IOP) vs delayed operation after active surveillance (AS) (DOP)]. BACKGROUND: AS has been adopted as an alternative to immediate surgery in patients with low-risk PTMC. Although some patients undergo surgery during AS, there is little information on surgical, and clinical outcomes after delayed operation after AS. METHODS: A multicenter prospective cohort study including 1177 patients was conducted at 3 tertiary hospitals in Korea from June 2016 to January 2020. Patients with low-risk PTMC were enrolled. The participants were self-assigned into AS or IOP, and during AS, the patients underwent surgery if there were signs of disease progression or if the patient's choice changed. RESULTS: A total of 516 patients underwent operation; 384 (74.4%) in the IOP group and 132 (25.6%) in the DOP group. Compared with the IOP group, the DOP group was significantly associated with a larger tumor size ( P =0.002), higher rates of lymphatic invasion ( P =0.002), and multifocality ( P =0.008). However, the rates of total thyroidectomy, postoperative hypoparathyroidism and vocal cord palsy did not differ significantly between the groups ( P = 0.283, P =0.184, and P =0.284, respectively). Of the 132 patients in the DOP group, disease progression was present in 39 (29.5%) patients. The DOP group with disease progression had a significantly higher rate of lymph node metastasis ( P =0.021) and radioiodine therapy ( P =0.025) than the DOP group without disease progression. CONCLUSIONS: These results suggest that AS might be considered an alternative treatment option for patients with low-risk PTMC regarding the extent of thyroidectomy and postoperative complications in the DOP group. To assess oncologic outcomes, long-term follow-up will be needed. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02938702.

US Predictors of Papillary Thyroid Microcarcinoma Progression at Active Surveillance.

Background Active surveillance (AS) is an accepted strategy for patients with low-risk papillary thyroid microcarcinoma (PTMC). While previous studies have evaluated the prognostic value of US features, results have been inconsistent. Purpose To determine if US features can help predict tumor progression in patients with low-risk PTMC undergoing AS. Materials and Methods This prospective study enrolled 1177 participants with PTMC from three hospitals between June 2016 and January 2021. Participants were self-assigned to either immediate surgery or AS, and those with two or more US examinations in the absence of surgery were included in the analysis. A χ2 test was used to compare estimated tumor progression rate at 4 years between participants stratified according to US features. Multivariable Cox regression analysis was used to assess the association of clinical and US features with overall tumor progression and specific progression criteria. Results Among 699 participants included in the analysis, 68 (mean age, 49 years ± 12 [SD]; 40 female participants) showed tumor progression (median follow-up, 41.4 months ± 16 [SD]). Tumor progression was associated with the US features of diffuse thyroid disease (DTD) (hazard ratio [HR], 2.3 [95% CI: 1.4, 3.7]; P = .001) and intratumoral vascularity (HR, 1.7 [95% CI: 1.0, 3.0]; P = .04) and the participant characteristics of male sex (HR, 2.8 [95% CI: 1.7, 4.6]; P < .001), age less than 30 years (HR, 2.9 [95% CI: 1.2, 6.8]; P = .01), and thyroid-stimulating hormone level of 7 µU/mL or higher (HR, 6.9 [95% CI: 2.7, 17.4]; P < .001). The risk of tumor progression was higher for participants with DTD (14%, P = .001) or intratumoral vascularity (14%, P = .02) than for participants without these features (6%). DTD and intratumoral vascularity were associated with tumor enlargement (HR, 2.7 [95% CI: 1.4, 5.1]; P = .002) and new lymph node metastasis (HR, 5.0 [95% CI: 1.3, 19.4]; P = .02), respectively. Conclusion DTD and intratumoral vascularity were associated with an increased risk of tumor progression in participants with PTMC undergoing AS. Clinical trial registration no. NCT02938702 © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Reuter and the review "International Expert Consensus on US Lexicon for Thyroid Nodules" by Durante et al in this issue.

Effect of postoperative radiotherapy for patients with differentiated thyroid cancer.

OBJECTIVE: We evaluated the efficacy and safety of postoperative radiotherapy (PORT) for differentiated thyroid cancer (DTC) with high risk features. MATERIALS AND METHODS: This retrospective study analyzed 187 patients treated for DTC from 1985 to 2019. DTC referred to nonanaplastic thyroid cancer originating from follicular cells. PORT was defined as the administration of external beam radiation to the thyroid and regional lymph nodes following surgery for initially diagnosed DTC. The patients were included in the analysis if they received PORT or exhibited any of the following features: (a) pT4 or pN1b according to the 8th American Joint Committee on Cancer, (b) poorly differentiated thyroid cancer (PDTC), or (c) unfavourable variants such as anaplastic foci and etc. After 1:1 propensity matching, a total of 108 patients were analyzed according to PORT receipt. The median follow-up duration of the matched group was 10.4 years. RESULTS: After matching, most of the variables became balanced, but the PORT group still had more PDTC and DTC with anaplastic foci. Radioactive iodine (RAI) was less frequently administered in the PORT group. PORT yielded a significantly higher 5-year locoregional recurrence free survival (LRFS) than the No PORT group (5-year LRFS 86.1% vs. 72.7%, p = 0.022), but the 10-year cancer specific survival (CSS) was similar between them (97.8% vs. 85.9%, p = 0.122). The multivariable analysis indicated that PORT was a favourable prognostic factor (Hazard ratio 0.3, 95% Confidence interval 0.1-0.8, p = 0.02) for LRFS, but not for CSS. Among 133 patients without PORT for initial disease, 39 of them received salvage surgery followed by salvage PORT. No severe toxicity after PORT was reported. CONCLUSION: PORT reduced locoregional recurrence in DTC patients without severe toxicity. PORT can be an effective and safe treatment to improve locoregional control in DTC with high risk features. However, further study is warranted to identify those who can benefit from PORT.

High intakes of iodine among women during pregnancy and the postpartum period has no adverse effect on thyroid function.

PURPOSE: Given the high consumption of seaweed soup by pregnant and lactating Korean women, concerns have been raised about excessive iodine intake. We evaluated the effects of maternal iodine intake on maternal thyroid function and birth outcomes. We also evaluated iodine intake via seaweed soup during late pregnancy and the early postpartum period. METHODS: A total of 349 pregnant women of the Ideal Breast Milk cohort were recruited in late pregnancy, of whom 302 revisited after delivery. Three-day dietary records were assessed at each visit. Blood was collected for thyroid function test. Obstetrical and birth outcomes were obtained. RESULTS: The median dietary iodine intake was 459 µg/day (interquartile range [IQR] 326.5-647.4 µg/day) during pregnancy. Dietary iodine intake by quartile was not significantly associated with maternal thyroid status, or obstetrical or neonatal outcomes. However, the dietary iodine intake in the early postpartum period was 1759 µg/day (IQR 1026.7-2491.1 µg/day) because of a marked increase in seaweed soup consumption. Of all women, 25.8% consumed seaweed soup more than once over the 3 days of dietary records when pregnant, but the figure rose to 93.4% postpartum. Of postpartum women who consumed seaweed soup daily, the median dietary iodine intakes were 1355, 2394, and 3063 µg/day (soup at one, two, and three-or-four meals). CONCLUSIONS: In these iodine-replete pregnant women, dietary iodine intake during pregnancy showed no effect on maternal thyroid function or birth outcomes. However, iodine intake in the early postpartum period was markedly increased by the frequency of seaweed soup consumption.

Seroprevalence of Hepatitis C Virus Infection in North Korean Defectors Residing in Korea.

BACKGROUND: This study aimed to investigate the prevalence rate of hepatitis C virus (HCV) infection and identify the demographic, and sociological characteristics and changes in awareness of HCV infection by participating the study for North Korean defectors residing in South Korea. METHODS: This study prospectively enrolled participants. Demographic, sociological and clinical data, and questionnaire surveys focused on awareness of HCV infection were collected. RESULTS: In total, 211 North Korean defectors participated in this study from September 2020 until June 2021. There were 174 women (82.5%), and the overall mean age was 48.9 years (range, 20 to 80 years). Of these participants, 112 (53.1%) had immigrated to South Korea since 2011. The overall prevalence of anti-HCV antibody among North Korean defectors was 1.9%. Thirty participants (14.2%) had hepatitis B surface antigens. A huge lack of awareness regarding HCV infection has been observed among North Korean defectors. CONCLUSION: This is the first prospective study to investigate the prevalence rate of HCV infection among North Korean defectors residing in South Korea. As North Korean defectors are a vulnerable group concerning HCV infection, they may benefit from HCV screening policies and educational interventions for HCV infection.

Erratum: Correction of Text in the Article "Seroprevalence of Hepatitis C Virus Infection in North Korean Defectors Residing in Korea".

This corrects the article on p. e270 in vol. 38, PMID: 37644684.

Sex, menopause, and age differences in the associations of persistent organic pollutants with thyroid hormones, thyroxine-binding globulin, and peripheral deiodinase activity: A cross-sectional study of the general Korean adult population.

Persistent organic pollutants (POPs) can disrupt the thyroid hormone system in humans. We assessed the associations of several POPs with serum thyroid hormones (T3 and T4) and thyroid-stimulating hormone, and investigated the modulating effects of sex, menopausal status, and age on these associations, in a subgroup of the adult population (n = 1250) from the Korean National Environmental Health Survey. PCB105 and PCB118 were negatively associated with total T4 in premenopausal females and males aged <50, whereas the associations were insignificant in other groups. PCB180, p,p'-DDE, and p,p'-DDT showed positive associations with total T3 in postmenopausal females; however, among males aged ≥50, PCB118, PCB138, and p,p'-DDE showed negative associations with total T3. The effects of exposure to multiple POPs were examined in multi-factor analyses. Factor 2 comprised PCB52, hexachlorobenzene, and BDE-47 was associated with an increase in free T4 in premenopausal females (ß = 0.015, p = 0.024), while Factor 1, which contained most POPs, was associated with a change in total T3 in postmenopausal females (ß = 0.032, p = 0.040) and males aged ≥50 (ß = -0.039, p = 0.023). Changes in total T4 or total T3 could be explained by differences in thyroxine-binding globulin (TBG) and peripheral deiodinase activity (GD). Negative associations of TBG with PCB105 in premenopausal females and PCB153 in males aged <50 may mediate the effect of decreasing total T4. PCB180, p,p'-DDE, p,p'-DDT, and Factor 1 were positively associated with GD, which is consistent with an increased total T3 in postmenopausal females. PCB118 was negatively associated with GD and total T3 in males aged ≥50. BDE-47 and ß-hexachlorocyclohexane were associated with thyroid autoantibodies in premenopausal females and males aged <50. Our observations suggest that the thyroid-disrupting effects of POPs may differ by sex, sex hormonal status, and age, and may be mediated by TBG and GD.

Lead, mercury, and cadmium exposures are associated with obesity but not with diabetes mellitus: Korean National Environmental Health Survey (KoNEHS) 2015-2017.

BACKGROUND: Associations of heavy metal exposures with obesity and obesity-related traits have been suggested, while those with nonalcoholic fatty liver disease (NAFLD) and diabetes mellitus (DM) are often inconsistent. METHODS: This study included 3787 adults aged ≥19 years who participated in the Korean National Environmental Health Survey 2015-2017, and investigated the association of toxic heavy metals with metabolic diseases. Lead (Pb), mercury (Hg), and cadmium (Cd) were measured either in urine (uHg, uCd) or total blood (bPb, bHg). Body mass index (BMI) was calculated, and DM cases were identified through a self-answered medication history. Hepatic Steatosis Index (HSI) as a surrogating index of NAFLD, was calculated using hepatic enzyme measurements, including aspartate aminotransferase (AST) and alanine aminotransferase (ALT). RESULTS: Adults in the highest quartile of bPb, bHg, and uHg showed significantly elevated odds of obesity (BMI ≥25 kg/m2), compared to the lowest quartile (OR 1.58 for bPb, 1.92 for bHg, and 1.81 for uHg). HSI was positively correlated with bHg, uHg, and uCd concentrations. The odds of NAFLD (HSI ≥36) were also increased with increasing quartile of bHg, uHg, and uCd concentrations. For DM, bPb showed a significant negative association, while bHg and uCd exhibited non-monotonic and inconclusive associations. CONCLUSIONS: Among the general adult population of Korea, both Pb and Hg exposures were associated with an increased risk of obesity. In addition, both Hg and Cd exposures were associated with increased odds of NAFLD. These metals, however, were not associated with an increased risk of DM.

PERIPAPILLARY MICROVASCULATURE OF THE RETINA AND CHORIOCAPILLARIS IN UNINVOLVED FELLOW EYES OF UNILATERAL RETINAL VEIN OCCLUSION PATIENTS.

PURPOSE: To investigate peripapillary microvascularity of the retina and choriocapillaris in uninvolved fellow eyes of patients with branch retinal vein occlusion (RVO) compared with that of healthy controls. METHODS: Peripapillary optical coherence tomography angiography bilateral eye scans of 46 patients with unilateral RVO and 46 age-matched control eyes were reviewed. Microvascular density in radial peripapillary capillary plexus (RPCP), superficial capillary plexus, and deep capillary plexus and signal void parameters in choriocapillaris were assessed. Data were statistically adjusted for hypertension. RESULTS: Microvascular densities in the RPCP and superficial capillary plexus were lower in the fellow eyes of patients with RVO than in the controls (RPCP, P = 0.021; superficial capillary plexus, P = 0.040). There were fewer choriocapillaris signal voids in the fellow eyes than in the control (P = 0.043). In patients with a duration of RVO onset >12 months (n = 27), all signal void parameters were lower in the fellow eyes than in the control eyes (size, P = 0.03; number, P = 0.046; proportion of the total area, P = 0.029). CONCLUSION: Uninvolved fellow eyes of patients with unilateral RVO showed microvascular impairment in the retina and choriocapillaris, even after adjusting for age and hypertension, suggesting that an unknown systemic factor might affect both the affected and unaffected eyes.

NASAL CROWDING AND NASAL TILTING OF THE MACULA AFTER EPIRETINAL MEMBRANE SURGERY.

PURPOSE: To identify postoperative macula deviation after epiretinal membrane surgery and to investigate its clinical effects. METHODS: Patients who underwent idiopathic epiretinal membrane removal and followed up for >12 months were enrolled. Macular deviation was evaluated using disk margin-to-fovea distance, foveal angle, and horizontal and vertical asymmetry of retinal thickness and volume. Horizontal or vertical asymmetry was defined as percentile asymmetry between nasal and temporal quadrants or between superior and inferior quadrants, respectively. The association between macular deviation parameters and best-corrected visual acuity and metamorphopsia were evaluated. Baseline and postoperative parameters were compared depending on epiretinal membrane severity. RESULTS: Data from 102 eyes with a mean follow-up of 21.14 months were analyzed. Disk margin-to-fovea distance and foveal angle decreased with time and horizontal asymmetry of thickness and volume increased with time, showing nasal crowding and nasal tilting. Postoperative changes of disk margin-to-fovea distance and horizontal asymmetry were associated with best-corrected visual acuity. Severe epiretinal membrane eyes showed greater postoperative nasal deviation than mild epiretinal membrane eyes. CONCLUSION: Postoperative nasal crowding and tilting was quantitatively identified. The causative layers for nasal deviation might be the inner retinal layers, as the foveal angle decreased with time. Postoperative disk margin-to-fovea distance shortening and nasal-deviated horizontal asymmetry were correlated with best-corrected visual acuity improvement.

Thyroid nodules in childhood-onset Hashimoto's thyroiditis: Frequency, risk factors, follow-up course and genetic alterations of thyroid cancer.

OBJECTIVE: We evaluated the frequency, risk factors and the follow-up outcomes of thyroid nodules, and genetic alterations in thyroid cancer, in youth with childhood-onset Hashimoto thyroiditis (HT) residing in an iodine-sufficient country. DESIGN: A retrospective cohort study. PATIENTS AND MEASUREMENTS: A total of 213 patients (194 females, mean age 10.6 years at the time of HT diagnosis) were ultrasonographically evaluated. Thyroid nodules were categorized using the Korean Thyroid Imaging Reporting and Data System (K-TIRADS) and the American College of Radiology Thyroid Imaging Reporting and Data System (ACR-TI-RADS). RESULTS: Thyroid nodules were detected in 40 (18.8%) patients over a median follow-up period of 3.4 years, usually after the onset of puberty. A family history of thyroid disease (hazard ratio 2.1, p = .031) was predictive of thyroid nodule detection. Papillary thyroid carcinoma (PTC) was diagnosed in 9 (4.2% of all and 22.5% of nodule-positive patients). The malignant nodules had a higher K-TIRADS or ACR-TI-RADS risk level compared with benign nodules (p < .01 for both). Genetic alterations were revealed in 7 (BRAFV600E in 6 and RET-ERC1 fusion in 1) of the eight available tumour tissue samples. None showed evidence of disease over a median follow-up period of 3.4 years. CONCLUSIONS: The nodule detection rate was 18.8%, with a 22.5% risk of malignancy among the detected nodules in childhood-onset HT patients, showing increased risk in those with a family history. Additional large-scale studies are required to evaluate the usefulness of K-TIRADS or ACR-TI-RADS risk level for the differentiation of paediatric thyroid nodules.

Twenty-four-Hour Intraocular Pressure-Related Patterns from Contact Lens Sensors in Normal-Tension Glaucoma and Healthy Eyes: The Exploring Nyctohemeral Intraocular pressure related pattern for Glaucoma Management (ENIGMA) Study.

PURPOSE: To investigate 24-hour nyctohemeral intraocular pressure (IOP)-related patterns with contact lens sensors (CLSs) in eyes with primary open-angle glaucoma (POAG) with normal baseline IOP (i.e., normal-tension glaucoma [NTG]) and healthy controls. DESIGN: Prospective, case-control study. PARTICIPANTS: Thirty eyes of 30 patients with NTG, who had had a wash-out period for their IOP-lowering treatment, and 20 eyes of 20 healthy volunteer subjects. METHODS: Patients and subjects were hospitalized for the purposes of 24-hour CLS (SENSIMED Triggerfish; Sensimed AG, Lausanne, Switzerland) measurement. The IOP-related patterns during wake and sleep times over the course of the 24 hours were compared between the 2 groups. The 24-hour ambulatory blood pressure and posture were monitored simultaneously. A generalized linear model was used to find the factors associated with NTG. MAIN OUTCOME MEASURES: The IOP-related patterns, including mean and standard deviation (SD) of measurements, amplitude of cosine-fit curve, acrophase (signal peak), and bathyphase (signal trough) values (millivolt equivalents [mVEq]). RESULTS: The SDs of the 24-hour CLS measurements were significantly greater in NTG eyes than in healthy controls (112.51±26.90 vs. 85.18±29.61 mVEq, P = 0.002). The amplitudes of cosine-fit curve (141.88±39.96 vs. 106.08±41.49 mVEq, P = 0.004) and acrophase values (277.74±129.80 vs. 190.58±127.88 mVEq, P = 0.024), mostly measured during nocturnal period, were significantly greater in NTG eyes than in healthy controls. The NTG subjects slept longer in the lateral decubitus posture than the healthy controls (199.1±137.8 vs. 113.2±86.2 minutes, P = 0.009). In the multivariable generalized linear model, the greater amplitude of cosine-fit curve (ß = 0.218, P = 0.012) and greater time of decubitus posture during sleep (ß = 0.180, P = 0.004) were found to be significantly associated with NTG. CONCLUSIONS: Continuous monitoring of 24-hour IOP-related values with CLS can be useful for assessment of glaucoma risk, especially for patients with NTG whose IOP appears to be in the normal range. Fluctuation of 24-hour IOP-related values and posture during sleep time might be associated with NTG.

POSTTREATMENT POLYP REGRESSION AND RISK OF MASSIVE SUBMACULAR HEMORRHAGE IN EYES WITH POLYPOIDAL CHOROIDAL VASCULOPATHY.

PURPOSE: To study the association between the risk of massive submacular hemorrhage (SMH) and polyp regression after initial treatment of polypoidal choroidal vasculopathy using long-term follow-up data. METHODS: Retrospective study of 223 patients who were diagnosed with polypoidal choroidal vasculopathy and were followed up for up to 11 years. Subjects were categorized into "regression" and "no regression" groups, according to their polyp status after the initial treatment. Kaplan-Meier survival analyses were performed on development of massive SMH. The association between treatment methods and the occurrence of massive SMH was also analyzed. RESULTS: The incidence rates of massive SMH at 3, 6, and 9 years in the "no regression" group were 6.50, 22.59, and 38.03%, respectively, and in the "regression" group were 1.14, 6.47, and 10.92%, respectively (P = 0.005, log-rank test). The hazard ratio of massive SMH was 3.677 for cluster-type polyps and 0.271 for polyp regression after initial treatment. A higher rate of polyp regression was associated with photodynamic therapy (PDT) than anti-VEGF monotherapy (64.4 vs. 33.3%, P < 0.001). Additional anti-VEGF treatments after initial PDT showed lower risk of massive SMH than PDT only. (9.5 vs 38.5%, P = 0.005). CONCLUSION: The long-term risk of massive SMH after initial treatment on polypoidal choroidal vasculopathy is significantly higher in eyes with persistent polyps than those with regressed polyps. Ophthalmologists should pay attention to the risk of massive SMH and the polyp status when treating polypoidal choroidal vasculopathy.

Increased intracellular Ca2+ concentrations prevent membrane localization of PH domains through the formation of Ca2+-phosphoinositides.

Insulin resistance, a key etiological factor in metabolic syndrome, is closely linked to ectopic lipid accumulation and increased intracellular Ca2+ concentrations in muscle and liver. However, the mechanism by which dysregulated intracellular Ca2+ homeostasis causes insulin resistance remains elusive. Here, we show that increased intracellular Ca2+ acts as a negative regulator of insulin signaling. Chronic intracellular Ca2+ overload in hepatocytes during obesity and hyperlipidemia attenuates the phosphorylation of protein kinase B (Akt) and its key downstream signaling molecules by inhibiting membrane localization of pleckstrin homology (PH) domains. Pharmacological approaches showed that elevated intracellular Ca2+ inhibits insulin-stimulated Akt phosphorylation and abrogates membrane localization of various PH domain proteins such as phospholipase Cδ and insulin receptor substrate 1, suggesting a common mechanism inhibiting the membrane targeting of PH domains. PH domain-lipid overlay assays confirmed that Ca2+ abolishes the binding of various PH domains to phosphoinositides (PIPs) with two adjacent phosphate groups, such as PI(3,4)P2, PI(4,5)P2, and PI(3,4,5)P3 Finally, thermodynamic analysis of the binding interaction showed that Ca2+-mediated inhibition of targeting PH domains to the membrane resulted from the tight binding of Ca2+ rather than PH domains to PIPs forming Ca2+-PIPs. Thus, Ca2+-PIPs prevent the recognition of PIPs by PH domains, potentially due to electrostatic repulsion between positively charged side chains in PH domains and the Ca2+-PIPs. Our findings provide a mechanistic link between intracellular Ca2+ dysregulation and Akt inactivation in insulin resistance.

Histopathologic discrepancies between endoscopic forceps biopsy and endoscopic resection specimens in superficial esophageal squamous neoplasms.

BACKGROUND AND AIM: Endoscopic forceps biopsy results that reflect the final pathologic results of an entire lesion are essential for making accurate diagnoses and appropriate therapeutic decisions for patients with superficial esophageal squamous neoplasms (SESNs). This study investigated the histopathologic discrepancies between endoscopic forceps biopsy and endoscopic resection specimens to elucidate the factors contributing to such discrepancies. METHODS: This retrospective observational study involved 77 patients (84 lesions) who underwent endoscopic resections for SESNs, between January 2005 and August 2017, at the Pusan National University Hospital. The SESNs were classified as low-grade intraepithelial neoplasms (LGINs), high-grade intraepithelial neoplasms (HGINs), or squamous cell carcinomas (SCCs). Following slide reviews, the histopathologic concordance between endoscopic forceps biopsy and endoscopic resection specimens was assessed, in each case. RESULTS: The histopathologic discrepancy rate between the endoscopic forceps biopsy and endoscopic resection specimens was 34.5% (29/84 lesions). Among the 29 diagnostically discordant lesions, upgrades and downgrades of the histopathologic diagnoses occurred for 27 and 2 lesions, respectively. The predominant discrepancies results in lesion upgrades from HGIN to SCC (n = 21) and from LGIN to SCC (n = 5). The two downgraded cases included one from SCC to HGIN and one from HGIN to LGIN. Multivariate analyses identified two factors that were significantly associated with the histopathologic discrepancies: upper esophageal location (odds ratio, 7.743; 95% confidence interval, 1.031-58.174; P = 0.047) and tumor area per biopsy ≥ 158.6 mm2 /biopsy (odds ratio, 5.933; 95% confidence interval, 1.051-44.483; P = 0.044). CONCLUSION: Histopathologic discrepancies were observed between endoscopic forceps biopsy and endoscopic resection specimens in patients with SESNs. Tumor location and tumor area/biopsy were both significantly associated with the discrepancies.

Tumor doubling time predicts response to sorafenib in radioactive iodine-refractory differentiated thyroid cancer.

Sorafenib has emerged as an effective therapeutic option for radioactive iodine (RAI)-refractory, locally advanced or metastatic differentiated thyroid cancer (DTC). We investigated the efficacy and safety of sorafenib treatment in a real-world setting and unveil predictive markers of responsiveness to sorafenib. The treatment response, progression-free survival (PFS), overall survival, and adverse events (AEs) of sorafenib-treated RAI-refractory, locally advanced or metastatic DTC patients at three institutes were retrospectively reviewed, and their tumor doubling time was calculated by three investigators. Total eighty-five patients were treated with sorafenib, and seven patients discontinued sorafenib due to AEs before the first tumor assessment. The median PFS was 14.4 months, and the objective response rate was 10.3% in 78 patients who were able to evaluate the tumor response. Age, sex, histologic type, tumor location, RAI avidity, or the presence of FDG-PET uptake did not affect PFS. However, smaller tumor size (≤1.5 cm) of the target lesions in lung showed better PFS (hazard ratio [HR] 0.39, p = 0.01), and tumors with the shortest doubling time (≤6 months) had worse outcome (HR 2.70, p < 0.01). Because of AEs, dose reductions or drug interruptions were required in 64% of patients, and eventually, 23% of patients discontinued sorafenib permanently. The most common AE was hand-foot skin reaction (HFSR). Patients with severe HFSR showed better PFS, but there were no statistical significance (HR 0.65, p = 0.05). In conclusion, small tumor size and long doubling time of each target lesion can be a prognostic marker to predict the responsiveness to sorafenib in RAI-refractory DTC patients.

Comprehensive Analysis of the Transcriptional and Mutational Landscape of Follicular and Papillary Thyroid Cancers.

Follicular thyroid carcinoma (FTC) and benign follicular adenoma (FA) are indistinguishable by preoperative diagnosis due to their similar histological features. Here we report the first RNA sequencing study of these tumors, with data for 30 minimally invasive FTCs (miFTCs) and 25 FAs. We also compared 77 classical papillary thyroid carcinomas (cPTCs) and 48 follicular variant of PTCs (FVPTCs) to observe the differences in their molecular properties. Mutations in H/K/NRAS, DICER1, EIF1AX, IDH1, PTEN, SOS1, and SPOP were identified in miFTC or FA. We identified a low frequency of fusion genes in miFTC (only one, PAX8-PPARG), but a high frequency of that in PTC (17.60%). The frequencies of BRAFV600E and H/K/NRAS mutations were substantially different in miFTC and cPTC, and those of FVPTC were intermediate between miFTC and cPTC. Gene expression analysis demonstrated three molecular subtypes regardless of their histological features, including Non-BRAF-Non-RAS (NBNR), as well as BRAF-like and RAS-like. The novel molecular subtype, NBNR, was associated with DICER1, EIF1AX, IDH1, PTEN, SOS1, SPOP, and PAX8-PPARG. The transcriptome of miFTC or encapsulated FVPTC was indistinguishable from that of FA, providing a molecular explanation for the similarly indolent behavior of these tumors. We identified upregulation of genes that are related to mitochondrial biogenesis including ESRRA and PPARGC1A in oncocytic follicular thyroid neoplasm. Arm-level copy number variations were correlated to histological and molecular characteristics. These results expanded the current molecular understanding of thyroid cancer and may lead to new diagnostic and therapeutic approaches to the disease.

Thyroid Hormone-Disrupting Potentials of Major Benzophenones in Two Cell Lines (GH3 and FRTL-5) and Embryo-Larval Zebrafish.

Benzophenones (BPs) have been widely used in personal care products (PCPs) such as UV protectants. Sex endocrine-disrupting effects have been documented for some BPs, but, significant knowledge gaps are present for their thyroid-disrupting effects. To investigate the thyroid-disrupting potential of BPs, a rat pituitary (GH3) and thyroid follicle (FRTL-5) cell line were employed on six BPs, i.e., benzophenone (BP), benzophenone-1 (BP-1), benzophenone-2 (BP-2), benzophenone-3 (BP-3), benzophenone-4 (BP-4), and benzophenone-8 (BP-8). Subsequently, zebrafish ( Danio rerio) embryo exposure was conducted for three potent BPs that were identified based on the transcriptional changes observed in the cells. In GH3 cells, all BPs except BP-4 down-regulated the Tshß, Trhr, and Trß genes. In addition, some BPs significantly up-regulated the Nis and Tg genes while down-regulating the Tpo gene in FRTL-5 cells. In zebrafish embryo assay conducted for BP-1, BP-3, and BP-8, significant decreases in whole-body T4 and T3 level were observed at 6 day postfertilization (dpf). The up-regulation of the dio1 and ugt1ab genes in the fish suggests that decreased thyroid hormones are caused by changing metabolism of the hormones. Our results show that these frequently used BPs can alter thyroid hormone balances by influencing the central regulation and metabolism of the hormones.