Radiofrequency Ablation for the Treatment of Benign Thyroid Nodules: 10-Year Experience.

Background: Longer follow-up after radiofrequency ablation (RFA) of benign thyroid nodules is needed to understand regrowth and other causes of delayed surgery and long-term complications. Methods: This retrospective study included consecutive patients treated with RFA for symptomatic benign nonfunctioning thyroid nodules between March 2007 and December 2010. RFA was performed according to the standard protocol. We followed up patients at 1, 6, and 12 months, then yearly, until August 2022, and calculated the volume reduction ratio (VRR) at each follow-up. We assessed the incidence of regrowth according to three published criteria, delayed surgery, and complications. The Kaplan-Meier method was used to evaluate the cumulative incidence of regrowth, and univariable and multivariable Cox regression analyses were performed to identify risk factors for regrowth. Results: This study included 421 patients (mean age, 47 ± 13 years; 372 women) with 456 nodules (mean volume, 21 ± 23 mL). The median follow-up period was 90 months (interquartile range, 24-143 months). The mean VRR was 81% at 2 years, 90% at 5 years, and 94% at ≥10 years. Overall regrowth was noted in 12% (53/456) of nodules and was treated with repeat RFA (n = 33) or surgery (n = 4) or left under observation (n = 16). Thyroid nodules with ≥20 mL initial volume had significantly higher risk of regrowth compared with nodules with <10 mL initial volume (hazard ratio, 2.315 [95% confidence interval, 1.183-4.530]; p = 0.014 on multivariable Cox regression analysis). Delayed surgery was performed in 6% (26/421) of patients because of regrowth and/or persistent symptoms (n = 4) or newly detected thyroid tumors (n = 22), one benign and 21 malignant. The overall complication rate was 2.4% (10/421), with no procedure-related deaths or long-term complications. Conclusion: RFA is safe and effective for treating benign thyroid nodules, with a high VRR at long-term follow-up. Regular follow-up after initial success is warranted because of the possibility of regrowth of ablated nodules and the need for delayed surgery in some patients.

Differential effects of desvenlafaxine on hot flashes in women with breast cancer taking tamoxifen: a randomized controlled trial.

Hot flashes (HF) are a common adverse event of prolonged tamoxifen use in women with estrogen receptor-positive breast cancer, impacting psychiatric health and quality of life. While desvenlafaxine does not interact with tamoxifen, its efficacy and safety in breast cancer patients remain unstudied. This phase 3, four-week, multi-center, three-arm, parallel-group, randomized, double-blind, placebo-controlled trial investigated the efficacy and safety of desvenlafaxine for treating HF in women with breast cancer taking tamoxifen, assessing potential differential effects in patients with psychiatric and inflammatory conditions. Between December 2017 and February 2019, 57 women aged 19 or older, regularly taking tamoxifen as adjuvant therapy, experiencing moderate-to-severe HFs for more than a month, were randomized to receive desvenlafaxine 50 mg/day (D-50), desvenlafaxine 100 mg/day (D-100), or placebo for four weeks. The primary endpoint was the change rate in HF scores over four weeks, with adverse events as a secondary endpoint. Both desvenlafaxine arms demonstrated greater HF score reductions compared to placebo: D-50 (2.20 points/week, 95% CI: 0.71, 3.68) and D-100 (2.34 points/week, 95% CI: 0.92, 3.76). Notably, D-50 arm showed significantly greater efficacy in patients with depression or elevated inflammation. Desvenlafaxine offers an effective and safe treatment regimen for HF in women with breast cancer taking tamoxifen. The presence of depression and inflammation may guide optimal desvenlafaxine dosing. (Trial Registration: ClinicalTrials.gov Identifier: NCT02819921).

Differences in severity of chemotherapy-induced nausea and vomiting between neoadjuvant and adjuvant chemotherapy in patients with breast cancer: analysis of data from two prospective observational studies.

PURPOSE: We assessed the differences in chemotherapy-induced nausea and vomiting (CINV) severity in patients with breast cancer, receiving neoadjuvant chemotherapy (NAC) and adjuvant chemotherapy (AC). METHODS: CINV severity in patients on anthracycline-based NAC (n = 203) and AC (n = 79) was assessed at baseline (C0) and after the first and fourth chemotherapy using a 10-point Likert scale. Group-by-time interaction term was used to evaluate the effect of the group on changes in CIN (cCIN) and CIV (cCIV) from C0 to the follow-up periods (C1, C4). If insignificant, group effects were analyzed without the interaction term. Subgroup analysis was performed based on age 50. In statistical analyses, sociodemographic and clinical variables that differed between groups were adjusted for. RESULTS: The effect of group by follow-up period was not significant in cCIN and cCIV. The AC group showed a significantly higher change in the severity of cCIN compared to the NAC group (estimated mean = 1.133, 95% CI = 0.104-2.161, p = 0.031), but there was no difference in cCIV. In those ≤ 50 years, significant differences in cCIN severity (estimated mean = 1.294, 95% CI = 0.103-2.484, p = 0.033) were observed, but not in cCIV. In those > 50 years, neither cCIN nor cCIV differed significantly between groups. CONCLUSIONS: NAC in breast cancer patients showed less severe CIN than adjuvant chemotherapy AC, but not in those over 50. Clinicians should recognize that the severity of CIN may vary across different chemotherapy settings and adjust their management accordingly. TRIAL REGISTRATION: The clinical trial registration ( www. CLINICALTRIALS: gov ) numbers were NCT01887925 (the registration date is from June 20, 2013, to November 27, 2015) and NCT02011815 (the registration date is from December 10, 2013, to September 22, 2019).

Enhancement on CT for preoperative diagnosis of metastatic lymph nodes in thyroid cancer: a comparison across experience levels.

OBJECTIVES: To investigate the diagnostic performance and interobserver agreement of quantitative CT parameters indicating strong lymph node (LN) enhancement in differentiated thyroid cancer (DTC), comparing them with qualitative analysis by radiologists of varying experience. MATERIALS AND METHODS: This study included 463 LNs from 399 patients with DTC. Three radiologists independently analyzed strong LN enhancement on CT. Qualitative analysis of strong enhancement was defined as LN cortex showing greater enhancement than adjacent muscles on the arterial phase. Quantitative analysis included the mean attenuation value (MAV) of LN on arterial phase (LNA) and venous phase (LNV), LNA normalized to the common carotid artery (NAVCCA), internal jugular vein (NAVIJV), and sternocleidomastoid muscle (NAVSCM), attenuation difference [AD; (LNA - MAVSCM)], and relative washout ratio [((LNA - LNV)/LNA) × 100]. The interobserver agreement and diagnostic performance of the quantitative and qualitative analyses were evaluated. RESULTS: Interobserver agreement was excellent for all quantitative CT parameters (ICC, 0.83-0.94) and substantial for qualitative assessment (κ = 0.61). All CT parameters except for LNV showed good diagnostic performance for metastatic LNs (AUC, 0.81-0.85). NAVCCA (0.85, 95% CI: 0.8-0.9) and AD (0.85, 95% CI: 0.81-0.89) had the highest AUCs. All quantitative parameters except for NAVIJV had significantly higher AUCs than qualitative assessments by inexperienced radiologists, with no significant difference from assessments by an experienced radiologist. CONCLUSION: Quantitative assessment of LN enhancement on arterial phase CT showed higher interobserver agreement and AUC values than qualitative analysis by inexperienced radiologists, supporting the need for a standardized quantitative CT parameter-based model for determining strong LN enhancement. CLINICAL RELEVANCE STATEMENT: When assessing strong LN enhancement in DTC, quantitative CT parameters indicating strong enhancement can improve interobserver agreement, regardless of experience level. Therefore, the development of a standardized diagnostic model based on quantitative CT parameters might be necessary. KEY POINTS: Accurate preoperative assessment of LN metastasis in thyroid cancer is crucial. Quantitative CT parameters indicating strong LN enhancement demonstrated excellent interobserver agreement and good diagnostic performance. Quantitative assessment of contrast enhancement offers a more objective model for the identification of metastatic LNs.

Effectiveness of microvascular flow imaging for radiofrequency ablation in recurrent thyroid cancer: comparison with power Doppler imaging.

OBJECTIVES: To compare microvascular flow imaging (MVFI) and power Doppler ultrasonography imaging (PDUS) for detecting intratumoral vascularity in recurrent thyroid cancer both before and after radiofrequency ablation (RFA). METHODS: This retrospective study included 80 patients (age, 57 ± 12 years; 54 women) with 110 recurrent tumors who underwent RFA between January 2021 and June 2023. A total of 151 PDUS and MVFI image sets were analyzed (85 pre-RFA, 66 post-RFA). Two readers assessed vascularity on the images using a four-point scale with a 2-week interval between PDUS and MVFI to estimate inter-reader agreement. Intra-reader agreement was determined by reinterpreting images in reverse order (MVFI-PDUS) after a 1-month gap. Additionally, diagnostic performance for identifying viable tumors after RFA was assessed in 44 lesions using thyroid-protocol CT as a reference standard. RESULTS: MVFI demonstrated higher vascular grades than PDUS, both before (reader 1: 3.04 ± 1.15 vs. 1.93 ± 1.07, p < 0.001; reader 2: 3.20 ± 0.96 vs. 2.12 ± 1.07, p < 0.001) and after RFA (reader 1: 2.44 ± 1.28 vs. 1.67 ± 1.06, p < 0.001; reader 2: 2.62 ± 1.23 vs. 1.83 ± 0.99, p < 0.001). Inter-reader agreement was substantial (κ = 0.743) and intra-reader agreement was almost perfect (κ = 0.840). MVFI showed higher sensitivity (81.5%-88.9%) and accuracy (84.1%-86.4%) than PDUS (sensitivity: 51.9%, p < 0.01; accuracy: 63.6-70.5%, p < 0.04), without sacrificing specificity. CONCLUSION: MVFI was superior to PDUS for assessing intratumoral vascularity and showed good inter- and intra-reader agreement, highlighting its clinical value for assessing pre-RFA vascularity and accurately identifying post-RFA viable tumors in recurrent thyroid cancer. CLINICAL RELEVANCE STATEMENT: Microvascular flow imaging (MVFI) is superior to power-Doppler US for assessing intratumoral vascularity; therefore, MVFI can be a valuable tool for assessing vascularity before radiofrequency ablation (RFA) and for identifying viable tumors after RFA in patients with recurrent thyroid cancer. KEY POINTS: The value of microvascular flow imaging (MVFI) for evaluating intratumoral vascularity is unexplored. MVFI demonstrated higher vascular grades than power Doppler US before and after ablation. Microvascular flow imaging showed higher sensitivity and accuracy than power Doppler US without sacrificing specificity.

Adjuvant nivolumab plus chemotherapy versus placebo plus chemotherapy for stage III gastric or gastro-oesophageal junction cancer after gastrectomy with D2 or more extensive lymph-node dissection (ATTRACTION-5): a randomised, multicentre, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: In Asia, adjuvant chemotherapy after gastrectomy with D2 or more extensive lymph-node dissection is standard treatment for people with pathological stage III gastric or gastro-oesophageal junction (GEJ) cancer. We aimed to assess the efficacy and safety of adjuvant nivolumab plus chemotherapy versus placebo plus chemotherapy administered in this setting. METHODS: ATTRACTION-5 was a randomised, multicentre, double-blind, placebo-controlled, phase 3 trial conducted at 96 hospitals in Japan, South Korea, Taiwan, and China. Eligible patients were aged between 20 years and 80 years with histologically confirmed pathological stage IIIA-C gastric or GEJ adenocarcinoma after gastrectomy with D2 or more extensive lymph-node dissection, with an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1 and available tumour tissue for PD-L1 expression analysis. Patients were randomly assigned (1:1) to receive either nivolumab plus chemotherapy or placebo plus chemotherapy via an interactive web-response system with block sizes of four. Investigational treatment, either nivolumab 360 mg or placebo, was administered intravenously for 30 min once every 3 weeks. Adjuvant chemotherapy was administered as either tegafur-gimeracil-oteracil (S-1) at an initial dose of 40 mg/m2 per dose orally twice per day for 28 consecutive days, followed by 14 days off per cycle, or capecitabine plus oxaliplatin consisting of an initial dose of intravenous oxaliplatin 130 mg/m2 for 2 h every 21 days and capecitabine 1000 mg/m2 per dose orally twice per day for 14 consecutive days, followed by 7 days off treatment. The primary endpoint was relapse-free survival by central assessment. The intention-to-treat population, consisting of all randomly assigned patients, was used for analysis of efficacy endpoints. The safety population, defined as patients who received at least one dose of trial drug, was used for analysis of safety endpoints. This trial is registered with ClinicalTrials.gov (NCT03006705) and is closed. FINDINGS: Between Feb 1, 2017, and Aug 15, 2019, 755 patients were randomly assigned to receive either adjuvant nivolumab plus chemotherapy (n=377) or adjuvant placebo plus chemotherapy (n=378). 267 (71%) of 377 patients in the nivolumab group and 263 (70%) of 378 patients in the placebo group were male; 110 (29%) of 377 patients in the nivolumab group and 115 (31%) of 378 patients in the placebo group were female. 745 patients received assigned treatment (371 in the nivolumab plus chemotherapy group; 374 in the placebo plus chemotherapy group), which was the safety population. Median time from first dose to data cutoff was 49·1 months (IQR 43·1-56·7). 3-year relapse-free survival was 68·4% (95% CI 63·0-73·2) in the nivolumab plus chemotherapy group and 65·3% (59·9-70·2) in the placebo plus chemotherapy group; the hazard ratio for relapse-free survival was 0·90 (95·72% CI 0·69-1·18; p=0·44). Treatment-related adverse events occurred in 366 (99%) of 371 patients in the nivolumab plus chemotherapy group and 364 (98%) of 374 patients in the placebo plus chemotherapy group. Discontinuation due to adverse events was more frequent in the nivolumab plus chemotherapy group (34 [9%] of 371 patients) than the placebo plus chemotherapy group (13 [4%] of 374 patients). The most common treatment-related adverse events were decreased appetite, nausea, diarrhoea, neutrophil count decreased, and peripheral sensory neuropathy. INTERPRETATION: The results of this trial do not support the addition of nivolumab to postoperative adjuvant therapy for patients with untreated, locally advanced, resectable gastric or GEJ cancer. FUNDING: Ono Pharmaceutical and Bristol Myers Squibb.

Pragmatic nationwide master observational trial based on genomic alterations in advanced solid tumors: KOrean Precision Medicine Networking Group Study of MOlecular profiling guided therapy based on genomic alterations in advanced Solid tumors (KOSMOS)-II study protocol KCSG AL-22-09.

BACKGROUND: Next-generation sequencing (NGS) has been introduced to many Korean institutions to support molecular diagnostics in cancer since 2017, when it became eligible for reimbursement by the National Health Insurance Service. However, the uptake of molecularly guided treatment (MGT) based on NGS results has been limited because of stringent regulations regarding prescriptions outside of approved indications, a lack of clinical trial opportunities, and limited access to molecular tumor boards (MTB) at most institutions. The KOSMOS-II study was designed to demonstrate the feasibility and effectiveness of MGT, informed by MTBs, using a nationwide precision medicine platform. METHODS: The KOSMOS-II trial is a large-scale nationwide master observational study. It involves a framework for screening patients with metastatic solid tumors for actionable genetic alterations based on local NGS testing. It recommends MGT through a remote and centralized MTB meeting held biweekly. MGT can include one of the following options: Tier 1, the therapeutic use of investigational drugs targeting genetic alterations such as ALK, EGFR, ERBB2, BRAF, FH, ROS1, and RET, or those with high tumor mutational burden; Tier 2, comprising drugs with approved indications or those permitted for treatment outside of the indications approved by the Health Insurance Review and Assessment Service of Korea; Tier 3, involving clinical trials matching the genetic alterations recommended by the MTB. Given the anticipated proportion of patients receiving MGT in the range of 50% ± 3.25%, this study aims to enroll 1,000 patients. Patients must have progressed to one or more lines of therapy and undergone NGS before enrollment. DISCUSSION: This pragmatic master protocol provides a mass-screening platform for rare genetic alterations and high-quality real-world data. Collateral clinical trials, translational studies, and clinico-genomic databases will contribute to generating evidence for drug repositioning and the development of new biomarkers. TRIAL REGISTRATION: NCT05525858.

Dynamic Risk Model for the Medical Treatment of Graves' Hyperthyroidism according to Treatment Duration.

Background: Changes in thyrotropin receptor antibody (TRAb) levels are associated with the clinical outcomes of Graves' hyperthyroidism. However, the effects of the patterns of TRAb changes on patient prognosis according to the treatment duration of antithyroid drugs (ATDs) are not well established. Methods: In this retrospective cohort study, 1,235 patients with Graves' hyperthyroidism who were treated with ATDs for more than 12 months were included. Patients were divided into two groups according to treatment duration: group 1 (12-24 months) and group 2 (>24 months). Risk prediction models comprising age, sex, and either TRAb levels at ATD withdrawal (model A) or patterns of TRAb changes (model B) were compared. Results: The median treatment duration in groups 1 (n=667, 54%) and 2 (n=568, 46%) was 17.3 and 37.1 months, respectively. The recurrence rate was significantly higher in group 2 (47.9%) than in group 1 (41.4%, P=0.025). Group 2 had significantly more goiter, thyroid eye disease, and fluctuating and smoldering type of TRAb pattern compared with group 1 (all P<0.001). The patterns of TRAb changes were an independent risk factor for recurrence after adjusting for other confounding factors in all patients, except in group 1. Integrated discrimination improvement and net reclassification improvement analyses showed that model B performed better than model A in all patients, except in group 1. Conclusion: The dynamic risk model, including the patterns of TRAb changes, was more suitable for predicting prognosis in patients with Graves' hyperthyroidism who underwent longer ATD treatment duration.

Unveiling the Role of DMAP for the Se-Catalyzed Oxidative Carbonylation of Alcohols: A Mechanism Study.

Considering the remarkable catalytic activity (160 times higher) of Se/DMAP for the oxidative carbonylation of alcohols, unveiling the role of DMAP in catalysis is highly required. We investigated DFT calculations, and the proposed intermediates were verified with in situ ATR-FTIR analysis. DFT showed that the formation of [DMAP···HSe]δ-[DMAP(CO)OR]δ+ (IV) via nucleophilic substitution of DMAP at the carbonyl group of DMAP···HSe(CO)OR is the most energetically favorable. DMAP acts as both a nucleophile and a hydrogen bond acceptor, which is responsible for its remarkable activity.

Comparison between prefabricated ankle-foot orthoses, Dyna Ankle and UD Flex, in patients with hemiplegia.

OBJECTIVE: To compare the kinematic effects of two widely-used prefabricated ankle-foot orthoses (AFOs), the Dyna Ankle (DA) and UD Flex (UD), on the gait cycle of patients with hemiplegia due to cerebral palsy or acquired brain injury. METHODS: This was a retrospective cohort study involving 29 patients. Gait analysis results were assessed under three conditions: barefoot, with the DA, and with the UD. Friedman tests and post hoc analysis with Bonferroni correction were performed to assess differences between the three conditions. RESULTS: The DA significantly improved ankle dorsiflexion during the mid-swing phase, making it more effective in correcting foot drop compared with the UD (DA: 2.28°, UD: 0.44°). Conversely, the UD was more effective in preventing knee flexion during the loading response (DA: 28.11°, UD: 26.72°). CONCLUSIONS: The DA improved ankle dorsiflexion during the swing phase significantly more than that with the UD in patients with hemiplegia. Compared with the DA, the UD more effectively prevented increased knee flexion during the loading response. The choice to prescribe these orthoses should consider individual patient characteristics.

Knot-and-ear sign: a pathognomonic ultrasonographic feature of suture granuloma after thyroid surgery.

PURPOSE: This study investigated the clinical and ultrasonographic (US) findings of suture granulomas and recurrent tumors, and aimed to identify specific characteristics of suture granulomas through an experimental study. METHODS: This retrospective study included 20 pathologically confirmed suture granulomas and 40 recurrent tumors between January 2010 and December 2020. The clinical findings included suture material, surgery, and initial TNM stage. The US findings included shape, size, margin, echogenicity, heterogeneity, vascularity, and internal echogenic foci. The distribution, paired appearance, and "knot-and-ear" appearance of internal echogenic foci were assessed. An experiment using pork meat investigated the US configuration of suture knots. RESULTS: Eighteen patients with 20 suture granulomas (15 women; mean age, 52±13 years) and 37 patients with 40 recurrent tumors (24 women; 54±18 years) were included. Patients with suture granulomas exhibited earlier initial T and N stages than those with recurrent tumors. The knot-and-ear appearance, defined as an echogenic dot accompanied by two adjacent echogenic dots or lines based on experimental findings, was observed in 50% of suture granulomas, but not in recurrent tumors (P<0.001). Central internal echogenic foci (68.8%, P=0.023) and paired appearance (75.0%, P<0.001) were more frequent in suture granulomas. During follow-up, 94.1% of suture granulomas shrunk. CONCLUSION: The knot-and-ear appearance is a potential pathognomonic finding of suture granuloma, and central internal echogenic foci with paired appearance were typical US features. Clinically, suture granulomas showed early T and N stages and size reduction during follow-up. Understanding these features can prevent unnecessary biopsy or diagnostic surgery.

Standigm ASK™: knowledge graph and artificial intelligence platform applied to target discovery in idiopathic pulmonary fibrosis.

Standigm ASK™ revolutionizes healthcare by addressing the critical challenge of identifying pivotal target genes in disease mechanisms-a fundamental aspect of drug development success. Standigm ASK™ integrates a unique combination of a heterogeneous knowledge graph (KG) database and an attention-based neural network model, providing interpretable subgraph evidence. Empowering users through an interactive interface, Standigm ASK™ facilitates the exploration of predicted results. Applying Standigm ASK™ to idiopathic pulmonary fibrosis (IPF), a complex lung disease, we focused on genes (AMFR, MDFIC and NR5A2) identified through KG evidence. In vitro experiments demonstrated their relevance, as TGFß treatment induced gene expression changes associated with epithelial-mesenchymal transition characteristics. Gene knockdown reversed these changes, identifying AMFR, MDFIC and NR5A2 as potential therapeutic targets for IPF. In summary, Standigm ASK™ emerges as an innovative KG and artificial intelligence platform driving insights in drug target discovery, exemplified by the identification and validation of therapeutic targets for IPF.

Selenium reduction of ubiquinone via SQOR suppresses ferroptosis.

The canonical biological function of selenium is in the production of selenocysteine residues of selenoproteins, and this forms the basis for its role as an essential antioxidant and cytoprotective micronutrient. Here we demonstrate that, via its metabolic intermediate hydrogen selenide, selenium reduces ubiquinone in the mitochondria through catalysis by sulfide quinone oxidoreductase. Through this mechanism, selenium rapidly protects against lipid peroxidation and ferroptosis in a timescale that precedes selenoprotein production, doing so even when selenoprotein production has been eliminated. Our findings identify a regulatory mechanism against ferroptosis that implicates sulfide quinone oxidoreductase and expands our understanding of selenium in biology.

Blood Pb levels are associated with prostate cancer prevalence among general adult males: Linking National Cancer Registry (2002-2017) and KNHANES (2008-2017) databases of Korea.

BACKGROUND: Exposure to heavy metals may increase the risk of developing prostate cancer. However, these observations are often inconsistent and not based on clinically diagnosed cases. OBJECTIVE: To investigate the association of lead (Pb), cadmium (Cd), and mercury (Hg) exposure with clinically determined prostate cancer cases among adult males in South Korea. METHODS: Metal biomonitoring data and cancer information from the general Korean population were extracted by linking National Cancer Center (NCC) cancer registration data (2002-2017) with Korea National Health and Nutrition Examination Survey (KNHANES) data (2008-2017). Among them, 46 prostate cancer cases (designated as 'all-prostate'), including 25 diagnosed after heavy metal measurement (designated as 'post-prostate'), and 93 matching controls were chosen. Logistic regression analysis was used to calculate the odds ratios (ORs) and 95% confidence intervals (CIs) between the heavy metal levels and prostate cancer. RESULTS: Post-prostate patients exhibited higher blood Pb levels than controls (median 3.1 µg/dL vs. 2.38 µg/dL, p = 0.01). For all-prostate cancer, the OR of prostate cancer increased by 2.04-fold for every doubling of Pb levels (95% CI = 1.08-3.87, p = 0.03). The OR was also significantly elevated when comparing the third quartile (Q3) to the lowest quartile (Q1), with ORs ranging from 3.38 to 7.95, depending on model (p < 0.05). Blood Pb levels maintained a positive association with inconsistent significance for post-prostate cancer patients. For Cd and Hg, no statistically significant association was established. SIGNIFICANCE: By linking two national health databases for the first time, we constructed an unbiased database of prostate cancer cases and matching controls. We found that blood Pb concentrations were associated with the risk of prostate cancer in Korean men at the current level of exposure.

Comparison of atezolizumab plus bevacizumab and lenvatinib for hepatocellular carcinoma with portal vein tumor thrombosis.

BACKGROUND/AIM: Atezolizumab plus bevacizumab and lenvatinib are currently available as first-line therapy for the treatment of unresectable hepatocellular carcinoma (HCC). However, comparative efficacy studies are still limited. This study aimed to investigate the effectiveness of these treatments in HCC patients with portal vein tumor thrombosis (PVTT). METHODS: We retrospectively included patients who received either atezolizumab plus bevacizumab or lenvatinib as first-line systemic therapy for HCC with PVTT. Primary endpoint was overall survival (OS), and secondary endpoints included progressionfree survival (PFS) and disease control rate (DCR) determined by response evaluation criteria in solid tumors, version 1.1. RESULTS: A total of 52 patients were included: 30 received atezolizumab plus bevacizumab and 22 received lenvatinib. The median follow-up duration was 6.4 months (interquartile range, 3.9-9.8). The median OS was 10.8 months (95% confidence interval [CI], 5.7 to not estimated) with atezolizumab plus bevacizumab and 5.8 months (95% CI, 4.8 to not estimated) with lenvatinib (P=0.26 by log-rank test). There was no statistically significant difference in OS (adjusted hazard ratio [aHR], 0.71; 95% CI, 0.34-1.49; P=0.37). The median PFS was similar (P=0.63 by log-rank test), with 4.1 months (95% CI, 3.3-7.7) for atezolizumab plus bevacizumab and 4.3 months (95% CI, 2.6-5.8) for lenvatinib (aHR, 0.93; 95% CI, 0.51-1.69; P=0.80). HRs were similar after inverse probability treatment weighting. The DCRs were 23.3% and 18.2% in patients receiving atezolizumab plus bevacizumab and lenvatinib, respectively (P=0.74). CONCLUSION: The effectiveness of atezolizumab plus bevacizumab and lenvatinib was comparable for the treatment of HCC with PVTT.

The Diagnostic Role of Repeated Biopsy of Thyroid Nodules with Atypia of Undetermined Significance with Architectural Atypia on Core-Needle Biopsy.

BACKGRUOUND: We aimed to evaluate the utility of repeat biopsy of thyroid nodules classified as atypia of undetermined significance with architectural atypia (IIIB) on core-needle biopsy (CNB). METHODS: This retrospective study evaluated patients with thyroid nodules categorized as IIIB on CNB between 2013 and 2015. Demographic characteristics, subsequent biopsy results, and ultrasound (US) images were evaluated. The malignancy rates of nodules according to number of CNBs and the number of IIIB diagnoses was compared. Demographic and US features were evaluated to determine factors predictive of malignancy. RESULTS: Of 1,003 IIIB nodules on CNB, the final diagnosis was determined for 328 (32.7%) nodules, with 121 of them confirmed as malignant, resulting in a malignancy rate of 36.9% (95% confidence interval, 31.7% to 42.1%). Repeat CNB was performed in 248 nodules (24.7%), with 75 (30.2%), 131 (52.8%), 13 (5.2%), 26 (10.5%), one (0.4%), and two (0.8%) reclassified into categories II, IIIB, IIIA, IV, V, and VI, respectively. Malignancy rates were not significantly affected by the number of CNBs (P=0.291) or the number of IIIB diagnoses (P=0.473). None of the nodules confirmed as category II on repeat CNB was malignant. US features significantly associated with malignancy (P<0.003) included solid composition, irregular margins, microcalcifications, and high suspicion on the US risk stratification system. CONCLUSION: Repeat biopsy of nodules diagnosed with IIIB on CNB did not increase the detection of malignancy but can potentially reduce unnecessary surgery. Repeat biopsy should be performed selectively, with US features guiding the choice between repeat biopsy and diagnostic surgery.

Association of blood metal exposure with age at menarche in Korean women: KNHANES (2008-2017).

Humans are exposed to metals in their daily lives and this metal exposure is responsible for various adverse health effects. Delayed pubertal development has been suggested as an adverse outcome of metal exposure; however, evidence in nationally representative populations, especially in Asia, is limited. We evaluated the association of blood cadmium (Cd), lead (Pb), and mercury (Hg) levels with the age at menarche in Korean females whose blood heavy metals were measured as part of the Korean National Health and Nutrition Examination Survey (KNHANES) 2008-2017. Among the females 16 years of age or older, all measured heavy metals in blood, i.e., Cd, Pb, and Hg, were positively associated with age at menarche. These associations remained significant in a model adjusted for age, survey year, income, education, body mass index, smoking history, and menopausal status as covariates (ß: 0.10, 95% confidence interval (CI): 0.03-0.18 for Cd; ß: 0.17, 95%CI: 0.06-0.27 for Pb; ß: 0.12, 95%CI: 0.05-0.19 for Hg). When the population was separated by age group at the time of the survey, the significance between heavy metal levels and age at menarche became inconsistent, but the general trends were similar. Among those in their 20s and 40s, blood Cd showed a significant association, while Pb was significant among those in their 40s and 50s. A similar trend was observed in the sensitivity analysis in the girls aged 10-15 years at the time of the survey. Blood Cd levels were associated with decreased odds of precocious menarche (OR: 0.57, 95%CI: 0.31-1.03). Delayed menarche is a risk factor for cardiovascular and chronic kidney diseases in later life; hence, public health implication of heavy metal exposure warrants a public health attention.

Pemetrexed plus vinorelbine versus vinorelbine monotherapy in patients with metastatic breast cancer (KCSG-BR15-17): A randomized, open-label, multicenter, phase II trial.

INTRODUCTION: Metastatic breast cancer refractory to anthracycline and taxanes often shows rapid progression. The development of effective and tolerable combination regimens for these patients is needed. This phase II trial investigated the efficacy of pemetrexed plus vinorelbine in patients with metastatic breast cancer. METHODS: This randomized, open-label, phase II trial was conducted in 17 centers in Korea. Patients with advanced breast cancer who had previously been treated with anthracyclines and taxanes were randomly assigned in a 1:1 ratio to receive either vinorelbine or pemetrexed plus vinorelbine. Randomization was stratified by prior capecitabine treatment and hormone receptor status. The primary endpoint was investigator-assessed progression-free survival (PFS). Secondary endpoints included the objective response rate, overall survival, safety, and quality of life. RESULTS: Between March 2017 and August 2019, a total of 125 patients were enrolled. After a median follow-up duration of 14.1 months, 118 progression events and 88 death events had occurred. Sixty-two patients were assigned to the pemetrexed plus vinorelbine arm, and 63 were assigned to the vinorelbine arm. Pemetrexed plus vinorelbine significantly prolonged PFS compared to vinorelbine (5.7 vs. 1.5 months, p < 0.001). The combination arm had higher disease control rate (76.8% vs. 45.9%, p = 0.001) and a tendency toward longer overall survival (16.8 vs. 10.5 months, p = 0.102). Anemia was more frequent in the pemetrexed plus vinorelbine arm per cycle compared with vinorelbine (7.9% vs. 1.9%, p < 0.001), but there was no difference in the incidence of grade 3-4 neutropenia per cycle between the pemetrexed plus vinorelbine arm and the vinorelbine single arm (14.7% vs. 19.5%, p = 0.066). CONCLUSIONS: This phase II study showed that pemetrexed plus vinorelbine led to a longer PFS than vinorelbine. Adverse events of pemetrexed plus vinorelbine were generally manageable.

HER2 amplification level by in situ hybridization predicts survival outcome in advanced HER2-positive breast cancer treated with pertuzumab, trastuzumab, and docetaxel regardless of HER2 IHC results.

BACKGROUND: The role of HER2 amplification level in predicting the effectiveness of HER2-directed therapies has been established. However, its association with survival outcomes in advanced HER2-positive breast cancer treated with dual HER2-blockade remains unexplored. METHODS: This is a single-center retrospective study of patients with advanced HER2-positive breast cancer treated with first-line pertuzumab, trastuzumab, and docetaxel. The primary objective was to ascertain the relationship between treatment outcomes and the level of HER2 amplification by in situ hybridization (ISH). RESULTS: A total of 152 patients were included with a median follow-up duration of 50.0 months. Among the 78 patients who received ISH, a higher HER2/CEP17 ratio correlated significantly with longer PFS (HR 0.50, p = 0.022) and OS (HR 0.28, p = 0.014) when dichotomized by the median. A higher HER2 copy number also correlated significantly with better PFS (HR 0.35, p < 0.001) and OS (HR 0.27, p = 0.009). In multivariate analysis, the HER2/CEP17 ratio was an independent predictive factor for PFS (HR 0.66, p = 0.004) and potentially for OS (HR 0.64, p = 0.054), along with HER2 copy number (PFS HR 0.85, p = 0.004; OS HR 0.84, p = 0.049). Furthermore, the correlation between HER2 amplification level by ISH with PFS and OS was consistent across the HER2 IHC 1+/2+ and 3+ categories. CONCLUSIONS: This is the first study to report that a higher level of HER2 amplification by ISH is associated with improved PFS and OS in advanced HER2-positive breast cancer treated with dual HER2-blockade. Notably, HER2 amplification level had a predictive role regardless of IHC results. Even in patients with HER2 protein expression of 3+, treatment outcome to HER2-directed therapy was dependent on the level of HER2 gene amplification.

Impact of Additional Preoperative Computed Tomography Imaging on Staging, Surgery, and Postsurgical Survival in Patients With Papillary Thyroid Carcinoma.

OBJECTIVE: We investigated the impacts of computed tomography (CT) added to ultrasound (US) for preoperative evaluation of patients with papillary thyroid carcinoma (PTC) on staging, surgical extent, and postsurgical survival. MATERIALS AND METHODS: Consecutive patients who underwent surgery for PTC between January 2015 and December 2015 were retrospectively identified. Of them, 584 had undergone preoperative additional thyroid CT imaging (CT + US group), and 859 had not (US group). Inverse probability of treatment weighting (IPTW) and propensity score matching (PSM) were used to adjust for 14 variables and balance the two groups. Changes in nodal staging and surgical extent caused by CT were recorded. The recurrence-free survival and distant metastasis-free survival after surgery were compared between the two groups. RESULTS: In the CT + US group, discordant nodal staging results between CT and US were observed in 94 of 584 patients (16.1%). Of them, CT accurately diagnosed nodal staging in 54 patients (57.4%), while the US provided incorrect nodal staging. Ten patients (1.7%) had a change in the extent of surgery based on CT findings. Postsurgical recurrence developed in 3.6% (31 of 859) of the CT + US group and 2.9% (17 of 584) of the US group during the median follow-up of 59 months. After adjustment using IPTW (580 vs. 861 patients), the CT + US group showed significantly higher recurrence-free survival rates than the US group (hazard ratio [HR], 0.52 [95% confidence interval {CI}, 0.29-0.96]; P = 0.037). PSM analysis (535 patients in each group) showed similar HR without statistical significance (HR, 0.60 [95% CI, 0.31-1.17]; P = 0.134). For distant metastasis-free survival, HRs after IPTW and PSM were 0.75 (95% CI, 0.17-3.36; P = 0.71) and 0.87 (95% CI, 0.20-3.80; P = 0.851), respectively. CONCLUSION: The addition of CT imaging for preoperative evaluation changed nodal staging and surgical extent and might improve recurrence-free survival in patients with PTC.