Germline Mutations and Phenotypic Associations in Korean Patients With Pheochromocytoma and Paraganglioma: A Multicenter Study and Literature Review.

Genetic testing is recommended for all patients with pheochromocytomas and paragangliomas (PPGL) to establish genotype-phenotype associations. We investigated germline mutations in 59 patients with PPGL at six Korean university hospitals using next-generation sequencing (NGS) targeting 38 PPGL-associated genes, including those recommended by the Korean PPGL Task Force. Germline mutations were identified in 13 patients (22%), and affected four genes: RET, NF1, VHL, and SDHD. Germline mutations were significantly associated with a family history of PPGL, smaller tumor size, and the presence of other types of tumors. Using 95 Korean PPGL cases with germline mutations identified through a literature review and 13 cases from our cohort, we characterized genotype-phenotype correlations. Mutation hotspots were identified in specific codons of RET (codons 631 and 634), VHL (157 and 167), and SDHB (131 and 253). NF1 mutations varied, indicating the absence of common hotspots. These findings highlight the efficacy of the recommended NGS panel for Korean patients with PPGL and the importance of genetic testing in establishing clinical management and personalized therapeutic strategies.

Gut microbiome in the Graves' disease: Comparison before and after anti-thyroid drug treatment.

While several studies have proposed a connection between the gut microbiome and the pathogenesis of Graves's disease (GD), there has been a lack of reports on alteration in microbiome following using anti-thyroid drug treatment (ATD) to treat GD. Stool samples were collected from newly diagnosed GD patients provided at baseline and after 6 months of ATD treatment. The analysis focused on investigating the association between the changes in the gut microbiome and parameter including thyroid function, thyroid-related antibodies, and the symptom used to assess hyperthyroidism before and after treatment. A healthy control (HC) group consisting of data from 230 healthy subjects (110 males and 120 females) sourced from the open EMBL Nucleotide Sequence Database was included. Twenty-nine GD patients (14 males and 15 females) were enrolled. The analysis revealed a significant reduction of alpha diversity in GD patients. However, after ATD treatment, alpha diversity exhibited a significant increase, restored to levels comparable to the HC levels. Additionally, GD patients displayed lower levels of Firmicutes and higher levels of Bacteroidota. Following treatment, there was an increased in Firmicutes and a decrease in Bacteroidota, resembling levels found in the HC levels. The symptoms of hyperthyroidism were negatively associated with Firmicutes and positively associated with Bacteroidota. GD had significantly lower levels of Roseburia, Lachnospiraceaea, Sutterella, Escherichia-shigella, Parasuterella, Akkermansia, and Phascolarctobacterium compared to HC (all p < 0.05). Post-treatment, Subdoligranulum increased (p = 0.010), while Veillonella and Christensenellaceaea R-7 group decreased (p = 0.023, p = 0.029, respectively). Anaerostipes showed a significant association with both higher smoking pack years and TSHR-Ab levels, with greater abundantce observed in smokers among GD (p = 0.16). Although reduced ratio of Firmicutes/Bacteroidetes was evident in GD, this ratio recovered after treatment. This study postulates the involvement of the gut microbiome in the pathogenesis of GD, suggesting potential restoration after treatment.

The Impact of Physical Activity on Thyroid Health: Insights From Representative Data in Korea.

CONTEXT: Thyroid hormones are essential for energy metabolism related to thermogenesis and oxygen consumption. OBJECTIVE: This study evaluated the potential association of thyroid function including thyroid peroxidase antibodies (TPOAb) with physical activity in nationally representative data. DESIGN/SETTING/PARTICIPANTS: This retrospective cohort study used data from the Korean National Health and Nutrition Examination Survey between 2013 and 2015. Physical activity (PA) was assessed using metabolic equivalents based on the validated Korean version of the International Physical Activity Questionnaire Short Form. PA level was categorized into 3 groups of high, moderate, and low. Participants with abnormal thyroid function test, restricted activity, or previous history of thyroid disease were excluded in the study. RESULTS: A total of 5372 participants was finally selected. The free T4 level was lowest in the low PA group, while TSH was not significantly different among the groups. TPOAb titers increased in the following order: moderate PA, low PA, and high PA. After adjustment for confounding factors, moderate PA was associated with a high T4 level and a decrease in TSH and TPOAb with significance. However, there were no significant changes in free T4, TSH, or TPOAb titer in the high PA group. In a subanalysis, females with moderate PA showed a significant decrease in TSH and TPOAb. In both males and females, insulin sensitivity was increased with moderate PA. In obese participants, TSH negatively correlated with PA, and free T4 levels decreased in the low PA. The sensitivity to thyroid hormone did not differ in our study. CONCLUSION: The present study found an association between thyroid function and moderate PA. Therefore, moderate-intensity PA should be recommended to improve thyroid function.

Cost-Utility Analysis of Early Detection with Ultrasonography of Differentiated Thyroid Cancer: A Retrospective Study on a Korean Population.

BACKGRUOUND: There is debate about ultrasonography screening for thyroid cancer and its cost-effectiveness. This study aimed to evaluate the cost-effectiveness of early screening (ES) versus symptomatic detection (SD) for differentiated thyroid cancer (DTC) in Korea. METHODS: A Markov decision analysis model was constructed to compare the cost-effectiveness of ES and SD. The model considered direct medical costs, health outcomes, and different diagnostic and treatment pathways. Input data were derived from literature and Korean population studies. Incremental cost-effectiveness ratio (ICER) was calculated. Willingness-to-pay (WTP) threshold was set at USD 100,000 or 20,000 per quality-adjusted life year (QALY) gained. Sensitivity analyses were conducted to address uncertainties of the model's variables. RESULTS: In a base case scenario with 50 years of follow-up, ES was found to be cost-effective compared to SD, with an ICER of $2,852 per QALY. With WTP set at $100,000, in the case with follow-up less than 10 years, the SD was cost-effective. Sensitivity analysis showed that variables such as lobectomy probability, age, mortality, and utility scores significantly influenced the ICER. Despite variations in costs and other factors, all ICER values remained below the WTP threshold. CONCLUSION: Findings of this study indicate that ES is a cost-effective strategy for DTC screening in the Korean medical system. Early detection and subsequent lobectomy contribute to the cost-effectiveness of ES, while SD at an advanced stage makes ES more cost-effective. Expected follow-up duration should be considered to determine an optimal strategy for DTC screening.

Prognostic Roles of Inflammatory Biomarkers in Radioiodine-Refractory Thyroid Cancer Treated with Lenvatinib.

BACKGRUOUND: Inflammatory biomarkers, such as the neutrophil-to-lymphocyte ratio (NLR), lymphocyte-to-monocyte ratio (LMR), and platelet-to-lymphocyte ratio (PLR), serve as valuable prognostic indicators in various cancers. This multicenter, retrospective cohort study assessed the treatment outcomes of lenvatinib in 71 patients with radioactive iodine (RAI)-refractory thyroid cancer, considering the baseline inflammatory biomarkers. METHODS: This study retrospectively included patients from five tertiary hospitals in Korea whose complete blood counts were available before lenvatinib treatment. Progression-free survival (PFS) and overall survival (OS) were evaluated based on the median value of inflammatory biomarkers. RESULTS: No significant differences in baseline characteristics were observed among patients grouped according to the inflammatory biomarkers, except for older patients with a higher-than-median NLR (≥2) compared to their counterparts with a lower NLR (P= 0.01). Patients with a higher-than-median NLR had significantly shorter PFS (P=0.02) and OS (P=0.017) than those with a lower NLR. In multivariate analysis, a higher-than-median NLR was significantly associated with poor OS (hazard ratio, 3.0; 95% confidence interval, 1.24 to 7.29; P=0.015). However, neither the LMR nor the PLR was associated with PFS. A higher-than-median LMR (≥3.9) was significantly associated with prolonged OS compared to a lower LMR (P=0.036). In contrast, a higher-than-median PLR (≥142.1) was associated with shorter OS compared to a lower PLR (P=0.039). CONCLUSION: Baseline inflammatory biomarkers can serve as predictive indicators of PFS and OS in patients with RAI-refractory thyroid cancer treated with lenvatinib.

A rare case of secondary cutaneous lymphoplasmacytic lymphoma clinically presenting as acquired cutis laxa.

Lymphoplasmacytic lymphoma (LPL) is a rare variant of non-Hodgkin lymphoma, accounting for <1% of cases. Skin involvement in LPL is quite rare-accounting for approximately 5% of extramedullary disease-and includes a variety of clinical morphologies, such as erythematous-to-violaceous plaques, violaceous nodules or tumors, and ulceration at various anatomical sites. Herein, we report the case of a 45-year-old Korean woman who presented with generalized erythematous indurated plaques and pendulous skin growths, which were asymptomatic, with marked diffuse infiltration of lymphocytes and plasma cells in the dermis. Immunohistochemical studies revealed that the lymphoid cells expressed CD3, CD79a, and cytoplasmic IgG, but lacked CD10 and IgM. Moreover, kappa light chain restriction and monoclonal immunoglobulin heavy chain gene rearrangement were observed. Upon further workup, lymphoma involvement was reported in multiple lymph nodes, including those in the cervical and axillary regions. This case shows a unique form of cutaneous LPL clinically presenting as acquired cutis laxa, emphasizing the dermatologists' need to be vigilant for variant forms of this disease.

Cost-Effectiveness of Active Surveillance Compared to Early Surgery of Small Papillary Thyroid Cancer: A Retrospective Study on a Korean Population.

BACKGROUND: Recently, active surveillance (AS) has been introduced as an alternative to early surgery (ES) for the management of papillary thyroid microcarcinoma (PTMC), because of its indolent features and low mortality. However, its cost effects have not been determined and the findings of current studies differ, according to each country's medical system. METHODS: A Markov model was constructed to compare the cost-effectiveness of AS and ES, based on a reference case of a 40-year-old patient diagnosed with PTMC. Costs and transition probabilities were derived from previous clinical studies in Korean populations, and the incremental cost-effectiveness ratio (ICER) and net monetary benefit (NMB) were calculated. The willingness-to-pay (WTP) threshold was set at USD 100,000 per quality-adjusted life year (QALY) gained. Sensitivity analyses were conducted to address the uncertainties in the model's variables. RESULTS: From the base scenario, the cumulative costs and effectiveness were both higher in ES than AS. The ICER for ES, compared with AS, was USD 6,619.86/QALY, lower than the set WTP. The NMB difference between AS and ES increased across the stages (USD 5,980 at the first stage and USD 159,667 at the last stage). The ICER increased along with decreasing age and increasing cost of surgery. The higher the ES utility score and the lower that of AS, the more cost-effective ES, with WTP set at USD 30,000. CONCLUSION: In the current Korean medical system, ES is more cost-effective than AS. ES is more cost-effective as it is diagnosed at young age and followed-up for a long time.

Initial Experiences of Selective RET Inhibitor Selpercatinib in Adults with Metastatic Differentiated Thyroid Carcinoma and Medullary Thyroid Carcinoma: Real-World Case Series in Korea.

Recently, selpercatinib, a highly selective inhibitor of RET receptor tyrosine kinase, has been used for RET-altered thyroid cancer. We present four cases of patients with advanced thyroid cancer who were treated with selpercatinib. The first patient was a 63-year-old male with advanced medullary thyroid cancer (MTC) treated with vandetanib. Six months ago, he had an intracranial hemorrhage and swallowing difficulty. He started selpercatinib with percutaneous endoscopic gastrostomy (PEG). For 11 months, a partial response (PR) was observed stably with PEG administration without any more cardiovascular events. The second patient was a 67-year-old female with advanced MTC treated with vandetatib. After selpercatinib treatment, a PR was observed for most metastatic sites, including choroidal metastasis. The third patient was a 32-year-old female with advanced papillary thyroid cancer (PTC) without history of systematic treatment. For six months, a PR was observed at her metastatic site with manageable adverse events. The last patient was a 59-year-old female with advanced PTC treated with lenvatinib. She suffered from a panic disorder and pleural pain due to metastasis during lenvatinib treatment. After selpercatinib treatment, her pain and panic symptoms were improved. Facing varying clinical obstacles of the real world, selpercatinib safely proved remarkable therapeutic efficacy regardless of previous treatment or metastatic site.

Update on C-Cell Neuroendocrine Neoplasm: Prognostic and Predictive Histopathologic and Molecular Features of Medullary Thyroid Carcinoma.

Medullary thyroid carcinoma (MTC) is a C-cell-derived epithelial neuroendocrine neoplasm. With the exception of rare examples, most are well-differentiated epithelial neuroendocrine neoplasms (also known as neuroendocrine tumors in the taxonomy of the International Agency for Research on Cancer [IARC] of the World Health Organization [WHO]). This review provides an overview and recent evidence-based data on the molecular genetics, disease risk stratification based on clinicopathologic variables including molecular profiling and histopathologic variables, and targeted molecular therapies in patients with advanced MTC. While MTC is not the only neuroendocrine neoplasm in the thyroid gland, other neuroendocrine neoplasms in the thyroid include intrathyroidal thymic neuroendocrine neoplasms, intrathyroidal parathyroid neoplasms, and primary thyroid paragangliomas as well as metastatic neuroendocrine neoplasms. Therefore, the first responsibility of a pathologist is to distinguish MTC from other mimics using appropriate biomarkers. The second responsibility includes meticulous assessment of the status of angioinvasion (defined as tumor cells invading through a vessel wall and forming tumor-fibrin complexes, or intravascular tumor cells admixed with fibrin/thrombus), tumor necrosis, proliferative rate (mitotic count and Ki67 labeling index), and tumor grade (low- or high-grade) along with the tumor stage and the resection margins. Given the morphologic and proliferative heterogeneity in these neoplasms, an exhaustive sampling is strongly recommended. Routine molecular testing for pathogenic germline RET variants is typically performed in all patients with a diagnosis of MTC; however, multifocal C-cell hyperplasia in association with at least a single focus of MTC and/or multifocal C-cell neoplasia are morphological harbingers of germline RET alterations. It is of interest to assess the status of pathogenic molecular alterations involving genes other than RET like the MET variants in MTC families with no pathogenic germline RET variants. Furthermore, the status of somatic RET alterations should be determined in all advanced/progressive or metastatic diseases, especially when selective RET inhibitor therapy (e.g., selpercatinib or pralsetinib) is considered. While the role of routine SSTR2/5 immunohistochemistry remains to be further clarified, evidence suggests that patients with somatostatin receptor (SSTR)-avid metastatic disease may also benefit from the option of 177Lu-DOTATATE peptide radionuclide receptor therapy. Finally, the authors of this review make a call to support the nomenclature change of MTC to C-cell neuroendocrine neoplasm to align this entity with the IARC/WHO taxonomy since MTCs represent epithelial neuroendocrine neoplasms of endoderm-derived C-cells.

Inflammatory biomarkers predict outcomes of patients with radioactive iodine refractory thyroid cancer treated with sorafenib.

BACKGROUND: The objective of this multicenter, retrospective cohort study was to evaluate the ability of inflammatory biomarkers representing the host immune system to predict outcomes in 70 patients with progressive radioactive iodine (RAI)-refractory thyroid cancer who were treated with sorafenib. METHOD: Patients were divided into low and high inflammatory biomarker groups based on median values. Progression-free survival (PFS) and overall survival (OS) were assessed based on the lymphocyte-to-monocyte ratio (LMR), neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR). RESULTS: The median LMR, NLR, and PLR values were 3.4, 2.2, and 140.1, respectively. No significant differences were observed in baseline characteristics of high and low LMR, NLR and PLR groups. Median PFS values were 6.6 and 19.5 months in the low and high LMR groups, respectively (P < 0.001). Compared with the high NLR and PLR groups, PFS was significantly prolonged in the low NLR and PLR groups (P = 0.003 and P = 0.041 respectively). In the multivariate analysis, low LMR and high NLR were associated with poor PFS after adjusting for multiple confounding factors including age, sex, pathology, disease-related symptoms, serum thyroglobulin level, lung-only metastasis, cumulative RAI dose, time from diagnosis, and longer diameter of the target lesion (hazard ratio, HR = 2.42; 95% confidence interval, CI 1.25-4.71; P = 0.009, and HR = 2.09; CI, 1.06-4.14; P = 0.033, respectively). High LMR, low NLR, and low PLR were significantly associated with prolonged OS (P = 0.011, P = 0.023, and P = 0.007, respectively). Patients with at least one risk factors for inflammatory biomarkers presented a significantly lower PFS (HR 2.29; CI, 1.36-3.84; P = 0.003) and OS (HR 2.95; CI, 1.49-5.81; P = 0.006) than patients without any risk factor. CONCLUSION: Baseline inflammatory biomarkers successfully predicted PFS and OS in patients with progressive RAI-refractory thyroid cancer treated with sorafenib. These prognostic biomarkers might help arrive at appropriate clinical decisions regarding the use of sorafenib.

Lenvatinib Compared with Sorafenib as a First-Line Treatment for Radioactive Iodine-Refractory, Progressive, Differentiated Thyroid Carcinoma: Real-World Outcomes in a Multicenter Retrospective Cohort Study.

Background: Sorafenib and lenvatinib have been widely adopted to treat radioactive iodine (RAI)-refractory differentiated thyroid carcinoma (DTC). However, limited data exist regarding a direct comparison of these tyrosine kinase inhibitors (TKIs). We aimed to evaluate the clinical efficacy and safety of two TKIs as first-line therapy in patients with distant metastatic or locally advanced, progressive, RAI-refractory DTC in real-world practice. Methods: In this multicenter, retrospective cohort study, we evaluated 136 patients with progressive distant metastatic or locally advanced, progressive, RAI-refractory DTC or poorly differentiated thyroid carcinoma (PDTC) who received first-line sorafenib or lenvatinib treatment. The primary outcome was progression-free survival (PFS). We also evaluated the objective response rate, disease-control rate, clinical benefit rate, and safety. Results: The median age of the patients was 68 years, and 35% (47/136) were male. Eighty and fifty-six patients were included in the sorafenib and lenvatinib groups, respectively. The median PFS was 13.3 months [95% confidence interval, CI, 9.9-18.1 months] in the sorafenib group and 35.3 months [CI, 18.2 months to upper limit not reported as the median was not reached] in the lenvatinib group (p = 0.001). A significantly prolonged PFS was observed in the lenvatinib group (compared with the sorafenib group) after adjusting for age, sex, pathology, disease-related symptom, lung-only metastasis, cumulative RAI dose, time from diagnosis, treatment duration, and longest diameter of the target lesion (hazard ratio = 0.34, CI, 0.19-0.60, p < 0.001). The partial response rate was 24% and 59% in the sorafenib and lenvatinib groups, respectively (p < 0.001). More common grade 3-4 adverse events were hypertension (16%, 9/56 vs. 1%, 1/80, p = 0.002) and proteinuria (32%, 18/56 vs. 0%, p < 0.001) in the lenvatinib group, and hand-foot skin reaction (24%, 19/80 vs. 4%, 2/56, p = 0.001) in the sorafenib group. Conclusion: In our study of Asian patients, first-line lenvatinib treatment of metastatic or locally advanced, progressive, RAI-refractory DTC or PDTC was associated with a longer PFS compared with sorafenib. However, severe hypertension and proteinuria were observed more frequently after lenvatinib treatment than after sorafenib treatment.

Quality of Life of Survivors of Thyroid Cancer Is Not Inferior to That in Subjects without Cancer: Long-Term after Over 5 Years.

BACKGRUOUND: Patients with thyroid cancer undergo less extensive surgery and additional therapies compared to those with other cancers. We aimed to compare the quality of life (QoL) between patients with thyroid cancer and healthy subjects using representative data from Korea. Differences in QoL of thyroid cancer survivors according to the duration after cancer diagnosis was also evaluated. METHODS: This population-based cohort study included 50,278 subjects who participated in the Korea National Health and Nutrition Examination Survey between 2007 and 2017. QoL was compared between patients with thyroid cancer and healthy subjects using self-reported data from the EuroQoL (EQ)-5 dimension (5D) and EQ-visual analog scale (VAS). Propensity score matching was used to match thyroid cancer survivors to healthy subjects (1:5 matching). RESULTS: Linear regression with univariate analysis showed that the presence of thyroid cancer was positively correlated with better EQ-5D index scores (ß-coefficient=0.010, p=0.046). After adjusting for multiple covariables, statistical significance was maintained. EQ-VAS fails to demonstrate any significant correlation. Among the EQ-5D categories, patients with thyroid cancer showed better self-care than healthy subjects. Thyroid cancer duration did not correlate with the EQ-5D index score. In subgroup analyses, compared to patients with thyroid cancer duration of <5 years, no significant difference was observed in the correlation between the EQ-5D index score and survival duration in those with thyroid cancer duration of 5 to 9 years and ≥10 years. CONCLUSION: Using a large-scale nationwide population-based database, our study demonstrated better QoL, especially in terms of self-care, among thyroid cancer survivors than among healthy subjects without cancer.

Association between the type of thyroid dysfunction induced by immune checkpoint inhibitors and prognosis in cancer patients.

BACKGROUND: Immune checkpoint inhibitors (ICIs) cause thyroid immune-related adverse effects (irAEs). However, associations between each type of thyroid immune-related adverse effect (irAE) and the anti-tumor effect of ICI remains unknown. This study aimed to determine the effects of each type of thyroid dysfunction on patient survival. METHODS: Patients who initiated ICI treatment from January 2015 to December 2019 in Seoul St. Mary's Hospital were retrospectively analyzed. Thyroid dysfunction was classified into four types: newly developed overt or subclinical hypothyroidism, thyrotoxicosis, worsened hypothyroidism, and subclinical hyperthyroidism. Patients were divided into two groups according to the presence or absence of thyroid dysfunction. RESULTS: Among the 191 patients, 64 (33.5%) developed thyroid irAEs. There was no significant difference in age, sex, or cancer type between the two groups. The overall survival in patients with thyroid irAEs was significantly higher than that in patients without thyroid irAEs (25 months vs. 18 months, respectively, p = 0.005). After adjusting for confounding factors, the hazard ratio for mortality in the thyroid irAE group compared to the no thyroid irAE group was 0.480 (p = 0.006). Newly developed overt or subclinical hypothyroidism patients showed a significantly lower hazard ratio for mortality of 0.324 (p = 0.002). Patients with thyrotoxicosis showed a worse hazard ratio for mortality than those without thyroid irAE, although the difference was not statistically significant. CONCLUSIONS: It was verified that ICI treatment-induced thyroid dysfunction was associated with better survival, even in the real-world practice. Thus, endocrinologists should cooperate with oncologists to monitor patients treated with ICIs.

Comparison of the clinicopathological features and oncologic outcomes of the classic papillary thyroid carcinoma with tall cell features and tall cell variant.

BACKGROUND: The tall cell variant (TCV) of papillary thyroid carcinoma (PTC) (TCVPTC) is the most common aggressive variant of PTC. Classic PTC with tall cell features (TCF) is defined as PTC with noticeable tall cells but the percentage of these cells is lower than that required for the diagnosis of TCVPTC. We aimed to investigate the potential differences between TCVPTC and classic PTC with TCF with respect to clinicopathological characteristics and oncologic outcomes. METHODS: We retrospectively assessed 509 patients with TCVPTC or classic PTC with TCF who underwent thyroid surgery between January 2013 and December 2018 at the Seoul St. Mary's Hospital (Seoul, Korea). Clinicopathological characteristics and oncologic outcomes between TCVPTC and classic PTC with TCF were compared in terms of disease-free survival (DFS). The mean follow-up duration was 70.7±21.7 months. RESULTS: The mean tumor size was significantly larger in the TCVPTC group. There was no significant difference between the TCVPTC and classic PTC with TCF groups with respect to DFS. Tumor size >2 cm [odds ratio (OR), 1.922; P=0.019], bilaterality (OR, 1.668; P=0.030), extrathyroidal extension (ETE) (OR, 2.352; P=0.002), and lateral LN metastasis (OR, 1.700; P=0.045) were significantly associated with TCVPTC compared with classic PTC with TCF. CONCLUSIONS: TCVPTC and classic PTC with TCF have similar clinicopathological characteristics and oncologic outcomes. Therefore, we suggest a potential re-classification of classic PTC with TCF from low-risk to intermediate-risk category in the American Thyroid Association (ATA) risk stratification system.

Associations of variability in body weight and glucose levels with the risk of hip fracture in people with diabetes.

BACKGROUND: Diabetes is associated with a high risk of fragility fracture. However, there are controversies regarding the effect of fluctuations in metabolic parameters on the risk of fracture. We aimed to investigate the associations of body weight or glucose variability or their combination with the risk of hip fracture in people with diabetes. METHODS: A population-based cohort study with 480,539 subjects over 40 years who had undergone three or more health examinations was performed. The degree of variability was evaluated using variability independent of the mean (VIM, 100 × standard deviation / meanbeta), coefficient of variation (CV), and average real variability (ARV, average of the absolute differences between consecutive values). High variability was defined as having values in the highest quartile. Cox proportional hazards models were used to estimate the risk of hip fracture. RESULTS: There were 2834 hip fracture events (0.59%) during the mean follow-up of 8.1 years. After multivariable adjustment for age, sex, alcohol consumption, smoking, regular exercise, income, glucose, body mass index, hemoglobin, estimated glomerular filtration rate, diabetes duration, diabetes treatment with multiple agents, and osteoporosis, the HRs (95% CI) of hip fracture were 1.36 (1.24-1.50) and 1.29 (1.16-1.43) for high body weight VIM and high glucose VIM, respectively. The HR (95% CI) of both high VIM group was 1.63 (1.44-1.83), suggesting an additive effect of variabilities in body weight and glucose. The results were consistent when using CV and ARV and in various sensitivity analyses. CONCLUSIONS: High variability in body weight and glucose levels is associated with an increased incidence rate and risk of hip fracture in people with diabetes.

Clinicoprognostic implications of head and neck involvement by mycosis fungoides: A retrospective cohort study.

BACKGROUND: The clinicoprognostic implications of head and neck involvement of mycosis fungoides (MF) are poorly understood. OBJECTIVES: To evaluate the association of head and neck involvement on the clinicoprognostic features of MF. METHODS: The clinical features and survival outcomes of patients with MF in a Korean academic medical center database were retrospectively evaluated according to the presence of head and neck involvement at diagnosis. FINDINGS: Cases of MF with (group A, n = 39) and without (group B, n = 85) head and neck involvement at diagnosis were identified. Advanced-stage disease (stages IIB-IVB) was more common in group A (43.6%) than in group B (5.9%) (P < .001). MF progression, extracutaneous dissemination, and large-cell transformation more commonly occurred in group A than in group B. The 10-year overall survival rate was worse in group A (53.4%) compared with group B (81.6%) (P < .001). Head and neck involvement at diagnosis was associated with poor prognosis in early-stage MF (stages IA-IIA) and was independently associated with worse progression-free survival (hazard ratio, 24.4; 95% confidence interval, 2.2-267.6; P = .009). LIMITATIONS: A single center, retrospective design. CONCLUSION: Head and neck involvement of MF was associated with a poor prognosis.

Lobeglitazone, A Peroxisome Proliferator-Activated Receptor-Gamma Agonist, Inhibits Papillary Thyroid Cancer Cell Migration and Invasion by Suppressing p38 MAPK Signaling Pathway.

BACKGROUND: Peroxisome proliferator-activated receptor-gamma (PPAR-γ) ligands have been widely shown to correlate with epithelial-mesenchymal transition (EMT) and cancer progression. Lobeglitazone (LGZ) is a novel ligand of PPAR-γ; and its role in EMT and metastasis in papillary thyroid carcinoma (PTC) is poorly understood. We aimed to investigate the role of LGZ in metastatic behavior of PTC cells. METHODS: Half maximal inhibitory concentration (IC50) values of LGZ in BRAF-mutated PTC cell lines (BCPAP and K1) were determined using MTT assay. Rosiglitazone (RGZ), the PPAR-γ ligand was used as a positive control. The protein expression of PPAR-γ, cell-surface proteins (E-cadherin, N-cadherin), cytoskeletal protein (Vimentin), transcription factor (Snail), p38 mitogenactivated protein kinase (MAPK), extracellular signal-regulated kinase (ERK) 1/2 pathway, and matrix metalloproteinase (MMP)-2 expression were measured using Western blotting. Changes in E-cadherin expression were also determined using immunocytochemistry. Cell migration and invasion were analyzed using wound healing and Matrigel invasion assays. RESULTS: Treatment with LGZ or RGZ significantly inhibited transforming growth factor-beta1 (TGF-ß1)-induced EMT-associated processes such as fibroblast-like morphological changes, EMT-related protein expression, and increased cell migration and invasion in BCPAP and K1 cells. LGZ restored TGF-ß1-induced loss of E-cadherin, as observed using immunocytochemistry. Furthermore, LGZ and RGZ suppressed TGF-ß1-induced MMP-2 expression and phosphorylation of p38 MAPK, but not ERK1/2. Although there was no change in PPAR-γ expression after treatment with LGZ or RGZ, the effect of downstream processes mediated by LGZ was hampered by GW9662, a PPAR-γ antagonist. CONCLUSION: LGZ inhibits TGF-ß1-induced EMT, migration, and invasion through the p38 MAPK signaling pathway in a PPAR-γ-dependent manner in PTC cells.

Cost-Effectiveness Analysis of Active Surveillance Compared to Early Surgery in Small Papillary Thyroid Cancer: A Systemic Review.

Papillary thyroid microcarcinoma (PTMC) has indolent features and low mortality. Recently, active surveillance (AS) instead of early surgery (ES) has been introduced as one treatment option but economical preference has not been established. The study objective was to systemically review the literature relating to cost-effectiveness of AS compared to ES for PTMC. Keywords were selected through PICO (Population, Intervention, Comparison, and Outcomes) tools. The search was conducted using PubMed, Cochrane, EMBASE, and Elsevier databases. Papers that had irrelevant titles were written in foreign languages, or had no original results were excluded. Out of the 62 papers extracted, five relevant to the subject matter of this study were identified. Three papers made their own decision models and proceeded with cost-effectiveness analysis (CEA), but the remaining two simply compared costs rather than cost-effectiveness. In terms of cost-effectiveness, three papers preferred AS, one preferred ES, and one preferred neither. The major differences in the CEA might arise from variations in each country's medical insurance system, the utility score systems, and decision models used. In subgroup analysis, two papers preferred AS to ES for patients at a younger age at diagnosis in terms of cost-effectiveness as well as tumor biological characteristics. Although AS has been generally more cost-effective than ES in previous publications, younger age at diagnosis could be one factor contributing to preference for ES. The CEA of prospective cohorts based on the decision model and utility score for thyroid cancer should be undertaken to confirm the cost-effectiveness of AS.

Male sex is not an independent risk factor for recurrence of differentiated thyroid cancer: a propensity score-matching study.

Male patients have a significantly higher prevalence of advanced-stage thyroid cancer. However, sex differences in the risk of differentiated thyroid carcinoma (DTC) recurrence have not been fully elucidated. Therefore, the present study aimed to investigate male sex as a prognostic factor for DTC. We assessed 5566 patients with DTC who underwent thyroid surgery between January 2009 and December 2015 at Seoul St. Mary's Hospital (Seoul, Korea). Clinicopathological characteristics and long-term oncologic outcomes between female and male patients with DTC were compared using propensity score matching to reduce selection bias. The mean follow-up duration was 99.9 ± 18.7 months. The recurrence rate was significantly higher in male patients than female patients before matching (3.3% vs. 2.2%, p = 0.030), and there was no significant difference in recurrence rates between the matched groups after matching (3.0% vs. 2.5%, p = 0.591). Based on Kaplan-Meier analysis, the two groups did not significantly differ in disease-free survival after matching. Multivariate analysis revealed that male sex was not an independent prognostic factor of DTC recurrence. Male sex did not have a significant effect on DTC recurrence. Further studies with larger cohorts are required to validate the findings of this study.