Trends in use of sodium-glucose co-transporter 2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA) in Australia in the era of increased evidence of their cardiovascular benefits (2014-2022).

PURPOSE: To investigate trends in SGLT2i and GLP-1RA use in Australia in the era of increased evidence of their cardiovascular benefits. METHODS: We used national dispensing claims for a 10% random sample of Australians to estimate the number of prevalent and new users (no dispensing in the prior year) of SGLT2i or GLP-1RA per month from January 2014 to July 2022. We assessed prescriber specialty and prior use of other antidiabetic and cardiovascular medicines as a proxy for evidence of type 2 diabetes (T2D) and cardiovascular conditions, respectively. RESULTS: We found a large increase in the number of prevalent users (216-fold for SGLT2i; 11-fold for GLP-1RA); in July 2022 approximately 250,000 Australians were dispensed SGLT2i and 120,000 GLP-1RA. Most new users of SGLT2i or GLP-1RA had evidence of both T2D and cardiovascular conditions, although from 2022 onwards, approximately one in five new users of SGLT2i did not have T2D. The proportion of new users initiating SGLT2i by cardiologists increased after 2021, reaching 10.0% of initiations in July 2022. Among new users with evidence of cardiovascular conditions, empagliflozin was the most commonly prescribed SGLT2i, while dulaglutide or semaglutide was the most common GLP-1RA. CONCLUSION: SGLT2i and GLP-1RA use is increasing in Australia, particularly in populations with higher cardiovascular risk. The increased use of SGLT2i among people without evidence of T2D suggests that best-evidence medicines are adopted in Australia across specialties, aligning with new evidence and expanding indications.

Z-score discordance and contributing factors in healthy premenopausal women with low bone mineral density: the Korean National Health and Nutrition Examination Survey 2008-9.

The premenopausal period is important for bone health and prevention of future fractures, but measuring bone mineral density (BMD) at only one site may not be sufficient to determine therapeutic strategies for low BMD in premenopausal women due to the presence of Z-score discordance. In this study, we investigated Z-score discordance in addition to contributing factors of idiopathic low BMD in healthy premenopausal Korean women. We studied 3003 premenopausal women aged 18-50 years, without secondary causes for low BMD and history of fragility fracture, who had participated in the Fourth Korean National Health and Nutrition Examination Surveys (2008-2009). Low body mass index (BMI), low vitamin D level, and low body muscle mass were associated with low BMD even in premenopausal women. Risk factors differed depending on the anatomic site. Low BMI and low vitamin D level were risk factors for low femoral neck BMD (FN-BMD), but not for low lumbar spine BMD (LS-BMD). Only total muscle mass had a slight effect on low LS-BMD. Z-score discordance was much higher than expected, in 75 and 73.8 % of the low LS-BMD and low FN-BMD groups, respectively. Our findings suggest the need to consider BMD discordance in premenopausal women and also to provide information on correctable factors affecting low BMD in younger populations. Long-term follow-up is needed to evaluate the possible effect of Z-score discordance on the prognosis of osteoporosis and subsequent fracture risk.

Aortic calcification and bone metabolism: the relationship between aortic calcification, BMD, vertebral fracture, 25-hydroxyvitamin D, and osteocalcin.

The aim of this study was to investigate the relationship between aortic calcification (AC) and low bone mineral density (BMD), 25(OH)D, C-terminal telopeptide (CTx), and osteocalcin levels in Asian women. We also tried to find the association between AC and the risk of vertebral fracture. We included 769 patients in this study. All patients underwent QCT. Aortic calcium score (ACS) was quantified by the Agatston scoring method. Spinal fracture was defined by lumbar spine radiography. Among 769 subjects, 96 had at least one vertebral fracture and 345 had AC. ACS positively correlated with age. Osteocalcin, CTx, 25(OH)D, total-hip trabecular BMD (tBMD), femoral neck tBMD, and vertebral tBMD were inversely related with ACS. However, cortical BMD (cBMD) did not correlate with ACS. Among these parameters, only osteocalcin significantly correlated with ACS, even after adjusting for age. We divided the subjects into two groups based on the presence of AC to determine the association between AC and vertebral fracture. Multivariate logistic regression analysis showed that age, tBMD of each site, and AC were associated with vertebral fractures. After adjusting for confounding factors, patients with AC had more than a threefold increased risk of vertebral fracture (OR = 3.29-3.57, P < 0.05 according to site). This study suggests that high ACS is related to low tBMD but not cBMD. Furthermore, our findings indicate that this relationship is definitely age-dependent. Finally, we found that AC is significantly associated with the prevalence of vertebral fracture in Asian women.

Effect of teriparatide on pregnancy and lactation-associated osteoporosis with multiple vertebral fractures.

Pregnancy and lactation-associated osteoporosis (PLO) is very rare, but it can cause severe vertebral compression fractures with disabling back pain. PLO patients have commonly been treated with antiresorptive agents against high bone turnover. There are, however, some concerns regarding the use of bisphosphonates: (1) PLO occurs during the first pregnancy with a high possibility of recurrence during the second pregnancy, (2) long-term outcomes of bisphosphonates in PLO are lacking, and (3) there is a possibility of bisphosphonates accumulated in the bones crossing the placenta. Therefore, alternative therapies must be considered. We analyzed the effect of teriparatide (TPTD), the human recombinant parathyroid hormone (1-34), for 18 months in three women with PLO. Multiple vertebral fractures with severe back pain appeared within 6 months after their first childbirth. Two of them had a family history of osteoporosis. Lactation was discontinued immediately after diagnosis of PLO. Calcium carbonate, cholecalciferol, and TPTD were prescribed. The back pain immediately resolved. Bone mineral density (BMD) increased by 14.5-25.0% (mean 19.5%) at the lumbar spine and by 9.5-16.7% (mean 13.1%) at the femoral neck, after 18 months of treatment. The final Z scores in these PLO patients were nearly normalized. Two women had a second baby without any complication. BMD significantly improved after 18 months of treatment with TPTD without further fractures. In conclusion, TPTD should be considered to avoid long-term morbidity in young patients with PLO and is highly encouraged for use in PLO patients with multiple vertebral fractures.

Altered Glucose Metabolism and Glucose Transporters in Systemic Organs After Bariatric Surgery.

The Roux-en-Y gastric bypass (RYGB) is highly effective in the remission of obesity and associated diabetes. The mechanisms underlying obesity and type 2 diabetes mellitus remission after RYGB remain unclear. This study aimed to evaluate the changes in continuous dynamic FDG uptake patterns after RYGB and examine the correlation between glucose metabolism and its transporters in variable endocrine organs using 18F-fluoro-2-deoxyglucose positron emission tomography images. Increased glucose metabolism in specific organs, such as the small intestine and various fat tissues, is closely associated with improved glycemic control after RYGB. In Otsuka Long-Evans Tokushima Fatty rats fed with high-fat diets, RYGB operation increases intestine glucose transporter expression and various fat tissues' glucose transporters, which are not affected by insulin. The fasting glucose decrement was significantly associated with RYGB, sustained weight loss, post-RYGB oral glucose tolerance test (OGTT) area under the curve (AUC), glucose transporter, or glycolytic enzymes in the small bowel and various fat tissues. High intestinal glucose metabolism and white adipose tissue-dependent glucose metabolism correlated with metabolic benefit after RYGB. These findings suggest that the newly developed glucose biodistribution accompanied by increased glucose transporters is a mechanism associated with the systemic effect of RYGB.

Trends and risk factors in severe hypoglycemia among individuals with type 2 diabetes in Korea.

AIMS: Because of the development of new classes of antidiabetic drugs, hypoglycemic events were expected to decrease. We investigated the trends and risk factors for severe hypoglycemia in subjects with type 2 diabetes in Korea. METHODS: We conducted repeated cross-sectional analyses using a Korean National Health Insurance Service-National Sample Cohort from 2006 to 2015. Severe hypoglycemia was defined as hospitalization or a visit to an emergency department with diagnosis of hypoglycemia using ICD-10 codes. RESULTS: During the study period, the prevalence of type 2 diabetes continuously increased. The percentage of patients prescribed metformin and dipeptidyl peptidase-4 inhibitor increased, while the use of sulfonylurea decreased considerably, especially since 2009. The proportion of patients prescribed ≥3 classes of drugs continually increased. Age-standardized incidence of severe hypoglycemia per 1000 patients with diabetes increased from 6.00 to 8.24 between 2006 and 2010, and then fell to 6.49 in 2015. Predictors of severe hypoglycemia included female, older age, comorbidities, polypharmacy, and sulfonylurea or insulin usage. CONCLUSIONS: Trends of severe hypoglycemia were associated with changes in drug classes rather than number of antidiabetic drugs. Relentless efforts to reduce the prescription of drugs with a high risk of hypoglycemia should be implemented, particularly for older women with multiple comorbidities.

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

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

Risk for Acromegaly-related Comorbidities by Sex in Korean Acromegaly.

CONTEXT: Reports on the incidence, characteristics, and comorbidity in Asian patients with acromegaly are scarce. OBJECTIVE: To evaluate the incidence of acromegaly and the risk of comorbidities in East Asia, especially South Korea. DESIGN: This nationwide population-based cohort study using the Korean Health Insurance Review and Assessment claims database evaluated the incidence of acromegaly, initially diagnosed from 2010 to 2013. We identified comorbidities during, before, and 2 years after diagnosis. Acromegaly and control cases (718 and 7180, respectively) were included in the analysis. SETTING: A longitudinal case-control study using a nationwide population cohort. RESULTS: The mean annual incidence rate of acromegaly was 3.57 cases per 1 000 000. Malignancies occurred in 61 patients with acromegaly (8.5%) during the study period and thyroid cancer was the most common malignancy (n = 38). In the acromegaly group, the overall risk of malignancy was higher: hazard ratio (HR), 2.82 (95% confidence interval [CI]: 2.12-3.74). Malignancy risk was more pronounced in females, with increased risk from the prediagnosis period that is sustained until the postdiagnosis period. Prevalence of diabetes mellitus (DM) and heart failure increased significantly in acromegalic patients. Over the entire period, DM developed in 51.1% and 57.0% of male and female acromegalic patients, respectively. Mortality risk was higher (HR 1.65, 95%; CI: 1.13-2.41) and statistically significant in females (HR 1.75, 95%; CI: 1.07-2.84). CONCLUSION: Comorbidities associated with acromegaly differed by sex in Korean subjects. High malignancy and mortality risk should be considered in female patients when managing acromegaly in Korea.

Diagnosis and Treatment of Growth Hormone Deficiency: A Position Statement from Korean Endocrine Society and Korean Society of Pediatric Endocrinology.

Growth hormone (GH) deficiency is caused by congenital or acquired causes and occurs in childhood or adulthood. GH replacement therapy brings benefits to body composition, exercise capacity, skeletal health, cardiovascular outcomes, and quality of life. Before initiating GH replacement, GH deficiency should be confirmed through proper stimulation tests, and in cases with proven genetic causes or structural lesions, repeated GH stimulation testing is not necessary. The dosing regimen of GH replacement therapy should be individualized, with the goal of minimizing side effects and maximizing clinical improvements. The Korean Endocrine Society and the Korean Society of Pediatric Endocrinology have developed a position statement on the diagnosis and treatment of GH deficiency. This position statement is based on a systematic review of evidence and expert opinions.

Changes in the Diagnostic Efficiency of Thyroid Fine-Needle Aspiration Biopsy during the Era of Increased Thyroid Cancer Screening in Korea.

PURPOSE: The volume of thyroid cancer screening and subsequent thyroid fine-needle aspiration (FNA) have rapidly increased in South Korea. We analyzed the thyroid cancer diagnoses/thyroid FNA ratio according to the annual number of FNA to evaluate changes in the diagnostic efficiency of FNA. MATERIALS AND METHODS: This was a nationwide population-based retrospective cohort study. The overall thyroid cancer diagnoses/thyroid FNA ratio and annual incremental thyroid cancer diagnoses/incremental thyroid FNA ratio were indirectly calculated using data obtained from the Korea Central Cancer Registry database and the Korean National Health Insurance Service claims database from 2004 to 2012. Pearson correlation analyses were performed to evaluate the strength of linear associations between variables. RESULTS: The number of thyroid FNA increased from 28,596 to 177,805 (6.2-fold increase) from 2004 to 2012. The overall thyroid cancer diagnoses/thyroid FNA ratio decreased from 36.5% in 2004 to 25.1% in 2012 and was negatively correlated to the number of FNA (R=‒0.977, p < 0.001). The annual incremental thyroid cancer diagnoses/incremental thyroid FNA ratios (range, 15.3% to 30.7%) were always lower than the overall thyroid cancer diagnoses/thyroid FNA ratio in each year and also worsened according to the increase in the number of FNA (R=‒0.853, p=0.007). CONCLUSION: The diagnostic performance of both overall and annual incremental thyroid FNA worsened, whereas the number of thyroid FNA procedures increased. More sophisticated indications for FNA are required to improve its diagnostic efficiency, considering the increased burden of screening-detected thyroid nodules.

Medical Treatment with Somatostatin Analogues in Acromegaly: Position Statement.

The Korean Endocrine Society (KES) published clinical practice guidelines for the treatment of acromegaly in 2011. Since then, the number of acromegaly cases, publications on studies addressing medical treatment of acromegaly, and demands for improvements in insurance coverage have been dramatically increasing. In 2017, the KES Committee of Health Insurance decided to publish a position statement regarding the use of somatostatin analogues in acromegaly. Accordingly, consensus opinions for the position statement were collected after intensive review of the relevant literature and discussions among experts affiliated with the KES, and the Korean Neuroendocrine Study Group. This position statement includes the characteristics, indications, dose, interval (including extended dose interval in case of lanreotide autogel), switching and preoperative use of somatostatin analogues in medical treatment of acromegaly. The recommended approach is based on the expert opinions in case of insufficient clinical evidence, and where discrepancies among the expert opinions were found, the experts voted to determine the recommended approach.

Association between diffuse lymphocytic infiltration and papillary thyroid cancer aggressiveness according to the presence of thyroid peroxidase antibody and BRAFV600E mutation.

BACKGROUND: Diffuse lymphocytic infiltration (DLI) is frequently found with papillary thyroid cancer (PTC), so there has been long interest in how it affects the characteristics of PTC. This purpose of this study was to define the association between DLI and PTC aggressiveness according to thyroperoxidase antibody (TPOAb) and B-type Raf (BRAF)V600E mutation positivity. METHODS: There were 1879 patients with PTC who underwent surgery and were enrolled in this study. Clinicopathologic characteristics were compared between groups according to the presence of DLI and TPOAb. Multiple logistic regression analysis was conducted to assess odds ratio (OR) for each dependent variable (BRAFV600E mutation, tumor size >1.0 cm, multifocality, extrathyroidal extension, and lymph node metastasis) of each group according to the presence of DLI and TPOAb, with the group with neither DLI or TPOAb (DLI-negative TPOAb-negative PTC) as the reference. RESULTS: The DLI-positive PTC showed more frequent multifocality and less frequent BRAFV600E mutation than DLI-negative PTC. Among patients with DLI-positive PTC, extrathyroidal extension and BRAFV600E mutation was less frequent when serum TPOAb was positive. In multiple logistic regressions, DLI-positive TPOAb-positive PTC showed a high OR for multifocality (1.410; P = .017), but low ORs for BRAFV600E mutation (0.521; P < .001) and extrathyroidal extension (0.691; P = .008). The patients with DLI-positive TPOAb-positive PTCs showed a high OR for multifocality (1.588; P = .002), and high ORs for tumor size >1.0 cm (2.205; P = .019) and lymph node metastasis (2.005; P = .032) in subgroup analyses of PTC with wild-type BRAF. The DLI-negative TPOAb-positive group was not associated with any tumor aggressiveness-related variables. CONCLUSION: Although DLI was associated with multifocality regardless of TPOAb positivity, it was associated with an indolent feature when TPOAb was positive but with aggressive features in PTC with wild-type BRAF when TPOAb was negative. The TPOAb and BRAF status may help to define the clinical implication of lymphocytic infiltration found with PTC.

The relationship between visceral obesity and hepatic steatosis measured by controlled attenuation parameter.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is closely related with obesity. However, obese subjects, generally represented by high BMI, do not always develop NAFLD. A number of possible causes of NAFLD have been studied, but the exact mechanism has not yet been elucidated. METHODS: A total of 304 consecutive subjects who underwent general health examinations including abdominal ultrasonography, transient elastography and abdominal fat computed tomography were prospectively enrolled. Significant steatosis was diagnosed by ultrasonography and controlled attenuation parameter (CAP) assessed by transient elastography. RESULTS: Visceral fat area (VFA) was significantly related to hepatic steatosis assessed by CAP, whereas body mass index (BMI) was related to CAP only in univariate analysis. In multiple logistic regression analysis, VFA (odds ratio [OR], 1.010; 95% confidence interval [CI], 1.001-1.019; P = 0.028) and triglycerides (TG) (OR, 1.006; 95% CI, 1.001-1.011; P = 0.022) were independent risk factors for significant hepatic steatosis. The risk of significant hepatic steatosis was higher in patients with higher VFA: the OR was 4.838 (P<0.001; 95% CI, 2.912-8.039) for 100200 cm2, compared to patients with a VFA ≤100 cm2. CONCLUSIONS: Our data demonstrated that VFA and TG is significantly related to hepatic steatosis assessed by CAP not BMI. This finding suggests that surveillance for subjects with NAFLD should incorporate an indicator of visceral obesity, and not simply rely on BMI.

Epidemiology of Type 1 Diabetes Mellitus in Korea through an Investigation of the National Registration Project of Type 1 Diabetes for the Reimbursement of Glucometer Strips with Additional Analyses Using Claims Data.

BACKGROUND: The aim of this study was to estimate the prevalence and incidence of type 1 diabetes mellitus (T1DM) in Korea. In addition, we planned to do a performance analysis of the Registration Project of Type 1 diabetes for the reimbursement of consumable materials. METHODS: To obtain nationwide data on the incidence and prevalence of T1DM, we extracted claims data from July 2011 to August 2013 from the Registration Project of Type 1 diabetes on the reimbursement of consumable materials in the National Health Insurance (NHI) Database. For a more detailed analysis of the T1DM population in Korea, stratification by gender, age, and area was performed, and prevalence and incidence were calculated. RESULTS: Of the 8,256 subjects enrolled over the 26 months, the male to female ratio was 1 to 1.12, the median age was 37.1 years, and an average of 136 new T1DM patients were registered to the T1DM registry each month, resulting in 1,632 newly diagnosed T1DM patients each year. We found that the incidence rate of new T1DM cases was 3.28 per 100,000 people. The average proportion of T1DM patients compared with each region's population was 0.0125%. The total number of insurance subscribers under the universal compulsory NHI in Korea was 49,662,097, and the total number of diabetes patients, excluding duplication, was 3,762,332. CONCLUSION: The prevalence of T1DM over the course of the study was approximately 0.017% to 0.021% of the entire population of Korea, and the annual incidence of T1DM was 3.28:100,000 overall and 3.25:100,000 for Koreans under 20 years old.

The Relationship between Type 2 Diabetes Mellitus and Non-Alcoholic Fatty Liver Disease Measured by Controlled Attenuation Parameter.

PURPOSE: The severity of non-alcoholic fatty liver disease (NAFLD) in type 2 diabetes mellitus (T2DM) population compared with that in normal glucose tolerance (NGT) individuals has not yet been quantitatively assessed. We investigated the prevalence and the severity of NAFLD in a T2DM population using controlled attenuation parameter (CAP). MATERIALS AND METHODS: Subjects who underwent testing for biomarkers related to T2DM and CAP using Fibroscan® during a regular health check-up were enrolled. CAP values of 250 dB/m and 300 dB/m were selected as the cutoffs for the presence of NAFLD and for moderate to severe NAFLD, respectively. Biomarkers related to T2DM included fasting glucose/insulin, fasting C-peptide, hemoglobin A1c (HbA1c), glycoalbumin, and homeostasis model assessment of insulin resistance of insulin resistance (HOMA-IR). RESULTS: Among 340 study participants (T2DM, n=66; pre-diabetes, n=202; NGT, n=72), the proportion of subjects with NAFLD increased according to the glucose tolerance status (31.9% in NGT; 47.0% in pre-diabetes; 57.6% in T2DM). The median CAP value was significantly higher in subjects with T2DM (265 dB/m) than in those with pre-diabetes (245 dB/m) or NGT (231 dB/m) (all p<0.05). Logistic regression analysis showed that subjects with moderate to severe NAFLD had a 2.8-fold (odds ratio) higher risk of having T2DM than those without NAFLD (p=0.02; 95% confidence interval, 1.21-6.64), and positive correlations between the CAP value and HOMA-IR (ρ0.407) or fasting C-peptide (ρ0.402) were demonstrated. CONCLUSION: Subjects with T2DM had a higher prevalence of severe NAFLD than those with NGT. Increased hepatic steatosis was significantly associated with the presence of T2DM, and insulin resistance induced by hepatic fat may be an important mechanistic connection.

The effect of insulin resistance on postprandial triglycerides in Korean type 2 diabetic patients.

We hypothesized that the influence of metabolic parameters depends on metabolic syndrome (MetS) status. The clinical and metabolic implications of postprandial triglyceride (ppTG) in Korean type 2 diabetes were investigated in the presence or absence of MetS, MetS+, or MetS-. To investigate the relationship between ppTG and metabolic parameters, we analyzed plasma TG levels in 126 newly diagnosed, drug-naïve diabetic patients after ingestion of a standardized low calorie and fat (500 kcal, 17.5 g fat) liquid meal formula. We report that MetS+ patients have significantly higher BMI, waist/hip ratio, HOMA-IR, and HOMA-ß, but insignificantly higher fasting TG, ppTG, and ΔTG than MetS- patients. In the MetS+ patients, ppTG correlated with fasting TG and non-HDL, but was not related to HOMA-IR. In MetS- patients, ppTG correlated with fasting TG, non-HDL, blood pressure, waist/hip ratio, fasting C-peptide and insulin levels, and HOMA-IR. Multivariate analysis showed HOMA-IR to be a predictive factor for ppTG in MetS- patients but not in MetS+ patients. ppTG correlated with IR in MetS- type 2 diabetic patients but not in MetS+. This unexpected result implies that MetS+ diabetic patients already have high fasting TG and that IR influences fasting TG more dominantly than ppTG.

Body Mass Index Is Associated with Hypercholesterolemia following Thyroid Hormone Withdrawal in Thyroidectomized Patients.

Thyroid hormone withdrawal (THW) for postoperative radioiodine adjuvant therapy or diagnostic radioiodine whole body scan in patients with differentiated thyroid cancers results in acute thyroid hormone deficiency and abnormal lipid profiles. To better clarify the clinical pattern of dyslipidemia occurring after THW, we retrospectively analyzed the association between serum total cholesterol level after THW and various clinical factors in a total of 61 patients who underwent total thyroidectomy due to papillary thyroid cancers from January 2010 to March 2012, in Severance Hospital, Seoul, Korea. Preoperative baseline total cholesterol was significantly correlated with post-THW total cholesterol level; however, age, gender, or elevated TSH level after THW itself was not correlated with post-THW total cholesterol level. A significant correlation between preoperative measured BMI and post-THW total cholesterol level was found (r = 0.263, P = 0.041). In multiple logistic analysis, BMI was an independent determining factor of post-THW total cholesterol level (P = 0.012).

Thyroid cancers with benign-looking sonographic features have different lymph node metastatic risk and histologic subtypes according to nodule size.

A decision to perform fine needle aspiration (FNA) on thyroid nodules mainly depends on sonographic features. We investigated if lymph node metastasis (LNM) risk differed by tumor size of thyroid cancers without suspicious sonographic features. Three hundred sixty patients with thyroid cancers with benign looking sonographic features were grouped by nodule size on ultrasonography (US) (≤ or >1 cm). The clinicopathologic parameters were compared between the groups. A multivariate analysis was performed to discover the independent factors predicting the presence of LNM. The nodules greater than 10 mm on US (n = 157) demonstrated a larger tumor size on histology (17.9 ± 14.5 vs. 5.6 ± 2.4 mm, P < 0.001), a lower frequency of classical papillary thyroid carcinoma (PTC) (58.6 vs. 87.2 %, P < 0.001), and a higher frequency of follicular variant PTC and follicular thyroid carcinoma (19.7 and 17.8 % vs. 9.4 and 1.5 %, respectively, P < 0.01). In subgroup analysis of 269 patients with classical PTC, the larger nodule size on US was associated with a higher prevalence of LNM (28.3 vs. 14.7 %, P = 0.007). A multivariate analysis revealed that classical PTC, extrathyroidal extension, and the US nodule size >10 mm were independent predictive factors of LNM after adjusting for age, sex, TSH level, and multifocality. Thyroid cancers larger than 10 mm with benign US features are more likely to be nonclassical PTC than those with smaller diameters. The larger ones also have an increased risk of LNM in classical PTC. These cases require a more aggressive approach to FNA.

Two cases of humoral hypercalcemia of malignancy in metastatic cholangiocarcinoma.

Humoral hypercalcemia of malignancy (HHM) is rarely associated with cholangiocarcinoma (CC), and represents dismal prognosis. A 63-year-old male was admitted for evaluation of an intrahepatic mass. He was diagnosed with HHM associated with locally advanced CC. As the tumor responded to the concurrent chemoradiotherapy with capecitabine and cisplatin, serum calcium level was normalized. However, according to the disease progression, he suffered recurrence of HHM and he expired approximately one year after initial diagnosis. A 68-year-old male who presented with abdominal pain was diagnosed with metastatic CC. After the eighth cycle of gemcitabine and cisplatin, progression of the disease was found with HHM. He was treated with the best supportive care, until his demise approximately one month after the diagnosis of HHM. We report on two cases of HHM associated with CC that demonstrate strong correlation between hypercalcemia and disease burden.

A case of isolated metastatic hepatocellular carcinoma arising from the pelvic bone.

Reports of metastatic hepatocellular carcinoma (HCC) without a primary liver tumor are rare. Here we present a case of isolated HCC that had metastasized to the pelvic bone without a primary focus. A 73-year-old man presented with severe back and right-leg pain. Radiological examinations, including computed tomography (CT) and magnetic resonance imaging (MRI), revealed a huge mass on the pelvic bone (13×10 cm). He underwent an incisional biopsy, and the results of the subsequent histological examination were consistent with metastatic hepatocellular carcinoma. The tumor cells were positive for cytokeratin (AE1/AE3), hepatocyte paraffin 1, and glypican-3, and negative for CD56, chromogranin A, and synaptophysin on immunohistochemical staining. Examination of the liver by CT, MRI, positron-emission tomography scan, and angiography produced no evidence of a primary tumor. Radiotherapy and transarterial chemoembolization were performed on the pelvic bone, followed by systemic chemotherapy. These combination treatments resulted in tumor regression with necrotic changes. However, multiple lung metastases developed 1 year after the treatment, and the patient was treated with additional systemic chemotherapy.