Low Dose of Lenvatinib Treatment for Patients of Radioiodine-Refractory Differentiated Thyroid Carcinoma - A Real-World Experience.

BACKGROUND: Lenvatinib treatment of 24 mg/day for radioiodine-refractory differentiated thyroid carcinoma (RRDTC) patients was almost intolerable, with high rates of dose reduction, interruption and discontinuation. Balancing treatment safety with disease risks remains challenging, and the appropriate dosage remains unclear in Asia. PATIENTS AND METHODS: A total of 65 RRDTC patients treated with lenvatinib were retrospectively collected from Oct. 2015 to Jun. 2020 from two medical centers of South Taiwan. The drug tolerability, treatment efficacy and clinical outcomes were analyzed. RESULTS: Different doses of lenvatinib were initiated but ultimately maintained with a median dose of 10 mg/day within the first 3 months. The disease control rate reached 89.2%, including 24.6% partial response and 64.6% stable disease. Disease progression occurred in 10.8% of patients and increased to 40.0% at the end. Eventually, the treatment dose achieved a median progression-free survival (PFS) of 26.1 months (95% CI: 17.1-NA) with overall survival (OS) not reached yet (24.1~NA). Overall, the 48-month PFS rate was 35.6% (95% CI: 18.5-68.4) and 48-month OS was 54.3% (95% CI: 41.2-71.7). The dose was tolerable with a dose reduction rate of 44.6%, dose interruption rate of 40.0% and fewer high-graded adverse events. The drug discontinuation rate was only 3.1%. However, RRDTC patients with bone metastasis or maximal dose exposure to RAI (≥600 mCi) may have less efficacy to the low maintenance dose treatment. CONCLUSION: Assessing treatment intensity, safety and efficacy, low-dose lenvatinib treatment was well tolerated by RRDTC patients and displayed acceptable drug efficacy and outcomes.

Generalized anxiety disorder in type 2 diabetes mellitus: prevalence and clinical characteristics

Objective: This study investigated the prevalence of generalized anxiety disorder (GAD) in Taiwanese patients with type 2 diabetes mellitus (T2DM). Methods: This retrospective observational study was conducted with a random sample of patients from the entire population of National Health Insurance enrollees during 2000-2010 and used ICD-9-CM diagnostic codes to identify T2DM patients and GAD. The prevalence of GAD was compared between T2DM patients and the general population. Results: Between 2000 and 2010, the prevalence of GAD was significantly greater in the T2DM patients than the general population, while the increase of GAD was higher in the general population (from 0.25 to 0.63%) than among T2DM patients (from 0.81 to 1.03%). In T2DM patients, GAD was associated with female gender, a Charlson Comorbidity Index ≥ 1, diabetes mellitus duration > 9 years, and the following comorbidities: congestive heart failure, peripheral vascular disease, and depressive disorder. The prevalence of GAD among T2DM patients was negatively associated with rapid-acting insulin injection therapy and with the use of metformin and sulfonylureas. Conclusion: Since the prevalence of GAD was greater among T2DM patients than the general population, public health initiatives are needed to prevent and treat GAD in T2DM patients, specifically those with the above mentioned risk factors.

The role of postprandial very-low-density lipoprotein in the development of atrial remodeling in metabolic syndrome.

BACKGROUND: Negatively charged very-low-density lipoprotein (VLDL-χ) in metabolic syndrome (MetS) patients exerts cytotoxic effects on endothelial cells and atrial myocytes. Atrial cardiomyopathy, manifested by atrial remodeling with a dilated diameter, contributes to atrial fibrillation pathogenesis and predicts atrial fibrillation development. The correlation of VLDL-χ with atrial remodeling is unknown. This study investigated the association between VLDL-χ and remodeling of left atrium. METHODS: Consecutively, 87 MetS and 80 non-MetS individuals between 23 and 74 years old (50.6% men) without overt cardiovascular diseases were included in the prospective cohort study. Blood samples were collected while fasting and postprandially (at 0.5, 1, 2, and 4 h after a unified meal). VLDL was isolated by ultracentrifugation; the percentile concentration of VLDL-χ (%) was determined by ultra-performance liquid chromatography. The correlations of left atrium diameter (LAD) with variables including VLDL-χ, LDL-C, HDL-C, triglycerides, glucose, and blood pressure, were analyzed by multiple linear regression models. A hierarchical linear model was conducted to test the independencies of each variable's correlation with LAD. RESULTS: The mean LAD was 3.4 ± 0.5 cm in non-MetS subjects and 3.9 ± 0.5 cm in MetS patients (P < 0.01). None of the fasting lipid profiles were associated with LAD. VLDL-χ, BMI, waist circumference, hip circumference, and blood pressure were positively correlated with LAD (all P < 0.05) after adjustment for age and sex. Significant interactions between VLDL-χ and blood pressure, waist circumference, and hip circumference were observed. When adjusted for obesity- and blood pressure-related variables, 2-h postprandial VLDL-χ (mean 1.30 ± 0.61%) showed a positive correlation with LAD in MetS patients. Each 1% VLDL-χ increase was estimated to increase LAD by 0.23 cm. CONCLUSIONS: Postprandial VLDL-χ is associated with atrial remodeling particularly in the MetS group. VLDL-χ is a novel biomarker and may be a therapeutic target for atrial cardiomyopathy in MetS patients. TRIAL REGISTRATION: ISRCTN 69295295 . Retrospectively registered 9 June 2020.

Proton pump inhibitor use and risk of hip fracture in patients with type 2 diabetes.

Type 2 diabetes mellitus (T2DM) is associated with a high rate of comorbidity, including osteoporosis and peptic ulcers. Proton pump inhibitors (PPIs) are a group of acid-suppressing drugs commonly used for treating peptic ulcers. However, observational studies have reported an association between PPI therapy and osteoporotic fractures. This study investigated the association between PPI use and hip fracture (HFx) among patients with T2DM. We conducted this population-based propensity-matched retrospective cohort study using the National Health Insurance Research Database in Taiwan. Patients newly diagnosed with T2DM between 2000 and 2008 were identified. After excluding those who previously used PPIs or suffered HFx, 398,885 patients were recruited (44,341 PPI users; 354,544 non-users). HFx risk data from 2000 to 2013 were collected to calculate the cumulative rate of HFx in these two groups. Sensitivity analyses were conducted to evaluate the effects of PPI dose. After propensity score matching of 1:4, 44,431 and 177,364 patients were assigned to the PPI user and non-user groups, respectively. PPI user group showed an increased risk of HFx with an adjusted hazard ratio of 1.41 (95% CI 1.29-1.54) without dose-response relationship. Thus, there is an increased risk of HFx in patients with T2DM receiving long-term PPI treatment.

Association between Geriatric Nutrition Risk Index and Skeletal Muscle Mass Index with Bone Mineral Density in Post-Menopausal Women Who Have Undergone Total Thyroidectomy.

BACKGROUND: Osteoporosis is highly prevalent in postmenopausal women and may result in fractures and disabilities. Total thyroidectomy has also been associated with loss of bone mass. The aim of this cross-sectional study was to evaluate associations among nutritional status, skeletal muscle index and markers of bone turnover to bone mineral density in postmenopausal women who had undergone total thyroidectomy. METHODS: Fifty postmenopausal women who had undergone total thyroidectomy were included. Body composition was measured using dual-energy X-ray absorptiometry (DXA). The Geriatric Nutritional Risk Index (GNRI) was calculated using baseline body weight and serum albumin level. Skeletal muscle mass index was calculated as the appendicular skeletal muscle mass (ASM) divided by the height squared and assessed using DXA. RESULTS: Multivariate stepwise linear regression analysis showed that a low GNRI was significantly associated with low lumbar spine bone mineral density (BMD) and T-score, and that a low ASM/height2 was significantly associated with low femoral neck BMD and T-score. A low vitamin D level was significantly associated with low femoral neck BMD and T-score and low total hip BMD and T-score. A high bone alkaline phosphatase (ALP) level was significantly associated with low femoral neck T-score and low total hip BMD and T-score. A low insulin-like growth factor-1 (IGF-1) was significantly associated with low total hip BMD and T-score. CONCLUSION: In the postmenopausal women who had undergone total thyroidectomy in this study, BMD was positively associated with GNRI, skeletal muscle mass index, and levels of vitamin D and serum IGF-1, and inversely associated with bone ALP level. Nutritional status, skeletal muscle mass index and bone turnover biomarkers can be used to early identify patients with a high risk of osteoporosis in this high-risk group.

Stemness regulation of the adrenal mixed corticomedullary tumorigenesis-a case-control study.

Mixed corticomedullary tumor is an adrenal tumor intermixed with cortical and medullary cells. It is extremely rare with unclear tumorigenesis. We reported a 32-year-old female, manifested with typical Cushing's syndrome and hypertension, to be diagnosed with right huge adrenal mixed corticomedullary tumor (8.8 cm). Right adrenalectomy was done to document the tumor intimately admixed with adrenal cortical adenoma and pheochromocytoma by biochemistry and immunohistochemistry. A case-control study was designed to explore the tumorigenesis of mixed corticomedullary tumor by whole exome sequencing. Expression of the stemness markers was controlled by a tissue array of 80 adrenal tumors. Overall, 1559 identical variants coexisted in parts of adrenal cortical adenoma and pheochromocytoma, which mainly (85.8%) originated from germline mutations. These enriched mutations were engaged in stemness control, coherent with substantial expression of the stemness markers (SOX2, CD44 and OCT4) in both parts. The differential stemness expressions were demonstrated in other adrenal tumors as well. The germline mutations were also enriched in signaling involving cancer proliferation, hypoxia inducible factor-1, focal adhesion and extracellular matrix receptor interaction. Somatic mutations affecting mitogen-activated protein kinase signaling, glycolysis and the citrate cycle were found in some tumor elements. This is the first study to verify the rare mixed corticomedullary tumor by molecular and genetic evidence to link with its phenotype. Germline mutations involving the stemness regulation and cancer proliferative signaling may drive intermixed tumor formation. Somatic mutations related to glycolysis and the citrate cycle may contribute to greater tumor outgrowth.

Generalized anxiety disorder in type 2 diabetes mellitus: prevalence and clinical characteristics.

OBJECTIVE: This study investigated the prevalence of generalized anxiety disorder (GAD) in Taiwanese patients with type 2 diabetes mellitus (T2DM). METHODS: This retrospective observational study was conducted with a random sample of patients from the entire population of National Health Insurance enrollees during 2000-2010 and used ICD-9-CM diagnostic codes to identify T2DM patients and GAD. The prevalence of GAD was compared between T2DM patients and the general population. RESULTS: Between 2000 and 2010, the prevalence of GAD was significantly greater in the T2DM patients than the general population, while the increase of GAD was higher in the general population (from 0.25 to 0.63%) than among T2DM patients (from 0.81 to 1.03%). In T2DM patients, GAD was associated with female gender, a Charlson Comorbidity Index ≥ 1, diabetes mellitus duration > 9 years, and the following comorbidities: congestive heart failure, peripheral vascular disease, and depressive disorder. The prevalence of GAD among T2DM patients was negatively associated with rapid-acting insulin injection therapy and with the use of metformin and sulfonylureas. CONCLUSION: Since the prevalence of GAD was greater among T2DM patients than the general population, public health initiatives are needed to prevent and treat GAD in T2DM patients, specifically those with the above mentioned risk factors.

Clinical application of the ultrasound-guided fine needle aspiration for thyroglobulin measurement to diagnose lymph node metastasis from differentiated thyroid carcinoma-literature review.

Papillary thyroid carcinoma (PTC) generally has a good prognosis, but disease recurs in 25% to 30% of PTC patients and significantly reduces the survival rate. Lymph node metastasis (LNM) is reported in 20% to 50% of PTC patients, mainly in the neck, and 20% originates from recurrence. LNM of papillary thyroid carcinoma are a plausible prognostic factor to determine disease recurrence. Currently, fine needle lymph node aspiration for cytology (LN-FN-cytology) is the best modality to diagnose LNM but is limited by diagnostic sensitivity and sample error. Fine needle lymph node aspiration for thyroglobulin measurement (LN-FNA-Tg) could offer a reliable and quantitative diagnostic method for LNM. The combination of LN-FNA-cytology and LN-FNA-Tg could achieve almost 100% diagnostic sensitivity and specificity for LNM. Both treatment guidelines of the American Thyroid Association and European Thyroid Association recommend LN-FNA-Tg to diagnose LNM after total thyroidectomy. Diagnostic accuracy of the LN-FNA-Tg depends on optimal equipment, scanning protocol, skill, and experience of operators. Normal saline is mainly used for aspiration needle wash-out and buffer solution. And radioimmunoassay or immunoradiometric assay are widely used for the LN-FNA-Tg measurement. So far, there is no consensus about the diagnostic threshold of LN-FNA-Tg for positive LNM, but high LN-FNA-Tg, especially higher than 10 ng/mL, strongly favors LNM.

Lenvatinib complementary with radioiodine therapy for patients with advanced differentiated thyroid carcinoma: case reports and literature review.

BACKGROUND: The prognosis for patients with advanced differentiated thyroid carcinoma (ADTC) with disseminated distant metastases is very poor. Tyrosine kinase inhibitors targeting tumor angiogenesis have been shown to improve progression-free survival in patients with advanced thyroid carcinoma and progressive radioiodine-refractory thyroid carcinoma. Tyrosine kinase inhibitor has been reported as a successful neoadjuvant for total thyroidectomy to reduce tumor burden. However, the special indications for prompt treatment with lenvatinib as a rescue therapy to reduce tumor burden and prolong a durable response to radioiodine therapy have not been explored. CASE PRESENTATION: Here, we present two ADTC cases with distant metastases who were effectively treated by total thyroidectomy combined with lenvatinib to prolong a durable response to radioiodine therapy. Case 1 was a 66-year-old male diagnosed with ADTC and disseminated brain, lung, and bone metastases. Lenvatinib was initiated via compassionate access because of rapidly progressive tumor growth even after second doses of radioiodine therapy and external beam radiation therapy for his brain metastases. The result was a durable response to lenvatinib, slowing progressive tumor growth for 3 years and allowing a third course of radioiodine therapy to treat the bone metastases. Case 2 was a 45-year-old male diagnosed with ADTC and diffuse disseminated lung metastases. Respiratory failure ensued after total thyroidectomy, requiring mandatory support by respirator. Lenvatinib was started as a rescue therapy to reduce tumor burden rapidly. The patient was successfully weaned off the respirator only 1 week after using lenvatinib. The patient was then maintained on a low dose of lenvatinib, allowing three subsequent courses of radioiodine therapy. Currently, his lung metastasis remains well controlled with decreased lung infiltrating nodules and the patient can tolerate exercise well. CONCLUSION: Our case experience indicated that lenvatinib has significant value as salvage therapy, reducing tumor burden, producing a durable response and maintaining quality of life. For ADTC patients with progressive life-threatening metastases, our experience suggests that lenvatinib treatment can be used as an urgent rescue therapy as well as a complement to radioiodine therapy to improve tumor eradication.

Schizophrenia in type 2 diabetes mellitus: Prevalence and clinical characteristics.

BACKGROUND: This study investigated the prevalence and characteristics of schizophrenia in patients with type 2 diabetes mellitus (T2DM) in Taiwan. METHODS: National Health Insurance claims data for patients with principal diagnoses of schizophrenia and T2DM were analysed. RESULTS: Compared with patients with schizophrenia in the general population (GP), those with schizophrenia and T2DM were more likely to have higher Charlson comorbidity index (CCI) scores and multiple comorbidities, and were older. The prevalence of schizophrenia was significantly higher in patients with T2DM than in the GP from 2000 to 2010. In addition, during this period, the prevalence of schizophrenia in patients with T2DM increased from 0.64% to 0.85%; such an increase in the GP was also observed. A high prevalence of schizophrenia was observed in patients with T2DM aged less than 60 years old; those residing in eastern Taiwan; those with incomes of ≤NT$17,280, NT$17,281-NT$22,880, NT$22,881-NT$28,800, and NT$36,301-NT$45,800; and those with CCI > 2. CONCLUSIONS: Our study found the prevalence of schizophrenia is higher in patients with T2DM than in the GP, particularly those with earlier ages less than 60 years old. Public health initiatives are necessary to prevent and treat schizophrenia in patients with T2DM, specifically for those with the aforementioned and premature death risk.

Major depressive disorder in patients with type 2 diabetes mellitus: Prevalence and clinical characteristics.

BACKGROUND: This study investigated the prevalence of major depressive disorder (MDD) among Taiwanese patients with type 2 diabetes mellitus (T2DM). METHODS: We enrolled patients with at least one service claim for ambulatory or inpatient care with a principal diagnosis of MDD and at least two service claims for ambulatory care or one service claim for inpatient care with a principal diagnosis of T2DM, as listed in Taiwan's National Health Insurance database. RESULTS: We enrolled 715,756 people from the general population (GP), 61,589 patients with T2DM but without MDD, and 778 patients with both T2DM and MDD. The prevalence of MDD increased from 0.70% to 1.25% in the patients with T2DM, whereas it increased from 0.25% to 0.67% in the GP from 2000 to 2010. The higher prevalence of MDD was associated with the female sex, residing in the southern regions of Taiwan, and having comorbidities of cerebrovascular disease and anxiety disorder as well as higher comorbidity severity (Charlson comorbidity index, 1-2 and > 2). LIMITATIONS: One limitation is the use of secondary data on diagnoses of MDD and T2DM. Another limitation is that we could not access some crucial related variables. CONCLUSIONS: The prevalence of MDD was higher in the patients with T2DM than in the GP. In this study, the prevalence of MDD in the patients with T2DM was lower than that reported in Western countries.

Pioglitazone Enhances Cytosolic Lipolysis, ß-oxidation and Autophagy to Ameliorate Hepatic Steatosis.

Non-alcoholic fatty liver disease closely contributes to the development of obesity and insulin resistance. Even though pioglitazone has been reported to effectively lessen hepatic steatosis in human studies, its molecular mechanism remains unclear. This study is designed to investigate the regulation of cytosolic lipolysis, ß-oxidation and autophagy by pioglitazone in a mice model of high fat diet (HFD) and cell model incubated with palmitic acid. Our results revealed hepatic steatosis was apparently induced by HFD and it was significantly reversed by pioglitazone. The serum insulin and hepatic triglyceride content was significantly decreased by co-administered pioglitazone with HFD. Hepatic expression of cytosolic-lipolysis related proteins (ATGL, HSL), ß-oxidation (CPT-1A) and autophagy-related proteins (ATG7, LC3, LAL) was significantly enhanced by pioglitazone. Knockdown PPARα/PPARγ in AML12 cells significantly and proportionally reduced the expressions of ATGL, CPT-1A and LC3II, which was induced by pioglitazone. Furthermore, facilitation of the autophagic flux by pioglitazone was obviously blocked by lysosomal inhibitor, leupeptin, to demonstrate accumulation of the LC3II and intracellular lipid in AML12 cells. Our results demonstrated that pioglitazone attenuating the hepatic steatosis may be mediated by enhancing cytosolic lipolysis, ß-oxidation and autophagy in a PPARα and PPARγ dependent manner.

Prevalence of Depressive Disorder in Persons With Type 2 Diabetes: A National Population-Based Cohort Study 2000-2010.

BACKGROUND: Diabetes mellitus, a chronic and disabling disease, is epidemic worldwide. Depressive disorder affects the productivity of workers and leads to disability. OBJECTIVE: This study investigated the prevalence of depressive disorder among persons with type 2 diabetes in Taiwan. METHODS: We extracted service claims data for subjects who had at least 2 ambulatory care service claims or 1 inpatient service claim with a principal diagnosis of type 2 diabetes and at least 1 ambulatory or inpatient service claim with a principal diagnosis of depressive disorder from Taiwan's National Health Insurance Database. RESULTS: From 2000-2010, the prevalence of depressive disorder increased from 3.50-4.07% in people with type 2 diabetes, and from 1.05-2.27% in the general population. The higher prevalence of depressive disorder in persons with type 2 diabetes was associated with being female; residence in central, southern, and eastern Taiwan; residence in urban areas; the comorbidities of hemiplegia or paraplegia, cerebrovascular disease, and anxiety disorder; Charlson Comorbidity Index scores ≥1; diabetes duration >9 years; and the use of rapid-acting insulin injection therapy. CONCLUSIONS: The prevalence of depressive disorder is higher among persons with type 2 diabetes than the general population. Consequently, more public health attention should be devoted to the prevention and treatment of this debilitating disease in persons with type 2 diabetes, especially those with the earlier mentioned risk factors.

Prevalence of anxiety disorder in patients with type 2 diabetes: a nationwide population-based study in Taiwan 2000-2010.

This study investigates the prevalence of anxiety disorder (AD) in Taiwanese patients with type 2 diabetes (T2D). Study participants were identified based on at least one service claim for ambulatory or inpatient care with a principal diagnosis of AD and at least 2 service claims for ambulatory care or one service claim for inpatient care with a principal diagnosis of T2D, as listed in the National Health Insurance database of Taiwan. The prevalence of AD decreased from 13.75 to 11.00 % in patients with T2D, whereas it increased from 4.17 to 6.09 % in the general population during the 2000-2010 period. A high prevalence of AD in patients with T2D was associated with age >30 years, the female sex, living in the northern region, comorbidities of congestive heart failure, peripheral vascular disease, cerebrovascular disease, and depression disorder, and a Charlson participant comorbidity index of ≥1. A low prevalence of AD in patients with T2D was associated with residency in urban areas, the comorbidity of hemiplegia or paraplegia, the usage of metformin and sulfonylureas, and rapid-acting insulin injection therapy. The prevalence of AD was higher in patients with T2D than in the general population. Therefore, more public health emphasis is required for preventing and treating AD in patients with T2D, specifically those with the mentioned risk factors.

MTTP-297H polymorphism reduced serum cholesterol but increased risk of non-alcoholic fatty liver disease-a cross-sectional study.

BACKGROUND: Microsomal triglyceride transfer protein (MTP) works to lipidate and assemble the apoB-containing lipoproteins in liver. It closely links up the hepatic secretion of lipid to regulate serum lipid and atherosclerosis. Cases of MTTP gene mutation is characterized by abetalipoproteinemia and remarkable hepatic steatosis or cirrhosis. Several MTTP polymorphisms have been reported relating to metabolic syndrome, hyperlipidemia and steatohepatitis. We supposed the regulation of serum lipids and risk of non-alcoholic fatty liver disease (NAFLD) formation may be modified by individual susceptibility related to the MTTP polymorphisms. METHODS AND RESULTS: A cross-sectional population of 1193 subjects, 1087 males and 106 females mean aged 45.9 ± 8.9 years, were enrolled without recognized secondary hyperlipidemia. Fasting serum lipid, insulin, and non-esterified fatty acid were assessed and transformed to insulin resistance index, HOMA-IR and Adipo-IR. After ruling out alcohol abuser, non-alcoholic fatty liver disease (NAFLD) was diagnosed by abdominal ultrasound. Five common MTTP polymorphisms (promoter -493 G/T, E98D, I128T, N166S, and Q297H) were conducted by TaqMan assay. Multivariate regression analysis was used to estimate their impact on serum lipid and NAFLD risk. Assessment revealed a differential impact on LDL-C and non-HDL-C, which were sequentially determined by the Q297H polymorphism, insulin resistance, body mass index and age. Carriers of homozygous minor allele (297 H) had significantly lower LDL-C and non-HDL-C but higher risk for NAFLD. Molecular modeling of the 297 H variant demonstrated higher free energy, potentially referring to an unstable structure and functional sequence. CONCLUSION: These results evidenced the MTTP polymorphisms could modulate the lipid homeostasis to determine the serum lipids and risk of NAFLD. The MTTP 297 H polymorphism interacted with age, insulin resistance and BMI to decrease serum apoB containing lipoproteins (LDL-C and non-HDL-C) but increase the risk of NAFLD formation.

A case of acromegaly complicated with diabetic ketoacidosis, pituitary apoplexy, and lymphoma.

Acromegaly is always complicated with comorbidities and increased mortality. The disease activity and mortality outcomes are highly correlated to the level of growth hormone and insulin-like growth factor 1. A variety of clinical manifestations of acromegaly have been reported. We present a unique case where a 49-year-old male was diagnosed with acromegaly with a first manifestation as an episode of diabetic ketoacidosis. Because he refused any suggestion of treatment, a recurrent episode of diabetic ketoacidosis with pituitary apoplexy occurred. A huge B-cell lymphoma displaying as a huge facial mass followed within 1 year of the diagnosis of acromegaly. Death from advanced cancer ensued 3 years later. This clinical experience strongly reinforces the urgency of controlling growth hormone and insulin-like growth factor 1 as soon as possible once acromegaly is diagnosed.