The impact of bisphosphonates on mortality and cardiovascular risk among osteoporosis patients after cardiovascular disease.

BACKGROUND/PURPOSE: Bisphosphonates (BPs) impact on the survival and cardiovascular safety of osteoporosis patients after acute coronary syndrome (ACS) or acute ischemic stroke (AIS) was evaluated. METHODS: A nationwide epidemiological study was conducted using the Taiwan National Health Insurance Research Database from 2000 to 2010. From the 1456 osteoporosis patients with previous ACS or AIS, mortality and cardiovascular safety was compared between 464 patients who used BPs and 464 patients who did not. Primary outcomes included all-cause mortality, and major adverse cardiovascular events. RESULTS: The BPs group had a lower risk of all-cause mortality than the control group after the 8-year follow-up (HR, 0.64; 95% CI, 0.46-0.88; P = 0.006). The risks of myocardial infarction, ischemic stroke, cardiovascular death, hospitalization for heart failure or other causes of mortality were similar across groups. However, there was a higher risk of hospitalization for atrial fibrillation in the BPs group than the control group (HR, 1.76; 95% CI, 1.26-2.46; P = 0.001). CONCLUSION: Among osteoporosis patients after ACS or AIS, BPs use was associated with a reduced risk of all-cause mortality. However, patients with previous cardiovascular disease who received BP treatment should be careful about the risk of atrial fibrillation.

Long-term outcome and prognostic factors of single-dose Radioiodine Therapy in patients with Graves' disease.

BACKGROUND/PURPOSE: Few studies exist investigating the effectiveness of radioiodine (RAI) therapy for hyperthyroidism patients in Asia. We herein investigated the real-world efficacy of single-dose RAI therapy in Taiwanese patients with Graves' disease (GD). METHODS: This is a retrospective study of 243 patients with GD recorded between 1989 and 2016 in a tertiary referral hospital. Eu- or hypothyroid after RAI therapy were defined as the successful group. Kaplan-Meier curve and cox-regression model were used for analysis of prognostic factors. RESULTS: Of the 243 patients, 187 were females, with mean age of 46.9 ± 13.6 years. Most patients (63.8%) did not choose RAI as the first-line therapy. The median dose was 7 mCi, with a mean follow-up period of 107.1 ± 82.8 months. The overall success rate was 70.9%. Univariate analysis revealed calculated- or fixed-dose (P = 0.015), goiter size (P < 0.001), and RAI dose (P = 0.022) were the factors affecting RAI effectiveness, multivariate analysis indicated goiter size was the independent factor. Patients with grade 0-2 goiter had a higher success rate than patients with grade 3 goiter (HR = 2.1, 95%CI = 1.34-3.27, P = 0.001), although the former were treated with lower RAI dose than the latter (7.8 ± 3.2 mCi vs 8.8 ± 3.3 mCi, P = 0.049). However, if the grade 3 goiters became smaller within 3 months of therapy, the success rate was not inferior to grade 0-2 goiter. CONCLUSION: In Taiwan, RAI therapy for GD patients reached an overall success rate of 70.9%, with a median dose of 7 mCi. This study identified patients with grade 3 goiter need a more aggressive RAI regimen.

Factors associated with osteoarthritis in menopausal women: A registry study of osteoporosis sarcopenia and osteoarthritis.

Background: Bone and muscle mass decline after menopause. The risk of osteoarthritis (OA), sarcopenia, and osteoporosis increases in later life. Our objective aimed to assess the possible factors affecting osteoarthritis in menopausal women. Methods: This is a registry study of osteoporosis, sarcopenia, and osteoarthritis. All subjects accepted bone mineral density (BMD) and body composition studies, and X-rays of both knees were performed. A medical history was taken and biochemical data were recorded. Logistic regression analyses were used to examine the associations between the presence of osteoarthritis and BMD, muscle mass, and other parameters. Results: A total of 139 patients were enrolled. The mean age of the patients was 73.86 ± 5.83 years in the osteoarthritis group and 74.53 ± 9.90 in the non-osteoarthritis group (p = 0.663). The mean body mass index (BMI) was 24.36 ± 3.64 kg/m2 in the osteoarthritis group, compared with 23.78 ± 3.61 in the non-osteoarthritis group (p = 0.366). The lumbar spine T score was -2.06 ± 1.33 g/cm2 in the osteoarthritis group, and -1.25 ± 1.76 in the non-osteoarthritis group (p = 0.006). There were no significant differences in smoking, alcohol consumption, diabetes, hypertension, cardiovascular disease, neurological disease, and chronic kidney disease between the two groups. When we used osteoarthritis as the outcome, we found that the lumbar spine T score had a significant association with osteoarthritis, with a high T score associated with less osteoarthritis formation (p = 0.024, odds ratio (95% confidence interval) 0.06 (0-0.69)). Conclusions: Knee osteoarthritis was associated with lumbar spine bone density. This study provides the initial information required to develop clinical algorithms for the early identification of potential high-risk populations, as well as essential information for the development of policies for the detection and prevention of osteoarthritis in menopausal women.

Comparison of Glucose Lowering Efficacy of Human GLP-1 Agonist in Taiwan Type 2 Diabetes Patients after Switching from DPP-4 Inhibitor Use or Non-Use.

To determine the efficacy of glucose control in type 2 diabetes patients who switch from dipeptidyl peptidase-4 (DPP-4) inhibitors use or non-use to GLP-1 receptor agonists (GLP-1 RAs). We conducted a cohort study using data from the Chang Gung Research Database. Patients aged ≥18 years using newly initiated GLP-1 RAs between 1 January 2009, and 31 December 2016, were included. Cox proportional hazards models were used to adjust for treatment selection bias. The primary outcome was changes in the glycated hemoglobin (HbA1c) level. The HbA1c level fell substantially after initiating GLP-1 RAs in DPP-4 inhibitor users and nonusers. A mean HbA1c reduction of −0.42% was found in patients who received DPP-4 inhibitors. Those who were DPP-4 inhibitor nonusers had a reduction in HbA1c of −0.99%. The degree of reduction in HbA1c was significantly greater in patients who were DPP-4 inhibitor nonusers (p value < 0.01), compared to the DPP-4 inhibitor users. In routine care, DPP-4 inhibitor nonusers had better efficacy in glucose control than DPP-4 inhibitor users after switching to a GLP-1 agonist.

Effects of 12-Week Progressive Sandbag Exercise Training on Glycemic Control and Muscle Strength in Patients with Type 2 Diabetes Mellitus Combined with Possible Sarcopenia.

Patients with type 2 diabetes mellitus (T2DM) are at a three-fold increased risk of developing sarcopenia compared to those without diabetes. The objective of this study was to investigate whether an intervention involving progressive sandbag exercises is beneficial to patients with T2DM and possible sarcopenia in terms of enhancing muscle strength and controlling blood sugar levels. Forty patients with T2DM and possible sarcopenia (age > 50 years) were recruited and randomly divided into resistance training and control groups. Resistance exercises for the upper and lower extremities were performed using sandbags (0.5 kg at the beginning to 1 kg after 1 month). Patients in the control group were asked to maintain their usual daily lifestyle. After 12 weeks, the training group were significant better than the control group in terms of glycosylated hemoglobin, the five times sit-to-stand test, skeletal muscle mass and calf circumference, and the physiological domain of the World Health Organization Quality of Life Questionnaire. In conclusion, these simple home exercises are beneficial to patients with T2DM combined with possible sarcopenia. This approach can assist patients in controlling their levels of glycosylated hemoglobin as well as improve physical fitness and quality of life.

The effect of adjuvant radiotherapy on clinical outcomes in early major salivary gland cancer.

BACKGROUND: This study investigated the effects of adjuvant radiotherapy on outcomes in early-stage major salivary gland cancers. METHODS: A total of 655 patients were identified, including 355 (54.2%) received adjuvant radiotherapy and 300 (45.8%) had surgery alone. The effect of adjuvant radiotherapy on 5-year locoregional recurrence and disease-specific survival (DSS) was calculated using the Kaplan-Meier method, Wilcoxon rank sum test, and Cox proportional hazards model. RESULTS: There were no significant differences in locoregional recurrence and DSS between patients receiving adjuvant radiotherapy and those not in both univariate and multivariable analysis. Although patients with positive margin status had a higher locoregional recurrence and those with moderate/poor differentiation had a worse DSS, stratified analysis still indicated there were no protective effects from the use of adjuvant radiotherapy. CONCLUSIONS: The use of adjuvant radiation therapy was not associated with improved locoregional recurrence and DSS, even for those with high-risk histopathological factors.

High Expression of Folate Receptor Alpha (FOLR1) is Associated With Aggressive Tumor Behavior, Poor Response to Chemoradiotherapy, and Worse Survival in Rectal Cancer.

Objectives: Recently, molecular medicine targeting Folate Receptor Alpha (FOLR1), which mediates intracellular folate uptake and tumor cell proliferation, has been identified in several malignancies. However, the association between FOLR1 expression and rectal cancer remains unclear. Methods: Immunostaining of FOLR1 was performed on biopsy specimens from 172 rectal cancer patients undergoing preoperative chemoradiotherapy (CRT). FOLR1 expression was measured and divided into low (0+-2+) or high (3+-4+) level. Correlations between FOLR1 status and clinicopathologic features, tumor regression grade, disease-specific survival (DSS), local recurrence-free survival, and metastasis-free survival (MeFS) were analyzed, retrospectively. Results: High FOLR1 expression was significantly associated with advanced post-treatment tumor and nodal status (T3-4; N1-2, P = .001), vascular invasion (P = .042), perineural invasion (P = .012), and poor regression change after CRT (P = .001). In uni- and multi-variable survival analysis, FOLR1 overexpression remained a significant predictor of lower DSS (hazard ratio [HR], 2.328; 95% confidence interval [CI], 1.014-5.344; P = .046) and MeFS (HR, 2.177; 95% CI, 1.000-1.1286; P = .050). Conclusion: These results indicate that high FOLR1 status is associated with aggressive tumor behavior, poor response to CRT, and worse survival. Therefore, FOLR1 expression at initial biopsy may be useful in predicting outcomes and also be a target for the exploration of FOLR1-based therapeutic agents.

Adjuvant chemotherapy and survival outcomes in rectal cancer patients with good response (ypT0-2N0) after neoadjuvant chemoradiotherapy and surgery: A retrospective nationwide analysis.

Background: For rectal cancer, it remains unclear how to incorporate tumor response to neoadjuvant chemoradiotherapy (nCRT) when deciding whether to give adjuvant chemotherapy. In this study, we aim to determinate the survival benefit of adjuvant chemotherapy for rectal cancer patients with good response (ypT0-2N0) after nCRT and surgery. Methods: The study cohort included 720 rectal cancer patients who had good response (ypT0-2N0) after nCRT and surgery, who did or did not receive adjuvant chemotherapy between January 2007 and December 2017, from the Taiwan Cancer Registry and National Health Insurance Research database. The Kaplan-Meier method, log-rank tests, and Cox regression analysis were performed to investigate the effect of adjuvant chemotherapy on 5-year overall survival (OS) and disease-free survival (DFS). Results: Of 720 patients, 368 (51.1%) received adjuvant chemotherapy and 352 (48.9%) did not. Patients who received adjuvant chemotherapy were more likely to be female, younger (≤ 65), with advanced clinical T (3-4)/N (1-2) classification and ypT2 classification. No significant difference in 5-year OS (p=0.681) or DFS (p=0.942) were observed by receipt of adjuvant chemotherapy or not. Multivariable analysis revealed adjuvant chemotherapy was not associated with better OS (adjusted hazard ratio [aHR], 1.03; 95% Confidence Interval [CI], 0.88-1.21) or DFS (aHR, 1.05; 95% CI, 0.89-1.24). Stratified analysis for OS and DFS found no significant protective effect in the use of adjuvant chemotherapy, even for those with advanced clinical T or N classification. Conclusion: Adjuvant chemotherapy may be omitted in rectal cancer patients with good response (ypT0-2N0) after nCRT and surgery.

Adjuvant Radiotherapy Significantly Increases Neck Control and Survival in Early Oral Cancer Patients with Solitary Nodal Involvement: A National Cancer Registry Database Analysis.

We assessed the role of adjuvant radiotherapy on neck control and survival in patients with early oral cancer with solitary nodal involvement. We identified pT1-2N1 oral cancer patients with or without adjuvant radiotherapy from the 2007-2015 Taiwan Cancer Registry database. The effect of adjuvant radiotherapy on 5-year neck control, overall survival (OS) and disease-free survival (DFS) were calculated using the Kaplan-Meier method, log-rank tests, and Cox regression analysis. Of 701 patients identified, 505 (72.0%) received adjuvant radiotherapy and 196 (28.0%) had surgery alone. Patients receiving adjuvant radiotherapy were more likely to be aged <65 years, pT2 stage, poorly graded and without comorbid conditions (all, p < 0.05). The 5-year OS and DFS differed significantly by receipt of adjuvant radiotherapy. Multivariable analysis showed adjuvant radiotherapy significantly associated with better 5-year OS (adjusted hazard ratio (aHR), 0.72; 95% confidence interval (CI), 0.54-0.97; p = 0.0288) and DFS (aHR, 0.64; 95% CI, 0.48-0.84; p = 0.0016). Stratified analysis indicated the greatest survival advantage for both 5-year OS and DFS in those with pT2 classification (p = 0.0097; 0.0009), and non-tongue disease (p = 0.0195; 0.0158). Moreover, adjuvant radiotherapy significantly protected against neck recurrence (aHR, 0.30; 95% CI, 0.18-0.51; p < 0.0001). Thus, adjuvant radiotherapy is associated with improved neck control and survival in these early oral cancer patients.

Overexpression of MLPH in Rectal Cancer Patients Correlates with a Poorer Response to Preoperative Chemoradiotherapy and Reduced Patient Survival.

Data mining of a public transcriptomic rectal cancer dataset (GSE35452) from the Gene Expression Omnibus, National Center for Biotechnology Information identified the melanophilin (MLPH) gene as the most significant intracellular protein transport-related gene (GO:0006886) associated with a poor response to preoperative chemoradiation. An MLPH immunostain was performed on biopsy specimens from 172 rectal cancer patients receiving preoperative chemoradiation; samples were divided into high- and low-expression groups by H-scores. Subsequently, the correlations between MLPH expression and clinicopathologic features, tumor regression grade, disease-specific survival (DSS), local recurrence-free survival (LRFS), and metastasis-free survival (MeFS) were analyzed. MLPH expression was significantly associated with CEA level (p = 0.001), pre-treatment tumor status (p = 0.022), post-treatment tumor status (p < 0.001), post-treatment nodal status (p < 0.001), vascular invasion (p = 0.028), and tumor regression grade (p < 0.001). After uni- and multi-variable analysis of five-year survival, MLPH expression was still associated with lower DSS (hazard ratio (HR), 10.110; 95% confidence interval (CI), 2.178-46.920; p = 0.003) and MeFS (HR, 5.621; 95% CI, 1.762-17.931; p = 0.004). In conclusion, identifying MLPH expression could help to predict the response to chemoradiation and survival, and aid in personal therapeutic modification.

Optimal Lymph Node Yield for Survival Prediction in Rectal Cancer Patients After Neoadjuvant Therapy.

PURPOSE: A lymph node (LN) yield ≥12 is required to for accurate determination of nodal status for colorectal cancer but cannot always be achieved after neoadjuvant therapy. This study aims to determine the difference in LN yield from rectal cancer patients treated with and without neoadjuvant therapy and the effects of specific LN yields on survival. PATIENTS AND METHODS: The study cohort included a total of 4344 rectal cancer patients treated between January 2007 and December 2015, 2260 (52.03%) of whom received neoadjuvant therapy. Data were retrieved from the Taiwan nationwide cancer registry database. The minimum acceptable LN yield below 12 was investigated using the maximum area under the ROC curve. RESULTS: The median LN yield was 12 (8-17) for patients who received neoadjuvant therapy and 17 (13-24) for those who did not. The recommended LN yield ≥12 was achieved in 82.73% of patients without and 57.96% of those with neoadjuvant therapy (p < 0.0001). Patients with LN yield ≥12 had a higher OS probability than did those with LN <12 (OR, 1.33; 95% CI, 1.06-1.66; p = 0.0124). However, the predictive accuracy for survival was greater for LN yield ≥10 (AUC, 0.7767) than cut-offs of 12, 8, or 6, especially in patients with pathologically-negative nodes (AUC, 0.7660). CONCLUSION: Neoadjuvant therapy significantly reduces the LN yield in subsequent surgery. A lower yield (LN ≥ 10) may be adequate for nodal evaluation in rectal cancer patients after neoadjuvant therapy.

The Causal Role of Mitochondrial Dynamics in Regulating Insulin Resistance in Diabetes: Link through Mitochondrial Reactive Oxygen Species.

BACKGROUND: Mitochondrial dynamics (mtDYN) has been proposed as a bridge between mitochondrial dysfunction and insulin resistance (IR), which is involved in the pathogenesis of type 2 diabetes (T2D). Our previous study has identified that mitochondrial DNA (mtDNA) haplogroup B4 is a T2D-susceptible genotype. Using transmitochondrial cybrid model, we have confirmed that haplogroup B4 contributes to cellular IR as well as a profission mtDYN, which can be reversed by antioxidant treatment. However, the causal relationship between mtDYN and cellular IR pertaining to T2D-susceptible haplogroup B4 remains unanswered. METHODS: To dissect the mechanisms between mtDYN and IR, knockdown or overexpression of MFN1, MFN2, DRP1, and FIS1 was performed using cybrid B4. We then examined the mitochondrial network and mitochondrial oxidative stress (mtROS) as well as insulin signaling IRS-AKT pathway and glucose transporters (GLUT) translocation to plasma membrane stimulated by insulin. We employed Drp1 inhibitor, mdivi-1, to interfere with endogenous expression of fission to validate the pharmacological effects on IR. RESULTS: Overexpression of MFN1 or MFN2 increased mitochondrial network and reduced mtROS, while knockdown had an opposing effect. In contrast, overexpression of DRP1 or FIS1 decreased mitochondrial network and increased mtROS, while knockdown had an opposing effect. Concomitant with the enhanced mitochondrial network, activation of the IRS1-AKT pathway and GLUT translocation stimulated by insulin were improved. On the contrary, suppression of mitochondrial network caused a reduction of the IRS1-AKT pathway and GLUT translocation stimulated by insulin. Pharmacologically inhibiting mitochondrial fission by the Drp1 inhibitor, mdivi-1, also rescued mitochondrial network, reduced mtROS, and improved insulin signaling of diabetes-susceptible cybrid cells. CONCLUSION: Our results discovered the causal role of mtDYN proteins in regulating IR resulted from diabetes-susceptible mitochondrial haplogroup. The existence of a bidirectional interaction between mtDYN and mtROS plays an important role. Direct intervention to reverse profission in mtDYN provides a novel therapeutic strategy for IR and T2D.

Tardive akathisia related to the anti-hypertensive agent Sevikar-a case report.

BACKGROUND: Tardive akathisia (TA) is a subtype of tardive syndrome, and its etiology is still uncertain. Sevikar is an anti-hypertensive agent containing both amlodipine and olmesartan, and has never been reported to have an adverse reaction in patients with tardive syndrome. CASE PRESENTATION: A 57-year-old woman who took Sevikar for hypertension for 10 years developed TA one and a half years before receiving any psychiatric treatment. After switching from Sevikar to bisoprolol, she reported obvious improvement in her akathisia. CONCLUSIONS: It is noteworthy that her TA developed before receiving any antidepressant medication, and that her TA improved after discontinuation of Sevikar. In light of these pharmacodynamic properties, it is therefore concluded that use of amlodipine and olmesartan might have caused TA in this patient. We reported this rare case to remind clinicians to be aware of possible akathisia when using amlodipine and olmesartan in combination as anti-hypertensive agents.

Impact of baseline body mass index status on glucose lowering and weight change during sitagliptin treatment for type 2 diabetics.

AIMS: This study was designed to evaluate the efficacy of sitagliptin in Taiwanese diabetic subjects with different baseline BMI status. METHODS: This was a single-center, hospital-based, retrospective chart review in subjects (n=1874) with type 2 diabetes who received sitagliptin. Subjects were classified into subgroups depending upon their baseline BMI by Taiwan national weight classification: normal (BMI<24kg/m(2)) (n=504), overweight (BMI: 24-27kg/m(2)) (n=615), and obese (BMI⩾27kg/m(2)) (n=755). Changes in HbA1c and weight were evaluated over a 12month treatment period. RESULTS: For all three groups, the HbA1c levels declined over the first three months by about 8%, and subsequently plateaued for the next nine months. Obese subjects were slower in reducing HbA1c compared with normal and overweight subjects (P<0.05), but at nine months the reduction was similar across groups. Mean body weight increased over the first nine months of sitagliptin therapy in subjects with normal BMI (57.12-58.30kg), but there was no change in mean body weight in the overweight group. After three months the obese groups had significantly greater loss in body weight compared with the normal group. CONCLUSIONS: Baseline BMI status may influence the reduction of HbA1c levels within the first six months of sitagliptin therapy and affect weight change after three months. Being obese was associated with an initial lag in HbA1c reduction and greater weight loss compared with normal and overweight subjects.

Acute blood glucose fluctuations can decrease blood glutathione and adiponectin levels in patients with type 2 diabetes.

INTRODUCTION: Glutathione appears to have apparent antioxidant activity to counter regulate hyperglycemia induced oxidative stress. Adiponectin also plays a role in the suppression of the metabolic derangements in type 2 diabetes mellitus (DM). The aim of this study was to determine whether blood glucose fluctuations can alter blood levels of glutathione and adiponectin. METHODS: We enrolled 34 patients with type 2 DM. As a measure of short-term glycemic variability, the mean amplitude of glycemic excursions (MAGE) was computed from a continuous glucose monitor system (CGMS), and data were recorded over 72 h. For long-term glycemic variability, we calculated the standard deviation (SD) of HbA1c over a 2-year period. Glutathione and adiponectin levels were measured after completing the 72-h CGMS data collection. RESULTS: The blood levels of glutathione were significantly and negatively correlated with MAGE (r = -0.543; P < 0.001), but not with HbA1c and SD of HbA1c. Adiponectin levels were also significantly and negatively correlated with MAGE and SD of HbA1c (r = -0.64 and r = -0.55, respectively; P < 0.001). Using generalized estimating equations, multivariate regression analysis revealed that MAGE is an independent predictor of serum levels of adiponectin (P = 0.002) and glutathione (P = 0.004). CONCLUSIONS: We found strong associations between acute blood glucose variability, glutathione, and adiponectin in type 2 diabetic patients treated with oral hypoglycemic agent therapy.