Novel concepts for initiating multitargeted kinase inhibitors in radioactive iodine refractory differentiated thyroid cancer.

Multitargeted kinase inhibitors have been shown to improve progression-free survival in patients with structurally progressive, radioactive iodine refractory differentiated thyroid cancer. While the inclusion criteria for phase 3 clinical trials and clinical practice guidelines provide guidance with regard to the minimal requirements that need to be met prior to initiation of a multitargeted kinase inhibitor, a better way to integrate the rate of structural disease progression with the size of the metastatic foci to more precisely define the optimal time to recommend initiation of therapy for individual patients is needed. In this manuscript we describe how to use assessments of tumor size and growth rates (structural disease doubling times) to define the critical point in time when the volume and rate of progression of metastatic structural disease merits consideration for initiation of systemic therapy (the inflection point).

Patterns of Initial Recurrence in Completely Resected Papillary Thyroid Carcinoma.

BACKGROUND: Despite improvements in the surgical and medical treatment of papillary thyroid carcinoma (PTC), subsets of patients suffer from structural recurrence after initial treatment. This study evaluated the timing and patterns of recurrence in completely resected PTC patients. METHODS: A retrospective review of a prospectively maintained thyroid cancer database was performed. The timing and patterns of recurrence were reviewed in 2250 patients with PTC >1 cm who achieved complete remission after total thyroidectomy and/or radioactive iodine treatment. Univariate and multivariate analyses were performed to identify factors predictive of recurrence patterns. RESULTS: During 8.1 years of mean follow-up, 68 (3.0%) patients developed structural recurrences: 53 lymph node recurrences (LNR), 11 local soft tissue recurrences (LR), and four distant recurrences (DR). Two patients died of DR. Younger patients had a higher proportion of LNR, and older patients had a tendency toward LR/DR. LNR showed a peak incidence between one and three years after remission, but LR/DR showed a delayed peak incidence between two and four years. The factors that significantly increased the risk of LNR were multifocal tumor and lymph node metastasis (central/lateral). The factors that increased the risk of LR/DR were old age, large tumor size (>2 cm), and lateral lymph node metastasis. In addition, central neck dissection significantly reduced subsequent LR/DR. CONCLUSION: Patterns of recurrence after complete PTC resection are variable and associated with specific clinicopathologic factors. Understanding the timing and patterns of recurrence may lead to more effective adjuvant treatment and improved long-term follow-up strategies.

A Prospective Study of Serum Trace Elements in Healthy Korean Pregnant Women.

This prospective study sought to investigate serum levels of trace elements (cobalt, copper, zinc, and selenium) and to assess their effects on pregnancy and neonatal outcomes. Serum levels of trace elements in 245 Korean pregnant women (median gestational age at delivery was 39 + 4 weeks and interquartile range was 38 + 4-40 + 1 weeks) were compared with those of 527 general adults and those of previous studies in other ethnic groups. Pregnancy and neonatal outcomes including gestational diabetes, preeclampsia, neonatal birth weight, and congenital abnormalities were assessed. The median serum trace element concentrations of all pregnant women were: cobalt: 0.39 µg/L (interquartile range, IQR 0.29-0.53), copper: 165.0 µg/dL (IQR 144.0-187.0), zinc: 57.0 µg/dL (IQR 50.0-64.0), and selenium: 94.0 µg/L (IQR 87.0-101.0). Serum cobalt and copper concentrations were higher in pregnant women than in the general population, whereas zinc and selenium levels were lower (p < 0.01). Concentrations of all four trace elements varied significantly during the three trimesters (p < 0.05), and seasonal variation was found in copper, zinc, and selenium, but was not observed for cobalt. The prevalence of preeclampsia was significantly lower with high copper (p = 0.03). Trace element levels varied by pregnancy trimester and season, and alteration in copper status during pregnancy might influence pregnancy outcomes such as preeclampsia.

Role of age and sex in determining antibiotic resistance in febrile urinary tract infections.

OBJECTIVES: To identify the age- and sex-specific antimicrobial susceptibility patterns of Gram-negative bacteria (GNB) in outpatient febrile urinary tract infections (UTIs) in Korea. METHODS: A total 2262 consecutive samples collected from patients aged 1-101 years with febrile UTIs, during the period January 2012 to December 2014, were analyzed in this multicentre, retrospective cohort study. RESULTS: The sensitivities to cefotaxime and cefoxitin were over 85% for females but under 75% for males. Sex played an important role in the susceptibility of GNB to cefotaxime (p<0.001) and cefoxitin (p<0.001). The sensitivity to ciprofloxacin (age >20 years) was under 75% in both sexes, and was not influenced by sex (p=0.204). Age distributions of the incidences of resistance to cefotaxime, cefoxitin, and ciprofloxacin (age >20 years) were similar to the age distribution of the incidence of GNB, which indicates that the resistance patterns to these drugs were not affected by age (Kolmogorov-Smirnov test, female/male: p=0.927/p=0.509, p=0.193/p=0.911, and p=0.077/p=0.999, respectively). CONCLUSIONS: Age is not a considerable factor in determining the antibiotic resistance in febrile UTIs. Ciprofloxacin should be withheld from both sexes until culture results indicate its use. Second- or third-generation cephalosporins such as cefoxitin and cefotaxime can be used empirically only in females.

In Vitro and In Vivo Antiangiogenic Activity of Crowberry (Empetrum nigrum var. japonicum).

Crowberry, Empetrum nigrum var. japonicum, is widely used in folk medicine and grows naturally in Korea. Although some constituents and biological activity of Korean crowberry have been examined, there is little detailed information available. In this study, we investigated the effects of ethanol extracts of crowberry (EECB) on the inhibition of angiogenesis, both in vitro and in vivo. The effects of EECB were tested on in vitro models of angiogenesis, that is, tube formation and proliferation of human umbilical vein endothelial cells (HUVECs). EECB exhibited significant inhibitory effects on tube formation of HUVECs in a concentration-dependent manner. In addition, crowberry significantly suppressed the proliferation of HUVECs in a concentration-dependent manner. Furthermore, strong antiangiogenic activity of EECB samples was observed in the in vivo assay using chick embryo chorioallantoic membrane (CAM). These results indicate that crowberry may have potential applications in the prevention and treatment of angiogenesis-dependent human diseases.

Efficacy of Low-dose and High-dose Radioactive Iodine Ablation With rhTSH in Korean Patients With Differentiated Thyroid Carcinoma: The First Report in Nonwestern Countries.

OBJECTIVE: The aim of this study was to confirm the equivalent efficacy of recombinant human TSH (rhTSH) and thyroid hormone withdrawal (THW) as used in the preparation for low-dose and high-dose radioactive iodine (RAI) ablation in Korean patients with differentiated thyroid carcinoma. SUBJECTS AND METHODS: This retrospective study was designed to compare the efficacy of rhTSH and THW when used before ablation with low-dose (30 mCi) and high-dose (100 mCi) RAI, respectively. The study group included 570 patients with DTC with tumors staged T1 to T3, N0 to N1, and M0. Before RAI ablation, 190 patients used rhTSH and 380 patients matched by age, sex, T-stage, and N-stage used THW. The success of ablation was evaluated in each group based on 4 criteria: (1) stimulated thyroglobulin (sTg) <2 ng/mL, (2) sTg<2 ng/mL and negative diagnostic whole-body scan (DxWBS), (3) sTg<1 ng/mL, and (4) sTg<1 ng/mL and negative DxWBS. RESULTS: When both sTg<2 ng/mL and negative DxWBS were selected as criteria for success in patients treated with low-dose RAI, the success rates were 80.5% and 77.0% with rhTSH and THW, respectively (95% confidence interval, 5.9-12.8). Using both sTg<1 ng/mL and negative DxWBS as criteria, success rates were 78.2% and 71.8% with rhTSH and THW, respectively (95% confidence interval, 3.6-16.2). Using any criteria for success, low-dose RAI ablation with rhTSH was as effective as THW. Similar results were found for high-dose RAI ablation in patients using either rhTSH or THW. CONCLUSIONS: Low-dose and high-dose RAI ablation were equally effective using either rhTSH or THW before ablation in Korean patients with DTC, respectively.

Increased Risk of Leukemia After Radioactive Iodine Therapy in Patients with Thyroid Cancer: A Nationwide, Population-Based Study in Korea.

BACKGROUND: The use of radioactive iodine therapy (RAIT) is increasing in thyroid cancer management. The association between RAIT at high doses and leukemia is well known, but studies of this association in a large population are lacking. This study aims to investigate the association between RAIT and leukemia in the context of current practice. METHODS: Retrospective analysis of a 542,845 person-year (PY) follow-up of thyroid cancer patients was conducted using the Korean National Health Insurance claims database between January 2008 and December 2013. Patients were categorized according to RAIT dose (no RAI; low dose, ≤30 mCi; moderate dose, 31-100 mCi; high dose, 101-150 mCi; and very high dose, >150 mCi). RESULTS: Among 211,360 thyroid cancer patients, 72 (0.03%) patients developed leukemia during follow-up (median 877 days). The cumulative incidence of leukemia per 10(5) person-year (PY) was 9.8 in the no RAI [95% confidence interval (CI) 6.4-14.4]; 6.1 [CI 1.7-15.7] in the low-dose; 8.6 [CI 3.2-18.7] in the moderate-dose; 29.5 [CI 18.3-45.1] in the high-dose; and 20.9 [CI 11.7-34.4] in the very high-dose groups. The hazard ratios were elevated significantly in the high- and very high-dose groups (HR 3.1 and 2.1, respectively, p<0.001) when compared with the no RAI group. CONCLUSIONS: RAIT exceeding 100 mCi was strongly associated with the development of leukemia in a nationwide, population-based study, while lower RAIT doses were not. Considering the favorable survival of patients with thyroid cancer and the potential harm of RAIT, physicians need to consider the pros and cons of RAIT when using this treatment option.

Effect of muscle mass on toxicity and survival in patients with colon cancer undergoing adjuvant chemotherapy.

PURPOSE: The purpose of this study was to elucidate the effect of decreased muscle mass on the toxicity and survival of patients with colon cancer treated with adjuvant chemotherapy after surgery. METHODS: We reviewed the data of 229 consecutive patients with stage III colon cancer who received adjuvant oxaliplatin, 5-fluorouracil, and leucovorin chemotherapy at a single center between 2003 and 2010. Baseline muscle mass was assessed by measuring the cross-sectional area of the psoas muscle at the level of the fourth lumbar vertebra on computed tomography images. Effects of muscle mass on toxicity of chemotherapy and survival were assessed. RESULTS: The median age of the 229 patients was 61 years (range, 28-80) and 134 (58.5 %) were men. The mean psoas muscle mass index (PI, psoas muscle area divided by height(2) [mm(2)/m(2)]) was 548.3. A 1 SD decrement in the PI was associated with an increase in all grade 3-4 toxicities in univariate (OR = 1.69, 95 % CI = 1.18-2.27) and multivariate (OR = 1.56, 95 % CI = 1.05-2.38) analyses. In univariate analysis, the PI was not associated with overall survival. However, multivariate analysis showed that a 1 SD decrement in the PI increased the hazard of overall mortality by 85 % (HR = 1.85, 95 % CI = 1.10-3.13). This effect of the PI on mortality was maintained in subgroup analyses, especially in older and obese patients. CONCLUSIONS: Decreased muscle mass was associated with increased risk of grade 3-4 toxicity and poor prognosis in patients with stage III colon cancer.

The impact of iodinated contrast agent administered during preoperative computed tomography scan on body iodine pool in patients with differentiated thyroid cancer preparing for radioactive iodine treatment.

BACKGROUND: Iodine in iodinated contrast agents (ICAs) interferes with radioactive iodine treatment (RAIT) and diagnostic scans in patients with differentiated thyroid carcinoma (DTC) because it can compete with ¹³¹I. Published guidelines recommend delaying RAIT for three to four months in patients who have been exposed to ICA. Spot urinary iodine concentration is a useful marker to reflect the body iodine pool. We investigated the impact of ICAs administered at preoperative computed tomography (CT) scan on the body iodine pool to determine the proper time interval between preoperative CT and RAIT in DTC patients. METHODS: We performed a retrospective review of 1023 patients with DTC who underwent a preoperative CT scan with ICA, total thyroidectomy, and one week of low-iodine diet in preparation for RAIT. Urine iodine excretion (UIE) was measured in spot urine by inductively coupled plasma mass spectrometry and reported both in simple concentration (µg/L) and divided by gram creatinine (µg/gCr). Patients were divided into five groups by time interval in days between preoperative CT scan and spot urine iodine measurement (A, 31-60 [n=29]; B, 61-90 [n=155]; C, 91-120 [n=546]; D, 121-150 [n=226]; E, 151-180 [n=67]). RESULTS: The median (interquartile range) of UIE (µg/gCr) in each group was 44.4 (27.7-73.2) in group A, 33.3 (22.8-64.7) in group B, 32.7 (20.8-63.0) in group C, 32.0 (20.6-67.0) in group D, and 30.4 (19.6-70.8) in group E. There was no significant difference between group A and the remaining groups (p>0.05) Also, the proportion of patients who achieved the appropriate UIE for RAIT according to our hospital's cutoff (≤66.2 µg/gCr) was not different between groups (A, 72.4%; B, 76.1%; C, 77.5%; D, 74.8%; E, 74.6%) (p=0.78). CONCLUSION: This study shows that a UIE of one month after preoperative CT scan with ICA was not higher than that of six months after CT scan in patients who underwent total thyroidectomy for DTC. Thus, current guidelines that recommend delay of RAIT for three to four months after CT scan with ICA should be revisited and future studies to clarify the appropriate time interval between CT scan with ICA and RAIT are warranted.

Cardiac stem cells with electrical stimulation improve ischaemic heart function through regulation of connective tissue growth factor and miR-378.

AIMS: In this study, we investigated whether pre-conditioning (PC) by electrical stimulation (EleS) induces cytoprotective effect on cardiac stem cells (CSCs) and determined its underlying molecular mechanisms. METHODS AND RESULTS: Sca-1(+) CSCs were isolated from male C57BL6 mice (12 weeks) hearts. PC of CSCs with EleS ((EleS)CSCs) was carried out for 3 h at 1.5 V followed by exposure to 300 µM H2O2 for 5 h. Cytoprotective effects and cell adhesion ability were significantly increased by EleS as evaluated by transferase-mediated dUTP nick-end labelling (TUNEL), lactate dehydrogenase (LDH) release assay, and adhesion assay. EleS increased phosphorylation of AKT, focal adhesion kinase (FAK), and glycogen synthase kinase (GSK3ß), as well as decreased caspase-3 cleavage. Interestingly, inhibition of AKT or FAK abolished the pro-survival effects of EleS. We found that connective tissue growth factor (Ctgf) was responsible for EleS-induced CSC survival and adhesion.The survival rate of (EleS)CSCs after transplantation in the infarcted myocardium was significantly increased together with improvement in cardiac function. Importantly, knockdown of Ctgf abolished EleS-induced cytoprotective effects and recovery of cardiac function. Furthermore, we identified miR-378 as a potential Ctgf regulator in (EleS)CSCs. CONCLUSION: EleS enhanced CSC survival in vitro and in vivo as well as functional recovery of the ischaemic heart through an AKT/FAK/CTGF signalling pathway. It is suggested that Ctgf and miR-378 are novel therapeutic targets for stem cell-based therapy.

Association between excessive urinary iodine excretion and failure of radioactive iodine thyroid ablation in patients with papillary thyroid cancer.

BACKGROUND: A low-iodine diet (LID) is usually recommended for a week or two before radioactive iodine (RAI) ablation therapy in papillary thyroid cancer (PTC) patients after total thyroidectomy. However, it is still controversial whether an LID affects ablation outcomes. We therefore evaluated the association between urinary iodine excretion and the rate of successful ablation and investigated the determinants of successful RAI ablation outcomes. METHODS: We retrospectively reviewed the records of 295 consecutive patients with PTC who received 1110 MBq RAI remnant ablation therapy with thyroid hormone withdrawal after total thyroidectomy. Successful ablation was defined as either no visible or faint uptake on a follow-up scan (definition 1), or no visible or faint uptake on a follow-up scan and a stimulated thyroglobulin level <2 ng/mL (definition 2). RESULTS: The proportion of patients with appropriate LID status (defined as a urinary iodine concentration [UIC] <66.2 µg iodine/g creatinine [µg/gCr]) was significantly higher in the successfully ablated group (81% vs. 67%, p=0.03). Based on definition 1, 80.3% (237/295) of patients were successfully ablated. The ablation rate was significantly lower in patients who had a UIC >250 µg/gCr at the time of RAI ablation (p<0.05). In multivariate analysis, a UIC >250 µg/gCr was the only significant variable associated with ablation failure (p=0.002, odds ratio [OR] 4.74 [95% confidence interval (CI) 1.78-12.63]). Based on definition 2, 74.9% (221/295) of patients were successfully ablated. A UIC >250 µg/gCr at RAI administration showed a significant association with ablation failure (p<0.05). The OR of a UIC >250 µg/gCr for ablation failure was 3.88 [CI 1.42-10.57] (p=0.008). CONCLUSION: Excessive iodine intake (UIC >250 µg/gCr) was associated with poor RAI ablation outcomes. Because this amount of iodine is very high, we propose that the level of strictness of the LID protocol should be modified according to the region that the patient is from and the food that the patient is accustomed to eating. Even in those areas where iodine intake is high, overly strict compliance with an LID protocol is not necessary and simple recommendations to avoid iodine-rich foods would be appropriate.

Prognostic implication of thyroglobulin and quantified whole body scan after initial radioiodine therapy on early prediction of ablation and clinical response for the patients with differentiated thyroid cancer.

OBJECTIVE: To investigate predictors for successful ablation and disease-free status after high-dose radioiodine therapy in patients with differentiated thyroid cancer. METHODS: We enrolled 173 consecutive patients with differentiated thyroid cancer between November 2001 and December 2004 retrospectively (female 145, 46 ± 12 years). All patients underwent total thyroidectomy and I-131 ablative therapy (IAT) (3.7-5.4 GBq). The success or failure of ablation was assessed 6-9 months after the IAT with reference to undetectable thyroglobulin (Tg) and negative I-131 whole body scan (WBS). Afterward, the decision for disease-free status was evaluated using Tg and WBS (follow-up period after 1st IAT 7-81 months, median 43 months, criteria of disease-free: less than 10 ng/ml TSH-stimulated Tg or less than 2 ng/ml TSH-unstimulated Tg and/or negative WBS). Clinical and tumoral factors such as sex, age, pathologic type, the size of tumor, quantified cervical uptake in WBS1, pattern in WBS1, ablative therapy dose, AJCC stage, lymph node (LN) stage, Tg just before IAT (Tg1), and ablation status were assessed using logistic regression analyses. RESULTS: There were 93 successful ablations (54 %). Significant predictors for the ablation failure were Tg1 (OR = 8.42; 95 % CI = 2.76-25.69; p < 0.0001), LN metastasis (OR = 3.05; 95 % CI = 1.11-8.37; p = 0.031), and quantified cervical uptake in WBS1 (OR = 4.95; 95 % CI = 1.07-22.88; p = 0.041). One hundred fifty-five patients were determined as disease-free after follow-up. All the eighteen patients with persistent disease were identified as ablation failure after first IAT. Significant predictors for the disease-free status were Tg1 (OR = 0.98; 95 % CI = 0.97-0.99; p = 0.028), tumor size (OR = 0.53; 95 % CI = 0.28-0.96; p = 0.044), and quantified cervical uptake in WBS1 (OR = 0.87; 95 % CI = 0.76-0.98; p = 0.024). CONCLUSIONS: The thyroglobulin and quantified cervical uptake in whole body scan are significant predictors for the successful ablation and disease-free status after follow-up.