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To test the hypothesis that increased tumor expression of proteins such as aquaporin-1 (AQP1) and adipophilin (ADFP) in patients with renal cancer would result in increased urine AQP1 and ADFP excretion. Prenephrectomy and postnephrectomy (pseudocontrol) urine samples were collected from 42 patients with an incidental radiographically discovered renal mass and presurgical presumptive diagnosis of kidney cancer from July 8, 2008, through March 10, 2009. Also enrolled were 15 control patients who underwent nonrenal surgery and 19 healthy volunteers. Urine AQP1 and ADFP concentrations normalized to urine creatinine were determined by sensitive and specific Western blot assays. Mean ± SD preexcision urine AQP1 and ADFP concentrations (76±29 and 117±74 arbitrary units, respectively) in patients with a pathologic diagnosis of clear cell (n=22) or papillary (n=10) cancer were significantly greater than in patients with renal cancer of nonproximal tubule origin, control surgical patients, and healthy volunteers (combined values of 0.1±0.1 and 1.0±1.6 arbitrary units, respectively; n=44; P<.001). The AQP1 and ADFP concentrations decreased 88% to 97% in the 25 patients with clear cell or papillary cancer who provided postnephrectomy follow-up urine samples. In patients with clear cell and papillary carcinoma, a linear correlation (Spearman) was found between tumor size and preexcision urine AQP1 or ADFP concentration ( r=0.82 and 0.76, respectively; P<.001 for each). Urine AQP1 and ADFP concentrations appear to be sensitive and specific biomarkers of kidney cancers of proximal tubule origin. These biomarkers may be useful to diagnose an imaged renal mass and screen for kidney cancer at an early stage. Trial Registration: clinicaltrials.gov Identifier: NCT00851994

This study demonstrates a strong association of high urinary iodine with thyroid nodules and papillary thyroid cancer as well as aggressive cancer features, suggesting that high urinary iodine is a risk factor for thyroid cancer. The risk of high iodine intake for thyroid cancer has been suggested but not established. The objective of the study was to evaluate the relationship between urine iodine levels and thyroid nodule and thyroid cancer. We preoperatively tested fasting urine iodine in 154 thyroid nodule patients and correlated the results with pathological diagnoses and compared with 306 subjects as normal control. The median urine iodine (MUI) was 331.33 μg/L in patients with benign thyroid nodules versus 466.23 μg/L in patients with papillary thyroid cancer (PTC) ( P  = 0.003), both of which were in the excessive iodine state and higher than the MUI of 174.30 μg/L in the control group ( P  < 0.001), which was in the sufficient iodine state. Excessive iodine state (MUI > 300 μg/L) was seen in 62.75 % of patients with benign thyroid nodules and 66.99 % of patients with PTC, both of which were significantly higher than the iodine excessive rate of 19.93 % in the control group ( P  < 0.001). Moreover, MUI in patients with PTC with lymph node metastasis was significantly higher than that of PTC patients without lymph node metastasis ( P  < 0.001). Urine iodine of thyroid cancer patients with stage III and IV disease was significantly higher than that of patients with stage I and II diseases ( P  < 0.001). Multivariable analyses showed that, like sand calcification of thyroid nodule and TSH, urine iodine was an independent risk factor for PTC. These data demonstrate a significant association between high urinary iodine and benign and malignant thyroid nodules and PTC aggressiveness, supporting high urinary iodine as a risk factor for thyroid malignancy. Further studies are warranted to confirm these findings.

Background To evaluate the metabolic changes in urinary steroids in pre- and post-menopausal women and men with papillary thyroid carcinoma (PTC). Methods Quantitative steroid profiling combined with gas chromatography-mass spectrometry was used to measure the urinary concentrations of 84 steroids in both pre- (n = 21, age: 36.95 ± 7.19 yr) and post-menopausal female (n = 19, age: 52.79 ± 7.66 yr), and male (n = 16, age: 41.88 ± 8.48 yr) patients with PTC. After comparing the quantitative data of the patients with their corresponding controls (pre-menopause women: n = 24, age: 33.21 ± 10.48 yr, post-menopause women: n = 16, age: 49.67 ± 8.94 yr, male: n = 20, age: 42.75 ± 4.22 yr), the levels of steroids in the patients were normalized to the mean concentration of the controls to exclude gender and menopausal variations. Results Many urinary steroids were up-regulated in all PTC patients compared to the controls. Among them, the levels of three active androgens, androstenedione, androstenediol and 16α-hydroxy DHEA, were significantly higher in the pre-menopausal women and men with PTC. The corticoid levels were increased slightly in the PTC men, while progestins were not altered in the post-menopausal PTC women. Estrogens were up-regulated in all PTC patients but 2-hydroxyestrone and 2-hydroxy-17β-estradiol were remarkably changed in both pre-menopausal women and men with PTC. For both menopausal and gender differences, the 2-hydroxylation, 4-hydroxylation, 2-methoxylation, and 4-methoxylation of estrogens and 16α-hydroxylation of DHEA were differentiated between pre- and post-menopausal PTC women ( P < 0.001). In particular, the metabolic ratio of 2-hydroxyestrone to 2-hydroxy-17β-estradiol, which could reveal the enzyme activity of 17β-hydroxysteroid dehydrogenase, showed gender differences in PTC patients ( P < 1 × 10 -7 ). Conclusions These results are expected be helpful for better understanding the pathogenic differences in PTC according to gender and menopausal conditions.

Biochemical markers of bone turnover are often measured in patients treated with antiresorptive agents to monitor the effects of therapy. In order for a change in these markers to clearly indicate treatment effect, the change in the markers must exceed the amount of spontaneous variation typically seen with no treatment. Based on the measured long-term variability of markers in untreated patients, we defined a minimum significant change (MSC), that is, a change that was sufficiently large that it was unlikely to be due to spontaneous variability. We also examined the changes in markers of bone turnover in subjects treated with pamidronate to see how often observed changes in turnover after treatment exceeded the MSC. We found that urinary markers of bone resorption are best measured on 2-hour fasting samples, because results on random urine showed poor precision and less decline with therapy. We also found that of all the markers, urinary N-telopeptide cross-links (NTX) had the greatest decline after therapy (58%), although it also had the highest long-term variability (29.5%). The marker that most often showed a decline with treatment that exceeded the MSC was serum bone-specific alkaline phosphatase where 74% of observed changes exceeded the MSC. Other markers that often showed a decline with treatment that exceeded the MSC were 2-hour fasting urine NTX and free deoxypyridinoline, where 57% and 48%, respectively, of changes in therapy exceeded the MSC. The ideal marker would combine the large decline after treatment characteristic of NTX (60-70%) with the good precision of bone-specific alkaline phosphatase.

PurposeBoth deficient and excessive iodine intake leads to thyroid disease, which shows U-shaped curves. Our previous study showed that a relatively low [urinary iodine concentration (UIC) <300 μg/L] and extremely excessive (UIC ≥ 2500 μg/L) iodine intake were associated with thyroid cancer in Korea, an iodine-replete area. Papillary thyroid cancer (PTC) accounts for more than 97 % of thyroid cancer and 80% or more PTC cases harbor the BRAF mutation in Korea. We aimed to investigate the relationship between iodine intake and the prevalence of the BRAF mutation in PTC in Korea.MethodsUIC was measured by inductively coupled plasma mass spectrometry. The BRAF mutation was detected using both allele-specific polymerase chain reaction and mutant enrichment with 3′-modified oligonucleotide sequencing. Risk factors for the occurrence of BRAF mutations in PTC were evaluated using multivariate logistic regression models.ResultsThe median UIC in all patients with PTC was 287 μg/L (range from 7 to 7, 426 μg/L). Nearly half of the patients (102/215, 47%) belonged to the excessive iodine intake category (UIC ≥ 300 μg/L) according to the WHO iodine recommendations. The frequency of BRAF mutations was lowest in the 300–499 μg/L UIC group; it was significantly different compared to the relatively low (UIC < 300 μg/L) and more than excessive (UIC ≥ 500 μg/L) iodine intake groups. UIC was an independent predictor for BRAF mutations in PTC. The multivariate-adjusted odds ratios (95% confidence intervals) in the relatively low and more than excessive iodine intake groups for the BRAF mutation were 4.761 (1.764–12.850) and 6.240 (2.080–18.726), respectively, compared to the 300–499 μg/L UIC group.ConclusionRelatively low iodine intake and more than excessive iodine intake seem to be significant risk factors for the occurrence of BRAF mutations in the thyroid and, therefore, may be risk factors for the development of PTC in an iodine-replete area.

Background Environmental exposure to per- and polyfluoroalkyl substances (PFAS) has been related to some adverse health effects. An increasing number of people are suffering from nodular goiter (NG) and papillary thyroid carcinoma (PTC), the specific types of thyroid tumors with the highest prevalence. In vivo and in vitro studies have indicated that exposure to PFAS can disrupt thyroid homeostasis and exhibit apparent endocrine-disrupting toxicity, including the decreased thyroid hormone levels and abnormal expression of thyroid-related genes. However, epidemiological evidence supporting the cause-effect relationship between PFAS exposure and the risk of NG and PTC is still lacking. Methods We enrolled 290 participants to explore the relationship between PFAS exposure and NG/PTC risk. 21 urinary PFAS were detected by ultra-high performance liquid chromatography-triple quadrupole mass spectrometry (UPLC-MS/MS). Logistic regression, restricted cubic spline (RCS), Bayesian Kernel Machine Regression (BKMR) and quantile g-computation (qgcomp) models were adopted to examine effects of single and mixed PFAS exposure on NG/PTC risk. Results Our data showed that perfluoroheptane sulfonate (PFHpS) ( P  = 0.033) and perfluorohexane sulfonate (PFHxS) ( P  = 0.003) levels in NG cases and perfluoroheptanoic acid (PFHpA) ( P  = 0.008) levels in PTC cases were significantly higher than those in the controls. After adjustment for confounders, PFHxS was significantly related to higher NG/PTC risk (all P for trend < 0.05). A remarkable non-linear association was found between PFHpA exposure and PTC risk ( P -overall < 0.001, P -non-linear = 0.001). The BKMR model indicated that PFAS mixtures significantly increased NG risk, with PFHxS contributing the most (groupPIP: 0.886, condPIP: 0.658). In stratified analyses, PFAS mixtures were positively associated with NG/PTC risk in females and normal-weight subjects. Conclusion Our results suggest that environmental exposure to PFAS mixtures may be associated with increased NG/PTC risk, and each PFAS may contribute to NG/PTC risk in very different ways. To the best of our knowledge, this is the first epidemiological study to examine effects of PFAS exposure on NG/PTC risk.

Aim of this study was to evaluate the association between multiple essential microelements exposure and the aggressive clinicopathologic characteristics of papillary thyroid carcinoma (PTC). The concentrations of 10 essential microelements in urine [cobalt (Co), chromium (Cr), copper (Cu), iron (Fe), manganese (Mn), molybdenum (Mo), selenium (Se), strontium (Sr), zinc (Zn), and iodine (I)] were measured in 608 patients newly diagnosed with PTC, including 154 males and 454 females. Chi square test and Wilcoxon rank sum test were used to compare general characteristics among males and females. Multivariate logistic regression was used to evaluate the associations between essential microelements and PTC clinicopathologic characteristics in single- and multi-microelement models. In this study, we only observed that the frequency of lymph node metastasis in males was higher than in females, and males had higher levels of zinc than females, but males had lower levels of iodine than females. It was found that high levels of Fe were associated with decreased risk of PTC tumor size > 1 cm, capsular invasion, and advanced T stage (T3/4a/4b). High levels of Co and Mo were associated with decreased risk of capsular invasion and lymph node metastasis, respectively. However, high levels of Mn and Sr were associated with increased risk of capsular invasion and multifocality respectively, and both were associated with increased risk of advanced T stage (T3/4a/4b). These findings indicated that certain essential microelements might have potential effects on PTC progression and aggressiveness. Further studies are required to confirm these findings.

Background The association between iodine levels and the risk of papillary thyroid cancer (PTC) has been suggested, but not definitively established. This study is to compare the iodine status of a group of patients with PTC (with and without BRAF V600E ) with that of a healthy population cohort. Methods A cohort of patients scheduled for thyroidectomy was enrolled, along with a community-based health-screening cohort with no known history of thyroid disease. Median urinary iodine (UI) levels, creatinine-adjusted median UI levels, and food frequency questionnaire (FFQ) scores (mean ± SD) were compared. In a subgroup analysis, these values were compared between BRAF V600E -positive and BRAF V600E -negative patients in the PTC group. Results The PTC group consisted of 210 patients, and the control group consisted of 90 healthy individuals. Among the 191 PTC patients whose BRAF V600E mutational status was reported, 169 (88.5%) were revealed positive for the mutation. The median UI levels were significantly higher in the PTC group (786.0 μg/l) than the control group (112.0 μg/l; p  < 0.001), as was the case with creatinine-adjusted median UI levels (884.6 μg/g creatinine versus 182.0 μg/g creatinine; p  < 0.001) and FFQ scores (66.2 ± 17.5, range 13–114 versus 54.6 ± 21.5, range 16–134; p  < 0.001). No significant differences were seen in the subgroup analysis between BRAF V600E -positive and BRAF V600E -negative patients. Conclusions Our results indicate that iodine status differs significantly between patients with PTC and healthy controls, suggesting that iodine may be involved in the occurrence of PTC, although the association between iodine levels and BRAF mutational status did not reach statistical significance.

Intraductal papillary mucinous neoplasms (IPMN) are precursors of pancreatic cancer. Potential biomarkers of IPMN progression have not been identified in urine. A few urinary biomarkers were reported to be predictive of pancreatic ductal adenocarcinoma (PDAC). Here, we seek to assess their ability to detect high-risk IPMN. Urine was collected from patients undergoing pancreatic resection and healthy controls. TIMP-1(Tissue Inhibitor of Metalloproteinase-1), LYVE-1(Lymphatic Vessel Endothelial Receptor 1), and PGEM(Prostaglandin E Metabolite) levels were determined by ELISA and analyzed by Kruskal-Wallis. Median urinary TIMP-1 levels were significantly lower in healthy controls (n = 9; 0.32 ng/mg creatinine) compared to PDAC (n = 13; 1.95) but not significantly different between low/moderate-grade (n = 20; 0.71) and high-grade/invasive IPMN (n = 20; 1.12). No significant difference in urinary LYVE-1 was detected between IPMN low/moderate (n = 16; 0.37 ng/mg creatinine) and high/invasive grades (n = 21; 0.09). Urinary PGEM levels were not significantly different between groups. Urinary TIMP-1, LYVE-1, and PGEM do not correlate with malignant potential of pancreatic cysts. •Urinary TIMP-1 and LYVE-1 can differentiate healthy controls from pancreatic cancer.•Urinary TIMP-1 and LYVE-1 cannot distinguish between low- and high-risk IPMN.•Urinary PGEM does not correlate with malignant potential of pancreatic cysts.

Intraductal papillary mucinous neoplasm (IPMN) of pancreas has a high risk to develop into invasive cancer or co‐occur with malignant lesion. Therefore, it is important to assess its malignant risk by less‐invasive approach. Pancreatic juice cell‐free DNA (PJD) would be an ideal material in this purpose, but genetic biomarkers for predicting malignant risk from PJD are not yet established. We here performed deep exome sequencing analysis of PJD from 39 IPMN patients with or without malignant lesion. Somatic alterations and copy number alterations (CNAs) detected in PJD were compared with the histologic grade of IPMN to evaluate their potential as a malignancy marker. Somatic mutations of KRAS, GNAS, TP53, and RNF43 were commonly detected in PJD of IPMNs, but no association with the histologic grades of IPMN was found. Instead, mutation burden was positively correlated with the histologic grade (r = 0.427, P = 0.015). We also observed frequent copy number deletions in 17p13 (TP53) and amplifications in 7q21 and 8q24 (MYC) in PJDs. The amplifications in 7q21 and 8q24 were positively correlated with the histologic grade and most prevalent in the cases of invasive carcinoma (P = 0.002 and 7/11; P = 0.011 and 6/11, respectively). We concluded that mutation burden and CNAs detected in PJD may have potential to assess the malignant progression risk of IPMNs. Significantly amplified regions (red) and significantly deleted regions (green) by patient and by the histologic grade of IPMNs are shown. The 7q21 amplification and 8q24 amplification (MYC) showed significant association with invasive carcinoma of IPMN.