Search

ObjectiveSeveral cross-sectional studies on populations with iodine deficiency showed that TSH-levels are negatively associated with age, while in populations with high iodine intake TSH is positively associated with age. The question is whether such an age-thyroid function relation is an ongoing process apparent also in longitudinal studies and whether it reflects an actual iodine deficiency or an iodine insufficiency in the past.MethodsIn an area with a borderline iodine status in the past, we studied 980 participants of the Nijmegen Biomedical Study. We measured serum TSH, free thyroxine (FT4), total triiodothyronine (T3), peroxidase antibodies, and the urine iodine and creatinine concentration 4 years after our initial survey of thyroid function, in which we reported a negative association between TSH and age.ResultsWithin 4 years, TSH decreased by 5.4% (95% CI 2.5–8.3%) and FT4increased by 3.7% (95% CI 2.9–4.6%). Median urinary iodine concentration was 130 μg/l. Estimated 24-h iodine excretion was not associated with TSH, T3, change of TSH, or FT4over time or with the presence of antibodies against thyroid peroxidase. Only FT4appeared to be somewhat higher at lower urine iodine levels: a 1.01% (95% CI 0.17–1.84%) higher FT4for each lower iodine quintile.ConclusionsIn this longitudinal study, we found an ongoing decrease in TSH and increase in FT4in a previously iodine insufficient population, despite the adequate iodine status at present. This suggests that low iodine intake at young age leads to thyroid autonomy (and a tendency to hyperthyroidism) that persists despite normal iodine intake later in life.

Contains fulltext : 125950.pdf (Publisher’s version ) (Closed access) Relaxin is thought to be involved in vasodilation to pregnancy by increasing endothelium-dependent vasodilation and compliance, and decreasing myogenic reactivity. Primary (essential) hypertension predisposes to circulatory maladaptation and subsequent gestational hypertensive disease. This study aimed to determine that vascular responses to chronic exposure to relaxin are impaired in young female rats with primary hypertension. In 10-12 weeks old Wistar-Hannover rats (WHR) and spontaneous hypertensive rats (SHR), we determined vascular responses in isolated kidney and mesenteric arteries after 5-days of chronic exposure to relaxin (4 mug/h) or placebo. SHR show decreased sensitivity to phenylephrine (by 67%, p

Contains fulltext : 125783.pdf (Publisher’s version ) (Closed access) CONTEXT: Premature delivery is an important risk factor for child mortality and psychiatric, metabolic, and cardiovascular disease later in life. In the majority of cases, the cause of prematurity cannot be identified. Currently, it remains controversial whether abnormal maternal thyroid function during pregnancy increases the risk of premature delivery. Therefore, we investigated the relation between maternal serum thyroid parameters and the risk of premature delivery in a large prospective population-based study. DESIGN: Serum TSH, free T4 (FT4), T4, and TPO antibodies (TPOAbs) were determined during early pregnancy in 5971 pregnant women from the Generation R study. Data were available on maternal age, parity, smoking, socioeconomic status, ethnicity, maternal anthropometrics, and urinary iodine levels. RESULTS: Of all women, 5.0% had a premature delivery (

Item does not contain fulltext All cancers are caused by somatic mutations; however, understanding of the biological processes generating these mutations is limited. The catalogue of somatic mutations from a cancer genome bears the signatures of the mutational processes that have been operative. Here we analysed 4,938,362 mutations from 7,042 cancers and extracted more than 20 distinct mutational signatures. Some are present in many cancer types, notably a signature attributed to the APOBEC family of cytidine deaminases, whereas others are confined to a single cancer class. Certain signatures are associated with age of the patient at cancer diagnosis, known mutagenic exposures or defects in DNA maintenance, but many are of cryptic origin. In addition to these genome-wide mutational signatures, hypermutation localized to small genomic regions, 'kataegis', is found in many cancer types. The results reveal the diversity of mutational processes underlying the development of cancer, with potential implications for understanding of cancer aetiology, prevention and therapy.

Purpose: Pheochromocytomas and paragangliomas (PGL) are neuroendocrine tumors of sympathetic and parasympathetic paraganglia. This study investigated the relationships between genotype-specific differences in mitochondrial function and catecholamine content in PGL tumors. Experimental Design: Respiratory chain enzyme assays and 1H-nuclear magnetic resonance (NMR) spectroscopy at 500 MHz were conducted on homogenates of 35 sporadic PGLs and 59 PGLs from patients with hereditary mutations in succinate dehydrogenase subunits B and D (SDHB, SDHD), succinate dehydrogenase assembly factor 2, von Hippel-Lindau (VHL), rearranged during transfection (RET), neurofibromatosis type 1 (NF1), and myc-associated factor X. Results: In SDHx-related PGLs, a significant decrease in complex II activity (P < 0.0001) and a significant increase in complex I, III, and IV enzyme activities were observed when compared to sporadic, RET, and NF1 tumors. Also, a significant increase in citrate synthase (P < 0.0001) enzyme activity was observed in SDHx-related PGLs when compared to sporadic-, VHL-, RET-, and NF1-related tumors. An increase in succinate accumulation (P < 0.001) and decrease in ATP/ADP/AMP accumulation (P < 0.001) was observed when compared to sporadic PGLs and PGLs of other genotypes. Positive correlations (P < 0.01) were observed between respiratory chain complex II activity and total catecholamine content and ATP/ADP/AMP and total catecholamine contents in tumor tissues. Conclusions: This study for the first time establishes a relationship between determinants of energy metabolism, like activity of respiratory chain enzyme complex II, ATP/ADP/AMP content, and catecholamine content in PGL tumors. Also, this study for the first time successfully uses NMR spectroscopy to detect catecholamines in PGL tumors and provides ex vivo evidence for the accumulation of succinate in PGL tumors with an SDHx mutation. Clin Cancer Res; 19(14); 3787–95. ©2013 AACR.

Item does not contain fulltext AIM: Final 10-year analysis of the prospective randomised Chemo-N0 trial is presented. Based on the Chemo-N0 interim results and an European Organisation for Research and Treatment of Cancer (EORTC) pooled analysis (n=8377), American Society of Clinical Oncology (ASCO) and Arbeitsgemeinschaft Gynakologische Onkologie (AGO) guidelines recommend invasion and metastasis markers urokinase-type plasminogen activator (uPA)/plasminogen activator inhibitor-1 (PAI-1) for risk assessment and treatment decision in node-negative (N0) breast cancer (BC). METHODS: The final Chemo-N0 trial analysis (recruitment 1993-1998; n=647; 12 centres) comprises 113 (5-167) months of median follow-up. Patients with low-uPA and PAI-1 tumour tissue levels (n=283) were observed. External quality assurance guaranteed uPA/PAI-1 enzyme-linked immunosorbent assay (ELISA) standardisation. Of 364 high uPA and/or PAI-1 patients, 242 agreed to randomisation for CMF chemotherapy (n=117) versus observation (n=125). RESULTS: Actuarial 10-year recurrence rate (without any adjuvant systemic therapy) for high-uPA/PAI-1 observation group patients (randomised and non-randomised) was 23.0%, in contrast to only 12.9% for low-uPA/PAI-1 patients (plog-rank=0.011). High-risk patients randomised to cyclophosphamide-methotrexate-5-fluorouracil (CMF) therapy had a 26.0% lower estimated probability of disease recurrence than those randomised for observation (intention-to-treat (ITT)-analysis: hazard ratio (HR) 0.74 (0.44-1.27); plog-rank=0.28). Per-protocol analysis demonstrated significant treatment benefit: HR 0.48 (0.26-0.88), p=0.019, disease-free survival (DFS) Cox regression, adjusted for tumour stage and grade. CONCLUSIONS: Chemo-N0 is the first prospective biomarker-based therapy trial in early BC defining patients reaching good long-term DFS without adjuvant systemic therapy. Using a standardised uPA/PAI-1 ELISA, almost half of N0-patients could be spared chemotherapy, while high-risk patients benefit from adjuvant chemotherapy. These 10-year results validate the long-term prognostic impact of uPA/PAI-1 and the benefit from adjuvant chemotherapy in the high-uPA/PAI-1 group at highest level of evidence. They thus support the guideline-based routine use of uPA/PAI-1 for risk-adapted individualised therapy decisions in N0 breast cancer.

Contains fulltext : 118729.pdf (Publisher’s version ) (Closed access) OBJECTIVE: Currently, human chorionic gonadotropin (hCG) follow-up after evacuation of hydatidiform moles is essential to identify patients requiring chemotherapeutic treatment for gestational trophoblastic neoplasia (GTN). We propose a model based on linear regression of postevacuation serum hCG concentrations for the prediction of GTN. METHODS: One hundred thirteen patients with at least 3 serum samples from days 7 to 28 after evacuation were selected from the Dutch Central Registry for Hydatidiform Moles (1994-2009). The slopes of the linear regression lines of the first 3 log-transformed serum hCG and free beta-hCG values were calculated. Receiver operating characteristic curves were constructed to calculate areas under curve (AUCs). RESULTS: The slope of the hCG regression line showed an AUC of 0.906 (95% confidence interval, 0.845-0.967). Gestational trophoblastic neoplasia could be predicted in 52% of patients with GTN at 97.5% specificity (cutoff, -0.020). Twenty-one percent of patients with GTN could be predicted before diagnosis according to the International Federation of Gynecology and Obstetrics 2000 criteria. The slope of free beta-hCG showed an AUC of 0.844 (95% confidence interval, 0.752-0.935), 69% sensitivity at 97.5% specificity, and 38% of patients with GTN could be predicted before diagnosis according to the International Federation of Gynecology and Obstetrics criteria. CONCLUSIONS: The slope of the linear regression line of hCG proved to be a good test to discriminate between patients who will achieve spontaneous disease remission and patients developing GTN. The slope of free beta-hCG seems to be a better predictor for GTN than the slope of hCG. Although this model needs further validation for different assays, it seems a promising way to predict the more aggressive cases of GTN.

Contains fulltext : 118162.pdf (Publisher’s version ) (Closed access) OBJECTIVE: Formerly preeclamptic women are at increased risk for remote cardiovascular and thrombotic diseases. We studied co-occurrence of cardiovascular and prothrombotic risk factors within a cohort of formerly preeclamptic women and tested if prevalence of these risk profiles related to onset of preeclampsia in previous pregnancy. METHODS: We evaluated 1,297 nonpregnant formerly preeclamptic women (6-12 months postpartum) for the presence of four risk profiles: circulatory risk profile (hypertension or latent hypertension [low plasma volume, increased vascular resistance, or both]; metabolic syndrome (World Health Organization criteria); thrombophilia (factor V Leiden, prothrombin mutation, or protein C or S deficiency); and hyperhomocysteinemia. Trends between prevalence of these four profiles and onset of preeclampsia were studied using linear regression analysis. RESULTS: After exclusion of 63 women (4.9%) because of incomplete data, 1,234 women were included. One or more risk profiles were detected in 958 of 1,234 (77.6%) formerly preeclamptic women. Circulatory risk profile was more prevalent (66.1%) than hyperhomocysteinemia (18.7%), metabolic syndrome (15.4%), or thrombophilia (10.8%). Prevalence of circulatory risk profile, metabolic syndrome, and hyperhomocysteinemia decreased significantly with gestational age at delivery, whereas thrombophilia did not (P=.22). There was minimal overlap (less than 2%) between metabolic syndrome, thrombophilic profile, and hyperhomocysteinemia. CONCLUSION: Circulatory risk profile is present in two thirds of formerly preeclamptic women. Metabolic syndrome, thrombophilia, and hyperhomocysteinemia are prevalent in 10-20%. There is considerable overlap between circulatory risk profile and other profiles, but not among the three other profiles. Prevalence of these risk factors, except thrombophilia, decreases with gestational age at delivery in preceding pregnancy. LEVEL OF EVIDENCE: : II.

Item does not contain fulltext Treatment failure through radioresistance of tumours is associated with activation of the epidermal growth factor receptor (EGFR). Tumour cell proliferation, DNA-repair, hypoxia and metastases-formation are four mechanisms in which EGFR signalling has an important role. In clinical trials, a correlation has been demonstrated between high EGFR expression in tumours and poor outcome after radiotherapy. Inhibition of EGFR signalling pathways improves the effectiveness of radiotherapy of head and neck cancers by overcoming these main mechanisms of radioresistance. The fact that only a minority of the patients respond to EGFR inhibitors reflects the complexity of interactions between EGFR-dependent signalling pathways and the tumour microenvironment. Furthermore, many components of the microenvironment are potential targets for therapeutic interventions. Characterisation of the interaction of EGFR signalling and the tumour microenvironment is therefore necessary to improve the effectiveness of combined modality treatment with radiotherapy and targeted agents. Here, the current status of knowledge is reviewed and directions for future research are discussed.

Contains fulltext : 125273pub.pdf (Publisher’s version ) (Closed access) alphaB-crystallin is regarded as a biomarker for triple-negative and/or basal-like breast cancer. In normal breast cells, overexpression of alphaB-crystallin leads to neoplastic-like changes, which likely relate to enhanced expression of phosphorylated ERK1/2 (pERK1/2). In this study, we investigated whether alphaB-crystallin expression is correlated to pERK1/2 expression in breast cancer. In a balanced tissue microarray the expression of alphaB-crystallin and pERK1/2 kinase were determined immunohistochemically, together with the triple-negativity and basal-like markers CK5/6 and SMA and the signaling molecules pAKT, pmTOR, EGFR, and IGF-1R. alphaB-crystallin expression significantly correlated with triple negativity and basal-like markers CK5/6 and SMA (Pearson Chi-square test p=0.004, p=0.001, and p

Objective: To assess the value of breast MRI in size assessment of breast cancers in high risk patients, including those with a BRCA 1 or 2 mutation. Guidelines recommend invariably breast MRI screening for these patients and therapy is thus based on these findings. However, the accuracy of breast MRI for staging purposes is only tested in sporadic cancers. Methods: We assessed concordance of radiologic staging using MRI with histopathology in 49 tumors in 46 high risk patients (23 BRCA1, 12 BRCA2 and 11 Non-BRCA patients). The size of the total tumor area (TTA) was compared to pathology. In invasive carcinomas (n = 45) the size of the largest focus (LF) was also addressed. Results: Correlation of MRI measurements with pathology was 0.862 for TTA and 0.793 for LF. TTA was underestimated in 8(16%), overestimated in 5(10%), and correctly measured in 36(73%) cases. LF was underestimated in 4(9%), overestimated in 5(11%), and correctly measured in 36(80%) cases. Impact of BRCA 1 or 2 mutations on the quality of size estimation was not observed. Conclusions: Tumor size estimation using breast MRI in high risk patients is comparable to its performance in sporadic cancers. Therefore, breast MRI can safely be used for treatment planning. (C) 2013 Elsevier Ireland Ltd. All rights reserved

Purpose: Tumor hypoxia is associated with a poor prognosis, hypoxia modification improves outcome, and hypoxic status predicts benefit from treatment. Yet, there is no universal measure of clinical hypoxia. The aim of this study was to investigate whether a 26-gene hypoxia signature predicted benefit from hypoxia-modifying treatment in both cancer types. Experimental Design: Samples were available from 157 T2–T4 laryngeal cancer and 185 T1–T4a bladder cancer patients enrolled on the accelerated radiotherapy with carbogen and nicotinamide (ARCON) and bladder carbogen nicotinamide (BCON) phase III randomized trials of radiotherapy alone or with carbogen and nicotinamide (CON) respectively. Customized TaqMan low density arrays (TLDA) were used to assess expression of the 26-gene signature using quantitative real-time PCR. The median expression of the 26 genes was used to derive a hypoxia score (HS). Patients were categorized as TLDA-HS low (≤median) or TLDA-HS high (>median). The primary outcome measures were regional control (RC; ARCON) and overall survival (BCON). Results: Laryngeal tumors categorized as TLDA-HS high showed greater benefit from ARCON than TLDA-HS low tumors. Five-year RC was 81% (radiotherapy alone) versus 100% (CON) for TLDA-HS high (P = 0.009). For TLDA-HS low, 5-year RC was 91% (radiotherapy alone) versus 90% (CON; P = 0.90). TLDA-HS did not predict benefit from CON in bladder cancer. Conclusion: The 26-gene hypoxia signature predicts benefit from hypoxia-modifying treatment in laryngeal cancer. These findings will be evaluated in a prospective clinical trial. Clin Cancer Res; 19(17); 4879–88. ©2013 AACR.

Contains fulltext : 108161.pdf (Publisher’s version ) (Closed access) Background We present normograms for human chorionic gonadotropin (hCG) regression in patients with high-risk gestational trophoblastic neoplasia (GTN) successfully treated with multiagent chemotherapy in order to predict treatment resistance. Patients and methods We collected data for 46 patients with high-risk GTN treated with EMA/CO (etoposide, methotrexate, actinomycin D, cyclophosphamide and vincristine) who had hCG values available. Patients were classified as having methotrexate (MTX)-resistant disease (n = 22) or primary high-risk disease (n = 24). The 10th, 50th and 90th percentiles of the hCG before every chemotherapy course were calculated and plotted in normograms. Results Half of the patients treated for MTX-resistant disease and primary high-risk disease had normal hCG levels before the third and sixth course of chemotherapy, respectively. In patients with MTX-resistant disease, the 90th percentile line fell below normal before the start of the fourth course, whereas in patients with primary high-risk disease this was not the case until the eighth course of chemotherapy. Conclusion Resistance to EMA/CO treatment for high-risk GTN, as illustrated by examples, could be predicted using normograms for hCG resistance. Normograms differed depending on the indication for multiagent chemotherapy due to much higher initial hCG values in patients with primary high-risk disease compared with those treated for MTX-resistant disease.

Item does not contain fulltext Background:Previously we demonstrated that an mRNA signature reflecting cellular proliferation had strong prognostic value. As clinical applicability of signatures can be controversial, we sought to improve our marker's clinical utility by validating its biological relevance, reproducibility in independent data sets and applicability using an independent technique.Methods:To facilitate signature evaluation with quantitative PCR (qPCR) a novel computational procedure was used to reduce the number of signature genes without significant information loss. These genes were validated in different human cancer cell lines upon serum starvation and in a 168 xenografts panel. Analyses were then extended to breast cancer and non-small-cell lung cancer (NSCLC) patient cohorts.Results:Expression of the qPCR-based signature was dramatically decreased under starvation conditions and inversely correlated with tumour volume doubling time in xenografts. The signature validated in breast cancer (hazard ratio (HR)=1.63, P

Contains fulltext : 108532.pdf (Publisher’s version ) (Open Access) Breast cancer resistance protein (BCRP) is known for its protective function against the toxic effects of exogenous compounds. In addition to this, a role in the transport of endogenous compounds has been described. Since BCRP in the plasma membrane was shown to be regulated by sex steroids, we investigated the presence and possible role of BCRP in steroid hormone-producing organs. Therefore, the presence and localization of Bcrp was investigated in endocrine organs of wild-type mice. Furthermore, the interaction of various steroid hormones with human BCRP activity was studied. Quantitative PCR revealed Bcrp mRNA in the pituitary and adrenal glands, pancreas, ovary, testis and adipose tissue. Immunohistochemistry revealed the presence of Bcrp in the cortex of the adrenal gland and in plasma membranes of adipocytes. In the pituitary gland, pancreas, ovary and testis, Bcrp was mainly located in the capillaries. The interaction between BCRP and 12 steroid hormones was studied using membrane vesicles of HEK293-BCRP cells. Estradiol, testosterone, progesterone and androstenedione inhibited BCRP-mediated uptake of (3)H-estrone sulphate (E(1)S) most potently, with calculated inhibitory constant (Ki) values of 5.0 +/- 0.2, 36 +/- 14, 14.7 +/- 1.3 and 217 +/- 13 muM, respectively. BCRP function was attenuated non-competitively, which implies an allosteric inhibition of BCRP-mediated E(1)S transport by these steroids. In conclusion, localization of Bcrp in endocrine organs together with the efficient allosteric inhibition of the efflux pump by steroid hormones are suggestive for a role for BCRP in steroid hormone regulation. 01 augustus 2012

Macrophage migration inhibitory factor (MIF) is an abundantly expressed proinflammatory cytokine playing a critical role in innate immunity and sepsis and other inflammatory diseases. We examined whether functional MIF gene polymorphisms ( 794 CATT(5 8) microsatellite and 173 G/C SNP) were associated with the occurrence and outcome of meningococcal disease in children. The CATT(5) allele was associated with the probability of death predicted by the Pediatric Index of Mortality 2 (P=0.001) which increased in correlation with the CATT(5) copy number (P=0.04). The CATT(5) allele but not the 173 G/C alleles was also associated with the actual mortality from meningoccal sepsis [OR 2.72 (1.2 6.4) P=0.02]. A family based association test (i.e. transmission disequilibrium test) performed in 240 trios with 1 afflicted offspring indicated that CATT(5) was a protective allele (P=0.02) for the occurrence of meningococcal disease. At baseline and after stimulation with Neisseria meningitidis in THP 1 monocytic cells or in a whole blood assay CATT(5) was found to be a low expression MIF allele (P=0.005 and P=0.04 for transcriptional activity; P=0.09 and P=0.09 for MIF production). Taken together these data suggest that polymorphisms of the MIF gene affecting MIF expression are associated with the occurrence severity and outcome of meningococcal disease in children. Renner P. Roger T. Bochud P. Y. Sprong T. Sweep F. C. G. J. Bochud M. Faust S. N. Haralambous E. Betts H. Chanson A. L. Reymond M. K. Mermel E. Erard V. van Deuren M. Read R. C. Levin M. Calandra T. A functional microsatellite of the macrophage migration inhibitory factor gene associated with meningococcal disease.

Item does not contain fulltext The renin-angiotensin system (RAS) has mainly been categorized as a circulating and a local tissue RAS. A new component of the local system, known as the intracellular RAS, has recently been described. The intracellular RAS is defined as synthesis and action of ANG II intracellularly. This RAS appears to differ from the circulating and the local RAS, in terms of components and the mechanism of action. These differences may alter treatment strategies that target the RAS in several pathological conditions. Recent work from our laboratory has demonstrated significant upregulation of the cardiac, intracellular RAS in diabetes, which is associated with cardiac dysfunction. Here, we have reviewed evidence supporting an intracellular RAS in different cell types, ANG II's actions in cardiac cells, and its mechanism of action, focusing on the intracellular cardiac RAS in diabetes. We have discussed the significance of an intracellular RAS in cardiac pathophysiology and implications for potential therapies.

Item does not contain fulltext Breast cancer is one of the leading causes of cancer mortality in women. Recent advances in gene expression profiling have indicated that breast cancer is a heterogeneous disease and the current prognostication using clinico-pathological features is not sufficient to fully predict therapy response and disease outcome. In this retrospective study, we show that expression levels of BRE, which encodes a member of the BRCA1 DNA damage repair complex, predicted disease-free survival (DFS) in non-familial breast cancer patients. The predictive value of BRE expression depended on whether patients received radiotherapy as a part of their primary treatment. In radiotherapy-treated patients, high BRE expression predicted a favorable DFS (hazard ratio (HR) = 0.47, 95 % confidence interval (CI) = 0.28-0.78, p = 0.004), while in non-treated patients, high BRE expression predicted an adverse prognosis (HR = 2.59, 95 % CI = 1.00-6.75, p = 0.05). Among radiotherapy-treated patients, the prognostic impact of BRE expression was confined to patients with smaller tumors (HR = 0.23, 95 % CI = 0.068-0.75, p = 0.015) and it remained an independent factor after correction for the other prognostic factors age, tumor size, lymph node involvement, and histological grade (HR = 0.50, CI = 0.27-0.90, p = 0.021). In addition, high BRE expression predicted a favorable relapse-free survival in a publicly available dataset of 2,324 breast cancer patients (HR = 0.59, CI = 0.51-0.68, p < 0.001). These data indicate that BRE is an interesting candidate for future functional studies aimed at developing targeted therapies. 01 augustus 2012

Item does not contain fulltext OBJECTIVE: To estimate whether the imbalance of angiogenic factors (soluble fms-like tyrosine kinase-1, placental growth factor) and fibrinolytic factors (plasminogen activator inhibitor-2 [PAI-2]) might affect placentation in early pregnancy. METHODS: We studied the associations of maternal soluble fms-like tyrosine kinase-1, placental growth factor, and PAI-2 concentrations in the first trimester (before 18 weeks of gestation) and soluble fms-like tyrosine kinase-1 and placental growth factor concentrations in the second trimester (18-25 weeks of gestation) with placental function and adverse pregnancy outcomes. This study was embedded in a population-based prospective cohort study. Data were used from 7,519 women. Biomarker concentrations were divided into deciles and evaluated in multivariable linear and logistic regression models. RESULTS: First-trimester high soluble fms-like tyrosine kinase-1 was associated with a 5.2% lower uterine artery index in the second-trimester and a 1.6% higher birth weight (55 g, confidence interval [CI] 15-95). Neither in the first nor in the second trimester were soluble fms-like tyrosine kinase-1 concentrations significantly associated with preeclampsia. First-trimester low placental growth factor was associated with a 6.1% higher uterine artery index and a 3.4% lower birth weight (-115 g, CI -157 to -74). First-trimester low placental growth factor was associated with fetal growth restriction (odds ratio [OR] 2.62, CI 1.68-4.08) and preeclampsia (OR 2.46, CI 1.49-4.08). First-trimester low PAI-2 was associated with a 1.9% higher uterine artery index and a 2.7% lower birth weight (-94 g, CI -136 to -51). First-trimester low PAI-2 was associated with a higher risk of fetal growth restriction (OR 2.22, CI 1.39-3.55). CONCLUSION: First-half-of-pregnancy concentrations of soluble fms-like tyrosine kinase-1, placental growth factor, and PAI-2 are associated with uteroplacental vascular resistance, placental weight, and birth weight. Moreover, first-trimester placental growth factor and PAI-2 are associated with an increased risk of adverse pregnancy outcomes. LEVEL OF EVIDENCE: II. 01 juni 2012

Contains fulltext : 97392.pdf (Publisher’s version ) (Closed access) BACKGROUND: Tribbles homolog 3 (TRIB3) is a pseudokinase involved in the regulation of several signaling pathways involved in cell survival and/or cell stress. Here, we determined the correlation between breast cancer prognosis and TRIB3 protein levels and established the role of TRIB3 in cell survival after hypoxia and/or radiotherapy. MATERIAL AND METHODS: TRIB3 mRNA and protein were quantified in a new independent breast cancer patient cohort using QPCR and a new specific avian antibody against TRIB3. In addition, we used siRNA-mediated knockdown of TRIB3 in a colony-forming assay after hypoxia and radiotherapy. RESULTS: TRIB3 mRNA and protein levels did not correlate in breast cancer cell lines or human breast cancer material. We validated our earlier finding that high TRIB3 mRNA denotes a poor prognosis, but found that high TRIB3 protein levels were associated with a good prognosis in breast cancer patients. We also show that knockdown of TRIB3 resulted in an increased survival under hypoxic conditions. CONCLUSION: Whereas mRNA levels of TRIB3 are related with a poor prognosis, TRIB3 protein is associated with a good prognosis in human breast cancer patients, possibly due to the fact that TRIB3 is involved in hypoxia tolerance.

Item does not contain fulltext The ongoing development of the hippocampus in adolescence may be vulnerable to stressors. The effects of social instability stress (SS) in adolescence (daily 1 h isolation and change of cage partner postnatal days 30-45) on cell proliferation in the dentate gyrus (DG) in adolescence (on days 33 and 46, experiment 1) and in adulthood (experiment 2) was examined in Long Evans male rats and compared to nonstressed controls (CTL). Additionally, in experiment 2, a separate group of SS and CTL rats was tested on either a spatial (hippocampal-dependent) or nonspatial (nonhippocampal dependent) version of an object memory test and also were used to investigate hippocampal expression of markers of synaptic plasticity. No memory impairment was evident until the SS rats were adults, and the impairment was only on the spatial test. SS rats initially (postnatal day 33) had increased cell proliferation based on counts of Ki67 immunoreactive (ir) cells and greater survival of immature neurons based on counts of doublecortin ir cells on day 46 and in adulthood, irrespective of behavioral testing. Counts of microglia in the DG did not differ by stress group, but behavioral testing was associated with reduced microglia counts compared to nontested rats. As adults, SS and CTL rats did not differ in hippocampal expression of synaptophysin, but compared to CTL rats, SS rats had higher expression of basal calcium/calmodulin-dependent kinase II (CamKII), and lower expression of the phosphorylated CamKII subunit threonine 286, signaling molecules related to synaptic plasticity. The results are contrasted with those from previous reports of chronic stress in adult rats, and we conclude that adolescent stress alters the ongoing development of the hippocampus leading to impaired spatial memory in adulthood, highlighting the heightened vulnerability to stressors in adolescence. 01 juni 2012

Contains fulltext : 96336.pdf (Publisher’s version ) (Closed access) To date, concentrations of the promising biomarker hepcidin have only been assessed in serum of relatively small series of healthy volunteers and patients. We assessed age- and sex-stratified reference ranges of serum hepcidin concentration in a selected reference set and performed regression analyses to study associations between hepcidin and (biochemical) variables in a large, well-phenotyped sample of the general population (n = 2998). All participants filled out a questionnaire on lifestyle, health status, and medical history. Serum measurements of iron parameters, liver enzyme alanine aminotransferase, creatinine and C-reactive protein were available. Serum hepcidin concentrations were lower for premenopausal than for postmenopausal women (median, 4.1 nM vs 8.5 nM, respectively). Hepcidin concentrations in men were constant over age (median, 7.8 nM). Serum hepcidin was strongly associated with serum ferritin in men and women: beta-coefficient of log-transformed variables (95% confidence interval): 0.78 (0.74-0.82) and 0.83 (0.78-0.88), respectively. Additional significant, though less strong, associations were observed for C-reactive protein and total iron binding capacity in men and for total iron binding capacity, alanine aminotransferase, and glomerular filtration rate in women. Our study provides age- and sex-specific reference ranges of serum hepcidin concentration and indicates ferritin as the primary correlate of serum hepcidin concentration.

Contains fulltext : 96007.pdf (Publisher’s version ) (Closed access) OBJECTIVE: The objective of this study is to determine the incidence and time trends of gestational trophoblastic disease (GTD) in The Netherlands using population-based data. METHODS: Data on patients with a pathologically confirmed diagnosis of GTD from 1995 to 2008 were obtained from PALGA, a national archive containing all histopathology reports in The Netherlands. Data on number of deliveries were obtained from the Database of Statistics Netherlands. RESULTS: During the study period, 4249 GTD patients were registered. Overall incidence rates of hydatidiform mole (HM), choriocarcinoma and placental site trophoblastic tumor (PSTT) were 1.34 per 1000 deliveries, 3.1 per 100,000 deliveries, and 1.0 per 100,000 deliveries, respectively. Incidence rates of HM increased from 1.02 per 1000 deliveries in 1995 to 1.56 per 1000 in 2001, an increase of 0.091 per year (95% CI 0.081-0.101). After 2001 incidence rates remained constant (increase per year -0.010, 95% CI -0.045-0.024). Maternal age and ethnicity are known to influence the risk of HM. Highest incidences were observed in women under 20 and over 40years of age. The proportion of deliveries accounted for by women over 40years of age increased from 1.5% to 2.9%, whereas women under 20 accounted for 1.5% of deliveries. The proportion of live births of Asian descent increased from 2.6% to 3.7%. CONCLUSION: The incidence of GTD in The Netherlands increased significantly from 1995 to 2008. This can partially be explained by increased maternal age and increased proportion of live births of Asian descent. Part of the increase might result from improved diagnostic techniques. However, these factors do not seem to account for the total observed increase and part of the increase therefore remains unexplained.

Aims: Tamoxifen is metabolized by cytochrome P450s, with an important role for CYP2D6. Recently, we demonstrated in 80 patients that CYP2C19*2 is associated with increased survival in breast cancer patients using tamoxifen. Here, we aimed to confirm this in a large group of 499 patients. Materials & methods: A total of 499 estrogen receptor-positive primary breast tumor specimens of advanced disease patients treated with first-line tamoxifen were genotyped for CYP2C19*2 and *17 variant alleles, with primary end point time-to-treatment failure (TTF). Effects of CYP2C19, independent of treatment, were analyzed in 243 primary systematic untreated patients. Results: CYP2C19*2 hetero- and homozygote patients combined showed significantly longer TTFs (hazard ratio [HR]: 0.72; 95% CI: 0.57–0.90; p = 0.004). In multivariate analysis, including CYP2D6*4 status, CYP2C19*2 remained independently associated with TTF (HR: 0.73; 95% CI: 0.58–0.91; p = 0.007). In untreated patients, the CYP2C19*17 allele was significantly associated with a longer disease-free interval (HR: 0.66; 95%CI: 0.46–0.95; p = 0.025). Conclusion: CYP2C19 genotyping is potentially important for tamoxifen therapy for advanced disease and for breast cancer prognosis. Original submitted 14 February 2011; Revision submitted 8 April 2011

Contains fulltext : 98034.pdf (Publisher’s version ) (Closed access) BACKGROUND: Carriers of a premutation (CGG repeat length 55-200) in the fragile X mental retardation (FMR1) gene are at risk for primary ovarian insufficiency (FXPOI). The anti-Mullerian hormone (AMH) level acts as a useful marker of ovarian follicle reserve and, thus, may serve to predict when this ovarian reserve becomes too low to sustain ovarian function. We investigated the intra-individual variation of AMH levels over time for premutation carriers compared with non-carriers. METHODS: We determined AMH levels in blood samples from 240 women ascertained through fragile X families, of which 127 were premutation carriers and 113 were non-carriers. Linear mixed models were used to assess the effect of age and premutation status on AMH levels and to determine a modeled AMH value. The stability over time of the deviation of observed AMH levels from modeled levels, referred to as standardized AMH values, was assessed through correlation coefficients of 41 longitudinal samples. RESULTS: At all ages, premutation carriers exhibited lower AMH levels. For all women, AMH was found to decrease by 10% per year. The added effect of having a premutation decreased AMH levels by 54%. The deviation of an individual's AMH level from the modeled value showed a reasonable intra-individual correlation. The Pearson correlation coefficient of two samples taken at different ages was 0.36 (P = 0.05) for non-carriers and 0.69 (P = 0.01) for carriers. CONCLUSIONS: We developed a unique standardized AMH value, taking FMR1 premutation status and the subject's age into account, which appears to be stable over time and may serve as a predictor for FXPOI after further longitudinal assessment.

Contains fulltext : 95977.pdf (Publisher’s version ) (Closed access) BACKGROUND: LAMP3 is a newly described hypoxia regulated gene of potential interest in hypoxia-induced therapy resistance and metastasis. The prognostic value of LAMP3 in breast cancer was investigated. METHODS: Expression levels of LAMP3 in breast cancer cell lines and patient tissues were determined by real-time polymerase chain reaction and in a tissue microarray by immunohistochemistry. Immunofluorescent staining was used to evaluate the distribution of LAMP3 in tumor xenografts relative to pimonidazole. Kaplan-Meier analysis as well as multivariate Cox regression survival analyses were performed. RESULTS: LAMP3 was variably expressed in breast cancer cell lines and induced in an oxygen concentration-dependent manner. LAMP3 protein expression colocalized with hypoxic areas in breast cancer xenografts. LAMP3 mRNA was higher in breast tumors from patients with node-positive (P = .019) and/or steroid hormone receptor-negative tumors (P < .001). Breast cancer patients with high LAMP3 mRNA levels had more locoregional recurrences (P = .032 log-rank). This was limited to patients treated with lumpectomy and radiotherapy as primary treatment (n = 53, P = .009). No association with metastasis-free survival was found. In multivariate Cox regression analysis, LAMP3 remained as a statistically independent prognostic factor for locoregional recurrence (hazard ratio, 2.76; 95% confidence interval, 1.01-7.5; P = .048) after correction for menopausal status, histologic grade, tumor size, nodal status, therapy, and steroid hormone receptor status. LAMP3 protein in breast cancer tissue proved also to be of prognostic relevance. CONCLUSIONS: Evidence was provided for an association of LAMP3 with tumor cell hypoxia in breast cancer xenografts. In the current breast cancer cohorts, LAMP3 had independent prognostic value.

Contains fulltext : 96918.pdf (Publisher’s version ) (Closed access) Female classic galactosemia patients suffer from primary ovarian insufficiency (POI). The cause for this long-term complication is not fully understood. One of the proposed mechanisms is that hypoglycosylation of complex molecules, a known secondary phenomenon of galactosemia, leads to FSH dysfunction. An earlier study showed less acidic isoforms of FSH in serum samples of two classic galactosemia patients compared to controls, indicating hypoglycosylation. In this study, FSH isoform patterns of five classic galactosemia patients with POI were compared to the pattern obtained in two patients with a primary glycosylation disorder (phosphomannomutase-2-deficient congenital disorders of glycosylation, PMM2-CDG) and POI, and in five postmenopausal women as controls. We used FPLC chromatofocussing with measurement of FSH concentration per fraction, and discovered that there were no significant differences between galactosemia patients, PMM2-CDG patients and postmenopausal controls. Our results do not support that FSH dysfunction due to a less acidic isoform pattern because of hypoglycosylation is a key mechanism of POI in this disease.

Item does not contain fulltext The multicellular tumor spheroid model is a widely used culture system to mimic the three-dimensionality of tumors. Several methods and an even larger number of protocols are available to prepare spheroids from regular monolayers. This paper describes the assessment of several techniques frequently used to culture spheroids of breast cancer cells. We found that some methods produced suboptimal results. Ultimately, an adapted liquid overlay technique generated tight, compact and robust spheroids of the breast cancer cells tested.

Item does not contain fulltext

Item does not contain fulltext BACKGROUND AND PURPOSE: The epidermal growth factor receptor (EGFR) is overexpressed, amplified or mutated in various human epithelial tumors, and is associated with tumor aggressiveness and therapy resistance. Autophagy activation provides a survival advantage for cells in the tumor microenvironment. In the current study, we assessed the potential of autophagy inhibition (using chloroquine (CQ)) in treatment of EGFR expressing tumors. MATERIAL AND METHODS: Quantitative PCR, immunohistochemistry, clonogenic survival, proliferation assays and in vivo tumor growth were used to assess this potential. RESULTS: We show that EGFR overexpressing xenografts are sensitive to CQ treatment and are sensitized to irradiation by autophagy inhibition. In HNSSC xenografts, a correlation between EGFR and expression of the autophagy marker LC3b is observed, suggesting a role for autophagy in EGFR expressing tumors. This observation was substantiated in cell lines, showing high EGFR expressing cells to be more sensitive to CQ addition as reflected by decreased proliferation and survival. Surprisingly high EGFR expressing cells display a lower autophagic flux. CONCLUSIONS: The EGFR high expressing cells and tumors investigated in this study are highly dependent on autophagy for growth and survival. Inhibition of autophagy may therefore provide a novel treatment opportunity for EGFR overexpressing tumors.

Item does not contain fulltext BACKGROUND AND PURPOSE: Lysosome-associated membrane protein 3 (LAMP3) is induced by the PKR-like ER kinase (PERK)/activating transcription factor 4 (ATF4)-arm of the unfolded protein response (UPR) during hypoxia. LAMP3 has prognostic value in breast cancer patients treated with radiotherapy. Here, we specifically investigated the role of the PERK/ATF4/LAMP3-arm in the radiation response of breast cancer cells. MATERIAL AND METHODS: Radiosensitivity of breast cancer cells was examined after siRNA-mediated knockdown of PERK, ATF4 and LAMP3. Activation of DNA damage repair proteins was evaluated by Western blotting and immunocytochemistry. RESULTS: Knockdown of the PERK/ATF4/LAMP3-arm and chemical inhibition of PERK could radiosensitise MDA-MB-231 cells significantly. Western blot analysis of several DNA damage repair proteins showed that LAMP3 knockdowns had an attenuated DNA damage response after radiation compared to controls. gamma-H2AX foci analysis revealed that LAMP3 knockdowns had a reduced number of positive cells after irradiation, indicating that their DNA damage repair signalling response is decreased. In addition, the effect of autophagy inhibition was examined and revealed a radiosensitising effect and the presence of residual gamma-H2AX foci. CONCLUSIONS: The PERK/ATF4/LAMP3-arm causes radioresistance of breast cancer cells by increasing DNA damage repair signalling. Inhibition of PERK and/or autophagy may sensitise tumours to radiotherapy.

Item does not contain fulltext This prospective study used sequential PET with the proliferation tracer 3'-deoxy-3'-(18)F-fluorothymidine ((18)F-FLT) to monitor the early response to treatment of head and neck cancer and evaluated the association between PET parameters and clinical outcome. METHODS: Forty-eight patients with head and neck cancer underwent (18)F-FLT PET/CT before and during the second and fourth weeks of radiotherapy or chemoradiotherapy. Mean maximum standardized uptake values for the hottest voxel in the tumor and its 8 surrounding voxels in 1 transversal slice (SUVmax(9)) of the PET scans were calculated, as well as PET-segmented gross tumor volumes using visual delineation (GTVVIS) and operator-independent methods based on signal-to-background ratio (GTVSBR) and 50% isocontour of the maximum signal intensity (GTV50%). PET parameters were evaluated for correlations with outcome. RESULTS: (18)F-FLT uptake decreased significantly between consecutive scans. An SUVmax(9) decline >/= 45% and a GTVVIS decrease >/= median during the first 2 treatment weeks were associated with better 3-y disease-free survival (88% vs. 63%, P = 0.035, and 91% vs. 65%, P = 0.037, respectively). A GTVVIS decrease >/= median in the fourth treatment week was also associated with better 3-y locoregional control (100% vs. 68%, P = 0.021). These correlations were most prominent in the subset of patients treated with chemoradiotherapy. Because of low (18)F-FLT uptake levels during treatment, GTVSBR and GTV50% were unsuccessful in segmenting primary tumor volume. CONCLUSION: In head and neck cancer, a change in (18)F-FLT uptake early during radiotherapy or chemoradiotherapy is a strong indicator for long-term outcome. (18)F-FLT PET may thus aid in personalized patient management by steering treatment modifications during an early phase of therapy.

Adrenal vein sampling is used to establish the origins of excess production of adrenal hormones in primary aldosteronism. Correct catheter positioning is confirmed using adrenal vein measurements of cortisol, but this parameter is not always reliable. Plasma metanephrine represents an alternative parameter. The objective of our study was to determine the use of plasma metanephrine concentrations to establish correct catheter positioning during adrenal vein sampling with and without cosyntropin stimulation. We included 52 cosyntropin-stimulated and 34 nonstimulated sequential procedures. Plasma cortisol and metanephrine concentrations were measured in adrenal and peripheral venous samples. Success rates of sampling, using an adrenal to peripheral cortisol selectivity index of 3.0, were compared with success rates of metanephrine using a selectivity index determined by receiver operating characteristic curve analysis. Among procedures assessed as selective using cortisol, the adrenal to peripheral vein ratio of metanephrine was 6-fold higher than that of cortisol (94.0 versus 15.5; P P

Item does not contain fulltext PURPOSE: FDG PET is increasingly incorporated into radiation treatment planning of head and neck cancer. However, there are only limited data on the accuracy of radiotherapy target volume delineation by FDG PET. The purpose of this study was to validate FDG PET segmentation tools for volume assessment of lymph node metastases from head and neck cancer against the pathological method as the standard. METHODS: Twelve patients with head and neck cancer and 28 metastatic lymph nodes eligible for therapeutic neck dissection underwent preoperative FDG PET/CT. The metastatic lymph nodes were delineated on CT (NodeCT) and ten PET segmentation tools were used to assess FDG PET-based nodal volumes: interpreting FDG PET visually (PETVIS), applying an isocontour at a standardized uptake value (SUV) of 2.5 (PETSUV), two segmentation tools with a fixed threshold of 40% and 50%, and two adaptive threshold based methods. The latter four tools were applied with the primary tumour as reference and also with the lymph node itself as reference. Nodal volumes were compared with the true volume as determined by pathological examination. RESULTS: Both NodeCT and PETVIS showed good correlations with the pathological volume. PET segmentation tools using the metastatic node as reference all performed well but not better than PETVIS. The tools using the primary tumour as reference correlated poorly with pathology. PETSUV was unsatisfactory in 35% of the patients due to merging of the contours of adjacent nodes. CONCLUSION: FDG PET accurately estimates metastatic lymph node volume, but beyond the detection of lymph node metastases (staging), it has no added value over CT alone for the delineation of routine radiotherapy target volumes. If FDG PET is used in radiotherapy planning, treatment adaptation or response assessment, we recommend an automated segmentation method for purposes of reproducibility and interinstitutional comparison.

Drs Vink and Blankestijn1 suggest that patients before and after renal nerve ablation should have been investigated off antihypertensive medications or on a standardized treatment regimen. For studies on human physiology, highly standardized conditions are desirable. However, our goal was studying influences of renal nerve ablation on sympathetic nervous system regulation in a clinical setting. Indeed, patients in previous renal nerve ablation trials were on multiple medications. Drug withdrawal is difficult to justify in these …

Dr Schlaich et al1 suggest that differences in blood pressure and muscle sympathetic nerve responses to renal nerve ablation between studies could be explained by differences in patient characteristics. All of our patients fulfilled diagnostic criteria for treatment-resistant arterial hypertension and had office blood pressure measurements in the hypertensive range, despite treatment with multiple antihypertensive drugs. Yet, we assessed blood pressure after an almost 60-minute resting period in the supine position. In the SYMPLICITY trials, office blood pressure measurements were taken in the seated position. Thus, baseline blood pressure is difficult to compare between studies. Even if blood pressure readings were somewhat lower …

Item does not contain fulltext PURPOSE: Despite conventional radiation therapy, 54 Gy in single doses of 1.8 Gy (54/1.8 Gy) over 6 weeks, most children with diffuse intrinsic pontine glioma (DIPG) will die within 1 year after diagnosis. To reduce patient burden, we investigated the role of hypofractionation radiation therapy given over 3 to 4 weeks. A 1:1 matched-cohort analysis with conventional radiation therapy was performed to assess response and survival. METHODS AND MATERIALS: Twenty-seven children, aged 3 to 14, were treated according to 1 of 2 hypofractionation regimens over 3 to 4 weeks (39/3 Gy, n=16 or 44.8/2.8 Gy, n=11). All patients had symptoms for /=2 signs of the neurologic triad (cranial nerve deficit, ataxia, long tract signs), and characteristic features of DIPG on magnetic resonance imaging. Twenty-seven patients fulfilling the same diagnostic criteria and receiving at least 50/1.8 to 2.0 Gy were eligible for the matched-cohort analysis. RESULTS: With hypofractionation radiation therapy, the overall survival at 6, 9, and 12 months was 74%, 44%, and 22%, respectively. Progression-free survival at 3, 6, and 9 months was 77%, 43%, and 12%, respectively. Temporary discontinuation of steroids was observed in 21 of 27 (78%) patients. No significant difference in median overall survival (9.0 vs 9.4 months; P=.84) and time to progression (5.0 vs 7.6 months; P=.24) was observed between hypofractionation vs conventional radiation therapy, respectively. CONCLUSIONS: For patients with newly diagnosed DIPG, a hypofractionation regimen, given over 3 to 4 weeks, offers equal overall survival with less treatment burden compared with a conventional regimen of 6 weeks.

Item does not contain fulltext Epidermal growth factor receptor (EGFR) inhibition using cetuximab improves the efficacy of radiotherapy in only a subgroup of head and neck squamous cell carcinoma (HNSCC) patients. Therefore, to improve patient selection a better understanding of tumor characteristics that affect treatment is necessary. Here, we investigated the effect of cetuximab on repair of radiation-induced DNA damage in a HNSCC xenograft model, which shows a synergistic effect to cetuximab and radiotherapy (SCCNij185) and a HNSCC model, which shows no additive effect of cetuximab to radiotherapy (SCCNij153). In both tumor models, clear increases were seen in the number of 53BP1 and Rad51 foci after irradiation. 53BP1 foci were present at comparable levels in hypoxic and normoxic tumor areas of the tumor xenografts, while the number of Rad51 foci was significantly higher in normoxic areas compared to hypoxic areas (P < 0.05). In both SCCNij185 and SCCNij153 xenografts an increased number of 53BP1 foci was observed in tumors treated with cetuximab and radiotherapy compared to radiotherapy alone. In SCCNij185 this increase was statistically significant in normoxic tumor areas (P = 0.04) and in SCCNij153 in both hypoxic and normoxic areas (P = 0.007 and P = 0.02, respectively). The number of Rad51 foci was not significantly different when cetuximab was added to radiotherapy compared to radiotherapy alone. Levels of pEGFR and pERK1/2 were decreased when cetuximab was added to radiotherapy in SCCNij185, but not in SCCNij153. Apoptosis was also only increased in SCCNij185 tumors at 4 days after cetuximab and radiotherapy treatment (P < 0.01). In conclusion, cetuximab inhibited DNA repair in both HNSCC models, but this effect was not predictive for the radiosensitizing effect of cetuximab in vivo. This lack of correlation may be related to differential effects of cetuximab and radiotherapy on ERK1/2 signaling and a decreased induction of apoptosis by cetuximab and radiotherapy in the resistant model.

Contains fulltext : 118179.pdf (Publisher’s version ) (Open Access) BACKGROUND: Cisplatin-based chemotherapy (etoposide 100mg/m(2) days 1-5, methotrexate 300mg/m(2) day 1, cyclophosphamide 600mg/m(2) day 1, actinomycin D 0.6mg/m(2) day 2 and cisplatin 60mg/m(2) day 4, EMACP) was compared to EMA/CO (etoposide 100mg/m(2) days 1-2, methotrexate 300mg/m(2) day 1 and actinomycin D 0.5mg i.v. bolus day 1 and 0.5mg/m(2) day 2, alternating with cyclophosphamide 600mg/m(2) day 8 and vincristine 1mg/m(2) day 8) for the treatment of high-risk gestational trophoblastic neoplasia (GTN). PATIENTS AND METHODS: In the Netherlands, 83 patients were treated with EMACP and 103 patients with EMA/CO. Outcome measures were remission rate, median number of courses to achieve normal human chorionic gonadotrophin (hCG) concentrations, toxicity, recurrent disease rate and disease specific survival. RESULTS: Remission rates were similar (EMACP 91.6%, EMA/CO 85.4%). The median number of courses of EMA/CO to reach hCG normalisation for single-agent resistant disease and primary high-risk disease was three and five courses, respectively, compared to 1.5 (p=0.001) and three (p

Item does not contain fulltext

Contains fulltext : 118296.pdf (Publisher’s version ) (Open Access) Radboud Universiteit Nijmegen, 03 april 2013 Promotor : Sweep, C.G.J. Co-promotores : Span, P.N., Bussink, J.

Item does not contain fulltext BACKGROUND: Adrenal vein sampling (AVS) is the preferred test for subtyping primary aldosteronism. However, the procedure is technically demanding and costly. In AVS it is common practice to take duplicate blood samples at each location. In this paper we explore whether a single sample procedure leads to a different conclusion concerning the location of adrenal aldosterone secretion than a duplicate sample procedure. METHODS: AVS procedures with duplicate measurements performed in our university medical center between 2005 and 2010 were evaluated retrospectively. We compared the conclusions regarding selectivity and lateralization based on the first sample taken (A) to the conclusions based on the average of duplicate samples (AB). We also calculated the number needed to be sampled in duplicate to prevent one misclassification. RESULTS: Ninety-six AVS procedures of 82 patients were included. The concordance in AVS conclusions between samples A and AB was 98-100%, depending on the criteria used for selectivity and lateralization. With permissive and strict criteria the number needed to be sampled in duplicate were infinite and 48, respectively. CONCLUSIONS: The incremental benefit of duplicate sampling compared to single sampling is low. Therefore, in the case of technical difficulties during AVS, conclusions can also be reliably drawn from a single blood sample.

Contains fulltext : 101020.pdf (Publisher’s version ) (Open Access) Radboud Universiteit Nijmegen, 10 januari 2013 Promotores : Sweep, C.G.J., Witte, T.J.M. de Co-promotores : Dolstra, H., Voort, R. van der

Contains fulltext : 106929.pdf (Publisher’s version ) (Open Access) Radboud Universiteit Nijmegen, 22 maart 2013 Promotores : Sweep, C.G.J., Witte, T.J.M. de Co-promotores : Dolstra, H., Voort, R. van der 227 p.

Contains fulltext : 118851.pdf (Publisher’s version ) (Open Access) Radboud Universiteit Nijmegen, 15 januari 2013 Promotores : Sweep, C.G.J., Witte, T.J.M. de Co-promotores : Dolstra, H., Schaap, N.P.M.

Contains fulltext : 141743.pdf (Publisher’s version ) (Closed access) OBJECTIVE: Women with a history of vascular complicated pregnancy are at risk for developing remote cardiovascular disease. It is associated with underlying cardiovascular risk factors both jeopardizing trophoblast and vascular function. Subclinical hypothyroidism may relate to both conditions. METHODS: In 372 women with a history of vascular complicated pregnancy, we assessed thyroid function. RESULTS: Subclinical hypothyroidism was diagnosed in 73/372 women (19.6%). It occurred more often when pregnancy ended before 32 weeks of gestation (p = 0.008). CONCLUSION: In this cohort, subclinical hypothyroidism is more common after very preterm delivery. It may contribute to the elevated risk of remote cardiovascular disease.

Contains fulltext : 118299pub.pdf (Publisher’s version ) (Closed access) OBJECTIVES: Before diffusion-weighted imaging (DWI) can be implemented in standard clinical practice for response monitoring, data on reproducibility are needed to assess which differences outside the range of normal variation can be detected in an individual patient. In this study we assessed the reproducibility of the apparent diffusion coefficient (ADC) values in colorectal liver metastases. To provide a biological basis for these values, their relation with histopathology was assessed. METHODS: DWI was performed twice in 1 week in patients scheduled for metastasectomy of colorectal liver metastases. Correlation between ADC values and apoptosis marker p53, anti-apoptotic protein BCL-2, proliferation marker Ki67 and serum vascular endothelial growth factor (VEGF) concentration were assessed. RESULTS: A good reproducibility coefficient of the mean ADC (coefficient of reproducibility 0.20 x 10(-3) mm(2)/s) was observed in colorectal liver metastases (n = 21). The ADC value was related to the proliferation index and BCL-2 expression of the metastases. Furthermore, in metastases recently treated with systemic therapy, the ADC was significantly higher (1.27 x 10(-3) mm(2)/s vs 1.05 x 10(-3) mm(2)/s, P = 0.02). CONCLUSIONS: The good reproducibility, correlation with histopathology and implied sensitivity for systemic treatment-induced anti-tumour effects suggest that DWI might be an excellent tool to monitor response in metastatic colorectal cancer.

Angiogenesis inhibitors have remarkably improved the outcome of patients with several types of cancer. Hypertension is the most reported side effect of angiogenesis inhibitors interfering with vascular endothelial growth factor signaling. In this study, we test the hypothesis that circulating vascular endothelial growth factor at physiological concentrations is essential to preserve normal endothelial control of vasomotor tone. In 7 healthy male volunteers, infusion of bevacizumab (monoclonal vascular endothelial growth factor antibody) into the brachial artery for 15 minutes (144 μg/dL forearm volume per minute) did not affect forearm vasodilator tone as measured with venous occlusion strain gauge plethysmography. In a separate group of 12 male volunteers, a similar bevacizumab infusion reduced the vasodilator response to 2 dosages of acetylcholine from (mean±SE) 440±157% and 926±252% to 169±40% and 612±154% ( P

Thyroid hormone is essential for normal metabolism and development, and overt abnormalities in thyroid function lead to common endocrine disorders affecting approximately 10% of individuals over their life span. In addition, even mild alterations in thyroid function are associated with weight changes, atrial fibrillation, osteoporosis, and psychiatric disorders. To identify novel variants underlying thyroid function, we performed a large meta-analysis of genome-wide association studies for serum levels of the highly heritable thyroid function markers TSH and FT4, in up to 26,420 and 17,520 euthyroid subjects, respectively. Here we report 26 independent associations, including several novel loci for TSH (PDE10A, VEGFA, IGFBP5, NFIA, SOX9, PRDM11, FGF7, INSR, ABO, MIR1179, NRG1, MBIP, ITPK1, SASH1, GLIS3) and FT4 (LHX3, FOXE1, AADAT, NETO1/FBXO15, LPCAT2/CAPNS2). Notably, only limited overlap was detected between TSH and FT4 associated signals, in spite of the feedback regulation of their circulating levels by the hypothalamic-pituitary-thyroid axis. Five of the reported loci (PDE8B, PDE10A, MAF/LOC440389, NETO1/FBXO15, and LPCAT2/CAPNS2) show strong gender-specific differences, which offer clues for the known sexual dimorphism in thyroid function and related pathologies. Importantly, the TSH-associated loci contribute not only to variation within the normal range, but also to TSH values outside the reference range, suggesting that they may be involved in thyroid dysfunction. Overall, our findings explain, respectively, 5.64% and 2.30% of total TSH and FT4 trait variance, and they improve the current knowledge of the regulation of hypothalamic-pituitary-thyroid axis function and the consequences of genetic variation for hypo- or hyperthyroidism., Author Summary Levels of thyroid hormones are tightly regulated by TSH produced in the pituitary, and even mild alterations in their concentrations are strong indicators of thyroid pathologies, which are very common worldwide. To identify common genetic variants associated with the highly heritable markers of thyroid function, TSH and FT4, we conducted a meta-analysis of genome-wide association studies in 26,420 and 17,520 individuals, respectively, of European ancestry with normal thyroid function. Our analysis identified 26 independent genetic variants regulating these traits, several of which are new, and confirmed previously detected polymorphisms affecting TSH (within the PDE8B gene and near CAPZB, MAF/LOC440389, and NR3C2) and FT4 (within DIO1) levels. Gender-specific differences in the genetic effects of several variants for TSH and FT4 levels were identified at several loci, which offer clues to understand the known sexual dimorphism in thyroid function and pathology. Of particular clinical interest, we show that TSH-associated loci contribute not only to normal variation, but also to TSH values outside reference range, suggesting that they may be involved in thyroid dysfunction. Overall, our findings add to the developing landscape of the regulation of thyroid homeostasis and the consequences of genetic variation for thyroid related diseases.

Item does not contain fulltext PURPOSE: To validate the association of phosphorylated (p)AKT with lymph node metastasis in an independent, homogeneous cohort of patients with larynx cancer. METHODS AND MATERIALS: Seventy-eight patients with laryngeal cancer were included. Epidermal growth factor receptor, pAKT, vimentin, E-cadherin, hypoxia, and blood vessels were visualized in biopsy material using immunohistochemistry. Positive tumor areas and spatial relationships between markers were assessed by automated image analysis. In 6 laryngeal cancer cell lines, E-cadherin and vimentin messenger RNA was quantified by real-time polymerase chain reaction and by immunohistochemistry before and after treatment with the pAKT inhibitor MK-2206. RESULTS: A significant correlation was found between low pAKT in the primary tumor and positive lymph node status (P=.0005). Tumors with lymph node metastases had an approximately 10-fold lower median pAKT value compared with tumors without lymph node metastases, albeit with large intertumor variations, validating our previous results. After inhibition of pAKT in laryngeal cancer cells with MK-2206, up-regulation of vimentin and a downregulation of E-cadherin occurred, consistent with epithelial-mesenchymal transition. CONCLUSION: Low pAKT expression in larynx tumors is associated with lymph node metastases. Further, inhibition of pAKT in laryngeal cancer induces epithelial-mesenchymal transition, predisposing for an increased metastatic risk.