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Background Measurements of plasma free metanephrines are recommended for diagnosing pheochromocytomas and paragangliomas (PPGL). Metanephrines can be detected in saliva with LC-MS/MS with sufficient analytical sensitivity and precision. Because collecting saliva is noninvasive and less cumbersome than plasma or urine sampling, we assessed the diagnostic accuracy of salivary metanephrines in diagnosing PPGL. Methods This 2-center study included 118 healthy participants (44 men; mean age: 33 years (range: 19--74 years)), 44 patients with PPGL, and 54 patients suspected of PPGL. Metanephrines were quantified in plasma and saliva using LC-MS/MS. Diagnostic accuracy; correlation between plasma and salivary metanephrines; and potential factors influencing salivary metanephrines, including age, sex, and posture during sampling, were assessed. Results Salivary metanephrines were significantly higher in patients with PPGL compared with healthy participants (metanephrine (MN): 0.19 vs 0.09 nmol/L, P Conclusions Salivary metanephrines are a promising tool in the biochemical diagnosis of PPGL. Salivary metanephrines correlate with plasma free metanephrines and are increased in patients with PPGL. At this time, however, salivary metanephrines cannot replace measurement of plasma free metanephrines.

Objective Assessment of treatment outcome in current de-escalation for differentiated thyroid cancer (DTC) according to the 2015 Dutch thyroid cancer guidelines (NL-15) and American Thyroid Association guidelines (ATA-15). Design Retrospectively, the recommendations of the NL-15 and ATA-15 guidelines were evaluated to estimate potentially adequate, under- and overtreatment of DTC in patients treated in the University Medical Center Groningen between 2007 and 2017. Patients A total of 240 patients with a cT1-T3aN0-1aM0 DTC fulfilled the inclusion criteria. Measurements After actual treatment was given, patients were again categorized according to both guidelines into low, intermediate, or high-risk based on tumour status. Next, they were categorized into a congruent low-risk (n = 60), congruent high-risk (n = 73), or incongruent risk group (n = 107). Follow-up data were used to estimate the proportion of potentially adequate, under-, and overtreatment according to both guidelines. Results Comparing treatment recommended by NL-15 and ATA-15 showed significantly more over- and adequate treatment when following NL-15 recommendations, and more undertreatment following ATA-15 (all: p < .001). Subanalysis of the congruent low-risk group showed overtreatment in 64% when following NL-15 guidelines (p < .001). No treatment differences were found in the congruent high-risk group. Undertreatment was most often seen in the incongruent risk group when following ATA-15 (p < .001). Conclusions Low-risk patients were treated too aggressively when following NL-15 recommendations, where the less aggressive ATA-15 approach seemed more adequate. Treatment of intermediate risk DTC patients varies greatly, with a relative higher rate of undertreatment according to the recommendations of the ATA-15, advocating further refining of the risk classification in this patient group.

Background: Primary aldosteronism (PA) may confer increased cardiovascular risk beyond effects on systemic blood pressure, but contributing mechanisms remain incompletely understood. We compared plasma (apo)lipoproteins and lipoprotein particle characteristics, GlycA, a pro-inflammatory glycoprotein biomarker of enhanced chronic inflammation, and plasma total branched-chain amino acids (BCAA), measured using nuclear magnetic resonance (NMR) spectroscopy, between patients with PA, control subjects without hypertension, subjects with untreated hypertension and subjects with treated hypertension. Methods: Twenty PA patients were individually matched with 2819 control subjects without hypertension, 501 subjects with untreated hypertension and 878 subjects with treated hypertension participating in the PREVEND (Prevention of Renal and Vascular End-Stage Disease) cohort study with respect to age, sex, body mass index, smoking and statin use. The Vantera (R) Clinical Analyzer was used to determine NMR-based laboratory parameters. Results: Total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), apolipoprotein (apo) B, apolipoprotein A-I (apoA-I), LDL particle and HDL particle concentrations were all decreased in PA subjects vs control subjects and subjects with untreated hypertension (P Conclusions: Primary aldosteronism is associated with lower concentrations of LDL and HDL particles and to some extent also with lower TG and TRL particle concentrations. PA is also characterized by increased GlycA levels, indicating enhanced low-grade chronic inflammation. Low HDL particle concentrations and increased GlycA could contribute to accelerated cardiovascular disease development in PA.

Objective To assess the effect of somatostatin analogs (SSAs) on mortality in relation to disease control of acromegaly after pituitary surgery. Design A retrospective study in two large tertiary referral centers in The Netherlands. Methods Overall, 319 patients with acromegaly in whom pituitary surgery was performed as primary therapy between January 1980 and July 2017 were included. Postoperative treatment with SSA was prescribed to 174 (55%) patients because of persistent or recurrent disease. Disease control at last visit was assessed by IGF1 standard deviation score (SDS). Adequate disease control was defined as IGF1 SDS ≤2. Univariate determinants of mortality and standardized mortality ratios (SMRs) were calculated for groups with and without SSA at any moment postoperatively and at last visit. Results In total, 27 deaths were observed. In univariate analysis, determinants of mortality were inadequate disease control (relative risk (RR): 3.41, P = 0.005), surgery by craniotomy (RR: 3.53, P = 0.013) and glucocorticoid substitution (RR: 2.11, P = 0.047). There was a strong trend toward increased mortality for patients who used SSA (RR: 2.01, P = 0.067) and/or dopamine agonists (RR: 2.54, P = 0.052) at last visit. The SMR of patients with adequate disease control who used SSA at any moment postoperatively (1.07, P = 0.785) and at last visit (1.19; P = 0.600) was not increased. Insufficiently controlled patients had a significantly raised SMR (3.92, P = 0.006). Conclusions Postoperative use of SSA is not associated with increased mortality in patients with acromegaly who attain adequate disease control. In contrast, inadequate disease control, primary surgery by craniotomy and glucocorticoid substitution are associated with increased mortality.

Background Thyroid nodules are very common in general medical practice, but rarely turn out to be a medullary thyroid carcinoma (MTC). Calcitonin is a sensitive tumour marker for the detection of MTC (basal calcitonin). Sometimes a stimulation test is used to improve specificity (stimulated calcitonin). Although the European Thyroid Association's guideline advocates calcitonin determination in people with thyroid nodules, the role of routine calcitonin testing in individuals with thyroid nodules is still questionable. Objectives The objective of this review was to determine the diagnostic accuracy of basal and/or stimulated calcitonin as a triage or add-on test for detection of MTC in people with thyroid nodules. Search methods We searched CENTRAL, MEDLINE, Embase and Web of Science from inception to June 2018. Selection criteria We included all retrospective and prospective cohort studies in which all participants with thyroid nodules had undergone determination of basal calcitonin levels (and stimulated calcitonin, if performed). Data collection and analysis Two review authors independently scanned all retrieved records. We extracted data using a standard data extraction form. We assessed risk of bias and applicability using the QUADAS-2 tool. Using the hierarchical summary receiver operating characteristic (HSROC) model, we estimated summary curves across different thresholds and also obtained summary estimates of sensitivity and specificity at a common threshold when possible. Main results In 16 studies, we identified 72,368 participants with nodular thyroid disease in whom routinely calcitonin testing was performed. All included studies performed the calcitonin test as a triage test. Median prevalence of MTC was 0.32%. Sensitivity in these studies ranged between 83% and 100% and specificity ranged between 94% and 100%. An important limitation in 15 of the 16 studies (94%) was the absence of adequate reference standards and follow-up in calcitonin-negative participants. This resulted in a high risk of bias with regard to flow and timing in the methodological quality assessment. At the median specificity of 96.6% from the included studies, the estimated sensitivity (95% confidence interval (CI)) from the summary curve was 99.7% ( 68.8% to 100%). For the median prevalence of MTC of 0.23%, the positive predictive value (PPV) for basal calcitonin testing at a threshold of 10 pg/mL was 7.7% (4.9% to 12.1%). Summary estimates of sensitivity and specificity for the threshold of 10 pg/mL of basal calcitonin testing was 100% (95% CI 99.7 to 100) and 97.2% (95% CI 95.9 to 98.6), respectively. For combined basal and stimulated calcitonin testing, sensitivity ranged between 82% and 100% with specificity between 99% and 100%. The median specificity was 99.8% with an estimated sensitivity of 98.8% (95% CI 65.8 to 100) . Authors' conclusions Both basal and combined basal and stimulated calcitonin testing have a high sensitivity and specificity. However, this may be an overestimation due to high risk of bias in the use and choice of reference standard The value of routine testing in patients with thyroid nodules remains questionable, due to the low prevalence, which results in a low PPV of basal calcitonin testing. Whether routine calcitonin testing improves prognosis in MTC patients remains unclear.

Purpose Evidence accumulates that an active lifestyle positively influences cancer treatment outcome. A “smartphone application” (app) such as “RunKeeper,” to self-monitor physical activity (PA) might be helpful. This study aimed to examine whether using RunKeeper to increase self-reported PA is feasible in cancer patients and to evaluate patients’ opinion about using RunKeeper in a 12-week program. Methods Adult patients (n = 32), diagnosed with cancer, were randomized between usual care (n = 16) or a 12-week intervention with instructions to self-monitor PA with RunKeeper (n = 16). Changes in PA were determined with the Physical Activity Scale for the Elderly (PASE) at baseline (T0), 6 weeks (T1), and 12 weeks (T2). Usability and patients’ experiences were tested at T2 with the System Usability Scale (SUS) and a semi-structured interview. Results Patient mean age was 33.6 years. Between T0 and T1, an increase in PA of 51% (medium estimated effect size r = 0.40) was found in PASE sum score in the intervention group compared with usual care. In addition, total minutes of PA increased with 46% (r = 0.37). These effects decreased over time (T2). Sedentary time decreased with 19% between T0 and T1 and 27% between T0 and T2. Usability was rated “good” and most patients found RunKeeper use helpful to improve PA. Conclusions Self-monitoring PA with RunKeeper was safe and feasible in cancer patients. The RunKeeper use resulted in an increase in PA after 6 weeks. RunKeeper usability was rated good and can be used to study PA in cancer patients. Trial registration NCT02391454 Electronic supplementary material The online version of this article (10.1007/s00520-018-4263-5) contains supplementary material, which is available to authorized users.

Objective Exercise interventions benefit cancer patients. However, only low numbers of patients adhere to these interventions. This review aimed to identify predictors of exercise intervention adherence in patients with cancer, during and after multimodality cancer treatment. Methods A literature search was performed using electronic databases (PubMed, Embase, and Cochrane) to identify relevant papers published before February 1, 2017. Papers reporting randomized controlled trials, conducted in adult cancer patients who participated in an exercise intervention during and/or after multimodality cancer treatment, and providing outcome of factors predicting exercise adherence were included. Papers were assessed for methodological quality by using the Physiotherapy Evidence Database scale. Results The search identified 720 potentially relevant papers, of which 15 fulfilled the eligibility criteria. In these 15 studies, 2279 patients were included and 1383 of these patients were randomized to an exercise intervention. During cancer treatment, the factors predicting exercise adherence were as follows: location of the rehabilitation center, extensive exercise history, high motivation for exercise, and fewer exercise limitations. After cancer treatment, factors that predicted adherence were as follows: less extensive surgery, low alcohol consumption, high previous exercise adherence, family support, feedback by trainers, and knowledge and skills of exercise. Methodological quality of the included papers was rated “high”. Conclusions The most prominent predictors of adherence to exercise interventions were location of the rehabilitation center, extensive exercise history, high motivation for exercise, and fewer exercise limitations. To increase the number of cancer patients who will benefit, these results should be considered into the development and implementation of future exercise interventions.

Objective Amiodarone is used for the maintenance of sinus rhythm in patients with arrhythmias, but thyroid dysfunction (amiodarone-induced thyrotoxicosis (AIT) or amiodarone-induced hypothyroidism (AIH)) is a common adverse effect. As the onset of AIT and AIH may be unpredictable, the value of long-term regular monitoring of amiodarone treated patients for thyroid dysfunction is still uncertain. Design We retrospectively documented the frequency at which overt thyroid dysfunction was preceded by subclinical thyroid dysfunction. Methods We included 303 patients treated with amiodarone between 1984 and 2007. AIT was defined as a lowered TSH level with an elevated free thyroxine (FT4) and AIH was defined as an elevated TSH level with a decreased or subnormal FT4. Subclinical AIT was defined as a lowered TSH level with a normal FT4 and subclinical AIH as an elevated TSH level with a normal FT4. Results 200 men and 103 women, aged 62 ± 12.0 years, suffering from atrial (260) or ventricular (43) arrhythmias, were evaluated. During a median follow-up of 2.8 (1.0–25) years, 44 patients developed AIT and 33 AIH. In 42 (55%) patients who developed AIT/AIH, earlier thyroid function tests showed no subclinical AIT or subclinical AIH. In 35 (45%) patients, AIT/AIH was preceded by subclinical AIT or subclinical AIH (16/44 for AIT and 19/33 for AIH). Conclusions In a considerable proportion of patients who developed AIT/AIH, earlier thyroid function tests showed no subclinical AIT/AIH. Less than half of the patients with a subclinical event subsequently developed overt AIT/AIH. This study provides data to reconsider the yield of regular testing of thyroid function to predict overt thyroid dysfunction in amiodarone treated patients.

BACKGROUND: Cholesterol, required for adrenal steroid hormone synthesis, is at least in part derived from circulating lipoproteins. The contribution of high-density lipoproteins (HDL) and low-density lipoproteins (LDL) to adrenal steroidogenesis in humans is unclear.OBJECTIVE: The aim of the study was to determine the extent to which HDL and LDL are taken up by the adrenal glands using samples obtained during adrenal venous sampling (AVS).METHODS: AVS was successfully performed in 23 patients with primary aldosteronism. Samples were drawn from both adrenal veins and inferior vena cava (IVC). HDL cholesterol (HDL-C) and lipoprotein particle profiles were determined by nuclear magnetic resonance spectroscopy. Apolipoprotein (apo) A-I and apoB were assayed by immunoturbidimetry.RESULTS: Plasma HDL-C and HDL and LDL particle concentrations (HDL-P and LDL-P) were not lower in samples obtained from the adrenal veins compared with the IVC (HDL-C, P =.59; HDL-P, P = .06; LDL-P, P =.93). ApoB was lower in adrenal venous plasma than in IVC (P = .026; P CONCLUSION: These in vivo observations suggest that circulating LDL may contribute to adrenal steroidogenesis in humans as inferred from adrenal venous-IVC apoB concentration differences. AVS is a feasible method to investigate the relationships between lipoproteins and steroidogenesis. (C) 2017 National Lipid Association. All rights reserved.

Von Hippel-Lindau (VHL) disease is an autosomal dominant rare tumor syndrome characterized by high penetrance. VHL mutation carriers develop numerous manifestations in multiple organs during life. The natural course of development of new and growth of existing VHL-related manifestations is still unclear. In this study we aimed to gain insight into the development of subsequent manifestations in VHL disease. We retrospectively scored each new VHL-related manifestation as detected by standard follow-up (retina, central nervous system, kidneys and pancreas, excluding adrenal and endolymfatic sac manifestations) in 75 VHL mutation carriers. The Kaplan–Meier method was used to plot the cumulative proportions of all consecutive manifestations in each organ against age. The cumulative average number of manifestations in all organs during life was calculated by summating these cumulative proportions. Poisson model parameters were used to calculate average time to the detection of consecutive VHL manifestations in each organ. Consecutive VHL-related kidney and retina manifestations during life occur linearly according to Poisson distribution model. The total number of VHL manifestations rises linearly, with an average of seven VHL-related lesions at age 60 years. The incidence of consecutive VHL-related manifestations is constant during life in VHL mutation carriers. Our data is consistent with the notion that somatic inactivation of the remaining allele (Knudson’s “two-hit” hypothesis) is the determining factor in developing new VHL-related manifestations. Electronic supplementary material The online version of this article (10.1007/s10689-019-00131-x) contains supplementary material, which is available to authorized users.

Background: Thyroglobulin (Tg) is an established tumor marker in differentiated thyroid carcinoma (DTC). However, Tg assays can be subject to interference by autoantibodies against Tg (TgAbs). No clinical consensus exists on the cutoff value of TgAb positivity and its relationship to Tg assay interference. The aims of this study were to investigate the most applicable cutoff value for TgAb positivity in clinical practice and to evaluate whether tumor characteristics differ between TgAb+ and TgAb- patients during ablation therapy using the manufacturer's cutoff (MCO) and institutional cutoff (ICO). Methods: This single-center cohort study included 230 DTC patients diagnosed between January 2006 and December 2014. Serum Tg and TgAbs were measured with the Tg-IRMA (Thermo Fisher Scientific) and ARCHITECT Anti-Tg (Abbott Laboratories) assays. Patients were divided into TgAb- and TgAb+ based on the limit of detection (LoD; >= 0.07 IU/mL), functional sensitivity (FS; >= 0.31 IU/mL), MCO (>= 4.11 IU/mL), and ICO (>= 10 IU/mL). Results: All patients were TgAb+ based on the LoD; one patient was negative on FS. Fifty-five (23.9%) and 34 (14.8%) patients had TgAbs above the MCO and ICO, respectively. Histology, presence of multifocality, tumor-node-metastasis, and American Thyroid Assocation risk stratification did not differ between TgAb- and TgAb+ patients using MCO and ICO during ablation. Conclusions: This study supports the use of a higher cutoff value than that of the FS for TgAb positivity in clinical settings. The LoD and FS are too sensitive to discriminate TgAb positivity and negativity in DTC patients during ablation therapy. The presence of TgAbs during ablation is not related to tumor characteristics and risk profile. This implies that TgAb positivity should not be considered a separate risk factor.

Background Metastatic melanoma patients can have durable responses to systemic therapy and even long-term survival. However, a large subgroup of patients does not benefit. Tumour metabolic alterations may well be involved in the efficacy of both targeted and immunotherapy. Knowledge on in vivo tumour glucose uptake and its heterogeneity in metastatic melanoma may aid in upfront patient selection for novel (concomitant) metabolically targeted therapies. The aim of this retrospective study was to provide insight into quantitative 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) parameters and corresponding intra- and inter-patient heterogeneity in tumour 18F-FDG uptake among metastatic melanoma patients. Consecutive, newly diagnosed stage IV melanoma patients with a baseline 18F-FDG PET/CT scan performed between May 2014 and December 2015 and scheduled to start first-line systemic treatment were included. Volume of interests (VOIs) of all visible tumour lesions were delineated using a gradient-based contour method, and standardized uptake values (SUVs), metabolically active tumour volume (MATV) and total lesion glycolysis (TLG) were determined on a per-lesion and per-patient basis. Differences in quantitative PET parameters were explored between patient categories stratified by BRAFV600 and RAS mutational status, baseline serum lactate dehydrogenase (LDH) levels and tumour programmed death-ligand 1 (PD-L1) expression. Results In 64 patients, 1143 lesions ≥ 1 ml were delineated. Median number of lesions ≥ 1 ml was 6 (range 0–168), median maximum SUVpeak 9.5 (range 0–58), median total MATV 29 ml (range 0–2212) and median total TLG 209 (range 0–16,740). Per-patient analysis revealed considerable intra- and inter-patient heterogeneity. Maximum SUVs, MATV, number of lesions and TLG per patient did not differ when stratifying between BRAFV600 or RAS mutational status or PD-L1 expression status, but were higher in the patient group with elevated LDH levels (> 250 U/l) compared to the group with normal LDH levels (P

OBJECTIVE: Thyroglobulin (Tg) is an excellent tumour marker, as detectable or increasing Tg levels are highly indicative of persistent or recurrent differentiated thyroid carcinoma (DTC). The clinical value of a highly sensitive (hs)-Tg assay in patients with DTC has not yet been established. The aim of this study was to investigate the additional value of unstimulated hs-Tg measurements (Tg-on) compared to stimulated IRMA-Tg measurements (Tg-off) in the follow-up of patients with DTC. DESIGN, PATIENTS, MEASUREMENTS: We retrospectively studied patients treated for DTC between 2006 and 2013, and compared hs-Tg and IRMA-Tg measurements. The study group consisted of 99 DTC patients in remission; Tg-on was measured 3 months after remnant ablation and Tg-off 6 months after ablation. RESULTS: In the study group, 44 patients showed a hs-Tg-on

Patients with von Hippel-Lindau disease (VHL) are at risk to develop multiple tumors. The growth of lesions is unpredictable, and regular surveillance is critical for early treatment to control local damage. Vascular endothelial growth factor A (VEGF-A) produced locally is supposed to play an important role in development of disease manifestations and is a target for antiangiogenic therapy with the monoclonal antibody bevacizumab. We aimed to assess whether VHL manifestations can be visualized with Zr-89-bevacizumab PET and to explore whether Zr-89-bevacizumab PET can differentiate progressive from nonprogressive lesions. Methods: VHL patients with at least 1 measurable hemangioblastoma were eligible. Zr-89-bevacizumab (37 MBq) was administered intravenously 4 d before the scan. Maximum standardized uptake values were calculated. PET scans were fused with routine MRI of the central nervous system and abdominal MRI or CT. Progressive lesions were defined as new lesions, lesions that became symptomatic, and lesions >= 10 mm that increased >= 10% and >= 4 mm on repeated anatomic imaging within 12 mo. Results: Twenty-two patients were enrolled. At baseline, anatomic imaging showed 311 lesions. Zr-89-bevacizumab PET visualized 59 VHL manifestations, 0-17 per patient. The median of maximum standardized uptake values was 8.5 (range, 1.3-35.8). The detection rate for lesions >= 10 mm was 30.8%. Seven additional hotspots without substrate on baseline anatomic imaging were found; 2 were also detected with anatomic imaging during follow-up. Nine of 25 progressive lesions were visible on PET and 27 of 175 nonprogressive lesions, corresponding to a positive predictive value of 25% and a negative predictive value of 90%. SUVmax was similar in progressive and nonprogressive lesions (median, 4.8; range, 0.9-8.9 vs. median, 6.7; range, 1.3-35.8, P = 0.14). Conclusion: VHL manifestations can be visualized with Zr-89-bevacizumab PET with a striking heterogeneity in tracer accumulation. Zr-89-bevacizumab uptake does not predict progression within 12 mo. In one third of the lesions, the drug target VEGF is available and accessible. Zr-89-bevacizumab PET might offer a tool to select VHL patients for anti-VEGF therapy.

Background: There is a major lack of randomized controlled trials (RCTs) evaluating the effects of hydrocortisone (HC) substitution therapy in patients with secondary adrenal insufficiency. Therefore, we evaluated the effects of two different replacement doses of HC on health-related quality of life (HRQoL) in a RCT. Methods: This RCT with a double-blind cross-over design was performed at the University Medical Center Groningen. Forty-seven patients (29 men, age 51 ± 14 years, range 19-73 years) with secondary adrenal insufficiency participated. Patients received both a lower and a higher dose of HC (0.2-0.3 and 0.4-0.6 mg/kg body weight/day) for 10 weeks in random order. HRQoL was assessed with a daily mood and symptom checklist (Patient Health Questionnaire-15 [PHQ-15], Generalized Anxiety Disorder-7 [GAD-7], Patient Health Questionnaire-9 [PHQ-9]) and with questionnaires assessing general well-being (RAND 36-Item Health Survey [RAND-36]), mood (Hospital Anxiety and Depression Scale [HADS]) and fatigue (Multidimensional Fatigue Inventory-20 [MFI-20]). ClinicalTrials.gov identifier: NCT01546922. Results: Patients receiving the higher dose of HC reported significantly fewer symptoms of depression (p = 0.016 and p = 0.045 for HADS and PHQ-9, respectively), less general and mental fatigue (p = 0.004 and p = 0.003, respectively, both MFI-20), increased motivation (p = 0.021, MFI-20), better physical functioning (p = 0.041), better general health (p = 0.013) and more vitality (p = 0.025) (all RAND-36). In addition, while on the higher dose, fewer somatic symptoms (p = 0.022) and less pain (p < 0.001) (both PHQ-15) were experienced. Conclusions: On the higher dose of HC, patients reported a better HRQoL on various domains as compared to the lower dose of HC. The fact that a higher dose of HC may improve patient well-being should be taken into consideration when individualizing the HC substitution dose.

Objective: Elevated circulating levels of pro-inflammatory biomarkers are associated with adverse health effects, but the extent to which enhanced low-grade inflammation influences remaining life expectancy (LE) is uncertain. GlycA is a novel pro-inflammatory marker. We determined effects of GlycA and high sensitivity C-reactive protein (hsCRP) on LE.Methods: GlycA and hsCRP were determined in 5526 subjects. LE was compared in the upper quartile of both GlycA and hsCRP vs. the respective lower three quartiles combined, adjusted for LE of individuals in the Dutch general population of the same birth cohort and sex.Results: Median follow up was 8.5 years [interquartile range 7.9-9.0], during which 348 (6.3%) subjects had deceased. LE at the end of follow up was lower in the highest vs. the lower three quartiles of GlycA (P Conclusions: This population-based cohort study demonstrates that higher plasma levels of GlycA were associated with reduced LE in men and women. With regard to hsCRP this only applied to men.

Objective: The primary objective was to evaluate the short-and long-term toxic effects of radioiodine (I-131) therapy on bone marrow function in differentiated thyroid carcinoma (DTC) patients. The secondary objective was to define characteristics of patients at risk for impaired bone marrow function after I-131 treatment.Patients and Methods: DTC patients treated with I-131 between 1989 and 2013 were included. We excluded patients with morbidities or treatments that could have influenced blood count parameters. Baseline platelets, leukocytes, and hemoglobin levels were compared with blood counts at 3 and 6 months and at 1 and 5 years after treatment. Logistic multivariate regression analyses were performed to determine patient characteristics associated with thrombocytopenia.Results: We included 331 patients. Mean +/- SD age was 47.5 +/- 17.2 years, and 74.0% were female. Posttreatment platelets were significantly decreased at 6 months and 1 year, as compared with baseline. Leukocyte counts were also decreased at 3 and 6 months and at 1 year after treatment. No decreases in hemoglobin were found. Five years after treatment, platelet and leukocyte counts were comparable with baseline. Fourteen patients (4.2%) developed transient posttreatment thrombocytopenia. Risk factors for thrombocytopenia were older age, T4 tumor stage, male gender, and cumulative dose 131I. After a multivariate regression analysis, the cumulative dose 131I remained independently associated with thrombocytopenia.Conclusion: Posttreatment platelets and leukocytes were transiently decreased compared with pretreatment values in a general DTC population. Cumulative I-131 dose was independently associated with thrombocytopenia. Platelets and leukocytes normalized to baseline levels 5 years after treatment, implying that in most patients the clinical effects of bone marrow toxicity are limited.

Background and purpose: To assess and compare brain abnormalities on Magnetic Resonance Imaging (MRI) in non-functioning pituitary macro-adenoma (NFA) patients treated with or without postoperative radiotherapy (RT).Material and methods: In 86 NFA patients, treated between 1987 and 2008 at the University Medical Center Groningen, white-matter lesions (WMLs), cerebral atrophy, brain infarctions and abnormalities of the temporal lobes and hippocampi were assessed on pre- and-post-treatment MRI scans in patients treated with (n = 47) or without RT.Results: The median MRI follow-up time for RT patients was 10 (range 1-22) years and 5 (range 1-21) years in patients treated without RT. In RT patients the cumulative incidence of WMLs was significantly lower compared to patients treated without RT (log-rank test RR 0.49, 95% CI 0.25-0.97, p =.042). The cumulative incidences of cerebral atrophy, brain infarctions, abnormalities of the temporal lobes and hippocampi, and the severity of WMLs and cerebral atrophy ratings were not significantly different between the two treatment groups.Conclusions: Brain abnormalities on MRI are not observed more frequently in NFA patients treated with RT compared to patients treated with surgery-alone. Furthermore, RT was not associated with an increased severity of WMLs and cerebral atrophy ratings in this cohort of NFA patients. (C) 2015 Elsevier Ireland Ltd. All rights reserved.

Metastatic rectal cancer patients could benefit from novel therapeutic approaches. The signaling network formed by chemokines and their receptors can promote metastasis and resistance to current anticancer treatments. This study assessed the expression of chemokine receptor 4 (CXCR4) and its ligand CXCL12 immuhistochemically in stage IV rectal tumors. Paraffin-embedded primary tumor collected before and after local radiotherapy and systemic treatment with bevacizumab, oxaliplatin and capecitabine was analyzed. Receptor and ligand expression was assessed in the cytoplasm and nucleus of tumor, stromal and normal rectal crypt cells. Baseline expression of CXCR4 and CXCL12 was correlated with patients' pathologic response to treatment. At diagnosis (n=46), 89% of the rectal tumors expressed cytoplasmic CXCR4 and 81% CXCL12. Nuclear CXCR4 expression in tumor cells was present in 30% and nuclear CXCL12 expression in 35% of the tumors. After radiochemotherapy and administration of bevacizumab, nuclear CXCL12 expression was observed in 79% of residual tumors, as compared to 31% of the paired tumor samples expressing nuclear CXCL12 before treatment (P=0.001). There were no differences in CXCR4 or CXCL12 expression at baseline between the patients who had (n=9) and did not have (n=30) a pathologic complete response. Our results show that CXCR4 and CXCL12 are extensively expressed in primary rectal tumors of patients presenting with metastatic disease, while radiochemotherapy and bevacizumab further upregulate CXCL12 expression. These data indicate the importance of the CXCR4/CXCL12 axis in rectal tumor biology, and may suggest the CXCR4/CXCL12 receptor-ligand pair as a potential therapeutic target in metastatic rectal cancer.

Germline mutations of the gene encoding succinate dehydrogenase subunit B (SDHB) predispose to head-and-neck-paraganglioma (HNPGL), sympathetic PGL, pheochromocytoma and renal cell carcinoma for which regular surveillance is required. SDHB-associated tumors harbor germline and somatic mutations, consistent with Knudson's two-hit hypothesis. To assess the penetrance and optimal surveillance for different manifestations of SDHB mutation carriers. This study included all SDHB mutation carriers who were followed at the Department of Endocrinology at the University Medical Center of Groningen. Kaplan-Meier curves were used to assess the penetrance. Poisson process was used to assess the optimal age to start surveillance and intervals. Ninety-one SDHB-mutation carriers (38 men and 53 women) were included. Twenty-seven mutation carriers (30 %) had manifestations, with an overall penetrance 35 % at the age of 60 years. We calculated that optimal surveillance for HNPGL could start from an age of 27 years with an interval of 3.2 years. This study underscores the relatively low penetrance of disease in SDHB mutation carriers. Use of the Poisson approach provides a more accurate estimation of the age to initiate surveillance and length of intervals for HNPGL. These results may give rise to reconsider the current guidelines regarding the screening of these mutation carriers.

Everolimus increases progression-free survival in patients with advanced neuroendocrine tumors (NETs). Currently, no biomarkers are available for early selection of patients who will benefit from everolimus. Everolimus can reduce vascular endothelial growth factor A (VEGF-A) production by tumor cells. Therefore, we aimed to investigate the effect of everolimus on tumor uptake of the radioactive-labeled VEGF-A antibody bevacizumab with PET in NET patients. Methods: Patients with advanced progressive well-differentiated NETs underwent Zr-89-bevacizumab PET scans before and at 2 and 12 wk during everolimus treatment. Zr-89-bevacizumab uptake was quantified by the maximum standardized uptake value (SUVmax). Tumor response and the percentage change in the sum of target lesion diameters were determined according to Response Evaluation Criteria in Solid Tumors 1.1 on CT (3 monthly). Results: In 4 of the 14 patients entered, no tumor lesions were visualized with Zr-89-bevacizumab PET. In the remaining patients, 19% of tumor lesions 1 cm or greater known by CT were visualized. Tumor SUVmax decreased during everolimus treatment, with a median of -7% at 2 wk (P = 0.09) and a median of -35% at 12 wk (P

Background: Surgery and high-dose radioactive iodine (I-131) treatment are the cornerstones in the treatment of differentiated thyroid cancer. Patients without I-131 uptake on the post-therapeutic whole body scan (WBS), but with detectable thyroglobulin (Tg) during thyroxine withdrawal (Tg-off), are evaluated with an 18-fluorodeoxyglucose positron emission tomography (F-18-FDG-PET) for tumor localization within three months. The yield of F-18-FDG-PET imaging and clinical usefulness of a Tg-off cutoff value to predict a positive scan were assessed.Methods: From 2002 to 2011, 52 patients with a negative WBS and concurrent detectable Tg-off were evaluated. Thirty-five PET scans were performed during initial treatment, 17 after recurrent disease. Thirty-two patients were on substitution therapy, 17 were evaluated with endogenous thyrotropin elevation, and 3 after recombinant human thyrotropin stimulation. To determine the Tg-off cutoff value, a receiver operating characteristic curve was used.Results: Nine (17%) F-18-FDG-PET scans were true positive, 3 (6%) false positive, 36 (69%) true negative, and 4 (8%) false negative (sensitivity 69%, specificity 92%). In 13%, a true-positive scan resulted in a change in the clinical management. The area under the receiver operating characteristic curve is 0.82 [CI 0.64-0.99] (p 2.00 ng/mL.Conclusions: An F-18-FDG-PET within three months after a negative WBS with detectable Tg-off showed additional tumor localization in 17% of the patients, leading to a change in clinical management in 13%. A clinically useful Tg-off cutoff value was not found, but 90% of positive F-18-FDG-PET scans occurred in patients with a Tg-off >2.00 ng/mL.

Context:Follow-up after adrenalectomy for pheochromocytoma is recommended because of a recurrence risk. During follow-up, plasma and/or urinary metanephrine (MN) and normetanephrine (NMN) are interpreted using reference ranges obtained in healthy subjects.Objective:Because adrenalectomy may decrease epinephrine production, we compared MN and NMN concentrations in patients after adrenalectomy to concentrations in a healthy reference population.Design:A single-center cohort study was performed in pheochromocytoma patients after adrenalectomy between 1980 and 2011.Subjects:Seventy patients after unilateral and 24 after bilateral adrenalectomy were included.Main Outcome Measures:Plasma-free and urinary-deconjugated MN and NMN determined at 3 to 6 months and annually until 5 years after adrenalectomy were compared with concentrations in a reference population. Data are presented in median (interquartile range).Results:Urinary and plasma MN concentrations 3 to 6 months after unilateral adrenalectomy were lower compared with the reference population (39 [31–53] μmol/mol creatinine and 0.14 [0.09–0.18] nmol/L vs 61 [49–74] μmol/mol creatinine and 0.18 [0.13–0.23] nmol/L, respectively, both P < .05). Urinary MN after bilateral adrenalectomy was reduced even further (7 [1–22] μmol/mol creatinine; P < .05). Urinary and plasma NMN were higher after unilateral adrenalectomy (151 [117–189] μmol/mol creatinine and 0.78 [0.59–1.00] nmol/L vs 114 [98–176] μmol/mol creatinine and 0.53 [0.41–0.70] nmol/L; both P < .05). Urinary NMN after bilateral adrenalectomy was higher (177 [106–238] μmol/mol creatinine; P < .05). Changes in urinary and plasma MNs persisted during follow-up.Conclusion:Concentrations of MN are decreased, whereas NMN concentrations are increased after unilateral and bilateral adrenalectomy. Adjusted reference values for MN and NMN are needed in the postsurgical follow-up of pheochromocytoma patients.

Background Patients with von Hippel-Lindau (VHL) disease are prone to develop pancreatic neuroendocrine tumors (pNETs). However, the best imaging technique for early detection of pNETs in VHL is currently unknown. In a head-to-head comparison, we evaluated endoscopic ultrasound (EUS) and 11C-5-hydroxytryptophan positron emission tomography (11C-5-HTP PET) compared with conventional screening techniques for early detection of pancreatic solid lesions in VHL patients. Methods We conducted a cross-sectional, prospective study in 22 patients at a tertiary care university medical center. Patients with VHL mutation or with one VHL manifestation and a mutation carrier as first-degree family member, with recent screening by abdominal computed tomography (CT) or magnetic resonance imaging (MRI) and somatostatin receptor scintigraphy (SRS), were eligible. Patients underwent EUS by linear Pentax echoendoscope and Hitachi EUB-525, and 11C-5-HTP PET. Patient-based and lesion-based positivity for pancreatic solid lesions were calculated for all imaging techniques with a composite reference standard. Results In 10 of the 22 patients, 20 pancreatic solid lesions were detected: 17 with EUS (P < 0.05 vs CT/MRI+ SRS), 3 with 11C-5-HTP PET, 3 with SRS, 9 with CT/MRI, and 9 with CT/MRI + SRS. EUS evaluations showed solid lesions with a median size of 9.7 mm (range 2.9–55 mm) and most of them were homogeneous, hypoechoic, isoelastic, and hypervascular. Moreover, EUS detected multiple pancreatic cysts in 18 patients with a median of 4 cysts (range 1–30). Conclusions EUS is superior to CT/MRI + SRS for detecting pancreatic solid lesions in VHL disease.11C-5-HTP PET has no value as a screening method in this setting. EUS performs well in early detection of pNETs, but its role in VHL surveillance is unclear.

Bestraling is veilig bij behandeling voor goedaardige hypofysetumor. Patienten die met bestraling (radiotherapie) zijn behandeld voor een goedaardige tumor in de hypofyse vertoonden geen grote verschillen in late effecten ten opzichte van vergelijkbare patienten die niet bestraald waren. Hiervoor onderzocht Margriet Sattler patienten met een niet-functionerend hypofyse-adenoom, acromegalie of de ziekte van Cushing. Dat deze patienten geen aantoonbare schade oplopen, pleit voor deze behandeling, aldus de promovenda. Zij onderzocht de incidentie van secundaire tumoren, mortaliteit, cerebrovasculaire ziekte en radiologische afwijkingen van de hersenen, en van cognitie en seksueel functioneren als aspect van kwaliteit van leven van patienten die zijn behandeld voor hypofysetumoren. De behandeling voor een hypofysetumor bestaat meestal uit een operatie, eventueel gevolgd door radiotherapie en/of hormoononderdrukkende medicatie. Sattler bestudeerde de late effecten van radiotherapie in een grote groep patienten met een hypofysetumor. Er waren nog weinig vergelijkende studies verricht betreffende de late effecten onder bestraalde en niet bestraalde hypofysepatienten. Volgens de promovenda is het risico op late effecten van de radiotherapie klein met de radiotherapietechnieken die zijn toegepast in de laatste decennia en dit zal naar verwachting nog lager worden met de moderne en meer geavanceerde radiotherapietechnieken. Ze concludeert dat in de meeste patienten met een hypofysetumor die nadat opereren niet meer mogelijk is nog steeds ziekteactiviteit hebben, de voordelen van radiotherapie opwegen tegen het kleine risico op ernstige late effecten. Margriet Sattler studeerde Geneeskunde aan de Rijksuniversiteit Groningen en volgde haar opleiding tot radiotherapeut-oncoloog in het Universitair Medisch Centrum Groningen (UMCG). Zij verrichtte haar promotieonderzoek bij de afdelingen Radiotherapie en Endocrinologie van het UMCG.

AIM: To investigate whether the small bowel transit time (SBTT) influences the diagnostic yield of capsule endoscopy (CE).METHODS: Six hundred and ninety-one consecutive CE procedures collected in a database were analyzed. SBTT and CE findings were recorded. A running mean for the SBTT was calculated and correlated to the diagnostic yield with a Spearman's correlation test. Subgroup analyses were performed for the various indications for the procedure.RESULTS: There was a positive correlation between the diagnostic yield and SBTT (Spearman's rho 0.58, P CONCLUSION: The diagnostic yield in small bowel capsule endoscopy is positively correlated with the small bowel transit time. This is true for all indications except for suspected Crohn's disease. (C) 2012 Baishideng. All rights reserved.

Objective: We studied the reciprocal effect of pregnancy and von Hippel-Lindau (VHL) disease by analyzing the influence of pregnancy on VHL disease-related lesions and VHL disease on pregnancy outcome. Methods: Medical charts and imaging reports from the VHL disease expertise centers in the Netherlands were used to retrospectively assess lesion progression score before and after pregnancy and to obtain data on pregnancy outcome and VHL disease-related lesions. The Friedman test was used for analysis (p

BACKGROUND Determination of the aldosterone-to-renin ratio (ARR) in blood is the preferred screening test for primary aldosteronism. Renin can be measured as the plasma renin activity (PRA) or the plasma renin concentration (PRC). Consequently, the ARR can be measured either based on the PRA (ARRpra) or based on the PRC (ARRprc). In contrast with the ARRpra, the data on reference values for the ARRprc are limited. Moreover, whether the ARRpra or ARRprc is affected by variations in salt intake is unknown. METHODS We measured the PRA, the PRC, and serum aldosterone in 100 normotensive individuals between 20 and 70 years of age before and after a 3-day oral sodium-loading test (SLT). Participants were stratified according to age and sex. Data are presented as the median and interquartile range (IQR). RESULTS Urinary sodium excretion after the SLT was ≥200 mmol/24 h in all participants. Serum aldosterone, PRA, and PRC values were significantly reduced after the SLT. PRC and PRA results were highly correlated [Spearman rank correlation rs = 0.80 and 0.74 before and after SLT, respectively; P < 0.001 for both]. The central 95% reference intervals for ARRpra before and after SLT were 0.07–1.45 h−1 and 0.06–1.84 h−1, respectively. The corresponding reference intervals for ARRprc were 4.1–81.3 pmol/ng and 3.9–74.8 pmol/ng. The median ARRprc decreased after the SLT from 19.5 pmol/ng (IQR, 13.0–29.4 pmol/ng) to 18.6 pmol/ng (IQR, 9.4–27.1 pmol/ng) (P = 0.005), whereas the median ARRpra did not change (P = 0.12). Both the ARRprc and ARRpra at baseline were higher in women than in men, whereas no sex difference was observed after sodium loading. CONCLUSIONS We present reference values for the ARRprc for healthy individuals. The ARR is affected to a variable degree by sex and sodium intake.

Background A recent meta-analysis showed that both plasma lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) mass and activity independently predict cardiovascular events. Notably, Lp-PLA(2) activity but not mass was found to be a determinant of cardiovascular outcome in type 2 diabetes mellitus. We questioned whether relationships of carotid intima media thickness (IMT), a measure of subclinical atherosclerosis, with Lp-PLA(2) mass differ between diabetic and nondiabetic subjects. Materials and methods Relationships of IMT with plasma Lp-PLA(2) mass (turbidimetric immunoassay) were compared in 74 patients with type 2 diabetes and in 64 nondiabetic subjects. Results IMT was increased (P=0.016), but plasma Lp-PLA(2) mass was decreased in patients with diabetes compared to nondiabetic subjects (277 +/- 66 vs. 327 +/- 62 mu g L-1, P Conclusions Plasma Lp-PLA(2) may relate to early stages of atherosclerosis development. In diabetes mellitus, in contrast, the association of IMT with plasma Lp-PLA(2) mass is abolished, which could be partly ascribed to redistribution of Lp-PLA(2) mass from apolipoprotein B-containing lipoproteins towards HDL. These findings raise questions about the usefulness of plasma Lp-PLA(2) mass measurement as a marker of subclinical atherosclerosis in type 2 diabetes mellitus.

Purpose: Postoperative radiotherapy (PORT) results in excellent local tumour control and improvement of excessive hormonal secretion in pituitary adenoma patients where (repeated) surgery was unsuccessful. Despite this benefit, concerns related to possible long term side effects are often quoted to delay or reject this treatment. In previous studies. the incidence of second tumours and mortality in pituitary adenoma patients treated with PORT were compared with a normal reference population. For proper evaluation however, a direct comparison with similar patients treated with surgery alone should be made. The purpose of this study was to assess the impact of PORT on developing second tumours and mortality in pituitary adenoma patients by comparing the incidence with patients treated with surgery alone. Materials: A retrospective study was performed in 462 pituitary adenoma patients (non-functioning adenoma n=256. growth-hormone secreting n=139 and adrenocorticotropic-hormone secreting adenoma n= 67) treated between t959 and 2008 at the University Medical Center Groningen. PORT was performed in 236 pituitary adenoma patients. The different radiotherapy techniques used in this period were divided into techniques with (n=80) or without (n=153) a beam configuration directed into the central body axis of the patient. Most patients received a radiation fractionation scheme of 25 daily fractions of 1.8 Gy in 5 weeks.After pituitary adenoma diagnosis the incidence of tumours and death were investigated using median life expectancy (MLE). MLE was used to correct for year of birth and gender and with the application of years of follow up as a time base for a left-censored log-rank test. Results: Median age at diagnosis was 47 (range 10-83) years and median overall follow-up time was 9 (range 1-49) years. The median follow-up time of patients treated with PORT was 14 (range 1-49) years and 6 (range 134) years in patients treated with surgery alone. Four patients developed an intracranial tumour, 3 of them were treated with PORT. Twenty-one patients treated with PORT developed an extracranial tumour compared to 11 patients treated with surgery alone (RR 1.04 CI 95%, 0.50-2.17, P = 0.917). In 11 out of the 21 patients treated with PORT and diagnosed with an extracranial tumour a central body axis radiotherapy technique was used (RR 1.43 CI 95%, 0.60-3.41, P = 0.425).Forty-five patients treated with PORT died compared to 24 patients treated with surgery alone (RR 1.26 CI 95%, 0.77-2.08, P = 0.358). Conclusions: Postoperative radiotherapy did not increase the incidence of second tumours and mortality in pituitary adenoma patients. Central body axis radiotherapy technique was not associated with an increase in extracranlal tumours.

ObjectiveGH replacement lowers total cholesterol and low-density lipoprotein cholesterol (LDL-C) in GH-deficient adults, but effects on high-density lipoprotein (HDL) cholesterol (HDL-C) are variable. Both GH and glucocorticoids decrease cholesteryl ester transfer protein (CETP) activity, which is important in HDL metabolism. We determined the extent to which the changes in HDL-C in response to GH replacement are predicted by the −629C>A CETP promoter polymorphism, and questioned whether this association is modified by concomitant glucocorticoid treatment.Design and methodsA total of 91 GH-deficient adults (63 receiving glucocorticoids) were genotyped for the −629 CETP C>A polymorphism. Fasting serum lipids were measured before and after 1.2±0.4 years of GH treatment (Genotropin, Pfizer Inc., Stockholm, Sweden).ResultsIn the whole group, total cholesterol and LDL-C decreased (Pn=19), HDL-C rose by 0.15±0.25 mmol/l (P=0.02; PCETP polymorphism (CC versus AA+CC, P=0.006) in glucocorticoid users, independently of baseline HDL-C and other variables including apolipoprotein E4 carrier status; an opposite association with the CETP polymorphism was found in patients not receiving glucocorticoids (P=0.053).ConclusionsWe suggest a common CETP variant-glucocorticoid treatment interaction concerning the effect of GH replacement on HDL-C. This may explain some of the reported variation in the HDL-C response to GH.

Contains fulltext : 89256.pdf (Publisher’s version ) (Closed access) BACKGROUND: Currently, all patients with vulvar cancer with a positive sentinel node undergo inguinofemoral lymphadenectomy, irrespective of the size of sentinel-node metastases. Our study aimed to assess the association between size of sentinel-node metastasis and risk of metastases in non-sentinel nodes, and risk of disease-specific survival in early stage vulvar cancer. METHODS: In the GROningen INternational Study on Sentinel nodes in Vulvar cancer (GROINSS-V), sentinel-node detection was done in patients with T1-T2 (

Context: Catecholamine excess is rare, but symptoms may be life threatening.Objective: The objective of the study was to investigate the sensitivity of 6-[F-18]fluoro-L-dihydroxyphenylalanine positron emission tomography (F-18-DOPAPET), compared with I-123-metaiodobenzylguanidine (I-123-MIBG) scintigraphy and computer tomography (CT)/magnetic resonance imaging (MRI) for tumor localization in patients with catecholamine excess.Design and Setting: All consecutive patients with catecholamine excess visiting the University Medical Center Groningen, Groningen, The Netherlands, between March 2003 and January 2008 were eligible.Patients: Forty-eight patients were included. The final diagnosis was pheochromocytoma in 40, adrenal hyperplasia in two, paraganglioma in two, ganglioneuroma in one, and unknown in three.Main Outcome Measures: Sensitivities and discordancy between F-18-DOPA PET, I-123-MIBG, and CT or MRI were analyzed for individual patients and lesions. Metanephrines and 3-methoxytyramine in plasma and urine and uptake of F-18-DOPA with PET were measured to determine the whole-body metabolic burden and correlated with biochemical tumor activity. The gold standard was a composite reference standard.Results: F-18-DOPA PET showed lesions in 43 patients, I-123-MIBG in 31, and CT/MRI in 32. Patient-based sensitivity for F-18-DOPA PET, I-123-MIBG, and CT/MRI was 90, 65, and 67% (P Conclusion: To localize tumors causing catecholamine excess, F-18-DOPA PET is superior to I-123-MIBG scintigraphy and CT/MRI. (J Clin Endocrinol Metab 94: 3922-3930, 2009)

Background: Smoking is a remarkable risk factor for inflammatory bowel disease (IBD). aggravating Crohn's disease (CD) while having beneficial effects On Ulcerative colitis (UC). We Studied the effects of active and passive smoking in Dutch IBD patients.Methods: A questionnaire focusing Oil cigarette smoke exposure was sent to 820 IBD patients. Returned questionnaries were incorporated into a retrospective chart review, containing details about disease behavior and received therapy.Results: In all, 675 IBD patients (380 [56%] CD and 295 [44%] UC) responded. At diagnosis there were 52% smokers in CD, 41% it) the general Population, and 28% in UC. The number of present smokers in CD is lower than in the general population (26% versus 35%). No detrimental effects of active smoking oil CD were observed, but passive smokers needed immunosuppressants and infliximab more frequently than nonpassive smokers. Active smoking had beneficial effects oil UC, indicated by reduced rates of colectomy, primary sclerosing cholangitis, and backwash-ileitis in active smokers compared to never smokers, and higher daily cigarette dose correlated with less extensive colitis and a lower need for therapy. Furthermore, smoking cessation after diagnosis was, detrimental for UC patients, indicated by increased needs for steroids and hospitalizations for patients that stopped smoking after compared to before the diagnosis.Conclusions: Active smoking is a risk factor for CD, but does not affect the outcome passive smoking is detrimental for the outcome of CD patients. In UC, active smoking shows dose-dependent beneficial effects. Our data suggest that passive smoking is a novel risk factor for CD.

In type 2 diabetes mellitus, circulating C-reactive protein (CRP) is increased, whereas the high density lipoprotein (HDL)-associated, anti-oxidative and anti-inflammatory enzyme, paraoxonase-I, is decreased. Both high CRP and low paraoxonase-I activity may predict cardiovascular disease. It is unknown whether lower paraoxonase-I activity contributes to higher CRP levels in diabetes. In type 2 diabetic and control subjects, we determined the relationship of CRP with paraoxonase-I when taking account of plasma levels of pro- and anti-inflammatory adipokines. In 81 type 2 diabetic patients and 89 control subjects, plasma high-sensitive CRP, serum paraoxonase-I activity (arylesterase activity, assayed as the rate of hydrolysis of phenyl acetate into phenol), plasma leptin, adiponectin, resistin and lipids were determined. Body mass index (BMI), waist, insulin resistance, triglycerides, CRP, leptin and resistin levels were higher (P 0.20 for all). low paraoxonase-I activity is related to higher CRP, independently of adipokines, as well as of obesity and lipids. Low paraoxonase-I activity in type 2 diabetes mellitus may contribute to increased cardiovascular risk via an effect on enhanced systemic low-grade inflammation.

Context: Lecithin:cholesterol acyltransferase (LCAT), which esterifies free cholesterol to cholesteryl esters, is required for normal plasma lipoprotein structure and is instrumental in high density lipoprotein (HDL) remodeling, but the relationship of variation in plasma LCAT activity with subclinical atherosclerosis is unclear.Objectives: The aim of the study was to determine the effect of the metabolic syndrome (MetS) on plasma LCAT activity and its relationship with carotid artery intima media thickness (IMT).Setting: The study was conducted at the vascular laboratory of a university medical center.Methods: In 74 subjects with MetS and 90 subjects without MetS (National Cholesterol Education Program Adult Treatment Panel III criteria), mean carotid artery IMT, plasma lipids, LCAT activity (exogenous substrate method), high-sensitive C-reactive protein, and homeostasis model assessment insulin resistance (HOMAir) were documented.Results: IMT was greater (P = 0.01) and plasma LCAT activity was higher (P < 0.001) in subjects with MetS compared to subjects without MetS. Similar increases in IMT and LCAT were found in MetS subjects without type 2 diabetes mellitus. Multiple linear regression analysis demonstrated that plasma LCAT activity was independently and positively related to HOMAir, plasma triglycerides, non-HDL cholesterol, and HDL cholesterol (all P < 0.001). After adjustment for age and sex, IMT was positively associated with LCAT activity (P < 0.01), independently of the presence of MetS (or alternatively of plasma lipids), HOMAir, and high-sensitive C-reactive protein.Conclusions: Plasma LCAT activity is elevated in MetS and may be a marker of subclinical atherosclerosis. Our findings do not support the contention that strategies to elevate LCAT are necessarily beneficial for cardioprotection.

Objectives The effect of glucocorticoid substitution on the prevalence of metabolic syndrome components (NCEP ATP III criteria) and serum lipid levels was determined in GH-replaced hypopituitary patients. As glucocorticoid replacement is associated with a pronounced decrease in plasma cholesteryl ester transfer protein (CETP) activity, we also tested associations of HDL cholesterol with the -629C > A CETP promoter polymorphism in subjects with and without ACTH deficiency.Design and patients In a university setting, we retrieved protocolized clinical and laboratory data from 165 adult hypopituitary patients, who had received GH for 1 year.Results After adjustment for age, sex and smoking, non-HDL cholesterol (P = 0.05) and triglycerides (P = 0.004) were higher, but HDL cholesterol was not decreased in 117 glucocorticoid (mainly cortisone acetate in two divided doses) receiving subjects compared to 48 ACTH-sufficient subjects. The prevalence of elevated plasma glucose and/or diabetes (P = 0.04) and hypertriglyceridaemia (P = 0.005), but not of other metabolic syndrome components, was higher in glucocorticoid-replaced subjects. HDL cholesterol was higher in -629 A allele carriers compared to -629CC homozygotes in ACTH-sufficient subjects (P = 0.04), but not in glucocorticoid-treated subjects (P = 0.13). Multiple linear regression analysis demonstrated that only in ACTH-sufficient subjects, HDL cholesterol was independently related to this CETP gene variation (P = 0.03).Conclusions In GH- and glucocorticoid-replaced hypopituitary patients, serum non-HDL cholesterol and triglycerides are higher and the prevalence of hyperglycaemia is increased, but HDL cholesterol is not decreased. Conventional glucocorticoid replacement appears to diminish the association of HDL cholesterol with a common CETP gene variation.

Curative treatment for recurrent medullary thyroid cancer (MTC), diagnosed by rising serum calcitonin, is surgery, but tumor localization is difficult. Therefore, the value of 18F-dihydroxyphenylalanine PET (18F-DOPA PET), 18F-FDG PET, (99m)Tc-V-di-mercaptosulfuricacid (DMSA-V) scintigraphy, and MRI or CT was studied.Twenty-one patients with biochemical recurrent or residual MTC underwent 18F-DOPA PET, 18F-FDG PET, DMSA-V scintigraphy, and MRI or CT. Patient- and lesion-based sensitivities were calculated using a composite reference consisting of all imaging modalities.In 76% of all patients with MTC, one or more imaging modalities was positive for MTC lesions. In 6 of 8 patients with a calcitonin level of500 ng/L, imaging results were negative. In 15 patients with positive imaging results, 18F-DOPA PET detected 13 (sensitivity, 62%; with 4.6 lesions per patient [lpp]). Morphologic imaging (n = 19) was positive in 7 (sensitivity, 37%; 4.7 lpp), DMSA-V (n = 18) in 5 (sensitivity, 28%; 1.1 lpp), and 18F-FDG PET (n = 17) in 4 (sensitivity, 24%; 1.6 lpp). In a lesion-based analysis, 18F-DOPA PET detected 95 of 134 lesions (sensitivity, 71%), morphologic imaging detected 80 of 126 (sensitivity, 64%), DMSA-V detected 20 of 108 (sensitivity, 19%), and 18F-FDG PET detected 48 of 102 (sensitivity, 30%). In 2 of 3 patients with a calcitonin/carcinoembryonic antigen (CEA) doubling time ofor =12 mo, 18F-FDG PET performed better than 18FDOPA PET; in the third patient, 18F-FDG PET was not performed.MTC lesions are best detectable when serum calcitonin was500 ng/L. 18F-DOPA PET is superior to 18F-FDG PET, DMSA-V, and morphologic imaging. With short calcitonin doubling times (or =12 mo), 18F-FDG PET may be superior.

Purpose To evaluate and compare diagnostic sensitivity of positron emission tomography (PET) scanning in carcinoid and islet cell tumor patients with a serotonin and a catecholamine precursor as tracers. Patients and Methods Carcinoid (n = 24) or pancreatic islet cell tumor (n = 23) patients with at least one lesion on conventional imaging including somatostatin receptor scintigraphy (SRS) and computed tomography (CT) scan underwent 11C-5-hydroxytryptophan (11C-5-HTP) PET and 6-[F-18]fluoro-L-dihydroxy-phenylalanin (18F-DOPA) PET. PET findings were compared with a composite reference standard derived from all available imaging along with clinical and cytologic/histologic information. Results In carcinoid tumor patients, per-patient analysis showed sensitivities for 11C-5-HTP PET, 18F-DOPA PET, SRS, and CT of 100%, 96%, 86%, 96%, respectively, and in islet cell tumors of 100%, 89%, 78%, 87%, respectively. In carcinoid patients, per-lesion analysis revealed sensitivities for 11C-5-HTP PET, 11C-5-HTP PET/CT, 18F-DOPA PET, 18F-DOPA PET/CT, SRS, SRS/CT, and CT alone of, respectively, 78%, 89%, 87%, 98%, 49%, 73%, and 63% and in islet cell tumors of 67%, 96%, 41%, 80%, 46%, 77%, and 68%, respectively. In all carcinoid patients 18F-DOPA PET and 11C-5-HTP PET detected more lesions than SRS (P < .001). 11C-5-HTP PET was superior to 18F-DOPA PET in islet cell tumors (P < .0001). In all cases, CT improved the sensitivity of the nuclear scans. Conclusion 18F-DOPA PET/CT is the optimal imaging modality for staging in carcinoid patients and 11C-5-HTP PET/CT in islet cell tumor patients.

Background The extent to which plasma phospholipid transfer protein (PLTP) activity is affected by type 2 diabetes mellitus (DM) and metabolic syndrome (MetS) is still unknown. PLTP is synthesized in the liver, and elevated serum transaminases are considered to predict nonalcoholic fatty liver disease (NAFLD). In this study, we examined the relationship between plasma PLTP activity and liver enzymes in subjects with and without DM and MetS.Design Plasma PLTP activity, serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were measured in 71 subjects without DM or MetS, 21 without DM but with MetS, 26 with DM but without MetS and 55 with DM and MetS (WHO and NCEP-ATP III criteria).Results After controlling for age, sex and alcohol intake, PLTP activity was positively related to both MetS (P Conclusions Plasma PLTP activity is determined by MetS and by diabetes per se. Serum transaminases are independently associated with PLTP activity. We suggest that this lipid transfer protein may be a marker for NAFLD.

ObjectiveWe tested whether in metabolic syndrome (MetS) subjects the ability of plasma to stimulate cellular cholesterol efflux, an early step in the anti-atherogenic reverse cholesterol transport pathway, is maintained despite low high-density lipoprotein (HDL) cholesterol.DesignIn 76 subjects with and 94 subjects without MetS based on the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) criteria, we determined plasma (apo)lipoproteins, pre-β-HDL formation, phospholipid transfer protein (PLTP) activity, cholesterol esterification (EST), cholesteryl ester transfer (CET), adiponectin, and the ability of plasma from each subject to stimulate cholesterol efflux out of cultured fibroblasts obtained from a single donor.ResultsApo E, PLTP activity, EST, and CET were higher (P=0.04 to PP=0.05), but the difference was not significant after age, sex, and diabetes adjustment. Cellular cholesterol efflux was positively related to pre-β-HDL formation, EST, PLTP activity, and apo E (PConclusionsThe ability of plasma from MetS subjects to promote fibroblast cholesterol efflux is not defective, although HDL cholesterol is decreased. Higher cholesterol esterification, PLTP activity, and apo E levels may contribute to the maintenance of cholesterol efflux in MetS.

ObjectiveThis retrospective study describes the role of serum thyroglobulin (Tg) in relation to tumor characteristics in the prediction of persistent/recurrent disease in patients with differentiated thyroid cancer (DTC) with negative Tg at the time of ablation.DesignBetween 1989 and 2006, 94 out of 346 (27%) patients with DTC had undetectable Tg at the time of 131I ablation and were included in this evaluation. The group of 94 patients consisted of 15 males and 79 females in the age range of 16–89 years with a median follow-up of 8 years (range 1–17). All medical records and follow-up parameters of the 94 patients were evaluated for the occurrence of persistent/recurrent disease. In patients with persistent/recurrent disease hematoxylin-eosin-stained slides of the primary tumors and/or metastatic lesions were also reviewed for histological features including immunostains for Tg.ResultsDuring follow-up, 8 out of 94 (8.5%) patients showed persistent/recurrent disease: in the course of the disease two patients showed Tg positivity, three showed Tg antibody (TgAb) positivity, and the other three showed persistently undetectable Tg and TgAb. Patients who developed Tg and/or TgAb positivity during follow-up had a significantly shorter disease-free survival period when compared with patients with persistently undetectable Tg and TgAb (PConclusionsFollow-up of Tg and TgAb in patients with initially negative Tg and TgAb is useful since a number of patients had shown detectable Tg or TgAb during follow-up indicative for persistent/recurrent disease. Tg and TgAb negativity at the time of ablation is not a predictive determinant for future recurrent status.

Purpose To investigate the safety and clinical utility of the sentinel node procedure in early-stage vulvar cancer patients. Patients and Methods A multicenter observational study on sentinel node detection using radioactive tracer and blue dye was performed in patients with T1/2 (< 4 cm) squamous cell cancer of the vulva. When the sentinel node was found to be negative at pathologic ultrastaging, inguinofemoral lymphadenectomy was omitted, and the patient was observed with follow-up for 2 years at intervals of every 2 months. Stopping rules were defined for the occurrence of groin recurrences. Results From March 2000 until June 2006, a sentinel node procedure was performed in 623 groins of 403 assessable patients. In 259 patients with unifocal vulvar disease and a negative sentinel node (median follow-up time, 35 months), six groin recurrences were diagnosed (2.3%; 95% CI, 0.6% to 5%), and 3-year survival rate was 97% (95% CI, 91% to 99%). Short-term morbidity was decreased in patients after sentinel node dissection only when compared with patients with a positive sentinel node who underwent inguinofemoral lymphadenectomy (wound breakdown in groin: 11.7% v 34.0%, respectively; P < .0001; and cellulitis: 4.5% v 21.3%, respectively; P < .0001). Long-term morbidity also was less frequently observed after removal of only the sentinel node compared with sentinel node removal and inguinofemoral lymphadenectomy (recurrent erysipelas: 0.4% v 16.2%, respectively; P < .0001; and lymphedema of the legs: 1.9% v 25.2%, respectively; P < .0001). Conclusion In early-stage vulvar cancer patients with a negative sentinel node, the groin recurrence rate is low, survival is excellent, and treatment-related morbidity is minimal. We suggest that sentinel node dissection, performed by a quality-controlled multidisciplinary team, should be part of the standard treatment in selected patients with early-stage vulvar cancer.