The outcome of treatment in differentiated thyroid cancer according to recommendations in current Dutch and American guidelines.

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.

Diagnostic Accuracy of Salivary Metanephrines in Pheochromocytomas and Paragangliomas.

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 < 0.001; normetanephrine (NMN): 2.90 vs 0.49 nmol/L, P < 0.001). The diagnostic sensitivity and specificity of salivary metanephrines were 89% and 87%, respectively. Diagnostic accuracy of salivary metanephrines was 88%, with an area under the ROC curve of 0.880. We found a significant correlation between plasma and salivary metanephrines (Pearson correlation coefficient: MN, 0.86, P < 0.001; NMN, 0.83, P < 0.001). Salivary NMN concentrations were higher when collected in a seated position compared with supine (P < 0.001) and increased with age (P < 0.001). 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.

Calcitonin testing for detection of medullary thyroid cancer in people with thyroid nodules.

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.

Primary aldosteronism is associated with decreased low-density and high-density lipoprotein particle concentrations and increased GlycA, a pro-inflammatory glycoprotein biomarker.

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® 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 < 0.016). Triglycerides (TG) and triglyceride-rich lipoprotein (TRL) concentrations were lower in PA subjects vs subjects with (untreated) hypertension. GlycA was increased in PA vs the three comparator groups (P < 0.016). Total BCAA concentrations were unaltered in PA. 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.

Self-monitoring physical activity with a smartphone application in cancer patients: a randomized feasibility study (SMART-trial).

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.

Additional value of a high sensitive thyroglobulin assay in the follow-up of patients with differentiated thyroid carcinoma.

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 <0·15 µg/l (functional sensitivity); of these, 43 had an IRMA-Tg-off measurement <1·0 µg/l, resulting in a negative predictive value of 97·7% and a positive predictive value of 56·4%. CONCLUSIONS: The hs-Tg-on measurement is able to predict patients with an IRMA-Tg-off <1·0 µg/l, and therefore decreases the need for Tg stimulation after ablation.

Hydrocortisone Dose Influences Pain, Depressive Symptoms and Perceived Health in Adrenal Insufficiency: A Randomized Controlled Trial.

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.

Fewer cancer reoperations for medullary thyroid cancer after initial surgery according to ATA guidelines.

BACKGROUND: Surgery is still the only curative treatment for medullary thyroid cancer (MTC). We evaluated clinical outcome in patients with locoregional MTC with regard to adequacy of treatment following ATA guidelines and number of sessions to first intended curative surgery in different hospitals. METHODS: We reviewed all records of MTC patients (n = 184) treated between 1980 and 2010 in two tertiary referral centers in the Netherlands. Symptomatic MTC (palpable tumor or suspicious lymphadenopathy) patients without distant metastasis were included (n = 86). Patients were compared with regard to adequacy of surgery according to ATA recommendations, tumor characteristics, number of local cancer reoperations, biochemical cure, clinical disease-free survival (DFS), overall survival (OS), and complications. RESULTS: Adherence to ATA guidelines resulted in fewer cancer-related reoperations (0.24 vs. 0.60; P = 0.027) and more biochemical cure (40.9 vs. 20 %; P = 0.038). Surgery according to ATA-guidelines on patients treated in referral centers was significantly more often adequate (59.2 vs. 26.7 %; P = 0.026). Tumor size and LN+ were the most important predictors for clinical recurrence [relative risk (RR) 4.1 (size > 40 mm) 4.1 (LN+) and death (RR 4.2 (size > 40 mm) 8.1 (LN+)]. CONCLUSIONS: ATA-compliant surgery resulted in fewer local reoperations and more biochemical cure. Patients in referral centers more often underwent adequate surgery according to ATA-guidelines. Size and LN+ were the most important predictors for DFS and OS.

EUS is superior for detection of pancreatic lesions compared with standard imaging in patients with multiple endocrine neoplasia type 1.

BACKGROUND: In multiple endocrine neoplasia type 1 (MEN1), pancreatic neuroendocrine tumors (pNETs) are the leading MEN1-related cause of death. OBJECTIVE: To evaluate EUS and (11)C-5-hydroxytryptophan positron emission tomography ((11)C-5-HTP PET), compared with the recommended screening techniques in MEN1 patients for early detection of pNETs. DESIGN: Cross-sectional study. SETTING: Tertiary-care university medical center. PATIENTS: This study involved 41 patients with a proven MEN1 mutation or with one MEN1 manifestation and a mutation carrier as a first-degree family member, with recent screening by abdominal CT or magnetic resonance imaging (MRI) and somatostatin receptor scintigraphy (SRS). INTERVENTIONS: EUS by using a linear Pentax echoendoscope and Hitachi EUB-525 and (11)C-5-HTP PET. MAIN OUTCOME MEASUREMENTS: Patient-based and lesion-based positivity for pNET was calculated for all imaging techniques. The McNemar test was used to compare the yield of the 4 imaging techniques. RESULTS: In 35 of 41 patients, 107 pancreatic lesions were detected in total. EUS detected 101 pancreatic lesions in 34 patients, (11)C-5-HTP PET detected 35 lesions in 19 patients, and CT/MRI + SRS detected 32 lesions in 18 patients (P < .001). (11)C-5-HTP PET performed similarly to CT/MRI + SRS and better compared with SRS only (13 lesions in 12 patients), both at a patient-based and lesion-based level (P < .05). LIMITATIONS: Single-center study. CONCLUSION: EUS is superior to CT/MRI + SRS for pancreatic lesion detection in patients with MEN1. In this setting, (11)C-5-HTP PET is not useful. We recommend EUS as the first-choice pancreas imaging technique in patients with MEN1. ( CLINICAL TRIAL REGISTRATION NUMBER: NTR1668.).

Altered mitochondrial functioning induced by preoperative fasting may underlie protection against renal ischemia/reperfusion injury.

We reported previously that the robust protection against renal ischemia/reperfusion (I/R) injury in mice by fasting was largely initiated before the induction of renal I/R. In addition, we found that preoperative fasting downregulated the gene expression levels of complexes I, IV, and V of the mitochondrial oxidative phosphorylation (OXPHOS) system, while it did not change those of complexes II and III. Hence, we now investigated the effect of 3 days of fasting on the functioning of renal mitochondria in order to better understand our previous findings. Fasting did not affect mitochondrial density. Surprisingly, fasting significantly increased the protein expression of complex II of the mitochondrial OXPHOS system by 19%. Complex II-driven state 3 respiratory activity was significantly reduced by fasting (46%), which could be partially attributed to the significant decrease in the enzyme activity of complex II (16%). Fasting significantly inhibited Ca(2+) -dependent mitochondrial permeability transition pore opening that is directly linked to protection against renal I/R injury. The inhibition of the mitochondrial permeability transition pore did not involve the expression of the voltage-dependent anion channel by fasting. In conclusion, 3 days of fasting clearly induces the inhibition of complex II-driven mitochondrial respiration state 3 in part by decreasing the amount of functional complex II, and inhibits mitochondrial permeability transition pore opening. This might be a relevant sequence of events that could contribute to the protection of the kidney against I/R injury.

Rapid ultraperformance liquid chromatography-tandem mass spectrometry assay for a characteristic glycogen-derived tetrasaccharide in Pompe disease and other glycogen storage diseases.

BACKGROUND: Urinary excretion of the tetrasaccharide 6-α-D-glucopyranosyl-maltotriose (Glc4) is increased in various clinical conditions associated with increased turnover or storage of glycogen, making Glc4 a potential biomarker for glycogen storage diseases (GSD). We developed an ultraperformance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) assay to detect Glc4 in urine without interference of the Glc4 isomer maltotetraose (M4). METHODS: Urine samples, diluted in 0.1% ammonium hydroxide containing the internal standard acarbose, were filtered, and the filtrate was analyzed by UPLC-MS/MS. RESULTS: We separated and quantified acarbose, M4, and Glc4 using the ion pairs m/z 644/161, 665/161, and 665/179, respectively. Response of Glc4 was linear up to 1500 µmol/L and the limit of quantification was 2.8 µmol/L. Intra- and interassay CVs were 18.0% and 18.4% (10 µmol/L Glc4), and 10.5% and 16.2% (200 µmol/L Glc4). Glc4 in control individuals (n = 116) decreased with increasing age from a mean value of 8.9 mmol/mol to 1.0 mmol/mol creatinine. M4 was present in 5% of urine samples. Mean Glc4 concentrations per age group in untreated patients with Pompe disease (GSD type II) (n = 66) were significantly higher, ranging from 39.4 to 10.3 mmol/mol creatinine (P < 0.001-0.005). The diagnostic sensitivity of Glc4 for GSD-II was 98.5% and the diagnostic specificity 92%. Urine Glc4 was also increased in GSD-III (8 of 9), GSD-IV (2 of 3) and GSD-IX (6 of 10) patients. CONCLUSIONS: The UPLC-MS/MS assay of Glc4 in urine was discriminative between Glc4 and M4 and confirmed the diagnosis in >98% of GSD-II cases.

Riboflavin-responsive oxidative phosphorylation complex I deficiency caused by defective ACAD9: new function for an old gene.

Mitochondrial complex I deficiency is the most common oxidative phosphorylation defect. Mutations have been detected in mitochondrial and nuclear genes, but the genetics of many patients remain unresolved and new genes are probably involved. In a consanguineous family, patients presented easy fatigability, exercise intolerance and lactic acidosis in blood from early childhood. In muscle, subsarcolemmal mitochondrial proliferation and a severe complex I deficiency were observed. Exercise intolerance and complex I activity was improved by a supplement of riboflavin at high dosage. Homozygosity mapping revealed a candidate region on chromosome three containing six mitochondria-related genes. Four genes were screened for mutations and a homozygous substitution was identified in ACAD9 (c.1594 C>T), changing the highly conserved arginine-532 into tryptophan. This mutation was absent in 188 ethnically matched controls. Protein modelling suggested a functional effect due to the loss of a stabilizing hydrogen bond in an α-helix and a local flexibility change. To test whether the ACAD9 mutation caused the complex I deficiency, we transduced fibroblasts of patients with wild-type and mutant ACAD9. Wild-type, but not mutant, ACAD9 restored complex I activity. An unrelated patient with the same phenotype was compound heterozygous for c.380 G>A and c.1405 C>T, changing arginine-127 into glutamine and arginine-469 into tryptophan, respectively. These amino acids were highly conserved and the substitutions were not present in controls, making them very probably pathogenic. Our data support a new function for ACAD9 in complex I function, making this gene an important new candidate for patients with complex I deficiency, which could be improved by riboflavin treatment.

Statin and fibrate combination does not additionally lower plasma cholesteryl ester transfer in type 2 diabetes mellitus.

BACKGROUND: Plasma cholesteryl ester transfer (CET) from high density lipoproteins (HDL) to very low and low density lipoproteins (VLDL+LDL) may predict (subclinical) atherosclerosis. We tested the extent to which plasma CET and cholesterol esterification (EST) are decreased by statin and fibrate combination therapy compared to statin and fibrate administration alone in type 2 diabetic patients. METHODS: Plasma CET and EST were measured by isotope assays in 14 type 2 diabetic patients, in whom a randomized placebo-controlled crossover study was carried out (8 weeks treatment with simvastatin (40 mg daily), bezafibrate (400 mg daily) and their combination). Plasma CET and EST from diabetic patients were compared with 42 non-diabetic control subjects with similar triglyceride levels. RESULTS: Plasma CET and EST were elevated in diabetic patients at baseline compared to control subjects (p < 0.01), and were correlated positively with non-HDL cholesterol and triglycerides in non-diabetic subjects and in diabetic patients at baseline (p < 0.01). Decreases in CET during combined treatment (p < 0.05) were not greater than the changes during simvastatin and bezafibrate monotherapy (p > 0.20). EST only decreased during bezafibrate therapy (p < 0.05). Changes in CET during treatment were correlated positively with changes in non-HDL cholesterol (p < 0.05) and triglycerides (p < 0.001). Changes in HDL cholesterol were related inversely to changes in CET (p < 0.05). CONCLUSIONS: Diabetes-associated plasma CET elevations are ameliorated by statin and fibrate monotherapy, but combined lipid lowering drug treatment does not additively lower CET. CET lowering likely contributes to HDL cholesterol changes during statin and fibrate administration.

Postoperative external beam radiotherapy for locoregional control in iodine refractory differentiated thyroid cancer.

Background: The role of postoperative external beam radiotherapy (EBRT) in patients with residual iodine refractory-differentiated thyroid cancer (IR-DTC) is still inconclusive. The aim of this retrospective study was to evaluate locoregional control (LRC) and overall survival (OS), and potential side effects after postoperative EBRT for both microscopic and macroscopic non-radically resected, locally advanced IR-DTC. Methods: Between 1990 and 2016, 49 patients with locally advanced IR-DTC received EBRT for microscopic (R1; n = 28) or macroscopic (R2; n = 21) locoregional residual disease. For more insight into the added effect of EBRT, we performed an intrapatient sub-analysis in 32 patients who had undergone more than 1 surgical intervention, comparing LRC after primary, curative-intended surgery with LRC after repeated surgery plus EBRT. To estimate LRC and OS, we used Kaplan-Meier curves. From 2007 onward, we prospectively recorded toxicity data in our head and neck cancer database (n = 10). Results: LRC rates 5 years after EBRT were higher for R1 (84.3%) than for R2 (44.9%) residual disease (P = 0.016). The 5-year OS rate after EBRT was 72.1% for R1 and 33.1% for R2 disease (P = 0.003). In the intrapatient analysis (n = 32), LRC rates were 6.3% 5 years after only initial surgery and 77.9% after repeated surgery with EBRT (P < 0.001). Acute toxicity was limited to grade I and II xerostomia, mucositis, and hoarseness; only one patient developed late grade III dysphagia. Conclusions: Postoperative EBRT is associated with long-lasting LRC and OS with acceptable toxicity in patients with locally advanced IR-DTC, especially in microscopic residual disease.

Patients with Leber hereditary optic neuropathy fail to compensate impaired oxidative phosphorylation.

Ninety-five percent of Leber hereditary optic neuropathy (LHON) patients carry a mutation in one out of three mtDNA-encoded ND subunits of complex I. Penetrance is reduced and more male than female carriers are affected. To assess if a consistent biochemical phenotype is associated with LHON expression, complex I- and complex II-dependent adenosine triphosphate synthesis rates (CI-ATP, CII-ATP) were determined in digitonin-permeabilized peripheral blood mononuclear cells (PBMCs) of thirteen healthy controls and for each primary mutation of a minimum of three unrelated patients and of three unrelated carriers with normal vision and were normalized per mitochondrion (citrate synthase activity) or per cell (protein content). We found that in mitochondria, CI-ATP and CII-ATP were impaired irrespective of the primary LHON mutation and clinical expression. An increase in mitochondrial density per cell compensated for the dysfunctional mitochondria in LHON carriers but was insufficient to result in a normal biochemical phenotype in early-onset LHON patients.

Preoperative fasting protects mice against hepatic ischemia/reperfusion injury: mechanisms and effects on liver regeneration.

We show that brief periods of fasting induce functional changes similar to those induced by long-term dietary restriction in mice, and these changes include protection from ischemia/reperfusion (I/R) injury. In this study, we investigated the mechanisms of protection induced by fasting, and we determined the effect on liver regeneration after partial hepatectomy. Partial hepatic ischemia (75 minutes) was induced in ad libitum fed mice and in 1- to 3-day-fasted mice, and one-third or two-thirds hepatectomy was performed in ad libitum fed mice and 3-day-fasted mice. Preoperative fasting for 2 or 3 days significantly decreased hepatocellular I/R injury. Hepatic gene expression of heme oxygenase 1 (HO-1), superoxide dismutase 2 (SOD2), glutathione peroxidase 1 (Gpx1), and glutathione reductase (GSR) was significantly up-regulated in 3-day-fasted mice at the baseline and 6 hours after reperfusion. After reperfusion, p-selectin and interleukin-6 (IL-6) levels were significantly lower, and superoxide radical generation, lipid peroxidation, and neutrophil influx were significantly attenuated in 3-day-fasted mice. Preoperative fasting did not affect liver regeneration after one-third hepatectomy. Hepatic gene expression of IL-6 and transforming growth factor ß1 was significantly higher in 3-day-fasted mice before and after one-third hepatectomy. Tumor necrosis factor α expression significantly increased after one-third hepatectomy in 3-day-fasted mice. After a 3-day fast and two-thirds hepatectomy, liver regeneration and subsequent postoperative recovery were compromised. In conclusion, up-regulation of the stress response gene HO-1 and the antioxidant enzymes SOD2, Gpx1, and GSR at the baseline and a better response after reperfusion likely underlie the protection induced by fasting against hepatic I/R injury. Preoperative fasting may be a promising new strategy for protecting the liver against I/R injury during liver transplantation and minor liver resections, although its effect on extended hepatectomy warrants further exploration.

Reference values for aldosterone-renin ratios in normotensive individuals and effect of changes in dietary sodium consumption.

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 (ARR(pra)) or based on the PRC (ARR(prc)). In contrast with the ARR(pra), the data on reference values for the ARR(prc) are limited. Moreover, whether the ARR(pra) or ARR(prc) 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 r(s) = 0.80 and 0.74 before and after SLT, respectively; P < 0.001 for both]. The central 95% reference intervals for ARR(pra) before and after SLT were 0.07-1.45 h(-1) and 0.06-1.84 h(-1), respectively. The corresponding reference intervals for ARR(prc) were 4.1-81.3 pmol/ng and 3.9-74.8 pmol/ng. The median ARR(prc) 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 ARR(pra) did not change (P = 0.12). Both the ARR(prc) and ARR(pra) 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 ARR(prc) for healthy individuals. The ARR is affected to a variable degree by sex and sodium intake.

Carotid intima media thickness is associated with plasma lipoprotein-associated phospholipase A2 mass in nondiabetic subjects but not in patients with type 2 diabetes.

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±62µgL(-1) , P<0·001). In nondiabetic subjects, IMT was correlated positively with Lp-PLA(2) (r=0·325, P<0·009); multiple linear regression analysis confirmed an independent association of IMT with Lp-PLA(2) (ß=0·192, P=0·048). In contrast, IMT was unrelated to Lp-PLA(2) in patients with diabetes (r=0·021, P=0·86), and the relationship of IMT with Lp-PLA(2) was different in diabetic and control subjects (P<0·001). The relationship of Lp-PLA(2) with the total cholesterol/high-density lipoprotein (HDL) cholesterol ratio also differed between diabetic and nondiabetic subjects (P<0·001). 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.

Total 18F-dopa PET tumour uptake reflects metabolic endocrine tumour activity in patients with a carcinoid tumour.

PURPOSE: Positron emission tomography (PET) using 6-[18F]fluoro-L-dihydroxyphenylalanine (18F-dopa) has an excellent sensitivity to detect carcinoid tumour lesions. 18F-dopa tumour uptake and the levels of biochemical tumour markers are mediated by tumour endocrine metabolic activity. We evaluated whether total 18F-dopa tumour uptake on PET, defined as whole-body metabolic tumour burden (WBMTB), reflects tumour load per patient, as measured with tumour markers. METHODS: Seventy-seven consecutive carcinoid patients who underwent an 18F-dopa PET scan in two previously published studies were analysed. For all tumour lesions mean standardised uptake values (SUVs) at 40% of the maximal SUV and tumour volume on 18F-dopa PET were determined and multiplied to calculate a metabolic burden per lesion. WBMTB was the sum of the metabolic burden of all individual lesions per patient. The 24-h urinary serotonin, urine and plasma 5-hydroxindoleacetic acid (5-HIAA), catecholamines (nor)epinephrine, dopamine and their metabolites, measured in urine and plasma, and serum chromogranin A served as tumour markers. RESULTS: All but 1 were evaluable for WBMTB; 74 patients had metastatic disease. 18F-dopa PET detected 979 lesions. SUVmax on 18F-dopa PET varied up to 29-fold between individual lesions within the same patients. WBMTB correlated with urinary serotonin (r=0.51) and urinary and plasma 5-HIAA (r=0.78 and 0.66). WBMTB also correlated with urinary norepinephrine, epinephrine, dopamine and plasma dopamine, but not with serum chromogranin A. CONCLUSION: Tumour load per patient measured with 18F-dopa PET correlates with tumour markers of the serotonin and catecholamine pathway in urine and plasma in carcinoid patients, reflecting metabolic tumour activity.

Retrospective study on the treatment outcome of surgical closure of oroantral communications.

PURPOSE: A retrospective cohort study concerning the surgical closure of oroantral communications (OACs) was carried out to facilitate a comparison between treatment outcomes of conventional surgical treatment and new strategies for closure of OACs. Data were statistically analyzed to gather insight into possible predictor variables of recurrent OAC. PATIENTS AND METHODS: A cohort of patients treated for an OAC from 2004 through 2008 was reviewed. Recorded data included patient age and gender, location and duration of OAC, method of removal of the (pre)molar, presence of maxillary sinusitis, disturbed wound healing, and surgical treatment method. Data analysis included descriptive and multivariate logistic regression analyses with recurrence of OAC as the outcome variable. RESULTS: In total, 308 patients were included in the sample, of which 28 patients (9.1%) required a second intervention to repair an OAC. Of these 28 patients, 4 patients needed a third intervention, making the total number of recurrent OACs 32 (10.4%). In most cases (60.7%), a buccal advancement flap according to the method of Rehrmann was used to close the perforation. Multivariate regression analysis showed a 15 times higher risk of recurrence with maxillary sinusitis at follow-up. CONCLUSIONS: Overall results of the study showed that OACs recur in about 1 of 10 patients and requires a second intervention after surgical closure. New strategies should therefore result in an equal or better treatment outcome to be considered a suitable treatment option. Furthermore, it was demonstrated that the presence of maxillary sinusitis at follow-up is an important determinant of the treatment outcome of OAC repair.