Head-to-head comparison of [11C]methionine PET, [11C]choline PET, and 4-dimensional CT as second-line scans for detection of parathyroid adenomas in primary hyperparathyroidism.

PURPOSE: Accurate preoperative localization is imperative to guide surgery in primary hyperparathyroidism (pHPT). It remains unclear which second-line imaging technique is most effective after negative first-line imaging. In this study, we compare the diagnostic effectiveness of [11C]methionine PET/CT, [11C]choline PET/CT, and four dimensional (4D)-CT head-to-head in patients with pHPT, to explore which of these imaging techniques to use as a second-line scan. METHODS: We conducted a powered, prospective, blinded cohort study in patients with biochemically proven pHPT and prior negative or discordant first-line imaging consisting of ultrasonography and 99mTc-sestamibi. All patients underwent [11C]methionine PET/CT, [11C]choline PET/CT, and 4D-CT. At first, all scans were interpreted by a nuclear medicine physician, and a radiologist who were blinded from patient data and all imaging results. Next, a non-blinded scan reading was performed. The scan results were correlated with surgical and histopathological findings. Serum calcium values at least 6 months after surgery were used as gold standard for curation of HPT. RESULTS: A total of 32 patients were included in the study. With blinded evaluation, [11C]choline PET/CT was positive in 28 patients (88%), [11C]methionine PET/CT in 23 (72%), and 4D-CT in 15 patients (47%), respectively. In total, 30 patients have undergone surgery and 32 parathyroid lesions were histologically confirmed as parathyroid adenomas. Based on the blinded evaluation, lesion-based sensitivity of [11C]choline PET/CT, [11C]methionine PET/CT, and 4D-CT was respectively 85%, 67%, and 39%. The sensitivity of [11C]choline PET/CT differed significantly from that of [11C]methionine PET/CT and 4D-CT (p = 0.031 and p < 0.0005, respectively). CONCLUSION: In the setting of pHPT with negative first-line imaging, [11C]choline PET/CT is superior to [11C]methionine PET/CT and 4D-CT in localizing parathyroid adenomas, allowing correct localization in 85% of adenomas. Further studies are needed to determine cost-benefit and efficacy of these scans, including the timing of these scans as first- or second-line imaging techniques.

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.

MET-receptor targeted fluorescent imaging and spectroscopy to detect multifocal papillary thyroid cancer.

PURPOSE: Multifocal disease in PTC is associated with an increased recurrence rate. Multifocal disease (MD) is underdiagnosed with the current gold standard of pre-operative ultrasound staging. Here, we evaluate the use of EMI-137 targeted molecular fluorescence-guided imaging (MFGI) and spectroscopy as a tool for the intra-operative detection of uni- and multifocal papillary thyroid cancer (PTC) aiming to improve disease staging and treatment selection. METHODS: A phase-1 study (NCT03470259) with EMI-137 was conducted to evaluate the possibility of detecting PTC using MFGI and quantitative fiber-optic spectroscopy. RESULTS: Fourteen patients underwent hemi- or total thyroidectomy (TTX) after administration of 0.09 mg/kg (n = 1), 0.13 mg/kg (n = 8), or 0.18 mg/kg (n = 5) EMI-137. Both MFGI and spectroscopy could differentiate PTC from healthy thyroid tissue after administration of EMI-137, which binds selectively to MET in PTC. 0.13 mg/kg was the lowest dosage EMI-137 that allowed for differentiation between PTC and healthy thyroid tissue. The smallest PTC focus detected by MFGI was 1.4 mm. MFGI restaged 80% of patients from unifocal to multifocal PTC compared to ultrasound. CONCLUSION: EMI-137-guided MFGI and spectroscopy can be used to detect multifocal PTC. This may improve disease staging and treatment selection between hemi- and total thyroidectomy by better differentiation between unifocal and multifocal disease. TRIAL REGISTRATION: NCT03470259.

Management recommendations for pancreatic manifestations of von Hippel-Lindau disease.

Von Hippel-Lindau disease (VHL) is a multineoplasm inherited disease manifesting with hemangioblastoma of the central nervous system and retina, adrenal pheochromocytoma, renal cell carcinoma, pancreatic neuroendocrine tumors and cysts, and neoplasms/cysts of the ear, broad ligament, and testicles. During 2018-2020, the VHL Alliance gathered several committees of experts in the various clinical manifestations of VHL to review the literature, gather the available evidence on VHL, and develop recommendations for patient management. The current report details the results of the discussion of a group of experts in the pancreatic manifestations of VHL along with their proposed recommendations for the clinical surveillance and management of patients with VHL. The recommendations subcommittee performed a comprehensive systematic review of the literature and conducted panel discussions to reach the current recommendations. The level of evidence was defined according to the Shekelle variation of the Grading of Recommendations, Assessment, Development, and Evaluation grading system. The National Comprehensive Cancer Network Categories of Evidence and Consensus defined the committee members' interpretation of the evidence and degree of consensus. The recommendations encompass the main aspects of VHL-related pancreatic manifestations and their clinical management. They are presented in a clinical orientation, including general planning of screening and surveillance for pancreatic neuroendocrine tumors, utility of biochemical biomarkers, the optimal choice for imaging modality, indirect risk stratification, indications for tissue sampling of VHL-related pancreatic neuroendocrine tumors, and interventions. These recommendations are designed to serve as the reference for all aspects of the screening, surveillance, and management of VHL-related pancreatic manifestations.

Multidisciplinary integrated care pathway for von Hippel-Lindau disease.

BACKGROUND: Clinical pathways are care plans established to describe essential steps in the care of patients with a specific clinical problem. They translate (inter)national guidelines into local applicable protocols and clinical practice. The purpose of this article is to establish a multidisciplinary integrated care pathway for specialists and allied health care professionals in caring for individuals with von Hippel-Lindau (VHL) disease. METHODS: Using a modified Delphi consensus-making process, a multidisciplinary panel from 5 Dutch University Medical Centers produced an integrated care pathway relating to the provision of care for patients with VHL by medical specialists, specialized nurses, and associated health care professionals. Patient representatives cocreated the pathway and contributed quality criteria from the patients' perspective. RESULTS: The panel agreed on recommendations for the optimal quality of care for individuals with a VHL gene mutation. These items were the starting point for the development of a patient care pathway. With international medical guidelines addressing the different VHL-related disorders, this article presents a patient care pathway as a flowchart that can be incorporated into VHL expertise clinics or nonacademic treatment clinics. CONCLUSIONS: Medical specialists (internists, urologists, neurosurgeons, ophthalmologists, geneticists, medical oncologists, neurologists, gastroenterologists, pediatricians, and ear-nose-throat specialists) together with specialized nurses play a vital role alongside health care professionals in providing care to people affected by VHL and their families. This article presents a set of consensus recommendations, supported by organ-specific guidelines, for the roles of these practitioners in order to provide optimal VHL care. This care pathway can form the basis for the development of comprehensive, integrated pathways for multiple neoplasia syndromes.

State of the art and future directions in the systemic treatment of medullary thyroid cancer.

PURPOSE OF REVIEW: Systemic treatment is the only therapeutic option for patients with progressive, metastatic medullary thyroid cancer (MTC). Since the discovery of the rearranged during transfection (RET) proto-oncogene (100% hereditary, 60-90% sporadic MTC), research has focused on finding effective systemic therapies to target this mutation. This review surveys recent findings. RECENT FINDINGS: Multikinase inhibitors are systemic agents targeting angiogenesis, inhibiting growth of tumor cells and cells in the tumor environment and healthy endothelium. In the phase III EXAM and ZETA trials, cabozantinib and vandetanib showed progression-free survival benefit, without evidence of prolonged overall survival. Selpercatinib and pralsetinib are kinase inhibitors with high specificity for RET; phase I and II studies showed overall response rates of 73% and 71% in first line, and 69% and 60% in second line treatment, respectively. Although resistance mechanisms to mutation-driven therapy will be a challenge in the future, phase III studies are ongoing and neo-adjuvant therapy with selpercatinib is being studied. SUMMARY: The development of selective RET-inhibitors has expanded the therapeutic arsenal to control tumor growth in progressive MTC, with fewer adverse effects than multikinase inhibitors. Future studies should confirm their effectiveness, study neo-adjuvant strategies, and tackle resistance to these inhibitors, ultimately to improve patient outcomes.

Intraoperative MET-receptor targeted fluorescent imaging and spectroscopy for lymph node detection in papillary thyroid cancer: novel diagnostic tools for more selective central lymph node compartment dissection.

PURPOSE: Patients undergoing prophylactic central compartment dissection (PCLND) for papillary thyroid cancer (PTC) are often overtreated. This study aimed to determine if molecular fluorescence-guided imaging (MFGI) and spectroscopy can be useful for detecting PTC nodal metastases (NM) and to identify negative central compartments intraoperatively. METHODS: We used a data-driven prioritization strategy based on transcriptomic profiles of 97 primary PTCs and 80 normal thyroid tissues (NTT) to identify tumor-specific antigens for a clinically available near-infrared fluorescent tracer. Protein expression of the top prioritized antigen was immunohistochemically validated with a tissue microarray containing primary PTC (n = 741) and NTT (n = 108). Staining intensity was correlated with 10-year locoregional recurrence-free survival (LRFS). A phase 1 study (NCT03470259) with EMI-137, targeting MET, was conducted to evaluate safety, optimal dosage for detecting PTC NM with MFGI, feasibility of NM detection with quantitative fiber-optic spectroscopy, and selective binding of EMI-137 for MET. RESULTS: MET was selected as the most promising antigen. A worse LRFS was observed in patients with positive versus negative MET staining (81.9% versus 93.2%; p = 0.02). In 19 patients, no adverse events related to EMI-137 occurred. 0.13 mg/kg EMI-137 was selected as optimal dosage for differentiating NM from normal lymph nodes using MFGI (p < 0.0001) and spectroscopy (p < 0.0001). MFGI identified 5/19 levels (26.3%) without NM. EMI-137 binds selectively to MET. CONCLUSION: MET is overexpressed in PTC and associated with increased locoregional recurrence rates. Perioperative administration of EMI-137 is safe and facilitates NM detection using MFGI and spectroscopy, potentially reducing the number of negative PCLNDs with more than 25%. CLINICAL TRIAL REGISTRATION: NCT03470259.

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.

Use of Salivary Iodine Concentrations to Estimate the Iodine Status of Adults in Clinical Practice.

BACKGROUND: Measurement of the 24-h urinary iodine concentration or urinary iodine excretion (UIE) is the gold standard to determine iodine status; however, this method is inconvenient. The use of salivary iodine could be a possible alternative since salivary glands express the sodium-iodine symporter. OBJECTIVES: We aimed to establish the correlation between the salivary iodine secretion and UIE, to evaluate the clinical applicability of the iodine saliva measurement. METHODS: We collected 24-h urine and saliva samples from 40 participants ≥18 y: 20 healthy volunteers with no specific diet (group 1), 10 patients with differentiated thyroid cancer with a low dietary intake (<50 µg/d, group 2), and 10 patients with a high iodine status as the result of the use of amiodarone (group 3). Urinary and salivary iodine were measured using a validated inductively coupled plasma MS method. To correct for differences in water content, the salivary iodine concentration (SIC) was corrected for salivary protein and urea concentrations (SI/SP and SI/SU, respectively). The intra- and inter-individual CVs were calculated, and the Kruskal-Wallis test and Spearman's correlation were used. RESULTS: The intra-individual CVs for SIC, SI/SP, and SI/SU were 63.8%, 37.7%, and 26.9%, respectively. The inter-individual CVs for SIC, SI/SP, and SI/SU were 77.5%, 41.6% and 47.0%, respectively. We found significant differences (P < 0.01) in urinary and salivary iodine concentrations between all groups [the 24-h UIE values were 176 µg/d (IQR, 96.1-213 µg/d), 26.0 µg/d (IQR, 22.0-37.0 µg/d), and 10.0*103 µg/d (IQR, 7.57*103-11.4*103 µg/d) in groups 1-3, respectively; the SIC values were 136 µg/L (IQR, 86.3-308 µg/L), 71.5 µg/L (IQR, 29.5-94.5 µg/L), and 14.3*103 µg/L (IQR, 10.6*103-25.6*103 µg/L) in groups 1-3, respectively]. Correlations between the 24-h UIE and SIC, SI/SP, and SI/SU values were strong (ρ = 0.80, ρ = 0.90, and ρ = 0.86, respectively; P < 0.01). CONCLUSIONS: Strong correlations were found between salivary and urinary iodine in adults with different daily iodine intakes. A salivary iodine measurement can be performed to assess the total iodine body pool, with the recommendation to correct for salivary protein or urea.

Surgical Complications and Referral Patterns in 567 Patients with Differentiated Thyroid Cancer in the Northern Region of the Netherlands: A Population-Based Study Towards Clinical Management Implementation.

BACKGROUND: In the Netherlands, differentiated thyroid cancer (DTC) is treated surgically in three different hospital types, including university, teaching, and non- teaching peripheral hospitals. This study evaluates postoperative complications and referral patterns in patients with DTC in the northern region of the Netherlands to gain an understanding on how to improve management implementation. METHODS: Data from 567 patients diagnosed between 1989 and 2009 were obtained from the Netherlands Cancer Registry and were supplemented with information from hospital digital information systems and patient records from 15 hospitals: 1 university, 3 teaching, and 11 peripheral hospitals. Surgically treated patients with a histologically proven DTC derived from the original pathology reports were included. RESULTS: Surgical treatment could be performed in a single procedure in 234 patients (41.3%), but several surgeries were needed in the remaining 333 patients (58.7%). Recurrent laryngeal nerve (RLN) palsy occurred after all types of thyroid surgical procedures, but mostly after initial (hemi)thyroidectomy and reoperations. RLN was temporary in 3.2% of the nerves at risk and persistent in 1.8%. Temporary hypocalcemia developed in 13.7% of patients, and persistent hypocalcemia occurred in 4.8%. Patients were mainly referred to the university hospital from a non-teaching (40.7%, 48/118) or teaching hospital (11.1%, 16/144); however, 80% of patients were not referred. CONCLUSIONS: The complication rate and number of multiple surgeries support the efforts in optimizing clinical management in thyroid cancer. Careful considerations prior to initial surgical treatment by early discussion in telemedicine-based regional tumor boards could possibly prevent reoperations and potentially diminish complications.

Clinical implications of the oncometabolite succinate in SDHx-mutation carriers.

Succinate dehydrogenase (SDH) mutations lead to the accumulation of succinate, which acts as an oncometabolite. Germline SDHx mutations predispose to paraganglioma (PGL) and pheochromocytoma (PCC), as well as to renal cell carcinoma and gastro-intestinal stromal tumors. The SDHx genes were the first tumor suppressor genes discovered which encode for a mitochondrial enzyme, thereby supporting Otto Warburg's hypothesis in 1926 that a direct link existed between mitochondrial dysfunction and cancer. Accumulation of succinate is the hallmark of tumorigenesis in PGL and PCC. Succinate accumulation inhibits several α-ketoglutarate dioxygenases, thereby inducing the pseudohypoxia pathway and causing epigenetic changes. Moreover, SDH loss as a consequence of SDHx mutations can lead to reprogramming of cell metabolism. Metabolomics can be used as a diagnostic tool, as succinate and other metabolites can be measured in tumor tissue, plasma and urine with different techniques. Furthermore, these pathophysiological characteristics provide insight into therapeutic targets for metastatic disease. This review provides an overview of the pathophysiology and clinical implications of oncometabolite succinate in SDHx mutations.

Outcomes of surgery and postoperative radiation therapy in managing medullary thyroid carcinoma.

BACKGROUND AND OBJECTIVES: We evaluated the outcomes of surgery with or without postoperative radiation therapy (PORT) in the management of medullary thyroid carcinoma (MTC). METHODS: From two tertiary cancer centers, 297 consecutive patients with MTC treated with PORT (n = 46) between 1990 and 2016 or surgery alone (n = 251) between 2000 and 2016 were reviewed. RESULTS: Ten-year cumulative incidences of locoregional and distant failure were 30.2% and 24.9% in the surgery cohort, and 16.9% and 55.2% in the PORT cohort. In the surgery alone cohort, T4 disease, extrathyroidal extension, N1 disease, extranodal extension (ENE), and residual disease after surgery were associated with local failure. The PORT cohort had significantly higher proportions of patients with T4 disease, N1 disease, ENE, and residual disease. CONCLUSIONS: High-risk clinical features can help identify patients with MTC at high-risk for local failure after surgery alone. Patients with high-risk clinical features had effective locoregional control after PORT.

Blood sampling for metanephrines comparing venipuncture vs. indwelling intravenous cannula in healthy subjects.

Background To diagnose pheochromocytoma or sympathetic paraganglioma, guidelines recommend blood sampling after at least 30 min of supine rest and using an indwelling intravenous cannula is preferred. Although blood sampling by venipuncture is more convenient and cost-effective, it is unknown whether venipuncture affects plasma concentrations of free metanephrines (MNs). We therefore investigated whether there is a difference in plasma concentrations of free MNs collected by venipuncture or by an intravenous cannula. Methods We included 22 healthy participants (12 men and 10 women, median age 26 years). We collected blood using an indwelling cannula and venipuncture to determine plasma concentrations of free MNs and catecholamines, and calculated the median of the individually calculated absolute and relative differences. Results Plasma concentrations of free MN, normetanephrine (NMN) and epinephrine were higher with blood sampling using venipuncture compared to that when using an indwelling cannula. The median (interquartile range [IQR]) difference was MN 0.020 (-0.004 to 0.040) nmol/L, median percentage difference 20.5% (-2.4 to 35.2%), NMN 0.019 (-0.004 to 0.077) nmol/L, median percentage difference 4.6% (-1.1 to 25.4%) and epinephrine 0.022 (0.007-0.079) nmol/L, median percentage difference 24.9% (7.8-83.3%). When the two sampling conditions were compared, plasma-free 3-methoxytyramine (3-MT), norepinephrine and dopamine concentrations did not differ. Conclusions Blood sampling by venipuncture resulted in statistically significant higher concentrations of MN, NMN and epinephrine compared to sampling by means of an indwelling cannula. However, differences were small. For most patients it seems justifiable to collect blood via venipuncture.

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.

Plasma branched chain amino acids are lower in short-term profound hypothyroidism and increase in response to thyroid hormone supplementation.

Branched chain amino acids (BCAA) are implicated in the pathogenesis of cardiometabolic diseases conceivably by affecting insulin resistance and mitochondrial dysfunction. Circulating BCAA levels may predict (subclinical) atherosclerosis, diabetes and hypertension development but the factors involved in BCAA regulation are incompletely understood. Given the key role of thyroid hormones on many metabolic processes including protein metabolism, we aimed to determine effects of thyroid dysfunction on circulating BCAA. Effects of short-term profound hypothyroidism on plasma BCAA were determined in 17 patients who had undergone total thyroidectomy for differentiated thyroid carcinoma. Patients were studied during hypothyroidism, i.e. after thyroidectomy, and after thyroid hormone supplementation. Plasma BCAA (sum of valine, leucine and isoleucine) and alanine were measured by nuclear magnetic resonance spectroscopy. During hypothyroidism (median thyroid-stimulating hormone 81 (IQR 67-120.5) mU/L), plasma BCAA were lower (255 (IQR 222-289) µmol/L) compared to a euthyroid reference population (n = 5579; 377 µmol/L (2.5th to 97.5th percentile 258-548), p < 0.001). After 20 weeks of thyroid hormone supplementation (thyroid-stimulating hormone 0.03 (IQR 0.01-0.14 mU/L) plasma BCAA had increased (328 (IQR 272-392) µmol/L, p = .001), but plasma alanine concentrations were unaltered (p = .50). Changes in body weight in response to thyroid hormone supplementation were correlated with changes in plasma BCAA (r = 0.721 p = .001, but not with changes in cholesterol or glucose (p > .80). In conclusion, plasma BCAA concentrations are lower during short-term profound hypothyroidism in humans, and increase in response to thyroid hormone supplementation. Changes in BCAA and in body weight after reversal of the hypothyroid state appear to be interrelated.

Reasons for low uptake of a psychological intervention offered to cancer survivors with elevated depressive symptoms.

OBJECTIVE: In line with screening guidelines, cancer survivors were consecutively screened on depressive symptoms (as part of standard care), with those reporting elevated levels of symptoms offered psychological care as part of a trial. Because of the low uptake, no conclusions could be drawn about the interventions' efficacy. Given the trial set-up (following screening guidelines and strict methodological quality criteria), we believe that this observational study reporting the flow of participation, reasons for and characteristics associated with nonparticipation, adds to the debate about the feasibility and efficiency of screening guidelines. METHODS: Two thousand six hundred eight medium- to long-term cancer survivors were consecutively screened on depressive symptoms using the Patient Health Questionnaire-9 (PHQ-9). Those with moderate depressive symptoms (PHQ-9 ≥ 10) were contacted and informed about the trial. Patient flow and reasons for nonparticipation were carefully monitored. RESULTS: One thousand thirty seven survivors (74.3%) returned the questionnaire, with 147 (7.6%) reporting moderate depressive symptoms. Of this group, 49 survivors (33.3%) were ineligible, including 26 survivors (17.7%) already receiving treatment and another 44 survivors (30.0%) reporting no need for treatment. Only 25 survivors (1.0%) participated in the trial. CONCLUSION: Of the approached survivors for screening, only 1% was eligible and interested in receiving psychological care as part of our trial. Four reasons for nonparticipation were: nonresponse to screening, low levels of depressive symptoms, no need, or already receiving care. Our findings question whether to spend the limited resources in psycho-oncological care on following screening guidelines and the efficiency of using consecutive screening for trial recruitment in cancer survivors.

Emerging role of dopamine in neovascularization of pheochromocytoma and paraganglioma.

Dopamine is a catecholamine that acts both as a neurotransmitter and as a hormone, exerting its functions via dopamine (DA) receptors that are present in a broad variety of organs and cells throughout the body. In the circulation, DA is primarily stored in and transported by blood platelets. Recently, the important contribution of DA in the regulation of angiogenesis has been recognized. In vitro and in vivo studies have shown that DA inhibits angiogenesis through activation of the DA receptor type 2. Overproduction of catecholamines is the biochemical hallmark of pheochromocytoma (PCC) and paraganglioma (PGL). The increased production of DA has been shown to be an independent predictor of malignancy in these tumors. The precise relationship underlying the association between DA production and PCC and PGL behavior needs further clarification. Herein, we review the biochemical and physiologic aspects of DA with a focus on its relations with VEGF and hypoxia inducible factor related angiogenesis pathways, with special emphasis on DA producing PCC and PGL.-Osinga, T. E., Links, T. P., Dullaart, R. P. F., Pacak, K., van der Horst-Schrivers, A. N. A., Kerstens, M. N., Kema, I. P. Emerging role of dopamine in neovascularization of pheochromocytoma and paraganglioma.

Extra-Pulmonary Neuroendocrine Carcinomas: A Population-Based Study in the Netherlands.

BACKGROUND: Extra-pulmonary neuroendocrine carcinomas (EP-NEC) are rare tumours that require expertise for correct and timely diagnosis, which is essential for clinical decision making. The number of patients affected, treatment given, and the proportion surviving the disease is based on limited evidence. The aim of this study is to retrospectively analyse the incidence, treatment, and relative survival (RS) of EP-NEC patients in the Netherlands. METHODS: Patients diagnosed between 2008-2012 with EP-NEC or NEC with unknown primary site (UP-NEC) were selected from the Netherlands Cancer Registry based on combinations of tumour localisation and morphology code. Incidence was studied using the European standardised (ESR) and world standardised rates, and RS was calculated using the Ederer II method. RESULTS: In total, 1,544 cases were analysed, 1,045 EP-NEC and 499 UP-NEC. For EP-NEC, the incidence was 1.0 per 100,000 person-years (ESR), the mean age was 68 years, and the male to female ratio was 1: 0.6. Most frequent EP-NEC localisations were the bladder and the gastrointestinal tract, and the treatment most frequently given was surgery in combination with chemotherapy. The overall 5-year RS was 38% for patients with local/regional disease (n = 447), and 7% for patients with extensive disease (n = 582). For UP-NEC patients (n = 499), the 5-year RS was 6%. CONCLUSIONS: This study is the first nationwide study presenting an increase in the incidence of EP-NEC patients from 196 to 260 cases annually in the Netherlands. The best 5-year RS was found for EP-NEC patients with local disease located in the bladder, where the worst 5-year RS was found for patients with disease located in the oesophagus.

Kidney Involvement in Systemic Calcitonin Amyloidosis Associated With Medullary Thyroid Carcinoma.

A 52-year-old woman with widely disseminated medullary thyroid carcinoma developed nephrotic syndrome and slowly decreasing kidney function. A kidney biopsy was performed to differentiate between malignancy-associated membranous glomerulopathy and tyrosine kinase inhibitor-induced focal segmental glomerulosclerosis. Surprisingly, the biopsy specimen revealed diffuse glomerular deposition of amyloid that was proved to be derived from the calcitonin hormone (Acal), produced by the medullary thyroid carcinoma. This amyloid was also present in an abdominal fat pad biopsy. Although local ACal deposition is a characteristic feature of medullary thyroid carcinoma, the systemic amyloidosis involving the kidney that is presented in this case report has not to our knowledge been described previously and may be the result of long-term high plasma calcitonin levels. Our case illustrates that systemic calcitonin amyloidosis should be considered in the differential diagnosis of proteinuria in patients with medullary thyroid carcinoma.

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.