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Selenium Supplementation in Patients with Hashimoto Thyroiditis:A Systematic Review and Meta-Analysis of Randomized Clinical Trials.
Huwiler, VV, Maissen-Abgottspon, S, Stanga, Z, Mühlebach, S, Trepp, R, Bally, L, Bano, A
Thyroid : official journal of the American Thyroid Association. 2024
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Plain language summary
Hashimoto Thyroiditis (HT) is a disease of the thyroid gland, which can result in insufficient production of thyroid hormone. Thyroid hormone is responsible for numerous functions within the body, such as weight regulation and energy production. Selenium is a nutrient that is used in the body to make thyroid hormones and low levels have been seen in patients with HT. Selenium supplementation has been researched previously, but inconsistent results have been shown. This systematic review and meta-analysis of 35 and 32 randomised control trials respectively, aimed to determine the effect of selenium supplementation on HT. The results showed that selenium supplementation favourably influenced thyroid hormones and oxidative stress, without affecting inflammation, but only if individuals were not receiving thyroid hormone replacement therapy. Adverse events were similar between the supplementation and control groups. It was concluded that selenium supplementation is a safe and effective therapy for individuals with HT who are not receiving hormone replacement therapy. This study could be used by healthcare professionals to recommend selenium supplementation as a way to balance thyroid hormones and alleviate the effects of HT.
Abstract
Background: Hashimoto thyroiditis (HT) is the most common cause of hypothyroidism in iodine-sufficient areas. Selenium is an essential trace element required for thyroid hormone synthesis and exerts antioxidant effects. Therefore, it may be of relevance in the management of HT. Methods: We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) to evaluate the effect of selenium supplementation on thyroid function (thyrotropin [TSH], free and total thyroxine [fT4, T4], free and total triiodothyronine [fT3, T3]), thyroid antibodies (thyroid peroxidase antibodies [TPOAb], thyroglobulin antibodies [TGAb], thyrotropin receptor antibody [TRAb]), ultrasound findings (echogenicity, thyroid volume), immune markers, patient-reported outcomes, and adverse events in HT. The study protocol was registered on PROSPERO (CRD42022308377). We systematically searched MEDLINE, Embase, CINHAL, Web of Science, Google Scholar, and the Cochrane CENTRAL Register of Trials from inception to January 2023 and searched citations of eligible studies. Two independent authors reviewed and coded the identified literature. The primary outcome was TSH in patients without thyroid hormone replacement therapy (THRT); the others were considered secondary outcomes. We synthesized the results as standardized mean differences (SMD) or odds ratio (OR), assessed risk of bias using the Cochrane RoB 2 tool, and rated the evidence using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. Results: We screened 687 records and included 35 unique studies. Our meta-analysis found that selenium supplementation decreased TSH in patients without THRT (SMD -0.21 [confidence interval, CI -0.43 to -0.02]; 7 cohorts, 869 participants; I2 = 0%). In addition, TPOAb (SMD -0.96 [CI -1.36 to -0.56]; 29 cohorts; 2358 participants; I2 = 90%) and malondialdehyde (MDA; SMD -1.16 [CI -2.29 to -0.02]; 3 cohorts; 248 participants; I2 = 85%) decreased in patients with and without THRT. Adverse effects were comparable between the intervention and control groups (OR 0.89 [CI 0.46 to 1.75]; 16 cohorts; 1339 participants; I2 = 0%). No significant changes were observed in fT4, T4, fT3, T3, TGAb, thyroid volume, interleukin (IL)-2, and IL-10. Overall, certainty of evidence was moderate. Conclusions: In people with HT without THRT, selenium was effective and safe in lowering TSH, TPOAb, and MDA levels. Indications for lowering TPOAb were found independent of THRT.
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Effect of a four-week oral Phe administration on neural activation and cerebral blood flow in adults with early-treated phenylketonuria.
Maissen-Abgottspon, S, Steiner, L, Muri, R, Wijesinghe, D, Jann, K, Morishima, Y, Hochuli, M, Kreis, R, Trepp, R, Everts, R
NeuroImage. Clinical. 2024;:103654
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Abstract
BACKGROUND Phenylketonuria (PKU) is a rare inborn error of metabolism characterized by impaired catabolism of the amino acid phenylalanine (Phe) into tyrosine. Cross-sectional studies suggest slight alterations in cognitive performance and neural activation in adults with early-treated PKU. The influence of high Phe levels on brain function in adulthood, however, remains insufficiently studied. Therefore, we aimed to explore the effect of a four-week period of oral Phe administration - simulating a controlled discontinuation of Phe restriction and raising Phe to an off-diet scenario - on working memory-related neural activation and cerebral blood flow (CBF). METHODS We conducted a randomized, placebo-controlled, double-blind, crossover, non-inferiority trial to assess the effect of a high Phe load on working memory-related neural activation and CBF in early-treated adults with classical PKU. Twenty-seven patients with early-treated classical PKU were included and underwent functional magnetic resonance imaging (fMRI) of the working memory network and arterial spin labeling (ASL) MRI to assess CBF before and after a four-week intervention with Phe and placebo. At each of the four study visits, fMRI working memory task performance (reaction time and accuracy) and plasma Phe, tyrosine, and tryptophan levels were obtained. Additionally, cerebral Phe was determined by 1H-MR spectroscopy. RESULTS Plasma Phe and cerebral Phe were significantly increased after the Phe intervention. However, no significant effect of Phe compared to placebo was found on neural activation and CBF. Regarding fMRI task performance, a significant impact of the Phe intervention on 1-back reaction time was observed with slower reaction times following the Phe intervention, whereas 3-back reaction time and accuracy did not differ following the Phe intervention compared to the placebo intervention. CONCLUSION Results from this present trial simulating a four-week discontinuation of the Phe-restricted diet showed that a high Phe load did not uniformly affect neural markers and cognition in a statistically significant manner. These results further contribute to the discussion on safe Phe levels during adulthood and suggest that a four-week discontinuation of Phe-restricted diet does not demonstrate significant changes in brain function.
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Cognition after a 4-week high phenylalanine intake in adults with phenylketonuria - a randomized controlled trial.
Trepp, R, Muri, R, Maissen-Abgottspon, S, Haynes, AG, Hochuli, M, Everts, R
The American journal of clinical nutrition. 2024;(4):908-916
Abstract
BACKGROUND Phenylketonuria (PKU) is an autosomal recessive metabolic disorder characterized by increased phenylalanine (Phe) concentrations in the blood and brain. Despite wide agreement on treatment during childhood, recommendations for adults are still controversial. OBJECTIVE To assess the impact of a 4-week increase in Phe intake (simulating normal dietary Phe consumption) on cognition, mood, and depression in early-treated adults with PKU in a double-blind, randomized controlled trial (RCT). METHODS In a single-site crossover trial, 30 adult patients with classical PKU diagnosed at birth were recruited. All patients underwent a 4-week period of oral Phe administration (1500-3000 mg Phe/d) and a 4-week placebo period in a randomly assigned order with age, sex, and place of usual medical care as stratification factors. Analyses were based on the intention-to-treat (ITT) and per protocol (PP) approach to claim noninferiority (noninferiority margin -4%), with working memory accuracy as the primary endpoint and additional cognitive domains, mood, and depression as secondary endpoints. RESULTS For the primary endpoint, a 4-week increase of Phe intake was noninferior to placebo with respect to working memory accuracy in both the ITT [point estimate 0.49; lower limit 95% confidence interval (CI): -1.99] and the PP analysis (point estimate -1.22; lower limit 95% CI: -2.60). Secondary outcomes (working memory reaction time, manual dexterity, mood, and depression) did not significantly differ between the Phe and placebo period, except for sustained attention (point estimate 31.0; lower limit 95% CI: 9.0). Adverse events were more frequent during the Phe than during the placebo period (95% CI: 1.03, 2.28, P = 0.037). CONCLUSIONS In early-treated adult patients with PKU, a 4-week high Phe intake was noninferior to continuing Phe restriction regarding working memory accuracy, and secondary outcomes did not differ except for sustained attention. Longer-term RCTs are required to determine whether low Phe levels need to be maintained throughout different periods of adulthood. This trial was registered at the clinicaltrials.gov as NCT03788343.
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Transient brain structure changes after high phenylalanine exposure in adults with phenylketonuria.
Muri, R, Rummel, C, McKinley, R, Rebsamen, M, Maissen-Abgottspon, S, Kreis, R, Radojewski, P, Pospieszny, K, Hochuli, M, Wiest, R, et al
Brain : a journal of neurology. 2024
Abstract
Phenylketonuria is a rare metabolic disease resulting from a deficiency of the enzyme phenylalanine hydroxylase. Recent cross-sectional evidence suggests that early-treated adults with phenylketonuria exhibit alterations in cortical grey matter compared to healthy peers. However, the effects of high phenylalanine exposure on brain structure in adulthood need to be further elucidated. In this double-blind, randomised, placebo-controlled crossover trial, we investigated the impact of a four-week high phenylalanine exposure on the brain structure and its relationship to cognitive performance and metabolic parameters in early-treated adults with phenylketonuria. Twenty-eight adult patients with early-treated classical phenylketonuria (19-48 years) underwent magnetic resonance imaging before and after the four-week phenylalanine and placebo interventions (four timepoints). Structural T1-weighted images were preprocessed and evaluated using DL+DiReCT, a deep-learning-based tool for brain morphometric analysis. Cortical thickness, white matter volume, and ventricular volume were compared between the phenylalanine and placebo periods. Brain phenylalanine levels were measured using 1H spectroscopy. Blood levels of phenylalanine, tyrosine, and tryptophan were assessed at each of the four timepoints, along with performance in executive functions and attention. Blood phenylalanine levels were significantly higher after the phenylalanine period (1441µmol/L) than after the placebo period (873µmol/L, P<0.001). Morphometric analyses revealed a statistically significant decrease in cortical thickness in 17 out of 60 brain regions after the phenylalanine period compared to placebo. The largest decreases were observed in the right pars orbitalis (point estimate=-0.095mm, P<0.001) and the left lingual gyrus (point estimate=-0.070mm, P<0.001). Bilateral white matter and ventricular volumes were significantly increased after the phenylalanine period. However, the structural alterations in the Phe-placebo group returned to baseline measures following the washout and placebo period. Additionally, elevated blood and brain phenylalanine levels were related to increased bilateral white matter volume (rs=0.43 to 0.51, P≤0.036) and decreased cortical thickness (rs=-0.62 to -0.39, not surviving FDR correction) after the phenylalanine and placebo periods. Moreover, decreased cortical thickness was correlated with worse cognitive performance after both periods (rs=-0.54 to -0.40, not surviving FDR correction). These findings provide evidence that a four-week high phenylalanine exposure in adults with phenylketonuria results in transient reductions of the cortical grey matter and increases in white matter volume. Further research is needed to determine the potential long-term impact of high phenylalanine levels on brain structure and function in adults with phenylketonuria.
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Multidisciplinary recommendations for essential baseline functional and laboratory tests to facilitate early diagnosis and management of immune-related adverse events among cancer patients.
Özdemir, BC, Espinosa da Silva, C, Arangalage, D, Monney, P, Guler, SA, Huynh-Do, U, Stirnimann, G, Possamai, L, Trepp, R, Hoepner, R, et al
Cancer immunology, immunotherapy : CII. 2023;(7):1991-2001
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Abstract
Immune checkpoint inhibitors (ICIs) have fundamentally changed the treatment landscape of various cancers. While ICI treatments result in improved survival, quality of life and are cost-effective, the majority of patients experience at least one immune-related adverse event (irAE). Many of these side effects cause little discomfort or are asymptomatic; however, irAEs can affect any organ and are potentially life-threatening. Consequently, early diagnosis and appropriate treatment of irAEs are critical for optimizing long-term outcomes and quality of life in affected patients. Some irAEs are diagnosed according to typical symptoms, others by abnormal findings from diagnostic tests. While there are various guidelines addressing the management of irAEs, recommendations for the early recognition of irAEs as well as the optimal extent and frequency of laboratory tests are mostly lacking. In clinical practice, blood sampling is usually performed before each ICI administration (i.e., every 2-3 weeks), often for several months, representing a burden for patients as well as health care systems. In this report, we propose essential laboratory and functional tests to improve the early detection and management of irAEs and in cancer patients treated with ICIs. These multidisciplinary expert recommendations regarding essential laboratory and functional tests can be used to identify possible irAEs at an early time point, initiate appropriate interventions to improve patient outcomes, and reduce the burden of blood sampling during ICI treatment.
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Update on Histological Reporting Changes in Neuroendocrine Neoplasms.
Bräutigam, K, Rodriguez-Calero, A, Kim-Fuchs, C, Kollár, A, Trepp, R, Marinoni, I, Perren, A
Current oncology reports. 2021;(6):65
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Abstract
PURPOSE OF REVIEW Classification and nomenclature of neuroendocrine neoplasms (NEN) have frequently changed over the last years. These changes reflect both increasing knowledge and international standardisation. RECENT FINDINGS The most recent changes in the Gastro-Entero-Pancreatic system induced the concept of well-differentiated NET with high proliferation rate (NET G3), explaining partially the heterogeneity of G3 NEN. Even if the nomenclature in pulmonary NEN is still different, the terms 'carcinoid' and 'atypical carcinoid' are widely overlapping with NET G1 and NET G2. Molecular data shows an additional heterogeneity both in well-differentiated NET and poorly differentiated NEC. However, no studies are available demonstrating clinical usefulness yet. The heterogeneity of NEN regarding the organ of origin, differentiation and molecular subtypes make development of personalised therapy a challenge needing more international and interdisciplinary collaborations and clinical trials allowing stratification according to biological subgroups.
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Prevalence of Iodine-Induced Hyperthyroidism After Administration of Iodinated Contrast During Radiographic Procedures: A Systematic Review and Meta-Analysis of the Literature.
Bervini, S, Trelle, S, Kopp, P, Stettler, C, Trepp, R
Thyroid : official journal of the American Thyroid Association. 2021;(7):1020-1029
Abstract
Background: Iodine-induced hyperthyroidism (IIH) was a common issue in the early twentieth century after introduction of iodine supplementation in dietary salt. Currently, IIH is mostly encountered in Western countries as a consequence of radiographic procedures involving the administration of iodinated contrast media (ICM). However, little is known about the magnitude and clinical relevance of this issue. To assess the incidence of hyperthyroidism after ICM exposure, we performed a systematic review and meta-analysis of the literature. Methods: MEDLINE, Embase, and the Cochrane Library were systematically searched for studies published between 1946 and May 2018. Studies were considered eligible if they investigated the association between hyperthyroidism and iodinated contrast. Data on study design, baseline characteristics, and outcomes were extracted independently by two reviewers. Results: Thirty out of 1493 retrieved studies were included in the analysis. The time endpoint to assess thyroid hormone levels after ICM exposure varied between 1 and 541 days among studies, with most studies having a time endpoint between 7 and 56 days. The overall estimated prevalence of overt hyperthyroidism after ICM exposure was extremely low (0.1% [confidence interval, CI 0-0.6%]), and did not change after adjustments for baseline thyroid function status (0.3% in euthyroid patients at baseline [CI 0-1.7%]). There were no cases with overt hyperthyroidism at 7 days after ICM exposure, and the incidence was very low at 30 days (0.2% [CI 0-0.8%]). Conclusion: The incidence of IIH after ICM administration during radiographic procedures is extremely low.
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Impact of phenylalanine on cognitive, cerebral, and neurometabolic parameters in adult patients with phenylketonuria (the PICO study): a randomized, placebo-controlled, crossover, noninferiority trial.
Trepp, R, Muri, R, Abgottspon, S, Bosanska, L, Hochuli, M, Slotboom, J, Rummel, C, Kreis, R, Everts, R
Trials. 2020;(1):178
Abstract
BACKGROUND The population of adult patients with early-treated phenylketonuria (PKU) following newborn screening is growing substantially. The ideal target range of blood phenylalanine (Phe) levels in adults outside pregnancy is a matter of debate. Therefore, prospective intervention studies are needed to evaluate the effects of an elevated Phe concentration on cognition and structural, functional, and neurometabolic parameters of the brain. METHODS The PICO (Phenylalanine and Its Impact on Cognition) Study evaluates the effect of a 4-week Phe load on cognition and cerebral parameters in adults with early-treated PKU in a double-blind, randomized, placebo-controlled, crossover, noninferiority trial. PARTICIPANTS Thirty adult patients with early-treated PKU and 30 healthy controls comparable to patients with regard to age, sex, and educational level will be recruited from the University Hospitals Bern and Zurich, Switzerland. Patients are eligible for the study if they are 18 years of age or older and had PKU diagnosed after a positive newborn screening and were treated with a Phe-restricted diet starting within the first 30 days of life. INTERVENTION The cross-over intervention consists of 4-week oral Phe or placebo administration in patients with PKU. The study design mimics a Phe-restricted and a Phe-unrestricted diet using a double-blinded, placebo-controlled approach. OBJECTIVES The primary objective of the PICO Study is to prospectively assess whether a temporarily elevated Phe level influences cognitive performance (working memory assessed with a n-back task) in adults with early-treated PKU. As a secondary objective, the PICO Study will elucidate the cerebral (fMRI, neural activation during a n-back task; rsfMRI, functional connectivity at rest; DTI, white matter integrity; and ASL, cerebral blood flow) and neurometabolic mechanisms (cerebral Phe level) that accompany changes in Phe concentration. Cognition, and structural and functional parameters of the brain of adult patients with early-treated PKU will be cross-sectionally compared to healthy controls. All assessments will take place at the University Hospital Bern, Switzerland. RANDOMIZATION Central randomization will be used to assign participants to the different treatment arms with age, sex, and center serving as the stratification factors. Randomization lists will be generated by an independent statistician. Blinding: All trial personnel other than the statistician generating the randomization list and the personnel at the facility preparing the interventional product are blinded to the assigned treatment. DISCUSSION Using a combination of neuropsychological and neuroimaging data, the PICO Study will considerably contribute to improve the currently insufficient level of evidence on how adult patients with early-treated PKU should be managed. TRIAL REGISTRATION The study is registered at clinicaltrials.gov (NCT03788343) on the 27th of December 2018, at kofam.ch (SNCTP000003117) on the 17th of December 2018, and on the International Clinical Trials Registry Platform of the WHO.
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Correction to: Impact of phenylalanine on cognitive, cerebral, and neurometabolic parameters in adult patients with phenylketonuria (the PICO study): a randomized, placebo-controlled, crossover, noninferiority trial.
Trepp, R, Muri, R, Abgottspon, S, Bosanska, L, Hochuli, M, Slotboom, J, Rummel, C, Kreis, R, Everts, R
Trials. 2020;(1):561
Abstract
An amendment to this paper has been published and can be accessed via the original article.
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Treatment sequence in patients with neuroendocrine tumours: a nationwide multicentre, observational analysis of the Swiss neuroendocrine tumour registry.
Kollar, A, Bütikofer, L, Ochsenbein, A, Stettler, C, Trepp, R
Swiss medical weekly. 2020;:w20176
Abstract
BACKGROUND In recent years, several treatment modalities have proved to be effective in the treatment of neuroendocrine tumours (NETs). However, there is currently no consensus on the sequence in which these options are best used. METHODS In this observational study, we analysed the treatment modalities and sequences of all patients included in the Swiss NeuroEndocrine Tumour registry (SwissNET). SwissNET is a national registry, which has prospectively included patients with a NET from all regions of Switzerland since 2008. RESULTS The registry includes 1366 patients; 1063 had documented therapies after the main diagnosis and were included in the analysis. The median follow-up time was 1.86 years. The most common primary site was the small intestine (291 patients, 27%) followed by pancreas (254 patients, 24%), lung (172 patients, 16%) and appendix (163 patients, 15%). A total of 167 different therapy sequences were observed. In 708 (67%) patients, surgery was the only treatment. The sequence of surgery followed by chemotherapy was most frequently documented in poorly (G3) differentiated (24 patients, 60%) and pancreatic (15 patients, 34%) NETs. Tumours treated with surgery followed by biotherapy or followed by peptide receptor radionuclide therapy (PRRT) were predominantly well-differentiated G1 NETs of the small intestine. In patients who were treated with either PRRT or systemic therapy (chemotherapy or molecular therapy) or both, PRRT was used more frequently than systemic therapy in patients with a small intestinal NET (35 patients, 62% vs 30, 54%), whereas the opposite held true in pancreatic (44 patients, 59% vs 56, 70%) and lung NETs (6 patients, 14% vs 40, 97%). If both chemotherapy and molecular therapy were used, chemotherapy was applied prior to molecular therapy in 13 of 19 (68%) patients with a pancreatic NET. CONCLUSION Surgery represents the treatment of choice in most patients with a NET irrespective of tumour stage. In patients receiving additional treatment, an impressive variety of treatment sequences were documented. In small intestinal NETs, patients received PRRT more often than chemotherapy, whereas the opposite holds true for patients with pancreatic and lung NETs.