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.
The primary aim was to study the risk of cardiovascular mortality in patients with differentiated thyroid carcinoma (DTC). Secondary aims were to evaluate all-cause mortality and explore the relation ...between thyroid-stimulating hormone (TSH; also known as thyrotropin) level and these outcome parameters.
Subjects from two cohorts were retrospectively compared by Cox regression analyses; 524 patients with DTC and 1,572 sex- and age-matched controls from a large population-based study in the same geographic region.
Mean age plus or minus standard deviation was 49 ± 14 years. Median follow-up was 8.5 years (interquartile range IQR, 4.1 to 15.9 years) for patients with DTC and 10.5 years (IQR, 9.9 to 10.9 years) for controls. One hundred patients with DTC (19.1%) died, 22 (4.2%) as a result of cardiovascular disease, 39 (7.4%) as a result of DTC, and 39 (7.4%) as a result of other/unknown causes. Eighty-five controls (5.4%) died, 24 (1.5%) as a result of cardiovascular disease and 61 (3.9%) as a result of other/unknown causes. Patients with DTC had an increased risk of cardiovascular and all-cause mortality (hazard ratios HRs, 3.35 95% CI, 1.66 to 6.74 and 4.40 95% CI, 3.15 to 6.14, respectively, adjusted for age, sex, and cardiovascular risk factors). Within the DTC group, TSH level was predictive for cardiovascular mortality; the adjusted HR was 3.08 (95% CI, 1.32 to 7.21) for each 10-fold decrease in geometric mean TSH level.
The risk of cardiovascular and all-cause mortality is increased in patients with DTC, independent of age, sex, and cardiovascular risk factors. A lower TSH level is associated with increased cardiovascular mortality, supporting the current European Thyroid Association and the American Thyroid Association guidelines of tempering TSH suppression in patients with low risk of cancer recurrence. Furthermore, patients with DTC may benefit from assessment and treatment of cardiovascular risk factors.
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.
Metformin treatment is associated with improved outcome after myocardial infarction in patients with diabetes. In animal experimental studies metformin preserves left ventricular function.
To ...evaluate the effect of metformin treatment on preservation of left ventricular function in patients without diabetes presenting with ST-segment elevation myocardial infarction (STEMI).
Double-blind, placebo-controlled study conducted among 380 patients who underwent primary percutaneous coronary intervention (PCI) for STEMI at the University Medical Center Groningen, The Netherlands, between January 1, 2011, and May 26, 2013.
Metformin hydrochloride (500 mg) (n = 191) or placebo (n = 189) twice daily for 4 months.
The primary efficacy measure was left ventricular ejection fraction (LVEF) after 4 months, assessed by magnetic resonance imaging. A secondary efficacy measure was the N-terminal pro-brain natriuretic peptide (NT-proBNP) concentration after 4 months. The incidence of major adverse cardiac events (MACE; the combined end point of death, reinfarction, or target-lesion revascularization) was recorded until 4 months as a secondary efficacy measure.
At 4 months, all patients were alive and none were lost to follow-up. LVEF was 53.1% (95% CI, 51.6%-54.6%) in the metformin group (n = 135), compared with 54.8% (95% CI, 53.5%-56.1%) (P = .10) in the placebo group (n = 136). NT-proBNP concentration was 167 ng/L in the metformin group (interquartile range IQR, 65-393 ng/L) and 167 ng/L in the placebo group (IQR, 74-383 ng/L) (P = .66). MACE were observed in 6 patients (3.1%) in the metformin group and in 2 patients (1.1%) in the placebo group (P = .16). Creatinine concentration (79 µmol/L IQR, 70-87 µmol/L vs 79 µmol/L IQR, 72-89 µmol/L, P = .61) and glycated hemoglobin (5.9% IQR, 5.6%-6.1% vs 5.9% IQR, 5.7%-6.1%, P = .15) were not significantly different between both groups. No cases of lactic acidosis were observed.
Among patients without diabetes presenting with STEMI and undergoing primary PCI, the use of metformin compared with placebo did not result in improved LVEF after 4 months. The present findings do not support the use of metformin in this setting.
clinicaltrials.gov Identifier: NCT01217307.
Recent years have seen major changes in clinical practice which may have affected the incidence rates of pheochromocytoma(PCC)/sympathetic paraganglioma(sPGL). There is, however, a lack of up-to-date ...information describing trends in these incidence rates.
We searched the Dutch pathology registry to identify all histopathologically confirmed cases of PCC/sPGL diagnosed between 1995 and 2015. We calculated incidence rates according to age category as well as age-standardized incidence rates (ASR). We also searched Medline and Embase to find data on nationwide incidence rates of PCC/sPGL.
The nationwide pathology study revealed a total of 1493 patients with either PCC or sPGL. The ASR for PCC increased from 0.29 (95% CI: 0.24–0.33) to 0.46 (95% CI: 0.39–0.53) per 100,000 person-years in the periods 1995–1999 and 2011–2015, respectively. For sPGL the ASR in these same periods were 0.08 (95% CI: 0.06–0.10) and 0.11 (95% CI: 0.09–0.13) per 100,000 person-years, respectively. Concomitantly, PCC size decreased (β −0.17; P < .001) and age at diagnosis increased (β 0.13; P = .001). Our systematic search yielded 3 papers reporting on a total of 530 PCC/sPGL cases, showing a combined annual incidence rate varying from 0.04 to 0.21 per 100,000 person-years.
Incidence rates of PCC/sPGL have increased significantly over the past two decades. This trend coincides with a higher age and a smaller tumor size at diagnosis. Most likely these observations are at least in part the result of changes in clinical practice during the study period, with a more intensified use of both imaging studies and biochemical tests for detecting PCC/sPGL.
•Up-to-date epidemiological data on PCC/sPGL are lacking.•The incidence rate of PCC/sPGL has increased significantly during the past two decades.•This rise in incidence rate is accompanied by a reduction in tumor size and a higher age at diagnosis.•The observed epidemiological changes are most likely the result of more intensified use of better diagnostics.
The adrenal medulla is composed predominantly of chromaffin cells producing and secreting the catecholamines dopamine, norepinephrine, and epinephrine. Catecholamine biosynthesis and secretion is a ...complex and tightly controlled physiologic process. The pathways involved have been extensively studied, and various elements of the underlying molecular machinery have been identified. In this review, we provide a detailed description of the route from stimulus to secretion of catecholamines by the normal adrenal chromaffin cell compared to chromaffin tumor cells in pheochromocytomas. Pheochromocytomas are adrenomedullary tumors that are characterized by uncontrolled synthesis and secretion of catecholamines. This uncontrolled secretion can be partly explained by perturbations of the molecular catecholamine secretory machinery in pheochromocytoma cells. Chromaffin cell tumors also include sympathetic paragangliomas originating in sympathetic ganglia. Pheochromocytomas and paragangliomas are usually locally confined tumors, but about 15% do metastasize to distant locations. Histopathological examination currently poorly predicts future biologic behavior, thus long term postoperative follow-up is required. Therefore, there is an unmet need for prognostic biomarkers. Clearer understanding of the cellular mechanisms involved in the secretory characteristics of pheochromocytomas and sympathetic paragangliomas may offer one approach for the discovery of novel prognostic biomarkers for improved therapeutic targeting and monitoring of treatment or disease progression.
Data on hyperglycemia and glucose variability in relation to diabetes mellitus, either known or unknown in ICU-setting in COVID-19, are scarce. We prospectively studied daily glucose variables and ...mortality in strata of diabetes mellitus and glycosylated hemoglobin among mechanically ventilated COVID-19 patients.
We used linear-mixed effect models in mechanically ventilated COVID-19 patients to investigate mean and maximum difference in glucose concentration per day over time. We compared ICU survivors and non-survivors and tested for effect-modification by pandemic wave 1 and 2, diabetes mellitus, and admission HbA1c.
Among 232 mechanically ventilated COVID-19 patients, 21.1% had known diabetes mellitus, whereas 16.9% in wave 2 had unknown diabetes mellitus. Non-survivors had higher mean glucose concentrations (ß 0.62 mmol/l; 95%CI 0.20-1.06; ß 11.2 mg/dl; 95% CI 3.6-19.1; P = 0.004) and higher maximum differences in glucose concentrations per day (ß 0.85 mmol/l; 95%CI 0.37-1.33; ß 15.3; 95%CI 6.7-23.9; P = 0.001). Effect modification by wave, history of diabetes mellitus and admission HbA1c in associations between glucose and survival was not present. Effect of higher mean glucose concentrations was modified by pandemic wave (wave 1 (ß 0.74; 95% CI 0.24-1.23 mmol/l) ; (ß 13.3; 95%CI 4.3-22.1 mg/dl)) vs. (wave 2 (ß 0.37 (95%CI 0.25-0.98) mmol/l) (ß 6.7 (95% ci 4.5-17.6) mg/dl)).
Hyperglycemia and glucose variability are associated with mortality in mechanically ventilated COVID-19 patients irrespective of the presence of diabetes mellitus.
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.
We aimed to establish the correlation between the salivary iodine secretion and UIE, to evaluate the clinical applicability of the iodine saliva measurement.
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.
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).
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.
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