Efficacy of α-Blockers on Hemodynamic Control during Pheochromocytoma Resection: A Randomized Controlled Trial

CONTEXT: Pretreatment with α-adrenergic receptor blockers is recommended to prevent hemodynamic instability during resection of a pheochromocytoma or sympathetic paraganglioma (PPGL). OBJECTIVE: To determine which type of α-adrenergic receptor blocker provides the best efficacy. DESIGN: Randomized controlled open-label trial (PRESCRIPT; ClinicalTrials.gov NCT01379898). SETTING: Multicenter study including 9 centers in The Netherlands. PATIENTS: 134 patients with nonmetastatic PPGL. INTERVENTION: Phenoxybenzamine or doxazosin starting 2 to 3 weeks before surgery using a blood pressure targeted titration schedule. Intraoperative hemodynamic management was standardized. MAIN OUTCOME MEASURES: Primary efficacy endpoint was the cumulative intraoperative time outside the blood pressure target range (ie, SBP >160 mmHg or MAP <60 mmHg) expressed as a percentage of total surgical procedure time. Secondary efficacy endpoint was the value on a hemodynamic instability score. RESULTS: Median cumulative time outside blood pressure targets was 11.1% (interquartile range [IQR]: 4.3-20.6] in the phenoxybenzamine group compared to 12.2% (5.3-20.2)] in the doxazosin group (P = .75, r = 0.03). The hemodynamic instability score was 38.0 (28.8-58.0) and 50.0 (35.3-63.8) in the phenoxybenzamine and doxazosin group, respectively (P = .02, r = 0.20). The 30-day cardiovascular complication rate was 8.8% and 6.9% in the phenoxybenzamine and doxazosin group, respectively (P = .68). There was no mortality after 30 days. CONCLUSIONS: The duration of blood pressure outside the target range during resection of a PPGL was not different after preoperative treatment with either phenoxybenzamine or doxazosin. Phenoxybenzamine was more effective in preventing intraoperative hemodynamic instability, but it could not be established whether this was associated with a better clinical outcome

Integrative multi-omics analysis identifies a prognostic miRNA signature and a targetable miR-21-3p/TSC2/ mTOR axis in metastatic pheochromocytoma/ paraganglioma

Rationale: Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors that present variable outcomes. To date, no effective therapies or reliable prognostic markers are available for patients who develop metastatic PPGL (mPPGL). Our aim was to discover robust prognostic markers validated through in vitro models, and define specific therapeutic options according to tumor genomic features. Methods: We analyzed three PPGL miRNome datasets (n=443), validated candidate markers and assessed them in serum samples (n=36) to find a metastatic miRNA signature. An integrative study of miRNome, transcriptome and proteome was performed to find miRNA targets, which were further characterized in vitro. Results: A signature of six miRNAs (miR-21-3p, miR-183-5p, miR-182-5p, miR-96-5p, miR-551b-3p, and miR-202-5p) was associated with metastatic risk and time to progression. A higher expression of five of these miRNAs was also detected in PPGL patients’ liquid biopsies compared with controls. The combined expression of miR-21-3p/miR-183-5p showed the best power to predict metastasis (AUC=0.804, P=4.67·10-18), and was found associated in vitro with pro-metastatic features, such as neuroendocrine-mesenchymal transition phenotype, and increased cell migration rate. A pan-cancer multi-omic integrative study correlated miR-21-3p levels with TSC2 expression, mTOR pathway activation, and a predictive signature for mTOR inhibitor-sensitivity in PPGLs and other cancers. Likewise, we demonstrated in vitro a TSC2 repression and an enhanced rapamycin sensitivity upon miR-21-3p expression. Conclusions: Our findings support the assessment of miR-21-3p/miR-183-5p, in tumors and liquid biopsies, as biomarkers for risk stratification to improve the PPGL patients’ management. We propose miR-21-3p to select mPPGL patients who may benefit from mTOR inhibitors

Diagnosis of endocrine disease: Biochemical diagnosis of phaeochromocytoma and paraganglioma

Item does not contain fulltextAdrenal phaechromocytomas and extra-adrenal sympathetic paragangliomas (PPGLs) are rare neuroendocrine tumours, characterised by production of the catecholamines: noradrenaline, adrenaline and dopamine. Tumoural secretion of catecholamines determines their clinical presentation which is highly variable among patients. Up to 10-15% of patients present entirely asymptomatic and in 5% of all adrenal incidentalomas a PPGL is found. Therefore, prompt diagnosis of PPGL remains a challenge for every clinician. Early consideration of the presence of a PPGL is of utmost importance, because missing the diagnosis can be devastating due to potential lethal cardiovascular complications of disease. First step in diagnosis is proper biochemical analysis to confirm or refute the presence of excess production of catecholamines or their metabolites. Biochemical testing is not only indicated in symptomatic patients but also in asymptomatic patients with adrenal incidentalomas or identified genetic predispositions. Measurements of metanephrines in plasma or urine offer the best diagnostic performance and are the tests of first choice. Paying attention to sampling conditions, patient preparation and use of interfering medications is important, as these factors can largely influence test results. When initial test results are inconclusive, additional tests can be performed, such as the clonidine suppression test. Test results can also be used for estimation of tumour size or prediction of tumour location and underlying genotype. Furthermore, tumoural production of 3-methoxytyramine is associated with presence of an underlying SDHB mutation and may be a biomarker of malignancy

Central and cerebrovascular effects of leg crossing in humans with sympathetic failure

Leg crossing increases arterial pressure and combats symptomatic orthostatic hypotension in patients with sympathetic failure This study compared the central and cerebrovascular effects of leg crossing in patients with sympathetic failure and healthy controls. We addressed the relationship between MCA V-mean (middle cerebral artery blood velocity, using transcranial Doppler ultrasound), frontal lobe oxygenation [O(2)Hb (oxyhaemoglobin)] and MAP (mean arterial pressure), CO (cardiac output) and TPR (total peripheral resistance) in six patients (aged 37 67 years; three women) and age- and gender-matched controls during leg crossing. In the patients, leg crossing increased MAP from 58 (42-79) to 72 (52-89) compared with 84 (70-95) to 90 (74-94) mmHg in the controls. MCA V-mean increased from 55 (38-77) to 63(45-80) and from 56 (46-77) to 64 (46-80) cm/s respectively (P < 0.05), with a larger rise in O(2)Hb [1 12 (0.52-3.27)] in the patients compared with the controls [0 83 (-0.11 to 2.04) mu mol/l]. In the control subjects, CO increased 11% (P<0.05) with no change in TPR By contrast, in the patients. CO increased 9% (P<0.05), but also TPR increased by 13% (P<0.05). In conclusion, leg crossing improves cerebral perfusion and oxygenation both in patients with sympathetic failure and in healthy subjects However, in healthy subjects, cerebral perfusion and oxygenation were improved by a rise in CO without significant changes in TPR or MAP, whereas in patients with sympathetic failure, cerebral perfusion and oxygenation were improved through a rise in MAP due to increments in both CO and TP

Theophylline improves hypoglycemia unawareness in type 1 diabetes.

Item does not contain fulltextIatrogenic hypoglycemias and the subsequent occurrence of hypoglycemia unawareness are well-known complications of intensive insulin therapy in type 1 diabetic patients that limit glycemic management. From a pharmacological point of view, the adenosine-receptor antagonist theophylline might be beneficial in the management of hypoglycemia unawareness. Theophylline stimulates the release of catecholamines and reduces cerebral blood flow, thereby facilitating stronger metabolic responses to and a prompter perception of decreasing glucose levels. To test the effect of theophylline on responses to hypoglycemia, we performed paired hyperinsulinemic-hypoglycemic clamp studies in 15 diabetic patients with hypoglycemia unawareness and 15 matched healthy control subjects. In random order, we concurrently infused either theophylline or placebo. Measurements included counterregulatory hormones, symptoms, hemodynamic parameters, and sweat detection using a dew-point electrode. Additionally, middle cerebral artery velocities (V(MCA)) using transcranial Doppler were monitored as an estimate of cerebral blood flow. When compared with placebo, theophylline significantly enhanced responses of plasma epinephrine, norepinephrine, and cortisol levels in both diabetic patients and control subjects. Because of the theophylline, sweat production started at approximately 0.3 mmol/l higher glucose levels in both groups (P < 0.01), and symptom scores in diabetic patients approached those in control subjects. Theophylline decreased V(MCA) in both groups (P < 0.001), but significantly greater in diabetic patients (P < 0.01), and prevented the hypoglycemia-induced increase of V(MCA) that occurred during the placebo studies. We conclude that theophylline improves counterregulatory responses to and perception of hypoglycemia in diabetic patients with impaired awareness of hypoglycemia

Response to implementation of rapid cortisol during adrenal vein sampling

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An expert consensus statement on use of adrenal vein sampling for the subtyping of primary aldosteronism

Item does not contain fulltextAdrenal venous sampling is recommended by current guidelines to identify surgically curable causes of hyperaldosteronism but remains markedly underused. Key factors contributing to the poor use of adrenal venous sampling include the prevailing perceptions that it is a technically challenging procedure, difficult to interpret, and can be complicated by adrenal vein rupture. In addition, the lack of uniformly accepted standards for the performance of adrenal venous sampling contributes to its limited use. Hence, an international panel of experts working at major referral centers was assembled to provide updated advice on how to perform and interpret adrenal venous sampling. To this end, they were asked to use the PICO (Patient or Problem, Intervention, Control or comparison, Outcome) strategy to gather relevant information from the literature and to rely on their own experience. The level of evidence/recommendation was provided according to American Heart Association gradings whenever possible. A consensus was reached on several key issues, including the selection and preparation of the patients for adrenal venous sampling, the procedure for its optimal performance, and the interpretation of its results for diagnostic purposes even in the most challenging cases

Metabolome-guided genomics to identify pathogenic variants in isocitrate dehydrogenase, fumarate hydratase, and succinate dehydrogenase genes in pheochromocytoma and paraganglioma

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Alternative splice variant of the thiazide-sensitive NaCl cotransporter: a novel player in renal salt handling

The thiazide-sensitive NaCl cotransporter (NCC) is an important pharmacological target in the treatment of hypertension. The human SLC12A3 gene, encoding NCC, gives rise to three isoforms. Only the third isoform has been extensively investigated. The aim of the present study was, therefore, to establish the abundance and localization of the almost identical isoforms 1 and 2 (NCC1/2) in the human kidney and to determine their functional properties and regulation in physiological conditions. Immunohistochemical analysis of NCC1/2 in the human kidney revealed that NCC1/2 localizes to the apical plasma membrane of the distal convoluted tubule. Importantly, NCC1/2 mRNA constitutes approximately 44% of all NCC isoforms in the human kidney. Functional analysis performed in the Xenopus laevis oocyte revealed that thiazide-sensitive (22)Na(+) transport of NCC1 was significantly increased compared with NCC3. Mimicking a constitutively active phosphorylation site at residue 811 (S811D) in NCC1 further augmented Na(+) transport, while a nonphosphorylatable variant (S811A) of NCC1 prevented this enhanced response. Analysis of human urinary exosomes demonstrated that water loading in human subjects significantly reduces the abundance of NCC1/2 in urinary exosomes. The present study highlights that previously underrepresented NCC1/2 is a fully functional thiazide-sensitive NaCl-transporting protein. Being significantly expressed in the kidney, it may constitute a unique route of renal NaCl reabsorption and could, therefore, play an important role in blood pressure regulation