Andrew S Powlson

An in vivo nitric oxide clamp to investigate the influence of nitric oxide on continuous umbilical blood flow during acute hypoxaemia in the sheep fetus

1 The aims of this study in the ovine fetus were to (1) characterise continuous changes in umbilical blood flow and vascular conductance during acute hypoxaemia and (2) determine the effects of nitric oxide blockade on umbilical blood flow and vascular conductance during normoxic and hypoxaemic conditions using a novel in vivo‘nitric oxide clamp’. 2 Under 1–2 % halothane anaesthesia, seven ovine fetuses were instrumented between 118 and 125 days of gestation (term is ca 145 days) with vascular and amniotic catheters and a flow probe around an umbilical artery. At least 5 days after surgery, all fetuses were subjected to a 3 h protocol: 1 h of normoxia, 1 h of hypoxaemia and 1 h of recovery during fetal i.v. infusion with saline or, 1‐2 days later, during combined fetal treatment with the nitric oxide (NO) inhibitor NG‐nitro‐l‐arginine methyl ester (l‐NAME, 100 mg kg−1) and the NO donor sodium nitroprusside (NP, 5.1 ± 2.0 μg kg−1 min−1, the ‘nitric oxide clamp’). Following the end of the 3 h experimental protocol, the infusion of NP was withdrawn to unmask any persisting effects of fetal treatment with l‐NAME alone. 3 During acute hypoxaemia, the reduction in arterial partial pressure of O2 (Pa,O2) was similar in fetuses infused with saline or treated with the nitric oxide clamp. In all fetuses, acute hypoxaemia led to a progressive increase in mean arterial blood pressure and a fall in heart rate. In saline‐infused fetuses, acute hypoxaemia led to a rapid, but transient, decrement in umbilical vascular conductance. Thereafter, umbilical vascular conductance was maintained and a significant increase in umbilical blood flow occurred, which remained elevated until the end of the hypoxaemic challenge. In contrast, while the initial decrement in umbilical vascular conductance was prevented in fetuses treated with the nitric oxide clamp, the increase in umbilical blood flow during hypoxaemia was similar to that in fetuses infused with saline. After the 1 h recovery period of the acute hypoxaemia protocol, withdrawal of the sodium nitroprusside infusion from fetuses undergoing the nitric oxide clamp led to a significant, but transient, hypertension and a sustained umbilical vasoconstriction. 4 In conclusion, the data reported in this study of unanaesthetised fetal sheep (1) show that minute‐by‐minute analyses of haemodynamic changes in the umbilical vascular bed reveal an initial decrease in umbilical vascular conductance at the onset of hypoxaemia followed by a sustained increase in umbilical blood flow for the duration of the hypoxaemic challenge, (2) confirm that the increase in umbilical blood flow after 15 min hypoxaemia is predominantly pressure driven, and (3) demonstrate that nitric oxide plays a major role in the maintenance of umbilical blood flow under basal, but not under acute hypoxaemic, conditions.

Low DHEAS: A Sensitive and Specific Test for Detection of Subclinical Hypercortisolism in Adrenal Incidentalomas

Context Subclinical hypercortisolism (SH) occurs in 5% to 30% of adrenal incidentalomas (AIs). Common screening tests for adrenocorticotropin-independent hypercortisolism have substantial false-positive rates, mandating further time and resource-intensive investigations. Objective To determine whether low basal dehydroepiandrosterone sulfate (DHEAS) is a sensitive and specific screening test for SH in AI. Setting and Patients In total, 185 patients with AI were screened for adrenal medullary (plasma metanephrines) and cortical [1 mg overnight dexamethasone suppression test (ONDST), 24-hour urinary free cortisol (UFC), serum DHEAS, plasma renin, and aldosterone] hyperfunction. Positive ONDST [≥1.8 mcg/dL (≥50 nmol/L)] and/or UFC (more than the upper limit of reference range) results were further investigated. We diagnosed SH when at least 2 of the following were met: raised UFC, raised midnight serum cortisol, 48-hour dexamethasone suppression test (DST) cortisol ≥1.8 mcg/dL (≥50 nmol/L). Results 29 patients (16%) were diagnosed with SH. Adrenocorticotropin was <10 pg/mL (<2.2 pmol/L) in all patients with SH. We calculated age- and sex-specific DHEAS ratios (derived by dividing the DHEAS by the lower limit of the respective reference range) for all patients. Receiver operating characteristic curve analyses demonstrated that a ratio of 1.12 was sensitive (>99%) and specific (91.9%) for the diagnosis of SH. Cortisol following 1 mg ONDST of 1.9 mcg/dL (53 nmol/L) was a sensitive (>99%) screening test for SH but had lower specificity (82.9%). The 24-hour UFC lacked sensitivity (69%) and specificity (72%). Conclusion A single basal measurement of DHEAS offers comparable sensitivity and greater specificity to the existing gold-standard 1 mg DST for the detection of SH in patients with AIs.

A role for 11C-methionine PET imaging in ACTH-dependent Cushing's syndrome

OBJECTIVE We report our experience of functional imaging with (11)C-methionine positron emission tomography-computed tomography (PET-CT) co-registered with 3D gradient echo (spoiled gradient recalled (SPGR)) magnetic resonance imaging (MRI) in the investigation of ACTH-dependent Cushings syndrome. DESIGN Twenty patients with i) de novo Cushings disease (CD, n=10), ii) residual or recurrent hypercortisolism following first pituitary surgery (±radiotherapy; n=8) or iii) ectopic Cushings syndrome (n=2) were referred to our centre for functional imaging studies between 2010 and 2015. Six of the patients with de novo CD and five of those with persistent/relapsed disease had a suspected abnormality on conventional MRI. METHODS All patients underwent (11)C-methionine PET-CT. For pituitary imaging, co-registration of PET-CT images with contemporaneous SPGR MRI (1 mm slice thickness) was performed, followed by detailed mapping of (11)C-methionine uptake across the sella in three planes (coronal, sagittal and axial). This allowed us to determine whether suspected adenomas seen on structural imaging exhibited focal tracer uptake on functional imaging. RESULTS In seven of ten patients with de novo CD, asymmetric (11)C-methionine uptake was observed within the sella, which co-localized with the suspected site of a corticotroph microadenoma visualised on SPGR MRI (and which was subsequently confirmed histologically following successful transsphenoidal surgery (TSS)). Focal (11)C-methionine uptake that correlated with a suspected abnormality on pituitary MRI was seen in five of eight patients with residual or recurrent Cushings syndrome following first TSS (and pituitary radiotherapy in two cases). Two patients elected to undergo repeat TSS with histology confirming a corticotroph tumour in each case. In two patients with the ectopic ACTH syndrome, (11)C-methionine was concentrated in sites of distant metastases, with minimal uptake in the sellar region. CONCLUSIONS (11)C-methionine PET-CT can aid the detection of ACTH-secreting tumours in Cushings syndrome and facilitate targeted therapy.

Nuclear imaging in the diagnosis of primary aldosteronism

Purpose of reviewPrimary aldosteronism is increasingly recognized as a common secondary cause of hypertension. Successful demonstration of a unilateral cause (e.g. a classical ‘Conns adenoma’) offers the potential for curative adrenalectomy. Adrenal vein sampling (AVS), in conjunction with cross-sectional imaging, remains the ‘gold standard’ for distinguishing unilateral and bilateral disease, but is technically demanding and frequently unsuccessful or inconclusive. As such, alternative strategies for lateralization, including nuclear medicine techniques, are being developed and brought into clinical practice. Recent findingsMetomidate, a potent ligand of CYP11B1 and CYP11B2, can be C11H3-labelled as a PET tracer and has been shown to offer a rapid noninvasive alternative to AVS for localizing unilateral aldosterone-producing adenomas. SummaryIncreasing experience with 11C-metomidate PET-CT supports its use as an adjunct to AVS when this has failed, is ambiguous, or cannot be undertaken.

Familial adrenocortical carcinoma in association with Lynch syndrome

Context: Adrenocortical carcinoma (ACC) is a rare endocrine malignancy with a poor prognosis. Although the majority of childhood ACC arises in the context of inherited cancer susceptibility syndromes, it remains less clear whether a hereditary tumor predisposition exists for the development of ACC in adults. Here, we report the first occurrence of familial ACC in a kindred with Lynch syndrome resulting from a pathogenic germline MSH2 mutation. Case: A 54-year-old female with a history of ovarian and colorectal malignancy was found to have an ACC. A detailed family history revealed her mother had died of ACC and her sister had previously been diagnosed with endometrial and colorectal cancers. A unifying diagnosis of Lynch syndrome was considered, and immunohistochemical analyses demonstrated loss of MSH2 and MSH6 expression in both AACs (proband and her mother) and in the endometrial carcinoma of her sister. Subsequent genetic screening confirmed the presence of a germline MSH2 mutation (resulting in deletions of exons 1–3) in the proband and her sister. Conclusion: Our findings provide strong support for the recent proposal that ACC should be considered a Lynch syndrome-associated tumor and included in the Amsterdam II clinical diagnostic criteria. We also suggest that screening for ACC should be considered in cancer surveillance strategies directed at individuals with germline mutations in DNA mismatch repair genes.

Nephrogenic syndrome of inappropriate antidiuresis secondary to an activating mutation in the arginine vasopressin receptor AVPR2

Nephrogenic syndrome of inappropriate antidiuresis (NSIAD), resulting from activating mutations in the arginine vasopressin receptor type 2 (AVPR2), is a rare cause of hyponatraemia. However, its true prevalence may be underestimated and it should be considered in the investigation of unexplained hyponatraemia, with implications for management and targeted gene testing.

Targeted Molecular Imaging in Adrenal Disease—An Emerging Role for Metomidate PET-CT

Adrenal lesions present a significant diagnostic burden for both radiologists and endocrinologists, especially with the increasing number of adrenal ‘incidentalomas’ detected on modern computed tomography (CT) or magnetic resonance imaging (MRI). A key objective is the reliable distinction of benign disease from either primary adrenal malignancy (e.g., adrenocortical carcinoma or malignant forms of pheochromocytoma/paraganglioma (PPGL)) or metastases (e.g., bronchial, renal). Benign lesions may still be associated with adverse sequelae through autonomous hormone hypersecretion (e.g., primary aldosteronism, Cushing’s syndrome, phaeochromocytoma). Here, identifying a causative lesion, or lateralising the disease to a single adrenal gland, is key to effective management, as unilateral adrenalectomy may offer the potential for curing conditions that are typically associated with significant excess morbidity and mortality. This review considers the evolving role of positron emission tomography (PET) imaging in addressing the limitations of traditional cross-sectional imaging and adjunctive techniques, such as venous sampling, in the management of adrenal disorders. We review the development of targeted molecular imaging to the adrenocortical enzymes CYP11B1 and CYP11B2 with different radiolabeled metomidate compounds. Particular consideration is given to iodo-metomidate PET tracers for the diagnosis and management of adrenocortical carcinoma, and the increasingly recognized utility of 11C-metomidate PET-CT in primary aldosteronism.

Applying physical science techniques and CERN technology to an unsolved problem in radiation treatment for cancer: the multidisciplinary ‘VoxTox’ research programme

The VoxTox research programme has applied expertise from the physical sciences to the problem of radiotherapy toxicity, bringing together expertise from engineering, mathematics, high energy physics (including the Large Hadron Collider), medical physics and radiation oncology. In our initial cohort of 109 men treated with curative radiotherapy for prostate cancer, daily image guidance computed tomography (CT) scans have been used to calculate delivered dose to the rectum, as distinct from planned dose, using an automated approach. Clinical toxicity data have been collected, allowing us to address the hypothesis that delivered dose provides a better predictor of toxicity than planned dose.

Adult female with symptomatic AVPR2-related nephrogenic syndrome of inappropriate antidiuresis (NSIAD)

Summary Activating mutations in AVPR2 are associated with nephrogenic syndrome of inappropriate antidiuresis (NSIAD). NSIAD causes hyponatremia, decreased serum osmolality and clinical symptoms, which may present from birth or in infancy and include hypotonia, irritability, vomiting and/or seizures. Symptoms in later life are often less specific and include malaise, dizziness, confusion, tiredness and headache. NSIAD is a rare X-linked condition, which is associated with a variable phenotype in males, of whom some present in infancy but others do not become symptomatic until adulthood, or occasionally, never. Female carriers may present with episodes of hyponatremia, usually found incidentally. Literature in this field is limited; namely, two clinical reports describing a female proband, both diagnosed in infancy. We describe, for the first time, the case of an adult female proband with NSIAD, who had longstanding associated symptoms of tiredness, headache, temporary memory loss and mood changes as well as hyponatremia and decreased serum osmolality. A water load test demonstrated an inability to dilute urine and gene sequencing confirmed a recurrent activating mutation in AVPR2. The variant was inherited from the proband’s mother who had had longstanding episodes of transient asymptomatic hyponatremia. This is the third report of a female proband with NSIAD and is the first female reported who sought medical treatment for chronic symptoms from adulthood. This case acts as a reminder of the importance of considering NSIAD as a diagnosis in females of all ages with unexplained hyponatremia. Learning points: Activating mutations in the AVPR2 gene are associated with the rare X-linked condition nephrogenic syndrome of inappropriate antidiuresis. NSIAD is associated with hyponatremia, decreased serum osmolality and inappropriately increased urinary osmolality. Early clinical symptoms in infancy include hypotonia, irritability, vomiting and/or seizures. Symptoms in later life include malaise, dizziness, confusion, tiredness and headache. NSIAD should be considered in female, as well as male, patients who present with unexplained hyponatremia and decreased serum osmolality. Family history may reveal relevant symptoms or biochemical features in other family members. However, family history may not always be informative due to the variable nature of the condition or if the proband has a de novo pathogenic variant. A water load test with measurement of AVP may be informative in distinguishing NSIAD from SIADH. Measurement of co-peptin levels may be considered, in substitution for direct measurement of AVP. Patients with NSIAD should be counseled about appropriate daily fluid volume intake. Potential episodes of fluid overload should be avoided.

Successful treatment of primary aldosteronism with partial adrenalectomy, facilitated by the use of 11 C-Metomidate PET/CT

Primary aldosteronism (PA) is estimated to be responsible for 5-10% of all cases of hypertension (HTN)1. The current gold standard test for determining lateralisation in PA is adrenal vein sampling (AVS). 11C-Metomidate PET/CT (MTO-PET) has recently emerged as a potential non-invasive alternative to AVS2. As 11C-Metomidate is concentrated within ‘hyper-functioning’ nodules, MTO-PET potentially not only identifies the side, but the exact site of aldosterone hypersecretion, thus raising the possibility of more targeted surgical intervention.