The Value of Local Therapies in Advanced Adrenocortical Carcinoma.

International guidelines recommend local therapies (LTs) such as local thermal ablation (LTA; radiofrequency, microwave, cryoablation), transarterial (chemo)embolisation (TA(C)E), and transarterial radioembolisation (TARE) as therapeutic options for advanced adrenocortical carcinoma (ACC). However, the evidence for these recommendations is scarce. We retrospectively analysed patients receiving LTs for advanced ACC. Time to progression of the treated lesion (tTTP) was the primary endpoint. The secondary endpoints were best objective response, overall progression-free survival, overall survival, adverse events, and the establishment of predictive factors by multivariate Cox analyses. A total of 132 tumoural lesions in 66 patients were treated with LTA (n = 84), TA(C)E (n = 40), and TARE (n = 8). Complete response was achieved in 27 lesions (20.5%; all of them achieved by LTA), partial response in 27 (20.5%), and stable disease in 38 (28.8%). For the LTA group, the median tTTP was not reached, whereas it was reached 8.3 months after TA(C)E and 8.2 months after TARE (p < 0.001). The median time interval from primary diagnosis to LT was >47 months. Fewer than four prior therapies and mitotane plasma levels of >14 mg/L positively influenced the tTTP. In summary, this is one of the largest studies on LTs in advanced ACC, and it demonstrates a very high local disease control rate. Thus, it clearly supports the guideline recommendations for LTs in these patients.

Elevated sphingosine-1-phosphate lyase leads to increased metabolism and reduced survival in adrenocortical carcinoma.

OBJECTIVE: Adrenocortical carcinomas (ACCs) are invasive tumours arising in the adrenal cortex, and steroidogenic tumours are associated with worse prognostic outcomes. Loss-of-function mutations in sphingosine-1-phosphate lyase (SGPL1) cause primary adrenal insufficiency and as a key degradative enzyme in the sphingolipid pathway, SGPL1 also influences the balance of pro-proliferative and pro-apoptotic sphingolipids. We, therefore, hypothesized increased SGPL1 may be linked to increased disease severity in ACC. DESIGN: Analyse SGPL1 expression impact on patient survival and adrenal cancer cell phenotype. We analysed two ACC cohorts with survival and corresponding transcriptomic data, focusing on SGPL1 and sphingolipid pathway genes. In vitro, we generated SGPL1-knockout and overexpressing H295R adrenocortical cells to investigate the role of SGPL1 in cell signalling in ACCs. RESULTS: We found increased expression of several sphingolipid pathway receptors and enzymes, most notably SGPL1 correlated with reduced patient survival in both cohorts. Overexpression of SGPL1 in the H295R cell line increased proliferation and migration while reducing apoptosis, while SGPL1 knockout had the opposite effect. RNA-seq revealed a global increase in the expression of genes in the electron transport chain in overexpressing cells, correlating with increased aerobic respiration and glycolysis. Furthermore, the opposite phenotype was seen in cells lacking SGPL1. We subsequently found the increased proliferation is linked to metabolic substrate availability and increased capacity to use different fuel sources, but particularly glucose, in overexpressing cells. CONCLUSIONS: We, therefore, propose that SGPL1-overexpressing ACC tumours reduce patient survival by increasing fuel usage for anabolism and energy production to facilitate growth and invasion.

Efficacy and safety of radiation therapy in advanced adrenocortical carcinoma.

BACKGROUND: International guidelines emphasise the role of radiotherapy (RT) for the management of advanced adrenocortical carcinoma (ACC). However, the evidence for this recommendation is very low. METHODS: We retrospectively analysed all patients who received RT for advanced ACC in five European centres since 2000. PRIMARY ENDPOINT: time to progression of the treated lesion (tTTP). Secondary endpoints: best objective response, progression-free survival (PFS), overall survival (OS), adverse events, and the establishment of predictive factors by Cox analyses. RESULTS: In total, 132 tumoural lesions of 80 patients were treated with conventional RT (cRT) of 50-60 Gy (n = 20) or 20-49 Gy (n = 69), stereotactic body RT of 35-50 Gy (SBRT) (n = 36), or brachytherapy of 12-25 Gy (BT) (n = 7). Best objective lesional response was complete (n = 6), partial (n = 52), stable disease (n = 60), progressive disease (n = 14). Median tTTP was 7.6 months (1.0-148.6). In comparison to cRT20-49Gy, tTTP was significantly longer for cRT50-60Gy (multivariate adjusted HR 0.10; 95% CI 0.03-0.33; p < 0.001) and SBRT (HR 0.31; 95% CI 0.12-0.80; p = 0.016), but not for BT (HR 0.66; 95% CI 0.22-1.99; p = 0.46). Toxicity was generally mild and moderate with three grade 3 events. No convincing predictive factors could be established. CONCLUSIONS: This largest published study on RT in advanced ACC provides clear evidence that RT is effective in ACC.

The role of delta-like non-canonical Notch ligand 1 (DLK1) in cancer.

Delta-like non-canonical Notch ligand 1 (DLK1) is a cleavable single-pass transmembrane protein and a member of the Notch/Delta/Serrate family. It is paternally expressed and belongs to a group of imprinted genes located on chromosome band 14q32 in humans and 12qF1 in mice. DLK1 is expressed in many human tissues during embryonic development but in adults expression is low and is mostly restricted to (neuro)endocrine tissues and other immature stem/progenitor cells (notably hepatoblasts). However, DLK1 is expressed at a high frequency in many common malignancies (liver, breast, brain, pancreas, colon and lung). More recently, high levels of expression have been identified in endocrine-related cancers such as ovarian and adrenocortical carcinoma. There is growing evidence that DLK1 expression in cancer is associated with worse prognosis and that DLK1 may be a marker of cancer stem cells. Although the exact mechanism through which DLK1 functions is not fully understood, it is known to maintain cells in an undifferentiated phenotype and has oncogenic properties. These effects are partly exacted through interaction with the Notch signalling pathway. In this review, we have detailed the functional role of DLK1 within physiology and malignancy and posited a mechanism for how it exacts its oncogenic effects. In describing the expression of DLK1 in cancer and in healthy tissue, we have highlighted the potential for its use both as a biomarker and as a potential therapeutic target.

Bone Metabolism and Vitamin D Implication in Gastroenteropancreatic Neuroendocrine Tumors.

Patients affected by gastroenteropancreatic-neuroendocrine tumors (GEP-NETs) have an increased risk of developing osteopenia and osteoporosis, as several factors impact on bone metabolism in these patients. In fact, besides the direct effect of bone metastasis, bone health can be affected by hormone hypersecretion (including serotonin, cortisol, and parathyroid hormone-related protein), specific microRNAs, nutritional status (which in turn could be affected by medical and surgical treatments), and vitamin D deficiency. In patients with multiple endocrine neoplasia type 1 (MEN1), a hereditary syndrome associated with NET occurrence, bone damage may carry other consequences. Osteoporosis may negatively impact on the quality of life of these patients and can increment the cost of medical care since these patients usually live with their disease for a long time. However, recommendations suggesting screening to assess bone health in GEP-NET patients are missing. The aim of this review is to critically analyze evidence on the mechanisms that could have a potential impact on bone health in patients affected by GEP-NET, focusing on vitamin D and its role in GEP-NET, as well as on factors associated with MEN1 that could have an impact on bone homeostasis.

DLK1/PREF1 marks a novel cell population in the human adrenal cortex.

The adrenal cortex governs fundamental metabolic processes though synthesis of glucocorticoid, mineralocorticoids and androgens. Studies in rodents have demonstrated that the cortex undergoes a self-renewal process and that capsular/subcapsular stem/progenitor cell pools differentiate towards functional steroidogenic cells supporting the dynamic centripetal streaming of adrenocortical cells throughout life. We previously demonstrated that the Notch atypical ligand Delta-like homologue 1 (DLK1)/preadipocyte factor 1 (PREF1) is expressed in subcapsular Sf1 and Shh-positive, CYP11B1-negative and CYP11B2-partially positive cortical progenitor cells in rat adrenals, and that secreted DLK1 can modulate GLI1 expression in H295R cells. Here we show that the human adrenal cortex remodels with age to generate clusters of relatively undifferentiated cells expressing DLK1. These clusters (named DLK1-expressing cell clusters or DCCs) increased with age in size and were found to be different entities to aldosterone-producing cell clusters, another well-characterized and age-dependent cluster structure. DLK1 was markedly overexpressed in adrenocortical carcinomas but not in aldosterone-producing adenomas. Thus, this data identifies a novel cell population in the human adrenal cortex and might suggest a yet-to be identified role of DLK1 in the pathogenesis of adrenocortical carcinoma in humans.

Correction to: Bisphosphonate therapy for spinal osteoporosis in Hajdu-Cheney syndrome - new data and literature review.

After publication of this article [1], it is noticed reference no. 17 was incorrectly provided, details are shown below.

Pathobiology and genetics of adrenocortical carcinoma.

Adrenocortical carcinoma (ACC) is a rare malignancy with an incidence worldwide of 0.7-2.0 cases/million/year. Initial staging is the most important factor in determining prognosis. If diagnosed early, complete surgical resection +/- adjuvant treatment can lead to 5-year survival of up to 80%. However, often it is diagnosed late and in advanced disease, 5-year survival is <15% with a high recurrence rate even after radical surgery. The mainstay of adjuvant treatment is with the drug mitotane. Mitotane has a specific cytotoxic effect on steroidogenic cells of the adrenal cortex, but despite this, progression through treatment is common. Developments in genetic analysis in the form of next-generation sequencing, aided by bioinformatics, have enabled high-throughput molecular characterisation of these tumours. This, in addition to a better appreciation of the processes of physiological, homeostatic self-renewal of the adrenal cortex, has furthered our understanding of the pathogenesis of this malignancy. In this review, we have detailed the pathobiology and genetic alterations in adrenocortical carcinoma by integrating current understanding of homeostasis and self-renewal in the normal adrenal cortex with molecular profiling of tumours from recent genetic analyses. Improved understanding of the mechanisms involved in self-renewal and stem cell hierarchy in normal human adrenal cortices, together with the identification of cell populations likely to be co-opted by oncogenic mutations, will enable further progress in the definition of the molecular pathways involved in the pathogenesis of ACC. The combination of these advances eventually will lead to the development of novel, effective and personalised strategies to eradicate molecularly annotated ACCs.

Glucocorticoid replacement therapies: past, present and future.

Since the original description of adrenal insufficiency by Thomas Addison in 1855, there has been an exponential growth in the understanding of adrenal gland biology and its role in the hypothalamic-pituitary-adrenal axis. Despite this, the mainstay of therapeutic glucocorticoid replacement for most clinicians has remained unchanged for nearly 50 years. More recently, there has been better recognition of the morbidity and mortality associated with current approaches and the challenges to tackle in reducing this and improving clinical outcomes. In this review, we have summarised the history of glucocorticoid replacement therapy from its nascence in the 1930s, through common practice and culminating in more recent glucocorticoid replacement strategies plus the potential of stem cell therapy in the future.

Bisphosphonate therapy for spinal osteoporosis in Hajdu-Cheney syndrome - new data and literature review.

BACKGROUND: Hajdu-Cheney syndrome (HCS) (#OMIM 102500) is a rare, autosomal dominant condition that presents in early childhood. It is caused by mutations in the terminal exon of NOTCH2, which encodes the transmembrane NOTCH2 receptor. This pathway is involved in the coupled processes of bone formation and resorption. The skeletal features of HCS include acro-osteolysis of the digits and osteoporosis commonly affecting vertebrae and long bones. Fractures are a prominent feature and are associated with significant morbidity. There is no specific treatment, but with both acro-osteolysis and generalized osteoporosis, it is possible that anti-resorptive treatment might be of benefit. However, to date only a few case reports have evaluated the effectiveness of bisphosphonate treatment. METHODS: We describe the clinical features, treatment regimens and response to bisphosphonate treatment in 7 newly described patients aged 6-39 with HCS, and pooled the data with that from 8 previously published cases (a total of 17 courses of treatment in 15 individuals). RESULTS: The mean lumbar spine bone mineral density (BMD) z-score before treatment was - 2.9 (SD 1.2). In 14 courses of treatment (82%), there was an increase in BMD with bisphosphonate treatment, but the impact (in terms of change in spinal BMD z-score) appeared to be less with advancing age (p = 0.01). There was no evidence that acro-osteolysis was prevented. CONCLUSIONS: Although individual response is variable and age-related, the data support a role for bisphosphonates in preventing or treating spinal osteoporosis in HCS, but bone loss from the lumbar spine may be rapid after cessation.

Atrial flutter ablation in a case of diuretic resistant constrictive pericarditis.

We present a 66 year old gentleman with constrictive pericarditis and persistent atrial flutter. Initial management with oral loop diuretics was successful until he developed persistent atrial flutter. Once in atrial flutter the patient developed progressive signs of right heart failure resistant to high dose intravenous loop diuretics. He was referred to a tertiary electrophysiology service where he underwent successful isthmus catheter ablation and reverted to sinus rhythm. His responsiveness to diuretics improved immediately. His symptoms improved and he was discharged 48 h later on oral diuretics. He remains well one month after discharge. This is the first reported case of symptomatic improvement in a patient with constrictive pericarditis and persistent atrial flutter with targeted treatment of the dysrhythmia. This offers a possible short-term palliation option in a group of patients where definitive surgical management carries too high a risk.

Excitability parameters and sensitivity to anemone toxin ATX-II in rat small diameter primary sensory neurones discriminated by Griffonia simplicifolia isolectin IB4.

Sensory neurone subtypes (< or = 25 microm apparent diameter) express a variety of Na(+) channels, where expression is linked to action potential duration, and associated with differential IB4-lectin binding. We hypothesized that sensitivity to ATX-II might also discriminate neurones and report that 1 microm has negligible or small effects on action potentials in IB4 +ve, but dramatically increased action potential duration in IB4 ve, neurones. The toxin did not act on tetrodotoxin-resistant (TTX-r) Na(V)1.8 currents; discrimination was based on tetrodotoxin-sensitive (TTX-s) Na(+) channel expression. We also explored the effects of varying the holding potential on current threshold, and the effect of repetitive activation on action currents in IB4 +ve and ve neurones. IB4 +ve neurones became more excitable with depolarization over the range 100 to 20 mV, but IB4 ve neurones exhibited peak excitability near 55 mV, and were inexcitable at 20 mV. Eliciting action potentials at 2 Hz, we found that peak inward action current in IB4 +ve neurones was reduced, whereas changes in the current amplitude were negligible in most IB4 ve neurones. Our findings are consistent with relatively toxin-insensitive channels including Na(V)1.7 being expressed in IB4 +ve neurones, whereas toxin sensitivity indicates that IB4 ve neurones may express Na(V)1.1 or Na(V)1.2, or both. The retention of excitability at low membrane potentials, and the responses to repetitive stimulation are explained by the known preferential expression of Na(V)1.8 in IB4 +ve neurones, and the reduction in action current in IB4 +ve neurones with repetitive stimulation supports a novel hypothesis explaining the slowing of conduction velocity in C-fibres by the build-up of Na(+) channel inactivation.