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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 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.

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., This work was supported by Barts Charity grants MGU0361 to L.M. and R.P.; MGU0438 to L.M.; MGU0528 to R.K.; MGU0436 to L.G.; Government of Trinidad and Tobago Research Fellowship to A.M.; Medical Research Council (MRC) UK Clinical Academic Research Partner grant (MR/T02402X/1) to R.P. and MRC clinical research fellowships (MR/S022155/1) to J.P. and (MR/W015935/1) to R.K.

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.

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.

Local governments are in an ideal position to integrate government, private, and citizen data to deliver beneficial new digitally enabled public services. However, progress toward achieving the benefits has stagnated in many cases. This is because managers lack the requisite know-how to lead the implementation and enactment of integrated enterprise systems to improve the processes of public service delivery, part of a journey called ‘digital transformation’. If digital transformations are to progress, we need more nuanced empirical elaboration of the know-how managers require. To that end, this study reports evidence from case studies in 11 local governments in Canada. The findings provide the empirical basis for a theory of the know-how managers require to lead the implementation and enactment of integrated enterprise systems in support of digital transformation. We then propose a new theoretical model of how to transfer that requisite know-how to managers through public-private partnerships, and thereby mitigate barriers to that transfer.

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.

The adrenal cortex governs fundamental metabolic processes though synthesis of glucocorticoid, miner-alocorticoids 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.

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

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.

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.

The effective sharing of organizational knowledge is particularly relevant for multinational corporations, where firm-specific tacit knowledge (know-how) is considered a source of competitive advantage for subsidiaries participating in a global strategy. To that end, multinational corporations (MNCs) are asking their IT departments to support both the exploitation of existing knowledge and the unit-to-unit transfer of new know-how derived in units from exploration. Nonetheless, new know-how derived from exploratory research, development and experience in one unit can be difficult to transfer to units that can exploit that know-how to commercial ends. The factors that impede the transfer of new know-how have been conceptualized as ''factors of stickiness''. In this paper, we present a theoretical model of organizational factors that can cause (or conversely mitigate) stickiness in the flow of new know-how between MNC units. To test the six hypotheses of the model, we used meta-analytic structural equation modeling (MASEM) of 31 empirical studies, representing 10,432 cases of new know-how transfer between units. The result of MASEM shows that the factors of receiving units' potential absorptive capacity and transmission channel in form of social capital that is enacted through its three dimensions (i.e., embedded social ties between units, institutional shared vision of units, and interorganizational trust of units) affect recipient subsidiaries' capability to exploit new know-how in practice (i.e., realized absorptive capacity), thus effectuating its transfer. Based on our findings, we propose research directions within the context of agile information systems development, distributed software projects, and management of information systems functions in MNCs.

For more than a decade, healthcare reform has emphasized coordinated “patient-centered care”. To that end, policymakers have invested in integration of healthcare providers’ information flows. Research has studied healthcare providers’ information needs but overlooked communicative exchanges among participants in coordinating treatment plan decisions. Consequently, although medical literature asserts that patients should depend on information exchange with healthcare providers to enable participation in treatment plan decisions, the assertion has not been tested. In this paper, the authors conduct an empirical study to elucidate the structure of actors’ communications in support of their information dependencies. The findings illustrate that although patients are well connected through personal contact with healthcare providers, patients are disenfranchised from integrated healthcare information systems (IS) and the potential of IS to support patients’ participation in coordinated “patient-centered care” decisions. Furthermore, knowledge asymmetry between patients and healthcare providers should be considered in the selection and design of healthcare IS.

Sensory neurone subtypes (≤ 25 μm 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 μm 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) NaV1.8 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 NaV1.7 being expressed in IB4 +ve neurones, whereas toxin sensitivity indicates that IB4 −ve neurones may express NaV1.1 or NaV1.2, or both. The retention of excitability at low membrane potentials, and the responses to repetitive stimulation are explained by the known preferential expression of NaV1.8 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.

Medical interventions are often delayed or erroneous when information needed for diagnosing or prescribing is missing or unavailable. In support of increased information flows, the healthcare industry has invested substantially in standards intended to specify, routinize, and make uniform the type and format of medical information in clinical healthcare information systems such as Electronic Medical Record systems (EMRs). However, fewer than one in four Canadian physicians have adopted EMRs. Deeper analysis illustrates that physicians may perceive value in standardized EMRs when they need to exchange information in highly structured situations among like participants and like environments. However, standards present restrictive barriers to practitioners when they face equivocal situations, unforeseen contingencies, or exchange information across different environments. These barriers constitute a compelling explanation for at least part of the observed low EMR adoption rates. Our recommendations to improve the perceived value of standardized clinical information systems espouse re-conceptualizing the role of standards to embrace greater flexibility in some areas.