A Randomised Clinical Feasibility Trial of a Breast Immobilisation Device: The SuPPORT 4 All Bra.

AIMS: Despite the breast being a mobile organ, there is currently no standard suitable immobilisation device to optimise radiotherapy for women with larger breasts treated after a wide local excision. The SuPPORT 4 All (S4A) bra was co-designed with patients and radiotherapy professionals. The purpose of this study was to test the feasibility of using the S4A bra in the existing breast cancer radiotherapy pathway. MATERIALS AND METHODS: A randomised feasibility trial was conducted in a single institution; the primary feasibility endpoint was the recruitment of 50 participants. Efficacy endpoints were also tested, including assessment of skin reactions, dose to organs at risk and patient comfort. Fifty women were randomised to receive either standard radiotherapy with no immobilisation (control) or radiotherapy with the S4A bra (intervention). A separate planning study was undertaken on the cases randomised to receive the S4A bra. Participants in the intervention arm (S4A bra) underwent two planning computed tomography scans, one with the bra on and one without the bra; allowing direct comparison of organs at risk data for S4A bra versus no bra. RESULTS: All women who started radiotherapy wearing the S4A bra completed treatment with the bra; patient comfort did not change across the 3 weeks of treatment. Positional accuracy using the bra was comparable with existing published accuracy for methods without immobilisation. The mean ipsilateral lung doses showed some improvement when positioning with the S4A bra was compared with the no bra set-up (3.72 Gy versus 4.85 Gy for right-sided cases, 3.23 Gy versus 3.62 Gy for left-sided cases). CONCLUSIONS: The S4A bra is feasible to use in the radiotherapy pathway with good patient adherence. The S4A bra has potential to reduce dose to organs at risk (specifically ipsilateral lung dose) while maintaining good breast tissue coverage, and improved patient dignity, warranting further investigation on a larger scale.

Neurocircuit models of obsessive-compulsive disorder: limitations and future directions for research

Obsessive-compulsive disorder (OCD) is a common psychiatric condition classically characterized by obsessions (recurrent, intrusive and unwanted thoughts) and compulsions (excessive, repetitive and ritualistic behaviors or mental acts). OCD is heterogeneous in its clinical presentation and not all patients respond to first-line treatments. Several neurocircuit models of OCD have been proposed with the aim of providing a better understanding of the neural and cognitive mechanisms involved in the disorder. These models use advances in neuroscience and findings from neuropsychological and neuroimaging studies to suggest links between clinical profiles that reflect the symptoms and experiences of patients and dysfunctions in specific neurocircuits. Several models propose that treatments for OCD could be improved if directed to specific neurocircuit dysfunctions, thereby restoring efficient neurocognitive function and ameliorating the symptomatology of each associated clinical profile. Yet, there are several important limitations to neurocircuit models of OCD. The purpose of the current review is to highlight some of these limitations, including issues related to the complexity of brain and cognitive function, the clinical presentation and course of OCD, etiological factors, and treatment methods proposed by the models. We also provide suggestions for future research to advance neurocircuit models of OCD and facilitate translation to clinical application.

The use of computed tomography as a first-line imaging modality in patients with primary hyperparathyroidism.

BACKGROUND: The success of minimally invasive parathyroidectomy (MIP) relies on accurate localization of the abnormal parathyroid glands. Concordant findings on ultrasound (US) and 99mTc-scintigraphy (sestamibi) are currently considered the 'gold standard'. Computed tomography (CT) has also recently been used in preoperative planning. We sought to assess the accuracy of CT for localization of abnormal parathyroid glands in such patients. METHODS: An audit of 75 patients with primary hyperparathyroidism (PHPT) who underwent neck US and CT between 2017 and 2019 at our center as their first-line imaging. RESULTS: All 75 patients underwent US and CT and 54 (72.0%) also had sestamibi. CT alone identified a potential target in all patients, of which the location was correct in 63 (84.0%). The overall combined sensitivity of US and CT was 88% (95% CI 78-94) and was higher than the combined sensitivity of US and sestamibi (65% [95% CI 53-76]; p < 0.001). Twenty-one patients (28.0%) had an ectopic gland, and the sensitivity of US and CT was 86% (95% CI 64-96) versus US and sestamibi (57% [95% CI 34-77]; p = 0.016). For adenomas < 1.0 g (n = 36; 48%), the accuracy of CT was 81% (95% CI 64-91) compared with 62% (95% CI 44-77) for US and sestamibi (p = 0.04). The correct preoperative diagnosis of multiglandular disease (n = 9; 12%) seemed to be the most difficult, with similar accuracy for US and sestamibi (40% [95% CI 14-73]) and US and CT (50% [95% CI 20-80]) (p > 0.99). CONCLUSION: The combination of US and CT was able to correctly identify the location of the abnormal parathyroid in 88% of patients and, in comparison with US and sestamibi, had better diagnostic accuracy, especially for smaller and ectopic adenomas. This finding suggests that US and CT could be considered as a first-line imaging modality in patients with PHPT considered for MIP.

αv integrins on mesenchymal cells regulate skeletal and cardiac muscle fibrosis.

Mesenchymal cells expressing platelet-derived growth factor receptor beta (PDGFRß) are known to be important in fibrosis of organs such as the liver and kidney. Here we show that PDGFRß+ cells contribute to skeletal muscle and cardiac fibrosis via a mechanism that depends on αv integrins. Mice in which αv integrin is depleted in PDGFRß+ cells are protected from cardiotoxin and laceration-induced skeletal muscle fibrosis and angiotensin II-induced cardiac fibrosis. In addition, a small-molecule inhibitor of αv integrins attenuates fibrosis, even when pre-established, in both skeletal and cardiac muscle, and improves skeletal muscle function. αv integrin blockade also reduces TGFß activation in primary human skeletal muscle and cardiac PDGFRß+ cells, suggesting that αv integrin inhibitors may be effective for the treatment and prevention of a broad range of muscle fibroses.

Is there an optimal preoperative management strategy for phaeochromocytoma/paraganglioma?

Phaeochromocytomas and paragangliomas (PPGLs) are catecholamine secreting neuroendocrine tumours that predispose to haemodynamic instability. Currently, surgery is the only available curative treatment, but carries potential risks including hypertensive and hypotensive crises, cardiac arrhythmias, myocardial infarction and stroke, due to tumoral release of catecholamines during anaesthetic induction and tumour manipulation. The mortality associated with surgical resection of PPGL has significantly improved from 20-45% in the early 20th century (Apgar & Papper, AMA Archives of Surgery, 1951, 62, 634) to 0-2·9% in the early 21st century (Kinney et al. Journal of Cardiothoracic and Vascular Anesthesia, 2002, 16, 359), largely due to availability of effective pharmacological agents and advances in surgical and anaesthetic practice. However, surgical resection of PPGL still poses significant clinical management challenges. Preoperatively, alpha-adrenoceptor blockade is the mainstay of management, although various pharmacological strategies have been proposed, based largely on reports derived from retrospective data sets. To date, no consensus has been reached regarding the 'ideal' preoperative strategy due, in part, to a paucity of data from high-quality evidence-based studies comparing different treatment regimens. Here, based on the available literature, we address the Clinical Question: Is there an optimal preoperative management strategy for PPGL?

Cell therapy for bone repair: narrowing the gap between vision and practice.

This position paper summarises a vision of how cell-based therapies can be applied clinically to regenerate bone, as well as the steps needed to narrow the gap between that vision and clinical reality. It is a result of the presentations and discussion of the "Cell Therapy for Bone Repair" breakout session at the AO Foundation Symposium "Where Science Meets Clinics" in Davos, Switzerland from September 5-7, 2013. Participants included leaders from science, medicine, and industry from around the world. The session included clinical and scientific presentations, as well as an extended discussion among participants. Bone tissue has an innate regenerative capacity that in most cases allows functional healing at damage sites. However, there are a number of serious conditions in which bone does not fully heal and the result is significant morbidity. The clinical need for new therapies is clear, and the breakout session participants were enthusiastic about the potential impact on cell-based therapies for bone repair in the clinic. However, they also recognised the significant challenges that face the development of commercially viable cell therapy products. This paper outlines a vision in which patient selection is based on expected therapeutic outcome to create a consistently successful, cost-effective, cell-based therapy for bone repair. The need for a more complete understanding of bone repair, a better infrastructure for preclinical studies, and the need for collaboration among stakeholders is discussed.

The emerging role of cardiovascular MRI for risk stratification in hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is the most common inheritable cardiovascular disorder. Although many HCM patients remain asymptomatic, sudden death (SD) can occur as the initial manifestation of the disease. It has been hypothesized that myocardial architectural disorganization and scarring represent an unstable electrophysiological substrate that creates susceptibility to malignant ventricular arrhythmias. Cardiovascular magnetic resonance imaging (CMR) is widely used for the diagnosis of HCM, especially in patients with an incomplete or inconclusive echocardiography study. CMR can provide precise non-invasive assessment of biventricular function, wall thickness, and assessment of myocardial fibrosis, using inversion recovery gadolinium-enhanced sequences. CMR is also one of the most promising avenues of research in HCM, and in recent years, has provided many new insights and identified a number of potential adverse prognostic indicators for SD. Future work is still needed to integrate CMR findings into traditional risk assessment algorithms. This paper reviews the evolving role of CMR for risk stratification in HCM including assessment of myocardial hypertrophy, fibrosis and ischaemia.

Repeated cortico-striatal stimulation generates persistent OCD-like behavior.

Although cortico-striato-thalamo-cortical (CSTC) circuit dysregulation is correlated with obsessive compulsive disorder (OCD), causation cannot be tested in humans. We used optogenetics in mice to simulate CSTC hyperactivation observed in OCD patients. Whereas acute orbitofrontal cortex (OFC)-ventromedial striatum (VMS) stimulation did not produce repetitive behaviors, repeated hyperactivation over multiple days generated a progressive increase in grooming, a mouse behavior related to OCD. Increased grooming persisted for 2 weeks after stimulation cessation. The grooming increase was temporally coupled with a progressive increase in light-evoked firing of postsynaptic VMS cells. Both increased grooming and evoked firing were reversed by chronic fluoxetine, a first-line OCD treatment. Brief but repeated episodes of abnormal circuit activity may thus set the stage for the development of persistent psychopathology.

Phosphoenolpyruvate metabolism in Teladorsagia circumcincta: a critical junction between aerobic and anaerobic metabolism.

Nematodes which have adapted to an anaerobic lifestyle in their adult stages oxidise phosphoenolpyruvate (PEP) to oxaloacetate rather than pyruvate as the final product of glycolysis. This adaptation involves selective expression of the enzyme phosphoenolpyruvate carboxykinase (PEPCK), instead of pyruvate kinase (PK). However, such adaptation is not absolute in aerobic nematode species. We have examined the activity and kinetics of PEPCK and PK in larvae (L(3)) and adults of Teladorsagia circumcincta, a parasite known to exhibit oxygen uptake. Results revealed that PK and PEPCK activity existed in both L(3)s and adults. The enzymes had differing affinity for nucleotide diphosphates: while both can utilise GDP, only PK utilised ADP and only PEPCK utilised IDP. In both life cycle stages, enzymes showed similar affinity for PEP. PK activity was predominant in both stages, although activity of this enzyme was lower in adults. When combined, both the activity levels and the enzyme kinetics showed that pyruvate production is probably favoured in both L(3) and adult stages of T. circumcincta and suggest that metabolism of PEP to oxaloacetate is a minor metabolic pathway in this species.

The kinetics and regulation of phosphofructokinase from Teladorsagia circumcincta.

Phosphofructokinase (PFK-1) activity was examined in L(3) and adult Teladorsagia circumcincta, both of which exhibit oxygen consumption. Although activities were higher in the adult stage, the kinetic properties of the enzyme were similar in both life cycle stages. T. circumcincta PFK-1 was subject to allosteric inhibition by high ATP concentration, which increased both the Hill coefficient (from 1.4±0.2 to 1.7±0.2 in L(3)s and 2.0±0.3 to 2.4±0.4 in adults) and the K(½) for fructose 6 phosphate (from 0.35±0.02 to 0.75±0.05mM in L(3)s and 0.40±0.03 to 0.65±0.05mM in adults). The inhibitory effects of high ATP concentration could be reversed by fructose 2,6 bisphosphate and AMP, but glucose 1,6 bisphosphate had no effect on activity. Similarly, phosphoenolpyruvate had no effect on activity, while citrate, isocitrate and malate exerted mild inhibitory effects, but only at concentrations exceeding 2mM. The observed kinetic properties for T. circumcincta PFK-1 were very similar to those reported for purified Ascaris suum PFK-1, though slight differences in sensitivity to ATP concentration suggests there may be subtle variations at the active site. These results are consistent with the conservation of properties of PFK-1 amongst nematode species, despite between species variation in the ability to utilise oxygen.

Phase I study to determine the maximal tolerated dose and dose-limiting toxicities of orally administered idarubicin in dogs with lymphoma.

BACKGROUND: Idarubicin, a PO bioavailable anthracycline antibiotic-class chemotherapeutic, could have substantial convenience advantages over currently available similar class agents in use that require IV delivery. OBJECTIVES: The primary objective of this study was to determine the maximally tolerated dose (MTD), dose-limiting toxicities (DLTs), and basic pharmacokinetic parameters of oral idarubicin exposure in dogs with lymphoma after a single oral dose. A secondary objective was to document preliminary antitumor efficacy in an expanded treatment cohort using the established MTD. ANIMALS: Client-owned dogs with measurable lymphoma. METHODS: Dogs (n = 31) were enrolled in a prospective open label phase I study of oral idarubicin. By means of a 3 + 3 cohort design, dose escalations were made with 3 dogs per dose level, and the MTD was established based on the number of patients experiencing a DLT. Plasma concentrations of idarubicin and idarubicinol were determined by postdose sampling. Assessment of antitumor efficacy focused on evaluation of accessible, measurable lymph nodes and skin lesions by modified RECIST guidelines. RESULTS: The MTD in dogs > 15 kg body weight was 22 mg/m(2) . Adverse hematologic events (neutropenia and thrombocytopenia) were the predominant DLT and generally correlated with higher plasma concentrations of idarubicin and idarubicinol. CONCLUSIONS AND CLINICAL IMPORTANCE: PO administered idarubicin was generally well-tolerated and had preliminary antitumor activity in dogs with lymphoma. Furthermore, the potential clinical advantage of a safe and efficacious oral anthracycline alternative supports further investigations of this agent in repeated-dose, randomized clinical trials.

Temozolomide responsiveness in aggressive corticotroph tumours: a case report and review of the literature.

Pituitary carcinoma occurs in ~0.2% of resected pituitary tumours and carries a poor prognosis (mean survival <4 years), with standard chemotherapy regimens showing limited efficacy. Recent evidence suggests that temozolomide (TMZ), an orally-active alkylating agent used principally in the management of glioblastoma, may also be effective in controlling aggressive/invasive pituitary adenomas/carcinomas. A low level of expression of the DNA-repair enzyme O6-methylguanine-DNA methyltransferase (MGMT) predicts TMZ responsiveness in glioblastomas, and a similar correlation has been observed in the majority of aggressive pituitary adenomas/carcinomas reported to date. Here, we report a case of a silent pituitary corticotroph adenoma, which subsequently re-presented with Cushing's syndrome due to functioning hepatic metastases. The tumour exhibited low immunohistochemical MGMT expression in both primary (pituitary) and secondary (hepatic) lesions. Initial TMZ therapy (200 mg/m² for 5 days every 28 days-seven cycles) resulted in marked clinical, biochemical [>50% fall in adrenocorticotrophic hormone (ACTH)] and radiological [partial RECIST (response evaluation criteria in solid tumors) response] improvements. The patient then underwent bilateral adrenalectomy. However, despite reintroduction of TMZ therapy (further eight cycles) ACTH levels plateaued and no further radiological regression was observed. We review the existing literature reporting TMZ efficacy in pituitary corticotroph tumours, and highlight the pointers/lessons for treating aggressive pituitary neoplasia that can be drawn from experience of susceptibility and evolving resistance to TMZ therapy in glioblastoma. Possible strategies for mitigating resistance developing during TMZ treatment of pituitary adenomas/carcinomas are also considered.

Effects of Teladorsagia (Ostertagia) circumcincta infection on lambs selected for high fleece weight.

The physiological processes leading to the expression of the resilient phenotype, which allow animals to maintain a relatively higher production level during infection, have been investigated in lambs from a closed flock selected for 40 generations for high fleece weight (HFW), but with higher FEC and worm burdens than their unselected control (C) flock run in parallel. After recovery from surgery to implant abomasal cannulae, eight parasite-naive lambs from each flock were infected intraruminally at 4.5 months-of-age with 50,000 Teladorsagia circumcincta L3. Blood, abomasal fluid and faecal samples were collected daily for measurement of serum gastrin and pepsinogen concentrations, blood eosinophils, abomasal pH and FEC. Four lambs from each flock were euthanased on Day 8 post-infection and the other four on Day 28 post-infection. At necropsy, abomasal contents and tissues were collected for worm counts, abomasal lymph nodes and fundic tissue for cytokine gene expression and fundic tissue for histopathology. Expression of resilience appeared to be age-dependent as there were no significant differences in either FEC or worm burden between lambs from the two flocks, unlike older HFW lambs in a previous study. Abomasal secretion did not differ between flocks. Histopathological changes were typical of parasitism: inflammatory cells, mainly eosinophils and lymphocytes, were numerous in nodular areas and there were fewer TGF-alpha positive parietal cells, many of which were vacuolated. By Day 28 p.i., globule leucocytes were present. Mucosal thickness was significantly greater on Day 8 than Day 28 p.i. (p=0.000) and in C than HFW lambs. There were fewer parietal cells on Day 28 than on Day 8 p.i. (p=0.003) for pooled data. Circulating eosinophil counts increased moderately in both groups, significantly less in the HFW lambs. Fewer tissue and blood eosinophils in the HFW than C group on Day 8 p.i. were consistent with cytokine gene expression patterns, particularly lower IL-5 levels. Worm count decreased by 90% by Day 28 p.i., along with declining tissue eosinophil counts and IL-13 gene expression and increasing IL-10 and IL-4 gene expression. Food intake was depressed less in the HFW lambs, suggesting that maintenance of appetite could be an important aspect of the physiological basis for resilience. Although the resilient phenotype was not apparent at the younger age, lesser effects on food intake, differences in ALN cytokine profiles and lower blood and tissue eosinophil numbers in the HFW lambs may lead to the expression of resilience when older.

Pathophysiology in Teladorsagia (Ostertagia) circumcincta-infected sheep selected for high fleece weight.

Resilience to parasitism is considered to be the maintenance of growth and production during infection, probably associated with an immune response with lesser detrimental effects on the host relative to adverse effects on the parasite. Resilience to infection with Teladorsagia circumcincta was investigated in lambs from a flock selected for forty generations for high fleece weight (HFW), but with higher FEC and worm burdens than their unselected control (C) flock run in parallel. After recovery from surgery to implant abomasal cannulae, four parasite-naïve lambs from each flock were infected intraruminally at 6.5 months-of-age with 50,000 T. circumcincta L3, then from Day 35 to 70 post infection with 10,000 larvae at weekly intervals. Blood, abomasal fluid and faecal samples were collected daily to Day 35 and thence twice weekly for measurement of serum gastrin and pepsinogen concentrations, blood eosinophils, abomasal pH and FEC. Abomasal worm counts were made after necropsy on Day 94. Skin biopsies were collected weekly for estimation of the percentage of wool follicles containing paracortical cells. Total serum immunoglobulin and IgG1, IgG2, IgA and IgM titres specific for T. circumcincta antigens were estimated twice weekly to Day 42 p.i., then weekly. After the primary challenge, FEC were higher in the HFW lambs, whereas neither group shed many eggs during the 5-week trickle infection; worm burdens were small at post mortem. Resilient HFW lambs showed a lesser inflammatory response, but relatively small differences in abomasal secretion. Circulating eosinophil counts increased moderately in both groups, less in the HFW lambs, during the primary infection and more markedly during the subsequent trickle infection, when the increase in the C lambs became significantly greater. All measured serum antibody titres were low in both groups throughout. Selection for HFW altered the wool characteristics of parasite-naïve lambs (fewer follicles containing paracortical cells). There was a slower increase in the percentage of follicles containing these cells after primary infection. Abomasal function was similar in the two groups, both exhibiting typical increases in abomasal pH and serum gastrin and pepsinogen concentrations. The most marked differences in the HFW lambs were a greater rise in serum pepsinogen during the primary infection and the 2-day delay in onset of hypoacidity. Resilience to parasitism in this flock is consistent with maintenance of wool quality and small differences in abomasal secretion resulting from an attenuated immune response causing fewer detrimental effects on host tissues.

The use of 18-fluoro-dihydroxyphenylalanine and 18-fluorodeoxyglucose positron emission tomography scanning in the assessment of metaiodobenzylguanidine-negative phaeochromocytoma.

123I-metaiodobenzylguanidine (123I-MIBG) scintigraphy scanning is commonly used in the imaging of phaeochromocytoma (and paraganglioma) to confirm the site of disease and whether any spread has occurred. However, 123I-MIBG imaging is negative in 15% of cases of benign phaeochromocytoma and around 50% of cases of malignant phaeochromocytoma. In recent years, positron emission tomography (PET) scanning using various different radiotracers has been shown to be a good alternative or supplementary investigation in phaeochromocytoma. We present the cases of four patients with symptoms and signs suggestive of phaeochromocytoma, but who had negative 123I-MIBG scans, and illustrate the usefulness of 18-fluoro-dihydroxyphenylalanine PET scanning in their assessment. In one of the patients, we illustrate how fluorodeoxyglucose PETscanning can provide useful information about the extent of malignant disease. These illustrative cases lend further support for the use of PET scanning in the assessment of phaeochromocytoma and suggest that it may have a particularly important role in the investigation of patients in whom 123I-MIBG scanning is negative.

Relative ability of young and mature muscles to respond to limb lengthening.

The response of the muscle is critical in determining the functional outcome of limb lengthening. We hypothesised that muscle response would vary with age and therefore studied the response of the muscles during tibial lengthening in ten young and ten mature rabbits. A bromodeoxyuridine technique was used to identify the dividing cells. The young rabbits demonstrated a significantly greater proliferative response to the distraction stimulus than the mature ones. This was particularly pronounced at the myotendinous junction, but was also evident within the muscle belly. Younger muscle adapted better to lengthening, suggesting that in patients in whom a large degree of muscle lengthening is required it may be beneficial to carry out this procedure when they are young, in order to achieve the optimal functional result.

Vagal and splanchnic afferent nerves are not essential for anorexia associated with abomasal parasitism in sheep.

Heavy burdens of the abomasal nematode, Ostertagia (Telodorsagia) circumcincta, in growing lambs result in a reduction in liveweight gain due largely to a drop in voluntary feed intake. The present study investigated: (1) the role of subdiaphragmatic vagal and non-vagal visceral afferent nerves in mediating a reduction in voluntary feed intake, using subdiaphragmatic vagal deafferentation (vagotomy) either alone or in combination with coeliac-superior mesenteric ganglionectomy (vagotomy and sympathectomy); and (2) the association between appetite, abomasal pH, selected blood values (amidated gastrin (G-17-amide), glycine-extended gastrin (G-17-Gly), pepsinogen and leptin) and worm burden, in sheep experimentally infected with 100,000 O. circumcincta infective larvae per os. Neither vagotomy alone nor vagotomy and sympathectomy in combination adversely affected the establishment or course of development of the parasite burden, when compared with a control group subject to sham surgery. Furthermore, neither surgical procedure prevented the drop in appetite seen 5-10 days post-infection, although combined vagotomy and sympathectomy did reduce voluntary feed intake prior to the start of the study. Ostertagia infection resulted in a significant increase in abomasal pH in all three groups, which was accompanied by an increase in blood G-17-amide and in G-17-Gly, the latter reported for the first time in parasitized ruminants. There were no significant differences in blood leptin, also reported for the first time in parasitized sheep, either between groups or in comparison with pre-infection levels, though weak negative correlations were established between blood leptin and appetite from day 5 to the end of the study in all three groups and a positive correlation with blood G-17-amide in the control group over the same period. These data suggest that neither intact subdiaphragmatic vagal afferent nerves or coeliac-superior mesenteric ganglion fibres, nor changes in circulating gastrin and leptin concentrations play a major role in mediating the hypophagic effects of O. circumcincta in parasitized sheep.