In Vivo Formation of Adrenal Organoids in a Novel Porcine Model of Adrenocortical Cell Transplantation.

Recognizing the limitations of current therapies for Addison's disease, novel treatments that replicate dynamic physiologic corticosteroid secretion, under control of ACTH, are required. The aim of these experiments was to evaluate the feasibility of adrenocortical cell transplantation (ACT) in a large animal model, adapting methods successfully used for intracutaneous pancreatic islet cell transplantation, using a fully biodegradable temporizing matrix. Autologous porcine ACT was undertaken by bilateral adrenalectomy, cell isolation, culture, and intracutaneous injection into a skin site preprepared using a biodegradable temporizing matrix (BTM) foam. Hydrocortisone support was provided during adrenocortical cell engraftment and weaned as tolerated. Blood adrenocortical hormone concentrations were monitored, and the transplant site was examined at endpoint. Outcome measures included cellular histochemistry, systemic hormone production, and hydrocortisone independence. Transplanted adrenocortical cells showed a capability to survive and proliferate within the intracutaneous site and an ability to self-organize into discrete tissue organoids with features of the normal adrenal histologic architecture. Interpretation of systemic hormone levels was confounded by the identification of accessory adrenals and regenerative cortical tissue within the adrenal bed postmortem. Corticosteroids were unable to be completely ceased. ACT in a large animal model has not previously been attempted, yet it is an important step toward clinical translation. These results demonstrate rhe potential for ACT based on the development of adrenal organoids at the BTM site. However, the inability to achieve clinically relevant systemic hormone production suggests insufficient function, likely attributable to insufficient cells through delivered dose and subsequent proliferation.

Future Directions for Adrenal Insufficiency: Cellular Transplantation and Genetic Therapies.

Primary adrenal insufficiency (PAI) occurs in 1 in 5 to 7000 adults. Leading etiologies are autoimmune adrenalitis in adults and congenital adrenal hyperplasia (CAH) in children. Oral replacement of cortisol is lifesaving, but poor quality of life, repeated adrenal crises, and dosing uncertainty related to lack of a validated biomarker for glucocorticoid sufficiency persists. Adrenocortical cell therapy and gene therapy may obviate many of the shortcomings of adrenal hormone replacement. Physiological cortisol secretion regulated by pituitary adrenocorticotropin could be achieved through allogeneic adrenocortical cell transplantation, production of adrenal-like steroidogenic cells from either stem cells or lineage conversion of differentiated cells, or for CAH, gene therapy to replace or repair a defective gene. The adrenal cortex is a high-turnover organ and thus failure to incorporate progenitor cells within a transplant will ultimately result in graft exhaustion. Identification of adrenocortical progenitor cells is equally important in gene therapy, for which new genetic material must be specifically integrated into the genome of progenitors to ensure a durable effect. Delivery of gene-editing machinery and a donor template, allowing targeted correction of the 21-hydroxylase gene, has the potential to achieve this. This review describes advances in adrenal cell transplants and gene therapy that may allow physiological cortisol production for children and adults with PAI.

Ambulatory intravenous insulin and islet cell transplantation to treat severe type III insulin hypersensitivity in a patient with type 1 diabetes mellitus.

Allogenic pancreatic islet cell transplantation is an appropriate treatment option to consider in the management of refractory cases of severe hypersensitivity to insulin in patients with type 1 diabetes mellitus.

Obstructive sleep apnea is not an independent determinant of testosterone in men.

OBJECTIVE: Obstructive sleep apnea (OSA) is generally considered to lower serum testosterone concentration in men, although data supporting this as a direct effect are limited. The aim of this study was to determine the relationship between the presence and severity of OSA and testosterone in a community-based cohort of men aged over 40 years. DESIGN AND METHODS: Anthropometry, polysomnography and biomedical information were collected from enrolled, consenting men from the prospective, longitudinal MAILES study cohort. Fasting morning blood samples (n = 1869) were drawn between 2010 and 2012 for measurement of testosterone using liquid chromatography mass spectrometry. Home polysomnography was completed in 861 men between 2010 and 2012. The final analysis sample consisted of 623 men aged 41-86 years. The effect of OSA on testosterone were analyzed using linear regression models controlling for potential confounders (age, BMI and sex hormone binding globulin (SHBG)). RESULTS: The mean (s.d.) cohort characteristics were: age 59.0 (10.2) years, testosterone 16.8 (5.3) nmol/L, SHBG 32.9 (13.1) nmol/L, BMI 28.6 (4.2) kg/m2 and apnoea hypopnoea index (AHI) 14.9 (13.7). OSA was present in 51.5%. There was an inverse relationship between AHI and testosterone (P = 0.01), which was lost after covariate adjustment. CONCLUSIONS: These data suggest that obesity, rather than OSA per se, determine testosterone concentration. This accords with the graded effect of weight loss, but limited effect of continuous positive airway pressure to increase testosterone, and highlights the importance of managing obesity in men with low testosterone concentration, particularly in the context of OSA.

Should routine radiological assessment of anastomotic integrity be performed after oesophagectomy with cervical anastomosis? Best evidence topic (BET).

Rates of anastomotic leak in patients who undergo oesophagectomy with cervical anastomosis formation are reported within the literature to surpass those of patients undergoing thoracic anastomosis formation. Though preferred by a number of surgeons, cervical anastomosis is associated with higher rates of anastomotic leak, the consequences of which can be severe. Routine contrast oesophagograms are therefore utilised in a number of institutions as a means of recognising leaks early. They are not without potential complications, however, and the predictive value of contrast imaging has previously been debated. This best evidence topic reviews the use of contrast oesophagograms in screening for cervical anastamotic leak, concluding that their inherent risk of aspiration combined with poor sensitivity should preclude their use as a screening tool. High rates of specificity nevertheless indicate the potential utility of these studies in patients for whom there is clinical suspicion of a leak.

Should routine assessment of anastomotic integrity be undertaken using radiological contrast swallow after oesophagectomy with intra-thoracic anastomosis? Best evidence topic (BET).

Thoracic anastomotic leak is associated with significant postoperative morbidity and mortality. Routine contrast oesophagograms are consequently employed by a number of centres to routinely screen for this complication yet there exists little consensus as to if and when this assessment should occur. We have demonstrated within this BestBET analysis of five level IV case series that routine contrast oesophagograms lack adequate sensitivity or positive predictive value to be effective as screening tools, with leaks often arising clinically prior to scheduled routine assessment. We additionally demonstrate the significant risk of aspiration associated with contrast swallow use. The use of contrast swallow studies as diagnostic tools in patients for whom a leak is considered likely on the basis of clinical examination is nevertheless supported by relatively greater negative predictive values and specificity reported within the literature. There is additional evidence to support the use of CT imaging with oral contrast and endoscopic assessment of the anastomosis as valuable tools to assess for anastomotic integrity.