Copeptin as a surrogate marker for arginine vasopressin: analytical insights, current utility, and emerging applications.

Copeptin is a 39-amino-acid long glycosylated peptide with a leucine-rich core segment in the C-terminal part of pre-pro-vasopressin. It exhibits a rapid response comparable to arginine vasopressin (AVP) in response to osmotic, hemodynamic, and nonspecific stress-related stimuli. This similarity can be attributed to equimolar production of copeptin alongside AVP. However, there are markedly different decay kinetics for both peptides, with an estimated initial half-life of copeptin being approximately two times longer than that of AVP. Like AVP, copeptin correlates strongly over a wide osmolality range in healthy individuals, making it a useful alternative to AVP measurement. While copeptin does not appear to be significantly affected by food intake, small amounts of oral fluid intake may result in a significant decrease in copeptin levels. Compared to AVP, copeptin is considerably more stable in vitro. An automated immunofluorescent assay is now available and has been used in recent landmark trials. However, separate validation studies are required before copeptin thresholds from these studies are applied to other assays. The biological variation of copeptin in presumably healthy subjects has been recently reported, which could assist in defining analytical performance specifications for this measurand. An established diagnostic utility of copeptin is in the investigation of polyuria-polydipsia syndrome and copeptin-based testing protocols have been explored in recent years. A single baseline plasma copeptin >21.4 pmol/L differentiates AVP resistance (formerly known as nephrogenic diabetes insipidus) from other causes with 100% sensitivity and specificity, rendering water deprivation testing unnecessary in such cases. In a recent study among adult patients with polyuria-polydipsia syndrome, AVP deficiency (formerly known as central diabetes insipidus) was more accurately diagnosed with hypertonic saline-stimulated copeptin than with arginine-stimulated copeptin. Glucagon-stimulated copeptin has been proposed as a potentially safe and precise test in the investigation of polyuria-polydipsia syndrome. Furthermore, copeptin could reliably identify those with AVP deficiency among patients with severe hypernatremia, though its diagnostic utility is reportedly limited in the differential diagnosis of profound hyponatremia. Copeptin measurement may be a useful tool for early goal-directed management of post-operative AVP deficiency. Additionally, the potential prognostic utility of copeptin has been explored in other diseases. There is an interest in examining the role of the AVP system (with copeptin as a marker) in the pathogenesis of insulin resistance and diabetes mellitus. Copeptin has been found to be independently associated with an increased risk of incident stroke and cardiovascular disease mortality in men with diabetes mellitus. Increased levels of copeptin have been reported to be independently predictive of a decline in estimated glomerular filtration rate and a greater risk of new-onset chronic kidney disease. Furthermore, copeptin is associated with disease severity in patients with autosomal dominant polycystic kidney disease. Copeptin predicts the development of coronary artery disease and cardiovascular mortality in the older population. Moreover, the predictive value of copeptin was found to be comparable with that of N-terminal pro-brain natriuretic peptide for all-cause mortality in patients with heart failure. Whether the measurement of copeptin in these conditions alters clinical management remains to be demonstrated in future studies.

Adrenal Vein Sampling for Primary Aldosteronism: Recommendations From the Australian and New Zealand Working Group.

Adrenal vein sampling (AVS) is the current recommended procedure for identifying unilateral subtypes of primary aldosteronism (PA), which are amenable to surgery with the potential for cure. AVS is a technically challenging procedure usually undertaken by interventional radiologists at tertiary centres. However, there are numerous variations in AVS protocols relating to patient preparation, sampling techniques and interpretation which may impact the success of AVS and patient care. To reduce practice variations, improve the success rates of AVS and optimise patient outcomes, we established an Australian and New Zealand AVS Working Group and developed evidence-based expert consensus recommendations for the preparation, performance and interpretation of AVS. These recommendations can be used by all healthcare professionals in a multidisciplinary team who look after the diagnosis and management of PA.

Bone Density and Trabecular Bone Score Decline Rapidly in the First Year After Bone Marrow Transplantation with a Marked Increase in 10-Year Fracture Risk.

As outcomes from allogeneic bone marrow transplantation (BMT) have improved, prevention of long-term complications, such as fragility fractures, has gained importance. We aimed to assess areal bone mineral density (aBMD) and trabecular bone score (TBS) changes post BMT, and determine their relationship with fracture prevalence. Patients who attended the Royal Melbourne Hospital (RMH) BMT clinic between 2005-2021 were included. Patient characteristics and dual-energy X-ray absorptiometry (DXA) values were collected from the electronic medical record and a survey. TBS iNsight™ was used to calculate TBS for DXA scans performed from 2019 onwards. 337 patients with sequential DXAs were eligible for inclusion. Patients were primarily male (60%) and mean age ± SD was 45.7 ± 13.4 years. The annualised decline in aBMD was greater at the femoral neck (0.066g/cm2 (0.0038-0.17)) and total hip (0.094g/cm2 (0.013-0.19)), compared to the lumbar spine (0.049g/cm2 (- 0.0032-0.16)), p < 0.0001. TBS declined independently of aBMD T-scores at all sites. Eighteen patients (5.3%) sustained 19 fractures over 3884 person-years of follow-up post-transplant (median follow-up 11 years (8.2-15)). This 5.3% fracture prevalence over the median 11-year follow-up period is higher than what would be predicted with FRAX® estimates. Twenty-two patients (6.5%) received antiresorptive therapy, and 9 of 18 (50%) who fractured received or were on antiresorptive therapy. In BMT patients, aBMD and TBS decline rapidly and independently in the first year post BMT. However, FRAX® fracture probability estimates incorporating these values significantly underestimate fracture rates, and antiresorptive treatment rates remain relatively low.

Opportunistic screening for osteoporosis using routine clinical care computed tomography brain studies.

OBJECTIVE: Osteoporosis and falls are both prevalent in the elderly, and CT brain (CTB) is frequently performed post head-strike. We aim to validate the relationship between frontal bone density (Hounsfield unit) from routine CTB and bone mineral density from dual-energy X-ray absorptiometry (DEXA) scan for opportunistic osteoporosis screening. MATERIALS AND METHODS: Patients who had a non-contrast CTB followed by a DEXA scan in the subsequent year were included in this multi-center retrospective study. The relationship between frontal bone density on CT and femoral neck T-score on DEXA was examined using ANOVA, Pearson's correlation, and receiver operating curve (ROC) analysis. Sensitivity, specificity, negative and positive predictive values, and area under the curve (AUC) were calculated. RESULTS: Three hundred twenty-six patients (205 females and 121 males) were analyzed. ANOVA analysis showed that frontal bone density was lower in patients with DEXA-defined osteoporosis (p < 0.001), while Pearson's correlation analysis demonstrated a fair correlation with femoral neck T-score (r = 0.3, p < 0.001). On subgroup analysis, these were true in females but not in males. On ROC analysis, frontal bone density weakly predicted osteoporosis (AUC 0.6, 95% CI 0.5-0.7) with no optimal threshold identified. HU < 610 was highly specific (87.5%) but poorly sensitive (18.9%). HU > 1200 in females had a strong negative predictive value for osteoporosis (92.6%, 95% CI 87.1-98.1%). CONCLUSION: Frontal bone density from routine CTB is significantly different between females with and without osteoporosis, but not between males. However, frontal bone density was a weak predictor for DEXA-defined osteoporosis. Further research is required to determine the role of CTB in opportunistic osteoporosis screening.

Lrp5 controls bone formation by inhibiting serotonin synthesis in the duodenum.

Loss- and gain-of-function mutations in the broadly expressed gene Lrp5 affect bone formation, causing osteoporosis and high bone mass, respectively. Although Lrp5 is viewed as a Wnt coreceptor, osteoblast-specific disruption of beta-Catenin does not affect bone formation. Instead, we show here that Lrp5 inhibits expression of Tph1, the rate-limiting biosynthetic enzyme for serotonin in enterochromaffin cells of the duodenum. Accordingly, decreasing serotonin blood levels normalizes bone formation and bone mass in Lrp5-deficient mice, and gut- but not osteoblast-specific Lrp5 inactivation decreases bone formation in a beta-Catenin-independent manner. Moreover, gut-specific activation of Lrp5, or inactivation of Tph1, increases bone mass and prevents ovariectomy-induced bone loss. Serotonin acts on osteoblasts through the Htr1b receptor and CREB to inhibit their proliferation. By identifying duodenum-derived serotonin as a hormone inhibiting bone formation in an Lrp5-dependent manner, this study broadens our understanding of bone remodeling and suggests potential therapies to increase bone mass.

Utility of adrenocorticotropic hormone in adrenal vein sampling despite the occurrence of discordant lateralization.

BACKGROUND: Adrenal vein sampling (AVS) is crucial for accurate lateralization of aldosterone excess but it is technically challenging due to the difficulty of adrenal vein cannulation. The use of adrenocorticotropic hormone (ACTH) to improve cannulation success is controversial and can lead to discordant lateralization outcomes. OBJECTIVE: To evaluate the utility of ACTH in two centres with different levels of AVS expertise and formulate a strategy for interpreting discordant results. DESIGN: A retrospective cross-sectional analysis of AVS results and postoperative patient outcomes. SETTING: Two large tertiary hospitals with harmonized AVS protocols where adrenal venous samples are collected both before and after ACTH stimulation. MEASUREMENTS: Cannulation success (measured by selectivity index, SI), lateralization (measured by lateralization index, LI) and postoperative biochemical cure. RESULTS: Number of AVS procedures judged to have successful bilateral adrenal vein cannulation increased from 53% pre- to 73% post-ACTH. The increase in cannulation success was significantly higher in centre where AVS was performed by multiple radiologists with a lower basal success rate. In both centres, the proportion of cases deemed to display lateralization significantly decreased with the use of ACTH (70% pre- to 52% post-ACTH). Based on postoperative outcomes of patients with discordant results who underwent unilateral adrenalectomy, the combination of LI >3 pre-ACTH and LI >2 post-ACTH was predictive of a biochemical cure. CONCLUSION: Adrenocorticotropic hormone can increase the rate of cannulation success during AVS at the expense of reduced lateralization. The criteria for lateralization should be carefully determined based on local data when ACTH is used.

Quantifying Use of a Health Virtual Community of Practice for General Practitioners' Continuing Professional Development: A Novel Methodology and Pilot Evaluation.

BACKGROUND: Health care practitioners (HPs), in particular general practitioners (GPs), are increasingly adopting Web-based social media platforms for continuing professional development (CPD). As GPs are restricted by time, distance, and demanding workloads, a health virtual community of practice (HVCoP) is an ideal solution to replace face-to-face CPD with Web-based CPD. However, barriers such as time and work schedules may limit participation in an HVCoP. Furthermore, it is difficult to gauge whether GPs engage actively or passively in HVCoP knowledge-acquisition for Web-based CPD, as GPs' competencies are usually measured with pre- and posttests. OBJECTIVE: This study investigated a method for measuring the engagement features needed for an HVCoP (the Community Fracture Capture [CFC] Learning Hub) for learning and knowledge sharing among GPs for their CPD activity. METHODS: A prototype CFC Learning Hub was developed using an Igloo Web-based social media software platform and involved a convenience sample of GPs interested in bone health topics. This Hub, a secure Web-based community site, included 2 key components: an online discussion forum and a knowledge repository (the Knowledge Hub). The discussion forum contained anonymized case studies (contributed by GP participants) and topical discussions (topics that were not case studies). Using 2 complementary tools (Google Analytics and Igloo Statistical Tool), we characterized individual participating GPs' engagement with the Hub. We measured the GP participants' behavior by quantifying the number of online sessions of the participants, activities undertaken within these online sessions, written posts made per learning topic, and their time spent per topic. We calculated time spent in both active and passive engagement for each topic. RESULTS: Seven GPs participated in the CFC Learning Hub HVCoP from September to November 2017. The complementary tools successfully captured the GP participants' engagement in the Hub. GPs were more active in topics in the discussion forum that had direct clinical application as opposed to didactic, evidence-based discussion topics (ie, topical discussions). From our knowledge hub, About Osteoporosis and Prevention were the most engaging topics, whereas shared decision making was the least active topic. CONCLUSIONS: We showcased a novel complementary analysis method that allowed us to quantify the CFC Learning Hub's usage data into (1) sessions, (2) activities, (3) active or passive time spent, and (4) posts made to evaluate the potential engagement features needed for an HVCoP focused on GP participants' CPD process. Our design and evaluation methods for ongoing use and engagement in this Hub may be useful to evaluate future learning and knowledge-sharing projects for GPs and may allow for extension to other HPs' environments. However, owing to the limited number of GP participants in this study, we suggest that further research with a larger cohort should be performed to validate and extend these findings.

Polyuria-polydipsia syndrome: a diagnostic challenge.

The main determinants for the maintenance of water homeostasis are the hormone arginine vasopressin (AVP) and thirst. Disturbances in these regulatory mechanisms can lead to polyuria-polydipsia syndrome, which comprises of three different conditions: central diabetes insipidus (DI) due to insufficient secretion of AVP, nephrogenic DI caused by renal insensitivity to AVP action and primary polydipsia due to excessive fluid intake and consequent physiological suppression of AVP. It is crucial to determine the exact diagnosis because treatment strategies vary substantially. To differentiate between the causes of the polyuria-polydipsia syndrome, a water deprivation test combined with desmopressin administration is the diagnostic 'gold standard'. Thereby, AVP activity is indirectly evaluated through the measurement of urine osmolality after prolonged dehydration. However, this test has several limitations and may fail to distinguish precisely between patients with primary polydipsia and mild forms of central and nephrogenic DI. The direct measurement of AVP during the water deprivation test, which was reported in the 1980s, has not been widely adopted due to availability, assay issues and diagnostic performance. Recently, copeptin, the c-terminal portion of the larger precursor peptide of AVP, has been evaluated in the setting of polyuria-polydipsia syndrome and appears to be a useful candidate biomarker for the differential diagnosis. A standardised method for the water deprivation test is presented as part of a joint initiative of the Endocrine Society of Australia, the Australasian Association of Clinical Biochemists and the Royal College of Pathologists of Australasia to harmonise dynamic endocrine tests across Australia.

The use of bone turnover markers in chronic kidney disease-mineral and bone disorders.

Bone turnover markers assist in fracture risk prediction, management and monitoring of osteoporosis in patients without chronic kidney disease (CKD). The use in CKD-mineral bone disorder (MBD) has been limited as many of these markers and breakdown products are renally excreted, including the most commonly used and well standardized procollagen type I N propeptide and C-terminal cross-linking telopeptide of type I collagen. Of the markers unaffected by renal function, bone specific alkaline phosphatase is associated with mortality and fracture rate in CKD subjects and is now available on several automated analysers. When used in combination with PTH, bone specific alkaline phosphatase as a bone formation marker correlated well with bone biopsy histomorphometry in predicting adynamic bone disease. Tartrate-resistant acid phosphatase 5b is a resorption marker that is under development for automation. Both high and low bone turnover in CKD-MBD patients are associated with increased fracture and mortality risk. Bone biopsy as the gold standard to differentiate between adynamic bone disease and osteitis fibrosa is limited by availability and cost. Appropriate use of bone turnover markers is vital in the decision to commence anti-resorptive agents, and to monitor efficacy in order to avoid over suppression of bone turnover, which may lead to stress fractures. Further efforts are required to develop markers unaffected by renal function with standardized cut-off values and fracture as well as vascular calcification end-points.

Hypocalcemia post denosumab in patients with chronic kidney disease stage 4-5.

BACKGROUND: Denosumab, a RANK-ligand inhibitor, is an effective treatment for osteoporosis in postmenopausal women and men. Unlike the bisphosphonates, it is not excreted by the kidney. Little is known, however, about its efficacy and safety in patients with severe chronic kidney disease (CKD). METHODS: A retrospective study was performed in CKD 4-5D patients from a tertiary referral hospital who were treated with denosumab between 1st January 2011 and 31st March 2014. Data collected included information about the following: CKD stage, fracture history, bone mineral density, serum calcium levels pre and post denosumab treatment, episodes of hypocalcemia, relevant medications and adverse events. RESULTS: Eight patients with CKD-5 and 6 patients with CKD-4 were identified (all female, mean age 77.1 ± 9.9). The mean pre-denosumab calcium value was 2.42 ± 0.12 mmol/l, PTH 20.2 ± 14.7 pmol/l and 25-OH vitamin D 69.1 ± 30.1 nmol/l. After denosumab treatment, 6/8 patients with CKD-5/5D, and 2/5 patients with CKD-4 developed severe hypocalcemia. Two patients developed direct adverse complications of hypocalcemia (seizure, laryngospasm, prolonged QTc). Among the patients who developed hypocalcemia, the median time to serum calcium nadir was 21 days and the median time to correction of hypocalcemia was 71 days. Treatment of hypocalcemia required large doses of oral calcium and calcitriol, and increases in dialysate calcium concentration. CONCLUSIONS: A high rate of severe hypocalcemia was observed in patients with advanced CKD treated with denosumab. If denosumab is used in patients with severe CKD, close monitoring and aggressive replacement of calcium and calcitriol is required to avoid the development of hypocalcemia.

Hypoparathyroidism update.

PURPOSE OF REVIEW: Since the release of the 2022 Second International Workshop Evaluation and Management of Hypoparathyroidism Summary Statement and Guidelines, updates and advances are now available in the cause, complications, and treatment of adult chronic hypoparathyroidism (hypoPTH). This review aims to highlight these new findings and implications to patient care. RECENT FINDINGS: Postsurgical hypoparathyroidism remains the most common cause, immune-related hypoparathyroidism from checkpoint inhibitors is an emerging autoimmune cause. In a large retrospective cohort study of thyroidectomies, incident fracture was lower, particularly in the vertebra, in the hypoPTH cohort, compared with postthyroidectomy control group. Hypercalciuria increases risk for renal calculi in hypoPTH independent of disease duration and treatment dose. Quality of life is impaired in hypoPTH patients on conventional therapy, improvement was noted post-PTH replacement. TranCon PTH phase 3 RCT reported eucalcemia with reduced renal calcium excretion, normalization of bone turn-over markers, stable BMD and improved quality of life. SUMMARY: HypoPTH is a chronic disease associated with significant morbidity and poor Quality of Life. Awareness of treatment targets and follow-up investigations can alleviate patient anxiety regarding over-treatment and under-treatment. Progress in long-acting PTH replacement strategies might provide accessible, feasible alternatives to conventional therapy in brittle hypoPTH patients.

Biological Variation Estimates for Plasma Copeptin and Clinical Implications.

BACKGROUND: Plasma copeptin measurement is useful for the differential diagnoses of polyuria-polydipsia syndrome. It has also been proposed as a prognostic marker for cardiovascular diseases. However, limited information is available about the within- (CVI) and between-subject (CVG) biological variation (BV). This study presents BV estimates for copeptin in healthy individuals. METHODS: Samples were collected weekly from 41 healthy subjects over 5 weeks and analyzed using the BRAHMS Copeptin proAVP KRYPTOR assay after at least 8 h of food and fluid abstinence. Outlier detection, variance homogeneity, and trend analysis were performed followed by CV-ANOVA for BV and analytical variation (CVA) estimation with 95% confidence intervals. Reference change values (RCVs), index of individuality (II), and analytical performance specification (APS) were also calculated. RESULTS: The analysis included 178 results from 20 males and 202 values from 21 females. Copeptin concentrations were significantly higher in males than in females (mean 8.5 vs 5.2 pmol/L, P < 0.0001). CVI estimates were 18.0% (95% CI, 15.4%-21.6%) and 19.0% (95% CI, 16.4%-22.6%), for males and females, respectively; RCVs were -35% (decreasing value) and 54% (increasing value). There was marked individuality for copeptin. No result exceeded the diagnostic threshold (>21.4 pmol/L) for arginine vasopressin resistance. CONCLUSIONS: The availability of BV data allows for refined APS and associated II, and RCVs applicable as aids in the serial monitoring of patients with specific diseases such as heart failure. The BV estimates are only applicable in subjects who abstained from oral intake due to the rapid and marked effects of fluids on copeptin physiology.

A Quantification Method for Disorganized Bone Components: Application to the Femoral Shaft.

Based on the current paradigm, a healthy bone is one with adequate mass without microarchitectural decay. However, these two features may not be sufficient to ensure that a bone is healthy. In addition, components must be correctly assembled and aligned. This ensures "the right amount of bone, at the right place" and thus, an optimal cohesion or interplay between constituents. Disorganization may be an independent contributor to bone abnormalities including fragility fractures. Indeed, many bone diseases may be characterized by the presence of disorganized bone, including osteogenesis imperfecta, hypophosphatasia, and atypical femur fractures (AFFs). Despite its likely importance, currently, there are no tools to quantify disorganization in vivo. We address this unmet need by describing a novel method for quantifying bone disorganization from X-ray images. Disorganization is quantified as variations in the orientation of bone components in relation to a target reference point. True disorganization created by disarranging (misplacing) pixels within the bone served as "gold standard." To further validate the method in clinical settings, we compared disorganization in three groups of femurs: (i) femurs of women with AFFs (n = 9); (ii) fracture-free femurs contralateral to AFFs (n = 9); and (iii) fracture-free femurs from controls (n = 25). There was excellent agreement between measured disorganization and "gold standard," with R 2 values ranging from 0.84 to 0.99. Precision error ranged from 1.72% to 4.69%. Disorganization produced by abnormalities associated with AFFs was accurately captured. Disorganization level was lowest in fracture-free control femurs, higher in fracture-free contralateral femurs to AFFs, and highest in femurs with AFFs (all p < 0.0001). Quantification of disorganization, a novel biomarker, may provide novel insights into the pathogenesis of metabolic bone diseases beyond that provided by bone mineral density (BMD) or microarchitecture. We provide evidence that measurement of disorganization is likely to help identify patients at risk for fractures, especially in those poorly explained by BMD or microarchitecture such as AFFs. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Increased Thyroidal Activity on Routine FDG-PET/CT after Combination Immune Checkpoint Inhibition: Temporal Associations with Clinical and Biochemical Thyroiditis.

BACKGROUND: FDG-PET/CT used for immune checkpoint inhibitor (ICI) response assessment can incidentally identify immune-related adverse events (irAEs), including thyroiditis. This study aimed to correlate the time course of FDG-PET/CT evidence of thyroiditis with clinical and biochemical evolution of thyroid dysfunction. METHODS: A retrospective review was performed by two independent blinded nuclear medicine physicians (NMPs) of thyroidal FDG uptake in 127 patients who underwent PET/CT between January 2016 and January 2019 at baseline and during treatment monitoring of combination ICI therapy for advanced melanoma. Interobserver agreement was assessed and FDG-PET/CT performance defined by a receiver-operating characteristic (ROC) curve using thyroid function tests (TFTs) as the standard of truth. Thyroid maximum standardized uptake value (SUVmax) and its temporal changes with respect to the longitudinal biochemistry were serially recorded. RESULTS: At a median of 3 weeks after commencing ICI, 43/127 (34%) had a diagnosis of thyroiditis established by abnormal TFTs. FDG-PET/CT was performed at baseline and at a median of 11 weeks (range 3-32) following the start of therapy. ROC analysis showed an area under the curve of 0.87 (95% CI 0.80, 0.94) for FDG-PET/CT for detection of thyroiditis with a positive predictive value of 93%. Among patients with biochemical evidence of thyroiditis, those with a positive FDG-PET/CT were more likely to develop overt hypothyroidism (77% versus 35%, p < 0.01). In the evaluation of the index test, there was an almost perfect interobserver agreement between NMPs of 93.7% (95% CI 89.4-98.0), kappa 0.83. CONCLUSION: Increased metabolic activity of the thyroid on routine FDG-PET/CT performed for tumoral response of patients undergoing ICI therapy is generally detected well after routine biochemical diagnosis. Elevation of FDG uptake in the thyroid is predictive of overt clinical hypothyroidism and suggests that an ongoing robust inflammatory response beyond the initial thyrotoxic phase may be indicative of thyroid destruction.

Imaging for assessment of cancer treatment response to immune checkpoint inhibitors can be complementary in identifying hypophysitis.

Introduction: Hypophysitis is reported in 8.5%-14% of patients receiving combination immune checkpoint inhibition (cICI) but can be a diagnostic challenge. This study aimed to assess the role of routine diagnostic imaging performed during therapeutic monitoring of combination anti-CTLA-4/anti-PD-1 treatment in the identification of hypophysitis and the relationship of imaging findings to clinical diagnostic criteria. Methods: This retrospective cohort study identified patients treated with cICI between January 2016 and January 2019 at a quaternary melanoma service. Medical records were reviewed to identify patients with a documented diagnosis of hypophysitis based on clinical criteria. Available structural brain imaging with magnetic resonance imaging (MRI) or computed tomography (CT) of the brain and 2-deoxy-2-[18F]fluoro-D-glucose positron emission tomography with computed tomography (FDG-PET/CT) were assessed retrospectively. The main radiological outcome measures were a relative change in pituitary size or FDG uptake temporally attributed to cICI. Results: There were 162 patients (median age 60 years, 30% female) included. A total of 100 and 134 had serial CT/MRI of the brain and FDG-PET/CT, respectively. There were 31 patients who had a documented diagnosis of hypophysitis and an additional 20 who had isolated pituitary imaging findings. The pituitary gland enlargement was mild, and the largest absolute gland size was 13 mm, with a relative increase of 7 mm from baseline. There were no cases of optic chiasm compression. Pituitary enlargement and increased FDG uptake were universally transient. High-dose glucocorticoid treatment for concurrent irAEs prevented assessment of the pituitary-adrenal axis in 90% of patients with isolated imaging findings. Conclusion: Careful review of changes in pituitary characteristics on imaging performed for assessment of therapeutic response to iICI may lead to increased identification and more prompt management of cICI-induced hypophysitis.

Decreased body weight in young Osterix-Cre transgenic mice results in delayed cortical bone expansion and accrual.

Conditional gene inactivation using the Cre/loxP system has lead to significant advances in our understanding of the function of genes in a wide range of disciplines. It is becoming increasingly apparent in the literature, that Cre transgenic mice may themselves have a phenotype. In the following study we describe the bone phenotype of a commonly used Cre transgenic mouse line to study osteoblasts, the Osx-GFP::Cre (Osx-Cre) mice. Cortical and trabecular bone parameters were determined in the femurs of Osx-Cre mice at 6 and 12 weeks of age by microtomography (µCT). At 6 weeks of age, Osx-Cre mice had reduced body weight by 22% (P < 0.0001) and delayed cortical bone expansion and accrual, characterized by decreases in periosteal circumference by 7% (P < 0.05) and cortical thickness by 11% (P < 0.01), compared to wild type controls. Importantly, the cortical bone phenotype of the skeletally immature Osx-Cre mice at 6 weeks of age could be accounted for by their low body weight. The delayed weight gain and cortical growth of Osx-Cre mice was overcome by 12 weeks of age, with no differences observed between Osx-Cre and wild type controls. In conclusion, Osx-Cre expressing mice display a delayed growth phenotype in the absence of doxycycline treatment, evidenced by decreased cortical bone expansion and accrual at 6 weeks of age, as an indirect result of decreased body weight. While this delay in growth is overcome by adulthood at 12 weeks of age, caution together with appropriate data analysis must be considered when assessing the experimental data from skeletally immature Cre/loxP knockout mice generated using the Osx-Cre mouse line to avoid misinterpretation.

Acanthosis nigricans in a patient with metastatic insulinoma post peptide receptor radionuclide therapy.

Summary: Acanthosis nigricans (AN) is a common dermatosis associated with hyperinsulinemia and insulin resistance. However, AN has been rarely reported in patients with insulinoma, a state of persistent hyperinsulinemia. We present a case of metastatic insulinoma, in whom AN manifested after the first cycle of peptide receptor radionuclide therapy (PRRT). A 40-year-old man was diagnosed with metastatic insulinoma after 5 months of symptomatic hypoglycemia. Within 1 month post PRRT, the patient became euglycemic but developed a pigmented, pruritic rash which was confirmed on biopsy as AN. We discuss the rare manifestation of AN in subjects with insulinoma, the role of insulin in the pathogenesis of AN, malignant AN in non-insulin-secreting malignancies and association with other insulin-resistant endocrinopathies such as acromegaly. Learning points: Acanthosis nigricans (AN) is a common dermatosis which is typically asymptomatic and associated with the hyperinsulinemic state. Malignant AN can rapidly spread, cause pruritus and affect mucosa and the oral cavity. AN is extremely rare in patients with insulinoma despite marked hyperinsulinemia. Peptide receptor radionuclide therapy might have triggered TGF-α secretion in this subject which led to malignant AN. Rapid spread or unusual distribution of pruritic AN warrants further investigation to exclude underlying malignancy.

Bone microarchitecture and estimated failure load are deteriorated whether patients with chronic kidney disease have normal bone mineral density, osteopenia or osteoporosis.

INTRODUCTION: Measurement of bone mineral density (BMD) is recommended in patients with chronic kidney disease (CKD). However, most persons in the community and most patients with CKD have osteopenia, suggesting fracture risk is low. Bone loss compromises bone microarchitecture which increases fragility disproportionate to modest deficits in BMD. We therefore hypothesized that patients with CKD have reduced estimated failure load due to deterioration in microarchitecture irrespective of whether they have normal femoral neck (FN) BMD, osteopenia or osteoporosis. METHODS: We measured distal tibial and distal radial microarchitecture in 128 patients with CKD and 275 age- and sex-matched controls using high resolution peripheral quantitative computed tomography, FN-BMD using bone densitometry and estimated failure load at the distal appendicular sites using finite element analysis. RESULTS: Patients versus controls respectively had: lower tibial cortical area 219 (40.7) vs. 237 (35.3) mm2, p = 0.002, lower cortical volumetric BMD 543 (80.7) vs. 642 (81.7) mgHA/cm3 due to higher porosity 69.6 (6.19) vs. 61.9 (6.48)% and lower matrix mineral density 64.2 (0.62) vs. 65.1 (1.28)%, lower trabecular vBMD 92.2 (41.1) vs. 149 (43.0) mgHA/cm3 due to fewer and spatially disrupted trabeculae, lower FN-BMD 0.78 (0.12) vs. 0.94 (0.14) g/cm2 and reduced estimated failure load 3825 (1152) vs. 5778 (1467) N, all p < 0.001. Deterioration in microarchitecture and estimated failure load was most severe in patients and controls with osteoporosis. Patients with CKD with osteopenia and normal FN-BMD had more deteriorated tibial microarchitecture and estimated failure load than controls with BMD in the same category. In univariate analyses, microarchitecture and FN-BMD were both associated with estimated failure load. In multivariable analyses, only microarchitecture was independently associated with estimated failure load and accounted for 87% of the variance. CONCLUSIONS: Bone fragility is likely to be present in patients with CKD despite them having osteopenia or normal BMD. Measuring microarchitecture may assist in targeting therapy to those at risk of fracture.