Up-to 5-year efficacy of pasireotide in a patient with Cushing's disease and pre-existing diabetes: literature review and clinical practice considerations.

PURPOSE: Pasireotide is a multi-receptor-targeted somatostatin analogue approved in the EU and in the US for the treatment of adults with Cushing's disease (CD). Pasireotide has a safety profile similar to other somatostatin analogues with the exception of hyperglycemia. In this report and literature review, the current understanding of predicting a positive treatment response to pasireotide in CD and the management of diabetes mellitus (DM) during pasireotide treatment are discussed and analyzed. CASE PRESENTATION: We report a case of a 55-year-old woman with CD and DM who benefitted from long-term pasireotide. The patient, who was enrolled in a phase III trial of the drug, showed early clinical improvements with pasireotide [900 µg subcutaneously twice daily (bid)] but was classified as a non-responder as urinary free cortisol (UFC) levels, were not normalized. Continuation of pasireotide for 12 months at an increased dose (1,200 µg bid) normalized UFC levels and restored cortisol rhythm. The initial deterioration in her blood glucose was managed with insulin and metformin; however, after 12 months' treatment with pasireotide her DM was well controlled with oral hypoglycemic agents. Five years later, the patient is still receiving pasireotide (300 µg bid) with no loss of clinical or biochemical efficacy and with continued glycemic control. CONCLUSIONS: This case presentation indicates that uncontrolled UFC levels during the first few months of pasireotide treatment as well as worsening of glycemic control in patients with CD and DM are not always predictive of the efficacy and tolerability and appears to support the long-term continuation of pasireotide.

Salivary cortisol is a useful tool to assess the early response to pasireotide in patients with Cushing's disease.

PURPOSE: Late night salivary cortisol (LNSC) is useful for diagnosing hypercortisolism and monitoring patients with Cushing's disease (CD) following pituitary surgery. It may also be a better index of cortisol secretion than serum cortisol or urinary free cortisol (UFC). No data regarding the role of LNSC in the early monitoring of patients with CD receiving drug therapy has been published. We investigated the value of LNSC in monitoring the short-term efficacy of pasireotide. METHODS: Seven patients who were enrolled in a phase II study investigating the efficacy of pasireotide in CD (CSOM230B2208) were included in this analysis. Patients self-administered subcutaneous pasireotide 600 µg bid for 15 days. LNSC and UFC levels were assessed at baseline and day 15. RESULTS: At baseline, all patients had elevated LNSC which was correlated significantly with UFC levels (r = 0.97, P = .0002). At day 15, LNSC was reduced in six patients. LNSC decreases were observed from day 1 (-20%) and persisted until day 15 (overall mean reduction from baseline -51%), with the greatest decrease on day 5 (-58%). At day 15, UFC levels were decreased in all patients and normalized in one that restored also salivary cortisol rhythm. CONCLUSIONS: In patients with CD, pasireotide rapidly reduced and normalized both UFC and LNSC levels. LNSC may be a simple, non-invasive biomarker to assess the early response to pasireotide, particularly in determining whether cortisol rhythm is normalized in patients with normalized UFC levels. Further studies are warranted.

Fracture risk assessment before and after resolution of endogenous hypercortisolism: is the FRAX® algorithm useful?

PURPOSE: Fracture risk data following curative treatment of Cushing's syndrome (CS) are scarce and the role of bisphosphonates in bone recovery after remission is controversial. We evaluated the effects of hypercortisolism remission in bone recovery in CS. Then, we assessed if the FRAX(®) algorithm calculated before the cure can predict fracture risk after cure. METHODS: Thirty-six patients with CS were retrospectively investigated. Bone turnover markers, bone mineral density (BMD) at the lumbar spine (L1-L4) and left femur (both neck and total hip were considered), and fracture risk using FRAX(®) algorithm with femoral neck BMD were evaluated at diagnosis and after a median follow-up of 24 months (range 12-108 months) from hypercortisolism remission. Data about bone active therapy were analyzed. RESULTS: Hypercortisolism remission was associated with the improvement of all densitometric parameters and with the reduction of fracture risk. The percentage change in BMD and the fracture risk were not significantly different in bisphosphonate-treated vs. untreated patients. During follow-up, three fractured patients at baseline exhibited a new vertebral fracture. A baseline 10-year probability of major osteoporotic fractures (FRAX(®) Major) of 17 % was able to predict the occurrence of a new vertebral fracture during follow-up after cure with 100 % sensitivity, 77 % specificity, 81 % positive predictive value and 100 % negative predictive value. CONCLUSIONS: Osteoporosis and fracture risk may be reversible after curative treatment of CS, regardless of bisphosphonate therapy. We suggest applying the FRAX(®) algorithm to all active CS patients using a baseline FRAX(®) Major of 17 % as "intervention threshold".

Bulk-suppressed and surface-sensitive Raman scattering by transferable plasmonic membranes with irregular slot-shaped nanopores.

Raman spectroscopy enables the non-destructive characterization of chemical composition, crystallinity, defects, or strain in countless materials. However, the Raman response of surfaces or thin films is often weak and obscured by dominant bulk signals. Here we overcome this limitation by placing a transferable porous gold membrane, (PAuM) on the surface of interest. Slot-shaped nanopores in the membrane act as plasmonic antennas and enhance the Raman response of the surface or thin film underneath. Simultaneously, the PAuM suppresses the penetration of the excitation laser into the bulk, efficiently blocking its Raman signal. Using graphene as a model surface, we show that this method increases the surface-to-bulk Raman signal ratio by three orders of magnitude. We find that 90% of the Raman enhancement occurs within the top 2.5 nm of the material, demonstrating truly surface-sensitive Raman scattering. To validate our approach, we quantify the strain in a 12.5 nm thin Silicon film and analyze the surface of a LaNiO3 thin film. We observe a Raman mode splitting for the LaNiO3 surface-layer, which is spectroscopic evidence that the surface structure differs from the bulk. These results validate that PAuM gives direct access to Raman signatures of thin films and surfaces.

Six controversial issues on subclinical Cushing's syndrome.

Subclinical Cushing's syndrome is a condition of hypercortisolism in the absence of signs specific of overt cortisol excess, and it is associated with an increased risk of diabetes, hypertension, fragility fractures, cardiovascular events and mortality. The subclinical Cushing's syndrome is not rare, being estimated to be between 0.2-2 % in the adult population. Despite the huge number of studies that have been published in the recent years, several issues remain controversial for the subclinical Cushing's syndrome screening, diagnosis and treatment. The Altogether to Beat Cushing's syndrome Group was founded in 2012 for bringing together the leading Italian experts in the hypercortisolism-related diseases. This document represents the Altogether to Beat Cushing's syndrome viewpoint regarding the following controversial issues on Subclinical Cushing's syndrome (SCS): (1) Who has to be screened for subclinical Cushing's syndrome? (2) How to screen the populations at risk? (3) How to diagnose subclinical Cushing's syndrome in patients with an adrenal incidentaloma? (4) Which consequence of subclinical Cushing's syndrome has to be searched for? (5) How to address the therapy of choice in AI patients with subclinical Cushing's syndrome? (6) How to follow-up adrenal incidentaloma patients with subclinical Cushing's syndrome surgically or conservatively treated? Notwithstanding the fact that most studies that faced these points may have several biases (e.g., retrospective design, small sample size, different criteria for the subclinical Cushing's syndrome diagnosis), we believe that the literature evidence is sufficient to affirm that the subclinical Cushing's syndrome condition is not harmless and that the currently available diagnostic tools are reliable for identifying the majority of individuals with subclinical Cushing's syndrome.