ResearchPad - pituitary-tumors:-trials-and-studies https://www.researchpad.co Default RSS Feed en-us © 2020 Newgen KnowledgeWorks <![CDATA[OR23-03 Post-Operative Day One Morning Cortisol Value as a Biomarker to Predict the Recurrence of Cushing Disease]]> https://www.researchpad.co/article/elastic_article_8729 Tumor removal by transsphenoidal surgery (TSS) is the first line treatment for Cushing disease (CD). However, recurrence is relatively common. A one week post-operative (post-op) nadir cortisol has been used as a biomarker to predict recurrence1. We identified 299 CD patients from our longitudinal multidisciplinary clinic or our institutional RPDR search tool who met biochemical diagnostic criteria1 and had undergone TSS between May 2008 and May 2018, to evaluate post-op cortisol levels as biomarkers to predict long-term remission and to characterize clinical features of Cushing syndrome. Predictors of recurrence were identified with logistic regression, using recurrence as the dependent variable, and a Kaplan-Meier survival curve analysis was performed to compare long-term remission after TSS among the 202 patients who reached initial remission and had at least 1 year of follow-up. The post-op day 1 morning (AM) cortisol had significant association with CD recurrence (OR=1.025, 95%CI:1.002-1.048, p=0.032). The time to recurrence was significantly longer in patients with post-op day 1 AM cortisol <5 μg/dL. In contrast, one week post-op nadir cortisol (OR=1.081, 95%CI: 0.989-1.181, p=0.086), urinary free cortisol (OR=1.032,95%CI: 0.994-1.07, p=0.098), or late night salivary cortisol (OR=1.383, 95%CI:0.841-2.274, p=0.201) had no significant correlation with recurrence. There were no significant differences in time to recurrence for post-op day 2 AM cortisol <5 μg/dL. Among patients who developed post-op adrenal insufficiency, recurrence was significantly lower if glucocorticoid replacement continued for more than one year. In addition, tumor proliferative index (MIB-1) had a significant correlation with recurrence (OR=1.287, 95%CI:1.106-1.498, p=0.001). The most common symptoms and signs of initial presentation of CD were weight gain (91.6%), central obesity (79.6%), menstrual disorders (77.9%), round face (65.9%), hypertension (63.2%), mood disorders (60.2%), dorsocervical fat deposition (59.9%), supraclavicular fat deposition (59.9%), osteoporosis (58.9%), fatigue (58.2%), bruising (55.9%) and facial hirsutism (54.2%). Most of the best discriminating CD features did not have high sensitivity, such as purple striae (31.4%), facial plethora (33.4%) and proximal muscle weakness (30.8%). Our data show that post-op day one morning cortisol level above 5 μg/dL had significant association with recurrence. In contrast, the one week post-op nadir cortisol level had no significant value to predict recurrence. Our data also suggest that nonspecific symptoms and signs of CD are more common than stereotypical signs. Reference: Nieman LK, et al. Treatment of Cushing’s Syndrome: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2015; 100:2807-2831

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<![CDATA[OR23-01 Intrapatient ACTH Variability in Cushing’s Disease: Prognostic Significance]]> https://www.researchpad.co/article/elastic_article_8719 Introduction: In patients with Cushing’s Disease (CD), intrapatient variability of hormone measurements creates significant clinical challenges, therefore multiple measurements are recommended.1 Urinary and salivary cortisol variation has been well described. However, intrapatient variation of adrenocorticotropic hormone (ACTH) in CD remains unknown. In CD patients, ACTH levels are inherently elevated from baseline but the coefficient of diurnal variation is reduced.2Additionally, at each diurnal time point, these exists a significant variation around the mean for the ACTH levels. In this study, we first analyzed the intrapatient variablility of ACTH at each diurnal timepoint in patients with CD. CD is primarily a disorder of ACTH excess, and treatment directed at pituitary adenomas would presumably perturb ACTH levels prior to affecting serum or urine cortisol. We hypothesized that the coefficient of variation at each diurnal time-point can help predict remission from CD following surgery.

Methods: We conducted a retrospective review of patients (n = 645) who had histopathologically confirmed diagnosis of CD from 2005-2019 (NCT NCT00060541). We selected patients that had ≥ 3 plasma ACTH values over a 7 day span prior to surgical or medical intervention. We grouped the ACTH measurements into morning (AM) and midnight (PM) values to account for diurnal variation in ACTH secretion. We then analyzed post-operative hormone measurements performed every 6 hours prior to administration of replacement corticosteroids. Remission was assigned to patients with nadir serum cortisol level ≤5 mcg/dL within ten days post-operatively3,4.

Results: We found 54 patients with multiple PM (n = 27) and AM (n = 41) ACTH measurements within a 7 day span. We found that the median coefficient of variation (CV) of intra-patient variability was 19.7% (N=41) (95% CI:12.5-27.5) for the AM and was 24% (N=27) (95% CI: 9.6-31.8) for the PM. Age, the number of tests, or the length of test period were not correlated with CV or absolute levels of ACTH. The intraclass correlation coefficient (ICC) of the AM data set was 0.59 and the PM data set was 0.79 which demonstrates a good and excellent reliability respectively. We found that that, in general, 30-60% decrease from pre-operative ACTH levels predicted remission from CD. ACTH decrease >50% on POD2 and 3 had 100% specificity and sensitivity in predicting remission. The decrease in ACTH preceded cortisol nadir in 3/10 patients by 24 hours.

Conclusion: We found significant intra-patient variability in plasma levels of ACTH at individual diurnal timepoints in CD patients. We also found that the change in ACTH >50% on POD2 or 3 is an excellent predictor of remission from CD.

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<![CDATA[OR23-04 SST5 Expression and USP8 Mutation in Functioning and Silent Corticotroph Pituitary Tumors]]> https://www.researchpad.co/article/Nfc3aed3b-ccf0-4e16-89e6-bac337f3474f Context. Somatostatin receptor type 5 (SST5), a target of pasireotide, is inconsistently expressed by corticotroph tumors. Somatic driver mutations in the ubiquitin-specific protease 8 (USP8) gene have been describes in 35% to 60% of corticotropinomas. SST5 expression has been found to be higher in USP8mut corticotropinomas.

Objective. To study the correlation between clinical and biochemical characteristics of a large cohort of functioning and silent corticotroph tumor and SST5 expression or USP8 mutation status. To describe SST5 expression and the response to pasireotide in 5 patients.

Design. Retrospective cohort study.

Setting. University hospitals of Lyon.

Patients. 62 patients operated for a corticotroph tumors between 2013 and 2017.

Intervention. None.

Main Outcome Measure. Clinical, biological, radiological and pathological data were evaluated depending on SST5 expression measured by immunohistochemistry (rabbit monoclonal antibody, clone UMB-4, Abcam). Membrane immune-positivity with an IRS>1 was considered positive. USP8 analysis was performed by Sanger sequencing in 50 tumors.

Results. SST5 expression was positive in 26 (41.9%) pituitary tumors. A moderate or strong IRS was found in 24.2% of the cohort and in 32.5% of the functioning pituitary tumors. Compared to SST5-negative pituitary tumors, those expressing SST5 were more frequent in women (92.3% vs 55.6%; p=0.002), fewer were silent (7.7% vs 58.3%; p<0.001), smaller (7 vs 19mm; p=0.001) and less invasive (15.4% vs 44.4%; p=0.03).

USP8 mutations were identified in 26% of the cohort and more frequent in functioning (n=11/30, 36.7%) compared to silent corticotroph tumors (n=2/20, 10%; p=0.05). SST5 expression was more frequent in USP8mut vs USP8neg tumors (58.8% vs 7.7%; p<0.001).

Among treated patients, normal urinary free cortisol (UFC) levels were obtained in 3 patients (IRS 0, 2, and 6) and a 4-fold decrease of UFC in one patient (IRS 4).

Conclusion. SST5 expression seems to be associated with functioning, well-differentiated pituitary tumors and USP8 mutation. However, a correlation between SST5 expression or USP8mut and response to pasireotide treatment remains to be confirmed.

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<![CDATA[OR23-04 SST5 Expression and USP8 Mutation in Functioning and Silent Corticotroph Pituitary Tumors]]> https://www.researchpad.co/article/Na3f677d0-66eb-4408-8175-34611de687a0

Abstract

. Somatostatin receptor type 5 (SST5), a target of pasireotide, is inconsistently expressed by corticotroph tumors. Somatic driver mutations in the ubiquitin-specific protease 8 (USP8) gene have been describes in 35% to 60% of corticotropinomas. SST5 expression has been found to be higher in USP8mut corticotropinomas.

. To study the correlation between clinical and biochemical characteristics of a large cohort of functioning and silent corticotroph tumor and SST5 expression or USP8 mutation status. To describe SST5 expression and the response to pasireotide in 5 patients.

. Retrospective cohort study.

. University hospitals of Lyon.

. 62 patients operated for a corticotroph tumors between 2013 and 2017.

Intervention. None.

. Clinical, biological, radiological and pathological data were evaluated depending on SST5 expression measured by immunohistochemistry (rabbit monoclonal antibody, clone UMB-4, Abcam). Membrane immune-positivity with an IRS>1 was considered positive. USP8 analysis was performed by Sanger sequencing in 50 tumors.

. SST5 expression was positive in 26 (41.9%) pituitary tumors. A moderate or strong IRS was found in 24.2% of the cohort and in 32.5% of the functioning pituitary tumors. Compared to SST5-negative pituitary tumors, those expressing SST5 were more frequent in women (92.3% vs 55.6%; p=0.002), fewer were silent (7.7% vs 58.3%; p<0.001), smaller (7 vs 19mm; p=0.001) and less invasive (15.4% vs 44.4%; p=0.03).

USP8 mutations were identified in 26% of the cohort and more frequent in functioning (n=11/30, 36.7%) compared to silent corticotroph tumors (n=2/20, 10%; p=0.05). SST5 expression was more frequent in USP8mut vs USP8neg tumors (58.8% vs 7.7%; p<0.001).

Among treated patients, normal urinary free cortisol (UFC) levels were obtained in 3 patients (IRS 0, 2, and 6) and a 4-fold decrease of UFC in one patient (IRS 4).

. SST5 expression seems to be associated with functioning, well-differentiated pituitary tumors and USP8 mutation. However, a correlation between SST5 expression or USP8mut and response to pasireotide treatment remains to be confirmed.

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<![CDATA[OR23-06 Is the Improved Glucose Homeostasis in Patients with Acromegaly Treated with Pegvisomant Caused by Improved Glucagon Secretion?]]> https://www.researchpad.co/article/Nea2c2998-0c48-4d18-ad7c-d1984bcdbbd4

Abstract

: Active acromegaly is associated with impaired glucose metabolism, which improves upon treatment. Treatment with first generation somatostatin analogues (SSA) has a detrimental effect on insulin secretion, but the effect on glucose homeostasis is neutralized by the reduction in growth hormone (GH) and Insulin-like growth factor-1 (IGF-1). Treatment with GH receptor antagonists has a more favorable effect on glucose homeostasis.

: To describe the secretion of glucose, insulin, glucagon, glucagon-like peptide-1 (GLP1), and glucose-dependent insulinotropic polypeptide (GIP) in surgically treated patients with acromegaly treated or not with somatostatin analogues, either as monotherapy (SSA) or in co-treatment with pegvisomant (SSA+PEG), respectively, compared to healthy controls.

: Descriptive study of data from 23 surgically treated, non-diabetic patients with acromegaly and 6 healthy controls. After an overnight fast, all participants underwent a three-hour 75 g oral glucose tolerance test (OGTT) and subsequently a three-hour isoglycaemic intravenous glucose infusion on a separate day.

Baseline hormone concentrations, time to peak and area under the curve (AUC) on the OGTT-day, and the incretin effect in the patient groups and controls were compared using analysis of variance with

analysis.

: The total group of patients treated with somatostatin analogues (

=15) had numerically impaired glucose, insulin, GLP1 and glucagon responses (AUC, P>0.05 respectively), and an impaired GIP-response (AUC, P=0.007) during OGTT as compared to patients not treated with somatostatin analogues and healthy controls. Similarly, the incretin effect was numerically impaired.

Patients co-treated with pegvisomant (SSA+PEG,

=4) had a numerically increased secretion of insulin and glucagon compared to patients on SSA (

=11) during OGTT (insulin AUC mean (SEM), SSA+PEG 49 nmol/l*min (8.3) vs SSA 25 (3.4), P>0.05) [

)]; glucagon AUC, SSA+PEG 823 pmol/l*min (194) vs SSA 332 (69), P>0.05) [

)]). GIP secretion remained significantly impaired, whereas GLP1 secretion was numerically increased with PEG (SSA+PEG 3088 pmol/l*min (366) vs SSA 2401 (239), P>0.05) [

)] but remained without a glucose-dependant increase as in SSA. The incretin effect numerically increased in SSA+PEG compared to SSA (SSA+PEG 49.9% (13.9) vs SSA 33.6% (47.4), P>0.05) [

)].

: Somatostatin analogues impaired the secretion of both insulin, glucagon and incretin hormones secretion. Co-treatment with pegvisomant seemed to counteract the somatostatinergic inhibition of the glucagon secretion and improved the insulin response to OGTT. We speculate that pegvisomant exerts its action via GH-receptors on pancreatic δ-cells.

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<![CDATA[OR23-07 Results From the Phase 3, Randomized, Double-Blind, Placebo-Controlled CHIASMA OPTIMAL Study of Oral Octreotide Capsules in Adult Patients with Acromegaly]]> https://www.researchpad.co/article/Nb1352924-65ab-46ef-907a-fec7e163eda0 1.0 and ≥ 1.3x ULN for 2 consecutive visits). Safety and tolerability were assessed. The primary endpoint was met, as 58% of patients receiving octreotide capsules maintained IGF-I response vs 19% receiving placebo (P=0.008). Mean IGF-I levels in patients receiving octreotide capsules were within the reference range at treatment end (0.97 x ULN) vs patients receiving placebo (1.69 x ULN). All secondary endpoints were met. Of patients receiving octreotide capsules, 75% completed 36 weeks without need for rescue therapy. However, 68% of the placebo group required rescue therapy. GH response was maintained at week 36 in a significantly larger proportion of patients receiving octreotide capsules than placebo (78% vs 30%; P=0.001). Median time to loss of IGF-I response was not reached by the end of the study for patients receiving octreotide capsules vs 16 weeks for the placebo group (P <0.0001). Five patients in the placebo group had IGF-I levels in the reference range at the end of 36 weeks. Only 2 (7% of placebo group) did not meet loss of response criteria anytime throughout the study. Octreotide capsules were safe and well tolerated; no new/unexpected safety signals were observed. Most patients (55/56) experienced at least one treatment emergent adverse event; most were mild or moderate in intensity. Overall, 90% of patients who completed the trial on octreotide capsules opted to enter the open label extension phase. These phase 3 data demonstrate octreotide capsules to be potentially safe and effective for the treatment of adults with acromegaly. ]]> <![CDATA[OR23-05 Human Absorption, Metabolism, Excretion, and Absolute Oral Bioavailability of 14C-CRN00808, an Orally Bioavailable, Nonpeptide, Selective, Somatostatin Receptor 2 (sST2) Biased Agonist for the Treatment of Acromegaly]]> https://www.researchpad.co/article/Nba6dc1e2-b487-4e01-83dc-a62c0b2e147b 90% of radioactivity was recovered within 7 days of dosing. The primary route of excretion was the feces (>90%) with minimal excretion in the urine (<10%). Absorption of total [14C]-CRN00808-derived radioactivity in plasma was rapid (median Tmax=1 hour), and the mean Cmax, AUC0-∞, and t1/2 were determined to be 194 ng-equivalents/mL, 3340 ng-equivalents.hr/mL, and 31 hours, respectively. The pharmacokinetic parameters of unchanged CRN00808 in plasma were similar, suggesting that majority of the circulating drug-derived radioactivity is accounted for by unchanged CRN00808 and there are no abundant circulating metabolites. Treatment emergent adverse events associated with CRN00808 were generally mild and transient, and consistent with those reported with other somatostatin agonists. In conclusion, results from this clinical trial in healthy volunteers confirm that CRN00808 has excellent drug-like properties for chronic once-daily oral treatment of patients with acromegaly. ]]>