Search

Objective: The phase 3 CHIASMA OPTIMAL study assessed efficacy and safety of oral octreotide capsules (OOC) in patients with acromegaly controlled on injectable somatostatin receptor ligands (SRLs). Sensitivity analyses were conducted for efficacy endpoints using two methods of imputation (i.e., the process of replacing clinical data with substitution values) to address missing data points due to some subjects reverting back to their prior injectable SRL treatment. Methods: Patients were ≥18 years of age and had evidence of active acromegaly with an average IGF-I ≤ 1.0 x ULN (utilizing the IDS iSYS assay calibrated to WHO recombinant reference standard 02/254). At baseline, patients were randomized to receive OOC or placebo for 36 weeks. The primary endpoint was proportion of patients maintaining biochemical response, defined as IGF-I ≤1.0 x ULN (2-value average at weeks 34 and 36) (Samson et al. ENDO 2020). Per study protocol, patient study discontinuations were considered non-responders regardless of clinical response at the time of discontinuation (non-response imputation). Additional exploratory analyses were performed utilizing the last observation carried forward (LOCF) analysis, as well as a completers analysis of response among the subgroup that completed the entire 36 weeks on study drug. The response rates reported for the primary end point are slightly adjusted for stratification differences as prespecified in the statistical analysis plan. Results: Twenty-eight patients received OOC and 12 failed to maintain biochemical response based on the primary endpoint. Seven of these 12 patients discontinued treatment early - 5 due to treatment failure and 2 due to AEs. The remaining 5 patients completed the 36-week protocol on study drug. Of these 5 patients, 4 had IGF-I values between >1.0 and ≤1.3 x ULN and 1 completed the study with an IGF-I of 1.7 x ULN with no clinical symptoms. 58.2% of patients in the OOC group met the primary endpoint of maintenance of biochemical response at the end of study using the non-response imputation. Using LOCF imputation, 64.3% (18/28) of patients met this endpoint. Of those completing the study (N=21), 76.2% maintained response. Conclusion: CHIASMA OPTIMAL primary endpoint was assessed using the non-response imputation for patients who discontinued treatment early, with a 58.2% response rate. However, when assessing the response rate based on LOCF imputation, or in study completers, similar to other phase 3 studies for acromegaly, the rate was imputed at 64.3% and 76.2%, respectively.

Data on the impact of withdrawal from long-acting somatostatin receptor ligand (SRL) injections on disease activity in patients with acromegaly are limited. The phase 3 Octreotide capsules versus Placebo Treatment In MultinationAL centers (OPTIMAL) study assessed the efficacy and safety of oral octreotide capsules in adult patients with acromegaly responding to injectable SRL therapy. The placebo-controlled arm of this study allowed for assessment of acromegaly biochemical and disease activity in patients after withdrawal from SRL treatment. A multinational, randomized, placebo-controlled study was conducted in 56 adult patients with active acromegaly. Patients were ≥ 18 years of age, had evidence of active disease (defined as IGF-I ≥1.3 x ULN after last pituitary surgery), and an average IGF-I ≤ 1.0 x ULN in response to a stable dose of SRL injection. Patients were randomized, 1 month following their last injection, to octreotide capsule or placebo for 36 weeks, with an option to enroll in an open-label extension. The primary aim was to determine the proportion of patients maintaining biochemical response, defined as IGF-I ≤1.0 x ULN (average of week 34 and 36). The trial met the primary endpoint, with 58% (16/28) of patients receiving octreotide capsules maintaining IGF-I response vs 19% (5/28) receiving placebo (P=0.008). The median time to loss of response (2 criteria evaluated: IGF-I >1.0 and ≥ 1.3 x ULN for 2 consecutive visits) was 16 weeks in the placebo group, while it was not reached in the octreotide capsule group. Of the 5 patients in the placebo group who maintained their biochemical response at 36 weeks, only 2 (7% of placebo group) did not meet loss of response criteria. When IGF-I values for any 2 consecutive visits were analyzed for patients receiving placebo, 93% (26/28) lost response based on IGF-I > 1 x ULN and 79% (22/28) lost response based on IGF-I ≥ 1.3 x ULN. Irrespective of biochemical control of acromegaly, 26/28 patients receiving placebo experienced active disease-related symptoms reported as AEs of special interest (AESIs). Most common AESIs (≥ 5%) included arthralgia/arthritis (60.7%), soft tissue swelling (35.7%), headache (32.1%), hyperhidrosis (25%), carpal tunnel (14.3%), musculoskeletal pain (14.3%), weight increased (7.1%) and tongue disorders (7.1%). The 5 patients receiving placebo with controlled IGF-I at 36 weeks received active medical treatment in the open label extension by decision of their study PIs, as they were deemed to have either lost their response during the study or had continuing active acromegaly symptoms. 93% of patients receiving placebo lost response following withdrawal of injectable SRLs, with a median duration of 16 weeks. All 5 patients receiving placebo who met the primary endpoint criteria at the end of the study were assessed clinically to have active disease and were continued on oral SRL treatment in the open label extension.

BACKGROUND: Transsphenoidal surgery is the cornerstone of acromegaly treatment. However, cure is obtained in only ~50% of the cases. Until today, no biochemical marker has been identified to preoperatively predict surgical outcome and long-term remission. Recently, soluble alpha klotho (αKL) was proposed as new biomarker for diagnosis and follow-up of acromegaly. Therefore, we aimed to evaluate the potential of pre-surgery αKL concentrations as a prognostic factor to predict remission by surgery alone. Methods: We measured αKL concentrations (IBL-ELISA) and classical biomarkers (IGF-I and GHrandom, both by IDS-iSYS, GHnadir measured by IDS-iSYS (n=13) or DiaSorin-Liaison® (n=7)) in samples from a prospective study in treatment-naïve patients with acromegaly (total n=25). Patients were then followed for at least 6 months after surgery (median (range) 30.1 (6–142) months). Outcome was evaluated and classified as non-remission (NR: IGF-I>1.2xULN (n=2) or continued need for medical treatment with somatostatin analogues (n=10)) or remission (R: improvement on clinical signs and symptoms and IGF-I1.2xULN), GHnadir (>0.4 ng/mL) and GHrandom (>1.0 ng/mL). As expected, αKL (pg/mL) was also high (>1.2xULN) in 92% patients. Before surgery, αKL was significantly higher in NR compared to R [6648 (4408–13951) vs. 3389 (2132–6837); p0.05 for both comparisons). ROC analysis indicated that concentrations of αKL>4470pg/mL (~3.5xULN) (75% specificity, 62% sensitivity, AUC=0.72) and IGF-I>3.8xULN (67% specificity, 85% sensitivity, AUC=0.79) indicate lack of long-term remission. Conclusion: High αKL (>4470pg/mL, ~3.5xULN) and IGF-I (>3.8xULN) concentrations before surgery are significantly associated with persistent disease activity after surgery. However, both biomarkers alone or in combination have insufficient specificity (though acceptable sensitivity) as predictors of surgical outcome.

Introduction: Acromegaly (Acro) is a systemic disease characterized by high growth hormone (GH) and insulin like growth factor-I (IGF-I), insulin resistance, glucose intolerance (IGT) and higher diabetes mellitus (DM) risk in 15% - 38% of patients (pts). Moreover, different medical therapies of Acro are reported to have variable effects on glucose metabolism. An association between blood glucose (BG) and serum IGF-I levels in patients with DM and Acro has been suggested, while IGF-I levels and hemoglobin A1c (HbA1c) correlation is still controversial because of the multifactorial influence.Study aim: to investigate glucose metabolism in pts with Acro resistant to 1st gen somatostatin receptor ligands (SRLs) treated with Pegvisomant (Peg) or Pasireotide LAR (Pasi). Patients and Methods: Retrospective, international, multicenter study; consecutive pts enrolled according to following inclusion criteria for at least 6 consecutive months: (1) resistant to 1st gen SRLs, (2) treated with Pasi or Peg for active Acro. Patients with concomitant treatments with known action on glucose metabolism were excluded, with the exception of glucocorticoid replacement for central hypoadrenalism. Results: 72 pts with active Acro, mean age at study entry 37 ±15 yrs, 47 females (65.3%). 28 (38.9%) pts were treated with Pasi and 44 pts with Peg (61.1%). Peg was monotherapy in 18 pts (40.9%) and in combo with first generation SRLs for 26 pts (59.1%). The number of pts with IGT and DM2 was superimposable between the 2 groups (Pasi and Peg). In Pasi group, 19 pts had Acro control (67.9%); glucose metabolism worsened in 16 pts (57.1%). Worsening of glucose metabolism occurred most frequently in pts with persistently active Acro (62.5%) and in pts with higher BG and HbA1c values at study start. Similarly, HbA1c was higher in pts with active Acro, although HbA1c worsened during Pasi treatment both in euglycemic and IGT at study entry, regardless of Acro control. In Peg group, 31 pts reached Acro control (73%); glucose metabolism worsened in 12 (27.3%) but improved in 5 pts (11.4%). All pts who experienced glucose metabolism improvement had controlled Acro, regardless of the use of a combo with first generation SRL. Among the 13 pts with active Acro after Peg, BG worsened in 5 cases (38.4%). Moreover, we found that pts with worsening BG control had higher HbA1c (p=0.03) and required higher Peg doses (mean ±SD 25 ±10 mg/day; p=0.04). Patients with higher HbA1c had higher IGF-I, both at study entry and at study end and were treated with higher Peg dose (mean 25 mg/day). Conclusion: Impaired glucose metabolism was more frequent after Pasireotide treatment and in patients of both Pasireotide and Pegvisomant groups with altered pre-treatment glucose and persistently active disease. Therefore, in such acromegaly patients close monitoring of glucose status is recommended during treatment.

Introduction: somatostatin receptor ligands (SRL) represent the first-line medical therapy in acromegaly patients who were not cured by surgery and in those where surgical remission is unlikely. It is well known that SRL may negatively act on insulin secretion, with consequent hyperglycemia and diabetes mellitus (DM). Purpose: To evaluate whether the degree of response to surgical pre-treatment with SRL predicts alterations in blood glucose levels.Patients and Methods: We retrospectively studied 181 patients attending the Unit of Neurosurgery of our Hospital prior to transsphenoidal surgery. All patients had a biochemical and radiological diagnosis of acromegaly (nadir GH during OGTT >0.4 ng/mL; IGF-I above age-standardized UNL and pituitary adenoma at MRI scans); diagnosis of DM and impaired fasting glucose (IFG) was performed on fasting blood glucose (FBG) according to the American Diabetes Association guidelines; all parameters of the pituitary axes were determined. The response to SRL treatment was determined as percent change of GH levels. Data are presented as mean±SD; Continuous data normally distributed were analyzed using a two-tailed Student’s t-test to compare two groups, and one-way ANOVA to compare several groups, followed by the Bonferroni post-hoc procedure for pairwise comparison of groups after the null hypothesis was rejected (p

Background: Acromegaly is a disorder characterized by excessive growth hormone (GH) secretion, which, in most cases, is caused by a GH secreting adenoma. Surgical removal of the tumor via a transsphenoidal approach is the first choice treatment for most patients. The remission rate after an initial resection is 80 to 90 percent for microadenomas and less than 50 percent for macroadenomas. Objective: To analyze predictive factors of remission in acromegaly patients who underwent transsphenoidal surgery for GH secreting adenoma. Methods: From January 2006 to October 2019, 75 patients with GH secreting pituitary adenoma were evaluated at our center. Patients who had undergone medical treatment or radiotherapy as first treatment were excluded. A total of 60 patients were included in the analysis. Remission was defined as normal serum insulin-like growth factor-1 (IGF-1) age and sex adjusted and a random serum GH less than 1 ng/mL and/or nadir GH during oral glucose tolerance test Results: We evaluated 60 patients (41 females and 19 males), with a mean age at diagnosis of 49.6 (ranged from 23 to 77 years). Mean initial IGF-1 was 905.3 ng/mL (range 100-324) and mean initial GH was 25.0 ng/mL ( Conclusions: In our study, predictors of biochemical remission after surgery were smaller tumor size, lower Knosp grade, and lower preoperative GH and IGF-1 levels.

Background Patients (pts) with acromegaly (A) require long term follow up, as up to 15% will develop recurrence. Current guidelines for MRI surveillance recommend 12 week post-operative (postop) imaging for all pts and yearly if on pegvisomant (PEG). Many pts with residual tumor postop undergo repetitive imaging even when controlled with pituitary (PIT) directed therapies. However, gadolinium retention and healthcare costs are of increased concern. Aim Assess tumor growth postop and necessity of serial MRI in medically treated A pts. Methods Retrospective, IRB-approved, data analysis of pathology-proven A pts. Included were pts with at least 1 MRI at ≥1 year postop. Initial tumor size, invasion status, pathology, postop remission, MRIs, radiation and medical therapy data were collected. Biochemical (biochem) remission = normal IGF-1 and GH 1 year (9 on PEG alone.) 11/83 (13.25%) had tumor growth at median 3.5 years (range 1-11). Tumors that grew were larger at diagnosis (25.21±10.93 mm vs 17.45±8.37 mm, p=0.004), had larger residuals postop (23.83±5.0 mm vs 11.86±7.47 mm, p=0.0003), and tended to be invasive (77.78% (7/9) vs 53.03% (35/66), p=NS). 7/11 were sparsely granulated and 4 mixed GH-PRL. Of 11 that grew, 8 had postop residual tumor, 3 in remission, 4 with discrepant IGF-1/GH, 2 uncontrolled and 2 with no data at 3 months postop. At the time of growth, 9/11 pts were untreated (6 had active A, 1 with discrepant IGF-1/GH and 2 with no IGF-1/GH data), 1 was controlled on pasireotide and one in biochem remission. Only 1/50 (2%) pts on pasireotide had growth and no pts on PEG >1 year. Discussion 86.75% of pts with A did not have tumor growth after surgery. Only one pt on PIT-targeted medications and none on PEG experienced tumor growth. Almost all pts who had growth had large invasive adenomas, majority were sparsely granulated, residual tumor postop, were biochemically uncontrolled and not on medication at the time of growth. A previous metanalysis of SRLs in A showed that tumor increase occurs in 1.4% (follow up 3-36 months). In our study pt follow up was longer and 1.82% (1/55) of pts who were on SRL/Cab had growth. Conclusion We recommend less frequent MRI monitoring for pts treated with PIT-targeted medications. Conversely, pts with residual adenoma not on medical therapy should be closely monitored biochemically and by serial MRIs. Further studies are needed to identify appropriate imaging interval for pts on medications and based on characteristics of aggression (such as sparsely granulated, large residual tumors, lack of biochemical control despite medications).

Acromegaly is a rare, chronic disorder characterized by hypersecretion of growth hormone (GH) that stimulates the production of insulin-like growth factor 1 (IGF-1). In addition to the physical manifestations, such as acral soft-tissue enlargement and maxillofacial changes, patients may develop a number of comorbidities, often prior to diagnosis. The goal of acromegaly treatment is to achieve biochemical control (normalization of GH and IGF-1 levels), which may resolve or prevent worsening of comorbid conditions. The objective of this study was to quantify the economic burden of comorbidities associated with acromegaly, including diabetes, hypertension, colon cancer, sleep apnea, and hypopituitarism. Comparisons were made between patients with acromegaly and biochemical control, patients with acromegaly without biochemical control, and the general population. Literature was reviewed to identify the prevalence of comorbidities among the groups, as well as the influence of each comorbidity on healthcare costs, quality of life, and mortality. Inputs from the literature were synthesized using a decision-analytic cohort model with a starting age of 55 years old and 55% female and extrapolated over a lifetime. Acromegaly-associated morbidity and mortality were not modeled due to possible double counting between acromegaly and other comorbidities. The average comorbidity count measure (range from 0 to 5) was a sum across all 5 comorbidity prevalence rates for all those living in the cohort per year of survival. Comorbidity prevalence was higher among acromegalic patients vs the general population for all comorbidities. Within acromegaly, uncontrolled disorder was associated with a higher prevalence of diabetes, hypertension, and sleep apnea. Lifetime discounted comorbidity costs were ~$121,000, ~$313,000, and ~$406,000 in the general population, acromegaly controlled, and acromegaly uncontrolled populations, respectively. Lifetime discounted life years were 17.6, 16.9, and 16.7 in the general population, acromegaly controlled, and acromegaly uncontrolled populations, respectively. Lifetime discounted quality-adjusted life years were 14.6, 11.7, and 10.4 in in the general population, acromegaly controlled, and acromegaly uncontrolled populations, respectively. Lifetime discounted average comorbidity count was 0.8, 1.9, and 2.4 in each group, respectively. Compared with controlled acromegaly, uncontrolled disorder resulted in $93,000 additional comorbidity-related costs, 1.3 fewer years of perfect health, and 0.5 more comorbidities across the remaining lifespan. This simulation model suggests achieving biochemical control seems to be associated with improvements in cost, quality of life, and mortality. A multimodal treatment strategy including biochemical control and management of comorbidities is necessary to promote optimal patient outcomes.

Background: In clinical practice, most patients responding to injectable somatostatin receptor ligands exhibit IGF-I variability around the upper limit of normal (ULN) during long-term follow up. These fluctuations are thought to result from various factors such as assay variability, nutrition, comorbid conditions, concomitant medications and other unknown factors. The magnitude of this variability, and the factors affecting it, is not well understood in patients with acromegaly treated with injectable SRLs. Methods: IGF-I levels of patients responding to and stably treated with injectable SRLs were measured over time in the CHIASMA OPTIMAL phase III study. Two time periods were assessed - Period 1, three assessments during screening phase before randomization to octreotide capsules (N=56), and Period 2 - multiple assessments up to week 36, in patients rescued with SRL injections for at least 12 weeks (N=21). The time from the last injection to each of the 3 assessments in period 1 [Screening visits 1 and 2 (SV1 & SV2), and Baseline (BL)], was on average 6.8 ± 10.7 (SD), 15.8 ± 2.7, and 29.0 ± 1.8 days respectively. Correlation with various demographics and Baseline characteristics, including age, gender, weight, BMI and residual tumor size to IGF-I variability was assessed. Percent change for each individual patient from Minimal to Maximal IGF-I values within each period was computed and the overall population mean was calculated (lowest value was used as the denominator and all other values were expression as a positive % above this value). Results: The overall mean within-patient percent change of IGF-I levels during Period 1 was 20.48 ± 15.56 (range: 0.6-81). Mean IGF-I levels for SV1, SV2 and BL were 0.78 ± 0.18, 0.79 ± 0.18, and 0.85 ± 0.22 x ULN respectively. The overall increase in mean IGF-I levels from SV1 to BL (longest time interval) was statistically significant (p=0.0002; paired T-test). Analysis of IGF-I levels in patients during Period 2, revealed that the overall mean within-patient percent change of IGF-I levels was 15.27 ± 12.20 (range: 0-41.5). The mean duration of follow up during this period, after patients were already treated for ≥12 weeks with injectable SRL, was 1.72 (± 1.29) months. The variability observed in Period 2 was similar to that observed in the entire sample evaluated in Period 1. No significant differences were found in the mean IGF-I percent change between any demographic or baseline characteristic subgroup examined. Conclusion: IGF-I levels fluctuate in patients with acromegaly who are responsive to injectable SRLs. These fluctuations are wide and can be up to 81% higher than the lowest (most controlled) value, with an average increase of approximately 20%. Significant IGF-I increases were observed at the end of the long acting SRL injection interval. Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. Abstracts presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.

Surgical removal of the GH-secreting tumor is the initial treatment of choice for acromegaly. Outcome of surgery is assessed by measuring IGF-1 and glucose-suppressed GH levels. IGF-1 normalization is an essential biochemical criterion for remission. The cut-off for nadir GH after oral glucose that signifies remission, however, is debated. It also remains unclear whether GH levels provide additional prognostic or clinically relevant information when IGF-1 results are definitive. To address this question, we examined how initial postoperative glucose-suppressed GH levels change over time on serial testing in patients who achieve initial remission as defined by IGF-1 normalization. We studied 87 acromegaly patients (48M, 39F) who achieved a normal IGF-1 level after surgery alone longitudinally from 1996 to 2019. All had GH measured before and 60, 90 and 120 minutes after 75 or 100 mg oral glucose (OGTT) at ≥ 3 months after surgery and GH and IGF-1 repeated ≥ 1 year later. GH was by measured by sensitive, 22KDa GH specific assays, either a IRMA (DSL, International Reference Standard (IRS) 88/624) or a chemiluminescence immunoassay (IDS-iSYS, IRS 98/574). OGTT Nadir GH levels were also measured in healthy subjects; n=46 (26 M, 20 F, ages 19-71 yr.) by DSL and n=46 (29 M, 17 F; ages 20-66 yr.) by IDS-iSYS. Nadir GH levels in acromegaly patients were compared to the 95%CI of healthy subjects’ mean and categorized relative to healthy subjects’ 97.5 percentile, which was 0.14 µg/L for both assays. IGF-1 levels were compared to age and gender adjusted normal ranges. Subjects were grouped based on initial nadir GH ≤ or > 0.14 µg/L and the patterns of change in nadir GH and IGF-1 at last follow up or until IGF-1 became elevated (i.e. recurrence). Follow up durations are given as median(range). In follow up, 73 patients remained in remission (normal IGF-1) and 14 had a recurrence (elevated IGF-1). Of the 73 in remission, 55 had initial nadir GH ≤ 0.14 µg/L that persisted to 10 yr.(1-22yr.) of follow up, 5 had initial GH ≤ 0.14 µg/L that rose to > 0.14 µg/L by 9(3-21)yr., 10 had GH > 0.14 µg/L that persisted at 5.5(2-22)yr., and 3 had GH > 0.14 µg/L that fell to ≤ 0.14 µg/L at 5(4-7)yr. of follow up. Of the 14 that recurred, 11 had an initial and persistent GH > 0.14 µg/L and developed an elevated IGF-1 level after 6(1-23) yr.. The 3 other patients that recurred had an initial GH ≤ 0.14 µg/L that rose to > 0.14 µg/L by 1-6 years later and subsequently developed an elevated IGF-1 level by 14-16 years of follow up. In summary, we found that the pattern of normal IGF-1 along with nadir GH > 0.14 µg/L on initial testing or developing with time, was associated with recurrence in 14/32 patients. We also found that initial nadir GH ≤ 0.14 µg/L was highly predictive of long-term persistent remission: 60/63 such patients remained in remission. In conclusion, glucose-suppressed GH levels are of prognostic value in acromegaly patients with normal IGF-1 after surgery.

Background: Single- and multi-center studies have shown an increased incidence of malignancies in patients with acromegaly. These findings may be affected by selection bias. Our aim was therefore to investigate the incidence of malignancies in a nationwide unselected cohort of patients with acromegaly. Methods: Adult patients diagnosed with acromegaly due to a pituitary tumor between 1987 and 2017 were identified in the Swedish National Patient Registry. All malignancies following the diagnosis of acromegaly were identified in the Swedish Cancer Registry that has a coverage of over 96%. Standardized incidence ratios (SIRs) for malignancies, with 95% confidence intervals (CI), were calculated by using the Swedish general population as a reference. Incidence of malignancies was also analyzed in sub-groups of patients treated with radiotherapy and in those having diabetes mellitus and hypopituitarism. Results: A total of 1,296 patients with acromegaly were included (621 men, 675 women). The mean age (±SD) at diagnosis was 51.6±14.7 years. The mean follow-up was 12.7±8.3 years, with a total of 16,395 person years at risk. Pituitary surgery was performed in 842 (65%) patients and radiation therapy in 152 (12%) patients. The diagnosis of hypopituitarism and diabetes mellitus was recorded in 29% and 16% of patients, respectively. Overall, 186 malignancies were identified in patients with acromegaly as compared to 179 expected malignancies in the general population (SIR 1.04; 95% CI 0.90-1.20). Incidence of malignancies was similar in men and women [SIR 1.08 (95% CI 0.88-1.32) vs 1.00 (95% CI 0.80-1.23)]. Incidence of colorectal cancer (SIR 1.12; 95% CI 0.75-1.62) or malignancies of the respiratory system (SIR 1.22; 95% CI 0.76-1.84) was not increased. Incidence of kidney and ureter cancer (n=17) was, however, increased (SIR 3.81; 95% CI 2.22-6.11). In the entire study cohort, only three cases of thyroid cancer were recorded. SIR for malignancies in patients treated with radiotherapy (1.12; 95% CI 0.56-2.01) and in patients with hypopituitarism (SIR 0.91; 95% CI 0.68-1.18) or diabetes (SIR 1.08; 95% CI 0.78-1.45) did not differ from the general population. Conclusions: This large nationwide population-based study showed that the overall incidence of malignancies in patients with acromegaly was not different from the general population. In particular, incidence of colorectal and thyroid cancer was not increased. Incidence of malignancies of the urinary tract was, however, increased.

Acromegaly is associated with increased morbidity and mortality primarily attributed to cardiovascular and cerebrovascular diseases, thus demonstrating the negative arterial impact of chronic GH and IGF-1 excess. There are limited and conflicting data regarding coronary artery disease (CAD) in acromegaly that consists mainly of heterogeneous cohorts and pathological reviews of old case series. Increased arterial stiffness is associated with an increased risk of cardiovascular events such as myocardial infarction. Arterial stiffness may measured from pulse wave velocity(PWV). In this study we aimed to evaluate the association between pulse wave velocity and aortic augmentation index in acromegalic patients. Methods: Our study population consists of a consecutive subset of 32 acromegalic patients and 19 control. Acromegalic patients IGF 1 levels were noted. All patients BMI, age, blood pressure, gender also were noted. Also pulse pressure, central blood pressures were measured by non-invasive central blood pressure measurement device (SphygmoCor). Pulse wave velocity and aortic augmentation index were measured by the same device. Results: A total of 32 acromegalic patients and 19 control were enrolled in the study. Body mass index and gender were not significantly different between the groups. Aortic augmentation index (5 vs. 6, p =0,685) variables weren’t significantly different in the study. Systolic and diastolic blood pressures were significantly high in the acromegalic group. (130/82 vs. 120/70) PWV was significantly high in the acromegalic group. (13 vs 11,5 p=0,002)Conclusions: Our study results suggest that acromegaly patients have worse arterial stiffness due to increased pulse wave velocity. Acromegaly is associated with increased morbidity and mortality primarily attributed to cardiovascular problems. We thought that it may be a guiding method in disease management since it can be an early marker of cardiovascular risk.Keywords: acromegaly, pulse wave velocity, aortic augmentation index

Background: Injectable somatostatin receptor ligands (SRLs) are the most widely used therapy to control acromegaly. Oral octreotide capsules have been formulated as a potential therapy for this disorder and the efficacy and safety was evaluated in the CHIASMA OPTIMAL prospective phase 3 study in patients with acromegaly who were controlled on injectable SRL treatment of varying doses (Samson et al. ENDO 2020). Methods: Patients with confirmed acromegaly, who had been receiving a stable dose of injectable SRL (≥3 months) up until study entry, were randomized to receive octreotide capsules (40 mg/day) or placebo for 36 weeks. Patients were dose titrated to 60 or 80 mg of oral octreotide or equivalent placebo through week 24 at the investigator’s discretion based on increase of IGF-I levels or worsening of acromegaly signs and symptoms. The primary efficacy endpoint was the proportion of patients who maintained their biochemical response at the end of 36 weeks, defined as average IGF-I ≤1 x ULN between Weeks 34 and 36. An analysis evaluated maintenance of response based on prior dose of injectable SRL. Prior doses of injectable SRL were categorized based on the following classifications: octreotide 10 mg every 4 weeks or lanreotide 60 mg every 4 weeks or 120 mg every 8 weeks were stratified as low; octreotide 20 mg every 4 weeks or lanreotide 90 mg every 4 weeks or 120 mg every 6 weeks were stratified as medium; octreotide 30 mg or 40 mg or lanreotide 120 mg every 4 weeks were stratified as high. Randomization was stratified based on low dose vs med/high dose and efficacy results compared for these strata. The response rates reported for the primary end point are slightly adjusted for stratification differences as prespecified in the statistical analysis plan. Results: Six patients (21.4%) in the octreotide capsule group had received prior treatment with low doses of injectable SRLs while 22 (78.6%) had received prior treatment with medium-high doses of injectable SRLs. Maintenance of response was observed in 16 patients receiving oral octreotide. This included 66.7% of patients (n=4) previously receiving low doses of injected SRLs and 54.5% of patients (n=12) on medium-high injected doses. The treatment effect was consistent irrespective of prior dose of injectable SRL (odds ratio: 5.4 in low dose and 5.9 in medium-high dose). Conclusion: The CHIASMA OPTIMAL study recruited a population receiving predominantly medium-high doses of injectable SRLs and demonstrated maintenance of response in 58% of patients. Oral octreotide treatment effect was consistent irrespective of prior dose of injectable SRL.

Introduction: Acromegaly is a potentially fatal neuro-endocrinopathy caused by a growth hormone (GH)-secreting pituitary adenoma (PA). A lack of consensus on factors that reliably predict patient outcomes in acromegalic patients following endoscopic endonasal approaches (EEA) warrants additional investigation. Methods: Pre- and postoperative tumor and endocrinological characteristics from 55 acromegalic patients who underwent EEA for resection of a GH-secreting PA were evaluated as potential predictors of postoperative hormonal remission (defined as age- and sex- normalized IGF-1 levels). Results: The 55 patients included had a mean age of 50.1 ± 13.5 years and a mean follow-up time of 18 ± 17.4 months. Fifty-three patients (96%) presented with dysmorphic craniofacial features, with 22 (40%) presenting with prognathism, 22 (40%) exhibiting frontal bossing, and 18 (33%) presenting with macroglossia. Ten (18%) had microadenomas and 45 (82%) had macroadenomas. Five (9.4%) had giant adenomas. Forty-five (92%) tumors were invasive, with 44 (83%) exhibiting infrasellar invasion, 17 (32%) extending above the sella, and 9 (18%) with cavernous sinus invasion. Thirty-three patients (66%) underwent gross total resection (GTR; mean maximal tumor diameter = 1.52 cm), and 17 (34%) underwent subtotal resection (STR; mean maximal tumor diameter = 2.77 cm). Invasive tumors were significantly larger and Knosp scores were negatively correlated with GTR. Thirty-three patients (65%) achieved hormonal remission after EEA resection alone, which increased to 80% with adjunctive medical therapy. Additionally, 90% of patients who underwent GTR and 63% of patients who underwent STR demonstrated postoperative remission. Six patients (11%) exhibited biochemical remission after postoperative medical therapy with an average time to remission of 5.2 months. These patients all had significantly higher preoperative IGF-1 levels and larger tumors than patients who remitted immediately postoperatively. In all patients preoperative IGF-1 levels were inversely correlated with hormonal remission. Conclusions: This study indicates that endoscopic transsphenoidal resection of growth hormone secreting pituitary adenomas is a safe and highly effective management strategy for achieving hormonal remission and tumor control for patients with acromegaly. When combined with postoperative medical therapy, we observed endocrinological remission rates of 80% based on normalized IGF-1 levels. Our results support the conclusions of current literature that smaller and less invasive tumors are more likely to be fully resected. We additionally suggest that patients with lower preoperative IGF-1 are more likely to undergo postoperative biochemical remission, irrespective of tumor size and invasion.

Introduction: Transsphenoidal surgery is recommended as first line therapy in the vast majority of patients with acromegaly. Successful surgical intervention is determined by normalization of insulin like-growth factor (IGF) - 1 and adequate suppression of growth hormone (GH) during glucose GH suppression test or random GH levels Aim: To determine if IGF-1 levels at 6 weeks were equally predictive of surgical outcomes when compared to IGF-1 levels at 3–6 months postoperative. Methods: Retrospective review of patients with newly diagnosed acromegaly who had surgery between 2010–2019 and had post-operative IGF-1 level measured at 6 weeks and 3–6 months. IGF-1 was measured using the Siemens Immulite assay until 2016 when it was replaced by a LC-MS/MS assay. IGF-1 measurements at 6 weeks are obtained based on clinician discretion. Results: 69 patients (mean age 49 ± 14.8, female 31/69, 44.9%) with acromegaly had surgery and IGF-1 follow-up measurements at 6 weeks and 3–6 months. Persistent acromegaly was noted in 45/69 at 3–6 months. The median IGF-1 pre-operative was 701 ng/ mL (289–1600), 6 weeks postoperative was 286 ng/ mL (109–1038) and at 3–6 months was 267 ng/ mL (77–996). The median pre-operative IGF-1 was significantly higher than the median IGF-1 level at 6 weeks and 3–6 months (P= Conclusion: In the vast majority of patients, 6 weeks post-operative IGF-1 can be used to assess response to surgery avoiding a delay in treatment. However, we would recommend repeating IGF-1 levels at 3–6 months in those who have marginally elevated IGF-1 above normal (≤ 1.12), without cavernous sinus invasion and a post-operative GH of

Distinguishing non-specific signs and symptoms of acromegaly from treatment emergent adverse events (TEAEs) in patients treated with somatostatin receptor ligands has proven difficult given limited data from placebo-controlled studies. The phase 3 Octreotide capsules versus Placebo Treatment In MultinationAL centers (OPTIMAL) study provides a novel data set to evaluate the incidence of adverse events from patients randomized to octreotide capsules or placebo. A multinational, randomized, placebo-controlled study was conducted in 56 adult patients with active acromegaly. Eligible patients were ≥18 years of age, had active disease (IGF-I ≥1.3 x ULN after last pituitary surgery), and an average IGF-I ≤1.0 x ULN in response to a stable dose of somatostatin receptor ligand injection. Patients were randomized to octreotide capsule or placebo (28 per group) for 36 weeks, followed by an optional open-label extension for up to 1 year. Safety and tolerability were evaluated based on incidence of AEs, including incidence of new or worsening adverse events of special interest (AESIs). In this study, the safety profile of octreotide capsules was consistent with the known safety profile of injectable octreotide (Melmed et al 2015). No new or unexpected safety signals were detected. Nearly all patients (55/56) experienced a TEAE (28 patients [100.0%] in the octreotide capsule group and 27 patients [96.4%] in the placebo group). Thirty-three patients (58.9%) experienced a TEAE considered to be related to study drug by the blinded PI (64.3% of the octreotide capsule group [18 patients, 40 events] and 53.8% of the placebo group [15 patients, 41 events]). TEAEs with an incidence ≥5% that were more common in the octreotide capsule group vs placebo group included GI disorders, increased blood glucose, sinusitis, osteoarthritis, and cholelithiasis. TEAEs with an incidence ≥5% that were more common in the placebo group vs octreotide capsule group included arthralgia, headache, fatigue, hyperhidrosis, and peripheral swelling. GI disorders were the most common TEAE, reported in 64% of all patients (36/56) and at similar rates between octreotide capsule (68%) and placebo groups (61%). AESIs (defined as new or worsening signs of acromegaly) were observed in 15 patients (53.6%, 34 events total) in the octreotide capsule group and more frequently in 26 patients (92.9%, 82 events total) in the placebo group. In this study, the safety profile of octreotide capsules was consistent with the known safety profile of injectable octreotide. Most patients receiving octreotide capsules or placebo demonstrated TEAEs, although the profile of most common TEAEs varied between groups. TEAEs observed in the placebo group may be indicative of underlying disease activity. Further analysis may elucidate the difference between treatment related AEs and signs/symptoms of active disease in acromegaly.