Somatostatin Receptor Ligands Research Articles

Cytological, immunological and radiological predictors of the efficacy of first-generation somatostatin receptor ligands (fg-SRLs) in patients with acromegaly

Cytological, immunological and radiological predictors of the efficacy of first-generation somatostatin receptor ligands (fg-SRLs) in patients with acromegaly

Clinicopathological and Molecular Profile of Sellar Neurocytoma

Abstract Objective To investigate the clinical features, imaging characteristics and molecular profile of Sellar neurocytoma (SN). Methods Clinical, imaging, and pathological features of eleven cases of sellar neurocytoma were retrospectively analyzed. Electron microscopy was performed in five cases. Molecular features were detected in tumor tissue by RNA sequencing, qPCR and IHC. Results The clinical features of SN patients showed high incidence of hyponatremia (73%,8/11) and the tumors tended to invaded lateral side of saddle area from preoperative imaging analysis. The tumors had positive NeuN, SYN, NF, SSTR2 immunohistochemistry staining. Tumor transcriptomic analysis suggested a new LMCD1-AS1:GRM7-AS1 fusion gene event and increased expression of 10 hypothalamus-secreted hormones in SN. 15 differentially expressed genes were verified for qPCR verification. SSTR2 has been verified by immunohistochemistry. Conclusions Hyponatremia is the dominant clinical features of SN. Preoperative imaging suggests that growth toward the dorsal region is the imaging feature of SN. SSTR2 expression and LMCD1-AS1:GRM7-AS1 fusion gene event expected to become a new molecular marker for SN. Somatostatin receptor ligand therapy may be a potential therapy for SN.

Long-term pasireotide therapy in acromegaly: extensive real-life experience of a referral center.

Pasireotide is a novel therapeutic option for patients with acromegaly resistant to first-generation somatostatin receptor ligands. To date, real-life data are still scant, therefore, the aim of the current study is to evaluate the impact of long-term pasireotide therapy on disease control, pituitary tumor size, gluco-insulinemic and lipid profile in a real-life setting. Retrospective study of data prospectively collected, evaluating hormonal, tumoral, and metabolic data of 28 patients with acromegaly administered with pasireotide in a pituitary tertiary referral center. Within the first 12months of treatment, 70.4% of patients achieved normal IGF-I levels, whichwas maintained at 36-month evaluationin these responders patients. Patients who started with pasireotide 60mg monthly exhibited significantly lower IGF-I levels after 36months (p = 0.05) as compared to patients administered first with pasireotide 20 or 40mg monthly. The maximal tumoral diameter was significantly decreased after 12months of pasireotide (p < 0.001) and a further reduction was registered throughout the following months, with 41.2% of patients achieving a significant reduction (> 25% of baseline measurement) after 36months of treatment. Fasting glucose significantly increased during the first 6months (p < 0.001) with a gradual rise in diabetes prevalence during the following months, resulting diabetes prevalence after 36months of pasireotide significantly increased compared to baseline (p = 0.003), although with glycated hemoglobin levels within the normal range. Diabetes was managed using oral glucose-lowering drugs or glucagon-like peptide 1 agonists, with no patient requiring insulin therapy. Pasireotide improved lipid profile, mainly during the first 12months of treatment, by increasing HDL and decreasing triglycerides levels. Pasireotide is effective and safe in the long-term. Hyperglycemia is a common event and is manageable even without insulin treatment.

The Novel SSTR3 Agonist ITF2984 Exerts Antimitotic and Proapoptotic Effects in Human Non-Functioning Pituitary Neuroendocrine Tumor (NF-PitNET) Cells.

Somatostatin receptor ligands (SRLs) with high affinity for somatostatin receptors 2 and 5 (SSTR2 and SSTR5) are poorly efficacious in NF-PitNETs, expressing high levels of SSTR3. ITF2984 is a pan-SSTR ligand with high affinity for SSTR3, able to induce SSTR3 activation and to exert antitumoral activity in the MENX rat model. The aim of this study was to test ITF2984's antiproliferative and proapoptotic effects in NF-PitNET primary cultured cells derived from surgically removed human tumors and to characterize their SSTR expression profile. We treated cells derived from 23 NF-PitNETs with ITF2984, and a subset of them with octreotide, pasireotide (SRLs with high affinity for SSTR2 or 5, respectively), or cabergoline (DRD2 agonist) and we measured cell proliferation and apoptosis. SSTR3, SSTR2, and SSTR5 expression in tumor tissues was analyzed by qRT-PCR and Western blot. We demonstrated that ITF2984 reduced cell proliferation (-40.8 (17.08)%, p < 0.001 vs. basal, n = 19 NF-PitNETs) and increased cell apoptosis (+41.4 (22.1)%, p < 0.001 vs. basal, n = 17 NF-PitNETs) in all tumors tested, whereas the other drugs were only effective in some tumors. In our model, SSTR3 expression levels did not correlate with ITF2984 antiproliferative nor proapoptotic effects. In conclusion, our data support a possible use of ITF2984 in the pharmacological treatment of NF-PitNET.

Predictive factors and the management of hyperglycemia in patients with acromegaly and Cushing's disease receiving pasireotide treatment: post hoc analyses from the SOM230B2219 study.

Pasireotide, a somatostatin receptor ligand, is approved for treating acromegaly and Cushing's disease (CD). Hyperglycemia during treatment can occur because of the drug's mechanism of action, although treatment discontinuation is rarely required. The prospective, randomized, Phase IV SOM230B2219 (NCT02060383) trial was designed to assess optimal management of pasireotide-associated hyperglycemia. Here, we investigated predictive factors for requiring antihyperglycemic medication during pasireotide treatment. Participants with acromegaly or CD initiated long-acting pasireotide 40 mg/28 days intramuscularly (acromegaly) or pasireotide 600 μg subcutaneously twice daily during pre-randomization (≤16 weeks). Those who did not need antihyperglycemic medication, were managed with metformin, or received insulin from baseline entered an observational arm ending at 16 weeks. Those who required additional/alternative antihyperglycemic medication to metformin were randomized to incretin-based therapy or insulin for an additional 16 weeks. Logistic-regression analyses evaluated quantitative and qualitative factors for requiring antihyperglycemic medication during pre-randomization. Of 190 participants with acromegaly and 59 with CD, 88 and 15, respectively, did not need antihyperglycemic medication; most were aged <40 years (acromegaly 62.5%, CD 86.7%), with baseline glycated hemoglobin (HbA1c) <6.5% (<48 mmol/mol; acromegaly 98.9%, CD 100%) and fasting plasma glucose (FPG) <100 mg/dL (<5.6 mmol/L; acromegaly 76.1%, CD 100%). By logistic regression, increasing baseline HbA1c (odds ratio [OR] 3.6; P=0.0162) and FPG (OR 1.0; P=0.0472) and history of diabetes/pre-diabetes (OR 3.0; P=0.0221) predicted receipt of antihyperglycemic medication in acromegaly participants; increasing baseline HbA1c (OR 12.6; P=0.0276) was also predictive in CD participants. Investigator-reported hyperglycemia-related adverse events were recorded in 47.9% and 54.2% of acromegaly and CD participants, respectively, mainly those with diabetes/pre-diabetes. Increasing age, HbA1c, and FPG and pre-diabetes/diabetes were associated with increased likelihood of requiring antihyperglycemic medication during pasireotide treatment. These risk factors may be used to identify those who need more vigilant monitoring to optimize outcomes during pasireotide treatment.

Immunological signatures and predictive biomarkers for first-generation somatostatin receptor ligand resistance in Acromegaly.

Predicting resistance to first-generation Somatostatin Receptor Ligands (fg-SRL) in Acromegaly patients remains an ongong challenge. Tumor-associated immune components participate in various pathological processes, including drug-resistance. We aimed to identify the immune components involved in resistance of fg-SRL, and to investigate biomarkers that can be targeted to treat those drug-resistant Acromegaly. We conducted a retrospective study involving 35 Acromegaly patients with somatotropinomas treated postoperatively with fg-SRL. Gathering clinicopathological data, SSTR2 expression, and immunological profiles, we utilized univariate, binary logistic regression, and ROC analyses to assess their predictive roles in fg-SRL resistance. Spearman correlation analysis further examined interactions among interested characteristics. 19 patients (54.29%) exhibited resistance to postoperative fg-SRL. GH level at diagnosis, preoperative tumor volume, T2WI-MRI intensity, granularity, PD-L1, SSTR2, and CD8 + T cell infiltration showed association with clinical outcomes of fg-SRL. Notably, T2WI-MRI hyperintensity, PD-L1-IRS > 7, CD8 + T cell infiltration < 14.8/HPF, and SSTR2-IRS < 5.4 emerged as reliable predictors for fg-SRL resistance. Correlation analysis highlighted a negative relationship between PD-L1 expression and CD8 + T cell infiltration, while showcasing a positive correlation with preoperative tumor volume of somatotropinomas. Additionally, 5 patients with fg-SRL resistance underwent re-operation were involved. Following fg-SRL treatment, significant increases in PD-L1 and SSTR5 expression were observed, while SSTR2 expression decreased in somatotropinoma. PD-L1 expression and CD8 + T cell infiltration, either independently or combined with SSTR2 expression and T2WI-MRI intensity, could form a predictive model guiding clinical decisions on fg-SRL employment. Furthermore, targeting PD-L1 through immunotherapy and embracing second-generations of SRL with higher affinity to SSTR5 represent promising strategies to tackle fg-SRL resistance in somatotropinomas.

Methodology of the SORENTO clinical trial: a prospective, randomised, active-controlled phase 3 trial assessing the efficacy and safety of high exposure octreotide subcutaneous depot (CAM2029) in patients with GEP-NET

BackgroundThe current standard of care (SoC) for the initial treatment of unresectable or metastatic well-differentiated gastroenteropancreatic neuroendocrine tumours (GEP-NET) requires initiation of first-generation somatostatin receptor ligand (SRL) therapy, octreotide and lanreotide, which provide safe and efficacious tumour/symptom control in most patients. However, disease progression can occur with SoC SRL treatment and the optimal dose response of SRL remains unknown. Octreotide subcutaneous depot (CAM2029) is a novel, long-acting, high-exposure formulation that has shown greater bioavailability and improved administration than octreotide long-acting release (LAR) with a well-tolerated safety profile. Retrospective data have highlighted a potential benefit of high-exposure SRL for improved disease control in patients who did not adequately respond to the current SoC SRL treatment. This trial will investigate the efficacy and tolerability of CAM2029 compared to the current SoC, including octreotide LAR and lanreotide autogel (ATG).MethodsSORENTO is a prospective, multicentre, randomised, active-controlled, open-label phase 3 trial aiming to demonstrate superiority of treatment with 20 mg octreotide subcutaneous depot (CAM2029) every 2 weeks (Q2W) compared to treatment with the Investigator’s choice of SRL therapy at standard doses for tumour control (octreotide LAR 30 mg or lanreotide ATG 120 mg every 4 weeks [Q4W]) as assessed by progression-free survival (PFS) in approximately 300 patients with unresectable/metastatic and well-differentiated GEP-NET. Upon confirmation of disease progression (determined by a Blinded Independent Review Committee [BIRC] and defined as per RECIST 1.1), patients may enter an open-label extension treatment period with once weekly dosing, to investigate the effects of higher frequency dosing. Overall survival follow-up will end a maximum of 2 years after primary analysis. The primary endpoint will be analysed after 194 confirmed PFS events.DiscussionThis is the first trial investigating the efficacy of CAM2029 versus SoC SRL therapy using a head-to-head, superiority trial design. It is expected to be the first trial to investigate the efficacy of increased dosing frequency of a high-exposure SRL. A BIRC will limit bias and measurement variability and ensure high-quality efficacy data. Additionally, inclusion of patients with well-differentiated Grade 3 NET may elucidate treatment strategies for this rarely investigated patient population.Trial registrationClinicalTrials.gov NCT05050942. Registered on 21st September 2021.

Efficacy of cabergoline in non-irradiated patients with acromegaly: a multi-centre cohort study.

Elucidate the efficacy (as per current biochemical criteria) of cabergoline monotherapy or as addition to long-acting somatostatin receptor ligand (SRL) in patients with acromegaly and no previous pituitary radiotherapy. Multi-centre, retrospective, cohort study (four UK Pituitary centres: Birmingham, Bristol, Leicester, Oxford). Clinical, laboratory, imaging data were analysed. Sixty-nine patients on cabergoline monotherapy were included [median IGF-1 xUpper Limit of Normal (ULN) pre-cabergoline 2.13 (1.02-8.54), median treatment duration 23 months, median latest weekly dose 3 mg]. 31.9% achieved normal IGF-1 (25% GH-secreting, 60% GH+prolactin co-secreting tumours); median weekly cabergoline dose was similar between responders and non-responders. IGF-1 normalisation was related with GH+prolactin co-secreting adenoma (B 1.50, p=0.02) and lower pre-cabergoline IGF-1 xULN levels (B -0.70, p=0.02). Both normal IGF-1 and GH<1 mcg/L were detected in 12.9% of cases and tumour shrinkage in 29.4% of GH-secreting adenomas.Twenty-six patients on SRL+cabergoline were included [median IGF-1 xULN pre-cabergoline 1.7 (1.03-2.92), median treatment duration 36 months, median latest weekly dose 2.5 mg]. 23.1% achieved normal IGF-1 (15.8% GH-secreting, 33.3% GH+prolactin co-secreting tumours). Normal IGF-1 and GH<1 mcg/L were detected in 17.4%. In non-irradiated patients, cabergoline normalises IGF-1 in around one-third and achieves both IGF-1 and GH targets in approximately one out of ten cases. SRL+cabergoline is less efficient than previously reported possibly due to differences in studies methodology and impact of confounding factors.

Pasireotide: potential treatment option for McCune-Albright-associated acromegaly.

Only 30% of patients with McCune-Albright syndrome (MAS)-associated acromegaly achieve biochemical control under first-generation somatostatin receptor ligands (fg-SRLs), while pegvisomant fails to normalize insulin-like growth factor 1 (IGF-I) in >20% of cases. Here, we report all the patients with MAS-associated acromegaly treated with pasireotide long-acting release (LAR) in our center. Pasireotide LAR 20 mg/month resulted in rapid and long-term IGF-I normalization in patients #1 and #3. Patient #3 was resistant to fg-SRLs, while patient #1 was also controlled on fg-SRLs. In patient #2, resistant to fg-SRLs and uncontrolled on pegvisomant 40 mg/day combined with cabergoline 0.5 mg/day, pegvisomant was replaced with pasireotide LAR 40 mg/month, resulting in the near normalization of IGF-I levels. All 3 patients developed intermittent impaired fasting glucose, without the need for glucose-lowering drugs. Thus, pasireotide LAR is clearly useful as third-line therapy, and potentially even as second-line therapy, in MAS-associated acromegaly.

A novel somatostatin receptor ligand for human ACTH - and GH -secreting pituitary adenomas.

Somatostatin receptor ligands have come to play a pivotal role in the treatment of both ACTH- and GH-secreting pituitary adenomas. Clinical efficacy averages 30-50%, thus a considerable number of patients with Cushing's disease or acromegaly remain unresponsive to this therapeutic approach. HTL0030310 is a new somatostatin receptor ligand selective for subtype 5 over subtype 2, thus with a different receptor profile compared to clinical somatostatin receptor ligands. Assessment of the effect of HTL0030310 on hormone secretion in human ACTH- and GH-secreting pituitary adenomas in vitro. Primary cultures from 3 ACTH-secreting and 5 GH-secreting pituitary adenomas were treated with 1, 10 and 100 nM HTL0030310 alone or with 10 nM CRH or GHRH, respectively. Parallel incubations with 10 nM pasireotide were also carried out. ACTH and GH secretion were assessed after 4 and 24 hour incubation; SSTR2, SSTR3, SSTR5, GH and POMC expression were evaluated after 24 hours. HTL0030310 reduced unchallenged ACTH and POMC levels up to 50% in 2 ACTH-secreting adenomas and blunted CRH-stimulated ACTH/POMC by 20-70% in all 3 specimens. A reduction in spontaneous GH secretion was observed in 4 GH-secreting adenomas and in 2 specimens during GHRH co-incubation. SSTRs expression was detected in all specimens. This first study on a novel somatostatin receptor 5-preferring ligand indicates that HTL0030310 can inhibit hormonal secretion in human ACTH- and GH-secreting pituitary adenomas. These findings suggest a potential new avenue for somatostatin ligands in the treatment of Cushing's disease and acromegaly.

Predictors of Response to Treatment with First-Generation Somatostatin Receptor Ligands in Patients with Acromegaly

Predictors of first-generation somatostatin receptor ligands (fgSRLs) response in acromegaly have been studied for over 30 years, but they are still not recommended in clinical guidelines. Is there not enough evidence to support their use? This systematic review aims to describe the current knowledge of the main predictors of fgSRLs response and discuss their current usefulness, as well as future research directions. A systematic search was performed in the Scopus and PubMed databases for functional, imaging, and molecular predictive factors. A total of 282 articles were detected, of which 64 were included. Most of them are retrospective studies performed between 1990 and 2023 focused on the predictive response to fgSRLs in acromegaly. The usefulness of the predictive factors is confirmed, with good response identified by the most replicated factors, specifically low GH nadir in the acute octreotide test, T2 MRI hypointensity, high Somatostatin receptor 2 (SSTR2) and E-cadherin expression, and a densely granulated pattern. Even if these biomarkers are interrelated, the association is quite heterogeneous. With classical statistical methods, it is complex to define reliable and generalizable cut-off values worth recommending in clinical guidelines. Machine-learning models involving omics are a promising approach to achieve the highest accuracy values to date. This survey confirms a sufficiently robust level of evidence to apply knowledge of predictive factors for greater efficiency in the treatment decision process. The irruption of artificial intelligence in this field is providing definitive answers to such long-standing questions that may change clinical guidelines and make personalized medicine a reality.

Newer parameters of the octreotide test in patients with acromegaly.

Predicting the therapeutic effects of first-generation somatostatin receptor ligands (fg-SRLs) is important when assessing or planning effective treatment strategies in patients with acromegaly. The oft-used maximum growth hormone (GH) suppression rate parameter of the octreotide test has a suboptimal predictive value. Therefore, this study explored newer parameters of the octreotide test for predicting the therapeutic effect of long-acting fg-SRLs. In this single-center retrospective study, the octreotide test parameters and the therapeutic effects of fg-SRL at 3 months were investigated in 45 consecutive treatment-naïve patients with acromegaly between April 2008 and March 2023. Additionally, the relationship between the octreotide test parameters and the therapeutic effects of fg-SRLs was investigated. Tumor shrinkage was evaluated based on changes in the longitudinal diameter of the macroadenomas. The area GH suppression rate-time under the curve (AUC) and the time to nadir GH level were calculated and compared with the maximum GH suppression rate. The AUC estimated reductions in serum insulin-like growth factor I, and tumor shrinkage. The time to nadir GH level predicted tumor shrinkage more robustly than the maximum GH suppression rate in patients with macroadenoma. The AUC and time to nadir GH level may potentially be newer parameters of the octreotide test for estimating the therapeutic effect of fg-SRLs.

The Effect of Metformin Treatment on Disease Control in Patients with Acromegaly.

The increase in portal insulin levels has been shown to upregulate growth hormone receptor expression in the liver, leading to increased insulin-like growth hormone- 1 levels. Metformin inhibits hepatic gluconeogenesis and reduces fasting insulin. We evaluated the effect of metformin treatment in patients with acromegaly on growth hormone, insulin-like growth hormone-1, and pituitary adenoma size. Patients who were followed up with the diagnosis of acromegaly in Istanbul University- Cerrahpaşa, Cerrahpaşa Medical Faculty were evaluated. The patients were divided into three groups after pituitary adenectomy as those who received somatostatin receptor ligand and metformin treatment (group A), somatostatin receptor ligand treatment only (group B), and those who received metformin treatment only (group C). Groups A and B were compared with each other, and patients in group C were compared among themselves. While the median insulin-like growth factor-1 level decreased to 170 ng/ml in Group A after the treatment, the median insulin-like growth factor-1 level decreased to 229 ng/ml in Group B, and a statistically significant difference was found between the two groups (p =0.020). There was no significant difference in post-treatment growth hormone levels and residual adenoma sizes between groups A and B (p >0.005). In group C, there was no significant difference in growth hormone values pre-and post-metformin treatment (p =0.078); however, the median insulin-like growth factor-1 level decreased from 205 ng/ml to 168 ng/ml during metformin treatment and was found to be statistically significant (p =0.027). Due to the effect of metformin treatment on insulin-like growth factor-1 values in patients with acromegaly, it can be used in disease control, as well as diabetes treatment.

The Multibiomarker Acro-TIME Score Predicts fg-SRLs Response: Preliminary Results of a Retrospective Acromegaly Cohort.

The prompt control of acromegaly is a primary treatment aim for reducing related disease morbidity and mortality. First-generation somatostatin receptor ligands (fg-SRLs) are the cornerstone of medical therapies. A non-negligible number of patients do not respond to this treatment. Several predictors of fg-SRL response were identified, but a comprehensive prognostic model is lacking. We aimed to design a prognostic model based on clinical and biochemical parameters, and pathological features, including data on immune tumor microenvironment. A retrospective, monocenter, cohort study was performed on 67 medically naïve patients with acromegaly. Fifteen clinical, pathological, and radiological features were collected and analyzed as independent risk factors of fg-SRLs response, using univariable and multivariable logistic regression analyses. A stepwise selection method was applied to identify the final regression model. A nomogram was then obtained. Thirty-seven patients were fg-SRLs responders. An increased risk to poor response to fg-SRLs were observed in somatotropinomas with absent/cytoplasmatic SSTR2 expression (OR 5.493 95% CI 1.19-25.16, P = .028), with low CD68+/CD8+ ratio (OR 1.162, 95% CI 1.01-1.33, P = .032). Radical surgical resection was associated with a low risk of poor fg-SRLs response (OR 0.106, 95% CI 0.025-0.447 P = .002). The nomogram obtained from the stepwise regression model was based on the CD68+/CD8+ ratio, SSTR2 score, and the persistence of postsurgery residual tumor and was able to predict the response to fg-SRLs with good accuracy (area under the curve 0.85). Although our predictive model should be validated in prospective studies, our data suggest that this nomogram may represent an easy to use tool for predicting the fg-SRL outcome early.

Approach to the Patient: Insulinoma.

Insulinomas are hormone-producing pancreatic neuroendocrine neoplasms with an estimated incidence of 1 to 4 cases per million per year. Extrapancreatic insulinomas are extremely rare. Most insulinomas present with the Whipple triad: (1) symptoms, signs, or both consistent with hypoglycemia; (2) a low plasma glucose measured at the time of the symptoms and signs; and (3) relief of symptoms and signs when the glucose is raised to normal. Nonmetastatic insulinomas are nowadays referred to as "indolent" and metastatic insulinomas as "aggressive." The 5-year survival of patients with an indolent insulinoma has been reported to be 94% to 100%; for patients with an aggressive insulinoma, this amounts to 24% to 67%. Five percent to 10% of insulinomas are associated with the multiple endocrine neoplasia type 1 syndrome. Localization of the insulinoma and exclusion or confirmation of metastatic disease by computed tomography is followed by endoscopic ultrasound or magnetic resonance imaging for indolent, localized insulinomas. Glucagon-like peptide 1 receptor positron emission tomography/computed tomography or positron emission tomography/magnetic resonance imaging is a highly sensitive localization technique for seemingly occult, indolent, localized insulinomas. Supportive measures and somatostatin receptor ligands can be used for to control hypoglycemia. For single solitary insulinomas, curative surgical excision remains the treatment of choice. In aggressive malignant cases, debulking procedures, somatostatin receptor ligands, peptide receptor radionuclide therapy, everolimus, sunitinib, and cytotoxic chemotherapy can be valuable options.

Revisiting the usefulness of the short acute octreotide test to predict treatment outcomes in acromegaly.

We previously described that a short version of the acute octreotide test (sAOT) can predict the response to first-generation somatostatin receptor ligands (SRLs) in patients with acromegaly. We have prospectively reassessed the sAOT in patients from the ACROFAST study using current ultra-sensitive GH assays. We also studied the correlation of sAOT with tumor expression of E-cadherin and somatostatin receptor 2 (SSTR2) . A total of 47 patients treated with SRLs for 6 months were evaluated with the sAOT at diagnosis and correlated with SRLs' response. Those patients whose IGF1 decreased to <3SDS from normal value were considered responders and those whose IGF1 was ≥3SDS, were considered non-responders. The 2 hours GH value (GH2h) after s.c. administration of 100 mcg of octreotide was used to define predictive cutoffs. E-cadherin and SSTR2 immunostaining in somatotropinoma tissue were investigated in 24/47 and 18/47 patients, respectively. In all, 30 patients were responders and 17 were non-responders. GH2h was 0.68 (0.25-1.98) ng/mL in responders vs 2.35 (1.59-9.37) ng/mL in non-responders (p<0.001). GH2h = 1.4ng/mL showed the highest ability to identify responders (accuracy of 81%, sensitivity of 73.3%, and specificity of 94.1%). GH2h = 4.3ng/mL was the best cutoff for non-response prediction (accuracy of 74%, sensitivity of 35.3%, and specificity of 96.7%). Patients with E-cadherin-positive tumors showed a lower GH2h than those with E-cadherin-negative tumors [0.9 (0.3-2.1) vs 3.3 (1.5-12.1) ng/mL; p<0.01], and patients with positive E-cadherin presented a higher score of SSTR2 (7.5 ± 4.2 vs 3.3 ± 2.1; p=0.01). The sAOT is a good predictor tool for assessing response to SRLs and correlates with tumor E-cadherin and SSTR2 expression. Thus, it can be useful in clinical practice for therapeutic decision-making in patients with acromegaly.

Hindering the progression of cardiac fibrosis in acromegaly - the role of somatostatin receptor ligands

Hindering the progression of cardiac fibrosis in acromegaly - the role of somatostatin receptor ligands

THU078 The Definition And Epidemiology Of Giant Pituitary GH-Secreting Adenomas Based On Clinical, Imaging, And Hormonal Parameters: A Pilot Study

Abstract Disclosure: L.M. Del Corso: None. M.C. Silva: None. S.Z. Fidalski: None. C.L. Boguszewski: None. Acromegaly is a chronic disease, caused by a GH-secreting pituitary adenoma in most cases. At diagnosis, around 75% of patients have a macroadenoma, which constitute a heterogeneous group with variable biological behavior, therapeutic response, and prognosis. Giant adenomas (GA) have been defined as those which are more than 40 mm at their largest in diameter, but this is an arbitrary definition lacking comparative studies to investigate tumor size at diagnosis with clinical presentation, response to treatment and the evolution of acromegaly patients. Thus, the aim of our study was to compare the aforementioned variables according to the tumor size at diagnosis and review the diagnostic criteria for giant GH-secreting adenomas. In this observational, retrospective, single-centre pilot study, we have retrieved data from 161 medical records and evaluated age, sex, duration of symptoms, GH levels, presence of type 2 diabetes mellitus (T2DM), hypertension and hypopituitarism, imaging characteristics, and the need for adjuvant therapy with somatostatin receptor ligands (SRL) or other drugs. Study population was classified into four groups according to tumor size at diagnosis: (I) &amp;lt;10 mm (microadenomas; n=14); (II) 10-29 mm (n=84); (III) 30-39 mm (n=10); (IV) 40 mm or more (n=9). The final study group consisted of 117 individuals (49% men; mean age 43 ± 13 yrs). Hypopituitarism was significantly more frequent in groups III and IV compared to groups I and II (p=0.004), with no difference between groups III and IV (p=0,3). There was a higher proportion of invasive adenomas when the lesions ≥ 30 mm were compared to groups I and II (p=0.008), but with no difference between groups III and IV (p=0.62). Sixty percent of patients in group III (n=6) and 44% of patients in group IV (n=4) needed other drug therapy than SRL (cabergoline and/or pegvisomant), a higher proportion compared to those of groups I (n=1; 7%) and II (n=25; 30%) (p=0.04), again without difference between groups III and IV (p=0,7). Regarding the initial levels of GH, a significant difference was observed between groups I and IV (p=0.04), but this difference was not observed in the other groups. There were no statistical differences in relation to sex, duration of symptoms, need for SRL therapy, prevalence of hypertension and T2DM between study groups. Our study raises the hypothesis that giant adenomas should be defined as tumors larger than 30 mm, as the clinical behavior of tumors above this cutoff point seems to be similar in comparison with tumors larger than 40 mm but different from those of smaller sizes. Presentation: Thursday, June 15, 2023

THU061 Treatment Patterns In Acromegaly: Analysis Of Real-World US Insurance Claims From The MarketScan® Database

Abstract Disclosure: M. Fleseriu: Advisory Board Member; Self; Amryt, Ipsen, Recordati Rare Diseases, Pfizer, Inc. Grant Recipient; Self; Amryt, Crinetics, Ionis Pharmaceuticals Inc. A.L. Barkan: None. T.C. Brue: Advisory Board Member; Self; Advanz Pharma, Debio Pharm, Recordati Rare Diseases. Consulting Fee; Self; Ipsen, Recordati Rare Diseases, Novartis Pharmaceuticals, Pfizer, Inc. Grant Recipient; Self; Pfizer, Inc. Other; Self; Ipsen, Recordati Rare Diseases, Novartis Pharmaceuticals, Pfizer, Inc. E. Duquesne: Employee; Self; Ipsen. A. Houchard: Employee; Self; Ipsen. Stock Owner; Self; Ipsen. M. del Pilar Schneider: Employee; Self; Ipsen. A. Ribeiro-Oliveira Jr.: Employee; Self; Ipsen. Stock Owner; Self; Ipsen. S. Melmed: Advisory Board Member; Self; Ionis Pharmaceuticals Inc., Ipsen, Novo Nordisk, Recordati Rare Diseases. Grant Recipient; Self; Pfizer, Inc. Background: Medical treatment for acromegaly (characterized by excess growth hormone [GH] production) includes somatostatin receptor ligands (SRLs), dopamine agonists (DAs), and GH receptor antagonists (GHRAs). However, there are few real-world treatment evaluations in the US. We present treatment patterns for patients receiving medications for acromegaly (1/1/2010-7/31/2022). Methods: De-identified data were extracted from MarketScan®, a US health insurance claims database. Eligible patients: those receiving monotherapy or combination therapy (≥2 treatments overlapping for &amp;gt;3 months [m]) for ≥90 days without treatment gaps; ≥2 claims associated with acromegaly; data ≥3 m before and ≥6 m after diagnosis/first treatment claim (earlier date); and ≥18 years (y) old at diagnosis. Outcomes were: demographic characteristics; treatment frequency by line of treatment (LOT) and changes between LOTs (Sankey plot); treatment persistence for first LOT (LOT 1) monotherapies (Kaplan-Meier estimator); and treatment up-/downtitration (≥30% dose change, evaluated for octreotide long-acting release [OCT] and lanreotide depot [LAN]). Biochemical control values were unavailable in the database. Results: Of 882 patients, 50.1% were female; mean age at diagnosis was 48.6 y (standard deviation 13.6 y). In the cohort, 59.4% had exactly 1 LOT, 23.1% had exactly 2 LOTs, and 17.5% had exactly 3 LOTs. The most common LOT 1 medication class was first-generation SRLs: OCT (27.7%) and LAN (21.1%). Other LOT 1 classes were Das (cabergoline; 34.5%) and GHRAs (pegvisomant; 10.5%). Only 7 patients received second-generation SRL pasireotide and no patients received oral octreotide in LOT 1. Most patients initiated treatment with monotherapies (94.6%). In monotherapy LOT 1, GHRAs had the longest median persistence (pegvisomant; 24.8 m; 95% confidence interval [CI]: 16.59-32.49 m; n=93), followed by OCT and LAN (20.0 m; 95% CI: 16.98-23.87 m; n=430). Das had the shortest persistence (cabergoline; 14.4 m; 95% CI: 12.23-16.82 m; n=304). Among patients receiving OCT or LAN, 67.6% had ≥1 dose increase and 45.0% had ≥1 dose reduction. Conclusions: Despite guidelines recommending DA monotherapy for few select patients with acromegaly,1 our real-world analysis found that approximately one-third of patients initiated treatment with this class with the shortest treatment persistence. OCT and LAN monotherapies were also commonly used as LOT 1 and had longer persistence. GHRAs, the class with the longest persistence, were not common monotherapy in LOT 1, possibly because they do not target pituitary adenomas directly. Interestingly, only 5% of patients initiated treatment with combination therapies. Recommendations for individualized therapy2 should consider medication persistence and real-world treatment patterns. 1Giustina et al. Rev Endocr Metab Disord. 2020 2Fleseriu et al. Lancet Diabetes Endocrinol. 2022 Presentation: Thursday, June 15, 2023

THU028 Novel Approach To Management Of Acromegaly With De Novo Oral Octreotide Or Combination Therapy With Cabergoline: A Case Series

Abstract Disclosure: A. Halstrom: None. G.A. Dobri: None. Acromegaly is a rare disorder characterized by tumoral hypersecretion of growth hormone (GH) leading to overproduction of insulin-like growth factor 1 (IGF-1). Patients present with physical changes, and systemic complications. Treatment involves surgery and medical therapy with the goal of normalizing IGF-1. First line medical therapy consists of first-generation injectable somatostatin receptor ligands (SRL) (octreotide LAR, lanreotide autogel). Dopamine agonists (cabergoline) can be used in patients with mild IGF-1 elevation. If IGF-1 levels do not normalize, pasireotide or pegvisomant can be tried. Until recently, SRLs were administered only as a deep tissue injection. Patients have reported injection site reactions, frustration, and breakthrough acromegaly symptoms between doses. Two trials were conducted which showed that oral octreotide is an effective alternative for patients after achieving biochemical control with the injectable formulation. Two cases are presented below in which patients with acromegaly were treated with de novo oral octreotide either or as combination therapy with cabergoline, after a significant time lapse since injection SRL. Our first case is a 24 year old female with a 19mm mammosomatotroph adenoma, resected 8 years prior, with questionable remnant on postoperative MRI and biochemically active acromegaly. She was started on octreotide LAR 20mg which was titrated up to 30mg. However, she had not achieved biochemical control, with lowest IGF-1 543ng/mL (83-456ng/mL), Z-score 2.4, and GH 5.8ng/mL (&amp;lt;= 7.1ng/mL). She wanted a break from medical therapy and discontinued octreotide LAR. She was later started on pegvisomant 15mg but stopped after 10 days due to an allergic reaction and was switched to cabergoline. Cabergoline was up titrated to 3.5mg weekly, still without biochemical control, IGF-1 417ng/mL (103-326ng/mL), Z-score 2.5, GH 7.69ng/mL (0.05-8ng/mL), at which time oral octreotide 20mg twice daily was started and cabergoline decreased to 2.5mg weekly. Oral octreotide was increased to 60mg daily and IGF-1 levels normalized to 294ng/mL (83-456ng/mL), Z-score 1. The second case is a 70 year old female with type 2 diabetes, arthritis, left ventricular hypertrophy, obstructive sleep apnea and colon polyps found to have a 10mm pituitary adenoma with IGF-1 481ng/mL (32-238ng/mL), Z-score 3.1, GH 1.28ng/mL (0.05-8ng/mL). She declined surgical resection and opted for medical management. Oral octreotide 20mg twice daily was started and further increased to 60mg daily IGF-1 went as low as 327ng/mL (28-231ng/mL), Z-score 2.5 and GH 0.4ng/mL (0.05-8ng/mL). The dose was increased to 80 mg daily are lab results are pending. These are the first two published cases describing a novel approach to treating acromegaly in which patients were found to have a biochemical response to de novo oral octreotide either alone or combined with cabergoline. Presentation: Thursday, June 15, 2023