The Association Between Somatostatin Receptor Ligand and Vitamin B12 Levels in Patients With Acromegaly

Purpose: Vitamin B12 causes hematologic and neuropsychiatric disorders, so it is important to evaluate it in risky situations. In this study, we aimed to evaluate the association between somatostatin receptor ligands and vitamin B12 levels in patients with acromegaly.Methods: Patients who were followed up with the diagnosis of acromegaly in the Endocrinology and Metabolism outpatient clinic of Istanbul University-Cerrahpaşa Medical Faculty were evaluated. Patients were divided into groups according to their somatostatin receptor ligand use status. The groups were evaluated according to their vitamin B12 levels, demographic data, and biochemical parameters.Results: One hundred fifty-two patients were evaluated. Thirteen patients had vitamin B12 deficiency. The majority (11/13) of patients with vitamin B12 deficiency were patients using somatostatin receptor ligand. In addition, the number of patients with vitamin B12 deficiency who received lanreotide autogel treatment was significantly higher compared with patients who did not use somatostatin receptor ligand (p = 0.011). Vitamin B12 levels were higher in patients who received lanreotide autogel treatment than in patients who did not use somatostatin receptor ligand treatment (p = 0.040). There was a negative correlation between vitamin B12 levels and lanreotide autogel use time, cumulative lanreotide autogel dose.Conclusion: It is important to evaluate the level of vitamin B 12 in the follow-up of patients with acromegaly using somatostatin receptor ligand treatment.

Pasireotide: A Novel Treatment for Tumor-Induced Hypoglycemia Due to Insulinoma and Non-Islet Cell Tumor Hypoglycemia

Tumor-induced hypoglycemia is a serious disorder most commonly caused by insulinoma or non-islet cell tumor hypoglycemia (NICTH). The hypoglycemia can be severe and refractory to conventional therapy, leading to significant morbidity and mortality. The objective of this work is to describe a series of challenging cases in which refractory, tumor-induced hypoglycemia was shown to respond to the use of pasireotide, a second-generation somatostatin receptor ligand. We describe the clinical and biochemical features of 3 patients with tumor-induced hypoglycemia due to an occult insulinoma, malignant insulinoma, and non-islet cell tumor hypoglycemia. In these 3 individuals, the hypoglycemia remained refractory to guideline-recommended medical therapy, such as diazoxide, nonpasireotide somatostatin analogues, and glucocorticoids. Pasireotide was substituted to attenuate the refractory hypoglycemia for each patient. The addition of pasireotide led to prompt improvement in the frequency and severity of hypoglycemic episodes for each tumor-induced hypoglycemia patient. We demonstrate the successful treatment of 3 individuals with refractory, tumor-induced hypoglycemia with pasireotide. We offer the first reported use of pasireotide for the successful treatment of nonmalignant insulinoma and non-islet cell tumor hypoglycemia.

SAT-267 Pregnancy in Acromegaly: Report of Five Cases

Introduction: In acromegaly, there are changes in growth hormone (GH), insulin-like growth factor-1 (IGF-1) and insulin, hormones very important in pregnancy as well. Despite novel treatments, pregnancy in acromegaly is uncommon, remaining a challenge for clinicians. We report seven pregnancies in five women with acromegaly. Clinical Cases: Five acromegalic patients (17 – 35 years-old) underwent seven pregnancies. All patients had macroadenoma: four were submitted to non-curative neurosurgery and two of them had gamma-knife radiosurgery. One patient had medical treatment prior to curative transsphenoidal surgery (TSS). One patient being treated with estroprogestative for hypogonadism had a spontaneous pregnancy; three others had pregnancy just before biochemical diagnosis of acromegaly, one of them had also a spontaneous abortion and another successful pregnancy during treatment with somatostatin receptor ligand (SRL); the last patient become pregnant during treatment with SRL, prior to TSS. Monitoring was made with IGF-1, GH (assay with no distinction of pituitary GH versus placental GH), prolactin (PRL) and visual field; pituitary imaging was performed after pregnancies in all. All women conceived naturally, two being on treatment with SRL (discontinued after confirmation of pregnancy). No treatment for acromegaly was administered before delivery. All patients had physiologic pregnancies, delivered full-term healthy babies, no malformations or metabolic disruptions; one did not breast-feed; another one had a spontaneous abortion 2 days after confirmation of pregnancy. No patient developed either hypertension, pre-eclampsia or gestational diabetes. In three cases, the clinical suspicion of acromegaly had risen during pregnancy and the diagnosis was made 1 year after delivery. The one with three pregnancies had controlled secretion of GH on Lanreotide and GH and IGF-1 levels remained stable during pregnancy. The woman with gonadotroph deficiency after TSS and GK and substitutive therapy had a decrease in IGF-1 during pregnancy (45 %), which after delivery returned pathologically to before pregnancy values; GH levels remained stable. The last patient, who became pregnant with uncontrolled acromegaly on Pasireotide, had increased, but stable GH and IGF-1 (2 X upper limit of normal) before, during and after pregnancy. TSS performed 3 years after delivery cured the disease. Conclusion: From our experience, patients with acromegaly may have normal babies, even in patients with uncontrolled hypersecretion and lack of medical treatment during pregnancy. The consensus is, however, that there is no indication to use medication to control GH hypersecretion or tumor size in acromegaly patients during pregnancy (1). Reference: (1) Muhammad A, Neggers SJ, van der Lely AJ. Pregnancy andacromegaly. Pituitary. 2017;20(1):179–184. doi:10.1007/s11102-016-0740-3

MON-297 Withdrawal from Long-Acting Somatostatin Receptor Ligand Injections in Adult Patients with Acromegaly: Results from the Phase 3, Randomized, Double-Blind, Placebo-Controlled CHIASMA OPTIMAL Study

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.

Relationship of Renal Function in Mice to Strain, Sex and 177Lutetium-Somatostatin Receptor Ligand Treatment

Aim Aim of the study was to establish parameters for 99mTc-MAG3 SPECT renal uptake kinetics in healthy SCID mice as a function of mouse strain and sex and to evaluate the feasibility of this method for detecting 177Lu-somatostatin receptor ligand (177Lu-SRL) treatment effects on kidney function. Materials and Methods Dynamic semi-stationary SPECT acquisitions (68 frames, total duration 35 min) was started prior to i. v. injection of 99mTc-MAG3 in 12 female and 12 male SCID mice. Additionally, 6 female SCID mice with neuroendocrine tumors were imaged 1–5 months after 177Lu-SRL (5 DOTATOC, 1 DOTA-JR11) treatment. Kidney function is expressed as maximum time to peak (Tmax), T50 and T25 in minutes (median [interquartile range]). Differences between groups were tested using the Mann-Whitney-U test, and SCID mouse parameters were compared with data for C57BL/6N mice from a recent publication. Results Significant sex-based differences in Tmax between strains were observed (females: C57BL/6N 1.6 [1.4–1.7], SCID 1.4 [1.3–1.5], p = 0.05; males: C57BL/6N 1.4 [1.3–1.4], SCID 1.6 [1.4–1.7], p = 0.04). In C57BL/6N mice, females showed a later Tmax (p < 0.01) than males. SCID mice showed no difference (p = 0.14). Treated SCID mice showed no significant delay in Tmax (2.0 [1.4–2.7], p = 0.15) but a significant delay in T50 (p = 0.02) and T25 (p = 0.01) compared to healthy untreated mice. Conclusion This study demonstrated significant sex-related differences between SCID and C57BL/6N mouse strains in kidney function. Establishment of normal values for different strains and sexes therefore is important for experimental therapy studies. Renal SPECT imaging with 99mTc-MAG3 was sufficiently sensitive to detect 177Lu-SRL treatment toxic effects on kidney function in SCID mice.

Excellent response to pasireotide therapy in an aggressive and dopamine-resistant prolactinoma

Prolactinomas are the most commonly encountered pituitary adenomas in the clinical setting. While most can be controlled by dopamine agonists, a subset of prolactinomas are dopamine-resistant and very aggressive. In such tumors, the treatment of choice is neurosurgery and radiotherapy, with or without temozolomide. Here, we report a patient with an highly aggressive, dopamine-resistant prolactinoma, who only achieved biochemical and tumor control during pasireotide long-acting release (PAS-LAR) therapy, a second-generation somatostatin receptor ligand (SRL). Interestingly, cystic degeneration, tumor cell necrosis or both was observed after PAS-LAR administration suggesting an antitumor effect. This case shows that PAS-LAR therapy holds clinical potential in selective aggressive, dopamine-resistant prolactinomas that express somatostatin (SST) receptor subtype 5 and appears to be a potential new treatment option before starting temozolomide. In addition, PAS-LAR therapy may induce cystic degeneration, tumor cell necrosis or both in prolactinomas.