Octreotide LAR Treatment Research Articles

O-02 Inactivation of KDM1A with the concurrent presence of MGUS in a patient with GIP-dependent Cushing's syndrome and the vanishing effect of octreotide therapy

Abstract Introduction Glucose-dependent insulinotropic peptide (GIP)-dependent primary bilateral macronodular adrenal hyperplasia (PBMAH) is a rare cause of Cushing's syndrome. It has germline genetic predisposition and requires for personalized approaches to investigation and therapy. We aimed to present the rare case of a GIP-dependent PBMAH patient with unusually severe cortisol secretion and a KDM1A inactivation with an accompanying haematological co-morbidity related to that mutation. Clinical Case A 41-year-old woman presented with a 5-kg weight gain in last 6 months, irritability and fatique. Physical examination revealed elevated blood pressure, increased supraclavicular fat pads, and abdominal obesity. The cortisol level was 25.9 (6.7-22.6) µg/dL in the morning, 16.9 µg/dL in the late night, and 6.5 µg/dL in the morning after an overnight 1 mg of dexamethasone. Urinary free cortisol (UFC) level was also elevated to 2150 (58-403) µg/24-h. The early morning plasma ACTH level was 1.5 (7-63) pg/mL. Abdominal imaging revealed 29×23 mm adenomas on the right and 46×35 mm on the left with high fat content. Cortisol was stimulated by the administration of mixed meals (+537%) but not by TRH, GnRH, metoclopramide or upright posture. The response to mixed meals was blunted by pretreatment with subcutaneous 100 mg octreotide. Following the patient's diagnosis of GIP-dependent PBMAH, octreotide LAR therapy was initiated. Although inducing a significant acute suppression of UFC and improvement in symptoms during the first 3 months, the UFC began to rise due to the resistance in the following period (Figure 1). After 9 months of octreotide LAR treatment, left adrenalectomy was performed according to the adrenal volumetric assessment. Histopathology was reported as diffuse macronodular adrenal hyperplasia without internodular atrophy. Even though the patient had a unilateral adrenalectomy, adrenal insufficiency occurred in the postoperative period. Subsequently, the patient has been closely monitored and followed up with a physiological, divided-dose hydrocortisone replacement regimen for 7 months. A germline heterozygous variant in the KDM1A gene in the patient's blood sample and a recurrent deletion in the short p arm of chromosome 1 harboring the KDM1A locus in the adrenal sample were identified. When screened for diseases associated with the KDM1A mutation, monoclonal gammopathy of undetermined significance (MGUS) was detected in the patient with mild anemia, and genetic counseling was also provided. Conclusion The management of GIP-dependent PBMAH remains controversial, and further therapeutic options are under investigation. Due to the very limited number of case reports and the heterogeneous nature of the disease, special features of our case, which are severe cortisol excess, accompanying MGUS, the vanishing effect of octreotide, and adrenal insufficiency after unilateral adrenalectomy, might contribute to the existing literature.Figure 1.Urinary free cortisol levels following octreotide therapyUFC: Urinary free cortisol, ULN: Upper limit normal, LAR: Long acting release

Octreotide Lar in Patients with Autosomal Dominant Polycystic Kidney Disease: From Bench to A Novel Perspective of Therapy

Polycystins 1 or 2 congenital defects result in impaired Ca2+ inflow through the tubular cell membrane with reduced intracellular Ca2+ concentration and secondary adenylcyclase over-activation with increased intracellular cAMP. This activates chloride-driven fluid secretion and tubular cell proliferation and de-differentiation with cyst formation and growth. Thus, medications, such as the somatostatin analogue Octreotide LAR or the vasopressin antagonist Tolvaptan, that reduce intracellular cAMP, have been tested to inhibit cAMP-mediated chloride secretion and cell proliferation in experimental and human polycystic kidney disease. Seminal studies conducted in the early ‘80s by Franklin Epstein showed that in the shark rectal gland chloride secretion is markedly inhibited by somatostatin in a way suggesting inhibition of adenylcyclase. Evidence that specific receptors for somatostatin, in particular the sst2 subtype, are present in tubular cell membranes suggested that Octreotide LAR binding to its specific renal receptors could exert similar effects in ADPKD cells. In a pilot, cross-over safety study we found that 6-month Octreotide LAR therapy was safe and well tolerated in 12 patients with ADPKD and significantly decreased total kidney volume growth as compared to placebo. Then, the ALADIN and ALADIN II academic, prospective, randomized, placebo-controlled clinical trials found that 3-year Octreotide LAR treatment significantly slowed total kidney and cyst volume growth. In ALADIN treatment slowed chronic decline of directly measured GFR in 79 patients with estimated GFR ≥ 40 ml/min/1.73 m2. In ALADIN II treatment slowed progression to doubling of serum creatinine or ESKD in 100 patients with stage 3b-4 CKD. Treatment was equally safe and well tolerated in both studies. Sub-studies also showed that 3-year Octreotide LAR therapy reduced total liver volume in 27 ADPKD patients with associated polycystic livers and improved left ventricular twisting and untwisting function in 34 ADPKD patients assessed by speckled-tracked echocardiography. Future trials should confirm the long-term benefits of Octreotide LAR in larger populations of ADPKD patients. Moreover, recent studies found that somatostatin analogues and Tolvaptan have additional beneficial effects in experimental polycystic kidney disease. Thus, clinical trials should also explore whether Octreotide LAR and Tolvaptan in combined therapy may have an additional beneficial effect even in human disease.

SAT-435 Optimization of Pharmacological Treatment of Acromegaly: Impact on IGF-1 Levels Comparing Isolated Octreotide LAR and Combined Pharmacological Therapy

Background:Transphenoidal surgery remains the best treatment for acromegaly, although the disease is unlikely to be controlled with surgery in approximately half of macroadenomas. Unfortunately, invasive macroadenomas represents over than 65% of GH-secreting adenomas (1-4). Somatostatin analogues (SSAs) are widely recognized as the first choice of primary and postsurgical pharmacological therapy in patients with acromegaly. However, more than one third of the patients fail to control insulin-like growth factor I (IGF-I) and growth hormone (GH) levels. Previous studies have shown benefits arising from the combination of SSAs, cabergoline and even estrogen therapy in mild activity of disease. Objectives:The aim of this study was to compare the efficacy in decrease and normalization of IGF-I values, of Octreotide LAR treatment isolated compared to associated with cabergoline and or cabergoline and estrogen in patients that have not undergone any other pharmacological treatment. Patients and Methods: Case series studythat enrolled 54 patients, divided in two groups, receiving OCT-LAR initially administrated a dose of 20 mg/month (IM), adjusted individually, after 3 months, with the goal of achieving normal age-matched IGF-I values, reaching the maximum dose of 30 mg/month. The second group received OC-LAR 30 mg/month associated with CBG 2 mg per week.The third group received in combination estrogen therapy Results and Discussion:The baseline mean serum IGF-I was significantly higher than after 6 months of treatment with OCT-LAR (p=0,020) and OCT-LAR+CBG (p=0,004) but no significant difference was shown for the comparison of IGF-I after 6 and 12 months in OC-LAR group (p=0,960) or OC-LAR+CBG group (p=0,929). After de adjustment of IGF-1 levels for age, the data showed a significant reduction in ULNV% comparing the basal and 6 months values in OCT-LAR (p=0,013) and OCT-LAR+CBG (p=0,004). In group OCT-LAR, the best reduction of IGF-1 was obtained after 12 months of treatment. In the group OCT-LAR-CBG, the best control was achieved at six months and was not statistically different from 12 months (p=0,047). In multitreated patients, estrogen therapy benefited IGF-1 reduction. Conclusion: The percentage of patients that reached normalization of serum IGF-I was significantly higher in the OC-LAR + CBG group at 6 months. There was no statistically significant difference at 12 months post treatment .

Left ventricular dysfunction in ADPKD and effects of octreotide-LAR: A cross-sectional and longitudinal substudy of the ALADIN trial

Background and aimIn autosomal dominant polycystic kidney disease (ADPKD) cardiac abnormalities have been observed before the onset of hypertension or renal dysfunction. We sought to characterize, in ADPKD patients, left ventricular (LV) function and its changes after somatostatin-analogue octreotide-LAR treatment. MethodsIn a 1:1:1 cross-sectional study, we evaluated LV function by speckle-tracking echocardiography in 34 ADPKD patients from one ALADIN-trial center and in 34 age- and gender-matched healthy controls and 34 equally-matched renal controls with non-cystic chronic kidney disease. Changes in LV function were compared in the 16 and 18 ADPKD patients originally randomized to 3 year-treatment with octreotide-LAR or placebo, respectively. ResultsLV twist and untwisting rates were lower in ADPKD patients that in healthy or renal controls (6.1 ± 2.6° vs. 11.1 ± 2.1° and 10.2 ± 3.7°; −49.5 ± 18.1°/s vs. −79.8 ± 12.2°/s and −84.3 ± 25.9°/s, respectively, all p < 0.001). The correlation between LV mass or diastolic BP and untwisting rate was positive in ADPKD patients (r = 0.38, p = 0.025 and r = 0.44, p = 0.011, respectively), not significant in healthy controls and negative in renal controls (r = −0.38; p = 0.023 and r = −0.40, p = 0.012, respectively. LV untwisting rate improved from −49.9 ± 18.6°/s to −70.3 ± 27.5°/s with octreotide-LAR, but did not change with placebo (p = 0.027 for treatment effect). At adjusted linear regression analysis, octreotide-LAR therapy emerged as the only independent predictor of untwisting rate improvement at final visit [beta coefficient −0.504 (95% CI −46.905–−6.367), p = 0.014]. ConclusionsIn ADPKD patients LV function is early impaired. Somatostatin-analogue therapy might help in preventing or ameliorating LV dysfunction in this population.Clinical Trial Registration http://www.clinicaltrials.gov, NCT0030928.

Placebo-Controlled, Double-Blind, Prospective, Randomized Study on the Effect of Octreotide LAR in the Control of Tumor Growth in Patients with Metastatic Neuroendocrine Midgut Tumors (PROMID): Results of Long-Term Survival

Background: Somatostatin analogs have been shown to control the growth of well-differentiated metastatic neuroendocrine tumors. Their effect on overall survival is a matter of debate. We analyzed the prognostic significance of early treatment with octreotide LAR and of hepatic tumor load in the PROMID trial cohort. Patients and Methods: Between 2001 and 2008, 85 treatment-naïve patients were randomly assigned to monthly octreotide LAR 30 mg or placebo until tumor progression or death. Post-study treatment was at the discretion of the investigator. Upon disease progression, 38 out of 43 placebo patients (88.4%) received octreotide LAR. For survival, patients were followed until May 2014. Results: Forty-eight out of 85 patients (56.5%) died. In 38 patients (79.2%), death was tumor related. The median overall survival (84.7 and 83.7 months) was only slightly different in patients assigned to octreotide and placebo [HR = 0.83 (95% CI: 0.47-1.46); p = 0.51]. The median overall survival was 84.7 months for all 85 patients, 107.6 months in the low-tumor-load (n = 64) and 57.5 months in the high-tumor-load (n = 21) subgroups [HR = 2.49 (95% CI: 1.36-4.55); p = 0.002]. There was a trend towards improved overall survival in patients with a low hepatic tumor load receiving octreotide compared to placebo [‘median not reached' and 87.2 months; HR = 0.59 (95% CI: 0.29-1.2); p = 0.142]. Conclusion: The extent of tumor burden is a predictor for shorter survival. Overall survival was similar in patients receiving octreotide LAR or placebo treatment at randomization. Crossover of the majority of placebo patients to octreotide LAR may have confounded the data on overall survival.

Metformin Impact on Progression-Free Survival in Advanced Pancreatic Well-Differentiated Neuroendocrine Tumors (Pwdnets). Retrospective Evaluation in Diabetic Patients Receiving Everolimus Plus Octreotide Lar Treatment

ABSTRACT Aim: Abnormal PI3K–Akt–mTOR pathway signaling and autocrine activation of the mTOR pathway, mediated through insulin-like growth factor 1 (IGF1), has been implicated in the proliferation of pNET cells. Everolimus (EVE), an inhibitor of mTOR (a central regulator of growth/proliferation, cellular metabolism and angiogenesis) has shown antitumor benefit in pNETs alone and in combination with octreotide LAR (OCT) in RADIANT-1 and RADIANT-3 trials. An increasing number of studies have identified diabetic patients (pts) as having increased risk for the development of cancer and have associated metformin (MET) treatment with a decrease of cancer risk. MET has also been associated with improved outcomes in cancer pts. MET has recently shown some anti-cancer activity, both in vitro and in vivo studies by antisecretory properties to decrease insulin and IGF1 levels and by antitumor effect due to AMPK activation and consequently inhibition to TSC1-2/mTOR complex, mediated to LKB1 oncogene expression. The aims of this retrospective study, even if in a limited number of pts, was to evaluate the effect of concomitant MET administered during EVE plus OCT therapy in pts with pWDNETs and diabetes. Methods: We retrospectively evaluated the difference in terms of progression-free survival (PFS) between consecutive diabetic pts on MET and those on insulin (INS) as concomitant drugs during EVE plus OCT therapy. Normoglycemic pts served as controls. Results: Between 2009 and 2012, 31 pts (age 55.5 years; 22 males) were treated with EVE plus OCT. Six pts received MET, 6 received INS and 19 pts were normogycemic. In the overall population, median PFS was 12 months (mo) (95%CI 6.3-17.7); mPFS was 24 mo (95% CI 8.6-59.9) in diabetic pts and 12 mo (95% CI 8.7- 15.3) in normoglycemic pts (HR 3.17, 95% CI 1.18-8.49; p = 0.016). Median PFS in pts on MET was “not achieved” versus 12.2 mo in pts treated with INS (95% CI 0-28). At the time of this analysis, 4 pts (67%) on MET are still receiving EVE plus OCT, with a median duration of treatment of 19.5 mo (range 10-27+ mo). Conclusions: Although the limited number of pts hampers the analysis, these retrospective results may suggest that the addition of MET to EVE plus OCT can provide clinical benefits to pWDNETs pts. A prospective evaluation is required to either confirm or disprove these preliminary findings. Disclosure: All authors have declared no conflicts of interest.

Octreotide LAR treatment of acromegaly in "real life": long-term outcome at a tertiary care center.

To report our day-to day experience with the long-term use of octreotide LAR in the treatment of acromegaly. Patients with acromegaly managed between 2003 and 2012 with octreotide LAR for a median of 27 months (interquartile ranges 12-60) and who had not received radiation therapy or concomitant treatment with cabergoline were retrospectively evaluated. Both primarily treated patients (n = 33) and patients who received octreotide after failed pituitary surgery (adjunctive treatment, n = 124) were included. Full biochemical response was defined as the achievement of a GH <2.5 ng/mL and an IGF-1 <1.2 times the upper limit of normal (× ULN); we also evaluated efficacy using a GH cut off of <1 ng/mL. Over 60% of the patients achieved a GH of <2.5 ng/mL. The combined GH (<2.5 ng/mL) and IGF-1 (<1.2 × ULN) target was achieved by 35.5 and 33.6% of the patients treated primarily and adjunctively, respectively; these figures dropped to 22.6 and 23% when using a GH target of <1 ng/mL. All patients reported a significant improvement in acromegalic symptoms. Lower pretreatment GH and IGF-1 levels were both associated with a higher probability of achieving the composite biochemical target. Currently recommended GH and IGF-1 targets are reached by <36% of patients treated with octreotide LAR in a day-to day practice context. Nevertheless, in most instances a clinical benefit and an improvement in biochemical markers can be clearly documented.

ALADIN: wish granted in inherited polycystic kidney disease?

ALADIN: wish granted in inherited polycystic kidney disease?

Effect of longacting somatostatin analogue on kidney and cyst growth in autosomal dominant polycystic kidney disease (ALADIN): a randomised, placebo-controlled, multicentre trial

Autosomal dominant polycystic kidney disease slowly progresses to end-stage renal disease and has no effective therapy. A pilot study suggested that the somatostatin analogue octreotide longacting release (LAR) could be nephroprotective in this context. We aimed to assess the effect of 3 years of octreotide-LAR treatment on kidney and cyst growth and renal function decline in participants with this disorder. We did an academic, multicentre, randomised, single-blind, placebo-controlled, parallel-group trial in five hospitals in Italy. Adult (>18 years) patients with estimated glomerular filtration rate (GFR) of 40 mL/min per 1·73 m(2) or higher were randomly assigned (central allocation by phone with a computerised list, 1:1 ratio, stratified by centre, block size four and eight) to 3 year treatment with two 20 mg intramuscular injections of octreotide-LAR (n=40) or 0·9% sodium chloride solution (n=39) every 28 days. Study physicians and nurses were aware of the allocated group; participants and outcome assessors were masked to allocation. The primary endpoint was change in total kidney volume (TKV), measured by MRI, at 1 year and 3 year follow-up. Analyses were by modified intention to treat. This study is registered with ClinicalTrials.gov, NCT00309283. Recruitment was between April 27, 2006, and May 12, 2008. 38 patients in the octreotide-LAR group and 37 patients in the placebo group had evaluable MRI scans at 1 year follow-up, at this timepoint, mean TKV increased significantly less in the octreotide-LAR group (46·2 mL, SE 18·2) compared with the placebo group (143·7 mL, 26·0; p=0·032). 35 patients in each group had evaluable MRI scans at 3 year follow-up, at this timepoint, mean TKV increase in the octreotide-LAR group (220·1 mL, 49·1) was numerically smaller than in the placebo group (454·3 mL, 80·8), but the difference was not significant (p=0·25). 37 (92·5%) participants in the octreotide-LAR group and 32 (82·1%) in the placebo group had at least one adverse event (p=0·16). Participants with serious adverse events were similarly distributed in the two treatment groups. However, four cases of cholelithiasis or acute cholecystitis occurred in the octreotide-LAR group and were probably treatment-related. These findings provide the background for large randomised controlled trials to test the protective effect of somatostatin analogues against renal function loss and progression to end-stage kidney disease. Polycystic Kidney Disease Foundation.

The role of octreotide LAR treatment on BMI in patients with acromegaly

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

The influence of octreotide-LAR treatment on glucose homeostasis in acromegaly

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Octreotide LAR use among elderly patients with carcinoid syndrome and survival outcomes: A population-based analysis.

322 Background: Octreotide LAR is indicated for the treatment of carcinoid syndrome, diarrhea related to VIPoma, and may delay tumor growth in neuroendocrine tumors (NETs). The pattern of octreotide LAR use in clinical practice and its impact on survival outcomes has not been well-documented. Methods: Using the SEER-Medicare database, we identified NET patients diagnosed between 7/1999 and 12/2007. We excluded those under age 65, enrolled in HMOs, and without continuous Part A and B enrollment within 12 months of diagnosis. Potential indication for octreotide use was defined as ≥ 2 claims for carcinoid syndrome, flushing, diarrhea, or malignant islet cell neoplasm within first year of diagnosis, with the first claim occurring within 6 months of diagnosis. HCPCS codes, J2352 and J2353, were used to identify octreotide LAR treatment. Multivariate logistic regression and Cox proportional hazard survival analyses were performed to ascertain factors associated with octreotide use and evaluate impact of octreotide use on survival; covariates included age, race, region, comorbidity score, urban/rural status, tumor characteristics, neighborhood socioeconomic status and year of diagnosis. Results: Among those with potential indication for octreotide use (carcinoid syndrome and islet cell), 264 (49%) out of 539 distant stage patients, and 83 (10%) out of 850 patients with local regional disease were started on octreotide LAR within 6 months of diagnosis. Multivariate logistic regression showed that patients living in the southern region were less likely to use octreotide. Multivariate proportional hazard model showed that octreotide LAR provided a significant 5-year survival benefit for distant stage patients (HR=.80, p-value=.047); while this survival benefit was not shown for the local/regional stage patients (HR=.97, p-value=.89). Conclusions: This retrospective study suggests a possible survival benefit for use of octreotide LAR in distant stage elderly patients with carcinoid syndrome. Data also suggest that many elderly patients with claims for carcinoid syndrome did not receive octreotide LAR therapy within 6 months of diagnosis. Further studies and improved education are warranted.

Atherosclerotic Risk Factors and Premature Atherosclerosis in Acromegaly Before and After 48 Months of Octreotide-LAR Treatment

We studied premature atherosclerosis with carotid Doppler ultrasonography in active acromegaly before and after treatment. Patients (n = 27) with active acromegaly and 12 age-, gender-, and body mass index-matched healthy individuals were included in the study. Carotid intima-media thickness was decreased significantly in the inactive group after treatment (median: 0.6 mm, interquartile range [IQR]: 0.55-0.80]) when compared with the active group (median: 0.9 mm [IQR: 0.75-1.15], P < .0001), but there was no significant difference between the inactive and control groups. There was a correlation between homeostasis model of assessment-insulin resistance (P = .01, r = .41) and growth hormone (GH; P < .0001, r = .46). In conclusion, premature atherosclerosis was demonstrated in active acromegaly patients probably as a consequence of insulin resistance and direct vascular effects of GH and/or insulin-like growth factor 1.

First demonstration of the effectiveness of peptide receptor radionuclide therapy (PRRT) with 111In-DTPA-octreotide in a giant PRL-secreting pituitary adenoma resistant to conventional treatment

In prolactin-secreting giant adenomas, cabergoline treatment is the first line approach. Surgery and/or radiotherapy are indicated when the tumour is resistant to medical treatment and continues growing, causing visual field impairment. Data concerning other therapeutic approach are scanty. Although PRL-secreting tumours may express somatostatin receptors type 2, 3 and 5, somatostatin analogs treatment is generally ineffective and peptide receptor radionuclide therapy (PRRT) has never been reported. A 58 year-old woman complaining of severe neurological symptoms caused by a giant prolactinoma, relapsing after surgery and not-responding to dopamine-agonists and octreotide LAR treatment, underwent four cycles of PRRT with 111-Indium-DTPA-octreotide with remarkable tumour shrinkage and a significant improvement in clinical conditions. No side effects were reported. This is the first report on the effectiveness and safety of PRRT with radio-labelled somatostatin analogs in a patient with aggressive giant prolactinoma resistant to conventional treatment.

Effect of everolimus plus octreotide LAR treatment on chromogranin A and 5-hydroxyindoleacetic acid levels in patients with advanced neuroendocrine tumors: Phase III RADIANT-2 study results.

10527 Background: Chromogranin A (CgA) and 5-hydroxyindoleacetic acid (5-HIAA) are important biomarkers of tumor burden and carcinoid syndrome in patients with neuroendocrine tumors (NET). The goals of this analysis were to characterize serum CgA and 24-h urinary 5-HIAA level changes from baseline in response to treatment with everolimus, oral inhibitor of mTOR, + octreotide LAR vs placebo + octreotide LAR (P+O) in patients with advanced NET in the phase III RADIANT-2 trial. Methods: Patients (n=429) received everolimus 10 mg/d + octreotide LAR 30 mg IM q 28 days (E+O; n=216) or P+O (n=213). Serum samples were collected and analyzed for CgA and urine samples for 5-HIAA at baseline and, if elevated (>ULN), were repeated on day 1 of each subsequent cycle. CgA and 5-HIAA response, defined as normalization or ≥50% reduction, was described by treatment arm, and changes from baseline over time were analyzed using a mixed-effects model including least squares estimates of treatment effect. Results: Patients with elevated baseline values had biomarkers assessed for a median number of 10 cycles in both the E+O and the P+O arms. Patients on E+O had a higher incidence of CgA and 5-HIAA response (45.7% [75/164] and 60.7% [85/140]) than patients on P+O (28.8% [42/146] and 46.8% [66/141]). Patients in the E+O group vs those in the P+O group showed greater reductions of both serum CgA (P=0.0041) and urinary 5-HIAA (P<0.0001) over time. During the first cycle, the ratio in fold change from baseline for the E+O group vs the P+O group was 0.754/0.891=0.85 (95% CI, 0.70-1.02) and 0.749/0.891=0.84 (95% CI, 0.71-1.00) for CgA and 5-HIAA, respectively. A positive treatment effect with E+O was maintained over the subsquent treatment cycles. Conclusions: E+O resulted in early, sustained decreases in both serum CgA and urinary 5-HIAA vs P+O. In addition to the improvement in progression-free survival (PFS) seen in RADIANT-2, these results demonstrate that E+O provides a significant reduction in both biomarkers used to evaluate patients with carcinoid syndrome. Future studies should examine the correlation between serum CgA and urinary 5-HIAA response and PFS.

Effects of Long-acting Release Octreotide on Glucose Homeostasis in Acromegaly Patients after Trans-Sphenoidal Surgery

The present study was aimed to investigate glucose homeostasis and insulin secretion in acromegalic patients during octreotide-long acting release (LAR) therapy and designed as an observational prospective study. 18 acromegalic patients who had undergone trans-sphenoidal surgery with active disease were included. All patients were treated with octreotide-LAR injection for 1 year. These patients received oral glucose tolerance test (OGTT) before, 21 days after, and 1 year after octreotide-LAR treatment. Primary outcomes were changes in glucose levels and insulin secretion during an OGTT. We also determined the differences between subjects with normalized and uncontrolled IGF-1 levels. Of the 18 patients treated with octreotide-LAR for 1 year, 89% achieved fasting GH levels <2.5 μg/l, 85% reached the nadir GH concentration <1 μg/l, and 61% achieved normal age- and sex-matched IGF-1 values. 21 days after one dose of octreotide-LAR injection, insulin response during OGTT significantly decreased, and the Matsuda index increased significantly. One year after octreotide-LAR therapy, most parameters of glucose homeostasis returned to baseline levels. However, insulin response during OGTT at 30 and 60 min, and the insulinogenic index were still significantly decreased. Compared with the IGF-1-normalized group, the IGF-1 uncontrolled group had the same fasting GH and nadir GH levels and a higher insulin AUC and total insulin secretion. During octreotide-LAR treatment, the early-phase insulin response to OGTT is reduced and plasma glucose levels remained normal in most patients. The IGF-1 uncontrolled group had the same fasting GH and nadir GH levels during OGTT, but had better glucose homeostasis.

Polycythemia as rare secondary direct manifestation of acromegaly: management and single-centre epidemiological data

Polycythemia associated with acromegaly is usually caused by the systemic manifestations of the disease, such as sleep-apnea or concomitant erythropoietin-secreting kidney tumors. The recognition of underlying pathologies requires a thorough diagnostic process. We report a unique case of acromegaly with polycythemia, not caused by commonly described manifestations of the disease, and receding with octreotide therapy. The medical history of 141 acromegalic patients followed by the Endocrinology Unit of the San Martino University Hospital in Genoa has been also reviewed, together with the literature evidence for similar cases. The diagnostic workflow and 2-years follow-up of a 43-years old acromegalic, polycythemic man with a history of past smoking, moderate hypertension, and mental retardation are described. The hematological parameters of our cohort was retrospectively compared with those of a healthy, age/gender-related control group as well. Therapy with octreotide LAR, 20 mg i.m. q28d was begun soon after diagnosis of acromegaly in the polycythemic patient. Haematocrit level, hormonal setting, as well as pituitary tumor size and visual perimetry during treatment were recorded. Octreotide LAR treatment normalized hormonal alterations, as well as hematological parameters. Polycythemia has not recurred after 2 years of therapy. The median hemoglobin and hematocrit levels of the retrospectively analyzed cohort of acromegalic were significantly lower than normal ranges of a healthy, age/sex- related control population. In conclusions, polycythemia can be a direct, albeit rare, secondary manifestation of acromegaly, that must be considered during the diagnostic work-up of acromegalic patients presenting with such disorder.

A successful pregnancy in a patient with acromegaly under octreotide-LAR treatment: a case report

Hipofizer makroadenom nedeniyle opere olan 30 yasindaki bayan hastanin operasyon sonrasi yapilan oral glukoz testine GH cevabi yetersizdi. Bu nedenle Octreotide-LAR (OCT-LAR) tedavisi baslandi. Tedavinin 15. Ayinda, 4 aydan beri adet gormemesi nedeniyle yapilan gebelik testinde gebelik oldugu tespit edildi. Hasta bu donemde gebe oldugunu bilmedigi icin OCT-LAR tedavisi almisti. Hipofiz manyetik rezonans goruntulemede (MRG) adenomda buyume olmadigi goruldugu icin OCT-LAR tedavisi kesildi. Hasta gebeligin 37. haftasinda 50 cm boyunda ve 2650 gr agirliginda saglikli bir kiz dogurdu. Postpartum donemde adenoma degerlendirmek icin yapilan hipofiz MRG’de buyume olmadigi goruldu. Dogumdan 2 ay sonra yapilan OGTT’ye buyume hormon supresyonu yetersiz oldugu icin OCT-LAR tedavisi yeniden baslandi. Akromegali hastalarinda gebelik olustugunda tedaviye devam etme veya birakma kararini vermek icin adenoma boyutunun hipofiz MRG ile kontrol edilmesi gerektiginin en uygun yaklasim olduguna inaniyoruz. Ayrica daha guvenli veriler elde edilinceye kadar gebelik sirasinda OCT-LAR tedavisi kesilmesi gerektigini dusunuyoruz

Long‐term results of patients with malignant carcinoid syndrome receiving octreotide LAR

Octreotide LAR is an established treatment for malignant carcinoid syndrome. However, studies with large number of patients and long follow-up are lacking. To present long-terms results with octreotide LAR, assessing duration of clinical and objective response and treatment tolerance, in a large, homogeneous cohort of patients with malignant carcinoid syndrome. A total of 108 patients with metastatic midgut neuroendocrine tumours were included in this 8-year study. Clinical evaluation was based on a symptom score. Radiological assessment was based on RECIST (Response Evaluation Criteria In Solid Tumours) criteria. Of the 108 patients, 24% had a sustained symptomatic response. In the remaining patients, loss of symptomatic response with the initial dose was noted within 3-60 months. In 17% of them, symptoms were controlled by just an increase of octreotide LAR dose, whilst the other patients required additional treatment. Overall, in 45.3% of patients, symptoms were well controlled during the study period with only octreotide LAR, and no additional treatment was required. No significant adverse effects were noted. Octreotide LAR treatment provides a sustained symptomatic response in about half of the patients with malignant carcinoid syndrome and contributes to disease stabilization for a longer period than previously described.

Acromegaly: correlation between expression of somatostatin receptor subtypes and response to octreotide-lar treatment

About one-third of acromegalics are resistant to the clinically available somatostatin analogs (SA). The resistance is related to density reduction or different expression of somatostatin receptor subtypes (SSTR). This study analyzes SSTR's expression in somatotrophinomas, comparing to SA response, hormonal levels, and tumor volume. We analyzed 39 somatotrophinomas; 49% were treated with SA. The most expressed SSTR was SSTR5, SSTR3, SSTR2, SSTR1, and SSTR4, respectively. SSTR1 and SSTR2 had higher expression in patients that had normalized GH and IGF-I. SSTR3 was more expressed in patients with tumor reduction. There was a positive correlation between the percentage of tumor reduction and SSTR1, SSTR2 and SSTR3 expression. Also, a positive correlation between SSTR2 mRNA expression and the immunohistochemical reactivity of SSTR2 was found. Our study confirmed the association between the SA response to GH and IGF-I and the SSTR2. Additionally, this finding was also demonstrated in relation to SSTR1.