pasireotide and Adenoma

Pasireotide (PAS) is a novel somatostatin receptor ligands (SRL), used in controlling hormonal hypersecretion in both acromegaly and Cushing's Disease (CD). In previous studies and meta-analysis, first-generation SRLs were reported to be able to induce significant tumor shrinkage only in somatotroph adenomas. This systematic review and meta-analysis aim to summarize the effect of PAS on the shrinkage of the pituitary adenomas in patients with acromegaly or CD.. We searched the Medline database for original studies in patients with acromegaly or CD receiving PAS as monotherapy, that assessed the proportion of significant tumor shrinkage in their series. After data extraction and analysis, a random-effect model was used to estimate pooled effects. Quality assessment was performed with a modified Joanna Briggs's Institute tool and the risk of publication bias was addressed through Egger's regression and the three-parameter selection model.. The electronic search identified 179 and 122 articles respectively for acromegaly and CD. After study selection, six studies considering patients with acromegaly and three with CD fulfilled the eligibility criteria. Overall, 37.7% (95%CI: [18.7%; 61.5%]) of acromegalic patients and 41.2% (95%CI: [22.9%; 62.3%]) of CD patients achieved significant tumor shrinkage. We identified high heterogeneity, especially in acromegaly (I. PAS treatment is effective in reducing tumor size, especially in acromegalic patients. This result strengthens the role of PAS treatment in pituitary adenomas, particularly in those with an invasive behavior, with progressive growth and/or extrasellar extension, with a low likelihood of surgical gross-total removal, or with large postoperative residual tissue.. https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022328152, identifier CRD42022328152.

Topics: Acromegaly; ACTH-Secreting Pituitary Adenoma; Adenoma; Humans; Pituitary ACTH Hypersecretion; Pituitary Neoplasms; Somatostatin

The delay in controlling the disease in patients who do not respond to first-line treatment with first generation somatostatin receptor ligands (first-generation SRLs) can be quantified in years, as every modification in the medical therapy requires some months to be fully evaluated. Considering this, acromegaly treatment should benefit from personalized medicine therapeutic approach by using biomarkers identifying drug response. Pasireotide has been positioned mostly as a compound to be used in first-generation SRLs resistant patients and after surgical failure, but sufficient data are now available to indicate it is a first line therapy for patients with certain characteristics. Pasireotide has been proved to be useful in patients in which hyperintensity T2 MRI signal is shown and in those depicting low

Topics: Acromegaly; Adenoma; Algorithms; Biomarkers; Endocrine Gland Neoplasms; Genetic Markers; Growth Hormone-Secreting Pituitary Adenoma; Humans; Image Processing, Computer-Assisted; Insulin-Like Growth Factor I; Ligands; Machine Learning; Magnetic Resonance Imaging; Models, Genetic; Octreotide; Phosphorylation; Precision Medicine; Receptors, Somatostatin; Somatostatin; Treatment Outcome

Acromegaly is a disease due to chronic GH excess and a consequent rise in IGF-1 levels. This rare endocrine condition is associated with metabolic alterations such as hyperglycaemia, dyslipidaemia, and systemic arterial hypertension, which, in addition to GH excess-related cardiovascular changes, play critical roles in increasing cardiovascular risk and mortality rates. Biochemical control of acromegaly, achieved by means of surgical, and/or medical treatment, positively impacts on cardiovascular risk factors and metabolic alterations, reducing overall patient mortality. However, treatment modalities of acromegaly and disease control differently impact on glucose homeostasis and lipid changes, and consequently on cardiometabolic risk. In this regard, pasireotide was shown to significantly influence glucose metabolism. This review summarizes the cardiometabolic consequences of acromegaly and its treatment, focusing on available data around the effects of medical therapy with pasireotide on factors that influence cardiometabolic risk.

Topics: Acromegaly; Adenoma; Cardiovascular Diseases; Growth Hormone-Secreting Pituitary Adenoma; Heart Disease Risk Factors; Human Growth Hormone; Humans; Insulin-Like Growth Factor I; Risk Factors; Somatostatin; Treatment Outcome

Somatostatin receptors (SSTs) are widely co-expressed in pituitary tumors. SST. Critical revision of literature data correlating SST expression with patients' response to SRLs.. SST. The assumption "more target receptor, more drug efficacy" is not straightforward for SRLs. The complex pathophysiology of SSTs, and the technical challenges faced to translate research findings into clinical practice, still need our full commitment to make receptor evaluation a worthwhile procedure for individualizing treatment decisions.

Topics: Adenoma; Antineoplastic Combined Chemotherapy Protocols; Gene Expression Regulation, Neoplastic; Human Growth Hormone; Humans; Insulin-Like Growth Factor I; Molecular Targeted Therapy; Octreotide; Pituitary Neoplasms; Receptors, Somatostatin; Somatostatin

Cushing's syndrome is associated with multisystem morbidity and, when suboptimally treated, increased mortality. Medical therapy is an option for patients if surgery is not successful and can be classified into pituitary-directed drugs, steroid synthesis inhibitors, and glucocorticoid receptor antagonists. In the last decade there have been new developments in each drug category. Targeting dopamine and somatostatin receptors on corticotroph adenomas with cabergoline or pasireotide, or both, controls cortisol production in up to 40% of patients. Potential new targets in corticotroph adenomas include the epidermal growth factor receptor, cyclin-dependent kinases, and heat shock protein 90. Osilodrostat and levoketoconazole are new inhibitors of steroidogenesis and are currently being evaluated in multicentre trials. CORT125134 is a new selective glucocorticoid receptor antagonist under investigation. We summarise the drug therapies for various forms of Cushing's syndrome and focus on emerging drugs and drug targets that have the potential for new and effective tailor-made pharmacotherapy for patients with Cushing's syndrome.

Topics: ACTH Syndrome, Ectopic; ACTH-Secreting Pituitary Adenoma; Adenoma; Adrenal Gland Neoplasms; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Cabergoline; Cushing Syndrome; Dopamine Agonists; ErbB Receptors; Gefitinib; Hormones; Humans; Imidazoles; Isoquinolines; Molecular Targeted Therapy; Pituitary ACTH Hypersecretion; Pyrazoles; Pyridines; Receptors, Glucocorticoid; Roscovitine; Somatostatin; Temozolomide; Tretinoin

The most frequent cause of endogenous hypercortisolism is Cushing disease (CD), a devastating condition associated with severe comorbidities and high mortality. Effective tumor-targeting therapeutics are limited.. Search in PubMed with key words "corticotroph" and "Cushing's disease" plus the name of the mentioned therapeutic agent and in associated references of the obtained papers. Additionally, potential therapeutics were obtained from ClinicalTrials.gov with a search for "Cushing disease.". At present, the tumor-targeted pharmacological therapy of CD is concentrated on dopamine agonists (cabergoline) and somatostatin analogs (pasireotide) with varying efficacy, escape from response, and considerable side effects. Preclinical studies on corticotroph pathophysiology have brought forward potential drugs such as retinoic acid, silibinin, and roscovitine, whose efficacy and safety remain to be determined.. For many patients with CD, effective tumor-targeted pharmacological therapy is still lacking. Coordinated efforts are pivotal in establishing efficacy and safety of novel therapeutics in this rare but devastating disease.

Topics: ACTH-Secreting Pituitary Adenoma; Adenoma; Antineoplastic Agents; Cabergoline; Clinical Trials as Topic; Corticotrophs; Humans; Pituitary ACTH Hypersecretion; Roscovitine; Silybin; Somatostatin; Treatment Outcome; Tretinoin

Recent publications suggested that pasireotide could be a good therapeutic option in some dopamine-resistant or aggressive prolactinomas. We discussed the two published cases and describe another case of poorly differentiated plurihormonal PIT-1-positive adenoma with moderate SSTR2 expression and intense STTR5 expression successfully treated with PAS-LAR 40 mg/month.

Topics: Adenoma; Dopamine Agonists; Drug Resistance, Neoplasm; Female; Hormones; Humans; Middle Aged; Neuroendocrine Tumors; Pituitary Neoplasms; Prolactin; Prolactinoma; Somatostatin

In nearly all cases, acromegaly is caused by excess GH from a pituitary adenoma, resulting in elevated circulating levels of GH and, subsequently, IGF-1. Treatment goals are to eliminate morbidity and restore the increased mortality to normal rates. Therapeutic strategies aim to minimize tumor mass and normalize GH and IGF-1 levels. Somatostatin analogues are the medical treatment of choice in acromegaly, as first-line or post-surgical therapy, and have proven efficacy in pituitary tumor volume reduction (TVR).. Here we review the effects of somatostatin analogue therapy on pituitary tumor volume in patients with acromegaly.. TVR with somatostatin analogues may be mediated by direct anti-proliferative effects via activation of somatostatin receptors, or by indirect effects, such as angiogenesis inhibition, and is more pronounced when they are administered as first-line therapy. Various studies of first-line treatment with octreotide LAR have shown significant TVR in ≥73% of patients. First-line treatment with lanreotide Autogel has shown evidence of TVR, although more studies are needed. In a recent randomized, double-blind, 12-month trial in 358 medical-treatment-naïve acromegaly patients, significant TVR was achieved by 81% of patients administered pasireotide LAR and 77% administered octreotide LAR. Pre-operative somatostatin analogue therapy may also induce TVR and improve post-operative disease control compared with surgery alone. TVR is progressive with prolonged treatment, and decreased IGF-1 levels may be its best predictor, followed by age and degree of GH decrease. However, TVR does not always correlate with degree of biochemical control.. Somatostatin analogues (first- or second-line treatment) are the mainstay of medical therapy and, as first-line medical therapy, are associated with significant pituitary TVR in most patients.

Topics: Acromegaly; Adenoma; Antineoplastic Agents, Hormonal; Growth Hormone-Secreting Pituitary Adenoma; Humans; Octreotide; Peptides, Cyclic; Somatostatin; Treatment Outcome; Tumor Burden

Acromegaly is a hormonal disorder that arises when the pituitary gland secretes excess growth hormone (GH), which in turn stimulates a concomitant increase in serum insulin-like growth factor 1 (IGF-1) levels. Gastroenteropancreatic neuroendocrine tumours (GEP-NET) constitute a heterogeneous group of tumours that can secrete serotonin and a variety of peptide hormones that may cause characteristic symptoms known as carcinoid syndrome or other symptoms and hormonal hypersecretion syndromes depending on the tumour's site of origin. Current medical therapy for the treatment of acromegaly and GEP-NET involves the administration of somatostatin analogues that effectively suppress excess hormone secretion. After its discovery in 1979, octreotide became the first synthetic biologically stable somatostatin analogue with a short-acting formulation of octreotide introduced into clinical practice in the late 1980s. Lanreotide, another somatostatin analogue, became available in the mid-1990s initially as a prolonged-release formulation administered every 10 or 14 days. Long-acting release formulations of both octreotide (Sandostatin LAR and Novartis) and lanreotide (Somatuline Autogel, Ipsen), based on microparticle and nanoparticle drug-delivery technologies, respectively, were later developed, which allowed for once-monthly administration and improved convenience. First-generation somatostatin analogues remain one of the cornerstones of medical therapy in the management of pituitary and GEP-NET hormone hypersecretion, with octreotide having the longest established efficacy and safety profile of the somatostatin analogue class. More recently, pasireotide (Signifor), a next-generation multireceptor-targeted somatostatin analogue, has emerged as an alternative therapeutic option for the treatment of acromegaly. This review summarizes the development and clinical success of somatostatin analogues.

Topics: Acromegaly; Adenoma; Antineoplastic Agents; Growth Hormone-Secreting Pituitary Adenoma; Humans; Intestinal Neoplasms; Neuroendocrine Tumors; Octreotide; Pancreatic Neoplasms; Peptides, Cyclic; Somatostatin; Stomach Neoplasms

In almost every patient, acromegaly is caused by a growth hormone secreting pituitary adenoma. Clinical features are the result of excessive growth hormone secretion and the consecutive excess in insulin-like growth factor I levels. This results in somatic overgrowth and metabolic disturbances with a higher morbidity and mortality than in the general population. With optimal disease management, mortality can be reduced to that seen in the general population. The current treatment of acromegaly is based on a combination of surgery, radiotherapy and medical therapy. This review provides an overview of the current and upcoming therapies with a focus on medical therapy.

Topics: Acromegaly; Adenoma; Antineoplastic Agents; Dopamine Agonists; Human Growth Hormone; Humans; Octreotide; Pituitary Neoplasms; Somatostatin

Somatostatin (SST), an inhibitory polypeptide with two biologically active forms SST14 and SST28, inhibits GH, prolactin (PRL), TSH, and ACTH secretion in the anterior pituitary gland. SST also has an antiproliferative effect inducing cell cycle arrest and apoptosis. Such actions are mediated through five G-protein-coupled somatostatin receptors (SSTR): SSTR1-SSTR5. In GH-secreting adenomas, SSTR2 expression predominates, and somatostatin receptor ligands (SRLs; octreotide and lanreotide) directed to SSTR2 are presently the mainstays of medical therapy. However, about half of patients show incomplete biochemical remission, but the definition of resistance per se remains controversial. We summarize here the determinants of SRL resistance in acromegaly patients, including clinical, imaging features as well as molecular (mutations, SSTR variants, and polymorphisms), and histopathological (granulation pattern, and proteins and receptor expression) predictors. The role of SSTR5 may explain the partial responsiveness to SRLs in patients with adequate SSTR2 density in the cell membrane. In patients with ACTH-secreting pituitary adenomas, i.e. Cushing's disease (CD), SSTR5 is the most abundant receptor expressed and tumors show low SSTR2 density due to hypercortisolism-induced SSTR2 down-regulation. Clinical studies with pasireotide, a multireceptor-targeted SRL with increased SSTR5 activity, lead to approval of pasireotide for treatment of patients with CD. Other SRL delivery modes (oral octreotide), multireceptor-targeted SRL (somatoprim) or chimeric compounds targeting dopamine D2 receptors and SSTR2 (dopastatin), are briefly discussed.

Topics: Adenoma; Adrenocorticotropic Hormone; Apoptosis; Cell Cycle Checkpoints; Dopamine; Drug Resistance, Neoplasm; Hormones; Human Growth Hormone; Humans; Ligands; Pituitary Neoplasms; Prolactin; Receptors, Somatostatin; Signal Transduction; Somatostatin; Thyrotropin

Hypercortisolism induced by Cushing disease causes high morbidity and mortality. The treatment of choice is pituitary surgery, but it often fails to achieve cure, and other treatment modalities (radiotherapy, bilateral adrenalectomy) may therefore be required. If these treatments are not effective or while waiting for their results, hypercortisolism should be controlled with drugs. The classical drug treatments are those that act by inhibiting cortisol secretion by the adrenal gland (ketoconazole, metyrapone, mitotane, etomidate). The preliminary results of a new drug (LCI699) which is a potent enzyme inhibitor of cortisol secretion have been reported. A clinical trial of the safety and efficacy of mifepristone, a glucocorticoid receptor antagonist, has just been published. The drugs deserving more attention today are those with a direct action on the tumor by inhibiting ACTH secretion: somatostatin analogues (pasireotide), dopamine agonists (cabergoline), PPAR-γ, and retinoic acid. A special review is made of the available clinical trials with pasireotide and cabergoline.

Topics: Adenoma; Adrenocorticotropic Hormone; Animals; Cabergoline; Clinical Trials as Topic; Clinical Trials, Phase III as Topic; Drug Evaluation, Preclinical; Ergolines; Etomidate; Humans; Hydrocortisone; Imidazoles; Ketoconazole; Metyrapone; Mice; Mifepristone; Mitotane; Multicenter Studies as Topic; Pituitary ACTH Hypersecretion; Pituitary Neoplasms; PPAR gamma; Pyridines; Rats; Somatostatin; Therapies, Investigational; Tretinoin

Acromegaly is a rare disease with typical clinical manifestations. Untreated acromegaly carries a 2-4-fold increase in mortality in long-term outcome. The goal of treatment is double, including biochemical control of the disease (normalization of serum IGF1 levels compared to age and gender matched controls, GH levels below 1 ng/ml after oral glucose load, or random GH below 2.5 ng/ml) and control of the tumor mass. The therapeutic modalities currently available for the treatment of acromegaly are: surgery, medical therapy, radiation therapy and their combinations. The cornerstones of medical therapy in acromegaly are the somatostatin receptor ligands due to their effectiveness in controlling GH excess in 60-70 % of patients and their beneficial effects on tumor volume. Somatostatin analogues have an established role as adjuvant therapy after non-curative surgery, and evidence suggests their use as primary treatment for selected patients. The long-term use of somatostatin receptor ligands is safe and they are well tolerated. Future medical therapy consists of pasireotide, a novel, universal somatostatin receptor agonist, and a new class of drugs named dopastatins. The latter so-called chimeric molecules have strong affinity for somatostatin receptors and dopamine-2 receptors, resulting in a more effective blocking of GH secretion, according to preliminary data. The authors of this paper review the current medical therapy of acromegaly, focusing on the role of somatostatin receptor ligands.

Topics: Acromegaly; Adenoma; Case-Control Studies; Dopamine; Drug Administration Schedule; Female; Human Growth Hormone; Humans; Ligands; Male; Pituitary Neoplasms; Receptors, Somatostatin; Somatostatin

Acromegaly is a multisystem disease resulting from chronic exposure to supraphysiological levels of growth hormone (GH), and is associated with significant morbidity and excess mortality. The etiology is almost exclusively an underlying pituitary adenoma. Current therapeutic interventions include surgery, radiotherapy, and medical therapy.. Despite surgery, around 50% of patients fail to achieve the biochemical targets shown to correlate with normalization of mortality rates. Radiotherapy is efficacious in controlling tumor growth and GH secretion; still, achievement of biochemical targets may take up to a decade and a number of safety issues have been raised with this treatment modality. Medical therapy, therefore, has an important role as adjuvant therapy in patients who fail to achieve control with surgery, or while awaiting the effects of radiotherapy to be realized. Furthermore, medical therapy is increasingly being used as primary therapy. Current medical therapies include dopaminergic agonists, somatostatin analogs, and GH receptor (GHR) antagonists. Dopaminergic agonists achieve biochemical targets in up to 30% of patients, and somatostatin analogs in around 60%. The currently available GHR antagonist pegvisomant effectively controls insulin-like growth factor-I levels in over 90% of patients; however, it has no effect on the tumor itself and has considerable financial implications. Research into optimizing the somatostatin and dopaminergic systems has led to promising advances in agonist development. Moieties with selectivity for various combinations of somatostatin receptor subtype receptors have been examined, along with molecules that additionally show high affinity for the dopaminergic D2 receptor. Of the molecules studied in vitro, only pasireotide (SOM230) and BIM-23A760 are currently undergoing further development. Other innovations to improve convenience of currently available drugs are also being investigated.. Significant advances in under standing of the somatostatin and dopaminergic system have aided drug development. This may lead to new clinically available therapies enabling control of acromegaly in a larger proportion of patients, and at an earlier stage in their disease management.

Topics: Acromegaly; Adenoma; Combined Modality Therapy; Dopamine; Dopamine Agonists; Drug Discovery; Drug Evaluation; Human Growth Hormone; Humans; Insulin-Like Growth Factor Binding Protein 1; Pituitary Neoplasms; Radiotherapy; Receptors, Dopamine D2; Receptors, Somatotropin; Somatostatin; Treatment Outcome

According to epidemiological studies, the prevalence of pituitary adenomas is 16.5% and the majority of them are "incidentalomas". The symptoms of pituitary disorders are often non-specific; disturbances of pituitary function, compression symptoms, hypophysis apoplexy or accidental findings may help the diagnosis. The hormonal evaluation of pituitary adenomas is different from the algorithm used in the disorders of peripheral endocrine organs. The first-line therapy of prolactinomas are the dopamine agonists, and the aims of the treatment are to normalize the prolactin level, restore fertility in child-bearing age, decrease tumor mass, save or improve the residual pituitary function and inhibit the relapse of the disease. The available dopamine agonists in Hungary are bromocriptine and quinagolide. In case of tumors with good therapeutic response, medical therapy can be withdrawn after 3-5 years; hyperprolactinemia will not recur in 2/3 of these patients. Neurosurgery is the primary therapy of GH-, ACTH-, TSH-producing and inactive adenomas. In the last decades, significant improvement has been reached in surgical procedures, resulting in low mortality rates. Acromegalic patients with unresectable tumors have a great benefit from somatostatin analog treatment. The growth hormone receptor antagonist pegvisomant is the newest modality for the treatment of acromegaly. The medical therapy of Cushing's disease is still based on the inhibition of steroid production. A new, promising somatostatin analog, pasireotide is evaluated in clinical trials. The rare TSH-producing tumor can respond to both dopamine agonist and somatostatin analog therapy. The application of conventional radiotherapy has decreased; radiotherapy is mainly used in the treatment of invasive, incurable or malignant tumors. Further studies are needed to elucidate the exact role of radiosurgery and fractionated stereotaxic irradiation in the treatment of pituitary tumors.

Topics: Acromegaly; ACTH-Secreting Pituitary Adenoma; Adenoma; Adrenocorticotropic Hormone; Aminoquinolines; Bromocriptine; Cushing Syndrome; Dopamine Agonists; Female; Growth Hormone-Secreting Pituitary Adenoma; Human Growth Hormone; Humans; Hypophysectomy; Incidental Findings; Male; Pituitary Hormones; Pituitary Neoplasms; Pregnancy; Pregnancy Complications, Neoplastic; Prolactinoma; Radiosurgery; Receptors, Somatotropin; Somatostatin; Thyrotropin

For a considerable time, somatostatin analogs have been the medical therapy of choice for the treatment of acromegaly. In addition to their well-established use as an adjunctive therapy, primary therapy with somatostatin analogs has been investigated in recent years. Adjunctive therapy with octreotide long-acting release over 12-36 months allowed for sufficient GH suppression in 47-75% of patients (average 56%), as summarized by Freda. IGF-I was normalized in 41-75% (average 66%). Tumor shrinkage was observed in about 30% of patients, with a mass reduction of 20-50% in most cases. A bias in some of these studies cannot be excluded, with patients being selected on base of their octreotide responsiveness. Regarding primary treatment of acromegaly with long-acting somatostatin analogs, our review of five published studies, that applied stringent criteria for the analysis of biochemical normalization, revealed sufficient GH and IGF-I suppression in 68% and 61% of the 107 patients included, respectively, and significant tumor reduction in 51%. Therefore, somatostatin analogs represent an effective medical therapy in a significant proportion of patients with acromegaly. Resistance to currently available somatostatin analogs in some patients may be due to reduced density of SSTR2 on the tumors of these patients. New somatostatin receptor ligands with extended binding profile may have even higher efficacy in the biochemical control of patients with acromegaly.

Topics: Acromegaly; Adenoma; Animals; Human Growth Hormone; Humans; Insulin-Like Growth Factor I; Octreotide; Peptides, Cyclic; Pituitary Neoplasms; Receptors, Somatostatin; Somatostatin

Currently available medical treatment of acromegaly includes dopamine agonists, slow release formulation of somatostatin analogues and pegvisomant, a GH-receptor antagonist. Dopamine agonists are well tolerated, not expensive but poorly effective. Somatostatin analogues are highly effective in 60-70% of patients based on the receptor profile of individual tumors. Pegvisomant is reported to normalize IGF-I levels in nearly the totality of the patients, but is devoted of tumor shrinking effect. In a preliminary study in patients with acromegaly, a new somatostatin analogue with affinity to four of the five somatostatin receptors (SOM230) was shown to be similarly effective as octreotide in some patients and more effective than octreotide in other patients. Moreover, new molecules with selective activity on the somatostatin receptor type 2, or 5, or 1 have been reported in vitro to strongly suppress GH secretion. Other new promising alternatives are the chimeric compounds with both somatostatin receptor and dopamine receptor binding. These drugs have been also shown to possess strong GH-inhibitory activity in primary cultures from GH-secreting adenomas. These drugs are the future perspectives in the treatment of patients with GH-secreting or GH/PRL-secreting tumors.

Topics: Acromegaly; Adenoma; Adult; Animals; Delayed-Action Preparations; Dopamine Agonists; Female; Human Growth Hormone; Humans; Insulin-Like Growth Factor I; Male; Middle Aged; Octreotide; Pituitary Neoplasms; Receptors, Somatostatin; Receptors, Somatotropin; Somatostatin

In recent years, somatostatin analogs have been proposed and used in the diagnosis and therapy in Cushing's syndrome (CS). In these last few years, the potential therapeutic effects of somatostain analogs have been studied in different aspects of CS. The strong expression of somatostatin receptors (SSTR) type 5 in human corticotroph cells and the demonstrated efficacy of SOM230, a novel multi-ligand somatostatin analog, in inhibiting ACTH release in vitro suggest that this new drug may be effective in the treatment of ACTH hypersecretion. Very preliminary in vivo results suggest that SOM230 could be a promising drug in medical therapy for patients with Cushing's disease (CD). Prolonged treatment and more data will be needed in order to evaluate its long-term therapeutic efficacy.

Topics: Adenoma; Adrenal Gland Neoplasms; Adrenocorticotropic Hormone; Animals; Cushing Syndrome; Humans; Hydrocortisone; Octreotide; Pituitary Neoplasms; Receptors, Somatostatin; Somatostatin

OBJECTIVE To evaluate clinical signs, endocrine test results, and pituitary tumor size for dogs with medically managed pituitary-dependent hyperadrenocorticism (PDH) and macroadenoma following 6 months of concurrent treatment with pasireotide. DESIGN Prospective case series. ANIMALS 9 client-owned dogs with PDH and macroadenoma in which PDH had been successfully managed with adrenal-directed treatment (trilostane or mitotane). PROCEDURES Dogs were given pasireotide (0.03 mg/kg [0.014 mg/lb], SC, q 12 h) for 6 months, while adrenal-directed treatment was continued. Physical examination, basic clinicopathologic testing, ACTH stimulation testing, and plasma ACTH concentration measurement were performed before (baseline) and 3 and 6 months after treatment began. Measurements of pituitary gland volume and pituitary gland-to-brain ratio were performed via MRI at baseline and 6 months after treatment began. RESULTS No dog developed neurologic abnormalities or signs of adverse effects during the study period. No differences from baseline were identified in clinicopathologic values, ACTH stimulation test results, or plasma ACTH concentration at the 3- or 6-month assessment points. After 6 months of pasireotide treatment, 6 dogs had decreases in MRI-measured values, and 3 had increases. CONCLUSIONS AND CLINICAL RELEVANCE Pasireotide as administered in this study had no noted adverse effects on dogs with PDH and macroadenoma successfully managed with standard treatment. Placebo-controlled, randomized studies are needed to determine whether pasireotide protects from the development of neurologic signs or improves outcome in dogs with pituitary macroadenomas.

Topics: Adenoma; Adrenocortical Hyperfunction; Animals; Dog Diseases; Dogs; Female; Hormones; Male; Pituitary ACTH Hypersecretion; Pituitary Neoplasms; Prospective Studies; Somatostatin

Pasireotide, a multi-somatostatin receptor (SSTR)-ligand with high affinity for SSTR. A retrospective multicenter study investigating the efficacy and safety of long-acting (LAR) pasireotide treatment in 35 patients (20 males) with active acromegaly (28 macroadenomas).. Mean baseline insulin-like growth factor-1 (IGF-1) at diagnosis was 3.1 ± 1.3 × ULN. All but five patients have undergone pituitary surgery and six received sellar radiotherapy. All remained with active acromegaly despite first-generation somatostatin analogue (SSA) treatment. Immediately before pasireotide-LAR initiation, eighteen patients were under SSA monotherapy and one with pegvisomant. The remaining patients received combination therapy with SSA and pegvisomant, n = 9 (two received cabergoline also); SSA and cabergoline, n = 4; pegvisomant and cabergoline, n = 1. Two were untreated. Mean IGF-1 was 1.76 ± 0.9 ULN before pasireotide. Pasireotide-LAR starting dose was 40 mg/4 weeks in most patients. IGF-1 normalized in 19 patients, IGF-1 between 1-1.2 × ULN was reached in five, and in additional two patients IGF-1 was significantly suppressed. No effect was seen in nine patients. Pasireotide dose was reduced by 20 mg in six patients with excellent response, with preserved IGF-1 control in five. Severe headaches in six patients disappeared or improved with pasireotide. Side effects consisted of symptomatic cholelithiasis in one patient and deterioration of glucose control in 22 patients, requiring initiation or intensification of antidiabetic treatment in seventeen. One patient developed diabetic ketoacidosis.. In the real-life scenario ~54% of patients with acromegaly resistant to first-generation SSA, may normalize IGF-1 with pasireotide; however, 63% experienced glucose control deterioration.

Topics: Acromegaly; Adenoma; Adult; Delayed-Action Preparations; Drug Resistance, Neoplasm; Female; Growth Hormone-Secreting Pituitary Adenoma; Humans; Male; Middle Aged; Retrospective Studies; Somatostatin; Treatment Failure; Treatment Outcome

Many patients with acromegaly do not achieve biochemical control with first-generation somatostatin analogues. A large, multicenter, randomized, Phase III core study demonstrated that pasireotide LAR had significantly superior efficacy over octreotide LAR. This analysis explores the efficacy and safety of switching therapeutic arms in inadequately controlled patients during a 12-month crossover extension.. Patients with inadequate biochemical control (GH ≥2.5 μg/L and/or IGF-1 > ULN) at end of core study (month 12) were eligible to switch to pasireotide LAR 40 mg/28 days (n = 81) or octreotide LAR 20 mg/28 days (n = 38). One dose escalation to pasireotide LAR 60 mg/28 days or octreotide LAR 30 mg/28 days was permitted, but not mandatory, at month 17 or 20.. Twelve months after crossover, 17.3 % of pasireotide LAR and 0 % of octreotide LAR patients achieved GH <2.5 μg/L and normal IGF-1 (main outcome measure); 27.2 and 5.3 % of pasireotide LAR and octreotide LAR patients achieved normal IGF-1, respectively; 44.4 and 23.7 % of pasireotide LAR and octreotide LAR patients achieved GH <2.5 μg/L, respectively. Mean (±SD) tumor volume further decreased from the end of the core study by 25 % (±25) and 18 % (±28); 54.3 % of pasireotide LAR and 42.3 % of octreotide LAR patients achieved significant (≥20 %) tumor volume reduction during the extension. The safety profile of pasireotide LAR was similar to that of octreotide LAR, with the exception of the frequency and degree of hyperglycemia-related adverse events.. Pasireotide LAR is a promising treatment option for patients with acromegaly inadequately controlled with the first-generation somatostatin analogue octreotide LAR.. clinicaltrials.gov, NCT00600886 . Registered 14 January 2008.

Topics: Acromegaly; Adenoma; Adult; Aged; Aged, 80 and over; Biomarkers, Tumor; Cross-Over Studies; Drug Substitution; Female; Growth Hormone-Secreting Pituitary Adenoma; Human Growth Hormone; Humans; Insulin-Like Growth Factor I; Male; Middle Aged; Octreotide; Somatostatin; Treatment Outcome; Tumor Burden; Young Adult

A large, randomized, double-blind, Phase III core study demonstrated that pasireotide LAR was significantly superior to octreotide LAR at providing GH <2.5 μg/L and normalized IGF-1 after 12 months' treatment in patients with acromegaly. We report the efficacy and safety of pasireotide LAR and octreotide LAR after up to 26 months' treatment.. Patients with GH <2.5 μg/L and IGF-1 ≤1× ULN at month 12, or patients considered to be experiencing clinical benefit, were eligible to continue receiving their randomized therapy in the extension. Efficacy and safety in the pasireotide LAR and octreotide LAR groups were evaluated for up to 26 months.. Overall, 120 patients who completed the core study continued receiving pasireotide LAR (n = 74) or octreotide LAR (n = 46) in the extension. At month 25, biochemical control (GH <2.5 μg/L and normal IGF-1) was achieved by 48.6% (36/74) and 45.7% (21/46) of patients in the pasireotide LAR and octreotide LAR arms [60.8% (45/74) and 52.2% (24/46) when including patients with IGF-1 < LLN], respectively. In total, 74.7% of pasireotide LAR and 71.6% of octreotide LAR patients had tumor volume decrease ≥20% from baseline to month 26. Most AEs were mild or moderate. Hyperglycemia-related AEs were seen in 62.9 and 25.0% of pasireotide LAR and octreotide LAR patients, respectively. No new safety signals were observed in the extension compared with the core study.. GH and IGF-1 suppression is maintained for up to 25 months during pasireotide LAR treatment. The safety profile of pasireotide LAR is typical of a somatostatin analogue, except for the frequency and degree of hyperglycemia.

Topics: Acromegaly; Adenoma; Adult; Aged; Biomarkers, Tumor; Blood Glucose; Brazil; Double-Blind Method; Europe; Female; Growth Hormone-Secreting Pituitary Adenoma; Human Growth Hormone; Humans; Hyperglycemia; Insulin-Like Growth Factor I; Male; Middle Aged; North America; Remission Induction; Somatostatin; Time Factors; Treatment Outcome; Young Adult

Pasireotide has a broader somatostatin receptor binding profile than other somatostatin analogues. A 16-week, Phase II trial showed that pasireotide may be an effective treatment for acromegaly. An extension to this trial assessed the long-term efficacy and safety of pasireotide. This study was an open-label, single-arm, open-ended extension study (primary efficacy and safety evaluated at month 6). Patients could enter the extension if they achieved biochemical control (GH ≤ 2.5 μg/L and normal IGF-1) or showed clinically relevant improvements during the core study. Thirty of the 60 patients who received pasireotide (200-900 μg bid) in the core study entered the extension. At extension month 6, of the 26 evaluable patients, six were biochemically controlled, of whom five had achieved control during the core study. Normal IGF-1 was achieved by 13/26 patients and GH ≤ 2.5 μg/L by 12/26 at month 6. Nine patients received pasireotide for ≥24 months in the extension; three who were biochemically controlled at month 24 had achieved control during the core study. Of 29 patients with MRI data, nine had significant (≥20%) tumor volume reduction during the core study; an additional eight had significant reduction during the extension. The most common adverse events were transient gastrointestinal disturbances; hyperglycemia-related events occurred in 14 patients. Twenty patients had fasting plasma glucose shifted to a higher category during the extension. However, last available glucose measurements were normal for 17 patients. Pasireotide has the potential to be an effective, long-term medical treatment for acromegaly, providing sustained biochemical control and significant reductions in tumor volume.

Topics: Acromegaly; Adenoma; Adolescent; Adult; Aged; Aged, 80 and over; Female; Growth Hormone; Growth Hormone-Secreting Pituitary Adenoma; Humans; Injections, Subcutaneous; Insulin-Like Growth Factor I; Magnetic Resonance Imaging; Male; Middle Aged; Pituitary Neoplasms; Somatostatin; Treatment Outcome; Tumor Burden; Young Adult

Biochemical control reduces morbidity and increases life expectancy in patients with acromegaly. With current medical therapies, including the gold standard octreotide long-acting-release (LAR), many patients do not achieve biochemical control.. Our objective was to demonstrate the superiority of pasireotide LAR over octreotide LAR in medically naive patients with acromegaly.. We conducted a prospective, randomized, double-blind study at 84 sites in 27 countries.. A total of 358 patients with medically naive acromegaly (GH >5 μg/L or GH nadir ≥1 μg/L after an oral glucose tolerance test (OGTT) and IGF-1 above the upper limit of normal) were enrolled. Patients either had previous pituitary surgery but no medical treatment or were de novo with a visible pituitary adenoma on magnetic resonance imaging.. Patients received pasireotide LAR 40 mg/28 days (n = 176) or octreotide LAR 20 mg/28 days (n = 182) for 12 months. At months 3 and 7, titration to pasireotide LAR 60 mg or octreotide LAR 30 mg was permitted, but not mandatory, if GH ≥2.5μg/L and/or IGF-1 was above the upper limit of normal.. The main outcome measure was the proportion of patients in each treatment arm with biochemical control (GH <2.5 μg/L and normal IGF-1) at month 12.. Biochemical control was achieved by significantly more pasireotide LAR patients than octreotide LAR patients (31.3% vs 19.2%; P = .007; 35.8% vs 20.9% when including patients with IGF-1 below the lower normal limit). In pasireotide LAR and octreotide LAR patients, respectively, 38.6% and 23.6% (P = .002) achieved normal IGF-1, and 48.3% and 51.6% achieved GH <2.5 μg/L. 31.0% of pasireotide LAR and 22.2% of octreotide LAR patients who did not achieve biochemical control did not receive the recommended dose increase. Hyperglycemia-related adverse events were more common with pasireotide LAR (57.3% vs 21.7%).. Pasireotide LAR demonstrated superior efficacy over octreotide LAR and is a viable new treatment option for acromegaly.

Topics: Acromegaly; Adenoma; Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Female; Growth Hormone-Secreting Pituitary Adenoma; Humans; Male; Middle Aged; Octreotide; Somatostatin; Therapeutic Equivalency; Young Adult

N-of-1 trials can serve as useful tools in managing rare disease. We describe a patient presenting with a typical clinical picture of Cushing's Syndrome (CS). Further testing was diagnostic of ectopic Adrenocorticotropic Hormone (ACTH) secretion, but its origin remained occult. The patient was offered treatment with daily pasireotide at very low doses (300 mg bid), which resulted in clinical and biochemical control for a period of 5 years, when a pulmonary typical carcinoid was diagnosed and dissected. During the pharmacological treatment period, pasireotide was tentatively discontinued twice, with immediate flare of symptoms and biochemical markers, followed by remission after drug reinitiation. This is the first report of clinical and biochemical remission of an ectopic CS (ECS) with pasireotide used as first line treatment, in a low-grade lung carcinoid, for a prolonged period of 5 years. In conclusion, the burden of high morbidity caused by hypercortisolism can be effectively mitigated with appropriate pharmacological treatment, in patients with occult tumors. Pasireotide may lead to complete and sustained remission of hypercortisolism, until surgical therapy is feasible. The expression of SSTR2 from typical carcinoids may be critical in allowing the use of very low drug doses for achieving disease control, while minimizing the risk of adverse events.

Topics: Adenoma; Adrenocorticotropic Hormone; Carcinoid Tumor; Cushing Syndrome; Humans; Lung Neoplasms; Neuroendocrine Tumors

Acromegaly is a rare, chronic, debilitating disorder caused by prolonged hypersecretion of growth hormone (GH) and overproduction of insulin-like growth factor I (IGF-I). Medical therapies, including the somatostatin receptor ligand (SRL) pasireotide, are frequently used to restore biochemical control.. As patients often receive therapy over prolonged periods, long-term data from real-life settings are needed.. A retrospective analysis was performed using a prospectively maintained database of all patients with acromegaly from our primary care center who were enrolled in clinical studies with pasireotide (first visit November 2008). The main outcome measures were safety and biochemical control (age-adjusted IGF-I ≤ upper limit of normal).. Patients (n = 50) entered 4 parental studies and 30 continued in the rollover; at data cutoff (June 2022), 27 were still receiving pasireotide. Overall, median (range) exposure was 58 (3-137) months. Normal IGF-I was achieved in 54%, and acromegaly symptoms and quality of life were improved with treatment. No predictors of pasireotide response were identified; however, controlled patients had smaller tumors and lower GH at baseline. Tumor volume reduction occurred in 63% of evaluable patients (n = 10/16). Most patients presented hyperglycemic events, including 63.2% of patients with normal glucose before treatment. Older patients and those with higher IGF-I, glucose, and HbA1c at baseline had higher glucose and HbA1c during pasireotide treatment.. Pasireotide provided clinical benefit and was well tolerated for more than 11 years of treatment in acromegaly patients, most of whom were resistant to first-generation SRLs.

Topics: Acromegaly; Adenoma; Glucose; Glycated Hemoglobin; Growth Hormone; Human Growth Hormone; Humans; Insulin-Like Growth Factor I; Quality of Life; Retrospective Studies; Treatment Outcome

Hyperintensity signal in T2-weighted magnetic resonance imaging (MRI) has been related to better therapeutic response during pasireotide treatment in acromegaly. The aim of the study was to evaluate T2 MRI signal intensity and its relation with pasireotide therapeutic effectiveness in real-life clinical practice.. Retrospective multicentre study including acromegaly patients treated with pasireotide. Adenoma T2-weighted MRI signal at diagnosis was qualitatively classified as iso-hyperintense or hypointense. Insulin-like growth factor (IGF-I), growth hormone (GH) and tumour volume reduction were assessed after 6 and 12 months of treatment and its effectiveness evaluated according to baseline MRI signal. Hormonal response was considered 'complete' when normalization of IGF-I levels was achieved. Significant tumour shrinkage was defined as a volume reduction of ≥25% from baseline.. Eighty-one patients were included (48% women, 50 ± 1.5 years); 93% had previously received somatostatin receptor ligands (SRLs) treatment. MRI signal was hypointense in 25 (31%) and hyperintense in 56 (69%) cases. At 12 months of follow-up, 42/73 cases (58%) showed normalization of IGF-I and 37% both GH and IGF-I. MRI signal intensity was not associated with hormonal control. 19/51 cases (37%) presented a significant tumour volume shrinkage, 16 (41%) from the hyperintense group and 3 (25%) from the hypointense.. T2-signal hyperintensity was more frequently observed in pasireotide treated patients. Almost 60% of SRLs resistant patients showed a complete normalization of IGF-I after 1 year of pasireotide treatment, regardless of the MRI signal. There was also no difference in the percentage tumour shrinkage over basal residual volume between the two groups.

Topics: Acromegaly; Adenoma; Female; Human Growth Hormone; Humans; Insulin-Like Growth Factor I; Magnetic Resonance Imaging; Male; Octreotide; Treatment Outcome

Somatostatin analogues (SSAs) have been used for the treatment of acromegaly for several decades. However, a unified conclusion on the duration of SSAs therapy or the possibility of medication withdrawal is still missing. We aimed to report a case of acromegaly cured by pasireotide long-acting release (PAS-LAR) and provide some information on the withdrawal of SSAs after stable regression in acromegalic patients.. A 55-year-old male patient, who was diagnosed with acromegaly and refused surgery and received PAS-LAR as initial treatment, had maintained stability for ten years under the regular treatment with PAS-LAR. The pituitary microadenoma was also decreased during the treatment. After the PAS-LAR discontinuation for 21 months, no evidence of biochemical or clinical recurrence was found in this patient.. The use of PAS-LAR in a subset of naive-treatment patients is promising to induce long-term regression. A subgroup of patients with mild and well-controlled acromegaly might hope for perpetual remission after the withdrawal of medication.

Topics: Acromegaly; Adenoma; Growth Hormone-Secreting Pituitary Adenoma; Human Growth Hormone; Humans; Insulin-Like Growth Factor I; Male; Middle Aged; Octreotide; Somatostatin; Treatment Outcome

Topics: Acromegaly; Adenoma; Growth Hormone-Secreting Pituitary Adenoma; Humans; Somatostatin

First-generation somatostatin analogs, octreotide (OCT) and lanreotide, are the cornerstone for the medical treatment of growth hormone (GH)-secreting pituitary tumors. A new multireceptor analog, such as pasireotide (PAS), showed better activity than OCT in long-term treatment of patients with acromegaly, but modulation of intracellular key processes is still unclear in vitro. In this study, we evaluated the antitumor activity of OCT and PAS in two GH-secreting pituitary tumor cell lines, GH3 and GH4C1, after a long-term incubation.. The effects of PAS and OCT on the cell viability, cell cycle, apoptosis, GH secretion, and tumor-induced angiogenesis have been evaluated through a colorimetric method (MTS Assay), DNA flow cytometry with propidium iodide, and Annexin V-FITC/propidium iodide staining, ELISA assay and zebrafish platform, respectively.. PAS showed a more potent antitumor activity compared to OCT in GH3 cell line exerted through inhibition of cell viability, perturbation of cell cycle progression, and induction of apoptosis after 6 days of incubation. A concomitant decrease in GH secretion has been observed after 2 days of incubation only with PAS. No effect on tumor-induced angiogenesis has been reported after treatment with OCT or PAS in zebrafish/tumor xenograft model.. Long-term incubation with PAS showed a more potent antitumor activity than that reported after OCT in GH3 cells, mainly modulated by a cell cycle perturbation and a relevant induction in apoptosis.

Topics: Adenoma; Animals; Animals, Genetically Modified; Apoptosis; Embryo, Nonmammalian; Growth Hormone-Secreting Pituitary Adenoma; Octreotide; Peptides, Cyclic; Rats; Somatostatin; Somatotrophs; Time Factors; Tumor Cells, Cultured; Zebrafish

The treatment of acromegaly resistant to first-generation somatostatin receptor ligands (SRLs) is often difficult. Pegvisomant and Pasireotide LAR are mostly used in these subset of patients, as second line therapies. Choice of the type of second line therapies is difficult, since predictors of response are still unclear, impairing personalized therapy. We aimed to investigate predictors of response to Pegvisomant and Pasireotide LAR.. Seventy-four acromegaly patients entered this observational, cross-sectional and retrospective study if (i) resistant to high dose first-generation SRLs and (ii) treated with Pegvisomant and Pasireotide LAR for at least 12 consecutive months. Patients treated with radiotherapy in the previous 10 years were excluded.. Fourty-one patients were treated with Pegvisomant and 33 with Pasireotide LAR. At the end of the study, acromegaly was controlled in 35 patients treated with Pegvisomant (85.4%) and in 23 treated with Pasireotide LAR (69.7%). In this cohort, a poor Pegvisomant response and a shorter progression free time were observed in cases with tumor extension to the third ventricle (P = 0.004, HR: 1.6, 95%CI: 1.2-4.6), with a Ki67-Li >4% (P = 0.004, HR: 3.49, 95%CI: 1.4-4.0) and with pre-treatment IGF-I >3.3×ULN (P=0.03, HR: 1.3, 95%CI: 1.1-6.0). A poor Pasireotide LAR response and a shorter progression free time were observed in cases with tumor extension to the third ventricle (P=0.025, HR: 1.6 95%CI: 1.4-3.4), pre-treatment IGF-I >2.3×ULN (P=0.049, HR: 2.4, 95%CI: 1.4-8.0), absent/low SST5 membranous expression (P=0.023 HR: 4.56 95%CI: 1.3-6.4) and in patients carried the d3-delated GHR isoform (P=0.005, HR: 11.37, 95%CI: 1.3-20.0).. Molecular and clinical biomarkers can be useful in predicting the responsiveness to Pegvisomant and Pasireotide LAR.

Topics: Acromegaly; Adenoma; Adolescent; Adult; Aged; Chemotherapy, Adjuvant; Cross-Sectional Studies; Delayed-Action Preparations; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Growth Hormone-Secreting Pituitary Adenoma; Human Growth Hormone; Humans; Insulin-Like Growth Factor I; Male; Middle Aged; Prognosis; Retrospective Studies; Somatostatin; Treatment Outcome; Young Adult

T2-signal intensity and somatostatin (SST) receptor expression are recognized predictors of therapy response in acromegaly. We investigated the relationship between these predictors and the hormonal and tumoral responses to long-acting pasireotide (PAS-LAR) therapy, which were also compared with responsiveness to first-generation somatostatin receptor ligands (SRLs).. The PAPE study is a cohort study.. We included 45 acromegaly patients initially receiving SRLs, followed by combination therapy with pegvisomant, and finally PAS-LAR. We assessed tumor volume reduction (≥25% from baseline), IGF-1 levels (expressed as the upper limit of normal), and T2-weighted MRI signal and SST receptor expression of the adenoma.. Patients with significant tumor shrinkage during PAS-LAR showed higher IGF-1 levels during PAS-LAR (mean (S.D.): 1.36 (0.53) vs 0.93 (0.43), P = 0.020), less IGF-1 reduction after first-generation SRLs (mean (S.D.): 0.55 (0.71) vs 1.25 (1.07), P = 0.028), and lower SST2 receptor expression (median (IQR): 2.0 (1.0-6.0) vs 12.0 (7.5-12.0), P = 0.040). Overall, T2-signal intensity ratio was increased compared with baseline (mean (S.D.): 1.39 (0.56) vs 1.25 (0.52), P = 0.017) and a higher T2-signal was associated with lower IGF-1 levels during PAS-LAR (β: -0.29, 95% CI: -0.56 to -0.01, P = 0.045). A subset of PAS-LAR treated patients with increased T2-signal intensity achieved greater reduction of IGF-1 (mean (S.D.): 0.80 (0.60) vs 0.45 (0.39), P = 0.016).. Patients unresponsive to SRLs with a lower SST2 receptor expression are more prone to achieve tumor shrinkage during PAS-LAR. Surprisingly, tumor shrinkage is not accompanied by a biochemical response, which is accompanied with a higher T2-signal intensity.

Topics: Acromegaly; Adenoma; Adult; Cohort Studies; Delayed-Action Preparations; Drug Therapy, Combination; Female; Growth Hormone-Secreting Pituitary Adenoma; Hormones; Human Growth Hormone; Humans; Insulin-Like Growth Factor I; Ligands; Magnetic Resonance Imaging; Male; Middle Aged; Receptors, Somatostatin; Somatostatin; Treatment Outcome; Tumor Burden

Epidemiological data of rare diseases are important for understanding disease burden, improving treatment, and planning healthcare systems. However, those of acromegaly in Japan are not well known. Our study aimed to describe the prevalence, incidence, prediagnostic comorbidities, and treatment patterns of patients with acromegaly in Japan. Using the National Database of Health Insurance Claims and Specific Health Checkups of Japan, we retrospectively identified 12,713 patients with acromegaly aged ≥20 years between January 2014 and December 2017 (the prevalence cohort), 2,552 newly diagnosed patients between January 2013 and December 2017 (the incidence and comorbidity cohort), and 2,125 patients enrolled in the database at least 365 days after the diagnosis (the treatment-pattern cohort). The average annual prevalence in 2015-2017 was 9.2 cases per 100,000 in the prevalence cohort, and the average annual incidence in 2013-2017 was 0.49 cases per 100,000 in the incidence and comorbidity cohort. The most common prediagnostic comorbidities included hypertension (43%), diabetes (37%), and hyperlipidemia (27%). In the treatment-pattern cohort, 54% and 45% of patients received surgery and medical treatment as the primary treatment, respectively. Between the first surgery and 365 days after diagnosis, 15% of the patients in this cohort received medical treatment as the secondary treatment, mostly with somatostatin analogs (83%). Of the 1,569 patients who underwent surgery, 29% received medical treatment before surgery. The prevalence and incidence of acromegaly in Japan were similar to those in other countries. This epidemiological study provides the basis for better management of acromegaly nationwide.

Topics: Acromegaly; Adenoma; Adult; Aged; Antineoplastic Agents, Hormonal; Bromocriptine; Cabergoline; Comorbidity; Dopamine Agonists; Female; Growth Hormone-Secreting Pituitary Adenoma; Human Growth Hormone; Humans; Hyperlipidemias; Hypertension; Incidence; Japan; Male; Middle Aged; Neurosurgical Procedures; Octreotide; Peptides, Cyclic; Prevalence; Radiosurgery; Radiotherapy, Intensity-Modulated; Retrospective Studies; Somatostatin; Young Adult

Topics: Acromegaly; Adenoma; Aged; Humans; Magnetic Resonance Imaging; Male; Pituitary Gland; Pituitary Neoplasms; Somatostatin; Treatment Outcome

Topics: Acromegaly; Adenoma; Adult; Aged; Aged, 80 and over; Female; Follow-Up Studies; Growth Hormone-Secreting Pituitary Adenoma; Hormones; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Somatostatin

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.

Topics: Adenoma; Dopamine Agonists; Drug Resistance, Neoplasm; Female; Hormones; Humans; Middle Aged; Neoplasm Invasiveness; Pituitary Neoplasms; Prolactinoma; Somatostatin; Treatment Outcome; Tumor Burden

The treatment of acromegaly resistant to first- and second-line therapies can be extremely challenging.. We have described six patients who were successfully treated with a combination therapy of pasireotide and pegvisomant and compared them with a control group of patients resistant to conventional somatostatin analogs (SSAs), whose disease was controlled with other treatment, such as pasireotide (as monotherapy) or pegvisomant (as monotherapy or combined with conventional SSAs).. In these six patients, acromegaly was controlled with combined pasireotide and pegvisomant treatment after failure of all other treatments. Compared with the 49 patients in the control group, these six patients had giant and invasive pituitary adenomas (at both the cavernous sinus and other structures). Although not statistically significant, higher growth hormone levels, more elevated Ki-67 expression, greater somatostatin receptor (SSTR) subtype 5 expression, and lower SSTR subtype 2 expression at the diagnosis of acromegaly were detected in patients receiving combination treatment with pasireotide and pegvisomant compared with the control group.. Our data have reinforced the importance of personalized treatment of patients with acromegaly according to the clinical, biochemical, molecular, and morphological disease markers and suggest that combined treatment with pasireotide and pegvisomant can induce disease control in tumors with low SSTR2 expression, resistant to conventional SSAs (alone or combined with pegvisomant) and to new-generation SSAs alone (pasireotide).

Topics: Acromegaly; Adenoma; Adult; Drug Therapy, Combination; Female; Hormones; Human Growth Hormone; Humans; Longitudinal Studies; Male; Middle Aged; Pituitary Neoplasms; Retrospective Studies; Somatostatin; Treatment Outcome; Young Adult

Topics: Acromegaly; Adenoma; Humans; Pituitary Neoplasms; Somatostatin

Topics: Acromegaly; Adenoma; Humans; Pituitary Neoplasms; Somatostatin

Topics: Acromegaly; Adenoma; Adult; Aged; Female; Hormones; Humans; Male; Middle Aged; Pituitary Neoplasms; Precision Medicine; Somatostatin; Tumor Burden

An 8-year-old castrated male border terrier dog was diagnosed with acromegaly resulting from a growth hormone secreting pituitary tumor. Sixteen daily fractions of radiation therapy were delivered followed, approximately 1 year later, by administration of pasireotide. The aforementioned treatment was considered effective and should be further evaluated in similar cases.

Topics: Acromegaly; Adenoma; Animals; Diabetes Mellitus; Dog Diseases; Dogs; Growth Hormone-Secreting Pituitary Adenoma; Hormones; Male; Somatostatin; Treatment Outcome

First-generation somatostatin analogs (SSAs), such as octreotide (OCT), are the first line medical therapy for acromegaly. Pasireotide (PAS), a newly developed SSA, has shown promising results in the treatment of acromegaly.. To compare the antisecretory effect of OCT and PAS in primary cultures of growth hormone (GH)-secreting pituitary adenomas (GH-omas). To correlate responses with the adenoma somatostatin receptor (SSTR) profile.. The effect of OCT and PAS on GH (and PRL) secretion was tested in 33 GH-oma cultures. SSTR expression was evaluated in adenoma samples.. Patients with acromegaly referred to the Erasmus Medical Center (Rotterdam, The Netherlands).. OCT and PAS treatment for 72 hours (10 nM).. GH (and PRL) concentrations in cell culture media. SSTR expression in adenoma samples.. The overall effect of OCT (-36.8%) and PAS (-37.1%) on GH secretion was superimposable. We identified three adenoma groups: PAS+ (PAS more effective than OCT), n = 6; PAS = OCT, n = 22; and OCT+ (OCT more effective than PAS), n = 5. PAS+ adenomas showed lower somatostatin receptor subtype (sst)2 messenger RNA (mRNA) and sst2/sst5 mRNA ratio, compared with the other groups (P < 0.05). PAS inhibited PRL hypersecretion more than OCT (P < 0.01).. Overall, OCT and PAS equally reduced GH secretion in vitro. Adenomas with lower sst2 mRNA expression and lower sst2/sst5 mRNA ratio were better responders to PAS compared with OCT. SSTR evaluation in GH-omas may become a tool for tailored SSA treatment in acromegaly.

Topics: Adenoma; Adolescent; Adult; Aged; Antineoplastic Agents, Hormonal; Female; Growth Hormone-Secreting Pituitary Adenoma; Human Growth Hormone; Humans; Immunohistochemistry; In Vitro Techniques; Male; Middle Aged; Octreotide; Polymerase Chain Reaction; Prolactin; Receptors, Somatostatin; RNA, Messenger; Somatostatin; Tumor Cells, Cultured; Young Adult

To present two female patients with acromegaly inadequately controlled with long-acting octreotide who were subsequently treated with the multireceptor-targeted somatostatin analogue pasireotide that over-suppressed IGF-1 levels.. We report two patients who failed surgery and received long-acting octreotide 20-30 mg/month as part of two double-blind, Phase III clinical trials. After 6-12 months of octreotide treatment, both patients remained inadequately controlled and were switched to long-acting pasireotide 40 mg/month as part of a crossover extension phase.. During the core phase of the studies the patients received octreotide 20-30 mg/month, but GH and IGF-1 levels remained above normal. They were switched to pasireotide 40 mg/month after 6 and 12 months, according to the study protocols. After crossover, GH and IGF-1 decreased and normalized, but continued treatment led to further reduction of IGF-1 to below the normal; these reduced levels mildly increased following pasireotide dose reduction to 20 mg/month. Tumour volume was reduced and the clinical signs and symptoms of acromegaly also improved.. These patients achieved long-term biochemical control, tumour volume reduction and improvement of clinical signs/symptoms after switching from octreotide to pasireotide. IGF-1 over-suppression is observed in a few patients and requires dose adjustment of pasireotide.

Topics: Acromegaly; Adenoma; Adult; Antineoplastic Agents, Hormonal; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Growth Hormone-Secreting Pituitary Adenoma; Hormones; Humans; Middle Aged; Octreotide; Somatostatin

Cushing disease (CD) results from excessive exposure to glucocorticoids caused by an adrenocorticotropic hormone-secreting pituitary tumor. Inadequately treated CD is associated with significant morbidity and elevated mortality. Multicenter data on CD patients treated in routine clinical practice are needed to assess treatment outcomes in this rare disorder. The study purpose was to describe the burden of illness and treatment outcomes for CD patients.. Eight pituitary centers in four U.S. regions participated in this multicenter retrospective chart review study. Subjects were CD patients diagnosed at ≥18 years of age within the past 20 years. Descriptive statistical analyses were conducted to examine presenting signs, symptoms, comorbidities, and treatment outcomes.. Of 230 patients, 79% were female (median age at diagnosis, 39 years; range, 18 to 78 years). Length of follow-up was 0 to 27.5 years (median, 1.9 years). Pituitary adenomas were 0 to 51 mm. The most common presenting comorbidities included hypertension (67.3%), polycystic ovary syndrome (43.5%), and hyperlipidemia (41.5%). Biochemical control was achieved with initial pituitary surgery in 41.4% patients (91 of 220), not achieved in 50.0% of patients (110 of 220), and undetermined in 8.6% of patients (19 of 220). At the end of follow-up, control had been achieved with a variety of treatment methods in 49.1% of patients (110 of 224), not achieved in 29.9% of patients (67 of 224), and undetermined in 21.0% of patients (47 of 224).. Despite multiple treatments, at the end of follow-up, biochemical control was still not achieved in up to 30% of patients. These multicenter data demonstrate that in routine clinical practice, initial and long-term control is not achieved in a substantial number of patients with CD.. BLA = bilateral adrenalectomy CD = Cushing disease CS = Cushing syndrome eCRF = electronic case report form MRI = magnetic resonance imaging PCOS = polycystic ovary syndrome.

Topics: 14-alpha Demethylase Inhibitors; ACTH-Secreting Pituitary Adenoma; Adenoma; Adolescent; Adrenalectomy; Adult; Aged; Antineoplastic Agents; Cabergoline; Comorbidity; Enzyme Inhibitors; Ergolines; Female; Follow-Up Studies; Hirsutism; Hormone Antagonists; Hormones; Humans; Hyperlipidemias; Hypertension; Hypoglycemic Agents; Ketoconazole; Male; Metyrapone; Middle Aged; Mifepristone; Muscle Weakness; Muscular Atrophy; Neurosurgical Procedures; Obesity, Abdominal; Pituitary ACTH Hypersecretion; Pituitary Irradiation; Polycystic Ovary Syndrome; Retrospective Studies; Rosiglitazone; Somatostatin; Striae Distensae; Thiazolidinediones; Treatment Outcome; Tumor Burden; Young Adult

Topics: Adenoma; Humans; Male; Middle Aged; Pituitary Neoplasms; Somatostatin; Thyrotropin

The management of critically ill Cushing's disease (CD) patients is extremely challenging. Pasireotide is indicated for the treatment of CD patients when pituitary surgery is unfeasible or has not been curative, but no data are available about the use of this drug as pre-operative treatment in critically ill patients. We report the effects of presurgical pasireotide therapy in CD patients in whom hypercortisolism caused life-threatening hypokalemia, alkalosis, and cardio-respiratory complications precluding surgical approach. Clinical, biochemical, and radiological data of two critically ill patients with ACTH-secreting pituitary macroadenoma, before and during first-line presurgical pasireotide treatment (600 μg s.c. bid). During the first 21 days of treatment, pasireotide therapy induced a rapid, partial decrease of plasma ACTH, serum cortisol, and urinary free cortisol levels, with the consequent normalization of serum potassium concentration and arterial blood gases parameters, in both the patients. They did not experience unmanageable side effects and underwent endoscopic transsphenoidal surgery after 4 weeks of effective treatment. Pre-operative MRI evaluation did not show pituitary tumor shrinkage. Surgical cure of CD was obtained in the first patient, while debulking allowed the pharmacological control of hypercortisolism in the second case. We suggest that pasireotide can induce a rapid improvement of clinical and metabolic conditions in critically ill CD patients in whom surgical approach is considered hazardous and need to be delayed.

Topics: ACTH-Secreting Pituitary Adenoma; Adenoma; Adult; Antineoplastic Agents; Chemotherapy, Adjuvant; Combined Modality Therapy; Critical Illness; Female; Humans; Male; Middle Aged; Pituitary ACTH Hypersecretion; Preoperative Period; Somatostatin; Treatment Outcome

To gather data regarding factors predicting responsiveness to pasireotide in acromegaly.. SSTR2a, SSTR3, SSTR5, AIP, Ki-67 and the adenoma subtype were evaluated in somatotroph adenomas from 39 patients treated post-operatively with somatostatin analogues (SSAs). A standardized SSTR scoring system was applied (scores 0-3). All patients received first-generation SSAs, and 11 resistant patients were subsequently treated with pasireotide LAR.. None of the patients with negative or cytoplasmic-only SSTR2a expression (scores 0-1) were responsive to first-generation SSAs, as opposed to 20% (score 2) and 50% of patients with a score of 3 (P=0.04). None of the patients with an SSTR5 score of 0-1 were responsive to pasireotide, as opposed to 5/7 cases with a score of 2 or 3 (P=0.02). SSTR3 expression did not influence first-generation SSAs or pasireotide responsiveness. Tumours with low AIP were resistant to first-generation SSAs (100 vs 60%; P=0.02), while they had similar responsiveness to pasireotide compared to tumours with conserved AIP expression (50 vs 40%; P=0.74). Tumours with low AIP displayed reduced SSTR2 (SSTR2a scores 0-1 44.4 vs 6.7%; P=0.006) while no difference was seen in SSTR5 (SSTR5 scores 0-1 33.3 vs 23.3%; P=0.55). Sparsely granulated adenomas responded better to pasireotide compared to densely granulated ones (80 vs 16.7%; P=0.04).. The expression of SSTR5 might predict responsiveness to pasireotide in acromegaly. AIP deficient and sparsely granulated adenomas may benefit from pasireotide treatment. These results need to be confirmed in larger series of pasireotide-treated patients.

Topics: Acromegaly; Adenoma; Adult; Drug Resistance; Female; Growth Hormone-Secreting Pituitary Adenoma; Humans; Intracellular Signaling Peptides and Proteins; Ki-67 Antigen; Male; Middle Aged; Receptors, Somatostatin; Somatostatin; Treatment Outcome

The hypercortisolism is a rare endocrine disease characterized by an autonomous steroid secretion or excessive adrenal stimulation by ACTH. the Surgical removal of the lesion directly responsible hypercortisolism represents the treatment of choice. When neurosurgery for pituitary adenoma is contraindicated, radiotherapy is candidate as the second line of therapy. Currently, the recent advances in medical therapy provide a viable alternative to surgery and radiotherapy, when these are not feasible or followed by relapses (present in more than one third of cases) of the underlying disease. Recently, also in Italy, are available pharmacological agents with central activity (pasireotide) specifically indicated for treating Cushing's disease together with peripherally acting drugs (metyrapone and ketoconazole) that are used in a broader spectrum of hypercortisolemic clinical pictures. In addition, drugs active in the inhibition of steroidogenesis provide a valid support to the patient's surgical preparation allowing the reduction or normalization of plasma cortisol levels.

Topics: Adenoma; Cushing Syndrome; Humans; Hydrocortisone; Italy; Ketoconazole; Metyrapone; Pituitary Neoplasms; Somatostatin

Pasireotide is the only pituitary targeted medication registered for the treatment of Cushing's disease. Drug efficacy data are largely based on a major prospective study in which the vast majority of patients had microadenomas. The purpose of this study was to summarize results of pasireotide treatment of ACTH secreting macroadenomas from our center.. Retrospective review of data extracted from clinical files.. Three patients presented with large and invasive macroadenomas that required several surgical interventions and radiotherapy treatments. Patient 1 is a 57 year-old male who developed an extreme (27-fold) paradoxical response of urinary free cortisol (UFC) levels as measured 2 weeks after pasireotide institution, which increased further (71-fold) in response to dose increment but decreased to baseline levels after treatment interruption. Patient 2 is a 44 year old woman with a long standing (26 years) ACTH-secreting carcinoma metastatic to bone and after bilateral adrenalectomy. After an initial excellent response to pasireotide treatment, ACTH levels escaped suppression and a further rebound was noted 6 weeks after treatment interruption. Patient 3 is a 53 year old man that after escape from temozolomide therapy was started on pasireotide and rapidly responded by almost normalizing UFC excretion after 4 weeks, but returned to baseline UFC levels after four additional weeks of treatment.. We describe as yet unreported atypical responses to pasireotide treatment in patients with aggressive ACTH-secreting tumors. Increased vigilance is recommended during pasireotide treatment of such patients.

Topics: ACTH-Secreting Pituitary Adenoma; Adenoma; Adrenocorticotropic Hormone; Adult; Female; Humans; Male; Middle Aged; Somatostatin; Treatment Outcome

Gonadotroph pituitary adenomas (GPAs) often present as invasive macroadenomas not amenable to complete surgical resection. Radiotherapy is the only post-operative option for patients with large invasive or recurrent lesions. No medical treatment is available for these patients. The somatostatin analogs (SSAs) octreotide and lanreotide that preferentially target somatostatin receptor type 2 (SSTR2) have little effect on GPAs. It is widely accepted that the expression of specific SSTR subtypes determines the response to SSAs. Given that previous studies on mRNA and protein expression of SSTRs in GPAs have generated conflicting results, we investigated the expression of SSTR2, SSTR3, and SSTR5 (the main targets of available SSAs) in a clinically and pathologically well-characterized cohort of 108 patients with GPAs. A total of 118 samples were examined by immunohistochemistry using validated and specific MABs. Matched primary and recurrent tissues were available for ten patients. The results obtained were validated in an independent cohort of 27 GPAs. We observed that SSTR3 was significantly more abundant than SSTR2 (P<0.0001) in GPAs, while full-length SSTR5 was only expressed in few tumors. Expression of SSTR3 was similar in primary and recurrent adenomas, was high in potentially aggressive lesions, and did not change significantly in adenomas that recurred after irradiation. In conclusion, low levels of expression of SSTR2 may account for the limited response of GPAs to octreotide and lanreotide. Given the potent anti-proliferative, pro-apoptotic, and anti-angiogenic activities of SSTR3, targeting this receptor with a multireceptor ligand SSA such as pasireotide may be indicated for potentially aggressive GPAs.

Topics: Adenoma; Adult; Aged; Aged, 80 and over; Female; Humans; Male; Middle Aged; Molecular Targeted Therapy; Neoplasm Recurrence, Local; Pituitary Neoplasms; Receptors, Somatostatin; Somatostatin; Young Adult

Aggressive pituitary adenomas (PAs) are clinically challenging for endocrinologists and neurosurgeons due to their locally invasive nature and resistance to standard treatment (surgery, medical or radiotherapy). Two pituitary-directed drugs have recently been proposed: temozolomide (TMZ) for aggressive PA, and pasireotide for ACTH-secreting PA. We describe the experience of our multidisciplinary team of endocrinologists, neurosurgeons, neuroradiologists, oncologists, otolaryngologists and pathologists with TMZ and pasireotide treatment for aggressive PAs in terms of their radiological shrinkage and genetic features. We considered five patients with aggressive PA, three of them non-secreting (two ACTH-silent and one becoming ACTH secreting), and two secreting (one GH and one ACTH). TMZ was administrated orally at 150-200 mg/m(2) daily for 5 days every 28 days to all 5 patients, and 2 of them also received pasireotide 600-900 µg bid sc. We assessed the MRI at the baseline and during TMZ or pasireotide treatment. We also checked for MGMT promoter methylation and IDH, BRAF and kRAS mutations. Considering TMZ, two patients showed PA progression, one stable disease and two achieved radiological and clinical response. Pasireotide was effective in reducing hypercortisolism and mass volume, combined with TMZ in one case. Both treatments were generally well tolerated; one patient developed a grade 2 TMZ-induced thrombocytopenia. None of patients developed hypopituitarism while taking TMZ or pasireotide treatment. No genetic anomalies were identified in the adenoma tissue. TMZ and pasireotide may be important therapies for aggressive PA, alone or in combination.

Topics: Adenoma; Adult; Aged; Antineoplastic Agents, Alkylating; Dacarbazine; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Male; Middle Aged; Neoplasm Staging; Pituitary Neoplasms; Prognosis; Retrospective Studies; Somatostatin; Survival Rate; Temozolomide; Tertiary Care Centers

Recent discoveries in molecular biology offer new perspectives in the treatment of endocrine tumors. There is currently no medical therapy for Cushing's disease that targets the pituitary adenoma. Pasireotide, a new somatostatin analog, demonstrates a strong affinity for somatostatin receptors expressed by corticotroph adenomas. Some recent clinical trials showed a decrease of urinary free cortisol with pasireotide. This new treatment could be useful in case of pituitary surgery failure. Thyroid tumorigenesis involves kinase signaling cascade. Tyrosine-kinase inhibitors have now been tested in the treatment of progressive differentiated iodine refractory thyroid carcinomas or medullary carcinomas and showed modestly encouraging results.

Topics: ACTH-Secreting Pituitary Adenoma; Adenoma; Benzenesulfonates; Carcinoma; Carcinoma, Medullary; Clinical Trials as Topic; Endocrine Gland Neoplasms; Endocrinology; Humans; Niacinamide; Phenylurea Compounds; Pituitary ACTH Hypersecretion; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyridines; Receptors, Somatostatin; Somatostatin; Sorafenib; Thyroid Neoplasms; Treatment Outcome

Topics: ACTH-Secreting Pituitary Adenoma; Adenoma; Drug Approval; European Union; Humans; Hydrocortisone; Pituitary ACTH Hypersecretion; Somatostatin

Somatostatin is a widely distributed polypeptide that modulates endocrine and exocrine secretion, cell proliferation, and apoptosis by 5 somatostatin receptors (SSTR1-5). The inhibitory effects of somatostatin on tumor growth may be the result of its suppressing the synthesis and/or secretion of growth factors and growth-promoting hormones.. Very little information is available on the effect of somatostatin analogs on adrenal tumors, so we examined SSTR expression in adrenocortical tumors and studied the effect of a somatostatin analog (SOM230) on hormone secretion and cell viability in adrenal cells.. SSTR expression was analyzed by real-time PCR in 13 adrenocortical carcinomas (ACC), 24 aldosterone-producing adenomas (APA), 11 cortisol-producing adenomas (CPA), and 7 normal adrenals (NA), and verified by immunohistochemistry (IHC) in 14 samples. The effect of SOM230 on cortisol or aldosterone secretion in H295R and primary cell cultures was determined by radioimmunoassay, and its effect on viability in H295R and SW13 using the MTT test.. SSTR1 and SSTR2 mRNA was expressed in 100% of adrenal tumors. Compared to NA, ACC revealed an increase in almost all SSTR, while only some APA over-expressed SSTR3 and SSTR1. CPA expressed SSTR similar to NA. IHC confirmed the mRNA expression data. At nanomolar concentrations, SOM230 inhibited hormone secretion in primary adrenal cultures and H295R cells, but had no evident effect on cell viability.. The evidence of SSTR over-expression (particularly in ACC) and of hormone secretion being inhibited by SOM230 suggests a potential therapeutic role for this broad-spectrum somatostatin analog in adrenal tumors.

Topics: Adenoma; Adrenal Cortex Neoplasms; Adrenal Glands; Aldosterone; Apoptosis; Cell Cycle; Cell Proliferation; Flow Cytometry; Humans; Hydrocortisone; Immunoenzyme Techniques; In Vitro Techniques; Pituitary Neoplasms; Real-Time Polymerase Chain Reaction; Receptors, Somatostatin; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Somatostatin; Tumor Cells, Cultured

Pituitary adenomas can cause specific syndromes due to hormone excess and/or determine sellar mass symptoms. Pituitary cell growth can sometimes be influenced by medical therapy, such as for somatotroph adenomas treated with somatostatin analogs or prolactinomas treated with dopaminergic drugs. However, nonfunctioning pituitary adenomas (NFAs) are still orphans of medical therapy. Everolimus (RAD001), a derivative of rapamycin, is a well-known immunosuppressant drug, which has been recently shown to have antineoplastic activity in several human cancers.. The objective of the study was to investigate the possible antiproliferative effects of RAD001 in human NFAs.. We collected 40 NFAs that were dispersed in primary cultures, treated without or with 1 nm to 1 microm RAD001, 10 nm cabergoline, 10 nm SOM230 (a somatostatin receptor multiligand), and/or 50 nm IGF-I. Cell viability and apoptosis were evaluated after 48 h, and vascular endothelial growth factor (VEGF) secretion was assessed after an 8-h incubation. Somatostatin and dopamine subtype 2 receptor expression was investigated by quantitative PCR.. In 28 cultures (70%), Everolimus significantly reduced cell viability (by approximately 40%; P < 0.05 vs. control), promoted apoptosis (+30%; P < 0.05 vs. control), inhibited p70S6K activity (-20%), and blocked IGF-I proliferative and antiapoptotic effects. In selected tissues cotreatment with SOM230, but not cabergoline, exerted an additive effect. Everolimus did not affect VEGF secretion but blocked the stimulatory effects of IGF-I on this parameter.. Everolimus reduced NFA cell viability by inducing apoptosis, with a mechanism likely involving IGF-I signaling but not VEGF secretion, suggesting that it might represent a possible medical treatment of invasive/recurrent NFAs.

Topics: Adenoma; Aged; Apoptosis; Cabergoline; Cell Line, Tumor; Cell Survival; Ergolines; Everolimus; Female; Humans; Immunosuppressive Agents; Male; Middle Aged; Pituitary Neoplasms; Receptors, Somatostatin; Ribosomal Protein S6 Kinases, 70-kDa; Sirolimus; Somatostatin; Vascular Endothelial Growth Factor A

Topics: Acromegaly; Adenoma; Combined Modality Therapy; Comorbidity; Cranial Irradiation; Data Collection; Disease Management; Drug Therapy, Combination; Drug Utilization; History, 20th Century; History, 21st Century; Human Growth Hormone; Humans; Hypophysectomy; Peptides, Cyclic; Pituitary Neoplasms; Receptors, Somatostatin; Registries; Retrospective Studies; Somatostatin; Spain

Topics: Adenoma; Clinical Trials as Topic; Dacarbazine; Humans; Pituitary ACTH Hypersecretion; Pituitary Neoplasms; Somatostatin; Temozolomide; Treatment Outcome

Somatostatin (SRIF) analogs have been employed in medical therapy of non-functioning pituitary adenomas (NFA), with contrasting results. Previous evidence showed that SRIF can exert its antiproliferative effects by reducing vascular endothelial growth factor (VEGF) secretion and action, and that VEGF expression may be related to pituitary tumor growth. The aim of our study was to clarify the possible effects of a multireceptor SRIF ligand on VEGF secretion and cell proliferation in human NFA primary cultures. We assessed the expression of SRIF receptors (SSTR1-5), the in vitro effects on VEGF secretion, and on cell viability of SRIF and of the stable SRIF analog pasireotide (SOM230), which activates SSTR1, 2, 3, and 5. Twenty-five NFA were examined by RT-PCR for expression of alpha-subunit, SSTR, VEGF, and VEGF receptors 1 (VEGF-R1) and 2 (VEGF-R2). Primary cultures were tested with SRIF and with pasireotide. All NFA samples expressed alpha-sub, VEGF and VEGFR-1 and 2, while SSTR expression pattern was highly variable. Two different groups were identified according to VEGF secretion inhibition by SRIF. VEGF secretion and cell viability were reduced by SRIF and pasireotide in the 'responder' group, but not in the 'non-responder' group, including NFA expressing SSTR5. SRIF and pasireotide completely blocked forskolin-induced VEGF secretion. In addition, SRIF and pasireotide completely abrogated the promoting effects of VEGF on NFA cell viability. Our data demonstrate that pasireotide can inhibit NFA cell viability by inhibiting VEGF secretion, and suggest that the multireceptor-SSTR agonist pasireotide might be useful in medical therapy of selected NFA.

Topics: Adenoma; Adult; Aged; Cell Survival; Female; Hormones; Humans; Ligands; Male; Oligopeptides; Pituitary Neoplasms; Receptors, Somatostatin; RNA, Messenger; Somatostatin; Vascular Endothelial Growth Factor A

Somatostatin (SST) analogues play an important role in the medical management of somatotroph pituitary adenomas and new agonists have the potential to be effective in a wider group of pituitary and other tumours. The anti-proliferative effect of SST occurs through multiple mechanisms, one of which is cell-cycle arrest, where p27, a cyclin-dependent kinase inhibitor, is an important regulator. We hypothesised that SST may upregulate p27 protein levels and downregulate the MAP kinase pathway in these tumours.. Human pituitary adenoma cells and rat pituitary cell line (GH3) were cultured and treated in vitro with octreotide and the broad-spectrum SST agonist SOM230 (pasireotide). Immunoblotting for p27 and phospho-ERK (pERK) was performed and proliferation assessed by [3H]-thymidine incorporation. Histological samples from acromegalic patients treated with octreotide before surgery were immunostained for p27 and compared to samples from untreated patients matched for sex, age, tumour size, extension and invasiveness.. We detected upregulation of p27 protein levels with SST analogue treatment in vitro in human pituitary adenoma samples. pERK1/2 was inhibited by SST analogues in both the human samples and GH3 cells. SST and its analogues inhibited the proliferation of GH3 cells. p27 immunostaining was stronger in samples from patients with longer preoperative octreotide treatment (more than 6 months) than in samples from patients with shorter treatment periods.. This study demonstrates that SST-mediated growth inhibition is associated with the downregulation of pERK and upregulation of p27. More potent and broader-spectrum SST analogues are likely to play an increasing role in the treatment of tumours, where the MAP kinase pathway is overactivated.

Topics: Adenoma; Animals; Antineoplastic Agents, Hormonal; Cell Division; Cell Line, Tumor; Cyclin-Dependent Kinase Inhibitor p27; Down-Regulation; Extracellular Signal-Regulated MAP Kinases; Growth Hormone-Secreting Pituitary Adenoma; Humans; In Vitro Techniques; MAP Kinase Signaling System; Octreotide; Pituitary Gland; Pituitary Neoplasms; Prolactinoma; Rats; Somatostatin; Thymidine; Tritium; Up-Regulation

There is no tumor-directed medical therapy available for Cushing's disease.. The objective was to determine the in vitro effect of the somatostatin analog pasireotide (SOM230) on cell proliferation in human corticotroph tumors.. Expression of somatostatin receptors (SSTR 1-5) was determined by quantitative RT-PCR in 13 human corticotroph tumors and by immunohistochemistry (IHC) in 12 of the 13 tumors. SOM230 effects on cell proliferation and ACTH release were evaluated in vitro using primary cultures of six of the 13 human corticotroph adenomas.. In our series, we found expression of SSTR subtypes 1, 2, 4, and 5 in human corticotroph tumors by quantitative RT-PCR. All receptor subtypes were detected by IHC, with SSTR subtype 5 having the highest IHC score in 83% (10 of 12) of the cases. Significant suppression of cell proliferation was observed in all tumors cultured (percent suppression range: 10-70%; P = 0.045-0.001). SOM230 inhibited ACTH secretion in five of the six tumors cultured (percent suppression range: 23-56%; P = 0.042-0.001).. Corticotroph tumors express multiple SSTR subtypes. SOM230 significantly suppressed cell proliferation and ACTH secretion in primary cultures of human corticotroph tumors. These in vitro results support the hypothesis that SOM230 may have a role in the medical therapy of corticotroph tumors.

Topics: ACTH-Secreting Pituitary Adenoma; Adenoma; Adolescent; Adrenocorticotropic Hormone; Adult; Cell Proliferation; Child; Female; Humans; Immunohistochemistry; In Vitro Techniques; Male; Middle Aged; Pituitary ACTH Hypersecretion; Receptors, Somatostatin; RNA, Messenger; Somatostatin; Tumor Cells, Cultured

Currently, there is no effective medical treatment for patients with pituitary-dependent Cushing's disease. A novel somatostatin (SS) analogue, named SOM230, with high binding affinity to SS receptor subtypes sst(1), sst(2), sst(3) and sst(5) was recently introduced. We compared the in vitro effects of the sst(2)-preferring SS analogue octreotide (OCT) and the multi-ligand SOM230 on ACTH release by human and mouse corticotroph tumour cells.. By quantitative RT-PCR the sst subtype expression level was determined in human corticotroph adenomas. In vitro, the inhibitory effect of OCT and SOM230 on ACTH release by dispersed human corticotroph adenoma cells and mouse AtT20 corticotroph adenoma cells was determined. In addition, the influence of dexamethasone on the responsiveness to OCT and SOM230 was studied.. Corticotroph adenomas expressed predominantly sst(5) mRNA (six out of six adenomas), whereas sst(2) mRNA expression was detected at significantly lower levels. In a 72 h incubation with 10 nmol/l SOM230, ACTH release was inhibited in three out of five cultures (range -30 to -40%). Ten nmol/l OCT slightly inhibited ACTH release in only one of five cultures (- 28%). In AtT20 cells, expressing sst(2), sst(3) and sst(5), SOM230 inhibited ACTH secretion with high potency (IC(50) 0.2 nmol/l). Dexamethasone (10 nmol/l) pre-treatment did not influence the sensitivity of the cells to the inhibitory effect of SOM230, suggesting that sst(5) is relatively resistant to negative control by glucocorticoids.. The selective expression of sst(5) receptors in corticotroph adenomas and the preferential inhibition of ACTH release by human corticotroph adenoma cells by SOM230 in vitro, suggest that SOM230 may have potential in the treatment of patients with pituitary-dependent Cushing's disease.

Topics: Adenoma; Adrenocorticotropic Hormone; Animals; Gene Expression; Glucocorticoids; Humans; Mice; Octreotide; Pituitary Neoplasms; Receptors, Somatostatin; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Somatostatin; Tumor Cells, Cultured

Ghrelin stimulates while somatostatin inhibits GH release and they thus serve as functional antagonists. We have compared their effects on cell proliferation. Ghrelin stimulates while somatostatin inhibits cell proliferation in most tissues and cell lines. Here we show that ghrelin and desoctanoyl ghrelin stimulate cell proliferation in rat pituitary cell line (GH3), and these effects could be inhibited with mitogen-activated protein kinase (MAPK), tyrosine kinase and protein kinase C inhibitors. Somatostatin and its analogs negatively regulate the growth of pituitary cells, and we now show that they inhibit MAPK activation. We hypothesised that one of the mechanisms involved in the somatostatin effect is a stimulation of cell cycle inhibitor p27, as pituitary adenomas have decreased p27 peptide content. Both octreotide and a new somatostatin analog SOM230 treatment resulted in an upregulation of p27 protein levels in human somatotrophinoma cells. In summary, we suggest that ghrelin and somatostatin have opposite effects on somatotroph cells not just at the level of GH release but also in terms of cell proliferation. Ghrelin may play a role in pituitary tumorigenesis via an autocrine/paracrine pathway. Our results also suggest that the antiproliferative effect of somatostatin analogs octreotide and SOM230 involve the up-regulation of p27 and down-regulation of the MAPK pathway in human somatotrophinomas.

Topics: Adenoma; Cell Division; Cell Line, Tumor; Cyclin-Dependent Kinase Inhibitor p27; Enzyme Activation; Ghrelin; Human Growth Hormone; Humans; Mitogen-Activated Protein Kinases; Octreotide; Peptide Hormones; Pituitary Neoplasms; Receptors, Somatostatin; Somatostatin

To determine the inhibitory profile of the novel somatostatin (SRIF) analog SOM230 with broad SRIF receptor binding, we compared the in vitro effects of SOM230, octreotide (OCT), and SRIF-14 on hormone release by cultures of different types of secreting pituitary adenomas. OCT (10 nM) significantly inhibited GH release in seven of nine GH-secreting pituitary adenoma cultures (range, -26 to -73%), SOM230 (10 nM) in eight of nine cultures (range, -22 to -68%), and SRIF-14 (10 nM) in six of six cultures (range, -30 to -75%). The sst analysis showed predominant but variable levels of somatostatin receptor (sst)(2) and sst(5) mRNA expression. In one culture completely resistant to OCT, SOM230 and SRIF-14 significantly inhibited GH release in a dose-dependent manner with an IC(50) value in the low nanomolar range. In the other cultures, SOM230 showed a lower potency of GH release inhibition (IC(50), 0.5 nM), compared with OCT (IC(50), 0.02 nM) and SRIF-14 (IC(50), 0.02 nM). A positive correlation was found between sst(2) but not sst(5) mRNA levels in the adenoma cells and the inhibitory potency of OCT on GH release in vivo and in vitro, and the effects of SOM230 and SRIF-14 in vitro. In three prolactinoma cultures, 10 nM OCT weakly inhibited prolactin (PRL) release in only one (-28%), whereas 10 nM SOM230 significantly inhibited PRL release in three of three cultures (-23, -51, and -64.0%). The inhibition of PRL release by SOM230 was related to the expression level of sst(5) but not sst(2) mRNA. Several conclusions were reached. First, SOM230 has a broad profile of inhibition of tumoral pituitary hormone release in the low nanomolar range, probably mediated via both sst(2) and sst(5) receptors. The higher number of responders of GH-secreting pituitary adenoma cultures to SOM230, compared with OCT, suggest that SOM230 has the potency to increase the number of acromegalic patients which can be biochemically controlled. Second, compared with OCT, SOM230 is more potent in inhibiting PRL release by mixed GH/PRL-secreting adenoma and prolactinoma cells.

Topics: Adenoma; Adult; Dose-Response Relationship, Drug; Female; Hormone Antagonists; Human Growth Hormone; Humans; Male; Middle Aged; Octreotide; Pituitary Neoplasms; Prolactin; Protein Isoforms; Receptors, Somatostatin; RNA, Messenger; Somatostatin; Tumor Cells, Cultured

Currently available somatostatin analogs predominantly bind to the somatostatin receptor subtype (SSTR)2 subtype, and control GH and IGF-I secretion in approximately 65% of patients with acromegaly, their efficacy relating to receptor density and subtype expression. SOM230 is a somatostatin ligand with high affinity to four SSTR subtypes. In primary cultures of rat pituicytes, SOM230 dose-dependently inhibited GH release (P = 0.002) with an IC50 of 1.2 nM. Ten nanomoles SOM230 inhibited GH and TSH release by 40 +/- 7% (P < 0.001) and 47 +/- 21% (P = 0.09), respectively. No effect of SOM230 was observed on prolactin (PRL) or LH release. In cultures of human fetal pituitary cells, SOM230 inhibited GH secretion by 42 +/- 9% (P = 0.002) but had no effect on TSH release. SOM230 inhibited GH release from GH-secreting adenoma cultures by 34 +/- 8% (P = 0.002), PRL by 35 +/- 4% from PRL-secreting adenomas (P = 0.01), and alpha-subunit secretion from nonfunctioning pituitary adenomas by 46 +/- 18% (P = 0.34). In contrast, octreotide inhibited GH, PRL, and alpha-subunit from the respective adenoma by 18 +/- 12 (P = 0.39), 22 +/- 4 (P = 0.04), and 20 +/- 10% (P = 0.34). In all culture systems, no significant difference in the inhibitory action of SOM230, octreotide, and somatostatin 14 on hormone release was observed. SOM230, similar to somatostatin, has high-affinity binding to SSTR1, 2, 3, and 5 and, in keeping with this, has an equivalent inhibitory effect on pituitary hormone secretion. As a consequence of its broader binding profile, SOM230 is likely to find clinical utility in treating tumors resistant to SSTR-2-preferential analogs.

Topics: Adenoma; Animals; Antineoplastic Agents, Hormonal; Fetus; Human Growth Hormone; Humans; Male; Octreotide; Pituitary Gland, Anterior; Pituitary Neoplasms; Rats; Rats, Sprague-Dawley; Receptors, Somatostatin; Somatostatin; Tumor Cells, Cultured