Ilan Shimon

Pasireotide versus continued treatment with octreotide or lanreotide in patients with inadequately controlled acromegaly (PAOLA): a randomised, phase 3 trial

BACKGROUND Many patients with acromegaly do not achieve biochemical control despite receiving high doses of the first-generation somatostatin analogues octreotide or lanreotide. In the PAOLA trial, we aimed to assess the efficacy and safety of two different doses of the somatostatin analogue pasireotide long-acting release compared with active control (octreotide or lanreotide) in patients with inadequately controlled acromegaly. METHODS In a multicentre, randomised, phase 3 trial, we enrolled eligible patients aged 18 years or older with acromegaly who were inadequately controlled (5-point, 2 h mean growth hormone concentration >2·5 μg/L and insulin-like growth factor 1 [IGF-1] concentration >1·3 times the upper normal limit) and had received 30 mg octreotide long-acting repeatable or 120 mg lanreotide (Somatuline Autogel; Ipsen, UK) as monotherapy for 6 months or longer. We randomly assigned patients in a 1:1:1 ratio with an interactive voice-web response system to receive 40 mg pasireotide long-acting release once every 28 days for 24 weeks, 60 mg pasireotide long-acting release once every 28 days for 24 weeks, or continued treatment with octreotide or lanreotide (active control). Patients were stratified according to previous treatment (octreotide or lanreotide) and growth hormone concentrations at screening (2·5-10 μg/L and >10 μg/L). Patients and study investigators were not masked to study drug assignment but were masked to pasireotide dose allocation. The primary endpoint was number of patients achieving biochemical control, defined as mean growth hormone concentration less than 2·5 μg/L and normalised IGF-1 concentration. Efficacy analyses were based on intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01137682. FINDINGS Between Dec 17, 2010, and Aug 6, 2012, 198 patients were enrolled and randomly assigned to pasireotide 40 mg (n=65), pasireotide 60 mg (n=65), or active control (n=68) groups. At 24 weeks, ten (15%) patients in the pasireotide 40 mg group and 13 (20%) patients in the pasireotide 60 mg group achieved biochemical control, compared with no patients in the active control group (absolute difference from control group 15·4%, 95% CI 7·6-26·5, p=0·0006 for pasireotide 40 mg group, 20·0%, 11·1-31·8, p<0·0001 for pasireotide 60 mg group). The most common adverse events were hyperglycaemia (21 [33%] for treatment with 40 mg pasireotide, 19 [31%] with 60 mg pasireotide, and nine [14%] with active control), diabetes (13 [21%], 16 [26%], and five [8%]), and diarrhoea (ten [16%], 12 [19%], and three [5%]); most were grade 1 or 2 in severity. Serious adverse events were reported in six (10%) patients in the pasireotide 40 mg group, two (3%) in the pasireotide 60 mg group, and three (5%) in the active control group. INTERPRETATION Pasireotide provides superior efficacy compared with continued treatment with octreotide or lanreotide, and could become the new standard pituitary-directed treatment in patients with acromegaly who are inadequately controlled using first-generation somatostatin analogues. FUNDING Novartis Pharma AG. Financial support for medical editorial assistance was provided by Novartis Pharmaceuticals Corporation.

Somatostatin analogues in the control of neuroendocrine tumours: efficacy and mechanisms

Neuroendocrine tumours (NETs) represent a heterogeneous family of neoplasms, which may develop from different endocrine glands (such as the pituitary, the parathyroid or the neuroendocrine adrenal glands), endocrine islets (within the thyroid or pancreas) as well as from endocrine cells dispersed between exocrine cells throughout the digestive and respiratory tracts. The development of somatostatin analogues (SSA) as important diagnostic and treatment tools has revolutionised the clinical management of patients with NETs. However, although symptomatic relief and stabilisation of tumour growth for various periods of time are observed in many patients treated with SSA, tumour regression is rare. Possible mechanisms when this does occur include antagonism of local growth factor release and effects, probably including activation of tyrosine and serine-threonine phosphatases, and indirect effects via anti-angiogenesis. The development of new SSA, new drug combination therapies and chimaeric molecules should further improve the clinical management of these patients, as should a more complete understanding of their mode of action.

Safety and efficacy of oral octreotide in acromegaly: results of a multicenter phase III trial.

BACKGROUND A novel oral octreotide formulation was tested for efficacy and safety in a phase III, multicenter, open-label, dose-titration, baseline-controlled study in patients with acromegaly. METHODS We enrolled 155 complete or partially controlled patients (IGF-1 <1.3 × upper limit of normal [ULN], and 2-h integrated GH <2.5 ng/mL) receiving injectable somatostatin receptor ligand (SRL) for ≥ 3 months. Subjects were switched to 40 mg/d oral octreotide capsules (OOCs), and the dose escalated to 60 and then up to 80 mg/d to control IGF-1. Subsequent fixed doses were maintained for a 7-month core treatment, followed by a voluntary 6-month extension. RESULTS Of 151 evaluable subjects initiating OOCs, 65% maintained response and achieved the primary endpoint of IGF-1 <1.3 × ULN and mean integrated GH <2.5 ng/mL at the end of the core treatment period and 62% at the end of treatment (up to 13 mo). The effect was durable, and 85 % of subjects initially controlled on OOCs maintained this response up to 13 months. When controlled on OOCs, GH levels were reduced compared to baseline, and acromegaly-related symptoms improved. Of 102 subjects completing the core treatment, 86% elected to enroll in the 6-month extension. Twenty-six subjects who were considered treatment failures (IGF-1 ≥ 1.3 × ULN) terminated early, and 23 withdrew for adverse events, consistent with those known for octreotide or disease related. CONCLUSIONS OOC, an oral therapeutic peptide, achieves efficacy in controlling IGF-1 and GH after switching from injectable SRLs for up to 13 months, with a safety profile consistent with approved SRLs. OOC appears to be effective and safe as an acromegaly monotherapy.

Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia and the associated lung neuroendocrine tumors: clinical experience with a rare entity.

Normal adult lungs contain pulmonary neuroendocrine cells (PNECs). PNEC hyperplasia may be either reactive or idiopathic, and the idiopathic type is defined as diffuse idiopathic PNEC hyperplasia (DIPNECH). It is believed that DIPNECH is a neuroendocrine proliferative process associated with carcinoid tumors. The available data regarding this rare condition are very limited. The objective of the current study was to describe the clinical, radiologic, and pathologic characteristics of patients with DIPNECH and the effect of various therapeutic modalities on patient well being.

Differentiated Thyroid Cancer Is Associated With Less Aggressive Disease and Better Outcome in Patients With Coexisting Hashimotos Thyroiditis

BACKGROUND Evaluation of surgical specimens suggests that patients with Hashimoto thyroiditis (HT) have a higher prevalence of differentiated thyroid cancer. Although patients with HT are reported to present with earlier stage disease, there is controversy as to whether these patients have better prognosis when adjusted for histology and stage at presentation. OBJECTIVES To investigate differences between patients with differentiated thyroid cancer patients and without HT for aggressiveness of disease and clinical outcome, and the decline rate of antithyroglobulin antibodies titers over time. METHODS A retrospective study using the Rabin Medical Center Thyroid Cancer Registry. Seven hundred fifty-three patients were included and divided into 2 groups of patients with and without HT at diagnosis. Disease severity at presentation was evaluated using the entire cohort, whereas a control group matched for age, gender, histology, and stage was used to evaluate disease course and outcome. RESULTS HT was present in 14.2% (n = 107) of included patients and was associated with smaller primary tumor (17.9 vs 21.2 mm, P = .01) and less lymph node involvement (23% vs 34%, P = .02) at presentation. When matched groups were compared, patients with HT received less additional radioactive iodine (RAI) treatments (1.24 vs 1.45, P = .03) and showed lower rates of persistence at 1 year (13% vs 26%, P = .04) and higher rates of disease remission at the end of follow-up (90% vs 79%, P = .05). On multivariate analysis HT was predictive of a lower rate of lymph nodes involvement (odds ratio 0.34, 95% confidence interval 0.17-0.66) and persistent disease at the end of follow-up (odds ratio 0.48, 95% confidence interval 0.24-0.93). Antithyroglobulin antibodies slowly disappeared in most patients with no evidence of disease. CONCLUSION Our study demonstrates that HT is associated with a less aggressive form of differentiated thyroid cancer and a better long-term outcome.

Transient normal platelet counts and decreased requirement for interferon during pregnancy in essential thrombocythaemia

We report on the remarkable decrease in the platelet counts during pregnancy in two women with essential thrombocythaemia following treatment with recombinant interferon‐α (r‐IFN‐α). Prior to pregnancy, the first patient was treated for 10 months with r‐IFN‐α 3×106 units/d six times per week, and the platelet count ranged between 750 and 800×109/l. Starting from the sixth week of gestation, the platelet count decreased to normal levels and remained so, resulting in a lower r‐IFN‐α requirement. Following successful delivery of a healthy newborn an abrupt rise of the platelet count to pre‐gestation values was observed, necessitating increased r‐IFN‐α dosage as before pregnancy. The second patient when she became pregnant had been treated with r‐IFN‐α 3×106 units/d six times per week for 10 weeks. Starting from the 24th week of gestation the platelet count decreased, and despite reduction in the dose of r‐IFN‐α reached normal values at the time of delivery. The exact mechanism for the platelet count normalization during pregnancy is unclear, and several possibilities are discussed.

The rapamycin-derivative RAD001 (everolimus) inhibits cell viability and interacts with the Akt-mTOR-p70S6K pathway in human medullary thyroid carcinoma cells.

Over-expression of the proto-oncogene Akt/PKB has been demonstrated in some neuroendocrine tumor models. Akt may activate downstream proteins such as mTOR and p70S6K, inducing tumor proliferation. The rapamycin-derivative RAD001, everolimus, interacts with this pathway by antagonizing mTOR, but its effects on neuroendocrine tumors are largely unknown. We explored the mechanism of action of RAD001 on cell proliferation, hormonal secretion and on Akt/mTOR/p70S6K pathway activation, in a human medullary thyroid carcinoma (MTC) cell-line (TT) and in cells derived from human MTCs. Treatment with RAD001 significantly inhibited cell viability in a dose- and time-dependent fashion, and diminished phosphorylation of Akt downstream targets, mTOR and p70S6K, in both TT cell-line and cultured human MTCs. Akt phosphorylation was not affected by RAD001. RAD001 induced cell-cycle arrest in the G(0)/G(1) phase in TT cells, but had no effect on apoptosis. Moreover, RAD001 did not affect calcitonin and carcinoembryonic antigen secretion in TT cells and in human MTCs. RAD001 seems to have potent anti-proliferative effect in human MTC cells, which suggest that clinical trials of this agent are of considerable interest.

Subacute thyroiditis : Clinical characteristics and treatment outcome in fifty-six consecutive patients diagnosed between 1999 and 2005

Objective: To identify predictive factors of clinical outcome of subacute thyroiditis. Design: Retrospective case series of 56 consecutive patients treated in 3 outpatient clinics between 1999 and 2005. Medical records were reviewed for demographic data, seasonal disease distribution, laboratory and clinical course, treatment, and short-term outcome. Main outcome: Mean age was 48.6±12 yr; 70% were females. Twenty-five percent had antithyroid antibodies and 9% had recurrent disease. Differences in occurrence by season were not significant (p=0.28). Ultrasound, performed in 35 patients, revealed thyroid nodules in 25 (median size, 17 mm). Ten patients received no treatment, and 43 received either non-steroidal anti-inflamatory drugs (NSAID) (no.=25) or glucocorticoids (no.=18); data for 3 patients were missing. Median disease duration was 77 days; mean peak free T4 (FT4) level was 43.7±25.3 pmol/l. A hypothyroid phase was documented in 31 patients, and remained permanent in 6. Peak FT4 level, but not erythrocyte sedimentation rate or clinical score, was positively correlated with the highest TSH level and with disease duration. Untreated patients had less severe clinical disease than treated patients, but a similar outcome. Patients given glucocorticoids had a shorter overall disease duration (p=0.03), with no differences in duration of hyperthyroidism, peak FT4 or highest TSH levels, compared with patients given NSAID. Conclusion: Subacute thyroiditis follows an unpredictable clinical course that is hardly affected by its clinical features or treatment.

Pituitary-directed medical therapy with pasireotide for a corticotroph macroadenoma: pituitary volume reduction and literature review.

Hypercortisolism due to an ACTH-secreting pituitary adenoma (Cushing’s disease) is a chronic condition associated with high morbidity and mortality if inadequately managed. Pasireotide is a multireceptor-targeted somatostatin analogue and is the only approved medical therapy for Cushing’s disease that treats the underlying cause of the disorder. This paper reviews the available literature for medical-therapy-induced adenoma volume reduction in patients with Cushing’s disease and reports the experience of a 53-year-old surgically, radiologically and medically naïve (de novo) female with a pituitary macroadenoma who declined surgery. This patient was treated with pasireotide as first-line therapy as part of the largest randomized Phase III study evaluating a medical therapy in patients with Cushing’s disease (SOM230B2305 trial). Subcutaneous pasireotide significantly decreased tumor volume, suppressed cortisol secretion, and improved clinical signs and symptoms of Cushing’s disease in this patient. Based on this experience, first-line pasireotide has the potential to achieve substantial tumor volume reduction in addition to significant improvements in cortisol levels and signs and symptoms in patients with Cushing’s disease for whom surgery is not an option.

Adrenal incidentaloma: Clinical characteristics and comparison between patients with and without extra-adrenal malignancy

Adrenal incidentaloma (AI) is frequently found in patients with a history of malignancy and, as such, is not always considered a true incidental finding. Objective: To compare the short-term clinical and biochemical behavior of adrenal incidentalomas between oncology and non-oncology patients. Design: Retrospective comparative case series of 100 consecutive patients with adrenal incidentaloma, followed from 1995 to 2005 in the endocrinology clinic of a tertiary university medical center. Main outcome: A history of malignancy was present in 32 patients. Median follow-up was 24 months. Mean tumor size was 24±10 mm. Endocrine evaluation yielded functional abnormalities in 12.2% (subclinical Cushing’s 7.4%, Cushing’s syndrome 1.1 %, hyperaldosteronism 1.3%, pheochromocytoma 3.6%). During follow-up, adrenal function remained unchanged in all patients, but tumor growth was seen in 12.5%. Compared to the non-oncology patients, the oncology group had a higher mean age (67.5±9.6 vs 59.4±1.3 yr, p=0.001) and greater tumor growth (23.3% vs 7%, p=0.035), with no significant differences for tumor size, functional abnormalities, and extent of change in tumor size. Surgery was performed in 9 patients (3 oncologic) and revealed metastasis in one. None of the other patients had clinical or radiological findings suggesting adrenal malignancy. Conclusion: Our study suggests a similar clinical behavior of adrenal incidentaloma in oncology and non-oncology patients. More studies are needed to assist clinicians in selecting oncology patients with AI for whom a more conservative approach can be recommended.