2. ACROMEGALY Prof. Gaetano Lombardi Prof. Gaetano Lombardi Dept. of Clinical and Molecular Endocrinology and Oncology University “Federico II”, Naples, Italy

4. Sporadic pituitary tumor

5. Syndromic/Familial Pituitary Tumors

8. MEN1 Pituitary Tumor Primary Hyperparathyroidism Endocrine Pancreatic Tumor Autosomal dominant Gene Men1 11q13

9. McCune-Albright Syndrome Polyostotic fibrous dysplasia Skin pigmentation Hormonal dysfunction - Precocious puberty - Thyrotoxicosis - Gigantism - Cushing’s Syndrome Macroadenoma (50% of cases) Mutation di Gs-alpha

10. Carney Syndrome Autosomal dominant 2p16 Mutation of PRKAR1A Chiazze di iperpigmantazione cutanea Mixoma cardiaco Iperfunzione endocrina sindrome di Cushing acromegalia Hyperplasia or multiple microadenomas

11. RARE DISEASE

14. Balance of GH influences on cell growth regulation Pathogenesis of cell proliferation/apoptosis in acromegaly

15. COLON CANCER IN ACROMEGALY

19. TREATMENT GOALS Mortality rate reduction Tumor shrinkage Treatment of comorbidities Relief of symptoms directly caused by GH excess    

20. Medical Therapy SSA, DA, GH-A Radiotherapyconventional stereotactic stereotactic Surgery trans-cranium trans-sphenoidal

21. SURGERY SUCCESS RATE: 72% microadenomas, 50% macroadenomas, 17% giant adenomas Improvement in pituitary function in 60-97% Improvement of visual field defect in 70% Low morbidity and mortality (0-1%) Reduction in tumor size in 90% Tumor residual in 15-50% Complications in 5-18%

25. MEDICAL THERAPY Dopamine-AgonistsBromocriptineCabergoline Lisuride – Pergolide - Quinagolide Somatostatin Analogues OctreotideLanreotide GH-receptor antagonist GH-receptor antagonist

26. Headache Hypotension Nausea Gastro-intestinal SIDE EFFECTS

27. SOMATOSTATIN ANALOGUES EFFECTIVENESS Clinical Improvement in 70-90% Normalisation of GH levels in 65-70% Normalisation of IGF-I levels in 65-70% Tumor shrinkage >50%   

32. Baseline 5 month-OCT LAR 10 month-OCT LAR

35. SIDE EFFECTS Gastro-intestinal Biliary sludge Gallstones Diarrhea

38. PEGVISOMANT  GH analog (191 amino acids)  9 different amino acids  4 - 5 PEG  molecular weight 42 - 46000 D  half-life >70 hours  subcutaneous administration GH is not a marker of disease Goal of therapy – to reduce IGF-I levels to normal range for age and sex

39. STOP

44. IC50 nM ◊ sst1 9.3  0.1 ◊ sst21.0  0.1 ◊ sst31.5  0.3 ◊ sst4> 100 ◊ sst50.2  0.1

46. SOMATOSTATIN AND DOPAMINE RECEPTOR AGONIST

48. R.S. Auriemma, A. Cozzolino, M. De Leo, M.C. De Martino, C. Di Somma, A. Faggiano, M. Galdiero, L.F.S. Grasso, E. Guerra, F. Milone, R. Pivonello, M.C. Savanelli, P. Vitale, L. Vuolo & A. Colao Dept. of Clinical and Molecular Endocrinology and Oncology

49. QUESTION 1 Induce clinical improvement in 30% Normalize GH levels in 30% Normalize IGF-I levels in 65-70% Induce tumor shrinkage in <20%    SOMATOSTATIN ANALOGUES:

50. QUESTION 2 Normalize IGF-I levels in 30% Normalize IGF-I levels in 50% Normalize IGF-I levels in 70% Normalize IGF-I levels in up to 95%    THE GH-RECEPTOR ANTAGONIST PEGVISOMANT:

51. QUESTION 3 COLONIC NEOPLASM DEVELOPMENT IN ACROMEGALY: Is correlated to GH levels Is correlated to IGF-BP1 levels Is correlated to insulin levels Is correlated to tumor size   