1. עדכונים בטיפול במחלת קושינג »ד"ר גבי דיקשטין »ביה"ח בני ציון »חיפה

2. microadenoma (85%) hyperplasia (10%) macroadenoma (5%) Treatment Surgery RadiotherapyMedical therapy ? Disease persistence Disease recurrence ACTH-secreting pituitary tumors Cushing’s disease

5. RADIOSURGERY FOR CUSHING’S DISEAE CONVENTIONAL IRRADIATION LONG TIME TILL EFFECTIVE POSSIBLE RISK FOR CVA POSSIBLE RISK FOR BRAIN TUM GAMMA KNIFE GAMMA-RAY PHOTONS LINAC X-RAY PHOTONS

6. LINAC FOR CUSHING’S DISEASE IN ISRAEL “Beyond physical or theoretical considerations, the quality of any treatment has to be judged by its clinical results” (Spigelmann, IMAJ 2005) Similar outcome: AV malformations, Acoustic Neurinomas, Meningiomas, Brain Metastasis – no mention of pituitary tumors! "בבית חולים שיבא טופלו 6 חולים עם מחלת קושינג. נכון הוא שאף לא חולה אחד הבריא מהמחלה " (שפיגלמן, תצהיר לבית משפט, 2005)

7. Radiation therapy for Cushing’s disease: a review (Piruitary, 2002) Conventional Radiation: 10 studies, 255 patients, 64% remissions. Gamma Knife: 8 studies,185 patients, 78% remissions. LINAC 1 study, 1 patient, ? Remissions.

8. Stereotactic radiosurgery for Cushing’s disease (Neurosurg Focus, 2004) Gamma Knife 6 studies, Cure rate 35 – 90%. LINAC No studies mentioned.

9. Stereotactic radiosurgery for pituitary adenomas: a review of the literature (J Neuro-oncology, 2004) Gamma Knife 18 studies, 227 patients, 55% remissions. LINAC 2 studies, 6 patients, 33% remissions.

10. Efficacy of LINAC vs Gamma knife LINAC (Vanderbilt) 35 patients 17 (49%) remissions 4 (11%) recurrences 13 (37%) success 14 (40%) pit insuff. Gamma Knife (UVa) 45 patients 33 (73%) remissions 4 (9%) recurrences 29 (64%) success 14 (31%) pit insuff.

11. PATIENTS SENT FOR GAMMA KNIFE AT UVa FOLLOW UP (mo) TIME (mo) REM.TSSNAME 424+3O.A. 920+4S.G. *Response to caberg. 1* ?2C.S. *Borderline high UFC 6*?1N.N.

12. Compounds employed in Cushing’s disease Acting at peripheral receptor level – Glucocorticoid antagonist: mifepristone (RU486) –Acting at adrenal gland level – Cytotoxic effect : mitotane – Steroidogenesis inhibitors:metyrapone,ketoconazole –Acting at hypothalamic-pituitary level –Somatostatin analogs: octreotide, SOM230 –Dopamin agonists: bromocriptine, cabergoline –PPAR-γ binding agents: rosiglitazone (avandia)

13. METYRAPONE FOR CUSHING’S DISEASE Years – 1978 – 1988 11 patients, 6F, 5M, ages 15 – 47. Dose – 1.25 – 3.0 gr. Duration – 8 – 48 months. Basal UFC – 543 ± 108 µg/24h. Final UFC – 85 ± 6.5 µ g/24h.

14. KETOCONAZOLE FOR CUSHING’S DISEASE Years - 1986 – 1995. 11 patients, F11, M 0. Dose – 600 – 800 mg. Duration – 6 – 85 months. Basal UFC – 448 ± 76 µ g/24h. Final UFC – 75 ± 6.5 µ g/24h.

15. ROSIGLITAZONE IN CUSHING’S DISEASE RATIONAL Rosiglitazone (avandia) is a compound with peroxisome proliferator-activated receptor-γ (PPAR-γ) – binding affinity. It was found to suppress ACTH secretion in mice and in pituitary tumor cells.

18. SOM230 (pasireotide) SOM230 is a novel, multi-ligand, somatostatin analog with activity at sst 1, 2, 3 and sst 5 receptors Compared with octreotide, SOM230 has 30- and 40- fold higher binding affinity at sst 1 and sst 5 receptors, respectively, and comparable affinity for sst 2 receptors SOM230 potentially offers therapeutic benefits in classical somatostatin analog indications, such as acromegaly and neuroendocrine tumours SOM230 potentially offers therapeutic benefits in conditions where receptor subtypes other than sst 2 are important, such as Cushing’s Disease, where 75% are sst5 positive.

19. SOM230 IN CUSHING’S DISEASE – Boscaro 2005 Open – label, multicenter study. Nine Cushing’s disease patients. Fixed dose of SOM230 600 mcg sc bid for 15 days. Adverse effects – diarrhea, abdominal pain and nausea (mild). Six patients finished study (unrelated reasons). RESULTS All patients had reduction of UFC. One patients had normalization of UFC – 2546 nmol/24h to 115 nmol/24h. Five patients had 17-61% reduction in UFC.

20. Dopaminergic drugs were found to be sporadically effective in inhibiting ACTH and cortisol secretion in Cushing ’ s disease Dopamine receptors have never been demonstrated on corticotroph pituitary tumours Dopamine receptors have never been demonstrated on corticotroph pituitary tumours ACTH-secreting pituitary tumors Background

21. ACTH-secreting pituitary tumors “Lamberts Hypothesis” Two different types of ACTH-secreting tumors may be identified: those originating from the anterior lobe and those originating from the pars intermedia of the pituitary gland Two different types of ACTH-secreting tumors may be identified: those originating from the anterior lobe and those originating from the pars intermedia of the pituitary gland The ACTH-secreting tumors originating from the pars intermedia may be sensitive to dopamine agonists The dopamine agonist responsive ACTH-secreting tumors may be recognized by: 1)relative insensitivity to dexamethasone; 2)hyperprolactinemia; 3)ACTH suppression after acute administration of bromocriptine

22. ACTH-secreting pituitary tumors Cabergoline Experience: A case of Nelson Syndrome Before CAB After CAB plasma ACTH (pmol/L) 1-year treatment with Cabergoline Pivonello et al., J Clin Endocrinol, 1999

23. To evaluate dopamine receptor expression on corticotroph tumours derived from a series of patients with Cushing ’ s disease To evaluate the effect of 3-month cabergoline treatment on ACTH and cortisol secretion in a series of patients with Cushing ’ s disease Aims

25. In vivo Response to cabergoline treatment and Immunohistochemical results Case 1234 56 78 Urinary cortisol (nmol/day) Response to 3-month cabergoline treatment 910 Immunohistochemical results Histology ACTH PRL D 2 DR A+--A+-- H+++H+++ A+-+A+-+ A ++ + A ++ A ++ + ++ H ++ + - A ++ - ++ A ++ - ++ A ++ -

26. Dopamine D 2 receptors are heterogeneously expressed in 75% of ACTH-secreting pituitary tumours Short-term cabergoline treatment is able to induce normalization of ACTH and cortisol levels in 50% of cases with Cushing ’ s disease ACTH and cortisol suppression after cabergoline treatment significantly correlated with the presence of D 2 dopamine receptors on the corticotroph tumours The presence of the D 2 short seems to be associated to the best responsiveness of ACTH and cortisol to cabergoline treatment. Conclusions

27. UFC (  g/24h) TIME (MONTHS) GK D GAMMA KNIFE & DOSTINEX IN THREE PATIENTS

28. CABERGOLINE TREATMENT WEEKLY DOSE NEEDED – 2 – 3 MG. DOSTINEX (CABERGOLINE) – 0.5MG - 8 PILLS IN BOTTLE – 285 SHEKEL: 71 SHEKEL PER MG - 855 MONTHLY. CABASER (CABERGOLINE) – 2.0MG – 20 PILLS IN BOTTLE – 600 SHEKEL: 15 SHEKEL PER MG – 262 MONTHLY.

29. microadenoma (85%) hyperplasia (10%) macroadenoma (5%) Treatment Surgery RadiotherapyMedical therapy ? Disease persistence Disease recurrence ACTH-secreting pituitary tumors Cushing’s disease