Challenging Pituitary Cases

Transcription

1 Challenging Pituitary Cases Sue Samson, MD, PhD, FRCPC, FACE Associate Professor of Medicine and Neurosurgery Medical Director Pituitary Center Baylor College of Medicine, Houston TX Tom Blevins, MD, FNLA, FACE, ECNU Texas Diabetes and Endocrinology Austin, TX

2 Case of Recurrent Cushings Disease 42 y/o male In 2005 presented with facial swelling 24 hour ufc was 853 ug/day, ACTH 187 and random cortisol was 44 ug/dl Chest CT and Octroscan-neg and 8mg overnight dex suppression-cortisol was 25 ug/dl Pituitary MRI unremarkable-? Fullness on the L and IPSS lateralized to the L (MDA) 11/05 TPS, removal of L sided adenoma, cortisol to 1.2 ug/dl post op Post op MRI clear 4/07 ufc 317 ug/day and asymptomatic and 5/07 repeat TPS followed by persistent hypercortisolism 8/07 stereotactic radiosurgery followed by ketoconazole 8/08- off ketoconazole and cortisols normal 2012-gradual recurrence of hypercortisolism (ufg 123 ug/day) and restarted ketoconazole LFT elevation on ketoconazole Trial of cabergoline --nausea and headache What next?

3 Cushings Disease Transsphenoidal surgery is the primary therapy in most patients, with remission rates of 65 to 90% Relapse occurs in up to 30% of patients. Second-line options include the following: Repeat pituitary surgery Radiation therapy Bilateral adrenalectomy Medical therapy

4 Treatment of Cushing s Syndrome: An Endocrine Society Clinical Practice Guideline Nieman et al, J Clin Endocrinol Metab, August 2015, 100(8):

5 Pasireotide Indication Somatostatin analog indicated for the treatment of adult patients with Cushing s disease for whom pituitary surgery is not an option or has not been curative Mifepristone Indication Glucocorticoid receptor blocker indicated to control hyperglycemia secondary to hypercortisolism in adult patients with endogenous Cushing s syndrome who have type 2 diabetes mellitus or glucose intolerance and have failed surgery or are not candidates for surgery

6 Recurrent Cushings Back to our patient 2013-started Pasireotide 0.3mg bid and UFC was 12.7 ug/day 12/16 -On 0.5mg bid-no Cushing's sx. Ufc 35 ug/day. Glucose pre-pasireotide was mg/dl and since then has ranged between 94 and 105 mg/dl fasting 4/17 -fbs was 105 with an A1c of 6.0% Igf-1 was has ranged between 46 and 82 ng/ml on rx ( ng/ml)

7 Pasireotide Binds with high affinity to 4 of the 5 somatostatin receptor subtypes (sst)- particularly high affinity for sst5 Pituitary corticotroph adenomas primarily express sst5 Sst2-preferential somatostatin analogs (octreotide and lanreotide)- not effective in treating ACTH dependent hypercortisolism sst1, sst2, and sst5 expressed on 100, 44, and 87% of Beta cells 26, 89, and 35% of Alpha cells

8 NEJM 366;10 March 8, 2012 Double-blind, phase 3 study, 162 adults with Cushing s disease and a UFC of at least 1.5 times ULN to receive subcutaneous pasireotide at a dose of 600 μg (82 patients)or 900 μg (80 patients) twice daily.

9 Colao, et al. NEJM 366;10 March 8, 2012

10 Pasireotide-Hyperglycemia and Diabetes Hyperglycemia-related events. Hyperglycemia (40%), diabetes mellitus (18%), increased HbA1c (11%), and type 2 diabetes mellitus (9%). Increases in fasting plasma glucose (FPG) and hemoglobin A1c (HbA1c) were seen soon after initiation and were sustained during the treatment period. A new antidiabetic medication was initiated in 74 of the 162 patients. In patients not receiving glucose-lowering medications at baseline, at least one medication was started during the study in 53 of 129 patients (41%); 21 of 33 patients (64%) receiving antidiabetic medication at baseline received at least one additional agent At one-month follow-up visits following discontinuation, mean FPG and HbA1c levels decreased but remained above baseline values. Colao, et al. NEJM 366;10 March 8, 2012

11 Hyperglycemia Associated With Pasireotide: Results From a Mechanistic Study in Healthy Volunteers Henry et al, J Clin Endocrinol Metab, August 2013, 98(8):

12 45 healthy male volunteers randomized to pasireotide 600 (n 19), 900 (n 19) sc twice a day for 7 days. An OGTT, a hyperglycemic clamp test, a hyperinsulinemic -euglycemic clamp test were performed on 3 consecutive days at baseline and treatment end Henry et al, J Clin Endocrinol Metab, August 2013, 98(8):

13 Case of Recurrent Cushings Disease Back to our patient What would you do if his fbs was 134mg/dl and A1c was 7.5% after starting pasireotide? A. Stop the med as having diabetes is worse than having Cushing s B. Change to mifepristone C. Suggest seeing a dietitian and exercising and starting a medication if necessary

14 Case of Recurrent Cushings Disease Which med would you start for the hyperglycemia? a. Metformin and then an SGLT-2 if needed b. A TZD since pasireotide causes insulin resistance c. Metformin and then a DPP 4 inhibitor or GLP-RA d. Insulin since oral meds have been proven to be ineffective in this setting

15 Management of hyperglycemia associated with pasireotide: Healthy volunteer study 1 dose Pasireotide Metformin 7 days Pasireotide Nateglinide Vildigliptin Baseline Liraglutide Vildagliptin and liraglutide were most effective in minimizing pasireotide-associated hyperglycemia in healthy volunteers Breitschaft et al Diabetes Res Clinical Practice 103:

16 Managing hyperglycemia in patients with Cushing s disease treated with pasireotide: medical expert recommendations Colao et al, Pituitary (2014) 17:

17 Recurrent Cushings: Case 2 56 y/o female has a hx of Cushing's disease dxed in two TPS surgeries in 2002 and in After a petrosal sinus sampling in 2014 which was not directional, she had repeat TPS in 5/14 and an adenoma was removed. Pre surgery UFC was high at 92.0 ug/day and total cortisol was 24.2, ACTH was 40. Post op her 24 hour ufc was 54 ug/day (slightly elevated) and her am cortisol was Her 7/14-24 hour ufc was 63.9 with an am cortisol of Her 10/14 lab showed a 24 hour ufc of 66.7 mcg/24 hours and an ACTH of 26 and am cortisol of 22.4 She declined XRT and was placed on Pasireotide 0.6 mcg bid since late May (had h/a with cabergoline) She had a 24 hour ufc of 16.2 in 11/16 and her am cortisol was Her 24 hour ufc was 18.7 in 3/17 Her pre-pasireotide fbs was 98 mg/dl and her A1c was 5.8%. Her fbs rose to 128 mg/dl (SMBG mg/dl) and A1c to 7.2% after 6 months of pasireotide She didn t tolerate metformin and she had a minimal response to a DPP 4 med. She was placed on a GLP-1 RA in 2016 and her 3/17 fbs was 104mg/dl and her A1c was 6.4%.

18 Recurrent Cushings: Case 2 Would mifepristone have been a better choice for her?

19 Mifepristone Progesterone receptor antagonist that has glucocorticoid receptor antagonist activity at higher concentrations More than three times the binding affinity for the glucocorticoid receptor than dexamethasone It does not bind to the mineralocorticoid receptor

20 Mifepristone-Warnings and Precautions Adrenal insufficiency: Monitor for signs and symptoms of AI Hypokalemia: Correct prior and monitor for during treatment Vaginal bleeding and endometrial changes Use with caution if patient also has a hemorrhagic disorder or is on anticoagulant therapy QT interval prolongation: Avoid use with QT intervalprolonging drugs Use of Strong CYP3A Inhibitors: Concomitant use can increase mifepristone plasma levels Use only when necessary and limit mifepristone dose to 600 mg

21 24-wk multicenter, open-label trial after failed multimodality therapy 50 adults with endogenous CS associated with type 2 diabetes mellitus/impaired glucose tolerance (C-DM) or a diagnosis of hypertension alone (C-HT). Mifepristone was administered at doses of mg daily Main Outcome Measures: Change in area under the curve for glucose on 2-h oral glucose test for C-DM Change in diastolic blood pressure from baseline to wk 24 for C-HT Fleseriu et al. J Clin Endocrinol Metab, June 2012, 97(6):

22 During treatment, 72% of the 43 patients had at least a 2-fold increase in ACTH, cortisol, or both. These changes were observed early (by d 14), plateaued from wk 10 24, and declined to baseline levels at the follow-up visit 6 wk after discontinuation of mifepristone. Late-night salivary cortisol increased 7.92-fold (1.43) at wk 16, and urinary free cortisol increased 7.70-fold (15.29) at wk 24. At the 6-wk follow-up visit, ACTH and cortisol (serum and urine) declined to near baseline levels. Twenty-two patients had a serum potassium level less than 3.5 meq/liter, but only three experienced severe hypokalemia <2.5 meq/liter Mifepristone does not decrease cortisol production, measurement of this hormone should not be performed during treatment Fleseriu et al. J Clin Endocrinol Metab, June 2012, 97(6):

23 Significant decreases in plasma and fasting plasma glucose (P 0.03), as measured by OGTT from baseline to wk 24. The OGTT response curves at each visit were statistically different compared with baseline Fleseriu et al. J Clin Endocrinol Metab, June 2012, 97(6):

24 Fleseriu et al. J Clin Endocrinol Metab, June 2012, 97(6):

25 Mifepristone-safety AEs were reported in 88% of patients during mifepristone treatment, Nausea (48%) fatigue (48%) headache (44%) decreased blood potassium (34%) arthralgia (30%) vomiting (26%) Peripheral edema (26%) HTN (24%) dizziness (22%) Decreased appetite (20%) endometrial thickening (20%) Fleseriu et al. J Clin Endocrinol Metab, June 2012, 97(6):

26 Mifepristone Pituitary MRIs were obtained in 41patients; 17 had visible tumors, 10 of which were macroadenomas, and the remaining 24 did not have visible tumors after surgery. MRIs were stable at wk 10 and 24 in all cases except one. This patient s adenoma increased in size at wk 10, leading to treatment discontinuation. Fleseriu et al. J Clin Endocrinol Metab, June 2012, 97(6):

27 The Study of the Efficacy and Safety of Mifepristone in the Treatment of Endogenous Cushing s Syndrome (SEISMIC) was a 24-week, open-label study of mifepristone, Long-term extension (LTE) is a multicenter U.S. study. 43 CD patients were enrolled in SEISMIC with 27 continuing into the LTE study. Fleseriu et al. J Clin Endocrinol Metab, October 2014, 99(10):

28 Changes in ACTH Levels and Corticotroph Tumor Size LTE Mifepristone Fleseriu et al. J Clin Endocrinol Metab, October 2014, 99(10):

29 Recurrent Cushings: Case 3 35 y/o with Cushings disease diagnosed in She had transphenoidal resection in 2009, 2013 and most recently again in Her first 2 surgeries were performed in Austin, her most recent surgery UTSW in Dallas. Labs in 2017 show biochemical evidence for persistent Cushing's (UFC and salivary cortisol) Radiation is being considered. She takes desmopressin for DI and T4 hypothyroidism. Baseline weight was 175 lbs, she is now 380 lbs She has IGT, a recent HgA1C was 6.1%--acanthosis nigricans on exam. Her recent fasting glucose was 96 mg/dl She is on metformin She has infertility. She is seeing a Reproductive Endocrinologist and has findings consistent with secondary hypogonadism. She is interested in fertility and is currently on an OCP

30 What is the next step? a) Start cabergoline b) Start mifepristone c) Start pasireotide d) IPSS and consider another surgery e) Send her to see Dr Samsom

31 Challenging Pituitary cases Susan L Samson MD PhD FRCPC FACE Associate Professor of Medicine and Neurosurgery Medical Director Pituitary Center Baylor College of Medicine, Houston TX

32 Cushing s: When all else fails 64 yo female Presented Jan 2017 to outside clinic to establish care Had had mild weight gain (went on Weight watchers and lost 10 lbs) Increased BP and started on lisinopril No specific complaints Routine bloodwork Na 145/K 3.1/Glucose 154 mg/dl

33 Cushing s: When all else fails Repeat blood work 4 weeks later Na 145 K+ <2 Glucose 242 mg/dl Cortisol 110 mcg/dl, ACTH 162 pg/ml Started on spironolactone 50 mg, KCL 40 meq twice a day, metformin Referred to Endocrinologist who documented No history of rapid weight gain Muscle weakness and easy bruising Mild facial rounding, mildly increased dorsal cervical and supraclavicular fat pads No abdominal striae Bruise on leg from a fall Bilateral pedal edema, 2+ Normal mood and affect

34 Cushing s: When all else fails Repeat blood work 4 weeks later Na 145/K <2/Glucose 242 mg/dl Cortisol 110 mcg/dl, ACTH 162 pg/ml Started on spironolactone 50 mg, KCL 40 meq twice a day, metformin Referred to Endocrinologist who documented No history of rapid weight gain Muscle weakness and easy bruising Mild facial rounding, mildly increased dorsal cervical and supraclavicular fat pads No abdominal striae Bruise on leg from a fall Bilateral pedal edema, 2+ Normal mood and affect UFC 13000

35 Pituitary MRI Suspected right-sided subtle pituitary microadenoma maximal transverse dimension 4 mm seen only on dynamic

36 Cushing s: When all else fails Referred to the Pituitary Center

37 IPSS

38 IPSS Minutes post-crh ACTH Peripheral pg/ml Right pg/ml Left pg/ml

39 IPSS Minutes post-crh ACTH Peripheral pg/ml Right pg/ml Left pg/ml

40 What next? The search for ectopic sources

41 Chest CT 1 x 1.3 cm nodule is seen in the left lung base 7 mm calcified granuloma is seen in the right lower lobe

42 1.6 cm hypodense lesion in pancreatic tail

43 Abdominal CT

44 Tracer distribution is physiological. Bilateral pleural effusions. Octreotide Scan

45 PET Scan Chest: Within the right upper lobe there is a hypermetabolic nodule measuring 18 x 9 mm with maximal SUV of 3.31 Within the right lung apex there is a somewhat nodular area measuring 13 x 6 mm, with maximal SUV of 1.63

46 Work-up interrupted. 4/7 to 4/26/2017 Perforated bowel from diverticulitis Sigmoid colectomy with colostomy 5/2/2017 Readmitted from SNF for shortness of breath Required intubation and ICU care Trach

47 PET Scan Chest: Within the right upper lobe there is a hypermetabolic nodule measuring 18 x 9 mm with maximal SUV of 3.31 Within the right lung apex there is a somewhat nodular area measuring 13 x 6 mm, with maximal SUV of 1.63

48 Still looking. FNA by bronchoscopy Small fragments of bronchial epithelium Negative for malignancy Addendum: rare fungal hyphae elements 1 out of 4 media Aspergillus fumigatus

49 1.6 cm hypodense lesion in pancreatic tail

50 Radiation fractionated external beam or stereotactic radiosurgery cure in 50-60% of good candidates but requires years for full effect Cabergoline Targeting ACTH secretion at the level of the adenoma Not FDA approved for this indication A subset of patients with mild-moderate CD Steroidogenesis inhibitors (adrenostatic) Ketoconazole Multiple steps in cortisol synthesis EMA/FDA 2013 black box warning re: liver failure Cushing s is off-label Etomidate Multiple steps in cortisol synthesis ICU monitoring Metyrapone 11-β-hydroxylase inhibitor approved as a diagnostic agent Have to contact the distributer for special allocation Cushing s is off-label Mitotane (adrenolytic) Multiple steps in cortisol synthesis Adrenalectomy risk of Nelson s

51 Cushing s: When all else fails. Ketoconazole 200 mg BID Voriconazole Metyrapone 250 mg q6h Intubation Ketoconazole 200 mg BID Metyrapone 250 mg q6h Ketoconazole Etomidate 3 mg/h Ketoconazole 400 mg BID Metyrapone 500 mg q6h Metyrapone 750 mg q6h Metyrapone 1000 mg q6h

52 CT Abdomen Feb 22, 2017 April 10, 2017

53 Pathology "right adrenal" consists of a 35 gm adrenalectomy measuring 6.6 x 4.5 x 1.5 cm. "left adrenal" consists of a 47 gm adrenalectomy measuring 7 x 4 x 2 cm. adrenal gland to be mottled, red-brown, green-yellow discoloration with no distinct mass seen. Scattered extramedullary hematopoiesis is seen in the adrenal parenchyma. Focal nuclear atypia are seen in the hyperplastic adrenocortical tissue. No definitive mass or malignancy is seen.

54 Cushing s: when all else fails 6/26/2017 Discharged to rehabilitation at SNF Currently on maintenance dose hydrocortisone and fludrocortisone.

55 Where do we go from here? Could normalization of cortisol help to manifest an elusive ectopic tumor? 7-27% are remain occult after all imaging modalities explored Cortisol effects on SSTR expression? Removal of cortisol feedback on tumor? % octreotide inhibition of CRHstimulated ACTH secretion Tyrrell et al JCEM 40: Lamberts et al Acta Endocrinologica 120: De Bruins et al Mifepristone effects on Tumor somatostatin receptor expression.. JCEM 97:

56 Where do we go from here? 68 Ga-DOTATATE (DOTA-DPhe1,Tyr3-octreotate) approval by the U.S. Food and Drug in 2016 NETSPOT (SSTR Gallium 68 DOTATATE PET/CT imaging) now included in the National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology version 2017 update for the evaluation of neuroendocrine tumors Meta-analysis of 14 studies SSTR PET/CT after Octreotide scanning led to a change in management in 39% of patients Barrio et al J. Nucl. Med. 58(5):

57 68 Gallium-SSTR-PET/CT had 100% sensitivity among covert cases Isidori et al Conventional and Nuclear Medicine Imaging in Ectopic Cushing's Syndrome: A Systematic Review.J Clin Endocrinol Metab. 2015;100(9):

58 Octreotide is ineffective for patients with Cushing s disease (known since the 90s) % octreotide inhibition of CRHstimulated ACTH secretion +Dex AtT-20 cells Tyrrell et al JCEM 40: Lamberts et al Acta Endocrinologica 120:

59 Refractory Acromegaly 53 yo teacher from Colorado Increased ring size (up by 5 sizes)---prior to dx, now stable Increased shoe size 8 >>> 11--prior to dx, now stable Carpal Tunnel Syndrome- stable Skin Tags Hair Loss Snoring and diagnosis of sleep apnea Enlarged tongue and difficulty with speech Loss of menstrual cycles 6 years previous. Knee pain Uncontrolled diabetes on 180 units insulin per day (HbA1C 9%)

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61 53 yo teacher from Colorado Increased ring size (up by 2 sizes)---prior to dx, now stable Increased shoe size 8 >>> 11--prior to dx, now stable Carpal Tunnel Syndrome- stable Skin Tags Hair Loss Snoring and diagnosis of sleep apnea Enlarged tongue and difficulty with speech Loss of menstrual cycles 6 years previous. Knee pain Uncontrolled diabetes on 180 units insulin per day (HbA1C 9%)

62 Very Vascular tumor Pre-op

63 MRI FINDINGS: There is a lobulated, noncystic, diffusion restricted sellar based mass with negligible peripheral enhancement that measures 3.2 cm AP x 2.9 cm transverse x 3.5 cm craniocaudal. The mass extends superiorly to splay and thin the optic chiasm. The mass invades the left cavernous sinus. The mass remodels the floor of the sella turcica, with encroachment into the left greater than right sphenoid sinuses. The mass extends posteriorly to contact the left mammillary body and partially efface the interpeduncular and superior prepontine cisterns. The mass encircles, but does not compress, the left carotid siphon and P1 segment left posterior cerebral artery, which has a fetal origin. The mass partially encircles, but does not compress, the supraclinoid right internal carotid and distal basilar arteries. The native pituitary gland is displaced to the right, lying over the superior margin of the cavernous segment right internal carotid artery. The infundibulum is thinned and draped over the right superolateral margin of the tumor.

64 Dr. Yoshor (NSx) conveyed that there was a lot of involvement of the tumor around vascular structures including a posterior communicating artery which required caution rather than an aggressive resection. The pathology also was unique and with co-staining for GH and PRL and there was neuronal metaplasia.

65 MICROSCOPIC DIAGNOSIS: PITUITARY GLAND, TRANSSPHENOIDAL HYPOPHYSECTOMY (SPECIMEN #1): MIXED SOMATOTROPHIC AND PROLACTIN CELL ADENOMA WITH NEURONAL METAPLASIA PITUITARY GLAND, TRANSSPHENOIDAL HYPOPHYSECTOMY (SPECIMEN #3): MIXED SOMATOTROPHIC AND PROLACTIN CELL ADENOMA WITH NEURONAL METAPLASIA SMALL FRAGMENT OF ADENOHYPOPHYSIS Comment: The tumor cells are positive for growth hormone and prolactin, including the metaplastic neuronal component. Some of the neuronal component is also positive for epithelial markers (Cam 5.2 and pan-cytokeratin). Tumor is negative for GFAP and EMA. Stains for TSH, LH, FSH, p53, and ACTH are negative in tumor. Both neuropil and neurons are strongly positive for neurofilament. MIB-1 labeling index is less than 1%.

66 Post-op 1 month

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69 Cabergoline and Acromegaly: Sandret L et al. JCEM 2011;96: a Meta-analysis IGF-I levels during treatment with somatostatin analogs alone and after cabergoline addition 5 studies 52% achieved normal IGF-I levels The change in IGF-I was related to baseline IGF-I level not to the dose of cabergoline, the duration of treatment, or the baseline prolactin concentration.

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71 Post-op 1 month 6 months

72 1 month 6 months

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78 1 month 3 years

79 1 month 3 years

80 3 years

81 Pasireotide increases hyperglycemic evens or worsens glycemic control for patients without diabetes/igt/diabetes on oral medications BUT.for insulin dependent patients, decreased insulin requirements over time (down from 180 units to 40 units per day with episodes of hypoglycemia and improved HbA1C). Ref. Range 3/4/ :12 6/3/ :40 9/16/ :44 11/3/ :00 6/7/ :32 HbA1C Latest Ref Range: % 9.0 (H) 8.1 (H) 7.5 (H) 7.9 (H) 7.6 (H)

82 Cushing s Recurrence 38 yo presented with weight gain, diabetes and hypertension and found to have ACTH dependent CS in mm adenoma left gland

83 Case: EG TSR 2006 and went into remission HbA1C normalized off of medication Did not require BP meds

84 Case: EG 2011 had increased BP and re-diagnosed with Dm2 described similar symptoms to her initial presentation Second TSR 2012 of 5 mm area on left side

85 Case: EG Post-op, mild decrease in ACTH/cortisol but not in remission Worsening symptoms and cortisol levels over the next 6 months

86 Case: EG MRI of the sella at 3 months did not reveal any visible disease treatable by surgery or radiosurgery Ketoconazole resulted in elevated liver enzymes which normalized off of the medication

87 Case: EG MRI of the sella at 3 months did not reveal any visible disease treatable by surgery or radiosurgery Ketoconazole resulted in elevated liver enzymes which normalized off of the medication What are our Medical options for her?

88 Case: EG Started on 300 mg Mifepristone K+ 3.9 at 2 weeks, 3.5 at 4 weeks Added PO K+ and titrated up to 600 mg Patient called to say her legs were swollen. And she had a dark rash.

89 SEISMIC: AEs Peripheral edema Hypokalemia /Alkalosis K+ usually (occasionally <2.5) Increased BP (12/40 of all with HTN baseline) Fleseriu et al. J Clin Endocrinol Metab, June 2012, 97(6):

90 SEISMIC: AEs Peripheral edema Hypokalemia /Alkalosis K+ usually (occasionally <2.5) Increased BP (12/40 of all with HTN baseline) Action of cortisol at the aldosterone receptor as it overwhelms 11-β-HSD Treated with spironolactone Titrated to 900 mg Fleseriu et al. J Clin Endocrinol Metab, June 2012, 97(6):

91 Case: EG Baseline 1 month 6 months Cortisol (mcg/dl) ACTH (pg.ml)

92 SEISMIC LTE: Tumor Size Baseline Progressed >2 mm Stable (not visible or same size) Regressed Non-visible 20 1 (4 mm) Micro Macro 7 3* 3 1 N = 36, 12 to >30 months of therapy *Cavernous sinus invasion, 2 with radiation In the core, one patient discontinued due to growth which manifested at 10 weeks Fleseriu et al. J Clin Endocrinol Metab, 2014, 99:

93 Case:EG Call from ER that patient is there with nausea and vomiting and fever.

94 SEISMIC: AEs 88% of patients Nausea (48%) Fatigue (48%) Headache (44%) Low BP (34%) Arthralgia (30%) Vomiting (26%) Peripheral edema (26%) HTN (24%) Dizziness (22%) Decreased appetite (20% Endometrial thickening (20%)

95 SEISMIC: AEs 88% of patients Nausea (48%) Fatigue (48%) Headache (44%) Low BP (34%) Arthralgia (30%) Vomiting (26%) Peripheral edema (26%) HTN (24%) Dizziness (22%) Decreased appetite (20%) Endometrial thickening (20%)

96 SEISMIC: AEs Clinical adrenal insufficiency reported in two patients and symptoms consistent with AI in five instances Withdraw mifepristone Administer moderate dose dexamethasone (2-4 mg q6-12h) because need to overcome the high affinity of M for the receptor (hydrocortisone won t help you). Fleseriu et al. J Clin Endocrinol Metab, June 2012, 97(6):

97 Case: EG Call from ER that patient is there with nausea and vomiting and fever. Mifepristone stopped and Dex 2 mg BID administered for 5 days Rapid flu test positive Mifepristone re-instated

98 Case:EG Weight loss Increased exercise tolerance HbA1C 8.3% to 7.2% Improved wellness

99 SEISMIC: AEs Endometrial effects Vaginal bleeding in premenopausal women (5) Endometrial thickening was reported as an AE in 10 women Three women underwent dilatation and curettage for unresolved endometrial thickening. Prolonged metrorrhagia in two of them after discontinuing mifepristone Not thought to be a precancerous condition Fleseriu et al. J Clin Endocrinol Metab, June 2012, 97(6):

100 Why E.G? Mifepristone Positive Considerations Is a fast clinical response needed? (e.g. surgery, procedure) Hyperglycemia/Dm2 Negative considerations Reproductive/menstrual status? Adherence to medications/visits (K+, etc.) Tumor volume/aggressiveness

101 Acknowledgements Daniel Yoshor MD Mas Takashima MD Steve Carpenter MD Sherly Sebastian NP Baylor St. Luke s Medical Center