Anti-cytotoxic T-lymphocyte antigen-4 (CTLA-4) therapies represent a novel approach to cancer treatment via disruption of immune tolerance to antigens located on tumor cells. Disruption of immune tolerance, however, may occur at a cost. A host of immune related adverse events (IRAEs) are associated with anti-CTLA-4 therapy. Autoimmune hypophysitis has been reported in up to 17% of patients with melanoma and renal cell carcinoma treated with this therapy. Familiarity with the spectrum of IRAEs connected to these therapies is paramount for endocrinologists, oncologists and those involved in the care of these subjects. We review here key aspects of diagnosis and treatment of anti-CTLA-4 antibody therapy resultant IRAEs. We describe the first two cases of hypopituitarism in prostate cancer subjects undergoing experimental therapy with ipilimumab. The clinical evidence strongly suggests that the prostate cancer subjects developed autoimmune hypophysitis as a consequence of anti-CTLA-4 treatment. High dose glucocorticoid treatment resulted in markedly improved symptoms, and resolution of focal symptoms and diabetes insipidus. One subject recovered pituitary-thyroid axis function after 9 months; however, both continue to require GC replacement. These cases highlight the importance of early screening and treatment for hypopituitarism in all subjects undergoing treatment with anti-CTLA-4 therapy to prevent a potentially fatal outcome from secondary adrenal insufficiency, a readily treatable disease. We recommend mandatory long term follow-up to monitor the development of other hormonal deficits.

To highlight the potential of temozolomide (TMZ) to induce rapid tumor regression in patients with aggressive corticotroph adenomas (CA) that are refractory to surgery and radiation therapy and to review use of TMZ in other pituitary tumors. We present a case of a 56-year-old male with a 3 cm CA treated with transphenoidal surgery (TSS) and conventional radiotherapy in the same year. His hypercortisolemia recurred 11 years later with rapid tumor growth (to 4.2 × 2.5 cm) and he underwent a second TSS with good resection. The tumor recurred 6 months later with ophthalmoplegia. Over 16 months he underwent an additional three surgeries (two TSS, one craniotomy) and repeated conventional radiotherapy. Ki67 staining index on surgical specimens was 5-6%. Temozolomide is an oral alkylating agent approved for glioblastoma multiforme treatment that has only recently shown promise in treating some pituitary tumors. In this patient TMZ was started at 150 mg/m²/day, titrated to 200 mg/m²/day, taken 5 days per month. The only significant side effect was moderate nausea. After 10 weeks, the tumor showed a remarkable 60% regression with objective improvement in ophthalmoplegia. Treatment of aggressive CAs represents a therapeutic challenge and in some cases surgical debulking and radiotherapy are of limited success. Few reports of CAs responsive to TMZ have been reported in the literature. To our knowledge, this case represents the most rapid robust CA shrinkage response reported to date. Further randomized clinical trials of TMZ in the treatment of aggressive pituitary adenomas are warranted.

BACKGROUND Visceral adipose tissue (VAT) predicts incipient diabetes mellitus and cardiovascular disease. Human data is mixed regarding the benefits of selective VAT reduction. OBJECTIVES We investigated omentectomy added to laparoscopic Roux-en-Y gastric bypass (LRYGB) on glucose homeostasis and lipids, inflammatory markers and adipokines after 90-days in non-diabetic patients. SETTING Legacy Good Samaritan Hospital and Oregon Health & Science University in Portland, Oregon. METHODS A single-blinded, randomized study of LRYGB plus omentectomy vs. LYRGB alone in 28 subjects (7 male, 21 female). Groups were matched at baseline for gender, age, and body mass index (BMI). Eligibility included age ≥ 18 years old, a body mass index (BMI) ≥ 40 and < 50 kg/m2 without co-morbid conditions or BMI ≥ 35 and < 50 kg/m2 with co-morbid conditions. The primary outcome measures were changes in fasting plasma glucose, insulin and HOMA-IR. Secondary measures were BMI and levels of hs-CRP, TNF-α, interleukins, total and HMW adiponectin, fibrinogen, and PAI-1. RESULTS After surgery, BMI decreased significantly in both groups and was not different at follow-up. While many outcome parameters improved with weight loss in both groups post-operatively, only the omentectomy group experienced statistically significant decreases in fasting glucose (p<0.05), total (p=0.004) and VLDL (p=0.001) cholesterol, and an increase in the HMW:total adiponectin ratio (p=0.013). CONCLUSIONS Omentectomy added to a LRYGB results in favorable changes in glucose homeostasis, lipid levels, and adipokine profile at 90-days. These data support the hypothesis that selective ablation of VAT conveys metabolic benefit in non-diabetic humans.

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