Temozolomide treatment for aggressive pituitary tumors: correlation of clinical outcome with O(6)-methylguanine methyltransferase (MGMT) promoter methylation and expression.

CONTEXT: The typically indolent behavior of pituitary tumors is juxtaposed with high rates of tumor cell invasion into adjacent dural structures, and occasional aggressive behavior. Although clinically significant invasion and malignant transformation remain uncommon, there are limited treatment options available for the management of these aggressive tumors. Recently, case reports have described efficacy of temozolomide for the treatment of aggressive pituitary tumors. DESIGN: Seven patients with aggressive pituitary tumors have been treated with temozolomide. We compared O(6)-methylguanine methyltransferase (MGMT) promoter methylation and MGMT expression in 14 surgical specimens from these seven patients and correlated these molecular features with the clinical response to temozolomide. RESULTS: Significant tumor regression was seen in two patients (29%), a 20% reduction in tumor volume with subsequent stable tumor size was noted in one patient, arrest of tumor growth occurred in three patients, and progressive metastatic disease developed during treatment in one patient. The DNA promoter site for MGMT was unmethylated in all 14 adequate specimens, and variable MGMT expression was seen in all 14 cases. There was no correlation between MGMT expression and clinical outcomes. CONCLUSIONS: We conclude that medical therapy with temozolomide can be helpful in the management of life-threatening pituitary tumors that have failed to respond to conventional treatments. The optimal duration of treatment in patients with stabilization or reduction of tumor size has not been established, and long-term follow up studies are needed.

Immunohistochemistry of COUP-TFI: an adjuvant diagnostic tool for the identification of corticotroph microadenomas.

Cushing's disease is caused by an ACTH-producing pituitary tumor, and accounts for 10-15% of pituitary tumors. The majority of corticotroph tumors are microadenomas (<10 mm), and accurate histologic identification of these tumors can be challenging because of their small size and the presence of nests of normal corticotroph cells in the anterior pituitary. Retinoic acid has been shown to inhibit ACTH production and induce apoptosis in corticotroph tumor cells. The expression of the orphan nuclear receptor COUP-TFI antagonizes retinoic acid signaling and has been shown to be expressed in normal corticotroph cells, but absent in corticotroph tumor cell lines. We analyzed 34 corticotroph tumor specimens by immunohistochemistry using a goat polyclonal IgG antibody with epitope mapping to the N-terminus of human COUP-TFI. Segments of normal pituitary in each of the 34 specimens demonstrate COUP-TFI immunoreactivity in normal corticotroph cells. Twenty-nine of 34 ACTH producing tumors were immunonegative for COUP-TFI. All of the tumors measuring less than 5 mm by preoperative MRI were COUP-TFI immunonegative. Two tumors, measuring 9 and 11 mm, showed consistent (>90%) expression of COUP-TFI, and three adenomas (5, 11, and 18 mm) showed heterogenous (20-80%) expression of COUP-TFI. Immunohistochemistry of COUP-TFI may be a useful adjuvant diagnostic tool in distinguishing corticotroph microadenomas from nests of normal corticotroph cells in the anterior pituitary. Furthermore, this study identifies two unique corticotroph tumor populations which differ in their expression of COUP-TFI, the presence of which occurs more frequently in macroadenomas.

Management of acromegaly: is there a role for primary medical therapy?

Acromegaly is a chronic, debilitating disease caused by chronic growth hormone (GH) hypersecretion which results in chronic medical comorbidities, poor quality of life and high mortality rates. Successful treatment can improve clinical signs and symptoms and normalize mortality rates. Over 95% of acromegaly is caused by a somatotroph adenoma of the pituitary, and the first-line treatment is generally transsphenoidal surgery, which can be curative in 50-60% of patients. Nonetheless, high rates of persistent acromegaly following surgery and the limited efficacy of radiation therapy necessitate chronic medical treatment for many patients. Somatostatin analogues have become the preferred first-line medical therapy for many practitioners, as they achieve better biochemical and direct tumor control than the dopamine agonists, and long-acting preparations make once monthly administration possible. Cabergoline, a dopamine agonist, offers a lower-cost option and may be effective in patients with a pituitary tumor that co-secretes GH and prolactin. Pegvisomant is a GH receptor antagonist that produces exceptional biochemical response rates but lacks any direct effects on the tumor, which may limit its effectiveness as life-long monotherapy. Combinations of these three drug classes have not been rigorously studied, and preliminary trials do not suggest improved clinical outcomes. While medical treatment options for acromegaly have significantly improved over the last 30 years, limitations remain, and a multi-specialty team approach is necessary for the effective long-term management of patients with acromegaly.

Acute pancreatitis in HIV-infected patients: are etiologies changing since the introduction of protease inhibitor therapy?

INTRODUCTION: Hypertriglyceridemia is a well-established cause of acute pancreatitis in the general population. Protease inhibitor (PI) therapy, introduced in 1996 for HIV infection, is associated with moderate to severe hypertriglyceridemia. AIMS: To determine whether the prevalence of hyperlipidemic pancreatitis in HIV-infected patients has increased since the introduction of PIs. METHODOLOGY: This was a retrospective study of patients with acute pancreatitis and HIV infection admitted to three local hospitals between 1990 and 2001. RESULTS: Before PIs became available (1990-1995), 30 index cases of acute pancreatitis in the setting of HIV infection were identified, and one of these cases (3.3%) was attributed to hypertriglyceridemia. After the introduction of PIs (1996-2001), 54 cases of acute pancreatitis in HIV-infected patients were identified, and two of these cases were attributed to hypertriglyceridemia (3.7%; p = 0.6). In both time periods, medication-induced pancreatitis was the most common cause of pancreatitis in HIV-infected patients. CONCLUSION: Despite the well-established association between PIs and hypertriglyceridemia, there was no significant increase in the prevalence of hyperlipidemic pancreatitis in this HIV-infected population after the introduction of PIs. Medication-associated pancreatitis remains the most common cause of acute pancreatitis in the era of potent antiretroviral therapy.