Intraoperative Imaging of Pituitary Adenomas by OTL

Pituitary adenomas have an estimated prevalence in the population of approximately 10%, and
although they are predominantly benign tumors, they can cause significant disability from
mass effect (visual field deficits and cranial nerve deficits) and from hypersecretory
syndromes (Cushing's disease, acromegaly, hyperprolactinemia). Approximately 30% of all
pituitary adenomas are nonfunctioning or endocrinologically silent, and despite the lack of
hormonal overexpression they represent the great majority of patients of who undergo surgery
given the threat of apoplexy and compression of adjacent neural structures. Surgical
resection via transsphenoidal surgery remains the primary treatment modality for almost all
pituitary adenomas except prolactinomas. Residual tumor, however, is quite common after
surgical resection and is seen in up to 20% of surgical cases. By ensuring a negative margin
through imaging during surgery, it would be possible to minimize the need for postoperative
radiation therapy and/or radiosurgery and subsequent surgery as well.

Gross total resection (GTR) of a pituitary adenoma is theoretically simple but practically
difficult given the intimate association of the pituitary gland with critical neurovascular
structures including the internal carotid artery, optic nerves, cavernous sinus contents and
adjacent frontal lobe and third ventricle. In a recent meta-analysis, functioning pituitary
adenoma (Cushing's disease, prolactinoma, acromegaly) was demonstrated to have a gross total
resection rate of only 78% (n=664). In another review, tabulated through multiple studies,
demonstrated that for nonfunctioning pituitary adenoma, gross total resection rate ranged
from 66 to 93% (n=778). Moreover, a comparison of endoscopic and microscopic removal of
pituitary adenoma found the gross total resection rate was 66% using endoscopic pituitary
techniques. In this context of limited ability to achieve GTR, intraoperative MRI was
introduced for assessment of the degree of resection for pituitary adenoma. The
intraoperative MRI is expensive, cumbersome, and impractical. A simpler means of determining
the degree of resection is greatly needed in the field of brain surgery, and specifically
pituitary surgery.

Pituitary adenomas are the ideal disease to investigate intra-operative imaging. Multiple
studies have demonstrated that nonfunctioning pituitary adenomas express folate receptor
alpha (FRα), therefore making folate receptors (FR) the ideal targets for imaging agents.
While folate will initially distribute to all cells, redistribution, metabolism, and
excretion will eliminate most of this agent from healthy tissues within 2-3 hours. Tumor
cells that over express FRα will retain folate and any fluorescent labeled folate conjugate
(such as OTL38) and internalize this.

Inclusion Criteria:

1. Adult patients over 18 years of age

2. Patients presenting with a pituitary nodule presumed to be resectable on pre-operative
assessment

3. Good operative candidate

4. Subject capable of giving informed consent and participating in the process of
consent.

Exclusion Criteria:

1. Pregnant women as determined by urinary or serum beta human chorionic gonadotropin
(hCG) within 72 hours of surgery

2. Patients with a history of anaphylactic reactions to OTL38

3. Patients with a known allergy to Benadryl

4. Previous exposure to OTL38