Nonsecreting Pituitary Adenomas Research Articles

Extent of Endoscopic Resection for Anterior Skull Base Tumors: An MRI-Based Volumetric Analysis.

Objective To determine the volume of ventral skull base tumor removed following endoscopic endonasal (EEA) resection using MRI-based volumetric analysis and to evaluate the inter-rater reliability of such analysis. Design Retrospective case series. Setting Academic tertiary care hospital. Participants EEA patients November 2012 to August 2015. Main Outcome Measures Volumetric analysis of pre- and immediately postoperative MR imaging was performed independently by two investigators. The percentage of total tumor resected was evaluated according to resection goal and tumor type. Results A total of 39 patients underwent resection. Intraclass correlation coefficients between the raters were 0.9988 for preoperative and 0.9819 for postoperative images. Tumors (and average percentage removed) included 17 nonsecreting pituitary adenomas (95.3%), 8 secreting pituitary adenomas (86.2%), 4 meningiomas (81.6%), 3 olfactory neuroblastomas (100%), 2 craniopharyngiomas (100%), 1 large B-cell lymphoma (90.5%), 1 germ cell neoplasm (48.3), 1 benign fibrous connective tissue mass (93.4%), 1 epidermoid cyst (68.4%), and 1 chordoma (100%). For tumors treated with intent for gross total resection, 96.9 ± 4.8% was removed. Conclusion EEAs achieved tumor resection rates of ∼97% when total resection was attempted. The radiographic finding of residual tumor is of uncertain clinical significance. The volumetric analysis employed in this study demonstrated high inter-rater reliability and could facilitate further study.

Long-term outcomes of surgery and radiotherapy for secreting and non-secreting pituitary adenoma

Purpose:To investigate treatment outcome and long term complication after surgery and radiotherapy (RT) for pituitary adenoma.Materials and Methods:From 1990 to 2009, 73 patients with surgery and RT for pituitary adenoma were analyzed in this study. Median age was 51 years (range, 25 to 71 years). Median tumor size was 3 cm (range, 1 to 5 cm) with suprasellar (n = 21), cavernous sinus extension (n = 14) or both (n = 5). Hormone secreting tumor was diagnosed in 29 patients; 16 patients with prolactin, 12 patients with growth hormone, and 1 patient with adrenocorticotrophic hormone. Impairment of visual acuity or visual field was presented in 33 patients at first diagnosis. Most patients (n = 64) received RT as postoperative adjuvant setting. Median RT dose was 45 Gy (range, 45 to 59.4 Gy).Results:Median follow-up duration was 8 years (range, 3 to 22 years). In secreting tumors, hormone normalization rate was 55% (16 of 29 patients). For 25 patients with evaluable visual field and visual acuity test, 21 patients (84%) showed improvement of visual disturbance after treatment. The 10-year tumor control rate for non-secreting and secreting adenoma was 100% and 58%, respectively (p < 0.001). Progression free survival rate at 10 years was 98%. Only 1 patient experienced endocrinological recurrence. Following surgery, 60% (n = 44) suffered from pituitary function deficit. Late complication associated with RT was only 1 patient, who developed cataract.Conclusion:Surgery and RT are very effective and safe in hormonal and tumor growth control for secreting and non-secreting pituitary adenoma.

ACTH-dependent Cushing's Syndrome: Diagnostic Pitfalls in Concomitant Non-secreting Pituitary Adenomas.

ObjectivesTo describe the possible pitfalls in correctly interpreting clinical, radiological and biochemical findings in ACTH-dependent Cushing’s syndrome.MethodsWe describe a case of a pituitary adenoma visualized at MRI not correlated with an ACTH-dependent Cushing’s syndrome.ResultsRadiological imaging and hormonal testing can be misleading in suspected pituitary ACTH-related Cushing’s syndrome.ConclusionCorrect interpretation of the initial clinical presentation can help in the proper diagnosis and treatment of ACTH-dependent Cushing’s syndrome.LEARNING POINTSOccult neoplasia should always be excluded in cases of severe ACTH-dependent Cushing’s syndrome.A positive MRI result can be misleading. Ectopic ACTH-dependent syndrome is generally associated with a peculiar phenotype.

Pituitary Medicine From Discovery to Patient-Focused Outcomes.

This perspective traces a pipeline of discovery in pituitary medicine over the past 75 years. To place in context past advances and predict future changes in understanding pituitary pathophysiology and clinical care. Author's perspective on reports of pituitary advances in the published literature. Clinical and translational Endocrinology. Discovery of the hypothalamic-pituitary axis and mechanisms for pituitary control, have culminated in exquisite understanding of anterior pituitary cell function and dysfunction. Challenges facing the discipline include fundamental understanding of pituitary adenoma pathogenesis leading to more effective treatments of inexorably growing and debilitating hormone secreting pituitary tumors as well as medical management of non-secreting pituitary adenomas. Newly emerging pituitary syndromes include those associated with immune-targeted cancer therapies and head trauma. Novel diagnostic techniques including imaging genomic, proteomic, and biochemical analyses will yield further knowledge to enable diagnosis of heretofore cryptic syndromes, as well as sub classifications of pituitary syndromes for personalized treatment approaches. Cost effective personalized approaches to precision therapy must demonstrate value, and will be empowered by multidisciplinary approaches to integrating complex subcellular information to identify therapeutic targets for enabling maximal outcomes. These goals will be challenging to attain given the rarity of pituitary disorders and the difficulty in conducting appropriately powered prospective trials.

Three-Dimensional Endoscopic Endonasal Approach and Outcomes in Sellar Lesions: A Single-Center Experience of 104 Cases

Pituitary tumors account for approximately 15% of primary intracranial neoplasms and often are diagnosed incidentally. Common sellar lesions are pituitary adenomas, craniopharyngiomas, and Rathke cleft cysts. Currently endoscopic transsphenoidal approaches are largely used, and many centers also use 3-dimensional (3D) technology, although additional results of long-term follow-up are still being accumulated. We present a retrospective analysis of 104 patients with sellar lesions (57 male and 47 female, mean age 52 years) who underwent 3D endoscopic transsphenoidal surgery in our center from December 2011 to March 2015 and were followed up for a mean time of 18months. A total of 16 patients were diagnosed with growth hormone-secreting adenomas, 9 with adrenocorticotropic hormone-secreting, 5 with prolactin-secreting, and 2 with thyroid-stimulating hormone-secreting tumors and 58 with nonsecreting pituitary adenomas. Five patients had Rathke cleft cysts, 5 craniopharyngiomas, 2 fibrous solitary tumors, 1 a metastasis, and 1 a chordoma. At baseline, 47 patients (45.2%) had hormonal changes and 52 (50%) had visual field changes. Complete resection was achieved in 73 patients (70.1%). Follow-up evaluation detected hormonal remission in 7 patients with Cushing disease (77.7%) and in 11 patients with acromegaly (68.7%). Complications were cerebrospinal fluid leak in 5 cases (4.8%) and transient diabetes insipidus in 6 cases (5.7%). Atotal of 55 patients (52.9%) were discharged less than 72 hours after surgery. The use of an endoscopic endonasal approach with 3D technology provides several advantages relating to patient length of stay, rate of complications, postoperative recovery, and novice surgeons' training. Advantages of 3D endoscopy and long-term follow-up still need further elucidation.

Specific inhibition of mTOR pathway induces anti-proliferative effect and decreases the hormone secretion in cultured pituitary adenoma cells.

There are some evidences that pituitary tumors may be sensitive to the anti-proliferative effects of mammalian target of rapamycin (mTOR) inhibitors, while the mechanism and effects remains unclear, it is necessary to find if a specific mTOR inhibition, including the blocking of both mTOR function and expression, generate any effects on pituitary adenoma cells. The object of this study was to examine if specific inhibition of mTOR induced anti-proliferative effect and decreased the GH and PRL hormones secretion in GH3 and MtT/E pituitary adenoma cells by using a kind of mTOR shRNA lentiviral vector. The in vitro experiments results showed mTOR shRNA transfection robustly reduced the GH3 and MtT/E cells viability in all durations (1-6 days) we performed, also specifically decreased both GH and PRL hormones external secretion in GH3 cells. Further results suggested that specific inhibition of mTOR decreased the hormones secretion through anti-proliferation effects on GH3 cells and reducing the hormones synthesis, but not through affecting the process of hormones secretion. Then we used phosphatidic acid (PA), a kind of mTOR activator, to promote the cell proliferation and GH and PRL hormones secretion in GH3 cells while the effects were blocked by mTOR shRNA transfection. In addition, we examined in vitro effects of PA treatment and mTOR shRNA gene transfection on major proteins expressed in the mTOR pathway in GH3 cells, and confirmed that PA treatment significant increased the protein levels of pmTOR, pS6 K and p4EBP1 in the scramble shRNA group, while the increase of protein levels was blocked by mTOR shRNA gene transfection. Moreover, mTOR shRNA gene transfection definitely inhibited the expression of mTOR and reduced the expression of pmTOR, pS6K and p4EBP1 in either PA or no PA treatment groups. These findings indicated that specific inhibition of mTOR pathway induced anti-proliferative effect and decreased the GH and PRL hormones secretion in cultured pituitary adenoma cells, which may be a novel promising and potential treatment modality for patients with secreting or non-secreting pituitary adenomas.

High-throughput screening reveals enzyme and GPCR targets as putative binding sites for d-deprenyl

Abstract Aims In PET studies of patients suffering from chronic pain following whip lash trauma, d-deprenyl was shown to bind to painful sites in the neck [1]. High uptake points towards an existence of an inflammation-specific binding site. Thus, the aim of this study was to identify the binding site for d-deprenyl employing radioligand receptor binding and high-throughput analysis of its activity towards 165 G-protein coupled receptors and 84 enzyme targets commonly used in drug discovery and development. Methods D-Deprenyl activity towards GPCR targets was assessed by DiscoverX in CHO-K1 EDG1 β-arrest in EFC cell line utilizing the PathHunter™ technique. Enzyme inhibition by D-deprenyl was identified in the EnzymeProfiling™ screening panel provided by Eurofins Cerep Panlabs. [H3]D-deprenyl binding studies with specific GPCR agonists and enzyme inhibitors at newly identified targets were also performed. Results Our investigation revealed that a 10μM concentration of d-deprenyl inhibited MAO-B and MAO-A activity by 99% and 55%, respectively. In addition, a 70% inhibition of angiotens in converting enzyme (ACE) activity in rabbit lung preparations was found. Furthermore, binding studies in rat mitochondrial membrane homogenates confirmed a submicromolar [H3]D-deprenyl competition with a selective MAO-B inhibitor seligiline, but not with the selective MAO-A inhibitor pirlindole mesylate. No evident hits among GPCR targets were identified. However, attention was drawn towards the histamine HRH1 and HRH3 receptors to which d-deprenyl showed a 20% and 42% antagonistic activity. Conclusions MAO-B might be a candidate target for D-deprenyl, as many other studies documented higher d-deprenyl uptake in activated astrocytes, non-secreting pituitary adenomas and brown adipose tissue, where MAO-B is over expressed. Moreover, ACE inhibition was shown to hamper down-regulation of transcription factors preventing ROS-mediated cartilage damage.

Profiling of adrenocorticotropic hormone and arginine vasopressin in human pituitary gland and tumor thin tissue sections using droplet-based liquid-microjunction surface-sampling-HPLC-ESI-MS-MS.

Described here are the results from the profiling of the proteins arginine vasopressin (AVP) and adrenocorticotropic hormone (ACTH) from normal human pituitary gland and pituitary adenoma tissue sections, using a fully automated droplet-based liquid-microjunction surface-sampling-HPLC-ESI-MS-MS system for spatially resolved sampling, HPLC separation, and mass spectrometric detection. Excellent correlation was found between the protein distribution data obtained with this method and data obtained with matrix-assisted laser desorption/ionization (MALDI) chemical imaging analyses of serial sections of the same tissue. The protein distributions correlated with the visible anatomic pattern of the pituitary gland. AVP was most abundant in the posterior pituitary gland region (neurohypophysis), and ATCH was dominant in the anterior pituitary gland region (adenohypophysis). The relative amounts of AVP and ACTH sampled from a series of ACTH-secreting and non-secreting pituitary adenomas correlated with histopathological evaluation. ACTH was readily detected at significantly higher levels in regions of ACTH-secreting adenomas and in normal anterior adenohypophysis compared with non-secreting adenoma and neurohypophysis. AVP was mostly detected in normal neurohypophysis, as expected. This work reveals that a fully automated droplet-based liquid-microjunction surface-sampling system coupled to HPLC-ESI-MS-MS can be readily used for spatially resolved sampling, separation, detection, and semi-quantitation of physiologically-relevant peptide and protein hormones, including AVP and ACTH, directly from human tissue. In addition, the relative simplicity, rapidity, and specificity of this method support the potential of this basic technology, with further advancement, for assisting surgical decision-making. Graphical Abstract Mass spectrometry based profiling of hormones in human pituitary gland and tumor thin tissue sections.

Isolation and characterization of progenitor mesenchymal cells in human pituitary tumors.

The Cancer Stem Cells (CSCs) theory suggests that genetic alterations in stem cells are the direct cause for cancer. The evidence for a CSC population that results in pituitary tumors is poor. Some studies report the isolation of CSCs, but a deep characterization of the stemness of these cells is lacking. Here, we report the isolation and detailed characterization of progenitor mesenchymal cells (PMCs) from both growth hormone-secreting (GH(+)) and non-secreting (NS) pituitary adenomas, determining the immunophenotype, the expression of genes related to stemness or to pituitary hormone cell types, and the differentiative potential towards osteo-, chondro- and adipogenic lineages. Finally, the expression of CD133, known as a marker for CSCs in other tumors, was analyzed. Isolated cells, both from GH(+) and NS tumors, satisfy all the criteria for the identification of PMCs and express known stem cell markers (OCT4, SOX2, KLF4, NANOG), but do not express markers of pituitary hormone cell types (PITX2, PROP1, PIT1). Finally, PMCs express CD133. We demonstrated that pituitary tumors contain a stem cell population that can generate cell types characteristic of mesenchymal stem cells, and express CD133, which is associated with CSCs in other tumors.

Risk-adapted single or fractionated stereotactic high-precision radiotherapy in a pooled series of nonfunctioning pituitary adenomas: high local control and low toxicity.

PurposeThe purpose of this work was to evaluate a prospectively initiated two-center protocol of risk-adapted single-fraction (SRS) or fractionated radiotherapy (SRT) in patients with nonsecretory pituitary adenomas (NSA).Patients and methodsA total of 73 NSA patients (39 men/34 women) with a median age of 62 years were prospectively included in a treatment protocol of SRS [planning target volume (PTV) < 4 ccm, > 2 mm to optic pathways = low risk] or SRT (PTV ≥ 4 ccm, ≤ 2 mm to optic pathways = high risk) in two Novalis® centers. Mean tumor volume was 7.02 ccm (range 0.58–57.29 ccm). Based on the protocol guidelines, 5 patients were treated with SRS and 68 patients with SRT.ResultsMedian follow-up (FU) reached 5 years with 5-year overall survival (OS) of 90.4 % (CI 80.2–95 %) and 5-year local control and progression-free survival rates of 100 % (CI 93.3–100 %) and 90.4 % (CI 80.2–95 %), respectively. A post-SRS/SRT new visual disorder occurred in 2 patients (2.7 %), a new oculomotor nerve palsy in one pre-irradiated patient, in 3 patients (4.1 %) a pre-existing visual disorder improved. New complete hypopituitarism occurred in 4 patients (13.8 %) and in 3 patients (25 %) with pre-existing partial hypopituitarism. Pituitary function in 26 % of patients retained normal. Patients with tumor shrinkage (65.75 %) had a significantly longer FU (p = 0.0093). Multivariate analysis confirmed correlation of new hypopituitarism with duration of FU (p = 0.008) and correlation of new hypopituitarism and tumor volume (p = 0.023). No significant influence factors for occurrence of visual disorders were found.ConclusionOur SRS/SRT protocol proved to be safe and successful in terms of tumor control and protection of the visual system, especially for large tumors located close to optic pathways.

Etiology of hypopituitarism in tertiary care institutions in Turkish population: analysis of 773 patients from pituitary study group database

Hypopituitarism in adult life is commonly acquired and the main causes are known as pituitary tumors and/or their treatments. Since there are new insights into the etiology of hypopituitarism and presence of differences in various populations, more studies regarding causes of hypopituitarism are needed to be done in different ethnic groups with sufficient number of patients. Therefore, we performed a multi-center database study in Turkish population investigating the etiology of hypopituitarism in 773 patients in tertiary care institutions. The study was designed and coordinated by the Pituitary Study Group of SEMT (The Society of Endocrinology and Metabolism of Turkey). Nineteen tertiary reference centers (14 university hospitals and 5 training hospitals) from the different regions of Turkey participated in the study. It is a cross-sectional database study, and the data were recorded for 18 months. We mainly classified the causes of hypopituitarism as pituitary tumors (due to direct effects of the pituitary tumors and/or their treatments), extra-pituitary tumors and non-tumoral causes. Mean age of 773 patients (49.8 % male, 50.2 % female) was 43.9 ± 16.1 years (range 16-84 years). The most common etiology of pituitary dysfunction was due to non-tumoral causes (49.2 %) among all patients. However, when we analyze the causes according to gender, the most common etiology in males was pituitary tumors, but the most common etiology in females was non-tumoral causes. According to the subgroup analysis of the causes of hypopituitarism in all patients, the most common four causes of hypopituitarism which have frequencies over 10 % were as follows: non-secretory pituitary adenomas, Sheehan's syndrome, lactotroph adenomas and idiopathic. With regard to the type of hormonal deficiencies; FSH/LH deficiency was the most common hormonal deficit (84.9 % of the patients). In 33.8 % of the patients, 4 anterior pituitary hormone deficiencies (FSH/LH, ACTH, TSH, and GH) were present. Among all patients, the most frequent cause of hypopituitarism was non-secretory pituitary adenomas. However, in female patients, present study clearly demonstrates that Sheehan's syndrome is still one of the most important causes of hypopituitarism in Turkish population. Further, population-based prospective studies need to be done to understand the prevalence and incidence of the causes of hypopituitarism in different countries.

Update on Hypophysitis and TTF‐1 Expressing Sellar Region Masses

This article reviews recent literature on sellar region masses that most closely mimic nonsecretory pituitary adenomas: hypophysitis, pituicytoma, spindle cell oncocytoma, and granular cell tumor of neurohypophysis. Even today, these four entities often cannot be confidently distinguished from each other clinically or by preoperative neuroimaging features. Thus, they often come to biopsy/surgical resection and require tissue confirmation of diagnosis. Causes of secondary and primary hypophysitis will be discussed, including two newly described types, IgG4 plasma cell hypophysitis and hypophysitis caused by anti-cytotoxic T-lymphocyte antigen 4 antibody therapy for cancer. For the neoplastic conditions, emphasis will be placed on literature that has emerged since these entities were first codified in the 2007 World Health Organization fascicle. The finding that immunohistochemical staining for thyroid transcription factor-1 is shared by pituicytoma, spindle cell oncocytoma, and granular cell tumor of neurohypophysis suggests common lineage and explains why histological overlap can be encountered. We incorporate our own experiences over the last 30 years from two referral institutions with specialty practices in pituitary region masses.

Fusiform dilatation of the cavernous carotid artery in acromegalic patients

Surgeons undertaking transsphenoidal surgery in patients with acromegaly confront multiple unique challenges secondary to the anatomic alterations caused by growth hormone-secreting tumors. The senior author has noted a fusiform dilatation of the cavernous carotid artery in many acromegalic patients. The authors aim to quantify this dilatation and correlate it with potential contributing factors. Clinical and radiographic data were retrospectively assessed in acromegalic patients undergoing transsphenoidal surgery from 2000 through 2011. Randomly selected patients with nonsecreting pituitary adenomas were used as the control cohort. Demographic information, comorbidities, and preoperative growth hormone and insulin-like growth factor-1 levels were recorded. Magnetic resonance (MR) imaging variables included tumor size, diameters of the petrous, cavernous, and supraclinoid segments of the carotid artery, and extent and location of cavernous sinus invasion. Independent correlations between acromegaly and each variable were assessed with multivariate regression analysis. Forty randomly selected patients with growth hormone-secreting adenomas who underwent surgery and had MR imaging with thin coronal slices of the pituitary region were enlisted in our study cohort. The mean age was 45.7 years. Forty-two males (52.5 %) were included in the study. Mean carotid artery diameter measurements for acromegalic and control patients, respectively, were 4.2 vs. 3.8 mm (petrous carotid), 5.0 vs. 4.0 mm (cavernous carotid), and 3.3 vs. 2.9 mm (supraclinoid carotid). Multivariate analysis showed only age and cavernous carotid diameter were statistically significant independent variables (p = 0.02, p < 0.001, respectively). Age, tumor size, growth-hormone or insulin-like growth factor-1 levels, and cavernous sinus invasion did not correlate with cavernous carotid artery diameter. In patients with acromegaly, there is a fusiform dilatation of the cavernous carotid artery that must be considered when planning transsphenoidal surgery.

Pituitary apoplexy after hypo-fractionated stereotactic radiotherapy

Introduction : Pituitary apoplexy is a rare phenomenon in pituitary adenomas. We present a case of pituitary apoplexy that developed shortly after hypo-fractionated stereotactic radiotherapy (HF-SRT) for a pituitary adenoma. To our knowledge there is no prior report of pituitary apoplexy following stereotactic radiotherapy. Case Report : A 67 year old female initially presented with visual abnormalities. Workup then revealed a large sellar mass. She underwent a trans-sphenoidal resection then with pathology demonstrating a non-secretory pituitary adenoma. Her vision returned to normal after the resection. Five years later, follow-up MRI showed evidence of recurrence. The size of the lesion and its proximity to the optic apparatus were not considered adequate for a single fraction stereotactic radiosurgery (SRS). Based on this, HF-SRT was recommended as an alternative to re-operation. The tumor was treated to a dose of 4,000 cGy given at 400 cGy per fraction. Two months later, the patient presented with visual impairment and ocular palsies. She was diagnosed to have pituitary apoplexy. Although spontaneous tumor apoplexy cannot be excluded, a causal role for radiotherapy is hypothesized. Conclusion : Radiotherapy as a cause of pituitary apoplexy is not well understood or documented. Pituitary apoplexy should be suspected in a patient who develops new onset headaches and visual disturbance during or shortly after radiotherapy. Rapid diagnosis of pituitary apoplexy allows for aggressive management and neurosurgical decompression which decreases mortality and morbidity.

Serum prolactin concentration at presentation of non-functioning pituitary macroadenomas.

Serum PRL levels at presentation may be useful in distinguishing between disconnection hyperprolactinemia in non-secretory pituitary adenomas and prolactinomas in order to guide appropriate therapy; however, there is a debate regarding the discriminatory PRL thresholds. We aimed to examine PRL concentrations at presentation in a cohort of histologically proven non-functioning pituitary adenomas (NFPA). Retrospective case note analysis was performed. Clinical, biochemical, histopathological and radiological data were recorded and analyzed. Complete data were available for 250 subjects with NFPA. Of the study population, 44.8% were hyperprolactinemic at presentation, 55.3% of whom were female. Of those with hyperprolactinemia, 73.2% had PRL<1000 mIU/l on presentation, 24.1% had PRL between 1000 and 1999 mIU/l. Only 2.7% (no.=3 females, 1.2% whole cohort) had PRL>2000 mIU/l (94.3 ng/ml), 2 of whom were pregnant. No male subject and no subjects with an intrasellar macroadenoma had serum PRL>1000 mIU/l (47.2 ng/ml). Overall, serum PRL was not higher among 43 subjects taking medications known to raise PRL. Our data support recent evidence that the serum PRL concentration is rarely >1000 mIU/l in males, or >2000 mIU/l in females, with non-functioning macroadenomas and that, once other contributing factors to the hyperprolactinemia have been excluded, a trial of dopamine agonist therapy for such lesions is indicated.

Long term toxicity and prognostic factors of radiation therapy for secreting and non-secreting pituitary adenomas

BackgroundRadiotherapy is controversially discussed in the management of benign disorders for fear of late sequelae such as tumor induction. This study was initiated to investigate long-term toxicity, treatment outcome and prognostic factors after radiotherapy (RT) in patients with pituitary adenomas.Methods92 patients with pituitary adenomas were included in this analysis. RT was conducted using either 3D conformal (16%) or fractionated stereotactic techniques (83%) in a postoperative adjuvant setting (16%), as second-line treatment for recurring tumors (78%) or as primary treatment (6%). Postoperatively, RT was offered to patients with residual tumor tissue or in case of locally extensive adenomas, in whom early recurrence was deemed likely. Patients were followed for a median time of 152.5 months, and analysed for overall and local progression-free survival (OS and LPFS). Multiple factors were analysed for prognostic impact. Patients were contacted with an institutional questionnaire about qualiy of life (QOL). Statistical analysis was performed using the log-rank test and the Kaplan-Meier method using a software tool (SPSS 19.0).ResultsMedian follow-up was 152.5 months. Before treatment, 2% of all patients were diagnosed with adenoma-related hypopituitarism. Following surgery, 68% suffered from new pituitary deficits. RT was associated with mild toxicity, including visual deficits (5.4%) and hypopituitarism (10.9%). In particular, no radiation-induced brain necrosis or malignancy was observed. QOL was reported to be stable or improved in 92% of all patients, and RT was perceived to not compromise but increase QOL in the vast majority of patients (95%). OS after RT was 93.3% and 61.0% at 120 and 240 months. LPFS following RT was 90.4 and 75.5% at 120 and 240 months. Early initiation of RT after surgery instead of reserving it for recurring adenomas predisposed for improved outcome.ConclusionsRT for pituitary adenomas is safe and and self-reported QOL is stable or improved by almost all patients. Hypopituitarism rates are low. Local control appears improved in patients irradiated postoperatively over those undergoing RT for previously resected recurrent tumors.

Study of the Involvement of Pancreastatin in the Physiopathology of Diabetes Mellitus Associated with Nonsecreting Pituitary Adenomas

Pancreastatin, derived from chromogranin A, inhibits insulin and stimulates glucagon secretion in rodents. Immunohistochemistry localised pancreastatin in human pancreatic islet cells and gonadotroph pituitary cells. Nonsecreting pituitary adenomas, frequently associated with diabetes mellitus, arise quasi-constantly from gonadotroph cells. We evaluated the possible involvement of pancreastatin in the physiopathology of diabetes mellitus associated with nonsecreting pituitary adenomas. Plasma pancreastatin levels were measured by radioimmunoassay in 5 groups of subjects: 10 patients with nonsecreting pituitary adenomas associated with diabetes mellitus (group I), 10 patients with nonsecreting pituitary adenomas without diabetes (Group II), 10 patients with ACTH or GH-secreting pituitary adenomas and diabetes mellitus (Group III), 10 diabetic patients without pituitary adenomas (Group IV), and 10 healthy controls (Group V). Kidney and liver functions were normal in all of them and no patient was treated with a proton pump inhibitor. All pituitary adenomas were trans-sphenoidally removed. Immunohistochemistry against pancreastatin was performed in 5 patients of each of the 3 groups of pituitary adenomas. Plasma pancreastatin levels were not different between the different groups: 182±46 pg/ml (Group I), 195±57 pg/ml (Group II), 239±42 pg/ml (Group III), 134±31 pg/ml, (Group IV), and 122±29 pg/ml (Group V). In contrast, they were significantly (p<0.05) higher before (391±65 pg/ml) than after trans-sphenoidal surgery (149±18 pg/ml) without post-surgical change in diabetes. An immunostaining against pancreastatin was found in a majority of pituitary adenomas, associated or not with diabetes mellitus. These results argue against a role of pancreastatin in the pathogenesis of diabetes mellitus associated with nonsecreting pituitary adenomas.

Cranial nerve dysfunction following Gamma Knife surgery for pituitary adenomas: long-term incidence and risk factors

Gamma Knife surgery (GKS) has become a significant component of neurosurgical treatment for recurrent secretory and nonsecretory pituitary adenomas. Although the long-term risks of visual dysfunction following microsurgical resection of pituitary adenomas has been well studied, the comparable risk following radiosurgery is not well defined. This study evaluates the long-term risks of ophthalmological dysfunction following GKS for recurrent pituitary adenomas. An analysis of 217 patients with recurrent secretory (n = 131) and nonsecretory (n = 86) pituitary adenomas was performed to determine the incidence of and risk factors for subsequent development of visual dysfunction. Patients underwent ophthalmological evaluation as part of post-GKS follow-up to assess for new or worsened cranial nerve II, III, IV, or VI palsies. The median follow-up duration was 32 months. The median maximal dose was 50 Gy, and the median peripheral dose was 23 Gy. A univariate analysis was performed to assess for risk factors of visual dysfunction post-GKS. Nine patients (4%) developed new visual dysfunctions, and these occurred within 6 hours to 34 months following radiosurgery. None of these 9 patients had tumor growth on post-GKS neuroimaging studies. Three of these patients had permanent deficits whereas in 6 the deficits resolved. Five of the 9 patients had prior GKS or radiotherapy, which resulted in a significant increase in the incidence of cranial nerve dysfunction (p = 0.0008). An increased number of isocenters (7.1 vs 5.0, p = 0.048) was statistically related to the development of visual dysfunction. Maximal dose, margin dose, optic apparatus dose, tumor volume, cavernous sinus involvement, and suprasellar extension were not significantly related to visual dysfunction (p >0.05). Neurological and ophthalmological assessment in addition to routine neuroimaging and endocrinological follow-up are important to perform following GKS. Patients with a history of radiosurgery or radiation therapy are at higher risk of cranial nerve deficits. Also, a reduction in the number of isocenters delivered, along with volume treated, particularly in the patients with secretory tumors, appears to be the most reasonable strategy to minimize the risk to the visual system when treating recurrent pituitary adenomas with stereotactic radiosurgery.

LINAC-radiosurgery for nonsecreting pituitary adenomas

Stereotactic linear accelerator-based radiosurgery (LINAC-RS) is increasingly used for microsurgically inaccessible or recurrent pituitary adenomas. This single-center study evaluates the long-term follow-up after LINAC-RS of nonsecreting pituitary adenomas (NSA). Between 1992 and August 2008, 65 patients with NSA were treated. Patient treatment and follow-up were conducted according to a prospective protocol. Indications for LINAC-RS were (1) tumor recurrence or (2) residual tumor. Three patients were treated primarily. For analysis of prognostic factors, patients were grouped according to epidemiological or treatment-associated characteristics. A total of 61 patients with a follow-up ≥ 12 months (median 83 months, range 15-186 months, longest follow-up of published radiosurgery series) were evaluated with regard to their clinical, radiological, and endocrinological course. The median tumor volume was 3.5 ml (± 4.3 ml, range 0.3-17.3 ml) treated with a median surface and maximum dose of 13.0 Gy and 29.7 Gy, respectively. Local tumor control was achieved in 98%. One patient died of unrelated cause after 36 months and 1 patient developed a radiation-induced seizure disorder. Visual complications did not occur. In 37 of 41 patients (90.2%), pituitary function remained stable. Maximum dose to the pituitary ≤ 16 Gy and female gender were positive prognostic factors for the preservation of pituitary function. LINAC-RS is a minimally invasive, safe, and effective treatment for recurrent NSA or microsurgically inaccessible residual tumor. LINAC-RS yielded a high rate of local long-term tumor control with a small number of radiation-induced side effects.

P5-08-02: Mammographic Breast Texture Predicts Benign Biopsy Results and Composition.

Abstract Purpose: Investigate the relationship between pathology diagnosis, biopsy composition, and breast texture measured in digital mammogram in women who have had previous benign findings in their breast. The long-term goal of this project is to determine whether or not global breast texture is associated with tissue composition and biopsy results. Such a finding would be of interest because it would provide evidence that mammography images contain information related to breast biology beyond average density. Materials and Methods: A total of 124 women who had previously received benign biopsies underwent an additional dual-energy/low dose full-field digital mammography (DXA) scan of the unaffected breast. Three measures of breast density (percent dense area (PD), percent fibroglandular volume (%FGV), absolute fibroglandular volume (FGV) from mammogram, 15 biopsy types including apocrine metaplasia and non-secretory pituitary adenoma, and four tissue compositions (collagen percent area, fat percent area, ductal percent area, epithelial percent area) were estimated from biopsies for each participant. In addition 45 breast texture features were measured on each screening image taken during the dual-energy mammography using custom software. Tissue composition at the biopsy location was estimated based on the average percent area of stained collagen, fat, ductal, and epithelial from up to 3 slides taken from the biopsy. Pathology results from the three slides were taken to indicate the tissue type. Results: Neither mammographic percent density, %FGV, nor FGV showed significant association with either biopsy type or tissue composition. However, some of breast texture features were significantly associated with tissue type and tissue composition. The strongest associations were found between collagen percent area and the neighborhood gray tone difference matrix texture strength (R=0.26, P=0.005) and ductal percent area and the gray level contrast matrix homogeneity (GLCM HOM) (R=-0.30, P=0.001). When classified according to biopsy type, the univariate association between ductal percent area and GLCM HOM for apocrine metaplasia increased. (R=-0.55, P=0.007) Conclusion: 10 breast texture features of the unaffected breast were significantly associated with local tissue composition and biopsy type. Further study will be required to determine whether this association is related to masking effects related to breast complexity or changes in breast biology driving changes in breast morphology. CLINICAL RELEVANCE The use of texture measures as biomarkers of variations in breast biology is potentially clinically significant. This work indicates that texture measures are associated with some biological outcomes. It is possible that this work could be used to improve diagnostic utility of computer-aided diagnosis by weighting the probability of various benign outcomes according to the measured breast texture. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-08-02.