[Show abstract][Hide abstract] ABSTRACT: Purpose/Objective(s)
This study evaluated the efficacy and toxicity of proton therapy for functional pituitary adenomas (FPAs).
Methods and Materials
We analyzed 165 patients with FPAs who were treated at a single institution with proton therapy between 1992 and 2012 and had at least 6 months of follow-up. All but 3 patients underwent prior resection, and 14 received prior photon irradiation. Proton stereotactic radiosurgery was used for 92% of patients, with a median dose of 20 Gy(RBE). The remainder received fractionated stereotactic proton therapy. Time to biochemical complete response (CR, defined as ≥3 months of normal laboratory values with no medical treatment), local control, and adverse effects are reported.
With a median follow-up time of 4.3 years (range, 0.5-20.6 years) for 144 evaluable patients, the actuarial 3-year CR rate and the median time to CR were 54% and 32 months among 74 patients with Cushing disease (CD), 63% and 27 months among 8 patients with Nelson syndrome (NS), 26% and 62 months among 50 patients with acromegaly, and 22% and 60 months among 9 patients with prolactinomas, respectively. One of 3 patients with thyroid stimulating hormone—secreting tumors achieved CR. Actuarial time to CR was significantly shorter for corticotroph FPAs (CD/NS) compared with other subtypes (P=.001). At a median imaging follow-up time of 43 months, tumor control was 98% among 140 patients. The actuarial 3-year and 5-year rates of development of new hypopituitarism were 45% and 62%, and the median time to deficiency was 40 months. Larger radiosurgery target volume as a continuous variable was a significant predictor of hypopituitarism (adjusted hazard ratio 1.3, P=.004). Four patients had new-onset postradiosurgery seizures suspected to be related to generously defined target volumes. There were no radiation-induced tumors.
Proton irradiation is an effective treatment for FPAs, and hypopituitarism remains the primary adverse effect.
International journal of radiation oncology, biology, physics 11/2014; · 4.59 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Pituitary apoplexy is an infrequent occurrence that can require timely treatment. The term "pituitary apoplexy" as used in the literature describes a heterogeneous spectrum. There is controversy about which subsets require urgent as opposed to elective surgical treatment or even medical treatment alone. We present a retrospective series of 109 consecutive cases of pituitary apoplexy from a single institution from 1992 to 2012 and develop a comprehensive classification system to analyze outcome.
[Show abstract][Hide abstract] ABSTRACT: Cushing disease (CD) is caused by overproduction of adrenocorticotropin by a pituitary adenoma (or, rarely, carcinoma). The diagnosis of CD requires distinguishing it from other hypercortisolemic states with a thorough endocrine workup. CD remains a primarily surgical disease, with remission rates of 70% to 95% following microscopic or endoscopic transsphenoidal surgery.
Neurosurgery clinics of North America 10/2012; 23(4):639-51. · 1.73 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Patients with thyrotropin-secreting pituitary adenomas may present with mass effect, hypopituitarism, and/or hyperthyroidism. The spectrum of pathologic and clinical features of patients whose tumors demonstrate β-thyrotropin immunoreactivity (β-TSH IR) has not been characterized. To characterize the phenotype of patients with pituitary adenomas with positive β-TSH IR, we conducted a retrospective analysis of patient records of all adult patients (n = 1,223) undergoing pituitary surgery in our institution over one decade (1999-2009). The search identified 166 adults with tumors which had β-TSH IR. These patients were individually matched to 166 patients whose tumors revealed no β-TSH IR. Clinical, pathological, imaging and biochemical data were extracted. 332 patients, aged 51.4 ± 15.1 years [150 women (45 %) and 182 men (55 %)], with pituitary adenomas (mean tumor diameter ± SD: 22.7 ± 9.0 mm) were studied. The degree of β-TSH IR was associated with the presence of central hyperthyroidism (p < 0.0001) or goiter (p = 0.0217). Patients whose tumors expressed more extensive β-TSH IR were less likely to develop pituitary apoplexy than those without β-TSH IR (p = 0.0428). In addition, the degree of β-TSH IR correlated with the presence of immunoreactivity for β-FSH (p < 0.0001), β-LH (p < 0.0001), alpha subunit (p < 0.0001), and GH (p = 0.0036). Conclusions: Pituitary adenomas expressing β-TSH IR were more likely to demonstrate immunoreactivity for β-FSH, β-LH, GH or alpha subunit. Patients with such tumors were more likely to exhibit hyperthyroidism and goiter, but less likely to develop pituitary apoplexy than patients without β-TSH IR. These findings suggest that β-TSH IR is associated with specific phenotypic features in patients with pituitary adenomas.
[Show abstract][Hide abstract] ABSTRACT: Inferior petrosal sinus sampling (IPSS) is a useful technique for confirming a pituitary source of adrenocorticotropic hormone (ACTH) overproduction in Cushing disease. Uncertainty remains regarding the appropriate course of therapy when an ectopic tumor is predicted by IPSS but none can be found and in circumstances when the procedure cannot be successfully completed owing to technical or anatomic limitations.
To determine an appropriate course of action after nondiagnostic IPSS.
We reviewed 288 IPSS procedures in 283 patients between 1986 and 2010 at our center. An IPS:peripheral ACTH ratio ≥ 2 at baseline or ≥ 3 after corticotrophin-releasing hormone was considered predictive of a pituitary source of ACTH. A procedure was considered nondiagnostic if the procedure was successfully performed and the results predicted an ectopic source but none could be found despite extensive imaging or if the IPS could not be bilaterally cannulated because of technical difficulties or anatomic variants.
The sensitivity, specificity, positive predictive value, and negative predictive value of IPSS for detecting a pituitary source in Cushing disease were 94%, 50%, 98%, and 29%, respectively. We identified 3 categories of nondiagnostic IPSS comprising 44 of the total procedures. These patients underwent exploratory transsphenoidal surgery, and in 42 of these patients (95%), a pituitary source was surgically proven, with a remission rate of 83%.
Transsphenoidal surgery should be considered in cases of ACTH-dependent Cushing disease and noncentralized or technically unsuccessful IPSS without evidence of ectopic tumor.
[Show abstract][Hide abstract] ABSTRACT: Transsphenoidal surgery has an important role in the management of pituitary tumors and remains the primary treatment for most adenomas, with the exception of prolactinomas. This update will review the recent neurosurgical literature; modifications to the traditional microscopic approach, including the potential utility of endoscopy and intraoperative magnetic resonance imaging, are discussed. The value of experienced surgical judgment and expertise remains clear, over and above the possible advantages of current technology. Preliminary data on the relative cost-effectiveness of surgery vs. medical treatment suggest that surgical approaches compare favorably. It will be important to incorporate future technological advances in surgical technique with new medical therapies in a combined multidisciplinary approach for improved treatment algorithms.
The Journal of Clinical Endocrinology and Metabolism 02/2012; 97(4):1073-81. · 6.31 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Both growth hormone (GH) excess and GH deficiency are associated with abnormalities in body composition and biomarkers of cardiovascular risk in patients with pituitary disorders. However, the effects of developing GH deficiency after definitive treatment of acromegaly are largely unknown.
To determine whether development of GH deficiency after definitive therapy for acromegaly is associated with increased visceral adiposity and biomarkers of cardiovascular risk compared with GH sufficiency after definitive therapy for acromegaly.
We studied three groups of subjects, all with a history of acromegaly (n = 76): subjects with subsequent GH deficiency (GHD; n = 31), subjects with subsequent GH sufficiency (GHS; n = 25) and subjects with active acromegaly (AA; n = 20). No study subjects were receiving somatostatin analogues, dopamine agonists or hGH.
Body composition (by DXA), abdominal adipose tissue depots (by cross-sectional CT), total body water (by bioimpedance analysis) and carotid intima-media thickness (IMT) were measured. Fasting morning serum was collected for high-sensitivity C-reactive protein (hsCRP), lipids and lipoprotein levels. An oral glucose tolerance test was performed, and homoeostasis model of assessment-insulin resistance (HOMA-IR) was calculated.
Abdominal visceral adipose tissue, total adipose tissue and total body fat were higher in subjects with GHD than GHS or AA (P < 0·05). Subcutaneous abdominal fat was higher, and fibrinogen and IMT were lower in GHD (but not GHS) than AA (P < 0·05). Patients with GHD had the highest hsCRP, followed by GHS, and hsCRP was lowest in AA (P < 0·05). Fasting glucose, 120-min glucose, fasting insulin, HOMA-IR and per cent total body water were lower in GHD and GHS than AA (P < 0·05). Triglycerides were higher in GHS than AA (P < 0·05). Lean body mass, mean arterial pressure, total cholesterol, HDL and LDL were comparable among groups.
Development of GHD after definitive treatment of acromegaly may adversely affect body composition and inflammatory biomarkers of cardiovascular risk but does not appear to adversely affect glucose homoeostasis, lipids and lipoproteins, or other cardiovascular risk markers.
[Show abstract][Hide abstract] ABSTRACT: Pituicytomas are rare neoplasms of the sellar region. We report a case of vision loss and a junctional scotoma in a 43-year-old woman caused by compression of the optic chiasm by a pituitary tumor. The morphological and immunohistochemical characteristics of the tumor were consistent with the diagnosis of pituicytoma. The tumor was debulked surgically, and the patient's vision improved.
Case reports in ophthalmology. 01/2012; 3(2):190-6.
[Show abstract][Hide abstract] ABSTRACT: Modern transsphenoidal surgery for Cushing’s disease is usually curative, achieving durable remission in 70–90% of cases.
Comparison of remission and recurrence rates between series in the literature is difficult as many employ different remission
criteria. Complication rates are low, but include hypopituitarism, diabetes insipidus, and CSF rhinorhhea. Improved remission
rates can be obtained with early re-exploration after initial unsuccessful procedures, and reoperation remains an option after
recurrence. This chapter reviews current surgical techniques, including microscopic and endoscopic approaches.
KeywordsAdrenocorticotropic hormone-Hypercortisolemia-Hypophysectomy-Pituitary adenoma-Transsphenoidal surgery
[Show abstract][Hide abstract] ABSTRACT: DLK1-MEG3 is an imprinted locus consisting of multiple maternally expressed noncoding RNA genes and paternally expressed protein-coding genes. The expression of maternally expressed gene 3 (MEG3) is selectively lost in clinically nonfunctioning adenomas (NFAs) of gonadotroph origin; however, expression status of other genes at this locus in human pituitary adenomas has not previously been reported. Using quantitative real-time RT-PCR, we evaluated expression of 24 genes from the DLK1-MEG3 locus in 44 human pituitary adenomas (25 NFAs, 7 ACTH-secreting, 7 GH-secreting, and 5 PRL-secreting adenomas) and 10 normal pituitaries. The effects on cell proliferation of five miRNAs whose expression was lost in NFAs were investigated by flow cytometry analysis. We found that 18 genes, including 13 miRNAs at the DLK1-MEG3 locus, were significantly down-regulated in human NFAs. In ACTH-secreting and PRL-secreting adenomas, 12 and 7 genes were significantly down-regulated, respectively; no genes were significantly down-regulated in GH-secreting tumors. One of the five miRNAs tested induced cell cycle arrest at the G2/M phase in PDFS cells derived from a human NFA. Our data indicate that the DLK1-MEG3 locus is silenced in NFAs. The growth suppression by miRNAs in PDFS cells is consistent with the hypothesis that the DLK1-MEG3 locus plays a tumor suppressor role in human NFAs.
American Journal Of Pathology 08/2011; 179(4):2120-30. · 4.60 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To assess health care costs associated with Cushing disease and to determine changes in overall and comorbidity-related costs after surgical treatment.
In this retrospective cohort study, patients with Cushing disease were identified from insurance claims databases by International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) codes for Cushing syndrome (255.0) and either benign pituitary adenomas (227.3) or hypophysectomy (07.6×) between 2004 and 2008. Each patient with Cushing disease was age- and sex-matched with 4 patients with nonfunctioning pituitary adenomas and 10 population control subjects. Comorbid conditions and annual direct health care costs were assessed within each calendar year. Postoperative changes in health care costs and comorbidity-related costs were compared between patients presumed to be in remission and those with presumed persistent disease.
Of 877 identified patients with Cushing disease, 79% were female and the average age was 43.4 years. Hypertension, diabetes mellitus, and hyperlipidemia were more common among patients with Cushing disease than in patients with nonfunctioning pituitary adenomas or in control patients (P<.01). For every calendar year studied, patients with Cushing disease had significantly higher total health care costs (2008: $26 440 [Cushing disease] vs $13 708 [nonfunctioning pituitary adenomas] vs $5954 [population control], P<.01). Annual outpatient costs decreased significantly for patients in remission after surgery, and there was a trend towards improvement in overall disease-related costs with remission. A significant increase in postoperative health care costs was observed in those patients not in remission.
Patients with Cushing disease had more comorbidities than patients with nonfunctioning pituitary adenomas or control patients and incurred significantly higher annual health care costs; these costs decreased after successful surgery and increased after unsuccessful surgery.
Endocrine Practice 02/2011; 17(5):681-90. · 2.49 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Cushing disease is caused by a corticotroph tumor of the pituitary gland. Patients with Cushing disease are usually treated with transsphenoidal surgery, as this approach leads to remission in 70-90% of cases and is associated with low morbidity when performed by experienced pituitary gland surgeons. Nonetheless, among patients in postoperative remission, the risk of recurrence of Cushing disease could reach 20-25% at 10 years after surgery. Patients with persistent or recurrent Cushing disease might, therefore, benefit from a second pituitary operation (which leads to remission in 50-70% of cases), radiation therapy to the pituitary gland or bilateral adrenalectomy. Remission after radiation therapy occurs in ∼85% of patients with Cushing disease after a considerable latency period. Interim medical therapy is generally advisable after patients receive radiation therapy because of the long latency period. Bilateral adrenalectomy might be considered in patients who do not improve following transsphenoidal surgery, particularly patients who are very ill and require rapid control of hypercortisolism, or those wishing to avoid the risk of hypopituitarism associated with radiation therapy. Adrenalectomized patients require lifelong adrenal hormone replacement and are at risk of Nelson syndrome. The development of medical therapies with improved efficacy might influence the management of this challenging condition.
[Show abstract][Hide abstract] ABSTRACT: Pituitary adenomas are the most common lesions in the sellar region, but other pathologies need to be considered in the differential diagnosis.
To assess the prevalence of unusual sellar masses in a large series of patients and identify clinicopathological factors that may aid the pre-operative diagnosis.
Retrospective case series.
We analysed the records of 1469 transsphenoidal procedures performed between 1998 and 2009. One hundred sixteen cases (7·9%) were not pituitary adenomas.
Final pathological diagnosis.
One hundred sixteen patients (45 men, 71 women; mean age (±SD): 45 ± 17 years) with nonadenomatous lesions were divided into four major aetiological groups: cystic lesions (CYS) (53%); benign neoplasms (BEN) (22%); malignancies (MAL) (16%) and inflammatory lesions (INF) (9%). Rathke's cysts, the most common lesions, represented 42% of all cases. Twenty-five per cent of malignant lesions were metastases, and some of the MAL (e.g., fibrosarcoma, lung metastasis) had a radiographical appearance suggestive of a pituitary adenoma. The most common presenting symptoms were visual field impairment (51%) and headache (34%). Pre-operative pituitary dysfunction was present in 58% of cases, with hyperprolactinaemia (35%), hypogonadism (23%) and hypocortisolism (23%) found most frequently. Postoperative resolution of headache and visual symptoms occurred in 63% and 65% of patients, respectively. Hyperprolactinaemia resolved in 77% of cases.
A substantial minority of sellar masses are not pituitary adenomas. While they frequently present with the symptoms, hormone abnormalities and radiographical appearance typical of pituitary tumours, the possibility of a nonadenomatous lesion needs to be considered in the differential diagnosis.
[Show abstract][Hide abstract] ABSTRACT: Clinical manifestations and outcomes of pituitary adenomas in children are not clearly defined. We retrospectively reviewed cases of pituitary adenomas in children 0-18 years treated at MassGeneral Hospital for Children over 15 years. Thirty-five patients were identified. Age at presentation was 7-18 years. Seventeen had prolactinomas, 3 had somatotropinomas, and 15 had Cushing disease. Thirteen prolactinoma patients were female and most commonly presented with oligomenorrhea (10/13) and galactorrhea (7/13). Nine were successfully treated medically. Two somatotropinoma patients presented with visual disturbances; the third was an incidental finding. Two were cured by trans-sphenoidal surgery (TSS). Thirteen Cushing disease patients were initially cured by TSS; six recurred after 3-6 years. Patients with or without recurrence did not differ for age, tumor-size and hormone levels. The high recurrence rate of Cushing disease in our series (46%) compared with adults treated surgically at this institution (7%) emphasizes the need for long-term follow-up.
[Show abstract][Hide abstract] ABSTRACT: Context: The effects of GH replacement therapy in patients who develop GH deficiency (GHD) after cure of acromegaly have not been established in a placebo-controlled study. Objective: The objective of the study was to determine whether GH replacement improves body composition, cardiovascular risk markers and quality of life in patients with GHD and prior acromegaly. Design: This was a 6-month, randomized, placebo-controlled study. Setting: The study was conducted at a clinical translational science center. Study Participants: Participants included 30 subjects with prior acromegaly and current GHD. Intervention: Interventions included GH or placebo. Main Outcome Measures: Body composition (dual-energy x-ray absorptiometry and cross-sectional computed tomography at L4), cardiovascular risk markers (high-sensitivity C-reactive protein (hsCRP), total, high-density lipoprotein and low-density lipoprotein cholesterol, fibrinogen, and carotid intimal-medial thickness), and quality of life were measured. Results: The mean GH dose at 6 months was 0.58 +/- 0.26 mg/d. Total fat mass, visceral adipose tissue (-15.3 +/- 18.6 vs. 1.3 +/- 12.5%, P = 0.01), and total abdominal fat decreased, and fat-free mass increased, in the GH vs. placebo group. Mean hsCRP levels decreased, but there was no GH effect on other cardiovascular risk markers. There was no change in glycosylated hemoglobin or homeostasis model assessment insulin resistance index. Quality of life improved with GH. Side effects were minimal. Conclusions: This is the first randomized, placebo-controlled study of the effects of GH replacement therapy on body composition and cardiovascular end points in patients who have developed GH deficiency after treatment for acromegaly, a disease complicated by metabolic and body composition alterations and increased cardiovascular risk. GH replacement decreased visceral adipose tissue, increased fat-free mass, decreased hsCRP, and improved quality of life in patients with GHD after cure of acromegaly, with minimal side effects and without an increase in insulin resistance.
The Journal of Clinical Endocrinology and Metabolism 02/2010; 95(2):567-77. · 6.31 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background: Transsphenoidal surgery (TSS) is the treatment of choice for Cushing's disease (CD). Postoperative hypercortisolemia mandates further therapy. Objective: The aim of the study was to characterize patients without immediate postoperative remission who have a delayed decrease to normal or low cortisol levels without further therapy. Design and Setting: A retrospective case series was conducted at three tertiary care centers. Patients and Intervention: We reviewed the records of 620 patients (512 females, 108 males; mean age, 38 +/- 13 yr) who underwent transsphenoidal pituitary surgery for CD between 1982 and 2007. Results: Outcomes were classified into the following three groups based upon the postoperative pattern of cortisol testing: group IC (immediate control) included 437 of the 620 patients (70.5%) with hypocortisolism and/or cortisol normalization throughout the postoperative follow-up; group NC (no control) included 148 of 620 patients (23.9%) with persistent hypercortisolism; and group DC (delayed control) included 35 of 620 patients (5.6%) who had early elevated or normal UFC levels and developed a delayed and persistent cortisol decrease after an average of 38 +/- 50 postoperative days. The total rate of recurrence was 13% at a median follow-up time of 66 months after TSS; the cumulative rate of recurrence at 4.5 yr was significantly higher in group DC vs. group IC (43 vs. 14%; P = 0.02). Conclusions: Hormonal assessment in the immediate postoperative period after TSS for CD may be misleading because delayed remission can occur in a subset of patients. Expectant management and retesting may spare some patients from unnecessary further treatment. Optimal timing to determine the need for further therapy after TSS remains to be determined.
The Journal of Clinical Endocrinology and Metabolism 02/2010; 95(2):601-10. · 6.31 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The ability of combined dexamethasone-corticotropin releasing hormone (Dex-CRH) testing to distinguish pseudo-Cushing's syndrome (PCS) from Cushing's syndrome is controversial. One factor potentially impairing diagnostic efficacy is the concomitant use of commonly prescribed medications that may alter dexamethasone metabolism.
Our objective was to assess the diagnostic accuracy of the Dex-CRH test and evaluate the potential impact of concomitant drugs.
The study was a retrospective one.
Participants included 101 patients [60 Cushing's disease (CD); 41 PCS] who underwent 112 Dex-CRH tests. Patients were divided into two groups, depending on use of medications potentially interfering with dexamethasone metabolism: 58 tests were classified as No Meds (32 CD; 26 PCS) and 54 as Meds (34 CD; 20 PCS). The latter group was further subdivided into patients taking one medication vs. those taking multiple medications.
Diagnostic accuracy of different serum cortisol and ACTH thresholds at baseline and 15 min after CRH injection was assessed.
The specificity of a baseline post-low-dose-dexamethasone-suppressed test cortisol lower than 1.4 microg/dl (38 nmol/liter) was significantly higher in the No Meds vs. the Meds group (P = 0.014). Sensitivity and specificity using a post-CRH cortisol cutoff of 1.4 microg/dl (38 nmol/liter) were 93.1% (95% confidence interval = 88.4-97.8) and 92.3% (95% confidence interval = 87-97.6) in the No Meds group. The specificity of a cortisol lower than 1.4 microg/dl (38 nmol/l) at 15 min after CRH was significantly higher in patients taking only one medication vs. those on multidrug treatment (P < 0.05).
Medications commonly prescribed in hypercortisolemic patients undergoing Dex-CRH testing may contribute to the variable diagnostic accuracy of this test. Prospective studies to address this issue are needed.
The Journal of Clinical Endocrinology and Metabolism 10/2009; 94(12):4851-9. · 6.31 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Both GH deficiency (GHD) and GH excess are associated with a decreased quality of life. However, it is unknown whether patients with GHD after treatment for acromegaly have a poorer quality of life than those with normal GH levels after cure of acromegaly.
The aim of the study was to determine whether patients with GHD and prior acromegaly have a poorer quality of life than those with GH sufficiency after cure of acromegaly.
We conducted a cross-sectional study in a General Clinical Research Center.
Forty-five patients with prior acromegaly participated: 26 with GHD and 19 with GH sufficiency.
There were no interventions.
We evaluated quality of life, as measured by 1) the Quality of Life Adult Growth Hormone Deficiency Assessment (QoL-AGHDA); 2) the Short-Form Health Survey (SF-36); and 3) the Symptom Questionnaire.
Mean scores on all subscales of all questionnaires, except for the anger/hostility and anxiety subscales of the Symptom Questionnaire, showed significantly impaired quality of life in the GH-deficient group compared with the GH-sufficient group. Peak GH levels after GHRH-arginine stimulation levels were inversely associated with QoL-AGHDA scale scores (R = -0.53; P = 0.0005) and the Symptom Questionnaire Depression subscale scores (R = -0.35; P = 0.031) and positively associated with most SF-36 subscale scores.
Our data are the first to demonstrate a reduced quality of life in patients who develop GHD after cure of acromegaly compared to those who are GH sufficient. Further studies are warranted to determine whether GH replacement would improve quality of life for patients with GHD after cure from acromegaly.
The Journal of Clinical Endocrinology and Metabolism 05/2009; 94(7):2471-7. · 6.31 Impact Factor