Effect of distance from target on hypopituitarism after stereotactic radiosurgery for pituitary adenomas.

INTRODUCTION: Delayed hypopituitarism is the most common complication after stereotactic radiosurgery (SRS) for pituitary adenomas. The aim of this study was to investigate the relationship between the distance from the hypothalamic-pituitary axis to the treatment target and anterior pituitary function preservation after SRS. METHODS: Between 2007 and 2020, consecutive adult patients who underwent single-session SRS for non-functioning or hormone-secreting pituitary adenomas with ≥ 6 months of follow-up were included. Distance measurements between hypothalamic-pituitary axis structures and the SRS target volume were quantified on MRI. The primary outcome was anterior pituitary function preservation. Outcomes were compared using multivariable regression and area under the receiver operator characteristic curve (AUROC) analyses. RESULTS: The study cohort comprised 224 patients, who were categorized by preservation (n = 168) and no preservation (n = 56) of anterior pituitary function after SRS. The mean and median clinical follow-up durations were 53.7 (38.0) and 46.0 (17.0-75.0) months, respectively. Independent predictors of anterior pituitary function preservation were a greater distance between the center of the pituitary gland and center of the SRS target [OR 1.101 (1.000-1.213), p = 0.050], and a shorter clinical follow-up duration [OR 0.985 (0.977-0.993), p < 0.0001]. The adjusted AUROC for the distance from the center of the pituitary gland and center of the SRS target in predicting anterior pituitary function preservation was 0.595. The sensitivity, specificity, positive predictive value and negative predictive value in predicting anterior pituitary function preservation at the optimal cut-off distance of 15 mm were 30.0, 88.0, 89.9 and 26.2%, respectively. CONCLUSIONS: Greater distance between the normal pituitary gland and the SRS target is associated with anterior pituitary function preservation and increasing this distance should be a goal of adenoma resection. Larger prospective, multi-center studies are necessary to corroborate this finding and establish the effects of distance on hypopituitarism after SRS for pituitary adenomas.

Characterization of a paradoxical post-operative increase in serum cortisol in Cushing disease.

PURPOSE: In Cushing disease, early post-operative serum cortisol fluctuations have not been adequately characterized, and their association with initial remission and recurrence is unclear. METHODS: A retrospective cohort study of patients with Cushing disease was conducted at two institutions. A "riser" was defined a priori as a paradoxical increase in serum cortisol with an immediate incremental increase in serum cortisol over three consecutive cortisol draws separated by roughly 6-h (definition 1). Post hoc analyses used a definition of two consecutive increases (definition 2). Risers were compared to non-risers for initial remission and time-to-recurrence. RESULTS: A total of 505 patients with Cushing disease were screened, and 469 had adequate data for group assignment. Analysis of post-operative cortisol showed a subgroup of "risers" with a frequency of 3.6% for definition 1 and 42.6% for definition 2. In these patients, cortisol levels were significantly higher until approximately 36 h post-operatively, and cortisol had a significantly longer mean serum half-life. In the post hoc analysis, definition 2 risers had a lower remission rate compared to non-risers (162/196, 82.7%, versus 243/264, 92.0%) with an odds ratio of 0.41 (0.23-0.73; p = 0.003). For both definitions, recurrence was similar between groups. CONCLUSIONS: We found that almost half of Cushing disease patients experienced a temporary increase in serum cortisol level during the early post-operative period. Serum cortisol half-life was longer, and the remission rates were lower, however, recurrence rates were similar to non-risers.

Stereotactic radiosurgery before bilateral adrenalectomy is associated with lowered risk of Nelson's syndrome in refractory Cushing's disease patients.

BACKGROUND: Nelson's syndrome is a rare but challenging sequelae of Cushing's disease (CD) after bilateral adrenalectomy (BLA). We sought to determine if stereotactic radiosurgery (SRS) of residual pituitary adenoma performed before BLA can decrease the risk of Nelson's syndrome. METHODS: Consecutive patients with CD who underwent BLA after non-curative resection of ACTH secreting pituitary adenoma and had at least one follow-up visit after BLA were studied. Nelson's syndrome was diagnosed based on the combination of rising ACTH levels, increasing volume of the pituitary adenoma and/or hyperpigmentation. RESULTS: Fifty patients underwent BLA for refractory CD, and 43 patients (7 men and 36 women) had at least one follow-up visit after BAL. Median endocrine, imaging, and clinical follow-up were 66 months, 69 months, and 80 months, respectively. Nine patients (22%) were diagnosed with the Nelson's syndrome at median time after BLA at 24 months (range: 0.6-119.4 months). SRS before BLA was associated with reduced risk of the Nelson's syndrome (HR = 0.126; 95%CI [0.022-0.714], p=0.019), while elevated ACTH level within 6 months after BLA was associated with increased risk for the Nelson's syndrome (HR = 9.053; 95%CI [2.076-39.472], p=0.003). CONCLUSIONS: SRS before BLA can reduce the risk for the Nelson's syndrome in refractory CD patients requiring BLA and should be considered before proceeding to BLA. Elevated ACTH concentration within 6 months after BLA is associated with greater risk of the Nelsons' syndrome. When no prior SRS is administered, those with a high ACTH level shortly after BLA may benefit from early SRS.

Surgical and radiosurgical treatment strategies for Cushing's disease.

INTRODUCTION: Cushing's disease (CD) is rare disorder that should be adequately managed to optimize long-term prognosis. Treatment of CD is multidisciplinary and often includes surgical resection, adjuvant stereotactic radiosurgery (SRS), and medical treatment. Here we review surgical and radiosurgical treatment strategies for ACTH producing pituitary adenomas. METHODS: A comprehensive literature review was carried out to review remission and recurrence rates, and complications of surgical and SRS treatments of ACTH producing pituitary adenomas. RESULTS: Surgical resection plays a central role in the management of ACTH secreting pituitary adenomas and usually allows rapid endocrine remission that ranges from 69 to 90%. The most common complications after resection include some degree of new hypopituitarism, diabetes insipidus and CSF leak. Devastating complications, such as injury of vascular and neural structures, are very rare. Surgeon experience and adequate pre-operative imaging are important for safe and successful surgery. Endocrine recurrence rates after resection range from 9 to 30%. SRS is often employed for incompletely resected adenomas. Endocrine remission after SRS ranges from 35 to 72%. The most common complication of SRS is new anterior pituitary gland deficiency. Recurrence rates after GKRS range from 18 to 24%. CONCLUSIONS: Transsphenoidal resection of ACTH producing pituitary adenoma is a safe and highly effective procedure for CD in experienced hands. Radiosurgery is more frequently used as treatment of residual and recurrent adenoma and persistent CD. Long-term endocrine and imaging follow-up is important as delayed recurrences and hypopituitarism are not infrequent.

The role of Crooke's changes in recurrence and remission after gamma knife radiosurgery.

PURPOSE: The objective of this study is to evaluate the role of Crooke's changes (CC) in normal the peri-tumoral anterior pituitary gland, in patients with Cushing's disease (CD) with a histopathological confirmed corticotroph adenoma, and determine if there is any difference in the recurrence and remission rates in CD patients after treatment with Gamma Knife Radiosurgery (GKRS). METHODS: All patients treated with GKRS for CD from 2005 to 2016 at our institution were identified. Patients had a confirmed adrenocorticotropic (ACTH)-secreting adenoma, i.e. corticotroph adenoma, and normal pituitary gland included in the surgical specimen, and specimens were stained with hematoxylin and eosin and also immunostaining for cytokeratin and ACTH. Statistical analyses were performed in a total of 61 patients who met the inclusion criteria. Additionally, we analyzed 20 patients in each group, with and without CC, after they were matched in a propensity score fashion. RESULTS: Endocrine remission defined as, a normal 24 h urine free cortisol while off suppressive medication, occurred in 48 patients (78.7%), with 76.9% in those with CC and 81.8% in those without CC. There was no statistical significant difference between the two groups in regarding remission (p = 0.312) or recurrence (p = 0.659) in either the unmatched or matched cohorts. CONCLUSION: The presence or absence of CC in normal pituitary gland does not appear to confer a lower rate of remission or a higher rate of recurrence after GKRS. Patients with pituitary corticotroph adenomas that present with CC features may be well served by Stereotactic radiosurgery (SRS).

Repeat stereotactic radiosurgery for Cushing's disease: outcomes of an international, multicenter study.

Stereotactic radiosurgery (SRS) is frequently used for Cushing's disease (CD) after failed pituitary surgery. Management of patients with persistent CD after failed SRS is complex, as the alternative therapeutic options harbor significant risks. The outcomes of repeat pituitary radiosurgery, however, have not been described. We sought to determine the outcomes of repeat SRS in patients with CD. We pooled data from five institutions participating in the International Gamma Knife Research Foundation for patients with recurrent or persistent CD ≥ 12 months after initial SRS. Patients were included in the study if they had ≥ 6 months endocrine follow-up after repeat SRS. Twenty patients were included in the study. Repeat single-session SRS was performed 1.3-9.7 years after initial SRS. Median endocrine follow-up was 6.6 years (1.4-19.1 years). Median margin dose was 20 Gy (range 10.8-35 Gy). Endocrine remission after second SRS was noted in 12 patients (60%), with a median time to remission of 6 months (range 2-64 months). Biochemical recurrence occurred in two patients (17%) after initial remission. Overall, the cumulative rates of durable endocrine remission at 5 and 10 years were 47 and 53%, respectively. Two patients (10%) experienced adverse radiation effects, including transient visual loss and permanent diplopia. Repeat SRS achieves lasting biochemical remission in approximately half of patients with CD refractory to both prior microsurgery and SRS. Because of the morbidity of refractory or recurrent CD, repeat SRS should be considered for carefully selected patients with hypercortisolism confirmed one or more years after initial SRS.

Decrease of Serum IGF-I following Transsphenoidal Pituitary Surgery for Acromegaly.

BACKGROUND: In the immediate postoperative period following resection of growth hormone (GH)-secreting pituitary tumors, serum concentrations of GH have limited ability to predict remission of acromegaly. Since many actions of GH actions are mediated by insulin-like growth factor-1 (IGF-I), we aimed to determine the rates of fall of IGF-I during 72 h after surgical resection of pituitary tumors. METHODS: We studied patients who were undergoing pituitary surgery for acromegaly. IGF-I was measured by LC-MS and GH by immunoassay. Remission was defined by the combination of serum GH <0.4 ng/mL during oral glucose tolerance testing performed 8 weeks after the surgical procedure and normal IGF-I at ≥8 weeks. RESULTS: During the first 72 h after surgery, the mean (SD) rate of decline of IGF-I was 185 (61) ng/mL per 24 h in those who achieved remission (n = 23), with a mean (SD) apparent half-life of 55 (19) h. IGF-I had decreased to <65% of the preoperative IGF-I on postoperative day 2 in 20 of 23 remission patients (87%) vs none of 5 patients who did not achieve remission. GH was <2.7 ng/mL on day 2 in 21 of 23 remission patients (91%), but in none of the nonremission patients. The combination of IGF-I and GH on day 2 separated the remission and nonremission groups of patients. CONCLUSIONS: Rapid decline of serum IGF-I during the immediate postoperative period warrants further study as an analytically independent adjunct to GH measurement for early prediction of biochemical remission of acromegaly.

Surgical debulking of pituitary adenomas improves responsiveness to octreotide lar in the treatment of acromegaly.

BACKGROUND: Studies comparing primary medical treatment of acromegaly with surgery are often non-randomized, and not stratified by illness severity. We prospectively compared primary medical therapy with pituitary surgery in patients with acromegaly. All patients had macroadenomas, at least one random human growth hormone (GH) level ≥12.5 ng/mL, elevated IGF-I levels and failure to suppress GH to <1 ng/mL during an oral glucose tolerance test (oGTT). METHODS: Forty-one patients from seven centers were randomized to primary treatment with octreotide LAR, 30 mg every 4 weeks × 3 months (ARM A, N = 15), or pituitary surgery (ARM B, N = 26) using a 1:2 randomization design. Patients cured by surgery (defined as nadir GH during oGTT <1 ng/mL and normal IGF-I) received no subsequent treatment. Those not cured surgically were then treated with octreotide LAR (SubArm B1) for 3 months. RESULTS: Only one of the 15 patients in ARM A (6.7%) had normalization of both GH and IGF-I. In contrast, 13/26 patients had normalization of both GH and IGF-I after surgery alone (50%). Of the remaining 13 patients who did not normalize with surgery alone, treatment with octreotide LAR resulted in a normal nadir GH and normal serum IGF-I in 7 (53.9%). In total, 20/26 in ARM B (76.9%) experienced normalization of defined biochemical acromegaly parameters. CONCLUSIONS: Pituitary surgery alone was more effective than primary medical treatment (p = 0.006), and the combination of surgery followed by medical therapy was even more effective (p < 0.0001). Subjects treated with medical therapy after surgical debulking had a significant improvement in response rate compared to matched subjects treated with primary medical therapy.

Gamma knife radiosurgery in patients with persistent acromegaly or Cushing's disease: long-term risk of hypopituitarism.

INTRODUCTION: For patient with a recurrent or residual acromegaly or Cushing's disease (CD) after resection, gamma knife radiosurgery (GKRS) is often used. Hypopituitarism is the most common adverse effect after GKRS treatment. The paucity of studies with long-term follow-up has hampered understanding of the latent risks of hypopituitarism in patients with acromegaly or CD. We report the long-term risks of hypopituitarism for patients treated with GKRS for acromegaly or CD. METHODS: From a prospectively created, IRB-approved database, we identified all patients with acromegaly or CD treated with GKRS at the University of Virginia from 1989 to 2008. Only patients with a minimum endocrine follow-up of 60 months were included. The median follow-up is 159·5 months (60·1-278). Thorough radiological and endocrine assessments were performed immediately before GKRS and at regular follow-up intervals. New onset of hypopituitarism was defined as pituitary hormone deficits after GKRS requiring corresponding hormone replacement. RESULTS: Sixty patients with either acromegaly or CD were included. Median tumour volume at time of GKRS was 1·3 cm(3) (0·3-13·4), and median margin dose was 25 Gy (6-30). GKRS-induced new pituitary deficiency occurred in 58·3% (n = 35) of patients. Growth hormone deficiency was most common (28·3%, n = 17). The actuarial overall rates of hypopituitarism at 3, 5 and 10 years were 10%, 21·7% and 53·3%, respectively. The median time to hypopituitarism was 61 months after GKRS (range, 12-160). Cavernous sinus invasion of the tumour was found to correlate with the occurrence of a new or progressive hypopituitarism after GKRS (P = 0·018). CONCLUSIONS: Delayed hypopituitarism increases as a function of time after radiosurgery. Hormone axes appear to vary in terms of radiosensitivity. Patients with adenoma in the cavernous sinus are more prone to develop loss of pituitary function after GKRS.

Gamma Knife radiosurgery for medically and surgically refractory prolactinomas: long-term results.

INTRODUCTION: Prolactinomas are the most common functioning pituitary adenomas. Dopamine agonists (DA) are generally very effective in treating prolactinomas by inducing tumor volume regression and endocrine remission. A minority of patients do not respond to DA or are intolerant because of side-effects. Microsurgical resection when possible is the next treatment option, but cavernous sinus, dural, or bone involvement may not allow for complete resection. OBJECTIVE: We reviewed the outcome of patients with medically and surgically refractory prolactinomas treated with Gamma Knife radiosurgery (GKRS) during a 22 years follow-up period. METHODS: We reviewed the patient database at the University of Virginia Gamma Knife center during a 25-year period (1989-2014), identifying 38 patients having neurosurgical, radiological and endocrine follow-up. RESULTS: Median age at GKRS treatment was 43 years. Median follow-up was 42.3 months (range 6-207.9). 55.3 % (n = 21) were taking a dopamine agonist at time of GKRS. 63.2 % (n = 24) had cavernous sinus tumor invasion. Endocrine remission (normal serum prolactin off of a dopamine agonist) was achieved in 50 % (n = 19). GKRS induced hypopituitarism occurred in 30.3 % (n = 10). Cavernous sinus involvement was shown to be a significant negative prognosticator of endocrine remission. Taking a dopamine agonist drug at the time of GKRS showed a tendency to decrease the probability for endocrine remission. CONCLUSION: GKRS for refractory prolactinomas can lead to endocrine remission in many patients. Hypopituitarism is the most common side effect of GKRS.

Stereotactic radiosurgery for acromegaly: outcomes by adenoma subtype.

PURPOSE: The subtypes of somatotroph-cell pituitary adenomas have been correlated with clinical and histopathological variables. Densely granulated somatotroph-cell (DG) adenomas are typically highly responsive to somatostatin analog drugs, whereas sparsely granulated somatotroph-cell (SG) are less responsive. The aim of the study is to determine the effect of stereotactic radiosurgery (SRS) on remission and development of new pituitary deficiency according to the different subtypes of growth hormone (GH) secreting adenomas. METHODS: A total of 176 patients underwent SRS for acromegaly at the University of Virginia. Diagnosis of acromegaly was based on the combination of clinical features and biochemical assessment including the serum GH level, and age- and gender-matched serum insulin-like growth factor-1 level. All patients underwent endocrine and neuro-imaging evaluations before and after SRS. Histological specimens were available in 73 patients. RESULTS: The histopathological examination showed 34 patients had a DG adenoma, 19 had a SG adenoma, eight had a mixed DG/SG pattern, while other rare mixed subtypes were present in 12 patients. Patients who had a SG adenoma were more likely to be younger and female, and the SG adenomas appeared to be more invasive into the cavernous sinus. With a median follow-up of 67 months (range 6-188 months), 55/73 patients (75.3%) achieved remission. The median time to remission was 26 months (range 6-102 months). The actuarial remission rates in the DG adenoma group at 2, 4, and 6 years post-radiosurgery were 35.1, 71.4, and 79.3%, respectively, while those in SG adenoma group were 35.4, 73.1, and 82.1%, respectively. CONCLUSION: While patients who had a SG adenoma may be less responsive to medical therapy, they exhibited similar responses to SRS as patients with a DG adenoma. For SG adenomas, which respond less well to medical therapy, earlier SRS may be reasonable for consideration.

Stereotactic radiosurgery for nonfunctioning pituitary tumor: A multicenter study of new pituitary hormone deficiency.

BACKGROUND: Stereotactic radiosurgery (SRS) is used to treat recurrent or residual nonfunctioning pituitary neuroendocrine tumors (NFPA). The objective of the study was to assess imaging and development of new pituitary hormone deficiency. METHODS: Patients treated with single-session SRS for a NFPA were included in this retrospective, multicenter study. Tumor control and new pituitary dysfunction were evaluated using Cox analysis and Kaplan-Meier curves. RESULTS: A total of 869 patients (male 476 [54.8%], median age at SRS 52.5 years [Interquartile range (IQR): 18.9]) were treated using a median margin dose of 14Gy (IQR: 4) for a median tumor volume of 3.4 cc (IQR: 4.3). With a median radiological follow-up of 3.7 years (IQR: 4.8), volumetric tumor reduction occurred in 451 patients (51.9%), stability in 364 (41.9%) and 54 patients (6.2%) showed tumor progression.The probability of tumor control was 95.5% (95% Confidence Interval [CI]: 93.8-97.3) and 88.8% (95%CI: 85.2-92.5) at 5 and 10 years, respectively. A margin dose >14 Gy was associated with tumor control (Hazard Ratio [HR]:0.33, 95% CI: 0.18-0.60, P < 0.001). The probability of new hypopituitarism was 9.9% (95% CI: 7.3-12.5) and 15.3% (95% CI: 11-19.4) at 5 and 10 years, respectively. A maximum point dose >10 Gy in the pituitary stalk was associated with new pituitary hormone deficiency (HR: 3.47, 95% CI: 1.95-6.19). The cumulative probability of new cortisol, thyroid, gonadotroph, and growth hormone deficiency was 8% (95% CI: 3.9-11.9), 8.3% (95% CI: 3.9-12.5), 3.5% (95% CI: 1.7-5.2), and 4.7% (95% CI: 1.9-7.4), respectively at 10 years. CONCLUSIONS: SRS provides long-term tumor control with a 15.3% risk of hypopituitarism at 10 years.

Postoperative Serum Cortisol and Cushing Disease Recurrence in Patients With Corticotroph Adenomas.

CONTEXT: In Cushing disease, the association between the rate of serum cortisol decline and recurrent disease after corticotroph adenoma removal has not been adequately characterized. OBJECTIVE: To analyze postoperative serum cortisol and recurrence rates in Cushing disease. METHODS: Patients with Cushing disease and pathology-confirmed corticotroph adenoma were retrospectively studied. Cortisol halving time was estimated using exponential decay modeling. Halving time, first postoperative cortisol, and nadir cortisol values were collected using immediate postoperative inpatient laboratory data. Recurrence and time-to-recurrence were estimated and compared among cortisol variables. RESULTS: A total of 320 patients met inclusion/exclusion criteria for final analysis, and 26 of those patients developed recurrent disease. Median follow-up time was 25 months (95% CI, 19-28 months), and 62 patients had ≥ 5 years follow-up time. Higher first postoperative cortisol and higher nadir were associated with increased risk of recurrence. Patients who had a first postoperative cortisol ≥ 50 µg/dL were 4.1 times more likely to recur than those with a first postoperative cortisol < 50 µg/dL (HR 4.1, 1.8-9.2; P = .0003). Halving time was not associated with recurrence (HR 1.7, 0.8-3.8, P = .18). Patients with a nadir cortisol ≥2 µg/dL were 6.6 times more likely to recur than those with a nadir cortisol of < 2 µg/dL (HR 6.6, 2.6-16.6, P < .0001). CONCLUSION: Postoperative nadir serum cortisol is the most important cortisol variable associated with recurrence and time-to-recurrence. Compared to first postoperative cortisol and cortisol halving time, a nadir < 2 µg/dL showed the strongest association with long-term remission and typically occurs within the first 24 to 48 hours after surgery.

Silent Corticotroph Staining Pituitary Neuroendocrine Tumors: Prognostic Significance in Radiosurgery.

BACKGROUND AND OBJECTIVES: There is conflicting evidence on the significance of adrenocorticotrophic hormone (ACTH) staining in the prognosis of nonfunctioning pituitary neuroendocrine tumors (NFpitNETs). The objective of this study was to define the effect of ACTH immunostaining on clinical and radiographic outcomes of stereotactic radiosurgery (SRS) for NFpitNETs. METHODS: This retrospective, multicenter study included patients managed with SRS for NFpitNET residuals. The patients were divided into 2 cohorts: (1) silent corticotroph (SC) for NFpitNETs with positive ACTH immunostaining and (2) non-SC NFpitNETs. Rates of local tumor control and the incidence of post-treatment pituitary and neurological dysfunction were documented. Factors associated with radiological and clinical outcomes were also analyzed. RESULTS: The cohort included 535 patients from 14 centers with 84 (15.7%) patients harboring silent corticotroph NFpitNETs (SCs). At last follow-up, local tumor progression occurred in 11.9% of patients in the SC compared with 8.1% of patients in the non-SC cohort (P = .27). No statistically significant difference was noted in new-onset hypopituitarism rates (10.7% vs 15.4%, P = .25) or visual deficits (3.6% vs 1.1%, P = .088) between the 2 cohorts at last follow-up. When controlling for residual tumor volume, maximum dose, and patient age and sex, positive ACTH immunostaining did not have a significant correlation with local tumor progression (hazard ratio = 1.69, 95% CI = 0.8-3.61, P = .17). CONCLUSION: In contemporary radiosurgical practice with a single fraction dose of 8-25 Gy (median 15 Gy), ACTH immunostaining in NFpitNETs did not appear to confer a significantly reduced rate of local tumor control after SRS.

Routine postoperative fluid restriction to prevent syndrome of inappropriate antidiuretic hormone secretion after transsphenoidal resection of pituitary adenoma.

OBJECTIVE: Syndrome of inappropriate antidiuretic hormone secretion (SIADH) is a common problem during the postoperative course after pituitary surgery. Although treatment of this condition is well characterized, prevention strategies are less studied and reported. The authors sought to characterize outcomes and predictive factors of SIADH after implementation of routine postoperative fluid restriction for patients undergoing endoscopic transsphenoidal surgery for pituitary adenoma. METHODS: In March 2018, routine postoperative fluid restriction to 1000 ml/day for 7 days was instituted for all patients who underwent surgery for pituitary adenoma. These patients were compared with patients who underwent surgery for pituitary adenoma between March 2016 and March 2018, prior to implementation of routine fluid restriction. Patients with preoperative history of diabetes insipidus (DI) or concern for postsurgical DI were excluded. Patients were followed by neuroendocrinologists and neurosurgeons, and sodium levels were checked between 7 and 10 days postoperatively. SIADH was defined by a serum sodium level less than 136 mmol/L, with or without symptoms within 10 days after surgery. Thirty-day readmission was recorded and reviewed to determine underlying reasons. RESULTS: In total, 82 patients in the fluid-unrestricted cohort and 135 patients in the fluid-restricted cohort were analyzed. The patients in the fluid-restricted cohort had a significantly lower rate of postoperative SIADH than patients in the fluid-unrestricted cohort (5% vs 15%, adjusted OR [95% CI] 0.1 [0.0-0.6], p = 0.01). Higher BMI was associated with lower rate of postoperative SIADH (adjusted OR [95%] 0.9 [0.9-1.0], p = 0.03), whereas female sex was associated with higher rate of SIADH (adjusted OR [95% CI] 3.1 [1.1-9.8], p = 0.03). There was no difference in the 30-day readmission rates between patients in the fluid-unrestricted and fluid-restricted cohorts (4% vs 7%, adjusted OR [95% CI] 0.5 [0-5.1], p = 0.56). Thirty-day readmission was more likely for patients with history of hypertension (adjusted OR [95% CI] 5.7 [1.3-26.3], p = 0.02) and less likely for White patients (adjusted OR [95% CI] 0.3 [0.1-0.9], p = 0.04). CONCLUSIONS: Routine fluid restriction reduced the rate of SIADH in patients who underwent surgery for pituitary adenoma but was not associated with reduction in 30-day readmission rate.

Dose to neuroanatomical structures surrounding pituitary adenomas and the effect of stereotactic radiosurgery on neuroendocrine function: an international multicenter study.

OBJECTIVE: Stereotactic radiosurgery (SRS) provides a safe and effective therapeutic modality for patients with pituitary adenomas. The mechanism of delayed endocrine deficits based on targeted radiation to the hypothalamic-pituitary axis remains unclear. Radiation to normal neuroendocrine structures likely plays a role in delayed hypopituitarism after SRS. In this multicenter study by the International Radiosurgery Research Foundation (IRRF), the authors aimed to evaluate radiation tolerance of structures surrounding pituitary adenomas and identify predictors of delayed hypopituitarism after SRS for these tumors. METHODS: This is a retrospective review of patients with pituitary adenomas who underwent single-fraction SRS from 1997 to 2019 at 16 institutions within the IRRF. Dosimetric point measurements of 14 predefined neuroanatomical structures along the hypothalamus, pituitary stalk, and normal pituitary gland were made. Statistical analyses were performed to determine the impact of doses to critical structures on clinical, radiographic, and endocrine outcomes. RESULTS: The study cohort comprised 521 pituitary adenomas treated with SRS. Tumor control was achieved in 93.9% of patients over a median follow-up period of 60.1 months, and 22.5% of patients developed new loss of pituitary function with a median treatment volume of 3.2 cm3. Median maximal radiosurgical doses to the hypothalamus, pituitary stalk, and normal pituitary gland were 1.4, 7.2, and 11.3 Gy, respectively. Nonfunctioning adenoma status, younger age, higher margin dose, and higher doses to the pituitary stalk and normal pituitary gland were independent predictors of new or worsening hypopituitarism. Neither the dose to the hypothalamus nor the ratio between doses to the pituitary stalk and gland were significant predictors. The threshold of the median dose to the pituitary stalk for new endocrinopathy was 10.7 Gy in a single fraction (OR 1.77, 95% CI 1.17-2.68, p = 0.006). CONCLUSIONS: SRS for the treatment of pituitary adenomas affords a high tumor control rate with an acceptable risk of new or worsening endocrinopathy. This evaluation of point dosimetry to adjacent neuroanatomical structures revealed that doses to the pituitary stalk, with a threshold of 10.7 Gy, and doses to the normal gland significantly increased the risk of post-SRS hypopituitarism. In patients with preserved pre-SRS neuroendocrine function, limiting the dose to the pituitary stalk and gland while still delivering an optimal dose to the tumor appears prudent.

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.

Whole Sella vs Targeted Stereotactic Radiosurgery for Acromegaly: A Multicenter Matched Cohort Study.

BACKGROUND: Targeted stereotactic radiosurgery (SRS) with sparing of the residual pituitary is the traditional radiosurgical method for pituitary adenomas. Whole-sella SRS is an alternative choice for radiologically indeterminate or large adenomas, the safety and efficacy of which has yet to be determined. OBJECTIVE: To determine if whole-sella SRS in acromegaly would have comparable radiographic and biochemical control to targeted SRS. We performed a multicenter, retrospective matched cohort study to compare outcomes between groups. METHODS: We conducted a retrospective review of acromegalic patients who underwent SRS from 1990 to 2016 at 10 centers participating in the International Radiosurgery Research Foundation. Whole-sella and targeted SRS patients were then matched in a 1:1 ratio. RESULTS: A total of 128 patients were eligible for inclusion. Whole-sella patients had a higher pre-SRS random serum growth hormone, larger treatment volume, and higher maximum point dose to the optic apparatus. The rates of initial/durable endocrine remission, new loss of pituitary function, and new cranial neuropathy were similar between groups. Mortality and new visual deficit were higher in the whole-sella cohort, though not statistically significant. CONCLUSION: There was no difference in biochemical remission or recurrence between treatment groups. Although not statistically significant, the higher rates of tumor regression and lower rates of mortality and new visual deficit may suggest consideration of targeted SRS over whole-sella SRS in acromegaly treatment. Further research is needed to determine the association between visual deficits and mortality with whole-sella SRS.

Cushing's disease: radiation therapy.

The usual first treatment for Cushing's disease is surgical removal of the pituitary adenoma. In patients in whom surgery is unsuccessful or who decline an operation, radiation to the pituitary offers the possibility of remission. No form of radiation delivery results in immediate control of cortisol production. Thus, until radiation treatment becomes effective, medical therapy to lower cortisol production is indicated. The time to remission with radiation therapy cannot be predicted, medical therapy should be discontinued every 6 months to assess response to radiation treatment; a normal 24 h urine free cortisol being the optimal outcome. There are no prospective studies comparing the results among the different types of radiation delivery. The type of radiation delivery depends on several factors, including the availability of different treatment modalities and the size of the target area (focused high dose radiation with the Gamma knife is not suitable for a large lesion close to the optic nerves or optic chiasm). All types of radiation delivery cause loss of normal pituitary function and patients should be monitored regularly (every 6 months) for development of new hypopituitarism and appropriate hormone replacement(s). Complications of radiation therapy may include adverse effects on vision, normal brain tissue, and with older methods of fractionated radiation delivery, vasculopathy with an increased risk of cerebrovascular disease. Current use of more targeted methods of delivery will hopefully reduce this risk. If pituitary surgery is unsuccessful and the patient undergoes bilateral adrenalectomy, without pituitary radiation, there is a substantial risk, approximately 50% of patients, of development of Nelson's syndrome (growth of pituitary adenoma, increase in serum ACTH, hyperpigmentation). There is a role for pituitary radiation in the treatment of patients with Cushing's disease, most commonly as adjunctive therapy after unsuccessful pituitary surgery. Regular medical monitoring is necessary to determine the effectiveness of radiation therapy and development of new pituitary hormone deficiency.

Effects of an oral ghrelin mimetic on body composition and clinical outcomes in healthy older adults: a randomized trial.

BACKGROUND: Growth hormone secretion and muscle mass decline from midpuberty throughout life, culminating in sarcopenia, frailty, decreased function, and loss of independence. The decline of growth hormone in the development of sarcopenia is one of many factors, and its etiologic role needs to be demonstrated. OBJECTIVE: To determine whether MK-677, an oral ghrelin mimetic, increases growth hormone secretion into the young-adult range without serious adverse effects, prevents the decline of fat-free mass, and decreases abdominal visceral fat in healthy older adults. DESIGN: 2-year, double-blind, randomized, placebo-controlled, modified-crossover clinical trial. SETTING: General clinical research center study performed at a university hospital. PARTICIPANTS: 65 healthy adults (men, women receiving hormone replacement therapy, and women not receiving hormone replacement therapy) ranging from 60 to 81 years of age. INTERVENTION: Oral administration of MK-677, 25 mg, or placebo once daily. MEASUREMENTS: Growth hormone and insulin-like growth factor I levels. Fat-free mass and abdominal visceral fat were the primary end points after 1 year of treatment. Other end points were body weight, fat mass, insulin sensitivity, lipid and cortisol levels, bone mineral density, limb lean and fat mass, isokinetic strength, function, and quality of life. All end points were assessed at baseline and every 6 months. RESULTS: Daily administration of MK-677 significantly increased growth hormone and insulin-like growth factor I levels to those of healthy young adults without serious adverse effects. Mean fat-free mass decreased in the placebo group but increased in the MK-677 group (change, -0.5 kg [95% CI, -1.1 to 0.2 kg] vs. 1.1 kg [CI, 0.7 to 1.5 kg], respectively; P < 0.001), as did body cell mass, as reflected by intracellular water (change, -1.0 kg [CI, -2.1 to 0.2 kg] vs. 0.8 kg [CI, -0.1 to 1.6 kg], respectively; P = 0.021). No significant differences were observed in abdominal visceral fat or total fat mass; however, the average increase in limb fat was greater in the MK-677 group than the placebo group (1.1 kg vs. 0.24 kg; P = 0.001). Body weight increased 0.8 kg (CI, -0.3 to 1.8 kg) in the placebo group and 2.7 kg (CI, 2.0 to 3.5 kg) in the MK-677 group (P = 0.003). Fasting blood glucose level increased an average of 0.3 mmol/L (5 mg/dL) in the MK-677 group (P = 0.015), and insulin sensitivity decreased. The most frequent side effects were an increase in appetite that subsided in a few months and transient, mild lower-extremity edema and muscle pain. Low-density lipoprotein cholesterol levels decreased in the MK-677 group relative to baseline values (change, -0.14 mmol/L [CI, -0.27 to -0.01 mmol/L]; -5.4 mg/dL [CI, -10.4 to -0.4 mg/dL]; P = 0.026); no differences between groups were observed in total or high-density lipoprotein cholesterol levels. Cortisol levels increased 47 nmol/L (CI, 28 to 71 nmol/L (1.7 microg/dL [CI, 1.0 to 2.6 microg/dL]) in MK-677 recipients (P = 0.020). Changes in bone mineral density consistent with increased bone remodeling occurred in MK-677 recipients. Increased fat-free mass did not result in changes in strength or function. Two-year exploratory analyses confirmed the 1-year results. LIMITATION: Study power (duration and participant number) was insufficient to evaluate functional end points in healthy elderly persons. CONCLUSION: Over 12 months, the ghrelin mimetic MK-677 enhanced pulsatile growth hormone secretion, significantly increased fat-free mass, and was generally well tolerated. Long-term functional and, ultimately, pharmacoeconomic, studies in elderly persons are indicated.