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Pituitary adenomas account for about 15% of intracranial tumors. Clinical manifestations of disease reflect the oversecretion of the involved hormone, most commonly growth hormone, prolactin, corticotropin, or thyrotropin. Diagnosis and management of these disorders are reviewed.

Abstract Context Few data exist about the clinical course of acromegaly, surgical and medical outcomes in patients with GH- and prolactin cosecreting pituitary adenomas (GH&PRL-PAs). Nevertheless, some series described a more aggressive clinic-radiological behavior than in growth hormone–secreting pituitary adenomas (GH-PAs). Objective This work aims to evaluate differences in clinical presentation and in surgical outcomes between GH-PAs and GH&PRL-PAs. Methods A multicenter retrospective study was conducted of 604 patients with acromegaly who underwent pituitary surgery. Patients were classified into 2 groups according to serum PRL levels at diagnosis and immunohistochemistry (IHC) for PRL: a) GH&PRL-PAs when PRL levels were above the upper limit of normal (ULN) and IHC for GH and PRL was positive or PRL levels were greater than 100 ng/dL and PRL IHC was not available (n = 130) and b) GH-PA patients who did not meet the previously mentioned criteria (n = 474). Results GH&PRL-PAs represented 21.5% (n = 130) of patients with acromegaly. The mean age at diagnosis was lower in GH&PRL-PAs than in GH-PAs (P < .001). GH&PRL-PAs were more frequently macroadenomas (90.6% vs 77.4%; P = .001) and tended to be more invasive (33.6% vs 24.7%; P = .057) than GH-PAs. Furthermore, they had presurgical hypopituitarism more frequently (odds ratio 2.8; 95% CI, 1.83-4.38). Insulin-like growth factor ULN levels at diagnosis were lower in patients with GH&PRL-PAs (median 2.4 [interquartile range (IQR) 1.73-3.29] vs 2.7 [IQR 1.91-3.67]; P = .023). There were no differences in the immediate (41.1% vs 43.3%; P = .659) or long-term postsurgical acromegaly biochemical cure rate (53.5% vs 53.1%; P = .936) between groups. However, there was a higher incidence of permanent arginine-vasopressin deficiency (AVP-D) (7.3% vs 2.4%; P = .011) in GH&PRL-PA patients. Conclusion GH&PRL-PAs are responsible for 20% of acromegaly cases. These tumors are more invasive, larger, and cause hypopituitarism more frequently than GH-PAs and are diagnosed at an earlier age. The biochemical cure rate is similar between both groups, but patients with GH&PRL-PAs tend to develop permanent postsurgical AVP-D more frequently.

Abstract Context Transsphenoidal surgery (TSS) is the primary treatment of choice in acromegaly. It is important to identify patients in whom surgical cure is not attainable at an early stage, both to inform patients on expected treatment outcome and to select those who are more likely to need additional therapy. Objective To identify predictors for remission after TSS in acromegaly. Methods Large multicenter study with retrospective data collection from 3 tertiary neurosurgical referral centers in The Netherlands. We analyzed clinical data since 2000 from 3 cohorts (Groningen, Nijmegen, and Rotterdam, total n = 282). Multivariate regression models were used to identify predictors of early biochemical remission (12 weeks to 1 year postoperatively) according to the 2010 consensus criteria, long-term remission (age- and sex-normalized insulin-like growth factor 1 [IGF-1] and the absence of postoperative treatment until last follow-up), and relative IGF-1 and growth hormone [GH] reduction. Results A larger maximum tumor diameter (odds ratio [OR] 0.91, 95% CI 0.87-0.96, P ≤ .0001) was associated with a lower chance of early biochemical remission. A larger maximum tumor diameter (OR 0.93, 95% CI 0.89-0.97, P = .0022) and a higher random GH concentration at diagnosis (OR 0.98, 95% CI 0.96-0.99, P = .0053) were associated with a lower chance of long-term remission. Conclusion Maximum tumor diameter and random GH concentration at diagnosis are the best predictors for remission after TSS in acromegaly.

ContextSomatic mutations in the ubiquitin-specific protease 8 (USP8) gene have been recently identified as the most common genetic alteration in patients with Cushing disease (CD). However, the frequency of these mutations in the pediatric population has not been extensively assessed.ObjectiveWe investigated the status of the USP8 gene at the somatic level in a cohort of pediatric patients with corticotroph adenomas.Design and MethodsThe USP8 gene was fully sequenced in both germline and tumor DNA samples from 42 pediatric patients with CD. Clinical, biochemical, and imaging data were compared between patients with and without somatic USP8 mutations.ResultsFive different USP8 mutations (three missense, one frameshift, and one in-frame deletion) were identified in 13 patients (31%), all of them located in exon 14 at the previously described mutational hotspot, affecting the 14-3-3 binding motif of the protein. Patients with somatic mutations were older at disease presentation [mean 5.1 ± 2.1 standard deviation (SD) vs 13.1 ± 3.6 years, P = 0.03]. Levels of urinary free cortisol, midnight serum cortisol, and adrenocorticotropic hormone, as well as tumor size and frequency of invasion of the cavernous sinus, were not significantly different between the two groups. However, patients harboring somatic USP8 mutations had a higher likelihood of recurrence compared with patients without mutations (46.2% vs 10.3%, P = 0.009).ConclusionSomatic USP8 gene mutations are a common cause of pediatric CD. Patients harboring a somatic mutation had a higher likelihood of tumor recurrence, highlighting the potential importance of this molecular defect for the disease prognosis and the development of targeted therapeutic options.Mutations in the USP8 gene have been identified in one third of patients from a cohort of 42 pediatric patients with Cushing disease, in association with increased likelihood of disease recurrence.

Abstract BACKGROUND Stereotactic radiosurgery (SRS) is a treatment option for persistent or recurrent acromegaly secondary to a growth hormone secreting pituitary adenoma, but its efficacy is inadequately defined. OBJECTIVE To assess, in a multicenter, retrospective cohort study, the outcomes of SRS for acromegaly and determine predictors. METHODS We pooled and analyzed data from 10 participating institutions of the International Gamma Knife Research Foundation for patients with acromegaly who underwent SRS with endocrine follow-up of ≥6 mo. RESULTS The study cohort comprised 371 patients with a mean endocrine follow-up of 79 mo. IGF-1 lowering medications were held in 56% of patients who were on pre-SRS medical therapy. The mean SRS treatment volume and margin dose were 3.0 cm3 and 24.2 Gy, respectively. The actuarial rates of initial and durable endocrine remission at 10 yr were 69% and 59%, respectively. The mean time to durable remission after SRS was 38 mo. Biochemical relapse after initial remission occurred in 9%, with a mean time to recurrence of 17 mo. Cessation of IGF-1 lowering medication prior to SRS was the only independent predictor of durable remission (P = .01). Adverse radiation effects included the development of ≥1 new endocrinopathy in 26% and ≥1 cranial neuropathy in 4%. CONCLUSION SRS is a definitive treatment option for patients with persistent or recurrent acromegaly after surgical resection. There appears to be a statistical association between the cessation of IGF-1 lowering medications prior to SRS and durable remission.

Abstract Context Patients with nonfunctioning adrenal adenomas (NFA) and mild autonomous cortisol secretion (MACS) demonstrate an increased risk of chronic kidney disease (CKD); however, factors associated with CKD are unknown. Objective We aimed to identify the factors associated with CKD and assess the effect of adrenalectomy on kidney function in patients with NFA or MACS. Methods A single-center cohort study of patients with NFA and MACS, 1999 to 2020, was conducted. MACS was diagnosed based on post dexamethasone suppression test (DST) cortisol greater than or equal to 1.8 mcg/dL. Age, sex, dysglycemia, hypertension, therapy with statin, angiotensin-converting enzyme inhibitor, or angiotensin II receptor blocker were included in the multivariable analysis. Outcomes included estimated glomerular filtration rate (eGFR) at the time of diagnosis with MACS or NFA and postadrenalectomy delta eGFR. Results Of 972 patients, 429 (44%) had MACS and 543 (56%) had NFA. At the time of diagnosis, patients with MACS had lower eGFR (median 79.6 vs 83.8 mL/min/1.73 m2; P < .001) than patients with NFA. In a multivariable analysis, factors associated with lower eGFR were older age, hypertension, and higher DST. In 204 patients (MACS: 155, 76% and NFA: 49, 24%) treated with adrenalectomy, postadrenalectomy eGFR improved in both groups starting at 18 months up to 3.5 years of follow-up. Factors associated with increased eGFR were younger age, lower preadrenalectomy eGFR, and longer follow-up period. Conclusion DST cortisol is an independent risk factor for lower eGFR in patients with adrenal adenomas. Patients with both MACS and NFA demonstrate an increase in eGFR post adrenalectomy, especially younger patients with lower eGFR pre adrenalectomy.

Abstract Context Acromegaly registries constitute a valuable source of therapeutic outcome information in real-life. Objective The objective of this work is to analyze surgical and pharmacological outcomes in the Mexican Acromegaly Registry (MAR). Design and Methods Data were extracted from the MAR informatic platform. Surgical remission was defined by a postoperative postglucose (GH) of less than 1 ng/mL and an insulin-like growth factor 1 (IGF-1) of less than 1.2 × upper limit of normal (ULN). Pharmacological remission was defined by a basal GH of less than 1 ng/mL and an IGF-1 of less than 1.2 × ULN. Results A total of 650 surgical outcomes were analyzed (94.6% transsphenoidal). Surgical remission was achieved in 40.15%, whereas 44.15% remained biochemically active. Persistently active disease after surgery was significantly associated with harboring an invasive macroadenoma, a basal GH of greater than 10 ng/mL, and/or an IGF-1 of greater than 2 × ULN at diagnosis on bivariate and multivariate analysis. The outcome of monotherapy with first-generation somatostatin analogs (SSAs) was evaluated in 267 patients (adjunctive in 65%), of whom 28.4% achieved remission. Persistently active disease was significantly associated with harboring an invasive macroadenoma as well as with pretreatment basal GH and IGF-1 levels of greater than 10 ng/mL and greater than 2 × ULN, respectively, on bivariate and multivariate analysis. Combined therapy with SSA and cabergoline was analyzed in 100 patients, of whom 19% achieved remission and 44% remained active; in this subset of patients, only a pretreatment IGF-1 of greater than 2 × ULN was significantly associated with persistent disease activity. Conclusion Surgical and pharmacological outcomes in acromegaly are highly dependent on tumor size/invasiveness as well as on the degree of hypersomatotropinemia.

ContextCushing disease (CD) due to adrenocorticotropic hormone–secreting pituitary tumors can be a management challenge.ObjectiveTo better understand the outcomes of stereotactic radiosurgery (SRS) for CD and define its role in management.DesignInternational, multicenter, retrospective cohort analysis.SettingTen medical centers participating in the International Gamma Knife Research Foundation.PatientsPatients with CD with >6 months endocrine follow-up.InterventionSRS using Gamma Knife radiosurgery.Main Outcome MeasuresThe primary outcome was control of hypercortisolism (defined as normalization of free urinary cortisol). Radiologic response and adverse radiation effects (AREs) were recorded.ResultsIn total, 278 patients met inclusion criteria, with a mean follow-up of 5.6 years (0.5 to 20.5 years). Twenty-two patients received SRS as a primary treatment of CD. Mean margin dose was 23.7 Gy. Cumulative initial control of hypercortisolism was 80% at 10 years. Mean time to cortisol normalization was 14.5 months. Recurrences occurred in 18% with initial cortisol normalization. Overall, the rate of durable control of hypercortisolism was 64% at 10 years and 68% among patients who received SRS as a primary treatment. AREs included hypopituitarism (25%) and cranial neuropathy (3%). Visual deficits were related to treatment of tumor within the suprasellar cistern (P = 0.01), whereas both visual (P < 0.0001) and nonvisual cranial neuropathy (P = 0.02) were related to prior pituitary irradiation.ConclusionsSRS for CD is well tolerated and frequently results in control of hypercortisolism. However, recurrences can occur. SRS should be considered for patients with persistent hypercortisolism after pituitary surgery and as a primary treatment in those unfit for surgery. Long-term endocrine follow-up is essential after SRS.We studied the outcomes of stereotactic radiosurgery for Cushing disease in 278 patients and found that this treatment can result in durable endocrine remission in appropriately selected patients.

Mixed gangliocytoma-pituitary adenomas (MGPAs) are rare sellar tumors, often presenting with signs and symptoms of acromegaly due to the somatotrophic component. The pathogenesis is not well understood, with few cases reported. We present our institutional experience in surgical management and compare surgical outcomes in growth hormone (GH)-secreting MGPAs and GH-secreting pituitary adenomas (GHPAs). We retrospectively reviewed demographic and clinical data of adult patients with MGPAs and GHPAs operated at our institution from 2018 to 2024. Six MGPA patients (3 males, 3 females) and 40 GHPA patients (20 males, 20 females) were included. Mean age was 47 (range 36–65) and 49 years (range 19–76), respectively. Common symptoms in both groups were headaches, acral enlargement, and facial changes. All patients underwent endoscopic endonasal transsphenoidal approach (EETA). Preoperative mean IGF-1 levels were similar. Tumor diameter was larger in MGPA (23 mm vs. 15 mm, p = 0.034). Cavernous sinus invasion Knosp 4 was more common in MGPA (16 %) than GHPA (5 %) (p = 0.121). Hormonal remission, defined as normalized IGF-1 at 3–6 months postoperatively, was achieved in 50 % of MGPA and 48 % of GHPA patients. Mean follow-up time for MGPA and GHPA patients was 19 months and 34 months respectively. Neither group experienced disease recurrence. MGPA is a rare subtype of pituitary adenoma; however, it represented 12.8 % of operated GH-secreting tumors at our institution. In our series, MGPAs were larger tumors and more likely to invade the cavernous sinus than GHPAs. EETA was safe and effective in both groups, with similar remission rates. [Display omitted] •Mixed gangliocytoma-pituitary adenomas are rare sellar tumors.•A comparative analysis between growth-hormone producing tumors was performed.•Mixed gangliocytoma tumors were larger with higher rates of cavernous sinus invasion.•Endoscopic endonasal resection remains the primary surgical technique in these tumors.•Surgical outcomes and hormonal remission are comparable between both groups.

Introduction and purpose Re-intervention, either transsphenoidal surgery or radiotherapy, is suggested in patients who are not in remission after primary surgery for acromegaly; however, the evidence is weak. We aimed to assess the remission rate after re-intervention, and complications compared to a comparison group who had undergone primary interventions only. Methods Patients diagnosed with acromegaly between 2005–2021 at Oslo University Hospital were screened for inclusion. The study cohort included patients with two or more interventions. The comparison group included patients not in remission after primary surgery. Results Of 223 patients with acromegaly, 42 underwent re-interventions (study cohort). At diagnosis, median age was 38 (IQR 29–48) years and 41 patients (98%) had a macroadenoma. The comparison group consisted of 49 patients, median age 54 (IQR 44–60) years and 37 (76%) had a macroadenoma at diagnosis. Re-interventions in the study cohort consisted of surgery, radiotherapy and a combination of these (22, 12 and eight patients). After re-interventions, 22 patients (52%) were in remission and 12 (29%) had reduced disease activity. Seven patients (17%) acquired new hormone deficiencies, two of them corticotroph deficiency. One patient in remission developed spinal fluid leakage and meningitis. There was no significant difference in complications after surgery between the study cohort and the comparison group. Conclusion Re-interventions were safe and resulted in remission or substantial improvement in most patients. Re-intervention should be considered for patients who would otherwise require lifelong medical treatment.