Pregnancy and acromegaly: clinical outcomes of retrospectively analysed data from the German acromegaly registry.

CONTEXT: Acromegaly is a rare disease caused by excessive growth hormone (GH) secretion, mostly induced by pituitary adenomas. The care of pregnant women with acromegaly is challenging, in part due to existing clinical data being limited and not entirely consistent with regard to potential risks for mother and child. OBJECTIVE: To retrospectively examine data on pregnancy and maternal as well as neonatal outcomes in patients with acromegaly. DESIGN & METHODS: Retrospective data analysis from 47 pregnancies of 31 women treated in centers of the German Acromegaly Registry. RESULTS: 87.1% of the studied women underwent transsphenoidal surgery before pregnancy. In 51.1% a combination of dopamine agonists and somatostatin analogs were used before pregnancy. Three women did not receive any therapy for acromegaly. During pregnancy only 6.4% received either somatostatin analogs or dopamine agonists. In total, 70.2% of all documented pregnancies emerged spontaneously. Gestational diabetes was diagnosed in 10.6% and gravid hypertension in 6.4%. Overall, no preterm birth was detected. Indeed, 87% of acromegalic women experienced a delivery without complications. CONCLUSION: Pregnancies in women with acromegaly are possible and the course of pregnancy is in general safe for mother and child both with and without specific treatment for acromegaly. The prevalence of concomitant metabolic diseases such as gestational diabetes is comparable to the prevalence in healthy pregnant women. Nevertheless, larger studies with more data in pregnant patients with acromegaly are needed to provide safe and effective care for pregnant women with this condition.

Adrenal Crisis - Definition, Prevention and Treatment: Results from a Delphi Survey.

Based on recent data, a total number of about 29 000 patients with adrenal insufficiency can be calculated for Germany, and about 1500 fatalities due to adrenal crises have to be expected within the next decade. Management of adrenal crises is still unsatisfactory. The objectives of this study were to establish consensus for diagnostic criteria, prevention strategies, and treatment recommendations for adrenal crises. The study was conducted from January 2022 to April 2023, using Delphi technique. Four rounds of questionnaires were sent to 45 experts, selected by a coordinating group on behalf of the adrenal section of the German Society of Endocrinology. The survey was implemented online using the REDCap web application. Responses were captured anonymously. During the Delphi process the expert panel developed diagnostic criteria to identify patients likely to have an adrenal crisis. Education about adrenal insufficiency among patients as well as non-endocrine medical personnel were regarded as highly important. It was suggested that recommendations for the management of adrenal insufficiency have to be simplified and made widely available. This study provides pragmatic strategies to identify and treat patients prone to adrenal crisis, thereby highlighting the need for an improved management of patients with adrenal insufficiency.

Exploring potential influencing factors of inadherence to specialist aftercare and long-term medication in patients with acromegaly.

PURPOSE: To improve the understanding of adherence as one major factor of disease control in acromegaly patients, we systematically assessed patients' motivations to adhere to advised follow-up schedules and recommended medication for acromegaly. METHODS: Cross-sectional, postal questionnaire study on adult patients with acromegaly, operated upon a growth hormone producing pituitary adenoma more than 1 year ago in two tertiary treatment centers. We assessed demographic and clinical characteristics, disease status, adherence to acromegaly medication and/or aftercare, and the five dimensions defined by the World Health Organization influencing adherence. Wherever applicable, we included validated short scales. The answers of 63 patients (33 f, 30 m; mean age 56.1 y) were analyzed. RESULTS: Patients with problems in adherence to aftercare had a significantly lower subjective symptomload than those adherent to aftercare (p = 0.026) and a lower perceived need for treatment (p = 0.045). Patients with adherence problems to medication had a higher subjective symptomload than those without (p = 0.056). They also tended to have shorter consultations, were significantly more often dissatisfied with the duration of their medical consultations (42% vs 4.8%, p = 0.019) and tended to find that their physician explained potential difficulties with adherence less well than patients without adherence problems (p = 0.089). CONCLUSIONS: To our knowledge, this is the first study which explored adherence to medication and aftercare in patients with acromegaly, taking into account potential influencing factors from all areas defined by the WHO model of adherence. Of the modifiable factors of adherence, patient-doctor relationship seemed to play a crucial role and could be one leverage point to improve adherence.

Hypophysitis.

OBJECTIVE: Hypophysitis is considered a rare inflammatory disease of the pituitary gland. For a long time, primary autoimmune hypophysitis has stood out as the most relevant type of hypophysitis. However, with the advent of immunotherapy for the treatment of malignancies and identification of hypophysitis as an immune-related adverse event, hypophysitis has garnered increasing interest and recognition. Therefore, awareness, early recognition, and appropriate management are becoming important as the indication for immunomodulatory therapies broaden. METHODS: In this review, we discuss the epidemiology, diagnosis, and treatment of hypophysitis with a focus on recent data and highlight subtypes of particular interest while recognizing the gaps in knowledge that remain. RESULTS: Regardless of cause, symptoms and signs of hypophysitis may be related to mass effect (headache and visual disturbance) and hormonal disruption that warrant prompt evaluation. In the vast majority of cases, a diagnosis of hypophysitis can be made presumptively in the appropriate clinical context with radiologic findings consistent with hypophysitis and after the exclusion of other causes. CONCLUSION: Although subtle differences currently exist in management and outcome expectations between primary and secondary causes of hypophysitis, universally, treatment is aimed at symptom management and hormonal replacement therapy.

Differences in the expression of SSTR1-5 in meningiomas and its therapeutic potential.

Beyond microsurgical resection and radiation therapy, there are currently no established treatment alternatives for meningioma patients. In selected cases, peptide radio receptor therapy (PRRT) can be implemented. For this purpose, a radionuclide is bound to a substance targeting specific receptors in meningiomas. One of them is somatostatin receptor 2, which can be found in most meningiomas. However, other somatostatin receptors (SSTR) exist, but their expressions have only been described in small case series. In this study, we analyzed the expression of SSTR1, 2A, 3, 4, and 5 in a large cohort of meningiomas in order to enable further refinement of this innovative treatment option. Overall, 726 tumor samples were processed into tissue microarrays and stained for SSTR1, 2A, 3, 4, and 5 immunohistochemically. Microscopic evaluation was done with an established semiquantitative score regarding percentual quantification and staining intensity, and results were correlated with clinical data. There was a significant lower rate of SSTR1 expression in meningiomas of male patients. Older age was associated with higher expression of SSTR1, 2A, and 5 and lower scores for SSTR3 and 4. Tumors treated with radiotherapy before resection showed lower rates of SSTR1 and 5 expression, while recurrent meningiomas had lower SSTR1 scores. Tumor tissue from patients suffering from neurofibromatosis type 2 had lower expression scores for SSTR1, 2, and 5. For SSTR3 and 4, NF2 patients showed higher scores than sporadic tumors. Spinal meningiomas had higher scores for SSTR1, 4, and 5 compared tumor location of the skull base and convexity/falx. Overall, higher WHO grade was associated with lower SSTR scores. While all SSTRs were expressed, there are marked differences of SSTR expression between meningioma subgroups. This has the potential to drive the development of more selective PRRT substances with higher treatment efficacy.

The immunohistochemical expression of SSTR2A is an independent prognostic factor in meningioma.

The expression of somatostatin receptors in meningioma is well established. First, suggestions of a prognostic impact of SSTRs in meningioma have been made. However, the knowledge is based on few investigations in small cohorts. We recently analyzed the expression of all five known SSTRs in a large cohort of over 700 meningiomas and demonstrated significant correlations with WHO tumor grade and other clinical characteristics. We therefore expanded our dataset and additionally collected information about radiographic tumor recurrence and progression as well as clinically relevant factors (gender, age, extent of resection, WHO grade, tumor location, adjuvant radiotherapy, neurofibromatosis type 2, primary/recurrent tumor) for a comprehensive prognostic multivariate analysis (n = 666). The immunohistochemical expression scores of SSTR1, 2A, 3, 4, and 5 were scored using an intensity distribution score ranging from 0 to 12. For recurrence-free progression analysis, a cutoff at an intensity distribution score of 6 was used. Univariate analysis demonstrated a higher rate of tumor recurrence for increased expression scores for SSTR2A, SSTR3, and SSTR4 (p = 0.0312, p = 0.0351, and p = 0.0390, respectively), while high expression levels of SSTR1 showed less frequent tumor recurrences (p = 0.0012). In the Kaplan-Meier analysis, a higher intensity distribution score showed a favorable prognosis for SSTR1 (p = 0.0158) and an unfavorable prognosis for SSTR2A (0.0143). The negative prognostic impact of higher SSTR2A expression remained a significant factor in the multivariate analysis (RR 1.69, p = 0.0060). We conclude that the expression of SSTR2A has an independent prognostic value regarding meningioma recurrence.

Genetic and epigenetic characterization of posterior pituitary tumors.

Pituicytoma (PITUI), granular cell tumor (GCT), and spindle cell oncocytoma (SCO) are rare tumors of the posterior pituitary. Histologically, they may be challenging to distinguish and have been proposed to represent a histological spectrum of a single entity. We performed targeted next-generation sequencing, DNA methylation profiling, and copy number analysis on 47 tumors (14 PITUI; 12 GCT; 21 SCO) to investigate molecular features and explore possibilities of clinically meaningful tumor subclassification. We detected two main epigenomic subgroups by unsupervised clustering of DNA methylation data, though the overall methylation differences were subtle. The largest group (n = 23) contained most PITUIs and a subset of SCOs and was enriched for pathogenic mutations within genes in the MAPK/PI3K pathways (12/17 [71%] of sequenced tumors: FGFR1 (3), HRAS (3), BRAF (2), NF1 (2), CBL (1), MAP2K2 (1), PTEN (1)) and two with accompanying TERT promoter mutation. The second group (n = 16) contained most GCTs and a subset of SCOs, all of which mostly lacked identifiable genetic drivers. Outcome analysis demonstrated that the presence of chromosomal imbalances was significantly associated with reduced progression-free survival especially within the combined PITUI and SCO group (p = 0.031). In summary, we observed only subtle DNA methylation differences between posterior pituitary tumors, indicating that these tumors may be best classified as subtypes of a single entity. Nevertheless, our data indicate differences in mutation patterns and clinical outcome. For a clinically meaningful subclassification, we propose a combined histo-molecular approach into three subtypes: one subtype is defined by granular cell histology, scarcity of identifiable oncogenic mutations, and favorable outcome. The other two subtypes have either SCO or PITUI histology but are segregated by chromosomal copy number profile into a favorable group (no copy number changes) and a less favorable group (copy number imbalances present). Both of the latter groups have recurrent MAPK/PI3K genetic alterations that represent potential therapeutic targets.

Increased proliferation is associated with CNS invasion in meningiomas.

INTRODUCTION: Meningiomas are the most common benign intracranial neoplasms. CNS invasion in meningiomas has been integrated into the 2016 WHO classification of CNS tumors as a stand-alone criterion for atypia. Since then, its prognostic impact has been debated based on contradictory results from retrospective analyses. The aim of the study was to elucidate whether histopathological evidence of CNS invasion is associated with increased proliferative potential. METHODS: We have conducted a quantified measurement of the proliferation marker Ki67 and analyzed its association with CNS invasion determined by histology together with other established prognostic markers of progression. Routine, immunohistochemical staining for Ki67 were digitalized and automatic quantification was done using Image J software. RESULTS: Overall, 1718 meningiomas were assessed. Histopathological CNS invasion was seen in 108 cases (6.7%). Uni- and multivariate analysis revealed a significantly higher Ki67 proliferation rate in meningiomas with CNS invasion (p < 0.0001 and p = 0.0098, respectively). CONCLUSIONS: Meningiomas with histopathological CNS invasion show a higher proliferative activity.

The role of Simpson grading in meningiomas after integration of the updated WHO classification and adjuvant radiotherapy.

Since the introduction of the Simpson grading for the extent of resection in meningiomas in 1957, its usefulness in modern neurosurgery has been challenged. Especially, the updated WHO classification regarding brain invasion and the efficacy of radiation therapy has not been taken into account when evaluating the prognostic role of the Simpson grading in this era. We analyzed the clinical and histopathological data of 1571 meningiomas that were surgically resected in the authors' institution between July 2003 and March 2017. Operative reports were reviewed regarding the extent of resection according to Simpson grading. Meningioma subtype according to the updated WHO classification of 2016 and clinical characteristics and time to tumor progression were analyzed. The mean follow-up was 38.4 months (range 1.2 to 195.6). A higher rate of tumor recurrence was observed for male gender, younger age, recurrent tumors, non-spinal tumor localization, higher WHO, and Simpson grades in the univariate analysis. In the multivariate analysis older age, recurrent tumors and higher WHO grades remained negative prognostic factors. Among the different Simpson grades, the relative risk for recurrence was highest for grade IV compared to all other grades (each p < 0.0001), while there was no difference between Simpson grades I and II. Adjuvant radiotherapy showed lower rates of tumor recurrence. Subtotal microsurgical resection remains an independent prognostic factor with a higher rate of tumor recurrence. The prognostic benefit of radical treatment of the dural attachment is questionable and needs to be considered when weighing the intraoperative risks of radicality.

Granulomatous hypophysitis causing compression of the internal carotid arteries reversible with azathioprine and rituximab treatment.

INTRODUCTION: Compression of the internal carotid artery (ICA) in the cavernous sinus area is a rare event and is mostly associated with pituitary adenomas and meningiomas. Other causes of ICA compression are less well known. We present a rare case of granulomatous hypophysitis causing compression of the ICA, which was treated successfully with immune-suppressive agents. METHODS: The electronic database MEDLINE (PubMed) was searched systematically and other cases with ICA compression were identified and analyzed. RESULTS: A female patient with a history of two previous transsphenoidal operations for suspected pituitary adenoma and post-operative complete pituitary insufficiency presented with severe headaches, nausea, fatigue, and diplopia. Pituitary MRI scan suggested relapse of the pituitary lesion with atypical bilateral infiltration of cavernous sinuses and compression of ICAs. After histological reevaluation of her previous pituitary operations, granulomatous hypophysitis was diagnosed. Treatment was started with high doses of prednisolone. With decreasing doses of prednisolone, symptoms recurred, and azathioprine was started, followed by administration of rituximab resulting in clinical recovery and regression of ICA compression. Literature analysis disclosed 36 case reports with ICA compression in the cavernous sinus region (12 pituitary adenoma, 6 meningioma, 7 hypophysitis, 5 other tumors, and 4 other etiologies). Two cases of hypophysitis recovered completely; five cases improved only partly. CONCLUSION: In the case of ICA compression, clinical signs, onset of symptoms, radiological findings and pituitary insufficiencies should be thoroughly evaluated, and hypophysitis should be considered as a possible cause. In our patient, treatment with azathioprine and, finally, rituximab was successful.

Surgery for prolactinomas: a better choice?

PURPOSE: Renewed interest in transsphenoidal surgery (TSS) as a therapeutic option for prolactinomas has emerged. METHODS: Based on contemporary literature and own experience, the changing role of surgery for treatment of prolactinomas is discussed. RESULTS: Today, TSS is performed by minimally invasive microscopic or endoscopic techniques. Normoprolactinemia is obtained in 71-100% of patients with microprolactinomas by TSS. Almost equal results are found in circumscribed intrasellar macroprolactinomas. In experienced hands, pituitary function is preserved in TSS. The risk of cardiac valve disease is still a concern with ergot-derived dopamine-agonists (DAs) in patients requiring long-term, high-dose dopamine-agonist (DA) treatment. Cost-utility analysis favors TSS over DA treatment. The possible negative impact of DA treatment on future surgical results is still a controversial and unsettled issue. In patients who wish to become pregnant, the advantages of microprolactinoma removal to avoid DAs and macroprolactinoma debulking to avoid symptomatic enlargement during pregnancy should be discussed with the patients. Young patients' age is an argument for surgery to circumvent the unpredictable sequelae of long-term DA treatment. Surgery should be discussed in male gender because of a higher likelihood of DA resistance and aggressive behavior of prolactinoma. CONCLUSION: Given excellent results of TSS and concerns about medical treatment, the scale of indications for TSS as an alternative to DAs has increased. The patient's wishes concerning a chance at a cure with TSS instead of a long-term treatment with DAs has become an important and accepted indication. With DA medication and TSS, two effective treatment modalities for prolactinomas are available that can be used in a complementary fashion.

Identification of tumor residuals in pituitary adenoma surgery with intraoperative MRI: do we need gadolinium?

OBJECTIVE: To evaluate the diagnostic accuracy of high-resolution T2w intraoperative magnetic resonance imaging (iMRI) for detecting pituitary adenoma remnants compared to contrast-enhanced T1-weighted images. METHODS: 42 patients underwent iMRI-guided resection of large pituitary macroadenomas and fulfilled the inclusion criteria for this retrospective analysis. Intraoperative and postoperative imaging evaluation of tumor residuals and localization were assessed by two experienced neuroradiologists in a blinded fashion. The diagnostic accuracy of T2w and contrast-enhanced T1w images were evaluated. RESULTS: The diagnostic accuracy for detecting tumor residuals of high-resolution T2w images showed highly significant association to contrast-enhanced T1w images (p < 0.0001). Furthermore, identification rate of tumor remnants in different compartments, e.g., cavernous sinus, was comparable. In total, coronal T2w images provided a diagnostic sensitivity of 97.7% and specificity of 100% compared to the gold standard of contrast-enhanced T1w images. The postoperatively expected extent of resection proved to be true in 97.6% according to MRI 3 months after resection. CONCLUSIONS: High-resolution T2w intraoperative MR images provide excellent diagnostic accuracy for detecting tumor remnants in macroadenoma surgery with highly significant association compared to T1w images with gadolinium. The routine-use and need of gadolinium in these patients should be questioned critically in each case in the future.

A pitfall of bilateral inferior petrosal sinus sampling in cyclic Cushing's syndrome.

BACKGROUND: Clinical care of patients with cyclic Cushing's syndrome (CS) is challenging. Classical pitfalls include incorrect subtyping, unnecessary surgical procedures and delayed definite treatment. CASE PRESENTATION: A 43-year-old female suffered from a rapidly cycling ectopic CS. She experienced six cycles of severe hypercortisolism within a 2 year period (maximum plasma cortisol 5316 nmol/L, normal range 124.2-662.4 nmol/L; maximum urinary free cortisol 79,469 nmol/24 h, normal range < 414 nmol/24 h) lasting 2-9 weeks. The episodes were associated with pronounced hypokalemia (lowest K+ value recorded 2.4 mmol/l) and progressive signs and symptoms of CS. A bilateral inferior petrosal sinus sampling (BIPSS) performed during a trough phase was false positive for pituitary ACTH overproduction resulting in unnecessary transsphenoidal surgery while a second BIPSS performed during an active phase was indicative for ectopic CS. The 18F-DOPA PET/CT showed a pancreatic lesion, which was subsequently partially removed. Surprisingly, the histopathology was conclusive for ACTH-positive lymph node metastasis located in the retro-duodenal tissue of an occult neuroendocrine tumor WHO grade II. The primary tumor has not been identified so far and, because of the persistent hypercortisolism, the patient underwent bilateral adrenalectomy. Two years later, ACTH levels started to increase progressively. Percutaneous biopsy of a newly identified suspected lesion in the fifth thoracic vertebra revealed a metastasis with positive staining for ACTH, synaptophysin and chromogranin A. Therapy with carboplatin and etoposide was started and, since then, the patient underwent 12 cycles of chemotherapy. CONCLUSIONS: We report the challenging case of a rapidly cycling CS secondary to ACTH-secreting neuroendocrine intestinal tumor of unknown primary. We highlight the importance of performing diagnostic tests only during the phases of active cortisol secretion and as soon as first symptoms appear to avoid pitfalls.

Ki-67 labeling index and expression of p53 are non-predictive for invasiveness and tumor size in functional and nonfunctional pituitary adenomas.

BACKGROUND: It is still controversial whether an increased proliferation index is correlated with the tumor invasiveness of pituitary adenomas. A homogeneous large monocentric series of pituitary adenomas was retrospectively analyzed. The correlation between the proliferation indices (Ki-67 and p53 expression levels) and invasiveness and size of pituitary adenomas was investigated in primary operated and recurrent adenomas. METHOD: Four hundred thirty-nine patients after resection of pituitary adenomas were retrospectively included (43 recurrent tumors, 196 null cell adenomas, 86 somatotroph adenomas, 55 corticotroph adenomas, 55 prolactinomas, 4 thyreotroph adenomas). The maximum tumor diameter and tumor invasiveness in Knosp grading were assessed and Ki-67 and p53 immunostaining was performed. The role of invasiveness was evaluated using a cumulative odds ordinal logistic regression. For calculating the effect of tumor size, a one-way analysis of variance (ANOVA) was conducted. RESULTS: Overall and in the subgroups, no significant correlation between proliferation indices and mean tumor diameter was found. No significant predictive expression value of Ki-67 and p53 on tumor invasiveness and in recurrent tumors could be demonstrated. There was a tendency that Ki-67 LI and p53 LI are higher in recurrent corticotroph adenomas and lactotroph adenomas but values did not reach the significant level. CONCLUSION: Invasive character of pituitary adenomas is neither correlated with increased Ki-67 LI nor with increased p53 expression. Proliferation parameters are independent from adenoma size at initial presentation. The partly elevated expression of Ki-67 in recurrent tumors underlines the clinical importance of the marker.

[Pituitary adenomas]. / Hypophysenadenome.

Despite characteristic symptoms the diagnosis of clinically relevant pituitary adenomas is often delayed until an advanced stage due to the rarity of the disease. The typical clinical manifestations are presented in this review article. The recent discovery of the USP8 mutation in Cushing's disease and of X­linked acrogigantism (X-LAG) syndrome in early onset gigantism were milestones in the search for the molecular etiology of pituitary adenomas. The triad of endocrinological, radiological and ophthalmological diagnostics are the main pillars for the diagnostic work-up of pituitary adenomas. The standard treatment modalities, which include surgery, medical treatment and irradiation, have been further developed and refined. For transsphenoidal excision of pituitary adenomas, microsurgery and endoscopy are two equivalent surgical techniques with relatively few complications. Surgery represents the first-line treatment of pituitary adenomas. Prolactinomas are an exception as the medical treatment with dopamine agonists is highly efficient. Nowadays, new medical treatment options are available for acromegaly and Cushing's disease and are used for second-line treatment. The alkylating chemotherapeutic agent temozolomide is used for the first-line chemotherapy of rare aggressively growing pituitary adenomas. Irradiation is indicated if surgical and medical treatment options are insufficiently successful. Stereotactic one-stage irradiation (radiosurgery) is especially suitable for well-demarcated invasive residual or recurrent adenomas in the cavernous sinus. A new development is hypofractionated radiosurgery for protection of structures at risk. Fractionated irradiation is necessary with large radiation volumes and for pituitary adenomas with a close proximity to the optic tract.

[Neuro-Ophthalmological Considerations on Meningiomas of the Anterior Visual Pathways]. / Neuroophthalmologische Überlegungen zu Meningeomen der vorderen Sehbahn.

Meningiomas are slow growing tumours, usually becoming symptomatic with visual loss or diplopia, or they are found incidentally. Not all meningiomas need to be treated. Treatment consists of neuro-surgical removal or radiotherapy if surgery is not possible. Whether a meningioma of the anterior visual pathways needs to be treated is mainly determined by the ophthalmological state. This must also include assessment of the prognosis by evaluation of the clinical findings and OCT scanning. This contribution is intended as an overview of all relevant factors with meningiomas of the anterior visual pathways. It is mainly based on the authors' own experiences.

The USP8 mutational status may predict long-term remission in patients with Cushing's disease.

OBJECTIVE: Almost half of the cases of Cushing's disease (CD) tumours carry recurrent activating somatic mutations in the ubiquitin-specific protease eight gene (USP8). The USP8 mutational status could predict remission in patients with CD, so our objective was to correlate the presence of somatic USP8 mutations with the rate of recurrence after transsphenoidal surgery (TSS) retrospectively. DESIGN: Biochemical, radiological and clinical data were retrospectively assessed in 48 patients. USP8 mutational status was determined from corticotroph tumour samples. Association between USP8 mutational status, remission and recurrence was investigated. PATIENTS: Patients with Cushing's disease from a single-centre cohort who underwent TSS between 1991 and 2012. MEASUREMENTS: Long-term remission and recurrence rate after TSS with at least 6 months follow-up. Biochemical, radiological and clinical data, including sex, age at diagnosis, tumour size and pre-operative hormonal levels. USP8 mutational status. RESULTS: Patients with USP8 mutant corticotroph tumours (18 of 48; 37%) were diagnosed significantly earlier (mean ± SD 46 ± 10 years vs 53 ± 11 years; P = 0.028) and presented with higher pre-operative 24-hour urinary-free cortisol levels (median IQR µg/24 hours 1174.0, 1184.5 vs 480.0, 405.3; P = 0.045). The incidence of recurrence in a 10-year follow-up was significantly higher in patients with USP8 mutant tumours after the initial remission (58% vs 18% P = 0.026). Recurrence appeared significantly earlier in these patients (months 70, 44-97 95% CI vs 102, 86-119 95% CI; P = 0.019). CONCLUSION: Recurrence appears to be more frequent and earlier after TSS in patients with USP8 mutant corticotroph tumours.

The experience with transsphenoidal surgery and its importance to outcomes.

PURPOSE: Surgical experience is considered paramount for excellent outcome of transsphenoidal surgery (TSS). However, objective data demonstrating the surgical success in relation to the experience of pituitary surgery units or individual experience of pituitary surgeons is sparse. METHODS: Based on literature data, we have investigated the influence of experience with TSS for pituitary adenomas on endocrinological remission rates and on operative complications. The surgical experience was assessed by calculating the number of transsphenoidal operations per year. RESULTS: For TSS of microprolactinomas, mean remission rates were 77% in centers with < 2 operations per year for microprolactinomas, 82% with 2-4 operations, 84% with 4-6 operations, and 91% with > 6 operations. A yearly experience with more than 10 initial operations for Cushing's disease (CD) warrants a remission rate exceeding 70%. Remission rates in CD exceeding 86% have only been reported for single surgeon series. Extraordinarily high complication rates were found in some series with < 25 yearly total operations for pituitary adenomas. Major vascular complications were less than 2% and revision rates for rhinorrhea usually < 2.5% in centers performing > 25 transsphenoidal operations per year. CONCLUSIONS: We conclude that a center with experience of > 25 transsphenoidal operations for pituitary adenomas per year provides a high likelihood of safe TSS. Surgery for CD requires a particularly high level of practice to guarantee excellent remission rates. The endocrinologist has the unique opportunity to audit the surgical success by hormone measurement and to refer patients to neurosurgeons with proven excellence.