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Introduction: Prolactinoma account to the most common pituitary adenomas and current therapy regime constitutes of dopamine agonist therapy (DA) and surgery in selected cases [17]. Due to tumor fibrosis induced by previous DA therapy, surgical removal can be challenging though. Therefore, this study investigates how preoperative DA usage influences perioperative treatment and surgical outcome in prolactinoma and aims to ascertain whether a specific subgroup of prolactinoma patients could derive greater benefit from exclusive surgical intervention., Methods: We retrospectively analyzed n = 159 surgically treated and histologically confirmed prolactinomas in the sella region from 2013-2022 in our institution. Clinical, radiological and surgical features were analyzed. Univariate and multivariate analyses were performed., Results: Out of total of 159 prolactinoma patients, 83.6% received previous treatment with DA followed by surgery, while only 16.4% received exclusive surgery. Both groups presented similar initial tumor volumes (1.9cm 3 vs. 1.5cm 3 , p = 0.59) and equal preoperative prolactin levels (PRL) (199.7 µg/l vs. 191.0 µg/l, p = 0.44). Surgical procedures took significantly longer when patients received prior DA treatment (79 min. vs. 70 min., p = 0.0479). Six months after surgery, pretreated patients revealed significantly higher PRL compared to non-treated (107 g/l vs. 8.64 µg/, p = 0.0009). Additionally, untreated microprolactinoma presented a remission of 100%, whereas pretreated exhibited a remission rate of 88.75%., Conclusion: The current study demonstrates that prior DA treatment is associated with significantly longer surgeries, higher recurrence rates and lower rates of normalization of PRL levels after surgery, particularly in microprolactinomas and support the latest recommendations of the Pituitary Society's Consensus Statement 2023, which favors the option of surgery alone as first-line therapy for microprolactinomas., (© 2024. The Author(s).)

Background and Objectives: Skull base reconstruction is a crucial step during transsphenoidal surgery. Sphenoid mucosa is a mucosal membrane located in the sphenoid sinus. Preservation and lateral shifting of sphenoid mucosa as sphenoid mucosal flap (SMF) during the transsphenoidal exposure of the sella may be important for later closure. This is the first systematic review to evaluate the utility of sphenoid mucosal flap for sellar reconstruction after transsphenoidal surgery. Materials and Methods: A systematic literature search was performed in January 2023: Cochrane, EMBASE, PubMed, Scopus, and Web of Science. The following keywords and their combinations were used: "sphenoid mucosa", "sphenoid sinus mucosa", "sphenoid mucosal flap", "sphenoid sinus mucosal flap". From a total number of 749 records, 10 articles involving 1671 patients were included in our systematic review. Results: Sphenoid sinus mucosa used to be applied for sellar reconstruction as either a vascularized pedicled flap or as a free flap. Three different types of mucosal flaps, an intersinus septal flap, a superiorly based flap and an inferiorly based flap, were described in the literature. Total SMF covering compared to partial or no SMF covering in sellar floor reconstruction resulted in fewer postoperative CSF leaks ( p = 0.008) and a shorter duration of the postoperative lumbar drain ( p = 0.003), if applied. Total or partial SMF resulted in fewer local complications ( p = 0.012), such as fat graft necrosis, bone graft necrosis, sinusitis or fungal infection, in contrast to no SMF implementation. Conclusions: SMF seems to be an effective technique for skull base reconstruction after transsphenoidal surgery, as it can reduce the usage of avascular grafts such as fat along with the incidence of local complications, such as fat graft necrosis, bone graft necrosis, sinusitis and fungal infection, or it may improve the sinonasal quality of life by maintaining favorable wound healing through vascular flap and promote the normalization of the sphenoid sinus posterior wall. Further clinical studies evaluating sphenoid mucosal flap preservation and application in combination with other techniques, particularly for higher-grade CSF leaks, are required.

Objective: First-line prolactin-secreting tumor (PST) management typically involves treatment with dopamine agonists and the role of surgery remains to be further explored. We examined the international experience of 12 neurosurgical centers to assess the patient characteristics, safety profile, and effectiveness of surgery for PST management., Methods: Patients surgically treated for PST from January 2017 through December 2020 were evaluated for surgical characteristics, outcomes, and safety., Results: Among 272 patients identified (65.1% female), the mean age was 38.0 ± 14.3 years. Overall, 54.4% of PST were macroadenomas. Minor complications were seen in 39.3% of patients and major complications were in 4.4%. The most common major complications were epistaxis and worsened vision. Most minor complications involved electrolyte/sodium dysregulation. At 3-6 months, local control on imaging was achieved in 94.8% of cases and residual/recurrent tumor was seen in 19.3%. Reoperations were required for 2.9% of cases. On multivariate analysis, previous surgery was significantly predictive of intraoperative complications (6.14 OR, p < 0.01) and major complications (14.12 OR, p < 0.01). Previous pharmacotherapy (0.27 OR, p = 0.02) and cavernous sinus invasion (0.19 OR, p = 0.03) were significantly protective against early endocrinological cure. Knosp classification was highly predictive of residual tumor or PST recurrence on 6-month follow-up imaging (4.60 OR, p < 0.01). There was noted institutional variation in clinical factors and outcomes., Conclusion: Our results evaluate a modern, multicenter, global series of PST. These data can serve as a benchmark to compare with DA therapy and other surgical series. Further study and longer term outcomes could provide insight into how patients benefit from surgical treatment., Competing Interests: Declaration of Competing Interest The authors have no personal, financial, or institutional interest in any of the drugs, materials, or devices described in this article. Henry W.S. Schroeder has a financial relationship with Karl Storz SE & Co. KG., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Crooke cell adenomas (CCAs) are a rare, aggressive subset of secretory pituitary corticotroph adenomas (sCTAs) found in 5%-10% of patients with Cushing disease. Multiple studies support worse outcomes in CCAs but are limited by small sample size and single-institution databases. We compared outcomes in CCA and sCTA using a multicenter, international retrospective database of high-volume skull base centers., Methods: Patients surgically treated for pituitary adenoma from January 2017 through December 2020 were included., Results: Among 2826 patients from 12 international centers, 20 patients with CCA and 480 patients with sCTA were identified. No difference in baseline demographics, tumor characteristics, or postoperative complications was seen. Microsurgical approaches (60% CCA vs. 62.3% sCTA) were most common. Gross total resection was higher in CCA patients (100% vs. 83%, P = 0.05). Among patients with gross total resection according to intraoperative findings, fewer CCA patients had postoperative hormone normalization of pituitary function (50% vs. 77.8%, P < 0.01) and remission of hypersecretion by 3-6 months (75% vs. 84.3%, P < 0.01). This was the case despite CCA having better local control rates (100% vs. 96%, P < 0.01) and fewer patients with remnant on magnetic resonance imaging (0% vs. 7.2%, P < 0.01). A systematic literature review of 35 studies reporting on various treatment strategies reiterated the high rate of residual tumor, persistent hypercortisolism, and tumor-related mortality in CCA patients., Conclusions: This modern, multicenter series of patients with CCA reflects their poor prognosis and reduced postsurgical hormonal normalization. Further work is necessary to better understand the pathophysiology of CCA to devise more targeted treatment approaches., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Purpose: While MRI has become the imaging modality of choice in the diagnosis of sellar tumors, no systematic attempt has yet been made to align radiological reporting of findings with the information needed by the various medical disciplines dealing with these patients. Therefore, we aimed to determine the prevailing preferences in this regard through a nationwide expert survey., Methods: First, an interdisciplinary literature-based catalog of potential reporting elements for sellar tumor MRI examinations was created. Subsequently, a web-based survey regarding the clinical relevance of these items was conducted among board certified members of the German Society of Neurosurgery, German Society of Radiation Oncology, and the Pituitary Working Group of the German Society of Endocrinology., Results: A total of 95 experts (40 neurosurgeons, 28 radiation oncologists, and 27 endocrinologists) completed the survey. The description of the exact tumor location, size, and involvement of the anatomic structures adjacent to the sella turcica (optic chiasm, cavernous sinus, and skull base), occlusive hydrocephalus, relationship to the pituitary gland and infundibulum, and certain structural characteristics of the mass (cyst formation, hemorrhage, and necrosis) was rated most important (> 75% agreement). In contrast, the characterization of anatomic features of the nasal cavity and sphenoid sinus as well as the findings of advanced MRI techniques (e.g., perfusion and diffusion imaging) was considered relevant by less than 50% of respondents., Conclusion: To optimally address the information needs of the interdisciplinary treatment team, MRI reports of sellar masses should primarily focus on the accurate description of tumor location, size, internal structure, and involvement of adjacent anatomic compartments., (© 2023. The Author(s).)

Background and Objectives: There is considerable controversy as to which of the 2 operating modalities (microsurgical or endoscopic transnasal surgery) currently used to resect pituitary adenomas (PAs) is the safest and most effective intervention. We compared rates of clinical outcomes of patients with PAs who underwent resection by either microsurgical or endoscopic transnasal surgery., Methods: To independently assess the outcomes of each modality type, we sought to isolate endoscopic and microscopic PA surgeries with a 1:1 tight-caliper (0.01) propensity score-matched analysis using a multicenter, neurosurgery-specific database. Surgeries were performed between 2017 and 2020, with data collected retrospectively from 12 international institutions on 4 continents. Matching was based on age, previous neurological deficit, American Society of Anesthesiologists (ASA) score, tumor functionality, tumor size, and Knosp score. Univariate and multivariate analyses were performed., Results: Among a pool of 2826 patients, propensity score matching resulted in 600 patients from 9 surgery centers being analyzed. Multivariate analysis showed that microscopic surgery had a 1.91 odds ratio (OR) ( P = .03) of gross total resection (GTR) and shorter operative duration ( P < .01). However, microscopic surgery also had a 7.82 OR ( P < .01) for intensive care unit stay, 2.08 OR ( P < .01) for intraoperative cerebrospinal fluid (CSF) leak, 2.47 OR ( P = .02) for postoperative syndrome of inappropriate antidiuretic hormone secretion (SIADH), and was an independent predictor for longer postoperative stay (β = 2.01, P < .01). Overall, no differences in postoperative complications or 3- to 6-month outcomes were seen by surgical approach., Conclusion: Our international, multicenter matched analysis suggests microscopic approaches for pituitary tumor resection may offer better GTR rates, albeit with increased intensive care unit stay, CSF leak, SIADH, and hospital utilization. Better prospective studies can further validate these findings as matching patients for outcome analysis remains challenging. These results may provide insight into surgical benchmarks at different centers, offer room for further registry studies, and identify best practices., (Copyright © Congress of Neurological Surgeons 2023. All rights reserved.)

Objective: A somatic mutational hotspot in the SF3B1 gene was reported in lactotroph tumours. The aim of our study was to examine the prevalence of driver SF3B1 variants in a multicentre independent cohort of patients with lactotroph tumours and correlate with clinical data., Design and Methods: This was a retrospective, multicentre study involving 282 patients with lactotroph tumours (including 6 metastatic lactotroph tumours) from 8 European centres. We screened SF3B1 exon 14 hotspot for somatic variants using Sanger sequencing and correlated with clinicopathological data., Results: We detected SF3B1 variants in seven patients with lactotroph tumours: c.1874G > A (p.Arg625His) (n = 4, 3 of which metastatic) and a previously undescribed in pituitary tumours variant c.1873C > T (p.Arg625Cys) (n = 3 aggressive pituitary tumours). In two metastatic lactotroph tumours with tissue available, the variant was detected in both primary tumour and metastasis. The overall prevalence of likely pathogenic SF3B1 variants in lactotroph tumours was 2.5%, but when we considered only metastatic cases, it reached the 50%. SF3B1 variants correlated with significantly larger tumour size; higher Ki67 proliferation index; multiple treatments, including radiotherapy and chemotherapy; increased disease-specific death; and shorter postoperative survival., Conclusions: SF3B1 variants are uncommon in lactotroph tumours but may be frequent in metastatic lactotroph tumours. When present, they associate with aggressive tumour behaviour and worse clinical outcome., Competing Interests: Conflict of interest: None declared., (© The Author(s) 2023. Published by Oxford University Press on behalf of European Society of Endocrinology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Importance: Benchmarks aid in improve outcomes for surgical procedures. However, best achievable results that have been validated internationally for transsphenoidal surgery (TS) are not available., Objective: We aimed to establish standardized outcome benchmarks for TS of pituitary adenomas., Design: A total of 2685 transsphenoidal tumor resections from 9 expert centers in 3 continents were analyzed., Setting: Patients were risk stratified, and the median values of each center's outcomes were established. The benchmark was defined as the 75th percentile of all median values for a particular outcome. The postoperative benchmark outcomes included surgical factors, endocrinology-specific values, and neurology-specific values., Results: Of 2685 patients, 1149 (42.8%) defined the low-risk benchmark cohort. Within these benchmark cases, 831 (72.3%) patients underwent microscopic TS, and 308 (26.8%) patients underwent endoscopic endonasal resection. Of all tumors, 799 (29.8%) cases invaded the cavernous sinus. The postoperative complication rate was 19.6% with mortality between 0.0% and 0.8%. Benchmark cutoffs were ≤2.9% for reoperation rate, ≤1.9% for cerebrospinal fluid leak requiring intervention, and ≤15.5% for transient diabetes insipidus. At 6 months, benchmark cutoffs were calculated as follows: readmission rate: ≤6.9%, new hypopituitarism ≤6.0%, and tumor remnant ≤19.2%., Conclusions: This analysis defines benchmark values for TS targeting morbidity and mortality and represents the best outcomes in the best patients in expert centers. These cutoffs can be used to assess different centers, patient populations, and novel surgical techniques. It should be noted that the benchmark values may influence each other and must be evaluated in their own context., Competing Interests: Conflict of interest: The authors declare no conflict of interest., (© The Author(s) 2023. Published by Oxford University Press on behalf of European Society of Endocrinology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Cushing´s disease is a rare endocrinological disorder which is caused by an adrenocorticotropic hormone secreting pituitary adenoma. The condition is associated with an increased risk for venous thromboembolism. While there exist reports on symptomatic venous thromboses complicating Cushing's disease, the prevalence of incidental leg vein thromboses accompanying pituitary surgery for Cushing's disease is yet unknown. 30 consecutive patients (9 male; age 25-77 years) with histologically confirmed Cushing's disease underwent transsphenoidal adenomectomy between October 2018 and September 2019. All patients received perioperative pharmacological thromboprophylaxis. Whole leg compression ultrasound was performed within one week after surgery (median 2 days) to exclude leg vein thromboses (primary endpoint). Preoperative laboratory values including plasma cortisol and various coagulation parameters were evaluated as secondary outcome measures. A comparison was made between patients with and without thrombotic events (p value ≤ 0.05). A total of 2 out of 30 patients (6.7%; CI 0.8-24.1%) presented with asymptomatic perioperative deep vein thromboses of the lower legs. Thrombosis patients differed not significantly from their counterparts with respect to age, sex, and comorbidities, but preoperative morning plasma cortisol was significantly higher in patients with venous thromboses (421.0 ± 49.5 μg/l vs. 188.1 ± 78.2 μg/l; p = 0.01). Moreover, von Willebrand factor activity was markedly increased in one case (409.0%) compared to the mean value obtained from 28 patients without phlebothromboses (146.9 ± 60.7%; p < 0.01). Perioperative asymptomatic leg vein thrombosis can be found with the aid of compression ultrasound in a considerable proportion of patients undergoing transsphenoidal adenomectomy for Cushing's disease despite the administration of pharmacological thromboprophylaxis., (© 2023. The Author(s).)

Silent corticotrophic adenomas (SCAs) represent a rare group of non-functioning adenomas with a potentially aggressive clinical course. Cystic component is a very common finding among SCAs, but its clinical relevance has not yet been investigated. The aim of this study was to analyze clinical features of cystic and non-cystic SCAs, perioperative complications after microscopic transsphenoidal surgery, clinical outcome after first and repeat surgery along with risk factors for recurrence. We conducted a retrospective analysis of 62 silent corticotrophic adenomas treated at our university medical center via microscopic transsphenoidal surgery between January 2008 and July 2019. Parameters investigated included histology, invasiveness, intratumoral haemorrhage or cystic component on MRI, perioperative alteration of visual field, tumor size, pre- and postoperative ACTH, FSH, GH, LH, TSH, prolactin, cortisol, free T4, free T3, IGF-1, estrogen and testosterone levels, perioperative complications, neoadjuvant and adjuvant therapy along with clinical outcomes. A total of 62 patients were analyzed. The mean follow up was 28.3 months. Tumors with a cystic component occur statistically significant more often among male than non-cystic (80.6% vs. 44.4%, p = 0.02) and display lower rates of cavernous sinus invasion and sphenoid sinus invasion were significantly lower for cystic lesions comparing to non-cystic tumors (42.3% vs. 69.4%, p = 0.04 and 3.8% vs. 47.2%, p < 0.001). GTR after MTS was not statistically significant higher by cystic SCAs (80% vs. 57.1%, p = 0.09). Cystic lesions were also associated with higher risk of hyperprolactinemia (19.4% vs. 2.8%, p = 0.02) and only densely granulated cystic SCAs presented with preoperative intratumoral hemorrhage (19.2% vs. 0%, p = 0.01). Mean duration of first surgery was significantly shorter for cystic SCAs (71.6(± 18.7) vs. 94.8(± 31.1) minutes, p = 0.01). Preoperative pituitary insufficiency (25% vs. 16.7%, p = 0.49), intraoperative CSF space opening (21.1% vs. 37.5%, p = 0.32), along with postoperative new pituitary insufficiency (15% vs. 10%, p = 0.67) or diabetes insipidus/SIADH (10% vs. 13.3%, p > 0.99) with histological markers such as Ki67 (21.1% vs. 13.8%, p = 0.70) and p53 expression (6.3% vs. 0%, p = 0.39) as well as mitotic rate (5.3% vs. 10.3%, p > 0.99) were comparable between both groups. The presence of cystic component did not affect the tumor recurrence (10% vs. 16%, p = 0.68). Mean duration of surgery was first surgeries was not statistically shorter than repeat surgeries (85.4 ± 29.1 vs. 93.8 ± 28 min, p = 0.15). Patients undergoing first surgery had a higher probability of gross total resection (74.4% vs. 30%, p = 0.01) and lower probability of intraoperative CSF space opening (26% vs. 58.3%, p = 0.04) as well as a lower rate of preoperative anterior pituitary insufficiency (20% vs. 58.3%, p = 0.01). The incidence of new postoperative anterior pituitary insufficiency (10% vs. 0%, p = 0.57) and transient diabetes insipidus/SIADH (12% vs. 8.3%, p > 0.99) between those groups were comparable. No statistical difference was observed between patients with remission and with recurrent tumor regarding cortisol and ACTH levels, incidence of different histological subgroups, invasively growing tumors and lesions with cystic components as well as the percentage of cases with increased Ki67 proliferation index, p53 expression and mitotic indices. Our study presents one of the largest available cohorts of SCAs after microscopic transsphenoidal surgery and first clinical analysis of cystic versus non-cystic SCAs so far. We also performed the first comparison of index and repeat surgeries for this tumor entity. Cystic tumors presented with characteristic clinical aspects like male predominance, higher risk of hyperprolactinemia as well as lower rates of cavernous sinus and sphenoid sinus invasion comparing to non-cystic lesions. Mean duration of first surgery was significantly shorter for cystic SCAs. Moreover preoperative intratumoral hemorrhage had 100% specificity and 60% sensitivity for densely granulated cystic SCAs. All these clinical hallmarks may suggest a novel subgroup of SCAs with distinct clinical and biological features, however further clinical and molecular investigations are required. Second surgeries are associated with a higher incidence of preoperative pituitary insufficiency, and a higher risk of subtotal resection, and a higher probability of CSF space opening intraoperatively compared to first surgeries. On the other hand, the risk of new postoperative pituitary insufficiency was higher after first surgeries. In our cohort of patients, no prognostic factor for recurrence among histological diagnosis, Ki67-proliferation index, p53 expression, number of mitoses, invasive growth or cystic lesions for SCAs could be detected., (© 2023. The Author(s).)

(1) Background: We identified screening parameters and associated factors for delayed, symptomatic hyponatremia (DSH) following inpatient discharge after transsphenoidal surgery (TSS). (2) Methods: In this prospective, monocentric study, 108 patients who underwent TSS for pituitary pathologies were included, provided with a questionnaire and instructed to document urine specific gravity, fluid intake/urine output, body weight and clinical symptoms for every of five days following discharge from hospital. (3) Results: The overall incidence of DSH within 14 days following discharge from the hospital was 14.8% (n = 9). Symptomatic patients presented on average 8.6 days after surgery. Mild DSH was present in 3.3% of the patients, moderate in 1.6% and severe hyponatremia in 9.8% of patients. Female sex (p = 0.02) and lower BMI (p = 0.02), as well as nausea (66.7%; p < 0.01) and emesis (33.3%; p < 0.05), were associated with DSH. A significant weight delta between morning and afternoon weight two days before the event of DSH between both groups (1.26 kg (n = 5) vs. 0.79 kg (n = 52), p < 0.05) was detected. (4) Conclusions: Handing out a symptom questionnaire at discharge seems to be an easy and feasible tool for the detection of DSH after hospital discharge.

Microscopic and endoscopic transsphenoidal surgeries represent the standard treatment for Cushing's disease (CD). At our institution a new exoscopic approach was implemented. After proof of the general use for transsphenoidal pituitary surgery, the aim of this study was to compare the exoscopic 4K3D video microscope with the microscopic transsphenoidal surgery for patients with CD. We conducted a retrospective analysis on 388 patients with CD treated in our medical center via microscopic transsphenoidal surgery (MTS) between January 2008 and July 2019 or via exoscopic transsphenoidal surgery (ExTS) between May 2019 and May 2021. Parameters investigated included histology, pre- and postoperative MRI with tumor size, pre- and postoperative ACTH and cortisol levels, duration of surgery, perioperative and postoperative complications as well as clinical outcome. Patients who underwent ExTS in CD experienced a lower incidence of SIADH/diabetes insipidus (p = 0.0164), a higher rate of remission (p = 0.0422), and a shorter duration of surgery (p < 0.0001), compared to MTS. However, there was no significant difference regarding new postoperative pituitary insufficiency and intraoperative CSF space opening. We found that ExTS had multiple benefits compared to MTS for tumor resection in case of CD. These results are in line with our previous publication on the general applicability of an exoscope in pituitary surgery. To our knowledge, this is the first clinical study proving the superiority of ExTS in CD. These results are promising, nevertheless further studies comparing exoscopic with the endoscopic approach are necessary to finally evaluate the utility of the new technique., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Corticotroph macroadenomas are rare but difficult to manage intracranial neoplasms. Mutations in the two Cushing's disease mutational hotspots USP8 and USP48 are less frequent in corticotroph macroadenomas and invasive tumors. There is evidence that TP53 mutations are not as rare as previously thought in these tumors. The aim of this study was to determine the prevalence of TP53 mutations in corticotroph tumors, with emphasis on macroadenomas, and their possible association with clinical and tumor characteristics. To this end, the entire TP53 coding region was sequenced in 86 functional corticotroph tumors (61 USP8 wild type; 66 macroadenomas) and the clinical characteristics of patients with TP53 mutant tumors were compared with TP53/USP8 wild type and USP8 mutant tumors. We found pathogenic TP53 variants in 9 corticotroph tumors (all macroadenomas and USP8 wild type). TP53 mutant tumors represented 14% of all functional corticotroph macroadenomas and 24% of all invasive tumors, were significantly larger and invasive, and had higher Ki67 indices and Knosp grades compared to wild type tumors. Patients with TP53 mutant tumors had undergone more therapeutic interventions, including radiation and bilateral adrenalectomy. In conclusion, pathogenic TP53 variants are more frequent than expected, representing a relevant amount of functional corticotroph macroadenomas and invasive tumors. TP53 mutations associated with more aggressive tumor features and difficult to manage disease., (© 2022. The Author(s).)

Cushing's disease is a rare but devastating and difficult to manage condition. The somatostatin analogue pasireotide is the only pituitary-targeting pharmaceutical approved for the treatment of Cushing's disease but is accompanied by varying efficacy and potentially severe side effects. Finding means to predict which patients are more likely to benefit from this treatment may improve their management. More than half of corticotroph tumours harbour mutations in the USP8 gene, and there is evidence of higher somatostatin receptor 5 (SSTR5) expression in the USP8-mutant tumours. Pasireotide has a high affinity for SSTR5, indicating that these tumours may be more sensitive to treatment. To test this hypothesis, we examined the inhibitory action of pasireotide on adrenocorticotrophic hormone synthesis in primary cultures of human corticotroph tumour with assessed USP8 mutational status and in immortalized murine corticotroph tumour cells overexpressing human USP8 mutants frequent in Cushing's disease. Our in vitro results demonstrate that pasireotide exerts a higher antisecretory response in USP8-mutant corticotroph tumours. Overexpressing USP8 mutants in a murine corticotroph tumour cell model increased endogenous somatostatin receptor 5 (Sstr5) transcription. The murine Sstr5 promoter has two binding sites for the activating protein 1 (AP-1) and USP8 mutants possibly to mediate their action by stimulating AP-1 transcriptional activity. Our data corroborate the USP8 mutational status as a potential marker of pasireotide response and describe a potential mechanism through which USP8 mutants may regulate SSTR5 gene expression.

Purpose: To analyze the expression of somatostatin receptor (SSTR)2a and 5 by immunohistochemistry (IHC) in surgically resected somatotrophic pituitary adenomas and to associate expression rates with tumor size and clinical, biochemical, and histological parameters and response to somatostatin analog (SA) therapy., Methods: Forty-three microsurgically treated patients with histopathologically proven growth hormone (GH)-producing pituitary adenoma were included (WHO 2017). SSTR subtype expression was analyzed in adenoma tissues using monoclonal antibodies (Abcam, SSTR2a-UMB1, SSTR5-UMB4). Expression rates were classified as low (≤ 20% staining positivity), moderate (21-50%), and high (> 50%). Furthermore, biochemical parameters such as human growth hormone (hGH) and insulin-like growth factor-1 (IGF-1) levels were measured and clinical, biochemical, radiological, and histological data were evaluated., Results: Of the 43 patients included in this study, 28 were female and 15 were male. The median age was 52 years (range 17-72 years). The median tumor size was 1.2 cm (range: 0.13-3.93 cm). All resected tumors showed positivity for somatotrophic hormone (STH). In all tissue samples, SSTR2a signal expression was detectable in immunohistochemistry, while only 39 samples were positive for SSTR5. Thirty-six samples had a high expression of SSTR2a, while three had a moderate and four a low SSTR2a signal. In comparison, SSTR5 signal was high in 26 out of 43 samples, while seven adenomas showed a moderate and six cases a low expression rate of SSTR5. The median IGF-1 was 714.2 µg/l and the median GH 19.6 mU/l (= 6.53 µg/l). The present study indicates that there is no significant relationship between the expression rates of receptor subtypes and the parameters we analyzed. However, our study revealed that smaller adenomas have a lower baseline GH level (p = 0.015), CONCLUSION: IHC with monoclonal antibodies appears to be a suitable method to determine the expression rates of SSTR2a and 5 at protein levels, as it is not possible to draw conclusions regarding receptor subtypes solely on the basis of the parameters analyzed., (© 2021. The Author(s).)

Fast acquisition of a first computed tomography (CT) scan after traumatic brain injury (TBI) is recommended. This study is aimed at investigating whether the length of the period preceding initial CT scan influences mortality in patients with leading TBI. A retrospective cohort analysis of patients registered in the TraumaRegister DGU® was conducted including adult patients with TBI, defined as Abbreviated Injury Scale Head ≥ 3 and GCS ≤ 13 who had been treated in level 1 or 2 trauma centers from 2007-2016. Patients were grouped according to time intervals either from trauma or from admission to CT. A total of 6904 patients met the inclusion criteria. Mean time period from trauma to hospital admission was 68.8 min. From admission to first CT, a mean of 19.0 min elapsed. Trauma severity was higher in groups with a longer duration from trauma to CT as represented by a mean (± standard deviation) Injury Severity Score (ISS) of 19.8 ± 9.0, 20.7 ± 9.3, and 21.4 ± 7.5 and similar distribution of mortality of 24.9%, 29.9%, and 36.3% in the ≤ 60-min, 61-120-min, and ≥ 121-min groups, respectively. An adjusted multivariable logistic regression model showed a significant influence of the level of the trauma center (p = 0.037) but not for interval from admission to CT (p = 0.528). TBI patients with a longer time span from trauma to first CT were more severely injured and demonstrated a worse prognosis, but received a CT scan faster when duration from admission is observed. The duration until the CT scan was obtained showed no significant impact on the mortality., (© 2020. The Author(s).)

Background: In previous reports on experiences with an exoscope, this new technology was not found to be applicable for transsphenoidal pituitary surgery. As a specialized center for pituitary surgery, we were using a 4K 3D video microscope (Orbeye, Olympus) to evaluate the system for its use in transsphenoidal pituitary surgery in comparison to conventional microscopy., Method: We report on 296 cases performed with the Orbeye at a single institution. An observational study was conducted with standardized subjective evaluation by the surgeons after each procedure. An objective measurement was added to compare the exoscopic and microscopic methods, involving surgery time and the initial postoperative remission rate in matched cohorts., Results: The patients presented with a wide range of pathologies. No serious events or minor complications occurred based on the usage of the 4K 3D exoscope. There was no need for switching back to the microscope in any of the cases. Compared to our microsurgically operated collective, there was no significant difference regarding duration of surgery, complications, or extent of resection. The surgeons rated the Orbeye beneficial in regard to instrument size, positioning, surgeon's ergonomics, learning curve, image resolution, and high magnification., Conclusions: The Orbeye exoscope presents with optical and digital zoom options as well as a 4K image resolution and 3D visualization resulting in better depth perception and flexibility in comparison to the microscope. Split screen mode offers the complementary benefit of the endoscope which may increase the possibilities of lateral view but has to be evaluated in comparison to endoscopic transsphenoidal procedures in the next step., (© 2021. The Author(s).)

Introduction: Pseudotumor cerebri syndrome (PTCS) has anecdotally been described after successful treatment of Cushing's disease (CD), but the prevalence following transsphenoidal surgery has not been determined so far in a prospective study., Patients and Methods: 41 consecutive adult CD patients were prospectively screened for signs and symptoms of PTCS, headache-related impairment, and ophthalmological features associated with intracranial pressure elevation before surgery and at follow-up (mean 4 months)., Results: Biochemical remission was achieved in 36 of 41 (87.8%) patients after surgery. The most frequent preoperative complaints were visual acuity impairment (19 cases; 46.3%), headache (13 cases; 31.7%), and ear noise (9 cases; 22.0%). A significant reduction of visual disturbances was seen at follow-up. Overall, CD patients presented with fairly low headache-related emotional and functional restrictions before and after surgery. One of 34 (2.9%) patients with sufficient ophthalmological follow-up showed new-onset papilledema combined with temporary worsening of visual acuity and scotoma., Conclusion: Our results suggest a very low frequency of signs and symptoms of PTCS after surgical treatment for CD in adults. This estimate is in line with previous outcomes from retrospective pediatric CD series. Further large-scale studies are needed to determine the actual prevalence of this condition following biochemical remission of CD., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

Objective: To investigate bevacizumab as alternative treatment of aggressive pituitary adenomas after exhaustion of standard therapies., Design and Methods: Retrospectively, 3 patients undergoing microscopic transsphenoidal surgery of aggressive pituitary adenomas from 2008 till 2018 that were treated with bevacizumab were identified. Development of disease and treatment were evaluated., Results: Two patients suffered from ACTH-secreting adenomas, one from a non-functioning adenoma. All patients underwent multiple surgical, chemo- and radiotherapeutical approaches including temozolomide, showing favorable results in one patient. Deterioration of clinical condition in all patients led to an individual, palliative attempt of bevacizumab. Patients 1 and 2 showed a decrease of ACTH after first administrations, but therapy had to be ended shortly after due to a further deterioration of their condition. Patient 3 showed a stabilization of the disease for 18 months. Patients died 8, 15 and 7 years after initial diagnosis, respectively, and 2, 4, and 24 months after initiation of bevacizumab therapy, respectively., Conclusion: The demonstrated results suggest a considerable effect of bevacizumab in aggressive pituitary adenomas. The advanced stage of disease in all three patients, the overall short period of administration and just one patient showing a clinical benefit do not allow a general statement on the effectiveness. At the current stage of clinical experience, an approach with bevacizumab can be considered as an individual palliative attempt of treatment, when standard treatments are exhausted. Our results underline the need for further studies to evaluate this drug as potential player in therapy resistant aggressive pituitary tumors., Competing Interests: There is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported., (Thieme. All rights reserved.)

Objective: The purpose of this study was to analyze the clinical and biochemical outcome of consecutive patients with acromegaly after microscopic transsphenoidal surgery (MTS) at a single center over an 8-year period., Methods: A retrospective analysis of patients with acromegaly treated via MTS between 2008 and 2015 at the authors' center was performed. The mean follow-up was 29 months (range 1-120 months). Parameters investigated included tumor size, pre- and postoperative insulin-like growth factor-I, growth hormone levels, pretreatment, perioperative complications, and clinical outcome., Results: A total of 280 patients with acromegaly were treated surgically at the authors' center over the abovementioned time frame and were included in analyses. For 231 of these patients, complete follow-up data were available for evaluation. One hundred eighty-eight patients (81%) showed remission initially according to current criteria. So far, 23 of these patients relapsed in the further course, so that on follow-up 165 patients (71%) demonstrated full remission by surgery alone. Most patients in whom remission after surgery failed were treated with somatostatin receptor ligands and/or dopamine agonists as second-line treatment. The main postoperative complications included transient hyponatremia and diabetes insipidus (13/280; 4.6%). CSF leakage only occurred in 2 cases (2/280; 0.7%). No surgery-related death occurred., Conclusions: The data underline the effectiveness of MTS in acromegaly. Many patients with recurrent disease or incomplete tumor resection can be successfully managed pharmacologically.

Context: Cushing disease (CD) is a rare disorder with severe sequels and incompletely understood pathogenesis. The underlying corticotroph adenomas harbor frequently somatic mutations in the ubiquitin-specific peptidase 8 (USP8) gene. These mutations render USP8 hyperactive and prevent client proteins from degradation., Objective: To investigate the impact of USP8 mutations on proteins deregulated in CD., Design: One hundred eight pituitary adenomas (75 corticotroph [58 USP8 wild type (WT) and 17 USP8 mutated], 14 somatotroph, and 19 nonfunctioning) were investigated by immunohistochemistry. All evaluated proteins [USP8, arginine vasopressin receptor 1b and 2, corticotropin-releasing hormone receptor, cAMP response element-binding protein (CREB), p27/kip1, cyclin E, heat shock protein 90 (HSP90), orphan nuclear receptor 4, epidermal growth factor receptor, histone deacetylase 2, glucocorticoid receptor, cyclin-dependent kinase 5 and Abelson murine leukemia viral oncogene homolog 1 enzyme substrate 1] were known to be deregulated in CD. Furthermore, AtT20 cells were transfected with USP8 to investigate the expression of possible downstream proteins by immunoblot., Results: Whereas most of the investigated proteins were not differentially expressed, the cell-cycle inhibitor p27 was significantly reduced in USP8 mutated corticotroph adenoma (H-score 2.0 ± 1.0 vs 1.1 ± 1.1 in WT adenomas; P = 0.004). In contrast, the chaperone HSP90 was expressed higher (0.5 ± 0.4 vs 0.2 ± 0.4; P = 0.29), and the phosphorylation of the transcription factor CREB was increased in USP8 mutated adenomas (1.30.5 ± 0.40.9 vs 0.70.5 ± 0.40.7; P = 0.014). Accordingly, AtT20 cells transfected with the USP8 P720R mutant had higher phosphorylated CREB (pCREB) levels than WT transfected cells (1.3 ± 0.14 vs 1 ± 0.23; P = 0.13)., Conclusions: We could demonstrate that USP8 mutations are associated with deregulation of p27/kip1, HSP90, and pCREB. These findings suggest that these proteins are direct or indirect clients of USP8 and could therefore be potential targets for therapeutic approaches in patients with CD., (Copyright © 2019 Endocrine Society.)

Introduction: With the 2016 World Health Organization Classification of Tumors of the Central Nervous System (2016 CNS WHO), diagnosis of glioma is based on molecular parameters in addition to histology potentially leading to additional demands on quality of tissue samples. This may challenge the role of minimally invasive biopsy procedures. This study aims to evaluate the diagnostic yield of glioma samples from frameless stereotactic biopsies with focus on molecular information and explore the neuromolecular profile of a glioma biopsy cohort., Methods: In a case series analysis, 180 consecutive frameless stereotactic biopsies with the Brainlab® Varioguide system from January 2011 to October 2017 were reviewed and patients with suspected or verified glioma were identified. Neuropathological samples were reprocessed in accordance with 2016 CNS WHO standards., Results: One hundred nineteen glioma patients were identified. Analysis of IDH status could be performed in 95.8% resulting in a cumulative mutation rate of 9.6%. A complete diagnosis according to 2016 CNS WHO including grading and molecular features was achieved in 110 cases (92.4%). Entities were revised in four cases. Most common diagnosis was IDH-wildtype glioblastoma (66.4%) followed by IDH-wildtype anaplastic astrocytoma (21.8%)., Conclusions: A formally complete diagnosis according to 2016 CNS WHO was achieved in the majority of cases. The biopsy cohort showed a prognostically unfavorable distribution of diagnoses and molecular features. Frameless stereotactic biopsy seems to be confirmed as a useful diagnostic tool in contemporary neuro-oncology-however, certain potential limitations should be considered.

Purpose: Pituitary adenomas are rare in the pediatric population. We present a recent cohort of children operated transsphenoidally on pituitary adenoma from a single center., Methods: Inclusion criteria were age < 21 years and histopathological diagnosis of adenoma after transsphenoidal surgery. The electronic file was used for prospective and retrospective data collection on symptoms, pituitary function before/after surgical intervention, and surgical complications. Surgical reports were used for assessment of resection grade. Follow-up data were collected from outpatient clinical visit and/or correspondence concerning pituitary function and MRI., Results: Among 962 consecutive patients who underwent transsphenoidal surgery at the University Medical Center Hamburg-Eppendorf (Germany) between April 2013-December 2016, 50 patients (5.2%) were 21 years old or younger (range 6-21 years, mean 16.5). Twenty-five (50%) patients had pituitary adenomas; M:F = 13:12. Eight were macroadenomas (> 1cm 3 ). Time from onset of symptoms to first operation had a range of 0-48 months (mean 18.5 months). Nine (36%) patients overall complained of headaches preoperatively. One patient had objective (hemianopsia) and four subjective visual disturbances preoperatively. Histopathological diagnosis revealed 13 (52%) ACTH adenomas, 5 (20%) prolactinomas, 3 (12%) mixed GH-prolactinoma, 1 (4%) GH adenoma, 2 (8%) TSH-producing adenomas, and 1 (4%) non-functioning adenoma. There were no surgical complications. On clinical follow-up (range 1-34.5 months, mean 11.7 months), 21/24 (88%) patients with hormonally active tumors were in biochemical remission by surgery alone; 2 patients with Cushing disease and 1 with GH-hypersecretion required further treatment., Conclusions: Our recent series confirms the effectiveness and safety of transsphenoidal surgery, especially in the pediatric patient population.

Objective: There is no ideal marker to identify residual tumor tissue after surgery in patients with acromegaly. The purpose was to elucidate if early postoperative hormone testing gives reliable information regarding complete resection of a GH-producing pituitary adenoma., Design: Fourty-eight patients undergoing surgery for acromegaly from 04/2013-05/2014 were prospectively examined for random GH, IGF1, and GH levels after oral glucose tolerance testing (OGTT) in the early postoperative phase and on follow-up. Criterion for inclusion was a minimum follow-up of one year for each patient with respect to remission., Results: Thirty-three patients showed GH suppression below 1 μg/l after OGTT in the early postoperative phase. Follow-up GH, IGF1 and OGTT tests confirmed the initial findings in 30 patients. The three remaining patients showed biochemical signs of persisting acromegaly. In the remaining 15 patients early postoperative GH suppression was above 1 μg/l. Of those, six patients went into remission during follow-up, nine patients without postoperative GH suppression <1 μg/l remained acromegalic., Conclusions: GH suppression to <1 μg/l as well as random GH levels below 1 μg/l in the early postoperative phase seem to be of good positive predictive value for long-term remission. However, several patients without suppression of GH to <1 μg/l in the early postoperative OGTT went into delayed remission. These results have to be taken into account prior to initiation of further therapy., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Objective: To identify symptomatic vasospasms as a rare complication after transsphenoidal surgery, with emphasis on management and outcomes., Methods: In this retrospective study, the medical records of 1997 patients who underwent microscopic transsphenoidal surgery at our hospital between 2008 and 2016 were analyzed regarding postoperative vasospasm events, clinical management, and neurologic outcomes., Results: Four patients (0.2%) were identified who developed neurologic deficits in the postoperative phase caused by proven vasospasms due to subarachnoid hemorrhage (SAH). All 4 patients were treated according to current state-of-the-art recommendations for SAH-triggered vasospasms and, as ultima ratio, intra-arterial spasmolysis. Nonetheless, all patients developed multilocular ischemic infarctions. Three patients recovered with no or only slight neurologic deficits (2 with a Glasgow Outcome Score [GOS] of 5; 1 with a GOS of 4), and 1 patient died, at 24 days after surgery., Conclusions: Although a rare complication, vasospasms after transsphenoidal surgery can lead to severe and multilocular ischemic infarctions with a wide variety of neurologic impairments. This rare complication should be considered in patients with unexpected postoperative neurologic deficits. Computed tomography (CT)/magnetic resonance imaging and (contrast-enhanced) CT/magnetic resonance angiography are appropriate diagnostic tools. Treatment of vasospasms, including the option of intra-arterial spasmolysis, should not be delayed., (Copyright © 2017. Published by Elsevier Inc.)