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Abstract 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 0.99) 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.

Abstract 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

Abstract 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.

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.

BackgroundCerebral infarction (CI) is a known vascular complication following treatment of suprasellar tumors. Risk factors for CI, incidence rate, and long-term prognosis are unknown for patients with childhood-onset craniopharyngioma (CP).MethodsMRI of 244 CP patients, recruited between 2007 and 2019 in KRANIOPHARYNGEOM 2007, were reviewed for CI. Risk factors for CI and outcome after CI were analyzed.ResultsTwenty-eight of 244 patients (11%) presented with CI based on reference assessment of MRI. One CI occurred before initial surgery and one case of CI occurred after release of intracystic pressure by a cyst catheter. 26 of 28 CI were detected after surgical tumor resection at a median postoperative interval of one day (range: 0.5-53 days). Vascular lesions during surgical procedures were documented in 7 cases with CI. No relevant differences with regard to surgical approaches were found. In all 12 irradiated patients, CI occurred before irradiation. Multivariable analyses showed that hydrocephalus and gross-total resection at the time of primary diagnosis/surgery both were risk factors for CI. After CI, quality of life (PEDQOL) and functional capacity (FMH) were impaired.ConclusionsCI occurs in 11% of surgically-treated CP cases. Degree of resection and increased intracranial pressure are risk factors, which should be considered in the planning of surgical procedures for prevention of CI.

Cells release heterogeneous nano-sized vesicles either as exosomes, being derived from endosomal compartments, or through budding from the plasma membrane as so-called microvesicles, commonly referred to as extracellular vesicles (EVs). EVs are known for their important roles in mammalian physiology and disease pathogenesis and provide a potential biomarker source in cancer patients. EVs are generally often analysed in bulk using Western blotting or by bead-based flow-cytometry or, with limited parameters, through nanoparticle tracking analysis. Due to their small size, single EV analysis is technically highly challenging. Here we demonstrate imaging flow cytometry (IFCM) to be a robust, multiparametric technique that allows analysis of single EVs and the discrimination of distinct EV subpopulations. We used IFCM to analyse the tetraspanin (CD9, CD63, CD81) surface profiles on EVs from human and murine cell cultures as well as plasma samples. The presence of EV subpopulations with specific tetraspanin profiles suggests that EV-mediated cellular responses are tightly regulated and dependent on cell environment. We further demonstrate that EVs with double positive tetraspanin expression (CD63+/CD81+) are enriched in cancer cell lines and patient plasma samples. In addition, we used IFCM to detect tumour-specific GFP-labelled EVs in the blood of mice bearing syngeneic intracerebral gliomas, indicating that this technique allows unprecedented disease modelling. In summary, our study highlights the heterogeneous and adaptable nature of EVs according to their marker profile and demonstrates that IFCM facilitates multiparametric phenotyping of EVs not only in vitro but also in patient plasma at a single EV level, with the potential for future functional studies and clinically relevant applications. Abbreviation: EDTA = ethylenediamine tetraacetic acid