In contrast to the literature, hypogonadism was found to be the most frequent endocrine failure in PrHy. Weight gain was identified as a clinical sign of PrHy. In the majority of patients, PrHy can be reliably identified by characteristic clinical signs and symptoms, obviating histological confirmation. The diagnostic approach should be standardized in PrHy.

Context Cushing's 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 108 pituitary adenomas (75 corticotroph (58 USP8 wildtype (WT) and 17 USP8 mutated), 14 somatotroph and 19 non-functioning) were investigated by immunohistochemistry. All evaluated proteins (USP8, AVP receptor 1b & 2, CRH receptor, CREB, p27/kip1, cyclin E, HSP90, TR4, EGFR, HDAC2, GR, Cables1) 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 higher expressed (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 USP8 P720R mutant had higher pCREB levels than WT transfected cells (1.3 ±0.14 vs 1 ±0.23; p=0.13). ConclusionsWe could demonstrate that USP8 mutations are associated with deregulation of p27/kip1, HSP90, and phosphorylated CREB. 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.

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.

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.

Intracranial germinomas are fairly rare tumors occurring mostly in children or young adults with a comparatively good prognosis. Radiation is the preferred treatment of choice for this diagnosis. It has been thoroughly studied to what extent radiation doses and fields can be limited in order to avoid side effects in these young patients. The role of chemotherapy remains unclear, whereas surgery is limited to biopsy for proof of histology. Regarding the good overall survival rate, quality of life is a significant aspect to consider in these patients. We present a single institution analysis of patients with intracranial germinoma and analyze the long-term outcome with special regard to quality of life. Thirty-three patients with intracranial germinomas were analyzed by chart review, telephone interview, and neurological assessment. Additionally, a survey on quality of life was performed. The 10-year overall survival rate was 82.1 % at a mean follow-up of 141 (22-306) months. Three quarters (76 %) of the patients reached a favorable neurological outcome on the Modified Rankin Scale (mRS 0-2). However, the self-reported quality of life was significantly worse in germinoma patients compared with a healthy control group (p < 0.001). Surgical resection of the tumor led to no improvement regarding overall survival, neurological outcome, and quality of life. In terms of cognitive functioning, patients with tumor resection were significantly more impaired than biopsied patients (p = 0.04). Although germinomas are efficiently treatable tumors, the restrictions in quality of life in these often young patients are considerable, including financial difficulties. There seems no justification for tumor resection in newly diagnosed cases suspicious for germinoma as the cognitive outcome is worse than in biopsied patients, and there is no effect on overall survival.

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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.

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