Surgical Strategies in Childhood Craniopharyngioma

Craniopharyngiomas are biologically benign lesions (WHO Grade 1) of the sellar and suprasellar region, associated with a serious morbidity. About 50% of these tumors become clinically apparent during childhood. Clinical symptoms include headaches, chiasm syndrome, hydrocephalus, pituitary insufficiencies, and obesity. Growth arrest is a typical symptom in children. The treatment of craniopharyngiomas includes surgery as well as radiotherapy. The goal of surgery varies according to the tumor location and extension and may range from complete resection to biopsy. Surgical complications are well known and cause constant evaluation of surgical strategies. Diencephalic obesity is related to surgical manipulation of hypothalamic tissue. Therefore, a classification system for craniopharyngiomas based on preoperative MRI is suggested by the authors. Recurrences are frequent in craniopharyngiomas, even after complete or gross-total resection. Radiotherapy is therefore recommended to patients with incomplete resections. However, the ideal time for radiotherapy after surgery is under discussion. The treatment of craniopharyngiomas requires an interdisciplinary and multimodal approach. Each patient should receive an individually tailored treatment. Surgically, different approaches as well as different degrees of resection can be considered, depending on tumor location and tumor extension

Cerebral infarction in childhood-onset craniopharyngioma patients: results of KRANIOPHARYNGEOM 2007

BACKGROUND: Cerebral 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). METHODS: MRI 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. RESULTS: Twenty-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. CONCLUSIONS: CI 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

TP53 mutations in functional corticotroph tumors are linked to invasion and worse clinical outcome

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

FGF-21 levels in polyuria-polydipsia syndrome

The pathomechanism of primary polydipsia is poorly understood. Recent animal data reported a connection between fibroblast growth factor 21 (FGF-21) and elevated fluid intake independently of hormonal control by the hormone arginine-vasopressin (AVP) and osmotic stimulation. We therefore compared circulating FGF-21 levels in patients with primary polydipsia to patients with AVP deficiency (central diabetes insipidus) and healthy volunteers. In this prospective cohort study, we analyzed FGF-21 levels of 20 patients with primary polydipsia, 20 patients with central diabetes insipidus and 20 healthy volunteers before and after stimulation with hypertonic saline infusion targeting a plasma sodium level >= 150 mmol/L. The primary outcome was the difference in FGF-21 levels between the three groups. Baseline characteristics were similar between the groups except for patients with central diabetes insipidus being heavier. There was no difference in baseline FGF-21 levels between patients with primary polydipsia and healthy volunteers (122 pg/mL (52,277) vs 193 pg/mL (48,301), but higher levels in patients with central diabetes insipidus were observed (306 pg/mL (114,484);P=0.037). However, this was not confirmed in a multivariate linear regression analysis after adjusting for age, sex, BMI and smoking status. Osmotic stimulation did not affect FGF-21 levels in either group (difference to baseline: primary polydipsia -23 pg/mL (-43, 22);central diabetes insipidus 17 pg/mL (-76, 88);healthy volunteers -6 pg/mL (-68, 22);P=0.45). To conclude, FGF-21 levels are not increased in patients with primary polydipsia as compared to central diabetes insipidus or healthy volunteers. FGF-21 therefore does not seem to be causal of elevated fluid intake in these patients

Sphenoid Sinus Mucosal Flap after Transsphenoidal Surgery—A Systematic Review

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

4K 3-dimensional video microscope system (orbeye) for transsphenoidal pituitary surgery

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

Co-expression of intermediate filaments glial fibrillary acidic protein and cytokeratin in pituitary adenoma

Purpose!#!To analyze the co-expression of the intermediate filaments GFAP and cytokeratin in 326 pituitary adenomas with regard to the distribution pattern, the subtype of the adenoma and clinical prognostic data.!##!Methods!#!Tissue from 326 pituitary adenomas and 13 normal anterior pituitaries collected in the Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, between 2006 and 2009 was investigated by immunohistochemistry, immunofluorescence and electron microscopy.!##!Results!#!Co-expression of intermediate filaments GFAP and cytokeratin was associated with hormone expression in 62/278 cases (22%), but only found in 2/48 (4%) of null cell adenomas (p < 0.01). Simultaneous co-expression of GFAP and cytokeratin in the same cells was demonstrated in 26 out of 326 pituitary adenomas and in all 13 pituitaries. In pituitary intermediate filaments were demonstrated in a larger area of the cytoplasm than in adenoma (p < 0.01), however, overlapping expression was seen in 2.6% of the total area in both, pituitary and adenoma. Congenially, cells with overlapping expression were found near vessels and in follicles. Furthermore, adenomas with cellular co-expression of GFAP and cytokeratin were associated with a lower recurrence rate (7.7%) compared to adenomas without co-expression of intermediate filaments (17.8%).!##!Conclusions!#!Cellular co-expression of the intermediate filaments GFAP and cytokeratin in pituitary adenomas and the pituitary was demonstrated and shown to be associated with hormone expression and low recurrence rate. The results are discussed with regard to the biology of folliculostellate cells, neural transformation and tumor stem cells. This study may complement the understanding of pituitary adenoma biology

Tight junction protein claudin-1 is differentially expressed in craniopharyngioma subtypes and indicates invasive tumor growth

Background: Claudins are tight junction proteins expressed in epithelial tissues that play important roles in cell polarity and adhesion. Altered distribution of claudin-1(CLDN1) affects cell mobility and tumor invasiveness. Craniopharyngiomas (CPs) represent epithelial tumors of the sellar region, consisting of adamantinomatous (adaCP) and papillary (papCP) variants. Their tendency to infiltrate surrounding brain structures complicates successful surgery. Reliable markers are required to predict tumor behavior and to establish individualized treatment protocols. Methods: We describe the distribution pattern of CLDN1 in a large cohort of 66 adaCPs, 21 papCPs, and 24 Rathke`s cleft cyst (RCC) cases using immunohistochemistry. CLDN1 mRNA levels were analyzed with qRT-PCR in 33 CP samples. The impact on the migration potential was studied in primary adaCP cell cultures (n = 11) treated with small interfering RNA (siRNA) for CLDN1. Furthermore, CLDN1 distribution patterns and expression levels were compared between invasive (n = 16) and noninvasive (n = 17) tumor groups. Results: PapCPs and RCCs exhibited a distinct homogenous and membranous expression pattern, whereas CLDN1 immunoreactivity appeared weaker and more heterogeneous in adaCPs. In the latter cases, whirl-like cell clusters showed complete absence of CLDN1. mRNA analysis confirmed reduced CLDN1 levels in adaCPs versus papCPs. Interestingly, invasive tumors exhibited significantly lower CLDN1 expression compared with noninvasive counterparts regardless of CP subtype. Accordingly, siRNA treatment for CLDN1 altered tumor cell migration in vitro. Conclusion: CLDN1 represents a novel marker in the differential diagnosis of CP variants and RCCs. Low CLDN1 expression levels correlate with an invasive CP growth pattern and may serve as a prognostic marker

Poor quality of life and sleep in patients with adrenal insufficiency—another cause of increased mortality?

Background!#!Patients with adrenal insufficiency (AI) are treated with glucocorticoid replacement therapy (GRT). Although current glucocorticoid regimens aim to mimic the physiological circadian rhythm of cortisol secretion, temporary phases of hypo- and hypercortisolism are common undesired effects which lead to a variety of consequences like increased cardiovascular risk and premature mortality. Additionally, poor quality of life (QoL) and impaired sleep have been reported. However, little is known about these topics regarding the effects of daily dosage, duration of therapy, and patients with different forms of AI (primary, PAI, and secondary, SAI).!##!Methods!#!In this study, 40 adults with AI substituted with hydrocortisone (HC) and 20 matched healthy controls completed questionnaires evaluating depressive symptoms, subjective health status, quality of sleep and daytime sleepiness. Furthermore, demographic data, dosage of HC, duration of therapy and co-medication were evaluated. Patients were compared in different groups.!##!Results!#!Patients assessed general health significantly worse than controls; likewise, daytime sleepiness was reported significantly more often. Depressive symptoms differed significantly in the two groups but did not reach clinically relevant scores. There was no difference between patients with PAI and SAI. High dosage of hydrocortisone had negative impact on mental health but not on sleep quality or daytime sleepiness.!##!Conclusions!#!The present data highlight that poor QoL and impaired sleep are still severe and underrated issues in current GRT and might be additional factors for premature mortality in patients with AI. Some AI patients reach normal or near-normal self-assessed QoL and sleep, even despite unphysiological replacement