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.

Association of Intraventricular Fibrinolysis With Clinical Outcomes in Intracerebral Hemorrhage: An Individual Participant Data Meta-Analysis.

BACKGROUND: In patients with intracerebral hemorrhage (ICH), the presence of intraventricular hemorrhage constitutes a promising therapeutic target. Intraventricular fibrinolysis (IVF) reduces mortality, yet impact on functional disability remains unclear. Thus, we aimed to determine the influence of IVF on functional outcomes. METHODS: This individual participant data meta-analysis pooled 1501 patients from 2 randomized trials and 7 observational studies enrolled during 2004 to 2015. We compared IVF versus standard of care (including placebo) in patients treated with external ventricular drainage due to acute hydrocephalus caused by ICH with intraventricular hemorrhage. The primary outcome was functional disability evaluated by the modified Rankin Scale (mRS; range: 0-6, lower scores indicating less disability) at 6 months, dichotomized into mRS score: 0 to 3 versus mRS: 4 to 6. Secondary outcomes included ordinal-shift analysis, all-cause mortality, and intracranial adverse events. Confounding and bias were adjusted by random effects and doubly robust models to calculate odds ratios and absolute treatment effects (ATE). RESULTS: Comparing treatment of 596 with IVF to 905 with standard of care resulted in an ATE to achieve the primary outcome of 9.3% (95% CI, 4.4-14.1). IVF treatment showed a significant shift towards improved outcome across the entire range of mRS estimates, common odds ratio, 1.75 (95% CI, 1.39-2.17), reduced mortality, odds ratio, 0.47 (95% CI, 0.35-0.64), without increased adverse events, absolute difference, 1.0% (95% CI, -2.7 to 4.8). Exploratory analyses provided that early IVF treatment (≤48 hours) after symptom onset was associated with an ATE, 15.2% (95% CI, 8.6-21.8) to achieve the primary outcome. CONCLUSIONS: As compared to standard of care, the administration of IVF in patients with acute hydrocephalus caused by intracerebral and intraventricular hemorrhage was significantly associated with improved functional outcome at 6 months. The treatment effect was linked to an early time window <48 hours, specifying a target population for future trials.

Double adenomas of the pituitary reveal distinct lineage markers, copy number alterations, and epigenetic profiles.

PURPOSE: Pituitary adenoma (PA) constitutes the third most common intracranial neoplasm. The mostly benign endocrine lesions express no hormone (null cell PA) or the pituitary hormone(s) of the cell lineage of origin. In 0.5-1.5% of surgical specimens and in up to 10% of autopsy cases, two or three seemingly separate PA may coincide. These multiple adenomas may express different hormones, but whether or not expression of lineage-restricted transcription factors and molecular features are distinct within multiple lesions remains unknown. METHODS: Searching the data bank of the German Pituitary Tumor Registry 12 double pituitary adenomas with diverse lineage were identified among 3654 adenomas and 6 hypophyseal carcinomas diagnosed between 2012 and 2020. The double adenomas were investigated immunohistochemically for expression of hormones and lineage markers. In addition, chromosomal gains and losses as well as global DNA methylation profiles were assessed, whenever sufficient material was available (n = 8 PA). RESULTS: In accordance with the literature, combinations of GH/prolactin/TSH-FSH/LH adenoma (4/12), GH/prolactin/TSH-ACTH adenoma (3/12), and ACTH-FSH/LH adenoma (3/12) were observed. Further, two out of 12 cases showed a combination of a GH/prolactin/TSH adenoma with a null-cell adenoma. Different expression pattern of hormones were confirmed by different expression of transcription factors in 11/12 patients. Finally, multiple lesions that were molecularly analysed in 4 patients displayed distinct copy number changes and global methylation pattern. CONCLUSION: Our data confirm and extend the knowledge on multiple PA and suggest that such lesions may origin from distinct cell types.

Glioblastoma multiforme: Metabolic differences to peritumoral tissue and IDH-mutated gliomas revealed by mass spectrometry imaging.

Glioblastoma multiforme (GBM) is the most common malignant primary brain tumor. High infiltration rates and poor therapy responses make it the deadliest glioma. The tumor metabolism is known to differ from normal one and is influenced through various factors which can lead to longer survival. Metabolites are small molecules (< 1500 Da) that display the metabolic pathways in the tissue. To determine the metabolic alterations between tumor and peritumoral tissue in human GBMs, mass spectrometry imaging (MSI) was performed on thin sections from 25 resected tumors. In addition, the GBMs were compared with six gliomas harboring a mutation in the isocitrate dehydrogenase (IDH1) gene (IDH1). With this technique, a manifold of analytes can be easily visualized on a single tissue section. Metabolites were annotated based on their accurate mass using high resolution MSI. Differences in their mean intensities in the tumor and peritumoral areas were statistically evaluated and abundances were visualized on the tissue. Enhanced levels of the antioxidants ascorbic acid, taurine, and glutathione in tumor areas suggest protective effects on the tumor. Increased levels of purine and pyrimidine metabolism compounds in GBM areas indicate the high energy demand. In accordance with these results, enhanced abundances of lactate and glutamine were detected. Moreover, decreased abundance of N-acetylaspartate, a marker for neuronal health, was measured in tumor areas. Obtained metabolic information could potentially support and personalize therapeutic approaches, hence emphasizing the suitability of MSI for GBM research.

Characteristics in Non-Vitamin K Antagonist Oral Anticoagulant-Related Intracerebral Hemorrhage.

Background and Purpose- Given inconclusive studies, it is debated whether clinical and imaging characteristics, as well as functional outcome, differ among patients with intracerebral hemorrhage (ICH) related to vitamin K antagonists (VKA) versus non-vitamin K antagonist (NOAC)-related ICH. Notably, clinical characteristics according to different NOAC agents and dosages are not established. Methods- Multicenter observational cohort study integrating individual patient data of 1328 patients with oral anticoagulation-associated ICH, including 190 NOAC-related ICH patients, recruited from 2011 to 2015 at 19 tertiary centers across Germany. Imaging, clinical characteristics, and 3-months modified Rankin Scale (mRS) outcomes were compared in NOAC- versus VKA-related ICH patients. Propensity score matching was conducted to adjust for clinically relevant differences in baseline parameters. Subgroup analyses were performed regarding NOAC agent, dosing and present clinically relevant anticoagulatory activity (last intake <12h/24h or NOAC level >30 ng/mL). Results- Despite older age in NOAC patients, there were no relevant differences in clinical and hematoma characteristics between NOAC- and VKA-related ICH regarding baseline hematoma volume (median [interquartile range]: NOAC, 14.7 [5.1-42.3] mL versus VKA, 16.4 [5.8-40.6] mL; P=0.33), rate of hematoma expansion (NOAC, 49/146 [33.6%] versus VKA, 235/688 [34.2%]; P=0.89), and the proportion of patients with unfavorable outcome at 3 months (mRS, 4-6: NOAC 126/179 [70.4%] versus VKA 473/682 [69.4%]; P=0.79). Subgroup analyses revealed that NOAC patients with clinically relevant anticoagulatory effect had higher rates of intraventricular hemorrhage (n/N [%]: present 52/109 [47.7%] versus absent 9/35 [25.7%]; P=0.022) and hematoma expansion (present 35/90 [38.9%] versus absent 5/30 [16.7%]; P=0.040), whereas type of NOAC agent or different NOAC-dosing regimens did not result in relevant differences in imaging characteristics or outcome. Conclusions- If effectively anticoagulated, there are no differences in hematoma characteristics and functional outcome among patients with NOAC- or VKA-related ICH. Clinical Trial Registration- URL: https://www.clinicaltrials.gov . Unique identifier: NCT03093233.

Heparin for prophylaxis of venous thromboembolism in intracerebral haemorrhage.

OBJECTIVE: To determine the occurrence of intracranial haemorrhagic complications (IHC) on heparin prophylaxis (low-dose subcutaneous heparin, LDSH) in primary spontaneous intracerebral haemorrhage (ICH) (not oral anticoagulation-associated ICH, non-OAC-ICH), vitamin K antagonist (VKA)-associated ICH and non-vitamin K antagonist oral anticoagulant (NOAC)-associated ICH. METHODS: Retrospective cohort study (RETRACE) of 22 participating centres and prospective single-centre study with 1702 patients with VKA-associated or NOAC-associated ICH and 1022 patients with non-OAC-ICH with heparin prophylaxis between 2006 and 2015. Outcomes were defined as rates of IHC during hospital stay among patients with non-OAC-ICH, VKA-ICH and NOAC-ICH, mortality and functional outcome at 3 months between patients with ICH with and without IHC. RESULTS: IHC occurred in 1.7% (42/2416) of patients with ICH. There were no differences in crude incidence rates among patients with VKA-ICH, NOAC-ICH and non-OAC-ICH (log-rank p=0.645; VKA-ICH: 27/1406 (1.9%), NOAC-ICH 1/130 (0.8%), non-OAC-ICH 14/880 (1.6%); p=0.577). Detailed analysis according to treatment exposure (days with and without LDSH) revealed no differences in incidence rates of IHC per 1000 patient-days (LDSH: 1.43 (1.04-1.93) vs non-LDSH: 1.32 (0.33-3.58), conditional maximum likelihood incidence rate ratio: 1.09 (0.38-4.43); p=0.953). Secondary outcomes showed differences in functional outcome (modified Rankin Scale=4-6: IHC: 29/37 (78.4%) vs non-IHC: 1213/2048 (59.2%); p=0.019) and mortality (IHC: 14/37 (37.8%) vs non-IHC: 485/2048 (23.7%); p=0.045) in disfavour of patients with IHC. Small ICH volume (OR: volume <4.4 mL: 0.18 (0.04-0.78); p=0.022) and low National Institutes of Health Stroke Scale (NIHSS) score on admission (OR: NIHSS <4: 0.29 (0.11-0.78); p=0.014) were significantly associated with fewer IHC. CONCLUSIONS: Heparin administration for venous thromboembolism (VTE) prophylaxis in patients with ICH appears to be safe regarding IHC among non-OAC-ICH, VKA-ICH and NOAC-ICH in this observational cohort analysis. Randomised controlled trials are needed to verify the safety and efficacy of heparin compared with other methods for VTE prevention.

Use of intraoperative intracavitary (direct-contact) ultrasound for resection control in transsphenoidal surgery for pituitary tumors: evaluation of a microsurgical series.

BACKGROUND: Perisellar infiltration may be responsible for incomplete removal of pituitary tumors. Since intraoperative visualization of parasellar structures is difficult during transsphenoidal surgery, we are describing the use of intraoperative direct contact ultrasound (IOUS). METHODS: Within 5 years, in 113 transsphenoidal operations (58 male, 55 female, age 14-81 years, 110 pituitary adenomas (mean diameter 26.6 mm, 69 non-secreting adenomas, 41 secreting adenomas), and 1 of each Rathke's cleft cyst, craniopharyngioma, and xanthogranuloma), IOUS was applied. After wide opening of the sellar floor and removal of the intrasellar tumor portions, a commercially available side fire ultrasound probe is introduced, and in direct contact to the sellar envelope, the perisellar space is scanned perpendicular to the axis of the working channel. We compared the results of IOUS to postoperative MRI after 3-6 months. RESULTS: Identification of the intracavernous ICA, the anterior optic pathway, and the ACA, was possible, it was safe to operate close to them. In 65 operations (58%), further resection of tumor remnants was performed after IOUS. In this selected series, complete resection of tumors (stated by postoperative MRI after 3-6 months) was achieved in 75 operations (66%) and remission was achieved in 18 operations of secreting adenomas (44%). Compared to MRI after 3 to 6 months, the sensitivity of IOUS was 0.568 and the specificity was 0.907. No complications related to IOUS were seen. CONCLUSIONS: Visualization of the perisellar compartments by IOUS is easy and fast to perform. It allows the surgeon to identify resectable tumor remnants intraoperatively, which otherwise could be missed.

Management of therapeutic anticoagulation in patients with intracerebral haemorrhage and mechanical heart valves.

Aims: Evidence is lacking regarding acute anticoagulation management in patients after intracerebral haemorrhage (ICH) with implanted mechanical heart valves (MHVs). Our objective was to investigate anticoagulation reversal and resumption strategies by evaluating incidences of haemorrhagic and thromboembolic complications, thereby defining an optimal time-window when to restart therapeutic anticoagulation (TA) in patients with MHV and ICH. Methods and results: We pooled individual patient-data (n = 2504) from a nationwide multicentre cohort-study (RETRACE, conducted at 22 German centres) and eventually identified MHV-patients (n = 137) with anticoagulation-associated ICH for outcome analyses. The primary outcome consisted of major haemorrhagic complications analysed during hospital stay according to treatment exposure (restarted TA vs. no-TA). Secondary outcomes comprised thromboembolic complications, the composite outcome (haemorrhagic and thromboembolic complications), timing of TA, and mortality. Adjusted analyses involved propensity-score matching and multivariable cox-regressions to identify optimal timing of TA. In 66/137 (48%) of patients TA was restarted, being associated with increased haemorrhagic (TA = 17/66 (26%) vs. no-TA = 4/71 (6%); P < 0.01) and a trend to decreased thromboembolic complications (TA = 1/66 (2%) vs. no-TA = 7/71 (10%); P = 0.06). Controlling treatment crossovers provided an incidence rate-ratio [hazard ratio (HR) 10.31, 95% confidence interval (CI) 3.67-35.70; P < 0.01] in disadvantage of TA for haemorrhagic complications. Analyses of TA-timing displayed significant harm until Day 13 after ICH (HR 7.06, 95% CI 2.33-21.37; P < 0.01). The hazard for the composite-balancing both complications, was increased for restarted TA until Day 6 (HR 2.51, 95% CI 1.10-5.70; P = 0.03). Conclusion: Restarting TA within less than 2 weeks after ICH in patients with MHV was associated with increased haemorrhagic complications. Optimal weighing-between least risks for thromboembolic and haemorrhagic complications-provided an earliest starting point of TA at Day 6, reserved only for patients at high thromboembolic risk.

Association of Surgical Hematoma Evacuation vs Conservative Treatment With Functional Outcome in Patients With Cerebellar Intracerebral Hemorrhage.

Importance: The association of surgical hematoma evacuation with clinical outcomes in patients with cerebellar intracerebral hemorrhage (ICH) has not been established. Objective: To determine the association of surgical hematoma evacuation with clinical outcomes in cerebellar ICH. Design, Setting, and Participants: Individual participant data (IPD) meta-analysis of 4 observational ICH studies incorporating 6580 patients treated at 64 hospitals across the United States and Germany (2006-2015). Exposure: Surgical hematoma evacuation vs conservative treatment. Main Outcomes and Measures: The primary outcome was functional disability evaluated by the modified Rankin Scale ([mRS] score range: 0, no functional deficit to 6, death) at 3 months; favorable (mRS, 0-3) vs unfavorable (mRS, 4-6). Secondary outcomes included survival at 3 months and at 12 months. Analyses included propensity score matching and covariate adjustment, and predicted probabilities were used to identify treatment-related cutoff values for cerebellar ICH. Results: Among 578 patients with cerebellar ICH, propensity score-matched groups included 152 patients with surgical hematoma evacuation vs 152 patients with conservative treatment (age, 68.9 vs 69.2 years; men, 55.9% vs 51.3%; prior anticoagulation, 60.5% vs 63.8%; and median ICH volume, 20.5 cm3 vs 18.8 cm3). After adjustment, surgical hematoma evacuation vs conservative treatment was not significantly associated with likelihood of better functional disability at 3 months (30.9% vs 35.5%; adjusted odds ratio [AOR], 0.94 [95% CI, 0.81 to 1.09], P = .43; adjusted risk difference [ARD], -3.7% [95% CI, -8.7% to 1.2%]) but was significantly associated with greater probability of survival at 3 months (78.3% vs 61.2%; AOR, 1.25 [95% CI, 1.07 to 1.45], P = .005; ARD, 18.5% [95% CI, 13.8% to 23.2%]) and at 12 months (71.7% vs 57.2%; AOR, 1.21 [95% CI, 1.03 to 1.42], P = .02; ARD, 17.0% [95% CI, 11.5% to 22.6%]). A volume range of 12 to 15 cm3 was identified; below this level, surgical hematoma evacuation was associated with lower likelihood of favorable functional outcome (volume ≤12 cm3, 30.6% vs 62.3% [P = .003]; ARD, -34.7% [-38.8% to -30.6%]; P value for interaction, .01), and above, it was associated with greater likelihood of survival (volume ≥15 cm3, 74.5% vs 45.1% [P < .001]; ARD, 28.2% [95% CI, 24.6% to 31.8%]; P value for interaction, .02). Conclusions and Relevance: Among patients with cerebellar ICH, surgical hematoma evacuation, compared with conservative treatment, was not associated with improved functional outcome. Given the null primary outcome, investigation is necessary to establish whether there are differing associations based on hematoma volume.

Intraventricular melanocytoma diagnosis confirmed by gene mutation profile.

Primary leptomeningeal melanocytic tumors (PLMTs) are rare. They usually arise along the spinal cord and at the skull base. Here we report on a patient with a very rare intraventricular melanocytoma. Histologically, a melanocytic tumor was clearly diagnosed. However, to make the uncommon diagnosis of an intraventricular melanocytoma, metastatic melanoma needed to be excluded. Next generation sequencing covering gene mutations that may occur in PLMTs and cutaneous melanoma was performed. The unique gene mutation profile detected, consisting of an activating CYSLTR2 L129Q mutation and EIF1AX G9R mutation and a lack of mutations in genes known to occur in metastatic melanoma (i.e. BRAF or NRAS) confirmed the diagnosis of an intraventricular melanocytoma. This case report is the second intraventricular melanocytoma published to date and demonstrates the value of applying novel genetic assays to make this diagnosis.

Diagnosis of Constitutional Mismatch Repair-Deficiency Syndrome Based on Microsatellite Instability and Lymphocyte Tolerance to Methylating Agents.

BACKGROUND & AIMS: Patients with bi-allelic germline mutations in mismatch repair (MMR) genes (MLH1, MSH2, MSH6, or PMS2) develop a rare but severe variant of Lynch syndrome called constitutional MMR deficiency (CMMRD). This syndrome is characterized by early-onset colorectal cancers, lymphomas or leukemias, and brain tumors. There is no satisfactory method for diagnosis of CMMRD because screens for mutations in MMR genes are noninformative for 30% of patients. MMR-deficient cancer cells are resistant to genotoxic agents and have microsatellite instability (MSI), due to accumulation of errors in repetitive DNA sequences. We investigated whether these features could be used to identify patients with CMMRD. METHODS: We examined MSI by PCR analysis and tolerance to methylating or thiopurine agents (functional characteristics of MMR-deficient tumor cells) in lymphoblastoid cells (LCs) from 3 patients with CMMRD and 5 individuals with MMR-proficient LCs (controls). Using these assays, we defined experimental parameters that allowed discrimination of a series of 14 patients with CMMRD from 52 controls (training set). We then used the same parameters to assess 23 patients with clinical but not genetic features of CMMRD. RESULTS: In the training set, we identified parameters, based on MSI and LC tolerance to methylation, that detected patients with CMMRD vs controls with 100% sensitivity and 100% specificity. Among 23 patients suspected of having CMMRD, 6 had MSI and LC tolerance to methylation (CMMRD highly probable), 15 had neither MSI nor LC tolerance to methylation (unlikely to have CMMRD), and 2 were considered doubtful for CMMRD based on having only 1 of the 2 features. CONCLUSION: The presence of MSI and tolerance to methylation in LCs identified patients with CMMRD with 100% sensitivity and specificity. These features could be used in diagnosis of patients.

The role of surgical management for prolactin-secreting tumors in the era of dopaminergic agonists: An international multicenter report.

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.

Crooke Cell Adenoma Confers Poorer Endocrinological Outcomes Compared with Corticotroph Adenoma: Results of a Multicenter, International Analysis.

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.

Defining benchmark outcomes for transsphenoidal surgery of pituitary adenomas: a multicenter analysis.

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.

A Multicenter, Propensity Score-Matched Assessment of Endoscopic Versus Microscopic Approaches in the Management of Pituitary Adenomas.

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 (ß = 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.

Predictive Value of Early Postoperative Course of Serum Cortisol After Transsphenoidal Surgery for Cushing's Disease.

OBJECTIVE: To identify early available predictors for the long-term outcome of patients after transsphenoidal surgery (TSS) in the management of Cushing's disease. METHODS: This single-center, retrospective study included 93 consecutive patients with Cushing's disease (follow-up 12-129 months, mean 48, median 38) who underwent TSS (21 had previous operations elsewhere). Six cases had early re-operation, and the resulting data were evaluated instead of the respective first operation. During the postoperative course, serum cortisol levels were assessed every four hours at least until the next morning. An association of parameters with long-term outcomes was tested using binary logistic regression. Receiver operating characteristic curves were used to determine sensitivity, specificity, positive predictive value, and negative predictive value of different cut-off values of serum cortisol in the postoperative course in the event of recurrence after remission. RESULTS: Eighty out of 93 patients (86%) showed postoperative remission (after primary treatment, 60 out of 72 patients, 90.3%). Of these, 8 patients (10%) developed recurrence of hypercortisolism. Compared to patients with persisting long-term remission, those with recurrence differed in cortisol levels starting from 4 pm on the day of surgery plus an event of increasing cortisol during the early postoperative course ("peak"). Binary logistic regression showed the association between a peak of serum cortisol in the early postoperative course with an increased probability of recurrence. CONCLUSIONS: Patients with a peak of serum cortisol in the early postoperative course show an increased recurrence rate. A cut-off value of serum cortisol for clear identification of patients with later recurrence could not be determined.

An H3F3A K27M-mutation in a sonic hedgehog medulloblastoma.

Medulloblastomas are malignant embryonal brain tumours that may harbour mutations in histone-modifying genes, while mutations in histone genes have not been detected to date. We here describe the first SHH medulloblastoma with H3 K27M mutation. This may have diagnostic implications as H3 K27M mutations are the hallmark of diffuse midline gliomas, H3 K27M mutant, WHO grade IV. Medulloblastomas arise in midline structures and thus must not be mistaken for DMG when using an antibody detecting the H3 K27M mutation.

Multiple tumorous lesions of the pituitary gland.

PURPOSE/OBJECTIVE: Multiple tumorous lesions in one pituitary gland are rare and mostly described in case reports. Their incidences and combinations are defined in larger collectives. Therefore, we analyzed our large collection for double tumors and combinations of tumors, cysts, and inflammation. METHODS: The German Registry of Pituitary Tumors, including cases from 1990 to 2018, served as the database. Our collection comprises a total of 16,283 cases up until the end of 2018. Of these cases, 12,673 originated from surgical and 3,610 from autopsy material. All specimens were fixed in formalin and embedded in paraffin. The sections were stained with hematoxylin-eosin and PAS. Monoclonal (prolactin, TSH, FSH, LH, and α subunit) or polyclonal (GH and ACTH) antibodies were used to detect pituitary hormones in the lesions. Since 2017, antibodies against the transcription factors Pit-1, T-Pit, and SF-1 have been used in difficult cases. The criteria of the 2017 WHO classification have been basic principles for classification since 2018 (Osamura et al. 2017). For differentiation of other sellar tumors, such as meningiomas, chordomas, or metastases, the use of additional antibodies was necessary. For these cases, it was possible to use a broad antibody spectrum. Autopsy pituitaries were generally studied by H&E and PAS sections. If any lesions were demonstrated in these specimens, additional immunostaining was performed. RESULTS: Multiple tumorous lesions with more than one pituitary neuroendocrine tumor (PitNET) respectively adenoma make up 1.4% (232 cases) in our collection. Within the selected cases, synchronous multiple pituitary neuroendocrine tumors (PitNETs) account for 17.3%, PANCH cases (pituitary adenoma with neuronal choristoma) for 14.7%, PitNETs and posterior lobe tumors for 2.2%, PitNETs and metastases for 5.2%, PitNETs and mesenchymal tumors for 2.6%, PitNETs and cysts for 52.2%, and PitNETs and primary inflammation for 6.0%. The mean patient age was 53.8 years, with a standard deviation of 18.5 years. A total of 55.3% of the patients were female and 44.7% were male. From 1990 to 2018, there was a continuous increase in the number of multiple tumorous lesions. CONCLUSION: From our studies, we conclude that considering possible tumorous double lesions during surgeries and in preoperative X-ray analyses is recommended.

Atypical Presentation of Neurobrucellosis as Infection of Ventriculoperitoneal Shunt.

Brucellosis is a frequent zoonosis in some regions of the world and may cause various symptoms. Neurobrucellosis is a rare but serious complication of the infection. Our case report describes the course of neurobrucellosis in a patient who had received a ventriculoperitoneal shunt in his native country 13 years prior to diagnosis of brucellosis. He initially presented to us with symptoms of peritonitis, which misled us to perform abdominal surgery first. After the diagnosis of neurobrucellosis was confirmed and appropriate antibiotics were initiated, the symptoms soon disappeared. Although the ventriculoperitoneal shunt was subsequently removed, the patient did not develop a symptomatic hydrocephalus further on. This case displays the challenges in diagnosing an infection that occurred sporadically in Europe and may be missed by currently applied routine microbiological workup. Considering the political context, with increasing relocation from endemic areas to European countries, it is to be expected that the cases of brucellosis and neurobrucellosis will rise. Brucellosis should be considered and adequate investigations should be performed.

Rhinological Consequences of Microsurgical Endonasal-Transsphenoidal Surgery for Pituitary Tumors.

BACKGROUND: Transsphenoidal surgery for sellar lesions may affect patency and function of the nasal airways, smell and sinonasal quality of life. Below is our report on otorhinolaryngological data garnered from patients undergoing endonasal transsphenoidal pituitary microsurgery. METHODS: In a prospective study, 68 patients scheduled for transsphenoidal operations (32 female, 36 male, age 17-72 years) underwent otorhinolaryngological evaluation of their nasal morphology, a standardized smell test (sniffin' sticks) and rhinomanometry to analyse nasal breathing function preoperatively, 3-5 days postoperatively (without rhinomanometry), after 3-4 months and after 9 months. RESULTS: Immediately after surgery, a reduction in smell sensation was detected in almost all patients. Within 3 months, this impairment resolved in all cases except one. In 2 patients (3%) with preoperative anosmia, improvement of smell function to>6 out of 12 sniffin' sticks was observed. At final visit no patient was noted to have new anosmia. Within 3 months, the results of the rhinomanometry revealed that all patients except one, regained their preoperative nasal breathing function. In 6 patients (8.8%) an improvement in their nose breathing abilities compared to the preoperative state was found. Three patients (4.4%) underwent a LASER transection of mucosal synechiae. In one case with persistent nasal obstruction (1.5%), secondary septoplasty had to be performed. There was no case in which perforation of the nasal septum, nasal tip deflection, or saddle nose deformity was observed. CONCLUSION: Microsurgical resection of pituitary tumors via the endonasal transsphenoidal approach poses an acceptable risk with regards to sinonasal complications. The incidence of secondary rhinosurgical interventions is low. Standardized comparative studies between endoscopic and microsurgical transsphenoidal operations should be undertaken.