Faculty Bibliography

BACKGROUND:Pituitary neuroendocrine tumors (PitNETs) are the most common intracranial neuroendocrine tumors. PitNETs can be challenging to classify, and current recommendations include a large immunohistochemical panel to differentiate among 14 WHO-recognized categories. METHODS:In this study, we analyzed clinical, immunohistochemical and DNA methylation data of 118 PitNETs to develop a clinico-molecular approach to classifying PitNETs and identify epigenetic classes. RESULTS:CNS DNA methylation classifier has an excellent performance in recognizing PitNETs and distinguishing the three lineages when the calibrated score is ≥0.3. Unsupervised DNA methylation analysis separated PitNETs into two major clusters. The first was composed of silent gonadotrophs, which form a biologically distinct group of PitNETs characterized by clinical silencing, weak hormonal expression on immunohistochemistry, and simple copy number profile. The second major cluster was composed of corticotrophs and Pit1 lineage PitNETs, which could be further classified using DNA methylation into distinct subclusters that corresponded to clinically functioning and silent tumors and are consistent with transcription factor expression. Analysis of promoter methylation patterns correlated with lineage for corticotrophs and Pit1 lineage subtypes. However, the gonadotrophic genes did not show a distinct promoter methylation pattern in gonadotroph tumors compared to other lineages. Promoter of the NR5A1 gene, which encodes SF1, was hypermethylated across all PitNETs clinical and molecular subtypes including gonadotrophs with strong SF1 protein expression indicating alternative epigenetic regulation. CONCLUSION/CONCLUSIONS:Our findings suggest that classification of PitNETs may benefit from DNA methylation for clinicopathological stratification.

PURPOSE/OBJECTIVE:Clinical screening systems (CSSs) for Cushing syndrome (CS) validated in Europe have not been evaluated for CS or Cushing disease (CD) in the United States (US). We aimed to evaluate existing CSSs in US patients and develop two new symptom-based CSSs to identify patients with high pre-test probability of disease warranting referral for definitive biochemical workup-one for broad CS screening and one specifically for CD. METHODS:Data were obtained from the Registry of Adenomas of the Pituitary and Related Disorders (RAPID)-comprising 615 patients who underwent transnasal transsphenoidal resection for CD at one of 11 US pituitary centers, the Centers for Disease Control and Prevention's 2019 National Health Interview Survey (NHIS)-comprising 31,997 US respondents, and a single institution CD-NFA cohort-comprising 468 US patients diagnosed with either CD (n = 385) or nonfunctioning adenoma (n = 83). The RAPID Community Cushing CSS was derived from differences between the RAPID and NHIS cohorts, and the RAPID CD CSS from differences between patients with CD versus NFA. RESULTS:In external validation using US-based cohorts, the RAPID Community CSS achieved an AUC of 0.707, compared to the Spanish (AUC = 0.691) and Italian (AUC = 0.685) models, and the RAPID CD CSS demonstrated greater external sensitivity (0.836, threshold = 0.5) at the Youden-optimized threshold than the Spanish (0.605, threshold = 4) and Italian (0.735, threshold = 6) CSSs. CONCLUSIONS:In US patient populations, the RAPID Community Cushing CSS demonstrated superior discriminative ability for CD compared to the Italian and Spanish CSSs, and the RAPID CD CSS achieved the highest sensitivity for CD among all CSSs evaluated.

OBJECTIVES/UNASSIGNED:Patients undergoing surgery for Cushing's disease may be more likely to be readmitted to the hospital than other patients with pituitary disorders. We investigated rates, causes, and predictors of unplanned readmission following transsphenoidal surgery for Cushing's disease to identify areas for clinical, financial, and administrative improvements. DESIGN/UNASSIGNED:Retrospective cohort study. SETTING/UNASSIGNED:Academic pituitary centers in the United States participating in a multicenter surgical outcome registry. PARTICIPANTS/UNASSIGNED:Five hundred and nineteen patients underwent transsphenoidal surgery for treatment of Cushing's disease by 26 surgeons at nine participating institutions from 2003 to 2023. MAIN OUTCOME MEASURES/UNASSIGNED:Unplanned 90-day readmission rates and causes of readmission. RESULTS/UNASSIGNED:Unplanned readmissions occurred in 57/519 patients (11.0%), with hyponatremia in 12/57 (21%), cerebrospinal fluid leak evaluation in 8/57 (14%), epistaxis in 6/57 (10%), deep vein thrombosis in 4/57 (7%), syncope in 3/57 (5%), and headache in 3/57 (5%). Factors including no tumor on initial magnetic resonance imaging, return to the operating room during the index admission, lack of early remission, and inpatient complications were associated with a greater probability of readmission on univariate analysis. However, none remained predictive on multivariate analysis. CONCLUSION/UNASSIGNED:Our results show that readmission rates after transsphenoidal surgery for Cushing's disease are comparable to previously reported rates for all pituitary-related disorders, with the most common reason being hyponatremia. High-impact clinical protocols focused on preventing delayed hyponatremia may reduce the risk of readmission. Failure to identify significant predictors of readmission, even in this large clinical dataset, underscores the challenge of identifying high-risk clinical cohorts.

BACKGROUND:Molecular aberrations have been incorporated into tumour classification guidelines of meningioma. TERT-promoter (TERTp) mutation is associated with worse prognosis and is designated a WHO grade 3 biomarker. However, it remains unclear whether TERTp mutation is context-dependent, with other co-occurring genetic alterations potentially driving its association with prognosis. We sought to characterise the role of TERTp mutation in meningioma and guide TERTp sequencing. METHODS:We identified 1492 patients of all ages who had previously received surgery for meningioma across 14 medical centres in the USA, Canada, and Germany. Patients were eligible if they had post-surgical clinical or radiographical assessment of the resection site, and TERTp status evaluated by Nov 1, 2024. Multi-modal profiling was used to assess TERTp mutation, focal gene alterations-including CDKN2A/B loss-and copy number alterations. An adjusted WHO grade was calculated for TERTp-mutant meningiomas, incorporating all WHO criteria except TERTp status. Kaplan-Meier curves and multivariable Cox proportional hazards models were used to quantify the effect of TERTp mutation on the endpoints of overall survival and recurrence-free survival across adjusted WHO grade and co-occurring molecular alterations. FINDINGS/RESULTS:64 (4·3%) of 1492 meningiomas were TERTp-mutant and 1428 (95·7%) were TERTp-wildtype. Of the TERTp-mutant meningiomas, 33 (51·6%) were from female patients and 31 (48·4%) were from male patients, and the overall median age was 67 years (IQR 60-75). Of the wildtype meningiomas, 965 (67·6%) were from female patients and 463 (32·4%) were from male patients, and the overall median age of the patients was 59 years (IQR 48-70). Data on race was inconsistently reported and thus excluded. The TERTp-mutant patients had a 5-year overall survival (49·4% [95% CI 33·7-72·4]) and 5-year recurrence-free survival (27·6% [95% CI 16·8-45·5]) resembling that of patients with WHO grade 3 TERTp-wildtype tumours (5-year overall survival 32·3% [95% CI 17·2-60·5], p=0·28, 5-year recurrence-free survival 14·3% [5·8-35·2], p=0·28). However, the TERTp-mutant group had heterogenous histological grading and was enriched for aggressive molecular features, with 1p loss present in 44 (77·2%) of 57 profiled tumours and CDKN2A/B loss in 24 (41·4%) of the 58 profiled tumours. Adjusting tumour grade revealed a subset of TERTp-mutant meningiomas that were more molecularly and clinically benign. Among TERTp-mutant tumours, CDKN2A/B loss played a defining role in stratifying tumour behaviour. Multivariable analysis confirmed this, with CDKN2A/B loss being significantly associated with shorter overall survival (HR 3·04 [95% CI 1·67-5·52], p=0·00026) and faster time to recurrence (HR 5·22 [95% CI 3·10-8·79], p<0·0001), while TERTp-mutation did not independently affect overall survival (HR 1·00 [95% CI 0·53-1·87], p=0·99) or recurrence-free survival (1·17 [95% CI 0·75-1·83], p=0·49). Sequencing for TERTp-mutation demonstrated clinical impact only among histologically WHO grade 2 meningiomas. INTERPRETATION/CONCLUSIONS:The indolent behaviour of certain TERTp-mutant meningiomas suggests that TERTp mutation is not sufficient to assign the most aggressive meningioma grade. Instead, TERT sequencing might offer prognostic utility in identifying high-risk cases among WHO grade 2 meningiomas. FUNDING/BACKGROUND:National Institutes of Health, National Institute of Neurological Disorders and Stroke, Friedberg Charitable Foundation, Courtney Meningioma Research Fund, Fleming Meningioma Research Fund, and the Gray Family Foundation.

CONTEXT/BACKGROUND:Little is known about presenting clinical characteristics, tumor biology, and surgical morbidity of Cushing disease (CD) with aging. OBJECTIVE:Using a large multi-institutional data set, we assessed diagnostic and prognostic significance of age in CD through differences in presentation, laboratory results, tumor characteristics, and postoperative outcomes. METHODS:Data from the Registry of Adenomas of the Pituitary and Related Disorders (RAPID) were reviewed for patients with CD treated with transsphenoidal tumor resection at 11 centers between 2003 and 2023. Outcomes assessed included comorbidities, presenting features, preoperative endocrine evaluations, perioperative characteristics, postoperative endocrine laboratory values, and complications. RESULTS:Of the 608 patients evaluated, 496 (81.6%) were female; median age at surgery was 44 years (range, 10-78 years). Increasing age was associated with increasing comorbidities, frailty, rates of postoperative thromboembolic disease, Knosp grade, tumor size, and postoperative cortisol and adrenocorticotropin nadirs. Conversely, increasing age was associated with decreased hallmark CD features, preoperative 24-hour urinary free cortisol, Ki-67 indices, and arginine vasopressin deficiency. Younger patients presented more frequently with weight gain, facial rounding/plethora, abdominal striae, hirsutism, menstrual irregularities, dorsocervical fat pad, and acne. Obstructive sleep apnea and infections were more common with increasing age. CONCLUSION/CONCLUSIONS:There are age-dependent differences in clinical presentation, tumor behavior, and postoperative outcomes in patients with CD. Compared to younger patients, older patients present with a less classic phenotype characterized by fewer hallmark features, more medical comorbidities, and larger tumors. Notably, age-related differences suggest a more indolent tumor behavior in older patients, potentially contributing to delayed diagnosis and increased perioperative risk. These findings underscore the need for tailored diagnostic and therapeutic approaches across age groups, with a focus on managing long-term comorbidities and optimizing surgical outcomes.

BACKGROUND AND OBJECTIVES/OBJECTIVE:Iatrogenic cerebrovascular injury can cause intracranial hemorrhage and pseudoaneurysm formation, putting patients at high risk for postoperative bleeding. No consensus for management exists. This study describes endovascular treatment of these acute injuries with flow diverter stents. METHODS:Electronic medical records were retrospectively reviewed for injury type and etiology, timing of diagnosis, and endovascular management, including antiplatelet regimens, embolization results, and clinical outcome. RESULTS:Six patients were included. Three suffered an injury to the internal carotid artery, 1 suffered an injury to the left anterior cerebral artery, 1 suffered an injury to the right posterior cerebral artery, and 1 suffered an injury to the basilar artery. Four of the 6 injuries occurred during attempted tumor resection, 1 occurred during cerebrospinal fluid leak repair, and 1 occurred during an ophthalmic artery aneurysm clipping. All injuries resulted in pseudoaneurysm formation. Four were immediately detected on angiography; 2 were initially negative on imaging. Five were treated with a pipeline embolization device, and 1 was treated with a Silk Vista Baby. Two were treated with 2 pipeline embolization devices telescopically overlapped across the pseudoaneurysm. All devices deployed successfully. No pseudoaneurysm recurrence or rebleeding occurred. No parent artery occlusion or stenosis was observed, and complete pseudoaneurysm occlusion was observed in 4 patients (in 2 patients, follow-up imaging could not be obtained). CONCLUSION/CONCLUSIONS:With proper antiplatelet regimens, flow diverter stents can be used safely to successfully treat complex acute iatrogenic injuries. Early repeat angiogram is needed when immediate postinjury imaging does not discover the point of vessel injury.

Tethered postoperative drains are not uncommon complications that often require open removal in the operating room, which can increase risks of surgical site infection as well as length of hospitalization. We present a novel method of tethered drain removal through guidewire electrification. A retained deep drain following a posterior cervical laminectomy and fusion was identified after failed manual removal. Under fluoroscopic guidance, the retaining suture was indirectly identified through the obstruction of an inserted guidewire, through which monopolar cautery was applied, breaking the suture and allowing drain removal. The original incision did not need to be re-opened. While further investigation is necessary for validation, this technique shows great promise as an alternative to open removal.

OBJECTIVE:Reports of surgical outcomes for Cushing's disease are mostly limited to single-center experiences by expert surgeons. Therefore, no generalizable surgical outcome metrics for endoscopic endonasal Cushing's disease surgery are available for practitioners to guide quality-improvement efforts. This is potentially problematic, given the high morbidity and excess mortality observed in patients who do not achieve remission. This study proposes a bundle of evidence-based metrics for low-risk patients with Cushing's disease, for whom optimal outcomes would be expected, that focus on the cost efficiency of care and surgical outcomes from multicenter collaboration of US pituitary centers. METHODS:The steering committee of the Registry of Adenomas of the Pituitary and Related Disorders (RAPID) consortium proposed the metrics based on available data from 12 US pituitary centers. A benchmarking population of low-risk patients undergoing first-time surgery was identified. Patient characteristics and outcomes were aggregated and analyzed by a data coordinating center. Metrics were reported using 2 approaches. RESULTS:A total of 431 patients from 12 centers who underwent primary endoscopic transsphenoidal surgery from January 1, 2006, to December 31, 2022, were included. There were 227 patients in the low-risk cohort (age < 70 years, BMI < 50, microadenoma, and Knosp grade 0-2). For the cost-efficiency metrics, the mean (SD) length of stay was 3.8 (4.8) midnights, and the percentage of patients readmitted was 11.1%. The rate of disposition to a skilled nursing facility was 2.2%. For surgical outcomes, the rate of postoperative CSF leakage was 1.3%, and the rate of 1-year sustained surgical remission was 81.2%. The rates of permanent and temporary arginine vasopressin deficiencies were 1.8% and 11.9%, respectively. The 75th percentile performance by center was 3.0 midnights for length of stay, 6.3% for 90-day unplanned readmission, < 1% for disposition to a skilled nursing facility, < 1% for CSF leakage, and 92.2% for 1-year sustained remission. The 75th percentile was < 1% for both permanent and temporary arginine vasopressin deficiencies. CONCLUSIONS:An evidence-based bundle of metrics in a Cushing's disease patient population at low risk who underwent first-time endoscopic pituitary surgery is proposed. Surgeons can use these metrics to assess and improve the quality of their clinical pathways.

BACKGROUND AND IMPORTANCE/BACKGROUND:Rhino-orbital cerebral mucormycosis (ROCM) is an aggressive fungal infection involving the paranasal sinuses, orbit, and intracranial cavity, with a propensity for vascular invasion. This can lead to complications such as internal carotid artery (ICA) thrombosis and occlusion, presenting major neurosurgical challenges. Although surgical debridement and antifungal therapy are the mainstays of treatment, cases with significant neurovascular involvement require specialized intervention. We report a case of ROCM with severe flow-limiting ICA stenosis treated by direct extracranial-intracranial bypass. CLINICAL PRESENTATION/METHODS:tA 65-year-old man with diabetes presented with progressive left-sided blindness and facial numbness. Imaging revealed a left orbital mass extending into the paranasal sinuses and intracranially. Empiric antifungal therapy was started. Pathology confirmed Rhizopus species. Despite extensive surgical debridement and antifungal therapy, the patient developed progressive severe cavernous ICA stenosis, leading to watershed territory strokes. To restore cerebral perfusion, protect from distal emboli, and prepare for potential aggressive debridement, a flow-replacing direct (superficial temporal artery-middle cerebral artery (M2)) bypass was performed, and the supraclinoid carotid was trapped. Intraoperative angiography confirmed robust flow through the bypass. The patient was discharged on antifungal therapy and aspirin. At 6-month follow-up, the patient was neurologically intact with an modified Rankin Scale score of 1. Computed tomography angiography and transcranioplasty Doppler ultrasonography confirmed good flow through the bypass. CONCLUSION/CONCLUSIONS:In addition to antifungal therapy and surgical debridement, superficial temporal artery-middle cerebral artery bypass can be a lifesaving intervention in the management of ROCM with severe cerebrovascular compromise. This case highlights the critical role of cranial bypass in preserving cerebral perfusion in patients with flow-limiting ROCM-associated ICA invasion.

OBJECTIVES/OBJECTIVE:To assess a decade of experience of treating patients with high hearing risk cerebellopontine angle (CPA) epidermoid lesions and examine factors influencing postoperative outcomes, particularly hearing preservation. STUDY DESIGN/METHODS:Retrospective chart review. SETTING/METHODS:Single tertiary-referral center. PATIENTS/METHODS:Adults with CPA epidermoid lesions who presented with hearing loss or evidence of lesion involving vestibulocochlear nerve. INTERVENTIONS/METHODS:The studied intervention was microsurgical resection. MAIN OUTCOME MEASURES/METHODS:Main outcome measures included extent of resection, hearing preservation rate for patients with postoperative audiograms, and disease progression. RESULTS:Twenty-three adults with an average tumor volume of 15.63 ± 16.2 cm3 were included. Five lesions (22%) involved the full internal auditory canal (IAC), 11 (48%) had partial involvement, and 5 (22%) were IAC sparing. Most patients with IAC involvement (88%) had circumferential invasion of the canal. Patients underwent either a retrosigmoid (18, 79%) or combined retrolabyrinthine transpetrosal approach (5, 22%), and gross total resection was achieved in most cases (13, 57%). Of 12 patients with postoperative audiograms, 10 (83%) had preoperative hearing preserved. There was no statistically significant change in hearing scores with treatment based on preoperative extent of IAC involvement. Ten patients (43%) had residual lesions postoperatively, and 6 exhibited progression. One patient ultimately required reoperation 6 years after initial surgery. CONCLUSIONS:Preoperative hearing was preserved in the majority of the patients who underwent resection of CPA epidermoids via a retrosigmoid or transpetrosal approach. CPA epidermoids often invaded the IAC; however, degree of invasion was not associated with hearing outcomes.