Gompel, Jamie J. Van

Miller et al. maintain that thalamic SEEG can now be considered a cornerstone of standard clinical practice in individualized epilepsy care, helping to define seizure onset and spread, assess therapeutic stimulation, map connectivity, and identify target-specific biomarkers for responsive neurostimulation.

Abstract Objective Evidence on the duration of post-operative adrenal insufficiency (AI) in patients with endogenous hypercortisolism is scarce. We sought to determine the duration of post-operative AI and to identify factors associated with the duration of AI in patients undergoing surgery for endogenous hypercortisolism. Methods We conducted a single-center prospective cohort study, 2019-2025, of patients with endogenous hypercortisolism [Cushing syndrome (CS) or mild autonomous cortisol secretion (MACS)] treated with surgery. Associations of demographics, body mass index (BMI), clinical, and biochemical hypercortisolism severity, subtype of hypercortisolism, pre-surgical hypercortisolism duration, glucocorticoid type, and nadir cortisol in relation to duration of AI were investigated. Results The 242 patients [41% MACS, 46% pituitary CS, 12% adrenal CS, 1% ectopic CS, median age 50 years (IQR: 40-60), 85% women] who developed postsurgical AI were followed for a median duration of 13.7 months (IQR 7.2-26.3). The median time to recovery of AI was shorter in MACS vs. overt CS (3.9 months (95% CI: 3.3-6.2) vs. 13.5 months (95% CI 11.3-18.3), P value < .001). On multivariable analysis adjusting for age, sex, BMI, and glucocorticoid type, moderate to severe biochemical severity score (β = 11, P value < .001) and moderate to severe clinical severity score (β=8.7, P < .001), were associated with a longer duration of AI. Conclusions Baseline clinical and biochemical hypercortisolism severity scores may inform individualized counseling on post-operative AI duration in patients treated for CS and MACS.

BACKGROUND: Increasing interest in neurosurgery residency has led to a growing number of unmatched applicants, who often struggle to find appropriate guidance for their next steps. The authors examined trends, opinions, and options available to unmatched neurosurgery residency reapplicants. STUDY DESIGN: Demographic data of US applicants from MD programs obtained from the National Resident Matching Program (2009 to 2024) were analyzed using 1-way ANOVA analysis of time-interval averages. Opinions about reapplicants were assessed via an online survey of national neurosurgery leaders, including residency program directors and chairpersons (N = 356). RESULTS: All application trends showed greater change over time; however, the rate of accepted reapplicants showed no significant change among early (2009 to 2013: 4.8 ± 1.8), mid (2014 to 2018: 7.6 ± 4.8), and recent periods (2019 to 2024: 9.8 ± 2.5; p = 0.068). The survey had a 23.0% response rate (82 of 356). Commonly indicated reasons for failure to match included poor interview skills, weak recommendation letters, and personality issues. Although most survey respondents supported candidates reapplying, dual applications (applying to more than 1 specialty) were not widely encouraged. For those reapplying, pursuing a preliminary general surgery or research fellowship, obtaining new letters of recommendation from new subinternships, and publishing higher-quality research were the most endorsed uses of time before reapplying. However, most programs reported interviewing reapplicants sometimes to rarely and matching a reapplicant rarely to never. CONCLUSIONS: The number of reapplicants successfully matching into neurosurgery has not changed significantly during the past 15 years. Surveys indicate that leaders view reapplicants unfavorably, despite reapplicants’ efforts to improve their applications. These results suggest that neurosurgery mentors may do a disservice to potential reapplicants based on how residency program leadership considers reapplications. Candid guidance is needed for reapplicants in the residency matching process.

Objective The effects of deep brain stimulation (DBS) manifest across multiple timescales, spanning seconds to months, and involve direct electrical effects, neuroplasticity, and network reorganization. In epilepsy, the delayed impact of DBS on seizures presents challenges for optimization. Single‐pulse stimulation and resulting brain stimulation evoked potentials (BSEPs) provide a means to assess effective connectivity and network excitability. This study integrates BSEPs and short trials of DBS during stereoelectroencephalography (sEEG) to map seizure network engagement, modulate network dynamics, and monitor excitability and interictal abnormalities for biomarker informed neuromodulation. Methods Ten individuals with drug resistant epilepsy undergoing clinical sEEG were enrolled in this retrospective cohort study of epilepsy neuromodulation biomarkers. Each patient underwent a trial of high frequency (145Hz) thalamic DBS. BSEPs were acquired before and after DBS trials. Baseline BSEP amplitude assessed seizure network engagement, and modulation of amplitude (pre vs post DBS) assessed change in network excitability. Interictal epileptiform discharges were tracked by an automated classifier. Results Baseline BSEPs delineated distinct patterns of network engagement between thalamic subfields with maximal frontotemporal engagement achieved with stimulation of the anterior nucleus of the thalamus‐ventral anterior nucleus junction. DBS delivered for >1.5 hours reduced BSEP amplitudes compared to baseline, and the degree of modulation correlated with baseline connectivity strength. Shorter DBS trials did not induce reliable BSEP amplitude suppression, but did immediately suppress interictal epileptiform discharge rates in well‐connected seizure networks. Interpretation BSEPs and trials of DBS during sEEG provide novel network biomarkers to evaluate the modulation of large‐scale networks across multiple timescales, advancing biomarker informed neuromodulation. ANN NEUROL 2026;99:748–760

Abstract BACKGROUND The majority of pituitary neuroendocrine tumors (PitNETs) are effectively managed with medical therapy, surgery, and/or radiation therapy; however, a subset of pituitary adenomas exhibit aggressive behavior. Temozolomide is thought to be an effective treatment option for patients with PitNETs. METHODS We identified and retrospectively reviewed 11 patients with pituitary tumors treated with temozolomide. We then conducted a review of the literature, combining 114 previously published cases with our cohort. RESULTS 125 cases were identified with diagnoses of pituitary adenomas (n=45), aggressive pituitary tumors (n=61), and pituitary carcinoma (n=19) treated with temozolomide. 79 patients were male (68.1%) with a median age of 47.5 (range 9-72). A variety of tumor types were represented: 50 corticotroph adenomas (40.7%), 37 prolactinomas (30.1%), 22 hormone nonfunctioning adenomas (17.9%), 8 somatotroph adenomas (6.5%), 6 other functioning adenomas (4.9%), and 2 cases where the functional status was not mentioned. Median treatment duration was 9 cycles (n=91, 150-200 mg/m2 days 1-5, 28-day cycles; n=2, 75 mg/m2, days 1-21, 28-day cycles; n=1, 75 mg/m2 daily). 27 patients received concurrent therapy with a dopamine agonist/somatostatin analogue (n=10), other chemotherapy agent (n=9) or radiotherapy (n=8). Radiographic responses included stable disease (n=40), partial response (n=35), complete response (n=8), and progressive disease (n=30). Hormonal responses included complete response (n=13), partial response (n=32), and no response (n=16). 22 patients (47.8%; out of 46 patients where progression/recurrence was assessed) experienced progression/recurrence following temozolomide initiation with a median progression free survival (PFS) of 24 months. There was no significant association between MGMT methylation status and radiological or hormonal response. No unexpected toxicities were observed. CONCLUSION In this cohort, temozolomide was well-tolerated with a median PFS of 24 months. MGMT methylation status did not predict temozolomide response. Temozolomide is an option with a survival benefit for patients with PitNETs.

OBJECTIVE While endonasal transsphenoidal surgery (ETS) is the standard treatment for nonfunctioning pituitary adenomas (NFPAs), the postoperative recovery rates of secondary adrenal insufficiency and their predictive factors remain poorly understood. The authors investigated the relationship between the tumor resection rate and adrenal function recovery in patients with NFPAs. METHODS This retrospective study included 450 patients with NFPAs who underwent ETS between January 2013 and November 2023. The rates of preoperative hypopituitarism and postoperative recovery rates of secondary adrenal insufficiency and their associated factors were analyzed. Recovery was defined as normalization of serum cortisol levels without replacement therapy for at least 24 hours, accompanied by symptom resolution. The tumor resection rate was calculated as the percentage of the tumor volume resected. RESULTS The median follow-up period for the entire cohort was 52 months (range 1–131 months). A total of 246 (55%) patients had dysfunction in one or more pituitary axes. Fifty-three (47%) of 114 patients with preoperative adrenal insufficiency showed postoperative adrenal insufficiency recovery. The cumulative adrenal insufficiency recovery rates were 12% at 1 month, 19% at 3 months, 32% at 6 months, and 41% at 12 months. Among the 114 patients with preoperative adrenal insufficiency, the factors associated with postoperative adrenal insufficiency recovery were investigated. Patients with smaller tumor sizes of < 20 mm (log-rank test, p = 0.001) and those with tumor resection rates of more than 85% (log-rank test, p = 0.032) demonstrated better postoperative adrenal insufficiency improvement. Bivariate Cox proportional hazards analysis demonstrated that smaller tumor sizes (continuous, HR 0.97, 95% CI 0.93–0.98; p = 0.043) and higher tumor resection rates (HR 1.03, 95% CI 1.01–1.07; p = 0.001) were significantly associated with better postoperative adrenal insufficiency recovery. Multivariable analysis confirmed that only higher tumor resection rates were significantly associated with better postoperative adrenal insufficiency recovery (HR 1.03, 95% CI 1.01–1.06; p = 0.019). CONCLUSIONS Nearly half of the patients with preoperative adrenal insufficiency achieved recovery after ETS for NFPAs. The enhanced extent of tumor removal was an independent factor associated with better postoperative recovery, indicating that optimizing safe maximal resection procedures may be crucial in enhancing adrenal function.

Importance Adjuvant radiotherapy can improve locoregional control and survival in patients with olfactory neuroblastoma (ONB), particularly with advanced-stage and histologic-grade disease. Standard radiotherapy treatment is with intensity-modulated radiotherapy (IMRT). Proton beam radiotherapy (PBRT) provides theoretical advantages in greater sparing of dose to uninvolved organs at risk. Objective To investigate if there are differences in the effectiveness and radiation treatment–related adverse events (RTAEs) between adjuvant IMRT and PBRT for patients with ONB. Design, Setting, and Participants This propensity score–matched cohort study included patients with ONB treated between February 2005 and April 2021 with either IMRT or PBRT at 9 academic tertiary care centers in North America. Patients were matched 1:2 based on age, modified Kadish stage, and Hyams grade. Data were analyzed from July 2024 to January 2025. Exposure Adjuvant IMRT or adjuvant PBRT. Main Outcomes and Measures Local recurrence-free survival (RFS), any RFS, and overall survival (OS). RTAEs, ie, grade 2 events or higher based on Common Terminology Criteria for Adverse Events, were recorded for both modalities. Results Of 54 included patients, 27 (50%) were female, and the mean (SD) age was 46.2 (15.4) years. A total of 18 were treated with PBRT and 36 were treated with IMRT. Most patients had modified Kadish stage C disease (33 of 54 [61%]), and 24 patients (44%) had Hyams grade III or IV disease. The RTAE rate was 20% (8 of 40); IMRT had a rate of 21% (6 of 29), and PBRT had a rate of 18% (2 of 11). The difference in the point estimates for 10-year RFS showed a potential clinical benefit favoring IMRT, although the wide confidence interval indicates uncertainty (10-year RFS: IMRT, 63.3%; 95% CI, 44.6-89.8; PBRT, 37.8%; 95% CI, 14.2-100; difference, 25.5 percentage points; 95% CI, −17.6 to 68.6). There were no clinically meaningful differences in 10-year local RFS (IMRT, 75.6%; 95% CI, 59.8-95.4; PBRT, 72.7%; 95% CI, 45.2-100; difference, 2.9 percentage points; 95% CI, −35.9 to 41.7) or 10-year OS (IMRT, 61.8%; 95% CI, 42.8-89.1; PBRT, 57.1%; 95% CI, 24.3-100; difference, 4.7 percentage points; 95% CI, −49.2 to 58.6), although wide confidence intervals indicate considerable uncertainty. Conclusions and Relevance Due to the imprecision of estimates, no definitive conclusions can be made regarding the comparative effectiveness of IMRT vs PBRT for patients with ONB. These preliminary data may inform the design of appropriately powered prospective studies evaluating the efficacy of PBRT vs IMRT in this population.

Abstract Disclosure: S.R. Chacko: None. J. Saini: None. S. Sharma Sharma: None. S. Ahmadian: None. S.J. Achenbach: None. E. Atkinson: None. V. Fell: None. J.J. Van Gompel: None. W.F. Young, Jr.: None. I. Bancos: None. Context: Evidence on the duration of postoperative adrenal insufficiency (AI) in patients with endogenous hypercortisolism is scarce. Objective: To determine the duration of postoperative AI and to identify factors associated with the duration of AI in patients undergoing surgery for endogenous hypercortisolism.Methods: We conducted a single center prospective cohort study, 2019-2024, of patients with endogenous hypercortisolism [Cushing syndrome (CS) or mild autonomous cortisol secretion (MACS)] treated with surgery. Associations of demographics, BMI, clinical and biochemical hypercortisolism severity, subtype of hypercortisolism, presurgical hypercortisolism duration and glucocorticoid type in relation to duration of AI were investigated. Results: The 110 patients [36% MACS, 46% pituitary CS, 15% adrenal CS, 3% ectopic CS, median age 50 years (IQR: 40-60), 82% women] who developed postsurgical AI were followed for a median duration of 26 months (IQR: 15-38). By the end of follow up, 96 patients (87%) had recovery of AI. The median time to recovery of AI was shorter in MACS vs. Overt Cushing syndrome (3.0 months (95% CI: 2.5-6.2) vs. 12.3 months (95% CI 9.0-17.3), P =0.002). Biochemical severity score (r=0.32, P=0.002) and duration of preoperative hypercortisolism symptoms (r=0.29, P=0.005), but not age, sex, BMI, clinical severity, or glucocorticoid type were associated with the duration of AI. We found no differences in the duration of AI between patients with ACTH-dependent vs ACTH-independent CS (12.3 months (95% CI: 6.0-17.2) vs 13.9 months (95% CI: 9.0-25.5), P =0.7).Conclusion: In this interim analysis, we showed that after surgical remission of endogenous hypercortisolism, duration of postoperative AI was longer in CS compared to MACS. Additionally, higher biochemical hypercortisolism severity score and a longer duration of symptoms suggestive of hypercortisolism were associated with a longer duration of postoperative AI. Presentation: Sunday, July 13, 2025

OBJECTIVE Nonfunctioning pituitary adenomas (NFPAs) often present with associated mild hyperprolactinemia, described in literature as "stalk effect." The presence of preoperative hyperprolactinemia caused by tumor compression of the pituitary stalk and endocrinological outcomes has been noted; however, a detailed investigation on the impact on perioperative endocrinological outcome is lacking. The authors aimed to determine whether elevated preoperative serum prolactin concentrations are associated with increased risk of perioperative pituitary dysfunction in patients with NFPAs undergoing endonasal transsphenoidal surgery (ETS). METHODS The authors conducted a single-center retrospective cohort study of patients who underwent ETS for NFPAs between January 2013 and April 2023. Patients were divided into two groups based on preoperative prolactin concentrations: normal or hyperprolactinemic (prolactin values above upper limit of reference range, adjusted for sex). Outcomes included perioperative endocrinological function and surgical outcomes. Multivariable analysis was conducted to identify factors associated with perioperative endocrinological function outcomes. RESULTS Of 244 patients (140 [57%] males; median age 59 years) with a median follow-up of 65 months, 131 (54%) had hyperprolactinemia. Compared with patients with normal preoperative prolactin levels (n = 113), the hyperprolactinemia group had similar tumor size (median diameter 2.5 cm vs 2.3 cm, p = 0.102) but higher rates of cavernous sinus invasion (99% vs 91%, p = 0.035), pituitary stalk deviation (95% vs 74%, p = 0.001), stalk bending (14% vs 1%, p = 0.001), preoperative secondary hypothyroidism (39% vs 22%, p = 0.005), and adrenal insufficiency (AI; 34% vs 22%, p = 0.048). Postoperatively, the hyperprolactinemia group showed higher rates of new secondary hypothyroidism (16% vs 7%, p = 0.048) and new permanent AI (16% vs 6%, p = 0.046). Multivariable analysis revealed preoperative high prolactin as an independent predictor of preoperative secondary hypothyroidism (OR 1.83, 95% CI 1.17–3.44; p = 0.046) and its postoperative deterioration (OR 2.65, 95% CI 1.02–7.69; p = 0.042). Maximum tumor diameter was also a significant predictor of various endocrinological dysfunctions both pre- and postoperatively. CONCLUSIONS Preoperative hyperprolactinemia in patients with NFPA is associated with higher risks of specific perioperative endocrinological dysfunction and pronounced pituitary stalk deviation. These findings highlight the utility of preoperative prolactin levels as a biomarker for predicting postoperative endocrinological outcomes, potentially enhancing risk assessment and guiding personalized perioperative management.

Abstract BACKGROUND Adamantinomatous craniopharyngiomas (ACPs) are rare, partially cystic central nervous system tumors driven by the WNT/β-catenin pathway. As they grow, ACPs compress the surrounding pituitary gland, optic chiasm, and third ventricle. ACPs are highly morbid tumors with enormous quality of life impact on patients, often early in life. Thus, better treatments are needed. Current ACP treatment consists of maximally safe surgical resection with radiation for residual disease. Complete surgical resection is challenging, and recurrence is common. Targeted systemic chemotherapy is not routinely used for ACP treatment. Interleukin-6 (IL-6) levels are elevated within ACPs compared to normal brain tissue, making IL-6 an intriguing therapeutic target. Treatment response of ACP to tocilizumab alone or in combination with bevacizumab has been reported in children. MATERIAL AND METHODS We retrospectively reviewed the medical records of three adults with recurrent ACP who received combination treatment with bevacizumab and tocilizumab on a compassionate basis between June 2022 and April 2025 at Mayo Clinic in Rochester, MN. We collected demographic, clinical, treatment, radiologic, and outcome data. RESULTS All three patients were male and median age at initial ACP diagnosis was 38 years (range: 32-42 years). All patients underwent subtotal resection followed by radiation therapy. One patient had repeat surgical resection and two patients required interventions for hydrocephalus. At the time of ACP recurrence, all patients had visual impairment, endocrine dysfunction, and headaches. All patients received bevacizumab (7.5 mg/kg q3 weeks) and tocilizumab (8 mg/kg q3 weeks [n=2] or 4 mg/kg q4 weeks [n=1]). While receiving combination therapy, ACP tumor volume decreased on magnetic resonance imaging for all three patients (64%, 68%, and 29% reduction). None exhibited tumor growth since starting combination therapy. One patient had a small intraparenchymal hemorrhage, suspected secondary to radiation-induced cavernous malformation, so bevacizumab was discontinued, and he remains on tocilizumab alone. The other two patients continue combination therapy (for 344 and 351 days). Two patients experienced improvement in vision, and one had improvement in cognition. Possible adverse effects of treatment included sinus infections, fatigue, neutropenia, and hypertension. CONCLUSION Treatment with combination bevacizumab and tocilizumab was associated with shrinkage of ACP tumors and clinical improvements and obviated the need for further surgery or radiation in all three patients. This combination of medications may reprogram the tumor microenvironment, leading to ACP involution. This well-tolerated regimen provides a noninvasive option for treatment of recurrent ACP, and potentially initial ACP treatment, and may improve quality of life for patients.