Julie M. Silverstein

Objective: Aggressive pituitary neuroendocrine tumors (PitNETs) that progress despite surgery, radiotherapy (RT), and medical therapy are heterogenous; only a subset exhibits overtly malignant behavior. We examined genetic determinants of metastatic behavior and poor prognosis. Design: Retrospective genomic cohort study of 39 patients (62 tumor samples) with aggressive PitNETs. Methods: Next-generation sequencing was performed using the MSK-IMPACT platform on a sequencing protocol. Genetic alterations were correlated with metastatic status, and progression-free and overall survival (PFS and OS) from first progression following RT. Results: Cell-cycle alterations were found in 23.1% of patients and were more frequently identified in metastatic compared to non-metastatic tumors (42.1% vs 5.0%; OR=12.9; p=0.008). TP53, ATRX, DAXX, and/or SF3B1 alterations were associated with adverse clinical outcomes but did not differ by metastatic status (53% of metastatic vs 60% of non-metastatic tumors). Within the corticotroph lineage, gene-level alterations in TP53, ATRX, and/or DAXX captured corticotrophs with recurrent chromosomal loss-of-heterozygosity (rcLOH), and were associated with shorter PFS (10.1 vs 149.9 months; p=0.009) and OS (116.6 months vs not reached [NR]; p=0.022). A subset of corticotrophs lacking rcLOH harbored gain-of-function USP8 mutations and were associated with longer PFS (149.9 vs 11.5 months; p=0.022). In lactotroph PitNETs, TP53, ATRX, and/or SF3B1 mutations were associated with shorter PFS (4.6 vs 21.5 months; p=0.049). Conclusions: Cell-cycle alterations were enriched in metastatic PitNETs and may contribute to metastatic dissemination. Next-generation sequencing segregates aggressive PitNETs into prognostic subgroups.

BACKGROUND AND OBJECTIVES: Craniopharyngiomas (CPs) recur in 20% to 50% of cases after initial management. To date, there are no large multi-institutional series investigating outcomes in patients receiving surgery for recurrent CP. Here, we leverage the Registry of Adenomas of the Pituitary and Related Disorders to analyze outcomes after surgical treatment of recurrent CP. METHODS: Demographic, clinical, radiographic, surgical, and outcome variables were analyzed for 483 patients receiving surgery for primary or recurrent CP across 16 US-based academic skull-base centers comprising the Registry of Adenomas of the Pituitary and Related Disorders consortium from 2000 to 2024. RESULTS: Among the 483 patients, 360 (74.5%) had primary CP and 123 (25.5%) had recurrent CP. The recurrent cohort was younger at initial diagnosis ( P _adj < .01) and recurrence ( P _adj = .02). Adamantinomatous CPs were more common in the recurrent cohort but not significantly so, and 33.3% of cases had prior radiation therapy. Recurrent cases had more frequent preoperative endocrine dysfunction and hormone replacement ( P _adj < .01). Patients with recurrent CP had less frequent suprasellar tumor extension ( P _adj = .04) and more frequent preinfundibular/transinfundibular over retroinfundibular localization ( P _adj = .02). There were no differences in operative approach; endoscopic endonasal surgery was the most common, and procedures achieved similar distributions of gross and subtotal resection in both cohorts ( P _adj = .30) with similar low frequencies of unplanned reoperation and surgical complications. New postoperative arginine vasopressin deficiency (in patients without preoperative arginine vasopressin deficiency) was more common in the primary cohort ( P _adj = .04), but long-term follow-up demonstrated similar frequencies of endocrine dysfunction in both cohorts and comparably low rates (P _adj = .17). CONCLUSION: This study provides the largest comparative evaluation of patients undergoing surgery for recurrent vs primary CP. Despite prior treatment, patients with recurrent CP achieved comparable resection outcomes with similar rates of neuroendocrine dysfunction. These findings indicate surgical resection remains a safe and efficacious option for recurrent CP, especially as emerging targeted therapies become available.

Purpose 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.

Background: Readmission following endoscopic endonasal transsphenoidal surgery (EETS) for pituitary neuroendocrine tumor (PitNET) and other sellar pathology is most commonly due to delayed hyponatremia. Studies suggest postoperative fluid restriction (FR) reduces delayed hyponatremia. We present a prospective randomized controlled study evaluating post-EETS FR. Methods: 300 participants were scheduled for EETS (2016–2023) at a single institution. Patients with CKD, CHF, arginine vasopressin deficiency on postoperative day (POD) 3, chronic hyponatremia, and untreated adrenal insufficiency or hypothyroidism were excluded. Groups included control (ad-lib, n = 94), moderate FR (1.8 L/day or 2 L/day weight > 100 kg, n = 39), and strict FR (1 L/day or 1.2 L/day weight > 100 kg, n = 62) from POD 3–14. Incidence of overall, moderate, and severe hyponatremia (Na < 135, 125–129, and <125 mEq/L), readmission rates, fluid intake, and thirst were evaluated. Results: The incidence of overall hyponatremia was 31.9%, 28.2%, and 21.0% in control, moderate FR, and strict FR groups, and the incidence of severe hyponatremia was 7.4%, 5.1%, and 0% in control, moderate FR, and strict FR groups. Nadir Na level was higher (1.81 mEq/L; 95% CI, 0.34 to 3.27; P = .02) and severe hyponatremia occurred less frequently (95% CI, 0.00 to 1.02; P = .04) in the strict FR vs. control group. Readmission was lower in the strict FR (1.6%, n = 1) vs. control group (6.4%, n = 6). Conclusions: Postoperative FR decreases rates of delayed hyponatremia and related readmission compared to patients drinking ad-lib. Further studies are needed to assess the optimal volume and duration of FR after EETS. Trial registration number: NCT03636568

Pituitary tumor apoplexy (PTA) classically comprises sudden-onset headache, loss of vision, ophthalmoparesis, and decreased consciousness. It typically results from hemorrhage and/or infarction within a pituitary adenoma. Presentation is heterologous, and optimal management is debated. The time course of recovery of cranial nerve deficits (CNDs) and headaches is not well established. In this study, a retrospective series of consecutive patients with PTA managed at a single academic institution over a 22-year period is presented. Headaches at the time of surgery were more severe in the early and subacute surgical cohort and improved significantly within 72 h postoperatively (p < 0.01). At one year, 90% of CNDs affecting cranial nerves (CNs) 3, 4, and 6 had recovered, with no differences between early (14 d) time-to-surgery cohorts. Remarkably, half recovered within three days. In total, 56% of CN2 deficits recovered, with the early surgery cohort including more severe deficits and recovering at a lower rate (p = 0.01). No correlation of time-to-surgery and rapidity of recovery of CNDs was observed (p = 0.65, 0.72). Surgery for PTA is associated with rapid recovery of CNDs in the early, subacute, and delayed time frames, and with rapid headache improvement in the early and subacute time frames in 50% or more of patients.

Background: The most common cause for readmission after transsphenoidal surgery (TSS) is hyponatremia (hypoNa). Delayed hypoNa, defined as hypoNa occurring 3 to 14 days post TSS, occurs in up to 35% of patients and, if severe, can be life-threatening. We conducted a preliminary prospective study comparing two approaches of postoperative fluid management and hypothesized that patients treated with early postoperative fluid restriction would have decreased rates of delayed hypoNa. Methods: Patients scheduled for TSS were randomly assigned to the control (CON, n=65) or fluid restriction group (Total FR (EXP 1 + EXP 2), n=57). Patients with chronic kidney disease stage III or greater, diabetes insipidus, chronic hyponatremia, or untreated adrenal insufficiency or hypothyroidism were excluded. All patients were started on postoperative weight-based intravenous fluids until postoperative day (POD) 1 and allowed to drink freely. Patients in the EXP 1 group (n=39) were fluid restricted to 1.8 liters/day (2 liters/day if weight > 100 kg) from POD 3 through POD 14. The fluid restriction was changed to 1 liter/day (1.2 liters/day if weight > 100 kg) (EXP 2, n=18) during the study due to interim analysis suggesting a trend toward a reduction in the incidence of hypoNa with fluid restriction. Patients in the CON group were instructed to drink ad lib. Serum sodium (Na) levels were checked every 8 hours in the hospital and on POD 3, 7, 10, and 14. Average and nadir Na between POD 3 and POD 14, incidence of mild (130-134 mEq/L), moderate (125-129 mEq/L), and severe (< 125 mEq/L) hypoNa, and readmission for hypoNa were evaluated. Mann-Whitney U test, Fischer’s exact test, Pearson’s chi-square, and T-test were used for statistical analysis. Results: Nadir Na was lower in CON compared to EXP 2 (135.1 ± 5.8 vs 138.4 ± 2.8, p=0.024). There was a trend toward a decreased incidence of hypoNa in EXP 2 (11%) compared to CON (30%) (p=0.133). Although there was no significant difference in the incidence of hypoNa (p=0.323) between CON and the EXP 1 and EXP 2 groups combined (Total FR), there was a trend toward a lower nadir Na (135.1 ±5.8 vs 137 ± 4.6, p=0.082) and average Na (138.8 ± 3.1 vs139.8 ± 2.5, p=0.140) in CON versus Total FR group, respectively. There was no statistically significant difference in average Na or incidence of hypoNa in CON compared to EXP 1. The incidence of mild, moderate, and severe hyponatremia was similar among groups, except in EXP 2 which had a lower, although not statistically significant, incidence of severe hyponatremia (0% vs 7.7%) and readmission for hyponatremia (5.6% vs 17.5%) compared to CON. There was no difference in the incidence of acute kidney injury or hypernatremia between groups. Conclusion: Preliminary results suggest early moderate fluid restriction after TSS may reduce the incidence of delayed hyponatremia as compared to mild or no fluid restriction. Further analysis with more participants is needed.