Faculty Bibliography

Leptomeningeal disease (LMD) is a devastating complication of cancer, and its incidence is rising. The inaugural LMD Think Tank Meeting took place in 2023 during the Society for Neuro-Oncology (SNO) and American Society of Clinical Oncology (ASCO) Central Nervous System (CNS) annual meeting, convening an international group of clinicians and scientists dedicated to understanding and treating LMD in a multidisciplinary fashion. While this meeting laid the foundation for a SNO/ASCO consensus review on the clinical management of LMD, the frequent exclusion of LMD patients from trials was identified as a clear and pervasive challenge. To address this gap, a follow-up assembly convened in 2024 with a goal of developing an SNO/ASCO consensus on best practices for clinical research; this included addressing the role of industry and basic scientists in clinical trials, providing guidance for improved clinical trial design, and accelerating the enrollment of LMD patients into clinical trials. Academic-industry partnerships and multi-institutional collaborations are crucial to advance our understanding of LMD, expand treatment access, and ultimately, improve survival and quality of life for our patients.

Leptomeningeal metastasis (LM) is a fatal neurological complication of cancer. Proton craniospinal irradiation (pCSI) has emerged as a promising life-prolonging intervention for patients with LM, but response to this treatment varies. Here, we aimed to characterize the molecular basis of pCSI resistance and response. Proteomic analysis of cerebrospinal fluid (CSF) collected from patients with LM at baseline (before pCSI), and at multiple time points posttreatment, identified the chemokine C-X-C-motif ligand 1, CXCL1, associated with LM growth. Higher CXCL1 levels in the CSF before pCSI correlated with worse response to this treatment. To define the role of CXCL1 in LM, we established syngeneic mouse models of LM-CSI. We found that both metastatic cancer and host cells generate CXCL1. Genetic interruption of Cxcl1 expression in metastatic cancer, but not host cells, impaired cancer cell growth within the leptomeninges. Moreover, we found that Cxcr2, the primary receptor for Cxcl1, was widely expressed within the LM microenvironment. A subset of LM cancer cells expressed Cxcr2, and this population was enriched over time in the leptomeninges. Transcriptomic profiling of this rare population revealed enrichment in pathways associated with cell cycle progression. In patients, we found that higher expression of CXCR2 before pCSI correlated with worse overall survival. Last, in preclinical models, interruption of Cxcl1-Cxcr2 signaling with intrathecally delivered Cxcr2 antagonist hampered LM growth and sensitized cancer cells to CSI. Our results demonstrate that the Cxcl1-Cxcr2 signaling axis mediates LM growth and identifies a potential actionable intervention to improve response to pCSI and halt LM progression.

OBJECTIVE:Spinal meningiomas (SMs) are common primary spinal tumors for which surgery is considered the first-line treatment when safe and feasible. The ability to extrapolate the tumor grade from preoperative imaging may significantly inform early patient expectation-setting regarding recurrence. Building on radiomics studies in cranial meningiomas, the authors aimed to construct a benchmark radiomics model to preoperatively identify the histological grade of SMs. METHODS:Institutional surgical records from May 2012 to November 2025 were queried for pathology-confirmed meningiomas below the foramen magnum, with preoperative contrast-enhanced imaging available for segmentation. SMs were classified as low-grade (WHO grade 1) and high-grade (WHO grade 2 tumors and grade 1 tumors with atypia). Tumors were manually segmented, and features were extracted using the PyRadiomics software package. An ensemble model of k-nearest neighbors, random forest, and support vector machine classifiers was trained using nested cross-validation on a subset of 10 features to differentiate tumor grades. Clinical data for the cohort were also extracted, and disease control in an adjunctive clinical series was assessed. RESULTS:Seventy-four patients were included in radiomics analysis, with an area under the receiver operating characteristic curve of 0.879 and a mean F1 score of 0.748. The model's top 5 features were all texture features that differed significantly (p < 0.05) across low- and high-grade SMs. These included measures of tumor textural and contrast-enhancement heterogeneity, with overlap with features reported in radiomics models for histological grading of intracranial meningiomas. Fifty-five patients with a median radiographic follow-up of 22.2 (range 1.9-86.4) months remained for clinical analysis after exclusion of patients with less than 1 month of follow-up and syndromic meningiomas. Four recurrences occurred at a median of 20.8 (range 1.8-41.8) months. High-grade tumor pathology did not significantly impact progression-free survival (p = 0.682, log-rank test; Cox regression high vs low grade hazard ratio [HR] 0.62, 95% CI 0.06-6.11, p = 0.685). Subtotal resection was associated with poorer progression-free survival than gross-total resection (p = 0.004, log-rank test; Cox regression subtotal vs gross-total resection HR 10.62, 95% CI 1.46-77.05, p = 0.019). These findings remain contextualized within a relatively limited follow-up window and small recurrence event count, suggesting a need to characterize the interplay between tumor grade and extent of resection as drivers of local disease control in SMs. CONCLUSIONS:A preoperative radiomics model can stratify high-grade SMs using open-source tools applied to single-institution data.

BACKGROUND:Leptomeningeal disease (LMD) from solid tumors carries poor prognosis and substantial neurologic morbidity. Radiotherapy is used for palliation and disease control, but outcomes across whole-brain radiotherapy (WBRT), photon craniospinal irradiation (CSI), and proton CSI remain incompletely defined. METHODS:We conducted a PRISMA-based systematic review of PubMed-indexed studies reporting radiotherapy outcomes for adult solid-tumor LMD. Studies were categorized as photon WBRT/non-CSI, photon CSI, or proton CSI. Primary outcomes were median overall survival (OS) and progression-free survival (PFS), including CNS-PFS or intracranial PFS when reported. Grade ≥ 3 hematologic and non-hematologic toxicities were extracted when available. RESULTS:Thirty-two unique studies/reports were included: 21 photon WBRT/non-CSI, 6 photon CSI, and 6 proton CSI studies. The median of reported median OS values were 4.5 months for photon WBRT/non-CSI, 4.1 months for photon CSI, and 10.7 months for proton CSI. Median PFS was 3.9 months for photon WBRT/non-CSI and 4.6 months for proton CSI; no extractable median PFS was available for photon CSI. Among studies with extractable denominators, crude pooled grade ≥ 3 hematologic toxicity was 2.8% for photon WBRT/non-CSI, 80.0% for photon CSI, and 59.4% for proton CSI; however, toxicity reporting was limited and heterogeneous. CONCLUSION/CONCLUSIONS:Proton CSI cohorts had numerically longer reported survival, but cross-study comparisons are limited by heterogeneity, treatment-era and selection differences, and systemic therapy exposure. These findings do not establish superiority over photon CSI and warrant prospective comparative evaluation.

BACKGROUND AND OBJECTIVES/OBJECTIVE:Intradural extramedullary spinal tumors (IDEMs) are ideally managed with gross total resection (GTR) for optimal local disease control in the absence of established adjuvant regimens. In this retrospective cohort study, we investigated the utility of morphology-based analysis of optimal IDEM resection quality compared with current linear measurement benchmarks. METHODS:Tumors were manually segmented from preoperative contrast-enhanced MRI. Morphological features of sphericity, elongation, and volume were extracted from masks, along with manual anteroposterior, craniocaudal, and transverse linear measurements. Optimal resection was defined as Simpson Grade 1 or 2 for meningiomas or en bloc GTR for myxopapillary ependymomas (MPEs) and was predicted for dorsal and ventral spinal meningiomas plus conus and nonconus MPEs. RESULTS:We identified 103 tumors, including 71 meningiomas and 32 MPEs. Linear measurement did not reliably predict optimal resection across anatomic subtypes of meningiomas or MPEs (all P > .05). Instead, optimal resection was determined by higher sphericity across meningiomas and, specifically, dorsal meningiomas (optimal resection median 0.80 (IQR: 0.77-0.82) vs suboptimal 0.76 (0.72-0.77), P = .027). Shape features were not predictive in ventral meningiomas. En bloc GTR was limited to nonconus MPEs, in which sphericity again emerged as a predictor (0.74 (0.69-0.77) for en bloc vs 0.68 (0.64-0.72) for piecemeal, P = .047), likely reflecting resectability for encapsulated tumors. After excluding patients with <1 year of surveillance to determine nonrecurrence, 62 patients without genetic syndromes remained for recurrence analysis with a median follow-up of 36.1 months. Optimal resection was associated with significantly lower recurrence (optimal 8.6% vs suboptimal 29.6%, P = .045). This protective effect remained, although statistically insignificant after adjusting for adjuvant radiation and tumor grade (recurrence odds ratio = 0.22, 95% CI: 0.04-1.07, P = .077). CONCLUSION/CONCLUSIONS:IDEM tumor morphology is predictive of optimal resection for dorsal meningiomas and nonconus MPEs, whereas linear measurements offer less consistent predictive value. Morphological assessment is feasible with standard MRI and may be further automated.

OBJECTIVE:Patients with stage IV non-small cell lung cancer (NSCLC) often present with substantial symptom burden that impairs quality of life and tolerance of systemic therapy. Quad Shot (QS), a cyclical hypofractionated radiotherapy (RT) regimen, could provide effective symptom palliation while allowing concurrent systemic therapy. We evaluated the safety, feasibility, and patient-reported outcomes (PROs) of delivering up to three cycles of QS concurrently with systemic therapy. METHODS:This prospective phase I dose-escalation trial enrolled patients with stage IV NSCLC from June 2020 to February 2024. Allowable systemic therapy included immunotherapy alone, immunotherapy plus chemotherapy, or chemotherapy alone at the treating medical oncologist's discretion. Each QS cycle consisted of 14.8 Gy in 4 fractions delivered twice daily over 2 consecutive days within 1 week of systemic therapy. The primary endpoint was to determine the maximum tolerated number of QS cycles (MTD) using a modified 3+3 design, defined as a dose-limiting toxicity (DLT) rate ≤17% (1 of 6 patients). Secondary endpoints included feasibility, systemic therapy disruptions, RT-related toxicities, and PROs. RESULTS:Forty-five patients were enrolled in this study. One DLT occurred in the two-cycle cohort, and none occurred with three cycles, establishing three cycles as the MTD. In the expansion cohort, three patients developed grade 3 RT-related toxicities. All systemic therapies were administered without any interruptions. Among symptomatic patients, PROs demonstrated improvement in dyspnea (67%), cough (62%), and hemoptysis (100%). CONCLUSIONS:Three cycles of QS were associated with limited high-grade toxicities, no disruption of systemic therapy, and high rates of patient-reported symptom improvement, supporting its use as a palliative option within multidisciplinary care for advanced NSCLC.

BACKGROUND AND OBJECTIVES/OBJECTIVE:Myxopapillary ependymomas (MPE) and intradural lumbosacral schwannomas may be challenging to distinguish based on presenting characteristics and preoperative imaging. Accurate differentiation is crucial, as MPEs carry a risk of cerebrospinal fluid dissemination and warrant earlier intervention, a more tailored surgical strategy, consideration for adjuvant radiation, and frequent surveillance. Here, we describe our institutional experience with these tumors and develop a radiomics-based machine learning model to help distinguish them on preoperative imaging. METHODS:Institutional surgical records from 2011 to 2025 were queried and clinical data were extracted for the retrospective cohort analysis. Tumors were manually segmented in ITK-Snap from T1 postcontrast images, and radiomics features were extracted using the PyRadiomics package. An ensemble of random forest, k-nearest neighbors, and naive Bayes classifiers was trained on a subset of radiomics features using nested cross-validation. RESULTS:< .001) in MPEs, likely due to longitudinal tumor growth along the filum. Excluding scoliotic patients did not significantly alter discrimination, suggesting robustness to vertebral column malalignment that may coexist with intradural tumors. CONCLUSION/CONCLUSIONS:A radiomics-based machine learning model demonstrated excellent discriminative ability between MPE and lumbosacral schwannoma, achieving high accuracy and robustness to vertebral alignment variations. These results suggest that radiomics-based models may be developed into a useful tool for preoperative planning and patient counseling.

BACKGROUND:Surgical stabilization followed by postoperative radiotherapy (RT) is the standard of care for impending pathologic fractures due to bone metastases. Compared with conventional RT, stereotactic body RT (SBRT) provides more durable tumor control and palliation, but treatment volume constraints often preclude postoperative use. Preoperative SBRT limited to the tumor volume offers a solution by delivering an ablative dose before intraoperative tumor dissemination, but its safety is not established. METHODS:We conducted a phase I, nonrandomized clinical trial at a quaternary care cancer center, with accrual between June 2021 and April 2024. Eligible patients (N=38) had pelvic or long bone metastases with impending pathologic fractures requiring surgical stabilization. Patients received preoperative SBRT (27-30 Gy in 3 fractions or 18-24 Gy in 1 fraction) followed by surgical stabilization within 1 week. The primary endpoint was rate of wound complications within 6 weeks after preoperative SBRT and surgical stabilization. Secondary endpoints were rates of tumor recurrence and grade ≥3 treatment-related toxicities within 1 year. RESULTS:A total of 7 patients were excluded due to inability to receive treatment or death prior to the primary endpoint. Thirty-one patients were evaluated at 6 weeks postoperatively, 26 at 3 months, and 16 at 1 year. The median age was 66 years (IQR, 59-71), and 15 (48%) patients were male. At 6 weeks, 2 of 31 patients (6.5%; 95% CI, 0.79-21.4) experienced wound complications. At 3 months, 1 of 26 patients (3.8%; 95% CI, 0.10-19.6) experienced grade ≥3 treatment-related toxicity. At 12 months, 1 of 16 patients (6.3%; 95% CI, 0.16-30.2) had tumor recurrence. CONCLUSIONS:Preoperative SBRT is associated with a low risk of wound complications and durable local tumor control. A randomized controlled trial examining its efficacy, potential to facilitate less invasive surgery, and impact on functional outcomes is warranted. CLINICALTRIALS/RESULTS:gov identifier: NCT05038124.

Leptomeningeal disease (LMD) or leptomeningeal metastases (LM) occurs when tumor cells invade the leptomeningeal and cerebrospinal fluid (CSF) space. Melanoma is the most common cancer causing LMD (M-LMD). Its biology and pathophysiology are very poorly understood. Research efforts are being made to explore the mechanisms underlying the immune landscape and antitumor response in LMD. The significant advances in immunocellular and targeted therapies in unresectable or metastatic melanoma in the last decade have not translated to patients with LMD and the prognosis for these patients remains dismal. While several reviews in LMD have provided an overview including challenges in diagnosis and treatment, herein we highlight evidence-based findings with a focus on immunocellular and radiation therapies, as well as the challenges that we need to overcome to help breach the existing gap in research and treatments in M-LMD. This could potentially guide additional research avenues and a better understanding of the needs and challenges of M-LMD to find novel therapies and improve patient survival.

PURPOSE/OBJECTIVE:Growing evidence supports stereotactic body radiation therapy (SBRT) over conventional radiation therapy for spine bone metastases, with an expanding role in non-spine bone metastases (NSBM). Our case-based review aims to inform radiation oncologists in the appropriate utilization of SBRT for representative cases of NSBM. METHODS AND MATERIALS/METHODS:Three cases were selected for discussion: (1) rib, (2) skull base, and (3) femur. Relevant literature was reviewed, and areas for future investigation were discussed. RESULTS:SBRT can be effectively delivered in NSBM with appropriate patient selection, target volume delineation, prescription dose, organs at risk dose constraints, and treatment planning. CONCLUSIONS:The Radiosurgery Society's case-based review offers guidance on the appropriate use of SBRT in NSBM with discussions and consensus recommendations from experts. SBRT can be considered for an oligometastatic patient with favorable prognosis in whom the goal is durable local control and/or symptom relief. It can be considered for radioresistant histologies and improved OAR sparing. Available MRI or PET/CT should be fused to improve target volume delineation. A CTV margin, generally of 5 mm, should be considered to cover microscopic disease. As bones are easily visualized on daily images acquired for accurate and precise set-up of patients, a PTV margin should be kept less than or equal to 3 mm. While SBRT can be delivered in 1 fraction, fractionated SBRT may be preferred to meet dose constraints when the CTV is adjacent to the OARs. NSBM of long bones that are weight bearing, lytic, or have a high MIRELS score should be evaluated by an orthopedic surgeon.