Scott G. Soltys

Background: Leptomeningeal disease (LMD) is a devastating complication of metastatic breast cancer that leads to severe neurologic symptoms and poor prognosis. Current treatment options, including radiation and intrathecal chemotherapy, offer limited efficacy and are associated with significant toxicity. Generally, systemic therapy in LMD poorly penetrates the blood-brain barrier (BBB). Leveraging the L-type amino acid transporter 1 (LAT1) represents a unique therapeutic strategy, as LAT1 facilitates transport of medications across the BBB, and is also highly expressed in metastatic cancer cells. QBS72S is a first-in-class BBB-penetrant bifunctional molecule targeting overexpression of LAT1 to selectively eliminate cancer cells. It has shown preclinical efficacy in a mouse model of breast cancer LMD. Methods: This Phase 2a, single-arm, open-label clinical trial (NCT05305365) investigated the safety, cerebrospinal fluid (CSF) concentration, pharmacokinetics, and preliminary efficacy of QBS72S in participants with breast cancer brain metastases. Secondary endpoints included progression-free survival, overall survival, and duration of response. Correlative analyses included LAT1 immunohistochemistry and CSF cell-free RNA sequencing. Results: In this analysis, we report results from breast cancer participants with LMD (n = 10) treated with QBS72S. QBS72S was reliably detected in CSF, adequately tolerated, and two participants exhibited long-term radiographic stability or improvement lasting 6-7 months. Conclusions: These early findings support further investigation of QBS72S as a targeted therapy for LMD, addressing an urgent unmet need in metastatic breast cancer.

Malignant melanotic nerve sheath tumors (MMNSTs) are rare tumors with uncertain clinical behavior. Standard treatment includes surgical resection; however, the potential benefit of adjuvant radiotherapy remains unclear. We present four patients with MMNSTs who were treated with stereotactic radiosurgery following either partial or gross total resection. The series included two females and two males, ranging in age from 18 to 72 years, with tumors located in the spine or intracranially. At follow-up intervals of 1.6, 1.8, 3.5, and 6.0 years after radiosurgery, all tumors remained controlled, with radiographic stability and no evidence of metastatic disease.

Background: Brain metastasis (BM) occurs in < 3% of malignant mesothelioma (MM) cases and is associated with an aggressive disease course. While genomic profiling has provided insight into molecular alterations in MM, the characteristics of MM with brain involvement remain unexplored. Data are particularly limited for MM of pericardial origin, an exceedingly rare tumor which comprises < 1% of mesotheliomas. Cases: We describe the clinical course and genetic profiles of two patients with BM from MM, both of whom exhibited atypical presentations, including neurological symptoms, diagnosis at extremes of age for this condition, and absence of prior asbestos exposure. In Case 1, a 20–25‐year‐old male with pericardial MM presented for left arm shaking, with brain MRI at this time revealing 14 total lesions, 85.7% of which had vasogenic edema. He underwent whole‐brain radiotherapy (WBRT), passing away 21.25 months following initial diagnosis. In Case 2, an 85–90‐year‐old male reported expressive aphasia and was found to have a large hemorrhagic frontotemporal lesion. He was subsequently diagnosed with pleural MM and received stereotactic radiosurgery (SRS) for management of BM, with a favorable treatment response on follow‐up imaging. He succumbed to systemic progression 6 months after diagnosis of BM. Next‐generation sequencing identified a missense mutation in RAD51C in Case 1, and NF2 splice‐site and TP53 frameshift mutations in Case 2. Conclusion: To our knowledge, this represents the first reported genetic profiling of MM with BM. The TP53 frameshift mutation is unusual for MM, and its potential association with rapid disease progression warrants further investigation. Given the aggressive nature of MM, SRS may be preferable to WBRT due to its shorter treatment time and ease of combination with systemic regimens.

Accurate detection and segmentation of multiple brain metastases (BMs) on magnetic resonance image remain challenging, particularly for those involving small lesions (longest axis length <3 mm), due to limitations in sensitivity, precision, and feature representation in existing deep learning frameworks. To address this challenge, we develop TLC-nnUNet, a novel integration of two advancements into transformer-enhanced nnU-Net (T-nnUNet) architecture: (1) local region perceptron (LRP), a loss constraint prioritizing small BM detection by up-weighting underrepresented voxels; and (2) contrastive learning pretraining (CLP), a supervised model pre-training strategy to amplify latent-space divergence between BM and non-BM regions, reducing false positives (FPs). The developed TLC-nnUNet is trained and evaluated on a multi-institutional dataset and achieves state-of-the-art performance, with 89.70% sensitivity, 97.34% precision, and a Dice coefficient of 0.92 at patient level. Further ablation studies confirm the synergistic contributions of each component: LRP enhances small BM detection, while CLP refines feature contrast, reducing FPs. Visualization via t-distributed stochastic neighbor embedding underscores CLP’s role in disentangling BM and non-BM latent representations. Compared to existing methods, TLC-nnUNet demonstrates consistent accuracy of detection and segmentation cross lesion sizes. This framework holds significant promise for clinical workflows, enabling precise BM detection and segmentation in stereotactic radiosurgery and reducing manual contouring time.

BACKGROUND AND OBJECTIVES: Occipital condyle metastasis (OCM) is a rare condition characterized by severe occipital pain and neurological symptoms due to lower cranial nerve (CN) deficits, stemming from its anatomic location. Despite the widespread use of stereotactic radiosurgery (SRS) for cranial metastases, its specific impact on OCM remains underexplored. This study evaluates the efficacy and safety of CyberKnife SRS in treating OCM, focusing on occipital pain, dysfunctions of lower CNs, and local tumor control. METHODS: We retrospectively analyzed cases of OCM treated with SRS at our institute from 2012 to 2023, evaluating patient demographics, presenting symptoms, treatment parameters, and outcomes. RESULTS: Eighteen patients (10 females) with a mean age of 64 years (SD: 10.4) were treated. Common presentations included occipital pain (44.4%) and lower CN deficits (27.8%). The median target volume was 6.95 cc (IQR: 4.64-21.2). The mean single-fraction equivalent dose was 18.7 Gy₁₀ (SD: 1.9). Ten tumors received 15-20 Gy in 1 fraction (50%), 2 tumors received 20-28 Gy in 2 fractions (10%), 4 tumors received 27 Gy in 3 fractions (20%), and 4 tumors received 30-40 Gy in 5 fractions (20%). Based on Kaplan-Meier estimate, SRS achieved 93.8% local tumor control rate over 3 years, with a median overall survival of 13 months (95% CI: 0-32.2). Among patients presenting with symptoms, 87.5% reported occipital pain relief (P = .04), and 80% observed improvements in CN function (P = .003). Four patients experienced local recurrence. CONCLUSION: CyberKnife SRS is a promising treatment of OCM, offering significant pain relief and improvement in neurological symptoms, along with favorable local control rates. This noninvasive therapy provides a valuable alternative to surgery, potentially enhancing the quality of life for patients with limited treatment options due to this challenging condition.

Purpose We report outcomes of repeat stereotactic radiosurgery (rSRS) to sites of tumor progression following initial SRS. Additionally, we sought to determine if, at the time of recurrence following initial SRS, surgical resection of the tumor followed by SRS (surgery + rSRS) provided benefit compared to rSRS alone. Methods We retrospectively reviewed patients treated with rSRS for local recurrence after initial SRS. The cumulative incidences of LF and adverse radiation effect (ARE), with death as a competing risk, were estimated. Results From 2004 to 2022, we identified 77 patients with 429 brain metastases treated with initial SRS, of which 97 metastases were treated with rSRS for salvage of LF following initial SRS; 49 metastases had resection prior to rSRS. Of the 429 brain metastases treated with initial SRS, the cumulative incidence of LF was 12.6% [95% confidence interval (CI) 9.7–15.9] at 1 year; in 97 sites treated with rSRS, LF was 14.6% (95%CI 8.4–22.4) at 1 year. There was no significant difference (p = 0.3) in 1-year LF after surgery + rSRS [11.1% (95%CI 4.0–22.31)] versus rSRS alone [18.4% (95%CI 9.0–30.5)]. The 1-year rates of ARE were: 3.0% (95%CI 1.7–5.0%) for initial SRS (overall grade 1–4), 15.6% (95%CI 9.2–23.6) for rSRS (overall grade 1–4), and 12.6% (95%CI 6.8–20.1%) for rSRS (symptomatic grade 2–4). Conclusion Given that the 1-year local progression of 15% with rSRS is similar to the 13% of initial SRS, our data do not support that tumors recurrent after initial SRS are inherently radioresistant to salvage SRS. Tumor control must be balanced by the 1-year rates of adverse radiation effect (16% overall, 13% symptomatic).

Stereotactic radiosurgery (SRS) deploys image-guidance to deliver multiple beams of highly focused ionizing radiation to tightly conformed anatomical targets, leading to precise dosing of radiation-induced cellular injury and predictable biological responses that can be applied to treat a multitude of central nervous system (CNS) disorders. Herein we review the principles of CNS radiobiology, comparing differences between SRS and conventional radiation therapy. We then review the radiobiology of SRS as it pertains to the treatment of CNS tumors and vascular malformations and the emerging application of SRS for the treatment of functional and psychiatric neurological disorders. Finally, we look toward the future in combining SRS with other novel technologies to improve treatment outcomes for patients with CNS disorders.

Current standard of care treatment for patients with spine tumors includes multidisciplinary approaches, including the following: (1) surgical tumor debulking, epidural spinal cord decompression, and spine stabilization techniques; (2) systemic chemo/targeted therapies; (3) radiation therapy; and (4) surveillance imaging for local disease control and recurrence. Titanium pedicle screw and rod fixation have become commonplace in the spine surgeon’s armamentarium for the stabilization of the spine following tumor resection and separation surgery. However, the high degree of imaging artifacts seen with titanium implants on postoperative CT and MRI scans can significantly hinder the accurate delineation of vertebral anatomy and adjacent neurovascular structures to allow for the safe and effective planning of downstream radiation therapies and detection of disease recurrence. Carbon fiber-reinforced polyetheretherketone (CFR-PEEK) spine implants have emerged as a promising alternative to titanium due to the lack of artifact signals on CT and MRI, allowing for more accurate and safe postoperative radiation planning. In this article, we review the tenants of the surgical and radiation management of spine tumors and discuss the safety, efficacy, and current limitations of CFR-PEEK spine implants in the multidisciplinary management of spine oncology patients.