UCLA Department of Radiation Oncology

PURPOSE: Fibroblast Activation Protein (FAP) is an emerging theranostic target that is highly expressed on cancer-associated fibroblasts and on certain tumor cells including sarcoma. We investigated the anti-tumor efficacy of [225Ac]Ac-FAPI-46 as monotherapy or in combination with immune checkpoint blockade (ICB) in immunocompetent murine models of sarcoma sensitive or resistant to ICB. METHODS: [68Ga]Ga- and [225Ac]Ac-FAPI-46 were tested in subcutaneous FAP+ FSA fibrosarcoma bearing C3H/Sed/Kam mice. The efficacy of up to three cycles of 60 kBq [225Ac]Ac-FAPI-46 was evaluated as monotherapy and in combination with an anti-PD-1 antibody. Efficacy of [225Ac]Ac-FAPI-46 and/or ICB was further compared in FAP-overexpressing FSA (FSA-F) tumors that were sensitive to ICB or rendered ICB-resistant by tumor-induction in the presence of Abatacept. RESULTS: [225Ac]Ac-FAPI-46 was well tolerated up to 3 × 60 kBq but had minimal effect on FSA tumor growth. The combination of three cycles [225Ac]Ac-FAPI-46 and ICB resulted in growth delay in 55% of mice (6/11) and partial tumor regression in 18% (2/11) of mice. In FSA-F tumors with FAP overexpression, both [225Ac]Ac-FAPI-46 and ICB were effective without additional benefits from the combination. In locally immunosuppressed and ICB resistant FAP-F tumors, however, [225Ac]Ac-FAPI-46 restored responsiveness to ICB, resulting in significant tumor regression and tumor-free survival of 56% of mice in the combination group up to 60 days post treatment. CONCLUSION: [225Ac]Ac-FAPI-46 efficacy is correlated with tumoral FAP expression levels and can restore responsiveness to PD-1 ICB. These data illustrate that careful patient selection based on target expression and rationally designed combination therapies are critically important to maximize the therapeutic impact of FAP-targeting radioligands.

Cone beam computed tomography (CBCT) is a widely available modality, but its clinical utility has been limited by low detail conspicuity and quantitative accuracy. Convenient post-reconstruction denoising is subject to back projected patterned residual, but joint denoise-reconstruction is typically computationally expensive and complex. In this study, we develop and evaluate a novel Metric-learning guided wavelet transform reconstruction (MEGATRON) approach to enhance image domain quality with projection-domain processing. Projection domain based processing has the benefit of being simple, efficient, and compatible with various reconstruction toolkit and vendor platforms. However, they also typically show inferior performance in the final reconstructed image, because the denoising goals in projection and image domains do not necessarily align. Motivated by these observations, this work aims to translate the demand for quality enhancement from the quantitative image domain to the more easily operable projection domain. Specifically, the proposed paradigm consists of a metric learning module and a denoising network module. Via metric learning, enhancement objectives on the wavelet encoded sinogram domain data are defined to reflect post-reconstruction image discrepancy. The denoising network maps measured cone-beam projection to its enhanced version, driven by the learnt objective. In doing so, the denoiser operates in the convenient sinogram to sinogram fashion but reflects improvement in reconstructed image as the final goal. Implementation-wise, metric learning was formalized as optimizing the weighted fitting of wavelet subbands, and a res-Unet, which is a Unet structure with residual blocks, was used for denoising. To access quantitative reference, cone-beam projections were simulated using the X-ray based Cancer Imaging Simulation Toolkit (XCIST). In both learning modules, a data set of 123 human thoraxes, which was from Open-Source Imaging Consortium (OSIC) Pulmonary Fibrosis Progression challenge, was used. Reconstructed CBCT thoracic images were compared against ground truth FB and performance was assessed in root mean square error (RMSE), peak signal-to-noise ratio (PSNR), and structural similarity index (SSIM). MEGATRON achieved RMSE in HU value, PSNR, and SSIM were 30.97 ± 4.25, 37.45 ± 1.78, and 93.23 ± 1.62, respectively. These values are on par with reported results from sophisticated physics-driven CBCT enhancement, demonstrating promise and utility of the proposed MEGATRON method. We have demonstrated that incorporating the proposed metric learning into sinogram denoising introduces awareness of reconstruction goal and improves final quantitative performance. The proposed approach is compatible with a wide range of denoiser network structures and reconstruction modules, to suit customized need or further improve performance.

BACKGROUND: Epidermoid cysts (ECs) are rare, benign lesions which comprise less than 1 % of all spinal tumors. Calcification of spinal ECs is rare, and EC ossification within the lumbar spine has never been documented. We report the only known congenital lumbar epidermoid tumor with ossification and a literature review of intradural lumbar ECs. METHODS: Studies meeting the following criteria were included: 1) EC as the primary tumor type, 2) intradural location, 3) involvement of the lumbar spinal level, and 4) primary presentation. Studies lacking individual patient data or published in a non-English language were excluded. RESULTS: A total of 172 studies were reviewed and 43 were included in analysis. Of the 83 total patients, 37 (45.1 %) were male and 45 (54.9 %) female, at an average age of 26 years. The L3 and L4 spinal levels were most frequently involved. Acquired etiology was reported in 49 (59.0 %) patients, and 24 (28.9 %) cases were congenital. Multivariate analyses demonstrated trends between decreased age and improved outcome, decreased delay in diagnosis and improved outcome, and increased extent of resection with reduced recurrence. Nine calcified spinal ECs were identified, with no previous report of EC ossification in the lumbar spine. CONCLUSION: We present a case report of the only known ossified epidermoid tumor of the lumbar spine and a comprehensive literature review of 83 patients with intradural lumbar ECs. This review demonstrated trends between reduced age and improved outcome, reduced delay in diagnosis and improved outcome, and increased extent of resection with reduced recurrence.

BACKGROUND: We evaluated sociodemographic and clinical predictors of financial toxicity (FT) among patients with breast cancer with higher risk clinical factors warranting regional nodal irradiation (RNI). METHODS: Among 183 participants in a clinical trial of conventional vs. hypofractionated treatment with RNI, 125 (68 %) completed a pilot survey of FT measured using the validated Economic Strain and Resilience in Cancer (ENRICh) instrument, scored from 0 (minimal) to 10 (severe) FT. Associations with predictors were evaluated using Pearson correlation coefficients and Kruskal Wallis, Mann-Whitney U, and Jonckheere-Terpstra tests. Predictors of severe FT (ENRICh≥5) were tested using multivariable logistic regression with odds ratios converted to relative risks (RR). RESULTS: Of the sample, all received RNI, 92 % chemotherapy, 67 % axillary dissection, 26 % mastectomy without reconstruction, and 32 % mastectomy with reconstruction. At a median follow up of 1.48 years, median FT score was 2.13 (IQR 0.93-4.6), with 20.8 % of patients experiencing severe FT. Unadjusted worse FT score was associated with younger age (P = 0.003), Hispanic ethnicity (P = 0.006), lower income (P = 0.02), shorter interval from diagnosis to FT assessment (P = 0.02), and chemotherapy receipt (P = 0.05), but not with breast surgery type (P = 0.42), axillary surgery type (P = 0.33), or pathologic T (P = 0.68) or N stage (P = 0.47). In multivariable analysis, triple negative subtype was the sole clinical factor predicting severe FT (RR = 3.38; 95 % CI 1.48-4.99; P = 0.01). CONCLUSION: Among patients with breast cancer receiving RNI, triple negative subtype was associated with severe FT, suggesting that tumor receptor subtype may help identify a key breast cancer subpopulation for early FT intervention.

BACKGROUND: Sympathetic-mediated vasoconstriction from the superior cervical ganglion (SCG) is a significant contributor to cerebral vasospasm. Inhibition of the SCG has been shown to improve cerebral blood flow and reverse cerebral vasospasm in swine models. We evaluated the efficacy of a novel minimally invasive endovascular approach to target and pharmacologically inhibit the SCG, using a Micro-Infusion Device for transmural drug delivery. METHODS: Eight SCGs in four Yorkshire swine were surgically identified. After confirming appropriate sympathetic-mediated intracranial vasoconstriction response with SCG stimulation, an endovascular Micro-Infusion Device was used for transmural targeting of the SCG and delivery of 1.5-2 mL of 1% lidocaine-contrast mixture to the perivascular space. Digital subtraction angiography was obtained at: (1) baseline; (2) with SCG stimulation; and (3) after lidocaine delivery to the SCG using the Micro-Infusion Device with concurrent SCG stimulation. Vessel diameters were measured and compared. RESULTS: Endovascular transmural delivery of lidocaine to the SCG and carotid perivascular tissue using the Micro-Infusion Device successfully inhibited sympathetic-mediated vasoconstriction response. Measured vessel diameters after lidocaine delivery were comparable to baseline despite SCG stimulation. CONCLUSION: A novel endovascular technique of transmural delivery of lidocaine to the SCG and carotid artery perivascular tissues successfully inhibits the sympathetic input to the cerebral vasculature and modulates sympathetic-mediated cerebral vasospasm. These results suggest promising steps towards translation to potential clinical use for patients suffering from cerebral vasospasm.

Glioblastoma (GBM) is the most common malignant primary brain tumor and remains incurable. Previous work has shown that systemic administration of Decitabine (DAC) induces sufficient expression of cancer-testis antigens (CTA) in GBM for targeting by adoptive T-cell therapy in vivo. However, the mechanisms by which DAC enhances immunogenicity in GBM remain to be elucidated. Using New York esophageal squamous cell carcinoma 1 (NY-ESO-1) as a representative inducible CTA, we demonstrate in patient tissue, immortalized glioma cells, and primary patient-derived gliomaspheres that basal CTA expression is restricted by promoter hypermethylation in gliomas. DAC treatment of glioma cells specifically inhibits DNA methylation silencing to render NY-ESO-1 and other CTA into inducible tumor antigens at single-cell resolution. Functionally, NY-ESO-1 T-cell receptor-engineered effector cell targeting of DAC-induced antigen in primary glioma cells promotes specific and polyfunctional T-cell cytokine profiles. In addition to induction of CTA, DAC concomitantly reactivates tumor-intrinsic human endogenous retroviruses, interferon response signatures, and MHC-I. Overall, we demonstrate that DAC induces targetable tumor antigen and enhances T-cell functionality against GBM, ultimately contributing to the improvement of targeted immune therapies in glioma.

Significance

Chest wall pain syndromes can emerge following local therapies for lung cancer and can adversely affect patients quality-of-life. This can occur after lung surgery, radiation therapy, or percutaneous image-guided thermal ablation. This review describes the multifactorial pathophysiology of chest wall pain syndromes that develop following surgical and non-surgical local therapies for lung cancer and summarizes evidence-based management strategies for inflammatory, neuropathic, myofascial, and osseous pain. It discusses a step-wise approach to treating chest wall pain that begins with non-opioid oral analgesics and includes additional pharmacologic treatments as clinically indicated, such as anticonvulsants, serotonin and norepinephrine reuptake inhibitors, tricyclic antidepressants, and various topical treatments. For myofascial pain, physical medicine techniques, such as acupuncture, trigger point injections, deep tissue massage, and intercostal myofascial release can also offer pain relief. For severe or refractory cases, opioid analgesics, intercostal nerve blocks, or intercostal nerve ablations may be indicated. Fortunately, palliation of treatment-related chest wall pain syndromes can be managed by most clinical providers, regardless of the type of local therapy utilized for a patients lung cancer treatment. In cases where a patients pain fails to respond to initial medical management, clinicians can consider referring to a pain specialist who can tailor a more specific pharmacologic approach or perform a procedural intervention to relieve pain.

Glioblastoma (GBM) is the deadliest adult brain cancer. Under the current standard of care, almost all patients succumb to the disease and novel treatments are urgently needed. Recognizing that GBMs are addicted to cholesterol, past clinical trials have repurposed statins against GBM but failed. The purpose of this study was to test whether treatments that upregulate the cholesterol biosynthesis pathway in GBM would generate a metabolic vulnerability that can be exploited using statins and to determine the underlying mechanisms.Effects of radiotherapy and temozolomide or dopamine receptor antagonists on the mevalonate pathway in GBM were assessed in vitro and in vivo. The impact of statins on self-renewal of glioma stem cells and median survival was studied. Branches of the mevalonate pathway were probed to identify relevant effector proteins.Cells surviving combination treatments that converge in activating the immediate early response, universally upregulated the mevalonate pathway and increased stemness of GBM cells through activation of the Rho-GTPase Rac-1. Activation of the mevalonate pathway and Rac-1 was inhibited by statins, which led to improved survival in mouse models of glioblastoma when combined with radiation and drugs that target the glioma stem cell pool and plasticity of glioma cells.We conclude that a combination of dopamine receptor antagonists and statins could potentially improve radiotherapy outcome and warrants further investigation.

Significance

Although primary studies have reported the safety and efficacy of LITT as a primary treatment in glioma, they are limited by sample sizes and institutional variation in stereotactic parameters such as temperature and laser power. The current literature has yet to provide pooled statistics on outcomes solely for primary brain tumors according to the 2021 WHO Classification of Tumors of the Central Nervous System (WHO CNS5). In the present study, we identify recent articles on primary CNS neoplasms treated with LITT without prior intervention, focusing on relationships with molecular profile, PFS, and OS. This meta-analysis includes the extraction of data from primary sources across four databases using the Covidence systematic review manager. The pooled data suggest LITT may be a safe primary management option with tumor ablation rates of 94.8% and 84.6% in IDH-wildtype glioblastoma multiforme (GBM) and IDH-mutant astrocytoma, respectively. For IDH-wildtype GBM, the pooled PFS and OS were 5.0 and 9.0 months, respectively. Similar to rates reported in the prior literature, the neurologic and non-neurologic complication rates for IDH-wildtype GBM were 10.3% and 4.8%, respectively. The neurologic and non-neurologic complication rates were somewhat higher in the IDH-mutant astrocytoma cohort at 33% and 8.3%, likely due to a smaller cohort size.

Glioblastoma is a highly aggressive neoplasm and the most common primary malignant brain tumor. Endothelial tissue plays a critical role in glioblastoma growth and progression, facilitating angiogenesis, cellular communication, and tumorigenesis. In this review, we present an up-to-date and comprehensive summary of the role of endothelial cells in glioblastomas, along with an overview of recent developments in glioblastoma therapies and tumor endothelial marker identification.