Publications from the Li Lab
Publications
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KEAP1-mutant atypical meningioma: illustrative case.
Journal of neurosurgery. Case lessons
2024; 8 (11)
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Abstract
While genetic testing of tumors is commonly used to inform the selection of systemic therapies, there is limited evidence for the application of radiotherapy for brain cancer. Recent studies have shown that Kelch-like ECH-associated protein 1 (KEAP1), a key regulator of cellular responses to oxidative and electrophilic stress, is associated with radioresistance in multiple cancer types. Several studies have reported the clinical significance of KEAP1 mutation in brain metastasis; however, the effect of KEAP1 mutations on radioresponse in meningioma has never been reported.The authors present the case of a 40-year-old female with a KEAP1 mutation-positive atypical meningioma that was initially treated with resection followed by intensity-modulated radiation therapy (IMRT). Recurrence was observed at 15 months, requiring reoperation and adjuvant stereotactic radiosurgery (SRS). An excellent treatment response was observed at 7 months post-SRS with an improvement in reported symptoms, although bevacizumab was required for the resolution of radiation necrosis observed 2 months post-SRS.To the authors' knowledge, this is the first report of KEAP1-mutant meningioma, including its clinical course after comprehensive management. Notably, treatment included multimodal radiotherapy with IMRT followed by SRS. SRS led to an excellent treatment response at the 7-month follow-up. However, radiation necrosis developed after both radiotherapy treatments, suggesting that radiological modification can be beneficial in patients with KEAP1 mutations. https://thejns.org/doi/10.3171/CASE24387.
View details for DOI 10.3171/CASE24387
View details for PubMedID 39250830
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The CCR6-CCL20 axis promotes regulatory T cell glycolysis and immunosuppression in tumors.
Cancer immunology research
2024
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Abstract
Regulatory T cells (Tregs) are important players in the tumor microenvironment. However, the mechanisms behind their immunosuppressive effects are poorly understood. We found that CCR6-CCL20 activity in tumor-infiltrating Tregs is associated with greater glycolytic activity and ablation of Ccr6 reduced glycolysis and lactic acid production while increasing compensatory glutamine metabolism. Immunosuppressive activity towards CD8+ T cells was abrogated in Ccr6-/- Tregs due to reduction in activation-induced glycolysis. Furthermore, Ccr6-/- mice exhibited improved survival across multiple tumor models compared to wildtype mice, and Treg and CD8+ T-cell depletion abrogated the improvement. In addition, Ccr6 ablation further promoted the efficacy of anti-PD-1 therapy in a preclinical glioma model. Follow-up knockdown of Ccl20 with siRNA also demonstrated improvement in antitumor efficacy. Our results unveil CCR6 as a marker and regulator of Treg-induced immunosuppression and identify approaches to target the metabolic determinants of Treg immunosuppressive activity.
View details for DOI 10.1158/2326-6066.CIR-24-0230
View details for PubMedID 39133127
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Cross-cultural serious neurological illness communication: qualitative analysis of multidisciplinary perspectives.
Annals of palliative medicine
2024
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Abstract
Cultural competence is important in approaching serious illness communication with diverse patients about goals of care. Culture colors patients' perspectives on many healthcare issues, including end-of-life care, and impacts how clinicians make decisions with patients. Communication about serious neurological illnesses can be additionally challenging due to disease impact on patients' cognition and decision-making abilities. We aim to understand provider experiences regarding cross-cultural serious neurological illness communication with diverse patients and families.Using non-stratified purposive and snowball sampling, we conducted semi-structured interviews with 17 multidisciplinary participants, including neurosurgeons, neurologists, and social workers, who provide care for patients diagnosed with serious neurological disorders, at three hospital settings between 2021 and 2022. We used standard qualitative content analysis methods with dual review.Five themes reflected provider perspectives about serious neurological illness communication with diverse patients and families. Theme 1: providers recognize that patients' personal biases and lived experiences impact attitudes about healthcare and communication. Theme 2: challenges in communication can arise when providers miss chances to identify important cultural values. Theme 3: understanding how to engage with family members is important for effective communication about serious neurological illness. Theme 4: providers want to accommodate patients. Theme 5: cultivating trust builds a strong patientprovider partnership, even when racial or cultural discordance is present.Our study highlights elements of cross-cultural communication and opportunities for providers to approach diverse patients and families within a racial or culturally discordant context. Effective communication, fostered through respecting individual experiences and variation, eliciting cultural perspectives, engaging family, and cultivating trust reflects processes and learned skills required of highquality teams caring for patients with serious neurological conditions.
View details for DOI 10.21037/apm-24-37
View details for PubMedID 39129523
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The cytokine Meteorin-like inhibits anti-tumor CD8+ T cell responses by disrupting mitochondrial function.
Immunity
2024
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Abstract
Tumor-infiltrating lymphocyte (TIL) hypofunction contributes to the progression of advanced cancers and is a frequent target of immunotherapy. Emerging evidence indicates that metabolic insufficiency drives T cell hypofunction during tonic stimulation, but the signals that initiate metabolic reprogramming in this context are largely unknown. Here, we found that Meteorin-like (METRNL), a metabolically active cytokine secreted by immune cells in the tumor microenvironment (TME), induced bioenergetic failure of CD8+ T cells. METRNL was secreted by CD8+ T cells during repeated stimulation and acted via both autocrine and paracrine signaling. Mechanistically, METRNL increased E2F-peroxisome proliferator-activated receptor delta (PPARδ) activity, causing mitochondrial depolarization and decreased oxidative phosphorylation, which triggered a compensatory bioenergetic shift to glycolysis. Metrnl ablation or downregulation improved the metabolic fitness of CD8+ T cells and enhanced tumor control in several tumor models, demonstrating the translational potential of targeting the METRNL-E2F-PPARδ pathway to support bioenergetic fitness of CD8+ TILs.
View details for DOI 10.1016/j.immuni.2024.07.003
View details for PubMedID 39111315
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CyberKnife stereotactic radiosurgery for extramedullary plasmacytoma in the external auditory canal: illustrative case.
Journal of neurosurgery. Case lessons
2024; 7 (19)
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Abstract
Plasmacytoma, a rare plasma cell disorder, often presents as a solitary or multiple tumors within the bone marrow or soft tissues, typically associated with multiple myeloma. Extramedullary plasmacytomas (EMPs), particularly those located in the external auditory canal (EAC), are exceedingly rare and pose significant treatment challenges given their location, anatomical complexity, and high risk of recurrence.The authors report the case of a 72-year-old male with a history of multiple myeloma, presenting with recurrent left EAC plasmacytoma. After initial conventional radiotherapy for the lesion, a recurrence was documented in 7 years. The patient subsequently underwent stereotactic radiosurgery, which proved successful, leading to complete resolution of the lesion without any long-term adverse effects or radiation-related complications over a 45-month period.This case is a unique instance of utilizing stereotactic radiosurgery for recurrent EMP in the EAC, highlighting its potential as an effective approach in managing complex plasmacytomas.
View details for DOI 10.3171/CASE2479
View details for PubMedID 38710109
View details for PubMedCentralID PMC11076403
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Impact of language barriers and use of interpreters on hope among patients with Central Nervous System Malignancies and Bone Metastases.
International journal of radiation oncology, biology, physics
2023
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PURPOSE: Hope is important in serious illnesses, as it has been linked to patient quality of life. We aimed to determine factors associated with lower hope scores among patients with central nervous system (CNS) disease or bone metastases.METHODS: The Adult Dispositional Hope Scale (AHS) is a 12-item questionnaire that measures hope through two qualities: agency (goal-directed energy) and pathways (plan to meet goals). Total scores range from 8 to 64, with higher scores reflecting higher agency and pathways thinking. We prospectively collected scores from patients seen in two radiation oncology clinics at our institution from 10/2022 to 4/2023. The method of least squares to fit general linear models and Pearson's correlation coefficients (PCC) was used to determine relationships between AHS score and socioeconomic and disease factors.RESULTS: Of the 197 patients who responded, median age was 60.5 years (range 16.9-92.5 years), most patients were male (60.9%), white (59.4%), and had malignant disease (59.4%). Median overall AHS score was 54 (range 8-64), and median pathway and agency thinking scores were 27 (range 4-32) and 27 (range 4-32), respectively. Patients who needed an interpreter compared to those who did not had significantly lower overall AHS scores (mean score 45.4 versus 51.2, respectively; p=0.0493) and pathway thinking scores (mean score 21.5 versus 25.7, respectively; p=0.0085), and patients with poorer performance status had significantly worse overall AHS scores (PCC=-0.2703, p=0.0003).CONCLUSION: Patients with CNS disease or bone metastases requiring the use of an interpreter had lower AHS scores, highlighting the possible association of language barriers to hope. Addressing patient language barriers and further studies on the possible association of language barriers to hope may improve hope, quality of life and outcomes among these patients.
View details for DOI 10.1016/j.ijrobp.2023.11.056
View details for PubMedID 38056777
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Advancements without consensus: differing practice patterns highlight unanswered questions in the management of brain metastases from EGFR- and ALK-positive non-small cell lung cancer.
Journal of thoracic disease
2023; 15 (11): 5877-5884
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View details for DOI 10.21037/jtd-23-1483
View details for PubMedID 38090286
View details for PubMedCentralID PMC10713290
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MITOCHONDRIAL ATP BIOGENESIS REGULATED BY VDAC1 IN TMEM119+TUMOR-ASSOCIATED MICROGLIA AND MACROPHAGES MEDIATES HIGH-GRADE GLIOMA GROWTH
OXFORD UNIV PRESS INC. 2023
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View details for Web of Science ID 001115245401315
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Advancements without consensus: differing practice patterns highlight unanswered questions in the management of brain metastases from<i> EGFR-</i> and<i> ALK</i>-positive non-small cell lung cancer
JOURNAL OF THORACIC DISEASE
2023
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View details for DOI 10.21037/jtd-23-1483
View details for Web of Science ID 001096720900001
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Patterns of Progression in Patients with Newly Diagnosed Glioblastoma Treated with 5 mm Margins on a Phase I/II Trial of 5 Fraction Stereotactic Radiosurgery with Concurrent and Adjuvant Temozolomide.
Practical radiation oncology
2023
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Abstract
BACKGROUND: In patients with newly diagnosed glioblastoma (GBM), tumor margins of at least 20 mm are the standard of care. We sought to determine the pattern of tumor progression in patients treated with 5 fraction stereotactic radiosurgery (SRS) with 5 mm margins.METHODS: Thirty adult patients with newly diagnosed GBM were treated with 5 fraction SRS in escalated doses from 25 Gy to 40 Gy with a 5 mm total treatment margin. Progression was scored as 'in-field' if the recurrent tumor was within or contiguous with the 5 mm margin, 'marginal' if between 5 and 20 mm, and 'distant' if entirely occurring greater than 20 mm. As geometric patterns of progression do not reflect the biologic dose received, we calculated the minimum equieffective dose in 2 Gy per day (EQD2) at the site of tumor recurrence. Progression was 'dosimetrically in-field' if covered by a minimum EQD2 of 48 Gy10.RESULTS: From 2010 to 2016, 27 patients had progressed. Progression was in-field in 17 (63%), marginal in 3 (11%) and distant in 7 (26%) patients. In the 3 patients with marginal progression, the minimum EQD2 to recurrent tumor were 48 Gy10, 56 Gy10 (both considered dosimetrically in-field) and 7 Gy10 (i.e., dosimetrically out-of-field). Median overall survival (OS) was 12.1 months for in-field (95%CI 8.9-17.6), 15.1 months (95%CI 10.1-not achieved) for marginal and 21.4 months (95%CI 11.2-33.5) for distant progression. Patients with radiation necrosis were less likely to have in-field progression (1 of 7; 14%) compared to those without radiation necrosis (16 of 20; 80%; p = 0.003); those with necrosis had a median overall survival of 27.2 months (95%CI 11.2-48.3) compared to 11.7 months (95%CI 8.9-17.6) for patients with no necrosis (p = 0.077).CONCLUSION: In patients with newly diagnosed GBM treated with a 5 mm CTV margin, 3 patients (11%) had marginal progression within 5-20 mm; only 1 patient (4%) may have dosimetrically benefitted from conventional 20 mm margins. Radiation necrosis was associated with in-field tumor control.
View details for DOI 10.1016/j.prro.2023.01.008
View details for PubMedID 36736621
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A Protocol for Reducing Intensive Care Utilization After Craniotomy: A 3-Year Assessment.
Neurosurgery
2023
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Abstract
Craniotomy patients have traditionally received intensive care unit (ICU) care postoperatively. Our institution developed the "Non-Intensive CarE" (NICE) protocol to identify craniotomy patients who did not require postoperative ICU care.To determine the longitudinal impact of the NICE protocol on postoperative length of stay (LOS), ICU utilization, readmissions, and complications.In this retrospective cohort study, our institution's electronic medical record was queried to identify craniotomies before protocol deployment (May 2014-May 2018) and after deployment (May 2018-December 2021). The primary end points were average postoperative LOS and ICU utilization; secondary end points included readmissions, reoperation, and postoperative complications rate. End points were compared between pre- and postintervention cohorts.Four thousand eight hundred thirty-seven craniotomies were performed from May 2014 to December 2021 (2302 preprotocol and 2535 postprotocol). Twenty-one percent of postprotocol craniotomies were enrolled in the NICE protocol. After protocol deployment, the overall postoperative LOS decreased from 4.0 to 3.5 days (P = .0031), which was driven by deceased postoperative LOS among protocol patients (average 2.4 days). ICU utilization decreased from 57% of patients to 42% (P < .0001), generating ∼
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Stereotactic radiosurgery for trigeminal neuralgia secondary to tumor: a single-institution retrospective series.
Neurosurgical focus
2022; 53 (5): E3
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Abstract
Trigeminal neuralgia (TN) secondary to tumor represents a rare and diverse entity, and treatment for secondary TN remains controversial. This report reviews a single institution's experience in treating secondary TN with stereotactic radiosurgery (SRS) and focuses on the durability of pain relief with respect to various treatment targets, i.e., the trigeminal nerve, offending tumor, or both.Between the years 2009 and 2021, 21 patients with TN secondary to benign (n = 13) or malignant (n = 8) tumors underwent SRS. Barrow Neurological Institute (BNI) pain intensity scale scores were collected from patient electronic medical records at baseline, initial follow-up, and 1 and 3 years post-SRS. The interval change in BNI scale score (ΔBNI) at the various follow-up time points was also calculated to assess the durability of pain relief following SRS.The median follow-up period was 24 (range 0.5-155) months. Five patients (24%) received treatment to the trigeminal nerve only, 10 (48%) received treatment to the tumor only, and 6 (29%) had treatment to both the nerve and tumor. The overall radiation dosage ranged from 14 to 60 Gy delivered in 1-5 fractions, with a median overall dose of 26 Gy. The median dose to the tumor was 22.5 (range 14-35) Gy, delivered in 1-5 fractions. Of the treatments targeting the tumor, 25% were delivered in a single fraction with doses ranging from 14 to 20 Gy, 60% were delivered in 3 fractions with doses ranging from 18 to 27 Gy, and 15% were delivered in 5 fractions with doses ranging from 25 to 35 Gy. The most common dose regimen for tumor treatment was 24 Gy in 3 fractions. The median biologically effective dose (with an assumed alpha/beta ratio of 10 [BED10]) for tumor treatments was 43.1 (range 13.3-60.0) Gy. There was a significant difference in the proportion of patients with recurrent pain (ΔBNI score ≥ 0) at the time of last follow-up across the differing SRS treatment targets: trigeminal nerve only, tumor only, or both (p = 0.04). At the time of last follow-up, the median ΔBNI score after SRS to the nerve only was -1, 0 after SRS to tumor only, and -2 after SRS to both targets.SRS offers clinical symptomatic benefit to patients with TN secondary to tumor. For optimal pain relief and response durability, treatment targeting both the tumor and the trigeminal nerve appears to be most advantageous.
View details for DOI 10.3171/2022.8.FOCUS22381
View details for PubMedID 36321284
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MRGFUS-DELIVERED FLUORESCENT EGFR/EGFRVIII ANTIBODY ENABLES THERANOSTIC IMAGING OF PEDIATRIC HIGH-GRADE GLIOMA AND PREDICTS RESPONSE TO TARGETED THERAPY
OXFORD UNIV PRESS INC. 2022: 217
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View details for Web of Science ID 000888571001148
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Intracranial Control With Combination BRAF and MEK Inhibitor Therapy in Patients With Metastatic Melanoma.
Cureus
2022; 14 (11): e31838
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Abstract
Purpose/Objectives Combination BRAF (vemurafenib, dabrafenib, or encorafenib) plus MEK (trametinib, cobimetinib, or binimetinib) inhibitor therapy is now widely used in the treatment of metastatic melanoma. However, data for intracranial response to these drugs are limited. We aimed to evaluate the intracranial efficacy of BRAF plus MEK inhibitors in patients with BRAF-mutant melanoma with brain metastases (BM) and to determine patterns of failure of these new agents to inform optimal integration of local intracranial therapy. Materials and methods We retrospectively reviewed charts of patients with BRAF-mutant melanoma with metastasis to the brain with at least one untreated brain metastasis at the time of initiation of BRAF plus MEK inhibitors at our institution from 2006 to 2020. We collected per-patient and per-lesion data on demographics, treatment modality, and outcomes. The cumulative incidence of local (LF), distant intracranial (DF), and extracranial failure (EF) were calculated with competing risk analysis with death as a competing risk and censored at the last brain MRI follow-up. LF was calculated on a per-lesion basis while DF and EF were calculated on a per-patient basis. DF was defined as any new intracranial lesions. Overall survival (OS) was analyzed using Kaplan-Meier. Logistic regression was used to identify predictors for LF. Results We identified 10 patients with 63 untreated brain metastases. The median age was 50.5 years. The median sum of the diameters of the five largest untreated brain metastases per patient was 20 mm (interquartile range 15-39 mm) and the median diameter for all measurable lesions was 4 mm. Median follow-up time was 9.0 months (range 1.4 months-46.2 months). Median OS was 13.6 months. The one-year cumulative incidence of LF, DF, and EF was 17.1%, 88.6, and 71.4%, respectively. The median time to LF, DF, and EF from the start of BRAF plus MEK inhibitors was 9.0 months, 4.7 months, and 7.0 months, respectively. The larger size of the BM was associated with LF on univariate analysis (odds ratio 1.13 per 1 mm increase in diameter, 95% confidence interval 1.019 to 1.308, p<0.02). Two (20%) patients eventually received stereotactic radiosurgery, and 2 (20%) received whole-brain radiotherapy for intracranial progression. Conclusion Although patients with BRAF-mutant melanoma with BM had fair local control on BRAF plus MEK inhibitors, the competing risk of death and distant intracranial and extracranial progression was high. Patients with larger brain metastases may benefit from local therapy.
View details for DOI 10.7759/cureus.31838
View details for PubMedID 36579260
View details for PubMedCentralID PMC9788920
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Local Control of Brain Metastases with Osimertinib Alone in Patients with EGFR-Mutant Non-Small Cell Lung Cancer
ELSEVIER SCIENCE INC. 2022: E54-E55
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View details for Web of Science ID 000892639300120
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Stereotactic radiosurgery for recurrent pediatric brain tumors: clinical outcomes and toxicity.
Neurosurgical focus
2022; 53 (5): E2
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Abstract
Recurrence of brain tumors in children after the initial course of treatment remains a problem. This study evaluated the efficacy and safety of reirradiation using stereotactic radiosurgery (SRS) in patients with recurrent pediatric primary brain tumors.This IRB-approved retrospective review included pediatric patients with recurrent primary brain tumors treated at Stanford University from 2000 to 2019 using frameless SRS. Time to local failure (LF) and distant intracranial failure (DIF) were measured from the date of SRS and analyzed using competing risk analysis. Overall survival (OS) and progression-free survival (PFS) were analyzed with the Kaplan-Meier method.In total, 37 patients aged 2-24 years (median age 11 years at recurrence) were treated for 48 intracranial tumors. Ependymoma (38%) and medulloblastoma (22%) were the most common tumor types. The median (range) single fraction equivalent dose of SRS was 16.4 (12-24) Gy. The median (range) follow-up time was 22.9 (1.5-190) months. The median OS of all patients was 36.8 months. Eight of 40 (20%) lesions with follow-up imaging locally recurred. The 2-year cumulative incidence of LF after reirradiation with SRS was 12.8% (95% CI 4.6%-25.4%). The 2-year cumulative incidence of DIF was 25.3% (95% CI 12.9%-39.8%). The median PFS was 18 months (95% CI 8.9-44). Five (10.4%) patients developed toxicities potentially attributed to SRS, including cognitive effects and necrosis.Reirradiation using SRS for recurrent pediatric brain tumors appears safe with good local control. Innovations that improve overall disease control should continue because survival outcomes after relapse remain poor.
View details for DOI 10.3171/2022.8.FOCUS22361
View details for PubMedID 36321285
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Local control of brain metastases with osimertinib alone in patients with EGFR-mutant non-small cell lung cancer.
Journal of neuro-oncology
2022
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Abstract
Although osimertinib has excellent intracranial activity in metastatic non-small cell lung cancer (NSCLC) with exon 19 deletion or L858R EGFR alterations, measures of local control of brain metastases are less well-reported. We describe lesion-level outcomes of brain metastases treated with osimertinib alone.We retrospectively reviewed patients with EGFR-mutant NSCLC with untreated brain metastasis measuring ≥ 5 mm at the time of initiating osimertinib. Cumulative incidence of local recurrence in brain (LRiB) was calculated with death as a competing risk, and univariable and multivariable analyses were conducted to identify factors associated with LRiB.We included 284 brain metastases from 37 patients. Median follow-up was 20.1 months. On initial MRI after starting osimertinib, patient-level response was complete response (CR) in 11 (15%), partial response (PR) in 33 (45%), stable disease (SD) in 18 (25%) and progressive disease (PD) in 11 (15%). The 1-year cumulative incidence of LRiB was 14% (95% CI 9.9-17.9) and was significantly different in patients with a CR (0%), PR (4%), and SD (11%; p = 0.02). Uncontrolled primary tumor (adjusted hazard ratio [aHR] 3.78, 95% CI 1.87-7.66; p < 0.001), increasing number of prior systemic therapies (aHR 2.12, 95% CI 1.49-3.04; p < 0.001), and higher ECOG score (aHR 7.8, 95% CI 1.99-31.81; p = 0.003) were associated with LRiB.Although 1-year cumulative incidence of LRiB is < 4% with a CR or PR, 1-year cumulative incidence of LRiB is over 10% for patients with less than a PR to osimertinib on initial MRI. These patients should be followed closely for need for additional treatment such as stereotactic radiosurgery.
View details for DOI 10.1007/s11060-022-04145-x
View details for PubMedID 36227422
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Can tumor treating fields induce DNA damage and reduce cell motility in medulloblastoma cell lines?
Journal of neurosurgery. Pediatrics
2022: 1-12
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Abstract
Medulloblastoma (MB) is the most common malignant pediatric brain tumor and accounts for approximately 20% of all pediatric CNS tumors. Current multimodal treatment is associated with a 70%-90% 5-year survival rate; however, the prognosis for patients with tumor dissemination and recurrent MB remains poor. The majority of survivors exhibit long-term neurocognitive complications; thus, more effective and less toxic treatments are critically needed. Tumor treating fields (TTFields) are low-intensity, alternating electric fields that disrupt cell division through physical interactions with key molecules during mitosis. Side effects from TTField therapy are minimal, making it an ideal candidate for MB treatment.To determine if TTFields can be an effective treatment for MB, the authors conducted an in vitro study treating multiple MB cell lines. Three MB molecular subgroups (SHH [sonic hedgehog], group 3, and group 4) were treated for 24, 48, and 72 hours at 100, 200, 300, and 400 kHz. Combinatorial studies were conducted with the small-molecule casein kinase 2 inhibitor CX-4945.TTFields reduced MB cell growth with an optimal frequency of 300 kHz, and the most efficacious treatment time was 72 hours. Treatment with TTFields dysregulated actin polymerization and corresponded with a reduction in cell motility and invasion. TTFields also induced DNA damage (γH2AX, 53BP1) that correlated with an increase in apoptotic cells. The authors discovered that CX-4945 works synergistically with TTFields to reduce MB growth. In addition, combining CX-4945 and TTFields increased the cellular actin dysregulation, which correlated with a decrease in MB migration.The findings of this study demonstrate that TTFields may be a novel and less toxic method to treat patients with MB.
View details for DOI 10.3171/2022.8.PEDS22300
View details for PubMedID 36208441
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Brain Metastases from Gynecologic Primary Cancers: Prognostic Factors for Local Control and Overall Survival
LIPPINCOTT WILLIAMS & WILKINS. 2022: S34
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View details for Web of Science ID 000847787800072
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Tumor treating fields induce DNA damage and apoptosis in medulloblastoma
AMER ASSOC CANCER RESEARCH. 2022
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View details for Web of Science ID 000892509505511
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Modifiers of and Disparities in Palliative and Supportive Care Timing and Utilization among Neurosurgical Patients with Malignant Central Nervous System Tumors.
Cancers
2022; 14 (10)
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Abstract
Patients with primary or secondary central nervous system (CNS) malignancies benefit from utilization of palliative care (PC) in addition to other supportive services, such as home health and social work. Guidelines propose early initiation of PC for patients with advanced cancers. We analyzed a cohort of privately insured patients with malignant brain or spinal tumors derived from the Optum Clinformatics Datamart Database to investigate health disparities in access to and utilization of supportive services. We introduce a novel construct, "provider patient racial diversity index" (provider pRDI), which is a measure of the proportion of non-white minority patients a provider encounters to approximate a provider's patient demographics and suggest a provider's cultural sensitivity and exposure to diversity. Our analysis demonstrates low rates of PC, home health, and social work services among racial minority patients. Notably, Hispanic patients had low likelihood of engaging with all three categories of supportive services. However, patients who saw providers categorized into high provider pRDI (categories II and III) were increasingly more likely to interface with supportive care services and at an earlier point in their disease courses. This study suggests that prospective studies that examine potential interventions at the provider level, including diversity training, are needed.
View details for DOI 10.3390/cancers14102567
View details for PubMedID 35626171
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An integrated risk model stratifying seizure risk following brain tumor resection among seizure-naive patients without antiepileptic prophylaxis.
Neurosurgical focus
2022; 52 (4): E3
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Abstract
The natural history of seizure risk after brain tumor resection is not well understood. Identifying seizure-naive patients at highest risk for postoperative seizure events remains a clinical need. In this study, the authors sought to develop a predictive modeling strategy for anticipating postcraniotomy seizures after brain tumor resection.The IBM Watson Health MarketScan Claims Database was canvassed for antiepileptic drug (AED)- and seizure-naive patients who underwent brain tumor resection (2007-2016). The primary event of interest was short-term seizure risk (within 90 days postdischarge). The secondary event of interest was long-term seizure risk during the follow-up period. To model early-onset and long-term postdischarge seizure risk, a penalized logistic regression classifier and multivariable Cox regression model, respectively, were built, which integrated patient-, tumor-, and hospitalization-specific features. To compare empirical seizure rates, equally sized cohort tertiles were created and labeled as low risk, medium risk, and high risk.Of 5470 patients, 983 (18.0%) had a postdischarge-coded seizure event. The integrated binary classification approach for predicting early-onset seizures outperformed models using feature subsets (area under the curve [AUC] = 0.751, hospitalization features only AUC = 0.667, patient features only AUC = 0.603, and tumor features only AUC = 0.694). Held-out validation patient cases that were predicted by the integrated model to have elevated short-term risk more frequently developed seizures within 90 days of discharge (24.1% high risk vs 3.8% low risk, p < 0.001). Compared with those in the low-risk tertile by the long-term seizure risk model, patients in the medium-risk and high-risk tertiles had 2.13 (95% CI 1.45-3.11) and 6.24 (95% CI 4.40-8.84) times higher long-term risk for postdischarge seizures. Only patients predicted as high risk developed status epilepticus within 90 days of discharge (1.7% high risk vs 0% low risk, p = 0.003).The authors have presented a risk-stratified model that accurately predicted short- and long-term seizure risk in patients who underwent brain tumor resection, which may be used to stratify future study of postoperative AED prophylaxis in highest-risk patient subpopulations.
View details for DOI 10.3171/2022.1.FOCUS21751
View details for PubMedID 35364580
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Factors for differential outcome across cancers in clinical molecular-targeted fluorescence imaging.
Journal of nuclear medicine : official publication, Society of Nuclear Medicine
2022
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Abstract
Clinical imaging performance using a fluorescent antibody was compared across three cancers to elucidate physical and biological factors contributing to differential translation of epidermal growth factor receptor (EGFR) expression to macroscopic fluorescence in tumors. Methods: Thirty-one patients with high-grade glioma (HGG, n = 5), head-and-neck squamous cell carcinoma (HNSCC, n = 23) or lung adenocarcinoma (LAC, n = 3) were systemically infused with 50 mg panitumumab-IRDye800, 1 - 3 days prior to surgery. Intraoperative open-field fluorescent images of the surgical field were acquired, where imaging device settings and operating room lighting conditions were tested on tissue-mimicking phantoms. Fluorescence contrast and margin size were measured on resected specimen surface. Antibody distribution and EGFR immunoreactivity were characterized in macroscopic and microscopic histological structures. Integrity of the blood-brain barrier (BBB) was examined via tight junction protein (claudin-5) expression with immunohistochemistry. Stepwise multivariate linear regression of biological variables was performed to identify independent predictors of panitumumab-IRDye800 concentration in tissue. Results: Optimally acquired at the lowest gain for tumor detection with ambient light, intraoperative fluorescence imaging enhanced tissue-size dependent tumor contrast by 5.2-fold, 3.4-fold and 1.4-fold in HGG, HNSCC and LAC, respectively. Tissue surface fluorescence target-to-background ratio correlated with margin size and identified 78 - 97% of at-risk resection margins ex vivo. In 4 µm-thick tissue sections, fluorescence detected tumor with 0.85 - 0.89 areas under the receiver operating characteristic curves. Preferential breakdown of BBB in HGG improved tumor specificity of intratumoral antibody distribution relative to that of EGFR (96% vs 80%) despite its reduced concentration (3.9 ng/mg tissue) compared to HNSCC (8.1 ng/mg) and LAC (6.3 ng/mg). Cellular EGFR expression, tumor cell density, plasma antibody concentration and delivery barrier were independently associated with local intratumoral panitumumab-IRDye800 concentration with 0.62 goodness-of-fit of prediction. Conclusion: In multi-cancer clinical imaging of receptor-ligand based molecular probe, plasma antibody concentration, delivery barrier, as well as intratumoral EGFR expression driven by cellular biomarker expression and tumor cell density, led to heterogeneous intratumoral antibody accumulation and spatial distribution while tumor size, resection margin, and intraoperative imaging settings substantially influenced macroscopic tumor contrast.
View details for DOI 10.2967/jnumed.121.263674
View details for PubMedID 35332092
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18F-FSPG PET/CT Imaging of System xC- Transporter Activity in Patients with Primary and Metastatic Brain Tumors.
Radiology
2022: 203296
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Abstract
Background The PET tracer (4S)-4-(3-[18F]fluoropropyl)-l-glutamate (18F-FSPG) targets the system xC- cotransporter, which is overexpressed in various tumors. Purpose To assess the role of 18F-FSPG PET/CT in intracranial malignancies. Materials and Methods Twenty-six patients (mean age, 54 years ± 12; 17 men; 48 total lesions) with primary brain tumors (n = 17) or brain metastases (n = 9) were enrolled in this prospective, single-center study (ClinicalTrials.gov identifier: NCT02370563) between November 2014 and March 2016. A 30-minute dynamic brain 18F-FSPG PET/CT scan and a static whole-body (WB) 18F-FSPG PET/CT scan at 60-75 minutes were acquired. Moreover, all participants underwent MRI, and four participants underwent fluorine 18 (18F) fluorodeoxyglucose (FDG) PET imaging. PET parameters and their relative changes were obtained for all lesions. Kinetic modeling was used to estimate the 18F-FSPG tumor rate constants using the dynamic and dynamic plus WB PET data. Imaging parameters were correlated to lesion outcomes, as determined with follow-up MRI and/or pathologic examination. The Mann-Whitney U test or Student t test was used for group mean comparisons. Receiver operating characteristic curve analysis was used for performance comparison of different decision measures. Results 18F-FSPG PET/CT helped identify all 48 brain lesions. The mean tumor-to-background ratio (TBR) on the whole-brain PET images at the WB time point was 26.6 ± 24.9 (range: 2.6-150.3). When 18F-FDG PET was performed, 18F-FSPG permitted visualization of non-18F-FDG-avid lesions or allowed better lesion differentiation from surrounding tissues. In participants with primary brain tumors, the predictive accuracy of the relative changes in influx rate constant Ki and maximum standardized uptake value to discriminate between poor and good lesion outcomes were 89% and 81%, respectively. There were significant differences in the 18F-FSPG uptake curves of lesions with good versus poor outcomes in the primary brain tumor group (P < .05) but not in the brain metastases group. Conclusion PET/CT imaging with (4S)-4-(3-[18F]fluoropropyl)-l-glutamate (18F-FSPG) helped detect primary brain tumors and brain metastases with a high tumor-to-background ratio. Relative changes in 18F-FSPG uptake with multi-time-point PET appear to be helpful in predicting lesion outcomes. Clinical trial registration no. NCT02370563 © RSNA, 2022 Online supplemental material is available for this article.
View details for DOI 10.1148/radiol.203296
View details for PubMedID 35191738
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Fluorescence-guided craniotomy of glioblastoma using panitumumab-IRDye800.
Neurosurgical focus: Video
2022; 6 (1): V9
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Abstract
A contrast-enhancing lesion in the left temporal lobe of a 72-year-old woman was biopsied and diagnosed as glioblastoma. Near-infrared (NIR)-labeled epidermal growth factor receptor (EGFR) antibody, panitumumab-IRDye800, was infused 52 hours before craniotomy without pretreatment. Tumor fluorescence was detected through intact dura, and the visual contrast between disease and peritumoral healthy brain was enhanced after tumor exposure. Residual cancerous tissue was identified with strong fluorescence in resection cavity after en bloc tumor removal. Minimal fluorescence remained in the final wound bed, likely from nonenhancing tumor. Fluorescence was heterogeneously distributed at the infiltrative margin in resected tumor pieces imaged ex vivo. Postoperative MRI confirmed gross-total resection. The video can be found here: https://stream.cadmore.media/r10.3171/2021.10.FOCVID21201.
View details for DOI 10.3171/2021.10.FOCVID21201
View details for PubMedID 36284595
View details for PubMedCentralID PMC9557340
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DSC perfusion MRI-derived fractional tumor burden and relative CBV differentiate tumor progression and radiation necrosis in brain metastases treated with stereotactic radiosurgery.
American Journal of Neuroradiology
2022; 43 (5): 689-695
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View details for DOI 10.3174/ajnr.A7501
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Intracranial Response to Combination BRAF and MEK Inhibitor Therapy in Patients with Metastatic Melanoma
LIPPINCOTT WILLIAMS & WILKINS. 2021: S48-S49
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View details for Web of Science ID 000701779700077
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Tumor treating fields induce DNA damage and apoptosis in medulloblastoma.
AMER ASSOC CANCER RESEARCH. 2021
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View details for Web of Science ID 000680263506384
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Risk of secondary neoplasms after external-beam radiation therapy treatment of pediatric low-grade gliomas: a SEER analysis, 1973-2015.
Journal of neurosurgery. Pediatrics
2021: 1-9
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Abstract
Although past studies have associated external-beam radiation therapy (EBRT) with higher incidences of secondary neoplasms (SNs), its effect on SN development from pediatric low-grade gliomas (LGGs), defined as WHO grade I and II gliomas of astrocytic or oligodendrocytic origin, is not well understood. Utilizing a national cancer registry, the authors sought to characterize the risk of SN development after EBRT treatment of pediatric LGG.A total of 1245 pediatric patient (aged 0-17 years) records from 1973 to 2015 were assembled from the Surveillance, Epidemiology, and End Results (SEER) database. Univariable and multivariable subdistribution hazard regression models were used to evaluate the prognostic impact of demographic, tumor, and treatment-related covariates. Propensity score matching was used to balance baseline characteristics. Cumulative incidence analyses measured the time to, and rate of, SN development, stratified by receipt of EBRT and controlled for competing mortality risk. The Fine and Gray semiparametric model was used to estimate future SN risk in EBRT- and non-EBRT-treated pediatric patients.In this study, 366 patients received EBRT and 879 did not. Forty-six patients developed SNs after an LGG diagnosis, and 27 of these patients received EBRT (OR 3.61, 95% CI 1.90-6.95; p < 0.001). For patients alive 30 years from the initial LGG diagnosis, the absolute risk of SN development in the EBRT-treated cohort was 12.61% (95% CI 8.31-13.00) compared with 4.99% (95% CI 4.38-12.23) in the non-EBRT-treated cohort (p = 0.013). Cumulative incidence curves that were adjusted for competing events still demonstrated higher rates of SN development in the EBRT-treated patients with LGGs. After matching across available covariates and again adjusting for the competing risk of mortality, a clear association between EBRT and SN development remained (subhazard ratio 2.26, 95% CI 1.21-4.20; p = 0.010).Radiation therapy was associated with an increased risk of future SNs for pediatric patients surviving LGGs. These data suggest that the long-term implications of EBRT should be considered when making treatment decisions for this patient population.
View details for DOI 10.3171/2021.1.PEDS20859
View details for PubMedID 34144522
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Management of brain tumors presenting in pregnancy: a case series and systematic review
Management of brain tumors presenting in pregnancy: a case series and systematic review
2021; 3 (1)
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View details for DOI 10.1016/j.ajogmf.2020.100256