Browsing by Subject "Brain metastasis"
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Item c-Met Mediated Cytokine Network Promotes Brain Metastasis of Breast Cancer by Remodeling Neutrophil Activities(MDPI, 2023-05-05) Liu, Yin; Smith, Margaret R.; Wang, Yuezhu; D’Agostino, Ralph, Jr.; Ruiz, Jimmy; Lycan, Thomas; Kucera, Gregory L.; Miller, Lance D.; Li, Wencheng; Chan, Michael D.; Farris, Michael; Su, Jing; Song, Qianqian; Zhao, Dawen; Chandrasekaran, Arvind; Xing, Fei; Biostatistics and Health Data Science, School of MedicineThe brain is one of the most common metastatic sites among breast cancer patients, especially in those who have Her2-positive or triple-negative tumors. The brain microenvironment has been considered immune privileged, and the exact mechanisms of how immune cells in the brain microenvironment contribute to brain metastasis remain elusive. In this study, we found that neutrophils are recruited and influenced by c-Met high brain metastatic cells in the metastatic sites, and depletion of neutrophils significantly suppressed brain metastasis in animal models. Overexpression of c-Met in tumor cells enhances the secretion of a group of cytokines, including CXCL1/2, G-CSF, and GM-CSF, which play critical roles in neutrophil attraction, granulopoiesis, and homeostasis. Meanwhile, our transcriptomic analysis demonstrated that conditioned media from c-Met high cells significantly induced the secretion of lipocalin 2 (LCN2) from neutrophils, which in turn promotes the self-renewal of cancer stem cells. Our study unveiled the molecular and pathogenic mechanisms of how crosstalk between innate immune cells and tumor cells facilitates tumor progression in the brain, which provides novel therapeutic targets for treating brain metastasis.Item Cervical cancer metastasis to the brain: A case report and review of literature(Medknow Publications, 2017-08-09) Fetcko, Kaleigh; Gondim, Dibson D.; Bonnin, Jose M.; Dey, Mahua; Neurological Surgery, School of MedicineBackground: Intracranial metastasis from cervical cancer is a rare occurrence. Methods: In this study we describe a case of cervical cancer metastasis to the brain and perform an extensive review of literature from 1956 to 2016, to characterize clearly the clinical presentation, treatment options, molecular markers, targeted therapies, and survival of patients with this condition. Results: An elderly woman with history of cervical cancer in remission, presented 2 years later with a right temporo-parietal tumor, which was treated with surgery and subsequent stereotactic radiosurgery (SRS) to the resection cavity. She then returned 5 months later with a second solitary right lesion; she again underwent surgery and SRS to the resection cavity with no signs of recurrence 6 months later. According to the reviewed literature, the most common clinical presentation included females with median age of 48 years; presenting symptoms such as headache, weakness/hemiplegia/hemiparesis, seizure, and altered mental status (AMS)/confusion; multiple lesions mostly supratentorially located; poorly differentiated squamous cell carcinoma; and additional recurrences at other sites. The best approach to treatment is a multimodal plan, consisting of SRS or whole brain radiation therapy (WBRT) for solitary brain metastases followed by chemotherapy for systemic disease, surgery and WBRT for solitary brain lesions without systemic disease, and SRS or WBRT followed by chemotherapy for palliative care. The overall prognosis is poor with a mean and median survival time from diagnosis of brain metastasis of 7 and 4.6 months, respectively. Conclusion: Future efforts through large prospective randomized trials are warranted to better describe the clinical presentation and identify more effective treatment plans.Item CNS-Native Myeloid Cells Drive Immune Suppression in the Brain Metastatic Niche through Cxcl10(Cell Press, 2020) Guldner, Ian H.; Wang, Qingfei; Yang, Lin; Golomb, Samantha M.; Zhao, Zhuo; Lopez, Jacqueline A.; Brunory, Abigail; Howe, Erin N.; Zhang, Yizhe; Palakurthi, Bhavana; Barron, Martin; Gao, Hongyu; Xuei, Xiaoling; Liu, Yunlong; Li, Jun; Chen, Danny Z.; Landreth, Gary E.; Zhang, Siyuan; Medical and Molecular Genetics, School of MedicineBrain metastasis (br-met) develops in an immunologically unique br-met niche. Central nervous system-native myeloid cells (CNS-myeloids) and bone-marrow-derived myeloid cells (BMDMs) cooperatively regulate brain immunity. The phenotypic heterogeneity and specific roles of these myeloid subsets in shaping the br-met niche to regulate br-met outgrowth have not been fully revealed. Applying multimodal single-cell analyses, we elucidated a heterogeneous but spatially defined CNS-myeloid response during br-met outgrowth. We found Ccr2+ BMDMs minimally influenced br-met while CNS-myeloid promoted br-met outgrowth. Additionally, br-met-associated CNS-myeloid exhibited downregulation of Cx3cr1. Cx3cr1 knockout in CNS-myeloid increased br-met incidence, leading to an enriched interferon response signature and Cxcl10 upregulation. Significantly, neutralization of Cxcl10 reduced br-met, while rCxcl10 increased br-met and recruited VISTAHi PD-L1+ CNS-myeloid to br-met lesions. Inhibiting VISTA- and PD-L1-signaling relieved immune suppression and reduced br-met burden. Our results demonstrate that loss of Cx3cr1 in CNS-myeloid triggers a Cxcl10-mediated vicious cycle, cultivating a br-met-promoting, immune-suppressive niche.Item Current Treatment Approaches and Global Consensus Guidelines for Brain Metastases in Melanoma(Frontiers Media, 2022-05-05) Tan, Xiang-Lin; Le, Amy; Lam, Fred C.; Scherrer, Emilie; Kerr, Robert G.; Lau, Anthony C.; Han, Jiali; Jiang, Ruixuan; Diede, Scott J.; Shui, Irene M.; Graduate Medical Education, School of MedicineBackground: Up to 60% of melanoma patients develop melanoma brain metastases (MBM), which traditionally have a poor diagnosis. Current treatment strategies include immunotherapies (IO), targeted therapies (TT), and stereotactic radiosurgery (SRS), but there is considerable heterogeneity across worldwide consensus guidelines. Objective: To summarize current treatments and compare worldwide guidelines for the treatment of MBM. Methods: Review of global consensus treatment guidelines for MBM patients. Results: Substantial evidence supported that concurrent IO or TT plus SRS improves progression-free survival (PFS) and overall survival (OS). Guidelines are inconsistent with regards to recommendations for surgical resection of MBM, since surgical resection of symptomatic lesions alleviates neurological symptoms but does not improve OS. Whole-brain radiation therapy is not recommended by all guidelines due to negative effects on neurocognition but can be offered in rare palliative scenarios. Conclusion: Worldwide consensus guidelines consistently recommend up-front combination IO or TT with or without SRS for the treatment of MBM.Item Delivery of nanoparticles to brain metastases of breast cancer using a cellular Trojan horse(Springer, 2012) Choi, Mi-Ran; Bardhan, Rizia; Stanton-Maxey, Katie J.; Badve, Sunil; Nakshatri, Harikrishna; Stantz, Keith M.; Cao, Ning; Halas, Naomi J.; Clare, Susan E.As systemic cancer therapies improve and are able to control metastatic disease outside the central nervous system, the brain is increasingly the first site of relapse. The blood–brain barrier (BBB) represents a major challenge to the delivery of therapeutics to the brain. Macrophages originating from circulating monocytes are able to infiltrate brain metastases while the BBB is intact. Here, we show that this ability can be exploited to deliver both diagnostic and therapeutic nanoparticles specifically to experimental brain metastases of breast cancer.Item Does Graded Prognostic Assessment outperform Recursive Partitioning Analysis in patients with moderate prognosis brain metastases?(Future Medicine, 2016) Estabrook, Neil C.; Lutz, Stephen T.; Johnson, Cynthia S.; Lo, Simon S.; Henderson, Mark A.; Radiation Oncology, School of MedicineAIM: To compare the clinical utility of the Recursive Partitioning Analysis (RPA) and Graded Prognostic Assessment (GPA) in predicting outcomes for moderate prognosis patients with brain metastases. METHODS & MATERIALS: We reviewed 101 whole brain radiotherapy cases. RPA and GPA were calculated. Overall survival was compared. RESULTS: Sixty-eight patients had moderate prognosis. RPA patient characteristics for increased death hazard were ≤10 WBRT fractions or no surgery/radiosurgery. GPA patients had increased death risk with no surgery/radiosurgery or lower Karnofsky Performance Status. CONCLUSION: The indices have similar predicted survival. Patients scored by RPA with longer radiation schedules had longer survival; patients scored by GPA did not. This indicates GPA is more clinically useful, leaving less room for subjective treatment choices.Item GAD1 Upregulation Programs Aggressive Features of Cancer Cell Metabolism in the Brain Metastatic Microenvironment(American Association for Cancer Research, 2017-06-01) Schnepp, Patricia M.; Lee, Dennis D.; Guldner, Ian H.; O'Tighearnaigh, Treasa K.; Howe, Erin N.; Palakurthi, Bhavana; Eckert, Kaitlyn E.; Toni, Tiffany A.; Ashfeld, Brandon L.; Zhang, Siyuan; Medicine, School of MedicineThe impact of altered amino acid metabolism on cancer progression is not fully understood. We hypothesized that a metabolic transcriptome shift during metastatic evolution is crucial for brain metastasis. Here, we report a powerful impact in this setting caused by epigenetic upregulation of glutamate decarboxylase 1 (GAD1), a regulator of the GABA neurotransmitter metabolic pathway. In cell-based culture and brain metastasis models, we found that downregulation of the DNA methyltransferase DNMT1 induced by the brain microenvironment-derived clusterin resulted in decreased GAD1 promoter methylation and subsequent upregulation of GAD1 expression in brain metastatic tumor cells. In a system to dynamically visualize cellular metabolic responses mediated by GAD1, we monitored the cytosolic NADH:NAD+ equilibrium in tumor cells. Reducing GAD1 in metastatic cells by primary glia cell coculture abolished the capacity of metastatic cells to utilize extracellular glutamine, leading to cytosolic accumulation of NADH and increased oxidative status. Similarly, genetic or pharmacologic disruption of the GABA metabolic pathway decreased the incidence of brain metastasis in vivo Taken together, our results show how epigenetic changes in GAD1 expression alter local glutamate metabolism in the brain metastatic microenvironment, contributing to a metabolic adaption that facilitates metastasis outgrowth in that setting.Item Patterns of Failure Outcomes for Combination of Stereotactic Radiosurgery and Immunotherapy for Melanoma Brain Metastases(Wolters Kluwer, 2023-01-11) Abdulhaleem, Mohammed; Johnston, Hannah; D'Agostino, Ralph, Jr.; Lanier, Claire; Cramer, Christina K.; Triozzi, Pierre; Lo, Hui-Wen; Xing, Fei; Li, Wencheng; Whitlow, Christopher; White, Jaclyn J.; Tatter, Stephen B.; Laxton, Adrian W.; Su, Jing; Chan, Michael D.; Ruiz, Jimmy; Biostatistics and Health Data Science, Richard M. Fairbanks School of Public HealthBackground: Previous series have demonstrated central nervous system activity for immune checkpoint inhibitors (ICIs) and shown improved local control between stereotactic radiosurgery (SRS) and ICI for lung cancer brain metastases. Objective: To assess whether the addition of ICI to SRS for melanoma brain metastasis improves outcomes when compared with historical control group treated in the era before ICI availability. Methods: In this single institution retrospective series, outcomes of 24 patients with melanoma receiving concurrent ICI and SRS were compared with 111 historical controls treated before ICI era. Overall survival (OS) was estimated using the Kaplan-Meier method. Cumulative incidence of local and distant failures was estimated using a competing risk model that accounted for baseline differences using propensity score adjustments. Results: The median OS time was improved in patients receiving ICI compared with the historical control group (17.6 vs 6.6 months, hazard ratio [HR] = 0.056, P = .0005). Cumulative incidence at 1 year for local failure in the historical control and ICI groups was approximately 12.5% and 6.5%, respectively (HR = 0.25, P = .19), while cumulative incidence of distant brain failure in the historical control and ICI groups was approximately 48% and 28%, respectively (HR = 0.326, P = .015). Conclusion: Distant brain failure and OS were improved in patients receiving concurrent ICI with SRS compared with historical controls. Local failure trended in the same direction; however, owing to small sample size, this did not reach statistical significance. While these data remain to be validated, they suggest that patients with brain metastasis may benefit from concurrent use of ICI with SRS.Item Predicting early brain metastases based on clinicopathological factors and gene expression analysis in advanced HER2-positive breast cancer patients(Springer US, 2015-03) Duchnowska, Renata; Jassem, Jacek; Goswami, Chirayu Pankaj; Dundar, Murat; Gökmen-Polar, Yesim; Li, Lang; Woditschka, Stephan; Biernat, Wojciech; Sosińska-Mielcarek, Katarzyna; Czartoryska-Arłukowicz, Bogumiła; Radecka, Barbara; Tomasevic, Zorica; Stępniak, Piotr; Wojdan, Konrad; Sledge, George W. Jr.; Steeg, Patricia S.; Badve, Sunil; Department of Medical & Molecular Genetics, IU School of MedicineThe overexpression or amplification of the human epidermal growth factor receptor 2 gene (HER2/neu) is associated with high risk of brain metastasis (BM). The identification of patients at highest immediate risk of BM could optimize screening and facilitate interventional trials. We performed gene expression analysis using complementary deoxyribonucleic acid-mediated annealing, selection, extension and ligation and real-time quantitative reverse transcription PCR (qRT-PCR) in primary tumor samples from two independent cohorts of advanced HER2 positive breast cancer patients. Additionally, we analyzed predictive relevance of clinicopathological factors in this series. Study group included discovery Cohort A (84 patients) and validation Cohort B (75 patients). The only independent variables associated with the development of early BM in both cohorts were the visceral location of first distant relapse [Cohort A: hazard ratio (HR) 7.4, 95 % CI 2.4–22.3; p < 0.001; Cohort B: HR 6.1, 95 % CI 1.5–25.6; p = 0.01] and the lack of trastuzumab administration in the metastatic setting (Cohort A: HR 5.0, 95 % CI 1.4–10.0; p = 0.009; Cohort B: HR 10.0, 95 % CI 2.0–100.0; p = 0.008). A profile including 13 genes was associated with early (≤36 months) symptomatic BM in the discovery cohort. This was refined by qRT-PCR to a 3-gene classifier (RAD51, HDGF, TPR) highly predictive of early BM (HR 5.3, 95 % CI 1.6–16.7; p = 0.005; multivariate analysis). However, predictive value of the classifier was not confirmed in the independent validation Cohort B. The presence of visceral metastases and the lack of trastuzumab administration in the metastatic setting apparently increase the likelihood of early BM in advanced HER2-positive breast cancer.Item Prediction Model for Brain Metastasis in Patients With Metastatic Germ‐Cell Tumors(Wiley, 2025) Salous, Tareq; Ashkar, Ryan; Althouse, Sandra K.; Cary, Clint; Masterson, Timothy; Hanna, Nasser H.; King, Jennifer; Einhorn, Lawrence H.; Adra, Nabil; Medicine, School of MedicineBackground: Brain metastasis (BM) is an independent adverse prognostic factor in metastatic germ cell tumors (mGCT). We aimed to establish an effective and practical BM prediction model. Patients and methods: Between January 1990 and September 2017, 2291 patients with mGCT who were treated at Indiana University were identified. Patients were divided into two categories: BM present (N = 154) and BM absent (N = 2137). Kaplan-Meier methods were used to analyze progression free survival (PFS) and overall survival (OS). Logistic regression was used to determine a predictive model for whether BM was present. The data was separated into training and validation datasets with equal numbers of events in each. Results: The 2-year PFS and OS for patients with versus without BM: 17% versus 65% (p < 0.001) and 62% versus 91% (p < 0.001) respectively. Among the 154 patients with BM, 64 (42%) had radiation only (whole-brain radiotherapy or gamma knife), 22 (14%) had BM-surgery only, 14 (9%) had both radiation and BM-surgery. 54 patients (35%) did not receive local therapy for BM. Stepwise selection was used to determine the best model with p < 0.15 as the entry and staying criteria. The model with the largest ROC AUC was used moving forward. The model was tested in the validation dataset. A model was generated including age at diagnosis ≥ 40, choriocarcinoma predominant histology, pre-chemotherapy hCG≥ 5000, presence of pulmonary metastases size < 3, or ≥ 3 cm, and presence of bone metastasis. Patients with score of 0, 1, 2, 3, 4, 5, 6, 7, 8 points had a 0.6%, 1.4%, 3.5%, 8.2%, 18.3%, 36%, 58%, 78%, 90% probability of having BM, respectively. Conclusions: The prediction model developed in this study demonstrated discrimination capability of predicting BM occurrence in mGCT and can be used to identify high-risk patients.