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Kozono, David

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Kozono

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Kozono, David
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Now showing 1 - 9 of 9
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    Image-guided radiotherapy platform using single nodule conditional lung cancer mouse models
    (2014) Herter-Sprie, Grit S.; Korideck, Houari; Christensen, Camilla L.; Herter, Jan M.; Rhee, Kevin; Berbeco, Ross; Bennett, David G.; Akbay, Esra A.; Kozono, David; Mak, Raymond; Makrigiorgos, Gerassimos; Kimmelman, Alec C.; Wong, Kwok-Kin
    Close resemblance of murine and human trials is essential to achieve the best predictive value of animal-based translational cancer research. Kras-driven genetically engineered mouse models of non-small cell lung cancer faithfully predict the response of human lung cancers to systemic chemotherapy. Due to development of multifocal disease, however, these models have not been usable in studies of outcomes following focal radiotherapy (RT). We report the development of a preclinical platform to deliver state-of-the-art image-guided RT in these models. Presence of a single tumour as usually diagnosed in patients is modelled by confined injection of adenoviral Cre recombinase. Furthermore, three-dimensional conformal planning and state-of-the-art image-guided dose delivery are performed as in humans. We evaluate treatment efficacies of two different radiation regimens and find that Kras-driven tumours can temporarily be stabilized upon RT, whereas additional loss of either Lkb1 or p53 renders these lesions less responsive to RT.
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    Genome-wide shRNA screen revealed integrated mitogenic signaling between dopamine receptor D2 (DRD2) and epidermal growth factor receptor (EGFR) in glioblastoma
    (Impact Journals LLC, 2014) Li, Jie; Zhu, Shan; Kozono, David; Ng, Kimberly; Futalan, Diahnn; Shen, Ying; Akers, Johnny C.; Steed, Tyler; Kushwaha, Deepa; Schlabach, Michael; Carter, Bob S.; Kwon, Chang-Hyuk; Furnari, Frank; Cavenee, Webster; Elledge, Stephen; Chen, Clark C.
    Glioblastoma remains one of the deadliest of human cancers, with most patients succumbing to the disease within two years of diagnosis. The available data suggest that simultaneous inactivation of critical nodes within the glioblastoma molecular circuitry will be required for meaningful clinical efficacy. We conducted parallel genome-wide shRNA screens to identify such nodes and uncovered a number of G-Protein Coupled Receptor (GPCR) neurotransmitter pathways, including the Dopamine Receptor D2 (DRD2) signaling pathway. Supporting the importance of DRD2 in glioblastoma, DRD2 mRNA and protein expression were elevated in clinical glioblastoma specimens relative to matched non-neoplastic cerebrum. Treatment with independent si-/shRNAs against DRD2 or with DRD2 antagonists suppressed the growth of patient-derived glioblastoma lines both in vitro and in vivo. Importantly, glioblastoma lines derived from independent genetically engineered mouse models (GEMMs) were more sensitive to haloperidol, an FDA approved DRD2 antagonist, than the premalignant astrocyte lines by approximately an order of magnitude. The pro-proliferative effect of DRD2 was, in part, mediated through a GNAI2/Rap1/Ras/ERK signaling axis. Combined inhibition of DRD2 and Epidermal Growth Factor Receptor (EGFR) led to synergistic tumoricidal activity as well as ERK suppression in independent in vivo and in vitro glioblastoma models. Our results suggest combined EGFR and DRD2 inhibition as a promising strategy for glioblastoma treatment.
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    Low Incidence of Chest Wall Pain with a Risk-Adapted Lung Stereotactic Body Radiation Therapy Approach Using Three or Five Fractions Based on Chest Wall Dosimetry
    (Public Library of Science, 2014) Coroller, Thibaud; Mak, Raymond; Lewis, John H.; Baldini, Elizabeth; Chen, Aileen; Colson, Yolonda; Hacker, Fred; Hermann, Gretchen; Kozono, David; Mannarino, Edward; Molodowitch, Christina; Wee, Jon; Sher, David J.; Killoran, Joseph
    Purpose To examine the frequency and potential of dose-volume predictors for chest wall (CW) toxicity (pain and/or rib fracture) for patients receiving lung stereotactic body radiotherapy (SBRT) using treatment planning methods to minimize CW dose and a risk-adapted fractionation scheme. Methods: We reviewed data from 72 treatment plans, from 69 lung SBRT patients with at least one year of follow-up or CW toxicity, who were treated at our center between 2010 and 2013. Treatment plans were optimized to reduce CW dose and patients received a risk-adapted fractionation of 18 Gy×3 fractions (54 Gy total) if the CW V30 was less than 30 mL or 10–12 Gy×5 fractions (50–60 Gy total) otherwise. The association between CW toxicity and patient characteristics, treatment parameters and dose metrics, including biologically equivalent dose, were analyzed using logistic regression. Results: With a median follow-up of 20 months, 6 (8.3%) patients developed CW pain including three (4.2%) grade 1, two (2.8%) grade 2 and one (1.4%) grade 3. Five (6.9%) patients developed rib fractures, one of which was symptomatic. No significant associations between CW toxicity and patient and dosimetric variables were identified on univariate nor multivariate analysis. Conclusions: Optimization of treatment plans to reduce CW dose and a risk-adapted fractionation strategy of three or five fractions based on the CW V30 resulted in a low incidence of CW toxicity. Under these conditions, none of the patient characteristics or dose metrics we examined appeared to be predictive of CW pain.
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    Circulating miR-29a and miR-150 correlate with delivered dose during thoracic radiation therapy for non-small cell lung cancer
    (BioMed Central, 2016) Dinh, Tru-Khang T.; Fendler, Wojciech; Chałubińska-Fendler, Justyna; Acharya, Sanket S.; O’Leary, Colin; Deraska, Peter V.; D’Andrea, Alan D.; Chowdhury, Dipanjan; Kozono, David
    Background: Risk of normal tissue toxicity limits the amount of thoracic radiation therapy (RT) that can be routinely prescribed to treat non-small cell lung cancer (NSCLC). An early biomarker of response to thoracic RT may provide a way to predict eventual toxicities—such as radiation pneumonitis—during treatment, thereby enabling dose adjustment before the symptomatic onset of late effects. MicroRNAs (miRNAs) were studied as potential serological biomarkers for thoracic RT. As a first step, we sought to identify miRNAs that correlate with delivered dose and standard dosimetric factors. Methods: We performed miRNA profiling of plasma samples obtained from five patients with Stage IIIA NSCLC at five dose-points each during radical thoracic RT. Candidate miRNAs were then assessed in samples from a separate cohort of 21 NSCLC patients receiving radical thoracic RT. To identify a cellular source of circulating miRNAs, we quantified in vitro miRNA expression intracellularly and within secreted exosomes in five NSCLC and stromal cell lines. Results: miRNA profiling of the discovery cohort identified ten circulating miRNAs that correlated with delivered RT dose as well as other dosimetric parameters such as lung V20. In the validation cohort, miR-29a-3p and miR-150-5p were reproducibly shown to decrease with increasing radiation dose. Expression of miR-29a-3p and miR-150-5p in secreted exosomes decreased with radiation. This was concomitant with an increase in intracellular levels, suggesting that exosomal export of these miRNAs may be downregulated in both NSCLC and stromal cells in response to radiation. Conclusions: miR-29a-3p and miR-150-5p were identified as circulating biomarkers that correlated with delivered RT dose. miR-150 has been reported to decrease in the circulation of mammals exposed to radiation while miR-29a has been associated with fibrosis in the human heart, lungs, and kidneys. One may therefore hypothesize that outlier levels of circulating miR-29a-3p and miR-150-5p may eventually help predict unexpected responses to radiation therapy, such as toxicity. Electronic supplementary material The online version of this article (doi:10.1186/s13014-016-0636-4) contains supplementary material, which is available to authorized users.
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    Outcomes by Tumor Histology and KRAS Mutation Status After Lung Stereotactic Body Radiation Therapy for Early-Stage Non–Small-Cell Lung Cancer
    (Elsevier BV, 2015) Mak, Raymond; Hermann, Gretchen; Lewis, John H.; Aerts, Hugo J.W.L.; Baldini, Elizabeth; Chen, Aileen; Colson, Yolonda; Hacker, Fred; Kozono, David; Wee, Jon; Chen, Yu-Hui; Catalano, Paul; Wong, Kwok-Kin; Sher, David J.
    BACKGROUND: We analyzed outcomes after lung stereotactic body radiotherapy (SBRT) for early-stage non-small cell lung-carcinoma (NSCLC) by histology and KRAS genotype. PATIENTS AND METHODS: We included 75 patients with 79 peripheral tumors treated with SBRT (18 Gy × 3 or 10 to 12 Gy × 5) at our institution from 2009 to 2012. Genotyping for KRAS mutations was performed in 10 patients. Outcomes were analyzed by the Kaplan-Meier method/Cox regression, or cumulative incidence method/Fine-Gray analysis. RESULTS: The median patient age was 74 (range, 46 to 93) years, and Eastern Cooperative Oncology Group performance status was 0 to 1 in 63%. Tumor histology included adenocarcinoma (44%), squamous cell carcinoma (25%), and NSCLC (18%). Most tumors were T1a (54%). Seven patients had KRAS-mutant tumors (9%). With a median follow-up of 18.8 months among survivors, the 1-year estimate of overall survival was 88%, cancer-specific survival (CSS) 92%, primary tumor control 94%, and freedom from recurrence (FFR) 67%. In patients with KRAS-mutant tumors, there was a significantly lower tumor control (67% vs. 96%; P = .04), FFR (48% vs. 69%; P = .03), and CSS (75% vs. 93%; P = .05). On multivariable analysis, histology was not associated with outcomes, but KRAS mutation (hazard ratio, 10.3; 95% confidence interval, 2.3-45.6; P = .0022) was associated with decreased CSS after adjusting for age. CONCLUSION: In this SBRT series, histology was not associated with outcomes, but KRAS mutation was associated with lower FFR on univariable analysis and decreased CSS on multivariable analysis. Because of the small sample size, these hypothesis-generating results need to be studied in larger data sets.
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    Advanced nodal stage predicts venous thromboembolism in patients with locally advanced non-small cell lung cancer
    (Elsevier BV, 2016) Li, Richard Jay; Hermann, Gretchen; Baldini, Elizabeth; Chen, Aileen; Jackman, David M; Kozono, David; Nguyen, Paul; Nohria, Anju; Powell, Graham; Mak, Raymond
    Objectives: Patients with non-small cell lung cancer (NSCLC) are known to be at high risk for venous thromboembolism (VTE), but previous studies have not specifically analyzed locally advanced disease. We performed a retrospective VTE risk analysis in a cohort of locally advanced NSCLC treated with definitive intent including radiation therapy. Materials and Methods: The cohort consisted of 629 patients with stage II-III NSCLC treated at a single institution from January 2003 to December 2012. All patients received treatment with curative intent, including radiation therapy. Fine and Gray’s competing-risks regression model, accounting for death and distant metastasis as competing risks, was used to identify significant predictors of VTE risk, and cumulative incidence estimates were generated using the competing-risks model. Results and Conclusion: At a median follow-up of 31 months, 127 patients developed a VTE, with 80% of events occurring in the first year after treatment initiation. 1-year and 3-year overall cumulative incidence estimates were 13.5% and 15.4%, respectively. On univariate analysis, stage IIIB and N3 nodal disease were associated with increased VTE risk. In the final multivariable model, N3 nodal disease was associated with increased VTE risk (Hazard ratio 1.64; 95% CI 1.06-2.54; p=0.027). In conclusion, patients with locally advanced NSCLC are at high risk for VTE, especially in the first year after treatment initiation, with a 1-year cumulative incidence of 13.5%. N3 nodal staging was associated with significantly higher VTE risk compared to N0-N2 staging.
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    Lymph node volume predicts survival but not nodal clearance in Stage IIIA-IIIB NSCLC
    (Public Library of Science, 2017) Agrawal, Vishesh; Coroller, Thibaud; Hou, Ying; Lee, Stephanie W.; Romano, John L.; Baldini, Elizabeth; Chen, Aileen; Kozono, David; Swanson, Scott; Wee, Jon; Aerts, Hugo; Mak, Raymond
    Background: Locally advanced non-small cell lung cancer (LA-NSCLC) patients have poorer survival and local control with mediastinal node (N2) tumor involvement at resection. Earlier assessment of nodal burden could inform clinical decision-making prior to surgery. This study evaluated the association between clinical outcomes and lymph node volume before and after neoadjuvant therapy. Materials and methods CT imaging of patients with operable LA-NSCLC treated with chemoradiation and surgical resection was assessed. Clinically involved lymph node stations were identified by FDG-PET or mediastinoscopy. Locoregional recurrence (LRR), distant metastasis (DM), progression free survival (PFS) and overall survival (OS) were analyzed by the Kaplan Meier method, concordance index and Cox regression. Results: 73 patients with Stage IIIA-IIIB NSCLC treated with neoadjuvant chemoradiation and surgical resection were identified. The median RT dose was 54 Gy and all patients received concurrent chemotherapy. Involved lymph node volume was significantly associated with LRR and OS but not DM on univariate analysis. Additionally, lymph node volume greater than 10.6 cm3 after the completion of preoperative chemoradiation was associated with increased LRR (p<0.001) and decreased OS (p = 0.04). There was no association between nodal volumes and nodal clearance. Conclusion: For patients with LA-NSCLC, large volume nodal disease post-chemoradiation is associated with increased risk of locoregional recurrence and decreased survival. Nodal volume can thus be used to further stratify patients within the heterogeneous Stage IIIA-IIIB population and potentially guide clinical decision-making.
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    Aggressive therapy for patients with non-small cell lung carcinoma and synchronous brain-only oligometastatic disease is associated with long-term survival
    (Elsevier BV, 2014) Gray, Phillip; Mak, Raymond; Yeap, Beow; Cryer, Sarah K.; Pinnell, Nancy E.; Christianson, Laura W.; Sher, David J.; Arvold, Nils; Baldini, Elizabeth; Chen, Aileen; Kozono, David; Swanson, Scott; Jackman, David M; Alexander, Brian
    Objectives: Optimal therapy for patients with non-small cell lung carcinoma (NSCLC) presenting with synchronous brain-only oligometastases (SBO) is not well defined. We sought to analyze the effect of differing therapeutic paradigms in this subpopulation. Materials and Methods: We retrospectively analyzed NSCLC patients with 1-4 SBO diagnosed between 1/2000 and 1/2011 at our institution. Patients with T0 tumors or documented Karnofsky Performance Status <70 were excluded. Aggressive thoracic therapy (ATT) was defined as resection of the primary disease or chemoradiotherapy whose total radiation dose exceeded 45 Gy. Cox proportional hazards and competing risks models were used to analyze factors affecting survival and first recurrence in the brain. Results: Sixty-six patients were included. Median follow-up was 31.9 months. Intrathoracic disease extent included 9 stage I, 10 stage II and 47 stage III patients. Thirty-eight patients received ATT, 28 did not. Patients receiving ATT were younger (median age 55 vs. 60.5 years, p=0.027) but were otherwise similar to those who did not. Receipt of ATT was associated with prolonged median overall survival (OS) (26.4 vs. 10.5 months; p<0.001) with actuarial 2-year rates of 54% vs. 26%. ATT remained associated with OS after controlling for age, thoracic stage, performance status and initial brain therapy (HR 0.40, p=0.009). On multivariate analysis, the risk of first failure in the brain was associated with receipt of ATT (HR 3.62, p=0.032) and initial combined modality brain therapy (HR 0.34, p=0.046). Conclusion: Aggressive management of thoracic disease in NSCLC patients with SBO is associated with improved survival. Careful management of brain disease remains important, especially for those treated aggressively.
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    Targeting EGFR Induced Oxidative Stress by PARP1 Inhibition in Glioblastoma Therapy
    (Public Library of Science, 2010) Nitta, Masayuki; Stommel, Jayne; Ng, Kimberly; Kesari, Santosh; Furnari, Frank; Hoadley, Katherine A.; Cavenee, Webster K.; Kozono, David; Kennedy, Richard; Zinn, Pascal Olivier; Kushwaha, Deepa S; Chin, Lynda; DePinho, Ronald A.; D'Andrea, Alan; Chen, Clark Chin-Chung
    Despite the critical role of Epidermal Growth Factor Receptor (EGFR) in glioblastoma pathogenesis [1], [2], EGFR targeted therapies have achieved limited clinical efficacy [3]. Here we propose an alternate therapeutic strategy based on the conceptual framework of non-oncogene addiction [4], [5]. A directed RNAi screen revealed that glioblastoma cells over-expressing EGFRvIII [6], an oncogenic variant of EGFR, become hyper-dependent on a variety of DNA repair genes. Among these, there was an enrichment of Base Excision Repair (BER) genes required for the repair of Reactive Oxygen Species (ROS)-induced DNA damage, including poly-ADP ribose polymerase 1 (PARP1). Subsequent studies revealed that EGFRvIII over-expression in glioblastoma cells caused increased levels of ROS, DNA strand break accumulation, and genome instability. In a panel of primary glioblastoma lines, sensitivity to PARP1 inhibition correlated with the levels of EGFR activation and oxidative stress. Gene expression analysis indicated that reduced expression of BER genes in glioblastomas with high EGFR expression correlated with improved patient survival. These observations suggest that oxidative stress secondary to EGFR hyper-activation necessitates increased cellular reliance on PARP1 mediated BER, and offer critical insights into clinical trial design.