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1. The use of large language models to enhance cancer clinical trial educational materials

Author

Gao, Mingye, Varshney, Aman, Chen, Shan, Goddla, Vikram, Gallifant, Jack, Doyle, Patrick, Novack, Claire, Dillon-Martin, Maeve, Perkins, Teresia, Correia, Xinrong, Duhaime, Erik, Isenstein, Howard, Sharon, Elad, Lehmann, Lisa Soleymani, Kozono, David, Anthony, Brian, Dligach, Dmitriy, and Bitterman, Danielle S.

Subjects
Computer Science - Computation and Language, Computer Science - Artificial Intelligence
Abstract

Cancer clinical trials often face challenges in recruitment and engagement due to a lack of participant-facing informational and educational resources. This study investigated the potential of Large Language Models (LLMs), specifically GPT4, in generating patient-friendly educational content from clinical trial informed consent forms. Using data from ClinicalTrials.gov, we employed zero-shot learning for creating trial summaries and one-shot learning for developing multiple-choice questions, evaluating their effectiveness through patient surveys and crowdsourced annotation. Results showed that GPT4-generated summaries were both readable and comprehensive, and may improve patients' understanding and interest in clinical trials. The multiple-choice questions demonstrated high accuracy and agreement with crowdsourced annotators. For both resource types, hallucinations were identified that require ongoing human oversight. The findings demonstrate the potential of LLMs "out-of-the-box" to support the generation of clinical trial education materials with minimal trial-specific engineering, but implementation with a human-in-the-loop is still needed to avoid misinformation risks.

Published
2024

2. Magnetic resonance delta radiomics to track radiation response in lung tumors receiving stereotactic MRI-guided radiotherapy

Author

Zha, Yining, Kann, Benjamin H., Ye, Zezhong, Zapaishchykova, Anna, He, John, Hsu, Shu-Hui, Leeman, Jonathan E., Fitzgerald, Kelly J., Kozono, David E., Mak, Raymond H., and Aerts, Hugo J. W. L.

Subjects
Electrical Engineering and Systems Science - Image and Video Processing, Computer Science - Computer Vision and Pattern Recognition, Physics - Medical Physics
Abstract

Introduction: Lung cancer is a leading cause of cancer-related mortality, and stereotactic body radiotherapy (SBRT) has become a standard treatment for early-stage lung cancer. However, the heterogeneous response to radiation at the tumor level poses challenges. Currently, standardized dosage regimens lack adaptation based on individual patient or tumor characteristics. Thus, we explore the potential of delta radiomics from on-treatment magnetic resonance (MR) imaging to track radiation dose response, inform personalized radiotherapy dosing, and predict outcomes. Methods: A retrospective study of 47 MR-guided lung SBRT treatments for 39 patients was conducted. Radiomic features were extracted using Pyradiomics, and stability was evaluated temporally and spatially. Delta radiomics were correlated with radiation dose delivery and assessed for associations with tumor control and survival with Cox regressions. Results: Among 107 features, 49 demonstrated temporal stability, and 57 showed spatial stability. Fifteen stable and non-collinear features were analyzed. Median Skewness and surface to volume ratio decreased with radiation dose fraction delivery, while coarseness and 90th percentile values increased. Skewness had the largest relative median absolute changes (22%-45%) per fraction from baseline and was associated with locoregional failure (p=0.012) by analysis of covariance. Skewness, Elongation, and Flatness were significantly associated with local recurrence-free survival, while tumor diameter and volume were not. Conclusions: Our study establishes the feasibility and stability of delta radiomics analysis for MR-guided lung SBRT. Findings suggest that MR delta radiomics can capture short-term radiographic manifestations of intra-tumoral radiation effect.

Published
2024

6. Surgical complications and clinical outcomes after dose-escalated trimodality therapy for non-small cell lung cancer in the era of intensity-modulated radiotherapy

Author

Liu, Kevin X, Sierra-Davidson, Kailan, Tyan, Kevin, Orlina, Lawrence T, Marcoux, J Paul, Kann, Benjamin H, Kozono, David E, Mak, Raymond H, White, Abby, and Singer, Lisa

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Oncology and Carcinogenesis, Cancer, Lung Cancer, Clinical Research, Lung, Patient Safety, Evaluation of treatments and therapeutic interventions, 6.5 Radiotherapy and other non-invasive therapies, Aged, Carcinoma, Non-Small-Cell Lung, Chemoradiotherapy, Disease-Free Survival, Female, Humans, Lung Neoplasms, Radiotherapy Dosage, Radiotherapy, Intensity-Modulated, Retrospective Studies, Non-small cell lung cancer, Trimodality, Radiation, Intensity modulated radiotherapy, IMRT, Radiation dose, Other Physical Sciences, Oncology & Carcinogenesis, Clinical sciences, Oncology and carcinogenesis, Medical and biological physics
Abstract

BackgroundTrimodality therapy (TMT) with preoperative chemoradiation followed by surgical resection is used for locally-advanced non-small-cell lung cancer (LA-NSCLC). Traditionally, preoperative radiation doses ≤54 Gy are used due to concerns regarding excess morbidity, but little is known about outcomes and toxicities after TMT with intensity-modulated radiotherapy (IMRT) to higher doses.MethodsA retrospective analysis of patients who received planned TMT with IMRT for LA-NSCLC at Brigham and Women's Hospital/Dana-Farber Cancer Institute between 2008 and 2017 was performed. Clinical and treatment characteristics, pathologic response, and surgical toxicity were assessed. Kaplan-Meier method and log-rank test was used for survival outcomes. Cox proportional-hazards regression was used for multivariable analysis.ResultsForty-six patients received less than definitive doses of 7 days were associated with OS.ConclusionsWith IMRT, there was no increased rate of surgical complications in patients receiving higher doses of radiation. Survival outcomes or LOS did not differ based on radiation dose, but increased LOS was associated with worse OS. Larger prospective studies are needed to further examine outcomes after IMRT in patients with LA-NSCLC receiving TMT.

Published
2021

9. Dual HDAC and PI3K inhibition abrogates NFκB- and FOXM1-mediated DNA damage response to radiosensitize pediatric high-grade gliomas

Author

Pal, Sharmistha, Kozono, David, Yang, Xiaodong, Fendler, Wojciech, Fitts, Whitney, Ni, Jing, Alberta, John A, Zhao, Jean, Liu, Kevin X, Bian, Jie, Truffaux, Nathalene, Weiss, William A, Resnick, Adam C, Bandopadhayay, Pratiti, Ligon, Keith L, DuBois, Steven G, Mueller, Sabine, Chowdhury, Dipanjan, and Haas-Kogan, Daphne A

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Oncology and Carcinogenesis, Radiation Oncology, Brain Cancer, Cancer, Pediatric, Rare Diseases, Genetics, Pediatric Cancer, Brain Disorders, Neurosciences, Orphan Drug, 5.1 Pharmaceuticals, Animals, Brain Neoplasms, Cell Line, Tumor, Child, DNA Damage, DNA Repair, Forkhead Box Protein M1, Glioma, Histone Deacetylase Inhibitors, Histone Deacetylases, Homologous Recombination, Humans, Mice, Mice, Nude, Morpholines, NF-kappa B, Phosphoinositide-3 Kinase Inhibitors, Pyrimidines, Radiation-Sensitizing Agents, Oncology & Carcinogenesis, Biochemistry and cell biology, Oncology and carcinogenesis
Abstract

Aberrant chromatin remodeling and activation of the PI3K pathway have been identified as important mediators of pediatric high-grade glioma (pHGG) and diffuse intrinsic pontine glioma (DIPG) pathogenesis. As inhibition of these pathways are promising therapeutic avenues and radiation is the only modality to prolong survival of patients with DIPG, we sought to explore radiosensitizing functions of such inhibition and to explore mechanisms of action of such agents. Here, we demonstrate that combined treatment with radiotherapy and CUDC-907, a novel first-in-class dual inhibitor of histone deacetylases (HDAC) and PI3K, evokes a potent cytotoxic response in pHGG and DIPG models. CUDC-907 modulated DNA damage response by inhibiting radiation-induced DNA repair pathways including homologous recombination and nonhomologous end joining. The radiosensitizing effects of CUDC-907 were mediated by decreased NFκB/Forkhead box M1 (FOXM1) recruitment to promoters of genes involved in the DNA damage response; exogenous expression of NFκB/FOXM1 protected from CUDC-907-induced cytotoxicity. Together, these findings reveal CUDC-907 as a novel radiosensitizer with potent antitumor activity in pHGG and DIPG and provide a preclinical rationale for the combination of CUDC-907 with radiotherapy as a novel therapeutic strategy against pHGG and DIPG. More globally, we have identified NFκB and FOXM1 and their downstream transcriptional elements as critical targets for new treatments for pHGG and DIPG.Significance: These findings describe the radiosensitizing effect of a novel agent in pediatric high-grade gliomas, addressing a critical unmet need of increasing the radiation sensitivity of these highly aggressive tumors. Cancer Res; 78(14); 4007-21. ©2018 AACR.

Published
2018

16. A process to reanalyze clinical DNA sequencing data for biomarker matching in the Lung-MAP Master Protocol

Author

Neal, Joel W, primary, Minichiello, Katherine, additional, Brennick, Ryan, additional, Huang, Richard S P, additional, Hiemenz, Matthew C, additional, Amler, Cornel, additional, Patel, Jyoti, additional, Herbst, Roy, additional, Reckamp, Karen L, additional, Borghaei, Hossein, additional, Highleyman, Louise, additional, Redman, Mary W, additional, Pasquina, Lincoln W, additional, and Kozono, David E, additional

Published
2024
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18. The ASCENT Trial: a phase 2 study of induction and consolidation afatinib and chemoradiation with or without surgery in stage III EGFR-mutant NSCLC.

Author

Chang, Allison E B, Piper-Vallillo, Andrew J, Mak, Raymond H, Lanuti, Michael, Muzikansky, Alona, Rotow, Julia, Jänne, Pasi A, Mino-Kenudson, Mari, Swanson, Scott, Wright, Cameron D, Kozono, David, Marcoux, Paul, Piotrowska, Zofia, Sequist, Lecia V, and Willers, Henning

Subjects
CANCER treatment, PATIENT safety, CISPLATIN, PEMETREXED, CLINICAL trials, TERMINATION of treatment, CHEMORADIOTHERAPY, DESCRIPTIVE statistics, OPERATIVE surgery, DRUG efficacy, COMBINED modality therapy, ONCOGENES, GENETIC mutation, LUNG cancer, CONSOLIDATION chemotherapy, PROGRESSION-free survival, CONFIDENCE intervals, DISEASE relapse, EPIDERMAL growth factor receptors, INDUCTION chemotherapy, AFATINIB, HISTOLOGY, SPECIALTY hospitals, OVERALL survival, PATIENT aftercare, EVALUATION, DISEASE risk factors
Abstract

Background The role of tyrosine kinase inhibitors (TKIs) in early-stage and metastatic oncogene-driven non–small cell lung cancer (NSCLC) is established, but it remains unknown how best to integrate TKIs with concurrent chemoradiotherapy (cCRT) in locally advanced disease. The phase 2 ASCENT trial assessed the efficacy and safety of afatinib and cCRT with or without surgery in locally advanced epidermal growth factor receptor (EGFR)-mutant NSCLC. Patients and Methods Adults ≥18 years with histologically confirmed stage III (AJCC 7th edition) NSCLC with activating EGFR mutations were enrolled at Mass General and Dana-Farber/Brigham Cancer Centers, Boston, Massachusetts. Patients received induction afatinib 40 mg daily for 2 months, then cisplatin 75 mg/m2 and pemetrexed 500 mg/m2 IV every 3 weeks during RT (definitive or neoadjuvant dosing). Patients with resectable disease underwent surgery. All patients were offered consolidation afatinib for 2 years. The primary endpoint was the objective response rate (ORR) to induction TKI. Secondary endpoints were safety, conversion to operability, progression-free survival (PFS), and overall survival (OS). Analyses were performed on the intention-to-treat population. Results Nineteen patients (median age 56 years; 74% female) were enrolled. ORR to induction afatinib was 63%. Seventeen patients received cCRT; 2/9 previously unresectable became resectable. Ten underwent surgery; 6 had a major or complete pathological response. Thirteen received consolidation afatinib. With a median follow-up of 5.0 years, median PFS and OS were 2.6 (95% CI, 1.4-3.1) and 5.8 years (2.9-NR), respectively. Sixteen recurred or died; 6 recurrences were isolated to CNS. The median time to progression after stopping consolidation TKI was 2.9 months (95% CI, 1.1-7.2). Four developed grade 2 pneumonitis. There were no treatment-related deaths. Conclusion We explored the efficacy of combining TKI with cCRT in oncogene-driven NSCLC. Induction TKI did not compromise subsequent receipt of multimodality therapy. PFS was promising, but the prevalence of CNS-only recurrences and rapid progression after TKI discontinuation speak to unmet needs in measuring and eradicating micrometastatic disease. [ABSTRACT FROM AUTHOR]

Published
2024
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24. Loss of ADAR1 in tumours overcomes resistance to immune checkpoint blockade

Author

Ishizuka, Jeffrey J., Manguso, Robert T., Cheruiyot, Collins K., Bi, Kevin, Panda, Arpit, Iracheta-Vellve, Arvin, Miller, Brian C., Du, Peter P., Yates, Kathleen B., Dubrot, Juan, Buchumenski, Ilana, Comstock, Dawn E., Brown, Flavian D., Ayer, Austin, Kohnle, Ian C., Pope, Hans W., Zimmer, Margaret D., Sen, Debattama R., Lane-Reticker, Sarah K., Robitschek, Emily J., Griffin, Gabriel K., Collins, Natalie B., Long, Adrienne H., Doench, John G., Kozono, David, Levanon, Erez Y., and Haining, W. Nicholas

Published
2019
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25. Radiation-induced circulating microRNAs linked to echocardiography parameters after radiotherapy

Author

Chałubińska-Fendler, Justyna, primary, Nowicka, Zuzanna, additional, Dróżdż, Izabela, additional, Graczyk, Łukasz, additional, Piotrowski, Grzegorz, additional, Tomasik, Bartłomiej, additional, Spych, Michał, additional, Fijuth, Jacek, additional, Papis-Ubych, Anna, additional, Kędzierawski, Piotr, additional, Kozono, David, additional, and Fendler, Wojciech, additional

Published
2023
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33. Targeting DNA Repair with Combined Inhibition of NHEJ and MMEJ Induces Synthetic Lethality in TP53-Mutant Cancers

Author

Patterson-Fortin, Jeffrey, primary, Bose, Arindam, additional, Tsai, Wei-Chih, additional, Grochala, Carter, additional, Nguyen, Huy, additional, Zhou, Jia, additional, Parmar, Kalindi, additional, Lazaro, Jean-Bernard, additional, Liu, Joyce, additional, McQueen, Kelsey, additional, Shapiro, Geoffrey I., additional, Kozono, David, additional, and D'Andrea, Alan D., additional

Published
2022
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35. Smart Radiotherapy Biomaterials for Image-Guided In Situ Cancer Vaccination.

Author

Ainsworth, Victoria, Moreau, Michele, Guthier, Romy, Zegeye, Ysaac, Kozono, David, Swanson, William, Jandel, Marian, Oh, Philmo, Quon, Harry, Hobbs, Robert F., Yasmin-Karim, Sayeda, Sajo, Erno, and Ngwa, Wilfred

Subjects
CANCER vaccines, IMAGE-guided radiation therapy, ATOMIC number, IMMUNE response, RADIOTHERAPY, SMART structures, SMART materials
Abstract

Recent studies have highlighted the potential of smart radiotherapy biomaterials (SRBs) for combining radiotherapy and immunotherapy. These SRBs include smart fiducial markers and smart nanoparticles made with high atomic number materials that can provide requisite image contrast during radiotherapy, increase tumor immunogenicity, and provide sustained local delivery of immunotherapy. Here, we review the state-of-the-art in this area of research, the challenges and opportunities, with a focus on in situ vaccination to expand the role of radiotherapy in the treatment of both local and metastatic disease. A roadmap for clinical translation is outlined with a focus on specific cancers where such an approach is readily translatable or will have the highest impact. The potential of FLASH radiotherapy to synergize with SRBs is discussed including prospects for using SRBs in place of currently used inert radiotherapy biomaterials such as fiducial markers, or spacers. While the bulk of this review focuses on the last decade, in some cases, relevant foundational work extends as far back as the last two and half decades. [ABSTRACT FROM AUTHOR]

Published
2023
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36. Abstract 796: Dual inhibition of NHEJ and MMEJ induces synthetic lethality in TP53 mutant cancers

Author

Patterson-Fortin, Jeffrey, primary, Bose, Arindam, additional, Tsai, Wei-Chih, additional, Grochala, Carter, additional, Nguyen, Huy, additional, Zhou, Jia, additional, Parmar, Kalindi, additional, Lazaro, Jean-Bernard, additional, Liu, Joyce, additional, McQueen, Kelsey, additional, Shapiro, Geoffrey I., additional, Kozono, David, additional, and D'Andrea, Alan D., additional

Published
2022
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37. Elevated Coronary Artery Calcium Quantified by a Validated Deep Learning Model From Lung Cancer Radiotherapy Planning Scans Predicts Mortality

Author

Atkins, Katelyn M, Weiss, Jakob, Zeleznik, Roman, Bitterman, Danielle S, Chaunzwa, Tafadzwa L, Huynh, Elizabeth, Guthier, Christian, Kozono, David E, Lewis, John H, Tamarappoo, Balaji K, Nohria, Anju, Hoffmann, Udo, Aerts, Hugo J W L, Mak, Raymond H, Atkins, Katelyn M, Weiss, Jakob, Zeleznik, Roman, Bitterman, Danielle S, Chaunzwa, Tafadzwa L, Huynh, Elizabeth, Guthier, Christian, Kozono, David E, Lewis, John H, Tamarappoo, Balaji K, Nohria, Anju, Hoffmann, Udo, Aerts, Hugo J W L, and Mak, Raymond H

Abstract

PURPOSE: Coronary artery calcium (CAC) quantified on computed tomography (CT) scans is a robust predictor of atherosclerotic coronary disease; however, the feasibility and relevance of quantitating CAC from lung cancer radiotherapy planning CT scans is unknown. We used a previously validated deep learning (DL) model to assess whether CAC is a predictor of all-cause mortality and major adverse cardiac events (MACEs).METHODS: Retrospective analysis of non-contrast-enhanced radiotherapy planning CT scans from 428 patients with locally advanced lung cancer is performed. The DL-CAC algorithm was previously trained on 1,636 cardiac-gated CT scans and tested on four clinical trial cohorts. Plaques ≥ 1 cubic millimeter were measured to generate an Agatston-like DL-CAC score and grouped as DL-CAC = 0 (very low risk) and DL-CAC ≥ 1 (elevated risk). Cox and Fine and Gray regressions were adjusted for lung cancer and cardiovascular factors.RESULTS: The median follow-up was 18.1 months. The majority (61.4%) had a DL-CAC ≥ 1. There was an increased risk of all-cause mortality with DL-CAC ≥ 1 versus DL-CAC = 0 (adjusted hazard ratio, 1.51; 95% CI, 1.01 to 2.26; P = .04), with 2-year estimates of 56.2% versus 45.4%, respectively. There was a trend toward increased risk of major adverse cardiac events with DL-CAC ≥ 1 versus DL-CAC = 0 (hazard ratio, 1.80; 95% CI, 0.87 to 3.74; P = .11), with 2-year estimates of 7.3% versus 1.2%, respectively.CONCLUSION: In this proof-of-concept study, CAC was effectively measured from routinely acquired radiotherapy planning CT scans using an automated model. Elevated CAC, as predicted by the DL model, was associated with an increased risk of mortality, suggesting a potential benefit for automated cardiac risk screening before cancer therapy begins.

Published
2022

40. Rates of Guideline-Concordant Surgery and Adjuvant Chemotherapy Among Patients With Early-Stage Lung Cancer in the US ALCHEMIST Study (Alliance A151216)

Author

Kehl, Kenneth L., Zahrieh, David, Yang, Ping, Hillman, Shauna L., Tan, Angelina D., Sands, Jacob M., Oxnard, Geoffrey R., Gillaspie, Erin A., Wigle, Dennis, Malik, Shakun, Stinchcombe, Thomas E., Ramalingam, Suresh S., Kelly, Karen, Govindan, Ramaswamy, Mandrekar, Sumithra J., Osarogiagbon, Raymond U., and Kozono, David

Subjects
Cancer Research, Lung Neoplasms, Communication Barriers, Translating, Cohort Studies, Oncology, Chemotherapy, Adjuvant, Carcinoma, Non-Small-Cell Lung, Antineoplastic Combined Chemotherapy Protocols, Humans, Female, Cisplatin, Original Investigation, Aged, Neoplasm Staging, Retrospective Studies
Abstract

IMPORTANCE: Standard treatment for resectable non–small cell lung cancer (NSCLC) includes anatomic resection with adequate lymph node dissection and adjuvant chemotherapy for appropriate patients. Historically, many patients with early-stage NSCLC have not received such treatment, which may affect the interpretation of the results of adjuvant therapy trials. OBJECTIVE: To ascertain patterns of guideline-concordant treatment among patients enrolled in a US-wide screening protocol for adjuvant treatment trials for resected NSCLC. DESIGN, SETTING, AND PARTICIPANTS: This retrospective cohort study included 2833 patients with stage IB to IIIA NSCLC (per American Joint Committee on Cancer 7th edition criteria) who enrolled in the Adjuvant Lung Cancer Enrichment Marker Identification and Sequencing Trial (ALCHEMIST) screening study (Alliance for Clinical Trials in Oncology A151216) from August 18, 2014, to April 1, 2019, and who did not enroll in a therapeutic adjuvant clinical trial; patients had tumors of at least 4 cm and/or with positive lymph nodes. Statistical analysis was conducted from June 1, 2020, through October 1, 2021. EXPOSURES: Care patterns were ascertained overall and by sociodemographic and clinical factors, including age, sex, race and ethnicity, educational level, marital status, geography, histologic characteristics, stage, genomic variant status, smoking history, and comorbidities. MAIN OUTCOMES AND MEASURES: Five outcomes are reported: whether patients (1) had anatomic surgical resection, (2) had adequate lymph node dissection (≥1 N1 nodal station plus ≥3 N2 nodal stations), (3) received any adjuvant chemotherapy, (4) received any cisplatin-based adjuvant chemotherapy, and (5) received at least 4 cycles of adjuvant chemotherapy. RESULTS: Of the 2833 patients (1505 women [53%]; mean [SD] age, 66.5 [9.2] years) included in this analysis, 2697 (95%) had anatomic surgical resection, 1513 (53%) had adequate lymph node dissection, 1617 (57%) received any adjuvant chemotherapy, 1237 (44%) received at least 4 cycles of adjuvant platinum-based chemotherapy, and 965 (34%) received any cisplatin-based adjuvant chemotherapy. Rates were similar across race and ethnicity. CONCLUSIONS AND RELEVANCE: This cohort study found that among participants in a screening protocol for adjuvant clinical trials for resected early-stage NSCLC, just 53% underwent adequate lymph node dissection, and 57% received adjuvant chemotherapy, despite indications for such treatment. These results may affect the interpretation of adjuvant trials. Efforts are needed to optimize the use of proven therapies for early-stage NSCLC. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02194738

Published
2022
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41. Integration of immunotherapy into adjuvant therapy for resected non-small-cell lung cancer: ALCHEMIST chemo-IO (ACCIO)

Author

Sands, Jacob M, primary, Mandrekar, Sumithra J, additional, Kozono, David, additional, Oxnard, Geoffrey R, additional, Hillman, Shauna L, additional, Wigle, Dennis A, additional, Govindan, Ramaswamy, additional, Carlisle, Jennifer, additional, Gray, Jhanelle, additional, Salama, Joseph K, additional, Raez, Luis, additional, Ganti, Apar, additional, Foster, Nathan, additional, Malik, Shakun, additional, Bradley, Jeffrey, additional, Kelly, Karen, additional, Ramalingam, Suresh S, additional, and Stinchcombe, Thomas E, additional

Published
2021
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42. Radiation Induces Valvular Interstitial Cell Calcific Response in an in vitro Model of Calcific Aortic Valve Disease

Author

Meerman, Manon, Driessen, Rob, van Engeland, Nicole C.A., Bergsma, Irith, Steenhuijsen, Jacco L.G., Kozono, David, Aikawa, Elena, Hjortnaes, Jesper, Bouten, Carlijn V.C., Meerman, Manon, Driessen, Rob, van Engeland, Nicole C.A., Bergsma, Irith, Steenhuijsen, Jacco L.G., Kozono, David, Aikawa, Elena, Hjortnaes, Jesper, and Bouten, Carlijn V.C.

Abstract

Background: Mediastinal ionizing radiotherapy is associated with an increased risk of valvular disease, which demonstrates pathological hallmarks similar to calcific aortic valve disease (CAVD). Despite advances in radiotherapy techniques, the prevalence of comorbidities such as radiation-associated valvular disease is still increasing due to improved survival of patients receiving radiotherapy. However, the mechanisms of radiation-associated valvular disease are largely unknown. CAVD is considered to be an actively regulated disease process, mainly controlled by valvular interstitial cells (VICs). We hypothesize that radiation exposure catalyzes the calcific response of VICs and, therefore, contributes to the development of radiation-associated valvular disease. Methods and Results: To delineate the relationship between radiation and VIC behavior (morphology, calcification, and matrix turnover), two different in vitro models were established: (1) VICs were cultured two-dimensional (2D) on coverslips in control medium (CM) or osteogenic medium (OM) and irradiated with 0, 2, 4, 8, or 16 Gray (Gy); and (2) three-dimensional (3D) hydrogel system was designed, loaded with VICs and exposed to 0, 4, or 16 Gy of radiation. In both models, a dose-dependent decrease in cell viability and proliferation was observed in CM and OM. Radiation exposure caused myofibroblast-like morphological changes and differentiation of VICs, as characterized by decreased αSMA expression. Calcification, as defined by increased alkaline phosphatase activity, was mostly present in the 2D irradiated VICs exposed to 4 Gy, while after exposure to higher doses VICs acquired a unique giant fibroblast-like cell morphology. Finally, matrix turnover was significantly affected by radiation exposure in the 3D irradiated VICs, as shown by decreased collagen staining and increased MMP-2 and MMP-9 activity. Conclusions: The presented work demonstrates that radiation exposure enhances the calcific response i

Published
2021

46. MOESM1 of The impact of quantitative CT-based tumor volumetric features on the outcomes of patients with limited stage small cell lung cancer

Author

Kamran, Sophia, Coroller, Thibaud, Milani, Nastaran, Vishesh Agrawal, Baldini, Elizabeth, Chen, Aileen, Johnson, Bruce, Kozono, David, Idalid Franco, Nitish Chopra, Zeleznik, Roman, Aerts, Hugo, and Mak, Raymond

Subjects
respiratory tract diseases
Abstract

Additional file 1: Table S1. Univariate Analysis of predictors for Loco-regional recurrence (LRR), distant metastasis (DM), any progression and overall survival (OS) for patients with limited stage small cell lung cancer (LS-SCLC) treated with prophylactic cranial irradiation, (n = 63). Table S2. Multivariable Cox Analysis of predictors for Loco-regional recurrence (LRR), distant metastasis (DM), any progression and overall survival (OS) for patients with limited stage small cell lung cancer (LS-SCLC) treated with prophylactic cranial irradiation, (n = 63). Table S3. Univariate Analysis of predictors for Loco-regional recurrence (LRR), distant metastasis (DM), any progression and overall survival (OS) for patients with limited stage small cell lung cancer (LS-SCLC) treated without prophylactic cranial irradiation, (n = 42). Table S4. Univariate Analysis of predictors for Loco-regional recurrence (LRR), distant metastasis (DM), any progression and overall survival (OS) for patients with limited stage small cell lung cancer (LS-SCLC) treated with chemoradiation, (n = 105).

Published
2020
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