134 results on '"Cabanero M"'
Search Results
2. EP07.02-15 Longitudinal ctDNA Testing in Resected, Early Stage Non-small Cell Lung Cancers
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Feng, J., primary, Waddell, T., additional, Yasufuku, K., additional, Kelly, D., additional, Meti, N., additional, Pierre, A., additional, Keshavjee, S., additional, Yeung, J., additional, Cypel, M., additional, Donahoe, L., additional, Wakeam, E., additional, de Perrot, M., additional, Law, J., additional, Salvarrey, A., additional, Le, L.W., additional, Lister, J., additional, Cabanero, M., additional, Tsao, M.S., additional, Pipinikas, C., additional, Howarth, K., additional, and Leighl, N.B., additional
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- 2023
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3. 1151P Evolution of biomarker testing among non-squamous/non-small cell lung cancer (NSCLC) patients (Pts) and impact on turnaround times (TAT)
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Fan, Z., primary, Tudor, R., additional, Le, L., additional, Law, J., additional, Kuang, S., additional, Meti, N., additional, Fung, A., additional, Perdrizet, K., additional, Chen, K., additional, Li, J., additional, Ghumman, N., additional, Ranich, L., additional, Wei, C., additional, Sabatani, P., additional, Tsao, M-S., additional, Leighl, N., additional, and Cabanero, M., additional
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- 2022
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4. EP11.02-001 Natural Language Processing to Abstract Preneoplastic and Incidental Pulmonary Lesions from Pathology Reports
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Petricca, J., primary, French, C., additional, Ajaj, R., additional, Zelifan, A., additional, Grant, B., additional, Zhan, L., additional, Zhang, Y., additional, Thakral, A., additional, Nicholls, D., additional, Hsu, Y.-H.R., additional, Pal, P., additional, Cabanero, M., additional, Tsao, M.S., additional, and Liu, G., additional
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- 2022
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5. 1191TiP Nivolumab-ipilimumab with cfDNA-guided treatment intensification as a chemotherapy-sparing strategy in metastatic non-small cell lung cancer (ATLAS)
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Corke, L., primary, García Pardo de Santayana, M., additional, Meteleva, K., additional, Shepherd, F.A., additional, Bradbury, P., additional, Eng, L., additional, Kuang, S., additional, Cabanero, M., additional, Rogalla, P., additional, Liu, G., additional, Tsao, M-S., additional, Pugh, T.J., additional, Wang, B., additional, Ohashi, P., additional, Leighl, N., additional, and Sacher, A., additional
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- 2022
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6. 1058P Non-smokers with squamous lung cancers have a high incidence of HHV infections, DDR gene alterations and good prognosis
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Lau, S., primary, Makarem, M., additional, Cabanero, M., additional, Tsao, M-S., additional, Bradbury, P., additional, Shepherd, F.A., additional, Liu, G., additional, Leighl, N., additional, and Sacher, A., additional
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- 2022
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7. FP12.01 PD-L1 Assessment in Cytology is Comparable to Histology in Predicting Treatment Response to Checkpoint Inhibitors in NSCLC
- Author
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Lau, S., primary, Rabindranath, M., additional, Weiss, J., additional, Li, J., additional, Nirmalakumar, S., additional, Ruff, H., additional, Boerner, S., additional, Tong, L.C., additional, Tsao, M., additional, Pal, P., additional, Cabanero, M., additional, Hsu, Y.H., additional, Fung, A., additional, Sacher, A., additional, Shepherd, F.A., additional, Liu, G., additional, Bradbury, P., additional, Yasufuku, K., additional, Czarnecka-Kujawa, K., additional, Ko, H.M., additional, Leighl, N., additional, and Schwock, J., additional
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- 2021
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8. A genome-wide association study implicates diacylglycerol kinase eta (DGKH) and several other genes in the etiology of bipolar disorder
- Author
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Baum, A E, Akula, N, Cabanero, M, Cardona, I, Corona, W, Klemens, B, Schulze, T G, Cichon, S, Rietschel, M, Nöthen, M M, Georgi, A, Schumacher, J, Schwarz, M, Abou Jamra, R, Höfels, S, Propping, P, Satagopan, J, Detera-Wadleigh, S D, Hardy, J, and McMahon, F J
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- 2008
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9. P1.01-30 Non-Small Cell Lung Cancer (NSCLC) Next Generation Sequencing (NGS): Integrating Genomic Sequencing into a Publicly Funded Health Care Model
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Perdrizet, K., primary, Stockley, T., additional, Law, J., additional, Shabir, M., additional, Zhang, T., additional, Le, L., additional, Lau, A., additional, Tsao, M., additional, Kamel-Reid, S., additional, Pal, P., additional, Cabanero, M., additional, Schwock, J., additional, Ko, H., additional, Liu, G., additional, Bradbury, P., additional, Sacher, A., additional, Shepherd, F., additional, and Leighl, N., additional
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- 2019
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10. OA08.01 Organoid Cultures as Novel Preclinical Models of Non-Small Cell Lung Cancer
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Tsao, M., primary, Shi, R., additional, Radulovich, N., additional, Ng, C., additional, Notsuda, H., additional, Cabanero, M., additional, Martins-Filho, S., additional, Raghavan, V., additional, Li, Q., additional, Mer, A., additional, Liu, N., additional, Pham, N., additional, Haibe-Kains, B., additional, Liu, G., additional, and Moghal, N., additional
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- 2019
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11. P2.14-62 Early, Subclinical SCLC Transformation in Patients with EGFR Mutant Lung Cancer Receiving Osimertinib, Detected Through Cell-Free DNA
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Stewart, E., primary, Martins-Filho, S., additional, Cabanero, M., additional, Wang, A., additional, Huang, J., additional, Bao, H., additional, Wu, X., additional, Patel, D., additional, Chen, Z., additional, Law, J., additional, Bradbury, P., additional, Shepherd, F., additional, Leighl, N., additional, Tsao, M., additional, Pugh, T., additional, Bratman, S., additional, Liu, G., additional, and Sacher, A., additional
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- 2019
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12. CCTG IND 232: A phase II study of durvalumab with or without tremelimumab in patients with metastatic castration resistant prostate cancer (mCRPC)
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Hotte, S.J., primary, Winquist, E., additional, Chi, K.N., additional, Ellard, S.L., additional, Sridhar, S., additional, Emmenegger, U., additional, Salim, M., additional, Iqbal, N.N., additional, Canil, C., additional, Kollmannsberger, C.K., additional, Hansen, A.R., additional, Lalani, A-K A, additional, Gingerich, J., additional, Finch, D., additional, Cabanero, M., additional, Wyatt, A.W., additional, Tu, D., additional, Vera-Badillo, F., additional, Seymour, L.K., additional, and Smoragiewicz, M., additional
- Published
- 2019
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13. MA18.07 Identification of Neuroendocrine Transformation in Anaplastic Lymphoma Kinase Rearranged (ALK+) Tumors After Tyrosine Kinase Inhibitors
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Pal, P., primary, Fares, A., additional, Patel, D., additional, Stewart, E., additional, Perera-Low, N., additional, Grindley, A., additional, Allison, F., additional, Pham, N., additional, Shi, R., additional, Leighl, N., additional, Shepherd, F., additional, Bradbury, P., additional, Sacher, A., additional, Rogalla, P., additional, Yasufuku, K., additional, Cabanero, M., additional, Tsao, M., additional, Liu, G., additional, Martins-Filho, S., additional, and Nguyen, L., additional
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- 2019
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14. P3.16-07 The Impact of Clinical and Molecular Profile of Resected EGFR-Mutant Non-Small Cell Lung Cancer on the Risk of Developing Brain Metastases
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Moskovitz, M., primary, Cabanero, M., additional, Torchia, J., additional, Sorotsky, H., additional, Weiss, J., additional, Pintilie, M., additional, Leighl, N., additional, Bradbury, P., additional, Liu, G., additional, Zadeh, G., additional, Doherty, M., additional, Kia, A., additional, Torti, D., additional, Tsao, M., additional, Pugh, T., additional, and Shepherd, F., additional
- Published
- 2018
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15. P1.04-05 Elucidating the Role of Leukocyte-Associated Immunoglobin-Like Receptor 2 (LAIR2) in Lung Cancer Development
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Ly, D., primary, Cabanero, M., additional, Zhu, C., additional, Tsao, M., additional, and Zhang, L., additional
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- 2018
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16. P3.03-29 The Prognostic Effect of Tumor Mutation Burden and Smoking History in Resected EGFR Mutant Non-Small Cell Lung Cancer
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Sorotsky, H., primary, Cabanero, M., additional, Moskovitz, M., additional, Weiss, J., additional, Pintilie, M., additional, Leighl, N., additional, Bradbury, P., additional, Liu, G., additional, Kia, A., additional, Pugh, T., additional, Torti, D., additional, Torchia, J., additional, Tsao, M., additional, and Shepherd, F., additional
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- 2018
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17. MA24.05 Baseline Spatial Heterogeneity of T790M in Tyrosine Kinase Inhibitor Naïve EGFR-Mutant Lung Adenocarcinomas
- Author
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Cabanero, M., primary, Kuo, J., additional, Liu, N., additional, and Tsao, M., additional
- Published
- 2018
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18. P2.06-38 Mesothelioma Stem Cells May Be the Critical Factor of Treatment Failure
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Wu, L., primary, Chan, M., additional, Mckee, T., additional, Butt, S., additional, Cabanero, M., additional, Green, B., additional, Duong, B., additional, Yun, Z., additional, Kohno, M., additional, Murakami, J., additional, Zhao, Y., additional, Kelley, S., additional, and De Perrot, M., additional
- Published
- 2018
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19. MA27.01 Establishment of PDX From Tumors Characterized by EGFR Mutations or ALK Fusion Genes from Resections, Biopsies and Pleural Fluids
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Martins-Filho, S., primary, Cabanero, M., additional, Pham, N., additional, Stewart, E., additional, Ravi, D., additional, Patel, D., additional, Mcconnell, J., additional, Grindlay, A., additional, Allison, F., additional, Li, M., additional, Shepherd, F., additional, Tsao, M., additional, Yasufuku, K., additional, and Liu, G., additional
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- 2018
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20. MA27.03 Multi-Omic Characterization of TKI-Treated Drug-Tolerant Cell Population in an EGFR-Mutated NSCLC Primary-Derived Xenograft
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Stewart, E., primary, Cabanero, M., additional, Raghavan, V., additional, Bruce, J., additional, Guilhamon, P., additional, Singhania, R., additional, Pham, N., additional, Shen, S.Y., additional, Li, T., additional, Li, M., additional, Leighl, N., additional, Shepherd, F., additional, Pugh, T., additional, De Carvalho, D., additional, Lupien, M., additional, Liu, G., additional, and Tsao, M., additional
- Published
- 2018
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21. MA25.11 Clinical and Molecular Predictors of Outcome in Patients with EGFR mutant NSCLC Brain Metastases treated with RT
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Moraes, F., primary, Weiss, J., additional, Moskovitz, M., additional, Sorotsky, H., additional, Pintilie, M., additional, Leighl, N., additional, Bradbury, P., additional, Liu, G., additional, Zadeh, G., additional, Doherty, M., additional, Kia, A., additional, So, J., additional, Cabanero, M., additional, Pugh, T., additional, Sugumar, V., additional, Torti, D., additional, Tsao, M., additional, Torchia, J., additional, Shultz, D., additional, Shepherd, F., additional, and Lok, B., additional
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- 2018
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22. Circulating Tumour DNA in EGFR-Mutant Non-Small-Cell Lung Cancer
- Author
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Cabanero, M., primary and Tsao, M.S., additional
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- 2018
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23. P3.03-008 Organoid Cultures of Lung Squamous Cell Carcinoma for Drug Screening
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Shi, R., primary, Radulovich, N., additional, Cabanero, M., additional, Pintille, M., additional, Raghavan, V., additional, Quevedo, R., additional, Tamblyn, L., additional, Ng, C., additional, Stambolic, V., additional, Pugh, T., additional, Moghal, N., additional, and Tsao, M., additional
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- 2017
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24. P1.02-016 Establishment of Lung Adenocarcinoma Organoid Cultures
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Notsuda, H., primary, Radulovich, N., additional, Ng, C., additional, Tamblyn, L., additional, Cabanero, M., additional, Li, M., additional, Pham, N., additional, and Tsao, M., additional
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- 2017
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25. Management of Egfr-Mutated Non-Small-Cell Lung Cancer: Practical Implications from a Clinical and Pathology Perspective
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Cabanero, M., primary, Sangha, R., additional, Sheffield, B.S., additional, Sukhai, M., additional, Pakkal, M., additional, Kamel-Reid, S., additional, Karsan, A., additional, Ionescu, D., additional, Juergens, R.A., additional, Butts, C., additional, and Tsao, M.S., additional
- Published
- 2017
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26. LBA51 - CCTG IND 232: A phase II study of durvalumab with or without tremelimumab in patients with metastatic castration resistant prostate cancer (mCRPC)
- Author
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Hotte, S.J., Winquist, E., Chi, K.N., Ellard, S.L., Sridhar, S., Emmenegger, U., Salim, M., Iqbal, N.N., Canil, C., Kollmannsberger, C.K., Hansen, A.R., Lalani, A-K A, Gingerich, J., Finch, D., Cabanero, M., Wyatt, A.W., Tu, D., Vera-Badillo, F., Seymour, L.K., and Smoragiewicz, M.
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- 2019
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27. Prognostic Factors From Computer-Assisted Image Analysis of an Oral Cavity Squamous Cell Carcinoma Tissue Microarray
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Lee, S.L., primary, Cabanero, M., additional, Hyrcza, M., additional, Butler, M., additional, Liu, F.F., additional, Hansen, A., additional, Huang, S.H., additional, Tsao, M., additional, Song, Y., additional, Xu, W., additional, Goldstein, D., additional, Weinreb, I., additional, and Bratman, S.V., additional
- Published
- 2016
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28. Bioenergy Networks: Recommendations on Stakeholder Motivation
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Papapetrou, M., Cabanero, M., Sherrard, A., Epp, C., and Alakangas, E.
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Biomass - Abstract
There are rural areas in Europe that have managed over the past few years to make significant progress in the exploitation of their local bioenergy resources. However, the development of the regional bioenergy markets is not without challenges: Most projects are facing difficulties to raise the funding for their planning and implementation, to secure the long term supply of sufficient biomass resources with stable quality at reasonable prices and to demonstrate that they make a contribution to the greenhouse gasses reduction and to the sustainable development of their region. The aim of the BioRegions project is to support the creation of “bioenergy regions” in rural areas of Europe. A “bioenergy region” gets at least one third of its energy (excluding transportation) by fuels produced from regional and sustainable bioenergy sources, with main focus on solid biomass This paper discusses the results from a survey of existing bioenergy networks in Europe about lessons learnt and critical success factors from their experience. It includes: how stakeholders were attracted to join the network, their motivation and interests, what the funding and administration mechanisms of the networks were and how these are maintained., Proceedings of the 19th European Biomass Conference and Exhibition, 6-10 June 2011, Berlin, Germany, pp. 2478-2482
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- 2011
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29. Association Study of Phosphodiesterase Genes in the Sequenced Alternatives to Relieve Depression (STAR*D) Sample
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Cabanero, M., Laje, G., Detera-Wadleigh, S., and McMahon, F. J.
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Adult ,Male ,Psychiatric Status Rating Scales ,Depressive Disorder ,Adolescent ,Phosphoric Diester Hydrolases ,Middle Aged ,Cyclic Nucleotide Phosphodiesterases, Type 1 ,Polymorphism, Single Nucleotide ,Article ,Haplotypes ,3',5'-Cyclic-AMP Phosphodiesterases ,3',5'-Cyclic-GMP Phosphodiesterases ,Humans ,Female ,Genetic Predisposition to Disease ,Aged - Abstract
A recent study has reported a significant association of variants in phosphodiesterase (PDE) genes with antidepressant treatment outcome in a Mexican American sample. We set out to investigate these findings in a large sample of patients from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study. STAR*D is a longitudinal study of antidepressant outcome in depressed outpatients. We genotyped three single nucleotide polymorphisms (SNPs) in PDE11A (rs1880916), PDE1A (rs1549870), and PDE9A (rs729861) for replication and we also report three additional SNPs in PDE11A (rs3770016, rs4893975, rs6433687) that had been genotyped for a previous study. Single marker analysis of remission within the Hispanic subsamples (n=268) revealed no significant evidence of association with markers in PDE11A, PDE9A, or PDE1A. Additional analyses of remission within the total STAR*D sample (n=1914) were also largely negative, as were analyses utilizing a narrower definition of remission. Haplotype analyses were carried out with the four PDE11A SNPs we genotyped; these also failed to show significant evidence of association in the STAR*D sample. In conclusion, we could not reproduce the reported association between PDE genes and antidepressant outcome in a sample of participants comparable to that reported previously. We conclude that PDE11A, PDE9A, and PDE1A are unlikely to play an important role in antidepressant outcome in this sample.
- Published
- 2009
30. Reproducibility of Assessment of Lepidic (Noninvasive) Patterns in Lung Adenocarcinoma With Cytokeratin Immunostain Compared With Hematoxylin and Eosin and the Proposed New International Association for the Study of Lung Cancer (IASLC) Algorithm.
- Author
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Yang E, Alshamlan N, Hueniken K, Weiss J, Cabanero M, and Tsao MS
- Abstract
Introduction: Lepidic growth is considered noninvasive in lung nonmucinous adenocarcinoma, whereas other patterns are invasive. Considerable interobserver variability in assessing "invasion" has been reported. We assessed the utility of cytokeratin 7 (CK7) stain and recently proposed International Association for the Study of Lung Cancer criteria to improve assessment of noninvasion in lung adenocarcinoma., Methods: Four pathologists (two staff, two trainees) assessed 158 hematoxylin and eosin (HE)- and CK7-stained slides of 108 pT1N0-2 nonmucinous lung adenocarcinoma cases. Scoring took place in four rounds. First, sections were independently scored for percentage of noninvasive or probable noninvasive and invasive or probable invasive patterns. Second, after a consensus scoring algorithm for CK7 was formulated, the slides were rescored. Subsequent third-round scoring was conducted only on HE slides using the 2023 International Association for the Study of Lung Cancer proposed criteria, and fourth-round scoring on both HE and CK7 slides simultaneously. Intraclass correlation coefficient (ICC) was calculated for each round. Recurrence-free survival was assessed using Cox proportional hazards regression methods., Results: In the first two rounds, interobserver concordance was consistently higher with CK7 (ICC range = 0.44-0.6) than HE (range = 0.24-0.49) scores. The IASLC proposed algorithm improved ICC of HE scores to 0.60 (95% confidence interval: 0.52-0.67), and round 4 HE and CK7 combined improved ICC to 0.75 (95% confidence interval: 0.70-0.80). Continuous measures of averaged noninvasive and probable noninvasive scores on HE were associated with improved recurrence-free survival (hazard ratio: 0.83-0.86)., Conclusions: CK7 staining consistently increased interobserver concordance in assessment of invasive versus noninvasive patterns than HE. Combining CK7 with the 2023 IASLC criteria for morphologic features of invasion may further improve the interobservers' concordance for the recognition of lepidic growth in nonmucinous lung adenocarcinoma., Competing Interests: The authors declare no conflict of interest., (© 2024 The Authors.)
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- 2024
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31. An unusual case of interstitial lung disease: Revisiting peribronchiolar metaplasia interstitial lung disease (PBM-ILD).
- Author
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Jung F, Shapera S, Cabanero M, McInnis M, and Fisher J
- Abstract
Peribronchiolar metaplasia (PBM) is a histological finding of uncertain significance commonly seen in interstitial lung disease (ILD). PBM is thought to be secondary to small airway injury from insults such as tobacco smoke and other environmental exposures. The term PBM-ILD has been proposed for patients with ILD where PBM is the major histologic finding, however a lack of radiographic changes supportive of ILD in previously reported cases has limited recognition of the diagnosis. We present a rare case of welding-associated ILD with clinical, radiographic, and histologic evidence consistent with the proposed definition of PBM-ILD. We outline an approach to its consideration as a diagnosis based on our experience through multidisciplinary discussion., Competing Interests: Jolene Fisher reports grants from the Canadian Pulmonary Fibrosis Foundation and the University of Toronto, and personal fees from Boehringer‐Ingelheim and AstraZeneca, outside the submitted work. Shane Shapera reports honoraria for speaking engagements and participation in advisory boards with Boehringer‐Ingelheim, Hoffman‐La Roche and AstraZeneca. Micheal McInnis reports personal fees from Bayer and Boehringer‐Ingelheim, outside the submitted work., (© 2023 The Authors. Respirology Case Reports published by John Wiley & Sons Australia, Ltd on behalf of The Asian Pacific Society of Respirology.)
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- 2023
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32. Mitochondrial Aconitase ACO2 Links Iron Homeostasis with Tumorigenicity in Non-Small Cell Lung Cancer.
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Mirhadi S, Zhang W, Pham NA, Karimzadeh F, Pintilie M, Tong J, Taylor P, Krieger J, Pitcher B, Sykes J, Wybenga-Groot L, Fladd C, Xu J, Wang T, Cabanero M, Li M, Weiss J, Sakashita S, Zaslaver O, Yu M, Caudy AA, St-Pierre J, Hawkins C, Kislinger T, Liu G, Shepherd FA, Tsao MS, and Moran MF
- Subjects
- Mice, Animals, Iron metabolism, Aconitate Hydratase genetics, Aconitate Hydratase metabolism, Homeostasis, Membrane Proteins metabolism, Iron-Binding Proteins, Carcinoma, Non-Small-Cell Lung genetics, Lung Neoplasms genetics
- Abstract
The ability of a patient tumor to engraft an immunodeficient mouse is the strongest known independent indicator of poor prognosis in early-stage non-small cell lung cancer (NSCLC). Analysis of primary NSCLC proteomes revealed low-level expression of mitochondrial aconitase (ACO2) in the more aggressive, engrafting tumors. Knockdown of ACO2 protein expression transformed immortalized lung epithelial cells, whereas upregulation of ACO2 in transformed NSCLC cells inhibited cell proliferation in vitro and tumor growth in vivo. High level ACO2 increased iron response element binding protein 1 (IRP1) and the intracellular labile iron pool. Impaired cellular proliferation associated with high level ACO2 was reversed by treatment of cells with an iron chelator, whereas increased cell proliferation associated with low level ACO2 was suppressed by treatment of cells with iron. Expression of CDGSH iron-sulfur (FeS) domain-containing protein 1 [CISD1; also known as mitoNEET (mNT)] was modulated by ACO2 expression level and inhibition of mNT by RNA interference or by treatment of cells with pioglitazone also increased iron and cell death. Hence, ACO2 is identified as a regulator of iron homeostasis and mNT is implicated as a target in aggressive NSCLC., Implications: FeS cluster-associated proteins including ACO2, mNT (encoded by CISD1), and IRP1 (encoded by ACO1) are part of an "ACO2-Iron Axis" that regulates iron homeostasis and is a determinant of a particularly aggressive subset of NSCLC., (©2022 The Authors; Published by the American Association for Cancer Research.)
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- 2023
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33. Cell-free DNA methylation-defined prognostic subgroups in small-cell lung cancer identified by leukocyte methylation subtraction.
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Ul Haq S, Schmid S, Aparnathi MK, Hueniken K, Zhan LJ, Sacdalan D, Li JJN, Meti N, Patel D, Cheng D, Philip V, Tsao MS, Cabanero M, de Carvalho D, Liu G, Bratman SV, and Lok BH
- Abstract
Small-cell lung cancer (SCLC) methylome is understudied. Here, we comprehensively profile SCLC using cell-free methylated DNA immunoprecipitation followed by sequencing (cfMeDIP-seq). Cell-free DNA (cfDNA) from plasma of 74 patients with SCLC pre-treatment and from 20 non-cancer participants, genomic DNA (gDNA) from peripheral blood leukocytes from the same 74 patients, and 7 accompanying circulating tumor cell-derived xenografts (CDXs) underwent cfMeDIP-seq. Peripheral blood leukocyte methylation (PRIME) subtraction to improve tumor specificity. SCLC cfDNA methylation is distinct from non-cancer but correlates with CDX tumor methylation. PRIME and k-means consensus identified two methylome clusters with prognostic associations that related to axon guidance, neuroactive ligand-receptor interaction, pluripotency of stem cells, and differentially methylated at long noncoding RNA and other repeats features. We comprehensively profiled the SCLC methylome in a large patient cohort and identified methylome clusters with prognostic associations. Our work demonstrates the potential of liquid biopsies in examining SCLC biology encoded in the methylome., Competing Interests: S.S. reports grants from AstraZeneca, BMS, Janssen, Von Tobel foundation, Fill the Gap, and has served on all institutional advisory board for BMS, AstraZeneca, MSD. N.M. reports personal fees from Takeda Oncology, Pfizer, and Novartis, outside of the submitted work. M.-S.T. reports research grant from Bayer and AstraZeneca, outside the submitted work, and personal fees from AstraZeneca, Amgen, BMS, Daiichi-Sankyo and Lilly, outside the submitted work. D. de Carvalho received research funds from Pfizer and is co-founder and shareholder of Adela Inc. S.V.B. is inventor on patents related to cell-free DNA mutation and methylation analysis technologies that have been licensed to Roche and Adela, respectively, and is co-founder of, has ownership in, and serves in a leadership role at Adela. G.L. reports grants and personal fees from AstraZeneca and Takeda; grants from Boehringer Ingelheim; and personal fees from Hoffman La Roche, Merck, Bristol Myers Squibb, and Pfizer outside the submitted work. B.H.L. reports grants from Pfizer; and grants, personal fees, and non-financial support from AstraZeneca outside the submitted work., (© 2022 The Author(s).)
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- 2022
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34. Upfront Next Generation Sequencing in Non-Small Cell Lung Cancer.
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Kuang S, Fung AS, Perdrizet KA, Chen K, Li JJN, Le LW, Cabanero M, Karsaneh OAA, Tsao MS, Morganstein J, Ranich L, Smith AC, Wei C, Cheung C, Shepherd FA, Liu G, Bradbury P, Pal P, Schwock J, Sacher AG, Law JH, Stockley TL, and Leighl NB
- Subjects
- High-Throughput Nucleotide Sequencing, Humans, Mutation, Proto-Oncogene Proteins p21(ras) genetics, Carcinoma, Non-Small-Cell Lung drug therapy, Carcinoma, Non-Small-Cell Lung genetics, Carcinoma, Non-Small-Cell Lung pathology, Lung Neoplasms drug therapy, Lung Neoplasms genetics, Lung Neoplasms pathology
- Abstract
In advanced non-small cell lung cancer (NSCLC), patients with actionable genomic alterations may derive additional clinical benefit from targeted treatment compared to cytotoxic chemotherapy. Current guidelines recommend extensive testing with next generation sequencing (NGS) panels. We investigated the impact of using a targeted NGS panel (TruSight Tumor 15, Illumina) as reflex testing for NSCLC samples at a single institution. Molecular analysis examined 15 genes for hotspot mutation variants, including AKT1 , BRAF , EGFR , ERBB2 , FOXL2 , GNA11 , GNAQ , KIT , KRAS , MET , NRAS , PDGFRA , PIK3CA , RET and TP53 genes. Between February 2017 and October 2020, 1460 samples from 1395 patients were analyzed. 1201 patients (86.1%) had at least one variant identified, most frequently TP53 (47.5%), KRAS (32.2%) or EGFR (24.2%). Among these, 994 patients (71.3%) had clinically relevant variants eligible for treatment with approved therapies or clinical trial enrollment. The incremental cost of NGS beyond single gene testing ( EGFR , ALK ) was CAD $233 per case. Reflex upfront NGS identified at least one actionable variant in more than 70% of patients with NSCLC, with minimal increase in testing cost. Implementation of NGS panels remains essential as treatment paradigms continue to evolve.
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- 2022
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35. Repurposing Itraconazole and Hydroxychloroquine to Target Lysosomal Homeostasis in Epithelial Ovarian Cancer.
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Marastoni S, Madariaga A, Pesic A, Nair SN, Li ZJ, Shalev Z, Ketela T, Colombo I, Mandilaras V, Cabanero M, Bruce JP, Li X, Garg S, Wang L, Chen EX, Gill S, Dhani NC, Zhang W, Pintilie M, Bowering V, Koritzinsky M, Rottapel R, Wouters BG, Oza AM, Joshua AM, and Lheureux S
- Subjects
- Humans, Female, Itraconazole pharmacology, Hydroxychloroquine pharmacology, Antifungal Agents metabolism, Carcinoma, Ovarian Epithelial drug therapy, Drug Repositioning, Chloroquine metabolism, Lysosomes, Homeostasis, Antineoplastic Agents pharmacology, Ovarian Neoplasms drug therapy
- Abstract
Drug repurposing is an attractive option for oncology drug development. Itraconazole is an antifungal ergosterol synthesis inhibitor that has pleiotropic actions including cholesterol antagonism, inhibition of Hedgehog and mTOR pathways. We tested a panel of 28 epithelial ovarian cancer (EOC) cell lines with itraconazole to define its spectrum of activity. To identify synthetic lethality in combination with itraconazole, a whole-genome drop-out genome-scale clustered regularly interspaced short palindromic repeats sensitivity screen in two cell lines (TOV1946 and OVCAR5) was performed. On this basis, we conducted a phase I dose-escalation study assessing the combination of itraconazole and hydroxychloroquine in patients with platinum refractory EOC (NCT03081702). We identified a wide spectrum of sensitivity to itraconazole across the EOC cell lines. Pathway analysis showed significant involvement of lysosomal compartments, the trans-golgi network and late endosomes/lysosomes; similar pathways are phenocopied by the autophagy inhibitor, chloroquine. We then demonstrated that the combination of itraconazole and chloroquine displayed Bliss defined synergy in EOC cancer cell lines. Furthermore, there was an association of cytotoxic synergy with the ability to induce functional lysosome dysfunction, by chloroquine. Within the clinical trial, 11 patients received at least one cycle of itraconazole and hydroxychloroquine. Treatment was safe and feasible with the recommended phase II dose of 300 and 600 mg twice daily, respectively. No objective responses were detected. Pharmacodynamic measurements on serial biopsies demonstrated limited pharmacodynamic impact. In vitro , itraconazole and chloroquine have synergistic activity and exert a potent antitumor effect by affecting lysosomal function. The drug combination had no clinical antitumor activity in dose escalation., Significance: The combination of the antifungal drug itraconazole with antimalarial drug hydroxychloroquine leads to a cytotoxic lysosomal dysfunction, supporting the rational for further research on lysosomal targeting in ovarian cancer., Competing Interests: S. Marastoni reports a Canadian patent number 3,116,081 pending. A. Madariaga reports personal fees from Clovis and AstraZeneca outside the submitted work. Z.J. Li reports a Canadian patent number to CA3,116,081 pending. I. Colombo reports personal fees from MSD; other from GSK, AstraZeneca, MSD, Bayer, and Oasmia outside the submitted work. J.P. Bruce reports other from Bowhead Health outside the submitted work. M. Koritzinsky reports other from The Princess Margaret Cancer Foundation during the conduct of the study; in addition, M. Koritzinsky has a Canadian patent number number 3,116,081 pending. B.G. Wouters reports grants from Ontario Institute for Cancer Research, Canadian Institutes for Cancer Research, and Princess Margaret Cancer Foundation during the conduct of the study; other from Northern Biologics outside the submitted work; in addition, B.G. Wouters has a Canadian patent number 3,116,081 issued. A.M. Oza is PI and on clinical trial steer- ing committees for trials with Clovis, GSK, AstraZeneca—all uncompensated. A.M. Oza is uncompensated CEO of Ozmosis Research, a Not For Profit Clin- ical Trials Management company associated with UHN. A.M. Joshua reports non-financial support from Mayne Pharma during the conduct of the study; other from Pricilium outside the submitted work; in addition, A.M. Joshua has a Canadian patent number 3,116,081 pending. S. Lheureux reports grants from OICR - TRI Ovarian Cancer during the conduct of the study; grants and personal fees from AstraZeneca, GSK; personal fees from Eisai, Merck, Shattuck Labs; grants from Roche, and outside the submitted work. No other disclosures were reported., (© 2022 The Authors; Published by the American Association for Cancer Research.)
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- 2022
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36. Integrative analysis of non-small cell lung cancer patient-derived xenografts identifies distinct proteotypes associated with patient outcomes.
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Mirhadi S, Tam S, Li Q, Moghal N, Pham NA, Tong J, Golbourn BJ, Krieger JR, Taylor P, Li M, Weiss J, Martins-Filho SN, Raghavan V, Mamatjan Y, Khan AA, Cabanero M, Sakashita S, Huo K, Agnihotri S, Ishizawa K, Waddell TK, Zadeh G, Yasufuku K, Liu G, Shepherd FA, Moran MF, and Tsao MS
- Subjects
- Animals, Heterografts, Humans, Mice, Mice, SCID, Xenograft Model Antitumor Assays, Carcinoma, Non-Small-Cell Lung pathology, Lung Neoplasms genetics, Lung Neoplasms pathology
- Abstract
Non-small cell lung cancer (NSCLC) is the leading cause of cancer deaths worldwide. Only a fraction of NSCLC harbor actionable driver mutations and there is an urgent need for patient-derived model systems that will enable the development of new targeted therapies. NSCLC and other cancers display profound proteome remodeling compared to normal tissue that is not predicted by DNA or RNA analyses. Here, we generate 137 NSCLC patient-derived xenografts (PDXs) that recapitulate the histology and molecular features of primary NSCLC. Proteome analysis of the PDX models reveals 3 adenocarcinoma and 2 squamous cell carcinoma proteotypes that are associated with different patient outcomes, protein-phosphotyrosine profiles, signatures of activated pathways and candidate targets, and in adenocarcinoma, stromal immune features. These findings portend proteome-based NSCLC classification and treatment and support the PDX resource as a viable model for the development of new targeted therapies., (© 2022. The Author(s).)
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- 2022
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37. Integrating comprehensive genomic sequencing of non-small cell lung cancer into a public healthcare system.
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Perdrizet K, Stockley TL, Law JH, Smith A, Zhang T, Fernandes R, Shabir M, Sabatini P, Youssef NA, Ishu C, Li JJ, Tsao MS, Pal P, Cabanero M, Schwock J, Ko HM, Boerner S, Ruff H, Shepherd FA, Bradbury PA, Liu G, Sacher AG, and Leighl NB
- Subjects
- Canada, Delivery of Health Care, Genomics, Humans, Carcinoma, Non-Small-Cell Lung drug therapy, Lung Neoplasms drug therapy
- Abstract
Objectives: Standard molecular testing for patients with stage IV non-small cell lung cancer (NSCLC) in the Canadian publicly funded health system includes single gene testing for EGFR, ALK, and ROS-1. Comprehensive genomic profiling (CGP) may broaden treatment options for patients. This study examined the impact of CGP in a publicly funded health system., Methods: Consenting patients with stage IV NSCLC without known targetable alterations underwent CGP on diagnostic samples. Patients that had progressed on targeted therapy were also eligible. The CGP assay was a hybrid capture next generation sequencing (NGS) panel (Oncomine Comprehensive Assay Version 3, ThermoFisher). The number of actionable alterations, changes in treatment, clinical trial eligibility and costs as a result of CGP were evaluated and patient willingness-to-pay., Results: Of 182 screened patients,134 (74%) had successful CGP testing. Twenty percent had received prior targeted therapy. Incremental actionable alterations were identified in 31% of patients. The most common novel targets identified were mutations in ERBB2 (exon 20 insertions), MET (exon 14 skipping) and KRAS (G12C). At data cut off (31/12/2020), 16% of patients had a change in treatment as a result of CGP. Additional clinical trial options were identified for 75% of patients. The incremental direct laboratory cost for CGP beyond public reimbursement for single gene tests was $747 CAD/case., Conclusion: CGP identifies additional actionable targets beyond single gene tests with a direct impact on patient treatment and increased clinical trial eligibility. These benefits highlight the value of CGP in patients with NSCLC in public health systems., (Copyright © 2022. Published by Elsevier Ltd.)
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- 2022
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38. Tumor-Associated Regulatory T Cell Expression of LAIR2 Is Prognostic in Lung Adenocarcinoma.
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Ly D, Li Q, Navab R, Zeltz C, Fang L, Cabanero M, Zhu CQ, Tsao MS, and Zhang L
- Abstract
Cancer development requires a permissive microenvironment that is shaped by interactions between tumor cells, stroma, and the surrounding matrix. As collagen receptors, the leukocyte-associated immunoglobulin-like receptor (LAIR) family allows the immune system to interact with the extracellular matrix. However, little is known about their role in regulating tumor immunity and cancer progression., Methods: Genetic analysis of resected human lung adenocarcinoma was correlated to clinical-pathological characteristics, gene ontologies, and single cell RNA sequencing (scRNASeq). LAIR2 production was determined in subsets of immune cells isolated from blood leukocytes and lung adenocarcinoma tumor. Functional assays were used to determine the role of LAIR2 in tumorigenesis., Results: LAIR2 expression was adversely prognostic in lung adenocarcinoma. LAIR2 was preferentially produced by activated CD4
+ T cells and enhanced in vitro tumor invasion into collagen. scRNASeq analysis of tumor infiltrating T cells revealed that LAIR2 expression co-localized with FOXP3 expressing cells and shared a transcriptional signature with tumor-associated regulatory T (Treg ) cells. A CD4+ LAIR2+ Treg gene signature was prognostically significant in the TCGA dataset ( n = 439; hazard ratio (HR) = 1.37; 95% confidence interval (CI), 1.05-1.77, p = 0.018) and validated in NCI Director's Challenge lung adenocarcinoma dataset ( n = 488; HR = 1.54; 95% CI, 1.14-2.09, p = 0.0045)., Conclusions: Our data support a role for LAIR2 in lung adenocarcinoma tumorigenesis and identify a CD4+ LAIR2+ Treg gene signature in lung adenocarcinoma prognosis. LAIR2 provides a novel target for development of immunotherapies.- Published
- 2021
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39. Pathologically confirmed diffuse alveolar haemorrhage in lymphangioleiomyomatosis.
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Kobylianskii J, Hutchinson-Jaffe A, Cabanero M, and Thenganatt J
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- Adult, Female, Hemorrhage diagnostic imaging, Hemorrhage etiology, Humans, Vascular Endothelial Growth Factor D, Hemosiderosis, Lung Diseases diagnostic imaging, Lung Diseases drug therapy, Lymphangioleiomyomatosis diagnosis, Lymphangioleiomyomatosis diagnostic imaging
- Abstract
A 40-year-old woman was referred to pulmonology after presenting with dyspnoea and self-limiting haemoptysis. Chest CT revealed diffuse ground glass opacities and small thin-walled cysts. Bronchoalveolar lavage cultures were negative and cytology revealed haemosiderin-laden macrophages. Transthoracic echocardiogram was normal. Connective tissue disease and vasculitis work-up were negative. Vascular endothelial growth factor-D level was indeterminate. Lung function was normal. She underwent video-assisted thoracoscopic lung biopsy. In addition to findings consistent with lymphangioleiomyomatosis, histopathological examination identified haemosiderosis without capillaritis, confirming a diagnosis of diffuse alveolar haemorrhage in the context of the associated clinical and radiographic features. Follow-up imaging after 5 months showed resolution of the diffuse ground glass opacities. Pharmacotherapy with sirolimus was not initiated due to absence of deterioration in pulmonary function. Diffuse alveolar haemorrhage in patients with lymphangioleiomyomatosis is a rare but important presentation. The few previously reported cases progressed to respiratory failure requiring mechanical ventilation., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2021. No commercial re-use. See rights and permissions. Published by BMJ.)
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- 2021
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40. Prevalence and Heterogeneity of PD-L1 Expression by 22C3 Assay in Routine Population-Based and Reflexive Clinical Testing in Lung Cancer.
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Hwang DM, Albaqer T, Santiago RC, Weiss J, Tanguay J, Cabanero M, Leung Y, Pal P, Khan Z, Lau SCM, Sacher A, Torlakovic E, Cheung C, and Tsao MS
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- Biomarkers, Tumor genetics, Canada, Humans, Immunohistochemistry, Prevalence, B7-H1 Antigen, Lung Neoplasms genetics
- Abstract
Introduction: Programmed death-ligand 1 (PD-L1) is used as a biomarker for anti-programmed cell death protein-1 (PD-1) or anti-PD-L1 immunotherapies in NSCLC. We report here the results of population-based PD-L1 testing using the 22C3 IHC pharmDx Assay (Agilent Technologies) in a large Canadian regional reference pathology laboratory., Methods: Testing was conducted reflexively on biopsies and resections for NSCLC during an 8-month period. Tumor proportion score (TPS) cutoffs for low and high expression were 1% and 50%, respectively., Results: Altogether, 2031 PD-L1 tests were performed on specimens from 1795 patients, with 107 inconclusive results (5.3%). Excluding cases with inconclusive/missing data, proportions for the remaining 1713 patients were 41.6% for TPS less than 1%, 28.6% for TPS 1% to 49%, and 29.8% for TPS greater than or equal to 50%. Higher PD-L1 expression rates were noted in EGFR wild-type versus mutant tumors (p < 0.001), squamous versus adenocarcinoma (p < 0.001), and metastatic versus primary tumors (p < 0.001). PD-L1 among 103 patients with paired biopsy and resection specimens revealed moderate concordance (κ = 0.67). A total of 52% (25 of 48) of biopsies with TPS less than 1% had TPS greater than 1% in resection, whereas 84.6% (22 of 26) of biopsies with TPS greater than or equal to 50% were concordant in resected tumors. Discordance rates between biopsy and resection were 71.4% for biopsies with less than 8 mm
2 total area, compared with 33.3% for biopsies with greater than or equal to 8 mm2 area (p < 0.026). Concordance among 27 patients with paired primary lung and metastatic tumor biopsies revealed only weak concordance (κ = 0.48)., Conclusions: Intratumoral heterogeneity of PD-L1 expression may result in misclassification of PD-L1 status in a substantial proportion of PD-L1-negative small biopsy samples. Biopsy of metastatic site may increase proportion of patients with high PD-L1 expression., (Copyright © 2021 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)- Published
- 2021
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41. Blocking the GITR-GITRL pathway to overcome resistance to therapy in sarcomatoid malignant pleural mesothelioma.
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Chan M, Wu L, Yun Z, McKee TD, Cabanero M, Zhao Y, Kohno M, Murakami J, and de Perrot M
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- Animals, Cell Line, Tumor, Female, Glucocorticoid-Induced TNFR-Related Protein metabolism, Humans, Mesothelioma, Malignant therapy, Mice, Mice, Inbred NOD, Mice, SCID, Tumor Necrosis Factors metabolism, Antineoplastic Agents pharmacology, Cesium Radioisotopes pharmacology, Cisplatin pharmacology, Gene Expression Regulation, Neoplastic, Glucocorticoid-Induced TNFR-Related Protein genetics, Mesothelioma, Malignant genetics, Tumor Necrosis Factors genetics
- Abstract
Malignant pleural mesothelioma (MPM) is an aggressive neoplasm originating from the pleura. Non-epithelioid (biphasic and sarcomatoid) MPM are particularly resistant to therapy. We investigated the role of the GITR-GITRL pathway in mediating the resistance to therapy. We found that GITR and GITRL expressions were higher in the sarcomatoid cell line (CRL5946) than in non-sarcomatoid cell lines (CRL5915 and CRL5820), and that cisplatin and Cs-137 irradiation increased GITR and GITRL expressions on tumor cells. Transcriptome analysis demonstrated that the GITR-GITRL pathway was promoting tumor growth and inhibiting cell apoptosis. Furthermore, GITR+ and GITRL+ cells demonstrated increased spheroid formation in vitro and in vivo. Using patient derived xenografts (PDXs), we demonstrated that anti-GITR neutralizing antibodies attenuated tumor growth in sarcomatoid PDX mice. Tumor immunostaining demonstrated higher levels of GITR and GITRL expressions in non-epithelioid compared to epithelioid tumors. Among 73 patients uniformly treated with accelerated radiation therapy followed by surgery, the intensity of GITR expression after radiation negatively correlated with survival in non-epithelioid MPM patients. In conclusion, the GITR-GITRL pathway is an important mechanism of autocrine proliferation in sarcomatoid mesothelioma, associated with tumor stemness and resistance to therapy. Blocking the GITR-GITRL pathway could be a new therapeutic target for non-epithelioid mesothelioma., (© 2021. The Author(s).)
- Published
- 2021
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42. Short Communication: Stability of Glucose Levels in Serum and Plasma.
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Seydafkan S, Minkowitz J, Li G, Cabanero M, Wang Z, Wang H, Alexis H, Eid I, and Pincus MR
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- Glucose Tolerance Test methods, Humans, Insulin blood, Plasma, Protein Stability, Blood Glucose metabolism
- Published
- 2021
43. Acute Rejection in the Modern Lung Transplant Era.
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Renaud-Picard B, Koutsokera A, Cabanero M, and Martinu T
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- Graft Rejection, Humans, Immunosuppressive Agents adverse effects, Lung, Risk Factors, Lung Transplantation adverse effects
- Abstract
Acute cellular rejection (ACR) remains a common complication after lung transplantation. Mortality directly related to ACR is low and most patients respond to first-line immunosuppressive treatment. However, a subset of patients may develop refractory or recurrent ACR leading to an accelerated lung function decline and ultimately chronic lung allograft dysfunction. Infectious complications associated with the intensification of immunosuppression can also negatively impact long-term survival. In this review, we summarize the most recent evidence on the mechanisms, risk factors, diagnosis, treatment, and prognosis of ACR. We specifically focus on novel, promising biomarkers which are under investigation for their potential to improve the diagnostic performance of transbronchial biopsies. Finally, for each topic, we highlight current gaps in knowledge and areas for future research., Competing Interests: None declared., (Thieme. All rights reserved.)
- Published
- 2021
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44. Patient-derived tumor xenograft and organoid models established from resected pancreatic, duodenal and biliary cancers.
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Pham NA, Radulovich N, Ibrahimov E, Martins-Filho SN, Li Q, Pintilie M, Weiss J, Raghavan V, Cabanero M, Denroche RE, Wilson JM, Metran-Nascente C, Borgida A, Hutchinson S, Dodd A, Begora M, Chadwick D, Serra S, Knox JJ, Gallinger S, Hedley DW, Muthuswamy L, and Tsao MS
- Subjects
- Animals, Antineoplastic Agents pharmacology, Antineoplastic Agents therapeutic use, Biliary Tract Neoplasms drug therapy, Cell Proliferation drug effects, Dose-Response Relationship, Drug, Duodenal Neoplasms drug therapy, Humans, Mice, Inbred NOD, Mice, SCID, Mutation genetics, Organoids drug effects, Pancreatic Neoplasms drug therapy, Pancreatic Neoplasms genetics, Mice, Biliary Tract Neoplasms pathology, Duodenal Neoplasms pathology, Organoids pathology, Pancreatic Neoplasms pathology, Xenograft Model Antitumor Assays
- Abstract
Patient-derived xenograft (PDX) and their xenograft-derived organoid (XDO) models that recapitulate the genotypic and phenotypic landscape of patient cancers could help to advance research and lead to improved clinical management. PDX models were established from 276 pancreato-duodenal and biliary cancer resections. Initial, passage 0 (P0) engraftment rates were 59% (118/199) for pancreatic, 86% (25/29) for duodenal, and 35% (17/48) for biliary ductal tumors. Pancreatic ductal adenocarcinoma (PDAC), had a P0 engraftment rate of 62% (105/169). KRAS mutant and wild-type PDAC models were molecularly profiled, and XDO models were generated to perform initial drug response evaluations. Subsets of PDAC PDX models showed global copy number variants and gene expression profiles that were retained with serial passaging, and they showed a spectrum of somatic mutations represented in patient tumors. PDAC XDO models were established, with a success rate of 71% (10/14). Pathway activation of KRAS-MAPK in PDXs was independent of KRAS mutational status. Four wild-type KRAS models were characterized by one with EGFR (L747-P753 del), two with BRAF alterations (N486_P490del or V600E), and one with triple negative KRAS/EGFR/BRAF. Model OCIP256, characterized by BRAF (N486-P490 del), had activated phospho-ERK. A combination treatment of a pan-RAF inhibitor (LY3009120) and a MEK inhibitor (trametinib) effectively suppressed phospho-ERK and inhibited growth of OCIP256 XDO and PDX models. PDAC/duodenal adenocarcinoma have high success rates forming PDX/organoid and retaining their phenotypic and genotypic features. These models may be effective tools to evaluate novel drug combination therapies.
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- 2021
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45. Surgery for malignant pleural mesothelioma after radiotherapy (SMART): final results from a single-centre, phase 2 trial.
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Cho BCJ, Donahoe L, Bradbury PA, Leighl N, Keshavjee S, Hope A, Pal P, Cabanero M, Czarnecka K, McRae K, Tsao MS, and de Perrot M
- Subjects
- Adolescent, Adult, Aged, Chemotherapy, Adjuvant, Combined Modality Therapy, Disease-Free Survival, Female, Humans, Male, Mesothelioma, Malignant drug therapy, Mesothelioma, Malignant pathology, Middle Aged, Neoplasm Recurrence, Local, Radiotherapy, Intensity-Modulated adverse effects, Mesothelioma, Malignant radiotherapy, Mesothelioma, Malignant surgery, Pneumonectomy
- Abstract
Background: A novel approach for managing malignant pleural mesothelioma, surgery for mesothelioma after radiotherapy (SMART), consisting of a short accelerated course of high-dose, hemithoracic, intensity modulated radiotherapy (IMRT) followed by extrapleural pneumonectomy was developed. The aim of this study was to evaluate the clinical feasibility of the SMART protocol., Methods: In this single-centre, phase 2 trial, patients aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0-2, with histologically proven, resectable, cT1-3N0M0 disease who had previously untreated malignant pleural mesothelioma were eligible for inclusion. Patients received 25 Gy in five daily fractions over 1 week to the entire ipsilateral hemithorax with a concomitant 5 Gy boost to high risk areas followed by extrapleural pneumonectomy within 1 week. Adjuvant chemotherapy was offered to patients with ypN+ disease on final pathology. The primary endpoint was feasibility, which was defined as the number of patients with 30-day perioperative treatment-related death (grade 5 events) or morbidity (grade 3 or 4 events). A key secondary endpoint was cumulative incidence of distant recurrence. The final analysis was done on an intention-to-treat basis (including all eligible patients). This trial is registered with ClinicalTrials.gov, NCT00797719., Findings: Between Nov 1, 2008, and Oct 31, 2019, 102 patients were enrolled onto the trial and 96 eligible patients were treated with SMART on protocol and included in the analysis. Extrapleural pneumonectomy was done at a median of 5 days (range 2-12) after completing IMRT. 47 (49%) patients had 30-day perioperative grade 3-4 events and one (1%) patient died within 30 days perioperatively (grade 5 event; pneumonia). After a median follow-up of 46·8 months (IQR 13·4-61·2), the 5-year cumulative incidence of distant recurrence was 62 (63·3% [95% CI 52·3-74·4]). The most common first sites of recurrence were the contralateral chest (33 [46%] of 72 patients) and the peritoneal cavity (32 [44%])., Interpretation: Results from this study suggest that extrapleural pneumonectomy after radiotherapy can be done with good early and long-term results. However, minimising grade 4 events on the protocol is technically demanding and might affect survival beyond the post-operative period., Funding: Princess Margaret Hospital Foundation Mesothelioma Research Fund., (Copyright © 2021 Elsevier Ltd. All rights reserved.)
- Published
- 2021
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46. Adavosertib plus gemcitabine for platinum-resistant or platinum-refractory recurrent ovarian cancer: a double-blind, randomised, placebo-controlled, phase 2 trial.
- Author
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Lheureux S, Cristea MC, Bruce JP, Garg S, Cabanero M, Mantia-Smaldone G, Olawaiye AB, Ellard SL, Weberpals JI, Wahner Hendrickson AE, Fleming GF, Welch S, Dhani NC, Stockley T, Rath P, Karakasis K, Jones GN, Jenkins S, Rodriguez-Canales J, Tracy M, Tan Q, Bowering V, Udagani S, Wang L, Kunos CA, Chen E, Pugh TJ, and Oza AM
- Subjects
- Canada, Deoxycytidine therapeutic use, Double-Blind Method, Female, Humans, Middle Aged, Ovarian Neoplasms pathology, Survival, United States, Gemcitabine, Antimetabolites, Antineoplastic therapeutic use, Deoxycytidine analogs & derivatives, Enzyme Inhibitors therapeutic use, Ovarian Neoplasms drug therapy, Pyrazoles therapeutic use, Pyrimidinones therapeutic use
- Abstract
Background: The Wee1 (WEE1hu) inhibitor adavosertib and gemcitabine have shown preclinical synergy and promising activity in early phase clinical trials. We aimed to determine the efficacy of this combination in patients with ovarian cancer., Methods: In this double-blind, randomised, placebo-controlled, phase 2 trial, women with measurable recurrent platinum-resistant or platinum-refractory high-grade serous ovarian cancer were recruited from 11 academic centres in the USA and Canada. Women were eligible if they were aged 18 years or older, had an Eastern Cooperative Oncology Group performance status of 0-2, a life expectancy of more than 3 months, and normal organ and marrow function. Women with ovarian cancer of non-high-grade serous histology were eligible for enrolment in a non-randomised exploratory cohort. Eligible participants with high-grade serous ovarian cancer were randomly assigned (2:1), using block randomisation (block size of three and six) and no stratification, to receive intravenous gemcitabine (1000 mg/m
2 on days 1, 8, and 15) with either oral adavosertib (175 mg) or identical placebo once daily on days 1, 2, 8, 9, 15, and 16, in 28-day cycles until disease progression or unacceptable toxicity. Patients and the team caring for each patient were masked to treatment assignment. The primary endpoint was progression-free survival. The safety and efficacy analysis population comprised all patients who received at least one dose of treatment. The trial is registered with ClinicalTrials.gov, NCT02151292, and is closed to accrual., Findings: Between Sept 22, 2014, and May 30, 2018, 124 women were enrolled, of whom 99 had high-grade serous ovarian cancer and were randomly assigned to adavosertib plus gemcitabine (65 [66%]) or placebo plus gemcitabine (34 [34%]). 25 women with non-high-grade serous ovarian cancer were enrolled in the exploratory cohort. After randomisation, five patients with high-grade serous ovarian cancer were found to be ineligible (four in the experimental group and one in the control group) and did not receive treatment. Median age for all treated patients (n=119) was 62 years (IQR 54-67). Progression-free survival was longer with adavosertib plus gemcitabine (median 4·6 months [95% CI 3·6-6·4] with adavosertib plus gemcitabine vs 3·0 months [1·8-3·8] with placebo plus gemcitabine; hazard ratio 0·55 [95% CI 0·35-0·90]; log-rank p=0·015). The most frequent grade 3 or worse adverse events were haematological (neutropenia in 38 [62%] of 61 participants in the adavosertib plus gemcitabine group vs ten [30%] of 33 in the placebo plus gemcitabine group; thrombocytopenia in 19 [31%] of 61 in the adavosertib plus gemcitabine group vs two [6%] of 33 in the placebo plus gemcitabine group). There were no treatment-related deaths; two patients (one in each group in the high-grade serous ovarian cancer cohort) died while on study medication (from sepsis in the experimental group and from disease progression in the control group)., Interpretation: The observed clinical efficacy of a Wee1 inhibitor combined with gemcitabine supports ongoing assessment of DNA damage response drugs in high-grade serous ovarian cancer, a TP53-mutated tumour type with high replication stress. This therapeutic approach might be applicable to other tumour types with high replication stress; larger confirmatory studies are required., Funding: US National Cancer Institute Cancer Therapy Evaluation Program, Ontario Institute for Cancer Research, US Department of Defense, Princess Margaret Cancer Foundation, and AstraZeneca., (Copyright © 2021 Elsevier Ltd. All rights reserved.)- Published
- 2021
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47. Minimalist approaches to cancer tissue-of-origin classification by DNA methylation.
- Author
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Xia D, Leon AJ, Cabanero M, Pugh TJ, Tsao MS, Rath P, Siu LL, Yu C, Bedard PL, Shepherd FA, Zadeh G, Chetty R, and Aldape K
- Subjects
- Gene Expression Profiling methods, Humans, Biomarkers, Tumor genetics, DNA Methylation, Neoplasms diagnosis, Neoplasms genetics
- Abstract
Classification of cancers by tissue-of-origin is fundamental to diagnostic pathology. While the combination of clinical data, tissue histology, and immunohistochemistry is usually sufficient, there remains a small but not insignificant proportion of difficult-to-classify cases. These challenging cases provide justification for ancillary molecular testing, including high-throughput DNA methylation array profiling, which promises cell-of-origin information and compatibility with formalin-fixed specimens. While diagnostically powerful, methylation profiling platforms are costly and technically challenging to implement, particularly for less well-resourced laboratories. To address this, we simulated the performance of "minimalist" methylation-based tests for cancer classification using publicly-available and internal institutional profiling data. These analyses showed that small and focused sets of the most informative CpG biomarkers from the arrays are sufficient for accurate diagnoses. As an illustrative example, one classifier, using information from just 53 out of about 450,000 available CpG probes, achieved an accuracy of 94.5% on 2575 fresh primary validation cases across 28 cancer types from The Cancer Genome Atlas Network. By training minimalist classifiers on formalin-fixed primary and metastatic cases, generally high accuracies were also achieved on additional datasets. These results support the potential of minimalist methylation testing, possibly via quantitative PCR and targeted next-generation sequencing platforms, in cancer classification.
- Published
- 2020
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48. Cancer proteome and metabolite changes linked to SHMT2.
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Tong J, Krieger JR, Taylor P, Bagshaw R, Kang J, Jeedigunta S, Wybenga-Groot LE, Zhang W, Badr H, Mirhadi S, Pham NA, Coyaud É, Yu M, Li M, Cabanero M, Raught B, Maynes JT, Hawkins C, Tsao MS, and Moran MF
- Subjects
- Animals, Antifungal Agents pharmacology, Apoptosis, Biomarkers, Tumor genetics, Cell Proliferation, Glycine Hydroxymethyltransferase antagonists & inhibitors, Glycine Hydroxymethyltransferase genetics, HeLa Cells, Humans, Lung Neoplasms drug therapy, Lung Neoplasms genetics, Lung Neoplasms metabolism, Mice, Mice, Inbred NOD, Mice, SCID, Mitochondria drug effects, Mitochondria metabolism, Mitochondria pathology, Protein Interaction Domains and Motifs, Sodium Benzoate pharmacology, Tumor Cells, Cultured, Xenograft Model Antitumor Assays, Biomarkers, Tumor metabolism, Gene Expression Regulation, Neoplastic, Glycine Hydroxymethyltransferase metabolism, Lung Neoplasms pathology, Metabolome, Proteome analysis, Serine metabolism
- Abstract
Serine hydroxymethyltransferase 2 (SHMT2) converts serine plus tetrahydrofolate (THF) into glycine plus methylene-THF and is upregulated at the protein level in lung and other cancers. In order to better understand the role of SHMT2 in cancer a model system of HeLa cells engineered for inducible over-expression or knock-down of SHMT2 was characterized for cell proliferation and changes in metabolites and proteome as a function of SHMT2. Ectopic over-expression of SHMT2 increased cell proliferation in vitro and tumor growth in vivo. Knockdown of SHMT2 expression in vitro caused a state of glycine auxotrophy and accumulation of phosphoribosylaminoimidazolecarboxamide (AICAR), an intermediate of folate/1-carbon-pathway-dependent de novo purine nucleotide synthesis. Decreased glycine in the HeLa cell-based xenograft tumors with knocked down SHMT2 was potentiated by administration of the anti-hyperglycinemia agent benzoate. However, tumor growth was not affected by SHMT2 knockdown with or without benzoate treatment. Benzoate inhibited cell proliferation in vitro, but this was independent of SHMT2 modulation. The abundance of proteins of mitochondrial respiration complexes 1 and 3 was inversely correlated with SHMT2 levels. Proximity biotinylation in vivo (BioID) identified 48 mostly mitochondrial proteins associated with SHMT2 including the mitochondrial enzymes Acyl-CoA thioesterase (ACOT2) and glutamate dehydrogenase (GLUD1) along with more than 20 proteins from mitochondrial respiration complexes 1 and 3. These data provide insights into possible mechanisms through which elevated SHMT2 in cancers may be linked to changes in metabolism and mitochondrial function., Competing Interests: NO authors have competing interests.
- Published
- 2020
- Full Text
- View/download PDF
49. Early Detection of Multiple Resistance Mechanisms by ctDNA Profiling in a Patient With EGFR-mutant Lung Adenocarcinoma Treated With Osimertinib.
- Author
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Schmid S, Stewart EL, Martins-Filho SN, Cabanero M, Wang A, Bao H, Wu X, Patel D, Chen Z, Law JH, Bradbury PA, Shepherd FA, Leighl N, Tsao MS, Pugh T, Bratman SV, Sacher A, and Liu G
- Subjects
- Adenocarcinoma of Lung genetics, Adenocarcinoma of Lung pathology, Antineoplastic Agents therapeutic use, Circulating Tumor DNA analysis, ErbB Receptors genetics, Female, Humans, Lung Neoplasms drug therapy, Lung Neoplasms genetics, Lung Neoplasms pathology, Middle Aged, Prognosis, Acrylamides therapeutic use, Adenocarcinoma of Lung drug therapy, Aniline Compounds therapeutic use, Biomarkers, Tumor genetics, Circulating Tumor DNA genetics, Drug Resistance, Neoplasm, Mutation
- Published
- 2020
- Full Text
- View/download PDF
50. Paradoxical Stress Fracture in a Patient With Multiple Myeloma and Bisphosphonate Use.
- Author
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Chiu E, Cabanero M, and Sidhu G
- Abstract
Multiple myeloma (MM) is a plasma cell disorder with related organ dysfunction, including hypercalcemia, renal insufficiency, anemia, and bone disease. Osteolytic bone lesions that result in pain and pathologic fractures are a major source of morbidity and the use of bisphosphonates is generally safe and effective treatment in reducing myeloma-related skeletal fractures and associated morbidity. We present a 73-year-old African American woman with MM in remission and on intravenous (IV) bisphosphonate therapy in the past five years who reported gradually worsening bilateral thigh pain of six months duration. A bone survey showed no neoplastic focus, and bilateral hip X-rays showed incomplete insufficiency stress fractures with characteristic features suspicious for bisphosphonate-related atypical femoral fracture (AFF). Increasingly reported in the literature, bilateral AFF is a unique and serious adverse effect for patients on bisphosphonates. Our case illustrates the distinct challenges in managing a patient with MM on long-term bisphosphonate therapy who suffered bilateral atypical femoral fractures, an uncommon presentation of a relatively rare phenomenon. It is important to balance the established benefits of bisphosphonate therapy with potential fracture risk and be particularly vigilant about adverse effect monitoring and timely intervention., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2020, Chiu et al.)
- Published
- 2020
- Full Text
- View/download PDF
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