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253. TP53 mutation status divides myelodysplastic syndromes with complex karyotypes into distinct prognostic subgroups.

Author

Haase, Detlef, Haase, Detlef, Stevenson, Kristen E, Neuberg, Donna, Maciejewski, Jaroslaw P, Nazha, Aziz, Sekeres, Mikkael A, Ebert, Benjamin L, Garcia-Manero, Guillermo, Haferlach, Claudia, Haferlach, Torsten, Kern, Wolfgang, Ogawa, Seishi, Nagata, Yasunobu, Yoshida, Kenichi, Graubert, Timothy A, Walter, Matthew J, List, Alan F, Komrokji, Rami S, Padron, Eric, Sallman, David, Papaemmanuil, Elli, Campbell, Peter J, Savona, Michael R, Seegmiller, Adam, Adès, Lionel, Fenaux, Pierre, Shih, Lee-Yung, Bowen, David, Groves, Michael J, Tauro, Sudhir, Fontenay, Michaela, Kosmider, Olivier, Bar-Natan, Michal, Steensma, David, Stone, Richard, Heuser, Michael, Thol, Felicitas, Cazzola, Mario, Malcovati, Luca, Karsan, Aly, Ganster, Christina, Hellström-Lindberg, Eva, Boultwood, Jacqueline, Pellagatti, Andrea, Santini, Valeria, Quek, Lynn, Vyas, Paresh, Tüchler, Heinz, Greenberg, Peter L, Bejar, Rafael, International Working Group for MDS Molecular Prognostic Committee, Haase, Detlef, Haase, Detlef, Stevenson, Kristen E, Neuberg, Donna, Maciejewski, Jaroslaw P, Nazha, Aziz, Sekeres, Mikkael A, Ebert, Benjamin L, Garcia-Manero, Guillermo, Haferlach, Claudia, Haferlach, Torsten, Kern, Wolfgang, Ogawa, Seishi, Nagata, Yasunobu, Yoshida, Kenichi, Graubert, Timothy A, Walter, Matthew J, List, Alan F, Komrokji, Rami S, Padron, Eric, Sallman, David, Papaemmanuil, Elli, Campbell, Peter J, Savona, Michael R, Seegmiller, Adam, Adès, Lionel, Fenaux, Pierre, Shih, Lee-Yung, Bowen, David, Groves, Michael J, Tauro, Sudhir, Fontenay, Michaela, Kosmider, Olivier, Bar-Natan, Michal, Steensma, David, Stone, Richard, Heuser, Michael, Thol, Felicitas, Cazzola, Mario, Malcovati, Luca, Karsan, Aly, Ganster, Christina, Hellström-Lindberg, Eva, Boultwood, Jacqueline, Pellagatti, Andrea, Santini, Valeria, Quek, Lynn, Vyas, Paresh, Tüchler, Heinz, Greenberg, Peter L, Bejar, Rafael, and International Working Group for MDS Molecular Prognostic Committee

Abstract

Risk stratification is critical in the care of patients with myelodysplastic syndromes (MDS). Approximately 10% have a complex karyotype (CK), defined as more than two cytogenetic abnormalities, which is a highly adverse prognostic marker. However, CK-MDS can carry a wide range of chromosomal abnormalities and somatic mutations. To refine risk stratification of CK-MDS patients, we examined data from 359 CK-MDS patients shared by the International Working Group for MDS. Mutations were underrepresented with the exception of TP53 mutations, identified in 55% of patients. TP53 mutated patients had even fewer co-mutated genes but were enriched for the del(5q) chromosomal abnormality (p < 0.005), monosomal karyotype (p < 0.001), and high complexity, defined as more than 4 cytogenetic abnormalities (p < 0.001). Monosomal karyotype, high complexity, and TP53 mutation were individually associated with shorter overall survival, but monosomal status was not significant in a multivariable model. Multivariable survival modeling identified severe anemia (hemoglobin < 8.0 g/dL), NRAS mutation, SF3B1 mutation, TP53 mutation, elevated blast percentage (>10%), abnormal 3q, abnormal 9, and monosomy 7 as having the greatest survival risk. The poor risk associated with CK-MDS is driven by its association with prognostically adverse TP53 mutations and can be refined by considering clinical and karyotype features.

Published
2019

254. Contrast Phase Classification with a Generative Adversarial Network

Author

Tang, Yucheng, Lee, Ho Hin, Xu, Yuchen, Tang, Olivia, Chen, Yunqiang, Gao, Dashan, Han, Shizhong, Gao, Riqiang, Bermudez, Camilo, Savona, Michael R., Abramson, Richard G., Huo, Yuankai, Landman, Bennett A., Tang, Yucheng, Lee, Ho Hin, Xu, Yuchen, Tang, Olivia, Chen, Yunqiang, Gao, Dashan, Han, Shizhong, Gao, Riqiang, Bermudez, Camilo, Savona, Michael R., Abramson, Richard G., Huo, Yuankai, and Landman, Bennett A.

Abstract

Dynamic contrast enhanced computed tomography (CT) is an imaging technique that provides critical information on the relationship of vascular structure and dynamics in the context of underlying anatomy. A key challenge for image processing with contrast enhanced CT is that phase discrepancies are latent in different tissues due to contrast protocols, vascular dynamics, and metabolism variance. Previous studies with deep learning frameworks have been proposed for classifying contrast enhancement with networks inspired by computer vision. Here, we revisit the challenge in the context of whole abdomen contrast enhanced CTs. To capture and compensate for the complex contrast changes, we propose a novel discriminator in the form of a multi-domain disentangled representation learning network. The goal of this network is to learn an intermediate representation that separates contrast enhancement from anatomy and enables classification of images with varying contrast time. Briefly, our unpaired contrast disentangling GAN(CD-GAN) Discriminator follows the ResNet architecture to classify a CT scan from different enhancement phases. To evaluate the approach, we trained the enhancement phase classifier on 21060 slices from two clinical cohorts of 230 subjects. Testing was performed on 9100 slices from 30 independent subjects who had been imaged with CT scans from all contrast phases. Performance was quantified in terms of the multi-class normalized confusion matrix. The proposed network significantly improved correspondence over baseline UNet, ResNet50 and StarGAN performance of accuracy scores 0.54. 0.55, 0.62 and 0.91, respectively. The proposed discriminator from the disentangled network presents a promising technique that may allow deeper modeling of dynamic imaging against patient specific anatomies., Comment: 8 pages, 4 figures

Published
2019

255. Semi-Supervised Multi-Organ Segmentation through Quality Assurance Supervision

Author

Lee, Ho Hin, Tang, Yucheng, Tang, Olivia, Xu, Yuchen, Chen, Yunqiang, Gao, Dashan, Han, Shizhong, Gao, Riqiang, Savona, Michael R., Abramson, Richard G., Huo, Yuankai, Landman, Bennett A., Lee, Ho Hin, Tang, Yucheng, Tang, Olivia, Xu, Yuchen, Chen, Yunqiang, Gao, Dashan, Han, Shizhong, Gao, Riqiang, Savona, Michael R., Abramson, Richard G., Huo, Yuankai, and Landman, Bennett A.

Abstract

Human in-the-loop quality assurance (QA) is typically performed after medical image segmentation to ensure that the systems are performing as intended, as well as identifying and excluding outliers. By performing QA on large-scale, previously unlabeled testing data, categorical QA scores can be generatedIn this paper, we propose a semi-supervised multi-organ segmentation deep neural network consisting of a traditional segmentation model generator and a QA involved discriminator. A large-scale dataset of 2027 volumes are used to train the generator, whose 2-D montage images and segmentation mask with QA scores are used to train the discriminator. To generate the QA scores, the 2-D montage images were reviewed manually and coded 0 (success), 1 (errors consistent with published performance), and 2 (gross failure). Then, the ResNet-18 network was trained with 1623 montage images in equal distribution of all three code labels and achieved an accuracy 94% for classification predictions with 404 montage images withheld for the test cohort. To assess the performance of using the QA supervision, the discriminator was used as a loss function in a multi-organ segmentation pipeline. The inclusion of QA-loss function boosted performance on the unlabeled test dataset from 714 patients to 951 patients over the baseline model. Additionally, the number of failures decreased from 606 (29.90%) to 402 (19.83%). The contributions of the proposed method are threefold: We show that (1) the QA scores can be used as a loss function to perform semi-supervised learning for unlabeled data, (2) the well trained discriminator is learnt by QA score rather than traditional true/false, and (3) the performance of multi-organ segmentation on unlabeled datasets can be fine-tuned with more robust and higher accuracy than the original baseline method., Comment: 7 pages, 5 figures, Accepted by SPIE 2020: Medical Imaging

Published
2019

256. Proposed diagnostic criteria for classical chronic myelomonocytic leukemia (CMML), CMML variants and pre-CMML conditions

Author

Austrian Science Fund, Ludwig Institute for Cancer Research (US), Medical University of Vienna, Valent, Peter, Orazi, Attilio, Savona, Michael R., Patnaik, Mrinal M., Onida, Francesco, Loosdrecht, Arjan A. Van De, Haase, Detlef, Haferlach T., Elena, Chiara, Pleyer, Lisa, Kern, Wolfgang, Pemovska, Tea, Vladimer, Gregory I., Schanz, Julie, Keller, Alexandra, Lübbert, Michael, Lion, Thomas, Sotlar, Karl, Reiter, Andreas, De Witte, Theo, Pfeilstöcker, Michael, Geissler, Klaus, Padron, Eric, Deininger, Michael, Orfao, Alberto, Horny, Hans-Peter, Greenberg, Peter, Arber, Daniel A., Malcovati, Luca, Bennett, John M., Austrian Science Fund, Ludwig Institute for Cancer Research (US), Medical University of Vienna, Valent, Peter, Orazi, Attilio, Savona, Michael R., Patnaik, Mrinal M., Onida, Francesco, Loosdrecht, Arjan A. Van De, Haase, Detlef, Haferlach T., Elena, Chiara, Pleyer, Lisa, Kern, Wolfgang, Pemovska, Tea, Vladimer, Gregory I., Schanz, Julie, Keller, Alexandra, Lübbert, Michael, Lion, Thomas, Sotlar, Karl, Reiter, Andreas, De Witte, Theo, Pfeilstöcker, Michael, Geissler, Klaus, Padron, Eric, Deininger, Michael, Orfao, Alberto, Horny, Hans-Peter, Greenberg, Peter, Arber, Daniel A., Malcovati, Luca, and Bennett, John M.

Abstract

Chronic myelomonocytic leukemia (CMML) is a myeloid neoplasm characterized by dysplasia, abnormal production and accumulation of monocytic cells and an elevated risk of transforming into acute leukemia. Over the past two decades, our knowledge about the pathogenesis and molecular mechanisms in CMML has increased substantially. In parallel, better diagnostic criteria and therapeutic strategies have been developed. However, many questions remain regarding prognostication and optimal therapy. In addition, there is a need to define potential pre-phases of CMML and special CMML variants, and to separate these entities from each other and from conditions mimicking CMML. To address these unmet needs, an international consensus group met in a Working Conference in August 2018 and discussed open questions and issues around CMML, its variants, and pre-CMML conditions. The outcomes of this meeting are summarized herein and include diag nostic criteria and a proposed classification of pre-CMML conditions as well as refined minimal diagnostic criteria for classical CMML and special CMML variants, including oligomonocytic CMML and CMML associated with systemic mastocytosis. Moreover, we propose diagnostic standards and tools to distinguish between ‘normal’, pre-CMML and CMML entities. These criteria and standards should facilitate diagnostic and prognostic evaluations in daily practice and clinical studies in applied hematology.

Published
2019

257. Selective Inhibition of JAK1 Primes STAT5-Driven Human Leukemia Cells for ATRA-Induced Differentiation.

Author

Ramsey, Haley E., Stengel, Kristy, Pino, James C., Johnston, Gretchen, Childress, Merrida, Gorska, Agnieszka E., Arrate, Pia M., Fuller, Londa, Villaume, Matthew, Fischer, Melissa A., Ferrell Jr., P. Brent, Roe, Caroline E., Zou, Jing, Lubbock, Alexander L. R., Stubbs, Matthew, Zinkel, Sandra, Irish, Jonathan M., Lopez, Carlos F., Hiebert, Scott, and Savona, Michael R.

Abstract

Background: All-trans retinoic acid (ATRA), a derivate of vitamin A, has been successfully used as a therapy to induce differentiation in M3 acute promyelocytic leukemia (APML), and has led to marked improvement in outcomes. Previously, attempts to use ATRA in non-APML in the clinic, however, have been underwhelming, likely due to persistent signaling through other oncogenic drivers. Dysregulated JAK/STAT signaling is known to drive several hematologic malignancies, and targeting JAK1 and JAK2 with the JAK1/JAK2 inhibitor ruxolitinib has led to improvement in survival in primary myelofibrosis and alleviation of vasomotor symptoms and splenomegaly in polycythemia vera and myelofibrosis. Objective: While dose-dependent anemia and thrombocytopenia limit the use of JAK2 inhibition, selectively targeting JAK1 has been explored as a means to suppress inflammation and STAT-associated pathologies related to neoplastogenesis. The objective of this study is to employ JAK1 inhibition (JAK1i) in the presence of ATRA as a potential therapy in non-M3 acute myeloid leukemia (AML). Methods: Efficacy of JAK1i using INCB52793 was assessed by changes in cell cycle and apoptosis in treated AML cell lines. Transcriptomic and proteomic analysis evaluated effects of JAK1i. Synergy between JAK1i+ ATRA was assessed in cell lines in vitro while efficacy in vivo was assessed by tumor reduction in MV-4-11 cell line-derived xenografts. Results: Here we describe novel synergistic activity between JAK1i inhibition and ATRA in non-M3 leukemia. Transcriptomic and proteomic analysis confirmed structural and functional changes related to maturation while in vivo combinatory studies revealed significant decreases in leukemic expansion. Conclusions: JAK1i+ ATRA lead to decreases in cell cycle followed by myeloid differentiation and cell death in human leukemias. These findings highlight potential uses of ATRA-based differentiation therapy of non-M3 human leukemia. [ABSTRACT FROM AUTHOR]

Published
2021
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258. Apoptolidin family glycomacrolides target leukemia through inhibition of ATP synthase

Author

Reisman, Benjamin J., Guo, Hui, Ramsey, Haley E., Wright, Madison T., Reinfeld, Bradley I., Ferrell, P. Brent, Sulikowski, Gary A., Rathmell, W. Kimryn, Savona, Michael R., Plate, Lars, Rubinstein, John L., and Bachmann, Brian O.

Abstract

Cancer cells have long been recognized to exhibit unique bioenergetic requirements. The apoptolidin family of glycomacrolides are distinguished by their selective cytotoxicity towards oncogene-transformed cells, yet their molecular mechanism remains uncertain. We used photoaffinity analogs of the apoptolidins to identify the F1subcomplex of mitochondrial ATP synthase as the target of apoptolidin A. Cryogenic electron microscopy (cryo-EM) of apoptolidin and ammocidin–ATP synthase complexes revealed a novel shared mode of inhibition that was confirmed by deep mutational scanning of the binding interface to reveal resistance mutations which were confirmed using CRISPR–Cas9. Ammocidin A was found to suppress leukemia progression in vivo at doses that were tolerated with minimal toxicity. The combination of cellular, structural, mutagenesis, and in vivo evidence defines the mechanism of action of apoptolidin family glycomacrolides and establishes a path to address oxidative phosphorylation-dependent cancers.

Published
2022
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260. 46 - A Multi-Center Collaborative Study of Outcomes of TP53-Mutated MDS/AML Patients Following Allogeneic HCT

Author

Byrne, Michael, Kurian, Tony, Patel, Dilan, Tamari, Roni, Hong, Sanghee, Abdelhakim, Haitham, Klein, Victoria, Rojas, Patricio, Madhavan, Raksha, Kent, Andrew, Logan, Aaron C., Lee, Catherine J., Husnain, Muhammad, Manning, Benjamin, Tschernia, Nicholas, Dias, Ajoy, Margalski, Daniel, Goldenson, Benjamin, Byrne, Nathalie D., Chen, Heidi, Petrova-Drus, Kseniya, Sengsayadeth, Salyka, Goodman, Aaron, Howard, Dianna S., Wood, William A., Gill, Saar, Jimenez, Antonio Jimenez, Gutman, Jonathan A., Gowda, Lohith, Metheny III, Leland, Bhatnagar, Bhavana, Hamilton, Betty K., Mishra, Asmita, and Savona, Michael R.

Published
2022
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261. Real‐world diagnostic testing patterns for assessment of ring sideroblasts and SF3B1 mutations in patients with newly diagnosed lower‐risk myelodysplastic syndromes.

Author

Patel, Jay L., Abedi, Mehrdad, Cogle, Christopher R., Erba, Harry P., Foucar, Kathryn, Garcia‐Manero, Guillermo, Grinblatt, David L., Komrokji, Rami S., Kurtin, Sandra E., Maciejewski, Jaroslaw P., Pollyea, Daniel A., Revicki, Dennis A., Roboz, Gail J., Savona, Michael R., Scott, Bart L., Sekeres, Mikkael A., Steensma, David P., Thompson, Michael A., Dawn Flick, Elizabeth, and Kiselev, Pavel

Subjects
MYELODYSPLASTIC syndromes, MOLECULAR diagnosis, GENETIC mutation, DESCRIPTIVE statistics
Abstract

Introduction: The presence of ring sideroblasts (RS) and mutation of the SF3B1 gene are diagnostic of lower‐risk (LR) myelodysplastic syndromes (MDS) and are correlated with favorable outcomes. However, information on testing and reporting in community‐based clinical settings is scarce. This study from the Connect® MDS/AML Disease Registry aimed to compare the frequency of RS and SF3B1 reporting for patients with LR‐MDS, before and after publication of the 2016 World Health Organization (WHO) MDS classification criteria. Methods: Ring sideroblasts assessment and molecular testing data were collected from patients with LR‐MDS at enrollment in the Registry. Patients enrolled between December 2013 and the data cutoff of March 2020 were included in this analysis. Results: Among 489 patients with LR‐MDS, 434 (88.8%) underwent RS assessment; 190 were assessed prior to the 2016 WHO guidelines (Cohort A), and 244 after (Cohort B). In Cohort A, 87 (45.8%) patients had RS identified; 29 (33.3%) patients had RS < 15%, none of whom underwent molecular testing for SF3B1. In Cohort B, 96 (39.3%) patients had RS identified; 31 (32.3%) patients had < 15% RS, with 13 undergoing molecular testing of which 10 were assessed for SF3B1. Conclusions: In the Connect® MDS/AML Registry, only 32% of patients with <15% RS underwent SF3B1 testing after the publication of the WHO 2016 classification criteria. There was no change in RS assessment frequency before and after publication, despite the potential impact on diagnostic subtyping and therapy selection, suggesting an unmet need for education to increase testing rates for SF3B1 mutations. [ABSTRACT FROM AUTHOR]

Published
2021
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263. Toxicity and Outcomes in Octo- and Nonagenarians with AML Treated with Venetoclax and Hypomethylating Agent Therapy

Author

Madarang, Ellen, Lykon, Jillian, Zhao, Wei, Sekeres, Mikkael A., Bradley, Terrence, Chandhok, Namrata Sonia, Taylor, Justin, Koru-Sengul, Tulay, Iyer, Sunil G., Nanni, Jacopo, Papayannidis, Cristina, Miller, Ryan M, Kishtagari, Ashwin, Savona, Michael R., Gilbert, Jason, Pollyea, Daniel A., Sallman, David A., Al Ali, Najla, Komrokji, Rami S., and Watts, Justin

Published
2022
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266. Integrating Mosaic Chromosomal Alterations and Single-Nucleotide Variants to Predict Evolution of Clonal Hematopoiesis

Author

Kishtagari, Ashwin, Khan, MA Wasay, Li, Yajing, Bejan, Cosmin, Marneni, Naimisha, Silver, Alexander J., von Beck, Kelly, Spaulding, Travis, Stockton, Shannon, Snider, Christina A., Pugh, Kelly, Sochacki, Andrew, Dorand, Dixon, Mack, Taralynn, Vlasschaert, Caitlyn, Ferrell, Brent, Xu, Yaomin, Savona, Michael R., and Bick, Alexander G.

Published
2022
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271. Prospective Study of Cardiac Events During Proteasome Inhibitor Therapy for Relapsed Multiple Myeloma

Author

Cornell, Robert F., primary, Ky, Bonnie, additional, Weiss, Brendan M., additional, Dahm, Cherie N., additional, Gupta, Deepak K., additional, Du, Liping, additional, Carver, Joseph R., additional, Cohen, Adam D., additional, Engelhardt, Brian G., additional, Garfall, Alfred L., additional, Goodman, Stacey A., additional, Harrell, Shelton Lacy, additional, Kassim, Adetola A., additional, Jadhav, Trafina, additional, Jagasia, Madan, additional, Moslehi, Javid, additional, O’Quinn, Rupal, additional, Savona, Michael R., additional, Slosky, David, additional, Smith, Amanda, additional, Stadtmauer, Edward A., additional, Vogl, Dan T., additional, Waxman, Adam, additional, and Lenihan, Daniel, additional

Published
2019
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274. Guadecitabine (SGI-110) in patients with intermediate or high-risk myelodysplastic syndromes: phase 2 results from a multicentre, open-label, randomised, phase 1/2 trial

Author

Garcia-Manero, Guillermo, primary, Roboz, Gail, additional, Walsh, Katherine, additional, Kantarjian, Hagop, additional, Ritchie, Ellen, additional, Kropf, Patricia, additional, O'Connell, Casey, additional, Tibes, Raoul, additional, Lunin, Scott, additional, Rosenblat, Todd, additional, Yee, Karen, additional, Stock, Wendy, additional, Griffiths, Elizabeth, additional, Mace, Joseph, additional, Podoltsev, Nikolai, additional, Berdeja, Jesus, additional, Jabbour, Elias, additional, Issa, Jean-Pierre J, additional, Hao, Yong, additional, Keer, Harold N, additional, Azab, Mohammad, additional, and Savona, Michael R, additional

Published
2019
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275. Proposed diagnostic criteria for classical chronic myelomonocytic leukemia (CMML), CMML variants and pre-CMML conditions

Author

Valent, Peter, primary, Orazi, Attilio, additional, Savona, Michael R., additional, Patnaik, Mrinal M., additional, Onida, Francesco, additional, van de Loosdrecht, Arjan A., additional, Haase, Detlef, additional, Haferlach, Torsten, additional, Elena, Chiara, additional, Pleyer, Lisa, additional, Kern, Wolfgang, additional, Pemovska, Tea, additional, Vladimer, Gregory I., additional, Schanz, Julie, additional, Keller, Alexandra, additional, Lübbert, Michael, additional, Lion, Thomas, additional, Sotlar, Karl, additional, Reiter, Andreas, additional, De Witte, Theo, additional, Pfeilstöcker, Michael, additional, Geissler, Klaus, additional, Padron, Eric, additional, Deininger, Michael, additional, Orfao, Alberto, additional, Horny, Hans-Peter, additional, Greenberg, Peter L., additional, Arber, Daniel A., additional, Malcovati, Luca, additional, and Bennett, John M., additional

Published
2019
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277. An oral fixed-dose combination of decitabine and cedazuridine in myelodysplastic syndromes: a multicentre, open-label, dose-escalation, phase 1 study

Author

Savona, Michael R, primary, Odenike, Olatoyosi, additional, Amrein, Philip C, additional, Steensma, David P, additional, DeZern, Amy E, additional, Michaelis, Laura C, additional, Faderl, Stefan, additional, Harb, Wael, additional, Kantarjian, Hagop, additional, Lowder, James, additional, Oganesian, Aram, additional, Azab, Mohammad, additional, and Garcia-Manero, Guillermo, additional

Published
2019
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280. Discovery of Potent Myeloid Cell Leukemia-1 (Mcl-1) Inhibitors That Demonstrate in Vivo Activity in Mouse Xenograft Models of Human Cancer

Author

Lee, Taekyu, primary, Christov, Plamen P., additional, Shaw, Subrata, additional, Tarr, James C., additional, Zhao, Bin, additional, Veerasamy, Nagarathanam, additional, Jeon, Kyu Ok, additional, Mills, Jonathan J., additional, Bian, Zhiguo, additional, Sensintaffar, John L., additional, Arnold, Allison L., additional, Fogarty, Stuart A., additional, Perry, Evan, additional, Ramsey, Haley E., additional, Cook, Rebecca S., additional, Hollingshead, Melinda, additional, Davis Millin, Myrtle, additional, Lee, Kyung-min, additional, Koss, Brian, additional, Budhraja, Amit, additional, Opferman, Joseph T., additional, Kim, Kwangho, additional, Arteaga, Carlos L., additional, Moore, William J., additional, Olejniczak, Edward T., additional, Savona, Michael R., additional, and Fesik, Stephen W., additional

Published
2019
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284. High burden of clonal hematopoiesis in first responders exposed to the World Trade Center disaster

Author

Jasra, Sakshi, Giricz, Orsi, Zeig-Owens, Rachel, Pradhan, Kith, Goldfarb, David G., Barreto-Galvez, Angelica, Silver, Alexander J., Chen, Jiahao, Sahu, Srabani, Gordon-Mitchell, Shanisha, Choudhary, Gaurav S., Aluri, Srinivas, Bhagat, Tushar D., Shastri, Aditi, Bejan, Cosmin A., Stockton, Shannon S., Spaulding, Travis P., Thiruthuvanathan, Victor, Goto, Hiroki, Gerhardt, Jeannine, Haider, Syed Hissam, Veerappan, Arul, Bartenstein, Matthias, Nwankwo, George, Landgren, Ola, Weiden, Michael D., Lekostaj, Jacqueline, Bender, Ryan, Fletcher, Frederick, Greenberger, Lee, Ebert, Benjamin L., Steidl, Ulrich, Will, Britta, Nolan, Anna, Madireddy, Advaitha, Savona, Michael R., Prezant, David J., and Verma, Amit

Abstract

The terrorist attacks on the World Trade Center (WTC) created an unprecedented environmental exposure to aerosolized dust, gases and potential carcinogens. Clonal hematopoiesis (CH) is defined as the acquisition of somatic mutations in blood cells and is associated with smoking and exposure to genotoxic stimuli. Here we show that deep targeted sequencing of blood samples identified a significantly higher proportion of WTC-exposed first responders with CH (10%; 48 out of 481) when compared with non-WTC-exposed firefighters (6.7%; 17 out of 255; odds ratio, 3.14; 95% confidence interval, 1.64–6.03; P= 0.0006) after controlling for age, sex and race/ethnicity. The frequency of somatic mutations in WTC-exposed first responders showed an age-related increase and predominantly affected DNMT3A, TET2and other CH-associated genes. Exposure of lymphoblastoid cells to WTC particulate matter led to dysregulation of DNA replication at common fragile sites in vitro. Moreover, mice treated with WTC particulate matter developed an increased burden of mutations in hematopoietic stem and progenitor cell compartments. In summary, the high burden of CH in WTC-exposed first responders provides a rationale for enhanced screening and preventative efforts in this population.

Published
2022
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285. Luspatercept for myelodysplastic syndromes/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis

Author

Komrokji, Rami S., Platzbecker, Uwe, Fenaux, Pierre, Zeidan, Amer M., Garcia-Manero, Guillermo, Mufti, Ghulam J., Santini, Valeria, Díez-Campelo, María, Finelli, Carlo, Jurcic, Joseph G., Greenberg, Peter L., Sekeres, Mikkael A., DeZern, Amy E., Savona, Michael R., Shetty, Jeevan K., Ito, Rodrigo, Zhang, George, Ha, Xianwei, Backstrom, Jay T., and Verma, Amit

Published
2022
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286. A Novel MCL1 Inhibitor Combined with Venetoclax Rescues Venetoclax-Resistant Acute Myelogenous Leukemia

Author

Ramsey, Haley E., primary, Fischer, Melissa A., additional, Lee, Taekyu, additional, Gorska, Agnieszka E., additional, Arrate, Maria Pia, additional, Fuller, Londa, additional, Boyd, Kelli L., additional, Strickland, Stephen A., additional, Sensintaffar, John, additional, Hogdal, Leah J., additional, Ayers, Gregory D., additional, Olejniczak, Edward T., additional, Fesik, Stephen W., additional, and Savona, Michael R., additional

Published
2018
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287. Long Term Results of a Randomized Phase 2 Dose-Response Study of Guadecitabine, a Novel Subcutaneous (SC) Hypomethylating Agent (HMA), in 102 Patients with Intermediate or High Risk Myelodysplastic Syndromes (MDS) or Chronic Myelomonocytic Leukemia (CMML)

Author

Garcia-Manero, Guillermo, primary, Ritchie, Ellen K., additional, Walsh, Katherine J., additional, Savona, Michael R., additional, Kantarjian, Hagop M., additional, Kropf, Patricia L., additional, O'Connell, Casey L., additional, Tibes, Raoul, additional, Daver, Naval G., additional, Jabbour, Elias J., additional, Lunin, Scott D., additional, Rosenblat, Todd L., additional, Yee, Karen W.L., additional, Stock, Wendy, additional, Griffiths, Elizabeth A., additional, Mace, Joseph, additional, Podoltsev, Nikolai A., additional, Berdeja, Jesus G., additional, Issa, Jean-Pierre, additional, Naim, Sue, additional, Hao, Yong, additional, Azab, Mohammad, additional, and Roboz, Gail J., additional

Published
2018
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288. Ivosidenib or Enasidenib Combined with Induction and Consolidation Chemotherapy in Patients with Newly Diagnosed AML with an IDH1 or IDH2 Mutation Is Safe, Effective, and Leads to MRD-Negative Complete Remissions

Author

Stein, Eytan M., primary, DiNardo, Courtney D., additional, Fathi, Amir T., additional, Mims, Alice S., additional, Pratz, Keith W., additional, Savona, Michael R., additional, Stein, Anthony S., additional, Stone, Richard M., additional, Winer, Eric S., additional, Seet, Christopher S., additional, Döhner, Hartmut, additional, Pollyea, Daniel A, additional, McCloskey, James K, additional, Odenike, Olatoyosi, additional, Lowenberg, Bob, additional, Ossenkoppele, Gert J., additional, Patel, Prapti A., additional, Roshal, Mikhail, additional, Lersch, Frederik, additional, Nabhan, Salah, additional, Choe, Sung, additional, Wang, Hongfang, additional, Hua, Lei, additional, Almon, Caroline, additional, Cooper, Michael, additional, and Tallman, Martin S., additional

Published
2018
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289. The BET Inhibitor INCB054329 Primes AML Cells for Venetoclax-Induced Apoptosis

Author

Ramsey, Haley, primary, Zhang, Susu, additional, Zhao, Yue, additional, Fischer, Melissa Ann, additional, Gorska, Agnieszka Ewa, additional, Arrate, Maria, additional, Fuller, Londa, additional, Greenwood, Dalton, additional, Stubbs, Matthew C., additional, Liu, Phillip, additional, Rathmell, Jeffrey C, additional, Hiebert, Scott, additional, and Savona, Michael R., additional

Published
2018
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292. Geno-Clinical Model to Aid in the Diagnosis of Myelodysplastic Syndrome (MDS) Versus Chronic Myelomonocytic Leukemia (CMML)

Author

Hilton, C. Beau, primary, Sekeres, Mikkael A., additional, Meggendorfer, Manja, additional, Walter, Wencke, additional, Hutter, Stephan, additional, Padron, Eric, additional, Savona, Michael R., additional, Gerds, Aaron T., additional, Guan, Yihong, additional, Sallman, David A, additional, Mukherjee, Sudipto, additional, Patnaik, Mrinal M., additional, Smith, Brianna, additional, Nagata, Yasunobu, additional, Adema, Vera, additional, Hasipek, Metis, additional, Hirsch, Cassandra M., additional, Przychodzen, Bartlomiej P., additional, Komrokji, Rami S., additional, Jha, Babal K., additional, Haferlach, Claudia, additional, Maciejewski, Jaroslaw P., additional, Haferlach, Torsten, additional, and Nazha, Aziz, additional

Published
2018
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293. Dasatinib Versus Imatinib in Patients (Pts) with Chronic Myeloid Leukemia in Chronic Phase (CML-CP) Who Have Not Achieved an Optimal Response to 3 Months of Imatinib Therapy: Dascern

Author

Cortes, Jorge E., primary, Jiang, Qian, additional, Wang, Jianxiang, additional, Weng, Jianyu, additional, Zhu, Huanling, additional, Xiaoli, Liu, additional, Hochhaus, Andreas, additional, Kim, Dong-Wook, additional, Radich, Jerald, additional, Savona, Michael R., additional, Martin Regueira, Patricia, additional, Sy, Oumar, additional, Gurnani, Renuka, additional, and Saglio, Giuseppe, additional

Published
2018
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294. Factors Associated with Early Therapy Initiation in Patients (pts) with Myelodysplastic Syndromes (MDS) in the Connect® MDS/AML Disease Registry

Author

Cogle, Christopher R., primary, Garcia-Manero, Guillermo, additional, Grinblatt, David L., additional, Komrokji, Rami S., additional, Savona, Michael R., additional, Scott, Bart L., additional, Sekeres, Mikkael A., additional, Louis, Chrystal U., additional, Flick, E. Dawn, additional, Nifenecker, Melissa, additional, Kiselev, Pavel, additional, Swern, Arlene S., additional, and Steensma, David P., additional

Published
2018
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296. A geno-clinical decision model for the diagnosis of myelodysplastic syndromes

Author

Radakovich, Nathan, Meggendorfer, Manja, Malcovati, Luca, Hilton, C. Beau, Sekeres, Mikkael A., Shreve, Jacob, Rouphail, Yazan, Walter, Wencke, Hutter, Stephan, Galli, Anna, Pozzi, Sara, Elena, Chiara, Padron, Eric, Savona, Michael R., Gerds, Aaron T., Mukherjee, Sudipto, Nagata, Yasunobu, Komrokji, Rami S., Jha, Babal K., Haferlach, Claudia, Maciejewski, Jaroslaw P., Haferlach, Torsten, and Nazha, Aziz

Abstract

The differential diagnosis of myeloid malignancies is challenging and subject to interobserver variability. We used clinical and next-generation sequencing (NGS) data to develop a machine learning model for the diagnosis of myeloid malignancies independent of bone marrow biopsy data based on a 3-institution, international cohort of patients. The model achieves high performance, with model interpretations indicating that it relies on factors similar to those used by clinicians. In addition, we describe associations between NGS findings and clinically important phenotypes and introduce the use of machine learning algorithms to elucidate clinicogenomic relationships.

Published
2021
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298. SynSeg-Net: Synthetic Segmentation Without Target Modality Ground Truth

Author

Huo, Yuankai, Xu, Zhoubing, Moon, Hyeonsoo, Bao, Shunxing, Assad, Albert, Moyo, Tamara K., Savona, Michael R., Abramson, Richard G., Landman, Bennett A., Huo, Yuankai, Xu, Zhoubing, Moon, Hyeonsoo, Bao, Shunxing, Assad, Albert, Moyo, Tamara K., Savona, Michael R., Abramson, Richard G., and Landman, Bennett A.

Abstract

A key limitation of deep convolutional neural networks (DCNN) based image segmentation methods is the lack of generalizability. Manually traced training images are typically required when segmenting organs in a new imaging modality or from distinct disease cohort. The manual efforts can be alleviated if the manually traced images in one imaging modality (e.g., MRI) are able to train a segmentation network for another imaging modality (e.g., CT). In this paper, we propose an end-to-end synthetic segmentation network (SynSeg-Net) to train a segmentation network for a target imaging modality without having manual labels. SynSeg-Net is trained by using (1) unpaired intensity images from source and target modalities, and (2) manual labels only from source modality. SynSeg-Net is enabled by the recent advances of cycle generative adversarial networks (CycleGAN) and DCNN. We evaluate the performance of the SynSeg-Net on two experiments: (1) MRI to CT splenomegaly synthetic segmentation for abdominal images, and (2) CT to MRI total intracranial volume synthetic segmentation (TICV) for brain images. The proposed end-to-end approach achieved superior performance to two stage methods. Moreover, the SynSeg-Net achieved comparable performance to the traditional segmentation network using target modality labels in certain scenarios. The source code of SynSeg-Net is publicly available (https://github.com/MASILab/SynSeg-Net)., Comment: IEEE Transactions on Medical Imaging (TMI)

Published
2018
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299. Splenomegaly Segmentation on Multi-modal MRI using Deep Convolutional Networks

Author

Huo, Yuankai, Xu, Zhoubing, Bao, Shunxing, Bermudez, Camilo, Moon, Hyeonsoo, Parvathaneni, Prasanna, Moyo, Tamara K., Savona, Michael R., Assad, Albert, Abramson, Richard G., Landman, Bennett A., Huo, Yuankai, Xu, Zhoubing, Bao, Shunxing, Bermudez, Camilo, Moon, Hyeonsoo, Parvathaneni, Prasanna, Moyo, Tamara K., Savona, Michael R., Assad, Albert, Abramson, Richard G., and Landman, Bennett A.

Abstract

The findings of splenomegaly, abnormal enlargement of the spleen, is a non-invasive clinical biomarker for liver and spleen disease. Automated segmentation methods are essential to efficiently quantify splenomegaly from clinically acquired abdominal magnetic resonance imaging (MRI) scans. However, the task is challenging due to (1) large anatomical and spatial variations of splenomegaly, (2) large inter- and intra-scan intensity variations on multi-modal MRI, and (3) limited numbers of labeled splenomegaly scans. In this paper, we propose the Splenomegaly Segmentation Network (SS-Net) to introduce the deep convolutional neural network (DCNN) approaches in multi-modal MRI splenomegaly segmentation. Large convolutional kernel layers were used to address the spatial and anatomical variations, while the conditional generative adversarial networks (GAN) were employed to leverage the segmentation performance of SS-Net in an end-to-end manner. A clinically acquired cohort containing both T1-weighted (T1w) and T2-weighted (T2w) MRI splenomegaly scans was used to train and evaluate the performance of multi-atlas segmentation (MAS), 2D DCNN networks, and a 3D DCNN network. From the experimental results, the DCNN methods achieved superior performance to the state-of-the-art MAS method. The proposed SS-Net method achieved the highest median and mean Dice scores among investigated baseline DCNN methods., Comment: Accepted by IEEE Transactions on Medical Imaging

Published
2018

300. Germline risk of clonal haematopoiesis

Author

Silver, Alexander J., Bick, Alexander G., and Savona, Michael R.

Abstract

Clonal haematopoiesis (CH) is a common, age-related expansion of blood cells with somatic mutations that is associated with an increased risk of haematological malignancies, cardiovascular disease and all-cause mortality. CH may be caused by point mutations in genes associated with myeloid neoplasms, chromosomal copy number changes and loss of heterozygosity events. How inherited and environmental factors shape the incidence of CH is incompletely understood. Even though the several varieties of CH may have distinct phenotypic consequences, recent research points to an underlying genetic architecture that is highly overlapping. Moreover, there are numerous commonalities between the inherited variation associated with CH and that which has been linked to age-associated biomarkers and diseases. In this Review, we synthesize what is currently known about how inherited variation shapes the risk of CH and how this genetic architecture intersects with the biology of diseases that occur with ageing.

Published
2021
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