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1. Glaucoma Diagnosis Through the Integration of Optical Coherence Tomography/Angiography and Machine Learning Diagnostic Models

Author

Kooner KS, Angirekula A, Treacher AH, Al-Humimat G, Marzban MF, Chen A, Pradhan R, Tunga N, Wang C, Ahuja P, Zuberi H, and Montillo AA

Subjects
glaucoma, optical coherence tomography angiography, deep learning, Ophthalmology, RE1-994
Abstract

Karanjit S Kooner,1,2 Ashika Angirekula,1 Alex H Treacher,3 Ghadeer Al-Humimat,1,4 Mohamed F Marzban,5 Alyssa Chen,1 Roma Pradhan,1 Nita Tunga,1 Chuhan Wang,1 Pranati Ahuja,1 Hafsa Zuberi,1 Albert A Montillo3,6,7 1Department of Ophthalmology, University of Texas Southwestern Medical Center, Dallas, TX, USA; 2Department of Ophthalmology, Veteran Affairs North Texas Health Care System Medical Center, Dallas, TX, USA; 3Lyda Hill Department of Bioinformatics, University of Texas Southwestern Medical Center, Dallas, TX, USA; 4Department of Ophthalmology, King Hussein Medical Center, Amman, Jordan; 5Department of Electrical Engineering, University of Texas at Dallas, Dallas, TX, USA; 6Department of Radiology, University of Texas Southwestern Medical Center, Dallas, TX, USA; 7Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, TX, USACorrespondence: Karanjit S Kooner, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX, 75390-9057, USA, Tel +1 (214) 648-4733, Fax +1 (214) 648-2270, Email Karanjit.Kooner@UTSouthwestern.edu Albert A Montillo, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX, 75390-9057, USA, Email Albert.Montillo@UTSouthwestern.eduPurpose: To establish optical coherence tomography (OCT)/angiography (OCTA) parameter ranges for healthy eyes (HE) and glaucomatous eyes (GE) for a North Texas based population; to develop a machine learning (ML) tool and to identify the most accurate diagnostic parameters for clinical glaucoma diagnosis.Patients and Methods: In this retrospective cross-sectional study, we included 1371 eligible eyes, 462 HE and 909 GE (377 ocular hypertension, 160 mild, 156 moderate, 216 severe), from 735 subjects. Demographic data and full OCTA parameters were collected. A Kruskal–Wallis test was used to produce the normative database. Models were trained to solve a two-class problem (HE vs GE) and four-class problem (HE vs mild vs moderate vs severe GE). A rigorous nested, stratified, group, 5× 10 fold cross-validation strategy was applied to partition the data. Six ML algorithms were compared using classical and deep learning approaches. Over 2500 ML models were optimized using random search, with performance compared using mean validation accuracy. Final performance was reported on held-out test data using accuracy and F1 score. Decision trees and feature importance were produced for the final model.Results: We found differences across glaucoma severities for age, gender, hypertension, Black and Asian race, and all OCTA parameters, except foveal avascular zone area and perimeter (p< 0.05). The XGBoost algorithm achieved the highest test performance for both the two-class (F1 score 83.8%; accuracy 83.9%; standard deviation 0.03%) and four-class (F1 score 62.4%; accuracy 71.3%; standard deviation 0.013%) problem. A set of interpretable decision trees provided the most important predictors of the final model; inferior temporal and inferior hemisphere vessel density and peripapillary retinal nerve fiber layer thickness were identified as key diagnostic parameters.Conclusion: This study established a normative database for our North Texas based population and created ML tools utilizing OCT/A that may aid clinicians in glaucoma management.Keywords: glaucoma, optical coherence tomography angiography, deep learning

Published
2022

3. Atezolizumab, venetoclax, and obinutuzumab combination in Richter transformation diffuse large B-cell lymphoma (MOLTO): a multicentre, single-arm, phase 2 trial

Author

Tedeschi, Alessandra, Frustaci, Anna Maria, Condoluci, Adalgisa, Coscia, Marta, Chiarle, Roberto, Zinzani, Pier Luigi, Motta, Marina, Gaidano, Gianluca, Quaresmini, Giulia, Scarfò, Lydia, Catania, Gioacchino, Deodato, Marina, Jones, Rebecca, Tabanelli, Valentina, Griggio, Valentina, Stüssi, Georg, Calleri, Angelica, Pini, Katia, Cairoli, Roberto, Zenz, Thorsten, Signori, Alessio, Zucca, Emanuele, Rossi, Davide, and Montillo, Marco

Published
2024
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4. Activity of venetoclax in patients with relapsed or refractory chronic lymphocytic leukaemia: analysis of the VENICE-1 multicentre, open-label, single-arm, phase 3b trial

Author

Kater, Arnon P, Arslan, Önder, Demirkan, Fatih, Herishanu, Yair, Ferhanoglu, Burhan, Diaz, Marcos Gonzalez, Leber, Brian, Montillo, Marco, Panayiotidis, Panayiotis, Rossi, Davide, Skarbnik, Alan, Tempescul, Adrian, Turgut, Mehmet, Mellink, Clemens H, van der Kevie-Kersemaekers, Anne-Marie F, Lanham, Stuart, Sale, Ben, Del Rio, Luis, Popovic, Relja, Chyla, Brenda J, Busman, Todd, Komlosi, Viktor, Wang, Xifeng, Sail, Kavita, Pena, German E, Vizkelety, Tamas, and Forconi, Francesco

Published
2024
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7. Longitudinal prognosis of Parkinson’s outcomes using causal connectivity

Author

Cooper J. Mellema, Kevin P. Nguyen, Alex Treacher, Aixa X. Andrade, Nader Pouratian, Vibhash D. Sharma, Padraig O'Suileabhain, and Albert A. Montillo

Subjects
fMRI, Connectivity, Functional connectivity, Effective connectivity, Parkinson’s, Prognosis, Computer applications to medicine. Medical informatics, R858-859.7, Neurology. Diseases of the nervous system, RC346-429
Abstract

Despite the prevalence of Parkinson’s disease (PD), there are no clinically-accepted neuroimaging biomarkers to predict the trajectory of motor or cognitive decline or differentiate Parkinson’s disease from atypical progressive parkinsonian diseases. Since abnormal connectivity in the motor circuit and basal ganglia have been previously shown as early markers of neurodegeneration, we hypothesize that patterns of interregional connectivity could be useful to form patient-specific predictive models of disease state and of PD progression. We use fMRI data from subjects with Multiple System Atrophy (MSA), Progressive Supranuclear Palsy (PSP), idiopathic PD, and healthy controls to construct predictive models for motor and cognitive decline and differentiate between the four subgroups. Further, we identify the specific connections most informative for progression and diagnosis. When predicting the one-year progression in the MDS-UPDRS-III1*1* A summary of all acronyms used in this paper is presented in Appendix A. Supplementary Data. and Montreal Cognitive assessment (MoCA), we achieve new state-of-the-art mean absolute error performance. Additionally, the balanced accuracy we achieve in the diagnosis of PD, MSA, PSP, versus healthy controls surpasses that attained in most clinics, underscoring the relevance of the brain connectivity features. Our models reveal the connectivity between deep nuclei, motor regions, and the thalamus as the most important for prediction. Collectively these results demonstrate the potential of fMRI connectivity as a prognostic biomarker for PD and increase our understanding of this disease.

Published
2024
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10. Association between resting-state functional brain connectivity and gene expression is altered in autism spectrum disorder

Author

Stefano Berto, Alex H. Treacher, Emre Caglayan, Danni Luo, Jillian R. Haney, Michael J. Gandal, Daniel H. Geschwind, Albert A. Montillo, and Genevieve Konopka

Subjects
Science
Abstract

Gene expression patterns have been associated with functional activity patterns in the brain. Here the authors determine how gene expression patterns in the human brain supports brain phenotypes obtained from resting state fMRI imaging, identifying brain regions and genes relevant to autism.

Published
2022
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11. Enduring undetectable MRD and updated outcomes in relapsed/refractory CLL after fixed-duration venetoclax-rituximab

Author

Seymour, John F., Kipps, Thomas J., Eichhorst, Barbara F., D'Rozario, James, Owen, Carolyn J., Assouline, Sarit, Lamanna, Nicole, Robak, Tadeusz, de la Serna, Javier, Jaeger, Ulrich, Cartron, Guillaume, Montillo, Marco, Mellink, Clemens, Chyla, Brenda, Panchal, Anesh, Lu, Tong, Wu, Jenny Q., Jiang, Yanwen, Lefebure, Marcus, Boyer, Michelle, and Kater, Arnon P.

Published
2022
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16. Reproducible neuroimaging features for diagnosis of autism spectrum disorder with machine learning

Author

Cooper J. Mellema, Kevin P. Nguyen, Alex Treacher, and Albert Montillo

Subjects
Medicine, Science
Abstract

Abstract Autism spectrum disorder (ASD) is the fourth most common neurodevelopmental disorder, with a prevalence of 1 in 160 children. Accurate diagnosis relies on experts, but such individuals are scarce. This has led to increasing interest in the development of machine learning (ML) models that can integrate neuroimaging features from functional and structural MRI (fMRI and sMRI) to help reveal central nervous system alterations characteristic of ASD. We optimized and compared the performance of 12 of the most popular and powerful ML models. Each was separately trained using 15 different combinations of fMRI and sMRI features and optimized with an unbiased model search. Deep learning models predicted ASD with the highest diagnostic accuracy and generalized well to other MRI datasets. Our model achieves state-of-the-art 80% area under the ROC curve (AUROC) in diagnosis on test data from the IMPAC dataset; and 86% and 79% AUROC on the external ABIDE I and ABIDE II datasets (with further improvement to 93% and 90% after supervised domain adaptation). The highest performing models identified reproducible putative biomarkers for accurate ASD diagnosis in accord with known ASD markers as well as novel cerebellar biomarkers. Such reproducibility lends credence to their tremendous potential for defining and using a set of truly generalizable ASD biomarkers that will advance scientific understanding of neuronal changes in ASD.

Published
2022
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17. Do age, fitness, and concomitant medications influence management and outcomes of patients with CLL treated with ibrutinib?

Author

Tedeschi, Alessandra, Frustaci, Anna Maria, Mauro, Francesca Romana, Chiarenza, Annalisa, Coscia, Marta, Ciolli, Stefania, Reda, Gianluigi, Laurenti, Luca, Varettoni, Marzia, Murru, Roberta, Baratè, Claudia, Sportoletti, Paolo, Greco, Antonino, Borella, Chiara, Rossi, Valentina, Deodato, Marina, Biagi, Annalisa, Zamprogna, Giulia, Pelle, Angelo Curto, Lapietra, Gianfranco, Vitale, Candida, Morelli, Francesca, Cassin, Ramona, Fresa, Alberto, Cavalloni, Chiara, Postorino, Massimiliano, Ielo, Claudia, Cairoli, Roberto, Di Raimondo, Francesco, Montillo, Marco, and Del Poeta, Giovanni

Published
2021
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20. Higher-order connections between stereotyped subsets: implications for improved patient classification in CLL

Author

Agathangelidis, Andreas, Chatzidimitriou, Anastasia, Gemenetzi, Katerina, Giudicelli, Veronique, Karypidou, Maria, Plevova, Karla, Davis, Zadie, Yan, Xiao-Jie, Jeromin, Sabine, Schneider, Christof, Pedersen, Lone Bredo, Tschumper, Renee C., Sutton, Lesley-Ann, Baliakas, Panagiotis, Scarfò, Lydia, van Gastel, Ellen J., Armand, Marine, Tausch, Eugen, Biderman, Bella, Baer, Constance, Bagnara, Davide, Navarro, Alba, Langlois de Septenville, Anne, Guido, Valentina, Mitterbauer-Hohendanner, Gerlinde, Dimovski, Aleksandar, Brieghel, Christian, Lawless, Sarah, Meggendorfer, Manja, Brazdilova, Kamila, Ritgen, Matthias, Facco, Monica, Tresoldi, Cristina, Visentin, Andrea, Patriarca, Andrea, Catherwood, Mark, Bonello, Lisa, Sudarikov, Andrey, Vanura, Katrina, Roumelioti, Maria, Skuhrova Francova, Hana, Moysiadis, Theodoros, Veronese, Silvio, Giannopoulos, Krzysztof, Mansouri, Larry, Karan-Djurasevic, Teodora, Sandaltzopoulos, Raphael, Bödör, Csaba, Fais, Franco, Kater, Arnon, Panovska, Irina, Rossi, Davide, Alshemmari, Salem, Panagiotidis, Panagiotis, Costeas, Paul, Espinet, Blanca, Antic, Darko, Foroni, Letizia, Montillo, Marco, Trentin, Livio, Stavroyianni, Niki, Gaidano, Gianluca, Francia di Celle, Paola, Niemann, Carsten, Campo, Elias, Anagnostopoulos, Achilles, Pott, Christiane, Fischer, Kirsten, Hallek, Michael, Oscier, David, Stilgenbauer, Stephan, Haferlach, Claudia, Jelinek, Diane, Chiorazzi, Nicholas, Pospisilova, Sarka, Lefranc, Marie-Paule, Kossida, Sofia, Langerak, Anton W., Belessi, Chrysoula, Davi, Frederic, Rosenquist, Richard, Ghia, Paolo, and Stamatopoulos, Kostas

Published
2021
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21. Impact of the Types and Relative Quantities of IGHV Gene Mutations in Predicting Prognosis of Patients With Chronic Lymphocytic Leukemia

Author

Matthew Kaufman, Xiao-Jie Yan, Wentian Li, Emanuela M. Ghia, Anton W. Langerak, Laura Z. Rassenti, Chrysoula Belessi, Neil E. Kay, Frederic Davi, John C. Byrd, Sarka Pospisilova, Jennifer R. Brown, Mark Catherwood, Zadie Davis, David Oscier, Marco Montillo, Livio Trentin, Richard Rosenquist, Paolo Ghia, Jacqueline C. Barrientos, Jonathan E. Kolitz, Steven L. Allen, Kanti R. Rai, Kostas Stamatopoulos, Thomas J. Kipps, Donna Neuberg, and Nicholas Chiorazzi

Subjects
chronic lymphocytic leukemia, CLL, somatic mutations, immunoglobulin variable domain, prognosis, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Patients with CLL with mutated IGHV genes (M-CLL) have better outcomes than patients with unmutated IGHVs (U-CLL). Since U-CLL usually express immunoglobulins (IGs) that are more autoreactive and more effectively transduce signals to leukemic B cells, B-cell receptor (BCR) signaling is likely at the heart of the worse outcomes of CLL cases without/few IGHV mutations. A corollary of this conclusion is that M-CLL follow less aggressive clinical courses because somatic IGHV mutations have altered BCR structures and no longer bind stimulatory (auto)antigens and so cannot deliver trophic signals to leukemic B cells. However, the latter assumption has not been confirmed in a large patient cohort. We tried to address the latter by measuring the relative numbers of replacement (R) mutations that lead to non-conservative amino acid changes (Rnc) to the combined numbers of conservative (Rc) and silent (S) amino acid R mutations that likely do not or cannot change amino acids, “(S+Rc) to Rnc IGHV mutation ratio”. When comparing time-to-first-treatment (TTFT) of patients with (S+Rc)/Rnc ≤ 1 and >1, TTFTs were similar, even after matching groups for equal numbers of samples and identical numbers of mutations per sample. Thus, BCR structural change might not be the main reason for better outcomes for M-CLL. Since the total number of IGHV mutations associated better with longer TTFT, better clinical courses appear due to the biologic state of a B cell having undergone many stimulatory events leading to IGHV mutations. Analyses of larger patient cohorts will be needed to definitively answer this question.

Published
2022
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24. Idelalisib addition has neutral to beneficial effects on quality of life in bendamustine/rituximab-treated patients: results of a phase 3, randomized, controlled trial

Author

Marco Montillo, Árpád Illés, Tadeusz Robak, Alexander S. Pristupa, Malgorzata Wach, Miklós Egyed, Julio Delgado, Wojciech Jurczak, Franck Morschhauser, Anna Schuh, Herbert Eradat, Sanatan Shreay, Jacqueline C. Barrientos, and Andrew D. Zelenetz

Subjects
Idelalisib, Relapsed/refractory CLL, Patient-related outcomes, Health-related quality of life, Randomized phase 3 study, Computer applications to medicine. Medical informatics, R858-859.7
Abstract

Abstract Background In a phase 3 randomized, double-blind, placebo-controlled trial, treatment with idelalisib, a phosphoinositol-3 kinase δ inhibitor, + bendamustine/rituximab improved progression-free survival (PFS) and overall survival (OS) in adult patients with relapsed/refractory chronic lymphocytic leukemia (R/R CLL). Here we report the results of health-related quality of life (HRQL) analyses from this study. Methods From June 15, 2012 to August 21, 2014, 416 patients with R/R CLL were enrolled; 207 patients were randomized to the idelalisib arm and 209 to the placebo arm. In the 416 patients randomized to receive bendamustine/rituximab and either oral idelalisib 150 mg twice-daily or placebo, HRQL was assessed at baseline and throughout the blinded part of the study using the Functional Assessment of Cancer Therapy–Leukemia (FACT-Leu) and EuroQoL Five-Dimension (EQ-5D) visual analogue scale (VAS) questionnaires. The assessments were performed at scheduled patient visits; every 4 weeks for the first 6 months from the initiation of treatment, then every 8 weeks for the next 6 months, and every 12 weeks thereafter until end of study. Least-squares mean changes from baseline were estimated using a mixed-effects model by including treatment, time, and treatment-by-time interaction, and stratification factors as fixed effects. Time to first symptom improvement was assessed by Kaplan-Meier analysis. Results In mixed-effects model analysis, idelalisib + bendamustine/rituximab treatment led to clinically meaningful improvements from baseline in leukemia-associated symptoms. Moreover, per Kaplan-Meier analysis, the proportion of patients with symptom improvement was higher and time to improvement was shorter among patients in the idelalisib-containing arm compared with those who did not receive idelalisib. The physical and social/family FACT-Leu subscale scores, along with the self-rated health assessed by EQ-VAS, showed improvement with idelalisib over placebo, but the difference did not reach statistical significance. The functional and emotional FACT-Leu subscale scores remained similar to placebo. Conclusions Addition of idelalisib to bendamustine/rituximab, apart from improving PFS and OS, had a neutral to beneficial impact on HRQL in patients with R/R CLL, particularly by reducing leukemia-specific disease symptoms. Trial registration Clinicaltrials.gov NCT01569295. Registered April 3, 2012.

Published
2019
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25. Post-anaesthesia pulmonary complications after use of muscle relaxants (POPULAR): a multicentre, prospective observational study

Author

Abad Gurumeta, Alfredo, Abernethy, Caroline, Abigail, Patrick, Achaibar, Kira, Adam, Emily, Afshari, Arash, Agudelo Montoya, M. Elizabeth, Akgün, Fatma Nur, Aletti, Gabriele, Alkış, Neslihan, Allan, Katie, Allan, Ashley, Allaouchiche, Bernard, Allcock, Clare, Almasy, Emoke, Amey, Isobel, Amigoni, Maria, Andersen, Elin, Andersson, Peder, Anipchenko, Natalya, Antunes, Pedro, Armstrong, Earlene, Aslam, Tayyba Naz, Aslin, Bjorn, Assunção, José Pedro, Ausserer, Julia, Avvai, Mary, Awad, Nahla, Ayas Montero, Begoña, Ayuso, Mercedes, Azevedo, Patricia, Badarau, Victoria, Badescu, Roxana, Baiardo Redaelli, Martina, Baird, Colin, Baird, Yolanda, Baker, Tim, Balaji, Packianathaswamy, Bălan, Cristina, Balandin, Alina, Balescu-Arion, Carmen, Baliuliene, Vilda, Baltasar Isabel, Jorge, Baluch, Saif Nasr, Bandrabur, Daniela, Bankewitz, Carla, Barber, Katrina, Barbera, Francesco, Barcraft-Barnes, Helena, Barletti, Valentina, Barnett, Gill, Baron, Kirsty, Barros, Ana, Barsan, Victoria, Bartlett, Pauline, Batistaki, Chrysanthi, Baumgarten, Georg, Baytas, Volkan, Beauchamp, Nigel, Becerra Cayetano, Isabel A., Bell, Stephanie, Bellandi, Mattia, Belletti, Alessandro, Belmonte Cuenca, Julio, Benitez-Cano, Adela, Beretta, Luigi, Berger, Marc, Bergmann, Nicole, Bergmark, Kristina, Bermudez Lopez, Maria, Bernotaite, Monika, Beurskens, Charlotte, Bidd, Heena, Bifulco, Francesca, Bignami, Elena, Bilic, Aleksandar, Bilskiene, Diana, Bischoff, Petra, Bishop, Luke, Bjonness, Therese, Blaylock, Hether, Blethyn, Kate, Blincoe, Thomas, Blokhin, Ivan, Blunt, Nadia, Boer, Christa, Bois, Grégory, Bonicolini, Eleonora, Booth, Joanna, Borecka-Kedzierska, Miroslawa, Borstnar, Katarina, Borys, Michał, Boselli, Emmanuel, Bouvet, Lionel, Bouwman, Arthur, Bowen, Leonora, Bowrey, Sarah, Boxall, Leigh, Božić, Teodora, Bradley, Tom, Branco, Teresa, Brazzi, Luca, Brazzoni, Marcella, Brear, Tracy, Brogly, Nicolas, Brohi, Farooq, Broms, Jacob, Bubliauskas, Andrius, Bucolo, Gea Erika, Buerkle, Hartmut, Buggy, Donal, Buhre, Wolfgang, Bukauskas, Tomas, Butturini, Francesco, Byttner, Anders, Cabrera Díaz, Itahísa, Calderon, Adriana, Calhau, Ricardo, Callejo, Angel, Cammu, Guy, Campesato, Manuela, Can, Özlem S, Candeias, Margarida, Cantor, Andreea, Carise, Elsa, Carmona, Cristina, Carreteiro, Joana, Carrieri, Cosima, Carter, Anna, Casal, Manuela, Casanova, Irene, Cascella, Marco, Casero, Luis M., Casiraghi, Guiseppina Maria, Castelo-Branco, Laila, Castro Arranz, Carlos, Cernea, Daniela Denisa, Cervantes, Jesoporiol, Chandler, Ben, Charnock, Robert, Chatzimicali, Aikaterini, Chinery, Elane, Chishti, Ahmed, Chondhury, Priyakam, Christie, Emily, Christodoudiles, George, Ciardo, Stefano, Cimpeanu, Luminata, Cindea, Iulia, Cinnella, Gilda, Clark, Sebastian, Clayton, Matthew, Cocu, Simona, Collyer, Thomas, Colvin, Carie, Cope, Sean, Copeta, Filomena, Copotoiu, Sanda-Maria, Correia de Barros, Filinto, Corso, Ruggero Massimo, Cortegiani, Andrea, Costa, Gabriela, Cowton, Amanda, Cox, Nicolas, Craig, James, Cricca, Valentina, Cronin, John, Cunha, Mariana, Cuomo, Arturo, Curley, Katherine, Czuczwar, Mirosław, Dabrowska, Domenika, Damster, Sabrine, Danguy des Déserts, Marc, Daniliuc, Aura, Danninger, Thomas, Darwish, Imad, Dascalu, Corina, Davies, Kirsty, Davies, Simon, De Boer, Hans, De Flaviis, Adelisa, De Selincourt, Gabrielle, Deana, Cristian, Debaene, Bertrand, Debreceni, Gabor, Dedhia, Jatin, Delgado Garcia, Isabel, Della Rocca, Giorgio, Delroy-Buelles, Llana, Desai, Tejal, Dhillon, Parveen, Di Giacinto, Ida, Di Mauro, Piero, Diaz Gomez, Tamara V., Dimitrovski, Aleksandar, Dinic, Vesna, Dîrzu, Dan-Sebastian, Divander, Mona Britt, Dolinar, Janez, Domingues, Susana, Doolan, James, Downes, Charlotte, Dragoescu, Nicoleta Alice, Droc, Gabriela, Dum, Elisabeth, Dumitrescu, Alexandra, Duncan, Louise, Dzurňáková, Paul, Eberl, Susanne, Edwards, Jayne, Edwards, Mark, Ekelund, Kim, Ekengren, Patrik, Elghouty, Eyad, Ellerkmann, Richard, Ellis, Helen, Elme, Andreas, Ernst, Thomas, Errando, Carlos Luis, Estenes, Simao, Ewaldsson, Callis, Farid, Nahla, Featherstone, James, Febres, Daniela, Fedorov, Sergey, Feggeler, Johanna, Feijten, Prisca, Fellmann, Tobias, Fernandez Candil, Juan, Fernandez Castineira, Ana, Fernández Castineira, Juan, Fernando, Aruna, Ferrando, Carlos, Ferreira, Leonia, Ferreira, Patrick, Feyling, Anders, Filipescu, Daniela, Fleischer, Andreas, Floris, Leda, Foerster, Urs, Fox, Benjamin, Franke, Uwe, Frasca, Denis, Frey, Christian, Frost, Victoria, Fullin, Giorgio, Fumagalli, Jacopo, Furneval, Julie, Fusari, Maurizio, Gallacher, Stuart, Galushka, Svetlana, Gambale, Giorgio, Gambino, Irene, Garcia-Perez, Maria Luisa, Garg, Sanjeev, Garlak, Justyna, Gavranovic, Zeljka, Gavrilov, Roman, Gaynor, Lames, Gecaj Gashi, Agreta, Georghiou, Maria, Gerjevic, Bozena, Gferer, Gudrun, Giarratano, Antonino, Gibson, Andy, Gievski, Vanja, Giles, Julian, Gillberg, Lars, Gilowska, Katarzyna, Gilsanz Rodriguez, Fernando, Gioia, Antonio, Giovannoni, Cecilia, Girotra, Vandana, Gkinas, Dimitrios, Gkiokas, George, Godoroja, Daniela, Goebel, Ulrich, Goel, Vandana, Gonzalez, Matilde, Goranovic, Tatjana, Gornik-Wlaszczuk, Ewa, Gosavi, Smita, Gottfridsson, peter, Gottschalk, André, Granell, Manuel, Granstrom, Anna, Grassetto, Alberto, Greenwood, Anna, Grigoras, Ioana, Grintescu, Ioana, Gritsan, Alexey, Gritsan, Galina, Grynyuk, Andriy, Guadagnin, Giovanni Maria, Guarnieri, Marcello, Güçlü, Çiğdem, Guerrero Diez, Maria, Gunenc, Ferim, Günther, Ulf, Gupta, Pawan, Guttenthaler, Vera, Hack, Yvonne, Hafisayena, Ade, Hagau, Natalia, Haldar, Jagannath, Hales, Dawn, Hancı, Volkan, Hanna-Jumma, Sameer, Harazim, Hana, Harlet, Pierre, Harper, Daniel, Harris, Benjamin, Harvey, Orla, Hashimi, Medita, Hawkins, Lesley, Hayes, Conrad, Heaton, James, Heier, Tom, Helliwell, Laurence, Hemmes, Sabrine, Henderson, Kate, Hermanides, Jeroen, Hermanns, Henning, Herrera Hueso, Berta, Hestenes, Siv, Hettiarachchi, Roshane, Highgate, Judith, Hodgson, Keith, Hoelbling, Daniel, Holland, Jonathan, Horhota, Lucian, Hormis, Anil, Hribar, Renata, Hua, Alina, Humphreys, Sally, Humphries, Ryan, Humpliková, Simona, Hunt, Janez, Husnain, Ali, Hussein, Ahmed, Hyams, Benjamin, Iannuccelli, Fabrizio, Ilette, Katie, Ilyas, Carl, Inan, Turgay, India, Immaculada, Ionițăv, Victor, Irwin, Foo, Jain, Vipul, Janez, Benedikt, Jankovic, Radmilo, Jenkins, Sarah, Jenko, Matej, Jimenez, Raquel, Jiménez Gomez, Bárbara, Joachim, Sugganthi, Joelsson-Alm, Eva, John, John, Jonikaite, Lina, Jovic, Miomir, Jungwirth, Bettina, Junke, Etienne, Kabakov, Borys, Kadaoui, Salah-Din, Kanski, Andrzej, Karadag, Süheyla, Karbonskiene, Aurika, Karjagin, Juri, Kasnik, Darja, Katanolli, Fatos, Katsika, Eleni, Kaufmann, Kai, Keane, Helen, Kelly, Martin, Kent, Melanie, Keraitiene, Grazina, Khudhur, Ahmed, Khuenl-Brady, Karin, Kidd, Laurie, King, Siobhan, Kirchgäßner, Katharina, Klancir, Tino, Klucniks, Andris, Knotzer, Johann, Knowlden, Peter, Koers, Lena, Kompan, Janez, Koneti, Kiran K, Kooij, Fabian, Koolen, Eric, Koopman - van Gemert, Anna Wilhelmina Margaretha Maria, Kopp, Kristen, Korfiotis, Dimitrios, Korolkov, Oleg, Kosinová, Martina, Köstenberger, Markus, Kotzinger, Oskar, Kovačević, Marko, Kranke, Peter, Kranke, Eva, Kraus, Christiane, Kraus, Stephanie, Kubitzek, Christiane, Kucharski, Rafal, Kucukguclu, Semih, Kudrashou, Allaksandr, Kumar, Vinayak, Kummen, Live, Kunit, Cornelia, Kushakovsky, Vlad, Kuvaki, Bahar, Kuzmanovska, Biljana, Kyttari, Aikaterina, Landoni, Giovanni, Lau, Gary, Lazarev, Konstantin, Legett, Samantha, Legrottaglie, Anna Maria, Leonardi, Silvia, Leong, Maria, Lercher, Helene, Leuvrey, Matthieu, Leva, Brigitte, Levstek, Meta, Limb, James, Lindholm, Espen, Linton, Fiona, Liperi, Corradero, Lipski, Fabian, Lirk, Philipp, Lisi, Alberto, Lišková, Katarina, Lluch Oltra, Aitana, Loganathan, Vinothan, Lombardi, Stefania, Lopez, Eloisa, Lopez Rodríguez, Maria, Lorenzini, Laura, Lowicka, Malgorzata, Lugovoy, Alexander, Luippold, Madeleine, Lumb, Andrew, Macas, Andrius, Macgregor, Mark, Machado, Humberto, Maciariello, Maria, Madeira, Isabel, Maitan, Stefan, Majewski, Jacek, Maldini, Branka, Malewski, Georgia, Manfredini, Livia, Männer, Olja, Marchand, Bahareh, Marcu, Alexandra, Margalef, Jordi, Margarson, Michael, Marinheiro, Lucia, Markic, Ana, Markovic Bozic, Jasmina, Marrazzo, Francesco, Martin, Jane, Martin Ayuso, Maria, Martinez, Esteher, Martino, Enrico Antonio, Martinson, Victoria, Marusic-Gaser, Katarina, Mascarenhas, Catia, Mathis, Cindy, Matsota, Paraskevi, Mavrommati, Eleni, Mazul Sunko, Branka, McCourt, Killian, McGill, Neil, McKee, Raymond, Meço, Başak Ceyda, Meier, Sonja, Melbourne, Susan, Melbybråthen, Grethe, Meli, Andrea, Melia, Aiden, Melotti, Rita Maria, Menga, Maria Rosaria, Mercer, Pauline, Merotra, Susan, Mescolini, Silvia, Metterlein, Thomas, Michalov, Martin, Michlig, Sam, Midgley, Susan, Milić, Morena, Milojevic, Milan, Miñana, Amanda, Minto, Gary, Mirabella, Lucia, Mirea, Liliana, Mittelstädt, Ludger, Moeglen, Aude, Moise, Alida, Mokini, Zhirajr, Molin, Anna, Moltó, Luis, Monea, Maria Concetta, Montalto, Francesca, Montgomery, Jane, Montgomery, Claire, Montillo, Gerardo, Moore, Sally, Moore, Faye, Moreira, Zelia, Moreno, Tania, Moreno, Ricardo, Moret, Enrique, Moreton, Sarah, Morgan, Marianne, Moro Velasco, Concepción, Morri, Davide, Moull, Alice, Moura, Fernando, Mráz, Peter, Mrozek, Katarzyna, Mukhtar, Karim, Muniyappa, Sudeshkumar, Murray, Heather, Murthy, Burra VS, Mushambi, Mary, Nadolski, Maria, Nardelli, Pasquale, Nardin, Giordano, Navarro Pérez, Rosalía, Naveiro, Andrea, Negri, Manuela, Nesek Adam, Visnja, Neskovic, Vojislava, Neuwersch, Stefan, Neves, Miriam, Nguyen, Bavinh, Ní Eochagáin, Aisling, Nicholas, Caroline, Nightingale, Jeremy, Norrie, Kylie, Novak-Jankovic, Vesna, Novakova, Andrea, Novillo, Marta, Numan, Sandra, Oduro-Dominah, Louise, Oldner, Anders, Oliveira, Isabel, Ologoiu, Daniela, Oloktsidou, Irini, O'Reilly, Rosalind, Orlando, Alessandro, Ovezov, Alexey, Ozbilgin, Sule, Paal, Peter, Padin Barreiro, Lidia, Palugniok, Ryszard, Papaioannou, Alexandra, Papapostolou, Konstantinos, Paranthaman, Prabhakar, Pardey Bracho, Gilda, Parente, Suzana, Parfeni, Alexandru, Pasin, Laura, Passey, Samuel, Pastor, Ernesto, Patch, Sarah, Patil, Andan, Paunescu, Marilena-Alina, Pehboeck, Daniel, Pereira, Manuela, Pereira, Carla, Perez Caballero, Paula, Pérez García, Aníbal, Pérez Soto, Antonia, Perez Tejero, Gisela, Perez-Cerda, Francisco, Pesenti, Antonio, Petta, Rocco, Philippe, Simon, Pickering, David, Pico Veloso, Jandro, Pina, Pedro, Pinho-Oliveira, Vítor, Pinol, Santiago, Pinto, Rita, Pistidda, Laura, Pitterle, Manuela, Piwowarczyk, Paweł, Plotnikova, Olga, Pohl, Holger, Poldermann, Jorinde, Polkovicová, Lucia, Pompei, Livia, Popescu, Mihai, Popović, Radmila, Pota, Vincenzo, Potocnik, Miriam, Potręć, Beata, Potter, Alison, Pramod, Nalwaya, Prchalova, Martina, Preckel, Benedikt, Pugh, Richard, Pulletz, Mark, Radoeshki, Aleksandar, Rafi, Amir, Ragazzi, Riccardo, Raineri Santi, Maurizio, Rajamanickam, Tamiselvan, Rajput, Zahra, Ramachandran, Rajeskar, Ramasamy, Radhika, Ramessur, Suneil, Rao, Roshan, Rasmussen, Anders, Rato, André, Razaque, Usman, Real Navacerrada, M. Isabel, Reavley, Caroline, Reid, James, Reschreiter, Henrik, Rial, Erick, Ribas Carrasco, Patricia, Ribeiro, Sandy, Rich, Nathalie, Richardson, Lydia, Rimaitis, Kestutis, Rimaitis, Marius, Ringvold, Else-Marie, Ripke, Fabian, Ristescu, Irina, Ritchie, Keith, Ródenas, Frederic, Rodrigues, Patrícia, Rogers, Emma, Rogerson, David, Romagnoli, Stefano, Romero, Esther, Rondovic, Goran, Rose, Bernd Oliver, Roth, Winfried, Rotter, Marie-Therese, Rousseau, Guy, Rudjord, Anders, Rueffert, Henrik, Rundgren, Malin, Rupprecht, Korbinian, Rushton, Andrew, Russotto, Vincenzo, Rypulak, Elżbieta, Ryszka, Maciej, Sà, Jacinta, Sà Couto, Paula, Saby, Sandrine, Sagic, Jelena, Saleh, Omar, Sales, Gabriele, Sánchez Sánchez, Yván, Sanghera, Sumayer, Şanli Karip, Ceren, Santiveri Papiol, Francisco Javier, Santos, Sofia, Sarno, Stephen, Saul, Daniel, Saunders, David, Savic, Nenad, Scalco, Loïc, Scanlon, Deborah, Schaller, Stefan, Schax, Christoph, Scheffer, Gert Jan, Schening, Anna, Schiavone, Vincenzo, Schmidt-Ehrenberg, Florian, Schmidt-Mutter, Catherine, Schönberg, Christina, Schopflin, Christian, Schreiber, Jan-Uwe, Schultz, Marcus, Schurig, Marlen, Scott, Carmen, Sebestian, Siby, Sehgal, Selena, Sem, Victoria, Semenas, Egidijus, Serafini, Elena, Serchan, Pashalitsa, Shields, Martin, Shobha, Ramakrishnan, Shosholcheva, Mirjana, Siamansour, Tanja, Siddaiah, Narendra, Siddiqi, Khalid, Sinclair, Rhona, Singh, Permendra, Singh, Rajendra, Sinha, Aneeta, Sinha, Ashok, Skinner, Amanda, Smee, Elizabeth, Smekalova, Olga, Smith, Neil, Smith, Thomas, Smitz, Carine, Smole, Daniel, Sojčić, Nataša, Soler Pedrola, Maria, Somanath, Sameer, Sonksen, Julian, Sorella, Maria Christina, Sörmus, Alar, Soro, Marina, Soto, Carmen, Spada, Anna, Spadaro, Savino, Spaeth, Johannes, Sparr, Harald, Spielmann, Annika, Spindler-Vesel, Alenka, Stamelos, Matthaios, Stancombe L, Liucia, Stanculescu, Andreea, Standl, Thomas, Standley, Tom, Stanek, Ondrej, Stanisavljević, Snežana, Starczewska, Malgorzata, Stäuble, Christiane, Steen, Julie, Stefan, Oana Maria, Stell, Elizabeth, Stera, Caterina, Stevens, Markus, Stoerckel, Marlène, Stošić, Biljana, Stourac, Petr, Stroumpoulis, Konstantinos, Struck, Rafael, Suarez de la Rica, Alejandro, Sultanpori, Altaf, Sundara Rajan, Rajinikanth, Suying, Ong, Svensen, Christer, Swan, Louise, Syrogianni, Paulina, Sysiak, Justyna, Szederjesi, Janos, Taddei, Stefania, Tan Hao, Ern, Tanou, Virginia, Tarabová, Katarina, Tardaguila Sancho, Paula, Tarroso, Maria, Tartaglione, Marco, Taylor, Emma, Tbaily, Lee, Telford, Richard, Terenzoni, Massimo, Theodoraki, Kassiani, Thornley, Helen, Tiganiuc, Liviu, Toim, Hardo, Tomescu, Dana, Tommasino, Concezione, Toni, Jessica, Toninelli, Arturo, Toretti, Ilaria, Townley, Stephen, Trepenaitis, Darius, Trethowan, Brian, Tsaousi, Georgia, Tsiftsi, Aikaterini, Tudor, Adrada, Turan, Güldem, Turhan, Sanem Çakar, Unic-Stojanovic, Dragana, Unterbuchner, Christoph, Unzueta, Carmen, Uranjek, Jasna, Ursic, Tomaz, Vaida, Simona, Valldeperas Ferrer, Silvia, Valldeperas Hernandez, Maria Inmaculada, Valsamidis, Dimitri, Van Beek, Rienk, Van dasselaer, Nick, Van Der Beek, Tim, Van Duivenvoorde, Yoni, van Klei, Wilton A., Van Poorter, Frans, Van Zaane, Bas, Van Zundert, Tom, Van Zyl, Rebekka, Vargas Munoz, Ana Milena, Varsani, Nimu, Vasconcelos, Pedro, Vassilakis, Georgios, Vecchiatini, Tommaso, Vecera, Lubomir, Vercauteren, Marcel, Verdouw, Bas, Verheyen, Veerle, Verri, Marco, Vicari Sottosanti, Luigi Giancarlo, Vico, Manuel, Vidal Mitjans, Patricia, Vilardi, Anna, Vissicchio, Daniela, Vitale, Giovanni, Vitković, Bibiana, Vizcaychipi, Marcela Paola, Voicu, Alexandra, Voje, Minca, Volfová, Ivana, Volta, Carlo Alberto, Von Lutterotti, Theresa, von Tiesenhausen, Anna, Vrecic-Slabe, Simona, Vukcevic, Dejan, Vukovic, Rade, Vullo, P. Agostina, Wade, Andrew, Wallberg, Hanna, Wallden, Jakob, Wallner, Johann, Walther Sturesson, Louise, Watson, Davina, Weber, Stefan, Wegiel Leskiewiq, Anna, Weller, Debbie, Wensing, Carine, Werkmann, Markus, Westberg, Henrik, Wikström, Erik, Williams, Benedict, Wilson, Robin, Wirth, Steffen, Wittmann, Maria, Wood, Laura, Wright, Stella, Zachoval, Christian, Zambon, Massimo, Zampieri, Silvia, Zampone, Salvatore, Zangrillo, Alberto, Zani, Gianluca, Zavackiene, Asta, Zieglerder, Raphael, Zonneveldt, Harry, Zsisku, Lajos, Zucker, Tom-Philipp, Żukowski, Maciej, Zuleika, Mehrun, Zupanĕiĕ, Darja, Kirmeier, Eva, Eriksson, Lars I, Lewald, Heidrun, Jonsson Fagerlund, Malin, Hoeft, Andreas, Hollmann, Markus, Meistelman, Claude, Hunter, Jennifer M, Ulm, Kurt, and Blobner, Manfred

Published
2019
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26. The phase 3 DUO trial: duvelisib vs ofatumumab in relapsed and refractory CLL/SLL

Author

Flinn, Ian W., Hillmen, Peter, Montillo, Marco, Nagy, Zsolt, Illés, Árpád, Etienne, Gabriel, Delgado, Julio, Kuss, Bryone J., Tam, Constantine S., Gasztonyi, Zoltán, Offner, Fritz, Lunin, Scott, Bosch, Francesco, Davids, Matthew S., Lamanna, Nicole, Jaeger, Ulrich, Ghia, Paolo, Cymbalista, Florence, Portell, Craig A., Skarbnik, Alan P., Cashen, Amanda F., Weaver, David T., Kelly, Virginia M., Turnbull, Barry, and Stilgenbauer, Stephan

Published
2018
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28. Comparison of AlphaLISA and RIA assays for measurement of wool cortisol concentrations

Author

T. Peric, A. Comin, M. Corazzin, M. Montillo, and A. Prandi

Subjects
AlphaLISA, Glucocorticoids, Lamb, RIA, Sheep, Animal science, Science (General), Q1-390, Social sciences (General), H1-99
Abstract

Radioimmunoassay (RIA) methods have always represented a technique of choice for the determination of steroids in biological samples. The Amplified Luminescent Proximity Homogenous Assay-Linked Immunosorbent Assay (AlphaLISA) is now emerging as the new-generation immunoassay technology that does not require washing/separation steps. The aim of this study was to adapt the Perkin-Elmer's AlphaLISA kit for wool cortisol and compare it with a RIA wool cortisol assay. Wool from lambs, 35 at birth (A0) and 54 at two months old (A2), was collected and each extract was evaluated for wool cortisol concentrations (HCC) both by RIA and AlphaLISA immunoassay. The two methods showed good precision, sensitivity and specificity for determining HCC. Both methods were able to detect significant differences between the high and the low HCC assessed in lambs at A0 and A2 (P < 0.01). The HCC assessed with RIA were significantly higher than those assessed with AlphaLISA (P < 0.01). Moreover, the correlation between HCC measured using the AlphaLISA and RIA methods was strong (r = 0.878). The regression analyses show a constant and not proportional error. This could be due to the diversity in the dosage steps and to the diversity of the molecules used in the two methods. Results support the validity of using AlphaLISA as an alternative method to RIA for the quantification of cortisol in sheep wool and considering the performances showed it has a great potential to be further applied as an excellent tool to evaluate HCC in samples derived from animal species.

Published
2020
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29. Impact of ibrutinib dose adherence on therapeutic efficacy in patients with previously treated CLL/SLL

Author

Barr, Paul M., Brown, Jennifer R., Hillmen, Peter, O'Brien, Susan, Barrientos, Jacqueline C., Reddy, Nishitha M., Coutre, Steven, Mulligan, Stephen P., Jaeger, Ulrich, Furman, Richard R., Cymbalista, Florence, Montillo, Marco, Dearden, Claire, Robak, Tadeusz, Moreno, Carol, Pagel, John M., Burger, Jan A., Suzuki, Samuel, Sukbuntherng, Juthamas, Cole, George, James, Danelle F., and Byrd, John C.

Published
2017
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30. Idelalisib or placebo in combination with bendamustine and rituximab in patients with relapsed or refractory chronic lymphocytic leukaemia: interim results from a phase 3, randomised, double-blind, placebo-controlled trial

Author

Zelenetz, Andrew D, Barrientos, Jacqueline C, Brown, Jennifer R, Coiffier, Bertrand, Delgado, Julio, Egyed, Miklós, Ghia, Paolo, Illés, Árpád, Jurczak, Wojciech, Marlton, Paula, Montillo, Marco, Morschhauser, Franck, Pristupa, Alexander S, Robak, Tadeusz, Sharman, Jeff P, Simpson, David, Smolej, Lukáš, Tausch, Eugen, Adewoye, Adeboye H, Dreiling, Lyndah K, Kim, Yeonhee, Stilgenbauer, Stephan, and Hillmen, Peter

Published
2017
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33. Hair cortisol and testosterone concentrations and semen production of Bos taurus bulls

Author

Giuseppe Stradaioli, Tanja Peric, Marta Montillo, Antonella Comin, Mirco Corazzin, Maria Cristina Veronesi, and Alberto Prandi

Subjects
hair, bulls, cortisol, testosterone, semen, Animal culture, SF1-1100
Abstract

The experiment was aimed to evaluate the usefulness of hair cortisol concentrations (HCC) in revealing the activation of the hypothalamic-pituitary-adrenal (HPA) axis due to the passage of young bulls from genetic rearing stations to artificial insemination (AI) centre and the influence of this passage on hair testosterone concentrations (HTC). Hair samples on 33 yearling bulls were collected at the time of arrival (ST1) to the AI centre and 3 more hair samples (ST2, ST3, ST4) were collected at monthly intervals. After the end of quarantine each animal was submitted to the standard procedures for collection and production of semen. Overall HCC were significantly affected by period of collection (p .05). The effect of breed was observed only for HTC that was higher in PRI than BS (p .05). On the contrary, the effect of breed was evident. The results of this study replicated the effects of a major environmental stressor on mean cortisol concentrations assessed in hair, and add to the growing body of evidence that HCC is an effective and simply collected marker for long-term activity of the HPA system in response to persistent environmental challenge.

Published
2017
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34. Olaptesed pegol (NOX-A12) with bendamustine and rituximab: a phase IIa study in patients with relapsed/refractory chronic lymphocytic leukemia

Author

Michael Steurer, Marco Montillo, Lydia Scarfò, Francesca R. Mauro, Johannes Andel, Sophie Wildner, Livio Trentin, Ann Janssens, Sonja Burgstaller, Anna Frömming, Thomas Dümmler, Kai Riecke, Matthias Baumann, Diana Beyer, Stéphanie Vauléon, Paolo Ghia, Robin Foà, Federico Caligaris-Cappio, and Marco Gobbi

Subjects
Diseases of the blood and blood-forming organs, RC633-647.5
Abstract

Olaptesed pegol (NOX-A12) is a pegylated structured L-oligoribonucleotide that binds and neutralizes CXCL12, a chemokine tightly regulating the life cycle of chronic lymphocytic leukemia cells. The resulting inhibition of CXCR4 and CXCR7 signaling reduces the protective activity of the bone marrow and lymph node microenvironment. CXCL12 inhibition mobilizes chronic lymphocytic leukemia cells into the circulation and prevents their homing into the protective niches. In this phase I/II study, 28 patients with relapsed/refractory chronic lymphocytic leukemia were treated with olaptesed pegol in combination with bendamustine and rituximab. Combination treatment was preceded by single escalating pilot doses of olaptesed pegol in the first ten patients for evaluation of safety and pharmacokinetics. Peak concentrations and systemic exposure of olaptesed pegol were dose-linear; plasma elimination was monophasic with a 53.2 h half-life. A rapid increase in circulating chronic lymphocytic leukemia cells was observed already 1 h after administration of olaptesed pegol and lasted for at least 72 h. Single-agent treatment was well tolerated and no dose-limiting toxicity was observed. The combination regimen yielded an overall response rate of 86%, with 11% of patients achieving a complete response and 75% a partial response. Notably, all ten high-risk patients, including four with a 17p deletion, responded to treatment. The median progression-free survival was 15.4 (95% confidence interval: 12.2, 26.2) months while the median overall survival was not reached with >80% of patients alive after a median follow-up of 28 months. Olaptesed pegol was well tolerated and did not result in additional toxicity when combined with bendamustine and rituximab (ClinicalTrials.gov identifier: NCT01486797). Further clinical development of this novel CXCL12 inhibitor is thus warranted.

Published
2019
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35. Safety of obinutuzumab alone or combined with chemotherapy for previously untreated or relapsed/refractory chronic lymphocytic leukemia in the phase IIIb GREEN study

Author

Véronique Leblond, Melih Aktan, Christelle M. Ferra Coll, Caroline Dartigeas, Jens Kisro, Marco Montillo, João Raposo, Jean-Louis Merot, Susan Robson, Ekaterina Gresko, Francesc Bosch, Stephan Stilgenbauer, and Robin Foà

Subjects
Diseases of the blood and blood-forming organs, RC633-647.5
Abstract

The safety of obinutuzumab, alone or with chemotherapy, was studied in a non-randomized, open-label, non-comparative, phase IIIb study (GREEN) in previously untreated or relapsed/refractory chronic lymphocytic leukemia. Patients received obinutuzumab 1000 mg alone or with chemotherapy (investigator’s choice of fludarabine-cyclophosphamide for fit patients, chlorambucil for unfit patients, or bendamustine for any patient) on days 1, 8 and 15 of cycle 1, and day 1 of cycles 2–6 (28-day cycles), with the cycle 1/day 1 dose administered over two days. The primary end point was safety/tolerability. Between October 2013 and March 2016, 972 patients were enrolled and 971 treated (126 with obinutuzumab monotherapy, 193 with obinutuzumab-fludarabine-cyclophosphamide, 114 with obinutuzumab-chlorambucil, and 538 with obinutuzumab-bendamustine). Grade ≥3 adverse events occurred in 80.3% of patients, and included neutropenia (49.9%), thrombocytopenia (16.4%), anemia (9.6%), and pneumonia (9.0%); rates were similar in first-line and relapsed/refractory patients, and in first-line fit and unfit patients. Using expanded definitions, infusion-related reactions were observed in 65.4% of patients (grade ≥3, 19.9%; mainly seen during the first obinutuzumab infusion), tumor lysis syndrome in 6.4% [clinical and laboratory; highest incidence with obinutuzumab-bendamustine (9.3%)], and infections in 53.7% (grade ≥3, 20.1%). Serious and fatal adverse events were seen in 53.1% and 7.3% of patients, respectively. In first-line patients, overall response rates at three months post treatment exceeded 80% for all obinutuzumab-chemotherapy combinations. In the largest trial of obinutuzumab to date, toxicities were generally manageable in this broad patient population. Safety data were consistent with previous reports, and response rates were high. (clinicaltrials.gov identifier: 01905943).

Published
2018
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36. Chlorambucil plus ofatumumab versus chlorambucil alone in previously untreated patients with chronic lymphocytic leukaemia (COMPLEMENT 1): a randomised, multicentre, open-label phase 3 trial

Author

Hillmen, Peter, Robak, Tadeusz, Janssens, Ann, Babu, K Govind, Kloczko, Janusz, Grosicki, Sebastian, Doubek, Michael, Panagiotidis, Panagiotis, Kimby, Eva, Schuh, Anna, Pettitt, Andrew R, Boyd, Thomas, Montillo, Marco, Gupta, Ira V, Wright, Oliver, Dixon, Iestyn, Carey, Jodi L, Chang, Chai-Ni, Lisby, Steen, McKeown, Astrid, and Offner, Fritz

Published
2015
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37. Higher-order connections between stereotyped subsets

Author

Andrea Patriarca, Marco Montillo, Niki Stavroyianni, Claudia Haferlach, Lesley-Ann Sutton, Livio Trentin, Franco Fais, Raphael Sandaltzopoulos, Arnon P. Kater, Anton W. Langerak, Marine Armand, Davide Rossi, Diane F. Jelinek, Davide Bagnara, Lydia Scarfò, Andreas Agathangelidis, Krzysztof Giannopoulos, Eugen Tausch, Andrey Sudarikov, Silvio Veronese, Salem H. Alshemmari, B V Biderman, Zadie Davis, Chrysoula Belessi, Lisa Bonello, Achilles Anagnostopoulos, Gerlinde Mitterbauer-Hohendanner, David Oscier, Sofia Kossida, Lone Bredo Pedersen, Paolo Ghia, Csaba Bödör, Christian Brieghel, Andrea Visentin, Véronique Giudicelli, Matthias Ritgen, Panagiotis Panagiotidis, Panagiotis Baliakas, Stephan Stilgenbauer, Ellen J van Gastel, Renee C. Tschumper, Christiane Pott, Frederic Davi, Katerina Gemenetzi, Valentina Guido, Elias Campo, Gianluca Gaidano, Irina Panovska, Sabine Jeromin, Karla Plevová, Kostas Stamatopoulos, Kamila Brázdilová, Maria Karypidou, Alba Navarro, Christof W. Schneider, Theodoros Moysiadis, Larry Mansouri, Darko Antic, Cristina Tresoldi, Constance Baer, Šárka Pospíšilová, Maria Roumelioti, Katrina Vanura, Xiao-Jie Yan, Hana Skuhrová Francová, Richard Rosenquist, Blanca Espinet, Paola Francia di Celle, Monica Facco, Paul Costeas, Michael Hallek, Carsten Utoft Niemann, Teodora Karan-Djurasevic, Manja Meggendorfer, Kirsten Fischer, Aleksandar Dimovski, Letizia Foroni, Marie-Paule Lefranc, Mark Catherwood, Anne de Septenville, Anastasia Chatzidimitriou, Sarah Lawless, Nicholas Chiorazzi, Agathangelidis, Andrea, Chatzidimitriou, Anastasia, Gemenetzi, Katerina, Giudicelli, Veronique, Karypidou, Maria, Plevova, Karla, Davis, Zadie A, Yan, Xiao-Jie, Jeromin, Sabine, Schneider, Christof, Pedersen, Lone Bredo, Tschumper, Renee, Sutton, Lesley A, Baliakas, Panagioti, Scarfò, Lydia, van Gastel, Ellen J, Armand, Marine, Tausch, Eugen, Biderman, Bella, Baer, Constance, Bagnara, Davide, Navarro, Alba, de Septenville, Anne, Guido, Valentina, Mitterbauer-Hohendanner, Gerlinde, Dimovski, Aleksandar, Brieghel, Christian, Lawless, Sarah, Meggendorfer, Manja, Stranska, Kamila, Ritgen, Matthia, Facco, Monica, Tresoldi, Cristina, Visentin, Andrea, Patriarca, Andrea, Catherwood, Mark, Bonello, Lisa, Sudarikov, Andrey, Vanura, Katrina, Roumelioti, Maria, Skuhrova Francova, Hana, Moysiadis, Theodoro, Veronese, Silvio M, Giannopoulos, Krzysztof, Mansouri, Larry, Karan-Djurasevic, Teodora, Sandaltzopoulos, Raphael, Bödör, Csaba, Fais, Franco, Kater, Arnon P, Panovska-Stavridis, Irina, Rossi, Davide, Alshemmari, Salem, Panagiotidis, Panagioti, Costeas, Paul A, Espinet, Blanca, Antic, Darko, Foroni, Letizia, Montillo, Marco, Trentin, Livio, Stavroyianni, Niki, Gaidano, Gianluca, Francia di Celle, Paola, Niemann, Carsten Utoft, Campo, Elía, Anagnostopoulos, Achille, Pott, Christiane, Fischer, Kirsten, Hallek, Michael, Oscier, David Graham, Stilgenbauer, Stephan, Haferlach, Claudia, Jelinek, Diane F, Chiorazzi, Nichola, Pospisilova, Sarka, Lefranc, Marie-Paule, Kossida, Sofia, Langerak, Anton W, Belessi, Chrysoula, Davi, Frederic, Rosenquist, Richard, Ghia, Paolo, Stamatopoulos, Kostas, Experimental Immunology, Clinical Haematology, AII - Cancer immunology, CCA - Cancer biology and immunology, and Immunology

Subjects
Chronic lymphocytic leukemia, Immunology, B-cell receptor, Immunoglobulin Variable Region, Disease, Computational biology, Biology, Biochemistry, 03 medical and health sciences, 0302 clinical medicine, Gene Frequency, hemic and lymphatic diseases, Immunoglobulin, medicine, Humans, Chronic, 030304 developmental biology, Gene Rearrangement, 0303 health sciences, Leukemia, Lymphoid Neoplasia, Repertoire, B-Cell, breakpoint cluster region, Cell Biology, Hematology, Gene rearrangement, Somatic Hypermutation, medicine.disease, Leukemia, Lymphocytic, Chronic, B-Cell, Lymphocytic, Stereotypy (non-human), Immunoglobulin Heavy Chains, Somatic Hypermutation, Immunoglobulin, 030220 oncology & carcinogenesis, IGHV@
Abstract

Chronic lymphocytic leukemia (CLL) is characterized by the existence of subsets of patients with (quasi)identical, stereotyped B-cell receptor (BcR) immunoglobulins. Patients in certain major stereotyped subsets often display remarkably consistent clinicobiological profiles, suggesting that the study of BcR immunoglobulin stereotypy in CLL has important implications for understanding disease pathophysiology and refining clinical decision-making. Nevertheless, several issues remain open, especially pertaining to the actual frequency of BcR immunoglobulin stereotypy and major subsets, as well as the existence of higher-order connections between individual subsets. To address these issues, we investigated clonotypic IGHV-IGHD-IGHJ gene rearrangements in a series of 29 856 patients with CLL, by far the largest series worldwide. We report that the stereotyped fraction of CLL peaks at 41% of the entire cohort and that all 19 previously identified major subsets retained their relative size and ranking, while 10 new ones emerged; overall, major stereotyped subsets had a cumulative frequency of 13.5%. Higher-level relationships were evident between subsets, particularly for major stereotyped subsets with unmutated IGHV genes (U-CLL), for which close relations with other subsets, termed “satellites,” were identified. Satellite subsets accounted for 3% of the entire cohort. These results confirm our previous notion that major subsets can be robustly identified and are consistent in relative size, hence representing distinct disease variants amenable to compartmentalized research with the potential of overcoming the pronounced heterogeneity of CLL. Furthermore, the existence of satellite subsets reveals a novel aspect of repertoire restriction with implications for refined molecular classification of CLL. Key Points: • In a series of 29 856 CLL patients, the incidence of BcR stereotypy peaked at 41%. • Higher-order relations exist between stereotyped subsets, particularly for those from U-CLL, for which satellite subsets were identified.

Published
2021

38. UQ-ARMED: Uncertainty quantification of adversarially-regularized mixed effects deep learning for clustered non-iid data

Author

Treacher, Alex, Nguyen, Kevin, Owens, Dylan, Heitjan, Daniel, and Montillo, Albert

Subjects
Methodology (stat.ME), FOS: Computer and information sciences, Computer Science - Machine Learning, Artificial Intelligence (cs.AI), Statistics - Machine Learning, Computer Science - Artificial Intelligence, Machine Learning (stat.ML), Statistics - Methodology, Machine Learning (cs.LG)
Abstract

This work demonstrates the ability to produce readily interpretable statistical metrics for model fit, fixed effects covariance coefficients, and prediction confidence. Importantly, this work compares 4 suitable and commonly applied epistemic UQ approaches, BNN, SWAG, MC dropout, and ensemble approaches in their ability to calculate these statistical metrics for the ARMED MEDL models. In our experiment for AD prognosis, not only do the UQ methods provide these benefits, but several UQ methods maintain the high performance of the original ARMED method, some even provide a modest (but not statistically significant) performance improvement. The ensemble models, especially the ensemble method with a 90% subsampling, performed well across all metrics we tested with (1) high performance that was comparable to the non-UQ ARMED model, (2) properly deweights the confounds probes and assigns them statistically insignificant p-values, (3) attains relatively high calibration of the output prediction confidence. Based on the results, the ensemble approaches, especially with a subsampling of 90%, provided the best all-round performance for prediction and uncertainty estimation, and achieved our goals to provide statistical significance for model fit, statistical significance covariate coefficients, and confidence in prediction, while maintaining the baseline performance of MEDL using ARMED

Published
2022

39. Efficacy of bendamustine and rituximab as first salvage treatment in chronic lymphocytic leukemia and indirect comparison with ibrutinib: a GIMEMA, ERIC and UK CLL FORUM study

Author

Antonio Cuneo, George Follows, Gian Matteo Rigolin, Alfonso Piciocchi, Alessandra Tedeschi, Livio Trentin, Angeles Medina Perez, Marta Coscia, Luca Laurenti, Gerardo Musuraca, Lucia Farina, Alfredo Rivas Delgado, Ester Maria Orlandi, Piero Galieni, Francesca Romana Mauro, Carlo Visco, Angela Amendola, Atto Billio, Roberto Marasca, Annalisa Chiarenza, Vittorio Meneghini, Fiorella Ilariucci, Monia Marchetti, Stefano Molica, Francesca Re, Gianluca Gaidano, Marcos Gonzalez, Francesco Forconi, Stefania Ciolli, Agostino Cortelezzi, Marco Montillo, Lukas Smolej, Anna Schuh, Toby A. Eyre, Ben Kennedy, Kris M. Bowles, Marco Vignetti, Javier de la Serna, Carol Moreno, Robin Foà, and Paolo Ghia

Subjects
Diseases of the blood and blood-forming organs, RC633-647.5
Abstract

We performed an observational study on the efficacy of ben-damustine and rituximab (BR) as first salvage regimen in chronic lymphocytic leukemia (CLL). In an intention-to-treat analysis including 237 patients, the median progression-free survival (PFS) was 25 months. The presence of del(17p), unmutated IGHV and advanced stage were associated with a shorter PFS at multivariate analysis. The median time-to-next treatment was 31.3 months. Front-line treatment with a chemoimmunotherapy regimen was the only predictive factor for a shorter time to next treatment at multivariate analysis. The median overall survival (OS) was 74.5 months. Advanced disease stage (i.e. Rai stage III-IV or Binet stage C) and resistant disease were the only parameters significantly associated with a shorter OS. Grade 3-5 infections were recorded in 6.3% of patients. A matched-adjusted indirect comparison with ibrutinib given second-line within Named Patient Programs in the United Kingdom and in Italy was carried out with OS as objective end point. When restricting the analysis to patients with intact 17p who had received chemoimmunotherapy in first line, there was no difference in OS between patients treated with ibrutinib (63% alive at 36 months) and patients treated with BR (74.4% alive at 36 months). BR is an efficacious first salvage regimen in CLL in a real-life population, including the elderly and unfit patients. BR and ibrutinib may be equally effective in terms of OS when used as first salvage treatment in patients without 17p deletion.

Published
2018
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40. No improvement in long-term survival over time for chronic lymphocytic leukemia patients in stereotyped subsets #1 and #2 treated with chemo(immuno)therapy

Author

Panagiotis Baliakas, Mattias Mattsson, Anastasia Hadzidimitriou, Eva Minga, Andreas Agathangelidis, Lesley-Ann Sutton, Lydia Scarfo, Zadie Davis, Xiao-Jie Yan, Karla Plevova, Yorick Sandberg, Fie J. Vojdeman, Tatiana Tzenou, Charles C. Chu, Silvio Veronese, Larry Mansouri, Karin E Smedby, Véronique Giudicelli, Florence Nguyen-Khac, Panagiotis Panagiotidis, Gunnar Juliusson, Achilles Anagnostopoulos, Marie-Paule Lefranc, Livio Trentin, Mark Catherwood, Marco Montillo, Carsten U. Niemann, Anton W. Langerak, Sarka Pospisilova, Niki Stavroyianni, Nicholas Chiorazzi, David Oscier, Diane F Jelinek, Tait Shanafelt, Nikos Darzentas, Chrysoula Belessi, Frederic Davi, Paolo Ghia, Richard Rosenquist, and Kostas Stamatopoulos

Subjects
Diseases of the blood and blood-forming organs, RC633-647.5
Published
2018
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41. Clinical effect of stereotyped B-cell receptor immunoglobulins in chronic lymphocytic leukaemia: a retrospective multicentre study

Author

Baliakas, Panagiotis, Hadzidimitriou, Anastasia, Sutton, Lesley-Ann, Minga, Eva, Agathangelidis, Andreas, Nichelatti, Michele, Tsanousa, Athina, Scarfò, Lydia, Davis, Zadie, Yan, Xiao-Jie, Shanafelt, Tait, Plevova, Karla, Sandberg, Yorick, Vojdeman, Fie Juhl, Boudjogra, Myriam, Tzenou, Tatiana, Chatzouli, Maria, Chu, Charles C, Veronese, Silvio, Gardiner, Anne, Mansouri, Larry, Smedby, Karin E, Pedersen, Lone Bredo, van Lom, Kirsten, Giudicelli, Véronique, Francova, Hana Skuhrova, Nguyen-Khac, Florence, Panagiotidis, Panagiotis, Juliusson, Gunnar, Angelis, Lefteris, Anagnostopoulos, Achilles, Lefranc, Marie-Paule, Facco, Monica, Trentin, Livio, Catherwood, Mark, Montillo, Marco, Geisler, Christian H, Langerak, Anton W, Pospisilova, Sarka, Chiorazzi, Nicholas, Oscier, David, Jelinek, Diane F, Darzentas, Nikos, Belessi, Chrysoula, Davi, Frederic, Rosenquist, Richard, Ghia, Paolo, and Stamatopoulos, Kostas

Published
2014
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43. Clinical utility and patient considerations in the use of ofatumumab in chronic lymphocytic leukemia

Author

Frustaci AM, Tedeschi A, Picardi P, Cairoli R, and Montillo M

Subjects
Medicine (General), R5-920
Abstract

Anna Maria Frustaci, Alessandra Tedeschi, Paola Picardi, Roberto Cairoli, Marco MontilloDepartment of Hematology, Niguarda Cancer Center, Niguarda Ca' Granda Hospital, Milan, Italy Abstract: Treatment aim for chronic lymphocytic leukemia has been radically changed over the past years from providing only a palliative approach to reaching disease eradication and improving survival. Ofatumumab is a monoclonal humanized antibody with peculiar in vitro and in vivo properties, at present approved for double fludarabine and alemtuzumab refractory chronic lymphocytic leukemia. Its efficacy in this subset of patients, who typically have an unfavorable prognosis, facilitated its use in different Phase II and III trials. Ofatumumab as single agent or combined with chemotherapeutic or biologic agents, led to sundry results in the setting of both previously treated or untreated patients. Its role in maintenance therapy is also under investigation. Further advances concerning ofatumumab administration as first line therapy in combination with chlorambucil, came recently from the COMPLEMENT 1 study. Results from this trial will open the door to new perspectives of its use in treatment-naïve patients. Ofatumumab was well tolerated in almost all the studies, with the main adverse events relating mostly to infusion reaction. Hematologic toxicity, especially neutropenia, was also common. A significant improvement in patients' quality of life was reported following ofatumumab treatment and this was mainly due to its effect on constitutional symptoms. Nevertheless, some concerns remain regarding the long-term efficacy of the drug in terms of response duration and survival. The real strength of this drug needs to be confirmed by further studies and direct comparative trials. Keywords: ofatumumab, chronic lymphocytic leukemia, refractory, alemtuzumab, fludarabine, high risk

Published
2015

44. Evaluating How the Social Restriction, the Government Response, the Health, and Economic Indices Affected the Prediction of the Number of Deaths Provoked by COVID-19 in Brazil Using Classical Statistical and Machine Learning Models

Author

Marcello Montillo Provenza, Aderval Severino Luna, and Vinicius Layter Xavier

Subjects
Multidisciplinary, Jackknife, COVID-19 Deaths, Regression models, Machine learning, Statistical models
Abstract

The COVID-19 death predictions are helpful for the formulation of public policies, allowing the use of more effective social isolation strategies with less economic and social impact. This article evaluates a wide range of forecasting methods to identify the best models for predicting cumulative and daily deaths caused by COVID-19 in Brazil, considering a forecast for a seven-day horizon. With the seven-day horizon, the predictions have more accuracy. The dataset is from Oxford Covid-19 Government Response Tracker. The jackknife resampling technique was implemented, thus providing an accurate estimate for evaluating the predictive capacity of the models. Each model was fitted with 266 jackknife samples considering 30-day training bases. The comparison between predictions was made using the average results, considering R2, MAPE, RMSE, and MAE. Models from different classes were adopted: 1 ETS, 4 ARIMA, 18 regression models, and 7 machine learning algorithms. The cumulative death models produce better results than daily deaths, as the cumulative death models are less influenced by time series components: cycle and seasonality. The best results for predicting daily deaths were attained by the Ridge regression method. The best results for predicting cumulative deaths were obtained by the Cubist regression method.

Published
2022

45. Enduring undetectable MRD and updated outcomes in relapsed/refractory CLL after fixed-duration venetoclax-rituximab

Author

John F. Seymour, Thomas J. Kipps, Barbara F. Eichhorst, James D’Rozario, Carolyn J. Owen, Sarit Assouline, Nicole Lamanna, Tadeusz Robak, Javier de la Serna, Ulrich Jaeger, Guillaume Cartron, Marco Montillo, Clemens Mellink, Brenda Chyla, Anesh Panchal, Tong Lu, Jenny Q. Wu, Yanwen Jiang, Marcus Lefebure, Michelle Boyer, Arnon P. Kater, Human Genetics, Experimental Immunology, Clinical Haematology, CCA - Cancer Treatment and Quality of Life, and Hematology

Subjects
Sulfonamides, Neoplasm, Residual, Recurrence, Immunology, Antineoplastic Combined Chemotherapy Protocols, Bendamustine Hydrochloride, Humans, Cell Biology, Hematology, Bridged Bicyclo Compounds, Heterocyclic, Rituximab, Biochemistry, Leukemia, Lymphocytic, Chronic, B-Cell
Abstract

The MURANO trial (A Study to Evaluate the Benefit of Venetoclax Plus Rituximab Compared With Bendamustine Plus Rituximab in Participants With Relapsed or Refractory Chronic Lymphocytic Leukemia [CLL]; ClinicalTrials.gov identifier #NCT02005471) reported superior progression-free survival (PFS) and overall survival (OS) with venetoclax-rituximab (VenR) vs bendamustine-rituximab (BR) in relapsed/refractory (R/R) CLL. Patients were randomized to 2 years of VenR (n = 194; rituximab for the first 6 months) or 6 months of BR (n = 195). Although undetectable minimal residual disease (uMRD) was achieved more often with VenR, the long-term implications of uMRD with this fixed-duration, chemotherapy-free regimen have not been explored. We report MRD kinetics and updated outcomes with 5 years’ follow-up. Survival benefits with VenR vs BR were sustained (median PFS [95% confidence interval]: 53.6 [48.4, 57.0] vs 17.0 [15.5, 21.7] months, respectively, P < .0001; 5-year OS [95% confidence interval]: 82.1% [76.4, 87.8] vs 62.2% [54.8, 69.6], P < .0001). VenR was superior to BR, regardless of cytogenetic category. VenR-treated patients with uMRD at end of treatment (EOT; n = 83) had superior OS vs those with high-MRD+ (n = 12): 3-year post-EOT survival rates were 95.3% vs 72.9% (P = .039). In those with uMRD at EOT, median time to MRD conversion was 19.4 months. Of 47 patients with documented MRD conversion, 19 developed progressive disease (PD); median time from conversion to PD was 25.2 months. A population-based logistic growth model indicated slower MRD median doubling time post-EOT with VenR (93 days) vs BR (53 days; P = 1.2 × 10−7). No new safety signals were identified. Sustained survival, uMRD benefits, and durable responses support 2-year fixed-duration VenR treatment in R/R CLL.

Published
2022

46. Glaucoma Diagnosis Through the Integration of Optical Coherence Tomography/Angiography and Machine Learning Diagnostic Models

Author

Karanjit S Kooner, Ashika Angirekula, Alex H Treacher, Ghadeer Al-Humimat, Mohamed F Marzban, Alyssa Chen, Roma Pradhan, Nita Tunga, Chuhan Wang, Pranati Ahuja, Hafsa Zuberi, and Albert A Montillo

Subjects
Ophthalmology, Clinical Ophthalmology
Abstract

Karanjit S Kooner,1,2 Ashika Angirekula,1 Alex H Treacher,3 Ghadeer Al-Humimat,1,4 Mohamed F Marzban,5 Alyssa Chen,1 Roma Pradhan,1 Nita Tunga,1 Chuhan Wang,1 Pranati Ahuja,1 Hafsa Zuberi,1 Albert A Montillo3,6,7 1Department of Ophthalmology, University of Texas Southwestern Medical Center, Dallas, TX, USA; 2Department of Ophthalmology, Veteran Affairs North Texas Health Care System Medical Center, Dallas, TX, USA; 3Lyda Hill Department of Bioinformatics, University of Texas Southwestern Medical Center, Dallas, TX, USA; 4Department of Ophthalmology, King Hussein Medical Center, Amman, Jordan; 5Department of Electrical Engineering, University of Texas at Dallas, Dallas, TX, USA; 6Department of Radiology, University of Texas Southwestern Medical Center, Dallas, TX, USA; 7Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, TX, USACorrespondence: Karanjit S Kooner, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX, 75390-9057, USA, Tel +1 (214) 648-4733, Fax +1 (214) 648-2270, Email Karanjit.Kooner@UTSouthwestern.edu Albert A Montillo, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX, 75390-9057, USA, Email Albert.Montillo@UTSouthwestern.eduPurpose: To establish optical coherence tomography (OCT)/angiography (OCTA) parameter ranges for healthy eyes (HE) and glaucomatous eyes (GE) for a North Texas based population; to develop a machine learning (ML) tool and to identify the most accurate diagnostic parameters for clinical glaucoma diagnosis.Patients and Methods: In this retrospective cross-sectional study, we included 1371 eligible eyes, 462 HE and 909 GE (377 ocular hypertension, 160 mild, 156 moderate, 216 severe), from 735 subjects. Demographic data and full OCTA parameters were collected. A Kruskal–Wallis test was used to produce the normative database. Models were trained to solve a two-class problem (HE vs GE) and four-class problem (HE vs mild vs moderate vs severe GE). A rigorous nested, stratified, group, 5× 10 fold cross-validation strategy was applied to partition the data. Six ML algorithms were compared using classical and deep learning approaches. Over 2500 ML models were optimized using random search, with performance compared using mean validation accuracy. Final performance was reported on held-out test data using accuracy and F1 score. Decision trees and feature importance were produced for the final model.Results: We found differences across glaucoma severities for age, gender, hypertension, Black and Asian race, and all OCTA parameters, except foveal avascular zone area and perimeter (p< 0.05). The XGBoost algorithm achieved the highest test performance for both the two-class (F1 score 83.8%; accuracy 83.9%; standard deviation 0.03%) and four-class (F1 score 62.4%; accuracy 71.3%; standard deviation 0.013%) problem. A set of interpretable decision trees provided the most important predictors of the final model; inferior temporal and inferior hemisphere vessel density and peripapillary retinal nerve fiber layer thickness were identified as key diagnostic parameters.Conclusion: This study established a normative database for our North Texas based population and created ML tools utilizing OCT/A that may aid clinicians in glaucoma management.Keywords: glaucoma, optical coherence tomography angiography, deep learning

Published
2022

47. Coexisting conditions and concomitant medications do not affect venetoclax management and survival in chronic lymphocytic leukemia

Author

Anna Maria Frustaci, Giovanni Del Poeta, Andrea Visentin, Paolo Sportoletti, Alberto Fresa, Candida Vitale, Roberta Murru, Annalisa Chiarenza, Alessandro Sanna, Francesca Romana Mauro, Gianluigi Reda, Massimo Gentile, Marzia Varettoni, Claudia Baratè, Chiara Borella, Antonino Greco, Marina Deodato, Giulia Zamprogna, Roberta Laureana, Alessandra Cipiciani, Andrea Galitzia, Angelo Curto Pelle, Francesca Morelli, Lucio Malvisi, Marta Coscia, Luca Laurenti, Livio Trentin, Marco Montillo, Roberto Cairoli, Alessandra Tedeschi, Frustaci, A, Del Poeta, G, Visentin, A, Sportoletti, P, Fresa, A, Vitale, C, Murru, R, Chiarenza, A, Sanna, A, Mauro, F, Reda, G, Gentile, M, Varettoni, M, Barate, C, Borella, C, Greco, A, Deodato, M, Zamprogna, G, Laureana, R, Cipiciani, A, Galitzia, A, Curto Pelle, A, Morelli, F, Malvisi, L, Coscia, M, Laurenti, L, Trentin, L, Montillo, M, Cairoli, R, and Tedeschi, A

Subjects
CIRS, comorbiditie, discontinuations, fitne, venetoclax, CLL, ECOG, comorbidities, fitness, reduction, targeted therapies, Hematology, Settore MED/15 - MALATTIE DEL SANGUE, MED/15 - MALATTIE DEL SANGUE, targeted therapie, discontinuation
Abstract

Background: The question of which parameters may be informative on venetoclax outcome in chronic lymphocytic leukemia (CLL) is still unclear. Furthermore, the choice to treat with venetoclax can be challenging in patients with baseline characteristics or comorbidities that may potentially favor some specific adverse events. Objectives: This study was aimed to evaluate whether age, fitness status, patients’/disease characteristics, or concomitant medications may predict outcomes in CLL patients receiving venetoclax. Design: Retrospective observational study. Methods: Impact of age, presence of Cumulative Illness Rating Scale (CIRS) >6 or severe organ impairment (CIRS3+), Eastern Cooperative Oncology Group–Performance Status (ECOG-PS), renal function, and concomitant medications were retrospectively analyzed on treatment management (definitive discontinuation due to toxicity, discontinuation due to toxicity, Tox-DTD; permanent dose reduction, PDR) and survival [progression free survival (PFS), event free survival (EFS), overall survival (OS)] in unselected patients receiving venetoclax monotherapy in common practice. Results: A total of 221 relapsed/refractory patients were included. Tox-DTD and PDR were reported in 5.9% and 21.7%, respectively, and were not influenced by any fitness parameter, age, number or type of concomitant medication, baseline neutropenia, or impaired renal function. None of these factors were associated with tumor lysis syndrome (TLS) development. Age and coexisting conditions had no influence on PFS and EFS. At univariate analysis, OS was significantly shorter only in patients with ECOG-PS >1 ( p 6 ( p = 0.014) or CIRS3+ ( p = 0.031). ECOG-PS >1 retained an independent role only for EFS and OS. While Tox-DTD affected all survival outcomes, no differences in PFS were reported among patients permanently reducing dose or interrupting venetoclax for > 7 days. Conclusion: Clinical outcome with venetoclax is not influenced by comorbidities, patients’ clinical characteristics, or concomitant medications. Differently from other targeted therapies, this demonstrates that, except ECOG-PS, none of the parameters generally considered for treatment choice, including baseline neutropenia or impaired renal function, should rule the decision process with this agent. Anyway, if clinically needed, a correct drug management does not compromise treatment efficacy and may avoid toxicity-driven discontinuations. Plain Language Summary Chapter 1: Why was this study done? Chapter 2: Which are the main findings of the study? Chapter 3: How these findings may impact on clinical practice? Coexisting conditions and concomitant medications do not affect venetoclax management and survival in chronic lymphocytic leukemia • The question of which parameters may be informative on venetoclax outcome in chronic lymphocytic leukemia is still unclear. Furthermore, the choice to treat with venetoclax can be challenging in patients with baseline characteristics or comorbidities that may potentially favor some specific adverse events (e.g. compromised renal function or baseline neutropenia). • In our large series of patients treated outside of clinical trials, we demonstrated that neither age, fitness, comorbidities nor concomitant medications impact on venetoclax management and survival. Importantly, patients presenting with baseline neutropenia or impaired renal function did not have a higher rate of dose reductions or toxicity-driven discontinuations, thus further underlining that venetoclax may be safely administered even in those categories with no preclusions. • Differently from other targeted agents, our data demonstrate that none of the baseline factors commonly considered in treatment decision process retains a role with venetoclax. Finally, permanent dose reductions and temporary interruptions did not adversely impact PFS suggesting that, if clinically needed, a correct drug management should be adopted with no risk of compromising venetoclax efficacy.

Published
2022

48. Venetoclax–Rituximab in Relapsed or Refractory Chronic Lymphocytic Leukemia

Author

Seymour, John F., Kipps, Thomas J., Eichhorst, Barbara, Hillmen, Peter, DʼRozario, James, Assouline, Sarit, Owen, Carolyn, Gerecitano, John, Robak, Tadeusz, De la Serna, Javier, Jaeger, Ulrich, Cartron, Guillaume, Montillo, Marco, Humerickhouse, Rod, Punnoose, Elizabeth A., Li, Yan, Boyer, Michelle, Humphrey, Kathryn, Mobasher, Mehrdad, and Kater, Arnon P.

Published
2018
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49. Extended follow-up and impact of high-risk prognostic factors from the phase 3 RESONATE study in patients with previously treated CLL/SLL

Author

Brown, J R, Hillmen, P, OʼBrien, S, Barrientos, J C, Reddy, N M, Coutre, S E, Tam, C S, Mulligan, S P, Jaeger, U, Barr, P M, Furman, R R, Kipps, T J, Cymbalista, F, Thornton, P, Caligaris-Cappio, F, Delgado, J, Montillo, M, DeVos, S, Moreno, C, Pagel, J M, Munir, T, Burger, J A, Chung, D, Lin, J, Gau, L, Chang, B, Cole, G, Hsu, E, James, D F, and Byrd, J C

Published
2018
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