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2. SLC6A1 variant pathogenicity, molecular function and phenotype: a genetic and clinical analysis.

Author

Stefanski, Arthur, Pérez-Palma, Eduardo, Brünger, Tobias, Montanucci, Ludovica, Gati, Cornelius, Klöckner, Chiara, Johannesen, Katrine, Goodspeed, Kimberly, Macnee, Marie, Deng, Alexander, Aledo-Serrano, Ángel, Borovikov, Artem, Kava, Maina, Bouman, Arjan, Hajianpour, M, Pal, Deb, Engelen, Marc, Hagebeuk, Eveline, Shinawi, Marwan, Heidlebaugh, Alexis, Oetjens, Kathryn, Hoffman, Trevor, Striano, Pasquale, Freed, Amanda, Futtrup, Line, Balslev, Thomas, Abulí, Anna, Danvoye, Leslie, Lederer, Damien, Balci, Tugce, Nouri, Maryam, Butler, Elizabeth, Drewes, Sarah, van Engelen, Kalene, Howell, Katherine, Khoury, Jean, May, Patrick, Trinidad, Marena, Froelich, Steven, Lemke, Johannes, Tiller, Jacob, Freed, Amber, Kang, Jing-Qiong, Wuster, Arthur, Møller, Rikke, and Lal, Dennis

Subjects
SLC6A1, autism, epilepsy, genetics, neurodevelopmental disorder, Humans, GABA Plasma Membrane Transport Proteins, Genetic Association Studies, Mutation, Missense, Phenotype
Abstract

Genetic variants in the SLC6A1 gene can cause a broad phenotypic disease spectrum by altering the protein function. Thus, systematically curated clinically relevant genotype-phenotype associations are needed to understand the disease mechanism and improve therapeutic decision-making. We aggregated genetic and clinical data from 172 individuals with likely pathogenic/pathogenic (lp/p) SLC6A1 variants and functional data for 184 variants (14.1% lp/p). Clinical and functional data were available for a subset of 126 individuals. We explored the potential associations of variant positions on the GAT1 3D structure with variant pathogenicity, altered molecular function and phenotype severity using bioinformatic approaches. The GAT1 transmembrane domains 1, 6 and extracellular loop 4 (EL4) were enriched for patient over population variants. Across functionally tested missense variants (n = 156), the spatial proximity from the ligand was associated with loss-of-function in the GAT1 transporter activity. For variants with complete loss of in vitro GABA uptake, we found a 4.6-fold enrichment in patients having severe disease versus non-severe disease (P = 2.9 × 10-3, 95% confidence interval: 1.5-15.3). In summary, we delineated associations between the 3D structure and variant pathogenicity, variant function and phenotype in SLC6A1-related disorders. This knowledge supports biology-informed variant interpretation and research on GAT1 function. All our data can be interactively explored in the SLC6A1 portal (https://slc6a1-portal.broadinstitute.org/).

Published
2023

3. Phase 1 dose-finding study of rebastinib (DCC-2036) in patients with relapsed chronic myeloid leukemia and acute myeloid leukemia

Author

Cortes, Jorge, Talpaz, Moshe, Smith, Hedy P, Snyder, David S, Khoury, Jean, Bhalla, Kapil N, Pinilla-Ibarz, Javier, Larson, Richard, Mitchell, David, Wise, Scott C, Rutkoski, Thomas J, Smith, Bryan D, Flynn, Daniel L, Kantarjian, Hagop M, Rosen, Oliver, and Van Etten, Richard A

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Oncology and Carcinogenesis, Cancer, Clinical Research, Hematology, Rare Diseases, 6.1 Pharmaceuticals, 6.2 Cellular and gene therapies, 5.1 Pharmaceuticals, Adult, Aged, Aged, 80 and over, Drug Monitoring, Drug Resistance, Neoplasm, Female, Fusion Proteins, bcr-abl, Humans, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Leukemia, Myeloid, Acute, Male, Maximum Tolerated Dose, Middle Aged, Mutation, Protein Kinase Inhibitors, Quinolines, Treatment Outcome, Young Adult, Immunology
Abstract

A vailable tyrosine kinase inhibitors for chronic myeloid leukemia bind in an adenosine 5'-triphosphate-binding pocket and are affected by evolving mutations that confer resistance. Rebastinib was identified as a switch control inhibitor of BCR-ABL1 and FLT3 and may be active against resistant mutations. A Phase 1, first-in-human, single-agent study investigated rebastinib in relapsed or refractory chronic or acute myeloid leukemia. The primary objectives were to investigate the safety of rebastinib and establish the maximum tolerated dose and recommended Phase 2 dose. Fifty-seven patients received treatment with rebastinib. Sixteen patients were treated using powder-in-capsule preparations at doses from 57 mg to 1200 mg daily, and 41 received tablet preparations at doses of 100 mg to 400 mg daily. Dose-limiting toxicities were dysarthria, muscle weakness, and peripheral neuropathy. The maximum tolerated dose was 150 mg tablets administered twice daily. Rebastinib was rapidly absorbed. Bioavailability was 3- to 4-fold greater with formulated tablets compared to unformulated capsules. Eight complete hematologic responses were achieved in 40 evaluable chronic myeloid leukemia patients, 4 of which had a T315I mutation. None of the 5 patients with acute myeloid leukemia responded. Pharmacodynamic analysis showed inhibition of phosphorylation of substrates of BCR-ABL1 or FLT3 by rebastinib. Although clinical activity was observed, clinical benefit was insufficient to justify continued development in chronic or acute myeloid leukemia. Pharmacodynamic analyses suggest that other kinases inhibited by rebastinib, such as TIE2, may be more relevant targets for the clinical development of rebastinib (clinicaltrials.gov Identifier:00827138).

Published
2017

4. Minimax vs. Monte Carlo : A Comparative Case Study on the Use of Minimax with Alpha-Beta Pruning versus Monte Carlo Tree Search as Decision-Making Algorithms in an Android Chess Application

Author

Wilkens, Isak, El Khoury, Jean, Wilkens, Isak, and El Khoury, Jean

Abstract

This thesis presents a comparative analysis of two prominent decision-making algorithms: Minimax with Alpha-Beta Pruning and Monte Carlo Tree Search (MCTS), applied within an Android-based chess application. The research stems from the challenge of improving Artificial Intelligence(AI) performance and game play, particularly in resource-constrained environments such as a mobile device. The study explores the area of balancing computational efficiency and strategic depth. Minimax with Alpha-Beta pruning is traditionally favored for its exhaustive search approach, which provides a methodical and tactical advantage in game play. However, its deterministic nature can limit game play diversity and adaptability. These are traits that MCTS could enhance due to its probabilistic and explorative approach. The study methodically compared these algorithms by implementing them within a deployed chess application (Chess Rumble) to then evaluate them based on several performance metrics including decision time, win and draw rates, and strategic diversity. The experiments conducted revealed that while Minimax performs efficiently under stringent computational limits, MCTS offers a more dynamic and engaging game play experience as it scales with increased computational resources. The findings indicate that both algorithms have unique strengths without a clear overall winner in all scenarios. This highlights a potential for their complementary application depending on specific needs. MCTS excels in creating a dynamic and unpredictable gaming experience, pointing to valuable future applications in AI-driven games and other interactive environments. This study provides valuable insights in comparing the two algorithms in performance and strategic diversity. It also offers insights into the practical applications of AI in game development, particularly for mobile platforms., Denna rapport presenterar en jämförande analys av två framstående algoritmer för beslutsfattande: Minimax med Alpha-Beta Pruning och Monte Carlo Tree Search (MCTS), som tillämpas i en Android-baserad schackapplikation. Forskningen utgår från utmaningen att förbättra prestanda och spelupplevelse för artificiell intelligens (AI), särskilt i resursbegränsade miljöer som en mobil enhet. Studien utforskar området för att balansera beräkningseffektivitet och strategiskt djup. Minimax med Alpha-Beta-beskärning föredras traditionellt för sin uttömmande sökmetod, som ger en metodisk och taktisk fördel i spelet. Dess deterministiska natur kan dock begränsa spelets mångfald och anpassningsförmåga. Detta är egenskaper som MCTS kan förbättra tack vare sitt probabilistiska och utforskande tillvägagångssätt. I studien jämfördes dessa algoritmer metodiskt genom att implementera dem i en schackapplikation (Chess Rumble) och sedan utvärdera dem utifrån flera prestandamått, bland annat beslutstid, vinst- och oavgjortfrekvens samt strategisk mångfald. De genomförda experimenten visade att Minimax presterar effektivt under stränga beräkningsgränser, medan MCTS erbjuder en mer dynamisk och engagerande spelupplevelse när den skalas med ökade beräkningsresurser. Resultaten visar att båda algoritmerna har unika styrkor utan att det finns någon tydlig vinnare i alla scenarier. Detta visar på en potential för kompletterande tillämpningar beroende på specifika behov. MCTS utmärker sig genom att skapa en dynamisk och oförutsägbar spelupplevelse, vilket pekar på värdefulla framtida tillämpningar i AI-drivna spel och andra interaktiva miljöer. Denna studie ger värdefulla insikter i jämförelsen mellan de två algoritmerna vad gäller prestanda och strategisk mångfald. Den ger också insikter i de praktiska tillämpningarna av AI inom spelutveckling, särskilt för mobila plattformar.

Published
2024

6. Stark effect upon the effective mass and radius in a tight-binding exciton model

Author

El-khoury, Jean and Gallinar, Jean-Pierre

Subjects
Condensed Matter
Abstract

With a Green's function formalism we obtain the eigenvalue spectrum of a tight-binding one-dimensional exciton model characterized by a contact interaction, a Coulombic electron and hole attraction, the Heller-Marcus exciton-hopping energy and an external constant and homogeneous electric field. The resulting eigenvalue spectrum, in the form of an unevenly spaced Wannier-Stark ladder with envelope profiles, is used to obtain the effective mass of the exciton by the application of the Mattis-Gallinar effective mass formula [D. C. Mattis and J.-P. Gallinar, {\it Phys. Rev. Lett.} {\bf{53}}, 1391 (1984)]. We obtain positive and negative effective masses for the exciton. The inverse effective mass may oscillate periodically as a function of the inverse of the electric field, with the frequency of oscillation linearly dependent upon the tight-binding hopping matrix element. The exciton radius is also obtained with the Green's function formalism, and it too exhibits Keldysh-like field dependent oscillations, as well as abrupt variations associated to strongly avoided crossings in the eigenvalue spectrum. Finally, some comments are made about the experimental relevance of our results., Comment: Latex 7 pages (RevTeX4), 9 eps figures

Published
2002

7. SLC6A1 variant pathogenicity, molecular function, and phenotype: a genetic and clinical analysis

Author

Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Fonds National de la Recherche - FnR [sponsor], Stefanski, Arthur, Pérez-Palma, Eduardo, Brünger, Tobias, Montanucci, Ludovica, Gati, Cornelius, Klöckner, Chiara, Johannesen, Katrine M., Goodspeed, Kimberly, Macnee, Marie, Deng, Alexander T., Aledo-Serrano, Ángel, Borovikov, Artem, Kava, Maina, Bouman, Arjan M., Hajianpour, M. J., Pal, Deb K., Engelen, Marc, Hagebeuk, Eveline E. O., Shinawi, Marwan, Heidlebaugh, Alexis R., Oetjens, Kathryn, Hoffman, Trevor L., Striano, Pasquale, Freed, Amanda S., Futtrup, Line, Balslev, Thomas, Abulí, Anna, Danvoye, Leslie, Lederer, Damien, Balci, Tugce, Nabavi Nouri, Maryam, Butler, Elizabeth, Drewes, Sarah, van Engelen, Kalene, Howell, Katherine B., Khoury, Jean, May, Patrick, Trinidad, Marena, Froelich, Steven, Lemke, Johannes R., Tiller, Jacob, Freed, Amber N., Kang, Jing-Qiong, Wuster, Arthur, Møller, Rikke S., Lal, Dennis, Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Fonds National de la Recherche - FnR [sponsor], Stefanski, Arthur, Pérez-Palma, Eduardo, Brünger, Tobias, Montanucci, Ludovica, Gati, Cornelius, Klöckner, Chiara, Johannesen, Katrine M., Goodspeed, Kimberly, Macnee, Marie, Deng, Alexander T., Aledo-Serrano, Ángel, Borovikov, Artem, Kava, Maina, Bouman, Arjan M., Hajianpour, M. J., Pal, Deb K., Engelen, Marc, Hagebeuk, Eveline E. O., Shinawi, Marwan, Heidlebaugh, Alexis R., Oetjens, Kathryn, Hoffman, Trevor L., Striano, Pasquale, Freed, Amanda S., Futtrup, Line, Balslev, Thomas, Abulí, Anna, Danvoye, Leslie, Lederer, Damien, Balci, Tugce, Nabavi Nouri, Maryam, Butler, Elizabeth, Drewes, Sarah, van Engelen, Kalene, Howell, Katherine B., Khoury, Jean, May, Patrick, Trinidad, Marena, Froelich, Steven, Lemke, Johannes R., Tiller, Jacob, Freed, Amber N., Kang, Jing-Qiong, Wuster, Arthur, Møller, Rikke S., and Lal, Dennis

Abstract

Genetic variants in the SLC6A1 gene can cause a broad phenotypic disease spectrum by altering the protein function. Thus, systematically curated clinically relevant genotype-phenotype associations are needed to understand the disease mechanism and improve therapeutic decision-making. We aggregated genetic and clinical data from 172 individuals with likely pathogenic/pathogenic (lp/p) SLC6A1 variants and functional data for 184 variants (14.1% lp/p). Clinical and functional data were available for a subset of 126 individuals. We explored the potential associations of variant positions on the GAT1 3D structure with variant pathogenicity, altered molecular function, and phenotype severity using bioinformatic approaches. The GAT1 transmembrane domains 1, 6, and extracellular loop 4 (EL4) were enriched for patient over population variants. Across functionally tested missense variants (n = 156), the spatial proximity from the ligand was associated with loss-of-function in the GAT1 transporter activity. For variants with complete loss of in vitro GABA uptake, we found a 4.6-fold enrichment in patients having severe disease vs. non-severe disease (P = 2.9e-3, 95% CI: 1.5 - 15.3). In summary, we delineated associations between the 3D structure and variant pathogenicity, variant function, and phenotype in SLC6A1-related disorders. This knowledge supports biology-informed variant interpretation and research on GAT1 function. All our data can be interactively explored in the SLC6A1 Portal (https://slc6a1-portal.broadinstitute.org/).

Published
2023

8. SLC6A1 variant pathogenicity, molecular function and phenotype:a genetic and clinical analysis

Author

Stefanski, Arthur, Pérez-Palma, Eduardo, Brünger, Tobias, Montanucci, Ludovica, Gati, Cornelius, Klöckner, Chiara, Johannesen, Katrine M., Goodspeed, Kimberly, Macnee, Marie, Deng, Alexander T., Aledo-Serrano, Ángel, Borovikov, Artem, Kava, Maina, Bouman, Arjan M., Hajianpour, M. J., Pal, Deb K., Engelen, Marc, Hagebeuk, Eveline E.O., Shinawi, Marwan, Heidlebaugh, Alexis R., Oetjens, Kathryn, Hoffman, Trevor L., Striano, Pasquale, Freed, Amanda S., Futtrup, Line, Balslev, Thomas, Abulí, Anna, Danvoye, Leslie, Lederer, Damien, Balci, Tugce, Nouri, Maryam Nabavi, Butler, Elizabeth, Drewes, Sarah, van Engelen, Kalene, Howell, Katherine B., Khoury, Jean, May, Patrick, Trinidad, Marena, Froelich, Steven, Lemke, Johannes R., Tiller, Jacob, Freed, Amber N., Kang, Jing Qiong, Wuster, Arthur, Møller, Rikke S., Lal, Dennis, Stefanski, Arthur, Pérez-Palma, Eduardo, Brünger, Tobias, Montanucci, Ludovica, Gati, Cornelius, Klöckner, Chiara, Johannesen, Katrine M., Goodspeed, Kimberly, Macnee, Marie, Deng, Alexander T., Aledo-Serrano, Ángel, Borovikov, Artem, Kava, Maina, Bouman, Arjan M., Hajianpour, M. J., Pal, Deb K., Engelen, Marc, Hagebeuk, Eveline E.O., Shinawi, Marwan, Heidlebaugh, Alexis R., Oetjens, Kathryn, Hoffman, Trevor L., Striano, Pasquale, Freed, Amanda S., Futtrup, Line, Balslev, Thomas, Abulí, Anna, Danvoye, Leslie, Lederer, Damien, Balci, Tugce, Nouri, Maryam Nabavi, Butler, Elizabeth, Drewes, Sarah, van Engelen, Kalene, Howell, Katherine B., Khoury, Jean, May, Patrick, Trinidad, Marena, Froelich, Steven, Lemke, Johannes R., Tiller, Jacob, Freed, Amber N., Kang, Jing Qiong, Wuster, Arthur, Møller, Rikke S., and Lal, Dennis

Abstract

Genetic variants in the SLC6A1 gene can cause a broad phenotypic disease spectrum by altering the protein function. Thus, systematically curated clinically relevant genotype-phenotype associations are needed to understand the disease mechanism and improve therapeutic decision-making. We aggregated genetic and clinical data from 172 individuals with likely pathogenic/pathogenic (lp/p) SLC6A1 variants and functional data for 184 variants (14.1% lp/p). Clinical and functional data were available for a subset of 126 individuals. We explored the potential associations of variant positions on the GAT1 3D structure with variant pathogenicity, altered molecular function and phenotype severity using bioinformatic approaches. The GAT1 transmembrane domains 1, 6 and extracellular loop 4 (EL4) were enriched for patient over population variants. Across functionally tested missense variants (n = 156), the spatial proximity from the ligand was associated with loss-of-function in the GAT1 transporter activity. For variants with complete loss of in vitro GABA uptake, we found a 4.6-fold enrichment in patients having severe disease versus non-severe disease (P = 2.9 × 10-3, 95% confidence interval: 1.5-15.3). In summary, we delineated associations between the 3D structure and variant pathogenicity, variant function and phenotype in SLC6A1-related disorders. This knowledge supports biology-informed variant interpretation and research on GAT1 function. All our data can be interactively explored in the SLC6A1 portal (https://slc6a1-portal.broadinstitute.org/).

Published
2023

9. Predictive models for starting antiseizure medication withdrawal following epilepsy surgery in adults

Author

Projectafdeling KIND, Neurologen, Brain, Ferreira-Atuesta, Carolina, de Tisi, Jane, McEvoy, Andrew W, Miserocchi, Anna, Khoury, Jean, Yardi, Ruta, Vegh, Deborah T, Butler, James, Lee, Hamin J, Deli-Peri, Victoria, Yao, Yi, Wang, Feng-Peng, Zhang, Xiao-Bin, Shakhatreh, Lubna, Siriratnam, Pakeeran, Neal, Andrew, Sen, Arjune, Tristram, Maggie, Varghese, Elizabeth, Biney, Wendy, Gray, William P, Peralta, Ana Rita, Rainha-Campos, Alexandre, Gonçalves-Ferreira, António J C, Pimentel, José, Arias, Juan Fernando, Terman, Samuel, Terziev, Robert, Lamberink, Herm J, Braun, Kees P J, Otte, Willem M, Rugg-Gunn, Fergus J, Gonzalez, Walter, Bentes, Carla, Hamandi, Khalid, O'Brien, Terence J, Perucca, Piero, Yao, Chen, Burman, Richard J, Jehi, Lara, Duncan, John S, Sander, Josemir W, Koepp, Matthias, Galovic, Marian, Projectafdeling KIND, Neurologen, Brain, Ferreira-Atuesta, Carolina, de Tisi, Jane, McEvoy, Andrew W, Miserocchi, Anna, Khoury, Jean, Yardi, Ruta, Vegh, Deborah T, Butler, James, Lee, Hamin J, Deli-Peri, Victoria, Yao, Yi, Wang, Feng-Peng, Zhang, Xiao-Bin, Shakhatreh, Lubna, Siriratnam, Pakeeran, Neal, Andrew, Sen, Arjune, Tristram, Maggie, Varghese, Elizabeth, Biney, Wendy, Gray, William P, Peralta, Ana Rita, Rainha-Campos, Alexandre, Gonçalves-Ferreira, António J C, Pimentel, José, Arias, Juan Fernando, Terman, Samuel, Terziev, Robert, Lamberink, Herm J, Braun, Kees P J, Otte, Willem M, Rugg-Gunn, Fergus J, Gonzalez, Walter, Bentes, Carla, Hamandi, Khalid, O'Brien, Terence J, Perucca, Piero, Yao, Chen, Burman, Richard J, Jehi, Lara, Duncan, John S, Sander, Josemir W, Koepp, Matthias, and Galovic, Marian

Published
2023

10. Predictive models for starting antiseizure medication withdrawal following epilepsy surgery in adults

Author

Ferreira-Atuesta, Carolina, primary, de Tisi, Jane, additional, McEvoy, Andrew W, additional, Miserocchi, Anna, additional, Khoury, Jean, additional, Yardi, Ruta, additional, Vegh, Deborah T, additional, Butler, James, additional, Lee, Hamin J, additional, Deli-Peri, Victoria, additional, Yao, Yi, additional, Wang, Feng-Peng, additional, Zhang, Xiao-Bin, additional, Shakhatreh, Lubna, additional, Siriratnam, Pakeeran, additional, Neal, Andrew, additional, Sen, Arjune, additional, Tristram, Maggie, additional, Varghese, Elizabeth, additional, Biney, Wendy, additional, Gray, William P, additional, Peralta, Ana Rita, additional, Rainha-Campos, Alexandre, additional, Gonçalves-Ferreira, António J C, additional, Pimentel, José, additional, Arias, Juan Fernando, additional, Terman, Samuel, additional, Terziev, Robert, additional, Lamberink, Herm J, additional, Braun, Kees P J, additional, Otte, Willem M, additional, Rugg-Gunn, Fergus J, additional, Gonzalez, Walter, additional, Bentes, Carla, additional, Hamandi, Khalid, additional, O'Brien, Terence J, additional, Perucca, Piero, additional, Yao, Chen, additional, Burman, Richard J, additional, Jehi, Lara, additional, Duncan, John S, additional, Sander, Josemir W, additional, Koepp, Matthias, additional, and Galovic, Marian, additional

Published
2022
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11. The genomic landscape across 474 surgically accessible epileptogenic human brain lesions

Author

López-Rivera, Javier A, primary, Leu, Costin, additional, Macnee, Marie, additional, Khoury, Jean, additional, Hoffmann, Lucas, additional, Coras, Roland, additional, Kobow, Katja, additional, Bhattarai, Nisha, additional, Pérez-Palma, Eduardo, additional, Hamer, Hajo, additional, Brandner, Sebastian, additional, Rössler, Karl, additional, Bien, Christian G, additional, Kalbhenn, Thilo, additional, Pieper, Tom, additional, Hartlieb, Till, additional, Butler, Elizabeth, additional, Genovese, Giulio, additional, Becker, Kerstin, additional, Altmüller, Janine, additional, Niestroj, Lisa-Marie, additional, Ferguson, Lisa, additional, Busch, Robyn M, additional, Nürnberg, Peter, additional, Najm, Imad, additional, Blümcke, Ingmar, additional, and Lal, Dennis, additional

Published
2022
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12. Predictive models for starting antiseizure medication withdrawal following epilepsy surgery in adults.

Author

Ferreira-Atuesta, Carolina, Tisi, Jane de, McEvoy, Andrew W, Miserocchi, Anna, Khoury, Jean, Yardi, Ruta, Vegh, Deborah T, Butler, James, Lee, Hamin J, Deli-Peri, Victoria, Yao, Yi, Wang, Feng-Peng, Zhang, Xiao-Bin, Shakhatreh, Lubna, Siriratnam, Pakeeran, Neal, Andrew, Sen, Arjune, Tristram, Maggie, Varghese, Elizabeth, and Biney, Wendy

Subjects
EPILEPSY surgery, TEMPORAL lobectomy, PREDICTION models, DRUGS, SEIZURES (Medicine), ADULTS
Abstract

More than half of adults with epilepsy undergoing resective epilepsy surgery achieve long-term seizure freedom and might consider withdrawing antiseizure medications (ASMs). We aimed to identify predictors of seizure recurrence after starting postoperative ASM withdrawal and develop and validate predictive models. We performed an international multicentre observational cohort study in nine tertiary epilepsy referral centres. We included 850 adults who started ASM withdrawal following resective epilepsy surgery and were free of seizures other than focal non-motor aware seizures before starting ASM withdrawal. We developed a model predicting recurrent seizures, other than focal non-motor aware seizures, using Cox proportional hazards regression in a derivation cohort (n = 231). Independent predictors of seizure recurrence, other than focal non-motor aware seizures, following the start of ASM withdrawal were focal non motor-aware seizures after surgery and before withdrawal (adjusted hazards ratio [aHR] 5.5, 95% confidence interval [CI] 2.7-11.1), history of focal to bilateral tonic-clonic seizures before surgery (aHR 1.6, 95% CI 0.9-2.8), time from surgery to the start of ASM withdrawal (aHR 0.9, 95% CI 0.8-0.9), and number of ASMs at time of surgery (aHR 1.2, 95% CI 0.9-1.6). Model discrimination showed a concordance statistic of 0.67 (95% CI 0.63-0.71) in the external validation cohorts (n = 500). A secondary model predicting recurrence of any seizures (including focal non-motor aware seizures) was developed and validated in a subgroup that did not have focal non-motor aware seizures before withdrawal (n = 639), showing a concordance statistic of 0.68 (95% CI 0.64-0.72). Calibration plots indicated high agreement of predicted and observed outcomes for both models. We show that simple algorithms, available as graphical nomograms and online tools (predictepilepsy.github.io), can provide probabilities of seizure outcomes after starting postoperative ASMs withdrawal. These multicentre-validated models may assist clinicians when discussing ASM withdrawal after surgery with their patients. [ABSTRACT FROM AUTHOR]

Published
2023
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13. genomic landscape across 474 surgically accessible epileptogenic human brain lesions.

Author

López-Rivera, Javier A, Leu, Costin, Macnee, Marie, Khoury, Jean, Hoffmann, Lucas, Coras, Roland, Kobow, Katja, Bhattarai, Nisha, Pérez-Palma, Eduardo, Hamer, Hajo, Brandner, Sebastian, Rössler, Karl, Bien, Christian G, Kalbhenn, Thilo, Pieper, Tom, Hartlieb, Till, Butler, Elizabeth, Genovese, Giulio, Becker, Kerstin, and Altmüller, Janine

Subjects
EPILEPSY, FOCAL cortical dysplasia, BRAIN damage, HIPPOCAMPAL sclerosis, CHROMOSOME duplication, PARTIAL epilepsy
Abstract

Understanding the exact molecular mechanisms involved in the aetiology of epileptogenic pathologies with or without tumour activity is essential for improving treatment of drug-resistant focal epilepsy. Here, we characterize the landscape of somatic genetic variants in resected brain specimens from 474 individuals with drug-resistant focal epilepsy using deep whole-exome sequencing (>350×) and whole-genome genotyping. Across the exome, we observe a greater number of somatic single-nucleotide variants in low-grade epilepsy-associated tumours (7.92 ± 5.65 single-nucleotide variants) than in brain tissue from malformations of cortical development (6.11 ± 4 single-nucleotide variants) or hippocampal sclerosis (5.1 ± 3.04 single-nucleotide variants). Tumour tissues also had the largest number of likely pathogenic variant carrying cells. low-grade epilepsy-associated tumours had the highest proportion of samples with one or more somatic copy-number variants (24.7%), followed by malformations of cortical development (5.4%) and hippocampal sclerosis (4.1%). Recurring somatic whole chromosome duplications affecting Chromosome 7 (16.8%), chromosome 5 (10.9%), and chromosome 20 (9.9%) were observed among low-grade epilepsy-associated tumours. For germline variant-associated malformations of cortical development genes such as TSC2 , DEPDC5 and PTEN , germline single-nucleotide variants were frequently identified within large loss of heterozygosity regions, supporting the recently proposed 'second hit' disease mechanism in these genes. We detect somatic variants in 12 established lesional epilepsy genes and demonstrate exome-wide statistical support for three of these in the aetiology of low-grade epilepsy-associated tumours (e.g. BRAF) and malformations of cortical development (e.g. SLC35A2 and MTOR). We also identify novel significant associations for PTPN11 with low-grade epilepsy-associated tumours and NRAS Q61 mutated protein with a complex malformation of cortical development characterized by polymicrogyria and nodular heterotopia. The variants identified in NRAS are known from cancer studies to lead to hyperactivation of NRAS, which can be targeted pharmacologically. We identify large recurrent 1q21–q44 duplication including AKT3 in association with focal cortical dysplasia type 2a with hyaline astrocytic inclusions, another rare and possibly under-recognized brain lesion. The clinical-genetic analyses showed that the numbers of somatic single-nucleotide variant across the exome and the fraction of affected cells were positively correlated with the age at seizure onset and surgery in individuals with low-grade epilepsy-associated tumours. In summary, our comprehensive genetic screen sheds light on the genome-scale landscape of genetic variants in epileptic brain lesions, informs the design of gene panels for clinical diagnostic screening and guides future directions for clinical implementation of epilepsy surgery genetics. [ABSTRACT FROM AUTHOR]

Published
2023
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14. The genomic landscape across 474 surgically accessible epileptogenic human brain lesions

Author

López-Rivera, Javier A., primary, Leu, Costin, additional, Macnee, Marie, additional, Khoury, Jean, additional, Hoffmann, Lucas, additional, Coras, Roland, additional, Kobow, Katja, additional, Bhattarai, Nisha, additional, Pérez-Palma, Eduardo, additional, Hamer, Hajo, additional, Brandner, Sebastian, additional, Rössler, Karl, additional, Bien, Christian G., additional, Kalbhenn, Thilo, additional, Pieper, Tom, additional, Hartlieb, Till, additional, Butler, Elizabeth, additional, Genovese, Giulio, additional, Becker, Kerstin, additional, Altmüller, Janine, additional, Niestroj, Lisa-Marie, additional, Ferguson, Lisa, additional, Busch, Robyn M., additional, Nürnberg, Peter, additional, Najm, Imad, additional, Blümcke, Ingmar, additional, and Lal, Dennis, additional

Published
2022
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15. Sub-genic intolerance, ClinVar, and the epilepsies: A whole-exome sequencing study of 29,165 individuals

Author

Motelow, Joshua E., primary, Povysil, Gundula, additional, Dhindsa, Ryan S., additional, Stanley, Kate E., additional, Allen, Andrew S., additional, Feng, Yen-Chen Anne, additional, Howrigan, Daniel P., additional, Abbott, Liam E., additional, Tashman, Katherine, additional, Cerrato, Felecia, additional, Cusick, Caroline, additional, Singh, Tarjinder, additional, Heyne, Henrike, additional, Byrnes, Andrea E., additional, Churchhouse, Claire, additional, Watts, Nick, additional, Solomonson, Matthew, additional, Lal, Dennis, additional, Gupta, Namrata, additional, Neale, Benjamin M., additional, Cavalleri, Gianpiero L., additional, Cossette, Patrick, additional, Cotsapas, Chris, additional, De Jonghe, Peter, additional, Dixon-Salazar, Tracy, additional, Guerrini, Renzo, additional, Hakonarson, Hakon, additional, Heinzen, Erin L., additional, Helbig, Ingo, additional, Kwan, Patrick, additional, Marson, Anthony G., additional, Petrovski, Slavé, additional, Kamalakaran, Sitharthan, additional, Sisodiya, Sanjay M., additional, Stewart, Randy, additional, Weckhuysen, Sarah, additional, Depondt, Chantal, additional, Dlugos, Dennis J., additional, Scheffer, Ingrid E., additional, Striano, Pasquale, additional, Freyer, Catharine, additional, Krause, Roland, additional, May, Patrick, additional, McKenna, Kevin, additional, Regan, Brigid M., additional, Bennett, Caitlin A., additional, Leu, Costin, additional, Leech, Stephanie L., additional, O’Brien, Terence J., additional, Todaro, Marian, additional, Stamberger, Hannah, additional, Andrade, Danielle M., additional, Ali, Quratulain Zulfiqar, additional, Sadoway, Tara R., additional, Krestel, Heinz, additional, Schaller, André, additional, Papacostas, Savvas S., additional, Kousiappa, Ioanna, additional, Tanteles, George A., additional, Christou, Yiolanda, additional, Štěrbová, Katalin, additional, Vlčková, Markéta, additional, Sedláčková, Lucie, additional, Laššuthová, Petra, additional, Klein, Karl Martin, additional, Rosenow, Felix, additional, Reif, Philipp S., additional, Knake, Susanne, additional, Neubauer, Bernd A., additional, Zimprich, Friedrich, additional, Feucht, Martha, additional, Reinthaler, Eva M., additional, Kunz, Wolfram S., additional, Zsurka, Gábor, additional, Surges, Rainer, additional, Baumgartner, Tobias, additional, von Wrede, Randi, additional, Pendziwiat, Manuela, additional, Muhle, Hiltrud, additional, Rademacher, Annika, additional, van Baalen, Andreas, additional, von Spiczak, Sarah, additional, Stephani, Ulrich, additional, Afawi, Zaid, additional, Korczyn, Amos D., additional, Kanaan, Moien, additional, Canavati, Christina, additional, Kurlemann, Gerhard, additional, Müller-Schlüter, Karen, additional, Kluger, Gerhard, additional, Häusler, Martin, additional, Blatt, Ilan, additional, Lemke, Johannes R., additional, Krey, Ilona, additional, Weber, Yvonne G., additional, Wolking, Stefan, additional, Becker, Felicitas, additional, Lauxmann, Stephan, additional, Boßelmann, Christian, additional, Kegele, Josua, additional, Hengsbach, Christian, additional, Rau, Sarah, additional, Steinhoff, Bernhard J., additional, Schulze-Bonhage, Andreas, additional, Borggräfe, Ingo, additional, Schankin, Christoph J., additional, Schubert-Bast, Susanne, additional, Schreiber, Herbert, additional, Mayer, Thomas, additional, Korinthenberg, Rudolf, additional, Brockmann, Knut, additional, Wolff, Markus, additional, Dennig, Dieter, additional, Madeleyn, Rene, additional, Kälviäinen, Reetta, additional, Saarela, Anni, additional, Timonen, Oskari, additional, Linnankivi, Tarja, additional, Lehesjoki, Anna-Elina, additional, Rheims, Sylvain, additional, Lesca, Gaetan, additional, Ryvlin, Philippe, additional, Maillard, Louis, additional, Valton, Luc, additional, Derambure, Philippe, additional, Bartolomei, Fabrice, additional, Hirsch, Edouard, additional, Michel, Véronique, additional, Chassoux, Francine, additional, Rees, Mark I., additional, Chung, Seo-Kyung, additional, Pickrell, William O., additional, Powell, Robert, additional, Baker, Mark D., additional, Fonferko-Shadrach, Beata, additional, Lawthom, Charlotte, additional, Anderson, Joseph, additional, Schneider, Natascha, additional, Balestrini, Simona, additional, Zagaglia, Sara, additional, Braatz, Vera, additional, Johnson, Michael R., additional, Auce, Pauls, additional, Sills, Graeme J., additional, Baum, Larry W., additional, Sham, Pak C., additional, Cherny, Stacey S., additional, Lui, Colin H.T., additional, Delanty, Norman, additional, Doherty, Colin P., additional, Shukralla, Arif, additional, El-Naggar, Hany, additional, Widdess-Walsh, Peter, additional, Barišić, Nina, additional, Canafoglia, Laura, additional, Franceschetti, Silvana, additional, Castellotti, Barbara, additional, Granata, Tiziana, additional, Ragona, Francesca, additional, Zara, Federico, additional, Iacomino, Michele, additional, Riva, Antonella, additional, Madia, Francesca, additional, Vari, Maria Stella, additional, Salpietro, Vincenzo, additional, Scala, Marcello, additional, Mancardi, Maria Margherita, additional, Nobili, Lino, additional, Amadori, Elisabetta, additional, Giacomini, Thea, additional, Bisulli, Francesca, additional, Pippucci, Tommaso, additional, Licchetta, Laura, additional, Minardi, Raffaella, additional, Tinuper, Paolo, additional, Muccioli, Lorenzo, additional, Mostacci, Barbara, additional, Gambardella, Antonio, additional, Labate, Angelo, additional, Annesi, Grazia, additional, Manna, Lorella, additional, Gagliardi, Monica, additional, Parrini, Elena, additional, Mei, Davide, additional, Vetro, Annalisa, additional, Bianchini, Claudia, additional, Montomoli, Martino, additional, Doccini, Viola, additional, Barba, Carmen, additional, Hirose, Shinichi, additional, Ishii, Atsushi, additional, Suzuki, Toshimitsu, additional, Inoue, Yushi, additional, Yamakawa, Kazuhiro, additional, Beydoun, Ahmad, additional, Nasreddine, Wassim, additional, Khoueiry Zgheib, Nathalie, additional, Tumiene, Birute, additional, Utkus, Algirdas, additional, Sadleir, Lynette G., additional, King, Chontelle, additional, Caglayan, S. Hande, additional, Arslan, Mutluay, additional, Yapıcı, Zuhal, additional, Topaloglu, Pınar, additional, Kara, Bulent, additional, Yis, Uluc, additional, Turkdogan, Dilsad, additional, Gundogdu-Eken, Aslı, additional, Bebek, Nerses, additional, Uğur-İşeri, Sibel, additional, Baykan, Betül, additional, Salman, Barış, additional, Haryanyan, Garen, additional, Yücesan, Emrah, additional, Kesim, Yeşim, additional, Özkara, Çiğdem, additional, Tsai, Meng-Han, additional, Ho, Chen-Jui, additional, Lin, Chih-Hsiang, additional, Lin, Kuang-Lin, additional, Chou, I-Jun, additional, Poduri, Annapurna, additional, Shiedley, Beth R., additional, Shain, Catherine, additional, Noebels, Jeffrey L., additional, Goldman, Alicia, additional, Busch, Robyn M., additional, Jehi, Lara, additional, Najm, Imad M., additional, Ferguson, Lisa, additional, Khoury, Jean, additional, Glauser, Tracy A., additional, Clark, Peggy O., additional, Buono, Russell J., additional, Ferraro, Thomas N., additional, Sperling, Michael R., additional, Lo, Warren, additional, Privitera, Michael, additional, French, Jacqueline A., additional, Schachter, Steven, additional, Kuzniecky, Ruben I., additional, Devinsky, Orrin, additional, Hegde, Manu, additional, Greenberg, David A., additional, Ellis, Colin A., additional, Goldberg, Ethan, additional, Helbig, Katherine L., additional, Cosico, Mahgenn, additional, Vaidiswaran, Priya, additional, Fitch, Eryn, additional, Berkovic, Samuel F., additional, Lerche, Holger, additional, Lowenstein, Daniel H., additional, and Goldstein, David B., additional

Published
2021
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16. A phase II study of bortezomib added to rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone in patients with previously untreated indolent non-Hodgkinʼs lymphoma

Author

Cohen, Jonathon B., Switchenko, Jeffrey M., Koff, Jean L., Sinha, Rajni, Kaufman, Jonathan L., Khoury, Jean H., Bumpers, Nassoma, Colbert, Amanda, Hutchison-Rzepka, Amanda, Nastoupil, Loretta J., Heffner, Leonard T., Langston, Amelia A., Lechowicz, Mary Jo, Lonial, Sagar, and Flowers, Christopher R.

Published
2015
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17. Final analysis of the efficacy and safety of omacetaxine mepesuccinate in patients with chronic- or accelerated-phase chronic myeloid leukemia: Results with 24 months of follow-up

Author

Cortes, Jorge E., Kantarjian, Hagop M., Rea, Delphine, Wetzler, Meir, Lipton, Jeffrey H., Akard, Luke, Khoury, Jean H., Michallet, Mauricette, Guerci-Bresler, Agnès, Chuah, Charles, Hellmann, Andrzej, Digumarti, Raghunadharao, Parikh, Purvish M., Legros, Laurence, Warzocha, Krzysztof, Baccarani, Michele, Li, Elizabeth, Munteanu, Mihaela, and Nicolini, Franck E.

Published
2015
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18. Novel de novo TREX1 mutation in a patient with retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations mimicking demyelinating disease

Author

Macaron, Gabrielle, primary, Khoury, Jean, additional, Hajj-Ali, Rula A., additional, Prayson, Richard A., additional, Srivastava, Sunil, additional, Ehlers, Justis P., additional, Mamsa, Hafsa, additional, Liszewski, M. Kathryn, additional, Jen, Joanna C., additional, Bermel, Robert A., additional, and Ontaneda, Daniel, additional

Published
2021
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19. sj-pdf-1-msj-10.1177_1352458520981736.pdf – Supplemental material for Early age of onset predicts severity of visual impairment in patients with neuromyelitis optica spectrum disorder

Author

Macaron, Gabrielle, Khoury, Jean, Bena, James, Seay, Meagan, Bermel, Robert A, Cohen, Jeffrey A, and Rensel, Mary R

Subjects
FOS: Clinical medicine, 111702 Aged Health Care, FOS: Health sciences, 110904 Neurology and Neuromuscular Diseases
Abstract

Supplemental material, sj-pdf-1-msj-10.1177_1352458520981736.pdf for Early age of onset predicts severity of visual impairment in patients with neuromyelitis optica spectrum disorder by Gabrielle Macaron, Jean Khoury, James Bena, Meagan Seay, Robert A Bermel, Jeffrey A Cohen and Mary R Rensel in Multiple Sclerosis Journal

Published
2021
Full Text
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20. Sub-genic intolerance, ClinVar, and the epilepsies: A whole-exome sequencing study of 29,165 individuals

Author

Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Motelow, Joshua E., Povysil, Gundula, Dhindsa, Ryan S., Stanley, Kate E., Allen, Andrew S., Feng, Yen-Chen Anne, Howrigan, Daniel P., Abbott, Liam E., Tashman, Katherine, Cerrato, Felecia, Cusick, Caroline, Singh, Tarjinder, Heyne, Henrike, Byrnes, Andrea E., Churchhouse, Claire, Watts, Nick, Solomonson, Matthew, Lal, Dennis, Gupta, Namrata, Neale, Benjamin M., Cavalleri, Gianpiero L., Cossette, Patrick, Cotsapas, Chris, Jonghe, Peter De, Dixon-Salazar, Tracy, Guerrini, Renzo, Hakonarson, Hakon, Heinzen, Erin L., Helbig, Ingo, Kwan, Patrick, Marson, Anthony G., Petrovski, Slavé, Kamalakaran, Sitharthan, Sisodiya, Sanjay M., Stewart, Randy, Weckhuysen, Sarah, Depondt, Chantal, Dlugos, Dennis J., Scheffer, Ingrid E., Striano, Pasquale, Freyer, Catharine, Krause, Roland, May, Patrick, McKenna, Kevin, Regan, Brigid M., Bennett, Caitlin A., Leu, Costin, Leech, Stephanie L., O’Brien, Terence J., Todaro, Marian, Stamberger, Hannah, Andrade, Danielle M., Ali, Quratulain Zulfiqar, Sadoway, Tara R., Krestel, Heinz, Schaller, André, Papacostas, Savvas S., Kousiappa, Ioanna, Tanteles, George A., Christou, Yiolanda, Štěrbová, Katalin, Vlčková, Markéta, Sedláčková, Lucie, Laššuthová, Petra, Klein, Karl Martin, Rosenow, Felix, Reif, Philipp S., Knake, Susanne, Neubauer, Bernd A., Zimprich, Friedrich, Feucht, Martha, Reinthaler, Eva M., Kunz, Wolfram S., Zsurka, Gábor, Surges, Rainer, Baumgartner, Tobias, Wrede, Randi Von, Pendziwiat, Manuela, Muhle, Hiltrud, Rademacher, Annika, Baalen, Andreas Van, Spiczak, Sarah Von, Stephani, Ulrich, Afawi, Zaid, Korczyn, Amos D., Kanaan, Moien, Canavati, Christina, Kurlemann, Gerhard, Müller-Schlüter, Karen, Kluger, Gerhard, Häusler, Martin, Blatt, Ilan, Lemke, Johannes R., Krey, Ilona, Weber, Yvonne G., Wolking, Stefan, Becker, Felicitas, Lauxmann, Stephan, Boßelmann, Christian, Kegele, Josua, Hengsbach, Christian, Rau, Sarah, Steinhoff, Bernhard J., Schulze-Bonhage, Andreas, Borggräfe, Ingo, Schankin, Christoph J., Schubert-Bast, Susanne, Schreiber, Herbert, Mayer, Thomas, Korinthenberg, Rudolf, Brockmann, Knut, Wolff, Markus, Dennig, Dieter, Madeleyn, Rene, Kälviäinen, Reetta, Saarela, Anni, Timonen, Oskari, Linnankivi, Tarja, Lehesjoki, Anna-Elina, Rheims, Sylvain, Lesca, Gaetan, Ryvlin, Philippe, Maillard, Louis, Valton, Luc, Derambure, Philippe, Bartolomei, Fabrice, Hirsch, Edouard, Michel, Véronique, Chassoux, Francine, Rees, Mark I., Chung, Seo-Kyung, Pickrell, William O., Powell, Robert, Baker, Mark D., Fonferko-Shadrach, Beata, Lawthom, Charlotte, Anderson, Joseph, Schneider, Natascha, Balestrini, Simona, Zagaglia, Sara, Braatz, Vera, Johnson, Michael R., Auce, Pauls, Sills, Graeme J., Baum, Larry W., Sham, Pak C., Cherny, Stacey S., Lui, Colin H. T., Delanty, Norman, Doherty, Colin P., Shukralla, Arif, El-Naggar, Hany, Widdess-Walsh, Peter, Barišić, Nina, Canafoglia, Laura, Franceschetti, Silvana, Castellotti, Barbara, Granata, Tiziana, Ragona, Francesca, Zara, Federico, Iacomino, Michele, Riva, Antonella, Madia, Francesca, Vari, Maria Stella, Salpietro, Vincenzo, Scala, Marcello, Mancardi, Maria Margherita, Nobili, Lino, Amadori, Elisabetta, Giacomini, Thea, Bisulli, Francesca, Pippucci, Tommaso, Licchetta, Laura, Minardi, Raffaella, Tinuper, Paolo, Muccioli, Lorenzo, Mostacci, Barbara, Gambardella, Antonio, Labate, Angelo, Annesi, Grazia, Manna, Lorella, Gagliardi, Monica, Parrini, Elena, Mei, Davide, Vetro, Annalisa, Bianchini, Claudia, Montomoli, Martino, Doccini, Viola, Barba, Carmen, Hirose, Shinichi, Ishii, Atsushi, Suzuki, Toshimitsu, Inoue, Yushi, Yamakawa, Kazuhiro, Beydoun, Ahmad, Nasreddine, Wassim, Zgheib, Nathalie Khoueiry, Tumiene, Birute, Utkus, Algirdas, Sadleir, Lynette G., King, Chontelle, Caglayan, S. Hande, Arslan, Mutluay, Yapıcı, Zuhal, Topaloglu, Pınar, Kara, Bulent, Yis, Uluc, Turkdogan, Dilsad, Gundogdu-Eken, Aslı, Bebek, Nerses, Tsai, Meng-Han, Ho, Chen-Jui, Lin, Chih-Hsiang, Lin, Kuang-Lin, Chou, I.-Jun, Poduri, Annapurna, Shiedley, Beth R., Shain, Catherine, Noebels, Jeffrey L., Goldman, Alicia, Busch, Robyn M., Jehi, Lara, Najm, Imad M., Ferguson, Lisa, Khoury, Jean, Glauser, Tracy A., Clark, Peggy O., Buono, Russell J., Ferraro, Thomas N., Sperling, Michael R., Lo, Warren, Privitera, Michael, French, Jacqueline A., Schachter, Steven, Kuzniecky, Ruben I., Devinsky, Orrin, Hegde, Manu, Greenberg, David A., Ellis, Colin A., Goldberg, Ethan, Helbig, Katherine L., Cosico, Mahgenn, Vaidiswaran, Priya, Fitch, Eryn, Berkovic, Samuel F., Lerche, Holger, Lowenstein, Daniel H., Goldstein, David B., Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Motelow, Joshua E., Povysil, Gundula, Dhindsa, Ryan S., Stanley, Kate E., Allen, Andrew S., Feng, Yen-Chen Anne, Howrigan, Daniel P., Abbott, Liam E., Tashman, Katherine, Cerrato, Felecia, Cusick, Caroline, Singh, Tarjinder, Heyne, Henrike, Byrnes, Andrea E., Churchhouse, Claire, Watts, Nick, Solomonson, Matthew, Lal, Dennis, Gupta, Namrata, Neale, Benjamin M., Cavalleri, Gianpiero L., Cossette, Patrick, Cotsapas, Chris, Jonghe, Peter De, Dixon-Salazar, Tracy, Guerrini, Renzo, Hakonarson, Hakon, Heinzen, Erin L., Helbig, Ingo, Kwan, Patrick, Marson, Anthony G., Petrovski, Slavé, Kamalakaran, Sitharthan, Sisodiya, Sanjay M., Stewart, Randy, Weckhuysen, Sarah, Depondt, Chantal, Dlugos, Dennis J., Scheffer, Ingrid E., Striano, Pasquale, Freyer, Catharine, Krause, Roland, May, Patrick, McKenna, Kevin, Regan, Brigid M., Bennett, Caitlin A., Leu, Costin, Leech, Stephanie L., O’Brien, Terence J., Todaro, Marian, Stamberger, Hannah, Andrade, Danielle M., Ali, Quratulain Zulfiqar, Sadoway, Tara R., Krestel, Heinz, Schaller, André, Papacostas, Savvas S., Kousiappa, Ioanna, Tanteles, George A., Christou, Yiolanda, Štěrbová, Katalin, Vlčková, Markéta, Sedláčková, Lucie, Laššuthová, Petra, Klein, Karl Martin, Rosenow, Felix, Reif, Philipp S., Knake, Susanne, Neubauer, Bernd A., Zimprich, Friedrich, Feucht, Martha, Reinthaler, Eva M., Kunz, Wolfram S., Zsurka, Gábor, Surges, Rainer, Baumgartner, Tobias, Wrede, Randi Von, Pendziwiat, Manuela, Muhle, Hiltrud, Rademacher, Annika, Baalen, Andreas Van, Spiczak, Sarah Von, Stephani, Ulrich, Afawi, Zaid, Korczyn, Amos D., Kanaan, Moien, Canavati, Christina, Kurlemann, Gerhard, Müller-Schlüter, Karen, Kluger, Gerhard, Häusler, Martin, Blatt, Ilan, Lemke, Johannes R., Krey, Ilona, Weber, Yvonne G., Wolking, Stefan, Becker, Felicitas, Lauxmann, Stephan, Boßelmann, Christian, Kegele, Josua, Hengsbach, Christian, Rau, Sarah, Steinhoff, Bernhard J., Schulze-Bonhage, Andreas, Borggräfe, Ingo, Schankin, Christoph J., Schubert-Bast, Susanne, Schreiber, Herbert, Mayer, Thomas, Korinthenberg, Rudolf, Brockmann, Knut, Wolff, Markus, Dennig, Dieter, Madeleyn, Rene, Kälviäinen, Reetta, Saarela, Anni, Timonen, Oskari, Linnankivi, Tarja, Lehesjoki, Anna-Elina, Rheims, Sylvain, Lesca, Gaetan, Ryvlin, Philippe, Maillard, Louis, Valton, Luc, Derambure, Philippe, Bartolomei, Fabrice, Hirsch, Edouard, Michel, Véronique, Chassoux, Francine, Rees, Mark I., Chung, Seo-Kyung, Pickrell, William O., Powell, Robert, Baker, Mark D., Fonferko-Shadrach, Beata, Lawthom, Charlotte, Anderson, Joseph, Schneider, Natascha, Balestrini, Simona, Zagaglia, Sara, Braatz, Vera, Johnson, Michael R., Auce, Pauls, Sills, Graeme J., Baum, Larry W., Sham, Pak C., Cherny, Stacey S., Lui, Colin H. T., Delanty, Norman, Doherty, Colin P., Shukralla, Arif, El-Naggar, Hany, Widdess-Walsh, Peter, Barišić, Nina, Canafoglia, Laura, Franceschetti, Silvana, Castellotti, Barbara, Granata, Tiziana, Ragona, Francesca, Zara, Federico, Iacomino, Michele, Riva, Antonella, Madia, Francesca, Vari, Maria Stella, Salpietro, Vincenzo, Scala, Marcello, Mancardi, Maria Margherita, Nobili, Lino, Amadori, Elisabetta, Giacomini, Thea, Bisulli, Francesca, Pippucci, Tommaso, Licchetta, Laura, Minardi, Raffaella, Tinuper, Paolo, Muccioli, Lorenzo, Mostacci, Barbara, Gambardella, Antonio, Labate, Angelo, Annesi, Grazia, Manna, Lorella, Gagliardi, Monica, Parrini, Elena, Mei, Davide, Vetro, Annalisa, Bianchini, Claudia, Montomoli, Martino, Doccini, Viola, Barba, Carmen, Hirose, Shinichi, Ishii, Atsushi, Suzuki, Toshimitsu, Inoue, Yushi, Yamakawa, Kazuhiro, Beydoun, Ahmad, Nasreddine, Wassim, Zgheib, Nathalie Khoueiry, Tumiene, Birute, Utkus, Algirdas, Sadleir, Lynette G., King, Chontelle, Caglayan, S. Hande, Arslan, Mutluay, Yapıcı, Zuhal, Topaloglu, Pınar, Kara, Bulent, Yis, Uluc, Turkdogan, Dilsad, Gundogdu-Eken, Aslı, Bebek, Nerses, Tsai, Meng-Han, Ho, Chen-Jui, Lin, Chih-Hsiang, Lin, Kuang-Lin, Chou, I.-Jun, Poduri, Annapurna, Shiedley, Beth R., Shain, Catherine, Noebels, Jeffrey L., Goldman, Alicia, Busch, Robyn M., Jehi, Lara, Najm, Imad M., Ferguson, Lisa, Khoury, Jean, Glauser, Tracy A., Clark, Peggy O., Buono, Russell J., Ferraro, Thomas N., Sperling, Michael R., Lo, Warren, Privitera, Michael, French, Jacqueline A., Schachter, Steven, Kuzniecky, Ruben I., Devinsky, Orrin, Hegde, Manu, Greenberg, David A., Ellis, Colin A., Goldberg, Ethan, Helbig, Katherine L., Cosico, Mahgenn, Vaidiswaran, Priya, Fitch, Eryn, Berkovic, Samuel F., Lerche, Holger, Lowenstein, Daniel H., and Goldstein, David B.

Abstract

Summary Both mild and severe epilepsies are influenced by variants in the same genes, yet an explanation for the resulting phenotypic variation is unknown. As part of the ongoing Epi25 Collaboration, we performed a whole-exome sequencing analysis of 13,487 epilepsy-affected individuals and 15,678 control individuals. While prior Epi25 studies focused on gene-based collapsing analyses, we asked how the pattern of variation within genes differs by epilepsy type. Specifically, we compared the genetic architectures of severe developmental and epileptic encephalopathies (DEEs) and two generally less severe epilepsies, genetic generalized epilepsy and non-acquired focal epilepsy (NAFE). Our gene-based rare variant collapsing analysis used geographic ancestry-based clustering that included broader ancestries than previously possible and revealed novel associations. Using the missense intolerance ratio (MTR), we found that variants in DEE-affected individuals are in significantly more intolerant genic sub-regions than those in NAFE-affected individuals. Only previously reported pathogenic variants absent in available genomic datasets showed a significant burden in epilepsy-affected individuals compared with control individuals, and the ultra-rare pathogenic variants associated with DEE were located in more intolerant genic sub-regions than variants associated with non-DEE epilepsies. MTR filtering improved the yield of ultra-rare pathogenic variants in affected individuals compared with control individuals. Finally, analysis of variants in genes without a disease association revealed a significant burden of loss-of-function variants in the genes most intolerant to such variation, indicating additional epilepsy-risk genes yet to be discovered. Taken together, our study suggests that genic and sub-genic intolerance are critical characteristics for interpreting the effects of variation in genes that influence epilepsy.

Published
2021

22. Bosutinib efficacy and safety in chronic phase chronic myeloid leukemia after imatinib resistance or intolerance: Minimum 24-month follow-up

Author

Gambacorti-Passerini, Carlo, Brümmendorf, Tim H., Kim, Dong-Wook, Turkina, Anna G., Masszi, Tamas, Assouline, Sarit, Durrant, Simon, Kantarjian, Hagop M., Khoury, Jean H., Zaritskey, Andrey, Shen, Zhi-Xiang, Jin, Jie, Vellenga, Edo, Pasquini, Ricardo, Mathews, Vikram, Cervantes, Francisco, Besson, Nadine, Turnbull, Kathleen, Leip, Eric, Kelly, Virginia, and Cortes, Jorge E.

Published
2014
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28. Outcomes of Chronic Phase Chronic Myeloid Leukemia after Treatment with Multiple Tyrosine Kinase Inhibitors

Author

Kong, Jee Hyun, primary, Winton, Elliott F., additional, Heffner, Leonard T., additional, Gaddh, Manila, additional, Hill, Brittany, additional, Neely, Jessica, additional, Hatcher, Angela, additional, Joseph, Meena, additional, Arellano, Martha, additional, El-Rassi, Fuad, additional, Kim, Audrey, additional, Khoury, Jean Hanna, additional, and Kota, Vamsi K., additional

Published
2020
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30. Receiver operating characteristic curve analysis of circulating blood dendritic cell precursors and T cells predicts response to extracorporeal photopheresis in patients with chronic graft-versus-host disease

Author

Akhtari, Mojtaba, Giver, Cynthia R., Ali, Zahir, Flowers, Christopher R., Gleason, Charise L., Hillyer, Christopher D., Kaufman, Jonathan, Khoury, Jean H., Langston, Amelia A., Lechowicz, Mary Jo, Lonial, Sagar, Renfroe, Heather M., Roback, John D., Tighiouart, Mourad, Vaughn, Louette, and Waller, Edmund K.

Published
2010
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45. Efficacy of dasatinib for the treatment of intractable chronic myeloid leukemia

Author

Khoury, Jean, Lima, Arellano,Martha, Holloway, Shepard,Marian, McMillan,Stephanie, and Khoury,Jean

Subjects
Journal of Blood Medicine, hemic and lymphatic diseases, human activities
Abstract

Lisa M Lima, Martha Arellano, Stacie Holloway, Marian Shepard, Stephanie McMillan, Hanna Jean KhouryDepartment of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA, USAAbstract: Dasatinib (DAS) is a well tolerated oral dual SRC inhibitor with remarkable activity against all phases of imatinib-resistant chronic myeloid leukemia (CML). This paper focuses on the activity of DAS in intractable CML, and reviews outcomes of patients enrolled on DAS clinical trials. Safety and tolerability as well as practical tips for management of side-effects, and drug interactions are included.Keywords: dasatinib, resistant CML, outcomes

Published
2010

46. Phase 1 dose-finding study of rebastinib (DCC-2036) in patients with relapsed chronic myeloid leukemia and acute myeloid leukemia

Author

Cortes, Jorge, primary, Talpaz, Moshe, additional, Smith, Hedy P., additional, Snyder, David S., additional, Khoury, Jean, additional, Bhalla, Kapil N., additional, Pinilla-Ibarz, Javier, additional, Larson, Richard, additional, Mitchell, David, additional, Wise, Scott C., additional, Rutkoski, Thomas J., additional, Smith, Bryan D., additional, Flynn, Daniel L., additional, Kantarjian, Hagop M., additional, Rosen, Oliver, additional, and Van Etten, Richard A., additional

Published
2016
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47. Bosutinib: a SRC–ABL tyrosine kinase inhibitor for treatment of chronic myeloid leukemia

Author

Khoury, Jean and El Rassi

Subjects
Pharmacogenomics and Personalized Medicine, hemic and lymphatic diseases
Abstract

Fuad El Rassi, Hanna Jean KhouryDivision of Hematology, Department of Hematology and Medical Oncology, the Winship Cancer Institute at Emory University, Atlanta, Georgia, USAAbstract: Bosutinib is one of five tyrosine kinase inhibitors commercially available in the United States for the treatment of chronic myeloid leukemia. This review of bosutinib summarizes the mode of action, pharmacokinetics, efficacy and safety data, as well as the patient-focused perspective through quality-of-life data. Bosutinib has shown considerable and sustained efficacy in chronic myeloid leukemia, especially in the chronic phase, with resistance or intolerance to prior tyrosine kinase inhibitors. Bosutinib has distinct but manageable adverse events. In the absence of T315I and V299L mutations, there are no absolute contraindications for the use of bosutinib in this patient population.Keywords: bosutinib, chronic myeloid leukemia, treatment, review, SRC-ABL kinase inhibitor, clinical activity

Published
2013

49. Magnetic Resonance Imaging Susceptibility-Weighted Imaging Lesion and Contrast Enhancement May Represent Infectious Intracranial Aneurysm in Infective Endocarditis.

Author

Cho, Sung-Min, Rice, Cory, Marquardt, Robert J., Zhang, Lucy Q., Khoury, Jean, Thatikunta, Prateek, Buletko, Andrew B., Hardman, Julian, Uchino, Ken, and Wisco, Dolora

Subjects
INTRACRANIAL aneurysms, INFECTIVE endocarditis, MAGNETIC resonance imaging, DIAGNOSIS, DISEASE risk factors
Abstract

Background: Infectious intracranial aneurysm (IIA) can complicate infective endocarditis (IE). We aimed to describe the magnetic resonance imaging (MRI) characteristics of IIA. Methods: We reviewed IIAs among 116 consecutive patients with active IE by conducting a neurological evaluation at a single tertiary referral center from January 2015 to July 2016. MRIs and digital cerebral angiograms (DSA) were reviewed to identify MRI characteristics of IIAs. MRI susceptibility weighted imaging (SWI) was performed to collect data on cerebral microbleeds (CMBs) and sulcal SWI lesions. Results: Out of 116 persons, 74 (63.8%) underwent DSA. IIAs were identified in 13 (17.6% of DSA, 11.2% of entire cohort) and 10 patients with aneurysms underwent MRI with SWI sequence. Nine (90%) out of 10 persons with IIAs had CMB >5 mm or sulcal lesions in SWI (9 in sulci, 6 in parenchyma, and 5 in both). Five out of 8 persons who underwent MRI brain with contrast had enhancement within the SWI lesions. In a multivariate logistic regression analysis, both sulcal SWI lesions (p < 0.001, OR 69, 95% CI 7.8-610) and contrast enhancement (p = 0.007, OR 16.5, 95% CI 2.3-121) were found to be significant predictors of the presence of IIAs. Conclusions : In the individuals with IE who underwent DSA and MRI, we found that neuroimaging characteristics, such as sulcal SWI lesion with or without contrast enhancement, are associated with the presence of IIA [ABSTRACT FROM AUTHOR]

Published
2017
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50. The price of drugs for chronic myeloid leukemia (CML) is a reflection of the unsustainable prices of cancer drugs: From the perspective of a large group of CML experts

Author

Abboud, C, Berman, E, Cohen, A, Cortes, J, Deangelo, D, Deininger, M, Devine, S, Druker, B, Fathi, A, Jabbour, E, Jagasia, M, Kantarjian, H, Khoury, J, Laneuville, P, Larson, R, Lipton, J, Moore, J, Mughal, T, O'Brien, S, Pinilla-Ibarz, J, Quintas-Cardama, A, Radich, J, Reddy, V, Schiffer, C, Shah, N, Shami, P, Silver, R, Snyder, D, Stone, R, Talpaz, M, Tefferi, A, Van Etten, R, Wetzler, M, Abruzzese, E, Apperley, J, Breccia, M, Byrne, J, Cervantes, F, Chelysheva, E, Clark, R, De Lavallade, H, Dyagil, I, Gambacorti-Passerini, C, Goldman, J, Haznedaroglu, I, Hjorth-Hansen, H, Holyoake, T, Huntly, B, Le Coutre, P, Lomaia, E, Mahon, F, Marin-Costa, D, Martinelli, G, Mayer, J, Milojkovic, D, Olavarria, E, Porkka, K, Richter, J, Rousselot, P, Saglio, G, Saydam, G, Stentoft, J, Turkina, A, Vigneri, P, Zaritskey, A, Aguayo, A, Ayala, M, Bendit, I, Bengio, R, Best, C, Bullorsky, E, Cervera, E, Desouza, C, Fanilla, E, Gomez-Almaguer, D, Hamerschlak, N, Lopez, J, Magarinos, A, Meillon, L, Milone, J, Moiraghi, B, Pasquini, R, Pavlovsky, C, Ruiz-Arguelles, G, Spector, N, Arthur, C, Browett, P, Grigg, A, Jianda, H, Huang, X, Hughes, T, Jiang, Q, Jootar, S, Kim, D, Malhotra, H, Malhotra, P, Matsumura, I, Melo, J, Ohnishi, K, Ohno, R, Saikia, T, Schwarer, A, Takahashi, N, Tam, C, Tauchi, T, Usuki, K, Wang, J, Abdel-Rahman, F, Aljurf, M, Bazarba-Chi, A, Yehuda, D, Chaudhri, N, Durosinmi, M, Kamel, H, Louw, V, Matti, B, Nagler, A, Raanani, P, Salem, Z, Abboud, Camille, Berman, Ellin, Cohen, Adam, Cortes, Jorge, DeAngelo, Daniel, Deininger, Michael, Devine, Steven, Druker, Brian, Fathi, Amir, Jabbour, Elias, Jagasia, Madan, Kantarjian, Hagop, Khoury, Jean, Laneuville, Pierre, Larson, Richard, Lipton, Jeffrey, Moore, Joseph O., Mughal, Tariq, O'Brien, Susan, Pinilla-Ibarz, Javier, Quintas-Cardama, Alfonso, Radich, Jerald, Reddy, Vishnu, Schiffer, Charles, Shah, Neil, Shami, Paul, Silver, Richard T., Snyder, David, Stone, Richard, Talpaz, Moshe, Tefferi, Ayalew, Van Etten, Richard A., Wetzler, Meir, Abruzzese, Elisabetta, Apperley, Jane, Breccia, Massimo, Byrne, Jenny, Cervantes, Francisco, Chelysheva, Ekaterina, Clark, R. E., De Lavallade, Hugues, Dyagil, Iryna, Gambacorti-Passerini, Carlo, Goldman, John, Haznedaroglu, Ibrahim, Hjorth-Hansen, Henrik, Holyoake, Tessa, Huntly, Brian, Le Coutre, Philipp, Lomaia, Elza, Mahon, Francois-Xavier, Marin-Costa, David, Martinelli, Giovanni, Mayer, Jiri, Milojkovic, Dragana, Olavarria, Eduardo, Porkka, Kimmo, Richter, Johan, Rousselot, Philippe, Saglio, Giuseppe, Saydam, Guray, Stentoft, Jesper, Turkina, Anna, Vigneri, Paolo, Zaritskey, Andrey, Aguayo, Alvaro, Ayala, Manuel, Bendit, Israel, Bengio, Raquel Maria, Best, Carlos, Bullorsky, Eduardo, Cervera, Eduardo, Desouza, Carmino, Fanilla, Ernesto, Gomez-Almaguer, David, Hamerschlak, Nelson, Lopez, Jose, Magarinos, Alicia, Meillon, Luis, Milone, Jorge, Moiraghi, Beatriz, Pasquini, Ricardo, Pavlovsky, Carolina, Ruiz-Arguelles, Guillermo J., Spector, Nelson, Arthur, Christopher, Browett, Peter, Grigg, Andrew, Hu, Jianda, Huang, Xiao-jun, Hughes, Tim, Jiang, Qian, Jootar, Saengsuree, Kim, Dong-Wook, Malhotra, Hemant, Malhotra, Pankaj, Matsumura, Itaru, Melo, Junia, Ohnishi, Kazunori, Ohno, Ryuzo, Saikia, Tapan, Schwarer, Anthony P., Takahashi, Naoto, Tam, Constantine, Tauchi, Tetsuzo, Usuki, Kensuke, Wang, Jianxiang, Abdel-Rahman, Fawzi, Aljurf, Mahmoud Deeb Saeed, Bazarba-Chi, Ali, Yehuda, Dina Ben, Chaudhri, Naeem, Durosinmi, Muheez, Kamel, Hossam, Louw, Vernon, Matti, Bassam Francis, Nagler, Arnon, Raanani, Pia, Salem, Ziad, Abboud, C, Berman, E, Cohen, A, Cortes, J, Deangelo, D, Deininger, M, Devine, S, Druker, B, Fathi, A, Jabbour, E, Jagasia, M, Kantarjian, H, Khoury, J, Laneuville, P, Larson, R, Lipton, J, Moore, J, Mughal, T, O'Brien, S, Pinilla-Ibarz, J, Quintas-Cardama, A, Radich, J, Reddy, V, Schiffer, C, Shah, N, Shami, P, Silver, R, Snyder, D, Stone, R, Talpaz, M, Tefferi, A, Van Etten, R, Wetzler, M, Abruzzese, E, Apperley, J, Breccia, M, Byrne, J, Cervantes, F, Chelysheva, E, Clark, R, De Lavallade, H, Dyagil, I, Gambacorti-Passerini, C, Goldman, J, Haznedaroglu, I, Hjorth-Hansen, H, Holyoake, T, Huntly, B, Le Coutre, P, Lomaia, E, Mahon, F, Marin-Costa, D, Martinelli, G, Mayer, J, Milojkovic, D, Olavarria, E, Porkka, K, Richter, J, Rousselot, P, Saglio, G, Saydam, G, Stentoft, J, Turkina, A, Vigneri, P, Zaritskey, A, Aguayo, A, Ayala, M, Bendit, I, Bengio, R, Best, C, Bullorsky, E, Cervera, E, Desouza, C, Fanilla, E, Gomez-Almaguer, D, Hamerschlak, N, Lopez, J, Magarinos, A, Meillon, L, Milone, J, Moiraghi, B, Pasquini, R, Pavlovsky, C, Ruiz-Arguelles, G, Spector, N, Arthur, C, Browett, P, Grigg, A, Jianda, H, Huang, X, Hughes, T, Jiang, Q, Jootar, S, Kim, D, Malhotra, H, Malhotra, P, Matsumura, I, Melo, J, Ohnishi, K, Ohno, R, Saikia, T, Schwarer, A, Takahashi, N, Tam, C, Tauchi, T, Usuki, K, Wang, J, Abdel-Rahman, F, Aljurf, M, Bazarba-Chi, A, Yehuda, D, Chaudhri, N, Durosinmi, M, Kamel, H, Louw, V, Matti, B, Nagler, A, Raanani, P, Salem, Z, Abboud, Camille, Berman, Ellin, Cohen, Adam, Cortes, Jorge, DeAngelo, Daniel, Deininger, Michael, Devine, Steven, Druker, Brian, Fathi, Amir, Jabbour, Elias, Jagasia, Madan, Kantarjian, Hagop, Khoury, Jean, Laneuville, Pierre, Larson, Richard, Lipton, Jeffrey, Moore, Joseph O., Mughal, Tariq, O'Brien, Susan, Pinilla-Ibarz, Javier, Quintas-Cardama, Alfonso, Radich, Jerald, Reddy, Vishnu, Schiffer, Charles, Shah, Neil, Shami, Paul, Silver, Richard T., Snyder, David, Stone, Richard, Talpaz, Moshe, Tefferi, Ayalew, Van Etten, Richard A., Wetzler, Meir, Abruzzese, Elisabetta, Apperley, Jane, Breccia, Massimo, Byrne, Jenny, Cervantes, Francisco, Chelysheva, Ekaterina, Clark, R. E., De Lavallade, Hugues, Dyagil, Iryna, Gambacorti-Passerini, Carlo, Goldman, John, Haznedaroglu, Ibrahim, Hjorth-Hansen, Henrik, Holyoake, Tessa, Huntly, Brian, Le Coutre, Philipp, Lomaia, Elza, Mahon, Francois-Xavier, Marin-Costa, David, Martinelli, Giovanni, Mayer, Jiri, Milojkovic, Dragana, Olavarria, Eduardo, Porkka, Kimmo, Richter, Johan, Rousselot, Philippe, Saglio, Giuseppe, Saydam, Guray, Stentoft, Jesper, Turkina, Anna, Vigneri, Paolo, Zaritskey, Andrey, Aguayo, Alvaro, Ayala, Manuel, Bendit, Israel, Bengio, Raquel Maria, Best, Carlos, Bullorsky, Eduardo, Cervera, Eduardo, Desouza, Carmino, Fanilla, Ernesto, Gomez-Almaguer, David, Hamerschlak, Nelson, Lopez, Jose, Magarinos, Alicia, Meillon, Luis, Milone, Jorge, Moiraghi, Beatriz, Pasquini, Ricardo, Pavlovsky, Carolina, Ruiz-Arguelles, Guillermo J., Spector, Nelson, Arthur, Christopher, Browett, Peter, Grigg, Andrew, Hu, Jianda, Huang, Xiao-jun, Hughes, Tim, Jiang, Qian, Jootar, Saengsuree, Kim, Dong-Wook, Malhotra, Hemant, Malhotra, Pankaj, Matsumura, Itaru, Melo, Junia, Ohnishi, Kazunori, Ohno, Ryuzo, Saikia, Tapan, Schwarer, Anthony P., Takahashi, Naoto, Tam, Constantine, Tauchi, Tetsuzo, Usuki, Kensuke, Wang, Jianxiang, Abdel-Rahman, Fawzi, Aljurf, Mahmoud Deeb Saeed, Bazarba-Chi, Ali, Yehuda, Dina Ben, Chaudhri, Naeem, Durosinmi, Muheez, Kamel, Hossam, Louw, Vernon, Matti, Bassam Francis, Nagler, Arnon, Raanani, Pia, and Salem, Ziad

Abstract

As a group of more than 100 experts in chronic myeloid leukemia (CML), we draw attention to the high prices of cancer drugs, with the particular focus on the prices of approved tyrosine kinase inhibitors for the treatment of CML. This editorial addresses the multiple factors involved in cancer drug pricing and their impact on individual patients and health care policies, and argues for the need to (1) lower the prices of cancer drugs to allow more patients to afford them and (2) maintain sound long-term health care policies.

Published
2013

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