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1. An immune-protein score combining TRAIL, IP-10 and CRP for predicting severe COVID-19 disease

Author

Mastboim, Niv Samuel, Angel, Alon, Shaham, Oded, Ber, Tahel Ilan, Navon, Roy, Simon, Einav, Rosenberg, Michal, Israeli, Yael, Hainrichson, Mary, Avni, Noa, Reiner, Eran, Feigin, Paul, Oved, Kfir, Tadmor, Boaz, Singer, Pierre, Kagan, Ilya, Lev, Shaul, Diker, Dror, Jarjou'I, Amir, Kurd, Ramzi, Ben-Chetrit, Eli, Danziger, Guy, Tegethoff, Sina A., Papan, Cihan, Motov, Sergey, Shapira, Ma'anit, Stein, Michal, Gottlieb, Tanya M., Eden, Eran, and Klein, Adi

Published
2023
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2. Host test based on tumor necrosis factor-related apoptosis-inducing ligand, interferon gamma-induced protein-10 and C-reactive protein for differentiating bacterial and viral respiratory tract infections in adults: diagnostic accuracy study

Author

Halabi, Salim, Shiber, Shachaf, Paz, Meital, Gottlieb, Tanya M., Barash, Eran, Navon, Roy, Ilan-Ber, Tahel, Shani, Liran, Petersiel, Neta, Grupper, Mordechai, Simon, Einav, Kirshner, Daniel, Haber, Daniel, Stein, Michal, Maor, Yasmin, Guetta, Claire, Lishtzinsky, Ynon, Yanai, Shirly, Drescher, Michael J., Oved, Kfir, Eden, Eran, Neuberger, Ami, and Paul, Mical

Published
2023
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3. A host signature based on TRAIL, IP-10, and CRP for reducing antibiotic overuse in children by differentiating bacterial from viral infections: a prospective, multicentre cohort study

Author

Papan, Cihan, Argentiero, Alberto, Porwoll, Marian, Hakim, Ummaya, Farinelli, Edoardo, Testa, Ilaria, Pasticci, Maria Bruna, Mezzetti, Daniele, Perruccio, Katia, Etshtein, Liat, Mastboim, Niv, Moscoviz, Einat, Ber, Tahel Ilan, Cohen, Asi, Simon, Einav, Boico, Olga, Shani, Liran, Gottlieb, Tanya M., Navon, Roy, Barash, Eran, Oved, Kfir, Eden, Eran, Simon, Arne, Liese, Johannes G., Knuf, Markus, Stein, Michal, Yacobov, Renata, Bamberger, Ellen, Schneider, Sven, Esposito, Susanna, and Tenenbaum, Tobias

Published
2022
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4. Host biomarkers and combinatorial scores for the detection of serious and invasive bacterial infection in pediatric patients with fever without source

Author

Lacroix, Laurence, primary, Papis, Sebastien, additional, Mardegan, Chiara, additional, Luterbacher, Fanny, additional, L’Huillier, Arnaud, additional, Sahyoun, Cyril, additional, Keitel, Kristina, additional, Mastboim, Niv, additional, Etshtein, Liat, additional, Shani, Liran, additional, Simon, Einav, additional, Barash, Eran, additional, Navon, Roy, additional, Gottlieb, Tanya M., additional, Oved, Kfir, additional, Eden, Eran, additional, Combescure, Christophe, additional, Galetto-Lacour, Annick, additional, and Gervaix, Alain, additional

Published
2023
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5. The diagnostic value of nasal microbiota and clinical parameters in a multi-parametric prediction model to differentiate bacterial versus viral infections in lower respiratory tract infections

Author

Li, Yunlei, Van Houten, Chantal B., Boers, Stefan A., Jansen, Ruud, Cohen, Asi, Engelhard, Dan, Kraaij, Robert, Hiltemann, Saskia D., Ju, Jie, Fernandez, David, Mankoc, Cristian, Gonzalez, Eva, De Waal, Wouter J., De Winter-De Groot, Karin M., Wolfs, Tom F.W., Meijers, Pieter, Luijk, Bart, Oosterheert, Jan Jelrik, Sankatsing, Sanjay U.C., Bossink, Aik W.J., Stein, Michal, Klein, Adi, Ashkar, Jalal, Bamberger, Ellen, Srugo, Isaac, Odeh, Majed, Dotan, Yaniv, Boico, Olga, Etshtein, Liat, Paz, Meital, Navon, Roy, Friedman, Tom, Simon, Einav, Gottlieb, Tanya M., Pri-Or, Ester, Kronenfeld, Gali, Oved, Kfir, Eden, Eran, Stubbs, Andrew P., Bont, Louis J., Hays, John P., Li, Yunlei, Van Houten, Chantal B., Boers, Stefan A., Jansen, Ruud, Cohen, Asi, Engelhard, Dan, Kraaij, Robert, Hiltemann, Saskia D., Ju, Jie, Fernandez, David, Mankoc, Cristian, Gonzalez, Eva, De Waal, Wouter J., De Winter-De Groot, Karin M., Wolfs, Tom F.W., Meijers, Pieter, Luijk, Bart, Oosterheert, Jan Jelrik, Sankatsing, Sanjay U.C., Bossink, Aik W.J., Stein, Michal, Klein, Adi, Ashkar, Jalal, Bamberger, Ellen, Srugo, Isaac, Odeh, Majed, Dotan, Yaniv, Boico, Olga, Etshtein, Liat, Paz, Meital, Navon, Roy, Friedman, Tom, Simon, Einav, Gottlieb, Tanya M., Pri-Or, Ester, Kronenfeld, Gali, Oved, Kfir, Eden, Eran, Stubbs, Andrew P., Bont, Louis J., and Hays, John P.

Abstract

Background The ability to accurately distinguish bacterial from viral infection would help clinicians better target antimicrobial therapy during suspected lower respiratory tract infections (LRTI). Although technological developments make it feasible to rapidly generate patient-specific microbiota profiles, evidence is required to show the clinical value of using microbiota data for infection diagnosis. In this study, we investigated whether adding nasal cavity microbiota profiles to readily available clinical information could improve machine learning classifiers to distinguish bacterial from viral infection in patients with LRTI. Results Various multi-parametric Random Forests classifiers were evaluated on the clinical and microbiota data of 293 LRTI patients for their prediction accuracies to differentiate bacterial from viral infection. The most predictive variable was C-reactive protein (CRP). We observed a marginal prediction improvement when 7 most prevalent nasal microbiota genera were added to the CRP model. In contrast, adding three clinical variables, absolute neutrophil count, consolidation on X-ray, and age group to the CRP model significantly improved the prediction. The best model correctly predicted 85% of the 'bacterial' patients and 82% of the 'viral' patients using 13 clinical and 3 nasal cavity microbiota genera (Staphylococcus, Moraxella, and Streptococcus). Conclusions We developed high-accuracy multi-parametric machine learning classifiers to differentiate bacterial from viral infections in LRTI patients of various ages. We demonstrated the predictive value of four easy-to-collect clinical variables which facilitate personalized and accurate clinical decision-making. We observed that nasal cavity microbiota correlate with the clinical variables and thus may not add significant value to diagnostic algorithms that aim to differentiate bacterial from viral infections.

Published
2022

6. The diagnostic value of nasal microbiota and clinical parameters in a multi-parametric prediction model to differentiate bacterial versus viral infections in lower respiratory tract infections

Author

Arts-assistenten Kinderen, Child Health, Infectieziekten onderzoek1 (Bont), Longziekten patientenzorg, Infectiezieken, Infectieziekten patientenzorg, Infection & Immunity, Longziekten, MS Interne Geneeskunde, CTI Bont, Li, Yunlei, Van Houten, Chantal B., Boers, Stefan A., Jansen, Ruud, Cohen, Asi, Engelhard, Dan, Kraaij, Robert, Hiltemann, Saskia D., Ju, Jie, Fernandez, David, Mankoc, Cristian, Gonzalez, Eva, De Waal, Wouter J., De Winter-De Groot, Karin M., Wolfs, Tom F.W., Meijers, Pieter, Luijk, Bart, Oosterheert, Jan Jelrik, Sankatsing, Sanjay U.C., Bossink, Aik W.J., Stein, Michal, Klein, Adi, Ashkar, Jalal, Bamberger, Ellen, Srugo, Isaac, Odeh, Majed, Dotan, Yaniv, Boico, Olga, Etshtein, Liat, Paz, Meital, Navon, Roy, Friedman, Tom, Simon, Einav, Gottlieb, Tanya M., Pri-Or, Ester, Kronenfeld, Gali, Oved, Kfir, Eden, Eran, Stubbs, Andrew P., Bont, Louis J., Hays, John P., Arts-assistenten Kinderen, Child Health, Infectieziekten onderzoek1 (Bont), Longziekten patientenzorg, Infectiezieken, Infectieziekten patientenzorg, Infection & Immunity, Longziekten, MS Interne Geneeskunde, CTI Bont, Li, Yunlei, Van Houten, Chantal B., Boers, Stefan A., Jansen, Ruud, Cohen, Asi, Engelhard, Dan, Kraaij, Robert, Hiltemann, Saskia D., Ju, Jie, Fernandez, David, Mankoc, Cristian, Gonzalez, Eva, De Waal, Wouter J., De Winter-De Groot, Karin M., Wolfs, Tom F.W., Meijers, Pieter, Luijk, Bart, Oosterheert, Jan Jelrik, Sankatsing, Sanjay U.C., Bossink, Aik W.J., Stein, Michal, Klein, Adi, Ashkar, Jalal, Bamberger, Ellen, Srugo, Isaac, Odeh, Majed, Dotan, Yaniv, Boico, Olga, Etshtein, Liat, Paz, Meital, Navon, Roy, Friedman, Tom, Simon, Einav, Gottlieb, Tanya M., Pri-Or, Ester, Kronenfeld, Gali, Oved, Kfir, Eden, Eran, Stubbs, Andrew P., Bont, Louis J., and Hays, John P.

Published
2022

7. The diagnostic value of nasal microbiota and clinical parameters in a multi-parametric prediction model to differentiate bacterial versus viral infections in lower respiratory tract infections

Author

Li, Yunlei, primary, van Houten, Chantal B., additional, Boers, Stefan A., additional, Jansen, Ruud, additional, Cohen, Asi, additional, Engelhard, Dan, additional, Kraaij, Robert, additional, Hiltemann, Saskia D., additional, Ju, Jie, additional, Fernández, David, additional, Mankoc, Cristian, additional, González, Eva, additional, de Waal, Wouter J., additional, de Winter-de Groot, Karin M., additional, Wolfs, Tom F. W., additional, Meijers, Pieter, additional, Luijk, Bart, additional, Oosterheert, Jan Jelrik, additional, Sankatsing, Sanjay U. C., additional, Bossink, Aik W. J., additional, Stein, Michal, additional, Klein, Adi, additional, Ashkar, Jalal, additional, Bamberger, Ellen, additional, Srugo, Isaac, additional, Odeh, Majed, additional, Dotan, Yaniv, additional, Boico, Olga, additional, Etshtein, Liat, additional, Paz, Meital, additional, Navon, Roy, additional, Friedman, Tom, additional, Simon, Einav, additional, Gottlieb, Tanya M., additional, Pri-Or, Ester, additional, Kronenfeld, Gali, additional, Oved, Kfir, additional, Eden, Eran, additional, Stubbs, Andrew P., additional, Bont, Louis J., additional, and Hays, John P., additional

Published
2022
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8. Differential Serum and Urine CRP, IP-10, and TRAIL Levels in Pediatric Urinary Tract Infection

Author

Ashkenazi-Hoffnung, Liat, primary, Livni, Gilat, additional, Scheuerman, Oded, additional, Berger, Itay, additional, Eden, Eran, additional, Oved, Kfir, additional, Shani, Liran, additional, Kronenfeld, Gali, additional, Simon, Einav, additional, Boico, Olga, additional, Navon, Roy, additional, Gottlieb, Tanya M., additional, Barash, Eran, additional, Paz, Meital, additional, Yuhas, Yael, additional, Berent, Eva, additional, and Ashkenazi, Shai, additional

Published
2021
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9. 32. Host Immune-Protein Signature Combining TRAIL, IP-10 and CRP for Early and Accurate Prediction of Severe COVID-19 Outcome

Author

Angel, Alon, primary, Mastboim, Niv Samuel, additional, Shaham, Oded, additional, Ber, Tahel Ilan, additional, Navon, Roy, additional, Simon, Einav, additional, Rosenberg, Michal, additional, Israeli, Yael, additional, Hainrichson, Mary, additional, Avni, Noa, additional, Reiner, Eran, additional, Feigin, Paul, additional, Oved, Kfir, additional, Tadmor, Boaz, additional, Singer, Pierre, additional, Kagan, Ilya, additional, Lev, Shaul, additional, Diker, Dror, additional, Jarjou’i, Amir, additional, Kurd, Ramzi, additional, Ben-Chetrit, Eli, additional, Danziger, Guy, additional, Papan, Cihan, additional, Motov, Sergey, additional, Shapira, Maanit, additional, Stein, Michal, additional, Klein, Adi, additional, Gottlieb, Tanya, additional, and Eden, Eran, additional

Published
2021
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10. 1348. A Novel Host-Protein Signature Comprising TRAIL, IP-10 and CRP Differentiates Bacterial from Viral Infection in COPD Patients with Suspected Lower Respiratory Tract Infection

Author

Halabi, Salim, primary, Shiber, Shachaf, additional, Stein, Michal, additional, Paz, Meital, additional, Gottlieb, Tanya, additional, Barash, Eran, additional, Navon, Roy, additional, Moscoviz, Einat, additional, Ber, Tahel Ilan, additional, Shani, Liran, additional, Petersiel, Neta, additional, Boico, Olga, additional, Grupper, Mordechai, additional, Simon, Einav, additional, Kirshner, Dani, additional, Avni, Noa, additional, Haber, Daniel, additional, Maor, Yasmin, additional, Guetta, Claire S, additional, Lishtzinsky, Ynon, additional, Yanai, Shirly, additional, Drescher, Michael, additional, Oved, Kfir, additional, Eden, Eran, additional, Neuberger, Ami, additional, and Paul, Mical, additional

Published
2021
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12. Observational cohort study of IP-10’s potential as a biomarker to aid in inflammation regulation within a clinical decision support protocol for patients with severe COVID-19

Author

Lev, Shaul, primary, Gottesman, Tamar, additional, Sahaf Levin, Gal, additional, Lederfein, Doron, additional, Berkov, Evgeny, additional, Diker, Dror, additional, Zaidman, Aliza, additional, Nutman, Amir, additional, Ilan Ber, Tahel, additional, Angel, Alon, additional, Kellerman, Lior, additional, Barash, Eran, additional, Navon, Roy, additional, Boico, Olga, additional, Israeli, Yael, additional, Rosenberg, Michal, additional, Gelman, Amir, additional, Kalfon, Roy, additional, Simon, Einav, additional, Avni, Noa, additional, Hainrichson, Mary, additional, Zarchin, Oren, additional, Gottlieb, Tanya M., additional, Oved, Kfir, additional, Eden, Eran, additional, and Tadmor, Boaz, additional

Published
2021
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13. 426. Use of Real Time IP-10 Measurements to Identify and Monitor the Dysregulated Immune Response in COVID-19 Patients

Author

Lev, Shaul, primary, Gottesman, Tamar, additional, Levin, Gal Shachaf, additional, Ber, Tahel Ilan, additional, Angel, Alon, additional, Kellerman, Lior, additional, Barash, Eran, additional, Navon, Roy, additional, Simon, Einav, additional, Avni, Noa, additional, Hainrichson, Mary, additional, Gottlieb, Tanya, additional, Oved, Kfir, additional, Eden, Eran, additional, and Tadmor, Boaz, additional

Published
2020
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14. Antibiotic misuse in respiratory tract infections in children and adults—a prospective, multicentre study (TAILORED Treatment)

Author

van Houten, Chantal B., Cohen, Asi, Engelhard, Dan, Hays, John P., Karlsson, Roger, Moore, Edward, Fernández, David, Kreisberg, Racheli, Collins, Laurence V., de Waal, Wouter, de Winter-de Groot, Karin M., Wolfs, Tom F.W., Meijers, Pieter, Luijk, Bart, Oosterheert, Jan Jelrik, Heijligenberg, Rik, Sankatsing, Sanjay U.C., Bossink, Aik W.J., Stubbs, Andrew, Stein, Michal, Reisfeld, Sharon, Klein, Adi, Rachmilevitch, Ronit, Ashkar, Jalal, Braverman, Itzhak, Kartun, Valery, Chistyakov, Irena, Bamberger, Ellen, Srugo, Isaac, Odeh, Majed, Schiff, Elad, Dotan, Yaniv, Boico, Olga, Navon, Roy, Friedman, Tom, Etshtein, Liat, Paz, Meital, Gottlieb, Tanya M., Pri-Or, Ester, Kronenfeld, Gali, Simon, Einav, Oved, Kfir, Eden, Eran, Bont, Louis J., van Houten, Chantal B., Cohen, Asi, Engelhard, Dan, Hays, John P., Karlsson, Roger, Moore, Edward, Fernández, David, Kreisberg, Racheli, Collins, Laurence V., de Waal, Wouter, de Winter-de Groot, Karin M., Wolfs, Tom F.W., Meijers, Pieter, Luijk, Bart, Oosterheert, Jan Jelrik, Heijligenberg, Rik, Sankatsing, Sanjay U.C., Bossink, Aik W.J., Stubbs, Andrew, Stein, Michal, Reisfeld, Sharon, Klein, Adi, Rachmilevitch, Ronit, Ashkar, Jalal, Braverman, Itzhak, Kartun, Valery, Chistyakov, Irena, Bamberger, Ellen, Srugo, Isaac, Odeh, Majed, Schiff, Elad, Dotan, Yaniv, Boico, Olga, Navon, Roy, Friedman, Tom, Etshtein, Liat, Paz, Meital, Gottlieb, Tanya M., Pri-Or, Ester, Kronenfeld, Gali, Simon, Einav, Oved, Kfir, Eden, Eran, and Bont, Louis J.

Published
2019

15. Antibiotic misuse in respiratory tract infections in children and adults—a prospective, multicentre study (TAILORED Treatment)

Author

UMC Utrecht, Child Health, Infectieziekten onderzoek1 (Bont), Longziekten patientenzorg, Infectieziekten patientenzorg, Infection & Immunity, Longziekten, MS Interne Geneeskunde, CTI Bont, Infectiezieken, van Houten, Chantal B., Cohen, Asi, Engelhard, Dan, Hays, John P., Karlsson, Roger, Moore, Edward, Fernández, David, Kreisberg, Racheli, Collins, Laurence V., de Waal, Wouter, de Winter-de Groot, Karin M., Wolfs, Tom F.W., Meijers, Pieter, Luijk, Bart, Oosterheert, Jan Jelrik, Heijligenberg, Rik, Sankatsing, Sanjay U.C., Bossink, Aik W.J., Stubbs, Andrew, Stein, Michal, Reisfeld, Sharon, Klein, Adi, Rachmilevitch, Ronit, Ashkar, Jalal, Braverman, Itzhak, Kartun, Valery, Chistyakov, Irena, Bamberger, Ellen, Srugo, Isaac, Odeh, Majed, Schiff, Elad, Dotan, Yaniv, Boico, Olga, Navon, Roy, Friedman, Tom, Etshtein, Liat, Paz, Meital, Gottlieb, Tanya M., Pri-Or, Ester, Kronenfeld, Gali, Simon, Einav, Oved, Kfir, Eden, Eran, Bont, Louis J., UMC Utrecht, Child Health, Infectieziekten onderzoek1 (Bont), Longziekten patientenzorg, Infectieziekten patientenzorg, Infection & Immunity, Longziekten, MS Interne Geneeskunde, CTI Bont, Infectiezieken, van Houten, Chantal B., Cohen, Asi, Engelhard, Dan, Hays, John P., Karlsson, Roger, Moore, Edward, Fernández, David, Kreisberg, Racheli, Collins, Laurence V., de Waal, Wouter, de Winter-de Groot, Karin M., Wolfs, Tom F.W., Meijers, Pieter, Luijk, Bart, Oosterheert, Jan Jelrik, Heijligenberg, Rik, Sankatsing, Sanjay U.C., Bossink, Aik W.J., Stubbs, Andrew, Stein, Michal, Reisfeld, Sharon, Klein, Adi, Rachmilevitch, Ronit, Ashkar, Jalal, Braverman, Itzhak, Kartun, Valery, Chistyakov, Irena, Bamberger, Ellen, Srugo, Isaac, Odeh, Majed, Schiff, Elad, Dotan, Yaniv, Boico, Olga, Navon, Roy, Friedman, Tom, Etshtein, Liat, Paz, Meital, Gottlieb, Tanya M., Pri-Or, Ester, Kronenfeld, Gali, Simon, Einav, Oved, Kfir, Eden, Eran, and Bont, Louis J.

Published
2019

16. 1962. TRAIL Level and ImmunoXpert™ Score Complement Molecular Viral Detection in the Classification of Febrile Children: An Interim Analysis From the AutoPilotDx-Study

Author

Tenenbaum, Tobias, primary, Papan, Cihan, additional, Porwoll, Marian, additional, Hakim, Ummaya, additional, Argentiero, Alberto, additional, Testa, Ilaria, additional, Pasticci, Maria Bruna, additional, Mezzetti, Daniele, additional, Perruccio, Katia, additional, Etshtein, Liat, additional, Mastboim, Niv, additional, Cohen, Asi, additional, Simon, Einav, additional, Boico, Olga, additional, Shani, Liran, additional, Gottlieb, Tanya, additional, Navon, Roy, additional, Oved, Kfir, additional, Eden, Eran, additional, Simon, Arne, additional, Liese, Johannes, additional, Knuf, Markus, additional, Schneider, Sven, additional, Farinelli, Edoardo, additional, and Esposito, Susanna, additional

Published
2018
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17. 2241. Low Serum TRAIL Levels in Children with Severe Viral Infections

Author

Mastboim, Niv Samuel, Papan, Cihan, Farinelli, Edoardo, Shani, Liran, Gottlieb, Tanya, Simon, Einav, Etshtein, Liat, Cohen, Asi, Navon, Roy, Boico, Olga, Sitry, Naama, Oved, Kfir, Eden, Eran, Testa, Ilaria, Argentiero, Alberto, Pasticci, Maria Bruna, Mezzetti, Daniele, Perruccio, Katia, Hakim, Ummaya, Porwoll, Marian, Simon, Arne, Knuf, Markus, Schneider, Sven, Esposito, Susanna, and Tenenbaum, Tobias

Subjects
Abstracts, nervous system, Poster Abstracts, macromolecular substances
Abstract

Background TRAIL, TNF-related apoptosis-induced ligand, is a novel biomarker of viral infection. In healthy individuals, circulating levels are typically ~ 80 pg/mL, but in the setting of viral infection, levels increase within hours. Recent studies have found decreased TRAIL levels to be correlated with disease severity in conditions such as cardiovascular disease and ischemic stroke. However, nothing is known about its role as a severity marker for children with viral infections. Here we examined, for the first time, whether TRAIL levels are associated with viral disease severity in children. Methods “AutoPilot-Dx” (NCT03052088) is an EU funded, multinational, prospective study designed to validate diagnostic performance of a TRAIL, IP-10, and CRP protein signature for differentiating between bacterial and viral infections. We analyzed the first 657 eligible children. Viral etiology was assigned by majority adjudication of three experts based on comprehensive investigation including follow-up questionnaires and multiplex respiratory PCR panel (Allplex™). Children hospitalized for > 5 days, had lowest saturation of < 96% and appeared ill on physical examination were defined as having severe viral infection. Serum TRAIL levels were measured using ELISA (ImmunoXpert™). Results Of the 657 children adjudicated, 465 were classified as viral. Of them, 317 and 57 were defined as having non-severe and severe viral disease, respectively (Figure 1). TRAIL levels were markedly increased in all viral patients (mean ± SD [pg/mL]: 151 ± 111). Patients with severe viral infection exhibited significantly lower TRAIL levels when compared with non-severe infection (non-severe 158 ± 114; severe 107 ± 60; P = 0.001), implying that viral-induced TRAIL levels may be counterbalanced by the severity state. Age and time from fever onset were not found to be confounders. Notably, common bacterial markers such as CRP (non-severe 20 ± 26; severe 17 ± 16; P = 0.549), WBC (non-severe 11 ± 5; severe 12 ± 5; P = 0.074) and ANC (non-severe 7 ± 4; severe 7 ± 3; P = 0.410) exhibited no significant difference between the groups. Conclusion Serum TRAIL levels were significantly associated with viral disease severity, suggesting its potential as a prognostic marker for viral-infected children. Disclosures All authors: No reported disclosures.

Published
2019

22. Subclonality for BRAFMutation in Papillary Thyroid Carcinoma Is Associated With Earlier Disease Stage

Author

Finkel, Alona, Liba, Lior, Simon, Einav, Bick, Tova, Prinz, Elad, Sabo, Edmond, Ben-Izhak, Ofer, and Hershkovitz, Dov

Abstract

Context:The presence of driver mutations only in a subset of tumor cells within a single lesion, defined as subclonality, is being appreciated as a clinically significant factor. BRAFmutation is the most common driver mutation in papillary thyroid carcinoma (PTC). There are conflicting data in the literature regarding the presence of BRAFmutation subclonality in PTC and its clinical significance.Objective:The purpose of the present study was to use a molecular and morphometric approach to determine BRAFclonality status and its clinical-pathological correlates.Design:Fifty-nine cases of PTC were studied. DNA extracted from the tumors underwent deep sequencing to determine the percentage of BRAFmutant allele copies. Additionally, we used computerized morphometry to determine the fraction of tumor cells in each sample. Using both variables, we were able to determine the presence or absence of subclonality for BRAFmutation, which was further correlated with clinical, pathological, and prognostic data.Results:BRAFmutation was found in 49 (83%) cases. The average percentage of tumor cells and of BRAFmutant alleles in the samples were 68.1 ± 9.8 and 26 ± 6.7, respectively. Based on the molecular and morphometric analysis, 11 (24%) cases were found to be subclonal for BRAFmutation. Tumors with subclonal BRAFmutations were significantly smaller compared to tumors with clonal mutation (0.82 ± 0.38 cm vs 1.37 ± 0.57 cm, P= .005) and were less likely to have lymph node metastasis (0% vs 32%, P= .03).Conclusions:In PTC, subclonality for BRAFmutation is associated with earlier stage. Molecular-morphometric analysis of PTC can provide clonality information with potential clinical significance.

Published
2016
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