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2. Detection and localization of early- and late-stage cancers using platelet RNA

Author

Veld, S., Arkani, M., Post, E., Antunes-Ferreira, M., D'Ambrosi, S., Vessies, D.C.L., Vermunt, L., Vancura, A., Muller, Mirte, Niemeijer, A.N., Tannous, J., Meijer, L.L., Large, T.Y. Le, Mantini, G., Wondergem, N.E., Heinhuis, K.M., Wilpe, S. van, Smits, Josien, Drees, E.E.E., Roos, E., Leurs, C.E., Fat, L.A. Tjon Kon, Lelij, E.J. van der, Dwarshuis, G., Kamphuis, M.J., Visser, Leonie N.C., Harting, R., Gregory, A., Schweiger, M.W., Wedekind, L.E., Ramaker, J., Zwaan, K., Verschueren, H., Bahce, I, Langen, A.J. de, Smit, E.F., Heuvel, M.M. van den, Hartemink, K.J., Kuijpers, M.J., Egbrink, M.G.A. Oude, Griffioen, A.W., Rossel, R., Hiltermann, T.J.N., Lee-Lewandrowski, E., Lewandrowski, K.B., Hamer, P.C., Kouwenhoven, M., Reijneveld, J.C., Leenders, W.P.J., Hoeben, A., Verdonck-de Leeuw, I.M., Leemans, C.Rene, Baatenburg de Jong, R.J., Terhaard, Chris H. J., Takes, R.P., Langendijk, J.A., Jager, S.C. de, Kraaijeveld, A.O., Pasterkamp, G., Smits, M., Schalken, J.A., Łapińska-Szumczyk, S., Łojkowska, A., Żaczek, A.J., Lokhorst, H., Donk, N. van de, Nijhof, I., Prins, H.J., Zijlstra, J.M., Idema, S., Baayen, J.C., Teunissen, C.E., Killestein, J., Besselink, M.G.H., Brammen, L., Bachleitner-Hofmann, T., Mateen, F., Plukker, J.T., Heger, M., Mast, Q. de, Lisman, T., Pegtel, D.M., Bogaard, H.J., Jassem, J., Supernat, A., Mehra, N., Gerritsen, W.R., Kroon, C.D. de, Lok, C. A. R., Piek, J.M.J., Steeghs, N., Houdt, W.J. van, Brakenhoff, R.H., Sonke, G.S., Verheul, H.M.W., Giovannetti, E., Kazemier, G., Sabrkhany, S., Schuuring, E., Sistermans, E.A., Veld, S., Arkani, M., Post, E., Antunes-Ferreira, M., D'Ambrosi, S., Vessies, D.C.L., Vermunt, L., Vancura, A., Muller, Mirte, Niemeijer, A.N., Tannous, J., Meijer, L.L., Large, T.Y. Le, Mantini, G., Wondergem, N.E., Heinhuis, K.M., Wilpe, S. van, Smits, Josien, Drees, E.E.E., Roos, E., Leurs, C.E., Fat, L.A. Tjon Kon, Lelij, E.J. van der, Dwarshuis, G., Kamphuis, M.J., Visser, Leonie N.C., Harting, R., Gregory, A., Schweiger, M.W., Wedekind, L.E., Ramaker, J., Zwaan, K., Verschueren, H., Bahce, I, Langen, A.J. de, Smit, E.F., Heuvel, M.M. van den, Hartemink, K.J., Kuijpers, M.J., Egbrink, M.G.A. Oude, Griffioen, A.W., Rossel, R., Hiltermann, T.J.N., Lee-Lewandrowski, E., Lewandrowski, K.B., Hamer, P.C., Kouwenhoven, M., Reijneveld, J.C., Leenders, W.P.J., Hoeben, A., Verdonck-de Leeuw, I.M., Leemans, C.Rene, Baatenburg de Jong, R.J., Terhaard, Chris H. J., Takes, R.P., Langendijk, J.A., Jager, S.C. de, Kraaijeveld, A.O., Pasterkamp, G., Smits, M., Schalken, J.A., Łapińska-Szumczyk, S., Łojkowska, A., Żaczek, A.J., Lokhorst, H., Donk, N. van de, Nijhof, I., Prins, H.J., Zijlstra, J.M., Idema, S., Baayen, J.C., Teunissen, C.E., Killestein, J., Besselink, M.G.H., Brammen, L., Bachleitner-Hofmann, T., Mateen, F., Plukker, J.T., Heger, M., Mast, Q. de, Lisman, T., Pegtel, D.M., Bogaard, H.J., Jassem, J., Supernat, A., Mehra, N., Gerritsen, W.R., Kroon, C.D. de, Lok, C. A. R., Piek, J.M.J., Steeghs, N., Houdt, W.J. van, Brakenhoff, R.H., Sonke, G.S., Verheul, H.M.W., Giovannetti, E., Kazemier, G., Sabrkhany, S., Schuuring, E., and Sistermans, E.A.

Abstract

Contains fulltext : 281792.pdf (Publisher’s version ) (Open Access), Cancer patients benefit from early tumor detection since treatment outcomes are more favorable for less advanced cancers. Platelets are involved in cancer progression and are considered a promising biosource for cancer detection, as they alter their RNA content upon local and systemic cues. We show that tumor-educated platelet (TEP) RNA-based blood tests enable the detection of 18 cancer types. With 99% specificity in asymptomatic controls, thromboSeq correctly detected the presence of cancer in two-thirds of 1,096 blood samples from stage I-IV cancer patients and in half of 352 stage I-III tumors. Symptomatic controls, including inflammatory and cardiovascular diseases, and benign tumors had increased false-positive test results with an average specificity of 78%. Moreover, thromboSeq determined the tumor site of origin in five different tumor types correctly in over 80% of the cancer patients. These results highlight the potential properties of TEP-derived RNA panels to supplement current approaches for blood-based cancer screening.

Published
2022

3. Tumor-educated platelet blood tests for Non-Small Cell Lung Cancer detection and management.

Author

Antunes-Ferreira M, D'Ambrosi S, Arkani M, Post E, In 't Veld SGJG, Ramaker J, Zwaan K, Kucukguzel ED, Wedekind LE, Griffioen AW, Oude Egbrink M, Kuijpers MJE, van den Broek D, Noske DP, Hartemink KJ, Sabrkhany S, Bahce I, Sol N, Bogaard HJ, Koppers-Lalic D, Best MG, and Wurdinger T

Subjects
Humans, Biomarkers, Tumor genetics, Algorithms, RNA metabolism, Blood Platelets metabolism, Hematologic Tests, Carcinoma, Non-Small-Cell Lung genetics, Lung Neoplasms genetics
Abstract

Liquid biopsy approaches offer a promising technology for early and minimally invasive cancer detection. Tumor-educated platelets (TEPs) have emerged as a promising liquid biopsy biosource for the detection of various cancer types. In this study, we processed and analyzed the TEPs collected from 466 Non-small Cell Lung Carcinoma (NSCLC) patients and 410 asymptomatic individuals (controls) using the previously established thromboSeq protocol. We developed a novel particle-swarm optimization machine learning algorithm which enabled the selection of an 881 RNA biomarker panel (AUC 0.88). Herein we propose and validate in an independent cohort of samples (n = 558) two approaches for blood samples testing: one with high sensitivity (95% NSCLC detected) and another with high specificity (94% controls detected). Our data explain how TEP-derived spliced RNAs may serve as a biomarker for minimally-invasive clinical blood tests, complement existing imaging tests, and assist the detection and management of lung cancer patients., (© 2023. The Author(s).)

Published
2023
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5. Detection and localization of early- and late-stage cancers using platelet RNA.

Author

In 't Veld SGJG, Arkani M, Post E, Antunes-Ferreira M, D'Ambrosi S, Vessies DCL, Vermunt L, Vancura A, Muller M, Niemeijer AN, Tannous J, Meijer LL, Le Large TYS, Mantini G, Wondergem NE, Heinhuis KM, van Wilpe S, Smits AJ, Drees EEE, Roos E, Leurs CE, Tjon Kon Fat LA, van der Lelij EJ, Dwarshuis G, Kamphuis MJ, Visser LE, Harting R, Gregory A, Schweiger MW, Wedekind LE, Ramaker J, Zwaan K, Verschueren H, Bahce I, de Langen AJ, Smit EF, van den Heuvel MM, Hartemink KJ, Kuijpers MJE, Oude Egbrink MGA, Griffioen AW, Rossel R, Hiltermann TJN, Lee-Lewandrowski E, Lewandrowski KB, De Witt Hamer PC, Kouwenhoven M, Reijneveld JC, Leenders WPJ, Hoeben A, Verdonck-de Leeuw IM, Leemans CR, Baatenburg de Jong RJ, Terhaard CHJ, Takes RP, Langendijk JA, de Jager SC, Kraaijeveld AO, Pasterkamp G, Smits M, Schalken JA, Łapińska-Szumczyk S, Łojkowska A, Żaczek AJ, Lokhorst H, van de Donk NWCJ, Nijhof I, Prins HJ, Zijlstra JM, Idema S, Baayen JC, Teunissen CE, Killestein J, Besselink MG, Brammen L, Bachleitner-Hofmann T, Mateen F, Plukker JTM, Heger M, de Mast Q, Lisman T, Pegtel DM, Bogaard HJ, Jassem J, Supernat A, Mehra N, Gerritsen W, de Kroon CD, Lok CAR, Piek JMJ, Steeghs N, van Houdt WJ, Brakenhoff RH, Sonke GS, Verheul HM, Giovannetti E, Kazemier G, Sabrkhany S, Schuuring E, Sistermans EA, Wolthuis R, Meijers-Heijboer H, Dorsman J, Oudejans C, Ylstra B, Westerman BA, van den Broek D, Koppers-Lalic D, Wesseling P, Nilsson RJA, Vandertop WP, Noske DP, Tannous BA, Sol N, Best MG, and Wurdinger T

Subjects
Biomarkers, Tumor genetics, Blood Platelets, Early Detection of Cancer methods, Humans, Neoplasms diagnosis, Neoplasms genetics, RNA genetics
Abstract

Cancer patients benefit from early tumor detection since treatment outcomes are more favorable for less advanced cancers. Platelets are involved in cancer progression and are considered a promising biosource for cancer detection, as they alter their RNA content upon local and systemic cues. We show that tumor-educated platelet (TEP) RNA-based blood tests enable the detection of 18 cancer types. With 99% specificity in asymptomatic controls, thromboSeq correctly detected the presence of cancer in two-thirds of 1,096 blood samples from stage I-IV cancer patients and in half of 352 stage I-III tumors. Symptomatic controls, including inflammatory and cardiovascular diseases, and benign tumors had increased false-positive test results with an average specificity of 78%. Moreover, thromboSeq determined the tumor site of origin in five different tumor types correctly in over 80% of the cancer patients. These results highlight the potential properties of TEP-derived RNA panels to supplement current approaches for blood-based cancer screening., Competing Interests: Declaration of interests M.G. Best, R.J.A.N., and T.W. are inventors on relevant patent applications (PCT/NL2011/050518 and PCT/NL2018/050110). R.J.A.N. and T.W. are shareholders of Illumina, Inc. M.H. is chief formulation officer at Nurish.Me, Inc., and Camelina Sun LLC and has equity in those companies (whose business activities are unrelated to the present work). D.M.P. and D.K.L. are shareholders of ExBiome BV., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Published
2022
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6. Quantitative and qualitative changes in platelet traits of sunitinib-treated patients with renal cell carcinoma in relation to circulating sunitinib levels: a proof-of-concept study.

Author

Tullemans BME, Brouns SLN, Swieringa F, Sabrkhany S, van den Berkmortel FWPJ, Peters NAJB, de Bruijn P, Koolen SLW, Heemskerk JWM, Aarts MJB, and Kuijpers MJE

Subjects
Blood Platelets pathology, Humans, Indoles adverse effects, Pyrroles adverse effects, Sunitinib therapeutic use, Antineoplastic Agents adverse effects, Carcinoma, Renal Cell pathology, Kidney Neoplasms pathology
Abstract

Background: Tyrosine kinase inhibitors (TKIs), such as sunitinib, are used for cancer treatment, but may also affect platelet count and function with possible hemostatic consequences. Here, we investigated whether patient treatment with the TKI sunitinib affected quantitative and qualitative platelet traits as a function of the sunitinib level and the occurrence of bleeding., Methods: Blood was collected from 20 metastatic renal cell carcinoma (mRCC) patients before treatment, and at 2 weeks, 4 weeks and 3 months after sunitinib administration. We measured blood cell counts, platelet aggregation, and concentrations of sunitinib as well as its N-desethyl metabolite in plasma, serum and isolated platelets. Progression of disease (PD) and bleeding were monitored after 3 months., Results: In sunitinib-treated mRCC patients, concentrations of (N-desethyl-)sunitinib in plasma and serum were highly correlated. In the patients' platelets the active metabolite levels were relatively increased as compared to sunitinib. On average, a sustained reduction in platelet count was observed on-treatment, which was significantly related to the inhibitor levels in plasma/serum. Principal component and correlational analysis showed that the (N-desethyl-)sunitinib levels in plasma/serum were linked to a reduction in both platelet count and collagen-induced platelet aggregation. The reduced aggregation associated in part with reported bleeding, but did not correlate to PD., Conclusion: The sunitinib-induced reduction in quantitative and qualitative platelet traits may reflect the effective sunitinib levels in the patient. These novel results may serve as a proof-of-principle for other TKI-related drugs, where both platelet count and functions are affected, which could be used for therapeutic drug monitoring., (© 2022. The Author(s).)

Published
2022
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