23 results on '"Lak, Nathalie S. M."'
Search Results
2. A comprehensive overview of liquid biopsy applications in pediatric solid tumors
- Author
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Janssen, Ferdinand W., Lak, Nathalie S. M., Janda, Claudia Y., Kester, Lennart A., Meister, Michael T., Merks, Johannes H. M., van den Heuvel-Eibrink, Marry M., van Noesel, Max M., Zsiros, Jozsef, Tytgat, Godelieve A. M., and Looijenga, Leendert H. J.
- Published
- 2024
- Full Text
- View/download PDF
3. Focused Ultrasound-Enhanced Liquid Biopsy: A Promising Diagnostic Tool for Brain Tumor Patients
- Author
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ZL Neuro-Oncologie Medisch, Researchgr. Beeldg. Moleculaire Interv., Cancer, MS Medische Oncologie, Brain, Neurologen, Bakker, Akke, Ixkes, Anna E, Venugopal, Hema, Ries, Mario G, Lak, Nathalie S M, de Vos, Filip Y F L, van Vuurden, Dannis G, Snijders, Tom J, ZL Neuro-Oncologie Medisch, Researchgr. Beeldg. Moleculaire Interv., Cancer, MS Medische Oncologie, Brain, Neurologen, Bakker, Akke, Ixkes, Anna E, Venugopal, Hema, Ries, Mario G, Lak, Nathalie S M, de Vos, Filip Y F L, van Vuurden, Dannis G, and Snijders, Tom J
- Published
- 2024
4. Focused Ultrasound-Enhanced Liquid Biopsy: A Promising Diagnostic Tool for Brain Tumor Patients.
- Author
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Bakker, Akke, Ixkes, Anna E., Venugopal, Hema, Ries, Mario G., Lak, Nathalie S. M., de Vos, Filip Y. F. L., van Vuurden, Dannis G., and Snijders, Tom J.
- Subjects
MEDICAL information storage & retrieval systems ,GLIOMAS ,RESEARCH funding ,BLOOD-brain barrier ,BODY fluid examination ,CANCER patients ,MINIMALLY invasive procedures ,ULTRASONIC imaging ,MEDLINE ,SYSTEMATIC reviews ,ONLINE information services ,BRAIN tumors ,BIOMARKERS - Abstract
Simple Summary: Diagnosing brain tumors using minimally invasive methods, such as a liquid biopsy, is challenging due to the blood–brain barrier (BBB). The BBB blocks tumor biomarkers from entering the bloodstream. However, a technique called focused ultrasound with microbubbles (FUS-BBBO) can temporarily open the BBB, thereby potentially increasing the tumor biomarkers in the bloodstream. This systematic review collected data on FUS-BBBO-enhanced liquid biopsy for primary brain tumors. The review included five animal studies and two human studies. Animal studies have shown that biomarker levels were higher in groups subjected to FUS-BBBO compared to control groups. Clinical studies involving 14 patients also showed increased biomarker levels after FUS-BBBO treatment. It is worth noting that using stable cavitation during FUS-BBBO appeared promising for liquid biopsy. Overall, this technique has the potential to improve brain tumor diagnosis and disease monitoring. However, further investigation is necessary to ensure its safe and effective use in the clinical setting. The performance of minimally invasive molecular diagnostic tools in brain tumors, such as liquid biopsy, has so far been limited by the blood–brain barrier (BBB). The BBB hinders the release of brain tumor biomarkers into the bloodstream. The use of focused ultrasound in conjunction with microbubbles has been shown to temporarily open the BBB (FUS-BBBO). This may enhance blood-based tumor biomarker levels. This systematic review provides an overview of the data regarding FUS-BBBO-enhanced liquid biopsy for primary brain tumors. A systematic search was conducted in PubMed and Embase databases with key terms "brain tumors", "liquid biopsy", "FUS" and their synonyms, in accordance with PRISMA statement guidelines. Five preclinical and two clinical studies were included. Preclinical studies utilized mouse, rat and porcine glioma models. Biomarker levels were found to be higher in sonicated groups compared to control groups. Both stable and inertial microbubble cavitation increased biomarker levels, whereas only inertial cavitation induced microhemorrhages. In clinical studies involving 14 patients with high-grade brain tumors, biomarker levels were increased after FUS-BBBO with stable cavitation. In conclusion, FUS-BBBO-enhanced liquid biopsy using stable cavitation shows diagnostic potential for primary brain tumors. Further research is imperative before integrating FUS-BBBO for liquid biopsy enhancement into clinical practice. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
5. Novel Circulating Hypermethylated RASSF1A ddPCR for Liquid Biopsies in Patients With Pediatric Solid Tumors
- Author
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van Zogchel, Lieke M. J., Lak, Nathalie S. M., Verhagen, Onno J. H. M., Tissoudali, Ahmed, Gussmalla Nuru, Mohammed, Gelineau, Nina U., Zappeij-Kannengieter, Lily, Javadi, Ahmad, Zijtregtop, Eline A. M., Merks, Johannes H. M., van den Heuvel-Eibrink, Marry, Schouten-van Meeteren, Antoinette Y. N., Stutterheim, Janine, van der Schoot, C. Ellen, and Tytgat, Godelieve A. M.
- Published
- 2021
- Full Text
- View/download PDF
6. Targeted locus amplification to develop robust patient-specific assays for liquid biopsies in pediatric solid tumors
- Author
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van Zogchel, Lieke M. J., primary, Lak, Nathalie S. M., additional, Gelineau, Nina U., additional, Sergeeva, Irina, additional, Stelloo, Ellen, additional, Swennenhuis, Joost, additional, Feitsma, Harma, additional, van Min, Max, additional, Splinter, Erik, additional, Bleijs, Margit, additional, Groot Koerkamp, Marian, additional, Breunis, Willemijn, additional, Meister, Michael Torsten, additional, Kholossy, Waleed Hassan, additional, Holstege, Frank C. P., additional, Molenaar, Jan J., additional, de Leng, Wendy W. J., additional, Stutterheim, Janine, additional, van der Schoot, C. Ellen, additional, and Tytgat, Godelieve A. M., additional
- Published
- 2023
- Full Text
- View/download PDF
7. Cell-Free RNA from Plasma in Patients with Neuroblastoma: Exploring the Technical and Clinical Potential
- Author
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Lak, Nathalie S M, Seijger, Anne, van Zogchel, Lieke M J, Gelineau, Nina U, Javadi, Ahmad, Zappeij-Kannegieter, Lily, Bongiovanni, Laura, Andriessen, Anneloes, Stutterheim, Janine, van der Schoot, C Ellen, de Bruin, Alain, Tytgat, Godelieve A M, Lak, Nathalie S M, Seijger, Anne, van Zogchel, Lieke M J, Gelineau, Nina U, Javadi, Ahmad, Zappeij-Kannegieter, Lily, Bongiovanni, Laura, Andriessen, Anneloes, Stutterheim, Janine, van der Schoot, C Ellen, de Bruin, Alain, and Tytgat, Godelieve A M
- Abstract
Neuroblastoma affects mostly young children, bearing a high morbidity and mortality. Liquid biopsies, e.g., molecular analysis of circulating tumor-derived nucleic acids in blood, offer a minimally invasive diagnostic modality. Cell-free RNA (cfRNA) is released by all cells, especially cancer. It circulates in blood packed in extracellular vesicles (EV) or attached to proteins. We studied the feasibility of analyzing cfRNA and EV, isolated by size exclusion chromatography (SEC), from platelet-poor plasma from healthy controls ( n = 40) and neuroblastoma patients with localized ( n = 10) and metastatic disease ( n = 30). The mRNA content was determined using several multiplex droplet digital PCR (ddPCR) assays for a neuroblastoma-specific gene panel ( PHOX2B, TH, CHRNA3) and a cell cycle regulation panel ( E2F1, CDC6, ATAD2, H2AFZ, MCM2, DHFR). We applied corrections for the presence of platelets. We demonstrated that neuroblastoma-specific markers were present in plasma from 14/30 patients with metastatic disease and not in healthy controls and patients with localized disease. Most cell cycle markers had a higher expression in patients. The mRNA markers were mostly present in the EV-enriched SEC fractions. In conclusion, cfRNA can be isolated from plasma and EV and analyzed using multiplex ddPCR. cfRNA is an interesting novel liquid biopsy-based target to explore further.
- Published
- 2023
8. Cell-Free RNA from Plasma in Patients with Neuroblastoma: Exploring the Technical and Clinical Potential
- Author
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Pathobiologie, Dep Biomolecular Health Sciences, Lak, Nathalie S M, Seijger, Anne, van Zogchel, Lieke M J, Gelineau, Nina U, Javadi, Ahmad, Zappeij-Kannegieter, Lily, Bongiovanni, Laura, Andriessen, Anneloes, Stutterheim, Janine, van der Schoot, C Ellen, de Bruin, Alain, Tytgat, Godelieve A M, Pathobiologie, Dep Biomolecular Health Sciences, Lak, Nathalie S M, Seijger, Anne, van Zogchel, Lieke M J, Gelineau, Nina U, Javadi, Ahmad, Zappeij-Kannegieter, Lily, Bongiovanni, Laura, Andriessen, Anneloes, Stutterheim, Janine, van der Schoot, C Ellen, de Bruin, Alain, and Tytgat, Godelieve A M
- Published
- 2023
9. Targeted locus amplification to develop robust patient-specific assays for liquid biopsies in pediatric solid tumors
- Author
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CMM Groep Cuppen, Groep Holstege, Pathologie Pathologen staf, Cancer, van Zogchel, Lieke M J, Lak, Nathalie S M, Gelineau, Nina U, Sergeeva, Irina, Stelloo, Ellen, Swennenhuis, Joost, Feitsma, Harma, van Min, Max, Splinter, Erik, Bleijs, Margit, Groot Koerkamp, Marian, Breunis, Willemijn, Meister, Michael Torsten, Kholossy, Waleed Hassan, Holstege, Frank C P, Molenaar, Jan J, de Leng, Wendy W J, Stutterheim, Janine, van der Schoot, C Ellen, Tytgat, Godelieve A M, CMM Groep Cuppen, Groep Holstege, Pathologie Pathologen staf, Cancer, van Zogchel, Lieke M J, Lak, Nathalie S M, Gelineau, Nina U, Sergeeva, Irina, Stelloo, Ellen, Swennenhuis, Joost, Feitsma, Harma, van Min, Max, Splinter, Erik, Bleijs, Margit, Groot Koerkamp, Marian, Breunis, Willemijn, Meister, Michael Torsten, Kholossy, Waleed Hassan, Holstege, Frank C P, Molenaar, Jan J, de Leng, Wendy W J, Stutterheim, Janine, van der Schoot, C Ellen, and Tytgat, Godelieve A M
- Published
- 2023
10. Cell-Free DNA as a Diagnostic and Prognostic Biomarker in Pediatric Rhabdomyosarcoma
- Author
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Onderzoek Beeld, Cancer, Lak, Nathalie S M, van Zogchel, Lieke M J, Zappeij-Kannegieter, Lily, Javadi, Ahmad, van Paemel, Ruben, Vandeputte, Charlotte, De Preter, Katleen, De Wilde, Bram, Chicard, Mathieu, Iddir, Yasmine, Schleiermacher, Gudrun, Ruhen, Olivia, Shipley, Janet, Fiocco, Marta, Merks, Johannes H M, van Noesel, Max M, van der Schoot, C Ellen, Tytgat, Godelieve A M, Stutterheim, Janine, Onderzoek Beeld, Cancer, Lak, Nathalie S M, van Zogchel, Lieke M J, Zappeij-Kannegieter, Lily, Javadi, Ahmad, van Paemel, Ruben, Vandeputte, Charlotte, De Preter, Katleen, De Wilde, Bram, Chicard, Mathieu, Iddir, Yasmine, Schleiermacher, Gudrun, Ruhen, Olivia, Shipley, Janet, Fiocco, Marta, Merks, Johannes H M, van Noesel, Max M, van der Schoot, C Ellen, Tytgat, Godelieve A M, and Stutterheim, Janine
- Published
- 2023
11. Targeted locus amplification to develop robust patient-specific assays for liquid biopsies in pediatric solid tumors
- Author
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van Zogchel, Lieke M J, Lak, Nathalie S M; https://orcid.org/0000-0003-3743-8826, Gelineau, Nina U, Sergeeva, Irina, Stelloo, Ellen, Swennenhuis, Joost, Feitsma, Harma, van Min, Max, Splinter, Erik, Bleijs, Margit, Groot Koerkamp, Marian, Breunis, Willemijn, Meister, Michael Torsten, Kholossy, Waleed Hassan, Holstege, Frank C P; https://orcid.org/0000-0002-8090-5146, Molenaar, Jan J, de Leng, Wendy W J, Stutterheim, Janine; https://orcid.org/0000-0002-9828-0834, van der Schoot, C Ellen, Tytgat, Godelieve A M, van Zogchel, Lieke M J, Lak, Nathalie S M; https://orcid.org/0000-0003-3743-8826, Gelineau, Nina U, Sergeeva, Irina, Stelloo, Ellen, Swennenhuis, Joost, Feitsma, Harma, van Min, Max, Splinter, Erik, Bleijs, Margit, Groot Koerkamp, Marian, Breunis, Willemijn, Meister, Michael Torsten, Kholossy, Waleed Hassan, Holstege, Frank C P; https://orcid.org/0000-0002-8090-5146, Molenaar, Jan J, de Leng, Wendy W J, Stutterheim, Janine; https://orcid.org/0000-0002-9828-0834, van der Schoot, C Ellen, and Tytgat, Godelieve A M
- Abstract
BACKGROUND Liquid biopsies combine minimally invasive sample collection with sensitive detection of residual disease. Pediatric malignancies harbor tumor-driving copy number alterations or fusion genes, rather than recurrent point mutations. These regions contain tumor-specific DNA breakpoint sequences. We investigated the feasibility to use these breakpoints to design patient-specific markers to detect tumor-derived cell-free DNA (cfDNA) in plasma from patients with pediatric solid tumors. MATERIALS AND METHODS Regions of interest (ROI) were identified through standard clinical diagnostic pipelines, using SNP array for CNAs, and FISH or RT-qPCR for fusion genes. Using targeted locus amplification (TLA) on tumor organoids grown from tumor material or targeted locus capture (TLC) on FFPE material, ROI-specific primers and probes were designed, which were used to design droplet digital PCR (ddPCR) assays. cfDNA from patient plasma at diagnosis and during therapy was analyzed. RESULTS TLA was performed on material from 2 rhabdomyosarcoma, 1 Ewing sarcoma and 3 neuroblastoma. FFPE-TLC was performed on 8 neuroblastoma tumors. For all patients, at least one patient-specific ddPCR was successfully designed and in all diagnostic plasma samples the patient-specific markers were detected. In the rhabdomyosarcoma and Ewing sarcoma patients, all samples after start of therapy were negative. In neuroblastoma patients, presence of patient-specific markers in cfDNA tracked tumor burden, decreasing during induction therapy, disappearing at complete remission and re-appearing at relapse. CONCLUSION We demonstrate the feasibility to determine tumor-specific breakpoints using TLA/TLC in different pediatric solid tumors and use these for analysis of cfDNA from plasma. Considering the high prevalence of CNAs and fusion genes in pediatric solid tumors, this approach holds great promise and deserves further study in a larger cohort with standardized plasma sampling protocols.
- Published
- 2023
12. Cell-Free RNA from Plasma in Patients with Neuroblastoma: Exploring the Technical and Clinical Potential
- Author
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Lak, Nathalie S. M., primary, Seijger, Anne, additional, van Zogchel, Lieke M. J., additional, Gelineau, Nina U., additional, Javadi, Ahmad, additional, Zappeij-Kannegieter, Lily, additional, Bongiovanni, Laura, additional, Andriessen, Anneloes, additional, Stutterheim, Janine, additional, van der Schoot, C. Ellen, additional, de Bruin, Alain, additional, and Tytgat, Godelieve A. M., additional
- Published
- 2023
- Full Text
- View/download PDF
13. Molecular Characterization of Circulating Tumor DNA in Pediatric Rhabdomyosarcoma: A Feasibility Study
- Author
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Ruhen, Olivia, Lak, Nathalie S M, Stutterheim, Janine, Danielli, Sara G, et al, Surdez, Didier, Schäfer, Beat W, and University of Zurich
- Subjects
10036 Medical Clinic ,10061 Institute of Molecular Cancer Research ,570 Life sciences ,biology ,610 Medicine & health ,10046 Balgrist University Hospital, Swiss Spinal Cord Injury Center - Published
- 2022
14. Extracellular Vesicles: A New Source of Biomarkers in Pediatric Solid Tumors? A Systematic Review
- Author
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Lak, Nathalie S. M., Van Der Kooi, Elvera J., Enciso-martinez, Agustin, Lozano-andrés, Estefanía, Otto, Cees, Wauben, Marca H. M., Tytgat, Godelieve A. M., Celbiologie, dB&C I&I, Celbiologie, and dB&C I&I
- Subjects
Cancer Research ,neuroblastoma ,Oncology ,osteosarcoma ,pediatric oncology ,rhabdomyosarcoma ,solid tumors ,hepatoblastoma ,extracellular vesicles ,desmoplastic small round cell tumor - Abstract
Virtually every cell in the body releases extracellular vesicles (EVs), the contents of which can provide a “fingerprint” of their cellular origin. EVs are present in all bodily fluids and can be obtained using minimally invasive techniques. Thus, EVs can provide a promising source of diagnostic, prognostic, and predictive biomarkers, particularly in the context of cancer. Despite advances using EVs as biomarkers in adult cancers, little is known regarding their use in pediatric cancers. In this review, we provide an overview of published clinical and in vitro studies in order to assess the potential of using EV-derived biomarkers in pediatric solid tumors. We performed a systematic literature search, which yielded studies regarding desmoplastic small round cell tumor, hepatoblastoma, neuroblastoma, osteosarcoma, and rhabdomyosarcoma. We then determined the extent to which the in vivo findings are supported by in vitro data, and vice versa. We also critically evaluated the clinical studies using the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) system, and we evaluated the purification and characterization of EVs in both the in vivo and in vitro studies in accordance with MISEV guidelines, yielding EV-TRACK and PedEV scores. We found that several studies identified similar miRNAs in overlapping and distinct tumor entities, indicating the potential for EV-derived biomarkers. However, most studies regarding EV-based biomarkers in pediatric solid tumors lack a standardized system of reporting their EV purification and characterization methods, as well as validation in an independent cohort, which are needed in order to bring EV-based biomarkers to the clinic.
- Published
- 2022
15. Extracellular Vesicles: A New Source of Biomarkers in Pediatric Solid Tumors? A Systematic Review
- Author
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Celbiologie, dB&C I&I, Lak, Nathalie S. M., Van Der Kooi, Elvera J., Enciso-martinez, Agustin, Lozano-andrés, Estefanía, Otto, Cees, Wauben, Marca H. M., Tytgat, Godelieve A. M., Celbiologie, dB&C I&I, Lak, Nathalie S. M., Van Der Kooi, Elvera J., Enciso-martinez, Agustin, Lozano-andrés, Estefanía, Otto, Cees, Wauben, Marca H. M., and Tytgat, Godelieve A. M.
- Published
- 2022
16. Molecular Characterization of Circulating Tumor DNA in Pediatric Rhabdomyosarcoma: A Feasibility Study
- Author
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Ruhen, Olivia; https://orcid.org/0000-0002-4961-9352, Lak, Nathalie S M; https://orcid.org/0000-0003-3743-8826, Stutterheim, Janine; https://orcid.org/0000-0002-9828-0834, Danielli, Sara G; https://orcid.org/0000-0003-3101-3114, et al, Surdez, Didier; https://orcid.org/0000-0002-7118-7859, Schäfer, Beat W; https://orcid.org/0000-0001-5988-2915, Ruhen, Olivia; https://orcid.org/0000-0002-4961-9352, Lak, Nathalie S M; https://orcid.org/0000-0003-3743-8826, Stutterheim, Janine; https://orcid.org/0000-0002-9828-0834, Danielli, Sara G; https://orcid.org/0000-0003-3101-3114, et al, Surdez, Didier; https://orcid.org/0000-0002-7118-7859, and Schäfer, Beat W; https://orcid.org/0000-0001-5988-2915
- Abstract
PURPOSE Rhabdomyosarcomas (RMS) are rare neoplasms affecting children and young adults. Efforts to improve patient survival have been undermined by a lack of suitable disease markers. Plasma circulating tumor DNA (ctDNA) has shown promise as a potential minimally invasive biomarker and monitoring tool in other cancers; however, it remains underexplored in RMS. We aimed to determine the feasibility of identifying and quantifying ctDNA in plasma as a marker of disease burden and/or treatment response using blood samples from RMS mouse models and patients. METHODS We established mouse models of RMS and applied quantitative polymerase chain reaction (PCR) and droplet digital PCR (ddPCR) to detect ctDNA within the mouse plasma. Potential driver mutations, copy-number alterations, and DNA breakpoints associated with PAX3/7-FOXO1 gene fusions were identified in the RMS samples collected at diagnosis. Patient-matched plasma samples collected from 28 patients with RMS before, during, and after treatment were analyzed for the presence of ctDNA via ddPCR, panel sequencing, and/or whole-exome sequencing. RESULTS Human tumor-derived DNA was detectable in plasma samples from mouse models of RMS and correlated with tumor burden. In patients, ctDNA was detected in 14/18 pretreatment plasma samples with ddPCR and 7/7 cases assessed by sequencing. Levels of ctDNA at diagnosis were significantly higher in patients with unfavorable tumor sites, positive nodal status, and metastasis. In patients with serial plasma samples (n = 18), fluctuations in ctDNA levels corresponded to treatment response. CONCLUSION Comprehensive ctDNA analysis combining high sensitivity and throughput can identify key molecular drivers in RMS models and patients, suggesting potential as a minimally invasive biomarker. Preclinical assessment of treatments using mouse models and further patient testing through prospective clinical trials are now warranted.
- Published
- 2022
17. Specific and Sensitive Detection of Neuroblastoma mRNA Markers by Multiplex RT-qPCR
- Author
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van Zogchel, Lieke M. J., primary, Zappeij-Kannegieter, Lily, additional, Javadi, Ahmad, additional, Lugtigheid, Marjolein, additional, Gelineau, Nina U., additional, Lak, Nathalie S. M., additional, Zwijnenburg, Danny A., additional, Koster, Jan, additional, Stutterheim, Janine, additional, van der Schoot, C. Ellen, additional, and Tytgat, Godelieve A. M., additional
- Published
- 2021
- Full Text
- View/download PDF
18. Cell-Free DNA as a Diagnostic and Prognostic Biomarker in Pediatric Rhabdomyosarcoma.
- Author
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Lak NSM, van Zogchel LMJ, Zappeij-Kannegieter L, Javadi A, van Paemel R, Vandeputte C, De Preter K, De Wilde B, Chicard M, Iddir Y, Schleiermacher G, Ruhen O, Shipley J, Fiocco M, Merks JHM, van Noesel MM, van der Schoot CE, Tytgat GAM, and Stutterheim J
- Subjects
- Humans, Child, Prognosis, RNA, Biomarkers, Cell-Free Nucleic Acids genetics, Rhabdomyosarcoma diagnosis, Rhabdomyosarcoma genetics
- Abstract
Purpose: Total cell-free DNA (cfDNA) and tumor-derived cfDNA (ctDNA) can be used to study tumor-derived genetic aberrations. We analyzed the diagnostic and prognostic potential of cfDNA and ctDNA, obtained from pediatric patients with rhabdomyosarcoma., Methods: cfDNA was isolated from diagnostic plasma samples from 57 patients enrolled in the EpSSG RMS2005 study. To study the diagnostic potential, shallow whole genome sequencing (shWGS) and cell-free reduced representation bisulphite sequencing (cfRRBS) were performed in a subset of samples and all samples were tested using droplet digital polymerase chain reaction to detect methylated RASSF1A ( RASSF1A- M). Correlation with outcome was studied by combining cfDNA RASSF1A- M detection with analysis of our rhabdomyosarcoma-specific RNA panel in paired cellular blood and bone marrow fractions and survival analysis in 56 patients., Results: At diagnosis, ctDNA was detected in 16 of 30 and 24 of 26 patients using shallow whole genome sequencing and cfRRBS, respectively. Furthermore, 21 of 25 samples were correctly classified as embryonal by cfRRBS. RASSF1A -M was detected in 21 of 57 patients. The presence of RASSF1A -M was significantly correlated with poor outcome (the 5-year event-free survival [EFS] rate was 46.2% for 21 RASSF1A -M ‒ positive patients, compared with 84.9% for 36 RASSF1A -M ‒ negative patients [ P < .001]). RASSF1A -M positivity had the highest prognostic effect among patients with metastatic disease. Patients both negative for RASSF1A -M and the rhabdomyosarcoma-specific RNA panel (28 of 56 patients) had excellent outcome (5-year EFS 92.9%), while double-positive patients (11/56) had poor outcome (5-year EFS 13.6%, P < .001)., Conclusion: Analyzing ctDNA at diagnosis using various techniques is feasible in pediatric rhabdomyosarcoma and has potential for clinical use. Measuring RASSF1A- M in plasma at initial diagnosis correlated significantly with outcome, particularly when combined with paired analysis of blood and bone marrow using a rhabdomyosarcoma-specific RNA panel.
- Published
- 2023
- Full Text
- View/download PDF
19. Molecular Characterization of Circulating Tumor DNA in Pediatric Rhabdomyosarcoma: A Feasibility Study.
- Author
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Ruhen O, Lak NSM, Stutterheim J, Danielli SG, Chicard M, Iddir Y, Saint-Charles A, Di Paolo V, Tombolan L, Gatz SA, Aladowicz E, Proszek P, Jamal S, Stankunaite R, Hughes D, Carter P, Izquierdo E, Wasti A, Chisholm JC, George SL, Pace E, Chesler L, Aerts I, Pierron G, Zaidi S, Delattre O, Surdez D, Kelsey A, Hubank M, Bonvini P, Bisogno G, Di Giannatale A, Schleiermacher G, Schäfer BW, Tytgat GAM, and Shipley J
- Subjects
- Humans, Child, Mice, Animals, Feasibility Studies, Prospective Studies, Biomarkers, Tumor genetics, Mutation, Circulating Tumor DNA genetics, Neoplasms, Rhabdomyosarcoma, Embryonal
- Abstract
Purpose: Rhabdomyosarcomas (RMS) are rare neoplasms affecting children and young adults. Efforts to improve patient survival have been undermined by a lack of suitable disease markers. Plasma circulating tumor DNA (ctDNA) has shown promise as a potential minimally invasive biomarker and monitoring tool in other cancers; however, it remains underexplored in RMS. We aimed to determine the feasibility of identifying and quantifying ctDNA in plasma as a marker of disease burden and/or treatment response using blood samples from RMS mouse models and patients., Methods: We established mouse models of RMS and applied quantitative polymerase chain reaction (PCR) and droplet digital PCR (ddPCR) to detect ctDNA within the mouse plasma. Potential driver mutations, copy-number alterations, and DNA breakpoints associated with PAX3 / 7-FOXO1 gene fusions were identified in the RMS samples collected at diagnosis. Patient-matched plasma samples collected from 28 patients with RMS before, during, and after treatment were analyzed for the presence of ctDNA via ddPCR, panel sequencing, and/or whole-exome sequencing., Results: Human tumor-derived DNA was detectable in plasma samples from mouse models of RMS and correlated with tumor burden. In patients, ctDNA was detected in 14/18 pretreatment plasma samples with ddPCR and 7/7 cases assessed by sequencing. Levels of ctDNA at diagnosis were significantly higher in patients with unfavorable tumor sites, positive nodal status, and metastasis. In patients with serial plasma samples (n = 18), fluctuations in ctDNA levels corresponded to treatment response., Conclusion: Comprehensive ctDNA analysis combining high sensitivity and throughput can identify key molecular drivers in RMS models and patients, suggesting potential as a minimally invasive biomarker. Preclinical assessment of treatments using mouse models and further patient testing through prospective clinical trials are now warranted.
- Published
- 2022
- Full Text
- View/download PDF
20. Extracellular Vesicles: A New Source of Biomarkers in Pediatric Solid Tumors? A Systematic Review.
- Author
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Lak NSM, van der Kooi EJ, Enciso-Martinez A, Lozano-Andrés E, Otto C, Wauben MHM, and Tytgat GAM
- Abstract
Virtually every cell in the body releases extracellular vesicles (EVs), the contents of which can provide a "fingerprint" of their cellular origin. EVs are present in all bodily fluids and can be obtained using minimally invasive techniques. Thus, EVs can provide a promising source of diagnostic, prognostic, and predictive biomarkers, particularly in the context of cancer. Despite advances using EVs as biomarkers in adult cancers, little is known regarding their use in pediatric cancers. In this review, we provide an overview of published clinical and in vitro studies in order to assess the potential of using EV-derived biomarkers in pediatric solid tumors. We performed a systematic literature search, which yielded studies regarding desmoplastic small round cell tumor, hepatoblastoma, neuroblastoma, osteosarcoma, and rhabdomyosarcoma. We then determined the extent to which the in vivo findings are supported by in vitro data, and vice versa. We also critically evaluated the clinical studies using the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) system, and we evaluated the purification and characterization of EVs in both the in vivo and in vitro studies in accordance with MISEV guidelines, yielding EV-TRACK and PedEV scores. We found that several studies identified similar miRNAs in overlapping and distinct tumor entities, indicating the potential for EV-derived biomarkers. However, most studies regarding EV-based biomarkers in pediatric solid tumors lack a standardized system of reporting their EV purification and characterization methods, as well as validation in an independent cohort, which are needed in order to bring EV-based biomarkers to the clinic., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Lak, van der Kooi, Enciso-Martinez, Lozano-Andrés, Otto, Wauben and Tytgat.)
- Published
- 2022
- Full Text
- View/download PDF
21. The feasibility of using liquid biopsies as a complementary assay for copy number aberration profiling in routinely collected paediatric cancer patient samples.
- Author
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Van Paemel R, Vandeputte C, Raman L, Van Thorre J, Willems L, Van Dorpe J, Van Der Linden M, De Wilde J, De Koker A, Menten B, Devalck C, Vicha A, Grega M, Schleiermacher G, Iddir Y, Chicard M, van Zogchel L, Stutterheim J, Lak NSM, Tytgat GAM, Laureys G, Speleman F, De Wilde B, Lammens T, De Preter K, and Van Roy N
- Subjects
- Adolescent, Child, Child, Preschool, Feasibility Studies, Female, Humans, Male, Prospective Studies, Retrospective Studies, Biomarkers, Tumor genetics, Cell-Free Nucleic Acids genetics, DNA Copy Number Variations genetics, Liquid Biopsy methods
- Abstract
Background: Paediatric tumours are often characterised by the presence of recurrent DNA copy number alterations (CNAs). These DNA copy number profiles, obtained from a tissue biopsy, can aid in the correct prognostic classification and therapeutic stratification of several paediatric cancer entities (e.g. MYCN amplification in neuroblastoma) and are part of the routine diagnostic practice. Liquid biopsies (LQBs) offer a potentially safer alternative for such invasive tumour tissue biopsies and can provide deeper insight into tumour heterogeneity., Procedure: The robustness and reliability of LQB CNA analyses was evaluated. We performed retrospective CNA profiling using shallow whole-genome sequencing (sWGS) on paired plasma circulating cell-free DNA (cfDNA) and tissue DNA samples from routinely collected samples from paediatric patients (n = 128) representing different tumour entities, including osteosarcoma, Ewing sarcoma, rhabdomyosarcoma, Wilms tumour, brain tumours and neuroblastoma., Results: Overall, we observed a good concordance between CNAs in tissue DNA and cfDNA. The main cause of CNA discordance was found to be low cfDNA sample quality (i.e. the ratio of cfDNA (<700 bp) and high molecular weight DNA (>700 bp)). Furthermore, CNAs were observed that were present in cfDNA and not in tissue DNA, or vice-versa. In neuroblastoma samples, no false-positives or false-negatives were identified for the detection of the prognostic marker MYCN amplification., Conclusion: In future prospective studies, CNA analysis on LQBs that are of sufficient quality can serve as a complementary assay for CNA analysis on tissue biopsies, as either cfDNA or tissue DNA can contain CNAs that cannot be identified in the other biomaterial., Competing Interests: Conflict of interest statement The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)
- Published
- 2022
- Full Text
- View/download PDF
22. Improving Risk Stratification for Pediatric Patients with Rhabdomyosarcoma by Molecular Detection of Disseminated Disease.
- Author
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Lak NSM, Voormanns TL, Zappeij-Kannegieter L, van Zogchel LMJ, Fiocco M, van Noesel MM, Merks JHM, van der Schoot CE, Tytgat GAM, and Stutterheim J
- Subjects
- Child, Child, Preschool, Female, Humans, Infant, Male, Prospective Studies, Reverse Transcriptase Polymerase Chain Reaction, Rhabdomyosarcoma diagnosis, Rhabdomyosarcoma pathology, Risk Assessment, Rhabdomyosarcoma epidemiology, Rhabdomyosarcoma genetics
- Abstract
Purpose: Survival of children with rhabdomyosarcoma that suffer from recurrent or progressive disease is poor. Identifying these patients upfront remains challenging, indicating a need for improvement of risk stratification. Detection of tumor-derived mRNA in bone marrow (BM) and peripheral blood (PB) using reverse-transcriptase qPCR (RT-qPCR) is a more sensitive method to detect disseminated disease. We identified a panel of genes to optimize risk stratification by RT-qPCR., Experimental Design: Candidate genes were selected using gene expression data from rhabdomyosarcoma and healthy hematologic tissues, and a multiplexed RT-qPCR was developed. Significance of molecular disease was determined in a cohort of 99 Dutch patients with rhabdomyosarcoma (72 localized and 27 metastasized) treated according to the European pediatric Soft tissue sarcoma Study Group (EpSSG) RMS2005 protocol., Results: We identified the following 11 rhabdomyosarcoma markers: ZIC1, ACTC1, MEGF10, PDLIM3, SNAI2, CDH11, TMEM47, MYOD1, MYOG , and PAX3/7-FOXO1 . RT-qPCR was performed for this 11-marker panel on BM and PB samples from the patient cohort. Five-year event-free survival (EFS) was 35.5% [95% confidence interval (CI), 17.5%-53.5%] for the 33/99 RNA-positive patients, versus 88.0% (95% CI, 78.9%-97.2%) for the 66/99 RNA-negative patients ( P < 0.0001). Five-year overall survival (OS) was 54.8% (95% CI, 36.2%-73.4%) and 93.7% (95% CI, 86.6%-100.0%), respectively ( P < 0.0001). RNA panel positivity was negatively associated with EFS (Hazard Ratio = 9.52; 95% CI, 3.23-28.02), whereas the RMS2005 risk group stratification was not, in the multivariate Cox regression model., Conclusions: This study shows a strong association between PCR-based detection of disseminated disease at diagnosis with clinical outcome in pediatric patients with rhabdomyosarcoma, also compared with conventional risk stratification. This warrants further validation in prospective trials as additional technique for risk stratification., (©2021 The Authors; Published by the American Association for Cancer Research.)
- Published
- 2021
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23. Amitriptyline cream ingestion in a 1-year-old boy.
- Author
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Lak NS, Malingre MM, and Hogeman PH
- Subjects
- Arrhythmias, Cardiac chemically induced, Arrhythmias, Cardiac diagnosis, Humans, Infant, Male, Poisoning complications, Poisoning diagnosis, Amitriptyline poisoning, Antidepressive Agents, Tricyclic poisoning
- Abstract
A 1-year-old boy presented to the emergency department with drowsiness after intoxication from amitriptyline cream. The amitriptyline level in his blood was in the high-therapeutic range for adults. He was admitted for cardiac monitoring. Except for a short episode with irregular heart rate, he recovered completely within 24 hours without adjuvant treatment. Amitriptyline is known as an antidepressant but is also prescribed for neuropathic pain. It is usually prescribed in tablet form; the cream is a novel application. In children, intoxication with amitriptyline may cause drowsiness, seizures, coma, hypotension, tachycardia, and life-threatening cardiac arrhythmias. This is the first case report presenting intoxication in a child with amitriptyline cream. It stresses the importance of keeping children away from the medicine cabinet, even from creams or ointments.
- Published
- 2012
- Full Text
- View/download PDF
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