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  • 1.
    Bolin, Sara
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Borgenvik, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Savov, Vasil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Holmberg Olausson, Karl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Zhao, Miao
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Rosén, Gabriela
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Hutter, Sonja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Garancher, Alexandra
    umor Initiation & Maintenance Program, Sanford Burnham Prebys Medical Dis-covery Institute, La Jolla, USA..
    Rahmanto, Aldwin Suryo
    Departmentof Cell and Molecular Biology, Karolinska Institutet, Stockholm, Swe-den.
    Bergström, Tobias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Mainwaring, Oliver
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Sattanino, Damiana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Verbaan, Annemieke
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Rusert, Jessica
    Tumor Initiation & Maintenance Program, Sanford Burnham Prebys Medical Dis-covery Institute, La Jolla, USA.
    Sundström, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Dang, Yonglong
    Uppsala University, Science for Life Laboratory, SciLifeLab.
    Wenz, Amelie
    Uppsala University, Science for Life Laboratory, SciLifeLab.
    Richardson, Stacey
    Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK. .
    Fotaki, Grammatiki
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Giraud, Geraldine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Hill, Rebecca M
    Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK. .
    Dubuc, Adrian M
    The Arthur and Sonia Labatt Brain Tumor Research Centre, The Hospital for Sick Children, Toronto, Ontario, M5G 1X8, Canada. .
    Kalushkova, Antonia
    Uppsala University, Science for Life Laboratory, SciLifeLab.
    Remke, Marc
    The Arthur and Sonia Labatt Brain Tumor Research Centre, The Hospital for Sick Children, Toronto, Ontario, M5G 1X8, Canada. .
    Čančer, Matko
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Jernberg Wiklund, Helena
    Uppsala University, Science for Life Laboratory, SciLifeLab.
    Chen, Xingqi
    Uppsala University, Science for Life Laboratory, SciLifeLab.
    Taylor, Michael D
    The Arthur and Sonia Labatt Brain Tumor Research Centre, The Hospital for Sick Children, Toronto, Ontario, M5G 1X8, Canada.
    Sangfelt, Olle
    Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Swe-den. .
    Clifford, Steven C
    Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK. .
    Schüller, Ulrich
    Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Ham-burg, Germany. Department of Paediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. Research Institute Children’s Cancer Center Hamburg, Hamburg, Germany. .
    Wechsler-Reya, Robert J
    Tumor Initiation & Maintenance Program, Sanford Burnham Prebys Medical Dis-covery Institute, La Jolla, USA..
    Weishaupt, Holger
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Swartling, Fredrik J.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Dormant SOX9-positive cells behind MYC-driven medulloblastoma recurrenceIn: Article in journal (Refereed)
    Abstract [en]

    Tumor recurrence is a slow biological process involving therapy resistance, immune escape, and metastasis and is the leading cause of death in medulloblastoma, the most frequent malignant pediatric brain tumor. By studying paired primary-recurrent patient samples and patient-derived xenografts we identified a significant accumulation of SOX9-positive cells in relapses and metastases. They exist as rare, quiescent cells in Group 3 and Group 4 patients that constitute two-thirds of medulloblastoma. To follow relapse at the single-cell level we developed an inducible dual Tet model of MYC-driven MB, where MYC can be directed from treatment-sensitive bulk cells to resistant, dormant SOX9-positive cells by doxycycline. SOX9 promoted immune es-cape, DNA repair suppression and was essential for recurrence. Tumor cell dormancy was non-hierarchical, migratory, and depended on MYC suppression by SOX9 to promote relapse. By using computational modeling and treatment we further showed how doxorubicin and MGMT inhibitors are specifically targeting relapsing cells.

  • 2.
    Borgenvik, Anna
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neurooncology and neurodegeneration.
    Holmberg, Karl O.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Bolin, Sara
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Zhao, Miao
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neurooncology and neurodegeneration. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Savov, Vasil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Rosén, Gabriela
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neurooncology and neurodegeneration.
    Hutter, Sonja
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neurooncology and neurodegeneration.
    Garancher, Alexandra
    Sanford Burnham Prebys Med Discovery Inst, Tumor Initiat & Maintenance Program, San Diego, CA USA..
    Rahmanto, Aldwin Suryo
    Karolinska Inst, Dept Cell & Mol Biol, Stockholm, Sweden..
    Bergström, Tobias
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neurooncology and neurodegeneration.
    Olsen, Thale Kristin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neurooncology and neurodegeneration. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Mainwaring, Oliver
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neurooncology and neurodegeneration.
    Sattanino, Damiana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Verbaan, Annemieke D.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Rusert, Jessica M.
    Sanford Burnham Prebys Med Discovery Inst, Tumor Initiat & Maintenance Program, San Diego, CA USA..
    Sundström, Anders
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neurooncology and neurodegeneration.
    Ballester Bravo, Mar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neurooncology and neurodegeneration. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Dang, Yonglong
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Wenz, Amelie S.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Richardson, Stacey
    Newcastle Univ Ctr Canc, Wolfson Childhood Canc Res Ctr, Translat & Clin Res Inst, Newcastle Upon Tyne, Tyne & Wear, England..
    Fotaki, Grammatiki
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Hill, Rebecca M.
    Newcastle Univ Ctr Canc, Wolfson Childhood Canc Res Ctr, Translat & Clin Res Inst, Newcastle Upon Tyne, Tyne & Wear, England..
    Dubuc, Adrian M.
    Hosp Sick Children, Arthur & Sonia Labatt Brain Tumor Res Ctr, Toronto, ON, Canada..
    Kalushkova, Antonia
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer precision medicine.
    Remke, Marc
    Hosp Sick Children, Arthur & Sonia Labatt Brain Tumor Res Ctr, Toronto, ON, Canada..
    Čančer, Matko
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Jernberg Wiklund, Helena
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer precision medicine.
    Giraud, Geraldine
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neurooncology and neurodegeneration.
    Chen, Xingqi
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular Tools and Functional Genomics.
    Taylor, Michael D.
    Hosp Sick Children, Arthur & Sonia Labatt Brain Tumor Res Ctr, Toronto, ON, Canada..
    Sangfelt, Olle
    Karolinska Inst, Dept Cell & Mol Biol, Stockholm, Sweden..
    Clifford, Steven C.
    Newcastle Univ Ctr Canc, Wolfson Childhood Canc Res Ctr, Translat & Clin Res Inst, Newcastle Upon Tyne, Tyne & Wear, England..
    Schueller, Ulrich
    Univ Med Ctr Hamburg Eppendorf, Inst Neuropathol, Hamburg, Germany.;Univ Med Ctr Hamburg Eppendorf, Dept Paediat Hematol & Oncol, Hamburg, Germany.;Res Inst Childrens Canc Ctr Hamburg, Hamburg, Germany..
    Wechsler-Reya, Robert J.
    Sanford Burnham Prebys Med Discovery Inst, Tumor Initiat & Maintenance Program, San Diego, CA USA..
    Weishaupt, Holger
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neurooncology and neurodegeneration.
    Swartling, Fredrik J.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neurooncology and neurodegeneration.
    Dormant SOX9-Positive Cells Facilitate MYC-Driven Recurrence of Medulloblastoma2022In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 82, no 24, p. 4586-4603Article in journal (Refereed)
    Abstract [en]

    Relapse is the leading cause of death in patients with medulloblas-toma, the most common malignant pediatric brain tumor. A better understanding of the mechanisms underlying recurrence could lead to more effective therapies for targeting tumor relapses. Here, we observed that SOX9, a transcription factor and stem cell/glial fate marker, is limited to rare, quiescent cells in high-risk medulloblastoma with MYC amplification. In paired primary-recurrent patient samples, SOX9-positive cells accumulated in medulloblastoma relapses. SOX9 expression anti-correlated with MYC expression in murine and human medulloblastoma cells. However, SOX9-positive cells were plastic and could give rise to a MYC high state. To follow relapse at the single-cell level, an inducible dual Tet model of medulloblastoma was developed, in which MYC expression was redirected in vivo from treatment-sensitive bulk cells to dormant SOX9-positive cells using doxycycline treatment. SOX9 was essential for relapse initiation and depended on suppression of MYC activity to promote therapy resistance, epithelial-mesenchymal transition, and immune escape. p53 and DNA repair pathways were downregulated in recurrent tumors, whereas MGMT was upregulated. Recurrent tumor cells were found to be sensitive to treatment with an MGMT inhibitor and doxorubicin. These findings suggest that recurrence-specific targeting coupled with DNA repair inhibition comprises a potential therapeutic strategy in patients affected by medulloblastoma relapse.Significance: SOX9 facilitates therapy escape and recurrence in medulloblastoma via temporal inhibition of MYC/MYCN genes, revealing a strategy to specifically target SOX9-positive cells to prevent tumor relapse.

    Download full text (pdf)
    fulltext
  • 3.
    Hoffman, Lindsey M.
    et al.
    Childrens Hosp Colorado, Aurora, CO USA;Univ Colorado Denver, Aurora, CO USA.
    van Zanten, Sophie E. M. Veldhuijzen
    Vrije Univ, Univ Med Ctr, Amsterdam, Netherlands.
    Colditz, Niclas
    Univ Med Ctr Goettingen, Goettingen, Netherlands.
    Baugh, Joshua
    Cincinnati Childrens Hosp Med Ctr, 3333 Burnet Ave, Cincinnati, OH 45229 USA.
    Chaney, Brooklyn
    Cincinnati Childrens Hosp Med Ctr, 3333 Burnet Ave, Cincinnati, OH 45229 USA.
    Hoffmann, Marion
    Univ Med Ctr Goettingen, Goettingen, Netherlands.
    Lane, Adam
    Cincinnati Childrens Hosp Med Ctr, 3333 Burnet Ave, Cincinnati, OH 45229 USA.
    Fuller, Christine
    Cincinnati Childrens Hosp Med Ctr, 3333 Burnet Ave, Cincinnati, OH 45229 USA.
    Miles, Lili
    Nemours Childrens Hosp, Orlando, FL USA.
    Hawkins, Cynthia
    Hosp Sick Children, Toronto, ON, Canada.
    Bartels, Ute
    Hosp Sick Children, Toronto, ON, Canada.
    Bouffet, Eric
    Hosp Sick Children, Toronto, ON, Canada.
    Goldman, Stewart
    Ann & Robert H Lurie Childrens Hosp Chicago, Chicago, IL 60611 USA.
    Leary, Sarah
    Fred Hutchinson Canc Res Ctr, 1124 Columbia St, Seattle, WA 98104 USA;Univ Washington, Seattle Childrens Hosp, Seattle, WA 98195 USA.
    Foreman, Nicholas K.
    Childrens Hosp Colorado, Aurora, CO USA;Univ Colorado Denver, Aurora, CO USA.
    Packer, Roger
    Childrens Natl Hlth Syst, Washington, DC USA.
    Warren, Katherine E.
    NCI, Bethesda, MD 20892 USA.
    Broniscer, Alberto
    St Jude Childrens Res Hosp, 332 N Lauderdale St, Memphis, TN 38105 USA.
    Kieran, Mark W.
    Dana Farber Boston Childrens Canc & Blood Disorde, Boston, MA USA.
    Minturn, Jane
    Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA;Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA.
    Comito, Melanie
    Penn State Univ, Hershey, PA USA.
    Broxson, Emmett
    Wright State Univ, Dayton, OH 45435 USA;Childrens Med Ctr, Dayton, OH USA.
    Shih, Chie-Schin
    Indiana Univ, Indianapolis, IN 46204 USA.
    Khatua, Soumen
    Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA.
    Chintagumpala, Murali
    Baylor Coll Med, Texas Childrens Canc Ctr, Houston, TX 77030 USA;Baylor Coll Med, Hematol Ctr, Houston, TX 77030 USA.
    Carret, Anne Sophie
    Ctr Hosp Univ St Justine, Montreal, PQ, Canada.
    Escorza, Nancy Yanez
    Cincinnati Childrens Hosp Med Ctr, 3333 Burnet Ave, Cincinnati, OH 45229 USA.
    Hassall, Timothy
    Lady Cilento Childrens Hosp, Brisbane, Qld, Australia.
    Ziegler, David S.
    Sydney Childrens Hosp, Kids Canc Ctr, Randwick, NSW, Australia;Univ New South Wales, Sydney, NSW, Australia.
    Gottardo, Nicholas
    Princess Margaret Hosp Children, Perth, WA, Australia.
    Dholaria, Hetal
    Princess Margaret Hosp Children, Perth, WA, Australia.
    Doughman, Renee
    Cincinnati Childrens Hosp Med Ctr, 3333 Burnet Ave, Cincinnati, OH 45229 USA.
    Benesch, Martin
    Med Univ Graz, Graz, Austria.
    Drissi, Rachid
    Cincinnati Childrens Hosp Med Ctr, 3333 Burnet Ave, Cincinnati, OH 45229 USA.
    Nazarian, Javad
    Childrens Natl Med Ctr, Washington, DC 20010 USA.
    Jabado, Nada
    McGill Univ, Montreal, PQ, Canada.
    Boddaert, Nathalie
    Hop Necker Enfants Malad, Paris, France.
    Varlet, Pascale
    Univ Paris V Descartes, Sorbonne Paris Cite, Hop St Anne, Paris, France.
    Giraud, Geraldine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Univ Paris Saclay, Univ Paris Sud, Gustave Roussy, Villejuif, France.
    Castel, David
    Univ Paris Saclay, Univ Paris Sud, Gustave Roussy, Villejuif, France.
    Puget, Stephanie
    Hop Necker Enfants Malad, Paris, France.
    Jones, Chris
    Inst Canc Res, Sutton, Surrey, England.
    Hulleman, Esther
    Vrije Univ, Univ Med Ctr, Amsterdam, Netherlands.
    Modena, Piergiorgio
    St Anna Como Gen Hosp, Como, Italy.
    Giagnacovo, Marzia
    St Anna Como Gen Hosp, Como, Italy.
    Antonelli, Manila
    Sapienza Univ Rome, Rome, Italy.
    Pietsch, Torsten
    Univ Bonn, Med Ctr, Bonn, Germany.
    Gielen, Gerrit H.
    Univ Bonn, Med Ctr, Bonn, Germany.
    Jones, David T. W.
    German Consortium Translat Canc Res, Heidelberg, Germany;Natl Centrum Tumorerkrankungen Heidelberg, Hopp Childrens Canc Ctr, German Canc Res Ctr, Heidelberg, Germany.
    Sturm, Dominik
    German Consortium Translat Canc Res, Heidelberg, Germany;Natl Centrum Tumorerkrankungen Heidelberg, Hopp Childrens Canc Ctr, German Canc Res Ctr, Heidelberg, Germany;Heidelberg Univ Hosp, Heidelberg, Germany.
    Pfister, Stefan M.
    German Consortium Translat Canc Res, Heidelberg, Germany;Natl Centrum Tumorerkrankungen Heidelberg, Hopp Childrens Canc Ctr, German Canc Res Ctr, Heidelberg, Germany;Heidelberg Univ Hosp, Heidelberg, Germany.
    Gerber, Nicolas U.
    Univ Childrens Hosp Zurich, Zurich, Switzerland.
    Grotzer, Michael A.
    Univ Childrens Hosp Zurich, Zurich, Switzerland.
    Pfaff, Elke
    German Consortium Translat Canc Res, Heidelberg, Germany;Natl Centrum Tumorerkrankungen Heidelberg, Hopp Childrens Canc Ctr, German Canc Res Ctr, Heidelberg, Germany;Heidelberg Univ Hosp, Heidelberg, Germany.
    von Bueren, Andre O.
    Univ Geneva, Geneva, Switzerland;Univ Hosp Geneva, Geneva, Switzerland.
    Hargrave, Darren
    Great Ormond St Hosp Sick Children, London, England.
    Solanki, Guirish A.
    Birmingham Womens & Childrens Hosp, Birmingham, W Midlands, England.
    Cvrlje, Filip Jadrijevic
    Childrens Hosp Zagreb, Zagreb, Croatia.
    Kaspers, Gertjan J. L.
    Vrije Univ, Univ Med Ctr, Amsterdam, Netherlands;Childrens Hosp Zagreb, Zagreb, Croatia.
    Vandertop, William P.
    Acad Princess Maxima Ctr Pediat Oncol, Utrecht, Netherlands.
    Grill, Jacques
    Univ Paris Saclay, Univ Paris Sud, Gustave Roussy, Villejuif, France.
    Bailey, Simon
    Royal Victoria Infirm, Great North Childrens Hosp, Victoria Wing, Newcastle Upon Tyne, Tyne & Wear, England.
    Biassoni, Veronica
    Ist Nazl Tumori, Fdn Ist Ricovero & Cura Carattere Sci, Milan, Italy.
    Massimino, Maura
    Ist Nazl Tumori, Fdn Ist Ricovero & Cura Carattere Sci, Milan, Italy.
    Calmon, Raphael
    Hop Necker Enfants Malad, Paris, France.
    Sanchez, Esther
    Vrije Univ, Univ Med Ctr, Amsterdam, Netherlands.
    Bison, Brigitte
    Univ Med Ctr Goettingen, Goettingen, Netherlands.
    Warmuth-Metz, Monika
    Univ Med Ctr Goettingen, Goettingen, Netherlands.
    Leach, James
    Cincinnati Childrens Hosp Med Ctr, 3333 Burnet Ave, Cincinnati, OH 45229 USA.
    Jones, Blaise
    Cincinnati Childrens Hosp Med Ctr, 3333 Burnet Ave, Cincinnati, OH 45229 USA.
    van Vuurden, Dannis G.
    Vrije Univ, Univ Med Ctr, Amsterdam, Netherlands.
    Kramm, Christof M.
    Univ Med Ctr Goettingen, Goettingen, Netherlands.
    Fouladi, Maryam
    Cincinnati Childrens Hosp Med Ctr, 3333 Burnet Ave, Cincinnati, OH 45229 USA.
    Clinical, Radiologic, Pathologic, and Molecular Characteristics of Long-Term Survivors of Diffuse Intrinsic Pontine Glioma (DIPG): A Collaborative Report From the International and European Society for Pediatric Oncology DIPG Registries2018In: Journal of Clinical Oncology, ISSN 0732-183X, E-ISSN 1527-7755, Vol. 36, no 19, p. 1963-1972Article in journal (Refereed)
    Abstract [en]

    Purpose

    Diffuse intrinsic pontine glioma (DIPG) is a brainstem malignancy with a median survival of < 1 year. The International and European Society for Pediatric Oncology DIPG Registries collaborated to compare clinical, radiologic, and histomolecular characteristics between short-term survivors (STSs) and long-term survivors (LTSs).

    Materials and Methods

    Data abstracted from registry databases included patients from North America, Australia, Germany, Austria, Switzerland, the Netherlands, Italy, France, the United Kingdom, and Croatia.

    Results

    Among 1,130 pediatric and young adults with radiographically confirmed DIPG, 122 (11%) were excluded. Of the 1,008 remaining patients, 101 (10%) were LTSs (survival 2 years). Median survival time was 11 months (interquartile range, 7.5 to 16 months), and 1-, 2-, 3-, 4-, and 5-year survival rates were 42.3% (95% CI, 38.1% to 44.1%), 9.6% (95% CI, 7.8% to 11.3%), 4.3% (95% CI, 3.2% to 5.8%), 3.2% (95% CI, 2.4% to 4.6%), and 2.2% (95% CI, 1.4% to 3.4%), respectively. LTSs, compared with STSs, more commonly presented at age < 3 or > 10 years (11% v 3% and 33% v 23%, respectively; P < .001) and with longer symptom duration (P < .001). STSs, compared with LTSs, more commonly presented with cranial nerve palsy (83% v 73%, respectively; P = .008), ring enhancement (38% v 23%, respectively; P = .007), necrosis (42% v 26%, respectively; P = .009), and extrapontine extension (92% v 86%, respectively; P = .04). LTSs more commonly received systemic therapy at diagnosis (88% v 75% for STSs; P = .005). Biopsies and autopsies were performed in 299 patients (30%) and 77 patients (10%), respectively; 181 tumors (48%) were molecularly characterized. LTSs were more likely to harbor a HIST1H3B mutation (odds ratio, 1.28; 95% CI, 1.1 to 1.5; P = .002).

    Conclusion

    We report clinical, radiologic, and molecular factors that correlate with survival in children and young adults with DIPG, which are important for risk stratification in future clinical trials.

  • 4.
    Holmberg Olausson, Karl O.
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neurooncology and neurodegeneration.
    Borgenvik, Anna
    Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02215 USA.;Harvard Med Sch, Boston, MA 02115 USA.;Broad Inst MIT & Harvard, Cambridge, MA 02142 USA..
    Zhao, Miao
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neurooncology and neurodegeneration. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Giraud, Géraldine
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neurooncology and neurodegeneration. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatric oncology research with a special focus on side effects. Uppsala Univ, Dept Pediat Hematol & Oncol, Childrens Hosp, S-75185 Uppsala, Sweden..
    Swartling, Fredrik J.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neurooncology and neurodegeneration.
    Drivers Underlying Metastasis and Relapse in Medulloblastoma and Targeting Strategies2024In: Cancers, ISSN 2072-6694, Vol. 16, no 9, article id 1752Article, review/survey (Refereed)
    Abstract [en]

    Simple Summary In this review, we summarize reported molecular mechanisms underlying tumor progression and relapse of medulloblastoma, one of the most frequent malignant pediatric brain tumor entities. Medulloblastoma relapses are difficult to treat, and patients have, overall, a poor prognosis. Apart from describing the biology promoting brain tumor spread, the review will also highlight important preclinical models used to study leptomeningeal disease and recurrence. Finally, we identified clinical trials for medulloblastoma relapse and will discuss novel attempts to target therapy-escaping cancer cells responsible for recurrence.Abstract Medulloblastomas comprise a molecularly diverse set of malignant pediatric brain tumors in which patients are stratified according to different prognostic risk groups that span from very good to very poor. Metastasis at diagnosis is most often a marker of poor prognosis and the relapse incidence is higher in these children. Medulloblastoma relapse is almost always fatal and recurring cells have, apart from resistance to standard of care, acquired genetic and epigenetic changes that correlate with an increased dormancy state, cell state reprogramming and immune escape. Here, we review means to carefully study metastasis and relapse in preclinical models, in light of recently described molecular subgroups. We will exemplify how therapy resistance develops at the cellular level, in a specific niche or from therapy-induced secondary mutations. We further describe underlying molecular mechanisms on how tumors acquire the ability to promote leptomeningeal dissemination and discuss how they can establish therapy-resistant cell clones. Finally, we describe some of the ongoing clinical trials of high-risk medulloblastoma and suggest or discuss more individualized treatments that could be of benefit to specific subgroups.

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  • 5.
    Jadersten, Martin
    et al.
    Karolinska Univ Hosp, Dept Hematol, M64, SE-11186 Stockholm, Sweden.;Karolinska Inst, Ctr Hematol & Regenerat Med, Dept Med, Stockholm, Sweden..
    Lilienthal, Ingrid
    Karolinska Inst, Dept Womens & Childrens Hlth, Childhood Canc Res Unit, Tomtebodavagen 18a, SE-17176 Stockholm, Sweden..
    Tsesmetzis, Nikolaos
    Karolinska Inst, Dept Womens & Childrens Hlth, Childhood Canc Res Unit, Tomtebodavagen 18a, SE-17176 Stockholm, Sweden..
    Lourda, Magda
    Karolinska Inst, Dept Womens & Childrens Hlth, Childhood Canc Res Unit, Tomtebodavagen 18a, SE-17176 Stockholm, Sweden.;Karolinska Univ Hosp, Ctr Infect Med, Karolinska Inst, Dept Med Huddinge, Stockholm, Sweden..
    Bengtzen, Sofia
    Karolinska Inst, Ctr Hematol & Regenerat Med, Dept Med, Stockholm, Sweden..
    Bohlin, Anna
    Karolinska Inst, Ctr Hematol & Regenerat Med, Dept Med, Stockholm, Sweden..
    Arnroth, Cornelia
    Karolinska Inst, Dept Oncol Pathol, Sci Life Lab, Stockholm, Sweden..
    Erkers, Tom
    Karolinska Inst, Dept Oncol Pathol, Sci Life Lab, Stockholm, Sweden..
    Seashore-Ludlow, Brinton
    Karolinska Inst, Dept Oncol Pathol, Sci Life Lab, Stockholm, Sweden..
    Giraud, Geraldine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala Univ Hosp, Akad Childrens Hosp, Dept Pediat Oncol, Uppsala, Sweden..
    Barkhordar, Giti S.
    Sahlgrens Univ Hosp, Dept Clin Genet & Genom, Gothenburg, Sweden..
    Tao, Sijia
    Emory Univ, Sch Med, Dept Pediat, Atlanta, GA USA..
    Fogelstrand, Linda
    Sahlgrens Univ Hosp, Dept Clin Chem, Gothenburg, Sweden.;Univ Gothenburg, Inst Biomed, Dept Lab Med, Sahlgrenska Acad, Gothenburg, Sweden..
    Saft, Leonie
    Karolinska Inst, Dept Oncol & Pathol, Stockholm, Sweden.;Karolinska Univ Hosp, Dept Clin Pathol & Canc Diagnost, Stockholm, Sweden..
    Ostling, Paivi
    Karolinska Inst, Dept Oncol Pathol, Sci Life Lab, Stockholm, Sweden..
    Schinazi, Raymond F.
    Emory Univ, Sch Med, Dept Pediat, Atlanta, GA USA..
    Kim, Baek
    Emory Univ, Sch Med, Dept Pediat, Atlanta, GA USA..
    Schaller, Torsten
    Univ Hosp Heidelberg, Dept Infect Dis, Heidelberg, Germany.;Heidelberg ImmunoTherapeut GmbH, Max Jarecki Str 21, D-69115 Heidelberg, Germany..
    Juliusson, Gunnar
    Skane Univ Hosp, Dept Hematol, Lund, Sweden.;Lund Univ, Stem Cell Ctr, Dept Hematol, Dept Lab Med, Lund, Sweden..
    Deneberg, Stefan
    Karolinska Univ Hosp, Dept Hematol, M64, SE-11186 Stockholm, Sweden.;Karolinska Inst, Ctr Hematol & Regenerat Med, Dept Med, Stockholm, Sweden..
    Lehmann, Sören
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology. Karolinska Inst, Ctr Hematol & Regenerat Med, Dept Med, Stockholm, Sweden..
    Rassidakis, Georgios Z.
    Karolinska Inst, Dept Oncol & Pathol, Stockholm, Sweden.;Karolinska Univ Hosp, Dept Clin Pathol & Canc Diagnost, Stockholm, Sweden..
    Höglund, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Henter, Jan-Inge
    Karolinska Inst, Dept Womens & Childrens Hlth, Childhood Canc Res Unit, Tomtebodavagen 18a, SE-17176 Stockholm, Sweden.;Karolinska Univ Hosp, Astrid Lindgren Childrens Hosp, Dept Paediat Oncol, Stockholm, Sweden..
    Herold, Nikolas
    Karolinska Inst, Dept Womens & Childrens Hlth, Childhood Canc Res Unit, Tomtebodavagen 18a, SE-17176 Stockholm, Sweden.;Karolinska Univ Hosp, Astrid Lindgren Childrens Hosp, Dept Paediat Oncol, Stockholm, Sweden..
    Targeting SAMHD1 with hydroxyurea in first-line cytarabine-based therapy of newly diagnosed acute myeloid leukaemia: Results from the HEAT-AML trial2022In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 292, no 6, p. 925-940Article in journal (Refereed)
    Abstract [en]

    Background Treatment of newly diagnosed acute myeloid leukaemia (AML) is based on combination chemotherapy with cytarabine (ara-C) and anthracyclines. Five-year overall survival is below 30%, which has partly been attributed to cytarabine resistance. Preclinical data suggest that the addition of hydroxyurea potentiates cytarabine efficacy by increasing ara-C triphosphate (ara-CTP) levels through targeted inhibition of SAMHD1. Objectives In this phase 1 trial, we evaluated the feasibility, safety and efficacy of the addition of hydroxyurea to standard chemotherapy with cytarabine/daunorubicin in newly diagnosed AML patients. Methods Nine patients were enrolled and received at least two courses of ara-C (1 g/m(2)/2 h b.i.d. d1-5, i.e., a total of 10 g/m(2) per course), hydroxyurea (1-2 g d1-5) and daunorubicin (60 mg/m(2) d1-3). The primary endpoint was safety; secondary endpoints were complete remission rate and measurable residual disease (MRD). Additionally, pharmacokinetic studies of ara-CTP and ex vivo drug sensitivity assays were performed. Results The most common grade 3-4 toxicity was febrile neutropenia (100%). No unexpected toxicities were observed. Pharmacokinetic analyses showed a significant increase in median ara-CTP levels (1.5-fold; p = 0.04) in patients receiving doses of 1 g hydroxyurea. Ex vivo, diagnostic leukaemic bone marrow blasts from study patients were significantly sensitised to ara-C by a median factor of 2.1 (p = 0.0047). All nine patients (100%) achieved complete remission, and all eight (100%) with validated MRD measurements (flow cytometry or real-time quantitative polymerase chain reaction [RT-qPCR]) had an MRD level <0.1% after two cycles of chemotherapy. Treatment was well-tolerated, and median time to neutrophil recovery >1.0 x 10(9)/L and to platelet recovery >50 x 10(9)/L after the start of cycle 1 was 19 days and 22 days, respectively. Six of nine patients underwent allogeneic haematopoietic stem-cell transplantation (allo-HSCT). With a median follow-up of 18.0 (range 14.9-20.5) months, one patient with adverse risk not fit for HSCT experienced a relapse after 11.9 months but is now in second complete remission. Conclusion Targeted inhibition of SAMHD1 by the addition of hydroxyurea to conventional AML therapy is safe and appears efficacious within the limitations of the small phase 1 patient cohort. These results need to be corroborated in a larger study.

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  • 6.
    Krynina, Olha
    et al.
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden..
    Díaz de Ståhl, Teresita
    Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden..
    Jylhä, Cecilia
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden.;Karolinska Univ Hosp, Clin Genet & Genom, Stockholm, Sweden..
    Arthur, Cecilia
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden.;Karolinska Univ Hosp, Clin Genet & Genom, Stockholm, Sweden..
    Giraud, Geraldine
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neurooncology and neurodegeneration. Akademiska University Hospital, Uppsala, Sweden.
    Nyman, Per
    Linköping Univ Hosp, Crown Princess Victor Childrens Hosp, Dept Hlth, Linköping, Sweden.;Linköping Univ, Dept Med & Caring Sci, Linköping, Sweden.;Linköping Univ, Ctr Med Image Sci & Visualizat CMIV, Linköping, Sweden..
    Fritzberg, Anders
    Clin Pediat Falun Hosp, Daycare Unit Oncol & Hematol, Dalarna, Dalarna Region, Sweden..
    Sandgren, Johanna
    Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden.;Karolinska Univ Hosp, Clin Pathol & Canc Diagnost, Stockholm, Sweden..
    Tham, Emma
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden.;Karolinska Univ Hosp, Clin Genet & Genom, Stockholm, Sweden..
    Sandvik, Ulrika
    Karolinska Inst, Dept Clin Neurosci, Div Neurosurg, Stockholm, Sweden..
    The potential of liquid biopsy for detection of the KIAA1549-BRAF fusion in circulating tumor DNA from children with pilocytic astrocytoma2024In: Neuro-Oncology Advances, E-ISSN 2632-2498, Vol. 6, no 1, article id vdae008Article in journal (Refereed)
    Abstract [en]

    Background

    Low-grade gliomas (LGGs) represent children’s most prevalent central nervous system tumor, necessitating molecular profiling to diagnose and determine the most suitable treatment. Developing highly sensitive screening techniques for liquid biopsy samples is particularly beneficial, as it enables the early detection and molecular characterization of tumors with minimally invasive samples.

    Methods

    We examined CSF and plasma samples from patients with pilocytic astrocytoma (PA) using custom multiplexed droplet digital polymerase chain reaction (ddPCR) assays based on whole genome sequencing data. These assays included a screening test to analyze BRAF duplication and a targeted assay for the detection of patient-specific KIAA1549::BRAF fusion junction sequences or single nucleotide variants.

    Results

    Our findings revealed that 5 out of 13 individual cerebrospinal fluid (CSF) samples tested positive for circulating tumor DNA (ctDNA). Among these cases, 3 exhibited the KIAA1549::BRAF fusion, which was detected through copy number variation (CNV) analysis (n = 1) or a fusion-specific probe (n = 2), while 1 case each displayed the BRAF V600E mutation and the FGFR1 N577K mutation. Additionally, a quantitative analysis of cell-free DNA (cfDNA) concentrations in PA CSF samples showed that most cases had low cfDNA levels, below the limit of detection of our assay (<1.9 ng).

    Conclusions

    While CNV analysis of CSF samples from LGGs still has some limitations, it has the potential to serve as a valuable complementary tool. Furthermore, it can also be multiplexed with other aberrations, for example, to the BRAF V600 test, to provide important insights into the molecular characteristics of LGGs.

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  • 7.
    Lobon-Iglesias, M. J.
    et al.
    Gustave Roussy, Dept Pediat & Adolescent Oncol, Villejuif, France.;Univ Paris Saclay, Villejuif, France.;CNRS, Unite Mixte Rech 8203, Team Target Identificat & Innovat Anticanc Therap, Villejuif, France..
    Giraud, Geraldine
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Gustave Roussy, Dept Pediat & Adolescent Oncol, Villejuif, France.;Univ Paris Saclay, Villejuif, France.
    Castel, D.
    Gustave Roussy, Dept Pediat & Adolescent Oncol, Villejuif, France.;Univ Paris Saclay, Villejuif, France.;CNRS, Unite Mixte Rech 8203, Team Target Identificat & Innovat Anticanc Therap, Villejuif, France..
    Philippe, C.
    Univ Paris Saclay, Villejuif, France.;CNRS, Unite Mixte Rech 8203, Team Target Identificat & Innovat Anticanc Therap, Villejuif, France..
    Debily, M. A.
    Univ Paris Saclay, Villejuif, France.;CNRS, Unite Mixte Rech 8203, Team Target Identificat & Innovat Anticanc Therap, Villejuif, France.;Univ Evry Val dEssone, Evry, France..
    Briandet, C.
    Univ Hosp Dijon, Dept Pediat, Dijon, France..
    Fouyssac, F.
    Univ Hosp Nancy Brabois, Dept Pediat Oncol, Nancy, France..
    de Carli, E.
    Univ Hosp Angers, Dept Pediat Oncol, Angers, France..
    Dufour, C.
    Gustave Roussy, Dept Pediat & Adolescent Oncol, Villejuif, France.;Univ Paris Saclay, Villejuif, France.;CNRS, Unite Mixte Rech 8203, Team Target Identificat & Innovat Anticanc Therap, Villejuif, France..
    Valteau-Couanet, D.
    Gustave Roussy, Dept Pediat & Adolescent Oncol, Villejuif, France.;Univ Paris Saclay, Villejuif, France..
    Sainte-Rose, C.
    Necker Sick Childrens Univ Hosp, Dept Neurosurg, Paris, France.;Paris Descartes Univ, Paris, France..
    Blauwblomme, T.
    Necker Sick Childrens Univ Hosp, Dept Neurosurg, Paris, France.;Paris Descartes Univ, Paris, France..
    Beccaria, K.
    Univ Paris Saclay, Villejuif, France.;CNRS, Unite Mixte Rech 8203, Team Target Identificat & Innovat Anticanc Therap, Villejuif, France.;Necker Sick Childrens Univ Hosp, Dept Neurosurg, Paris, France.;Paris Descartes Univ, Paris, France..
    Zerah, M.
    Necker Sick Childrens Univ Hosp, Dept Neurosurg, Paris, France.;Paris Descartes Univ, Paris, France..
    Puget, S.
    Necker Sick Childrens Univ Hosp, Dept Neurosurg, Paris, France.;Paris Descartes Univ, Paris, France..
    Calmon, R.
    Paris Descartes Univ, Paris, France.;Necker Sick Childrens Univ Hosp, Dept Radiol, Paris, France.;Imagine Inst, Paris, France.;INSERM, U1163, Paris, France..
    Boddaert, N.
    Paris Descartes Univ, Paris, France.;Necker Sick Childrens Univ Hosp, Dept Radiol, Paris, France.;Imagine Inst, Paris, France.;INSERM, U1163, Paris, France..
    Bolle, S.
    Gustave Roussy, Dept Radiotherapy, Villejuif, France..
    Varlet, P.
    Paris Descartes Univ, Paris, France.;St Anne Hosp, Dept Neuropathol, Paris, France..
    Grill, J.
    Gustave Roussy, Dept Pediat & Adolescent Oncol, Villejuif, France.;Univ Paris Saclay, Villejuif, France.;CNRS, Unite Mixte Rech 8203, Team Target Identificat & Innovat Anticanc Therap, Villejuif, France..
    Diffuse intrinsic pontine gliomas (DIPG) at recurrence: is there a window to test new therapies in some patients?2018In: Journal of Neuro-Oncology, ISSN 0167-594X, E-ISSN 1573-7373, Vol. 137, no 1, p. 111-118Article in journal (Refereed)
    Abstract [en]

    Children with diffuse intrinsic pontine glioma (DIPG) need new and more efficient treatments. They can be developed at relapse or at diagnosis, but therefore they must be combined with radiotherapy. Survival of children after recurrence and its predictors were studied to inform the possibility to design early phase clinical trials for DIPG at this stage. Among 142 DIPG patients treated between 1998 and 2014, 114 had biopsy-proven DIPG with histone H3 status available for 83. We defined as long survivors' patients who survived more than 3 months after relapse which corresponds to the minimal life expectancy requested for phase I/II trials. Factors influencing post-relapse survival were accordingly compared between short and long-term survivors after relapse. Fifty-seven percent of patients were considered long survivors and 70% of them had a Lansky Play Scale (LPS) above 50% at relapse. Patients who became steroids-independent after initial treatment for at least 2 months had better survival after relapse (3.7 versus 2.6 months, p = 0.001). LPS above 50% at relapse was correlated with better survival after relapse (3.8 versus 1.8 months, p < 0.001). Patients with H3.1 mutation survived longer after relapse (4.9 versus 2.7 months, p = 0.007). Patients who received a second radiotherapy at the time of relapse had an improved survival (7.5 versus 4 months, p = 0.001). In the two-way ANOVA analysis, steroid-independence and LPS predicted survival best and the type of histone H3 (H3.1 or H3.3) mutated did not improve prediction. Survival of many DIPG patients after relapse over 3 months would make possible to propose specific trials for this condition. Steroid-independence, H3 mutation status and LPS should be considered to predict eligibility.

  • 8. Tesi, Bianca
    et al.
    Lagerstedt Robinson, Kristina
    Abel, Frida
    Díaz de Ståhl, Teresita
    Orrsjö, Sara
    Poluha, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Clinical Genetics, Uppsala University Hospital, Uppsala, Sweden.
    Hellberg, Maria
    Wessman, Sandra
    Samuelsson, Sofie
    Frisk, Tony
    Vogt, Hartmut
    Henning, Karin
    Sabel, Magnus
    Ek, Torben
    Pal, Niklas
    Nyman, Per
    Giraud, Géraldine
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neurooncology and neurodegeneration. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatric oncology research with a special focus on side effects. Pediatric Oncology, Uppsala University Children’s Hospital, Uppsala, Sweden.
    Wille, Joakim
    Pronk, Cornelis Jan
    Norén-Nyström, Ulrika
    Borssén, Magnus
    Fili, Maria
    Stålhammar, Gustav
    Herold, Nikolas
    Tettamanti, Giorgio
    Maya-Gonzalez, Carolina
    Arvidsson, Linda
    Rosén, Anna
    Ekholm, Katja
    Kuchinskaya, Ekaterina
    Hallbeck, Anna-Lotta
    Nordling, Margareta
    Palmebäck, Pia
    Kogner, Per
    Kanter Smoler, Gunilla
    Lähteenmäki, Päivi
    Fransson, Susanne
    Martinsson, Tommy
    Shamik, Alia
    Mertens, Fredrik
    Rosenquist, Richard
    Wirta, Valtteri
    Tham, Emma
    Grillner, Pernilla
    Sandgren, Johanna
    Ljungman, Gustaf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatric oncology research with a special focus on side effects. Pediatric Oncology, Uppsala University Children’s Hospital, Uppsala, Sweden.
    Gisselsson, David
    Taylan, Fulya
    Nordgren, Ann
    Diagnostic yield and clinical impact of germline sequencing in children with CNS and extracranial solid tumors: a nationwide, prospective Swedish study2024In: The Lancet Regional Health: Europe, E-ISSN 2666-7762, Vol. 39, article id 100881Article in journal (Refereed)
    Abstract [en]

    Background

    Childhood cancer predisposition (ChiCaP) syndromes are increasingly recognized as contributing factors to childhood cancer development. Yet, due to variable availability of germline testing, many children with ChiCaP might go undetected today. We report results from the nationwide and prospective ChiCaP study that investigated diagnostic yield and clinical impact of integrating germline whole-genome sequencing (gWGS) with tumor sequencing and systematic phenotyping in children with solid tumors.

    Methods

    gWGS was performed in 309 children at diagnosis of CNS (n = 123, 40%) or extracranial (n = 186, 60%) solid tumors and analyzed for disease-causing variants in 189 known cancer predisposing genes. Tumor sequencing data were available for 74% (227/309) of patients. In addition, a standardized clinical assessment for underlying predisposition was performed in 95% (293/309) of patients.

    Findings

    The prevalence of ChiCaP diagnoses was 11% (35/309), of which 69% (24/35) were unknown at inclusion (diagnostic yield 8%, 24/298). A second-hit and/or relevant mutational signature was observed in 19/21 (90%) tumors with informative data. ChiCaP diagnoses were more prevalent among patients with retinoblastomas (50%, 6/12) and high-grade astrocytomas (37%, 6/16), and in those with non-cancer related features (23%, 20/88), and ≥2 positive ChiCaP criteria (28%, 22/79). ChiCaP diagnoses were autosomal dominant in 80% (28/35) of patients, yet confirmed de novo in 64% (18/28). The 35 ChiCaP findings resulted in tailored surveillance (86%, 30/35) and treatment recommendations (31%, 11/35).

    Interpretation

    Overall, our results demonstrate that systematic phenotyping, combined with genomics-based diagnostics of ChiCaP in children with solid tumors is feasible in large-scale clinical practice and critically guides personalized care in a sizable proportion of patients.

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