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1. Tumor Location-weighted MRI-Report Contrastive Learning: A Framework for Improving the Explainability of Pediatric Brain Tumor Diagnosis

Author

Ketabi, Sara, Wagner, Matthias W., Hawkins, Cynthia, Tabori, Uri, Ertl-Wagner, Birgit Betina, and Khalvati, Farzad

Subjects
Electrical Engineering and Systems Science - Image and Video Processing, Computer Science - Computer Vision and Pattern Recognition, Computer Science - Machine Learning
Abstract

Despite the promising performance of convolutional neural networks (CNNs) in brain tumor diagnosis from magnetic resonance imaging (MRI), their integration into the clinical workflow has been limited. That is mainly due to the fact that the features contributing to a model's prediction are unclear to radiologists and hence, clinically irrelevant, i.e., lack of explainability. As the invaluable sources of radiologists' knowledge and expertise, radiology reports can be integrated with MRI in a contrastive learning (CL) framework, enabling learning from image-report associations, to improve CNN explainability. In this work, we train a multimodal CL architecture on 3D brain MRI scans and radiology reports to learn informative MRI representations. Furthermore, we integrate tumor location, salient to several brain tumor analysis tasks, into this framework to improve its generalizability. We then apply the learnt image representations to improve explainability and performance of genetic marker classification of pediatric Low-grade Glioma, the most prevalent brain tumor in children, as a downstream task. Our results indicate a Dice score of 31.1% between the model's attention maps and manual tumor segmentation (as an explainability measure) with test classification performance of 87.7%, significantly outperforming the baselines. These enhancements can build trust in our model among radiologists, facilitating its integration into clinical practices for more efficient tumor diagnosis.

Published
2024

4. Combination treatment with histone deacetylase and carbonic anhydrase 9 inhibitors shows therapeutic potential in experimental diffuse intrinsic pontine glioma

Author

Fujita, Naohide, Bondoc, Andrew, Simoes, Sergio, Ishida, Joji, Taccone, Michael S., Luck, Amanda, Srikanthan, Dilakshan, Siddaway, Robert, Levine, Adrian, Sabha, Nesrin, Krumholtz, Stacey, Kondo, Akihide, Arai, Hajime, Smith, Christian, McDonald, Paul, Hawkins, Cynthia, Dedhar, Shoukat, and Rutka, James

Published
2024
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6. Improving Pediatric Low-Grade Neuroepithelial Tumors Molecular Subtype Identification Using a Novel AUROC Loss Function for Convolutional Neural Networks

Author

Namdar, Khashayar, Wagner, Matthias W., Hawkins, Cynthia, Tabori, Uri, Ertl-Wagner, Birgit B., and Khalvati, Farzad

Subjects
Electrical Engineering and Systems Science - Image and Video Processing, Computer Science - Computer Vision and Pattern Recognition, Quantitative Biology - Quantitative Methods
Abstract

Pediatric Low-Grade Neuroepithelial Tumors (PLGNT) are the most common pediatric cancer type, accounting for 40% of brain tumors in children, and identifying PLGNT molecular subtype is crucial for treatment planning. However, the gold standard to determine the PLGNT subtype is biopsy, which can be impractical or dangerous for patients. This research improves the performance of Convolutional Neural Networks (CNNs) in classifying PLGNT subtypes through MRI scans by introducing a loss function that specifically improves the model's Area Under the Receiver Operating Characteristic (ROC) Curve (AUROC), offering a non-invasive diagnostic alternative. In this study, a retrospective dataset of 339 children with PLGNT (143 BRAF fusion, 71 with BRAF V600E mutation, and 125 non-BRAF) was curated. We employed a CNN model with Monte Carlo random data splitting. The baseline model was trained using binary cross entropy (BCE), and achieved an AUROC of 86.11% for differentiating BRAF fusion and BRAF V600E mutations, which was improved to 87.71% using our proposed AUROC loss function (p-value 0.045). With multiclass classification, the AUROC improved from 74.42% to 76. 59% (p-value 0.0016).

Published
2024

8. Generating 3D Brain Tumor Regions in MRI using Vector-Quantization Generative Adversarial Networks

Author

Zhou, Meng, Wagner, Matthias W, Tabori, Uri, Hawkins, Cynthia, Ertl-Wagner, Birgit B, and Khalvati, Farzad

Subjects
Computer Science - Computer Vision and Pattern Recognition, Computer Science - Machine Learning
Abstract

Medical image analysis has significantly benefited from advancements in deep learning, particularly in the application of Generative Adversarial Networks (GANs) for generating realistic and diverse images that can augment training datasets. However, the effectiveness of such approaches is often limited by the amount of available data in clinical settings. Additionally, the common GAN-based approach is to generate entire image volumes, rather than solely the region of interest (ROI). Research on deep learning-based brain tumor classification using MRI has shown that it is easier to classify the tumor ROIs compared to the entire image volumes. In this work, we present a novel framework that uses vector-quantization GAN and a transformer incorporating masked token modeling to generate high-resolution and diverse 3D brain tumor ROIs that can be directly used as augmented data for the classification of brain tumor ROI. We apply our method to two imbalanced datasets where we augment the minority class: (1) the Multimodal Brain Tumor Segmentation Challenge (BraTS) 2019 dataset to generate new low-grade glioma (LGG) ROIs to balance with high-grade glioma (HGG) class; (2) the internal pediatric LGG (pLGG) dataset tumor ROIs with BRAF V600E Mutation genetic marker to balance with BRAF Fusion genetic marker class. We show that the proposed method outperforms various baseline models in both qualitative and quantitative measurements. The generated data was used to balance the data in the brain tumor types classification task. Using the augmented data, our approach surpasses baseline models by 6.4% in AUC on the BraTS 2019 dataset and 4.3% in AUC on our internal pLGG dataset. The results indicate the generated tumor ROIs can effectively address the imbalanced data problem. Our proposed method has the potential to facilitate an accurate diagnosis of rare brain tumors using MRI scans., Comment: Preprint, In Submission

Published
2023

9. Toward standardized brain tumor tissue processing protocols in neuro-oncology: a perspective for gliomas and beyond.

Author

Rodriguez, Analiz, Ahluwalia, Manmeet, Bettegowda, Chetan, Brem, Henry, Carter, Bob, Chang, Susan, Das, Sunit, Eberhart, Charles, Garzon-Muvdi, Tomas, Hadjipanayis, Costas, Hawkins, Cynthia, Jacques, Thomas, Khalessi, Alexander, McDermott, Mike, Mikkelsen, Tom, Orr, Brent, Phillips, Joanna, Rosenblum, Mark, Shelton, William, Solomon, David, von Deimling, Andreas, Woodworth, Graeme, and Rutka, James

Subjects
biobank, brain tumors, gliomas, precision medicine, tissue processing
Abstract

Implementation of standardized protocols in neurooncology during the surgical resection of brain tumors is needed to advance the clinical treatment paradigms that use tissue for diagnosis, prognosis, bio-banking, and treatment. Currently recommendations on intraoperative tissue procurement only exist for diffuse gliomas but management of other brain tumor subtypes can also benefit from these protocols. Fresh tissue from surgical resection can now be used for intraoperative diagnostics and functional precision medicine assays. A multidisciplinary neuro-oncology perspective is critical to develop the best avenues for practical standardization. This perspective from the multidisciplinary Oncology Tissue Advisory Board (OTAB) discusses current advances, future directions, and the imperative of adopting standardized protocols for diverse brain tumor entities. There is a growing need for consistent operating room practices to enhance patient care, streamline research efforts, and optimize outcomes.

Published
2024

10. High detection rate of circulating-tumor DNA from cerebrospinal fluid of children with central nervous system germ cell tumors

Author

Nakano, Yoshiko, Burns, Ian, Nobre, Liana, Siddaway, Robert, Rana, Mansuba, Nesvick, Cody, Bondoc, Andrew, Ku, Michelle, Yuditskiy, Richard, Ku, Dennis T. L., Shing, Matthew M. K., Cheng, Kevin K. F., Ng, Ho-Keung, Das, Anirban, Bennett, Julie, Ramaswamy, Vijay, Huang, Annie, Malkin, David, Ertl-Wagner, Birgit, Dirks, Peter, Bouffet, Eric, Bartels, Ute, Tabori, Uri, Hawkins, Cynthia, and Liu, Anthony P. Y.

Published
2024
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12. Immuno-oncologic profiling of pediatric brain tumors reveals major clinical significance of the tumor immune microenvironment

Author

Levine, Adrian B., Nobre, Liana, Das, Anirban, Milos, Scott, Bianchi, Vanessa, Johnson, Monique, Fernandez, Nicholas R., Stengs, Lucie, Ryall, Scott, Ku, Michelle, Rana, Mansuba, Laxer, Benjamin, Sheth, Javal, Sbergio, Stefanie-Grace, Fedoráková, Ivana, Ramaswamy, Vijay, Bennett, Julie, Siddaway, Robert, Tabori, Uri, and Hawkins, Cynthia

Published
2024
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13. Impact of trametinib on the neuropsychological profile of NF1 patients

Author

Lalancette, Eve, Cantin, Édith, Routhier, Marie-Ève, Mailloux, Chantal, Bertrand, Marie-Claude, Kiaei, Dorsa Sadat, Larouche, Valérie, Tabori, Uri, Hawkins, Cynthia, Ellezam, Benjamin, Décarie, Jean-Claude, Théoret, Yves, Métras, Marie-Élaine, McKeown, Tara, Ospina, Luis H., Vairy, Stéphanie, Ramaswamy, Vijay, Coltin, Hallie, Sultan, Serge, Legault, Geneviève, Bouffet, Éric, Lafay-Cousin, Lucie, Hukin, Juliette, Erker, Craig, Caru, Maxime, Dehaes, Mathieu, Jabado, Nada, Perreault, Sébastien, and Lippé, Sarah

Published
2024
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17. Diffuse Midline Glioma-Pons

Author

Vanan, Magimairajan Issai, Erker, Craig, Mehta, Vivek, Hawkins, Cynthia, Eisenstat, David D., Scheinemann, Katrin, editor, and Bouffet, Eric, editor

Published
2024
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18. Generative Adversarial Networks for Weakly Supervised Generation and Evaluation of Brain Tumor Segmentations on MR Images

Author

Yoo, Jay J., Namdar, Khashayar, Wagner, Matthias W., Nobre, Liana, Tabori, Uri, Hawkins, Cynthia, Ertl-Wagner, Birgit B., and Khalvati, Farzad

Subjects
Electrical Engineering and Systems Science - Image and Video Processing, Computer Science - Computer Vision and Pattern Recognition
Abstract

Segmentation of regions of interest (ROIs) for identifying abnormalities is a leading problem in medical imaging. Using machine learning for this problem generally requires manually annotated ground-truth segmentations, demanding extensive time and resources from radiologists. This work presents a weakly supervised approach that utilizes binary image-level labels, which are much simpler to acquire, to effectively segment anomalies in 2D magnetic resonance images without ground truth annotations. We train a generative adversarial network (GAN) that converts cancerous images to healthy variants, which are used along with localization seeds as priors to generate improved weakly supervised segmentations. The non-cancerous variants can also be used to evaluate the segmentations in a weakly supervised fashion, which allows for the most effective segmentations to be identified and then applied to downstream clinical classification tasks. On the Multimodal Brain Tumor Segmentation (BraTS) 2020 dataset, our proposed method generates and identifies segmentations that achieve test Dice coefficients of 83.91%. Using these segmentations for pathology classification results with a test AUC of 93.32% which is comparable to the test AUC of 95.80% achieved when using true segmentations.

Published
2022

19. Improving Deep Learning Models for Pediatric Low-Grade Glioma Tumors Molecular Subtype Identification Using 3D Probability Distributions of Tumor Location

Author

Namdar, Khashayar, Wagner, Matthias W., Kudus, Kareem, Hawkins, Cynthia, Tabori, Uri, Ertl-Wagner, Brigit, and Khalvati, Farzad

Subjects
Computer Science - Computer Vision and Pattern Recognition, Computer Science - Machine Learning
Abstract

Background and Purpose: Pediatric low-grade glioma (pLGG) is the most common type of brain tumor in children, and identification of molecular markers for pLGG is crucial for successful treatment planning. Convolutional Neural Network (CNN) models for pLGG subtype identification rely on tumor segmentation. We hypothesize tumor segmentations are suboptimal and thus, we propose to augment the CNN models using tumor location probability in MRI data. Materials and Methods: Our REB-approved retrospective study included MRI Fluid-Attenuated Inversion Recovery (FLAIR) sequences of 143 BRAF fused and 71 BRAF V600E mutated tumors. Tumor segmentations (regions of interest (ROIs)) were provided by a pediatric neuroradiology fellow and verified by a senior pediatric neuroradiologist. In each experiment, we randomly split the data into development and test with an 80/20 ratio. We combined the 3D binary ROI masks for each class in the development dataset to derive the probability density functions (PDF) of tumor location, and developed three pipelines: location-based, CNN-based, and hybrid. Results: We repeated the experiment with different model initializations and data splits 100 times and calculated the Area Under Receiver Operating Characteristic Curve (AUC). The location-based classifier achieved an AUC of 77.90, 95% confidence interval (CI) (76.76, 79.03). CNN-based classifiers achieved AUC of 86.11, CI (84.96, 87.25), while the tumor-location-guided CNNs outperformed the formers with an average AUC of 88.64 CI (87.57, 89.72), which was statistically significant (Student's t-test p-value 0.0018). Conclusion: We achieved statistically significant improvements by incorporating tumor location into the CNN models. Our results suggest that manually segmented ROIs may not be optimal., Comment: arXiv admin note: text overlap with arXiv:2207.14776

Published
2022

20. Therapeutic targeting of prenatal pontine ID1 signaling in diffuse midline glioma.

Author

Messinger, Dana, Harris, Micah, Cummings, Jessica, Thomas, Chase, Yang, Tao, Sweha, Stefan, Woo, Rinette, Siddaway, Robert, Burkert, Martin, Stallard, Stefanie, Qin, Tingting, Mullan, Brendan, Siada, Ruby, Ravindran, Ramya, Niculcea, Michael, Dowling, Abigail, Bradin, Joshua, Ginn, Kevin, Gener, Melissa, Dorris, Kathleen, Vitanza, Nicholas, Schmidt, Susanne, Spitzer, Jasper, Li, Jiang, Filbin, Mariella, Cao, Xuhong, Castro, Maria, Lowenstein, Pedro, Mody, Rajen, Chinnaiyan, Arul, Desprez, Pierre-Yves, McAllister, Sean, Dun, Matthew, Hawkins, Cynthia, Waszak, Sebastian, Venneti, Sriram, Koschmann, Carl, and Yadav, Viveka

Subjects
CBD, DMG, ID1, ROS, invasion/migration, Animals, Humans, Mice, Brain, Brain Neoplasms, Calcium-Binding Proteins, Extracellular Matrix Proteins, Glioma, Histones, Inhibitor of Differentiation Protein 1, Mutation, Signal Transduction
Abstract

BACKGROUND: Diffuse midline gliomas (DMG) are highly invasive brain tumors with rare survival beyond two years past diagnosis and limited understanding of the mechanism behind tumor invasion. Previous reports demonstrate upregulation of the protein ID1 with H3K27M and ACVR1 mutations in DMG, but this has not been confirmed in human tumors or therapeutically targeted. METHODS: Whole exome, RNA, and ChIP-sequencing was performed on the ID1 locus in DMG tissue. Scratch-assay migration and transwell invasion assays of cultured cells were performed following shRNA-mediated ID1-knockdown. In vitro and in vivo genetic and pharmacologic [cannabidiol (CBD)] inhibition of ID1 on DMG tumor growth was assessed. Patient-reported CBD dosing information was collected. RESULTS: Increased ID1 expression in human DMG and in utero electroporation (IUE) murine tumors is associated with H3K27M mutation and brainstem location. ChIP-sequencing indicates ID1 regulatory regions are epigenetically active in human H3K27M-DMG tumors and prenatal pontine cells. Higher ID1-expressing astrocyte-like DMG cells share a transcriptional program with oligo/astrocyte-precursor cells (OAPCs) from the developing human brain and demonstrate upregulation of the migration regulatory protein SPARCL1. Genetic and pharmacologic (CBD) suppression of ID1 decreases tumor cell invasion/migration and tumor growth in H3.3/H3.1K27M PPK-IUE and human DIPGXIIIP* in vivo models of pHGG. The effect of CBD on cell proliferation appears to be non-ID1 mediated. Finally, we collected patient-reported CBD treatment data, finding that a clinical trial to standardize dosing may be beneficial. CONCLUSIONS: H3K27M-mediated re-activation of ID1 in DMG results in a SPARCL1+ migratory transcriptional program that is therapeutically targetable with CBD.

Published
2023

21. The proteomic landscape of glioblastoma recurrence reveals novel and targetable immunoregulatory drivers

Author

Tatari, Nazanin, Khan, Shahbaz, Livingstone, Julie, Zhai, Kui, Mckenna, Dillon, Ignatchenko, Vladimir, Chokshi, Chirayu, Gwynne, William D, Singh, Manoj, Revill, Spencer, Mikolajewicz, Nicholas, Zhu, Chenghao, Chan, Jennifer, Hawkins, Cynthia, Lu, Jian-Qiang, Provias, John P, Ask, Kjetil, Morrissy, Sorana, Brown, Samuel, Weiss, Tobias, Weller, Michael, Han, Hong, Greenspoon, Jeffrey N, Moffat, Jason, Venugopal, Chitra, Boutros, Paul C, Singh, Sheila K, and Kislinger, Thomas

Subjects
Biomedical and Clinical Sciences, Neurosciences, Rare Diseases, Orphan Drug, Brain Cancer, Clinical Research, Brain Disorders, Biotechnology, Cancer, Genetics, 2.1 Biological and endogenous factors, Aetiology, Good Health and Well Being, Humans, Glioblastoma, Brain Neoplasms, Proteomics, Neoplasm Recurrence, Local, Transcriptome, Immunosuppression, OAS2, Clinical Sciences, Neurology & Neurosurgery
Abstract

Glioblastoma (GBM) is characterized by extensive cellular and genetic heterogeneity. Its initial presentation as primary disease (pGBM) has been subject to exhaustive molecular and cellular profiling. By contrast, our understanding of how GBM evolves to evade the selective pressure of therapy is starkly limited. The proteomic landscape of recurrent GBM (rGBM), which is refractory to most treatments used for pGBM, are poorly known. We, therefore, quantified the transcriptome and proteome of 134 patient-derived pGBM and rGBM samples, including 40 matched pGBM-rGBM pairs. GBM subtypes transition from pGBM to rGBM towards a preferentially mesenchymal state at recurrence, consistent with the increasingly invasive nature of rGBM. We identified immune regulatory/suppressive genes as important drivers of rGBM and in particular 2-5-oligoadenylate synthase 2 (OAS2) as an essential gene in recurrent disease. Our data identify a new class of therapeutic targets that emerge from the adaptive response of pGBM to therapy, emerging specifically in recurrent disease and may provide new therapeutic opportunities absent at pGBM diagnosis.

Published
2022

25. Clinical and biological landscape of constitutional mismatch-repair deficiency syndrome: an International Replication Repair Deficiency Consortium cohort study

Author

Ercan, Ayse Bahar, Aronson, Melyssa, Fernandez, Nicholas R, Chang, Yuan, Levine, Adrian, Liu, Zhihui Amy, Negm, Logine, Edwards, Melissa, Bianchi, Vanessa, Stengs, Lucie, Chung, Jiil, Al-Battashi, Abeer, Reschke, Agnes, Lion, Alex, Ahmad, Alia, Lassaletta, Alvaro, Reddy, Alyssa T, Al-Darraji, Amir F, Shah, Amish C, Van Damme, An, Bendel, Anne, Rashid, Aqeela, Margol, Ashley S, Kelly, Bethany L, Pencheva, Bojana, Heald, Brandie, Lemieux-Anglin, Brianna, Crooks, Bruce, Koschmann, Carl, Gilpin, Catherine, Porter, Christopher C, Gass, David, Samuel, David, Ziegler, David S, Blumenthal, Deborah T, Kuo, Dennis John, Hamideh, Dima, Basel, Donald, Khuong-Quang, Dong-Anh, Stearns, Duncan, Opocher, Enrico, Carceller, Fernando, Baris Feldman, Hagit, Toledano, Helen, Winer, Ira, Scheers, Isabelle, Fedorakova, Ivana, Su, Jack M, Vengoechea, Jaime, Sterba, Jaroslav, Knipstein, Jeffrey, Hansford, Jordan R, Gonzales-Santos, Julieta Rita, Bhatia, Kanika, Bielamowicz, Kevin J, Minhas, Khurram, Nichols, Kim E, Cole, Kristina A, Penney, Lynette, Hjort, Magnus Aasved, Sabel, Magnus, Gil-da-Costa, Maria Joao, Murray, Matthew J, Miller, Matthew, Blundell, Maude L, Massimino, Maura, Al-Hussaini, Maysa, Al-Jadiry, Mazin F, Comito, Melanie A, Osborn, Michael, Link, Michael P, Zapotocky, Michal, Ghalibafian, Mithra, Shaheen, Najma, Mushtaq, Naureen, Waespe, Nicolas, Hijiya, Nobuko, Fuentes-Bolanos, Noemi, Ahmad, Olfat, Chamdine, Omar, Roy, Paromita, Pichurin, Pavel N, Nyman, Per, Pearlman, Rachel, Auer, Rebecca C, Sukumaran, Reghu K, Kebudi, Rejin, Dvir, Rina, Raphael, Robert, Elhasid, Ronit, McGee, Rose B, Chami, Rose, Noss, Ryan, Tanaka, Ryuma, Raskin, Salmo, Sen, Santanu, Lindhorst, Scott, Perreault, Sebastien, Caspi, Shani, Riaz, Shazia, Constantini, Shlomi, Albert, Sophie, Chaleff, Stanley, Bielack, Stefan, Chiaravalli, Stefano, Cramer, Stuart Louis, Roy, Sumita, Cahn, Suzanne, Penna, Suzanne, Hamid, Syed Ahmer, Ghafoor, Tariq, Imam, Uzma, Larouche, Valerie, Magimairajan Issai, Vanan, Foulkes, William D, Lee, Yi Yen, Nathan, Paul C, Maruvka, Yosef E, Greer, Mary-Louise C, Durno, Carol, Shlien, Adam, Ertl-Wagner, Birgit, Villani, Anita, Malkin, David, Hawkins, Cynthia, Bouffet, Eric, Das, Anirban, and Tabori, Uri

Published
2024
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26. Genomic predictors of response to PD-1 inhibition in children with germline DNA replication repair deficiency

Author

Das, Anirban, Sudhaman, Sumedha, Morgenstern, Daniel, Coblentz, Ailish, Chung, Jiil, Stone, Simone C, Alsafwani, Noor, Liu, Zhihui Amy, Karsaneh, Ola Abu Al, Soleimani, Shirin, Ladany, Hagay, Chen, David, Zatzman, Matthew, Cabric, Vanja, Nobre, Liana, Bianchi, Vanessa, Edwards, Melissa, Sambira Nahum, Lauren C, Ercan, Ayse B, Nabbi, Arash, Constantini, Shlomi, Dvir, Rina, Yalon-Oren, Michal, Campino, Gadi Abebe, Caspi, Shani, Larouche, Valerie, Reddy, Alyssa, Osborn, Michael, Mason, Gary, Lindhorst, Scott, Bronsema, Annika, Magimairajan, Vanan, Opocher, Enrico, De Mola, Rebecca Loret, Sabel, Magnus, Frojd, Charlotta, Sumerauer, David, Samuel, David, Cole, Kristina, Chiaravalli, Stefano, Massimino, Maura, Tomboc, Patrick, Ziegler, David S, George, Ben, Van Damme, An, Hijiya, Nobuko, Gass, David, McGee, Rose B, Mordechai, Oz, Bowers, Daniel C, Laetsch, Theodore W, Lossos, Alexander, Blumenthal, Deborah T, Sarosiek, Tomasz, Yen, Lee Yi, Knipstein, Jeffrey, Bendel, Anne, Hoffman, Lindsey M, Luna-Fineman, Sandra, Zimmermann, Stefanie, Scheers, Isabelle, Nichols, Kim E, Zapotocky, Michal, Hansford, Jordan R, Maris, John M, Dirks, Peter, Taylor, Michael D, Kulkarni, Abhaya V, Shroff, Manohar, Tsang, Derek S, Villani, Anita, Xu, Wei, Aronson, Melyssa, Durno, Carol, Shlien, Adam, Malkin, David, Getz, Gad, Maruvka, Yosef E, Ohashi, Pamela S, Hawkins, Cynthia, Pugh, Trevor J, Bouffet, Eric, and Tabori, Uri

Subjects
Rare Diseases, Pediatric, Cancer, Neurosciences, Pediatric Cancer, Genetics, 2.1 Biological and endogenous factors, Aetiology, Adolescent, Adult, B7-H1 Antigen, Biomarkers, Tumor, Child, DNA Repair, DNA Replication, Female, Germ-Line Mutation, Humans, Immune Checkpoint Inhibitors, Male, Neoplasms, Prospective Studies, Retrospective Studies, Survival Analysis, Tumor Microenvironment, Young Adult, Medical and Health Sciences, Immunology
Abstract

Cancers arising from germline DNA mismatch repair deficiency or polymerase proofreading deficiency (MMRD and PPD) in children harbour the highest mutational and microsatellite insertion-deletion (MS-indel) burden in humans. MMRD and PPD cancers are commonly lethal due to the inherent resistance to chemo-irradiation. Although immune checkpoint inhibitors (ICIs) have failed to benefit children in previous studies, we hypothesized that hypermutation caused by MMRD and PPD will improve outcomes following ICI treatment in these patients. Using an international consortium registry study, we report on the ICI treatment of 45 progressive or recurrent tumors from 38 patients. Durable objective responses were observed in most patients, culminating in a 3 year survival of 41.4%. High mutation burden predicted response for ultra-hypermutant cancers (>100 mutations per Mb) enriched for combined MMRD + PPD, while MS-indels predicted response in MMRD tumors with lower mutation burden (10-100 mutations per Mb). Furthermore, both mechanisms were associated with increased immune infiltration even in 'immunologically cold' tumors such as gliomas, contributing to the favorable response. Pseudo-progression (flare) was common and was associated with immune activation in the tumor microenvironment and systemically. Furthermore, patients with flare who continued ICI treatment achieved durable responses. This study demonstrates improved survival for patients with tumors not previously known to respond to ICI treatment, including central nervous system and synchronous cancers, and identifies the dual roles of mutation burden and MS-indels in predicting sustained response to immunotherapy.

Published
2022

28. Using comprehensive genomic and functional analyses for resolving genotype–phenotype mismatches in children with suspected CMMRD in Lebanon: an IRRDC study

Author

Hamideh, Dima, Das, Anirban, Bianchi, Vanessa, Chung, Jiil, Negm, Logine, Levine, Adrian, Basbous, Maya, Sanchez-Ramirez, Santiago, Mikael, Leonie, Jabado, Nada, Atweh, Lamya, Lteif, Mireille, Mahfouz, Rami, Tarek, Nidale, Abboud, Miguel, Muwakkit, Samar, Hawkins, Cynthia, Tabori, Uri, and Saab, Raya

Published
2023
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29. The 2021 WHO Classification of Tumors of the Central Nervous System: a summary

Author

Louis, David N, Perry, Arie, Wesseling, Pieter, Brat, Daniel J, Cree, Ian A, Figarella-Branger, Dominique, Hawkins, Cynthia, Ng, HK, Pfister, Stefan M, Reifenberger, Guido, Soffietti, Riccardo, von Deimling, Andreas, and Ellison, David W

Subjects
Brain Disorders, Cancer, Brain Cancer, Rare Diseases, Neurosciences, Brain, Central Nervous System, Central Nervous System Neoplasms, Humans, Pathology, Molecular, World Health Organization, brian tumor, central nervous system, classification, diagnosis, brain tumor, Oncology and Carcinogenesis, Oncology & Carcinogenesis
Abstract

The fifth edition of the WHO Classification of Tumors of the Central Nervous System (CNS), published in 2021, is the sixth version of the international standard for the classification of brain and spinal cord tumors. Building on the 2016 updated fourth edition and the work of the Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy, the 2021 fifth edition introduces major changes that advance the role of molecular diagnostics in CNS tumor classification. At the same time, it remains wedded to other established approaches to tumor diagnosis such as histology and immunohistochemistry. In doing so, the fifth edition establishes some different approaches to both CNS tumor nomenclature and grading and it emphasizes the importance of integrated diagnoses and layered reports. New tumor types and subtypes are introduced, some based on novel diagnostic technologies such as DNA methylome profiling. The present review summarizes the major general changes in the 2021 fifth edition classification and the specific changes in each taxonomic category. It is hoped that this summary provides an overview to facilitate more in-depth exploration of the entire fifth edition of the WHO Classification of Tumors of the Central Nervous System.

Published
2021

31. Clinical Outcomes and Patient-Matched Molecular Composition of Relapsed Medulloblastoma.

Author

Kumar, Rahul, Smith, Kyle, Deng, Maximilian, Terhune, Colt, Robinson, Giles, Orr, Brent, Liu, Anthony, Lin, Tong, Billups, Catherine, Chintagumpala, Murali, Bowers, Daniel, Hassall, Timothy, Hansford, Jordan, Khuong-Quang, Dong, Crawford, John, Bendel, Anne, Gururangan, Sridharan, Schroeder, Kristin, Bouffet, Eric, Bartels, Ute, Fisher, Michael, Cohn, Richard, Partap, Sonia, Kellie, Stewart, McCowage, Geoffrey, Paulino, Arnold, Rutkowski, Stefan, Fleischhack, Gudrun, Dhall, Girish, Klesse, Laura, Leary, Sarah, Nazarian, Javad, Kool, Marcel, Wesseling, Pieter, Ryzhova, Marina, Zheludkova, Olga, Golanov, Andrey, McLendon, Roger, Packer, Roger, Dunham, Christopher, Hukin, Juliette, Fouladi, Maryam, Faria, Claudia, Pimentel, Jose, Walter, Andrew, Jabado, Nada, Cho, Yoon-Jae, Perreault, Sebastien, Croul, Sidney, Zapotocky, Michal, Hawkins, Cynthia, Tabori, Uri, Taylor, Michael, Pfister, Stefan, Klimo, Paul, Boop, Frederick, Ellison, David, Merchant, Thomas, Onar-Thomas, Arzu, Korshunov, Andrey, Jones, David, Gajjar, Amar, Ramaswamy, Vijay, and Northcott, Paul

Subjects
Biomarkers, Tumor, Cerebellar Neoplasms, Child, Child, Preschool, Clinical Trials as Topic, DNA Methylation, Disease Progression, Epigenome, Epigenomics, Female, High-Throughput Nucleotide Sequencing, Humans, Infant, Male, Medulloblastoma, Neoplasm Recurrence, Local, Retreatment, Time Factors, Treatment Outcome
Abstract

PURPOSE: We sought to investigate clinical outcomes of relapsed medulloblastoma and to compare molecular features between patient-matched diagnostic and relapsed tumors. METHODS: Children and infants enrolled on either SJMB03 (NCT00085202) or SJYC07 (NCT00602667) trials who experienced medulloblastoma relapse were analyzed for clinical outcomes, including anatomic and temporal patterns of relapse and postrelapse survival. A largely independent, paired molecular cohort was analyzed by DNA methylation array and next-generation sequencing. RESULTS: A total of 72 of 329 (22%) SJMB03 and 52 of 79 (66%) SJYC07 patients experienced relapse with significant representation of Group 3 and wingless tumors. Although most patients exhibited some distal disease (79%), 38% of patients with sonic hedgehog tumors experienced isolated local relapse. Time to relapse and postrelapse survival varied by molecular subgroup with longer latencies for patients with Group 4 tumors. Postrelapse radiation therapy among previously nonirradiated SJYC07 patients was associated with long-term survival. Reirradiation was only temporizing for SJMB03 patients. Among 127 patients with patient-matched tumor pairs, 9 (7%) experienced subsequent nonmedulloblastoma CNS malignancies. Subgroup (96%) and subtype (80%) stabilities were largely maintained among the remainder. Rare subgroup divergence was observed from Group 4 to Group 3 tumors, which is coincident with genetic alterations involving MYC, MYCN, and FBXW7. Subgroup-specific patterns of alteration were identified for driver genes and chromosome arms. CONCLUSION: Clinical behavior of relapsed medulloblastoma must be contextualized in terms of up-front therapies and molecular classifications. Group 4 tumors exhibit slower biological progression. Utility of radiation at relapse is dependent on patient age and prior treatments. Degree and patterns of molecular conservation at relapse vary by subgroup. Relapse tissue enables verification of molecular targets and identification of occult secondary malignancies.

Published
2021

32. The clinical utility of integrative genomics in childhood cancer extends beyond targetable mutations

Author

Villani, Anita, Davidson, Scott, Kanwar, Nisha, Lo, Winnie W., Li, Yisu, Cohen-Gogo, Sarah, Fuligni, Fabio, Edward, Lisa-Monique, Light, Nicholas, Layeghifard, Mehdi, Harripaul, Ricardo, Waldman, Larissa, Gallinger, Bailey, Comitani, Federico, Brunga, Ledia, Hayes, Reid, Anderson, Nathaniel D., Ramani, Arun K., Yuki, Kyoko E., Blay, Sasha, Johnstone, Brittney, Inglese, Cara, Hammad, Rawan, Goudie, Catherine, Shuen, Andrew, Wasserman, Jonathan D., Venier, Rosemarie E., Eliou, Marianne, Lorenti, Miranda, Ryan, Carol Ann, Braga, Michael, Gloven-Brown, Meagan, Han, Jianan, Montero, Maria, Spatare, Famida, Whitlock, James A., Scherer, Stephen W., Chun, Kathy, Somerville, Martin J., Hawkins, Cynthia, Abdelhaleem, Mohamed, Ramaswamy, Vijay, Somers, Gino R., Kyriakopoulou, Lianna, Hitzler, Johann, Shago, Mary, Morgenstern, Daniel A., Tabori, Uri, Meyn, Stephen, Irwin, Meredith S., Malkin, David, and Shlien, Adam

Published
2023
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33. Senescence Induced by BMI1 Inhibition Is a Therapeutic Vulnerability in H3K27M-Mutant DIPG

Author

Balakrishnan, Ilango, Danis, Etienne, Pierce, Angela, Madhavan, Krishna, Wang, Dong, Dahl, Nathan, Sanford, Bridget, Birks, Diane K, Davidson, Nate, Metselaar, Dennis S, Meel, Michaël Hananja, Lemma, Rakeb, Donson, Andrew, Vijmasi, Trinka, Katagi, Hiroaki, Sola, Ismail, Fosmire, Susan, Alimova, Irina, Steiner, Jenna, Gilani, Ahmed, Hulleman, Esther, Serkova, Natalie J, Hashizume, Rintaro, Hawkins, Cynthia, Carcaboso, Angel M, Gupta, Nalin, Monje, Michelle, Jabado, Nada, Jones, Kenneth, Foreman, Nicholas, Green, Adam, Vibhakar, Rajeev, and Venkataraman, Sujatha

Subjects
Biochemistry and Cell Biology, Biological Sciences, Rare Diseases, Genetics, Stem Cell Research, Biotechnology, Cancer, Brain Disorders, Stem Cell Research - Nonembryonic - Non-Human, Brain Cancer, Aging, Astrocytoma, Brain Stem Neoplasms, Cell Differentiation, Cell Line, Tumor, Cell Proliferation, Child, Child, Preschool, Chromatin, Diffuse Intrinsic Pontine Glioma, Epigenomics, Female, Glioma, Histones, Humans, Lysine, Male, Mutation, Neoplasm Recurrence, Local, Polycomb Repressive Complex 1, BH3 mimetics, BMI1, DIPG, H3K27M mutant, H3WT, PTC 028, RNAi screen, SASP, senescence, Bmi1, PTC028, Medical Physiology, Biological sciences
Abstract

Diffuse intrinsic pontine glioma (DIPG) is an incurable brain tumor of childhood characterized by histone mutations at lysine 27, which results in epigenomic dysregulation. There has been a failure to develop effective treatment for this tumor. Using a combined RNAi and chemical screen targeting epigenomic regulators, we identify the polycomb repressive complex 1 (PRC1) component BMI1 as a critical factor for DIPG tumor maintenance in vivo. BMI1 chromatin occupancy is enriched at genes associated with differentiation and tumor suppressors in DIPG cells. Inhibition of BMI1 decreases cell self-renewal and attenuates tumor growth due to induction of senescence. Prolonged BMI1 inhibition induces a senescence-associated secretory phenotype, which promotes tumor recurrence. Clearance of senescent cells using BH3 protein mimetics co-operates with BMI1 inhibition to enhance tumor cell killing in vivo.

Published
2020

34. cIMPACT‐NOW update 6: new entity and diagnostic principle recommendations of the cIMPACT‐Utrecht meeting on future CNS tumor classification and grading

Author

Louis, David N, Wesseling, Pieter, Aldape, Kenneth, Brat, Daniel J, Capper, David, Cree, Ian A, Eberhart, Charles, Figarella‐Branger, Dominique, Fouladi, Maryam, Fuller, Gregory N, Giannini, Caterina, Haberler, Christine, Hawkins, Cynthia, Komori, Takashi, Kros, Johan M, Ng, HK, Orr, Brent A, Park, Sung‐Hye, Paulus, Werner, Perry, Arie, Pietsch, Torsten, Reifenberger, Guido, Rosenblum, Marc, Rous, Brian, Sahm, Felix, Sarkar, Chitra, Solomon, David A, Tabori, Uri, Bent, Martin J, Deimling, Andreas, Weller, Michael, White, Valerie A, and Ellison, David W

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Cancer, Rare Diseases, Central Nervous System Neoplasms, Humans, Neoplasm Grading, brain tumors, central nervous system, classification, neoplasms, Clinical Sciences, Neurosciences, Neurology & Neurosurgery, Clinical sciences
Abstract

cIMPACT-NOW (the Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy) was established to evaluate and make practical recommendations on recent advances in the field of CNS tumor classification, particularly in light of the rapid progress in molecular insights into these neoplasms. For Round 2 of its deliberations, cIMPACT-NOW Working Committee 3 was reconstituted and convened in Utrecht, The Netherlands, for a meeting designed to review putative new CNS tumor types in advance of any future World Health Organization meeting on CNS tumor classification. In preparatory activities for the meeting and at the actual meeting, a list of possible entities was assembled and each type and subtype debated. Working Committee 3 recommended that a substantial number of newly recognized types and subtypes should be considered for inclusion in future CNS tumor classifications. In addition, the group endorsed a number of principles-relating to classification categories, approaches to classification, nomenclature, and grading-that the group hopes will also inform the future classification of CNS neoplasms.

Published
2020

35. Pattern of Relapse and Treatment Response in WNT-Activated Medulloblastoma

Author

Nobre, Liana, Zapotocky, Michal, Khan, Sara, Fukuoka, Kohei, Fonseca, Adriana, McKeown, Tara, Sumerauer, David, Vicha, Ales, Grajkowska, Wieslawa A, Trubicka, Joanna, Li, Kay Ka Wai, Ng, Ho-Keung, Massimi, Luca, Lee, Ji Yeoun, Kim, Seung-Ki, Zelcer, Shayna, Vasiljevic, Alexandre, Faure-Conter, Cécile, Hauser, Peter, Lach, Boleslaw, van Veelen-Vincent, Marie-Lise, French, Pim J, Van Meir, Erwin G, Weiss, William A, Gupta, Nalin, Pollack, Ian F, Hamilton, Ronald L, Rao, Amulya A Nageswara, Giannini, Caterina, Rubin, Joshua B, Moore, Andrew S, Chambless, Lola B, Vibhakar, Rajeev, Ra, Young Shin, Massimino, Maura, McLendon, Roger E, Wheeler, Helen, Zollo, Massimo, Ferruci, Veronica, Kumabe, Toshihiro, Faria, Claudia C, Sterba, Jaroslav, Jung, Shin, López-Aguilar, Enrique, Mora, Jaume, Carlotti, Carlos G, Olson, James M, Leary, Sarah, Cain, Jason, Krskova, Lenka, Zamecnik, Josef, Hawkins, Cynthia E, Tabori, Uri, Huang, Annie, Bartels, Ute, Northcott, Paul A, Taylor, Michael D, Yip, Stephen, Hansford, Jordan R, Bouffet, Eric, and Ramaswamy, Vijay

Subjects
Cancer, Clinical Research, Evaluation of treatments and therapeutic interventions, 5.1 Pharmaceuticals, Development of treatments and therapeutic interventions, 6.1 Pharmaceuticals, Adolescent, Antineoplastic Combined Chemotherapy Protocols, Biomarkers, Tumor, Cerebellar Neoplasms, Child, Cyclophosphamide, Female, Humans, Ifosfamide, Male, Medulloblastoma, Middle Aged, Neoplasm Recurrence, Local, Progression-Free Survival, medulloblastoma, WNT, genomics, cyclophosphamide, chemotherapy, prognosis, survival
Abstract

Over the past decade, wingless-activated (WNT) medulloblastoma has been identified as a candidate for therapy de-escalation based on excellent survival; however, a paucity of relapses has precluded additional analyses of markers of relapse. To address this gap in knowledge, an international cohort of 93 molecularly confirmed WNT MB was assembled, where 5-year progression-free survival is 0.84 (95%, 0.763-0.925) with 15 relapsed individuals identified. Maintenance chemotherapy is identified as a strong predictor of relapse, with individuals receiving high doses of cyclophosphamide or ifosphamide having only one very late molecularly confirmed relapse (p = 0.032). The anatomical location of recurrence is metastatic in 12 of 15 relapses, with 8 of 12 metastatic relapses in the lateral ventricles. Maintenance chemotherapy, specifically cumulative cyclophosphamide doses, is a significant predictor of relapse across WNT MB. Future efforts to de-escalate therapy need to carefully consider not only the radiation dose but also the chemotherapy regimen and the propensity for metastatic relapses.

Published
2020

37. Clinicogenomic associations in childhood Langerhans cell histiocytosis: an international cohort study

Author

Kemps, Paul G., Zondag, Timo C. E., Arnardóttir, Helga B., Solleveld-Westerink, Nienke, Borst, Jelske, Steenwijk, Eline C., van Egmond, Demi, Swennenhuis, Joost F., Stelloo, Ellen, Trambusti, Irene, Verdijk, Robert M., van Noesel, Carel J. M., Cleven, Arjen H. G., Scheijde-Vermeulen, Marijn A., Koudijs, Marco J., Krsková, Lenka, Hawkins, Cynthia, Egeler, R. Maarten, Brok, Jesper, von Bahr Greenwood, Tatiana, Svojgr, Karel, Beishuizen, Auke, van Laar, Jan A. M., Pötschger, Ulrike, Hutter, Caroline, Sieni, Elena, Minkov, Milen, Abla, Oussama, van Wezel, Tom, van den Bos, Cor, and van Halteren, Astrid G. S.

Published
2023
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39. Recurrent ACVR1 mutations in posterior fossa ependymoma

Author

Pratt, Drew, Lucas, Calixto-Hope G., Selvam, Pavalan Panneer, Abdullaev, Zied, Ketchum, Courtney, Quezado, Martha, Armstrong, Terri S., Gilbert, Mark R., Papanicolau-Sengos, Antonios, Raffeld, Mark, Choo-Wosoba, Hyoyoung, Chan, Priya, Whipple, Nicholas, Nasrallah, MacLean, Santi, Mariarita, Ramaswamy, Vijay, Giannini, Caterina, Ritzmann, Timothy A., Grundy, Richard G., Burford, Anna, Jones, Chris, Hawkins, Cynthia, Venneti, Sriram, Solomon, David A., and Aldape, Kenneth

Published
2022
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40. cIMPACT-NOW: a practical summary of diagnostic points from Round 1 updates.

Author

Louis, David N, Ellison, David W, Brat, Daniel J, Aldape, Kenneth, Capper, David, Hawkins, Cynthia, Paulus, Werner, Perry, Arie, Reifenberger, Guido, Figarella-Branger, Dominique, von Deimling, Andreas, and Wesseling, Pieter

Subjects
Humans, Central Nervous System Neoplasms, Brain Neoplasms, Neuropathology, Brain Cancer, Brain Disorders, Neurosciences, Rare Diseases, Cancer, Clinical Sciences, Neurology & Neurosurgery
Abstract

cIMPACT-NOW (the Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy) was established to provide a forum to evaluate and recommend proposed changes to future CNS tumor classifications. From 2016 to 2019 (Round 1), cIMPACT published four updates. Update 1 clarified the use of the term NOS (Not Otherwise Specified) and proposed use of the additional term NEC (Not Elsewhere Classified). Update 2 issued clarifications regarding two diagnoses: Diffuse Midline Glioma, H3 K27M-mutant and Diffuse Astrocytoma/Anaplastic Astrocytoma, IDH-mutant. Update 3 proposed molecular criteria that could be used in the setting of an IDH-wildtype diffuse or anaplastic astrocytic glioma without histological features of glioblastoma to infer that the tumor would behave similarly to a grade IV glioblastoma. Update 4 suggested that, in children and young adults, subtypes of IDH-wildtype/H3-wildtype diffuse gliomas may have distinct clinical features in the setting of a BRAFV600E mutation, FGFR1 alteration, other MAPK pathway alteration, or a MYB or MYBL1 rearrangement. The practical diagnostic relevance of these cIMPACT proposals is highlighted in this summary.

Published
2019

41. A C19MC-LIN28A-MYCN Oncogenic Circuit Driven by Hijacked Super-enhancers Is a Distinct Therapeutic Vulnerability in ETMRs: A Lethal Brain Tumor

Author

Sin-Chan, Patrick, Mumal, Iqra, Suwal, Tannu, Ho, Ben, Fan, Xiaolian, Singh, Irtisha, Du, Yuchen, Lu, Mei, Patel, Neilket, Torchia, Jonathon, Popovski, Dean, Fouladi, Maryam, Guilhamon, Paul, Hansford, Jordan R, Leary, Sarah, Hoffman, Lindsey M, Levy, Jean M Mulcahy, Lassaletta, Alvaro, Solano-Paez, Palma, Rivas, Eloy, Reddy, Alyssa, Gillespie, G Yancey, Gupta, Nalin, Van Meter, Timothy E, Nakamura, Hideo, Wong, Tai-Tong, Ra, Young-Shin, Kim, Seung-Ki, Massimi, Luca, Grundy, Richard G, Fangusaro, Jason, Johnston, Donna, Chan, Jennifer, Lafay-Cousin, Lucie, Hwang, Eugene I, Wang, Yin, Catchpoole, Daniel, Michaud, Jean, Ellezam, Benjamin, Ramanujachar, Ramya, Lindsay, Holly, Taylor, Michael D, Hawkins, Cynthia E, Bouffet, Eric, Jabado, Nada, Singh, Sheila K, Kleinman, Claudia L, Barsyte-Lovejoy, Dalia, Li, Xiao-Nan, Dirks, Peter B, Lin, Charles Y, Mack, Stephen C, Rich, Jeremy N, and Huang, Annie

Subjects
Rare Diseases, Neurosciences, Cancer, Genetics, Biotechnology, 5.1 Pharmaceuticals, Development of treatments and therapeutic interventions, Biomarkers, Tumor, Brain Neoplasms, Cell Cycle, Cell Transformation, Neoplastic, Chromosomes, Human, Pair 19, Chromosomes, Human, Pair 2, DNA Copy Number Variations, Enhancer Elements, Genetic, Epigenesis, Genetic, Gene Expression Regulation, Gene Regulatory Networks, Genetic Association Studies, Genetic Predisposition to Disease, Humans, MicroRNAs, Models, Biological, Multigene Family, N-Myc Proto-Oncogene Protein, Neoplasms, Germ Cell and Embryonal, Oncogenes, RNA-Binding Proteins, C19MC, ETMR, LIN28A, MYCN, brain tumor, cell-cycle, epigenetics, microRNA, super-enhancer, therapeutics, Oncology and Carcinogenesis, Oncology & Carcinogenesis
Abstract

Embryonal tumors with multilayered rosettes (ETMRs) are highly lethal infant brain cancers with characteristic amplification of Chr19q13.41 miRNA cluster (C19MC) and enrichment of pluripotency factor LIN28A. Here we investigated C19MC oncogenic mechanisms and discovered a C19MC-LIN28A-MYCN circuit fueled by multiple complex regulatory loops including an MYCN core transcriptional network and super-enhancers resulting from long-range MYCN DNA interactions and C19MC gene fusions. Our data show that this powerful oncogenic circuit, which entraps an early neural lineage network, is potently abrogated by bromodomain inhibitor JQ1, leading to ETMR cell death.

Published
2019

42. Combined MEK and JAK/STAT3 pathway inhibition effectively decreases SHH medulloblastoma tumor progression

Author

Zagozewski, Jamie, Borlase, Stephanie, Guppy, Brent J., Coudière-Morrison, Ludivine, Shahriary, Ghazaleh M., Gordon, Victor, Liang, Lisa, Cheng, Stephen, Porter, Christopher J., Kelley, Rhonda, Hawkins, Cynthia, Chan, Jennifer A., Liang, Yan, Gong, Jingjing, Nör, Carolina, Saulnier, Olivier, Wechsler-Reya, Robert J., Ramaswamy, Vijay, and Werbowetski-Ogilvie, Tamra E.

Published
2022
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46. A Hematogenous Route for Medulloblastoma Leptomeningeal Metastases

Author

Garzia, Livia, Kijima, Noriyuki, Morrissy, A Sorana, De Antonellis, Pasqualino, Guerreiro-Stucklin, Ana, Holgado, Borja L, Wu, Xiaochong, Wang, Xin, Parsons, Michael, Zayne, Kory, Manno, Alex, Kuzan-Fischer, Claudia, Nor, Carolina, Donovan, Laura K, Liu, Jessica, Qin, Lei, Garancher, Alexandra, Liu, Kun-Wei, Mansouri, Sheila, Luu, Betty, Thompson, Yuan Yao, Ramaswamy, Vijay, Peacock, John, Farooq, Hamza, Skowron, Patryk, Shih, David JH, Li, Angela, Ensan, Sherine, Robbins, Clinton S, Cybulsky, Myron, Mitra, Siddhartha, Ma, Yussanne, Moore, Richard, Mungall, Andy, Cho, Yoon-Jae, Weiss, William A, Chan, Jennifer A, Hawkins, Cynthia E, Massimino, Maura, Jabado, Nada, Zapotocky, Michal, Sumerauer, David, Bouffet, Eric, Dirks, Peter, Tabori, Uri, Sorensen, Poul HB, Brastianos, Priscilla K, Aldape, Kenneth, Jones, Steven JM, Marra, Marco A, Woodgett, James R, Wechsler-Reya, Robert J, Fults, Daniel W, and Taylor, Michael D

Subjects
Brain Cancer, Cancer, Neurosciences, Pediatric Cancer, Pediatric, Rare Diseases, Brain Disorders, Allografts, Animals, Cell Line, Tumor, Chemokine CCL2, Chromosomes, Human, Pair 10, Female, Humans, Male, Medulloblastoma, Meningeal Neoplasms, Mice, SCID, Neoplastic Cells, Circulating, Parabiosis, brain tumors, circulating tumor cells, medulloblastoma, metastases, pediatric cancer, Biological Sciences, Medical and Health Sciences, Developmental Biology
Abstract

While the preponderance of morbidity and mortality in medulloblastoma patients are due to metastatic disease, most research focuses on the primary tumor due to a dearth of metastatic tissue samples and model systems. Medulloblastoma metastases are found almost exclusively on the leptomeningeal surface of the brain and spinal cord; dissemination is therefore thought to occur through shedding of primary tumor cells into the cerebrospinal fluid followed by distal re-implantation on the leptomeninges. We present evidence for medulloblastoma circulating tumor cells (CTCs) in therapy-naive patients and demonstrate in vivo, through flank xenografting and parabiosis, that medulloblastoma CTCs can spread through the blood to the leptomeningeal space to form leptomeningeal metastases. Medulloblastoma leptomeningeal metastases express high levels of the chemokine CCL2, and expression of CCL2 in medulloblastoma in vivo is sufficient to drive leptomeningeal dissemination. Hematogenous dissemination of medulloblastoma offers a new opportunity to diagnose and treat lethal disseminated medulloblastoma.

Published
2018

47. Pediatric low-grade gliomas: next biologically driven steps.

Author

Jones, David TW, Kieran, Mark W, Bouffet, Eric, Alexandrescu, Sanda, Bandopadhayay, Pratiti, Bornhorst, Miriam, Ellison, David, Fangusaro, Jason, Fisher, Michael J, Foreman, Nicholas, Fouladi, Maryam, Hargrave, Darren, Hawkins, Cynthia, Jabado, Nada, Massimino, Maura, Mueller, Sabine, Perilongo, Giorgio, Schouten van Meeteren, Antoinette YN, Tabori, Uri, Warren, Katherine, Waanders, Angela J, Walker, David, Weiss, William, Witt, Olaf, Wright, Karen, Zhu, Yuan, Bowers, Daniel C, Pfister, Stefan M, and Packer, Roger J

Subjects
Pediatric, Brain Disorders, Neurosciences, Pediatric Research Initiative, Cancer, Rare Diseases, Brain Cancer, Adult, Animals, Brain Neoplasms, Child, Disease Models, Animal, Glioma, Humans, Neoplasm Grading, Pathology, Molecular, Treatment Outcome, low-grade glioma, MAPK pathway, molecular diagnostics, neurooncology, pediatric brain tumor, targeted therapy, Oncology and Carcinogenesis, Oncology & Carcinogenesis
Abstract

Despite the fact that they are not typically life-threatening, low-grade gliomas (LGGs) remain a significant clinical challenge in pediatric neuro-oncology due to comorbidities associated with these tumors and/or their treatments, and their propensity to multiply recurs. LGGs, in total the most common brain tumors arising in childhood, can often become a chronic problem requiring decades of management. The Second International Consensus Conference on Pediatric Low-Grade Gliomas held in Padua, Italy in 2016 was convened in an attempt to advance the pace of translating biological discoveries on LGGs into meaningful clinical benefit. Topics discussed included: the implications of our growing biological understanding of the genomics underlying these tumors; the assessment of the model systems available; the implications of the molecular and histopathologic differences between adult and pediatric diffuse gliomas; and steps needed to expedite targeted therapy into late-stage clinical trials for newly diagnosed cases. Methods for the diagnostic assessment of alterations in the Ras/mitogen-activated protein kinase pathway, typical for these tumors, were also considered. While the overall tone was positive, with a consensus that progress is being and will continue to be made, the scale of the challenge presented by this complex group of tumors was also acknowledged. The conclusions and recommendations of the meeting panel are provided here as an outline of current thinking and a basis for further discussion.

Published
2018

49. Comprehensive Analysis of Hypermutation in Human Cancer

Author

Campbell, Brittany B, Light, Nicholas, Fabrizio, David, Zatzman, Matthew, Fuligni, Fabio, de Borja, Richard, Davidson, Scott, Edwards, Melissa, Elvin, Julia A, Hodel, Karl P, Zahurancik, Walter J, Suo, Zucai, Lipman, Tatiana, Wimmer, Katharina, Kratz, Christian P, Bowers, Daniel C, Laetsch, Theodore W, Dunn, Gavin P, Johanns, Tanner M, Grimmer, Matthew R, Smirnov, Ivan V, Larouche, Valérie, Samuel, David, Bronsema, Annika, Osborn, Michael, Stearns, Duncan, Raman, Pichai, Cole, Kristina A, Storm, Phillip B, Yalon, Michal, Opocher, Enrico, Mason, Gary, Thomas, Gregory A, Sabel, Magnus, George, Ben, Ziegler, David S, Lindhorst, Scott, Issai, Vanan Magimairajan, Constantini, Shlomi, Toledano, Helen, Elhasid, Ronit, Farah, Roula, Dvir, Rina, Dirks, Peter, Huang, Annie, Galati, Melissa A, Chung, Jiil, Ramaswamy, Vijay, Irwin, Meredith S, Aronson, Melyssa, Durno, Carol, Taylor, Michael D, Rechavi, Gideon, Maris, John M, Bouffet, Eric, Hawkins, Cynthia, Costello, Joseph F, Meyn, M Stephen, Pursell, Zachary F, Malkin, David, Tabori, Uri, and Shlien, Adam

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Oncology and Carcinogenesis, Human Genome, Cancer, Rare Diseases, Cancer Genomics, 2.1 Biological and endogenous factors, Good Health and Well Being, Adult, Child, Cluster Analysis, DNA Polymerase II, DNA Polymerase III, DNA Replication, Humans, Mutation, Neoplasms, Poly-ADP-Ribose Binding Proteins, DNA repair, DNA replication, cancer genomics, cancer predisposition, hypermutation, immune checkpoint inhibitors, mismatch repair, mutator, Medical and Health Sciences, Developmental Biology, Biological sciences, Biomedical and clinical sciences
Abstract

We present an extensive assessment of mutation burden through sequencing analysis of >81,000 tumors from pediatric and adult patients, including tumors with hypermutation caused by chemotherapy, carcinogens, or germline alterations. Hypermutation was detected in tumor types not previously associated with high mutation burden. Replication repair deficiency was a major contributing factor. We uncovered new driver mutations in the replication-repair-associated DNA polymerases and a distinct impact of microsatellite instability and replication repair deficiency on the scale of mutation load. Unbiased clustering, based on mutational context, revealed clinically relevant subgroups regardless of the tumors' tissue of origin, highlighting similarities in evolutionary dynamics leading to hypermutation. Mutagens, such as UV light, were implicated in unexpected cancers, including sarcomas and lung tumors. The order of mutational signatures identified previous treatment and germline replication repair deficiency, which improved management of patients and families. These data will inform tumor classification, genetic testing, and clinical trial design.

Published
2017

50. Immunohistochemical analysis of H3K27me3 demonstrates global reduction in group-A childhood posterior fossa ependymoma and is a powerful predictor of outcome

Author

Panwalkar, Pooja, Clark, Jonathan, Ramaswamy, Vijay, Hawes, Debra, Yang, Fusheng, Dunham, Christopher, Yip, Stephen, Hukin, Juliette, Sun, Yilun, Schipper, Matthew J, Chavez, Lukas, Margol, Ashley, Pekmezci, Melike, Chung, Chan, Banda, Adam, Bayliss, Jill M, Curry, Sarah J, Santi, Mariarita, Rodriguez, Fausto J, Snuderl, Matija, Karajannis, Matthias A, Saratsis, Amanda M, Horbinski, Craig M, Carret, Anne-Sophie, Wilson, Beverly, Johnston, Donna, Lafay-Cousin, Lucie, Zelcer, Shayna, Eisenstat, David, Silva, Marianna, Scheinemann, Katrin, Jabado, Nada, McNeely, P Daniel, Kool, Marcel, Pfister, Stefan M, Taylor, Michael D, Hawkins, Cynthia, Korshunov, Andrey, Judkins, Alexander R, and Venneti, Sriram

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Brain Disorders, Genetics, Brain Cancer, Rare Diseases, Neurosciences, Clinical Research, Pediatric Cancer, Cancer, Clinical Trials and Supportive Activities, Pediatric, Child, Child, Preschool, Disease-Free Survival, Ependymoma, Female, Humans, Infant, Infratentorial Neoplasms, Jumonji Domain-Containing Histone Demethylases, Male, Prognosis, Registries, Survival Rate, Childhood ependymoma, Epigenetics, H3K27me3, Molecular subgrouping, Neurology & Neurosurgery
Abstract

Posterior fossa ependymomas (EPN_PF) in children comprise two morphologically identical, but biologically distinct tumor entities. Group-A (EPN_PFA) tumors have a poor prognosis and require intensive therapy. In contrast, group-B tumors (EPN_PFB) exhibit excellent prognosis and the current consensus opinion recommends future clinical trials to test the possibility of treatment de-escalation in these patients. Therefore, distinguishing these two tumor subtypes is critical. EPN_PFA and EPN_PFB can be distinguished based on DNA methylation signatures, but these assays are not routinely available. We have previously shown that a subset of poorly prognostic childhood EPN_PF exhibits global reduction in H3K27me3. Therefore, we set out to determine whether a simple immunohistochemical assay for H3K27me3 could be used to segregate EPN_PFA from EPN_PFB tumors. We assembled a cohort of 230 childhood ependymomas and H3K27me3 immunohistochemistry was assessed as positive or negative in a blinded manner. H3K27me3 staining results were compared with DNA methylation-based subgroup information available in 112 samples [EPN_PFA (n = 72) and EPN_PFB tumors (n = 40)]. H3K27me3 staining was globally reduced in EPN_PFA tumors and immunohistochemistry showed 99% sensitivity and 100% specificity in segregating EPN_PFA from EPN_PFB tumors. Moreover, H3K27me3 immunostaining was sufficient to delineate patients with worse prognosis in two independent, non-overlapping cohorts (n = 133 and n = 97). In conclusion, immunohistochemical evaluation of H3K27me3 global reduction is an economic, easily available and readily adaptable method for defining high-risk EPN_PFA from low-risk posterior fossa EPN_PFB tumors to inform prognosis and to enable the design of future clinical trials.

Published
2017

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