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54. Efficacy and safety of gefitinib and potential prognostic value of soluble EGFR, EGFR mutations, and tumor markers in a Gynecologic Oncology Group phase II trial of persistent or recurrent endometrial cancer

Author

Leslie, K. K., primary, Sill, M. W., additional, Darcy, K. M., additional, Baron, A. T., additional, Wilken, J. A., additional, Godwin, A. K., additional, Cook, L., additional, Schilder, R. J., additional, Schilder, J. M., additional, and Maihle, N. J., additional

Published
2009
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61. Quality-of-life results of a randomized phase III trial of four cisplatin (Cis) containing doublet combinations in stage IVB cervical carcinoma: A gynecologic oncology group (GOG) study

Author

Wenzel, L. B., primary, Huang, H., additional, Cella, D., additional, Monk, B. J., additional, Sill, M. W., additional, McMeekin, S. D., additional, Cohn, D. E., additional, Ramondetta, L. M., additional, Boardman, C. H., additional, and Benda, J., additional

Published
2008
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64. Relationship of angiogenesis biomarkers and clinical response to bevacizumab (Bev) in persistent or recurrent epithelial ovarian cancer (EOC) and primary peritoneal cancer (PPC) patients treated in a Phase II Gynecologic Oncology Group study

Author

Han, E. S., primary, Burger, R. A., additional, Randall-Whitis, L., additional, Parmakhtiar, B., additional, Darcy, K., additional, Sill, M., additional, Connelly, P., additional, Monk, B. J., additional, and Fruehauf, J. P., additional

Published
2007
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66. Plated nickel wire mesh makes superior catalyst bed

Author

Sill, M

Subjects
Materials
Abstract

Porous nickel mesh screen catalyst bed produces gas evolution in hydrogen peroxide thrust chambers used for attitude control of space vehicles. The nickel wire mesh disks in the catalyst bed are plated in rugose form with a silver-gold coating.

Published
1965

76. What are providers' reporting requirements for children who witness domestic violence?

Author

Zink T, Kamine D, Musk L, Sill M, Field V, and Putnam F

Abstract

Each year, 3.3 to 10 million children are exposed to domestic violence/abuse (DV). Providers' reporting obligations for these children are unclear. The child maltreatment statutes available on state's web sites (through August 2003) were reviewed. Only Alaska defines DV in the presence of a child as child abuse within its juvenile code. Within their child abuse definition and reporting statutes, many states include language such as 'substantial risk' or 'imminent danger' of 'physical harm' or 'mental injury.' Although knowledge of the state law is an important first step, abiding by it may be challenging because most statutes are open to wide interpretation. As a result, providers are encouraged to seek advice from local child maltreatment specialists who understand the local legal interpretations and resources. [ABSTRACT FROM AUTHOR]

Published
2004

77. Intimate partner violence and job instability.

Author

Zink T and Sill M

Abstract

ObjectiveResearch has shown that intimate partner violence (IPV) affects the physical and mental health of victims. It can also compromise work performance, leading to job loss. We explored the potential link between job loss and IPV as part of a larger study on IPV and health care.MethodsThirty-two mothers in Midwestern IPV shelters or support groups were interviewed to gather information about their abuse histories, health care experiences, and demographic characteristics. Interviews were audio taped, transcribed, and reviewed for themes.ResultsHalf of participants had lost jobs because of IPV Reasons included. the abuser told the victim to quit, in order to be safe, excessive absences because of covering up the abuse, and health issues exacerbated by IPVConclusionJob instability was common among IPV victims in this study. Although this study did not address cause and effect, evidence of job instability may be another 'red flag symptom' indicating that providers should screen for IPV. [ABSTRACT FROM AUTHOR]

Published
2004

80. Cepaea; nemoralis

Author

Sill, M. and Sill, M.

Abstract

http://name.umdl.umich.edu/IC-MOLLUSK1IC-X-153316%5DUMMZ-MOL-153297-153337, https://quod.lib.umich.edu/cgi/i/image/api/thumb/mollusk1ic/153316/UMMZ-MOL-153297-153337/!250,250, The University of Michigan Library provides access to these materials for educational and research purposes. These materials may be under copyright. If you decide to use any of these materials, you are responsible for making your own legal assessment and securing any necessary permission. If you have questions about the collection, contact the UMMZ Mollusks Division professional staff: mollusk1ic-dlps-help@umich.edu. If you have concerns about the inclusion of an item in this collection, please contact Library Information Technology: libraryit-info@umich.edu.

81. Achatinella; livida

Author

Sill, M. and Sill, M.

Abstract

http://name.umdl.umich.edu/IC-MOLLUSK1IC-X-145209%5DUMMZ-MOL-145184-145225, https://quod.lib.umich.edu/cgi/i/image/api/thumb/mollusk1ic/145209/UMMZ-MOL-145184-145225/!250,250, The University of Michigan Library provides access to these materials for educational and research purposes. These materials may be under copyright. If you decide to use any of these materials, you are responsible for making your own legal assessment and securing any necessary permission. If you have questions about the collection, contact the UMMZ Mollusks Division professional staff: mollusk1ic-dlps-help@umich.edu. If you have concerns about the inclusion of an item in this collection, please contact Library Information Technology: libraryit-info@umich.edu.

82. Bradybaena; similaris

Author

Sill, M. and Sill, M.

Abstract

http://name.umdl.umich.edu/IC-MOLLUSK1IC-X-144739%5DUMMZ-MOL-144722-144763, https://quod.lib.umich.edu/cgi/i/image/api/thumb/mollusk1ic/144739/UMMZ-MOL-144722-144763/!250,250, The University of Michigan Library provides access to these materials for educational and research purposes. These materials may be under copyright. If you decide to use any of these materials, you are responsible for making your own legal assessment and securing any necessary permission. If you have questions about the collection, contact the UMMZ Mollusks Division professional staff: mollusk1ic-dlps-help@umich.edu. If you have concerns about the inclusion of an item in this collection, please contact Library Information Technology: libraryit-info@umich.edu.

83. Physa; parkeri

Author

Sill, M. and Sill, M.

Abstract

http://name.umdl.umich.edu/IC-MOLLUSK1IC-X-122094%5DUMMZ-MOL-122082-122122, https://quod.lib.umich.edu/cgi/i/image/api/thumb/mollusk1ic/122094/UMMZ-MOL-122082-122122/!250,250, The University of Michigan Library provides access to these materials for educational and research purposes. These materials may be under copyright. If you decide to use any of these materials, you are responsible for making your own legal assessment and securing any necessary permission. If you have questions about the collection, contact the UMMZ Mollusks Division professional staff: mollusk1ic-dlps-help@umich.edu. If you have concerns about the inclusion of an item in this collection, please contact Library Information Technology: libraryit-info@umich.edu.

84. Endodonta; lamellosa

Author

Sill, M. and Sill, M.

Abstract

http://name.umdl.umich.edu/IC-MOLLUSK1IC-X-136720%5DUMMZ-MOL-136718-136758, https://quod.lib.umich.edu/cgi/i/image/api/thumb/mollusk1ic/136720/UMMZ-MOL-136718-136758/!250,250, The University of Michigan Library provides access to these materials for educational and research purposes. These materials may be under copyright. If you decide to use any of these materials, you are responsible for making your own legal assessment and securing any necessary permission. If you have questions about the collection, contact the UMMZ Mollusks Division professional staff: mollusk1ic-dlps-help@umich.edu. If you have concerns about the inclusion of an item in this collection, please contact Library Information Technology: libraryit-info@umich.edu.

85. Galba; humilis

Author

Sill, M. and Sill, M.

Abstract

http://name.umdl.umich.edu/IC-MOLLUSK1IC-X-075874%5DUMMZ-MOL-75858-75894, https://quod.lib.umich.edu/cgi/i/image/api/thumb/mollusk1ic/075874/UMMZ-MOL-75858-75894/!250,250, The University of Michigan Library provides access to these materials for educational and research purposes. These materials may be under copyright. If you decide to use any of these materials, you are responsible for making your own legal assessment and securing any necessary permission. If you have questions about the collection, contact the UMMZ Mollusks Division professional staff: mollusk1ic-dlps-help@umich.edu. If you have concerns about the inclusion of an item in this collection, please contact Library Information Technology: libraryit-info@umich.edu.

86. Achatinella; lorata

Author

Sill, M. and Sill, M.

Abstract

http://name.umdl.umich.edu/IC-MOLLUSK1IC-X-145211%5DUMMZ-MOL-145184-145225, https://quod.lib.umich.edu/cgi/i/image/api/thumb/mollusk1ic/145211/UMMZ-MOL-145184-145225/!250,250, The University of Michigan Library provides access to these materials for educational and research purposes. These materials may be under copyright. If you decide to use any of these materials, you are responsible for making your own legal assessment and securing any necessary permission. If you have questions about the collection, contact the UMMZ Mollusks Division professional staff: mollusk1ic-dlps-help@umich.edu. If you have concerns about the inclusion of an item in this collection, please contact Library Information Technology: libraryit-info@umich.edu.

87. Hadra; semicastanea

Author

Sill, M. and Sill, M.

Abstract

http://name.umdl.umich.edu/IC-MOLLUSK1IC-X-075122%5DUMMZ-MOL-75117-75153, https://quod.lib.umich.edu/cgi/i/image/api/thumb/mollusk1ic/075122/UMMZ-MOL-75117-75153/!250,250, The University of Michigan Library provides access to these materials for educational and research purposes. These materials may be under copyright. If you decide to use any of these materials, you are responsible for making your own legal assessment and securing any necessary permission. If you have questions about the collection, contact the UMMZ Mollusks Division professional staff: mollusk1ic-dlps-help@umich.edu. If you have concerns about the inclusion of an item in this collection, please contact Library Information Technology: libraryit-info@umich.edu.

88. Musculium; lacustre

Author

Sill, M. and Sill, M.

Abstract

http://name.umdl.umich.edu/IC-MOLLUSK1IC-X-106567%5DUMMZ-MOL-106552-106592, https://quod.lib.umich.edu/cgi/i/image/api/thumb/mollusk1ic/106567/UMMZ-MOL-106552-106592/!250,250, The University of Michigan Library provides access to these materials for educational and research purposes. These materials may be under copyright. If you decide to use any of these materials, you are responsible for making your own legal assessment and securing any necessary permission. If you have questions about the collection, contact the UMMZ Mollusks Division professional staff: mollusk1ic-dlps-help@umich.edu. If you have concerns about the inclusion of an item in this collection, please contact Library Information Technology: libraryit-info@umich.edu.

89. Pomatiopsis; lapidaria

Author

Sill, M. and Sill, M.

Abstract

http://name.umdl.umich.edu/IC-MOLLUSK1IC-X-091559%5DUMMZ-MOL-91545-91585, https://quod.lib.umich.edu/cgi/i/image/api/thumb/mollusk1ic/091559/UMMZ-MOL-91545-91585/!250,250, The University of Michigan Library provides access to these materials for educational and research purposes. These materials may be under copyright. If you decide to use any of these materials, you are responsible for making your own legal assessment and securing any necessary permission. If you have questions about the collection, contact the UMMZ Mollusks Division professional staff: mollusk1ic-dlps-help@umich.edu. If you have concerns about the inclusion of an item in this collection, please contact Library Information Technology: libraryit-info@umich.edu.

90. Ventridens; intertextus

Author

Sill, M. and Sill, M.

Abstract

http://name.umdl.umich.edu/IC-MOLLUSK1IC-X-115548%5DUMMZ-MOL-115522-115562, https://quod.lib.umich.edu/cgi/i/image/api/thumb/mollusk1ic/115548/UMMZ-MOL-115522-115562/!250,250, The University of Michigan Library provides access to these materials for educational and research purposes. These materials may be under copyright. If you decide to use any of these materials, you are responsible for making your own legal assessment and securing any necessary permission. If you have questions about the collection, contact the UMMZ Mollusks Division professional staff: mollusk1ic-dlps-help@umich.edu. If you have concerns about the inclusion of an item in this collection, please contact Library Information Technology: libraryit-info@umich.edu.

91. Achatinella; vulpina

Author

Sill, M. and Sill, M.

Abstract

http://name.umdl.umich.edu/IC-MOLLUSK1IC-X-145271%5DUMMZ-MOL-145268-145309, https://quod.lib.umich.edu/cgi/i/image/api/thumb/mollusk1ic/145271/UMMZ-MOL-145268-145309/!250,250, The University of Michigan Library provides access to these materials for educational and research purposes. These materials may be under copyright. If you decide to use any of these materials, you are responsible for making your own legal assessment and securing any necessary permission. If you have questions about the collection, contact the UMMZ Mollusks Division professional staff: mollusk1ic-dlps-help@umich.edu. If you have concerns about the inclusion of an item in this collection, please contact Library Information Technology: libraryit-info@umich.edu.

92. Discus; whitneyi

Author

Sill, M. and Sill, M.

Abstract

http://name.umdl.umich.edu/IC-MOLLUSK1IC-X-126569%5DUMMZ-MOL-126551-126591, https://quod.lib.umich.edu/cgi/i/image/api/thumb/mollusk1ic/126569/UMMZ-MOL-126551-126591/!250,250, The University of Michigan Library provides access to these materials for educational and research purposes. These materials may be under copyright. If you decide to use any of these materials, you are responsible for making your own legal assessment and securing any necessary permission. If you have questions about the collection, contact the UMMZ Mollusks Division professional staff: mollusk1ic-dlps-help@umich.edu. If you have concerns about the inclusion of an item in this collection, please contact Library Information Technology: libraryit-info@umich.edu.

93. Achatinella; byronii

Author

Sill, M. and Sill, M.

Abstract

http://name.umdl.umich.edu/IC-MOLLUSK1IC-X-145167%5DUMMZ-MOL-145142-145183, https://quod.lib.umich.edu/cgi/i/image/api/thumb/mollusk1ic/145167/UMMZ-MOL-145142-145183/!250,250, The University of Michigan Library provides access to these materials for educational and research purposes. These materials may be under copyright. If you decide to use any of these materials, you are responsible for making your own legal assessment and securing any necessary permission. If you have questions about the collection, contact the UMMZ Mollusks Division professional staff: mollusk1ic-dlps-help@umich.edu. If you have concerns about the inclusion of an item in this collection, please contact Library Information Technology: libraryit-info@umich.edu.

95. Desmoplastic myxoid tumor, SMARCB1-mutant: clinical, histopathological and molecular characterization of a pineal region tumor encountered in adolescents and adults

Author

Werner Paulus, Martin Sill, Annika K. Wefers, Susanne Bens, Fanny Burel-Vandenbos, Christian Thomas, Michael C. Frühwald, Torsten Pietsch, Francesca Brett, Florian Oyen, Abbas Agaimy, Marcel Kool, Karolina Nemes, Silke Vogelgesang, Guido Reifenberger, Frantz Rom Poulsen, Reiner Siebert, Fausto J. Rodriguez, Roger E. McLendon, Caterina Giannini, Pascal Johann, Eric S. Lipp, Stefan Tippelt, Kathy Keyvani, Klaus Kuchelmeister, Martin Hasselblatt, Andreas von Deimling, Uwe Kordes, Istvan Bodi, Thomas C., Wefers A., Bens S., Nemes K., Agaimy A., Oyen F., Vogelgesang S., Rodriguez F.J., Brett F.M., McLendon R., Bodi I., Burel-Vandenbos F., Keyvani K., Tippelt S., Poulsen F.R., Lipp E.S., Giannini C., Reifenberger G., Kuchelmeister K., Pietsch T., Kordes U., Siebert R., Fruhwald M.C., Johann P.D., Sill M., Kool M., von Deimling A., Paulus W., and Hasselblatt M.

Subjects
0301 basic medicine, Adult, Male, Pathology, medicine.medical_specialty, Proliferation index, Adolescent, Medizin, Brain tumor, Biology, Pineal Gland, Pathology and Forensic Medicine, Frameshift mutation, Cohort Studies, 03 medical and health sciences, Cellular and Molecular Neuroscience, Young Adult, 0302 clinical medicine, Atypical teratoid/rhabdoid tumor (ATRT), myxoid stroma, pineal region, medicine, Humans, SMARCB1, Rhabdoid Tumor, Brain Neoplasms, Myxoid tumor, Age Factors, SMARCB1 Protein, Middle Aged, medicine.disease, Survival Rate, 030104 developmental biology, Tumor progression, Atypical teratoid rhabdoid tumor, Mutation, Atypical teratoid/rhabdoid tumor, SMARCB1 gene, pineal, Female, Neurology (clinical), Epithelioid cell, 030217 neurology & neurosurgery
Abstract

Atypical teratoid/rhabdoid tumor (ATRT) is a highly malignant brain tumor predominantly occurring in infants. Mutations of the SMARCB1 gene are the characteristic genetic lesion. SMARCB1-mutant tumors in adolescents and adults are rare and may show uncommon histopathological and clinical features. Here we report seven SMARCB1-deficient intracranial tumors sharing distinct clinical, histopathological and molecular features. Median age of the four females and three males was 40years (range 15–61years). All tumors were located in the pineal region. Histopathologically, these tumors displayed spindled and epithelioid cells embedded in a desmoplastic stroma alternating with a variable extent of a loose myxoid matrix. All cases showed loss of nuclear SMARCB1/INI1 protein expression, expression of EMA and CD34 was frequent and the Ki67/MIB1 proliferation index was low in the majority of cases (median 3%). Three cases displayed heterozygous SMARCB1 deletions and two cases a homozygous SMARCB1 deletion. On sequencing, one tumor showed a 2bp deletion in exon 4 (c.369_370del) and one a short duplication in exon 3 (c.237_276dup) both resulting in frameshift mutations. Most DNA methylation profiles were not classifiable using the Heidelberg Brain Tumor Classifier (version v11b4). By unsupervised t-SNE analysis and hierarchical clustering analysis, however, all tumors grouped closely together and showed similarities with ATRT-MYC. After a median observation period of 48months, three patients were alive with stable disease, whereas one patient experienced tumor progression and three patients had succumbed to disease. In conclusion, our series represents an entity with distinct clinical, histopathological and molecular features showing epigenetic similarities with ATRT-MYC. We propose the designation desmoplastic myxoid tumor (DMT), SMARCB1-mutant, for these tumors.

Published
2020

96. Heterogeneity within the PF-EPN-B ependymoma subgroup

Author

Almos Klekner, David W. Ellison, Vijay Ramaswamy, Betty Luu, Marcel Kool, David Shih, Eugene Hwang, Andrey Korshunov, Mariarita Santi, Michal Zapotocky, Juliette Hukin, Marta M. Alonso, Hendrik Witt, Caterina Giannini, Stephen C. Mack, Thomas E. Merchant, Tanvi Sharma, Ulrich Schüller, Marie Lise C. van Veelen, Jennifer A. Chan, Kristian W. Pajtler, Martin Sill, Christopher Dunham, Amulya A. Nageswara Rao, Benjamin Y. Lu, Maura Massimino, Sarah Leary, Daniela Pretti da Cunha Tirapelli, Eric S. Lipp, Tong Lin, Andrew J. Grossbach, Massimo Zollo, Carlos Gilberto Carlotti, Eric Bouffet, Matthias A. Karajannis, Terri S. Armstrong, Jaume Mora, Jens Martin Hübner, Ben Ho, Charles G. Eberhart, Lola B. Chambless, Roger E. McLendon, Veronica Ferrucci, Linda M. Liau, Kenneth Aldape, Florence M.G. Cavalli, Claudia C. Faria, Stefan M. Pfister, Sridharan Gururangan, Shin Jung, Pim J. French, Michael D. Taylor, Uri Tabori, Lyndsey Emery, Marina Ryzhova, Johan M. Kros, Mark R. Gilbert, Cavalli F.M.G., Hubner J.-M., Sharma T., Luu B., Sill M., Zapotocky M., Mack S.C., Witt H., Lin T., Shih D.J.H., Ho B., Santi M., Emery L., Hukin J., Dunham C., McLendon R.E., Lipp E.S., Gururangan S., Grossbach A., French P., Kros J.M., van Veelen M.-L.C., Rao A.A.N., Giannini C., Leary S., Jung S., Faria C.C., Mora J., Schuller U., Alonso M.M., Chan J.A., Klekner A., Chambless L.B., Hwang E.I., Massimino M., Eberhart C.G., Karajannis M.A., Lu B., Liau L.M., Zollo M., Ferrucci V., Carlotti C., Tirapelli D.P.C., Tabori U., Bouffet E., Ryzhova M., Ellison D.W., Merchant T.E., Gilbert M.R., Armstrong T.S., Korshunov A., Pfister S.M., Taylor M.D., Aldape K., Pajtler K.W., Kool M., Ramaswamy V., Neurology, Pathology, Neurosurgery, Cavalli, Florence M. G., Hübner, Jens-Martin, Sharma, Tanvi, Luu, Betty, Sill, Martin, Zapotocky, Michal, Mack, Stephen C., Witt, Hendrik, Lin, Tong, Shih, David J. H., Ho, Ben, Santi, Mariarita, Emery, Lyndsey, Hukin, Juliette, Dunham, Christopher, Mclendon, Roger E., Lipp, Eric S., Gururangan, Sridharan, Grossbach, Andrew, French, Pim, Kros, Johan M., van Veelen, Marie-Lise C., Rao, Amulya A. Nageswara, Giannini, Caterina, Leary, Sarah, Jung, Shin, Faria, Claudia C., Mora, Jaume, Schüller, Ulrich, Alonso, Marta M., Chan, Jennifer A., Klekner, Almo, Chambless, Lola B., Hwang, Eugene I., Massimino, Maura, Eberhart, Charles G., Karajannis, Matthias A., Lu, Benjamin, Liau, Linda M., Zollo, Massimo, Ferrucci, Veronica, Carlotti, Carlo, Tirapelli, Daniela P. C., Tabori, Uri, Bouffet, Eric, Ryzhova, Marina, Ellison, David W., Merchant, Thomas E., Gilbert, Mark R., Armstrong, Terri S., Korshunov, Andrey, Pfister, Stefan M., Taylor, Michael D., Aldape, Kenneth, Pajtler, Kristian W., Kool, Marcel, and Ramaswamy, Vijay

Subjects
Oncology, Ependymoma, Male, PFA, Posterior fossa, PFB, Infratentorial Neoplasms, Kaplan-Meier Estimate, Subgrouping, Cohort Studies, 0302 clinical medicine, Age Factor, Young adult, Child, Cancer, DNA Copy Number Variation, Infratentorial Neoplasm, Age Factors, Methylation, Orvostudományok, Middle Aged, Subependymoma, 030220 oncology & carcinogenesis, DNA methylation, Female, Human, Adult, medicine.medical_specialty, DNA Copy Number Variations, Adolescent, CITOGENÉTICA, Clinical Sciences, Biology, Klinikai orvostudományok, Article, Clustering, Pathology and Forensic Medicine, 03 medical and health sciences, Cellular and Molecular Neuroscience, Young Adult, Rare Diseases, Clinical Research, Internal medicine, Genetics, medicine, Humans, Microarray Analysi, Neurology & Neurosurgery, Microarray analysis techniques, Gene Expression Profiling, Human Genome, Neurosciences, DNA Methylation, Microarray Analysis, medicine.disease, Brain Disorders, Brain Cancer, Gene expression profiling, Neurology (clinical), Cohort Studie, 030217 neurology & neurosurgery
Abstract

Posterior fossa ependymoma comprise three distinct molecular variants, termed PF-EPN-A (PFA), PF-EPN-B (PFB), and PF-EPN-SE (subependymoma). Clinically, they are very disparate and PFB tumors are currently being considered for a trial of radiation avoidance. However, to move forward, unraveling the heterogeneity within PFB would be highly desirable. To discern the molecular heterogeneity within PFB, we performed an integrated analysis consisting of DNA methylation profiling, copy-number profiling, gene expression profiling, and clinical correlation across a cohort of 212 primary posterior fossa PFB tumors. Unsupervised spectral clustering and t-SNE analysis of genome-wide methylation data revealed five distinct subtypes of PFB tumors, termed PFB1-5, with distinct demographics, copy-number alterations, and gene expression profiles. All PFB subtypes were distinct from PFA and posterior fossa subependymomas. Of the five subtypes, PFB4 and PFB5 are more discrete, consisting of younger and older patients, respectively, with a strong female-gender enrichment in PFB5 (age: p = 0.011, gender: p = 0.04). Broad copy-number aberrations were common; however, many events such as chromosome 2 loss, 5 gain, and 17 loss were enriched in specific subtypes and 1q gain was enriched in PFB1. Late relapses were common across all five subtypes, but deaths were uncommon and present in only two subtypes (PFB1 and PFB3). Unlike the case in PFA ependymoma, 1q gain was not a robust marker of poor progression-free survival; however, chromosome 13q loss may represent a novel marker for risk stratification across the spectrum of PFB subtypes. Similar to PFA ependymoma, there exists a significant intertumoral heterogeneity within PFB, with distinct molecular subtypes identified. Even when accounting for this heterogeneity, extent of resection remains the strongest predictor of poor outcome. However, this biological heterogeneity must be accounted for in future preclinical modeling and personalized therapies.

Published
2018

97. Anaplastic astrocytoma with piloid features, a novel molecular class of IDH wildtype glioma with recurrent MAPK pathway, CDKN2A/B and ATRX alterations

Author

Camelia M. Monoranu, Andreas von Deimling, Albert J. Becker, Joerg Felsberg, Jens Schittenhelm, Martina Deckert, Marco Prinz, Rolf Buslei, Till Acker, Katharina Heß, Ute Pohl, Volker Hovestadt, Wolf Mueller, Patricia Kohlhof, Dorothee Gramatzki, Muin S. A. Tuffaha, Amulya NageswaraRao, Andrey Korshunov, Benjamin Brokinkel, Daniel Schrimpf, David T.W. Jones, Annekathrin Reinhardt, Ulrich W. Thomale, Werner Paulus, Ekkehard Hewer, Christian Koelsche, Christian Mawrin, Damian Stichel, Ori Staszewski, Wolfgang Wick, David E. Reuss, Almuth F. Kessler, Caterina Giannini, Annika K. Wefers, Michael Platten, Martin Sill, Daniel Hänggi, Kristin Huang, Christian Hartmann, Adriana Olar, David Capper, Volkmar Hans, Andreas Unterberg, Zane Jaunmuktane, Sebastian Brandner, Nuno Miguel Nunes, Christel Herold-Mende, Felix Sahm, Uri Tabori, Guido Reifenberger, Arend Koch, Mario Loehr, Michael Weller, Hildegard Dohmen, Stefan M. Pfister, Fausto J. Rodriguez, Reinhardt A., Stichel D., Schrimpf D., Sahm F., Korshunov A., Reuss D.E., Koelsche C., Huang K., Wefers A.K., Hovestadt V., Sill M., Gramatzki D., Felsberg J., Reifenberger G., Koch A., Thomale U.-W., Becker A., Hans V.H., Prinz M., Staszewski O., Acker T., Dohmen H., Hartmann C., Mueller W., Tuffaha M.S.A., Paulus W., Hess K., Brokinkel B., Schittenhelm J., Monoranu C.-M., Kessler A.F., Loehr M., Buslei R., Deckert M., Mawrin C., Kohlhof P., Hewer E., Olar A., Rodriguez F.J., Giannini C., NageswaraRao A.A., Tabori U., Nunes N.M., Weller M., Pohl U., Jaunmuktane Z., Brandner S., Unterberg A., Hanggi D., Platten M., Pfister S.M., Wick W., Herold-Mende C., Jones D.T.W., von Deimling A., and Capper D.

Subjects
0301 basic medicine, Male, Medizin, Kaplan-Meier Estimate, Mitogen-Activated Protein Kinase Kinase, Histones, 0302 clinical medicine, CDKN2A, Retrospective Studie, Age Factor, 610 Medicine & health, Child, DNA Modification Methylases, Aged, 80 and over, Pilocytic astrocytoma, Brain Neoplasms, DNA Repair Enzyme, Age Factors, CDKN2A/B, Middle Aged, Molecular characterization, Isocitrate Dehydrogenase, Histone, ATRX, Child, Preschool, DNA methylation, Female, MGMT, Human, Signal Transduction, Adult, X-linked Nuclear Protein, IDH1, Adolescent, Panel sequencing, Biology, Astrocytoma, Pathology and Forensic Medicine, BRAF, DNA copy number alteration, Brain Neoplasm, 03 medical and health sciences, Cellular and Molecular Neuroscience, Young Adult, Glioma, DNA Modification Methylase, medicine, Humans, Gene, neoplasms, Cyclin-Dependent Kinase Inhibitor p16, Retrospective Studies, Pilocytic astrocytoma with anaplasia, Aged, Mitogen-Activated Protein Kinase Kinases, Tumor Suppressor Protein, Methylation profile based classification, Tumor Suppressor Proteins, Infant, DNA Methylation, medicine.disease, Anaplastic pilocytic astrocytoma, 030104 developmental biology, DNA Repair Enzymes, FGFR1, NF1, Mutation, Cancer research, 570 Life sciences, biology, Neurology (clinical), 030217 neurology & neurosurgery, Anaplastic astrocytoma
Abstract

Tumors with histological features of pilocytic astrocytoma (PA), but with increased mitotic activity and additional high-grade features (particularly microvascular proliferation and palisading necrosis) have often been designated anaplastic pilocytic astrocytomas. The status of these tumors as a separate entity has not yet been conclusively demonstrated and molecular features have only been partially characterized. We performed DNA methylation profiling of 102 histologically defined anaplastic pilocytic astrocytomas. T-distributed stochastic neighbor-embedding(t-SNE) and hierarchical clustering analysis of these 102 cases against 158 reference cases from 12 glioma reference classes revealed that a subset of 83 of these tumors share a common DNA methylation profile that is distinct from the reference classes. These 83 tumors were thus denominated DNA methylation class anaplastic astrocytoma with piloid features (MC AAP). The 19 remaining tumors were distributed amongst the reference classes, with additional testing confirming the molecular diagnosis in most cases. Median age of patients with MC AAP was 41.5years. The most frequent localization was the posterior fossa (74%). Deletions of CDKN2A/B (66/83, 80%), MAPK pathway gene alterations (49/65, 75%, most frequently affecting NF1, followed by BRAF and FGFR1) and mutations of ATRX or loss of ATRX expression (33/74, 45%) were the most common molecular alterations. All tumors were IDH1/2 wildtype. The MGMT promoter was methylated in 38/83 tumors (45%). Outcome analysis confirmed an unfavorable clinical course in comparison to PA, but better than IDH wildtype glioblastoma. In conclusion, we show that a subset of histologically defined anaplastic pilocytic astrocytomas forms a separate DNA methylation cluster, harbors recurrent alterations in MAPK pathway genes in combination with alterations of CDKN2A/B and ATRX, affects patients who are on average older than those diagnosed with PA and has an intermediate clinical outcome.

Published
2018

98. Treatment response as surrogate to predict risk for disease progression in pediatric medulloblastoma with persistent magnetic resonance imaging lesions after first-line treatment.

Author

Obrecht-Sturm D, Schömig L, Mynarek M, Bison B, Schwarz R, Pietsch T, Pfister SM, Sill M, Sturm D, Sahm F, Kortmann RD, Gerber NU, von Bueren AO, Fleischhack G, Schüller U, Nussbaumer G, Benesch M, and Rutkowski S

Subjects
Humans, Male, Child, Female, Child, Preschool, Adolescent, Follow-Up Studies, Prognosis, Retrospective Studies, Survival Rate, Infant, Neoplasm, Residual diagnostic imaging, Neoplasm, Residual pathology, Medulloblastoma diagnostic imaging, Medulloblastoma pathology, Magnetic Resonance Imaging methods, Cerebellar Neoplasms diagnostic imaging, Cerebellar Neoplasms pathology, Disease Progression
Abstract

Background: This study aims at clarifying the impact of persistent residual lesions following first-line treatment for pediatric medulloblastoma., Methods: Data on 84 pediatric patients with medulloblastoma and persistent residual lesions on centrally reviewed magnetic resonance imaging (MRI) at the end of first-line therapy were analyzed., Results: Twenty patients (23.8%) had residual lesions in the tumor bed (R+/M0), 51 (60.7%) had distant lesions (R0/M+) and 13 (15.5%) had both (R+/M+). Overall response to first-line therapy was minor or partial (≥ 25% reduction, minor response [MR]/PR) for 64 (76.2%) and stable disease (SD) for 20 patients (23.8%). Five-year post-primary-treatment progression-free (pptPFS) and overall survival (pptOS) were superior after MR/PR (pptPFS: 62.5 ± 7.0%[MR/PR] vs. 35.9 ± 12.8%[SD], P = .03; pptOS: 79.7 ± 5.9[MR/PR] vs. 55.5 ± 13.9[SD], P = .04). Furthermore, R+/M + was associated with a higher risk for progression (5-year pptPFS: 22.9 ± 17.9%[R+, M+] vs. 72.4 ± 12.0%[R+, M0]; P = .03). Watch-and-wait was pursued in 58 patients, while n = 26 received additional treatments (chemotherapy only, n = 19; surgery only, n = 2; combined, n = 3; valproic acid, n = 2), and their outcomes were not superior to watch-and-wait (5-year pptPFS: 58.5 ± 7.7% vs. 51.6 ± 10.7% P = .71; 5-year pptOS: 76.3 ± 6.9% vs. 69.8 ± 9.7%, P = .74). For the whole cohort, 5-year pptPFS by molecular subgroup (58 cases) were WNT: 100%, SHH: 50.0 ± 35.4%, group-4, 52.5 ± 10.5, group-3 54.2 ± 13.8%; (P = .08)., Conclusions: Overall response and extent of lesions can function as surrogate parameters to predict outcomes in pediatric MB patients with persistent lesions after first-line therapy. Especially in the case of solitary persistent medulloblastoma MRI lesions, additional therapy was not beneficial. Therefore, treatment response, extent/kind of residual lesions and further diagnostic information need consideration for indication of additional treatments for persisting lesions., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Published
2024
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99. Clinical and molecular risk factors in extracranial malignant rhabdoid tumors - Towards an integrated model of high-risk tumors.

Author

Fincke VE, Steinbügl M, Chun HE, Nemes K, Mucha M, Loßner M, Dorn F, Gastberger K, Bühner S, Sill M, Kröncke T, Siebert R, Melchior P, Furtwängler R, Schlesner M, Vokuhl C, Rocken C, Johann PD, and Frühwald MC

Abstract

Purpose: Extracranial malignant rhabdoid tumors (eMRT) are a challenging entity. Despite the use of multimodal treatment approaches, therapy failure occurs in 55-67%. Molecular markers for identification of patients at increased risk for relapse or refractory (R/R) disease are not available. Clinical characteristics may only insufficiently predict the individual course of disease., Experimental Design: Using the EU-RHAB database, we analyzed a cohort of 121 patients with eMRT clinically. For 81 patients, molecular and clinical data was available, which was complemented with publicly available DNA molecular data from 92 further eMRT. We aimed to delineate molecular risk factors by dissecting the DNA methylome of these tumors. Moreover, we establish clinical characteristics and treatment details of R/R disease in a subcohort of 80 patients., Results: Using consensus hierarchical clustering, we identified three distinct subgroups, one of which (eMRT standard risk) was associated with significantly improved survival, irrespective of germline status and/or localization. At the transcriptome level, this subgroup is characterized by an overexpression of genes involved in muscle development. A relevant proportion of patients develop distant relapses or progressions; median time to the event was four months, underlining the need for early identification and risk-stratification of R/R disease. Overall survival was significantly decreased in patients with progressive disease when compared to relapse cases and reaching complete remission during salvage therapy provided a survival benefit., Conclusions: Our analysis of eMRT in this comprehensive cohort provides novel insights into the patterns of relapse and integrates molecular and clinical risk factors to guide clinical decision making.

Published
2024
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100. EpiDiP/NanoDiP: a versatile unsupervised machine learning edge computing platform for epigenomic tumour diagnostics.

Author

Hench J, Hultschig C, Brugger J, Mariani L, Guzman R, Soleman J, Leu S, Benton M, Stec IM, Hench IB, Hoffmann P, Harter P, Weber KJ, Albers A, Thomas C, Hasselblatt M, Schüller U, Restelli L, Capper D, Hewer E, Diebold J, Kolenc D, Schneider UC, Rushing E, Della Monica R, Chiariotti L, Sill M, Schrimpf D, von Deimling A, Sahm F, Kölsche C, Tolnay M, and Frank S

Subjects
Humans, Unsupervised Machine Learning, Cloud Computing, DNA Methylation, Epigenomics, Neoplasms diagnosis, Neoplasms genetics
Abstract

DNA methylation analysis based on supervised machine learning algorithms with static reference data, allowing diagnostic tumour typing with unprecedented precision, has quickly become a new standard of care. Whereas genome-wide diagnostic methylation profiling is mostly performed on microarrays, an increasing number of institutions additionally employ nanopore sequencing as a faster alternative. In addition, methylation-specific parallel sequencing can generate methylation and genomic copy number data. Given these diverse approaches to methylation profiling, to date, there is no single tool that allows (1) classification and interpretation of microarray, nanopore and parallel sequencing data, (2) direct control of nanopore sequencers, and (3) the integration of microarray-based methylation reference data. Furthermore, no software capable of entirely running in routine diagnostic laboratory environments lacking high-performance computing and network infrastructure exists. To overcome these shortcomings, we present EpiDiP/NanoDiP as an open-source DNA methylation and copy number profiling suite, which has been benchmarked against an established supervised machine learning approach using in-house routine diagnostics data obtained between 2019 and 2021. Running locally on portable, cost- and energy-saving system-on-chip as well as gpGPU-augmented edge computing devices, NanoDiP works in offline mode, ensuring data privacy. It does not require the rigid training data annotation of supervised approaches. Furthermore, NanoDiP is the core of our public, free-of-charge EpiDiP web service which enables comparative methylation data analysis against an extensive reference data collection. We envision this versatile platform as a useful resource not only for neuropathologists and surgical pathologists but also for the tumour epigenetics research community. In daily diagnostic routine, analysis of native, unfixed biopsies by NanoDiP delivers molecular tumour classification in an intraoperative time frame., (© 2024. The Author(s).)

Published
2024
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