The look of the cinema to cancer: when pediatric oncology is the protagonist. La mirada del cine al cáncer: cuando la Oncología pediátrica es la protagonista

Rev Pediatr Aten Primaria vol.14 no.56 Madrid oct./dic. 2012

http://dx.doi.org/10.4321/S1139-76322012000500013 

COLABORACIONES ESPECIALES

La mirada del cine al cáncer (II): cuando la Oncología pediátrica es la protagonista

The look of the cinema to cancer (II): when pediatric oncology is the protagonist

J. González de Dios^a, M. Tasso Cereceda^b y B. Ogando Díaz^c

^aServicio de Pediatría, Unidad de Neonatología. Hospital General Universitario de Alicante. Departamento de Pediatría. Universidad Miguel Hernández. Alicante. España. Autor del libro Cine y Pediatría: una oportunidad para la docencia y la humanización en nuestra práctica clínica
^bServicio de Pediatría, Unidad de Oncología Pediátrica. Hospital General Universitario de Alicante. Alicante. España. Magíster en Bioética y en Medicina Humanitaria
^cMédico de Familia. CS Casa de Campo. Madrid. España. Magíster en Bioética y en Cuidados Paliativos.

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RESUMEN

El cáncer infantil es la segunda causa más frecuente de mortalidad infantil en niños con edades comprendidas entre 1 y 14 años. El cáncer infantil en el cine camina entre la ciencia y la ficción.
El cáncer infantil llevado a la gran pantalla se puede clasificar en dos grandes grupos: 1) la leucemia es, con gran diferencia, el principal protagonista entre las enfermedades oncológicas en el cine; 2) el otro grupo es un cajón de sastre en el que podemos incluir el resto de enfermedades oncológicas de la infancia y adolescencia.
En este artículo establecemos un recorrido por la Oncología pediátrica a través de 15 títulos de películas (nueve con la leucemia como protagonista y otras seis con otros tipos de cánceres).
De la recopilación realizada, destacamos diez títulos, por ser películas que atesoran valores y que pueden ayudar a mejorar la relación médico-paciente: y de ellas, hemos considerado cinco títulos como imprescindibles (Camino, Cartas a Dios, Cartas al Cielo, Declaración de guerra y Surviving Amina) y cinco títulos como adecuados (El llanto de la mariposa, La decisión de Anne, Maktub, Planta 4.^a y Vivir para siempre).
En una patología tan sensible para pacientes, familiares y profesionales sanitarios como es el cáncer en la infancia y adolescencia, no solo hay que prescribir sofisticadas pruebas diagnósticas y modernos tratamientos, sino también películas (antiguas y modernas), que ayudan a comprender la enfermedad, a mejorar el duelo, a humanizar la atención y a mejorar la relación entre profesionales sanitarios y pacientes.

Palabras clave: Cáncer. Cine. Contexto social. Enfermedad. Oncología. Pediatría. Relación médico-paciente.

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ABSTRACT

Childhood cancer is the second most common cause of infant mortality in children aged 1 to 14 years. Childhood cancer in films walks between science and fiction.
Childhood cancer brought to the cinema can be classified into two groups: 1) leukemia is, by far, the main protagonist of oncological diseases in films, 2) the other group is a rag bag in which we can include the rest of oncological diseases of childhood and adolescence.
In this article we make a tour of the childhood cancer diseases through 15 movies: nine with leukemia as protagonist and another six with other types of cancers. From this compilation, we want to highlight ten titles that can help to improve the humanization and doctor-patient relationship: five of them are essential (Camino, La guerre est déclarée, Letters to God, Oscar et la dame rose and Surviving Amina) and the five other are appropriate (Der Schrei des Schmetterlings, Maktub, My Sister´s Keeper, Planta 4.^a and Vivir para siempre).
In a disease such as cancer in childhood and adolescence, so sensitive to patients, families and health professionals, it is important not only to prescribe modern and sophisticated diagnostic tests and treatments, but also movies (old and new), films that help to understand disease, improve the duel, to humanize care and improve the relationship between health professionals and patients.

Key words: Cinema. Cancer. Social context. Disease. Oncology. Pediatrics. Physician-patient relationship.

More information: http://scielo.isciii.es/scielo.php?script=sci_arttext&pid=S1139-76322012000500013

El doctor Javier González de Dios nos facilita el enlace de la Asociación de Médicos Escritores y Artistas (ASEMEYA) que trabaja por la humanización a través del séptimo arte:

https://asemeya.com/trabajos/literarios/javier-gonzalez-de-dios/cine-y-medicina

También este enlace donde se muestran los libros publicados sobre pediatría y cine:

http://www.luaediciones.com/lua/index.php/publicaciones/libros/coleccion-pediatria/cine-y-pediatr%C3%ADa-6-79-detail

O la página de facebook "Cine, solo cine".
https://www.facebook.com/groups/165845516760682/?%20jazoest=2651001198470711119978976611895116531199571661021131061107211982119519911995709510251117851197453767410784678158651001197712076835012165107746710187674985759910211582105114869953110121901185211883906910990109687365111117103

Aunque en el artículo no se menciona esta película, Paco Arango, su director y presidente de ALADINA, la dirigió donando los beneficios en su totalidad a campamentos para niños enfermos.

Molecular features of pleomorphic xanthoastrocytoma. Características moleculares del xantoastrocitoma pleomórfico

Molecular features of pleomorphic xanthoastrocytoma☆

Author links open overlay panelHanZouMDabYumeiDuanMAcDongliangWeiMAdYiqianZhangMDaJiachengDaiMAeJunzhiLiMAfXiaojieLiMAgJianhuaZhouMDchZhixiongLiuMDbZhongyuanJinMDchZhouZhangPhDiYangYuMDaZhongliangHuMD PhDchj

https://doi.org/10.1016/j.humpath.2018.08.038Get rights and content

Highlights

•

Mutations of BRAF, FANC family, PRKDC, NF1, and NOTCH family are common in PXA.

•

Mutations of FANCA and BRAF and CNV in CDKN2A/B may distinguish PXA from glioblastoma multiforme.

•

The MAPK pathway is involved in the pathogenesis of PXA.

Summary

Pleomorphic xanthoastrocytoma (PXA) is a rare central nervous system tumor occurring mostly in children and young adults. Next-generation sequencing of 295 cancer-related genes was used to investigate the molecular profiles of 13 cases of PXA. We found that BRAF V600E (5/13; 38%), FANCA/D2/I/M (5/13; 38%), PRKDC (4/13; 31%), NF1 (3/13; 23%), and NOTCH2/3/4 (3/13; 23%) alterations were the most frequent somatic gene mutations. However, neither PTEN nor EGFR mutation, which is frequently present in glioblastoma, was detected. The KRAS mutation in PXA is reported for the first time in these tumors. Microsatellite stability was present in all cases. Because mutations of FANCA and BRAF and copy number variations of CDKN2A/B are more frequent in PXA than in glioblastoma, they might be used to distinguish the two tumors. The MAPK pathway is involved in the pathogenesis of PXA and may be an effective target for treatment.

Keywords

MAPK Pathway

Next-Generation Sequencing

Pleomorphic Xanthoastrocytoma

☆

Conflict of interest: The authors declare no conflicts of interest.

Funding: This work was supported by the Undergraduate Free Exploration Program of Central South University (Grant Number ZY2016715) and the Undergraduate Innovation Training Program of Central South University (Grant Number CX20170481).

© 2018 Elsevier Inc. All rights reserved.

Article | Open | Published: 24 September 2018

Pleomorphic xanthoastrocytomas of adults: MRI features, molecular markers, and clinical outcomes

• Jing Yan,
• Jingliang Cheng,
• Furong Liu &
• Xianzhi Liu 

Scientific Reportsvolume 8, Article number: 14275 (2018) | Download Citation

Abstract

Fifty adult patients with pathologically-confirmed pleomorphic xanthoastrocytomas (PXAs) were retrospectively analyzed. Adult PXAs appeared as a single lesion in 47 patients and multiple lesions in 3 patients. Temporal lobe was the most common location (17/50). Twenty-two cases were superficial with obvious meningeal contact and 9 were closely adjacent to lateral ventricles. Three imaging patterns were differentiated, including a predominantly solid mass with or without cystic changes (n = 33), a predominantly cystic mass with an obvious mural nodule (n = 14), and a predominantly cystic mass with an uneven wall thickness (n = 3). The mean tumoral apparent diffusion coefficient (ADC) was 0.83 ± 0.17 × 10−3 mm2/s, and the mean ADC ratio was 1.02 ± 0.22. The V-raf murine sarcoma viral oncogenes homolog B1 (BRAF)V600E mutation was found in 12 of 29 patients. In 36 patients with isocitrate dehydrogenases 1 and 2 (IDH1/2) data, only one had IDH1 mutation and no patient had IDH2 mutation. Anaplastic features were common (24/50) and significantly associated with high rates of recurrence or progression (P < 0.001). In conclusion, this study expands our knowledge on the MRI features, molecular markers, and clinical outcomes of adult PXAs, to some extent different from pediatric PXAs.

...

Patient characteristics

Of these 50 patients, 31 were males and 19 were females. The median age at diagnosis was 36 years, ranged from 18 to 67 years. Headaches were the most frequent symptoms at diagnosis and were seen in 24 patients (48%), followed by seizures in 15 patients (30%), focal neurological deficits in 13 patients (26%), and visual disturbances in 11 patients (22%). The duration of symptoms ranged from 4 days to 20 years.

...

Clinical outcomes

As shown in Table 1, 30 patients, including 17 cases with Grade II PXA and 13 cases with Grade III anaplastic PXA, were successfully followed up (range: 3 months to 4.5 years). Out of the 30 patients, 14 cases had evidence of recurrence or progression (including 2 cases with Grade II PXA and 12 cases with Grade III anaplastic PXA), and one case eventually died. The rates of recurrence or progression were higher in patients diagnosed with Grade III anaplastic PXA (92%) compared to those diagnosed with Grade II PXA (12%), with statistical significance (P < 0.001).

...

BRAFV600E and IDH1/2 mutations analysis

Five 10-µm sections from each selected FFPE block were subjected to genomic DNA extraction. DNA was isolated using E.Z.N.A.® FFPE DNA kit (D3399-02; Omega Bio-tek, US) according to the manufacturer’s instructions. Next, the genomic DNA was amplified by polymerase chain reaction (PCR) and the PCR products were purified. The purified products were sequenced and then analyzed using Chromas Lite software. Compared with the reference sequence, the BRAFV600E mutation and IDH1/2 alterations in the hotspot codons R132H and R172K were obtained.

...

https://rdcu.be/bbxLI

About this article

Publication history

Received

16 February 2017

Accepted

31 August 2018

Published

24 September 2018

DOI

https://doi.org/10.1038/s41598-018-32273-w

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About Xanthoastrocytoma: Mayo Clinic Connect

Mayo Clinic Connect is an online community where you can share your experiences and find support from people like you. You can also read Mayo Clinic expert blogs and take part in educational events.

Follow the groups that interest you. Choose from the groups below or search by keywords. 

In the braint tumor group there is a line on the xanthoastrocytoma where the people related to the turmoil tell us about their experience.

Here you can find people who are in a similar situation to us and maybe they will give us some interesting information.

https://connect.mayoclinic.org/discussion/pxa-help/

If you want to share other activa chats the other clinics or hospital about xanthoastrocytoma, send me the information to publish it.

I show you a piece of conversation ... Of course insist that professional and good neurosurgeons, oncologists and radiotherapists we can find them in Spain, Germany, France, Canada, Israel, the United States and many other countries ...

Posted by audrapopp @audrapopp, Wed, Jun 28, 2017 9:21pm
In reply to @colleenyoung "Welcome to Connect, @lmp1. I'd like to introduce you to @audrapopp. She,..." + (show)

First, thank you Colleen for connecting us… because it is such a rare tumor it is difficult, if ever to connect with others and I am happy to be an advocate, support and here for any questions you or your daughter may have. First of all~ Complete surgical resection is currently the best treatment option for this tumor type, that being said~ your best defense is truly “the best neurosurgeon” you can find! If I understand correctly she has not had radiation treatment or chemotherapy of any kind yet. I’m saddened they haven’t connected you with a Neuro-Oncologist yet… sorry, but that alone makes me question her neurosurgeon. Second, what is the pathology report showing from her first tumor? Is it Anaplastic (Grade 3?) I can only assume it is since it has recurred so quickly. Have they tested for the BRAF V600e mutation? Many PXA’s are showing it to be positive for this mutation and there have been a few reports of using targeted mutation therapy with BRAF inhibitors that are shrinking the tumors (Tafinlar & Mekinist drug combination or Veberafinib alone.) I have a lot more info on these if you need and have recently been on them. The BRAF mutation has been found in melanoma, lung and colon cancers and these drugs have been FDA approved for Melanoma so far. Unfortunately, since PXA is so rare my insurance company would not approve the drugs for me, even with an appeal…but luckily the pharmaceutical supplier Novartis granted me a one year supply of the drugs thru the Novartis patient assistance Foundation. If your daughter goes the drug route her MD needs to get applications started ASAP. My insurance process (application, denial & appeal) took well over a quite agonizing month! If she doesn’t do surgery she may want to consider a biopsy to see if her pathology has changed since her surgery 4 months ago. I can’t emphasize enough that she needs to be seen sooner than later by a well qualified Neuro-oncologist to get the best treatment advice going forward. It may mean getting on a plane..but trust me, it will be worth it. Mayo has an easy referral request process. My Neuro-oncologist sees patients both in Rochester, MN and the Mayo campus in Jacksonville, FL. I hope this helps and can continue the conversation. I’m sure you have lots of questions and I’m happy to answer.
With HOPE all things are possible, Audra

Colleen Young, Connect Director send us this information:

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Cancer Cell

Cancer Cell. 2018 May 14; 33(5): 829–842.e5.

doi:  [10.1016/j.ccell.2018.04.004]

PMCID: PMC5956280

PMID: 29763623

Molecular, Pathological, Radiological, and Immune Profiling of Non-brainstem Pediatric High-Grade Glioma from the HERBY Phase II Randomized Trial

Alan Mackay,^1,2 Anna Burford,^1,2 Valeria Molinari,^1,2 David T.W. Jones,^3,4 Elisa Izquierdo,^1,2 Jurriaan Brouwer-Visser,⁶ Felice Giangaspero,^7,8 Christine Haberler,^9,10 Torsten Pietsch,¹¹ Thomas S. Jacques,^12,13 Dominique Figarella-Branger,¹⁴ Daniel Rodriguez,¹⁵ Paul S. Morgan,¹⁵ Pichai Raman,^16,17 Angela J. Waanders,^16,18 Adam C. Resnick,^16,17,18 Maura Massimino,¹⁹ Maria Luisa Garrè,²⁰ Helen Smith,²¹ David Capper,^22,23,24 Stefan M. Pfister,^3,4,5 Thomas Würdinger,²⁵ Rachel Tam,²⁶ Josep Garcia,²¹ Meghna Das Thakur,²⁶ Gilles Vassal,²⁷ Jacques Grill,²⁷ Tim Jaspan,¹⁵ Pascale Varlet,²⁸ and Chris Jones^1,2,29,∗

Alan Mackay

¹Division of Molecular Pathology, The Institute of Cancer Research, 15 Cotswold Road, Sutton, London, Surrey SM2 5NG, UK
²Division of Cancer Therapeutics, The Institute of Cancer Research, 15 Cotswold Road, Sutton, London, Surrey SM2 5NG, UK

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Anna Burford

¹Division of Molecular Pathology, The Institute of Cancer Research, 15 Cotswold Road, Sutton, London, Surrey SM2 5NG, UK
²Division of Cancer Therapeutics, The Institute of Cancer Research, 15 Cotswold Road, Sutton, London, Surrey SM2 5NG, UK

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Valeria Molinari

¹Division of Molecular Pathology, The Institute of Cancer Research, 15 Cotswold Road, Sutton, London, Surrey SM2 5NG, UK
²Division of Cancer Therapeutics, The Institute of Cancer Research, 15 Cotswold Road, Sutton, London, Surrey SM2 5NG, UK

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David T.W. Jones

³Hopp Children's Cancer Center at the NCT Heidelberg (KiTZ), Heidelberg, Germany
⁴Division of Paediatric Neuro-oncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany

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Elisa Izquierdo

¹Division of Molecular Pathology, The Institute of Cancer Research, 15 Cotswold Road, Sutton, London, Surrey SM2 5NG, UK
²Division of Cancer Therapeutics, The Institute of Cancer Research, 15 Cotswold Road, Sutton, London, Surrey SM2 5NG, UK

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Jurriaan Brouwer-Visser

⁶Roche Innovation Center, New York, NY, USA

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Felice Giangaspero

⁷Department of Radiology, Oncology and Anatomic-Pathology Sciences, Sapienza University, Rome, Italy
⁸IRCCS Neuromed, Pozzilli, Italy

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Christine Haberler

⁹Institute of Neurology, Medical University of Vienna, Vienna, Austria
¹⁰Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria

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Torsten Pietsch

¹¹DGNN Brain Tumor Reference Center, Institute of Neuropathology, University of Bonn Medical Center, Bonn, Germany

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Thomas S. Jacques

¹²UCL Great Ormond Street Institute of Child Health, London, UK
¹³Department of Histopathology, Great Ormond Street Hospital for Children, London, UK

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Dominique Figarella-Branger

¹⁴Department of Pathology and Neuropathology, La Timone Hospital, Aix Marseille University, Marseille, France

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Daniel Rodriguez

¹⁵Nottingham University Hospitals, Nottingham, UK

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Paul S. Morgan

¹⁵Nottingham University Hospitals, Nottingham, UK

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Pichai Raman

¹⁶The Center for Data Driven Discovery in Biomedicine (D³b), Children's Hospital of Philadelphia, Philadelphia, PA, USA
¹⁷Division of Neurosurgery, Children's Hospital of Philadelphia, Philadelphia, PA, USA

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Angela J. Waanders

¹⁶The Center for Data Driven Discovery in Biomedicine (D³b), Children's Hospital of Philadelphia, Philadelphia, PA, USA
¹⁸Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA, USA

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Adam C. Resnick

¹⁶The Center for Data Driven Discovery in Biomedicine (D³b), Children's Hospital of Philadelphia, Philadelphia, PA, USA
¹⁷Division of Neurosurgery, Children's Hospital of Philadelphia, Philadelphia, PA, USA
¹⁸Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA, USA

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Maura Massimino

¹⁹Pediatric Oncology Unit, Fondazione IRCCS, Istituto Nazionale Tumori, Milan, Italy

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Maria Luisa Garrè

²⁰Centro di Neuro-Oncologia, Istituto Giannina Gaslini, Genoa, Italy

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Helen Smith

²¹F. Hoffmann-La Roche Ltd, Basel, Switzerland

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David Capper

²²Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany
²³Berlin Institute of Health, Institute of Neuropathology, Berlin, Germany
²⁴Department of Neuropathology, University Hospital Heidelberg and Clinical Cooperation Unit Neuropathology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany

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Stefan M. Pfister

³Hopp Children's Cancer Center at the NCT Heidelberg (KiTZ), Heidelberg, Germany
⁴Division of Paediatric Neuro-oncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany
⁵Department of Pediatric Hematology and Oncology, Heidelberg University Hospital, Heidelberg, Germany

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Thomas Würdinger

²⁵Department of Neurosurgery, Brain Tumor Center Amsterdam, VU Medical Center, Amsterdam, the Netherlands

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Rachel Tam

²⁶Genentech, South San Francisco, CA, USA

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Josep Garcia

²¹F. Hoffmann-La Roche Ltd, Basel, Switzerland

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Meghna Das Thakur

²⁶Genentech, South San Francisco, CA, USA

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Gilles Vassal

²⁷Pediatric and Adolescent Oncology and Unite Mixte de Recherche 8203 du Centre National de la Recherche Scientifique, Gustave Roussy, Paris-Saclay University, Villejuif, France

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Jacques Grill

²⁷Pediatric and Adolescent Oncology and Unite Mixte de Recherche 8203 du Centre National de la Recherche Scientifique, Gustave Roussy, Paris-Saclay University, Villejuif, France

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Tim Jaspan

¹⁵Nottingham University Hospitals, Nottingham, UK

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Pascale Varlet

²⁸Sainte-Anne Hospital, Paris-Descartes University, Paris, France

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Chris Jones

¹Division of Molecular Pathology, The Institute of Cancer Research, 15 Cotswold Road, Sutton, London, Surrey SM2 5NG, UK
²Division of Cancer Therapeutics, The Institute of Cancer Research, 15 Cotswold Road, Sutton, London, Surrey SM2 5NG, UK

Find articles by Chris Jones

¹Division of Molecular Pathology, The Institute of Cancer Research, 15 Cotswold Road, Sutton, London, Surrey SM2 5NG, UK

²Division of Cancer Therapeutics, The Institute of Cancer Research, 15 Cotswold Road, Sutton, London, Surrey SM2 5NG, UK

³Hopp Children's Cancer Center at the NCT Heidelberg (KiTZ), Heidelberg, Germany

⁴Division of Paediatric Neuro-oncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany

⁵Department of Pediatric Hematology and Oncology, Heidelberg University Hospital, Heidelberg, Germany

⁶Roche Innovation Center, New York, NY, USA

⁷Department of Radiology, Oncology and Anatomic-Pathology Sciences, Sapienza University, Rome, Italy

⁸IRCCS Neuromed, Pozzilli, Italy

⁹Institute of Neurology, Medical University of Vienna, Vienna, Austria

¹⁰Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria

¹¹DGNN Brain Tumor Reference Center, Institute of Neuropathology, University of Bonn Medical Center, Bonn, Germany

¹²UCL Great Ormond Street Institute of Child Health, London, UK

¹³Department of Histopathology, Great Ormond Street Hospital for Children, London, UK

¹⁴Department of Pathology and Neuropathology, La Timone Hospital, Aix Marseille University, Marseille, France

¹⁵Nottingham University Hospitals, Nottingham, UK

¹⁶The Center for Data Driven Discovery in Biomedicine (D³b), Children's Hospital of Philadelphia, Philadelphia, PA, USA

¹⁷Division of Neurosurgery, Children's Hospital of Philadelphia, Philadelphia, PA, USA

¹⁸Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA, USA

¹⁹Pediatric Oncology Unit, Fondazione IRCCS, Istituto Nazionale Tumori, Milan, Italy

²⁰Centro di Neuro-Oncologia, Istituto Giannina Gaslini, Genoa, Italy

²¹F. Hoffmann-La Roche Ltd, Basel, Switzerland

²²Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany

²³Berlin Institute of Health, Institute of Neuropathology, Berlin, Germany

²⁴Department of Neuropathology, University Hospital Heidelberg and Clinical Cooperation Unit Neuropathology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany

²⁵Department of Neurosurgery, Brain Tumor Center Amsterdam, VU Medical Center, Amsterdam, the Netherlands

²⁶Genentech, South San Francisco, CA, USA

²⁷Pediatric and Adolescent Oncology and Unite Mixte de Recherche 8203 du Centre National de la Recherche Scientifique, Gustave Roussy, Paris-Saclay University, Villejuif, France

²⁸Sainte-Anne Hospital, Paris-Descartes University, Paris, France

Chris Jones: ku.ca.rci@senoj.sirhc

^∗Corresponding author ku.ca.rci@senoj.sirhc

²⁹Lead contact

Author information Article notes Copyright and License information Disclaimer

Received 2018 Jan 12; Revised 2018 Feb 28; Accepted 2018 Apr 10.

Copyright © 2018 The Author(s)

This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

This article has been cited by other articles in PMC.

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Summary

The HERBY trial was a phase II open-label, randomized, multicenter trial evaluating bevacizumab (BEV) in addition to temozolomide/radiotherapy in patients with newly diagnosed non-brainstem high-grade glioma (HGG) between the ages of 3 and 18 years. We carried out comprehensive molecular analysis integrated with pathology, radiology, and immune profiling. In post-hoc subgroup analysis, hypermutator tumors (mismatch repair deficiency and somatic POLE/POLD1 mutations) and those biologically resembling pleomorphic xanthoastrocytoma ([PXA]-like, driven by BRAF_V600E or NF1 mutation) had significantly more CD8⁺ tumor-infiltrating lymphocytes, and longer survival with the addition of BEV. Histone H3 subgroups (hemispheric G34R/V and midline K27M) had a worse outcome and were immune cold. Future clinical trials will need to take into account the diversity represented by the term “HGG” in the pediatric population.

Keywords: immune, CD8, MAPK, hypermutator, H3F3A, pediatric high-grade glioma

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Significance

We validate in the prospective clinical trial setting the biological and clinical diversity of pediatric high-grade glioma previously described in large retrospective series, underpinned by detailed pathological and radiological analysis. Although adding bevacizumab (BEV) to standard temozolomide/radiotherapy did not improve survival across the whole cohort, we identify disease subgroups with MAPK activation to harbor an enhanced CD8⁺ T cell immune response, which may derive benefit from the addition of BEV. If confirmed in another study, this would represent a useful predictive biomarker for this regimen in these tumors, and points the way for therapeutic strategies for subgroups of children with high-grade glioma.

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Introduction

High-grade gliomas (HGGs) in children, like their adult counterparts, continue to have a bleak prognosis, with a median overall survival (OS) of 9–15 months (Cohen et al., 2011, Jones et al., 2016, Ostrom et al., 2015). Recent integrated molecular-profiling initiatives have shown that pediatric HGGs (pHGGs) are biologically distinct from their adult counterparts, with subgroups of the disease marked by recurrent mutations in genes encoding histone H3 variants having different age of incidence, anatomical location, clinical outcome, and a range of biological parameters (Jones and Baker, 2014, Mackay et al., 2017, Paugh et al., 2010, Schwartzentruber et al., 2012, Sturm et al., 2012, Wu et al., 2012, Wu et al., 2014). Histone wild-type (WT) tumors have widely differing mutational burdens, ranging from infant cases (<3 years) driven by single gene fusion events through to patients with biallelic mismatch repair deficiency harboring some of the highest mutational rates in human cancer (Jones and Baker, 2014, Mackay et al., 2017, Shlien et al., 2015, Wu et al., 2014).

The rapid advances in our understanding of pHGGs have come predominantly from the accumulation of numerous disparate retrospective collections, a reflection of the rarity of the disease. Clinical trial cohorts with ancillary biomarker analyses have been relatively limited in their scope, and historically have focused on single-marker analyses. These include the Children's Oncology Group ACNS0126 (radiotherapy [RT]/temozolomide [TMZ]) (Cohen et al., 2011) and ACNS0423 (RT/TMZ followed by TMZ and lomustine) (Jakacki et al., 2016) studies, which report on the frequency and clinical correlations of O6-methylguanine-DNA methyltransferase (MGMT) expression (ACNS0126) (Jakacki et al., 2016, Pollack et al., 2006), IDH1 mutation (ACNS0423) (Pollack et al., 2011), as well as phosphorylated Akt expression (Pollack et al., 2010a) and microsatellite instability (both) (Pollack et al., 2010b). The CCG-945 study (“8 in 1” chemotherapy) (Finlay et al., 1995) reported on the prognostic significance of p53 expression/mutation (Pollack et al., 2002), in addition to the presence/absence of 1p19q co-deletion (Pollack et al., 2003b).

This last study (Pollack et al., 2003b) also highlighted the critical importance of pathological review in the diagnosis of pHGG, and subsequent interpretation of clinical trial results (Gilles et al., 2008, Pollack et al., 2003a), particularly in midline locations (Eisenstat et al., 2015). It has subsequently become clear that numerous histological subtypes of HGG can harbor distinct genetic drivers and have considerably better clinical outcomes, such as BRAF_V600E mutations in epithelioid glioblastoma (GBM), anaplastic ganglioglioma, and anaplastic pleomorphic xanthoastrocytoma (PXA) (Hatae et al., 2016); in the latter two categories, this mutation is also found in lower-grade entities lacking obvious anaplasia. Additional histone WT cases of otherwise uncontroversial HGGs have been found to be biologically and clinically more similar to several types of low-grade glioma (LGG) and PXA (Korshunov et al., 2015), highlighting the importance of an integrated diagnosis combining molecular and histological features.

The HERBY trial (study BO25041; clinicaltrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01390948","term_id":"NCT01390948"}}NCT01390948) was a phase II, open-label, randomized, multicenter, comparator study of the addition of the anti-angiogenic agent bevacizumab (BEV) to RT and TMZ in patients between the ages of 3 and 18 years with newly diagnosed non-brainstem HGG (Grill et al., 2018). Central confirmation of HGG diagnosis was mandatory before randomization, followed by consensus review by five independent expert neuropathologists. Real-time panel radiological assessment was also incorporated. An exploratory endpoint of the study was to establish a biospecimen repository for correlative molecular profiling. In addition to its role in tumor angiogenesis, vascular endothelial growth factor (VEGF) restricts immune cell activity, and BEV has been demonstrated to facilitate recruitment of T cells to infiltrate tumors (Wallin et al., 2016), as well as increase the ratio of CD8⁺CD3⁺ T cells in adult GBM specimens (Scholz et al., 2016). We therefore also sought to explore the immune profile of cases within the HERBY cohort.

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Results

The Translational Research Cohort Is Representative of the Whole Clinical Trial Population

The total HERBY cohort comprised 121 randomized patients at diagnosis (3–18 years) plus 3 infant cases (<3 years) at relapse. Of these, 113 patients consented to the translational research program (Table S1). Tumor tissue was collected from either resection (n = 93) or biopsy (n = 20), although 24 cases failed to provide sufficient quantity or quality of sample for molecular analysis. For the remaining 89 cases, material was available in the form of either fresh-frozen material (n = 36), formalin-fixed paraffin-embedded pathology specimens (n = 79), or both (n = 26). These were subjected to Sanger sequencing for H3F3A (n = 89), exome sequencing (n = 86), Illumina 450k methylation BeadChip profiling (n = 74), CD8 immunohistochemistry (n = 70), methylation-specific PCR for MGMT promoter methylation (n = 36), a capture-based sequencing panel for common fusion gene detection (n = 68), and RNA sequencing (RNA-seq) (n = 20) (Figure 1A).

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https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5956280/