EPSA Science!Monthly: The Science of Paediatric Cancer

The Science of Paediatric Cancer

February Edition 2023

Dear reader,

I am happy to welcome you to the first edition of S!M in 2023; the February edition. Each year in February, all EPSA members are dedicated to raising awareness about cancer, and so does S!M. In this edition, we are tackling childhood cancer, a topic that is sometimes overseen in the world of cancer and innovative therapies, therefore, in S!M we are shedding the light on it considering how important it is.

Cancer can be treated and, sometimes, cured; however, treatment traces are very harsh, especially in children. In the first article, you will learn with NCODA what it means to be cured of paediatric cancer. Is it always good news that the cancer is gone?

There are diverse types of childhood malignancies, but the most common ones are nervous system and blood cancers which will be explained in the second and third articles

Besides that, you will get to know more about the humanitarian work and campaigns organised by NCODA and by our member association NAPSer to defeat cancer and increase awareness towards it. Have you heard of “Be The Match” and what you can donate to people with cancer to enhance its cure? If not yet, do not miss reading about NCODA’s contribution to this initiative.

Enjoy reading and reach out to me if you want to become an author of the upcoming editions.

Rahaf Alsayyed Science Coordinator 2022-2023

National Community Oncology Dispensing Association (NCODA)

NCODA is an international not-for-profit oncology organisation committed to developing unique resources to help medically integrated oncology teams deliver toptier care. NCODA’s focus is centered around patient-centered, collaborative care. NCODA’s vision is to become the world leader in oncology by building a patientcentered medically-integrated community whose focus is to innovate the continuity of cancer care so every patient receives the maximum benefit from their cancer treatment. All healthcare students worldwide can register for complimentary NCODA membership using the following link: https://www.ncoda.org/join-ncoda/

Association nationale des etudiants en pharmacie de france (ANEPF)

ANEPF is the national association of French pharmacy students, created in 1968. It is a non-profit association, which represents all pharmacy faculties in France, and therefore all pharmacy students in France from the first to the sixth year of study, representing 33 000 students.

Our main goal is to bring the claims of students to several different levels, with the aim of enhancing initial studies while promoting interprofessionalism and the proper care of patients.

We advocate on many issues for students, such as public health, social affairs, academic affairs, environmental transition, European and international affairs and mobility, mentoring, industry, pharmacy, digital health, solidarity, and student representatives, which testify to the deep involvement of the future generation of pharmacists in solidarity commitments, peer support and outreach for our profession.

What it Means To Be Cured: Long-term Side Effects of Childhood Cancer

Cancer is nondiscriminatory and affects people of all races, religions, ethnicities, genders, and ages. More importantly, it affects children across the world. It is estimated that each year 400,000 children aged 0-19 will develop cancer globally1 . The most common childhood cancer is acute lymphoblastic leukaemia, which is estimated to account for 19% of total childhood cancer incidence, followed by nonHodgkin lymphoma (5%), nephroblastoma (5%), Burkitt lymphoma (5%) and retinoblastoma (5%)1. In 2020, 16,000 children were diagnosed with cancer in Europe, and it is estimated that around 10,000 children under the age of 15 in the United States will be diagnosed with cancer in 20232,3. However, with the advances in technology and cancer treatment, 85% of children with cancer now survive 5 years or more2 . According to the National Cancer Institute, a person is considered to be a cancer survivor from the time of diagnosis to until the end of life. Currently, there are between 300,000 and 500,000 childhood cancer survivors in Europe and an estimated 17 million childhood cancer survivors in the United States4

Although remission and cure rates are promising in paediatric cancer patients, the cure often comes with a cost and puts them at a higher risk for other health complications. Ensuring paediatric patients are cared for after treatment will help increase their quality of life and allow them to get back to everyday activities. Longterm survivors of childhood cancer are more likely to have diminished health status and die prematurely5 Exposure to radiation and chemotherapy puts children at a high risk of developing side effects. These complications of childhood cancer treatment can appear months or years after being cured (late effects), while others appear during active treatment and remain for some time after completion (long-term effects)5,6 Approximately two-thirds of childhood cancer survivors experience at least one chronic medical problem5 The most common late side effects of childhood cancer are neurocognitive and psychological, cardiopulmonary, endocrine, musculoskeletal, and secondary malignancies5,6

Neurocognitive

Neurocognitive late effects are prominent in children whose cancer or treatment involves the central nervous system5. Treatment including radiation to the whole brain, systemic chemotherapy with high-dose methotrexate or cytarabine, or intrathecal chemotherapy can lead to neurocognitive side effects6. These late effects are some of the most debilitating and can become apparent within 1-2 years after receiving treatment6 . They may include learning problems, social difficulties, functional deficits, and long-term educational difficulties5 About 50%-60% of childhood cancer survivors will experience neurocognitive impairment resulting from their cancer or its treatment5 Since these long-term effects can be so debilitating, a baseline neuropsychological evaluation is recommended for patients who received treatment that may impact their neurocognitive functioning6. Screening should be repeated as clinically indicated and at key educational transition points to make sure children stay on track with their educational goals6

Psychological/Behavioral

Dealing with the burden of childhood cancer often leads to the development of psychological, social, and spiritual difficulties. Secondary to cancer treatment, patients may worry about the many aspects of survivorship, including the risk of relapses, dying, more treatments, potential problems with sexuality and fertility, body image, school and work performance, and social and family relationships. Risk factors for psychological complications can include CNS-directed therapy, hearing loss, female sex, family history of mental illness, younger age at diagnosis, lower household income, and lower educational achievement6. Despite the risk of dealing with these late side effects, most survivors and their families achieve normal levels of psychological and social functioning5. All childhood cancer survivors should undergo yearly exams focusing on education and/or vocational progress, social withdrawal, and mental health disorders. If needed, school counsellors or social workers can help children navigate their life post-cancer treatment6 .

Cardiopulmonary

Children with a history of childhood cancer can have long-term cardiopulmonary effects due to the various chemotherapy regimens their bodies were exposed to. 5year childhood cancer survivors have an 8.8-fold increased risk of mortality related to pulmonary complications6. There is an elevated risk when children receive bleomycin and alkylating agents such as cyclophosphamide and melphalan5,6. It is recommended that children who received these medications have an annual pulmonary exam along with pulmonary function tests to diagnose any problems as soon as possible6

Along with pulmonary complications, patients who were treated with anthracyclines and thoracic radiation are at risk for long-term cardiotoxic effects5. An estimated 60% of all childhood cancer survivors have a history of previous anthracycline exposure and/or radiation to the chest area6. Cardiotoxic side effects can include cardiomyopathy, congestive heart failure, ischemia, valvular disease, arrhythmias, and pericarditis6. It is recommended that children receive an annual comprehensive cardiac exam as well as an echocardiogram every 1-5 years depending on patientspecific factors6 .

Endocrine Function

Late side effects of the endocrine system can include thyroid dysfunction (hypo and hyperthyroidism), growth hormone deficiency, delayed puberty, and hypopituitarism5 . Approximately, 20-50% of childhood survivors experience some sort of endocrine complication5. Treatment with radiation and chemotherapy can also affect fertility and reproduction in these patients5. Depending on the age and intended treatment, fertility preservation should be offered if possible5

Screening for endocrine abnormalities is vital in childhood cancer survivors. Female survivors should have an annual exam focused on puberty, menstruation, pregnancy, and sexual function. Lab tests such as follicle-stimulating hormone, luteinizing hormone, and estradiol should be evaluated at age 13 and beyond as clinically indicated. Male survivors should have an annual exam focusing on puberty and sexual function. Measurement of testicular volume and semen analysis are two ways for patients to ensure proper development has occurred following cancer treatment. Testosterone levels can also be drawn if clinically indicated6

Musculoskeletal

Growing children are subject to the effects of chemotherapy and radiation on their bones5. Osteoporosis/osteopenia, avascular necrosis, scoliosis, and bone atrophy or hypoplasia are some of the skeletal side effects that can occur after cancer treatment6 Radiation effects on the bone might not be able to be seen during treatment but are more prominent as children continue to grow, especially during puberty5 Chemotherapy agents such as methotrexate can affect bone growth directly and indirectly by disrupting hormone systems. This is also the case for some ancillary (or supportive care) medications, such as corticosteroids5. Long-term survivors should have their bone density evaluated at baseline and then repeated as necessary6. An annual exam should also include a history of joint pain, swelling, immobility, and limited range of motion6. Children who are receiving treatment before they go through puberty should also have an annual spine exam for scoliosis and kyphosis until their growth is complete6

Secondary Malignancies

Childhood cancer survivors are at an increased risk of developing secondary malignancies6. The cumulative risk of secondary malignancies 20 years following primary treatment for childhood cancer is between 3%-10% and is 5 to 20 times greater than that expected in the general population5. Secondary malignancies are defined as a new (or different) type of cancer that develops at least 2 months after finishing treatment for the primary malignancy6. Radiation therapy has been linked with the development of thyroid cancer, breast cancer, melanoma, brain tumours, and bone and soft tissue sarcomas. Certain types of chemotherapy, such as alkylating agents and topoisomerase II inhibitors, are associated with the development of leukemia5. Eliminating radiation or reducing doses, along with altering chemotherapy schedules, can help reduce the risk of secondary malignancies5. Children who received radiation or chemotherapeutic agents with known carcinogenic effects should be informed of their risk and should be seen regularly by a healthcare provider familiar with their treatment and risks who can evaluate early signs and symptoms appropriately5

Survivors that received alkylating agents and anthracyclines should undergo yearly exams, for up to 10 years after exposure to the agent, focusing on fatigue, bleeding, and easy bruising. They should be counselled to report fatigue, pallor, or bone pain and should have a complete blood count and bone marrow examination as clinically indicated6 . Children who received radiation therapy should undergo yearly physical exams as well. Physicals should focus on the inspection of the skin and soft tissues in the irradiated field(s)6. It is important that childhood cancer survivors know about the proper screening to help reduce the risk of secondary malignancies.

New technology and advances in childhood cancer treatment have helped children diagnosed with cancer reach remission and cure and continue on with life. However, the long-term effects of cancer treatment can cause lingering physical and mental stress throughout the life of the child and into adulthood. It is important as healthcare professionals to be aware of these side effects and how to help survivors when needed. Furthermore, connecting the paediatric survivor (including necessary

caregivers) to proper follow-up care for monitoring and survivorship programs to promote continued overall wellness is essential to allow survivors to continue a healthy way of life.

Author: Yarelis Diaz-Rohena, PharmD | Oncology, Advocacy, Health Policy, and Equity Fellow | NCODA

Author: Elizabeth Engel, PharmD Candidate 2023 | NCODA Advanced Pharmacy Practice Intern | University of Toledo College of Pharmacy

Author: Kristie Fox, PharmD | Manager of Clinical Initiatives | NCODA

Paediatric Astrocytoma

Overall definition of Astrocytoma

Astrocytomas belong to the glioma types of cancer1. They are the most common type of brain and spinal cord tumour in children. Children may develop an astrocytoma at any age and both boys and girls are likely to be affected. An astrocyte is a large, starshaped cell that holds nerve cells in place and helps them develop and work the way they should by bringing them food and oxygen, for example. They also provide a protective effect to prevent diseases and infections.

In children, astrocytoma is usually located at the base of the brain. It is typically low grade, meaning that it develops slowly. However, there is a possibility that it will develop into a faster-growing tumor2

Most brain tumours result from gene or chromosomal mutations. However, researchers are uncertain about the cause of these mutations. Some chemicals may play a role in it, but research is still ongoing.

Symptoms and Diagnosis

The symptoms of astrocytomas are not very specific and can often evoke other pathologies found in children. They include nausea and vomiting, balance and walking problems, morning headaches, slowness of speech, and vision or hearing problems. Some of these symptoms may appear several months before a worsening of the general condition and are variable in their appearance because they depend on the location of the tumour3 .

In order to diagnose astrocytoma, the first step is taking the history of the patient's symptoms, followed by a basic neurological examination including balance and vision tests3 Following this examination, if general practitioners suspect a brain tumour, they prescribe a second battery of tests, mainly imaging. There are usually two choices, cranial tomography using X-rays or magnetic resonance imaging (MRI). These two techniques can confirm the presence of an abnormal mass in the brain4 . In order to confirm the nature of the tumour, a biopsy is necessary and consists of a sample of the tumour that is analysed in a pathology laboratory5

6-9

Treatments and prognosis

Prognosis is determined by the symptoms, age and general health status of the child, as well as by the severity of the condition. Staging is the process used to determine the spread and severity of cancer in children. However, there is no standard staging system for childhood astrocytomas. Rather, the treatment is based on whether the tumour is low-grade or high-grade. Also, if the tumour was recently diagnosed or it is a recurrence. The stage of the tumour describes how abnormal the cancer cells look under the microscope and how fast the tumour is likely to grow and spread.

Low-grade astrocytomas grow slowly and rarely spread to other parts of the brain and spinal cord or to other parts of the body. However, it should be watched closely because it may develop into a faster-growing tumour. On the contrary high-grade astrocytomas grow and spread quickly.

Childhood astrocytomas do not ordinarily spread to other areas of the body, but sometimes, keep growing or return after treatment. Progressive childhood astrocytoma is a type of cancer that continues to grow, spread and get worse. Progression of the disease may indicate a refractory (unresponsive) cancer to treatment. A recurrent childhood astrocytoma is a cancer that has recurred after being treated. The cancer might reappear in the same place as the first tumour or in other parts of the body. High-grade astrocytomas often recur within three years, either at the site where the cancer first formed or elsewhere in the CNS.

Astrocytoma management involves one or several of the options below:

Observation is monitoring a patient's condition closely without treatment until signs or symptoms appear or change. It may be used if the patient has no symptoms, such as patients with low-grade cancer, or if the tumour is small and discovered at the same time as another health problem. It is also important to follow the surgical removal of tumours until signs or symptoms appear or change.

Surgery is used for diagnosis and treatment purposes. After surgery, Magnetic Resonance Imaging (MRI) is performed to determine if any cancer cells remain. If any cancer cells are found, further treatment depends on either the location, grade and age of the child. Once all cancer cells are removed, and visible at the time of surgery, some patients may undergo chemotherapy or radiation therapy after surgery to kill the remaining cancer cells. Treatment given after surgery to lower the risk of cancer recurring is called adjuvant therapy.

Radiation: uses high-energy x-rays or other types of radiation to kill cancer cells or prevent them from growing. An external machine delivers radiation to the affected areas of the body. Some ways of delivering radiation therapy help to prevent the radiation from damaging nearby healthy tissue. Radiation therapy can affect growth and development, especially in young children. For children under 3 years old, chemotherapy can be used instead to delay or reduce the need for radiation therapy.

Chemotherapy: uses drugs to stop the growth of cancer cells, either by killing them or by stopping their division. When chemotherapy is administered orally or injected through veins or muscles, the drugs pass into the bloodstream and are delivered to cancer cells throughout the body (systemic chemotherapy). When chemotherapy is administered into the spinal fluid, an organ or a cavity such as the abdomen, the drugs primarily affect cancer cells in these areas (regional chemotherapy). The administered chemotherapy depends on the type of tumour and where the tumour has formed in the brain or spinal cord. Systemic combination chemotherapy is used to treat children with astrocytoma, and high-dose chemotherapy may be used to treat children with newly diagnosed high-grade astrocytoma.

Other options may include: high-dose chemotherapy followed by a stem cell transplant, targeted therapy, corticosteroids, antiseizure medicine, ventriculoperitoneal (VP) shunt, Supportive care Antibiotics, and hormones.

Cancer treatments are aggressive and associated with many harmful side effects. Usually, they start after the beginning of the treatment and can last for months or years after the end of the therapy. Short-term side effects are directly linked to the therapy

used and the underlying toxicity while late effects mechanisms (vision issues, endocrine dysregulation, blood vessel problems…) are still not totally understood10 .

Ongoing research

Actually, research on astrocytoma and more generally children's brain tumours is focused on different lines of sight. The first axis is mostly on the actual treatment and its effects on the normal cognitive development of children's brains. The global concern about long-term effects, especially on still-developing brain environments (neurons and supportive cells), emerged only a few years ago after an observation was made on children with cognitive impairment after being treated by both chemotherapy and radiotherapy for acute leukaemia. This kind of impairment is commonly called “chemobrain” and lasts for years, drastically affecting patients in their daily life11

The second research field is on innovative therapies leading to new targets or processes to reduce the tumour. A promising path emerging is the field of immunotherapy, a kind of biotherapy. Immunotherapy is based on the enhancement of the immune system specifically by targeting cancer cell markers allowing to improve T cell efficacy12 .

Besides these two research axes, there is still an underlying process of improvement in the global knowledge and understanding of the mechanisms involved in tumour formation and resistance to chemotherapy.

Childhood Leukaemia

Blood cancer is the main cancer that affects children stealing their smiles and future dreams. Leukaemia and lymphoma are two types of blood cancer that can affect children and are, alone, accountable for half of childhood cancer cases, as Leukaemia comes in the first place and lymphoma in the third place of the most common paediatric malignancies1. The main difference between lymphoma and leukaemia is that the former starts in the lymphocytes and the latter in blood cells precursors2

Leukaemia is classified into acute (fast growing) and chronic (slowly growing) leukaemia. Given that chronic Leukaemia is rare in children, it will not be addressed in this article. Acute leukaemia is divided into Acute Myeloid Leukaemia (AML) and Acute Lymphocytic Leukaemia (ALL) where the former starts in myeloid cells and the latter in lymphoid cells3 .

ALL is the most common leukaemia type in children and has two main subtypes: Tcell ALL and B-cell ALL, where B-cell ALL is responsible for roughly 85% of ALL cases in children1,3. The incidence of ALL is very high at the age between 2 and 3 years old, and studies showed that this malignancy starts in the uterus. Whereas AML, is less common and starts in myeloid cells (cells responsible for the formation of granulocytes, monocytes and macrophages, erythrocytes, and megakaryocytes)3 AML has a peak of incidence in the first two years that declines to nothing from 2 to 6 years old1

Some risk factors of leukaemia are1,3:

1. Genetic syndromes like Down Syndrome.

2. Inherited Immune system problems such as Shwachman-Diamond syndrome and ataxia-telangiectasia.

3. Having siblings with leukaemia

4. Lifestyle and environmental risks. Some studies found an association between drinking alcohol in pregnancy and leukaemia. Also, exposure to radiation and immune system suppression are important risk factors.

Childhood leukaemia is characterised by the following signs and symptoms: Leukaemia starts in bone marrow and after excessive proliferations, leukaemia cells leave the bone marrow to the circulation. Having that said, signs and symptoms can be related to the malfunction of any of the cellular blood components, and can be3:

1. Related to the lack of red blood cells

● Tiredness, weakness and feeling cold

● Dizziness

● Short breath and pale skin

2. Infections and fever are symptoms related to the shortage of functional white blood cells

3. Bruises and bleedings, for example nose and gum bleeding, are common symptoms resulting from platelets shortage.

4. Leukaemia cells accumulation in other parts of the body can lead to other symptoms specific to the accumulation site such as bones, joints, or abdomen leading to their swelling and appetite loss, respectively. Furthermore, this accumulation can lead to swollen lymph nodes and thymus, causing, therefore, breathing issues and cough.

Surprisingly, leukaemia can lead to enlarged face and arms due to thymus enlargement, which, in turn, presses on the superior vena cava congesting the blood in the veins and preventing it from returning to heart. All that can lead to consciousness problems, as well as headache and dizziness.

5. Leukaemia can develop further and cause chloroma or granulocytic sarcoma which are dark rashes that result from AML spread in the skin.

Leukaemia treatment

Selecting leukaemia treatment regimen depends on many factors such as leukaemia’s type, child age, and having genetic or chromosomal changes. Given that ALL is more common than AML in children, the following part will focus on ALL treatment that is composed of four main classes4:

1. Chemotherapy: can either be systemic or regional, where the former means a general exposure of the body to chemicals, meanwhile the latter means local exposure like injecting drugs directly in the abdomen, cerebrospinal fluid, or a specific organ.

2. Radiation therapy: counts on an external source of x-ray. It is mainly used to prepare the body for stem cell transplant but is also important when the ALL is spread in the body.

3. Stem cells transplant requires a donor who donates stem cells to the cancer patient (receiver) see be the match. The main goal is replacing the malignant cells with healthy cells. Transplant starts after the completion of radio and chemotherapy regimens.

Advanced therapies of ALL5

Despite the good survival rates achieved by chemotherapy, its adverse effects are still devastating, and targeted therapy is an urgent need. Immunotherapy is an essential part of targeted therapy. In 2014, blinatumomab, and in 2017 inotuzumab ozogamicin and tisagenlecleucel were approved by the FDA.

Blinatumomab is a bispecific antibody that increases the toxicity of T-cells in the combat against cancer. By being bispecific, it can bind to the T-cells from one side and to an excessively expressed protein on cancer cells from another, therefore, bringing them closer to each other and facilitating the cytotoxic properties of T-Cells. Despite this advancement, cancer cells developed mechanisms to tolerate Blinatumomab as they can stop the expression of its target.

Inotuzumab Ozogamicin is an antibody conjugated to calicheamicin. After it binds to the cancerous cells, it is internalised and the active substance is released in the acidic environment of the lysozyme. Calicheamicin, in turn, is a potent antibiotic that intercalates in the DNA leading to cell apoptosis.

Kymriah® (tisagenlecleucel)6

It was approved by the FDA and EMA for the treatment of refractory and relapsed cases of B-cell ALL in paediatric and adults younger than 25 years old. Tisagenlecleucel is a Chimeric Antigen Receptor, the T-cells of the patient are engineered with a transgene encoding the chimeric antigen of CD-19 (a protein excessively expressed on malignant B-cells and not on normal ones), so they selectively recognize cancer cells and destroy them

Philadelphia chromosome and leukaemia: Philadelphia chromosome (Ph) is the first chromosomal abnormality found in leukaemia. It is very common in CML as it reaches up to 95% of cases, but very rare in AML (1%). Regarding ALL, Ph is very rare as it is found in 3% of childhood cases but is common in adults ALL and its incidence augments with age. Ph+ in Acute leukaemia is an indication of a bad prognosis7

This chromosome (infographic 3) results from breaks in chromosomes 9 and 22, and then the two broken pieces exchange places giving rise to the abnormal chromosome 22. ABL gene (infographic), a proto-oncogene found on chromosome 9, fuses with the BCR gene on chromosome 22 giving rise to the BCR-ABL hybrid gene. Proteins coded by this hybrid gene have deregulated TK activity that leads to excessive proliferation of immune cell precursors7 .

Many therapies have been developed to target Leukaemia’s TK and are called Tyrosine Kinase Inhibitors (TKI). Imatinib was the first selective TKI to be developed, but due to cancer resistance, Imatinib loses its efficacy so fast. More generations of TKI were developed to overcome the tolerance to Imatinib such as nilotinib and dasatinib (2nd generation) and Bosutinib (3rd generation)8

Author: Rahaf Alsayyed, EPSA Science Coordinator 2022-2023

Be The Match is operated by the National Marrow Donor Program, which conducts research on blood cancer survival and helps cure those with leukaemia, lymphoma, and other life-threatening diseases by facilitating bone marrow or cord blood transplants. Be The Match is the hub of a global transplant network that connects 446 leading centres worldwide, including 163 transplant centres in the United States and 48 international transplant centres.

NCODA and Be The Match have been working in partnership for the past 5 years with the goal of fundraising for blood cancer research and increasing donor participation. Thus far, NCODA has raised over $45,000 and attracted over 500 new donors to the registry. The majority of the donor registries emanated from NCODA Professional Student Organization (PSO) chapters hosting student-led bone marrow registration drives. In the past three years, four students have been matched as a direct result of NCODA PSO donor drives. Two of these students have donated their bone marrow and saved the life of a patient in need. NCODA PSO will look to host over 30 bone marrow registration drives in 2023 as we look to amplify our efforts to match more donors with

If you are interested in getting involved with NCODA and Be The Match’s mission, please visit: ncoda.org/be-the-match/ or scan the QR code below.

References:

Article and infographic 1:

1. CureAll framework: WHO Global Initiative for Childhood Cancer. Increasing access, advancing quality, saving lives. Geneva: World Health Organization; 2021.

2. “Key Statistics for Childhood Cancers.” American Cancer Society

3. Cancer in Europe: 5 things the Data tells us. EU Science Hub. (2022, January 13). Retrieved January 23, 2023.

4. “Childhood Cancer Survivor Study: An Overview.” National Cancer Institute

5. Childhood Cancer Survivorship: Improving Care and Quality of Life. National Academies Press; 2003. doi:10.17226/10767

6. Childhood cancer survivorship and long-term outcomes. doi:10.1016/j.yapd.2017.03.014

Article and infographic 2:

1. Dictionnaire de l’Académie Nationale de Médecine.

http://dictionnaire.academie-medecine.fr/index.php?q=Astrocytome (accessed 2023-02-12).

2. Philadelphia, T. C. H. of. Pediatric Brain Tumors

https://www.chop.edu/conditions-diseases/pediatric-brain-tumors (accessed 2023-02-06)

3. Astrocytoma in children | Children’s brain tumours | Cancer Research UK

https://www.cancerresearchuk.org/about-cancer/childrens-cancer/braintumours/types/astrocytoma (accessed 2023-02-06).

4. Snapshot. https://www.cedars-sinai.org/health-library/diseases-andconditions pediatrics/a/astrocytoma-in-children.html (accessed 2023-02-15).

5. Articles. Cedars-Sinai. https://www.cedars-sinai.org/health-library/articles.html (accessed 2023-02-06).

6. Kleihues, P.; Burger, P. C.; Scheithauer, B. W. The New WHO Classification of Brain Tumours. Brain Pathol. Zurich Switz. 1993, 3 (3), 255–268.

https://doi.org/10.1111/j.1750-3639.1993.tb00752.x.

7. Définition bilan d’extension. https://www.e-cancer.fr/Dictionnaire/B/bilan-dextension (accessed 2023-02-12).

8. Astrocytome anaplasique. Fondation canadienne des tumeurs cérébrales.

https://www.braintumour.ca/fr/types_de_tumeurs_cerebrales/astrocytomeanaplasique/ (accessed 2023-02-12).

9. Astrocytoma | Concise Medical Knowledge

https://www.lecturio.com/concepts/astrocytoma/ (accessed 2023-02-12).

10. Childhood Astrocytomas Treatment (PDQ®)–Patient Version - NCI

https://www.cancer.gov/types/brain/patient/child-astrocytoma-treament-pdq (accessed 2023-02-06).

11. Kristiansen, I.; Eklund, C.; Strinnholm, M.; Strömberg, B.; Törnhage, M.; Frisk, P. Cognitive, Language, and School Performance in Children and Young Adults Treated for Low-Grade Astrocytoma in the Posterior Fossa in Childhood. Cancer Rep. Hoboken NJ 2022, 5 (3), e1494.

https://doi.org/10.1002/cnr2.1494.

12. Yu, M. W.; Quail, D. F. Immunotherapy for Glioblastoma: Current Progress and Challenges. Front. Immunol. 2021, 12, 676301.

https://doi.org/10.3389/fimmu.2021.676301.

Article and infographic 3:

1. Guillerman, R. P., Voss, S. D., & Parker, B. R. (2011). Leukemia and Lymphoma. Radiologic Clinics of North America, 49(4), 767–797.

https://doi.org/10.1016/j.rcl.2011.05.004

2. What are Leukemia and Lymphoma? (n.d.). Guithrie. Retrieved 24 February 2023, from https://www.guthrie.org/services-treatments/leukemia-andlymphoma#:~:text=What%20are%20Leukemia%20and%20Lymphoma,bone %20marrow%20and%20lymph%20system.

3. Leukemia in Children. (2023, August 21).

https://www.cancer.org/cancer/leukemia-in-children.html

4. Childhood Acute Lymphoblastic Leukemia Treatment (PDQ®)–Patient Version. (2023, February 22).

https://www.cancer.gov/types/leukemia/patient/child-all-treatment-pdq

5. Hiroto Inaba & Ching-Hon Pui. (n.d.). Immunotherapy in Pediatric Acute Lymphoblastic Leukemia 38(4), 595–610. https://doi.org/10.1007/s10555019-09834-0.

6. Ali, S., Kjeken, R., Niederlaender, C., Markey, et al. (2020). The European Medicines Agency Review of Kymriah (Tisagenlecleucel) for the Treatment of Acute Lymphoblastic Leukemia and Diffuse Large B-Cell Lymphoma. The Oncologist, 25(2), e321–e327. https://doi.org/10.1634/theoncologist.20190233

7. Harrison, C. J. (2001). Philadelphia Chromosome. In Encyclopedia of Genetics (pp. 1449–1450). Elsevier. https://doi.org/10.1006/rwgn.2001.0991

8. Rossari, F., Minutolo, F., & Orciuolo, E. (2018). Past, present, and future of Bcr-Abl inhibitors: From chemical development to clinical efficacy. Journal of Hematology & Oncology, 11(1), 84. https://doi.org/10.1186/s13045-018-06242