Systematic Review and Meta-analysis of Neuroblastoma Bone Metastases

This report presents a systematic review and meta-analysis focused on neuroblastoma bone metastases, a critical area in pediatric oncology. The study investigates the use of PET scans with NaF and FDG tracers, and MIBG scintigraphy for evaluating bone metastases in children diagnosed with neuroblastoma. The report begins by framing the research question using the PICO model, detailing patient population, interventions, comparisons, and outcomes. It then outlines the search strategy, including the databases used and the selection criteria for articles. The methodology includes a data extraction table and statistical analysis to assess the sensitivity and specificity of each tracer. Eligible studies are evaluated for risk of bias, and a discussion section synthesizes the findings, addressing the strengths and limitations of the included studies. The report concludes with a summary of the key findings and their implications for the diagnosis and management of neuroblastoma bone metastases. This comprehensive analysis provides valuable insights into the current state of research and potential future directions in this field.

Systematic Review and Meta-analysis

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Table of Contents
Introduction......................................................................................................................................1
PICO model.....................................................................................................................................1
Search Strategy................................................................................................................................2
Selection of Articles........................................................................................................................4
Data Extraction Table......................................................................................................................5
Statistical Analysis...........................................................................................................................6
Eligible Studies and Risk of Bias....................................................................................................7
Discussion........................................................................................................................................8
Conclusion.....................................................................................................................................15
Reference.......................................................................................................................................16
Introduction

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In this study the detailed description of the disease nerublastoma is studied. As it is a kind of the
cancer and all type of cancer has ability to spread or to change the location of tumor, they may
shift to any part of the body; in this analytical report the transfer of the tumor in bones is
mentioned. This report is also included with the treatment of the disease and how to trace the
tumor, for the tracing of the tumor the method which are described are through PET scan and
MIBG sinctigraphy both the process are nuclear methods because the element which are used to
trace the location of tumor are radioactive in nature. In the report the statistics about the
treatment and diagnosis is also briefly explained. This complete report is prepared by the
analyzing the journal articles which were prepared by the experts, their data and information
about this disease and methods to diagnose is also mentioned.
PICO model:
The model which is used to define clinical observations by analyzing medical problem, it helps
to provide support to specific patient from his/her observations. Basically this model is used to
prepare the design strategies for observations or literature. Here PICO stands for:
P= Patient, problem, population
I= Intervention
C= Comparison
O= Outcomes
How PET scan can be used for the evaluation of bone metastases of neuroblastoma with NaF and
FDG tracers and MIBG scintigraphy?
The above question compiles the elements of PICO model.
Parameter Description
P (Patient, Problem) A child of Age 5 years who is suffering from Neuroblastoma, it was
observed that his cancer getting migrate in bone.
I (Intervention) Evaluation by PET scan and MIBG scintigraphy
C (Comparison) NaF and FDG tracers
O (Outcomes) Metastases of Neuroblastoma in bone.

Systematic Review and Meta-analysis 3
Neuroblastoma
The disease which is observed commonly in children who are under 5 years or younger, which is
developed from immature cells in distinct parts of body. It is the disease which generally arises
in or near around of the adrenal gland. It may also arise in areas of abdomen, neck and near the
spine. Neuroblastoma is the third most common cancer among children after leukemia and brin
cancer. The disease mainly can examine in boys compared to girls. Infants have the chances
better than older children for survival. There are four stages which are defined for the
Neuroblastoma and they are mentioned below:
Stage 1. In this stage cancer remains at one place, and it did not spread it can be removed withg
the surgery.
Stage2. Cancer of this stage did not spread but the risk increases in this stage due to which it
cannot be spread safely by surgery.
Stage M. Now the cancer starts spreading to other parts of the body and the situation become
critical.
Stage Ms. The cancer spread all over the body in this stage to skin, liver or bone marrow.
By considering all these stages and after proper analysis of the patient the treatments are
suggested.
Bone Metastases
The term defines when any cancer or tumor of any part of body relocates its primary position of
occurrence towards bone. In bones no any cancer develops but it shifts from their origin.
PET Scan
The term PET stands for positron emission tomography which is used to analyze type of disease
occur in body it helps doctor to treat their patient according to it. In this scan some radioactive
tracers are used which are injected into body through veins of arm later on those tracers get
absorbed by the organs and cells of body (Bellinge, Majeed, Carr, Jones, Hong, Francis, and
Schultz, 2019). The scan is very effective in detecting the activities which are executing in body
parts by the chemicals. This scan can help to find the different conditions in cancer, heart
diseases or brain disorders are included.

Systematic Review and Meta-analysis 4
Cancer: The cells which causes cancers are observed as bright spots in the scan as their rate of
metabolism is higher than the normal cells. The cancers can be examined by the PET scan and it
can be cured as soon as after the detection. There are many types of Tumor which can detect by
the PET scan are:
 Brain
 Cervical
 Colorectal
 Esophageal
 Head and Neck
 Lung
 Lymphoma
 Melanoma
 Pancreatic
 Prostate
 Thyroid
Heart Disease: PET scan have tendency to show the areas where the blood flow in the heart is
decreased.
Brain Disorders: The scan can be used to examine the brain disorders likes Alzheimer’s
dementia, Seizures, or tumors.
Risk in PET scan: In the PET scan the tracers which are used are in radioactive in nature; they
get injected in the body through veins. Due to radioactive nature of the tracers there are rare
chances of some negative effects which may exposed and they are mentioned below:
 It may cause an allergic reaction.
 It may affect the baby if the patient is pregnant by exposition of the radiations.
 If mother is breast-feeding to their children than radiation may affect the child.
Before the scan the patient should tell everything to doctor so they may perform the test
according to it.
i. If the patient has the issue of allergic reaction
ii. If the patient was sick or have some other medical issues
iii. If the person is taking other vaccinations

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iv. If the patient is pregnant
v. If the patient have phobia of closed space.
Search Strategy
The search strategy is the method in which definite key words are used to examine any database
in constructive pattern. This process helps to obtain accurate results by the combination of main
concepts of the searched question.
Image Source: (Priola, 2018)
Case Studies: This method totally focused upon the single case or different small number of
cases. Usually in case study the information is derived from different research papers, surveys,
observations or interviews.
Qualitative Interviews: This method is effective and broad way for collecting data or any
information. For this strategy a complete structure is prepared in which the questions to be asked,
the methods of recording and to analyze them are included.

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Quantitative Surveys: In this process the data or information is collected from practical work or
through the data obtained by experiments. Those obtained data or information compared with the
other statistics which were declared by the other examiners or specialists. This analysis helps to
find the errors or mistakes; also if there were any flaws in old surveys they can be changed.
Action orientation search: In this strategy on the basis of actions performed on subjects they are
analyzed by the experts and later results which are obtained by those particular actions. These are
the assumptions which are made by the experts.
Analytical research strategy: In this strategy the data or the information which are already
available are used. In this process any data which is already available is examined by an expert
and they try to resolve the problems related with it.
Published database: The databases which are already published in form of article, journals,
newspapers or reports by experts of the topic. These databases are prepared by research
performed by different plans and by applying different methods. These methods are practically
and theoretically analyzed with facts and all the necessary data related to subject. The
information or data which are available in these databases are valid because they are prepared
under guidance and with complete supervision.
Selection of Articles
The articles which are selected for the study of this topic are critically analyzed as they are
prepared by the observers who complete their research through implementing different methods
and strategies. In these articles the complete description are briefly explained on the provided
topic which is Neuroblastoma in bone metastases. They have provided all the statistics related to
the disorder of different countries. In all of the article treatment, causes, and preventive methods
are provided. The articles which are selected are mentioned below:
Name of Article Publisher
Research in advance US National Library of

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Neuroblastoma. Medicine National Institutes
of Health
Stars in cytoplasm: Pediatric
Neuroblastoma
International Journal of
Clinical Pediatrics
Neuroblastoma Japanese Journal of Clinical
Oncology
Neuroblastoma treatment in
the post genomic era
Journal of Biomedical Science
Neuroblastoma Cancer Insight of gynecology
oncology
Neuroblastoma: Pediatric
Oncology
American Journal of
Neuroradiology
According to the entire above journal neuroblastoma is the cancer that is caused in immature
nerve cells and it can change its position on wide scale that sometimes it is not easy to trace the
origination location of the tumor.
Data Extraction Table
S.No. Authors Year Country/Place
1 John M. Maris 2012 Rockville
Pike
2 Monazza Chaudhary, Shahzad Sarwar, Natasha
Ali
2016 Pakistan
3 Esposito MR, Aveic S., Seydel A., Tonini GP. 2017 Rockville
Pike
4 Akira Nakagawara, Yuanyuan Li, Hideki
Izumi, Katsumi Muramori, Hiroko Inada,
Masanori Nishi
2018 Japan
5 Ina Oehme, Hedwig
E. Deubzer, Dennis Wegener, Diana Pickert, Jan
-Peter Linke, Barbara Hero, Annette Kopp-
Schneider, Frank Westermann, Scott
M. Ulrich, Andreas von
2009 America

Systematic Review and Meta-analysis 8
Deimling, Matthias Fischer and Olaf Witt
6 Harold W. Dargeon 1962 New York
Statistical Analysis
Neuroblastoma is most commonly disease which can be seen in infants who are less than 1 years
old, which is 6 % of the cancer occurs in children. Every year there are 800 cases for
neuroblastoma can be seen in United States of America. In very rare case through ultrasound this
disorder can be identified before birth. At the age of 5 years 90% cases are identified, it is very
rare to seen in children of 10 years or more. In 90% of the cases PET scan helped the doctors and
pathologiststo avoid the CT scan or imaging. In Canada 50% of the cases get changed in plan of
treatment due to PET scan. In an analysis 20 patients were selected whose age were from 3-4.5
years and they were categorized into two different groups according to process of the disease.
Out of 6 (30%) patient who were in the developmental phase of the disease 1(5%) of them died
during the treatment. For the sensitivity and specificity of MIBG treatment which is mostly used
for the tracing of neuroblastoma is 90% or above out of which only 70% of them are successfully
get detected by the MIBG scan. In the month of December 2015, 65 patients were examined as
neuroblastoma, PET-FDG was performed on them to diagnose their tumor. Out of 65 cases 20 of
them were diagnosed by the PET-FDG scanning but most of them favored the diagnosis through
MIBG scintigraphy.

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Image Source:
Image Source: (Vallin , et al., 2014)
Eligible Studies and Risk of Bias
In this assignment the articles which are selected they are totally selected on the basis of their
provided statistics and their qualitative analysis or research on the disease and its treatment.
These articles consists all the required data and information about the term neuroblastoma and
cause factors. Authors performed studies on different period of time for different patient
according to their symptoms. They have considered the cases which were recorded by the
medical association of a particular city or country. They analyzed the factors and on the basis of
those they made strategy and start examine patient of a particular area. They checked the
preference of the pathologist as well and their favorable methods to diagnose the disease. The
risk of the bias was that they provide the data and facts about the disease and their treatment but
they left some mistakes in their studies, they never examined the data which was related to the
people who were not able to get the diagnosis. Other factor which they forget to mentioned the
cost of the diagnosis varies according to country and city, however if the same techniques is
available. They did not provide the information about the failed cases of the diagnosis by the
methods.

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Complications in Neuroblastoma
The complications which are included in neuroblastoma are defined below:
i. Spreading of Cancer: This disease may spread to other parts of the body like lymph
nodes, bone marrow, liver, skin and bones.
ii. Spinal cord compression: If the tumor will grow it will start pressing the spinal cord,
by causing spinal cord compression, this compression will leads to pain in bones or
paralysis.
iii. Symptoms caused by tumor secretion: Tumor cells of neuroblastoma secrets
chemicals they start bothering other normal or healthy tissues, which may cause
paraneoplastic syndromes. In such syndrome the patient faces challenges with the
movement of eyes and coordination.
Discussion
In this report the complete study is conducted upon the nuroblastoma and its metastases in bone.
In this analysis methods are also mentioned to find out the disorder in body and also for its cure.
Neurobalstoma is a cancer which usually occurs in the children of age group 5 years or less, it is
cancer which mostly occurs in adrenal gland. This cancer usually occurs in the early form of
nerve cells, it also founds in embryo or fetus. In neuroblastoma the term neuro refers to nerve
and blastoma refers to cancer which affects the developing cells (Chen, Sun, Metelitsa, Dotti,
and Savoldo, 2019). The disorder mainly occurs in sympathetic nerve ganglia which are nearby
to spine or neck. In very rare chance neuroblastoma spread in wide range that, experts also not
able to examine the origin position of this cancer. Sometime this cancer goes away from their
own when the cell of cancer dies for no reason.
NaF and FDG tracers:
Both of the elements NaF and FDG are the radioactive tracers which are used to identify the
metastases of the cancer in bone. In this process the Sodium Flouride 18 is used which is injected
in the body of patient. The first radiopharmaceutical which was used in skeletal scitingraphy was
NaF 18 but later on after the development of technology and introduction of the technology of

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Gamma camera it is fall out of preference (Hanaoka, Watanabe, Kaida, Hosono, and Ishii, 2019).
In recent NaF is getting used with the PET/CT scan, another advantage of this process is that it
takes less time than other process which are getting use in tracing of metastases of the cancer by
providing the PET images along with the CT scans.
Image Source: (Manov , et al., 2017 )
Another radioactive pharmaceutical element i.e. FDG also known as fluorodeoxyglucose which
is used to examine the metastases of the cancer in bone. When the radioactive tracer is injected in
the body of the patient it starts to perform its action in body. Its isotopes scattered with in the
tissue and on the basis of the career molecule positron get emits Scattering of the radioactive
particle is identified by the method which is known as back projection method (Zheng, and
Khariwala, 2019).

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Image Source: (Omami , et al., 2014 )
Symptoms
Symptoms of this cancer totally depend on which area it is affecting. Some of the symptoms are
mentioned below:
i. Neuroblastoma in abdomen: It is most common form of this disorder, the symptoms
which can be observed in this type of Neuroblastoma are defined below:
 Abdominal pain
 Diarrhea or constipation
 The mass present under skin is not soft when it is touched.
ii. Neuroblastoma in chest: The symptoms of this form of neuroblastoma are:
 Wheezing
 Pain in chest
 Unequal size of Pupil, or dropping of eyelids
Some other symptoms which can be observed in neuroblastoma which includes are mentioned
below:
 Clusting of tissue under skin
 Dark circles
 Back pain
 Fever
 Loss of weight
 Pain in bone (Neviani, Wise, Murtadha, Liu, Wu, Jong, Seeger, and Fabbri, 2019).

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Cause of the Disease
Generally any cancer caused due to mutation in the cells in which normal cells grow rapidly
without getting stopped. The cancer cells get multiplied and grow continuously, and these cells
causes tumor in body. When the fetus or the embryo getting turn in the nerve cells and fiber
which develops adrenal gland and that is ho a neuroblastoma found in newborns. This disorder
arises in immature cells and taking along with it as development part it grows in fetus (Hwang,
and Perry, 2019).
Risk Factors
After the detection of cancer the risk level are classified as Low, medium or high risks. These
risk level are determined after analyzing following factors which are mentioned below:
 Stage of Cancer
 Histology of the Tumor
 Biology of Tumor ‘
 Age of the patient(child) (Nguyen, and Dyer, 2019)
Diagnosis
Doctors may use several methods to diagnose the cancer in body, they also examine if cancer
spreads or shift to different part of the body from where it was originated, this phenomenon is
known as Metastasis. In most of the cases biopsy is the process which provides the complete
information about the tumor and its origin area in the body. In biopsy small part of the tissue is
taken for the testing and it kept under examination in laboratory (Jin, Li, Yang, and Tian, 2019).
In some of the cases when biopsy is not possible than doctors suggest some other checkups
which are as mentioned below:
 Type of cancer which is suspected
 Signs and symptoms of child
 Age and Health of the child
 Reports or the outcomes of previous medical tests.
There are some additional tests which are performed for detection of tumor but all of these tests
are not conducted on every patient.

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Blood Tests and Urine Tests: In blood test complete blood count are checked if the child has
the signs of anemia in which the red blood count will be found to low. For the evaluation of liver
and kidney functions additional blood tests are performed. For the confirmation of tumor
markers which are generated by the neuroblastoma are analyzed by Urine test. The people or the
children who are suffering from any kind of tumor inn their body the amount of the marker are
higher than normal amount in blood. Patient of neuroblastoma have 85% of Urinary
catecholamine metabolites (Johnsen, Dyberg, and Wickstrom, 2019). Including the hormones
epinephrine (adrenaline), norepinephrine (noradrenaline) and dopamine, Catecholamines are
organic compounds. Releasing of these hormones will lead to response of fight in adrenal gland,
these hormones secrets from the adrenal medulla of the adrenal glands. The body breaks down
catecholamines in small parts known as metabolites which later on passed out of the body
through urine (Lin, Chu, Chao, Sun, and Yen, 2019).
Biopsy: The process in which small pieces of tissues are taken and examined through
microscope in known as Biopsy. The person who has the specialization of interpreting laboratory
also known as pathologist, performed this task. The biopsy is totally depend upon the position of
tumor, if it get detected than the whole tumor can be removed from the body and there would be
no need for further biopsy (Verly, Leen, Meinsma, Hooijer, 2019). DNA is used to to find the
nature of oncogene MYCN, for the growth of every cell a gene is responsible. When there is 10
copies of gene it is known as amplification which is related to the tumor which grows rapidly
while non-amplified MYCN gene is totally related to less aggressive tumors and its growth rate
is slow (Rainusso, Seghers, Egler, Hicks, and Russell, 2019).
Genetic Study: In the change of number of chromosome or parts of the chromosome because of
tumor for its detection additional tests are performed. To check if mutation of Anaplastic
lymphoma kinase is also commonly done DNA sequencing tests is performed. The tumors which
came back again increase the frequencies of mutation which are identified through the studies.
Computed Tomography: This is scan which is done by X-rays in which pictures of the body is
taken by different angles. In the scan the three dimensional pictures are obtained by which the
abnormalities of tumors can be identified. To obtain the better picture a special dye is used, this
dye is inserted in the body of patient through different medium.
MIBG Scan: The term stands for meta-iodobenzylguanidine it is the protein which is absorbed
by the cells of neuroblastoma. In this process some amount of radioactive iodine when linked

Systematic Review and Meta-analysis 15
with protein and inject in the body the disorder neruoblastoma can be detected easily in bones,
bone marrow, and other parts of the body.
Positron emission tomography (PET-Scan): This scan is also termed as PET-CT scan because
in this scan CT scan is also combined. In this scan a radioactive substance is injected in the body
of patient which later on absorbed by the organs. Cancer have tendency to attract the energy
towards itself and due to which it absorbs the radioactive particles. This test is performed with
those patients whose examines or results were not identified by the MIBG (Piccardo, Foppiani,
Righi, Garaventa, Sorrentino, and Lopci, 2019).
Treatment: Treatment of Neuroblastoma is based upon the age of child and stage of the cancer.
The different types of Treatment are mentioned below:
i. Surgery
ii. Chemotherapy
iii. Radiation Therapy
iv. Immunotherapy
v. Transplant of Stem cell
Chemotherapy: In this therapy anti-cancer drugs are provided to patient, which start killing the
cells of cancer. These drugs are provided through injection or orally as well. There are so ne
side-effects also of this therapy but they go away once the treatments get finished (Ocak, Kebudi,
Cebeci, Buyukbabani, Bilgic, and Tuncer, 2019).
 Loss of Hair
 Mouth Sores
 Nausea
 Vomiting
 Immune System will become weak
 Fatigue
Radiation Therapy: In this treatment the infected areas are targeted with the X-rays, these rays
are aimed and kill the infected cells. This treatment causes many side affected which are related
to skin i.e. skin irritation diarrhea, fatigue etc.

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Immunotherapy: It is a biologic therapy which is used to improve the immune system to fight
with disease.
Stem Cell transplantation: It is also known as transplantation of bone marrow, after the treatment
of radiation and chemotherapy a replacement of stem cell is injected in the body into the
bloodstream of the children (Rodrigo, Buchtelova, Jimenez, Adam, Babula, Heger, and Adam,
2019).
Image Source: (Maris , 2018)
Facts about Neuroblastoma:
Those children who are in low risk of neuroblastoma have the survival rate of 90-95% while rate
of the survival becomes 40-45% when the patient is in high risk of neuroblastoma. After the
successful treatment of the cancer the patient has to visit doctor for their checkup for a particular
period of time to identify other things or to check if there is no any sign of cancer is left. These
checkups are also important to develop the immune system again (Shen, Li, Lu, Luo, Guan, and
Cheng, 2019). There are some disorders which may arise after the treatment of cancer and they
are mentioned below:

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 Problem related to development
 Difficulties in learning
 Problem with Vision
 Seizure
 Muscle and bone issue
 Secondary cancer
Conclusion
In this report the study is conducted upon the neuroblastoma which is a type of cancer mainy
arise in the children or infants, it arises due in the immature nerve cells and unstoppable growth
of the cells due to which when an embryo or fetus get develop completely than they are observed
with this disorder. In the study the discussion is also made upon the method by which it is
diagnosed, there are several methods introduced to identify the or to check the location of tumor,
sometimes this tumor get eliminate in some children itself, but most of the time it get spread on
such a wide scale that the origin location of the tumor cannot be identified. In this study the
radioactive particles are mentioned which are named as NaF and FDG, the scanning which is
used in the study is PET which stands for positron emission tomography, it is a nuclear
methodology in which nuclear tracers are injected in veins of patient to detect location of tumor
and to eliminate it. Another scan which is used in research of this study is MIBG sinctigraphy, it
is the process in which is also used for the diagnosis of the disorder and its location but most of
the time the outcomes from this analysis are not satisfactory and on the place of which PET scan
is used. Apart from this statistical analysis about the cancer and its methods which were provided
by different experts or observer is mentioned, the articles which were written by them after their
research on this cancer. The articles which are selected in this study are critically examined by
their quantitative and qualitative work.
Reference

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Bellinge, J.W., Majeed, K., Carr, S.S., Jones, J., Hong, I., Francis, R.J. and Schultz, C.J., 2019.
Coronary artery 18F-NaF PET analysis with the use of an elastic motion correction
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Chen, Y., Sun, C., Metelitsa, L., Dotti, G. and Savoldo, B., 2019. Abstract A025: Eradication of
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