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Syst Revw Schematic Summary
Syst Revw Schematic Summary
Syst Revw Schematic Summary
Temporary title:
Dr Lasica
Supervisor/Project PI
Dr Bondulich
To be established
Clinical Portfolio Group
Project title (if different To be established
from review title)
Protocol development
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Data Extraction
Synthesis
Writing up
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1. Background to review
Brief introduction to the subject of the review, including rationale for undertaking the review and overall aim
Craniopharyngioma (CP) is a highly comorbid rare non-malignant epithelial tumour originating during early
embryonal development, presenting two histological variants, adamantinomatous (ACP), and papillary type
(CPC). Patients’ age at time of the diagnosis is divided into two main groups, 5 to 14 year and 45 to 60 years
olds. Although, rare cases diagnosed in early adulthood do occur.
Histopathologic exams conducted in recent years suggest that β-catenin in pituitary progenitor cells gives rise to
the tumour during embryogenesis. CTNNB1 mutations with β-catenin immunopositivity and BRAFV600E
mutations with anti-VE positivity. These have been respectively observed in each tumour type. In ACP,
mutations of the main regulator of the Wnt-pathway were found, which are the gene encoding protein β-catenin
CTNNB1, whilst in PCP it was observed that activating mutations occurred in BRAF pVal600Glu. Such
discovery further promotes the idea of non-invasive strategies to target both pathways as their dysfunction is
linked to tumour formation as well as HPA axis dysfunction, which is the epicentre of most comorbidities related
to this tumour type.
The tumour mass itself is also quite peculiar not only in location, but also in terms of biophysical characteristics,
as it calcifies overtime, forming a toxic cystic fluid (CCF) on the inside. Literature analysing specifically its
characterises is limited, but very recent research proved that cells, i.e., astrocytes and neurons, will notably
decrease in number when exposed to higher concentration of CCF, and it also causes higher expression of a
known marker of apoptotic cell death, the hypothalamic cells Caspase-3.
Specific research gaps identified in respect to Wnt/Beta catenin pathways: Research has only recently
started looking into how natural compounds can help the Wnt/b-catenin pathways and its molecular diagnostic
and prognostic values in a number of cancers and illnesses. Additionally, the excessive production of prolactin
due to the dysfunctional pathways has been found to also respond to against dopaminergic drugs, which is a
very new area of interest which could allow addressing both medical and psychological apsects.
However, since drugs can also have severe side effects and give that specifically cancer patients are more
susceptible to these, in addition to the fact that many CP patients are children, and whose liver is more
sensitive, working on coadjuvant natural compounds seem reasonable to help those non-responsive to main
therapies as well as supporting their health so to effectively improve quality of life by acting on multiple aspects.
Such coadjuvants become particularly useful those affected by allergies and/or intolerances.
Recently, researchers have selected and experimented on the use of 15 natural compounds with initial success.
Henceforth, promoting the idea that a cooperative approach in this respect could bring together studies related
to multiple illnesses. Therefore, offering the opportunity to explore the matter more in depth by comparing all
stages of development as well as the connections with the peculiar cystic fluid present in such tumour, whose
powerful characteristics cause cell death and brain tissue damage.
Specific research gaps identified in respect to research gaps identified: The CCF specific characteristics
have not been consistently explored over the years, but the studies looking into it have helped gaining a deeper
understanding of the specificity of the tumour itself. Hence allowing exploration of hypothalamic neurons’
apoptotic cell death along with recurrence levels and tumour progression. But more can be done in terms of
exploring how this fluid helps tumour formation during gestation, and one of the main questions arising is: can
blood samples from the pregnant mothers help identifying the presence of the fluid itself during early gestation?
Experiments on animal models could help finding such answers..
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Hypothalamic syndrome and its links to further endocrinological complications
The post- radiation and/or post-operational lesions involving of the hypothalamic structures are linked to
significantly severe sequelae, mostly hypothalamic obesity (HO) with significant impact on the quality of life
(QoL) of patients.
Recent research shows that the vast majority of CP survivors present hypothalamic dysfunction manifestations
i.e., HO, neuropsychological deficits, circadian rhythms disturbance, diabetes insipidus, non-alcoholic fatty liver,
low libido, and anxiety and depression. The incidence of hypothalamic dysfunction increases to sharply
following radical surgical treatment, this is mainly due to the lesions of the hypothalamic structures. And these
are also associated with high morbidity. HO begins after the lesions of posterior hypothalamic structures
including the mammillary bodies have occurred, but further studies have continued to prove that this is an initial
condition likely to be exacerbated by lack of drive and significant withdrawal from sports and general physical
activities. Furthermore, at least three pituitary hormone deficiencies are observed in the vast majority of the
patients’ population, GH-, gonadotropin-, adrenocorticotropin- and TSH-deficiency and prevalence of diabetes
insipidus (DI) all ranged between 81% and 93% within the CP population I all age groups examined.
Pituitary deficiency metabolic treatments’ effects could certainly contribute to cardiovascular morbidity and
mortality reported epidemiological studies. But panhypopituitarism is linked to high recurrences of this tumour,
and because of the need for cranial radio therapy CRT) it’s is not possible at present to determine whether or
not hypopituitarism is an independent risk factor.
However, GH deficiency has been identified as the most frequent pituitary hormone deficiency, which is also
related to increased levels of cardiovascular risk factors. GH therapy reports that it has beneficial effects on lean
and body fat mass, total and low-density lipoprotein cholesterol, and diastolic blood pressure, but to reduced
insulin sensitivity. Furthermore, adrenocorticotropic hormone (ACTH) deficiency and glucocorticoid
supplementation are relevant to this tumour treatment as well as other illnesses such as Addison disease,
whereas high substitution doses of cortisone are strongly linked to significant increases in cardiovascular
mortality in CP patients with acromegaly. Additional research findings have also determined that subclinical
hypothyroidism too is a cause of increased cardiovascular risk. Meanwhile, more recent studies proved that
high levels of serum free T4 in the upper normal range is related to a lower body mass index (BMI) and high-
density lipoprotein cholesterol decrease, hence offering new routes to explore to address multiple issues by
looking into dietary intake and possibly herbal supplements.
It appears that hypothalamic damage is strongly linked to hyperinsulinemia, because of the destruction of the
ventro-medial hypothalamic (VMH) nuclei. Which in turn causes autonomic nervous system’s imbalance, hence
resulting in suppression of the sympathetic nervous system and stimulation of the vagus nerve, and is also
related to tumour growth. This is a very serious factor to explore and work on in light of attempting to improve
patients’ QoL because hyperinsulinemia increases lipogenesis in the liver and adipose tissues, while lipoprotein
lipase activity accelerates endogenous lipid production (specifically low-density lipoproteins and triglycerides).
Thus, mass is accumulated causing significant weight increase over short periods of time.
Specific research looking into the effect of GH therapy are limited, and when compared to non-functioning
pituitary adenoma patients, the CP population present a higher prevalence of pituitary deficiencies. They are
also more often obese and have dyslipidaemia. GH replacement successfully showed the same effect on fat-
free mass and lipids on both patients types, but CP survivors seem less likely to lose body fat, which is plausibly
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Aims:
1. Systematic review of the literature to produce a database of outcome measures that have been used (or
developed for use) in CP ongoing treatments and interventions.
2. Appraisal of outcome measures to identify and highlight those that have been developed and evaluated
using high-quality, fully rigorous methods.
(2) diet, satiety level control, eating behaviours, and related self-control, and making structured and
specific dietary changes where combination/elimination of chemical compounds at managing Wnt/beta
catenin and HPA axis disruptions,
(4) using the methods in point 5 to affect the behaviour of the entire system along with possible positive
psychological outcomes relative to dopamine and serotonin production
(5) using physical activity and sports to address dopamine production and cardiovascular disease where
significant
(6) overall psychological and general QoL improvements combining treatments and making multiple
observation from the same experiments; quality of life
(7) environmental effects on CP patients, level of pollution, access to outdoor spaces, green areas can
affect patients with cancer as well as depression, CP patients should benefit from additional data
collected; and (10) Making constructive use of CP research to bridge
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2. Specific objectives
1. To clarify the evidence base available around the relationships of anxiety and depression to
exacerbations of QoL issues that lead to negative psychological outcomes by combining biological
research applied to dietary controlled changes aimed at also improving behaviour and motivation, by
working on the chemical aspects of nutrition and supplements. Clarification will be made by a
systematic review of the evidence base of journals and abstracts in this topic area, looking at all
designs of study.
2. To identify additional, also inflammatory, factors that are thought to also be involved in worsening the
condition, along with anxiety and depression that strongly add to the neurological post-operational
existing aspects.
3. To address psychological factors, including the ability to cope and self-manage their condition, the
other comorbidities, and the social factors that may affect their ability to cope or self-esteem. This
cannot be more specific until an examination of the evidence is collected on how dietary and lifestyle
changes can help. As literature specific to CP is limited studies involving psychological changes in
mental health will be included as long as the HPA axis is key to the neighbouring illness included in the
analyses, i.e., bipolar disorder, which has already been linked to CP patients behaviour.
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Criteria for including studies in the review
If the PICOS format does not fit the research question of interest, please split up the question into separate concepts and
put one under each heading
Patients who have undergone brain surgery for the removal of Craniopharyngioma,
both adamantinomatous (ACP), and papillary type (PCP) both age groups are
included (most diagnosis occur between the ages of 5 and 14 and 45 to 60 circa),
gender, and any severity levels of quality of life (QoL) post-operation will be
included.
i.Population/participants,
Population not restricted to the UK, will examine papers from all over the world will
conditions of
interest be included in the study with the aim of gathering as much as information as
possible about differences in respect to how climate and geographical location (It is
plausible to assume climate may affect response to post-operational assistance in
light of : dietary and lifestyle changes, reaction to medication/hormonal treatments,
and it can effect psychological factors such as depression, which have been found in
multiple studies to be directly linked to external conditions such light, temperature,
ability to spend time outdoors.
Patients with higher numbers of comorbidities and those who have fewer.
iii. Comparisons or
Comparisons will be made in reference to age groups, sex, and intervention
control groups response level to both pharmaceutical and non-pharmaceutical.
Secondary care
v. Setting
RCT’s and Systematic reviews wherever available. However, given the rarity of the
tumour, cohort studies shall be considered.
vi. Study designs
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Exclusion criteria to be established, however studies purely focusing on surgery, and/or analysing single
aspects of the illness should not be considered for this review.
4. Search methods
The top 3 are my main ones but I am looking into different languages too
(French, Italian, Spanish, German, so I should, include more to this-your input
on this would be very much appreciated)
Electronic databases
Please list all databases that PUBMED/MEDLINE
are to be searched and include COCHRANE
the interface (eg NHS, ORCID
EBSCO, etc) and date ranges
searched for each (and possibly according to your guidance an dexperience: EMBASE
Cinhal
PsychInfo
Keele Web of Science
CDR/DARE databases)
Other methods used for Reference checking and hand searching of:
identifying relevant Contacting experts in this field
research
ie contacting experts and I am working on this aspect. I was thinking to contact
reference checking research centre in the US and UK and other countries via
email. I speak three languages fluently and one at basic
level, I assume you speak more than two too sir, so these
skills may help speeding up the process of including non-
English studies
Methods of review
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Grading evidence
System used, if any, such as
GRADE
6. Presentation of results
7. Timeline for review – when do you aim to complete each stage of the review
Protocol 2 months
Synthesis 2 months
2 months
I made an estimation based on research conducted in light of systematic
Writing up
reviews structure and planning processes suggested by BMC and
PubMed library support articles
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