MRI Techniques in Diagnosis of Pituitary Disorders

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Table of Contents
CHAPTER ONE 4
INTRODUCTION 4
1.1 Background Information 4
1.1.1 Harm and Risk Factors of Pituitary Disorders 4
Figure 1: Tumor within the Pituitary Glands in the Brain (Wattson et al, 2014) 5
1.1.2 Pathophysiology of Pituitary Disorders 5
1.2 Role of MRI in Diagnosis of Pituitary Disorders 7
1.3 Anatomy of the Pituitary Gland 7
Figure 2: Anatomy of the Pituitary Gland 8
CHAPTER 2 9
LITERATURE REVIEW 9
2.1 Literature Review 9
2.1.1 Definition 9
2.1.2 Sources of Information 9
2.2 The reasons for choosing literature review 11
2.2.1 Thorough understanding of the topic 11
Figure 3: Major Hormones Released within the Pituitary Glands (Rogers, Karavitaki, & Wass, 2014) 12
2.2.2 Identification of Similar works within the area of research 13
2.2.3 Identification of the Gaps 13
2.2.4 Comparison between previous findings 14
2.2.5 Critiques of the Existing Findings 15
2.2.6 Suggestions of Further Studies 15
2.2.7 Identification of Potential Areas for Research 16
CHAPTER THREE 18
METHODOLOGY 18
3.1 Research Design and Methodology 18
3.1.1 Introduction 18
3.1.2 Research Philosophy 18
3.1.3 Positivism 19
3.2 Justification of Adopted Philosophy 19
3.3 Research Design and Justification of Choice 20
3.4 Secondary Analysis 22
3.5 Data Collection Procedure 23
3.6 Meta-Analysis 23
3.7 Data Analysis 24
3.8 Limitations of the Study 24
CHAPTER FOUR 25
RESULTS 25
4.1 Targeting Epidermal Growth Factor Receptor Family 25
Figure 4: Anterior and Posterior of the Pituitary Gland (Maret et al, 2014) 26
4.1.1 EGFR Inhibitors 26
4.1.2 HER2 Inhibitors 27
4.1.3 EGFR and HER2 Dual Inhibitors 28
Figure 5: Intraglandular Cleft in the Pituitary Glands (Sorbi et al, 2012) 29
CHAPTER FIVE 30
DISCUSSIONS 30
5.0 Discussions 30
CHAPTER SIX 35
CONCLUSION 35
References 37

MRI Techniques in Diagnosis of Pituitary Disorders
CHAPTER ONE
INTRODUCTION
1.1 Background Information
The pituitary gland is a small pea-sized organ attached to the part of the brain system. Over the years, researchers have focused their attention towards understanding the major function of the pituitary gland with the most basic usage of this gland being the ability to control growth and development. Growth and development is one of the notable elements within the human body, as it promotes ability to comprehend with regard to the surrounding environment. Although the pituitary gland may be considered as being small in size, it is one of the most important glands within the human brain, as it helps in controlling the functionality of endocrine glands including the eyes and ears. According to Sawyer, Corsentino, Sachs-Ericsson, & Steffens (2012), pituitary glands are important in children in defining their rate of development, which indicates the importance of having to conduct regular check-ups in identifying any disorders.
1.1.1 Harm and Risk Factors of Pituitary Disorders
Pituitary disorders result from a tumor growth within the brain system, which may result in cases of cancer thereby causing fatalities. The tumor may start as a pea-sized growth in the brain (as indicated in figure 1) and may grow significantly depending on the severity of the condition and the time taken to identify and treat the disorders. No matter in the developed or the developing world, pituitary disorders are the most common invasive tumor in different populations. It accounts for 22.9% of invasive cancers in women and 16% among men, which is according to a report by the World Health Organization (WHO). In the year of 2008, pituitary disorders caused 458,503 deaths around the world, which takes up 13.7% of cancer-induced deaths in women and 6% in both men and women (Tang et al, 2006). The incidence of pituitary disorders varies worldwide. The rate in the less-developed world is much lower than the one in the more-developed world. In most developing regions, the rates are below 40 per 100,000 (Sawyer, Corsentino, Sachs-Ericsson, & Steffens, 2012). These figures show the effects of life style as a risk factor. Beside of the life style, obesity, inadequate physical exercise, alcohol, hormone replacement therapy, ionizing radiation, early age at first menstruation and late age of first baby or not having children are all proved to be risk factors for pituitary disorders.

Figure 1: Tumor within the Pituitary Glands in the Brain (Wattson et al, 2014)
1.1.2 Pathophysiology of Pituitary Disorders
In order to effectively treat with pituitary disorder, the pathophysiology of it should be made clear first. Like all other kinds of tumors, the risk factors for it include both external factors and internal factors such as genetic factor and molecular events. Pituitary disorders are a kind of tumors that forms in tissues of the brain. Normal cells divide as many times as needed and then stop. They find their own place in tissues and maintain the position, attaching to other cells. When the cells become cancerous, they will lose their ability to stop dividing, to attach to other cells, to maintain in one place and to die. Normal cells could kill their selves when they are no longer in use. Before that, they are protected by the protein clusters and pathways from suicide. These protective ways include PI3K/AKT pathway and RAS/MEK/ERK pathway. Sometimes the genes along these protective pathways are mutated in a way that turns them permanently “on”, rendering the cell incapable of committing suicide when it is no longer needed. This is one of the steps that cause tumor in combination with other mutations. Normally, the PTEN protein turns off the PI3K/AKT pathway when the cell is ready for cell suicide. In some pituitary disorders, the gene for the PTEN protein is mutated, so the PI3K/AKT pathway is stuck in the “on” position, and the cancer cell will then no longer commit suicide.
Pituitary disorders and cancers have been proved to be highly correlated with family history. For example, in the United States of America, 10% to 20% of patients with pituitary disorders and patients with ovarian cancer have a first- or second-degree relative with one of these diseases (Tang et al, 2006). This phenomenon is named as hereditary pituitary cancer syndrome. The BRCA mutations are the best known of these, which could bring a lifetime risk of pituitary disorders to the individuals between 60 and 85 percent and a lifetime risk of ovarian cancer to individuals between 15 and 40 percent. Some mutations occur to correct errors in DNA, such as p53, BRCA1 and BRCA2. Some of the mutations are inherited and some of them are required after birth. Researchers assume that they allow further mutations. The further mutations then will allow uncontrolled division, lack of attachment, and metastasis to distant organs. However some unobserved risk factors cause that residual risk variation that will go beyond hereditary BRCA gene mutations between carrier families. Thus, external factors, such as environmental factors could be triggers for pituitary disorders. The carcinogens cause DNA damage such as DNA cross links and double strand breaks that often require repairs by pathways containing BRCA1 and BRCA2. Yet, mutations in BRCA genes only take up 2 to 3 percent of all pituitary disorders. Levin et al. say that cancer may be evitable for some of the carriers of BRCA1 and BRCA2 mutations. A number of unknown genes, more than half, are involved in the pituitary disorder.
1.2 Role of MRI in Diagnosis of Pituitary Disorders
In recent years, neurologists have focused on usage of MRI scanners when trying to identify some of the key problems within the brain system. MRI scanners are able to provide these neurologists with clear images of the brain system, which will provide them with a defined course of action. In the case of pituitary disorders, MRI scanners help in identification of any anomalies in the pituitary glands, which may help towards identification of any major disorders. One of the key element to consider is that MRI scanners may focus on specific sectors of the brain system when trying to improve visibility thereby making it easier for the neurologists involved to identify any underlying problems in the scans. In addition, the role of MRI in diagnosis of pituitary disorders is evident when dealing with cases of deformities in the pituitary glands. Any notable deformities in the pituitary glands may have a major impact towards reducing the efficiency of the glands with regard to performance abilities as expected within the brain system.
1.3 Anatomy of the Pituitary Gland
The pituitary gland is divided into major parts, anterior and posterior, with each of these parts having its own subgroupings. In the anterior pituitary, the key subgroups include pars distalis, pars tuberalis, and part intermedia while the posterior pituitary comprising of neurohypophysis (as highlighted in figure 2). The anterior pituitary is responsible for the production of specific hormones including growth and thyroid stimulating hormones, which play a key role in the growth and development process. The anterior pituitary is the largest part of the pituitary gland, which indicates its importance within the glands. On the other hand, the posterior pituitary is responsible for the release of oxytocin and ADH (vasopressin) as a way of promoting the growth and development process especially in younger children and women. One key element to consider about pituitary glands is that they tend to change in size depending on the hormonal status of the gland and the age of the individual.

Figure 2: Anatomy of the Pituitary Gland

CHAPTER 2
LITERATURE REVIEW
2.1 Literature Review
2.1.1 Definition
A literature review is a kind of scholarly paper. It is a text to provide background information on the subject area of the research and find the details of the pervious relevant researches. It is also a comprehensive document to provide information rather than list the researchers, topics, and dates. The main contents of a literature review include the current knowledge including substantive findings, theoretical contributions, and methodological contributions to a particular topic. It uses secondary sources and does not include new or original experimental work, which is always included in other scholarly works. Sometimes, when read through the literature, we can find conflicting views or results obtained by different researchers. Then, it is important for a literature review to point out these distinctions and explain the reasons for the differences and conclude the personal point for the topic.
2.1.2 Sources of Information
The dissertation work begins at searching library catalogue to find books relevant to the subject area – MRI techniques in diagnosis of pituitary disorders. Books will give general background information on a topic or a subject, though the information may not be the latest. Some publishing companies such as Elsevier, allow the researchers to search for new books by the subject. However, books are the most serious and rigorous sources and the up-to date researches are always not included. In addition, to write a complete literature review, it is important to find scientific papers, conference proceedings and other materials, which could present cutting edge information of a subject area to obtain up-to-date information. To some extent, researchers may rely more on the primary literature such as scientific papers, conference proceedings and dissertations rather than the secondary literature such as the books. In terms of the subject area, these kinds of literature are more specific and they will also represent the cutting-edge of science.
Generally speaking, it will take up to a year from submission of a scientific paper to publication. However, in order to be published in a scientific journal, a paper must pass the peer-review process and ensure itself as an original piece of work. Thus, a scientific paper could represent the up-to-date research result. It could also act as a kind of reliable source of information for scientists. They could be found on the publication companies’ website, such as Science Direct and Elsevier. Another kind of primary literature is conference proceeding. Researchers always present their research results at national as well as international science conferences. The presenters provide written reviews of their presentations, which will be given to the conference attendees in the form of conference proceedings. It is difficult to find them unless you are one of the attendees. However, searching for the titles of the conferences and finding the relevant materials will be the most effective way.
This paper tries to find the relevant materials on the websites of the institutes and organizations for pituitary disorder researches, such as National Cancer Institute at the National Institute of Health and American Cancer Society etc. Other related conferences could also be found through particular searching engines such as ISI Proceedings, ProceedingsFirst and PapersFirst. The last important sources for the literature are the dissertations, sometimes called theses. They are the graduate work of undergraduate, MSc, MPhil and PhD students. The advantage of the dissertations is that they always include a comprehensive literature review in the very beginning. The literature review of them is useful to find related materials and make the development of the subject area clearly to the readers. In addition to the primary literature mentioned above, secondary literature is another important source of information to be used to write a literature review. There are also three kind of secondary literature – books, websites, and review in journals.
2.2 The reasons for choosing literature review
2.2.1 Thorough understanding of the topic
According to Schmalisch, Milian, Schimitzek, Lagrèze, & Honegger (2012), there have been numerous theories that have emerged to about carcinogenesis. Out of all the theoretical assumptions that have emerged, the boveri’s somatic mutation theory emerged as the most relevant theory in this class of thought. According to this assumption, the pituitary disorders may come about due to the release of 6 major hormones resulting in cases of dysfunction with regard to the pituitary glands. The hormones causing the dysfunction in the glands may affect the main organ, known as “master gland” (as highlighted in figure 3). According to Di Iorgi et al (2012) the boveri’s somatic mutation theory become the framework for cancer description and the theory conceptualised the description of cancer as the outcome of irregular genetic mutations that occur in the germinal cells in the human body. This irregular cells or mutations as mostly referred in the medical world influence a high number of cellular pathways especially the MAPK, RB/E2F, 13K/AKT/mTOR as well as the TP53 pathways. This cellular pathway takes part in the increase and growth of cells in the body. Gutiérrez et al (2015) argue that hence affecting these cellular pathways increases the chance of having irregular cell formation in the body. Pituitary disorders, which are malignant, reported to be very intricate form of disease in the human body whereby changes occur in the genes responsible cellular pathways charged with the increase and growth of cells in the body.

Figure 3: Major Hormones Released within the Pituitary Glands (Rogers, Karavitaki, & Wass, 2014)
The most common form of pituitary disorders is irregular in its structure attributed by oncogense, which at the inception of their formation are already irregular hence later increased growth of cell in the body to individual affected. According to Gutiérrez et al (2015) other irregular cell formation that occurs particularly in the TSGs which stands for the tumor suppressor genes are believed to irregular growths. According to Gabery et al (2015) in pituitary disorders which is thought to arise as a result of a family history having the disease and account for less than 10 percent of the pituitary disorders report cases is known to be controlled by resistance genes which are the most beneficial. What most researchers in the medical field cannot explain is when a normal pituitary tissue changes into a malignant pituitary tissue. Despite of this setback, researchers have been embarking on therapies that target the molecular changes that occur when the pituitary tissue starts becoming malignant (Gabery et al, 2015). The old therapy that was used to treat cancer such as the traditional chemotherapy was not effective treating the cancer since it was a general treatment while cancer specifically affects the cells. Target therapy is more vital in pituitary disorder since it specially target cancer cell.
2.2.2 Identification of Similar works within the area of research
Target MRI technique diagnosis the ErbB2-targeting trastuzumab has already entered the clinical trial phase. The medicine targets helps in regression of the tumor in those tested for the drug and have metastatic cancer. When the drug is used together with chemotherapy, it is able to increase the survival rate amongst pituitary disorder patients and the research showed that an average of 20% had their cancer regressed if the process was could be started early enough (Sorbi et al, 2012). When researcher started by understanding ErbB2 in their determination to understand and find a cure to cancer, they were able to come up with the trastuzumab as well as creation of the receptor endocytosis.
2.2.3 Identification of the Gaps
When it comes to finding a cure for pituitary disorder using the genetic approach, researchers have to first understand the framework where molecules in the brain organ especially looking at the brain carcinogenesis as well as the treatment therapy approach and how doctors are able to prevent this disease. When it comes to the understanding of the human molecular system, researchers have to establish the pathways as well as their underlying development and setup hence knowing the genes. According to the research Braverman et al (2015) 10 genes were identified a pituitary disorders patient who inherited the disease but this genes only accounting for half the cases reported of pituitary disorders. Another side of pituitary disorders research that needs further development is in understanding the tumours internal structures, which initiates the cancer as well as offer an environment for the tumour to develop. According to Zilio et al (2014), the internal environment of the tumour is recognised as the guiding system for the growth and development of the tumour. Zilio et al (2014) the internal environment, which has been changed, is significant to cancers, which later bring about malignant change of the surrounding epithelium tissue surrounding the tumour which travel using the oncogenic pathways. According to Gutiérrez et al (2015), the mutated genes are so that contributes to the internal environment of tumour as well as their makeup.
2.2.4 Comparison between previous findings
Studies reveal that the tyrosine kinase function of the ErbB members is a vital mechanism used in cell communication as well as their alteration. As a results when any hindrance of the binding of more than one reaction to the total reaction provides logical grounds for the introduction of target therapy which is the tyrosine kinase inhibitor. Hence, the problem emerges when the researchers are looking for a medication, which is able to target the affective cells since the catalytic kinase environment of the ErbB protein have the same homology as the as the kinome hence the difficulty in assessing which is the mutated cell and those without. Pituitary disorders molecular target medication, which consist of quinazoline are more able to target the ErbB. Such compounds then are effective in biding with ATP bind areas of kinase areas or the ErbB receptors. Such medicines are able to block the signals, which move down since the block the ErbB tyrosine kinase area. According to Carrion, Wong, & Kletter (2013) the kinase regions of the EGFR functions in a methodical un-inhibited dormant state and only become active when introduced with receptor dimerization asymmetrically. The EGFRs, which are mutant cells, reduced or made inactive by the use of Erlotinib and gefitinib combine with the kinase ratio.
The pituitary disorders drug Trastuzumab has been made fit for humans which then allows those patients who have been administered with the drug, free from HAMA which is an outcome when drugs are not fit for humans and increase the chances of immunity and drugs administered cleared very fast in the blood stream. According to Di Iorgi et al (2012) experiments undertaken show that forty percent of patients treated for pituitary disorders using the trastuzumab drug had side effects such as fever and cold chills, which they experienced at the start of the medication. Other side effect from the pituitary disorders treatement using the trastuzumab drug included patients having diarrhear, headaches as well as had rashed on their bodies. When the medication is taken up well without many side effects, later medication continues within thirty minutes.
2.2.5 Critiques of the Existing Findings
According to major critics of pituitary disorders medications, many have felt that the trastuzumab administration caused cardiac toxicity in pituitary disorder patients. According to Kasaliwal et al (2013) in the year 2002 research that was undertaken in a total of 1219 test pituitary disorders patient with the trastuzumab medication was undertaken in phases revealed that there was a link between the trastuzumab and cardiac problems. The cardiac problem that were brought about by trastuzumab consisted of the cardiomyopathy which was a problem affecting the LVEF by decreasing its level.
2.2.6 Suggestions of Further Studies
According to researcher such as Kasaliwal et al (2013) The lifestyles human undertake to possess and the composition of what they eat, how they exercise if and when they do are some of the common factors that could be include in a pituitary disorders prevention measures. According to research undertaken by Kasaliwal et al (2013) when an individual is able to exercise and maintain a body weight of a having a body mass index of 19–25 kg/m2) have been known to reduce the risks of having pituitary disorders by half to 30 percent. Studies have to be undertaken into diet especially since studies reveal that having foods that are low in fats and having a high vegetable content as well as those with fruits do not reduce the risk of developing cancer after the first initial treatment for those treated early enough. This aspect need to be further investigated has it could lead to a long awaited cure for the disease. Another avenue, which also needs further investigation, is in effects of cigarettes smoke as well as being exposed to harmful smokes in the environment despite being implicated as known causes of pituitary disorders, research still does not give a definitive conclusion to their effect on low risk individuals. Pituitary disorders treatment still has a long way to go and a great level of research time should be given to researcher in order to fully understand its creation as well as find way of preventing the disease from attacking anybody.
2.2.7 Identification of Potential Areas for Research
Oncogense
According to Storr et al (2014) oncology genes were perhaps the first gene the researcher studied to determine their molecular composition. Moreover, by doing so, they have been able to modify their proto-oncogenes vital in the cell growth and increase regulation in the body. The outcome from the modification of the proto-oncogenes is known as gain-in-function. In reality, this process involves the slowing down on cell development drastically by influencing the genes instrumental in cell development in the human body. The oncogenes, which are widespread, can need to be changed in order to awake them to do a particular thing. This is undertaken by over stimulating them or modifying their protein, which then results in different outcomes for the genes. Mutation allows the function of protein in the gene to be enhancing. The protein in the oncogenes is those, which are responsible for the spread of cancer in the body and is mostly seen in those who have pituitary disorders. Researcher in the field of medicine according to Kahl et al (2014) found that thought the oncogenes, which were involved in the creation of cancer cell, in the later stages of cancer, was not significant in spreading the disease. The different types of oncogenes in pituitary disorders patients consist of HER2, c-MYC, and RAS
HER2
According to Schmalisch, Milian, Schimitzek, Lagrèze, & Honegger (2012), HER2 gene is the human epithelial receptor 2 and this gene was amongst the first to be discovered by medical researcher in their search for a cancer cure. According to Kaptain et al (2001), the human epithelial receptor 2 is found in the 17q12 chromosome. According to Schmalisch, Milian, Schimitzek, Lagrèze, & Honegger (2012), the human epithelial receptor 2, which is a protein, consists of kDa transmembrane tyrosine kinases, which are growth factor receptors.
C-MYC
According to Storr et al (2014) the c-MYC gene this gene if located at the 8q24 chromosome. Three genes consist of three isoforms according to Kahl et al (2014). The three isoforms found in the c-MYC gene consist of c-MYC1, c-MYC2, and c-MYCS which the principal isoforms being the c-MYC2 having the 62 kDa protein.

CHAPTER THREE
METHODOLOGY
3.1 Research Design and Methodology
3.1.1 Introduction
This chapter presents the research design and methodology used in this study on. The research methodology is important in examining the path taken in the research focusing on first determining the research philosophy. This then forms the basis of how the best research method chosen, which will enable the researcher to be able to have access to relevant information, able to answer the research objectives as well as questions. The chapter’s presentation is based on the following sections: research design, data collection instruments, data collection procedure and data analysis. Other important aspects of the research such as ethical consideration considered even though the research will be carried out using secondary data. The limitation of the research as well as the conclusion will end this section of the research.
3.1.2 Research Philosophy
When it comes to research philosophy in research work, this term is used to describe the model the research is to be undertaken by the researcher to establish the research objectives and questions. According to Braverman (2015) this will include individual basis of how information is to be collected, analysed and how the researcher utilises this data while carrying out the research will then. The main underlying assumption researcher perceive while undertaking a research is to establish whether an occurrences or situation is based on factual evidence or is believed to be true. Any of these two views to the researcher determine the research approach, which the researcher then chooses as the most appropriate for the research paper. The importance of scientific approach to the research then emerges as one where the researcher is driven to change the concept of believed perception to factual evidence, which can then be relied upon by scholars. This assumption led to two emerging theories, positivist based on what is true and interpretive based on adding the human factor into deliverable outcomes hence subjectivity.
3.1.3 Positivism
The positivist view is based on the underlying theory or reality in an occurrence or trend and hence, such occurrences can be seen to exist and are of a factual nature and neither interferes nor influences the outcome of a research. The researcher should set events that happen during the research aside and observations in the researcher should be repeated has often as possible. Such a phenomena then achievable when the researcher able to influence those aspects of the research which are factual and this is undertaken by the use of themes which then allow the researcher to place single occurrences separately and at the same time find links between the different themes in the research. Those occurrences known to occur during a research, allow the researcher to forecast outcomes since such occurrences are based on factual evidence of past research work undertaken as well as relationships, which have been established to exist.
3.2 Justification of Adopted Philosophy
This research paper will only utilise the positivism since the role of the researcher in this paper is to remain objective since the results are outcome from experimental analysis and not influenced by different understanding or assumption the researcher may have. Since the research objective in this paper is based on factual experiments as well as recordable outcomes in the medical field concerning diagnosis of pituitary disorders, only factual data is to be used in the analysis. The researcher in this paper decided the correct philosophy is the positivism view. By utilising this philosophy, the researcher will collect results from different experiments undertaken my medical professionals and the positivism philosophy emerges as the best approach when the researcher is keen on collecting independent as well as true published results from journals as well as medical journals and books. This allows the researcher to be free from influencing the research outcomes and this leads to an independent research based on factual evidence.
The results that will be used in this research paper will consist of numerical results and this is best achieved when the researcher uses positivism approach to their research. The results, which are collected, are quantifiable in nature and hence useful for the researcher in comparing as well as determining underlying occurrences in the research. The interpretive approach is not used in this case, since the results sought are of a factual nature and there is not room for results, which are not factual.
Even though there is no research, method is better than the other when it comes to research, when the results sought are of a medical nature and based on experimental analysis, only the method, which does not include bias, is used. Thus, the research approach chosen by the researcher is the most appropriate for this research paper.
3.3 Research Design and Justification of Choice
This study employed an exploratory research design. This research design enables the researcher to determine the best research design, data collection method and selection of subjects to be investigated. Moreover, this research design is convenient especially in situations where primary data proves to be difficult to collect. As such, this research design was found to be effective in this study of molecular targeted therapies for pituitary disorders diagnosis.
According to Saunders, Lewis and Thornhill (2007) research design was very important in while carrying out research by making sure that the research question was answered in this paper. By undertaking a research design, the researcher is able determine a path used in conducting the research which then allows the researcher to measure outcomes as well as use literature in answering the research objectives.
Based on Di Iorgi et al (2012), research experiments can be grouped into two categories starting with the casual and finally the correlation. In this research essay, the researcher has chosen to utilise the correlation research-investigation approach since the researcher would like to measure variables, which then will be analysed to determine relationship between them. MRI techniques for diagnosis of pituitary disorders are two variables, which will be investigated in order to establish a correlation in terms of their type of therapy and outcome in trying to understand treatment for pituitary disorders from those ailing from the disease. In this research essay, the researcher will also try to find a relationship, which could exist in the multi-tier variables that will be investigated in the beginning and incorporate all the variables in this paper. The researcher will look at the individual target cancer treatments for pituitary disorders to determine their strengths as well as experimental results from past literature. In order to recognize as well as describe the plausible link between the molecular targeted therapies and the resulting outcome to the pituitary disorders treatment, the researcher will use numerical published evidence from credible published material. Hence, this research will take the direction of a quantitative research. Kasaliwal et al (2013) found out that quantitative research approach was vital in utilizing numerical data outcomes, which was beneficial to the researcher in giving the researcher a true picture about a certain situation investigated. This kind of research approach also enabled the researcher to determine as well as investigate likely links in the variables.
For this research paper, the researcher has chosen to only use secondary data, which will be collected from scholar journals, and articles as well as books from those writers have been able to make an impact in the diagnosis of pituitary research area. The research design hence was not of an experimental nature but included an expressly correlated approach to the research paper.
3.4 Secondary Analysis
According to Kahl et al (2014), the researcher was able to determine the importance of secondary analysis on already published research and the researcher found out that, when an independent person carried out the research, the outcomes strengthened the first research. To date, a large number of researchers use this method as a means of gathering vital information especially if another scholar has already carried out the research. Empirical work for this research paper is extremely difficult due to the complexity as well as the instruments that are likely to aid the researcher. The other aspect touches on the pituitary disorders subjects that are a legal process likely to lead to litigations if the patients felt the process contributed to an increased harm to their disease. Hence secondary research made available with the use of primary datasets aids the researcher especially when facing elusive populations which is difficult to utilise in the research. Based on this assumptions and the sensitivity of the research theme in this paper, the researcher chose to utilise the secondary research method.
When carrying out secondary analysis of a primary dataset, the researcher should first ensure they have a path showing the original work, the method used by the first researcher to analyse the data as well as the analytical process that was used in the research analysis process. Other aspects such as the research methodology that was used as well as determines whether the researcher with the primary data set complied with ethical consideration during the research. The researcher also has to determine whether there was any missing data to ensure the findings and analysis process was transparent and inclusive of all parameters relevant in the research. It is then vital for the researcher to then determine how the already published primary dataset will fit with the secondary analysis to be used in the research work.
3.5 Data Collection Procedure
Upon approval and clearance by the institution on the research proposal the researcher went ahead to investigate on the area under study. To obtain information, the researcher visited various online libraries to obtain journals and textbooks written concerning the area under study for review. Moreover, with the help of internet, the research was also able to retrieve more articles on the area under study.
3.6 Meta-Analysis
According to Storr et al (2014), meta-analysis falls under the quantitative research whereby statistical data that has been derived from different sources are used to determine the research questions. The quantitative research approach is able to offer the researcher a thorough process to offer an analysis summary of the research study. The process was developed as a mechanism in which different outcomes from different studies could be combines to present the best alternative. This is the best approach to undertake in this research essay since different examination has been undertaken in the science field of diagnosis for pituitary disorders. Especially since the field of pituitary disorders has seen numerous studies as well as treatments brought up are different specialists, which have not been able to yield a single cure hence by combining the different studies, the researcher may be able to discover underlying signifiers as well as offer a better chance for MRI techniques in diagnosis of pituitary disorders. Meta analysis has not been used much in the field of science thought such a research approach offers the most valuable alternative as well as focused research approach which is likely to determine relevant links from the different approach to diagnosis of pituitary disorders.
3.7 Data Analysis
Upon clearance of the data collection, the researcher was in a position to critically look at the available data for analysis. The main approach of analysis used was the qualitative data analysis approach. The raw materials collected were critically reviewed and the meaningful information obtained was incorporated within the study for analysis. The data was synthesized into themes based on the research objectives. They were later then presented in a narrative form.
When gathering the information while undertaking secondary research, the researcher has to ensure that an analysis is made based on relevance and appropriateness of the information that will be used in the research paper and if the already published primary research will be effective in answering the research question in this paper. Analysis has to be undertaken in order to increase the chances of getting only the most vital information that is relevant and can be relied upon when used in the research. When the data to be used is relevant and sufficient concerning the theme of the research is able to provide for better research paper. The published information that is to be used then has to be enough for the researcher to be able to accomplish their research. The researcher has to be able to sort the outcomes from published results based on the research methodology used and the data collecting instruments, used for the research.
3.8 Limitations of the Study
This aspect however is very complex due to the knowledge and skills needed to carry out such a research method, which is practically experimental with tissue culture used and experimental medication. Time was also of concern in this research paper considering the numerous published research papers the researcher had to read and determine whether they were. With increased cancer detection mechanism in place today such as the utilization of the MRI machine used in the diagnosis process for patients with pituitary disorders.
CHAPTER FOUR
RESULTS
The improvement of understanding of molecular events and critical pathways has led to important improvement in targeted therapies in treatment of pituitary disorders. The improvement mainly involves identification of novel targets and development of anticancer therapies. Targeted therapies are aimed at inhibiting important molecular events in cancer cells, including cell growth, survival, migration, invasion, metastasis, apoptosis, cell cycle progression and angiogenesis. The approved targeted agents responsible for pituitary disorders include trastuzumab and lapatinib, directed against human epidermal growth factor receptor 2 (HER2) and bevacizumab, directed against vascular endothelial growth factor (VEGF). Other agents are under evaluation in preclinical and clinical trials, including inhibitors of epidermal growth factor receptor, dual epidermal growth factor receptor and HER2 inhibitors, VEGF/ VEGFR inhibitors and agents that inhibit critical signaling pathways such as PI3K/AKT/mTOR and RAS/MEK/ERK. There are also agents who work against other tyrosine kinases such as Src, insulin-like growth factor and those promote apoptosis such as Poly ADP ribose polymerse inhibitors. Other agents may target invasion and metastasis such as matrix metalloproteinases inhibitors and some other kinds of agents. In the following parts, this paper will review the research findings of each kind of agents to show the current status of research in this field. These most promising targeted agents will also be combined with mainstream chemotherapeutic drugs in clinical trials, which will also be discussed in this paper.
4.1 Targeting Epidermal Growth Factor Receptor Family
Epidermal growth factor receptor (EGFR) is a family of transmembrane growth factor receptor tyrosine kinases involved in regulation of cell proliferation and survival of epithelial cells, which affects both the anterior and posterior lobe of the pituitary glands (as highlighted in figure 4). EGFR family includes four receptors: EGFR/ErbB1, HER2/ErbB2, HER3/ErbB3, and HER4/ErbB4. EGFR and HER2 are overexpressed in approximately 40% and 25% of pituitary disorders, respectively, and are associated with aggressive clinical behavior and poor prognosis. Preclinical studies suggested that inhibiting this target might have anti-tumor activity and reverse chemoresistance.

Figure 4: Anterior and Posterior of the Pituitary Gland (Maret et al, 2014)
4.1.1 EGFR Inhibitors
Cetuximab (Erbitux) is a Mab that competitively binds with the extracellular domain of EGFR and prevents the receptor from activating EGF ligand, thereby inhibiting intracellular signal transduction. Preclinical studies demonstrated synergistic effect of cetuximab with paclitaxel in pituitary disorders models, but it failed to show efficacy in a phase I study with MBC patients. In the recent mid-stage study results presented at the European Society for Medical Oncology Congress, cetuximab in combination with cisplatin was indicated to significantly reduce the risk of disease progression in heavily pretreated women with metastatic triple negative pituitary disorders. Cetuximab plus cisplatin increased median time of progression-free survival (PFS) to 3.7 months compared to 1.5 months by cisplatin alone. A phase II trial is currently testing efficacy of cetuximab alone and in combination with carboplatin in metastatic triple negative pituitary disorder (TNBC). Other ongoing clinical trials with cetuximab include combination with agents such as irinotecan, bortezomib, ixabepilone, and trastuzumab in triple negative locally advanced non-resectable and/or MBC.
4.1.2 HER2 Inhibitors
Trastuzumab (commonly referred to as herceptin) was the first recombinant bivalent humanized Mab targeted against extracellular domain of HER2 reported in 1998, which blocks intracellular signaling. It is shown that approximately 25% to 30% of primary pituitary disorders are due to overexpressing of HER2. Those patients who overexpress HER2 will survive shorter than those without. The Trastuzumab was shown to inhibit tumor cells overexpressing HER2 both in vitro and in vivo. It is a kind of humanized monoclonal antibody, which will target at the out-cell part of HER2. Unlike chemotherapy, trastuzumab did not have toxic effects such as nausea, vomiting, hair loss, and bone marrow toxicity. Although cardiotoxicity events are concerns with trastuzumab these effects appear to be mostly treatable and reversible. Anti-HER2 therapies have significantly improved the clinical outcome of aggressive tumors. Large multicentre randomized trials revealed effectiveness of trastuzumab as adjuvant therapy when added in sequential or concurrently with taxane-based chemotherapy in HER2-positive early and advanced MBC.
4.1.3 EGFR and HER2 Dual Inhibitors
Despite initial efficacy, a large number of patients with MBC develop acquired resistance to trastuzumab. Moreover, the inability of trastuzumab to cross blood-brain barrier has been a major reason behind brain metastasis in patients on trastuzumab therapy. A viable option to improve trastuzumab performance is to combine them with other signal transduction pathways inhibitors. Therefore, small molecule tyrosine kinase inhibitors (TKI) that target HER2 overexpressing tumors and cross blood-brain barrier could show activity against brain metastases. Dual EGFR-HER2 inhibitors for pituitary disorders include lapatinib, cetuximab, pertuzumab, canertinib, and neratinib.
Lapatinib is an oral dual TKI that targets both EGFR and HER2, by blocking the downstream signaling pathways from these receptors. Lapatinib has been extensively studied in multiple clinical settings for treatment of patients with advanced or MBC. Studies have demonstrated promising clinical activity of lapatinib monotherapy in previously untreated patients and those progressed on trastuzumab-containing therapy. Despite disease progression on prior trastuzumab-based therapy, lapatinib in combination with trastuzumab significantly improved PFS and CBR versus lapatinib alone, thus offering a chemotherapy-free option with an acceptable safety profile to patients with ErbB2-positive MBC, which reduces the intraglandular cleft (as highlighted in figure 5). The most common treatment-related adverse events were rash, diarrhea, nausea, and fatigue (Blackwell KL, et al, 2010). A subgroup of HER2-overexpressing pituitary tumors were found to co-express p95HER2, which is responsible for intrinsic trastuzumab resistance. Lapatinib monotherapy or in combination with capecitabine was found effective in patients with p95HER2-positive and p95HER2-negative HER2-positive pituitary tumors (Van Boven et al, 2009).

Figure 5: Intraglandular Cleft in the Pituitary Glands (Sorbi et al, 2012)

CHAPTER FIVE
DISCUSSIONS
5.0 Discussions
There are currently six major targeted MRI techniques used in the diagnosis of pituitary disorders: Herceptin, Tykerb, Avastin, Perjeta, Afinitor, and Kadcyla. With the development of research in the field of pituitary disorders, some new researches are also ongoing for some particular type of pituitary disorders, such as the triple- negative pituitary disorders. The latest research is now working to find the best way to treat triple-negative pituitary disorders. 10% – 20% of pituitary disorders falls into this category, which means that the pituitary disorders test negative for bother hormone receptors and HER2 in the lab. For the reason that hormones are not supporting its growth, the cancer is possibly not to respond to hormonal therapies including tamoxifen, Arimidex, Aromasin , Femara, and Faslodex. This kind of pituitary disorder seems to be more aggressive than other kinds of pituitary disorders. Studies have shown that triple-negative pituitary disorders is more likely to spread beyond the brain and more likely to recur (come back) after treatment.
These risks appear to be greatest in the first few years after treatment. For example, a study of more than 1,600 women in Canada published in 2007 found that women with triple-negative pituitary disorders were at a higher risk of having the cancer recur outside the brain — but only for the first 3 years. Other studies have reached similar conclusions. As years go by, the risks of the triple-negative pituitary disorders recurring become similar to those risk levels for other types of pituitary disorders. Five-year survival rates also tend to be lower for triple-negative pituitary disorders. A 2007 study of more than 50,000 women with all stages of pituitary disorders found that 77% of women with triple-negative pituitary disorders survived at least 5 years, versus 93% of women with other types of pituitary disorders. Another study of more than 1,600 men and women published in 2007 found that participants with triple-negative pituitary disorders had a higher risk of death within 5 years of diagnosis, but not after that time period. The recurrence and survival figures in these and other studies are averages for all women with triple-negative pituitary disorders.
Factors such as the grade and stage of the pituitary disorders will influence an individual woman’s prognosis. It also tends to be higher grade than normal type of pituitary disorders. The higher the grade, the less the cancer cells resemble normal, healthy brain cells in their appearance and growth patterns. On a scale of 1 to 3, triple-negative pituitary disorders often is grade 3. In addition to linical trials trying to compare the old and new chemotherapy medications, there are clinical trials trying to find out whether some targeted therapies are could effectively deal with it or not. Different from those traditional therapies including chemotherapy and radiation, targeted therapies could stop the cancer cells from growing and thriving. It is already known that targeting estrogen and progesterone receptors and HER2 is not helpful for triple-negative pituitary disorders. Treatments that target other processes are of potential to be helpful and this kind of research is still at its most early stage. The most potential agents include RARP inhibitors, VEGF inhibitors and EGFR-targeted therapies.
VEGF inhibitors are also potential to deal with the triple-negative pituitary disorders. The process angiogenesis is the process that tumors get the oxygen and nutrients they need to grow and spread to create new blood vessels. Avastin is used for interfering with the activity of the VEGF protein which stimulates the process that tumor gets larger. The medicine could attach itself to VEGF, preventing VEGF from interacting with receptors on the blood vessels. On Nov. 18, 2011, the US Food and Drug Adimistration have announced that it had removed the pituitary disorders indication from Avastin for the reason that the drug has not yet been shown to be safe and effective for the use to treat by blocking this interaction, Avastin keeps VEGF from stimulating angiogenesis. Another therapy that works in a similar way is Sutent. Other agents that could deal with the certain type of cancer are EGFR-targeted therapies, which have been introduced in the previous chapters. As introduced in the previous chapters, the pituitary disorders cells are known to overexpress EGFR.
The new medicine Erbitus, whose chemical name is cetuximab is a medication that attaches to the EGFR. According to the results of clinical trials, there are many new ways to use targeted therapies to effectively treat cancer. Thus, the new therapies need approval from the clinical trials. Since dozens of new, innovative targeted therapies have not yet been approved by the Food and Drug Administration, clinical trials may be the only opportunity for patients to access them at present. Only 3 percent of adults with cancer choose this route and enroll in clinical trials. A recent study has indicated that 65 percent of patients would have been receptive to clinical trial enrollment if they had been made aware of the option at the time of initial diagnosis. Eighty-seven percent of patients would consider participating in a clinical trial their initial treatment failed (Mulligan et al, 2012). Physicians have the responsibility to talk to their patients about clinical trials and help them identify appropriate trials if the patients are interested. There are targeted therapies for cancer in all phases of clinical study.
The participation rate for the clinical trials may be a great problem for delivering new therapies. Another challenge for developing therapeutic solutions to combat resistance is de novo and acquired tamoxifen resistance as always. There’s few effective regimens to treat tamoxifen-resistant pituitary disorders. The complexity of tamoxifen resistance calls for diverse therapeutic approaches. Medicinal chemistry holds the key to effective, personalized combination therapy for tamoxifen-resistant pituitary disorders by making available a diverse arsenal of small-molecule drugs that specifically target signaling pathways modulating hormone resistance. These combination therapy candidates should have the desired specificity, selectivity and low toxicity to resensitize tumor response to tamoxifen and/or inhibit the growth and proliferation of resistant pituitary disorder tumors. The selective estrogen receptor (ER) modulator tamoxifen has been the mainstay therapeutic regimen for ER-positive (ER+) pituitary disorders for several decades. However, de novo and acquired tamoxifen resistance remains a major clinical challenge in the course of hormone therapy that has few effective remedies. The molecular complexity of tamoxifen resistance requires the availability of diverse treatment strategies.
Clinically ER+ pituitary disorders often retains the expression of ER after acquired resistance to tamoxifen, therefore, targeting the ER may still represent a viable intervention strategy for the resistant disease. Alternative selective ER modulators (SERMs) can be designed and synthesized to substitute for tamoxifen against resistant pituitary disorders, provided that the tumor still relies on ER-regulated survival signaling. To this end, two classes of SERMS, tamoxifen-like and fixed-ring compounds have been developed and tested, some of which have made it into Phase I and Phase II clinical trials. While the utility of alternative SERMs may be diminished due to cross-resistance, response to selective estrogen downregulators (SERDs) such as the prototype fulvestrant is still possible for pituitary disorders that remain ER+. To overcome the poor bioavailability of the only clinically approved SERD, fulvestrant, a number of novel SERDs have been reported, both nonsteroidal and steroidal. These developments offer potential second-line regimens for tamoxifen-resistant pituitary disorders. While aromatase inhibitors (AIs) have become standard therapy for postmenopausal woman with ER+ pituitary disorders, the use of AIs as second-line treatment for tamoxifen-resistant pituitary disorders has yet to be proven clinically.
Phase III clinical trials conducted using three US FDA-approved AIs have reported promising results with significant response from patients no-longer responding to tamoxifen. Ongoing development of next-generation AIs may provide a wider range of choices for AIs that can be used as treatment of tamoxifen-resistant pituitary disorders. In addition to advances in the use of SERMs, SERDs and AIs for the treatment of tamoxifen-resistant pituitary disorders, novel therapeutic approaches targeting ER signaling pathways via different mechanisms continue to be explored. These include ER ligands that can block both AF-1 and AF-2 transactivation functions of ER and those targeting the ER zinc finger. Intrinsic tamoxifen resistance represents approximately 30% of all diagnosed ER+ pituitary disorders, a significant number to which clinical solutions are few and often ineffective. Recent development in addressing de novo resistance includes approaches that overcome CYP2D6 polymorphism and designing more potent and selective compounds against ER+ and HER-positive pituitary disorders subtypes that often respond poorly to initial tamoxifen therapy.

CHAPTER SIX
CONCLUSION
According to the discussions in the above chapters, there are normally ten popular agents working as the therapies for pituitary disorders. The most recent and approved targeted agent is working against human epidermal growth factor receptor 2 (HER2) and vascular endothelial growth factor (VEGF). Review in 2003 regarding the HER2 in pituitary disorders, they identified HER2 as the target of therapy. As the most primary agent, the advent of HER2-directed therapies has importantly improved the outlook for patients with HER2-positive in early stage of pituitary disorders. However, statistics show that a large proportion of these patients finally relapsed or died of pituitary disorders. Thus, the research to refine and optimize the use of the two approved HER2 agents, which are trastuzumab and lapatinib is still ongoing. In addition, promising new approaches are being developed including monoclonal antibodies and small-molecule tyrosine kinase inhibitors targeting HER2 or other HER family members, antibodies linked to cytotoxic moieties or modified to improve their immunological function, immunostimulatory peptides, and targeting the PI3K and IGF-1R pathways.
Improved understanding of the HER2 signaling pathway, its relationship with other signaling pathways and mechanisms of resistance has also led to the development of rational combination therapies and to a greater insight into treatment response in patients with HER2-positive pituitary disorders. Based on promising results with new agents in HER2-positive advanced-stage disease, a series of large trials in the adjuvant and neoadjuvant settings are planned or ongoing. This Review focuses on current treatment for patients with HER2-positive pituitary disorders and aims to update practicing clinicians on likely future developments in the treatment for this disease according to ongoing clinical trials and translational research. The research showed that there have been numerous theories that have emerged to about carcinogenesis. Out of all the theoretical assumptions that have emerged, the boveri’s somatic mutation theory emerged as the most relevant theory in this class of thought.
This irregular cells or mutations as mostly referred in the medical world influence a high number of cellular pathways especially the MAPK, RB/E2F, 13K/AKT/mTOR as well as the TP53 pathways. This cellular pathway takes part in the increase and growth of cells in the body. oncology genes were perhaps the first gene the researcher studied to determine their molecular composition. Moreover, by doing so, they have been able to modify their proto-oncogenes vital in the cell growth and increase regulation in the body. The outcome from the modification of the proto-oncogenes is known as gain-in-function. Target molecular cancer therapy treatment the ErbB2-targeting trastuzumab has already entered the clinical trial phase. The medicine targets helps in regression of the tumor in those tested for the drug and have metastatic cancer. When it comes to finding a cure for pituitary disorders using the genetic approach, researchers have to first understand the framework where molecules in the brain organ especially looking at the brain carcinogenesis as well as the treatment therapy approach and how doctors are able to prevent this disease.

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