Sonette+Steczina

A Battle Against Brain Metastatic Melanoma
Due to Eva Steczina’s religious beliefs, she did not under go any form of treatment against her metastatic melanoma that had traveled to the brain. This decision led to the cancer ravaging her body with very slow progression – 9 months, though the normal prognosis is 4-6 months – causing extreme degeneration to the locations of the brain that involved in speech and sight. My research indicates that from the treatment options available in 1977, had she made the decision to under treatment, her overall survival time would not have been any different than the reality. There may have been slight improvement to the quality of life in the final months, but no increase in months on this earth. If she was living in present day and making the decision to undergo treatment, her life could have been extended by only a few months by a combination of the chemotherapy drug nivolumab alongside steriotactic radiotherapy.
 * Aperçu **

My grandmother, Eva Steczina, grew up and began her family in Budapest, Hungary where with her husband she ran a nylon stocking repair business. Eva was a devout Christian Science practitioner and lived by the values and teachings of the Christian Science Church. Her faith and beliefs called her to abstain from drinking and smoking, as well as to culminate the power of the mind to heal the body instead of medicinal treatments. Soon after Eva and her family moved to Seattle, Washington in search of freedom from the turmoil and horror of the 1956 Hungarian Revolution, a small black growth appeared and began to take form on her upper cheek, directly under her eye. This was the first sign of what was later diagnosed as melanoma, but due to her Christian Science values she did not immediately seek treatment. In 1976, 10 years after Eva’s husband passed away from brain cancer, this dark spot had morphed into a larger growth. It was the concerned voices of loved ones that finally persuaded her to have the skin growth removed. Eva was 53 years old. Although she led a healthy lifestyle, during her younger years she had spent much time in the strong summer sun of inland Hungary. While it was not directly malignant melanoma that ended her life in 1977, her decision to not have the dark growth removed at its first manifestation resulted in its metastasis to the brain.
 * The Cancer **

Melanoma of the skin is the sixth most prevalent type of cancer in the United States [[|1]]. Melanoma is cancer of the melanocytes, the pigment producing cells of our skin. A prediction by the American Cancer Society states that “59,940 new cases of melanoma occurred in 2007 (4% of all cancer cases). Of those cases, 8100 patients (13%) died, predominantly because of widespread metastases (1–2% of all cancer deaths)” [[|2]]. Although melanoma has one of the highest 5-year survival rates (90%), just behind testicular cancer, if left untreated, melanoma can become extremely aggressive and metastasizes to other organs of the body, primarily the lung, liver, or brain [[|3]]. The location of the lesion can influence the site to which metastasis occurs; melanoma on the head is a risk factor for metastasis to the brain [[|4]]. The risk of metastasis specifically to the brain once the original melanoma has reached stage IV is 60%.

Exact details of my grandmother’s primary cancer are not known by my father. Around the time that the growth was removed from Eva’s face, my father was away for extended periods of time and therefore, does not know specific details. Research has led me to conclude that if medical records were to be located, it would most likely state that it was identified as Lentigo maligna. One of the subgroups of melanoma that takes form on the outer layer of the skin, lentigo maligna is most often diagnosed in the elderly, caused by severe sun exposure, and is characterized by a dark brown or black, elevated mark [[|5]]. If the lesion is greater than 4 cm, the likelihood of this form of melanoma becoming invasive drastically increases.

This was very likely the prognosis for Eva. Since the dark growth that my father describes as a “birthmark” on her cheek was not treated for an extended period of time, it grew and developed unchecked. Within a year that the malignant tumor was removed from her face, Eva started experiencing a cascade of abnormal symptoms. What was thought to have been a mild stroke progressed into more frequent seizures and uncontrollable muscle twitching. The prognosis: her skin cancer had metastasized to the brain resulting in metastatic brain cancer, which will be the focus of my research. During embryonic development, the neural crest gives rise to both melanocytes and many neural cell populations, including sensory neurons [[|6]]. According to Denkins et al., “malignant melanoma metastasizes to the brain with one of the highest frequencies of any cancer capable of colonizing the CNS. Patients with disseminated malignant melanoma frequently develop metastatic lesions in the brain and spinal cord that can result in severe and debilitating neurological complications.” The relationship between the origins of these cell populations offers reasons as to the increased prevalence of metastatic melanoma targeting the brain – as was the case for Eva. By the time the growth on her face was removed, it is very likely the cancer had already metastasized. Another, albeit lesser, possibility is that all of the growth was not successfully removed.

Still, due to her religious beliefs, Eva did not undergo any form of treatment, although treatment options for brain cancer were available. Thus, for Eva, no tests were performed, no surgery was done in order to remove the brain tumor, and no therapies were administered. Eva’s symptoms worsened and soon she was bed ridden. Once a cancer has metastasized to the brain, the average survival rate is approximately 4-5 months [[|4]]. Eva’s progression was slow and debilitating, much exceeding the typical 4-5 month prognosis. The tumor had most likely metastasized to the occipital, temporal and frontal lobes of the brain. Notable symptoms of this metastasis were that Eva had become blind and was also unable to communicate orally with individuals around her. The occipital lobe at the back of the brain, which controls vision, had been impaired by the tumors as well as the left temporal lobe and the frontal lobe, which among many other things are involved in speech [[|7]]. These symptoms are associated with degeneration to the above-mentioned locations of the brain.

Her decision to not undergo any treatment or therapy caused the cancer to ravage her body with very slow progression. Since no tests were performed, it was unknown to Eva and her family if the melanoma had metastasized to other organs of the body as well. Eva’s body fought and at last succumbed to the all-consuming effects of cancer after 9 months. She passed away on the third of December 1977.

In biology, a molecular mechanism is a system cascade by which molecules affect one another, ultimately, resulting in a larger effect or effects. As an analogy, a beautiful detailed structure can be built from dominoes; each domino being an individual molecule. The domino line or structure, like a physiological structure or mechanism, remains intact and functional as long as each domino piece functions normally, that is, it stays standing. If, as a single faulty molecular step, one domino falls over, it will begin a cascade effect that cannot stop by itself, and ultimately the entire structure will be destroyed.
 * Molecular Mechanisms **

In terms of cancer metastasis, there are molecular mechanisms that drive invasion from a primary tumor site all the way to final colonization at the secondary tumor location. These molecular mechanisms are unique to each cancer type. Certain cancers metastasize to specific locations in the body with higher likelihood than other locations. In case of melanoma, the molecular mechanisms, that are not yet fully understood, cause metastasis to occur in the brain with high prevalence. This was the case for my grandmother, Eva Steczina. The mechanism is influenced both from the malignant cells, with its accompanying environment at the primary tumor site, as well as the cells and environmental characteristics of the location to which metastasis is occurring. As proposed by Stephen Paget, a “seed” has a certain attraction to a “soil” type, which parallels a particular cancer cell’s affinity toward another location of the body [[|8]]. This hypothesis, although proposed more than a century ago, still lends itself as a metaphor as to why some cancers eventually undertake the notable hallmark of “invasion and metastasis,” but not by randomly selecting the secondary location. One example of this non-random selectivity to the brain’s microenvironment is that “the microenvironment of the [central nervous system] CNS is exceptional in having a high chloride content, enabling tumors which prefer this environment, such as neuroepithelial tumors like small cell cancer of the lung and melanoma, to colonize, while potentially inhibiting invasion by other cancer cell types without this predilection” [[|8]]. Although the full mechanism and reasons for this prevailing disease progression is primarily unknown, the three molecules, Claudin-1 (CLDN1), Neurotrophin receptor (NTR), and signal transducer and activator of transcription-3 (Stat3), are all part of a greater molecular mechanism that play important roles in melanoma’s metastatic potential and its targeting of the brain.

If changes occur in a cell’s ability to migrate or adhere and take root at new locations, this will in turn affect cancer cells ability to metastasize. Specifically, an increase in cell adhesion capabilities to the extracellular matrix (ECM) will increase the metastatic potential by the cells. CLDN1, a human gene, regulates cell adhesion. A loss of CLDN1 gene function (low gene expression) results in increased migration or metastatic potential. A recent study published in 2014 demonstrated the opposite, that “ CLDN1- overexpressing melanoma cells expressed a lower ability to migrate and adhere to extracellular matrix, reduced tumor aggressiveness in nude mice and, most importantly, eliminated the formation of micrometastases in the brain...CLDN1-mediated interactions between these cells and brain endothelial cells constitute the mechanism underlying these results” [[|9]]. Therefore, restoring the function of CLDN-1 has the ability to render melanoma cells incapable of migrating.

Neurotrophin receptors (NTR), specifically p75 NTR, Low-affinity Nerve Factor Receptor, are being investigated as molecular markers (indicators) for invasion of aggressive melanoma cells [[|10]]. An in-vitro experiment, conducted by Marchetti et al., studying “the presence of these NTR’s (among others, p75 NTR ) in brain- metastatic melanoma resulted in enhancement of melanoma cell invasion” in comparison to metastasis to other locations [[|11]]. At the time that this study was published, mechanism behind this increase in invasion capabilities was not understood. A couple years later the same lab discovered that increased production of NTR’s by melanoma cells subsequently increased the synthesis of heparanase, an enzyme that acts to degrade the extracellular matrix and components of the blood-brain barrier [[|6],[|11]]. Overstimulation of the NTR’s and in consequence, increased levels of heparanase – influenced by elevated levels of paracrine invasion factors in the microenvironment – increases the melanoma cells’ propensity to colonize the brain.

The role of another human brain metastasis-influencing molecule, signal transducer and activator of transcription-3 (Stat3), was initially proposed in 2006 by Xie et al. Xie et al’s research led to the conclusion that increased levels of Stat3 resulted in over-expression of three different proteins: matrix metalloproteinase-2 (MMP- 2), basic fibroblast growth factor (bFGF), and vascular endothelial growth factor (VEGF) [[|12]]. These proteins play notable roles in invasion and angiogenesis, the development of new blood vessel networks, necessary for brain metastasis to occur. In 2008, further research by the same group revealed that Stat3 wasn't the primary player in de- regulating this pathway [[|13]]. Loss of function (love gene expression) of cytokine signaling-1 (SOCS-1), which is upstream of Stat3 was identified as causing an increase in the expression levels of Stat3. The entire molecular mechanism is displayed in Figure 1.



Fully understanding these pathways to the point of being able to manipulate or deactivate them will allow development of different targets against the metastatic potential of melanoma to the brain. As a proof of concept, Huang et al. experimentally regained the SOCS-1 function in-vitro that led to an inhibition of the capacity of melanoma to metastasize to the brain [[|13]]. After successfully accomplishing this in-vitro, the next step is to perform it in-vivo, which could lead to a therapy that halts the spread of melanoma to the brain. Intervention methods would have to suppress the interference in mechanism leading to metastasis. Using the domino analogy, if fall of the faulty domino is prevented or if a method is created to stabilize the structure just after initial disruption, the entirety of the structure remains intact. In the realm of cancer research, these intervention methods utilized to halt the metastatic progression of melanoma are under much investigation.

In very simple terms, scientific discovery(s) can be placed in one of two categories: 1) Discovery by chance. Discovery of this sort is like groping through the darkness, when at one miraculous moment one comes across the answer that no researcher knew was even a possibility, yet on discovery it seems all too obvious. 2) Discovery in small steps whereby the road to discovery is paved by one small, but crucial brick at a time. Discovery of this sort is the sequential, but collective effort of hundreds of scientists and often takes many, many decades. Cancer research, and to date, research of brain metastatic melanoma in particular, belongs to the latter category.
 * Treatments and Outcomes **

As such, although it has taken ~ 40 years, much progress has been made in the screening and intervention methods against brain metastatic melanoma. The 1970s brought drastic change to the standard methods of screening and care for brain cancer patients, both primary and metastatic forms. The first successful computed tomography (CT) brain scan using X-rays to visualize brain tumors was documented during the 1970s and it replaced any form of exploratory surgery that may have been performed to determine the precise location of a tumor [[|14]]. The same decade also gave rise to the first successful chemotherapy drug approved for use against metastatic melanoma – Dacarbazine. Followed closely by radiation therapy, this radiological method was “the first time a treatment [was] proven effective against brain cancer.”

Although Eva Steczina chose, due to her religious beliefs, not to undergo any treatment, this paper will detail how her treatment options in 1977 would differ from those recommended at present day, would she have been diagnosed today. Treatment options for brain metastatic melanoma are directly indicative of the number of brain metastases present and the location of these lesions – especially if the tumor is located in the ‘eloquent brain.’ The eloquent brain denotes the regions of the brain that are involved in speech or motor related actions [[|15]]. Although no imaging tests were performed to confirm, my suspicion is that Eva, at the time that clinical symptoms arose, had multiple metastases in 3 lobes of her brain (the occipital, temporal, and frontal lobes), ultimately causing loss of her vision and speech. With CT scans being the newly established tumor visualization method, if Eva had seen an oncologist when her seizures had first begun, CT scans of her brain would have been performed, showing multiple melanoma metastases in the brain. Indicated by the precise locations of the tumors, resection would not have been selected due to the functionality of those locations, thus no surgery date would have been set. Initially, to control her seizures, she would have been given phenytoin, which was utilized in the 1970s as an anti-seizure medication. In order to treat her inoperable tumor, whole brain radiation would most likely have been performed. The concern with irradiating the entire brain is its potential harmful effect on cognitive functions especially for children during critical brain development stages. Since Eva was diagnosed at age 54, I do not believe doctors would have been deterred had she made the decision to undergo treatment.

Although, at this time, there was very limited scientific data related to the treatment of the cancers of the central nervous system (CNS), chemotherapy was increasingly becoming an alternative treatment option to radiation. Decarbazine (DTIC), a chemotherapy drug, was approved by the FDA in 1975 for metastatic melanoma [[|16]]. Unfortunately, my research indicates that at the time that DTIC was developed, it was not targeted toward a specific type of metastatic melanoma. In 2004, a phase III study was released comparing DTIC and fotemustine chemotherapies, specifically their CNS responses [[|17]]. Fotemustine was initially approved for treatment of metastatic melanoma, but received heightened attention when success against brain metastases became evident [[|18]]. DTIC and fotemustine have very similar mechanisms of action; they both initiate alkylation of a particular component of DNA [[|19], [|20]]. Although the proportion of patients that had complete or partial response to the two chemotherapies did not differ significantly between experimental groups, CNS response (overall response rate) was calculated as 6% for fotemustine, while no response rate of the CNS was seen for the DTIC patient group [[|17]]. Another noteworthy result from this study was that, “ the median time of occurrence of these brain metastases was about three times longer in the fotemustine group (22.7 months) than in the DTIC group (7.2 months; //P// = .059).” Since fotemustine had not yet been discovered in 1977, Eva’s chemotherapy option would have been DTIC. Retrospectively, from the data collected in 2004, we can hypothesize that if she had received DTIC at the time that her late stage melanoma growth was removed from her face, but prior to full clinical manifestation of brain metastatic melanoma, there could have been a chance that DTIC was effective in eliminating micro-metastases. In comparison, if she had been given DTIC when clinical signs of the brain metastasis had already manifested, her prognosis most likely would not have been any different. Her overall survival would have been similar to her actual survival, but with a possible slight improvement in quality of life. This is because the clinical data indicates that DTIC is not affective at promoting CNS response once brain metastases are already present.

Although small, progress has been made since the 1970s on treatment methods available for patients diagnosed with metastatic melanoma to the brain. Given the specific characteristic’s of Eva’s cancer (i.e. multiple lesions, in ‘eloquent brain’ regions), in 2016, she would be advised to either undergo whole brain radiation, as discussed above, or depending on the size of the tumors, be treated with stereotactic radiosurgery. Gamma knife surgery, a radiosurgery method where high intensity beams of gamma radiation are focused on one cancerous lesion in the brain, causing damage to the cells DNA, eventually causing them to die, has shown promise against tumors in the brain [[|21]]. This method has been proven effective when lesions in the brain are small to medium in size, ~3cm or less in diameter, and is used when the lesions are located in the eloquent brain, as was Eva’s [[|15]]. According to a study published in 2005 by Koc et al., gamma knife radiosurgery is most successful when used alone as a therapy. Results indicated that neoadjuvent and adjuvent therapies alongside gamma knife radiosurgery led to decreased survival in patients [[|22]]. My research found conflicting information as to the use of accompanying treatment to gamma knife radiosurgery; the American Brain Tumor Association states that radiosurgery can be given in combination with whole brain radiation.

Another potential treatment option that would be available to her at present day is a targeted therapy regiment. Recent clinical research indicates success and efficacy of nivolumab in combination with ipilimumab. This resulted in its combined “accelerated approval” by the FDA in September 2015 for “ BRAF V600 wild-type, unresectable or metastatic melanoma” [[|23]]. Although these monoclonal antibody drugs are not specific to metastatic melanoma to the brain, a study published this year discussing the treatment effects of nivolumab alongside stereotactic radiation showed that for patients with tumors that could not be surgically removed, the overall survival was approximately doubled in comparison to the median overall survival of individuals with brain metastasis, as was reported in many other studies (12 months versus 4-6 months, respectively) [[|24], [|25]]. Nivolumab acts to inhibit the activity of the human cell surface receptor programmed death-1 (PD-1), which “negatively regulates T-cell activation and plays a key role in tumor evasion from host immunity” by blocking its activation [[|24]].

From the treatment options discussed, Eva’s best prognoses today, would she decided to undergo treatment would be to receive the chemotherapy nivolumab alongside stereotactic radiotherapy. Eva’s strength and dedication to remain true to her religious beliefs and not undergo any cancer treatment is empowering emotionally and philosophically, but it resulted in a physical battle that utterly ravaged her body. At the time that she was suffering from this disease, treatment options were limited and survival rates were not promising. However, research on brain metastatic melanoma has and will continuously progress forward with promising treatment options to improve prognosis of survival are constantly being researched and developed. Scientific investigation will continue to offer new and improved screening and treatment methods for future generations.

[1] “SEER Stat Fact Sheets: Melanoma of the Skin.” National Cancer Institute. 2016. http://seer.cancer.gov/statfacts/html/melan.html
 * Work Cited: **

[2] Zbytek, Blazej, J. Andrew Carlson, Jacqueline Granese, Jeffrey Ross, Martin Mihm, and Andrzej Slominski. "Current Concepts of Metastasis in Melanoma." Expert Review of Dermatology 3.5 (2008): 569-85. Web. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2601641/

[3] “Cancer survival for common cancers.” Cancer Research UK. http://www.cancerresearchuk.org/health-professional/cancer-statistics/survival/common-cancers-compared#heading-Zero

[4] “Understanding Melanoma: Stages of Melanoma – Brain Metastases.” AIM At Melanoma Foundation. 2014. https://www.aimatmelanoma.org/stages-of-melanoma/brain-metastases/

[5] “Types of Melanoma.” The Skin Cancer Foundation. New York, 2016. http://www.skincancer.org/skin-cancer-information/melanoma/types-of-melanoma

[6] Denkins, Yvonne et al. “Brain Metastases in Melanoma: Roles of Neurotrophins.” Neuro-Oncology 6.2 (2004): 154–165. PMC. Web. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1871977/

[7] “Anatomy and physiology of the brain and spinal cord.” Canadian Cancer Society. 2016. http://www.cancer.ca/en/cancer-information/cancer-type/brain-spinal/anatomy-and-physiology/?region=on

[8] Rahmathulla, Gazanfar, Steven A. Toms, & Robert J. Weil. “The Molecular Biology of Brain Metastasis.” Journal of Oncology 2012: 1-16. 2012. Web. http://www.hindawi.com/journals/jo/2012/723541/

[9] Izraely, Sivan, Orit Sagi-Assif, Anat Klein, Tsipi Meshel, Shlomit Ben-Menachem, Assaf Zaritsky, Marcelo Ehrlich, Victor G. Prieto, Menashe Bar-Eli, Christine Pirker, Walter Berger, Clara Nahmias, Pierre-Olivier Couraud, Dave S.b. Hoon, and Isaac P. Witz. "The Metastatic Microenvironment: Claudin-1 Suppresses the Malignant Phenotype of Melanoma Brain Metastasis." International Journal of Cancer Int. J. Cancer 136.6 (2014): 1296-307. Web. http://onlinelibrary.wiley.com/doi/10.1002/ijc.29090/epdf

[10] Marchetti, Dario, Rebecca Aucoin, Jason Blust, Brian Murry, and Andrea Greiter-Wilke. "P75 Neurotrophin Receptor Functions as a Survival Receptor in Brain-metastatic Melanoma Cells." Journal of Cellular Biochemistry J. Cell. Biochem. 91.1 (2003): 206-15. Web. http://onlinelibrary.wiley.com/doi/10.1002/jcb.10649/epdf

[11] Marchetti, Dario & Nicolson, Garth L. “Human melanoma cell invasion: selected neurotrophin enhancement of invasion and heparanase activity.” The Society of Investigative Dermatology 2(1): 99-105. August 1997. Web. https://www.researchgate.net/profile/Garth_Nicolson/publication/13744695_Human_melanoma_cell_invasion_selected_neurotrophin_enhancement_of_invasion_and_heparanase_activity/links/0deec514d30fe925d5000000.pdf

[12] Xie, T.-X., F.-J. Huang, K. D. Aldape, S.-H. Kang, M. Liu, J. E. Gershenwald, K. Xie, R. Sawaya, and S. Huang. "Activation of Stat3 in Human Melanoma Promotes Brain Metastasis." Cancer Research 66.6 (2006): 3188-196. Web. http://cancerres.aacrjournals.org/content/66/6/3188.long

[13] Huang, F.-J., P. S. Steeg, J. E. Price, W.-T. Chiu, P.-C. Chou, K. Xie, R. Sawaya, and S. Huang. "Molecular Basis for the Critical Role of Suppressor of Cytokine Signaling-1 in Melanoma Brain Metastasis." Cancer Research 68.23 (2008): 9634-642. Web. http://cancerres.aacrjournals.org/content/68/23/9634.long

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[17] Avril, M.f. et al. "Fotemustine Compared With Dacarbazine in Patients With Disseminated Malignant Melanoma: A Phase III Study." //Journal of Clinical Oncology// 22.6 (2004): 1118-125. Web. http://jco.ascopubs.org/content/22/6/1118.long#ref-11

[18] Jacquillat, Claude et al. "Chemotherapy by Fotemustine in Cerebral Metastases of Disseminated Malignant Melanoma." //Cancer Chemother. Pharmacol. Cancer Chemotherapy and Pharmacology// 25.4 (1990): 263-66. Web (Inter-Library Loan). http://www.ncbi.nlm.nih.gov/pubmed/2403853

[19] “Dacarbazine.” //National Center for Biotechnology Information. PubChem Compound Database;// CID=5353562. https://pubchem.ncbi.nlm.nih.gov/compound/5353562#section=Top

[20] Hayes, Mark T. et al. "Mechanism of Action of Fotemustine, a New Chloroethylnitrosourea Anticancer Agent: Evidence for the Formation of Two DNA-Reactive Intermediates Contributing to Cytotoxicity." //Biochemistry// 36.35 (1997): 10646-0654. Web (Inter-Library Loan). http://www.ncbi.nlm.nih.gov/pubmed/9271495

[21] “Gamma Knife Radiosurgery.” //Columbia University Department of Neurological Surgery.// 2016. Web. http://www.columbianeurosurgery.org/conditions/gamma-knife-radiosurgery/

[22] Koc, Mehmet et al. "Gamma Knife Radiosurgery for Intracranial Metastatic Melanoma: An Analysis of Survival and Prognostic Factors." //J Neurooncol Journal of Neuro-Oncology// 71.3 (2005): 307-13. Web. http://link.springer.com/article/10.1007/s11060-004-2027-1#/page-1

[23] “Nivolumab in combination with ipilimumab.” //U.S.// //Food and Drug Administration.// 2015. Web. http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm465274.htm

[24] “Nivolumab.” //National Cancer Institute. 2016.// Web. http://www.cancer.gov/about-cancer/treatment/drugs/nivolumab

[25] Ahmed, K.a. et al. "Clinical Outcomes of Melanoma Brain Metastases Treated With Stereotactic Radiation and Anti-PD-1 Therapy." //Annals of Oncology// 27.3 (2016): 434-41. Web. http://www.medscape.com/viewarticle/859974_2