Daniel+Horvath

__** Mesothelioma **__

** Part I - Nancy's Artistic Curse ** media type="custom" key="28596189"Nancy Fisher was seventy-eight years old when she received her terminal cancer diagnosis. As the oldest of three sisters she was considered the matriarch of her side of the family; a role that came about primarily from the facts that she was the only sister who did not pursue higher education and that she was always self-employed. This allowed her to be the only relative that maintained constant contact with all the separate branches of her family and made her well fit for the role despite not living close to any relatives or having a family of her own. All these things combined made this diagnosis particularly hard on the rest of her relatives, however, as difficult as this news was, it was not unexpected.

media type="custom" key="28596191"Nancy had spent the better part of her life trying to find work as an artist. From sculptures and murals to painting and drawing, Nancy did whatever she could to pay for her expenses every month. Many of Nancy’s sculptures were created on request and were short in the way of artistic expression. But, the few sculptures that she made for herself or her family would prove to embody who she was as a person. Many of her personal works depicted children in deep contemplation, most often by themselves. Frozen scenes, plastered in time that close family members say remind them of Nancy as a young girl. Despite her obvious talent, her career as a freelance artist never granted her a large expendable income, and as a result she never left her childhood home in the row houses of north Philadelphia; a house that was originally purchased by her father in the early 20th century. Her time spent in this home, in conjunction with her near constant work on art projects not only made her who she was, but unfortunately cursed her with the presence of airborne particles of asbestos. A compound that conceals its dangerous qualities so well, one might think it innately evil.

media type="custom" key="28596193"Asbestos is a type of silicate mineral with several varieties in structure and composition. While the material has many interesting properties and its history is unique, by far the most important things about the mineral in Nancy’s case is the unfortunate reality that it is both found everywhere and it is extremely carcinogenic. 4 At the time Nancy started using it, asbestos use had already proliferated throughout the world of consumer products. 5 Worst of all for Nancy, asbestos was in many different types of plasters. This included the type of cement plasters Nancy frequently used in her sculpting. 5 There is often no risk of exposure to these products today because the link between asbestos and mesothelioma is well known and people protect themselves accordingly. 6 However, in Nancy’s day, it was totally normal to work completely unprotected while using asbestos containing products. This is the reason that mesothelioma was so prevalent among blue-collar construction based professions like ship and homebuilders. In addition to all the exposure from her artistry materials, her electrical wiring was insulated with asbestos impregnated cloth. It’s no surprise then that around the age of seventy-seven Nancy realized she could not kick a persistent cough for almost nine months. She first assumed her growing fatigue was merely a result of old age, and she just didn’t have the energy or the will to make it through a day she used to consider a normal. But being who she was, a financially challenged, deeply reclusive artist, she decided to wait even longer. Rationalizing her decision from a combination of reluctance to spend needless money, and a fundamental distrust of medicine, Nancy waited for another two months before finally scheduling an appointment. By waiting this long, Nancy made her attempts to get better almost futile, but its doubtful she knew that.

media type="custom" key="28596195"When Nancy eventually worked her way through the diagnostic process from a typical physician to a full-blown oncological surgeon, her diagnosis was grim. She had stage-IV mesothelioma of the pulmonary pleurae, the epidermal lining of the lungs known as the mesothelium. 3 The asbestos had triggered several major events in the mesothelial cells of her right lung. Largely through the mutation of two genes coding for epidermal growth factor receptor (EGFR) and c-Met (a receptor tyrosine kinase that serves as a hepatocyte growth factor receptor) the cells in the lining of her lung began proliferating with growing irregularity for the past several years. 1,2 The result of which was a massive build up of plaque-like cells on the interior of both lungs and some surrounding tissues.

media type="custom" key="28596197"Surprisingly enough, the doctors said it was likely the sanding and chiseling of the dried plaster in her basement that left her so exposed to the carcinogenic particles of asbestos. 5 It was these actions that allowed so much of the mineral to go airborne and also explains why the cancer started in the mesothelium of her lungs. Despite the presence of mesothelial tissue around the stomach and heart as well, the particles of asbestos were most prevalent in a place she did not eat, but spent much time breathing. Because the cancer had so much time to develop, the cancerous plaque that formed in her right lung had metastasized to the other lung as well as several other areas in her abdomen. The wheezing cough and chest pains she had be waiting to treat for eleven months allowed the build up of this plaque to the point that it was now covering a large portion of her lung’s viable surface for gas exchange and irritating and inflaming the surrounding tissue on every breath. The lack of oxygen exchange in her lungs also brought her great fatigue, forcing her into a wheelchair through fits of spontaneous unconsciousness. She then made the freedom ending decision that she could no longer take care of herself, spurring relatives from around the country to take care of her. It was at this point she had to contemplate treatment, with knowledge that she likely would not live for more than a year due to the slow creep of the carcinoma over her lungs. She could live through the treatment, but it was likely that the lack of oxygen exchange or the spread of the carcinoma to her heart sac could kill her in the process. Even in the best scenario, Nancy’s life would never be the same; the cancer had progressed to far to allow for treatment that was not extremely destructive.

** Part II - A Tale of Two Hydroxyls ** media type="custom" key="28596199"Every time the world’s engineers and scientists solve one problem, they find tens more that are inexplicably harder to solve. This reality can be easily witnessed in the realm of materials science. Often times, when a great scientist discovers a material with excellent physical and chemical properties to solve a specific problem, they do not understand the chemical fully, and only look at it through the lens in which they wish to apply it. However, the very properties that make a material so promising in the first place are often the properties that can cause long term health and environmental damage. Whether it is the Freon in cooling systems or Chlorofluorocarbons in aerosol dispensers, the grim environmental effects of these chemicals were overshadowed by their great utility and potential. Thus, they were in use for decades before ozone depletion was even a known phenomenon. Asbestos has a very similar story to tell. It wasn’t until tens of thousands had died from exposure to the material that scientists began to wonder if it was harmful at all. 10

media type="custom" key="28596201"Asbestos has a hallmark physical structure of being long and fibrous with a typical length to diameter ratio of 20:1, but has three common variants that differ in length, rigidity and shape. 6 It is the longest and most rigid of these variants, known as amphibole asbestos, that poses the greatest risk of inducing mesothelioma and it is these fibers that Nancy inadvertently interacted with a great deal. 8,9 At the molecular level, subunits of amphibole asbestos are linked by extremely stable silicon-oxygen and iron-oxygen bonds, making asbestos flame resistant. By mixing any variant of the asbestos fiber in some sort of resin or greater matrix, asbestos can strengthen a material in the same fashion rebar strengthens concrete. 9 What makes this particularly valuable is that it also retains its innate combustion resistance. 9 Thus, it can be used in many applications where someone wants to insulate or reinforce an object that can be exposed to heat or flame. This is why it was used so commonly added to plasters and cements intended for home use. Although, mainly serpentine asbestos was used in plasters, it was common to see the presence of amphibole asbestos impurities in all asbestos products. 12 Unfortunately for Nancy, the house-hold plasters she used in her sculptures were full of amphibole impurities. Sadly then, her art came at a price.



**Figure 1.** (Left) An Ordinary model of serpentine asbestos structure. 16 (Right) An estimated model of amphibole asbestos using the Chemspider drawing tool. 15,17

media type="custom" key="28596203"The carcinogenic properties of asbestos, like the strength of the mineral, begin with the particles’ shape and inter-subunit bonds. Specifically, these properties make it difficult for the body to remove the fibers through its typical means. 11 Most small molecules that work their way into the lungs can be removed through tiny pores on the lung lining (mesothelium) called stomata that bring them into a cavity between the inner and out lining of the lung walls called the pleural space. 13 In this small space there are a large number of macrophages that can perform phagocytosis on the molecules and then flush them out of the body. 13 However, the lengths of the asbestos fibers make it impossible for two things to happen correctly. First, the fibers cannot be fully brought into the cavity between the lung layers because they are simply too long, so they get stuck in the stomata and begin to accumulate around them. 11,13 Second, the particles are also too long for the macrophages to completely consume the fibers, resulting in an inflammatory response as the macrophages trigger further action by the immune system to break down the fibers. 11,13 Typically, this response would break down long molecules like asbestos fibers so that phagocytosis can be performed, but the fibers of amphibole asbestos have a hardwired ability to resist sharp changes in pH and electro-chemical interactions due to their extreme stability. 12 What results is the slow, but steady accumulation of asbestos fibers, macrophages, as well ass other human immune-system-response molecules and cells that build a plaque-like compound on the surface of the lungs as well as within the pleural space. 13,14 It is this plaque itself that causes genomic damage necessary for the cells to become cancerous, largely because of the presence of reactive oxygen species (ROS) groups present within both the side chains of the asbestos strands and the oxidants secreted by the macrophages while attempting to breakdown the fibers. 11,12,13,14 As time passes, and a greater number of human-immune-response cells and molecules form on the surface of the fibers, a greater number of ROS producing entities come into play.



media type="custom" key="28596205"Within the plaque itself, there are three things that its ROS producing nature can be attributed to. The first, is the surface reactivity of the fibers themselves. 12 As seen in figure one, the asbestos fibers have hydroxyl side chains present on their subunits that readily react with the surrounding environment. 12 To make matters worse for Nancy, even a small amount of iron impurity in serpentine asbestos or the presence of iron from amphibole asbestos can augment the number of hydroxyls present by catalyzing a reaction with the surrounding environment that continually produces ROS. 12 The second source of ROS in the plaque-like compound that forms on the lungs of asbestos exposed individuals comes from the immune-system response, the macrophages in particular. 12 While attempting to break down the asbestos fibers stuck in the pleural space, the macrophages undergo a process known as frustrated phagocytosis. 12 A process that produces both NADPH oxidases and Tumor-necrosis-factor-alpha (TNF-α), both of which readily produce ROS during their intended use but are present in overwhelming numbers in macrophages and surrounding tissue within the plaque. 12 Finally, the last source of ROS in the plaque is a dysfunctional electron transport chain in the mitochondria of macrophages that are undergoing frustrated phagocytosis. 12 The mitochondria, and therefore the macrophages themselves, secret ROS in the form of hydrogen peroxide due to an increase in expression of Rac1 that changes the reactivity of Complex III in a way such that it continually reacts with its surroundings to create ROS. 12

media type="custom" key="28596207"The presence of the ROS causes a slow but steady damage to the mesothelial cells that eventually forms into cancer as it did in Nancy’s case. Most importantly, the ROS interact with guanines to produce 8-hydroxyl-guanines, a base that will pair with adenines instead of cytosines. 12,13 Therefore, as more and more 8-hydroxyl-guanines are formed, a growing number of single base pair mutations occur. This becomes particularly important when the cell attempts to repair these single-base-pair lesions because the same hydroxyls that caused the base pairs to mutate in the first place also interfere with the apoptotic pathways surrounding the p53 and Bax proteins in a way that is not fully understood. 13 This creates a positive feedback loop of genomic instability and evasion of cell death in which amphibole asbestos and its related hydroxyl groups act as triggers. This is especially troubling in Nancy’s case because her exposure to asbestos lasted for more than forty years. Meaning the shear concentration and accretion of the asbestos fibers is creating a vast supply of hydroxyls and other reactive oxygen species at all times. So even if the cancer is effectively treated, the presence of mutagens and the root of the cancer will never leave. In her case, nothing short of a full lung transplant could have removed the cancer in a permanent way. There is hope, however, in a relatively novel treatment method known as a pleurectomy/decortication that involves cutting into the pleural space and removing everything inside as well as a thin layer of both pleural walls. 11 Unfortunately, this is only possible when the cancer has not spread to the heart sac or diaphragm. 1

** Part III - Extreme Disease Calls for Extreme Treatment ** media type="custom" key="28596209"Stage IV mesothelioma is not to be taken lightly. It is a terrible scourge that has a median overall survival rate around 10 months with multi-modal therapy; and the statistic gets much worse with radiation, chemotherapy or surgery alonae. 10 In particular, Nancy’s cancer was extremely hard to treat due to a metastasis to another mesothelial tissue directly surrounding the heart known as the pericardial sac. So like many patients in her scenario, Nancy opted for comfort care. However, for the purposes of gaining a better understanding of treatment options this essay will pretend that she pursued life-extending treatment.

media type="custom" key="28596211"Beyond her initial thoroscopy and the confirmation of her cancer by a pathologist, Nancy was given a number of immuno-stains to identify the excessive presence of both epithelial growth factor receptors (EFGRs) and c-Met human growth factor receptors. 10,17 Both of these are a form of receptor tyrosine kinases (RTKs) that result in irregularly large amount of proliferation. 10 But, the c-Met receptor is unique because it is much more typical of mesenchymal cells. 10 This makes their presence a good indicator of cells that have gone through the epithelial to mesenchymal transition (EMT) which is important because mesenchymal cells have the ability to slip through basal tissue and move throughout the body. 10,19 It is these cells then that tend to be the source of many metastases. Of the insights revealed by the various immune-stains, the malignancy on the pericardial space was the hardest individual tumor to treat because of its proximity to the heart. 10 But what really worried the doctors was the shear number of metastases throughout her chest cavity that were identified because they were either c-Met or EGFR positive. This is because there is no easy process of removing them all surgically and traditional radiation/chemo therapy was shown to extend median overall survival to only 13.5 and 12 months respectively. 10 Due to the invasion of cancerous tissue into and around the mesothelium of both lungs, and the appearance of tumors on the pericardial sac, there were only a few extreme routes that could be taken in order to save Nancy’s life.

media type="custom" key="28596213"Starting with surgery, there are two main routes through which most individuals are treated. One, called a pleurectomy (PR) allows doctors to spare most of the lung by only removing the walls on either side of the pleural space. 10 It is usually quite successful in stage I-III mesothelioma. 10 However, because the cancer had metastasized all over the chest cavity, only the most aggressive surgical option, known as an extrapleural pneumonectomy (EPP) is available. 10 EPP involves the resection of any affected lung tissue, the entirety of the pleura, the pericardium and the diaphragm en bloc, followed by the stitching up of whatever lung tissue remains to the bronchial stump. 10 Paired with image guided radiation therapy (IGRT), this surgery is shown to be quite effective but has a pitfall in the fact that the radiation tends to be lethal at a much lower than average dose when used for adjuvant therapy. 10,20 For this reason, the doctors thought it best to use radiation as a neoadjuvant therapy and do any and all adjuvant therapy with chemotherapy.

media type="custom" key="28596215"Unfortunately for victims of mesothelioma most chemotherapies have a partial effect in only 10-20% of people even when they are combined together. 10 The only exception to this phenomenon is cisplatin. 10 Cisplatin is then the main non-targeted chemotherapy used to combat mesothelioma via the inhibition of the production of DNA by crosslinking the strands. 18 Normally, a heated intraoperative chemotherapy (HIOC) is often applied at the time of surgery. 10,18 This involves the use of cisplatin heated to 42 degrees Celsius as a lavage of the entire chest cavity to get rid of any micro-metastases in the tissue surrounding the lungs. 10,18 It is also accompanied by intravenous sodium thiosulfate to limit the toxic effects of the cisplatin on the rest of the body. 18 The combination of the neoadjuvant IGRT, surgery and HIOC extends the overall survival of stage IV mesothelioma patients dramatically to around twenty-seven months; however, the occurrence of complications during and after the surgery is very common and grows in frequency with age. 10,20,21 At seventy-eight, Nancy was in a position of massive risk if she decided to opt for this surgery due to both the normal surgical risks associated with the elderly as well as the risks with chemotherapy from her weaker than average kidneys and liver. 20,21 Assuming she went along with the entirety of the procedures and no complications arose, there is one more step that doctors would recommend to attempt to ensure there are no diseased cells left in her body at all. The final push involves the use of a targeted drug from the mid 2000s known as Gefitinib; A small molecule drug that is shown to act as a competitive inhibitor of EGFR. 19,22 By inhibiting EGFR, there would be significantly less signaling for growth, angiogenesis and EMT in Nancy’s cancerous cells (see Figure 3).



**Figure 3.** Example of the EGFR pathway resulting in proliferative and angiogenic effects as well as assiting the epithelial to mesenchymal transition. 17

media type="custom" key="28596217"The final push involves the use of a targeted drug from the mid 2000s known as Gefitinib; A small molecule drug that is shown to act as a competitive inhibitor of EGFR. 19,22 By inhibiting EGFR, there would be significantly less signaling for growth, angiogenesis and EMT in Nancy’s cancerous cells (see Figure 3). Gefitinib is extremely relevant for use as an adjuvant therapy on Nancy for two main reasons. First, her cancer was shown to overexpress EGFR from her very first thoroscopy and was even effectively used as a means to identify tumors through immuno-staining. Second, the drug has a long history of use with the 70+ age range and is shown to work well in this age group while also minimizing negative side effects. 22 Despite this, it is unlikely Nancy would manage to survive through all these treatments. This is because EGFR, while oftentimes present in stage IV pleural mesotheliomas, is not always a good target for treatment. There are cases where treatment of EGFR appears to have no affect on the growth of tumors. 22 It is not known if this is due to downstream mutations or if EGFR simply isn’t the main mutation driving growth. 22 Regardless, it is also unknown whether or not Nancy falls into the category of people that Gefitinib effectively treats. However, it is fair to say that by going through all of these treatments, hope for her survival would be much higher than it was in reality.

**Apercu** media type="custom" key="28596261"Stage IV Mesothelioma is a testament to the failures of cancer treatment today. When the modern medical community does not have any non-invasive treatment, prevention is always the best measure to take to avoid falling ill. Unfortunately for Nancy, preventing mesothelioma was just as much about fighting corporate greed as it was about staying safe and informed.

** Citations **

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