CADMIUM: The 1st Class Carcinogen Served Unknowingly on Dinner Tables

iweatherman-food

Fig: A sumptuous selection of food. Food is the major pathway of build-up of carcinogenic Cadmium in our bodies (Picture from flickr.com/creativecommons)

Food especially the high fatty type always draws people closer. However, there has been an increased interest in the cultivation and consumption of healthier foods in our age due to the prevalence of lifestyle diseases. A number of people have resorted to avoiding meaty diets in order to have healthier and more vibrant lifestyle. It is however becoming increasingly clear in the scientific community that some instances of lifestyle diseases such as cancer are as a result not of the kind of diet we have but the kind of soils the plants grow on.Plants take up nutrients from the soil for growth.  However some other substances present in the soil mimic the behaviour of nutrients but have no biological significance and end up being absorbed by crops. One such kind of a substance is the rarely known Cadmium.

Cadmium is a metallic element found in the earth’s crust. Together with Lead, Mercury, Chromium and Arsenic (also known as the big five), it forms a group of highly notorious,  persistent,  top-notch and non-biodegradable pollutants generally found in the environment commonly referred to as Toxic Heavy Metals.  Cadmium is rare but quite evenly distributed on the surface of the earth mostly associated with zinc or phosphate related rocks. It is therefore present in very small amounts in agricultural soils all over the world. Even though it is not as abundant as Iron or Potassium, it has no biological significance in the body which makes it a toxic element to humans. Some heavy metals like Lead and Mercury are in the same toxic category as Cadmium. However, what sets Cadmium in a class of its own is that it is readily absorbed by some agricultural crops. What is even more stunning is that these crops such as green leafy vegetables, potatoes, some cereals, rice and even tobacco are not affected by the accumulation of Cadmium in their tissues. This makes the element available for storage in plant parts which form sources of food for humans such as the roots and tubers, leaves and even the stem. Because of its accumulation in food crops, cadmium becomes very mobile in the food chain ending up in our diets and accumulating in our bodies since it has no use biologically. This build-up of cadmium can take place over a very long time before its toxic effects are noted. According to the Centre for Diseases Control, the reduction of Cadmium in the body to half its quantity may take place after 10-30 years if no additional Cadmium is taken up (which is rarely the case).  Therefore a diet composed of food high in Cadmium levels may lead to its bio-accumulation in the body.

Cadmium has been classified adversely by several Cancer research institutes with the International Agency for Research on Cancer (IARC) which is a department of the WHO and The American Cancer Society categorizing it as  a first class carcinogen. What this means is that there is a very high likelihood of developing either lung or prostate cancer as a result of accumulation of even small amounts of Cadmium in the body. Cadmium causes cancer by damaging the DNA or inhibiting its repair. The interference with the self repair process of DNA is known to cause mutations (DNA faults) which may lead to the over- expression of certain genes which are responsible for cell multiplication or the suppression of others responsible for healthy cell destruction. It also has been known to cause the release of very toxic substances also called Reactive Oxygen Species (ROS) as a result of DNA breakdown. Cadmium is also known to be a deadly kidney toxin. It inflicts injury to the kidney tissues which more often than not leads to kidney failure. It is also known to accumulate around the liver.

SOURCES OF CADMIUM IN OUR ENVIRONMENT

Phosphate fertilizers

Phosphate fertilizers such as DAP and TSP are used in planting of agricultural crops. Phosphate fertilizers are produced from phosphate rocks called hydroxyappatite which usually contains trace levels of Cadmium. The removal of these trace amounts of Cadmium is very hard without compromising the standard of the fertilizers or may be too expensive. Therefore quite some amount Cadmium finds its way into the soils and by extension crops through fertilization.

judson-reid-maize-and-buckwheat

Fig: Well fertilized corn field. Cadmium enters our food chain through phosphate fertilizers (Picture by flickr.com/creativecommons)

Plastic stabilizers

A substance known as Cadmium Stearate is used as a plastic stabilizer in the manufacture of plastics. This is a substance added to the plastic material to make it more resistance to temperature and pressure thereby boosting its durability. Such trace amounts of Cadmium can be released into foods stored in such kinds of plastics or even in the air when these plastics are burnt.

Industrial Processes

Several kind of industrial processes release Cadmium into the environment. Nickel/Cadmium battery plants may release effluents rich in Cadmium into the nearby sewers; Zinc ores might release traces of Cadmium into the environment during smelting processes; and some electroplating processes may also lead to the release of cadmium into the soil and water around the industries. Some industrial processes involving high temperature may also release traces of Cadmium Oxide into the atmosphere.

Waste

The amount of toxic heavy metals contained in waste material is considerably high. This is because these materials are not biodegradable thus end up being released from a source to an accumulator called a sink and on many occasions,  the vicious cycle is continuous with no end in sight.  Some of the important waste sources are such as incinerators, burning rubbish, sewage and industrial waste.

AKA_Eutrophication

Fig: Wastewater. Cadmium and other toxic heavy metals are re-introduced into the environment through human and animal waste (picture through flickr.com/creativecommons)

Natural Activities

Natural occurrences such as volcanoes can release some traces of heavy metals like Cadmium into the atmosphere and even onto soils. This is however less of an occurrence.

CADMIUM EXPOSURE ROUTES

Food

Food perhaps is the most potent exposure route especially to an unsuspecting population. Crops grown on soils even with trace amounts of Cadmium lead to the accumulation of the element in the crops and later on in the food sources. Continuous consumption of such foods by an unsuspecting population will expose them to a build-up of the toxin leading to medical complications. Also, livestock which are exposed to pasture grown on cadmium contaminated soils may lead to the accumulation of the substance in their kidneys and livers leading to its transfer to the meat consumers up the food chain.

Pollution

Burning rubbish can be one of the most subtle modes of exposure to Cadmium. Plastics which have been stabilized by Cadmium compounds can end up releasing cadmium in the atmosphere in the form of Cadmium Oxide which is known to be a very potent carcinogen when inhaled. Human and animal wastes are also very key sources of cadmium which is being excreted after being bio-accumulated in the body for a long time.

Tobacco Smoking

The tobacco leaves are known to be very conducive hosts for cadmium. This means that tobacco smokers face a double risk of Cadmium toxicity through smoking and even through food.

PRACTICAL STEPS TO REDUCE CADMIUM TOXICITY

Buying Vegetables from reputable sources

Since Cadmium accumulates more readily in leafy vegetables, it is essential to be careful when purchasing and consuming them. Vegetables grown near rubbish dumpsites and sewer lines have a greater risk of Cadmium accumulation. It is important to ensure that the vegetable sources one is consuming are from a hygienic environment in order to mitigate against heavy metal contamination.

Washing Vegetables thoroughly

It is important to wash vegetables thoroughly before cooking them in order to remove traces of Cadmium if possible. A good practice is washing the vegetables three times in clean water. Also ensure to wash one’s own hands during and after washing the vegetables.

Eating a balance diet

The dependence on one form of food might lead to over exposure to considerable Cadmium levels. Leafy vegetables, potatoes, some meats like beef and some cereals like maize have been known to accumulate considerably higher levels of Cadmium compared to other crops. In order to reduce the risk of exposure, it is essential to diversify one’s diet to include fruits, pulses etc.Also foods rich in vitamins E and C found in colored foods like fruits are known anti oxidants which reduce the toxicity of Cadmium in the body.  

 

References and further reading

https://www.ncbi.nlm.nih.gov › NCBI › Literature › PubMed Central (PMC)

www.efsa.europa.eu/sites/default/files/scientific_output/files/main…/980.pdf

http://www.cfs.gov.hk › Programme Areas › Risk Assessment in Food Safety

 

https://www.atsdr.cdc.gov/phs/phs.asp?id=46&tid=15

 

https://monographs.iarc.fr/ENG/Monographs/vol100C/mono100C-8.pdf

 

http://www.cdc.gov › NIOSH Publications & Products › Publication Types

http://pressroom.cancer.org/releases?item=245

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PAHs: The Indiscriminate and Silent Carcinogens among us

SONY DSC
SONY DSC

Fig: Burning of garbage can be one of the most potent and common sources of Polycyclic Aromatic Hydrocarbons (Photo by Mark Williams courtesy of flickr.com/creativecommons).

Ever enjoyed a sumptuous meal of roasted meat? It is a delicious and sumptuous delicacy loaded with cancer- causing potential due to the presence of polycyclic aromatic hydrocarbons (PAHs).  Polycyclic Aromatic Hydrocarbons (PAHs) are a class of organic chemical compounds found generally everywhere in the environment. They are polycyclic derivatives of the Benzene ring (a six- carbon hexagonal compound which is cyclic in nature). Some of the most popular PAHs include naphthalene (used in disinfection in toilets) and phenanthrene.  They are usually found in the environment as a result of incomplete combustion of fuel from vehicle engines, incinerators, fossil fuels, forest fires, tobacco smoke and also high temperature cooking of foods such as meat and vegetables.

The International Association for Research on Cancer has classified a number of PAHs as carcinogens or potentially carcinogenic including naphthalene derivatives such as naphthylamines and pyrene derivatives such as benzo-pyrene. PAHs can be inhaled through the air or ingested through foods. They are not completely metabolized in the human body ending up as very reactive species capable of causing mutating changes in the DNA structure resulting into conditions such as cancer. PAHs have been known to be culpable of stomach, skin, lung and liver cancers. Due to their prevalence in everyday life, it is essential to appreciate the routes of exposure to them in order to find ways of minimizing their effects in our lives:

AIR POLLUTION

This is the most common way through which PAH exposure takes place. Populations living in urban areas or on the road sides have a high likelihood of exposure to PAHs due to the incomplete combustion of diesel in vehicle exhausts. Many vehicles emit a high amount of PAHs from their exhausts resulting into air pollution and exposing the population around to cancerous risks. Also, forest fires and the usage of fossil fuels such as charcoal for cooking may expose many people especially in the developing nations to higher risks of cancer due to exposure to PAHs. Populations living near industries, especially those using fossil fuels like coal, may also be exposed to high PAHs levels in the environment.

francesco falciani

Fig: Air pollution from industries. A major source of PAHs in urban areas (photo by Francesco Falciani through flickr.com/creativecommons)

DIET

Foods such as meats cooked under very high temperatures can result in the formation of several forms of PAHs. When foods are cooked over a low and regulated heat, the disintegration of the organic bonds in the food is gradual resulting into much more tender and healthier foods as opposed to when they are cooked under extremely high heat which results into incomplete breakdown of the chemical bonds in the foods producing some PAHs. Smoked or roasted foods are very big carriers of PAHs and if ingested regularly may increase the chances of development of several kinds of cancers.

marilyn acosta

Fig: Roasted meat on a grill. High temperature cooking methods such as roasting may end up elevating the levels of PAHs in foods leading to more instances of Cancer (Photo by Maryline Acosta through flickr.com/creativecommons)

TOBACCO SMOKING

Tobacco is composed of a cocktail of PAHs. It also contains other cancer causing substances such as Cadmium and benzene derivatives therefore making it one of the most potent causes of cancer of the lungs. Secondary smokers are also at the risk of interacting with the PAHs from tobacco which could result into cancer.

Polycyclic Aromatic Hydrocarbons are very potent carcinogens due to their metabolism in the body. They are usually completely broken down by some animals but are not fully metabolized in Humans leading to the formation of very reactive intermediates in the process. These reactive intermediates can alter the structure of DNA through bonding or transferring of important DNA bases leading to gene mutation and ultimately cancer. Some of the well known potentially cancer-causing PAHs include naphthalene and pyrene derivatives. Some enzymes have however been known to deter the cancer causing effects of these PAHs in a number of cases thus suppressing the occurrence of cancer.

PAHs are environmental pollutants which should be of concern at the local and national level. Monitoring of the levels of PAHs requires the usage of techniques such as liquid chromatography and mass spectrometry. These instruments could be stationed government environmental or quality control labs.

References and further reading

https://www.epa.gov/sites/production/files/2014-03/documents/pahs_factsheet_cdc_2013.pdf

https://www.dhs.wisconsin.gov/chemical/pah.htm

http://www.idph.state.il.us/envhealth/factsheets/polycyclicaromatichydrocarbons.htm

https://nepis.epa.gov/Exe/ZyNET.exe/30003UP9.TXT?ZyActionD=ZyDocument&Client=EPA&Index=1991+Thru+1994&Docs=&Query=&Time=&EndTime=&SearchMethod=1&TocRestrict=n&Toc=&TocEntry=&QField=&QFieldYear=&QFieldMonth=&QFieldDay=&IntQFieldOp=0&ExtQFieldOp=0&XmlQuery=&File=D%3A%5Czyfiles%5CIndex%20Data%5C91thru94%5CTxt%5C00000002%5C30003UP9.txt&User=ANONYMOUS&Password=anonymous&SortMethod=h%7C-&MaximumDocuments=1&FuzzyDegree=0&ImageQuality=r75g8/r75g8/x150y150g16/i425&Display=hpfr&DefSeekPage=x&SearchBack=ZyActionL&Back=ZyActionS&BackDesc=Results%20page&MaximumPages=1&ZyEntry=1&SeekPage=x&ZyPURL

https://uk-air.defra.gov.uk/networks/network-info?view=pah

https://en.wikipedia.org/wiki/Polycyclic_aromatic_hydrocarbon

AFLATOXINS: A Cancerous Battalion hidden in Food

Aspergillus fungi twin and twin trading cdc

Fig: A microscopic view of the Aspergillus fungus (Photo by Twin and Twin Trading/ CDC through flickr.com/creativecommons)

Aflatoxins are poisonous chemicals released by a special kind of fungi called the Aspergillus species. These fungi dwell in dry foodstuffs such as maize, peanuts and groundnuts. Aflatoxins can also be found in livestock milk after the animals feed on pasture infected by these fungi. Aflatoxins have been known to cause liver cancer if ingested over time. Since maize and peanuts are staple foods in many parts of the African continent, there is a need to mitigate against Aflatoxin contamination of these foodstuffs to avoid a growing Cancer epidemic.

Aflatoxins are produced by two kinds of fungi called Aspergillus parasiticus and Aspergillus flavus. These fungi can be found in dry foodstuffs such as maize, peanuts, legumes, cereals and even in groundnuts. There are four major types of Aflatoxins produced which include B1, B2, G1 and G2 types. Aflatoxin B1 (AfB1) is the most potent type which has been classified by the International Agency for  Research on Cancer as a class 1 carcinogen. Aflatoxins can also occur in milk if the livestock feed on feeds that have been infested by the Aspergillus species fungi. They are metabolized and then converted to a different but potent form of Aflatoxins called either AfM1 or AfM2.

Intl Instut of Tropical Agric

Fig: Maize Infected by Aspergillus Fungi (Photo by International Institute of Tropical Agriculture through flickr.com/creativecommons)

Since the Aspergillus fungi grow on maize and peanuts, the likelihood of great exposure to aflatoxin poisoning exists for those populations which rely on maize and peanuts as major food sources. This puts many populations in the developing nations at risk of aflatoxin poisoning. In order to avoid the possibility of exposure, it is advisable to purchase foodstuffs like maize meal and peanuts from reputable retail outlets. Also, before purchasing, observe for signs like discoloration, mold or shriveling of nuts and maize. Storage of these foodstuffs must be in cool and dry conditions to avoid such contamination. It must be noted that Aflatoxins are extremely hard to remove due to the prevalence of fungi in many foodstuffs. Good food storage especially in cool and dry conditions is essential in reducing the possibility of aflatoxin poisoning. 

Aflatoxins have a variety of health effects in the body. Aflatoxicosis is a condition resulting from the poisoning of the human body due to the ingestion of Aflatoxins which may result into death. They can also be taken in the body through breathe especially by farmers or farm workers in fungi infested areas. Liver Cancer is the major ailment brought about by ingesting of Aflatoxins. Aflatoxins are also known as DNA mutating agents (substances that cause an alteration of the DNA pattern) which are some of the major causes of cancer in humans. The most potent of the Aflatoxins in its carcinogenicity is tge B1 type. 

The concentration of Aflatoxins in food stuffs can be determined using a technique called liquid chromatography. In this procedure, a portion of the foodstuffs is reacted with an organic liquid capable of dissolving the Aflatoxins from the foodstuffs. This aflatoxin solution is then subjected to a chromatographic column which detects its presence in solution and even quantifies it’s concentration in mg or ng/L. other more modern methods of aflatoxin quantification include the use of a High Performance liquid Chromatography and Enzyme Linked Immuno- Sorbent Assay or ELISA.

Aflatoxin contamination can be mitigated against by the use of substances that bind to the Aflatoxins thereby reducing their bio-availability in the body. Silicates (Sands) such as zeolites, montmorillonite and various clays have been used in reacting with Aflatoxins in cattle feeds. They are able to reduce their bio-availability thus reducing their toxicity to the animals’ bodies.

References and further reading/

http://poisonousplants.ansci.cornell.edu/toxicagents/aflatoxin/aflatoxin.html

https://www.cancer.gov/about-cancer/causes-prevention/risk/substances/aflatoxins

https://ec.europa.eu/food/safety/chemical_safety/contaminants/catalogue/aflatoxins_en

https://medlineplus.gov/ency/article/002429.htm

http://ajcn.nutrition.org/content/80/5/1106.full

LUNG CANCER: Nanotechnology and Treatment

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Fig. : Quantum Dots being used to label microorganisms in disease diagnostics. Courtesy of microbiologybytes.com. Through flickr.com/creativecommons.

The treatment of lung cancer is much more effective before it gets to its final stages (stage III and IV). The stages of cancer can be summarized in the following way according to Cancer Research UK: Stage I- Tumor localized in a specific location within the organ; Stage II- Tumor is still localized in the organ but has grown in size; Stage III- Tumor is larger and may have started spreading to other surrounding tissues; and Stage IV- Tumor has spread from where it had started to another body organ also known as metastasis.

Conventional treatment of lung cancer is dependent on whether is Small Cell or Non Small Cell Lung Cancer. Small Cell Lung Cancer is very aggressive in spreading so it may be hard to employ treatment methods such as Radiotherapy without destroying many healthy cells.

CONVENTIONAL TREATMENT METHODS

Chemotherapy

This involves the usage of drugs that have a toxic effect on the cancerous cells. They end up being taken up by the tumors and metabolized leading to the death of the cells. Research is going on in the area of targeted therapy where the destruction of healthy cells is drastically reduced by packaging the drugs in substances such as metal or polymeric nanoparticles which have an affinity for the cancer cells leading to targeted destruction of the tumors. Chemotherapy can be used for both SCLC and NSCLC.

Radiotherapy

This involves the usage of very high frequency radiation such as X-Rays in the destruction of cancerous cells. It is comfortably applicable in tumors which are localized and have not yet started spreading such as in Non Small Cell Lung Cancer (NSCLC). Research is ongoing to come up with much more target friendly ways to destroy cancer cells in order to reduce collateral damage using nanotechnology. Some of these research initiatives are being geared by the US National Cancer Institute’s Alliance for Nanotechnology in Cancer.

Surgery

This is one of the ways used to remove localized tumors especially before they start spreading. 

NANOTECHNOLOGY IN LUNG CANCER TREATMENT

Inhalation Nano-Chemotherapy

Nanotechnology offers a range of opportunities for research in the treatment of lung cancer. Being a disease affecting the respiratory organs, treatment of lung cancer can be carried out by the use of inhalation of cancer-toxic drugs which are carried by biodegradable nano-particles such as polymer(1). These nano-particles, some of which have an affinity for cancerous cells, can contain the drug substances within them or attached to them chemically then dispatched specifically to the lung cells using an asthma- type of inhaler. More research is still ongoing in this area.

Photodynamic Therapy

This technique is still under active research but has been employed in various hospitals in the UK and USA. It involves the usage of the unique light- interacting capabilities of some nano-particles such as those of Gold (AuNPs), Iron Oxide and quantum dots (QDs) in destroying cancer cells (26).  The nano-particles are taken up by the cancer cells then activated by light of a specific wavelength range in order to destroy the cancer cells by emitting radiation in the Near Infrared range (NIR).

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Fig: Iron Oxide Nanoparticles can be used in cancer diagnosis and treatment (through flickr.com/creativecommons)

Nano-structured Pharmaceuticals

The action of some anti- cancer drugs is usually impeded due to their fast secretion from the body, fast action of the body defenses against them or their low solubility in water (2,3,4). Fast secretion of the drugs from the body after marginal effect can be corrected by encapsulating the drugs in substances like polymeric nanoparticles which ensure slow and sustained release of the drugs to the specific targets while avoiding macrophages (body defenses). Some drugs which are not water soluble can be enclosed in water soluble nanoparticles for delivery to their targets for fast action.

 

DISCLAIMER: The information in this article is written for general information purposes and MUST NOT be used as a substitute for personalized medical care from a qualified medical practitioner. This blog platform will not be responsible for any injury or damage to persons or property arising from any errors or omissions.

 

References

1.      Javed Ahmad,1,* Sohail Akhter,2,3,* Md Rizwanullah,1 Saima Amin,1 Mahfoozur Rahman,4 Mohammad Zaki Ahmad,5Moshahid Alam Rizvi,6 Mohammad A Kamal,7 and Farhan Jalees Ahmad1,2. Nanotechnology-based inhalation treatments for lung cancer: state of the art. Nanotechnol Sci Appl. 2015; 8: 55–66.

  1. -M. Lü, X. Wang, C. Marin-Muller, et al. Current advances in research and clinical applications of PLGA-based nanotechnology Expert Rev Mol Diagn, 9 (2009), pp. 325–341
  1. A. Gabizon, H. Shmeeda, S. Zalipsky Pros and cons of the liposome platform in cancer drug targeting J Liposome Res, 16 (2006), pp. 175–183
  1. Wing-Hin Lee,   Ching-Yee Loo,   Daniela TrainiPaul M. Young. Inhalation of nanoparticle-based drug for lung cancer treatment: Advantages and challenges. Asian Journal of Pharmaceutical Sciences Volume 10, Issue 6, December 2015, Pages 481–489
  1. ipcrc.net/pdfs/Kenya-National-Cancer-Control-strategy.pdf
  1. or.ke/wp-content/uploads/2013/10/NAtional-CANCER-REGISTRY-.ppt)

7.      https://www.cancer.gov/about-cancer/diagnosis-staging/diagnosis/tumor-markers-fact-sheet

  1. https://www.cancer.gov/about-cancer/diagnosis-staging/diagnosis/tumor-markers-fact-sheet
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  1. https://www.cancer.org/cancer/small-cell-lung-cancer/about/what-is-small-cell-lung-cancer.html
  1. https://medlineplus.gov/ency/article/000122.htm
  1. http://www.cancerresearchuk.org/about-cancer/lung-cancer/treatment
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  2. Horn L, Eisenberg R, Gius D, et al. Cancer of the lung. In: Niederhuber JE, Armitage JO, Doroshow JH, Kastan MB, Tepper JE, eds.Abeloff’s Clinical Oncology. 5th ed. Philadelphia, PA: Elsevier Churchill Livingstone; 2014:chap 72.
  1. National Cancer Institute. PDQ Small cell lung cancer treatment.Bethesda, MD. http://www.cancer.gov. Date last modified January 23, 2015.
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  1. Silvestri GA, Pastis NJ, Tanner NT, Jett JR. Clinical aspects of lung cancer. In: Broaddus VC, Mason RJ, Ernst JD, et al, eds.Murray and Nadel’s Textbook of Respiratory Medicine. 6th ed. Philadelphia, PA: Elsevier Saunders; 2016:chap 53.
  1. https://www.cancer.org/cancer/non-small-cell-lung-cancer/about/what-is-non-small-cell-lung-cancer.html
  1. http://www.ipcrc.net/pdfs/Kenya-National-Cancer-Control-strategy.pdf
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  1. https://www.mycancergenome.org/content/disease/lung-cancer/kras/
  1. Meyers JD1,Cheng Y2Broome AM1Agnes RS1Schluchter MD3Margevicius S3Wang X1Kenney ME2Burda C2Basilion JP Peptide-Targeted Gold Nanoparticles for Photodynamic Therapy of Brain Cancer. Part Part Syst Charact. 2015 Apr; 32(4): 448–457.Published online 2014 Oct 6. doi:  10.1002/ppsc.201400119

LUNG CANCER: Genetic Signatures

wellcome-images

Fig: A DNA Double Helix model (flickr.com/creativecommons)

Lung Cancer is a group of diseases which are not easily detected due to diverse the nature of their manifestation. There are no specific and dependable biomarkers (molecules that signify disease) present in the blood or tissues which could be used to confirm the existence of the disease in all of its manifestations. However, genetics is a very important tool that can be employed in the tracking, detecting and treatment of lung cancer especially at the early stages.

Genetics is the study of genes. Genes are codes on DNA which express characteristics of organisms. The DNA is a double strand formed out of molecules called nucleotide bases which complement each other on the opposite side of the strands. There are four nucleotides in the DNA strands: Guanine (G), Adenine (A), Cytosine (C) and Thymine (T). Guanine (G) usually complements with Cytosine (C) while Adenine (A) usually complements with Thymine (T). The different combinations of these nucleotide bases code for specific amino acids which in turn are joined together to form proteins which are the building blocks of life and are important in the formation of enzymes and hormones. A group of nucleotide bases arranged to code for a certain protein on a DNA strand is called a gene. The body manufactures proteins on a need to need basis as required by the cells and the tissues. For example, when one has an injury, the DNA in the cells around the injured area may code for the manufacture of specific proteins such as melanin (skin pigment) to be able to accelerate recovery from the wound.

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Fig: Representation of nucleotide base sequence as depicted (Photo by Miki Ashihito through flickr.com/creativecommons)

Sometimes however, genetic expressions on the DNA may be altered due to a person’s heritage (family line) or environmental factors e.g. chemicals such as aflatoxins, aromatic hydrocarbons and radioactivity which can alter the expression of certain genes, also known as gene mutation. When gene mutation occurs, the coding of some proteins can be exaggerated or suppressed leading to the development of diseases like cancer.

In lung cancer, some proteins which are located on the lung cell walls may be affected by this genetic disorder and are crucial in the understanding of the disease.

EGFR (Epidermal Growth Factor Receptor)

EGFR is a protein that doubles up as an enzyme. It is found on the surface of healthy cells and is crucial in the process of cell division. It is encoded in the EGFR gene on the DNA. Genetic mutations on the DNA strand may lead to an over-expression of this gene leading to the synthesis of excessive EGFR resulting into excessive and abnormal cell division. About 15% of patients with Non Small Cell Lung Cancer exhibit mutations of this gene (24). EGFR belongs to a group of enzymes known as Tyrosine Kinases which are very important in cell division. In Lung Cancer treatment, substances known as ‘Tyrosine Kinase Inhibitors’ or TKI are employed in the control of excessive and abnormal cell division.

ALK (Anaplastic Lymphoma Kinase)

ALK is also a protein which functions as an enzyme and is found on the cell surface and is also responsible for cell division belonging to the class enzymes called Tyrosine Kinases. It is coded by the ALK gene on the DNA. Gene mutation leads to an over- expression of its code leading to its excessive synthesis and promotion of rapid and abnormal cell division in the body. About 3-7% of lung cancer patients display this gene mutation especially among smokers and non- smokers who are young (25). Its cancerous nature can be suppressed by Tyrosine Kinase Inhibitor drugs.

KRAS (Kirsten Rat Sarcoma) Viral Oncogene Homolog

KRAS is a protein which functions as an enzyme in healthy cells. It belongs to a group of enzymes called the GTPases which are also very important in cell division. It is encoded by the KRAS gene on the DNA which is also known as an oncogene (genes expressing proteins that are very key in cell division). A mutation of this gene may lead to production of excessive KRAS in the cells leading to abnormal cell division and cancer. KRAS gene mutation is usually expressed in about 15- 20% of Non Small Cell Lung Cancer (NSCLC) patients with the Adenocarcinoma variety.

Genetic mutations of can be detected in a biotechnological or biochemistry lab by using methods such as FISH (Fluorescent In- Situ Hybridization) as approved by the US Food and Drug Administration. It involves the labeling of specific genes on DNA extracted from a patient with light- emitting substances and reacting them with healthy DNA in order to mark out the over-expressed or missing genes for disease diagnosis.

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Fig: Fluorescent In-Situ Hybridization (FISH) technique displaying genetic mutations as emitted light (Photo by Wellcome Images through flickr.com/creativecommons)

DISCLAIMER: The information in this article is written for general information purposes and MUST NOT be used as a substitute for personalized medical care from a qualified medical practitioner. This blog platform will not be responsible for any injury or damage to persons of property arising from any errors or omissions.

 

References

1.      Javed Ahmad,1,* Sohail Akhter,2,3,* Md Rizwanullah,1 Saima Amin,1 Mahfoozur Rahman,4 Mohammad Zaki Ahmad,5Moshahid Alam Rizvi,6 Mohammad A Kamal,7 and Farhan Jalees Ahmad1,2. Nanotechnology-based inhalation treatments for lung cancer: state of the art. Nanotechnol Sci Appl. 2015; 8: 55–66.

  1. -M. Lü, X. Wang, C. Marin-Muller, et al. Current advances in research and clinical applications of PLGA-based nanotechnology Expert Rev Mol Diagn, 9 (2009), pp. 325–341
  1. A. Gabizon, H. Shmeeda, S. Zalipsky Pros and cons of the liposome platform in cancer drug targeting J Liposome Res, 16 (2006), pp. 175–183
  1. Wing-Hin Lee,   Ching-Yee Loo,   Daniela TrainiPaul M. Young. Inhalation of nanoparticle-based drug for lung cancer treatment: Advantages and challenges. Asian Journal of Pharmaceutical Sciences Volume 10, Issue 6, December 2015, Pages 481–489
  1. ipcrc.net/pdfs/Kenya-National-Cancer-Control-strategy.pdf
  1. or.ke/wp-content/uploads/2013/10/NAtional-CANCER-REGISTRY-.ppt)

7.      https://www.cancer.gov/about-cancer/diagnosis-staging/diagnosis/tumor-markers-fact-sheet

  1. https://www.cancer.gov/about-cancer/diagnosis-staging/diagnosis/tumor-markers-fact-sheet
  1. https://www.cancer.gov/types/lung/patient/non-small-cell-lung-treatment-pdq
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  1. http://www.cancerresearchuk.org/about-cancer/lung-cancer/treatment
  1. knh.or.ke/wp-content/uploads/2013/10/NAtional-CANCER-REGISTRY-.ppt
  2. Horn L, Eisenberg R, Gius D, et al. Cancer of the lung. In: Niederhuber JE, Armitage JO, Doroshow JH, Kastan MB, Tepper JE, eds.Abeloff’s Clinical Oncology. 5th ed. Philadelphia, PA: Elsevier Churchill Livingstone; 2014:chap 72.
  1. National Cancer Institute. PDQ Small cell lung cancer treatment.Bethesda, MD. http://www.cancer.gov. Date last modified January 23, 2015.
  1. http://www.cancer.gov/cancertopics/pdq/treatment/small-cell-lung/healthprofessional. Accessed October 7, 2015.
  1. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Small cell lung cancer. Version 1.2016.http://www.nccn.org/professionals/physician_gls/pdf/sclc.pdf.Accessed October 7, 2015.National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Small cell lung cancer. Version 1.2016.
  1. http://www.nccn.org/professionals/physician_gls/pdf/sclc.pdf. Accessed October 7, 2015.
  1. Silvestri GA, Pastis NJ, Tanner NT, Jett JR. Clinical aspects of lung cancer. In: Broaddus VC, Mason RJ, Ernst JD, et al, eds.Murray and Nadel’s Textbook of Respiratory Medicine. 6th ed. Philadelphia, PA: Elsevier Saunders; 2016:chap 53.
  1. https://www.cancer.org/cancer/non-small-cell-lung-cancer/about/what-is-non-small-cell-lung-cancer.html
  1. http://www.ipcrc.net/pdfs/Kenya-National-Cancer-Control-strategy.pdf
  1. http://jme.endocrinology-journals.org/content/47/1/R11.full
  1. http://www.cancer.net/research-and-advocacy/asco-care-and-treatment-recommendations-patients/epidermal-growth-factor-receptor-egfr-testing-advanced-non-small-cell-lung-cancer
  1. https://www.mycancergenome.org/content/disease/lung-cancer/kras/

LUNG CANCER: Unmasking the Killer

Lung Cancer diagnosis can take several forms in hospitals. Sometimes the cancer may be discovered accidentally while aggressively progressing forms may trigger symptoms in an individual leading to diagnosis. This is a brief analysis of some of the diagnostic methods and tools employed the detection of lung cancer in the body:

CT SCAN

The CT Scan is a computerized image produced by the penetrative capabilities of X-Rays in  body organs and tissues. This is one of the most used procedures in the detection of lung cancer since it can be able to draw images of the cell tissues in the lungs and related organs helping in detecting the presence of tumors by contrasting their images in relation to the other healthy cells.

yale rosen ct

Fig: A CT Scan of the lungs showing a tumor on the top right (Photo by Yale Rosen through flickr.com/creativecommons)

SPUTUM TESTING

One of the symptoms of lung cancer is the removal of sputum after coughing. Some forms of lung cancers can develop among cells which produce mucus leaving their remnants in the removed sputum. The sputum can be extracted and taken to a lab where it can be observed for the presence of cancerous cells and tissues.

BIOPSY

A biopsy involves the removal of a tissue of an infected area in order to analyze it in a lab for infection. In lung cancer diagnosis, removal of the lung tissue can be carried out in one of the following ways:

Fine Needle Aspiration (FNA) Biopsy: Here, a very fine needle is inserted into the lung and used to extract lung fluid or tissue which can be inspected by a pathologist for cancerous cells under a microscope.

Bronchoscopy: In this procedure, a tube fitted with a camera is inserted into the trachea and then the bronchi of the patient and used to scan for possible signs of tumor development. It can also possess a small scalpel which can be used in the removal of some tissue if need be for further examination in a lab.

Thoracentesis: This is the removal of the fluid between the lungs and the chest for observation of the signs of tumor cell development.

ELECTRON MICROSCOPY

Electron microscopy is a technique employed in physical sciences and also in medicine. It involves the usage of a high level of magnification lenses to draw up an extremely fine details of the surface or contents of an object such as a body organ in order to understand it. In cancer diagnostics, it can be used to highlight the surface of the lungs (areas of interest) in order to check if there is tumor development.

Zeiss microscopy- skin cancer cells

Fig: High resolution micro-graph of rapidly dividing skin cancer cells (photo by Zeiss Microscopy through flickr.com/creativecommons)

BIOMARKER ANALYSIS

A biomarker is a substance such as a protein produced by a disease which can be used to ascertain its existence. It could be present in the blood or in body tissues. In lung cancer two major biomarkers are of utmost importance in mapping the disease: ALK (Anaplastic Lymphoma Kinase) and EGFR (Epidermal Growth Factor Receptor). These biomarkers, which are proteins, are usually located on the surfaces of cells of interest in the lungs. They have the capability to alter the cell division process of the cells after binding unique substances called ligands, leading to increased and abnormal cell division and ultimately cancer.They are useful in monitoring the patient’s response to lung cancer treatment. Since DNA is responsible for the coding and manufacture of proteins in the body, the abnormal production of these biomarkers can be assessed by the mapping of the DNA genes of interest which can be done in a biochemistry or biotechnology lab.

261445720_2f253a1336_z

Fig: A gene sequence in DNA represented by the different colors. The alteration of these sequences can lead to the over- expression of a certain gene and ultimately over production of proteins such as ALK and EGFR which are important in Lung Cancer Diagnosis (Photo by Andy Leppard through flickr.com/creativecommons)

DISCLAIMER: The information contained in this article is written for general information purposes and MUST NOT be used as a substitute for personalized medical care from a qualified medical practitioner. This blog platform will not be responsible for any injury or damage to persons of property arising from any errors or omissions.

References and further reading

1.      Javed Ahmad,1,* Sohail Akhter,2,3,* Md Rizwanullah,1 Saima Amin,1 Mahfoozur Rahman,4 Mohammad Zaki Ahmad,5Moshahid Alam Rizvi,6 Mohammad A Kamal,7 and Farhan Jalees Ahmad1,2. Nanotechnology-based inhalation treatments for lung cancer: state of the art. Nanotechnol Sci Appl. 2015; 8: 55–66.

 

  1. -M. Lü, X. Wang, C. Marin-Muller, et al. Current advances in research and clinical applications of PLGA-based nanotechnology Expert Rev Mol Diagn, 9 (2009), pp. 325–341

 

 

  1. A. Gabizon, H. Shmeeda, S. Zalipsky Pros and cons of the liposome platform in cancer drug targeting J Liposome Res, 16 (2006), pp. 175–183

 

  1. Wing-Hin Lee,   Ching-Yee Loo,   Daniela Traini,  Paul M. Young. Inhalation of nanoparticle-based drug for lung cancer treatment: Advantages and challenges. Asian Journal of Pharmaceutical Sciences Volume 10, Issue 6, December 2015, Pages 481–489

 

 

  1. www.ipcrc.net/pdfs/Kenya-National-Cancer-Control-strategy.pdf

 

  1. knh.or.ke/wp-content/uploads/2013/10/NAtional-CANCER-REGISTRY-.ppt)

7.      https://www.cancer.gov/about-cancer/diagnosis-staging/diagnosis/tumor-markers-fact-sheet

 

  1. https://www.cancer.gov/about-cancer/diagnosis-staging/diagnosis/tumor-markers-fact-sheet

 

  1. https://www.cancer.gov/types/lung/patient/non-small-cell-lung-treatment-pdq

 

  1. https://www.cancer.gov/types/lung/patient/small-cell-lung-treatment-pdq

 

  1. https://www.cancer.org/cancer/small-cell-lung-cancer/about/what-is-small-cell-lung-cancer.html

 

  1. https://medlineplus.gov/ency/article/000122.htm

 

  1. http://www.cancerresearchuk.org/about-cancer/lung-cancer/treatment

 

  1. or.ke/wp-content/uploads/2013/10/NAtional-CANCER-REGISTRY-.ppt
  2. Horn L, Eisenberg R, Gius D, et al. Cancer of the lung. In: Niederhuber JE, Armitage JO, Doroshow JH, Kastan MB, Tepper JE, eds.Abeloff’s Clinical Oncology. 5th ed. Philadelphia, PA: Elsevier Churchill Livingstone; 2014:chap 72.

 

  1. National Cancer Institute. PDQ Small cell lung cancer treatment.Bethesda, MD. http://www.cancer.gov. Date last modified January 23, 2015.

 

  1. http://www.cancer.gov/cancertopics/pdq/treatment/small-cell-lung/healthprofessional. Accessed October 7, 2015.

 

  1. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Small cell lung cancer. Version 1.2016.http://www.nccn.org/professionals/physician_gls/pdf/sclc.pdf.Accessed October 7, 2015.National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Small cell lung cancer. Version 1.2016.

 

  1. http://www.nccn.org/professionals/physician_gls/pdf/sclc.pdf. Accessed October 7, 2015.

 

  1. Silvestri GA, Pastis NJ, Tanner NT, Jett JR. Clinical aspects of lung cancer. In: Broaddus VC, Mason RJ, Ernst JD, et al, eds.Murray and Nadel’s Textbook of Respiratory Medicine. 6th ed. Philadelphia, PA: Elsevier Saunders; 2016:chap 53.

 

  1. https://www.cancer.org/cancer/non-small-cell-lung-cancer/about/what-is-non-small-cell-lung-cancer.html

 

  1. http://www.ipcrc.net/pdfs/Kenya-National-Cancer-Control-strategy.pdf

 

  1. http://jme.endocrinology-journals.org/content/47/1/R11.full

LUNG CANCER: Cryptic but Crushing

 

 

SONY DSC

Fig: Air Pollution from burning waste material. A couple of cancer- causing substances are released through polluted air such as Cadmium and Poly-Cyclic Aromatic Hydrocarbon (PAHs) compounds (through flickr.com/creativecommons)

Lung Cancer refers to a collection of diseases that can affect the lungs and the areas that are related to the respiratory system such as the bronchi, trachea and the larynx. It accounts for about 1.3 million deaths worldwide (5). Its prevalence in Kenya is about 7.9% of the population (6). The disease can cause difficulty in the functioning of the respiratory system but could also spread to other parts of the body such as the liver, brain and bones.

The respiratory system functions by letting air through the nose which is passed into the lungs through the larynx, the trachea then the bronchi. The trachea is the main tube which divides into two bronchi before ending up in the lungs. The right lung is usually slightly larger than the left lung due to space displacement on the left side by the heart. The bronchi (singular- bronchus) divides into many small tubes called the bronchioles which deliver the air to small sacs called alveoli where gaseous exchange takes place. Here the lungs absorbs the oxygen and releases the Carbon dioxide for exhalation.

Lung cancer is categorized by the American Cancer Society into either Small Cell Lung Cancer or SCLC (affects about 10-15% of people) and Non- Small Cell Lung Cancer or NSCLC (affects about 80-85% of people).

Small Cell Lung Cancer (SCLC) or Oat Cell Cancer is most common among tobacco smokers and is very aggressive in its growth and spread (metastatic). It begins in the lungs but moves rapidly to other organs such as the liver, brain and bones. It is referred to this way because the cells it affects are small, flat cells in the lungs.

Yale Rosen Small cell carcinoma

Fig: Small Cell Lung Carcinoma Cells seen through a microscope (Photo by Yale Rosen through flickr.com/creativecommons)

Non- Small Cell Lung Cancer (NSCLC) is a much less aggressive form of lung cancer but most common type. One of the most common forms of NSCLC is known as Adenocarcinoma which accounts for about 40% of all cases of lung cancer. It affects younger people, non- smokers and smokers alike and is found in the areas of the lungs that secrete mucus mostly on the lung- lining. It is also most common form of Lung cancer among women.  Another form of NSCLC affects the flat cells lining the air passageways of the lungs also called squamous cells. It accounts for about 30% of all lung cancer cases. A much less common form of NSCLC is called the Large Cell Carcinoma which is very aggressive in its growth and spread but less specialized in location thus can be found anywhere in the lungs. These facts make it very difficult to identify and treat.

Ed Uthman nsclc

Fig: Non Small Cell Cancer Cells seen using a microscope (Photo by Ed Uthman through flickr.com/creativecommons)

The main cause of lung cancer is tobacco smoking. However, tobacco can be considered with other relevant risk factors which together or individually can accelerate the occurrence of lung cancer.

TOBACCO SMOKING

Tobacco smoking is the best known cause of lung cancer. Some of the substances present in tobacco are well- known carcinogens such as Cadmium, aromatic organic compounds such as benzene and tar. The risk of contracting lung cancer increases with the length of time one has been smoking tobacco and even their age. Tobacco smoking is such a potent cause of lung cancer that even people who have stopped smoking could still be exposed to the risk of cancer later on in their lives. Secondary smoking has also been known to cause lung cancer. Some nations like Kenya have legislated laws to confine tobacco smoking to specific areas so as to reduce instances of secondary smoking.

RADON

Radon is a gas produced due to the radioactive decay of Uranium. It is not a very common substance in the environment but could be present especially near Uranium mines and people exposed to radio activity especially occupationally such as radiologists in the hospitals. The concentrations of the gas especially in residential areas near Uranium mines needs to be checked to reduce the occurrence of lung cancer among the population.

ASBESTOS AND RELATED SUBSTANCES

Asbestos is a very fine silicate substance that is used in construction. The danger it poses to those exposed to it is its very fine nature which can lead to it accumulating in the lungs without removal leading to respiratory infections and later cancer. Construction workers, cement factory workers and people working in mines are very much at risk from asbestos and other related and fine materials which could put them in at risk of contracting lung cancer.

GENETICS

A family history of lung cancer is an important factor to consider when assessing the risk factors. Genes are fragments of the DNA which express certain characteristics of an individual passed down to them by the parents. Lung cancer can be caused by abnormal expression of certain inherited genes which might trigger excessive and abnormal cell division (onco-genes) while suppressing genes which control or stop rapid cell division (suppressor genes). It is therefore essential to note any family member with a history of lung cancer in order to assess it as a risk factor.

AIR POLLUTION

In most industrialized cities, the air is polluted by toxic gases such as motor vehicle exhaust, nitrogen oxides, sulfur oxides, carbon monoxide, cadmium, Polycyclic Aromatic Hydrocarbons such as benzene derivatives like styrene,  naphthalene,  phenanthrene etc.  and soot among others. This is also dependent on the location of the cities and the industrial activities around it. Some of these pollutants are well known carcinogens such as Cadmium and benzene. Exposure to highly polluted air in cities has been known to be one of the risk factors that could trigger contracting of lung cancer.

HIV/ AIDS

HIV/ AIDS being a condition which breaks down the body immune system could also expose the body to the risk of contracting an opportunistic disease like lung cancer. Due to the degradation of the body’s immune system, there is a breakdown of its ability to regulate activities such as cell division which could proceed abnormally leading to various forms of cancer.

The symptoms of lung cancer are varied depending on the nature and the location of the disease in the respiratory tract. However, some common features include: Chest pain and discomfort; Persistent Coughing; Wheezing; Weight- loss; Swelling in the Face; Sputum in the blood; and trouble while breathing.

DISCLAIMER: The information contained in this article is written for general information purposes and MUST NOT be used as a substitute for personalized medical care from a qualified medical practitioner. This blog platform will not be responsible for any injury or damage to persons of property arising from any errors or omissions.

References and Further Reading

1.      Javed Ahmad,1,* Sohail Akhter,2,3,* Md Rizwanullah,1 Saima Amin,1 Mahfoozur Rahman,4 Mohammad Zaki Ahmad,5Moshahid Alam Rizvi,6 Mohammad A Kamal,7 and Farhan Jalees Ahmad1,2. Nanotechnology-based inhalation treatments for lung cancer: state of the art. Nanotechnol Sci Appl. 2015; 8: 55–66.

  1. -M. Lü, X. Wang, C. Marin-Muller, et al. Current advances in research and clinical applications of PLGA-based nanotechnology Expert Rev Mol Diagn, 9 (2009), pp. 325–341
  1. A. Gabizon, H. Shmeeda, S. Zalipsky Pros and cons of the liposome platform in cancer drug targeting J Liposome Res, 16 (2006), pp. 175–183
  1. Wing-Hin Lee,   Ching-Yee Loo,   Daniela Traini,  Paul M. Young. Inhalation of nanoparticle-based drug for lung cancer treatment: Advantages and challenges. Asian Journal of Pharmaceutical Sciences Volume 10, Issue 6, December 2015, Pages 481–489
  1. www.ipcrc.net/pdfs/Kenya-National-Cancer-Control-strategy.pdf
  1. knh.or.ke/wp-content/uploads/2013/10/NAtional-CANCER-REGISTRY-.ppt)

7.      https://www.cancer.gov/about-cancer/diagnosis-staging/diagnosis/tumor-markers-fact-sheet

 8.https://www.cancer.gov/about-cancer/diagnosis-staging/diagnosis/tumor-markers-fact-sheet

  1. https://www.cancer.gov/types/lung/patient/non-small-cell-lung-treatment-pdq

 

  1. https://www.cancer.gov/types/lung/patient/small-cell-lung-treatment-pdq

 

  1. https://www.cancer.org/cancer/small-cell-lung-cancer/about/what-is-small-cell-lung-cancer.html

 

  1. https://medlineplus.gov/ency/article/000122.htm

 

  1. http://www.cancerresearchuk.org/about-cancer/lung-cancer/treatment

 

  1. or.ke/wp-content/uploads/2013/10/NAtional-CANCER-REGISTRY-.ppt
  2. Horn L, Eisenberg R, Gius D, et al. Cancer of the lung. In: Niederhuber JE, Armitage JO, Doroshow JH, Kastan MB, Tepper JE, eds.Abeloff’s Clinical Oncology. 5th ed. Philadelphia, PA: Elsevier Churchill Livingstone; 2014:chap 72.

 

  1. National Cancer Institute. PDQ Small cell lung cancer treatment.Bethesda, MD. http://www.cancer.gov. Date last modified January 23, 2015.

 

  1. http://www.cancer.gov/cancertopics/pdq/treatment/small-cell-lung/healthprofessional. Accessed October 7, 2015.

 

  1. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Small cell lung cancer. Version 1.2016.http://www.nccn.org/professionals/physician_gls/pdf/sclc.pdf.Accessed October 7, 2015.National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Small cell lung cancer. Version 1.2016.

 

  1. http://www.nccn.org/professionals/physician_gls/pdf/sclc.pdf. Accessed October 7, 2015.

 

  1. Silvestri GA, Pastis NJ, Tanner NT, Jett JR. Clinical aspects of lung cancer. In: Broaddus VC, Mason RJ, Ernst JD, et al, eds.Murray and Nadel’s Textbook of Respiratory Medicine. 6th ed. Philadelphia, PA: Elsevier Saunders; 2016:chap 53.

 

  1. https://www.cancer.org/cancer/non-small-cell-lung-cancer/about/what-is-non-small-cell-lung-cancer.html

 

  1. http://www.ipcrc.net/pdfs/Kenya-National-Cancer-Control-strategy.pdf

 

  1. http://jme.endocrinology-journals.org/content/47/1/R11.full