According to the National Cancer Institute cancer has a massive impact on society in the US and around the globe. When it comes to the US, it is estimated that in 2016, about 1,685,210 new cases of cancer were diagnosed and 595,690 people died due to this severe disease.
Table of Contents [Hide]
- What is bladder cancer?
- How common is bladder cancer?
- What are the types of bladder cancer
- Causes of bladder cancer
- Risk factors for bladder cancer
- Symptoms of bladder cancer
- How is bladder cancer diagnosed?
- Treatment options for bladder cancer
- Coping with bladder cancer
The most common cancers are breast cancer, lung cancer, non-Hodgkin lymphoma, thyroid cancer, kidney and renal pelvis cancer, leukemia and endometrial (Uterine) cancer, prostate cancer, colon cancer, and rectum cancer, pancreatic cancer, and bladder cancer. As you can see, bladder cancer is prevalent in the US, but little is known about it. This post aims to inform you about this cancer including causes, types, symptoms, and other necessary information everyone should know.
What is Bladder Cancer?
We’re going to start it off with a simple overview of the bladder. Your bladder is a hollow organ shaped like a balloon and consisting of muscle primarily. The main function of the bladder, located in the lower abdomen, is to store urine until a person is ready to go to the bathroom and release it.
The kidneys filter waste from the blood and produce* urine which reaches the bladder through two tubes called ureters. Then, urine leaves your bladder through a yet another tube, named urethra. In men, the urethra is longer and passes through the prostate and penis while in women the tube is shorter and opens in front of the vagina.
Cancer is defined as the growth of abnormal cells that crowd out normal cells in the body and it can affect any tissue or organ. Therefore, bladder cancer is a disease characterized by the growth of malignant cells in the urinary bladder. It is also important to bear in mind that bladder cancer is oftentimes associated with cancers of urethra, ureters, and kidneys.
In most cases, cancer starts in the urothelial cells that line the inside of your bladder and although quite common, the good news is that 7 out of 10 diagnosed cases of this severe disease start out in early stages when it is highly treatable.
That said, if cancer is discovered in early stages, a patient still needs to do follow-up tests in order to make sure it did not come back. Read more about causes, risk factors, prevalence, treatments, and other important info below.
How Common is Bladder Cancer?
As shown above, bladder cancer accounts for one of the most common cancers in Americans. But, one still has to wonder* just how common it is. According to the American Cancer Society, about 79,030 new cases of bladder cancer will be diagnosed in 2017. Of these, 60,490 bladder cancer cases will be among men while 18,540 account for women. This year, about 16,870 deaths will occur due to this severe disease; 12,240 in men and 4,630 in women.
Estimates show that the incidence and death rates of this cancer are decreasing* among women. Although new cases of bladder cancer are dropping among men, death rates remain unchanged. In fact, this disease accounts for 5% of all new cancers in the United States and it is the 4th most common type of cancer in men. The most recent data show that 5-year survival rate for bladder cancer is 77%, the 10-year survival rate is 70%, while 15-year survival rate is about 65%.
American men and women are in unfavorable position when it comes to bladder cancer. Although it is prevalent around the globe, the prevalence and incidence rates in other countries such as the UK are lower.
In the UK, about 10,100 new cases of bladder cancer are diagnosed, which is about 28 diagnosed cases a day. This severe disease accounts for the 10th most common cancer among UK adults, but evidence shows that 42% of cases of this cancer are preventable.
What are the Types of Bladder Cancer?
Just like with other kinds of the disease, bladder cancer occurs in different stages and types. In order to learn more about bladder cancer, it is also important to get informed into how the disease can progress and different categories.
Bladder Cancer Staging
Different stages of bladder cancer include:
- Stage 0a – Early cancer found on the surface of the inner lining of the bladder. Cancerous cells are grouped together and it is easy for doctors to remove* them. In this stage, cancer did not invade the muscle or connective tissue of the bladder wall
- Stage 0 – Found only on the inner lining of the bladder, but it hasn’t spread to the hollow part of the bladder or the thick layer of muscle or connective tissue. Stage 0is is always considered high-grade cancer and an aggressive disease due to its potential to lead to muscle-invasive disease
- Stage I – At this point, cancer grew through the bladder’s inner lining, but it has not spread to the thick layer of the muscle, lymph nodes, and other organs
- Stage II – In this stage, cancer spreads to the thick muscle wall of your bladder and it is referred to as invasive cancer. However, the disease did not spread to lymph nodes and other organs
- Stage III – Cancer spreads throughout the muscle wall to the fatty layer of tissue that surrounds your bladder. In some cases, stage III bladder cancer spreads to the prostate gland in men or uterus and vagina in women. But the disease still did not spread to lymph nodes and other organs
- Stage IV – Accounts or any of the following: cancer/tumor spreads to the pelvic wall or abdominal wall but not to lymph nodes and other organs, cancer/tumor has spread to 1 or more regional lymph nodes but not to other parts of your body, and tumor may or may not have spread to organs and lymph nodes in other parts of your body
- Recurrent Cancer – This is self-explanatory, the term refers to cancer which returns even after treatment
Types of Bladder Cancer
Not all cases of bladder cancer are the same primarily because different types of cells in this organ can become cancerous. The type of bladder cancer is determined by the sort of bladder cell where the disease begins.
Categorizing bladder cancer into different kinds gives doctors an opportunity to recommend an adequate treatment to the patient who can overcome this severe condition effectively. Three main types of bladder cancer are identified and they are listed below.
Squamous Cell Carcinoma
Squamous cells are defined as flat cells that resemble fish scales. The term squamous derives from the Latin word squama meaning “the scale of fish or serpent”. The human body has a lot of these cells which are primarily located in the epidermis (outer layer of your skin), the passages of digestive and respiratory tracts, and the linings of hollow organs. Remember, your bladder is hollow.
Squamous cells carcinoma, in this case, is linked to a chronic irritation and inflammation of the bladder e.g. infection or long-term use of the catheter. Over time, these cells can become cancerous.
Unlike urothelial carcinoma, this type of bladder cancer is not as common and accounts for 4% of all cases in the US and 5% of total bladder cancer diagnoses in the UK.
Typically, this form of bladder cancer is more prevalent in developing nations where schistosomiasis (a parasitic infection) can lead to irritation and inflammation in the bladder.
Urothelial carcinoma, previously known as transitional cell carcinoma, is the most common type of bladder cancer accounting for 90% of all diagnosed cases. It affects the urothelial cells found inside your bladder. When the bladder is full, urothelial cells expand, but when it is empty these cells contract. Ureters and urethra also have these cells inside, which is why tumors can develop there as well. These particular cells come into contact with waste products found in the urine e.g. various chemicals including those from cigarette smoke. These toxic waste products are known for their potential to cause or contribute to the formation of cancer.
Adenocarcinoma is a type of cancer that starts in the glands that line the inside your organs. In this case, cancer develops in cells that are located in the mucus-secreting glands in your bladder. Adenocarcinoma of the bladder is very rare in the US and occurs in only 2% of all bladder cancer cases. In most cases, this type of cancer is invasive.
A sarcoma is a rare kind of cancer; there are more than 50 types of sarcoma but we can divide them into two main categories: osteosarcoma (bone sarcoma) and soft tissue sarcoma. When it comes to bladder cancer, sarcoma starts in the fat or muscle layers of the organ.
Small Cell Anaplastic Cancer
Small cell anaplastic cancer is a rare type of bladder carcinoma that is highly likely to spread to other organs and tissues. Although rare, small cell anaplastic carcinoma is aggressive and usually diagnosed in advanced stages and it has a high metastatic potential. Due to the aggressive nature and late diagnosis, this type of bladder cancer is usually associated with poorer outcomes.
It is a well-known fact that cancer can spread to other organs and tissues as the disease is progressing. In some instances, cancer affects some other parts of the body and then spreads to the bladder, this is called secondary cancer. Most commonly, cancers of prostate, rectum, cervix, ovary, and womb can spread and reach bladder as well.
Types of Bladder Cancer Based on Invasiveness
Along with categorization of bladder cancer based on the cells and the area of onset, we can also classify the disease according to its invasiveness. Therefore, bladder cancer can be:
- Non-Muscle-Invasive – Cancer usually grows into the lamina propria (a thin layer of loose areolar connective tissue). Another term for this type of bladder carcinoma is “superficial cancer”. Doctors and scientist avoid using this term due to the fact it may imply the cancer is not serious
- Muscle-Invasive – Carcinoma grows into the muscle of the bladder wall. In some instances, this cancer can spread to surrounding tissue outside the bladder as well as fatty layers
- Transitional Cell Carcinoma – Cancer starts in the renal pelvis, part of the kidney where urine collects before it moves to the bladder. Although kidney cancer, it is usually treated like bladder cancer because it affects urothelial cells.
Differentiation Based on Grades
Another manner of categorizing bladder cancer is according to how cancer cells look when viewed under microscope. This process is referred to as a tumor grade. Therefore, bladder cancer can be:
- Low-Grade – Cells are closer in appearance and organization to normal cells. This type of tumor grows more slowly and does not invade muscular wall
- High-Grade – Cells are abnormal-looking and do not bear any resembles normal tissues. This form of bladder cancer grows more aggressively and is likely to spread to other organs and tissues in an affected individual
What are the Causes of Bladder Cancer?
As shown above, bladder cancer occurs when cells in this organ start growing abnormally. Instead of growing and dividing properly, they create mutations that make them multiply out of control*. These abnormal cells are the ones that cause cancer. But, what makes them act that way? Unfortunately, the exact cause of bladder cancer still remains unknown, scientists speculate that a combination of different factors plays a role. Below, you can see the basic rundown of causes that contribute to the formation of bladder cancer.
Your genes play a major role in overall health and wellbeing. A wide array of diseases and health conditions are strongly related to one’s genes, and bladder cancer is not an exception. In fact, changes in the genetic DNA are considered as one of the most common causes of bladder cancer, scientists explain.
The American Cancer Society explains that some genes control* when cells grow, divide into new cells, and die. Genes that help cells grow, divide, and stay alive are called oncogenes while genes that regulate cell division, repair mistakes in DNA, or cause cell death are referred to as tumor suppressor genes.
Basically, bladder cancer can be caused by mutations that turn on the oncogenes and turn off tumor suppressor genes. More than one gene change is necessary for a cell to become cancer, in most cases. Evidence shows that genetic mutations in chromosomal genes such as FGFR3, RB1, HRAS, TP53, TSC1, and others are strongly associated with bladder carcinoma.
The CDC reports that cigarette smoking is the primary cause of preventable disease and death in the US. More than 480,000 deaths occur every year due to smoking, which is about 1 in 5 death cases. Shockingly, about 15 out of 100 US adults aged 18 and older smoked cigarettes in 2015 (the last year for which data is available).
More precisely, 36.5 million American adults are smokers while approximately 16 million people have a smoking-related disease.
Why is this important?
Even though it may seem that smoking has no any connection with bladder cancer, it is considered as one of the most frequent causes of this severe disease. This occurs primarily due to toxins from cigarette smoke that remain in your body and pass through it in urine. The link between smoking and bladder cancer is nothing new, multiple studies have confirmed it. For example, a research from JAMA found that both men and women can develop bladder carcinoma due to smoking and the risk is highest for current smokers.
Exposure to Chemicals
Long-term exposure to different chemicals is yet another cause of bladder cancer and it primarily occurs in individuals who are exposed to these compounds in working environment. For instance, chemicals called aromatic amines like beta-naphthylamine and benzidine sometimes found in hair dyes are well-known for their ability to cause bladder carcinoma.
Furthermore, industries, where workers are exposed to bladder cancer-causing chemicals, include leather, rubber, textiles, printing, and those associated with paint products. One study found that exposure to arsenic in drinking water at concentrations higher than 300 µg/l can lead to this severe disease.
What are the Risk Factors for Bladder Cancer?
The truth is that everyone can develop bladder cancer, but some people are at a higher risk. The most common risk factors that increase* your chances of developing this disease are as follows:
- A diet high in nitrates or abundant in meat and fatty foods
- Age – Your risk of developing bladder cancer enhances* as you age, more than 70% patients are older than 65
- Being a man i.e. men are 3 to 4 times more likely to develop bladder carcinoma than women
- Chronic bladder infection
- Chronic bladder inflammation and irritations
- Congenital bladder defects
- Early menopause
- Exposure to arsenic in drinking water
- Exposure to chemicals
- Family history of bladder cancer
- Having other medical conditions including diabetes, spinal cord injury, systemic sclerosis, Crohn’s disease, and kidney transplant
- Having some form of parasitic disease such as schistosomiasis
- Insufficient fluid intake
- Lynch syndrome, an inherited condition that was previously known as hereditary nonpolyposis colorectal cancer also increases* bladder cancer risk
- Not having children i.e. women who have had children are at a lower risk of developing bladder cancer
- Overweight and obesity, some studies show that carrying extra weight is yet another risk factor for bladder cancer
- Personal history of bladder cancer
- Race – White adults are at higher risk than African-American, Asian, and Hispanic individuals
- Sedentary lifestyle
- Some medications and dietary supplements such as Actos (piogliatazone) and aristolochic acid (primarily from plants in the Aristolochia family)
- Undergoing chemotherapy and radiation therapy
Despite the wider prevalence of bladder carcinoma among white men, estimates reveal significant differences in survival rates regarding ethnicity. One research discovered that African-American men had higher stage disease than Caucasians, Hispanic, and others. In fact, five-year disease-specific survival rates were consistently worse for blacks than other ethnic groups.
What are the Symptoms of Bladder Cancer?
In some instances, an affected individual does not experience symptoms associated with bladder cancer while in other cases, the cause of symptoms is related to another medical condition.
The most common symptom of bladder cancer is hematuria or blood or blood clots in urine. In 9 out of 10 cases of bladder cancer, patients experience this symptom. It is important to mention that hematuria is not painful. You can see the blood in your urine and it usually looks bright red but in some cases, it can appear dark brown. That said, sometimes blood is present in urine but in smaller amounts and it is difficult to notice. Blood and blood clots in urine do not have to be persistent; this symptom can come and go. As soon as you notice this symptom, see your doctor
Other symptoms associated with this carcinoma are:
- Feeling the need to urinate many times throughout the night
- Feeling the need to urinate, but not passing urine
- Frequent UTIs (urinary tract infections)
- Painful urination
- Pelvic pain
- Urinating small amounts frequently
In advanced cases of bladder cancer, patients may experience the following symptoms:
- Back pain
- Bone pain
- Complete inability to urinate
- Pain in the rectal, anal, and pelvic area
- Swelling in the feet
- Weight loss*
Due to the similarity of symptoms of bladder cancer to other conditions affecting this organ, it is strongly recommended seeing the doctor in order to receive an accurate diagnosis and an adequate treatment.
How is Bladder Cancer Diagnosed?
Generally, you should see your doctor whenever you experience problems with passing urine and particularly if you also notice blood. It is a major mistake to ignore these symptoms and hope they will go away. When you see your physician, you should mention all symptoms you experience even if you assume they are not important.
Also, do not be surprised if a healthcare provider asks you about the family history of bladder cancer or problems affecting this part of your body. The doctor may also ask whether you are a smoker or not.
Based on the provided information and physical exam (including rectal, prostate, pelvic exam), the doctor will suspect bladder cancer is the problem, but to rule out other conditions and make an accurate diagnosis he/she will order different tests. Your doctor may also order a urine test and urine culture in order to check the presence of blood, infection, and abnormal cells. In addition to that, a urine test can serve to look for tumor markers (a sign of cancer).
Other tests include
- Cystoscopy – Features a narrow tube containing a camera and lighting system that is inserted into your bladder through the urethra. Basically, this test allows the doctor to have a clear insight into your bladder and identify potential problems. For instance, cystoscope can collect cell samples for a biopsy as well. Cystoscopy is usually performed under local anesthetic, but doctor may also opt for general anesthesia when necessary
- Biopsy – Samples collected through cystoscopy are tested through a procedure called transurethral resection of bladder tumor (TURBT). This same procedure can also help treat* bladder carcinoma
- Imaging Tests – These tests reveal how far cancer has spread in your body. They include pyelogram, CT, and ultrasound. During pyelogram, the contrast dye is inserted into the bladder and it outlines this and other organs, thus making tumors noticeable on x-ray. On the other hand, CT helps doctor determine the shape, size, and position of cancer while ultrasound determines the size of tumors and shows whether cancer has spread to other organs and tissues
- Urine Cytology – A procedure wherein urine is analyzed under microscope to check for cancerous cells
If these tests show that a patient has bladder cancer, the healthcare provider proceeds to determine the stage, grade, and type of the disease. As shown above, knowing this information allows physicians to recommend an effective treatment.
What are the Treatment Options for Bladder Cancer?
The treatment for bladder cancer depends on type and grade. Of course, the best chance to overcome this disease is to see your doctor as soon as you notice symptoms and receive a prompt diagnosis. Treatment usually revolves around four options listed below.
The most common treatment for bladder cancer is, by far, surgery which refers to the removal of the tumor and surrounding healthy tissue. Again, the type of surgery depends on the stage or grade of cancer. Below, you can see the most common surgical options:
- TURBT – As seen above, this procedure is versatile and can be used for both diagnosis and treatment of bladder cancer. During this surgical procedure, a surgeon inserts a cystoscope through the urethra into a patient’s bladder and removes* the tumor. Although the surgery can eliminate* non-muscle-invasive bladder cancer, the doctor will probably recommend additional treatments to lower the risk of recurring. Patients who are diagnosed with muscle-invasive bladder cancer additional treatments are necessary to remove* the disease entirely
- Cystectomy – Removal of the bladder and, in some cases, surrounding tissues and organs. In female patients, the uterus, fallopian tubes, ovaries, and a part of the vagina may be removed. In men, a surgeon may remove* the prostate gland and the urethra. Doctor may also perform a partial cystectomy and remove* only a portion of the bladder
- Urinary Diversion – In patients who have undergone cystectomy, the surgeon creates a new way to pass urine. To accomplish this task, he/she uses a section of the small intestine or colon to navigate urine to a stoma or ostomy outside your body
The main goal of chemotherapy is to use drugs to destroy cancer cells or minimize the size of tumors so they can be removed during surgery. Essentially, chemotherapy can be used to treat* bladder carcinoma prior to or right after surgical procedure. A typical chemotherapy regimen consists of a certain number of cycles given over a certain period of time. The treatment can be administered intravenously, orally, or in the bladder with a catheter.
Based on the grade and type of bladder cancer, your doctor can determine the best chemotherapy option for you. These options include:
- Systemic (whole body) Chemotherapy – Gets into the bloodstream to make an impact on cancer cells throughout the body. It is usually administered with IV (intravenous) tube placed into the vein using needle, but patient can also take pills
- Intravesical Chemotherapy – Unlike systemic chemotherapy which is given by oncologist, this procedure is administered by a urologist. Here, pills are delivered to your penis with a catheter that has been interested through the urethra. It is important to mention that this treatment for bladder cancer destroys superficial tumor cells, but it is unable to reach tumor cells in the bladder wall or tumor stress that also affected other organs in your body
Drugs administered during chemotherapy can affect other, healthy cells within the body. The most common side effects due to this reason include:
- Appetite loss
- Constipation or diarrhea
- Hair loss
- Higher risk of infection
- Increased bleeding and bruising
- Mouth sores
Biological therapy, also called immunotherapy, works to enhance* the body’s natural defenses to fight cancer and it is recommended to patients with early stages of bladder carcinoma. This treatment revolves around the use of materials made either by the body itself or in the laboratory to target and improve* the functionality of the immune system.
The immunotherapy for bladder cancer usually involves a drug called bacillus Calmette-Guerin) (BCG), a small bacteria that also causes tuberculosis. The drug is placed right into the bladder through a patient’s catheter. There, the drug attracts and activates immune system cells which are, then, able to find cells associated with bladder cancer.
The primary role of radiation therapy is to kill cancer cells with high-dose x-rays or some other high-energy rays. The treatment is usually combined with other therapy options for bladder cancer.
For example, it can be given before or after surgery and a patient may receive it while undergoing chemotherapy. The most common type of this treatment is external-beam radiation therapy administered from a machine outside the body. In instances when the treatment involves radiation with the use of implants, it is called internal radiation therapy or brachytherapy.
Radiation therapy is associated with side effects such as skin irritation, nausea, and vomiting, diarrhea, fatigue, discomfort in the bladder, hematuria.
Coping with Bladder Cancer
Being diagnosed with bladder cancer can be difficult to take and cope with, primarily because the word “cancer” automatically makes us things everything is over for us. It is entirely possible to beat bladder cancer, as you have seen above, but besides an effective treatment, you also have to know how to cope with the disease.
First, start it off by coping with side effects caused by treatments for bladder cancer. While these treatments are effective, they can still induce adverse effects whose severity varies according to the stage and type of the disease. Although your doctor will inform you about everything you should know about chemotherapy, don’t feel bad for asking more questions. Also, feel free to get informed about treatment options and potential side effects. Knowing what you can expect makes it easier for you to avoid common pitfalls.
Besides coping with chemotherapy and other treatment types, you also have to learn how to cope with emotional and social effects. A cancer diagnosis may induce a wide array of emotions ranging from sadness to fury. While it is easy to look up this information online, don’t underestimate the power of seeing a therapist who can show you how to cope with the physical burden of the disease.
Treatment of bladder cancer can also raise concerns regarding financial situation. These treatments are not cheap and for patients who are on the tight budget, it can be difficult to focus on the therapy entirely. Numerous resources are found online, including at Cancer.Net, that aim to inform you how to understand costs related to cancer care, tips for organizing financial information, and more.
Things you can include:
- Connect with other bladder cancer survivors.
- Keep a schedule of follow-up tests near you and strive not to miss an appointment.
- Adjust your diet.
- Exercise at least 30 minutes a day, most days of the week.
What are the Prevention for Bladder Cancer ?
Bear in mind that even though bladder cancer is not entirely and completely preventable, there are numerous things you can do to minimize your risk of developing it. Even if you had bladder cancer before, you can still prevent it from returning. A healthy lifestyle is always important and it can help you minimize the risk of developing the disease. Here are some useful prevention tips to bear in mind:
- Quit Smoking – As seen above, smoking is a major cause and risk factor for bladder cancer. That way, cancer-causing chemicals do not build up in your bladder. It is needless to mention that smoking is a major risk factor for numerous health conditions. As a result, you can minimize bladder cancer risk and improve* your health at the same time
- Avoid Exposure To Industrial Chemicals – Use proper protection at work just like with smoking, this way toxic or cancer-causing chemicals will not accumulate in your bladder
- Keep Weight in a Healthy Range – Being overweight or obese puts you at a higher risk of developing bladder cancer, which is why you should exercise regularly to minimize that risk
- Healthy Diet – Well-balanced diet goes hand in hand with regular exercise. A sedentary lifestyle is yet another risk factor for bladder cancer. Limit or avoid intake of sugary foods and trans fats and increase* intake of fruits and vegetables and other foods that are abundant in vitamins, minerals, antioxidants, and fiber
- Stay Hydrated – Increase* your daily fluid intake, but make sure you focus on water primarily. Water helps you increase* urine output and flushes cancer-causing chemicals out of your body immediately
- Medical Consultation – If taking medications, consult your doctor to see whether they can lead to some unwanted scenarios. Also, feel free to ask a physician about dietary supplements, if they are safe and when to take them
Bladder cancer attacks, as you already know, your bladder and it appears in different forms, types, and stages. Symptoms of this cancer are similar to those of other conditions affecting this organ, which is why consulting a doctor is a must in order to get proper, effective treatment. Various treatment options are available and doctor recommends them based on the type of the disease.
- Cancer Statistics, National Cancer Institute https://www.cancer.gov/about-cancer/understanding/statistics
- Bladder Cancer Statistics, Cancer Research UK http://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/bladder-cancer#heading-Zero
- Bladder Cancer: Stages and Grades, Cancer.Net http://www.cancer.net/cancer-types/bladder-cancer/stages-and-grades
- What Causes Bladder Cancer? American Cancer Society https://www.cancer.org/cancer/bladder-cancer/causes-risks-prevention/what-causes.html
- Current Cigarette Smoking among Adults in the United States, CDC https://www.cdc.gov/tobacco/data_statistics/fact_sheets/adult_data/cig_smoking/index.htm
- Sun JW, Zhao LG, Yang Y et al, Obesity and risk of bladder cancer: a dose-response meta-analysis of 15 cohort studies. PLoS One, March 2015, Doi: 10.1371/journal.pone.0119313 http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0119313
- Yee DS, Ishill NM, Lowrance WT, Herr HW, Elkin EB. Ethnic differences in bladder cancer survival. Urology. 2011;78(3):544-549. doi:10.1016/j.urology.2011.02.042. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3710780/
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