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Welcome to the Why Urology podcast with Dr. Todd Brandt.

This podcast is my personal attempt to teach you about your genito-urinary tract, what can go wrong, and how your urologist may just become your superhero.

The name of the podcast comes from my ongoing need to answer the question that I get so often from patients, friends, and family, “Why Urology? Why did you choose to become a urologist?”

Nov 12, 2017

November is National Bladder Health Awareness Month.  According to the Urology Care Foundation the cost of treating bladder problems in the United States is 70 Billion dollars annually. Nursing home costs due to urinary incontinence are estimated at 6 billion dollars annually.  Urinary tract infections create more than 8 million doctor visits every year (5.3 of those 8 million visits are women with infections, 1.3 and 1.2 of those 8 million are children and men respectively). Millions of Americans have neurogenic bladder from a spinal cord injury, multiple sclerosis, Parkinson’s disease, stroke, spina bifida, or nerve problems caused by diabetes or major pelvic surgery. More than 1 in 10 military service members injured in Afghanistan and Iraq have urologic trauma injuries, damaging the urinary tract or reproductive organs. For National Bladder Health Awareness Month, we are talking about bladder cancer. Bladder cancer is the 5th most common non-skin cancer in the United States. It is the 4th most common cancer diagnosed in men and by the Veterans Affairs Health System. Nearly 600,000 Americans live with bladder cancer today and 75-80,000 people will be diagnosed in the United States with bladder cancer this year. An estimated 16-17,00 people will die from bladder cancer this year. You are at risk for bladder cancer if you are over 55 years of age and you have one of the following five risk factors: 1. You smoke tobacco, either in the past or currently. 2. you are exposed to chemicals in the workplace used to make plastics, paints, textiles, leather and rubber, 3. you have had prior pelvic radiation, 4. you have chronic urinary tract infections associated with neurologic disease and chronic catheterization 5. you are a patient taking medications linked with increasing bladder cancer risk. In the last episode, we talked about how bladder cancer grows as a papillary tumor within the bladder. It begins on the surface of the bladder, in the lining cells of the bladder called transitional cells. Most bladder cancers then grow into the bladder on a stalk. As tumors grow they can grow roots and invade into the deeper layers of the bladder. As tumors invade the deeper layers of the bladder the stage increases and the chance that the cancer metastasizes or spreads to organs beyond the bladder also increases. Superficial tumors can be resected from the surface of the bladder as their only treatment. Recurrence rates for bladder cancer are at least 50% after initial diagnosis.  Careful, scheduled followup cystoscopy in the office on a routine basis is required to check for recurrent tumors. Higher stage tumors that are invading into the bladder muscle or beyond often will need to be treated with other treatments such as chemotherapy, radiation or even removal of the bladder. A bladder cancer can also grow in another way that we did not touch on during the last episode, the tumor can also grow up along the surface of the bladder. When the cancer behaves in this way it does not create a papillary lesion but rather takes up a large surface area of the bladder or is even present in several patches within the bladder. That type of growth is called carcinoma in situ (CIS). I want to illustrate this with an analogy. Picture an empty room stripped of all furniture and decoration. Pretend that is the inside of the bladder. Take a lamp and place it in the middle of the floor. That’s a papillary tumor. Now let’s carpet the floor. That’s carcinoma in situ. In the case of bladder cancer growing as carcinoma in situ it is nearly impossible to resect or cut away all of the tumor both because of the large surface area of the bladder that may be involved. Microscopic changes may also be found within other parts of the bladder that cannot be seen by the cystoscope that will become carcinoma in situ. To treat carcinoma in situ we then need to treat the entire surface of the bladder. We are fortunate that the bladder is a hollow cavity. We can simply place the treatment in a fluid within the bladder itself and it will naturally get to the entire bladder surface if we can hold the treatment in the bladder for a time. There are currently two forms of treatment that can be instilled into the bladder, chemotherapy and immunotherapy. Our most effective and most common treatment is called BCG, Bacillus Calmette-Guerin. (BCG).  It is a form of immunotherapy, stimulating the body’s natural immune response to recognize and kill cancer cells. Immunotherapy uses the body’s natural defense cells to fight a cancer. Cancer grows hiding in plain sight from the body’s immune system.  Cancer cells are abnormal cells but the body does not kill the cancer in the same way that it tries to kill a bacterium or a virus. A cancer cell is derived from the body’s normal cells within an organ. Bladder cancer cells, as are all cancer cells, created when normal cells get faulty DNA instructions and grow aggressively, without organization, and without stopping. The cancer cell is allowed to grow because the body does not see it as foreign because it comes from the body’s cells in the first place. If we can make a body recognize a cancer cell as foreign, then the body has incredible tools in the immune system to kill a cancer on its own. That is the essence of immunotherapy. There is currently a lot of research being done using immunotherapy to treat all kinds of cancer including bladder, kidney, colon, skin, lung and others. To date nothing has surpassed BCG. The odd and interesting thing about BCG and putting it into the bladder is that it BCG was originally developed and is still used as a vaccine for tuberculosis. How urologists began to use BCG in the bladder is a bit of a convoluted tale that I will tell at the end of this episode. BCG is used in several circumstances. It is employed: (1) to treat carcinoma in situ or occasionally residual papillary tumors; (2) to reduce the number and frequency of recurrent high grade superficial tumors; and (3) to prevent disease progression (although this remains a controversial point, on which there is no consensus view). BCG treatment is usually started a few weeks after an initial resection and biopsy of the bladder tumor to allow the bladder time to heal. The usual treatment is given once a week for 6 weeks. In the office patients are given live attenuated BCG mixed in 50 ml of normal saline instilled into the bladder via a urethral catheter. Before instillation urinary tract infection is excluded and the catheter is introduced in an atraumatic way. The patient retains the fluid within the bladder for an hour or two. This is to ensure that all the bladder mucosa comes into contact with the BCG. There is a small risk of infection with BCG, therefore the staff administering the BCG are suitably protected with masks, goggles, gloves, and gowns. Patients are advised to bleach their toilets after urinating, so as to neutralize and kill any BCG from the urine. BCG works about 50-60% of the time after its first treatment. The initial 6-week treatment can be repeated if needed, providing an additional 20-30% benefit. Sometimes longer treatment regimens are used. An immune booster called interferon can be added. Long-term maintenance BCG therapy where short courses of three weeks given every few months is also used to try to prevent recurrent bladder cancer. Patients not responding to BCG need to have alternative treatments and have a high risk of disease progression and metastatic disease. Treatment with BCG can cause symptoms and side effect that feel like having the flu, such as fever, chills, and fatigue. It can also cause a burning feeling in the bladder that may increase through the course of a treatment. Rarely, BCG can spread through the body, leading to a systemic infection. How does BCG work? The exact mechanism of action of BCG is not completely understood. It is known that an intact immune system is important for the antitumor activities of BCG. The body’s immune system cells are attracted to the bladder and activated by BCG, which in turn affects the bladder cancer cells. But how the body suddenly recognizes and kills a bladder cancer that it did not previously recognize is not well understood. Now let’s take a bit of a diversion. BCG is a tuberculosis vaccine. Let’s talk about tuberculosis. We don’t hear about tuberculosis much in the United States. There are between 9-10,000 cases of tuberculosis reported in the United States annually, with HIV-positive immunocompromised patients being the most susceptible. But tuberculosis recently has made the front page of our local newspapers here in Minnesota because of a small outbreak of difficult to treat tuberculosis within our community. According to the World Health Organizations, Tuberculosis (TB) is one of the top 10 causes of death worldwide. In 2016, 10.4 million people fell ill with tuberculosis, and 1.7 million died from the disease (including 0.4 million among people with HIV). Over 95% of tuberculosis deaths occur in low- and middle-income countries. Seven countries account for 64% of the total, with India leading the count, followed by Indonesia, China, Philippines, Pakistan, Nigeria, and south Africa. in 2016, an estimated 1 million children became ill with tuberculosis and 250 000 children died of tuberculosis (including children with HIV associated tuberculosis). Tuberculosis (TB) is caused by bacteria (Mycobacterium tuberculosis) that most often affect the lungs. tuberculosis is spread from person to person through the air. When people with lung tuberculosis cough, sneeze or spit, they propel the tuberculosis germs into the air. A person needs to inhale only a few of these germs to become infected. About one-quarter of the world's population has latent tuberculosis, which means people have been infected by tuberculosis bacteria but are not (yet) ill with the disease and cannot transmit the disease. People infected with tuberculosis bacteria have a 5–15% lifetime risk of falling ill with tuberculosis. Worse yet, strains of tuberculosis that are resistant to the most common therapy are becoming more common. The World Health Organization estimates that there were 600, 000 new cases last year with resistance to rifampicin – the most effective first-line drug, of which 490 000 had Multiple drug resistant-tuberculosis. The cost or treating drug resistant tuberculosis is very high, as much as $134,000 per patient. By comparison, first-line therapy requires at least six months of drugs at a cost of $17,000. Here is where our story begins to take on a local note. According to a recent article in the MPLS paper the Star Tribune at least 17 people have been diagnosed within our community recently with active drug resistant Tuberculosis. Health officials are scrambling to identify those closest to those diagnosed to see if those people have either active or latent infections. Testing on 125 people has already turned up 58 cases of latent tuberculosis infection, meaning they carry the disease, and may go on to develop symptoms and become infectious, especially if they have chronic health conditions or as they age and their immune systems weaken. Like those who show symptoms, those with latent infections are being urged to take the second-tier antibiotics for up to 18 to 24 months. Another 150 potential contacts known to investigators of our local outbreak had incomplete date of birth or address information, complicating the efforts to track them down. That means there are potential latent infections in our community left untreated. This is especially chilling as we enter the cough and cold season here in Minnesota. On a positive note, The World Health Organization believes Tuberculosis is curable and preventable. Globally, tuberculosis incidence is falling at about 2% per year. An estimated 53 million lives were saved through tuberculosis diagnosis and treatment between 2000 and 2016. Ending the tuberculosis epidemic by 2030 is among the health targets of the Sustainable Development Goals for the world Health Organization. One goal of the strategy is to immunize against tuberculosis. The United States does not actively immunize against tuberculosis, but many other countries do. The tuberculosis vaccine used is BCG. It was first given as a vaccine in 1921. Development of the BCG vaccine goes back many years prior to 1921. In 1904, scientists isolated Mycobacterium bovis from a cow with tuberculous mastitis. Bovine tuberculosis was a significant cause of death among cattle in the early 20th century and remains a risk today. Scientists quickly got to work studying bovine TB in the lab. But initially working with bovine TB in the laboratory proved difficult. The mycobacterium culture in the laboratory showed a strong tendency to clump. In order to prevent adhesion, in 1908, working together at the Pasteur Institute Albert Calmette, a physician by training and research bad-ass who, according to Wikipedia, had invented the first anti-venom for snake venom and Camille Guérin, a veterinarian by training added bovine bile to the bovine TB culture medium to prevent clumping. After this culture, the M bovis showed a loss of virulence for animals. With each subsequent culture the bovine TB would show less virulence. In 1920, after a period of 13 years and 231 culture passages through the laboratory the culture was regarded as being avirulent or noninfectious. This special M bovis strain was named Bacillus of Calmette and Guérin (Bacille de Calmette et Guérin, BCG), and a vaccine for tuberculosis was born. BCG was first used in humans in 1921 when it was given to a child in Paris. The baby’s mother, who had tuberculosis, had died just after the baby was born, and the baby was due to be brought up by its grandmother who also had tuberculosis. The baby developed into a perfectly normal boy. During the next three years (up to July 1924) a further 317 infants were also vaccinated. The story of BCG then takes a cloudy turn when, in 1930, when 72 vaccinated children developed tuberculosis in Lübeck, Germany, due to a contamination of some batches of the vaccine. Mass vaccination of children was stopped after the disaster but then reinstated in many countries after 1932, when new and safer production techniques were implemented. Strains of BCG are still used today in vaccination programs around the world. BCG vaccine has a documented protective effect against meningitis and disseminated tuberculosis in children. It does not prevent primary infection and, more importantly, does not prevent reactivation of latent pulmonary infection, the principal source of bacillary spread in the community. The impact of BCG vaccination on transmission of Human TB is therefore limited. Next in our tale about how BCG came to be used for bladder cancer comes thanks to Dr. Raymond Pearl, a prolific writer and biologist from Johns Hopkins. Pearl reported in 1929 that among the first autopsy studies at Johns Hopkins there was a negative association of patients with tuberculosis and cancer and he proposed that tuberculosis infection somehow prevents cancer. That assertion is false. Later analysis of his data by others showed that his data had significant selection bias. Criticism of this paper and his analytical methods at the time in particular was to be a stumbling block in his career advancement when Dr. Pearl was being considered for a position at the Bussey Institute at Harvard. The most vociferous critic considered Pearl’s work superficial, self-promoting, and a nuisance likening it to “boyish whittling.” But that initial analysis by Pearl sparked interest in the immunobiology of tuberculosis infection as a way to stimulate the immune system to treat cancer. Interest in BCG and tuberculosis as a cancer treatment waxed and waned between 1930 and 1970 but the story continues after intra-lesion injections of BCG for melanoma of the skin proved successful.  After the melanoma treatments proved successful for the skin an adventurous urologist injected and successfully treated a melanoma of the bladder through cystoscopic injection, published in the Journal of urology in 1975. This success sparked an interest in BCG treatments of other forms of bladder cancer. In 1976 the first report of BCG treatment for transitional cell carcinoma was published by Dr. A. Morales in the Journal of Urology. This paper is included in a series of papers in an anniversary edition of the Journal of Urology now celebrating its 100th year of publication.  You can find it at www.JU100.org. The author was applauded for his “courage as well as his results” by the editorial accompanying the initial publication. It’s still not clear if the appropriate animal modeling had been performed prior to clinical experimentation on people, but the successful treatment created the spark that ignited larger research studies that proved the efficacy of BCG and resulted today in many of our patients being treated with BCG. More “academic” studies followed. Dr. Donald Lamm was awarded the initial NIH-funded contract to evaluate BCG immunotherapy of superficial bladder cancer in a randomized clinical trial (1978). This work, accruing an eventual 231 patients, resulted in the first controlled trial demonstrating the efficacy of intra-vesical BCG immunotherapy. Urologists have been using BCG as a treatment for superficial bladder cancer ever since. Let’s stop there. I have really taken us on a journey in this episode. I wonder what Drs. Calmette and Guerin would have thought in 1908 as they were adding bile to a bovine TB culture medium if you told them we would eventually use a tuberculosis vaccine they would develop to treat bladder cancer. To get from there to here otherwise cautious urologist had to become the adventurous surgeons and scientists that we have talked about in previous podcasts, the phrase that caught my eye from the editorial introducing the 100th anniversary edition of the Journal of Urology. You can read the article at http://www.ju100.org/. Bibliography/Reference:  

  1. https://extranet.who.int/sree/Reports?op=Replet&name=%2FWHO_HQ_Reports%2FG2%2FPROD%2FEXT%2FTBCountryProfile&ISO2=US&LAN=EN&outtype=html
  2. https://www.cancer.org/cancer/bladder-cancer/treating/intravesical-therapy.html
  3. http://www.startribune.com/tb-outbreak-has-health-officials-on-alert/455468773/
  4. https://www.researchgate.net/publication/11202692_BCG_use_of_bacille_Calmette-Guerin_in_superficial_bladder_cancer [accessed Nov 11 2017].
  5. https://en.wikipedia.org/wiki/Albert_Calmette
  6. https://en.wikipedia.org/wiki/Camille_Guérin