December 19, 2019
Greetings and Happy Holidays!
As I stated last year and will reiterate, the days are very long and the years are very short. It is Christmastime and the holiday season once again, which means it is time for my annual letter I hope continues to be well-received. I enjoy hearing from those who write or comment to me about what you like and do not like about the letter, and I hope you will continue to give me feedback.

CLINICAL UPDATE: We continue to advance techniques to manage prostate cancer at all stages. There is much work being done on identifying genetic changes associated with prostate cancer. I use many of these techniques in clinically evaluating patients. Patients will often ask me if it is worth it to run various genetic tests that are available. Those tests range in price from $5,000 to $12,000. They provide a genetic panel/array of changes that will have some relevance to prostate cancer, but often little relevance to managing prostate cancer for those with the disease. Having a BCRA2 gene positive for prostate certainly puts a man at increased risk but still does not guarantee he will get the disease. A positive genetic test does not drive me to biopsy the patient without other indicators typically used for making the decision to biopsy. These tests include a free and total PSA, 4K test or prostate health index test. For patients with elevated PSA, these are all means of evaluating their risk of actually having prostate cancer. Genetic tests that provide a wide variety of results currently do not help us refine the decision to biopsy or not.

Nonetheless, it is interesting that a recent article in the journal Cancer reported an increase in prostate cancer incidence among adolescents and young adults in the United States and other countries over the past three years. Although still uncommon, the incidence in all groups between ages 15 and 40 increased at a steady rate of 2% per year. Of course, young men tend to be less adequately staged at diagnosis; therefore, their cancer is found at a more advanced stage. Consequently, they are at higher risk for metastatic disease and death compared to older men. This reality raises my concerns and makes me more diligent in evaluating younger men with a family history of prostate cancer. I am considering testing my patients not at age 40, but as young as age 30. We need to do more work on this. However, I continue to state that prostate cancer awareness is critically important, especially among those whose families have been affected by this disease.

To that end, I was recently given the opportunity to discuss prostate cancer in the media. The Houston Chronicle was kind enough to publish a letter I wrote in September during Prostate Cancer Awareness Month. In the letter, I expressed my desire to have professional athletes pay attention to prostate cancer. The majority of professional athletes are African-American men, a cohort who has the highest risk of prostate cancer and the highest mortality rate from this disease in the world. These wonderful men are very supportive of their mothers, sisters, aunts and daughters in building breast cancer awareness by wearing pink ribbons, pink socks and so on. But during Prostate Cancer Awareness Month, you will never see athletes wearing blue ribbons, blue socks or other blue paraphernalia designed to show their support for prostate cancer awareness. I implored through this op-ed piece that our athletes would serve our community well if they showed as much concern for their brothers, fathers, uncles, sons and male friends. Hopefully that message will get out. KUHF, our national public radio station at the University of Houston, recently interviewed me regarding robotic surgery and allowed me to emphasize my strong belief in the need for increased prostate cancer awareness.

The Men’s Health Center at Houston Methodist has been open for a year now. The Hamill Foundation has provided remarkable funds to help get this center off the ground, and it is functioning well. As with any new endeavor, we have had our ups and downs, but the curve continues to be up and improvements are noticeable. I am trying to create a clinical organization that finds a new way to address the health concerns of the aging male. If a man comes in to a physician’s office without his wife, daughter or partner accompanying or directing him, he is often concerned about his testosterone or erectile capabilities. This is an excellent opportunity to engage men and educate them to take their overall health seriously.

Erectile dysfunction is often a manifestation of microvascular disease within the body that relates to heart disease and other organ problems throughout the body. It is also associated with diabetes mellitus, obesity, high blood pressure, etc. Men are increasingly choosing to visit the Men’s Health Center because they know they can sign up online to come to clinic with the understanding that we will treat whatever problem concerns them. They also know we will direct them to cardiology, endocrinology, the weight loss center or another area to help improve their overall health. We can solve the impotence and low testosterone problem but are reluctant to do so when men do not see a family practice doctor to take care of their overall health.

RESEARCH UPDATE: High-Intensity, Focused Ultrasonography (HIFU).
I have been discussing high-intensity, focused ultrasonography over the past three years. We obtained a HIFU machine right after the Food and Drug Administration approved this technique. It is an excellent way to ablate, or destroy, prostatic tissue and plays a role in managing the disease. It gives patients another option besides radiation and surgery. Thanks to The Hamill Foundation’s kind and generous support, this past summer I purchased the newest HIFU machine known as the Focal One produced by the EDAP Corp. It is terrific technology and allows me to treat the whole prostate or small focal areas of the prostate in order to manage prostate cancer. Prior forms of treatment using HIFU were very limited and had little flexibility as far as changing the treatment areas during ongoing treatment. The new machine allows me to do that. I now have the capacity to perform a male lumpectomy, where I treat only one area of concern found on MRI, for instance. I can do this without treating the rest of the prostate gland. As I point out to patients, HIFU should not be considered standard of care but rather an available therapy. Patients who wish to have treatment using HIFU understand that I will collect data on them because I need to study this treatment to be sure it is beneficial and helpful to many of my patients. This machine is remarkably flexible, and finding those patients who benefit from it the most and respond well to it is paramount.

When I treat an area of concern with high-intensity focused ultrasonography, I can give intravenous medication that has micro bubbles, or nano bubbles. Given intravenously, the medication goes where the blood supply goes. Since I am carrying out real-time ultrasonography of the prostate when I inject the medication, the areas that I have treated within the prostate should show a dark hole with no blood supply whatsoever. However, there is little data that shows that this truly is effective in showing areas that might truly have not been treated adequately. My plan is to give half my patients this micro bubble intravenous solution, and the other half will not get it. Both patient groups will be biopsied at a year post-procedure, and I should be able to evaluate whether the contrast-enhanced imaging was, in fact, predictive of prostate cancer persistence in the area I treated. If it is, it will be a great step forward that shows us we have completely eradicated the disease in the area that we targeted.

RESEARCH UPDATE: Telomeres.
This year, a Spanish company asked me to participate in a study on the use of telomeres in diagnosing prostate cancer. They hope to develop a predictive model using telomeres. Telomeres are a very interesting part of our genetic code, but most of us do not understand what they are. We all have DNA strands. DNA is a double-helix, with two strands wrapped together in the form of a helix. Think of a DNA strand as a cord, much like your shoelaces. Telomeres are at the end of each of the DNA strands. They keep the DNA from unraveling, just like the plastic at the end of your shoelaces keep your shoelaces from unraveling. As we age, however, telomeres shorten. When this happens, there is a chance our DNA strands will change. We know shortening of the telomeres is associated with aging, age-related dementia, heart disease, cancer, etc. Like mitochondria, telomeres have a role to play. I am sure the processes involving telomeres and mitochondria are going to prove very important as we make headway in treating prostate cancer.

The Spanish company has identified chromosomes associated with prostate cancer and can identify shortened telomeres on these chromosomes. They have quantitated a pattern that predicts when a patient with an elevated PSA is likely/at high risk to have prostate cancer. There is an algorithm — a proprietary formula — that allows them to calculate risk from the telomeres in these chromosomes, and we are helping refine that formula. We have started the study. To date, we have enrolled 25 patients. We hope to have 100 patient enrollees over the next few months. We will see how useful this formula is in deciding how to appropriately avoid biopsies in men who really do not need those procedures. There is also data from this company that shows the risk of disease progression, therapy response and value in managing prostate cancer. Instead of looking only at DNA, we will look at other aspects of the genetic profile. By doing this, I am hopeful patients will have a better handle on ways to manage this disease.

RESEARCH UPDATE: Brain imaging in men with urinary tract symptoms. As a supportive investigator with my colleague, Dr. Rose Khavari, I am studying how the brain is involved in lower urinary tract symptoms. This research will hopefully help us identify the association between the urinary center in the brain with urinary leakage in men who undergo a radical prostatectomy. We still do not know why some men have leakage issues after surgery and most do not. Although the study is designed to look at lower urinary tract symptomatology, I think it will help me understand pre-surgery which patients are at a significant risk for urinary leakage issues after surgery. It might allow us to consider doing a minor operation called a urethral sling at the same time as surgery in order to prevent urinary leakage issues for patients. This is a pilot, multimodal unique study we hope will identify the structural and functional brain
contributions to urinary symptoms in men for the first time.

RESEARCH UPDATE: Stem cells.
My slow, but very progressive stem cell studies have finally matured. Studies have revealed the stem cell protocol we used can be both intravenous and intrapenile. Our rat model has shown stems cells are effective in recovering erections. As you may know from past letters, in this study we permanently injure the rats’ nerves that stimulate erections. In the control group, erections are gone forever. In those rats that received stem cells both intravenous and intrapenile, erection recovery was excellent in essentially all the animals. I have used this data to finally submit an application to the Food and Drug Administration for an investigational new drug protocol (IND).

Stem cells have a checkered history in the United States. The FDA wants to have real data. Most stem cell data is point-of-service data — not well-studied and certainly not well-reported. And most stem cell data is anecdotal. This explains why the FDA is not too supportive of stem cell usage in general—there is very little data to support so many claims of effectiveness for treating various diseases and conditions.

Our goal is to do our stem cell research with FDA approval. To my knowledge, there is no other program that has asked for FDA approval for what I hope to accomplish. At the time of surgery, my patients will receive their own stem cells intravenous and intrapenile in an effort to see if we can improve total recovery of sexual function and shorten recovery time. This study will be a blinded crossover trial. “Blinded” means that half my patients will receive saline and half will receive the stem cells. The patients will not know whether they are receiving saline or stem cells. At six months, the patients will be un-blinded. Those who were given saline or saltwater will be crossed over and given their own stem cells at that time. The principle objective is to evaluate both the total recovery of sexual function to preoperative state and the time to recovery. As a secondary objective, we will look at the time to recovery of urinary control.

RESEARCH UPDATE: Positron emission tomography.
Positron emission tomography, or a PET scan, is advanced technology that allows us to find metastatic disease long before it is visible on a bone scan, CT scan or MRI. A PET scan can identify very small areas of concern that may allow us to carry out early salvage therapy in areas testing positive for cancer. Until recently, there were no good PET scans for prostate cancer. A new one known as Gallium-68 prostate-specific membrane antigen PET appears to be exceptionally good in evaluating and helping us manage this disease. PSMA, or prostate-specific membrane antigen, is very specific for the prostate. Gallium-68 will attach itself to any prostate-specific membrane antigens present. We have been fortunate to have obtained a PSMA PET machine with the support of the Houston Methodist Research Institute. I believe this will be the first such machine in Houston. We have protocols we are going to carry out in men who have recurrent disease as measured by post-radical prostatectomy PET scans. If they had a biochemical recurrence and we find positive areas on PET, then we will either manage this with focused radiation or surgical removal to see whether early treatment of cancerous areas will help alter the course of the disease.

We are also carrying out a study preoperatively on men who are not going to undergo surgery for their prostate. We will compare our pathologic findings with the PET scan findings, especially in those men who appear to have lymphatic disease on PET scan but not in any other modality such as MRI, etc. Our goal is to see the role that the Gallium-68 PSMA PET can have in early evaluation and management of this disease.

RESEARCH UPDATE: National trial for metastatic prostate cancer.
We have joined the Southwest Oncology Group in a large national trial evaluating men with metastatic prostate cancer who have their prostate intact. The study aims to treat the metastatic disease and then either remove the prostate, follow the patient with standard hormonal therapy or radiate the prostate. The hypothesis is cancer cells that spread to other sites in the body can only come from the primary cancer. However, there is also a theory the prostate can be repopulated by cells from nearby metastatic sites, such as lymph glands. The hypothesis is if we successfully treat the systemic disease and get a response, treating the primary will delay further metastatic disease and help prolong the life of the patient. We do not anticipate finding a cure by using this therapy. The goal is to extend life. This study will involve more than 1,000 patients nationally.

RESEARCH UPDATE: Role of Mitochondria and prostate cancer genesis.
Dr. Dale Hamilton, his laboratory colleagues and I are actively studying the role of mitochondria and the genesis of prostate cancer. Our belief is there are changes in electron transport within the mitochondria that lead to abnormal DNA patterns forming. A momentary change in the DNA affects how the messenger RNA reads the DNA with the distinct possibility of transcription errors leading to formation of abnormal and cancer cells. We continue to work in close collaboration with the physics and biochemistry departments at the University of Houston for this very novel way of looking at how cancer starts and how it might be managed. Transcription errors have to do with radical oxygen species (ROS), or what we know as free radicals. When I talk to my patients about their prostate cancer, so many of them are very interested immediately in what kind of diet they can go on. They are thinking of antioxidant diets that they have read so much about and wonder whether they are helpful. Our research has indicated possible dietary changes that may have a role in managing prostate cancer and its formation. As mentioned earlier, we can identify many changes that exist in prostate cancer. We hope that our mitochondrial research will shed light on how those changes take place in the first place. We continue to hope that the federal government will fund what we need for a very long clinical trial. We can do this.

RESEARCH UPDATE: Nerve-cancer interaction.
Mitochondria are part of what I refer to as a tumor cellular micro environment. For many years my colleague, Dr. Gustavo Ayala, has carried out original studies on nerve-cancer interaction. He found that increased nerve density leads to dramatic increase in cancer growth and formation. We used to believe that cancer growth was simply growing due to an increase in blood vessels, but his research has shown is not true and appears to be caused by increased nerve proliferation. This was a novel and challenging concept that has been not well-received by the scientific community until recently. However, Science Magazine, the premier magazine for scientific study, recently published an article on Dr. Ayala and his work in nerve-cancer interactions and how these interactions play an important role in how cancers start and progress. I think this article stimulated renewed research, certainly by us.

In our nerve-cancer interaction work, we found that cutting nerves or decreasing nerve supply to an area in rats that had prostate cancer growing in their flanks caused the cancer to shrink or disappear. In our next step, we wanted to do the same thing but with Botox. It had the same effect as cutting the nerves. Since a doctor can inject Botox, we are very excited this can possibly have a role in managing locally advanced disease and helping us achieve better cure rates. We plan to inject Botox into the prostate, carry out surgery six weeks later and see the impact on the disease. We hope this process will lead to trials where we inject Botox into the metastatic sites of prostate cancer. I will keep you updated on this exciting new arena!

ACADEMIC UPDATE: Our research led to lectures and visiting professorships throughout the world. I have spoken at national meetings in Miami and visiting professorships in Michigan, San Francisco and other venues. I have also spoken internationally in Athens, Seoul, Paris and Milan. The lectures involve a team effort, and our research has been well-received.Canadian Medical Journal is publishing the paper we submitted about 18 months ago related to surgeons’ ages. This study showed a surgeon’s age affected outcomes. In this case, outcomes means complications or the need for rehospitalization; better outcomes means fewer complications and reduced need for rehospitalization. Surgeons over the age of 65 had better outcomes compared to those under the age of 65. There are many reasons this may be the case. Those reasons include surgeons self-limiting what they do. Older surgeons may self-select and limit the cases they do. They may choose to perform surgeries they know do very well and not do a whole array of cases. There is the possibility that our experience informs our
decisions of when to be courageous for patients.

In my opinion: Prostate cancer is a manageable disease. If you drive around Houston, you see a remarkable number of billboards purporting to wage war on cancer and easily eradicate it. At some level, this is reassuring to patients. On another level, the subliminal message is that if your cancer is not eradicated you are going to do poorly. I try to help patients understand that prostate cancer is a manageable disease, perhaps like diabetes or high blood pressure. These are diseases that can kill you. If managed appropriately, however, patients can live long and comfortable lives. Prostate cancer can be managed. Men can live with uncured disease for 25 years or more as long as we manage that disease at each point in time with the appropriate
therapy. Some of my colleagues refer to it as “kicking the can down the road.” I believe if I can keep kicking that can down the road for 25 years and keep a normal quality of life for my patients, then I have accomplished something valuable for them.

Final thought: I try to give all my patients hope. There is no such thing as false hope. Hope is valuable. A professor I once had told me that hope is free, but science needs funding! I am grateful to the many patients and friends who continue to contribute and support my research. We must prove the concepts that we hold before we can apply for large public grants from funders like the National Institutes of Health and the National Cancer Institute. Early trials are generally funded at 10% or less; this means 10% of projects applied for are what get funded. If you would like to know how you can help support my research, please contact JoAnn Grisanti with the Houston Methodist Foundation at 832.667.5839 or jmgrisanti@houstonmethodist.org. She is happy to answer any questions you may have.

In conclusion, it has been another busy and fruitful year. I will continue to publish and lecture because I really enjoy it, and I sincerely hope that I am making contributions that will matter to my patients and to my colleagues. I will continue to work with patients to advance prostate cancer awareness and to seek funds to carry out leading research to help us deal with this disease that will not go away.

Thanks again for trusting me with your health. And thanks again for continuing to support me with your presence in my office and faith in my ability to handle your health care concerns. I wish you good health, good fortune and a great 2020.
Best personal regards,

Brian J. Miles, M.D.
Centennial Chair in Urologic Oncology
Professor of Urology, Weill Cornell Medical College
Vice Chair, Department of Urology
Medical Director of Robotic Surgery
Houston Methodist Hospital