Research Update

Urologic oncology is my specialty.  I am involved in all aspects of cancers that affect the urinary system and male genital system.  My dominant focus remains prostate cancer, and I am also very involved in the robotic surgical management of kidney and bladder cancer.

You are probably aware of the significance of prostate cancer as a health issue for men in the United States.  It remains the number one cause of cancer and the number two cause of cancer deaths among men.  I know in the past there have been concerns about over-diagnosis and over-treatment of prostate cancer.  There is much discussion in the medical literature and lay press about these issues.  My own personal bias is that the discussions about over-diagnosis are not correct.  The discussions about over-treatment historically have been correct.

In order not to miss significant cancers it is important to appropriately diagnose the disease.  Once the diagnosis of prostate cancer is made, many patients can go on active surveillance.  I continue to follow a large group of such men.  Recently there was an article in the New England Journal of Medicine that was published in many of the newspapers throughout the country, including The New York Times and the Houston Chronicle.  This article showed that men with prostate cancer who had been treated either with the removal of the prostate, radiation therapy, or just active surveillance had, relatively speaking, an equal number of men alive at ten years in each group.  An interesting and well-done study.  Three-quarters of the patients were what we call very low risk, with a Gleason score of 3+3 cancer.  Men with this Gleason score and not too high a volume of cancer are excellent candidates for active surveillance.

What the newspaper articles did not share was that by five years into the study, almost half of the men on active surveillance had been treated, and over half were treated by the end of the study.  That means that the men on active surveillance did not go ten years without treatment; they were carefully followed and moved on to appropriate therapy as their disease progressed.  I just do not want people to think that you can ignore prostate cancer when diagnosed.  Appropriate follow-up is necessary.  These studies really help us know who we can follow and who and when we should treat.

As you may recall, last year we finished a Phase One trial for a specific gene injected into the prostate to cause cancer cells to die.  This gene is called the “reduced expression of immortalized cells (REIC)”.  This Phase One trial was designed to find the highest and safest dose of an agent that we could give to patients.  During the trial we found that dose but also found significant responses that gave us focus to continue.  We are now conducting a Phase Two trial and accruing patients somewhat slowly, but consistently.  At this higher dose we are seeing some responses, but it is too early to see whether the earlier Phase One trial results will expand and be clinically significant.  Hopefully this one is a winner.  As you know, many of the other trials that I have been involved with for sixteen years now had early good results, but not durable results.

I continue to be involved in stem cell research.  Stem cells are unique, interesting cells that are capable of becoming any other cell in the body.  They are important in the healing process from injury of any kind, because they are capable of self-renewal and have the ability to repair or replace other cell types.

One of my research objectives is to see if we can help men regain their potency and urinary control in a shorter period of time after robotic prostatectomy.  A significant number of men are rendered impotent by the procedure, and a smaller number also continue to have urinary issues.  When removing the prostate we bruise the nerves that help with potency and, to some degree, may do the same thing to those nerves that help with urinary control.  Nerve injury causes a relatively sudden and significant decrease in muscle cell size and overall health.  For example, someone who is wheelchair bound due to paraplegia will have very thin legs.   This is not due to inactivity, it is due to lack of nerve stimulation.  The same thing can happen for erections and urinary control.

My plan is to use stem cells from a patient’s own body.  These stem cells will be obtained from fat or adipose tissue, cultured and expanded so that we can inject millions into the penis and into the control valve to see if we can quickly help the injured cells recover and prevent impotence and incontinence.

I am required by the Food and Drug Administration (FDA) first to do laboratory studies on animal models (rats) to prove the safety of this approach.  The data that I have reviewed would suggest that stem cells are very safe, but there is always the undercurrent of concern that stem cells may provoke cancer growth or recurrence.  Again, I doubt this, but I must prove safety and some efficacy with their use.  Therefore, I am working with a colleague in his lab to test our theories in three different groups of rats.  There will be a group that is the control group, and there will be two groups where the nerves that give erections will be crushed to simulate surgical injury.  Of those two groups, one will receive stem cells into the penis and the other will receive stem cells into the penis and intravenously through the tail vein.  My hypothesis is that the combination of intravenous and in the penis will be better.

In order to prove that the cancer does not grow in the face of stem cells, we will carry out what is called an in vitro study.  That is, we will grow cancer cells in a Petri dish.  The cancer cells will be exposed to different concentrations of stem cells to see whether they enhance cancer growth, or as I believe, negatively impact the growth of cancer.  I am very excited to finally get a trial going with this.  If proof of concept is positive in these animals, I will then be able to quickly start a human trial this coming year.  This is an expensive trial, but I have been able to squirrel away research dollars that I will use to implement the rat studies. Housing for these animals and caring for them, as well as carrying out the stem cell studies, remains expensive.  I must continue to seek support for these studies as well as the human trials.

Our study of urinary metabolomics to find easier ways to diagnose prostate cancer has come to a conclusion as far as data collection goes.  We have had over 150 patients enrolled.  Metabolomic studies involve finding byproducts of human metabolism in urine to detect various illnesses and disorders.  We have identified a panel of ten possible metabolites in men with prostate cancer.  We are hopeful that these may assist us in diagnosing prostate cancer without biopsy.  This was carried out with my colleagues at the Baylor College of Medicine. I am obtaining the data and will work through these metabolites using my patient data base to see if one or more are very promising.  Since they were all my patients, I have the data that will allow us to see whether or not we can predict cancer.  The patient population came from those who were going to undergo biopsies and those with benign prostate issues.   The people who collected the metabolites and identified them are completely “blinded” as to who ended up having cancer and who did not.  Again, there will be more information to follow when I work through this.

My work with my close colleague, Dr. Gustavo Ayala in the University of Texas Medical School Department of Pathology, continues to grow.  We have different ways of predicting which men with prostate cancer and on active surveillance might progress and now need treatment.  There are lots of genetic tests out there now which cost thousands of dollars to help predict who might be good candidates for active surveillance, who might avoid repeat biopsy, etc.  I do not find them very helpful, although I do order them if patients want them.  I have not found that they really add more than my own clinical judgment and experience.

Last year I discussed stromagenic cancers.  Again, prostate cancer is a glandular cancer, but all glands have a large fibromuscular component called stroma.  You can think of this as a skeletal system upon which glands that produce seminal fluid sit.  In many cancers, you will see an interaction between the stroma and the cancer of the gland itself.  They synergistically seem to enhance growth of the primary cancer within the gland.  We believe that this is occurring in prostate cancer, too.  You do not see it that often, but in low-grade tumors you can see what we call a stromagenic carcinoma component.  A patient with this should not go on active surveillance even if the Gleason score is 3+3 or low-volume 3+4.  These cancers are bad actors and the presence of a stroma carcinogenic component predicts a higher risk of death from the disease, even those that appear to be nonaggressive.  Happily, these changes can be found on standard biopsy slides if the pathologist just looks for it.  It requires a particular stain technique that Dr. Ayala has developed.  We recently presented updated validation studies on patients for many academic standards across the country (well over a thousand patients) at the International Society of Urology.  Our work won Best Poster and was excitedly received.

We also remain involved in studying the role of nerves in cancer.  We have discovered over the years that an absolute increase in the small nerves that go into the prostate is important in the growth and aggressiveness of cancers.  The nerves/cancer interaction allows both of these to synergistically proliferate.  The neurogenic basis of carcinogenesis appears to be very real.  Invasion of the small nerves within the prostate by cancer should always be looked for by the pathologist.  It also should be measured for size insofar as the diameter of invasion is very predictive of progressiveness and pathologic stage. Patients with perineural invasion tend to fail, and this has been validated by studies by the University of Michigan and in a number of centers in Europe.  So when I see perineural invasion, even in low-grade tumors, I recommend treatment. When I see nerve invasion, it also allows me to refine the operation that I perform and prepares the patient for a potential partial or significant resection of some of the main neurovascular bundles.  It is an exciting surgical approach concept and one that you will see more about in the future.

Academic Endeavors

My primary focus has been and continues to be in prostate cancer and men’s health issues.  This year I was asked to write three book chapters and submitted a number of publications, all of which have been accepted.  These requests are an important validation of my work.  In addition, it has been a busy year of international travel for academic purposes—lectures, advisory boards, and invited professorships took me to Viet Nam, the Netherlands, Mexico, Costa Rica and Argentina.

I would like to share with you some special news about what my colleagues and I are doing in the way of education.

Advances in Patient Care

This year I received generous support from The Hamill Foundation to create the first true Men’s Health Center in Texas.  My goal is to improve health care delivery for men using urologic issues such as hypogonadism (low T), erectile dysfunction and prostate issues as a portal of entry for better health care for men.  You see, all these issues often go hand in hand with diabetes, obesity and the metabolic syndrome.  Many studies will be written to help us understand health issues for the aging male and the best way to approach health care delivery for this ever expanding segment of our population.

I was able to obtain the technology called HIFU, or high intensity focused ultrasonography, earlier this year.  This technology creates heat within the prostate by focusing the high ultrasound waves tightly, much like using a magnifying glass to focus the sun’s rays on a piece of paper and setting it on fire.  It is really very effective and will have a significant role to play in the management of prostate cancer.  I am presently writing a protocol to use HIFU as focal therapy–only treating the area where the cancer exists and not necessarily the whole gland.

I remain actively involved in observational studies of residents, fellows, and staff surgeons to understand how learning takes place and how one moves from a novice to an expert.  We are trying to develop simulators whereby we can reproduce and deconstruct essential elements of robotic surgical procedures.  In order to teach robotics, we prefer that surgeons get their skill-set to a higher level before touching patients.  If we can create great simulators, then we can help these individuals perform to a high level without ever putting a patient at risk.

Hopefully this newsletter finds you in good health.  It is always a pleasure and privilege for me to be involved in your health care.  I wish you and your family a very happy holiday season and hope nothing but good visits you in the months and years to come.  I look forward to seeing you once again in the clinic.

Warmest regards,

Brian J. Miles, M.D.

Professor of Urology, Weill Cornell Medical College

Medical Director of Robotic Surgery