Tag Archives: medicine

A perfect death


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This week in which the country will come together to mourn the passing of a true American original, John McCain, it might be worth considering our (your) own mortality. Even as the ongoing progress toward controlling prostate cancer is underway, it remains clear that “something else” will get us. As an example, in a study I was privileged to lead among patients with high risk prostate cancer, other cancers (many of which were caused by our adjuvant mitoxantrone treatment) were as likely to lead to death and prostate cancer was the cause of dying only ~20% of the time

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As oncologists, we face the “end of life” issues more frequently than most physicians, and certainly deal with the reality of death more than folks in most other professions. I distinctly remember one lovely woman in her 50’s who was very open in discussing her wishes. She wanted to die while lying on her favorite beach in Florida watching the sunlight sparkling on the ocean – not an easy thing to arrange (and it didn’t happen). My own fantasy would be to have a lovely vacation in Hawaii (without this week’s rain) with my entire family, say my good-byes as I put them all on the plane, and stay over an extra day to pay for the hotel and be sure all of my financial affairs were up to date – then die of a heart attack on the way home the next day. Perfect. The airline would be carrying my carcass home for the mere cost of a coach seat and I wouldn’t even have to suffer that long in the crunched position with no leg room.

Short of these fantasies, however, I recently undertook an exercise that anyone could do and I herewith commend to you as well. My wife and I were lucky enough to score tickets to the London production of Hamilton last February. In it, there were two numbers that grabbed me by the heart. First was Washington’s “teach ’em how to say goodbye” song, “One Last Time”. As with John McCain’s final commentaries over the past few months, Hamilton’s farewell speech written for Washington was masterful (as is Lin-Manuel Miranda’s reprise).

But the song that most moved me to tears (and action) was “Who Lives, Who Dies, Who Tells Your Story”. After listening to it about a dozen times, I realized that we all have a story. It may not be as honest/noble as John McCain’s, or as consequential as Hamilton’s or Washington’s, but for some small group of your relatives or children or grandchildren, your story will have special meaning. If you don’t write it, your memories of your father, your grandfather, your family in general will die with you. In my case, I read a couple of autobiographies, self-published, from friends/acquaintances and decided that their stories were highly personal, and not terribly interesting. But when I started writing the story of my own grandfather and father, and my story, it was a joyful experience of reliving many happy memories, and a way of reconnecting with my first love affair, our children’s births, and the many blessings that have come my way. The result is not a literary masterpiece, but I am going to have it bound and give a copy to each of my kids to gather dust on their bookshelves.

In the arc of history, some things have not changed. “Our days may come to seventy years, or eighty, if our strength endures; yet the best of them are but trouble and sorrow, for they quickly pass, and we fly away.” (Psalm 90:10). Although trouble and sorrow are a part of life (and of dying), there can be real joy in pausing to appreciate all life has given you. Carpe diem!

 

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Filed under General Prostate Cancer Issues, Prostate cancer therapy

The Hits Just Keep on Coming


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I have a hiking companion who loves math, computers, and to a large extent, eugenics. He posits that we will eventually understand the human genome so well that we will be able to make all humans “smart” or “better” through genetic engineering. I argue back endlessly, with little success, that his definition of “smart” and “better” may not be shared  by everyone (he counters that these definitions will be left to the parents…) and that there will be unintended consequences of diving into our DNA with CRISPR/Cas9 technology.

The wonderful complexity of humankind is, of course, reflected in every single cell in our bodies and in all of our cancer cells as well. The debate over the number of synapses (or permutations) in our brains versus atoms (or stars etc.) in the observable universe is well beyond my comprehension. Unfortunately the “much simpler” question of how many things go wrong in cancer cells is also mind boggling. Hence, the phenomenal work of one of the West Coast Dream Team’s recent publications is not surprising. A reductionist view is shown in this diagram from their paper published last month:

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The scientific team, using funds from PCF, SU2C, and Movember (among others), did a whole genome analysis of metastatic tumor specimens from 101 men with castration resistant (hormone insensitive) prostate cancer. There is an excellent report on this work from the UCSF News Center here. Lest you believe that the results have resulted in an “aha moment” that will lead to “A prostate cancer cure”, you might do as I had to do and Google the word I had not heard of in the above figure, “chromothripsis“. Rather, the research leads to some very important insights that will doubtless contribute towards more effective therapy for 1000’s of patients eventually. By looking at the structural variants in the DNA that occurs outside of expressed genes, a much more complex picture of what drives castration resistant prostate cancer (CRPC) becomes evident. For example the androgen receptor (AR) is over-expressed in the majority of metastases and this study found a region of the “junk DNA” (non-coding for genes) that lies 66.94 million base pairs upstream of the AR that was amplified in 81% of the cases. This was 11% more common than the amplification of AR itself – an indication of how important the DNA controlling a gene like AR is, compared to the gene itself. So much for calling the DNA that doesn’t code for a protein “junk”!

A second example is the insight into patients who have alterations in a gene called CDK12 that may render them more sensitive to one of the “hottest” areas of cancer research, the use of checkpoint inhibitors of the PD-1 pathway I described in my last post.  This abnormality results in the cancer cells having an increased number of “neoantigens” (targets) for the immune system to attack as shown in this illustration from another recent exceptional paper.

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The ongoing research from the many scientific teams focused on prostate cancer is awe-inspiring when you consider the complexities involved in the two figures in this post alone. Even getting a complete picture from a single patient is impossible, given the genetic instability and the variable mutations found in different metastases. Remember, this team looked at the DNA from only one (or a few) of the many metastatic sites found in each patient. Other studies have shown lots of different mutations depending on which site is evaluated as I reviewed here.  In spite of all of this complexity, the ability to at least begin to understand what is going on “underneath the hood” is the way forward, and just as we can recognize Fords vs Chevys vs Toyotas, “brands” that emerge from such studies will lead to treatments that are more appropriate for certain classes of patients. As we have known for a very long time, the most common feature is the “gasoline” of testosterone, and how it fuels the amplified AR has remained an effective target for the newer drugs like abiraterone, enzalutamide, and apalutamide. Perhaps studies such as this one will lead to a way of kinking the hose upstream of the gasoline nozzle, or throwing sand (immunotherapy) into the engine itself. But… to admit that we will never understand it all (or design the “perfect human”) still seems an appropriate expression of humility to me.

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Filed under General Prostate Cancer Issues

Of Prostates and Teslas


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If you thought this might be an article about how your urologist shops for his/her newest fancy car, you are mistaken (sadly…). Nikola Tesla was a fascinating inventor and ultimately “mad scientist” at the turn of the last century. Every time you plug your cuisinart into the wall to chop something up, you are the beneficiary of his contributions to the alternating current coming to your kitchen and the motor driving the chopper. My favorite story (because of the local connection) was his laboratory in Colorado Springs, where he attempted to develop a method of transmitting power without wires. By creating YUUUGE electromagnetic fields, he could make lots of electrical things happen at considerable distances, including knocking out the power station for the city. Here’s a quote from the Wikipedia article:

He produced artificial lightning, with discharges consisting of millions of volts and up to 135 feet (41 m) long.[11] Thunder from the released energy was heard 15 miles (24 km) away in Cripple Creek, Colorado. People walking along the street observed sparks jumping between their feet and the ground. Sparks sprang from water line taps when touched. Light bulbs within 100 feet (30 m) of the lab glowed even when turned off. Horses in a livery stable bolted from their stalls after receiving shocks through their metal shoes. Butterflies were electrified, swirling in circles with blue halos of St. Elmo’s fire around their wings.[12]

Of course, for purposes of this blog, the key thing is that the strength of magnetic fields was named after him. When you get an MRI of your prostate, brain, or anything else, you are put into a machine with a superconducting magnet that produces 1.5 or 3 “T” of strength. At the risk of being completely wrong and oversimplifying, what happens in the MRI machine is that a strong magnetic field temporarily lines up the hydrogen atoms in the water that is 70% of “you”, and when these atoms “relax” they give off radio signals that can be converted to images. Details and images are here. Early on, my colleagues and I were fascinated by the possibility of using MR to investigate the prostate gland and published an article (completely ignored – cited only 3 times, so must not have been that important…) showing changes in MR that occurred after testosterone administration to castrated rats.

Now there are complex MRI protocols to image the prostate using techniques I don’t fully understand (multiparametric imaging) that give us remarkable pictures of the prostate gland. Here is one:

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Prostate gland with red arrow indicating a suspicious lesion that could be biopsied or followed closely.

As with any radiologic imaging technique, the skill of the radiologist as well as the equipment being used determine the accuracy of the MRI to diagnose a cancer.

While most of us learned how to “read X-rays” in medical school, it is beyond most clinicians to read MRI’s of the prostate. Fortunately, the radiologists have developed a system that helps us think about “how abnormal” some area of the gland is, called PI-RADS.  This can be very useful in thinking about what area to concentrate on when biopsying a patient, or in trying to determine whether surgery or radiation therapy should be altered if there is concern that the cancer is outside of the gland. An interesting question that is still controversial is whether the MRI could replace repetitive biopsies in a man who has chosen active surveillance. Particularly when combined with molecular techniques (see my previous blog here) to characterize biopsies, it may be that Tesla will be helping to do more than get you from one place to another or run your electric shaver. (Rock on, Elon Musk) To me, that is a pretty interesting outcome from knocking out all of the lights in Colorado Springs!

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Filed under General Prostate Cancer Issues, Prostate cancer therapy, Targeted treatment

The billionaire cancer researcher


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Several patients/friends told me this week about the 60 Minutes piece highlighting the ongoing efforts of Patrick Soon-Shiong, a surgeon who was involved in the development of abraxane and has become worth $11B as a result. So I did my duty and watched on the Internet tonight and will share my thoughts with you loyal followers. Let it first be said that the optimism in this video is compelling, and for the most part based on science that has been going on for the past decade or so in labs all over the country. The 60 Minutes team working with Dr. Soon-Shiong highlighted in a visually compelling, and mostly understandable way, the progress that is being made using the latest technology and understanding of cancer biology. I will highlight this as follows: 1) massive computer technology and sequencing advances allow “all” of the mutations that characterize a cancer cell to be displayed. 2) Drug development to attack vulnerable biologic pathways within cancer cells is accelerating. 3) The possibility of finding the gene mutations driving these cells by looking at circulating tumor cells portends a [mostly] promising way of sampling what is going on within a patient, yet not having to biopsy the tumors. 4) The recent breakthroughs in enhancing immune responses to tumors by shutting down the innate immune checkpoint controls appears to offer great promise for “wiping out” residual/resistant tumor cells.

With that summary, let me urge anyone who watches/watched the video to pay close attention to my good friend, Derek Raghavan’s commentary. Derek is one of the most insightful and honest translational medical scientists I know. In essence, he points out that although Dr Soon-Shhiong is applying an “all of the above” approach to the attack on cancer, there will still be enormous amounts of work to be done and thereby hints at the problem I have  with the video – overselling hype/hope is a specialty of the media. Presenting the single patient with pancreatic cancer who is doing well is an example of this focus on the “sizzle and not the steak” approach. I take nothing away from what a billion dollars can do to pull the existing technologies together and applaud Dr. Soon-Shiong’s efforts. As a matter of fact, one of the techniques he touches on, using low continuous doses of chemotherapy, is something we may have been the first to try in prostate cancer several years ago and published here.

So what are the cautionary issues? 1) The sheer number of mutations found in most cancers (and perhaps especially prostate cancer where the term “shredding of the genome” has been used, make attacking ALL of the pathways at once nearly impossible.  If even one cell can further mutate in the face of having, say 6 or 7 drugs being given to shut down the mutations, it will survive to become the dominant and lethal metastatic problem. This is layered onto the challenge of using “all 6 drugs” together, which will more than likely compound the toxicities to the host when compared to using one of them at the optimal dose. 2) Tumor heterogeneity. In an incredible tour-de-force, a team of scientists at the Cancer Research UK London Research Institute  did whole genome analysis of the original kidney cancer in four patients as well as in their metastases. The graphic of how the research was done is shown here:

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Each spot in the original tumor as well as each metastasis had a somewhat unique set of mutations. Thus “personalized medicine”, the favorite buzzword of the moment in medicine, has a huge challenge in cancer, since there might be different combinations of drugs required for each metastatic site in some patients. The same might apply even for the evaluation of individual circulating tumor cells of course, which is now possible. A cell coming into the research syringe at one time might reflect a tumor deposit in one area, while the next cell isolated could be coming from somewhere else. 3) The excitement over using the most clever of the immune approaches, including the checkpoint inhibitors and the CART cell approach have significant challenges, either because of unleashing autoimmunity, or the very high costs of manipulating each individual patient’s T-cells in order to come up with the autologous cancer-fighting cell treatment.

So, here’s to the optimism and billionaire strategies, and we all hope it moves forward quickly and successfully. And here’s to 60 Minutes for highlighting the amazing biology and progress that is being made. Hope is one of the keystones of human progress, whether it is landing on Mars or repairing a broken relationship. Love and hope are what make life worth living. May your holiday celebrations be filled with both!

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Is medicine a profession or a business?


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I have been thinking about writing a blog like this for some time. So first let me make some disclosures: ONE: I am generally a “liberal” and would favor a single payor health care system. TWO: I grew up in a small town in Nebraska where the local doctors were beloved, cared for the families in our town, and drove Buicks (BMWs, Teslas, Lexi, etc. were unknown – the two bankers drove Cadillacs) THREE: Medicine was much less complex, much cheaper, and much less effective. FOUR: I have had a wonderful career in academics where I received a paycheck from the State of Colorado and was usually required to earn >90% of my salary through grants or clinical earnings – I could talk more about “tenure” if anyone is interested. Academic salaries are generally less than private practice, but the advantages of no/minimal night call and working with residents and students and exploring new treatments in the lab and clinic are great rewards that can’t be measured in dollar terms.

With that out of the way, I remain saddened by what has happened to my profession. For all kinds of reasons, many physicians now consider themselves as much “small businessmen” as they do physicians. As the business of medicine has become more and more complex, they provide jobs for increasing numbers of staff, pay higher malpractice premiums than they used to, and look for ways increase their incomes. But few if any are missing any meals, and many are privileged to be in the top 1% of wage earners. Nothing wrong with that.

BUT… This week’s New England Journal article exposes a very disturbing issue that I happen to know a lot about. Some urologists, who only a decade ago were constantly arguing with their radiation therapy counterparts on how much better surgery is for treating prostate cancer, have been buying radiation therapy equipment and hiring “their own” radiation oncologist to run the equipment, then self-referring. The reason is obvious and it has nothing to do with what is best for patients. It is to increase their already very substantial incomes, which (to be fair) have been decreased somewhat by lesser reimbursement for surgery, less for giving lupron, and no doubt other cuts. The outcome of radiation and surgery treatment in terms of cure is the same. The side effects are somewhat different and deserving of discussion with each man who chooses treatment. The figure shows the magnitude of this trend.

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There are many examples of similar trends when doctors stand to make money by ordering tests, buying their own equipment, setting up their own “surgicenters”, or in my own subspecialty, giving one chemotherapy that has a higher reimbursement than another that is equally efficacious. Other articles have dealt with how hospitals maximize their profits with the “chargemaster”. And still others have dealt with the practice of pharmaceutical companies charging huge amounts for novel drugs – expensive to develop for sure, but also hugely profitable.

So the answer to my question seems to be that medicine is both a profession and a business. My view is that the patient should always come first, not the pursuit of profit. Thus there is a built-in conflict if the goal of business is to make as much money as possible. Herein lies the challenge for our health care system. I don’t have any idea if the ACA will help, but I do know that the current system is in dire need of reform, and that the entering medical students who say they want to be doctors “because they love science and love people” will have a long ways to go in realizing that dream if there aren’t changes.

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October 27, 2013 · 5:29 pm

Something fishy with fish oil?


Several patients have commented/questioned recent news blurbs about fish oil causing prostate cancer. The article from which news sources developed  alarming headlines comes from the SELECT trial investigators. In that trial, 35,000 men over age 50-55, with PSA <4.0, and normal DRE were randomized to receive vitamin E, Selenium, both, or placebo. The results, in spite of earlier evidence for protection, did not find any protective value in the supplements.

That fact in itself should be a cautionary note in considering what supplements do and don’t do. I, myself, took selenium for a number of years based on what I thought was pretty good evidence that it might prevent prostate cancer. In the study I was relying on, patients with a history of skin cancer took selenium to see if they could prevent further skin cancers from developing. A secondary endpoint in the trial was the evaluation of other cancers, and sure enough, there was “statistically significant” less prostate cancer in men who took selenium compared to placebo. That gave rise to the proper, prospective SELECT trial which was negative. However in the article, a secondary endpoint, the rate of prostate cancer as related to long chain omega 3 fatty acid levels in serum, was evaluated. The conclusion was as follows:

“This study confirms previous reports of increased prostate cancer risk among men with high blood concentrations of LCω-3PUFA.”

Now we have the fish oil story. How can you evaluate trials like this that hit the news all the time? First, you might ask yourself how many patients were in the trial. For example, I blogged about Pomi-T earlier this summer. You can look at that blog and find that it was a very small study AND that there might have been a commercial bent to it’s analysis and presentation. I hope my blog was sufficiently cautionary – although I have suggested a few patients might try it if they want, after reading the blog. The SELECT trial passes muster with a large number of patients.

Second, it can be worthwhile to look at other articles on the same subject. My favorite way to do this is via Google Scholar. Open Google and look at “other” in the pulldown menu and you will find it – you can bookmark that or go there via this link and save the bookmark. Enter “fish oil prostate cancer” and you will find a large number of previous trials to go through. Add the word “meta” and you can find some additional articles, like this one. The conclusion seems at odds with the fish oil hype of the media last month:

“Our analyses provide no strong evidence of a protective association of fish consumption with prostate cancer incidence but showed a significant 63% reduction in prostate cancer–specific mortality.”

So my bottom line is that if you simply read the headlines, you are often misled. The real story seems more complex. I continue to recommend reducing fat intake in patients who have metastatic prostate cancer and are watching their psa. I have previously blogged on this topic here. And as for the fish oil story, maybe it could help your heart, (see this reference for the controversies there…obtained by entering “fish oil cardiac meta” at Google Scholar – then restricting to articles since 2012) but I’d say the jury is still out as regards prostate cancer. And whatever YOU decide, be aware of the media’s tendency to hype the latest finding and tell a simplified story.

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