CURING CANCER

It’s far more important to know what person the disease has than what disease the person has.  – Hippocrates 

Let me pull the thread that ties this bag of goodies together and unveil something that intuitively we all know to be true, yet we suspend disbelief and merge our dreams with our reality.

The bag as I call it is filled with loud and wondrous achievements and purports to advance the science of man and his life to greater heights through medical advancements.

You might have heard about the ongoing revolutionary breakthroughs touted in various journals and newspaper claims; human genomics, microbiome and of course targetable therapies and personalized medicine. Each of these headliners have the nectar to entice even the most discerning eye into the lull of vacant imaginary breezes.

But with an eye to reality all the “breaking news” and the “breakthrough” events that unfold daily on the television and internet scene are within the margin of error. Margin of error? you ask? Well there is no more breakthrough in medical science that falls in the outlier status, so to speak. There are small steps either side of the regression line within the safety of 1 or 2 sigma deviations. For sure, there are incremental pieces of information that advance thought a bit, but that is all. That is all!

Let me take the issue of the genomic revolution. Once proclaimed to bring cure all, for all diseases after the Human Genomic Project completed analyzing the DNA of the human genomic structure. Yet with time this revolutionary knowledge has given way to a certain but deeper and subdued understanding of the lack of knowledge that exists in our true knowledge sphere. Where once we thought that 100,000 genes existed and that one gene equated to one disease and that snuffing the bad protein/gene would eliminate the disease, such as cancer has now revealed a much more complex organizational network of messaging within the nucleus of the cell.

We have found more than 4,500 associations between genes and diseases but with varying degrees of success in harnessing the implied benefit. "Association," as any epidemiologist worth his salt would say, "is not causation." And if you were to swim deeper in these waters you might find that 75% of the medicines in use in oncology are "ineffective" based on a single study that the FDA took notice from. Bias aside, there is a some notional value in this exposition.  (http://www.fda.gov/downloads/ScienceResearch/SpecialTopics/PersonalizedMedicine/UCM372421.pdf. )

Whats more, in this complex cell’s genetic environment is the presence of viral genomic material that has some influence on the workings of the 1.5 -2% of the protein coding genes! Thus snuffing out cancer by retarding one specific gene or accentuating another’s activity is akin to the a kindergartner’s understanding of mathematics. Science has similarly unearthed a series of pathways that transduce signals from the surface of the cell to its nucleus programmed information for the nucleus to divide. These pathways interact in a myriad of ways and this knowledge of shutting down pathways from anchoring the cell surface receptors, has liberated information that blocking such pathway leads in the best case scenario, to a temporary relief from the growth of the wayward cell.

On the personalized medicine front, there are many a head winds that buffet the desired effect. While we tout individualized therapy, the chorus of population medicine continues to grow. How one size fits all, ultimately equates care for an individual with cancer is hard to fathom in many respects (except if you reside in an ivory tower silo). Individualized care means having complete or near complete information about the cancer before selecting therapy that targets the levers of the disease. Our knowledge of the genomic structure remains incomplete at best. We still have a small fund of knowledge about the 800 pound gorilla called the epigenomic structure that drives and modulates individual genes. Knowing that leads one to believe that we are quite a ways away from the promised land. It is impossible to constantly listen to the buzz and not call it a symphony. It is equally impossible to limit your thoughts to a certain movable threshold and never cry eureka. And yet in our daily grind the constance of this cacophony has exacted a prejudice and that is expecting excellence from mediocrity.

Using targeted therapy has yielded some initial results that are promising, but here again we are targeting the cell surface receptors that shut down the signal transduction pathways and given the cross-talk between the intracellular pathways, permanency of cure is not guaranteed in the least.

Yes we have made headway, but we have ways to go, as mentioned. So the next time you see the terms “Breakthrough Cancer Therapy!” or “Breaking News” on the television screen and fight breathlessly to listen to the talking heads, calm down and carry on. It is mostly hype!

The most egregious example of hype comes from California where a company named Theranos was to upend the diagnostic workup of blood testing via a single drop of blood in a Direct to Consumer mechanism. The premise it turns out was hyped and now a $9 Billion book valued  company awaits criminal complaints. The future possibility of such mechanism cannot be denied, but for now the hype has traumatized 890,000 individuals with falsified test results and possible unnecessary harm through imposed faulty decision making.

This hype in spin is all consuming. The more the “scientists, agencies, journalists and experts” involved in carrying out their own personal spin, the faster the merry-go-around spins.

Progress is made in steps and not in giant leaps. Even the first step on the moon by Armstrong was made possible by a series of very small steps in physics and mathematics.

Converting cancer into a chronic disease in the next 20 years, of that I am confident but as yet not sure, of curing cancer; I am less. Cancer as we know is not one but many diseases with an underlying breakdown of the principles of functional physiology. The breakdown differs in different organs and in different individuals and therein lies the difficulty.

In the meantime, it will behoove us all to take the daily dose of breakthroughs with a grain of salt. Calm down, take a chill pill and carry on with our finite lives.

Can all cancer be cured?
Hope, as they say, springs eternal.

HOW LONG DO I HAVE...?

Imagine accidentally falling off of an abyss. One simply cannot fully understand the gravity of the situation! You might skip a beat thinking about it while sitting on a chair in your living room, if you have tons of empathy, as you try to get into the shoes that are flailing for survival.

But there he was ashen as if impaled by a spear through his heart. He sat motionless, ossified as his thoughts tumbled end over end. I could see the fine tremors on his fingers. His eyes bloodshot from the riot in his brain, the cacophony of cries, the chaotic mixture of black and white, of right and wrong, of good and bad, of fear and strength, of a past and a finite future, of children, of this and that and of time. I sat on a chair by his bedside and on the other side was his wife of a few years putting a brave face on. Her eyes too were bloodshot holding back the deluge that would be spent in the bathroom alone. Her face red from a mix of emotions; anger, frustration, denial and absolute fury at fate that would befall upon them soon. Her one love, stranded alone against all odds of his overall good health, slipping away. Her knuckles paled as she fought her emotions against reality. She held firm, mouth pursed in defiance and her body arched and angry.

“So doc, how long do I have to live?” he asked. His voice a whisper between dried words that took an effort to escape his lips with the limited force of the breath that wished not to be heard.

What do I say to him?

How do I answer that question?

Do I cite the statistics and tell him the median survival rate? Or do I simply tell him that 50% of the people with his diagnosis live less than x-months and the other 50% live longer than that? Or do I tell him the average survival rate, which was slightly lower than the median in his case? What would that do to him? And as much, what about his wife? How would she interpret her future? What about the unborn child that gave her the tiny bump in her belly? How would she interpret that answer? Do I simply state the statistics? But then he might be one of those outliers that we all live to tell about in medical conferences. He might have a certain unknown mutant gene in him that could be exploited by one or the other drugs available that could lend him more time. Do I play the nice card and say something so banal as “As long as you want to live?” Trite as it sounds, it has some truth to it too. But then the respect between us three, might be lost. Wouldn't it?

I did not realize that my hands were clenched tightly too cutting off the circulation in the capillaries turning my knuckles a shade whiter. I shifted in the chair, uncomfortable with the demands placed on me, measuring the impact of my words, his life and the gravity of the situation oozing through ever corner of that four walled room. Time seemed to stand still. The seconds creeped and still my thoughts were end over end; a state of turmoil. The ghosts in both our human machines seem to have lot to say.

“What I am about to tell you has to be understood carefully by both of you. I don't offer false hopes. I cannot offer the permanency of a cure, but what I am suggesting are the facts as they exist today. These facts might change over the course of your illness and propel us to a better future tomorrow, but today, I can offer you only these facts.”

He relaxed as I drew some graphs of survival data. I showed him the slightly fat tail in the graph where the outliers lived. I explained to both that therapy in its current form could offer him some relief but the limits were imposed upon the data by arbitrary numbers based on 95% Confidence Intervals and assumptions (as all statistical probabilities are). As our conversation proceeded, he relaxed, his eyes shed some isolated tears, the color on his face returned. I do not know how the subject of Stephen Jay Gould came up but I found myself quoting him, “All evolutionary biologists know that variation itself is nature’s only irreducible essence…I had to place myself amidst the variation.” The evolutionary biologist, I told him was given six months to live and after research he realized that the outliers could live well past 10 years with the disease that he had. He did! There was hope for time. More color filtered back into his face and as confidence built, a partial smile broke out, I said, “Do some of of your own research and run that by me. I will help you along.” 

The next day, I walked by his room and found that he had been discharged from the hospital. I cared for him after that hospital day for a fairly long time. He defied the odds against him. He fought the battle and won his outlier status. He saw the birth of his child and a few birthdays to boot. He created a company that employed ten employees and was lucrative in the first few months. Ah life the eternal source of human innovation was in full bloom. He lived life well or that finite time he was allotted.

Hope fights despair. It encourages choices, it readies us for the necessary toil. Hope is the first step on an uphill climb. How can we in good conscience empty that priceless ether of goodwill from a living being. What a person can do with a finite amount of time can change the world.

So how does one answer the question, “How long do I have?” It depends on the individual asking the question and the physician answering it. There must never be barriers between the two. Eye to eye contact and a controlled tincture of empathy. There should never be the burden on either during the conversation. No impediments to confiscate that precious time between a patient and his/her physician in discussions of such weighty matter. None!

DECISION MAKING SKILLS

Consider this logic; “I think therefore I am.” Rene Descartes was the father of those words and yet everything we do seems to come from those words. Our thoughts become actions and then those become habits and they eventually develop our character.

So let us look at it in matters of aviation safety. Two pilots from the same household develop differing characteristics of behavior. One is judicious in thought and action, careful in planning and argues within himself all observable points of view with an eye towards flexibility due to changing environments, thus creating various scenarios and plans of action. The other pilot is laissez faire. He gets up, looks out the window at the sun peaking though the clouds ands heads to the airport. He is our “kick the tire and light the fire, barnstormer.”

The logic of decision making is based on information primarily. Asymmetry of information is the main reason for our first pilot to have deliberation over multiple plans of action. He deals with the Boolean logic of “If this then that.” The barnstormer cares a wit about information per se. He believes he is the epitome of an aviator and the sky is his oyster. So to each, thought is his own way.

Both the pilots are borne of the discovery and justification process. The discovery of biases and the justification to do things. The careful pilot has turned information into knowledge and understanding, while the barnstormer is, shall we say more about his own fully developed sense of “greatness,” then any sense of reality. 

While the former takes in all the available bits of data and compiles them into a cohesive sense of the environment, both past and future, the latter has built within himself the fire-walls of confidence rich in confirmatory bias. 

Ah I am glad you asked about confirmatory bias. Basically if you do something repetitively and it works, you consider that as a successful and repeatable enterprise. Not withstanding Taleb’s “Black Swan” effect the barnstormer can go on for a finite period of time with that bias lingering within him, until one day the ailerons fly off the hinges. An example would be a pilot who scud runs. As he continues to press on while the cloud ceiling lowers the boom and confirmatory bias continues to ride the wave, until one day the pilot mangles himself on a cell tower or becomes a statistic of a CFIT (obscured mountain). That happens quite a few times a year unfortunately. Justification of actions are a human mechanism steeped in hubris and confirmed through the passage of time by similar acts of carelessness. Its like the teenager who after watching a video of an expert skateboarding champion decides he can go down the rails on flat concrete surface, only to break some young bones in the process, trying to up the ante down a steep staircase.

On the other hand the careful pilot looks at the weather briefing diligently, has acquired the instrument rating, is always instrument proficient and even then takes into consideration the weaknesses of his own skills with “what if scenarios.”

How do we make decisions?

Carefully with as many pieces of information as are available!

Daniel Kahnemann a Nobel laureate has grafted the idea that we have two internal systems in our brain that are employed in the decision making process. System 1 is a knee-jerk type, quick on the pedal to the metal with little reverence to the conditions of the equipment or the surroundings. System 2 is a more careful, slow, methodical and judiciously employed consideration of all available pieces of information that go on to making a decision.

While System 1 is more of the emergent nature that triggers the frontal lobe of the brain into quick-firing of electrical stimuli, System 2 is the careful process that takes into account from the temporal, visual, auditory and parietal lobes of the brain before committing the fire from the frontal lobe. So in essence with deliberate care.

Which is correct?

If you have to ask that question as a pilot then, I suggest, you take some classes to govern your impulsive, hazardous attitude.

The old story about that, “there are no old, bold pilots!” is a truism. There are only the methodical careful ones that define the risks, mitigate as many known hazards as possible and only then undertake an action.

Conquering space did not happen because someone decided to tie a rocket on their back and lit the fuse. It happened because of hundreds of scientists, mathematicians, astronomers, physicists and a few brave astronauts took on the arduous task of understanding space.

Pilots are not all pioneers in space. Most of us are just pilots. There are a few aviators amongst us, not mere technicians in flight but who understand each motion as they are strapped into the seats of an aircraft flying at many hundreds of miles per hour across space.

Understanding natural science and the design of science that is created to embark through that nature is as important as knowing when to apply the force on the rudder to prevent a slip and when to create a slip in flight.

Decisions are made on a daily basis in life. We decide to buy, to sell, to go to movies, to read a book, to cook a meal, to wash clothes. All these decisions have a precedent of understanding and need. Similarly flying has a precedent and need. The need however must be met with an equal tincture of understanding of the surrounding space and its vagaries.

All flights are possibilities and as they proceed in space and time, they become probabilities and then are added to the ledger of understanding based on the information gleaned from those flights. These flights then become the justification for future ones. It is equally easy to fall into the trap of hubris as it is into the comforts of a carefully crafted methodology. Therefore it is important to learn about good habits from others and discern about bad habits. Accident cases abound in the aviation literature, most (70%+) point against the pilot actions as the causality of aircraft accidents. One would even consider the number higher. But then I digress.

How not to fall into the System 1, knee-jerk, barnstorming trap?


Develop good habits
Employ careful and methodical Instructors to give instructions.
Create a log of all flights outside than those in the logbook, detailing each flight and errors.
Critique every flight and what was learnt from each.
Point out to other’s bad habits (you might save their lives one day).
Rash car drivers make bad pilots.
Egocentric machoism is dangerous to a pilot’s health.
Keep learning. Get all that aviation certification has to offer. Get the Instrument rating if you are a private pilot, a commercial ticket and all the way to the Airline Transport rating. Then consider sea pilot rating, Soaring, Upset training, etc.. All these fill your bag of tricks when one day, you might need them.
Always emulate good behavior.
Do not drink and fly (Consider more than 8 hours from bottle to throttle, because you as pilot might be a slow metabolizer of alcohol).
Consider the FAA’s IMSAFE (Illness, Medication, Stress, Alcohol, Fatigue and Eating) before each flight.

HELICOPTER POLICIES

Ever heard of “Helicopter Money?” No? Ok the skinny on this is the TARP and then the QEs. TARP stands for Troubled Asset Relief Program and QE (I,II,III, IV) all denote Quantitative Easing or in other words Printing Money to devalue it. (Total TARP + QEs since 2009 = $4.5 Trillion (4 followed by 12 zeros). These monetary mechanisms are designed to bring Liquidity to an illiquid market. Liquidity is implied as a means for the banks to have the money to loan to people and companies to make the business cycle function. Oh but a tiny bit of wrinkle sets in when the QEs start flying…the banks use the free money (since the interest rates were/are down to ZERO or 0%) to shore up their own balance sheets so they can survive a “Run on the bank” in case the plebeians decide to withdraw their savings, which have been leveraged to gain big gains for the banks in risky derivative markets (enter Lehman Brothers with $600 Billion assets declaring bankruptcy in September 2008) The net result of all these machinations at the Federal Reserve to prevent “pain and suffering” to other financial institutions and to the gentry was to blow up the balloon to its popping point from it’s sub-sub popping point. You see, currently, given these ballooning opportunities, the more the experts in Davos delay the inevitable of paying the piper, the more they postpone from what could have been a sustainable downturn with pain into a collapse the likes never seen. No, not even the 1929 depression will match this one.

On equal footing is the top-down machination of the healthcare policy makers headed by some geniuses who have begun helicoptering mandates akin to the QEs. The QEs in Medicine are no different. They have used a single point of reference (Costs) as their ends and used their personal genius means (like Mr. Gruber) to come up with a complex series of unintelligible verbiage to confuse and obfuscate the basic reasoning beneath; reduce cost at whatever the cost (notwithstanding patient’s real care). The demographics are changing as aging population in the US continues to grow. Controlling costs via simple-mindedness fails to realize the issues of tomorrow.

How do these mandates and policies effect medicine. Well, they are no different than the monetary QEs. They bloat the policy ledger creating a widespread net of regulatory reasonings to entrap an individual - patient and physician. Acronyms abound; PCORI, SGR, APM, MACRA, PQRS, etc. that have little do with the health of any individual but more to do with the flawed reasonings of a few. Let me throw in for gratuitous reasons the good ol' 5-6 PhD Quants of the 1998 who nearly took down the world economy with their asymmetric exploitation shenanigans. These same Quant incarnations are working hard with their statistical models in medicine today. Just Saying!

The reasonings fit perfectly well from the middling manager’s point of view since they reward larger and larger benefits to the intermediation between the two parties involved in healthcare (patient and physician). If you have doubts consider that the average CEO of healthcare industry makes $11.7 million in annual salary. The average Insurance agency makes $1-2 Billion (with a B as in 1 followed by 9 zeros) annually in revenue and a handsome bonus to its managers and the patients get denial for services and the patient gets denial of services for cost reasons arbitrarily created and physicians gets an annual cut in their reimbursements.

Therein lies the network of cables that push and pull within the net to warp the landscape of healthcare similar, I might say to what is going on in the financial sector, the FED and its bank-comforting policies that ultimately lead to the detriment to the working class.

Meanwhile both in the financial and the healthcare sectors there is a constant barrage of media reports of the blame game. The finger points and moves on to the next target as the distractions keep the citizenry occupied. “Yes,” the media and the spokespersons claim, “the Regulatory bodies are doing a yeoman’s work to preserve and protect the innocent citizen.” All this as the ground beneath is shifting, poised for a tectonic upheavel.

Helicoptering money and ideas is an old game, “keep the gentry happy and the bourgeois distracted,” practiced by evil pseudo-scientists whose weightless thoughts are all about the self and their cronies. We know money works for a while and similarly ideas manufactured in the marbled silos handed down as mandates work for the same duration until the citizenry reaches a breaking point and then all hell breaks loose, when “Let them eat cake” does not suffice.

One finally asks the question, “How will it end?”

The answer is not a happy one.

“There’s a special providence in the fall of a sparrow. If it be now, 'tis not to come; if it be not to come, it will be now; if it be not now, yet it will come. The readiness is all.” - Shakespeare

RADON, DNA and CANCER

Radon, the environmental carcinogen is ubiquitous. The EPA estimates levels of 4 PcI/L (4-Picocuries/liter) or more are hazardous to health. By hazardous to health they mean cancer inducing.

Uranium238 with a 4.1 billion years of half life and the only naturally occurring fissile isotope, decays to Thorium232 and that decays to Radium226 ultimately yielding Radon222. Radon emits alpha particles into the air. Humans breathing a high concentrations of these Radon particles into their lungs can develop Lung Cancer.

                                           

In 1898 from a Uranium ore, Marie Curie (Maria Sklodowska 1867-1934) discovered radioactivity after grinding, dissolving, filtering, precipitating, collecting, redissolving, crystallising and recrystallizing the uranium ore into tiny parts of Radium (she is the only woman to have received a Nobel Prize in Physics and Chemistry). Thus began the journey of radioactivity that cost her, her life to Aplastic Anemia and her daughter’s life to Leukemia while studying the properties of Uranium and its decay products. Both illnesses a consequence of the radioisotope exposure!

"Nothing in life is to be feared; it is only to be understood."  - Marie Curie

15,000 to 22,000 cases of Lung Cancer are estimated as consequence of Radon exposure from over 200,000 cases of Lung cancer a year in the United States. The Radon gas is emitted from the soil and is based on the Uranium/Thorium concentrates within the soil. The highest concentrations within homes appear in the unventilated basements located over Uranium/Thorium rich-soils. Radon emits high energy He2+ ions as Linear Energy Transfers or LET.

                                            

The alpha particle is helium nuclei, composed of two protons and two neutrons. Because the nuclei have no electrons, they have a +2 charge. Because of its mass, alpha radiation does not penetrate healthy skin. However, entry of alpha radiation via the mouth or nose, may cause cancers in lungs. These emissions breathed into the lungs disrupt the alveolar/bronchial cell DNA Mutations, Single and Double stranded Breakage due to disrupted phosphate bonds, Single Nucleotide Polymorphisms, Cell Cycle disruptions, Mismatch DNA Repair ( NER -Nucleotide Excision Repair, BER -Base Excision Repair, MMR -Mismatch Repair))mechanism function (cells have the ability to repair the damage done to DNA by radiation, chemicals, or physical trauma. The effectiveness of these cellular repair mechanisms depends on the kind of cell, the type and dose of radiation, the individual and other biological factors), over expressions of oncogenes or suppression of tumor suppressor genes and even successful apoptosis if the p53 gene is fully functional and not overwhelmed or any combination of above can start the nidus of the cancer within the lung. Since alpha particles are massive and highly charged, they are extremely damaging to living tissue. Alpha particle emissions from decay of radon progeny in the lungs cannot reach cells in any other organs, except breathed into the lungs. Even with a fully functional DNA Repair mechanism intact, a single genetic aberration passed down to the cellular progeny can play havoc and create the malignancy. Additionally the active Alpha Particles also inexact with whole cells and their mitochondria releasing Oxygen Reactive Species and creating oxidative stresses thru direct cell damage leading to molecular disturbances within the genome and thus propagation. Thus lungs are the main target of developing cancers.

Recent data from Scandinavia seems to suggest that there is a slightly higher incidence of “blood cancers” (Leukemia, Lymphoma and other Bone Marrow Disorders) in women. The authors did a meta-analysis and discovered a 60% increase of such cancers in women that showed a dose response curve to the Radon exposure. The Author of the study, Dr. Teras stated, “The overall lifetime risk of hematological cancers in the United States is about 2%, so even a 60% relative increase would still mean a relatively small absolute risk.” The data came from an analysis including 140,652 participants among whom there were 3,019 hematologic cancers during 19 years of follow-up. The entry of the alpha particles via the pulmonary vasculature and into the bone marrow may if proven in future studies turn out to be the proposed mechanism.

The logical question that follows is what if anything that can be done about risk mitigation strategies to limit Radon exposure:

1. Have surrounding soil samples checked for Uranium/Thorium levels.

2.Vacuum the dust over a period of 30-90 days in the home’s basement and using a Geiger counter determine the extent of the exposure. A crude but reasonable estimate can be made. Nowadays Test Kits are sold in various stores. The reliability is never completely guaranteed. 

3. Ventilate the basement and the first floors periodically with fresh air. For more information review the website provided below.

https://www.health.ny.gov/environmental/radiological/radon/mitigation/what_is_mitigation.htm

Can we eliminate all risks? Probably not. But mitigate a percentage of the risk? Probably so.

References:

Darby S, Hill D, Deo H, et al. Residential radon and lung cancer: Scandinavian Journal of Work, Environment and Health 2006; 32(Suppl 1):1–83. Erratum in Scandinavian Journal of Work, Environment and Health 2007; 33(1):80.

Field RW. A review of residential radon case-control epidemiologic studies performed in the United States. Reviews on Environmental Health 2001; 16(3):151–167.

Harley NH, Robbins ES. Radon and leukemia in the Danish study: another source of dose. Health Physics 2009; 97(4):343–347.

Möhner M, Gellissen J, Marsh JW, Gregoratto D. Occupational and diagnostic exposure to ionizing radiation and leukemia risk among German uranium miners. Health Physics 2010; 99(3):314–321.

Lauren R. Teras et al, Residential radon exposure and risk of incident hematologic malignancies in the Cancer Prevention Study-II Nutrition Cohort, Environmental Research (2016)DOI: 10.1016/j.envres.2016.03.002