Sunday, August 24, 2014

THE "EPIDEMIC"


When one comes up on two diametrically opposing views, it turns into a learning experience of how both sides cannot proverbially see the forest of the trees? When one side claims and tugs and pushes its viewpoint to the point of abstraction and the other emulates with equal passion somewhere in that monologue from either side lies the seed for a dialog, a seed, that neither one sees. Don’t you think?


Two households both alike in dignity, are drawn to ancient grudge to bring proof of their supreme excellence. The Epidemiological house derides the Randomized Controlled Trial house as too focused and limited in scope due to its optimized conditions, which does not meet the requirements of the large populations. And that is true to a large extent, even Thomas Bayes, he of the English statistician, philosopher and Presbyterian minister fame would agree that using random samples can only have so much strength and integrity to export validity of a meager sampled experiment to an entire population.

Meanwhile the reductionist household of empiricists are also employing the same war chest. Both sides want to win the argument: Population statistics and results equate at the individual level and small samples of the population equate to the whole population is the new creed of this crude thought. Both sides employing similar tools are being drawn to a similar conclusion: The “missionary” work of the empiricists however would look at it the other way and say, “we, of the reductionist point of view, from deciphering the needs of a few can determine what ails the whole society. Our carefully crafted experiments see the forest as it represents itself !” They however momentarily forget those new saplings and an occasional oak on either side of their 95% curved landscape.

So who is right? Maybe neither!

The Epidemiologists now have a new war chest. The Biggish Data that they are fond of using for proof of their methodology seems to satisfy their needs. They no longer find the need to get their hands dirty. They merely need to ascertain the weight of the compiled digits that someone has keyed into the servers.  Data defines reality for all! Or does it? Is it the data, its selection or its manipulation that defines the concocted reality? One must also remember the Bird Flu A(H1N1) rallied by the World Health Organization as an pandemic in 2009, wasn't! It is a stark reminder of the strong carry-trade of emotional currency, when projections based on math overwhelm logic and reason! Not only was the logic denuded of reliable data but the fear-mongering projections thus mathematically reasoned were accentuated only by the comparisons between the Bird Flu of 2009 to the Influenza of 1918.

From the ePluribus Unum we have arrived at ex multis! John Snow, he of Cholera as a waterborne disease rather than air-borne fame, would be resigned to depression today. After all, epidemiology certainly has a part to play in protecting the population from potential risk, but utilizing the large umbrella of public safety could these experts venture into the habitat of the empiricists without so much as a nod to the causality, except by dint of thought or bias? In other words can the protective umbrella of the epidemiologist wrongfully detract from reality by force-seeking the causality without hurtling through the rigors of the empiricist’s evidence, which are similar in scope and therefore be blinded to project false causality to the whole or a select portion of the citizenry? Ah therein lie the seeds of discord!

Epidemiology studies are a boon for societies as a whole, if they are done correctly to find causal factors of potential vectors of the flame that incite wide-spread epidemics. But using limited data arrived at through statistical torture and casting it as a wide net of causality can prove a detriment to science itself. Today the rigors go so far as to admit and deny the causal factors of an affliction in the same breath. There are a lot of “mays” and “mights” thrown around for full disclosure and future immunity.

The purity of science is in the rigor and not in the shortcuts that one seeks today to publish, gain recognition, make a name for oneself, get a promotion and seek further advancement among one’s peers. That desire of self-aggrandizement, based on the mishmash of the scientific conversations in print seems diametrically at odds with good science. John Iannodis, MD in his article, “Why Most Published Research Findings Are False,” found that more than 50% of the experimental studies were unverifiable! With the 15-minute fame over, the focus of the scientist-statistician moves on towards new mining.

In the world of data-mining from large data-warehouses where any selected digit is a means to an end and reliance upon the statistical methodology so employed a means to a better future, science suffers from such inaccuracies. Both sides are embroiled in the latest rendition of such thought that would compile the argument into a tightly bound Confidence Interval and then determine the 95% probability making all other nuances of differing thoughts, mere distractions.

There is an epidemic of false starts and forced understanding in medical science today. It is time to unwind the clocks and rethink our future otherwise this pleiotropic nature of “one size fits all” will indeed one day end individualism, creativity and innovation. It is time for each side to think its own set of tools and merge the information for a unified theory of existence where real world problems are handled through real world thinking, not some sham-based probabilities!

http://m.ghspjournal.org/content/2/3/253.full

http://blogs.scientificamerican.com/the-curious-wavefunction/2013/05/20/cancer-genomics-and-technological-solutionism-a-time-to-be-wary/



Monday, August 18, 2014

MIND and the MEMORY

The crispness of the morning breeze brings with it a shudder to the blanketed-warm skin, its freshness evokes desires and wants for more. Such is with truth, undiluted by the perpetual sea of falsehood, it forces within the mind, a revolution. Away from the interlocking strains of glorified lies, this monastery of reality stands firm against these manipulating truth defying savages.

It is the mark of an educated mind to be able to entertain a thought without accepting it. - Aristotle

The mind, the organ of intuit and reason, the wisp of nothingness that holds within its nebulous architecture, a version of reality, seems oddly the place where reality or for that matter anything should exist. Yet it does and no one has yet been able to decipher, what “mind” is or for that matter where it is?

Is mind a concoction of the human brain, deflecting responsibility of its own action or inaction? Is it the personage of the being? An oddly relevant companion that lurks in the shadows of existence, who no one can see, measure or understand, yet is probed for all things seemingly justified.

The new PET/reporter gene-PET/reporter probes might give this invisible existence, structure one day or may rob us humans of a perfectly legitimate scapegoat for our own misdoings. How then will we ascribe our socially wayward behaviors to the aegis of mind-control? And speaking of mind-control what about the realm of psychic warriors where exactly will their battalion of “seers” end up? If we can see the “mind” in action then the psychic domain becomes a visual for all to see.

This mind probing thing could bring with it an upheaval in human rational thought, couldn’t it? How would one translate, “In my mind there exists…” Yeah, okay, now where would that existence next find habitat?
Conjuring up the next artificial intelligent robot then could we sprinkle a little dust of the “mind” in it so that one day Asimov’s dream would come alive but at what human peril? I shudder to think about the HALs; their next generation! Imagine HAL 10000. “No you may not drink the 16oz big gulp…if you disobey my laser is set on stun.”

Yes but, some might like that idea. Why not empower robots to modify human behavior on the streets, after all those that envision such a life seem to want control and safety against all liberties. It would be well, until the laser is pointed at them.

Indeed life is about to change with 20 petabytes of data emerging every day and being harnessed in “warehouses,” “lakes,” and soon “cities” and “states” appear not too far behind. Analyzing them through the wonders of predictive models will bring the era of machine ordered security of the Jetsons or was it the Flintstones? And might not we humans end up in the “planet of the robots?” Something for Hollywood to consider!


So I ask you dear reader after that first chill of the morning air, a loaded cup of hot coffee and a desire, what would you do differently?

Tuesday, August 12, 2014

TARGETING CANCER

Targeting Therapy: Kinase Inhibitors



The human body functions on the backs of proteins called enzymes that modulate cellular behavior. These enzymes act as catalysts for a biochemical reaction within the human body milieu. One such class of enzymes called Kinases has a profound effect on the internal machinery of the cell. The human genome of 25,000 genes has a total of 500 kinase genes that have the ability to modify 30% of the genome.

With the advent of tumor genomics and high throughput machines the gene expression signatures has brought forth an array of medicines to counter malignancies.
Our understanding of the normal function of the kinases has enabled us to realize the pathology within. The governing gene of the kinases and their mutations, rearrangements and copy number variations can thus enhance, inhibit or modify the normal physiological function of the cell by interfering in the cellular signals and create chaos. It is this understanding and our ability to recognize that will help transform cancer care in the very near future.


A Kinase
acts as a mediator to transfer a phosphate moiety from the ATP molecule to a target substrate. A receptor recruited kinase most commonly such as EGFR is activated when the receptor plus ligand dimerizes the receptors and initiates the downstream cascade. The kinase phosphorylate other protein substrates to transduce the signal downstream via pathways directly or indirectly to the nucleus for enhancing proliferation or arresting growth. This act of phosphate transfer is called “phosphorylation.” Kinases have the ability to orient the substrate and the phosphate in such a manner so as to stabilize a high level energy reaction.
Courtesy McGraw Hill Companies

It is this activity that signals the interior of the cells to modify, grow, and self-destruct or cease-function. The kinases govern such initiation, inhibition or disruption of cellular activities, all through the charged phosphoryl-group. This regulatory function of the kinases comes from their ability to have reversible covalent modification of the substrates.
Courtesy McGraw Hill Companies

Such external modifying measures also create allosteric activity (feedback loops) within the interior of the cells that can potentiate and maximize the initial reaction.

Biotechnology companies are creating various Kinase Inhibitors. These inhibitors are used to suppress the kinase turned rouge -due to modification of its function as a forerunner of gene mutation. To prevent the mutated kinase from over-function and excessive uncontrolled cellular proliferation as happens in cancer, the inhibitors shut the signals emanating from the kinase and thus arrest any untoward cellular behavior.


There are a total of 60 Receptor Tyrosine Kinases (RTK) and an additional 30 intracellular Tyrosine Kinases that have been identified. Amongst the RTKs include the well-known families of: EGFR, PDGFR, VEGF, MET and ALK and amongst the non-RTKs included are: ABL, FES, FAK, SRC, IGFR and SCFR(c-kit) and JAK families. The various TKIs thus far developed include: Crizotinib (Xalkori), Dasatinib (Sprycel), Erlotinib (Tarceva), Imatinib (Gleevec), Lapatinib (Tykerb), Nilotinib (Tasigna), Sorafenib (Nexavar), Sunitinib (Sutent). Most are familiar with Imatinib against the BCR-ABL mutation in CML, Crizotinib against the ALK mutated lung cancer and Sunitnib against renal cell carcinoma. The list of TKIs in development currently exceeds 38 at this time and future studies will highlight the benefits of these developments.

Aside from the RTKs there are three other kinases worth mentioning: Cycle Dependent kinases (CDKs), Phosphoinositol kinase (PIKs) and Mitogen Activated Protein Kinases (MAPKs).The CDK enzymes regulate the cell cycle in mitosis. CDKs control transcription, metabolism and because of their role in cell division they are vested heavily via mutation in creating malignancies within lymphatic tissue, pancreas and breast tissues. The PIKs phosphorylate the Inositol, which regulates the Insulin signaling pathways and is involved in both cancer and Insulin resistance. The MAPKs are activated by mitogens such as Epidermal growth factor (EGF), platelet derived growth factor (PDGF) and Insulin growth factor (IGF) to initiate a downstream signal transduction into the nucleus via the RAF-MEK-ERK pathway for cellular proliferation. Again kinase mutations cause dysregulation of the cell growth in most cases leading to cancer.

A word of caution
as we explore and enhance our understanding of the new TKIs is that the benefits from TKIs appear to be temporary in most cases.
The reasons are many-fold; the feedback loop mechanism within the cellular interior may abrogate the inhibitor function, cellular cross-talk between different pathways may take over the function of the kinase and cancer controlled degradation of the inhibitor might undermine the kinase inhibitor activity.
A case in point recently featured in the New England Journal of Medicine showed that a mutation of the Bruton Kinase in patients with Chronic Lymphocytic Leukemia (CLL) resulted in resistance to Ibrutinib a BTK inhibitor that is very effective in this disease!


The changing face of Cancer Care...Sustainability, Durability and the hope of longer term survival!

(Hey, I didn't say Science was easy, but it sure the heck beats contemplating the navel!)

References:

Manning G, Whyte DB. et al. (2002). "The protein kinase complement of the human genome". Science 298 (5600): 1912–1934

Higashiyama, Shigeki, Iwabuki, Hidehiko, Morimoto, Chie, Hieda, Miki, Inoue, Hirofumi, Matsushita, Natsuki (February 2008). "Membrane-anchored growth factors, the epidermal growth factor family: Beyond receptor ligands". Cancer Science 99 (2): 214–20.

Stout TJ, Foster PG, Matthews DJ (2004).”High throughput structural biology in drug discovery: protein kinases.” Curr. Pharm. Des. 10 (10): 1069–82

Hunter T (1991). "Protein kinase classification". Meth. Enzymol. Methods in Enzymology 200: 3–37

Cantley, Lewis C (2012). "PI 3-kinase and disease". BMC Proceedings 6 (Suppl 3)

Canavese, Miriam; Santo, Loredana; Raje, Noopur (1 May 2012). "Cyclin dependent kinases in cancer: Potential for therapeutic intervention". Cancer Biology & Therapy 13(7): 451–457

Tony S. K. Mok Personalized medicine in lung cancer: what we need to know

Nature Reviews Clinical Oncology 8, 661-668 (November 2 2012).

Jennifer A. Woyach, M.D. et al. Resistance Mechanisms for the Bruton's Tyrosine Kinase Inhibitor Ibrutinib. N Engl J Med 2014; 370:2286-2294. June 12, 2014

Monday, July 28, 2014

DISTRACTIONS of Majoring in Minors





I recently visited the Vasa Museum in Stockholm, Sweden. The three hundred year old warship sits majestically in the middle of this beautiful museum. You can look at it from every angle. The wooden ship is a master craftsman’s envy. The figurines on the transom are alive and tell the fascinating tale of the logic within illogic, of demand and uncertainty, of powerful words that drowned the truth seeking muted voices, of hubris, of inattention, of layered differences between the knowers of truth and the seekers of fame and ideology. In short, Vasa remains a memory to Sweden's famous warrior King Gustavus Adolphus, his ambition of military expansionism, his impulsive desire and the fearful silence of the knowers who deemed Vasa unfit for sea.


Vasa completed its 300 meter maiden voyage in 1628 and at the first hint of a strong breeze displayed its instability due to a high center of gravity and promptly sank to the bottom, lost for 300 years. It was resurrected in 1959 and after carefully organizing 95% of the remains of the warship, Vasa was brought back to its current life and rests in the Vasa Museum in Stockholm, Sweden.

The impetus of the ship-builders was to have the state of the art battle ship with two rows of cannons on either side. Unfortunately there was not enough ballast to keep it righted when the sails filled. 


The desire was craftsmanship, the regal beauty and potential  deadlyforce the vessel could unleash, however not enough measure was taken of its ability to sail. Today Vasa Museum remains the most visited museum in Europe. It is a testament to the folly of majoring in minor thoughts!

Consider the current vogue in medicine where the physician (the determiner of facts, the allocator of resources and the captain of the healthcare ship) is relegated to majoring in the minors! (you know I was going there weren't you?)

Let us consider the following issues:

1.       EMR: The object of EMRs is to create a large data-bank so that errors are minimized in the practice of medicine and additionally duplication of services is limited to reduce costs. A 2-fer! How could anyone ignore the virtue behind this logic? Well, and that is a deep one, there are many hurdles to overcome. Learning the EMR system takes time, but that is of no concern to the makers of the system (who gain from it), after all it is the responsibility of the physician. Okay, moving on, the information is to be entered close to the time of the encounter so that memory does not waiver, but then the sacred patient-physician contact is minimized by the doctor’s constant attention on the computer screen to prevent errors that can mislead the reader with incoherent information (both to the detriment of the patient and the physician). That sacred faith and the personal trust gets lodged somewhere between distrust and lack of faith. Right about there the 14% placebo effect of the comforting hand on the shoulder benefit is drowned in the sea of digital ink. Physicians spend between 40-50% of their time in “charting” while the nurses spend 50-60% of their time doing the same on the hospital units. Who takes care of the patients during that timeThe answer should not surprise you.

2.       Reimbursements for services rendered: the Medical Revenue Cycle is alive and well, thanks to the insurer models of denial of coverage and denial of payments because of lack of documentation. 11% of all medical bill submissions by physicians, hospitals get denied automatically via the software algorithms built into the large main frames of the insurers. While the Blues, the Aetna(s) and the United(s) cleanup with soaring revenues and net incomes showering their managers with huge bonuses. Meanwhile it notoriously takes the physician 6-10 weeks to collect payments from these insurers. Besides the declining present value of the money, the doctor has to keep his office afloat before he can recover the payments. (S)he at times has to take bridge loans for stability. The doctor now has to master the issue of medical reimbursement by dealing with the insurers. (S)he spends time discussing the merits of care with someone at the insurer level who may not even have a high school diploma but is using guidelines to deny care!

3.       There is also a push for physicians to enter whole-heartedly into the Social Media realm and converse with their patients. The voices are getting strong and these voices seem to take a one-better attitude against those that do not interact through the social media by calling them out. Is that the right mode for a patient-physician interaction? Is this another minor activity that the doctor will be forced to major in? Given the HIPAA laws there are optional pitfalls, sinkholes and avalanches that await the unguarded word of a physician in the digital realm. You be careful out there doc!

 Statistics: 50% of scientific medical studies are not reproducible (false, biased, improperly done or statistically manipulated)! That statement must give us pause. Physicians rely on a properly done study to determine its need in governance of their patient's care. Currently with the fudged data, biased output, conflicted interests of publish or perish, the scientific offerings are limited and it is up to the physician to major in the biostatistics to weed out the right from wrong, the good from the bad, even though both may appear the same.  This simplified .pdf book would serve everyone involved in medicine well “Know Your Chances" by Woloshin, Schwartz, Welch Complete book in pdf via @Medicalskeptic (my thanks). It would behoove us doctors to acquire this knowledge for knowledge's sake anyway.

5.       Regulations: The physician office is governed by no less than 38 different federal and State laws, rules and regulatory bodies that can with impunity shut down his/her practice of medicine. A physician is required to know these laws, rules and regulation and ignorance is never an excuse. Another major is needed to discern the legal word behind the regulatory capture of medicine. The fear alone from this is enough to drive anyone insane.
6.       Maintenance of Certification or MOC: This is a product of the private enterprise that assiduously enforces certain demands on the physicians without the clear bounds of verifiable and or validated data. They claim that the MOC process is necessary to determine the knowledge and learning of the physician. These claims are embraced by the hospitals and insurers as a means to weed out physicians from their roster should the physicians be found not in compliance to the MOC standards. There are some very relevant issues in this thinking. If those physicians involved in the MOC process compared with those not undertaking the exercise have similar patient care then how does one better the other? And to boot more than 17,000 physicians have signed a petition to eliminate the new MOC requirements. Most physicians consider MOC to be an unnecessary imposition that actually harms care by usurping physician time away from patients. All this is designed unfortunately to create mistrust in the patient towards his doctor and that leads to despondency and  and with absolutely no known benefits in patient outcomes! 



Just like the Vasa, medicine is replete with the bling of hubris, the shine of pomp and the laurels of asymmetry in thought while the underlying goal of patient care suffers. Might I suggest that the best way forward just maybe a direct patient-physician access without the intermediaries? Or pay as you go or PAYGO! Responsibility on both sides of the aisle as much as the skin in the game like the days of yore!
Healthcare Facts:
1950s = 5% of GDP
1960s = 6% of GDP
2014  = 17% of GDP
If the Trend was allowed to continue the math logic states that the cost would be:
2010s = 11% of GDP not 18% of GDP even with the population growth and demographic change! But somewhere in there by "All the way with LBJ" was inserted the 1965 Medicare Amendment to the Social Security Act and the rest is history! And that 7% of extras in GDP translates to  $17.7trillion x 0.07 = $1.24 trillion of crony pocket change.  Now that is a foreign and abhorrent concept among the elites who wish to partake in other people’s money. Here are some other facts: Direct patient care without the intermediaries will bring the cost of care down, increase the patient outcomes and get rid of this art of majoring in minor activities! It might come as a surprise to the vast enterprise of the “good-intentioned” that medical care is about caring. It is between the patient and his or her physician. Removing the barriers/layers removes the unnecessary burden and gives more stability to the enterprise of caring.

Clearly the healthcare foundational -ballast is grossly under-weighted while the top-heavy self-serving-intermediary-instability continues to increase.
Vasa Replica at the museum

A storm is brewing and history reminds us, with the shaky foundation in place, the first chill of the brisk breeze will surely sink this ship!


Wednesday, July 23, 2014

Of Mice and Men

A little rain must fall...

We plan. We live. We try to understand.

Somewhere in this universe there is a record-keeping device that ascribes to Steinbeck’s famous quote, “the best laid plans of mice and men oft go awry.” Being George Milton is no solace when you lose a friend Lennie Small to your own hands. It is an act of love albeit a murderous one. Somewhere in that flow of thought, the curse of knowledge comes to mind. You know, like, George understood what would not be; the happiness of a life on the ranch. George could not bear to see Lennie sad or lynched by Curly's mob, so he killed him.

Lennie’s soul must cry out somewhere in this universe of being wronged. Ah compassion of the wrong kind heralded by the slow of mind, by the fast of claimed virtue, by the unwitting and by the rest of the herd seem to fall into their personal trap of emotional comfort. For they seem to think that the act justifies and thus soothes the emotional vein of feeling. Does it? Snuffing a life that can be helped live out some future is a good thing? Justification in the name of empathy is an emotional recoil for reason. “How can you not,” some will say, to ward off future suffering. They forget that the future changes moment to moment. Time lapse photographs of a blooming rose, a fracturing fallen pitcher of milk or the penetration of a bullet through time all change the future. The suffering never goes on. It ends sometime. It ends with time!

How can we in good conscience allow denial of care to a human in need? When did we get bestowed with the rationalization of a George Milton mind? How do we know of what is yet to come? The three days, three months, three years or three decades of a future might through the act of one life change the course of human existence, much like a certain human named Hawking has done. Was Lennie Small in need of protection from his own strength that became his weakness? Was Lennie Small’s simplemindedness nature’s cruel joke or nature’s argument for understanding? Whatever it was, he deserved a better fate! To sit in judgment of a future that is yet to be is to sit and revel in the ultimate hubris a human mind can conjure.

Time to think and comprehend what is real and what could be in the as yet fictional future.


A little rain must fall in everyone’s life. Humanity calls for giving shelter, not the gun to blow off Lennie Small’s head!

Friday, July 18, 2014

MEDICAL RESIDENCY

A few years ago a group of recent medical graduates came to our house for dinner. An exciting conversation of their hopes and dreams followed. What would they do and where would they go in search of fulfilling their dreams. One wanted to go and serve in the rural areas with a large backyard where he could be “one with nature” and when duty called he would step into his home/office and care for the patient. Another wanted to follow in his father’s footsteps, become a sub-specialist and regale the specialty with new knowledge through discovery. A third quiet and more subdued graduate sulked in the background, not willing to express her desires.

As the dinner progressed the graduate magnetized towards the rural bent stated, “I don’t get it,” he said, “Why do I have to go see another surgical procedure?” He put his fork down with an emphasis. “You see one, you do one and you teach one!” There was a momentary silence. As a host, I asked, “don’t you think an aggregated knowledge would make for better decision making?” He fired back immediately, “Repetition is not necessarily the best education.” Not exactly true, but as a host, I volunteered,  “But more exposure leads to more information and that becomes a sort of experiential reference to draw upon, don’t you think?”

Ah but for the infinite regress of a mental intent...

 “A cholecystectomy is a cholecystectomy!” he stated with a smirk. “Fair enough,” I replied, “but each individual is different and each gall bladder therefore is different. You might find one gallbladder fixed from chronic inflammation to other tissues, another might be filled with stones, still another might have a nidus of gall bladder cancer in it stuck to the liver and so on, how can one know how to deal with all those contingencies?” He remained quiet for a moment and then not to be held down with a technicality suggested, “when you go in (operate) that is when you find the problem and you deal with what you find. The procedure of going in is the same!” This young Turk had a lot to learn and maybe he would in due course of his residency, only time would tell.

The sulking violet meanwhile quietly listened to the exchange and the cloud over her head seemed to darken. I asked her what was bothering her and she replied, “I wouldn't know what to do!” she said haltingly in veiled terror. “What do you mean?” I asked. “In the ER for instant a patient with abdominal pain, you cannot open the text book to look through all the differential diagnoses, how would one go about determining the diagnosis and the right treatment?” Ah, I thought from the bullish to the bearish the entire spectrum was covered here. “That is why you have the residency program to help you sort out the problems. It gives you the confidence based on the knowledge you accumulate from your peers, experienced nurses and attending physicians. That is the purpose for the residency, to help put the didactic into the practical format. Medicine is difficult both in the expanse of its knowledge-base and in its practice. The sorting and weeding out of what is right and wrong, is done early on in the residency to help gain confidence in one’s ability and in proper management of a patient’s illness when you embark on the life-long journey of being a doctor.” That might have sounded pompous, but it had the elements of truth in it. She sighed unconvinced and her head went back into the thoughtful repose. She would benefit from the experience of the residency “baptism under fire!” I thought. They had no idea what kind of an immediate future they were up against. Yet it would come and readiness was all they needed.

The night ended with laughter and fun. As we closed the door behind our departing guests, it struck me how arduous a path it is to becoming a doctor. All these graduates had their hopes and dreams, some had the arrogance of youth and others the timidity and fear of the unknown. Graduation from a medical school is only the first step towards the learning process. Residency is an important bridge between what one knows and how it is utilized. But learning goes on for the lifetime of a physician!

The recent legislation passed in Missouri to cover for the physician shortage is a bit discomfiting. Not only does it speak volumes about the expert policy makers but it broadcasts the potential future. What kind of impact would it have upon the actions of the “fearless” and the “timid” without supervision and their behavioral impact on patient care?

Maybe it will all work out. But in medicine, a lot of maybes can lead to a lot of oops!

Wednesday, July 16, 2014

A Very Brief History of CANCER

From there to here in cancer care...

Cancer has been around as long as life. The incidence of cancer remains true to the cumulative DNA mutations over the eons. The mutations whether heritable (Darwinian) or acquired (Lamarckian) bestow a similar consequence upon the cell; they subvert its function and give it sustainable powers. It is a disease that does not comport itself to utilitarian essentialism. Each cancer is unique in form, structure, behavior and outcome and requires precise understanding of the levers and cogs that hide within the shadows.

Discovery:
Back in the 1600 BC the earliest information cataloged on a papyrus, cancer is chronicled as a malady. Bone specimens from mummies have revealed cancer in the bones as chewed out bone fragments. There are spotty viewpoints in isolated silos for a thousand years. No real cogent hypothesis was offered. The deadly disease was taken at face value and left at that for the remainder of the century. Along came Hippocrates in 460-370 BC who posited the “Humoral Theory.”

Within his theory was the dark, evil “Black bile” the harbinger of carcinos or “karkinos” (cancer). With that theory perched on his mind, he lamented in resignation, “There is no cure.” And in those times, there was none, let alone knowledge of how this “beastly tragedy” where posited subsumed life.

Five centuries later Claudius Galenus “Galen” 131-201 AD influenced by the “Humor Theory” used his anatomic skills and known knowledge of medicine as a physician, philosopher and made further strides into the nature of malignancy through the Hippocratic lens of “Humor.” The pervasive sense of nihilism inversely controlled knowledge and treatment of cancer for almost a century and a half thereafter.

Not until 1775 when Sir Percival Pott deduced that chimney sweeps in London contracted scrotal cancer from the soot, did the cause and effect of environment on cancer become known. For the first time a verifiable concrete causality was bared. Something to point a finger at!

Other notables in the field included Rudolf Virchow 1821-1902 a German polymath who viewed cancer tissue under microscopy to determine that it was “a collection of cells derived from other cells.” and repudiated the Hippocratic "Humoral" view of life and disease. The pace quickened. The knowledge advanced. Yet the fear remained.

In 1902 Theodor Boveri a German zoologist in Munich postulated that the centrosome, an “especial organ of cell division” was required in mitosis (cell division) and that aberrant mitosis was the prelude to cancer. He theorized that special check points in the mitotic cycle when mutated could lead to a genetic predisposition towards a malignancy. We were slowly breaching the firewall. We still had a long way to go.

In 1911 Peyton Rous of Johns Hopkins University in Baltimore, Maryland used a cell free filtrate from a chicken sarcoma to cause cancer in a healthy fowl. This transmission was due to a virus named appropriately as the Rouse Sarcoma Virus. Thus the viral etiology of cancer transmission was brought to fore in the field of cancer medicine. We had progressed from soot to a cell free filtrate (virus) as the central cause of this hard to control tragedy. We were peering at the mechanism for the first time.

Yamagiva and Ichikawa in 1915 used the Percival Pott concept to induce skin cancer in rabbits using coal tar and prove chemical carcinogenesis.  And then in 1964 we added tobacco, another vile substance to the growing list of “evil doers!” Chemicals and Viruses ruled the domain of causality in cancer!

"If everyone is thinking alike, then somebody isn't thinking." George Patton

Cancer medicine was to undergo an exponential increase in knowledge flow after the discovery by Watson and Crick of the DNA helix in 1953. Subsequent hypotheses and experimental thrust in understanding cancer was relegated to the study of genetic dysfunction and its relation to disease, more specifically cancer.
In her book “Natural Obsessions” by Natalie Angier the descriptive evidence of how the Weinberg Labs under the tutelage of Robert A. Weinberg discovered the first human oncogene Ras (a promoter gene causing cancer) and the Retinoblastoma (Rb), a tumor suppressor gene is worth a read. The trials and tribulations of discovery and the dogged pursuit all exemplify the enormous grind required in bringing a hypothesis to reality through series of experimentation and validations. Basic science has to toil over experiments and not be reliant on the dubious distinction of transposed conditionality as employed nowadays by the Frequentists. In 1990 another dedicated scientist, Mary Claire King through diligent work discovered the BRCA I and 2 tumor suppressor genes. BRCA 1 and 2 both involved in initiating cancer via mutation triggering malignancies in Breast, Ovaries, Prostate, among other organs. Another door had opened into the nebulous innards of the cancer cell!

There has been a flurry of activity since in the discovery of various cellular pathways and their cell-surface molecules that could incite mischief in extremely well regulated cell machinery through disruption. This disrupting influence can be over-expressions of pro-proliferation molecules for continuous cell growth or suppression of the anti-proliferation molecules akin to a driver using the accelerator without a brake or releasing the brake in neutral gear on a downhill road. There are many known allosteric feed-back loops within the cells that promote and suppress cell activity as well. These discoveries have now taken biology into the realm of epigenetics (study of genetic control by factors outside of the DNA sequence) where small collaborators called micro-RNA, peptides and other proteins have influential impact on the genetic domain to coax the wayward cell.We had arrived at today!

Surgery:

While these discoveries were taking place some stalwarts in medicine were taking note and deciding how best to treat this devastating malady. Overtime these innovators discarded the Hippocratic and Galen nihilism and opted for surgical removal of the cancer to help life along. In 1878 Thomas Beatson realized that removal of the ovaries resulted in a shrinkage of the breast cancer. Twelve years later,William Halstead of Baltimore, Maryland came up with the idea of Radical mastectomy for breast cancer to achieve the R0 state. This was to be later known  as the Halstead procedure.

In 1928 Charles Huggins came to a similar conclusion in men with prostate cancer, removal of the testicles (orchiectomy) resulted in longevity.

From radical Mastectomy and other highly invasive procedures a refinement of thought occurred. What if we could do more with less surgery to prevent future infirmity and disability to the patient? Those “what ifs” were rewarded with the advent of combined approach of limited surgery and radiation therapy. The 1985-90 data showed equivalent survival for radical mastectomy and partial mastectomy combined with radiation therapy. More would be done to determine between those patients that would need radiation after surgery based on the genetic makeup of the cancer itself. Today OncoType DX gene screening arrays help determine the aggressiveness of breast cancer and treatment can be based on select cases. Others gene arrays exist and are in use for lymphomas and prostate cancer. We are currently grappling with the need for intervention and bearing the costs of caring by invoking concepts of “Lead Time Bias” in an effort to reduce potential harm by limiting “early/over diagnosis.” Newer forms of diagnostic tests arrive at the doctor's doorstep everyday to find and weed out this wretched disease and we as doctors use them all. But the constraints of money seem hell bent on controlling further progress. But that will not hold! After all when there was no money the DNA helix was discovered, smallpox vaccine was created out of cowpox and Penicillin grew out of the mold. I am sure the real creators and innovators will find what is needed to carve out a better destiny for the human race against cancer, independent of the regulatory arm twists. Progress in knowledge and understanding will happen, the scale of which only time will tell..

Radiation Therapy:

Radiation therapy started as a low voltage X-Rays (where “X” stood for unknown quantity) after Wilhelm Conrad Roentgen’s discovery of the x-rays in 1896. From those humble beginnings of large penumbras of low voltage radiation therapy to focused conformal radiation therapy of millions of electron voltage tailored to the tumor via Intensity Modulated Radiation therapy (IMRT) to Intraoperative Radiation Therapy IORT to gated modulations based on respiratory movements to the Stereotactic Radiation therapy (Gamma knife/Cyber-knife), the movement has an accelerated pace to provide the maximum tumor cell kill while sparing the normal cells surrounding the cancer. Proton beam therapy a newer more expensive methodology based on the sharp division of Braggs Peak is geared towards a similar methodology as the IMRT and currently used in certain tertiary centers as the radiation therapy of choice with equivalency in results compared to IMRT.

Chemotherapy:

The field of Oncology is the study of cancer and all relevant treatment modalities that will favor the patient. The tools in the field of Medical Oncology started with the advent of World War I. In 1917 the German Army used Mustard Gas against the enemy. The victims showed an absence of white cells in their blood. The modification of the Mustard Gas as nitrogen mustard was then used as treatment in patients with Hodgkin Disease in 1919.  After the bombing of Nagasaki and Hiroshima, in World War II the victims of the bombing showed a complete bone marrow wipe out. With that information, cancer treatment took another step of using radiation therapy to destroy the bone marrow in cancer cases, specifically Lymphomas and used it for Bone Marrow Transplantation as a method of curing the disease. From adversity grew a serendipitous and successful mode of treatment for an un-treatable disease.

Sydney Farber of Boston, Mass used Aminopterin, (DNA inhibitor that competes with the folate binding site of the tetrahydrofolate reductase enzyme) a precursor to Methotrexate in treatment for Acute Lymphoblastic Leukemia in children and achieved excellent results, as a consequence Methotrexate was then used to treat Choriocarcinoma a cancer in the uterus (womb) with gratifying full remissions.

From single drug therapy, a combination of drugs came into vogue to escalate the remissions in cancer. Slow and steady success followed with incremental improvement in remissions and subsequently in overall survival of the cancer patient with these treatments. In treatment of Malignant Lymphoma (DLCBCL) a four drug regimen of  Cyclophosphamide (Alkylating agent), Doxorubicin (DNA intercalator), Oncovin (a Vinca alkaloid that functions as a mitotic inhibitor) and Prednisone (steroid) (CHOP) was used with great success. Even with further modifications and additions of various other chemical agents to CHOP the cure rate remained fixed around the 50%+ range until the advent of Rituximab. When Rituximab was added to (R-CHOP) there was a significant rise in the complete remission rates and subsequent improvement in survival.

Biologic Response Modifiers:

What is Rituximab?  It is a monoclonal antibody directed against the CD-20 cell surface antigen. Since most lymphoma cells expressed CD-20 on their surface, Rituximab complied, attached itself to the surface and prevented further transmission of signals to the nucleus of the cell to grow. However this was not the first immune modulator by any means, Immune modulators or Biological Response Modifiers had been employed previously. The use of Interferon in melanoma and Chronic Myelogenous Leukemia and Interleukin-2 or IL-2 in both melanoma and Kidney cancer were examples of attempts to modify the immune response against the cancer. Additionally studies utilized programming the Dendritic Cells in the bone marrow to activate the T Killer cells (Lymphocytes) into storming and destroying cancer (prostate) with limited success. Companies such as Dendreon produced a product in that fashion called Provenge that afforded a limited improvement in survival of 4 months to patientwith prostate cancer at a cost of $100,000. Newer attempts at modifying immune behavior is via the Check Point Inhibitors to allow the full scale of immune surveillance unhampered by cancer in throwing another mortar attack against the disease.

Infused with the epistemological experience, both perceived and real, the current focus has gravitated to the Tyrosine Kinases (more on these critters in a different post) as the next targets to control. These are extra and intra-cellular proteins that modify cell behavior through manipulation of the cell signal. Various TK inhibitors include Erbitux (Anti EGFR) and Bevacizumab (Anti VEGF) and Imatinib (Anti  c-Kit or Stem cell Growth Receptor) are in use today and more are in the pipeline of the various biotechnology companies.

The idea is to starve the flow of information (Anti EGFR) or flow of nourishment (Anti VEGF) and now possibly manipulate the epigenetics via the override of the microRNAs to calm or speed-up the genetics into forcing the cell into submission.

The next few years will be a bounty of ideas and actions against Hippocrates’ carcinos. Stay tuned...

(There are many other notables that have meant so much in the field of cancer, unfortunately space does not permit for the historical reference to each).

References:
1.       Sara Gandini Tobacco smoking and cancer: A meta-analysis Epidemiology: International Journal of cancer http://onlinelibrary.wiley.com/doi/10.1002/ijc.23033/full
      
      Galen:
       http://www.nlm.nih.gov/hmd/greek/greek_galen.html

      Sir Percival Pott:
      http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1037746/
      
      Rudolf Virchow:
      http://www.science-of-aging.com/timelines/virchow-pathology-cell-formation.php

      Theodor Boveri:
       http://jcs.biologists.org/content/121/Supplement_1/1.long

      Peyton Rous:
      http://www.nobelprize.org/nobel_prizes/medicine/laureates/1966/rous-bio.html

      Wilhelm Conrad Roentgen:
      http://www.nobelprize.org/nobel_prizes/physics/laureates/1901/rontgen-bio.html

      Sydney Farber:
      http://www.learntoquestion.com/seevak/groups/2007/sites/farber/bio.html