Sunday, July 24, 2016

TUMOR INFILTRATING LYMPHOCYTES (TILs)

Much to the chagrin of the astrology experts, Shakespeare had a thing to say about it, “It is not in our stars to hold our destiny but in ourselves.” So what is in ourselves that we need to look at?

Interestingly, plenty of stuff!

In the 1990s there were articles about the importance of the presence of lymphocytes infiltrating the cancerous tissue. Physicians looked at these findings and compared outcomes with and without the presence of lymphocytes. They came away with the unassailable thought that the presence of the lymphocytes had some positive impact on survival. In early stage II/III colorectal cancer for instance they were able to determine that the presence of tumor infiltrating lymphocytes (TILs) in the tumor tissues were associated with longer term survival. Curious indeed, but at that time the tools were not there to study them further.


In Melanoma for instance a similar viewpoint held that TILs helped improve a person’s chances in overcoming the disease. In Melanoma, however, the immunity issue became a singular focus for a long time. Treatments included Interferon therapy, Interleukin-2 (as well in Renal Cel cancer) therapy and Vaccination against the epitope on the melanoma cells. These treatments were quite debilitating in nature, giving symptoms of a aggressive “Flu-like syndrome” each time the patient received the IFN or IL-2. One had to get the Interferon shot daily for 30 days, then three times a week for a year. It wreaked havoc on the patient, but there were responses. People not supposed to live, survived.




Breast Cancer data also seemed to suggest the presence of TILs in the surrounding tissue of the cancer. Little evidentiary information has been gathered or experimented in this malignancy, however, since there are much better methods of treatment available for this malady.

Modern Medicine dating back five or so years has resurrected the whole TIL concept once again and it seems successfully given another kick in the pants.


Knowing that the composition of the lymphocytes is T cells, B cells, NK (Natural Killer) cells, Helper Cells, Dendritic Cells that sample the antigen and macrophages, medicine has figured out how to manipulate the immune system in those patients that have an army of these TILs lurking around the tumor tissue. Since these cells are present, it is obvious that they have sampled the antigen on the cancer cells and having done so, if one were to enhance their effect, one could gain another foothold against this scourge called “The emperor of Maladies.”



Further knowledge development from studying this cellular machinery revealed that the cancer cells have accommodated this immune onslaught quite successfully by using the cell’s own defense mechanism of cloaking their anticancer activity with a protein. This protein, the scientists realized, was preventing the immune function from destroying the tumor. From the alternate point of why, one might ask, why does the body not want to protect itself? The answer was clear, allowing a rampant immune response without any checkpoints would lead the body to “destroy” itself when attacked by a simple infection, akin to a pleasant breeze turning into a hurricane. So checks and balances needed to be present to prevent such hyperbolic activity. 

Well now having delineated the mechanisms of action the Immune brigade can be carefully turned against the cancer itself. First the presence of the TILs is an important precursor to the present thinking. The determination of the protein called PD-1 (receptor on the lymphocyte that limits its anticancer function) and PD-L1 (the receptor present on the cancer cells itself). Inhibiting the function of these receptors has resulted in a plethora of drugs armed and aimed at these two proteins (the guardians against hyperbolic responses). Once the checkpoint has been blocked the immune cells can go on to demolish the enemy (cancer). It goes without saying; the more the TILs the better the body is equipped to be helped or conversely if the disease is advanced with a large tumor burden and low to absent TILs, the lower the chances of response.


We tread slowly towards a better future and I end with Shakespeare again, “ Wisely and slow. They stumble that run fast.”


References:

Adam, S et al. Prognostic value of tumor-infiltrating lymphocytes in triple-negative breast cancers from two phase III randomized adjuvant breast cancer trials: ECOG 2197 and ECOG 1199. J Clin Oncol. 2014 Sep 20;32(27):2959-66.

https://www.researchgate.net/profile/Claudio_Clemente/publication/14591062_Clemente_CG_Mihm_Jr_MC_Bufalino_R_Zurrida_S_Collini_P_Cascinelli_NPrognostic_value_of_tumor_infiltrating_lymphocytes_in_the_vertical_growth_phase_of_primary_cutaneous_melanoma._Cancer_77_1303-1310/links/541c00f00cf203f155b34fb0.pdf

http://www.cancernetwork.com/oncology-journal/high-dose-interleukin-2-it-still-indicated-melanoma-and-rcc-era-targeted-therapies

http://bmcmedicine.biomedcentral.com/articles/10.1186/s12916-015-0431-3

http://jnci.oxfordjournals.org/content/108/11/djw144.short

Wednesday, July 13, 2016

HAWTHORNE EFFECT

You might wonder what this is about. And I, for starting this have a bit of concern too. But this is a story not about the author, Nathaniel Hawthorne of the House of Seven Gables, nor is it about the City in New York. It is about an effect.


Effect, you say, what about it? Actually it is a fascinating insight into the human condition. Let me trace it back to its origins. A town named Cicero in the Chicago burbs, housed a manufacturing plant called Hawthorne Works. 


The Illinois City named after the one in New York, which was named after the Roman statesman Marcus Tullius Cicero . Both the city and the Roman it was named after suffered; the city lost 5/6th of its land due to weak politicians and its manufacturing status and Cicero’s head and hands were displayed in the Rome’s Forum after his assassination for angering Julius Caesar (34 BC).

Hawthorne Works enjoyed prosperity in the early 20th century and there is where it was determined that when observation and positive interest is shown in a worker’s work, productivity goes up and vice versa. Meanwhile the display of Cicero’s body parts in the Roman Forum were of equal force preventing any further threat against Mark Antony’s reign -  a negative feedback. Funny how the ghosts in names play out the future with equal measure gained from their history.


The Hawthorne Effect has been written about and “studies” done on hand washing among physicians and nurses in an effect to reduce the potential for spreading infections. The reality goes this way…if one is being observed to do a job, one is psychologically forced to comply. Thus the rate of hand washing among the observed goes up against the unobserved. It might be called oversight in another document, but in the Hawthorne effect the simple act of observation even via cameras or other digital means conspires to inspire an individual to take action. All well and good. Good actions beget good results.

Extrapolating from this act of “observation” as an “observational interest” and giving that “interest” some term such as “value” might have an identical effect, if not profound, at least above the zero mark in a person’s productivity? Again, don't take this to the bank, because where I am going with this is a hotbed of molten lava created from fire and brimstone. You fall in, you are done! So look, Learn and Understand!

“Moon walking” back to the premise of interest and productivity we find that if an employee feels his worth by the company, he or she tries harder. The idea behind that is simple incentive, create value for the company and be rewarded with promotions and higher salary.

You with me so far? Ok, so what gives in the environment of Medical care then?

Physicians are “burnt out!” Indeed, more and more reports seem to not only suggest, but also correlate that with higher rates of suicides by physicians. The metaphor of “losing a jumbo jet filled with physicians every year.” Or if you prefer, “Losing an “entire year’s worth of medical graduates from medical school” every year. Disabling thought, isn't it?
And you must ask why? Ah there in that three lettered word is the essence of science. 

Why, indeed?

Let me posit a simpler solution; maybe in medicine, there is a negative Hawthorne Effect. with no cheerleaders for the once noble profession, only grim reapers always crying, "foul!" Maybe, physicians are being railed against in the media 365/24/7 and characterized as bad actors. So if you are a physician and work the 12 hour weary days and find the profession maligned on the television and media when you sit down at the table for dinner, something’s got to go "kerplunk!" The negative Hawthorne Effect comes to play - remember Cicero’s head and hands on display as deterrence? When every observation is a negative event, work becomes a chore, the shoulders get slumped, the days get longer, the work becomes weary, soon depressing thoughts arrive, unannounced, the devolving gyre tightens and finally the mind cannot hold.

But don't take me wrong on this, the powers that be seem to have absolutely NO interest in the Medical care of the patients, it seems. The powers that be have an interest in their own interests. For instance, The Insurers are interested in making higher and higher profits (the average Healthcare company CEO salary in 2014 was $11.7 million) and they blame the claims from the physicians and make them go through hoops of the medical Revenue Cycle to collect their reimbursement on behalf of the work completed. The government has an inverse viewpoint; to lower the costs of healthcare as a percentage of GDP (currently 17% of the GDP) and they too blame the physicians as the drivers. To that effect they have the annual CMS “Data Dumps” showing what physicians have received in payments (BTW: in 2012 out of $1.2 Trillion only $70 Billion went to pay the 850,000 physicians that translates to 5.8% of total). They also have a “Sunshine Act” displaying any gifts from pharmaceutical agencies to physicians; citing that $10 lunches invoke a severe Conflict of Interest in prescribing medications. Then there are quasi, not for profit agencies that have their hand in the pot like the ABIM, ABMS (claiming public interest as their only mantra while fleecing the physicians in millions of dollars - NAV as of 2014: $134 million), PWRS, PCORI (Reporting agencies that create pseudo-science on the go to determine efficacy of care) and other shenanigans like SGR, MACRA, MIP, APM (designed to create and maintain an ever-ascending vertical bureaucracy that deems who and how payments are to be made for service rendered). The list goes on...

You still with me?

Consider this; The physician is now a "data logger," a well-educated scribe so to speak, on the computer (EHR) and the computer spits out (based on an algorithm) a defined set of tests to order for compliance. All this cataloging is nothing more than information gleaned by and for other companies to sell data for analysis to insurers and governmental agencies to better control expenses in some cases, raise revenues in others and further the interests of all involved in their Net Asset Values. For instance CERNER an EHR computer company, for the year 2014, revenues were up 16.9% to $3.4 billion from $2.9 billion in 2013. Net income for the 2014 fourth quarter jumped 146% to $147.9 million, up from $60.1 million in the 2013 third quarter. Hmm… Judgment and Reason, need not apply when it comes to patient care anymore. Its about dollars and cents and a large public pot for any company to pull out oodles and oodles of cash. In this “One size fits all,“ for better or worse, EHR world, the actual “fit” is immaterial. So what if the helm shows, the shoulders sag on the jacket, the stitching is subpar. So what? And it will all get worse, I predict, because the non-practicing physicians who have taken on the mantle of “experts” have decided that programs such as “Choosing Wisely” and “Less is More” need to be the bully-pulpit from where to scream down into the trenches, “Do this and Not that, or else…” 

There is a pathological obsession in replicating an idea that is profoundly destabilizing and will ricochet through humanity transecting the tether that binds us all as humans. Ah "disruption" they cry and all fall down to their knees in unison to the lure of the ethereal enriching beast. The capacity to think of the whole and not always the parts in isolation can bring to view the unintended consequences; those things that go "crunch" in the long winter nights are never a part of their thought.

The Mocking Jay



So while this rant appears like a rant and maybe is, it does have the potential of the sound of a “Mocking Jay.” As the people realize what the future holds for them a band of brothers and sisters will finally say, “I’m mad as hell and I’m not going to take this anymore!” The physicians might lead on this and then as care is depleted and noticed, the rest of us will follow suit.

Monday, July 4, 2016

ASPIRIN & CANCER


Every so often a product comes along that defies augury. And yet with each passing future it provides tiny visages of it’s abilities to predict what may lie ahead. Aspirin, the old Salicylic Acid, the most used and ofttimes reviled substance comes to the fore in cancer care.



But barely so, because the pockets of the high and mighty pharmaceuticals continue to whip up a storm of this and that in small incremental advances through complex machinations of the human cellular biology, while Aspirin continues along its merry way easing the burdens of diseases unbeknownst to its takers.

Aspirin and Colorectal Cancer:

Aspirin continues on its quest to impair the mechanism of inflammation; the hallmark of most diseases such as cardiovascular and rheumatological diseases and including cancer. We will leave the heart to the cardiologists, but for now let us delve into the wayward cancer cell.



Low dose Aspirin continues to be a constant nagging positive feature in cancer prevention, much to the delight of many. The most recently studied data disclosed suggest a significant reduction of risk and death from Colorectal cancer in those using a daily dose of lo-dose Aspirin. Looking at the mechanism, it becomes clear that COX-2 inhibition may be at play here. 


The implications stem from the reduced inflammatory effect and the production of polyp formation. Since most such polyp formations precede colon cancer and with the steady stream of sequential and sometime concurrent genetic mutation is at play in the polyps. Preventing the polyp formation itself becomes the “Strike three” (in baseball analogy) against the cancer. 



Aspirin and Esophageal and Stomach Cancer:

Continuing on the gastrointestinal tract issues, there is also abundance of proof that suggests that the same lowly lo-dose Aspirin taken over 5 years also may reduce the risk of Esophageal and Stomach cancers by 30% and death from these malignancies by 35-40% (1). A meta analysis of eight studies using individual patient data showed an overall lower deaths from common cancers in those patients consuming daily Lo-Dose Aspirin (3).

Aspirin and Colon, Breast and Prostate Cancers:

Another study highlighted benefits of risk and death reduction in bowel, breast and prostate cancer patients who took Lo-Dose Aspirin by 15-20% (2).

Given such accrued overwhelming data the USPSTF added Colorectal prevention with Lo-Dose Aspirin in their Preventative Recommendations in 2015 (4).

Liquid Aspirin:

A more interesting and provocative study from Britain shows that Liquid Aspirin in the form of IP1867B when given intravenously leads to cell kill in brain tumors (Glioblastoma Multiform or GBM). The nuance from this study has significant implications in overall cancer care in the future (5). Keep your eyes peeled on this development!

So with such a preponderance of information it behooves people over the age of 45 and beyond to take Lo-Dose Aspirin (as long as no allergy or sensitivity towards gastric bleeding exists) as a cheap form of prevention. This when added to exercise and a healthy 2000 calorie diet (fruits, vegetables, legumes etc.) will keep most in good health longer.



And just for the record, don’t forget Aspirin’s effect against Cardiovascular Diseases: heart attacks and strokes!

REFERENCES:

1. Jack Cuzick, Ph.D., head, Center for Cancer Prevention, Queen Mary, University of London, England; Leonard Lichtenfeld, M.D., deputy chief medical officer, American Cancer Society; Aug. 6, 2014, Annals of Oncology.

2. Peter C. Elwood, Gareth Morgan, Janet E. Pickering, Julieta Galante, Alison L. Weightman, Delyth Morris, Mark Kelson, Sunil Dolwani. Aspirin in the Treatment of Cancer: Reductions in Metastatic Spread and in Mortality: A Systematic Review and Meta-Analyses of Published Studies. PLOS ONE, 2016; 11 (4)

3. Rothwell PM1, Fowkes FG, Belch JF, Ogawa H, Warlow CP, Meade TW.Effect of daily aspirin on long-term risk of death due to cancer: analysis of individual patient data from randomised trials. Lancet. 2011 Jan 1;377(9759):31-41. doi: 10.1016/S0140-6736(10)62110-1. Epub 2010 Dec 6. 
 
4. Chubak J, Kamineni A, Buist DS, et al. Aspirin Use for the Prevention of Colorectal Cancer: An Updated Systematic Evidence Review for the U.S. Preventive Services Task Force. Evidence Synthesis No. 133. AHRQ Publication No. 15-05228-EF-1. Rockville, MD: Agency for Healthcare Research and Quality; 2015 

5. http://www.dailymail.co.uk/sciencetech/article-3663188/How-liquid-aspirin-help-fight-brain-cancer-Special-version-drug-ten-times-effective-killing-cancer-cells-chemotherapy.html

Wednesday, June 29, 2016

THE SOUL of a HUMAN


Is it my misery that beckons you? Is it the pain that I suffer that invites your eyes? Is it the torment of my daily life or the once in the blue moon event that attracts your attention? Is it the muted cry of my humanness that plucks wildly at your heartstrings? Or is it the weakness of my being that encourages a look? What is it? What drives you to peer at my destiny? What makes you realign your focus? Is it empathy? Or is it to feed on my despair? Does that make you feel good about yourself? Does my misfortune make less yours? Do my cries wash your selfpity away? Am I the monster of your dreams gone ugly? Or am I the wretched soul that gives you comfort that you are not me? Where are you, at?

Or is it the art of tutoring? The fawning over tragedies that make for a resonating vibration, which has the magnetic pull since the invention of the written word. Shakespeare’s Hamlet, Macbeth and Romeo and Juliet, enjoy more recognition then comedies like Midsummer Nights Dream and Taming of the Shrew. Or is it the constant chatter of the pain of loneliness, the sense of ostracism from an inwardly turned society or just a game of the mind. Or do the far away Roman prisoners fighting for their lives idealized in movies, in the Coliseum bring forth the unholy desire to peer at a similar carnage?

Is it my fame that calls your attention? Is it my material trappings that invite your disdain? Is it my knowledge or my intellect or lack of it that triggers the belligerence? Is it the soft-spoken nature of truth that undoes your passionate anger towards success? Is it the blind rage towards the goals that I have achieved or desire? What is it? What drives you into this riveting narrow focus of hate directed towards me? Am I the monster that quashes your ego? Or am I the beacon of truth that you wish to demonize? Or is it my soul that I have carefully crafted over my lifetime to succeed that governs your wrath? What makes you greave in fits of anger directed at my visage that haunts your very being? What gives you such vehemence?

Or is it the greed and jealousy of a few that fan the flames of hate of the many, cloaking their better angels? Is it in us or is it inbred? Is it Darwinian or Lamarckian? Or is it the implied flow of human emotions festering like a sore sprinkled with salt? Where does this pain of greed originate that feeds and simultaneously bleeds us of our better self. What nerve root, what impulse, what receptors deliver and receive these poisoning emotions?

These are the questions that tear a soul apart. These questions force an inward look. These are the questions that change life. Answer them and then look at yourself. Answer them quietly in the comfort of your being and you will change – for the better. They will force you into a place where superficial comfort is not given entry. It is a lonely place, a place of horrors, of soul mutilation, of ego deflation, of ghostly demons, of the id forced beneath the murmurs of human thought. Go there and look deep and what might emerge is a pure soul. The soul of a human! The oneness of being! The solemnity of truth!

You!

Saturday, June 18, 2016

THE WOLVES OF MIS-MEASURE


Measurement…

01001101 01100101 01100001 01110011 01110101 01110010 01100101 01101101 01100101 01101110 01110100

The mismeasure of life falls on shoulders that bear no burden. Now that is quite provocative a statement as any, don't you think? It is true! Here goes…

The Yesteryears:
In the world today Charles Dickens’ Thomas Gradgrind(s); he of the ready with “a pocket’s rule and a pair of scales,” excel in their merchandising, selling whatever it is they do not or need not understand, except in return, they must receive a fair amount of monetary advantage. They talk of measuring the essence of all things material. Indeed nothing can pass without a metric that cannot be reality-weighed in pounds, kilograms, tonnes or if not then by virtual means. Such recursive abstractions using manufactured evidence is the bane of true understanding. The days when Johannes Kepler stood on Tyco Brahe's shoulders and figured out the ellipses of the solar system and Sir Issac Newton's claim of the equatorial bulge of our earthly planet (26.58 miles) from the spin, are long gone. Gone also are the days of polymaths like Eratosthenes who calculated the earth's circumference in stadia and also created a sieve to determine the Prime numbers. Today it is "publish" nonsense or "perish," into academic oblivion.



Society has flourished with measurement. From the clay tablets of the 4000 BC to the modern day smart phones where abacus is but a long past antiquity. Today everything is being measured form body mass index to the Higgs Boson. And each measurement reflects a differing set of metrics. Some in weight (Archimedes and his “Eureka”), others in volume and even the tiny bosons in electromagnetic voltage (Higgs = 125 GeV). You see even Plato's Socrates had a detection meter called the “Elenchus,” which through questioning ultimately elicited the truth. Alas today, "sincerity and purpose" displace true rigor as the touchstone. We have fallen into the trap of shielding ourselves against questions to protect our vulnerable and unverifiable results. And to boot, those false prophets of measures are being associated/correlated/linked with other measures creating a a population of mis-measured "Roaches" that make it difficult to defy the inherent Augury.

The Yesterdays:
Erroneous numbers can cause economic damage when the metric of measurement is different. A $125 million Mars orbiter was lost in 1999 due to a serious mismeasure between the NASA and Lockheed Martin. One side used the English metric system and the the other used the conventional one. The net result was a spectacular news splash. Only after such a catastrophe and a quiet contest of the wills, did the rules of mental engagement change.




The Todays:
Today quantification is akin to reality and real science. "Economists" and "Scientists" revel in this measurement sort of thing. They measure a nation’s output in various different ways as GDP or GNP and Liabilities in the form of debt and deficit. All are material to a nation’s well being. Quite simply if you produce 2 of anything and consume 1 of the same then you will be 1 richer over time. The reverse is equally true making a nation poorer. Solutions from these gifted snake-oil people in a stagnating economy is "don't worry about the debt, print the money, spend with abandon and everyone will be happier," (I often wonder and worry about the "everyone") forgetting the value of the paper money will go down as there will be more of that paper around (inflation). The touchy feely state of affairs is cloaking the sense of foreboding temporarily, expertly employing, kicking the can down the road philosophy.


In medicine one wonders if Lord Kelvin’s, he of the absolute temperature fame, statement was taken to heart by the expert physicians, “when you can measure what you are speaking about and express it in numbers you know something about it, but when you cannot measure it numbers, your knowledge is of a meagre and unsatisfactory kind.” So every form of medical study to date about newer treatment has graphs and numbers that deal with benefits over something else as a means to convince others about the validity of the new treatment vs. the old. The manipulations of the numbers is a whole different story (Read: p-Hacking). As a consequence of this riddled thought 54% of all medical landmark studies cannot be validated in re-experiemtnation (Read: John Ionnadis).

Today we have gone into a “Measurement” overdrive. Using the computing power and a set of simple mathematical formulae with assumed variables quantified through axiomatic weighting we arrive at results that give us implied “Values” and “Benefits.” We determine statistically the Quality of Life using arbitrary numerical values laced with, again, assumptions that may or may not invoke Thomas Bayes’ name. Going far into the realm of this “Science” where everything has a weighted measure of value-that we pull out of a hat, we then ascribe a monetary reward for that achievement. It isn't anything like 1-lb of this equals 10 Shekels and therefore 2-lbs equals 20 Shekels. It is more like this ethereal “value” is worth 10 Shekels and failing the arbitrary metric of that value equals 0 Shekel or even -5 Shekels. And of course lack of value is a simple complaint away from the worker receiving any Shekels. The perpetual engine of revolution has ceased. No oil, no grease just a jammed up thought of yesterday’s todays.

The Mis-measure of Emotions:
Lets look at Satisfaction Scores as a measure of value. I leased a car from a car dealer and the salesman said, “You will receive an email asking if you are satisfied with our dealership. If you are not going to give us 5 stars then please call me before you submit that form.” Curious as to what the was about, I called him and lo and behold he said he would be willing to forgo the expense of the next car service charge. Some would consider that a bribe others would say “take it, what do you have to lose?” The problem is the awards emanating from the "award bestowing agencies" are fraught with hidden moral hazard. But you knew that already!


Taking that a step further, look at the “Pain” issue among patients. The Joint Commission for Hospitals and all "expert" endowed policy determiners recommended that “Pain” be considered a “5th Vital Sign.” In other words every doctor must assess the pain of his of her patient. And there were many formats to measure pain also devised by other well-meaning people. In one measure emoticons were used as means to determine intensity (Wong-Baker FACES). Patients needing pain medications used it to their advantage and a physician not wishing to get his “Satisfaction Score” in the gutter complied. Soon the opioid epidemic became a newsworthy item with “Breaking News” and “Alerts.” And a few doctors, worried about "Satisfaction Scores," on which depended their income got themselves into legal and regulatory muddle writing prescriptions with abandon. The husk of this ceaseless proliferating misinformation grows as the core of real knowledge atrophies and dies in the hearts and minds of those "grunting and sweating under the weary life.".


The Tomorrows:
The desire to measure is fed by our own hubris and grows and grows to overwhelm us with its unintended consequences. Today the elite speak only with the experts and the experts communicate only within themselves, thus propagating the myth of their "far-reaching knowledge and intellect." Thus the only piece of information is a rehashed version of manufactured evidence processed as knowledge and distributed via ventriloquists posing as teachers across the campuses.

"For who would bear the whips and scorns of time,
Th' oppressor’s wrong, the proud man’s contumely,
The pangs of despised love, the law’s delay,
The insolence of office, and the spurns
That patient merit of th' unworthy takes..."
Indeed, who would?
But the people with a conscience and the fear and dread of the potential ill that might befall them from the "slings and arrows," hurled at them via "The insolence of office."

So measurement used in things that remain unmeasurable creates a false sense of illusion of expertise and intellect.

The Warning:
Remember whenever numbers are thrown out and percentages are flickered on and off in conversations or written on paper, know to cast a weary eye on them. There is a deeper, darker and more sinister mechanism at play; Self Advantage under the guise of intellect. And if you should hear the words, “Public Good” be equally afraid. The real boogey man is nearby.

Be very leery about…

01010011 01101110 01100001 01101011 01100101 00100000 01001111 01101001 01101100

Friday, June 10, 2016

BIRTH and DEATH (A Poem on How Cells Transcribe)


CELLULAR TRANSCRIPTION


The ebb and flow

Of the storm;

Overhead crackles

And flashes of movement

While

The vacant crucible

Sits and ponders

Silence.




The shell fluid

In motion,

Transmitting and morphing

Signaling.


The rash of messages

On passages that move,

The hum of machinery.


Action and reaction

Touch and turn

Each touch a turn

Each turn a touch.




Molecules within

Molecules around

Floating, ethereal.


Each molecule, a war

And peace within.

Captured in time,

Enslaved to the cause

Of motion.


Some blessed to grow

Others to cease.

Some move 

Others stand

Some change


Others hide,

Some ugly in folds

Reveal beauty in action

Others ethereal in looks

Sit idly by.




Time lingers

As each motion intensifies

The girding machine rumbles

In silence.


There are no cynics

No arbiters

Only touch and go

And time.


The epi on genes

Like an umbrella

Of shades.

A fountain

Of truths.


Of present and days of yore

Of futures to be realized

Of stories yet to be told.

Sunk in the touch.


How this fits

And that doesn't

How this molds

And that swims away.


Motion, is all

Yet all is in mirth.

Transcribing they touch

The actions of another.


In so doing, death

In so doing, birth.


Tuesday, May 31, 2016

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.