Saturday, March 28, 2015

DIGITAL IMPERIALISM


There is a flawed nature of perfection that we seek. Today this goal is governed under the continuous creation within the digital context. The present and future are heralded while the simplicity of the past is ground down into flakes of an imperfect horror of backwardness.



This leviathan has sprawled into the architecture of our humanity. It invades our privacy, dictates our lives and imposes the conforming principles of compliance without hesitation with all the ingredients of the 1 and 0s.

We seemed to have forgotten Robert Browning’s words,

 “Heart, or whate’er else, than goes on to prompt
  This low-pulsed forthright craftsman’s hand of mine.”


Ah the low pulsed forthright craftsman’s hand is forever replaced by the tedium of a glowing screen. Yet there may be light in this. Yet there may be some truth in this. But where that is, I cannot see, for it invades and usurps my own vision and thought.

We clamor for wearables to motivate us while we sit in front of the glow of the screen. Our every move is charted, dictated, governed and recorded for all to see. The digital 1s and 0s in their inhuman repose slip through the slipstream and house in large warehouses to be massaged and manipulated to create an alternate world view to suit the algorithm sponsors.

“Where does machine stop and man begin?” is a question a Dr. Salwitz asked recently. Indeed where does the fine thread of division exist? Our very life is governed and ritualized within the spectrum of the digital universe. Our sleep patterns, our movements, our heart rates, respiratory rates, everything is coded. Indeed how many steps we take symbolizes how healthy we are or will be.

We can share our photographs with a flick of the thumb, place the entire library of Congress on the head of a pin, watch a movie on our smartphones, immerse in the virtual world and never know any difference between what is real and what is implied. We see our doctors not through the eyes of patients as healers but as detached souls clamoring for time, rushed and oblivious to the real underpinnings of disease and illness. We see our patients not through the eyes of watchful vigilance, but through the lens of “one size fits all.” Somewhere there is a loss of trust, of empathy, of living and a gulf that seems to grow large every day.

The digital imperialism is upon us in every walk. We have mountains of data on human behavior that some select to govern the rest. We have burgeoning library of genomics, proteomics and epigenetics and we know less of the interactions between these molecules and human survival. We know more about the cell and less about how it governs itself. The reductionism brings us the mountains of data, unfortunately thus far it remains elusive to tie them all together. Yet there are among us who feel that we have all that we need. We have the tools to march in a certain direction or to take the specific path. But they like the rest of us are pleading to the merciful gods of their desires that they are right in their assumptions.

The digital dynasty is upon us and it has brought many good things to our lives. But there are the swirling storms of desire that every aspect of our existence should be cataloged and governed within the digital domain. As Lao Tsu stated, "He who knows when enough is enough, will always have enough."



Life is mathematics, there is little question about that, but it is also that subtle fine art that cannot be reduced to the simplicity of the 1 and 0. But for that small undetectable grain of truth that garners the spice of life, we would be all robots. Today all we are trying to do is smear, suppress, stomp on or hide that tiny piece of reality that makes us who we are.

The question then remains where should we as humans define the fine line between what is and what is assumption?

Ah, life…

“Life is simple but we insist on making it complicated.” – Confucius 

Saturday, March 21, 2015

FORCES IN MEDICINE



Medicine is forever in a flux. There are innovations, new products, new diseases, new therapies that create and disrupt the ebb and flow of this profession. But through it all, medicine continues to prosper with better alignment of resources and improving the overall human health. The life span of humans has progressively increased over the past six decades. Man is enjoying better health then did his grandfather. A woman far exceeds that comparison because of reduced maternal mortality related to birth and enjoys four more years of life then her male counterpart.

Porter’s Five Forces in business seem to apply well to the current model of medicine. 

Rivals: 
a. Primary Care Physicians (MD,DO)
b. Specialists (MD,DO)
c. Non MDs

Assuming that the current business model of medicine is the practice of medicine and ingrained within this model are the competing forces of the Primary Care Physician and the Specialists. All are gathered to compete for the individual patient to provide a service. These forces although typically are unified in purpose, also compete as rivals for the patient to provide that care. They compete with the latest and greatest options as a means of product differentiation, that they can apply to achieve the larger patient load. For example, the dentist advertising the clear braces, or the Radiation Facility its Proton Beam Therapy unit or the surgeon advertising his adeptness at Robotic Surgery. Outpatient facilities compete between themselves and against the hospitals for the patients. The non MDs including the Physican Assistants, Nurse Practitioners, RFNAs, are all examples of healthcare givers who are eating up the distance between true medical knowledge and experience and gaining freedoms of providing independent care to the patients through lobbying and political fiat - for cheap. These are the inherent forces of rivalry that exist today. 



The rivalry that exists within the current model exposes inefficiencies and this constant tug from the buyer and supplier should lead to price discounting with more products availability as a cause of the competition. Alas with the intervening governmental and non governmental insurers, the price discounting has been tempered by mandates and regulations that seem to protect intermediaries more than the buyers (patients). Additionally the forces of new entrants makes it interesting by keeping the levers of commerce constantly in motion. These levers however add to the cackle of the intermediaries.



Buyers: 
a.Patients

The Buyers are the Patients. In the days gone by, the patient was remarkably innocent to the workings of medicine and at most times in history believed in the potions and magic of the physician and the snake oilmen. Some got better while others did not. That was the way of the past. There was a certain faith in the alchemy of medicine and in it’s practitioner. Times have changed. The patient is now more informed about diseases, less exposed to financial risk if he or she is insured and thus less concerned about the costs.



 Although the information on costs and appropriate therapy is available, it is not easily comprehensible by the patient, both by the complexity of the information and/or by the sheer fear of knowing. The amount of information in the form of data is overwhelming to any one person and more and more is being piled on.



Currently families and Advocacy Groups fulfill the needs of the patient by navigating the complex medical jungle. Even within the advocacy groups a certain ignorance lives, because asymmetry of information remains. The "well-informed patient" will have the power of negotiation at price discounting on a one on one basis. Unfortunately the term "well informed" lives within the limits of the acquired information and one-on-one is the least exercised version in this complex. The bargaining power however will also determine the ability of being able to rationally ascertain quality. The focused Decision Making guarantees a successful outcome. It is a forced responsibility at both ends of the spectrum, between the Buyer-Patient and the Supplier-Physician/Nurse. The ultimate benefit will be in the hands of the Buyer-Patient. The media unfortunately berates the idea of fiscal responsibility for the patient, infantilizing their existence and in so doing prevent the "skin in the game" of a social contract.



Other stakeholders with significant influence on the Buyer-Patient are the governmental and non-governmental insurers. Both unfortunately have competing arguments that limit their function. The non-governmental insurers are concerned with their own shareholders’ profitability. Their decision making is based on the profit margins accrued as a result of the balance between Revenues and Expenses, which cause them to continually raise the premiums and or add hurdles to decrease provision of services to their clients, the Buyer-Patients. There subtle agency issues of bonuses that insinuate themselves into the arguments and most times rule at the end of the day. The governmental insurers have a different, albeit under a different lens, purpose; the desire to limit the expense and control 17.9% of the GDP. They use their influence through attacking over utility of services, which is at times a noble cause and at other times a fallacy of thought. However in their zeal to balance the budget (an oxymoron)  demonize all services that are deemed expensive. The push of the costs and the pull of the voters force the governmental agencies into a firestorm of marginalizing one entity in favor of the other an altered perspective through their lens. Thus bureaucracy holds a huge sway in the marketplace and distorts the markets and their freedom to exercise caution, benefit, self-control and innovation. 




Suppliers:
a. Insurers
b. Government
c. Pharmaceutical Companies
d. Biotechnology Companies
e. Medical Device Manufacturers
f. EMR makers
g. App makers and other Wearable technologies
h. Attorneys

Physicians are bearing the burdens of this costs as most of the ire is directed at them. But, what of the physicians? Lets look through their lists quickly:

Total allowable billing is $2.9 Trillion in total healthcare as of 2014. However only about $77 Billion were direct payments to the physicians for their care and the cost of keeping their medical practices operated by CMS alone, which expensed a total of $1.04 trillion in 2012. Of the $150 billion billed by physicians and other providers, 49.7% was never collected. It costs the physicians 3.3 statements per patient before being paid at a labor cost of $12 per statement. There is an automatic 11% denial of all reimbursements for service rendered, which creates a $300 billion windfall for the insurers. Physicians are governed by the Medical Revenue Cycle as no other business in the world! There is a 40% of cost in providing the doctors their reimbursement as a part of this Revenue Cycle. The suppliers therefore have a large stake in collecting their fees. These include the government, insurers, pharma and device makers. Of these four large supplier groups, the latter two actually provide service. Modern medicine is in the folds of a large-scale disruption. These disruptive forces are varied and all have influence over the patient-physician interaction. One of these influencers of medical care includes the FDA and the media outlets who determine, marketing and or manufacturing need. The evolving pressure ensues through scientific studies, radio and television advertising and via the print media. These pressures change the behavior of both, physicians and patient, over time and at every turn of the screw. A discord between the "buyer's" desire and his or her need creates forces of demand and denial.


Listed in the supplier category are also the Hardware manufacturers, Pharmaceutical Companies, Software creators, Monitoring Device manufacturers, Curators, EMR and EHR advocates. The Hardware Manufacturers are the innovators that create Defibrillators, Pacemakers, Artificial joints, catheters, hearing devices, viewing devices, Biomedical monitoring Devices like Heart Monitors and EKG machines etc. and personal monitoring devices that are the rage of today. Their pitch is the same; every new device is tantamount to better health, all things being equal. Both the buyer and the supplier are equally influenced in their decision making as a result. Some suppliers are influenced through financial pressures and others through contractual obligations. The free market forces albeit active are subdued under the influence of the larger cult of regulations and thus never are able to set the correct pricing or the need.



The Pharmaceutical companies produce the drugs and bring them to the market at an exorbitant cost (Recent estimates are between $800 million to almost $ 1.8 billion. At times the drug fails and a one-trick-pony company’s dreams ends in a single day. Other times it works and the company can go on to become a behemoth enterprise. Proving benefit of the drug is foremost in a company’s mind and that translates directly into future profitability and solvency for the company. Given the expense and the future earnings potential for a favorable drug, there are large scale statistical-force-manipulation of the data to achieve positive results. Unfortunately John Ionnides, MD has taken the "critical studies" to task and found them wanting in over 50%. In other words, a majority of the "impact" studies cannot be validated and are not reproducible!

The Supply-Demand model of healthcare is climbing the hill of uncertainty due to the limitation of the finite dollars, even during the Quantitative Easing or QE and the printing and supplying of more dollars to provide liquidity to the demand chain. As the value of the dollar recedes, the cost of healthcare in those dollars increases. This increase is levied by the "someone else pays mentality," "availability of transformative innovations," " an aging population," and "increasing burdens of the metabolic-chronic disease from lack of self-control in the land of plenty," terminologies and an over supply of desire.



There is also a constant tug of war between the Brand Labels and the Generics. Patent loss, continually erodes the bottom-line for the brand label drug companies and simultaneously enhance the profitability for the generic drug companies, but sometime that results in a cost of product integrity (Ranbaxy of India and the New England Compounding Center company of Massachusetts debacle). Large biotechnology companies like Amgen, Genzyme(Sanofi-Aventis), Genentech (Roche), Biogen, Celgene and others are the innovators in medical care through molecular research and by creating biologics (inhibitors and enhancers of gene and protein function) as treatment remedies. There is a continuing consolidation through Mergers and Acquisitions occurring between the Pharmaceutical companies and the Biotechnology companies to continue innovation or consolidation of resources at a faster pace. New innovators take the open space and are often gobbled up by the larger predatory ones due to the steep price of new entrants in the marketplace, while the predators are looking for their own survival due to a dried up pipelines and or the loss of R and D accrued at the cost of Stock buybacks to keep their shareholders happy.


There is a new breed availing itself of this dynamic marketplace and they are the curators of the data. Their main purpose is to store data in various formats. Like the libraries of the past, the digital age has spawned large databases housed in various servers.  There is a price for obtaining the data. The data mining folk are busy extracting information from the data, albeit at times the results are colored with the premise of selection bias. This bias has a tremendous impact on patient care. The seemingly perfect potion or pill based on selected bias or population medicine causes more harm than any good. These purveyors play a pivotal role in masking, enhancing premises that color thinking of the supplier, sometime to the detriment of the buyers.

The legal system  influences every aspect of the medical care system. Lawyers are involved in Medical malpractice, they team up as Lobbyists for self enrichment and sustenance, as Regulators and creators of new Regulations to bolster their own needs. The field enriches itself through the pervasiveness of the litigious mind-set of the populace with the continuing precept that more regulation is better and "zero-tolerance" for error or any unfortunate "event." The forget that to err is human and to err is universal. It is through error that we learn and progress.

The EMR (Electronic Medial Records) and EHR Electronic Health Records) advocates are the ones who have helped foster the software and hardware services to a new hype in medicine. The implied view is to help improve patient care but at $40,000.00 a clip and no evidence that patient care or cost reduction has been achieved,  the uncertainty remains. The costs have risen due to the ICD coding embedded in the EMR software for each complaint the patient might have. Notwithstanding the lack of formal evidence, the influence to force this digital climate upon the physician is here and now when implemented stands as a huge barrier between the physician and the patient. The cost of the EMR program envisioned by the government has cost the tax-payer $300 Billion and it will cost an additional $9 Billion for maintenance. meanwhile the physician incurs the annual costs of service contracts, software enhancements and computer outage risks. The EMRs will work only when they become an invisible background and actually increase efficiency of the care rendered! Until then they are nothing more than a shiny piece of gadget that collects information for the insurers and the government entities and stands in between the buyer and supplier as a deterrent.



Substitutions:
a. Homeopathy
b. Acupuncture
c. Reiki Therapy
d. Alternate Medicine
e. Over the Counter Medicines


Addressing the needs of the skeptical mind, there are forces that carve a niche for themselves in the medical care field. The driving force here is the alternative form of healthcare remedies. The homeopathic medicines, Herbals and the vitamin industrial complex (here the pharmaceutical industry is also a force supplying ingestible medical products not needing FDA approval) is in full dress rehearsal touting the wild and wily benefits of various extracts from plants, fruits and vegetables-some might be helpful, but most are hype.



 Other Substitutions include the various fields of Acupuncture, Reiki therapy etc. These do provide service to the Buyer-Patient at a different level and feature the “Alternative Medicine” route. Their function seems to be attributed mostly through the placebo effect of an energized mind. Meanwhile under the shadows of marketing, the constant tug of war continues between the Allopathic and the Alternate Medical proponents. The influence created by the dynamics of advertising between the two industries brings to bear on both the Buyer and Supplier forces.



Entrants:
a. Medical Students
b. ABIM/ABMS
c. Obamacare

The entry barriers in the field of professional medical care, is extremely high. The cost is prohibitive for the Suppliers, where licensing, regulatory demands and constant evolution is more a need then a want. The physician for instance has to bear a cost of medical education that can run between $250,000 to $500,000. Even after they graduate, they have to apply and maintain a license.



The various medical Organizations that have taken seats of power in the governance of the physician activities create more and more guidelines, eventually turning them into mandates. Initially for instance, the physicians were encouraged to certify themselves from their specialty Boards, Now realizing the financial bonanza, the American Boards of Medical Specialties, have crafted a 10-year recertification requirements and within that a Maintenance of Certification that requires a biannual cost to the individual physician. These costs are not trivial. Every two years the physicians are forced to spend $2000.00 and a two to four week of rote learning, with no patient benefit as proof, to pass the tests. Not only does that take away time from patient care, but it has not shown to have any benefit in caring for the patient. The Boards themselves have a financial incentive to stay in the game as their hired staff gets large salaries to the tune of $1,000,000 annually, lofty condominiums in ritzy neighborhoods supplied by Mercedes Benz limousines, to drive them around and bonuses to fly first class just to advance their own financial agenda. ABIM now has net assets worth over $50+ million an increase of over 300% in under a decade. Meanwhile the Insurers continue to reduce reimbursements to the physicians, especially the ones who have taken assignments to accept insurance payments directly and the doctor works harder and harder to keep his or her doors open, squeezed at both ends. Seems that the puppeteers are having a field day at the Fair.

There are consequences...

Mergers and Acquisitions in Biotechnology and Pharmaceutical Industry curbs innovation. Some products are shelved arbitrarily, some promoted for more research. The end result is a smaller pie. 
Since the exit barriers are extremely low but unfortunately the cost borne by the Entrants is enormous. A failure is a shuttered door with losses in hundreds if not thousands of employees seeking unemployment. Short term benefits succumb clear thinking of Innovation. Innovation brings together new approaches and ideas and creates a milieu for new efficiencies. It also announces itself as a substitution at times. Innovation in product, a creative new methodology or even at gaining a new understanding of an old product or service is the hallmark of future success and sustainability.

The PPACA (Patient Protection and Affordable Care Act)  signed into law is a new entrant in the market place. The cost of bringing this mandate into fruition is expected to climb over $2.9 Trillion.





There are hidden taxes, penalties and a large numbers of new regulations embedded within the Act. The Entry barrier was low since the government was the entrant, although challenged at the state level and at the Supreme Court level where the measure was approved with a 5 to 4 vote. The state level issue has yet to be resolved, with challenges remaining related to economic downturn, fiscal restraints and the burgeoning rolls of the indigent population under Medicaid. The full and direct influence of this mandate is yet to be felt by the nation as the healthcare costs continue to outstrip the GDP. Litigation at The Supreme Court of the United States via the King v. Burwell still has the potential to throw the whole scheme into disarray at a further cost to the tax payers.





Porter’s Five Forces in Medical Care are vibrant and meaningful in their influence over the care rendered to the patient.


In essence as all transactions ultimately relate to the desire and need of the buyer. The patient is the buyer in Medical Care and he or she should decide what is the best form. Times have changed from a one-on-one interaction of the past where only two forces existed; the patient/buyer and the physician/supplier. There were no intermediaries in the profession. The business net has been cast and the forces of business are at the gate. These forces exist to mature the system into the very essence of it being a business and to that effect, the once patient-physician relationship is also filtered through many lenses before the eye catches a glint of the other eye. The patient once viewed as an afflicted soul from nature’s wrath is now viewed through the lens of currency. There is a certain shame in that, but then I digress.

https://www.mckinseyquarterly.com/Health_care_costs_A_market-based_view_2201

Saturday, March 14, 2015

IN SEARCH OF IDEAL

Is perfect vision a perfect vision? Now, I've got your attention, I’m sure. The answer is, it is not. You know why? There is a “blind spot” that is photo-shopped out of our perceived viewpoint through “fuzzy logic” by our brain. So our perceived view of the world is in slight variance with the real reality out there. And besides, perfect is a relative term.



So what is this romance with the ideal?

As humans we look to achieve goals and based on the perceived intrinsic value of that goal we conjure up an honesty factor to it and work towards it. Is that a bad thing? No! Absolutely not! Yet as we move through the path of that progress we arrive at something that we then perceive to have a higher value than the one previously and that then becomes the ideal. An example that many have used in ethics where a person who claims absolute honesty, lies to protect a friend has thus changed the value stream order: friendship supplants his virtue of honesty. Is that right or wrong? Now before you sit on that high horse, think a little. An ideal is an unattainable goal, but something we all aspire. Our limits never reach the limits of the ideal, as the mixture of thought and small successes keep us grinding towards it. Ideals change, mutate as more information and experiences rush in.

It is easy to live in the world of idealism, where everyone follows the tradition of the ideal except you. That would be easy, wouldn't it? A person who pontificates the virtues of timeliness, yet always shows up late. The vice of that stalemate remains elusive to that person. It goes back to Marie Antoinette also with her view in the secluded world from regressive taxation and the brewing economic crisis, “Let them eat cake!” she cried on the day as the bourgeois cried "Liberty, Equality, Brotherhood"  and stormed the Bastille. Different world views, wouldn't you say. Different ideals, for sure!

These ideal-makers exploit a few traits and in so doing, create a simpler more appealing archetype and then wish to rubber-stamp everyone’s ethics and morals. It does not matter what discipline or field that is in their express thought, whatever it is, it falls within their crucible of ideal. Unfortunately as the play goes on and the fragmented thoughts are pulled together unwittingly or unknowingly, a complex fabric of dos and don’ts quickly follow and soon become the charter of dogmas. In fact none other than a socialist, Bernard Crick, had to point that out, ideals should be descriptive of a process not outcomes. One should ponder on that a bit.

If human life is considered an ideal, then the seven billion mini-subsets of that consciousness should also be considered the same. It is the vagary, variety and diversity of each thought and action that creates the fabric of the whole human race. Artificial segmentation into ideal and not-ideal negate the gravitas of human life itself. Thus humans are imperfect in nature but ideal on to themselves in their own mental domain.

“In the mathematical field of set theory for instance an ideal is a collection of sets that are considered to be "small" or "negligible". Every subset of an element of the ideal must also be in the ideal (this codifies the idea that an ideal is a notion of smallness), and the union of any two elements of the ideal must also be in the ideal.” Simple and straightforward, don’t you think? Kind of what the previous paragraph seems to infer.

Schrodinger's ?


In experimentation the closest ideal is the thought experiment called Gedankenexperiment in German. Now, now hear me out! When you do a thought experiment, you utilize your intuit and the knowledge base from where stems the likely thought experiment. It runs its course in your mind and the faults in the virtual landscape are exposed where potential landmines of unknowns exist. You correct for them as you move on, a step at a time. Ultimately you arrive at the solution and that solution may or may not be what you had anticipated. Yet today in this “Ideal-minded” culture the answer must always be what we envision it to be. So we create the statistical torture of simple numbers and use ratios and percentages to fill in the blanks. Even when there was every opportunity blank out there yelling at you not to follow the proverbial yellow brick road. You still did! Alas the yellow color has magical, mystical and magnetic powers in it.

The philosophical analogy of an ideal then can be crafted around a set of characteristics akin to samples from a population that fit those characteristics and not necessarily the entire population. That would be the Max Weberian approach, so to speak. Such ideals are limited in scope and do not encompass the whole. And thus ideals are a process driven of limited-value-ethereal-entities that reside in one’s mind and not as a totality of the envisioned outcome. The problem arises when such ideals are utilized in a way to express outcomes and thus become the be-all, end-all of the human endeavor. An ideal should be like the epistemic thought governed more under the shroud of skepticism rather than as a brazen finality. Conjuring idealism is a tautological concept that bubbles and boils in the form, both ethereal in nature and conceived only in the nebulous sector called the mind. As Bertrand Russell elegantly said, "If we say that the things known must be in the mind, we are either un-duly limiting the mind's power of knowing, or we are uttering a mere tautology. We are uttering a mere tautology if we mean by 'in the mind' the same as by 'before the mind', i.e. if we mean merely being apprehended by the mind.”

tautology


“Happiness is not an ideal of reason, but of imagination.” -Immanuel Kant

The philosophers wallow in their own tumult. Kant separated perception from reality as one would an object called beautiful as in “beauty is in the eye of the beholder.” Nietzsche called him out on that. Whereas Hegel charted out his belief of the perfect system of God and man’s ideals, Kierkegaard countered that God’s Reality and human reality were on two different planes and man was inadequate to realize God’s system of reality and therefore man’s ideal is but a very small portion of the whole and certainly under the imposed limits of its beholders power of observation and knowledge.



Ideal then is held back by existence, observation and time, whereas thought transcends the latter two. It merely exists. Ideal is a conjured abstract. Reality is observable and existential. The observability reins in and devours the very essence of a human ideal.  We paint an image in color that may only be viewed as black and white. Thus existence and idealism cannot coexist.

For mere mortals to promote idealism in its raw sense shows ignorance. As Voltaire famously quipped, “Perfection is the enemy of good,”   and Confucius remarked, “Better a diamond with a flaw then a pebble without.”


Wednesday, March 11, 2015

The FUTURE in Metastatic LUNG CANCER

If you shake the branches of a tree, sometime the hidden fruit drops down. And so it is with Metastatic Lung Cancer. From here to there at the speed of molecular inhibition/excitation we have come a long way baby!.



Long heralded as an open and shut case of short-term limited survival lung cancer is now exposing its roots for targeted attacks and the survival is improving. We can take down this tree!

The treatment for metastatic lung cancer has long been combination chemotherapy with a doublet regimen and the benefits are displayed below:

Metric
Prior to 1990s
1990 – 2000
Overall Response
15%
25%
Median Survival
6 months
8-10 months
1-year Survival
15-20%
30%
2-year Survival
Less than 5%
10-15%
Time to Progression
2 months
4 months

The new molecular targeting agents are changing the present and the future. Survival in those with genomic-target-able regions is being enhanced substantially. See below:

Metric
2000s
Present
Overall Response
35%
35-65%
Median Survival
12-14 months
15-24 months
1-year Survival
40-50%
50-60%
2-year Survival
20%
25-505
Time to Progression
6 months
7-12 months

Among the various forms of Non-Small Cell Lung Cancer, Adenocarcinoma seems to have opened itself to therapeutic intervention. The population of patients with NSCLC can now be stratified into those with target-laden actionable groups and others where knowledge is still wanting. None of these new targets however result in curative outcomes, only prolonged survival at the present time but that might change in the future. In the Squamous Cell type NSCLC various molecular targets have been determined, but at present they are not actionable. These include the following kinases and receptors: MAPK, PI3K, FGFR, EGFR, TOR. Recently however a drug called Opdivo was approved by the FDA yielding 3 months extra survival in late stage Squamous cell lung cancer. Small step but that is how paths emerge.

In Adenocarcinoma sub-type however there are target-able switches:

Mutation
Frequency
KRAS
22%
EGFR
17%
EML4-ALK
7-8%
BRAF
Less than 2%




The IPASS trial was the first to show the advantage of actionable targets with improved Progression-Free Survival (PFS). Since then we have come a long way and the information is cascading as voluminous cataract. The IPASS trial showed a 71.2% Response Rate (RR) and a 3.4 month improvement in median PFS (n=261). The OPTIMAL trial with erlotinib showed an 83% RR and a 8.5 month PFS improvement (n=154). Other confirmatory trials also showed similar benefits, yet none showed an actual increase in Overall Survival, indicating temporary phenomena.



Further teasing the data revealed that almost 60% of the EGFR target developed a mutation called the T790M. A CO-1686 selective inhibitor of the EGFR T790M resulted in further improvement of the PFS by >12 months and the CO-1686 inhibitor passed through the Blood Brain Barrier exhibiting Central Nervous System responses! With current 1-year survival rates more than doubled from 15-20% to 40-50% and the 2-year survivals from less than 5% to almost 20%, this is indeed a success story that does not get the press it deserves.



Another target on the Adenocarcinoma NSCLC  is the EML4-ALK mutation in 3-8% of the NSCLC population . In a study of 141 patients 13% were positive for the mutation. An agent named Crizotinib resulted in a 60% RR. (n = 261). Resistance was further chipped away with newer agents such as Ceritinib and AP 21163 (preliminary unpublished data from ASCO). Additionally a minor mutation called ROS-1 (in 1% of NSCLC) has a targetable interface that has resulted in improved outcomes in that very specific patient population. Median Survival has also improved from 6 months to 12-15+ months. All indications appear to suggest a paradigm shift occurring with the advent of targetable sites on the NSCLC cell lines.

The future in NSCLC is primed for further enhancements given that we have molecular targets; KRAS, BRAF, PIK3CA, Her 2, MET amplification, MEK-1, NRAS, AKT. Using molecular target inhibitors in doublets concurrently or in sequence might be one future to behold. Other mechanisms using HSP-90, mTOR inhibitors might also play a part downstream. All options are open. We are no longer relegated to the chemicals only. A combination of the chemicals and molecular targeting might be another approach. Recently the FDA approved Nivolumab (Opdivo) a PD-1 inhibitor for Squamous Cell NSCLC. PD-1 negatively regulates T cell responses and inhibiting that regulatory behavior allows for a more robust immune directed response against the cancer.

If one lets the imagination wander a bit, as in a thought experiment for instance, you might find a whole array of gold nano discs and nano wires circulating in the blood stream looking for a match against one of the targets and upon contact send a message to a "Tricorder"about the existence of the disease in its infancy and voila a slew of antibodies are released against the targets. The cancer wouldn't know what hit it. Of course we might even pick up the first inkling of the disease before targets are needed, like the adenomas in colon and remove them to prevent cancer. Ah the possibilities are endless, as is our desire to cure as is the imagination running wild and free.

Like all futures they are always different than what we imagine, because there are 7+ billion minds out there vying for chance to subdue this disease and from that diversity, where ever these paths lead us, will be a better place for us all.

GO ON DREAM! IMAGINE! then INNOVATE!

Have Fun doing it!

References:

Geftinib or carboplatin-placlitaxel in pulmonary adenocarcinoma. Mok TS, Wu YL, Thongprasert S, Yang CH, Chu DT, Saijo N, Sunpaweravong P, Han B, Margono B, Ichinose Y, et al. N Engl J Med361(10):947-957, 2009

Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study.Lancet Oncol. 2011 Aug ;12(8):735-42.

Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. Shaw AT, Kim DW, Nakagawa K, Seto T, Crinó L, Ahn MJ, De Pas T, Besse B, Solomon BJ, Blackhall F, Wu YL, Thomas M, O’Byrne KJ, Moro-Sibilot D, Camidge DR, Mok T, Hirsh V, Riely GJ, Iyer S, Tassell V, Polli A, Wilner KD, Jänne PA:  N Engl J Med 2013, 368(25):2385-2394

Crizotinib in ROS1-rearranged non-small-cell lung cancer. Shaw AT, Ou SH, Bang YJ, Camidge DR, Solomon BJ, Salgia R, Riely GJ, Varella-Garcia M, Shapiro GI, Costa DB, et al.N Engl J Med. 2014 Nov 20; 371(21):1963-71. Epub 2014 Sep 27.

Wednesday, March 4, 2015

HIS STORY IS A GOOD ONE

The mighty oak appears a little barren now as the leaves continue to fall from its branches and these precious few men of The Greatest Generation walk into the sunset, one by one. We summon courage at times that are the bleakest. We hope our integrity will remain virtuous in moments that defy such reasoning.

Chuck McHenry

“Integrity is doing the right thing, even when no one is watching!” Chuck McHenry taught us that.

It is not with a sense of loss that we gather here, but a sense of pride that we knew him.

How does a person honor this good and kind and gentle man? Do we salute him as one would the pride, courage and strength of a flag? Indeed he embodied all those virtues as a WWII veteran. Or should we close our eyes and bow our head in humility, and say a prayer of thanks to the good fortune of the many memories he graced within us?

“Honesty is the highest form of intimacy!”

His story has been written and it is a good one! He is lucky because of the luck he created from hard work, dedication to his family and the abundance of love within him. If you knew him, you were touched by his honesty. Your heart and soul were the better for it. A gas station attendant was equal in his eye to any judge, general or politician. They were all equally rewarded with a composition of the larger mosaic of good he scattered throughout his life.

His grandchildren if they hold his words true will one day say; “Dear Grandpa thanks for all the lessons. Dear future, I’m ready!”

If you strain hard even now, you can hear his belly laugh, of how he turned his past into a treasure trove of stories. And just as an Irishman would do, each time at a gathering, the stories tumbled out effortlessly and each time there was a sparkle, a glint in his eye and the embellishments that only he could conjure. For the most part, his words were grace under pressure, to educate and inform. His living of his life was the reason we looked down and smiled inwardly and then absent-mindedly walked into a pole. The stories became parables for his children and then for our children, of how not to do and of how to be. After all he was an endearing husband, a wonderful father, a jovial grandpa and a tender great grandpa. He had wisdom. He coached life. But for all that he was always our cousin Chuck.

Churchill said, “Courage is what it takes to stand up and speak; courage is also what it takes to sit down and listen.” Churchill must have been thinking of him.

So how do we toast him?

With an ice cream sundae? He would love that! He never drank though, of that he was slightly at odds with the rest of the Irish clan. He loved life, and as he would say, "AND HOW," more so because he loved his family and friends. He lived on without regrets and mostly because he did not want to miss in the joy of a new birth or a potential birth of a new story. He was a-shirt-off-his-back kind of a guy, generous to a fault, with his time, money and emotions and expected very little in return. The richness of his wealth cannot be measured in metrics only in love for his family and friends and theirs for him. He was truly blessed.

At family gatherings of the future there will always be a place for him as the echoes of the stories he told will float in and out of our minds and from our lips. The memory of his hearty laughter will ring true and bring smiles across the table as he looks down and double winks while flying on the wings of our better angels. His stories will be long remembered. His laughter will echo within us. His temperate soul will help us through our crises. His quiet strength will be a place to come home for rest.

We will miss you.
We loved you.
He will forever be with us.
He was a good and kind and gentle man, the likes of whom I have never known.
And as this day mourns, the night will find him in a peaceful slumber.
Good Night gentle Chuck
Rest in Peace Dad.

Saturday, February 28, 2015

CHRONIC LYMPHOCYTIC LEUKEMIA

The dysfunction within the follicular center of the lymph nodes and the gathering swarm of functionally incompetent (anergic) self-reactive cells within the bone marrow produce poly-reactive autoantibodies creating Chronic Lymphocytic Leukemia (CLL).



CLL affects between 16,000 to 17,000 individuals mostly older ones with a median age of 58 years in the United States. Whites outrank other ethnic origins.

The CLL differentiated clusters of cells mostly include CD 19, CD20, C21, CD23 and CD5. Targeting the largest cohort is the latest game in therapeutics to suppress the wayward lymphocytic cell. Other Surface antigen markers are also listed in references.



·        Stage: From a prognostic point of view CLL had classically been staged based initially on Lymphocytosis. In the Rai model: Stage I: 25% Lymphocytosis. StageII: 50% Lymphocytosis with Nodes. Stage III: Stage II and Lymphocytosis with Nodes and Anemia Hgb less than 11g per deciliter and Platelets of  less than 100,000 per dL. 
Binet created a slightly better system anchoring on the values of Hemoglobin, nodes and platelets. Stage I = Hgb >10 g/dL, Platelets >100/dL and < 3 nodal regions involved. Stage II was essential Stage I with >3 Nodal regions involved. Stage III was Hgb <10g and="" or="" platelet="">3 Nodes. Favorable subsets emerged based on these gradations. However recent data has been able to disambiguate within the stages based upon the molecular nuances.



·         Chromosomal Data:
o   About 50% of CLL patients have 13q14 abnormality and are usually benign.
o   19% have 11q22-23 abnormality and are mostly aggressive
o   15% have 17p13 abnormality and have large nodal disease and aggression.

·         Molecular Data (Overexpression associated with lowering survivals):
o   ZAP70 (Zeta-associated Peptide of 70 kilodaltons) expression is associated with 8 year survival. ZAP70 non-expression CLL has >25 year survival.
o   CD38
o   IgVH (Immunoglobulin Variable Heavy Chain) (un-mutated) immunoglobulin gene. Interestingly high risk patients have low DNA mutation at the IgVH gene region and vice versa.
o   Bcl-2 (Down regulation of miRNA 15a and miRNA 16-1 increases Bcl-2)
o   Beta-2-Microglobulin
o   Lymphocytic doubling Time

·         Current Chemotherapy Regimens:
o   Chlorambucil
o   Fludarabine
Whereas Chlorambucil and Fludarabine PFS were identical at 18 and 19 months respectively, the Overall survival was 64 months and 46 months respectively, but it did not achieve significance.
o   Fludarabine(F) + Cyclophosphamide(C)
o   FC+Mitoxantrone or FCM
o   FC+ Rituxan or FCR

Adding Rituxan to FC improved the PFS significantly although the overall survival was not greatly impacted. It appears that monoclonal antibodies that target specific CD markers have short term increased responses but limited survival benefits. The escape velocity of this recurrence might suggest antibody production against the antibody being used in therapy, methods of dosing, or the CLL cells aggregating newer mutations over time. It is important to note that treatment of early CLL is not indicated as it is harmful through risk of infections and shortening of survival. CLL patients due to their inability to produce functional B humoral antibodies are not able to fight off bacterial infections.
o   CVP (Cyclophosphamide (C) + Vincristine (V or O) + Prednisone(P))
o   CHOP (H = Doxorubicin)
o   Revlimid (Thalidomide analog) was associated with 47% Responses and 9% Complete Remissions with complete elimination of Minimal Residual Disease MRD).

·         Monoclonal Antibodies and Cytolytics:
o   Rituxan (CD20 antibody)
o   Alemtuzumab (Anti CD 52) Effective against the aggressive 17p13 cases.
o   Ofatumumab (Anti CD 20)
o   Obinutumumab (Anti CD 20 cytolytic agent)
o   Ibrutinb (Bruton Tyrokinase Inhibitor) In a small number of cases with BTK mutation Ibrutinib is ineffective. In the RESONATE study Ibrutinib had a 58% response with a tripling of survival 24.2 vs. 5.5 months in previously treated patients.

Unfortunately what has plagued longer term survival is the existence of MRD following therapy. Comparing the newer agent Obinutumumab + Chlorambucil vs. Rituxan + Chlorambucil resulted in 78% vs. 65% Response, 27 months vs. 15 months PFS and the MRD in Blood was 37.7% vs. 3.3%, in the Bone Marrow MRD was 19.5% vs. 2.6%.  

·         Other Therapies:
o   Genetically modified T-Cell to express CD 19 used against CLL resulted in 26 of 59 patients with complete remissions (Proof of Concept study)
o   Allogeneic Bone Marrow Transplants: This therapy is the only known curative therapy known against CLL. It has an inherent risk of mortality as a consequence of the Induction and Conditioning related complications pre transplant and GVHD post-transplant. ABMT is utilized as an option in younger (50-65 years of age) patients with known molecularly determined aggressive disease who can withstand the rigors and risks of such therapy.
o   Duvelisib a dual PI3K gamma/delta inhibitor showed an impressive 98% nodal response noted on CT scan in 43 patients. This drug showed activity in 17p13 cases and at least one Ibrutinib refractory case.
o   Future pipeline include Anti-Bcl-2 drugs to enhance apoptosis in the errant lymphocytic population

Understanding the very nature of malignant biological diseases is the doubling time. A slow growing disease takes longer to accumulate cancer cells, thus the patient (host) survives longer with the disease. Also in most solid malignancies 2/3rds of the disease span is invisible and un-diagnosable due to malignant cell quantity as is depicted on the graphs posing variable doubling time. An aggressive disease grows faster and has a higher mortality lacking effective therapies. You can observe from this graph that the growth explosion occurs in the very late stages of the disease when it becomes (semi)resistant to therapy due to acquired DNA mutations and immune-surveillance blunting modalities.


Doubling
months
months
months
months
1
2
6
12
18
24
2
4
12
24
36
48
3
16
18
36
72
96
4
256
24
48
144
192
5
65536
30
60
288
384
6
4294967296
36
72
576
768

Will CLL yield to cure other than using ABMT?
Will multimodality therapies improve overall survival of each molecular subsets of the disease spectrum?

References:

 Shanshal, Mohammed; Haddad, Rami Y. (April 2012). "Chronic Lymphocytic Leukemia". Disease-a-Month 58 (4): 153–167. doi:10.1016/j.disamonth.2012.01.009.PMID 22449365.

 Jump up^ National Cancer Institute. "General Information About Chronic Lymphocytic Leukemia". Retrieved 2007-09-04.

 http://www.nature.com/leu/journal/v16/n2/full/2402363a.html#tbl4

Rai, KR; Sawitsky, A; Cronkite, EP; Chanana, AD; Levy, RN; Pasternack, BS (Aug 1975). "Clinical staging of chronic lymphocytic leukemia.". Blood 46 (2): 219–34.

Binet, JL; Auquier, A; Dighiero, G; Chastang, C; Piguet, H; Goasguen, J; Vaugier, G; Potron, G; Colona, P; Oberling, F; Thomas, M; Tchernia, G; Jacquillat, C; Boivin, P; Lesty, C; Duault, MT; Monconduit, M; Belabbes, S; Gremy, F (Jul 1, 1981). "A new prognostic classification of chronic lymphocytic leukemia derived from a multivariate survival analysis.".Cancer 48 (1): 198–206.
Shanafelt TD, Byrd JC, Call TG, Zent CS, Kay NE (2006).


Dohner H, Stilgenbauer S, Benner A, "" et al. (2000). "Genomic aberrations and survival in chronic lymphocytic leukemia". NEJM 343 (26): 1910–6 

Mraz, M.; Mraz, M.; Pospisilova, S.; Malinova, K.; Slapak, I.; Mayer, J. (2009). "MicroRNAs in chronic lymphocytic leukemia pathogenesis and disease subtypes".Leukemia & Lymphoma 50 (3): 506–509
 
Keating MJ, Flinn I, Jain V, Binet JL, Hillmen P, Byrd J, Albitar M, Brettman L, Santabarbara P, Wacker B, Rai KR (2002). "Therapeutic role of alemtuzumab (Campath-1H) in patients who have failed fludarabine: results of a large international study". Blood99 (10): 3554–61. 
 
Urba WJ et al. (2011). "Redirecting T Cells". N. Engl. J. Med. 365 (8): 110810110014063 

Dreger P, Brand R, Hansz J, Milligan D, Corradini P, Finke J, Deliliers GL, Martino R, Russell N, Van Biezen A, Michallet M, Niederwieser D; Chronic Leukemia Working Party of the EBMT (2003). "Treatment-related mortality and graft-versus-leukemia activity after allogeneic stem cell transplantation for chronic lymphocytic leukemia using intensity-reduced conditioning". Leukemia 17 (5): 841–8.