Sunday, January 24, 2016

OXYGEN AND FLIGHT

As humans we depend on energy. Our energy is created in little biological machinery present in the cells called mitochondria. these tiny powerhouses generate phosphates from converting (Adenosine Triphosphate or ATP) to Adenosine Diphosphate or ADP). phosphate groups are needed to move cells within organs to do their jobs, example muscles to contract (locomotion) hearts to pump, kidneys to filter, livers to digest and brains to process information. Absent phosphate and we are looking at an abyss. Oxygen is needed for the generation of the phosphate groups, hence the importance of this element in all things governed with "life.


Oxygen, the quintessence of all elements breathes life into living creatures. Without it there is no water, nor breathable air, nor the lusty energy that makes us want to fly.

The breathable air contains 20.946% Oxygen. Humans exchange carbon dioxide for oxygen to replenish the stores of renewable energy for every one of the trillion cells that make us. This energy is in the form of Adenosine Triphosphate (ATP). ATP releases a phosphate group that acts as an energy bar for the cell to chew on so that it can accomplish its functions. These functions include manufacturing proteins, hormones, keeping the integrity of the cell wall etc. From our aviation point of view the function that cannot be clouded is the brain activity. The brain weighs about 3 pounds and consumes 25% of the oxygen supply. The brain’s hefty consumption is a testimony to its integrated and creative functions. 100% of the brain is at work 100% of the time and it needs its constant and uninterrupted energy supply.

The rarified air at altitude has reduced content of oxygen, which causes our brains, first to compensate by increasing blood pressure, then the respiration and heart rate to maintain the steady oxygen supply. When oxygen levels lower further, portions of the brain function capitulate, akin to losing the alternator, one reduces power load by keeping only the most important instruments on the panel active so as not to drain the battery. So flying in un-pressurized aircraft without oxygen, your cognitive skills diminish. Your communication and math skills suffer as do interpretative skills. Missing calls, airway intersections or flying into adverse conditions becomes possible. To unscramble the brain a little oxygen rich air is mandatory. A “Chamber Ride” at an aviation facility confirms this.

Remember an intensely low oxygen level for a short time or a low-level prolonged oxygen restriction can have similar short term and long term consequences on cellular behavior.

If you fly above 5000 feet at night or above 8000 feet during the day use oxygen. It is good for the cerebral soul.



Think about these problems reading this on the ground than in the air:
1.      Mathematics
Skill deterioration
2.      Cognitive Skill deterioration
3.      Instant Recall diminished (Frequency recall)
4.      Remote Recall diminished (experiential references)
5.      Decision Making Skills deteriorate (Time, distance and fuel consumption)
6.      Risk Assessment Impaired (eg. Go, No go decision into weather)
7.      Physical functional Impairment (muscle weakness)

8.      Lethargy/Fatigue.

Sunday, January 17, 2016

CANCER MOON SHOT


Truly a remarkable call for action; A Cancer “moon shot.” It is worth about $2 Billion and purports to cure cancer. It has the faint echo from some thirty years and tries to mimic the “landing on the moon” challenge proposed by President Kennedy. 


The difference between landing on the moon and the “cancer moon shot” is one of technology and biology. Whereas technology is based on referential absolutes of certain laws, aerodynamic and physics, biology has no such laws etched onto its book covers. Try as we might using arbitrary metrics of measurement and outcomes, the cancer moon shot terminology is one of jumping the shark. 

Ok, I have to admit that even with the success of finding the right trajectory of the rocket to reach the moon based on the earth’s circulation and orbital path, a malfunction in the carbon dioxide scrubber can create spectacular drama. Other times a space travel can be cut short by the frozen “O” Rings (hazard) and the peeled away tiles (another hazard) off the space shuttles. Barring those events that have been understood and placed in the “Risk categories” the flight to ideas into space travel continues successfully. The travel to the Moon and Mars and flying weightlessness in space are a thing of the present with known knowns.

Now drifting off to the biology related issues, we are faced with a myriad of problems; the most certain being; indeterminate end points or outcomes. Let us take the cell as the primary focus of our attention for the moment. Each cell from each organ is faced with a diversity of external pressures. A stomach, for instance, learns to live with the Helicobacter Pylori bacterium causing peptic ulcers in some all the way through chronic inflammation and cancer of the stomach in others, but not in all. Not all humans are affected equally. The bacterium finds solace in some as a subdued accomplice (saprophyte) and in others as a deadly weaponized life-form? Why so? 


The landscape of lung cancer is also changing as we speak. Squamous cell type lung cancer once in majority as a form of Non Small Cell Lung Cancer initiated by smoking and other external pollutants seems to have given way to an Adenocarcinoma NSCLC sub-type increasing from 8.9% to 19.5% over the past 6 years. Interestingly this form is increasing in women-never-smoker category. Why so? Is it the transposon function playing through the generations as the sperm and ovum date? 



Or let us look at something called GUCY2C receptor anchored by the Guanylin hormone, which appears to protect humans from colon cancer. Obesity seems to stem the function of the GUCY2C receptors and thus the normal proliferation of the colon cells goes awry. The dysfunction of the GUCY2C receptor seems to correlate well with weight gain and obesity. But what happens in lean individuals who develop colon cancer? What is the trigger there? There are other mechanisms in play, for sure; including the Lynch Syndrome, Inflammatory diseases of the colon etc. So there are many paths that lead to cancer formation in the colon. The next question then is, is there a final common pathway where arrests can be made to prevent the unholy and tortuous realm of malignancy so that the “cancer moon shot” may find success? Maybe, but (groan) there are many upstream and downstream pathways within the cellular interior, teaming with cross-talks (between pathways) within cellular signaling in force, to offset any specific targetable site. And just so we understand that the final common pathway if successfully arrested, might also lead to normal cellular function. 


Another disturbing point of view is the heterogeneity of the cancer itself. Recently shown in Multiple Myeloma, where sub clones of the Myeloma cells exist within the same patient. Each sub-clone has a different set of mutated genes, some subtle, some overt and others manipulated through the epigenetic realm. These sets create the same havoc from sheets of plasma cells that cause fractured bones, kidney failures and other assortment of maladies on us, humans.

You might be able to see this non-linear malady a bit clearer. It is truly a dilemma crafted from the inherent variability of the cellular function. The cellular functions are like a flower blowing in the wind, as it holds on to its petals only to be lost in a gale event. From the seeds scattered by the gale-force breezes, mutated seeds give rise to a multitude of colored flowers and each bush with its own might, beauty and future. The gales or hurricanes can come and go and be of any intensity but the effect is never the same. Each iteration of exposure to hardship lends itself to a newness in the genetic structure and signaling. Robust flowers are borne of harsh climates and delicate ones arise in moderate climes. The mutation goes on and the targets keep varying in expression. A cancer thus has many facets to its etiology even in the same organ and the delicate balance of norm is upset by factors inside as well as outside of its milieu.


“Moon Shot” the so-called precision shot to a known celestial body, where the trajectory and orbital paths are known is a cinematic presentation for the mind’s eye in trying to capture the imagination. A well-meaning concept that attempts to target a moving target. Given the gravitational pulls of the various heavenly bodies viewable by naked eye, curing cancer with the moon shot is more like a shot in the dark. And shooting in the dark where the dark matter has its own set of rules creates another blind eye’s dilemma.

The $2 Billion outlay added to the NIH budget, may and probably will find a few new oncogenes or epigenetic pathways, tumor suppressor genes or other epiphenomena and with those, tiny blind alleys in the process, but will they give us an atlas to the cure for cancer? I have doubts. But some progress in the oncology field will be made, of that I am certain. Progress, means more alleys and pathways down the rabbit hole.

Friday, January 8, 2016

IN WHOSE INTEREST?


In Whose Interest is all this anyway?

Cleverly we design our future. Softening the lights to reduce the shadows. The soft haze beckons us and we follow suit dutifully in line.

Sometimes a question arises. but most times the question is drowned out by fear. The question is “In whose interest is any of this, anyway?”

The trumpets have heralded that all things arriving in the form of gratis are from a benevolent master. And the benevolent master with a tearful eye informs that all things meted out are for the “Public Good.” Indeed the writers write, the bobble-heads on television agree with thrills up their legs and all is a calm sea of bright azure blue.

Is it?


Let us take the mundane but hotly contested yet relentless issue of the EMRs for physicians. The digital interface is designed and promoted as the coming of age in medicine for the “public good.” Touted that the EMRs would lead to portability of patient data and therefore less chance of medical errors. But that is not what happened. The error rate in some cases increased. However there was a bonanza for cyber-charlatans in stealing multi-million patient information. The insurers using it to determine who was being reimbursed and how much, created alternate realities of abuse and through it all the face time, eye-to-eye contact between patients and physicians decreased dramatically. The questions from the physician to the patients were directed at the computer screen in an attempt to reduce the time impact in order to fulfill their goal of filling the boxes and crossing the “t”s and dotting the “i”s to the agencies. The alienation between the patient and physician increased. And as a consequence the “Satisfaction Scores” for physicians took a dive. The dominoes of interests however continued to erect themselves. Software and hardware companies like EPIC and CERNER made billions in the process through government subsidies and contracts. Meanwhile the payments to the doctors dwindled substantially. The declining incomes combined with the will to keep their offices open sent many a doctor to the banks for loans, others to leave the field of medicine and still others into depression.

In whose Interest was the EMRs?


Another commonly used belief that is the care of the patient should be based on the population medicine statistics; a new paradigm. let us dissect that one a bit. Imagine if you will that we take a sample of data from a cohort of patients in a urban hospital or two or three and then based on the statistics conjure up a reality that treatment ‘x’ worked in that sample in, lets say 2/3rd of the patients, would that be appropriate for the entire population? If from that tiny experiment of say a 1000 (the world population is 7,100,000,000) we extrapolate that treatment ‘x’ is the best treatment. That is why most studies are not reproducible! Is that wise? and if it does not work then is it “so be it,” because the data says so and we did the best (based on some guidelines) there is. Allowing the physician who is treating the patient with the right to determine the correct therapy that may be ‘y’ or ‘z’ would be the best for the patient, but that is not the case with this new population medicine format. The insurer having agreed on a contractual and budgetary basis that the cost per patient with ‘x’ is cheaper than alternative therapy with ‘y’ or ‘z’ will opt for wherever the costs are lower. In their context the shareholders ultimately benefit with rising stock prices from the higher EPS as well as the CEOs. The critical thinking of the physician is circumvented by the bulldozing baskets of insufficient data. And patient care is mediocre at best.

In whose Interest is the population medicine mode of therapy?  

ABIM Philadelphia Condominium (Doorman included)


It appears that a third party always seems to insert itself and avows itself as the defender of the public good. Case in point is the American Board of Internal Medicine or ABIM, which is a privately held foundation that saw its coffers filled up from net asset value of $13 million to $132 million in short order. It appears that the ABIM in promising that certification of physicians initially was the way to test the knowledge-base of the doctors. But then came the 10-year recertification to prove that the knowledge was still fresh. The physicians complied, as insurers (who pay) and hospitals (who employ) had bought into the zeitgeist. But that was not enough for the ABIM who doubled down and helped them conjure up the Maintenance of Certification (MOC) as a money making annual endeavor.(even though their argument about recertification and MOC had been debunked over and over in the scientific press) This endeavor helped ABIM increase their own salaries and help buy expensive Philadelphia condominium for retreats replete with Mercedes Benzes to drive them around. Ah the vagaries of such banal thought. Interestingly the examinations and the maintenance “modules” designed by the ABIM were merely a mechanism of esoteric questions that had virtually no value in daily patient care by a physician. It was all about money! Or so it seems.

In whose interest is the Maintenance of Certification?

Lets not forget the multitudes of policies, regulations enacted by the Federal and State agencies that control the “public good.” There are many acronyms that the reader is welcome to look into: ACOs, AMP, P4P, AHQR, PCORI, HIPAA, OSHA, IOM, HICPAC, DHQP all these and more in one way or another impact the functionality of the patient’s care. Is it any wonder that 29% of 1st year residents are depressed with thoughts of suicide and 58% of practicing physicians are depressed with 93% of the doctors not advocating their children to go into medicine? Pamela Wible, MD states that the physicians are abused not depressed. I agree. The suicide rate from such regulatory abuse is killing the field of medicine through depression and overall ill health. filling paperwork now consumes around 40% of a physician’s time. A mistake in not crossing a “t” or dotting an “i” is being construed as fraud by the digital sleuths. The relentless drumbeat of “public good” goes on.

In whose interests are all these agencies?

And then again, there are others that have a stake in this algorithm of human interaction. Read: The Black Cloud of Medical Board Investigations . These politically appointed figures to the Board (physicians, attorneys and public members) by the governors of the state have the power to do "public good." Their power remains subservient to the power of the State governmental oversight and as such they, to a large extent, remain pawns in the chess game. In that "public good" is a lot of pride and prejudice as is decreed in the soul of man. A well publicized case, no matter the cause must be found guilty for political expediency while a well-connected one can be suppressed with a reprimand. Their decisions are final no matter the innocence or guilt while professional lives are buried in the heap. No matter the issue, the attempt is to win a consent of guilt and that proves that the system is working at peak capacity. The poor soul caught in the widening gyre of hurled allegations never sees it coming and proof after proof against the allegations mean nothing. The goose is cooked and the chefs are fattened. To be sure there are a few bad apples (as in any aspect of society) and they should be removed from patient care, but with careful reasoning and judgment and not solely by prosecutorial discretion. From a well-designed and well-meaning system of oversight over physician indiscretion, the system has evolved into a numbers game of how many are thrown to the wolves. If less per 1000 then the oversight is not good. If more, then the state is an exemplar. The evil that men do lives after them; the good is oft interred with their bones. - Shakespeare

In whose interest?

This kind of pain of logic might take you from point A to B but only as Einstein said, “Imagination will take you everywhere.” It appears that the reason has ceased to be the power of wisdom, logic and numbers rule the day. And as Charlotte Bronte expressed, “Better to be without logic than without feelings.” Do the pundits “feel?” in this “for the public good?” Or are they so entrenched in their little silos of punditry that only the artificial hue of fluorescence reaches their retinas?

What makes them tick? Money? Wealth? Greed? Job Security? Power? Influence?

Monday, January 4, 2016

The NORMATIVES

Normatives need some understanding. These declarative (normative) statements over time and through constant rekindling efforts of the followers turn into factual statements. Widely shared statements in this day and age are; blanket the airwaves and digitally swarm the social media and you have a new Norm. It is like the use of the term "social responsibility" that is ubiquitous and bandied anytime when logic is in short supply. The very social structure morphs through the beating drums of the normative clan changes and small "n" numbered polls confirm the selected-biased answer through the tortured network of statistics. Entertainment becomes reality and the human misery index rises to new levels for most are buried in the sea of daily existence. "Oh the web we weave!" The illogic in this "Normative" logic is the fount of the current zeitgeist. Let me clue you in on a conversation that I had with one of these stalwarts.

Really?


“Normative”: You know physicians are destroying medicine!

Me: How so?”

“Normative”: Look at the costs, they are going sky-high. In fact healthcare is costing the US $3Trillion a year. almost 18% of the GDP.

Me: And you think all those costs are related to physicians?

“Normative”: Well yes. Who else controls medicine.

Me: Did you know that medicine has been subverted by the third party-goers?

“Normative”: Like whom?

Me: Lets see, for one, the middleman-businessman/woman managers who have grown 3000+% in the last 30 years compared to around 180% of the physician population. The cost rise is proportionate to the rise in these bean counting busy-bodies. For another the Insurance industry who keep raising the premiums and conflating the stockholder dividends and CEO bonus payouts and three, the pharmaceutical companies with a constant increase of the costs of drugs. 



“Normative”: What about the excess diagnostics and procedures?

Me: That is a two-part problem: One, The patient demands to know what is wrong when afflicted by a symptom and he or she will go to multiple doctors and facilities till they get the answer and two, The legal aristocracy is just waiting to pounce on the doctor for a missed diagnosis.

“Normative”: What about the CT scans causing cancer?

Me: Maybe if you read the study, you would realize that out of 81 million CT scans done a total of 15,000 MIGHT develop cancer. The “MIGHT” was based on a hypothetical risk extrapolated from the Hiroshima and Nagasaki related fallout.

“Normative” Maybe, but you know the doctor’s fiefdom is just about over, don’t you?

Me: How so?

“Normative”: Soon population medicine will clear the hurdle based on guidelines and mandates. And there will be little need for doctors. The Nurse Practitioners and Physician Assistants will be able to handle most of the problems.

Me: The educational basis of the NPs and PAs is not on par with physicians. Thus decision making skills are different. And besides, the NPs and PAs increase the diagnostic use because of their own insecurity in making judgement calls about diagnoses.

“Normative”: Yes, but if the guidelines tell you what to do based on population medicine then what good is all that knowledge for?

Me: Population medicine is based on sampling errors. Even taking the Bayesian rules and accounting for the statistical probability at 95% Confidence Intervals, we are left with information of about 50-60% of the population at best. The remaining 40-50% are not in the running for the appropriate therapy.

“Normative”: What do you mean?

Me: Say you have hospital conducting a trial and it draws most of its patients from a specific catchment area and the population of that area is mostly “X” type. Would treatment of the “X” population fit the “Y” population? The answer is no since phylogenetic variance are common in communities based on the growth and expansion of the community. Not every community is a “melting pot.” Even adding multiple institutional data fails to conquer this conundrum.

“Normative”: Even so, computers like IBM’s Watson will be able to differentiate between diseases and give a fairly robust diagnosis on an individual basis.

Me: It might but it will be based on percentage probabilities. For example a person with cough might have the following tape readout: 90% Allergy, 85% Bronchitis, 80% Pneumonia, 70% Cancer, 40% Drug effect etc. It will still take a physician to weed out the reality. And that is what physicians do today with their mental calculations, non-verbally.

“Normative”: What about the DIY laboratory tests. That should help empower the patients to make their own decisions. Right?

Me: Actually it will create a larger state of chaos when small abnormalities are noted in the lab tests. Who will interpret these abnormalities?

“Normative”: IBM’s Watson, for one.

Me: We are in a circular argument here, aren't we?

“Normative”: How about most medicine will be conducted via telemedicine based on wearable technology?

Me: Now you are getting somewhere. That is entirely possible one day. The data can be fed into the computers and analyzed for probabilities and then the physician becomes the decision maker on the computer screen. Unfortunately the need for surgical procedures will still be needed until we have Star Trek technology to cure diseases without intervention.

“Normative”: I think you are wrong. The change is coming and soon.

Me: Prove me wrong.

“Normative”: This time next year.

Progress in medicine has been steady. It is geared through trials and tribulations, tests and studies, drug “A” vs. drug “B” and rarely placebo nowadays. Medicine is changing. The Star Trek Hologram “Doctor” is still far away. We should continue on that quest, but not denigrate the current best medical system in the world methinks. Normatives, they will have their day of reckoning, one day…Maybe or maybe not and we will have advanced to a feckless, fact-less, opinion-anchored society. But, then I digress.

Sunday, December 20, 2015

MEANINGFUL=MEANINGLESS

It occurred to me, as it might have to scores of others in the legion of medical care that there is something very disturbing going on. Now before we get ourselves in bunches, let me say, this only affects the physicians in very meaningful ways. (There, I’ve lost the majority of the readers). For those still hanging on, lets look at what is exactly going on.
Remember the Electronic Medical Records (heretofore mentioned as EMR or EHR interchangeably)? I’m sure you do. But here is the rub, When the powers that be, all comfortably seated in deep cushioned chairs on marbled floors designed the concept, they failed to understand the basic patient-physician interaction. After all their paradigm was based on the ICD and IPT coding mechanics buried within a sea of paper data within the vaults of the Centers for Medicare and Medicaid Services (heretofore called CMS). The digits when subjected to the rigors of algorithms would displace all worries. So using their best or only information, they (the powers to be) deduced that if all information could be inputted by the physicians directly into the digital format, why, then the CMS could make meaningful decisions, such as appropriate payments for services rendered. Rampant in that thought process like dust scattering from an ailing fantasy was the concept of cost-containment. After all the cost of healthcare was going up and usurping 18% of the Gross Domestic Product. “That could not be!” they cried. So the EMR “Meaningful Use” was invented. Some coddled the green fantasy as well, “Less paper invoice use would save the trees!” Nothing better than that, sliced bread, apple pie and gaia-hood all packaged in one.

The carrot placed upon the dying breed of physicians who really cared for their patients was, “If you implement an EMR in your medical practice, CMS would give you “X” amount of dollars. Doctors felt, “Hey why not. I get to digitize my medical records and have them available 24/7 to me for decision making.” A win-win concept they thought. “Everything on my little smartphone or tablet.” Not so fast, you graphene-loving-silicone-dependent gadget lovers, not so fast.


Along came an enterprising agency with the best ceramic wafers, bestowed as “the EMR provider” by the CMS, whose CEO had paid a significant amount of money in election campaigns, and won nearly half if not more of the software/hardware installations across the global field of healthcare in the United States. But the software was proprietary and therefore not easily, if at all interactive, with other software vendors vying for the same multi-billion-dollar pie (not in the sky). The doctor’s records could not interface with the hospital medical records nor with other physician’s and lo and behold silos developed within the software empires where dollars were raining down by the bushels. from millions into billions overnight, just like the tech-boom of 1999.

Physicians, oh yes lets not forget those “middlemen” as some called them, were stuck with thousands of out of pocket dollars in purchasing, implementing, training employees and themselves, losing hundreds if not thousands of hours that should have rightly been spent in caring for their patients. The reward after expensing a large supposedly reimbursable “X” amount from CMS they were shocked to realize that of they paid $30,000.00 for a system and $10,000 for implementation, the reimbursement was around $16,000.00 - $18,000.00. But, hey the Return on Investment would be the speedy reimbursement from CMS that would take a bite out of the Medical Revenue Cycle, and that, the physicians thought was worth the loss they were incurring. The only caveat was if you were tied to medicare for reimbursement for services rendered and you did not dive into the EMR business you would face a cut in payments also.

Not so fast Watson, CMS decided to implement the ICD-10 coding system and told physicians to take a loan for keeping themselves afloat during the governmental transition and delayed payments. Oh okay, but everything would be alright afterwards. No worries!

The stick followed the carrot in lock-step. And as we all know accepting money from a governmental agency is filled with a stack of papers that have to be signed, boxes to be checked, “Ts” crossed and “Is” dotted. The next hammer was a Medicare (CMS) Audit of all the physicians who had claimed the EMR bonuses. If the use was not “Meaningful” in the auditor’s opinion then doctor would have to return the bonus back to CMS. Oh and by the way, the auditors were outside agencies empowered to go and find out those that had not complied and these auditors for their efforts were to receive 20-30% of the returned bonus bounty. This might sound sarcastic, but the incentive for the auditors makes them slightly porous to the wild idea of “dinging” the doctors (agency theory) to improve their own bottom line (hey that’s human nature -  don’t blame me, I’s just pointing it out to you).
Meanwhile studies started tumbling down the express corridor that “EMR Meaningful Use” had not improved medical care for the patient at all. In fact patients began complaining (as if anyone was listening to them in the bureaucratic stronghold of CMS) that the doctor spent more time looking at the computer screen then at them. The doctors ambushed with costs, audits, denials of service, patient dissatisfaction, became disillusioned and depressed (over 54% if not more). They were told that their expertise was subpar to the algorithm based on some wide eyed, bushy-tailed 18-year old software engineer and may not based on decades of experiential reference. Oh no, the codes told the story and treatment had to be based on the codes or the rain of sparking embers from CMS would engulf the physicians into a spectacular conflagration. Care would be based on Costs from now on and more and more Societies and expert physician bodies mirrored the meme of this rapidly unfolding paradigm. 

The story goes on…


The fingers keep pointing at the patient - physician interaction and at the physicians. In one breath Healthcare costs ($3 TRILLION) are tied to care delivered by the physician to his or her patient. No where is mentioned the 800lb businessman/woman gorilla that loves to ransack the honey-ladened spread under the tent.     

Don’t get me wrong, there are a few bad (apples) physicians and other providers in the healthcare field that give a bad name to us all. But they are few and can be weeded out easily without destroying the best medical care in the world.


The answer… cometh soon.

Wednesday, December 16, 2015

TARGETING LUNG CANCER


Lung cancer is the second most common cancer in both women and men, eclipsed only by breast cancer in women and prostate cancer in men. ACS estimates 221,200 cases in 2015 with 158,040 related cancer deaths. It accounts for 13% of all cancer occurrences and 27% of all deaths related to cancer. Early diagnosis and treatment meets with cures although only 15% of the NSCLC are diagnosed early.

NSCLC treatment has mostly revolved around, surgery, radiation therapy and chemotherapy for the longest time. The marginal successes have had little impact on overall survival. Today the era of Molecular medicine hopes to change that paradigm.

Non Small Cell Lung Cancers are grouped into Adenocarcinoma (50%), Squamous Cell (30%) and Others (20%). Each subset carries its own characteristics of genetic mutations, although overlap is commonly seen amongst the groups.

Common known Mutations in Adenocarcinoma: 

  1. Epidermal Growth Factor Receptor (EGFR) is the most common one and is present in 50% of the Asian patients and 10% in the non-Asians.
  2. KRAS mutations in 25% of cases are less common among smokers and absent in Asians.
  3. ALK and EML4 fusion is present in 2-7% of the NSCLC (mostly adenocarcinoma) non-smoker patients.

Targeted Inhibitors designed to target these molecular structures include:

  1.              Erlotinib and Geftinb are most effective in cases with exon 19 deletion, exon 21 L858R, and exon 18 G719X. The Pan-Asia study showed a 9.6 months survival in gefitinib-treated patients, versus a 41% ORR with a median duration of response of 5.5 months for the carboplatin/paclitaxel chemotherapy group. (Maemondo M, Inoue A, Kobayashi K, Sugawara S, Oizumi S, Isobe H, et al. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med. 2010 Jun 24. 362 (25):2380-8). However resistance is noted after one year of therapy with these Kinase Inhibitors. A specific mutation noted at the exon 20 T790M is found in the resistant cell lines. these mutations have been targeted effectively with another Inhibitor Afatinib with modest success. In the LUX-Lung Trial, results showed the Afatinib group’s progression-free survival (PFS) was 11.1 months compared with 6.9 months for those treated with pemetrexed/cisplatin chemotherapy regimen. (Sequist LV, Yang JC, Yamamoto N, O'Byrne K, Hirsh V, Mok T, et al. Phase III Study of Afatinib or Cisplatin Plus Pemetrexed in Patients With Metastatic Lung Adenocarcinoma With EGFR Mutations. J Clin Oncol. 2013 Jul 1)
  2.          However Cetuximab a monoclonal antibody to EGFR noted to have activity in NSCLC (adenocarcinoma) without the EGFR mutation, later a post hoc analysis revealed that the EGFR mutation status conferred a better response rate.
  3.          For patients with ALK mutations Crizotinib and Ceritinib have modest efficacy. Trilas showed response rates of approximately 50% to 60% with crizotinib. Response duration was 42-48 weeks. (Kwak EL, Bang YJ, Camidge DR, et al. Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med. 2010 Oct 28. 363(18):1693-703). (Shaw AT, Kim DW, Mehra R, Tan DS, Felip E, Chow LQ, et al. Ceritinib in ALK-rearranged non-small-cell lung cancer. N Engl J Med. 2014 Mar 27. 370(13):1189-97).

In (Squamous Cell Cancer or SCC) NSCLC The demonstrated impact of molecular targeting is less clear since the targets have as yet to be clearly defined. in about 5% of SCC cases the EGFR, KRAS and ALK mutations are noted presumably from the mixture of cell types (adenocarcinoma + Squamous Cell) these patients after a Cisplatin based chemotherapy regimen show a 18% response rate to the small molecule targeted inhibitors such as Erlotinib, Afatinib. SCC is a well known entity that occurs secondary to dysplastic changes in smokers and other environmental toxins. These dysplastic cells have variable damage to the genetic structure early on. Further oxidative stresses to these dysplastic cell lines increases the genetic mutation burden and leads to cancer.

The following targets have shown success in SCC:

  1.        Monoclonal Antibody PD-1 (Nivolumab) and (Pembrolizumab or MK-3475 an Anti PD-1) an immune checkpoint blockade in unselected SCC cases lead to a 16-23% response rate and disease control rates of up to 50%, especially with the PD-L1 over-expressers. Smokers seem to benefit from the anti PD-1 and PD-L1 checkpoint blockades. Anti PD-L1 agents currently in Phase i/II trials with encouraging early results include MPDL3280A (atezolizumab) showing a 25% improvement over Docetaxol in a head to head comparison.
  2.        Anti CTLA-4 (Iplimumab) that restores downstream immune activation against the cancer has had limited success in SCC with Phase I/II trials in progress against advanced NSCLC SCC patients.

We have come a long way in securing newer targets to attack against Lung Cancer. The success will ultimately depend on the durability of the response in improving overall survival hopefully with improvement in the Quality of life as well. Combinations of molecular targeted therapy with Immune checkpoint blockade as well as Restoring Immune surveillance in limited disease lung cancer can be personalized to the patient in the future.

There are many other paths that have yet to be travelled...



Only the curious have, if they live, a tale worth telling at all - Alistair Reid

Tuesday, December 8, 2015

PHILOSOPHY OF PATIENT CARE

"There are more things in heaven and earth, (Horatio), than are dreamt of in your philosophy"
-Shakespeare



Cold or warm, tired or well rested, despised or honored, hated or loved, happy or sad, we all face life in its many varied forms. The trauma of existence is placated only by the moments of free thought, of fulfilled desire, of understanding. So what is in these many moments where life exists that makes us want more.

Turns out, if you have time to pay attention to little matters of time where true grit as true happiness lives, you might come away with that it is in seeing the joy in another’s face.

Nowhere is life more evident, more clear, more raw as in caring for another human in need. Physicians qualify in this realm more than in any other discipline.

Physicians live in a unique world of elation and despair. The wildly gyrating confines of this existence gives motive and cover to the mind of a physician. That one patient who finds cure from an interminable illness promises the healing for the many in despair. Each person is a life, each person a story, each person a face of society, brings with him or her a quality unique to humanity. No two individuals are alike. Therefore no two can be treated alike.

The former President Jimmy Carter just made news with a report from his recent cancer follow up MRI that showed complete radiological remission of the brain metastasis from the malignant melanoma.  His treatment included radiation therapy and Keytruda, an anti PD-1 immune therapy. There are several interesting and promising signs from this reveal. First, healing an individual and especially a former president at the age of 91 is worth noting. So age should not be a limit to proper treatment at any age. Notwithstanding experts like Zeke Emmanuel, MD who implied that after 75 years of age, people should not be treated and that they should be retired to the pastures. The obvious flaw stands out in stark relief now, doesn't it? Second, aging individuals have a lot of wisdom to offer and the young ones should take note of any pearls they drop in their communications. it is obvious that President Carter has a lot to say about his life and the world he has inhabited. Whatever that wisdom is. Wisdom is a philosophy on to itself. And you ask what is Philosophy? nothing more than the “love of wisdom” as Pythagoras called it, or the knowing the underlying fundamental nature of reality. One can tease at the fibers of this philosophy fabric and even in its threadbare form it reeks of some ancient understanding steeped deep into the veins of knowledge-keepers where blood flows.



Philosophy must be wise and therefore rational? Right? “ça dépend!” It depends on many things, but most of all on the questioning of all that is there. An individual’s philosophy would differ, based epistemologically on his or her beliefs, ideas, attitudes of the community and nurturing.

Our philosophy is nothing more than an improvement in our understanding of nature and ourselves. So should we then change the current thought paradigm that places age and cost ahead of fixing illness?

Consider this question; Should we advocate death as the primary focus in healthcare? Some will proffer the cost as a major hurdle for treating the elderly. They will claim that healthcare costs are currently 17% of the GDP in the United States. But they fail to recognize that costs are not due to the care administered, but as New York Times recently pointed out; a direct result of the business people involved in administrating the business of medicine.  So if that vital middling managers can be eliminated, the cost of care would come down drastically and become at once really affordable. More people would get treated and their insurance carriers would not be averse to paying for the care while still making oodles of money for their CEOs (Median total compensation in 2014 for the 117 CEOs for whom Modern Healthcare collected compensation data was $5.4 million, with a median increase of 9.6% over the prior year) and their shareholders.

Consider another question; Should we use a standardized lesson plan of “Choosing Wisely” as advocated by the American Board of Internal Medicine and co-opted by other entities like American College of Physicians as the correct model of patient care?  Experts say these programs are based on “Evidence based Medicine.” What is “Evidence?” I ask. Evidence changes as new information is received. So what is standard today becomes an “old thought: tomorrow. And further if the evidence is conjured by a set of tortured statistics, that furthers the illness within the science of medicine, how exactly does that further the agenda of good patient care? It is akin to building a perfect emptiness contained within straight lines in a chaotic world. Most of us would love to live within those bounds of comfort, happily suckling on sweet nectar without a care, but is that reality? Defining evidence is at best difficult! Yet if we claim “Evidence” as evidence enough to change belief of the majority, then all is pardoned and acceptable. And therein emerges the concept of “Evidentialism,” writ large "Evidentialism is a theory of justification according to which the justification of a conclusion depends solely on the evidence for it." The new subconscious is derived from consciousness at individual level and new belief becomes the new zeitgeist for that individual. And justification upon justification becomes the unwieldy latticework difficult to untangle for most except for those independent thinkers.

As the Big Data scientists gather their tools and computers, a cry from one of its own Hannes Leitgeib said, “ Overall and ultimately, mathematical methods are necessary for philosophical progress.” Ah yes, this progress, where we find the sinews of medicine wasting away today under the hard, weighty chains of pseudo-scientific tortured statistics. The general and special belief system slowly mutates to the turn of their statistical screw.

So, what is your philosophy as a physician in caring for your patient?

Maybe it is time for some Critical Thinking?
Maybe it is time for some thoughtful analysis?
Maybe it is time!