Tuesday, November 29, 2016

TO TREAT or NOT TO TREAT


That is the question...

An argument ensues and the voices get louder. The points of view are bandied about and the loudest voice has the sway. Today the voice with the most promoted resonance is one that deems that “Less is More” and is couched in the premise that doing more, causes “harm.” Harm is defined as potential risks related to interventional therapy, be it surgery, radiation therapy or drug therapy. Citing examples of prostatic infections from biopsies in establishing diagnosis of prostate cancer to emotional stress and in some cases establishing PTSD as a causation of diagnostic and treatment intervention.

What is even more striking is that physicians not wanting to standout against the zeitgeist and be ridiculed are following the piper in lockstep and agreeing with the “Rationing “ concept of healthcare(1).

Allow me to dissect this new frame of reference.


Let us start with a malignancy such as Ductal Carcinoma in Situ (DCIS). Some ivory wall experts believe that DCIS is not even a malignancy. They harp at the 98% survival rate at 10 years for such a diagnosis. But clearly there is more than meets the non-discerning eye.

The difference between the DCIS and invasive cancer is the breach of the basement membrane (a membrane that keeps the contents of the duct within the duct). So a breach indicates that the cancer cell has transmigrated to the tissues outside the duct. But here is a path less travelled in their minds. 



A duct is a convoluted path of continuity (seen in these radiology duct images), not a straight line as represented on the cartoon above and pathology slides are cut in a linear razor sharp format, so the duct can from the pathologist point of view present with multiple views in the specimens but not all. 



Hence where a breach might have happened might not be represented in the pathologist’s slide at all. And no two are the same

Arrows point to cancer outside the duct

On the other hand, sitting out the DCIS for months in a “Less is More” policy the cancer cells continue to, as is their wont, acquire more DNA mutation and ultimately seek the outside the duct environment to flourish. As this article suggests that radiation therapy benefits patients with DCIS versus Observation, further negates the argument of “sitting on one’s hands” (2).


Look no further than  the Prostate Cancer scenario, where a “low risk” defined prostate cancer relegated to the “observation deck or watchful waiting” policy has led to an increased risk of more aggressive prostate cancer diagnoses. Again one shouldn’t be mystified as the experts are and try to rationalize in pretzel fashion the reasoning behind that transgression (4).

Clearly in the legal circles, “delay in diagnosis” is a big money maker for the plaintiffs and their legal eagles. The lawyers dressed up in pin-striped suits and charming ties make pitches to the jury by using terms like “negligence and such” to get a better pay day. And most such large verdicts are clearly in their favor and against the physicians. And yet the ivory walled tower consultants seem uninterested in that aspect of the disproportionately weighted coin (3). For individual cases of such “malpractice” are the domain of the doctor and their insurer not the matters for the policy experts.


What to do?

Clearly, the answer lies in the physician’s personal judgment. Unfortunately the drumbeat in the medical literature by the experts, who use statistical graphics of “waterfalls” and “forest plots” constantly hammering the ear drums holds a sway to some physicians (Nowadays, it appears the majority 53.1%). Bombarded by the constant level of rhetoric from the “Choosing Wisely” crowd and the “Less is More” cost container segment of the experts the mistruths seem to be gaining ground and impacting patient care (1).

Isn't it ironic that causation is definitely implied through correlation in most of the “studies.” Isn't it further sad that the belief in such idiocy continues to gain ground and the vast conspiratorial impact of the probability function of p-value through tortuous mathematical indiscretion has become the mainstay of medical science. Using the p-value one can create any scenario to befit any belief , thought or nuance. There are legions of “P-Hackers” among us (6, 7)!

Pushing the needle further a study suggests that metastatic renal cell cancer should be placed on the observation deck also since many survive longer than anticipated (5). Assuming that DNA mutations are a function of biology and thus can happen anytime as Immune surveillance can be overwhelmed anytime, the logic in this “study” escapes, especially when there are newer therapies available for care of these patients. The thought comes to mind that it is all about costs at this point and time. The administrators and Managers point the finger of fault while they collect handsome bonuses. The average hospital cost devoted to administrative serves was 24.3% in 2015 (8). And that my friends is in the Billions.

The irony of it all in costs and purported care

So what do we do? If you still believe in the coffee enemas, then all hope is lost. Barring that, a self imposed moratorium in instant belief of the “studies” should be the way to go. The ability to understand, the ability to reason, the ability to weigh the consequences and the ability to define the world according to those fundamental principles of reality and not some hogwash pseudo-science.

If we only had a bulletproof mechanism to establish the indolent versus the aggressive, things could be different. But we don’t. Even Genome Assays are a point in time and do not presage further change in the genetic structure. So we remain in the dark and in so doing we stretch the limits of our understanding into policy mistakes that harm our patients in the end.


REFERENCES:
1. http://link.springer.com/article/10.1007/s11606-016-3756-5






7. http://fivethirtyeight.com/features/science-isnt-broken/#part1


8. http://www.nejm.org/doi/full/10.1056/NEJMsa022033#t=article

Saturday, October 29, 2016

CANCER MEDICINE COSTS

Some of the successes have not and may never be shared with patients if the current policies remain in effect. Or to put it in the current metaphorical terms; the spoils of the battles won in the war against cancer may never reach the most vulnerable patients with cancer.


There is a drumbeat of the rising cost of medical care, so much so that experts are twisting their already convoluted selves into pretzels to prove that the cost of care is directly correlated to the over diagnosis, over harm, over use and over reach in caring for the patients by their physicians. One wonders at the wisdom of that. But what is true, reveals itself easily. 



In every article written, an element of cost seems to take center stage. In fact most articles in medicine are not complete unless a paragraph on cost is couched to win over the publication mantle. Most of the blame is hurled at the doorstep of the treating physicians. Thus the rise of mantras such as “Choosing Wisely” and “Less is More.”

Digging through the morass of expense, a few easy to locate, issues are self-evident:
Administrative Costs: CMS alone projects them to be at $361 Billion in 2014 and these are conservative estimates at best. 

Hospital Costs especially the “facility fees” that make cost of care to the patients treble if not quadruple. 

Overuse of Diagnostics estimated by Peter Orzag to run in the $700 Billion range and that includes Defensive medicine, Newer technology use, and excess use for profit.
Pharmaceutical costs…this is the subject we discuss below.

If one were to use $1 as the total cost of healthcare in the United States, estimates suggest the following (based on the CMS Data Dump of 2012-2013:
$0.36 are for hospital costs
$0.15 Administrative costs
$0.26 for Pharmaceutical Costs
$0.07 for Physician care
$0.16 other, including fraud and abuse

The Pharmaceutical costs have been inching or rather “yarding” upwards at a scale not seen before.


A recent research letter termed, “The Rising Price of Cancer Drugs—
A New Old Problem?” in the JAMA Oncology authored by Vinay Prasad, MD, MPH is a fascinating read on the explosive increase in cancer medicines. The first salvo that brought the issue to the public consciousness is when Turing Pharmaceutical company raised the price of pyrimethamine overnight by 5000%.This was followed shortly after by the price increase of the oft used in pediatric/adult allergic response, Epipen by 600%. In fact, Eighty-six cancer drugs reported average sales price in both January 2010 and January 2015. “ The following 11 drugs underwent price increases of 100% or more: carmustine, oral methotrexate, cyclophosphamide injection, oral cyclophosphamide, mitomycin, oral busulfan, leucovorin, vinblastine, oral etoposide, pegaspargase, and oral melphalan." The Authors in the article further state; “For in- stance, although our investigation finds that the price of oral cyclophosphamide increased 300% after adjusting for inflation, absolute Medicare Part B spending on this drug increased from 1 million to 90 million dollars.”

What is most disconcerting is that older drugs have increased dramatically in price even when inflation adjustments are taken into account. This does not bode well for the average citizen who will find with their rising premiums, deductibles and Copays that medical care for their cancer is out of their reach, either by insurer denial or by the cost of the drug itself.


The ills in the recent rise of the pharmaceutical costs can be deciphered fairly easily, if one were to wear a neutral, non partisan hat. How does the Pharmaceutical company advance the costs to such astronomical levels? However one must keep in mind that innovation does come at a price, as long as it is not beyond the reach of the average individual and not dependent on a third party to the exclusion of reasonableness.

Answer: Easy

If there is a policy in the government, which has been strongly bandied about by lobbyists that there be a Non-Compete clause and that free market principles of supply demand and negotiations are not to be considered, then raising prices to any level are borne off the rising premiums for all and the burden on tax payers who cover expenses for Medicare and Medicaid.

Speaking of newer drug costs per year, such as the Biologics; Some are given below:
Perjeta - $126,000 / year
Keytruda - $150,000 / year
Opdivo - $158,000 / year
Ibrance - $142,440 / year

These newer biologics aim for individualized therapy based on available molecular diagnostic criteria (these have their own inherent costs). So the advances in medicine are restricted to most patients given the exorbitant costs of diagnosis and the drug treatment. The costs of the drugs are in most cases arbitrary and capricious. If one remembers the “Provenge” debacle that led to the bankruptcy of the parent company Dendreon because they marketed “Provenge" for Prostate Cancer at $104,000. The problem; drug seemed to give an average of 4 months increase in the Progression Free Survival. Perjeta, however gives us a progressive increase in survival over the 3 year period noted in the CLEOPATRA trial (encircled). ( http://cancerres.aacrjournals.org/content/72/24_Supplement/P5-18-26.short )

Perjeta on the other hand shows an increasing Survival rate (CLEOPATRA Trial) with time as shown below:

With Ibrance for instance, “The median PFS by blinded independent central review was 30.5 months versus 19.3 months, respectively. The objective response rate was 42 percent with the combination versus 35 percent in the control group,” in the PALOMA-2 Trial.

The most encouraging drug remains Keytruda with a 3- year 40% survival rate at present in Malignant Melanoma.

To solve the problem, one has to look at the mechanics that increase it’s complexity. A simpler Free Market in drug pricing where patient needs are aligned with the profits of the company. The so called “Social Responsibility” mantra bandied about by the C suite only satisfies their conscience of “doing good.” The government is not without blame either in allowing this form of wealth recapture from ordinary citizens. The positive regression line points to un-affordability...


Newer drug costs are mostly blamed on the $1.2 - $2 Billion needed to do Research and Development. These are overly inflated numbers by the pharmaceutical companies. The attempt here is to justify the high price point. 



Some blame also lies at the feet of the FDA where ties to the pharmaceutical industry make choices in their self interests to raise or lower the bar for approvals and designations. Dr. Saurabh Jha (@RogueRad) writes eloquently about the revolving door of the FDA and the Pharmaceutical Industry citing Dr. Vinay Prasad (@vinayprasad82) in a recent article, Money and virtue: An odd tension in health care; “In public choice economics there’s a phenomenon known as “regulatory capture.” Briefly, regulators sculpt regulations which benefit certain industries, and industry influences regulators, by promising a lucrative career, to create regulations which give them an advantage. Remember, regulations are a barrier to entry — successful capitalists love regulations, aspiring capitalists hate regulations.” And so it is in the deeper dungeons where policy and people meet, the clink of champagne glasses occurs.

In all, the system is badly broken. if the falcon cannot hear the falconer anymore, the center cannot hold and chaos is about to reign.

Tuesday, October 18, 2016

SMOKING & CANCER

The unflinching bastion of self destruction, smoking, remains the killer of killers. 7000 chemicals and 70 of those cancer provoking, makes smoking a scourge on humanity.  The information about smoking is well distributed to the general populace but common, stale news is no news in this hyped, always new information gathering world. Yet in face of all that information smokers still continue to live in the, “its all about the present and the past is who cares,” world. They live the mantra of “be in the present” and damn themselves to a continuity of misery for the future.


Statistics:
480,000 Americans succumb to cigarette and tobacco related products each year. That in itself is a travesty until you find out alcohol, car accidents, HIV, guns and illicit drugs combined do not wreck similar havoc on humanity. And to be sure smokers live shorter and unhealthier lives than non-smokers. And you can take that to the bank!

Chemicals associated with burnt tobacco:
Acetone – found in nail polish remover
Acetic Acid – an ingredient in hair dye
Ammonia – a common household cleaner
Arsenic – used in rat poison
Benzene – found in rubber cement
Butane – used in lighter fluid
Cadmium – active component in battery acid
Carbon Monoxide – released in car exhaust fumes
Formaldehyde – embalming fluid
Hexamine – found in barbecue lighter fluid
Lead – used in batteries
Naphthalene – an ingredient in mothballs
Methanol – a main component in rocket fuel
Nicotine – used as insecticide
Tar – material for paving roads
Toluene - used to manufacture paint

As most articles proclaim correctly, “smoking not only causes cancer. It can damage nearly every organ in the body, including the lungs, heart, blood vessels, reproductive organs, mouth, skin, eyes, and bones.”

This means each year smoking causes about 1 out of 5 deaths in the US. 30% of all cancers deaths are tobacco related, must give us pause. This complex tapestry of probabilities from smoking gets rolled up into a single tube conveying bad or worse news. The scale and damage caused by smoking is the single biggest healthcare problem wielded on humanity. In a multibillion dollar industry, the expenses in dealing with this disaster are close proxies for the truth.

Smoking and Cancer:

So, lung cancer is not he only cancer to materialize from a cigarette smoke. Many others fit the bill and include:

Mouth Cancer
Larynx Cancer
Pharynx Cancer
Esophagus Cancer
Kidney Cancer
Cervix Cancer
Bladder Cancer
Pancreas Cancer
Liver Cancer
Stomach Cancer
Colon/rectum Cancer
Myeloid leukemia

With so many cancers linked to cigarette smoke one wonders why and how? A recent article seems to suggest some possibilities in answering just such a question.

A study in Circgenetics; Epigenetic Signatures of Cigarette Smoking caught my eye. The Authors claimed that the epigenetic “footprint” of cigarette smoking became a carrier on the DNA for 30 years or longer. Now let us dissect that issue just a bit. If the “footprint” of the damaging effects on cigarette smoking resides as a methylating influence on the DNA, such influence can be furthered in its impact through other superimposed “nurturing” influences as well over time? In other words “piling on” of genetic influence can be the mitigating etiology of cancers found several years after cessation of cigarette smoking. Or putting it another way, say a person was exposed to a chemical but nothing really happened for a long time and then he/she started smoking, the “piling on” of such epigenetic burden on the DNA may influence mutation of a gene at a critical point to elicit unmitigated cell growth. Another example being Asbestos; a silicate material can slowly damage the lung by causing scarring of the lung lining resulting in Mesothelioma. Now add cigarette smoking to the burden and a higher rate of lung cancer occurs in these unfortunate individuals. The referenced study below describes at least ONE influence on at least 7000 genes. It makes it easier to understand from this, the far-reaching health impact and the various diseases that emanate from the act of smoking; the wide array from cancer to cardiovascular disease such as heart attacks and strokes, from emphysema, to miscarriages and low birth-weight infants and from osteoporosis of the bones to early deaths. The composite of this giant and dark tapestry unfolds a story like no other in the untimely frost that silences a voice.

For those needing to see more scientific methodological proof behind the study:

“To comprehensively determine the association between cigarette smoking and DNA methylation, we conducted a meta-analysis of genome-wide DNA methylation assessed using the Illumina BeadChip 450K array on 15,907 blood derived DNA samples from participants in 16 cohorts (including 2,433 current, 6,518 former, and 6,956 never smokers). Comparing current versus never smokers, 2,623 CpG sites (CpGs), annotated to 1,405 genes, were statistically significantly differentially methylated at Bonferroni threshold of p<0 .0000001.="" font="">
Conclusions—Cigarette smoking has a broad impact on genome-wide methylation that, at many loci, persists many years after smoking cessation. Many of the differentially methylated genes were novel genes with respect to biologic effects of smoking, and might represent therapeutic targets for prevention or treatment of tobacco-related diseases. Methylation at these sites could also serve as sensitive and stable biomarkers of lifetime exposure to tobacco smoke.
https://www.ncbi.nlm.nih.gov/pubmed/27651444
Oh and speaking about costs, that everyone nowadays is screaming about in healthcare, the CDC states, “Smoking-related illness in the United States costs more than $300 billion each year, including: Nearly $170 billion for direct medical care for adults. More than $156 billion in lost productivity, including $5.6 billion in lost productivity due to secondhand smoke exposure.” Reducing cost of the healthcare burden by 1/3rd on both the private and public sector would be easy if we educated strongly and stopped nurturing victimhood of addiction.

A word to the wise: Please don’t smoke!

REFERENCES:
American Cancer Society. Cancer Prevention & Early Detection Facts & Figures 2015-2016. Atlanta, Ga: American Cancer Society; 2015.

American Heart Association. Smoking & Cardiovascular Disease (Heart Disease). February 17, 2014. Accessed at www.heart.org/HEARTORG/GettingHealthy/QuitSmoking/QuittingResources/Smoking-Cardiovascular-Disease_UCM_305187_Article.jsp#.VjuXViu8SxY on November 5, 2015.

American Lung Association. How Serious is COPD. Accessed at www.lung.org/lung-health-and-diseases/lung-disease-lookup/copd/learn-about-copd/how-serious-is-copd.html on November 5, 2015.

Monday, October 3, 2016

TO WATCH OR TREAT?

That is again the question.

You might have heard this, or not. It was big news and yet it was not. After years of slaying the beast of PSA screening that was conjured up as over treatment and harm, the swallows once again came back to their nests.

If one looks at it objectively and without bias, one finds a disdain for early intervention. But why if it saves lives. And now we have a formal basis to declare that PSA screening followed by surgical intervention saves lives. 


Had they taken the Tyrol regional (Western Austria) study to heart, a place where free healthcare is the norm and everyone gets a PSA screening followed by definitive treatment, the conclusions drawn were: “In the Tyrol region where treatment is freely available to all patients, where widespread PSA testing and treatment with curative intent occurs, there was a reduction in prostate cancer mortality rates which was significantly greater than the reduction in the rest of Austria. This reduction in prostate cancer mortality is most probably due to early detection, consequent down-staging and effective treatment of prostate cancer.”

Now comes data from the latest ProtecT Trial study that accrued 82,429 men aged between 50 to 69 years. 2,664 (3.2 percent) had clinically localized prostate cancer. 1643 were randomized. Cancer specific deaths included 8 in the “watchful waiting” group, 5 in the Surgical intervention arm and 4 in the Radiation therapy arm. Progression of disease was noted as follows:

112 patients in the “watchful waiting” group (or 22.9 events per 1,000 person-years). 46 in the surgery group. 46 in the Radiation group.“All cause mortality” deaths from any cause were equal in all three groups: 59 in the active monitoring group. 55 in the surgery group. 55 in the EBRT group. (The difference in the rates of all-cause mortality was not statistically significant (P = 0.87).

An interesting data from the trial revealed that:

27 men would have needed immediate initial surgery as opposed to initial active monitoring to avoid 1 case of metastatic disease

9 men would have needed immediate initial treatment (with surgery or EBRT) as opposed to active monitoring to avoid 1 case of clinical progression.


The question raised is of consequence to the lives of the many. Was the “watchful waiting” a science driven enterprise of empiricism or a pseudoscientific undertaking of tortured probabilities to prove that “Less is more” resource utility? A question that should haunt the experts at some level.

The Editorial on New England Journal of Medicine by Anthony D’Amico, MD PhD caught my attention. Now that the cat is out of the bag, even now there are statements that trouble the mind; for instance…Therefore, if a man wishes to avoid metastatic prostate cancer and the side effects of its treatment,3 monitoring should be considered only if he has life-shortening coexisting disease such that his life expectancy is less than the 10-year median follow-up of the current study.” This sentence lends itself to further scrutiny, “if a man wishes to avoid metastatic prostate cancer and the side effects of its treatment, monitoring should be considered…” What does the author/doctor who wrote this think? The patient’s response as, “No sir I do not wish to avoid the dastardly effects of the malignancy and the necessitated treatment of the said metastatic disease?”

A sort of cover is also used here implying the following, “However, the increasing use of surveillance is already of potential concern, considering that men enrolled in PIVOT had a shorter life expectancy owing to coexisting disease than men of similar age entered into the Surveillance, Epidemiology, and End Results database.” In other words using PSA screening in these patients with co-morbidities lends itself to a potential bias in favor for the surgical side. True we need to use the modalities of treatments judiciously and with care to represent in the best interests of the patient.

In the end, however, the author goes on to say, “First, men assigned to active monitoring were significantly more likely to have metastatic disease than those assigned to treatment (P=0.004 for the overall comparison), with an incidence that was more than twice as high (6.3 per 1000 person-years vs. 2.4 to 3.0 per 1000 person-years). There was also a trend toward decreased death from prostate cancer among men assigned to surgery (hazard ratio, 0.63; 95% confidence interval [CI], 0.21 to 1.93) or radiation and androgen-deprivation therapy (hazard ratio, 0.51; 95% CI, 0.15 to 1.69) versus active monitoring.” 

Reasonable people make reasonable assumptions and thus reasoned judgment is called into play. The PSA screening tool is a worthwhile endeavor especially when conjugated with surgical intervention, as the Tyrol data from 2008 shows  and the current ProtecT Trial seems to suggest. Screening and early intervention improves people’s lives. Although Disease specific mortality is lowered the all cause mortality is not. A consideration here might be the age and co-morbid states of the population under study? You might argue about “All cause mortality” and “disease specific mortality” here but anyway you look at it the answer just stares back at you, defiantly.

So is PSA Screening a good thing? Answer: Yes.
Is Definitive surgical intervention in Early Prostate Cancer vs. "watchful waiting" a good thing? Answer: Yes.
Both answers appear accurate to date, unless you have extricated yourself from the predicate of being mortal. In that case, you might assign yourself the throne of a consultant expert and beam down guidelines to the plebeians.


REFERENCES:

1. Treatment or Monitoring for Early Prostate Cancer. Anthony V. D’Amico, M.D., Ph.D
http://www.nejm.org/doi/full/10.1056/NEJMe1610395#t=article

2. http://www.forbes.com/forbes/welcome/?/sites/benjamindavies/2016/09/14/prostate-cancer-screening-trial-shows-psa-screening-works-sort-of/&toURL=http://www.forbes.com/sites/benjamindavies/2016/09/14/prostate-cancer-screening-trial-shows-psa-screening-works-sort-of/&refURL=https://www.google.com/&referrer=https://www.google.com/

3. Bartsch, G et al. Tyrol Prostate Cancer Demonstration Project: early detection, treatment, outcome, incidence and mortality. BJU Int. 2008 Apr;101(7):809-16 http://www.ncbi.nlm.nih.gov/pubmed/18321314

Thursday, September 29, 2016

HOW PRECISE IS PRECISION MEDICINE?


Precision Medicine: “An emerging approach for disease treatment and prevention that takes into account individual variability in genes, environment, and lifestyle for each person."

The world is changing and fast. We live on the edges of discovery as we always have. Coupled with our computing prowess, things are moving a bit faster. Add that to the knowledge about the double helix that controls and motivates us, life is becoming interesting. And disease is beginning to show vulnerabilities.

Medicine has always been about progress. How to make our lives better, healthier and how we can thwart disease.

Treating patients with some degree of precision has many decades of experience. Although the concept of population medicine was first invoked as similar and only available treatment for most all diseases and blood-letting was it, for any and all disease, understanding real and basic science changed all that. In fact George Washington, the first U.S. president, died after having 3.75 liters of blood removed from his body within a 10 hour period as treatment for a throat infection. Some success in precision medicine goes back to the ABO grouping for blood transfusions. Transfusion reactions are rare nowadays with proper ABO group matching between donor and recipient of the blood.

In 1956 G6PD deficiency was found as the underpinning for favism; toxicity to fave beans and the antimalarial drug primaquine.

As medical research advanced, more interesting phenomena were noted as an impaired CYP2C19 led to Plavix (an anticlotting drug) to become inactive and ineffective. And discovery showed PCSK9 mutation resulted in Lower LDL and consequently people with such mutation had low risk of Cardiovascular Disease. So subsets of humanity with selective gene drivers are making their vulnerabilities and invulnerabilities become known through genomic data.

And that brings me to the…
Human Genome Project (HGP), which cost $3 Billion and 13 years of research. At the time the unflinching desire to have HGP cure most human disease was predicted, wrongly. The concept of one gene equals one disease turns out is untrue except in a tiniest of minorities.


Precision Medicine Initiative: Established a $215 millions in 2016 of which $140 million for cohort group (blood, nail, hair samples and follow through) and $75 million for sequencing the genome/administration of the cohort. many successes and an equal amount of misfires will come from this as well.

Intra-tumoral Diversity: Our understanding of the heterogeneity of tumors (cancer cell cluster) shows that a varied number of cancer cells, normal supporting cells, and transitional cells comprise the whole ball of this disaster. Sub-clones within the tumors grow as a Branching Tree adding new genetic mutations as the growth continues. In addition the tumor cell for its own existence is extremely adaptable and therefore plastic.

Multiple cellular pathways with associated Cross talk. Each cell has many different pathways that carry signals from the surface to the core where the engine of division feeds to replicate. Improper signaling can lead to over exuberant growth as in cancer or an arrest of growth and senescence and death of the cell.

Driver Mutation: In cancer there are many mutations that actually drive the cancer growth. Thus far 50 such mutations are known. Some are noted below:


Actionable mutations

i. HER2neu Overexpression of the HER2 protein appeared to occur in approximately 20-25% of breast cancer cases. Herceptin, a drug manufactured against the protein product of the Her 2neu mutation arrests the growth of the cancer. Additionally a newer drug Perjeta is believed to work by targeting a different part of the HER-protein than Herceptin, resulting in further reduction in growth and survival of HER2-positive breast cancer cells.

ii. BRAF V600E: B-Raf mutation on Chromosome 7 drives cell growth via the RAS-RAF-MEK-ERK-MAP Kinase pathway. Vermurafenib a BRAF V600E inhibitor is also a determinant of sensitivity to Proteasome Inhibitor (CARFILZOMIB). 92% BRAF mutation is actually a T(hymine) - A(denine) nucleotide 1796 switch.

iii. BCR-abl mutation Using Imatinib as the drug of choice in CML. Newer refinements of the drugs have managed to enhance the survival of patient afflicted with the chronic myelogenous leukemia.
Dasatinib (Sprycel)
Nilotinib (Tasigna)
Bosutinib (Bosulif)
Ponatinib (Iclusig)

iv. In Lung Cancer EGFR mutation in 50%, Treated with Erlotinib and Geftinib directed against exon 19 deletion, exon 21 L858R, and exon 18 G719X, and Afatinib worked against exon 20 T790M mutation. KRAS mutation in 25% without any specific inhibitors and ALK-EML4 mutation 5-7% of patients with NSCLung Cancer respond well to Crizotinib and Ceritinib.


Passenger Mutation: When certain known driver mutations are located in the part of the DNA that is not proximate to the signaling source, their function is reduced and the risk exposure to the cancer is reduced. BRCA gene is author suppressor gene that overrides any anomalies of organ (breast) cell, therefore mutation that leads to its dysfunction results in cancer:


a. BRCA mutation: BRCA -1 on Chromosome 17 q21.2 
19,581 patients: 
46% had Breast Cancer,
12% Ovarian Cancer,
5% Both
37% None
(The effect size is based on the specific location of the mutation. JAMA 4/2015)

c. BRCA-2 on Chromosome13
11,900 patients: 
52% Breast Cancer,
6% Ovarian Cancer,
2% Both,
40% None

c. DiGeorge Syndrome or 22q11.2 deletion syndrome: In this disease, location matters. A slight shift in the placement of this mutation can lead to none of the learning disabilities, congenital heart issues or other disabling anomalies.

d. Cystic Fibrosis: Loss of function mutation as in G551D mutation carrier may not have Cystic Fibrosis but a higher risk of infection…Invacaftor (Kalydeco) helps 4-5% of CF cases.

Not all Mutations are functional (as in location next to the driver gene or further away)or actionable (therapy may be ineffective since the action directed against the wrong gene). JAMA September 2016 article.

Clinical Trials in Precision Medicine (PM):

a. SHIVA Trial: (n=195) No Progression Free Survival or Hazard Ratio differences in genetically matched vs. unmatched.

b. SAFIR-01 Trial: (n=55) 4 Partial Responses and 9 stable disease cases noted in the trial.

c. IMPACT-COMPACT Trial: (n=84) 20% Response Rate in molecular matched vs. 11% in unmatched

d. Basket Trial of 122 patients suggested a BRAF mutation alongside of RAS mutations found in Malignant melanoma, Colorectal and Ovarian Cancers. So the mutations exist not only in selective cancers but these mutations are also shared among other cancers as well. Using Vermurafenib a BRAF V600E inhibitor in these cancer yielded activity.

e. MAP( Molecular Analysis for Personalised Therapy (MAP) conference)Trial: Results from the trial, which took place at the Gustave Roussy Cancer Campus in Paris, found that 199 out of 1110 patients with advanced heavily treated cancer, who had their genes mapped and their treatment tailored, had around 30 per cent longer survival benefit before their cancer started growing again compared to any of the previous therapies the patients had tried. This ranged from between 5 and 32 months.The patients on this trial had diverse types of advanced cancer including lung, breast, head and neck, prostate, bladder, bowel and stomach cancer.


Cost of Precision Drugs

1. As of 2015,150 FDA Approved drugs based on DNA mutations

a. Cystic Fibrosis Drug effective in 5% patients with specific CFTR mutation cost $300,000/year

b. Duchene Muscular Dystrophy: Eteplirsen cost $300,000/ year and recently approved by FDA due to advocacy.

c. A well known debacle in the last decade brought to light a product called Provenge for prostate cancer at a cost of $114,000 that forestalled disease by only 4 months.

These and other costly medications are sticky issues when there are alarm bells sounding on the cost of healthcare. Yet humanity needs to be helped. Reducing administrative and other management costs and redirecting finances to research will auger new advances. As long as a third party insurer dictates the price and governmental policies prevent negotiation of costs, precision medicine may remain a dream for most patients.

Multiple Signal Transduction Pathways.

Example of a single PI3Kinase pathway

a. All such treatments based on Biologics have limiting successes. The major one is the plasticity and adaptability of the cancer cells. Cancer cells as normal cells have multiple signaling pathways between the surface and the core and as one is shut down, the cancer cell adapts to create a Cross talk bridge with another pathway to keep the core fed and growing. That is why the response to Biologics are time limited and eventually cancers after an initial regression start to grow. This same mechanism is elicited with resistance to chemotherapy also.

CTCs, Cell Free DNA (cfDNA) and their potential in PM. Although the CTCs and cfDNA have the potential to diagnose and detect abnormal genetic mutations in cancer cells broken free in the blood stream, the problem remains that the mutation noted maybe from part of that branched tree where the cancer has been destroyed but the other branches with ewer mutations might be alive and well. This leads to a conundrum of appropriate therapy as you can surmise.
CTC analyzers

Layered Information: The answer might be in layering information together rather than in piece-meal approaches. One can use the Family history, layer with the genetic mutation, add to that the lifestyle behaviors, which modulate the genome (via an epigenome, as in miRNA) add that to the gut bacterial genome and its impact on the protein production products of said gene modification and there you have a better handle on the disease and its present and future impact. Layering via:
a. Genome
b. Epigenome
c. Microbiome
d. Proteome

NIH in partnership with the FDA and the Biomarkers Consortium embarked on a iSPY 2 Trial where driver mutations in observed sets of patients will be used to treat other sets of patients. this is an attempt to accelerate and advance the process of cancer medicine.

Friday, September 23, 2016

"ANOTHER DAY, ANOTHER DREAM"



Hope Springs Eternal!

He leaned into the curtains to see who was there. The crowds were milling around. Some taking to their seats, others standing and observing others, still others wanting to be noticed cast their eyes hither and yon for recognition. The porcelain white skinned women gowned and beautified hovered on the arms of their escorts while some with their noses pitched slightly higher walked alone. Their aloneness a symbol of their success as men gathered around them, showering them with cheek to cheek fake kisses. These, he thought were the famously rich people and he, an off the street hobo had been cast to play a part in the play. This was going to be the answers to his prayers. Who knows, he thought, I might be able to mingle with them someday. His prayers had been answered.



The crowd stilled in their seats. The lights dimmed. A trumpet sounded and then all was abuzz with stagehands, actors and set mobility. He was told as he had rehearsed many times now to appear in his native clothing of the smelly rags that had seen the street water, rain water and other unnatural fluids dried and permanently stained on the brown threadbare cloak. His face unshaven with a dark stubble and his mind was set to memorize the few words he was supposed to speak. He went over and over them in his mind, half reciting to himself and to the walls and curtains around him.




Time speeded and slowed as he watched with admiration, the efficiency and alacrity of the stagehands changing the set to keep the spectators mesmerized to the underlying theme of the play. The lights brightened, then dimmed and then brightened again in cycles to keep the spectators memorized by the mirage. The actors laughed, cried, showed anger and disgust and it all appeared real. He was transfixed. From his eyes that had seen a stainless steel pen fall from the pocket of a man on a fast gallop on the street, late for work, he had called out to him as he retrieved it from the street corner for him, the man had turned, looked at him and the offering and shook his head after seeing his pen clasped in dirty hands and walked on, to now in front of these wealthy and important people, all under the same majestic canopy. He still had the pen. He considered it his good fortune, since it was the same afternoon, when another well dressed man had asked him if he would be interested to play a part in a play for money.

The curtain was lit up once again as the intermission ended and the shuffling crowd gathered in their seats. The middle act created the scene of playful elegance and chivalry on stage.

He could hear his breathing and the faint whistle of years long exposure to the pollutants from the automobile exhausts as he sat begging for food on the street corners. The fume had taken some toll on his bronchioles. He was unable to walk the entire street without stopping and catching his breath. His pulse quickened as the play continued to hurtle towards the end and the gasps and muted sounds of disbelief in this suspended disbelief echoed through the large auditorium. He could from his perch see the two mezzanines filled with awestruck spectators watched spellbound as his moment of fame approached.

His moment had come. He walked on to the stage, the bright lights dimmed and he shuffled on the staged street corner where he was meant to stand. The streetlamp overhead on the spot lit the floor brightly encircling him in its lumens. All else was dark. He could not see beyond the first row of the spectators. He shuffled to the spot near the lamp and leaned against it for a few seconds as he and been told. He looked down on the floor and picked up a coin placed strategically for him to acquire. He rubbed the coin against his ragged clothes and uttered the words he had memorized.

“Another day, another dream.” As he pocketed the coin, he collapsed on the stage floor. The streetlamp light dimmed to dark. He got up as the stagehands scurried past him.

The stage brightened and the an actor took center stage, To the last syllable of recorded time, “And all our yesterdays have lighted fools the way to dusty death. Out, out, brief candle!
Life’s but a walking shadow, a poor player that struts and frets his hour upon the stage and then is heard no more. It is a tale told by an idiot, full of sound and fury, signifying nothing.” 

A thunderous ovation broke out as the crimson gilded curtain came down and swallowed the stage. He felt his heart swell with pride. His moment in life had come.

The man who had asked him to play the part appeared from nowhere, “Thank you. You were great,” he says. He hands him two hundred dollar bills. “This should help you,” as he looks back towards someone unseen, “Joe” he points out to a stagehand, “could you please walk him to where he has to go.” And he was gone.

Back out on the cold street, he watches the limousines gorging themselves with people covered in satins and silks as the parade of the beautiful people leaves the theater. Soon the normal late night bustle begins to take over and he is left staring at the marquee.


He realizes, he is the idiot. His minute of glory was to bring a real wretched down trodden from the street to magnify the imagery and pretense of the play. The rich and famous were back clinking glasses in some expensive restaurants or brick lined carpeted homes pretending to diminish the evils of poverty in society as they absolved themselves off their guilty pleasures. “Did you see that poor wretched person in the end. He was so real!” they would claim. “Nah! he was a high paid actor! its Broadway after all, dear.” “Either case,” a slightly corpulent gentleman confided, “don’t look at me, I empty my pockets to all the beggars on the street every day.” Alas discussing the wretched  distilled away the humor in the air and made everyone uneasy and restless.

“Yeah John,” the young financial district upstart chimed, “only with quarters and nickels?” The fat man ignored the slant, “Hey, doesn't anyone know the borough politician, I think having beggars lowers the real estate values and doesn’t look good either.” A general consensus of nodding heads followed. Silence broke out for a while. Someone argued about taxes and the conversation shifted to vacation homes, yachts and airplanes.

A muted repentance of hypocrisy, well, is still hypocrisy.

Sunday, September 11, 2016

PHYSICIAN SUICIDE



PHYSICIAN SUICIDE
&

The misshapen chaos of well seeming forms

Were I a soldier in an infinite army of like minded individuals, I might march to the same beat, move the limbs in the slow and sculpted movement of experienced sinews, hold my head in the temperate form paralleling the majesty of the uniform, sing to the tunes of the collective, view the world from the same pulpit as the preacher and file away the dreams of my youth in the forbidden corners of my imprisoned personal vanity. All semblance of me buried in the form of a single line made of the infinite numbers of similar dots.

But I am not a wanton of simplistic pleasures of agreeability or contextually. I am not the victim of the mind that seeks to swim in the collective tank. I am the unum that desires to seek the fortunes of knowledge, not the pecuniary one but the enlightened angel that hides behind the soft covers of group think beast.

The misshapen chaos of the well seeming forms have come to haunt us. They disguise in the costumes so appealing and seemingly enduring that the lust for the luster and desire for the hues overpowers the senses. These chaotic circles envelope us in our entirety casting a stranglehold on our imagination, our essence, our individuality and our thoughts.

Such is the price we pay for these well seeming forms that caress and cajole our minds. A price too steep, I think, that threatens our very humanity.

Does the calculated mind that oversees such calamity not understand the consequence of its actions? I dare say, it does not. For even as it displeases, it continues to erect newer barriers and rings of confusion around the substance of those well meaning forms. The barriers get higher and higher as their depth gets deeper and deeper, becoming fortresses within fortresses all encased in the realm of meaning well.

Forms such as these, so cruel to the touch that they freeze the fingers, which probe. So dense that they repel the thought that dares and so vicious that they resort to violence against the mind that wonders, captivatingly ossifying any inkling that might threaten them.


These forms take human lives in the form of suicide. Physician suicides. Doctor losses arising from the untimely frost on the wisest minds that roam. These forms bury the architecture of experiential wisdom under the guise of “think not, do,” a form so beguiling that baser natures cannot repudiate. So what if a few die, so what if the many don't get what they should, in the end there is no readiness.

The chaos that ensues destroys the very foundation of the structure that once stood for health and happiness guarded by the wiser angels amongst us. Now the ruins spread like a conflagration, destroying everything but leaving behind a trail of embers; the charred remains of a once polite and very human loving thought.

Physicians take their own lives, mentally shattered from the compressive force of bureaucracy that claims other’s safety by erecting maze upon maze of uncertainty and demand. The maze so clever that exits are all but closed after the entry. Only the solid wall of policies, regulations and mandates exist as you run through the maze, constantly reaching dead ends that never seem to end. Retracing steps to see where one went wrong only to find another dead end. In these hurdles, faced with the never ceasing complexity of the demands, the mind gives up. The center ceases to fathom and cannot hold together the psyche made so fragile by the fear that grinds at the root of every measured step taken. No one is the wiser of the scars that never felt the wound. it seems that no one cares.

When 300-400 physicians commit suicide and female physicians have a 250-400% increased risk of suicides as compared to females in other professions, and 9.4% of the final year medical students are dazed and lost to this monster annually, something is terribly wrong! Something rots at the core of this accelerating phenomenon.

Medicine is complex, Medical care is an art and less of a science than what is believed in the current reductionist society, so tempered with the lust of prediction and probability. The demise of good medical care is near and continues to collapse at the periphery under the erected weighty barriers and threatens one day soon to collapse the center as well. It is humanity’s Hadrian wall.

What resurfaces from this creative destruction is a future of disembodied humans, of virtual machines, of deprivation and an unimaginable lust for the shiny object that will fail to define the better angels of our humanity.

“Virtue itself turns vice, being misapplied
And vice sometimes by action dignified”

Am I a nihilist? I often wonder. But the recent past has been accelerating at breakneck speed for me to be otherwise. We have arrived at the misshapen chaos that no one seems to understand all erected on the foundation of well seeming forms!