Saturday, April 30, 2016



See that word up there in the headline? It has the overbearing overhang like a bushy eye-browed, heavyset red-faced teacher hanging over the desk, peering down at you with menacing eyes. Foreboding to say the least. But there is some truth in it. It conjures up wild images of ideology, anger and destruction. Doesn't it? Our first thoughts move oceans away into dark corners of the world where grim faces beset with hatred fill clean slates with squiggles of confusion and ill-willed determination.

Now look at what happens in an idealized world of civility. The daily ritual of a mother and father speaking to a preteen, telling her about the vagaries of human nature, of where not to go for fear of danger, of when not to go for a similar foreboding. But more than the voice of reason the learning upon which such nurture thrives is the action of the adult. Thus life long Democrats and Republicans are nurtured growing into the temporary space of life and filling more tiny brains with similar ideology. The specter of anger slowly and imperceptibly grows and divisions among humanity take place. So indoctrination is a common thread in the flow of generational information; surreptitiously capricious. But as the doubters are constantly vilified and demonized the indoctrination evolves especially as "evidence" is created for a greater good.

Far be it for me to delve into such a deep topic, yet I have over the years found a perfect corollary in the field of medicine, which is similarly nuanced.

When I was a resident, our main aim was health followed by life must be our focus. No matter the disease, illness, malady we as young physicians were charged with understanding and curing the ills and rendering individual patients with such afflictions healthy. We were told not everyone will survive the ordeal but a concerted all-out effort must be made towards that aim. And we did; breaking the textbook spines, jotting information on note books and coalescing the information to guide the individual patient. Those were heady times. Those were freer times. Those were responsible times.

As time went on, the learned lessons continued but the environment changed, slowly at first and then gaining break-neck speed. The suggestions of what to do and when to do started popping in and out of the medical literature. And as surely as the slow pavlovian reflexes were being developed through a concerted effort in the ivory tower silos, the paradigm of care started to shift.

Everyone started pointing to the cost of healthcare and comparing it with the Western world. Spurious correlations later, almost everyone had agreed that indeed the cost was too high and something had to be done about it. Happy in their numerical discovery, they set out with statistical impertinence to prove their bias, not one of these voices however looked at the factors that were raising the cost of patient care. Not one.

Where does one look to control costs? The finger pointing started and of course the physicians were on the standby to take the blame and reap the maligning. The malignant zeitgeist spread tentacles into the seats of power and congressional beasts rose with booming voices filibustering their way into the mental landscape. And so it was set in stone, temporarily, that all manner of costs in healthcare were borne of the greed and complicity of the human physician. Armies of well-meaning intellectuals rose up in arms to defy such augury. They proclaimed that they for a hefty price of a few extra zeros at the end of 1 would change this abomination. They would bring in the new era of non-human and unbiased mechanisms into place and take away the arbitrariness and self-aware needs of the human and use the mountains of data contained in the Big Data networks as a repository base to change the paradigm. The digital universe of the promised cheap care took hold and many fortunes were made and many lives were destroyed in the process. Yet the constant pounding of the vices of the humans and the virtues of the machines slowly and perceptibly changed the human belief albeit with lingering skepticism. Man was indeed flawed and machines with their unbiased view were more in keeping with the future all ready at hand. The young medical students spent countless hours studying their vocation on computers, barely listening to the lectures given by aging teachers. They used algorithms to answer questions to pass the tests and arrived at the threshold of patient care with little experience. Their “work” was decidedly in favor of arriving at work at 9 O’clock and departing from their “shift” at 5 O’clock to spend their free time, freed of all burdens. While at work they became adept at typing furiously on the computer keyboards to fulfill their contractual obligations with their employer for reimbursements. The game was afoot and the loser in the grand bargain was none other than the vulnerable.

Meanwhile housed in a small cottage in the far rural corner of the middle western state an aging physician sat on the creaky chair holding the hand of a weakened soul, speaking softly about the malady that afflicted the patient and comforting her in how it could be addressed. These were the dying breed of human physicians, cast aside by the runaway train of progress. These few, happy few band of brothers, were determined to hold their ground till their last breath and promised to care for the people of their community that they had lived amongst. The small creaky cottage industry of the dying breed of physicians was being overtaken by the shiny glass and steel buildings of tomorrow where industrial-sized medicine was being processed. In these esthetically beautiful architectural abodes was the circuitry of efficiency. The human physicians, once called "providers" now termed as "scribes," feverishly input information of every encounter and the digital output was almost immediate. Guidelines were printed out for the patient, who walked out with a folio of information that he or she could not decipher, but happy in beholding a meaningless treasure trove of something. Contained within the thousands of repetitive words were the potential seeds of the ill, the affliction, the disease and that made the patients happy. After all it was all about information. Management was based on age and morbidity and if both were immodestly extreme according to the algorithm then a comforting prescription of sedatives and analgesics were contained within the package, if not then a time in the future was mentioned to show up at another shiny building where robotically the malady would be handled. Modern medicine had achieved the pinnacle of human caring. One could assuage a fear from the computer screen by telecommunicating via the computer with an expert. Ah life was so rich!

The powerhouses of venture capitalists and managing partners who owned or shared in the such buildings grew large bank accounts that were off shored to some remote exotic lands. Vacations were planned and more investments were undertaken. The media constantly ran reports of the bane of human doctor’s weaknesses and the virtues of the mechanical unbiased machines that had taken over care under the strict guidelines imposed upon the machines by the experts. Ah the fruits of hard labor were being replicated to scale and enjoyed by the few. Sometime however in their hubris to multiply their fortunes, they made mistakes as exemplified in the Theranos debacle. A lesson worth learning from.

Not to be outdone, the diagnostic version of medical care was also in full bloom. promises of ultra cheap with minimal discomfort diagnostics was in full force. Again money flowed in the billions to satisfy the insatiable appetites of the middle and upper management to reap quick riches. Pharmacies rebranded themselves as care givers and pharmaceutical agencies merged to create incremental advances most times of meaningless values, touted as new discoveries and inventions costing millions but yielding very little in benefits.

The game is afoot and the process is quickly unfolding…where it will end, no one knows.

Sunday, April 24, 2016


There are the Kings and Queens, Bishops and Knights cornered by the Rooks. All are protected by the Pawns that line up in front to spill their blood in allegiance. A game of strategy, deception and aggression is in play.

But what of the Pawns?

Pushed from the rear in a single step, sometimes in deception and other times as defense, the Pawns ride the crest of the oncoming slaughter from the Bishops, Knights, Rooks and especially the unfathomable actions of the Queen. She lurks stealthily behind a facade to deceive and obfuscate the real desire of bringing the opposing King to his knees while her Lord remains quietly “Castled” behind in the protectorate. She is cunning, crafty and deceptive, she uses her Bishops and Knights to set up the Rooks in cornering the King while with equal aplomb arresting the equally devious opposing Queen. Whose charm and alacrity will win the day is anyone’s guess. But in this deep dark world of war blood is spilt and it rarely is the Queen or the King, who quietly surrender, but of the lowly pawns, the Bishops, Knights and the Rooks. Victory is pyrrhic under most circumstance. The waste of life is pronounced as Victory. The vanquished and sometime the victor are left with no armies to speak of. And therein lies the Art of War.

We are all Pawns in this game being played at higher levels. Crafted in the tidy epicenters of power the players sip on expensive wine, bid on barren canvases, satiate their desires on aged cheese while the war goes on with each move of the Pawn. They smother their squeals of laughter when deception wins and kick down the opposing Pawn in abject condescension. Such is the game that lays bare the inner desires of warring factions that stride to win at all costs.

Such is the case when a non medical self-styled intellectual becomes the boss? Actually in more ways then one. A CEO of a hospital makes “rounds” around the hospital spewing euphemisms and pleasantries while in the Board Room he or she is exhaling fiery breaths. The “revenues” are down and heads must fall. “Find the doctors that are costing the system and furnish them with threats and reprisals.” “Cut some of the ancillary staff; maybe transporters, aides and the like.” The sentences barked in extreme condescension bear little evidence to the smiling exterior that meanders the corridors. His main purpose is to increase the bottom line. His main purpose is to enhance the image and hope for a merger with a bigger hospital where he can gain a seat of power and continue the climb to even better prosperity for the self. After all isn't it always the self that a business person strives for? Of course it is. Even an accountant who finds such easy low-lying fruit is going to have a field day picking. One such personality is alleged to have done some real nasty stuff to the hospice patients to increase his bottom-line. This behavior is inhuman in a lot of respects, but if we are true to ourselves, we might find that the current push for limiting care because of costs sets up this kind of a mindset. Doesn’t it? Think about that for a bit.

Physicians have little say in the matter when it comes to the high and mighty business-mettle, hard-hitting, fierce -bottom-line protector CEOs. Patient care is exported to some ethereal realm. The only purpose is to fill the beds and empty them as soon as possible irrespective of the patient needs. The zeitgeist is how a hotel is evaluated by the shareholders by per room occupancy or an airline is viewed per passenger mile.

So pawns we are, as physicians, to the business minded Kings and Queens that populate and copulate within the halls of power and make policies to govern other’s behaviors to improve the bottom-lines.

Someday the White Knight will find a backbone and together with the White Queen will decimate the Maleficent dark enemies and her armies of bean counters. Someday the Pawns will rise up and gain their respect for all the daily wonders they accomplish. Someday patient care will be true patient care and not one made up of false statistical premises and arbitrary and capricious guidelines based on costs. Someday the King and Queen will have climbed the ladder of true knowledge and wisdom of medicine and become the arbiters of goodness and not grief.

Some day…

Monday, April 18, 2016


Hepatitis B Virus  (HBV) Is ubiquitous around the world. 1/3rd of the world population has been infected by it with 240 million people living with a chronic HBV infection. In the United States alone that number is 1.4 million and growing annually. HBV infection remains a serious world-wide healthcare issue.

Hepatitis B Virus (SM image)

While previously it was thought that only “high risk” individuals should be screened for the virus, the MSKCC (Memorial Sloan Kettering Cancer Center) experience teaches us that 50% of the infected individuals can be from the “low risk” category. (High Risk defined as country of birth, sexual history, blood transfusion etc. and Low Risk defined as no prior such risky behavior)

The HBV is a hepadnaviridae family of viruses. It has a partially double stranded DNA with up to 3320 nucleotides. The virus is encoded with three identified genes, The P gene or the Polymerase gene, The S gene or the Surface antigen gene and the X gene (function still debated). 

The mechanism of spread into the human body is quite simple and ingenious at the same time. After gaining entry, the viral core goes straight to the nucleus of the cell where it hijacks the cellular machinery for its own use to replicate producing a boatload of the viral cores. These cores are then shunted to the cytoplasm where the endoplasmic reticulum gives them the protein coating to move into the extracellular space to infect more cells. The process continues in perpetuity until the human body antibody defenses arrive to fight the virus colonies.

In most cases the diagnosis of past infection is established with anti-HBVs (surface antibody) or anti-HBVc (core antibody). A few people might harbor a small viral DNA load (via Polymerase Chain Reaction) but without symptoms or knowledge of the infection. 30% of the infected population does not know they ever had the infection.

In Oncology patients who undergo anti-neoplastic chemotherapy the risk of reactivation becomes a serious dilemma. Varying degree of reactivation risks are noted from 20-70% with an average of 49% associated with various immune suppressive agents.

Reactivation occurs as consequence of the suppression of the immune surveillance due to the chemotherapy, which leads to the viral cores liberation again in the liver causing the inflammation and the resultant 3x or more increase in the transaminases (the diagnostic criterion for reactivation). Although denovo infection and a reactivation can never be truly proven without a past history of the infection. The HBV reactivation can be sudden, dramatic and can occur up to 12 months after chemotherapy. The degree of inflammatory response in the liver can lead to liver failure and even death at times. Most times however it follows the traditional flare of the hepatitis with slow resolution. The derepression of the immune surveillance by the chemotherapeutic agents remains the causal key.

HBV reactivation has been noted in Breast Cancer patients following Cytoxan and Adriamycin chemotherapy, among Lymphoma patients undergoing CHOP regimens with and without the use of Rituxan an anti CD-20 drug, which on its own weight as a single agent can invoke the reactivation process and even patients taking TNFa inhibitors like Adilumumab used in Rheumatoid Arthritis and other chronic immune inflammatory diseases. 

The current recommendation is that history taking and considerations of the HBV risk must be taken into account for each individual. Screening with anti HBVs and anti HBVc should be done and if a positive Viral DNA Load is determined prior to initiation of any immunosuppressive therapy, those individuals are treated prophylactically with oral Entecavir daily through the entire course of chemotherapy. Lumividine (a cheaper drug) has been used extensively as well but Entecavir and Tenofovir are more potent HBV inhibitors to date.

It is incumbent upon the oncologist to elicit a history of potential risk and then screen for that risk prior to initiating the chemotherapeutic regimens. Prevention against reactivation, given the widespread nature of the infection worldwide, is an important tool for patient safety and good patient care.

Saturday, April 9, 2016


Detecting and monitoring cancer is the mainstay of cancer care. To capture and contain the dreaded disease and mitigate its reach and power, studying and defining the cancer cell without resorting to organ biopsies using Circulating Tumor Cells (CTCs) is the new paradigm. The design of this (Liquid Biopsy) architecture was to fathom the following:

Estimate the Risk of Metastatic Relapse
Estimate the Risk of Progression
Real Time monitoring the efficacy of Therapy
Identifying Resistant mechanism
Identifying Molecular Targets
Estimating evolutionary changes in the cancer cell 

Several mechanisms were developed and are currently being put through the paces; a) Liquid Biopsy Microchips, b) PCR assays using reverse transcription, c) Automated microscopy systems d) Multiplex approach to determine the Epithelial-Mesenchymal Transition, e) cell-free (cf)DNA assessment, f) Single Cell genomics with specific genetic mutations, g) Sequencing circulating (40-150 nanometer-sized membrane bound extracellular vesicles) exosomes, h) Using miRNA 

The major problems that still exist are to be able to discern between the normal cell DNA and that of a malignant cell. Known mutations inherent to certain malignancies using micro-array chip technologies and other technological advances have overcome such restrictions to date and further analysis and experimentation will most certainly push the field into the clinical realm quickly. Dr. Geoffrey Oxnard of the Dana Farber Cancer Institute who did the (Liquid Biopsy) study "in 180 lung cancer patients," which showed their EGFR assay exhibited 100 percent positive predictive value for the detection of these mutations," they wrote in the Journal of the American Medical Association's JAMA Oncology.  Wafik el-Deiry, MD recently said about the above study, "This study is not about the promise, it's about realizing the promise,"it's about realizing the promise."  

Using some of these techniques researchers have been able to determine cell free and cell-bound DNA to contain targetable mutated genes and other amplified ones. For example determination of an emergence of EGFR amplification within lung caner, ERBB2 amplification in lung nodule (cancerous) BRCA2 mutation, KRAS mutation and others. Defining the genomic architecture of a heterogenous malignancy such as Clear Cell Carcinoma of the Kidney using driver prevalence through deep sequencing revealed evolutionary changes in the molecular determinants of the primary cancer. the deep multi- region sequencing is affording Precision Medicine a leg up in potentially improving cancer care for the individual. Diagnostic use of Liquid Biopsy is underway in various Trials across the world. Therapeutic modulations based on the diagnostics will certainly follow soon.

Currently with the Immunotherapy challenges against malignancies, Adoptive therapies are being linked to mutation-specific CD4+T cells and using this technique is affording success in the Immunotherapy field.

Liquid Biopsy is on the horizon for pathologists and clinicians to change the way we detect, define, measure and ascertain the extent of the disease and evolutionary changes in cancer. Predictably this innovation will open the doors for a better understanding of cancer management and the one-size-fits-all method of cancer care will morph into true individualized patient care in the future.

One needs to imagine the future when a blood test will function as the pivotal point of patient care in cancer care and potentially in other chronic diseases as well. From detection to cure all through the eye of a molecular vision. Time will tell how this technology evolves and we as humans prosper from it.

Do you think that Liquid Biopsy will afford better Cancer management?


Gerlinger M, Horswell S, Larkin J et al. Genomic architecture and evolution of clear cell renal cell carcinomas defined by multiregion sequencing. Nat Genet 2014; 46: 225–233.

Tran E, Turcotte S, Gros A et al. Cancer immunotherapy based on mutation-specific CD4+ T cells in a patient with epithelial cancer. Science 2014; 344: 641–645.

Taly V, Pekin D, Benhaim L et al. Multiplex picodroplet digital PCR to detect KRAS mutations in circulating DNA from the plasma of colorectal cancer patients. Clin Chem 2013; 59: 1722–1731.

Murtaza M, Dawson SJ, Tsui DW et al. Non-invasive analysis of acquired resistance to cancer therapy by sequencing of plasma DNA. Nature 2013; 497: 108–112.

Kahlert C, Kalluri R. Exosomes in tumor microenvironment influence cancer progression and metastasis. J Mol Med (Berl) 2013; 91: 431–437.

E. Zandberga, V. Kozirovskis, A. Abols, D. Andrejeva, G. Purkalne, A. Line

Cell-free microRNAs as diagnostic, prognostic, and predictive biomarkers for lung cancer. Genes, Chromosomes Cancer, 52 (4) (2013 Apr), pp. 356–369

E. Sunami, A.T. Vu, S.L. Nguyen, A.E. Giuliano, D.S. Hoon

Quantification of LINE1 in circulating DNA as a molecular biomarker of breast cancer. Ann N Y Acad Sci, 1137 (2008 Aug), pp. 171–174

Sunday, April 3, 2016


Fatigue, is the final frontier. No, seriously, from that threshold nothing is achieved, nothing improved and nothing is gained. Only problems ensue...

Definition: “Fatigue is a condition characterized by increased discomfort with lessened capacity for work, reduced efficiency of accomplishment, loss of power or capacity to respond to stimulation, and is usually accompanied by a feeling of weariness and tiredness.”

It is a burnout, or feeling tired…minor change in mood, energy, or sleep; the lowest reaches of wellness. Fatigue is a symptom of your brain reaching a point of dysfunction…a large spectrum of dysfunction. The spectrum ranges from momentary blips on the radar of simply needing a break, a catnap for instance, or needing to eat lunch, to more severe, devastating, life-altering, neurodegenerative disorders of complete exhaustion…Yikes!

There are two kinds of Fatigue:  Acute (short-term) and Chronic (long-term).  Short term acute fatigue is easily cured by a sound sleep and is a normal daily occurrence. The chronic fatigue however has deeper psychological roots and causes significant psychosomatic ailments, which can lead to long term disability from debilitation. Some of these include: tiredness, heart palpitations, breathlessness, headaches, or irritability. Sometimes chronic fatigue even creates stomach or intestinal problems and generalized aches and pains throughout the body and even depression. Self-help cures in these circumstances are rare.

 Above all, when in the throes of chronic stress, don't fly (or operate any machinery)!

Let’s look at some of the common issues encountered: sleepiness, difficulty concentrating, apathy, feelings of isolation, annoyance, increased reaction time to stimulus, slowing of higher-level mental functioning, decreased vigilance, memory problems, task fixation, and increased errors while performing tasks. Fatigued individuals consistently underreport how tired they are, as measured by physiologic parameters. No degree of experience, motivation, medication, coffee, other stimulants, or will power can overcome fatigue. Nine hours into his 33-hour flight, Charles Lindbergh wrote in his journal that, "...nothing life can attain, is quite so desirable as sleep."
Synaptic flow is disturbed with mental fatigue.

A special kind of fatigue that can afflict a pilot with profound ramifications is “Skill Fatigue.” Skill Fatigue involves two main disruptions:
  • Timing disruption – Performing a task as usual, but with the timing of each component is slightly off, makes the pattern of the operation less smooth and fluid. There is a higher chance of disruption in finishing the task.
  • Disruption of the perceptual field - You concentrate your attention upon movements or objects in the center of your vision and neglect those in the periphery. This leads to loss of accuracy and smoothness in control movements. The effects are magnified in high task saturated environments eg. turbulent weather in instrument conditions.

Other symptoms include: memory fog (where did I leave my keys), difficulty following instructions, lowered retention, lack of motivation, tire easily, poor focus, emotional meltdown and psychosomatic pains and digestive complaints. And while it is felt in the peripheral muscles as weakness it is a central dogma arising in the brain; Brain (Central Governance Model-CGM) generates the sensations of fatigue during exercise (MIND OVER MATTER) - Fatigue is a Brain-Derived Emotion that Regulates the Exercise Behavior to Ensure the Protection of Whole Body Homeostasis. ( Timothy David Noakes,* Front Physiol. 2012; 3: 8) While initially fatigue causes a reduction in muscular force, the brain executes a second phenomenon of fatigue as a sensation. The central psychical station influencing the peripheral muscular network might appear as an imperfection, yet it is an extraordinary perfection of support and human self-preservation.

Imaging brain fatigue from sustained mental workload: An ASL perfusion study of the time-on-task effect. Julian Lim NeuroImage 49 (2010) 3426–3435

Fatigue is common among Americans. It is estimated 37% of U.S. citizens are sleep deprived and that many a driver of a vehicle goes through the "micro sleep" (a 3-5 second nap while driving) during the daytime. It is estimated that 5000 accidents (probably more) occur annually on the U.S. highways. Commerce carrying semi trucks pose the greatest hazard for large  numbers of injuries. It is no wonder the churn rate in semi truck drivers is 129%. So fatigue kills indiscriminately on the ground as well.

Fatigue as a phenomenon has been extensively studied by the FAA in Commercial Pilots flying over multiple time zones and the Rules require mandatory rests crossing over 4 time zones and 8/9 accumulated flight hours. (Prevalence of fatigue among commercial pilots Craig A. Jackson 1 and Laurie Earl 2 Occup Med (Lond)(June 2006) 56(4): 263-268.)

The current regulations for airline pilots are:

“The new regulations, which don't apply to cargo pilots, require that pilots get at least 10 hours of rest between shifts. Eight of those hours must involve uninterrupted sleep. In the past, pilots could spend those eight hours getting to and from the hotel, showering and eating. Pilots will be limited to flying eight or nine hours, depending on their start times. They must also have 30 consecutive hours of rest each week, a 25% increase over previous requirements.”

We must remember that the ultimate risk of pilot fatigue is an aircraft accident and potential fatalities. Example: Colgan Air Crash that occurred in early 2009 (
What is the ultimate antidote to Fatigue?  Answer: SLEEP.
Here are some Dos and Don’ts for pilots and surely-bonded- land-lubbers to live by:
1. Be mindful of the side effects of certain medications, even over-the-counter medications – where drowsiness or impaired alertness is a concern.
2. Consult a physician to diagnose and treat any medical conditions causing sleep problems.
3. Create a comfortable sleep environment at home. Adjust heating and cooling as needed. Get a comfortable mattress.
4. When traveling, select hotels that provide a comfortable environment.
5. Get into the habit of sleeping eight hours per night. When needed, and if possible, nap during the day, but limit the nap to less than 30 minutes. Longer naps produce sleep inertia, which is counterproductive. 6. Try to turn in at the same time each day. This establishes a routine and helps you fall asleep quicker.
7.  If you can’t fall asleep within 30 minutes of going to bed, get up and try an activity that helps induce sleep (watch non-violent TV, read, listen to relaxing music, etc).
8. Get plenty of rest and minimize stress before a flight. If problems preclude a good night’s sleep, rethink the flight and postpone it accordingly.
1. Consume alcohol or caffeine 3-4 hours before going to bed.
2. Eat a heavy meal just before bedtime.
3. Take work to bed.
4. Exercise 2-3 hours before bedtime. While working out promotes a healthy lifestyle, it shouldn’t be done too close to bedtime.
5. Use sleeping pills (prescription or otherwise).

Fatigue is a slow inebriation of senses and its harm lies menacingly in the wings. Early recognition and prevention is the key to safety!