Saturday, June 30, 2012


How to extract blood from a stone? A metaphor you say? After all the inanimate does not blend well with the flow of life. Well maybe, but there is a lot of truth in this, as we shall see.

Preface that with the word “how” and the story begins.

I remember him as a jovial sort of a person, quick with words, effusive with complements, tall and thin, leonine in looks with a short crop of dark hair that forced a turn of the head. His life’s work was determining problems related to the heart issues. He was a soft-spoken cardiologist, gentle in his demeanor and positive in his outlook. He had a smell of spring about him. Now who would not love that kind of a person? So everyone did. 

One day, seated next to his friend of twenty some years, he looked over at the changing color of his colleague who was suffering a heart attack and life changed for him. His friend passed away in spite of all the resuscitative measures that could be employed. The world changed.

His nature remained but how he saw the world refracted differently. Every person he encountered as his patient was a disaster waiting to happen. His sleep became interrupted, his clothing a little disheveled, his gorgeous neck ties lost their color and his eyes sank deeper into their sockets. His worries climbed, his comforts declined. He became a one-man machine trying to solve the problem for all humanity that intersected his path. His professional acumen and his deliberate thought remained unfettered in the mosaic of life only the zeal and desire heightened to another level. The summer of his life was in full bloom.

One day while discussing a case with a colleague, his heart started to ache, shooting bullets of pain up his neck, he collapsed in a heap. He was fortunate to be in the hospital and with normal measures of protection he climbed out of the menagerie of “lets check this and do that.” Two weeks later he was back at it trying to save lives. He would routinely drive his patients personally from his office directly to the hospital, if he thought the acuity of the problem rose to the level of emergent. He spent more hours then allotted in a day to his craft. His hair turned grey and then a shock of white all in the matter of a few months. Yet he plodded. He persevered in his desire to heal humanity.

And then the Autumn rains came. He felt a pain on one side and within an hour of its intensity a diagnosis arrived via the CT scan; he had cancer of the kidney. His friends took care of that. He was up again, leaner in his physique but more determined in his desires albeit the pace of his gait a bit slower. Something egged him to fight for others. A noble cause for sure.

Days merged into nights and every moment started to bump into one another. The hospital became his home and his home a little more alienated. Time fractured into shards of glass, splintering over a vast desert of isolation. And surely as the night follows the day, a subpoena arrived at his doorstep, someone claiming something about nothing. The devastation was complete. The last painful pound of flesh had been extracted. The cold winter’s breeze blew in through the shutters. And yet they squeezed and squeezed, but the warmth had turned cold. There was no more. 

What now?

             The Seasons of a Beautiful Life...

Tuesday, June 26, 2012

Ancient Mission – The Art of Medicine

There is a story in every life. There is time, space and a multitude of conversations embedded within. From a medicine's perspective, it could be a crippled limb, a diseased heart, an aging kidney, a ravaged lung or a shrinking brain; all share the common thread of history with a tincture of the spice of life. Every story is a colorful rainbow to be explored. Life, however limits some of the rainbows. Disease comes scampering, nudging and irritating at the doorstep all too often. It is our task as physicians to heal, where possible, comfort where not and above all drown doubt with a clarity of purpose.

"We work in the dark – we do what we can – we give what we have. Our doubt is our passion and our passion is our task " ~ Leo Tolstoy

For disease is not some mysterious wrath of God, or extroversions of internal vagaries of human thought, or the punishment for limitless joy. It is the perversion of a physiologic process, a manifest function of precise circuitry, gone awry.

"Medicine like “(Art) is a discovery and development of elementary principles of nature into beautiful forms…?" ~Frank Lloyd Wright.

Medicine invites passion. It is purity of purpose. It is raw with emotions on both sides of the disease spectrum. It is humanity in suffering. It is a rejoicing in the discovery of new perspectives. These discoveries lead to new principles of patient care for the benefit of all.

“To labor in the (Medicine) arts for any reason other than love is prostitution”. ~ Steven Pressfield  (Substitution mine)

The art of medicine resides in the desire. It is all encompassing. It is a virtuoso experience. Medicine is all consuming. It becomes life. 

"As with other tastes, taste in science will only be found in people with a genuine love of science." ~ W.I.B. Beveridge

The charlatans and the snake oil proponents continue to obfuscate the real medicine. There is a dire need for the pursuit of real science to improve the overall health of medicine and that of its physicians. Failing which, the unintended consequences will overrun the banks of reason. The shores will get muddied and appearances will confound. Only passionate individuals, who are passionate for the survival of this science of humanity will be able to steer the course. 

"Art (of medicine) resides in the quality of doing; process is not magic."~  Charles Eames (Substitution mine)

Medicine invokes such a passion that it becomes life. It is a continuum. It demands, moderates, brings joy and is most rewarding amongst all of human endeavors. The slow methodical plod through time is a gift to humanity. Real science brings real discovery. There is never any magic involved. It is hard work, a daily grind and focus that directs the vision to brighter days for humanity.

"Art (of Medicine) is not a thing – it is a way." ~ Elbert Hubbard (Substitution mine)

Medicine is a composite of give and take. It is two life forms bartering at alter of health. It is the best understanding and knowledge from one and the total reliance of one’s life and a future life of another. The art of medicine denies selfish behavior. The way of medicine is the profound desire to know and the ultimate "want" to heal. 

"Art (of Medicine) enables us to find ourselves and lose ourselves at the same time."~ Thomas Merton (Substitution mine)

In medicine as in any process of nature, there is risk. The risk of uncontrollable disease, the risk of frustration and despondency, the risk of potential harm, the risk of alienation and diminished life itself. The thread of hazard exists entwined into the very fabric of our existence.

"An essential element of any art is risk." ~ Francis Ford Coppola

The art of medicine suffers from a myriad of mystical thoughts. There is an ever bloating, burgeoning cavern of “do this or that” rather than what is best in the wisdom of knowledge. There is a constant state of perversion to the best endeavors that seek only for reasons other than true reason. There are voices that push and pull. There is anger and disdain from passionate self interest groups. There is talk of change in the corridors of power. Yet medicine flows from the soul. It has to transgress these limitations imposed upon it. To survive at its penultimate propensity it must defeat resistance and the confounding entanglements of self-serving interests.

"Art (of Medicine) begins with resistance – at the point where resistance is overcome." ~ Andre Gide (Substitution mine)

The care of a patient is embedded within the shell of his being. Nature, life, history and the world interacting to create the disease all become a continuous composite of the diseased and the infirmed. Disease has an autobiography that must be delved into and understood. Without that autobiography, medical intervention is only a snapshot in time - meaningless. In a single event intervention, the visible shell is cared for and not the history of the illness, which can rear its ugly head again.

"All art (as in medicine) is autobiographical; the pearl is the oyster's autobiography." ~ Frederico Fellini (Substitution mine)

The axiom that holds the truth; the healing art of medicine in its pure form is both joyous and rewarding to the physician and to the patient. No pecuniary amounts will make it any better, but will damage it for the worse.

"Art (like medicine) suffers the moment other people start paying for it." ~ Hugh MacLeod (Substitution mine)

It is in this ring of truth where most have turned up a blind eye. All of modern medicine is in the rigor of power and control. The competing forces, those that wish to do the right and those that wish only for their own self-serving benefits are in a modern day battle to wrest the soul of medicine.

"This is the power of art (of medicine): The power to transcend our own self-interest, our solipsistic zoom-lens on life, and relate to the world and each other with more integrity, more curiosity, more wholeheartedness." ~ Maria Popova  (Substitution mine)

The age-old "carbon-dated" thought holds true, that the power of medicine lies in the well-reasoned, well-researched, well-executed realm of good science and patient's trust. Manipulating good science as well as destroying the trust between the patient and physician with intermediary firewalls of "opportunities" established by "outsiders" and self-serving "insiders" is the slow bleed of the "Destruction of Medicine."

Friday, June 22, 2012

Daydream Believer

Medical Intelligence and the Healing Art.

Is intellect the agency for a medical cure?

Is the patient the sum total of his illness?

These questions invoke, provoke and ultimately revoke the currently held sway, which rings freely today.

The modern human mind is plagued with the notion that all problems can be solved through enumeration. The increasing value being placed on technology is a testament to the desire to farm that thought into action. It is all about creation, replication and enumeration. The science of discovery has taken a back seat to the numbers game. 

The computer generated data, with all its wonderful gains and purported ills makes for a charting scheme. Charting the numbers to create a graph to prove an unproven hypothesis is the call of today’s intelligentsia.

In medicine we lord over and frown upon, with impunity, those that want time and discussion, a moment with the patient, unencumbered with the contrivances of “fill this form and appeal that one.” Time has been force-morphed into money. Everything, even diseases have been converted into a series of 1 and 0s and dollars. But dare I ask the question? Dare I inquire whether knowing this hefty bag of minutiae harbors any benefit for the patient? 

Didn’t think so. 

Our knowledge too has become superficial, yet deeply filled with mindless data. We feed off of each other, nuances of this and that and when it comes to the original calamity that we hope to fix, we turn our eyes away from the other set of eyes and stare into the flickering screen with nothing left but a deeply furrowed forehead, eyes reduced to slits and all nose, and the screen in front of us. We have become the caricatures of our own creation. Oh yes we may know that a certain Wnt signaling mechanism is needed to create and possibly propagate colon cancer and even prostate cancer, but what does that do for the patient? Or for that matter the knowledge of the manifest KRAS mutation in a large percentage of pancreatic cancer patients, or the SHANK-2 or -3 gene mutation and the haplo-insufficient Copy Number Variants (CNV) known as a disruptive influence in brain neural network leads to Autism Spectrum Disorder, but what of that? Can that mutation ever be fixed and if so, might that lead to some other downstream malady? Especially when we don’t even know whether the genetic mutation was a cause or an effect of nature or nurture. The SCN5a (Sodium Channel gene) at 3p24-p21, one of 30 such mutations in coronary artery disease is well known and we would look awfully smart when we propound that information to the laity, but does that fix any problems? My point is, information is coming at us in zeta-fold containers of bits, yet we still have to fight each illness one patient at a time. Don’t we?  And each disease manifests differently in different patients because of many, many underlying factors. Don’t get me wrong; new scientific information is good and one-day the accumulated knowledge will presage the dawn of newer therapy. But until such time, let us tend to the problems at hand and use the partial information wisely.
by Brian Christie

And there in lies the conundrum of intelligence. What is medical intelligence? Is it the bookish data of this and that, which impresses rather then seeks to heal? Is that why modern medicine considers a patient a sum total of his or her illness, rather then a human being with illness? Is “healing” just another art form defined by someone in some esoteric journal with a given set of data-points?

No wonder our primitive brain where human emotions and connections reside, is atrophying at a grand scale. Forgetting, for a while patients, the society has built and fortified a wall between humans, Human affairs have undergone a paradigm shift of sorts. We are isolated, more and more, from the emotions of his and her. We seem attracted to every disaster, or morbid event broadcast on television and revel with goose pumps and shrieks watching scary movies about, death and dismemberment, about vampires and vultures and aliens that grow inside and suck life away. Maybe in some surrogate way our lives are being lived via this art form. Human life is now a game.  Maybe what we have imagined has become us.

Where is the connection? Where is the warm kind hand placed on a shivering shoulder? Where is the comfort of an embrace? Where has knowing the essence of a human through his or her life, gone? Where are the details of his or her marriage, birth of a child, divorce, loss of a livelihood, the very quintessence of each person’s humanity logged in the medical chart? Where is that historical reference of a patient’s real call for help? Where? Who really cares anymore? Why should they? Information is everything and time is money.

Maybe we need to exploit that limbic connection once again. Maybe we should have mothers mothering, so that no more “Columbines” happen. Maybe we should have father’s attentive to the needs of their children and not their wants. Maybe we should spend time as a family reveling in each other’s daily exploits, rather than glued to the macabre flickers of far-away disasters, tragedies and inhuman behavior on the television screen. Maybe we should rejoice in the birth and not spend countless years worrying about death. Maybe we should smile more and frown less. Maybe we can say, “Hello friend” and shake someone’s hand without wanting something in return. Maybe we can rejoice in the hard work and creativity rather then in the greed, desire satisfaction and selfish pursuits.  Maybe we can think about the patient and only about the patient. Knowing that all grand pursuits of pure thought and action ultimately lead to great joy in health, wealth and human connections. 

Maybe we can. Maybe we will. It lies within us. Dig deeper and find that humanity once again. Therein lies the salvation for our species.

Dream Big.
Live life to the fullest.
Help those in need.
And your fortunes will multiply manifold.

"Oh I could hide 'neath the wings
Of the bluebird as she sings..."

Be a Daydream Believer.

Sunday, June 17, 2012

Are Doctors Irrelevant?

My grandmother used to say, “Be careful of what you wish for.” She was right. We have come a long way down this current  path of guileless uncertainty. The charm of the “reap and find reward” seems to be over. Now is the time of reconciliation with the thinner concepts that run freely.

Are doctors irrelevant? Many will and do say yes! These voices are rising in decibels. The din is starting to reverberate through the halls of policymakers and even the laity is mind-numbed into echoing, “The King is dead.” They are ready to worship the new one, “Long live the King.”

Cartoon from the Economist

It seems that in caring for patients, the doctors are on the periphery looking in. Everyone else seems to have a better handle on how patients should be treated. Experts are proliferating and ripping the shroud from under which they have been opining. They are now openly writing editorials. “Ah,” they say, “the doctors are recalcitrant in their thinking.” Maybe we are. Maybe we, out of concern for our patients need to think through things to determine the best course for the diseased, the infirm and the unhealthy. “The doctors are greedy,” they clamor. Maybe we are but mostly about the best possible care that can be rendered. “The doctors are rich and fat,” the headlines grapple with our attention. Maybe we are rich, in knowledge and fat with understanding of it. But in finance most are barely able to keep their heads above water.  At most points in our career we have generously donated our time and monies towards someone’s care without demanding any returns. Here, at the threshold of transformational change to medicine, we look to discard the virtues that have brought recovery from illness, comfort from grief and solace from the inconsolable dissonance of disease, to the shimmering mirage of a vacuous future.

Graph from The Economist

The experts are now billowing through their mouths about how foreign countries like India have only 5 doctors for every 10,000 people, whereas there are 24 per 10,000 in the US. Somehow it has now been determined by The Economist that India has a wonderful concept of Healthcare delivery as compared with the United States. They go on to describe how an ophthalmologist has two patients on either side while he turns from one to the other to save time.  “The Aravind Eye Care System offers surgery to about 350,000 patients a year. Operating rooms have at least two beds, so surgeons can swivel from one patient to the next.” What about transmission of infectious disease? Are there pitfalls to this assembly-line like workshop of surgeries? Oh but that is not discussed. The intent is to marginalize the facts and propound the potential. The largest employer for this form of delivery by the name of Dr. Shetty who has thousands of bed hospitals across India has pushed a bill to reduce the medical education to 3 and ½ years in India. That he says will produce more general doctors to handle the mundane form of health care (as if there was any mundane form). “Dr Shetty’s goal is to offer as many surgeries as possible, without compromising on quality. To do that, he ensures that his surgeons do only the most complex procedures; an army of other workers do everything else. The result is surgeries that cost less than $2,000 each, about one-fifteenth as much as a similar procedure in America.” I wonder what "comprising quality" means to him. There are murmurs from the mimes in the US also, where three years of medical education seems to fit the budget. Are they right? IS the current four-year rigor too rigorous and expensive? What are we missing? I look back and think, was there any redundancy in my training? The answer is a resounding, No! The fundamentals of medicine are the most important ingredient in the doctor’s quiver. Absent that and the understanding of disease will falter. It is quite simple, if you don't know what makes it tick, how do you know what could make it stop ~ ticking that is.

The experts claim that the health service provided by the nurses was non-inferior to that of a doctor. Really?  It boggles my mind as to the difference in education and comprehension of the disease complex in a patient with multiple co-morbidities. Will the nurses have it? Will the physician assistants bear the brunt of understanding a cardiac patient with emphysema and poor renal function going into right-heart failure as the atria fibrillate? Will the nurse practitioner differentiate in a cancer patient, between the potential side effects of the monoclonal antibody therapy, hypertension and an impending stroke? Unfortunately the many nuances in medicine, garnered over years of experiential knowledge, are being laid at the altar of expediency and fiscal prudence.

The television and online presence gives us a preview of the "doctors." Anyone wearing a white coat with a stethoscope around their neck; diagnosing plumbing problem, roach infestation, swimming pool service and the best one yet, the "doctor of democracy." So put a white coat and sport a stethoscope and the knowledge of medicine they seem to imply will magically appear through osmosis.

“Be careful for what you wish for.”

In all of this "transformation and disruption" of medical care, there is good that never gets registers on the meter: newer training concepts are on the threshold of enhancing the experience of the medical students in the US and this, potentially, may help make the medical students more adept in handling patient care. At the North Shore Long Island Medical College the training of the new up and coming doctors is being done in the real world scenarios: (Video Link Below)


Tuesday, June 12, 2012

T-DM1 and Breast Cancer

Fewer agents raise my eyebrow now that every new cancer drugs is labeled as some form of a “nib” or a “mab.” All such categories of targeted antibody to a defined mutated receptor, an epigenetic related loss or gain of function of a gene, or specific protein product of a gene-gone-haywire therapy assault the surface antigen of the cell where the “nib” or “mab” meet the  cell and prevent the flow of a signal from reaching the nucleus (interior) of the cell and thus preventing its (the cells) reduplication.

 Cellular Internalization of the T-DM1 molecule

Signal Transduction:

The signal, you see, is the message from the outside (the exterior of the cell wall) that tells the interior (nuclear) machinery to go into action and replicate another one like itself. On the other hand, the unmitigated growth of the cancer cell is reliant on promoting that signal in a loop mechanism and by virtue of that and the multiple transduction pathways, this leads to the constant barrage of signals to the nucleus giving the continuous directive to grow.

The intracellular communication:

Consider a branching railway line all merging into a single line as so happens at Railway Junctions. If one line goes bad at the junction, it can be piggy-backed/connected to another track or at the station the  passengers can board another train that can be programmed for similar destination. But once the rail lines merge into one, there is only one way out of the station. We are inching our way to disrupting that single railway line. 

At present disrupting the pre-merged railway lines just invites the train to take another line enroute to the common outbound line. That is the reason for the many targeted therapies to have a moment of success in sunshine with cancer but they ultimately fail to maintain the momentum


So what caught my eye was this new drug called T-DM1. Fascinating name to begin with, this drug inspired a closer look. The “T” in the T-DM1 stands for the Trastuzumab as in Herceptin.  Trastuzumab is directed at the HER 2 receptors (The surface antigens I mentioned earlier) present on the breast and various other cancer cells.  So this drug interferes with the signal from the surface (mediated via the HER-2 receptor) to the interior of the cell, required for the cancer cells to grow. The hitch in some cases is the absence of over expression of these receptors on the cancer cell surface of the HER 2 or  the Trastuzumab (Monoclonal antibody to HER 2) cannot collocate to the HER-2 receptor to get internalized and therefore becomes impotent in its action to subvert the HER-2 function from generating the signal.

A (very) Few of the Pathways (Medscape)

Additionally,  another mechanism for failure is the cross-talk between the pathways (interconnecting tracks at the railway junction) merge to allow the signal to be redirected to the interior of the cell via another pathway and once message is delivered, the cancer cell resumes its wayward growth (this then also represents the time delay garnered as "Response" to the targeted therapy followed by failure).

You might ask, why did the body do this multiple pathway “train-station” business inside the cell and make it so difficult to treat? The reason being that these receptors are needed for the growth of the normal cells, but in the normal cells the growth is limited to the need and once that need is satisfied, everything goes back to the quiescent phase of “wait and watch” demand. In cancer, the cells acquire this innate ability to keep themselves in business of growth, (a constant state of demand) much like a politician always promising.

Cancer Cell

So we now get down to the DM1 part. And here is where the real science behind this drug may be transformational. You see back in the late 1900s, there was a drug called Myatansinoid antimicrotubular agent or DM1((N2′-deacetyl-N2′-(3-mercapto-1-oxopropyl)-maytansine C35H48ClN3O10S). DM1 is a derivative of the natural microbial fermentation product and extraordinarily potent antimicrotubule agent ansamitocin P-3.4  It was first studied back in the 1970s.

T-DM1 attached to HER2 Receptor on Cell Surface

The Chemistry behind:

Chemical derivatization of maytansine resulted in the synthesis of a maytansine derivative DM1, which is three- to 10-fold more potent than maytansine, with an inhibitory concentration (IC50) in the picomolar range and broad cytotoxic activity against a wide range of human cancers. Maytansine, although active at extremely low concentrations, exhibited too narrow a therapeutic safety margin, with significant and sometimes unpredictable gastrointestinal toxic side effects that prevented further clinical development. The mode of action determined at that time was that the cleavage between T and DM1 occurs intra-cellularly and also in the plasma, resulting in the progressive depletion of DM1 molecules eventually yielding the individual components of unconjugated antibody and “free” DM1.

Mertansine is linked via a complicated structure – 4-(3-mercapto-2,5-dioxo-1-pyrrolidinylmethyl)-cylohexanecarboxylic acid or MCC –, in which case the International Nonproprietary Name of the conjugate is formed with emtansine as in T-DM1.

Antibody Drug Conjugate (ADC):

So T-DM1 is an "Antiibody Drug Conjugate" (ADC) between the Trastuzumab (Herceptin) and the DM1. The idea behind this immuno-conjugate (ADC) is that the Trastuzumab is attracted to the HER-2 receptor on the cell surface and binds with it. The Trastuzumab is “swallowed” (internalized) into the cell cytoplasm where the delinking between the Trastuzumab and the DM1 occur and then the DM1 is free to play its role of arresting cell division via the microtubulin assembly (An assembly of microtubules that anchor at polar opposites of a dividing cell to "pull" 50% of the nuclear pieces to form "baby cells") and thus rendering it to “programmed cell death” or apoptosis. “The trastuzumab moiety of this ADC binds to HER2 on tumor cell surface surfaces; upon internalization, the DM1 moiety is released and binds to tubulin, thereby disrupting microtubule assembly/disassembly dynamics and inhibiting cell division and the proliferation of cancer cells that overexpress HER2.”


The benefits of T-DM1 were determined from the EMELIA trial that suggest a Progression Free Survival (PFS) in the T-DM1 group of patients compared with the therapy regimen of Capecitabine and Lapatinib.  The translated benefit is 3.2 months (9.6 vs 6.4 months). Median overall survival for patients treated with T-DM1 was not reached, but median overall survival for those treated with standard therapy was 23.3 months (hazard ratio [HR], 0.621; P = .0005)”. Although this does not seem so grand in scale, these patients have been pretreated significantly before, prior to being accrued in this study and that is what gives some solace to the drug designers and those caring for cancer patients and hopefully, down the line, to the patient’s and their families.

In the EMELIA trial  a total of 978 patients in the cohort received treatment. The median durations of follow-up were 12.9 months in the T-DM1 group and 12.4 months in the standard-therapy group. The baseline demographics, previous therapy, and disease characteristics were balanced between the 2 groups.”

Standard Therapy
Overall Survival at 1 Year, %
Overall Survival at 2 Years, %
Objective Response Rate, Months (95% CI)
43.6 (38.6–48.6)
30.8 (26.3–35.7)
Duration of Response in Patients
With Overall Response, Months
Adverse Events of Grade 3 or Higher, %

The drug is by no means a one of a kind. The immuno-conjugations (ADCs) have been created previously between DM1 and other “mabs;” Bivatuzumab, Cantuzumab and Lorvutuzumab. The fact that the benefit is modest with lowered toxicity gives a whole new meaning to immuno-conjugation and the future of cancer therapy.

Oh and if you are forward thinking, you might ask can this be used in early stage cancer as adjuvant therapy? And the answer is why yes of course, as long as future studies continue to sho robust responses. Why that is how all medications are first tried in advanced stage disease and then showing benefit, they are tailored back in the adjuvant (read preventative) settings.

Will the FDA approve T-DM1? It is not a question of if but when.

So now we know of what is to come in the future.

Chari RV, Martell BA, Gross JL, et al: Immunoconjugates containing novel maytansinoids: Promising anticancer drugs. Cancer Res 52:127–131, 1992

Chabner BA, Levine AS, Johnson BL, et al: Initial clinical trials of maytansine, an antitumor plant alkaloid. Cancer Treat Rep 62:429–433, 1978

Blum RH, Kahlert T: Maytansine: A phase I study of an ansa macrolide with antitumor activity. Cancer Treat Rep 62:435–438, 1978

Cabanillas F, Rodriguez V, Hall SW, et al: Phase I study of maytansine using a 3-day schedule. Cancer Treat Rep 62:425–428, 1978

Eagan RT, Ingle JN, Rubin J, et al: Early clinical study of an intermittent schedule for maytansine (NSC-153858): Brief communication. J Nat Cancer Inst 60:93–96, 1978

Issell BF, Crooke ST: Maytansine. Cancer Treat Rev 5:199–207, 1978

2012 Annual Meeting of the American Society of Clinical Oncology (ASCO): Abstract LBA1.

Friday, June 8, 2012

PET Scan

An error doesn't become a mistake until you refuse to correct it. ~ Orlando A. Battista

A while ago, a PET scan report landed on my desk. It was a six-page document, detailing the methodology, the operative procedure with organ-by-organ detailed results. All in all, it was a very impressive presentation. The conclusion however after all the words suggested that the results were negative; in other words the patient so tested failed to show any abnormal activity in any of the organs.

“Good” I said and picked up the receiver and called to inform the patient, which made her happy too. But there was this lingering dark cloud turgid with contrary thought that lurked over my head. I pulled out the previous report and compared them. Hmm. There was a discrepancy in the followup diagnostic testing somewhere and I, for my patient's sake, needed to find that out.

Follow up Algorithm of patient care

Sleuthing is a strange vocation. It keeps opening new doors and closing others. The rabbit hole of progress takes you through some very deep and dark alleys.

What is PET scan?

PET stands for Positron Emission Tomography: The positron is a positively charged ion, the emission indicates a radioactive decay that is being witnessed and captured by the sensors and the tomography is the detailed radiological view of multiple planes of the human body. The single plane technology was created by Robertson and colleagues in the Brookhaven Lab in 1961. Following that Wolf and associates discovered the 18F-FDG (Fluorodeoxy-D Glucose) for use as a radiopharmaceutical as a scanned material in 1968. Abbas Alvi in University of Pennsylvania was the first to use the 18F-FDG in normal human volunteers for the first time in 1972.

Emissions: Signal to Noise Ratio

Let us focus on the emission aspect of this wonderful new technology for all its worth.  A radiopharmaceutical agent is a radio-nucleotide that by virtue of their instability undergoing decay leading to gamma emissions, which are captured by the scanner. These gamma emissions from the sites that accumulate based on oxygenation needs, occur at such a rapid pace that detectors with less than 10 nanosecond rate get very poor results due to the inability to resolve the “signal to noise ratio.” Thus the results are sub-par and a lot of interpolation and guesswork is involved. While newer machines with capabilities in the 100 picoseconds will have crisp data, it will be almost like comparing the new digital OLED TV screens to the cathode ray tube of the yesteryear when these new machines come online.

18F-Fluoro Deoxy-Glucose and the Periodic Table

In the Periodic Table, Oxygen is the 8th element and is followed by Fluorine, which is number nine. So the concept of creating an 18-Fluorine from the 18-Oxygen arose initially by using electrochemical fluoridation. Nowadays this is done by means of a Cyclotron, bombarding protons at the 18-oxygen ions in a 18-Oxygen “enriched water” and with a “knockout reaction” displacing it with 18-Fluorine ions. The 18-Fluorine ions have a half-life of 109.8 minutes or under two hours.

FDG and the cell

Since the 18F-FDG is an analog of the 18-Glucose the metabolically active cells take it up for energy production. The phosphorylation of the 18F-FDG ~> 18F-FDG-6-Phosphate prevents release of the glucose out of the cell. Since 18F-FDG is missing the 2’OH (Hydroxyl group) it is also unable to be utilized in the glycolysis (glucose breakdown). This combined inability of phosphorylation and non-utilization leads to an accumulation of the 18F-FDG-6P within the cell, thus represents the glucose requirement of a functionally active cell as is seen in the normal brain and the kidney and in the “high-octane” cancer cells.
PET scan result

 18F-FDG Metabolism and Excretion

The normal radioactive decay of 18F-FDG yields 18-Oxygen-deoxyglucose, which picks up an H+ from the hydronium ion in the liquid medium of the cell, thus creating an OH (hydroxyl) group and a non-radioactive trans mutated 18O-Glucose-6 Phosphate that remains in the cell, which is then metabolized through the usual pathway.
18F-FDG half life

Even though the half-life of 18F-FDG is 109.8 minutes, the disposal however is via two methods. 1) 75% is by metabolism as described above into a harmless non-radioactive metabolite and 2) 25% is via direct kidney excretion in its radioactive mode (rapid elimination prevents the half-life decay) in the form of radioactive urine excreted by the patient. However, within 24 hours (13 half-lives), the radioactivity in the patient and in any initially voided urine which may have contaminated bedding or objects after the PET exam, will have decayed to 2^−13 = 1/8192 of the initial radioactivity of the dose. So it is imperative to be careful of the radioactive waste for at least 48 hours.

Okay now that we have figured this out, let me take you deeper into the puzzle posed above in that PET scan report:

18F-FDG Half-Life and Transportation

Given the half-life of 18F-FDg is 109.8 minutes or under 2 hours, it means a facility without an in-house cyclotron to create the 18F-FDG would have to import such from another facility. That transportation time then has to be incorporated into the value of the half-life. In other words if the transport of the 18F-FDg took 2 hours then more than half of the 18F-FDg would have decayed and rendered useless, correct? So the game is to estimate into the transport system the time lag of the transportation and send a larger dose that when it reaches the facility will have enough volume and still be optimally radioactive and capable of appropriate use. This is done via specially designed and regulated transportation services. A further hitch would be the time the radiopharmaceutical agent arrives at the hospital or facility and the radiopharmaceutical-pharmacist accounts for it and then it gets transported to the patient room and is dripped through the IV infusion into the patient.

By now you have guessed my confusion of that PET scan result that I had obtained. Indeed the uptake was normal because not enough of the functional 18F-FDG remained to give a valid test. Repeating it with more stringent criteria revealed the error.

Pitfalls and other considerations in PET scanning

Another problem that sometime might happen is if there are two metastatic cancer sites in an organ. One may have cells in an active state of division, that site will necessarily uptake the majority of the 18F-FDG leaving little for the other less functionally active site and therefore the PET results may show a high intensity uptake or SUV (standardized uptake value) in the small tumor and a weak signal uptake in the larger one, even though both are malignantly active. The size of the tumors are better judged by a CT or an MRI scans and nowadays the images of the PET can be merged with the CT and the MRI for better volume delineation of the state of the human disease.
PET/CT scanner

As might be obvious, a high blood sugar value will minimize the uptake of 18F-FDG since 18-F and 18-O are “kissing cousins” on the periodic table, the high limit of blood sugar has to be maintained below 180 mg/DL in order for the test to be performed accurately. Additionally an active source of infection or chronic inflammation will garner a major share of the 18F-FDG, due to the glucose needs of the infected/inflamed sites. The differentiation between the myriad issues that surround PET scanning is the purview of the physician.

PETs are PETs but they still need to be patted on the head and deloused occasionally.

 An error does not become truth by reason of multiplied propagation, nor does truth become error because nobody sees it. ~ Mahatma Gandhi

Tuesday, June 5, 2012

Major Timms

My name is Major Timms,” his voice echoed in the classroom of fifty students. He stood 6 feet tall but for his straight spine, slight chest protrusion and impeccable dress code made him look like a giant. He towered over you in demeanor. A strange and disquieting feature when one is just sprouting the adolescent features. He had command. There was no turning back. If you had remotely patterned yourself towards an easy year, those words from his mouth dispelled such a thought.

There was something in the way he moved about the room, gazing back at anyone that dared to see where he was at any one moment. Before you knew it, he was breathing down your neck, examining the search for answers in your eyes, “What seems to be the problem?” he would say and you shrugged your shoulders with a, “nothing, sir, nothing at all!” With a qualified loud “Hrrmph” he would be perched over someone else’s shoulder with an empty pipe dangling from the corners of his mouth firmly clenched in between his teeth. The image had along lasting effect on a twelve-year old mind.

Soon however as the first month of the year passed, you grew comfortable. It wasn’t like Oliver Twist looking for “more.” It was more like the plate was always filled with more even without the asking.

Major Timms was a joy as a teacher. His “hrrmphs” got quieter as he gauged your discipline and desire and then stoked the energies of the youth. Even the laziest of the lazy were compelled and propelled. Somehow everyone learned. He allowed questioning at its basic level. The “whys” were always answered with a “because” if he knew them and “lets find out,” if he didn’t. He was like an adventurer at the helm of an expedition, always knowing the currents, tides and winds for the sails to fill and the direction towards the rising sun. 

There was more knowledge received from him then can be quantified. He would take an algebra problem and equate it to Al Khwarizmi and how people back then solved complex issues of society. He had a knack for metaphors, an eye for the needle in the haystack, an ear for the subtlest of sounds emerging in the youthful understanding and above all he prodded, poked and stoked the fires of passion to learn. From DaVinci and Shakespeare to Newton and Einstein everyone and everything was fair game.

Every day in his class, I changed my mind to follow a different goal in life; a mathematician one day changed into an astrophysicist, a writer morphed into a philosopher the next and in the end the rocket scientist finally settled on medicine and within medicine later, from an immunologist to a medical oncologist. But oh, the pleasures of those multiple desires still evoke a memory that continues to ignite the conflagration within.

I have often wondered if I could find in myself a sliver of what he had, so I may be able to mold journeys the way he did? He was a special person. He wanted the best in everyone. He told stories, he brought fables to life, spoke of myths and fashioned arguments for and against till you saw the meaning behind the words. He was special indeed. For he gave me the wisdom to learn and I will forever be grateful for that.

So long Major Timms, your inspiration lives. 

Friday, June 1, 2012


The Sun Drenched Elastic Band

"From 0 to 80 in a blink of an eye!” Yes that is how life progresses. The leaves form and fall, the flowers bloom and wither and the spring is replaced by winter. The discontent of the cold and biting weather is the common refrain that echoes and echoes.

From the soft, moist elasticity of the newborn skin to the weathered, dry, fragile paper machete of the aged, lurks the rub of time. What happens is a slow but progressive march.

From the fantasy of a future to the hope of accomplishments to the mindset of invulnerability resides the essence of youth. Here all systems are on full alert, all mechanisms are a go and all actions are unpredictable. Somewhere in that beautiful garden of blossoms and birth lies the propagation of the species. There is the elastic band that stretches and fires and the pebble of procreation hits the mark.

But what happens with age?

Even though the whole play of life will take many a scene and act, let us use some latitude of brevity to consider it.

If you are young, you wont know or for that purpose want to know, what this is all about, just yet. But if you are older this will fit perfectly in that drawer where you keep all your passports hidden. The same passports that have seen the image of you perceptibly morph from the smiling, wide-eyed, wonder-struck youth to the frowning, eyelids at half-mast, loss of enthusiasm elderly. It is not what has happened but rather, why it happened?

From the inner workings of thought, to the whips and scorns of time, to the slings and arrows of physical abuse that have encompassed the human body, this is a story of the underpinnings of the basic mechanisms of life. I will leave the “thought” and “enthusiasm” issues for another time. This will be about some of the changes in the inner circuitry that underlie our being.

The Cell and its Interior

Cells are the basic component of the human body. There are trillions of them that form the surface of the skin and the various organs within. Each cell is endowed with thousands, if not millions, of bits of functioning material within that interact with each other and outside of the cell’s domain to continue the process of existence.

One of those pieces inside the cell is called the mitochondrium, an exquisite piece of machinery that governs and creates energy from the foods that we eat and distributes it along the rest of the cell for creation of the various hormones such as Insulin, Thyroid stimulating hormone etc, chemicals as in acetylcholine, epinephrine etc, neurotransmitters in the brain cells for electrical transmission of neural impulses (that which make the muscles twitch, the eyes to see, the eyelids to blink, the heart to beat, the liver to metabolize etc). All that is accomplished through creation and liberation of energy. 

The mitochondrium is a actually a cyanobacterium that was incorporated into the unicellular organisms some 1.5*10^9 years ago as a self-sufficient, independent, energy-producing unit. It was the merger of plant-life and animal-life to achieve a self-contained unit. Due to it’s “Eve” derived unmodified DNA, we are able to trace the human species evolution from the oldest (African) to the newest (South American) based on the mitochondrial DNA.

As we age, the mitochondrial function becomes “leaky,” for lack of better word, and in doing so, there is nascent oxygen created in the process of making energy, that is normally slurped up by an enzyme called SOD (Superoxide Desmutase), which accumulates. As more and more nascent oxygen (Oxygen radical or “free radical”) is not gathered up, it begins to cause damage. The radical oxygen is O of the O2. It has an extra electron hanging out that latches onto any other weak bond within the cell. Those weak bonds exist in the nucleus of the cells in the form of DNA.

The DNA as is well known, is comprised of four nucleic acids, Adenine, Thymine, Guanine and Cytosine. They have complimentary linkage with one another. Adenine always links to Thymine and Guanine to Cytosine, or AT, CG.  Since each strand of the double helix carries a nucleic acid, the other carries the complimentary one. These bonds that unite the four to each other are extremely tenuous hydroxyl groups, and easily broken. Imagine if a stray electron comes charging, it will easily disrupt one of those hydroxyl groups and the break might change the nucleic acid itself, thus changing the three nucleic acid code (codon) and that single nucleotide substitution may change the entire composition of the operating gene. SNPs (Single Nucleotide Polymorphisms) as they are called, are a well known entity detected through a mechanism called polymerase chain reaction or PCR, whereby the aberrant DNA portion of the target diseased cell is amplified many-fold for study. This subtle change can convert a “pro” to an “anti” and a “helper” might turn into a “suppressor” and all the while we go from “May I…?” to “Can I…?” to “Am I...?”  indicating a slow but progressive loss of function.

True, that both young and old fare the same way in regards to these hits, the free-radicals, the sun rays, the UV light, X-Rays, and all the rest of the daily bombardment that constitute around 10,000 hits daily on our DNA.

"A thousand natural shocks that the flesh is heir to." Shakespeare.

In the young however, the robustness of the Mis-Match Repair mechanisms within the cell (that get rid of deranged DNA) protect very well, but as one ages and takes the hits, eventually overwhelming the repair mechanism, ultimately the cellular function does go awry. This then creates the mischief that wreaks havoc. It creates disease, like cancer and other chronic ailments.

For more reading on Genetics please read:

Another mechanism involved is more akin to a Mission Impossible self-destruct mechanism that makes everything go up in smoke. These entities are called Telomeres. At the end of each chromosome there is a tail that wags the entire dog so to speak. And it is not the tiny vestigial coccyx of the human tail either, this one is potent in its absence. These telomeres are identified as “Caps” on each end of the chromosome. 

Telomere is a series of nucleic acids in the form of TTAGGG present in the form of tandem repeats. These repeats are 3-20 kilobases long and have a100-300 kb overall length.

Their function is to prevent overall chromosomal integrity by not allowing fusion between one another and also to safeguard against gene degradation within the chromosome. These Telomeres were discovered as a follow up discovery to the cellular Hayflick limit, which states that a cell placed in a culture medium will divide for a finite number of times and then die. Telomeres were actually discovered in 1978 by Elizabeth Blackburn and Joseph Gall and confirm the causal basis of the Hayflick Limit.

In their discovery, was the inherent map of the gradual shortening of the telomeres with each division of the cell -chop off a piece of the Telomere tail at each cellular division, this then confirmed the Leonard Hayflick’s finding and gave credence to the predefined demise of the organism. The loss of telomere chain leads to chromosomal anomalies, such as fusion and subsequent degradation of the genes contained within the chromosomes leading to the disharmony of aging of the cells (loss of pliability, loss of function, loss of growth) and also the resulting uncontrolled disruptive influence from these signals that culminate in cancer.

It makes perfect sense when one considers the rate of breast cancer in the young vs. the old and the disruptive function of age. At 20 years the risk of cancer is calculated at 1 in 22,000 and graduating to the age of 80, the risk increases to 1 in 5.

For more information on Breast Cancer Energetics please see this link:

There is an enzyme that can continue the constant elongation of the telomeric tail, called the Telomerase. 

This enzyme, replicates the Telomere chain and is found in the constantly dividing and replenishing germ cells and skin cells. Both organs lose the ability to continue fostering this enzyme as evidenced by the loss of sperm or ova production with age and the dry crackling, abrasion-ready, paper-thin pock-marked with various small and large benign and malignant growths, skin of the aged. The cancer cell on the other hand being devious in its wayward behavior co-opts the ability to create Telomerase enzyme by gerrymandering the gene-regulating abilities so that it can continue its endless replication ability.

The linear dimension of time follows birth to its death and has a life-limiting script writ large in the scroll of human life. These are the definable limits of human survival. 

The elastic band is stretched and with the heat and temper of sun-drenched aging, it snaps! 

This, the is our destiny!

Postponed possibly, Eventuality inevitable.