The STUFF of EXCELLENCE

The glint on a raw surface exposes the value beneath. It is not a charm that outshines the content but the slow plod of inherent epistemic stability of virtue.  It is not a sudden ideal that is fashioned onto an unsuspecting world but the slow build of hundreds and thousands of tiny concrete actions that define the character as it takes shape. And none of this is for the purpose of grand epistemological vision of the self, the glory of recognition, or the plastered glossy image of the self on some wall or building. It is from the passion and desire of the mind. Much like the Maxwellian demon with its infinite industry and focus separates the fast from the slow and the true from the false, these few that live in their ideal world of passion and desire live for the sake of accomplishing their dreams and separate themselves through their excellence.

                                                    

I met this fourteen year youth a long time ago. My bicycle needed a repair for a flat tire and having walked it down to the local shop.  I came face to face with this person. His face was unwashed and he wore rags for clothes. He seemed to have right lazy eye that lagged the other a bit as he turned to look. And he smelled of tobacco. He took my bicycle and sat on a squared piece of concrete which was to be his “shop.” He immediately went to work prying open the tire and finding the nail within the cavity and using glue and a patch he had it inflated in no time. During the intensity of his work his eyes darted back and forth across the floor where seeing a cigarette butt, he picked it up and inhaled and not being lit, he took it out from in between his lips and stacked it next to his “concrete-block-seat,” adding to his collection.

The bike was repaired and as he was about to hand it over to me, he stopped in mid movement and with his hands on the bicycle walked around it inspecting it. Then he shook his head and held up his index finger for a moment implying, I should wait. I did. After a few more minutes of some clanking wrenches and screw drivers, he stood up again and looked at his project. His eyes seemed to sparkle beneath his dirt covered face. His lips broke into a smile exposing his discolored teeth. He seemed happy with his work. I thanked him and nodded his head. I paid for the repair at the desk and then tendered some money as a tip. He refused with the wave of his hand as he eyed my bicycle, looking for imperfections. As he handed over the bicycle to me, he used the tattered sleeve on his shirt to clean some of the grease that had gotten on the handlebars. He inspected once again and gave the bike one last pat before moving over to receive the next customer who had arrived.

Many years later, I drove by the shop and found that it was no longer there. Next to the empty spot was a huge building for automotive services. I stopped and decided to get an oil change.

With my car on the hydraulic lift, several young men were working in the automotive bays. I saw a man look in from the large picture window. Moments later he was in the bay helping out one of the workers. I was transfixed with his demeanor and his constantly darting eyes. His hands were flying over underneath the car that the worker was helping change the oil. As he came closer to where I was sitting waiting for my car, I noticed he had a lazy right eye that lagged the other when he turned to look. He was him! Him! the little youth, bumming cigarette butts several years ago, he was now an auto-mechanic!

I introduced myself and reminded him about our past encounter. He was amused and courteous and soon went back to his rigor of inspections and perfection. He helped with the oil change and checked brake fluids, brake-pads and all relevant things that were visible and might be out of frame. He now chewed gum constantly. The smell of grease had over taken the smell of tobacco and the gum was a good substitute for innocent indulgence.

Later I found out that the fourteen year old had grown up to become the owner of this large facility. Good on him! I thought. This was a well-deserved success for “The Stuff of Excellence.”

GOODNIGHT MOON

There are nights when the wolves are silent and only the moon howls... George Carlin

The sky turned an azure blue as twilight approached. I sat on the grassy knoll looking up at the sky and there in its shiniest silvery polish was the moon. It looked like a sand dollar sea shell broken in half. I stared at it and it stared back. There was a mystery to it. The more I gaped at it, the more images I saw.

Pretty soon, I was close enough to see a flurry of activity on its broken surface. There were swarms of tiny people going about their work with pick axes, chisels and shovels. There were supervisory individuals with headlamps shouting orders to the workers and directing them to the correct places. There were a few fat and bloated individuals that reminded me of “Jabba the Hut” lounging on elaborate silk covered Emperor Hadrian’s Roman era style chaise lounge smoking hookahs.

They were breathing orders in a deep low pitch echoing sound and creating frenzy amongst the helmet-lamped people. And there on top of the sharp pinnacled broken edge of the moon stood a monocle-wearing character dressed up like Indiana Jones. I could vaguely see his features under his safari hat; he had serpentine eyes, a beak for a nose and forked tongue that would lick the sides of his mouth periodically. He seemed to be in charge of the entire demolition derby.

The workers busied themselves as they chipped away at the beautiful silvery moon. Piece by piece the size of the moon diminished as the axes and shovels continued with their fury.

The sky was now getting darker and the shine of the moon that bathed the earth dimmed. The darkness captured the ferocious work on the moon in stark detail. There were now louder voices as the half sea shell turned into a quarter of its size and then into an eighth. The darkness of the night became intense on earth and the birds quietly huddled in the trees, fearful of hazards their eyes could not define. Chaos reigned on night-earth now in concert with what was happening on the moon.

As the moon grew thinner, the heavy individuals panicked, for now they could see the mined lunar surface was all but gone. The helmet-lamp supervisors turned to look at the “Jabba the Hut” characters in anger as the little workers collaborated with them to overthrow these bounty hunters. The riots started. The helmet lamps and the little workers joined forces to stop working. They had finally realized that their efforts were destroying everything that they needed to survive. The “Jabba the Huts” could not move because of their exaggerated corpulence and were easily crushed. The Indiana Jones character was nowhere to be found. Apparently he had realized what was going on and disappeared.

There was a moment of reflection among those left standing. As the realization took anchor a small group of builders and creators came along from their quiet abode hidden at “Lands End.” The two groups called a meeting and the work to rebuild began. It was hard, but joyful. They saw the beauty in their art and their science. They saw the harmony in their collective effort. They saw progress in their effort. They worked tirelessly without compromise or complaint. The object was to rebuild the beautiful silvery shiny disk-city once again. They would create a city of fullness and majesty that would shine over the other beautiful pale blue dot that they could see from afar and give light at night to the other’s inhabitants. Slowly and surely the work began.

The cycle of life as the cycle of business are made of ferocious and damaging declines and a slow duty-inspired willed climbs. The destroyers take down quickly what the builders build in long arduous spells. The builders resist the destroyers but when most is lost, their will, brings them back to work for a new dawn.

These cycles exist in every form of life. Humans cannot control their destiny of building and destroying, for in that rebuilding they find some element of peace. They often make it better in comfort but not necessarily in living. Yet the destroyers are always looking to forage, to take and to undermine the hard work of the builders.

Much as in all human affairs, Medicine is in the throes of the destroyers. The science is being bastardized through data manipulation. Everywhere there are echoes of cost overruns and false comparisons to patient care. The real enemies of the cost over-runs, like “Jabba the Hut” are hiding behind in their Romanesque mansions pointing fingers as they accumulate wealth and get the desire for even more.

Ah but like that dream, I had, when all seems lost, the few, the brave and selfless spirits will once again rule reality for the sake of our humanity.

The new moon lurks and peeks from behind the golden under bellies of the spotty clouds as the sun sets in the distant horizon. Time marches on and the future once again seems bright.

Goodnight Moon!

IN SEARCH OF A KNIGHT

I came to a zone
Whose time I had not known
There was no will
And silence was a shill

The morning hour
Felt a little sour
The printed words cried aloud
Nowhere, no one was about

The streets were bare
And all the faces stared
Looking for stuff
That didn't matter enough

The eyes glared away
As monitors held their sway
Nary a hand comforted a shoulder
And each voice was iced and colder

They wrote beautiful words
Everyone expressed their hurt
Not a hand was at work
Consumed in its shirk

Time died
As no one replied
To the restless souls
With long forgotten goals

Houses gathered dust
Bare steel wore rust
While Silence ran astray
And flowers wilted to grey

The cold approaching night
Without a twinkle of light
Bereft of all care
Buried the town in despair

On top of the hill
Where bright lights filled
Laughter heard in pair
And wine glasses clinked till bare

The music could be heard
At the outskirts of dirt
Now nary a voice was raised
As roasted pigs were braised

The dusty road
Finally paced to the hoard
Rotting the House walls
And it's soul-less calls

The silence hit
Where the lamps once lit
And the lone voice cried
But the music had died

There is no more
No road, no store
No heart to care
No mind to despair

The town now is dead
False hope has fled
Time ticks for a knight
To bring day to this night

HUMANITY

"Love and compassion are necessities not luxuries. Without them humanity cannot survive." -Dalai Lama

It happened the other day at a U.S. International Airport. A man in his flight suit hurrying toward the gate tripped and fell face forward. His Airline cap tumbled a few feet away ahead of him but the rest of him stayed perfectly put together. If you didn't know, you might think he was lying quietly face down. But in a busy airport where there are hundreds of travelers rushing to get somewhere this was not the scene for a quiet slumber.

Most travelers looked as they hurried past and then glanced back for a second look without slowing their pace. A woman hurried past the seeing and avoiding crowd, rushed to the scene  and knelt before the gentleman  to ascertain his physiological functions. Was he breathing?  Does he have a pulse? Is he alive? Did he break a bone? Did he have a seizure?  She could not tell. The pulse was feeble, the breath barely audible. She put her hand on his chest and was immediately reprimanded,

“Move away Ma’am!” A stern voice of authority called out.

“But I am just trying to help. I am a nurse.” She pleaded.

 “No Ma’am you can’t do that.”

“He might be having a heart attack?” She cried desperately trying to help a fellow human being.

“No Ma’am, I wouldn't touch him, if I were you. It might be considered inappropriate.”

“But…!” She flailed her arms as the police man followed by a female associate pulled her off the floor and gently pushed her away. The wall around the “fallen” was now complete, stern faces on top of six-foot frames were stern and still. The nurse looked bewildered. She was trying to be a Good Samaritan, a human with humanity. And the Police were doing their duty.  Somewhere there was a clarion call of the legal eagles: Do not touch. Let the experts take care of the situation rather than face a lawsuit allowing a nurse to take care of the airline captain.

20 minutes to the dot, the wailing siren of the ambulance arrived and the EMT personnel expeditiously transferred the gentleman into the ambulance and with them, the sirens receded into the background.

What happened to the airline pilot is a mystery.

Imagine what has become of us as a people?

Imagine what this regulatory and legal compliance has wrought on us as humans?

Where has the compassion, the human to human connection gone?

A plague has fallen on the house that George (Washington) built!

Let us clean up this mess together!

"My humanity is bound up in yours. For we can only be human together." -Desmond Tutu

OVER/EARLY-DIAGNOSIS

Currently there is an intriguing concept in medicine, especially in oncology, which suggests that physicians have a tendency to over-diagnose. The argument goes that because of the amplified diagnostic abilities we as physicians are able to make diagnosis of a disease such as cancer earlier. And that is projected to be bad thing? A correlated argument forced as causality states that over-utilization of the diagnostic capabilities leads to “harm.”  What would be considered a laudable form of care provided to the patient in terms of early diagnosis, intervention and potential cure from the malady (cancer in this case), the experts go to extreme length, to define that as harm (1).  This “over-diagnosis” in their minds is the same as early diagnosis and therefore by using their statistical correlates it is considered a travesty. Usually the authors of these articles are policy-wonks or involved in policy making. They cite psychological harm as well as physical harm behind the reasoning for their premise. The “psychological” harm is a subjective methodology steeped in questions whose answers are created to evoke emotions. The physical harm cited however is real and are the complications related to the surgical procedure, which unfortunately is the unintended consequence of any surgical intervention.

The question arises whether we as oncologists think that Early diagnosis is the same as Over diagnosis?

The consequence of such a thought process if followed through brings us to the conclusion that we should wait till potential cancer related symptoms become apparent and then intervene, even though as the saying goes, “The cat is out of the bag.” Is that ethical reasoning? What is even more puzzling is the use of lead-time-bias that is being used to further the argument that if intervention is done early and survival is shown to increase that is nothing more than the biology of a slow growing tumor and that the lead time in diagnosis gave the false representation of increased survival. This purported argument has been very strong in the field of uro-oncology especially with the use of the PSA screening methodology. The problem that arises here is that we are nowhere close to determining the aggressiveness of the cancer except by obtaining multiple biopsies and evaluating the Gleason’s score. Arriving at this juncture then, the argument suggests that “Watchful waiting’ would be a good measure rather than subjecting patients to a radical surgical prostatectomy or a brachytherapy +/- external beam radiation therapy as a curative intent. Yet recent studies have shown that upfront intervention saves lives over the “Watchful waiting!” (2)

Given the controversy that surrounds prostate cancer, is watchful waiting the right approach in oncology care for a patient with prostate cancer?

The current data-driven analytical mind-set of correlations assumed as causations is behind a lot of these illogical thought processes and is borne of the meaningful use objectives. Unfortunately some of these data analytics give enormous weight to the cost factor in their analysis and tend to forget the individual patient. Scientific literature is replete with such cost-to-care articles especially since the global economic downturn of 2000. A more reasoned approach would be to use hard empiricism borne of a well thought out hypothesis and validated through repeatability before using the power of media blitz.

The Jeremy Bentham utilitarian concept, through the eyes of the epidemiologists has created a tall mountain to climb for the individual with cancer. The defining art of oncology care remains that each patient is an individual who has specific needs and comes with his or her set of co-morbidities that confound the unified pluralistic ideology driven motive of “one size fits all.”

Kant’s “Reason” then must be applied to the medical care we deliver to each individual patient rather than the broad brush strokes of the multitudes that have been sampled into the Bell curve and bounded confines of the 95% Confidence Intervals to yield the biased p-value paradigm of the “truth.”

There is a fine line between menace and utility. Where upon we as physicians must decide how to shape the destiny of oncological care. Soon there will be algorithms that will drive medical care and through the rigors of data crunching a holographic representation of a “healthcare provider” will render the physician moot. When that day comes, let us hope not too soon, age and cost hopefully do not drive utility and need to become the technological menace for humanity.

1.       http://www.kevinmd.com/blog/2013/12/overdiagnosis-health-services-harm.html

2.       http://www.boston.com/lifestyle/health/blogs/daily-dose/2014/03/05/study-fuels-debate-surgery-watchful-waiting-for-early-prostate-cancer/B6lvBw0mkEjzNC1GEv6Z3J/blog.html

2a.  Radical Prostatectomy or Watchful Waiting in Early Prostate Cancer — NEJM http://nej.md/1jWzJ02

Immunological Dreams at #ASCO14

Two things caught my attention: 1) The 5-year survival rate of all cancers has improved from 49% to 68% in the past two decades with more than 19 million cancer survivors expected by 2024 and the knowledge of how to manipulate the immune system against the dreaded disease. We will discuss the latter further.

The hallmark of scientific work seems to have been in the realm of Immunosurveillance and cancer. The thrust of the argument for better control of the malignant tragedy is based on the Adaptive Immunity against cancer.

The knowledge that there are lymphocytic infiltrates found within the cancer milieu is well known for decades. It was realized some 30 years ago in the colorectal cancer domain that those patients who had lymphocytic infiltrates in their cancers did better with stage, disease progression and overall survival. Now with the journey of these lymphocytic infiltrates laid out, actionable sites have become visible for the probing and assault against this deadly scourge.

The adaptive Immunity to be effective has to have two components of T-lymphocytes: The T Helper cells (Th1) and the Cytotoxic T-Cells (CTL). The CTL upon stimulation secrete TNF-α and Interferon-ϒ, both of which have limited immunity. The Regulatory cells are the T-regs that oppose the inflammatory signals via TGF-β and Interleukin to suppress the CTL from further activity in order to limit immune activity and tissue destruction. A balance therefore exists between the T-regs and the Th-cells.

The universal knowledge states that Immunity is based on the “Self” and the “Non-Self.” The T-Cells are programmed to recognize and destroy any foreign invaders. However as a means of checks and balances there is a proviso that allows for some self-control to prevent an all-out attack against the “self” should the invaders be contained. This mechanism is available via control-points also called appropriately “Check-Points.” 

The express function of modern-day immune manipulation against cancer is to unbalance the inhibitory signals to the checkpoints to allow for a full-throated attack against the wayward cancer cells. Meanwhile, not to be outdone, the cancer cells have tricks up their sleeves too and try to fool the Immune T-Cells with their vile secretory expressions of TGF- β and Interleukins along with other co-stimulatory cytokines like CD28, CD137 and OX40 to force the immune cells to lay down their arms in quietude. This fight is worth a few more words.

As the cancer cell invades tissues, it is also invaded by these immune cells. The Immune cells have to recognize the cancer cell surface antigens (Major HistoCompatibility Loci) and then” express their outrage” via their secretory products to limit growth of these invaders. Three mechanistic offenses are launched against the cancer cells:

Retaliation 1: The recruitment of the Th1 and CTLs to gear for a limited response. This is followed by an assessment of the damage against the enemy. If the immunity is weak this is the last signal and the cancer enjoys free reign without any further intervention. In this scenario, for example, therapeutic intervention with Herceptin and Chemotherapy are the mainstay of therapy in breast cancer.

Retaliation 2: In this format, the initial response is followed by ancillary assault via the co-stimulatory APCs and the Checkpoint regulations. PD-, PD-L1,PD-L2, which are “programmed cell death” inhibitors.   Inhibition of these checkpoints asserts limitations on the immune response and allows cancer cell growth. By inhibiting the inhibitors, the immune attack continues. The PD-, PD-L1,PD-L2 molecules fit the cell receptor sites on the CTLs and abrogate their ability to fight. Anti PD-1, PD-L1 and PD-L2 antibodies therefore allow a new breed of T-Cells to invade along with their co-stimulatory cytokines such as TNF- α and the Interleukins to play havoc with the inflammatory phenomenon and thus destroy the cancerous invaders. Checkpoint inhibitors and Monoclonal antibodies directed against the tumor cell expressed proteins are the mainstay in this approach. Disease such as Melanoma, Non-Small Cell Lung Cancer and Colorectal cancer has been successfully treated with this form of immune modulation.

Retaliation 3: Inactivation of the TGF-Beta and the Interleukins. The cancer cells co-opt the protein expression and inactivate the inflammatory signaling secretions. Again the Checkpoint inhibitors and Monoclonal Antibodies along with other conventional measures can be used with impunity against the cancer.

Would you agree that the knowledge of immune function activity in and around the cancer has meaningful repercussions in our battle against this disease? We have yet to determine the EMT (Epithelial Mesenchymal Transition) effect on Immune modulation and that may hold more answers in the future. Is that a concept worth exploring?

Checkpoints: Initial phase= CTLA-4 (Iplimumab-binds to APC via CD28), Secondary phase when cytokines have been released then PD-1(expressed by  T-cells, NK cells), PD-L1 (APCs and Epithelial cells), PD-L2 ligands inhibit CTL activity, (Melanoma, NSCLC, CRC) LAG-3

Antibodies against Checkpoints and in development: Iplimumab CTLA-4, Nivolumab PD-1, PD-L1(BMS-936559, PD-L2 (AMP-224, LAG3 (IMP321.

Speaking about MoAbs, Ibrutinib against the Bruton Tyrosine Kinase against CLL is a big story that we can discuss in the future.

References:

Scott N. Mueller, PD-L1 has distinct functions in hematopoietic and nonhematopoietic cells in regulating T cell responses during chronic infection in mice J Clin Invest. 2010;120(7):2508–2515.

Shoba Amarnath The PDL1-PD1 Axis Converts Human TH1 Cells into Regulatory T Cells. Sci Transl Med 30 November 2011: Vol. 3, Issue 111, p. 111ra120

Sharpe AH, Wherry EJ, Ahmed R, Freeman GJ. The function of programmed cell death 1 and its ligands in regulating autoimmunity and infection. Nat Immunol. 2007;8(3):239–245.

http://jedismedicine.blogspot.com/search?q=PD-1

Ahmed Tarhini, Earnest Lo, David, Minor.  Releasing the Brake on the Immune System: Ipilimumab in Melanoma and Other Tumors. Cancer Biother Radiopharm. Dec 2010; 25(6): 601–613. Article online: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3011989/