CTCs ( CIRCULATING TUMOR CELLS )

Some years ago sitting in on a cancer conference just barely keeping my eyes at half mast, the discussion was circumnavigating chemotherapy and the cell cycle. The genetics were being discussed but in a oh so "we do not know what this does yet?" sort of a way, that one could barely perceive the many shades of reality and fiction that mixed in the soup of the unknown. As the conference was winding down an older gentleman, a retired physician, happen to raise his hand and inquire whether it was possible to prevent metastasis by placing patients with cancer on anticoagulants? It was for that time a bold queation. But the only response it was able to garner was a few hrrmphs and a couple of snickers. I don’t quite remember the official answer the speaker rendered but suffice it is to say, it was wanting.

It was a plausible question. In fact it was a well-thought through question. Aside from the dearth of data availability he had questioned the very nature of vascular metastasis.

There were several interesting studies that kept raising the bar of this thought in years to come. The CALGB (Cancer and Leukemia Group B) study done in Stage 1 Lung cancer suggested that when the pleural (lining of the lung) was washed with sterile water and the fluid analyzed, the results showed that 40% of the patients had viable lung cancer cells in the fluid, even though the primary cancer was deep in the lung tissue (parenchyma). Stage I Lung cancer has a 60+% 5-year survival. And  then as in now the question asked, is why should 40% of people with such early resected cancer fall victim to their disease? Or another way to put it; why after all, is it considered stage I and a full, in-toto, resection of the cancer done and yet the patient has only a 60+% chance of survival? One would have to hazard a guess that the resection did not quite reach the R0 state. Something remained rotten in the state. Something surreptitiously ethereal and famously wicked continued to haunt the neighborhood of survival. Something that is in the form of a cancer cell!

Interestingly a Japanese study of Breast Cancer patients showed that almost 40% of the patients in early stage cancer had cancer cells in their bone marrow! These findings gave credence to the fact that even early stage cancers of different origins are already outside of their initial site, meaning they had spread, or more technically speaking "Metastasized."

The concept of Circulating Cells is not a new one. In 1869, yes, we are talking back in the late 19^th Century when Thomas Ashworth observed circulating tumor cells in the blood of a man with metastatic cancer. He surmised that the presence of these cells that looked identical to the ones in the original cancer may “throw some light upon the origins upon the mode of origin of multiple tumours existing in the same person…“One thing is certain, that if they [CTC] came from an existing cancer structure, they must have passed through the greater part of the circulatory system to have arrived at the internal saphena vein of the sound leg.”

Sage musings of a scientific mind, don't you think?

Now comes an even more substantial progression of this thought. Lately and notably there has been a significant impetus in “Circulating Tumor Cells.” These CTCs as they are called are found wading in the blood stream of both early stage and late stage cancers. The early stages have fewer then 5 CTCs in a given quantity (7.5ccs) versus the late stage cancers. But what is interesting is the fact that now we have the capability of detection at a very early level.  In a large multi institutional double-blind prospective clinical trial of breast cancer patients Swaby et al. state; "One hundred and seventy-seven patients with measurable disease had CTCs tested prior to beginning a new palliative treatment regimen for progressive disease, followed by repeat assessment at first follow-up visit approximately 4 weeks later. This landmark trial prospectively identified a CTC cut-off level of ≥5 cells per 7.5 ml of blood to be a reliable identifier of patients at higher risk for disease progression and decreased survival from metastatic breast cancer. Regardless of histology, hormone receptor and HER2/neu status, or whether the patient had recurrent or de novo metastatic disease, those with less than 5 CTCs at baseline, and more importantly, at first follow-up after beginning a new treatment regimen, had superior progression free (PFS) and overall survival (OS) (7 vs 2.1 months [p < 0.001] and 10.1 vs more than 18 months, [p < 0.001], respectively).

These CTCs present an attractive surrogate phenotypic and genotypic markers for disease status in a more dynamic and real-time basis.

Several new studies have been undertaken to be able to decipher their presence and use them as predictor of metastasis and survival. Powell et.al reported:

Patients in a training set with levels of circulating tumor cells equal to or higher than 5 per 7.5 ml of whole blood, as compared with the group with fewer than 5 circulating tumor cells per 7.5 ml, had a shorter median progression-free survival (2.7 months vs. 7.0 months, P<0 .001=".001">

Other related studies have demonstrated with equal aplomb the benefits of CTCs as predictors of response much before radiological data becomes confirmatory, eg. CT scan findings lag behind the drop in the CTCs in the peripheral blood samples.

Left bank shows viable CTC cells, Central bank shows damaged CTCs, Right bank shows sheared cells.

The problems and there are always more then one, are how to confirm that the cells being viewed are indeed cancer cells and if they are cancer cells are they effete (apoptotic) or viable? If they were viable did they have the capability to establish an anchor on to the blood vessels and thence spread into far away organs? If they did have the capability did they have the efficient mode of the EMT (Epithelial Mesenchymal Transition) ability to be able to harness the biochemical powers needed to broach the basement membrane? Additional problems that confound have a molecular basis to them and we will address those by the by.

Circulating Tumor Cells morphologically are distinguishable by their appearance in a majority of cases. Tumor cells have a distinct nuclear/cytoplasmic dys-synchrony, meaning that the nucleus of the cells is a large polyploidal, angry-looking-mushroomy globular structure and the cytoplasm (the surrounding fluid) is small and sometimes negligibly invisible. This is in stark contrast to a normal cell, which has a small well delineated nucleus and a large volume of cytoplasm.

Breast Cancer CTCs

Present State:

Our current modus-operandi is to be able to evaluate the presence of the CTCs. Having done that and shown the presence of such CTCs at a certain limit signifies a poorer prognosis in survival. As Powell et al. and others have shown that there is value in such determinations. Built into this simplicity one still has to undo the large conspiracy of “Is it or is it Not? In other words where the dilemma keeps haunting the researchers, is the ability to accurately decipher that the cell they earmark as a cancer cell in circulation is truly a cancer cell and functional at that!

Colon Cancer CTCs:

(Bonus) Here is one method of isolating the cancer cells from the blood sample (CTCs)

http://www.jove.com/video/4248/rapid-isolation-viable-circulating-tumor-cells-from-patient-blood

Several roads lead to this land of promise; from morphologically deciphering via visual inspection (thus based only on reliance of the observer) to using immuno-histochemical means where chemicals added to the cells can make them more prominent, to using molecular means are all different methodologies currently in vogue.

1.   Since the white cells are the ones that confabulate the issue of recognition between them and the cancer cells. The problem arises when you force the blood through shearing stressors of mechanical corralling in a machine for identification and is related to forces of fluid dynamics. The cellular distortion causes the nucleus to appear as all kinds of monsters even in normal cells and gives the nucleus a "naked" distorted appearance resembling a cancer cell. Thus attempts to verify a good cell from a bad cell has taken many a turn and twist. Using Flourescein labeled antibodies to CD45,  an antigenic determinant for the white cells and also utilizing EP-CAM or Epithelial-Cell adhesion molecules with antibody coated magnetic bead for cancer cells that express Cytokeratin is one way of differentiating between the two: “The procedure enriches the sample for cells expressing the epithelial-cell adhesion molecule with antibody-coated magnetic beads, and it labels the cells with the fluorescent nucleic acid dye 4,2-diamidino-2-phenylindole dihydrochloride. Fluorescently labeled monoclonal antibodies specific for leukocytes (CD45allophycocyan) and epithelial cells (cytokeratin 8,18,19phycoerythrin) are used to distinguish epithelial cells from leukocytes. The identification and enumeration of circulating tumor cells were performed with the use of the CellSpotter Analyzer, a semiautomated fluorescence-based microscopy system that permits computer-generated reconstruction of cellular images. Circulating tumor cells were defined as nucleated cells lacking CD45 and expressing cytokeratin.”

However there is another twist in this particular fate; Aggressive cancer cells lose the ability to project the Ep-CAM on their surface, hence looking for CTC just on the basis of the CD45 and Ep-CAM may falsely eliminate cancer cells and that is exactly what happens in the real world scenarios. For example in the aggressive Inflammatory Breast Cancer or IBC patients the CTC detection based on the two immuno-histochemical technique fails miserably for that specific reason. Maryam B. Lustberg, M.D., MPH, study investigator and assistant professor of internal medicine at The Ohio State University College of Medicine, explains: "Some of the most aggressive forms of cancer, including triple negative breast cancer (TNBC), downregulate EpCAM and have high numbers of EpCAM negative CTCs, cells that would be missed by the most commonly utilized technologies. The results of this study support the theory that there is a heterogeneous population of circulating cells in the blood of cancer patients which may hold clues regarding the metastatic process."

Lung Cancer CTCs:

2. Facing diminishing returns, the incorporation of the genomic makeup of the cancer cell is a more predictable one and is based on mutated genes from the primary source. This has been applied to eliminate the false negativity related to antibody mediated histochemical determinations. Although this may appear to be the answer to the conundrum, it is far from it. Powel et al. again make the following references; “the MagSweeper - a cell purification technology, which gently isolates rare CTCs with high specificity. availed recent advances in microfluidics, isolation protocol does not impact viability and RNA integrity of isolated cells nor gene expression, and as evident here by consistent detection of multiple reference gene transcripts, comprehensive genomic studies on robust subpopulations of cells is greatly facilitated. gene expression profiling of primary tumors and its application in the molecular subtyping of breast cancer has provided a biological framework for defining the clinical heterogeneity of this disease. addressing the issue of how to eliminate the contributions of potentially large numbers of contaminating WBCs to overall gene expression profiles when measuring genes common to both 63% of MagSweeper-captured cells showed robust, non-degraded reference gene expression: of cells with non-degraded reference RNA, 60% were defined as CTCs and 21% expressed the CD45 WBC marker.” So here lies another minor issue; the commonality of genes between normal cells and the cancer cells has also to be taken into consideration. The puzzle pieces thus proliferate from the simple to the very complex. Then one has to address the mutated genes and the lack of commonality of the mutated genes between different metastatic site CTCs. Oh what a web nature weaves!

3. While we are involved in this complicated issue (as it exists – Remember I am just the messenger), here is another dollop of mischief that the cancer cells have in store. The Primary cancer at its initial site has a completely different set of genetic mutations as compared to the cancer that is spreading or one that has already spread but circulating its wealth around. Within the circulating cancer cells there may be a large numbers of populations of metastatic cancer cells from different sites that have different genetic determinants. To elaborate that further; CTCs from the primary cancer cell and others from various metastatic sites (eg. lung, liver, bone etc) all will have differing degrees of mutated genes. So even though we can with clarity state that the cells we are looking at are cancer they will have differing sense of  behavior and create a much different sense of foreboding for the molecular geneticists. “Intriguingly, high levels of PTEN expression in 83% of the CTCs were observed despite the known inverse association between this gene and TGFβ expression. It is possible that repression of this gene by TGFβ requires receptor tyrosine kinase signaling (such as EGFR). which might be compromised as indicated by undetectable EGFR expression in the CTCs in our study.. Consistent with the acquisition of invasive and migratory characteristics is the absence of the cell adhesion protein, CDH1, in migrating cells such as CTCs, as illustrated by our expression data. Ostensibly, systematic implementation of single cell CTC profiling will shed new light on the dynamics of migratory tumor cell biology during metastatic dissemination.”

 Image (Heatmap of single cell gene expression of 87 genes within seven individual cells isolated from three primary tumor-derived (pink: CCdl054, orange: CCdl672, gold: CCdl675), and four metastatic effusion-derived (red: MDA-231 plum: SKBR3, dark green: MCF7, and bright green: T47D) breast cancer cell lines. Yellow indicates high gene expression; gray is median expression; blue indicates low expression; and black represents undetectable expression. All cells showed expected expression patterns. The breast cancer cell lines used represent a spectrum of cell differentiation, e.g., from less differentiated and more mesenchymal/stem cell-like ER-negative (basal-like) cells (MDA-231 and SKBR3) to more differentiated ER-positive (luminal-like) cells represented)

Additional data which should come as no surprise is that CTCs seem to be in abundance in patients with bone metastases and are underrepresented in non-bone metastatic patients. The conjecture here is that bone metastases occur via vascular spread and the marrow of the bone that carry the blood-vessels to and from called vaso-vasorum bring in and take out the CTCs from circulation. Hence the discrepancy of finding CTCs in various forms of stage IV cancers.

Future of CTCs

Okay we seem to be getting better at determining what the CTCs are, how they look like, what their chemical characteristics are and what makes their genetic makeup tick. Looking at how we can possibly manipulate this information to better serve humanity, we will focus on the probabilities ahead.

1. The epitope (antigenic) expression of the cancer cells can be used to target these cancer cells both in the blood stream, metastatic and ultimately also at the primary site  Knowing the cell surface antigens of the various gene-expressions can result in utilizing a targeted set of antibodies directed at these epitopes to neutralize their action in thus suppressing the proliferating cancer cell. For example if gene “A” causes an antigen “X” to be expressed then an antibody “Xa” directed at the antigen “X” will prevent the cells from receiving the signal for growth. That will cut short the cell survival and ultimately put the cancer into a remission. However here too there are some relevant issues that have to be addressed before we  arrive at the Utopian paradise. The cancer cell being visualized may lose some of these expressive antigens and thus their pathways of signal transduction by merely undergoing the shearing stresses mentioned previously. Thus available data may be compromised for relevance. For example Powel et al explain;  “Therapy that targets only one CTC population might not ablate other subpopulations, which may continue to spread and grow.” They also go on to explain that, “Our expression profiling analyses demonstrated that CTC populations are relatively quiescent. Transcript levels of growth factors and their receptors, such as VEGFA, MET, ESR1, EGFR, and HER2 were relatively undetectable in CTCs compared to cancer cell lines. Consequently, expression of downstream effectors involved in cell cycle progression and proliferation such as MYC, ATF3, TERT, RAC1, FOXA1, RRM1, CCNB1, and BIRC5 were significantly diminished in CTCs in contrast to breast cancer cell lines. On the other hand, we found that some CTCs maintained the expression of genes associated with the PI3K-AKT-mTOR cell survival pathway.”

CTC understanding has taken on a whole different meaning since the days of Thomas Ashworth. Oh what a path we have taken, full of glorious achievements and the agony of new found hurdles. Yet each hurdle is a challenge to accept and surpass. Therein lies the wonders of Science and human ingenuity.

One day in not too distant a future, Real-Time analysis will better monitor cancer responses to targeted and non-targeted therapy. These therapeutic responses will be able to predict survival data and in so doing add to the armamentarium of cancer therapy. The resultant decrease in the CTCs will open the door for more selective therapy attacking the unaffected (resistant) cells with specifically directed treatment towards them. Thus with the new bag of tricks we will come ever so close to the ultimate aim of "cure."

Oh and that elderly physician who raised the question about using anticoagulants to prevent or delay metastases, after all may not have been too far off course in his thinking. New data suggests that Heparin interferes with metastasis by mechanisms other than direct interference:  "the anti-metastatic effect of heparin is not a result of its anticoagulant activity but rather its ability to inhibit the interactions between some oligosaccharides present on tumor cells and P-selectin on platelets."

So all in all, the gentleman was correct in his thinking and in his musings too.

Here's to all the thinkers!
Here's to all the doers!

Here’s to human intelligence!

Here’s to human perseverance!

And to all of us; Keep Searching for the Truth!

Circulating Tumor Cells: a Window Into Cancer Metastasis by Daniel Haber - Harvard Medical School/MGH:

http://mit.tv/zh4TXd

References:

Ashworth, T. R (1869). "A case of cancer in which cells similar to those in the tumours were seen in the blood after death". Australian Medical Journal 14: 146–7

Kagan M, Howard D, Bendele T, et al. A sample preparation and analysis system for identification of circulating tumor cells. J Clin Ligand Assay 2002;25:104-10.

Kagan M, Howard D, Bendele T, et al. Circulating tumor cells as cancer markers: a sample preparation and analysis system. In: Diamandis EP, Fritsche HA, Lilja H, Chan DW, Schwartz M, eds. Tumor markers: physiology, pathobiology, technology, and clinical applications. Washington, D.C.: AACC Press, 2002:495-8.

Guller U, Zajac P, Schnider A, et al. Disseminated single tumor cells as detected by real-time quantitative polymerase chain reaction represent a prognostic factor in patients undergoing surgery for colorectal cancer. Ann Surg 2002;236:768-776.

Terstappen LW, Rao C, Gross S, Weiss AJ. Peripheral blood tumor cell load reflects the clinical activity of the disease in patients with carcinoma of the breast. Int J Oncol 2000;17:573-578.

Fehm T, Sagalowsky A, Clifford E, et al. Cytogenetic evidence that circulating epithelial cells in patients with carcinoma are malignant. Clin Cancer Res 2002;8:2073-2084.

Cristofanilli M, Budd GT, Ellis MJ, Stopeck A, Matera J, Miller MC, Reuben JM, Doyle GV, Allard WJ, Terstappen LWMM, Hayes DF: Circulating tumor cells, disease progression, and survival in metastatic breast cancer. N Engl J Med 2004, 351:781-789

Smirnov DA, Zweitzig DR, Foulk BW, Miller MC, Doyle GV, et al. (2005) Global gene expression profiling of circulating tumor cells. Cancer Research 65: 4993–4997

Sieuwerts AM, Kraan J, Bolt-de Vries J, van der Spoel P, Mostert B, et al. (2009) Molecular characterization of circulating tumor cells in large quantities of contaminating leukocytes by a multiplex real-time PCR. Breast Cancer Res Treat 118: 455–468

Talasaz AH, Powell AA, Huber DE, Berbee JG, Roh KH, et al. (2009) Isolating highly enriched populations of circulating epithelial cells and other rare cells from blood using a magnetic sweeper device. Proc Natl Acad Sci U S A 106: 3970–3975.

Kalisky T, Quake SR (2011) Single-cell genomics. Nat Methods 8: 311–314.

Thiery JP (2002) Epithelial-mesenchymal transitions in tumour progression. Nat Rev Cancer 2: 442–454.

Chow JY, Dong H, Quach KT, Van Nguyen PN, Chen K, et al. (2008) TGF-beta mediates PTEN suppression and cell motility through calcium-dependent PKC-alpha activation in pancreatic cancer cells. Am J Physiol Gastrointest Liver Physiol 294: G899–905.

Chow JY, Quach KT, Cabrera BL, Cabral JA, Beck SE, et al. (2007) RAS/ERK modulates TGFbeta-regulated PTEN expression in human pancreatic adenocarcinoma cells. Carcinogenesis 28: 2321–2327.

Courtney KD, Corcoran RB, Engelman JA (2010) The PI3K pathway as drug target in human cancer. J Clin Oncol 28: 1075–1083.

Habib AA, Chatterjee S, Park SK, Ratan RR, Lefebvre S, et al. (2001) The epidermal growth factor receptor engages receptor interacting protein and nuclear factor-kappa B (NF-kappa B)-inducing kinase to activate NF-kappa B. Identification of a novel receptor-tyrosine kinase signalosome. J Biol Chem 276: 8865–8874.

A Tunable Cancer Cell Filter Using Magnetic Beads: Cellular And Fuid Dynamic Simulations. ariv.org/abs/1110.0995

Akl EA, et al.: Parenteral anticoagulation for prolonging survival in patients with cancer who have no other indication for anticoagulation.

Cochrane Database Syst Rev; CD006652 2007.

Zielinski CC, Hejna M: Warfarin for cancer prevention.

N Engl J Med 2000, 342:1991-1993.

Fuster MM, Brown JR, Wang L, Esko JD: A disaccharide precursor of sialyl Lewis X inhibits metastatic potential of tumor cells.

Cancer Res 2003, 63:2775-2781.

Giordano A, Giuliano M, Jackson S, Reuben JM, De Laurentiis M, Handy BC, Ueno NT, Andreopoulou E, Alvarez RH, Valero V, De Placido S, Horotobagyi GN, Cristofanilli M: Circulating tumor cells (CTCs) in metastatic breast cancer: Prognosis, molecular subtypes and metastatic sites.

2011,

Cristofanilli M, Budd GT, Ellis MJ, Stopeck A, Matera J, Miller MC, Reuben JM, Doyle GV, Allard WJ, Terstappen LWMM, Hayes DF: Circulating tumor cells, disease progression, and survival in metastatic breast cancer.

N Engl J Med 2004, 351:781-789

Ashley A. Powell Single Cell Profiling of Circulating Tumor Cells: Transcriptional Heterogeneity and Diversity from Breast Cancer Cell Lines PLoS ONE 7(5): e33788. doi:10.1371/journal.pone.0033788

MAKE A DIFFERENCE

In theory there is no difference between theory and practice. In practice there is. ~ Yogi Berra

It is like ancient air trapped in an airtight vault that with the turn of the key and the release of the bolt comes out hissing with its enriched aroma of time. It is thick with meaning, for it has conspired within for a long time, that none can decipher the true meaning, but many contemplate upon its virtuous or deviant past. These pent up emotions seize on the same lore of the yesteryears. They come wafting out in a series of thoughts words and actions. They imply a past, closed and unfathomable, but delivered in the present, it appears old, recalcitrant and most times meaningless.

Why must we act out a pulse of emotions hitched exclusively to the desires of the past? Why can we not move on? Why must we gather, enrich, embellish, cogitate and then regurgitate an emotion so devoid of reason, due to lack of understanding, that sometime when thought seizes us by the neck of reason, we shy away from our own actions.

Impulse is an enemy of reason as equally as reason betrays impulse most times. These quick and slow acts are the Yin and Yang of our being.

I see people arguing over basic facts, one side denouncing while the other side heralds them. How can there be a debate over facts? The answer is as simple as the question that explores it. We each have our own sets of perceptions and built in library of prejudices that speak to those facts.

The difference between false memories and true ones is the same as for jewels: it is always the false ones that look the most real, the most brilliant. ~ Salvador Dali

What gives?

So I ask the question…

Is Science evil? Some say it might be because it is distorting the reality. But whose reality, one might ask? Science is nothing but a set of principles upon which observations are held. So how can there be two answers to a single question? The answer might not make you sit up straight; it is the interpretation of the applied principles.

Is Religion a myth? It might appear as a myth for some and a solid belief for other. Religion has a vast historical background but ultimately falls on our allegiance to faith. Yet arguing about the Genesis of the Universe, one comes to a screeching halt at the "Big Bang" evidence. The question that haunts and can be answered easily by the religious is Who sparked the Big Bang? Answering as some do that a set of laws of physics, did. Well then Who created those Laws? And there rests the argument that cannot be teased or reduced further.

So then why must one pack of wolves howl louder than the other? Is their only one perception? Or is it territorial? Is it not inherent to man given the set of senses to perceive the reality to his or her own desire and thereby make of this world what becomes for him or her? Do we not have enough reason based on knowledge to understand that reasonable people have enough reason to possess a differing opinion? Or is it the cascading emoticans dripping into the brain that counsel our better angels?

Maybe, and this is my fervent hope that, we can learn from others for in each mind a drop of difference is instilled to saturate ideas from whence new thoughts, different thoughts emerge and make life spicy. It is that Lorentz Attractor that gives that slight twist of fate to the DNA library and storage of memory, that makes us who we are.

Let us all rejoice in each other’s differences. We are no better, no worse, just different. We each have a story to tell. We each have a mind full of thoughts and ideas. We each make a difference.

It occurred to me that there was no difference between men, in intelligence or race, so profound as the difference between the sick and the well. ~ F. Scott Fitzgerald

The Fundamental Frequency of Coupling

There is something strange, if not deranged about this whole concept. For instance how can someone have an opinion so disturbingly idiotic that even rationale and reason cannot go near it. But then, I look inside me and wonder what the other person is thinking. Am I the same in their eyes? Of course I am. I am the same monster in their idea of demons as they appear to be in mine all because we hold differing opinions about a common issue. How can one be diametrically opposed to another in this, the world where information travels at blinding speed from here to there and back without taking a breath? But then, if the same information is reaching all corners at the same time why must someone look at it in an opposing manner.

Chills the mind a bit don’t you think?

The “why” is an articulate question, weighted in it is the burden of the past. What I mean is that everyone has a “Samsonite” full of baggage from the past. It is the culmination of a series of unfortunate or fortunate events that have brought forth such a thought process that now dictates.

Let me explain…

Ptolemy and Galileo:

Remember the Ptolemiac pronouncements of the geocentric Universe? Well back in the days of 1512 up until 1609, the held ground was that the earth was the center of the universe and all other objects swirled and twirled around her. And if you would take a time-lapse photography of the sly at night the myriads of stars do seem to enter from the east and get swallowed by the west. The belief was so strong that it ended up in the religious fervor of that century. So when Galileo acting on Copernicus’s thought peered through the telescope and found a differing view of the universe; the sun was the center. All hell broke loose in the religious order thereafter. How dare he (Galileo) challenge the authority of the church that the Pope had decreed to be the infallible truth. The inquisition followed and eventually rational minds prevailed. So for almost a hundred years the prevailing view was deranged, so to speak.

http://youtu.be/3V3rmDG5J8A

Blood Letting:

In medicine there are many such examples, but foremost amongst them is the “blood-letting” therapy for all ailments. The Mesopotamians, Egyptians, Mayans, Greeks and the Aztecs all believed in the benefits of “blood letting.” 

This source of thought seems to have emanated from the likes of Hippocrates who believed that menstruation in women was largely a function of “purging women of bad humors.” And as students are sure to follow their teachers, Galen followed Hippocrates lead and devised a complex measurement of the need for “blood letting” based on age, sex, weather and place. The process had been ongoing for at least 2000 years and even through Sir William Harvey’s denunciation of it in 1628, the ongoing cause was further celebrated by Sir William Osler all the way into 1923 edition of his textbook “The Principles and Practice of Medicine” In fact “Blood-Letting” was the celebrated treatment for disease as varied as acne to asthma, from cancer to cholera, insanity to tuberculosis and even nosebleed, excessive menstruation, and even hemorrhoidal bleeding. So much so that as scientific minded doctors in the early 20^th Century started to move away from this form of therapy. The “barber doctors” continued for while, that is why the Barber-Poles have the red and white striped poles outside their shops even today. The red represented “blood-letting” and the white represents the tourniquet while the pole is the lancing “stick.”

Demonic Possessions:

In millennia preceding and during those times there was also a resident concept of “demonic possession of the soul.” Insanity and psychological ailments were considered nothing more than the “the devil in you.” Exorcisms and prayers to various gods was practiced to expel the “evil spirits.” These concepts held sway just as the “Witches of Salem,” in 1692 in Massachusetts. These emotional frequencies of resident thought that pervaded the human minds and belief were only a “I think so” away from finding "reality" and fitting in the closet of "truths.".

The best available science is just that, “best available.” It is not the end-all, be-all. It is a doctrine of a practice accepted by most if not all. It is the practice of medicine. Will it be different tomorrow? You bet! Will it be better the day after tomorrow? Maybe, but it will be different!

Resonance:

So consider our current thought and reflect upon it. When one states unequivocally that he or she has the answer and that everyone is swimming in the sea of idiocy, for not seeing the truth. Something is rotten in his or her state of state. Is he or she drumming to the beat of his/her own drum, rather then the chorus that surrounds? Probably! Where is in him/her that fundamental of all frequency, which makes knowledge complete with all the facts?

Most time there is no resonance, only dissonance, unfortunately.

Most time there is a grand bias that inflates a prospect to glory.

And only some time there is coherence of the frequencies.

Crucible of Wisdom:

That brings me to another whispering thought: I was young and foolish once, as I will remind myself to be when I am older; that, opinions of all code and conduct, of all decree and thought, of all majesty and commonness, of all gale and silence, of all loud and soft, of all innocence and guilt, of all that matters, should comport themselves into the crucible of wisdom. It is here, where we draw the elixir of the future and quench our desire through progress. It is in this mix that much is told and much is revealed. It is in this that, that is found; the truth, which we seek. It is in here that true Evidence lies, one that resonates with all known hypotheses, facts and known human truths.

http://youtu.be/JEHm-XUHwNw

BLOT OF NOTHINGNESS

Every word is like an unnecessary stain on silence and nothingness. ~Samuel Beckett

The other day, I came across a painting with a big white area of canvas without any paint. Oh it was part of the painting alright, I surmised. There was an eclectic pull and push from the corners with bright and enticing blues and stark reds and a bright evanescent yellow thrown in for good artistic measure to mix and merge. The unpainted part stood out in stark relief to the rest. It was there bold as ever, imaginative as could be and inspiring as all possibilities are.

That night I drove by the shop that had the painting hanging in the window and stopped to look at it again. A certain magnetic force tugged at me. I could not place my proverbial finger on it. After pondering at the ware for several minutes, I got out of the car and went in the shop.

“How much is that painting in the window?” I inquired.

“That’s not for sale!” The owner politely answered and then dutifully in his most salesmanship voice proceeded to show others.

“No, no thanks. I was just curious.” I said.

“Interesting…” The owner murmured to himself.

“I’m sorry…” I asked in as polite a manner as possible.

“Oh nothing, you must be the tenth customer to have inquired about the painting.” He said and continued, “I cannot imagine why?”

“As far as I am concerned,” I answered, “it has something to do with that unpainted spot.”

“Really? That is surprising,” he countered, and started laughing.

Curiosity controlled the moment for a while and then he said, “It is a serigraph, you know!” He forced his fingers through his thick grey-white hair. “I have been pondering over it for a while. I am not sure what to do with it just yet?”

“Oh but it is perfect, in its asymmetry!” I said. That very reason is what makes it so attractive. Did you ever see the Broadway play called “Art” it was written by someone by the name of Yasmina Reza. The play was absolutely hilarious but there was strong undertone of complexity of human behavior that was so arresting. All three actors ponder upon the complexity of an expensive piece of art that is an unpainted canvas. This kind of reminds of that play”

“Yes,” he said, “I vaguely remember that.”

Why do we humans get so enchanted with open spaces? Indeed why does a blank sheet of paper offer so much value? It does you know! Because thoughts have as yet not materialized in either of them. Some can conjure up a campground, others a football field, and still others a gigantic skyscraper in the open field and the blank sheet? The possibilities are endless there too.

We are humans, the paragons of all life as Shakespeare put it eloquently. We defy nothingness. We preach filling, building, creating, scaffolding, decorating anything. Our natures are unique and yet it is that blot of nothingness that invites and attracts our viewpoint. Our creative thoughts are to perpetuate a phenomenon of surrounding ourselves with our achievements. It borders on the narcissistic path of life, but that is how progress occurs also: in leaps and bounds followed by step by painfully backward step. Find a blank page and write. Find a blank canvas and paint. Find a open land and build. So that blot of nothingness has a pull and a push. It simultaneously tugs and repels at you, it forces you to think, what could be or must be.

This is a pocket of resistance, like the air turbulence in an aircraft that makes your confidence lurch onto a shaky plank across a gulf where the only view is a burning cauldron below. It happened in real time once and then many others like it have followed. The most memorable and remote was a young man who came in with reams of papers from many a consultant. There was this and that for diagnoses; from a quasi-psychological to a temporal psychophysical, all the way to a potential malignancy. The diagnoses spanned a broad range of esoteric medical ICD codes. I looked at his papers without tempering my mind with the preempts of other’s thoughts and came away with nothing. Absolutely Nothing! Nada! Now what to do? Maybe I wasn’t as smart or knowledgeable or the many myriad of fallacies that become human were more deeply entrenched within. But there really was nothing there. His diagnosis if there was one, for which there was no ICD code was “Healthy.”

He sat across from me with my desk in between. I walked over the gulf that separated us and sat besides him. “You know from all I can see, you are a healthy young man.” I said with a hand on his shoulder.

His eyes betrayed the plethora of emotions from shock, to surprise, to an utter disbelief.

“But everyone, I have seen has come up with something.” All of them say it is potentially benign, but we have to keep an eye on it and nothing to worry about.”

“Well, that is exactly it then. There is no diagnosis to be had. All your tests prove that. There is no sword of Damocles. You are as healthy as I am, assuming I am healthy!” I smiled.

“But what of these diagnoses?” He clamored.

“Take them off your mind.” I replied. Eventually he walked out of the office leaving the invisible cloak of dread on the floor, a beaming smile on his face and an arched back to face any and everything that could come his way.

Now how could this happen?

Maybe one has to find an ICD code to get paid? Maybe one has to show the understanding of the complex knowledge of medicine or maybe, just maybe, one has to fill that “Blot of Nothingness.”

 If you give people nothingness, they can ponder what can be achieved from that nothingness. ~Tadao Ando

"ALL ARE PUNISHED"

Am I a heartless baboon? Some might think so. But then so are we all. We share 99.6% of the genetic structure, so yes we are kissing cousins on the evolutionary tree. But that is not what provokes me to write this post. What I have to say might cause some irritation and position changing discomfort to some and I am sure the invectives will follow. I am sure there will be an incantation of the Bonobo species, but I digress.

The disassembly of the former edifice of healthcare is underway. The passion and logic rings loud. Thoughts and words abound to please the emotions of the heart and smoothen the wrinkles of the soul.

What gives?

Why the tempest?

Maybe there are mitigating circumstances that rattle the bottled-up fears and emotions. But what of this new Law? Let us look at it with open eyes for a change. After all the Supreme Court of the United States of America voted 5:4 in favor.

What are all the things I love about the Healthcare called Affordable Care Act?

1)    It invokes the premise that everyone will get insured even with pre-existing conditions and be granted medical care. And we will all live happily ever after. A laudable intent!

So what is it about the ACA that raises concern?

1)    Stating that it covers the 43 million people who did not have insurance or did not choose to have it before. It raises the premiums of the remaining 270 million people in the USA who had it before. Mine went up 44% last year and I had to increase my deductible to maintain the same policy premium. (Anecdotal, but true)

2)    Forcing a tax on people who cannot afford it or who do not want the healthcare insurance. The semantics of Penalty or Tax do not matter since both take money out of the pocket of an individual. Hiring 15,000 IRS agents to play guardsmen to oversee those that refuse to have health insurance is a burgeoning travesty on an individual's right. Although that money would be better spent on healthcare itself don’t you think?

3)    The ACA increases the volume of patients to an already burdened system. With less doctors (a projected deficiency of 125,000 in a few years) whilst adding millions to the roll, the writing of a Greek Tragedy is underway. The solution probed is to allow Nurse Practitioners and Physician Assistants to assume the role of the doctor while the doctor takes the back seat and the legal responsibility. Not too many doctors will be happy about that either, I think. The terminology of “Healthcare Providers” levels the playing field, doesn’t it? Doctors, Nurses you are in the same category as the transporters and house-keepers. If you ask the question why? No! you may not! Words, you see, have powerful connotation. Call someone "Hey you," demeans whoever the "you"is.

4)    A few will decide the fate of the many. The IPAB will ration the care based on expense and age and not on need. The stalwarts point to the NICE in the United Kingdom as the model to model after. Really? The Pluribus comes before the Unum. Although I do agree that sometime we spend an enormous amount of resource in a futile cause and a more judicious path might be to educate the patient and let them make the decision, rather than mandate. But that is too common sensical.  Advocating a single mantra for the many will not bring comfort to the one and for that matter to the many in the long run.

5)    Taking $575 Billion out of an already cash-strapped Medicare system that is currently unsustainable, as an unfunded liability and based on the targeted costs of the entire care running up $2.6 Trillion, projected to engulf over 20% of the GDP is akin to a titanic struck by the iceberg and the Captain says, "Everything is okay folks, this is an unsinkable ship." That in a $15.7 Trillion economy is a mammoth burden. Might I add just for the bean counters that the current debt is running at $15.933 Trillion or 103% of GDP while accruing billions each hour. Oh, the future horror of it all!

6)    Establishing 13,000 pages of regulations from a 2,500 ACA Law, that gives legal eagles powers in the legal system to rip and shred the patient-physician relationship further as they please (as if it is not already tattered and lies bleeding). The current system is already forcing the doctors out of business given the regulatory environment. The present mandate and its future unintended consequences seem inexorably marching the doctors to the disenfranchised, disillusioned and some to the unemployment line. Of course it would make some very happy at the thought, but I digress again.

7)    Completely ignoring the desires and wishes of the physicians in the enactment of the Law, is a one-sided affair in the extreme. The AMA as an arbiter does not count since this was in the organization's bag with the earnings from the ICD coding business for several millions a year contracted with the government. As a matter of fact neither the AARP which stands to gain a $1 Billion or more from the Law over the next five years is a real advocate. By invoking insurance for all and receiving large wads of money from the premium payors and the government, their motives are unwashed at best. Neither entity in this case benefit others but themselves. Ultimately the beneficiaries are the Group Insurers who have and will collaborate to bring the masses in their fold with impunity and do the devils work of premium surcharge. Even the hospitals stand to make money for their corporate heads by slicing and dicing the running-scared physicians, (Hospitalists: who will account for 75% of all newly minted and old practitioners in this field of science, within two years) who ultimately are going to suffer the grave consequences. The simple equation is: The CMS controls payment to the hospitals and the hospitals ratchet down reimbursements to the doctors and they in turn acquiesce to the "deemed unnecessary care" in the patient management by eagerly discharging or not admitting or denying expensive care. The doctors and the patients will be the pawns in this game of chess, sponsored by the “movers and shakers.” “Queen to Pawn: Checkmate!”

8)   In all this the one main concern of Medical Malpractice Reform is never mentioned. I wonder why? I guess it is easy to understand that the lawmakers are the lawmakers and they are the  ones that reap the benefit from frivolous litigation.

9)    The very poor people on Medicaid who will now not be covered by the States since the SCOTUS deemed that the Federal Government cannot impose penalties upon the states for non-compliance are the ones this ACA was aimed at. But that is another story. From their perspective it all becomes "Much ado about nothing!"

10)    The Hospitalist physician being an employee, having no skin in the game will treat it just as others in the public sector do, look at the clock unwind. This will create a two-tiered system just like the one that exists in the UK, Europe and Canada. Oh how we have eyed, lusted over and loved their system of healthcare. We are there now and we have arrived. But hold on! now where will the rich and famous go? Cuba? India? or some Fashionable Boutique Institute of heated stones and coffee enemas?

11)  In the end it comes to this: a) The poor will suffer. b) Middle class and the wealthy will have higher premiums or face a fine/tax/penalty and they will suffer. c) The corporations with medium sized individual covered entities will take the penalty/tax of $2000 for each individual rather than make payments of $10,000 average per person coverage and shift some of that in compensation. That will reduce expense for the corporations and businesses and "raise" the salary component for each individual as an inducement. d) Overall care will deteriorate but the talking heads will talk it up gathering slices of data to shore their arguments. e) Innovation will suffer as mandated prices of equipment and drugs is lowered and regulatory stimuli peck and tatter the remains of a once golden age of Medicine. And as Prince Escalus exclaimed his bitterness over the battles between the Capulets and the Montagues and the loss of Romeo and Juliet, with this warning, "All are punished."


http://youtu.be/jEv8WleGMb4




12)  Eventually charity care will rise for those that cannot afford and fee for service for those who can. The cycle will renew itself. The Ouboros dragon will have chewed on its tail.

Be careful of what you wish for, it just might come true. And there may be no turning back.But then maybe calmer minds will prevail.

But I digress...