TUMOR INFILTRATING LYMPHOCYTES (TILs)

Much to the chagrin of the astrology experts, Shakespeare had a thing to say about it, “It is not in our stars to hold our destiny but in ourselves.” So what is in ourselves that we need to look at?

Interestingly, plenty of stuff!

In the 1990s there were articles about the importance of the presence of lymphocytes infiltrating the cancerous tissue. Physicians looked at these findings and compared outcomes with and without the presence of lymphocytes. They came away with the unassailable thought that the presence of the lymphocytes had some positive impact on survival. In early stage II/III colorectal cancer for instance they were able to determine that the presence of tumor infiltrating lymphocytes (TILs) in the tumor tissues were associated with longer term survival. Curious indeed, but at that time the tools were not there to study them further.

In Melanoma for instance a similar viewpoint held that TILs helped improve a person’s chances in overcoming the disease. In Melanoma, however, the immunity issue became a singular focus for a long time. Treatments included Interferon therapy, Interleukin-2 (as well in Renal Cel cancer) therapy and Vaccination against the epitope on the melanoma cells. These treatments were quite debilitating in nature, giving symptoms of a aggressive “Flu-like syndrome” each time the patient received the IFN or IL-2. One had to get the Interferon shot daily for 30 days, then three times a week for a year. It wreaked havoc on the patient, but there were responses. People not supposed to live, survived.

Breast Cancer data also seemed to suggest the presence of TILs in the surrounding tissue of the cancer. Little evidentiary information has been gathered or experimented in this malignancy, however, since there are much better methods of treatment available for this malady.

Modern Medicine dating back five or so years has resurrected the whole TIL concept once again and it seems successfully given another kick in the pants.

Knowing that the composition of the lymphocytes is T cells, B cells, NK (Natural Killer) cells, Helper Cells, Dendritic Cells that sample the antigen and macrophages, medicine has figured out how to manipulate the immune system in those patients that have an army of these TILs lurking around the tumor tissue. Since these cells are present, it is obvious that they have sampled the antigen on the cancer cells and having done so, if one were to enhance their effect, one could gain another foothold against this scourge called “The emperor of Maladies.”

https://youtu.be/AbmEt_E8kfo

Further knowledge development from studying this cellular machinery revealed that the cancer cells have accommodated this immune onslaught quite successfully by using the cell’s own defense mechanism of cloaking their anticancer activity with a protein. This protein, the scientists realized, was preventing the immune function from destroying the tumor. From the alternate point of why, one might ask, why does the body not want to protect itself? The answer was clear, allowing a rampant immune response without any checkpoints would lead the body to “destroy” itself when attacked by a simple infection, akin to a pleasant breeze turning into a hurricane. So checks and balances needed to be present to prevent such hyperbolic activity. 

Well now having delineated the mechanisms of action the Immune brigade can be carefully turned against the cancer itself. First the presence of the TILs is an important precursor to the present thinking. The determination of the protein called PD-1 (receptor on the lymphocyte that limits its anticancer function) and PD-L1 (the receptor present on the cancer cells itself). Inhibiting the function of these receptors has resulted in a plethora of drugs armed and aimed at these two proteins (the guardians against hyperbolic responses). Once the checkpoint has been blocked the immune cells can go on to demolish the enemy (cancer). It goes without saying; the more the TILs the better the body is equipped to be helped or conversely if the disease is advanced with a large tumor burden and low to absent TILs, the lower the chances of response.

We tread slowly towards a better future and I end with Shakespeare again, “ Wisely and slow. They stumble that run fast.”

References:

Adam, S et al. Prognostic value of tumor-infiltrating lymphocytes in triple-negative breast cancers from two phase III randomized adjuvant breast cancer trials: ECOG 2197 and ECOG 1199. J Clin Oncol. 2014 Sep 20;32(27):2959-66.

https://www.researchgate.net/profile/Claudio_Clemente/publication/14591062_Clemente_CG_Mihm_Jr_MC_Bufalino_R_Zurrida_S_Collini_P_Cascinelli_NPrognostic_value_of_tumor_infiltrating_lymphocytes_in_the_vertical_growth_phase_of_primary_cutaneous_melanoma._Cancer_77_1303-1310/links/541c00f00cf203f155b34fb0.pdf

http://www.cancernetwork.com/oncology-journal/high-dose-interleukin-2-it-still-indicated-melanoma-and-rcc-era-targeted-therapies

http://bmcmedicine.biomedcentral.com/articles/10.1186/s12916-015-0431-3

http://jnci.oxfordjournals.org/content/108/11/djw144.short

HAWTHORNE EFFECT

You might wonder what this is about. And I, for starting this have a bit of concern too. But this is a story not about the author, Nathaniel Hawthorne of the House of Seven Gables, nor is it about the City in New York. It is about an effect.

Effect, you say, what about it? Actually it is a fascinating insight into the human condition. Let me trace it back to its origins. A town named Cicero in the Chicago burbs, housed a manufacturing plant called Hawthorne Works. 

The Illinois City named after the one in New York, which was named after the Roman statesman Marcus Tullius Cicero . Both the city and the Roman it was named after suffered; the city lost 5/6th of its land due to weak politicians and its manufacturing status and Cicero’s head and hands were displayed in the Rome’s Forum after his assassination for angering Julius Caesar (34 BC).

Hawthorne Works enjoyed prosperity in the early 20th century and there is where it was determined that when observation and positive interest is shown in a worker’s work, productivity goes up and vice versa. Meanwhile the display of Cicero’s body parts in the Roman Forum were of equal force preventing any further threat against Mark Antony’s reign -  a negative feedback. Funny how the ghosts in names play out the future with equal measure gained from their history.

The Hawthorne Effect has been written about and “studies” done on hand washing among physicians and nurses in an effect to reduce the potential for spreading infections. The reality goes this way…if one is being observed to do a job, one is psychologically forced to comply. Thus the rate of hand washing among the observed goes up against the unobserved. It might be called oversight in another document, but in the Hawthorne effect the simple act of observation even via cameras or other digital means conspires to inspire an individual to take action. All well and good. Good actions beget good results.

Extrapolating from this act of “observation” as an “observational interest” and giving that “interest” some term such as “value” might have an identical effect, if not profound, at least above the zero mark in a person’s productivity? Again, don't take this to the bank, because where I am going with this is a hotbed of molten lava created from fire and brimstone. You fall in, you are done! So look, Learn and Understand!

“Moon walking” back to the premise of interest and productivity we find that if an employee feels his worth by the company, he or she tries harder. The idea behind that is simple incentive, create value for the company and be rewarded with promotions and higher salary.

You with me so far? Ok, so what gives in the environment of Medical care then?

Physicians are “burnt out!” Indeed, more and more reports seem to not only suggest, but also correlate that with higher rates of suicides by physicians. The metaphor of “losing a jumbo jet filled with physicians every year.” Or if you prefer, “Losing an “entire year’s worth of medical graduates from medical school” every year. Disabling thought, isn't it?

And you must ask why? Ah there in that three lettered word is the essence of science. 

Why, indeed?

Let me posit a simpler solution; maybe in medicine, there is a negative Hawthorne Effect. with no cheerleaders for the once noble profession, only grim reapers always crying, "foul!" Maybe, physicians are being railed against in the media 365/24/7 and characterized as bad actors. So if you are a physician and work the 12 hour weary days and find the profession maligned on the television and media when you sit down at the table for dinner, something’s got to go "kerplunk!" The negative Hawthorne Effect comes to play - remember Cicero’s head and hands on display as deterrence? When every observation is a negative event, work becomes a chore, the shoulders get slumped, the days get longer, the work becomes weary, soon depressing thoughts arrive, unannounced, the devolving gyre tightens and finally the mind cannot hold.

But don't take me wrong on this, the powers that be seem to have absolutely NO interest in the Medical care of the patients, it seems. The powers that be have an interest in their own interests. For instance, The Insurers are interested in making higher and higher profits (the average Healthcare company CEO salary in 2014 was $11.7 million) and they blame the claims from the physicians and make them go through hoops of the medical Revenue Cycle to collect their reimbursement on behalf of the work completed. The government has an inverse viewpoint; to lower the costs of healthcare as a percentage of GDP (currently 17% of the GDP) and they too blame the physicians as the drivers. To that effect they have the annual CMS “Data Dumps” showing what physicians have received in payments (BTW: in 2012 out of $1.2 Trillion only $70 Billion went to pay the 850,000 physicians that translates to 5.8% of total). They also have a “Sunshine Act” displaying any gifts from pharmaceutical agencies to physicians; citing that $10 lunches invoke a severe Conflict of Interest in prescribing medications. Then there are quasi, not for profit agencies that have their hand in the pot like the ABIM, ABMS (claiming public interest as their only mantra while fleecing the physicians in millions of dollars - NAV as of 2014: $134 million), PWRS, PCORI (Reporting agencies that create pseudo-science on the go to determine efficacy of care) and other shenanigans like SGR, MACRA, MIP, APM (designed to create and maintain an ever-ascending vertical bureaucracy that deems who and how payments are to be made for service rendered). The list goes on...

You still with me?

Consider this; The physician is now a "data logger," a well-educated scribe so to speak, on the computer (EHR) and the computer spits out (based on an algorithm) a defined set of tests to order for compliance. All this cataloging is nothing more than information gleaned by and for other companies to sell data for analysis to insurers and governmental agencies to better control expenses in some cases, raise revenues in others and further the interests of all involved in their Net Asset Values. For instance CERNER an EHR computer company, for the year 2014, revenues were up 16.9% to $3.4 billion from $2.9 billion in 2013. Net income for the 2014 fourth quarter jumped 146% to $147.9 million, up from $60.1 million in the 2013 third quarter. Hmm… Judgment and Reason, need not apply when it comes to patient care anymore. Its about dollars and cents and a large public pot for any company to pull out oodles and oodles of cash. In this “One size fits all,“ for better or worse, EHR world, the actual “fit” is immaterial. So what if the helm shows, the shoulders sag on the jacket, the stitching is subpar. So what? And it will all get worse, I predict, because the non-practicing physicians who have taken on the mantle of “experts” have decided that programs such as “Choosing Wisely” and “Less is More” need to be the bully-pulpit from where to scream down into the trenches, “Do this and Not that, or else…” 

There is a pathological obsession in replicating an idea that is profoundly destabilizing and will ricochet through humanity transecting the tether that binds us all as humans. Ah "disruption" they cry and all fall down to their knees in unison to the lure of the ethereal enriching beast. The capacity to think of the whole and not always the parts in isolation can bring to view the unintended consequences; those things that go "crunch" in the long winter nights are never a part of their thought.

The Mocking Jay

Jennifer Lawrence - The Hanging Tree (The Hunger Games) from Emma Plunkett on Vimeo.

So while this rant appears like a rant and maybe is, it does have the potential of the sound of a “Mocking Jay.” As the people realize what the future holds for them a band of brothers and sisters will finally say, “I’m mad as hell and I’m not going to take this anymore!” The physicians might lead on this and then as care is depleted and noticed, the rest of us will follow suit.

ASPIRIN & CANCER

Every so often a product comes along that defies augury. And yet with each passing future it provides tiny visages of it’s abilities to predict what may lie ahead. Aspirin, the old Salicylic Acid, the most used and ofttimes reviled substance comes to the fore in cancer care.

But barely so, because the pockets of the high and mighty pharmaceuticals continue to whip up a storm of this and that in small incremental advances through complex machinations of the human cellular biology, while Aspirin continues along its merry way easing the burdens of diseases unbeknownst to its takers.

Aspirin and Colorectal Cancer:

Aspirin continues on its quest to impair the mechanism of inflammation; the hallmark of most diseases such as cardiovascular and rheumatological diseases and including cancer. We will leave the heart to the cardiologists, but for now let us delve into the wayward cancer cell.

Low dose Aspirin continues to be a constant nagging positive feature in cancer prevention, much to the delight of many. The most recently studied data disclosed suggest a significant reduction of risk and death from Colorectal cancer in those using a daily dose of lo-dose Aspirin. Looking at the mechanism, it becomes clear that COX-2 inhibition may be at play here. 

The implications stem from the reduced inflammatory effect and the production of polyp formation. Since most such polyp formations precede colon cancer and with the steady stream of sequential and sometime concurrent genetic mutation is at play in the polyps. Preventing the polyp formation itself becomes the “Strike three” (in baseball analogy) against the cancer. 

Aspirin and Esophageal and Stomach Cancer:

Continuing on the gastrointestinal tract issues, there is also abundance of proof that suggests that the same lowly lo-dose Aspirin taken over 5 years also may reduce the risk of Esophageal and Stomach cancers by 30% and death from these malignancies by 35-40% (1). A meta analysis of eight studies using individual patient data showed an overall lower deaths from common cancers in those patients consuming daily Lo-Dose Aspirin (3).

Aspirin and Colon, Breast and Prostate Cancers:

Another study highlighted benefits of risk and death reduction in bowel, breast and prostate cancer patients who took Lo-Dose Aspirin by 15-20% (2).

Given such accrued overwhelming data the USPSTF added Colorectal prevention with Lo-Dose Aspirin in their Preventative Recommendations in 2015 (4).

Liquid Aspirin:

A more interesting and provocative study from Britain shows that Liquid Aspirin in the form of IP1867B when given intravenously leads to cell kill in brain tumors (Glioblastoma Multiform or GBM). The nuance from this study has significant implications in overall cancer care in the future (5). Keep your eyes peeled on this development!

So with such a preponderance of information it behooves people over the age of 45 and beyond to take Lo-Dose Aspirin (as long as no allergy or sensitivity towards gastric bleeding exists) as a cheap form of prevention. This when added to exercise and a healthy 2000 calorie diet (fruits, vegetables, legumes etc.) will keep most in good health longer.

And just for the record, don’t forget Aspirin’s effect against Cardiovascular Diseases: heart attacks and strokes!

REFERENCES:

1. Jack Cuzick, Ph.D., head, Center for Cancer Prevention, Queen Mary, University of London, England; Leonard Lichtenfeld, M.D., deputy chief medical officer, American Cancer Society; Aug. 6, 2014, Annals of Oncology.

2. Peter C. Elwood, Gareth Morgan, Janet E. Pickering, Julieta Galante, Alison L. Weightman, Delyth Morris, Mark Kelson, Sunil Dolwani. Aspirin in the Treatment of Cancer: Reductions in Metastatic Spread and in Mortality: A Systematic Review and Meta-Analyses of Published Studies. PLOS ONE, 2016; 11 (4)

3. Rothwell PM1, Fowkes FG, Belch JF, Ogawa H, Warlow CP, Meade TW.Effect of daily aspirin on long-term risk of death due to cancer: analysis of individual patient data from randomised trials. Lancet. 2011 Jan 1;377(9759):31-41. doi: 10.1016/S0140-6736(10)62110-1. Epub 2010 Dec 6. 

 
4. Chubak J, Kamineni A, Buist DS, et al. Aspirin Use for the Prevention of Colorectal Cancer: An Updated Systematic Evidence Review for the U.S. Preventive Services Task Force. Evidence Synthesis No. 133. AHRQ Publication No. 15-05228-EF-1. Rockville, MD: Agency for Healthcare Research and Quality; 2015 

5. http://www.dailymail.co.uk/sciencetech/article-3663188/How-liquid-aspirin-help-fight-brain-cancer-Special-version-drug-ten-times-effective-killing-cancer-cells-chemotherapy.html