Holocaust impact on medicine

How The memory of the Holocaust Influences My Practice of Medicine

My parents were survivors of the Holocaust.  That has had a profound influence on whom  I am.  And who I am is a significant part of how I practice medicine

Both of my parents were in Poland when the greatest tragedy of their lives, the greatest tragedy that has ever befallen the Jewish people, occurred. The statistics of that event include a net 10% survival rate for Jews in Poland.  Both of my parents were  the sole survivors of  very large families. When I am told that the probability of survival for some cancer is low, I think about these statistics.  I know that it is possible, even if it is unlikely to survive.  I also know that it is important to survive.  Survival has huge  consequences.

It is hard to know whether the actions that my parents took during this extremely dangerous time contributed to their success.  I cannot know how much is the result of chance, how much came from their effort. Most of the others who took similar actions died. 

 But I do know that their effort was enormous.  They were willing to live buried alive, outdoors, in  the frigid Polish winter.  They were willing to beg , steal food from animals; they were willing to endure every indignity, compromise most of their beliefs,  in order to survive.

 I also remember the pain, shame, and regret - the ambivalence- that came with remembering these events. These memories color how I feel about putting people through toxic treatments, helping them survive while suffering.  From my parents I see that it is possible.  From my parents I see that it is costly - it is a choice.  It is my duty to present the information honestly, make the choice clear, and helps the patient's decide without imposing any dogma.


I remember a cousin from my boyfriend, Chana.  She came to America before the war.  She would say." You will find everything in the struggle."  Standing ,as a child, next to my parents, I understood this comment to  be both true and cruel.


There are  also an important lessons from the tormentors.  It is important to recognize that many of the senior officer is in charge of concentration and death camps were physicians.  It is important to recognize how the organized death of all Jews, Romani, homosexual, etc. evolved from the euthanasia program.  The death camps evolved from the idea that death was better than a life of disability.  In the eyes of the tormentor, death was better than life as a Jew.  The physician, the person with power and authority, cannot decide how low a quality of life is unacceptable. 

The NAZI crime of  experimentation on the victims  has become part of the medical ethics curriculum; it is the paradigm of unethical behavior.  It is a moral crime guide a person into an experimental therapy when a less risky treatment, of at least equal efficacy, is available.  Unfortunately, I see this transgression frequently done in a name of Science.  The NAZI's also did it  in the name of Science.  I will not do it.

I am privileged to try to help victims.  I must give this my best efforts.

I am privileged to meet people who come  from very different places and backgrounds.  My background in the holocaust tells me I must give them full respect.

One can fight the odds, and some people will win.  Honesty and respect for others is the only acceptable position

By  conveying these values, the souls of my ancestors remain involved in the concerns of the living

Responsibility

 Two weeks ago, I went to Warsaw, Poland to participate in an award ceremony.  The State of Israel presents an award to people who bravely helped Jews, like my parents, who were hunted by the Nazi regime and their local sympathizers.  My wife, in the course of writing a book and blog  about my parents' experiences in the holocaust, identified the descendants of  the people who help my parents hide.  This led to their certification, by the Israeli holocaust center, Yad V'shem, as "Righteous among the Nations."  The honor was bestowed in the Royal Palace in Warsaw.  I spoke at the ceremony about the extraordinary bravery of these people and how they permitted my birth.  

I recognize that I exist because of the courage of these people.  I feel that I owe the world a measure of courage, as a partial payment for this benevolence.  

I am a physician, a hematologist and oncologist.  I try to help people with very serious, often life threatening, diseases.  I am in a field that has made remarkable  progress since I  entered it, more than 30 years ago.  I try to channel that progress into better outcomes for my patients.

I perceive  several forces in this field.  There is a strong force for progress, bringing new medicines to improve outcomes.  There are economic forces, resulting in exorbitant price tags for  many of these new medicines.  Typically, these new medicines are priced at $300 per pill, $100,000. per year.  Some are even more costly. There are forces to test and validate  the efficacy  of these new approaches through "well designed clinical trials" Below the surface, there are considerations for payers (insurance companies and governments), stockholders in drug companies, researchers and their careers. 

I am obligated, by virtue of the rescues that brought me life, to focus on the benefit of the patient.  I must rescue the patient from all the considerations that ignore or impede her benefit.  That means practicing beyond medicine, practicing honesty. 

I have patients who have been encouraged to enter clinical trials, when information is emerging that an approved therapy (for a different disease) has demonstrated efficacy for their problem.  There is often an issue of the adequacy of evidence, in the absence of a "well designed clinical trial." One does not have the right to claim efficacy prematurely.  But sometimes, it is clear that the probability of a good outcome is far better with the treatment that is "rumored" to be effective.  I have used the "rumored" medicines ( imatinib, venetoclax, Pembrolizumab) as an early adopter and seen them become standard months or years later.  This is a kind of rescue that I can be proud of.

There is certainly a place for clinical trials.  There are situations where a clinical trial is the best alternative for the patient, as well as for the scientific community and the drug company.  But the risk/benefit needs to be assessed in perfect honesty, free from the pressures of economics and institutional politics.  This kind of patient protection can  call for courage.  I want to have that courage.  I want to encourage that bravery in my colleagues . 

Evidence Based ⓡ

Evidence Based ⓡ

When I was a boy, many products advertised that they had The Good Housekeeping Seal.  Despite the battle between the Federal Trade Commission and the Hearst backed publication (1939) that implied that the seal was primarily an advertising gimmick, the Good Housekeeping Seal remained something that could be touted as a sign of  quality. 

In medicine, the seal of quality is called Evidence Based. The Evidence Based  label has come to  mean something close to "correct", something better- and at the same time,  not  as good as - true  Evidence is better than truth because it is a body of information that is  ( or should be) available for all to examine.  An evidence based conclusion is one that follows logically from the data, any rational, knowledgeable person would come to a similar, if not identical, conclusion.  But it is only as good as the data... and the interpretation. 

Evidence Based is  usually associated with  an  expert consensus opinion.  Very few practicing physicians have ever examined the evidence upon which the conclusion is based.  The evidence itself is rarely available.  Articles  that represent the conclusions of the authors, the people who oversaw the gathering of the evidence,  are the only readily available material that is derived from the evidence. The actual evidence is  in a silo, a private storehouse. 

Fifty years ago, handling numbers was out of the reach of most people.  Only engineers had calculators and  computers were rare.   At that time,  it made no  sense to supply raw, undigested  data to a broad audience.  Nothing could be done with it.  Who was going to copy long columns of numbers and do long divisions by hand?  But now, we all have powerful computers in our pockets and downloading vast amounts of data requires only a click.  But, the actual  data remains hidden.   And we call quoting the conclusions of the authors "evidence."  This is applying a veneer of science to an edifice of opinion. This is scientism.

It is clear that were such raw data available, few would have the time or the skills to independently analyze the data.  Opening the data to public examination could lead to misleading, incorrect analyses. The information could be politicized and reinterpreted for profit or the benefit of a particular cause.  Presumably the data had been open to the scrutiny of reviewers who share expertise in the field.

There are dangers in democratization of data.  I think they are worth the risk. Monolithic science is not the optimal solution.

Most importantly, when a conclusion is called Evidence Based or Data Driven, we should identify who analyzed the data...and who confirmed the conclusion. 

  

Creativity inLeukemia

I think that there is value in bringing the maximum information to bear in every case. One  must be careful in the application of the ideas that emerge

I recently saw  a 50 year old woman. She was very Northwest.  Atheletic, her profession was environmental preservation.  I could feel that she had a life that was filled with love , the outdoors, living an ethical and healthy life.  She had an annual blood test, a Complete Blood Count (CBC).   In modern machines, the concentration of various white blood cells  is reported.  This patient had an excess of lymphocytes.

Lymphocytes make me wince.  The word denotes a cell, present in the blood, with a single,nonsegmented, mature appearing nucleus.  T-cells, B cells, natural killer cells, are all classes of cells with this appearance.  In addition T cells and B cells come in at least 300,000 varieties, defined by DNA rearrangements that determine their targets.  This array of distinct cells and classes of cells is lumped together and called lymphocytes.

The most common disease caused by a abnormal proliferation of "lymphocytes" is B cell CLL.  B cells, under the appropriate conditions, become factories for the production of antibodies. Leukemic cells do not progress, they are abnormal. CLL  B cells have T cell markers  that identify them as abnormal. 

In my patient, the typical abnormal pattern for chronic lymphocytic leukemia was  identified. An  elevation of CD38 was also identified. Increased CD38  is associated with a poorer prognosis in CLL.  It predicts for more extensive nodal disease and earlier progression from the time of diagnosis.

But sometimes negative prognostic factors are targets for new  therapies; and the new therapies  turn the negative into a positive. A drug  called  Daratumumab was  recently  approved by the FDA for  multiple myeloma ,a disease that is distantly related to CLL,  It is directed against CD 38. Multiple myeloma is a malignancy of plasma cells.  Plasma cells are the antibody producing cells that the B  lymphocytes mature into, after they are stimulated. Plasma cells have CD38. Daratumumab has not been approved for chronic lymphocytic leukemia.  Research into the use of this drug  is just beginning for chronic lymphocytic leukemia. 

In order to characterize the patient's disease further,  we had sent an analysis of the Chromosomal changes that are often seen in chronic lymphocytic leukemia. This test brought another result that needed  explanation. Her CLL was missing one copy of the ATM gene.  This is another negative prognostic marker.  But a closer look might turn the situation.

ATM is one of several genes that are involved in DNA repair.  A class of drugs, including some that are FDA approved, makes the mutation  in ATM  into an Achilles heel.  The drug turns this defect in DNA repair ( which probably contributed to the malignant process by increasing mutations) into a lethal problem for the cells that carry it.  Drugs that target DNA repair defects are approved for breast and ovarian cancer, not for  CLL or other cancers .  However, a clinical trial in prostate cancer  showed that a  drug in this class prolonged survival along a spectrum of DNA repair defects, including ATM.  Studies have begun to investigate  the utility of this approach in CLL and related diseases.

The relevance of all this biology is not clear because the  treatment of CLL, regardless of negative prognostic factors, has improved so much... and it continues to improve.  In  the past year , the FDA has approved ibrutinib  (response rate 85%), venetoclax ( response rate 84%, complete response rate 50%)  and idelalisib (resposne rate 50 % CR 15%) .  These drugs target  enzymes that are common to (almost) all CLL cells.  They are  approved because they are known to be tolerable and effective

On the horizon, CART cells are now being tested for refractory cases.  These are genetically modified immune cells directed at a chemical that is on the surface of the malignant ( and some normal) cells.  This technique, newly approved for acute leukemia, has had dramatic success.

There is value in bringing our expanded understanding of disease and the wider range of treatment options to bear on every case. The  safest and best  outcome for the patient must always be the top priority. It is important to avoid seduction by your own thoughts. "Don't let the sound of your own wheels drive you crazy" ( The Eagles)

The diagnosis cloud

Data Clouds

I've looked at clouds from both sides now
From up and down and still somehow
It's cloud's illusions I recall
I really don't know clouds at all

Judy Collins

All real world, "scientific" information comes as a cloud.There is a penumbra of uncertainty that surrounds every "fact"  Even physical constants, like the  universal gravitational constant, G,  are never quite exact because of measurement issues.  Data in medicine is usually very inexact.  Accumulation of large samples is the standard method for improving the resolutions; but more data always leads to more cloud.  The kernel of truth is always shrouded, the veils  are too thick.  The truth is imagined be a point of light, encased in translucent noise,  A more sophisticated ( but, perhaps no more correct) view is that the truth, itself is a cloud.  Perhaps the Heisenberg Uncertainty Principle  ( there is an absolute limit to the accuracy of a measurement) also applies to  medicine

 Treatment depends upon definition.  The definition of  diseases has a significant  traditional component.  The diseases of the Bible, Hippocrates and Galen are now understood  to be mixtures of entities.  The signs and symptoms that these extraordinary ancient observers  could identify come from a variety of very different processes.   To them, jaundice was a disease entity.  We understand that jaundice, yellow discoloration of the skin and eyes, can be the result of liver disease, diseases of the red blood cells, gallstones, etc.  We can identify these differences using biochemical  blood tests, the microscope and CT scans.

 As I say this, I am reminded of a Saturday Night Live skit from the 1970's,  Theodoric of York, Medieval Barber. In that clip, the medieval medical practitioner reassures the patient's mother by talking about how medical science had progressed from ideas of demonic possession to understanding that disease is caused by imbalance of humors.brought on by toads  How ridiculous will our models look in 50 years? 

The models of disease  that emerged in the nineteenth century, with  the application of the microscope  and the use of dissection emphasized a cellular basis of disease.  The discovery of pathogenic bacteria led to a simple model of infection that continues to be the basis of the greatest of medical interventions.  In the current era, most diseases  are still viewed  through the lens of the light microscope.  The incorporation of molecular and interactive (immune)  information has lagged.
It is hard to improve upon success. But we, who care for the sick, understand the challenge; we see how limited is this success. 

Current imaging, blood tests, and microscopic techniques give us a working understanding of the varieties of disease processes.  It has led to real advances. The main block to further success has been the  limited treatment options.  The improved vision afforded by molecular and immune systems techniques will give us a better understanding  of the disease process and  lead to improved outcomes.  These are radar that will penetrate some of the clouds. 

Too many drugs? Too few patients?

The article by Gina Kolata in the New York Times ( August 13, 2017) is written from  a perspective that favors drug companies over the patients.    

The current system of clinical trials  started when the average American lifespan was less than 70 years for men, before we knew anything about the molecular basis of cancer, and the slide rule was the most sophisticated, widely available, computational tool. It has always been clear that this system slowed drug availability and, consequently, led to deaths.  

From the patient's (and the caring provider's) perspective anything that improves the chance of more effective therapy is welcome. "Too many drugs" is when there are adequate treatments for all diseases.  "Too few patients " is universal wellness...at reasonable cost. 

The article quotes two Genetech executives (see same day NYT page 7 for the ad for an unrelated Genentech product)  questioning how many immunotherapeutic  agents can be tested.  Genentech's entry in this field,  TECENTRIQ®,,is having trouble proving its worth .  The company  may want to beat its competitors.  The irony of a Merck vice president saying: "How many  PD-1 antibodies does Planet earth need? " is not lost on me.  He might well think that the Merck product, Keytruda, is enough. We do not know that .

The idea of "outstrip[ping] our progress in understanding the basic underlying science"  is incredibly arrogant.  Most of our currently effective  cancer treatments  were developed in the context of models that have been long abandoned.   Our current understanding of immunology and  gene interactions remains primitive and will almost certainly be changed in the future.   Part of refining the model  will depend on the results of treatment with these medicines.  That is the history of medicine. 

In the article the "cost" of genetic testing is quoted at $5000. I find that interesting .  The cost depends on who is paying.  Currently, the materials cost is less than $100.  The amount billed to the insurance company is often about $8500.  If the patient pays directly, it is no more than $3500.

From the  cancer  victim's perspective, the problem is not too many drugs.  The  problem is  the cancer.  The drug companies, the  FDA  and insurance companies are standing between patients and their treatment.  The system needs to change.   

An  applications for computers in medicine

I think about what I do as a physician and a specialist in hematology and oncology,  and how it could be made automatic. If it we're automatic, it would be done more uniformly and rigorously and the calculations would be more reliable.

I believe that machines can do many  things better than I can. Their memories are  perfect,.  Their calculations are exact.

I also believe that, at least at this point, I can add something to the machine. I can be more skeptical. I can understand the motivations of the people who create the input. I can understand the implications of suffering, the feelings of relief and loss.

I look forward to a collaboration with the machine. I do my best to foster it. I have brought the internet to clinical conferences for the last 30 years. Do not forget the sounds of the telephone modem connection in the 1980's.

I would like to see an expanded role for computers in medical decisions. .The  Electronic Medical Record was supposed to help with this integration. It has done a very poor and limited job. Sometimes, it has stood in the way of using the capabilities of computers to help analyze and solve problems. It is very difficult to export  data to a spreadsheet for analysis. This will undoubtedly get better. But the structure of incompatibility among electronic medical records is a violation of one of the main motives of the government that encouraged,  with sizable economic incentives,  their adoption.

In my hematology practice, I am often confronted with the question of the cause and treatment of low blood counts. I have found an analysis of the time course of the fall of such blood counts is useful. Often, a point in time can be identified when the fall began. A pattern can be seen suggesting either a slow, gradual fall or a rapid fall or both phenomena superimposed upon one another. Although these consultations are a welcome source of income for me, I recognize that the algorithm that I use could be made  automatic.  Such an automatic algorithm would help me do this work. Currently, an automatic solution would need to be checked by a human health care provider. Over time, the level of training of that provider might not require subspecialty certification. The primary care provider could do an adequate job of spotting unusual circumstances

I would like to see the machine identify the time course of variations in laboratory tests and then, automatically, correlate these with variations in treatment. This is not a hard algorithm. Thinking about it was somewhat entertaining. I would do it by going back to the definition of the derivative. One would then look at the slopes of the segments that make up the overall change and identify the more dramatic slopes as times of dramatic change to be correlated with alterations that might be identified in the history, especially medication changes. ( After doing the calculations, I realized that this was probably  the beginning of Newton’s method of difference,  the origin of calculus that I had recently read about in James Gleick’s biography of Isaac Newton.)  

This approach could also be used to monitor whether interventions are effective. Improvements could be correlated with interventions directed at those parameters.

Such an algorithm does not replace the human It simply helps her. I think we need it.

Model curve

"derivative" curve identifying days of greater and lesser change