Eamonn Boyle, M.D. says, "Most Things Get Better..."

Having “no grand plan” for his life after high school the young man was idling in front of a bookcase when he spotted a volume on zoology and thought to himself, “That might be interesting.” A few months later, in 1963, he entered the government-sponsored seven-year medical school program at University College, Dublin. Half of the lads (there were very few women) left after the first demanding year.

Eamonn Boyle, M.D., F.A.C.P.

Our protagonist did well and continued his studies. He enjoyed zoology, but also chemistry, biology, physics and, especially, botany.  Dr. John Harman,  “a great pathology professor,” introduced him to the study of inflammation, how the body defends and protects itself, and Dr. Ruy Pérez-Tamayo taught him about tumors. But his interests were still broad and as Dr. Eamonn Boyle (the young man of the story) finished his studies he wondered, “What am I going to do now?”

While preparing to “put in papers” for an internship at the hospital where he trained (as did most of his fellow graduates)  he ran into his alphabetically-arranged classmate Frank Bonner (Bonner, Boyle, etc., you know how it was in the old days when life was simple and orderly). Frank was from Philadelphia, and said, “Why don’t you come to America? I think I can get you in. They’re missing a player!”

So he landed his rotating internship and two-year medicine residency at Bryn Mawr Hospital from 1970 to 1973.  His interest in oncology that was sparked while in medical school became more definite as he closely watched and learned all he could from the “legendary and revered” (according to her 2005 obituary), Dr. Abigail Silvers.  

She let Dr. Boyle know that even if you could not cure their cancers, patients still had general medical needs, and that you could alleviate their symptoms and relieve their suffering, and that they “didn’t all die in one day.” He was deeply affected by her humanity and thought, “This would be a good fit.”  And, he reasoned, treatment for cancer “is only going to get better with the passage of time, since most things get better.”   

Emil Freireich, M.D.

After his time in suburban Philadelphia, he took a fellowship at the M.D. Anderson Cancer Center in Houston, Texas, one of the first comprehensive cancer centers and (according to U.S. News) ranked #1 for 11 of the past 14 years. He spent five intense years in Texas as he worked alongside true cancer treatment pioneers, including Dr. Emil Freireich.

While sleep-deprived (he was on call every third night) but well-fed (they provided “three squares”) at Bryn Mawr he had met a local student-nurse who would later agree to become his wife. When thinking about where to go into practice (academic medicine was not for him) proximity to Philly, where her family lived, was important.   

He interviewed for a position in Lancaster but there was no need for a full-time oncologist at the small Catholic hospital. The radiation therapist there referred him to York Hospital “just down the road” since Dr. Ross Moquin was unexpectedly leaving practice.   On the short drive from Lancaster to York that beautiful cool Mother’s Day weekend the trees and flowers were in bloom and the rolling hills were a welcome break from flat and steamy Houston.  He could be comfortable here, he thought. 

He liked what he saw, particularly when he met several of the general internists at the hospital, including Drs. Leo Samuelson and Jack Kline.  Dr. Moquin queried him and quickly said, “The job is yours.”  Dr. Boyle began to see patients here in 1978, joining Dr. Miodrag Kukrika who had been in York for a few years and, together, they formed “Cancer Care Associates.”  Their practice expanded and evolved over the next 40 years.

The field of oncology, of course, has also changed dramatically in four decades.

Blood Smear of ALL

In the beginning.  Watching children with acute lymphoblastic leukemia (ALL) quickly succumb to their devastating illness Dr. Sidney Farber felt helpless. In 1947 he and his team used the folic acid antagonist aminopterin to block DNA synthesis. Many of the children had their disease go into remission, but they all subsequently developed resistance to the single drug and relapsed and died. 

Treatment was then refined by the aforementioned Dr. Freireich as he gave the kids several agents in combination (similar in concept to the treatment for tuberculosis, it was noted), and the therapy was then continued beyond the acute stage.  

Thus began the era of “multiple-drug induction followed by maintenance chemotherapy.”  By 1971 the cure rate in ALL was 50%.  Dr. Boyle witnessed this, and there was new optimism as he noted that, “Little children could go from inevitably dying, to being cured most of the time.”  The cure rate now at St. Jude is 90+%. 

After the spectacular success with ALL, curative treatment for advanced Hodgkin’s lymphoma followed in 1965, and advanced testicular carcinoma became a very treatable disease in 1975.  For a young optimistic cancer doctor, this was evidence that aggressive chemotherapy might also even halt, for example, metastatic breast, colon, prostate, and lung cancers. As Dr. Boyle said, “That was the proof (we needed).”

In the middle.  The intense and complicated chemotherapy regimens of the 1980s and early 1990s often made patients feel terrible, and as their white blood cell counts dropped precipitously they sometimes developed life-threatening infections.  This “slowed down” but did not really cure many cancers. Colony-stimulating factors helped limit anemia and falling white counts, but that was not enough. Discouraged, Dr. Boyle waited patiently for something better.

(From "Rewire Me")

Along the way, he noted that there were “rough areas” (emotionally) but that he “never thought of doing anything else.” He was a “round peg in a round hole” as a front-line practitioner serving the York community.  As he reflected on this, he noted that the “relationship with people” as he gently guided them along in their cancer travels and helped them cope with the “assault on their personhood and control” was “the biggest thing” for him. As it is for most physicians, he believes.  

But he feels that, ”There could be a little bit more done psychologically for the cancer patient who has trouble keeping the balance," and that "this (struggle) relates to their nature before the cancer, and how much cancer and its treatment is interfering with their life.” 

The current era.  (Here is where things get really complicated, and Dr. Boyle, with patience, and in his gently nudging way, took the time to allow me to get things reasonably straight.) Cancer, he noted, is now recognized "fundamentally" as a gene disorder. Damaged genes (hence called oncogenes) go haywire, causing the affected cells to grow uncontrollably, to spread to other organs, or to block the effects of the body’s usually-protective immune system.  

The damage to the DNA of the genome may be caused by environmental factors including tobacco, chemicals, radiation, and others, still unknown. A number of viruses may alter host genes or introduce new genes that may eventually lead to cancer.

Location of BRCA Genes

There may also be an inherited (i.e., hereditary)  tendency (Dr. Boyle was careful to emphasize this latter point) to develop to certain cancers, such seen in carriers of mutated tumor-suppressor BRCA1 and BRCA2 genes that substantially increase the risk of breast and ovarian cancers. But even here, subsequent gene damage is necessary for the development of a cancer cell.

It was dreamed decades ago that by knowing the exact genome of the cancer cell it might be possible to design agents to attack only those specific altered functions.  It took some time, but this "sequencing" of the gene can now be done relatively easily, and an antibody to the precise target, a so-called monoclonal antibody, can be created in any amounts needed (yes, this is truly amazing science and technology). 

Rituxan, the first monoclonal antibody therapy was introduced in 1997. It attacks the B cells of the immune system that have a unique cell-surface marker called CD20.
  

Structure of Rituximab (Wikipedia)

Other therapeutic antibodies, including what are known as checkpoint inhibitors, have been developed. These include, among others, Herceptin in 1998 for breast cancers, Avastin in 2004 to block the vascular supply to certain tumors, Erbitux, an epidermal growth factor inhibitor, in 2009, for colon, lung and head and neck tumors, and Keytruda, in 2017, that blocks the cancer’s own sneaky self-protective adaptive system to then permit the patient’s immune cells to do their job and attack and destroy the tumor.  

There is already a genetic test to see if the patient will not respond to Erbitux or Keytruda, so, less guessing, making Dr. Boyle's job is a wee-bit easier.

Dr. Boyle notes that in addition to the advanced “biologic” monoclonals (whose tongue-twister generic names all end in -mab, by the way) conventional drugs with simple chemical structures have been designed to attack specific tumor cells.  This may be done by blocking a protein, or enzyme, necessary for the activity of the rogue cells.  Gleevec (released in 2001)  for chronic myelogenous leukemia and certain stomach tumors, and Imbruvica (in 2015), for chronic lymphocytic leukemia, are examples of this.  

More immunology; old and new. Since the 1980s the BCG vaccine used to prevent tuberculosis in countries where TB is endemic has been employed surprisingly effectively to treat minor bladder cancers.  At Duke University a vaccine derived from the patient’s tumor itself is being tested with remarkable success in treating glioblastoma, the highly aggressive and feared primary brain tumor. In fact, it has, on average, tripled survival times. 

Recent experiments in mice showed that when they are vaccinated with their own induced stem cells they eradicated many different types of tumor cells, raising the hope that the same will occur in our species.

Cartoon of CAR-T

The newest immune system therapy, noted Dr. Boyle, is called CAR-T(cell).  This takes the patient’s own T killer-cells and engineers them to have a specific surface marker. It then makes a bunch of these cells to infuse back into the patient.  This has been partially effective in otherwise resistant childhood leukemia and certain stubborn lymphomas. CAR-T is given as a single treatment. Novartis has currently priced its version at $475,000 (while Gilead charges a measly $373,000).  

Multiple Factors in Disease

The future. After a cancer diagnosis or, better yet, after finding a pre-cancer picked up by sophisticated screening, we will calmly sit down with our doctor and be offered perfectly-customized “precision” care uniquely matched to our genetics and epigenetics (the turning-on and turning-off of specific genes), the offending gene mutations of the cancerous cells, the activity (or lack thereof) of our protective immune system, and our personal history of other risk factors and unique biology. There will be less fear, fewer side effects from treatment, less suffering, occasional miraculous cures, and longer survival.

"But, won’t cancer one day be totally eradicated?" I asked. 

Regrettably, but with soft gentle honesty, Dr. Boyle said, "I don’t think so." He noted, instead, that "cancer may be tied up in the way we are.” Implying that this is an integral part of our animal biology, of our evolutionary zoological heritage.

The Pulitzer Prize-winning author of The Emperor of All Maladies, Dr. Siddhartha Mukherjee, agrees:

"The Emperor.."

Cancer, we have discovered, is stitched into our genome. Oncogenes arise from mutations in essential genes that regulate growth. Mutations accumulate in our genes when the DNA is damaged by carcinogens, but also by seemingly random errors in copying genes when cells divide. ..Cancer is a flaw in our growth, but this flaw is deeply entrenched in ourselves. We can rid ourselves of cancer, then, only in as much as we can rid ourselves of the processes in our physiology that depend on growth--aging, regeneration, healing, reproduction...It is possible that we are fatally conjoined to this ancient illness, forced to play its cat-and-mouse game for the foreseeable future of our species...But if cancer deaths can be prevented before old age it will transform the way we imagine this ancient illness...It would be a victory over our own inevitability, (p. 462-3).

I think Dr. Eamonn Boyle would be satisfied with that.

Required Reading: Mukherjee, Siddhartha. "The Emperor of All Maladies; A Biography of Cancer."  New York; Scribner, 2010.

John Mathai, M.D., F.A.C.S., F.A.C.C.

The 23-year-old young man arrived at midnight in Pune after a fifteen-hour train ride from Trivandrum.  He slept on a bench on the platform and awoke to someone sticking him in the side. He looked up and the policeman said, “You have a suitcase. Put your feet on top of it so  no one will steal it.”   He left the station and thought, “What have I done now?"  His appointment was in a few days.  He washed up and walked into the main parking area of the busy Indian railway station.

Coastal SW India

With no hotel reservations, he looked around.  He spotted a priest and thought to himself, “He must be an honest guy.”  He went up to him and told him that he was there for an interview and was looking for a place to stay for a few nights. The priest said he had a friend at the university who could give him a room. He was instructed to take a bus and to meet him at a specific stop.  It was very hot, and, after arrival, the young man looked around anxiously for the priest and waited, and was relieved when he finally saw him on his bicycle.  

Lodging at the empty school was arranged (it was summer) and he was told where he could get his suit pressed.  He did what was suggested and he had the interview.  With a “first place” in surgery and “second place” in medicine he was, of course, selected.  He would go to the States for a general internship at Somerset Hospital in Somerville, New Jersey.
.   

John Mathai, M.D.

Dr. John Mathai was that young man with dreams. He finished medical school in lush Kerala on the southwest coast of India in 1962 and decided to go into surgery like his father, a tuberculosis specialist. The hope was to leave India and study and practice in Great Britain where he could learn from the best, and be one of them. He would be a Fellow of the coveted Royal College of Surgeons.  

That would be nice, but he didn’t have the right contacts.  However, he could first get to the U.S. through an Indian foundation and then go to England from there. Thus, the preceding little story.

Yet, arranging the trip to New Jersey was not so simple. India was at war with China and doctors were being denied passports; maybe he would have to stay.  But “someone with money,” noted Dr. Mathai, petitioned the Supreme Court, and it was decided that “it was everyone’s right to get a passport.” He did that and was on his way.

With the help of the then-current “Fly Now; Pay Later” program (this was before credit cards, so we can all “fly now and pay later” ), and a split ticket, he left Bombay.  He flew from there through Cairo to Rome on TWA, and then to New York City on Pan Am.

With the help of his cousin who worked for the Federal Reserve Bank, he had filled out the proper governmental forms so he could take money out of the country for travel. How much did he have with him? Why, the maximum, of course...75 rupees (about fifteen dollars!).  And one flimsy suitcase.

Approaching New York in winter the pilot announced,"Even with snow on the ground we will be landing on schedule."  Dr. Mathai was puzzled at first and didn’t recognize the last word since he was used to the British (and Indian) pronunciation of it as “shedule.”  Was “Skedule” another city? He thought for a moment and then understood.  

More connections…

A sign held up by an airline employee alerted him that the assistant director of the hospital was there to greet him, and he was ready. Walking through the terminal together to get to the car they came upon an escalator.  Having not seen “this animal” before he was baffled as the moving steps appeared and disappeared. Dr.Mathai said, “I watched how these guys got on this thing and I got up my courage and stepped on.”   He was a quick learner.

Mumbai, not N.J.

The director drove through New York City and Dr. Mathai witnessed some of the things he had read about while he was in India, and that was fine. But the most impressive sight by far was the scene when they got to the turnpike.  He was utterly “amazed” by the orderliness of the traffic, with all the cars in a line, and all going in the same direction!  This was not the chaos that he felt in India.
   
After the internship year in Somerville his plan was still to go to England, of course.  So, at a camera shop just off Times Square, he bought a fine Voightlander (he still cherishes it) to preserve his memories of being in America.  Of being in a country where, he noted, “Everything works.”

As it turned out, though, Dr. Mathai didn’t leave after his internship.  There were four years of general surgery at Albert Einstein Hospital in Philadelphia,“York and Tabor,” (where I, the writer, just happened to have been whelped).  He then needed to specialize, and first considered neurosurgery; it was fascinating, but too “depressing.”  But “somehow” he was “attracted to Dryden Morse” a heart surgeon at Hahnemann who had worked with Dr. Charles Bailey (“the father of direct heart surgery” according to Dr. Denton Cooley).   

Pioneer: Dr. Favorolo at Cleveland

Dr. Morse took a special interest in Dr. Mathai and mentored him in the exploding field of open heart surgery in the mid-1960s. The young surgeon considered going to the Cleveland Clinic next, where bypass grafting was being perfected, but was convinced instead to pursue his passion at the university level, and he planned to go to the University of Maryland with the renowned trauma innovator Dr. R Adams Cowley.

Not so fast, buddy boy!  This was the time of the Vietnam Tet Offensive in 1968 and Dr. Mathai was called to serve his new country. He passed his perfunctory physical (”Can you see? Can you walk?”) at the Draft Board in Philadelphia and was ready to go to war, but Dr. Cowley “needed” him in his program.  He pulled strings and used his military contacts and, as a result, Dr. Mathai was able to start his Thoracic Surgery residency.

After completing that grueling program Dr. Cowley steered him to York where he joined the staff in 1970.  He  started work ominously (he felt) on August 6th, “the date of Hiroshima,” and soon realized that he was, in his words, “the only foreigner” on the clinical medical staff, and that “nobody looked like (him).”

Surgical Team in Cleveland

He quickly fit in, however, and was urged by Dr. Jack Gracey (of Cardiology) and Paul Keiser (the CEO of the hospital) to start a full cardiac surgery program.  This had to be approved by the medical staff but they were bitterly divided and needed to be convinced. So Dr. Mathai took a fellowship at the Cleveland Clinic where he met Dr. Joe Hooper.  They became friends and decided to work together to start things in York.  With chutzpah, they brought the Clinic’s Cardiac OR nurse manager, and the capable Physician’s Assistant working with her, to the York Hospital.  The plan was to “duplicate exactly” what was done in Cleveland, and the program here began in 1975.

Two Types of Bypasses

The team was very careful in selecting patients, and the statistics for the first year were excellent.  The service then continued with several other surgeons (including Drs. Peter, Levin, Fried, Haupt., etc.), and Dr. Mathai practiced open heart surgery at York day and night until 2007 when the health system changed.  He then did cardiac procedures for several productive years at  Holy Spirit Hospital in Camp Hill and Pinnacle in Harrisburg with Dr. Brad Levin before unforeseen circumstances forced him in another direction.  After a few months, he started a practice limited to vein surgery, and he enjoys seeing patients even now. 

Dr. Mathai returned to India several times a year for 30 years to work with a Hindu charity, and for the last 20 he went to private hospitals, mostly the Kerala Institute of Medical Sciences.  He has seen many changes over the decades and notes that the facilities in his homeland are now comparable “and sometimes a little better” than hospitals here.

Today, at 79 (that’s correct), Dr. Mathai can look back at his own career and see the history of coronary artery bypass graft surgery.  The first successful CABG was done by Dr. Robert

Goetz (from Frankfurt by way of South Africa) on May 2, 1960, at Albert Einstein in New York.  Unfortunately, his “colleagues were violently against the procedure” and, as a result, he was not permitted to further pursue his exciting technique (the actual artery-to-artery anastomosis itself took...are you ready?...17 seconds!).  

Time passed before Dr. Rene Favorolo (a fiery Argentinian) at the Cleveland Clinic did the first aortocoronary bypass using the patient’s own saphenous vein as the donor vessel in 1967, and by 1970 he and his colleagues had performed more than 1,000 such procedures.  

A Robotic Procedure

Surgeons throughout the United States adopted this technique and have been modifying and perfecting the operation ever since. The number of bypasses performed yearly in the U.S. peaked in 2000 at around 500,000 and has steadily declined since as advances in coronary stenting (by clearing the blocked artery from within rather than going around it)  and preventive therapies (to halt progression or even reverse some of the plaque build-up) have appeared. In fact, coronary artery bypass grafting is now often done robotically, without the need to split the sternum, without the need to open the chest, without the need for the surgeon to touch the patient.  

When It's Over...

Over his nearly 40 years practicing heart surgery, Dr. Mathai has seen and done much as he has been part of and has adapted to changes in medicine.  As stated by the Nobel Laureate cardiologist Dr. Bernard Lown, "No doubt what one does is largely the result of who one is." This is clearly so for the resourceful and resilient Dr. John Mathai who noted that change is woven into the fabric of life, that the trace of the heart’s rhythm changes moment to moment, until one day it doesn’t.

Complex open heart surgery and, specifically, coronary artery bypass, like all significant medical interventions, has been the product of the prodigious talents and sustained efforts of many dedicated individuals. Individuals whose path may not be a straight line, and whose journey may start in a faraway land, on a train platform, in the dark of night.  

We thank them all.