Vivian McAlister

James IV Travelling Fellowship Report

 Vivian McAlister

London, Ontario and Halifax, Nova Scotia

vmcalist@uwo.ca

Destinations

England, Ireland, Germany, Australia

Dates of Travel

August 20, 2000 – September 16, 2000;
April 12, 2001 – May 5, 2001

Table of Contents

Preparation: James  IV, James IV Association of Surgeons, Presentations

XVIII  International Congress of the Transplantation Society, Rome

Oxford and London, Sir Peter Morris

Birmingham, Professor Paul MacMaster

Dublin, Professor Niall O’Higgins

Dublin, Professor John Fitzpatrick

Brisbane, Professors Russell Strong and Jonathan Fawcett

Sydney, Professor Ross Sheil, Dr. Graham Stewart

Berlin, Professor Peter Neuhaus

Appendix:  The renaissance of xenotransfusion

Appendix:  Macrocyclic lactones, tacrolimus and sirolimus, in clinical transplantation

Appendix:  Liposomal drug delivery

Appendix:  Biliary reconstruction, lessons from transplantation

Preparation

            When I received notice that I had been chosen as a Traveling Fellow by the James IV Association of Surgeons, I was confused by the conflicting emotions of pride in the honor that had been bestowed and perplexity as to why I had been chosen.  Throughout my career I have had the good fortune to have been mentored by Professors, who were members of the James IV Association of Surgeons.  When I completed fellowship training and entered the practice of surgery in Canada I learned much from colleagues in the field who preceded me.  I soon discovered that many of them had received James IV Traveling Fellowships.  On being informed of my award I sought the advice of these mentors and colleagues regarding the travelling fellowship.  Professor Bernard Perey of Dalhousie University, Nova Scotia who had been a principle guide during the first decade of my practice, advised me to seek out information regarding the Association and the person after whom it was named.  Alan S. MacDonald, Nova Scotia, who gently guided me as a partner through all the surgical achievements that were likely considered by the selection committee, buoyed the spirits of my family with wonderful tales of his own travelling fellowship in 1988.  When I received the list of members of the Association and travellers who had preceded me, I was concerned that this was a mighty group to follow.  Professor John Duff, London, Ontario, who guided me through post-residency fellowship, gently reassured me that I would not let the Association down.  The honor came at a time when I felt some uncertainty regarding my career.  Dr. Duff suggested that I would find the travels a wonderful opportunity to renew my commitment.  The travels occurred when I had to transfer my practice from Halifax, Nova Scotia to London, Ontario.  One of the factors in this decision was the changing environment which ensued from Health Care Reform in Canada.  Professor Robert Stone, Dalhousie University, Nova Scotia gave me sound advice and insight regarding leadership in surgery and delivery of health care.  He told me how my travels would be a good opportunity to review different models in use throughout the world.

James IV

When I read that James IV wore an iron chain around his waist as a penance for his (unwilling) involvement in the death of his father, from whom he took the Crown of Scotland at the age of 15, I was curious as to what possible involvement he might have had in surgery and how he became an icon for surgeons.  James was interested in surgery and as a monarch he is said to have extracted a tooth, set a broken leg and bled a patient.  While this might seem insufficient today, in his time monarchs had the ‘healing touch’ and I could see how an interest expressed by the monarch in the hitherto lowly occupation of surgery might elevate that profession.  Indeed in 1505 he granted the charter to the Royal College of Surgeons of Edinburgh, a patronage that was soon emulated by his contemporary monarchs in England and France.  At a time when an anatomical dissection was frowned upon he granted the College the right to the corpse of a hanged criminal every year for the study of human anatomy.  However, I began to really see his importance when I discovered that he also granted the guild of barbers and physicians sole right to sell whiskey, then considered a medicine.

The McAlisters descend from Alexander the grandson of Somerled, Lord of the Isles.  Lordship of the Isles was invested in the descendants of his son Donald.  The McAlisters have remained close to the MacDonalds ever since.  There was, therefore, some concern when I read that James took the Lordship of the Isles away from the MacDonalds and annexed their lands. Worse, in an effort to create a united Scotland he favored the stronger clans, the Campbells and the Gordons, to keep order.  He succeeded in making peace with England and through his marriage to the daughter of Henry VII he established the Stewart claim to the throne of England.  Not long before this, repeated wars between England and Scotland had caused his grandfather, James II, to issue an edict in 1457 that “fute-ball and golfe be utterly cryed down and not be used.”  This ban was renewed by James III in 1471.  It was believed that golf prevented archers from obtaining sufficient practice to defend Scotland.  My concerns regarding the political activities of James IV were assuaged when I discovered that in 1502 he repealed this ban.  He issued the repeal only after careful consideration.  It is said that interested nobles took him to Perth and showed him the game of golf.  James played so badly that he was not inclined to meet their request.  However, the next day he arose early and before others were awake, he took clubs and, with the assistance of a local player, he improved his game.  When, on the following day, he beat his hosts, he repealed the law.  On record in the Scottish treasury archives is a large bill for the purchase from a bowmaker of clubs and balls for the King and another for the payment of a considerable wager, 14 shillings, for a match lost by the James IV to the Earl of Bothwell in 1504.  These I took to be good omens for a travelling fellowship in his name.

James IV Association of Surgeons, Inc.

Growing up in Ireland and Canada, I learned how the practice of medicine had been inspired by influences from Britain and from the United States. In both countries we often adopted what we thought was the “mid-Atlantic position”.  I was therefore fascinated to learn that Professor Ian Aird, Sir John Bruce and Dr. J. William Hinton with distinguished surgeons from Britain and the United States formed the James IV Association of Surgeons in October 1957 to foster surgical ties across the Atlantic initially and across the world eventually. The requirement for an exchange of knowledge must have been abundantly clear to the founders of the Association in a time when intercontinental travel meant long sea voyages or expensive short hop air flights.  With the advent of easier travel and more frequent international surgical congresses the impediment to the exchange of knowledge might seem to have been removed.  It became clear to me reading about the Association that the new departure in surgical education was still valid in our time.  The concept of a sabbatical away from one’s responsibilities and the welcome offered to James IV travelers into the heart of the surgical programs they visited gave the travelers an unparalleled opportunity to learn and to grow.  From my own experience being in the audience when travelers visited it was also clear that the distinguished travelers who preceded me were a source of knowledge and a focus for learned discussion.

Presentations

In preparation for my travels I gathered material for four talks.  In my letters to my prospective hosts, I emphasized how I hoped to learn from my visit to their center and that I was happy to present my research on their choice of the following topics for discussion, only if it suited their plans:

The renaissance of xenotransfusion;

Macrocyclic lactones, tacrolimus and sirolimus, in clinical transplantation;

Liposomal drug delivery;

Biliary reconstruction: lessons from liver transplantation.

XVIII  International Congress of the Transplantation Society, Rome

The International Congress is the largest meeting of clinicians and scientists interested in Transplantation.  It was an ideal opportunity to launch my fellowship.  I had the chance to meet many of my hosts in relaxed surroundings.  We used the opportunity to finalize details of the visits to come.  My wife, Christiane, and children, Chioni, Chryssa and Chloe, accompanied me.  We stayed in a small pensione “Hotel S. Anselmo” in the Aventine quarter.  I recommend this hotel as an opportunity to live in the ambiance of two centuries ago with the conveniences of today.  It meant a short bus or taxi ride to the convention center but only a short walk to the Colosseum and other sights of classical Rome.  My paper on the combination of tacrolimus and sirolimus immunosuppression in liver transplantation was presented on Thursday August 31st.   It was well received with a prolonged discussion regarding details of the patients’ care.  A second paper on the renal sparing effect of this combination on recipients of kidney – pancreas grafts was nicely presented by the Fellow in our program, Dr Anastasio Salazar.

During the meeting I had the opportunity to meet and talk with Dr. Suren Sehgal who discovered rapamycin (sirolimus) in 1968 while he worked in Ayerst Laboratories in Montreal.  He provided me with fascinating details regarding the discovery and development of the drug.  As we talked, we were joined by Dr. Allan MacDonald and Sir Roy Calne.  Dr. Sehgal confirmed the legend that his wife stored in her freezer the precious cultures of Streptomyces hygroscopicus that he had isolated from soil samples retrieved by the 1964/5 Canadian Medical Expedition to Easter Island but were then about to be discarded by Ayerst as they moved to join Wyeth in Princeton.  Sir Roy recalled the adventurous path his letter of inquiry regarding rapamycin took before it found Dr. Sehgal.  Sehgal replied with an account of how he retrieved the residuum of a sample of rapamycin 5 years after he sent it to Dr. Finlay of the University of New Brunswick, who described the structure of rapamycin.  Sehgal used this old sample to prove to skeptical chemists in Wyeth-Ayerst that his compound was stable.

Rome is a wonderful city in which to spend enough time to reflect.  The trips to and from the Convention center allowed me to become very familiar with life in Rome.  My family and I took many trips to visit the monuments and museums including the Vatican.  Two highlights were an open-air concert of classical music at the Terme di Caracalla, performed by the Santa Cecilia Orchestera and the congress gala dinner that was held in the center of Piazza Navona, which had been closed to the public for the occasion.

University of Oxford, Sir Peter Morris.

I arrived in Oxford on Sunday evening after a delightful ride through the English summer countryside on the bus from Heathrow Airport.  Sir Peter had kindly asked me to stay in Balliol College.  When I arrived at the forbidding wooden gates, I saw no obvious entry.  I walked around Balliol to arrive at the wooden gates again.  After a few minutes I was relieved when a small door within the door swung open and some residents stepped out.  This door had been open all the time; I stepped through and found the porter who was charming in his welcome as he took me through the cloistered campus, up a winding flight of stairs to my room.  The next morning, after a magical breakfast in Balliol, I met with Peter Friend, newly arrived from Cambridge as Professor of Transplantation.

Professor Friend took me through the Transplant Unit in the Churchill Hospital.  The unit would be more properly called a Transplant Hospital as it sat in its own building in the parkland campus of the Churchill.  This gave the staff and patients a unity of purpose.  The principal handicap appeared to be a limit on expansion, especially if the program hoped to develop liver transplantation.  Sir Peter has concentrated on kidney and pancreas transplantation.  Islet transplantation, tissue typing and transplantation immunology are research strengths of the program.  A desire to move into transplantation of other abdominal organs was apparent and would likely have to be placed in the John Radcliffe Hospital.  Professor Derek Gray, Professor of Experimental Surgery, took me through the office and medical record section that is quite large in this independent arrangement.  A major problem with which he wrestled was the incompatibility of old hand written records with modern electronic alternatives.  In addition, programs with a history as long as Oxford’s has a storage problem that grows with time.  Professor Gray showed me a solution that he was testing using SCANPLAN, an electronic process developed for building plans, which he hoped would scan old records.  The problem and the solution seemed troublesome and while I admired Professor Gray’s determination, I was glad to leave the archive and retire to his office to discuss research.

Professor Gray, who is an expert in islet transplantation research, was an eloquent tutor.  We discussed xenogeneic sources of pancreatic islets, immuno-isolation and animal models.  Our conversation developed into a tutorial on the role of MHC presentation and suppression of T-cells which I enjoyed thoroughly, understood partially and noted completely.

Later in the afternoon I gave a seminar to the Transplant Group.  At the appointed hour, staff and students appeared out of rooms, laboratories and cubbyholes scattered throughout the building.  Professor Friend had asked me to talk on the topic of “Reducing the toxicity of immunosuppressive drug therapy”.  I tried to abstract from our experience with low dose tacrolimus and sirolimus combination therapy the principles of non-toxic effective immunosuppression.  There was a full house and a lively discussion from which I learned a lot.  At the end, several of these bright researchers including Sara Marshall and Peter Kelliher asked me to continue the discussion in the Angel and Child on St Giles.  Our ideas improved as the beer came and for a brief moment I thought I got a handle on antigen presentation and suppression of immune response.

During my visit, I spent hours in the laboratories of a large number of fellows supervised by Professor Friend including: Baljit Singh, Christian Motett, Inigo, Dicken Koo and David Hughes.  I reviewed work on preservation injury, extracorporeal liver perfusion, and renal fine needle biopsy documentation of changes with reperfusion injury.  Sara Marshall showed me her work on cytokine gene polymorhism, the role of minor histo-incompatibility and on tetramer-MHC recombinations.  I spent an afternoon in the laboratory of Professor Kathryn Wood, Professor of Immunology, who was a charming host.  She has a worldwide reputation for research and teaching of transplantation immunology.  Her laboratory had the hum of an efficient factory floor.  She supervised students and fellows from all over the world.  I saw work on animal models to test co-stimulation pathways of T-cells; we discussed the importance of suppressor T-cells and considered the possibilities for gene therapy interventions.  Dr. Mike Bunce kindly allowed me hang around his tissue-typing laboratory where I had the opportunity to learn about their progress in genotyping.  Description of a transplant candidate’s HLA (human leukocyte antigen) that used to be expressed as 6 antigens now occupies a small telephone directory.  Dr. Bunce showed me computer programs he is developing to analyze these genotypes.  In addition to transplantation, he has applied these techniques to diseases such inflammatory bowel disease and psoriasis.

My time in Oxford was busy and fulfilling.  Time off from the hospitals I spent in the Bodleian Library where I had the chance to further my own research into the history of xenotransfusion.  It was wonderful be in surroundings so rich in history, to have purpose in being there and to be able, from time to time, to look around and reflect.  During my visit Sir Peter was increasing his role in the Royal College of Surgeons, where I would later visit with him.

London, Royal College of Surgeons of England

In London, I stayed at the Nuffield building of the Royal College of Surgeons of England.  I visited with Dr. Barnaby Reeves, Director of the Clinical Effectiveness Unit.  National audit has gained considerable prominence in Britain.  The UK Liver Transplantation Audit is led by Professor Paul McMaster, who would be my host in Birmingham.  We were able to compare notes as I explained the function of the Canadian Organ Replacement Registry of which I am the chairman.  We developed ideas for collaboration.  Mr. Martyn Coomer, Development officer of the College, took me on a tour that included a visit to the new surgical teaching laboratories.

One evening I attended the College lecture where Mr. Richard Neave, a medical artist at the University of Manchester and a leading pioneer in the development of facial reconstruction techniques, described his anthropological detective work with his partner, John Prag who is Keeper of Archaeology at the Manchester Museum.  Together they have developed techniques for the forensic reconstruction of the faces of victims of crime from buried remains.  They applied these techniques to reconstruct skull fragments that confirmed a burial site in Vergina as the grave of Philip II, father of Alexander, complete with a model likeness of Philip.

At a reception in the Hunter Museum, Sir Peter introduced me to Sir Barry Jackson, President of the College.  We had a wonderful conversation about the role of the Royal College of Surgeons in the daily life of the surgeon, comparing the Canadian and English colleges.  Although great distances and small populations are impediments to the Royal College of Physicians and Surgeons of Canada emulating the programs of our English counterparts, I learned how the attitude of the English college would find fertile ground if applied in Canada.  Sir Barry intended to visit Canada for our annual meeting and we hoped to have the opportunity to continue discussions there.

Finally, the central location of the College allowed me visit its library, the British library and the library of the Royal Society.  At the Royal Society, I explained to Ms. Christine Woollett, Librarian, that I was looking for an article sent to Philosophical Transactions by Jean Baptiste Denis in 1667, in which he described the first blood transfusion in humans.  Henry Oldenburg, editor of Transactions, was confined to the Tower at the time and the printer published the article.  On his release, Oldenburg withdrew and destroyed the article in an effort to maintain English priority in transfusion research.  Although she thought it all a bit fantastic, Ms. Woollett patiently helped me until we located a copy of the lost article in the society archives.  Kindly she arranged for me to receive a microfilm to study.

University of Birmingham, Professor Paul McMaster.

Professor Paul McMaster runs one of the busiest liver surgery and transplantation units in Europe.  Accommodation was arranged for me in Lucas House.  This Victorian mansion in the heart of Edgebaston was set in gardens stretching out to the fields in the surrounding countryside.  I had wonderful weather and over several walks I imagined the good fortune of wealthy Victorian families.  On occasion I walked to the Queen Elizabeth Hospital, but the fast traffic on the small roads made it more exciting and less pleasant than the back yard strolls.  On the first morning, Mr. David Mayer kindly picked me up.  We went to the Children’s hospital and joined Professor Deirdre Kelly and Dr Jean de Ville de Goyet for a busy round of the hepatology and transplant patients followed by an x-ray conference.  I was impressed with the efficiency of diagnosis and the expertise of treatment regardless of the challenge.  I felt the constant urge to take notes.  I was not surprised to learn that Professor Kelly had just edited a newly published textbook entitled “Paediatric Gastroenterology and Hepatology”.  Dr. de Ville de Goyet has become an expert in pediatric liver and intestinal transplantation.  With Mr. Mayer, I was able to discuss in detail the Birmingham method for back table splitting of the liver.

At the Queen Elizabeth Hospital, Professor McMaster kindly spent a long time explaining to me the inner mechanisms of an NHS trust and the newer systems of health care delivery evolving in Britain.  The Birmingham unit, like that in Oxford, is a hospital within a hospital with its own clinic, operating rooms, intensive care and wards.  Professor McMaster discussed to advantages and limitations of such an approach.  A movement to centralize services such as intensive care was underway.  Because of the limitations of unit resources, this movement was not being vigorously opposed.  Professor McMaster is an inspiring leader who is greatly admired by his team for his kindness and wisdom however challenging the situation.

Mr. Darius Mirza kindly became my guide through the maze like corridors of the hospital.  We visited the wards and the operating room where I observed him expertly perform a liver transplantation.  The large operating room easily accommodated constantly but quietly moving staff who recorded each stage of the operation directly on the computer.  In the adjacent room Mr. John Buckels efficiently completed two liver resections.

I visited the Liver Laboratories of Mr. Daniel Candinas.  We discussed the impact of tissue ischemia and the molecular responses.  He gathered the trainees and staff to listen to three presentations that were made for my visit.  Mr. Mirza presented an account of the Birmingham experience of split livers.  Techniques in children included use of arterial conduits and delayed abdominal closure with good results.  Mr. Simon Bramhall described trials of adjuvant and neo-adjuvant chemo-radiotherapy in patients undergoing surgery for pancreatic cancer using external beam radiotherapy, gemcitabine and cisplatin in three different combinations.  Mr. Val Usatoff presented interesting data regarding the technique and outcome of radio-frequency ablation of liver tumors.  These talks generated lively discussion and we went well over time.

I was entertained royally in Birmingham.  Professor McMaster hosted a wonderful dinner for the team in my honor, in the Bay Street Restaurant where we had good wine, nouvelle cuisine and lively conversation.  Professor Deirdre Kelly invited me to dinner at her lovely home in Edgebaston.  We celebrated the publication of her book and the recent knighthood conferred on her husband Ian Byatt for his contributions to the civil service.  Ian was very insightful regarding the functions of management.  I was particularly struck by his solution to the logarithmic growth of committees.  He required all attendees to provide costs of their preparation for, travel to, accommodation at, and action after central committee meetings.  When it was discovered that some of these meetings were costing thousands of pounds, the rationale for holding each meeting was appropriately questioned.  I also had time to tour the renovated canal district and the (new) Birmingham concert hall.

University College Dublin, St. Vincent’s University Hospital, Professor Niall O’Higgins.

                        My visit to Dublin was a homecoming of great significance to me.  I left Ireland in 1981 having completed early training to prepare me for family practice.  I worked as a general practitioner in Northern Saskatchewan and on the Prairie for four years before returning to training as a general surgeon.  During this time I had the opportunity to work with Professor Niall O’Higgins who introduced me to liver surgery.  This resulted in my transfer to the University of Western Ontario where I trained with Dr. William Wall and Professor John Duff.  I feel a particular debt of gratitude for my good fortunate to these three individuals.

After introductions at St. Vincent’s University Hospital I went with the professorial surgical team for inpatient rounds.  These were attended by surgeons, James Murphy, Enda McDermott and Arnold Hill.  This team looks after a very large patient load with a variety of general surgical problems.  The team specializes in surgical oncology and endocrine surgery.  Many medical students attended rounds.  They were put through their paces and performed very well.  Later I had an opportunity to meet with Mr. Justin Geoghgan, who with Professor Oscar Trainer and Mr. Gerry McEntee looks after the liver transplantation program.  The program is very similar in size and function to the program in Halifax.  We were able to trade very useful ideas and I learned several new techniques and methods for management from Justin who had recently completed his training in Europe.  I spent an interesting session with Dr. M.J. Duffy who is developing isotope markers of breast cancer.

I was shown around the new education and research center by Dr. Cliona O’Farrelly.  Dr. O’Farrelly is an immunologist with a special interest in liver physiology and liver disease.  She has used her collaboration with the transplant team to identify some populations of NK cells and T cells which have distinct cytotoxic activity and the potential for disease modification.  In addition, this group has identified lymphoid and myeloid markers differentiating hematopoietic stem cells in normal and tumor bearing human livers.  Her laboratory has an air of infectious enthusiasm for research and she almost convinced me to stay there for the rest of my visit.  One afternoon I had a pleasant walk from St. Vincent’s University to the campus of University College, Dublin.  There in the parkland setting, I visited Dr. Peter Smyth at the Woodview Research Centre.  Peter had taught me techniques of histochemistry during my time in Dublin and it was a particular thrill to review the interval since we last met over a nice lunch.  One of the academic interests that we discussed was the relationship between the thyroid and the breast.

Dr. Smith described to me several studies he has performed both in the lab and in populations regarding the relationship of thyroid function with breast disease.  He described an intresting hypothesis regarding a common mechanism of ion transport under hormone control, which may link the two glands.  On Wednesday morning Professor O’Higgins asked me to present my talk on biliary reconstruction to Surgery Grand Rounds.  These rounds are interesting in that they are attended by surgeons of all specialties and the cases presented before my talk all had interesting teaching points that were cleverly discussed by the attendees.  Professor O’Higgins generously hosted a dinner in my honor at the Commons Restaurant in Newman House on St. Stephen’s Green.  The conversation was hilarious and laughter almost prevented me from savoring the fine food, which was served in this lovely restaurant situated in an old georgian mansion built in the center of Dublin.

University College Dublin, Mater Misericordiae Hospital, Professor John M. Fitzpatrick

On the north side of Dublin, another large teaching hospital, “The Mater”, is associated with University College, Dublin.  Professor John Fitzpatrick is Chairman of the Department of Surgery and he organized for me a wonderful visit, which included operating room experience, clinical presentations and a dedicated research afternoon.  Mr. Ronan O’Connell specializes in colorectal surgery.  He brought me to the operating room for his list where he demonstrated expertly the mesorectal excision and lower anterior resection of the rectum.  The easy relationship between nurses and surgeons in the operating room was a pleasure to observe.  I then went on a ward round with Mr. O’Connell and his team, where we reviewed a wide range of surgical problems.  I had an opportunity to sit down and discuss liver surgery with Mr. Gerry McEntee who is a hepatobiliary and liver transplant surgeon.  At surgery rounds, Professor Fitzpatrick asked me to present my talk on biliary reconstruction.  Mr. McEntee had many insightful and helpful comments to make regarding the experience I presented.  In the afternoon Professor Fitzpatrick organized the trainees to present five clinical cases that we discussed.  These all had interesting aspects that gave the physician pause and required careful strategy to achieve a good result.  Mr. McEntee’s team described a patient who developed portal hypertension after trauma due to the development of a fistula from the hepatic arterial system into the portal vein.  Various strategies to deal with this until resection were well described and presented.

Dr. Bill Watson is a research scientist in Professor Fitzpatrick’s department.  With the professor he supervises a large body of trainees all of whom are undertaking cutting edge research.  Professor Fitzpatrick organized a research session during which we listened to seven presentations of different research projects. A particular interest of the group is caspase expression and the control of prostate cancer.  Dr. Watson presented on neutrophil apoptosis in the resolution of inflammation, while Ms. Belinda Doyle described inhibitors of apoptosis expressed during differentiation.  Dr. Kevin McEleny used different cell lines of prostate cancer to apply this research regarding inhibitors of apoptosis.  Ms. Ophelia Blake presented research undertaken with Professor Fitzpatrick regarding the presence of prostate specific antigen in the urine looking at different isoforms and means to concentrate the antigen in the hope of correlating this with early disease detection and prognostication.  Ms. Suzanne Shine was undertaking basic science studies regarding the control of PSA production, which was initially thought but found not to be under the control of insulin like growth factor.  Mr. Ronan O’Connell supervised the research of Dr. David Beddy who in collaboration with Dr. Watson looked at cytokine expression in Crohn’s disease, in particular the ability of TNF-alpha and ICAM-1 to increase fibroblast proliferation in patients with inflammatory bowel disease.  The presentations were completed by Ms. Deidre O’Hanlon, who described the advantages of a posterior fourchette incision in anal sphincter repair.  This team has become well known for the repair of obstetric induced trauma to the anal sphincter.  Professor Fitzpatrick kindly asked me to present our research regarding liposomal encapsulation of immunosuppressive agents and the research group provided me with helpful tips for the continuation of that research.

I spent one day with Mr. David Hickey in the Beaumont Hospital situated several miles north of the Mater Hospital.  This is the site of the kidney transplant program and Mr. Hickey has been a leader in the development of pancreas transplantation in Ireland.  I had the opportunity to go on a ward round of all the patients with Mr. Hickey and the entire team.  We spent some time in the transplant coordinator’s office where I was able to develop an understanding regarding organ sharing in Britain and Europe.  I was fascinated to learn that living donor kidney transplantation is not often performed in Ireland because there is an adequate supply of cadaver kidneys so much so that the prevalence of dialysis is actually in decline.  Mr. Hickey considered the very high rate of organ donation in Ireland to be related to a spirit of volunteerism and a high degree of public education.  I gave a talk on means to reduce calcineurin inhibitor toxicity describing elements of our combination chemotherapy protocol and a few words on liposomal encapsulation of tacrolimus.

Finally we reviewed a pancreas recipient who had unfortunately developed necrosis of the duodenum because of the lack of communication between the gastroduodenal artery and the superior mesenteric artery in the graft.  Mr. Hickey decided to resect the head of the pancreas and the duodenum but to retain the graft and invaginate the neck into the bladder.  On last report during my visit this patient remained well and off insulin.  During the visit Professor Fitzpatrick generously hosted a wonderful meal in one of Dublin’s many new restaurants.  We enjoyed excellent wine and modern cuisine in surroundings I never thought possible when I left Ireland.

University of Queensland, Brisbane, Princess Alexandra Hospital, Professor Jonathan Fawcett

My visit to Australia was initially hosted by Professors Russell Strong and Ross Sheil.  For a variety of uncontrollable reasons both professors were out of Australia during my visit.  However, they kindly passed responsibility for my care to their colleagues and I am happy to report that I had a marvelous time.  Professor Strong agreed to undertake a sabbatical in Oxford and left the week before I arrived.  I was hosted in Brisbane by Professor Jonathan Fawcett, who had arrived in Brisbane from Oxford some years before.   Professor Fawcett has a strong basic science research interest and a clinical focus in hepatobiliary and transplantation surgery.  During my visit I had the good fortune to operate with both Dr. Stephen Lynch and Professor Fawcett.  I observed liver resections and liver transplantations as well as colon surgery.  The new Princess Alexandra Hospital had just opened and the operating rooms were spacious.  Electronic record keeping of operating room activities was being introduced.  It seemed to run fairly smoothly although more duties were being transferred to the surgeon.  The new hospital has a spectacular look but in my time there I never figured out directions I should take to get from one place to another and I was constantly seeking help.

I spent time with Drs. Tony Griffin and Daryl Wall, general surgeon who complete the transplant team.  We had an opportunity to discuss partial liver transplantation for which this team has world renown.  Dr. Stephen Lynch is Director of the Queensland liver transplant service and as such he is responsible for resource allocation.  I met with Dr. David Nickel, a urologist in charge of kidney transplantation. Dr. Nickel undertook some of his fellowship training in Halifax, Nova Scotia and we had the opportunity to reminisce.  I noted how both liver and kidney programs were integrated into routine hospital care and training programs so that the registrar and house officer trainees were part of the day-to-day activities of the team.  I spent an afternoon with Dr. Paul Taylor, a clinical chemist, who has developed a worldwide reputation in therapeutic drug monitoring.  Both of us were working on the interaction of sirolimus with other drugs and we were able to compare data to good effect.  The entire transplant group was invited to a fine dinner after which I was asked to speak on “reducing the toxicity of modern immunosuppression”.  Following this, Dr. Lynch and Professor Fawcett took to me to see and experience the outdoor nightlife of downtown Brisbane, which I much enjoyed.

University of Sydney, Royal Prince Alfred Hospital, Professor Ross Sheil, Dr. Graham Stewart.

Before going to Sydney I had the opportunity to take my family up to the Barrier Reef, then down by the coast to Sydney with a trek inland to the rainforest for a very pleasant break.  Professor Sheil delegated Dr. Graham Stewart to coordinate as he himself was called away.  In addition, I had the good fortune to spend time with Professor James May who gave me a history of the James IV Association of Surgeons in Australia and an opportunity to discuss his research in vascular surgery.  Professor May had kindly come to hear my talk on “Combination Chemotherapy in Transplantation”, which I gave in the Scot Skirving lecture theatre.  He had insightful and helpful comments on our work.  During my time in the Department of Surgery, I went on several ward rounds with Dr. Debbie Verran, a transplant surgeon who completed her training in London, Ontario, and Dr. Simone Strasser, hepatologist.  One patient I will remember had appeared close to death with fulminant liver failure when an offer of a donor liver became available.  Dr. Verran recognized a slight improvement in liver function and felt that the patient’s cerebral edema would make liver transplantation hazardous.  I saw the patient one week later where her recovery seemed certain.  It was a courageous but correct clinical decision.  Dr. Stewart gathered the research group including Alexander Koshman, Li Wei Shi, Taras Kysuk, Doug Mears and Alex Bishop.  I presented my talk on Xenotransfusion, which was discussed by the group following which we spent the afternoon reviewing research being undertaken in the department.

During my visit to Sydney I came to realize how relaxed but stylish life is in Australia.  I was able to spend time with relations who live in Sydney.  With my family, I took the opportunity to make a trip to Ayers Rock where we guided by members of the local aboriginal families.

University of Berlin, Professor Peter Neuhaus

I had come to know the work of Professor Neuhaus through the literature and international surgical meetings.  I had met Dr. Jan Langrehr through collaboration in clinical trials.  I was very eager to visit their center because of their pioneering work in liver surgery and liver transplantation.  In preparation for the visit I researched the visits made over 100 years ago by William Osler to Virchow.  Germany was at the time the leading country in medicine where many surgical operations were invented 50 years before their general application.  I was disappointed then when I had to cancel the visit with the first leg of my fellowship because of a conflict of dates.  Again, I was unable to link it to the visit to Australia.  I eventually visited Berlin in June of 2002 and I include the report here because I believe it would be a very rewarding site for other travelers.  During my visit I was able to retrace Osler’s steps many of which were taken through what became East Berlin.

Professor Neuhaus and Dr. Langrehr gave me a thorough welcome to their program.  Although the daily language is German, many people spoke English and a great effort was made so that I would understand.  The day started with a gathering of all the staff and trainees.  New admissions were discussed, x-rays were presented and operations for the day were allocated.  This was done in the name of the professor by a duty surgeon.  We then went on a ward round.  All staff wore white hospital tunics under their laboratory coats.  I changed and joined them.  When we entered the high intensity care area we donned gowns and masks.  I was uncertain if these measures were taken for infection control or for the sense of discipline they imparted.  More importantly, the care I observed was of a very high standard.

I had the opportunity to assist in several operations.  Dr. Andrea Mueller performed one of the slickest liver transplantations I have observed.  She demonstrated a new technique of retrograde perfusion where the venous clamps were removed immediately after completion of the caval anastomoses and blood was allowed to slowly return to the organ expelling the perfusate while the portal anastomosis was constructed.  Biliary reconstruction was by a side-to-side anastomosis using continuous suture over a T-tube.  I assisted Professor Neuhaus while he resected a hilar cholangiocarcinoma using the technique he has described involving trisegmentectomy and resection of the portal vein bifurcation.  Professor Neuhaus was generous with his teaching.  He showed me how he placed the T-tube using a blunt needle he has designed.  He gave me several of these needles and a large self-retaining retractor he has designed for use in multi-organ donors.  The highlight of my time in the research unit was the demonstration of the hepatic bioreactor by Dr. Gerlach, its inventor.  This module has recreated the conditions required for hepatocyte growth in a device that can be used for extracorporeal perfusion.

With the unification of Berlin a huge building program is underway.  The modern buildings, with the preserved historic buildings and magnificent museums, make Berlin an architectural mecca.  My wife Christiane, who is studying architecture, enjoyed this place and took me to see many of these new structures, which she explained to me.  Professor Neuhaus took Dr. Langrehr, myself and our families to a sleek new restaurant in one of these new buildings at Potsdamer Platz for a most enjoyable dinner.  In the way it combines the old and the new, I could see how Berlin has become the center for architectural study.  I believe the same can be said for its surgical program.

Summary Statement

The James IV Travelling Fellowship has been a life changing opportunity for me.  I am grateful to the members of the James IV Association of Surgeons for this opportunity.  I wish to thank my hosts, their faculty and their office assistants for making it such a special time for me and my family.

Appendix:  The renaissance of xenotransfusion

Interest in xenotransplantation and the prospects it offers to not only meet the unsatisfied demand for organs in transplantation but also to extend therapies beyond the current limits reached a peak around the time of my travels.  Hyperacute rejection which prevents the use of organs from animals in human transplantation is an analogous to the transfusion reaction with incompatible red blood cells.  Investigation of the human reaction to the animal organs is difficult because small animal models are not generally available and large animal models involve primates.  I have been using red cell cross match as a means to overcome this.  In the process of grant writing I realized that allotransfusion had been the source of considerable infections in the past and that efforts to avoid this in the future would be expensive.  In addition, certain parts of the world have such high rates of infection with HIV and hepatitis viruses that a source for blood transfusion would not be available.  I therefore changed the orientation of my research from xenotransplantation to xenotransfusion.  In collaboration with Leslie MacLaren of the Agricultural College in Truro, Nova Scotia, I investigated herds of pigs and cows with respect to the antigenecity and the physiological compatibility of their red cells with humans.  We found that considerable variation existed between different pigs but that even the lowest expressers of the foreign antigen, a-gal, were prohibitively incompatible with human serum.  a-gal is the prominent foreign antigen and we used specific and nonspecific methods to neutralize this antigen with the result that compatibility with human serum improved considerably.  We then investigated herds of cows and found that a-gal expression is much lower in these animals and that certain bovine erythrocytes are compatible with human serum on first exposure.  Flow cytometry showed that although complement was not fixed, human antibodies were still bound by the bovine red cells.  This suggested that the cow red cells would sensitize the recipient and eventually cause an immune reaction.  In seeking a basis for this unusual research we looked to history and discovered that transfusion itself had begun with the use of animal donors in the 17th century.  Interesting aspects of this history included suppression of the original report by Jean Baptiste Denis of Paris by Henry Oldenburg of the Royal Society.  I hoped to investigate this aspect of the history during my visit to London.  Further historical review showed that xenotransfusion was used until the 19th Century when transfusion reactions and the clinical effect of hemolysis were observed.  Landsteiner at the turn of the 20th Century used human reactions to different animal red cells as means of eventually describing the different human blood groups.  He actually observed the difference between New World and Old World monkeys, which is based on the presence of a gal, but failed to define this, possibly because it was not in his focus of interest.  More recently porcine Factor VIII has been used in the treatment of hemophilia in patients who have developed inhibitors to human Factor VIII.  It is interesting to note that no evidence of disease transmission has occurred with porcine Factor VIII at a time when the human equivalent was associated with the large scale transmission of HIV and hepatitis C virus.

Appendix:  Macrocyclic lactones, tacrolimus and sirolimus, in clinical transplantation

Rapamycin (sirolimus) was discovered in Montreal in the late 1960’s from a soil sample retrieved from Eastern Island during the Canadian medical expedition to that place.  Initial enthusiasm for the compound as an antifungal was dampened by the discovery that it had anti-neoplastic and anti-lymphocytic properties.  Consequently drug development was halted.  In the late 1980’s tacrolimus was found to be 50 times more potent than cyclosporine in lymphocyte inhibition.  During its development for transplantation, Sir Roy Calne noticed the striking similarity in structure between tacrolimus and sirolimus.  It was soon found that sirolimus did not share with tacrolimus and cyclosporine the nephrotoxic effects that limit those drugs.  Tacrolimus and sirolimus were found to competitively inhibit each other at high concentrations and this lead to the search and discovery of intracellular binding proteins that were named immunophylins.  Both tacrolimus and sirolimus bind FKBP 12.  For this reason it was thought that the two drugs could not be used together in clinical transplantation.  For a variety of reasons including predictable pharmacokinetics we thought the combination of tacrolimus and sirolimus would be useful at lower doses.  Synergy between these two drugs had been shown in the animal models.  With Alan MacDonald, I commenced a program of investigation of the combination therapy in liver, kidney and pancreas transplantations.  Our data showed that tacrolimus and sirolimus could be administered simultaneously, that they had predictable pharmacokinetics, that they enhance the effect of each other so that sub therapeutic doses could be used with minimization of side effects.

Appendix:  Liposomal drug delivery

Liposomal drug delivery of amphotericin is used clinically to minimize the severe nephrotoxicity associated with that drug.  Commonly used immunosuppressants, tacrolimus and cyclosporine, are also nephrotoxic.  With the help of the late Professor Michael Mezei of Halifax, I commenced a program of investigation regarding liposomal drug delivery of these immunosuppressants.  We found that the smaller molecule, tacrolimus which was 50 times more potent than cyclosporine, was more suitable for liposomal encapsulation.  We tested a variety of lipids and optimized our manufacturing strategy.  We were careful to use processes that could be scaled up for commercial application.  Initial animal tests showed that liposomal encapsulation indeed reduced the nephrotoxicity but did not prevent the immunosuppressive effect of tacrolimus.  We manufactured small liposomes, which we hoped would cross the intestinal barrier allowing for oral administration.  We developed a freeze-dried formulation that would form these liposomes in the stomach with a drink of water.  Animal tests showed that the liposomes passed the intestinal barrier intact and that nephrotoxicity was again reduced without compromise to the immunosuppressant activity.  We developed a dermatological preparation, which showed promise in preventing skin graft rejection and in the ablation of immune mediated skin disorders.  Finally, we combined tacrolimus and sirolimus in single liposomes to exploit the synergistic effect of these two drugs.

Appendix:  Biliary reconstruction, lessons from transplantation

In this talk I hoped to present to a general surgery audience my personal experience with several hepatobiliary procedures.  I drew a thread through the presentation to show how techniques developed for transplantation could be exploited by the hepatobiliary surgeon.  I first presented our series from Halifax of bile duct reconstruction after transplantation using Peter Neuhaus’ technique of side-to-side anastomosis.  Our variation of this was to perform the anastomosis without the use of T-tubes.  This resulted in a decreased requirement for imaging after transplantation and a very low re-operation rate.  I then described a series of patients who underwent resection of hilar tumors with a variety of biliary reconstructions.  I gathered a series of 30 patients who had suffered bile duct injury from laparoscopic cholecystectomy.  In presenting this series I tried to demonstrate how a large number of these injuries occurred by misidentification of Calot’s triangle with the left side of the common bile duct.  I also showed x-rays of two patients who had injuries low entering right posterior hepatic ducts.  Diagnosis and management of bile leaks and jaundice after laparoscopic cholecystectomy, and definitive biliary repairs were discussed.