John Alexander Society News

John Alexander Society NewsW I N T E R 2 0 0 5

A Note from Mark B. Orringer, M.D.Section Head of Thoracic Surgery

and Thoracic Surgery Residency Program DirectorIn my twenty years as Director of the University of Michigan ThoracicSurgery Residency Program, I do not recall a period such as this wherethere has been such tremendous pressure to change our historictraditional system for cardiothoracic residency education. These aretimes of change! The 80-hour work week mandate is compressing thetime previously available to our residents for operating and honingclinical skills. There is a need to teach Thoracic Surgery better andmore efficiently than we have in the past. The reduction in clinicalexposure (both in General and Thoracic Surgery) our residents nowhave has stymied the efforts of some to reduce the overall length ofThoracic Surgery residency training. Uncertainties about the “cardiacsurgery job market” have created a “market place force” for thoseprograms which have the clinical volume to “track” residents in GeneralThoracic Surgery – i.e., provide a more flexible residency experiencewhich allows them to obtain their minimum index case requirements incardiac surgery while devoting the majority of their Thoracic Surgeryresidency (12-13 months) to what they intend to do professionally –General Thoracic Surgery. This year, the University of MichiganThoracic Surgery Residency will “track” one of its three new residentsinto General Thoracic Surgery, the other two residents focusing uponeither Adult or Pediatric Cardiac Surgery.

There has been concern nation-wide that the contracted numberof available cardiac surgery jobs will sharply reduce the numberof Thoracic Surgery resident applicants. The “upper-echelon” ofThoracic Surgery residency programs, which includes theUniversity of Michigan, will likely be among the last to feel thedecline in resident applicants. For the last ten years of theNational Thoracic Surgery Residency Match, 75-80 candidateshave applied annually for our three residency positions, 20-30have been invited to interview, and we have never gone belownumber 10 on our rank order list to fill our positions, our residentstypically coming from our top six candidates. The caliber of ourresidents remains superb. The University of Michigan ThoracicSurgery Residency Program remains among the strongest in thecountry.

The Section of General Thoracic Surgery has also experiencedquite a bit of change. Two of our faculty, both former John AlexanderSociety residents, Drs. John Yee and Mark Iannettoni, were recruitedaway to head their own programs at the University of British Columbiain Vancouver and the University of Iowa, respectively. Dr. AndrewChang (University of Michigan Thoracic Surgery resident – 2000-2002) joined the faculty in 2004. Dr. Allan Pickens (University ofMichigan Thoracic Surgery resident – 2002-2004) has just returned to

join the faculty after completing a six month fellowship in California inmini-invasive pulmonary resections. Dr. Christine Lau, who iscompleting her Thoracic Surgery training with Dr. Alec Patterson in St.Louis, will be joining the faculty in July – the first University ofMichigan female Thoracic Surgery faculty – to head our LungTransplant program. Our faculty of four general thoracic surgeonsshould provide an extraordinarily broad educational experience for ourresidents. David Beer, Ph.D., Director of our Thoracic Surgery TumorBiology Program, has made extraordinary contributions to ourknowledge of thoracic oncogenesis.

The University of Michigan Thoracic Surgery Residency ingeneral, and the General Thoracic Surgery Program in particular,continue to flourish in Ann Arbor!

A Note from Edward L. Bove, M.D.Section Head of Cardiac Surgery

As I write this newsletter on a cold and sunny January day, thoughts ofspring begin to emerge. The upcoming year promises to bring anumber of exciting events for our Section. Construction continues tobe on schedule for the Cardiovascular Center building on the old mainhospital site with the official opening due in late 2006. This remarkableproject will allow us to consolidate all adult cardiovascular care underone roof with dedicated new cardiac OR’s and ICU beds. The kick-off

for the new children’s hospital replacement project has alsoofficially begun and planning teams are already active.

The hospital will be located on the main medicalcampus, behind the current Mott Hospital andTaubman parking lot. The congenital heart centerwill benefit greatly from this project by additionalspace in a modern, child and family-oriented,facility. Recently, the Section of Cardiac Surgery

announced the establishment of The Center forCirculatory Support. Generously supported by a gift

from Terumo Cardiovascular Systems, the Center willserve to advance the medical center’s leadership role in developing thefield of circulatory support from ECMO to the total artificial heart.

In May, we will host a John Alexander Society reunion in AnnArbor. A scientific session will be held with a number of exciting andnovel presentations planned. This event will also allow us to officiallyacknowledge the remarkable career of Marvin Kirsh, who will retire atthe end of the academic year. This unique cardiac surgeon, scientist,and educator has influenced so many of us during our residency yearsthat I’m sure you will all want to come back to honor Marvin. TheHelen and Marvin Kirsh Professorship will be inaugurated at thisreunion and I am honored to be its first recipient.

I hope to see you all this May in Ann Arbor.

John Alexander, the 17th President of theAmerican Association for Thoracic Surgery,was born in Philadelphia on February 24,1891. He received his BS, MA and MDdegrees from the University of Pennsylvaniawhere he was an outstanding student athlete,achieving multiple academic honors andserving as Captain of the Varsity Crew.Following an internship at the PennsylvaniaHospital, he enlisted with an American unit inthe French Army transferring to the UnitedStates Army Medical Corps when the UnitedStates entered World War I. At the end of thewar, he studied at the University of Lyon withLeon Berard where he first becameacquainted with the surgical treatment oftuberculosis, a disease which consumed muchof his career, both as a patient, and aninnovator and advocate of surgicaltreatment. During his lifetime, Dr.Alexander was hospitalized multipletimes for treatment of tuberculosisand its complications.

Following his return to theUnited States, he served a shortperiod at the University ofPennsylvania and in 1920 joined thestaff of the Department of Surgery atthe University of Michigan. Shortlythereafter, complications oftuberculosis required a protractedperiod at Saranac Lake. Despite theneed for a plaster body cast and thesupport of a Bradford frame, he persevered inwriting the first English text on the surgicaltreatment of pulmonary tuberculosis, forwhich he received the Samuel D. Gross Prizeof the Philadelphia Academy of Surgery.

In 1926, Dr. Alexander returned to theUniversity of Michigan and within a shorttime his interest and attention was devotedentirely to thoracic surgery. In 1928, heestablished a thoracic service and the firstsurgical residency program in thoracicsurgery. Dr. Alexander took great pride in themany thoracic surgeons completing his

program, many of whom became leaders inthe field.

In addition to employing the thenaccepted operations for pulmonarytuberculosis, Dr. Alexander was innovative inproposing new procedures. He popularizedanterior thorocoplasty and resection of thetransverse processes of the vertebrae toimprove the thorocoplastic collapse. He earlyrecognized the advantages of resection forpulmonary tuberculosis, but not to theexclusion of collapse therapy measures whichhe considered advantageous in many cases.He was an early advocate of two-stagelobectomy for bronchiectisis and earlyrecognized the effectiveness of resection ofpulmonary metastases in selected cases.

In 1932, Dr. Alexander was namedProfessor of Surgery.Shortly thereafter, arecurrence of his owndisease requiredhospitalization whichafforded the opportunity tocomplete the authoritativeclassic text on “TheCollapse Therapy ofPulmonary Tuberculosis”.

A man of hisaccomplishments accruedmany well deservedhonors including the

honorary degree of Doctor of Science fromthe University of Pennsylvania, the TrudeauMedal by the National TuberculosisAssociation, the Bruce H. Douglas Awardfrom the Michigan Trudeau Society, theHenry Russell Award and Lectureship fromthe University of Michigan given to amember of the faculty who has attained thehighest distinction in the field of scholarship.Dr. Alexander was President of the AmericanAssociation for Thoracic Surgery from 1934-1935 and President Elect of the TrudeauSociety, an honor he had to relinquishbecause of recurrence of his illness. He was a

member of the American SurgicalAssociation, the Central Surgical Association,The International Society of Surgery, theSociety for Clinical Surgery, the AmericanMedical Association, the Michigan StateMedical Society, and the NationalTuberculosis Association. He was anhonorary member of the Society of ThoracicSurgery of Great Britain and Ireland, DetroitAcademy of Surgery, Sociedad de Argentiande Cirurjanos, Societe Belge de Chirugie,Societe Francaise de la Tuberlose, SociedadParaguaya de Tisiologia, and the SociedadEcutoriana de Tisiologia. He was also amember of Alpha Omega Alpha, Sigma Xi,Phi Kappa Phi, Alpha Mu Pi Omega, DeltaTau Delta and an honorary member of NuSigma Nu.

Dr. Alexander has been described as abrilliant scholar and an inspiring teacher. Inhis later years, he enjoyed gardening andduck hunting with his wife, the former EmmaWard Woolfolk, whom he married in 1936.His contributions to thoracic surgery andespecially the inauguration of residenttraining in thoracic surgery and the manysurgeons he trained assured him of a place inthe annals of thoracic surgery. His legacyunquestionably is the surgeons he trainedwhose fondness for him and memories of himare legendary. Thanksgiving dinners for staffand family with turkey carved expertly by Dr.Alexander, the weekly trips to the MichiganState Sanatorium with the resident driving theantique black Buick while Dr. Alexanderworked in the back seat, the undauntedcourage Dr. Alexander demonstrated incoping with multiple recurrences of his illnessnecessitating multiple hospitalizations anddaily rest periods have left indelible memorieswith those who knew him. As Dr. JohnStrieder, on of his earliest residents, wroteabout his first meeting with Dr. Alexander, “Ihad come on a man - as so many did – withnot just a talent, but a genius for that rarestand most sensitive of all arts, friendship.”


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Historical Perspectives of the American Association for Thoracic SurgeryBy Herbert Sloan, MD, UM Thoracic Surgery (’49)

Dr. Herbert Sloan


We are planning the next John Alexander Society Ann Arbor reunion in 2005. As in

the past the reunion will include a scientific program, operative clinics, and social

events. Coincidentally, Dr. Marvin Kirsh is retiring, an endowed chair in his and

Helen’s name has been established, and Dr. Edward Bove will be the first recipient.

The Sections of Cardiac and Thoracic Surgery would like to coordinate the John Alexander Society

reunion with the investiture of the Helen and Marvin Kirsh Professorship in Cardiac Surgery.

The Helen and Marvin Kirsh Ceremony will take place Thursday, May 5th and we hope to include

the John Alexander Society Scientific session throughout Friday, May 6th.

The ceremony for the investiture of the Helen and Marvin Kirsh Professorship will take

place the afternoon of Thursday, May 5, 2005, beginning at 4:00pm. The John Alexander

Society Meeting will begin the morning of Friday, May 6th and will end with a social day on

Saturday, May 7th.

Please indicate below your interest in returning to Ann Arbor for this reunion of the John

Alexander Society.

Yes, I am interested in returning to Ann Arbor in 2005 for the next JAS reunion.

My schedule will allow me to attend the following days:

_____ Thursday, May 5th Helen and Marvin Kirsh Professorship Ceremony

_____ Friday, May 6th JAS Reunion _____ Saturday, May 7th JAS Social Day

_____ I will need accommodations for my time in Ann Arbor.* (see note below)

_____ No, I am unable to attend.

Name ________________________ Guest Name __________________________

Address____________________________________________________________

City __________________________ State________________ Zip __________

Phone ________________________ Email_______________________________

WE LOOK FORWARD TO SEEING YOU IN ANN ARBOR – GO BLUE!

HELEN & MARVIN KIRSH PROFESSORSHIP CEREMONYslated for May 5, 2005 beginning 4pm

in Ford Auditorium

Save the Date

If you prefer to email your response please do so to Ann Boyd Stewart, Development and Alumni Relationsat [email protected] or call toll free 800-588-5844 to let us know you can attend.

To reserve rooms for the reunion please callCampus Inn by 4/5/05 or are subject toavailability. Call toll free 800-666-8693.

Jennifer C. Hirsch was raised in Kalamazoo,Michigan and attended the University ofMichigan Honors College and received aBachelor of Science degree in Biology in1991. She graduated from Harvard MedicalSchool in 1996 and has been at the Universityof Michigan Medical Center since 1996.During that time, she completed her GeneralSurgery residency, a Surgical Critical Care

fellowship, and an Extracorporeal Life Supportfellowship. Upon completing her final year of Thoracic surgerytraining, Dr. Hirsch will begin a fellowship in PediatricCardiothoracic surgery at the University of Michigan.

Sanjeer Aggarwal grew up in Rochester NewYork and attended the University ofPennsylvania for his undergraduate educationand Baylor College of Medicine for hismedical degree. He then returned to New Yorkfor a general surgery residency at New YorkUniversity Medical Center. Upon completinghis thoracic surgery residency at the Universityof Michigan, Dr. Aggarwal will returning home

for a fellowship in mechanical assist devices,cardiac transplantation, and minimally invasive surgery at ColumbiaPresbyterian hospital in New York City.

Jonathan W. Haft grew up in Miami Beach,Florida, and attended the U of Pennsylvania for his undergraduate education before...Hecame north to the University of Michigan forboth his general and thoracic surgeryresidencies. After graduation, he will join thecardiac surgery faculty here and focus uponICU care and ECMO.


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2004 Graduates - Thoracic SurgerySang Lee, M.D. - Private Practice, Fremont, CaliforniaSantosh Krishnan, M.D. - Private Practice, Milwaukee, WisconsinAllan Pickens, M.D. - Thoracic Surgery Faculty, Univ. of Michigan

2003 Graduates - Thoracic SurgeryDavid Kulick, M.D. - Private Practice, Austin, TexasWilliam Lynch, M.D. - Private Practice, Muskegon, MichiganKanti Uppal, M.D. - Private Practice, Monterey, California

2002 Graduates - Thoracic SurgeryShahab Akhter, M.D. - Cardiac Surgery Faculty,

University of Cincinnati Andrew Chang, M.D. - Thoracic Surgery Faculty,

University of MichiganHimanshu Patel, M.D. - Cardiac Surgery Faculty,

University of Michigan2001 Graduates - Thoracic Surgery

Eric Devaney, M.D. - Pediatric Cardiac Surgery Faculty,University of Michigan

Charles Hoopes, M.D. - Cardiothoracic Surgery Faculty, Duke University

Srinivas Kolla, M.D. - Private Practice, Carnegie, Pennsylvania 2000 Graduates - Thoracic Surgery

Michael Eppinger, M.D. - Private Practice, San Antonio, TexasKenneth Fox, M.D. - Pediatric Cardiac Surgery, Private Practice

Austin, TexasDavid Polidori, M.D. - Fellowship, University of Pennsylvania

1999 Graduates - Thoracic SurgeryNeil Devejian, M.D. - Pediatric Cardiac Surgery,

Albany Medical College, New YorkJeffrey Everett, M.D. - Thoracic Surgery Faculty,

University of IowaIva Smolens, M.D. - Cardiac Surgery, Private Practice,

Detroit, Michigan

June 2005 Graduates

Jennifer C. Hirsch

Sanjeev Aggarwal

Cardiac Surgery Scholarship GivenJonathan Green, M1, is the first Cardiac Surgery Medical SchoolScholarship recipient. Raised in Los Angeles, Jonathan graduatedfrom Yale in 2002 and then spent twoyears in China teaching English andstudying Chinese in Changsha, Hunan,China. He is looking to return to Chinaagain this summer to do research andhopes that international work will alwaysbe an element of his career. The CardiacSurgery Scholarship was endowed with$500,000 from the faculty of the Sectionof Cardiac Surgery and will allowJonathan a tuition free medical schooling.

Jonathan Green

Allan Pickens, M.D. joined the University of Michigan, Section of Thoracic Surgery, on January 1, 2005. He is an Alabama nativewho attended the University of Alabama for his undergraduate studies as well asmedical school.

Dr. Pickens did his General SurgeryResidency at the University Hospital inBirmingham, Alabama. During residency, hisresearch included molecular biology of lungcancer. His interests in lung cancer and other

thoracic diseases led him to the birthplace of thoracic surgery, theUniversity of Michigan.

Dr. Pickens completed his Thoracic Surgery Residency at theUniversity of Michigan in July, 2004. An additional MinimallyInvasive Thoracic Surgery Fellowship was completed at Cedar-SinaiHospital in Los Angeles, California. He has published numerouspeer reviewed articles and book chapters. Dr. Pickens returns to AnnArbor to start a Minimally Invasive Pulmonary Resection Program.

Dr. Allan Pickens

Welcome New Faculty

Graduating Residents 1999-2004and what they are doing today

Jonathan W. Haft

The University of Michigan Section of Cardiac Surgery has created a newCardiac Surgery program at Crittenton Hospital in Rochester, Michigan.Two of our faculty [Drs. Fazzalari and Paone] are full-time surgeons atCrittenton. Dr. Richard Prager is Medical Director for the program.

Crittenton: UM Section of Cardiac Surgery

Frank Fazzalari, MD, FACS, has beenappointed as Clinical Assistant Professor inthe Section of Cardiac Surgery. He receivedhis MD from the University of Michigan andstayed on for his General Surgery residencyhere. He completed his Thoracic Surgeryresidency at Massachusetts General Hospitalin Boston. He was in private practice inSouth Carolina, then joined the faculty of theUniversity of Pittsburgh. He will be Chief ofCardiothoracic Surgery at the new Universityof Michigan Heart Surgery Program at

Crittenton Hospital in Rochester, Michigan.

Gaetano Paone, MD,FACS, has beenappointed as Clinical Assistant Professor inthe Section of Cardiac Surgery. He receivedhis MD from the New York UniversitySchool of Medicine, where he also completedhis General Surgery residency. He completedhis Thoracic Surgery residency at theUniversity of Illinois Hospitals in Chicago.He was an attending surgeon at Boston CityHospital, University Hospital in Boston, andat Henry Ford Hospital in Detroit. He will bepart of the Heart Surgery Program atCrittenton Hospital in Rochester, Michigan.

Dr. GaetanoPaone

The Department of Surgery is delighted to announce theinauguration ceremony of the Herbert Sloan Professorship inCardiac Surgery and installation of G. Michael Deeb, MD, asthe first Herbert Sloan Professor on Thursday, May 6th, 2004.

Sloan Professorship Inaugurated

5John Alexander Society News

W I N T E R 2 0 0 5

The Blades vs.The PillsBenefiting Heart Transplant Patients

Saturday,April 30, 20055:00 pm Face-off

Ann Arbor Ice CubeTickets: $5

12 & under FREE

Call 800-588-5844 for more [email protected]

S A V E T H E D A T E F O R :

Hearts on IceS A V E T H E D A T E F O R :

Hearts on Ice

Dr. FrankFazzalari

Cameron Haight LectureThe fifth annual Cameron Haight Lecture was delivered byformer Michigan resident, Dr. Douglas E. Wood, Head ofGeneral Thoracic Surgery at the University of Washington,Seattle. Dr. Wood's lecture titled “Lung Volume ReductionSurgery: Science, Politics, and the future” was given at theDepartment of Surgery's Grand Rounds on Thursday, January6, 2005. The Cameron Haight lecture was founded andfunded from a gift of the estate of Dr. Joe Morris (UMThoracic Residency '54) in honor of Dr. Cameron Haight andsupported by the Sections of Thoracic and Cardiac Surgery.

Hearts on IceThe 4th Annual Hearts on Ice Hockey Game is upon usagain. The Blades, coached by Dr. Ed Bove, will again crushthe Pills and coach Dr. Kim Eagle. All are invited to watchcutting edge defense from goalie Pagani and the infamousPump Line: Ohye, Devaney, Bolling and Spoor.

The Deeb Family

The Sloan Family

Dr. Richard S. Hahn was born in Nebraska asa first generation Korean-American. He grewup in Chicago, Illinois, and knew at an earlyage that he would be a doctor. “When I was 9and 10, I spent days at the 1933-34 World’sFairs on the lakefront. I remember thefuturistic Science Museum…captivated bythe life-sized clear plastic replica of a humanwith a beating heart, red and blue fluidcirculating in arteries and veins, pulsinglungs and all organs in various colors.”

After graduating with honors from theprestigious Carleton University and medicalschool at Northwestern University, Dr. Hahntook an appointment with cardiac surgeon Dr.Claude Beck at Western Reserve Hospital inCleveland. Dr.Beck was alreadythe first surgeon tobring a patientback to life bydefibrillation. Dr.Beck at the timewas working on acure for coronaryartery disease.

In two yearsand after 300operations in boththe dog laboratoryand hospital, Dr. Hahn went west toCalifornia for his general surgery training atStanford. He then came to Ann Arbor tocomplete a two-year thoracic surgeryresidency. The University of Michigan “was--and may still be--the premier Cardiothoracictraining center in America. I only wanted thebest,” he stated. In the spring of 1955 Dr.Beck spoke with then UM ChairmanFrederick A. Coller who urged Dr. Hahn toperform a series of experimental cardiacoperations. These operations, called the Beck

II, were two stage procedures requiring thepatient to undergo a second open-heartoperation 2-3 weeks later. Hahn had alreadyperformed such procedures in Cleveland indogs and patients.

These were very exciting and headytimes for cardiac surgeons eager to cure thenumber one disease in the country, (coronaryartery disease). Given that the heart lungapparatus was not available for anotherdecade, this was a procedure done on thebeating heart. All six patients survived.Moreover, this procedure became theprototype for coronary by-pass operations.

Dr. Hahn reflected that at the conclusionof the first operation, he remembers a soft

voice and Dr.Coller’s hand onhis shoulder,“Good work,son.” Dr. Hahnsaid this was themost touchingstatement andact of kindnesshe receivedduring hisentire medicaltraining, “AndI can still feel

his hand on my back.”After graduating from UM, Dr. Hahn

practiced in Marin County, California. Adecade later, he took up another challenge: “Iwanted to accomplish something more than isrequired of me by the Hippocratic Oath. Aphysician spends his life learning his practice,and he has to make a business out of it tosurvive. But it is still possible to return nowand then to the original ethic.”

In 1963, he traveled with the secondmission of SS Hope to Peru where he left the

boat to travel up to remote villages at highaltitude to treat patients with tuberculosis. Hethen made trips to Mexico in 1964 and 1965to immunize 15,000 children against TB andother deadly diseases. In 1966, he formed theAlliance for Health, a non-profit organization,and completed missions to South Korea,India, Bhutan and China.

He feels strongly that “all young studentswho enter medical school are motivated bythe altruism of healing the world’s wretchedsick. The profession offers many diverseways in which this passion can beaccomplished. Unfortunately, there are manyobstacles that increase in difficulty as oneattempts to achieve the pure goal…the desiresand fire begins to be damped from the veryfirst day in medical school.”

In honor of Dr. Frederick Coller, Dr. Hahn has offered to make a gift to theUniversity of Michigan and Department ofSurgery for global volunteerism. Dr. Hahnwill be inducted as an honorary member ofthe Frederick A. Coller Surgical Society.

Oddly enough, while in Peru, Dr. Hahnmet Dr. Carlos Peschiera (Thoracic Surgeryresidency 1944) both trained at UM, theydrank a toast to John Alexander.

Dr. Richard S. Hahn, Class of 1955By Ann Boyd Stewart

Dr. Hahn with faculty and residents of 1954


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Dr. Hahn and Chairman Mulhollandstanding outside Dr. Hahn’s home

overlooking San Francisco.


Esophageal Adenocarcinoma:An Increasing Deadly Problem

The incidence of esophageal adenocarcinoma hasincreased steadily and dramatically over the pastthree decades. The development of esophagealadenocarcinoma from Barrett’s mucosa has beeninvestigated in the laboratory through the use of aDNA-based tool called two-dimensional genomescanning. Regions of DNA that are amplified andtherefore present in multiple copies often containpotential oncogenes that are involved in thedevelopment and progression of cancer. We firstidentify the chromosomal regions involved,determine the genes that are both amplified at theDNA and overexpressed at the mRNA level andthen characterize the potential cancer-related genes(1-5). We have been at the fore-front in theidentification and characterization of theseamplicons in esophageal adenocarcinomas andnow are utilizing this information to begin totherapeutically target these alterations in thiscancer. For example, we have demonstrated thatamplification of the erbB2 oncogene is present inover 20% of esophageal adenocarcinomas (5), asimilar to the frequency of erbB2 geneamplification in breast cancer which is a currentlytargeted for therapy using drugs that inhibit thetyrosine kinase activity or by antibodies that targetthe receptor. By targeting this gene and others thatwe observe as amplified and over-expressed, wehope to increase the survival of patients withesophageal cancer.

To identify genes and biological processesthat might be involved in the progression ofBarrett’s metaplasia to dysplasia and ultimately toadenocarcinoma, we have utilized gene expressionprofiling using oligonucleotide arrays that cansimultaneously examine the expression of 22,000genes in these tissues. We have uncovered genesthat are highly expressed in the cancers includingthe L-type amino acid transporter gene (LAT-1)and the MAGE (melanoma-associated antigen)genes. Both of these studies have been recentlypublished (6,7). Importantly, we demonstrate thetumors that overexpress LAT-1 also use thistransporter to bring into cells the chemotherapeuticagent melphalan, which we show effectively killsthe tumor cells. Further we observe extremely high

and specific overexpression of the MAGE mRNAand protein in the esophageal adenocarcinomas (7).This is an important finding as these proteins arepotentially excellent candidates forimmunotherapeutic targeting.

Technological Advancementsto Combat Lung Cancer

Progress in lung cancer has proceeded rapidly intwo major areas. We have also used geneexpression profiling with oligonucleotidemicroarray technology and have identified a set ofgenes that are significantly associated withaggressive clinical behavior in early stage lungadenocarcinomas. Most importantly, an indexbased on the expression of this set of genes canalso predict the clinical outcome of an independentset of lung adenocarcinomas. The implications arethat if we can identify the group of patients withstage I lung tumors that are at risk for metastasisthese patients may benefit from adjuvant therapywhich is often not provided to these patients. Thisstudy was published in Nature Medicine (8) andprovided a large amount of publicity for theUniversity of Michigan and Thoracic Surgery.Further, analysis was also performed on the samelung adenocarcinoma samples examined for geneexpression at the protein level using two-dimensional protein electrophoresis combined withprotein identification with mass spectrometry. Asshown for the survival-related genes (8) we alsoidentified a set of 46 proteins that weresignificantly associated with patient survival (9).This study revealed that there is complementaryinformation provided by the use of the twoapproaches of mRNA and protein analysistogether, and revealed the glycolytic pathway asbeing significantly increased and associated withthe aggressive lung adenocarcinomas. Ongoingstudies have greatly expanded the number oftumors that have been gene profiled with 22,000gene microarrays to now over 340 lung cancersand thus will allow the potential identification ofsubgroups of tumors and the genes that best predictthe biological and clinical behavior of theselesions.

By examining individual genes and proteinsthat are associated with aggressive lung tumors weare defining the critical changes that may be future

targets for therapy as well as potential biomarkersthat may be useful for early detection (10-15).Current studies are examining the presence ofhighly expressed gene and proteins in the serum ofthe lung cancer patients with the goal of beingbetter able to diagnose cancer early, as well asbeing able to monitor for potential tumorrecurrence in the these patients. We are creatingtumor specific microarrays that are then probedwith the patient’s serum to examine the antibodieseach patient produces to specific tumor antigens.These “auto-antibodies” that are produced by thecancer patients own immune system, have thepotential to be present significantly earlier thancurrent technology is able to identify lung lesionsand thus may provide a window of opportunity forearly cancer detection, early treatment and betterpatient survival.

REFERENCES:Lin L, Aggarwal S, Glover TW, Orringer, MB, Hanash S, Beer DG. A minimal critical region of the8p22-23 amplicon in esophageal adenocarcinomas defined using STS-amplification mapping andquantitative PCR includes the GATA-4 gene. Cancer Res. 60:1341-1347, 2000.Lin L, Prescott MS, Zhu Z, Singh P, Chun SY, Kuick RD, Hanash S, Orringer, MB, Glover TW, BeerDG. Identification and characterization of a 19q12 amplicon in esophageal adenocarcinomas revealscyclin E as the best candidate gene for this amplicon. Cancer Res. 60:7021-7027, 2000.Lin L, Miller CT, Contreras JI, Prescott MS, Yee J, Orringer MB, Misek DE, Hanash SM, GloverTW, Beer DG. The Hepatocyte Nuclear Factor 3 Alpha FOXA1 (HNF3a) gene on chromosome band14q13 is amplified and overexpressed in esophageal and lung adenocarcinomas. Cancer Res 62:5273-5279, 2002.Miller CT, Aggarwal S, Lin TK, Contreras JI, Dagenais SL, Orringer MB, Glover TW, Beer DG, LinL. Amplification and overexpression of the dual-specificity Yak-related kinase 2 (DYRK2) gene inesophageal and lung adenocarcinomas indicate a potential oncogenic role in tumorigenesis. CancerRes. 63: 4136-4143, 2003.Miller CT, Lin L, Moy JR, Schipper M, Normolle D, Brenner DE, Iannettoni MD, Orringer MB,Beer DG. Gene amplification in esophageal adenocarcinomas and Barrett’s with high-grade dysplasia.Clin. Cancer Res. 9:4819-4825, 2003.Lin J, Raoof D, Thomas DG, Greenson GK, Giordano TJ, Robinson GS, Barve RA, Orringer MB,Beer DG. L-type amino acid transporter-1 overexpression mediates uptake of melphalan in Barrett’sadenocarcinoma. Neoplasia 6:74-84, 2004.Lin J, Lin L, Thomas DG, Giordano TJ, Robinson GS, Barve RA, Orringer MB, Beer DG.Melanoma-associated Antigens in Esophageal Adenocarcinoma: Identification of Novel MAGE-A10Splice Variants. Clin. Cancer Res. 10:5708-5716, 2004.Beer DG, Kardia SLR, Huang CC, Misek DE, Lin L, Chen, G, Gharib TG, Giordano, TJ, ThomasDG, Lizyness ML, Kuick R, Taylor JMG, Iannettonni MD, Orringer MB, Hanash S. Gene Expressionprofiles define a high-risk group among stage I lung adenocarcinomas. Nature Medicine 8:816-824,2002.Chen G, Gharib TG, Wang H, Huang CC, Thomas DG, Sheddon KA, Misek DE, Taylor JMG,Giordano, TJ, Iannettoni MD, Orringer MB, Hanash S, Beer DG. Protein expression profiles predictpatient survival in stage I lung adenocarcinoma. Proc. Natl. Acad. Sci (USA) 100:13537-13542, 2003.Chen, G, Gharib TG, Huang CC, Taylor JMG, Kardia SLR, Misek DE, Giordano, TJ, IannettonniMD, Orringer MB, Hanash S, Beer DG. Discordant protein and mRNA expression in lungadenocarcinomas Cellular and Molecular Proteomics 1:304-313. 2002.Chen, G, Gharib TG, Huang CC, Thomas DG, Sheddon KA, Taylor JMG, Kardia SLR, Misek DE,Giordano, TJ, Iannettonni MD, Orringer MB, Hanash S, Beer DG. Proteomic analysis of proteinsoverexpressed in lung adenocarcinomas with correlation to mRNA abundance. Clin Cancer Res8:2298-2305, 2002.Gharib TG, Chen G, Wang H, Huang CC, Prescott MS, Sheddon KA, Misek DE, Thomas DG,Giordano, TJ, Taylor JMG, Yee, J, Orringer MB, Hanash S, Beer DG. Proteomic analysis ofcytokeratin isoforms associated with survival in lung adenocarcinoma. Neoplasia 4(5) 440-448, 2002.Moran CJ, Arenberg DA, Huang CC, Giordano, TJ, Misek DE, Iannettonni MD, Orringer MB,Hanash S, Beer DG. Rantes expression by lung adenocarcinomas is a predictor of survival in stage Ipatients. Clin Cancer Res 8:3803-3812, 2002.Miller CT, Chen G, Gharib TG, Thomas DG, Misek DE, Giordano TJ, Yee J, Orringer MB, HanashS, Beer DG. Increased c-crk proto-oncogene expression is associated with an aggressive phenotype inlung adenocarcinomas. Oncogene 22(39):6006-6013, 2003.Chen G, Wang H, Miller CT, Thomas DG, Gharib TG, Misek DE, Giordano TJ, Orringer MB,Hanash S, Beer DG. Reduced selenium-binding protein 1 expression is associated with poor outcomein lung adenocarcinomas. J. Pathol. 204:321-329, 2004.

Thoracic Surgery Research at MichiganBy David G. Beer, Ph.D., Professor of Surgery

The Section of Thoracic Surgery has continued the tradition of a strong research program not only in clinical medicine, but also in basic and translational scienceespecially as it relates to thoracic diseases such as cancer. A major role and goal of the Thoracic Surgery Research Laboratory is to provide research training forsurgical residents, medical students and undergraduates. These trainees receive valuable laboratory experience and very often publish the results of their research.The Thoracic Surgery Research laboratory is directed by David G. Beer, Ph.D. and is funded by R01 grants from the NIH as well as foundation and industry grants.Research from the laboratory has resulted in over 40 published papers since the year 2000 including many high profile publications in journals such as NatureMedicine, Proceedings of the National Academy of Sciences, Journal of Clinical Investigation and Cancer Research. Our research has focused on two major areas,the molecular genetics of esophageal adenocarcinoma development and the gene and proteomic analysis of lung cancer.

We are interested in understandingmodulation of the multimeric troponincomplex by signaling pathways incardiac muscle. Troponin is locatedwithin the thin filament of thecontractile apparatus, and it regulatesCa2+-activated contraction in striatedmuscle. The inhibitory troponinsubunit, troponin I (TnI), plays a criticalrole and acts as a molecular switchduring Ca2+-activated musclecontraction. TnI is phosphorylated byseveral signaling pathways, includingthe protein kinase C (PKC) pathway,which is activated by a number ofendogenous hormones. We areinvestigating the TnI residuesphosphorylated in the intact cell byPKC, and the contribution ofphosphorylated TnI to PKC-mediatedchanges in contractile performance.Advances in molecular biology andviral-mediated gene delivery now allowus to exchange endogenous TnI withTnI containing substitutions at sitesphosphorylated by PKC in adult cardiacmyocytes. Recent results from ourlaboratory demonstrated PKC-mediatedTnI phosphorylation plays an importantrole during relaxation, and is necessaryto prevent diastolic dysfunction withincardiac myocytes. We are currently inthe process of identifying individualphospho-amino acids responsible forthis important modulatory influence onrelaxation.

Our earlier work also led us toinvestigate the role of individual PKCisoforms in mediating the contractileresponse to specific neuro-humoralagonists. The primary PKC isoformsexpressed in adult rat myocytesincludes the classical a isoform, and the

novel d and e isoforms. These isoformsalso are expressed in adult humanmyocardium. The a isoform, as well as PKCb, another classical isoform,both up-regulate during heart failure.Initial studies from our groupdemonstrated that PKCa directlymodulates contractile function, but doesnot influence TnI phosphorylation.Instead, PKCa modulates contraction by regulating Ca2+ uptake by thesarcoplasmic reticulum via effects onthe protein phosphatase I pathway.Interestingly, we observe that PKCadecreases in human patients receivingventricular assist device therapy. Wehope to one day develop gene therapytools to further reduce PKCa expressionand restore ventricular function inpatients experiencing heart failure. Inongoing studies, we are alsoinvestigating the influence of otherPKC isoforms on TnI phosphorylationand contractile function. Ultimately, we hope that knowledge gained fromthese studies may lead to an improvedunderstanding of the underlyingmechanisms responsible forpathophysiological conditions in theheart, and to better treatment of theseconditions.


Cardiac Surgery Research LabBy Margaret Westfall, Ph.D., Assistant Professor of Surgery

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Center forCirculatory Support

M E D I C I N E A T M I C H I G A NG O E S S O U T H

Receptions will be held in Naples, FL on Feb 22and Palm Beach, FL on Feb 23.

Please RSVP to Ann Boyd Stewart, Alumni Relations and Development

at 800-588-5844

The Section of Cardiac Surgery is pleasedto announce a gift of $450,000 fromTerumo Cardiovascular for the Center for Circulatory Support. This gift willenhance existing research and clinicalprograms, establishing education forumsand backing other CCS initiativesincluding training sites for artificial heart implants and minimally invasivecardiac surgery.

Co-Director of Centerfor Circulatory Support,

Dr. Frank Pagani


We are planning another reception at the AATS in San Francisco. If you are coming to San Francisco, please notify Ann Boyd Stewart

either via email at [email protected] or call her toll-free 800-588-5844 and let her know your availability in San Francisco. She will be

there from April 10-14, 2005.

Left to right: David and Rhonda Saint, Sandra Vontz, Robert Tate, Himanshu Patel, Frederick Vontz, Andrew Chang, Richard Whyte, Ann and Mark Iannettoni, Mark Orringer,

Richard Prager, Jennifer Hirsch, Santosh Krishnan, Bill Lynch, Susan Orringer, Sanjeev Aggarwal,Cynthia Steimle, Jonathan and Jennifer Haft, Marilee and Kenneth Oberhue.

Marvin Kirsh Personal RecollectionsIn conjunction with Dr. Kirsh's ceremony, we are interested in

gathering letters from colleagues, residents and friends to be bound

for the May 6th John Alexander Reunion. If you would like to

participate please prepare a letter on your letterhead as well as any

photos you would like to pass along for the upcoming San

Francisco event,

or mail them to

Ms. Stewart. She can

also make arrangements

to pick them up at the

host hotel lobby or you

could bring them

to the planned

reception/dinner.

You are Invited...All John Alexander Society members are invited to join

host Dr. Richard Whyte for a dinner at the bestAsian restaurant in San Francisco and just off

the Embarcadero: The Slanted Door.

The reception will begin

at 6:00pm on Monday, April 11, 2005

followed by dinner.

To rsvp please call Ann Boyd Stewart,

Alumni Relations and Development,

by March 31st, 800-588-5844 toll-free

or email [email protected].

Note: If respondents prefer a different

evening, another dinner will be arranged.


10

THORACIC SURGERY HISTORICAL NOTE:The surrounding images were taken by the late Dr. Joe Morris.They were created by a thoracic surgeon when he was a TBpatient at the Trudeau Sanatorium in Saranac Lake, NY. The murals include nine scenes of a T.B.‘s Progress and wasbrought to UM Hospital and hung on the walls of the TB Wardbefore the hospital was destroyed.

Who painted the murals? Who brought them to UM? Where are the panels now? And, can you name the doctors on the tombstones and when they died?

Answers will be available in the next issue of the John Alexander Society Newsletter.

ohn Alexander, the Head of Thoracic Surgery at the University of Michigan, started the first formal

thoracic surgery training program in the United States at the University of Michigan in 1928. A Venezuelan

surgeon, Cesar Rodriguez, was one of Dr. Alexander’s early residents. Returning home, Dr. Rodriguez urged his

young cousin, Otto Gago, to consider training in thoracic surgery at the University of Michigan.

Following his cousin’s advice,Dr.Gago began his internship in 1961 at the University of Michigan Hospital and

completed his general surgery residency under Dr. William E. Adams at the University of Chicago where he

participated in pioneering work of pulmonary and cardiopulmonary transplantation and developed techniques

of pulmonary lobar transplantation in the early 60s. He returned to Ann Arbor in 1965 for his thoracic training

under Drs. Cameron Haight, Herbert Sloan and Joe Morris.

Well respected and acknowledged as a superior technical surgeon and physician, he returned to his home in

Caracas, Venezuela, but acceptance of techniques learned at the University of Michigan were slow in coming.

After 2 years, Dr. Gago returned to Ann Arbor to join the Section of Thoracic Surgery at the University of

Michigan and in 1972, he moved to St. Joseph Mercy Hospital full time to help Dr. Joe Morris build

an Adult Cardiac Service.

Dr. Gago’s brilliance as a cardiac surgeon has enhanced the lives of countless people throughout the Midwest and internationally. He also never forgot

his heritage. Nearly every year he returned home to treat the indigent Venezuelans who could never repay him for his skills and compassion, nor were

they asked to do so.

It is his generosity of spirit that has earned him long and cherished friendships. From his innumerable friends, to his

surgical team in the operating room and hospital, Dr. Gago deeply values his time with people. As his good friend and

grateful patient, Bo Schembechler, will attest: “Otto Gago is the role model for the Michigan Tradition; he strives for

excellence in medicine through honesty, integrity and hard work. I am very, very grateful Otto was my doctor.”

The University of Michigan is fortunate that Otto Gago, M.D., returned to Ann Arbor. His skills as a surgeon

and teacher were utilized at both the University of Michigan and St. Joseph Mercy Hospital and he has

remained a committed friend and supporter of the University. The time has come to honor his achievement

and legacy with the creation of the Otto Gago, M.D. Professorship in Cardiac Surgery at the University of

Michigan Medical School.

Together, we can build an appropriate, enduring legacy to this brilliant and elegant man who has touched so

many lives. This professorship will be invested in perpetuity.

Please join us! It is time to embrace a Michigan Champion.

O T T O G A G O , M . D .P r o f e s s o r s h i p i n C a r d i a c S u r g e r y

TO M A K E A C O N T R I B U T I O N T O T H E P R O F E S S O R S H I P, P L E A S E C O N T A C T

Ann Boyd Stewart, Development OfficerDepartment of Surgery 2101 Taubman Center, 1500 E. Medical Center Dr. • Ann Arbor, MI 48109-0346 • 800-588-5844 • [email protected]

"Otto Gago is the role model for the Michigan Tradition; he strives

for excellence in medicine through honesty, integrity and hard

work. I am very, very grateful Otto was my doctor."

– B O S C H E M B E C H L E R

"Otto Gago is the role model for the Michigan Tradition; he strives

for excellence in medicine through honesty, integrity and hard

work. I am very, very grateful Otto was my doctor."

– B O S C H E M B E C H L E R

O T T O G A G O , M . D .P r o f e s s o r s h i p i n C a r d i a c S u r g e r y

Centered on Life...Focused on the Future THE VISION OF THE UNIVERSITY OF MICHIGAN CARDIOVASCULAR CENTER

The University of Michigan has launched unprecedented plans to build upon its already strong foundation of care and takeon the nation’s leading killer. Cardiovascular disease kills more Americans than the next five leading causes of deathcombined. Among all 50 states, Michigan has the nation’s eighth worst coronary death rate. However, U-M has plans tochange that by creating the future of cardiovascular care at the new U-M Cardiovascular Center (CVC).

This is a major endeavor that requires major support. U-M has launched the Cardiovascular Center Fundraising Project toraise $50 million. The success of this project will make it possible to create an internationally recognized center...prominentin scientific research and discovery, committed to excellence in education, and known for state-of-the-art, compassionatecare that meets and exceeds our patient needs.

C O M I N G T O A N N A R B O R I N 2 0 0 7 !

THE MAGNITUDE OF CARDIOVASCULAR DISEASE• #1 Cause of death in the U.S.• 2,600 deaths daily, one every 34 seconds• Claims more lives than the next five leading causes of death combined• U.S. cost is approximately $370 billion, representing more than 21% of U.S. total health care costs.• State of Michigan has the 8th highest coronary death rate in the nationSource: American Heart Association 2004 Heart and Stroke Statistical Update www.americanheart.org

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