F A L L 2005 volume four

Research and News for Physicians from the Cleveland Clinic Department of Pulmonary, Allergy and Critical Care Medicine and Section of General Thoracic Surgery

ALSO IN THIS ISSUE

Adapting GPS-Like Technology to Bronchoscopy: Electromagnetic Navigation –pg. 4

Advanced Imaging Technology AllowsFaster, More Confident Diagnoses–pg. 6

Electronic Nose Sniffs Out Lung Cancer

–pg. 8

Aspirin Sensitivity and Aspirin Desensitization–pg. 10

With 64 lung transplants performed in 2004 – the most of this typeever performed in one year at a single U.S. hospital – The ClevelandClinic became the nation’s leading lung transplantation center. TheClinic’s cadaveric lung transplantation program is considered thelargest and most active in the United States. In 2004, we performed64 transplants: 28 single-lung, 35 double-lung and one combinedlung and heart/lung transplants.

Last year was the Cleveland Clinic Lung and Heart/Lung Trans-plantation Program’s most successful since its inception over 15 yearsago. Our lung transplant recipients now have an 82 percent one-yearsurvival rate, compared with the national average of 72 percent.

In addition, we have one of the shortest waiting times in the country,so patients are likely to receive transplants sooner. This means thatsicker patients can be listed faster and have a better chance of survival.

Any patient within a 1,000-mile radius of The Cleveland Clinic canwait at home without having to relocate prior to transplantationuntil a donor organ is located.

In 2004, 30-day mortality associated with pulmonary transplantationin our program was just 2 percent, despite an increasing complexityof cases. Post-transplant length of stay decreased from a median of 14 days in 2003 to 12 days last year, while ICU stays decreased to seven days.

Lung Transplant: High Volumes,

ShortWaiting Times, Superior Survival Rates

continued on page 2

THE CLEVELAND CLINICFOUNDATION

ExchangeRespiratory

Marie Budev, D.O., M.P.H., Atul C.Mehta, M.D., and Gosta Pettersson, M.D., Ph.D

At The Cleveland Clinic, COPD is the primary diagnosis for patients undergoing lung transplant and accounts for34% of cases.

In 2004, the mean waiting time for lung transplant was 92 daysfor Cleveland Clinic patients, some of whom were listed for onlytwo to 10 days before receiving organs. The average waiting timehas steadily declined, despite an increase in transplant volume,from 360 days in 1999 to 346 days in 2000 and 157 days in 2001to the current 92 days.

The expertise of our surgeons and pulmonary transplant team allows them to consider and transplant more complex cases thatmay be declined listing at other centers. We have successfully combined valvular repair and transplantation, coronary bypassgrafting and transplantation, transplantation of patients with hepatitis C, and transplantation of cystic fibrosis patients withmulti-drug-resistant organisms.

Meanwhile, both before and after lung transplantation, we offerpatients and families affordable on-campus residential units inthe Transplant Hospitality Center. This allows for rapid pre-trans-plant evaluation, short lengths of stay and easy access to our outpatient thoracic and pulmonary clinics.

While they are wait-listed, transplant candidates can await notifi-cation of a donor organ at home, as long as they live within 1,000miles of The Cleveland Clinic. Once a donor organ is found, patients are transported via private plane to Cleveland within hours.

To refer a patient for consideration for lung transplant or heart-lung transplant, please call a Cleveland Clinic lung/heart-lungtransplant coordinator at 216/444-8282, option 3.

D E A R C O L L E A G U E S :

Welcome to the 4th issue of Respiratory Exchange, a publi-cation for physicians with an interest in management of pul-monary and allergic conditions. Whereas the initial issues ofRespiratory Exchange were produced by the ClevelandClinic Department of Pulmonary, Allergy and Critical CareMedicine, this 4th issue is co-published with our colleaguesin thoracic surgery, pulmonary pathology and thoracic imaging. We believe that patients at our institution benefitfrom the expertise of a multidisciplinary team, collaboratingin the management of complex respiratory disorders.

For additional information about the array of ongoing clin-ical and research activities in respiratory disorders at TheCleveland Clinic, please visit our department Web sites atclevelandclinic.org/pulmonary (current and previous issuesof Respiratory Exchange are available here) and cleveland-clinic.org/thoracic.

We hope that you – the specialist managing patients withrespiratory diseases – find Respiratory Exchange to be valu-able and informative. Please feel free to contact us at our toll-free number for physicians, 866/CCF-LUNG (223-5864), if you have any questions or if you would like to refer a patient. We welcome the opportunity to work with you.

Sincerely,

COPD/Emphysema

34%

continued from page 1

IdiopathicPulmonary

Fibrosis23%

CysticFibrosis

23%

Alpha1-AntitrypsinDeficiency

4.7%

Sarcoidosis4.7%

Other LungDisease

9.4%

W I T H 6 4 L U N G T R A N S P L A N T S P E R F O R M E D I N 2 0 0 4 –T H E M O S T O F T H I S T Y P E E V E R P E R F O R M E D I N O N EY E A R AT A S I N G L E U . S . H O S P I TA L – T H E C L E V E L A N DC L I N I C B E C A M E T H E N A T I O N ’ S L E A D I N G L U N GT R A N S P L A N TAT I O N C E N T E R

Herbert P. Wiedemann, M.D.Chairman, Department ofPulmonary, Allergy & Critical Care Medicine

Carol F. Farver, M.D.Director, PulmonaryPathologyDivision of Pathology &Laboratory Medicine

Thomas W. Rice, M.D. Head, Section of GeneralThoracic SurgeryDepartment of Thoracic &Cardiovascular Surgery

Moulay A. Meziane, M.D.Head, Section of Thoracic ImagingDivision of Radiology

{3}

Transplant volume has grown significantly over the past five years. Overall lungtransplant volume since the program’s inception in 1990 exceeds 450 cases. In 2004, The Cleveland Clinic became the most active lung transplantation center inthe United States.

*Projected total for 2005 in green, based on 42 transplants performed through July 26, 2005.

2001 2002 2003 2004 2005*

L U N G T R A N S P L A N TAT I O N AT T H E C L E V E L A N D C L I N I C

5

15

25

35

45

55

75

65

100

9090%80

70

60

50

40

30

20

10

0

0 6 12 18 24Months

82%

71%

1,000

Mile

s

1,000 Miles

The Cleveland Clinic

L I S T E D PAT I E N T S C A N W A I T AT H O M E

In addition to a short wait time – 92days in 2004 – patients living within a1,000-mile radius of The Cleveland Cliniccan wait at home until a donor organ islocated. Once a donor organ is found,patients are transported via pr ivateplane to Cleveland within hours.

1999 – 360 days

2000 – 346 days

2001 – 157 days

2002 – 126 days

2003 – 158 days

2004 – 92 days

2005 YTD*– 60 days

PAT I E N T W A I T I N G T I M E

*As of July 26, 2005

{4}

GPS (global positioning system) technol-ogy has become commonplace in the automotive industry, and now, similartechnology is available for diagnosticbronchoscopy. The Cleveland Clinic is involved in the first North American pilottrial utilizing electromagnetic navigationtechnology for the diagnosis of peripherallesions and mediastinal adenopathy.

The superDimension/Bronchus system(Herzliya, Israel) being used by ClevelandClinic pulmonologists was FDA-approvedin November 2004 as an adjunct to diagnostic bronchoscopy. A pilot trial inGermany demonstrated that the systemproduced definitive diagnoses for 69 percent of peripheral lesions biopsied. Theresults were published in the Journal ofBronchology (J Bronchol 2005;12:9-13).

Between November 2004 and June 2005,we recruited more than 50 patients for oursingle-center trial of electromagnetic nav-igation bronchoscopy. Results were pub-lished in Lung Cancer. (Gildea, TR.Electromagnetic navigation bronchoscopy.Lung Cancer 2005; 49(suppl 2):S1-S433.)

Prior to the procedure, data from each pa-tient’s chest CT scan is saved in DICOMformat (3-mm cuts at 1.5-mm intervals).The data are then transferred to a CD-ROM, loaded onto a laptop computerand configured into a multiplanar (axial,coronal and sagittal) CT scan and virtualbronchoscopy images.

The lesion of interest is identified in theplanning program, along with normalanatomic landmarks. The main carinaand left and right secondary carina anda few other distal carinae are plotted toprovide points of reference. Once com-puter planning is complete, the physicianperforms a virtual bronchoscopy to determine the bronchus that leads mostdirectly to the lesion.

The patient is laid on a standard bron-choscopy table, under which an electro-magnetic field generator has beeninstalled. Cutaneous leads attached to thepatient serve as points of reference insidethe electromagnetic field. These leadsalso help the computer adjust for chestmotion with normal breathing.

The bronchoscope is introduced in theusual fashion. A locatable guide servingas the probe is connected to the systemand passed through an extended work-ing channel, which is introduced throughthe working channel of an adult thera-peutic bronchoscope.

Registration is performed, allowing thecomputer to correlate actual anatomicimages on the bronchoscope’s videomonitor with virtual bronchoscopy images. When registration is complete,the virtual model of the patient runsalongside the actual bronchoscopy imageon the monitor.

The locatable guide is then attached to adirectional instrument that allows its tipto move in eight different directions.Once the scope is advanced as far as possible, the locatable guide is advanced through the extended workingchannel. Using directional instruments,the probe is advanced toward the lesionin the actual patient using the “virtualpatient” for electromagnetic navigation.

As the probe approaches the lesion, thevirtual target comes into view. The com-puter displays the distance between theend of the probe and the lesion. Whenthe probe is placed as close as possibleto the lesion, the locatable guide is retracted, but the extended workingchannel is left in place. This allows theintroduction of the usual biopsy instru-ments – brushes, transbronchial biopsyforceps and, if possible, 22-gauge peripheral transbronchial needles.

Adapting GPS-Like Technology to Bronchoscopy:

Electromagnetic NavigationThomas Gildea, M.D., Peter Mazzone, M.D., and Atul C. Mehta, M.D.

Monitor of the “bronchussystem” depicting multi-planar CT scan and virtualbronchoscopy images,along with registration of anatomical landmarks.

Note anastomotic sutureline in left mainstembronchus from prior lung transplant.

{5}

A case in which this approach proved idealinvolved a patient whose listing for lungre-transplant was jeopardized by the emer-gence of a new, enlarging left upper lobelesion. Her lung function was too poor to recommend resection; percutaneousbiopsy appeared to be too dangerous forsimilar reasons. Using electromagneticnavigation technology, however, the lesionwas successfully biopsied, and aspergilluswas identified. The patient was started onVoriconazole and was re-transplanted afew weeks later.

Results from our first 30 patients, with lesions as small as 1 cm in the periphery,showed that we could reach a definitive diagnosis in approximately 70 percentwith electromagnetic navigation bron-choscopy. Results of the ongoing studywere presented in July 2005, at the 11thWorld Conference on Lung Cancer inBarcelona, Spain.

Future uses for this technology are beingconsidered for directive therapy. Perhapsin the future, we may be able to placebrachytherapy catheters or perform radiofrequency ablation on small lesionsusing electromagnetic navigation bron-choscopy. We also may be able to apply it to other techniques requiring preciseplacement of drugs or devices.

Thomas R. Gildea, M.D., and Peter Maz-zone, M.D., M.P.H., are members of theDepartment of Pulmonary, Allergy andCritical Care Medicine, along with AtulMehta, M.D., who heads the Section ofBronchology.

The Cleveland Clinic was the first

medical center in North America to

use electromagnetic navigation

technology to diagnose peripheral

lesions and mediastinal adenopathy.

Locatable guide and its tip(inset), which can be steeredin eight different directions.

CT scan of chest depictingtype of the lesions (arrow)sampled using electromag-netic navigation (see text).

Images courtesy ofsuperDimension, Ltd.,Herzliya, Israel

The Cleveland Clinic’s Section of ThoracicImaging, with its four full-time chest radiologists, manages over 100,000 non-cardiac thoracic studies in a year in a fullydigital environment. Studies ranging fromthe simple chest X-ray taken at an acutelyill patient’s bedside to highly complex 3-D CT scan images are obtained both lo-cally and remotely and are processed andanalyzed at the Thoracic Imaging Center.

To ensure the highest level of patient care,we have integrated cutting-edge imagetechnology into our daily clinical practice.Our multi-slice CT scans allow for a sig-nificant improvement in image quality fora faster and more confident diagnosis in awide range of conditions, including lungcancer, pulmonary embolic disease, emphysema and interstitial lung disease.Hundreds of images offering resolution at the sub-millimeter level can now be obtained in less than 10 seconds with noincrease in radiation dose to the patient.

Advanced Imaging TechnologyAllows Faster, More Confident Diagnoses

Moulay A. Meziane, M.D.

With new technology, characterization ofdisease, such as distinguishing benignfrom malignant nodules, is becoming easier and more accurate, which helps tospeed diagnosis. Using the latest soft-ware, Clinic radiologists can preciselymeasure nodule volume and evaluategrowth in suspected malignancy (figures1a and 1b). Diffuse lung disease also canbe quantified, allowing for measurementof disease burden.

Thanks to improved speed and resolution,virtual bronchoscopy images of unprece-dented quality now are available. A pilotstudy is under way at The ClevelandClinic to formulate a scoring method forevaluating alveolar proteinosis and its response to treatment (figure 2).

Such studies are being used for trans-bronchial interventional procedures forthe diagnosis of peripheral pulmonarynodules (superDimension project) (figure 3).

Figure 1a. Computer-generated analysis of RUL nodule.

Figure 1b. Computer-generated volume measure-ment of nodule and comparison for growth.

Figure 2. Color mapping of distribution of disease in pulmonary alveolar proteinosis. Figure 3. Virtual bronchoscopy

{6}

Cleveland Clinic eRadiology:World-Class Imaging at Your Doorstep

Michael Recht, M.D.

The Department of eRadiology began as a natural progressionof the Cleveland Clinic’s need to integrate multiple hospitals,family health centers and outpatient imaging centers into one cohesive radiology service model. Over the past five years, thismodel has grown to include more than 40 separate imaging locations in 12 states, and e-radiologists perform more than50,000 exams annually.

Modalities include magnetic resonance imaging, computedtomography and nuclear medicine, including PET scans. Each ofour client locations is integrated with our radiologists via a high-speed virtual private network that allows Cleveland Clinicradiologists to receive each exam in real time, while conformingto all aspects of HIPAA regulations.

Technologists from our client locations receive training at TheCleveland Clinic in the use of the appropriate modalities as wellas in our RIS and PACS systems. We provide exam protocols forevery procedure based upon patients’ medical indications andhistories. Reports from our radiologists are typically availablewithin 24 hours, with STAT reports available upon request. Ifunexpected findings surface, our radiologists call the referringphysician immediately.

Our services are truly integrated with the physician practice. The radiologists associated with the Department of eRadiologyprovide services full time to our client locations; the radiologistsare available throughout the day for consultations and follow-upwith the referring physician.

By integrating subspecialty radiology interpretations to local imaging centers and physician practices, we are able to providethe best in patient care. All in all, it is better medicine.

For more information about eRadiology consults, contact Dr. Michael Recht, Chairman of the Department of eRadiology,at 216/444-2285 or 800/553-5056, ext. 42285, or via e-mail atrechtm@ccf.org.

eRadiologyConsults

{7}

Through the use of new developments in information technology systems, theCleveland Clinic Department of eRadiology, headed by Dr. Michael Recht, offerssubspecialized radiology interpretations to physicians anywhere in the country.

{8}

At The Cleveland Clinic, a team of pulmonologists and oncologistsis utilizing several gaseous chemical sensing and identification devices designed to study the exhaled gases of lung cancer patients.

The new devices are able to detect a single (or patterns of) odorantmolecule(s) such as volatile organic compounds (e.g., alkanes andmethylated alkanes) in breath. Volatile organic compounds (VOCs),which result from lipid peroxidation of polyunsaturated fatty acidsin cell membranes, are felt to be markers of oxidative stress. There isevidence that the production and processing of reactive oxygen speciesdiffers in individuals who have lung cancer, suggesting that the breathVOCs of lung cancer patients may be distinct. In addition, studiesusing gas chromatography and mass spectroscopy (GC-MS) haveconfirmed that distinct patterns of breath VOCs exist in lung cancerpatients. Unfortunately, GC-MS is not readily available at most centers and is not a tool that is easy to apply as a point-of-care test.

A N A LY Z I N G S M E L L P R I N T S

Gaseous chemical sensing and identification devices have employeda variety of sensor arrays, including conductive polymers, non-con-ductive polymer/carbon black composites, metal oxide semicon-ductors, fluorescent dye/polymer systems, quartz microbalancesensors coated with metalloporphyrins and polymer coated surfaceacoustic wave devices. The premise with most of the devices is thatabsorption of gases onto the sensor system causes a change in theconductivity, mass or vibration of the sensor, altering its output. Thesystems generally employ an array of sensors that can be tuned totheir task. The composite output of the array requires complex multivariate statistical techniques to analyze the patterns, or “smell-prints,” of output produced, thus aiding in decision making.

Electronic Nose Sniffs Out Lung Cancer Peter Mazzone, M.D., M.P.H., Serpil C. Erzurum, M.D., and Tarek Mekhail, M.D.

The Cyranose system contains 32 sensors, each a composite ofa nonconducting polymer and conductive carbon black parti-cles. The sensor swells as it absorbs vapor analytes (based onspecific stereochemical characteristics of the odorant molecules),breaking pathways in the conducting film and altering the resistance of the sensor. Because each sensor contains a uniqueand adjustable polymer composite, each responds differently toa given vapor analyte. The combined output of the sensors isanalyzed to develop a smellprint of the gases that were sampled.Once a smellprint has been established for a particular substanceor condition, subsequent samples can be tested to see howclosely the patterns match.

We hypothesized that this device could detect lung cancer on thebasis of the complex smellprints of VOCs in exhaled breath.Smellprints were obtained on the exhaled breath of 14 individ-uals with bronchogenic carcinoma, 19 with alpha1-antitrypsindeficiency (α1-ATD), six with chronic beryllium disease (CBD),and 20 healthy controls. Unlike α1-ATD and CBD, exhaledbreath of lung cancer patients clustered distinctly from controls.These data indicated that the exhaled breath of lung cancer patients has distinct characteristics that can be identified with acarbon polymer sensor system. Subsequently, a cancer predictionmodel was prospectively evaluated in a group of 52 individuals,12 with and 40 without cancer. In the prospective study, exhaledbreath analyses by the electronic nose had 83.3 percent sensitivity(95 percent CI: 51.5 to 97.9 percent) and 87.5 percent specificity(95 percent CI: 73.2 to 95.8 percent) for the diagnosis of lungcancer (see figure below).

A

0

3

2

1

-1

-2

-3

0

B

CD

E

F

* *

G

NON-CANCER

Y1

SVM

CANCER

Prospective analysis of exhaled breath from individuals with and without lung cancer.Positive deflections are predictions of cancer, and negatives are predictions of nocancer. Overall sensitivity was 83.3 percent, and specificity was 87.5 percent.

Reprinted with permission from the American Journal of Respiratory and CriticalCare Medicine. Am J Respir Crit Care Med 2005; 171:1-6.

E VA L U AT I N G C O L O R F I N G E R P R I N T S

We are continuing to study the use of gaseous chemical sensingdevices for the diagnosis of lung cancer. In addition to the Cyra-nose system, we are evaluating a colorimetric sensor array system.Using a novel optical chemical sensor, the colorimetric sensorarray system takes advantage of the color changes that occur inan array of chemoresponsive dyes upon the binding of ligands(e.g., breath VOCs) to identify the composition of a compoundor a pattern of many compounds. Color changes are viewedthrough a scanner that sends signals to a computing device foranalysis. The color fingerprint from a given exposure is the difference between the pre- and post-exposure images as processedby dedicated software (see images above). Further study will clarify the test characteristics of these sensor systems for the diagnosis of lung cancer and small pulmonary nodules.

Lung cancer accounts for approximately 29 percent of all cancerdeaths. Efforts at early detection and treatment have been frus-trating to date, and the overall prognosis remains poor, withroughly one in eight lung cancer patients surviving five years afterdiagnosis. Unlike current diagnostic techniques, the testing of exhaled breath using these new sensor systems is non-invasive,free of complications and inexpensive. Assuming the new sensorsprovide necessary accuracy, they will be a welcome addition todiagnostic and screening programs for lung cancer.

Publication

Machado RF, Laskowski D, Deffenderfer O, Burch T, Zheng S, Mazzone PJ,Mekhail T, Jennings C, Stoller JK, Pyle J, Duncan J, Dweik RA, and Erzurum SC.Detection of lung cancer by sensor array analysis of exhaled breath. Am JRespir Crit Care Med 2005; 171:1286-1291.

E X PA N D E D S E R V I C E S F O R L U N G C A N C E R PAT I E N T S

Lung cancer patients can take advantage ofexpanded services at the Cleveland Clinic’snew multidisciplinary Lung Cancer Clinic.The goal of clinic professionals is to provide comprehensive assessment andmanagement recommendations for patients with lung cancer. A host of supportive care services, including painmanagement, pulmonary rehabilitationand nutrition, also are available to patientsto help them better cope with treatment demands. Consultations, including secondopinions, are based on a team approach,with same-day assessment provided byphysicians from a range of medical and surgical disciplines. Patients may call theCleveland Clinic Taussig Cancer Center’sCancer Answer Line at 866/CCF-8100 for appointments.

Colorimetric sensor array. Sample of a color fingerprint demonstrating changes incolor due to exposure to exhaled breath generated froma colorimetric sensor array.

{9}

{10}

Aspirin Sensitivity and

Aspirin DesensitizationDavid M. Lang, M.D

Patients claiming an “aspirin allergy” due to respiratory, cutaneousor other adverse reactions are being encountered with increasingfrequency. At the same time, indications for aspirin are expanding.

Aspirin-exacerbated respiratory disease (AERD) is a syndromeaffecting an estimated 4 to10 percent of adult asthmatics that mayappear only after years of progression of rhinosinusitis andasthma. Marked by aggressive upper and lower airway inflam-mation, AERD is provoked by ingestion of aspirin and other non-steroidal anti-inflammatory drugs. Despite avoidance of aspirin and cross-reacting drugs, patients with AERD typicallyexperience refractory rhinosinusitis and asthma, are steroid-dependent and require repeated sinus surgery. Once AERD develops, it is present for life.

The term “desensitization” has traditionally described a proce-dure involving the modification of IgE-mediated (allergic/ana-phylactic) potential to a substance – usually a drug such aspenicillin – through repeated re-exposure in a graded-dose fash-ion. Desensitization can permit patients with AERD to receive aspirin for cardiovascular or rheumatologic conditions and mayalso have a salutary effect on the course of rhinosinusitis andasthma. The Cleveland Clinic is one of only a few centers in theUnited States offering oral aspirin desensitization.

The aspirin desensitization procedure, which induces and maintains a state of “tolerance” to aspirin and aspirin-like drugs,entails administration of incremental oral doses of aspirin overthe course of several days, until 650 mg (two tablets) can be takenwithout adverse reaction. Because serious bronchospasm mayoccur at any time during aspirin desensitization, the procedure isperformed in a monitored setting.

At The Cleveland Clinic, we desensitize patients in a short-proce-dure unit, where reactions can be promptly treated, a l:l physician- ornurse-to-patient ratio can be maintained throughout, and emer-gency-resuscitative equipment and trained personnel are readilyavailable. We also stipulate that AERD patients undergo this pro-cedure when their asthma is well-controlled. In order to proceed,FEV1 should be > 70 percent predicted (or prior best measurement).

Because an aspirin-provoked reaction may be delayed, the mini-mum interval between doses is three hours; for this reason, thechallenge may span three to four days. After doses are given at 8a.m., 11 a.m., and 2 p.m., the aspirin challenge is suspended untilthe following day. Patients undergoing this procedure are admittedfor observation, leaving the hospital three hours after the finaldose of aspirin and returning the following morning.

Aspirin desensitization entails provoking respiratory reaction toaspirin, then administering the same dose, such that an individualmay have repeated reactions. When there is no reaction, the aspirin dosage can be increased as specified in the protocol, until650 mg is taken without untoward reaction. Note that aspirin-provoked reaction, resulting in significant bronchospasm, is usually observed at a dosage of 60 mg, less than one-fifth of an aspirin tablet (325 mg).

When desensitization is complete, patients are instructed to continue aspirin on a daily basis. In this fashion, desensitizationcan be perpetuated indefinitely. Studies in which patients take anoptimal daily dose of aspirin (650 mg b.i.d.) have consistentlyshown statistically significant improvement in the course ofAERD, including a lower level of symptoms and reduced med-ication reliance. The economic savings associated with aspirin desensitization treatment accrue from reduced rates of hospitalization and sinus surgery procedures. This interventionhas substantial potential for improving health care outcomes andquality of life for patients with AERD.

In select patients who have avoided aspirin because of“aspirin allergy” but now need it for an indication with no effective alternative, a cautious challenge by an allergist/immunologist may be advisable.

{11}

Serial FEV1 measurements are displayed for GR, a 54-year-old man who underwent successful aspirindesensitization and, in the course of this procedure, experienced two bronchospastic responses to graded-dose aspirin challenge. On day 1 (shown in brown), 60-mg aspirin challenge dose was associated with a 26 percent decline in FEV1, which responded to administration of beta-agonist bronchodilator. Lungfunction improved over several hours. On day 2 (shown in blue), 100-mg dose provoked a 29 percentdecline in FEV1. Protracted bronchospasm continued for several hours despite administration of nebulizedbronchodilator; 100-mg aspirin dose then was tolerated without reaction. On day 3, 150-mg, 325-mg, and650-mg aspirin doses were tolerated without upper or lower airway reaction.

Time Aspirin dosage

Day 1

8 a.m. 30 mg

11 a.m. 60 mg

2 p.m. 100 mg

5 p.m. End of day 1

Day 2

8 a.m. 150 mg

11 a.m. 325 mg

2 p.m. 650 mg

5 p.m. End!

AERD patients who require aspirin (e.g., for cardioprotection)may also be candidates for desensitization. For patients who claim“aspirin allergy” – based on cutaneous or other adverse reaction–a role for desensitization has not clearly been established. However,for properly selected patients who claim “aspirin allergy” and whohave avoided aspirin and aspirin-like drugs for many years butnow require aspirin for an indication for which there is no equallyeffective alternative, cautious challenge performed by a board-certified allergy/immunology physician may be advisable.

W H E N T O C O N S I D E R A S P I R I N D E S E N S I T I Z AT I O N

• When reliance on medication (e.g., systemic corticosteroids) forcontrol of asthma and/or rhinosinusitis is unacceptably high

• When moderate or severe persistent asthma is poorly controlled

• When refractory rhinosinusitis mandates repeated polypec-tomies and sinus surgeries

• When aspirin is required for treatment of cardiovascular, cerebrovascular, rheumatologic or other conditions

2.6

2.2

1.8

30 mg

100 mg

150 mg

60 mg

100 mg

650 mg

60 mg

325 mg

1.4

18 AM 9 AM 10 AM 11 AM 12 Noon 1 PM 2 PM 3 PM 4 PM 5 PM 6 PM

Day 1nebulized beta agonist

Day 2

Day 3

FEV

1 (li

ters

)

29%

26%

Template for Aspirin Desensitization

The new field of molecular biology has brought about significantadvances in the field of genomics, including a first draft of thehuman genome. With this new genetic information, scientists havebegun to define a number of potential tumor markers that mayhave diagnostic, prognostic and therapeutic significance for lungcancer patients. However, taking a new gene from discovery toclinical use is an extremely laborious process, requiring signifi-cant time and resources. A new technique used by pathologists atThe Cleveland Clinic allows the study of hundreds of newly discovered genes and reduces both the time and cost of this validation phase.

Using tissue microarrays, multiple cylindrical tissue biopsy coresare built into a recipient block with defined array coordinates (figure 1). These tissue biopsy cores are taken from individualparaffin-embedded tissue blocks from well-characterized, archivalcancer specimens. The cores of tissue range from 0.6 mm to

2.0 mm in diameter and are placed using a precision instrumentfor optimal tissue block assembly. Depending upon the biopsydensity, the recipient block may contain up to 1,000 tissue samples (figure 2). From this block, up to 400 sections can be cutto place on glass slides for use in immunohistochemical studies oftumor markers (figure 1). In this way, these tissue microarraysallow for a number of different pathologies and tissue types to bestudied at one time, using a minimal amount of reagents.

This new technique is now being used in the Molecular Mor-phology Laboratory in the Division of Pathology and LaboratoryMedicine at The Cleveland Clinic to study large cohorts of lungcancer patients with the hope of finding new ways to improve patient therapy and survival.

Dr. Carol Farver can be reached at 216/445-7695 or atfarverc@ccf.org.

Tissue Microarrays: A New Way of Studying the Pathology of Lung Cancer

Carol Farver, M.D.

To arrange for pulmonary pathology con-sultation services, please send pathologyslides and reports to:

Carol Farver, M.D.Department of Anatomic Pathology/L-25The Cleveland Clinic 9500 Euclid AvenueCleveland, Ohio 44195

PulmonaryPathology Consults

{8}

0.6 mm 1.5 mm

Figure 1. Preparing glass slides from tissue microarrays.

Figure 2. Immunohistochemical studies of tumor markers from tissue microarrays.

Raed A. Dweik, M.D., is the new directorof the Pulmonary Vascular Program atThe Cleveland Clinic. He maintains anactive practice in pulmonary and criticalcare medicine with special interest in pul-monary hypertension. As Director of thePulmonary Vascular Program, Dr. Dweikleads a team of five physicians, two advanced practice nurses, two researchfellows and two research nurse coordi-nators, all with special expertise and in-terest in the various forms of pulmonaryhypertension. He also coordinates inter-action and collaboration with cardiology,cardiothoracic surgery, lung transplanta-tion, hepatology, liver transplantation,sleep medicine and rheumatology.

Dr. Dweik has been involved in pul-monary hypertension research for morethan eight years. His research contributedto the findings of low nitric oxide (NO)in pulmonary hypertension and identifiedthe hypoxic regulation of NO in thelungs. His current NIH-funded work isfocused on the role of NO in normal lungphysiology and in the pathophysiology ofpulmonary hypertension.

Dweik NamedNew Directorof PulmonaryVascular Program

Pulmonary Notes

The Cleveland Clinic is pleased to introduce the first edition of its RespiratoryDiseases Outcomes Book, a summary review of medical and surgical trends, approaches and results. The Clinic is publishing its outcomes data by departmentas a quality measure. Patients and referring physicians can now have the infor-mation they need to make informed decisions when choosing or recommendinga hospital or specialist for medical or surgical care. Outcomes booklets were created for more than 20 Cleveland Clinic surgical and medical areas and are currently being sent to more than 600,000 physicians across the country. Viewthe data online at www.clevelandclinic.org/quality.

C L E V E L A N D C L I N I C 1 2 T H A N N U A L P U L M O N A RY R E S E A R C H D AY S C H E D U L E D

The Cleveland Clinic’s 12th Annual Research & Alumni Day is scheduled for December 9, 2005.

For information about the upcoming 12th Annual Research & Alumni Day, pleasecontact Herbert P. Wiedemann, M.D., Chairman, Department of Pulmonary, Allergy and Critical Care Medicine, at 216/444-8335.

Acute respiratory distress syndrome (ARDS)Allergic rhinitisAllergies (drug and food; latex)Aspirin desensitizationAsthmaBeryllium-induced lung diseaseChronic obstructive pulmonary disease (COPD),

including alpha1-antitrypsin deficiencyInterstitial lung diseaseInterventional bronchology Lung cancerLymphangioleimyomatosis (LAM)Pulmonary alveolar proteinosis (PAP)Pulmonary vascular diseaseSarcoidosisSepsis Sleep-disordered breathing

UrticariaWeaning from mechanical ventilationIn collaboration with thoracic surgery colleagues, we evaluate patients for:Lung transplantationLung-volume reduction surgery (LVRS) for emphysemaPulmonary thromboendarterectomy (for chronic

pulmonary hypertension secondary to thromboemboli)

R E F E R R A L S / I N F O R M AT I O N

For more information, or to refer patients to theCleveland Clinic’s Department of Pulmonary,Allergy and Critical Care Medicine, call toll-free866/CCF-LUNG (223-5864).

For additional information, please visit our Web site at:www.clevelandclinic.org/pulmonary

D E PA R T M E N T O F P U L M O N A RY, A L L E R G Y A N D C R I T I C A L C A R E M E D I C I N E : A R E A S O F E X P E R T I S E

OutcomesBooks

Now Available

{10}

Loutfi Aboussouan, M.D.Office: 216/839-3820Specialty Interests: general pulmonary medicine, neuro-muscular diseases, sleep medi-cine, long-term ventilator care

Muzaffar Ahmad, M.D.Office: 216/444-6506Specialty Interests: pulmonaryfunction lab, diagnostic tech-niques (including fiberopticbronchoscopy), bronchialasthma, lung cancer

Alejandro C. Arroliga, M.D.Head, Section of Critical Care Medicine

Office: 216/445-5765Specialty Interests: criticalcare, pulmonary hypertension, paraneoplastic disorders, pulmonary thromboembolism, lung cancer

Marie Budev, D.O., M.P.H.Associate Medical Director,Lung Transplantation

Office: 216/444-3194

Specialty interests: lung trans-plantation, pulmonary hyper-tension, gender specific pul-monary issues

Jeffrey T. Chapman, M.D.Director, Interstitial Lung Disease Program

Office: 216/444-4222Specialty Interests: interstitial lung disease, pulmonary hypertension, lung transplantation, exhaledmarkers of lung inflammation

Daniel Culver, D.O.Director, Sarcoidosis Program

Office: 216/444-6508Specialty interests: sarcoidosis

DirectoryHerbert P. Wiedemann,M.D.Chairman, Department ofPulmonary, Allergy and CriticalCare Medicine

Office: 216/444-8335Specialty Interests: intensive care (including adult respiratory distress syndrome and sepsis), general pulmonary medicine, exercise testing(dyspnea evaluation)

Thomas W. Rice, M.D.Head, Section of GeneralThoracic Surgery

Office: 216/444-1921Specialty Interests: esophageal,pulmonary, mediastinal, chestwall and diaphragm surgery;minimally invasive (laparoscopicand thoracoscopic) and pediatricgeneral thoracic surgery; lungvolume reduction surgery

Carol F. Farver, M.D.Residency Program Director,Division of Pathology andLaboratory Medicine

Office: 216/445-7695Specialty Interest: pulmonarypathology

Moulay A. Meziane, M.D.Head, Section of ThoracicImaging

Office: 216/444-0282Specialty Interests: thoracic radi-ology, computerized tomography,transthoracic chest biopsies,occupational lung diseases

Raed A. Dweik, M.D.Director, Pulmonary Vascular Disease Program; JointAppointment with Pathology

Office: 216/445-5763Specialty Interests: asthma, pulmonary hypertension, chronicberyllium disease, critical care,bronchoscopy, nitric oxide inlung physiology and disease,exhaled markers in lung disease

Serpil C. Erzurum, M.D.Director, Cleveland ClinicGeneral Clinical ResearchCenter; Chairman, Departmentof Pathobiology, LernerResearch Institute

Office: 216/445-5764Specialty Interests: asthma,pulmonary hypertension, lung cancer

Thomas R. Gildea, M.D.Co-Director, Center for Major Airway Diseases

Office: 216/444-6490Specialty Interests: pulmonaryhypertension, interventionalbronchology, lung transplanta-tion, critical care

Joseph A. Golish, M.D.Head, Section of Sleep Medicine

Office: 216/839-3820Specialty Interests: sleep apnea, hypersomnia, sleep disorders, pulmonary disease and sleep, asthma, lower respiratory infection

David Holden, M.D.Office: 216/986-4000Specialty Interests: general pulmonary medicine

Constance A. Jennings, M.D.Director, Pulmonary Vascular Disease Program; JointAppointment with Pathology

Office: 216/445-4184Specialty Interests: pulmonaryhypertension, pulmonary throm-boembolism, interstitial lungdisease, advanced lung disease

Peter Mazzone, M.D., M.P.H.Director, Lung Cancer Program

Office: 216/445-4812Specialty Interests: lung cancer, intensive care,physician education

Atul C. Mehta, M.D.Head, Section of Bronchology;Vice Chairman, Department ofPulmonary, Allergy and CriticalCare Medicine; Medical Director,Lung Transplantation

Office: 216/444-2911Specialty interests: lung transplantation, lung volume reduction surgery, endobronchialand bronchoscopic proceduresand interventions, transtrachealoxygen therapy, alpha1-anti-trypsin deficiency

Omar A. Minai, M.D.Office: 216/445-2610Specialty Interests: pulmonary hypertension, interstitial lung diseases, lung cancer, COPD, sleep apnea

Beverly V. O’Neill, M.D.Office: 216/839-3820Specialty Interests: general pulmonary medicine, long-term ventilator patients

James K. Stoller, M.D., M.S.Head, Section of RespiratoryTherapy; Joint Appointment with Medical Division Office -Vice Chairman

Office: 216/444-1960Specialty Interests: bronchoscopy, clinical epidemi-ology, alpha1-antitrypsindeficiency, respiratory therapy

Michael Recht, M.D.Chairman

Office: 216/444-2285Specialty Interests: musculoskeletal radiology,magnetic resonance imaging,e-radiology

Staff

D E PA RT M E N T O F

PulmonaryA N D Critical Care

Medicine

D E PA RT M E N T O F

eRadiology

Charles V. Biscotti, M.D.Office: 216/444-0046Specialty Interests: cytopathology,gynecologic pathology

D E PA RT M E N T O F

Pulmonary Pathology

{11}

S E C T I O N O F Allergy A N D

Clinical Immunology

David M. Lang, M.D.Head, Section of Allergy & Clinical Immunology

Office: 216/445-5810Specialty Interests: asthma, allergic disorders, sinusitis, urticaria anaphylaxis,latex allergy, aspirin sensitivity

Mark A. Aronica, M.D.Joint Appointment with Pathology

Office: 216/444-6933Specialty Interests: asthma, allergic disorders

Mercedes Arroliga, M.D.Office: 216/444-6933Specialty Interests: pediatric and adult drug allergy,asthma, sinusitis, rhinitis

Sudish Murthy, M.D., Ph.D.Co-Director, Center for Major Airway Diseases

Office: 216/444-5640Specialty Interests: esophageal,pulmonary, mediastinal, chestwall and diaphragm surgery;minimally-invasive lung volumereduction surgery, lung trans-plant surgery

Gosta Pettersson, M.D.,Ph.D.Surgical Director, LungTransplantation

Office: 216/444-2035Specialty Interests: lung andheart-lung transplantation

Nicholas G. Smedira, M.D.Surgical Director of HeartTransplantation and MechanicalCirculatory Support

Office: 216/445-7052Specialty Interests: lung andheart-lung transplantation; pul-monary thromboendarterectomy

Fred H. Hsieh, M.D.Joint Appointmentwith Pathology

Office: 216/444-3504Specialty Interests: asthma, allergic disorders, mast cell function

Lily C. Pien, M.D.Office: 216/444-6933Specialty Interests: allergic rhinitis, asthma, drug allergies

Cristine Radojicic, M.D.Office: 216/444-6933Specialty Interests: pediatric and adult allergic rhinitis, asthma

DE PA RT M E N T O F

Thoracic A N D

CardiovascularSurgery

SE C T I O N O F GeneralThoracic Surgery

David Mason, M.D.Office: 216/444-4053Specialty Interests: general tho-racic surgery; minimally invasivethoracoscopic and laparaoscopicsurgery, lung cancer, esophagealcancer, malignant mesothelioma,lung transplantation

Cleveland Clinic Pulmonary,Allergy and Critical CareCME CalendarPhysicians are welcome to attend the following upcoming symposia:

H A N D S - O N A P P R O A C H T OD I A G N O S T I C PAT H O L O G Y

Sept. 24-25 InterContinental Hotel & MBNA Conference Center, Cleveland, OH

A I R W AY M A N A G E M E N T

Nov. 12-13InterContinental Hotel & MBNA Conference Center, Cleveland, OH

T H E S E C O N D A N N U A L S Y M P O S I U MO N P U L M O N A RY A R T E R I A LH Y P E R T E N S I O N : PAT I E N T S F I R S T

Nov. 19 InterContinental Hotel & MBNA Conference Center, Cleveland, OH

2 N D A N N U A L L U N G S U M M I T

April 20-22, 2006InterContinental Hotel & MBNA Conference Center, Cleveland, OH

Unless otherwise noted, for more information about the above events,call the Cleveland Clinic Departmentof Continuing Education at 216/444-5696 or 800/762-8173, or visitwww.clevelandclinicmeded.com.

D E PA RT M E N T O F

DiagnosticRadiology

Ruffin J. Graham, M.DOffice: 216/444-8756Specialty Interests: pulmonarythromboembolism, lung cancer and thromboembolic disease

Tan-Lucien Mohammed, M.D.Office: 216/444-3869Specialty Interest: thoracic imagingrelated to lung cancer, lung trans-plantation, upper airway disease

Barbara Risius, M.D.Office: 216/444-6422Specialty Interest: thoracic radiology

ExchangeRespiratory

Herbert P. Wiedemann, M.D., Medical Editor

Yen Izanec, Marketing Manager

Laura Greenwald, Managing Editor

Michael Viars, Graphic Designer

Respiratory Exchange is written for physicians and should

be relied upon for medical education purposes only. It does not

provide a complete overview of the topics covered and should

not replace the independent judgment of a physician about the

appropriateness or risks of a procedure for a given patient.

© 2005 The Cleveland Clinic Foundation

Department of Pulmonary, Allergy

and Critical Care Medicine/W14

The Cleveland Clinic Foundation

9500 Euclid Avenue

Cleveland, OH 44195

Non-Profit Org.

U.S. Postage

PAIDCleveland, Ohio

Permit No. 4184

Research and News for Physicians

from the Cleveland Clinic’s

Department of Pulmonary, Allergy

and Critical Care Medicine and

Section of General Thoracic Surgery

THE CLEVELAND CLINICFOUNDATION

The Cleveland Clinic Department of Pulmonary, Allergyand Critical Care Medicine will hold its second annual

Lung Summit April 20-22, 2006, at the InterContinentalHotel & MBNA Conference Center in Cleveland. The summit

will focus on the interfaces among innovative technology, researchand clinical care.

Topics from last year’s Lung Summit included frontiers in a variety of pulmonaryand critical care areas, including electromagnetic navigation in bronchoscopy,electronic nose technology, carbon monoxide in lung disease, newer modes of mechanical ventilation and artificial lung technology, to name but a few.

Twenty-four visiting speakers including academicians and industry repre-sentatives from Germany, Sweden, Canada and Japan joined Cleveland

Clinic faculty and other experts from around the country for last year’stwo-day summit in Cleveland.

For more information about Lung Summit 2006, call 216/444-5696or 800/762-8173, or visit www.clevelandclinicmeded.com.

Cleveland Clinic plans

Lung Summit 2006: Focus is Innovation

R E F E R R A L S /I N F O R M AT I O N

For more information,

or to refer patients to

the Cleveland Clinic’s

Department of Pulmonary,

Allergy and Critical Care

Medicine, or Section of

General Thoracic Surgery,

call toll-free 866/CCF-LUNG

(223-5864).

P L E A S E V I S I T U S O N L I N E :

Department of Pulmonary,

Allergy and Critical Care

Medicine www.cleveland

clinic.org/pulmonary/

Department of Cardiovascular

and Thoracic Surgery

www.cleveland

clinic.org/heartcenter/