PulmonaryUpdate

Pulmonary Medicine News Vol. 32, No. 1, 2016

INSIDE THIS ISSUE New Definitions and Diagnoses

Anti-Fibrotic Therapy in Interstitial Pneumonia
4 in the Treatment of IPF:
Ongoing Concerns and
Current Practices
The interstitial pneumonias (IPs) are a het-
erogeneous group of diffuse parenchymal
An additional category, unclassifiable,
has also been added to include interstitial
lung diseases characterized by specific clini- pneumonia not fitting a particular pathologic

Lung Transplantation: cal, radiologic and pathologic features. While pattern. PPFE, the newest pathologic sub-

5 Challenges and
Opportunities
pathologically defined, significant overlap in
terms of presentation as well as association
with secondary diseases is known and may
confound initial work-up and diagnosis. This
category, is rare and highlighted by pleural
thickening predominantly in the upper lobes.
It is often associated with parenchymal or
interstitial findings on CT, most commonly

7
review focuses on recent changes and addi- UIP and NSIP (Figure 1). Given the rarity
Current Studies and tions to definitions and diagnostic criteria with of presenting cases, a confident diagnosis
Clinical Trials implications for management. of PPFE is likely best achieved by biopsy as
clinical and radiologic presentation alone may
Revised interstitial pneumonia classification be equivocal.
Eight pathologically defined interstitial pneumo- While IPs have been studied and recog-
nias are included in a newly revised classifica- nized over several decades, the new classifica-
tion system, published in the American Journal of tion system provides a more intuitive organiza-
Respiratory and Critical tion of both the prevalence and natural course
Care Medicine in 2013 of specific histologic patterns and their related
(Table, pages 2-3). clinical findings. A first approach is to separate
Usual interstitial the eight pathologically defined patterns into
pneumonia (UIP) six major (UIP, NSIP, COP, DIP, RB-ILD, AIP)
Nonspecific interstitial and two rare or less commonly encountered
pneumonia (NSIP) entities (LIP and PPFE).
Cryptogenic organiz- Of the six major patterns, a review of
ing pneumonia (COP) their courses and presentations as well as
Desquamative intersti- associated clinical findings further leads to
tial pneumonia (DIP) three subcategorizations:
Respiratory bronchi- Chronically fibrosing (UIP and NSIP)
olitis-interstitial lung Smoking related (DIP and RB-ILD)
disease (RB-ILD) Acutely presenting (COP and AIP)

Figure 1. Suspected PPFE in a 73-year-old female with Acute interstitial This approach may better assist the clinician
progressive dyspnea and hypoxemia. Note upper-lobe- pneumonia (AIP) in terms of recognition and work-up of initially
predominant pleural thickening with significant volume loss Lymphoid interstitial undifferentiated presenting disease. While any of
of the left lung and compensating hyperinflation of the right
pneumonia (LIP) the eight may appear independently as primary
lung (red arrows). Underlying interstitial pneumonia pattern
Idiopathic or idiopathic disease, many are involved in the
appeared consistent with possible UIP characterized by
bibasilar reticular and mild honeycomb changes. pleuroparenchymal progressive lung injury associated with chronic
fibroelastosis (PPFE) organic or inorganic exposures, drug toxicity, and
 survival and clinical course for interstitial lung
disease (ILD) with specifically elicited clinical
and serologic features of autoimmune disease.
While several definitions have been previously
proposed, a recent international consensus
statement, published in American Journal of
Respiratory and Critical Care Medicine in 2013,
has delineated specific criteria for interstitial
pneumonias with incompletely diagnosed but
suggestive autoimmune disease, currently
described as interstitial pneumonia with auto-
immune features (IPAF). Exact criteria involve
the confirmation of an interstitial process by
radiologic or pathologic presentation, exclu-
sion of other associated causes including
Figure 2. Acute exacerbation in a 57-year-old male presenting defined connective tissue disease and at least
with ILD fitting IPAF criteria (positive antinuclear antibodies two features from three representative clinical
titer > 1:2560, Raynauds phenomenon and possible UIP CT domains. These domains include specific auto-
pattern). Rapid decline over several weeks was noted while on immune clinical signs and symptoms, positive
immunosuppressive therapy, where patient presented profoundly
hypoxemic and was ultimately diagnosed with Pneumocystis findings on any of 12 autoimmune serolo-
jiroveci pneumonia. This case highlights two important dis- gies, and morphologic findings of interstitial
cussion points: 1. The inclusion of UIP in IPAF criteria where pneumonia. Remaining morphologic criteria
UIP findings on CT appear to progress in a similar fashion to also include nonparenchymal and extrapulmo-
idiopathic pulmonary fibrosis. 2. While Pneumocystis jiroveci nary features such as evidence of serositis with
pneumonia was eventually diagnosed, new definitions would
frame this under the category of a triggered acute exacerbation pleural or pericardial disease, vasculopathy, or
and not simply infectious pneumonia. intrinsic airway disease.
It is important to note the inclusion of UIP
autoimmune disease. A combined approach of pathology and radiologic patterns despite prior
not only characterizing the presenting clini- studies assessing the presence of autoimmune
cal and radiologic features but also seeking a serology or clinical symptoms in these patients,
secondary cause is important to diagnosis and noting little difference in their clinical course
subsequent management. or survival as compared to those with idio-
pathic pulmonary fibrosis (Figure 2). Questions
Interstitial pneumonia with remain as to the utility of these disease criteria
autoimmune features (IPAF) in clinical practice and implications for long-
Prior studies have suggested differences in term management or follow-up. It is unknown

Pathology type Clinical findings Radiologic features

Usual interstitial pneu- Defining of idiopathic pulmonary fibrosis but Dominated by reticular
monia (UIP) also associated with other chronically pro- and honeycomb findings;
gressive fibrotic disease such as connec- peripheral and bibasilar in
tive tissue disease-interstitial lung disease, distribution
chronic hypersensitivity pneumonitis and
pneumoconioses; portends poorer prognosis
in the idiopathic setting when compared to
other histology

Nonspecific interstitial Frequently associated with autoimmune Dominated by reticular

pneumonia (NSIP) disease; portends a better prognosis when and ground-glass findings;
compared with UIP; generally responsive honeycombing rare, though
to directed anti-inflammatory therapy but has been reported; peripheral
may be chronically progressive and fibrotic; and central distribution, often
biopsy confirmation often needed as up to bibasilar more than upper
one-third of so-called radiologic NSIP may be lobe; characteristic sub-
pathologic UIP pleural sparing may be seen

2 MAYO CLINIC | PulmonaryUpdate

 Pathology type Clinical findings Radiologic features

Cryptogenic organizing May present with waxing and waning Migratory, consolidative and
pneumonia (COP) infectious-type symptoms, often requiring ground-glass infiltrates, often
biopsy assessment to confirm after exclusion bilateral and peripheral with
of other known causes, such as infection; lower lobe predominance;
generally responsive to empiric steroids, atoll (reverse halo) sign
though repeat treatment may be needed supportive but not frequent;
along with occasional short-term immuno- minimal fibrosis or long-term
suppression sequelae

Desquamative interstitial Smoking related in over 80 percent of cases; More centrally located and dif-
pneumonia (DIP) prognosis better than UIP, particularly with fuse ground-glass infiltrates;
smoking cessation; shared spectrum of clini- occasional reticular findings
cal and pathologic overlap with RB-ILD centrally located without
peripheral predominance

Respiratory bronchi- Younger age predilection in prior or active Patchy bilateral centrilobular
olitis-interstitial lung smokers; nonspecific presentation of ground-glass infiltrates or
disease (RB-ILD) dyspnea and cough with pigment-laden fine nodules, with airway
macrophages seen on pathology; smoking enlargement or thickening;
cessation is first order of management fol- minimal reticular or fibrotic
lowed by steroid suppression findings

Acute interstitial pneu- Acute presentation of hypoxemic respira- Patchy ground-glass

monia (AIP) tory failure with diffuse infiltrates, often infiltrates and consolidation,
indistinguishable from idiopathic acute absent of underlying fibrotic
respiratory distress syndrome with typical or chronic appearing
diffuse alveolar damage seen on pathology; interstitial process
equivocal response to steroid therapy with
high inpatient mortality

Lymphoid interstitial Rare, and now considered to be more associ- Thin-walled cystic findings
pneumonia (LIP) ated with secondary disease (rheumatologic, in the majority, with underly-
immunodeficient or hematologic) rather ing patchy ground-glass or
than idiopathic; characterized by extensive consolidative features with
interstitial polyclonal lymphoid cell infiltrates lower lobe predominance
on pathology

Pleuroparenchymal Pleural elastosis seen on pathology when Upper-lobe-predominant

fibroelastosis (PPFE) biopsy is obtained, though clinical presenta- bilateral pleural thickening,
tion nonspecific and often associated with often associated with under-
underlying parenchymal disease of which UIP lying parenchymal interstitial
is most common; prognosis poor based on process and varying degrees
limited case series of fibrosis (possibly UIP vs.
NSIP-like)

Table. Characterizing features of interstitial pneumonias.

how many initial IPAF evolve to diagnosable Reframing acute exacerbation

connective tissues over time, and if connec- Acute exacerbation (AE) represents punctuated
tive tissue disease is not diagnosed, whether decline in respiratory function (less than 30
survival is simply reflective of the underlying days) with new and superimposed infiltrates
histopathology where UIP often portends in the setting of idiopathic pulmonary fibrosis.
poorer outcome as compared with NSIP or The exclusion of secondary causes, including
other histologic patterns. performance of bronchoscopy or tracheal aspi-
rate to assess infection, is key to diagnosis.

MAYO CLINIC | PulmonaryUpdate 3

 Despite well-defined criteria, a standard- important to diagnosis, in effect framing AE as
ized approach to initial work-up remains an idiopathic phenomenon.
elusive as institutional approaches vary and In many ways, the discussion correlates
complete exclusion of secondary causes is often with the Berlin definition of acute respiratory
difficult in real-world practice. An example distress syndrome (ARDS), a conceptual
is the reluctance associated with performing model where severity of hypoxemia along with
bronchoscopy in patients who are not intubated bilateral infiltrates and clinical absence of heart
and presenting with significant respiratory failure frame the acute event. Indeed, associ-
distress and hypoxemia. This aversion is not ated triggers such as pneumonia, aspiration,
unfounded as further decompensation leading septicemia or pancreatitis in acute respiratory
to intubation and mechanical ventilation is distress syndrome are part and parcel of the
known to be associated with greater morbidity work-up and management, but the focus is
and mortality in this setting. directed at broadly managing the acute respira-
On the other hand, delay in performing tory failure syndrome, which may behave
bronchoscopy and the selection of obtained independently of the original inciting etiology.
microbiologic studies may theoretically Whether this model holds similar implications
decrease its yield, particularly when broad- for the future management of acute exacerba-
spectrum antibiotics are often empirically tion in ILD is yet unknown, as historical use
provided. The term suspected acute exac- of low tidal volume strategies has not proved
erbation was therefore recently advocated beneficial. In fact, mechanical ventilation
for acute worsening of respiratory symptoms appears to be associated with worse survival,
unexplained by secondary causes but with though it is unknown whether mechanical
incomplete work-up. ventilation truly causes additional harm in this
Recent updates to the international consen- setting or is simply a surrogate of more-severe
sus definition of AE, published in the American and perhaps irreversible lung injury.
Journal of Respiratory and Critical Care Medicine
in 2016, have reflected on these difficulties and For more information
modified prior criteria in the hopes of better Travis WD, et al. An official American Thoracic
reflecting clinical practice and outcomes. Society/European Respiratory Society statement:
New definitions no longer require complete Update of the international multidisciplinary
exclusion of secondary causes, but instead classification of the idiopathic interstitial
include known findings as triggers of AE. An pneumonias. American Journal of Respiratory
initial approach is to ensure the absence of and Critical Care Medicine. 2013; 188:733.
pulmonary edema or volume overload where
AE may be excluded, followed by a reasonable Collard HR, et al., Acute exacerbation of
assessment for secondary etiologies where idiopathic pulmonary fibrosis. An international
known and unspecified causes of respiratory working group report. American Journal of
failure are all categorized as forms of AE. This Respiratory and Critical Care Medicine. 2016:
approach contrasts with the prior definition, 194;265.
where exclusion of secondary causes was

Anti-Fibrotic Therapy in the Treatment of IPF:

Ongoing Concerns and Current Practices
While multiple trials assessing different drugs mirrored each other in the number of
mechanisms and approaches to treatment phase III clinical trials leading to approval
have proved negative over the past decade and slowing of forced vital capacity (FVC)
and a half, two drug therapies have recently decline, with pirfenidone touting a signal for
become available for the directed treatment of improved mortality, and nintedanib suggest-
idiopathic pulmonary fibrosis (IPF). Pirfeni- ing decreased incidence of acute exacerbation
done, a well-known anti-fibrotic drug already in two of its three large trials.
approved outside the U.S., and nintedanib, While the availability of two agents for a
a tyrosine kinase inhibitor, both became progressive and fatal disease is welcomed,
available internationally in October 2014. The questions remain regarding indications and

4 MAYO CLINIC | PulmonaryUpdate

timing of initiation, side effects, and long-term When pooling data for two of the pirfeni-
outcomes. Clinical trials to date have excluded done trials, 21 percent of participants still had
people with FVC of less than 50 percent FVC decline greater than 10 percent while on
predicted, leaving little understanding of how therapy. Furthermore, patient variables that pre-
treatment affects people with more-advanced dict a medication response are yet to be deter-
disease. The careful selection of trial partici- mined. Indeed, pirfenidone has been available
pants limits applicability of outcomes to for a number of years outside the U.S. for IPF
patients typically seen in practice. For exam- treatment, yet few long-term follow-up studies
ple, in clinical practice, up to 50 percent of exist and are limited to center-specific reviews of
patients with IPF may have possible usual clinical experience. Unfortunately, such studies
interstitial pneumonia pattern on chest CT have been more equivocal than confirmatory
scans, while patients in clinical trials, sub- of clinical or survival benefit. Finally, for some
jected to diagnostic adjudication by commit- patients, disease stability (defined by a relative
tee, represent a purer diagnostic group. In lack of symptoms or minimally changed FVC)
addition, trials often exclude concomitant may be justification for deferring initiation of
emphysema on chest imaging, not an uncom- drug therapy, though the expectation of future
mon finding in clinical practice. progression must be acknowledged.
Side effects, including photosensitivity At this time, use of both anti-fibrotic drugs
rash with pirfenidone and loose stools with is limited to the diagnosis of IPF but will likely
nintedanib, may lead to drug intolerance see expansion to non-IPF interstitial lung
and early discontinuation. As both medica- disease in the near future. Where patients had
tions are intended to slow disease progression, little opportunity to fight disease in the past,
perhaps measured over months or years, current therapies offer a chance to slow disease
drug adherence remains an important issue, progression and delay severity of symptoms.
particularly as clinical symptoms such as Research continues to optimize selection of the
dyspnea or cough may not be expected to target population that will most benefit and
significantly improve. experience the fewest side effects.

Lung Transplantation: Challenges and Opportunities

The care of patients with progressive lung disease
has been transformed by orthotopic lung trans-
plantation. This therapy, limited by the number
of donor organs and by the need to select patients
who are able to tolerate the twin demands of sur-
gery and immunosuppression, nevertheless offers
the potential of years of disease-free living.
As the nationwide need for organs con-
tinues to grow, the shortage of donor lungs
is a major limitation. It is estimated that less
than 20 percent of all donor lungs are suitable
for transplant. In the face of such a shortage
of donor organs, Mayo Clinic in Jackson-
ville, Florida, is developing novel approaches
to maintaining donor organs. In a unique
academic-industry partnership with United
Therapeutics Corp., Mayo Clinic is furthering
the study of ex vivo lung perfusion and ventila- Figure 1. Ex vivo perfusion and ventilation of a
tion to resuscitate and support donor lungs that donor lung.
would otherwise be unavailable for transplant
(Figure 1). This technology, which is currently pressure, low-inspired oxygen) ventilation, and
confined to use within clinical trials, deliv- close monitoring for indicators of improving
ers low-pressure oxygenated perfusate that function. Ex vivo lung perfusion (EVLP) offers
comprises hyperosmolar solutions to isolated the potential of providing many more organs
organs, combined with protective (low- for transplant.

MAYO CLINIC | PulmonaryUpdate 5

 Figure 2. Construction of a three-story lung restoration center at Mayo Clinics
campus in Florida will begin in 2017.

The combined venture is a multiyear lungs following cardiac death and the tradi-
development with plans to begin construction tional donors following brain death, although
of a three-story lung restoration center within the former involves a more resource-intense
the heart of Mayo Clinics campus in Florida in commitment from the transplant procurement
2017 (Figure 2). This facility will house the lung team. The patient with interstitial lung disease
perfusion program as well as space for research presents a few unique challenges, particularly
carried out by the Center for Individualized if the lung condition is a manifestation of a
Medicine and Center for Regenerative Medicine, systemic disease such as a rheumatologic dis-
to further investigation for years to come. All order. The activity and course of extrapulmo-
three Mayo Clinic sites now have active lung nary manifestations may impact the patients
transplant programs; Mayo Clinics campus in candidacy for transplant. Finally, because the
Arizona launched a program in 2016. new anti-fibrotic agent nintedanib has been
Nationwide, one-year survival following associated with arterial thrombosis, this drug
lung transplant continues to improve, but is typically discontinued upon the patients
longer term outcomes remain a challenge, listing for transplant.
due in large part to chronic allograft rejection The decision concerning single- or double-
from bronchiolitis obliterans, characterized by lung transplantation is often of major concern
inexorable small airways obstruction. Manage- to patients and is influenced by organ avail-
ment is aimed primarily toward prevention, ability, age and functional status single lung
but strong evidence is lacking for a specific is generally a shorter, less complex operation
approach. In the absence of any reliable treat- as well as past surgical history, but in general,
ments for established bronchiolitis obliterans, carefully selected patients have good quality
investigators from Mayo Clinic in Jackson- of life and often excellent lung function after
ville, Florida, are conducting a clinical trial of single-lung transplantation.
mesenchymal stem cells in lung transplant
recipients with chronic rejection. For more information
Patients with interstitial lung disease, who Mayo Clinic. Mesenchymal stem cell therapy
have the highest death rates among patient for lung rejection. ClinicalTrials.gov.
diagnostic groups awaiting transplant, make https://clinicaltrials.gov/ct2/show/NCT02181712
up one of the largest groups referred for
transplantation. The current allocation system Lung Bioengineering Inc. Extending preserva-
favors such patients by adjusting the lung tion and assessment time of donor lungs using
allocation score based on underlying disease, the Toronto EVLP system at a dedicated EVLP
in the hopes of a more timely intervention. facility. ClinicalTrials.gov. https://clinicaltrials.
However, patients may still wait several years. gov/ct2/show/NCT02234128
Additional strategies include the use of donor

6 MAYO CLINIC | PulmonaryUpdate

Current Studies and Clinical Trials
See all Pulmonary and Critical Care Medicine current clinical trials at http://www.mayoclinic.org/departments-centers/pulmonary-critical
-care-medicine/clinical-trials.

Extending Preservation and Assessment Time Home-Based Health Management of COPD Patients
of Donor Lungs Using the Toronto EVLP Principal investigator: Roberto P. Benzo, M.D.
System at a Dedicated EVLP Facility Primary outcome measure: Change in number of daily steps
Principal investigator: Cesar A. Keller, M.D. between the intervention and control conditions as measured
Primary outcome measure: Primary graft dysfunction (PGD), by the SenseWear Pro ArmBand and change in quality of life
grade 3 and patient survival. between the intervention and control conditions as measured by
Time frame: PGD grade 3 at 72 hours; survival at 30 days the Chronic Respiratory Disease Questionnaire.
Contact study coordinator: Cesar A. Keller, M.D., at 904-956- Time frame: Daily steps and quality of life measured at weeks
3271 or keller.cesar@mayo.edu one, nine and 17
NCT02234128 Contact study coordinator: Johanna P. Hoult, CCRP, at 507-293-
0190 or hoult.johanna@mayo.edu
A Prospective Assessment of Patient NCT02557178
Characteristics in Thoracic Transplantation and
Their Relationship to Important Transplant Outcomes Mesenchymal Stem Cell Therapy for Lung Rejection
Principal investigator: Cassie C. Kennedy, M.D. Principal investigators: Cesar A. Keller, M.D.,
Synopsis: A multisite prospective survey of pre-heart and pre- and Abba C. Zubair, M.D., Ph.D.
lung transplant patients examining factors such as resilience, Primary outcome measure: Number of participants with serious
attitude, self-management and quality of life. and nonserious adverse events (patients will be assessed for
Synopsis: A prospective qualitative research study designed their capacity to tolerate IV infusion of MSC without acute clinical
to explore patients experiences while on the heart or lung or physiological deterioration) and changes in pulmonary function
transplant waiting list. tests (vital signs, pulmonary function tests FEV1 and FCV), and
Contact study coordinator: Elizabeth N. Stevens at 507-266- Borg Dyspnea Index will be evaluated, and chest radiograph, CBC
7765 or stevens.elizabeth1@mayo.edu and serum chemistry will be performed.
1K23HL128859 Time frame: Up to two weeks
Contact study coordinator: Abba C. Zubair, M.D., Ph.D.,
A Registry for Patients by the Pulmonary Fibrosis Foundation at 904-956-3318 or zubair.abba@mayo.edu
Principal investigator: Andrew H. Limper, M.D. NCT02181712
Primary outcome measure: Analysis of registry data to lead to
aggregated reports summarizing the epidemiology of interstitial Qualitative Assessment of
lung diseases, as well as disease, treatment and outcomes. Pre-Transplant Patients Experiences
Time frame: Five years Principal investigator: Cassie C. Kennedy, M.D.
Contact study coordinator: Pulmonary Clinical Research Unit at Synopsis: A prospective qualitative research study designed
800-753-1606 or PCRUE18@mayo.edu to explore patients experiences while on the heart or lung
NCT02758808 transplant waiting list.
Contact study coordinator: Elizabeth N. Stevens at 507-266-
A Study Comparing the Effectiveness and Safety of 7765 or stevens.elizabeth1@mayo.edu
High-Titer Versus Low-Titer Anti-Influenza Immune 1K23HL128859
Plasma for the Treatment of Severe Influenza A
Principal investigator: Philippe R. Bauer, M.D., Ph.D.
Primary outcome measure: Subjects clinical status (6-point
ordinal scale): death; in ICU; non-ICU hospitalization requiring
supplemental oxygen; non-ICU hospitalization not requiring
supplemental oxygen; not hospitalized but unable to resume
normal activities; not hospitalized with full resumption of
normal activities.
Time frame: Measured at Day Seven
Contact study coordinator: Sueanne (Sue) M. Weist, R.N., CCRP,
at 507-255-6804 or weist.sueanne@mayo.edu
NCT02572817

MAYO CLINIC | PulmonaryUpdate 7

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Pulmonary Update
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