Tuesday October Interstitial Lung Disease I continued DISCLOSURE Osman by bigmekahlo


									Tuesday, October 24, 2006
Interstitial Lung Disease I, continued

  DISCLOSURE: Osman Ozes, University grant monies No; Grant                      pirfenidone (1 mM), then treated with TGF- . Cellular lysates were
monies (from sources other than industry) No; Grant monies (from                 prepared and Western blot was used to measure expression and activation
industry related sources) T. Takuma and M. Taylor: Grant from Inter-             of p38 and p38 . Using a human in vitro kinase panel, we also
Mune; Shareholder O. Ozes, J. Derrick, S. Stevens, L. Blatt: InterMune           discovered that p38 and p38 are directly inhibited by pirfenidone.
shareholders; Employee O. Ozes, J. Derrick, S. Stevens, L. Blatt: Inter-            RESULTS: Western blot analysis revealed that both p38 and p38
Mune employees; Fiduciary position (of any organization, association,            are expressed in normal and IPF human lung fibroblasts. Additionally,
society, etc, other than ACCP No; Consultant fee, speaker bureau,                activation of p38 and p38 was induced by the exposure of cells to
advisory committee, etc. No; Other No; Product/procedure/technique               TGF- . Pretreatment of lung fibroblasts with 1mM pirfenidone signifi-
that is considered research and is NOT yet approved for any purpose, All.        cantly attenuated TGF- -induced activation of p38 and p38 , and
                                                                                 comparative analysis of collagen synthesis in HFL-1 cells over-expressing
                                                                                 wild-type and pirfenidone-resistant mutants of p38 and p38 confirmed
CLINICAL PROFILE OF PATIENTS WITH UIP EXACERBA-                                  inhibition in wild-type, but not mutant forms of p38 following exposure to
TIONS                                                                            pirfenidone.
Krishna M. Sundar MB, BS, MD* David Nielsen RRT Michael J. Pearce                   CONCLUSION: Our results demonstrate that p38 MAPK, previ-
MD William T. Alward MD Utah Valley Regional Medical Center, Provo,              ously believed to be expressed only in smooth muscle cells, is expressed in
UT                                                                               normal and IPF human lung fibroblasts. The inhibition of TGF- -induced
                                                                                 p38 and p38 activation/activity in fibroblasts suggests that pirfenidone’s
   PURPOSE: Analysis of acute exacerbations (AEs) of usual interstitial          antifibrotic activity is mediated at least partly through inhibition of the p38
pneumonia (UIP).                                                                 MAPK signal transduction pathway.
   METHODS: Retrospective analysis of clinical profiles, laboratory                 CLINICAL IMPLICATIONS: Further study is warranted to eluci-
parameters and outcomes of patients with acute exacerbations of chronic          date the clinical utility of this novel compound.
interstitial lung disease seen at our center over a 3-year period.                  DISCLOSURE: Osman Ozes, University grant monies No; Grant
   RESULTS: Seven patients met the criteria for acute exacerbations of           monies (from sources other than industry) No; Grant monies (from
chronic ILD. All patient had underlying UIP, had acute worsening of              industry related sources) No; Shareholder O. Ozes, S. Stevens, R. Phillips,
dyspnea, and developed new ground-glass opacities without specific               L. Blatt: InterMune shareholders; Employee O. Ozes, S. Stevens, R.
evidence for infection. Patients were Caucasian with male to female ratio        Phillips, L. Blatt: InterMune employees; Fiduciary position (of any
of 4:3. All but one were non-smokers. In two patients, AEs were the initial      organization, association, society, etc, other than ACCP No; Consultant
presentation of underlying IPF. In six patients, the diagnosis of UIP was        fee, speaker bureau, advisory committee, etc. No; Other No; Product/
made by video-assisted thoracoscopic (VATS) biopsy; in two of these              procedure/technique that is considered research and is NOT yet approved
patients, VATS biopsy was done during their AEs and both these patients          for any purpose, All.
died being unable to be weaned off mechanical ventilatory support. In the
other five patients, two patients died within a few months of their AEs,
one required lung transplantation and two improved with steroids.
Response of AEs to high-dose steroids was variable and not dependent on
severity of underlying UIP. In two patients, ground-glass opacities on
HRCT involved one side predominantly. Four patients had laboratory               Lung Cancer: Screening and Diagnosis
abnormalities that suggested autoimmune phenomena (elevated rheuma-
toid factor in 2, elevated antinuclear antibodies in 3, increased Scl-70 in 1)
                                                                                 10:30 AM - 12:00 PM
but exhibited no other features of a connective tissue disorder. In none of
these patients did the underlying UIP respond to steroids or cytotoxic           DANTE: A RANDOMIZED STUDY ON LUNG CANCER
agents.                                                                          SCREENING WITH LOW-DOSE SPIRAL CT (LDCT): END OF
   CONCLUSION: Outcomes from acute exacerbations of UIP are poor.                ACCRUAL AND PRELIMINARY RESULTS
Abnormalities in laboratory autoimmune parameters in patients with UIP           Maurizio V. Infante MD* Lutman R. Fabio MD Silvio Cavuto PhD
may indicate a covert connective tissue disorder; however the lack of other      Giorgio Brambilla MD Giuseppe Chiesa MD Eliseo Passera MD Um-
features of a connective tissue disorder and failure to respond to               berto Cariboni MD Marco Alloisio MD Anna Destro PhD Maurizio
immunosuppressive agents makes these autoimmune phenomena being                  Chiarenza MD Massimo Roncalli MD, Ph.D Aranzulla Giuseppe MD
associated with IPF rather than a specific autoimmune disorder.                  Angeli Enzo MD Ravasi Gianni MD Ist. Clinico Humanitas, Milan, Italy
   CLINICAL IMPLICATIONS: Surgical biopsy during UIP exacerba-
tions may be associated with increased mortality. Whether autoimmune                PURPOSE: To assess the possibility of reducing lung cancer mortality
abnormalities on laboratory testing in patients with IPF makes these             in a high risk population. Lung Cancer (LC) incidence, prevalence, stage
patients prone to AEs remains to be proven.                                      at presentation, resectability and survival are secondary endpoints. A set of
   DISCLOSURE: Krishna Sundar, None.                                             specific genetic abnormalities in blood and sputum is also being assessed.
                                                                                    METHODS: Inclusion Criteria were: male sex, age 60-75, smokers of
                                                                                 20 pack-years, quit less than 10 yrs ago. Subjects were randomized in
PIRFENIDONE ATTENUATES TRANSFORMING GROWTH                                       two groups: LDCT Screening or Control (Ctrl). On accrual, all subjects
FACTOR-BETA-INDUCED ACTIVATION OF P38-ALPHA AND                                  underwent a baseline physical examination, and once-only Chest X-ray
P38-GAMMA MITOGEN–ACTIVATED PROTEIN KINASES IN                                   (CXR) and sputum cytologic examination. Screening-arm subjects have
HUMAN LUNG FIBROBLASTS: IMPLICATIONS FOR TREAT-                                  then undergone yearly LDCT while controls get yearly interview/physical
MENT OF FIBROTIC LUNG DISEASES                                                   examination only and investigation upon clinical suspicion.
Osman N. Ozes PhD* Sarah K. Stevens MS Roderick J. Phillips PhD                     RESULTS: From June 2001 to February 2006, 2472 cases (LDCT
Lawrence M. Blatt PhD InterMune, Inc., Brisbane, CA                              1276, Ctrls 1196) were randomized. Age, smoking and comorbidities are
                                                                                 evenly distributed. 40% have had at least one follow-up examination.Base-
   PURPOSE: Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease          line screening by CXR/Sputum cytology revealed lung cancer in 21
characterized by progressive destruction of alveolar structures, excessive       patients. First-year LDCT revealed 12 LCs. 9 LDCT patients (2 interval
fibroproliferation, and unrestrained extracellular matrix deposition. Trans-     cases ) and 13 Controls developed LC during follow-up.More LCs and
forming growth factor beta (TGF- ), a profibrotic cytokine aberrantly            more Stage I LC have been detected in the LDCT group, while resection
expressed in IPF lungs, is a potent regulator of fibrogenesis and connec-        rates are similar. Non-LC malignancies were detected in 3,06 % of LDCT
tive tissue synthesis. We recently reported that pirfenidone binds com-          and in 1,92% of Controls.So far, 8 (0,63%) LDCT and 6 (0,50%) Ctrl
petitively to the ATP-binding site of two isoforms of p38 MAPK (p38 and          patients have died of lung cancer, while 14 (1.1%) LDCT and 11 (0.92%)
p38 ), a key intracellular mediator of TGF- -induced collagen synthesis.         Ctrl patients have died of competing causes of death.
In order to further explore the potential therapeutic utility of pirfenidone        CONCLUSION: DANTE has shown the feasibility of a randomized
in IPF, we sought to confirm the expression of p38 in human lung                 LDCT screening trial with no intervention in the control arm. Baseline
fibroblasts and investigate the inhibitory activity of pirfenidone against       screening results are in agreement with the LSS baseline data. Mortality
TGF- -induced p38 and p38 activation in these cells.                             figures are still too small to be meaningful.
   METHODS: Human lung fibroblasts (HFL-1) were cultured in F12K                    CLINICAL IMPLICATIONS: The potential advantages of LDCT
medium; serum-starved cells were pre-treated with medium or with                 screening for reducing lung cancer mortality must be weighted against

114S                                                                                                                      CHEST 2006 —Slide Presentations

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