Supplementum 163 - Swiss Medical Weekly

33 S SWISS MED WKLY 2008;138(Suppl 163) · www.smw.ch
Poster Session 3 - SSP / SGP
P152
A successful treatment of mediastinal fibrosis with low-dose
prednisone combined with mycophenolate mofetil
M. Witschi, L.P. Nicod.
Inselspital (Bern, CH)
Background: Mediastinal fibrosis is associated with several
syndromes such as retroperitoneal fibrosis, Reidel’s thyroiditis,
sclerosing cholangitis, pulmonary hyalinizing granuloma or multifocal
fibrosclerosis. These syndromes are believed to be different
manifestations of the same disease. It’s a rare disease. It is estimated
that its incidence is 1/1’000’000 person-year and its prevalence is
1.38 cases/100’000 inhabitants. It is idiopathic or secondary seen in
autoimmune diseases, infections or drug induced. The age at disease
onset peaks between 50 and 60 years. Pathohistological research
show a mixture of chronic inflammation with B- and T-cells and
fibrosis. Immunosuppressive therapy with prednisone was the basic
therapy regimen for years next to surgery in cases of complications.
Because of the rarity of this disease there are lacking endemic
studies and no evidence based therapy is determined. Several case
report studies show successful treatments with newer
immunosuppressive agents.
History: We present a case of a 67 year old man with mediastinal
fibrosis. On his holidays in spain he was suffering from a syncope.
After returning home, a progressive dyspnoe developed. Further
examinations revealed a aortic stenosis and a stenosis of the right
coronary artery. A surgical intervention was planed. The preoperative
evaluation with a CT-scan showed a soft-tissue density mediastinal
mass surrounding the aorta. The histopathological examinations were
consistent with periaortitis as seen in retroperitoneal fibrosis and
mediastinal fibrosis. Laboratory findings showed normal function of
the kidneys and autoimmune antibodies were normal.
Therapy and follow up: Because of his diabetic state, he was treated
with a steroidsparing agent. We tried mycophenolate mofetil because
of its relatively few adverse reactions. He was treated with prednisone
10mg/d and mycophenolate mofetil 2 g/d.
A follow up 3 months after starting the therapy showed a regression
of the mediastinal and retrocrural mass. No signs of aneurism were
detectable. The medication was well tolerated, the diabetes was
under control.
Conclusion: Mycophenolate mofetil and low dose steroids is a safe
and efficacious therapy in mediastinal fibrosis.
P153
Engineered nanoparticles for gene delivery in a bleomycininjured
lung fibrosis model
C. von Garnier1 , A. Gazdhar1 , A. Fink2 , H. Hofmann2 , P. Gehr3 ,
L.P. Nicod1 , T. Geiser1 .
1 Inselspital (Bern, CH); 2 EPFL (Lausanne, CH); 3 Universität Bern
(Bern, CH)
Background: Pulmonary fibrosis is a progressive disease with a poor
prognosis. To date the mechanisms of this devastating disease are
still unclear and no specific therapy exists. Increasing evidence
suggests that the changes present in pulmonary fibrosis result from
sequential alveolar epithelial injury and abnormal alveolar wound
repair. Complex cell interactions and mediators including growth
factors are involved in this repair process. Hepatocyte growth factor
(HGF) has been implicated in the prevention and also treatment of
pulmonary fibrosis. Our own results have shown that pulmonary
fibrosis was attenuated by in vivo electroporation-mediated gene
transfer of hHGF (Gazdhar A et al, Am J Physiol Lung Cell Mol
Physiol. 2007;292(2):L529–36). For future clinical applications, gene
therapy applications require safe and efficient methods for gene
delivery. Anticipated applications for engineered nanoparticles (NP) in
medicine include the use of bioengineered NP for novel therapeutic or
diagnostic approaches. Biocompatible NP may therefore represent an
efficient, safe, yet minimally invasive method for gene delivery in the
respiratory tract. We herein present the development of a protocol for
NP-based gene transfer to the bleomycin injured lung.
Methods: Super-paramagnetic iron oxide NP (SPION) were produced
that contain an iron oxide core coated with a fluorochrome-labelled
polymer shell (PVA). SPION (250 mg) were administered in a volume of
250 ml unilaterally to the left lung through intra-tracheal intubation 7
days after bleomycin-induced lung injury in a rat model. The
experiments were terminated at 24 hrs post NP instillation and NP
deposition in fibrotic lung tissue was evaluated by confocal
microscopy.
Results: In preliminary proof-of-concept studies, confocal
microscopy showed homogenous NP deposition in the lung confined
to the alveolar epithelium and macrophages without inducing marked
alveolar inflammation. Further characterisation by EM is underway for
detailed characterisation of SPION-cell interactions.
Conclusions: Initial proof-of-principle experiments showed an
preferential deposition of NP to alveolar epithelial cells that are a
target for novel gene therapies in lung fibrosis. Engineered NP may
therefore provide a novel approach for gene delivery in pulmonary
fibrosis.
P154
Comparison of batch adjustment methods for the analysis
of gene expression microarray data
M. Gao1 , F. Baty1 , M. Schumacher2 , M. Brutsche1 .
1 Universitätsspital Basel (Basel, CH); 2 Novartis AG (Basel, CH)
Background: Microarray experiments are often performed in batches
due to the characteristics of sample acquisition (multi-institutions, cell
culture experiments, different microarray platforms), or due to
practical reasons (load capacity for RNA extraction, labeling or
hybridization). As a consequence microarray datasets are often
affected by non-biological experimental variance or “batch effects”.
Different batch adjustment methods have been proposed aiming to
reduce this technical variance.
Methods: We benchmarked 3 different batch adjustment methods,
which are Correspondence Analyses with respect to Instrumental
Variables (CAIV), Empirical Bayes (EB) and Orthogonal Projections to
Latent Structures (OPLS). Calculations were done on 4 publicly
available lung cancer datasets, which are Bhattacharjee et al. (2001),
Beer et al. (2002), Bild et al. (2006) and Yap et al. (2005). Data preprocessing
by these algorithms were compared using multivariate
correlation coefficients (RV). The gain obtained in terms of
identification of differentially expressed genes and classification
accuracy was assessed.
Results: CAIV, EB and OPLS successfully adjusted batch effects.
Data pre-processed using CAIV and EB showed a higher accuracy to
identify differentially expressed genes. OPLS showed a higher
classification accuracy than CAIV and EB. The choice of the
appropriate algorithm also depends on the experimental design. For
CAIV and EB, specific batch information is required. In contrast to EB,
CAIV can simultaneously handle nested batch information. OPLS,
which requires a priori phenotypic information, may be more prone to
overfitting.
Conclusion: Batch effects can significantly correct, but also distort
the results of microarray data analysis. Different batch adjustment
methods have different characteristics, which impact on the results of
downstream statistical analysis. Among the three methods, CAIV
appears particularly interesting due to its high flexibility.
Figure 1: Hierarchical clustering comparing the RV correlation
coefficient which measures the similarity between two datasets
before and after batch adjustment pre-processing. CAIV, EB and
OPLS perform equally well and give comparable result. The
integrated table summarises the characteristics of the 3 methods in
question (“+” efficient, “0” indifferent, “–” inefficient or “NA” not
applicable).