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					TUBITAK Grant No:SBAG-2567(102S045)
    Asbestos Usage In Turkey




• Interior of house plastered with   • Outdoors and floors of the same house
asbestos-containing ‘white soil’.    plastered with asbestos-containing ‘white
                                     soil’.
Fairy Chimneys in Cappadocia
                 Erionite fibre




 From A. Umran Dogan




• Houses constructed with bricks
containing erionite fibres
             INTRODUCTION
Intrapleural inoculation of erionite displayed 300-
800 and 100-500 times more carcinogenic activity
than chrysotile and crocidolite respectively
Carthew P, Hum Exp Toxicol 1992; 11: 530-4



Patients     with  erionite-induced   MPM     have
significantly shorter life time. Hence, erionite
induced cases have higher aneuploidy compared with
asbestos induced cases (72.7% vs 13.8%) suggesting
more aggressive tumor behavior.
Emri S. Lung Cancer 2001; 33: 109-114
HYPOTHESIS
Since erionite and asbestos induced
MPM differs in biological behavior,
their contributions of apoptotic
pathways in tumor development could
be different.
    Mitochondrial pathway
  Anti-       Pro-          HR3
apoptotic   apoptotic   Homology Only
 Bcl-2        Bax           Bad
 Bcl-XL       Bak            Bid
 Bcl-W       Bcl-XS          Bik
 Mcl-1      Bok/Mtd       Bim/Bod
Boo/Diva                    Hrk
 NR-13                      Nix
Bcl-2 Prevents The Cancer Cell
            Death
                         Bcl-2/bax: Worse
                         prognosis
                         Advance tumor grade

                        ↓Bcl-2/Bax :Lower tumor
                        grade.
                        Better prognosis
                        Better treatment response
The Final Common
    Pathway



                  Cytochrome c

     Fas –Fas L

 Caspase Activation

    Cell Death
                 AIM
• Bcl 2/Bax and Fas/Fas L pathways were
  studied in vivo in a comparative manner
  in tissue sections from patients with
  erionite and asbestos induced MPM.
• The association of expression pattern
  and survival has been evaluated.
• Sections from adenocarcinoma served
  as control group.
MATERIAL AND METHOD
52 patients including 16 (30.7%)
patients with erionite and 19 (36.5%)
patients with asbestos induced MPM
were enrolled in the study.
Tissue samples from patients with
adenocarcinoma [n=17 (32.6%)] served
as control groups.
METHOD 2
•Immunohistochemically
semiquantitative
          the staining extension
          expressing the percentages
of positive cells/tissue section
          the staining intensity
     0=null, 1=weak, 2=moderate and
3=strong.
        Statistical Analysis
 SPSS 10.01 for Windows (1999) was
  used for statistical analysis. Chi square,
  Fisher’s exact chi square, Kruskal Wallis
  ANOVA and, Mann Whitney U tests
  were performed for comparisons .
 Survival analysis was done by Kaplan
  Meier Survival analysis
 Prognostic factors were analysed by
  Cox’s Multivariate Regression Model.
RESULTS
Patient           Erionite MPM Asbestos    Adenocarcino
characteristics   N=16(%)      MPM         mama
                               N=19 (%)    N=17 (%)
E/K               11/5        10/9         14/3
Mean age (year) 48.7312.42   47.8911.7   53.8811.25
                              3
Stage
Stage I           2 (14.3)    8 (42.1)     3 (18.8)
Stage II          2 (14.3)    1 (5.3)      1 (6.3)
Stage III         6 (42.9)    7 (36.8)     8 (50.0)
Stage IV          4 (28.6)    3 (15.8)     4 (25.0)
Tumor type
Epithelial        10 (62.5)   12 (63.2)
Sarcomatous       3 (18.8)    2 (10.5)
Mixed             3 (18.8)    5 (26.3)
Diagnostic method   Erionit MPM   Asbest MPM   Adenokarsinoma
                    N=16(%)       N=19 (%)     N=17 (%)


Toracotomy+open         8 (50)     16 (84.2)       8 (47)
biopsy


Torachoscopy            4 (25)      3 (15.8)         0




Closed pleural          4 (25)         0          3 (17.6)
biopsy
Bronchoscopic                          0          3 (17.6)
biopsy
Trucut Biopsy                          0          3 (17.6)
                              Erionite   Asbestosis
                              MPM        MPM
                              N=16 (%)   N=19 (%)
Surgery                       9 (56.3)   16 (84.2)
Type of Surgery
Paliative tumor
reduction surgery
    Extrapleural          0              1 (5.3)
    pneumonectomy
    Pleurectomy+decort    3 (18.8)       9 (47)
    ication
Paliative minor surgery

    Toracoscopy+intrac    6 (37.5)       6 (32)
    avitary cisplatin
Antibody     Intensity    Erionite MPM   Asbestos MPM   Adenocarcinoma
                          No (%)         No (%)         No (%)

Bcl-2        Null         14 (88)        18 (95)        17 (100)

             Weak         2 (13)         1 (5)          0

Fas          Null         15 (94)        18 (95)        14 (82)

             Weak         1 (6)          0              3 (18)

             Moderate     0              1 (5)          0

BAX: 14 %, 5 %, 8 %
Bax        Null           10 (63)        12 (63)        8 (47)

             47
Fas L: 27 %,Weak%, 26 %   2 (13)         5 (26)         6 (35)

             Moderate     4 (25)         2 (11)         3 (18)

Fas Ligand   Null         4 (25)         2 (11)         1 (6)

             Weak         6 (38)         5 (26)         1 (6)

             Moderate     6 (38)         10 (53)        15 (88)

             Strong       0              2 (11)         0
Fig. 1: Sections with antibody stainings (X400).
a) Skin epidermis. Positive control for Fas antibody. The image
shows positive staining.
Fig. 1: Sections with antibody stainings (X400).
 Section from sarcomatous type MPM (asbestos).     Moderately
intense staining with Fas Ligand antibody.
Fig. 1: Sections with antibody stainings (X400).
Section from mixed type MPM (erionite). Moderately intense
staining with Bax antibody.
 Survival 1
The median survival time in erionite
induced MPM (14 months) was similar
to time in asbestosis induced MPM (14
months).
Difference      in    median    survival
according to tumor stage, different
treatment modalities and different
histological     subtypes    was    not
statistically significant in whole MPM
group.
Survival 2
In conjunction with antibody staining, Bax
negative erionite patients had better survival
(18 months) than bax positive erionite
patients (14 months, OR: 18.83)
This was not true for the asbestosis group.
In Whole MPM group, Fas L positive patients
(15 months) showed statistically better
survival when compared to Fas L negative
patients (12 months) (OR: 3.12, p=0.05) in
whole MPM group
    1,2


    1,0


     ,8


     ,6


     ,4
                                                  BAX

     ,2                                             Exp

                                                    Alive
    0,0
                                                    No exp

    -,2                                             Alive
          0           10           20   30   40


          Survival time (months)


Patients with no Bax expression showed better survival than
patients with Bax expression in erionite group (p=0.06).
      1, 2


      1, 0


       ,8


       ,6


       ,4
                                                         FAS L IGAND

       ,2                                                  Exp

                                                           Aliv e
      0, 0
                                                           No exp

      -,2                                                  Aliv e
             0        10         20       30   40   50


             Survival tim e (m on th s)


Patients with Fas Ligand expression showed better survival
than patients without expression in whole MPM group
(p=0.05).
TARTIŞMA
   This is the first study that compares common
    apoptotic protein expression in erionite and
    asbestos induced MPM.

   As similar to previous studies, Bcl-2 expression
    was not showed in the MPM sections. This may
    imply that Bcl 2 does not take an important
    part in the pathogenesis of MPM.
    Narasimhan et al. Am J Physiol 1998.
Bax  is a proapoptotic protein. We have shown
that it expresses similarly in all groups.

A previous study has shown that Bax had
extensively expressed in MPM cell lines.
However, they concluded that Bax has been
disfunctional in MPM.
Narasimhan et al. Am J Physiol 1998.
•There is only one study that investigate
the relation of apoptotic protein
expression and survival.
•Accordingly, there is no relation of Bax
and Bcl-2 and survival.
Soini Y et al. Clin Cancer Res 1999.

•In our study, in only erionite group, Bax
had been inversely related with survival.
   Bax is a proapoptotic protein

   RELATED WITH WORSE PROGNOSIS
   Other antiapoptotic proteins may use this
    pathway to exert their activity
   This finding indicates a possible different
    mechanism in apoptotic pathways in erionite
    group.
   INDICATES FURTHER STUDIES IN CELL
    LINES
•Stewart et al have shown that Fas/Fas
L pathway may intact in MPM and may be
enhanced by chemotherapeutics.
Stewart et al. J Thorac Cardiovasc Surg 2002.

•In our study there is almost no
expression of Fas expression. This was
also true for adenocarcinoma. However,
Fas L expressed heavily and showed
better prognosis.
In Conclusion,
•Bcl-2 may not involve         in   the
tumorigenesis of MPM.
Bax expression was associated with
poor prognosis in only erionite induced
MPM. This may imply a difference in
apoptotic behaviour in erionite and
asbestos induced MPM.
•Fas L pathway may be intact and may
be associated with better survival in
whole MPM group.

				
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