title: Clinical and prognostic significance of apoptotic profile in patients with newly diagnosed nodal diffuse large B-cell lymphoma (DLBCL).
abstract: BACKGROUND
  Apoptosis-related proteins might play an important role in the pathogenesis of lymphoma and sensibility to chemotherapy (CH) in patients with non-Hodgkin's lymphoma. We have analyzed the relationship between expression of two proapoptotic (CD95, caspase-3) and four antiapoptotic proteins (c-FLIP, bcl-2, survivin, and XIAP) and clinical outcome of patients with nodal diffuse large B-cell lymphoma (DLBCL).
  
  
  METHODS
  We have analyzed lymph node biopsy specimens obtained from 78 patients with newly diagnosed nodal DLBCL. The expression of apoptotic parameters was analyzed using the standard immunohistochemical method (antibodies against caspase-3, CD95, c-FLIP, XIAP, survivin, and bcl-2) on formalin-fixed and routinely processed paraffin-embedded lymph node specimens. The expression of immunohistochemical parameters has been evaluated semiquantitatively as a percentage of tumor cells.
  
  
  RESULTS
  Immunoexpression of caspase-3, CD95, c-FLIP, survivin, XIAP, and bcl-2 has been found in 48 (61.5%), 39 (50%), 45 (57.7%), 41 (52.6%), 43 (55.12%), and 39 (50.0%) patients, respectively. The therapy response was achieved in 53 (67.9%) patients. Besides numerous clinical parameters, survivin and XIAP positivity along with CD95 negativity were found to be unfavorable factors for therapy response and shorter survival in univariate analysis. According to this finding, an 'apoptotic score' that includes unfavorable apoptotic parameters has been defined. In multivariate analysis, only International Prognostic Index (IPI) and apoptotic score remained independent prognostic predictors for the chance to reach the complete remission (P = 0.003 and P = 0.044, respectively) and longer overall survival (OS) (P = 0.002 and P = 0.046, respectively). Significantly, the better response to immunochemotherapy (ICH) in comparison with CH has been achieved in patients with expression of caspase-3, c-FLIP, and survivin and in patients without the immunoexpression of XIAP. In addition, ICH was superior to CH in both bcl-2-positive and bcl-2-negative patients.
  
  
  CONCLUSIONS
  The results of this study showed that the dysregulation of apoptosis can appear on different places of apoptotic cascade in DLBCL. Apoptotic score is a more useful tool in predicting therapy response and OS of patients with DLBCL than single apoptotic parameters and along with IPI could help to identify a high-risk group of newly diagnosed nodal DLBCL.
authors.affiliation: KBC "Bezanijska kosa", Belgrade, Serbia. dragano@ptt.rs
authors.forename: Olivera
authors.initials: O
authors.lastname: Markovic
authors.forename: Dragomir
authors.initials: D
authors.lastname: Marisavljevic
authors.forename: Vesna
authors.initials: V
authors.lastname: Cemerikic
authors.forename: Maja
authors.initials: M
authors.lastname: Perunicic
authors.forename: Sasa
authors.initials: S
authors.lastname: Savic
authors.forename: Branka
authors.initials: B
authors.lastname: Filipovic
authors.forename: Biljana
authors.initials: B
authors.lastname: Mihaljevic
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000627:therapeutic use; D017209:Apoptosis; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D003520:Cyclophosphamide / Q000008:administration & dosage; D004317:Doxorubicin / Q000008:administration & dosage; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D051034:Inhibitor of Apoptosis Proteins; D053208:Kaplan-Meier Estimate; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008875:Middle Aged; D015999:Multivariate Analysis; D011241:Prednisone / Q000008:administration & dosage; D011379:Prognosis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D000077022:Survivin; D014750:Vincristine / Q000008:administration & dosage; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000378:metabolism; D055815:Young Adult; D019014:fas Receptor / Q000378:metabolism
chemical_list: C107489:BIRC5 protein, human; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506386:CFLAR protein, human; C491901:FAS protein, human; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D000077022:Survivin; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; D019014:fas Receptor; D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; C505407:CASP3 protein, human; D053148:Caspase 3; D011241:Prednisone