title: Addition of rituximab to chemotherapy overcomes the negative prognostic impact of cyclin E expression in diffuse large B-cell lymphoma.
abstract: BACKGROUND
  High levels of cyclin E (CCNE) are accompanied by shorter survival in cyclophosphamide, hydroxydaunorubicin, oncovin and prednisone (CHOP)-treated diffuse large B-cell lymphomas (DLBCL), independent of the international prognostic index (IPI). Data on the prognostic role of CCNE in the 'rituximab (R)-era' are lacking.
  
  
  METHODS
  To test reproducibility and applicability of observations from the 'pre-R era' to the 'R era', we examined the prognostic role of CCNE expression by immunohistochemistry in 1579 DLBCL on tissue microarrays (TMA); 339 patients were treated by CHOP and 635 by R-CHOP.
  
  
  RESULTS
  1209 samples (77%) were evaluable; failures were due to missing TMA punches and fixation artefacts. Mean expression of CCNE was 13% (0-85%); applying a cut-off of >16%, 382 DLBCL (31%) were positive. CCNE did not correlate with any of the known variables (IPI, primary site, cell of origin, proliferation, and BCL2- or C-MYC rearrangements). We were able to reproduce data suggesting an IPI- and response to therapy independent, negative prognostic impact of CCNE in CHOP-treated DLBCL patients: CCNE-positive cases had a median survival of 16 months compared with 57 months in negative ones (p=0.012). In R-CHOP-treated patients the prognostic impact of CCNE was abrogated and only IPI, cell of origin and response to therapy had a prognostic significance.
  
  
  CONCLUSIONS
  Addition of R to CHOP overcomes the negative prognostic impact of CCNE in DLBCL. Thus, R not only prolongs survival in DLBCL but also serves a cautionary note that prognostic factors should not be transferred into the 'R era' without proper scientific studies.
authors.affiliation: Institute of Pathology, University Hospital, , Basel, Switzerland.
authors.forename: E
authors.initials: E
authors.lastname: Frei
authors.forename: C
authors.initials: C
authors.lastname: Visco
authors.forename: Z Y
authors.initials: ZY
authors.lastname: Xu-Monette
authors.forename: S
authors.initials: S
authors.lastname: Dirnhofer
authors.forename: K
authors.initials: K
authors.lastname: Dybkær
authors.forename: A
authors.initials: A
authors.lastname: Orazi
authors.forename: G
authors.initials: G
authors.lastname: Bhagat
authors.forename: E D
authors.initials: ED
authors.lastname: Hsi
authors.forename: J H
authors.initials: JH
authors.lastname: van Krieken
authors.forename: M
authors.initials: M
authors.lastname: Ponzoni
authors.forename: R S
authors.initials: RS
authors.lastname: Go
authors.forename: M A
authors.initials: MA
authors.lastname: Piris
authors.forename: M B
authors.initials: MB
authors.lastname: Møller
authors.forename: K H
authors.initials: KH
authors.lastname: Young
authors.forename: A
authors.initials: A
authors.lastname: Tzankov
mesh_terms: D000368:Aged; D058846:Antibodies, Monoclonal, Murine-Derived / Q000008:administration & dosage*; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D015331:Cohort Studies; D019927:Cyclin E / Q000378:metabolism*; D003520:Cyclophosphamide / Q000008:administration & dosage; D004317:Doxorubicin / Q000008:administration & dosage; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007150:Immunohistochemistry; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D015513:Oncogene Proteins / Q000378:metabolism*; D011241:Prednisone / Q000008:administration & dosage; D011379:Prognosis; D015203:Reproducibility of Results; D000069283:Rituximab; D046888:Tissue Array Analysis; D016896:Treatment Outcome; D014750:Vincristine / Q000008:administration & dosage
chemical_list: D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents; C475820:CCNE1 protein, human; D019927:Cyclin E; D015513:Oncogene Proteins; D000069283:Rituximab; D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; D011241:Prednisone
keywords: Cell Cycle Regulation; Haematopathology; Lymphoma