title: Prognostic and biological significance of survivin expression in patients with diffuse large B-cell lymphoma treated with rituximab-CHOP therapy.
abstract: Survivin, a member of the inhibitor of apoptosis protein family, is overexpressed in a variety of human neoplasms. The prognostic significance of survivin expression in diffuse large B-cell lymphoma patients treated with rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) is unclear. We used standard immunohistochemistry methods to quantify survivin expression in 463 patients with de novo diffuse large B-cell lymphoma who received the R-CHOP. Of the 463 patients, 269 (58%) had survivin overexpression with a cutoff of >25%, associated with an International Prognostic Index score of >2 (P=0.015), disease in ≥2 extranodal sites (P=0.011), and a high Ki-67 index (P<0.0001). Among patients with activated B cell-like disease, the overall survival rate of survivin-positive patients was significantly lower than that of survivin-negative patients (P=0.033); multivariate analysis confirmed that in these patients, survivin overexpression was an independent prognostic factor for survival. Among patients with wild-type p53 overexpression, the overall survival and progression-free survival rates of the survivin-positive group were significantly lower than those of the survivin-negative group (P=0.035 and P=0.04 respectively). In STAT3-positive patients, survivin overexpression was associated with significantly better survival. Among patients with activated B cell-like disease, survivin-positive compared with survivin-negative groups had significantly different gene expression signatures, including genes involved in mitosis or tumor cell proliferation. Our results indicate that survivin is an independent prognostic factor for poor outcome in patients with activated B cell-like disease treated with the R-CHOP regimen, and patients with survivin-positive activated B cell-like diffuse large B-cell lymphoma seem to benefit less from this treatment and may require additional novel agents.
authors.affiliation: Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Zhiyu
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Zijun Y
authors.initials: ZY
authors.lastname: Xu-Monette
authors.affiliation: Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Cao
authors.affiliation: Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Ganiraju C
authors.initials: GC
authors.lastname: Manyam
authors.affiliation: Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Xiaoxiao
authors.initials: X
authors.lastname: Wang
authors.affiliation: University Hospital, Basel, Switzerland.
authors.forename: Alexandar
authors.identifier: http://orcid.org/0000-0002-1100-3819
authors.initials: A
authors.lastname: Tzankov
authors.affiliation: Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Xia
authors.affiliation: Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Li
authors.affiliation: San Bortolo Hospital, Vicenza, Italy.
authors.forename: Carlo
authors.initials: C
authors.lastname: Visco
authors.affiliation: Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Ruifang
authors.initials: R
authors.lastname: Sun
authors.affiliation: Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Hospital Universitario Marques de Valdecilla, Santander, Spain.
authors.forename: Santiago
authors.identifier: http://orcid.org/0000-0002-3565-8262
authors.initials: S
authors.lastname: Montes-Moreno
authors.affiliation: Aalborg University Hospital, Aalborg, Denmark.
authors.forename: Karen
authors.initials: K
authors.lastname: Dybkær
authors.affiliation: Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
authors.forename: April
authors.initials: A
authors.lastname: Chiu
authors.affiliation: Weill Medical College of Cornell University, New York, NY, USA.
authors.forename: Attilio
authors.initials: A
authors.lastname: Orazi
authors.affiliation: Houston Methodist Hospital, Houston, TX, USA.
authors.forename: Youli
authors.initials: Y
authors.lastname: Zu
authors.affiliation: Columbia University Medical Center and New York Presbyterian Hospital, New York, NY, USA.
authors.forename: Govind
authors.identifier: http://orcid.org/0000-0001-6250-048X
authors.initials: G
authors.lastname: Bhagat
authors.affiliation: University of North Carolina School of Medicine, Chapel Hill, NC, USA.
authors.forename: Kristy L
authors.identifier: http://orcid.org/0000-0001-5765-6631
authors.initials: KL
authors.lastname: Richards
authors.affiliation: Cleveland Clinic, Cleveland, OH, USA.
authors.forename: Eric D
authors.initials: ED
authors.lastname: Hsi
authors.affiliation: University of Hong Kong Li Ka Shing Faculty of Medicine, Hong Kong, China.
authors.forename: William W L
authors.initials: WW
authors.lastname: Choi
authors.affiliation: Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
authors.forename: J Han
authors.initials: JH
authors.lastname: van Krieken
authors.affiliation: Asan Medical Center, Ulsan University College of Medicine, Seoul, Korea.
authors.forename: Jooryung
authors.initials: J
authors.lastname: Huh
authors.affiliation: San Raffaele H Scientific Institute, Milan, Italy.
authors.forename: Maurilio
authors.initials: M
authors.lastname: Ponzoni
authors.affiliation: San Raffaele H Scientific Institute, Milan, Italy.
authors.forename: Andrés J M
authors.initials: AJ
authors.lastname: Ferreri
authors.affiliation: Gundersen Lutheran Health System, La Crosse, WI, USA.
authors.forename: Ben M
authors.initials: BM
authors.lastname: Parsons
authors.affiliation: Odense University Hospital, Odense, Denmark.
authors.forename: Michael B
authors.initials: MB
authors.lastname: Møller
authors.affiliation: Hospital Universitario Marques de Valdecilla, Santander, Spain.
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Piris
authors.affiliation: Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
authors.forename: Jane N
authors.initials: JN
authors.lastname: Winter
authors.affiliation: Clarient Pathology Services, Aliso Viejo, CA, USA.
authors.forename: Dennis P
authors.initials: DP
authors.lastname: O'Malley
authors.affiliation: Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: L Jeffrey
authors.initials: LJ
authors.lastname: Medeiros
authors.affiliation: Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.|The University of Texas School of Medicine, Graduate School of Biomedical Sciences, Houston, TX, USA.
authors.forename: Ken H
authors.initials: KH
authors.lastname: Young
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D058846:Antibodies, Monoclonal, Murine-Derived; D000971:Antineoplastic Combined Chemotherapy Protocols; D014408:Biomarkers, Tumor / Q000032:analysis*; D003520:Cyclophosphamide; D018572:Disease-Free Survival; D004317:Doxorubicin; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D051034:Inhibitor of Apoptosis Proteins / Q000096:biosynthesis*; D053208:Kaplan-Meier Estimate; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy / Q000401:mortality / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D011241:Prednisone; D011379:Prognosis; D016016:Proportional Hazards Models; D000069283:Rituximab; D000077022:Survivin; D046888:Tissue Array Analysis; D059467:Transcriptome; D014750:Vincristine; D055815:Young Adult
chemical_list: D058846:Antibodies, Monoclonal, Murine-Derived; C107489:BIRC5 protein, human; D014408:Biomarkers, Tumor; D051034:Inhibitor of Apoptosis Proteins; C571759:R-CHOP protocol; D000077022:Survivin; D000069283:Rituximab; D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; D011241:Prednisone