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NEOPLASIA
From the Department of Pathology, Boyer Center for
Molecular Medicine, Yale University School of Medicine, New Haven, CT;
Service d'Hématologie, Département de Pathologie, and
Unité d'Informatique Médicale, Hôpital Henri Mondor,
AP-HP, Créteil, France; Service d'Hématologie, Centre
Hospitalier du Dr Schaffner, Lens, France; Service d'Anatomie
Pathologique, AP-HP, and Institut d'Hématologie, Hôpital
Saint-Louis, Paris, France; Service d'Anatomie Pathologique,
Hôtel-Dieu, AP-HP, Paris, France; and Service
d'Hématologie, Centre Hospitalier Lyon-Sud, Pierre-Bénite,
France.
Survivin is an inhibitor of apoptosis overexpressed in various
human cancers but undetectable in normal differentiated tissues. A
potential expression and prognostic significance of survivin was
studied in 222 patients with diffuse large B-cell lymphomas (centroblastic, 96%; immunoblastic, 4%). All patients were enrolled between 1987 and 1993 (median follow-up, 7 years) in the LNH87 protocol
of the Groupe d'Etudes des Lymphomes de l'Adulte (GELA) and treated
either with the reference ACVBP arm (doxorubicin, cyclophosphamide,
vindesine, bleomycin, and prednisone)[AU3A] (n = 79) or other
experimental anthracycline-containing regimens (n = 143). The
characteristics of these patients were median age of 56 years; serum
lactate dehydrogenase (LDH) greater than 1N, 60%; stage III-IV, 55%;
performance status, according to the Eastern Cooperative Oncology Group
(ECOG) scale, more than 1, 23%; extranodal sites more than 1, 29%; mass more than 10 cm, 44%; bone marrow involvement, 15%. Of the
222 patients studied, 134 (60%) revealed survivin expression in
virtually all tumor cells by immunohistochemistry. The overall 5-year
survival rate was significantly lower in patients with survivin
expression than in those without (40% vs 54%, P = .02).
Multivariate analysis incorporating prognostic factors from the
International Prognostic Index (IPI) identified survivin expression as
an independent predictive parameter on survival (P = .03,
relative risk [RR] = 1.6) in addition to LDH
(P = .02, RR = 1.6), stage (P = .03,
RR = 1.7), and ECOG scale (P = .05, RR = 1.6). A
second analysis incorporating IPI as a unique parameter demonstrated
that survivin expression (P = .02, RR = 1.6) remained a
prognostic factor for survival independently of IPI
(P = .001, RR = 1.5). Survivin expression may be
considered a new unfavorable prognostic factor of diffuse large B-cell lymphoma.
(Blood. 2000;96:1921-1925) Diffuse large B-cell lymphomas represent the most
frequent type of non-Hodgkin's lymphoma (NHL) Molecular abnormalities of the cell death-cell viability balance
as reflected in bcl-2 overexpression7-10 or p53
mutation11,12 have emerged as important prognostic
indicators of diffuse large B-cell lymphomas. A candidate molecule to
influence the apoptotic balance in cancer was recently identified as
survivin,13 a member of the inhibitor of apoptosis (IAP)
gene family.14 Unique among other IAP proteins, survivin
is expressed during embryonic and fetal development,15
becomes undetectable in normal adult tissues, and is prominently
overexpressed in a variety of human cancers in vivo.13
Accordingly, a recent analysis of 3.5 million human "transcriptomes" identified survivin among the top 4 transcripts uniformly up-regulated in cancer but not in normal
tissues.16 At a molecular level, survivin is expressed
during mitosis in a strict cell cycle-dependent manner, and it
localizes to mitotic spindle microtubules in a reaction required for
apoptosis inhibition.17 This pathway may provide a
selective cytoprotective mechanism at cell division, because targeting
endogenous survivin with antisense or a dominant negative mutant caused
spontaneous apoptosis and a profound dysregulation of mitotic
progression with supernumerary centrosomes, multipolar mitotic
spindles, and generation of multinucleated cells.18
Although retrospective predictive or prognostic studies on the impact
of the survivin pathway in selected solid tumors have been
reported,19-23 little is known about the potential role of
this molecule in hematopoietic malignancies. In this study, we sought
to investigate the potential expression of survivin in 222 patients
with diffuse large B-cell lymphoma enrolled in the prospective LNH87
protocol of the Groupe d'Etudes des Lymphomes de l'Adulte (GELA) and
to dissect its potential prognostic value for disease progression and
clinical outcome.
Patient selection
Treatment and assessment of response
Histologic and immunophenotypic study The histologic diagnosis of diffuse large B-cell lymphoma of patients enrolled in the LNH87 protocol was made independently by 3 pathologists according to the updated Kiel classification,29 and to the morphologic variants in the new proposed WHO classification,3 as centroblastic, immunoblastic, or anaplastic large cell. The anaplastic variant of diffuse large B-cell lymphomas was excluded from this study. The diagnosis was based on morphologic examination of slides from routinely paraffin-embedded samples stained with hematoxylin-eosin, Giemsa, and Gordon-Sweet stains and on immunophenotyping results. In all cases, immunophenotyping was performed by panel review with antibodies including CD20/L26, for the B-cell lineage and CD3 and CD45RO for the T-cell lineage (UCHL1) (Dako, Glostrup, Denmark) to determine the B- or T-cell lineage, respectively, using an indirect immunoperoxidase or alkaline phosphatase antialkaline phosphatase method.Patient selection for survivin expression Survivin expression in diffuse large B-cell lymphomas was analyzed on the basis of availability of 3 unstained slides per case. Cases fixed in Bouin's liquid were excluded, and only formalin-fixed cases were selected. To avoid bias related to treatment, only patients who received an anthracycline-containing regimen were included in the study. Therefore, patients enrolled in group 4 treated by CVP were excluded. Overall, 222 cases were studied for survivin expression by immunohistochemistry. Tissue sections measuring 5 µm were put on high adhesive slides, boiled for 5 minutes in a standard pressure cooker for antigen retrieval, blocked in 10% normal goat serum, and incubated for 14 hours at 4°C with affinity-purified antisurvivin polyclonal rabbit antibody used and characterized previously.13 After
washes, the slides were incubated with biotin-conjugated goat
antirabbit immunoglobulin G (Vector, Burlingame, CA) for 30 minutes at
22°C. Binding of the primary antibody was revealed by addition of
streptavidin-conjugated peroxidase (Boehringer Mannheim, Indianapolis,
IN) and 3'3'-diaminobenzidine followed by counterstaining with
hematoxylin. In control experiments, slides were incubated with
comparable concentrations of nonimmune rabbit serum. Cases were scored
as positive (70%-90% of cells exhibiting intracytoplasmic staining)
or negative (fewer than 5% of stained cells). The immunohistochemical
study was performed twice per case and interpreted without any
knowledge of the clinical data.
Statistical analysis Patient characteristics and CR rates were compared using the chi-square test. Overall survival time was calculated from the date of randomization until death or last follow-up examination. Survival curves were estimated using the product-limit method of Kaplan-Meier30 and were compared using the log-rank test. Univariate analyses were made using the chi-square test and the log-rank test. A multivariate regression analysis according to the Cox proportional hazards regression model,31 with the overall survival as the dependent variable, was used to adjust the effect of survivin expression for potential independent prognostic factors. P < .05 was considered to indicate statistical significance. All calculations were performed on an SAS software, version 6.10 (SAS Institute, Cary, NC).
Survivin expression was demonstrated in 60% of the patients
examined by immunohistochemistry (134 of 222) (Figure
1). The median age of the population was
56 years. The main clinical characteristics and treatment regimens of
this group were similar to those of the remaining group of 1182 patients with diffuse large B-cell lymphomas involved in the LNH87
trial (Table 1). The clinical characteristics and allocated treatment regimens were well balanced between the survivin-positive and survivin-negative groups analyzed (Table 2). The CR rate of
survivin-positive cases (61%) did not significantly differ from that
of the survivin-negative population (68%, P = .29). The
event-free survival was lower in survivin-positive patients than the
survivin-negative group, but it did not reach statistical significance
(P = .09) (Figure 2). Of
note, there was also a more pronounced decreased survival after relapse
in the survivin-positive group as compared with the survivin-positive patients (P = .08).
With a median follow-up of the surviving patients of 91 months (range,
20-140 months), the 5-year overall survival rate was significantly
lower in patients expressing survivin as compared with the
survivin-negative group: 40% (CI 32-48) versus 54% (CI 44-64),
P = .02 (Figure 3). The
estimated relative risk (RR) of death for patients with survivin
expression was 1.6, which was similar to that of other well-known
prognostic factors (Table 3). After
incorporating IPI as a unique parameter in a second multivariate
analysis, survivin expression remained a prognostic factor
(P = .02, RR = 1.6) independently of IPI
(P = 0.001, RR = 1.5).
In this series of 222 patients with diffuse large B-cell lymphomas treated with an anthracycline-containing regimen, we found that survivin expression predicted a shorter overall survival. This selected series is representative of the whole population of aggressive non-Hodgkin's B-cell lymphomas enrolled in the LNH87 trial as shown by the similar repartition of main clinical characteristics. The classical prognostic parameters in aggressive B-cell lymphomas (advanced clinical stage, unfavorable performance status, elevated lactate dehydrogenase values) and, consequently, IPI score were significantly associated with a poor outcome in this series of 222 patients. Importantly, multivariate analyses demonstrated that the influence of survivin expression on overall survival was independent of these well-established prognostic factors. Although not reaching statistical significance, survivin-positive patients exhibited shorter event-free survival and relapse-free survival than the survivin-negative group. This suggests that, at least in this limited number of patients, the lower overall survival of survivin-positive patients may be due to a combination of higher relapse rates and a poor efficiency of salvage treatment. Although age was not identified as a predictive factor, it should be considered that patients of 70 years and older who did not receive an anthracycline-based regimen were withdrawn from the study, thus reducing the potential number of patients over 60 years of age. The observation that survivin expression influenced overall survival but did not predict response to treatment suggests that residual tumor cells in patients in CR may have a growth advantage when survivin is present. This is consistent with the cell cycle-regulated expression of the survivin gene during mitosis17 and its role in inhibition of apoptosis at G2/M.18 Consistent with a general role of this mechanism in cancer progression,16 survivin expression correlated with aggressive forms of neuroblastoma,19,23 abbreviated survival rates in colorectal20,22 and lung cancer,21 and increased rate of recurrences in bladder cancer.32 Moreover, overexpression of survivin counteracted apoptosis induced by a variety of stimuli in vitro33 and was associated with considerably reduced apoptotic indices in gastric and colorectal cancers in vivo.20,34 Concerning large-cell lymphoma, it is intriguing that expression of both survivin (this study) and bcl-2 7-10 correlated with abbreviated survival rates, thus emphasizing how dysregulation of apoptosis may dramatically influence disease outcome. Functionally, bcl-2 and survivin have been positioned in nonoverlapping antiapoptotic pathways, with preservation of mitochondrial integrity by bcl-2 35 and interference with caspase activation/function by survivin.14 It is therefore plausible that expression of bcl-2 and survivin may synergistically provide nonredundant cytoprotective signals in large-cell lymphoma, affording broad resistance to multiple death-inducing pathways initiated by radiation or chemotherapeutic agents.33,36 In summary, we have identified survivin as a new independent prognostic factor for poor outcome in diffuse large B-cell lymphomas. Combined with bcl-2 overexpression,7-10 and p53 mutations,11,12 these findings may provide a new molecular framework to identify patients harboring aggressive B-cell lymphomas.6 On the other hand, molecular targeting of bcl-2 and survivin improved disease in vivo37 and caused spontaneous apoptosis in vitro,18 thus suggesting that manipulation of this antiapoptotic pathway may offer a potential therapeutic strategy to achieve stable remissions in lymphoma.
The authors are indebted to Catherine Balmale, Antoine Allain, and Catherine Belorgey for expert assistance with data management. The authors thank the following clinicians and pathologists who actively participated in the study: I. Abdalsamad, R. Angonin, B. Audhuy, J. Audouin, A. C. Baglin, P. Bensimon, F. Berger, P. Biron, M. Blanc, F. Boman, A. Boehn, J. Boniver, D. Bordessoule, A. Bosly, R. Bouabdallah, J. Bouvier, P. Brice, J. Brière, N. Brousse, J. P. Carbillet, D. Cazals, A.M. Chesneau, B. Christian, B. Coiffier, E. Deconinck, M. Delos, G. Delsol, M. Divine, C. Doyen, H. Duplay, B. Dupriez, C. Duval, J. C. Eisenmann, J. M. Emberger, J. P. Fermand, Y. Fonck, N. Froment, J. Gabarre, O. Gasser, B. Gosselin, H. Guy, J. Hamels, R. Herbrecht, O. Hopfner, N. Horschowski, R. Jeandel, J. P. Knopf, C. Lavignac, M. Lecomte-Houcke, P. Lederlin, R. Loire, R. Marcellin, G. Marit, C. Martin, C. Marty-Double, A. de Mascarel, C. Merignargues, F. Morvan, J. F. Mosnier, G. Nedellec, C. Nouvel, N Patey, P. Y. Peaud, G. Perie, M. Peuchmaur, T. Petrella, B. Pignon, J. P. Pollet, M. Raphael, M. C. Raymond-Gelle, M. Rochet, A. Rozenbaum, C. Sebban, S. Thiebaut, A. Thyss, H. Tilly, P. Travade, and L. Xerri.
Submitted January 17, 2000; accepted May 3, 2000.
Supported by National Institutes of Health grants CA78810 and CA82130 (D.C.A.). Supported in part by grants of the French Ministry of Health (Programme Hospitalier de Recherche Clinique), the Délégation á la Recherche Clinique de l'AP-HP, and the Ligue contre le Cancer, France. C.A. is a fellow of the Lymphoma Research Foundation of America.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: Dario C. Altieri, Yale University School of Medicine, BCMM436B, 295 Congress Ave, New Haven, CT 06536; e-mail: dario.altieri{at}yale.edu.
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B. Z. Carter, D. H. Mak, W. D. Schober, M. Cabreira-Hansen, M. Beran, T. McQueen, W. Chen, and M. Andreeff Regulation of survivin expression through Bcr-Abl/MAPK cascade: targeting survivin overcomes imatinib resistance and increases imatinib sensitivity in imatinib-responsive CML cells Blood, February 15, 2006; 107(4): 1555 - 1563. [Abstract] [Full Text] [PDF]
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 H. Asanuma, T. Torigoe, K. Kamiguchi, Y. Hirohashi, T. Ohmura, K. Hirata, M. Sato, and N. Sato Survivin Expression Is Regulated by Coexpression of Human Epidermal Growth Factor Receptor 2 and Epidermal Growth Factor Receptor via Phosphatidylinositol 3-Kinase/AKT Signaling Pathway in Breast Cancer Cells Cancer Res., December 1, 2005; 65(23): 11018 - 11025. [Abstract] [Full Text] [PDF]
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C. Haioun, E. Itti, A. Rahmouni, P. Brice, J.-D. Rain, K. Belhadj, P. Gaulard, L. Garderet, E. Lepage, F. Reyes, et al. [18F]fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) in aggressive lymphoma: an early prognostic tool for predicting patient outcome Blood, August 15, 2005; 106(4): 1376 - 1381. [Abstract] [Full Text] [PDF]
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S. Idenoue, Y. Hirohashi, T. Torigoe, Y. Sato, Y. Tamura, H. Hariu, M. Yamamoto, T. Kurotaki, T. Tsuruma, H. Asanuma, et al. A Potent Immunogenic General Cancer Vaccine That Targets Survivin, an Inhibitor of Apoptosis Proteins Clin. Cancer Res., February 15, 2005; 11(4): 1474 - 1482. [Abstract] [Full Text] [PDF]
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A. M. Glas, M. J. Kersten, L. J. M. J. Delahaye, A. T. Witteveen, R. E. Kibbelaar, A. Velds, L. F. A. Wessels, P. Joosten, R. M. Kerkhoven, R. Bernards, et al. Gene expression profiling in follicular lymphoma to assess clinical aggressiveness and to guide the choice of treatment Blood, January 1, 2005; 105(1): 301 - 307. [Abstract] [Full Text] [PDF]
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 M. E. Johnson and E. W. Howerth Survivin: A Bifunctional Inhibitor of Apoptosis Protein Vet. Pathol., November 1, 2004; 41(6): 599 - 607. [Abstract] [Full Text] [PDF]
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 P. N. Span, F. C.G.J. Sweep, E. T.G. Wiegerinck, V. C.G. Tjan-Heijnen, P. Manders, L. V.A.M. Beex, and J. B. de Kok Survivin Is an Independent Prognostic Marker for Risk Stratification of Breast Cancer Patients Clin. Chem., November 1, 2004; 50(11): 1986 - 1993. [Abstract] [Full Text] [PDF]
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 K. H. Emami, C. Nguyen, H. Ma, D. H. Kim, K. W. Jeong, M. Eguchi, R. T. Moon, J.-L. Teo, S. W. Oh, H. Y. Kim, et al. A small molecule inhibitor of {beta}-catenin/CREB-binding protein transcription PNAS, August 24, 2004; 101(34): 12682 - 12687. [Abstract] [Full Text] [PDF]
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I. Tamm, S. Richter, D. Oltersdorf, U. Creutzig, J. Harbott, F. Scholz, L. Karawajew, W.-D. Ludwig, and C. Wuchter High Expression Levels of X-Linked Inhibitor of Apoptosis Protein and Survivin Correlate with Poor Overall Survival in Childhood de Novo Acute Myeloid Leukemia Clin. Cancer Res., June 1, 2004; 10(11): 3737 - 3744. [Abstract] [Full Text] [PDF]
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E. J. Schlette, L. J. Medeiros, A. Goy, R. Lai, and G. Z. Rassidakis Survivin Expression Predicts Poorer Prognosis in Anaplastic Large-Cell Lymphoma J. Clin. Oncol., May 1, 2004; 22(9): 1682 - 1688. [Abstract] [Full Text] [PDF]
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 I. S. Lossos, D. K. Czerwinski, A. A. Alizadeh, M. A. Wechser, R. Tibshirani, D. Botstein, and R. Levy Prediction of Survival in Diffuse Large-B-Cell Lymphoma Based on the Expression of Six Genes N. Engl. J. Med., April 29, 2004; 350(18): 1828 - 1837. [Abstract] [Full Text] [PDF]
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A. Martinez, B. Bellosillo, F. Bosch, A. Ferrer, S. Marce, N. Villamor, G. Ott, E. Montserrat, E. Campo, and D. Colomer Nuclear Survivin Expression in Mantle Cell Lymphoma Is Associated with Cell Proliferation and Survival Am. J. Pathol., February 1, 2004; 164(2): 501 - 510. [Abstract] [Full Text] [PDF]
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C. P. Hans, D. D. Weisenburger, T. C. Greiner, R. D. Gascoyne, J. Delabie, G. Ott, H. K. Muller-Hermelink, E. Campo, R. M. Braziel, E. S. Jaffe, et al. Confirmation of the molecular classification of diffuse large B-cell lymphoma by immunohistochemistry using a tissue microarray Blood, January 1, 2004; 103(1): 275 - 282. [Abstract] [Full Text] [PDF]
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B. Z. Carter, S. M. Kornblau, T. Tsao, R.-Y. Wang, W. D. Schober, M. Milella, H.-G. Sung, J. C. Reed, and M. Andreeff Caspase-independent cell death in AML: caspase inhibition in vitro with pan-caspase inhibitors or in vivo by XIAP or Survivin does not affect cell survival or prognosis Blood, December 1, 2003; 102(12): 4179 - 4186. [Abstract] [Full Text] [PDF]
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S. P. Tu, X. H. Jiang, M. C. M. Lin, J. T. Cui, Y. Yang, C. T. Lum, B. Zou, Y. B. Zhu, S. H. Jiang, W. M. Wong, et al. Suppression of Survivin Expression Inhibits in Vivo Tumorigenicity and Angiogenesis in Gastric Cancer Cancer Res., November 15, 2003; 63(22): 7724 - 7732. [Abstract] [Full Text] [PDF]
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S. M. Schmidt, K. Schag, M. R. Muller, M. M. Weck, S. Appel, L. Kanz, F. Grunebach, and P. Brossart Survivin is a shared tumor-associated antigen expressed in a broad variety of malignancies and recognized by specific cytotoxic T cells Blood, July 15, 2003; 102(2): 571 - 576. [Abstract] [Full Text] [PDF]
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 S. Paydas, K. Tanriverdi, S. Yavuz, U. Disel, B. Sahin, and R. Burgut Survivin and aven: two distinct antiapoptotic signals in acute leukemias Ann. Onc., July 1, 2003; 14(7): 1045 - 1050. [Abstract] [Full Text] [PDF]
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M. Zeis, S. Siegel, A. Wagner, M. Schmitz, M. Marget, R. Kuhl-Burmeister, I. Adamzik, D. Kabelitz, P. Dreger, N. Schmitz, et al. Generation of Cytotoxic Responses in Mice and Human Individuals Against Hematological Malignancies Using Survivin-RNA-Transfected Dendritic Cells J. Immunol., June 1, 2003; 170(11): 5391 - 5397. [Abstract] [Full Text] [PDF]
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N. Mounier, J. Briere, C. Gisselbrecht, J.-F. Emile, P. Lederlin, C. Sebban, F. Berger, A. Bosly, P. Morel, H. Tilly, et al. Rituximab plus CHOP (R-CHOP) overcomes bcl-2--associated resistance to chemotherapy in elderly patients with diffuse large B-cell lymphoma (DLBCL) Blood, June 1, 2003; 101(11): 4279 - 4284. [Abstract] [Full Text] [PDF]
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M. Kappler, M. Kotzsch, F. Bartel, S. Fussel, C. Lautenschlager, U. Schmidt, P. Wurl, M. Bache, H. Schmidt, H. Taubert, et al. Elevated Expression Level of Survivin Protein in Soft-Tissue Sarcomas Is a Strong Independent Predictor of Survival Clin. Cancer Res., March 1, 2003; 9(3): 1098 - 1104. [Abstract] [Full Text] [PDF]
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I. S. Lossos, A. A. Alizadeh, R. Rajapaksa, R. Tibshirani, and R. Levy HGAL is a novel interleukin-4-inducible gene that strongly predicts survival in diffuse large B-cell lymphoma Blood, January 15, 2003; 101(2): 433 - 440. [Abstract] [Full Text] [PDF]
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J. F. Garcia, F. I. Camacho, M. Morente, M. Fraga, C. Montalban, T. A. C. Bellas, A. Castano, A. Diez, T. Flores, C. Martin, et al. Hodgkin and Reed-Sternberg cells harbor alterations in the major tumor suppressor pathways and cell-cycle checkpoints: analyses using tissue microarrays Blood, January 15, 2003; 101(2): 681 - 689. [Abstract] [Full Text] [PDF]
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 M. Zhou, L. Gu, F. Li, Y. Zhu, W. G. Woods, and H. W. Findley DNA Damage Induces a Novel p53-Survivin Signaling Pathway Regulating Cell Cycle and Apoptosis in Acute Lymphoblastic Leukemia Cells J. Pharmacol. Exp. Ther., October 1, 2002; 303(1): 124 - 131. [Abstract] [Full Text] [PDF]
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L Leoncini, S Lazzi, C Bellan, and P Tosi Cell kinetics and cell cycle regulation in lymphomas J. Clin. Pathol., September 1, 2002; 55(9): 648 - 655. [Abstract] [Full Text] [PDF]
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K. Leroy, C. Haioun, E. Lepage, N. Le Metayer, F. Berger, E. Labouyrie, V. Meignin, B. Petit, C. Bastard, G. Salles, et al. p53 gene mutations are associated with poor survival in low and low-intermediate risk diffuse large B-cell lymphomas Ann. Onc., July 1, 2002; 13(7): 1108 - 1115. [Abstract] [Full Text] [PDF]
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C. G. Ferreira, M. Epping, F. A. E. Kruyt, and G. Giaccone Apoptosis: Target of Cancer Therapy Clin. Cancer Res., July 1, 2002; 8(7): 2024 - 2034. [Abstract] [Full Text] [PDF]
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D. F. Dukers, C. J. L. M. Meijer, R. L. ten Berge, W. Vos, G. J. Ossenkoppele, and J. J. Oudejans High numbers of active caspase 3-positive Reed-Sternberg cells in pretreatment biopsy specimens of patients with Hodgkin disease predict favorable clinical outcome Blood, June 17, 2002; 100(1): 36 - 42. [Abstract] [Full Text] [PDF]
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A. Chakravarti, E. Noll, P. McL. Black, D. F. Finkelstein, D. M. Finkelstein, N. J. Dyson, and J. S. Loeffler Quantitatively Determined Survivin Expression Levels Are of Prognostic Value in Human Gliomas J. Clin. Oncol., February 15, 2002; 20(4): 1063 - 1068. [Abstract] [Full Text] [PDF]
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 J. R. Kanwar, W.-P. Shen, R. K. Kanwar, R. W. Berg, and G. W. Krissansen Effects of Survivin Antagonists on Growth of Established Tumors and B7-1 Immunogene Therapy J Natl Cancer Inst, October 17, 2001; 93(20): 1541 - 1552. [Abstract] [Full Text] [PDF]
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S. Fukuda and L. M. Pelus Regulation of the inhibitor-of-apoptosis family member survivin in normal cord blood and bone marrow CD34+ cells by hematopoietic growth factors: implication of survivin expression in normal hematopoiesis Blood, October 1, 2001; 98(7): 2091 - 2100. [Abstract] [Full Text] [PDF]
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D. S. Rickman, M. P. Bobek, D. E. Misek, R. Kuick, M. Blaivas, D. M. Kurnit, J. Taylor, and S. M. Hanash Distinctive Molecular Profiles of High-Grade and Low-Grade Gliomas Based on Oligonucleotide Microarray Analysis Cancer Res., September 1, 2001; 61(18): 6885 - 6891. [Abstract] [Full Text] [PDF]
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I. S. Lossos, C. D. Jones, R. Warnke, Y. Natkunam, H. Kaizer, J. L. Zehnder, R. Tibshirani, and R. Levy Expression of a single gene, BCL-6, strongly predicts survival in patients with diffuse large B-cell lymphoma Blood, August 15, 2001; 98(4): 945 - 951. [Abstract] [Full Text] [PDF]
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M. H. Andersen, L. O. Pedersen, B. Capeller, E.-B. Brocker, J. C. Becker, and P. thor Straten Spontaneous Cytotoxic T-Cell Responses against Survivin-derived MHC Class I-restricted T-Cell Epitopes in Situ As Well As ex Vivo in Cancer Patients Cancer Res., August 1, 2001; 61(16): 5964 - 5968. [Abstract] [Full Text] [PDF]
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C. G. Ferreira, P. van der Valk, S. W. Span, I. Ludwig, E. F. Smit, F. A. E. Kruyt, H. M. Pinedo, H. van Tinteren, and G. Giaccone Expression of X-linked Inhibitor of Apoptosis as a Novel Prognostic Marker in Radically Resected Non-Small Cell Lung Cancer Patients Clin. Cancer Res., August 1, 2001; 7(8): 2468 - 2474. [Abstract] [Full Text] [PDF]
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L. Granziero, P. Ghia, P. Circosta, D. Gottardi, G. Strola, M. Geuna, L. Montagna, P. Piccoli, M. Chilosi, and F. Caligaris-Cappio Survivin is expressed on CD40 stimulation and interfaces proliferation and apoptosis in B-cell chronic lymphocytic leukemia Blood, May 1, 2001; 97(9): 2777 - 2783. [Abstract] [Full Text] [PDF]
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Abstract
Introduction
