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.

Diffuse large B-cell lymphomas represent the most frequent type of non-Hodgkin's lymphoma (NHL)—30% to 40% of adult NHL1—diagnosed on morphology and immunophenotype.2,3 Although combination chemotherapy has improved the outcome, many patients do not achieve complete remission (CR) and they ultimately relapse, making the search for parameters identifying patients at high risk of recurrent disease particularly urgent.4 The formulation of an International Prognostic Index (IPI) has provided a widely accepted set of criteria to predict the evolution of aggressive lymphomas5 and thus to design appropriate therapies. IPI takes into account factors that are mostly linked to the patient's characteristics or to the disease's extension and growth, including age, lactate dehydrogenase level, performance status, clinical stage, and number of extranodal sites. However, one limitation of this prediction strategy is that IPI does not encompass molecular abnormalities of tumor cells, which may play a critical role in determining profoundly different clinical outcomes in patients within the same group defined by IPI.6 

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,15becomes undetectable in normal adult tissues, and is prominently overexpressed in a variety of human cancers in vivo.13Accordingly, 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.18Although 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

The NHL series of the present study included patients registered in the LNH87 trial with a diagnosis of diffuse large B-cell lymphoma confirmed by pathologic review. The LNH87 trial, conducted by GELA, recruited patients from 50 participating French and Belgian centers who were at least 15 years old and had intermediate- or high-grade NHL, according to the Working Formulation. Disease dissemination was evaluated before treatment by physical examination, bone marrow (BM) biopsy, and computed tomography scan of the chest and abdomen. Patients were staged according to the Ann Arbor system. The number of extranodal sites and larger tumor mass diameter were also determined. Performance status was assessed according to the Eastern Cooperative Oncology Group (ECOG) scale, in which 0 indicated that the patient had no symptoms; 1, the patient had symptoms but was ambulatory; 2, the patient was bedridden less than half the day; 3, the patient was bedridden half the day or longer; and 4, the patient was chronically bedridden and required assistance with activities of daily living. Performance status was classified as 0 or 1 (the patient was ambulatory) or 2, 3, 4 (the patient was not ambulatory). The lactate dehydrogenase level was expressed as the ratio over the maximal normal value. From October 1, 1987, to April 1, 1993, 3232 patients had been included in the LNH87 trial. At the time of the analysis, 88% of the slides were available for pathologic review and 1404 patients were considered to have diffuse large B-cell lymphomas (centroblastic and immunoblastic).

Treatment and assessment of response

Patients were stratified into 4 groups according to age and the presence of the following adverse prognostic factors: performance status greater than 1; 2 or more extranodal sites; tumor diameter 10 cm or larger; and BM or central nervous system involvement. Details of the chemotherapy regimens have been reported elsewhere.24,25 Group 1 included patients younger than age 70 without any adverse prognostic factors. Patients were randomly assigned to receive 8 cycles of mBACOD (Adriamycin, cyclophosphamide, bleomycin, methotrexate, Decadron) or 3 courses of ACVB (Adriamycin, cyclophosphamide, vindesine, bleomycin, prednisone) followed by the consolidation treatment according to the LNH84 protocol.26Group 2 included patients 15 to 54 years old with at least one adverse prognostic factor. Patients were randomly assigned to receive 4 inductive cycles of ACVB or NCVB (same as ACVB but with mitoxantrone instead of Adriamycin) and, if they reached CR, were randomized between consolidation with autologous BM transplantation or sequential chemotherapy as per the LNH84 protocol.25 Group 3 included patients 55 to 70 years old with at least one adverse prognostic factor. Patients were randomized to receive 4 cycles of ACVB followed by the consolidation of the LNH84 protocol or 4 alternating induction cycles every 3 weeks of VIM3 (mitoxantrone, ifosfamide, methyl-GAG, Vehem, prednisone, methotrexate) and ACVB and then a maintenance therapy with alternative cycles of VIM (mitoxantrone, vepesid, ifosfamide) and ACVM (Adriamycin, cyclophosphamide, vindesine, methotrexate).27 Group 4 included patients over 70 years old. They were randomly assigned to receive CVP (cyclophosphamide, Vehem, prednisone) or CTVP (CVP plus tetrahydropyranyladriamycin) for 6 cycles.28 Response to therapy was evaluated after induction treatment. CR was defined as the disappearance of all clinical evidence of disease and the normalization of all laboratory values, radiographs, computed tomography scans, and BM.

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) (Figure1). 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).

Fig. 1.

Expression of survivin in diffuse large B-cell lymphomas by immunohistochemistry.

Sections measuring 5 μm from paraffin-embedded tissues were cut on high adhesive slides, boiled for 5 minutes for antigen retrieval, blocked in 10% normal goat serum, and incubated with an antibody to survivin followed by biotin-conjugated goat antirabbit immunoglobulin G and streptavidin-conjugated peroxidase. Binding of the primary antibody was revealed by addition of 3′3′-diaminobenzidine followed by counterstaining with hematoxylin. (A) Representative case of large B-cell lymphoma negative for survivin expression. (B) Representative case positive for survivin expression. (C) Representative control staining of a survivin-positive case with nonimmune rabbit antibody.

Fig. 1.

Expression of survivin in diffuse large B-cell lymphomas by immunohistochemistry.

Sections measuring 5 μm from paraffin-embedded tissues were cut on high adhesive slides, boiled for 5 minutes for antigen retrieval, blocked in 10% normal goat serum, and incubated with an antibody to survivin followed by biotin-conjugated goat antirabbit immunoglobulin G and streptavidin-conjugated peroxidase. Binding of the primary antibody was revealed by addition of 3′3′-diaminobenzidine followed by counterstaining with hematoxylin. (A) Representative case of large B-cell lymphoma negative for survivin expression. (B) Representative case positive for survivin expression. (C) Representative control staining of a survivin-positive case with nonimmune rabbit antibody.

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Table 1.

Clinical characteristics of the survivin group and diffuse large B-cell lymphomas patients enrolled in the LNH87 protocol

CharacteristicSurvivin group
(n = 222)
Diffuse large B-cell lymphoma
(n = 1182)
P
Median age, y 56 57  
Clinical stage III, IV, % 55 57 .51  
Bulky disease > 10 cm, % 44 51 .07  
Bone marrow involvement, % 15 17 .59  
Entranodal sites > 1, % 29 30 .78 
ECOG PS > 1, % 23 26 .50  
Lactate dehydrogenase > 1N, % 60 57 .39  
IPI score, %   .87 
 Low (0-1) 41 39  
 Low intermediate (2) 21 23  
 High intermediate (3) 21 20  
 High (4-5) 17 18  
Evolution, %   .77  
 Complete remission 64 65  
CharacteristicSurvivin group
(n = 222)
Diffuse large B-cell lymphoma
(n = 1182)
P
Median age, y 56 57  
Clinical stage III, IV, % 55 57 .51  
Bulky disease > 10 cm, % 44 51 .07  
Bone marrow involvement, % 15 17 .59  
Entranodal sites > 1, % 29 30 .78 
ECOG PS > 1, % 23 26 .50  
Lactate dehydrogenase > 1N, % 60 57 .39  
IPI score, %   .87 
 Low (0-1) 41 39  
 Low intermediate (2) 21 23  
 High intermediate (3) 21 20  
 High (4-5) 17 18  
Evolution, %   .77  
 Complete remission 64 65  

ECOG PS indicates performance status according to the Eastern Cooperative Oncology Group scale.

Table 2.

Clinical characteristics of the 222 patients with diffuse large B-cell lymphoma according to survivin expression

CharacteristicSurvivin negativeSurvivin positiveP
No. of patients (%) 88  (40) 134  (60)  
Age (%)   .56  
 No older than 60 y 56  (64) 80  (60)  
 Older than 60 y 32  (36) 54  (40)  
Histologic subtype (%)   .10  
 Centroblastic 81  (92) 130  (97)  
 Immunoblastic 7  (8) 4  (3)  
Clinical stage (%)   .12  
 I or II 45  (52) 54  (41)  
 III or IV 42  (48) 78  (59)  
Bulky disease > 10 cm (%)   .31  
 No 43  (52) 76  (59)  
 Yes 40  (48) 53  (41)  
Bone marrow involvement (%)   .11  
 No 71  (90) 103  (82)  
 Yes 8  (10) 23  (18)  
Extranodal sites (%)   .91  
 0-1 site 63  (72) 95  (71)  
 More than 1 site 25  (28) 39  (29)  
Performance status (%)   .07  
 0-1 69  (83) 95  (73)  
 More than 1 14  (17) 36  (27)  
Lactate dehydrogenase (%)   0.99 
 Normal 33  (40) 48  (40)  
 Elevated 50  (60) 73  (60)  
IPI Score (%)   0.48 
 0-1 37  (46) 45  (38)  
 2 17  (21) 26  (22)  
 3 17  (21) 24  (20)  
 4-5 10  (12) 24  (20)  
Treatment (%)   0.72 
 ACVB 30  (34) 49  (36)  
 m-BACOD (group 1) 18  (21) 20  (15)  
 NCVB (group 2) 16  (18) 20  (15)  
 VIM3 (group 3) 15  (17) 29  (22)  
 CTVP (group 4) 9  (11) 16  (12)  
Evolution (%)   0.29  
 Complete remission 57  (68) 74  (61)  
 No complete remission 27  (32) 48  (39)  
CharacteristicSurvivin negativeSurvivin positiveP
No. of patients (%) 88  (40) 134  (60)  
Age (%)   .56  
 No older than 60 y 56  (64) 80  (60)  
 Older than 60 y 32  (36) 54  (40)  
Histologic subtype (%)   .10  
 Centroblastic 81  (92) 130  (97)  
 Immunoblastic 7  (8) 4  (3)  
Clinical stage (%)   .12  
 I or II 45  (52) 54  (41)  
 III or IV 42  (48) 78  (59)  
Bulky disease > 10 cm (%)   .31  
 No 43  (52) 76  (59)  
 Yes 40  (48) 53  (41)  
Bone marrow involvement (%)   .11  
 No 71  (90) 103  (82)  
 Yes 8  (10) 23  (18)  
Extranodal sites (%)   .91  
 0-1 site 63  (72) 95  (71)  
 More than 1 site 25  (28) 39  (29)  
Performance status (%)   .07  
 0-1 69  (83) 95  (73)  
 More than 1 14  (17) 36  (27)  
Lactate dehydrogenase (%)   0.99 
 Normal 33  (40) 48  (40)  
 Elevated 50  (60) 73  (60)  
IPI Score (%)   0.48 
 0-1 37  (46) 45  (38)  
 2 17  (21) 26  (22)  
 3 17  (21) 24  (20)  
 4-5 10  (12) 24  (20)  
Treatment (%)   0.72 
 ACVB 30  (34) 49  (36)  
 m-BACOD (group 1) 18  (21) 20  (15)  
 NCVB (group 2) 16  (18) 20  (15)  
 VIM3 (group 3) 15  (17) 29  (22)  
 CTVP (group 4) 9  (11) 16  (12)  
Evolution (%)   0.29  
 Complete remission 57  (68) 74  (61)  
 No complete remission 27  (32) 48  (39)  
Fig. 2.

Kaplan-Meier curves of event-free survival of 222 patients with diffuse large B-cell lymphoma according to survivin expression.

Survivin-negative cases, n = 88; survivin-positive cases, n = 134.

Fig. 2.

Kaplan-Meier curves of event-free survival of 222 patients with diffuse large B-cell lymphoma according to survivin expression.

Survivin-negative cases, n = 88; survivin-positive cases, n = 134.

Close modal

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).

Fig. 3.

Kaplan-Meier curves of overall survival of 222 patients with diffuse large B-cell lymphoma according to survivin expression.

Survivin-negative cases, n = 88; survivin-positive cases, n = 134.

Fig. 3.

Kaplan-Meier curves of overall survival of 222 patients with diffuse large B-cell lymphoma according to survivin expression.

Survivin-negative cases, n = 88; survivin-positive cases, n = 134.

Close modal
Table 3.

Cox regression analysis for overall survival with factors identified by the International Prognostic Index

FactorPRisk ratio label
(95% confidence interval)
Age .27 1.2  (0.8-1.8) 
Extranodal sites .63 1.1  (0.7-1.8)  
Performance status .05 1.6  (1.0-2.4)  
Clinical stage .03 1.7  (1.1-2.7)  
Lactate dehydrogenase .02 1.6  (1.1-2.5) 
Survivin .03 1.6  (1.1-2.3) 
FactorPRisk ratio label
(95% confidence interval)
Age .27 1.2  (0.8-1.8) 
Extranodal sites .63 1.1  (0.7-1.8)  
Performance status .05 1.6  (1.0-2.4)  
Clinical stage .03 1.7  (1.1-2.7)  
Lactate dehydrogenase .02 1.6  (1.1-2.5) 
Survivin .03 1.6  (1.1-2.3) 

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,16survivin 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.32Moreover, 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) andbcl-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 bybcl-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 ofbcl-2 and survivin improved disease in vivo37and 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.

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.

1
Armitage
JO
Weisenburger
DD
New approach to classifying non-Hodgkin's lymphomas: clinical features of the major histologic subtypes. Non-Hodgkin's Lymphoma Classification Project.
J Clin Oncol.
16
1998
2780
2795
2
Harris
NL
Jaffe
ES
Stein
H
et al
A revised European-American classification of lymphoid neoplasms: a proposal from the International Lymphoma Study Group.
Blood.
84
1994
1361
1392
3
Jaffe
ES
Harris
NL
Diebold
J
Muller-Hermelink
HK
World Health Organization classification of neoplastic diseases of the hematopoietic and lymphoid tissues. A progress report.
Am J Clin Pathol.
111
1999
S8
S12
4
Coiffier
B
Gisselbrecht
C
Vose
JM
et al
Prognostic factors in aggressive malignant lymphomas: description and validation of a prognostic index that could identify patients requiring a more intensive therapy. The Groupe d'Etudes des Lymphomes Agressifs.
J Clin Oncol.
9
1991
211
219
5
A predictive model for aggressive non-Hodgkin's lymphoma. The International Non-Hodgkin's Lymphoma Prognostic Factors Project.
N Engl J Med.
329
1993
987
994
6
Alizadeh
AA
Eisen
MB
Davis
RE
et al
Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling.
Nature.
403
2000
503
511
7
Hermine
O
Haioun
C
Lepage
E
et al
Prognostic significance of bcl-2 protein expression in aggressive non- Hodgkin's lymphoma. Groupe d'Etude des Lymphomes de l'Adulte (GELA).
Blood.
87
1996
265
272
8
Kramer
MH
Hermans
J
Parker
J
et al
Clinical significance of bcl2 and p53 protein expression in diffuse large B-cell lymphoma: a population-based study.
J Clin Oncol.
14
1996
2131
2138
9
Hill
ME
MacLennan
KA
Cunningham
DC
et al
Prognostic significance of BCL-2 expression and bcl-2 major breakpoint region rearrangement in diffuse large cell non-Hodgkin's lymphoma: a British National Lymphoma Investigation Study.
Blood.
88
1996
1046
1051
10
Gascoyne
RD
Adomat
SA
Krajewski
S
et al
Prognostic significance of Bcl-2 protein expression and Bcl-2 gene rearrangement in diffuse aggressive non-Hodgkin's lymphoma.
Blood.
90
1997
244
251
11
Koduru
PR
Raju
K
Vadmal
V
et al
Correlation between mutation in p53, p53 expression, cytogenetics, histologic type, and survival in patients with B-cell non-Hodgkin's lymphoma.
Blood.
90
1997
4078
4091
12
Ichikawa
A
Kinoshita
T
Watanabe
T
et al
Mutations of the p53 gene as a prognostic factor in aggressive B-cell lymphoma.
N Engl J Med.
337
1997
529
534
13
Ambrosini
G
Adida
C
Altieri
DC
A novel anti-apoptosis gene, survivin, expressed in cancer and lymphoma.
Nat Med.
3
1997
917
921
14
Deveraux
QL
Reed
JC
IAP family proteins-suppressors of apoptosis.
Genes Dev.
13
1999
239
252
15
Adida
C
Crotty
PL
McGrath
J
Berrebi
D
Diebold
J
Altieri
DC
Developmentally regulated expression of the novel cancer anti-apoptosis gene survivin in human and mouse differentiation.
Am J Pathol.
152
1998
43
49
16
Velculescu
VE
Madden
SL
Zhang
L
et al
Analysis of human transcriptomes.
Nat Genet.
23
1999
387
388
17
Li
F
Ambrosini
G
Chu
EY
et al
Control of apoptosis and mitotic spindle checkpoint by survivin.
Nature.
396
1998
580
584
18
Li
F
Ackermann
EJ
Bennett
CF
et al
Pleiotropic cell-division defects and apoptosis induced by interference with survivin function.
Nat Cell Biol.
1
1999
461
466
19
Adida
C
Berrebi
D
Peuchmaur
M
Reyes-Mugica
M
Altieri
DC
Anti-apoptosis gene, survivin, and prognosis of neuroblastoma.
Lancet.
351
1998
882
883
20
Kawasaki
H
Altieri
DC
Lu
C-D
Toyoda
M
Tenjo
T
Tanigawa
N
Inhibition of apoptosis by survivin predicts shorter survival rates in colorectal cancer.
Cancer Res.
58
1998
5071
5074
21
Monzo
M
Rosell
R
Felip
E
et al
A novel anti-apoptosis gene: re-expression of survivin messenger RNA as a prognosis marker in non-small-cell lung cancers.
J Clin Oncol.
17
1999
2100
22
Sarela
AI
Macadam
RC
Farmery
SM
Markham
AF
Guillou
PJ
Expression of the antiapoptosis gene, survivin, predicts death from recurrent colorectal carcinoma.
Gut.
46
2000
645
650
23
Islam
A
Kageyama
H
Takada
N
et al
High expression of survivin, mapped to 17q25, is significantly associated with poor prognostic factors and promotes cell survival in human neuroblastoma.
Oncogene.
19
2000
617
623
24
Coiffier
B
Gisselbrecht
C
Herbrecht
R
Tilly
H
Bosly
A
Brousse
N
LNH-84 regimen: a multicenter study of intensive chemotherapy in 737 patients with aggressive malignant lymphoma.
J Clin Oncol.
7
1989
1018
1026
25
Haioun
C
Lepage
E
Gisselbrecht
C
et al
Benefit of autologous bone marrow transplantation over sequential chemotherapy in poor-risk aggressive non-Hodgkin's lymphoma: updated results of the prospective study LNH87–2. Groupe d'Etude des Lymphomes de l'Adulte.
J Clin Oncol.
15
1997
1131
1137
26
Tilly
H
Mounier
N
Lederlin
P
et al
Randomized comparison of ACVBP and m-BACOD for patients with low-risk aggressive lymphoma: the LNH87–1 study. Groupe d'Etudes des Lymphomes de l'Adulte.
J Clin Oncol.
18
2000
1309
1315
27
Bosly
A
Lepage
E
Dupriez
B
et al
Alternance of chemotherapy does not improve results in aggressive non-Hodgkin's lymphoma: a prospective randomized study on 884 patients LNH 87 protocol group 3: a GELA study.
Br J Haematol.
93(suppl 2)
1996
142
28
Bastion
Y
Blay
JY
Divine
M
et al
Elderly patients with aggressive non-Hodgkin's lymphoma: disease presentation, response to treatment, and survival—a Groupe d'Etude des Lymphomes de l'Adulte study on 453 patients older than 69 years.
J Clin Oncol.
15
1997
2945
2953
29
Stansfeld
AG
Diebold
J
Noel
H
et al
Updated Kiel classification for lymphomas.
Lancet.
1
1988
292
293
30
Kaplan
E
Meier
P
Nonparametric estimation from incomplete observations.
J Am Stat Assoc.
53
1958
457
31
Cox
DR
Regression models and life-tables.
J R Stat Soc.
34
1972
187
32
Swana
HS
Grossman
D
Anthony
JN
Weiss
RM
Altieri
DC
Tumor content of the antiapoptosis molecule survivin and recurrence of bladder cancer.
N Engl J Med.
341
1999
452
453
33
Tamm
I
Wang
Y
Sausville
E
et al
IAP-family protein survivin inhibits caspase activity and apoptosis induced by Fas (CD95), Bax, caspases, and anticancer drugs.
Cancer Res.
58
1998
5315
5320
34
Lu
C-D
Altieri
DC
Tanigawa
N
Expression of a novel antiapoptosis gene, survivin, correlated with tumor cell apoptosis and p53 accumulation in gastric carcinomas.
Cancer Res.
58
1998
1808
1812
35
Adams
JM
Cory
S
The Bcl-2 protein family: arbiters of cell survival.
Science.
281
1998
1322
1326
36
Miyashita
T
Reed
JC
Bcl-2 oncoprotein blocks chemotherapy-induced apoptosis in a human leukemia cell line.
Blood.
81
1993
151
157
37
Webb
A
Cunningham
D
Cotter
F
et al
BCL-2 antisense therapy in patients with non-Hodgkin lymphoma.
Lancet.
349
1997
1137
1141

Author notes

Dario C. Altieri, Yale University School of Medicine, BCMM436B, 295 Congress Ave, New Haven, CT 06536; e-mail:dario.altieri@yale.edu.

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