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 Previous Article | Table of Contents | Next Article 
Blood, Vol. 91 No. 8 (April 15), 1998:
pp. 3011-3016
Serum Level of the Soluble Form of the CD30 Molecule Identifies
Patients With Hodgkin's Disease at High Risk of Unfavorable Outcome
By
Gianpaolo Nadali,
Luisa Tavecchia,
Elisabetta Zanolin,
Valeria Bonfante,
Simonetta Viviani,
Edgarda Camerini,
Pellegrino Musto,
Nicola Di Renzo,
Mario Carotenuto,
Marco Chilosi,
Mauro Krampera, and
Giovanni Pizzolo
From the Departments of Hematology, Medical Statistics, and
Pathology, Verona University School of Medicine, Verona; Department of
Medical Oncology, Istituto Nazionale per lo Studio e la Cura dei
Tumori, Milano; and the Department of Hematology, IRCCS "Casa
Sollievo della Sofferenza," S. Giovanni Rotondo, Italy.
 |
ABSTRACT |
Preliminary reports suggested a prognostic significance for serum
levels of soluble CD30 (sCD30) in patients with Hodgkin's disease
(HD). In this study, we investigated the prognostic impact of sCD30
concentration at diagnosis in relation to the other recognized prognostic parameters in 303 patients with HD observed in three different institutions between 1984 and 1996. sCD30 levels were correlated with stage, presence of B symptoms, and tumor burden. High
sCD30 levels entailed a higher risk of poor outcome, and the event-free
survival (EFS) probability at 5 years for patients with sCD30 levels
 100 and less than 100 U/mL was 59.9% (95% confidence interval
[CI], 40.6% to 65.9%) and 87.5% (95% CI, 81.5% to 91.6%), respectively (P < .001). On the basis of the results of
univariate analysis of 14 pretreatment characteristics, we included
five prognostic factors (high sCD30 serum level, stage III-IV, B
symptoms, low hemoglobin level, and age 50 years) into a
multivariate model. High sCD30 and advanced stage were independently
associated with an unfavorable prognosis. Their combined evaluation
identified patients at high risk (stages III and IV and sCD30 100
U/mL: EFS, 46.9%) and low risk (stages I and II with sCD30 <100
U/mL: EFS, 88.7%) of treatment failure (P < .001). We
conclude that the combined evaluation of sCD30 serum level and stage at
presentation identifies patients with HD at high risk of an unfavorable
outcome.
| |
INTRODUCTION |
THE PROGRESS MADE in the treatment of
Hodgkin's disease (HD) during the last 20 years offers the chance to
cure the majority of patients affected by this disease.1,2
However, with current upfront therapeutic strategies, 20% to 40% of
patients either fail to reach a complete remission or subsequently
relapse.1-4 A proportion of these patients can still be
cured using salvage regimens, which have recently included intensified
protocols with or without autologous stem-cell support.5
However, the cumulative toxicity of therapy can induce a variety of
long-term adverse effects that eventually affect the quality of life
and life expectancy in a consistent proportion of
patients.6-8 The availability of reliable indices capable
of identifying patients on the basis of their prognostic risk would
help to optimize the intensity of treatment, thus avoiding
overtreatment of good-risk and undertreatment of high-risk patients.
A number of disease-related and patient-related features have been
investigated to assess their possible prognostic
relevance.2,9-13 Although some of these features have been
recognized and used in therapeutic decision-making,10-13
their role in predicting the individual outcome within patient
subgroups is still unsatisfactory.
In a previous report, we demonstrated that the circulating level at
presentation of the soluble form of the CD30 molecule (sCD30) in HD
represents an independent prognostic factor associated with reduced
disease-free survival.14 The rationale for investigating sCD30 in HD derived from the knowledge that this molecule is likely to
play a pathogenetic role in this disease. In fact, CD30 is a 120-kD
surface molecule, functioning as a transmembrane cytokine receptor,
that belongs to the tumor necrosis factor (TNF)/nerve growth factor
(NGF) receptor family,15,16 which is
consistently expressed by Hodgkin's and Reed-Sternberg (H-RS)
cells.17 The interaction between CD30 and its ligand
(CD30L) is involved in the growth regulation of HD-derived cell
lines.18 sCD30 is an 88-kD molecule released by
CD30+ cells in vitro and in vivo.18,19 Its
serum concentration increases in different pathologic conditions,
including HD, as the result of the release by neoplastic or reactive
cells expressing CD30.19-26 In this study, we investigated
the prognostic significance of the serum level of sCD30 at diagnosis,
in relation to other features of possible prognostic relevance, in a
large series of patients with HD observed in three different
institutions.
| |
MATERIALS AND METHODS |
Patients.
A total of 303 patients with HD were included in this study on the sole
basis of availability of serum sample collected at diagnosis. Informed
consent was obtained from all patients. Patients were observed between
November 1984 and April 1996 at three different institutions in Italy:
the Department of Hematology, University of Verona (147 patients); the
Department of Medical Oncology, Istituto Nazionale per lo Studio e la
Cura dei Tumori, Milano (89 patients); and the Department of
Hematology, S. Giovanni Rotondo (67 patients). The mean and median
follow-up times, calculated from diagnosis, were 55 and 48 months
(range, 6 to 169), respectively. One hundred fifty-one patients were
males and 152 females, aged 6 to 78 years (median age, 28 years). The
diagnosis was based on histologic findings supported by
immunohistochemical analysis in the large majority of cases. A
well-established panel of antibodies was used, including reagents
specific for CD30, CD15, and CD20. A nodular sclerosis (NS) subtype was
found in 210 patients, mixed cellularity (MC) in 53, lymphocyte
predominance (LP) in 21, and lymphocyte depletion (LD) in six. In the
remaining 13 patients, a confident classification of the histologic
subtype could not be ascertained.
Among cases classified as LP or LD, immunohistologic analysis was
available in 15 of 21 and five of six, respectively. In LP, the classic
immunophenotypic pattern of atypical cells (L&H) was documented,
including the absence of CD30 on paraffin preparations and its faint
expression on cryostat sections, the absence of CD15, and the
expression of B-cell-associated antigens, in the presence of a
consistent number of CD57+ lymphocytes surrounding
L&H cells.27 In cases defined as LD, immunohistologic analysis documented the expression of CD30 and CD15
and the absence of expression of EMA, as well as of
B-cell- and T-cell-associated antigens by H-RS cells. Thus, a
diagnosis of CD30+ anaplastic large-cell lymphoma (ALCL)
was ruled out in these cases on the basis of morphology and
immunohistologic phenotype.
Staging and treatment.
Depending on the results of staging procedures, patients were
classified according to the Cotswold's meeting criteria28 as follows: stage I = 39, stage II = 163, stage III = 55, stage IV = 46, stage B = 136, and stage A = 167 patients. Eighty-five patients had
bulky disease, defined as a mediastinal mass exceeding one third of the
thoracic diameter measured at the D5-D6 level, and/or as an
extramediastinal mass greater than 10 cm. Stages were defined as
unfavorable in the presence of extranodal extent, bulky disease, more
than three involved sites, and/or pulmonary hilus adenopathies.
Blood and serum levels of hemoglobin and lactic acid dehydrogenase
(LDH) were available for all 303 patients. Erythrocyte sedimentation
rate (ESR), albumin, and fibrinogen were available in 214.
Treatment was stage-directed29,30 and was based on
radiotherapy (RT) alone or vinblastine, bleomycin, and methotrexate (VBM)31 or ABVD32 chemotherapy
combined with RT for patients with limited disease (stages I to IIA and
IIIA without risk factors) and on chemotherapy (ABVD, MOPP/ABVD, VEBEP,
or MOPP/EBV/CAD),33-36 with or without involved-field RT in
advanced stages (IIIB, IVA, or IVB) or in the presence of risk factors
(IIB, IIE, IIA bulky, and IIIA unfavorable).
Patient outcome.
All patients were considered assessable for treatment outcome, since
those who received fewer than four cycles of chemotherapy or an
incomplete course of RT were not included in this study.
Complete response (CR) was defined as the complete disappearance of all
abnormalities (clinical, physical, radiologic, and biochemical)
attributable to HD. Partial response (PR) was defined as a reduction of
at least 50% for at least 4 weeks in the sum of the products of the
perpendicular diameters of all measurable masses with no new lesions
appearing and no progression at the original sites of disease.
Progression was defined as an increase of any measured lesion or the
appearance of new lesions. Follow-up reports were required every 3 months for the first year after treatment and every 6 months
thereafter. Failure to achieve a CR, or disease progression, or the
occurrence of a relapse after CR, were considered as events.
Among 303 patients, 287 (94.7%) obtained a CR and 16 either failed to
reach a CR or progressed during treatment (five initial and 11 advanced
stages, three A and 13 B, five bulky). Thirty-nine (13.5%) of 287 patients relapsed after achievement of a CR.
Thirty-three of 303 patients received only RT. The event rate among
these patients was 21.2% (seven of 33), similar to that observed in
patients treated with chemotherapy alone or combined modality therapy
(49 of 270; 18.15%). At the end of the study, 20 patients had died: 18 as a direct consequence of disease and two of causes related to
treatment toxicity. None of the patients died before the assessment of
response to treatment.
sCD30 assay.
sCD30 levels were determined in serum samples stored at  70°C by a
sandwich enzyme-linked immunosorbent assay (CD30 [Ki-1 antigen]
ELISA; DAKO, Glostrup, Denmark), based on the use of two monoclonal
antibodies reacting with two different epitopes on the 88-kD soluble
form of the CD30 molecule, as previously described.37 Sera
from 113 blood donors (79 males and 34 females; median age, 30 years)
served as normal controls.
Statistical analysis.
As sCD30 values were not normally distributed, results are reported
both as the mean (±SEM) and median (range) sCD30 serum levels. Median
levels for different groups of patients were compared using the
nonparametric Mann-Whitney U and Kruskal-Wallis tests as
appropriate. The cut-off point for sCD30 serum level (100 U/mL) was
chosen as the dividing point based on the maximum ratio of the
estimated hazard for the groups. Cox's proportional hazards model was
used for univariate and multivariate analysis. The variates fibrinogen,
ESR, and LDH were coded as the ratio above the normal value for each
participating center. Hemoglobin and albumin were considered as
continuous variables, being normal values comparable among the three
centers. sCD30 was also evaluated as a continuous variable in the Cox
model. Missing data were dealt with by excluding from particular
analyses those patients without data on the required variables.
Actuarial event-free survival (EFS) curves were constructed by the
Kaplan-Meier method and differences were analyzed by the log-rank test.
Statistical significance obtained by repeated log-rank testing of
subgroups of patients was adjusted by Bonferroni's correction.38 EFS was defined as the interval between
diagnosis and the achievement either of a PR or the occurrence of
disease relapse after CR. For patients who experienced disease
progression under treatment, an EFS time of 0 was assigned. All
variables found to have a P value  .05 were considered to be
statistically significant.
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RESULTS |
Correlations with clinical features.
Serum levels of sCD30 in samples collected at diagnosis before
treatment are listed in Table 1. Increased
levels (>20 U/mL) were observed in 237 of 303 patients (78.2%). The
median value (45 U/mL; range, 1 to 815) was significantly higher as
compared with controls (P < .001).
No differences were found between male and female patients (43 and 47 U/mL, respectively; P = .66). Age 50 years was associated with higher sCD30 serum levels (43 v 68 U/mL in patients < or >50 years, respectively; P = .01). Patients with advanced
disease (stages III and IV) had higher sCD30 levels compared with those with more limited disease (stages I and II) (93 v 37 U/mL,
respectively; P .001). In addition, patients with B
symptoms had higher values compared with those with stage A (66 and 33 U/mL, respectively; P < .001). Higher sCD30 levels were
detected in patients with bulky disease (n = 85) as compared with
patients without bulky mass (77 v 37 U/mL;
P < .001). The analysis of variance performed to compare
sCD30 median levels in LP, MC, NS, and LD subtypes showed a significant
difference (P = .028), with the highest value being detected
in six patients with LD subtype.
Relationship between sCD30 values at diagnosis and outcome.
sCD30 values 100 U/mL entailed a higher risk of poor outcome, since
either failure to reach a CR or a subsequent relapse occurred more
frequently in patients with sCD30 values 100 U/mL (32 of 78; 41%)
than in those with values less than 100 U/mL (23 of 225; 10.2%). The
difference between the EFS curves of patients with sCD30 level at
diagnosis above and below 100 U/mL was highly significant
(P < .001), with a 5-year EFS probability of 59.9% (95%
confidence interval [CI], 40.6% to 65.9%) and 87.5% (95% CI,
81.5% to 91.6%), respectively (Fig 1).
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| Fig 1.
EFS probability of 303 patients with HD according to
sCD30 serum levels at diagnosis. Tick marks indicate last follow-up. Vertical bars indicate 95% CI.
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Fourteen prognostic parameters, including treatment by each one of the
participating centers (center 1, 2, or 3), age (<50 v 50
years), gender, stage (I and II v III and IV), A versus B
symptoms, bulky versus nonbulky presentation, ESR (ratio), albumin (continuous), LDH (ratio), hemoglobin (continuous), fibrinogen (ratio),
and sCD30 serum level (continuous), were considered in the univariate
analysis by Cox's regression. As reported in Table 2, sCD30 serum level, advanced stage,
presence of B symptoms, and age 50 years at presentation were found
to be associated with a significantly higher risk of poor outcome.
These four variables were then included in the final Cox regression
model for multivariate analysis (Table 3).The variable hemoglobin was also included in this model, because of its
borderline statistical significance (hazards ratio, 0.99;
P = .064). Only sCD30 serum level and advanced-stage disease
retained independent prognostic significance. We therefore combined the
sCD30 serum level as a dichotomous variable (<100 U/mL and 100
U/mL) with the extension of disease (stage I and II and III and IV) to
maximize their prognostic impact on outcome and to obtain a combined
prognostic index (Table 4). Figure
2 illustrates the Kaplan-Meier plot of EFS
according to the combination of the two major prognostic factors. The
5-year EFS was 88.7% (95% CI, 82% to 93%) (stages I and II and
sCD30 <100 U/mL: group 1), 83.1% (95% CI, 67% to 92%) (stages III
and IV and sCD30 <100 U/mL: group 2), 72.5% (95% CI, 52% to 85%)
(stages I and II and sCD30 100 U/mL: group 3), and 50.5% (95% CI,
35% to 64%) (stages III and IV and sCD30 100 U/mL: group 4). The
overall P value among the four groups of patients was less than
.001. In particular, for group 1 versus group 2, P = not
significant; group 2 versus group 3, P = not significant; group
1 versus group 3, P = .04; and group 3 versus group 4, P = .05 (Table 4).
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Table 2.
Univariate Analysis for Event Occurrence (failure to
achieve CR or relapse) by Cox's Proportional Hazards Regression
Model
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Table 3.
Multivariate Analysis for Event Occurrence (failure to
achieve CR or relapse) by Cox's Proportional Hazards Regression
Model
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Table 4.
Estimation of EFS of 303 Patients With HD According to
Cumulative Effect of sCD30 Serum Level and Stage of Disease Assessed at
Diagnosis
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| Fig 2.
EFS probability of 303 patients with HD according to
sCD30 serum levels and stage at diagnosis. 1, sCD30 <100 U/mL and
stages I-II; 2, sCD30 <100 U/mL and stages III-IV; 3, sCD30 100
U/mL and stages I-II; and 4, sCD30 100 U/mL and stages III-IV. 1 v 2, P = not significant; 2 v 3, P
= not significant; 1 v 3, P = .04; 3 v 4, P = .05. Tick marks indicate last follow-up.
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DISCUSSION |
Current treatment strategies are able to cure the majority of patients
with HD.1,2,29,30,34 However, between 20% and 40% of
patients with newly diagnosed HD either fail to respond completely to
induction therapy, with subsequent disease progression, or relapse
after an initial CR. A proportion of these patients, poor responders to
standard treatment, can be subsequently rescued by high-dose therapy
associated with autologous hematopoietic progenitor-cell
transplantation,5 which raises the question of the role of
such an intensive approach as upfront treatment for high-risk patients.
Unfortunately, the search for adverse prognostic features at
presentation, which are capable of identifying high-risk patients
eligible for more intensive treatment, has so far been largely
unsatisfactory.9-13,39,40
Our previous observation suggesting that sCD30 evaluation in patients
with HD at diagnosis has prognostic significance14 led us
to investigate this issue further in a larger series of patients,
treated at three Italian centers during the last 12 years. Although
patients were submitted to different regimens, the treatment programs
shared a common stage-directed strategy. Patients with localized
disease (stages I and II) were treated with RT ± chemotherapy,
depending on the presence of risk factors. Patients with advanced
disease experienced slightly different induction chemotherapy regimes
(ABVD, MOPP/ABVD, VEBEP, or MOPP/EBV/CAD), with or without
consolidation RT, according to the protocol in use in each center
during the 12 years of the study. However, in terms of EFS, which is
the outcome variable evaluated in this study, no significant difference
among groups of patients treated at different centers could be
demonstrated (Table 2). In addition, the event rate among patients with
localized disease treated with RT alone (seven of 33; 21.2%) was
similar to that observed in patients treated with chemotherapy alone or
combined modality therapy (49 of 270; 18.15%). Therefore, we assumed
treatment modality to be a nonprognostic variable in our cases.
sCD30 levels were increased in the vast majority of patients (78%) and
correlated with disease stage, presence of B symptoms, and tumor
burden. In addition, higher sCD30 levels were detected in patients with
LD histology as compared with the other histologic subtypes. These
correlations, which cannot be merely explained on the basis of the
number of H-RS cells, as previously reported,14 suggest
that serum sCD30 in HD reflects the functional behavior of the
neoplastic cells (ie, H-RS) and their relationship with the
heterogeneous microenvironment and the complex network of cytokines
observed in HD.18
Since the final goal of our study was to assess the specific role of
sCD30 in identifying high-risk patients, we have evaluated its
prognostic significance in terms of EFS in comparison to 13 other
presentation features that have been previously reported to hold
prognostic significance. At univariate analysis, advanced stage,
presence of B symptoms, age 50 years, and sCD30 serum level (as a
continuous variable) were all associated with a significant high risk
of treatment failure (Table 2). sCD30 serum level 100 U/mL at
diagnosis was confirmed to have a strong adverse prognostic significance as a single factor, as shown by the difference between the
EFS curves of patients with sCD30 levels less than 100 U/mL and 100
U/mL (Fig 1).
None of the other variables included in the model was significant.
Hemoglobin level (evaluated as a continuous variable) showed borderline
significance (P = .064), whereas in previous studies, hemoglobin/hematocrit was identified as a prognostic factor that maintained its significance when included in a multivariate
analysis.9,39 The adverse effect on outcome of advanced age
at diagnosis has been reported in different studies.9,39,40
In our series, the risk of treatment failure increased significantly
for patients 50 years of age (hazards ratio, 2.26;
P = .007), whereas it was only of borderline significance
when we considered a cut-off of 45 years (hazards ratio, 1.69;
P = .072). One of the possible explanations for the adverse
role of advanced age on outcome is the reduction of treatment
intensity, probably related to impaired performance status. In our
study, we could not address this issue, since reliable information on
performance status at diagnosis and actual dose of drug delivered was
available only for a minority of patients.
The extent of mediastinal disease has also been reported to be a
prognostic factor.9,11,41 Although in our study this parameter was not evaluated separately, it was included in the definition of bulky disease and the presence of high tumor burden did
not correlate with a higher risk of treatment failure. This could be
related to the fact that patients with localized bulky disease were
treated with combined modality therapy, which could have hampered the
adverse prognostic effect of tumor burden.
On the basis of the results of the univariate analysis, we included in
the final multivariate analysis the four factors with a statistical
significance, plus hemoglobin, which had a borderline significant
P value. Only sCD30 serum level (continuous) and advanced stage
retained an independent prognostic significance in identifying high-risk patients (Table 3). The combined evaluation of sCD30 and
stage at presentation clearly showed that patients with both adverse
prognostic factors, ie, stages III and IV and sCD30 100 U/mL, had an
expected EFS at 5 years significantly lower than those with stages I
and II and sCD30 less than 100 U/mL. These results are striking if
compared with other large cooperative lymphoma studies aimed at
detecting possible prognostic factors by including multiple variables
and different types of score or numerical indices.13,40,42
In particular, from the combined evaluation of sCD30 and stage at
presentation, it is possible to identify patients with a very high and
very low risk of treatment failure with standard therapy. This seems to
fulfil the requirements of any prognostic modeling, which should
provide a reliable and simple guideline to predict patients' outcome.
A more accurate definition of risk of treatment failure in patients
with HD at presentation would help to tailor treatment strategies
further in individual cases. This could possibly allow the reduction of
initial treatment intensity in low-risk patients, thus reducing early
and late treatment-related morbidity and the incidence of long term
secondary effects. On the other hand, the reliable identification of
high-risk patients could possibly improve their cure rate using more
intensive upfront treatment, which has already produced promising
results in relapsed HD.
The prognostic usefulness in HD of the combined evaluation of sCD30 and
clinical stage emerged from our study now has to be validated in large
prospective clinical trials.
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FOOTNOTES |
Submitted September 17, 1997;
accepted December 2, 1997.
Supported by grants from Associazione Italiana per la Ricerca sul
Cancro (AIRC, Milano) and from the Italian National Research Council,
Special Project "Clinical Application of Oncological Research."
Address reprint requests to Giovanni Pizzolo, MD, Cattedra di
Ematologia, Policlinico Borgo Roma, 37134 Verona, Italy.
The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" is accordance with 18 U.S.C. section 1734 solely to indicate this fact.
| |
ACKNOWLEDGMENT |
The authors thank Professor V. Diehl and Dr D. Hasenclever for helpful
discussion. The excellent technical assistance provided by Lorella
Morosato and Rosella Matera is also gratefully acknowledged.
| |
REFERENCES |
1.
Straus DJ:
Treatment of Hodgkin's disease: The role of radio- and/or chemotherapy in advanced stages.
Bailliere's Clin Haematol
9:553,
1997
2.
Canellos GP,
Anderson JR,
Propert KJ,
Nissen N,
Cooper MR,
Henderson ES,
Green MR,
Gottlieb A,
Paterson BA:
Chemotherapy of advanced Hodgkin's disease with MOPP, ABVD, or MOPP alternating with ABVD.
N Engl J Med
327:1478,
1992[Abstract]
3.
Bartlett NL,
Rosenberg SA,
Hoppe RT,
Hancock SL,
Horning SJ:
Brief chemotherapy, Stanford V, and adjuvant radiotherapy for bulky or advanced stage Hodgkin's disease: A preliminary report.
J Clin Oncol
13:1080,
1995[Abstract]
4.
Gause BL,
Longo DL:
Treatment of relapsed Hodgkin's disease.
Bailliere's Clin Haematol
9:559,
1997
5.
Horning J,
Chao NJ,
Negrin RS,
Hoppe RT,
Long GD,
Wendy WH,
Wong RM,
Brown BW,
Blume KJ:
High-dose therapy and autologous hematopoietic progenitor cell transplantation for recurrent or refractory Hodgkin's disease: Analysis of the Stanford University results and prognostic indices.
Blood
3:801,
1997
6.
Abrahamsen JF,
Andersen A,
Hannisdal E,
Nome O,
Abrahamsen AF,
Kvaloy S,
Host H:
Second malignancies after treatment of Hodgkin's disease: The influence of treatment, follow-up time and age.
J Clin Oncol
11:255,
1993[Abstract/Free Full Text]
7.
Henry-Amar M:
Treatment sequelae and quality of life.
Bailliere's Clin Haematol
9:559,
1997
8.
van Tulder MW,
Aaronson NK,
Bruning PF:
The quality of life of long term survivors of Hodgkin's disease.
Ann Oncol
5:153,
1994[Abstract/Free Full Text]
9.
Straus DJ,
Gaynor JJ,
Myers J,
Merke DP,
Caravelli J,
Chapman D,
Yahalom J,
Clarkson BD:
Prognostic factors among 185 adults with newly diagnosed advanced Hodgkin's disease treated with alternating potentially noncross-resistant chemotherapy and intermediate-dose radiation therapy.
J Clin Oncol
8:1173,
1990[Abstract]
10.
Somers R,
Carde P,
Henry-Amar M,
Tarayre M,
Thomas J,
Hagenbee KA,
Monconduit M,
de Pauw BE,
Breed WPM,
Verdonk L,
Burgers JMV,
Eghbali H,
Zittoun R:
A randomized study in stage IIIB and IV Hodgkin's disease comparing eight courses of MOPP versus an alternation of MOPP with ABVD: A European Organization for Research and Treatment of Cancer Lymphoma Cooperative Group and Groupe Pierre-et-Marie-Curie controlled clinical trial.
J Clin Oncol
12:279,
1994[Abstract]
11.
Colonna P,
Jais JP,
Desablens B,
Harousseau JL,
Brière J,
Boasson M,
Lemevel A,
Casassus P,
La Prisé PY,
Guilhot F,
Ghandour C,
Lejeune F,
Andrieu JM:
Mediastinal tumor size and response to chemotherapy are the only prognostic factors in supradiaphragmatic Hodgkin's disease treated by ABVD plus radiotherapy: Ten-year results of the Paris-Ouest-France 81/12 trial, including 262 patients.
J Clin Oncol
14:1928,
1996[Abstract/Free Full Text]
12.
Anderson H,
Jenkins JPR,
Brigg DJ:
The prognostic significance of mediastinal bulk in patients with stage IA-IVB Hodgkin's disease: A report from the Manchester Lymphoma Group.
Clin Radiol
36:449,
1985[Medline]
[Order article via Infotrieve]
13. (suppl 1, abstr)
Hasenclever D,
Diehl V:
A numerical index to predict tumor control in advanced Hodgkin's disease.
Blood
88:673a,
1996
14.
Nadali G,
Vinante F,
Ambrosetti A,
Todeschini G,
Veneri D,
Zanotti R,
Meneghini V,
Ricetti MM,
Benedetti F,
Vassanelli A,
Perona G,
Chilosi M,
Menestrina F,
Fiacchini M,
Stein H,
Pizzolo G:
Serum levels of soluble CD30 are elevated in the majority of untreated patients with Hodgkin's disease and correlate with clinical features and prognosis.
J Clin Oncol
12:793,
1994[Abstract]
15.
Durkop H,
Latza U,
Hummel M:
Molecular cloning and expression of a new member of the nerve growth factor receptor family that is characteristic for Hodgkin's disease.
Cell
68:421,
1992[Medline]
[Order article via Infotrieve]
16.
Smith C,
David T,
Anderson D,
Solam L,
Beckmann MP,
Jerzy R,
Dower SK,
Cosman D,
Goodwin RG:
A receptor for tumor necrosis factor defines an unusual family of cellular and viral proteins.
Science
248:1019,
1990[Abstract/Free Full Text]
17.
Schwab U,
Stein H,
Gerdes J:
Production of a monoclonal antibody specific for Hodgkin's and Sternberg-Reed cells of Hodgkin's disease and a subset of normal lymphoid cells.
Nature
299:65,
1982[Medline]
[Order article via Infotrieve]
18.
Gruss HJ,
Pinto A,
Duyster J,
Poppema S,
Herrmann F:
Hodgkin's disease: A tumor with disturbed immunological pathways.
Immunol Today
18:156,
1997[Medline]
[Order article via Infotrieve]
19.
Josimovic-Alasevic O,
Dürkop H,
Schwarting R,
Backe E,
Stein H,
Diamantstein T:
Ki-1 (CD30) antigen is released by Ki-1 positive tumor cells in vitro and in vivo. Partial characterization of soluble Ki-1 antigen and detection of the antigen in cell culture supernatants and in serum by an enzyme-linked immunosorbent assay.
Eur J Immunol
19:157,
1989[Medline]
[Order article via Infotrieve]
20. Dallenbach F, Josimovic-Alasevic O, Durkop H: Soluble CD30
antigen in the sera of patients with adult T-cell lymphoma/leukaemia (ATL): A marker for disease activity, in Knapp W, Dorken B, Gilks WR,
Rieber EP, Schmidt RE, Stein H, von dem Borne AEGKr (eds): Leucocyte
Typing IV: White Cell Differentiation Antigens. Oxford, UK, Oxford
University Press, 1989, p 426
21.
Pizzolo G,
Vinante F,
Chilosi M,
Dallenbach F,
Josimovic-Alasevic O,
Diamantstein T,
Stein H:
Serum levels of soluble CD30 molecule (Ki-1 antigen) in Hodgkin's disease: Relationship with disease activity and clinical stage.
Br J Haematol
75:282,
1990[Medline]
[Order article via Infotrieve]
22.
Pizzolo G,
Stein H,
Josimovic-Alasevic O,
Vinante F,
Zanotti R,
Chilosi M,
Feller AC,
Diamantstein T:
Increased serum levels of soluble IL-2 receptor, CD30, and CD8 molecules, and gamma interferon in angioimmunoblastic lymphadenopathy. Possible pathogenetic role of immunoactivation mechanisms.
Br J Haematol
75:485,
1990[Medline]
[Order article via Infotrieve]
23.
Gause A,
Pohl C,
Tschiersch A,
Da Costa L,
Jung W,
Diehl V,
Hasenclever D,
Pfreundschuh M:
Clinical significance of soluble CD30 antigen in the sera of patients with untreated Hodgkin's disease.
Blood
77:1983,
1991[Abstract/Free Full Text]
24.
Pizzolo G,
Romagnani S:
CD30 molecule (Ki-1 Ag): More than just a marker of CD30+ lymphoma.
Haematologica
80:357,
1995[Free Full Text]
25.
Del Prete G,
Maggi E,
Pizzolo G,
Romagnani S:
CD30, Th2 cytokines and HIV infection: A complex and fascinating link.
Immunol Today
16:76,
1995[Medline]
[Order article via Infotrieve]
26.
Falini B,
Pileri S,
Pizzolo G,
Durkop H,
Flenghi L,
Stirpe F,
Martelli MF,
Stein H:
CD30 (Ki-1) molecule: A new cytokine receptor of the tumor necrosis factor receptor superfamily as a tool for diagnosis and immunotherapy.
Blood
85:1,
1995[Free Full Text]
27.
Harris NL,
Jaffe ES,
Stein H,
Banks PM,
Chan JK,
Cleary ML,
Delsol G,
De Wolf-Peeters C,
Falini B,
Gatter KC,
Grogan TM,
Isaacson PG,
Knowles DM,
Mason DY,
Muller-Hermelink HK,
Pileri SA,
Piris MA,
Ralfkiaer E,
Warnke RA:
A revised European-American classification of lymphoid neoplasms: A proposal from the International Lymphoma Study Group.
Blood
84:1361,
1994[Free Full Text]
28.
Lister TA,
Crowther D,
Sutcliffe SB,
Glatstein E,
Canellos GP,
Young RC,
Rosenberg SA,
Coltman CA,
Tubiana M:
Report of a committee convened to discuss the evaluation and staging of patients with Hodgkin's disease: Cotswolds meeting.
J Clin Oncol
7:1630,
1989[Abstract]
29.
Hoppe RT:
Radiation therapy in the management of Hodgkin's disease.
Semin Oncol
17:704,
1990[Medline]
[Order article via Infotrieve]
30.
Longo DL:
The use of chemotherapy in the treatment of Hodgkin's disease.
Semin Oncol
17:716,
1990[Medline]
[Order article via Infotrieve]
31.
Gobbi PG,
Pierasca C,
Frassoldati A,
Carotenuto M,
Di Renzo N,
La Sala A,
Bertè R,
Avanzini P,
Federico M,
Silingardi V,
Ascari E:
Vinblastine, bleomycin, and methotrexate chemotherapy plus extended-field radiotherapy in early, favorably presenting, clinically staged Hodgkin's patients: The Gruppo Italiano per lo Studio dei Linfomi experience.
J Clin Oncol
14:527,
1996[Abstract/Free Full Text]
32. (abstr)
Bonfante V,
Santoro A,
Viviani S:
ABVD plus radiotherapy (subtotal vs involved field) in early-stage Hodgkin's disease.
Proc Am Soc Clin Oncol
13:1262a,
1994
33.
Bonadonna G,
Zucali R,
Monfardini S,
De Lena M,
Uslenghi C:
Combination chemotherapy of Hodgkin's disease with Adriamycin, bleomycin, vinblastine, and imidazole carboxamide versus MOPP.
Cancer
36:252,
1975[Medline]
[Order article via Infotrieve]
34.
Viviani S,
Bonadonna G,
Santoro A,
Bonfante V,
Zanini M,
Devizzi L,
Soncini F,
Valagussa P:
Alternating versus hybrid MOPP and ABVD combinations in advanced Hodgkin's disease: Ten-year results.
J Clin Oncol
14:1421,
1996[Abstract/Free Full Text]
35. (abstr)
Viviani S,
Santoro A,
Devizzi L:
VEBEP plus involved-field RT: Efficacy and feasibility of an intensive regimen for advanced Hodgkin's disease (HD).
Proc Am Soc Clin Oncol
14:1239a,
1995
36.
Gobbi PG,
Pierasca C,
Federico M,
Di Renzo N,
Narni F,
Iannitto E,
Grignani G,
Cavanna L,
Avanzini P,
Partesotti G,
Pitini V,
Ascari E,
Silingardi V,
Mauri C:
MOPP/EBV/CAD hybrid chemotherapy with or without limited radiotherapy in advanced or unfavorably presenting Hodgkin's disease: A report from the Italian Lymphoma Study Group.
J Clin Oncol
11:712,
1993[Abstract]
37.
Pizzolo G,
Vinante F,
Morosato L,
Nadali G,
Chilosi M,
Gandini G,
Sinicco A,
Raiteri R,
Semenzato G,
Stein H,
Perona G:
High serum level of CD30 molecule in the early phase of HIV-1 infection as an independent predictor of progression to AIDS.
AIDS
8:741,
1994[Medline]
[Order article via Infotrieve]
38. Altman DG: Practical Statistics for Medical Research. London,
UK, Chapman & Hall, 1992
39.
Jaffe NS,
Cadman EC,
Farber LR:
Pretreatment hematocrit as an independent prognostic variable in Hodgkin's disease.
Blood
68:562,
1986[Abstract/Free Full Text]
40.
Proctor SJ,
Taylor P,
Donnan P,
Boys R,
Lennard A,
Prescott RJ:
A numerical index for clinical use in identification of poor-risk patients with Hodgkin's at diagnosis.
Eur J Cancer
27:624,
1991
41.
Specht L,
Nissen NI,
Walbom-Jorgensen S:
Therapeutic implications of mediastinal involvement in advanced Hodgkin's disease.
Scand J Haematol
35:166,
1985[Medline]
[Order article via Infotrieve]
42.
International Non-Hodgkin's Lymphoma Prognostic Factors Project:
A predictive model for aggressive non-Hodgkin's lymphoma.
N Engl J Med
329:987,
1993[Abstract/Free Full Text]
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Abstract
Introduction
Abstract