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 Previous Article | Table of Contents | Next Article 
Blood, Vol. 91 No. 3 (February 1), 1998:
pp. 806-812
Elevated Serum Concentrations of Hepatocyte Growth Factor in
Patients With Multiple Myeloma
By
Carina Seidel,
Magne Børset,
Ingemar Turesson,
Niels Abildgaard,
Anders Sundan, and
Anders Waage for th e Nordic Myeloma Study Group
From the Institute of Cancer Research and Molecular Biology,
Norwegian University of Science and Technology, Trondheim, Norway; the
Department of Medicine, Malmö University Hospital, Malmö,
Sweden; the Department of Medicine and Hematology, Aarhus University
Hospital, Aarhus, Denmark; and the Section of Hematology, University
Hospital, Norwegian University of Science and Technology, Trondheim,
Norway.
 |
ABSTRACT |
Serum from 398 myeloma patients at diagnosis and serial samples from
29 patients were analysed for hepatocyte growth factor (HGF). HGF was
elevated at diagnosis in 43% of myeloma patients compared with healthy
controls (median 1.00 ng/mL and 0.44 ng/mL, respectively;
P < .00001). In the group with elevated HGF levels 46% of
the patients reached plateau phase, as compared with 60% of the
patients with low HGF levels (P = .005), and the median survival time was 21 and 32 months, respectively
(P = .002). In a univariate Cox regression analysis, HGF
was a significant predictor of mortality (P = .02). In the
subgroup of patients with  2-microglobulin levels less than or equal
to 6 mg/L, high versus low HGF was a prognostic factor when a
multivariate Cox regression analysis was performed. In serial samples
HGF was higher at the time of diagnosis and relapse (median 0.57 ng/mL
and 0.52 ng/mL, respectively; P = .0018) than at response
(median 0.24 ng/mL, P = .008). We conclude that HGF may be
a useful follow-up parameter in myeloma patients. Measurement of HGF
may identify a group of patients with poor response to
melphalan-prednisone treatment and short survival. HGF was a prognostic
factor in patients with high levels of 2-microglobulin.
| |
INTRODUCTION |
MULTIPLE MYELOMA is a disorder of unknown
origin of clonal malignant plasma cells. It is associated with
production of monoclonal immunoglobulins, painful bone destruction,
anemia, hypercalcemia, and renal dysfunction. The cause of these
features is only partly understood, but production of soluble factors
by the myeloma cells is likely to be involved. Hepatocyte growth factor
(HGF) was originally purified by its ability to cause growth
stimulation of hepatocytes1 but is now known as a
mitogenic, motogenic, and morphogenic factor with potential involvement
in diverse biological processes.2 In vitro HGF has the
ability to cause destruction of tight junctions, thereby inducing
spread of confluent cells. This property led to the designation
"scatter factor",3 a name that is still used
synonymously with HGF. The receptor for HGF is a transmembrane tyrosine
kinase that is encoded by the proto-oncogene c-met.4 In
normal tissue c-met is expressed primarily in epithelial cells, but it
has also been detected on a small fraction of cells in the bone
marrow,5,6 half of which were identified as hematopoietic precursor cells because of their expression of CD34.5
Because of HGF's ability to cause blood vessel formation7
and to promote cell proliferation, invasion, and motility,3 it is proposed to be involved in the process of cancer growth and
metastasis. In breast cancer patients HGF levels were increased in 36%
of the patients, and in sequential measurements an increase in serum
HGF was associated with the appearance of relapse.8 An
interesting finding in the context of myeloma is that HGF promotes formation of osteoclasts from hematopoietic precursor
cells,9 attracts osteoclasts to sites of bone
resorption,10 and in coculture with osteoblasts increases
the level of resorption.9,10 The HGF receptor c-met is
expressed by both the bone forming osteoblasts and the bone resorbing
osteoclasts, and HGF stimulates the growth of both these cell types in
vitro.11
We recently reported that HGF and c-met are simultaneously expressed in
both myeloma cell lines and freshly isolated myeloma cells.12,13 Furthermore, HGF was detected in 17 of 20 different supernatants from highly purified myeloma cell
cultures.13 In a preliminary study we found that sera drawn
at diagnosis from 13 myeloma patients had significantly elevated levels
of HGF as compared with age- and sex-matched normal
controls.13 The purpose of this study was to define the
levels of HGF in a large well-characterized population of myeloma
patients and to examine the HGF levels during the course of the
disease. Moreover, we wished to examine the relation between HGF and
known parameters of prognosis, tumor load, and bone destruction.
| |
PATIENTS AND METHODS |
Patients.
A total of 592 patients were entered in the Nordic Myeloma Study Group
(NMSG) randomized trial in the period from June 1990 until November
1992. In this study, patients were randomized to receive melphalan and
prednisone with or without addition of low-dose interferon- . The diagnostic and eligibility criteria
and results were as described elsewhere.14 Our study
population consisted of the 398 patients from whom serum samples drawn
at diagnosis were available.
The median age of the patients in the study population was 66.5 ± 9.1 years (mean ± SD, range 32 to 87). There were 241 men and 157 women. The distribution of characteristics was typical with respect to
class of monoclonal component (M-protein): IgG in 58%, IgA in 21%,
IgD in 0.8%, and light chain disease in 20%. According to the staging
of Durie and Salmon,15 8.5% of patients were in stage I,
33.2% in stage II, and 58.3% in stage III disease.
Registered parameters at diagnosis were age, sex, World Health
Organization (WHO) performance status, bone morbidity as judged by
radiograph, urine immunoglobulin, percentage of plasma cells in the
bone marrow, hemoglobin, and serum (s-) M-protein concentration, albumin, calcium, creatinine, alanine transaminase (ALAT), total alkaline phosphatase, and 2-microglobulin. After
completion of the study, more than 400 sera drawn at diagnosis were
analyzed for interleukin-6 (IL-6), IL-6 receptor, C-reactive protein
(CRP), osteocalcin, and C-terminal telopeptide of type I collagen
(ICTP). In addition, C-terminal propeptide of procollagen
type I (PICP) and N-terminal propeptide of procollagen type III
(PIIINP) were analyzed in 109 sera.
In the NMSG study the date of response was recorded, and in a few
patients serum samples were collected and frozen at this point.
Criteria for response included clear clinical improvement and absence
of hypercalcemia and anemia, no progress of osteolytic lesions, or
rising s-creatinine. The response was defined as minor when the
s-M-protein had decreased by more than 25% but less than 50%, or the
M-protein in urine had decreased by greater than 50% but not to less
than 0.2 g in 24 hours. Partial response was defined as a decrease of
s-M-protein of greater than 50% of the initial concentration and of
M-protein in urine to less than 0.2 g in 24 hours. Complete response
was defined as an undetectable s-M-protein and a percentage of plasma
cells in a marrow aspirate less than 5%. The date of plateau phase,
defined as the time point when the M-protein had varied with less than
10% from the mean in three consecutive measurements in a responding
patient, was recorded.
At the Section of Hematology, University Hospital of Trondheim, sera
from multiple myeloma patients have been collected since 1991. By the
same criteria for diagnosis and response as above, 13 additional
patients were included for analysis of HGF at diagnosis and response.
Serum samples.
All serum samples from the time of diagnosis were taken before the
initiation of treatment. For the analysis of changes in HGF levels from
diagnosis to response, serum samples from 29 patients (13 with complete
response and 9 with partial 6 minor response) were included. Sixteen of
these patients belonged to the NMSG study group, and 13 of them were
additional patients from the Section of Hematology, University of
Trondheim. In 9 of the 13 patients in the latter group, serum drawn at
the time of relapse was also available. In these patients, relapse was
defined as the time from which treatment was reindicated. Three
patients, from whom serum had been drawn at regular intervals ( 1
sample/6 months) over a period of at least 18 months, were included for a detailed analysis of change in HGF levels over time. s-M-protein and
treatment periods were recorded from their medical records. Control
samples were obtained from 61 healthy age- and sex-matched individuals.
All samples were stored at  70°C.
HGF enzyme-linked immunosorbent assay (ELISA).
A sandwich HGF ELISA was developed in our laboratory. Two mouse
monoclonal antibodies (MoAbs) were established and used as catching
antibodies. A polyclonal antibody against HGF was prepared from a
rabbit immunized with a mixture of complete Freund's adjuvant and HGF,
boosted at 2-week intervals before blood was collected. Microtiter
96-well plates were coated with the two anti-HGF MoAbs, each at a
concentration of 10 µg/mL. After blocking with 0.5% bovine serum
albumin (BSA) in phosphate-buffered saline (PBS) for 1 hour at 37°C,
plates were washed with 0.1% BSA + 0.05% Tween 20 in PBS, and 50 µL
of standard HGF or serum samples were dispensed into the wells. The
plate was sealed and incubated for 2 hours and then washed three times.
After the addition of 50 µL of the anti-HGF polyclonal antibody
diluted to 1:800, the plate was sealed and incubated for 1 hour. It was
then washed three times with the same buffer as above. Next, 50 µL
peroxidase-labeled goat anti-rabbit IgG (Zymed, South San Francisco,
CA) diluted 1:3,000 was added for 30 minutes, and after 3 washes ortho-phenylene diamine was added. The reaction was stopped
after 10 minutes by the addition of 50 µL 1 mol/L
H2SO4. Absorbance was read at 490 nm. The
sensitivity of this assay was 0.15 ng/mL HGF. The interassay
coefficient of variation was less than 10% of the mean. The assay was
not affected by the presence of 10% human or mouse serum, nor by the
presence of plasminogen, which has a 38% similarity to HGF. Up to five freeze-thaw cycles of serum samples did not affect the level of detected HGF.
ICTP and PICP were analyzed by radioimmunoassays from
Farmos Diagnostica (Oulunsab, Finland) as described
earlier.16 Serum osteocalcin was analyzed by
immunoradiometric assay from Diagnostica Systems Laboratories (Webster,
TX). IL-6 was analyzed by ELISA from Biosource Europe S.A (Fleurs,
Belgium).
Statistical analyses.
All statistical analyses were done with the SPSSX/PC computer program
(SPSS Inc., Chicago, IL). Results were considered statistically significant when P values were less than .05. Skewed variables were logarithmically transformed before entering a parametric analysis.
Comparisons between groups were performed by the Mann-Whitney U test or
Chi-square test when appropriate. For comparison of HGF levels at
diagnosis, response and relapse Wilcoxon matched-Pairs Signed-Ranks
test was used. Correlation between two parameters was estimated by the
Spearman rank correlation analysis. For investigation of linear
correlations multiple regression analysis was used. Response to
treatment was analyzed with the chi-square test and multiple logistic
regression techniques. The method of Kaplan and Meyer was used to
compute the survival curves and to estimate the median
survival17 and the log-rank test for
significance.18 Survival was modeled with the Cox
regression analysis.19 Patients with missing variables were
excluded in the multivariate model. The NMSG study found no significant
survival difference or difference in response rate between the two arms
of treatment,14 thus it was possible to pool data from the
treatment arms in the evaluation of prognostic significance and
treatment response for the studied parameters.
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RESULTS |
Serum analyses.
The serum HGF values in patients at the time of diagnosis and in
controls are shown in Fig 1. The median HGF
concentration in the myeloma and control sera was 1.00 ng/mL (0.68 to
1.47) and 0.44 ng/mL (0.18 to 0.69), respectively (25th to 75th
percentile). This difference was statistically significant
(P < .0001). In 174 patients, ie, 43% of the patients, the
HGF levels were above the mean level +2 SD of HGF in the control group
(>1.10 ng/mL), and can thus be considered to be above the normal
range according to conventional criteria. As shown in Fig
2, in 29 patients responding to treatment,
the HGF levels were significantly lower at the time of response than
before treatment (median 0.24 ng/mL [0.00 to 0.74] and 0.57 ng/mL
[0.37 to 1.47], respectively; P = .0018). Furthermore, in 9 of these responding patients the disease relapsed, which was
accompanied by a new rise in the levels of serum HGF (median 0.52 ng/mL
at relapse versus median 0.16 ng/mL at response; P = .008).
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| Fig 1.
Serum HGF levels at diagnosis in 398 patients with
multiple myeloma (median 1.00 ng/mL) and 61 healthy age- and
sex-matched controls (median 0.44 ng/mL), measured by ELISA. The
difference between the two groups is highly significant
(P < .00001).
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| Fig 2.
Serum HGF in serial samples from 29 responding patients.
The difference between diagnosis (median 0.57 ng/mL) and response (median 0.24 ng/mL) was significant (P = .0018), as was the
difference between response and relapse (median 0.52 ng/mL, n = 9,
P = .008).
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In three patients, consecutive serum samples from the time of diagnosis
until the point of death or last follow-up were analyzed. Patient No. 1 (Fig 3A), was followed for 5 years and had
normal but detectable levels of HGF at diagnosis. He responded to
melphalan/prednisone treatment, with a fall in s-M-protein of more
than 50% and a fall in HGF to undetectable levels. Both HGF and
s-M-protein levels remained low for over 1 year after termination of
treatment. When new treatment was indicated, as judged by s-M-protein
levels and clinical status, HGF levels were also rising. The patient
received two further courses of melphalan/prednisone with declining
s-M-protein as well as HGF levels as a result. However, both
s-M-protein and HGF tended to rise at the end of the follow-up period.
Patient No. 2 (Fig 3B) had high levels of HGF at diagnosis (>3 ng/mL) and was followed for 2 years. The response to treatment with
melphalan/prednisone was minor, with a 30% reduction in s-M-protein.
HGF decreased in response to treatment but remained relatively high
(>1.10 ng/mL). After termination of treatment there was a rise in HGF
and s-M-protein, which subsequently decreased in concert with response
to new treatment courses. Patient No. 3 (Fig 3C), followed for 2 years,
had elevated HGF levels at diagnosis (1.40 ng/mL), and did not respond
to treatment as judged by s-M-protein levels and clinical evaluation.
HGF values remained high and increased after an initial reduction
during melphalan/prednisone treatment. Thus, HGF values in these three patients tended to fluctuate in concordance with the s-M-protein levels. In one case (Patient No. 1), the fluctuation in HGF levels tended to lag slightly behind the fluctuations in s-M-protein levels.
Correlation to other parameters.
We wished to correlate HGF at diagnosis to other registered parameters,
primarily markers of disease severity, tumor load, and bone destruction
and formation. As shown in Table 1 the
correlation coefficient was small but significant for ICTP, PICP, IL-6,
CRP, s-calcium, WHO performance status, 2-microglobulin,
and IL-6 receptor. A multiple linear regression was performed by
forward selection of the above significantly correlated variables. The analysis yielded lnICTP in a simple linear regression as the best predictor of HGF with an adjusted r-square of 0.071. However, the
unexplained variance was 93%. There was no significant correlation between HGF and pretreatment age, stage, s-M-protein concentration, percent plasma cells in the bone marrow, radiographic staging of bone
destruction, PIIINP, osteocalcin, leukocyte counts, or ALAT (not
shown).
Response to treatment.
The study population was divided into patients with high (1.10 ng/mL,
n = 174) and low (<1.10 ng/mL, n = 224) HGF concentrations based
on the mean value +2 SD of controls. There was no significant difference between the two groups with respect to age, sex, treatment arm, 2-microglobulin, percent plasma cells in the bone
marrow, PICP, PIIINP, osteocalcin, CRP, IL-6 receptor, serum
creatinine, s-M-protein concentration, or stage (data not shown). The
HGF high group had significantly higher levels of ICTP, s-calcium, and
IL-6 (see Table 2). As shown in Table
3, a significantly higher percentage of the
responding patients in the group low-HGF serum concentrations achieved
plateau phase after treatment with melphalan/prednisone as compared
with the high HGF group (60% and 46%, respectively;
P = .005). In the small (n = 25) group of patients with
extremely elevated s-HGF values (3.00 ng/mL) only 27% reached
plateau phase (P = .002). The finding of high or low HGF
serum concentrations retained its significance in predicting plateau
phase when entered in a multiple logistic regression analysis with
other putative prognostic parameters (2-microglobulin,
IL-6, IL-6 receptor, serum calcium, ICTP, age, and stage).
Survival analyses.
The median follow-up period of surviving patients was 38 months (range
24 to 54). The follow-up period of surviving patients did not differ in
the HGF high and low groups. The overall mortality in the study was
58%. When HGF was analyzed as a dichotomous variable with cutoff level
at 1.10 ng/mL, there was a significant survival difference between the
groups, as shown in Fig 4A, with high or low serum HGF
survival times of 32 and 21 months, respectively (P = .02).
As shown in figure 4B, this difference was especially marked for the 25 patients with extremely high (3 ng/mL) values of HGF, where the
median survival was 11 months from diagnosis (P = .001).
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| Fig 4.
(A) Kaplan-Meyer survival curves for 398 myeloma patients
separated by HGF high (1.10 ng/mL, n = 174;  ) versus low
(<1.10 ng/mL, n = 224;  ). The survival difference was
significant (P = .02). (B) Kaplan Meyer survival curves for
25 myeloma patients with extremely high pretreatment values of HGF
(3.00 ng/mL; ) and for 224 patients with low pretreatment values
(<1.10 ng/mL; ). The survival difference was significant
(P = .001).
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When HGF was logarithmically transformed and entered in a univariate
Cox regression analysis, it was a significant predictor of mortality
(P = .02). However, in a multivariate Cox regression analysis
involving all patients only six factors retained independent prognostic
information: s-calcium, s-IL-6 receptor, age, WHO performance status
(0 to 2 v 3 to 4), s-IL-6, and
s-2-microglobulin. As shown in Fig 5,
the power of high or low HGF concentrations as a variable predicting
survival is observed in the group of 143 patients with high (6 mg/L)
2-microglobulin. The median survival was 13 months for
the 2-microglobulin-high/HGF-high group as compared
with 23 months in the 2-microglobulin-high/HGF-low
group (P = .04). There was no significant difference between
the two 2-microglobulin groups with regard to the number
of patients with high or low HGF, but the mean HGF level was
significantly higher in the group with 2-microglobulin
6.00 mg/L (1.20 ng/mL v 1.67 ng/mL; P = .02). A
multivariate Cox regression analysis with the six factors retaining prognostic information in the NMSG study (mentioned above) as well as
high or low HGF was performed in the patient group with 2-microglobulin greater than or equal to 6.00 mg/L. High
or low HGF was then a powerful prognostic factor (P = .003)
along with age (P = .009), IL-6 receptor (P = .04),
and 2-microglobulin (P = .04).
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| Fig 5.
Kaplan Meyer survival curves for patients separated by
2-microglobulin and HGF. ( )
2-microglobulin low (<6.00 mg/L), HGF low (<1.10
ng/mL), n = 140; ( ) 2-microglobulin low (<6.00
mg/L), HGF high (1.10 ng/mL), n = 96; ()
2-microglobulin high (6.00 mg/L), HGF low (<1.10
ng/mL), n = 72; () 2-microglobulin high (6.00
mg/L), HGF high (1.10 ng/mL), n = 71. The survival difference between () and () was not significant. The survival difference between () and () was significant (P = .04).
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DISCUSSION |
The main finding in this study is that in a large, well-defined
population of untreated myeloma patients, the median HGF concentration in serum at the time of diagnosis is more than twice as high as in a
normal population, and more than 40% of the patients have abnormally
elevated values. Furthermore, we here report that the serum HGF levels
decrease after treatment response and increase during disease relapse.
This extends our previous observations that myeloma cells can produce
HGF and express the receptor for HGF. Together these observations
firmly establish that HGF is related to multiple
myeloma.
Several parameters have been examined in serial measurements to
determine their usefulness as clinical markers of disease progression
as compared with s-M-protein, which is an accepted marker of the tumor
load.20 IL-6 levels have been reported to rise in leukemic
phases of the disease, to fall in response to treatment, and to rise
during relapse.21-24 However, in another study of 34 patients, IL-6 levels were not predictive of remission, recurrence, or
progression of malignant myeloma.25 Measurements of the
IL-6 receptor revealed a significant correlation between the
concentrations of serum IL-6 receptor and the disease
activities.26-28 The mean plasma
cell acid phosphatase scores in 25 patients in remission/plateau were
significantly lower than the mean score at diagnosis.29
Although 2-microglobulin is an important prognostic factor in myeloma, its role in monitoring the disease is
disputed.30-35 On this background we examined whether HGF
concentrations in serum could be useful as a follow-up parameter. At
the time point of response HGF in a group of patients was significantly
lower than at diagnosis, only to rise again at relapse. To obtain more
detailed information of the variability of the HGF levels during and
after treatment, we analyzed a few patients over a long time period. There was a tendency for the HGF concentrations to decrease in response
to effective treatment whereas ineffective treatment caused only small
or no decrease in HGF concentrations. After termination of treatment
HGF levels remained low for some time, contesting the argument that low
HGF levels in treatment periods are merely a result of suppressed
cytokine production. Before relapse, HGF rose in concert with or lagged
slightly behind the change in s-M-protein levels. Although the data do
not permit statistical evaluation, they suggest that the serum levels
of HGF may fluctuate in concordance with the tumor burden and that HGF
is a candidate in the search for markers of disease activity. The
changes were also present in patients with low HGF values at the time
of diagnosis (Fig 2), and serial measurements could prove valuable both
in patients with low and elevated HGF levels at diagnosis. However,
because of the small patient numbers in our study, larger prospectively
designed studies are necessary to confirm our results.
Renal failure has been reported to cause high serum HGF.36
However, in our material there was no correlation between HGF levels
and serum creatinine (data not shown), suggesting that the high HGF
levels measured were not caused by renal failure. Furthermore, no
correlation was seen between HGF and leukocyte counts, suggesting that
infection did not make a major contribution to the elevated HGF levels.
The supernatants of cultured bone marrow mononuclear cells from myeloma
patients contain an osteoclast-stimulating factor.37 Recent
work has shown that HGF is involved in the process of osteoclast recruitment, growth, motility, and activation.9-11 We
therefore examined our material with particular interest for a relation between HGF and markers of bone disease. In a bivariate correlation analysis HGF correlated significantly but weakly to a few variables of
interest (Table 1). In a large patient material even small correlations
are often highly significant, and a multivariate regression analysis is
better to discern the importance of these correlations. In our material
lnICTP, a marker of bone resorption rate,38,39 in a simple
regression model came out as the best predictor for HGF. This result
could give some support to the hypothesis of HGF as a bone-destructive
cytokine in myeloma. However, with an unexplained variance of more than
90%, less than 10% of the variability in HGF is accounted for by
changes in ICTP, it is obvious that a causal relationship between the
variables cannot be drawn from this material. It should also be
underlined that bone destruction is a local tissue process that may not
be reflected by levels of mediators in the systemic circulation.
The achievement of plateau phase is a marker of response to
conventional chemotherapy treatment in multiple myeloma.40
Previously reported pretreatment markers of reaching plateau phase are
hemoglobin, albumin, and
2-microglobulin.41,42 In the patient group
with high HGF values at diagnosis, a lesser percentage of patients achieved plateau phase; this group also had a significantly lower median survival. Interestingly, these characteristics were especially pronounced in a small group of patients with extremely high HGF values
at diagnosis, where only one fourth of patients reached plateau and the
median survival time was less than 1 year. Furthermore, HGF seems to
provide extended prognostic information in the patient group with high
2-microglobulin, and the combination of HGF and 2-microglobulin may help to identify patients with
extremely poor prognosis.
Elevation of serum HGF has been described in patients with breast
cancer and gastric cancer, but this elevation tended to be significant
only in patients with recurrent disease.8,43 The present
study is the first report suggesting a prognostic information of serum
HGF levels measured at the time of diagnosis in cancer patients. We
conclude that HGF levels are significantly increased in a large
proportion of myeloma patients at diagnosis and that the levels varies
according to treatment response and relapse. The study adds HGF to the
list of factors that are related to multiple myeloma, although its
precise biological significance is still not known.
| |
FOOTNOTES |
Submitted June 19, 1997;
accepted September 22, 1997.
Supported by the Norwegian Cancer Society and The Cancer Fund,
Trondheim, Norway.
Address reprint requests to Carina Seidel, MD, Institute of Cancer
Research and Molecular Biology, Norwegian University of Science and
Technology, Medisinsk Teknisk Senter, N-7005 Trondheim, Norway.
The publication costs of this article were defrayed in part by page
charge payment. This article must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. section 1734 solely
to indicate this fact.
| |
ACKNOWLEDGMENT |
We are grateful to Hege Skjellerudsveen for excellent technical
assistance, to Geir Jacobsen for comments on the the statistical calculations, and to Erik Holmberg for help in the transmission of
data.
| |
APPENDIX |
Members of the directory board of the Nordic Myeloma Study Group in
alphabetical order: I.M.S. Dahl, P. Gimsing, E. Hippe, M. Hjort, E. Holmberg, J. Lamvik, E. Löfvenberg, S. Magnusson, J.L. Nielsen,
I. Palva, S. Rödjer, I. Talstad, I. Turesson, J. Westin, and F. Wisløff.
| |
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Abstract
Introduction
Abstract
) and
M-protein (