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The Journal of Clinical Endocrinology & Metabolism 86(9):4133– 4138
Copyright © 2001 by The Endocrine Society
Hypocalcemic and Normocalcemic Hyperparathyroidism
in Patients with Advanced Prostatic Cancer
R. M. L. MURRAY, V. GRILL, N. CRINIS, P. W. M. HO, J. DAVISON,
AND
P. PITT
Peter MacCallum Cancer Institute (R.M.L.M., N.C., J.D., P.P.), Melbourne 3002; and St. Vincent’s Institute of Medical
Research (V.G., P.W.M.H.), Melbourne 3065, Australia
PTH and ionized calcium levels were measured in 131 patients
with advanced prostate cancer, all of whom had received at
least first-line hormone therapy. Patients were classified into
those in remission, those with stable disease, or those with
progressive disease according to their prostate-specific antigen response and their clinical status.
Thirty-four percent of all patients had PTH levels above the
upper level of normal for controls of similar age (7.0 pmol/
liter), and in 44% of these patients this was associated with a
normal ionized calcium. Patients with proven bone metastases had significantly higher PTH levels than those without.
(7.3 ⴞ 0.5 vs. 4.3 ⴞ 0.4 pmol/liter, P < 0.0005).
There was evidence for a difference in the PTH levels between the three response groups. The PTH levels tended to be
higher in patients with progressive disease. Thirty-seven of 65
patients (57%) with both progressive disease and proven bone
P
ROSTATE CANCER IS the most common cancer in men
and a leading cause of cancer deaths, usually associated
with widespread bony metastases. Men with prostate cancer
and bony metastases face a bleak future with increasing
incapacity, debility, bone pain, and, not infrequently, spinal
cord compression and paraplegia.
Metastatic deposits in bone have been found at autopsy in
60 – 85% of patients diagnosed with prostate cancer (1). In
general, the characteristic feature of bone metastases in prostate cancer is an osteoblastic reaction rather than the osteolytic reaction usually seen with metastases from breast,
bowel, or lung cancer. Some studies have suggested, however, that there is an osteolytic component associated with
osteoclastic bone destruction in conjunction with this osteoblastic reaction (2– 6). The relationship between these osteoblastic and osteolytic reactions and the spread of prostate
cancer through bone is not clear.
It is known that high levels of PTH are associated with
increased bone resorption and degradation of the bone matrix (7, 8). There are isolated reports of low serum calcium
(9 –13) and high PTH levels (14 –16) in a number of studies
involving small numbers of patients with advanced prostate
cancer. The extent of these abnormalities and their pathophysiological significance is not well defined.
In this study of 131 patients with advanced prostatic cancer we report on the relationships between PTH, ionized
calcium, urinary deoxypyridinoline (DPD), and cAMP in
Abbreviations: ALP, Alkaline phosphatase; BM, bone metastases;
DPD, deoxypryidinoline; 25-OHD, 25-hydroxyvitamin D; PD, progressive disease; PSA, prostate-specific antigen; R, remission; S, stable
disease.
metastases had elevated PTH levels. Mean levels of urinary
deoxypyridinoline and cAMP were significantly greater in
patients with high PTH than in those with a normal PTH.
Treatment with oral calcium supplements in 32 patients
with a high PTH seemed to have only a transient effect on
elevated PTH or low ionized calcium levels.
These data show that secondary hyperparathyroidism occurs frequently in patients with advanced prostate cancer,
particularly in those with both progressive disease and bone
metastases. The increased PTH levels are associated with an
increase in bone resorption markers. These findings raise important questions about the role of PTH in progression of
prostatic cancer in bone and the potential limitations of the
use of bisphosphonates in patients with a raised PTH or low
serum calcium. (J Clin Endocrinol Metab 86: 4133– 4138, 2001)
patients in remission (R), with stable (S) or progressive disease (PD) and with or without bone metastases (BM).
Patients and Methods
Between January 1998 and October 1998, 146 patients with proven
advanced prostatic cancer attended the Endocrine Department at Peter
MacCallum Cancer Institute. All patients had blood taken for measurement of serum PTH, ionized calcium, creatinine, prostatic-specific antigen (PSA), alkaline phosphatase (ALP), and 25 hydroxyvitamin D
(25-OHD) on at least one occasion during the study period. When possible, urine samples were also collected for measurement of urinary
cAMP and DPD. Patients with impaired renal function (serum creatinine, ⬎0.13 mmol/liter), vitamin D deficiency (25-OHD, ⬍25 mmol/
liter), and elevated PTHrP (⬎2 pmol/liter), and patients receiving calcium or vitamin D supplements or who had received bisphosphonate
in the previous 3 months were excluded. For each patient, the results
from the first occasion within the study period for which measurements
of all the variables were available were used for analyses. That is, the
data set contained only one set of measurements per patient.
The study was approved by the Research and Ethics Committees of
the Peter MacCallum Cancer Institute, and all patients and controls gave
informed consent.
Before estimation of PTH patients were classified as in R, with S,
or with PD according to their PSA response or their clinical status if
the PSA response was considered to be unreliable because of recent
radiotherapy.
PD was defined as a progressive increase in PSA of greater than or
equal to 25% above the nadir. R was defined as a progressive decrease
in PSA of at least 50%, whereas S was defined as a decrease of less than
50% or an increase of less than 25%.
The presence or absence of BM was determined by isotope bone scan
within 3 months of the sampling date.
Blood and urine samples were taken at the time of clinic visits.
The normal range for PTH was determined in 108 male controls of
similar age (median age, 73 yr; range, 55– 86) to the study cohort who
all had normal serum creatinine (ⱕ0.13 mmol/liter) and no evidence of
4133
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The Journal of Clinical Endocrinology & Metabolism, September 2001, 86(9):4133– 4138
Murray et al. • Hyperparathyroidism in Prostate Cancer
prostatic cancer. The controls were men who were attending Returned
Service League Clubs and who volunteered for the study.
Blood samples for PTH measurement were collected into 10-ml EDTA
tubes, centrifuged, and plasma was stored frozen at ⫺20 C until assay.
Intact PTH was measured by a two-site chemiluminescent enzyme
immunometric assay on the Immulite Automated Immunoassay system
(Diagnostic Products, Los Angeles, CA). For the purpose of the study,
a high PTH was defined as a value that was greater than 7.0 pmol/liter.
PTHrP was measured by an N-terminal RIA (17).
Ionized calcium was determined using a Bayer 850 Blood Gas Analyzer (normal range, 1.13–1.30 mmol/liter; Bayer Corp., Terrytown,
NY). For the purpose of the study, a low ionized calcium was defined
as a value of less than 1.13 mmol/liter.
25-OHD (25-hydroxycalciferol) was determined in serum by RIA
following solvent extraction (25-Hydroxyvitamin D 125I RIA kit; DiaSorin, Inc., Stillwater, MN) (reference range, 25–108 nmol/liter).
PSA was determined in serum by a two-site sandwich immunoassay
using a chemiluminescent label (Bayer Corp.ACS:180 PSA2) (reference
range, 0 – 4.0 ␮g/liter).
Urinary DPD was measured by a competitive direct chemiluminescent immunoassay on the ACS:180 Automated Immunoassay analyser
(Chiron Corp., East Walpole, MAs).
Urinary cAMP was measured by RIA using an antiserum supplied by
Dr. P. Marley (Department of Pharmacology, University of Melbourne,
Melbourne, Australia). Urine samples were diluted 1:100 in 50 mm
sodium acetate, 1 mm theophylline buffer (pH 5), and100 ␮l were assayed. One hundred microliters of cAMP standard (adenosine 3⬘,5⬘
cyclic phosphate) were diluted to give 0 –5000 pmol/ml. One hundred
microliters of antibody and 100 ␮l iodinated cAMP (2⬘-o monosuccinyladenosine 3⬘,5⬘ cyclic monophosphate tyrosylmethylester) were added
to assay tubes. All tubes were vortexed and incubated at 4 C overnight.
One milliliter of charcoal mixture was then added to all tubes. The tubes
were vortexed and incubated at 15 min before centrifugation for 10 min
at 4 C. Supernatants were aspirated, and pellets were counted in a
Pardard Cobra Auto-␥ counter. This assay has a detection limit of 2.5
pmol/ml. The intra-assay and interassay coefficients of variation were
5% and 10.8%, respectively.
Statistical methods
Clinical characteristics and biochemical parameters were compared
across the response categories using a nonparametric ANOVA test for
trend (Jonckheere-Terpstra test) for continuous data and the CochranArmitage test for trend for ordinal categorical data.
A test of the equality of the slopes in Fig. 1, A and B, was performed
by regressing the logarithm of PTH level on the response status adjusting
for BM status (absent of present). The natural logarithm of PTH was used
in analyses as the distribution of PTH was highly skewed to the right.
A test of the equality of the slopes in Fig. 2, A and B, was performed
by regressing the logarithm of PTH level on ionized calcium adjusting
for BM status. The test was repeated after including a term for the
response status and an interaction term for the response status and BM
status in the model.
Comparisons of ionized calcium levels measured at monthly intervals
during a 3-month period for patients who received calcium supplements
were carried out to assess changes in calcium levels over time. All
possible pairs from the four measurement times (at pretreatment and 1,
2, and 3 months after treatment) were tested using paired t tests, and P
values were adjusted for multiple testing using Hochberg’s method (18).
Comparisons of the logarithm of PTH levels over the 3-month period
were performed similarly.
Ninety-five percent confidence intervals for percentages were obtained based on the exact binomial distribution. All statistical tests
carried out were two-sided. No formal adjustments were made for
multiple comparisons, with the exception discussed above. The analyses
were carried out using StatXact (CYTEL Software Corp., Cambridge,
MA) and SPSS software (SPSS, Inc., Chicago, IL). Graphs were plotted
using the SPSS software and the S-PLUS statistical package (MathSoft,
Inc., Seattle, WA).
FIG. 1. A, Log PTH for each response category in patients with no BM
(the horizontal lines represent the mean values). B, Log PTH for each
response category in patients with BM (the horizontal lines represent
mean values). The relationship between PTH and response status in
the BM⫺ and BM⫹ groups were different (P ⫽ 0.001): there was no
significant relationship between PTH and response in patients with
no BM, whereas there was a significant increase in PTH from the R
group to the S group to the PD group in patients with BM.
Results
Of the 146 patients attending the Endocrine Department at
Peter MacCallum Cancer Institute between January 1998 and
October 1998, 131 patients satisfied the eligibility criteria. The
results of 25-OHD measurements were excluded for 12 patients because of a laboratory error. Measurement of PTH
and urinary DPD and urinary cAMP was available in 51 and
57 patients, respectively.
The mean (⫾2 sd) PTH in controls was 3.8 ⫾ 3.2 pmol/
liter. For the study, the upper limit of normal PTH was
defined as 7.0 (mean ⫹ 2 sd) pmol/liter.
Summaries of the clinical characteristics and biochemical
parameters for all patients and by response status are shown
in Table 1. Forty-five patients (34%; 95% confidence interval,
Murray et al. • Hyperparathyroidism in Prostate Cancer
The Journal of Clinical Endocrinology & Metabolism, September 2001, 86(9):4133– 4138 4135
FIG. 2. A, Log PTH vs. ionized calcium in patients with no BM. B, Log
PTH vs. ionized calcium in patients with BM. The correlation between
PTH and ionized calcium seemed to be stronger in the BM⫹ group,
however, it was not significantly different from the BM⫺ group
(P ⫽ 0.14).
26 – 43%) had an elevated PTH level. There was evidence for
a difference in the PTH levels between the three response
groups (P ⬍ 0.00005). The PTH level tended to be higher in
patients with PD. The levels of other biochemical parameters
that were significantly different between the three response
groups were PSA (P ⬍ 0.00005), Ca⫹⫹ (P ⫽ 0.0022), ALP (P ⬍
0.00005), DPD (P ⫽ 0.0072), and cAMP (P ⫽ 0.022).
Patients with BM (BM⫹) had higher PTH levels than those
without (BM⫺) (P ⬍ 0.0005, t test). The mean (⫾se) PTH
levels for patients with and without BM were 7.3 ⫾ 0.5
pmol/liter and 4.3 ⫾ 0.4 pmol/liter, respectively. Patients
with BM also had lower ionized calcium levels than those
without BM (1.13 ⫾ 0.01 mmol/liter and 1.17 ⫾ 0.01 mmol/
liter, respectively).
PTH levels for each of the response groups subdivided
according to their BM status are shown in Fig. 1, A and B,
respectively. The relationships between PTH and response
status in the BM⫹ and BM⫺ groups were different (P ⫽
0.001): there was a significant increase in the PTH level from
the R group to the S group to the PD group in patients with
BM, whereas there was no significant relationship between
the PTH level and response status in patients with no BM.
There was a significant inverse relationship between PTH
and ionized calcium (Table 2; P ⫽ 0.0001, Fisher’s exact test).
Fifty-eight percent of patients who had a low ionized calcium
had an elevated PTH level whereas only 23% of patients with
normal ionized calcium had an elevated PTH. The relationships between PTH and ionized calcium in patients according to their BM status are shown in Fig. 2, A and B, respectively. The correlation between PTH and ionized calcium
seemed to be stronger in the BM⫹ group (Pearson correlation
coefficient, r ⫽ ⫺0.48) compared with the BM⫺ group (r ⫽
⫺0.12). However, the result of a test of the equality of the
slopes in the plots using a regression model was not statistically significant (P ⫽ 0.14). This conclusion remained unaltered after allowing for the response status (P ⫽ 0.20).
Patients with elevated PTH levels had higher serum levels
of ALP and lower ionized calcium than patients with normal
PTH (P ⫽ 0.009 and P ⬍ 0.0005, respectively, t tests; Table 3).
Urinary cAMP and urinary DPD were greater in patients
with a raised PTH (P ⫽ 0.023 and P ⫽ 0.001, respectively, t
tests; Table 3).
Thirty-two patients with high PTH levels were treated
with oral calcium supplements (Caltrate 600 mg twice a day,
increasing to 1200 mg twice a day if there was no response).
Plots of mean ionized calcium and PTH levels over a 3-month
period are shown in Fig. 3. The plot suggests ionized calcium
increases to a plateau level after 1 month of treatment and
decreased by 3 months. However, none of the results of
testing for the differences in Ca⫹⫹ levels over the 3-month
period were statistically significant after adjusting for multiple testing. The plot also suggests that PTH decreases to a
plateau level at 1 month and increased by 3 months. The
results of testing the PTH levels at 1 and 2 months relative
to the pretreatment level were statistically significant (P ⫽
0.002 and P ⫽ 0.009, respectively). These significant findings,
however, need to be interpreted with caution as the possible
effect of calcium supplements is confounded with the phenomenon of “regression toward the mean”: patients who
received calcium supplements all had high PTH levels at
pretreatment and would be expected to have lower PTH
levels at subsequent measurement even when calcium supplements were not given.
Patients were treated with a variety of therapies—all patients had had a medical or surgical orchidectomy before
entering the study. Patients who had PD or relapsed after a
R to orchidectomy were subsequently treated with one or
more of the following: antiandrogen withdrawal, antiandrogens (flutamide, biclatamide, or cyproterone acetate), aminoglutethimide, prednisolone, oestrogen, and x-ray therapy.
It did not appear that the type of treatment had any effect
on PTH levels.
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The Journal of Clinical Endocrinology & Metabolism, September 2001, 86(9):4133– 4138
Murray et al. • Hyperparathyroidism in Prostate Cancer
TABLE 1. Clinical characteristics and biochemical parameters: all patients and by response status
No. of patients
Age
All patients
R
SD
PD
131
72
45–93
4.8
35
71
63– 86
4.9
14
72
63– 85
6.3
82
74
45–93
4.6
0.02–15
95 (73%)
51
⬍0.1– 6850
5.6
1.5–26.6
45 (34%)
1.16
0.82–1.28
43 (33%)
148
44 –3044
70
26 –160
9.7
2.0 –35.4
24.0
6.2–151.2
1.6 –15
18 (51%)
0.4
⬍0.1–317
3.6
1.5–11.3
3 (9%)
1.18
0.91–1.25
7 (20%)
92
54 – 897
74
28 –150
5.9
2.0 –29.5
19.3
7.8 –25.6
0.09 –12
12 (86%)
49
9.8 –719
4.9
1.5–11.0
3 (21%)
1.17
1.08 –1.28
4 (29%)
204
94 –903
65
41–120
11.9
5.1–21.0
29.9
22.5– 46.1
0.02–14
65 (79%)
88
0.6 – 6850
6.4
1.7–26.6
39 (48%)
1.15
0.82–1.25
32 (39%)
196
44 –3044
68
26 –160
12.2
4.1–35.4
34.0
6.2–151.2
Median
Range
Median
Time (yr) from diagnosis to measurement
(129 evaluable cases)
Range
Present
Median
Range
Median
Range
High PTH
Median
Range
Low calcium
Median
Range
Median
Range
Median
Range
Median
Range
BM
PSA (␮g/liter)
PTH (pmol/liter)
Ionized calcium (mmol/liter)
ALP (U/liter)
25-OHD (mmol/liter) (119 evaluable cases)
DPD (nmol/mM) (51 evaluable cases)
cAMP (nmol/mM) (57 evaluable cases)
P
0.47
0.27
0.0038
⬍0.00005
⬍0.00005
0.0022
⬍0.00005
0.075
0.0072
0.022
TABLE 2. Cross-tabulation of PTH and ionized calcium (Row
percentages are displayed)
PTH
Ca⫹⫹
Low
Normal
Total
Normal
High
18 (42%)
68 (77%)
86
25 (58%)
20 (23%)
45
TABLE 3. Biochemical parameters (mean ⫾
(normal or high)
SE)
Total
43
88
131
by PTH status
PTH
Ca⫹⫹
(mmol/liter)
ALP
(U/liter)
DPD
(nmol/mM)
Cyclic AMP
(nmol/mM)
High
n
Normal
n
P
1.11 ⫾ 0.01
45
1.16 ⫾ 0.01
86
⬍0.0005
360 ⫾ 75
45
229 ⫾ 32
86
0.009a
15.8 ⫾ 1.7
20
9.4 ⫾ 1.1
31
0.001a
39.7 ⫾ 8.0
16
26.8 ⫾ 2.5
41
0.023a
a
Tests based on the natural logarithmic transformation of the data
as the distributions of ALP, DPD, and cAMP were highly skewed to
the right.
Discussion
This study shows that secondary hyperparathyroidism
occurs frequently in patients with advanced prostate cancer,
with an incidence of 57% in patients with PD and BM. Patients who had other known possible causes of secondary
hyperparathyroidism, such as renal failure or vitamin D deficiency, were excluded from this series. Our finding that
elevated PTH was associated with high urinary cAMP and
with high urinary DPD suggests that PTH was biologically
active and that this increase was responsible, in part at least,
for increased bone breakdown.
It has been known for many years that hypocalcemia can
occur in patients with osteoblastic metastases from prostate
cancer (9 –13). In 1962, Ludwig (16) postulated the following
sequence: osteoblastic metastases cause increased deposition
of calcium and phosphate in bone, tending to decrease serum
FIG. 3. Ionized calcium and PTH levels (mean ⫾ SE) in patients given
calcium supplementation over a 3-month period. The numbers of
patients available for analysis of PTH at 0, 1, 2, and 3 months were
32, 31, 27, and 23, respectively. The numbers of patients available for
analysis of Ca⫹⫹ at 0, 1, 2, and 3 months were 32, 31, 27, and 24,
respectively. The results of testing the PTH levels at 1 and 2 months
relative to the pretreatment level were statistically significant (P ⫽
0.002 and P ⫽ 0.009, respectively).
concentrations of both ions. The resulting hypocalcemia
stimulates PTH secretion. Secondary hyperparathyroidism
then causes a further decrease in serum phosphate concentration that, in some instances, ultimately reaches hypophosphatemic levels. In our series, patients with BM had a lower
mean ionized calcium level than those without. Forty-three
(33%) patients had a low ionized calcium, and, of these, 35
(81%) were in the group with BM.
Elevated PTH levels, usually in association with a low
corrected calcium, have also been previously reported in
prostate cancer. Minisola et al. (12) in 1987 reported that 2 of
14 patients with BM from prostate cancer had elevated PTH
Murray et al. • Hyperparathyroidism in Prostate Cancer
The Journal of Clinical Endocrinology & Metabolism, September 2001, 86(9):4133– 4138 4137
levels. Rico et al. (14) reported high levels in 2 of 20 patients.
Charhon et al. (15) reported that serum PTH was significantly
increased in 14 patients with osteosclerotic BM compared
with age-matched controls. In our series of 131 patients, 45
(34%) had elevated PTH levels, and in 20 (44%) patients this
was associated with a normal ionized calcium. This may
represent a compensated state, with serum ionized calcium
being maintained within the normal range by increased circulating PTH.
Mean PTH levels were higher in patients with BM and in
those with PD with a strikingly high incidence (57%) occurring in those who had both PD and BM. Our findings are
consistent with the hypothesis that osteoblastic metastases in
prostate cancer are the primary phenomenon inducing hypocalcemia and compensatory hyperparathyroidism in these
patients.
PTH is the principal hormonal agent that controls bone
resorption, and elevated levels are associated with increased
bone turnover, secondary to an increase in numbers of and
activity of osteoclasts. High levels of PTH are associated with
increased bone resorption and degradation of the bone matrix (7, 8). Evidence of increased bone resorption with elevated urinary pryidinoline and DPD (19 –22) levels has been
reported in patients with prostate cancer. In one study, bone
resorption markers were high in patients with active cancer
but not in those with controlled disease. Histomorphological
studies have also confirmed increased bone resorption in
metastatic prostate cancer (14). In our patients there was an
association of PTH levels with urinary DPD excretion, consistent with a PTH-driven generalized increase in bone resorption. High PTH levels could also explain the observation
reported by Urwin et al. (5) that in patients with BM from
prostate cancer there was histological evidence of increased
bone resorption at sites distant from skeletal metastases.
A number of substances, including proteases released by
tumors, are thought to result in extracellular matrix breakdown and lysis facilitating tumor invasiveness (8, 23). The
capacity to destroy mineralized matrix, however, requires
the involvement of the osteoclast (24). The growth of prostate
cancer is often accelerated once it has spread to bone, suggesting that the bone microenvironment may provide a proliferation-stimulating factor for metastatic prostate cancer
cells (23). Substances have been suggested as possible prostate cancer-stimulating factors, including bone fibroblastderived factor and transferrin.
A systemic “vicious cycle” could occur in prostate cancer
patients with increased PTH causing bone matrix degradation and release of proliferation-stimulating substances,
leading to stimulation and progression of the prostate cancer
and, in turn, further deposition of calcium in sclerotic metastases with a subsequent further elevation of PTH. A similar local mechanism has been postulated for the progression
of breast cancer in bone, with PTHrP causing osteoclastic
bone resorption, leading to the release of growth factors (in
particular TGF␤) and stimulation of cancer cell proliferation
(23). Whereas PTHrP has been shown to be present in some
prostatic tissue (25), circulating levels are generally undetectable in patients with prostatic cancer— only 1 of 100 of
our patients had a detectable level.
Three patients who seemed to be in R also had high levels
of PTH in our series. PD may not always be reflected by a
rising PSA, however, these patients were both biochemically
and clinically in R. Evidence of BM was not an absolute
prerequisite for a high PTH in our patients, but it is possible
that the one patient who had a high PTH but did not have
proven BM may have had occult BM, which were not yet
apparent on bone scan.
Supplementation with oral calcium in 32 of our patients
had only a transient effect on ionized calcium and elevated
PTH levels. Ionized calcium seemed to increase to a plateau
level after 1 month and to decrease again by 3 months.
However, none of the changes in Ca⫹⫹ were statistically
significant after adjusting for multiple testing. PTH values
fell significantly (but not to normal) to a plateau level at 1
month but had returned to pretreatment by 3 months (Fig.
3). These findings suggest that large amounts of calcium may
be necessary to significantly raise serum calcium and lower
serum PTH in these patients and clearly have significant
implications for current and planned studies evaluating the
effect of bisphosphonates in patients with prostate cancer.
The use of bisphosphonates in such patients would be expected to result in further falls in serum calcium and, thus,
further increases in PTH, as has been reported in the treatment of hypercalcemia of malignancy (26). This could, in
turn, cause increased bone lysis and limit the therapeutic
effectiveness of bisphosphonates unless calcium supplements were given in doses sufficient to maintain PTH in the
normal range.
Acknowledgments
We thank Kally Yuen for hard work and expert advice in carrying out
the statistical analysis. We also thank Bruce Ruxton (President of the
Victorian Branch of the Returned Services League) for help in organizing
the volunteers who gave blood as controls.
Received October 13, 2000. Accepted May 24, 2001.
Address all correspondence and requests for reprints to: Robin Murray, M.D., Peter MacCallum Cancer Institute, Locked Bag 1, A’Beckett
Street, Victoria 8006, Australia.
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