Cancer survival is dependent on season of diagnosis and sunlight exposure.

Abstract

Sunlight is essential for the production of vitamin D in the body. Evidence exists to suggest that vitamin D metabolites may have a role in tumor growth suppression. In this large study, involving over a million cancer patients from the United Kingdom, we have analyzed the role of season of diagnosis and sunlight exposure in cancer survival for cancers of the breast, colorectum, lung, prostate and at all sites combined. We used population-based data from the Thames Cancer Registry to analyze cancer survival in periods 0-1 and 0-5 years after diagnosis. The analysis was performed using Cox proportional regression analysis adjusting for age and period at diagnosis and including season of diagnosis and sunlight exposure in the preceding months as factors in the analysis. We found evidence of substantial seasonality in cancer survival, with diagnosis in summer and autumn associated with improved survival compared with that in winter, especially in female breast cancer patients and both male and female lung cancer patients (hazard ratios 0.86 [95% CI 0.83-0.89], 0.95 [95% CI 0.92-0.97] and 0.95 [95% CI 0.93-0.98] respectively). Cumulative sunlight exposure in the months preceding diagnosis was also a predictor of subsequent survival, although season of diagnosis was a stronger predictor than cumulative sunlight exposure. We found seasonality in cancer survival to be stronger in women than in men. Our results add to a growing body of evidence that vitamin D metabolites play an important role in cancer survival.

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FAST TRACK
Cancer survival is dependent on season of diagnosis and sunlight exposure
Hyun-Sook Lim1*, Rahul Roychoudhuri1, Julian Peto2,3, Gary Schwartz4, Peter Baade5and Henrik Møller1,2
1King’s College London, Thames Cancer Registry, London, United Kingdom
2Non-Communicable Disease Epidemiology Unit, Department of Epidemiology and Population Health,
London School of Hygiene & Tropical Medicine, London, United Kingdom
3Institute of Cancer Research, Sutton, United Kingdom
4Department of Cancer Biology and Public Health Sciences, Wake Forest Comprehensive Cancer Center,
Wake Forest University, Winston-Salem, NC
5Viertel Centre for Research in Cancer Control, Queensland Cancer Fund, Spring Hill, Australia
Sunlight is essential for the production of vitamin D in the body.
Evidence exists to suggest that vitamin D metabolites may have a
role in tumor growth suppression. In this large study, involving
over a million cancer patients from the United Kingdom, we have
analyzed the role of season of diagnosis and sunlight exposure in
cancer survival for cancers of the breast, colorectum, lung, pros-
tate and at all sites combined. We used population-based data
from the Thames Cancer Registry to analyze cancer survival in
periods 0–1 and 0–5 years after diagnosis. The analysis was per-
formed using Cox proportional regression analysis adjusting for
age and period at diagnosis and including season of diagnosis and
sunlight exposure in the preceding months as factors in the analy-
sis. We found evidence of substantial seasonality in cancer sur-
vival, with diagnosis in summer and autumn associated with
improved survival compared with that in winter, especially in
female breast cancer patients and both male and female lung can-
cer patients (hazard ratios 0.86 [95% CI 0.83–0.89], 0.95 [95% CI
0.92–0.97] and 0.95 [95% CI 0.93–0.98] respectively). Cumulative
sunlight exposure in the months preceding diagnosis was also a
predictor of subsequent survival, although season of diagnosis was
a stronger predictor than cumulative sunlight exposure. We found
seasonality in cancer survival to be stronger in women than in
men. Our results add to a growing body of evidence that vitamin
D metabolites play an important role in cancer survival.
' 2006 Wiley-Liss, Inc.
Key words: season; sunlight; cancer; survival; vitamin D
Sunlight is essential for the cutaneous production of vitamin D
in the body: ultraviolet B photons are absorbed by 7-dehydrocho-
lesterol within the skin to form cholecalciferol (vitamin D3). This
then undergoes hydroxylation within the liver to form the prohor-
mone, calcidiol (25-hydroxycholecalciferol; 25(OH)D). A second
hydroxylation by 1a-hydroxylase occurs within renal tissues,
forming the biologically active hormone calcitriol (1,25-dihydroxy-
cholecalciferol; 1,25(OH)2D). There are further contributions from
dietary intake of both cholecalciferol and ergocalciferol (vitamin
D2) synthesized by plants.
Sunlight is thought to contribute about 90% of serum vitamin D
levels.1,2In northwestern Europe, including within the United
Kingdom, levels of vitamin D are highly dependent on sunlight,
compared with populations in the rest of Europe and the United
States.3–5International comparison studies have shown that die-
tary vitamin D levels are low in Europe, especially in areas of high
latitude (from 40?N to 64?N), including the United Kingdom.6
Additionally, European populations are thought to be at risk of
hypovitaminosis D due specifically to large seasonal variations in
sunlight.7,8
A protective role of sunlight in cancer incidence was first sug-
gested by observation of an inverse association between cancer
incidence rates and sun exposure.9It was later proposed that this
protective role might be attributed to a mechanism involving vita-
min D metabolites in the risk of colon cancer.10–12
Most epidemiological studies investigating the relationship
between sunlight and cancer have focused on latitudinal associa-
tions. For example, Hanchette and Schwartz reported an inverse
correlation between the geographic distribution of solar UV radia-
tion intensity and prostate cancer mortality in North America, with
lower mortality in the South.13
Such correlational observations have been supported by numer-
ous analytic epidemiological investigations: A cohort study con-
ducted by John et al. reported substantial reductions in prostate
cancer risk to be associated with residence in the south of the
United States.14Freedman et al. found residential exposure to sun-
light to be associated with reduced mortality from breast, ovarian,
prostate and colon cancers.15Another innovative case–control
study by John et al. reported that sun exposure, as measured by
the difference between constitutive skin pigmentation in the axil-
lary fossa and facultative pigmentation on the forehead, was asso-
ciated with reduced risk of prostate cancer.16
In Norway, Robsahm et al. found that breast, colon and prostate
cancer patients diagnosed in the summer and autumn months
showed much better survival than those diagnosed in winter and
spring.17Moan et al. also reported a strong seasonal variation in
cancer survival, with better survival in colon cancer patients diag-
nosed in the summer and autumn.18Porojnicu et al. similarly dem-
onstrated a seasonal variation in the prognosis of Hodgkin’s lym-
phoma patients.19
These recent findings support the hypothesis that the season of
diagnosis and treatment affects cancer survival, perhaps through
variation in the cutaneous production of vitamin D3.
Within the United Kingdom, there is large seasonal variation in
sunlight, and vitamin D deficiency (hypovitaminosis D) is rela-
tively common during the winter season.20In this study, we have
investigated whether seasonal variation in cancer survival exists in
the United Kingdom, and have attempted to associate this directly
to sunlight exposure.
Material and methods
Cancer patients
The Thames Cancer Registry (TCR) is a population-based
registry which collects data on cancer in residents of South East
England, including London (currently a population of 14 million).
The patients registered at the TCR represent a cohort of individu-
als followed up from diagnosis to death, and the database currently
contains over 1.5 million incident cancers. All cases of primary
malignant cancer diagnosed during the period from December 1,
1971 to November 30, 2002 were extracted. Cases with an
unknown month of diagnosis were excluded from the analysis. In
total 588,435 men and 606,127 women were included in the analy-
sis. Of these, colorectal, lung, female breast and prostate cancer
*Correspondence to: King’s College London, Thames Cancer Regis-
try, 1st Floor, Capital House, 42 Weston Street, London SE1 3QD, UK.
Fax: 144-20-7378-9510. E-mail: hyunsook.lim@kcl.ac.uk
Received 11 January 2006; Accepted 17 March 2006
DOI 10.1002/ijc.22052
Published online 2 May 2006 in Wiley InterScience (www.interscience.
wiley.com).
Int. J. Cancer: 119, 1530–1536 (2006)
' 2006 Wiley-Liss, Inc.
Publication of the International Union Against Cancer

Page 2

patients were analyzed separately. As a result, 71,723 men and
76,266 women with colorectal cancer, 131,770 men and 60,353
women with lung cancer, 182,895 women with breast cancer and
92,312 men with prostate cancer were analyzed. Cancer patients
were followed up until June 2005 and all-cause mortality data
were calculated for periods 0–1 and 0–5 years after diagnosis.
Using the date of diagnosis, the season of diagnosis was
defined, as follows: Winter (December 1–February 28 or 29),
Spring (March 1–May 31), Summer (June 1–August 31) and
Autumn (September 30–November 30). To assess cancer survival,
we defined 2 survival periods: 0–1 years and 0–5 years after diag-
nosis.
Exposure to sunlight
We obtained data on sunlight from the British Meteorological
Office which has maintained monthly total sunlight hours data
since 1959 at 26 meteorological stations located within the United
Kingdom.21In this study, we used monthly data collected at
Greenwich (located within the TCR catchment area) over the
entire study period, 1971–2002. Sunlight data were merged by
year and month with incident cancer data by using the date of di-
agnosis. Cumulative sunlight hours in periods 1, 3, 6 and 9 months
before diagnosis were calculated for each month of diagnosis
since 1971 and adjusted into a monthly mean figure over those
periods which were then divided by 100. Thus, measures of mean
cumulative sunlight exposure over periods of 1, 3, 6 and 9 months
before diagnosis were established for each month of diagnosis
such that 1 unit represents 100 mean sunlight hours per month.
Statistical analysis
A Cox proportional hazards regression model was used to
assess the role of exposure to sunlight before diagnosis and season
of diagnosis as factors affecting cancer survival. Age and period
of diagnosis were grouped into 5 and 4 yearly intervals respec-
tively.
All analyses were adjusted for age and period at diagnosis. Con-
cerning the seasonal comparison, winter was the reference group.
First, the season of diagnosis and the 4 monthly cumulative mean
measures of sunlight before diagnosis were analyzed separately.
Then, these separate analyses were extended to mutual adjust-
ment, such that the analysis of seasonal variation in survival was
adjusted for mean cumulative sunlight exposure and vice versa.
Analysis was performed using SAS version 8.2 (SAS Institute,
Cary, NC).
Results
From 1971 to 2002, mean monthly sunlight exposure was high-
est in the month of August (194.3 6 31.9 hr [mean 6 SD]) and
lowest in December (35.8 6 10.5 hr). Figure 1 shows the distribu-
tion of cumulative sunlight hours for each month of diagnosis
averaged over 32 years, which was highest in the summer and
autumn months. As the intervals over which cumulative sunlight
exposure was calculated increased from 1 month to 9 months, the
seasonal variation was reduced and the maximum moved from
August to November.
Tables I–IV show mortality hazard ratios (HRs) within either 1
or 5 years of diagnosis by season of diagnosis for cancers of the
breast, colorectum, lung and at all sites combined. Results are
given without adjustment for sunlight hours, or adjusted for mean
cumulative sunlight hours over 4 different time periods (1, 3, 6
and 9 months) before diagnosis.
The results for women are presented in Tables I and II. Signifi-
cantly reduced mortality HRs were observed in the summer for
cancers of the breast (0.86), colorectum (0.94), lung (0.95) and all
sites combined (0.94) at 0–1 years after diagnosis and without
adjustment for sunlight exposure. Adjusting for sunlight hours did
not substantially change the observed reduction in mortality HRs
in the summer.
A reduction in the mortality HR similar to that seen in the
summer was also observed in patients diagnosed in the autumn
months, but the reduction was slightly lower and not statistically
significant in colorectal cancer. As for the summer effect, the
reduction in the HR in the autumn was not sensitive to adjustment
for the actual sunlight hours (Table I).
Overall, the HRs for 0–5 year survival in women were slightly
higher compared with the 0–1 year survival but the general pattern
was the same. Regardless of adjustment for cumulative sunlight
hours, consistently lower HRs in summer and autumn were
observed for breast, colorectal and lung cancer, and at all sites
combined (Table II).
Tables III and IV show the results in men. The mortality HRs
0–1 years after diagnosis in men showed little or no seasonal vari-
ation at most cancer sites apart from in the case of lung cancer
which showed a significantly lower mortality HR (0.94) in the
summer. Adjusting for sunlight exposure in the preceding 3 months
yielded lower summer HRs: prostate (0.92), colorectum (0.93),
lung (0.91), and all sites combined (0.95) (Table III).
In the 0–5 year interval, there was a lack of seasonal variation
as in the 0–1 year interval in men except with lung cancer. When
adjustment was made for sunlight hours, the seasonal effect was
weaker than that at 0–1 years (Table IV).
Tables V and VI show mortality HRs in relation to mean cumu-
lative sunlight exposure during periods 1, 3, 6 and 9 months before
diagnosis for women and men respectively. Results are given both
without and with adjustment for season of diagnosis.
When season of analysis was not considered, cumulative sun-
light exposure was associated with reduced mortality HRs, with
values down to 0.92 per 100 sunlight hours for breast cancer in the
0–1 year period of analysis when 3-month cumulative sunlight ex-
posure was used. In women, all estimates derived from cumulative
sunlight hours 1, 3 and 6 months before diagnosis were lower than
1.00 and the majority were statistically significant (Table V).
In men, the pattern was less clear but a reduction was evident
for lung cancer (Table VI). For both men and women, the apparent
association with sunlight disappeared completely when adjustment
was made for season.
Figure 2 summarizes the seasonal variation in mortality HRs,
adjusting only for age and period at diagnosis.
Discussion
In this study, we have examined the effect of season and sun-
light on cancer survival. Our results can be summarized as fol-
lows: for breast cancer in females, as well as lung cancer and can-
cers at all sites combined in both sexes, patients diagnosed in
FIGURE 1 – The distribution of cumulative sunlight hours over the
preceding 1, 3, 6 and 9 months for each month of diagnosis averaged
over 32 years (1971–2002) recorded at Greenwich.
1531
SEASON OF DIAGNOSIS AND SUNLIGHT EXPOSURE IN CANCER SURVIVAL

Page 3

summer and autumn showed increased survival compared with
those diagnosed in the winter. In addition, sunlight exposure in the
months preceding diagnosis was found to be a predictor of sur-
vival, though it did not contribute to this increased survival as an
independent factor when season of diagnosis was considered.
The main question then is why season of diagnosis is a better
predictor of cancer survival than cumulative sunlight hours before
diagnosis, which show not only seasonal but yearly variation.
We found that when adjusting only for age and period of diag-
nosis, both season of diagnosis and sunlight exposure showed an
association with cancer survival. In contrast, when season of diag-
nosis and cumulative sunlight hours were mutually adjusted, the
seasonal effect persisted without attenuation, but the sunlight
effect was eliminated. Although seasonal variation in cancer sur-
vival has been demonstrated already in recent Norwegian studies
for colon, breast and prostate cancer, and Hodgkin’s lym-
phoma,17–19our result that sunlight was not an independent factor
was unexpected and requires careful interpretation. Our a priori
expectation would have been that sunlight hours would prevail as
an independent predictor of survival, and that its inclusion in the
model would eliminate the apparent effect of season. This result
could have been interpreted as supporting the hypothesis that vari-
ation in vitamin D levels, through sunlight exposure, lies behind
the observed seasonal variation in survival. In the light of the pres-
ent results, it is important to consider the possibility that the sea-
sonal effect might be due to other factors than sunlight and vita-
min D, such as a relatively higher diagnosis rate in summer, mod-
ulation of behavior and the prevalence of infections in winter
leading to early cancer death.
We investigated relative incidence by month of diagnosis and
found little variation except 2 months with low incidence: August
and December, which probably reflect the summer and Christmas
vacations. Robsahm et al. made the same analysis and also found
that the seasonal variation in survival did not coincide with sea-
sonal variation in incidence.17
It is recognized that the winter season is associated with an
increased mortality rate due to influenza and other infections. We
have calculated mortality HRs for both the first year and the first
5 years after diagnosis. Especially in the first year, survival tended
to be higher in patients diagnosed in summer and autumn. Since
the excess mortality in cancer patients is highest in the first months
after diagnosis, it is unlikely that the higher cancer mortality in the
TABLE I – MORTALITY HAZARD RATIOS BY SEASON OF DIAGNOSIS IN THE PERIOD 0–1 YEARS AFTER DIAGNOSIS IN WOMEN1
Cancer siteSeason of diagnosis
Unadjusted Adjusted for sunlight hours
HR2
HR3
HR4
HR5
HR6
BreastWinter
Spring
Summer
Autumn
Winter
Spring
Summer
Autumn
Winter
Spring
Summer
Autumn
Winter
Spring
Summer
Autumn
1.00 1.00 1.001.001.00
0.95 (0.91–0.98)
0.86 (0.83–0.89)
0.91 (0.88–0.95)
1.00
0.99 (0.96–1.02)
0.94 (0.91–0.97)
0.98 (0.95–1.01)
1.00
0.97 (0.95–1.00)
0.95 (0.92–0.97)
0.96 (0.93–0.98)
1.00
0.98 (0.97–0.99)
0.94 (0.93–0.95)
0.95 (0.94–0.96)
0.95 (0.90–1.00)
0.87 (0.81–0.93)
0.91 (0.87–0.96)
1.00
0.98 (0.94–1.03)
0.93 (0.88–0.98)
0.97 (0.93–1.01)
1.00
0.96 (0.93–0.99)
0.92 (0.88–0.97)
0.94 (0.91–0.98)
1.00
0.97 (0.95–0.98)
0.92 (0.90–0.93)
0.93 (0.92–0.95)
0.94 (0.90–0.98)
0.84 (0.78–0.90)
0.89 (0.84–0.95)
1.00
0.99 (0.96–1.02)
0.94 (0.89–1.00)
0.98 (0.93–1.03)
1.00
0.96 (0.94–0.99)
0.92 (0.87–0.96)
0.93 (0.89–0.97)
1.00
0.97 (0.96–0.98)
0.91 (0.89–0.93)
0.92 (0.90–0.94)
0.97 (0.93–1.02)
0.84 (0.81–0.88)
0.86 (0.82–0.91)
1.00
0.99 (0.95–1.03)
0.94 (0.91–0.97)
0.98 (0.93–1.02)
1.00
0.98 (0.95–1.01)
0.94 (0.91–0.97)
0.94 (0.90–0.97)
1.00
0.99 (0.98–1.01)
0.93 (0.92–0.94)
0.93 (0.91–0.94)
0.97 (0.93–1.02)
0.88 (0.84–0.92)
0.90 (0.87–0.94)
1.00
1.00 (0.96–1.05)
0.95 (0.91–0.99)
0.97 (0.94–1.00)
1.00
0.98 (0.95–1.01)
0.95 (0.92–0.98)
0.96 (0.93–0.98)
1.00
0.98 (0.97–1.00)
0.94 (0.93–0.95)
0.95 (0.94–0.96)
Colorectum
Lung
All sites
1Values in parentheses indicate 95% confidence intervals.–2Mortality hazard ratios adjusted for age and period of diagnosis.–3Mortality haz-
ard ratios also adjusted for cumulative mean sunlight hours during 1 month before diagnosis.–4Mortality hazard ratios also adjusted for cumula-
tive mean sunlight hours during 3 months before diagnosis.–5Mortality hazard ratios also adjusted for cumulative mean sunlight hours during
6 months before diagnosis.–6Mortality hazard ratios also adjusted for cumulative mean sunlight hours during 9 months before diagnosis.
TABLE II – MORTALITY HAZARD RATIOS BY SEASON OF DIAGNOSIS IN THE PERIOD 0–5 YEARS AFTER DIAGNOSIS IN WOMEN1
Cancer siteSeason of diagnosis
Unadjusted Adjusted for sunlight hours
HR2
HR3
HR4
HR5
HR6
BreastWinter
Spring
Summer
Autumn
Winter
Spring
Summer
Autumn
Winter
Spring
Summer
Autumn
Winter
Spring
Summer
Autumn
1.001.001.001.001.00
0.99 (0.97–1.01)
0.93 (0.91–0.95)
0.94 (0.92–0.96)
1.00
0.99 (0.97–1.02)
0.96 (0.94–0.99)
0.98 (0.96–1.01)
1.00
0.98 (0.95–1.00)
0.95 (0.93–0.98)
0.97 (0.94–0.99)
1.00
0.99 (0.98–1.00)
0.96 (0.95–0.97)
0.95 (0.95–0.96)
1.00 (0.97–1.03)
0.94 (0.90–0.98)
0.95 (0.92–0.97)
1.00
0.98 (0.95–1.01)
0.94 (0.90–0.98)
0.97 (0.94–1.00)
1.00
0.96 (0.93–0.99)
0.93 (0.89–0.97)
0.95 (0.92–0.98)
1.00
0.98 (0.96–0.99)
0.93 (0.92–0.95)
0.94 (0.93–0.95)
0.99 (0.97–1.01)
0.93 (0.89–0.96)
0.94 (0.90–0.97)
1.00
0.99 (0.96–1.01)
0.95 (0.91–0.99)
0.97 (0.94–1.02)
1.00
0.97 (0.95–1.00)
0.93 (0.89–0.97)
0.95 (0.91–0.98)
1.00
0.98 (0.97–0.99)
0.93 (0.92–0.95)
0.93 (0.92–0.95)
1.00 (0.97–1.02)
0.93 (0.90–0.95)
0.93 (0.90–0.96)
1.00
0.99 (0.96–1.02)
0.96 (0.94–0.99)
0.98 (0.95–1.02)
1.00
0.99 (0.96–1.01)
0.95 (0.92–0.97)
0.95 (0.92–0.98)
1.00
1.00 (0.98–1.01)
0.95 (0.94–0.96)
0.94 (0.93–0.96)
0.99 (0.97–1.02)
0.93 (0.91–0.96)
0.94 (0.92–0.96)
1.00
0.99 (0.96–1.03)
0.96 (0.94–0.99)
0.98 (0.96–1.01)
1.00
0.98 (0.95–1.01)
0.96 (0.93–0.98)
0.96 (0.94–0.99)
1.00
0.98 (0.97–1.00)
0.95 (0.94–0.96)
0.96 (0.95–0.97)
Colorectum
Lung
All sites
1Values in parentheses indicate 95% confidence intervals.–2Mortality hazard ratios adjusted for age and period of diagnosis.–3Mortality haz-
ard ratios also adjusted for cumulative mean sunlight hours during 1 month before diagnosis.–4Mortality hazard ratios also adjusted for cumula-
tive mean sunlight hours during 3 months before diagnosis.–5Mortality hazard ratios also adjusted for cumulative mean sunlight hours during
6 months before diagnosis.–6Mortality hazard ratios also adjusted for cumulative mean sunlight hours during 9 months before diagnosis.
1532
LIM ET AL.

Page 4

winter months would lead to an apparent better survival in patients
diagnosed in summer and autumn. If anything, the effect would be
in the opposite direction.
One possible explanation lies in that we used meteorological
sunlight hours data as a surrogate for true patient exposure. How-
ever, our assumption that sunlight hours data provide a good
measure of true sunlight exposure is simplistic for a variety of rea-
sons: sunlight hours only represent the cumulative time over
which the sun has shone in a given month, but give no measure of
the intensity of that incident light. Adjustment for this factor
would serve to increase the difference between exposures in the
winter and summer months. In addition, behavioral changes asso-
ciated with warmer outdoor temperatures and psychosocial associ-
ations of the summer months might result in patients spending
more time outdoors undergoing exposure to sunlight. Considering
these 2 factors alone, it is very probable that our sunlight hours
data provide us with a substantially underestimated measure of the
true difference in the exposure of patients to sunlight between
winter and summer. If this is the case, then sunlight hours provide
a dampened and potentially noisier measure of sunlight exposure
than season, which could in reality be the better measure of sun-
light exposure and vitamin D production. Indeed, the use of more
representative measures of sunlight, or more specifically, UVB ex-
posure in large epidemiological studies remains areas for future
work.
Laboratory studies support the hypothesis that 1,25(OH)2D
exerts antiproliferative effects22–25and it is plausible that these
underlie the observed seasonality in cancer survival. However, it
is well established that while the serum concentration of biologi-
cally inert 25(OH)D shows variation with ultraviolet light expo-
sure, active 1,25(OH)2D does not, since its production and thus
systemic release requires hydroxylation of 25(OH)D in the kid-
neys, a conversion that is tightly regulated and not correlated with
systemic levels of the 25(OH)D.26However, evidence of extrare-
nal synthesis of 1,25(OH)2D might offer a plausible explanation
for the seasonal variation in survival. Recent studies have reported
1a-hydroxylase expression in the prostate, breast and colon and
thus the ability of these cells to locally synthesize 1,25(OH)2D
which can then exert its antiproliferative and antimetastatic effects
in an autocrine or paracrine fashion.27–31There is evidence that
this extrarenal production is not subject to the tight regulation
present in the kidneys.32
TABLE III – MORTALITY HAZARD RATIOS BY SEASON OF DIAGNOSIS IN THE PERIOD 0–1 YEARS AFTER DIAGNOSIS IN MEN1
Cancer site Season of diagnosis
UnadjustedAdjusted for sunlight hours
HR2
HR3
HR4
HR5
HR6
Prostate Winter
Spring
Summer
Autumn
Winter
Spring
Summer
Autumn
Winter
Spring
Summer
Autumn
Winter
Spring
Summer
Autumn
1.00 1.001.00 1.00 1.00
1.01 (0.97–1.05)
0.96 (0.92–1.00)
0.97 (0.94–1.01)
1.00
1.03 (0.99–1.06)
0.99 (0.95–1.02)
1.02 (0.98–1.05)
1.00
0.98 (0.96–1.00)
0.94 (0.92–0.95)
0.98 (0.96–0.99)
1.00
1.01 (1.00–1.02)
0.99 (0.98–1.00)
0.98 (0.97–0.99)
0.99 (0.94–1.04)
0.92 (0.86–0.99)
0.95 (0.90–1.00)
1.00
1.00 (0.96–1.05)
0.94 (0.89–1.00)
0.99 (0.95–1.04)
1.00
0.97 (0.95–0.99)
0.92 (0.89–0.95)
0.97 (0.95–0.99)
1.00
0.99 (0.98–1.01)
0.95 (0.93–0.97)
0.96 (0.95–0.97)
1.00 (0.96–1.04)
0.92 (0.85–0.98)
0.94 (0.88–1.00)
1.00
1.01 (0.98–1.05)
0.93 (0.87–0.98)
0.97 (0.92–1.02)
1.00
0.97 (0.95–0.99)
0.91 (0.88–0.94)
0.96 (0.93–0.98)
1.00
1.00 (0.99–1.01)
0.95 (0.93–0.97)
0.95 (0.93–0.97)
1.03 (0.99–1.08)
0.95 (0.91–0.99)
0.94 (0.89–1.00)
1.00
1.07 (1.03–1.11)
0.96 (0.93–1.00)
0.95 (0.91–1.00)
1.00
0.99 (0.97–1.01)
0.93 (0.91–0.94)
0.95 (0.93–0.98)
1.00
1.02 (1.01–1.04)
0.98 (0.97–0.99)
0.96 (0.94–0.97)
1.05 (0.99–1.10)
0.98 (0.94–1.03)
0.96 (0.92–1.00)
1.00
1.06 (1.02–1.11)
1.01 (0.97–1.05)
1.01 (0.97–1.04)
1.00
0.99 (0.97–1.02)
0.95 (0.93–0.97)
0.97 (0.95–0.99)
1.00
1.02 (1.01–1.03)
0.99 (0.98–1.00)
0.98 (0.97–0.99)
Colorectum
Lung
All sites
1Values in parentheses indicate 95% confidence intervals.–2Mortality hazard ratios adjusted for age and period of diagnosis.–3Mortality haz-
ard ratios also adjusted for cumulative mean sunlight hours during 1 month before diagnosis.–4Mortality hazard ratios also adjusted for cumula-
tive mean sunlight hours during 3 months before diagnosis.–5Mortality hazard ratios also adjusted for cumulative mean sunlight hours during
6 months before diagnosis.–6Mortality hazard ratios also adjusted for cumulative mean sunlight hours during 9 months before diagnosis.
TABLE IV – MORTALITY HAZARD RATIOS BY SEASON OF DIAGNOSIS IN THE PERIOD 0–5 YEARS AFTER DIAGNOSIS IN MEN1
Cancer siteSeason of diagnosis
UnadjustedAdjusted for sunlight hours
HR2
HR3
HR4
HR5
HR6
Prostate Winter
Spring
Summer
Autumn
Winter
Spring
Summer
Autumn
Winter
Spring
Summer
Autumn
Winter
Spring
Summer
Autumn
1.001.001.001.001.00
1.01 (0.99–1.04)
0.98 (0.96–1.01)
1.00 (0.97–1.02)
1.00
1.02 (1.00–1.05)
1.00 (0.97–1.02)
1.01 (0.98–1.04)
1.00
0.98 (0.97–1.00)
0.94 (0.92–0.95)
0.97 (0.96–0.99)
1.00
1.01 (1.00–1.02)
0.99 (0.98–1.00)
0.98 (0.97–0.99)
0.99 (0.95–1.02)
0.94 (0.89–0.98)
0.97 (0.94–1.00)
1.00
1.00 (0.97–1.04)
0.96 (0.92–1.01)
0.99 (0.96–1.03)
1.00
0.98 (0.96–1.00)
0.92 (0.89–0.95)
0.96 (0.93–0.98)
1.00
0.99 (0.98–1.01)
0.96 (0.95–0.98)
0.96 (0.95–0.97)
1.00 (0.98–1.03)
0.95 (0.91–1.00)
0.97 (0.93–1.01)
1.00
1.01 (0.99–1.04)
0.96 (0.92–1.01)
0.98 (0.94–1.02)
1.00
0.99 (0.98–1.01)
0.93 (0.92–0.95)
0.96 (0.93–0.98)
1.00
1.00 (0.99–1.01)
0.96 (0.95–0.98)
0.95 (0.94–0.97)
1.02 (0.99–1.06)
0.98 (0.95–1.00)
0.98 (0.94–1.01)
1.00
1.04 (1.01–1.07)
0.98 (0.96–1.01)
0.98 (0.94–1.01)
1.00
0.99 (0.98–1.01)
0.93 (0.92–0.95)
0.96 (0.93–0.98)
1.00
1.02 (1.01–1.03)
0.99 (0.98–1.00)
0.96 (0.95–0.98)
1.02 (0.99–1.06)
0.99 (0.96–1.02)
0.99 (0.97–1.02)
1.00
1.04 (1.01–1.08)
1.01 (0.98–1.04)
1.00 (0.97–1.03)
1.00
0.99 (0.97–1.01)
0.94 (0.93–0.96)
0.97 (0.96–0.99)
1.00
1.02 (1.00–1.03)
1.00 (0.99–1.01)
0.98 (0.97–0.99)
Colorectum
Lung
All sites
1Values in parentheses indicate 95% confidence intervals.–2Mortality hazard ratios adjusted for age and period of diagnosis.–3Mortality haz-
ard ratios also adjusted for cumulative mean sunlight hours during 1 month before diagnosis.–4Mortality hazard ratios also adjusted for cumula-
tive mean sunlight hours during 3 months before diagnosis.–5Mortality hazard ratios also adjusted for cumulative mean sunlight hours during
6 months before diagnosis.–6Mortality hazard ratios also adjusted for cumulative mean sunlight hours during 9 months before diagnosis.
1533
SEASON OF DIAGNOSIS AND SUNLIGHT EXPOSURE IN CANCER SURVIVAL

Page 5

While the vitamin D hypothesis might apply to multiple cancer
sites, breast, prostate and colorectal cancers have been the focus
of past research.33We have extended the analysis to lung cancer
and cancers at all sites combined, finding breast, lung and colorec-
tal cancer survival to be associated with season of diagnosis in
women. Men showed less seasonal variation in survival, and only
in lung cancer did patients have increased survival when diag-
nosed in the summer and autumn months. That this variation was
much stronger in women than in men is noteworthy: it is well
established that hypovitaminosis D is more common in women
than in men in the winter season.34–36Data from previous studies
show a similar increased seasonality in women compared with
men, although such differences are not commented upon.15,17,18
These differences merit further investigation.
In the case of colorectal cancer, we found survival to be slightly
increased in patients who were diagnosed in the summer months,
a result that is consistent with other studies.18However, we found
the seasonal association to be refractory to adjustment for sunlight
exposure.
We found a substantial seasonal variation in lung cancer mortal-
ity that was present in both sexes. Little attention has been given to
the effect of season and sunlight on lung cancer survival in the past.
However, recently Zhou et al. have found both surgery season and
dietary vitamin D intake to be predictors of early-stage non-small
cell lung cancer mortality in surgical patients, with those treated in
the summer experiencing improved survival.37That vitamin D
metabolites exert an effect on tumor growth is plausible. Indeed,
through the identification of vitamin D receptor expression in cer-
tain lung cancer cell lines, it has been proposed that a subset of lung
cancers may be susceptible to the differentiating effects of vitamin
D metabolites.38However, little evidence of 1a-hydroxylase activ-
ity in lung cells has been found. Recently however, Yokomura et al.
reported an elevation in 1a-hydroxylase activity in the alveolar
macrophages of patients with lung cancer, with expression of this
enzyme correlated with levels of 1,25(OH)2D in the serum.29This
significant source of the active hormone may account for the con-
sistent seasonal variation observed among both men and women.
Breast cancer showed the largest seasonal variation in survival.
Both human and animal studies support this finding39which con-
firms and extends previous work by Robsahm et al.17
In our study, we have not examined the effect of ethnicity on sea-
sonality in cancer survival despite the important effect of skin pig-
mentation in modulating ultraviolet absorption. Clemens et al. have
shown that dark-skinned populations may require 10–50 times the
TABLE V – MORTALITY HAZARD RATIOS IN RELATION TO CUMULATIVE SUNLIGHT EXPOSURE PRECEDING DIAGNOSIS IN THE 0–1 AND 0–5 YEAR
PERIODS AFTER DIAGNOSIS IN WOMEN1
Cancer Site
Exposure to sunlight
(months)
0–1 Years0–5 Years
Unadjusted2
Adjusted3
Unadjusted2
Adjusted3
Breast1
3
6
9
1
3
6
9
1
3
6
9
1
3
6
9
0.93 (0.90–0.95)
0.92 (0.90–0.95)
0.96 (0.93–1.00)
1.11 (1.04–1.19)
0.97 (0.95–0.99)
0.96 (0.94–0.99)
0.98 (0.95–1.01)
1.05 (0.99–1.12)
0.98 (0.96–0.99)
0.98 (0.96–0.99)
0.99 (0.96–1.01)
1.03 (0.98–1.08)
0.97 (0.97–0.98)
0.97 (0.96–0.97)
0.97 (0.96–0.98)
1.00 (0.98–1.02)
1.00 (0.96–1.04)
1.03 (0.97–1.08)
1.11 (1.03–1.19)
1.11 (0.99–1.23)
1.01 (0.97–1.04)
1.00 (0.96–1.04)
1.00 (0.94–1.06)
1.05 (0.96–1.16)
1.02 (0.99–1.05)
1.03 (1.00–1.07)
1.04 (0.99–1.09)
1.02 (0.94–1.10)
1.02 (1.01–1.03)
1.03 (1.02–1.05)
1.04 (1.02–1.06)
1.01 (0.97–1.04)
0.96 (0.95–0.98)
0.95 (0.94–0.97)
0.95 (0.93–0.97)
0.99 (0.95–1.04)
0.99 (0.97–1.00)
0.98 (0.96–1.00)
0.99 (0.96–1.01)
1.03 (0.98–1.08)
0.98 (0.97–1.00)
0.98 (0.96–0.99)
0.99 (0.96–1.01)
1.02 (0.98–1.07)
0.98 (0.98–0.99)
0.97 (0.97–0.98)
0.97 (0.96–0.98)
0.98 (0.96–0.99)
0.99 (0.97–1.02)
1.01 (0.97–1.04)
1.02 (0.98–1.07)
1.01 (0.95–1.08)
1.02 (0.99–1.05)
1.01 (0.98–1.05)
1.00 (0.99–1.05)
1.01 (0.94–1.09)
1.02 (0.99–1.05)
1.02 (0.99–1.06)
1.03 (0.98–1.08)
1.01 (0.95–1.09)
1.02 (1.01–1.03)
1.02 (1.00–1.04)
1.02 (1.00–1.04)
0.98 (0.95–1.01)
Colorectum
Lung
All sites
1Values in parentheses indicate 95% confidence intervals.–2Mortality hazard ratios adjusted for age and period of diagnosis.–3Mortality haz-
ard ratios also adjusted for season of diagnosis.
TABLE VI – MORTALITY HAZARD RATIOS IN RELATION TO CUMULATIVE SUNLIGHT EXPOSURE PRECEDING DIAGNOSIS IN THE 0–1 AND 0–5 YEAR
PERIODS AFTER DIAGNOSIS IN MEN1
Cancer Site
Exposure to sunlight
(months)
0–1 Years0–5 Years
Unadjusted2
Adjusted3
Unadjusted2
Adjusted3
Prostate1
3
6
9
1
3
6
9
1
3
6
9
1
3
6
9
0.99 (0.97–1.01)
0.98 (0.95–1.01)
0.97 (0.94–1.01)
1.03 (0.96–1.11)
1.00 (0.98–1.03)
1.00 (0.98–1.03)
1.02 (0.99–1.05)
1.06 (0.99–1.12)
0.97 (0.96–0.98)
0.97 (0.96–0.98)
1.00 (0.98–1.01)
1.07 (1.04–1.10)
1.00 (0.99–1.01)
0.99 (0.98–1.00)
0.98 (0.97–0.99)
0.98 (0.96–1.00)
1.03 (0.99–1.08)
1.05 (0.99–1.10)
1.06 (0.98–1.15)
1.13 (1.01–1.27)
1.04 (1.00–1.07)
1.06 (1.01–1.11)
1.13 (1.06–1.21)
1.14 (1.03–1.26)
1.01 (0.99–1.03)
1.03 (1.00–1.05)
1.05 (1.01–1.08)
1.05 (1.00–1.11)
1.03 (1.01–1.04)
1.04 (1.02–1.05)
1.04 (1.02–1.06)
1.03 (1.00–1.06)
1.00 (0.99–1.02)
0.99 (0.98–1.01)
0.99 (0.97–1.02)
1.01 (0.96–1.06)
1.01 (0.99–1.02)
1.00 (0.98–1.02)
1.00 (0.98–1.03)
1.02 (0.97–1.07)
0.97 (0.96–0.98)
0.97 (0.96–0.98)
0.99 (0.97–1.00)
1.05 (1.02–1.08)
1.00 (1.00–1.01)
0.99 (0.99–1.00)
0.98 (0.97–0.99)
0.97 (0.95–0.98)
1.04 (1.01–1.07)
1.03 (0.99–1.07)
1.04 (1.00–1.09)
1.04 (0.96–1.12)
1.02 (1.00–1.05)
1.03 (0.99–1.07)
1.06 (1.01–1.12)
1.07 (1.00–1.16)
1.02 (1.00–1.04)
1.03 (1.00–1.08)
1.03 (1.00–1.07)
1.03 (0.99–1.08)
1.02 (1.01–1.03)
1.03 (1.02–1.04)
1.03 (1.01–1.04)
1.01 (0.99–1.04)
Colorectum
Lung
All sites
1Values in parentheses indicate 95% confidence intervals.–2Mortality hazard ratios adjusted for age and period of diagnosis.–3Mortality haz-
ard ratios also adjusted for season of diagnosis.
1534
LIM ET AL.

Page 6

exposure to ultraviolet B radiation to produce an equivalent amount
of vitamin D as do those with lighter skin.40Ethnicity also affects
diet. Some authors have speculated that the low incidence of breast
and prostate cancer in some Asian countries might be due to the
increased consumption of phytoestrogens present in soy, which
through down regulating expression of CYP enzymes, might lead to
an enhancement of local 1,25(OH)2D levels and an increase in its
differentiating effects.27We have not examined the role of dietary
vitamin D intake in attenuating cancer survival and mortality,
although other studies have identified such associations.11,37
The present study has methodological strengths. We have
directly examined the effect of season of diagnosis and sunlight
exposure on cancer survival in a cohort of over 1 million cancer
patients and yielded results consistent with existing literature. In
conclusion, we found substantial seasonality in cancer survival,
with diagnosis in the summer and autumn months being associated
with improved survival, especially in lung and breast cancer
patients. The magnitude of the observed seasonality was smaller
than that reported in Norway by Moan et al.18and dependent on
sex and cancer site. We also found sunlight exposure to be a pre-
dictor of cancer survival, although season of diagnosis was a
stronger predictor than sunlight. Our results add to a growing body
of evidence that vitamin D may play an important role in cancer
survival.
References
1. Holick MF. Vitamin D: a millennium perspective. J Cell Biochem
2003;88:296–307.
Holick MF. Vitamin D: importance in the prevention of cancers, type
1 diabetes, heart disease, and osteoporosis. Am J Clin Nutr 2004;79:
362–71.
McKenna MJ. Differences in vitamin D status between countries in
young adults and the elderly. Am J Med 1992;93:69–77.
Lips P, Chapuy MC, Dawson-Hughes B, Pols HAP, Holick MF. An
international comparison of serum 25-hydroxy-vitamin D measure-
ments. Osteoporos Int 1999;9:394–7.
Ovesen L, Anderson R, Jakobsen J. Geographical differences in vita-
min D status, with particular reference to European countries. Proc
Nutr Soc 2003;62:813–21.
Zittermann A. Vitamin D in preventive medicine: are we ignoring the
evidence? Br J Nutr 2003;89:552–72.
van de Wielen RPJ, Lowik MRH, van den Berg H, de Groot LC, Hal-
ler J, Moreiras O, van Staveren WA. Serum vitamin D concentrations
among elderly people in Europe. Lancet 1995;346:207–10.
Zittermann A. Seasonal variation in bone turnover: dependence on
calcium nutrition. J Bone Miner Res 2001;16:1733.
2.
3.
4.
5.
6.
7.
8.
9.Apperly F. The relation of solar radiation to cancer mortality in North
America. Cancer Res 1941;1:191–5.
10. Garland CF, Garland FC. Do sunlight and vitamin D reduce the likeli-
hood of colon cancer. Int J Epidemiol 1980;9:227–31.
11. Garland C, Shekelle RB, Barrett-Connor E, Criqui MH, Rossof AH,
Paul O. Dietary vitamin D and calcium and risk of colorectal cancer:
a 19-year prospective study in men. Lancet 1985;1:307–9.
12. Garland CF, Comstock GW, Garland FC, Helsing KJ, Shaw EK, Gor-
ham ED. Serum 25-hydroxyvitamin D and colon cancer: eight-year
prospective study. Lancet 1989;2:1176–8.
13. Hanchette CL, Schwartz GG. Geographic patterns of prostate cancer
mortality—Evidence for a protective effect of ultraviolet radiation.
Cancer 1992;70:2861–9.
14. John EM, Dreon DM, Koo J, Schwartz GG. Residential sunlight expo-
sure is associated with a decreased risk of prostate cancer. J Steroid
Biochem Mol Biol 2004;89:549–52.
15. Freedman DM, Dosemeci M, McGlynn K. Sunlight and mortality
from breast, ovarian, colon, prostate, and non-melanoma skin cancer:
a composite death certificate based case-control study. Occup Environ
Med 2002;59:257–62.
FIGURE 2 – Seasonal variation
in mortality both in the 0–1 and 0–
5 year periods after diagnosis given
by sex and site. (u) Hazard ratio
for 0–1 years after diagnosis. (n)
Hazard ratio for 0–5 years after di-
agnosis. All HRs are adjusted for
age and period of diagnosis. p < 0.05.
Winter is the reference category
(HR 5 1.00).
1535
SEASON OF DIAGNOSIS AND SUNLIGHT EXPOSURE IN CANCER SURVIVAL

Page 7

16. John EM, Schwartz GG, Koo J, Van Den Berg D, Ingles SA. Sun ex-
posure, vitamin D receptor gene polymorphisms, and risk of advanced
prostate cancer. Cancer Res 2005;15:5470–9.
17. Robsahm TE, Tretli S, Dahlback A, Moan J. Vitamin D3 from sun-
light may improve the prognosis of breast-, colon- and prostate can-
cer. Cancer Causes Control 2004;15:149–58.
18. Moan J, Porojnicu AC, Robsahm TE, Dahlback A, Juzeniene A, Tretli S,
Grant W. Solar radiation, vitamin D and survival rate of colon cancer in
Norway. J Photochem Photobiol B 2005;78:189–93.
19. Porojnicu AC, Robsahm TE, Ree AH, Moan J. Season of diagnosis is
a prognostic factor in Hodgkin’s lymphoma: a possible role of sun-
induced vitamin D. Br J Cancer 2005;93:571–4.
20. Kimlin MG. The climatology of Vitamin D producing ultraviolet radi-
ation over the United States. J Steroid Biochem Mol Biol 2004;89/
90:479–83.
21. British Meteorological Office. Greenwich data in historic station
data. 2005. Available at www.met-office.gov.uk/climate/uk/stationdata/
greenwichdata.txt.
22. Wood AW, Chang RL, Huang MT, Uskokovic M, Cooney AH.
1a,25-Dihydroxyvitamin D3 inhibits phorbol ester-dependent chemi-
cal carcinogenesis in mouse skin. Biochem Biophys Res Commun
1983;116:605–11.
23. Hansen CM, Binderup L, Hamberg KJ, Carlberg C. Vitamin D and
cancer: effects of 1,25(OH)2D3 and its analogs on growth control and
tumorigenesis. Front Biosci 2001;6:D820–D848.
24. Trump DL, Hershberger PA, Bernardi RJ, Ahmed S, Muindi J, Fakih M,
Yu WD, Johnson CS. Anti-tumor activity of calcitriol: pre-clinical and
clinical studies. J Steroid Biochem Mol Biol 2004;89/90:519–26.
25. Ordonez-Moran P, Larriba MJ, Pendas-Franco N, Aguilera O, Gonza-
lez-Sancho JM, Munoz A. Vitamin D and cancer: an update of in vitro
and in vivo data. Front Biosci 2005;10:2723–49.
26. Chesney RW, Rosen JF, Hamstra AJ, Smith C, Mahaffey K, DeLuca
HF. Absence of seasonal variation in serum concentrations of 1,25-
dihydroxyvitamin D despite a rise in 25-hydroxyvitamin D in
summer. J Clin Endocrinol Metab 1981;53:139–42.
27. Cross HS, Kallay E, Farhan H, Weiland T, Manhardt T. Regulation of
extrarenal vitamin D metabolism as a tool for colon and prostate can-
cer prevention. Recent Results Cancer Res 2003;164:413–25.
28. Friedrich M, Rafi L, Mitschele T, Tilgen W, Schmidt W, Reichrath J.
Analysis of the vitamin D system in cervical carcinomas, breast can-
cer and ovarian cancer. Recent Results Cancer Res 2003;164:239–46.
29. Yokomura K, Suda T, Sasaki S, Inui N, Chida K, Nakamura H.
Increased expression of the 25-hydroxyvitamin D(3)-1a-hydroxylase
gene in alveolar macrophages of patients with lung cancer. J Clin
Endocrinol Metab 2003;88:5704–9.
30. Zehnder D, Bland R, Williams MC, McNinch RW, Howie AJ, Stew-
art PM, Hewison M. Extrarenal expression of 25-hydroxyvitamin
D(3)-1a-hydroxylase. J Clin Endocrinol Metab 2001;86:888–94.
31. Schwartz GG. Vitamin D and the epidemiology of prostate cancer.
Semin Dial 2005;18:276–89.
32. Young MV, Schwartz GG, Wang L, Jamieson DP, Whitlatch LW,
Flanagan JN, Lokeshwar BL, Holick MF, Chen TC. The prostate 25-
hydroxyvitamin D-1a-hydroxylase is not influenced by parathyroid
hormone and calcium: implications for prostate cancer chemopreven-
tion by vitamin D. Carcinogenesis 2004;25:967–71.
33. Giovannucci E. The epidemiology of vitamin D and cancer incidence
and mortality: a review (United States). Cancer Causes Control 2005;
160:83–95.
34. Boutron MC, Faivre J, Marteau P, Couillault C, Senesse P, Quipourt V.
Calcium, phosphorus, vitamin D, dairy products and colorectal car-
cinogenesis: a French case-control study. Br J Cancer 1996;74:145–
51.
35. Martinez ME, Giovannucci EL, Colditz GA, Stampfer MJ, Hunter DJ,
Speizer FE, Wing A, Willett WC. Calcium, vitamin D, and the occur-
rence of colorectal cancer among women. J Natl Cancer Inst 1996;88:
1375–82.
36. Marcus PM, Newcomb PA. The association of calcium and vitamin
D, and colon and rectal cancer in Wisconsin women. Int J Epidemiol
1998;27:788–93.
37. Zhou W, Suk R, Liu G, Park S, Neuberg DS, Wain JC, Lynch TJ,
Giovannucci E. Vitamin D is associated with improved survival in
early-stage non-small cell lung cancer patients. Cancer Epidemiol
Biomarkers Prev 2005;14:2303–9.
38. Kaiser U, Schilli M, Wegmann B, Barth P, Wedel S, Hofmann J,
Havemann K. Expression of vitamin D receptor in lung cancer. J Can-
cer Res Clin Oncol 1996;122:356–9.
39. Welsh J. Vitamin D and breast cancer: insights from animal models.
Am J Clin Nutr 2004;80 (Suppl.):1721S–1724S.
40. Clemens TL, Henderson SL, Adams JS, Henderson SL, Holick MF.
Increased skin pigment reduces the capacity of skin to synthesize vita-
min D3. Lancet 1982;9:74–6.
1536
LIM ET AL.