Scientific Writing Lab

August 2010

Abstract Samples
A long-term survival analysis of prediagnostic body mass index, plasma C-peptide concentration, and
prostate cancer-specific mortality among men with prostate cancer

Background—Excess body mass index (BMI) has been associated with adverse outcomes in
prostate cancer, and hyperinsulinemia is a candidate mediator, but prospective data are sparse. We
assessed the influence of prediagnostic BMI and plasma C-peptide (reflecting insulin secretion) on
prostate cancer-specific mortality after diagnosis.
Methods—BMI was available at baseline (1982) and in 1990 among 2,546 men who developed
prostate cancer (281 prostate cancer deaths). Baseline C-peptide concentration were available in 827
men (117 prostate cancer deaths). We used Cox proportional hazards regression models controlling
for age, smoking, time between BMI measurement and prostate cancer diagnosis, and competing
causes of death.
Findings—Compared with men of normal weight (BMI<25 kg/m2) at baseline, overweight men
(BMI 25–29.9 kg/m2) and obese men (BMI=30 kg/m2) had significantly higher risk of prostate cancer
mortality; the proportional hazard ratio (HR)s (95% confidence interval, CI) were 1.47 (1.16–1.88)
for overweight and 2.66 (1.62–4.39; Ptrend<0.0001) for obesity. The trend remained significant after
controlling for clinical stage and Gleason grade and was stronger for prostate cancer diagnosed during the PSA
screening era (1991–2007) or using BMI obtained in 1990. Men with C-peptide
concentrations in the highest quartile (high), versus the lowest quartile (low), also had higher risk
(HR=2.38; 1.31–4.30). Compared with men with BMI<25 kg/m2 and low C-peptide concentrations,
those with BMI=25 kg/m2 and high C-peptide concentration had a four times higher risk (HR=4.12;
1.97–8.61; Pinteraction=0.001) independent of clinical predictors.
Interpretation—Excess body weight and high plasma concentration of C-peptide each predispose
men with a subsequent diagnosis of prostate cancer to increased likelihood of dying of this disease;
those with both factors have the worst outcome.

Prospective Study of Predictors of Vitamin D Status and Cancer Incidence and Mortality in Men
Background:
Vitamin D has potent anticancer properties, especially against digestive-system cancers. Many human studies
have used geographic residence as a marker of solar ultraviolet B and hence vitamin D exposure. Here, we
considered multiple determinants of vitamin D exposure (dietary and supplementary vitamin D, skin
pigmentation, adiposity, geographic residence, and leisure-time physical activity — to estimate sunlight
exposure) in relation to cancer risk in the Health Professionals Follow-Up Study.
Methods:
Among 1095 men of this cohort, we quantified the relation of these six determinants to plasma 25- hydroxy-
vitamin D [25(OH)D] level by use of a multiple linear regression model. We used results from the model to
compute a predicted 25(OH)D level for each of
47 800 men in the cohort based on these characteristics. We then prospectively examined this variable in
relation to cancer risk with multivariable Cox proportional hazards models.
Results:
From 1986 through January 31, 2000, we documented 4286 incident cancers (excluding organ-confined
prostate cancer and nonmelanoma skin cancer) and 2025 deaths from cancer. From multivariable models, an
increment of 25 nmol/L in predicted 25(OH)D level was associated with a 17% reduction in total cancer
incidence (multivariable relative risk [RR] = 0.83, 95% confidence interval [CI] = 0.74 to 0.92), a 29% reduction

1
Scientific Writing Lab
August 2010

Abstract Samples
in total cancer mortality (RR = 0.71, 95% CI = 0.60 to 0.83), and a 45% reduction in digestive-system cancer
mortality (RR = 0.55, 95% CI = 0.41 to 0.74). The absolute annual rate of total cancer was 758 per 100 000 men
in the bottom decile of predicted 25(OH)D and 674 per 100 000 men for the top decile; these respective rates
were 326 per 100 000 and 277 per 100 000 for total cancer mortality and 128 per 100 000 and 78 per 100 000
for digestive-system cancer mortality. Results were similar when we controlled further for body mass index or
physical activity level.
Conclusions:
Low levels of vitamin D may be associated with increased cancer incidence and mortality in men, particularly
for digestive-system cancers. The vitamin D supplementation necessary to achieve a 25(OH)D increment of 25
nmol/L may be at least 1500 IU/day. [J Natl Cancer Inst 2006;98:451 – 9]

Gleason Score and Lethal Prostate Cancer: Does 3 + 4 = 4 + 3?

Purpose
Gleason grading is an important predictor of prostate cancer (PCa) outcomes. Studies using surrogate PCa end
points suggest outcomes for Gleason score (GS) 7 cancers vary according to the predominance of pattern 4+
These studies have influenced clinical practice, but it is unclear if rates of PCa mortality differ for 3 + 4 and 4 +
3 tumors. Using PCa mortality as the primary end point, we compared outcomes in Gleason 3 + 4 and 4 + 3
cancers, and the predictive ability of GS from a standardized review versus original scoring.
Patients and Methods
Three study pathologists conducted a blinded standardized review of 693 prostatectomy and 119 biopsy
specimens to assign primary and secondary Gleason patterns. Tumor specimens were from PCa patients
diagnosed between 1984 and 2004 from the Physicians’ Health Study and Health Professionals Follow-Up
Study. Lethal PCa (n = 53) was defined as development of bony metastases or PCa death. Hazard ratios (HR)
were estimated according to original GS and standardized GS. We compared the discrimination of
standardized and original grading with C-statistics from models of 10-year survival.
Results
For prostatectomy specimens, 4 + 3 cancers were associated with a three-fold increase in lethal PCa compared
with 3 + 4 cancers (95% CI, 1.1 to 8.6). The discrimination of models of standardized scores from
prostatectomy (C-statistic, 0.86) and biopsy (C-statistic, 0.85) were improved compared to models of original
scores (prostatectomy C-statistic, 0.82; biopsy C-statistic, 0.72).
Conclusion
Ignoring the predominance of Gleason pattern 4 in GS 7 cancers may conceal important prognostic
information. A standardized review of GS can improve prediction of PCa survival.

A Prospective Study of Plasma Vitamin D Metabolites, Vitamin D Receptor Polymorphisms, and Prostate
Cancer
Background
Vitamin D insufficiency is a common public health problem nationwide. Circulating 25hydroxyvitamin D3
(25[OH]D), the most commonly used index of vitamin D status, is converted to the active hormone 1,25
dihydroxyvitamin D3 (1,25[OH]2D), which, operating through the vitamin D receptor (VDR), inhibits in vitro cell
proliferation, induces differentiation and apoptosis, and may protect against prostate cancer. Despite
intriguing results from laboratory studies, previous epidemiological studies showed inconsistent associations
of circulating levels of 25(OH)D, 1,25(OH)2D, and several VDR polymorphisms with prostate cancer risk. Few
studies have explored the joint association of circulating vitamin D levels with VDR polymorphisms.
2
Scientific Writing Lab
August 2010

Abstract Samples
Methods and Findings
During 18 y of follow-up of 14,916 men initially free of diagnosed cancer, we identified 1,066 men with
incident prostate cancer (including 496 with aggressive disease, defined as stage C or D, Gleason 7–10,
metastatic, and fatal prostate cancer) and 1,618 cancer-free, age-and smoking-matched control participants in
the Physicians’ Health Study. We examined the associations of prediagnostic plasma levels of 25(OH)D and
1,25(OH)2D, individually and jointly, with total and aggressive disease, and explored whether relations
between vitamin D metabolites and prostate cancer were modified by the functional VDR FokI polymorphism,
using conditional logistic regression. Among these US physicians, the median plasma 25(OH)D levels were 25
ng/ml in the blood samples collected during the winter or spring and 32 ng/ml in samples collected during the
summer or fall. Nearly 13% (summer/fall) to 36% (winter/spring) of the control participants were deficient in
25(OH)D (,20 ng/ml) and 51% (summer/fall) and 77% (winter/spring) had insufficient plasma 25(OH)D levels
(,32 ng/ml). Plasma levels of 1,25(OH)2D did not vary by season. Men whose levels for both 25(OH)D and
1,25(OH)2D were below (versus above) the median had a significantly increased risk of
Aggressive prostate cancer (odds ratio [OR] ¼ 2.1, 95% confidence interval [CI] 1.2–3.4), although the
interaction between the two vitamin D metabolites was not statistically significant (pinteraction ¼0.23). We
observed a significant interaction between circulating 25(OH)D levels and the VDR FokI genotype (pinteraction
, 0.05). Compared with those with plasma 25(OH)D levels above the median and with the FokI FF or Ff
genotype, men who had low 25(OH)D levels and the less functional FokI ff genotype had increased risks of
total (OR ¼1.9, 95% CI 1.1–3.3) and aggressive prostate cancer (OR ¼2.5, 95% CI 1.1–5.8). Among men with
plasma 25(OH)D levels above the median, the ffgenotype was no longer associated with risk. Conversely,
among men with the ff genotype, high plasma 25(OH)D level
(above versus below the median) was related to significant 60%;70% lower risks of total and aggressive
prostate cancer.
Conclusions
Our data suggest that a large proportion of the US men had suboptimal vitamin D status (especially during the
winter/spring season), and both 25(OH)D and 1,25(OH)2D may play an important role in preventing prostate
cancer progression. Moreover, vitamin D status, measured by 25(OH)D in plasma, interacts with
the VDR FokI polymorphism and modifies prostate cancer risk. Men with the less functional FokI ff genotype
(14% in the European-descent population of this cohort) are more susceptible to this cancer in the presence of
low 25(OH)D status.

Docking, the initial association of secretory vesicles with the plasma membrane, precedes formation of the
SNARE complex, which drives membrane fusion. For many years, the molecular identity of the docked state,
and especially the vesicular docking protein, has been unknown, as has the link to SNARE complex assembly.
Here, using adrenal chromaffin cells, we identify the vesicular docking partner as synaptotagmin-1, the calcium
sensor for exocytosis, and SNAP-25 as an essential plasma membrane docking factor, which, together with the
previously known docking factors Munc18-1 and syntaxin, form the minimal docking machinery. Moreover, we
show that the requirement for Munc18-1 in docking, but not fusion, can be overcome by stabilizing syntaxin/
SNAP-25 acceptor complexes. These findings, together with cross-rescue, double-knockout, and
electrophysiological data, lead us to propose that vesicles dock when synaptotagmin-1 binds to syntaxin/
SNAP-25 acceptor complexes, whereas Munc18-1 is required for the downstream association of synaptobrevin
to form fusogenic SNARE complexes.

3
Scientific Writing Lab
August 2010

Abstract Samples

Acrylamide exposure measured by food frequency questionnaire and hemoglobin adduct levels and
prostate cancer risk in the Cancer of the Prostate in Sweden Study

Acrylamide, a probable human carcinogen, is formed during the cooking of many commonly consumed foods.
Data are scant on whether dietary acrylamide represents an important cancer risk in humans. We studied the
association between acrylamide and prostate cancer risk using 2 measures of acrylamide exposure: intake
from a food frequency questionnaire (FFQ) and acrylamide adducts to hemoglobin. We also studied the
correlation between these 2 exposure measures. We used data from the population-based case-control study
Cancer of the Prostate in Sweden (CAPS). Dietary data was available for 1,499 cases and 1,118 controls.
Hemoglobin adducts of acrylamide were measured in blood samples from a subset of 170 cases and 161
controls. We calculated odds ratios (ORs) for the risk of prostate cancer in high versus low quantiles of
acrylamide exposure using logistic regression. The correlation between FFQ acrylamide intake and acrylamide
adducts in non-smokers was 0.25 (95% confidence interval: 0.14– 0.35), adjusted for age, region, energy
intake, and laboratory batch. Among controls the correlation was 0.35 (95% CI: 0.21– 0.48); among cases it
was 0.15 (95% CI: 0.00–0.30). The OR of prostate cancer for the highest versus lowest quartile of acrylamide
adducts was 0.93 (95% CI: 0.47–1.85, p-value for trend 5 0.98). For FFQ acrylamide, the OR of prostate cancer
for the highest versus lowest quintile was 0.97 (95% CI: 0.75–1.27, p trend 5 0.67). No significant associations
were found between acrylamide exposure and risk of prostate cancer by stage, grade, or PSA level. Acrylamide
adducts to hemoglobin and FFQ-measured acrylamide intake were moderately correlated. Neither measure of
acrylamide exposure—hemoglobin adducts or FFQ—was associated with risk of prostate cancer.

Key words:
acrylamide; diet; prostate cancer