M J Stampfer’s research while affiliated with Harvard Medical School and other places

Background Proximal aortic stiffness (PAS) reflects arterial aging and is strongly associated with increased cardiovascular risk. Plant-rich, specifically Mediterranean-style, diets are associated with reduced cardiovascular risk. The effect of dietary interventions on PAS remains unclear. Methods We randomized participants with abdominal-obesity/dyslipidemia to healthy-dietary-guidelines (HDG), Mediterranean, or green-Mediterranean diets combined with physical activity (PA). Both Mediterranean diets were similarly hypocaloric and included 28g/day walnuts. The green-Mediterranean group also consumed green tea (3–4 cups/day) and a Wolffia-globosa (Mankai) plant green-shake. PAS was estimated based on aortic-arch pulse-wave-velocity using magnetic resonance imaging (MRI) at baseline and after 18-months. Results Among 294 participants [age=51±10.6 years, body-mass-index 31.3±4.0 kg/m2, PAS = 6.1±2.7 m/sec, retention rate = 89.8%], 281 had valid PAS measurements. Higher PAS was mostly associated with aging, hypertension, dyslipidemia, diabetes, and increased visceral adiposity (p<0.05 for all). After 18-months of intervention, all diet groups significantly reduced their PAS ([HDG: −4.8% (interquartile-range [IQR]: −22.3 to 8.7); Mediterranean: −7.3%, IQR (−20.8 to 11.9); green-Mediterranean: −14.0%, IQR (−27.0 to 2.4); p<0.05 for within-groups changes). Green-Mediterranean dieters had significantly greater PAS reduction than HDG dieters (p=0.007), also after controlling for age, sex, baseline-PAS, and Δweight. Further adjustment to baseline dyslipidemia, diabetes, and hypertension also revealed significant differences in PAS reduction between green-Mediterranean and Mediterranean groups (p=0.027). Specifically, greater green tea consumption was associated with greater PAS regression (p=0.04). ΔPAS was significantly associated with improvements in Δlow-density-lipoprotein cholesterol and Δtotal-cholesterol (p<0.05, multivariable models). All lifestyle intervention showed aortic age regression as compared to the expected (1.8±0.14 years vs.: HDG: −2.9±7.5 years; MED: −4.1±7.4 years; green-MED:-4.9±8.0 years; p<0.001). Conclusions Higher PAS is strongly related to aging and is associated with traditional cardiovascular risk factors. Lifestyle intervention promotes PAS reduction. Green-Mediterranean diet may be associated with more remarkable aortic rejuvenation. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): The Deutsche Forschungsgemeinschaft (DFG, German Research Foundation); the Israel Ministry of Health

Background Pancreatic cancer presents as advanced disease in >80% of patients; yet, appropriate ages to consider prevention and early detection strategies are poorly defined. We investigated age-specific associations and attributable risks of pancreatic cancer for established modifiable and non-modifiable risk factors. Patients and methods We included 167 483 participants from 2 prospective US cohort studies with 1190 incident cases of pancreatic cancer during >30 years of follow-up; 5107 pancreatic cancer cases and 8845 control participants of European ancestry from a completed multicenter genome-wide association study (GWAS); and 197 490 pancreatic cancer cases documented in the US Surveillance, Epidemiology, and End Results (SEER) Program. Across different age categories, we investigated cigarette smoking, obesity, diabetes, height, and non-O blood group in the prospective cohorts; weighted polygenic risk score (PRS) of 22 previously identified single nucleotide polymorphisms in the GWAS; and male sex and Black race in the SEER program. Results In the prospective cohorts, all 5 risk factors were more strongly associated with pancreatic cancer risk among younger participants, with associations attenuated among those >70 years. The hazard ratios comparing participants with 3-5 risk factors to those with no risk factors were 9.24 (95% confidence interval [CI], 4.11-20.77) among those aged ≤60 years, 3.00 (95% CI, 1.85-4.86) among those aged 61-70 years, and 1.46 (95% CI, 1.10-1.94) among those over 70 years (Pheterogeneity = 3×10⁻⁵). These factors together were related to 65.6%, 49.7%, and 17.2% of incident pancreatic cancers in these age groups, respectively. In the GWAS and the SEER Program, the associations with the polygenic risk score, male sex, and Black race were all stronger among younger individuals (Pheterogeneity ≤ .01). Conclusions Established risk factors are more strongly associated with earlier-onset pancreatic cancer, emphasizing the importance of age at initiation for cancer prevention and control programs targeting this highly lethal malignancy.

Background: Increased vitamin B6 catabolism related to inflammation, as measured by the PAr index (the ratio of 4-pyridoxic acid over the sum of pyridoxal and pyridoxal-5'-phosphate), has been positively associated with lung cancer risk in two prospective European studies. However, the extent to which this association translates to more diverse populations is not known. Materials and methods: For this study, we included 5323 incident lung cancer cases and 5323 controls individually matched by age, sex, and smoking status within each of 20 prospective cohorts from the Lung Cancer Cohort Consortium. Cohort-specific odds ratios (ORs) and 95% confidence intervals (CIs) for the association between PAr and lung cancer risk were calculated using conditional logistic regression and pooled using random-effects models. Results: PAr was positively associated with lung cancer risk in a dose-response fashion. Comparing the fourth versus first quartiles of PAr resulted in an OR of 1.38 (95% CI: 1.19-1.59) for overall lung cancer risk. The association between PAr and lung cancer risk was most prominent in former smokers (OR: 1.69, 95% CI: 1.36-2.10), men (OR: 1.60, 95% CI: 1.28-2.00), and for cancers diagnosed within 3 years of blood draw (OR: 1.73, 95% CI: 1.34-2.23). Conclusion: Based on pre-diagnostic data from 20 cohorts across 4 continents, this study confirms that increased vitamin B6 catabolism related to inflammation and immune activation is associated with a higher risk of developing lung cancer. Moreover, PAr may be a pre-diagnostic marker of lung cancer rather than a causal factor.

Background: Few studies have evaluated the association between early life adiposity and ovarian cancer risk. Adiposity during different periods of life may be differentially associated with the risk. Patients and methods: We prospectively followed 133 526 women in the Nurses' Health Study (NHS; 1980-2012) and NHSII (1989-2013). Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for incident ovarian cancer (N = 788) according to validated measures for early life adiposity [body mass index (BMI) at age 10 imputed from somatotype and recalled BMI at age 18) as well as BMI change between age 10 and 18 and after age 18 (current weight assessed on every biennial questionnaire since baseline). Results: After mutual adjustment for BMI at age 10, BMI at age 18 and current BMI, the HR (95% CI) for ovarian cancer risk per 5 kg/m2 was 0.84 (0.74-0.96) for BMI at age 10 (P-trend = 0.01), 1.17 (1.03-1.33) for BMI at age 18 (P-trend = 0.02), and 1.06 (0.99-1.14) for current BMI (P-trend = 0.08). However, the inverse association with BMI at age 10 was attenuated after adjusting for BMI change between age 10 and 18 and BMI change after age 18 (HR per 5 kg/m2: 1.04; 95% CI 0.91-1.20; P-trend = 0.55). By contrast, BMI change between age 10 and 18 was strongly positively associated with ovarian cancer risk (HR per 5 kg/m2 increase: 1.24; 95% CI 1.11-1.39; P-trend = 0.0002), whereas BMI change since age 18 was only slightly associated with risk (HR per 5 kg/m2 increase: 1.06; 95% CI 0.99-1.14; P-trend = 0.10). These associations were in general stronger for premenopausal cases or non-serous tumors. Conclusion: Early life changes in adiposity were more strongly associated with ovarian cancer risk than adulthood changes. The specific mechanisms underlying the associations with adiposity changes during early life warrant further investigation.

Background: Prostate cancer (PCa) is a leading cause of mortality and genetic factors can influence tumour aggressiveness. Several germline variants have been associated with PCa-specific mortality (PCSM), but further replication evidence is needed. Methods: Twenty-two previously identified PCSM-associated genetic variants were genotyped in seven PCa cohorts (12,082 patients; 1544 PCa deaths). For each cohort, Cox proportional hazards models were used to calculate hazard ratios and 95% confidence intervals for risk of PCSM associated with each variant. Data were then combined using a meta-analysis approach. Results: Fifteen SNPs were associated with PCSM in at least one of the seven cohorts. In the meta-analysis, after adjustment for clinicopathological factors, variants in the MGMT (rs2308327; HR 0.90; p-value = 3.5 × 10-2) and IL4 (rs2070874; HR 1.22; p-value = 1.1 × 10-3) genes were confirmed to be associated with risk of PCSM. In analyses limited to men diagnosed with local or regional stage disease, a variant in AKT1, rs2494750, was also confirmed to be associated with PCSM risk (HR 0.81; p-value = 3.6 × 10-2). Conclusions: This meta-analysis confirms the association of three genetic variants with risk of PCSM, providing further evidence that genetic background plays a role in PCa-specific survival. While these variants alone are not sufficient as prognostic biomarkers, these results may provide insights into the biological pathways modulating tumour aggressiveness.

Background: There is observational evidence suggesting that high vitamin D concentrations may protect against lung cancer. To investigate this hypothesis in detail, we measured circulating vitamin D concentrations in pre-diagnostic blood from 20 cohorts participating in the Lung Cancer Cohort Consortium (LC3). Patients and methods: The study included 5,313 lung cancer cases and 5,313 controls selected from. Blood samples for the cases were collected, on average, 5 years prior to lung cancer diagnosis. Controls were individually matched to the cases by cohort, sex, age, race/ethnicity, date of blood collection, and smoking status in 5 categories. Liquid chromatography coupled with tandem mass spectrometry was used to separately analyze 25-hydroxyvitamin D2 (25(OH)D2) and 25-hydroxyvitamin D3 (25(OH)D3) and their concentrations were combined to give an overall measure of 25(OH)D. We used conditional logistic regression to calculate odds ratios (OR) and 95% confidence intervals (CI) for 25(OH)D as both a continuous and categorical variable. Results: Overall, no apparent association between 25(OH)D and risk of lung cancer was observed (multivariable adjusted OR for a doubling in concentration: 0.98, 95% confidence interval: 0.91, 1.06). Similarly, we found no clear evidence of interaction by cohort, sex, age, smoking status, or histology. Conclusion: This study did not support an association between vitamin D concentrations and lung cancer risk.

The aim of this study was to evaluate the reproducibility and validity of a 61-item semiquantitative food frequency questionnaire used in a large prospective study among women. This form W88 administered twice to 173 particIpants at an interval of approximate'y one year (1980-1981), and four one-week diet records for each subject were collected during that period. Intraclass correlation coeffidents for nutrient intakes estimated by the one-week diet records (range = 0.41 for total Vitamin A without supplements to 0.79 for Vitamin B, with supplements) were similar to those computed from the questionnaire (range = 0.49 for total Vitamin A without 8upplements to 0.71 for sucrose), indicating that these methods were generally comparable with respect to reproducibility. With the exception of sucrose and total carbohydrate, nutilent Intakes from the diet records tended to correlate more strongly with those computed from the questionn&re after adjustment for total caloric Intake. Correlation coefficients between the mean calorie-adjusted intakes from the four one-week diet records and those from the questionna ire completed after the diet records ranged from 0.36 for Vitamin A without supplements to 0.75 for vitamin C with supplements. Overall, 48% of 8ubjects n the lowest quintile of calorie-Adjusted intake computed from the diet records were also in the lowest questionnaire quintile, and 74% were in the lowest one of two questionnaire quintiles. SImilarly, 49% of those in the highest diet record quintile were also in the highest questionnaire quintile, and 77% were In the highest one or two questionnafre quintiles. These data indicate that a simple self-administered dietary questionnaire can provide u8efuI information about indMdual nutrient intakes over a one-year penod.